Comprehensive Organometallic Chemistry IV. Volume 12: Applications II. d- and f-Block Metal Complexes in Organic Synthesis - Part 1 [12] 9780128202067

Citation preview

COMPREHENSIVE ORGANOMETALLIC CHEMISTRY IV

COMPREHENSIVE ORGANOMETALLIC CHEMISTRY IV EDITORS-IN-CHIEF

GERARD PARKIN Department of Chemistry, Columbia University, New York, NY, United States

KARSTEN MEYER Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität, Erlangen, Germany

DERMOT O’HARE Department of Chemistry, University of Oxford, Oxford, United Kingdom

VOLUME 12

APPLICATIONS II. d- AND f-BLOCK METAL COMPLEXES IN ORGANIC SYNTHESIS - PART 1 VOLUME EDITOR

IAN A. TONKS Department of Chemistry, University of Minnesota, Minneapolis, United States

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2022 Elsevier Ltd. All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-820206-7 For information on all publications visit our website at http://store.elsevier.com

Publisher: Oliver Walter Acquisition Editor: Blerina Osmanaj Content Project Manager: Claire Byrne Associate Content Project Manager: Fahmida Sultana Designer: Christian Bilbow

CONTENTS OF VOLUME 12 Editor Biographies

vii

Contributors to Volume 12

xiii

Preface 12.01

xv

Volume 12 and 13: Applications II. d- and f- Block Metal Complexes in Organic Synthesis

1

Ian A Tonks

12.02

CdC Bond Formation Through Heck-Like Reactions

2

Shenghan Teng and Jianrong Steve Zhou

12.03

Metal-Mediated Reductive C–C Coupling of p Bonds

46

Yukun Cheng, Steven K Butler, Daniel N Huh, and Ian A Tonks

12.04

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

89

Kirsten A Hewitt, Patricia C Lin, Ethan TA Raffman, and Elizabeth R Jarvo

12.05

CdC Bond Formation Through C-H Activation

120

Chen-Xu Liu, Quannan Wang, Qing Gu, and Shu-Li You

12.06

Direct C–E (E = Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

190

Nupur Goswami, Resma Mohan, and Debabrata Maiti

12.07

Synthetic Applications of Carbene and Nitrene CdH Insertion

251

Yannick Takinda Boni, Bo Wei, and Huw Madoc Lynn Davies

12.08

Metal-Catalyzed Amination: CdN Bond Formation

294

Alexander Haydl, Arne Geissler, and Dino Berthold

12.09

Synthetic Applications of CdC Bond Activation Reactions

332

Tao Xu

12.10

Synthetic Applications of C–O and C–E Bond Activation Reactions

347

Mamoru Tobisu, Takuya Kodama, and Hayato Fujimoto

12.11

CdF Bond Activation Reactions

421

Kohei Fuchibe, Takeshi Fujita, and Junji Ichikawa

12.12

Polymerization Reactions via Cross Coupling

465

Anthony J Varni, Manami Kawakami, Michael V Bautista, and Kevin JT Noonan

v

EDITOR BIOGRAPHIES Editors in Chief Karsten Meyer studied chemistry at the Ruhr University Bochum and performed his Ph.D. thesis work on the molecular and electronic structure of first-row transition metal complexes under the direction of Professor Karl Wieghardt at the Max Planck Institute in Mülheim/Ruhr (Germany). He then proceeded to gain research experience in the laboratory of Professor Christopher Cummins at the Massachusetts Institute of Technology (USA), where he appreciated the art of synthesis and developed his passion for the coordination chemistry and reactivity of uranium complexes. In 2001, he was appointed to the University of California, San Diego, as an assistant professor and was named an Alfred P. Sloan Fellow in 2004. In 2006, he accepted an offer (C4/W3) to be the chair of the Institute of Inorganic & General Chemistry at the Friedrich-Alexander-University ErlangenNürnberg (FAU), Germany. Among his awards and honors, he was elected a lifetime honorary member of the Israel Chemical Society and a fellow of the Royal Society of Chemistry (UK). Karsten received the Elhuyar-Goldschmidt Award from the Royal Society of Chemistry of Spain, the Ludwig Mond Award from the RSC (UK), and the Chugaev Commemorative Medal from the Russian Academy of Sciences. He has also enjoyed visiting professorship positions at the universities of Manchester (UK) and Toulouse (F) as well as the Nagoya Institute of Technology (JP) and ETH Zürich (CH). The Meyer lab research focuses on the synthesis of custom-tailored ligand environments and their transition and actinide metal coordination complexes. These complexes often exhibit unprecedented coordination modes, unusual electronic structures, and, consequently, enhanced reactivities toward small molecules of biological and industrial importance. Interestingly, Karsten’s favorite molecule is one that exhibits little reactivity: the Th symmetric U(dbabh)6. Dermot O’Hare was born in Newry, Co Down. He studied at Balliol College, Oxford University, where he obtained his B.A., M.A., and D.Phil. degrees under the direction of Professor M.L.H. Green. In 1985, he was awarded a Royal Commission of 1851 Research Fellowship, during this Fellowship he was a visiting research fellow at the DuPont Central Research Department, Wilmington, Delaware in 1986–87 in the group led by Prof. J.S. Miller working on molecular-based magnetic materials. In 1987 he returned to Oxford to a short-term university lectureship and in 1990 he was appointed to a permanent university position and a Septcentenary Tutorial Fellowship at Balliol College. He has previously been honored by the Institüt de France, Académie des Sciences as a leading scientist in Europe under 40 years. He is currently professor of organometallic and materials chemistry in the Department of Chemistry at the University of Oxford. In addition, he is currently the director of the SCG-Oxford Centre of Excellence for chemistry and associate head for business & innovation in the Mathematics, Physical and Life Sciences Division. He leads a multidisciplinary research team that works across broad areas of catalysis and nanomaterials. His research is specifically targeted at finding solutions to global issues relating to energy, zero carbon, and the circular economy. He has been awarded numerous awards and prizes for his creative and

vii

viii

Editor Biographies

ground-breaking work in inorganic chemistry, including the Royal Society Chemistry’s Sir Edward Frankland Fellowship, Ludwig Mond Prize, Tilden Medal, and Academia–Industry Prize and the Exxon European Chemical and Engineering Prize. Gerard Parkin received his B.A., M.A., and D.Phil. degrees from the Queen’s College, Oxford University, where he carried out research under the guidance of Professor Malcolm L.H. Green. In 1985, he moved to the California Institute of Technology as a NATO postdoctoral fellow to work with Professor John E. Bercaw. He joined the Faculty of Columbia University as assistant professor in 1988 and was promoted to associate professor in 1991 and to professor in 1994. He served as chairman of the Department from 1999 to 2002. He has also served as chair of the New York Section of the American Chemical Society, chair of the Inorganic Chemistry and Catalytic Science Section of the New York Academy of Sciences, chair of the Organometallic Subdivision of the American Chemical Society Division of Inorganic Chemistry, and chair of the Gordon Research Conference in Organometallic Chemistry. He is an elected fellow of the American Chemical Society, the Royal Society of Chemistry, and the American Association for the Advancement of Science, and is the recipient of a variety of international awards, including the ACS Award in pure chemistry, the ACS Award in organometallic chemistry, the RSC Corday Morgan Medal, the RSC Award in organometallic chemistry, the RSC Ludwig Mond Award, and the RSC Chem Soc Rev Lecture Award. He is also the recipient of the United States Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring, the United States Presidential Faculty Fellowship Award, the James Flack Norris Award for Outstanding Achievement in the Teaching of Chemistry, the Columbia University Presidential Award for Outstanding Teaching, and the Lenfest Distinguished Columbia Faculty Award. His principal research interests are in the areas of synthetic, structural, and mechanistic inorganic chemistry.

Volume Editors Simon Aldridge is professor of chemistry at the University of Oxford and director of the UKRI Centre for Doctoral Training in inorganic chemistry for Future Manufacturing. Originally from Shrewsbury, England, he received both his B.A. and D.Phil. degrees from the University of Oxford, the latter in 1996 for work on hydride chemistry under the supervision of Tony Downs. After post-doctoral work as a Fulbright Scholar at Notre Dame with Tom Fehlner, and at Imperial College London (with Mike Mingos), he took up his first academic position at Cardiff University in 1998. He returned to Oxford in 2007, being promoted to full professor in 2010. Prof. Aldridge has published more than 230 papers to date and is a past winner of the Dalton Transactions European Lectureship (2009), the Royal Society of Chemistry’s Main Group Chemistry (2010) and Frankland Awards (2018), and the Forschungspreis of the Alexander von Humboldt Foundation (2021). Prof. Aldridge’s research interests are primarily focused on main group organometallic chemistry, and in particular the development of compounds with unusual electronic structure, and their applications in small molecule activation and catalysis (website: http:// aldridge.web.ox.ac.uk). (Picture credit: John Cairns)

Editor Biographies

ix

Eszter Boros is associate professor of chemistry at Stony Brook University with courtesy appointments in radiology and pharmacology at Stony Brook Medicine. Eszter obtained her M.Sc. (2007) at the University of Zurich, Switzerland and her Ph.D. (2011) in chemistry from the University of British Columbia, Canada. She was a postdoc (2011–15) and later instructor (2015–17) in radiology at Massachusetts General Hospital and Harvard Medical School. In 2017, Eszter was appointed as assistant professor of chemistry at Stony Brook University, where her research group develops new approaches to metal-based diagnostics and therapeutics at the interfaces of radiochemistry, inorganic chemistry and medicine. Her lab’s work has been extensively recognized; Eszter holds various major federal grants (NSF CAREER Award, NIH NIBIB R21 Trailblazer, NIH NIGMS R35 MIRA) and has been named a 2020 Moore Inventor Fellow, the 2020 Jonathan L. Sessler Fellow (American Chemical Society, Inorganic Division), recipient of a 2021 ACS Infectious Diseases/ACS Division of Biological Chemistry Young Investigator Award (American Chemical Society), and was also named a 2022 Alfred P. Sloan Research Fellow in chemistry. Scott R. Daly is associate professor of chemistry at the University of Iowa in the United States. After spending 3 years in the U.S. Army, he obtained his B.S. degree in chemistry in 2006 from North Central College, a small liberal arts college in Naperville, Illinois. He then went on to receive his Ph.D. at the University of Illinois at Urbana-Champaign in 2010 under the guidance of Professor Gregory S. Girolami. His thesis research focused on the synthesis and characterization of chelating borohydride ligands and their use in the preparation of volatile metal complexes for chemical vapor deposition applications. In 2010, he began working as a Seaborg postdoctoral fellow with Drs. Stosh A. Kozimor and David L. Clark at Los Alamos National Laboratory in Los Alamos, New Mexico. His research there concentrated on the development of ligand K-edge X-ray absorption spectroscopy (XAS) to investigate covalent metal–ligand bonding and electronic structure variations in actinide, lanthanide, and transition metal complexes with metal extractants. He started his independent career in 2012 at George Washington University in Washington, DC, and moved to the University of Iowa shortly thereafter in 2014. His current research interests focus on synthetic coordination chemistry and ligand design with emphasis on the development of chemical and redox noninnocent ligands, mechanochemical synthesis and separation methods, and ligand K-edge XAS. His research and outreach efforts have been recognized with an Outstanding Faculty/Staff Advocate Award from the University of Iowa Veterans Association (2016), a National Science Foundation CAREER Award (2017), and a Hawkeye Distinguished Veterans Award (2018). He was promoted to associate professor with distinction as a College of Liberal Arts and Sciences Deans Scholar in 2020. Lena J. Daumann is currently professor of bioinorganic and coordination chemistry at the Ludwig Maximilian Universität in Munich. She studied chemistry at the University of Heidelberg working with Prof. Peter Comba and subsequently conducted her Ph.D. at the University of Queensland (Australia) from 2010 to 2013 holding IPRS and UQ Centennial fellowships. In 2013 she was part of the Australian Delegation for the 63rd Lindau Nobel Laureate meeting in chemistry. Following postdoctoral stays at UC Berkeley with Prof. Ken Raymond (2013–15) and in Heidelberg, funded by the Alexander von Humboldt Foundation, she started her independent career at the LMU Munich in 2016. Her bioinorganic research group works on elucidating the role of lanthanides for bacteria as well as on iron enzymes and small biomimetic complexes that play a role in epigenetics and DNA repair. Daumann’s teaching and research have been recognized with numerous awards and grants. Among them are the national Ars Legendi Prize for chemistry and the Therese von Bayern Prize in 2019 and the Dozentenpreis of the “Fonds der Chemischen Industrie“ in 2021. In 2018 she was selected as fellow for the Klaus Tschira Boost Fund by the German Scholars Organisation and in 2020 she received a Starting grant of the European Research Council to study the uptake of lanthanides by bacteria.

x

Editor Biographies

Derek P. Gates hails from Halifax, Nova Scotia (Canada) where he completed his B.Sc. (Honours Chemistry) degree at Dalhousie University in 1993. He completed his Ph.D. degree under the supervision of Professor Ian Manners at the University of Toronto in 1997. He then joined the group of Professor Maurice Brookhart as an NSERC postdoctoral fellow at the University of North Carolina at Chapel Hill (USA). He began his independent research career in 1999 as an assistant professor at the University of British Columbia in Vancouver (Canada). He has been promoted through the ranks and has held the position of professor of chemistry since 2011. At UBC, he has received the Science Undergraduate Society—Teaching Excellence Award, the Canadian National Committee for IUPAC Award, and the Chemical Society of Canada—Strem Chemicals Award for pure or applied inorganic chemistry. His research interests bridge the traditional fields of inorganic and polymer chemistry with particular focus on phosphorus chemistry. Key topics include the discovery of novel structures, unusual bonding, new reactivity, along with applications in catalysis and materials science. Patrick Holland performed his Ph.D. research in organometallic chemistry at UC Berkeley with Richard Andersen and Robert Bergman. He then learned about bioinorganic chemistry through postdoctoral research on copper-O2 and copper-thiolate chemistry with William Tolman at the University of Minnesota. His independent research at the University of Rochester initially focused on systematic development of the properties and reactions of three-coordinate complexes of iron and cobalt, which can engage in a range of bond activation reactions and organometallic transformations. Since then, his research group has broadened its studies to iron-N2 chemistry, reactive metal–ligand multiple bonds, iron–sulfur clusters, engineered metalloproteins, redox-active ligands, and solar fuel production. In 2013, Prof. Holland moved to Yale University, where he is now Conkey P. Whitehead Professor of Chemistry. His research has been recognized with an NSF CAREER Award, a Sloan Research Award, Fulbright and Humboldt Fellowships, a Blavatnik Award for Young Scientists, and was elected as fellow of the American Association for the Advancement of Science. In the area of N2 reduction, his group has established molecular principles to weaken and break the strong N–N bond, in order to use this abundant resource for energy and synthesis. His group has made a particular effort to gain an insight into iron chemistry relevant to nitrogenase, the enzyme that reduces N2 in nature. His group also maintains an active program in the use of inexpensive metals for transformations of alkenes. Mechanistic details are a central motivation to Prof. Holland and the wonderful group of over 80 students with whom he has worked. Steve Liddle was born in Sunderland in the North East of England and gained his B.Sc. (Hons) and Ph.D. from Newcastle University. After postdoctoral fellowships at Edinburgh, Newcastle, and Nottingham Universities he began his independent career at Nottingham University in 2007 with a Royal Society University Research Fellowship. This was held in conjunction with a proleptic Lectureship and he was promoted through the ranks to associate professor and reader in 2010 and professor of inorganic chemistry in 2013. He remained at Nottingham until 2015 when he was appointed professor and head of inorganic chemistry and co-director of the Centre for Radiochemistry Research at The University of Manchester. He has been a recipient of an EPSRC Established Career Fellowship and ERC Starter and Consolidator grants. He is an elected fellow of The Royal Society of Edinburgh and fellow of the Royal Society of Chemistry and he is vice president to the Executive Committee of the European Rare Earth and Actinide Society. His principal research interests are focused on f-element chemistry, involving exploratory synthetic chemistry coupled to detailed electronic structure and reactivity studies to elucidate structure-bonding-property relationships. He is the recipient of a variety of prizes, including the IChemE Petronas Team Award for Excellence in Education and Training, the RSC Sir Edward Frankland Fellowship, the RSC Radiochemistry

Editor Biographies

xi

Group Bill Newton Award, a 41st ICCC Rising Star Award, the RSC Corday-Morgan Prize, an Alexander von Humboldt Foundation Friedrich Wilhelm Bessel Research Award, the RSC Tilden Prize, and an RSC Dalton Division Horizon Team Prize. He has published over 220 research articles, reviews, and book chapters to date. David Liptrot received his MChem (Hons) in chemistry with Industrial Training from the University of Bath in 2011 and remained there to undertake a Ph.D. on group 2 catalysis in the laboratory of Professor Mike Hill. After completing this in 2015 he took up a Lindemann Postdoctoral Fellowship with Professor Philip Power FRS (University of California, Davis, USA). In 2017 he began his independent career returning to the University of Bath and in 2019 was awarded a Royal Society University Research Fellowship. His interests concern new synthetic methodologies to introduce main group elements into functional molecules and materials.

David P. Mills hails from Llanbradach and Caerphilly in the South Wales Valleys. He completed his MChem (2004) and Ph.D. (2008) degrees at Cardiff University, with his doctorate in low oxidation state gallium chemistry supervised by Professor Cameron Jones. He moved to the University of Nottingham in 2008 to work with Professor Stephen Liddle for postdoctoral studies in lanthanide and actinide methanediide chemistry. In 2012 he moved to the University of Manchester to start his independent career as a lecturer, where he has since been promoted to full professor of inorganic chemistry in 2021. Although he is interested in all aspects of nonaqueous synthetic chemistry his research interests are currently focused on the synthesis and characterization of f-block complexes with unusual geometries and bonding regimes, with the aim of enhancing physicochemical properties. He has been recognized for his contributions to both research and teaching with prizes and awards, including a Harrison-Meldola Memorial Prize (2018), the Radiochemistry Group Bill Newton Award (2019), and a Team Member of the Molecular Magnetism Group for the Dalton Division Horizon Prize (2021) from the Royal Society of Chemistry. He was a Blavatnik Awards for Young Scientists in the United Kingdom Finalist in Chemistry in 2021 and he currently holds a European Research Council Consolidator Grant. Ian Tonks is the Lloyd H. Reyerson professor at the University of MinnesotaTwin Cities, and associate editor for the ACS journal Organometallics. He received his B.A. in chemistry from Columbia University in 2006 and performed undergraduate research with Prof. Ged Parkin. He earned his Ph.D. in 2012 from the California Institute of Technology, where he worked with Prof. John Bercaw on olefin polymerization catalysis and early transition metal-ligand multiply bonded complexes. After postdoctoral research with Prof. Clark Landis at the University of Wisconsin, Madison, he began his independent career at the University of Minnesota in 2013 and earned tenure in 2019. His current research interests are focused on the development of earth abundant, sustainable catalytic methods using early transition metals, and also on catalytic strategies for incorporation of CO2 into polymers. Prof. Tonks’ work has recently been recognized with an Outstanding New Investigator Award from the National Institutes of Health, an Alfred P. Sloan Fellowship, a Department of Energy CAREER award, and the ACS Organometallics Distinguished Author Award, among others. Additionally, Prof. Tonks’ service toward improving academic safety culture was recently recognized with the 2021 ACS Division of Chemical Health and Safety Graduate Faculty Safety Award.

xii

Editor Biographies

Timothy H. Warren is the Rosenberg professor and chairperson in the Department of Chemistry at Michigan State University. He obtained his B.S. from the University of Illinois at Urbana-Champaign in 1992 and Ph.D. from the Massachusetts Institute of Technology in 1997. After 2 years of postdoctoral research at the Organic Chemistry Institute of the University of Münster, Germany with Prof. Dr. Gerhart Erker, Dr. Warren started his independent career at Georgetown University in 1999 where he was named the Richard D. Vorisek professor of chemistry in 2014. He moved to Michigan State University in 2021. Prof. Warren’s research interests span synthetic and mechanistic inorganic, organometallic, and bioinorganic chemistry with a focus on catalysis. His research group develops environmentally friendly methods for organic synthesis via C–H functionalization, explores the interconversion of nitrogen and ammonia as carbon-free fuels, and decodes ways that biology communicates using nitric oxide as a molecular messenger. Mechanistic studies on these chemical reactions catalyzed by metal ions such as iron, nickel, copper, and zinc enable new insights for the development of useful catalysts for synthesis and energy applications as well as lay the mechanistic groundwork to understand biochemical nitric oxide misregulation. Dr. Warren received the NSF CAREER Award, chaired the 2019 Inorganic Reaction Mechanisms Gordon Research Conference, and has served on the ACS Division of Inorganic Chemistry executive board and on the editorial boards of Inorganic Synthesis, Inorganic Chemistry, and Chemical Society Reviews.

CONTRIBUTORS TO VOLUME 12 Michael V Bautista 4400 Fifth Ave, Pittsburgh, PA, United States Dino Berthold Institut für Organische Chemie, Albert-LudwigsUniversität Freiburg, Freiburg, Germany Yannick Takinda Boni Department of Chemistry, Emory University, Atlanta, GA, United States Steven K Butler Department of Chemistry, University of Minnesota, Minneapolis, United States Yukun Cheng Department of Chemistry, University of Minnesota, Minneapolis, United States Huw Madoc Lynn Davies Department of Chemistry, Emory University, Atlanta, GA, United States Kohei Fuchibe Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan Hayato Fujimoto Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan

Qing Gu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Alexander Haydl Chemical Process Development, Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim am Rhein, Germany Kirsten A Hewitt Department of Chemistry, University of California, Irvine, CA, United States Daniel N Huh Department of Chemistry, University of Minnesota, Minneapolis, United States Junji Ichikawa Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan Elizabeth R Jarvo Department of Chemistry, University of California, Irvine, CA, United States Manami Kawakami 4400 Fifth Ave, Pittsburgh, PA, United States

Arne Geissler Institut für Organische Chemie, Albert-LudwigsUniversität Freiburg, Freiburg, Germany

Takuya Kodama Department of Applied Chemistry, Graduate School of Engineering and, Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives (ICS-OTRI), Osaka University, Suita, Osaka, Japan; Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan

Nupur Goswami Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India

Patricia C Lin Department of Chemistry, University of California, Irvine, CA, United States

Takeshi Fujita Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan

xiii

xiv

Contributors to Volume 12

Chen-Xu Liu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Debabrata Maiti Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India Resma Mohan Centre for Integrated Studies, Cochin University of Science and Technology, Kochi, Kerala, India Kevin JT Noonan 4400 Fifth Ave, Pittsburgh, PA, United States Ethan TA Raffman Department of Chemistry, University of California, Irvine, CA, United States Shenghan Teng State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China Mamoru Tobisu Department of Applied Chemistry, Graduate School of Engineering and, Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives (ICS-OTRI), Osaka University, Suita, Osaka, Japan; Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan

Ian A Tonks Department of Chemistry, University of Minnesota, Minneapolis, United States Anthony J Varni 4400 Fifth Ave, Pittsburgh, PA, United States Quannan Wang State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Bo Wei Department of Chemistry, Emory University, Atlanta, GA, United States Tao Xu Molecular Synthesis Center & Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China Shu-Li You State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Jianrong Steve Zhou State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China

PREFACE Published 40 years ago in 1982, the first edition of Comprehensive Organometallic Chemistry (COMC) provided an invaluable resource that enabled chemists to become efficiently informed of the properties and reactions of organometallic compounds of both the main group and transition metals. This area of chemistry continued to develop at a rapid pace such that it necessitated the publication of subsequent editions, namely Comprehensive Organometallic Chemistry II (COMC2) in 1995 and Comprehensive Organometallic Chemistry III (COMC3) in 2007. Organometallic chemistry has continued to be vibrant in the 15 years following the publication of COMC3, not only by affording compounds with novel structures and reactivity but also by having important applications in organic syntheses and industrial processes, as illustrated by the awarding of the 2010 Nobel prize to Heck, Negishi, and Suzuki for the development of palladium-catalyzed cross couplings in organic syntheses. Comprehensive Organometallic Chemistry IV (COMC4) thus serves the same important role as its predecessors by providing an indispensable means for researchers and educators to obtain efficiently an up-to-date analysis of a particular aspect of organometallic chemistry. COMC4 comprises 15 volumes, of which the first provides a review of topics concerned with techniques and concepts that feature prominently in current organometallic chemistry, while 5 volumes are devoted to applications that include organic synthesis, materials science, bio-organometallics, metallo-therapy, metallodiagnostics, medicine, and environmental chemistry. In this regard, we are very grateful to the volume editors for their diligent efforts, and the authors for producing high-quality chapters, all of which were written during the COVID-19 pandemic. Finally, we wish to thank the many staff at Elsevier for their efforts to ensure that the project, initiated in the winter of 2018, remained on schedule. Karsten Meyer, Erlangen, March 2022 Dermot O’Hare, Oxford, March 2022 Gerard Parkin, New York, March 2022

xv

12.01 Volume 12 and 13: Applications II. d- and f- Block Metal Complexes in Organic Synthesis Ian A Tonks, Department of Chemistry, University of Minnesota, Minneapolis, United States © 2022 Elsevier Ltd. All rights reserved.

12.01.1 Introduction Volumes 12 and 13 of Comprehensive Organometallic Chemistry are focused on the application of stoichiometric and catalytic organometallic reactions toward organic synthesis. The intervening 15 years since the last edition of these volumes in COMC III have seen remarkable growth and advancement of organometallics in organic synthesis: another Nobel prize was awarded (in 2010, to Suzuki, Negishi, and Heck for Pd-catalyzed cross coupling reactions) and organometallic methods have flourished across almost all areas of organic chemistry. Anecdotally, it seems rarer and rarer that one would find an organic chemist not using organometallic approaches! In this regard, as the field of organometallic chemistry matures, it has come full-circle, building off of physical organic principles and now being applied (to great success) in new ways in that same arena. Given the breadth of applications of organometallics methods in synthesis, it is not possible to present a fully comprehensive view of the field. Instead, the purpose of these volumes is to introduce the reader to some of the major developments in the field over the past 15 years, across all levels of technical development: some chapters dedicated to continued refinement and precision control in “classical” transformations; some chapters on fields that were only nascent at the publication of COMC III; and further, some chapters focused on forward-looking applications and strategies of great promise. Applications II: d- and f-Block Metal Complexes in Organic Synthesis is divided into two thematic volumes. Volume 12, Synthetic strategies involving bond activations and coupling reactions, highlights the sweeping advances in all types of bond activation reactions C-H, C-C, and C-X (X = B, halogen, O) and also advances in new cross-coupling strategies. These research areas are often thematically connected through common reaction intermediates, and present complementary approaches to constructing many types of organic frameworks. Volume 13, Advances in ligand, catalyst, and reaction design for small molecule and polymer synthesis, details the impressive methods of control that organometallic chemists can exert over many classes of reactions. In this regard, control can come in the form of intentional ligand or catalyst design, or through information gained by using emerging modern catalytic tools such as high throughput design or detailed reaction parameterization. Across all of the chapters, there are several common themes that emerge. For example, detailed mechanistic understanding of well-established reactions is leading to the development of highly (regio-, chemo-, enantio-, and diastereo-) selective catalysts, as can be seen in detailed chapters on metal-catalyzed hydrogenation (13.1; by Dobereiner, Wang, and Zhang), C-H activation (12.5; by You et al; Maiti et al; 12.7; by Davies et al) and olefin metathesis (13.7; by Michaudel et al). Additionally, new retrosynthetic strategies continue to drive innovation in methodology development, building off of these classical reactions—for example, in the application of challenging-to-activate bonds to chemical synthesis, including through C-C bond activation (12.9; by Xu et al), C-O/ C-E bond activation (12.10; by Tobisu et al), and C-F activation (12.11; by Ichikawa et al), and through incorporation of nontraditional reactive partners, such as in cross-electrophile coupling (12.4; by Jarvo et al). Looking forward, the last 15 years have seen renewed interest in single-electron strategies in organic methods (13.8; by Fu et al) that are certainly primed for growth; while new tools such as multivariate techniques for reaction parameterization (13.11; by Nolan et al) and high through-put techniques (13.12; by Leitch et al) are already beginning to drive breakthroughs and understanding of the organometallic chemistry that underlies the methods herein. Indeed, as organometallic chemistry continues to flourish as an established discipline, there remain significant opportunities for innovation by examining the fundamental reactions presented in COMC IV through a new light.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00168-2

1

12.02

CdC Bond Formation Through Heck-Like Reactions

Shenghan Teng and Jianrong Steve Zhou, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China © 2022 Elsevier Ltd. All rights reserved.

12.02.1 Brief history 12.02.2 Heck reaction of aryl and alkenyl (pseudo)halides 12.02.2.1 Heck reaction of cyclic alkenes 12.02.2.2 Heck reaction of acyclic alkenes 12.02.2.3 Nickel-catalyzed Heck reaction 12.02.2.4 Synthetic applications 12.02.3 Heck-Matsuda reaction 12.02.3.1 Introduction 12.02.3.2 Arylation of cyclic olefins 12.02.3.3 Arylation of acyclic olefins 12.02.4 Heck-type reaction of unactivated alkyl electrophiles 12.02.4.1 Introduction 12.02.4.2 Pd-catalyzed thermal Heck-type alkylation 12.02.4.3 Pd-catalyzed photoinduced Heck-type alkylation 12.02.4.4 Cobalt- and nickel-catalyzed Heck-type alkylation 12.02.5 Heck-type alkylation of activated alkyl halides 12.02.6 Heck reaction of benzylic electrophiles 12.02.7 Heck reaction of allylic and propargylic electrophiles 12.02.7.1 Heck reaction of allylic electrophiles 12.02.7.2 Heck reaction of propargylic electrophiles 12.02.8 Narasaka-Heck reaction 12.02.9 Heck reaction of silyl electrophiles 12.02.10 Heck reaction of boryl electrophiles 12.02.11 Conclusion Acknowledgment References

3 4 5 5 9 10 11 11 12 16 18 18 20 22 24 26 28 31 31 34 35 39 42 42 43 43

Nomenclature Ac BINAP Bn Bu Bz DCM DMF dppb dppe dppf dpph dr ee Et Hex LED Me Ms Ph Pr rt Tf THF

2

Acetyl 2,20 -Bis(diphenylphosphino)-1,10 -binaphthyl Benzyl Butyl Benzoyl Dichloromethane N,N-dimethylformamide 1,4-Bis(diphenylphosphino)butane 1,2-Bis(diphenylphosphino)ethane 1,10 -Bis(diphenylphosphino)ferrocene 1,6-Bis(diphenylphosphino)hexane Diastereomeric ratio Enantiomeric excess Ethyl Hexyl Light-emitting diodes Methyl Methanesulfonyl Phenyl Propyl Room temperature Trifluoromethanesulfonyl Tetrahydrofuran

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00156-6

CdC Bond Formation Through Heck-Like Reactions

Ts Xantphos

3

Toluenesulfonyl 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

12.02.1 Brief history The Heck reaction or Mizoroki-Heck reaction refers to a class of palladium-catalyzed carbon-carbon bond forming reactions between organic halides and alkenes that give olefinic products. Aryl and alkenyl halides are the most commonly used. Today, many other types of organic electrophiles have become viable substrates, including aryl sulfonates, aryldiazonium salts, alkyl, benzylic and allylic electrophiles and even nitrogen, boryl and silyl electrophiles. Palladium can also be replaced by nickel and in Heck-type alkylations, other 3d metals can also be used. In 2011, Oestreich edited a comprehensive book which covered all aspects of recent developments of the named reaction until that time.1 In 1968 Richard Heck reported on stoichiometric reactions of organopalladium salts with various alkenes such as styrene, acrylates, 1,3-dienes and allylic alcohols. Organopalladium salts were prepared from organomercuric acetate and palladium chloride or acetate.2–4 For example, the reaction of a phenylpalladium salt with ethylene gas produced styrene and a minor product of stilbene after double arylation. These works laid the foundation for the renowned Heck reaction, which has become a very powerful tool in organic synthesis today.5,6 In 1971, Mizoroki et al. briefly reported a singular study on PdCl2-catalyzed arylation of ethylene, styrene and acrylate using PhI in methanol, representing the first example of so-called ligandless conditions.7 In 1972, Heck et al. also reported that Pd(OAc)2 can catalyze CdC coupling of aryl iodides and benzyl chloride with aryl olefins and acrylates.8 Later, triphenylphosphine and tri(o-tolyl)phosphine were added as ancillary ligands which enabled less reactive aryl bromides to couple with styrene, acrylates and even 1-hexene (see Fig. 1).9,10 Remarkably, the use of phosphines in Heck reaction also marked the dawn of modulating catalyst activity of metal complexes by tuning electronic and steric properties of ancillary ligands.11 However, it should be pointed out that sometimes the use of arylphosphines in palladium catalysis caused unwanted side reactions, such as aryl exchange of arylphosphines with aryl halides and sulfonates.12,13 Oxidative addition of CdP bonds in arylphosphines also resulted in undesirable decomposition of aryl palladium complexes of halides, which limited catalytic turnover numbers.14 The reaction of terminal aliphatic alkenes, for example, 1-hexene, generally afforded a mixture of olefinic isomers due to poor regioselectivity of insertion and further double bond migration in products. The latter process was catalyzed by residue PdH species. In a typical catalytic cycle of the Heck reaction of aryl halides, Pd(II) salts are first in situ reduced to active Pd(0) complexes, which are stabilized by coordination of phosphines or stabilized by acetate and halide anions under ligandless conditions. The concerted oxidative addition of Pd(0) to aryl halides provides cis-complexes of aryl palladium halides, which often undergo cisto-trans isomerization to form more stable trans-complexes. Olefin insertion and subsequent b-hydrogen elimination affords olefins

Fig. 1 Early examples of the Heck reaction.

4

CdC Bond Formation Through Heck-Like Reactions

as products (Fig. 1A). Usually trans-olefins are dominant products due to steric factors in syn b-hydrogen elimination. Tertiary alkylamines are often added to remove palladium hydrides to regenerate active Pd(0) catalysts. When aryl halides are used in excess, diarylation of styrene and acrylates may also occur (Fig. 1B). The Heck reaction has been utilized to synthesize complex products. As a simple illustration, o-iodoaniline was coupled with a maleate and the immediate Heck product underwent cyclization to afford a quinolone ring (Fig. 1C). The reaction of alkenyl halides can lead to products other than simple Heck adducts. For example, the reaction of 2-bromopropene and methallyl alcohol gave a g,d-unsaturated aldehyde as the main product after iterative b-hydrogen elimination and reinsertion in the direction of the alcohol (Fig. 2A). When secondary alkylamines such as piperidine were used, the reaction provided not only a ketone product, but also a three-component adduct via amine trapping of a putative p-allyl complex (Fig. 2B). After alkenyl insertion, alternative b-hydrogen elimination at the allylic position produced the p-allyl complex. In recent years, the strategy of palladium migration towards terminal carbinols and other functional groups was successfully exploited by Sigman et al. to develop enantioselective redox-relay Heck arylations and alkenylations.15–18 Similar three-component domino couplings were observed in the alkenylation of terminal olefins and 1,3-dienes in the presence of secondary amines. In the first example, the amine attacked selectively at the disubstituted terminus of the p-allyl complex, which formed a weaker Pd-C bond than the less-substituted end and thus had more partial positive charge (Fig. 3A). In the second example, after alkenyl insertion of isoprene, the p-allyl complex was formed directly, but the terminal selectivity of amine attack was not good (Fig. 3B). These works lay the foundation for recent discoveries of enantioselective domino couplings which were terminated by nucleophilic trapping of allylic intermediates.19–22

12.02.2 Heck reaction of aryl and alkenyl (pseudo)halides The topic of asymmetric Heck reaction was reviewed by Guiry et al. in 2010, including reaction discovery, design of an assortment of chiral phosphorus ligands and synthetic applications in complex molecule synthesis.23 Since then, significant advances have been made, including enantioselective intermolecular Heck reactions using different classes of organic halides and challenging trisubstituted alkenes. In 2021 Jia et al. and Bahamonde et al. have separately provided updates on the state-of-art in asymmetric Heck reaction.24,25

Fig. 2 Heck reactions of alkenyl halides with allylic alcohols.

Fig. 3 Domino reactions of alkenyl halides with terminal olefins and 1,3-dienes.

CdC Bond Formation Through Heck-Like Reactions

5

12.02.2.1 Heck reaction of cyclic alkenes The Heck reaction of cyclic olefins produces arylated alkenes which are useful building blocks in organic synthesis. Further transformations of alkene groups in Heck adducts allow quick diversification of structures. In the past two decades, many novel phosphorus ligands have been synthesized and tested against model reactions between aryl triflates and cycloalkenes, but a general-purpose catalyst with broad substrate scope was still lacking. A sampling of representative examples is shown below. By a chance discovery, Zhou et al. found that bisphosphine monoxides26 on a spiro-diindanyl backbone, Xyl-SDP(O) was superior to many chiral phosphorus ligands in terms of catalytic activity and substrate scope (>97% ee in many cases) (Fig. 4A and B).27 The origin of high catalytic activity originated from relatively weak P,O-donation to cationic palladium centers, which significantly accelerates the alkene insertion in the catalytic cycle. The weak donation also helped to avoid double bond migration of products, by helping the removal of PdH species by bases. The oxidative adduct of an aryl halide was isolated and characterized (Fig. 4C). The P-aryl group was situated trans to the phosphine oxide to avoid strong trans influence with the phosphine arm. Treatment of the complex with AgOTf led to highly stereoselective insertion of cycloalkenes. The spiro P,O-ligands opened new opportunities in asymmetric Heck reactions, for example, arylative desymmetrization of 4-substituted cyclopentenes provided trans-disubstituted cyclopentenes in excellent ees (Fig. 5A).28 In the second example, stereoselective annulation of o-vinylphenyl triflate and N-Boc-dihydropyrrole produced an azatricycle which was converted to the core structure of (−)-martinellic acid after ozonolysis and Hoffman rearrangement (Fig. 5B).29 The latter is an active ingredient of folk medicine used to treat eye infection in South America. The spiro catalyst Xyl-SDP(O) was also successfully applied to asymmetric intermolecular Heck couplings of aryl bromides (Fig. 6A).30 The substrate scope also included some alkenyl bromides and aryl chlorides. Hydrogen bond donors were employed to promote reversible ionization of PddX bonds so as to access cationic aryl palladium species for stereoselective insertion. Thus, both trialkylammonium salts and alcoholic solvents of methanol and ethylene glycol were necessary, as shown in the stoichiometric insertion reaction using an isolated oxidative adduct of ArBr. In 1,4-dioxane solvent, no Heck product was formed at all (Fig. 6B). In asymmetric Heck reaction, trisubstituted cycloalkenes have much lower reactivity of insertion than disubstituted ones. The spiro-diphosphine oxide SDP(O) enabled asymmetric arylation of 2-substituted-4,5-dihydrofuran, which produced fully substituted stereocenters, as reported by Hou et al. in 2015 (Fig. 7A).31 Mazat et al. also achieved this transformation by using a novel P,N-ligand (Fig. 7B).32 In general, aryl triflates having electron-withdrawing groups gave poor yields and moderate ees. To solve this problem, the ancillary ligand was switched to Difluorphos. The arylated products were formed in good yields, but extensive double bond migration occurred to give the more stable isomers as major products (Fig. 7C).

12.02.2.2 Heck reaction of acyclic alkenes In the past decade, Sigman’s group has made impressive progress in enantioselective Heck reactions and related processes using challenging linear internal alkenes as substrates (for an early example of asymmetric Heck-Matsuda reaction using aryldiazonium salts reported in 2012, see Section 12.02.3.3).15 A few attributes of Pyrox ligands and alkenols are keys to success (see Fig. 8).33–36

Fig. 4 Asymmetric arylation of aryl triflates with cycloalkenes.

6

CdC Bond Formation Through Heck-Like Reactions

Fig. 5 Arylative desymmetrization and stereoselective annulation of o-vinylphenyl triflate.

Fig. 6 Asymmetric intermolecular Heck reaction of aryl and alkenyl halides.

CdC Bond Formation Through Heck-Like Reactions

Fig. 7 Asymmetric arylation of aryl triflates with trisubstituted cycloalkenes.

Sigman (2014)

(A)

Pd(CH 3CN) 2(OTs) 2 6 mol% CF 3-Pyrox-tBu 9 mol%

Me PhB(OH) 2

OH

3Å MS, Cu(OTf) 2 3 mol% DMF, O 2 (balloon), rt

Et

O

Ph Et Me

H

81% yield, 96% ee

Ph PdL+

Ph Et Me

PdL+

PdHL+

Ph Et Me

OH H

OH CF 3

O CF 3

N

H

N

Ph Et Me

N

O N + Pd

OH

t-Bu

CF 3-Pyrox-tBu

transition state of insertion

(B)

n-Bu Sigman (2020)

n-Bu

NPhth

Pd(CH 3CN) 2(OTs) 2 10 mol% CF 3-Pyrox-tBu 15 mol%

Et or

Cu(OTf) 2, 3Å MS, O2, DMF, rt Ac

n-Bu Me

OH PdL+

PhB(OH) 2

N Me

Et NPhth Ph

83% yield, 96% ee or Ph Me Ac n-Bu N Ph Me 67% yield, 98% ee

Sigman (2019) Pd(CH 3CN) 2(OTs) 2 10 mol% CF 3-Pyrox-tBu 12 mol%

(C)

F PhB(OH) 2

n-Bu

OH

Fig. 8 Asymmetric oxidative Heck arylation of trisubstituted cycloalkenes.

dba, 3Å MS, MeOH, O2, rt then NaBH4

OH n-Bu

F Ph

90% yield, 98% ee

7

8

CdC Bond Formation Through Heck-Like Reactions

(a) As an important electronic feature, Pyrox ligands (e.g., CF3-Pyrox-tBu) are less donating to metal centers than bisoxazolines, which accelerates insertion of alkenes, even di- and even trisubstituted alkenes of low reactivity. Consequently, there is intrinsic electronic bias to insert and form new CdC bonds at the distal olefinic carbon of carbinols. (b) Pyrox ligands provide ideal stereo-differentiation during olefin insertion. Detailed DFT calculations have been performed on the aryl insertion step and chain walking. During aryl insertion of alkenols, there is CH-p attractive interaction between the pyridyl C2dH bond and Pd-aryl ring, which stabilizes this isomer of the square-planar complex (see Fig. 8). The large t-butyl group is strategically positioned to provide steric differentiation of the neighboring olefinic substituent. (c) The hydroxy groups in alkenols act inductively as electron-withdrawing groups, which render electronic differentiation of two olefinic carbons of carbinols during insertion. (d) The carbinol groups also bias the reversible chain walking towards hydroxyl groups to form carbonyl products, which prevents backward b-hydrogen elimination that erases the newly formed stereocenters. Several examples of oxidative Heck reactions using organoboronic acids from Sigman’s lab are featured in Fig. 8. It should be pointed out that transmetalation of arylboronic acids produces aryl palladium species without introducing (weakly) coordinating anions, as happens from oxidative addition of aryl halides and sulfonates. As a consequence, “naked” cationic aryl palladium species generated this way have enhanced reactivity in alkene insertion. For example, palladium/Pyrox catalysts promoted asymmetric insertion of disubstituted alkenols that formed tertiary centers in excellent ees.37 In 2016, the oxidative Heck reaction was extended to trisubstituted alkenols, which formed quaternary all-carbon stereocenters in excellent ees (Fig. 8A).38 Later, oxidative arylation of 1,1-disubstituted homoallylic alcohols was also performed to construct b-stereocenters on alkenols.17 The formation of enamides and enimides can also terminate chain walking in redox-relay Heck manifolds. Thus, oxidative arylation of these special alkenes afforded different products depending on the type of nitrogen directing groups (Fig. 8B).39 For example, reactions of homoallylic phthalimides, trifluoroacetamides and sulfonamides led to allylic amine derivatives. But in reactions of allylic acetamides, for example, enamides were the initial products, which quickly underwent second arylation. The oxidative Heck arylation was also applied to enantioselective arylation of fluoroalkenes (Fig. 8C), which have ameliorated reactivity because of the strongly electron-withdrawing fluorine atom. It is one of a handful of catalytic methods capable of constructing fully substituted stereocenters carrying a CdF bond.40 In 2015, Sigman and co-workers reported asymmetric alkenylation of disubstituted alkenols using cyclic enonyl triflates to form tertiary stereocenters.16 These electron-deficient alkenyl electrophiles destabilized unwanted allyl palladium intermediates and thus, prevented backward chain walking. In 2016, the alkenylation was extended to trisubstituted alkenols to forge all-carbon quaternary centers (Fig. 9A).41 The simple alkenyl triflates were selected so that the reacting carbons are not too hindered for insertion of alkenes. Alkenyl boronic acids were also tested, but they produced 1,3-dienes as side products due to fast double transmetalation. Asymmetric redox-relay Heck alkenylation was also applied to internal (aryloxyl)alkenes, which produced chiral allylic ethers (Fig 9B).42 The alkenylation occurred selectively at the olefinic carbon a to the ethers, because this site can better stabilize partial positive charge in the cationic transition state of insertion. Replacing aryloxy groups with alkoxy groups resulted in b-alkoxy elimination to form dienes. After alkenylation of internal alkenes, chain walking can form stabilized 3-benzyl complexes if arenes are present at the end of aliphatic chains. This manifold was recently reported by Sigman et al. in 2019 (Fig. 9C).43

(A)

Sigman (2016) Me

Ph

OTf

OH

Pd2(dba) 3•CHCl3 5 mol% NO2-Pyrox-tBu 12 mol%

Et

3Å MS, DMA, rt

O

Et Me

O H

O2N

Ph 81% yield, 90% ee

Sigman (2018) (B)

MeO2C

OTf PhO

OH

Pd2(dba) 3•CHCl3 5 mol% NO2-Pyrox-tBu 12 mol% 3 Å MS, DMF, rt

PhO MeO2C

OH

then NaBH4, MeOH 90% yield, 98% ee Sigman (2019)

(C)

O Me

Et

Ph

Pd(dba) 2 10 mol% CF 3-Pyrox-tBu 12 mol%

OTf

Fig. 9 Asymmetric Heck alkenylation of internal alkenes.

dba, 4Å MS. DMF, rt 4-OMe-PhB(OH) 2

O Me Et

Ph

64% yield, 93% ee

N

N

NO2-Pyrox-tBu

t-Bu

CdC Bond Formation Through Heck-Like Reactions

(A)

Sigman (2017)

TIPS

I

Et

O

TIPS

Pd(MeCN) 2(OTs) 2 8 mol% CF 3-Pyrox-iPr 10 mol%

OH

9

O CF 3

3Å MS, dioxane, rt

Et

CHO

65% yield, 93% ee

O TIPS-EBX

N

N

i-Pr

CF 3-Pyrox-iPr

TIPS

(B)

D D TIPS-EBX

Et

D >95% D

same as above

OH

Et

O D >95% D β-H elimination

TIPS

TIPS

D

D D Et

OH PdL+

TIPS

Et D

OH PdL+

D PdL+ Et

OH D

Fig. 10 Asymmetric Heck alkynylation and a deuterium labelling experiment.

In 2017, Sigman and co-workers employed TIPS-EBX for alkynylation of internal alkenols, producing propargylic stereocenters in excellent ees, but alkynylation of trisubstituted alkenols was low-yielding, unfortunately (Fig. 10A).18 A deuterium labelling experiment indicated that at the end of chain walking, b-hydrogen elimination from the hydroxyl group produced the aldehyde, rather than enol tautomerism (Fig. 10B).

12.02.2.3 Nickel-catalyzed Heck reaction Back in the 1980s, Ronchi et al. and Lebedev et al. documented initial studies on nickel-catalyzed Heck and reductive Heck reactions of aryl halides (or hydroarylation) with styrene and acrylates, respectively.44,45 Later in 1997, Iyer et al. found that Heck products can also be obtained from acrylates by switching to Ni[P(OPh)3]4 and Ni[(P(OEt)3]4 catalysts.46 In these reactions, zinc and manganese powders were commonly used for the reduction of nickel(II) salts back to nickel(0) in catalytic cycles. In 2014 Jamison et al. developed a nickel catalyst ligated by a strongly donating, bis(trialkylphosphine), which can bias regioselective arylation at internal positions of aliphatic alkenes such as 1-octene.47 In those examples, unactivated aryl chlorides, mesylates, tosylates and sulfamates were utilized. In 2019, Sevov et al. reported that electrochemical reduction enabled an expedient access to aryl nickel(I) species, which can arylate not only styrene and acrylates, but also unactivated olefins including 1-hexene and cycloalkenes.48 The topic of nickel-catalyzed Heck reaction was reviewed by Ghosh in 2020.49 Garg et al. also discovered that a nickel/ carbene catalyst can activate CdC bonds in activated aryl amides for Heck-type cyclizations.50 But for many years, enantioselective variants of these reactions have remained elusive until recently.51 Unlike palladium, which is an expensive rare noble metal, nickel is cheap Earth-abundant base metal. There are a few key differences in the reactivity of nickel and palladium catalysts in Heck-type reactions: (a) nickel(0) complexes can easily undergo oxidative addition with aryl electrophiles containing strong CdX and CdO bonds, such as chlorides and aryl mesylates, tosylates, pivalates and carbamates, as used in Heck reactions of styrene reported by Watson.52 (b) Unlike their palladium counterparts, nickel-carbon bonds in catalytic intermediates are very prone to hydrolysis by water and weak acids. (c) b-Hydrogen elimination on alkyl nickel(II) complexes is known to be slow, but according to DFT calculations, b-hydrogen elimination on alkyl nickel(I) complexes and reinsertion are fast in general. (d) Owing to shorter bonds formed with nickel than palladium, chiral ancillary ligands are brought closer to substrates on nickel centers during key bond formation. Zhou et al. in 2017 reported that nickel/semicorrin catalysts promoted asymmetric reductive Heck cyclization on aryl halides onto indoles (Fig. 11A).53 A control experiment using deuterated water indicated that after insertion, the benzyl nickel bond was protonated in situ. Addition of alkyl bromides also produced domino coupling products that formed two CdC bonds stereoselectively. Later, this reductive Heck reactivity was exploited for stereoselective cyclization of o-halochalcones (Fig. 11B).54 The catalytic indanone synthesis was applied in a concise synthesis of natural product (+)-multisianthol (Fig. 11C). In 2019 Wang and co-workers also accomplished reductive Heck cyclization of aryl halides onto unactivated alkenes, using nickel/Pyrox catalysts.55

10

CdC Bond Formation Through Heck-Like Reactions

Fig. 11 Nickel-catalyzed asymmetric Heck reaction and reductive Heck reactions.

In 2017, Desrosiers, Kozlowski and co-workers reported asymmetric Heck cyclization of N-o-bromoaryl acrylamides that produced oxindoles possessing quaternary stereocenters at C3 positions (Fig. 11D).56 Notably, an isolated complex NiCl2(QuinoxP ) was much more efficient than a combination of nickel salts and the chiral diphosphine due to slow complexation in situ. However, the reaction produced only a handful of products with >90% ees. In 2021, Zhou et al. applied successfully the same nickel catalyst in intermolecular Heck coupling of cycloalkenes with an array of aryl halides and sulfonates, including chlorides and tosylates (Fig. 11E).57 After aryl insertion, the initial Heck products underwent complete double bond migration to form the more stable isomers, suggesting that alkyl nickel(I) species, rather than nickel(II), may be involved at least during olefin isomerization. A similar catalyst NiCl2(DuanPhos) was used to promote stereoselective reductive Heck coupling of a cyclopentenone ketal, in which the addition of water was necessary (Fig. 11F).

12.02.2.4 Synthetic applications The enantioselective variants of Heck cyclization reactions can reliably establish quaternary stereocenters during ring closure. Thus, these reactions have been extensively exploited in total synthesis of complex natural products. Overman and Shibasaki have

CdC Bond Formation Through Heck-Like Reactions

(A)

Ozeki, Yamashita (2013) Me TfO

O O i-Pr

H

O

O

Pd(OAc) 2 20 mol% (R)-Synphos 40 mol%

RhCl(PPh 3) 3

Cs2CO3, DMF, 80 °C

H2, MeOH

11

Me

i-Pr

72% yield, 98% ee

E/Z 1:4

9 steps

HO

OH

O Me

OMe

Me

i-Pr

i-Pr

OH

O CHO

CHO (-)-taiwaniaquinone D O

(B)

(+)-taiwaniaquinol D

O

O

Guerrero (2017) TfO Me O O

HO

Me

Pd(OAc) 2 (S)-t-Bu-PHOX

6 steps

PMP, toluene microwave, 175 °C

O

Me

O

HO

O TBS 75% yield, >99% ee

TBS

MeO

O (-)-viridiol

O TEMPO MeO PhI(OAc) 2

HO

Me

O

O O (-)-viridin

Fig. 12 Synthetic applications of asymmetric Heck cyclization.

reviewed the topic in 2003.58,59 In 2005 Nicolaou et al. also gave a detailed account of applications of Heck reaction and other palladium-catalyzed coupling reactions in total synthesis.60 Two recent enantioselective examples are depicted in Fig. 12 as an illustration. Both engaged cyclization of aryl triflates to form 5- or 6-membered rings. In the second synthesis, the alkene group from the Heck cyclization provided a means to strategically introduce several oxygenated groups which are present in (−)-viridiol and (−)viridin. To access more elaborate ring systems, double Heck cyclizations61 were artfully designed to construct two new rings, for example, in total synthesis of (+)-xestoquinone62 and the pentacyclic core of the lycorane family of alkaloids (Fig. 13A and B).63 The lycorane alkaloids possess a multitude of biological activities with medicinal values. In both cases, the first 6-exo-trig cyclization forged the new quaternary stereocenter, for which the asymmetric Heck cyclization has been renowned. The second ring closure in both syntheses proceeded via the “6-endo-trig” mode.

12.02.3 Heck-Matsuda reaction 12.02.3.1 Introduction Aryldiazonium salts are easily prepared from anilines and sodium nitrite in the presence of acids. The salts of chlorides and acetates are unstable at room temperature, but other salts of tetrafluoroborates, tosylates and mesylates are stable crystalline solids. To ameliorate the safety hazard associated with the preparation and handling of aryldiazonium salts, procedures have been

12

CdC Bond Formation Through Heck-Like Reactions

(A)

OMe

OMe

Me OTf

O

O

PdL+

Keay (1996) OMe

Pd2(dba) 3 2.5 mol% (S)-BINAP 10 mol%

OMe

Me

Me O

O

PMP, toluene, 110 °C

OMe

O

OMe

O

82% yield, 68% ee O

Me

Pd/C, H2 O

then CAN O O (+)-xestoquinone (B)

Lete (2015) O O

I Me N

PdL+

Pd(OAc) 2 10 mol% (R)-BINAP 28 mol%

O

PMP, MeCN, 80 °C

O

Me

Me O N

O

N

60% yield, 65% ee OH HO H steps

O H O

N

lycorine Fig. 13 Synthetic applications of asymmetric Heck cyclization.

developed for in situ generation from arylamines and nitrites such as tBuONO, especially in the context of flow synthesis in recent years. The use of aryldiazonium salts in transition metal-catalyzed reactions has been covered in some reviews, including cross-couplings, CdH activation and alkene insertion.64,65 In 1977, Matsuda et al. reported the first example of the Heck-type coupling of aryldiazonium salts. The named reaction exhibited good compatibility of polar functional groups and can be conducted in air and water under very mild conditions.66,67 Most Heck–Matsuda reactions use aryldiazonium tetrafluoroborate.68–70 They are much more reactive towards palladium catalysts than aryl iodides. In fact, they undergo facile oxidative addition on palladium without the need of ancillary phosphines or bases. Aryldiazonium salts can react directly with phosphines. Furthermore, in oxidative addition, the leaving group of aryl diazonium salts is dinitrogen and a cationic arylpalladium species is produced directly without coproduction of weakly coordinating anions (leaving groups). This feature made it possible to produce highly active cationic ArPd species under Heck-Matsuda conditions which can undergo insertion of di- and even trisubstituted alkenes of low intrinsic reactivity. These attributes make Heck-Matsuda reaction ideal for large-scale applications, for example, Syngenta’s production of herbicide Prosulfuron involved arylation of 3,3,3-trifluoroprop-1-ene (Fig. 14A). In a recent example, Sharpless et al. used aryldiazonium salts to arylate ethenesulfonyl fluoride (ESF) that afforded (E)-isomers, which are useful precursors in a new generation of click reactions (Fig. 14B).71

12.02.3.2 Arylation of cyclic olefins The development of enantioselective Heck–Matsuda reaction has lagged behind asymmetric Heck reactions of aryl triflates and halides in the past, largely because of fast reduction of aryldiazonium salts by chiral phosphines. In the last decade, the Correia and Sigman groups have pioneered the use of Pyrox ligands for asymmetric Heck-Matsuda reaction and significantly improved the efficiency of enantiomeric induction. The topic was reviewed by Correia in 2020 and 2021.72,73 In 2012, Correia et al. made a breakthrough in the asymmetric Heck-Matsuda reaction, by applying chiral bisoxazolines in arylative desymmetrization of cyclopentene-4,4-diesters (Fig. 15A).74 Further improvement in the desymmetrization was brought forth in 2016 by using pyridine-oxazolines (Pyrox) which are weaker donors than bisoxazolines (Fig. 15B).75 Consequently, the cationic aryl palladium species have much high insertion activity towards alkenes than those ligated by bisoxazolines. Thus, arylative desymmetrization of 4-cyclopentenol produced the cis-isomer with 99% ee, meaning that aryl group selectively added syn to the carbinol group.

CdC Bond Formation Through Heck-Like Reactions

13

Fig. 14 Synthetic applications of Heck-Matsuda reactions.

Fig. 15 Asymmetric Heck-Matsuda arylation of cyclic olefins.

Later, this abnormal result was rationalized by DFT calculations, which revealed surprisingly electrostatic attraction between the hydroxyl group and the cationic palladium center in the transition state of insertion. Different from classical dative bonds of directing groups on transition metals, no formal dative bonds are formed due to coordinative saturation of the Pd centers. The distance of the hydroxyl oxygen and the palladium center was calculated to be 2.9 A˚ , much longer than a formal dative bond. This kind of electrostatic interaction was enhanced by the binding with weakly donating Pyrox. The weak electrostatic attraction was also found to be operating in arylations of cyclic alkenes carrying other directing groups, such as the hydroxyl group in meso-cis-cyclohex-4-ene-1,2-diol (Fig. 16A)76 and amide groups in spirooxindoles (Fig. 16B).77 In the former, DFT calculation implied that only one of two hydroxyl groups acted as an electrostatic directing group, with a calculated Pd ⋯ O distance of 2.7 A˚ . Potassium tris(triflyl)methide KCTf3 contains a large soft anion having highly delocalized negative charge

14

CdC Bond Formation Through Heck-Like Reactions

Fig. 16 Heck-Matsuda desymmetrization of cyclic alkenes.

and it can undergo exchange to form ion pair with large cationic organometallic complexes.78 It was added as to improve the chemical yield of the products, probably serving as the counteranion of the cationic palladium complexes. In the latter, the rigidity of the spiro rings helped to place the carbonyl oxygen close to palladium to maintain such a noncovalent interaction. (S,S)-VPC01091 is a selective sphingosine 1-phosphate receptor-1 (S1PR1) agonist and sphingosine 1-phosphate receptor-3 (S1PR3) antagonist. In biological testing on mice models, it confers protection against lung injury and dysfunction after ischemia reperfusion. Correia et al. has developed several routes for its asymmetric synthesis using Heck-Matsuda arylation (Fig. 17A and B). One route involved arylation of cyclopentene which was spiro-fused with an N-Boc-carbamate. The arylation occurred selectively anti to the N-Boc substituent. However, the substrate scope of aryldiazonium salts was limited that gave excellent ee and dr values. In another synthesis, a carbonyl group of spirohydantoin was artfully employed as an electrostatic directing group which improved substrate scope.79

Fig. 17 Stereoselective synthesis of VPC01091 via Heck-Matsuda reaction.

CdC Bond Formation Through Heck-Like Reactions

15

Fig. 18 Stereoselective synthesis of (partially) saturated P- and S-containing heterocycles.

The strategy of electrostatic directing groups was later applied to stereoselective syntheses of (partially) saturated P- and S-containing heterocycles, via desymmetrization of partially unsaturated cyclic sulfones, sulfoxides and phosphine oxides (Fig. 18).80 The excellent dr and ee were a testament to the power of this type of noncovalent electrostatic attraction. According to DFT calculations, the distance of one sulfoxide oxygen and Pd was around 3.0 A˚ , shorter than those found in calculated structures of sulfones and phosphine oxides (around 3.4 A˚ ). This helps to explain the relatively low diastereoselectivity (7:1) observed in the arylation of a phosphine oxide. The enantioselective Heck-Matsuda arylation of cyclic olefins also occurred even in the absence of electrostatic directing groups. For example, Correia et al. capitalized on the high reactivity of Heck-Matsuda conditions and achieved arylation of 2,3-dihydrofuran and 2,5-dihydrofuran using sterically hindered aryl rings (Fig. 19A and B).81 After successive b-hydride elimination and reinsertion, 2-aryl-2,3-dihydrofurans were in situ hydrated to produce lactols (rather than nucleophilic substitution of alkyl palladium species as suggested by authors). Subsequent sodium borohydride reduction and spontaneous lactone formation provides a chiral phthalide, a key intermediate towards (+)-spirolaxine methyl ether. The latter is a metabolite of fungus Sporotrichum laxum with an inhibitory activity against Helicobacter pylori. It may be useful for the treatment of gastroduodenal disorders and the prevention of gastric cancer. In 2017, Sunoj and Toste et al. reported an asymmetric Heck–Matsuda reaction of cyclopentene, cyclohexene, and cycloheptene derivatives using large H8-BINOL-derived phosphoric acid (H8-BINOL-PA) and a BINAM-derived phosphoric acid (BINAM-PA)

Fig. 19 Stereoselective synthesis of arylated lactols.

16

CdC Bond Formation Through Heck-Like Reactions

Fig. 20 Desymmetrization of 4,4-disubstituted cyclopentenes.

(Fig. 20A and B).82 It was proposed that chiral ion pairs with arylpalladium cations were active species for asymmetric olefin insertion. The vacant sites on palladium in the ion pair may be filled by coordinating solvents or dba introduced from Pd2(dba)3. The dba association was detected by electrospray MS studies of Heck-Matsuda reactions without added chiral ligands.83 But the active species may also be a neutral aryl palladium complex with a bound phosphate which is coordinately saturated. After insertion, the PdH species was quickly removed by bases, which helped to prevent alkene isomerization in both starting material and products. The BINAM-phosphate anion was more basic than H8-BINOL-phosphate and helped to prevent alkene isomerization in the starting material encountered in some reactions.

12.02.3.3 Arylation of acyclic olefins In enantioselective Heck-Matsuda arylations, cyclic alkenes are usually preferred substrates in which b-hydride elimination cannot destroy newly formed stereocenters. Asymmetric Heck arylation of acyclic internal alkenes is more difficult to achieve because of the lack of electronic differentiation of two olefinic positions during insertion. In 2012, Sigman et al. published a breakthrough in enantioselective Heck-Matsuda reaction by using acyclic (homo)allylic alcohols (Fig. 21A and B).15 The stereo- and regioselective arylation occurred at the distal carbon of alkenols which is further away from the electron-withdrawing hydroxyl group. Subsequent b-H elimination and reinsertion moved mostly in the direction of the carbinols and thus, afforded aldehydes and ketones as final products. In 2015, Correia et al. reported Heck-Matsuda arylation of an internal olefin, trans-1,4-butenodiol which was a challenging substrate for insertion due to inductive effect of two hydroxy groups (Fig. 22A).84 The use of analogous N,N-ligands PyraBox and PyriBox enabled aryl insertion to proceed in high enantioselectivity and perfect regiocontrol. Moreover, the arylation of trans1,5-pentenadiol provided an expedient route towards calcium channel blocker (R)-verapamil (Fig. 22B). Correia et al. also developed domino couplings of aryldiazonium salts involving carbopalladation followed by methoxycarbonylation (Fig. 23).85 The acyl palladium species can also be intercepted by (hetero)arylboronic acids. More recently, Han and coworkers employed palladium/H8-BINOL-derived phosphate in asymmetric arylation of acyclic allylic alcohols (Fig. 24).86 One electron-deficient dba derivative was added to improve yields, likely by stabilizing the palladium(0) catalyst. A catalytic amount of dimethyl sulfoxide was added to dissolve Na2CO3 in order to suppress olefin isomerization of the starting material (which was catalyzed by palladium hydride species).

CdC Bond Formation Through Heck-Like Reactions

Fig. 21 Asymmetric Heck-Matsuda arylation of (homo)allylic alcohols.

Fig. 22 Asymmetric Heck-Matsuda reactions of (homo)allylic alcohols to form quaternary stereocenters.

17

18

CdC Bond Formation Through Heck-Like Reactions

Fig. 23 Asymmetric domino couplings using aryldiazonium salts.

Fig. 24 Asymmetric Heck-Matsuda arylation of allylic alcohols catalyzed by palladium and a bulky phosphate.

12.02.4 Heck-type reaction of unactivated alkyl electrophiles 12.02.4.1 Introduction The topic of transition metal-catalyzed Heck-type alkylation was reviewed by Gevorgyan et al. in 2019.87 Chiba et al. also summarized the reactivity pattern of transition metal complexes in the activation of different types of alkyl electrophiles.88 Compared to the well-developed Heck arylation and alkenylation, the development of Heck-type alkylation has lagged behind, for several reasons. (1) In concerted oxidative addition of unactivated alkyl halides by palladium(0) complexes, there are prohibitively high barriers. Alkyl electrophiles, unlike aryl ones, lack p orbitals to stabilize three-centered transition states of oxidative addition, and CH bonds and substituents on the reacting C(sp3) center also shield the carbon centers.89 (2) In SN2-type reactions of Pd(0) complexes, hindered primary, secondary and tertiary alkyl halides undergo slow backside attack by (phosphine)palladium(0) complexes, owing to steric effect. (3) Radical reactivity of low-valent metal complexes with alkyl halides is rather restricted to those having weak CdBr and CdI bonds and producing relatively stabilized secondary and tertiary alkyl radicals. Even if the oxidative addition occurs, the resulting alkyl palladium species can easily undergo facile b-H elimination on palladium(II) centers. Moreover, alkyl insertion of alkenes on transition metals is much slower than aryl insertion. Phosphine complexes of palladium(0) can undergo SN2-type oxidative addition with unhindered primary alkyl halides, but the resulting alkyl palladium complexes are usually prone to b-hydride elimination. In 2002, Fu and coworkers isolated and characterized the first oxidative adduct of a primary alkyl bromide possessing eliminable b-hydrogens with a L2Pd(0) complex ligated by two large and strongly donating ligands of trialkylphosphine P(t-Bu)2Me (Fig. 25).90 The isolated alkyl palladium complex proved chemically competent in Suzuki coupling. The stoichiometric reactions of complex PdL2 [L ¼ P(t-Bu)2Me] with alkyl halides exhibited typical behaviors of SN2 substitution, including reaction rate dependence on leaving groups, steric hindrance of alkyl groups and solvent polarity.91 Later, in stoichiometric reactions of deuterium-labelled alkyl tosylates, the result supported that the oxidative addition step proceeded mainly via an SN2 substitution with the inversion of configuration.92 Thus, strong donation of two trialkylphosphines helped to lower the barrier of oxidative addition; the large size of two trialkylphosphines impeded the undesirable b-hydride elimination in the tetracoordinated oxidative adduct, but at the same time, sufficient surface area of PdL2 is exposed to react with unhindered alkyl halides. Ph Br

Ph

PdL2

Et2O, 0 oC

L = P(t-Bu)2Me Fig. 25 Stoichiometric oxidative addition of an alkyl bromide and a PdL2 complex.

L Pd L Br (X-ray structure)

CdC Bond Formation Through Heck-Like Reactions

19

Fig. 26 Intramolecular Heck reaction of primary alkyl bromides.

In 2007, Fu et al. reported the seminal example of Pd-catalyzed Heck cyclization of primary alkyl bromides and chlorides with pendent olefins (Fig. 26A and B).93 The electron-rich and bulky N-heterocyclic carbine, SIMes was selected to facilitate SN2-type oxidative addition on the palladium center, as judged from the inversion of configuration in a deuterium labelling experiment. The bulky ligand also inhibited premature b-hydride elimination of the resulting alkyl palladium complexes. However, the nature of the SN2-type reaction restricted the substrates to primary alkyl halides of low steric demand, while more hindered secondary and tertiary alkyl halides remained unreactive. Back in the 1970s, Osborn et al. reported that stoichiometric reactions of Pd(0) complexes of phosphines and secondary and tertiary alkyl halides produced alkyl radicals. The transient existence of the alkyl radicals was detected by chemically induced dynamic nuclear polarization effect (CIDNP) (Fig. 27).94,95 The formation of both radical combination and disproportionation products also confirmed the involvement of the alkyl radicals. The reactivity of alkyl radicals initiated by palladium catalysts remained unexplored for many years，until in 1991 Suzuki and Miyaura reported carbonylative coupling of iodoalkenes and alkyl 9-BBNs in the presence of CO.96 Primary, secondary and tertiary alkyl iodides reacted well, indicating that the sterically sensitive SN2 pathway was not operating (Fig. 28A). Photoexcitation of the

Fig. 27 Radical generation from phosphine complexes of platinum(0) and palladium(0).

Fig. 28 Palladium-catalyzed carbonylative reactions and atom transfer radical addition reaction.

20

CdC Bond Formation Through Heck-Like Reactions

palladium(0) complexes generates triplet states which are prone to halogen abstraction from alkyl halides, especially alkyl iodides. The reaction above involved a key step of alkyl radical addition to a pendent alkene. In another example, Ryu et al. reported the involvement of atom transfer radical addition of alkyl iodides initiated by a palladium(0) catalyst under UV light (Fig. 28B).97 Ryu et al. also reported carbonylative Heck reaction of alkyl iodides, which involved a step of acyl radical addition to aryl alkenes (Fig. 28C).98

12.02.4.2 Pd-catalyzed thermal Heck-type alkylation In 2011, Alexanian and coworkers reported Pd-catalyzed cyclization of alkyl iodides under 10 atm CO (Fig. 29A and B).99 The Heck-type alkylation took place exclusively without CO insertion. The result of TEMPO-trapping supported the involvement of alkyl radicals in this reaction. The Alexanian group later developed a CO-free method for an intramolecular Heck-type reaction of alkyl bromides and iodides (Fig. 30A).100 The use of a large, strongly donating ferrocene-derived diphosphine dtbpf significantly increased the reaction efficiency. Mechanistically, the product of atom transfer radical cyclization (ATRC) was detected from a model alkyl bromide at a short reaction time; it underwent quantitative dehydrohalogenation when subjected to catalytic conditions (Fig. 30B). The addition of radical scavengers or replacement of Pd(0) catalyst by simple radical initiators led to low conversions (Fig. 30C). These results indicated that the cyclization of alkyl bromides proceeded via an ATRA pathway, in which the palladium served as a true catalyst in each catalytic cycle, rather than acting as an initiator in a radical chain reaction. For reactions of alkyl iodides, however, the

Fig. 29 Intramolecular Heck reaction of alkyl iodides in the presence of CO.

Fig. 30 Heck-type cyclization of alkyl halides under CO-free conditions.

CdC Bond Formation Through Heck-Like Reactions

21

Fig. 31 6- and 7-Endo-trig Heck-type cyclization of unactivated alkyl iodides.

palladium catalyst was only required in the initiation step. After the initial formation of alkyl radicals, radical chain reaction took over to deliver ATRC products. Subsequent dehydrohalogenation by the palladium catalyst or base delivered the final alkenyl products. Most intramolecular Heck reactions of alkyl halides were limited to 5- or 6-exo-cyclization. In 2016, Liu et al. developed a rare 6-endo-selective cyclization of unactivated alkyl iodides (Fig. 31A and B).101 The a-aryl groups on the alkenes were crucial to inducing endo-selectivity by stabilizing the transition state leading to tertiary-benzyl radical intermediates. The result of partial deuterium loss also supported the involvement of hybrid palladium-radical catalysis. Later, the endo-selective reaction was extended to epoxides (Fig. 31C).102 The role of Et3N
HI may be perceived to in situ convert epoxides to b-halohydrins, but DFT studies revealed that (Josiphos)PdH(I) interacted with the epoxide which led directly to epoxide opening and 7-endo-trig cyclization and formed a hydride palladium-alkyl radical in a single rate-limiting step. Interestingly, Gevorgyan and coworkers reported 7-endo-selective silylmethylative cyclization (Fig. 32).103 The ring-closure was assisted by the Thorpe-Ingold effect of silyl gem-dialkyl groups and the lack of eliminable b-hydrogens in the resulting alkyl palladium species. The 7-endo-trig selectivity originated from the relatively long SidC bond and stabilization of the endo transition state by terminal alkenes. The Heck-type reaction involving 5- and 6-exo-trig radical cyclization is a generally fast process, whereas in the intermolecular alkyl radical addition, the rate of radical addition is highly dependent on the electronic nature and substituents of alkenes. In a continued work, Alexanian et al. expanded the scope of the Pd radical catalysis to intermolecular alkylation (Fig. 33).104 A combination of PdCl2(dppf ) and Pd(PPh3)4 enabled primary and secondary alkyl iodides to couple with styrene, albeit with low E/Z ratio. The coupling also worked well with electron-deficient acrylate and acrylonitrile.

Fig. 32 7-Endo-selective Heck-type cyclization of iodomethylsilyl ethers.

22

CdC Bond Formation Through Heck-Like Reactions

Fig. 33 Pd-catalyzed intermolecular Heck-type reaction of alkyl iodides.

Fig. 34 Pd-catalyzed intermolecular Heck-type reaction of unactivated alkyl halides.

Around the same time, Zhou et al. independently developed an intermolecular Heck-type alkylation of aryl alkenes and 1,3-dienes using a combination of Pd(PPh3)4 and dppf as the precatalyst (Fig. 34A and B).105 Notably, alkyl bromides and chlorides were in situ converted to alkyl iodides by heating with lithium iodide and became suitable coupling partners. 1-Iodopropylbenzene, when subjected to a living catalytic reaction, proceeded in moderate conversion with 41% yield of dehydrohalogenation (Fig. 34C). Later, Zhou et al. developed an intermolecular Heck coupling of epoxides using a combination of Pd(PPh3)4 and Xantphos (Fig. 35A).106 A catalytic amount of Et3NHI was used to in situ convert epoxides to the corresponding alkyl iodides. Mechanistic studies and cyclic voltammetry suggested that halogen abstraction by the palladium(0) catalysts produced alkyl radicals, which then underwent radical addition to alkenes followed by b-hydrogen elimination of alkylpalladium(II) species. Remarkably, enantiopure glycidyl alcohols and ethers provided the corresponding Heck products with excellent conservation of the b-stereocenters (Fig. 35B).

12.02.4.3 Pd-catalyzed photoinduced Heck-type alkylation Recently, photoexcitation of (phosphine)Pd(0) complexes has enabled activation of alkyl halides under mild conditions, even at room temperature. In particular, blue LED was used to excite the tri(phosphine)Pd(0) complexes to triplet states, which became much more reactive toward halogen abstraction (or so-called inner-sphere electron transfer) of unactivated alkyl halides to generate

CdC Bond Formation Through Heck-Like Reactions

23

Fig. 35 Pd-catalyzed intermolecular Heck-type reaction of epoxides.

alkyl radicals and tri(phosphine)Pd(I) halides.107 According to DFT calculations, the triplet state of the hybrid alkyl Pd(I) radical is kinetically prohibited from combining to form alkyl palladium(II) halides. The radical recombination is also disfavored energetically by large bite-angle diphosphines, for example, Xantphos (Fig. 36).108 In 2017, Gevorgyan et al. employed visible light to facilitate Pd-catalyzed Heck-type radical alkylation (Fig. 37).109 a-Heteroatom-substituted alkyl halides lacking b-hydrogens coupled efficiently with (hetero)aryl alkenes, examples including a-silylmethyl iodides. The photoexcitation of the palladium(0) catalysts into the triplet states allowed the catalytic reaction to proceed at room temperature. In 2017, Fu, Shang et al. also reported that photoirradiation enabled Heck-type reaction with 1 , 2 and 3 alkyl bromides at room temperature (Fig. 38A).110 In a competition experiment, oxidative addition of alkyl halides delivered the tert-alkylation much

Fig. 36 Oxidation addition tri(phosphine)Pd0 complexes with alkyl halides under photoexcitation.

Gevorgyan (2017)

TMS

Pd(OAc) 2 10 mol% Xantphos 20 mol%

I

Ph

TMS Ph

Cs2CO3, benzene, rt Blue LED

85% yield, E/Z 49:1

PdLn*

- HPdXLn radical addition

TMS

PdXL n N

TMS

71% yield

TMS PdXL n

Ph

BPin (EtO) 3Si

Ph

65% yield

Fig. 37 Visible light-induced Heck-type reaction of a-heteroatom substituted alkyl halides.

Me2PhSi

90% yield

Ph

24

CdC Bond Formation Through Heck-Like Reactions

Fig. 38 Photoirradiation-induced Heck-type reaction of alkyl bromides.

Fig. 39 Pd-catalyzed radical alkylation of silyl enol ethers and enamides under blue LED irradiation.

faster than the prim-alkylation (Fig. 38B). This result was consistent with halogen abstraction (or so-called inner-sphere electron transfer) and excluded an SN2-type oxidative addition. The reaction completely stopped in the absence of light, which excluded the possibility in which the light only served as an initiator of a radical chain process. Moreover, the tri(phosphine)Pd(0) complex was determined to be the only light-absorbing species in the reaction. In 2020, Fu et al. applied the palladium radical catalysis under blue light irradiation to the alkylation of silyl enol ethers and enamides, which afforded a-alkylated ketones and N-acyl ketimines (Fig. 39A and B).108 Theoretical studies indicated that the coordinative saturation by a large bite-angle diphosphine and PPh3 and spin prohibition prevented the recombination of the alkyl radical with the PdI center to form an alkyl palladium species. Aliphatic N-(acyloxy)phthalimides have half-wave reduction potentials between −1.25 and −1.37 V (vs SCE). They can also serve as alkyl radical precursors upon reduction. In 2018, Fu, Shang et al. reported the decarboxylative Heck reaction under the irradiation of blue LED (Fig. 40). After single electron transfer from the excited state of LnPd and subsequent decarboxylative fragmentation, the resulting alkyl radical underwent the hybrid palladium-radical catalysis to give the Heck-type coupling products.

12.02.4.4 Cobalt- and nickel-catalyzed Heck-type alkylation In 2002, Oshima et al. reported that a cobalt complex ligated with dpph promoted Heck coupling of alkyl halides and olefins (Fig. 41A–C).111 The strongly basic Grignard reagents were essential to generate catalytically active low-valent cobalt(0) species. The halogen abstraction of alkyl halide by the cobalt(0) complex produced alkyl radicals, which then underwent radical addition to styrene. The combination of benzylic radical with (CH2SiMe3)(dpph)Co and subsequent b-H elimination delivered the Heck products. The cobalt-catalyzed reaction was also applied to epoxides as substrates.112 TMSCH2MgBr promoted in situ formation of alkyl bromides from epoxides, although the regioselectivity of epoxides ring-opening were poor in some cases.

CdC Bond Formation Through Heck-Like Reactions

25

Fig. 40 Decarboxylative Heck-type reaction of alkyl N-(acyloxy)phthalimides.

Fig. 41 Cobalt-catalyzed Heck-type reaction of alkyl halides.

In 2011, Carreira et al. reported that a cobaloxime complex catalyzed Heck-type cyclization of alkyl iodides (Fig. 42A and B).113 The air-stable stannyl cobaloxime can act as a CoI precursor. After SN2-type oxidative addition, the weak cobalt-carbon bond can undergo homolysis to generate an alkyl radical and a CoII complex under visible light. After radical addition and b-hydrogen elimination, Hünig’s base was used to deprotonate the hydridocobalt(III) species to complete the catalytic cycle. The method avoided the use of basic Grignard reagents, so polar functional groups such as esters and ketones were tolerated.

(A)

SnPh 3

Carreira (2011)

I CO2Bn

(SnPh 3) Co(dmg) 2(py) 15 mol%

CO2Bn Me

i-Pr2NEt, blue LED MeCN, rt (B)

MeO

Me

76% yield MeO

I O

O 96% yield

Fig. 42 Heck-type cyclization of alkyl iodides catalyzed by cobaloximes.

N O

H Co N

O N

Me Me

H pyO

(SnPh 3)Co(dmg) 2(py)

(SnPh 3)Co(dmg) 2(py) 15 mol% in flow, hn, MeCN, rt

O N

26

CdC Bond Formation Through Heck-Like Reactions

Fig. 43 Cobalt-catalyzed intramolecular Heck-type cyclization of epoxides.

Later, Morandi and coworkers investigated Heck-type cyclization of alkene-tethered epoxides using cobaloxime catalysts (Fig. 43).114 The epoxides underwent SN2-type oxidative addition with an anionic CoI complex. The ring-opening occurred regioselectively at the terminal carbon to produce a b-hydroxyalkylcobalt(III) intermediate, which was followed by photolysis of the weak cobalt–carbon bond to produce an alkyl radical. KOt-Bu was used to regenerate the low-valent cobalt complex. Similarly, aziridines were also suitable substrates. In 1986, Lebedev first reported initial studies that NiCl2(PPh3)2 catalyzed Heck-type addition of alkyl halides with styrene and reductive Heck reaction (or hydroalkylation) with acrylates, in the presence of zinc powder.45 Recently, Alexanian et al. has successfully replaced palladium catalysts with nickel complexes in Heck-type alkylation using unactivated alkyl bromides in the presence of manganese powder (Fig. 44).115 Mechanistic investigations suggested atom-transfer radical cyclization was not operating. Instead, after halogen abstraction and alkene insertion, the resulting alkyl radical and nickel(I) bromide species combined to give an alkylnickel(II) complex, which underwent b-H elimination to release the desired product.

12.02.5 Heck-type alkylation of activated alkyl halides Alkyl radicals bearing a-electron-withdrawing substituents are electrophilic radicals in nature, with low-lying SOMOs, so they generally couple well with aryl alkenes, conjugated dienes and electron-rich alkenes. In 2003, Glorius reported intermolecular Heck reactions of 2-chloroacetamides with 2,3-dihydrofuran, styrene and n-butyl vinyl ether (Fig. 45).116 The adduct of 2,3-dihydrofuran was generated as a mixture of olefinic isomers, whereas the bond formation occurred selectively at the terminal position of styrene

Fig. 44 Nickel-catalyzed Heck-type reaction of alkyl bromides.

Fig. 45 Pd-catalyzed Heck-type reaction of a-chloroamides and a-bromoacetonitrile.

CdC Bond Formation Through Heck-Like Reactions

27

Fig. 46 Pd-catalyzed intermolecular Heck-type reaction of activated alkyl halides.

and internal position of butyl vinyl ether. In the reaction between 2-bromoacetamide, however, the addition occurred selectively at the C4 position of 2,3-dihydrofuran instead. The switch of the regioselectivity suggested that cyanomethyl radical was involved in the addition to dihydrofuran. In 2017 Gevorgyan et al. reported that palladium/Xantphos can catalyze radical alkylation of aryl alkenes using alkyl iodides carrying a-electron-withdrawing phosphonyl and tosyl groups under blue LED conditions (Fig. 46A).109 Later, tert-alkyl bromides bearing a-ester, phosphonyl and tosyl groups were also found to couple with styrene and electron-rich enamides near room temperature (Fig. 46B).117 The Xantphos Pd G3 precatalyst can quickly release (Xantphos)Pd(0) catalyst via CdN reductive elimination under basic conditions. This condition was also applicable to similar alkylation using a-halomethyl Bpin reagents.109 The a-Bpin-substituted methyl radical is considered to be an electrophilic radical. In the Heck-type reaction of fluoroalkyl bromides reported by Zhang et al. (Fig. 47),118 halogen abstraction of perfluoroalkyl bromides by Pd(0)-Xantphos complex produced fluoroalkyl radicals, which then added efficiently to styrene, conjugated dienes, and electron-rich alkenes like 2,3-dihydropyran and enamides. The ring opening of a radical clock, a-cyclopropylstyrene, supported a radical pathway. The cobaloxime-catalyzed method reported by Carreira et al. can also be applied to the Heck reaction of trifluoroethyl iodide and styrenes under blue LED light (Fig. 48). This process can be adapted to a photochemical flow synthesis, providing allylic trifluoromethanes in increased yields. Other late 3d metal complexes can also catalyze this kind of Heck-type alkylation by promoting the formation of stabilized alkyl radicals. In 2012, Lei et al. reported a nickel-catalyzed Heck reaction of secondary and tertiary a-halocarbonyl compounds with aromatic olefins (Fig. 49A).119 NiCl(PPh3)3 was synthesized and subjected to a model catalytic condition, which proceeded smoothly, but not Ni(PPh3)4, suggesting that NiI complexes catalyzed this reaction. In 2013, Nishikata et al. reported that a

Fig. 47 Pd-catalyzed Heck-type reaction of perfluoroalkyl bromides.

28

CdC Bond Formation Through Heck-Like Reactions

F 3C

I

Carreira (2013) (SnPh 3)Co(dmg) 2(py) 20 mol% tBu

i-Pr2NEt, blue LED MeCN/DMSO, rt

F 3C tBu 83% yield

Fig. 48 Cobaloxime-catalyzed Heck-type reaction of trifluoroethyl iodide.

Fig. 49 Heck-type alkylation of a-haloesters using by nickel, copper and iron catalysts.

copper-triamine complex catalyzed alkylation of styrene with tertiary a-bromomalonates and a-bromonitroalkanes (Fig. 49B).120 When a secondary a-bromomalonate was used instead, the reaction afforded a cyclopropane as the final product (Fig. 49C). This result indicated that this reaction likely proceeded via atom transfer radical addition (ATRA). Iron catalysts have been widely used in atom transfer radical polymerization (ATRP). In 2017, Thomas et al. reported ligand-free iron-catalyzed alkenylation of tertiary a-halomalonates (Fig. 49D).121 When iron complexes of a-diimines were used, dimerization of alkyl radicals was observed instead of the desired radical addition.

12.02.6 Heck reaction of benzylic electrophiles The review by Gevorgyan et al. in 2019 also covers recent progress in Heck-type benzylation.87 The Heck reaction of unactivated benzyl electrophiles is often plagued with slow olefin insertion and a proclivity to form products as a mixture of olefinic isomers. The first example of Heck reaction of benzyl halides was reported by Richard Heck et al. in 1972,8 but the benzylation of acrylates afforded a mixture of olefinic isomers via nonselective b-hydride elimination (Fig. 50A). This benzylation reaction did not receive much attention in subsequent years. In 1995, Zhang et al. employed benzyltrin-butylammonium salts as electrophiles for benzylation of several types of alkenes without additional bases.122 In 2003, Kita et al. utilized the benzyl reaction in a synthesis of Beraprost, a prostacyclin analog used for the treatment of pulmonary hypertension. The mixture of alkenyl isomers from the Heck reaction were subsequently hydrogenated (Fig. 50B).123

CdC Bond Formation Through Heck-Like Reactions

29

Fig. 50 Heck reaction of benzyl chloride and synthetic application.

Shimizu, Yamamoto (2008)

(A)

O CF 3

PdL2(styrene)

Ph

O

(B)

OC(O)CF 3

cis-( h1-benzyl)(s)PdL 2+ CF 3CO2or cis-(h 3-benzyl)PdL2+ CF 3CO2-

major (X-ray structure)

minor

Pd(OAc) 2 10 mol% PPh 3 20 mol%

O CF 3

L Pd L

acetone, rt 93% yield

L = PMePh2

Ph

O

CO2Me

Ph

Ph

DMF, 100 oC

CO2Me

61% yield isomeric ratio 20:1 Fig. 51 Heck reaction of benzyl electrophiles and stoichiometric oxidative addition.

The oxidative addition of benzyl halides and carboxylates by palladium(0) complexes has been examined in details by Shimizu and Yamamoto et al. (Fig. 51A).124 The reaction of benzyl trifluoroacetate with di(phosphine)(styrene)Pd(0) resulted in oxidative addition complexes as a mixture of a neutral trans-1-benzyl complex and an ionized species. The latter was suggested to be either a cationic 1-benzyl complex with solvation or more likely, a 3-benzyl complex. Treatment of the isolated complexes with methyl acrylate led to the formation of the Heck adduct in 25% yield in DMF at 100  C. A catalytic process using benzyl trifluoroacetates was also developed without added bases (Fig. 51B). No product was formed, however, in the less polar solvents such as toluene and THF, suggesting the cationic benzyl palladium species was involved in the insertion step.125 In 2012, Zhou et al. reported the first enantioselective Heck reaction of benzyl electrophiles (Fig. 52A and B).126 Oxidative addition of benzyl trifluoroacetates produced cationic benzyl palladium complexes ligated by bulky phosphoramidites, which were responsible for enantioselective insertion of cycloalkenes. The oxidative addition of the activated benzyl electrophiles proceeded

(A)

OCOCF 3

O

Zhou (2012) Pd(dba) 2 2 mol% phosphoramidite 3 mol% Li2CO3, 2-MeTHF 40 °C

10 mmol

Ph O

O

O

Me P N

72% yield, 94% ee ligand

(B)

OCOCF 3 MeO

Boc N

Li2CO3, 2-MeTHF 60 °C

Fig. 52 Asymmetric Heck reaction of benzylic trifluoroacetates.

H N

Boc N

Pd(dba) 2 10 mol% ligand 12 mol%

MeO

MeO

AcO 86% yield, 92% ee

(-)-Anisomycin

OH

30

CdC Bond Formation Through Heck-Like Reactions

Fig. 53 Intramolecular Heck cyclization of secondary benzyl carbonates.

efficiently without the aid of strongly donating ancillary ligands. In one example, the anisylation of N-Boc-2,3-dihydropyrrole produced a key intermediate for asymmetric synthesis of anisomycin, an antiprotozoan and antifungal agent. Recently, Miura et al. reported the Pd-catalyzed intramolecular Heck cyclization of diarylmethyl carbonates onto pendent alkenes (Fig. 53A).127 The OBoc leaving group also acted as an internal base in the catalytic cycle. When Mandyphos was used as ancillary ligand, excellent kinetic resolution of the enantiomers of the secondary Boc-carbamate was observed (Fig. 53B). In a stereochemical matched case of the catalyst and the substrate, complete inversion of the configuration in the product was seen, which suggested that an SN2-type oxidative addition occurred to form p-benzyl palladium species as the key intermediate (Fig. 53C). Based on this intramolecular benzyl cyclization, the Miura group subsequently designed a domino coupling that combined benzyl insertion and Suzuki coupling (Fig. 54).128 A bulky triarylphosphine DTBMP was selected to provide almost complete inversion of configuration and high trans-selectivity. The large aryl groups on the phosphine not only suppressed unwanted b-hydride elimination, but also promoted trans-selective insertion to form the indanes. In general, palladium-catalyzed Heck arylation of electronically unbiased terminal alkenes produces a mixture of olefinic isomers due to poor regioselectivity, with few exceptions.129,130 In 2011 Jamison et al. disclosed that nickel-catalyzed Heck reaction of benzyl chlorides and terminal aliphatic olefins gave 1,1-disubstituted olefins with excellent regioselectivity (Fig. 55).131 (PCy2Ph)2Ni(0) was believed to be the catalytically active catalyst. The oxidative addition of benzyl chloride produced an 3-benzyl nickel(II) complex. Triethylsilyl triflate then performed halide abstraction to generate a cationic benzyl nickel(II) species, which then underwent the insertion. Positioning the substituents of alkenes away from large PCy3 on nickel resulted in internally selective benzylation. As Ni(COD)2 introduced COD into catalytic reactions which had a detrimental effect on the catalytic performance, Jamison et al. later developed an air-stable nickel precatalyst, trans-(PCy2Ph)2Ni(o-tolyl)Cl, which allowed less reactive alkenes to couple (Fig. 56A).132 Mechanistically, no Heck product was detected during stoichiometric precatalyst activation. Instead, trans(PCy2Ph)2Ni(o-tolyl)Cl underwent disproportionation with one equivalent of A and subsequent aryl-aryl reductive elimination produced the active catalyst L2Ni(0) and the biaryl was detected indeed (Fig. 56B).

Fig. 54 Domino couplings of benzhydryl carbonates with arylboronic acid derivatives.

CdC Bond Formation Through Heck-Like Reactions

31

Jamison (2011) Ni(cod) 2 10 mol% PCyPh 2 20 mol%

Cl

n-Hex

n-Hex

Ph

Et3SiOTf, Et 3N, rt 94% yield, regio >95:5

L2Ni

β-H elimination

Ph Et3SiOTf

insertion

R

L Ni

L Cl (x-ray structure)

L

Ni

L

Ni

OTf

L

OTf

OTBS O 77% yield, regio 91:9

OMe 99% yield, regio >95:5 rr

91% yield from C2H4

Fig. 55 Nickel-catalyzed regioselective Heck reactions of benzyl chlorides.

(A)

Cl

Jamison (2013) trans-(PCy 2Ph) 2Ni(o-tolyl)Cl 5 mol%

n-Hex

n-Hex TMSOTf, Et 3N, DCM, rt 92% yield, 98:2 rr

I

Cl PCy2Ph Ni Ar PhCy2P Ar = o-tolyl precatalyst

Me Me

F

Me

n-Bu MeO2S

84% yield, regio 95:5

75% yield, regio 96:4

80% yield, regio 98:2

(B)

Cl PCy2Ph Ni TMSOTf Ar PhCy2P A

TfO PhCy2P

Ni

PCy2Ph olefin insertion; (PCy 2Ph) 2Ni0 x Ar β-H elimination A

1/2 (PCy 2Ph) 2NiCl(OTf) + 1/2 (PCy 2Ph) 2Ni0 + Ar-Ar active catalyst Fig. 56 Nickel-catalyzed regioselective benzylation and activation of an arylnickel(II) precatalyst.

In 2014, Jarvo et al. reported nickel-catalyzed Heck cyclizations of chiral secondary benzylic ethers (Fig. 57A). In an example of Heck cyclization of a 1,2-disubstituted olefin, the syn requirement of both insertion and b-H elimination resulted in an olefinic product with a defined geometry (Fig. 57B). Furthermore, complete inversion of configuration at the benzyl position supported an SN2-type oxidative addition. Subsequent 5-exo-trig cyclization afforded ethylene-substituted cyclopentanes (Fig. 57C).

12.02.7 Heck reaction of allylic and propargylic electrophiles 12.02.7.1 Heck reaction of allylic electrophiles Metallo-ene reactions refer to the addition of allyl metal species across alkenes. In a series of studies on metallo-ene cyclizations, Oppolzer et al. discovered that palladium complexes in 1987 and later, other transition metal complexes of Ni, Rh and Pt catalyzed Heck-type cyclization of allylic acetates onto pendent alkenes.133–135 Today, the reaction has become a useful tool to construct five-

32

CdC Bond Formation Through Heck-Like Reactions

(A)

H 2-Naph

Jarvo (2014)

OMe

NiCl2(PCy 3) 2 10 mol% MeMgI, toluene, rt

99% ee

S

H 2-Naph 74% yield, 99% ee

H

O

H

73% yield

Me Me

H 2-Naph

76% yield

95% yield

(B)

Ph MeO HMe Me

NiCl2(PCy 3) 2 10 mol% Ph

2-Naph

Me H Me 2-Naph 80% yield 89% ee, E/Z >20:1

MeMgI, toluene, 50 °C

89% ee, E/Z >20:1

(C)

OMe

NiL+

H

same as B O

H O 74% yield, dr >20:1

O

Fig. 57 Nickel-catalyzed Heck cyclization of secondary benzylic ethers.

Boc N

(A)

OAc

(B)

Pd(PPh 3) 4

COCF 3 N

H

L

Me

Me 64% yield, 100% ee

H Pd(dba) 2 10 mol% PPh 3 30 mol% AcOH, CO then CH2N2

AcO

Boc N

H + Pd

AcOH, 70 °C 100% inversion

Me

Boc N

Oppolzer

CF 3OC

CF 3OC

N

N

PdL+

CF 3OC

N

CO2Me

PdL+ H endo TS

70% yield, trans only

Fig. 58 Stereoselective Heck cyclization of allylic acetates or Oppolzer cyclization.

and six-membered carbocycles and heterocycles. It has also enabled stereoselective formation of fused and spiro rings. For example, palladium-catalyzed Oppolzer cyclization of an enantiopure 4-aza-1,7-dienyl acetate possessing a secondary stereocenter produced 3-alkenyl-4-methylenepyrrolidine with complete stereo-inversion (Fig. 58A). The endo- and exo-cyclization transition states can lead to cis and trans rings respectively, after the alkyl palladium species was intercepted by alkoxycarbonylation rather than b-H elimination. The palladium catalysts gave trans products exclusively (Fig. 58B), while nickel catalysts provided predominantly cis products. In many subsequent years, it remained unclear whether the key step of alkene insertion proceeded via s- or p-allyl palladium complexes. In 2002, Echavarren et al. conducted DFT calculation on the CdC bond forming step of the Oppolzer cyclization and concluded that the stereo-determining alkene insertion took place on a cationic 3-allylpalladium complex. The fourth coordinative site was occupied by a phosphine which enhanced the electron density on palladium. Consequently, an increase in back donation to the bound alkene accelerated the insertion.136 This insight on the 3-allyl binding mode and monodentate binding of phosphines may explain the difficulty encountered in developing palladium-catalyzed enantioselective variants of these transformations. As an illustration of synthetic utility, in 2007 Takahashi et al. designed a domino Oppolzer cyclization which was terminated by Heck cyclization to construct a spiro[4.4]nonane (Fig. 59). The spiro ring is the core structure of gloiosiphone A, which exhibited antimicrobial activity. The highly organized transition state of the Oppolzer cyclization rendered excellent diastereoselectivity.137

CdC Bond Formation Through Heck-Like Reactions

E

33

Takahashi (2007)

E

Pd(OAc) 2 10 mol% PPh 3 40 mol% RO

OR

O

E

OMe

E

AcOH

OMe

OAc E = SO Ph 2 R = 4-MeOBz

66% yield, dr 1.5:1 Heck

E

PdL+

E Oppolzer cyclization

E

O OMe

PdL+

O

E

HO OMe

H

H

OR

RO

OMe

dimethyl gloiosiphone A

Fig. 59 Domino cyclization to construct a spiro ring.

Typically, allylic electrophiles having good leaving groups have been used in Oppolzer cyclizations. In 2014, de Bruin and Reek et al. disclosed that allylic alcohols can couple with aryl olefins intermolecularly in the presence of a palladium/phosphoramidite catalyst (Fig. 60A),138 without the need of added activators. Based on kinetic studies, a PdH species was proposed for the activation of allyl alcohols to form active p-allyl complexes. Notably, the insertion of styrene occurred selectively at the less-substituted terminus of the p-allyl complex. The coupling of styrene with prenol produced two isomers (ratio 1:1.3), which stem from rapid isomerization of the initial p-prenyl complex (Fig. 60B). In 2010 Jamison and coworkers reported that nickel/PCy2Ph promoted Heck coupling of allyl electrophiles with ethylene and terminal aliphatic alkenes to produce 1,4-dienes. (Fig. 61).139 Many leaving groups can be used such as halides, OEt, OAc and OH. Et3SiOTf was added to abstract anions after oxidative addition, in order to create a cationic p-allyl nickel species for olefin insertion. The allyl insertion occurred regioselectively at the internal positions of terminal alkenes. Overall, the intermolecular couplings still suffer from poor regiocontrol for other types of alkenes. In 2014 Carreira et al. reported an iridium-catalyzed asymmetric coupling of racemic allylic alcohols and 1,1-disubstituted alkenes that afforded 1,5-dienes (Fig. 62). Mechanistically, this reaction proceeded via nucleophilic alkene attack at a cationic 3-allyl complex, rather than Heck-type alkene insertion.140

de Bruin, Reek (2014)

(A)

L Ph

OH

Pd

MeO

L

t-Bu Bn

BF4

Ph

O Ph

P NH

Ph

O

dioxane, 120 °C 90% yield

+ PdL2

L

Ph

+ Pd

Ph insertion Ph

MeO

t-Bu ligand

+

Ph

+ PdL Ph

Ph

(B)

same as above OH

Ph

Ph dioxane, 120 °C

13% yield

L

Fig. 60 Palladium-catalyzed regioselective coupling of allylic alcohols and alkenes.

+ Pd

17% yield

Ph

L

+ Pd

Ph

CO2Me

34

CdC Bond Formation Through Heck-Like Reactions

Jamison (2010)

Ph

Ni(COD) 2 10 mol% PCy2Ph 10 mol% P(OPh) 3 10 mol%

OEt

n-hexyl TESOTf, Et 3N toluene, rt

n-hexyl

Ph 79% yield

L2Ni β-H elimination

L

Ni

OEt

L

Et3SiOTf

insertion

Ni

L

R Ph

Ph

Ph CH2OTES

R

Ph CH2CH2OTBS

Ph

73% yield

Ni

CH2CHMe2

Ph

87% yield

83% yield

Fig. 61 Nickel-catalyzed regioselective allylation of alkenes.

Carreira (2014) [Ir(cod)Cl] 2 4 mol% phosphoramidite 16 mol%

OH Ph

cocatalyst 50 mol% CHCl3, 25 °C

O P N

Ph 80% yield, >99% ee

O

Me Ph CF 3 Ph

Ph OMe

71% yield, >99% ee 82% yield, >99% ee 67% yield, >99% ee

O O O O S S N H i-Pr CF 3

i-Pr

i-Pr

cocatalyst

Fig. 62 Iridium-catalyzed enantioselective allyl-ene couplings.

12.02.7.2 Heck reaction of propargylic electrophiles Examples of simple Heck reactions of propargyl electrophiles are rare.141 After initial alkene insertion, the resulting allenyl groups have a high tendency of bicyclization to form fused cyclopropanes. For example, the bicyclization of propargylic carbonates produced bicyclo[3.1.0]hexanes and analogous azabicycles (Fig. 63). In these processes, the alkenyl palladium species can be trapped by organometallic regents such as NaBPh4, Bu3SnR and Et2Zn and methoxycarbonylation.142–144 In 2020, Zhou et al. reported an enantioselective bicyclization of propargylic acetates to produce 3-aza-bicyclo[3.1.0]hexanes by using a palladium/Norphos catalyst (Fig. 64). The alkenyl palladium species can be trapped by silane and terminal alkynes, but not other organometallic reagents or organoboronic acids reacted due to the crowded environment of the trisubstituted alkenyl palladium species.145 In 2017, Zhou et al. achieved an asymmetric annulation of propargyl acetates with cycloalkenes such as 2,3-dihydrofuran and N-Boc-2,3-dihydropyrrole, which generated fused cyclobutenes (Fig. 65A).146 The high ring strain in the products manifested as spontaneous decomposition of some purified products in neat during storage! In the reaction of cyclopentene, the simple Heck product was isolated as a minor product after initial allenyl insertion, while the major product was formed after bicyclization (Fig. 65B).

CdC Bond Formation Through Heck-Like Reactions

MeO2CO Me

Pd(OAc) 2 10 mol% PPh 3 20 mol%

L+ Pd

.

anisole, 85 oC

+LPd

alkene insertion

Me

. Me N Ts

N Ts

N Ts

35

allene insertion Me

Ph

Me

MeO2C

N Ts with NaBPh4

Me

R

N Ts with CO, MeOH

Me

+PdL

N Ts

N Ts with RSnBu3 R = 2-thienyl, 2-furyl alkynyl

Fig. 63 Heck bicyclization of propargylic carbonates.

OAc

Pd(dba) 2 5 mol% (S)-Norphos 5 mol%

Ph

.

Ph2SiH 2, NaOAc

L+ Pd

Ph

silane

(S)-NorPhos

Ph

+PdL

N Ts

Ph2P

88% yield, 97% ee

Ph N Ts

Ph2P

N Ts

Ph

+LPd

.

N Ts

N Ts

Me

alkene insertion

N Ts

78% yield, 92% ee

Ph

MeO2C CO2Me 72% yield, 80% ee

Me TsN 60% yield, 98% ee

Ph Ph

N Ts 75% yield, 88% ee (alkyne, K 2CO3)

Fig. 64 Enantioselective Heck bicyclization of propargylic carbonates.

12.02.8 Narasaka-Heck reaction Narasaka-Heck reactions refer to coupling reactions of alkene with oxime derivatives. In these reactions, the NdO single bonds are cleaved by palladium(0) catalysts. The resulting iminyl and amido complexes can insert alkenes, but they have mower activity than corresponding alkenyl complexes. The topic of Narasaka-Heck reactions was covered in a review in 2019.147 In 1999, Narasaka et al. first reported that g,d-unsaturated oxime esters acted as nitrogen electrophiles in the presence of Pd(PPh3)4, affording substituted pyrroles (Fig. 66A).148 The reaction proceeded via putative oxidative addition to cleave NdO single bonds, aza-palladation of pendent olefins and b-hydride elimination, and finally TMSCl-promoted isomerization afforded heteroaromatic pyrroles. The pentafluorobenzoate leaving group was critical to generating cationic palladium species which can undergo slow alkene insertion; the use of a tosylate leaving group led to a side reaction, Beckmann rearrangement instead. In 2010, Hartwig et al. isolated the first oxidative adduct of a pentafluorobenzoyl oxime with Pd(PCy3)2 complex (Fig. 66B). The trans complex was stabilized by strong donation and the large size of two PCy3 ligands. Thus, the structural characterization provided indisputable support for the oxidative cleavage of oximes by palladium(0). The isolated complex can form indole in 31% yield upon heating at 150  C.

36

CdC Bond Formation Through Heck-Like Reactions

Fig. 65 Enantioselective annulation of propargylic acetates and cycloalkenes.

Fig. 66 An Example of Narasaka-Heck reaction of pentafluorobenzoyl oximes and studies of oxidative addition.

It took many years for the first enantioselective variant of the Narasaka-Heck reaction to emerge. Bower et al. in 2017 reported 5-exo iminyl cyclization of pentafluorobenzoyl oximes onto a trisubstituted alkene (Fig. 67).149 The insertion produced a tetrasubstituted stereocenter which avoided stereo abrasive backward b-H hydrogen elimination. A SPINOL-phosphinooxazoline helped to induce a high level of enantioselectivity during the insertion. Soon after, Zhu et al. adopted this iminyl cyclization in enantioselective domino coupling with oxadiazoles (Fig. 68).150 The oxadiazoles have relatively acidified CdH bonds, which was activated by bases via a mechanism of nonconcerted metalationdeprotonation on palladium. More recently, Gong and coworkers adopted the iminyl insertion in nickel-catalyzed desymmetrization of oxime esters on 1,4-cyclohexdiene (Fig. 69).151 As in the aforementioned examples, a good leaving group, pentafluorobenzoate, was critical to this insertion reactivity. According to DFT calculations, b-H elimination had a higher barrier than alkene insertion, implying that the

CdC Bond Formation Through Heck-Like Reactions

37

Fig. 67 Enantioselective Narasaka-Heck reaction of pentafluorobenzoyl oximes.

Fig. 68 Enantioselective domino coupling of pentafluorobenzoyl oximes with oxadiazoles.

latter was reversible. This is consistent with common perception that b-H elimination has relatively high barriers on nickel(II) centers. Therefore, b-hydrogen elimination is likely the enantio-determining step in this reaction. In 2019, Bower et al. reported that (tosyloxy)carbamates can participate in Pd-catalyzed enantioselective insertion of pendent alkenes (Fig. 70A and B).152 Thus, palladium catalysts ligated by SPINOL-derived phosphoramidates promoted 5- and 6-exo-trig cyclizations. In comparison, low ee was obtained when a better leaving group, pentafluorobenzoate, was used in substrates. This suggested that during enantiofacial insertion, the tosylate ion remained bound to the neutral palladium complex.

38

CdC Bond Formation Through Heck-Like Reactions

Fig. 69 Enantioselective nickel-catalyzed desymmetrization of pentafluorobenzoyl oximes.

Fig. 70 Enantioselective aza-Heck reaction of (tosyloxy)carbamates.

CdC Bond Formation Through Heck-Like Reactions

39

Fig. 71 Aza-Heck reaction of O-phenyl hydroxamates.

In 2016 Watson et al. found the NdO bonds in O-phenyl hydroxamates can also be cleaved and participate in aza-Heck cyclization.153 In a competition experiment with an O-tosyl hydroxamate, no cyclization of the latter was detected, thus the aza-Wacker pathway was ruled out (Fig. 71).

12.02.9 Heck reaction of silyl electrophiles The Heck reaction of silyl electrophiles converts terminal alkenes to vinyl and allyl silanes. In the last decade, the Watson group has contributed significantly to the development of this special variant of the Heck reaction. The topic was reviewed in 2017 and 2019.147,154 Back in 1988, Tanaka and coworkers first studied oxidative addition of (PEt3)3Pt(0) with trimethylsilyl bromide, which yielded a trans silyl complex (Fig. 72A).155 However, the isolated Pt complex had little insertion reactivity. Upon treatment with styrene, only 5% of the silyl-Heck product was formed, owing to the relatively strong PtdSi bond. In comparison, a palladium complex of triethylphosphine can catalyze the silyl-Heck reaction of TMSI and styrene in moderate yield, but the reaction occurred very slowly over three days (Fig. 72B). These works laid the foundation for recent advancement in the silyl-Heck reaction. In 2012 Watson et al. discovered that the reaction was much improved by employing a relatively big phosphine, t-BuPPh2.156 The silylation of styrenes provided (E)-vinylsilanes in high yields (Fig. 73A). TMSCl can react if an iodide salt was added to produce TMSI in situ. In contrast, both P(t-Bu)3 and PCy3 were ineffective. It is believed that t-BuPPh2 has a good balance of electron donating property and size to allow oxidative addition to proceed and has sufficient space around the Pd(II) center to accommodate the bulky trimethylsilyl group in the oxidative addition complex, by rotating the two P-phenyl groups. The silylation of terminal aliphatic alkenes preferentially furnished terminal (E)-allylsilanes by preferentially eliminating an allylic hydrogen after insertion, but the yields were only moderate (Fig. 73B). The hydrogens a to the silyl group do not have much hydride character and thus, are less prone to b-hydrogen elimination. In subsequent studies, Pd/PPh2(t-Bu) also enabled a Heck reaction of silyl ditriflates (Fig. 74). Its reaction with aromatic alkenes produced vinyl silyl ethers and disiloxanes,157 after alcohols or water were added to cleave the second silyl triflate. In general, alkenes having electron-rich aryl rings reacted faster than those with electron-withdrawing groups. The Pd catalyst of t-BuPPh2 often caused PdH-catalyzed isomerization of aliphatic alkenes, which depleted the starting material. Ligand modification resulted in a second generation ligand, JessePhos in 2014, which allowed efficient preparation of allylsilanes in

Fig. 72 Pioneering works on silyl-Heck reaction.

40

CdC Bond Formation Through Heck-Like Reactions

Fig. 73 Palladium-catalyzed silyl-Heck reaction using silyl iodides.

Fig. 74 Palladium-catalyzed silyl-Heck reaction using silyl ditriflates.

good yields from terminal alkenes (Fig. 75A).158 The installation of t-butyl groups made JessePhos more electronically donating and thus, accelerated oxidative addition of silyl halides. Oxidative addition of Me3SiI provided a T-shaped complex ligated by a structurally similar phosphine, whose structure was resolved by X-ray diffraction. The silyl group is located cis to the bulky phosphine to avoid strong trans influence (Fig. 75B). The two P-aryls rings are oriented in such a way to accommodate the large trimethylsilyl ligand in between. This explains why very large monophosphines P(t-Bu)3 and PCy3 cannot catalyze this process. The Watson group reported in 2014 that Ni(COD)2/PCy3 catalyzed similar silylative coupling between silyl triflates and styrene.159 In 2018 Shimada and Nakajima et al. also disclosed that silyl Heck reaction of styrene with tri-, di- and monochlorosilanes can also be promoted by NiCl2(PCy3)2, in which a stoichiometric amount of Me3Al acted as a halide abstractor.160 In 2020, Watson et al. reported a three-component carbosilylation between silyl halides, internal alkynes and primary alkylzinc iodides, which generated tetrasubstituted alkenes. Depending on the size of the phosphines, either cis- or trans-difunctionalization of alkynes was achieved (Fig. 76A and B).161 When PPh3 and (3,5-t-Bu2C6H3)3P were used, syn-addition occurred. The bulkier

Fig. 75 Palladium-catalyzed silyl-Heck reaction using JessePhos ligand.

Fig. 76 Domino carbosilylation of silyl halides, alkynes and alkylzinc iodides.

42

CdC Bond Formation Through Heck-Like Reactions

Fig. 77 Boryl-Heck reaction of terminal alkenes.

Fig. 78 Boryl-Heck reaction of disubstituted alkenes.

ligand JessePhos, however, switched to anti-addition! After syn silyl insertion, the interaction of JessePhos with the large b-silyl group destabilized the cis-silylalkenyl complex of palladium. Thus, cis-to-trans isomerization occurred and subsequent transmetalation and CdC coupling released the trans product in the end. Alkylzinc reagents were added slowly to avoid unwanted addition to silyl halides.

12.02.10

Heck reaction of boryl electrophiles

The palladium catalyst of JessePhos was also found to promote the Heck reaction of boryl electrophiles. The Watson group applied palladium/JessePhos to achieve Heck-type reactions of terminal alkenes with catecholboryl triflate and iodides prepared from catecholboryl chloride (Fig. 77).162 JessePhos was the most effective ligand for this reaction, presumably because of the balance of its electron-donating ability to promote oxidative addition of boryl electrophiles and its proper large size to prevent deactivation by the boryl electrophiles. Bulky alkylamine Cy2NMe was necessary to promote the desired reaction. Notably, Et3N formed a stable amine-borane adduct, which inhibited the boryl-Heck pathway. In the Heck reaction, disubstituted alkenes are generally less reactive than terminal ones. In boryl-Heck reaction, catecholboryl bromide was found to be more reactive in oxidative addition than the chloride, which helped to achieve good yields in these reactions. Thus, trisubstituted alkenyl boronic esters were obtained in satisfactory E/Z ratios (Fig. 78).163

12.02.11

Conclusion

Through the collective efforts of many scientists in the last two decades, significant progress has been made in the area of Heck reaction. Some examples are highlighted as follows in this chapter. (a) Among recent achievements in asymmetric Heck reactions of cyclic olefins, domino couplings and stereoselective formation of quaternary stereocenters were realized. In (oxidative) Heck reactions of acyclic internal olefins, especially alkenols, enantioselective arylation and alkenylation succeeded to form quaternary stereocenters. One major problem, however, is the high catalyst loading in most of the procedures, which remains to be solved for practical applications. (b) In Heck-Matsuda reactions, the first enantioselective variants have been achieved, which enabled challenging internal alkenes to form quaternary stereocenters. The key to the success was the use of weakly donating Pyrox as ancillary ligands. (c) The Heck-type reactions of alkyl electrophiles have become full-fledged, many of which bypassed b-insertion on palladium centers. Instead, hybrid palladium-radical catalysis became well-established for the Heck-type alkylation using both unactivated alkyl halides (Br and I) and activated halides (e.g., a-bromoacetates and a-bromomalonates). Halogen abstraction of

CdC Bond Formation Through Heck-Like Reactions

43

Pd(0) catalysts produced (phosphine)PdIX species and either nucleophilic or electrophilic alkyl radicals; the latter added directly to alkenes to form new C-C bonds. (d) The first examples of enantioselective or regioselective benzylation and allylation of alkenes have been made possible, respectively. (e) In the Narasaka-Heck and related aza-Heck reactions of electrophilic nitrogen reagents, the first enantioselective examples have been realized. (f ) Heck-type reactions of silyl and boryl halides also emerged in the last decade. In future, enantioselective coupling of alkyl halides is considered to be the Holy Grail in the area of Heck reaction. Typically, alkyl palladium(II) complexes can undergo rapid b-hydrogen elimination, an intrinsic dilemma in the catalytic cycle. At present, our understanding is that most Heck-type reactions of alkyl halides, especially secondary and tertiary ones, proceed via hybrid palladium-radical catalysis. Owing to spin inhibition and ligand destabilization, for example, by Xantphos, the alkyl radicals don’t combine with (phosphine)PdIX species to form alkyl palladium(II) complexes as previously expected. Certainly, this radical reactivity may provide an opportunity to realize asymmetric CdC bond formation. In another direction, replacing palladium catalysts with Earth-abundant metals such as nickel is still at its infancy. Recently, exciting progress has emerged in nickel-catalyze (reductive) Heck reactions and related domino couplings, even including enantioselective variants of these reactions.164–171 We believe that more breakthroughs in nickel-catalyzed Heck-type reactions will emerge in the near future.

Acknowledgment JSZ thanks Peking University Shenzhen Graduate School and Shenzhen Bay Laboratory Institute of Chemical Biology for financial support.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

Oestreich, M. The Mizoroki-Heck Reaction; Wiley: New York, 2009. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5542–5546. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5526–5531. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518–5526. Heck, R. F. Acc. Chem. Res. 1979, 12, 146–151. Heck, R. F. Org. React. 1982, 27, 345–390. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–2322. Dieck, H. A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133–1136. Patel, B. A.; Ziegler, C. B.; Cortese, N. A.; Plevyak, J. E.; Zebovitz, T. C.; Terpko, M.; Heck, R. F. J. Org. Chem. 1977, 42, 3903–3907. Zhou, J. S. Phosphorus Ligands. In Comprehensive Coordination Chemistry III; Constable, E. C., Parkin, G., Que, L., Eds.; Elsevier: Oxford, 2021; pp 32–59. Goodson, F. E.; Wallow, T. I.; Novak, B. M. J. Am. Chem. Soc. 1997, 119, 12441–12453. Grushin, V. V. Organometallics 2000, 19, 1888–1900. Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 16330–16333. Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455–1458. Patel, H. H.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 3462–3465. Chen, Z.-M.; Hilton, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 11461–11464. Chen, Z.-M.; Nervig, C. S.; DeLuca, R. J.; Sigman, M. S. Angew. Chem. Int. Ed. 2017, 56, 6651–6654. Ohshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1996, 118, 7108–7116. Wu, X.; Gong, L.-Z. Synthesis 2019, 51, 122–134. Zhang, Y.; Shen, H.-C.; Li, Y.-Y.; Huang, Y.-S.; Han, Z.-Y.; Wu, X. Chem. Commun. 2019, 55, 3769–3772. Zhu, D.; Jiao, Z.; Chi, Y. R.; Gonçalves, T. P.; Huang, K.-W.; Zhou, J. S. Angew. Chem. Int. Ed. 2020, 59, 5341–5345. Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122–5150. Bahamonde, A. Trends Chem. 2021, 3, 863–876. Xie, J.-Q.; Liang, R.-X.; Jia, Y.-X. Chin. J. Chem. 2021, 39, 710–728. Oestreich, M. Angew. Chem. Int. Ed. 2014, 53, 2282–2285. Hu, J.; Lu, Y.; Li, Y.; Zhou, J. Chem. Commun. 2013, 49, 9425–9427. Liu, S.; Zhou, J. Chem. Commun. 2013, 49, 11758–11760. Hu, J.; Hirao, H.; Li, Y.; Zhou, J. Angew. Chem. Int. Ed. 2013, 52, 8676–8680. Wu, C.; Zhou, J. J. Am. Chem. Soc. 2014, 136, 650–652. Zhang, Q.-S.; Wan, S.-L.; Chen, D.; Ding, C.-H.; Hou, X.-L. Chem. Commun. 2015, 51, 12235–12238. Borrajo-Calleja, G. M.; Bizet, V.; Bürgi, T.; Mazet, C. Chem. Sci. 2015, 6, 4807–4811. Dang, Y.; Qu, S.; Wang, Z.-X.; Wang, X. J. Am. Chem. Soc. 2014, 136, 986–998. Hilton, M. J.; Xu, L.-P.; Norrby, P.-O.; Wu, Y.-D.; Wiest, O.; Sigman, M. S. J. Org. Chem. 2014, 79, 11841–11850. Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.; Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960–1967. Rosales, A. R.; Ross, S. P.; Helquist, P.; Norrby, P.-O.; Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2020, 142, 9700–9707. Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135, 6830–6833. Mei, T.-S.; Patel, H. H.; Sigman, M. S. Nature 2014, 508, 340–344. Ross, S. P.; Rahman, A. A.; Sigman, M. S. J. Am. Chem. Soc. 2020, 142, 10516–10525. Liu, J.; Yuan, Q.; Toste, F. D.; Sigman, M. S. Nat. Chem. 2019, 11, 710–715. Patel, H. H.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 14226–14229. Patel, H. H.; Prater, M. B.; Squire, S. O.; Sigman, M. S. J. Am. Chem. Soc. 2018, 140, 5895–5898. Chen, Z.-M.; Liu, J.; Guo, J.-Y.; Loch, M.; DeLuca, R. J.; Sigman, M. S. Chem. Sci. 2019, 10, 7246–7250. Boldrini, G. P.; Savoia, D.; Tagliavini, E.; Trombini, C.; Ronchi, A. U. J. Organomet. Chem. 1986, 301, C62–C64.

44

45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115.

CdC Bond Formation Through Heck-Like Reactions

Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J. Organomet. Chem. 1988, 344, 253–259. Iyer, S.; Ramesh, C.; Ramani, A. Tetrahedron Lett. 1997, 38, 8533–8536. Tasker, S. Z.; Gutierrez, A. C.; Jamison, T. F. Angew. Chem. Int. Ed. 2014, 53, 1858–1861. Walker, B. R.; Sevov, C. S. ACS Catal. 2019, 9, 7197–7203. Bhakta, S.; Ghosh, T. Adv. Synth. Catal. 2020, 362, 5257–5274. Desrosiers, J.-N.; Hie, L.; Biswas, S.; Zatolochnaya, O. V.; Rodriguez, S.; Lee, H.; Grinberg, N.; Haddad, N.; Yee, N. K.; Garg, N. K.; Senanayake, C. H. Angew. Chem. Int. Ed. 2016, 55, 11921–11924. Wang, X.-X.; Lu, X.; Li, Y.; Wang, J.-W.; Fu, Y. Sci. China Chem. 2020, 63, 1586–1600. Ehle, A. R.; Zhou, Q.; Watson, M. P. Org. Lett. 2012, 14, 1202–1205. Qin, X.; Lee, M. W. Y.; Zhou, J. S. Angew. Chem. Int. Ed. 2017, 56, 12723–12726. Qin, X.; Yao Lee, M. W.; Zhou, J. S. Org. Lett. 2019, 21, 5990–5994. Yang, F.; Jin, Y.; Wang, C. Org. Lett. 2019, 21, 6989–6994. Desrosiers, J.-N.; Wen, J.; Tcyrulnikov, S.; Biswas, S.; Qu, B.; Hie, L.; Kurouski, D.; Wu, L.; Grinberg, N.; Haddad, N.; Busacca, C. A.; Yee, N. K.; Song, J. J.; Garg, N. K.; Zhang, X.; Kozlowski, M. C.; Senanayake, C. H. Org. Lett. 2017, 19, 3338. Huang, X.; Teng, S.; Chi, Y. R.; Xu, W.; Pu, M.; Wu, Y.-D.; Zhou, J. S. Angew. Chem. Int. Ed. 2021, 60, 2828–2832. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964. Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181–191. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442–4489. Ju, B.; Kong, W. Asian J. Organ. Chem. 2020, 9, 1154–1161. Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B. A. J. Am. Chem. Soc. 1996, 118, 10766–10773. Coya, E.; Sotomayor, N.; Lete, E. Adv. Synth. Catal. 2015, 357, 3206–3214. Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622–4643. Mo, F.; Qiu, D.; Zhang, L.; Wang, J. Chem. Rev. 2021, 121, 5741–5829. Kikukawa, K.; Nagira, K.; Terao, N.; Wada, F.; Matsuda, T. Bull. Chem. Soc. Jpn. 1979, 52, 2609–2610. Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron 1981, 37, 31–36. Darses, S.; Pucheault, M.; Genêt, J.-P. Eur. J. Org. Chem. 2001, 2001, 1121–1128. Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia, C. R. D. Org. Lett. 2003, 5, 305–308. Pastre, J. C.; Duarte Correia, C. R. Org. Lett. 2006, 8, 1657–1660. Qin, H.-L.; Zheng, Q.; Bare, G. A. L.; Wu, P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2016, 55, 14155–14158. Oliveira, C. C.; Correia, C. R. D. Curr. Opin. Green Sustain. 2020, 26, 100360. Oliveira, C. C.; Correia, C. R. D. Chem. Rec. 2021, 21, 2688–2701. Correia, C. R. D.; Oliveira, C. C.; Salles, A. G.; Santos, E. A. F. Tetrahedron Lett. 2012, 53, 3325–3328. de Oliveira Silva, J.; Angnes, R. A.; Menezes da Silva, V. H.; Servilha, B. M.; Adeel, M.; Braga, A. A. C.; Aponick, A.; Correia, C. R. D. J. Org. Chem. 2016, 81, 2010–2018. Angnes, R. A.; Thompson, L. M.; Mashuta, M. S.; Correia, C. R. D.; Hammond, G. B. Adv. Synth. Catal. 2018, 360, 3760–3767. Kattela, S.; Heerdt, G.; Correia, C. R. D. Adv. Synth. Catal. 2017, 359, 260–267. Han, J.; Lu, Z.; Wang, W.; Hammond, G. B.; Xu, B. Chem. Commun. 2015, 51, 13740–13743. de Oliveira, V. C.; de Oliveira, J. M.; Menezes da Silva, V. H.; Khan, I. U.; Correia, C. R. D. Adv. Synth. Catal. 2020, 362, 3395–3406. Azambuja, F. D.; Carmona, R. C.; Chorro, T. H. D.; Heerdt, G.; Correia, C. R. D. Chem. Eur. J. 2016, 22, 11205–11209. Kattela, S.; de Lucca Jr, E. C.; Correia, C. R. D. Chem. Eur. J. 2018, 24, 17691–17696. Avila, C. M.; Patel, J. S.; Reddi, Y.; Saito, M.; Nelson, H. M.; Shunatona, H. P.; Sigman, M. S.; Sunoj, R. B.; Toste, F. D. Angew. Chem. Int. Ed. 2017, 56, 5806–5811. Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin, M. N. Angew. Chem. Int. Ed. 2004, 43, 2514–2518. Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Angew. Chem. Int. Ed. 2015, 54, 14036–14039. Carmona, R. C.; Köster, O. D.; Correia, C. R. D. Angew. Chem. Int. Ed. 2018, 57, 12067–12070. Zhang, T.; Li, W.-A.; Shen, H.-C.; Chen, S.-S.; Han, Z.-Y. Org. Lett. 2021, 23, 1473–1477. Kurandina, D.; Chuentragool, P.; Gevorgyan, V. Synthesis 2019, 51, 985–1005. Kaga, A.; Chiba, S. ACS Catal. 2017, 7, 4697–4706. Ariafard, A.; Lin, Z. Organometallics 2006, 25, 4030–4033. Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662–13663. Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 5749–5752. Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 3910–3912. Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340–11341. Kramer, A. V.; Labinger, J. A.; Bradley, J. S.; Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7145–7147. Kramer, A. V.; Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7832–7833. Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1991, 32, 6923–6926. Sumino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563–1574. Sumino, S.; Ui, T.; Hamada, Y.; Fukuyama, T.; Ryu, I. Org. Lett. 2015, 17, 4952–4955. Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146. Venning, A. R. O.; Kwiatkowski, M. R.; Roque Peña, J. E.; Lainhart, B. C.; Guruparan, A. A.; Alexanian, E. J. J. Am. Chem. Soc. 2017, 139, 11595–11600. Dong, X.; Han, Y.; Yan, F.; Liu, Q.; Wang, P.; Chen, K.; Li, Y.; Zhao, Z.; Dong, Y.; Liu, H. Org. Lett. 2016, 18, 3774–3777. Dong, X.; Xu, L.-P.; Yang, Y.; Liu, Y.; Li, X.; Liu, Q.; Zheng, L.; Wang, F.; Liu, H. Org. Chem. Front. 2021, 8, 6009–6018. Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J. Am. Chem. Soc. 2014, 136, 17926–17929. McMahon, C. M.; Alexanian, E. J. Angew. Chem. Int. Ed. 2014, 53, 5974–5977. Zou, Y.; Zhou, J. Chem. Commun. 2014, 50, 3725–3728. Teng, S.; Tessensohn, M. E.; Webster, R. D.; Zhou, J. S. ACS Catal. 2018, 8, 7439–7444. Kancherla, R.; Muralirajan, K.; Maity, B.; Zhu, C.; Krach, P. E.; Cavallo, L.; Rueping, M. Angew. Chem. Int. Ed. 2019, 58, 3412–3416. Zhao, B.; Shang, R.; Wang, G.-Z.; Wang, S.; Chen, H.; Fu, Y. ACS Catal. 2020, 10, 1334–1343. Kurandina, D.; Parasram, M.; Gevorgyan, V. Angew. Chem. Int. Ed. 2017, 56, 14212–14216. Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y. J. Am. Chem. Soc. 2017, 139, 18307–18312. Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2002, 124, 6514–6515. Ikeda, Y.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Adv. Synth. Catal. 2004, 346, 1631–1634. Weiss, M. E.; Kreis, L. M.; Lauber, A.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50, 11125–11128. Prina Cerai, G.; Morandi, B. Chem. Commun. 2016, 52, 9769–9772. Kwiatkowski, M. R.; Alexanian, E. J. Angew. Chem. Int. Ed. 2018, 57, 16857–16860.

CdC Bond Formation Through Heck-Like Reactions

116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171.

Glorius, F. Tetrahedron Lett. 2003, 44, 5751–5754. Kurandina, D.; Rivas, M.; Radzhabov, M.; Gevorgyan, V. Org. Lett. 2018, 20, 357–360. Feng, Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.; Zhang, X. Angew. Chem. Int. Ed. 2015, 54, 1270–1274. Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem. Int. Ed. 2012, 51, 3638–3641. Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc. 2013, 135, 16372–16375. Zhu, K.; Dunne, J.; Shaver, M. P.; Thomas, S. P. ACS Catal. 2017, 7, 2353–2356. Pan, Y.; Zhang, Z.; Hu, H. Synthesis 1995, 1995, 245–247. Higuchi, K.; Sawada, K.; Nambu, H.; Shogaki, T.; Kita, Y. Org. Lett. 2003, 5, 3703–3704. Narahashi, H.; Shimizu, I.; Yamamoto, A. J. Organomet. Chem. 2008, 693, 283–296. Narahashi, H.; Yamamoto, A.; Shimizu, I. Chem. Lett. 2004, 33, 348–349. Yang, Z.; Zhou, J. J. Am. Chem. Soc. 2012, 134, 11833–11835. Matsude, A.; Hirano, K.; Miura, M. Adv. Synth. Catal. 2020, 362, 518–522. Matsude, A.; Hirano, K.; Miura, M. Org. Lett. 2020, 22, 3190–3194. Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 9692–9695. Qin, L.; Ren, X.; Lu, Y.; Li, Y.; Zhou, J. Angew. Chem. Int. Ed. 2012, 51, 5915–5919. Matsubara, R.; Gutierrez, A. C.; Jamison, T. F. J. Am. Chem. Soc. 2011, 133, 19020–19023. Standley, E. A.; Jamison, T. F. J. Am. Chem. Soc. 2013, 135, 1585–1592. Oppolzer, W.; Gaudin, J.-M. Helv. Chim. Acta 1987, 70, 1477–1481. Oppolzer, W. Angew. Chem. Int. Ed. Engl. 1989, 28, 38–52. Oppolzer, W. Pure Appl. Chem. 1990, 62, 1941–1948. Cárdenas, D. J.; Alcamí, M.; Cossío, F.; Méndez, M.; Echavarren, A. M. Chem. Eur. J. 2003, 9, 96–105. Doi, T.; Iijima, Y.; Takasaki, M.; Takahashi, T. J. Org. Chem. 2007, 72, 3667–3671. Gumrukcu, Y.; de Bruin, B.; Reek, J. N. H. Chem. Eur. J. 2014, 20, 10905–10909. Matsubara, R.; Jamison, T. F. J. Am. Chem. Soc. 2010, 132, 6880–6881. Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3006–3009. Mandai, T.; Ogawa, M.; Yamaoki, H.; Nakata, T.; Murayama, H.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1991, 32, 3397–3398. Grigg, R.; Rasul, R.; Redpath, J.; Wilson, D. Tetrahedron Lett. 1996, 37, 4609–4612. Oppolzer, W.; Pimm, A.; Stammen, B.; Hume, W. E. Helv. Chim. Acta 1997, 80, 623–639. Bagutski, V.; Moszner, N.; Zeuner, F.; Fischer, U. K.; de Meijere, A. Adv. Synth. Catal. 2006, 348, 2133–2147. Huang, X.; Nguyen, M. H.; Pu, M.; Zhang, L.; Chi, Y. R.; Wu, Y.-D.; Zhou, J. S. Angew. Chem. Int. Ed. 2020, 59, 10814–10818. Jiao, Z.; Shi, Q.; Zhou, J. S. Angew. Chem. Int. Ed. 2017, 56, 14567–14571. Korch, K. M.; Watson, D. A. Chem. Rev. 2019, 119, 8192–8228. Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 28, 45–46. Race, N. J.; Faulkner, A.; Fumagalli, G.; Yamauchi, T.; Scott, J. S.; Rydén-Landergren, M.; Sparkes, H. A.; Bower, J. F. Chem. Sci. 2017, 8, 1981–1985. Bao, X.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2017, 56, 9577–9581. Shen, H.; Chen, Y.; Zhang, Y.; Jiang, H.-M.; Zhang, W.-Q.; Li, W.-A.; Sayed, M.; Zhang, X.; Wu, Y.-D.; Gong, L.-Z. CCS Chem. 2021, 3, 421–430. Ma, X.; Hazelden, I. R.; Langer, T.; Munday, R. H.; Bower, J. F. J. Am. Chem. Soc. 2019, 141, 3356–3360. Shuler, S. A.; Yin, G.; Krause, S. B.; Vesper, C. M.; Watson, D. A. J. Am. Chem. Soc. 2016, 138, 13830–13833. Vulovic, B.; Watson, D. A. Eur. J. Org. Chem. 2017, 2017, 4996–5009. Yamashita, H.; Hayashi, T.; Kobayashi, T.; Tanaka, M.; Goto, M. J. Am. Chem. Soc. 1988, 110, 4417–4418. McAtee, J. R.; Martin, S. E. S.; Ahneman, D. T.; Johnson, K. A.; Watson, D. A. Angew. Chem. Int. Ed. 2012, 51, 3663–3667. Martin, S. E. S.; Watson, D. A. J. Am. Chem. Soc. 2013, 135, 13330–13333. McAtee, J. R.; Yap, G. P. A.; Watson, D. A. J. Am. Chem. Soc. 2014, 136, 10166–10172. McAtee, J. R.; Martin, S. E. S.; Cinderella, A. P.; Reid, W. B.; Johnson, K. A.; Watson, D. A. Tetrahedron 2014, 70, 4250–4256. Matsumoto, K.; Huang, J.; Naganawa, Y.; Guo, H.; Beppu, T.; Sato, K.; Shimada, S.; Nakajima, Y. Org. Lett. 2018, 20, 2481–2484. Wisthoff, M. F.; Pawley, S. B.; Cinderella, A. P.; Watson, D. A. J. Am. Chem. Soc. 2020, 142, 12051–12055. Reid, W. B.; Spillane, J. J.; Krause, S. B.; Watson, D. A. J. Am. Chem. Soc. 2016, 138, 5539–5542. Reid, W. B.; Watson, D. A. Org. Lett. 2018, 20, 6832–6835. Derosa, J.; Apolinar, O.; Kang, T.; Tran, V. T.; Engle, K. M. Chem. Sci. 2020, 11, 4287–4296. Poremba, K. E.; Dibrell, S. E.; Reisman, S. E. ACS Catal. 2020, 10, 8237–8246. Qi, X.; Diao, T. ACS Catal. 2020, 10, 8542–8556. Shu, X.-Z.; Pang, X.; Peng, X. Synthesis 2020, 52, 3751–3763. Tu, H.-Y.; Wang, F.; Huo, L.; Li, Y.; Zhu, S.; Zhao, X.; Li, H.; Qing, F.-L.; Chu, L. J. Am. Chem. Soc. 2020, 142, 9604–9611. Wei, X.; Shu, W.; García-Domínguez, A.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2020, 142, 13515–13522. Bhakta, S.; Ghosh, T. Eur. J. Org. Chem. 2021, 2021, 4201–4215. Wickham, L. M.; Giri, R. Acc. Chem. Res. 2021, 54, 3415–3437.

45

12.03

Metal-Mediated Reductive C–C Coupling of p Bonds

Yukun Cheng, Steven K Butler, Daniel N Huh, and Ian A Tonks, Department of Chemistry, University of Minnesota, Minneapolis, United States © 2022 Elsevier Ltd. All rights reserved.

12.03.1 12.03.2 12.03.2.1 12.03.2.2 12.03.2.3 12.03.3 12.03.3.1 12.03.3.1.1 12.03.3.1.2 12.03.3.2 12.03.3.3 12.03.3.4 12.03.4 12.03.4.1 12.03.4.1.1 12.03.4.1.2 12.03.4.2 12.03.4.2.1 12.03.4.2.2 12.03.4.2.3 12.03.4.2.4 12.03.4.2.5 12.03.5 12.03.6 References

Introduction Lanthanides and group 3 metals Stoichiometric reductive coupling of alkenes with aldehydes and ketones Stoichiometric reductive coupling of aldehydes and ketones (pinacol type) Catalytic reductive coupling of alkenes with ketones Early-mid transition metals Early transition metal-mediated examples Stoichiometric early transition metal coupling of alkenes and alkynes Stoichiometric couplings of p bonds with aldehydes, imines, ketones, and nitriles Catalytic early transition metal coupling Fe-catalyzed reductive cyclization Ru-catalyzed reductive coupling Late transition metals Reductive coupling of alkynes and alkenes p bonds Hydrosilylation/cyclization Dihydrogenative reductive coupling Reductive coupling of alkenes and alkynes with aldehydes and aldimines Enantioselective synthesis on unactivated alkenes Enantioselective synthesis using alkynes Mild reductants Tandem reactions Miscellaneous noteworthy reactions Photocatalytic reductive coupling with photoredox reagents Conclusion

46 46 47 52 53 55 55 55 58 61 62 64 65 66 68 70 73 73 76 77 80 80 82 86 86

12.03.1 Introduction Molecular complexity is, to a large extent, dependent on the linkage- and functionality-complexity of the molecule’s backbone. In many cases, the formation of relatively inert C–C bond is a limiting factor on the synthetic accessibility to complex molecules.1–3 Metal-mediated reductive coupling of p bonds is an important method to construct carbon backbones efficiently and atom-economically from simpler fragments. Metals can play multiple roles in reductive coupling reactions—as electron donors, directing groups, or activating the p system of substrates. Metal-mediated reductive coupling has attracted enduring research interest in the past decades, while some challenges remain unsettled. Stereoselectivity arises when a disubstituted substrate participates in reductive coupling, giving a tertiary carbon chiral center. Substrates without electronic bias across the p bond, e.g. dialkyl-substituted alkynes, face the issue of regioselectivity.4 The traditional reductants applied to the reaction are main group metals such as Mg and Zn, whose reactive nature leads to harsh reaction conditions and hindered functional group tolerance. In this chapter, we will discuss both stoichiometric and catalytic reductive coupling in the categories of the metals and the coupling partners involved. The chapter will include the recent (15 years) advances in both intra- and intermolecular reductive coupling. Reductive coupling involving s-bond activation will be reviewed elsewhere. Formal reductive coupling with reductive cleavage or reduction occurring after a neutral C–C bond formation will not be covered. Two-staged reactions with coupling partner introduced after the reductive activation of the first substrate will not be covered. Metal-mediated reductive coupling has been extensively reviewed many times in the last two decades by active contributors in the field. Readers will be directed to these detailed reviews for the aspects that have been summarized recently.

12.03.2 Lanthanides and group 3 metals The rare-earth metals, which include Y, Sc, and the lanthanide metals, have shown to be capable of C–C forming reactions. Since the first report of the facile solution synthesis of SmI2 by Kagan in 1977,5,6 generations of SmI2-promoted reductive functional group transformations and C–C couplings have solidified the importance of Sm in organic synthesis.7,8 Most notably, SmI2 has been shown to be capable of Barbier, Reformatsky, ketyl/olefin and pinacol coupling reactions as well as radical additions to alkene/alkynes.8,9

46

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00137-2

Metal-Mediated Reductive C–C Coupling of p Bonds

47

Many of these stoichiometric C–C bond forming reactions invoke bimetallic SmIII intermediates as a consequence of the two-electron C–C coupling.8,10,11 Reductive C–C coupling using SmII has been recently reviewed by Procter and co-workers.12 In this section, examples of SmII engendered C–C coupling from after 2014 will be discussed. Additionally, a previous review has covered Y-catalyzed reductive cyclization in the presence of silanes via alkene-alkene coupling.13

12.03.2.1 Stoichiometric reductive coupling of alkenes with aldehydes and ketones Many recent examples of reductive C–C coupling involve intramolecular ketyl/olefin cycliclization using stoichiometric amounts of SmI2. Like in the aforementioned precedented examples, SmI2 initiates the reaction by reducing the organic carbonyl (1) to generate a radical ketyl. This radical intermediate is often coordinated to the now SmIII ion which can facilitate in cross-coupling with the alkene partner 2 (Fig. 1). However, it is worthy to note that recent mechanistic studies have suggested that particular systems could initiate by reduction of the alkene first rather than the carbonyl.14 Additionally, a consequence of these intramolecular cyclizations is that these reactions often demonstrate high regioselectivity. In nearly all of these intramolecular examples, d.r. > 20:1 was reported. Two ketyl-alkene coupling reactions involving stoichiometric SmI2 have been reported to undergo cascade cyclization. In this example, a dialdehyde and alkene precursor (4) goes through a sequential cyclization forming a tricyclic product 5 containing four stereocenters (Fig. 2).15 In all but two cases, a single diastereomer was isolated except for when X ¼ CH2 and CHOPiv. In the case of X ¼ CH2, Thorpe-Ingold effect leads to initial reduction on the aldehyde chain that contains the terminal alkene, resulting in the more accessible cyclization. When X ¼ CHOPiv, a 1:1 mixture of diastereomers was observed at the stereocenter containing the OPiv group. A report of a reductive cyclization of an indole-ketone 6 demonstrated the generation of spirolactones 7 in 71–77% yields (Fig. 3).16 The cyclization mechanism is suggested to undergo an indole-first reduction which then cyclizes with the ketone to form a fused 6-membered ring with the indole (INT1). The intermediate prior to the formation of the final spirolactone contains a nucleophilic SmIII-enolate which could (1) directly cyclizes with the ester linkage (INT2) to form the product (Path A) or (2) form an unstable tetracyclic intermediate (INT4) which undergoes a nucleophilic acyl substitution reaction (INT5) to form the final product (Path B to C). Many of these SmI2 mediated cross-coupling reactions have also been optimized using various solvents and additives. The most common solvents used to assist in these reactions are water and HMPA. The primary role of these solvents, especially water, continues to be rigorously investigated. In the presence of water, the yields of these reactions are often reported to be higher than when water is rigorously excluded. Reports have claimed that the presence of water more rapidly generates the ketyl radical thus accelerating the reaction which subsequently increases yields.17 Along with various methodological developments, several successful reports of total syntheses using SmI2 and various additives have shown this reducing agent to be applicable in natural product synthesis and tolerable toward functional groups in multistep synthetic schemes.18–29 In a cyclic ether containing an N-acylpyrrole (8), cyclization proceeds with an aldehyde-alkene moiety to generate a polycyclic ether while preserving the pyrrole (9) (Fig. 4).30 In this example, a single stereoisomer was isolated, however, the yield of the reaction strongly depends on the temperature and concentration of the reaction. The best yield (88%) was obtained at 0  C using a 0.01 M MeOH solution. Higher concentrations and lower temperatures (−78  C to 0  C) gave lower yields and undesirable side reactions.

Fig. 1 SmI2-facilitated alcohol formation via C–C bond formation between a ketone and an alkene.

Fig. 2 Synthesis of a polycycle via cascade cyclization from a tethered dialdehyde-alkene precursor.

48

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 3 Synthesis of spirolactones from a tethered indole-ketone, depicting direct cyclization with the ester linkage via Path A, or formation of a tetracyclic intermediate prior to nucleophilic acyl substitution via Path B and C.

Fig. 4 Synthesis of a polycyclic ethers from a tethered aldehyde-alkene moiety containing an N-acylpyrrole.

Reductive cyclization of 5- and 6-membered cyclic imides containing an alkene tether (10) forms 2-azabicycles 11 (Fig. 5).31 The cyclic imide forms an aminoketyl radical intermediate which cyclizes with the alkene tether with >95:5 d.r. These reactions tolerate a range of functional groups including halides, ethers, CF3, heterocycles, and electron-deficient arenes. Steric hindrance was also not found to affect these reactions significantly. Similarly to the previously described indole-ketone cyclization reaction,16 a reductive indole-imine cyclization involving a sulfinyl imine (12) forms a tricyclic product 13 containing tertiary carbinamines (Fig. 6).32 In these rapid reactions, an excess of SmI2, LiBr, and water are required to generate a 90% yield with d.r. of 67:33. When only LiBr or water is used as an additive, the yields decrease to 67% and 60%, respectively. This indole-imine cyclization also demonstrated the first desulfinylation of N-sulfinyl imines using SmI2.

Fig. 5 Synthesis of 2-azabicycles from cyclic imides containing an alkene tether using water additives.

Metal-Mediated Reductive C–C Coupling of p Bonds

49

Fig. 6 Formation of a carbinamine polycycle via indole-imine cyclization involving a sulfinyl imine in the presence of water and LiBr additives.

Fig. 7 Water concentration dependent synthesis of ketyl alkene cyclization and lactone reduction.

Mechanistic studies examining the SmI2-H2O mediated reduction of lactones containing a tethered alkene (14) were examined. It was demonstrated that the absence of water promoted lactone reduction to alcohol without cyclization (16) whereas increasing the presence of water facilitates ketyl-alkene cyclization (15) (Fig. 7).33 Water was found to stabilize the intermediate radical anion and proton transfer was not the rate-determining step for lactone, ketone, and aldehyde reduction. The rate-determining step, however, was found to be the 2nd electron transfer based on the thermodynamic control of this step. Additionally, the rate of reduction decreased linearly when the concentration of water was increased. In a similar study, radical cyclization of a 5-membered lactone 17 yielded a cyclohexyldiol product 18 (Fig. 8).34 Addition of water and HMPA additives improved yields with high diastereoselectivity in comparison to the only water and only NEt3 additive. Like the above study,33 small amounts of reduced ring-opened diol with the preserved alkene were observed. Studies on the cyclization of N-tethered cyclic imides 19 to generate indolizidine lactams 20 have also been explored (Fig. 9).35 Upon reduction using SmI2 in the presence of various additives including water, MeOH, tBuOH, Et3N, trifluoroethanol (TFE), LiCl, and HMPA were examined. These optimization studies concluded that water was the most suitable additive for this cyclization reaction. Functional group tolerance was also demonstrated for ethers, benzyl fluorides, aryl bromides, napthalenes, and heterocycles. Intermolecular competition studies were also carried out and it was determined that the reaction does not proceed through a directing group mechanism even when the R4 ester directing group is incorporated (21). Reduction of a 7-membered lactone containing a tethered alkene (23) generates a 1,4-cyclooctandiol 24 (Fig. 10).36 This proceeds through a 5-exo-trig radical cyclization (INT7) which is unlike the more common 8-endo attack.37 The alkene tether can be varied with a number of aryl substituents and the diastereoselectivity of this reaction was examined by oxidation with Dess-Martin periodinane to simplify the diastereomeric mixture and generate a crystalline product for SC-XRD structural analysis. Yields ranged from 62% to 93% and the diastereoselectivities ranged from 75:25 to 89:11 d.r.

Fig. 8 Radical cyclization from lactone to cyclohexyldiol with water and HMPA additives.

50

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 9 Syntheses of indolizidine lactams from cyclic imides containing N-tethered alkenes in the presence of water additive.

Fig. 10 Water-assisted reductive formation of 1,4-cyclooctandiols via exo-attack followed by bicyclicfuran formation using Dess-Martin periodinane.

Reduction of a 6-membered lactone bearing a tethered alkene and allene (29) was reported to generate a mixture of products (Fig. 11).38 In the presence of excess SmI2 and 800–8000 equivalents of water, low yields of a mixture of products INT9 and 30 formed. Upon initial reduction, the 5-exo-cyclization proceeds via ketyl-allene cyclization forming INT9. In the presence of an additional equivalent of reductant, INT9 can proceed through ketal-opening (INT10) and undergo 6-exo-cyclization to yield the carbo[5.4.0]bicycle 30. At lower concentrations of water, INT9 was obtained as the product whereas higher concentrations of water gave lower conversion. Despite the moderate yields, these complex reductive cascade reactions diastereoselectively generate two carbocyclic rings and four stereocenters. A chelating aminodiol chiral ligand L1 in the presence of MeOH has shown to facilitate the enantioselective and diastereoselective formation of radically cyclized bicyclic tertiary alcohols 32 from unsaturated ketoesters 31 (Fig. 12).39 The proposed model for cyclization has been a 1:1:1 complex of L1, SmI2, and the unsaturated ketoester. The reaction is initiated by single-electron reduction from the L1–SmII center (INT12) to generate the L1–SmIII ketyl complex. Steric interactions between the tethered alkene, Ph group, and the methyl group adjacent to the ketyl center are proposed to direct the selectivity of this reaction. This allows for ketyl-alkene cyclization through intermediate INT13, rationalizing the enantioselectivity for anti-configuration of this reaction.

Metal-Mediated Reductive C–C Coupling of p Bonds

51

Fig. 11 Proposed mechanism of lactone cascade radical cyclization in the presence of 8 equiv. of SmI2 and 4000 equiv. of H2O.

Fig. 12 Synthesis of bicyclic tertiary alcohols via radical cyclization of unsaturated ketoesters in the presence of a SmI2 supported by a chiral ligand.

Intermolecular reductive coupling of aldehydes (34, 37) and 2-amido arenol (R5) substituted crotonates 36 or acrylates 33 have shown to form g-lactones (35, 38) (Fig. 13).40 The presence of the amide group was proposed to facilitate selectivity by coordinating to the SmIII enolate (INT14). This intermediate allows for the high diastereoselective protonation with 90:10 to 98:2 d.r. In a rare example using an organolanthanide rather than SmI2, a SmII supported by various cyclopentadienyl ligands was shown to reductively couple allyl/propargyl ethers 39 and d-ketoesters 40 (Fig. 14).41 Cyclopentadienyl ligands bearing sufficiently bulky substituents prevented product formation. This was attributed to the bulky ligand preventing the substrates from coordinating to the Sm metal center and subsequently diminishing diastereoselective control. When an unsubstituted cyclopentadienyl ligand is utilized, no reaction was also observed. This was rationalized by the lower reducing ability of Cp2Sm(THF)2 in comparison to the other substituted CpR2Sm(THF)1–2 complexes. The best Sm metallocenes were when CpR ¼ C5Me5 and C5H4(SiPh2Me).

52

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 13 Synthesis of lactones by reductive coupling of aldehydes and crotonates or acrylates.

O 2

R

O

O

R4 R4

2.4 equiv CpR2Sm(THF)1-2

+ R1

R3

OBn 39 39

OEt

R

PhMe, rt

R4

40 CpR2Sm(THF)1-2

CpR CpR Sm R1

R2

R2

O 4

R3 41

R1

(84-88%)

CpR CpR Sm R

1

CpR CpR Sm R

2

1

R

R

EtO 40

O

2

R

INT15 1

R = Me, Ph R2 = H, Me

4

R4 R1

O

Sm

R3

R3 = alkyl R4 = H, alkyl CpR = C5Me5, C5H4(SiPh2Me)

CpR CpR

R2 INT16

Fig. 14 Synthes of lactones by reductive coupling of allyl/propargyl ethers and ketoesters facilitated by Sm-metallocenes.

12.03.2.2 Stoichiometric reductive coupling of aldehydes and ketones (pinacol type) One of the effective uses for SmI2 is pinacol coupling reaction which cross-couples two ketones, two aldehydes, or one ketone and one aldehyde (42 and 43) (Fig. 15). While these reactions are well established in the literature,12 a few new examples of pinacol coupling reactions have recently been reported. In these examples, the intramolecular pinacol reactions were found to be regioselective with reasonable yields. Additionally, there have been recent total synthesis examples that have successfully utilized SmI2 for pinacol coupling reactions.42–45 An intramolecular pinacol cyclization of diketones 46 using mild conditions has been reported.46 A series of cyclopentadiols (47) have been synthesized by reacting with SmI2 in the presence of LiBr as an additive (Fig. 16). The presence of this additive improved the isolated yield and all products in this reaction were isolated as a single diastereomer (>20:1).

Metal-Mediated Reductive C–C Coupling of p Bonds

53

Fig. 15 SmI2-facilitated pinacol formation via C–C bond formation between ketones and/or aldehydes.

Fig. 16 Synthesis of cyclopentadiols from diketones assisted by LiBr additives.

Fig. 17 Aliphatic chain dependent pinacol coupling of barbituric acids containing ketones and O-methyl oximes forming an intramolecular bicyclic product or intermolecular dimerized product.

In a comparative study, the stereoselective C–C pinacol coupling of barbituric acids with aliphatic ketones and O-methyl oximes (48, 50) by electroreduction and chemical reduction was examined (Fig. 17).47 Electroreduction yielded primarily the 5- and 6-membered intramolecular cyclized product 49 whereas SmI2 provided the 5-membered cyclized product when the ethylene (-CH2CH2-) aliphatic chain bearing the ketone was sufficiently short. However, when the aliphatic chain contained a propylene (-CH2CH2CH2-) chain, the pinacol coupling proceeds intermolecularly to generate product 51.

12.03.2.3 Catalytic reductive coupling of alkenes with ketones Catalytic reductive C–C coupling reactions mediated by SmII are rare,9,48 however, there are an increasing number of reports. These SmIII/SmII redox reactions are not like other rare-earth metal catalyzed reactions, where the rare-earth acts as a Lewis acid.49 Accessing this redox couple is thermodynamically challenging since the +3 oxidation state is the most stable for all the lanthanides including Sm.50 Despite this challenge, SmIII/SmII redox catalysis has successfully been demonstrated for C–C bond forming reactions with a wide range of functional groups. For example, Greeves demonstrated a catalytic pinacol coupling reaction and proposed that SmII reduces aldehydes 52 to form a bimetallic SmIII 2 –pinacol intermediate INT17, where catalytic turnover is engendered through Si–Cl metathesis (53) and reduction of the subsequent Sm–Cl by a strong metal reductant such as Mg0.51 However, the vast majority of these SmIII/SmII redox catalytic reactions do not have well-defined models and primarily use unsupported SmI2 (Fig. 18).

54

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 18 Catalytic synthesis of pinacols from aldehydes in the presence of SmII, Mg0, and a silyl chloride reagent.

Fig. 19 Catalytic synthesis of cyclopentanols via ketyl-alkene reductive cyclization in the presence of SmII, Mg0, TFE, TMSCl, and tetraglyme or HMPA.

Recently, the catalytic synthesis of cyclopentanol 55 via ketone-olefin reductive cyclization has been reported (Fig. 19).48,52 Similar to the reported stoichiometric examples, a ketyl radical is first generated forming a SmIII–ketyl complex INT18. When this intermediate is treated with TMSCl, TMS substitutes SmIII and the ketyl radical INT19 cyclizes with the olefin to generate the cyclopentanol 55. The SmII catalyst is regenerated upon treatment with Mg metal. Importantly, this catalytic reaction has been fine-tuned using various additives including trifluoroethanol (TFE; proton donor), tetraglyme (coordinating solvent), and HMPA (coordinating solvent).

Metal-Mediated Reductive C–C Coupling of p Bonds

55

12.03.3 Early-mid transition metals 12.03.3.1 Early transition metal-mediated examples There are many examples of early transition metals mediating reductive C–C couplings. Both catalytic and stoichiometric examples often involve formation of a low-valent metal center. This can be achieved in several ways, the most common of which are reduction of metal halides or isopropoxides (56) with strongly reducing alkali metals (Fig. 20) or via b-H abstraction (INT20, Fig. 21) as shown in Fig. 21.53–61 These low-valent metal ions can bind to pi bonds of alkenes and alkynes to form 3-membered metallacycles. These can then be intercepted by electrophiles (often other unsaturated species) to form C–C bonds and further react to undergo reductive coupling. This chemistry is the basis of many coupling reactions such as Fagan-Nugent, Kulinkovich, Pauson-Khand, and many other stoichiometric examples.

12.03.3.1.1

Stoichiometric early transition metal coupling of alkenes and alkynes

Ti and Zr Cp complexes meditate alkene and alkyne couplings via low valent metal species, however, regioselectivity has historically been a problem.62,63 Recent advances include several examples using directing groups such as hydroxy and amidates to afford regioselective reactions leading to synthetic routes for natural products. While the Ti examples presented here are stoichiometric, it is important to note that even stoichiometric amounts of Ti sources are often cheaper than catalytic amounts of noble metals such as Ru, Pd, and even most Ni catalysts. There have been a series of reactions using substrate control of 6-hydroxy alkynes to provide regioselectivity in Ti-promoted reductive couplings.64 Reaction of ClTi(O-iPr)3 with c-C5H9MgCl and 6-hydroxy alkynes with a variety of substituted alkynes gives the corresponding dienes.65 A related reaction class, shown in Fig. 22, generates asymmetric hydroindanes through regioselective coupling of TMS-substituted alkynes with tethered enyne 61.66 The reductive cyclization reaction starts with the formation of a low valent Ti species through reaction of Ti(OiPr)4 with c-C5H9MgCl. The TMS-alkyne 60 first forms the 3-membered titanacycle 63, which then undergoes alkoxide directed [2 + 2] cyclization with the alkyne of 64 (generated via deprotonation of 61). The cyclization step is highly stereoselective due to the alkoxy directing group coordinating prior to insertion. This gives the bicyclic titanacycle INT21 which is in equilibrium with INT22. From INT22 a [4 + 2] cyclization gives the Ti bridged intermediate INT23. Elimination of OPMB (PMB ¼ 4-methoxybenzyl) from INT23 gives diene INT24 which readily undergoes a 1,3-Ti shift to form INT25. Quenching with water gives the product hydroindane 62 as a mixture of diastereomers with 64% yield. Selective formation of the trans-fused dihydroindane 67 was achieved using an alcohol instead of water to quench the reaction, as shown in Fig. 23.67,68 The Ti-alcohol interaction forms a 6-membered transition state (TS1), leading to the trans protonation. This isomer of the transition state is lower energy than that leading to the cis protonation. The lower energy is due to the steric interaction between the Ti and the Ph group which forms products in a trans:cis ratio of up to 15:1. It was also found that addition of TMSCl drastically increases the rate of the couplings which allowed for alkyne-alkyne coupling reactions to proceed in 2.4 M nBuLi.69 Four examples of TMS-alkynes 66 coupled with 3-hydroxy alkynes 65 with yields from 67% to 74% and high regioselectivity (20:1) were reported.

Fig. 20 Formation of low-valent early transition metal species with strongly reducing alkali metals.

Fig. 21 Formation of low-valent early transition metal species via b-H abstraction.

56

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 22 Ti-mediated hydroindane synthesis.

Fig. 23 Ti-mediated synthesis of trans-fused hydroindanes.

Metal-Mediated Reductive C–C Coupling of p Bonds

57

Fig. 24 Directing group effect from arylamidate on Ti-mediated alkyne coupling.

Changing the directing group from hydroxyl to an aryl amidate facilitates formation of an in situ dimeric species that can engender regioselective couplings (Fig. 24).70 The reaction initially forms a dimeric arylamidate complex by addition of the low valent Ti species to the alkyne-amidate. The Ti is capped by the alkyne fragment of one equivalent of 68 while the amidate of the other equivalent of 68, formed by reaction with Grignard, binds the Ti to form the dimeric species INT27. Addition of the terminal alkyne 69 results in coupling of the two alkyne fragments to give a conjugated diene. The rigid dimeric intermediate is responsible for the exclusive formation of E,E-dienes 70. This is the first example of amidate and carbamate direction in metal-mediated reductive coupling and provides a synthetic pathway to a variety of natural products such as NFAT-68. Synthesis of 7-membered ring natural products are often desirable in total synthesis. Ring strain and entropy make these rings often harder to access than their 5- and 6-membered counterparts.71 Ti-mediated reductive coupling of 1,8-enynes 71 was found to generate a series of methylene cycloheptanes 72 (Fig. 25).72 Ti(OiPr)4 activated by a Grignard can be used to mediate this coupling, which undergoes metallacycle formation to form titanacyclopropene INT28 and alkene insertion to give titanabicyclo[5.3.0]decene INT29. This reactive 5-membered titanacycle can be captured with either a proton or electrophile to give the final products. Much like Ti, Zr has been used in the coupling of alkenes and alkynes. A recent report has shown that Cp2ZrCl2 along with nBuLi can be used to mediate the coupling of tethered diynes 73 to form polycyclic structures 75 (Fig. 26).73 In fact, this strategy has been used to form expanded helicene structures.74 Low-valent Zr is reacted with diynes tethered by two aromatic rings. The Zr cyclizes the diynes to give a new 6-membered ring and a 5-membered zirconacycle 74. Acidic workup gives the conjugated cyclic diene, which can be further reacted to give expanded polycyclic species.

Fig. 25 Ti-mediated methylene cycloheptane synthesis.

58

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 26 Zr-mediated polyaromatics synthesis via zirconacyclopentadiene.

12.03.3.1.2

Stoichiometric couplings of p bonds with aldehydes, imines, ketones, and nitriles

Similar to the alkene and alkyne couplings presented above, low-valent Ti can also facilitate coupling reactions between alkenes/ alkynes and aldehydes/imines. McMurry and pinacol type couplings have also seen further advances in recent years. In the presence of Ti(OiPr)4 and iPrMgCl, TMS-alkynes 76 can react with an aldehyde (77) or a ketone (79) to from dihydroxy alkenes 78 and 80 diastereoselectively (Fig. 27).75 The alkyne initially coordinates to a low-valent Ti to form a titanacyclopropene, which is then intercepted by a ketone or aldehyde via insertion into the Ti–C bond to give the dihydroxy alkenes with diastereoselectivities of up to >20:1. The diastereoselectivity is promoted by the propargylic hydroxy directing group; use of a PMB-protected propargylic alcohol only affords a diasteroemeric ratio of 2:1. However, the exact mechanism is not known. This system has been utilized in the synthetic route for the core of thapsigargin, a SERCA inhibitor.76 Initiating the reaction from imine (81) instead of an olefin or alkyne leads to the formation of titanaaziridine INT30 (Fig. 28), which can further react with allylic alcohols through insertion.77 The alcohol is deprotonated to become an alkoxide 82, which serves as a directing group in the insertion through coordination to the metal center (INT31). This positions the alkene for addition (TS2) to give a azatitanaoxabicyclo[3.2.0]heptane INT32 over the opposite addition that would give a tricyclic species. A syn-elimination gives the homoallyl amine product 83 and Ti]O. McMurry couplings, i.e. the coupling of two carbonyls to give a new double bond, is well established to be mediated by low valent Ti.78 Recently, a new system was reported using Ti(OiPr)4 and Mg powder under mild conditions (Fig. 29). A low valent Ti species is generated in situ which reductively couples aldehydes 84 to generate a dialkoxide species, followed by deoxygenation via formation of TiO2 to give the alkene product. In this case, a mixture of alkene (85) and diol (86) products is isolated. This method is effective in the polymerization of aryl dialdehydes (87, 89). It can also be adapted to the pinacol coupling of aldimine substrates (91) to give diamine products. Both Ti and Hf can be used to couple 1,3-dienes and isonitriles. Ti-diene complex 93 is prepared by reaction of Cp TiCl3 (Cp ¼ C5Me5) with 2,3-dimethylbutadiene in THF with reduction by iBuMgCl (Fig. 30, top).79 Reaction of 2 equivalents of tBuNC with the preformed 93 results in a 1,1-insertion of nitrile (INT33). Reductive elimination gives a bicyclic titanacycle (INT34), which undergoes b-H elimination to form a cyclopentadiene (INT35). Insertion of a second equivalent of isonitrile gives INT36, and reductive elimination of the isonitrile to give an asymmetric 1,2-bis(imine) complex (94). 94 undergoes elimination at 55  C in pyridine to give a Ti-imido 95 and the formal [4 + 1] imine product 96 through isonitrile cleavage. The Hf analog 97 is prepared by reaction of Cp HfCl3 with Na/Hg and diene.80 When 2,6-Me2C6H3NC reacts with the Hf-diene adduct (Fig. 30, bottom), a unique bicyclic diamine product 98 is obtained through 1,2-insertion of the 2-imine carbon into the 1-imine (INT37). Similar to the alkyne couplings above, both Ti and Zr can mediate nitrile couplings.81 A Rosenthal type reagent, Cp 2M (Me3SiC^CSiMe3) (99, M ¼ Ti, Zr, Fig. 31), was used as the low-valent metal source. Loss of Me3SiC^CSiMe3 and nitrile association precedes oxidative cyclization of nitriles to give the 5-membered metallacycle. The metallacycles can be reacted with several reagents to give distinct products from the diazametallacyclopentadiene 100. Reaction with H2 gives metal-bound bis-imine 101 through cleavage of the C–C bond. Reaction with CO2 also cleaves the C–C and forms a new C–C bond through exchange

Fig. 27 Ti-mediated alkyne coupling with aldehydes and ketones.

Fig. 28 Synthesis of homoallyl amines via titanaaziridines.

Fig. 29 Ti-mediated McMurry coupling of aldehydes and aldimines.

60

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 30 Reductive coupling of 1,3-dienes and isonitriles mediated by low valent Ti and Hf half-sandwich complexes.

Fig. 31 Reductive homocoupling of nitrile mediated by low valent Ti and Zr complexes.

between one nitrile and CO2 to give 102. Protonation with HCl gives free diimine 103 and Cp 2MCl2 (104). The system has also been explored using Fc-Nitriles (105) to give similar results as well as diamine products.82 A modified Kulinkovich-de Meijere reaction (Ti-catalyzed cyclopropanation of amides) has been reported to synthesize carbocyclic amino ketones 107 through intercepting the cyclopropanation step (Fig. 32).83 Ti(OiPr)4/cC5H9MgBr catalyzes this intramolecular reaction of allyl-substituted lactams 106. Following Bredt’s rule, the structure of titanacycle intermediate (INT38)

Metal-Mediated Reductive C–C Coupling of p Bonds

61

Fig. 32 Intercepted Kulinkovich-de Meijere reaction.

prevents formation of the double bond on the bridgehead (INT39), and instead remains as the 5-membered titanacycle.84 This allows for rearrangement on acidic work up to the 7-membered ring amino ketone 107.

12.03.3.2 Catalytic early transition metal coupling Most of the catalytic early transition metal coupling examples employ TiIII catalysts instead of the TiII used in the stoichiometric examples. Generally, the TiIII catalysts perform single electron reduction to the substrates and are regenerated through Zn and TMSCl. Recent examples include pinacol couplings and ketonitrile couplings. The coupling of ketonitriles 108 to form acyloins 110 can be catalyzed by a (EBTHI)Ti precatalyst 109 (Fig. 33, top).85 Acyloins are very common structures in natural products, with over 1500 known compounds containing this moiety, rendering its synthesis

Fig. 33 Ti-catalyzed reductive cyclization of ketonitriles.

62

Metal-Mediated Reductive C–C Coupling of p Bonds

with Ti an important advance for early transition metal catalysis. The reaction leads off with Ti coordination to a ketone and reduction to form the stabilized benzylic ketyl radical INT40 (Fig. 33, bottom). This stabilized radical adds to the nitrile and cyclizes to form the cyclopentyliminyl radical INT41. A second equivalent of TiIII reduces the nitrile in the presence of a protic acid to give the metalated imine intermediate INT42. Addition of Zn and TMSCl regenerates the low-valent Ti and gives the silylated product INT42a, which on aqueous or acidic work up gives the a-hydroxyketone (acyloin) 110. Another advance comes in a heterobimetallic catalyst 111, a salen derived ligand housing Ti and V.86 This system allows selective aldehyde hetero-pinacol coupling through differing affinities for aryl and alkyl aldehydes, giving significant selectivity toward the hetero-coupled product (Fig. 34). The Ti center has a higher activity for aldehyde binding and thus binds the alkyl aldehyde 112 in solution (INT43), whereas the slowly added aryl aldehyde 113 binds to the vacant V center (INT44). The proximity of the two ketyl radicals facilitates the pinacol coupling to give the hetero-coupled product INT45, acidic work up gives diol 114. Umpolung reactions allow the coupling of equally polarized alkenes. It was recently demonstrated by a alkene-alkene coupling between a,b-unsaturated ketones 115 and acrylonitriles 116 with Cp2TiCl catalyst formed via in situ reduction of Cp2TiCl2 (117) with Zn (Fig. 35).87 This mechanism is similar to the ketonitrile coupling above where TiIII reduces the a,b-unsaturated ketone to give a stabilized radical INT46. A following Giese-type radical addition to the acylonitrile allows the intermolecular C–C bond formation (INT47). Reduction with a second equivalent of Ti and protonation from HCl
NEt3 gives the Ti enolate INT48. Zn and TMSCl regenerate the catalyst and aqueous or acidic work up to form the final TMS-protected ketonitrile INT49, which is deprotected during the acidic workup to give 117.

12.03.3.3 Fe-catalyzed reductive cyclization Fe chemistry is of significant interest to the chemical community as it is the most earth abundant transition metal.88 There are several modern reactions that take advantage of Fe to accomplished noble-metal-type chemistry such as alkyl cross couplings, oxidations, and reductions.89,90 Of particular interest for this section is the emerging field of catalytic Fe reductive cyclizations.91 For Fe-catalyzed intermolecular reductive couplings and stoichiometric Fe-mediated reductive couplings, we direct the readers to the recent related reviews.92,93 Bis(imino)pyridine iron bis(dinitrogen)complex 119 has been reported to catalyze the reductive cyclization of enynes and diynes (118) with hydrogen (Fig. 36). For example, enyne substrate 120 in C6D6 reacts with 119 via oxidative cyclization to metallacyclic INT50, which can then undergo near quantitative conversion to the 3,4-substituted heterocycle 122 via hydrogenolysis. The reaction is catalytic under 4 atm H2, however some over reduction to the alkane is observed. Low-valent Fe catalysts can also be formed in situ using Grignard reagents as reductants.94,95 Fe-L2 can be made in situ to similarly catalyze the reductive coupling of enynes 123 to 124 (Fig. 37). The reaction proceeds at room temperature with FeCl2, L2, ZnEt2, and MgBr2
Et2O. For example, similar to the reductive cyclization catalyzed by 119, enyne 125 is activated through oxidative

Fig. 34 Ti/V heterobimetallic-catalyzed cross coupling of aldehydes.

Fig. 35 Ti-catalyzed umpolung coupling of a,b-unsaturated ketones and acrylonitriles.

Fig. 36 Fe-catalyzed hydrogenative reductive cyclization of 1,6-enynes.

64

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 37 Fe-catalyzed reductive cyclization of 1,6-enynes with Grignard reagents.

cyclization with the Fe complex (INT53), followed by transmetallation with Et2Zn (INT54). The resulting alkenyl ethyl iron INT54 then undergoes b-H elimination/reductive elimination to regenerate the active Fe catalyst Fe-L2, while the remaining organozinc intermediate INT55 is converted to the methylenecyclopentane product 126 during aqueous workup. Fe is also capable of mediating radical coupling through single-electron transfer (SET) processes. The Fe-catalyzed reductive cyclization of dienes 127 uses PhSiH3 as the terminal reductant (Fig. 38).96 The radical coupling mechanism begins with H-atom transfer from the FeIII hydride to an un-activated olefin (INT56), followed by intramolecular radical attack onto the electron deficient alkene (INT57). The subsequent reduction with the catalyst occurs before the anionic intermediate INT58 is quenched with an alcohol. The active catalyst FeIII hydride is regenerated after treating with PhSiH3. The system is very robust and air stable. It was shown to successfully catalyze the synthesis of systems with hindered bicyclic structures, vicinal quaternary centers, and cyclopropanes all in good yields. Additionally, it has been reported that tuning of one alkene partner with a radical stabilizing group allows for switching the reactive side of the olefin for intermolecular couplings.97

12.03.3.4 Ru-catalyzed reductive coupling Ru-catalyzed transfer hydrogenation, where an alcohol is oxidized to an aldehyde through formal transfer of H2 to the substrate, is well studied and utilized owing to its high efficiency and broad applications.98,99 Recently, transfer hydrogenation has been adopted in Ru-catalyzed reductive couplings, allowing access to mild reductants such as benzyl alcohol 130 and isopropanol (Fig. 39).100 This has been shown in a series of reactions coupling aldehydes and alcohols to various dienes (131, 134), a,b-unsaturated ketones, and conjugated enynes (141). These advances are summarized in the following scheme and presented in detail in Ref. 100. The advances involve both new substrates as well as regioselectivity. These advances can be achieved by tuning of ligands, such as dppf (L4) and SEGPHOS ligands (L3, L5).101 Besides the conjugated systems above, Ru can also be used to catalyze the coupling of other olefin substrates such as terminal allenes 143 with paraformaldehyde (Fig. 40).102 Hydride transfer from the [Ru]-H of the active catalyst 145 to allene 143 gives an 3-allyl adduct of Ru (INT59). Formaldehyde is inserted into the Ru–C bond of the tertiary carbon of INT59 to give the Ru alkoxide INT60, which is further protonated by iPrOH to form 1,4-ene-ol 144 and Ru isopropoxide INT61. Lastly, a b-H elimination regenerates 145 and releases acetone.

Metal-Mediated Reductive C–C Coupling of p Bonds

65

Fig. 38 Fe-catalyzed reductive cyclization of dienes via SET process.

Ru reductive coupling chemistry has also advanced in terms of both stereoselectivity and regioselectivity. Iodide salts, such as Bu4NI, significantly aid in regioselective coupling. In the reductive coupling of propyne derivatives and aldehydes, switching to iodide salts can facilitate an E:Z selectivity as high as 20:1.103 On the other hand, a combination of 1,4-bis(diphenylphosphino) butane (dppb) with HClRu(CO)(PPh3)3 (132) can catalyze transfer hydrogenation of 1,3-enynes 146 with aldehydes 147 diastereoselectively (Fig. 41).104 Anti-configuration products 148 are achieved through the intermediate formed via hydride insertion into the alkene (INT62), which isomerizes to give the Ru-bound allene (INT64) with the following coordination of the aldehyde (INT64). The propargylic alcohol in the substrate is necessary for the anti-selectivity as it facilitates the rearrangement from allene and aldehyde to alkyne and alkoxide (INT65). Exocyclic dienes 154 can be synthesized through Ru-catalyzed reductive cyclization of tethered diynes 152, using methanol as a transfer hydrogenation reagent (Fig. 42).105 Tethered alkynes undergo oxidative cyclization to form a ruthenacyclopentadiene. Addition of methanol leads to the reversible protonation of 2-C of ruthenacyclopentadiene and the association of a methoxide ligand. b-H abstraction of Ru methoxide by the 6-C of the ruthenacycle gives formaldehyde and the reductively coupled product 154 in p backbonding with Ru. The Ru complex then releases exocyclic diene 154 via binding of an additional equivalent of 152. The reaction is viable across 10 different substrates with various substituents with several examples giving quantitative yield.

12.03.4 Late transition metals Compared to f-block metals and early-mid transition metals, the lower oxophilicity of late transition metals provides them better compatibility with alcoholic solvents and oxygen-containing, unsaturated functional groups such as carbonyl and carboxyl.106 This grants the reductive coupling with a wide variety of choices for hydrogen source, good functional group tolerance, and allows the development of catalytic reductive coupling with carbonyl substrates for the synthesis of alcohols and ethers. This section will cover the recent developed catalytic methods for reductive coupling utilizing late transition metal catalysts.

66

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 39 Recent advances in Ru-catalyzed transfer hydrogenative reductive coupling reactions.

12.03.4.1 Reductive coupling of alkynes and alkenes p bonds Late transition metal catalyzed reductive coupling of two alkynes, alkenes or allenes is a common strategy used in dimerization and cyclization of simple unsaturated hydrocarbons. Many salient methods have been developed for intra- and intermolecular reductive coupling with high stereo- and regioselectivity using Co, Rh, Ni, Pd, and other metal catalysts. This topic has been summarized in depth several times in the past two decades and we direct readers to these comprehensive reviews and book chapters.13,91,107–112 Instead of an exclusive review, this section will focus on some of the interesting progress on the reductive of unactivated alkynes and alkenes, which has been relatively under-reviewed recently.

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 40 Ru-catalyzed reductive coupling of terminal allenes with paraformaldehyde.

Fig. 41 Ru-catalyzed diastereoselective reductive coupling of 1,3-enynes and aldehydes.

67

68

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 42 Ru-catalyzed transfer hydrogenative reductive cyclization of tethered diynes.

12.03.4.1.1

Hydrosilylation/cyclization

Catalyzed hydrosilylation/cyclization is a versatile and well-studied reaction in constructing cyclic carbon backbone. 1,6-enynes have been used as a class of model substrates in the synthesis of silyl methylene cyclopentane since the early discovery of the reaction.113–115 Traditional conditions employ Rh or Rh-Co catalysts on the reaction of 1,6-enynes with trialkylhydrosilanes, yielding 2-methyl silylmethylenecyclopentanes. The generic plausible mechanism for hydrosilylation/cyclization (Fig. 43, left) starts from a silyl metal hydride (INT68), which then undergoes silylmetallation of alkyne to IM70. The alkyne of the enyne typically precoordinates to the metal and inserts since it is a better 2-ligand than the alkene. Thus, the following silylmetallation has a high chemoselectivity on alkyne, resulting in the vinylsilane product IM70. Migratory insertion of the alkene into INT70 gives the cyclization product INT71, which can further react with hydrosilane to give vinylsilane 155 and regenerate INT68. This mechanism has also been recently proposed in Ni catalysis, while in some systems an alternative pathway based on oxidative cyclization of Ni(0) with enyne has been proposed.116,117

Fig. 43 Catalytic hydrosilylation/cyclization of 1,6-enynes yielding vinylsilanes (left) and homoallylsilanes (right).

Metal-Mediated Reductive C–C Coupling of p Bonds

69

An alternative reaction pathway can be envisioned (Fig. 43, right), initiating the catalysis through hydrometallation from IM72 to generate a vinyl intermediate (INT74). Subsequent insertion (INT75) and silylation would give homoallylsilane 156 as the regioisomeric product. Pioneering in this strategy, Molander has reported a series of work using Cp2LnMe(THF) (Ln ¼ Y, Lu) as catalysts in late 1990s.118–120 In the past two decades, this hydride pathway has become an emerging research topic. Previously, [(3-C3H5)Pd(cod)](PF6) (159) was shown to be a catalyst for hydrosilylation/cyclization of diynes, but it was recently reported to also catalyze the hydrosilylation/cyclization of 1,6-enynes (158) with HSiCl3 to form homoallylic silanes (161) (Fig. 44, top).121 Both terminal and internal enynes have been investigated and good yields have been obtained. It is noteworthy that when a diyne-ene 162 is used as the substrate, the chemoselectivity of the hydrosilylation/cyclization is dominated by the choice of silane. HSiCl3 leads to enyne-cyclized product 163 in 3:1 selectivity, while HSiMeCl2 gives 13:1 selectivity favoring the diyne-cyclized product 164 in a lower yield (Fig. 44, bottom). More modular reactions using base metal catalysts have been developed in the last decade. The pyridylimine Co catalyst 166 has been reported in the hydrosilylation/cyclization synthesis of homoallylsilanes 167 from various internal enynes 165 and H2SiPh2 (Fig. 45, top).122 A sub-stoichiometric loading of NaBHEt3 reductant is used to activate the Co(II) catalysts. The reaction has a broad substrate scope of substituents on the tethered alkyne and can tolerate a variety of functional groups. An enyne substrate bearing 1,1-disubstituted alkene 168 was found to give only 9% cyclization product 169 due to the increased steric hindrance disfavoring the alkene insertion (Fig. 45, middle). As a result, simple alkyne hydrosilylation of the alkyne (170 and 171, obtained in 59% combined yield and 3.5:1 ratio favoring anti-Markovnikov selectivity) was the major product. One of the interesting findings in this study is a reversed regioselectivity to vinylsilane 173 observed when terminal enyne 172 is used as the substrate (Fig. 45, bottom), although mechanism remains unclear. More recently, substrate-controlled switchable regioselectivity has been achieved for hydrosilylation/cyclization of 1,6-enynes by using a Co(acac)2/(R,Sp)-Josiphos (L7) catalyst system (Fig. 46).123 Enynes bearing aryl substituents on the alkyne (174) selectively form homoallylsilane products 175, while enynes with alkyl alkyne substituents (176) form vinylsilane products 177 under the same reaction condition. The unique switchable regioselectivity originates from the [Co]-H active catalyst undergoing hydrocobaltation preferably with alkene (INT78) when the alkyne is bearing an alkyl substituent. The use of the chiral biphosphine (R,Sp)-Josiphos (L7) provides the reaction with excellent enantioselectivity on the alpha-carbon of methylenecyclopentane, where a similar approach has been recently reported in Rh catalysis using bisphosphino-1,10 -spirobiindane ligands.124 Homoallylsilanes have also demonstrated their versatility in further deprotection/functionalization of the methylenecyclopentane framework, providing complementary approaches to the established Pd-catalyzed cross-coupling of vinylsilanes with aryl halides.125

Fig. 44 Pd-catalyzed hydrosilylation/cyclization of 1,6-enynes with HSiCl3.

70

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 45 Co-catalyzed hydrosilylation/cyclization of 1,6-enynes with silanes and NaBHEt3.

Recent effort on hydrosilylation/cyclization has also been devoted to incorporating it into domino reaction sequences. Building on the facile b-hydride elimination of Pd,4 [Pd]-H could induce cycloisomerization of 1,n-dienes via a chain walking mechanism.126 As an extension of this research, a catalytic hydrosilylation/cyclization of 1,n-dienes 178 based on chain walking was recently reported (Fig. 47).127 The proposed mechanism of the reaction undergoes selective anti-Markovnikov palladasilylation (INT81), with the cyclization achieved by chain walking (INT82 & INT83) and migratory insertion in forming the trans-cyclopentane moiety. Deuterium labeling experiments support the reversibility of the chain walking mechanism. A certain feature that differs from other chain walking reactions is the need to suppress dissociative alkene exchange during the chain walking. The chain walking intermediate palladium hydride is different from the active catalyst palladium silyl, hence an alkene exchange will lead to dehydrogenative silylation (181) and reductive cyclization (182), generating two equivalents of side products. Various lengths of methylene linkers and functional groups have been examined, giving good yields and excellent regio- and diastereoselectivity.

12.03.4.1.2

Dihydrogenative reductive coupling

Reductive coupling reactions to dihydrogenated products share a common initial step, where typically the coupling partners (alkynes, alkenes) undergo oxidative addition onto a low valent metal catalyst, forming the C–C bond. Protic solvents or additives are usually used as the source of hydrogen in the reaction. Linear conjugated polyenes are found in a variety of natural products, antibiotics, and dyes.128,129 Oligomerization of alkynes is one of the most atom-economical routes in their synthesis. Similarly, Ni-catalyzed cyclotetramerization of alkynes has been achieved using acetylene or tethered diynes (Fig. 48, top).130–132 Recently, Ni-catalyzed reductive tetramerization of internal alkynes (183) to octa-substituted linear tetrenes (184) was reported using a NiBr2(dppe) catalyst with Zn as reductant and H2O as proton

Metal-Mediated Reductive C–C Coupling of p Bonds

71

Fig. 46 Co-catalyzed hydrosilylation/cyclization of 1,6-enynes using Josiphos ligand.

source.133 The proposed mechanism (Fig. 48, middle) starts from the oxidative cyclization of two alkynes on Ni(0), and the resulting nickellacyclopentadiene (INT85) dimerizes to give dinickellacyclodecatetraene (INT86) in an all-cis configuration. Hydrolysis of INT86 followed by b-H abstraction from the Ni-OH and subsequent Ni-mediated cis-trans isomerization yields alkenyl Ni hydride INT88 and NiO. INT88 will generate the tetraene product 184 and Ni0 via reductive elimination. The NiO is regenerated back to Ni0 through reduction by Zn. The reaction was examined with various symmetric diarylalkynes and good yields were obtained. When asymmetric alkynes are used, the regioselectivity of the reductive coupling vastly depends on the steric bias of the alkyne substrate—4-(phenylethynyl)-1-(trifluoromethyl)benzene (185a) leads to mixture of regioisomers, while 1-phenyl-1propyne (185b) gives tetraene 186b as a single product (Fig. 48, bottom). Later, B2pin2 was found as an alternative mild reductant in a similar reaction system using NiCl2(PPh3)2 catalyst with MeOH as the proton source (Fig. 49, top).134 The use of alcohol for protonolysis enables the transmetallation of Ni-OR with B2pin2 for terminal reduction. Detailed mechanistic studies have been performed to support the proposed mechanisms. Deuterium labeling of MeOH confirms its role as a proton source in protonolysis. In situ IR monitoring of the formation of pinB-OR, suggests the transmetallation of Ni-OR with B2pin2 and the existence of a Ni-Bpin intermediate. Additionally, the reaction rate was found to be on second-order dependent on the Ni catalyst while zero order of both the alkyne and B2pin2, indicating a dimerization event. Based on these observations, a plausible mechanism (Pathway I) similar to the catalytic alkyne tetramerization with Zn was proposed (Fig. 49, bottom left). After the oxidative cyclization and the rate-limiting dimerization of nickellacyclopentadiene INT85, dinickellacyclodecatetraene INT86 would undergo methanolysis twice to give tetraene 184 and dimethoxydinickel (INT89). Transmetallation with B2pin2 leads to Ni-Bpin species INT90 by eliminating methoxy (pinacolato)boron (MeOBpin). Reductive elimination of INT90 will regenerate the Ni(0) catalyst. An alternative mechanism (Pathway II, Fig. 49, bottom right) was also proposed with methanolysis occurring on nickellacyclopentadiene (INT91) followed by transmetallation with B2pin2 (INT92), although this mechanism is not in good accordance with observations from the rate studies. Interestingly, the aforementioned alternative mechanism was proposed as the main pathway of a more recent example of Ni-catalyzed alkyne reductive dimerization.135 Ni(OAc)2 can catalyze the reductive coupling of various diarylacetylenes with stoichiometric B2pin2 in MeOH, giving dimerization product 187 and 188 in a near 1:1 mixture (Fig. 50, top). Similar to Pathway II,

72

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 47 Pd-catalyzed hydrosilylation/cyclization of 1,6-enynes based on chain walking mechanism.

it was proposed that nickellacyclopentadiene undergoes methanolysis to INT91 followed by transmetallation to give INT92 (Fig. 50, bottom). The subsequent Csp2-B reductive elimination gives borylation product 188 and closes the catalytic cycle. INT91 can also be intercepted by an aryl boronic acid, resulting in aryl dienyl Ni intermediate INT94, which gives hydroarylation product 190 after reductive elimination (Fig. 50, middle). Methods for reductive coupling between alkenes and unsaturated C–C coupling partners (alkynes, allenes) have been predominantly developed for electronically activated alkenes such as those with electron-withdrawing groups. Unactivated alkenes, on the other hand, usually require the use of noble metal catalysts such as Rh, Pd and Au, and base metal catalysis is rare.136–140 An example of Ni-catalyzed reductive cyclization of unactivated 1,6-enynes 191 using iPr2Zn as reductant was reported recently (Fig. 51, top).141 Though originally proposed for a Pauson-Khand reaction under CO atmosphere, the use of i Pr2Zn provides a hydrogen source through b-hydride elimination, leading the reaction to a different outcome. Enyne 191 will first undergo oxidative cyclization with Ni0 to give bicyclic nickellacycle INT95 (Fig. 51, middle), followed by transmetallation with iPr2Zn to give INT96 or INT97. Both INT96 and INT97 will have the Ni-iPr converted into Ni-H through b-H elimination. The subsequent reductive elimination gives vinylzinc INT100 and homoallylzinc INT101, with both giving methylenecyclopentane 192 as product. Deuterium incorporated products 194 and 195 were found when CD3COOD was used to quench the reaction (Fig. 51, bottom), supporting the presence of INT100 and INT101. Meanwhile, non-deuterated product 196 was also found in a small amount, indicating that b-hydride elimination of Zn-iPr is also viable though a minor route. Both electron-donating and withdrawing substituents on the alkyne can be tolerated, and notably this reaction has excellent selectivity in the formation of cis-alkenes.

Metal-Mediated Reductive C–C Coupling of p Bonds

73

Fig. 48 Ni-catalyzed reductive tetramerization of alkynes.

12.03.4.2 Reductive coupling of alkenes and alkynes with aldehydes and aldimines Reductive coupling of carbonyl and imine compounds has been studied extensively due to its importance as a versatile C–C bond formation method. The relatively low oxophilicity of late transition metals avoids the product inhibition issues commonly observed in early transition metal chemistry due to the strong binding of oxygen-containing substituents. This renders late transition metals a popular choice as catalyst in reductive coupling of carbonyl compounds. In this section, the discussion will focus on the update of recent progress on selected topics including selectivity, functionality, mild reductants and conditions, with an emphasis on base metal catalysis. This research area has been an enduring topic of interest summarized repeatedly over years on more specific coupling partners used with the carbonyl compounds, and the readers are directed to these exclusive reviews for the earlier studies.4,13,109,110,142–153

12.03.4.2.1

Enantioselective synthesis on unactivated alkenes

Ni and Cu catalytic reductive couplings of unactivated alkenes with carbonyl or imine substrates have shown to be promising in generating new C–C bonds. In the following reactions, chiral supporting ligands facilitate diastereoselective or enantioselective formation of chiral products.

Fig. 49 Ni-catalyzed reductive tetramerization of alkynes using B2pin2 as a mild reductant.

Fig. 50 Ni-catalyzed reductive dimerization and borylation of alkynes.

Metal-Mediated Reductive C–C Coupling of p Bonds

75

Fig. 51 Ni-catalyzed reductive cyclization of unactivated 1,6-enynes.

Cu(OAc)2, (S,S)-Ph-BPE (L8), (EtO)2MeSiH, and a tBuOD additive can catalytically couple aldiminylstyrenes 197 to 2,3-disubstituted indolines 198 in a diastereo or enantioselective fashion (Fig. 52).154 It was proposed that Cu(OAc)2 reacts with the chiral, bidentate phosphine ligand (S,S)-Ph-BPE (L8) and a hydrosilane to generate an active L CuH species. The alkene moiety of the aldiminylstyrene 197 then inserts into the [Cu]–H bond to form a Markovnikov alkylcopper intermediate, which then undergoes intramolecular cyclization with the nearby aldimine which can subsequently protonated by tBuOH to generate the product. A hydrosilane then can intercept the now L CuOtBu intermediate to regenerate the L CuH active species. Interestingly, use of tBuOD was found to have improved yields which was attributed to the deuterium isotope effect. In some cases, an additional PPh3 ligand additive improved catalyst turnover. When styrene 199 and N-phosphinoaldimine 200 undergo intermolecular reaction under similar conditions, the active L CuH intermediate can facilitate highly enantioselective addition of the styrene to the N-phosphinoaldimine (Fig. 53).155 Reaction

76

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 52 Cu-catalyzed reductive cyclization of aldiminylstyrenes.

Fig. 53 Cu-catalyzed reductive coupling of styrenes and N-phosphinoaldimines.

progress analysis was also performed on this system using calorimetric analysis. It was determined that the undesirable aldimine reduction rate was diminished when using Ph-BPE (L8) in comparison to SEGPHOS and DTBM-SEGPHOS. DFT calculations for styrene hydrocupration found that the activation barrier with Ph-BPE was similar to DTBM-SEGPHOS and 100 times faster than SEGPHOS. Ni-catalyzed intramolecular reductive coupling of aldehydes and alkenes has also been demonstrated with a TNSi complex 203 and Et3SiH (Fig. 54).156 The o-allylbenzaldehyde substrate 202 cyclizes to form 1-triethylsiloxy-2-methylindane 204. Attempts to use phosphine supporting ligands in the presence of Ni(COD)2 were not effective, whereas Ni(COD)2/NHC gave slightly improved yields. When the isolated TNSi 203 was used as the precatalyst, yields were significantly increased. A screen demonstrated that several alkyl silanes were effective, whereas (EtO)3SiH decreased yields significantly. It was proposed that the aldehyde moiety undergoes oxidative cyclization with the Ni metal center to generate an oxanickelacycle intermediate. This subsequently is followed by s-bond metathesis with the silane and the Ni–O bond followed by reductive elimination to generate the 1-triethylsiloxy2-methylindan product 204.

12.03.4.2.2

Enantioselective synthesis using alkynes

Reductive cyclization of alkynes and carbonyls are important methods for the formation of allylic alcohols. This transformation is possible catalytically with both Ni and Rh.157–160 In all these reactions, the presence of a chiral ligand facilitates the diastereoselective or enantioselective formation of the allylic alcohol product.

Fig. 54 Reductive cyclization/silylation of o-allylbenzaldehyde catalyzed by NHC-Ni complex.

Metal-Mediated Reductive C–C Coupling of p Bonds

77

Fig. 55 Ni-catalyzed reductive coupling of alkynes and alkdehydes.

Chiral allylic alcohols containing a tetrasubstituted alkene were catalytically synthesized from intermolecular alkylative coupling of an alkyne 205 and aldehyde 206 (Fig. 55).161 These products were generated in the presence of ZnMe2 and catalytic amounts of Ni(COD)2 and a chiral spiro phosphoramidite ligand 207. When ZnEt2 was used in place of ZnMe2, a mixture of products formed likely due to the potential for b-H elimination, and no reaction was observed when using ZnPh2. High regioselectivity (208:209; 85:15 to 95:5) was observed when using 1-phenyl-1-propyne; however, regioselectivity decreases when 1-phenyl-1-butyne and 1-phenyl-1-hexyne were used as the alkyne substrate. This was attributed to the smaller difference in sterics between phenyl and the alkyl group. Enantioselective intramolecular reductive cyclizations of N-alkynones 210 to form pyrrolidines (211) and piperidines (Fig. 56) were shown to be facilitated by Et3SiH and catalytic amounts of Ni(COD)2 and (S,S)-DI-BIDIME (L9).162 A broad substrate screen demonstrated that both electron withdrawing and donating substituents gave high yields (76–98%) and enantioselectivity (98:2 to >99:1 er). It was proposed that the (S,S)-DI-BIDIME coordinates to two Ni(0) centers to form a bimetallic complex. The N-alkynone then coordinates to each Ni and cyclizes to form the pyrrolidine/piperidine moiety while remaining coordinated to the Ni center through the alkoxy and alkenyl moiety. Et3SiH then engenders s-bond metathesis to generate a silyloxide and Ni-H species which promptly undergoes reductive elimination to form the pyrrolidine/piperidine product.

12.03.4.2.3

Mild reductants

The choice of reductant is important to the practical use of the reaction. Traditionally, reductive coupling relies on metal reductants such as Zn or ZnEt2, whose reactive nature lower the compatibility of the reaction and limits the potential substrate scope. Alternatively, mild reduction can be achieved with organic reductants like silanes or boranes, although their higher cost is undesired for large scale applications. Two methods have been sought to address this issue. First, internal redox has been demonstrated as an atom-economical design strategy (Fig. 57, top), where the reductant 214 shares a dual role as a substrate.163 Second, transfer hydrogenation has also been adopted in late transition metal catalysis (Fig. 57, middle), where a sacrificial alcohol 216 acts as the reductant and hydrogen donor in the reaction.164 A combined strategy, namely hydrogen autotransfer (Fig. 57, bottom), has also been developed with the aldehyde byproduct INT103 from transfer hydrogenation used as the carbonyl substrate.100,165,166 Selected recent reports will be discussed below to highlight the features of these strategies. As a widely used donor in transfer hydrogenation, iPrOH has been adopted in intramolecular reductive coupling as a mild reductant.164 Recently its application has been further extended to the intermolecular alkyne-aldimine coupling using catalytic amounts of Ni(COD)2 and an N-heterocyclic carbene (NHC), as shown in Fig. 58.167 The use of bulky, electron-rich NHC L10 as a ligand instead of traditional phosphine ligands was considered to be the origin of the significantly enhanced reactivity. The reaction of diphenylacetylene with aldimines bearing electron-donating aryl groups generally performed better, with yields ranging from 68% to 89%, whereas aldimines containing electron-withdrawing groups had lower yields of 29–74%.

Fig. 56 Ni-catalyzed reductive cyclization/silylation of N-alkynones.

78

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 57 Novel strategies for application of mild reductants and conditions on reductive coupling.

Fig. 58 Ni-catalyzed reductive coupling of imines and alkynes using iPrOH as transfer hydrogenation donor.

Reductive cyclization using tethered tosylamide-alkynal substrates 222 in the presence of an in situ generated [Rh(L11)][BF4] forms cyclic allyl esters 223 (Fig. 59).168 This internal redox reaction consumes two equivalents of the enal, with the first enal performing an intramolecular reductive coupling while the second enal acting as the hydrogen donor and being oxidized to an ester. In a screen of ligand effects, the chiral (R)-H8-BINAP ligand (L11) was shown to be the most effective ligand with enantioselectivity up to 99% (+) ee and isolated yields of 78%. Other supporting bis-phosphine ligands such as dppb and dppf did not provide isolable products, except for BIPHEP which gave 33% isolated yield. (R)-BINAP was also found to be a comparable ligand, with isolated yield of 72% with 98% (+) ee. Using the most effective ligand, (R)-H8-BINAP, a series of tosylamide-alkynal substrates containing R ¼ alkyl and phenyl and Z ¼ NTs and O were shown to form the cyclic allyl ester in good yields (72–83%) and with high ee (98% to >99%). Hydrogen autotransfer can also be incorporated into a tandem reaction. This has been demonstrated in a recent report, where the Rh-catalyzed reductive coupling of butadiene (134) and alcohols 224 results in sec-butyl ketones (225) instead of homoallyl alcohols (Fig. 60).169 The initial steps of the reaction share the same mechanism as transfer hydrogenative reductive coupling, where

Metal-Mediated Reductive C–C Coupling of p Bonds

79

Fig. 59 Rh-catalyzed reductive cyclization of enals based on internal redox mechanism.

Fig. 60 Rh-catalyzed reductive coupling of primary alcohols and butadiene based on a hydrogen autotransfer mechanism.

the alcohol is converted to an aldehyde 226 and inserted into the Rh allyl bond (INT105). Rather than alcoholysis (217), the resulting homoallyl alkoxide of Rh undergoes an internal transfer hydrogenation from alkoxide to allyl. A Rh-alkyl (INT109) is formed through b-H elimination of the alkoxide gem-C-H (INT105) then allyl isomerization via insertion and b-H elimination (INT107 & INT108). The alcoholysis of INT109 gives 225 and regenerates Rh hydride through b-H elimination. The reaction was found to be sensitive to water, where wet PhCl can promote the solubilization of K2CO3 while additional water additive will lead to catalyst inhibition.

80

Metal-Mediated Reductive C–C Coupling of p Bonds

12.03.4.2.4

Tandem reactions

Metal alkyl or metal vinyl intermediates from reductive coupling of alkynes and alkenes can be intercepted for the insertion of carbonyl compounds. Such a tandem reaction can be considered as a tandem reductive coupling of alkyne/alkene/carbonyl. A recent example was demonstrated by a catalytic alkalative enal-alkyne C–C coupling facilitated by Ni(COD)2, BEt3, and triarylphosphines to generate a mixture of d,g-unsaturated aldehydes 230 and cyclopentenols 231 (Fig. 61).170 The product distribution can be modulated by varying the phosphine ligand employed. For example, PBu3 and P(2,4,6-(OMe)3-C6H2)3 chemoselectively form cyclopentenol 231 via tandem intramolecular coupling with carbonyl insertion in yields ranging from 79% to 85%, whereas P(1-naphthyl)3 and P(o-tolyl)3 favor the formation of d,g-unsaturated aldehydes 230 in yields ranging from 12% to 45%. Reductive cross-coupling of two unsymmetrical internal alkynes in the presence of Ni(OAc)2
4H2O and a supporting ligand can catalytically form pentasubstituted dienes (Fig. 62).171 These reactions have been found to be regioselective and tolerant toward a variety of functional groups. A series of bidentate chiral ligands were screened and (R)-R-Phox ligand (R)-L12 in a TFE:HFIP (4:1) solvent mixture was found to be the most effective ligand. Reaction of 232 using (R)-L12 generated the self-coupled diene 233 with yields up to 90%,97% ee and 20:1 rr. Treating 232 with and alkyne partner in the presence of (S)-L12 and an acrylate additive generated a cross-coupled product 234. Several alkyne substituents were also screened and this reaction was found to tolerate a wide range of aryl and heterocycle groups.

12.03.4.2.5

Miscellaneous noteworthy reactions

Regioselectivity remains as one of the major challenges when sterically non-hindered aliphatic alkynes are involved in reductive coupling reactions, where the inductive effect from the alkyl substituent of alkynes cannot provide large enough electronic bias to prefer a certain orientation of the alkyne.4 A recent report demonstrated that catalyst-controlled regioselective intramolecular reductive coupling of an alkyne and an aldehyde can be achieved with delicate design of the ligand (Fig. 63).172 The catalysis was carried out using Ni(COD)2 and Et3SiH in the presence of an NHC ligand to generate 11- or 12-membered macrocycles. When

Fig. 61 Ligand-controlled chemoselectivity in Ni-catalyzed reductive coupling/cyclization of hex-2-enal and phenylpropyne.

Fig. 62 Ni-catalyzed reductive coupling/cyclization cascade of alkynones with alkynes.

Metal-Mediated Reductive C–C Coupling of p Bonds

81

Fig. 63 Ligand-controlled regioselectivity in Ni-catalyzed reductive cyclization in the synthesis of macrocyclic lactones.

IMes
HCl (L13
HCl) is used as the NHC, the ynal 235 undergoes endocyclization to form the 12-membered macrocycle 236 containing an internal alkene whereas the reaction containing DP-IPr
HBF4 (L14
HBF4) undergoes exocyclization generating the 11-membered macrocycle 237 containing a terminal methylene. It was proposed that the mesityls on IMes can access an eclipsed position allowing the alkyne approaching the Ni in an endo-orientation (INT110). On the other hand, the bulkier diisopropylphenyls on DP-IPr adopts a more sterically demanding staggered position (INT111), forcing the alkyne to undergo a sterically less favored exocyclization. Catalytic intermolecular cross-coupling of a nitrile 238 and an acrylamide 239 to form a pyrrolidinone 240 was been reported with Co(dppe)I2, Zn, and ZnI2 (Fig. 64).173 These reactions are highly regio- and stereoselective and are proposed to initiate via reduction of the initial CoII complex to CoI. The CoI species undergoes cyclometallation with the nitrile and acrylamide substrates

82

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 64 Co-catalyzed reductive coupling of nitriles and acrylamides.

(INT112) to generate the CoIII complex INT113. Water then hydrolyzes the metallacycle to release a keto-amide intermediate INT114. This then undergoes keto-amide cyclization (INT115) and dehydration to form the final pyrrolidinone product 243.

12.03.5 Photocatalytic reductive coupling with photoredox reagents Reductive coupling can also be achieved photochemically, where a photosensitizer absorbs light and serve as the photoreductant of the reaction. The harvesting of light energy allows the use of mild organic reductants for higher compatibility with sensitive functional groups. It can be further extended to become a catalytic process when a sacrificial reductant is used to complete the redox cycle. Compared to organic photosensitizers, photosensitizers in general have longer excited state lifetime due to facile intersystem crossing.174,175 This allows them to potentially be good photocatalysts through bimolecular electron transfer process in reductive coupling reactions. In this section, we will focus on the photocatalytic reductive coupling reaction using photoredox reagents as reductants via outer-sphere electron transfer. Stoichiometric photoreactions and photocatalytic reductive coupling with organic photosensitizers will be covered in reviews and other chapters in this book series.175 One of the limitations of photoredox catalysis with transition metal complexes is the limited range of redox potential accessible. Many of the commercialized transition metal photosensitizers for photoredox chemistry, such as [Ru(bpy)3]2+ (245, bpy ¼ 2,20 bipyridine), [Ir(ppy)2(dtbpy)]+ (246, ppy ¼ 2-phenylpyridine, dtbpy ¼ 4,40 -di(tert-butyl)-2,20 -bipyridine) and their analogs, have mild photoreduction potentials between −0.8 to −1.6 V vs SCE.174,176–178 On the other hand, ketones have a wide-range of reduction potentials depending on the substituents, ranging from near −1.0 V to up to −2.2 V vs SCE.179 As a result, direct

Metal-Mediated Reductive C–C Coupling of p Bonds

83

photoinduced electron transfer from a photosensitizer to carbonyls has mainly been limited to electron deficient ketones or aldehydes, as shown by the early work from Pac et al. on the Ru-catalyzed photoreduction of ketones and aldehydes to alcohols.180,181 To compensate for the insufficient reduction potential, a common strategy is to apply a Bronsted acid to activate the carbonyl. In fact, it has been observed decades ago that acid additive could lower the reduction potential of carbonyl compounds and “turnon” the photoinduced electron transfer from [Ru(bpy)3]2+ to unactivated ketones.179 This demonstrates the potential of proton-coupled electron transfer (PCET) in the photoreduction of carbonyl compounds with acid additive. In such a reaction, typically a photoredox reagent would undergo reductive quenching of its photoexcited state [Mn] by a sacrificial reductant [Red] to give the reduced species [Mn−1], as shown in Fig. 65. [Mn−1] acts as the actual photoreductant to reduce the carbonyl substrate in the assistance of the acid additive HX in a PCET process. The resulting neutral ketyl radical INT116 reacts with an unsaturated substrate through radical addition to give INT117. A hydrogen atom transfer (HAT) would generate the reductive coupling product from INT117. It is common in photoredox catalysis that the sacrificial reductant also acts as the hydrogen source in HAT and the regeneration of acid additive. The PCET strategy has been recently demonstrated by a Ru-catalyzed intramolecular reductive coupling between tethered acrylates and unactivated ketones 248 (Fig. 66).182 In this reaction, the cis- reductive coupling product would further undergo lactone formation to give 250. It was found that the stronger photoreductants Ir(ppy)2(dtbpy)PF6 (246) and Ir(ppy)3 can improve the reaction yield and turn-on the PCET of the weaker Brønsted acid additive lutidine
HBF4. Benefiting from the PCET strategy, the reaction can be performed on a wide scope of ketones, including electron rich ketones (248, R ¼ p-MeOC6H4) that has much higher reduction potentials than the photoredox catalyst being used. Mechanistic studies suggest that the PCET is a concerted event by ruling out the stepwise process through Stern-Volmer fluorescence quenching experiments and pKa comparisons. The PCET strategy has been further developed to be enantioselective by using a chiral phosphoric acid additive (Fig. 67).183 It was proposed that after the proton transfer in the PCET, the resulting phosphate would be bound to the ketyl O-H through hydrogen bond (INT118). In the case when chiral phosphoric acid is used, enantioselectivity could be induced in the subsequent radical addition if it occurs within the time scale the hydrogen bond interaction lasts. An aza-pinacol cyclization of tethered ketone-aldimine 252 was used as a model reaction to study the selectivity induced by substituted BINOL-phosphoric acids, where Ph3Si-substituted BINOL-phosphoric acid L15 was found to be the most enantioselective. The ketone scope revealed sterically hindered substituents, such as ortho-substituted phenyl, would lead to lowered reactivity while the selectivity would not be hampered. DFT and control reactions support the mechanism in that the neutral ketyl radical forms a reasonably strong hydrogen bond with phosphate, and that only one molecule of chiral phosphate is involved in the radical addition step. More recently, photoreductive pinacol coupling has been extended to the intermolecular coupling between unactivated aldehydes, ketones and aldimines (255, 258) (Fig. 68, top).184 The photoredox catalyst 256 (E1/2red ¼ −1.31 vs SCE), similar to

Fig. 65 General mechanism of photocatalytic reductive coupling of carbonyl compounds, and common transition metal photoredox catalysts.

Fig. 66 Photocatalytic reductive cyclization of tethered acrylate-ketones based on PCET strategy.

84

Metal-Mediated Reductive C–C Coupling of p Bonds

Fig. 67 Enantioselective photocatalytic reductive cyclization with a chiral phosphoric acid.

Fig. 68 Ir-catalyzed photoreductive pinacol coupling of ketones, aldehydes and aldimines.

Metal-Mediated Reductive C–C Coupling of p Bonds

85

the previous studies, is no match from the reduction potentials of many of the substrates such as benzaldehyde (E1/2red ¼ −1.73 V vs SCE) and acetophenone (Ered 1/2 ¼ − 2.10 V vs SCE). Two mechanisms (Fig. 68, middle) were proposed for the reductive coupling of carbonyl to ketyl radical through two-center three-electron interaction with amine radical cation (INT120) or hydrogen bond with a-ammonium radical (INT122). Brønsted acid additive oxalic acid and (PhO)2PO2H could promote the reaction whereas K2CO3 and K3PO4 were found to be suppressive (Fig. 68, bottom), indicating that the carbonyl is reductively activated through PCET with INT122 being involved. Acid-assisted photoreductive activation has also been applied to a,b-unsaturated ketones. While Lewis acid additives give formal [2 + 2] cycloaddition products through stepwise radical additions (261, Fig. 69 left), Brønsted acid additives lead to reductive cyclization instead (262, Fig. 69 right).185,186 It was proposed that the protonation of carbonyl occurs prior to the reduction of the a,b-unsaturated ketone moiety, namely a stepwise proton-transfer/electron-transfer PCET instead of a concerted PCET. iPr2NEt is used as the sacrificial reductant in the reaction in the reductive quenching of the photoredox catalyst. Various enones with trans-alkenes (260) can undergo intramolecular photoreductive cyclization to form trans-1,2-disubstituted cyclopentanes 262 in high yields and good diastereoselectivity. The reaction outcome of Lewis acid assisted photoreduction of a,b-unsaturated ketone will also be largely affected by the absence of linker on the substrates. An intermolecular [3 + 2] reductive cyclization (264) was observed when chalcone 263 was used, instead of the expected [2 + 2] cycloaddition product 265 from tethered bis(enone) substrates (Fig. 70).187 It was proposed that after the

Fig. 69 Acid-assisted photocatalysis of alkene-tethered a,b-unsaturated ketones. Left: Lewis acid induced formal [2 + 2] cycloaddition. Right: Brønsted acid induced reductive cyclization.

Fig. 70 Sm-promoted intermolecular [3 + 2] reductive cyclization of chalcones.

86

Metal-Mediated Reductive C–C Coupling of p Bonds

photoreduction, radical anion INT123 would undergo bimolecular radical coupling to give dianionic INT124. The following mono-protonation triggers aldol cyclization (INT125), resulting in the [3 + 2] adduct 264 after another protonation. Notably, SmIII is involved not only in the cyclization but also the reduction of chalcone. However, a formal SmII intermediate was not presented as the process is proposed to be a ligand-centered reduction, different from the previously mentioned recent SmII/III redox catalysis (Section 12.03.2.3, Sm-catalyzed reductive cyclization of 54). The chemoselectivity of the reaction can be tuned by the acid additive, where using the Brønsted acid CH3CO2H to replace the Lewis acid will lead to di-protonation of INT124 which cannot undergo further cyclization, leaving a mixture of diketone 266 and the reductive pinacol coupling of 263 as products. Interestingly, replacing aryl to methyl on the ketone (263, R1 ¼ Me) will let the reaction stop before the cyclization and yield 266, showing the aryl group being crucial to the stability of the dianion INT124.

12.03.6 Conclusion Metal-mediated reductive coupling has seen many advances in the past decade. Stereoselectivity continues to be one of the central foci for reductive coupling across all substrates and metal classes. Increasing interest has focused on base metal catalysis, where Fe, Co and Ni have met their prosper. As a result of the decreasing study of noble metal catalysis, H2 has seen less appearance as the reductant in reductive coupling compared to earlier studies. In contrast, a number of new strategies for mild and inexpensive reductants has been applied, including B2pin2, iPrOH via transfer hydrogenation, and internal redox methods. As an emerging field, photoredox catalysis has also sought its application in reductive coupling, where acid additives significantly widen its substrate scope to unactivated carbonyls and imines via PCET.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

von Korff, M.; Sander, T. Sci. Rep. 2019, 9 (1), 967. Ertl, P.; Schuffenhauer, A. J. Cheminf. 2009, 1 (1), 8. Hsu, I. T.; Tomanik, M.; Herzon, S. B. Acc. Chem. Res. 2021, 54 (4), 903–916. Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509 (7500), 299–309. Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1 (1), 5–7. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102 (8), 2693–2698. Procter, D. J.; Flowers, R. A.; Skrydstrup, T. Organic Synthesis Using Samarium Diiodide: A Practical Guide; The Royal Society of Chemistry, 2009. Szostak, M.; Procter, D. J. Angew. Chem. Int. Ed. 2012, 51 (37), 9238–9256. Péter, Á.; Procter, D. J. Chim. Int. J. Chem. 2020, 74 (1), 18–22. Evans, W. J.; Keyer, R. A.; Ziller, J. W. Organometallics 1993, 12 (7), 2618–2633. Evans, W. J.; Keyer, R. A.; Ziller, J. W. Organometallics 1990, 9 (9), 2628–2631. Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev. 2014, 114 (11), 5959–6039. Krische, M. J.; Jang, H.-Y. Comprehensive Organometallic Chemistry III; Elsevier, 2007; pp 493–536. Sono, M.; Hanamura, S.; Furumaki, M.; Murai, H.; Tori, M. Org. Lett. 2011, 13 (21), 5720–5723. Ruscoe, R. E.; Fazakerley, N. J.; Huang, H.; Flitsch, S.; Procter, D. J. Chem. A Eur. J. 2016, 22 (1), 116–119. Beemelmanns, C.; Reissig, H.-U. Chem. A Eur. J. 2015, 21 (23), 8416–8425. Chciuk, T. V.; Flowers, R. A. J. Am. Chem. Soc. 2015, 137 (35), 11526–11531. Pan, S.; Gao, B.; Hu, J.; Xuan, J.; Xie, H.; Ding, H. Chem. A Eur. J. 2016, 22 (3), 959–970. Fukaya, K.; Tanaka, Y.; Sato, A. C.; Kodama, K.; Yamazaki, H.; Ishimoto, T.; Nozaki, Y.; Iwaki, Y. M.; Yuki, Y.; Umei, K.; et al. Org. Lett. 2015, 17 (11), 2570–2573. Pan, S.; Xuan, J.; Gao, B.; Zhu, A.; Ding, H. Angew. Chem. Int. Ed. 2015, 54 (23), 6905–6908. Suizu, H.; Shigeoka, D.; Aoyama, H.; Yoshimitsu, T. Org. Lett. 2015, 17 (1), 126–129. Shen, Y.; Li, L.; Pan, Z.; Wang, Y.; Li, J.; Wang, K.; Wang, X.; Zhang, Y.; Hu, T.; Zhang, Y. Org. Lett. 2015, 17 (21), 5480–5483. Chuang, H.-Y.; Isobe, M. J. Org. Chem. 2017, 82 (4), 2045–2058. Su, F.; Lu, Y.; Kong, L.; Liu, J.; Luo, T. Angew. Chem. Int. Ed. 2018, 57 (3), 760–764. Gao, Y.; Wei, Y.; Ma, D. Org. Lett. 2019, 21 (5), 1384–1387. Turlik, A.; Chen, Y.; Scruse, A. C.; Newhouse, T. R. J. Am. Chem. Soc. 2019, 141 (20), 8088–8092. Kasamatsu, A.; Kuwabara, M.; Matsuzawa, A.; Sugita, K. Tetrahedron Lett. 2019, 60 (2), 113–114. Classen, M. J.; Böcker, M. N. A.; Roth, R.; Amberg, W. M.; Carreira, E. M. J. Am. Chem. Soc. 2021, 143 (22), 8261–8265. Komine, K.; Lambert, K. M.; Savage, Q. R.; Cox, J. B.; Wood, J. L. Chem. Sci. 2020, 11 (35), 9488–9493. Law, K. R.; McErlean, C. S. P. Tetrahedron Lett. 2016, 57 (29), 3113–3116. Shi, S.; Szostak, M. Org. Lett. 2015, 17 (20), 5144–5147. Rao, C. N.; Lentz, D.; Reissig, H.-U. Angew. Chem. Int. Ed. 2015, 54 (9), 2750–2753. Szostak, M.; Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2014, 136 (23), 8459–8466. Just-Baringo, X.; Morrill, C.; Procter, D. J. Tetrahedron 2016, 72 (48), 7691–7698. Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. Chem. A Eur. J. 2016, 22 (34), 11949–11953. Just-Baringo, X.; Clark, J.; Gutmann, M. J.; Procter, D. J. Angew. Chem. Int. Ed. 2016, 55 (40), 12499–12502. Mehta, G.; Singh, V. Chem. Rev. 1999, 99 (3), 881–930. Yalavac, I.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Chem. Commun. 2014, 50 (85), 12863–12866. Kern, N.; Plesniak, M. P.; McDouall, J. J. W.; Procter, D. J. Nat. Chem. 2017, 9 (12), 1198–1204. Lai, Y.; Sun, L.; Sit, M. K.; Wang, Y.; Dai, W.-M. Tetrahedron 2016, 72 (5), 664–673. Plesniak, M. P.; Just-Baringo, X.; Ortu, F.; Mills, D. P.; Procter, D. J. Chem. Commun. 2016, 52 (92), 13503–13506. Pu, L.-Y.; Yang, F.; Chen, J.-Q.; Xiong, Y.; Bin, H.-Y.; Xie, J.-H.; Zhou, Q.-L. Org. Lett. 2020, 22 (19), 7526–7530. Pu, L.; Yang, F.; Chen, J.; Xiong, Y.; Xie, J.; Zhou, Q. Adv. Synth. Catal. 2021, 363 (3), 785–790. Nagatomo, M.; Hagiwara, K.; Masuda, K.; Koshimizu, M.; Kawamata, T.; Matsui, Y.; Urabe, D.; Inoue, M. Chem. A Eur. J. 2016, 22 (1), 222–229.

Metal-Mediated Reductive C–C Coupling of p Bonds 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117.

87

Zhang, Y.; Milkovits, A.; Agarawal, V.; Taylor, C. A.; Snyder, S. A. Angew. Chem. Int. Ed. 2021, 60 (20), 11127–11132. Aretz, C. D.; Escobedo, H.; Cowen, B. J. Eur. J. Org. Chem. 2018, 2018 (16), 1880–1884. Kise, N.; Tuji, T.; Sakurai, T. Tetrahedron Lett. 2016, 57 (16), 1790–1793. Maity, S.; Flowers, R. A. J. Am. Chem. Soc. 2019, 141 (7), 3207–3216. Qiu, R.; Chen, Y.; Yin, S.-F.; Xu, X.; Au, C.-T. RSC Adv. 2012, 2 (29), 10774. Morss, L. R. Chem. Rev. 1976, 76 (6), 827–841. Aspinall, H. C.; Greeves, N.; Valla, C. Org. Lett. 2005, 7 (10), 1919–1922. Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, E.; Flowers, R. A. J. Am. Chem. Soc. 2008, 130 (23), 7228–7229. Grant, L. N.; Miehlich, M. E.; Meyer, K.; Mindiola, D. J. Chem. Commun. 2018, 54 (16), 2052–2055. Kurogi, T.; Miehlich, M. E.; Halter, D.; Mindiola, D. J. Organometallics 2018, 37 (2), 165–167. Chomitz, W. A.; Sutton, A. D.; Krinsky, J. L.; Arnold, J. Organometallics 2009, 28 (12), 3338–3349. Waratuke, S. A.; Johnson, E. S.; Thorn, M. G.; Fanwick, P. E.; Rothwell, I. P. Chem. Commun. 1996, (23), 2617. Kamitani, M.; Searles, K.; Chen, C. H.; Carroll, P. J.; Mindiola, D. J. Organometallics 2015, 34 (11), 2558–2566. Cavaliere, V. N.; Crestani, M. G.; Pinter, B.; Pink, M.; Chen, C.-H.; Baik, M.-H.; Mindiola, D. J. J. Am. Chem. Soc. 2011, 133 (28), 10700–10703. Crestani, M. G.; Hickey, A. K.; Gao, X.; Pinter, B.; Cavaliere, V. N.; Ito, J.-I.; Chen, C.-H.; Mindiola, D. J. J. Am. Chem. Soc. 2013, 135 (39), 14754–14767. Rassadin, V. A.; Six, Y. Tetrahedron 2014, 70 (4), 787–794. Negishi, E.-I.; Takahashi, T. Acc. Chem. Res. 1994, 27 (5), 124–130. Cohen, S. A.; Bercaw, J. E. Organometallics 1985, 4 (6), 1006–1014. Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am. Chem. Soc. 1987, 109 (8), 2544–2546. Reichard, H. A.; McLaughlin, M.; Chen, M. Z.; Micalizio, G. C. Eur. J. Org. Chem. 2010, 2010 (3), 391–409. Perez, L. J.; Shimp, H. L.; Micalizio, G. C. J. Org. Chem. 2009, 74 (19), 7211–7219. Greszler, S. N.; Reichard, H. A.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134 (5), 2766–2774. Jeso, V.; Aquino, C.; Cheng, X.; Mizoguchi, H.; Nakashige, M.; Micalizio, G. C. J. Am. Chem. Soc. 2014, 136 (23), 8209–8212. Cheng, X.; Micalizio, G. C. Org. Lett. 2014, 16 (19), 5144–5147. Cassidy, J. S.; Mizoguchi, H.; Micalizio, G. C. Tetrahedron Lett. 2016, 57 (34), 3848–3850. Cai, B.; Panek, J. S. J. Am. Chem. Soc. 2020, 142 (8), 3729–3735. Nguyen, T.; Hartmann, J.; Enders, D. Synthesis (Stuttg). 2013, 45 (07), 845–873. Bodinier, F.; Sanogo, Y.; Ardisson, J.; Lannou, M.-I.; Sorin, G. Chem. Commun. 2021, 57 (29), 3603–3606. Kiel, G. R.; Ziegler, M. S.; Tilley, T. D. Angew. Chem. Int. Ed. 2017, 56 (17), 4839–4844. Kiel, G. R.; Patel, S. C.; Smith, P. W.; Levine, D. S.; Tilley, T. D. J. Am. Chem. Soc. 2017, 139 (51), 18456–18459. Tian, G.-Q.; Kaiser, T.; Yang, J. Org. Lett. 2010, 12 (2), 288–290. Sanogo, Y.; Othman, R. B.; Dhambri, S.; Selkti, M.; Jeuken, A.; Prunet, J.; Férézou, J.-P.; Ardisson, J.; Lannou, M.-I.; Sorin, G. J. Org. Chem. 2019, 84 (9), 5821–5830. Chen, M. Z.; McLaughlin, M.; Takahashi, M.; Tarselli, M. A.; Yang, D.; Umemura, S.; Micalizio, G. C. J. Org. Chem. 2010, 75 (23), 8048–8059. Okamoto, S.; He, J.-Q.; Ohno, C.; Oh-Iwa, Y.; Kawaguchi, Y. Tetrahedron Lett. 2010, 51 (2), 387–390. Valadez, T. N.; Norton, J. R.; Neary, M. C. J. Am. Chem. Soc. 2015, 137 (32), 10152–10155. Blenkers, J.; Hessen, B.; Van Bolhuis, F.; Wagner, A. J.; Teuben, J. H. Organometallics 1987, 6 (3), 459–469. Becker, L.; Arndt, P.; Jiao, H.; Spannenberg, A.; Rosenthal, U. Angew. Chem. Int. Ed. 2013, 52 (43), 11396–11400. Becker, L.; Strehler, F.; Korb, M.; Arndt, P.; Spannenberg, A.; Baumann, W.; Lang, H.; Rosenthal, U. Chem. A Eur. J. 2014, 20 (11), 3061–3068. Finn, P. B.; Derstine, B. P.; Sieburth, S. M. Angew. Chem. Int. Ed. 2016, 55 (7), 2536–2539. Fawcett, F. S. Chem. Rev. 1950, 47 (2), 219–274. Streuff, J.; Feurer, M.; Bichovski, P.; Frey, G.; Gellrich, U. Angew. Chem. Int. Ed. 2012, 51 (34), 8661–8664. Miyasaka, A.; Amaya, T.; Hirao, T. Chem. A Eur. J. 2014, 20 (6), 1615–1621. Streuff, J. Chem. Rec. 2014, 14 (6), 1100–1113. Hunt, A. J.; Farmer, T. J.; Clark, J. H. Element Recovery and Sustainability; The Royal Society of Chemistry, 2013; pp 1–28. Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47 (18), 3317–3321. Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41 (11), 1500–1511. Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37 (9), 653–661. Casnati, A.; Lanzi, M.; Cera, G. Molecules 2020, 25 (17), 3889. Fürstner, A. ACS Cent. Sci. 2016, 2 (11), 778–789. Lin, A.; Zhang, Z.-W.; Yang, J. Org. Lett. 2014, 16 (2), 386–389. Fürstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130 (27), 8773–8787. Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136 (4), 1304–1307. Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. Nature 2014, 516 (7531), 343–348. Wang, D.; Astruc, D. Chem. Rev. 2015, 115 (13), 6621–6686. Tyagi, N.; Borah, G.; Patel, P.; Ramaiah, D. Ruthenium—An Element Loved by Researchers [Working Title]; IntechOpen, 2021. Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J. Science 2016, 354 (6310), aah5133. McInturff, E. L.; Yamaguchi, E.; Krische, M. J. J. Am. Chem. Soc. 2012, 134 (51), 20628–20631. Sam, B.; Montgomery, T. P.; Krische, M. J. Org. Lett. 2013, 15 (14), 3790–3793. Leung, J. C.; Patman, R. L.; Sam, B.; Krische, M. J. Chem. A Eur. J. 2011, 17 (44), 12437–12443. Geary, L. M.; Leung, J. C.; Krische, M. J. Chem. A Eur. J. 2012, 18 (52), 16823–16827. Yamashita, K.; Nagashima, Y.; Yamamoto, Y.; Nishiyama, H. Chem. Commun. 2011, 47 (41), 11552. Mecking, S. Angew. Chem. Int. Ed. 2001, 40 (3), 534–540. Jeganmohan, M.; Cheng, C.-H. Chem. A Eur. J. 2008, 14 (35), 10876–10886. Gandeepan, P.; Cheng, C.-H. Acc. Chem. Res. 2015, 48 (4), 1194–1206. Montgomery, J. Acc. Chem. Res. 2000, 33 (7), 467–473. Montgomery, J. Angew. Chem. Int. Ed. 2004, 43 (30), 3890–3908. Ikeda, S. Acc. Chem. Res. 2000, 33 (8), 511–519. Broene, R. D. Metal Catalyzed Reductive C–C Bond Formation; Springer: Berlin, Heidelberg, 2007; pp 209–248. Ojima, I.; Donovan, R. J.; Shay, W. R. J. Am. Chem. Soc. 1992, 114 (16), 6580–6582. Chakrapani, H.; Liu, C.; Widenhoefer, R. A. Org. Lett. 2003, 5 (2), 157–159. Park, K. H.; Kim, S. Y.; Son, S. U.; Chung, Y. K. Eur. J. Org. Chem. 2003, 2003 (22), 4341–4345. Takachi, M.; Chatani, N. Org. Lett. 2010, 12 (22), 5132–5134. Yu, M.; Yong, X.; Gao, W.; Ho, C. Chin. J. Chem. 2021, 39 (6), 1587–1592.

88 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187.

Metal-Mediated Reductive C–C Coupling of p Bonds Molander, G. A.; Retsch, W. H. J. Am. Chem. Soc. 1997, 119 (38), 8817–8825. Molander, G. A.; Retsch, W. H. J. Org. Chem. 1998, 63 (16), 5507–5516. Molander, G. A.; Corrette, C. P. J. Org. Chem. 1999, 64 (26), 9697–9703. Wakayanagi, S.; Shimamoto, T.; Chimori, M.; Yamamoto, K. Chem. Lett. 2005, 34 (2), 160–161. Xi, T.; Lu, Z. J. Org. Chem. 2016, 81 (19), 8858–8866. You, Y.; Ge, S. Angew. Chem. Int. Ed. 2021, 60 (21), 12046–12052. Fan, B.-M.; Xie, J.-H.; Li, S.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem. Int. Ed. 2007, 46 (8), 1275–1277. Denmark, S. E.; Liu, J. H.-C. J. Am. Chem. Soc. 2007, 129 (12), 3737–3744. Kochi, T.; Hamasaki, T.; Aoyama, Y.; Kawasaki, J.; Kakiuchi, F. J. Am. Chem. Soc. 2012, 134 (40), 16544–16547. Kochi, T.; Ichinose, K.; Shigekane, M.; Hamasaki, T.; Kakiuchi, F. Angew. Chem. 2019, 131 (16), 5315–5319. Zotchev, S. Curr. Med. Chem. 2003, 10 (3), 211–223. Lam, J. W. Y.; Tang, B. Z. Acc. Chem. Res. 2005, 38 (9), 745–754. Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Justus Liebigs Ann. Chem. 1948, 560 (1), 1–92. Wender, P. A.; Christy, J. P.; Lesser, A. B.; Gieseler, M. T. Angew. Chem. Int. Ed. 2009, 48 (41), 7687–7690. Goswami, A.; Ito, T.; Saino, N.; Kase, K.; Matsuno, C.; Okamoto, S. Chem. Commun. 2009, (4), 439–441. Wu, T.-C.; Chen, J.-J.; Wu, Y.-T. Org. Lett. 2011, 13 (18), 4794–4797. Zhang, G.; Xie, Y.; Wang, Z.; Liu, Y.; Huang, H. Chem. Commun. 2015, 51 (10), 1850–1853. Liu, Y.; Zhang, G.; Huang, H. Org. Lett. 2017, 19 (24), 6674–6677. Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120 (31), 8007–8008. Oh, C. H.; Jung, H. H.; Kim, J. S.; Cho, S. W. Angew. Chem. Int. Ed. 2000, 39 (4), 752–755. Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115 (21), 9421–9438. Fairlamb, I. J. S. Angew. Chem. Int. Ed. 2004, 43 (9), 1048–1052. Jang, H.-Y.; Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. J. Am. Chem. Soc. 2005, 127 (17), 6174–6175. Chen, M.; Weng, Y.; Guo, M.; Zhang, H.; Lei, A. Angew. Chem. Int. Ed. 2008, 47 (12), 2279–2282. Meyer, C. C.; Ortiz, E.; Krische, M. J. Chem. Rev. 2020, 120 (8), 3721–3748. Streuff, J.; Gansäuer, A. Angew. Chem. Int. Ed. 2015, 54 (48), 14232–14242. Guo, H.-C.; Ma, J.-A. Angew. Chem. Int. Ed. 2006, 45 (3), 354–366. Holmes, M.; Schwartz, L. A.; Krische, M. J. Chem. Rev. 2018, 118 (12), 6026–6052. Montgomery, J.; Sormunen, G. J. Metal Catalyzed Reductive C–C Bond Formation; Springer: Berlin, Heidelberg, 2007; pp 1–23. Iida, H.; Krische, M. J. Metal Catalyzed Reductive C–C Bond Formation; Springer: Berlin, Heidelberg, 2007; pp 77–104. Nishiyama, H.; Shiomi, T. Metal Catalyzed Reductive C–C Bond Formation; Springer: Berlin, Heidelberg, 2007; pp 105–137. Breit, B. Metal Catalyzed Reductive C–C Bond Formation; Springer: Berlin, Heidelberg, 2007; pp 139–172. Kimura, M.; Tamaru, Y. Metal Catalyzed Reductive C–C Bond Formation; Springer: Berlin, Heidelberg, 2007; pp 173–207. Juliá-Hernández, F.; Gaydou, M.; Serrano, E.; van Gemmeren, M.; Martin, R. Top. Curr. Chem. 2016, 374 (4), 45. Ng, S.-S.; Ho, C.-Y.; Schleicher, K. D.; Jamison, T. F. Pure Appl. Chem. 2008, 80 (5), 929–939. Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, (43), 4441. Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137 (14), 4666–4669. Yang, Y.; Perry, I. B.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138 (31), 9787–9790. Hayashi, Y.; Hoshimoto, Y.; Kumar, R.; Ohashi, M.; Ogoshi, S. Chem. Commun. 2016, 52 (37), 6237–6240. Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119 (38), 9065–9066. Chevliakov, M. V.; Montgomery, J. Angew. Chem. Int. Ed. 1998, 37 (22), 3144–3146. Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129 (31), 9568–9569. Rhee, J. U.; Krische, M. J. J. Am. Chem. Soc. 2006, 128 (33), 10674–10675. Yang, Y.; Zhu, S.-F.; Zhou, C.-Y.; Zhou, Q.-L. J. Am. Chem. Soc. 2008, 130 (43), 14052–14053. Liu, G.; Fu, W.; Mu, X.; Wu, T.; Nie, M.; Li, K.; Xu, X.; Tang, W. Commun. Chem. 2018, 1 (1), 90. Herath, A.; Li, W.; Montgomery, J. J. Am. Chem. Soc. 2008, 130 (2), 469–471. Beaver, M. G.; Jamison, T. F. Org. Lett. 2011, 13 (15), 4140–4143. Bausch, C. C.; Patman, R. L.; Breit, B.; Krische, M. J. Angew. Chem. Int. Ed. 2011, 50 (25), 5687–5690. Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.; Krische, M. J. Science 2012, 336 (6079), 324–327. Yao, W.-W.; Li, R.; Li, J.-F.; Sun, J.; Ye, M. Green Chem. 2019, 21 (9), 2240–2244. Tanaka, R.; Noguchi, K.; Tanaka, K. J. Am. Chem. Soc. 2010, 132 (4), 1238–1239. Spinello, B. J.; Wu, J.; Cho, Y.; Krische, M. J. J. Am. Chem. Soc. 2021, 143 (34), 13507–13512. Li, W.; Montgomery, J. Chem. Commun. 2012, 48 (8), 1114–1116. Zhou, Z.; Chen, J.; Chen, H.; Kong, W. Chem. Sci. 2020, 11 (37), 10204–10211. Shareef, A.-R.; Sherman, D. H.; Montgomery, J. Chem. Sci. 2012, 3 (3), 892–895. Wong, Y.-C.; Parthasarathy, K.; Cheng, C.-H. J. Am. Chem. Soc. 2009, 131 (51), 18252–18253. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113 (7), 5322–5363. Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116 (17), 10075–10166. Singh, A.; Teegardin, K.; Kelly, M.; Prasad, K. S.; Krishnan, S.; Weaver, J. D. J. Organomet. Chem. 2015, 776, 51–59. Pavlishchuk, V. V.; Addison, A. W. Inorg. Chim. Acta 2000, 298 (1), 97–102. Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159–244. Fukuzumi, S.; Ishikawa, K.; Hironaka, K.; Tanaka, T. J. Chem. Soc. Perkin Trans. 2 1987, (6), 751. Ishitani, O.; Pac, C.; Sakurai, H. J. Org. Chem. 1983, 48 (17), 2941–2942. Ishitani, O.; Yanagida, S.; Takamuku, S.; Pac, C. J. Org. Chem. 1987, 52 (13), 2790–2796. Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135 (27), 10022–10025. Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135 (47), 17735–17738. Nakajima, M.; Fava, E.; Loescher, S.; Jiang, Z.; Rueping, M. Angew. Chem. Int. Ed. 2015, 54 (30), 8828–8832. Yoon, T. P. Acc. Chem. Res. 2016, 49 (10), 2307–2315. Du, J.; Espelt, L. R.; Guzei, I. A.; Yoon, T. P. Chem. Sci. 2011, 2 (11), 2115. Zhao, G.; Yang, C.; Guo, L.; Sun, H.; Lin, R.; Xia, W. J. Org. Chem. 2012, 77 (14), 6302–6306.

12.04

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Kirsten A Hewitt, Patricia C Lin, Ethan TA Raffman, and Elizabeth R Jarvo, Department of Chemistry, University of California, Irvine, CA, United States © 2022 Elsevier Ltd. All rights reserved.

12.04.1 Introduction 12.04.2 Proposed mechanisms of cross-electrophile coupling (XEC) reactions 12.04.3 XEC reactions employing stoichiometric reductants 12.04.3.1 Reactions of C(sp2) electrophiles (Type A) 12.04.3.1.1 Dimerization reactions of C(sp2) electrophiles 12.04.3.1.2 Cross-selective XEC reactions of C(sp2) electrophiles 12.04.3.2 XEC reactions of C(sp2) and C(sp3) electrophiles (Type B) 12.04.3.2.1 XEC reactions of aryl and vinyl electrophiles with C(sp3) electrophiles 12.04.3.2.2 XEC reactions of acyl electrophiles with C(sp3) electrophiles 12.04.3.2.3 Cyclization reactions of C(sp2) and C(sp3) electrophiles 12.04.3.3 XEC reactions of C(sp3) electrophiles (Type C) 12.04.3.3.1 Dimerization reactions of C(sp3) electrophiles 12.04.3.3.2 Cross-selective XEC reactions of C(sp3) electrophiles 12.04.3.3.3 XEC reactions of allylic trifluoromethyl electrophiles and C(sp3) electrophiles 12.04.3.3.4 Cyclization reactions of C(sp3) electrophiles 12.04.3.3.5 XEC reactions of C(sp) electrophiles (Type D) 12.04.4 XEC reactions employing electrochemical reductions 12.04.4.1 XEC reactions of C(sp2) electrophiles (Type A) 12.04.4.2 XEC reactions of C(sp2) and C(sp3) electrophiles (Type B) 12.04.4.3 XEC reactions of C(sp3) electrophiles (Type C) 12.04.5 XEC reactions in natural product syntheses 12.04.6 Closing remarks Acknowledgment References

89 90 92 92 92 93 94 94 98 99 100 100 101 102 103 104 105 105 106 107 107 110 110 110

12.04.1 Introduction Cross-electrophile coupling (XEC) reactions are excellent methods to construct carbon–carbon bonds from widely commercially available electrophiles.1–14 An advantage of XEC reactions is that they do not require preformed organometallic reagents. Typically, the organometallic reagents used in traditional cross-coupling (XC) reactions are prepared from the corresponding alkyl or aryl halides, whereas XEC reactions allow for the direct conversion of these electrophiles. Unlike traditional XC reactions where the electrophile favors oxidative addition and the organometallic reagent favors transmetallation, XEC reactions contain two electrophiles that both favor oxidative addition. Therefore, the transition metal catalyst must be able to differentiate the two electrophiles in order to obtain cross-selectivity. This inherent challenge resulted in delayed efforts to explore and optimize these reactions when compared to traditional XC reactions. The strategies for optimal cross-selectivity that have been developed include electronic differentiation of starting materials, steric matching between catalyst and substrate, and tethering of the electrophiles.1,8 In this chapter, inter- and intramolecular XEC reactions will be discussed. First, dimerization and cross-selective XEC reactions of C(sp2) electrophiles, including aryl and vinyl halides will be examined (Scheme 1, Type A). The next class of XEC reactions between C(sp2) and C(sp3) electrophiles, inherently cross-selective reactions, will be presented (Type B). Then, inter- and intramolecular reactions of C(sp3) electrophiles will be discussed (Type C). Finally, the least common XEC reaction, coupling of C(sp) and C(sp3) electrophiles, are outlined (Type D). The article will be broken into two sections to highlight the use of stoichiometric reducing metals (Section 12.04.3) and electrochemical reductions (Section 12.04.4).

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00092-5

89

90

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Scheme 1 Patterns in cross-electrophile coupling reactions.

The focus of this article will be transition metal-catalyzed XEC reactions with stoichiometric reducing agents or electrochemical reductions to forge C–C bonds. Commonly in the literature, these transformations are referred to as “reductive coupling,” “reductive cross-coupling” or “cross-electrophile coupling” reactions. Furthermore, XEC reactions of type A are often referred to as “Ullman-type coupling” reactions.15–19 We will employ the term XEC reaction for all of these carbon–carbon bond forming reactions conducted under reducing conditions. We will not include examples of dual photoredox-transition metal catalysis for the formation of C–C bonds.20–25 In addition, reductive coupling reactions utilizing CO226–28 or carbonyls29–31 have been extensively covered elsewhere. Conjunctive or interrupted XEC reactions, where two organohalides are combined with an olefin or alkyne, will also not be included in this article.32–37

12.04.2 Proposed mechanisms of cross-electrophile coupling (XEC) reactions Several mechanisms have been proposed for XEC reactions to account for formation of the observed products.3,5,8 The mechanisms are outlined below, using as an example a nickel catalyst and a reducing metal, designated as M, to illustrate general features of each catalytic cycle. The common mechanisms include: (I) in situ formation of the organometallic reagent, (II) sequential reduction, (III) radical chain, and (IV) oxidative addition, intramolecular SN2 (Fig. 1). All mechanisms share certain key features with traditional cross-coupling (XC) reactions such as oxidative addition (OA) and reductive elimination (RE) steps.38 As in XC reactions, oxidative events can occur via polar or radical pathways. However in XEC reactions, excluding mechanism (I), there are no stoichiometric organometallic reagents, and reduction events are crucial for product formation and catalytic turnover. In addition, the reduction steps can be achieved with stoichiometric reducing metals, such as Zn or Mn, or electrochemically. When stoichiometric reducing metals, such as Zn, are employed, it is feasible to propose in situ formation of organometallic reagents (Fig. 1, I). The catalytic cycle is then that of a traditional cross-coupling reaction, wherein oxidative addition occurs with one electrophile. Transmetallation (TM) occurs with the organometallic reagent that was formed in situ. Finally, reductive elimination (RE) produces the desired C–C bond. Identifying this mechanistic manifold is often reasonably straightforward by substitution of one electrophile and the reducing metal with the corresponding organometallic reagent. An alternative test to exclude this mechanism is to demonstrate that the XEC reaction can be conducted with organic reductants, such as tetrakis(dimethylamino)ethylene (TDAE), which is inconsistent with the formation of organometallic reagent in situ.2,39 The majority of XEC reactions typically undergo either sequential reduction or radical chain mechanisms (Fig. 1, II and III). The Weix and Durandetti groups have performed extensive studies to elucidate the key steps of these mechanisms.1,5,40,41 The two catalytic cycles are similar, in that both involve two oxidative events and two reductive events, and one oxidative event often involves formation of an alkyl radical. In a sequential reduction mechanism (Fig. 1, II), one electrophile selectively engages the catalyst for oxidative addition, frequently by a concerted oxidative addition. This step is followed by reduction of the catalyst to form the Ni(I) intermediate. A second OA then occurs, and when C(sp3) electrophiles are employed, this step frequently involves halogen atom abstraction and a short-lived organic radical.42,43 Subsequent reductive elimination produces the C–C bond. A second reduction step turns over the catalyst.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

91

In contrast, the radical chain mechanism involves a radical propagation step (Fig. 1, III). The Ni(II) intermediate generated from oxidative addition captures the radical intermediate and leads to a Ni(III) complex. This species promptly undergoes reductive elimination, generating the desired product and a Ni(I) intermediate.44,45 Next, the Ni(I) species generates the alkyl radical via halogen atom abstraction. The resulting Ni(II) halide complex can be reduced to Ni(0) to turnover the catalytic cycle. Recently, the Jarvo and Hong groups reported a distinct mechanism for the intramolecular XEC reaction (Fig. 1, IV).46,47 In contrast to the sequential reduction and radical chain mechanisms, this mechanism involves a single oxidative addition and reductive event. These reactions have employed methylmagnesium iodide, not as a coupling partner, but as the terminal reducing agent. In this mechanism, oxidative addition selectively occurs at the benzylic or secondary electrophile. Transmetallation with the Grignard reagent produces the key alkylnickel intermediate which undergoes the proposed intramolecular SN2 reaction to afford the cyclized product. Subsequent transmetallation and reductive elimination of ethane regenerates the active nickel catalyst. The mechanism for a given XEC reaction can be difficult to predict by simple inspection of the starting materials, catalyst, and reagents. In particular, deciphering whether the sequential reduction or radical chain mechanism is operative is quite difficult and requires extensive mechanistic studies. However, it is crucial to identify and elucidate the key mechanistic steps as it allows for development of new methods that build upon these elementary steps.

I. In Situ Formation of Organometallic Reagent

II. Sequential Reduction 1/

Ni0Ln

R R'

R X

1/

2

2

MIIX2 Ni0Ln

M0

1st OA

2nd Red. RE

OA

NiILnX

R R' R NiIILn R'

XLnNiII R

XLnNiII R

1st Red.

RE X R NiIIILn R'

TM

MIIX

R'

Red.

· R'

Radical Generation

R X

Me Me

Ni0Ln

XLnNiII R

Radical Addition

red. by RE

Me NiIILn Me

NiILnX

2

MIIX2

X ( )n

R

XLnNiIII R R' RE

OA X NiIILn X R

MgX2 2nd

( )n

TM

MeMgX 1st TM

MeMgX X

1/

OA

NiIILnX2

R'

M0

X

X Ni0Ln

M0

2

IV. Oxidative Addition, SN2

III. Radical Chain MIIX2

1/

LnNiI R

2nd OA

II R' X R' M X M0

2

R X

Me NiIILn X Intramolecular SN2

MgX2 Me Ln NiII R

X

( )n

R R' R

( )n

Fig. 1 Proposed mechanisms for cross-electrophile coupling (XEC) reactions. OA ¼ oxidative addition, RE ¼ reductive elimination, Red. by RE ¼ reduction.

92

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

12.04.3 XEC reactions employing stoichiometric reductants 12.04.3.1 Reactions of C(sp2) electrophiles (Type A) 12.04.3.1.1

Dimerization reactions of C(sp2) electrophiles

The reductive dimerization reaction of aryl halides has been known since the early 19th century when Ullman and co-workers reported the first reductive dimerization reaction of an aryl bromide in the presence of copper powder in 1901.15–19,48 This original report employed stoichiometric copper powder and high temperatures (>200  C). Since this publication, stoichiometric and catalytic variations have been developed to accomplish C–C bond formation. A wide range of aryl, heteroaryl, and vinyl halides and pseudohalides have been employed (Table 1).

Table 1 Entry

Dimerization reactions of C(sp2) electrophiles. Starting material 1a

Starting material 2

Metal catalyst

Reducing agent

References

1

Ni, Pd, Co

Cu, Zn, Mn, TDAE, Mg, LiH, Li

39,48–69

2

Ni, Pd

Cu, Zn, polyethylene glycol

51,55–64,67,68,70–77

3

Cu, Ni

Zn

50,51,55,64

4

Cu, Ni

Zn

51,55

a

X ¼ I, Br, Cl, OTs, OTf, or OMs.

Early examples of reductive dimerization reactions were mediated by reducing metals such as Cu, Ni and Pd to accomplish the C–C bond formation.39,48–51,53–55 In 1975, Kende and co-workers reported the synthesis of highly substituted biaryls with one equivalent of a nickel triphenylphosphine complex (Eq. 1).50

ð1Þ

In addition, stoichiometric metals have been utilized to synthesize dimeric heterocycles.70 Asymmetric variations have been developed for the synthesis of biphenyl compounds by incorporating a chiral auxiliary on the aryl halide moiety.71–74 This strategy has been applied to the total synthesis of axially chiral natural products, such as o-permethyl tellimagrandin I (vide infra).78 It was realized in the early 1990s that catalytic quantities of metal complexes could also accomplish biaryl bond formation, if a stoichiometric amount of a sacrificial reducing agent was included.51,52,56–69 Such bimetallic methods are advantageous because an abundant reducing agent can be employed to affect turnover of a transition-metal catalyst that is more precious and/or more toxic.79 Typically zinc and manganese powder are utilized as the sacrificial reductants in XEC reactions. As an example, in 1995 Percec and co-workers reported the dimerization reaction of aryl sulfonates in the presence of a nickel catalyst and zinc powder (Eq. 2).59 In addition to aryl electrophiles, the reductive dimerization reactions of vinyl halides have been employed to afford symmetrical dienes.50,51,55,64

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

93

ð2Þ

The dimerization reaction of halopyridines has also been established.58,61,67,75 This method has been employed for the synthesis of bipyridine ligands, which are a common ligand scaffold used in XEC reactions themselves.80–83 Additionally, heterocycles such as thiophene, thiazole, pyrrole, and furan undergo efficient dimerization reactions.51,55–57,64,67,68,76,77 Finally, intramolecular variations have been reported, including formation of medium-sized rings.51,55 For example, Liebeskind and co-workers demonstrated that seven-membered rings could be constructed via an intramolecular XEC reaction (Eq. 3).55

ð3Þ

12.04.3.1.2

Cross-selective XEC reactions of C(sp2) electrophiles

The XEC reaction between two different C(sp2) hybridized electrophiles was not realized until the early 2000s.84 Since then, a wide range of cross-selective reactions that combine aryl halides and pseudohalides, as well as vinyl halides and pseudohalides, acid chlorides, and enones have been reported (Table 2). Table 2

Cross-selective XEC reactions of C(sp2) electrophiles. Metal catalyst

Reducing agent

References

1

Ni, Pd, Co, Fe

Zn, Mn, Mg, B2(pin)2, Polyethylene Glycol

39,48–51,67,84–98

2

Ni, Co, Fe

Zn, Mn, Mg

98–104

3

Ni, Pd

Zn

103,104

4

Ni, Pd

Zn

105–107

5

Ni

Mn

108

6

Co

Mn

109

Entry

a

Starting material 1a

Starting material 2

Product

X ¼ I, Br, Cl, CN OTs, OTf, OMs, OAc, SO2CF2H, NR2, OC(O)R, or Ot-Bu.

94

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

A major goal in the development of these reactions is achieving cross-selectivity between two electrophiles under practical conditions with synthetically useful yields. There have been several successful strategies employed including using excess of one aryl electrophile,67,84,85 electronic differentiation of the two C(sp2) electrophiles86–88, and the use of co-catalysts.89–93 For example, in a reaction of aryl halides, Gosmini and co-workers utilized an excess of the more reactive aryl iodide to ensure conversion of the less reactive aryl bromide to the cross product (Eq. 4). In addition, the authors noted that the aryl halides must be electronically differentiated in order to achieve the desired unsymmetrical biaryl.85 This requirement can lead to limitations in substrate scope. Similar methods, including nickel- and palladium-catalyzed reactions, involve the XEC reaction of heterocyclic electrophiles.38,48–51,67,84–86,89,91,98

ð4Þ

Another successful strategy to promote cross-reactivity is to employ two C(sp2) electrophiles with different electronic or steric features. For example, Wangelin and co-workers exhibited cross-selectivity between aryl bromides and vinyl bromides (Eq. 5).98 Interestingly, they utilized an earth abundant iron catalyst. The XEC reaction of vinyl halides have also been realized with nickeland cobalt catalysts.98–104 In addition, functionalized ketones have been synthesized via XEC reactions of acyl electrophiles.105–107

ð5Þ

Reductive coupling reactions have been expanded to include a,b-unsaturated ketones108 and a-bromo enones.109 An interesting example of a reductive conjugate addition involves an aryl iodide with a,b-unsaturated enone (Eq. 6).108 The authors demonstrated that aryl boronic acids are well tolerated which can potentially lead to subsequent Suzuki-Miyaura coupling reactions.110

ð6Þ

Finally, the Weix and Lian research groups independently demonstrated that a co-catalysis strategy could selectivity engage two different sulfonates to achieve cross-selectivity (Eq. 7)92,93 In order for this strategy to be successful, each catalyst must preferentially engage one electrophile. It was previously demonstrated that electron-rich palladium complexes could selectively engage aryl triflates over aryl halides.111 The authors propose that the nickel complex catalyzes conversion of the aryl tosylate to the arylzinc reagent, which then undergoes palladium-catalyzed XC reaction with the aryl triflate.89,112

ð7Þ

12.04.3.2 XEC reactions of C(sp2) and C(sp3) electrophiles (Type B) 12.04.3.2.1

XEC reactions of aryl and vinyl electrophiles with C(sp3) electrophiles

The most abundant type of XEC reactions involve C(sp2) and C(sp3) electrophiles (Table 3). Unlike Type A and C reactions, the two partners frequently have quite different reactivity, which can be exploited to favor cross-selectivity. For example, aryl halides typically undergo a concerted oxidative addition whereas alkyl halides often engage via halogen atom abstraction and radical formation.42,43 A broad range of alkyl electrophiles have been employed, including many that are considered alkyl radical precursors, including N-phthalimido esters, oxalates, and Katritzky salts. As such, reaction design often builds on advances in related fields including photoredox reactions.174,175

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Table 3 Entry

95

XEC reactions of aryl C(sp2) and Alkyl C(sp3) electrophiles. C(sp2) starting materiala

C(sp3) starting materialb

Product

Metal catalyst

Reducing agent

References

1

Ni, Pd, Co, Fe

Zn, Mn, Mg, TDAE

113–139

2

Ni

Zn, Mn

140–142

3

Ni, Pd, Co, Ti

Zn, Mn, Mg

142–152

4

Ni

Mn

153

5

Ni, Co, Zr

Zn, Mn

154–157

6

Ni

Mn

158,159

Cu

160

7

8

Ni

Zn

161

9

Ni

Zn, Mn

162–164

10

Ni

Zn

165

11

Ni

Zn

166

12

Ni

Zn

167

13

Ni

Zn

168,169

14

Ni, Ti

Zn, Mn

170–173

a

X ¼ I, Br, Cl, OTs, OTf, OMs, ONf, or OAc. Y ¼ I, Br, Cl, OTs, OMs, OH, OAc, OPiv, OMe, OC(O)Cl, or NMe3OTf.

b

96

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

As with aryl electrophiles, vinyl halides and pseudohalides undergo XEC reactions with a wide range of alkyl electrophiles, including alkyl halides and radical precursors such as oxalates and N-hydroxy phthalimido esters (Table 4).148,159,176–184,190,191 While vinyl and aryl electrophiles have similar reactivity, vinyl electrophiles provide access to a different structural motif bearing an olefin handle and are thus highly useful in synthesis. For example, reactions are tolerant of metalloids like boron and silicon, providing allylic boronates and silanes which can undergo further functionalization.185,186 Similarly, copper-mediated reactions can be employed to generate allylic fluorides.160,186 Additionally, if the vinyl electrophile is an enone, the enolate can be trapped with silyl reagents.189 Table 4 Entry

XEC reactions of vinyl C(sp2) and alkyl C(sp3) electrophiles. C(sp2) starting materiala

C(sp3) starting materialb

Product

Metal catalyst

Reducing agent

References

1

Ni, Pd

Zn, Mn, B2(pin)2

176–180

2

Ni, Pd, Co

Zn, Mn

148,181–183

3

Ni

Mn

159,184

4

Ni

Mn

185

5

Ni, Co

Mn

186

Cu

160

6

7

Ni

TDAE

187

8

Fe

Zn

188

9

Ni

Zn

168,169

10

Ni

Mn

189

a

X ¼ I, Br, Cl, F, or OTf. Y ¼ I, Br, Cl, OTs, OMs, or, OPiv.

b

The largest category of C(sp2) coupling partners is aryl halides and pseudohalides (Table 3), and general cross selective alkyl-aryl XEC reactions have been accomplished with a wide variety of metal catalysts and reagents. Reactions additionally can incorporate a wide variety of heteroaryl compounds.40,77,113,115–137,145,192–194 One of the first reports of C(sp2)–C(sp3) XEC reactions combined aryl halides with allylic acetates in the presence of a cobalt catalyst and zinc dust (Eq. 8).155 Allylic acetates undergo rapid oxidative addition when compared to alkyl acetates.154–157

ð8Þ

Between 2009 and 2010 reports with iron, palladium, cobalt, and nickel catalysts established cross-selective C(sp2)–C(sp3) coupling between aryl halides and unactivated alkyl electrophiles employing stoichiometric metal reductants. The iron- and

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

97

palladium-catalyzed reactions were proposed to produce organometallic reagents, Grignard and Negishi reagents, respectively, in situ.113,114 For the cobalt-catalyzed reaction, Amatore and Gosmini proposed a sequential reduction mechanism in which the manganese powder reduced the cobalt catalyst (Eq. 9).118

ð9Þ

Soon after, the Weix group reported a cross-selective XEC reaction between aryl halides and unactivated alkyl halides in the presence of a nickel catalyst (Eq. 10).119 Based on mechanistic experiments, the authors proposed a sequential reduction mechanism for this reaction.

ð10Þ

Since then, nickel has emerged as the dominant transition metal for XEC reactions. A report from Molander and co-workers is illustrative of a typical set of reaction conditions: a Ni(II) or Ni(0) precatalyst, a tailored nitrogen-based L-type ligand system, either Zn or Mn as a stoichiometric reductant, and other additives such as ionic salts to aid the reaction (Eq. 11).120

ð11Þ

The mechanism for many C(sp2)–C(sp3) XEC reactions is proposed to involve the generation of an alkyl radical, which favors cross-selectivity with the C(sp2)–X partner (vide supra). While the alkyl electrophile does not need to be activated, certain substrates more easily undergo XEC reactions. For example, reactions of a-halocarbonyls are among the oldest XEC reactions.158 A variety of methods have been developed to facilitate the formation of the less stable alkyl radicals. One such method uses a second metal co-catalyst, often Co, Ti, or Zr, to either act as Lewis acid and activate the electrophile or generate the radical intermediate. For example, Weix and co-workers utilized a titanium co-catalyst to trigger radical formation from epoxides (Eq. 12).170–173

ð12Þ

Additionally, methods that take inspiration from photoredox catalysis employ redox active functional groups, such as NHP esters, oxalates, and Katritzky salts, which produce alkyl radicals.161–165,187,188,195 An example, Weix and co-workers reported nickel-catalyzed coupling of NHP esters with aryl halides (Eq. 13).161 In addition, Hughes and Fier demonstrated that a redox-active sulfone could forge the desired C–C bond.166

ð13Þ

Acetals also undergo cross-selective XEC reactions with aryl halides to generate branched ethers. Doyle and co-workers utilized benzylic acetals to synthesize a variety of benzhydryl alcohol derivatives (Eq. 14), while Gong and co-workers applied this methodology to afford aryl and vinyl glycosides.167–169

98

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

ð14Þ

In many cases, C(sp2)–C(sp3) XEC reactions are tolerant of fluorine atoms, allowing for the synthesis of fluorinated and trifluoromethylated compounds (Eq. 15).140 The XEC reaction to add fluorine-containing electrophiles allows for late stage modification of pharmaceutical targets.138–142,153

ð15Þ

In addition to the highlighted examples, benzylic electrophiles have been utilized in numerous XEC reactions and have often served as model substrates when developing new methods.143,144,146–152,196,197 Due to the generation of a radical intermediate, the XEC reaction is often stereoablative at the alkyl electrophile. Building on enantioselective cross-coupling strategies,198 stereoconvergent methods have been developed by employing chiral ligands. This strategy has been extensively developed by Reisman and co-workers.3 For example, an enantioselective XEC reaction of a vinyl bromide with a benzylic chloride provides excellent yield and enantioselectivity. Bisoxazoline ligands are frequently employed as the chiral ligands for asymmetric XEC reactions (Eq. 16).181

ð16Þ

12.04.3.2.2

XEC reactions of acyl electrophiles with C(sp3) electrophiles

XEC reactions between acyl and alkyl electrophiles have been established for synthesis of substituted ketones (Table 5). Acyl halides and carboxylic acid derivatives undergo a range of XEC reactions with C(sp3) electrophiles.199–214 This section will focus on the XEC reactions of acyl electrophiles that do not involve decarboxylation or decarbonylation. Decarboxylation or decarbonylation XC and XEC reactions have been reviewed elsewhere.215–219 Table 5 Entry

XEC reactions of acyl C(sp2) and alkyl C(sp3) electrophiles. C(sp2) starting materiala

C(sp3) starting materialb

Product

Metal catalyst

Reducing agent

References

1

Ni, Zr

Zn, Mn

199–209

2

Ni

Zn

210

3

Ni

Mn

211

4

Ni

Mn

212

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Table 5 Entry

99

(Continued) C(sp2) starting material

C(sp3) starting material

Product

Metal catalyst

Reducing agent

References

5

Ni

Zn

213

6

Ni

Zn

205,208

a

X ¼ Br, Cl, F, OH, OPh, OPy, or SPy. Y ¼ I, Br, Cl, or OTs.

b

While acyl chlorides undergo facile XEC reactions, a significant amount of attention has gone to engaging carboxylic acid derivatives, due to the relative stability and availability of these starting materials. In the early 1980s, XEC reactions employing activated benzoic esters with alkyl iodides to afford ketones were reported (Eq. 17).199

ð17Þ

Additional strategies to activate the C–O bonds in acids or esters have been developed. One such strategy, employed extensively by the Gong group, has been to produce mixed anhydrides in situ. For example, carboxylic acids react with Boc2O to afford mixed anhydrides and these reagents are compatible with nickel-catalyzed XEC reactions. This strategy has been applied to formation of C-acyl glycosides (Eq. 18).208

ð18Þ

12.04.3.2.3

Cyclization reactions of C(sp2) and C(sp3) electrophiles

Intramolecular C(sp2)–C(sp3) XEC reactions are less frequently employed compared to their intermolecular counterparts, however several strategies have been developed for the formation of five-, six-, and seven-membered rings (Table 6).220–223 Table 6

Cyclization reactions of C(sp2) and C(sp3) electrophiles. Starting materiala

Productb

Metal catalyst

Reducing agent

References

1

Ni, Pd, Fe

Zn, Mg, DMA

220–222

2

Pd

DMA

221

3

Ni

Zn

223

Entry

a

X ¼ I, Br, Cl, OMs, OTs, or ONs. Y ¼ CH2, O, NTs, or NCO2Et.

b

100

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Peng and co-workers published a nickel-catalyzed, zinc-mediated intramolecular C(sp2)–C(sp3) XEC reaction (Eq. 19). This highly versatile reaction provided access to a broad range of five-, six-, and seven-membered ring heterocycles.222

ð19Þ

12.04.3.3 XEC reactions of C(sp3) electrophiles (Type C) 12.04.3.3.1

Dimerization reactions of C(sp3) electrophiles

The first dimerization reactions of alkyl halides employed stoichiometric amounts of metal reagents.52 More recently, the development of transition metal-catalyzed dimerization reactions have emerged (Table 7). Table 7 Entry

Dimerization reactions of C(sp3) electrophiles. Starting materiala

Product

Metal catalyst

Reducing agent

References

1

Cu, Ni

Zn, Li

52,224–226

2

Cu, Ni

Mn

226,227

3

Co, Ni

Zn, Mn, B2(pin)2

227–231

4

Ni

Zn, Mn, B2(pin)2

227–229,231

a

X ¼ I, Br, Cl, OMs, OTs, OAc, or OC(O)CF3.

Early examples of reductive dimerization reactions of benzylic and allylic halides employed stoichiometric metals such as copper.52,224–226 In 1982, Rieke and co-workers reported the dimerization reaction of benzylic halides with 1.25 equivalents of activated nickel metal per halogen atom on the electrophile (Eq. 20).52

ð20Þ

Ebert and co-workers employed stoichiometric copper metal to achieve the reductive dimerization reaction of allyl, benzyl, and n-heptyl halides. They report that allyl bromides can afford the desired dimer product in 95% yield after 1 h (Eq. 21).226 ð21Þ Moving beyond stoichiometric metals, catalytic nickel227–229,231 as well as co-catalytic nickel/cobalt230 reductive dimerization reactions have been developed by various groups. From a design perspective, cobalt co-catalysts are often evaluated if it appears that halogen atom abstraction is sluggish. The Komeyama group has demonstrated that vitamin B12 (VB12) can be employed as a cobalt catalyst to achieve nickel/cobalt co-catalysis for the dimerization reaction of alkyl tosylates.230 In this example, manganese metal serves as the stoichiometric reductant (Eq. 22). These methods have been applied to the synthesis of rotaxanes and natural products (vide infra).228,229

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

101

ð22Þ

12.04.3.3.2

Cross-selective XEC reactions of C(sp3) electrophiles

Cross-selective XEC reactions between two different C(sp3) electrophiles were reported as early as 2011.232,233 Numerous alkyl electrophiles have exhibited exquisite reactivity in XEC reactions. Examples include alkyl halides and pseudohalides,200,234,235 allylic acetates and carbonates,233,236–239 oxalates,240,241 and more recently, Katritzky salts and cyclic anhydrides (Table 8).164,242 Table 8 Entry

Cross selective XEC reactions of C(sp3) electrophiles. Starting material 1a

Starting material 2

Product

Metal catalyst

Reducing agent

References

1

Ni, Co

Zn, Mn

232,235

2

Cu, Co, Ni

Zn, Mn, Mg, B2(pin)2

231,232,234,235

3

Ni

Zn

164

4

Ni

Zn, B2(pin)2

231,232

5

Ni

Mn

240

6

Ni

Mn

240

7

Co, Ni

Mn, Zn

233,236

8

Co, Ni

Mn, Zn

233,236,237

9

Co, Ni

Mn, Zn

233,238,239

10

Fe

Zn

241

11

MeOTs

Ni

B2(pin)2

200

12

MeOTs

Ni

B2(pin)2

200

Ni

Zn

242

13

a

X ¼ I, Br, Cl, OTs, OMs, OAc, or OCO2Me.

102

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

As previously discussed, one of the main challenges in XEC reactions is achieving cross-selectivity over homodimerization reactions or reduction of starting materials. Cross-selectivity can be achieved simply by using excess of the more reactive partner (vide supra). In order to overcome the selectivity challenge, Gong and co-workers in 2011 employed a threefold excess of one electrophilic partner in order to achieve the desired cross-coupled product in good yield (Eq. 23).232 In a subsequent report, the authors noted that by employing B2pin2 as the terminal reductant, they could reduce the number of equivalents and 1.5 equivalents of the more reactive partner was required.231

ð23Þ

Another strategy to achieve cross-selectivity in XEC reactions is to design one partner as a polar partner and the other as a radical precursor, in line with either radical chain or sequential oxidative addition mechanisms (Fig. 1). In 2011, Gosmini and co-workers reported the allylation of alkyl halides with allylic acetates and carbonates utilizing a cobalt/manganese system (Eq. 24). The allyl acetate is thought to undergo oxidative addition to form an allyl cobalt intermediate, and the alkyl halide serves as a radical precursor.233

ð24Þ

Electrophiles that are frequently employed as radical precursors in related reactions, such as photoredox reactions, also participate in XEC reactions. These redox active electrophiles include oxalates (Eq. 25), which can undergo either polar oxidative oxidation with nickel240 or serve as a radical precursor with an iron catalyst.241 Finally, Katritzky salts can serve as radical precursors.164

ð25Þ

More recently, the Walsh group reported the XEC reaction between cyclic anhydrides and alkyl bromides to afford carboxylic acids.242 The authors propose the following mechanism which begins with oxidative addition of the anhydride followed by decarbonylation to afford a nickel carboxylate complex. This complex then captures the alkyl radical produced from a radical chain mechanism (Scheme 2).

Scheme 2 Proposed mechanism of XEC reaction between cyclic anhydrides and alkyl bromides.

12.04.3.3.3

XEC reactions of allylic trifluoromethyl electrophiles and C(sp3) electrophiles

The synthesis of gem-difluoroalkenes can be achieved via an emerging class of C(sp3)–C(sp3) XEC reactions that react alkyl electrophiles with allylic trifluorides (Table 9).243–249 Strategically, these methods are similar to coupling reactions of allylic halides, however, they provide synthetic access to complex difluoroalkenes.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Table 9

XEC reactions of allylic trifluoromethyl electrophiles and C(sp3) electrophiles.

Entry

Starting material 1

Starting material 2a

Product

103

Metal catalyst

Reducing agent

References

1

Ni, Ti

Zn

243,244

2

Ni

Zn

245

3

Ni

Zn

246

4

Ni

Zn

247

5

Ni, Ti

Zn

248,249

a

X ¼ I or Br.

For example, Wang and co-workers established a XEC reaction of an allylic trifluoride with an alkyl iodide (Eq. 26).243 The reaction was tolerant of heterocyclic functionality, an important feature for medicinal chemistry applications. Various other methods have been developed since then, often exploiting the formation of an alkyl radical either through the use of radical precursors such as NHP esters or a metal co-catalyst.244–249

ð26Þ

12.04.3.3.4

Cyclization reactions of C(sp3) electrophiles

Cyclization reactions of tethered alkyl electrophiles have been accomplished for the formation of a variety of ring sizes, from cyclopropanes to cyclopentanes and cyclohexanes (Table 10).47,226,250–252,257–259 The stereochemical outcome of the reactions is limited to those that employ secondary electrophiles, and in these cases the known preference for polar oxidative addition versus radical generation have proven quite predictive. Table 10 Entry

Cyclization reactions of C(sp3) electrophiles. Starting materiala

Metal catalyst

Reducing agent

References

1

Ni

Cu, Cr, Co, Zn, MeMgI

47,226,250–256

2

Ni

MeMgI

257,258

3

Ni

MeMgI

251

4

Ni

MeMgI

259

a

X ¼ I, Br, Cl, F, OMs, OTs, or NMeTs.

Product

104

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Reducing metals including zinc have been known to affect the cyclization of 1,3-dihalides for formation of cyclopropanes since the late 19th century.253–256 In 1968, Kochi and Singleton reported cyclopropane formation from 1,3-diiodides using a chromium(II) ethylene diamine reagent (Eq. 27).250 Ebert and co-workers developed a similar procedure for the cyclization of dihaloalkanes using activated copper.226

ð27Þ

In 2015, the Jarvo lab reported the XEC reaction of 2-aryl-4-chlorotetrahydropyrans to synthesize substituted cyclopropanes (Eq. 28).257 The ring-contraction reaction is stereospecific with regards to both the benzylic ether and the alkyl chloride. This is due to a catalytic cycle that involves stereospecific oxidative addition of the benzylic ether, and cyclization via an intramolecular SN2-like transition state. Most recently, this method has been extended to include synthesis of fluorinated cyclopropanes through the nickel-catalyzed XEC reaction of the difluoromethyl group.259

ð28Þ

Intramolecular XEC reactions have also been used by Gong and co-workers to synthesize five-, six-, and seven-membered rings.252 Syntheses of five-membered rings have proved to be more efficient than the syntheses of six- and seven-membered rings (Eq. 29).

ð29Þ

12.04.3.3.5

XEC reactions of C(sp) electrophiles (Type D)

While the XEC reactions of C(sp2) and C(sp3) electrophiles have been well established, the incorporation of C(sp) electrophiles has lagged. Traditionally, the Sonogashira coupling reaction is used for the formation of C(sp)–C(sp2) bonds and is typically a straightforward approach to synthesis of these compounds.260,261 XEC reactions provide a mechanistically interesting alternative that allows for facile coupling of bromoalkynes with alkyl electrophiles C(sp)–C(sp3) (Table 11). Table 11

XEC reactions of C(sp) and C(sp3) electrophiles.

Entry

Starting material 1

Starting material 2

Product

Metal catalyst

Reducing agent

References

1

Ni

Mn

262

2

Ni

Zn

164

Both reported examples employed alkynyl bromides and radical precursors to achieve the C(sp)–C(sp3) coupling reaction.164,262 For example, in 2016, the Weix group reported the XEC reaction of bromoalkynes and NHP esters (Eq. 30).262

ð30Þ

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

105

12.04.4 XEC reactions employing electrochemical reductions Electrochemical reductions have been utilized in XEC reactions.263–265 These methods avoid the need for stoichiometric reducing metals. This can be beneficial, since a difficulty associated with employing metal powders, such as Zn and Mn, is the formation of heterogenous reaction mixtures which often require the use of high boiling point amide solvents, such as DMA and DMF. Electrochemistry, on the other hand, is a simple, homogenous, and inexpensive method that provides the electrons necessary for catalyst turnover. Additionally, electroreductive methods are ideal for industrial scale processes because large amounts of metallic waste are not produced. Furthermore, there is less of a need for metal scavengers to remove trace metals in reaction products. This can facilitate rapid and efficient syntheses of potential drug candidates. Despite these advantages, electroreductive coupling reactions are less common that the methods employing stoichiometric reductants. Nonetheless, it has been demonstrated that electrochemical conditions can be used for the majority of substrate classes typically employed in XEC reactions.

12.04.4.1 XEC reactions of C(sp2) electrophiles (Type A) Some of the earliest examples of XEC reactions of aryl electrophiles employed electroreductive methods to forge the desired C–C bond. The methods have allowed for the synthesis of unsymmetrical biaryls including heterocyclic compounds. In addition, styrenes, dienes, and unsymmetrical ketones have also been efficiently constructed with electroreductive methods. With judicious choice of cathode, anode, electrolyte, and solvent, successful XEC reactions are possible (Table 12). Table 12

Electrochemical XEC reactions of C(sp2) electrophiles. Metal catalyst

Electrodeb

References

1

Ni, Pd, Co

Ni/Cu; Pb/Pt; Pt/Pt; Au/Mg; Ni/Fe; Ni/Zn; Pt/Ni; Fe/Fe; Glassy Carbon/Pt; Carbon Cloth/Mg

66,266–282

2

Ni, Co

Fe/Fe; Ni/Zn; Ni/Al

41,283,284

3

Ni

Au/Zn

285

4

Ni

Au/Mg; Ni/Al

271,283

5

Ni

Ni/Ni

286

Entry

Starting material 1a

Starting material 2a

Product

a

X ¼ I, Br, Cl, OTf, or OAc. Cathode/anode.

b

Dimerization reactions have been a useful method to forge biaryls.66,266–268,270–277 This concept has been applied to the synthesis of bipyridines which are common ligands in metal-catalyzed reactions (Eq. 31).270,278,279

ð31Þ

Cross-selective examples of electroreductive XEC reactions lagged behind the dimerization of aryl electrophiles because of the difficulties associated with cross-selectivity (vida supra).272,273,280–282 The Gosmini group reported the cross-selective reaction between aryl bromides and 2-chloropyrimidine (Eq. 32).287 Key to their success was the use of sub-stoichiometric FeBr2 which prevented strong ligation of pyrimidine to the nickel catalyst.

ð32Þ

Similar strategies have been employed to achieve the cross-selective XEC reaction of other aryl electrophiles and heterocyclic substrates.287–293 Additionally, vinyl electrophiles are well suited to undergo reductive dimerization reactions271,283 and cross-

106

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

selective reactions.41,283,284 Finally, XEC reactions have been achieved with acid chlorides.285,286 For example, Marzouk et al. reported the cross-selective XEC reaction between aryl iodides and acid chlorides (Eq. 33).285

ð33Þ

12.04.4.2 XEC reactions of C(sp2) and C(sp3) electrophiles (Type B) Similar to XEC reaction with reducing agents, the most common combination reported for electrochemical XEC reactions is C(sp2)–C(sp3) coupling reactions (Table 13). This is because the partners often engage the catalyst in mechanistically distinct pathways (vide supra). The partners are differentiated therefore promoting cross-selectivity. Table 13

Electrochemical XEC reactions of C(sp2) and C(sp3) electrophiles. Metal catalyst

Electrodeb

References

1

Ni

RVC/Zn; Ni/Zn; RVC/HN(i-Pr)2 Graphite/Ni

294–297

2

Ni

Ni/Zn; Ni/Al Graphite/Ni

41,297

3

Ni, Co

Ni/Zn; Ni/Al, Fe/Fe

41

4

Ni

Au/Hg; Ni/Zn; Ni/Al Carbon Fiber/Al Carbon Fiber/Zn

41,298–301

5

Ni

RVC/RVC; RVC/Zn

302,303

6

Ni

RVC/Zn; Ni/Zn

304

7

Ni

Ni/Al

283

8

Ni

Au/Zn;Au/Mg

285

9

Ni

Au/Zn; Au/Mg

285

Entry

Starting material 1a

Starting material 2a

Product

a

X ¼ I, Br, Cl, OH, or OAc. Cathode/anode.

b

A common functional group utilized in the 1990s and early 2000s was the a-chlorocarbonyl.41,283,298–301 This electrophile cleanly undergoes an XEC reaction with a variety of electrophiles including aryl, heterocyclic and vinylic halides. For example, Durandetti and co-workers reported the coupling of aryl bromides with a-chloroketones (Eq. 34).300

ð34Þ

Additionally, electroreductive methods have been applied to coupling of aryl and alkyl electrophiles. 41,294–297,302,303,305 Recently, a group at Pfizer developed an electrochemical XEC reaction with a range of heterocyclic bromides, including an aza-indole

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

107

(Eq. 35).294 The authors noted that XEC reactions are ideal targets for drug design and electrochemistry can improve their scale-up processes significantly compared to stoichiometric metals.

ð35Þ

Building on previous enantioselective XEC reactions of vinyl bromides from their laboratory,181 the Reisman group demonstrated that an enantioselective reaction under electroreductive conditions was feasible (Eq. 36).304 The high enantioselectivity achieved with a bisoxazoline ligand is consistent with the proposed mechanisms involving halogen atom abstraction, since the enantio determining step should remain the same whether catalyst turnover is electrochemical or medicated by a reducing metal.

ð36Þ

12.04.4.3 XEC reactions of C(sp3) electrophiles (Type C) Although less common than the cross-selective XEC reactions of C(sp2) and C(sp3) electrophiles, reductive dimerization reactions of benzylic and aliphatic electrophiles have been established (Table 14).266,267,271,306 Table 14

Electrochemical dimerization reactions of C(sp3) electrophiles.

Entry

Starting materiala

Metal catalyst

Electrodeb

References

1

Ni

Cu/Ni; Pt/Pt; Au/Mg

266,267,271

2

Ni

Au/Mg

271

3

Ni, Fe

Ni/Ni; Al/Al; Pt/Pt; Au/Mg; Hg/Pt

267,271

4

Fe

Ni/Ni

266

Product

a

X ¼ I, Br, Cl, OTf. Cathode/anode.

b

To illustrate, the Jennings group reported the dimerization reaction of benzyl bromide in good yield (Eq. 37).266 In this report they were also able to achieve a good yield for a simple aliphatic electrophile, 1-octylbromide. Another report has demonstrated that secondary alkyl halides can efficiently undergo an iron-catalyzed dimerization reaction utilizing a Ni/Ni undivided cell.306

ð37Þ

12.04.5 XEC reactions in natural product syntheses Transition metal-catalyzed cross-coupling reactions, specifically the Suzuki-Miyaura coupling, are some of the most commonly used reactions in the synthesis of pharmaceutically relevant compounds and natural products.307 XEC reactions are less frequently employed compared to traditional XC reactions. However, they allow for the direct coupling of two electrophiles, which are more abundant and typically are the starting materials for preparation of organometallic reagents required for cross-coupling. Therefore, XEC reactions typically provide higher step economy than traditional XC reactions. XEC reactions also allow for reasonably mild

108

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

reaction conditions which are often tolerated by heterocycles, as demonstrated in previous sections. Natural products that have been prepared by XEC reactions are illustrated in Fig. 2.

Fig. 2 Natural products prepared by XEC reactions.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

109

To the best of our knowledge, the first example of a XEC reaction in natural product synthesis was reported by Semmelhack and co-workers in 1981 for the synthesis of alnusone.51 In the penultimate step of the synthesis, an intramolecular XEC reaction between the two aryl iodides afforded the methoxymethyl ether derivative of alnusone (Scheme 3). The reaction employs a stoichiometric amount of nickel (0) tetrakis(triphenylphosphine) to achieve the cyclization.

Scheme 3 Synthesis of alnusone.

Early examples of XEC reactions used in natural product syntheses involve dimerization reactions of aryl halides.78,308–311 In 1994, the first asymmetric synthesis of a subunit of the o-permethyl tellimagrandin I was completed with a copper-promoted dimerization reaction. Meyers and co-worker employed a chiral auxiliary to control axial chirality in the forming biaryl moiety (Scheme 4).78

Scheme 4 Dimerization reaction on route to o-permethyl tellimagrandin I.

More recently, XEC reactions have been used in natural product syntheses to form C–C bonds between separate fragments in cross-selective reactions.185,223,306–314,317–320 Christmann and co-workers utilized a nickel-catalyzed XEC reaction between an alkyl iodide and a bromopyrrole as the last step in the synthesis of vitepyrroloid A (Eq. 38).315 This afforded the target natural product in five steps without the use of protecting groups. Further reaction of vitepyrroloid A with ethyl 4-bromobutyrate provided vitepyrroloid B in 79%.

ð38Þ

Stoltz and co-workers joined two cyclic fragments by employing the, previously developed, dual Pd/Ni catalytic system.89,103,316 It is hypothesized that the palladium catalyst selectively reacts with the vinyl triflate while the nickel catalyst selectively reacts with the vinyl bromide. This allowed for the cross-selective XEC reaction of a vinyl bromide with a vinyl triflate. Using the dual catalytic system, they were able to perform this reaction on a multigram scale to achieve the synthesis of the tricyclic core of curcusones A–D (Scheme 5).316

Scheme 5 Intermolecular XEC reaction towards tricyclic core of curcusone A–D.

110

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

Intramolecular XEC reactions to produce key cyclic motifs have been developed; however, these reactions have not been used in the syntheses of natural products as widely as the dimerization reactions and cross-selective reactions. The first example of an intramolecular XEC reaction to achieve cyclization in natural product syntheses was completed by Semmelhack and co-workers (Scheme 3).51 Since then, the Jarvo lab has employed the intramolecular XEC reaction of 4-fluorotetrahydropyrans to synthesize dictyopterene A (Scheme 6).258

Scheme 6 Intramolecular XEC reaction for the synthesis of ()-dictyopterene.

As more XEC reactions are developed, and reliable strategies that provide cross-selectivity, cyclization, and control of absolute configuration are described, it is anticipated that XEC reactions will be more widely employed in the syntheses of pharmaceutically relevant compounds and natural products. In particular, continued expansion to develop more methods that involve cross-selective reactions using alkyl coupling partners will allow for more widespread use of XEC reactions among synthetic chemists. Furthermore, given the general tolerance for heterocycles and functional group compatibility, we anticipate to see application of XEC reactions in late-stage functionalization reactions in the field of medicinal chemistry.

12.04.6 Closing remarks Transition metal-catalyzed XEC reactions have gained popularity over the past two decades as an efficient method to construct carbon-carbon bonds. Many of the methods discussed employ sustainable first-row transition metal catalysts. As mechanistic insights grow and more general methods emerge, we anticipate that XEC reactions will become an essential tool in the organic chemist synthetic toolbox.

Acknowledgment This work was supported by the National Science Foundation (NSF CHE-1900340).

References 1. Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793–4798. https://doi.org/10.1021/jo500507s. 2. Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi Von Wangelin, A. Reductive Cross-Coupling Reactions Between Two Electrophiles. Chem. Eur. J. 2014, 20, 6828–6842. https://doi.org/10.1002/chem.201402302. 3. Poremba, K. E.; Dibrell, S. E.; Reisman, S. E. Nickel-Catalyzed Enantioselective Reductive Cross-Coupling Reactions. ACS Catal. 2020, 10, 8237–8246. https://doi.org/ 10.1021/acscatal.0c01842. 4. Gu, J.; Wang, X.; Xue, W.; Gong, H. Nickel-Catalyzed Reductive Coupling of Alkyl Halides With Other Electrophiles: Concept and Mechanistic Considerations. Org. Chem. Front. 2015, 2, 1411–1421. https://doi.org/10.1039/c5qo00224a. 5. Weix, D. J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides With Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767–1775. https://doi.org/ 10.1021/acs.accounts.5b00057. 6. Iwasaki, T.; Kambe, N. Ni-Catalyzed C–C Couplings Using Alkyl Electrophiles. Top. Curr. Chem. 2016, 374, 1–36. https://doi.org/10.1007/s41061-016-0067-6. 7. Wang, X.; Dai, Y.; Gong, H. Nickel-Catalyzed Reductive Couplings. Top. Curr. Chem. 2016, 374, 1–29. https://doi.org/10.1007/s41061-016-0042-2. 8. Lucas, E. L.; Jarvo, E. R. Stereospecific and Stereoconvergent Cross-Couplings Between Alkyl Electrophiles. Nat. Rev. Chem. 2017, 1, 0065. https://doi.org/10.1038/s41570017-0065. 9. Campeau, L. C.; Hazari, N. Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future. Organometallics 2019, 38, 3–35. https://doi.org/10.1021/acs.organomet.8b00720. 10. Jin, Y.; Wang, C. Nickel-Catalyzed Asymmetric Cross-Electrophile Coupling Reactions. Synlett 2020, 31, 1843–1850. https://doi.org/10.1055/s-0040-1707216. 11. Liu, J.; Ye, Y.; Sessler, J. L.; Gong, H. Cross-Electrophile Couplings of Activated and Sterically Hindered Halides and Alcohol Derivatives. Acc. Chem. Res. 2020, 53, 1833–1845. https://doi.org/10.1021/acs.accounts.0c00291. 12. Sanford, A. B.; Jarvo, E. R. Harnessing C–O Bonds in Stereoselective Cross-Coupling and Cross-Electrophile Coupling Reactions. Synlett 2020. https://doi.org/10.1055/s0040-1705987. 13. Xue, W.; Jia, X.; Wang, X.; Tao, X.; Yin, Z.; Gong, H. Nickel-Catalyzed Formation of Quaternary Carbon Centers Using Tertiary Alkyl Electrophiles. Chem. Soc. Rev. 2021, 50, 4162–4184. https://doi.org/10.1039/D0CS01107J. 14. Li, Y.; Fan, Y.; Jia, Q. Recent Advance in Ni-Catalyzed Reductive Cross-Coupling to Construct C(sp2)–C(sp2) and C(sp2)–C(sp3) Bonds. Chin. J. Org. Chem. 2019, 39, 350. https://doi.org/10.6023/cjoc201806038. 15. Fanta, P. E. The Ullmann Synthesis of Biaryls. Chem. Rev. 1946, 38, 139–196. https://doi.org/10.1021/cr60119a004. 16. Sainsbury, M. Modern Methods of Aryl-Aryl Bond Formation. Tetrahedron 1980, 36, 3327–3359. https://doi.org/10.1016/0040-4020(80)80185-2. 17. Bringmann, G.; Walter, R.; Weirich, R. The Directed Synthesis of Biaryl Compounds: Modern Concepts and Strategies. Angew. Chem. Int. Ed. Engl. 1990, 29, 977–991. https:// doi.org/10.1002/anie.199009771.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

111

18. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Aryl− Aryl Bond Formation One Century After the Discovery of the Ullmann Reaction. Chem. Rev. 2002, 102, 1359–1470. https://doi.org/10.1021/cr000664r. 19. Fanta, P. E. The Ullmann Synthesis of Biaryls. Synthesis 1974, 1974, 9–21. https://doi.org/10.1055/s-1974-23219. 20. Prier, C. K.; MacMillan, D. W. C. Dual Photoredox Catalysis: The Merger of Photoredox Catalysis With Other Catalytic Activation Modes. In Visible Light Photocatalysis in Organic Chemistry, Wiley-VCH: Weinheim, Germany, 2018; pp 299–333. https://doi.org/10.1002/9783527674145.ch10. 21. Milligan, J. A.; Phelan, J. P.; Badir, S. O.; Molander, G. A. Alkyl Carbon–Carbon Bond Formation by Nickel/Photoredox Cross-Coupling. Angew. Chem. Int. Ed. 2019, 58, 6152–6163. https://doi.org/10.1002/anie.201809431. 22. Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Single-Electron Transmetalation Via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp3–sp2 Cross-Coupling. Acc. Chem. Res. 2016, 49, 1429–1439. https://doi.org/10.1021/acs.accounts.6b00214. 23. Tóth, B. L.; Tischler, O.; Novák, Z. Recent Advances in Dual Transition Metal–Visible Light Photoredox Catalysis. Tetrahedron Lett. 2016, 57, 4505–4513. https://doi.org/ 10.1016/j.tetlet.2016.08.081. 24. Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical Synthesis. Chem. Rev. 2016, 116, 10035–10074. https://doi.org/10.1021/acs. chemrev.6b00018. 25. Gui, Y.-Y.; Sun, L.; Lu, Z.-P.; Yu, D.-G. Photoredox Sheds New Light on Nickel Catalysis: From Carbon–Carbon to Carbon–Heteroatom Bond Formation. Org. Chem. Front. 2016, 3, 522–526. https://doi.org/10.1039/C5QO00437C. 26. Börjesson, M.; Moragas, T.; Gallego, D.; Martin, R. Metal-Catalyzed Carboxylation of Organic (Pseudo)Halides With CO2. ACS Catal. 2016, 6, 6739–6749. https://doi.org/ 10.1021/acscatal.6b02124. 27. Moragas, T.; Correa, A.; Martin, R. Metal-Catalyzed Reductive Coupling Reactions of Organic Halides With Carbonyl-Type Compounds. Chem. Eur. J. 2014, 20, 8242–8258. https://doi.org/10.1002/chem.201402509. 28. Correa, A.; León, T.; Martin, R. Ni-Catalyzed Carboxylation of C(sp2)– And C(sp3)–O Bonds With CO2. J. Am. Chem. Soc. 2014, 136, 1062–1069. https://doi.org/10.1021/ ja410883p. 29. Fürstner, A. Carbon −Carbon Bond Formations Involving Organochromium(III) Reagents. Chem. Rev. 1999, 99, 991–1046. https://doi.org/10.1021/cr9703360. 30. Hargaden, G. C.; Guiry, P. J. The Development of the Asymmetric Nozaki–Hiyama–Kishi Reaction. Adv. Synth. Catal. 2007, 349, 2407–2424. https://doi.org/10.1002/ adsc.200700324. 31. Santana, C. G.; Krische, M. J. From Hydrogenation to Transfer Hydrogenation to Hydrogen Auto-Transfer in Enantioselective Metal-Catalyzed Carbonyl Reductive Coupling: Past, Present, and Future. ACS Catal. 2021, 11, 5572–5585. https://doi.org/10.1021/acscatal.1c01109. 32. Durandetti, M.; Hardou, L.; Lhermet, R.; Rouen, M.; Maddaluno, J. Synthetic Applications of the Nickel-Catalyzed Cyclization of Alkynes Combined With Addition Reactions in a Domino Process. Chem. Eur. J. 2011, 17, 12773–12783. https://doi.org/10.1002/chem.201100967. 33. Derosa, J.; Tran, V. T.; van der Puyl, V. A.; Engle, K. M. Carbon-Carbon p Bonds as Conjunctive Reagents in Cross-Coupling. Aldrichimica Acta 2018, 51, 21–32. 34. Dhungana, R. K.; KC, S.; Basnet, P.; Giri, R. Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins. Chem. Rec. 2018, 18, 1314–1340. https://doi.org/ 10.1002/tcr.201700098. 35. Qi, X.; Diao, T. Nickel-Catalyzed Dicarbofunctionalization of Alkenes. ACS Catal. 2020, 10, 8542–8556. https://doi.org/10.1021/acscatal.0c02115. 36. Derosa, J.; Apolinar, O.; Kang, T.; Tran, V. T.; Engle, K. M. Recent Developments in Nickel-Catalyzed Intermolecular Dicarbofunctionalization of Alkenes. Chem. Sci. 2020, 11, 4287–4296. https://doi.org/10.1039/C9SC06006E. 37. Diccianni, J.; Lin, Q.; Diao, T. Mechanisms of Nickel-Catalyzed Coupling Reactions and Applications in Alkene Functionalization. Acc. Chem. Res. 2020, 53, 906–919. https:// doi.org/10.1021/acs.accounts.0c00032. 38. Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to Catalysis; University Science Books, 2010. 39. Kuroboshi, M.; Waki, Y.; Tanaka, H. Palladium-Catalyzed Tetrakis(Dimethylamino)Ethylene-Promoted Reductive Coupling of Aryl Halides. J. Org. Chem. 2003, 68, 3938–3942. https://doi.org/10.1021/jo0207473. 40. Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Halides With Alkyl Halides. J. Am. Chem. Soc. 2013, 135, 16192–16197. https://doi.org/10.1021/ja407589e. 41. Durandetti, M.; Nédélec, J. Y.; Périchon, J. Nickel-Catalyzed Direct Electrochemical Cross-Coupling Between Aryl Halides and Activated Alkyl Halides. J. Org. Chem. 1996, 61, 1748–1755. https://doi.org/10.1021/jo9518314. 42. Kehoe, R.; Mahadevan, M.; Manzoor, A.; McMurray, G.; Wienefeld, P.; Baird, M. C.; Budzelaar, P. H. M. Reactions of the Ni(0) Compound Ni(PPh3)4 With Unactivated Alkyl Halides: Oxidative Addition Reactions Involving Radical Processes and Nickel(I) Intermediates. Organometallics 2018, 37, 2450–2467. https://doi.org/10.1021/acs. organomet.8b00244. 43. Diccianni, J. B.; Katigbak, J.; Hu, C.; Diao, T. Mechanistic Characterization of (Xantphos)Ni(I)-Mediated Alkyl Bromide Activation: Oxidative Addition, Electron Transfer, or Halogen-Atom Abstraction. J. Am. Chem. Soc. 2019, 141, 1788–1796. https://doi.org/10.1021/jacs.8b13499. 44. Tsou, T. T.; Kochi, J. K. Mechanism of Oxidative Addition. Reaction of Nickel(0) Complexes With Aromatic Halides. J. Am. Chem. Soc. 1979, 101, 6319–6332. https://doi.org/ 10.1021/ja00515a028. 45. Tsou, T. T.; Kochi, J. K. Mechanism of Biaryl Synthesis With Nickel Complexes. J. Am. Chem. Soc. 1979, 101, 7547–7560. https://doi.org/10.1021/ja00519a015. 46. Chen, P.-P.; Lucas, E. L.; Greene, M. A.; Zhang, S.-Q.; Tollefson, E. J.; Erickson, L. W.; Taylor, B. L. H.; Jarvo, E. R.; Hong, X. A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study. J. Am. Chem. Soc. 2019, 141, 5835–5855. https://doi.org/10.1021/jacs.9b00097. 47. Sanford, A. B.; Thane, T. A.; McGinnis, T. M.; Chen, P. P.; Hong, X.; Jarvo, E. R. Nickel-Catalyzed Alkyl-Alkyl Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for the Synthesis of Alkylcyclopropanes. J. Am. Chem. Soc. 2020, 142, 5017–5023. https://doi.org/10.1021/jacs.0c01330. 48. Ullmann, F.; Bielecki, J. Ueber Synthesen in Der Biphenylreihe. Ber. Dtsch. Chem. Ges. 1901, 34, 2174–2185. https://doi.org/10.1002/cber.190103402141. 49. Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. Synthesis With Zerovalent Nickel. Coupling of Aryl Halides With Bis(1,5-Cyclooctadiene)Nickel(0). J. Am. Chem. Soc. 1971, 93, 5908–5910. https://doi.org/10.1021/ja00751a062. 50. Kende, A. S.; Liebeskind, L. S.; Braitsch, D. M. Generation of a Solvated Zerovalent Nickel Reagent. Biaryl Formation. Tetrahedron Lett. 1975, 16, 3375–3378. https://doi.org/ 10.1016/S0040-4039(00)91402-3. 51. Semmelhack, M. F.; Helquist, P.; Jones, L. D.; Keller, L.; Mendelson, L.; Ryono, L. S.; Gorzynski Smith, J.; Stauffer, R. D. Reaction of Aryl and Vinyl Halides With Zerovalent Nickel—Preparative Aspects and the Synthesis of Alnusone. J. Am. Chem. Soc. 1981, 103, 6460–6471. https://doi.org/10.1021/ja00411a034. 52. Inaba, S.; Matsumoto, H.; Rieke, R. D. Metallic Nickel as a Reagent for the Coupling of Aromatic and Benzylic Halides. Tetrahedron Lett. 1982, 23, 4215–4216. https://doi.org/ 10.1016/S0040-4039(00)88707-9. 53. Matsumoto, H.; Inaba, S.; Rieke, R. D. Activated Metallic Nickel as a Reagent for the Dehalogenative Coupling of Halobenzenes. J. Org. Chem. 1983, 48, 840–843. https://doi. org/10.1021/jo00154a018. 54. Reisch, H. A.; Enkelmann, V.; Scherf, U. A Novel Nickel(0)-Mediated One-Pot Cascade Reaction to Cis-9,10-Dihydroxy-9,10-Dihydrophenanthrenes and 9-Phenanthrones. J. Org. Chem. 1999, 64, 655–658. https://doi.org/10.1021/jo9817523. 55. Zhang, S.; Zhang, D.; Liebeskind, L. S. Ambient Temperature, Ullmann-Like Reductive Coupling of Aryl, Heteroaryl, and Alkenyl Halides. J. Org. Chem. 1997, 62, 2312–2313. https://doi.org/10.1021/jo9700078. 56. Zembayashi, M.; Tamao, K.; Yoshida, J.; Kumada, M. Nickel-Phosphine Complex-Catalyzed Homo Coupling of Aryl Halides in the Presence of Zinc Powder. Tetrahedron Lett. 1977, 18, 4089–4091. https://doi.org/10.1016/S0040-4039(01)83434-1.

112

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

57. Colon, I.; Kelsey, D. R. Coupling of Aryl Chlorides by Nickel and Reducing Metals. J. Org. Chem. 1986, 51, 2627–2637. https://doi.org/10.1021/jo00364a002. 58. Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Homocoupling of Aryl Halides Using Nickel(II) Complex and Zinc in the Presence of Et4NI. An Efficient Method for the Synthesis of Biaryls and Bipyridines. Bull. Chem. Soc. Jpn. 1990, 63, 80–87. https://doi.org/10.1246/bcsj.63.80. 59. Percec, V.; Bae, J. Y.; Zhao, M.; Hill, D. H. Aryl Mesylates in Metal-Catalyzed Homocoupling and Cross-Coupling Reactions. 1. Functional Symmetrical Biaryls from Phenols via Nickel-Catalyzed Homocoupling of Their Mesylates. J. Org. Chem. 1995, 60, 176–185. https://doi.org/10.1021/jo00106a031. 60. Massicot, F.; Schneider, R.; Fort, Y. Lithium Hydride Mediated Nickel(0) Catalysed Biaryl Synthesis from Aryl Chlorides and Bromides. J. Chem. Res. 1999, 2, 664–665. https:// doi.org/10.1039/a905378f. 61. Leadbeater, N. E.; Resouly, S. M. The Use of Ni(CO)2(PPh3)2 in Aryl and Pyridyl Coupling Reactions. Tetrahedron Lett. 1999, 40, 4243–4246. https://doi.org/10.1016/S00404039(99)00695-4. 62. Howarth, J.; James, P.; Dai, J. The Coupling of Aryl Halides in the Ionic Liquid [Bmim]PF6. Tetrahedron Lett. 2000, 41, 10319–10321. https://doi.org/10.1016/S0040-4039 (00)01854-2. 63. Zuo, Z.; Kim, R. S.; Watson, D. A. Synthesis of Axially Chiral 2,20 -Bisphosphobiarenes via a Nickel-Catalyzed Asymmetric Ullmann Coupling: General Access to Privileged Chiral Ligands Without Optical Resolution. J. Am. Chem. Soc. 2021, 143, 1328–1333. https://doi.org/10.1021/jacs.0c12843. 64. Takagi, K.; Hayama, N.; Sasaki, K. Ni(0)-Trialkylphosphine Complexes. Efficient Homo-Coupling Catalyst for Aryl, Alkenyl, and Heteroaromatic Halides. Bull. Chem. Soc. Jpn. 1984, 57, 1887–1890. https://doi.org/10.1246/bcsj.57.1887. 65. Jutand, A.; Mosleh, A. Palladium and Nickel Catalyzed Synthesis of Biaryls From Aryl Triflates in the Presence of Zinc Powder. Synlett 1993, 568–570. https://doi.org/10.1055/ s-1993-22531. 66. Jutand, A.; Mosleh, A. Nickel- and Palladium-Catalyzed Homocoupling of Aryl Triflates. Scope, Limitation, and Mechanistic Aspects. J. Org. Chem. 1997, 62, 261–274. https:// doi.org/10.1021/jo961464b. 67. Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. Palladium-Catalyzed Homocoupling and Cross-Coupling Reactions of Aryl Halides in Poly(Ethylene Glycol). J. Org. Chem. 2006, 71, 1284–1287. https://doi.org/10.1021/jo052300a. 68. Bhattacharjya, A.; Klumphu, P.; Lipshutz, B. H. Kumada-Grignard-Type Biaryl Couplings on Water. Nat. Commun. 2015, 6, 1–6. https://doi.org/10.1038/ncomms8401. 69. Moncomble, A.; Le Floch, P.; Gosmini, C. Cobalt-Catalyzed Formation of Symmetrical Biaryls and Its Mechanism. Chem. Eur. J. 2009, 15, 4770–4774. https://doi.org/ 10.1002/chem.200900542. 70. Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci, M. A Convenient Synthesis of Bipyridines by Nickel-Phosphine Complex-Mediated Homo Coupling of Halopyridines. Synthesis 1984, 1984, 736–738. https://doi.org/10.1055/s-1984-30951. 71. Meyers, A. I.; McKennon, M. J. C2 Symmetric Amines. I. The Asymmetric Ullmann Synthesis of a New C2-Symmetric Binaphthyl. Tetrahedron Lett. 1995, 36, 5869–5872. https://doi.org/10.1016/00404-0399(50)1180P-. 72. Nelson, T. D.; Meyers, A. I. The Synthesis of a Useful Chiral Biaryl Catalyst. An Oxazoline-Mediated Ullmann Reaction. Tetrahedron Lett. 1993, 34, 3061–3062. https://doi.org/ 10.1016/S0040-4039(00)93379-3. 73. Nelson, T. D.; Meyers, A. I. The Asymmetric Ullmann Reaction III. Application of a First-Order Asymmetric Transformation to the Synthesis of C2-Symmetric Chiral, Non-Racemic Biaryls. Tetrahedron Lett. 1994, 35, 3259–3262. https://doi.org/10.1016/S0040-4039(00)76879-1. 74. Nelson, T. D.; Meyers, A. I. The Asymmetric Ullmann Reaction. 2. The Synthesis of Enantiomerically Pure C2-Symmetric Binaphthyls. J. Org. Chem. 1994, 59, 2655–2658. https://doi.org/10.1021/jo00088a066. 75. Chan, K. S.; Tse, A. K. S. Synthesis of Bis(Trifluoromethyl)-2,2’-Bipyridines by Nickel Catalysed Homocoupling Reactions. Synth. Commun. 1993, 23, 1929–1934. https://doi. org/10.1080/00397919308009849. 76. Venkatraman, S.; Li, C.-J. Carbon −Carbon Bond Formation via Palladium-Catalyzed Reductive Coupling in Air. Org. Lett. 1999, 1, 1687. https://doi.org/10.1021/ol991094o. 77. Sessler, J. L.; Hoehner, M. C. An Efficient, High-Yield Preparation of Substituted 2,20 -Bipyrroles. Synlett 1994, 211–212. https://doi.org/10.1055/s-1994-22798. 78. Nelson, T. D.; Meyers, A. I. A Rapid Total Synthesis of an Ellagitannin. J. Org. Chem. 1994, 59, 2577–2580. https://doi.org/10.1021/jo00088a046. 79. Kasprzak, K. S.; Diwan, B. A.; Rice, J. M.; Misra, M.; Riggs, C. W.; Olinski, R.; Dizdaroglu, M. Nickel(II)-Mediated Oxidative DNA Base Damage in Renal and Hepatic Chromatin of Pregnant Rats and Their Fetuses. Possible Relevance to Carcinogenesis. Chem. Res. Toxicol. 1992, 5, 809–815. https://doi.org/10.1021/tx00030a013. 80. Constable, E. C.; Morris, D.; Carr, S. Functionalised 3,30 -Bipyridines—A New Class of Dinucleating Ligands. New J. Chem. 1998, 22, 287–294. https://doi.org/10.1039/ a708334c. 81. Zhang, B.; Breslow, R. Ester Hydrolysis by a Catalytic Cyclodextrin Dimer Enzyme Mimic With a Metallobipyridyl Linking Group. J. Am. Chem. Soc. 1997, 119, 1676–1681. https://doi.org/10.1021/ja963769d. 82. Janiak, C. Synthesis of 6,60 -Diamino-2,20 -Biquinoline and 2,20 -Bi-1,6-Naphthyridine. Synthesis 1999, 959–964. https://doi.org/10.1055/s-1999-6064. 83. Wong, H. L.; Tian, Y.; Chan, K. S. Electronically Controlled Asymmetric Cyclopropanation Catalyzed by a New Type of Chiral 2,20 -Bipyridine. Tetrahedron Lett. 2000, 41, 7723–7726. https://doi.org/10.1016/S0040-4039(00)01306-X. 84. Hassan, J.; Hathroubi, C.; Gozzi, C.; Lemaire, M. Preparation of Unsymmetrical Biaryls via Palladium-Catalyzed Coupling Reaction of Aryl Halides. Tetrahedron 2001, 57, 7845–7855. https://doi.org/10.1016/S0040-4020(01)00752-9. 85. Amatore, M.; Gosmini, C. Efficient Cobalt-Catalyzed Formation of Unsymmetrical Biaryl Compounds and Its Application in the Synthesis of a Sartan Intermediate. Angew. Chem. Int. Ed. 2008, 47, 2089–2092. https://doi.org/10.1002/anie.200704402. 86. Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides. Synlett 2013, 24, 619–624. https://doi.org/10.1055/s0032-1318237. 87. Chen, Z.; Wang, X. A Pd-Catalyzed, Boron Ester-Mediated, Reductive Cross-Coupling of Two Aryl Halides to Synthesize Tricyclic Biaryls. Org. Biomol. Chem. 2017, 15, 5790–5796. https://doi.org/10.1039/c7ob01237c. 88. Dorval, C.; Tricoire, M.; Begouin, J. M.; Gandon, V.; Gosmini, C. Cobalt-Catalyzed C(sp2)−CN Bond Activation: Cross-Electrophile Coupling for Biaryl Formation and Mechanistic Insight. ACS Catal. 2020, 10, 12819–12827. https://doi.org/10.1021/acscatal.0c03903. 89. Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Multimetallic Catalysed Cross-Coupling of Aryl Bromides With Aryl Triflates. Nature 2015, 524, 454. https://doi.org/10.1038/ nature14676. https://www.nature.com/articles/nature14676#supplementary-information. 90. Hanna, L. E.; Jarvo, E. R. Selective Cross-Electrophile Coupling by Dual Catalysis. Angew. Chem. Int. Ed. 2015, 54, 15618–15620. https://doi.org/10.1002/anie.201509444. 91. Huang, L.; Ackerman, L. K. G.; Kang, K.; Parsons, A. M.; Weix, D. J. LiCl-Accelerated Multimetallic Cross-Coupling of Aryl Chlorides With Aryl Triflates. J. Am. Chem. Soc. 2019, 141, 10978–10983. https://doi.org/10.1021/jacs.9b05461. 92. Xiong, B.; Li, Y.; Wei, Y.; Kramer, S.; Lian, Z. Dual Nickel-/Palladium-Catalyzed Reductive Cross-Coupling Reactions Between Two Phenol Derivatives. Org. Lett. 2020, 22, 6334–6338. https://doi.org/10.1021/acs.orglett.0c02165. 93. Kang, K.; Huang, L.; Weix, D. J. Sulfonate Versus Sulfonate: Nickel and Palladium Multimetallic Cross-Electrophile Coupling of Aryl Triflates With Aryl Tosylates. J. Am. Chem. Soc. 2020, 142, 10634–10640. https://doi.org/10.1021/jacs.0c04670. 94. Gosmini, C.; Bassene-Ernst, C.; Durandetti, M. Synthesis of Functionalized 2-Arylpyridines From 2-Halopyridines and Various Aryl Halides Via a Nickel Catalysis. Tetrahedron 2009, 65, 6141–6146. https://doi.org/10.1016/j.tet.2009.05.044. 95. Liao, L. Y.; Kong, X. R.; Duan, X. F. Reductive Couplings of 2-Halopyridines Without External Ligand: Phosphine-Free Nickel-Catalyzed Synthesis of Symmetrical and Unsymmetrical 2,2’-Bipyridines. J. Org. Chem. 2014, 79, 777–782. https://doi.org/10.1021/jo402084m. 96. Gong, C.; Huo, C.; Wang, X.; Quan, Z. Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Bromides With Pyrimidin-2-yl Tosylates. Chin. J. Chem. 2017, 35, 1137–1366. https://doi.org/10.1002/cjoc.201700071.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

113

97. Miao, W.; Ni, C.; Xiao, P.; Jia, R.; Zhang, W.; Hu, J. Nickel-Catalyzed Reductive 2-Pyridination of Aryl Iodides With Difluoromethyl 2-Pyridyl Sulfone. Org. Lett. 2021, 23, 711–715. https://doi.org/10.1021/acs.orglett.0c03939. 98. Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Iron-Catalyzed Reductive Aryl-Alkenyl Cross-Coupling Reactions. ChemCatChem 2011, 3, 135–138. https://doi.org/ 10.1002/cctc.201000276. 99. Liu, J.; Ren, Q.; Zhang, X.; Gong, H. Preparation of Vinyl Arenes by Nickel-Catalyzed Reductive Coupling of Aryl Halides With Vinyl Bromides. Angew. Chem. Int. Ed. 2016, 55, 15544–15548. https://doi.org/10.1002/anie.201607959. 100. Xiong, B.; Wang, T.; Sun, H.; Li, Y.; Kramer, S.; Cheng, G. J.; Lian, Z. Nickel-Catalyzed Cross-Electrophile Coupling Reactions for the Synthesis of Gem-Difluorovinyl Arenes. ACS Catal. 2020, 10, 13616–13623. https://doi.org/10.1021/acscatal.0c03993. 101. Amatore, M.; Gosmini, C.; Périchon, J. Cobalt-Catalyzed Vinylation of Functionalized Aryl Halides With Vinyl Acetates. Eur. J. Org. Chem. 2005, 2005, 989–992. https://doi.org/ 10.1002/ejoc.200400897. 102. Moncomble, A.; Le Floch, P.; Lledos, A.; Gosmini, C. Cobalt-Catalyzed Vinylation of Aromatic Halides Using b-Halostyrene: Experimental and DFT Studies. J. Org. Chem. 2012, 77, 5056–5062. https://doi.org/10.1021/jo3005149. 103. Olivares, A. M.; Weix, D. J. Multimetallic Ni- and Pd-Catalyzed Cross-Electrophile Coupling to Form Highly Substituted 1,3-Dienes. J. Am. Chem. Soc. 2018, 140, 2446–2449. https://doi.org/10.1021/jacs.7b13601. 104. Sha, Y.; Liu, J.; Wang, L.; Liang, D.; Wu, D.; Gong, H. Nickel-Catalyzed Reductive 1,3-Diene Formation From the Cross-Coupling of Vinyl Bromides. Org. Biomol. Chem. 2021https://doi.org/10.1039/D1OB00791B. 105. Ni, S.; Zhang, W.; Mei, H.; Han, J.; Pan, Y. Ni-Catalyzed Reductive Cross-Coupling of Amides With Aryl Iodide Electrophiles via C–N Bond Activation. Org. Lett. 2017, 19, 2536–2539. https://doi.org/10.1021/acs.orglett.7b00831. 106. Lin, T.; Mi, J.; Song, L.; Gan, J.; Luo, P.; Mao, J.; Walsh, P. J. Nickel-Catalyzed Desymmetrizing Cross-Electrophile Coupling of Cyclic Meso-Anhydrides. Org. Lett. 2018, 20, 1191–1194. https://doi.org/10.1021/acs.orglett.8b00114. 107. Zhu, Z.; Gong, Y.; Tong, W.; Xue, W.; Gong, H. Ni-Catalyzed Cross-Electrophile Coupling of Aryl Triflates With Thiocarbonates via C–O/C–O Bond Cleavage. Org. Lett. 2021, 23, 2158–2163. https://doi.org/10.1021/acs.orglett.1c00313. 108. Shrestha, R.; Dorn, S. C. M.; Weix, D. J. Nickel-Catalyzed Reductive Conjugate Addition to Enones via Allylnickel Intermediates. J. Am. Chem. Soc. 2013, 135, 751–762. https://doi.org/10.1021/ja309176h. 109. Beng, T. K.; Sincavage, K.; Silaire, A. W. V.; Alwali, A.; Bassler, D. P.; Spence, L. E.; Beale, O. Direct Access to Functionalized Benzotropones, Azepanes, and Piperidines by Reductive Cross-Coupling of a-Bromo Enones With a-Bromo Enamides. Org. Biomol. Chem. 2015, 13, 5349–5353. https://doi.org/10.1039/c5ob00517e. 110. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. 111. Kamikawa, T.; Hayashi, T. Control of Reactive Site in Palladium-Catalyzed Grignard Cross-Coupling of Arenes Containing Both Bromide and Triflate. Tetrahedron Lett. 1997, 38, 7087–7090. https://doi.org/10.1016/S0040-4039(97)01655-9. 112. Roy, A. H.; Hartwig, J. F. Oxidative Addition of Aryl Sulfonates to Palladium(0) Complexes of Mono- and Bidentate Phosphines. Mild Addition of Aryl Tosylates and the Effects of Anions on Rate and Mechanism. Organometallics 2004, 23, 194–202. https://doi.org/10.1021/om034187p. 113. Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Domino Iron Catalysis: Direct Aryl-Alkyl Cross-Coupling. Angew. Chem. Int. Ed. 2009, 48, 607–610. https://doi.org/ 10.1002/anie.200804434. 114. Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. Zn-Mediated, Pd-Catalyzed Cross-Couplings in Water at Room Temperature Without Prior Formation of Organozinc Reagents. J. Am. Chem. Soc. 2009, 131, 15592–15593. https://doi.org/10.1021/ja906803t. 115. Komeyama, K.; Ohata, R.; Kiguchi, S.; Osaka, I. Highly Nucleophilic Vitamin B12-Assisted Nickel-Catalysed Reductive Coupling of Aryl Halides and Non-Activated Alkyl Tosylates. Chem. Commun. 2017, 53, 6401–6404. https://doi.org/10.1039/c7cc01932g. 116. Lu, X.; Yi, J.; Zhang, Z.-Q.; Dai, J.-J.; Liu, J.-H.; Xiao, B.; Fu, Y.; Liu, L. Expedient Synthesis of Chiral a-Amino Acids through Nickel-Catalyzed Reductive Cross-Coupling. Chem. Eur. J. 2014, 20, 15339–15343. https://doi.org/10.1002/chem.201405296. 117. Krasovskiy, A.; Thomé, I.; Graff, J.; Krasovskaya, V.; Konopelski, P.; Duplais, C.; Lipshutz, B. H. Cross-Couplings of Alkyl Halides with Heteroaromatic Halides, in Water at Room Temperature. Tetrahedron Lett. 2011, 52, 2203–2205. https://doi.org/10.1016/j.tetlet.2010.11.160. 118. Amatore, M.; Gosmini, C. Direct Method for Carbon-Carbon Bond Formation: The Functional Group Tolerant Cobalt-Catalyzed Alkylation of Aryl Halides. Chem. Eur. J. 2010, 16, 5848–5852. https://doi.org/10.1002/chem.201000178. 119. Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides With Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920–921. https://doi.org/ 10.1021/ja9093956. 120. Molander, G. A.; Traister, K. M.; O’Neill, B. T. Engaging Nonaromatic, Heterocyclic Tosylates in Reductive Cross-Coupling with Aryl and Heteroaryl Bromides. J. Org. Chem. 2015, 80, 2907–2911. https://doi.org/10.1021/acs.joc.5b00135. 121. Wang, X.; Wang, S.; Xue, W.; Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl Bromides With Tertiary Alkyl Halides. J. Am. Chem. Soc. 2015, 137, 11562–11565. https:// doi.org/10.1021/jacs.5b06255. 122. Wang, X.; Ma, G.; Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T. D.; Wang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl Iodides With Tertiary Alkyl Halides. J. Am. Chem. Soc. 2018, 140, 14490–14497. https://doi.org/10.1021/jacs.8b09473. 123. Wang, J.; Zhao, J.; Gong, H. Nickel-Catalyzed Methylation of Aryl Halides/Tosylates With Methyl Tosylate. Chem. Commun. 2017, 53, 10180–10183. https://doi.org/10.1039/ C7CC06106D. 124. Dumas, A.; Garsi, J. B.; Poissonnet, G.; Hanessian, S. Ni-Catalyzed Reductive and Merged Photocatalytic Cross-Coupling Reactions Toward sp3/sp2-Functionalized Isoquinolones: Creating Diversity at C-6 and C-7 to Address Bioactive Analogues. ACS Omega 2020, 5, 27591–27606. https://doi.org/10.1021/acsomega.0c04181. 125. Sumida, Y.; Sumida, T.; Hosoya, T. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Triflates and Nonaflates with Alkyl Iodides. Synthesis 2017, 49, 3590–3601. https://doi. org/10.1055/s-0036-1588464. 126. Duplais, C.; Krasovskiy, A.; Lipshutz, B. H. Organozinc Chemistry Enabled by Micellar Catalysis. Palladium-Catalyzed Cross-Couplings between Alkyl and Aryl Bromides in Water at Room Temperature. Organometallics 2011, 30, 6090–6097. https://doi.org/10.1021/om200846h. 127. Molander, G. A.; Traister, K. M.; ONeill, B. T. Reductive Cross-Coupling of Nonaromatic, Heterocyclic Bromides with Aryl and Heteroaryl Bromides. J. Org. Chem. 2014, 79, 5771–5780. https://doi.org/10.1021/jo500905m. 128. Liu, H.; Liang, Z.; Qian, Q.; Lin, K. Nickel-Catalyzed Reductive Alkylation of Halogenated Pyridines with Secondary Alkyl Bromides. Synth. Commun. 2014, 44, 2999–3007. https://doi.org/10.1080/00397911.2014.924141. 129. Kadunce, N. T.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between Heteroaryl Iodides and a-Chloronitriles. J. Am. Chem. Soc. 2015, 137, 10480–10483. https://doi.org/10.1021/jacs.5b06466. 130. Nimmagadda, S. K.; Korapati, S.; Dasgupta, D.; Malik, N. A.; Vinodini, A.; Gangu, A. S.; Kalidindi, S.; Maity, P.; Bondigela, S. S.; Venu, A.; Gallagher, W. P.; Aytar, S.; GonzálezBobes, F.; Vaidyanathan, R. Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate. Org. Process Res. Dev. 2020, 24, 1141–1148. https://doi.org/10.1021/acs.oprd.0c00134. 131. Anka-Lufford, L. L.; Huihui, K. M. M.; Gower, N. J.; Ackerman, L. K. G.; Weix, D. J. Nickel-Catalyzed Cross-Electrophile Coupling With Organic Reductants in Non-Amide Solvents. Chem. Eur. J. 2016, 22, 11564–11567. https://doi.org/10.1002/chem.201602668. 132. Everson, D. A.; Buonomo, J. A.; Weix, D. J. Nickel-Catalyzed Cross-Electrophile Coupling of 2-Chloropyridines with Alkyl Bromides. Synlett 2014, 25, 233–238. https://doi.org/ 10.1055/s-0033-1340151.

114

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

133. Hansen, E. C.; Li, C.; Yang, S.; Pedro, D.; Weix, D. J. Coupling of Challenging Heteroaryl Halides with Alkyl Halides via Nickel-Catalyzed Cross-Electrophile Coupling. J. Org. Chem. 2017, 82, 7085–7092. https://doi.org/10.1021/acs.joc.7b01334. 134. Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing Conventional Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134, 6146–6159. https://doi.org/10.1021/ja301769r. 135. Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.; Weix, D. J. New Ligands for Nickel Catalysis From Diverse Pharmaceutical Heterocycle Libraries. Nat. Chem. 2016, 8, 1126–1130. https://doi.org/10.1038/nchem.2587. 136. Kim, S.; Goldfogel, M. J.; Gilbert, M. M.; Weix, D. J. Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides. J. Am. Chem. Soc. 2020, 142, 9902–9907. https://doi.org/10.1021/jacs.0c02673. 137. Charboneau, D. J.; Barth, E. L.; Hazari, N.; Uehling, M. R.; Zultanski, S. L. A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies. ACS Catal. 2020, 10, 12642–12656. https://doi.org/10.1021/acscatal.0c03237. 138. Li, X.; Feng, Z.; Jiang, Z. X.; Zhang, X. Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Iodides with Fluorinated Secondary Alkyl Bromides. Org. Lett. 2015, 17, 5570–5573. https://doi.org/10.1021/acs.orglett.5b02716. 139. Li, X.; Gao, X.; He, C.-Y.; Zhang, X. Using Chlorotrifluoroethane for Trifluoroethylation of (Hetero)Aryl Bromides and Chlorides via Nickel Catalysis. Org. Lett. 2021, 23, 1400–1405. https://doi.org/10.1021/acs.orglett.1c00058. 140. Xu, C.; Guo, W.-H.; He, X.; Guo, Y.-L.; Zhang, X.-Y.; Zhang, X. Difluoromethylation of (Hetero)Aryl Chlorides with Chlorodifluoromethane Catalyzed by Nickel. Nat. Commun. 2018, 9, 1170. https://doi.org/10.1038/s41467-018-03532-1. 141. Yin, H.; Sheng, J.; Zhang, K. F.; Zhang, Z. Q.; Bian, K. J.; Wang, X. S. Nickel-Catalyzed Monofluoromethylation of (Hetero)Aryl Bromides via Reductive Cross-Coupling. Chem. Commun. 2019, 55, 7635–7638. https://doi.org/10.1039/c9cc03737c. 142. He, X.; Gao, X.; Zhang, X. Nickel-Catalyzed Difluoroalkylation of (Hetero)Aryl Bromides with Unactivated 1-Bromo-1,1-Difluoroalkanes. Chin. J. Chem. 2018, 36, 1059–1062. https://doi.org/10.1002/cjoc.201800276. 143. Zhang, Q.; Wang, X.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Halides with Aryl Halides. Synthesis 2016, 48, 2829–2836. https://doi.org/ 10.1055/s-0035-1562442. 144. Pan, Y.; Gong, Y.; Song, Y.; Tong, W.; Gong, H. Deoxygenative Cross-Electrophile Coupling of Benzyl Chloroformates with Aryl Iodides. Org. Biomol. Chem. 2019, 17, 4230–4233. https://doi.org/10.1039/c9ob00628a. 145. Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling to Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139, 5684–5687. https://doi.org/10.1021/jacs.7b01705. 146. Pal, S.; Chowdhury, S.; Rozwadowski, E.; Auffrant, A.; Gosmini, C. Cobalt-Catalyzed Reductive Cross-Coupling Between Benzyl Chlorides and Aryl Halides. Adv. Synth. Catal. 2016, 358, 2431–2435. https://doi.org/10.1002/adsc.201600378. 147. Duplais, C.; Krasovskiy, A.; Wattenberg, A.; Lipshutz, B. H. Cross-Couplings Between Benzylic and Aryl Halides “on Water”: Synthesis of Diarylmethanes. Chem. Commun. 2010, 46, 562–564. https://doi.org/10.1039/B922280D. 148. He, R.-D.; Li, C.-L.; Pan, Q.-Q.; Guo, P.; Liu, X.-Y.; Shu, X.-Z. Reductive Coupling Between C–N and C–O Electrophiles. J. Am. Chem. Soc. 2019, 141, 12481–12486. https:// doi.org/10.1021/jacs.9b05224. 149. Guo, P.; Wang, K.; Jin, W. J.; Xie, H.; Qi, L.; Liu, X. Y.; Shu, X. Z. Dynamic Kinetic Cross-Electrophile Arylation of Benzyl Alcohols by Nickel Catalysis. J. Am. Chem. Soc. 2021, 143, 513–523. https://doi.org/10.1021/jacs.0c12462. 150. Zhang, J.; Lu, G.; Xu, J.; Sun, H.; Shen, Q. Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Chlorides With Aryl Chlorides/Fluorides: A One-Pot Synthesis of Diarylmethanes. Org. Lett. 2016, 18, 2860–2863. https://doi.org/10.1021/acs.orglett.6b01134. 151. Shen, Z. W.; Meng, D. D.; Imran, S.; Yan, C. H.; Sun, H. M. Heteroleptic Ni(II) Complexes Bearing a Bulky Yet Flexible ibiox-6 Ligand: Improved Selectivity in Cross-Electrophile Coupling of Benzyl Chlorides With Aryl Chlorides/Fluorides. Organometallics 2020, 39, 3540–3545. https://doi.org/10.1021/acs.organomet.0c00515. 152. Suga, T.; Ukaji, Y. Nickel-Catalyzed Cross-Electrophile Coupling Between Benzyl Alcohols and Aryl Halides Assisted by Titanium Co-Reductant. Org. Lett. 2018, 20, 7846–7850. https://doi.org/10.1021/acs.orglett.8b03367. 153. Sheng, J.; Ni, H.-Q.; Zhang, H.-R.; Zhang, K.-F.; Wang, Y.-N.; Wang, X.-S. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation. Angew. Chem. Int. Ed. 2018, 57, 7634–7639. https://doi.org/10.1002/anie.201803228. 154. Wang, S.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl Halides with Secondary Alkyl Bromides and Allylic Acetate. Org. Lett. 2012, 14, 3352–3355. https:// doi.org/10.1021/ol3013342. 155. Gomes, P.; Gosmini, C.; Périchon, J. New Chemical Cross-Coupling Between Aryl Halides and Allylic Acetates using a Cobalt Catalyst. Org. Lett. 2003, 5, 1043–1045. https:// doi.org/10.1021/ol0340641. 156. Cui, X.; Wang, S.; Zhang, Y.; Deng, W.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Allylation of Aryl Bromides with Allylic Acetates. Org. Biomol. Chem. 2013, 11, 3094–3097. https://doi.org/10.1039/c3ob40232k. 157. Jia, X. G.; Guo, P.; Duan, J.; Shu, X. Z. Dual Nickel and Lewis Acid Catalysis for Cross-Electrophile Coupling: The Allylation of Aryl Halides with Allylic Alcohols. Chem. Sci. 2018, 9, 640–645. https://doi.org/10.1039/c7sc03140h. 158. Durandetti, M.; Gosmini, C.; Périchon, J. Ni-Catalyzed Activation of a-Chloroesters: A Simple Method for the Synthesis of a-Arylesters and b-Hydroxyesters. Tetrahedron 2007, 63, 1146–1153. https://doi.org/10.1016/j.tet.2006.11.055. 159. Tao, X.; Chen, Y.; Guo, J.; Wang, X.; Gong, H. Preparation of a-Amino Acids: via Ni-Catalyzed Reductive Vinylation and Arylation of a-Pivaloyloxy Glycine. Chem. Sci. 2021, 12, 220–226. https://doi.org/10.1039/d0sc05452f. 160. Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.; Kumadaki, I. Synthesis of Alkenyl-and Aryldifluoroacetate Using a Copper Complex from Ethyl Bromodifluoroacetate. Chem. Pharm. Bull. 1999, 47, 1013–1016. 161. Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.; Spiewak, A. M.; Johnson, K. A.; Dibenedetto, T. A.; Kim, S.; Ackerman, L. K. G.; Weix, D. J. Decarboxylative Cross-Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides. J. Am. Chem. Soc. 2016, 138, 5016–5019. https://doi.org/10.1021/jacs.6b01533. 162. Yue, H.; Zhu, C.; Shen, L.; Geng, Q.; Hock, K. J.; Yuan, T.; Cavallo, L.; Rueping, M. Nickel-Catalyzed C-N Bond Activation: Activated Primary Amines as Alkylating Reagents in Reductive Cross-Coupling. Chem. Sci. 2019, 10, 4430–4435. https://doi.org/10.1039/c9sc00783k. 163. Liao, J.; Basch, C. H.; Hoerrner, M. E.; Talley, M. R.; Boscoe, B. P.; Tucker, J. W.; Garnsey, M. R.; Watson, M. P. Deaminative Reductive Cross-Electrophile Couplings of Alkylpyridinium Salts and Aryl Bromides. Org. Lett. 2019, 21, 2941–2946. https://doi.org/10.1021/acs.orglett.9b01014. 164. Ni, S.; Li, C. X.; Mao, Y.; Han, J.; Wang, Y.; Yan, H.; Pan, Y. Ni-Catalyzed Deaminative Cross-Electrophile Coupling of Katritzky Salts with Halides via C–N Bond Activation. Sci. Adv. 2019, 5, 9516–9544. https://doi.org/10.1126/sciadv.aaw9516. 165. Gao, M.; Sun, D.; Gong, H. Ni-Catalyzed Reductive C–O Bond Arylation of Oxalates Derived from a-Hydroxy Esters with Aryl Halides. Org. Lett. 2019, 21, 1645–1648. https:// doi.org/10.1021/acs.orglett.9b00174. 166. Hughes, J. M. E.; Fier, P. S. Desulfonylative Arylation of Redox-Active Alkyl Sulfones with Aryl Bromides. Org. Lett. 2019, 21, 5650–5654. https://doi.org/10.1021/acs. orglett.9b01987. 167. Arendt, K. M.; Doyle, A. G. Dialkyl Ether Formation by Nickel-Catalyzed Cross-Coupling of Acetals and Aryl Iodides. Angew. Chem. Int. Ed. 2015, 54, 9876–9880. https://doi. org/10.1002/anie.201503936. 168. Liu, J.; Lei, C.; Gong, H. Nickel-Catalyzed Reductive Coupling of Glucosyl Halides with Aryl/Vinyl Halides Enabling b-Selective Preparation of C-Aryl/Vinyl Glucosides. Sci. China: Chem. 2019, 62, 1492–1496. https://doi.org/10.1007/s11426-019-9501-4.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

115

169. Liu, J.; Gong, H. Stereoselective Preparation of a-C-Vinyl/Aryl Glycosides via Nickel-Catalyzed Reductive Coupling of Glycosyl Halides with Vinyl and Aryl Halides. Org. Lett. 2018, 20, 7991–7995. https://doi.org/10.1021/acs.orglett.8b03567. 170. Zhao, Y.; Weix, D. J. Nickel-Catalyzed Regiodivergent Opening of Epoxides With Aryl Halides: Co-Catalysis Controls Regioselectivity. J. Am. Chem. Soc. 2014, 136, 48–51. https://doi.org/10.1021/ja410704d. 171. Banerjee, A.; Yamamoto, H. Nickel Catalyzed Regio-, Diastereo-, and Enantioselective Cross-Coupling of 3,4-Epoxyalcohol with Aryl Iodides. Org. Lett. 2017, 19, 4363–4366. https://doi.org/10.1021/acs.orglett.7b02076. 172. Zhao, Y.; Weix, D. J. Enantioselective Cross-Coupling of Meso-Epoxides with Aryl Halides. J. Am. Chem. Soc. 2015, 137, 3237–3240. https://doi.org/10.1021/jacs.5b01909. 173. Woods, B. P.; Orlandi, M.; Huang, C.-Y.; Sigman, M. S.; Doyle, A. G. Nickel-Catalyzed Enantioselective Reductive Cross-Coupling of Styrenyl Aziridines. J. Am. Chem. Soc. 2017, 139, 5688–5691. https://doi.org/10.1021/jacs.7b03448. 174. Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898–6926. https://doi.org/10.1021/acs.joc.6b01449. 175. Stephenson, C.; Yoon, T.; MacMillan, D. W. C. Visible Light Photocatalysis in Organic Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2018. https://doi. org/10.1002/9783527674145. 176. Johnson, K. A.; Biswas, S.; Weix, D. J. Cross-Electrophile Coupling of Vinyl Halides with Alkyl Halides. Chem. Eur. J. 2016, 22, 7399–7402. https://doi.org/10.1002/ chem.201601320. 177. Gu, J.; Qiu, C.; Lu, W.; Qian, Q.; Lin, K.; Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Vinyl Bromides with Unactivated Alkyl Halides. Synthesis 2017, 49, 1867–1873. https://doi.org/10.1055/s-0036-1588132. 178. Duan, J.; Du, Y. F.; Pang, X.; Shu, X. Z. Ni-Catalyzed Cross-Electrophile Coupling between Vinyl/Aryl and Alkyl Sulfonates: Synthesis of Cycloalkenes and Modification of Peptides. Chem. Sci. 2019, 10, 8706–8712. https://doi.org/10.1039/c9sc03347e. 179. Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. Stereoselective Negishi-Like Couplings Between Alkenyl and Alkyl Halides in Water at Room Temperature. Org. Lett. 2010, 12, 4742–4744. https://doi.org/10.1021/ol101885t. 180. Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of Gem-Difluoroalkenes with Unactivated Secondary and Tertiary Alkyl Halides. J. Am. Chem. Soc. 2017, 139, 12632–12637. https://doi.org/10.1021/jacs.7b06469. 181. Cherney, A. H.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between Vinyl and Benzyl Electrophiles. J. Am. Chem. Soc. 2014, 136, 14365–14368. https://doi.org/10.1021/ja508067c. 182. Krasovskaya, V.; Krasovskiy, A.; Bhattacharjya, A.; Lipshutz, B. H. “On Water” sp3–sp2 Cross-Couplings Between Benzylic and Alkenyl Halides. Chem. Commun. 2011, 47, 5717. https://doi.org/10.1039/c1cc11087j. 183. Cai, Y.; Benischke, A. D.; Knochel, P.; Gosmini, C. Cobalt-Catalyzed Reductive Cross-Coupling Between Styryl and Benzyl Halides. Chem. Eur. J. 2017, 23, 250–253. https:// doi.org/10.1002/chem.201603832. 184. Qiu, C.; Yao, K.; Zhang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of a-Halocarbonyl Derivatives With Vinyl Bromides. Org. Biomol. Chem. 2016, 14, 11332–11335. https:// doi.org/10.1039/c6ob02269c. 185. Qiao, J. B.; Zhao, Z. Z.; Zhang, Y. Q.; Yin, K.; Tian, Z. X.; Shu, X. Z. Allylboronates from Vinyl Triflates and a-Chloroboronates by Reductive Nickel Catalysis. Org. Lett. 2020, 22, 5085–5089. https://doi.org/10.1021/acs.orglett.0c01683. 186. Hofstra, J. L.; Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 139–142. https://doi.org/10.1021/jacs.7b11707. 187. Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Nickel-Catalyzed Enantioselective Cross-Coupling of N-Hydroxyphthalimide Esters with Vinyl Bromides. Org. Lett. 2017, 19, 2150–2153. https://doi.org/10.1021/acs.orglett.7b00793. 188. Ye, Y.; Chen, H.; Yao, K.; Gong, H. Iron-Catalyzed Reductive Vinylation of Tertiary Alkyl Oxalates with Activated Vinyl Halides. Org. Lett. 2020, 22, 2070–2075. https://doi.org/ 10.1021/acs.orglett.0c00561. 189. Shrestha, R.; Weix, D. J. Reductive Conjugate Addition of Haloalkanes to Enones to form Silyl Enol Ethers. Org. Lett. 2011, 13, 2766–2769. https://doi.org/10.1021/ ol200881v. 190. Su, L.; Ma, G.; Song, Y.; Gong, H. Nickel-Catalyzed Reductive Vinylation of Chloro-Hexahydropyrroloindoline Derivatives with Vinyl Triflates. Org. Lett. 2021, 23, 2493–2497. https://doi.org/10.1021/acs.orglett.1c00431. 191. Tao, X.; Yao, K.; Xue, W. Ni-Catalyzed Cross-Electrophile Coupling of a-Hydroxy Carbonyl Compound-Derived Oxalates with Vinyl Triflates. Tetrahedron Lett. 2021, 73, 153129. https://doi.org/10.1016/j.tetlet.2021.153129. 192. Hu, L.; Liu, X.; Liao, X. Nickel-Catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide. Angew. Chem. Int. Ed. 2016, 55, 9743–9747. https://doi.org/10.1002/ anie.201604406. 193. Sun, D.; Ma, G.; Zhao, X.; Lei, C.; Gong, H. Nickel-Catalyzed Asymmetric Reductive Arylation of a-Chlorosulfones with Aryl Halides. Chem. Sci. 2021, 12, 5253–5258. https:// doi.org/10.1039/D1SC00283J. 194. Wu, S.; Shi, W.; Zou, G. Mechanical Metal Activation for Ni-Catalyzed, Mn-Mediated Cross-Electrophile Coupling Between Aryl and Alkyl Bromides. New J. Chem. 2021. https:// doi.org/10.1039/D1NJ01732B. 195. Martin-Montero, R.; Yatham, V. R.; Yin, H.; Davies, J.; Martin, R. Ni-Catalyzed Reductive Deaminative Arylation at sp3 Carbon Centers. Org. Lett. 2019, 21, 2947–2951. https:// doi.org/10.1021/acs.orglett.9b01016. 196. Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt CO-Catalysis for Cross-Electrophile Coupling: Diarylmethanes from Benzyl Mesylates and Aryl Halides. Chem. Sci. 2015, 6, 1115–1119. https://doi.org/10.1039/C4SC03106G. 197. Cao, Z. C.; Luo, Q. Y.; Shi, Z. J. Practical Cross-Coupling Between O-Based Electrophiles and Aryl Bromides via Ni Catalysis. Org. Lett. 2016, 18, 5978–5981. https://doi.org/ 10.1021/acs.orglett.6b02656. 198. Choi, J.; Fu, G. C. Transition Metal-Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in Cross-Coupling Chemistry. Science 2017, 356, eaaf7230. https://doi.org/ 10.1126/science.aaf7230. 199. Onaka, M.; Matsuoka, Y.; Mukaiyama, T. A Convenient Method for the Direct Preparation of Ketones from 2-(6-(2-Methoxyethyl)Pyridyl)Carboxylates and Alkyl Iodides by Use of Zinc Dust and a Catalytic Amount of Nickel Dichloride. Chem. Lett. 1981, 10, 531–534. https://doi.org/10.1246/cl.1981.531. 200. Liang, Z.; Xue, W.; Lin, K.; Gong, H. Nickel-Catalyzed Reductive Methylation of Alkyl Halides and Acid Chlorides with Methyl p-Tosylate. Org. Lett. 2014, 16, 5620–5623. https://doi.org/10.1021/ol502682q. 201. Yang, F.; Ding, D.; Wang, C. Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters With Alkyl Bromides. Org. Lett. 2020, 22, 9203–9209. https://doi.org/ 10.1021/acs.orglett.0c03342. 202. Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic a,a-Disubstituted Ketones. J. Am. Chem. Soc. 2013, 135, 7442–7445. https://doi.org/10.1021/ja402922w. 203. Wotal, A. C.; Ribson, R. D.; Weix, D. J. Stoichiometric Reactions of Acylnickel(II) Complexes with Electrophiles and the Catalytic Synthesis of Ketones. Organometallics 2014, 33, 5874–5881. https://doi.org/10.1021/om5004682. 204. Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Ketone Formation Via Mild Nickel-Catalyzed Reductive Coupling of Alkyl Halides With Aryl Acid Chlorides. Org. Lett. 2012, 14, 3044–3047. https://doi.org/10.1021/ol3011198. 205. Jia, X.; Zhang, X.; Qian, Q.; Gong, H. Alkyl-Aryl Ketone Synthesis via Nickel-Catalyzed Reductive Coupling of Alkyl Halides With Aryl Acids and Anhydrides. Chem. Commun. 2015, 51, 10302–10305. https://doi.org/10.1039/c5cc03113c.

116

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

206. Zheng, M.; Xue, W.; Xue, T.; Gong, H. Ester Formation via Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Chloroformates. Org. Lett. 2016, 18, 6152–6155. https:// doi.org/10.1021/acs.orglett.6b03158. 207. Wotal, A. C.; Weix, D. J. Synthesis of Functionalized Dialkyl Ketones from Carboxylic Acid Derivatives and Alkyl Halides. Org. Lett. 2012, 14, 1476–1479. https://doi.org/ 10.1021/ol300217x. 208. Zhao, C.; Jia, X.; Wang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of Alkyl Acids with Unactivated Tertiary Alkyl and Glycosyl Halides. J. Am. Chem. Soc. 2014, 136, 17645–17651. https://doi.org/10.1021/ja510653n. 209. Ai, Y.; Ye, N.; Wang, Q.; Yahata, K.; Kishi, Y. Zirconium/Nickel-Mediated One-Pot Ketone Synthesis. Angew. Chem. Int. Ed. 2017, 56, 10791–10795. https://doi.org/10.1002/ anie.201705520. 210. Wang, J.; Cary, B. P.; Beyer, P. D.; Gellman, S. H.; Weix, D. J. Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters. Angew. Chem. Int. Ed. 2019, 58, 12081–12085. https://doi.org/10.1002/anie.201906000. 211. Wang, J.; Hoerrner, M. E.; Watson, M. P.; Weix, D. J. Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids. Angew. Chem. Int. Ed. 2020, 59, 13484–13489. https://doi.org/10.1002/anie.202002271. 212. Yu, C.-G.; Matsuo, Y. Nickel-Catalyzed Deaminative Acylation of Activated Aliphatic Amines with Aromatic Amides via C–N Bond Activation. Org. Lett. 2020, 22, 950–955. https://doi.org/10.1021/acs.orglett.9b04497. 213. Yin, H.; Zhao, C.; You, H.; Lin, K.; Gong, H. Mild Ketone Formation via Ni-Catalyzed Reductive Coupling of Unactivated Alkyl Halides with Acid Anhydrides. Chem. Commun. 2012, 48, 7034–7036. https://doi.org/10.1039/c2cc33232a. 214. Yahata, K.; Ye, N.; Ai, Y.; Iso, K.; Kishi, Y. Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel-Mediated One-Pot Ketone Synthesis as the Final Coupling Reaction. Angew. Chem. Int. Ed. 2017, 56, 10796–10800. https://doi.org/10.1002/anie.201705523. 215. Konev, M. O.; Jarvo, E. R. Decarboxylative Alkyl-Alkyl Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2016, 55, 11340–11342. https://doi.org/10.1002/anie.201605593. 216. Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. Practical Ni-Catalyzed Aryl–Alkyl Cross-Coupling of Secondary Redox-Active Esters. J. Am. Chem. Soc. 2016, 138, 2174–2177. https://doi.org/10.1021/jacs.6b00250. 217. Zheng, Y.; Xie, P.; Daneshfar, O.; Houk, K. N.; Hong, X.; Newman, S. G. Direct Synthesis of Ketones from Methyl Esters by Nickel-Catalyzed Suzuki–Miyaura Coupling. Angew. Chem. Int. Ed. 2021, 60, 13476–13483. https://doi.org/10.1002/anie.202103327. 218. Parida, S. K.; Mandal, T.; Das, S.; Hota, S. K.; De Sarkar, S.; Murarka, S. Single Electron Transfer-Induced Redox Processes involving N-(Acyloxy)Phthalimides. ACS Catal. 2021, 11, 1640–1683. https://doi.org/10.1021/acscatal.0c04756. 219. Rodríguez, N.; Goossen, L. J. Decarboxylative Coupling Reactions: A Modern Strategy for C–C-Bond Formation. Chem. Soc. Rev. 2011, 40, 5030. https://doi.org/10.1039/ c1cs15093f. 220. Li, Z.; Sun, H. M.; Shen, Q. Iron-Mediated Inter- and Intramolecular Reductive Cross-Coupling of Unactivated Alkyl Chlorides with Aryl Bromides. Org. Biomol. Chem. 2016, 14, 3314–3321. https://doi.org/10.1039/c6ob00247a. 221. Liu, H.; Wei, J.; Qiao, Z.; Fu, Y.; Jiang, X. Palladium-Catalyzed Intramolecular Reductive Cross-Coupling of Csp2–Csp3. Chem. Eur. J. 2014, 20, 8308–8313. https://doi.org/ 10.1002/chem.201403093. 222. Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Nickel-Mediated Inter- and Intramolecular Reductive Cross-Coupling of Unactivated Alkyl Bromides and Aryl Iodides at Room Temperature. Chem. Eur. J. 2012, 18, 6039–6048. https://doi.org/10.1002/chem.201200190. 223. Konev, M. O.; Hanna, L. E.; Jarvo, E. R. Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides. Angew. Chem. Int. Ed. 2016, 55, 6730–6733. https://doi.org/10.1002/anie.201601206. 224. Inaba, S.; Matsumoto, H.; Rieke, R. D. Highly Reactive Metallic Nickel: Reductive Homocoupling Reagent for Benzylic Mono- and Polyhalides. J. Org. Chem. 1984, 49, 2093–2098. https://doi.org/10.1021/jo00186a003. 225. Iyoda, M.; Sakaitan, M.; Otsuka, H.; Oda, M. Reductive Coupling of Benzyl Halides Using Nickel(0)-Complex Generated In-Situ in the Presence of Tetraethylammonium Iodide, a Simple and Convenient Synthesis of Bibenzyls. Chem. Lett. 1985, 14, 127–130. https://doi.org/10.1246/cl.1985.127. 226. Ginah, F. O.; Donovan, T. A.; Suchan, S. D.; Pfennig, D. R.; Ebert, G. W. Homocoupling of Alkyl Halides and Cyclization of a,o-Dihaloalkanes via Activated Copper. J. Org. Chem. 1990, 55, 584–589. https://doi.org/10.1021/jo00289a037. 227. Prinsell, M. R.; Everson, D. A.; Weix, D. J. Nickel-Catalyzed, Sodium Iodide-Promoted Reductive Dimerization of Alkyl Halides, Alkyl Pseudohalides, and Allylic Acetates. Chem. Commun. 2010, 46, 5743–5745. https://doi.org/10.1039/c0cc01716g. 228. Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal, P. R.; Plant, A. Ligand-Assisted Nickel-Catalysed sp3–sp3 Homocoupling of Unactivated Alkyl Bromides and Its Application to the Active Template Synthesis of Rotaxanes. Chem. Sci. 2010, 1, 383–386. https://doi.org/10.1039/c0sc00279h. 229. Peng, Y.; Luo, L.; Yan, C. S.; Zhang, J. J.; Wang, Y. W. Ni-Catalyzed Reductive Homocoupling of Unactivated Alkyl Bromides at Room Temperature and its Synthetic Application. J. Org. Chem. 2013, 78, 10960–10967. https://doi.org/10.1021/jo401936v. 230. Komeyama, K.; Tsunemitsu, R.; Michiyuki, T.; Yoshida, H.; Osaka, I. Ni/Co-Catalyzed homocoupling of Alkyl Tosylates. Molecules 2019, 24, 1458–1469. https://doi.org/ 10.3390/molecules24081458. 231. Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Nickel-Catalyzed Cross-Coupling of Unactivated Alkyl Halides using Bis(Pinacolato)Diboron as reductant. Chem. Sci. 2013, 4, 4022–4029. https://doi.org/10.1039/C3SC51098K. 232. Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides. Org. Lett. 2011, 13, 2138–2141. https://doi.org/10.1021/ ol200617f. 233. Qian, X.; Auffrant, A.; Felouat, A.; Gosmini, C. Cobalt-Catalyzed Reductive Allylation of Alkyl Halides with Allylic Acetates or Carbonates. Angew. Chem. Int. Ed. 2011, 50, 10402–10405. https://doi.org/10.1002/anie.201104390. 234. Liu, J.-H.; Yang, C.-T.; Lu, X.-Y.; Zhang, Z.-Q.; Xu, L.; Cui, M.; Lu, X.; Xiao, B.; Fu, Y.; Liu, L. Copper-Catalyzed Reductive Cross-Coupling of Nonactivated Alkyl Tosylates and Mesylates with Alkyl and Aryl Bromides. Chem. Eur. J. 2014, 20, 15334–15338. https://doi.org/10.1002/chem.201405223. 235. Komeyama, K.; Michiyuki, T.; Osaka, I. Nickel/Cobalt-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides With Alkyl Tosylates. ACS Catal. 2019, 9, 9285–9291. https://doi. org/10.1021/acscatal.9b03352. 236. Dai, Y.; Wu, F.; Zang, Z.; You, H.; Gong, H. Ni-Catalyzed Reductive Allylation of Unactivated Alkyl Halides With Allylic Carbonates. Chem. Eur. J. 2012, 18, 808–812. https://doi. org/10.1002/chem.201102984. 237. Anka-Lufford, L. L.; Prinsell, M. R.; Weix, D. J. Selective Cross-Coupling of Organic Halides with Allylic Acetates. J. Org. Chem. 2012, 77, 9989–10000. https://doi.org/ 10.1021/jo302086g. 238. Chen, H.; Jia, X.; Yu, Y.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic Carbonates. Angew. Chem. Int. Ed. 2017, 56, 13103–13106. https://doi.org/10.1002/anie.201705521. 239. Yu, Y.; Chen, H.; Qian, Q.; Yao, K.; Gong, H. An Extension of Nickel-Catalyzed Reductive Coupling between Tertiary Alkyl Halides with Allylic Carbonates. Tetrahedron 2018, 74, 5651–5658. https://doi.org/10.1016/j.tet.2018.07.057. 240. Yan, X. B.; Li, C. L.; Jin, W. J.; Guo, P.; Shu, X. Z. Reductive Coupling of Benzyl Oxalates with Highly Functionalized Alkyl Bromides by Nickel Catalysis. Chem. Sci. 2018, 9, 4529–4534. https://doi.org/10.1039/c8sc00609a. 241. Chen, H.; Ye, Y.; Tong, W.; Fang, J.; Gong, H. Formation of Allylated Quaternary Carbon Centers via C-O/C-O Bond Fragmentation of Oxalates and Allyl Carbonates. Chem. Commun. 2020, 56, 454–457. https://doi.org/10.1039/c9cc07072a. 242. Lin, T.; Gu, Y.; Qian, P.; Guan, H.; Walsh, P. J.; Mao, J. Nickel-Catalyzed Reductive Coupling of Homoenolates and Their Higher Homologues with Unactivated Alkyl Bromides. Nat. Commun. 2020, 11, 5638. https://doi.org/10.1038/s41467-020-19194-x.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

117

243. Lan, Y.; Yang, F.; Wang, C. Synthesis of Gem-Difluoroalkenes via Nickel-Catalyzed Allylic Defluorinative Reductive Cross-Coupling. ACS Catal. 2018, 8, 9245–9251. https://doi. org/10.1021/acscatal.8b02784. 244. Lin, Z.; Lan, Y.; Wang, C. Reductive Allylic Defluorinative Cross-Coupling Enabled by Ni/Ti Cooperative Catalysis. Org. Lett. 2019, 21, 8316–8322. https://doi.org/10.1021/acs. orglett.9b03102. 245. Lu, X.; Wang, X.-X.; Gong, T.-J.; Pi, J.-J.; He, S.-J.; Fu, Y. Nickel-Catalyzed Allylic Defluorinative Alkylation of Trifluoromethyl Alkenes with Reductive Decarboxylation of Redox-Active Esters. Chem. Sci. 2019, 10, 809–814. https://doi.org/10.1039/C8SC04335C. 246. Jin, Y.; Wu, J.; Lin, Z.; Lan, Y.; Wang, C. Merger of C–F and C–N Bond Cleavage in Cross-Electrophile Coupling for the Synthesis of Gem-Difluoroalkenes. Org. Lett. 2020, 22, 5347–5352. https://doi.org/10.1021/acs.orglett.0c01592. 247. Lin, Z.; Lan, Y.; Wang, C. Synthesis of Gem-Difluoroalkenes via Nickel-Catalyzed Reductive C–F and C–O Bond Cleavage. ACS Catal. 2019, 9, 775–780. https://doi.org/ 10.1021/acscatal.8b04348. 248. Lu, X. Y.; Jiang, R. C.; Li, J. M.; Liu, C. C.; Wang, Q. Q.; Zhou, H. P. Synthesis of Gem-Difluoroalkenes via Nickel-Catalyzed Allylic Defluorinative Reductive Cross-Coupling of Trifluoromethyl Alkenes With Epoxides. Org. Biomol. Chem. 2020, 18, 3674–3678. https://doi.org/10.1039/d0ob00535e. 249. Lin, Z.; Lan, Y.; Wang, C. Titanocene-Catalyzed Reductive Domino Epoxide Ring Opening/Defluorinative Cross-Coupling Reaction. Org. Lett. 2020, 22, 3509–3514. https://doi. org/10.1021/acs.orglett.0c00960. 250. Kochi, J. K.; Singleton, D. M. Reductive Cyclization of a,o-Dihalides With Chromium-(II) Complexes. J. Org. Chem. 1968, 33, 1027–1034. https://doi.org/10.1021/ jo01267a019. 251. Lucas, E. L.; Hewitt, K. A.; Chen, P.-P.; Castro, A. J.; Hong, X.; Jarvo, E. R. Engaging Sulfonamides: Intramolecular Cross-Electrophile Coupling Reaction of Sulfonamides with Alkyl Chlorides. J. Org. Chem. 2020, 85, 1775–1793. https://doi.org/10.1021/acs.joc.9b02603. 252. Xue, W.; Xu, H.; Liang, Z.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Cyclization of Alkyl Dihalides. Org. Lett. 2014, 16, 4984–4987. https://doi.org/10.1021/ol502207z. 253. Freund, A. Ueber Trimethylen. J. Prakt. Chem. 1882, 26, 367–377. https://doi.org/10.1002/prac.18820260125. 254. Gustavson, G. Ueber Eine Neue Darstellungsmethode Des Trimethylens. J. Prakt. Chem. 1887, 36, 300–303. https://doi.org/10.1002/prac.18870360127. 255. Shortridge, R. W.; Craig, R. A.; Greenlee, K. W.; Derfer, J. M.; Boord, C. E. The Synthesis of Some Cyclopropane and Spirane Hydrocarbons. J. Am. Chem. Soc. 1948, 70, 946–949. https://doi.org/10.1021/ja01183a017. 256. Chock, P. B.; Halpern, J. The Reactions of Pentacyanocobaltate(II) with Some Organic Halides. J. Am. Chem. Soc. 1969, 582–588. https://doi.org/10.1021/ja01031a010. 257. Tollefson, E. J.; Erickson, L. W.; Jarvo, E. R. Stereospecific Intramolecular Reductive Cross-Electrophile Coupling Reactions for Cyclopropane Synthesis. J. Am. Chem. Soc. 2015, 137, 9760–9763. https://doi.org/10.1021/jacs.5b03870. 258. Erickson, L. W.; Lucas, E. L.; Tollefson, E. J.; Jarvo, E. R. Nickel-Catalyzed Cross-Electrophile Coupling of Alkyl Fluorides: Stereospecific Synthesis of Vinylcyclopropanes. J. Am. Chem. Soc. 2016, 138, 14006–14011. https://doi.org/10.1021/jacs.6b07567. 259. Lucas, E. L.; McGinnis, T. M.; Castro, A. J.; Jarvo, E. R. Nickel-Catalyzed Cross-Electrophile Coupling of the Difluoromethyl Group for Fluorinated Cyclopropane Synthesis. Synlett 2021. https://doi.org/10.1055/s-0040-1706013. 260. Chinchilla, R.; Nájera, C. The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry. Chem. Rev. 2007, 107, 874–922. https://doi.org/10.1021/ cr050992x. 261. Chinchilla, R.; Nájera, C. Recent Advances in Sonogashira Reactions. Chem. Soc. Rev. 2011, 40, 5084. https://doi.org/10.1039/c1cs15071e. 262. Huang, L.; Olivares, A. M.; Weix, D. J. Reductive Decarboxylative Alkynylation of N-Hydroxyphthalimide Esters with Bromoalkynes. Angew. Chem. Int. Ed. 2017, 56, 11901–11905. https://doi.org/10.1002/anie.201706781. 263. Jutand, A. Contribution of Electrochemistry to Organometallic Catalysis. Chem. Rev. 2008, 108, 2300–2347. https://doi.org/10.1021/cr068072h. 264. Nédélec, J.-Y.; Périchon, J.; Troupel, M. Organic Electroreductive Coupling Reactions using Transition Metal Complexes as Catalysts. Top. Curr. Chem. 1997, 141–173. https:// doi.org/10.1007/3-540-61454-0_72. 265. Gale-Day, Z. J. Recent Advances in Metal-Catalyzed, Electrochemical Coupling Reactions of sp2 Halides/Boronic Acids and sp3 Centers. Synthesis 2021, 53, 879–888. https:// doi.org/10.1055/s-0040-1706085. 266. Jennings, P. W.; Pillsbury, D. G.; Hall, J. L.; Brice, V. T. Carbon-Carbon Bond Formation via Organometallic Electrochemistry. J. Org. Chem. 1976, 41, 719–722. https://doi.org/ 10.1021/jo00866a036. 267. Schiavon, G.; Bontempelli, G.; Corain, B. Coupling of Organic Halides Electrocatalyzed by the Ni(II)/Ni(I)/Ni(0)–PPh3 System. A Mechanistic Study Based on an Electroanalytical Approach. J. Chem. Soc. Dalton Trans. 1981, 202, 1074–1081. https://doi.org/10.1039/DT9810001074. 268. Mori, M.; Hashimoto, Y.; Ban, Y. Preparation and Synthetic Use of the Zerovalent Nickel Complex by Electrochemical Reduction. Tetrahedron Lett. 1980, 21, 631–634. https:// doi.org/10.1016/S0040-4039(01)85577-5. 269. Troupel, M.; Rollin, Y.; Sibille, S.; Perichon, J.; Fauvarque, J.-F. Catalyse Par Des Complexs s-Aryl-Nickel de l’electroreduction En Biaryles Des Halogenures Aromatiques. J. Organomet. Chem. 1980, 202, 435–446. https://doi.org/10.1016/S0022-328X(00)81872-0. 270. Torii, S.; Tanaka, H.; Morisaki, K. Pd(0)-Catalyzed Electro-Reductive Coupling of Aryl Halides. Tetrahedron Lett. 1985, 26, 1655–1658. https://doi.org/10.1016/S0040-4039 (00)98576-9. 271. Rollin, Y.; Troupel, M.; Tuck, D. G.; Perichon, J. The Coupling of Organic Groups by the Electrochemical Reduction of Organic Halides: Catalysis by 2,20 -Bipyridinenickel Complexes. J. Organomet. Chem. 1986, 303, 131–137. https://doi.org/10.1016/0022-328X(86)80118-8. 272. Meyer, G.; Rollin, Y.; Perichon, J. A Zerovalent Nickel-2,20 -Bipyridine Complex: An Efficient Catalyst for Electrochemical Homocoupling of Ortho-Substituted Halides and Their Heterocoupling With meta- and para-Substituted Halides. J. Organomet. Chem. 1987, 333, 263–267. https://doi.org/10.1016/0022-328X(87)85158-6. 273. Fox, M. A.; Chandler, D. A.; Lee, C. Electrocatalytic Coupling of Aryl Halides With (1,2-bis(di-2-Propylphosphino)Benzene)Nickel(0). J. Org. Chem. 1991, 56, 3246–3255. https://doi.org/10.1021/jo00010a014. 274. Jutand, A.; Négri, S.; Mosleh, A. Palladium Catalysed Electrosynthesis using Aryl Trifluoromethanesulfonates (Triflates). Synthesis of Biaryls and Aromatic Carboxylic Acids. J. Chem. Soc. Chem. Commun. 1992, 1729–1730. https://doi.org/10.1039/C39920001729. 275. Courtois, V.; Barhdadi, R.; Troupel, M.; Périchon, J. Electroreductive Coupling of Organic Halides in Alcoholic Solvents. An Example: The Electrosynthesis of Biaryls Catalysed by Nickel-2,2’ Bipyridine Complexes. Tetrahedron 1997, 53, 11569–11576. https://doi.org/10.1016/S0040-4020(97)00744-8. 276. Yasuhara, A.; Kasano, A.; Sakamoto, T. Electrochemical Generation of Highly Reactive Nickel and Its Utilization for Organic Reactions. J. Synth. Org. Chem., Jpn. 2000, 58, 192–198. https://doi.org/10.5059/yukigoseikyokaishi.58.192. 277. Courtois, V.; Barhdadi, R.; Condon, S.; Troupel, M. Catalysis by Nickel-2,2’-Dipyridylamine Complexes of the Electroreductive Coupling of Aromatic Halides in Ethanol. Tetrahedron Lett. 1999, 40, 5993–5996. https://doi.org/10.1016/S0040-4039(99)01157-0. 278. Cassol, T. M.; Demnitz, F. W. J.; Navarro, M.; Neves, E. A. D. Two Convenient and High-Yielding Preparations of 6,60 -Dimethyl-2,20 -Bipyridine by Homocoupling of 6-Bromopicoline. Tetrahedron Lett. 2000, 41, 8203–8206. https://doi.org/10.1016/S0040-4039(00)01310-1. 279. de França, K. W. R.; Navarro, M.; Léonel, É.; Durandetti, M.; Nédélec, J.-Y. Electrochemical Homocoupling of 2-Bromomethylpyridines Catalyzed by Nickel Complexes. J. Org. Chem. 2002, 67, 1838–1842. https://doi.org/10.1021/jo016280y. 280. Amatore, C.; Carré, E.; Jutand, A.; Tanaka, H.; Ren, Q.; Torii, S. Oxidative Addition of Aryl Halides to Transient Anionic a-Aryl–Palladium(0) Intermediates–Application to Palladium-Catalyzed Reductive Coupling of Aryl Halides. Chem. Eur. J. 1996, 2, 957–966. https://doi.org/10.1002/chem.19960020810.

118

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

281. Meyer, G.; Troupel, M.; Périchon, J. Synthèse de Biaryles Dissymétriques Par Électroréduction d’halogénures Aromatiques Catalysée Par Des Complexes Du Nickel Associé à La 2,20 -Bipyridine. J. Organomet. Chem. 1990, 393, 137–142. https://doi.org/10.1016/0022-328X(90)87206-S. 282. Gomes, P.; Fillon, H.; Gosmini, C.; Labbé, E.; Périchon, J. Synthesis of Unsymmetrical Biaryls by Electroreductive Cobalt-Catalyzed Cross-Coupling of Aryl Halides. Tetrahedron 2002, 58, 8417–8424. https://doi.org/10.1016/S0040-4020(02)01030-X. 283. Cannes, C.; Condon, S.; Durandetti, M.; Périchon, J.; Nédélec, J.-Y. Nickel-Catalyzed Electrochemical Couplings of Vinyl Halides: Synthetic and Stereochemical Aspects. J. Org. Chem. 2000, 65, 4575–4583. https://doi.org/10.1021/jo000182f. 284. Gomes, P.; Gosmini, C.; Périchon, J. Cobalt-Catalyzed Electrochemical Vinylation of Aryl Halides using Vinylic Acetates. Tetrahedron 2003, 59, 2999–3002. https://doi.org/ 10.1016/S0040-4020(03)00404-6. 285. Marzouk, H.; Rollin, Y.; Folest, J. C.; Nédélec, J. Y.; Périchon, J. Electrochemical Synthesis of Ketones from Acid Chlorides and Alkyl and Aryl Halides Catalysed by Nickel Complexes. J. Organomet. Chem. 1989, 369, C47–C50. https://doi.org/10.1016/0022-328X(89)85195-2. 286. Folest, J. C.; Pereira-Martins, E.; Troupel, M.; Périchon, J. Electrochemical Synthesis of Symmetrical Ketones from Acid Chlorides. Tetrahedron Lett. 1993, 34, 7571–7574. https://doi.org/10.1016/S0040-4039(00)60403-3. 287. Gosmini, C.; Nédélec, J. Y.; Périchon, J. Electrochemical Cross-Coupling Between Functionalized Aryl Halides and 2-Chloropyrimidine or 2-Chloropyrazine Catalyzed by Nickel 2,20 -Bipyridine Complex. Tetrahedron Lett. 2000, 41, 201–203. https://doi.org/10.1016/S0040-4039(99)02037-7. 288. Gosmini, C.; Lasry, S.; Nedelec, J. Y.; Perichon, J. Electrochemical Cross-Coupling between 2-Halopyridines and Aryl or Heteroaryl Halides Catalysed by Nickel-2,2’-Bipyridine Complexes. Tetrahedron 1998, 54, 1289–1298. https://doi.org/10.1016/S0040-4020(97)10225-3. 289. Gosmini, C.; Nédélec, J. Y.; Périchon, J. Electrosynthesis of Functionalized 2-Arylpyridines from Functionalized Aryl and Pyridine Halides Catalyzed by Nickel Bromide 2,20 -Bipyridine Complex. Tetrahedron Lett. 2000, 41, 5039–5042. https://doi.org/10.1016/S0040-4039(00)00760-7. 290. Sengmany, S.; Léonel, E.; Polissaint, F.; Nédélec, J.-Y.; Pipelier, M.; Thobie-Gautier, C.; Dubreuil, D. Preparation of Functionalized Aryl- and Heteroarylpyridazines by Nickel-Catalyzed Electrochemical Cross-Coupling Reactions. J. Org. Chem. 2007, 72, 5631–5636. https://doi.org/10.1021/jo070429+. 291. Sengmany, S.; Le Gall, E.; Léonel, E. An Electrochemical Synthesis of Functionalized Arylpyrimidines from 4-Amino-6-Chloropyrimidines and Aryl Halides. Molecules 2011, 16, 5550–5560. https://doi.org/10.3390/molecules16075550. 292. Sengmany, S.; Vitu-Thiebaud, A.; Le Gall, E.; Condon, S.; Léonel, E.; Thobie-Gautier, C.; Pipelier, M.; Lebreton, J.; Dubreuil, D. An Electrochemical Nickel-Catalyzed Arylation of 3-Amino-6-Chloropyridazines. J. Org. Chem. 2013, 78, 370–379. https://doi.org/10.1021/jo3022428. 293. Sengmany, S.; Vasseur, S.; Lajnef, A.; Le Gall, E.; Léonel, E. Beneficial Effects of Electrochemistry in Cross-Coupling Reactions: Electroreductive Synthesis of 4-Aryl- or 4-Heteroaryl-6-Pyrrolylpyrimidines. Eur. J. Org. Chem. 2016, 2016, 4865–4871. https://doi.org/10.1002/ejoc.201600790. 294. Perkins, R. J.; Pedro, D. J.; Hansen, E. C. Electrochemical Nickel Catalysis for sp2-sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides. Org. Lett. 2017, 19, 3755–3758. https://doi.org/10.1021/acs.orglett.7b01598. 295. Perkins, R. J.; Hughes, A. J.; Weix, D. J.; Hansen, E. C. Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile. Org. Process Res. Dev. 2019, 23, 1746–1751. https://doi.org/10.1021/acs.oprd.9b00232. 296. Truesdell, B. L.; Hamby, T. B.; Sevov, C. S. General c(sp2)–c(sp3) Cross-Electrophile Coupling Reactions Enabled by Overcharge Protection of Homogeneous Electrocatalysts. J. Am. Chem. Soc. 2020, 142, 5884–5893. https://doi.org/10.1021/jacs.0c01475. 297. Li, Z.; Sun, W.; Wang, X.; Li, L.; Zhang, Y.; Li, C. Electrochemically Enabled, Nickel-Catalyzed Dehydroxylative Cross-Coupling of Alcohols with Aryl Halides. J. Am. Chem. Soc. 2021, 143, 3536–3543. https://doi.org/10.1021/jacs.0c13093. 298. Folest, J. C.; Périchon, J.; Fauvarque, J. F.; Jutand, A. Synthèse Électrochimique d’esters Arylacétique et Arylpropionique via Des Complexes Du Nickel. J. Organomet. Chem. 1988, 342, 259–261. https://doi.org/10.1016/S0022-328X(00)99463-4. 299. Conan, A.; Sibille, S.; D’Incan, E.; Périchon, J. Nickel-Catalysed Electroreductive Coupling of a-Halogenoesters with Aryl or Vinyl Halides. J. Chem. Soc. Chem. Commun. 1990, 48–49. https://doi.org/10.1039/C39900000048. 300. Durandetti, M.; Sibille, S.; Nédélec, J.-Y.; Périchon, J. A Novel Method of Arylation of a-Chloroketones. Synth. Commun. 1994, 24, 145–151. https://doi.org/ 10.1080/00397919408013812. 301. Durandetti, M.; Périchon, J.; Nédélec, J.-Y. Asymmetric Induction in the Electrochemical Cross-Coupling of Aryl Halides with a-Chloropropionic Acid Derivatives Catalyzed by Nickel Complexes. J. Org. Chem. 1997, 62, 7914–7915. https://doi.org/10.1021/jo971279d. 302. Li, H.; Breen, C. P.; Seo, H.; Jamison, T. F.; Fang, Y. Q.; Bio, M. M. Ni-Catalyzed Electrochemical Decarboxylative C–C Couplings in Batch and Continuous Flow. Org. Lett. 2018, 20, 1338–1341. https://doi.org/10.1021/acs.orglett.8b00070. 303. Koyanagi, T.; Herath, A.; Chong, A.; Ratnikov, M.; Valiere, A.; Chang, J.; Molteni, V.; Loren, J. One-Pot Electrochemical Nickel-Catalyzed Decarboxylative sp2–sp3 CrossCoupling. Org. Lett. 2019, 21, 816–820. https://doi.org/10.1021/acs.orglett.8b04090. 304. Delano, T. J.; Reisman, S. E. Enantioselective Electroreductive Coupling of Alkenyl and Benzyl Halides via Nickel Catalysis. ACS Catal. 2019, 9, 6751–6754. https://doi.org/ 10.1021/acscatal.9b01785. 305. Gomes, P.; Gosmini, C.; Périchon, J. Cobalt-Catalyzed Direct Electrochemical Cross-Coupling between Aryl or Heteroaryl Halides and Allylic Acetates or Carbonates. J. Org. Chem. 2003, 68, 1142–1145. https://doi.org/10.1021/jo026421b. 306. Mabrouk, S.; Pellegrini, S.; Folest, J.-C.; Rollin, Y.; Perichon, J. Catalyse Chimique Par Le Systeme Nickel-2,20 -Bipyridine de La Reduction Electrochimique d’halogenures Aliphatiques. J. Organomet. Chem. 1986, 301, 391–400. https://doi.org/10.1016/0022-328X(86)80044-4. 307. Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have all the New Reactions Gone?J. Med. Chem. 2016, 59, 4443–4458. https://doi.org/10.1021/acs.jmedchem.5b01409. 308. Trécourt, F.; Mallet, M.; Mongin, O.; Gervais, B.; Quéguiner, G. New Synthesis of Orelline by Metalation of Methoxypyridines. Tetrahedron 1993, 49, 8373–8380. https://doi. org/10.1016/S0040-4020(01)81920-7. 309. Meyers, A. I.; Willemsen, J. J. An Asymmetric Synthesis of (+)-Apogossypol Hexamethyl Ether. Tetrahedron Lett. 1996, 37, 791–792. https://doi.org/10.1016/0040-4039(95) 02296-1. 310. Meyers, A. I.; Willemsen, J. J. The Synthesis of (S)-(+)-Gossypol via an Asymmetric Ullmann Coupling. Chem. Commun. 1997, 1573–1574. https://doi.org/10.1039/a703043f. 311. Hauser, F. M.; Gauuan, P. J. F. Total Synthesis of ()-Biphyscion. Org. Lett. 1999, 1, 671–672. https://doi.org/10.1021/ol990758r. 312. Ma, X.; Vo, Y.; Banwell, M. G.; Willis, A. C. Total Synthesis of Marinoquinoline A Using a Palladium(0)-Catalyzed Ullmann Cross-Coupling Reaction. Asian J. Org. Chem. 2012, 1, 160–165. https://doi.org/10.1002/ajoc.201200037. 313. Fegheh-Hassanpour, Y.; Arif, T.; Sintim, H. O.; Al Mamari, H. H.; Hodgson, D. M. Synthesis of (−)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition-Rearrangement and Cross-Electrophile Coupling. Org. Lett. 2017, 19, 3540–3543. https://doi.org/10.1021/acs.orglett.7b01513. 314. Boeckman, R. K.; Niziol, J. M.; Biegasiewicz, K. F. Scalable Synthesis of (−)-Rasfonin Enabled by a Convergent Enantioselective a-Hydroxymethylation Strategy. Org. Lett. 2018, 20, 5062–5065. https://doi.org/10.1021/acs.orglett.8b02222. 315. Menger, M.; Lentz, D.; Christmann, M. Synthesis of (+)-Vitepyrroloid A and (+)-Vitepyrroloid B by Late-Stage Ni-Catalyzed c(sp2)–c(sp3) Cross-Electrophile Coupling. J. Org. Chem. 2018, 83, 6793–6797. https://doi.org/10.1021/acs.joc.8b00882. 316. Wright, A. C.; Stoltz, B. M. Enantioselective Construction of the Tricyclic Core of Curcusones A-D: via a Cross-Electrophile Coupling Approach. Chem. Sci. 2019, 10, 10562–10565. https://doi.org/10.1039/c9sc04127c.

C–C Bond Formation Through Cross-Electrophile Coupling Reactions

119

317. Luo, L.; Zhai, X. Y.; Wang, Y. W.; Peng, Y.; Gong, H. Divergent Total Syntheses of C3 A −C70 Linked Diketopiperazine Alkaloids (+)-Asperazine and (+)-Pestalazine A Enabled by a Ni-Catalyzed Reductive Coupling of Tertiary Alkyl Chloride. Chem. Eur. J. 2019, 25, 989–992. https://doi.org/10.1002/chem.201805682. 318. Ahmad, A.; Burtoloso, A. C. B. Total Synthesis of ()-Brussonol and ()-Komaroviquinone via a Regioselective Cross-Electrophile Coupling of Aryl Bromides and Epoxides. Org. Lett. 2019, 21, 6079–6083. https://doi.org/10.1021/acs.orglett.9b02221. 319. McGeough, C. P.; Strom, A. E.; Jamison, T. F. Ni-Catalyzed Cross-Electrophile Coupling for the Synthesis of Skipped Polyenes. Org. Lett. 2019, 21, 3606–3609. https://doi.org/ 10.1021/acs.orglett.9b01019. 320. Bolte, B.; Bryan, C. S.; Sharp, P. P.; Sayyahi, S.; Rihouey, C.; Kendrick, A.; Lan, P.; Banwell, M. G.; Jackson, C. J.; Fraser, N. J.; Willis, A. C.; Ward, J. S. Total Syntheses of the 3 H-Pyrrolo[2,3-c]Quinolone-Containing Alkaloids Marinoquinolines A–F, K, and Aplidiopsamine A using a Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Pathway. J. Org. Chem. 2020, 85, 650–663. https://doi.org/10.1021/acs.joc.9b02725.

12.05

CdC Bond Formation Through C-H Activation

Chen-Xu Liu, Quannan Wang, Qing Gu, and Shu-Li You, State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China © 2022 Elsevier Ltd. All rights reserved.

12.05.1 12.05.2 12.05.2.1 12.05.2.1.1 12.05.2.1.2 12.05.2.1.3 12.05.2.1.4 12.05.2.1.5 12.05.2.1.6 12.05.2.2 12.05.2.3 12.05.2.4 12.05.2.5 12.05.2.6 12.05.3 12.05.3.1 12.05.3.2 12.05.3.3 12.05.3.4 12.05.3.5 12.05.3.6 12.05.3.7 12.05.4 References

Introduction Pd-catalyzed CdH bond functionalization CdH bond arylation C(sp2)dH bond arylation with aryl halides and aryl organometallic reagents C(sp2)dH bond arylation with simple aromatic ring meta-C(sp2)-H arylation C(sp3)-H arylation C-H arylation using transient directing group Pd(0)-initiated C-H arylation CdH bond alkenylation CdH bond alkylation CdH bond alkynylation Enantioselective C-H activation Applications in organic synthesis Rh-catalyzed CdH bond functionalization CdH bond arylation CdH bond alkenylation CdH bond alkylation CdH bond alkynylation CdH bond annulation Enantioselective C-H activation Applications in organic synthesis Concluding remarks

120 121 122 122 126 129 130 134 136 137 141 145 147 156 160 161 165 167 170 170 176 184 185 186

12.05.1 Introduction Carbon-carbon bond forming reactions represent a class of fundamental transformations in synthetic organic chemistry. These transformations play a vital role in organic synthesis, medicinal chemistry, and materials. The 2010 Nobel Prize in chemistry was awarded to Heck, Negishi and Suzuki for their contributions on transition-metal catalyzed carbon-carbon bond formations. Typically, these reactions involve the coupling of an aryl halide or pseudo halide with an organometallic reagent. The requirement for installing a functional group prior to the desired CdC bond formation largely increases the synthetic steps and labor cost. As such, circumventing these issues will not only improve atom economy but also increase the overall efficiency of multistep synthetic sequences. CdH bonds are ubiquitous in organic molecules. However, CdH bonds are not generally viewed as the viable functional groups owing to their inertness with high bond dissociation energies (BDEs) (>96 kcal/mol).1 If carbon-carbon bonds could be forged directly by transformation of CdH bonds, similar to these activated CdX (or CdM) bonds, it would represent one of the most valuable and straightforward methods for the synthesis of complex molecules, and offer a distinct retrosynthetic approach (Fig. 1). Compared with conventional coupling reactions, where the reactive organometallic intermediate was generated via C-H activation, this provides a more step-economic and eco-friendly alternative. Therefore, direct catalytic functionalization of CdH bonds has been a highly intriguing research subject for a long time. In recent decades, intensive research efforts have witnessed the development of various transition-metal catalyzed CdH bond functionalizations. Considering that palladium and rhodium are the most-investigated transition metals in this field, this chapter aims to outline recent representative advances on Pd- and Rh- catalyzed CdC bond formations via C-H direct functionalization. This chapter mainly details the development of C(sp2)-H and C(sp3)-H functionalizations according to the types of reactions including C-H arylation, alkenylation, alkylation, alkynylation and annulation. Asymmetric C-H functionalization via a transient carbon–metal species and the applications of C-H functionalization towards the synthesis of structurally complex molecules will also be introduced. However, CdH bond functionalizations through carbene insertion reactions are not included.2 Early works on this topic before 2005 have been discussed in the chapter titled “Synthetic Reactions via CdH Bond Activation: CdC and CdE Bond Formation” contributed by Pfeffer and Spencer in Comprehensive Organometallic Chemistry III.3 Therefore,

120

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00087-1

CdC Bond Formation Through C-H Activation

121

Fig. 1 Carbon-carbon bond formation by C-H activation.

only selected literatures after 2005 will be covered in this chapter. Unfortunately, many important contributions are not included in this chapter for which the authors would like to apologize due to limited space.

12.05.2 Pd-catalyzed CdH bond functionalization Pd-catalyzed CdH bond functionalization has witnessed significant progress over the past decades. In this field, there are mainly three accepted reaction cycles (Fig. 2): (1) Pd(0)/Pd(II) cycle; (2) Pd(II)/Pd(0) cycle; (3) Pd(II)/Pd(IV) cycle. The first strategy starts with oxidative addition of Pd(0) catalyst to aryl halide (or pseudo halide) to afford an arylpalladium(II) species. Then the CdH bond cleavage may occur via concerted metallation deprotonation (CMD) to generate the Pd(II) intermediate. After reductive elimination, Pd(0) catalyst is regenerated. The overall redox process does not require an external stoichiometric oxidant. In the second strategy, the CdH bond is initially cleaved with Pd(II) catalyst, then transmetallation with an organometallic reagent, and finally reductive elimination gave the C-C coupling product. The released Pd(0) is oxidized by an external oxidant to complete the catalytic cycle. The third strategy involves the generation of Pd(IV) intermediate at the expense of an oxidant after the CdH bond activation.

Fig. 2 Catalytic cycles for Pd-catalyzed C-H functionalization, (a) Pd(0)/Pd(II) catalytic cycle, (b) Pd(II)/Pd(0) catalytic cycle, (c) Pd(II)/Pd(IV) catalytic cycle.

122

CdC Bond Formation Through C-H Activation

12.05.2.1 CdH bond arylation 12.05.2.1.1

C(sp2)dH bond arylation with aryl halides and aryl organometallic reagents

The biaryl subunit is an important structural motif found in a wide range of natural products, polymers, liquid crystals, etc. It is one of the most straightforward platforms to achieve aryl-aryl coupling via C-H direct functionalization. It has been known that specific aromatic compounds and heteroarenes can undergo the C-H arylations with high regioselectivity.4 Following these pioneering works, significant progresses of C-H arylations have been achieved. In 2005, Daugulis and coworkers developed diarylations of anilides 1 via C-H activation catalyzed by Pd(OAc)2 (0.2–5 mol%) with aryl iodide in the presence of 2 equivalents of AgOAc in CF3COOH. This arylation reaction proceeded with very high functional group compatibility and tolerated halogens on the anilide and bromine on the aryl iodide (Scheme 1).5

Scheme 1 Pd-catalyzed C-H diarylation of anilides with aryl iodides.

Given the importance of 2-arylpyridines in material and medicinal chemistry, Fagnou and coworkers performed a direct arylation reaction of pyridine N-oxides with aryl bromides, providing a wide range of 2-arylpyridines in 45–97% yields with complete regioselectivity. The 2-arylated pyridines 4 could be readily obtained via Pd-catalyzed arylation of pyridine N-oxides 3. This C-H arylation reaction not only improves the synthetic efficiency of 2-arylated pyridines but also avoids the use of unstable 2-pyridyl organometallics (Scheme 2).6a The detailed mechanistic studies were investigated by the Hartwig group. They found that

Scheme 2 Pd-catalyzed C-H arylation of pyridine N-oxides with aryl bromides.

the cyclometalated complex [Pd(OAc)(tBu2PCMe2-CH2)]2, generated from decomposition of (PtBu3)Pd(Ar)(OAc), was the active catalytic species in this direct arylation of pyridine N-oxide.6b This method could be extended to the C-H arylation of diazine N-oxides under slightly modified reaction conditions. By replacing toluene with dioxane, the arylations of pyrazine and pyridazine N-oxides gave the corresponding cross-coupled products 5 in 75% and 76% yield, respectively (Table 1, entries 1 and 2). Moreover, the addition of 10 mol% CuCN could allow the arylation of pyrimidine N-oxide in 61% yield (Table 1, entry 3). Notably, this reaction is compatible with aryl bromides, iodides and chlorides.7 Table 1

Pd-catalyzed C-H arylations of diazine N-oxides.

Entry

Conditions

1

Ar-Br Pd(OAc)2 (5 mol%) PtBu3-HBF4 (15 mol%) K2CO3 (2 equiv) dioxane, 110  C

Yield 75%

76%

2

3

Product (5)

Ar-Br Pd(OAc)2 (5 mol%) PtBu3-HBF4 (15 mol%) K2CO3 (2 equiv) CuCN (10 mol%) dioxane, 110  C

61%

CdC Bond Formation Through C-H Activation

123

Electron-deficient arenes were seldom employed for the catalytic C-H arylation until Fagnou and coworkers developed the intermolecular arylation reactions of fluorobenzenes 6 with aryl halides. The key C-H activation step occurs via a concerted metalation-deprotonation (CMD) mechanism, which largely relies on the acidity of the CdH bond (Scheme 3A).8 Subsequently, the authors developed a direct arylation of benzene in the presence of Pd(OAc)2 and pivalic acid (Scheme 3B). Mechanistic study indicates that the pivalate anion plays a key role in CdH bond cleaving step.9

Scheme 3 Pd-catalyzed C-H arylation reactions of fluorobenzenes and benzene.

Sanford and coworkers reported an elegant C-H arylation reaction of 2-phenyl-3-methylpyridine (10) with [Ph2I]BF4, giving the phenylation product 11 in 88% yield. Besides pyridine, quinoline, pyrrolidinone and oxazolidinone are also effective directing groups in this transformation, providing diverse biaryl products. Notably, this reaction does not require the use of extra base or ligand. Preliminary mechanistic experiments more likely support a Pd(II)/(IV) catalytic cycle (Scheme 4A).10 This method could be extended to C-H 2-arylation of indoles 12 in up to 89% yield. Remarkably, this reaction proceeds well at room temperature (Scheme 4B).11

Scheme 4 Pd-catalyzed C-H arylation reactions with [Ph2I]BF4.

Remarkably, Fu, Liu and coworkers achieved the acyloxy-directed C-H arylation with [Ph2I]OTf at room temperature, affording ortho-arylated products 15 in up to 95% yield. The utility of the reaction was further demonstrated by the synthesis of 3,30 -bisarylated BINOL 17 in 43% yield over three steps (Scheme 5).12

Scheme 5 Acyloxy-directed C-H arylation with [Ph2I]OTf.

124

CdC Bond Formation Through C-H Activation

Aryl carboxylic acid is among the abundant chemical feedstocks. Accordingly, their C-H arylations would allow a one-step synthesis of 2-arylbenzoic acid derivatives. In addition, the carboxyl group could be conveniently removed or undergo diverse transformations. In 2007, two methods for direct ortho-arylation of benzoic acids were developed by Daugulis and coworkers. The first method for the arylation of electron-rich to moderately electron-poor benzoic acids 18 employed aryl iodide as the aryl reagent. Chloride and bromide substituents on both coupling partners were well tolerated. The second method relied on the use of aryl chloride, cesium carbonate and n-butyl-di-1-adamantylphosphine ligand. This reaction was compatible with both electron-rich and electron-poor benzoic acids 20 (Scheme 6).13

Scheme 6 Pd-catalyzed ortho C-H arylations of benzoic acids.

Intramolecular C-H arylations with unactivated arenes suffered from poor selectivity and low catalyst turnover number until Fagnou and coworkers developed a highly efficient catalytic system in 2004. They found that the combination of Pd(OAc)2 and [1,10 -biphenyl]-2-ylbis(4-(trifluoromethyl)phenyl)phosphine could unprecedently enable the intramolecular C-H arylation of bromoarene 22a with catalyst loading as low as 0.1 mol% (Table 2, entry 1).14 While they achieved the C-H arylation with aryl Table 2 Entry

Pd-catalyzed intramolecular C-H arylations. Substrate (22)

Product (23)

Conditions

Yield

References

1

Pd(OAc)2 (0.1 mol%)

96

13

2

(0.2 mol%) K2CO3 (2 equiv) DMA, 145  C Pd(OAc)2 (1 mol%) PCy3-HBF4 (2 mol%) K2CO3 (2 equiv) DMA, 130  C

97

14

90

14

93

14

3

4

Pd(OAc)2 (5 mol%) PCy3-HBF4 (10 mol%) Ag2CO3 (0.5 equiv) K2CO3 (2 equiv) dioxane, 100  C

CdC Bond Formation Through C-H Activation

125

chlorides by using an N-heterocyclic carbene (NHC) as the ligand, the catalytic system exhibited low efficiency for sterically hindered substrates.15 Finally, they identified that the combination of Pd(OAc)2 and PCy3-HBF4 could efficiently enable the intramolecular direct arylation of arenes with aryl chloride, bromide, and iodide 22b-d in 90–97% yields (Table 2, entries 2–4). The addition of Ag2CO3 was essential for the arylation with aryl iodides to prevent catalyst poisoning due to the facile accumulation of iodide anions.16 C-H arylation with aryl tosylates as the electrophile is highly desirable due to their ready availability and low cost. The pioneering Pd-catalyzed direct arylations using aryl tosylates 25 and mesylates as the electrophiles were reported by Ackermann and coworkers. A catalytic system comprising Pd(OAc)2 and X-Phos enabled a broadly applicable C-H arylation of various heterocycles including benzoxazole (24), oxazole, caffeine and 1,2,3-triazole (Scheme 7).17

Scheme 7 Pd-catalyzed C-H arylation with aryl tosylate.

Polyaryl-substituted thiophenes are privileged structures within many interesting functional molecules. Itami and coworkers reported an efficient method for the programmed synthesis of tetraarylthiophenes via the sequential C-H/C-H/C-H/C-O arylations of 3-methoxythiophene (27). The regioselective C-H arylations were composed of C2-arylation by RhCl(CO){P[OCH(CF3)2]3}2 (Cat-1), C4-arylation by PdCl2/P[OCH(CF3)2]3 (Cat-2), and C5-arylation by PdCl2/2,20 -bipyridine (Cat-3) (Scheme 8).18

Scheme 8 Sequential C-H/C-H/C-H/C-O arylations of 3-methoxythiophene.

Compared with redox neutral Pd-catalyzed C-H activations, the oxidative Pd-catalyzed C-H arylations rely on the reoxidation of Pd(0) and suffer from facile homocoupling side reactions. The pioneering example of Pd-catalyzed alkylation of aryl CdH bonds with a variety of primary-alkyl tin reagents was reported by Yu and coworkers in 2006.79 Shi and coworkers then developed Pd(II)-catalyzed oxidative C-H arylation of N-alkyl acetanilides 33 with aryl boronic acids in a Suzuki-Miyaura-type coupling reaction (Scheme 9). A plausible pathway for this transformation involves generation of a palladacyclo intermediate via C-H activation, transmetalation with aryl boronic acid and reductive elimination.19 In addition, they also developed Hiyama-type coupling reaction of acetanilides with trialkoxyarylsilanes via C-H activation, affording ortho arylation products in up to 92% yield.20

126

CdC Bond Formation Through C-H Activation

Scheme 9 Pd(II)-catalyzed C-H arylation of N-alkyl acetanilides with aryl boronic acids.

Soon afterwards, Pd(II)-catalyzed C-H arylations of electron-rich (hetero)arenes (35, 37) with aryl boronic acids, benzaldimines (39) with aryl-BF3K salts, and ferrocenes (41) with aryl boronic acids were developed successively (Scheme 10).21

Scheme 10 Pd(II)-catalyzed C-H arylations.

12.05.2.1.2

C(sp2)dH bond arylation with simple aromatic ring

From the viewpoint of atom and step economy, C-H/C-H cross-coupling reaction of two unfunctionalized arenes undoubtedly is the most straightforward approach for C-C formation.22 As early as in 2006, Lu and coworkers pioneeringly reported an intermolecular cross-coupling of simple arenes via double C-H activation with a catalytic system of Pd(OAc)2/CF3CO2H/K2S2O8, albeit with moderate efficiency and selectivity.23 Breakthroughs were achieved by Fagnou and co-workers, who discovered Pd-catalyzed cross-coupling reactions of N-acetylindoles 43 with simple arenes. This transformation afforded highly C3-selective arylation product 44 in 42–84% yields (Scheme 11A).24a Interestingly, the C2-selective arylation of indole 45 was also accomplished when Cu(OAc)2 was replaced by AgOAc (Scheme 11B).24b

CdC Bond Formation Through C-H Activation

127

Scheme 11 Pd(II)-catalyzed C-H/C-H cross-coupling reactions.

Shortly thereafter, the cross-coupling of benzofuran (47) with benzene catalyzed by Pd(OAc)2 with oxygen as the terminal oxidant was developed by DeBoef and coworkers, giving the C2-selecitve phenylation product 48 in 98% yield (Scheme 12).25 Subsequently, they extended this double C-H functionalization method to the oxidative cross-coupling of indoles with simple aromatics. Mechanistic studies indicated that the acidity of the medium had effect on the regioselectivity for this cross-coupling reaction.26

Scheme 12 Pd(II)-catalyzed cross-coupling of benzofuran with benzene.

The directing group on arene can suppress the undesired C-H/C-H homocoupling in the direct cross-coupling reaction of two unfunctionalized arenes. Sanford and coworkers described a Pd-catalyzed coupling of benzo[h]quinoline (49) with simple arenes, and high chemo- and regioselectivity were obtained by using Ag2CO3 as the oxidant. The site selectivity is predominantly controlled by the directing group for the first C-H activation and by the steric environment around the simple arene CdH bond for the second C-H activation. Mechanistic studies suggest that BQ (benzoquinone) is bound to the Pd center during the arene C-H activation process and affects the regioselectivity of arene C-H activation as well (Scheme 13).27

Scheme 13 Pd(II)-catalyzed coupling of benzo[h]quinoline with simple arenes.

Subsequently, Shi and Buchwald also achieved Pd-catalyzed C-H/C-H cross-arylation of N-acetyl-1,2,3,4-tetrahydroquinoline or anilides by using O2 as the terminal oxidant, respectively (Fig. 3A and B).28 In 2010, the cross-coupling of O-phenylcarbamates with simple arenes was achieved by Dong and coworkers using sodium persulfate (Na2S2O8), an inexpensive and easy-to-handle oxidant (Fig. 3C). Trifluoroacetic acid (TFA) plays a critical role for the cyclopalladation of O-phenylcarbamate. Two discrete CdH bond activations including directing-group assisted cyclopalladation and electrophilic metalation were proposed.29 When a simple monosubstituted arene was employed as the arylation partner, a mixture of regioisomers was always encountered in these C-H/ C-H coupling reactions. In the presence of N-fluorobenzenesulfonimide (NFSI), high para-selectivity for the C-H/C-H coupling of benzamides with monosubstituted arenes was achieved by Yu and coworkers. NFSI as an oxidant is crucial for this high para-selectivity (Fig. 3D).30

128

CdC Bond Formation Through C-H Activation

Fig. 3 Pd-catalyzed C-H/C-H cross-coupling products, (a) C-H arylation of 1,2,3,4-tetrahydroquinolines, (b) C-H arylation of anilides, (c) C-H arylation of o-phenylcarbamates, (d) C-H arylation of benzamides.

Perfluorinated aromatic rings are a prominent structural motif found in numerous functional materials. In 2010, Zhang and coworkers developed a Pd-catalyzed C-H/C-H cross-coupling of perfluoroarenes 55 with heteroarenes including (benzo)thiophenes, (benzo)furans, and indoles by using Ag2CO3 as the oxidant (Scheme 14A).31 Almost at the same time, Wei and Su described a Pd-catalyzed cross-coupling of perfluoroarenes with simple arenes via twofold C-H functionalization by using Cu(OAc)2 as the oxidant (Scheme 14B).32

Scheme 14 Pd-catalyzed cross-coupling of perfluoroarenes with arenes.

The heteroaryl-heteroaryl fragment is widely distributed in many electronic materials, natural products and pharmaceuticals. It has been a challenge to avoid the homo-coupling side reaction in these C-H/C-H cross-coupling reactions. Hu, You and coworkers developed Pd(II)-catalyzed oxidative cross-coupling of heteroarenes with high regioselectivity via double C-H functionalization. The success was probably ascribed to the instability of intermediate in the process of homo-coupling product formation. This catalytic system works for a wide range of substrates, allowing the C-H/C-H hetero-coupling of diverse N-containing heteroarenes (e.g., caffeines, imidazoles, azoles, quinolines and pyridine N-oxides) with (benzo)thiophene, (benzo)furan (Scheme 15A). In addition, this strategy could be further extended to the C-H/C-H cross-coupling of caffeine (60) with indoles and pyrroles (Scheme 15B).33

Scheme 15 Pd-catalyzed C-H/C-H cross-coupling of heteroarenes.

CdC Bond Formation Through C-H Activation

129

The C-H/C-H cross-coupling reactions of heteroarenes with similar electronic properties are quite challenging because of their tendency to undergo homo-coupling side reaction. In 2011, Ofial and coworkers accomplished an efficient Pd-catalyzed C-H/C-H cross-coupling of benzothiazoles (62) or benzimidazoles (64) with N-, O-, and S-containing azoles. Silver salts effectively suppressed the formation of homo-coupling products by facilitating the cleavage of the second CdH bond selectively at the other azole (Scheme 16).34

Scheme 16 Pd-catalyzed cross-coupling of benzothiazoles with azoles.

12.05.2.1.3

meta-C(sp2)-H arylation

While numerous ortho C-H arylations of arenes have been extensively developed, meta-selective C-H arylation of electronically unbiased arenes remains a difficult task. Dong and coworkers reported meta-selective C-H arylations by using Pd/norbornene catalysis in 2015. The key NBE (norbornene)-bridged five-membered palladacycle, generated via C-H activation, reacts with an aryl halide through a Pd(IV) intermediate to generate a meta-substituted complex. The resulting Pd intermediate then undergoes bcarbon elimination followed by reprotonation at the ortho position to furnish the desired meta product (Scheme 17). This meta C-H arylation with aryl iodides bearing an ortho electron-withdrawing group (ester, acyl, and nitro group etc.) could give reasonable yields (up to 80%).35

Scheme 17 meta-Selective C-H arylation by Pd/norbornene catalysis.

Soon after, Yu and coworkers identified a class of 3-acetylamino-2-hydroxypyridine ligands (L2), which could promote the metaC-H arylations of a wide range of arenes 68 including anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator (Scheme 18). A variety of aryl iodides and heteroaryl iodides could be used as effective coupling partners.36

Scheme 18 3-Acetylamino-2-hydroxypyridine promoted meta-C-H arylation.

130

CdC Bond Formation Through C-H Activation

12.05.2.1.4

C(sp3)-H arylation

To date, a wide variety of C(sp2)–H arylations have been well developed. Meanwhile, much attention has also been paid on more challenging C(sp3)dH bond functionalization. Significant progress has been made despite of inherent difficulties such as low acidity, and unreactive molecular orbital profiles. Daugulis and coworkers pioneeringly developed a regioselective Pd-catalyzed C(sp3)–H arylation of aliphatic carboxylic amides 70 at the b-position by utilizing the aminoquinoline (AQ) directing group (Scheme 19A). Notably, extremely high efficiency was observed, and the arylation of propionamide with p-iodoanisole was complete in less than 5 min. This approach could also be applicable to C(sp3)–H arylation of amine derivatives 72 at the g-position (Scheme 19B).37 In addition, C(sp3)–H monoarylation of primary C(sp3)dH bonds can be achieved by employing 2-methylthioaniline auxiliary.38

Scheme 19 Secondary b-and g-C-H arylations of aliphatic acids and amines.

The use of the carboxyl group to facilitate C-H activation/C-C coupling processes proved of great value in developing CdC bond forming reactions. Yu and coworkers reported the first catalytic protocol for the coupling of b-C(sp3)dH bonds in aliphatic acids 74 with an organoboron reagent via Pd(II)/Pd(0) catalysis, albeit with moderate yield (up to 38% yield) (Scheme 20A). This C(sp3) dH bond arylation reaction with ArI as the arylating reagent was also feasible, leading to mono- (77) and diarylation (78) of aliphatic acid 76 in 72% combined yield (mono/di ¼ 5:2) (Scheme 20B). It likely involves a COOH directed CdH bond activation and subsequent formation of Pd(IV) intermediate oxidized by ArI.39

Scheme 20 Primary b-C-H arylation of aliphatic acids.

To further improve the versatility and efficiency of C(sp3)dH bond arylation reactions of aliphatic acid derivatives, the more strongly binding directing group O-methyl hydroxamic acid was introduced. The arylation reaction with various aryl boronic acids in the presence of Pd(OAc)2 proceeded smoothly to afford arylation products 80 in up to 94% yield, which could be readily converted to esters and amides (Scheme 21).40

Scheme 21 Primary b-C-H arylation of aliphatic acids.

CdC Bond Formation Through C-H Activation

131

Activation of methylene CdH bonds is more challenging than primary CdH bonds mainly due to their steric hinderance. Previous studies showed that Pd-catalyzed C–H activation of methylene CdH bonds usually requires strongly coordinating pyridine auxiliaries.37,38 Encouraged by their ligand acceleration in a number of Pd(II)-catalyzed C(sp2)-H functionalizations, Yu and coworkers achieved Pd(II)-catalyzed arylation of acyclic b-methylene C(sp3)dH bonds (81) enabled by a 2-isobutoxyquinoline ligand (L3) (Scheme 22). This catalytic system was also compatible for cyclic b-methylene CdH bonds, giving the monoarylated product as a single cis-substituted diastereomer.41

Scheme 22 Secondary b-C-H arylation of aliphatic acids.

The synthesis of unnatural amino acids via direct C(sp3)-H functionalization has been an area of extensive research. Yu and coworkers developed an unprecedented ligand-controlled sequential b-C(sp3)–H arylation of alanine derivatives 83 using pyridine and quinoline derivatives as the ligands (Scheme 23). The pyridine ligand (L4) enabled primary C(sp3)–H monoarylation exclusively and subsequently the quinoline ligand (L5) enabled secondary C(sp3)–H arylation in one pot. A wide range of b-Ar-b-Ar0 -a–amino acids 84 with excellent diastereoselectivity could be efficiently prepared by using two different aryl iodides.42 The N-methoxyamide (CONHOMe) directing group displayed excellent efficiency. Moreover, it can be conveniently installed and removed. Yu then realized Pd-catalyzed C(sp3)–H mono- and diarylation of a broad range of carboxylic acids using the CONHOMe auxiliary promoted by pyridine-type ligands. 2-Picoline ligand promoted the selective monoarylation of primary C(sp3)dH bonds, and 2,6-lutidine ligand enabled the subsequent arylation of secondary C(sp3)dH bonds in one pot. The utility of this efficient method was further demonstrated by gram-scale synthesis of various unnatural amino acids.43

Scheme 23 Sequential b-C-H arylations of amino acid derivatives.

Significant achievements have been made toward directed b-C(sp3)-H arylations of carboxylic acids and their derivatives through five-membered palladium intermediate. Development of g-C-H activation at more distal carbon center through six-membered palladacycle greatly expanded the synthetic utility of C(sp3)-H functionalization reactions. In 2016, Yu and coworkers realized a g-C(sp3)-H arylation of aliphatic acid-derived amides 85 promoted by a tricyclic quinoline ligand (L6) (Scheme 24).44 Importantly, the g-C(sp3)-H arylation of amino acids including valine (87), isoleucine, and tert-leucine was also achieved by employing a modified quinoline ligand (L7).

Scheme 24 g-C-H arylations of aliphatic acid-derived amide and amino acid derivatives.

132

CdC Bond Formation Through C-H Activation

The C(sp3)-H arylations of amino acids bearing CONHArF or CONHOMe as a directing group have been well-developed by ligand-accelerated Pd catalysis. C-H activation directed by the carboxyl group is more practical due to its ready availability and diverse transformations. Yu and coworkers developed b-(sp3)-H arylation of a-amino acids 89 promoted by a pyridine-based ligand L8. No requirement of an exogenous directing group further enhances the synthetic utility of this method (Scheme 25).45

Scheme 25 Sequential b-C-H arylation of amino acids.

Site-selective functionalization of C(sp3)dH bonds in a peptide side chain will improve the efficiency and step economy of peptide syntheses and allow for postsynthetic modification of peptides. Yu and coworkers pioneeringly accomplished C(sp3) − H arylations of various dipeptides 91 directed by native amino acid embedded in the peptide backbone (Scheme 26).46 A wide range of arylated dipeptides at the N-terminus were obtained in up to 90% yield. Importantly, this arylation method is also suitable for esterified tripeptides and tetrapeptides under slightly modified reaction conditions.

Scheme 26 Pd-catalyzed C(sp3) − H arylation of dipeptides.

Inspired by Yu’s C(sp3) − H arylation of peptides, Noisier, Albericio and co-workers reported an elegant C(sp3)-H peptide macrocyclization. Pd-catalyzed intramolecular C-H cross-coupling between an alanine (Ala) and a phenylalanine (Phe) residue proceeded smoothly to afford a novel class of stapled peptides 94 in up to 54% yield (Scheme 27).47

Scheme 27 Pd-catalyzed intramolecular C-H arylation between alanine (Ala) and phenylalanine (Phe) residue.

Based on Pd-catalyzed secondary C(sp3)-H arylation of triazolyldimethylmethyl (TAM) amide, Ackermann and coworkers extended this method to an intermolecular reaction of peptides bearing two viable sites of potential reactivity. Surprisingly, the unprecedented positional selective C(sp3)-H arylations of the internal peptide position were realized with the aid of the peptidebond-isosteric triazole (Scheme 28).48

CdC Bond Formation Through C-H Activation

133

Scheme 28 Pd-catalyzed C(sp3)-H arylation of peptides.

The use of directing groups has proven to be a powerful, common, and practical strategy to directly functionalize CdH bond. An ideal directing group should be readily available, easily introduced and removed. Ma and coworkers developed 2-methoxyiminoacetyl (MIA) assisted g-C(sp3)-H arylation of aminobutanoic acid derivatives 99 (Scheme 29A).49 The MIA auxiliary could be conveniently removed with KOH at room temperature. Shi and coworkers disclosed the commercially available 2-picolinamide to be a novel directing group for Pd-catalyzed C(sp3)-H arylations. Sequential primary and secondary C(sp3)-H arylations could also be realized with different aryl iodides. Notably, this directing group can be removed at room temperature (Scheme 29B).50

Scheme 29 2-Methoxyiminoacetyl (MIA) and 2-picolinamide assisted C(sp3)-H arylations.

While Pd-catalyzed aliphatic C-H arylations directed by imine generated in situ and oxime have been well investigated, the use of amine as a directing group for C-H activation is less investigated but attractive. In 2015, Gaunt and coworkers described a general Pd-catalyzed g-C(sp3)–H arylation of aliphatic amino alcohols. With a hindered N,O-ketal motif derived from cis-3,5-dimethyl cyclohexanone as an efficient directing group, Pd-catalyzed arylations with hypervalent iodine reagent (Ph2IOTf ) afforded a variety of arylation products 104 in up to 84% yield (Scheme 30A).51 The hindered environment around the Pd center promotes the formation of the active mono ligated Pd species by destabilizing the unreactive Pd/bis(amine) complex. In addition, a hydrogen bond between the acetate ligand on the palladium and the N–H of amine substrate are also responsible for this facile C–H arylation. Subsequently, they reported Pd-catalyzed C-H arylations of hindered secondary aliphatic amines 105 with arylboronic esters through an uncommon four-membered-ring cyclopalladation pathway. The addition of amino acid ligand significantly improved the reaction efficiency (Scheme 30B).52

134

CdC Bond Formation Through C-H Activation

Scheme 30 Pd-catalyzed C(sp3)-H arylations of aliphatic amino alcohols and aliphatic amines.

C-H functionalization of aliphatic amines by employing a directing-group strategy always occurred at the g-position owing to the formation of five-membered metallacycle preferentially. Gulia and Daugulis developed a Pd-catalyzed pyrazole-directed C(sp3)-H arylation with aryl iodides, which tolerated a wide range of functional groups (Scheme 31).53 b-Phenethylamine derivatives 109 were afforded by ozonolysis of the pyrazole moiety.

Scheme 31 Pd-catalyzed pyrazole-directed C(sp3)-H arylation.

Regioselective Pd-catalyzed C(sp3)–H activation reactions were developed generally through a five-membered cyclopalladation pathway, which is kinetically and thermodynamically favorable over its six-membered counterparts. In 2019, Gaunt and coworkers achieved g-C(sp3)-H arylation of aliphatic alcohols 110 via six-membered cyclopalladation by a pyruvic acid-derived directing group in combination with 3-nitro-5-chloro-2-pyridone ligand L9 (Scheme 32).54 The 5,5-fused ring is more strained than the 5,6-fused ring due to the existence of double bond in the bicyclic palladacycle, and thus favors the six-membered cyclopalladation.

Scheme 32 Pd-catalyzed g-C(sp3)–H arylation of aliphatic alcohols.

12.05.2.1.5

C-H arylation using transient directing group

While great progresses on C-H functionalization assisted by covalent directing groups have been made, the requirement of installing and removing the directing group diminishes the synthetic efficiency and functional group compatibility. The strategy of using a temporary directing group that reversibly reacts with the substrate and binds to the metal center can well address these disadvantages. The condensation of benzaldehyde with amino acid gives imine reversibly, which serves as a transient directing group. The imine moiety and the carboxyl group act as a bidentate directing group. In 2016, Yu and coworkers accomplished Pd-catalyzed C(sp3)–H arylations of 2-methylbenzaldehyde (112) by employing such a transient directing group strategy (Scheme 33).55 This method can also be applicable to aliphatic ketone substrates by using 50 mol% glycine and a mixture of HFIP:AcOH as the

CdC Bond Formation Through C-H Activation

135

co-solvent. Importantly, the enantioselective C–H arylation of benzaldehydes 114 bearing a methylene C(sp3)dH bond using L-tert-leucine as a transient directing group is also feasible. More works on Pd-catalyzed asymmetric CdH bond functionalizations will be described in Section 12.05.2.5.

Scheme 33 Pd-catalyzed C(sp3)–H arylations by employing transient directing group.

Aliphatic aldehydes are ubiquitous structural units in biologically active natural products and pharmaceuticals, and the key intermediates in organic synthesis. Therefore, functionalization of aliphatic aldehydes has attracted much attention in organic chemistry community. Ge and coworkers discovered b-C(sp3)-H arylation reaction of aliphatic aldehydes 116 with aryl iodides by using 3-aminopropanoic acid (TDG1) as a novel transient directing group (Scheme 34).56 Notably, this highly site-selective arylation occurred preferentially at the primary b-C(sp3)–H position over the secondary b-methylene, g- or d-terminal C − H positions. The C-H arylation was also compatible with cyclic aldehyde, affording the desired cis product 118 with 20:1 dr.

Scheme 34 b-C(sp3)-H arylation reaction of aliphatic aldehydes.

The development of Pd-catalyzed C(sp3)-H functionalization of aliphatic amines is of great interest due to their popularity and importance in organic synthesis and medicinal chemistry. Ge and coworkers reported a Pd-catalyzed direct g-arylation of primary amines 119 (Scheme 35).57 With glyoxylic acid as a transient directing group, a wide range of primary g-arylation alkylamines 120 were prepared in up to 74% yield without any additional protection or deprotection manipulations. Moreover, the key cyclopalladated intermediate was obtained from the reaction of glyoxylic acid, tert-amylamine and Pd(OAc)2 in the presence of stoichiometric amounts of pyridine.

Scheme 35 Pd-catalyzed g-arylation of primary amines.

Encouraged by their previous outstanding findings that pyridone ligands can accelerate both C(sp2) − H and C(sp3) − H activations, Yu and coworkers further developed pyridine enabled g-methylene C(sp3) − H arylation and d-C(sp3) − H arylation of aliphatic amines using two different transient directing groups, respectively (Scheme 36).58 The combination of 5-trifluoromethyl pyridine L10 and phenol-based TDG2 coordinate with Pd via a six-membered chelate that favors g-C − H

136

CdC Bond Formation Through C-H Activation

Scheme 36 Pyridone promoted g- and d-C(sp3)-H arylations of aliphatic amines.

arylation, whereas 5-nitro pyridine L11 together with 2-oxo-2-phenylacetic acid TDG3 coordinates with Pd via a five membered chelate that favors d-C − H arylation. A cooperative effect between the transient directing group and the pyridone ligand plays an important role in the regioselectivity. Young and coworkers reported the first example of CO2-mediated C-H arylation of aliphatic amines 125. In this reaction, the carbamate moiety as a transient directing group was generated by the reversible reaction of amine with CO2 (Scheme 37).59 Both primary and secondary aliphatic amines (127) can be arylated selectively at the g-C-H position. Mechanistic studies suggest that CO2 acts as a transient DG through a rare seven-membered palladacycle.

Scheme 37 CO2-Mediated C-H arylation of aliphatic amines.

12.05.2.1.6

Pd(0)-initiated C-H arylation

In Pd(II)-initiated C(sp3)-H arylation reactions, the stoichiometric amount of metal salts as external oxidants is always required, impeding the practical utility of these methods. Therefore, Pd(0)-catalysis allowing redox neutral reaction conditions has attracted much attention. Generally speaking, Pd(0) is produced by reducing Pd(II) with a reducing agent such as phosphine ligand in the system. In 2007, Fagnou and coworkers reported a Pd(0)-initiated intramolecular C(sp3)-H arylation in the presence of Pd(OAc)2 and PCy3-HBF4 with pivalic acid affording 2,2-dialkyldihydrobenzofurans (129 in 97% yield) (Scheme 38A).60 Later,

Scheme 38 Pd(0)-initiated C(sp3)-H arylation reactions.

CdC Bond Formation Through C-H Activation

137

Yu and coworkers described Pd(0)-catalyzed intermolecular C(sp3)-H arylation with aryl iodide by using a CONH-C6F5 directing group and cyclohexyl JohnPhos ligand (L12). Notably, both reactions can be performed with stable phosphine-HBF4 salt (Scheme 38B).61 The intramolecular C(sp3)-H arylations usually afforded five-membered ring products. In this context, the synthesis of six-membered or larger rings is relatively challenging. In 2014, Shi and coworkers developed a Pd(0)-catalyzed intramolecular C(sp3)-H arylation through a seven-membered palladacycle intermediate, providing a wide range of 3,4-dihydroquinolinones 133 in up to 78% yield (Scheme 39).62 The intramolecular KIE (kH/kD ¼ 6.2) indicated that the C(sp3)dH bond cleavage is involved in the rate-determining step.

Scheme 39 Pd(0)-catalyzed intramolecular C(sp3)-H arylation for six-member ring synthesis.

12.05.2.2 CdH bond alkenylation Over the past decades, the direct oxidative Heck reaction has become one of the most fundamental CdC bond formation methods, in which preactivated reaction partners are not needed. In this aspect, pioneering works on Pd-catalyzed oxidative coupling of arenes and activated alkenes were developed by Fujiwara and Moritani.63 In 2005, Gaunt and coworkers developed a Pd-catalyzed intermolecular oxidative Heck reaction of indoles at either the C2- or the C3-position by varying the solvent and additives. The alkenylation reaction took place preferentially at the C3-position (135) in a mixed solvent of DMSO and DMF. When the reactions were performed in dioxane/AcOH, the regioselectivity was switched in favor of C2-position (136) (Scheme 40A).64a Furthermore, the regio-divergent oxidative Heck reactions of pyrroles were realized by sterically and electronically tuned N-pyrrole protecting groups, affording either the C2 or C3 alkenylated products (138, 139) (Scheme 40B).64b

Scheme 40 Pd-catalyzed oxidative Heck reaction of indoles and pyrroles.

Arrayás, Carretero and coworkers reported a Pd-catalyzed regioselective direct C2 alkenylation of indoles 140 directed by a N-(2pyridyl)sulfonyl group. Multi-substituted alkenes are also suitable substrates in this reaction. The 2-pyridylsulfonyl group could be removed conveniently to generate the unprotected C2 alkenylative indoles 142 (Scheme 41A).65 Furthermore, this general and reliable strategy could be applied in the C-H olefination of N-alkyl aniline 143, benzylamine, and phenethylamine derivatives by using N-fluoro-2,4,6-trimethylpyridinium triflate [F] as an oxidant (Scheme 41B).66

138

CdC Bond Formation Through C-H Activation

Scheme 41 Pd-catalyzed alkenylation reaction directed by the N-(2-pyridyl)sulfonyl group.

Both pyridine N-oxides and perfluoroarenes are suitable substrates for C-H functionalization (e.g., C-H arylations) as described above. In 2008, Chang and coworkers achieved a Pd-catalyzed C-H alkenylation of pyridine N-oxide (3), which exhibited highly high site-selectivity at the 2-position, generating (E)-products 145 exclusively in up to 91% yield (Scheme 42A).67 Zhang and coworkers reported a Pd(OAc)2 catalyzed direct olefination of electron-deficient perfluoroarenes 55 with a broad range of alkenes in up to 73% yield (Scheme 42B).68

Scheme 42 Pd-catalyzed alkenylation of pyridine N-oxide and perfluoroarenes.

The utilization of pyridyl N-oxide substrates has allowed for C-H olefination and arylation reactions at the C-2 position.6,67 Interestingly, the Pd-catalyzed C-3 selective alkenylation of pyridines 147 was achieved by introducing a bidentate ligand (1,10-phenanthroline), which weakens the coordination between Pd center and the pyridyl N atom through the trans-influence (Scheme 43).69 A small amount of Pd(II)/p-ring complex was sufficient to initiate this catalytic reaction. A significant isotope effect (kH/kD ¼ 4.0) suggested that this reaction undergoes via a Pd-catalyzed C-H activation rather than a Lewis acid mediated Friedel-Crafts pathway.

Scheme 43 Pd-catalyzed C-3 selective alkenylation of pyridines.

CdC Bond Formation Through C-H Activation

139

The previous examples of Pd-catalyzed C–H olefination are restricted to specific cases, generally including electron-rich heterocycles, such as indoles and pyrroles, or electron-deficient arenes such as pyridine N-oxides and perfluoroarenes. Breakthrough was made by Yu and co-workers in 2010, and they succeeded in ligand-controlled, position-selective C–H olefination through carboxyl group directed CdH bond activation (Scheme 44).70 In this elegant study, amino acids were able to increase the reactivity significantly and the regioselectivity for multi-substituted phenylacetic acids 149. Mechanistic studies suggest that the increased reaction rates stem from the acceleration in the C-H cleavage step.

Scheme 44 Amino acid promoted C–H olefination reaction.

Generally, the N- or O-containing directing groups are usually installed in the substrates in order to control the regioselectivity and assist C-H activation. Gandeepan and Cheng reported a Pd-catalyzed ortho C-H olefination of arenes 152 with excellent regioselectivity at ambient temperature by utilizing an allylic alkenyl double bond as a directing group for the first time (Scheme 45).71 Mechanistic studies supported the existence of coordination of C ¼ C to Pd(II) and an electrophilic C-H functionalization process.

Scheme 45 Pd-catalyzed ortho C-H olefination directed by the double bond.

ortho-Directed metalation of CdH bond has been used as a powerful approach for achieving ortho-selective functionalizations of aromatic compounds. On the other hand, a generally applicable approach for remote meta-C–H activation is challenging mainly due to the difficulty in forming a macrocyclic pre-transition state. In 2012, meta CdH bond olefination of benzyl alcohols was accomplished by using a nitrile-containing template (T1). In this reaction, a series of di- or tri-substituted olefins were also found to be suitable substrates. The authors proposed that the nitrile group in the template was weakly coordinated to the [Pd(II)–Ar] intermediate and thus could be effectively coordinated with disubstituted olefins (Scheme 46A). Having established this nitrile-containing end-on template to activate meta-CdH bond, this

Scheme 46 Pd-catalyzed meta-CdH bond olefination directed by a nitrile-containing template.

140

CdC Bond Formation Through C-H Activation

approach could further be applied to meta CdH bond olefination of hydrocinnamic acids 156. Mono-N-protected amino acid ligands such as N-acetyl-protected glycine were found to be essential to accelerate C–H olefinations (Scheme 46B).72 The nitrile template T2 could also efficiently direct meta C − H olefination of a-phenoxyacetic acids 158 (Scheme 46C).73 Nondirected C-H functionalization is highly attractive, as it allows the functionalization of more distant sites and enable further useful reactions without the directing group. In 2017, Yu and coworkers discovered an electron-deficient 2-pyridone ligand L13, which could enable Pd-catalyzed non-directed C–H olefination of both electron-deficient and electron-rich arenes (160) as the limiting reagent (Scheme 47).74 These ligands not only accelerate the reaction but also prevent the catalyst from forming a stable and less reactive palladium complex. Importantly, this non-directed C-H olefination allows late-stage functionalization of CdH bonds that are not accessible by directing group strategy.

Scheme 47 Pd-catalyzed non-directed C-H olefination promoted by 2-pyridone ligand.

While C(sp2)-H olefination has been extensively explored, Pd-catalyzed olefination of unactivated C(sp3)dH bonds remains a challenge since it is mechanistically distinct from that of aryl C-H olefination. Encouraged by Fu’s pioneering work concerning intramolecular olefination of alkyl halides,75a Yu and coworkers developed a Pd(II)-catalyzed direct olefination of C(sp3)dH bond assisted by an N-arylamide (CONHAr) directing group in 2010 (Scheme 48A).75b After C-H olefination, the amide products underwent 1,4-conjugate aza-addition to give the corresponding lactams 163 in up to 87% yield. They also reported Pd-catalyzed g-C(sp3)-H olefination of Tf-protected amines enabled by pyridine-based ligand L14. This protocol was also compatible with styrenes besides acrylates. A variety of C-2 alkylated pyrrolidines 165 were accessed after subsequent aza-Wacker oxidative cyclization or conjugate addition of the olefinated intermediates (Scheme 48B).76

Scheme 48 Pd-catalyzed C(sp3)-H olefination reactions.

Sanford and coworkers reported Pd/polyoxometalate-catalyzed olefination of unactivated C(sp3)dH bonds with pyridine or quinoline as a directing group and air as the terminal oxidant. The products underwent reversible intramolecular Michael addition,

CdC Bond Formation Through C-H Activation

141

affording pyridinium salts 167 in up to 89% yield (Scheme 49).77 Notably, the cationic Michael adduct undergoes facile elimination to release a,b-unsaturated ester 168 in the presence of DBU.

Scheme 49 Pd/polyoxometalate-catalyzed C(sp3)-H olefination.

Apart from Pd(II)-initiated C(sp3)-H olefination reactions, Baudoin and coworkers developed Pd(0)-catalyzed intramolecular C(sp3)-H alkenylation from easily accessible bromoalkenes 169, providing a variety of strained a-alkylidene-b-lactams 170 in up to 92% yield (Scheme 50).78

Scheme 50 Pd(0)-catalyzed intramolecular C(sp3)-H alkenylation.

12.05.2.3 CdH bond alkylation In 2006, Yu and coworkers developed a Pd-catalyzed alkylation of aryl CdH bonds with a variety of primary-alkyl tin reagents for the first time (Scheme 51A).79 The alkylation reactions with benzoquinone as a crucial promoter proceeded smoothly to give monoand dimethylation products (172, 173) in 20% and 64% yield, respectively. To a certain extent, however, the toxicity of organotin reagents limited its applications. They subsequently developed a Pd(II)-catalyzed alkylation with methylboronic acid (Scheme 51B).80 Ag2O is an efficient promoter for the transmetalation as well as co-oxidant with benzoquinone.

Scheme 51 Pd-catalyzed alkylation of aryl CdH bond.

Amino carboxylic acids are the most used transient directing group (TDGs) in C-H arylation reactions described above. The imine linkage was generated reversibly via aldehyde condensation to facilitate C − H activation. Chen and Sorensen utilized orthanilic acid (TDG4) as a transient directing group to achieve ortho C − H methylation of benzaldehyde 176 with potassium methyl trifluoroborate and by using 1-fluoro-2,4,6-trimethylpyridinium salt [F] as the oxidant (Scheme 52).81

142

CdC Bond Formation Through C-H Activation

Scheme 52 ortho C − H methylation of benzaldehyde.

Direct intramolecular C-H alkylations of heteroarenes provide a straightforward access to condensed heterocyclicheteropolycyclic compounds. Chang and coworkers developed a Pd-catalyzed C-H cyclization of N-(2-halobenzyl)-substituted pyrroles (178) by using 2-(di-tert-butylphosphino) biphenyl (L15) as the optimal ligand, providing condensed pyrroloindoles (179) in up to 97% yield (Scheme 53).82 The catalytic step involves oxidative addition of benzyl halide to Pd(0), intramolecular C-H activation, and reductive elimination.

Scheme 53 Pd-catalyzed C-H cyclization of N-(2-halobenzyl)-substituted pyrroles.

Yu and coworkers reported a Pd(II)-catalyzed intermolecular alkylation of benzoic acids (180) with alkyl halides such as 1,2-dichloroethane and dibromomethane (Scheme 54). Control experiments show that direct ortho C-H alkylation occurs first, followed by an SN2 reaction to give the corresponding lactone 181. Kinetic isotope effect studies do not support the Friedel–Crafts-type reaction process.83

Scheme 54 Pd(II)-catalyzed intermolecular alkylation of benzoic acids.

By employing a directing group on the nitrogen atom of indole, regioselective C-H functionalization at the C2 position could be achieved. Innovatively, Bach and coworkers developed a Pd-catalyzed direct C2-alkylation of free N-H indoles 182 mediated by norbornene (Scheme 55A).84 The mechanism was proposed as follows: direct C3 palladation of indole with a Pd(II) complex leading to the formation of indole- and norbornyl-fused palladaheterocycle at the C2 position as a key intermediate, then followed by oxidative addition with an alkyl halide, reductive elimination and norbornene expulsion. This reaction is compatible with a wide range of primary alkyl bromides. Furthermore, this Pd(II)/norbornene co-catalyzed method could be applied to C-H alkylation of

Scheme 55 Pd-catalyzed C2-alkylation of free N-H indoles and pyrroles.

CdC Bond Formation Through C-H Activation

143

electron-deficient pyrrole derivatives 184 (Scheme 55B).85 An electron-withdrawing substituent on pyrrole is essential since pyrrole is more electron rich and less acidic than indole derivatives. 8-Aminoquinoline (AQ) is a popular bidentate directing group for Pd-catalyzed C-H functionalizations.86 Chen and coworkers developed a Pd-catalyzed ortho-C-H alkylation of N-quinolyl benzamides 186 with both primary and secondary alkyl halides by employing an AQ directing group (Scheme 56).87 Interestingly, the amount of NaHCO3 influenced significantly the mono- or diselectivity, most likely because HCO−3 anion is a slightly less basic ligand in the CMD process. Notably, the reaction of an isolated palladacycle with both cis- and trans-3-methylcyclohexyl iodides gave their corresponding alkylated products with excellent stereoretention (>15/1). These results suggest that the oxidative addition of secondary alkyl iodides to palladacycle proceeds via a concerted pathway.

Scheme 56 Pd-catalyzed ortho-C-H alkylation of N-quinolyl benzamides with alkyl halides.

C-Aryl glycosides play an important role in drug discovery due to the high stability of C-glycosidic bonds. Chen and coworkers reported a stereoselective synthesis of C-aryl glycosides via Pd-catalyzed ortho C − H glycosylation of AQ-coupled benzamide and phenol derivatives (189, 191) with readily available glycosyl chloride donors (Scheme 57).88 The soft aryl palladacycle nucleophile generated via C − H activation reacted with glycosyl oxocarbenium ion partners with high efficiency and excellent stereo control. These reactions also exhibited excellent functional group compatibility. It could be applied to a wide range of arene and heteroarene substrates, glycosyl chloride donors even including maltotriose and tetrasaccharide.

Scheme 57 Pd-catalyzed ortho C − H glycosylation.

From the viewpoint of step- and atom-economy, it is the most ideal approach for C-H alkylation of arenes by oxidative coupling of C(sp2)-H and C(sp3)dH bonds. In 2017, Shi and coworkers developed an intramolecular oxidative coupling between phenyland aliphatic CdH bonds to construct a variety of dihydrobenzofurans 194 (Scheme 58).89 Both the weakly coordinated carboxylate and acridine ligand L16 were found to be essential for the success of this cross-coupling reaction.

144

CdC Bond Formation Through C-H Activation

Scheme 58 Pd-catalyzed oxidative C(sp2)-H and C(sp3)-H coupling.

Compared with the significant achievements concerning Pd-catalyzed C(sp2)-H alkylation, only limited progresses on unactivated C(sp3)-H alkylations have been made. Yu and Daugulis independently developed Pd-catalyzed alkylations of C(sp3)dH bonds with alkyl boronic acids, and with alkyl iodides, respectively. These catalytic systems were also suitable for C(sp2)-H alkylations.38,40,80 Following these early works, Chen and coworkers achieved a Pd-catalyzed g-C(sp3) − H alkylation of aliphatic amines 195 with primary alkyl iodides by using picolinamide as a directing group (Scheme 59).90 They proposed that this C − H alkylation reaction likely proceeds through C − H activation and subsequent oxidative addition with the alkyl iodide via an SN2 mechanism, although a radical mechanism or Pd(III) pathway cannot be ruled out.

Scheme 59 Pd-catalyzed g-C(sp3) − H alkylation of aliphatic amines.

Soon after that, they developed a Pd-catalyzed alkylation of unactivated methylene C(sp3)dH bonds of aminoquinolyl aliphatic carboxamides with a-haloacetate and methyl iodide. This C(sp3)-H alkylation could also be applied to N-Phth-protected amino acids 197, allowing the synthesis of various natural and unnatural amino acids in a highly diastereoselective manner (Scheme 60).91 Additionally, isotopes could be conveniently introduced with isotopically enriched reagents.

Scheme 60 Pd-catalyzed C(sp3)-H alkylation of N-Phth-protected amino acids.

Almost at the same time, a similar work for Pd-catalyzed primary and secondary C(sp3)dH bond alkylation with alkyl halides for the synthesis of optically active unnatural a-amino acids was also achieved by Shi and coworkers.92 Furthermore, Shi et al. found that the addition of 4-Cl-C6H4SO2NH2 (L17) instead of (BnO)2PO2H was critical in the alkylation of unactivated b-methylene C(sp3)dH bonds of a-amino acids 199 (Scheme 61).93 The stereoselective synthesis of various b, b-disubstituted a-amino acids were accomplished through sequential C(sp3)-H alkylations. They speculated that 4-Cl-C6H4SO2NH2 facilitated both oxidative addition of alkyl halide to the Pd(II) center and reductive elimination for the formation of C(alkyl)-C(alkyl).

Scheme 61 Pd-catalyzed C(sp3)dH bond alkylation promoted by 4-Cl-C6H4SO2NH2.

CdC Bond Formation Through C-H Activation

145

12.05.2.4 CdH bond alkynylation Aryl and heteroaryl alkynes are highly valuable compounds widely used in contemporary organic synthesis and materials science. These compounds are commonly prepared by Sonogashira cross-coupling reactions of hetero(aryl) halides with terminal alkynes. On the other hand, great progresses on the C-H alkynylation of arenes with alkynyl halides have been made. In 2007, Gevorgyan and coworkers reported the first example of Pd-catalyzed C-H alkynylation of electron-rich N-fused heterocycles 201 (Scheme 62).94 In the presence of PdCl2(PPh3)2, the C-H alkynylation of indolizine and pyrroloquinoline etc. underwent smoothly with bromoalkynes in high regioselectivity.

Scheme 62 Pd-catalyzed C-H alkynylation of indolizines.

The oxidative cross-coupling between (hetero)arenes and terminal alkynes is a straightforward and efficient method for constructing C(sp2)dC(sp) bond. The challenge lies in how to avoid the formation of undesired homo-coupling (Glaser coupling) of terminal alkyne under oxidative conditions. Owing to the importance of alkynylated thiophenes in material science, natural product and medicinal chemistry, Su and coworkers developed a Pd-catalyzed cross-coupling reaction between terminal alkynes and heteroarenes such as thiophenes (203), furans, pyrroles and indoles in the presence of 0.2 mol% [Pd2(dba)3] (Scheme 63).95 Interestingly, the low palladium catalyst loading is most likely responsible for overcoming alkyne homocoupling.

Scheme 63 Pd-catalyzed C-H alkynylation of thiophenes with alkynes.

Encouraged by the success of meta-C-H arylation and alkylation reactions using norbornene as a transient mediator,35,36,84,85 Pd(II)-catalyzed meta-C − H alkynylation with bulky silyl-protected alkynyl bromides through a Pd(II)/Pd(IV) process was achieved by Yu and coworkers for the first time (Scheme 64). In this reaction, a modified norbornene, NBE-CO2Me (methyl bicyclo[2.2.1] hept-2-ene-2-carboxylate),96 was identified to be the most efficient mediator. The TFA protected 3-amino-2-hydroxy pyridine ligand (L13b) gave the highest selectivity of meta- to ortho- products. Thus, a variety of desired meta-alkynylated products 206 were obtained in up to 72% yield. Unfortunately, simple alkyl and aryl alkynyl bromides only led to a trace amount of the desired products.97

Scheme 64 Pd(II)-catalyzed meta-C − H alkynylation.

146

CdC Bond Formation Through C-H Activation

While the C(sp2)dH bond alkynylation of (hetero)arenes has been accomplished by palladium catalysis, the development of C(sp3)dH bond alkynylation is as challenging as the C(sp3)dH bond arylation and olefination reactions. Tobisu, Chatani and coworkers reported the first example of Pd(II)-catalyzed C(sp3)-H alkynylation of aliphatic carboxylic acids (207) with 8-aminoquinoline as a directing group (Scheme 65).98 This alkynylation reaction proceeded with excellent functional group compatibility, allowing for the straightforward introduction of an ethynyl group into aliphatic acid derivatives.

Scheme 65 Pd(II)-catalyzed C(sp3)-H alkynylation of aliphatic carboxylic acids.

Pd(0)-initiated intermolecular C(sp3)dH bond activations are more attractive due to the compatibility with a wide range of ligands and free of external-oxidants. Based on their work concerning Pd(0)/PR3-catalyzed b-arylation of amides in 2009, Yu and coworkers reported a b-C(sp3) − H alkynylation of aliphatic amides with sterically hindered alkynyl halides by using Pd(0)/NHC catalysts (Scheme 66).99 Pd(0)-catalyzed C − H activation reaction pathway was supported by performing the reaction of pre-prepared alkynyl Pd(II) complex with aliphatic amides.

Scheme 66 Pd(II)-catalyzed b-C(sp3) − H alkynylation of aliphatic amides.

To broaden the substrate scope of C(sp3)-H alkynylation, Yu and coworkers developed the ligand enabled C(sp3)-H alkynylation by Pd(II)/Pd(IV) catalysis. This reaction is compatible with a wide range of carboxylic acid derivatives 83, including a-amino acids as well as a-quaternary and cyclic amides (Scheme 67A).100 The C(sp3)-H alkynylation could be further extended to oligopeptides 212 with tetrabutylammonium acetate as a key additive. They proposed that the acetate anion in NBu4OAc facilitated the C-H activation process, and that the quaternary ammonium cation enhanced the stability of the palladium species during C-H activation (Scheme 67B).101

Scheme 67 Pd(II)-catalyzed C(sp3)-H alkynylation of a-amino acids and oligopeptides.

CdC Bond Formation Through C-H Activation

147

12.05.2.5 Enantioselective C-H activation A breakthrough for Pd-catalyzed enantioselective C-H functionalization, applying the mono-N-protected chiral amino acids (MPAAs) as viable ligands, was first made by the Yu group. Prochiral pyridines 214 reacted with alkylboronic acids in the presence of Pd(OAc)2 and (−)-Men-L-Leu-OH (L19), affording triarylmethane compounds 215 in up to 96% yield with 95% ee (Scheme 68A).102a This work greatly promoted the development of Pd-catalyzed asymmetric CdH bond functionalizations. Later, the Yu group extended the method to the carboxylate or N-nosyl group directed asymmetric CdH bond olefination and arylation (Scheme 68B and C).102b,c Kinetic resolution, which relies on the different reaction rates of enantiomers, is widely used in organic synthesis. In 2015, Yu and coworkers described a kinetic resolution of racemic mandelic and phenylglycine pivalate derivatives 220 via dehydrogenative Mizoroki − Heck reaction (Scheme 68D).102d In addition, C-H arylation of N-nosyl benzylamines 222 with arylboronic acid pinacol esters was achieved, provideind enantioenriched bezylamine derivatives 223 with up to 135 s value (Scheme 68E).102e The utilization of Pd(II)/Pd(0) catalysis also led to the synthesis of P-stereogenic phosphoamides. Han and workers found that MPAA ligand L20 provided high levels of enantiocontrol in the desymmetric C-H arylation of phosphoamides compound 224. The reaction could be successfully conducted on a gram-scale, and the utility of this methodology was further demonstrated by derivatization of products 225 to potentially useful ligands without significant erosion in enantiopurity (Scheme 68F).102f

Scheme 68 Pd-catalyzed enantioselective C(sp2)dH bond functionalization to construct central chirality.

Based on the Sokolov’s and Richards’ works regarding the synthesis of planar chiral ferrocene palladacycle compounds with stoichiometric amounts of MPAA, several groups developed Pd/MPAA-catalyzed enantioselective CpdH bond functionalization using the Pd(II)/Pd(0) catalytic system. In 2013, Gu, You and their coworkers achieved Pd-catalyzed asymmetric C-H arylation of dialkylaminomethylferrocene derivatives 226 with arylboronic acids by using Boc-L-Val-OH as the chiral ligand. This reaction could well tolerate various substituted arylboronic acids, affording their corresponding mono-arylated ferrocene derivatives 227 in up to 81% yield with 99% ee (Scheme 69A).103a Meanwhile, Wu, Cui and their coworkers also achieved an asymmetric oxidative Heck reaction using Pd/MPAA catalyst under similar conditions. Various olefins, such as vinylcyclohexanes, acrylates and styrene

148

CdC Bond Formation Through C-H Activation

Scheme 69 Pd-catalyzed enantioselective C(sp2)dH bond functionalization to construct planar chirality.

derivatives were found to be suitable for this reaction with up to 98% yield and 99% ee (Scheme 69B).103b To further improve the atom economy, the You group accomplished an enantioselective twofold C-H oxidative cross-coupling reaction of ferrocene 226 with heteroarenes in up to 86% yield with 99% ee (Scheme 69C).103c Unfortunately, electron-deficient and electron-neutral arenes, such as imidazole, oxazole and pentafluorobenzene did not occur under the optimized conditions. In addition, the You group found that oxazoles and thiazoles were also suitable substrates in the Pd(II)-catalyzed enantioselective C-H/C-H heteroarylation of ferrocenes 226 (Scheme 69D).103d This method showed excellent regioselectivity toward C5dH bond of various substituted oxazoles and thiazoles. Apart from dialkylaminomethyl as a feasible directing group, other directing groups were less investigated in Pd(II)-catalyzed asymmetric CdH bond functionalization of ferrocenes. Until recently, the carboxylic acid was identified as an effective directing group in the Pd-catalyzed ortho-alkenylation reaction reported by Wu, Cui, and coworkers. Planar chiral 1,2-disubstituted ferrocenecarboxylic acids 232 were generated in up to 94% yield with 92% ee (Scheme 69E).103e Under Pd(II)/Pd(0) catalysis, the efficient construction of axially chiral compounds has also been successfully realized. In 2012, Yamaguchi, Itami and coworkers reported the Pd-catalyzed asymmetric coupling reaction of thiophene 233 and arylboronic acids 234 to construct sterically hindered heteroaromatic biaryl compounds. With chiral bisoxazoline L21 as the ligand and TEMPO as the oxidant, the corresponding axially chiral thiophenes 235a were obtained in 63% yield with 41% ee. With the steric hindrance increased, the ee value was further improved to 72%, albeit with decreased yield (27%)(Scheme 70A).104a In 2017, the Yang group

Scheme 70 Pd-catalyzed enantioselective C(sp2)dH bond functionalization to construct axial chirality.

CdC Bond Formation Through C-H Activation

149

used phosphine oxide as the directing group to develop a Pd-catalyzed asymmetric alkenylation reaction, constructing various axially chiral biaryl phosphine oxides 237 efficiently in up to 73% yield with 96% ee (Scheme 70B).104b Shi and coworkers accomplished a highly atroposelective synthesis of axially chiral styrenes 239 bearing an open-chained alkene via asymmetric C-H olefination reaction in up to 99% and 99% ee assisted by L-pyroglutamic acid (Scheme 70C).104c This reaction could be also applicable to the enantioselective synthesis of atropisomeric anilides 241 in up to 99% yield with 99% ee (Scheme 70D).104d The transient directing group strategy has been widely utilized in the C–H arylation reactions as described (Section 12.05.2.1). In 2017, the Shi group successfully applied this strategy for the asymmetric synthesis of axially chiral compounds. With tert-leucine as a chiral transient directing group, the enantioselective CdH bond alkenylation reaction proceeded smoothly with oxygen as the oxidant, generating the axially chiral alkenyl substituted biaryl compounds 243 with up to 99% ee (Scheme 71A). 105a The kinetic resolution process of biaryl compounds was also studied, with s value up to 600. Hereafter, they extended this strategy to the asymmetric allylation of biaryl compounds. The allyl-substituted biaryl compounds 244 were obtained in up to 74% yield and 99% ee by using tert-leucine as the chiral transient directing group and benzoquinone (BQ) as the oxidant (Scheme 71B).105b Additionally, the Shi group also successfully realized the asymmetric C-H naphthylation reaction of biaryl compounds with 7-oxabenzonorbornadiene (Scheme 71C).105c Further transformation of the naphthylation product 245 provided an efficient chiral aldehyde catalyst in the asymmetric reaction of (E)-chalcone with glycine derived amides. A novel enantioselective palladaelectro-catalyzed C–H olefination reaction was achieved by Ackermann et al. through the synergistic cooperation with the transient directing group in 2020. Enantioenriched biaryls 246 were obtained in up to 71% yield with 99% ee (Scheme 71D).105d This method also provides an access to novel chiral BINOL, dicarboxylic acid and spirene which are potentially valuable in asymmetric catalysis. Soon after, with bulky amino amide TCA as a transient directing group, an effective and practical method to construct a new type of axially chiral styrene by Pd-catalyzed enantioselective C-H olefination reaction was reported by the Shi group. Various axially chiral styrenes 248 were generated in up to 95% yield and 99% ee (Scheme 71E).105e The axially chiral styrene carboxylic acids obtained by further transformation exhibited superior enantiomeric control in the Co(III)-catalyzed enantioselective C(sp3)-H amidation reaction.

Scheme 71 Synthesis of axially chiral compounds by the transient directing group strategy.

The pioneering example of Pd-catalyzed enantioselective C(sp3)-H functionalization was reported by Yu in 2008. The directed C(sp3) − H butylation of 2-isopropylpyridine 249 with t-BuB(OH)2 was achieved by employing cyclopropyl amino acid L22 as the ligand under Pd(II)/Pd(0) catalysis, albeit in 38% yield with 37% ee (Scheme 72A).106a In 2011, the amide-directed intermolecular

150

CdC Bond Formation Through C-H Activation

Scheme 72 Pd-catalyzed enantioselective C(sp3)dH bond functionalization to construct central chirality.

asymmetric C(sp3)-H arylation of cyclopropane 251 with organoboron reagents was developed in up to 81% yield with 92% ee (Scheme 72B).106b This methodology was later extended to asymmetric C(sp3) − H arylation of cyclobutyl amides 253 (Scheme 72C).106c In 2018, they achieved Pd(II)-catalyzed asymmetric g-C(sp3) − H arylation of alkyl amines 255 via desymmetrization by using chiral acetyl-protected aminomethyl oxazoline L25 (APAO) as the optimal ligand. Various vinyl- or arylboron reagents can be used as coupling partners (Scheme 72D).106d Carboxylic acids are commonly used feedstocks. Pd-catalyzed asymmetric C(sp3) − H arylation of cyclopropane carboxylic acids 257 and 259 with an inherent directing group was realized with chiral monoprotected aminoethyl amine ligand L26 or L27 (Scheme 72E).106e This reaction provides a new method for preparing chiral carboxylic acid derivatives 258 and 260 with high efficiency. The combination of chiral phosphoric acid (CPA) with palladium catalysis has also been demonstrated to enable enantioselective C − H functionalizations. In 2016, the Yu group reported that Pd(II)-catalyzed enantioselective C(sp3) − H a-arylation of thioamide 261 with aryl boronic acid, affording enantioenriched products 262. Among the tested ligands, chiral phosphoric acid CPA1 gave the best results in up to 90% yield and 98% ee (Scheme 73A).107a The Shi group achieved an asymmetric C-H alkenylation reaction of 8-arylquinoline 263 using chiral SPINOL-derived phosphoric acid CPA2 combined with Pd(OAc)2, constructing a class of axially chiral quinoline derivatives with high efficiency. With silver acetate as an oxidant, axially chiral alkenyl-substituted 8-arylquinoline derivatives 264 were obtained with up to 98% ee (Scheme 73B).107b The free amine could also act as a directing group to enable the Pd(II)-catalyzed asymmetric C(sp3)-H alkenylation reaction. Various axially chiral biaryl2-amines 265 were obtained in up to 91% yield and up to 97% ee in the presence of chiral phosphate anion of CPA3 (Scheme 73C).107c In a gram-level synthesis, the loading of CPA3 could be reduced to 1 mol% without any erosion in terms of enantioselectivity.

CdC Bond Formation Through C-H Activation

151

Scheme 73 Enantioselective C − H functionalizations enabled by the combination of palladium and chiral phosphoric acid.

Besides these Pd(II)-initiated asymmetric C − H functionalizations through Pd(II)/Pd(0) catalytic cycle under oxidative conditions, notable progresses on asymmetric C(sp3) − H functionalizations have also been made through Pd(II)/Pd(IV) catalytic cycle. An elegant example of Pd(II)-catalyzed asymmetric C(sp3)dH bond arylation was accomplished by the Yu group in 2015. In this work, trifluoromethyl-protected cyclopropylmethylamine 267 was coupled with aryl iodides to provide arylation products 268 with up to >99% ee (Scheme 74A).108a Both oxidative addition and reductive elimination were promoted by the addition of silver

Scheme 74 Asymmetric C(sp3) − H functionalizations through Pd(II)/Pd(IV) catalytic cycle.

152

CdC Bond Formation Through C-H Activation

carbonate. In addition, coupling a wide range of a-substituted cyclopropanecarboxylic acids 269 with aryl iodides was accomplished by chiral monoprotected aminoethyl amine ligand L28 in up to 90% yield with 98% ee (Scheme 74B).108b Recently, they also realized Pd-catalyzed enantioselective C(sp3) − H arylation of free aliphatic amines 271 with a chiral bidentate thioether ligand L29 (Scheme 74C).108c In 2016, Yu, Houk and coworkers reported a procedure for asymmetric C(sp3)dH bond arylation of acyclic amide derivatives 273. With the bidentate acetyl-protected aminoquinoline L30 as the optimal ligand, diverse arylated amide products 274 were obtained in 35–89% yields with 78–92% ee (Scheme 74D).108d Bidentate N-acetyl-protected aminomethyl chiral oxazoline L25 (APAO) could enable the enantioselective arylation of isobutyramide 275 in up to 85% yield with 98% ee (Scheme 74E).108e In 2015, the Duan group demonstrated for the first time that chiral phosphoramide CPA4 could be utilized in the generation of stereochemical C(sp3)-H activation events through Pd(II)/Pd(IV) catalytic cycle albeit with relatively low enantioselective control (up to 80% ee) (Scheme 75A).109a One year later, Chen, He and coworkers achieved picolinamide-directed benzylic C(sp3) − H arylation of amides 279 with aryl iodides under slightly modified conditions. With BINOL-derived phosphate CPA5, a variety of structurally multiple arylation products 280 were obtained in up to 99% yield and 97% ee (Scheme 75B).109b In 2018, Shi and coworkers reported a Pd(II)-catalyzed asymmetric C-H arylation of unbiased methylene b-C(sp3)dH bonds, combining a strongly coordinating bidentate 2-pyridinylisopropyl (PIP) directing group with chiral phosphoric acid (CPA6) (Scheme 75C).109c.

Scheme 75 Asymmetric C(sp3)-H arylation enabled by Pd/chiral phosphoric acid (phosphoramide).

BINOLs were introduced by the Shi group as suitable ligands in Pd(II)-catalyzed enantioselective alkynylation of methylene b-C(sp3)dH bonds in 2017. 3,30 -Fluorinated-BINOL L31 was identified to have a prominent effect on both reactivity and enantioselectivity (up to 96% ee) (Scheme 76A).110a Subsequently, Shi and coworkers described an elegant cascade reaction involving Pd(II)-catalyzed asymmetric aliphatic methylene C(sp3)-H olefination and aza-Wacker cyclization through syn-aminopalladation. The g-lactams 284 with a broad range of functionalities were obtained with up to 98% ee (Scheme 76B).110b Recently, the synthesis of acyclic aliphatic amides 286 bearing continuous chiral centers was accomplished via Pd(II)-catalyzed enantioselective methylene C(sp3)-H arylation. The method can be applicable to a wide range of aryl iodides, providing a practical platform for constructing a,b-chiral aliphatic amides 286 in up to 93% yield with >20:1 dr and 98% ee (Scheme 76C).110c

CdC Bond Formation Through C-H Activation

153

Scheme 76 Enantioselective C(sp3) − H alkynylation, alkenylation, and arylation enabled by Pd/ BINOLs.

In 2018, Jin, Xu and coworkers employed L-tert-leucine as a transient directing group to achieve Pd-catalyzed enantioselective C(sp2)-H arylation of ferrocenyl ketones 287 (Scheme 77A).111a In general, various electron-withdrawing aryl iodides, such as nitro, ester and amide, were well tolerated, while neutral and electron-rich aryl iodides showed lower reactivity. In the same year, the Shi group also applied this transient directing group strategy to enantioselective C(sp3)dH bond alkynylation reaction of biaryl compounds 242. Various axially chiral alkynyl substituted biaryl compounds 289 were obtained with up to 99% ee (Scheme 77B).111b

Scheme 77 Pd-catalyzed enantioselective C(sp2)-H arylation by transient directing group strategy.

The pioneering example of asymmetric C–H arylation reaction via Pd(0)/Pd(II) catalysis was developed by the Cramer group in 2009. The intramolecular arylation of vinyl triflates 290 gave chiral indanes 291 bearing an all-carbon quaternary stereocenter in up to 99% yield and 97% ee (Scheme 78A).112a In 2013, Saget and Cramer extended this method to the asymmetric C–H arylation of amides 292, providing a variety of dibenzozeheptanones 293 in up to 99% yield with 95% ee. It is worth mentioning that this reaction proceeds via a rare eight-member palladacycle (Scheme 78B).112b In 2018, Baudoin and coworkers reported the design and synthesis of novel chiral difunctional ligands by incorporating the phosphine and carboxylic acid moieties into a binaphthyl backbone. The optimal ligand L35 enabled asymmetric C(sp2)-H arylation reaction, resulting in 5,6-dihydro-phenanthridine 295 in up to 93% yield with 97% ee (Scheme 78C).112c Subsequently, the Cramer group disclosed an enantioselective synthesis of 1H-isoindoles 297 by asymmetric C-H arylation of trifluoroacetimidoyl chlorides 296 in the presence of phosphordiamidite ligand L36 (Scheme 78D).112d In 2012, Shintani, Hayashi and coworkers developed a Pd-catalyzed enantioselective synthesis of Si-stereogenic dibenzosiloles 299 through desymmetrization of triarylsilanes 298 with Josiphos-type ligand L37 (Scheme 78E).112e

154

CdC Bond Formation Through C-H Activation

Scheme 78 Central chirality construction by Pd(0)-catalyzed C-H arylation reactions.

The development of highly efficient synthesis of P-chiral ligands has been an important topic due to their wide applications in asymmetric catalysis. An asymmetric C-H arylation of prochiral phosphinic amides 300 was described by the Duan group in 2015, providing azaphosphinine oxides 301 bearing a P-stereogenic center in up to 94% yield with 93% ee (Scheme 78F).112f A great number of asymmetric C-H activation for constructing axial and planar chiral compounds have also been disclosed. In 2014, You and Gu, and Gu and Kang independently reported the synthesis of planar chiral ferrocenes by enantioselective intramolecular C-H arylation. You and Gu developed a Pd-catalyzed asymmetric cyclization of 2-bromobenzoylferrocenes 302 with BINAP as the ligand, affording arylated products 303 in up to 99% yield and 99% ee.113a At the same time, Gu, Kang and co-workers disclosed the same C-H arylation reaction of aryl iodides under similar conditions (Scheme 79A).113b Of particular note,

Scheme 79 Axial and planar chirality construction by Pd(0)-catalyzed C-H arylation reactions.

CdC Bond Formation Through C-H Activation

155

ruthenocene derivatives were also suitable substrates. In 2017, the Gu group developed an intramolecular C-H arylation for the construction of indole-based atropisomers 305. With TADDOL-phosphoramidite L38, the products were obtained in up to 99% yield with 91% ee in this dynamic kinetic resolution (Scheme 79B).113c The synthesis of axially chiral dibenzazepinones 307 similarly by intramolecular C-H arylation was reported by the Cramer group in 2015. Excellent enantiocontrol was achieved, by employing a simple TADDOL-derived phosphoramidite ligand L34. DFT calculations indicated that C–H activation proceeded via an enantiodetermining CMD step to generate a configurationally stable 8-membered palladacycle (Scheme 79C).113d Very recently, they realized an intermolecular enantioselective C-H arylation of heteroarenes 309 with aryl bromides 308, providing an efficient access to atropisomeric heterobiaryls 310 in up to 97% yield with 95% ee (Scheme 79D).113e Several groups have been engaged in the Pd(0)-catalyzed asymmetric C(sp3)dH bond functionalization reactions for the synthesis of enantioenriched indoline derivatives. In 2011, Kündig and coworkers pioneeringly achieved the asymmetric CdH bond arylation of N-cycloalkyl substituted carbamates 311 by a chiral Pd complex derived from a bulky NHC ligand (from precursor L40) (Scheme 80A).114a The same year, Kagan and coworkers found that chiral bisphosphine (R, R)-Me-DuPhos (L41) could be utilized in Pd-catalyzed CdH bond arylation reaction.114b In 2012, the Cramer group synthesized a new class of monodentate phosphine ligand L42, which could efficiently promote C-H arylation of 311 in up to 85% yield with 96% ee.114c Baudoin et al. applied an intramolecular C-H arylation to the asymmetric synthesis of fused cyclopentane compounds. The combination of Pd(OAc)2 and binepine ligand L43 could give an array of desired products 314 in up to 97% yield with up to > 20:1 dr and 92% ee (Scheme 80B).114d b-Lactams 316 could be prepared from

Scheme 80 Pd(0)-catalyzed asymmetric C(sp3)dH bond functionalizations.

156

CdC Bond Formation Through C-H Activation

chloroacetamides 315 by an intramolecular C-H alkylation (Scheme 80C).113e The palladium catalyst derived from bulky phosphoramidite ligand L44 together with adamantyl carboxylic acid as a co-catalyst provided excellent enantioselectivity. Cyclopropane motifs are found in many natural products and bioactive compounds. The Cramer group accomplished an efficient access to functionalized enantioenriched tetrahydroquinolines 318 through the direct CdH bond functionalization of cyclopropanes 317 (Scheme 81A).115a Remarkably, a gram-scale reaction could be completed with only 1 mol% Pd catalyst. With TADDOL-derived phosphoramidite L46 as chiral ligand in combination with adamantane-1-carboxylic acid as a cocatalyst, an array of g-lactams 320 could also be accessed via the intramolecular alkylation of cyclopropyl C(sp3)dH bonds (Scheme 81B).115b In 2017, the Cramer group reported that a new diazaphospholane ligand L47 enabled highly enantioselective cyclopropane CdH bond activation with trifluoroacetimidoyl chlorides 321 as electrophilic partners (Scheme 81C).115c The resulting cyclic ketimines 322 reacted smoothly with diverse nucleophiles in one-pot process, yielding multi-substituted pyrrolidines.

Scheme 81 Pd(0)-catalyzed asymmetric C(sp3)–H functionalizations of cyclopropanes.

12.05.2.6 Applications in organic synthesis Versatile C-H functionalization reactions have witnessed wide applications in the total synthesis of naturally occurring compounds with interesting biological activity. Several notable examples are introduced here. The total synthesis of (+)-lithospermic acid was accomplished in 12 steps and 11% overall yield from o-eugenol, reported by the Yu group (Scheme 82). First, acid 323 from readily

Scheme 82 The total synthesis of (+)-lithospermic acid.

CdC Bond Formation Through C-H Activation

157

available o-eugenol in three steps was esterified with chiral hydroxyamide 324 and underwent two-step sequence to give 325. Second, treatment of 325 with diazo transfer reagent followed by a diastereoselective carbene insertion and ester hydrolysis provided the trans-dihydrobenzofuran core 327. Gratifyingly, Pd-catalyzed C(sp2)–H olefination with olefin 328 directed by the free carboxyl group furnished the protected natural product 329 in 93% yield. Finally, demethylation of 329 gave (+)-lithospermic acid (330).116 Shen, Li, Zhang and co-workers accomplished an asymmetric total synthesis of delavatine A on a gram-scale, via a longest linear sequence of 13 steps (Scheme 83). First, a syn-selective hydrogenation of 331, prepared from a commercially available indanone over five steps, delivered racemic 332. Second, kinetic resolution of 332 through Pd-catalyzed triflamide-directed C-H olefination provided enantioenriched olefinated product 333 in 46% yield on multigram scale. After ozonolysis/reduction, a four-step sequence gave the tricyclic coupling partner 335. The Stille coupling with pulegone-derived fragment 336 finally afforded delavatine A (337).117

Scheme 83 The total synthesis of delavatine A.

In 2011, Baran and co-workers achieved a rapid divergent total synthesis of piperarborenine B (7 steps, 7% overall yield, Scheme 84). The concise routes demonstrate the power of guided C-H functionalization logic to enable a fundamentally novel approach to cyclobutane natural product synthesis. Notable elements of this synthesis include: (1) a one-step, stereo-controlled preparation of 339 from methyl coumalate (338); (2) sequential C(sp3)-H arylation reactions of 339; (3) divergent epimerization of 341 to provide both proposed piperarborenine stereoisomers; (4) second arylation of 342, followed by ester hydrolysis and acylation with 345 finished piperarborenine B (346).118

Scheme 84 Total synthesis of piperarborenine B.

Taking advantage of this method, a concise synthesis of pipercyclobutanamide A (352) was obtained from methyl coumalate (338) in 7 steps with 5% overall yield (Scheme 85). Salient features of the synthesis include: (1) sequential Pd-catalyzed C-H olefination and C-H arylation on an unactivated cyclobutane ring; (2) stereo-controlled access to highly strained all cis substituted cyclobutanes; (3) direct conversion of aminoquinoline amides to aldehydes.119

158

CdC Bond Formation Through C-H Activation

Scheme 85 Total synthesis of the proposed structure of pipercyclobutanamide A.

Maimone and coworkers realized a concise total synthesis of podophyllotoxin in six steps, enabled by a late-stage directed Pd-catalyzed C(sp3)–H arylation reaction (Scheme 86). Deprotonation of free cyclobutanol 353 (2 steps from 6-bromopiperonal) and a subsequent highly diastereoselective cycloaddition with 2-methylthioaniline-containing amide 354 generated intermediate 355, which underwent in situ reduction and protection to afford acetal 356. Importantly, a C–H arylation installed the requisite aryl motif in 357 as a single diastereomer, which could then be directly cyclized under acidic conditions to give podophyllotoxin (358).120

Scheme 86 Total synthesis of podophyllotoxin.

The implementation of C(sp3)–H arylation strategy could also be applied into the construction of (−)-quinine (Scheme 87). In 2018, Maulide and coworkers reported an elegant synthesis of quinine in 10 steps based on two stereoselective key steps consisting of 1 C-H activation and one aldol reaction. Starting with 359, installation of a picolinamide handle to give 360 enabled a diastereoselective C(sp3)–H arylation of the quinuclidine scaffold. The arylated product 361 can be oxidatively manipulated to reveal the free acid and amidated to the corresponding Weinreb amide 362, followed by a three-step sequence for the de novo generation of the vinyl group in 363. The subsequent oxidation, diastereoselective aldol addition and Wolff-Kishner reduction furnished (−)-quinine (366).121

CdC Bond Formation Through C-H Activation

159

Scheme 87 Total synthesis of (−)-quinine.

Incarviatone A is a hybrid natural product, which revealed as a potent inhibitor of monoamine oxidase. The enantioselective synthesis of (−)-incarviatone A was reported in 2015 by Li, Lei and coworkers (Scheme 88). The n-propyl group was introduced to the phenyl ring by the carboxylic acid directed C-H alkylation. Subsequently, the cyclopentane ring in 371 was constructed by intramolecular Rh(II)-catalyzed C-H insertion from diazo precursor 370. The carboxylic acid directed, PdII-catalyzed C-H iodination afforded 372 in a scalable manner. Overall, (−)-incarviatone A was obtained in 14 steps starting from commercially available phenylacetic acid.122

Scheme 88 Total synthesis of (−)-incarviatone A.

The total synthesis of the cytotoxic natural product (+)-psiguadial B (379) was completed in 15 steps from diazoketone 374, employing Pd-catalyzed C(sp3)–H alkenylation as the key CdC bond forming reaction towards constructing the overall skeleton for the target molecule (Scheme 89). Reduction of the amide, treatment with KOH in methanol, methylenation and hydrolysis provided (+)-378, which could give the natural product (+)-psiguadial B in nine steps.123

Scheme 89 Total synthesis of (+)-psiguadial B.

160

CdC Bond Formation Through C-H Activation

Thesmar and Baudoin successfully achieved the asymmetric total synthesis of the natural dithiodiketopiperazines (−)-epicoccinG and (−)-rostratin A in 14 and 17 steps, respectively, with high overall yields from inexpensive starting materials (Scheme 90). The common precursor 385 to access both target molecules was readily synthesized using an enantioselective organocatalytic epoxidation and a bidirectional C(sp3)–H alkenylation strategy to close the pentacycle as the key steps.124

Scheme 90 The total synthesis of (−)-epicoccin G and (−)-rostratin A.

12.05.3 Rh-catalyzed CdH bond functionalization Rh-catalyzed C-H functionalization has witnessed significant progress over the past decades. There are mainly two accepted reaction cycles, exemplified by C-H alkylation with alkene (Fig. 4A, Rh(I)/Rh(III) cycle), C-H arylation with aryl halide (Fig. 4B, Rh(I)/

Fig. 4 Catalytic cycles for Rh-catalyzed C-H functionalization, (a) Rh(I)/Rh(III) catalytic cycle (olefin insertion), (b) Rh(I)/Rh(III) catalytic cycle (oxidative addition of aryl halide), (c) Rh(III)/Rh(I) catalytic cycle.

CdC Bond Formation Through C-H Activation

161

Rh(III) cycle) and C-H annulation with alkyne (Fig. 4C, Rh(III)/Rh(I) cycle). For the C-H alkylation with alkene, the Rh(I)-catalyzed reaction initiates via oxidative addition of a Rh(I) species into the CdH bond, giving Rh–H complex (I). Subsequent migratory insertion into the alkene, followed by reductive elimination, provides the alkylation product and regenerates the active Rh(I) catalyst (Fig. 4A). For the C-H arylation with aryl halide, Rh(I)-catalyzed reaction initiates via concerted metallation deprotonation (CMD) to give Rh − R complex (III). Subsequent oxidative addition of aryl halide, followed by reductive elimination, provides the arylation product and regenerates the active Rh(I) catalyst (Fig. 4B). For the Rh(III)-catalyzed C-H annulation with alkyne, the directing group assisted CdH bond activation step occurs via concerted metalation-deprotonation (CMD) mechanism, giving Rh(III) intermediate (III), which inserts alkyne to form a rhodacycle (IV). Then reductive elimination gives the desired annulation product and generates a rhodium(I) species which can undergo oxidation to regenerate the catalytically active rhodium(III) species (Fig. 4C).

12.05.3.1 CdH bond arylation In 2004, Bergman, Ellman and coworkers pioneeringly reported Rh(I)-catalyzed C-H arylation of a variety of heterocycles, providing the arylated products in moderate to good yields (Scheme 91A, left). Then, the bulky trialkylphosphine L49 (mixture of two isomers) significantly improved the yield and widened the scope of the Rh-catalyzed C-H arylation of N-heterocycles (388). The unique structure of [4.2.1]-Cy-Phob ligand (L49) maintains the spatial and electronic properties of PCy3, while reducing the tendency of PCy3 to undergo dehydrogenation. The use of more hindered amine base (i-Pr2i-BuN) and the microwave heating significantly improved the reaction efficiency. Under the optimized conditions, this reaction was also suitable for a wide range of aryl bromides besides aryl iodides (Scheme 91A, right).125

Scheme 91 Rh(I)-catalyzed C-H arylation of heteroarenes.

In 2006, the catalytic C-H arylation of heteroarenes 390 (thiophenes, furans and pyrroles) with broad substrate scope in the presence of electron-deficient Rh catalyst [Rh] was developed by Itami and coworkers. The rhodium catalyst bearing a strongly p-accepting ligand, prepared from [Rh(CO)2Cl]2 and P[OCH-(CF3)2]3, is stable in air, realizing catalytic C-H arylation of heteroarenes that shows high activity paired with broad scope (Scheme 91B).126 The selective ortho-arylation of pyridine was also enabled by electron-deficient Rh catalysts. The C-H arylation of pyridine and quinoline derivatives (392) at the C2 position with aryl bromides took place in the presence of [Rh(CO)2Cl]2 without any additives, giving the arylation products (393) in up to 86% yield (Scheme 92).127

Scheme 92 Rh(I)-catalyzed C-H arylation of pyridines with aryl bromides.

162

CdC Bond Formation Through C-H Activation

In 2008, Zhao and Yu realized an efficient regioselective C-H arylation of benzoquinoline (49) by Rh(I) catalysis with acid chloride as the coupling partner under ligand-free conditions via decarbonylative C-H activation (Scheme 93A).128a Then, Li and coworkers discovered a novel method for the synthesis of biaryl compounds (395), involving oxidative decarbonylative coupling of 2-phenylpyridine (174) with aryl aldehydes (Scheme 93B).128b In 2013, the Shi group reported the cross-coupling of aryl carboxylic acids with 2-phenylpyridine (174) through the decarbonylation of carboxylic acids. This method exhibits a broad substrate scope with benzoic acids (Scheme 93C).128c Chatani, Tobisu and coworkers reported a Rh-catalyzed cross-coupling of aryl carbamates with arenes bearing a 4-methyl-4,5-dihydrooxazol-2-yl directing group (396) by using an in situ generated bis(NHC) (L51) complex of Rh(I) as the catalyst. (Scheme 93D).128d

Scheme 93 Rh(I)-catalyzed C-H arylations with benzoyl chlorides, aryl aldehydes, aryl carboxylic acids and aryl carbamates.

In 2004, You and coworkers found that a novel catalytic system, composed of the Wilkinson catalyst [Rh(PPh3)3Cl] and TFA, enabled highly regioselective C-H cross-coupling reactions of aromatic amines (398) with various of heteroarenes (benzothiophene, benzofuran, etc.) through twofold direct C-H functionalizations (Scheme 94).129 This method provides a convenient access to highly extended p-conjugated heteroarenes (399) from readily available substrates.

Scheme 94 Rh(I)-catalyzed C-H arylation of aromatic amines with heteroarenes.

Despite the presence of coordination, phosphine can still be used as a transient or pre-installed directing group to achieve CdH bond activation. In 2003, major breakthrough was made by Bedford and colleagues, who developed a Rh-catalyzed ortho-arylation of substituted phenol (400) using phosphinates as a cocatalyst (Scheme 95A).130a Then, Ye and coworkers applied this protocol to develop a highly efficient Rh-catalyzed one-step synthetic route to 3,30 -diaryl BINOLs (404) from BINOLs (16) and readily available aryl halides. The diene ligand (Ph2-cod:1,5-diphenylcycloocta-1,5-diene) used in the newly developed system proved to greatly promote the C-H arylation reaction (Scheme 95B).130b In 2017, the Shi group constructed a structurally diverse substituted monophosphine ligand library (403) by Rh(I)-catalyzed C-H arylation reaction of commercially available ligands (402). This direct coupling reaction with various aryl bromides or aryl chlorides by using the dialkyl or diaryl phosphino directing group proceeded smoothly free of an external ligand (Scheme 95C).130c They subsequently reported an efficient C7-selective direct decarbonylative arylation of indoles (405) by Rh(I) catalysis with the aid of a PIII-directing group. Inexpensive and commercially available carboxylic acids or anhydrides were employed as the coupling partner in this reaction (Scheme 95D).130d

CdC Bond Formation Through C-H Activation

163

Scheme 95 Rh(I)-catalyzed ortho-arylations directed by built-in PIII groups.

Besides Pd- and Rh(I)-catalysts, Rh(III) catalysts have also been shown to be particularly efficient for C-H arylation. In 2012, Glorius and coworkers reported a Rh(III)-catalyzed Ar-Ar cross-coupling by means of double C-H functionalization between benzamides (407) and halobenzenes (Scheme 96A).131 Indeed, these halobenzenes (408) act as not only the coupling partners, but also cooxidants and/or catalyst modifiers. The kinetic isotope effect (KIE) experiments clearly suggest that the CdH bond activation occurs on both coupling partners. The scope of this transformation is broad with regard to both coupling partners, leading to the regioselective formation of valuable meta substituted biphenyl products (409) in up to 89% yield.

Scheme 96 Rh(III)-catalyzed dehydrogenative aryl-aryl bond formation.

Meanwhile, they demonstrated Rh(III)-catalyzed cross-dehydrogenative coupling (CDC) of furans (410) with benzothiophenes or thiophenes (411), leading to the corresponding 2,20 -bi(heteroaryl) compounds (412) in up to 84% yield and excellent regioselectivity (Scheme 96B).132 Additionally, the reaction conditions could also be applied to the cross-coupling of Nbenzylindoles and benzyl protected 2-acetylpyrroles. In 2012, Glorius and coworkers also realized a Rh(III)-catalyzed dehydrogenative cross-coupling reaction of a large range of simple arenes and heterocycles with benzamides (413) (Scheme 97A).133a Hexabromobenzene (C6Br6) as a key additive enabled a highly chemo- and regioselective dehydrogenative cross-coupling reactions. In 2013, You and coworkers reported a Rh(III)catalyzed oxidative cross-coupling of phenylpyridines (415) with thiophenes by twofold C-H functionalization, providing a direct access to p-conjugated systems (416) (Scheme 97B).133b Afterwards, Rh(III)-catalyzed dehydrogenative coupling of indoles/ pyrroles (417) with heteroarenes was described by You, Lan and coworkers (Scheme 97C).133c This strategy can effectively suppress the homo-coupling pathway, and dramatically extend the substrate scope, showcasing the beneficial aspect of the Rh(III) catalysis. In 2018, Lan, You and coworkers reported a Cp -free RhCl3/TFA catalytic system to enable an oxidative C-H/C-H cross-coupling reaction of N-acylanilines (419) and benzamides through a dual-chelation-assisted strategy (Scheme 97D).133d The RhCl3/TFA catalytic system exhibits high catalytic activity and excellent functional group tolerance.

164

CdC Bond Formation Through C-H Activation

Scheme 97 Rh(III)-catalyzed oxidative C-H/C-H cross-coupling reactions.

In 2015, Su and coworkers reported a tandem Rh(III)-catalyzed C-H arylation/Ag-catalyzed decarboxylative C-H/C-H cross-coupling of carboxylic acids (421) with thiophenes (Scheme 98).134 This method is compatible with a broad range of functional groups and substitution patterns on the arene ring.

Scheme 98 Rh(III)-catalyzed decarboxylative C-H arylation of thiophenes.

In 2018, Glorius and coworkers developed a Rh(III)-catalyzed coupling of N-phenoxyacetamide (423) with cyclopropenyl esters (424) for the synthesis of arylated furans (425) (Scheme 99).135 Mechanistic studies suggested that the arylated furans are formed via arylation of the cyclopropenyl esters followed by cycloisomerization.

Scheme 99 Rh(III)-catalyzed arylation and cycloisomerization of cyclopropenes.

Although many exciting achievements have been made in Rh(III)-catalyzed C(sp2)-H functionalization, on the contrary, much less research attention has been devoted to the activation of C(sp3)dH bonds. In 2015, the Cp Rh(III)-catalyzed arylation of unactivated C(sp3)dH bonds was realized by the Glorius group (Scheme 100A).136a Various 2-alkylpyridine derivatives (426) reacted smoothly with diverse triarylboroxines. This method efficiently built new C(sp3)daryl bonds and afforded functionalized pyridine derivatives (427) in up to 85% yield. Subsequently, they also reported an elegant non-directed and cross-dehydrogenative coupling of allylic C(sp3)dH bonds with C(sp2)dH bonds of (hetero)arenes (Scheme 100B).136b

CdC Bond Formation Through C-H Activation

165

Scheme 100 Rh(III)-catalyzed C(sp3)-H arylations.

12.05.3.2 CdH bond alkenylation The oxidative Heck reaction, utilizing a CdH instead of a CdX bond, avoids the need for prior functionalization steps and is thus more atom-economic and versatile. In 2010, Glorius and coworkers reported a Rh(III)-catalyzed oxidative C-H olefination of acetanilides (430) with styrenes or ethylene (Scheme 101A).137a In addition, electron-poor substrates such as acetophenones and benzamides are also suitable substrates in this C-H activation process. In 2011, they extended this method to ortho C-H olefination reaction of acetophenones and benzamides with alkenes under identical optimized conditions (Scheme 101B).137b Furthermore, both electron-poor and electron-rich styrenes were well tolerated. In 2012, Huang and coworkers reported the first triazene-directed Rh(III)-catalyzed oxidative olefination reactions under mild conditions (Scheme 101C).137c The triazene directing group could either be removed at room temperature in quantitative yield, or undergo further transformations, such as cross-coupling reactions. In 2013, Zhu and coworkers developed a Rh(III)-catalyzed C-H olefination of arenes (436) by using an N-nitroso directing group (Scheme 101D).137d Competition experiments suggest that electrophilic aromatic substitution (EAS), rather than concerted metalation-deprotonation (CMD), is responsible for the C-H functionalization step. The kinetic isotope effect (KIE) experiments support a reaction pathway involving electrophilic C-H activation as the turnover-limiting step. A five-membered rhodacycle is the key intermediate in the catalytic cycle. In 2016, Tan, Ma and coworkers reported a highly efficient method for the Rh(III)-catalyzed

Scheme 101 Rh(III)-catalyzed oxidative C-H alkenylations.

166

CdC Bond Formation Through C-H Activation

C7-selective olefination of N-pivaloylindole derivatives (438) (Scheme 101E).137e In this process, the size of the directing group plays an important role. With larger acyl groups, higher selectivity for the C7-position and conversion were observed. Generally, the use of an external oxidant is problematic due to the cost factors and stoichiometric waste produced by the external oxidant. An efficient Rh(III)-catalyzed oxidative olefination of N-methoxybenzamides was reported by the Glorius group. In this reaction, the NdO bond cleavage acts as an internal oxidant without any external oxidants (Scheme 102A).138a In the presence of 1 mol% [Cp RhCl2]2, the reaction of N-methoxybenzamide (440) provided around 99% of the desired olefination product (441), together with a small amount of the diolefination product, whereas benzamide largely remained unreacted. These results clearly showed that the N-methoxy amide group acts as not only an internal oxidant but also a better DG than the N-unsubstituted primary amide. In 2013, You and coworkers also developed Rh(III)-catalyzed C-H olefination of tertiary aniline N-oxides (442), which acted as an internal oxidant (Scheme 102B).138b In 2014, Wang and coworkers developed an efficient synthesis of ortho-alkenyl phenols (445) via Rh(III)-catalyzed CdH bond functionalization of N-phenoxyacetamides (444) with N-tosylhydrazones/diazoesters similarly taking advantage of internal NdO bond cleavage for oxidation (Scheme 102C), similarly taking advantage of internal NdO bond cleavage for oxidation.138c

Scheme 102 Rh(III)-catalyzed C-H alkenylations with substrates bearing an internal oxidant.

In 2015, Feng, Loh and coworkers presented a Rh(III)-catalyzed tandem C-H/C-F activation for the synthesis of (hetero)arylated monofluoroalkenes (446) (Scheme 103).139 The use of readily available gem-difluoroalkenes as electrophiles provided a highly efficient and operationally simple method for the introduction of a-fluoroalkenyl motifs onto (hetero)arenes (417) under oxidant-free conditions. Furthermore, the alcoholic solvent and the in-situ generated hydrogen fluoride were found to be beneficial in this transformation, indicating the possibility of the involvement of a hydrogen bond activation mode with regards to the CdF bond cleavage step.

Scheme 103 Rh(III)-catalyzed a-fluoroalkenylation of indoles.

In recent years, electrosynthesis has gained significant attention owing to the use of waste-free and inexpensive electric current as a redox equivalent, thereby avoiding the use of costly chemical redox agents. In 2020, Ackermann and coworkers realized a Rh(III)-catalyzed electrooxidative C-H olefination of benzamides (447) (Scheme 104).140 Notably, both electron-poor and electron-rich styrenes bearing sensitive functional groups such as bromo, hydroxyl, and nitro groups were well tolerated.

Scheme 104 Rh(III)-catalyzed electrooxidative C-H olefination of benzamides.

CdC Bond Formation Through C-H Activation

167

In 2017, Sun, Yu and coworkers developed a Rh(III)-catalyzed meta-C-H olefination of hydrocinnamic acid derivatives (449) using a modified U-shaped mononitrile template (Scheme 105A).141 The KIE (kH/kD ¼ 1.8) suggested that the meta-CdH bond cleavage may be the rate-determining step. In 2017, Maiti and coworkers applied 2-hydroxy-4-methoxy benzonitrile template to achieve a Rh(III)-catalyzed meta-selective olefination of benzylsulfonyl esters (451) and phenylacetic acid esters using XPhos as the ligand (Scheme 105B).142 Complete mono-selectivity was achieved for a broad range of substrates with various olefins and functional groups attached to arene.

Scheme 105 Rh(III)-catalyzed meta-C-H olefination.

In 2014, Wang and coworkers developed a Rh(III)-catalyzed alkenylation reaction of 8-methylquionline (453) with alkynes to afford 8-allylquinolines (454) in up to 91% yield (Scheme 106).143 Notably, the reaction is highly regio- and stereoselective. A catalytically competent five-membered rhodacycle was structurally characterized, thus revealing the key intermediate in the catalytic cycle.

Scheme 106 Rh(III)-catalyzed C(sp3)-H alkenylation of 8-methylquionline.

12.05.3.3 CdH bond alkylation In 2001, Bergman and Ellman developed a novel method for the synthesis of functionalized tetralane, indane, dihydroindole, and dihydrobenzofuran derivatives by using imine directed CdH bond functionalization in up to 90% yield and with high selectivity (Scheme 107A).144 This method is well tolerated with different tether lengths, the incorporation of heteroatoms into the tether, and multiple substituents on olefins. In addition, the cyclization products can undergo diverse transformations.

Scheme 107 Rh(I)-catalyzed intramolecular C-H coupling of alkene.

168

CdC Bond Formation Through C-H Activation

They also developed a general method for C-H alkylation without the directing group. The new carbocyclization could be applied to the construction of both five and six membered rings via intramolecular coupling of an alkene to benzimidazole (458). Various substrates including mono-, di-, and trisubstituted alkenes allowed the formation of tricyclic products (459) in up to 79% yield (Scheme 107B).145 In 2007, the Chatani group reported an unusual example of endo-selective hydroarylation with norbornene. 8-Aminoquinoline as a directing group is critical to the success of this reaction (Scheme 108).146 The addition of a sterically bulky carboxylic acid enhanced the internal selectivity. A high degree of endo-selectivity was obtained for a variety of substrates (460) with excellent functional group tolerance.

Scheme 108 Rh(I)-catalyzed hydroarylation with norbornene.

Many achievements have been made by Bergman, Ellman and coworkers in the field of Rh(I)-catalyzed C-H alkylation with alkenes. They developed intermolecular C-H alkylation of pyridine and quinoline derivatives with acrylates and acrylamides in 2007. Steric interactions caused by the ortho-substituent presumably increased the equilibrium from an N-bound to a C-bound Rh complex by undertaking efforts to isolate intermediate complexes and performing DFT calculations on model structures (Scheme 109A).147a In Rh(I)-catalyzed ortho-selective alkylation of azines, a complete linear or branched selectivity was controlled exclusively by a catalytic amount of base (Scheme 109B).147b A highly efficient rhodium catalyst system for the direct hydroheteroarylation reaction was reported by Cho, Chang and coworkers in 2012 (Scheme 109C).148 A base co-catalyst was crucial for the hetereoarene CdH bond activation step. This method exhibited a broad substrate scope with various substituted electron-deficient pyridine N-oxides. The identical catalytic system could also be applicable to the hydroheteroarylation of alkynes with excellent regio- and stereoselectivity.

Scheme 109 Rh(I)-catalyzed intermolecular C-H alkylation of pyridine, pyridine N-oxide and quinoline derivatives.

In 2018, the Shi group developed an effective system for Rh(I)-catalyzed remote terminal hydroarylation of indoles (466) and anilines by introducing a N-PtBu2 directing group. This transformation was realized through long-range olefin isomerization (Scheme 110).149 With the aid of a sterically hindered NPtBu2 as the optimal directing group, the reaction overrides electronic biases at the indole C3-position and the conjugate reactivity of actived olefins to generate the indole C7-alkylation products (467) with excellent regioselectivity.

Scheme 110 Rh(I)-catalyzed remote terminal hydroarylation of indoles.

CdC Bond Formation Through C-H Activation

169

In 2011, the groups of Bergman and Ellman, and the Shi group independently reported Rh(III)-catalyzed C-H addition of 2-arylpyridines to N-Boc- and N-sulfonyl-imines, giving branched amine products (468) in up to 95% yield (Scheme 111A).150a The method was compatible with many common functional groups, such as ketone, aldehyde, ester, halide, trifluoromethyl, amide, and nitro. In 2012, Yu and coworkers reported a Rh(III)-catalyzed intermolecular coupling of diazomalonates with arene CdH bonds (Scheme 111B).150b In most cases, arenes with oxime, carboxylic acid, and amine as the directing group could couple with diazomalonates with excellent regioselectivity and functional group tolerance. In 2012, Ma and coworkers developed a Rh(III)-catalyzed allylation of N-methoxybenzamides with poly-substituted allenes (Scheme 111C).150c In 2013, Glorius and coworkers demonstrated a Rh(III)-catalyzed intermolecular C-H allylation reaction by using readily available allyl carbonates as the allyl sources (Scheme 111D).150d The reaction proceeded under mild conditions with excellent g-selectivity and displaying a broad substrate scope. In 2013, Li, Wang and coworkers achieved a Rh(III)-catalyzed C-C coupling of aziridines with electron-poor arenes, affording a variety of b-branched amines (472) (Scheme 111E).150e In 2016, Li and coworkers achieved the first combination of CdH bond activation with ring opening of cyclopropanols under Rh(III)-catalysis, affording b-aryl ketones (473) (Scheme 111F).150f

Scheme 111 Rh(III)-catalyzed C-H alkylations.

In 2014, Li and coworkers developed a Rh(III)-catalyzed coupling of quinoline N-oxide (474) with internal alkynes, leading to the synthesis of substituted acetophenones (475) in up to 95% yield (Scheme 112).151 In this process, the N-oxide acts as both a directing group for C-H activation and an oxidant.

Scheme 112 Rh(III)-catalyzed coupling of quinolone N-oxides with alkynes.

In 2020, Rh(III)-catalyzed highly regioselective C(sp3)-H methylation of 8-methylquinolines (476) with bench stable organoboron reagent was described by the Sharma group (Scheme 113).152 This process was achieved through direct alkylation instead of hydroarylation of olefin. Substituted 8-ethylquinolines (477) were obtained in up to 92% yield through the direct functionalization of primary C(sp3)dH bond.

Scheme 113 Rh(III)-catalyzed C(sp3)-H alkylation of 8-methylquinolines.

170

CdC Bond Formation Through C-H Activation

12.05.3.4 CdH bond alkynylation Although aryl alkynes are usually prepared from aryl halides with alkynes by the Sonogashira reaction, it is desirable and attractive to take advantage of the abundance of CdH bonds in arenes by Rh(III)-catalyzed C-H direct functionalization. In 2014, the Li group and the Loh group independently developed an efficient Rh(III)-catalyzed C-H alkynylation of (hetero)arenes (478) using hypervalent iodine-alkyne reagents (Scheme 114).153a,b Heterocycles, N-methoxy imines, azomethine imines, secondary carboxamides, azo compounds, N-nitrosoamines, and nitrones were all feasible directing groups to enable ortho C-H alkynylation. It is worth noting that Rh(III)-catalyzed C-H alkynylation of indoles can proceed in mixer mills under solvent-free conditions reported by the Bolm group.153c

Scheme 114 Rh(III)-catalyzed C-H alkynylation with hypervalent iodine-alkyne reagent.

In 2018, Echavarren and coworkers reported a Rh(III)-catalyzed C(sp2)-H alkynylation with bromoalkynes (Scheme 115).154 Amine, thioether, sulfoxide, sulfone, carbamate, and phenol esters are suitable directing groups in this transformation. Furthermore, the experimental and theoretical mechanistic studies suggested that the Rh(III)-catalyzed C-H alkynylation occurs by a turnover-determining C-H activation, wherein a five-membered ring metallacycle is formed by an electrophilic aromatic substitution process.

Scheme 115 Rh(III)-catalyzed C-H alkynylation with bromoalkynes.

12.05.3.5 CdH bond annulation Polycyclic heteroarenes have attracted considerable attention because of their interesting electrochemical and photochemical properties. Structurally diverse polycyclic arenes could be accessed by annulation of CdH bond with alkynes, alkenes, allenes and diazo compounds. In 2008, Satoh, Miura and coworkers demonstrated that polyarylated naphthyl- and anthrylazole derivatives (482) were efficiently constructed by the direct coupling of phenylazoles with internal alkynes in the presence of a rhodium catalyst and a copper oxidant (Scheme 116A).155a In 2008, Fagnou and coworkers reported a novel method for the construction of highly

Scheme 116 Rh(III)-catalyzed C(sp2)-H annulations with alkynes.

CdC Bond Formation Through C-H Activation

171

functionalized indoles (483) based on a Rh(III)-catalyzed C − H annulation of acetanilides with alkynes (Scheme 116B).155b In 2010, Rovis et al. developed a Rh(III)-catalyzed oxidative C-H annulation for the synthesis of isoquinolones (484) via a transient five-membered rhodacycle generated from ortho C-H/N-H activation. Additionally, unsymmetrical alkynes were also suitable substrates, leading to isoquinolones with high regioselectivity (Scheme 116C).155c The mechanistic studies suggested that C-H activation is involved in the turnover-limiting step. Competition experiments indicated that the regioselectivity is largely governed by steric factors of alkyne. In 2011, Fagnou and coworkers reported a Rh(III)-catalyzed redox-neutral isoquinolone (485) synthesis (Scheme 116D).155d The NdO bond in the substrate was cleaved during the reaction and found to obviate the need for an external oxidant. The annulations with alkenes led to the formation of 3,4-dihydroisoquinolones. Mechanistic investigations revealed that concerted metalation-deprotonation (CMD) is proposed to be the turnover limiting step. In addition, DFT calculations are also consistent with a stepwise CdN bond reductive elimination/NdO bond oxidative addition mechanism. In 2011, the Glorius group and the Cheng group independently developed Rh(III)-catalyzed C-H annulations of phenone derivatives (486) with internal alkynes, giving diverse indenol derivatives (487) (Scheme 117A).156a,b Amides have proved to possess sufficient electron density to coordinate with the metal center to facilitate the ortho metalation. In 2012, Shi and coworkers developed a Rh(III)-catalyzed C-H annulation between benzimides (488) and alkynes for the synthesis of indenones (489) (Scheme 117B).156c The proper directing ability and electrophilicity of N-benzoyloxazolidinones provided a handle for the annulation with concomitant C-H and C-N cleavage.

Scheme 117 Rh(III)-catalyzed C-H annulation of aryl ketones/benzimides with alkynes.

In 2013, Lu, Liu and coworkers disclosed a mild Rh(III)-catalyzed redox-neutral C-H functionalization of N-phenoxyacetamides with alkynes for the synthesis of benzofuran derivatives (490) through CdC/CdO bond formation (Scheme 118A).157a With cyclopropene as a three-carbon unit, Wang and coworkers also realized a Rh(III)-catalyzed annulation of N-phenoxyacetamide, leading to 2H-chromenes (491) in 2015 (Scheme 118B).157b

Scheme 118 Rh(III)-catalyzed redox-neutral C-H annulation of N-phenoxyacetamides.

In 2014, Lin and coworkers reported a Cp Rh(III)-catalyzed cyclization of N-hydroxybenzamides and alkyne-tethered cyclohexadienone for the formation of tetracyclic isoquinolones (492) (Scheme 119A).158a In 2017, Li and coworkers reported Rh(III)-catalyzed C-H activation of indoles and coupling with 1,6-enynes for the formation of fused cycles. The alkyne insertion follows 2,1-regioselectivity with an intramolecular Diels–Alder reaction to afford [6,5]-fused cycles (493) in up to 83% yield (Scheme 119B).158b

172

CdC Bond Formation Through C-H Activation

Scheme 119 Rh(III)-catalyzed couplings of indoles with 1,6-enynes.

In 2014, Gulías and coworkers developed a Rh(III)-catalyzed [5 + 2] cycloaddition of vinylphenols (494) with alkynes (Scheme 120A).159a The reaction generated highly valuable benzoxepine skeletons (495) by cleavage of the terminal CdH bond of the alkenyl moiety. Surprisingly, the reaction of 2-(prop-1-en-2-yl)phenol (496) and alkynes underwent a dearomatizing [3 + 2] annulation, giving highly appealing spirocyclic products (497) in up to 93% yield (Scheme 120B).159b This reaction involves the cleavage of the terminal CdH bond of the alkenyl moiety and the dearomatization of the phenol ring.

Scheme 120 Rh(III)-catalyzed C-H annulation of 2-alkenylphenols and alkynes.

In 2014, Li and coworkers described a novel Rh(III)-catalyzed [3 + 2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles (498) with internal alkynes for building a spirocyclic ring system (499) with excellent functional group tolerance and good regioselectivity (Scheme 121A).160a In 2015, they presented a Rh(III)-catalyzed [3 + 2]/[5 + 2] sequential annulation of 4-aryl 1-tosyl-1,2,3triazoles (500) with internal alkynes through dual C-H functionalization for the synthesis of indeno-[1,7-cd]azepin-1-ols (591) in up to 71% yield (Scheme 121B).160b

Scheme 121 Rh(III)-catalyzed [3 + 2] annulation with alkynes.

CdC Bond Formation Through C-H Activation

173

In 2018, Mascareñas, Gulías and coworkers discovered that a Rh(III) complex bearing an electron-deficient ŋ5-cyclopentadienyl ligand could enable an unusual annulation between alkynes and 2-alkenyl anilides (502), giving synthetically appealing 2-substituted indolines (503) in up to 89% yield (Scheme 122).161 Mechanistic experiments revealed that this transformation involves an unusual rhodium migration with a concomitant 1,5-H shift.

Scheme 122 Rh(III)-catalyzed annulation between alkynes and 2-alkenyl anilides.

In 2011, Fagnou and coworkers developed a Rh(III)-catalyzed [3 + 2] annulation of acetanilides (504) with 1,3-enynes, leading to the construction of unsymmetrical 2,3-disubstituted indoles (505) and pyrroles in up to 80% yield (Scheme 123A).162a In 2014, Lam and coworkers discovered a new mode of Rh(III)-catalyzed oxidative annulation of 2-aryl cyclic 1,3-dicarbonyl compounds (506) with 1,3-enyne containing an allylic hydrogen cis to alkyne as a one-carbon partner (Scheme 123B).162b This unexpected transformation was proposed to occur through double C-H activation, involving a hitherto rare example of the 1,4-migration of Rh(III) species. Subsequently they reported Rh(III)-catalyzed all-carbon [3 + 3] oxidative annulation of 5-arylbarbituric acids (508) with 1,3-enynes (Scheme 123C).162c This annulation further demonstrated the power of alkenyl-to-allyl 1,4-Rh(III) migration in generating electrophilic allylrhodium species for the construction of polycyclic systems.

Scheme 123 Rh(III)-catalyzed annulation with 1,3-enynes.

In 2012, Glorius and coworkers developed an efficient Rh(III)-catalyzed intermolecular annulation of benzamide derivatives with allenes for the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones (510) (Scheme 124).163 This reaction features high regio- and stereoselectivity, broad substrate scope for both coupling partners, and excellent functional group tolerance.

Scheme 124 Rh(III)-catalyzed intermolecular annulation of benzamides with allenes.

174

CdC Bond Formation Through C-H Activation

In 2013, Rovis and coworkers developed Rh(III)-catalyzed regioselective synthesis of pyridines (512) from alkenes and a,b-unsaturated oxime esters (Scheme 125A).164a Mechanistic studies suggested that heterocycle formation proceeds via reversible C-H activation, alkene insertion, and a CdN bond formation/NdO bond cleavage process. Encouraged by this work, they then developed an efficient Rh(III)-catalyzed synthesis of semi-saturated pyridine derivatives (514) (Scheme 125B).164b A significant ligand effect was observed that the electron-deficient trifluoromethyl-substituted Cp CF3 ligand was the optimal one.

Scheme 125 Rh(III)-catalyzed C-H annulation with alkenes.

In 2015, Glorius and coworkers reported Rh(III)-catalyzed synthesis of 1-aminoindolines (516) from arylsubstituted diazenecarboxylates (515) and alkenes (Scheme 126).165 Mechanistic studies supported that this transformation proceeds via reversible C-H activation, alkene insertion, and Grignard-type addition. This intermolecular annulation proceeded at room temperature, featuring free of external oxidants and broad substrate scope.

Scheme 126 Rh(III)-catalyzed intermolecular annulation of diazenecarboxylates and alkenes.

In 2017, Li, Wang and coworkers reported Rh(III)-catalyzed C-H annulation of benzamides with 2,2-difluorovinyl tosylate for the synthesis of fluorinated heterocycles (Scheme 127).166 With N-OMe benzamide as a directing group, the reaction delivered a monofluorinated alkene with the retention of the tosylate functionality. Subsequent one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1(2H)-ones (517) in up to 95% yield. When N-OPiv benzamides were used, [4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1(2H)-ones (518) in up to 81% yield.

Scheme 127 Rh(III)-catalyzed C-H annulation of benzamides with 2,2-difluorovinyl tosylate.

CdC Bond Formation Through C-H Activation

175

In 2013, Rovis and coworkers demonstrated that diazo compounds could be applied in Rh(III)-catalyzed C-H functionalization reaction to afford lactam derivatives (519) in up to 97% yield (Scheme 128A).167a Mechanistic experiments suggested that C-H activation is irreversible and involved in the turnover-limiting step. Subsequently, Wang, Li and coworkers also realized Rh(III)-catalyzed redox-neutral C-H coupling of phenacyl ammonium salts with diazoesters to afford benzocyclopentanones (520) in up to 94% yield. In this reaction, the quaternary ammonium group acted as an oxidizing directing group to facilitate the ortho C-H activation (Scheme 128B).167b a,a-Difluoromethylene alkyne could be used as a nontraditional one-carbon reaction partner. In 2017, Feng, Loh and coworkers reported a novel method for the construction of isoindolin-1-one derivatives (521) via Rh(III)-catalyzed [4 + 1] annulation reaction (Scheme 128C).167c

Scheme 128 Rh(III)-catalyzed coupling with a-diazoesters and a,a-difluoromethylene alkyne.

In 2012, Cheng and coworkers demonstrated a Rh(III)-catalyzed dual C-H activation of N-methoxybenzamides with aryl boronic acids (Scheme 129).168 The catalytic reaction provided various substituted phenanthridinones (522) in excellent yields with high regioselectivity through C-C and CdN bond formation.

Scheme 129 Rh(III)-catalyzed annulation of benzamides with aryl boronic acid.

In 2010, Glorius and coworkers reported a novel Rh(III) catalyzed C(sp3)-H functionalization of enamines and successive coupling with unactivated alkynes for the synthesis of multi-substituted pyrroles (523) in up to 71% yield (Scheme 130A).169a In 2012, Wang and coworkers described a Rh(III)-catalyzed cascade oxidative annulation reaction of benzoylacetonitrile with alkyne, affording substituted naphtho[1,8-bc]pyrans (524) in 82% yield (Scheme 130B).169b Moreover, this cascade annulation reaction with unsymmetrical alkynes is highly regioselective. Further experiments suggested that the first-step reaction proceeds by sequential cleavage of C(sp2)-H/C(sp3)dH bonds and annulation with an alkyne, leading to 1-naphthols. Subsequently, 1-naphthols reacted with alkyne by cleavage of C(sp2)dH/OdH bonds to afford the 1:2 coupling products.

176

CdC Bond Formation Through C-H Activation

Scheme 130 Rh(III)-catalyzed C(sp3)-H annulation with alkyne or diazo compound.

In 2015, Zhou, Yang, Zhu and coworkers developed an unprecedented Rh(III)-catalyzed regioselective redox-neutral annulation reaction of 1-naphthylamine N-oxides with diazo compounds by dual cleavage of C(sp3)-H/C(sp2)dH bonds to form biologically important 1H-benzo[g]indolines (525) (Scheme 130C). This coupling reaction proceeds under mild reaction conditions without the requirement of external oxidants.169c In 2018, Ackermann and coworkers described electrochemical Rh(III)-catalyzed C-H/C-H coupling reactions of benzoic acids with acrylates, generating H2 as the sole byproduct (Scheme 131A).170 In 2020, Ackermann and coworkers reported a modular electrochemical synthesis of aza-PAHs (527) via a Rh(III)-catalyzed cascade C-H annulation of O-methylamidoximes with alkynes (Scheme 131B).171 The electrosynthesis displays broad substrate scope and excellent functional group tolerance, including iodo and azido groups.

Scheme 131 Rh(III)-catalyzed electrochemical C-H activation.

12.05.3.6 Enantioselective C-H activation In 2004, Bergman, Ellman and coworkers described a highly enantioselective intramolecular imine-directed C-H/olefin coupling reaction by using Rh(I)/chiral phosphoramidite complex (Scheme 132A).172a Then the Tanaka group utilized a cationic Rh(I)/(R)H8-BINAP species to achieve CdH bond functionalization of electron-rich aryl ketones (530), which reacted with 1,6-enynes to give ortho-functionalized aryl ketones (531) with excellent regio- and enantioselectivity (Scheme 132B).172b In 2011, the Cramer group developed an asymmetric Rh(I)-catalyzed C-H annulation of unsubstituted ketimines (532) with internal alkynes

CdC Bond Formation Through C-H Activation

177

Scheme 132 Rh(I)-catalyzed asymmetric C(sp2)-H functionalizations.

(Scheme 132C).172c Subsequently, they extended the catalytic system to the C-H annulation reaction with racemic allenes (Scheme 132D).172d The use of readily available racemic allenes and unprotected ketimines (534) significantly increased the complexity of the target molecules, thereby providing synthetically valuable, highly substituted indenylamines. In 2013, the Rovis group accomplished an enantioselective hydroheteroarylation reaction of benzoxazoles and a-substituted methacrylate compounds (Scheme 132E).172e This reaction delivered various elaborated benzoxazole products (536) in moderate to good yields and excellent enantioselectivity. In 2016, Glorius and coworkers reported an elegant example of Rh(I)-catalyzed asymmetric intermolecular C(sp3)-H arylation (Scheme 133A).173a Enantioenriched triarylmethanes (538) were obtained with up to 80% ee by using a chiral NHC ligand (L51). Subsequently, the same group reported an enantioselective arylation of various heterocycles such as tetrahydroquinolines, piperazines, piperidines, pyrrolidines, azetidines, and azepanes (Scheme 133B).173b The combination of a Rh(I) precatalyst and

Scheme 133 Rh(I)-catalyzed asymmetric C(sp2)-H arylations.

178

CdC Bond Formation Through C-H Activation

monodentate phosphonite ligand (L55) was shown to be a powerful catalytic system to generate various important enantioenriched arylative heterocycles. This redox-neutral method provided a new synthetic approach to a-N-arylated heterocycles (540) with high chemo- and enantioselectivity (up to 97% ee). You, Gu, and coworkers developed Rh(I)-catalyzed thioketone-directed asymmetric C–H arylation of ferrocenes (541) with L55 (Scheme 133C).173c Aryl iodides were used as the coupling partners, leading to planar chiral ferrocenes (542) in good yields and excellent enantioselectivity (up to 82% yield, 99% ee). More recently, they also reported Rh(I)-catalyzed pyridine assisted enantioselective C–H arylation of ferrocenes (543) with aryl halides (Scheme 133D).173d This method proceeded with excellent levels of mono-arylation selectivity, enantioselectivity, and high catalytic efficiency. The relatively low catalyst loading (down to 1 mol% based on [Rh]) improved the practicality of the reaction. Notably, You group also developed an efficient Rh(I)-catalyzed atroposelective C − H arylation of heterobiaryls (545) in up to 99% yield and 97% ee (Scheme 133E).173 Chiral Cp ligands enabled asymmetric rhodium catalysis have emerged to be an extremely useful synthetic tool to achieve enantioselective C-H functionalizations. In 2012, the Cramer group pioneeringly reported that Rh(III) complexes bearing a class of simple C2-symmetric Cp derivatives (Rh-1) proved to be highly efficient for the [4 + 2] annulation reaction of benzamides and alkenes (Scheme 134A).174a Simultaneously, Ward, Rovis and coworkers ingeniously synthesized a biotinylated [Cp Rh(III)] complex and combined it with engineered tetrameric streptavidin (tSav) to create an artificial metalloenzyme, which proved to be highly efficient for the same type reaction (Scheme 134B).174b

Scheme 134 Rh(III)-catalyzed enantioselective [4 + 2] annulation reactions.

In 2013, the Cramer group reported highly tunable chiral Cp ligands based on binaphthyl backbone. The chiral environment at the metal center originates from both the rigid backwall and the 3,30 -substituents of BINOL-derived Cp ligands. The corresponding Rh complex (Rh-2) was used for enantioselective C–H allylation of N-methoxybenzamides with allenes, giving 549 up to 97% yield and 98% ee (Scheme 135).175

Scheme 135 Enantioselective C–H allylation of N-methoxybenzamides with allenes.

Subsequently, Cramer and coworkers reported an enantioselective Rh(III)-catalyzed hydroarylation, and functionalized dihydrobenzofurans (550) bearing a quaternary stereocenter with 93% ee were obtained (Scheme 136A).176a Notably, the meta-alkoxy group acts as a secondary directing group, which allows for the site-selective reaction at the more hindered ortho-position. In 2019, they reported an enantioselective C-H activation/ring-opening sequence of aryl ketoxime ethers and 2,3-diazabicyclo [2.2.1]hept-5-enes for the construction of highly functionalized 2-arylated cyclopentenyl amines (551) (Scheme 136B).176b The transformation was enabled by the combination of a chiral CpxRh(I)(cod) complex (Rh-4) with a matching aroyl peroxide

CdC Bond Formation Through C-H Activation

179

Scheme 136 Rh(III)-catalyzed asymmetric C(sp2)-H functionalizations.

additive for the oxidative catalyst activation. Notably, both the cyclooctadiene group and the aroyl peroxide additive displayed pronounced effects on the reaction efficiency and enantioinduction. In 2019, Zheng, Li and coworkers realized Rh(III)-catalyzed C-H activation of indoles and desymmetrizative coupling with 7-azabenzonorbornadienes (Scheme 136C).176c AgSbF6 was found to enhance the catalytic activity by suppressing C3-H activation of the indoles. Cyclopropane rings are a prominent structural motif in biologically active molecules. A dual directing group-assisted C-H activation strategy was used to realize a mild and redox-neutral Rh(III)-catalyzed C-H activation and cyclopropylation of N-phenoxylsulfonamides with cyclopropenyl secondary alcohols (Scheme 136D).176d Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a RhV nitrenoid intermediate, and Noyori-type outer sphere concerted proton-hydride transfer from the secondary alcohol to the Rh]N bond produces the observed trans selectivity. Asymmetric Rh-catalyzed C-H annulations have emerged as a novel enabling method for the rapid construction of cyclic products. In 2014, Cramer and coworkers reported a mild and highly enantioselective Rh(III)-catalyzed [4 + 1] C-H annulation to access functionalized isoindolones (554) in up to 94% yield and 93% ee (Scheme 137A).177a In 2019, Cramer and coworkers realized an enantioselective alkenyl C-H activation of acrylamides by chiral CpxRh(III) complexes (Rh-8) and their subsequent

Scheme 137 Rh(III)-catalyzed asymmetric [4 + 1] C-H annulation.

180

CdC Bond Formation Through C-H Activation

CdC and CdN bond formation with allenes (Scheme 137B).177b This net [4 + 1]-annulation gave a straightforward access to chiral functionalized a,b-unsaturated g-lactams (555) with a quaternary stereocenter in good enantioselectivity. Notably, allene serves as a one-carbon unit in the [4 + 1] annulation. Of particular note, the multi-substituents on the Cp ring exhibited distinct reactivity, chemo- and regioselectivity in a few C–H functionalization reactions. In 2020, You and coworkers designed a series of chiral binaphthyl-based CpxRh bearing multisubstituent groups on the Cp ring to tune the steric and electronic effects, by utilizing Co2(CO)8-mediated [2 + 2 + 1] cyclization as a key step in ligand formation. Employing such a chiral CpxRh (Rh-9) bearing trimethyl-substituents on the Cp ring, unprecedented enantioselective [4 + 1] annulation reaction of benzamides and alkenes was achieved, yielding a variety of isoindolinones (556) in up to 94% yield with 94% ee (Scheme 137C).177c In 2018, the Wang group reported a solvent-dependent enantioselective synthesis of alkynyl and monofluoroalkenyl isoindolinones from N-methoxybenzamides and a,a-difluoromethylene alkynes with the SCpRh catalyst (Rh-10) developed by the You group (Scheme 138).178 The alkynyl isoindolinones (557) were generated in MeOH whereas the monofluoroalkenyl isoindolinones (558) were formed in iPrCN.

Scheme 138 Asymmetric synthesis of isoindolinones by C-H activation.

The [4 + 2] annulation reactions have attracted much attention since the pioneering works by the groups of Rovis and Ward, and Cramer.174 In 2017, Cramer and coworkers presented a Rh(III)-catalyzed asymmetric [4 + 2] annulation for the synthesis of P-chiral compounds from easily accessible diaryl phosphinamides (Scheme 139A).179a The use of Rh(III) complex (Rh-3) was shown to enable an enantio-determining C-H activation step. Upon trapping with alkynes, a broad range of cyclic phosphinamides (559) with a stereogenic phosphorus(V) atom were generated in up to 86% yield with 92% ee. In 2018, Perekalin and coworkers developed a class of novel planar chiral rhodium catalyst [(C5Ht2Bu2CHt2Bu)RhI2]2 in two steps from [Rh(cod)Cl]2 and tertbutylacetylene. Pure enantiomers of the catalyst were obtained by separation of its diastereomeric adducts with (S)-proline. This Rh catalyst (Rh-11) promoted enantioselective reaction of aryl hydroxamic acids with strained alkenes to give dihydroisoquinolones (560) in up to 97% yield with 95% ee (Scheme 139B).179b

Scheme 139 Rh(III)-catalyzed asymmetric [4 + 2] annulation.

In 2018, Li and coworkers realized an enantiodivergent [4 + 2] annulative coupling of sulfoximines and diazo compounds by Rh(III)-catalyzed desymmetrizing C-H activation (Scheme 140A).180a The reaction proceeded with a broad scope of sulfoximines and several classes of diazo compounds in good to excellent enantioselectivity. The enantioselectivity of the reaction seems to be correlated to the steric bias between the benzoic acid additive and the arene substrate. A similar work was reported by the Cramer group in 2019. They developed an efficient kinetic resolution of racemic sulfoximines via Rh(III)-catalyzed asymmetric C-H annulation reaction (Scheme 140B).180b This kinetic resolution gave a very impressive s value (up to >200).

CdC Bond Formation Through C-H Activation

181

Scheme 140 [4 + 2] annulative coupling of sulfoximines with diazo compounds.

The development of efficient access to chiral spirocycles has been the subject of intensive research. In 2015, You and coworkers achieved an asymmetric C-H activation/dearomatization reaction of b-naphthol derivatives by a chiral Rh catalyst (Rh-3) (Scheme 141A).181a The reaction allowed a dearomative transformation of naphthol derivatives into chiral spirocyclic

Scheme 141 Chiral spirocyclic compounds through Rh(III)-catalyzed C-H functionalizations.

182

CdC Bond Formation Through C-H Activation

b-naphthalenones (565) bearing an all-carbon quaternary stereogenic center in 98% yield with 94% ee. Interestingly, Lam and coworkers developed an enantioselective synthesis of spiroindenes (566) from the oxidative annulation of aryl cyclic 1,3-dicarbonyl compounds (or their enol tautomers) with alkynes, in the presence of chiral cyclopentadienyl rhodium catalyst (Rh-10) (Scheme 141B).181b This process tolerated a wide range of substrates to give diverse products containing an all carbon-quaternary stereocenter with up to 97% ee. In 2017, You and coworkers described an asymmetric synthesis of spiropyrazolones from pyrazolones and alkynes by Rh(III)-catalyzed C(sp2-H) activation/annulation (Scheme 141C).181c The use of chiral SCpRh catalyst (Rh-7) provided excellent enantioselectivity, reactivity, and regioselectivity. This method enabled the transformation of a wide range of simple substrates into highly enantioenriched spiropyrazolones (567) containing an all-carbon quaternary stereogenic center. Later, the Waldmann group reported the annulation of a-arylidene pyrazolones through formal C(sp3)-H activation in the presence of Rh(III)-Cpx catalyst (Rh11) (Scheme 141D).181d This method gave access to a class of structurally diverse spiropyrazolones (568) in up to 90% yield with 94% ee. The synthetic utility of this method was demonstrated by the late-stage functionalization of drugs and natural products as well as the preparation of enantioenriched [3]dendralenes. Axial-to-central chirality transfer is an important strategy to construct chiral centers. Recently, Li and coworkers realized a Rh(III)-catalyzed enantioselective spiroannulative synthesis of nitrones (Scheme 141E).181e The annulation proceeded via C-H arylation to give an atropomerically metastable biaryl, followed by intramolecular dearomative trapping under oxidative conditions with high degree of chirality transfer. C-H activation steps often proceed through a carboxylate-assisted CMD mechanism, and thus in principle, in such a process a chiral carboxylic acid or a chiral carboxylate base can enable the selective cleavage of enantiotopic CdH bonds, even in the absence of a chiral Cpx ligand. In 2018, Yoshino, Matsunaga and coworkers ingeniously developed an enantioselective conjugate addition of aromatic CdH bond to a, b-unsaturated ketones catalyzed by Cp Rh(III)/BINSate (BINSate ¼ 1,10 -binaphthyl-2,20 -disulfonate) (Rh-16), which was readily prepared by treatment of (S)-1,10 -binaphthyl-2,20 -disulfonic acid ((S)-BINSA) with Ag2CO3, followed by [Cp RhCl2]2 in CH3CN. Various addition products (570) were obtained with good enantioselectivity (up to 95:5 er) in the presence of a catalytic amount of 2-methylquinoline (Scheme 142A).182a Lin, Yoshino, Matsunaga and coworkers reported an achiral CpxRh(III)/chiral carboxylic acid (A3) catalyzed asymmetric C-H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-ones (571) (Scheme 142B).182b The transformation of secondary alkylamines as well as nonprotected primary alkylamines underwent with high enantioselectivity by using a newly developed chiral carboxylic acid as the sole source of chirality.

Scheme 142 Enantioselective C-H functionalizations by achiral Rh(III) with chiral acid.

Chiral binaphthyl-derived CpxRh complexes could be employed to induce good enantioselective control for the synthesis of axially chiral biaryls. In 2014, You and coworkers developed an asymmetric C-H oxidative alkenylation of biaryl derivatives (572) with olefins by using chiral binaphthyl-derived CpxRh catalyst (Rh-3), affording axially chiral biaryls (573) in 97% yield with 86% ee (Scheme 143A).183a In 2016, You and coworkers reported a series of novel cyclopentadienyl ligands (SCps) based on 1,10 -spirobiindane scaffold. One of the Rh complexes derived from SCp behaved as a superior catalyst in asymmetric oxidative C–H alkenylation of biaryl derivatives with olefins (Scheme 143B).183b Comparison of the X-ray crystal structures of binaphthyl-based CpxRh (Rh-3) and 3,30 -dimethoxy substituted SCpRh complex (Rh-10) revealed that the two methoxy groups as side walls are closer to the Rh center creating a better chiral environment in the SCpRh complex.

CdC Bond Formation Through C-H Activation

183

Scheme 143 Axially chiral biaryls by Rh(III)-catalyzed asymmetric oxidative C–H alkenylation.

Axially chiral 4-arylisoquinolones are endowed with pronounced bioactivity, and methods for their efficient synthesis have gained widespread attention. In 2018, Antonchick, Waldmann and co-workers realized a Rh(III)-catalyzed C-H intramolecular annulation reaction for the synthesis of axially chiral 4-arylisoquinolones (Scheme 144A).184a The use of chiral cyclopentadienyl ligand bearing a piperidine ring backbone afforded the atropisomers (574) in up to 95% yield with 93% ee. In 2019, Li and coworkers realized oxidative coupling of indoles with o-alkynylanilines/phenols employing binaphthyl-derived CpxRh catalyst (Rh-5) (Scheme 144B).184b The reaction proceeded via initial C–H activation, followed by alkyne cyclization, affording 2,30 -biindolyls (575). Importantly, the chiral rhodacyclic intermediate was isolated and its crystal structure revealed that the bulky iodide group is disposed distal to the methoxy group of the Cp ligand.

Scheme 144 Axially chiral biaryls by Rh(III)-catalyzed asymmetric C-H annulations.

The C-N axial chirality is less studied than C-C axial chirality. In 2019, Wang and coworkers developed an asymmetric Rh(III)-catalyzed dual C-H activation reaction of N-aryloxindoles and alkynes for the synthesis of a variety of C-N axially chiral N-aryloxindoles (576) in up to 99% yield with 99% ee (Scheme 144C).184c Recently, the atroposelective synthesis of biaryl isoquinolones (577) by Rh(III)-catalyzed C-H [4 + 2] annulation of benzamides and 2-substituted 1-alkynylnaphthalenes was reported by the Li group (Scheme 144D).184d Both benzamides and heteroaryl carboxamides were found to be suitable substrates in this reaction, and excellent regioselectivity and enantioselectivity were obtained. The enantiomerically and diastereomerically pure

184

CdC Bond Formation Through C-H Activation

rhodacyclic complex was prepared and offered insights into enantiomeric control of this annulation reaction, wherein the steric interactions between the amide directing group and the alkyne substrate dictated both the regio- and enantioselectivity.

12.05.3.7 Applications in organic synthesis Because of their remarkable biological profiles and unusual pentacyclic architectures, phenanthroindolizidine alkaloids, such as antofine (584) and tylophorine (585), are attractive synthetic targets. Alkaloids 583, 584, and 585 could be readily prepared from amides 578a and 578b (Scheme 145). In the presence of [(Cp RhCl2)2] (2.5 mol%), the intramolecular C-H annulation reaction of 578a and 578b produced 2-pyridones 579a and 579b in excellent yields, respectively. Under Mitsunobu conditions, 579a and 579b were converted to indolizidines. Removal of the TMS group gave 581a and 581b in 82% and 86% yields, respectively. After reduction of 581a and 581b, seco-antofine (582) and alkaloid septicine (583) were provided in high yields. Finally, synthesis of antofine (584) and tylophorine (585) was achieved by oxidative coupling of secoantofine (582) and septicine (583). 185

Scheme 145 Total synthesis of alkaloids 583, 584, and 585.

In 2007, Bergman, Ellman and coworkers developed an effective and flexible route to synthesize potent kinase inhibitor 589, the key transformation of which is an intramolecular alkylation via Rh-catalyzed C-H functionalization (Scheme 146). Compound 587 was synthesized from commercially available tertbutyldimethylsiloxyacetaldehyde 586 over 4 steps. Ultimately, the cyclization of 588 proceeded in 50% yield and 92% ee in the presence of 5 mol% [RhCl(coe)2]2, 15 mol% PCy3, and 5% MgBr2 as an additive at 180  C. The subsequent three-step reactions efficiently afforded the final product 589.186

Scheme 146 Enantioselective synthesis of potent kinase inhibitor 589.

Bergman, Ellman and coworkers accomplished the concise asymmetric synthesis of (−)-incarvillateine (594) in 11 total steps, with 15.4% overall yield, which was significantly improved compared with the previously reported synthesis (Scheme 147). Rh-catalyzed diastereoselective C-H alkylation of 591 simultaneously installed two of the five necessary stereocenters in the bicylic piperidine 592 while stereospecifically generating the tetrasubstituted, exocyclic alkene that enabled the rapid synthesis of (−)-incarvillateine (594).187

CdC Bond Formation Through C-H Activation

185

Scheme 147 Asymmetric total synthesis of (−)-incarvillateine (594).

Then, Houk, Ellman and coworkers reported an efficient synthesis of ent-ketorfanol (600) starting from simple and commercially available materials (Scheme 148). The fused bicyclic 1,2-dihydropyridine as a key intermediate (597) was generated by Rh(I)-catalyzed intramolecular C-H alkenylation/6p electrocyclization cascade reaction. The ketone functional group and the final ring were introduced in one-step by redox-neutral acid catalyzed rearrangement of the vicinal diol to obtain the desired carbonyl group, and then followed by an intramolecular Friedel-Crafts alkylation.188

Scheme 148 Asymmetric total synthesis of ent-ketorfanol.

12.05.4 Concluding remarks Great progresses on Pd- and Rh-catalyzed carbon-carbon bond forming reactions such as arylation, alkylation, olefination and annulation via C-H functionalization have been made in the past decades. These methods have significant advantages over traditional methods for the construction of CdC bond in terms of step and atom economies. These newly developed C-H functionalization reactions offer straightforward and distinct retrosynthetic approaches for the synthesis of complex molecules, which display remarkably high efficiency. Notably, the development of enantioselective variants of these C-H functionalization reactions provides a new avenue for the field of asymmetric catalysis. Deep mechanistic understandings of the C-H functionalization processes have enabled rational design of ligand, catalyst, and transformations. Despite the impressive achievements, the C-H functionalization field is still far from mature. More transformations based on novel C-H activation modes are still underdeveloped.

186

CdC Bond Formation Through C-H Activation

The site-selective reactions rely heavily on the introduction of directing groups, which often require pre-installation and subsequent removal. Directing group free C-H functionalization processes are rare and will likely to be the future research topic. Catalytic systems that enable highly enantioselective CdH bond activation are limited, and the design and synthesis of chiral ligands and catalysts will play a key role here. In terms of practicality, catalysts with higher efficiency or those based on cheap metals will be explored and ultimately have a better chance for application in the production of pharmaceutical intermediates and fine chemicals. Therefore, the development of highly efficient and selective (regio-, chemo- and enantioselective) C-H functionalizations will continue and more applications of C-H functionalization reactions in the synthesis of functional molecules will be expected in future.

References 1. (a) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255; (b) Gronert, S. J. Org. Chem. 2006, 71, 1209. 2. (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861; (b) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417; (c) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704; (d) Davies, H. M.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857. 3. Pfeffer, M.; Spencer, J. In Comprehensive Organometallic Chemistry III; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier: Oxford, 2007, pp 101–166. Vol. 10, Chapter 10.03. 4. (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1740; (b) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286; (c) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897; (d) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2000, 41, 2655. 5. Daugulis, O.; Zaitsev, V. G. Angew. Chem. Int. Ed. 2005, 44, 4046. 6. (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020; (b) Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 3683. 7. Leclerc, J.-P.; Fagnou, K. Angew. Chem. Int. Ed. 2006, 45, 7781. 8. Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. 9. Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496. 10. Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. 11. (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972; (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. 12. Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468. 13. Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. 14. Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186. 15. Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857. 16. Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. 17. Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem. Int. Ed. 2009, 48, 201. 18. Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622. 19. Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem. Int. Ed. 2007, 46, 5554. 20. Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. 21. (a) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1473; (b) Tredwell, M. J.; Gulias, M.; Bremeyer, N. G.; Johansson, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 1076; (c) Cai, Z.-J.; Liu, C.-X.; Gu, Q.; You, S.-L. Angew. Chem. Int. Ed. 2018, 57, 1296. 22. (a) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540; (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215; (c) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780; (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068; (e) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 10236. 23. Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25, 5973. 24. (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172; (b) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. 25. Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137. 26. Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676. 27. (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904; (b) Lyons, T. W.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 4455; (c) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651. 28. (a) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1115; (b) Brasche, G.; García-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. 29. Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837. 30. Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 13864. 31. He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850. 32. Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. 33. (a) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822; (b) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem. Int. Ed. 2011, 50, 5365. 34. Han, W.; Mayer, P.; Ofial, A. R. Angew. Chem. Int. Ed. 2011, 50, 2178. 35. Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137, 5887. 36. Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. E.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 9269. 37. Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. 38. Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. 39. Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. 40. Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. 41. Wasa, M.; Chan, K. S. L.; Zhang, X.-G.; He, J.; Miura, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 18570. 42. He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q. Science 2014, 343, 1216. 43. Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.; Mapelli, C.; Miller, M. M.; Poss, M. A.; Scola, P. M.; Yeung, K.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 3338. 44. Li, S.; Zhu, R.-Y.; Xiao, K.-J.; Yu, J.-Q. Angew. Chem. Int. Ed. 2016, 55, 4317. 45. Chen, G.; Zhuang, Z.; Li, G.-C.; Saint-Denis, T. G.; Hsiao, Y.; Joe, C. L.; Yu, J.-Q. Angew. Chem. Int. Ed. 2017, 56, 1506. 46. Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 16940. 47. Noisier, A. F. M.; García, J.; Ionut¸ , I. A.; Albericio, F. Angew. Chem. Int. Ed. 2017, 56, 314. 48. Bauer, M.; Wang, W.; Lorion, M. M.; Dong, C.; Ackermann, L. Angew. Chem. Int. Ed. 2018, 57, 203. 49. The Fan, M.; Ma, D. Angew. Chem. Int. Ed. 2013, 52, 12152. 50. Zhang, Y.-F.; Zhao, H.-W.; Wang, H.; Wei, J.-B.; Shi, Z.-J. Angew. Chem. Int. Ed. 2015, 54, 13686.

CdC Bond Formation Through C-H Activation

51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.

64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102.

103.

104.

105.

106.

187

Calleja, J.; Pla, D.; Gaunt, M. J. Nature Chemistry 2015, 7, 1009. He, C.; Gaunt, M. J. Angew. Chem. Int. Ed. 2015, 54, 15840. Gulia, N.; Daugulis, O. Angew. Chem. Int. Ed. 2017, 56, 3630. Xia, G.; Weng, J.; Liu, L.; Verma, P.; Li, Z.; Yu, J. Q. Nat. Chem. 2019, 11, 571. Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science 2016, 351, 252. Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H. J. Am. Chem. Soc. 2016, 138, 12775. Liu, Y.; Ge, H. Nature Chemistry 2017, 9, 26. Chen, Y.-Q.; Wang, Z.; Wu, Y.; Wisniewski, S. R.; Qiao, J. X.; Ewing, W. R.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 17884. Kapoor, M.; Liu, D.; Young, M. C. J. Am. Chem. Soc. 2018, 140, 6818. Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886. Yan, J.-X.; Li, H.; Liu, X.-W.; Shi, J.-L.; Wang, X.; Shi, Z.-J. Angew. Chem. Int. Ed. 2014, 53, 4945. (a) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 1119; (b) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166; (c) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097; (d) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586; (e) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew. Chem. Int. Ed. 2003, 42, 3512; (f ) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476; (g) Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 1221; (h) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156. (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem. Int. Ed. 2005, 44, 3125; (b) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528. Garca-Rubia, A.; Arrayás, R. G.; Carretero, J. C. Angew. Chem. Int. Ed. 2009, 48, 6511. Garca-Rubia, A.; Urones, B.; Arrayás, R. G.; Carretero, J. C. Angew. Chem. Int. Ed. 2011, 50, 10927. Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (a) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315; (b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137. Gandeepan, P.; Cheng, C.-H. J. Am. Chem. Soc. 2012, 134, 5738. Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518. Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 7567. Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K. S.; Yu, J. Q. Nature 2017, 551, 489. (a) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340; (b) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. Jiang, H.; He, J.; Liu, T.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 2055. Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. Holstein, P. M.; Dailler, D.; Baudoin, O. Angew.Chem. Int. Ed. 2016, 55, 2805. Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78. Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. Chen, X.-Y.; Sorensen, E. J. J. Am. Chem. Soc. 2018, 140, 2789. Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 16158. Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 6097. (a) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990; (b) Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563. Jiao, L.; Bach, T. Angew. Chem. Int. Ed. 2013, 52, 6080. Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726. Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2015, 137, 531. Wang, Q.; An, S.; Deng, Z.; Zhu, W.; Huang, Z.; He, G.; Chen, G. Nat. Catal. 2019, 2, 793. Shi, J.-L.; Wang, D.; Zhang, X.-S.; Li, X.-L.; Chen, Y.-Q.; Li, Y.-X.; Shi, Z.-J. Nat. Commun. 2017, 8, 238. Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124. Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2013, 135, 12135. Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 3906. Chen, K.; Shi, B.-F. Angew. Chem. Int. Ed. 2014, 53, 11950. (a) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742; (b) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096. Jie, X.; Shang, Y.; Hu, P.; Su, W. Angew. Chem., Int. Ed. 2013, 52, 3630. Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 11574. Wang, P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 14092. Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 3387. Fu, H.; Shen, P.-X.; He, J.; Zhang, F.; Li, S.; Wang, P.; Liu, T.; Yu, J.-Q. Angew. Chem. Int. Ed. 2017, 56, 1873. Liu, T.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Angew. Chem. Int. Ed. 2017, 56, 10924. (a) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882; (b) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460; (c) Laforteza, B. N.; Chan, K. S. L.; Yu, J.-Q. Angew. Chem. Int. Ed. 2015, 54, 11143; (d) Du, Z. J.; Guan, J.; Wu, G. J.; Xu, P.; Gao, L. X.; Han, F. S. J. Am. Chem. Soc. 2015, 137, 632; (e) Xiao, K.-J.; Chu, L.; Yu, J.-Q. Angew. Chem. Int. Ed. 2016, 55, 2856; (f ) Xiao, K.-J.; Chu, L.; Chen, G.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 7796. (a) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 86; (b) Pi, C.; Li, Y.; Cui, X.; Zhang, H.; Han, Y.; Wu, Y. Chem. Sci. 2013, 4, 2675; (c) Gao, D.-W.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2016, 138, 2544; (d) Cai, Z.-J.; Liu, C.-X.; Gu, Q.; Zheng, C.; You, S.-L. Angew. Chem. Int. Ed. 2019, 58, 2149; (e) Huang, Y.; Pi, C.; Cui, X.; Wu, Y. Adv. Synth. Catal. 2020, 362, 1385. (a) Yamaguchi, K.; Yamaguchi, J.; Studer, A.; Itami, K. Chem. Sci. 2012, 3, 2165; (b) Li, S. X.; Ma, Y.-N.; Yang, S.-D. Org. Lett. 2017, 19, 1842; (c) Jin, L.; Yao, Q.-J.; Xie, P.-P.; Li, Y.; Zhan, B.-B.; Han, Y.-Q.; Hong, X.; Shi, B.-F. Chem 2020, 6, 497; (d) Yao, Q.-J.; Xie, P.-P.; Wu, Y.-J.; Feng, Y.-L.; Teng, M.-Y.; Hong, X.; Shi, B.-F. J. Am. Chem. Soc. 2020, 142, 18266. (a) Yao, Q.-J.; Zhang, S.; Zhan, B.-B.; Shi, B.-F. Angew. Chem. Int. Ed. 2017, 56, 6617; (b) Liao, G.; Li, B.; Chen, H.-M.; Yao, Q.-J.; Xia, Y.-N.; Luo, J.; Shi, B.-F. Angew. Chem. Int. Ed. 2018, 57, 17151; (c) Liao, G.; Chen, H.-M.; Xia, Y.-N.; Li, B.; Yao, Q.-J.; Shi, B.-F. Angew. Chem. Int. Ed. 2019, 58, 11464; (d) Dhawa, U.; Tian, C.; Wdowik, T.; Oliveira, J. C. A.; Hao, J.; Ackermann, L. Angew. Chem. Int. Ed. 2020, 59, 13451; (e) Song, H.; Li, Y.; Yao, Q.-J.; Jin, L.; Liu, L.; Liu, Y.-H.; Shi, B.-F. Angew. Chem. Int. Ed. 2020, 59, 6576. (a) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882; (b) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598; (c) Xiao, K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong, W.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 8138; (d) Shao, Q.; Wu, Q.-F.; He, J.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 5322; (e) Hu, L.; Shen, P.-X.; Shao, Q.; Hong, K.; Qiao, J. X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2019, 11, 2134.

188

CdC Bond Formation Through C-H Activation

107. (a) Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Nat. Chem. 2017, 9, 140; (b) Luo, J.; Zhang, T.; Wang, L.; Liao, G.; Yao, Q.-J.; Wu, Y.-J.; Zhan, B.-B.; Lan, Y.; Lin, X.-F.; Shi, B.-F. Angew. Chem. Int. Ed. 2019, 58, 6708; (c) Zhan, B.-B.; Wang, L.; Luo, J.; Lin, X.-F.; Shi, B.-F. Angew. Chem. Int. Ed. 2020, 59, 3568. 108. (a) Chan, K. S. L.; Fu, H.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 2042; (b) Shen, P.-X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 6545; (c) Zhuang, Z.; Yu, J.-Q. J. Am. Chem. Soc. 2020, 142, 12015; (d) Chen, G.; Gong, W.; Zhuang, Z.; Andra, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Science 2016, 353, 1023; (e) Wu, Q.-F.; Shen, P.-X.; He, J.; Wang, X.-B.; Zhang, F.; Shao, Q.; Zhu, R.-Y.; Mapelli, C.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Science 2017, 355, 499. 109. (a) Yan, S. B.; Zhang, S.; Duan, W. L. Org. Lett. 2015, 17, 2458; (b) Wang, H.; Tong, H.-R.; He, G.; Chen, G. Angew. Chem. Int. Ed. 2016, 55, 15387; (c) Yan, S.-Y.; Han, Y.-Q.; Yao, Q.-J.; Nie, X.-L.; Liu, L.; Shi, B.-F. Angew. Chem. Int. Ed. 2018, 57, 9093. 110. (a) Han, Y.-Q.; Ding, Y.; Zhou, T.; Yan, S.-Y.; Song, H.; Shi, B.-F. J. Am. Chem. Soc. 2019, 141, 4558; (b) Ding, Y.; Han, Y.-Q.; Wu, L.-S.; Zhou, T.; Yao, Q.-J.; Feng, Y.-L.; Kong, K.-X.; Shi, B.-F. Angew. Chem. Int. Ed. 2020, 59, 14060; (c) Han, Y.-Q.; Yang, X.; Kong, K.-X.; Deng, Y.-T.; Wu, L.-S.; Ding, Y.; Shi, B.-F. Angew. Chem. Int. Ed. 2020, 59, 20455. 111. (a) Xu, J.; Liu, Y.; Zhang, J.; Xu, X.; Jin, Z. Chem. Commun. 2018, 54, 689; (b) Liao, G.; Yao, Q.-J.; Zhang, Z.-Z.; Wu, Y.-J.; Huang, D.-Y.; Shi, B.-F. Angew. Chem. Int. Ed. 2018, 57, 3661. 112. (a) Albicker, M. R.; Cramer, N. Angew. Chem. Int. Ed. 2009, 48, 9139; (b) Saget, T.; Cramer, N. Angew. Chem. Int. Ed. 2013, 52, 7865; (c) Yang, L.; Neuburger, M.; Baudoin, O. Angew. Chem. Int. Ed. 2018, 57, 1394; (d) Grosheva, D.; Cramer, N. Angew. Chem. Int. Ed. 2018, 57, 13644; (e) Shimizu, M.; Mochida, K.; Hiyama, T. Angew. Chem., Int. Ed. 2008, 47, 9760; (f ) Lin, Z. Q.; Wang, W. Z.; Yan, S. B.; Duan, W. L. Angew. Chem. Int. Ed. 2015, 54, 6265. 113. (a) Gao, D.-W.; Yin, Q.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 4841; (b) Deng, R.; Huang, Y.; Ma, X.; Li, G.; Zhu, R.; Wang, B.; Kang, Y.; Gu, Z. J. Am. Chem. Soc. 2014, 136, 4472; (c) He, C.; Hou, M.; Zhu, Z.; Gu, Z. ACS Catal. 2017, 7, 5316; (d) Newton, C. G.; Braconi, E.; Kuziola, J.; Wodrich, M. D.; Cramer, N. Angew. Chem. Int. Ed. 2018, 57, 11040; (e) Nguyen, Q.-H.; Guo, S.-M.; Royal, T.; Baudoin, O.; Cramer, N. J. Am. Chem. Soc. 2020, 142, 2161. 114. (a) Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, E. P. Angew. Chem. Int. Ed. 2011, 50, 7438; (b) Anas, S.; Cordi, A.; Kagan, H. B. Chem. Commun. 2011, 47, 11483; (c) Saget, T.; Lemouzy, S. J.; Cramer, N. Angew. Chem. Int. Ed. 2012, 51, 2238; (d) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.; Baudoin, O. Chem. Eur. J. 2012, 18, 4480; (e) Pedroni, J.; Boghi, M.; Saget, T.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 9064. 115. (a) Saget, T.; Cramer, N. Angew. Chem. Int. Ed. 2012, 51, 12842; (b) Pedroni, J.; Cramer, N. Angew. Chem. Int. Ed. 2015, 54, 11826; (c) Pedroni, J.; Cramer, N. J. Am. Chem. Soc. 2017, 139, 12398. 116. Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767. 117. Zhang, Z.; Wang, J.; Li, J.; Yang, F.; Liu, G.; Tang, W.; He, W.; Fu, J.-J.; Shen, Y.-H.; Li, A.; Zhang, W.-D. J. Am. Chem. Soc. 2017, 139, 5558. 118. Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076. 119. Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem. Int. Ed. 2012, 51, 7507. 120. Ting, C. P.; Maimone, T. J. Angew. Chem. Int. Ed. 2014, 53, 3115–3119. 121. O’Donovan, D. H.; Aillard, P.; Berger, M.; de la Torre, A.; Petkova, D.; Knittl-Frank, C.; Geerdink, D.; Kaiser, M.; Maulide, N. Angew. Chem. Int. Ed. 2018, 57, 10737. 122. Hong, B.; Li, C.; Wang, Z.; Chen, J.; Li, H.; Lei, X. J. Am. Chem. Soc. 2015, 137, 11946. 123. Chapman, L. M.; Beck, J. C.; Wu, L.; Reisman, S. E. J. Am. Chem. Soc. 2016, 138, 9803. 124. Thesmar, P.; Baudoin, O. J. Am. Chem. Soc. 2019, 141, 15779. 125. (a) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35; (b) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem. Int. Ed. 2006, 45, 1589; (c) Lewis, J. C.; Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493. 126. Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748. 127. Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926. 128. (a) Zhao, X.; Yu, Z. J. Am. Chem. Soc. 2008, 130, 8136; (b) Shuai, Q.; Yang, L.; Guo, X.; Baslé, O.; Li, C.-J. J. Am. Chem. Soc. 2010, 132, 12212; (c) Pan, F.; Lei, Z.-Q.; Wang, H.; Li, H.; Sun, J.; Shi, Z.-J. Angew. Chem. Int. Ed. 2013, 52, 2063; (d) Tobisu, M.; Yasui, K.; Aihara, Y.; Chatani, N. Angew. Chem. Int. Ed. 2017, 56, 1877. 129. Huang, Y.; Wu, D.; Huang, J.; Guo, Q.; Li, J.; You, J. Angew. Chem. Int. Ed. 2014, 53, 12158. 130. (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem. Int. Ed. 2003, 42, 112; (b) Yang, J.-F.; Wang, R.-H.; Wang, Y.-X.; Yao, W.-W.; Liu, Q.-S.; Ye, M. Angew. Chem. Int. Ed. 2016, 55, 14116; (c) Qiu, X.; Wang, M.; Zhao, Y.; Shi, Z. Angew. Chem. Int. Ed. 2017, 56, 7233; (d) Qiu, X.; Wang, P.; Wang, D.; Wang, M.; Yuan, Y.; Shi, Z. Angew. Chem. Int. Ed. 2019, 58, 1504. 131. Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 2247. 132. Kuhl, N.; Hopkinson, M. N.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 8230. 133. (a) Wencel-Delord, J.; Nimphius, C.; Wang, H.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 13001; (b) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.; Lan, J.; You, J. Angew. Chem. Int. Ed. 2013, 52, 580; (c) Qin, X.; Liu, H.; Qin, D.; Wu, Q.; You, J.; Zhao, D.; Guo, Q.; Huang, X.; Lan, J. Chem. Sci. 2013, 4, 1964; (d) Shi, Y.; Zhang, L.; Lan, J.; Zhang, M.; Zhou, F.; Wei, W.; You, J. Angew. Chem. Int. Ed. 2018, 57, 9108. 134. Zhang, Y.; Zhao, H.; Zhang, M.; Su, W. Angew. Chem. Int. Ed. 2015, 54, 3817. 135. Wang, X.; Lerchen, A.; Daniliuc, C. G.; Glorius, F. Angew. Chem. Int. Ed. 2018, 57, 1712. 136. (a) Wang, X.; Yu, D.-G.; Glorius, F. Angew. Chem. Int. Ed. 2015, 54, 10280; (b) Lerchen, A.; Knecht, T.; Koy, M.; Ernst, J. B.; Bergander, K.; Daniliuc, C. G.; Glorius, F. Angew. Chem. Int. Ed. 2018, 57, 152482. 137. (a) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982; (b) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 1064; (c) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y. Angew. Chem. Int. Ed. 2012, 51, 7242; (d) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 468; (e) Xu, L.; Zhang, C.; He, Y.; Tan, L.; Ma, D. Angew. Chem. Int. Ed. 2016, 55, 321. 138. (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350; (b) Huang, X.; Huang, J.; Du, C.; Zhang, X.; Song, F.; You, J. Angew. Chem. Int. Ed. 2013, 52, 12970; (c) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2014, 53, 1364. 139. Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. 140. Zhang, Y.; Struwe, J.; Ackermann, L. Angew. Chem. Int. Ed. 2020, 59, 15076. 141. Xu, H.-J.; Lu, Y.; Farmer, M. E.; Wang, H.-W.; Zhao, D.; Kang, Y.-S.; Sun, W.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139, 2200. 142. Bera, M.; Agasti, S.; Chowdhury, R.; Mondal, R.; Pal, D.; Maiti, D. Angew. Chem. Int. Ed. 2017, 56, 5272. 143. Liu, B.; Zhou, T.; Li, B.; Xu, S.; Song, H.; Wang, B. Angew. Chem. Int. Ed. 2014, 53, 4191. 144. Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692. 145. (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 2685; (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 3202; (c) Wiedemann, S. H.; Lewis, J. C.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2006, 128, 2452. 146. Shibata, K.; Natsui, S.; Tobisu, M.; Fukumoto, Y.; Chatani, N. Nat. Commun. 2017, 8, 1448. 147. (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332; (b) Tran, G.; Hesp, K. D.; Mascitti, V.; Ellman, J. A. Angew. Chem. Int. Ed. 2017, 56, 5899. 148. Ryu, J.; Cho, S. H.; Chang, S. Angew. Chem. Int. Ed. 2012, 51, 3677. 149. Borah, A. J.; Shi, Z. J. Am. Chem. Soc. 2018, 140, 6062. 150. (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248; (b) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem. Int. Ed. 2011, 50, 2115; (c) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. J. Am. Chem. Soc. 2012, 134, 13565; (d) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597; (e) Wang, H.; Schrçder, N.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52, 5386; (f ) Li, X.; Yu, S.; Wang, F.; Wan, B.; Yu, X. Angew. Chem. Int. Ed. 2013, 52, 2577; (g) Zhou, X.; Yu, S.; Kong, L.; Li, X. ACS Catal. 2016, 6, 647.

CdC Bond Formation Through C-H Activation

189

151. Zhang, X.; Qi, Z.; Li, X. Angew. Chem. Int. Ed. 2014, 53, 10794. 152. Kumar, R.; Sharma, R.; Kumar, R.; Sharma, U. Org. Lett. 2020, 22, 305. 153. (a) Xie, F.; Qi, Z.; Yu, S.; Li, X. J. Am. Chem. Soc. 2014, 136, 4780; (b) Feng, C.; Loh, T.-P. Angew. Chem. Int. Ed. 2014, 53, 2722–2726; (c) Hermann, G. N.; Unruh, M. T.; Jung, S.-H.; Krings, M.; Bolm, C. Angew. Chem. Int. Ed. 2018, 57, 10723. 154. Tan, E.; Quinonero, O.; de Orbe, M. E.; Echavarren, A. M. ACS Catal. 2018, 8, 2166. 155. (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2008, 47, 4019; (b) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474; (c) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565; (d) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449. 156. (a) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154; (b) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem. Int. Ed. 2011, 50, 4169; (c) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem. Int. Ed. 2012, 51, 3948. 157. (a) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem. Int. Ed. 2013, 52, 6033; (b) Zhang, H.; Wang, K.; Wang, B.; Yi, H.; Hu, F.; Li, C.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2014, 53, 13234. 158. (a) Fukui, Y.; Liu, P.; Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.; Lin, G.-Q. J. Am. Chem. Soc. 2014, 136, 15607; (b) Zhou, X.; Pan, Y.; Li, X. Angew. Chem. Int. Ed. 2017, 56, 8163. 159. (a) Seoane, A.; Casanova, N.; Quinñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 834; (b) Seoane, A.; Casanova, N.; Quinñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 7607. 160. (a) Zhou, M.-B.; Pi, R.; Hu, M.; Yang, Y.; Song, R.-J.; Xia, Y.; Li, J.-H. Angew. Chem. Int. Ed. 2014, 53, 11338; (b) Yang, Y.; Zhou, M.-B.; Ouyang, X.-H.; Pi, R.; Song, R.-J.; Li, J.-H. Angew. Chem. Int. Ed. 2015, 54, 6595. 161. Font, M.; Cendόn, B.; Seoane, A.; Mascareñas, J. L.; Gulías, M. Angew. Chem. Int. Ed. 2018, 57, 8255. 162. (a) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew. Chem. Int. Ed. 2011, 50, 1338; (b) Burns, D. J.; Lam, H. W. Angew. Chem. Int. Ed. 2014, 53, 9931; (c) Burns, D. J.; Best, D.; Wieczysty, M. D.; Lam, H. W. Angew. Chem. Int. Ed. 2015, 54, 9958. 163. Wang, H.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 7318. 164. (a) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66; (b) Romanov-Michailidis, F.; Sedillo, K. F.; Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 8892. 165. Zhao, D.; Vásquez-Céspedes, S.; Glorius, F. Angew. Chem. Int. Ed. 2015, 54, 1657. 166. Wu, J.-Q.; Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chen, Y.; Li, Q.; Li, X.; Wang, H. J. Am. Chem. Soc. 2017, 139, 3537. 167. (a) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364; (b) Yu, S.; Liu, S.; Lan, Y.; Wan, B.; Li, X. J. Am. Chem. Soc. 2015, 137, 1623; (c) Wang, C.-Q.; Ye, L.; Feng, C.; Loh, T.-P. J. Am. Chem. Soc. 2017, 139, 1762. 168. Karthikeyan, J.; Haridharan, R.; Cheng, C.-H. Angew. Chem. Int. Ed. 2012, 51, 12343. 169. (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585; (b) Tan, X.; Liu, B.; Li, X.; Li, B.; Xu, S.; Song, H.; Wang, B. J. Am. Chem. Soc. 2012, 134, 16163; (c) Zhou, B.; Chen, Z.; Yang, Y.; Ai, W.; Tang, H.; Wu, Y.; Zhu, W.; Li, Y. Angew. Chem. Int. Ed. 2015, 54, 12121. 170. Qiu, Y.; Kong, W.-J.; Struwe, J.; Sauermann, N.; Rogge, T.; Scheremetjew, A.; Ackermann, L. Angew. Chem. Int. Ed. 2018, 57, 5828. 171. Kong, W.-J.; Shen, Z.; Finger, L. H.; Ackermann, L. Angew. Chem. Int. Ed. 2020, 59, 5551. 172. (a) Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192; (b) Tanaka, K.; Otake, Y.; Sagae, H.; Noguchi, K.; Hirano, M. Angew. Chem. Int. Ed. 2008, 47, 1312; (c) Tran, D. N.; Cramer, N. Angew. Chem. Int. Ed. 2011, 50, 11098; (d) Tran, D. N.; Cramer, N. Angew. Chem. Int. Ed. 2013, 52, 10630; (e) Filloux, C. M.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 508. 173. (a) Kim, J. H.; Greßies, S.; Boultadakis-Arapinis, M.; Daniliuc, C.; Glorius, F. ACS Catal. 2016, 6, 7652; (b) Greßies, S.; Klauck, F. J. R.; Kim, J. H. Angew. Chem. Int. Ed. 2018, 57, 9950; (c) Cai, Z.-J.; Liu, C.-X.; Wang, Q.; Gu, Q.; You, S.-L. Nat. Commun. 2019, 10, 4168; (d) Liu, C.-X.; Cai, Z.-J.; Wang, Q.; Wu, Z.-J.; Gu, Q.; You, S.-L. CCS Chem. 2020, 2, 642; (e) Wang, Q.; Cai, Z.-J.; Liu, C.-X.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2019, 141, 9504. 174. (a) Ye, B.; Cramer, N. Science 2012, 338, 504; (b) Hyster, T. K.; Knörr, L.; Ward, T. R.; Rovis, T. Science 2012, 338, 500. 175. Ye, B.; Cramer, N. J. Am. Chem. Soc. 2013, 135, 636. 176. (a) Ye, B.; Donets, P. A.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 507; (b) Wang, S.-G.; Cramer, N. Angew. Chem. Int. Ed. 2019, 58, 2514; (c) Yang, X.; Zheng, G.; Li, X. Angew. Chem. Int. Ed. 2019, 58, 322; (d) Zheng, G.; Zhou, Z.; Zhu, G.; Zhai, S.; Xu, H.; Duan, X.; Yi, W.; Li, X. Angew. Chem. Int. Ed. 2020, 59, 2890. 177. (a) Ye, B.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 7896; (b) Wang, S.-G.; Liu, Y.; Cramer, N. Angew. Chem. Int. Ed. 2019, 58, 18136; (c) Cui, W.-J.; Wu, Z.-J.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2020, 142, 7379. 178. Li, T.; Zhou, C.; Yan, X.; Wang, J. Angew. Chem. Int. Ed. 2018, 57, 4048. 179. (a) Sun, Y.; Cramer, N. Angew. Chem. Int. Ed. 2017, 56, 364; (b) Trifonova, E. A.; Ankudinov, N. M.; Mikhaylov, A. A.; Chusov, D. A.; Nelyubina, Y. V.; Perekalin, D. S. Angew. Chem. Int. Ed. 2018, 57, 7714. 180. (a) Shen, B.; Wan, B.; Li, X. Angew. Chem. Int. Ed. 2018, 57, 15534; (b) Brauns, M.; Cramer, N. Angew. Chem. Int. Ed. 2019, 58, 8902. 181. (a) Zheng, J.; Wang, S.-B.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 4880; (b) Chidipudi, S. R.; Burns, D. J.; Khan, I.; Lam, H. W. Angew. Chem. Int. Ed. 2015, 54, 13975; (c) Zheng, J.; Wang, S.-B.; Zheng, C.; You, S.-L. Angew. Chem. Int. Ed. 2017, 56, 4540; (d) Li, H.; Gontla, R.; Flegel, J.; Merten, C.; Ziegler, S.; Antonchick, A. P.; Waldmann, H. Angew. Chem. Int. Ed. 2019, 58, 307; (e) Kong, L.; Han, X.; Liu, S.; Zou, Y.; Lan, Y.; Li, X. Angew. Chem. Int. Ed. 2020, 59, 7188. 182. (a) Satake, S.; Kurihara, T.; Nishikawa, K.; Mochizuki, T.; Hatano, M.; Ishihara, K.; Yoshino, T.; Matsunaga, S. Nat. Catal. 2018, 1, 585; (b) Lin, L.; Fukagawa, S.; Sekine, D.; Tomita, E.; Yoshino, T.; Matsunaga, S. Angew. Chem. Int. Ed. 2018, 57, 12048. 183. (a) Zheng, J.; You, S.-L. Angew. Chem. Int. Ed. 2014, 53, 13244; (b) Zheng, J.; Cui, W.-J.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2016, 138, 5242. 184. (a) Shan, G.; Flegel, J.; Li, H.; Merten, C.; Ziegler, S.; Antonchick, A. P.; Waldmann, H. Angew. Chem. Int. Ed. 2018, 57, 14250; (b) Tian, M.; Bai, D.; Zheng, G.; Chang, J.; Li, X. J. Am. Chem. Soc. 2019, 141, 9527; (c) Li, H.; Yan, X.; Zhang, J.; Guo, W.; Jiang, J.; Wang, J. Angew. Chem. Int. Ed. 2019, 58, 6732; (d) Wang, F.; Qi, Z.; Zhao, Y.; Zhai, S.; Zheng, G.; Mi, R.; Huang, Z.; Zhu, X.; He, X.; Li, X. Angew. Chem. Int. Ed. 2020, 59, 13288. 185. Xu, X.; Liu, Y.; Park, C.-M. Angew. Chem. Int. Ed. 2012, 51, 9372. 186. Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490. 187. Tsai, A. S.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316. 188. Phillips, E. M.; Mesganaw, T.; Patel, A.; Duttwyler, S.; Mercado, B. Q.; Houk, K. N.; Ellman, J. A. Angew. Chem. Int. Ed. 2015, 54, 12044.

12.06 Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation Nupur Goswamia, Resma Mohanb, and Debabrata Maitia, aDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai, India; bCentre for Integrated Studies, Cochin University of Science and Technology, Kochi, Kerala, India © 2022 Elsevier Ltd. All rights reserved.

12.06.1 Introduction 12.06.2 Metal-catalyzed CdB bond formation 12.06.2.1 Ir-catalyzed CdH borylation 12.06.2.1.1 Ir-catalyzed non-directed CdH borylation 12.06.2.1.2 Ir-catalyzed directed CdH borylation 12.06.2.2 Rh-catalyzed CdH borylation 12.06.2.3 Pd-catalyzed CdH borylation 12.06.2.4 Other metal catalyzed CdH borylation 12.06.3 Metal-catalyzed C-X (X ¼ cl, Br, I) bond formation 12.06.3.1 Pd-catalyzed CdH halogenation 12.06.3.2 Rh-catalyzed CdH halogenation 12.06.3.3 Cu-catalyzed CdH halogenation 12.06.3.4 Other metal catalyzed CdH halogenation 12.06.4 Metal-catalyzed CdO bond formation 12.06.4.1 Pd-catalyzed CdH oxygenation 12.06.4.1.1 Pd-catalyzed CdH acetoxylation 12.06.4.1.2 Pd-catalyzed CdH hydroxylation 12.06.4.1.3 Pd-catalyzed CdH lactonization 12.06.4.2 Other metals catalyzed CdO bond formation 12.06.5 Conclusion Acknowledgment References

190 190 190 190 203 216 217 219 220 220 228 229 231 232 232 232 241 243 244 247 247 247

12.06.1 Introduction The conversion of CdH bonds to their corresponding CdC, CdO, CdX, CdN analogs is still challenging and relevant to organic chemistry. Over years the use of organometallic reagents1,2 (Grignard, organolithium) have served as an extremely useful toolbox for such conversions. However, special reaction conditions and formation of excessive metal salt by-product are pervasive side flaws of these transformations. There are fewer alternative routes to cleave CdH bonds for the direct installation of functional groups. It is challenging mainly due to two reasons, (i) the inert nature of CdH bonds mostly in aliphatic systems, (ii) their comparable energy demands in both aromatic and aliphatic systems give rise to huge selectivity issue. In this regard, direct conversion of CdH bonds via transition metal catalyzed CdH activation is an efficient and more sustainable method. This transformations proceeds through cyclometallation as the key step. Thus a typical CdH bond first gets cleaved to form C-M (transition metal) bond which is more activated than the former to get functionalized, i.e., CdH activation. This cyclometallation mainly forms in the presence of an external ligand (such as dtbpy with Ir, MPAA ligands with Pd, etc.,) coordination that helps in minimizing the energy requirement for the process. Metals such as Rh, Ru, Cu, Pd, Ir are the most efficient in the race.3 This chapter describes the comprehensive development of transition metal catalyzed direct C-E (E ¼ B, O, halogen) bond formation through CdH activation from mid-2000s.

12.06.2 Metal-catalyzed CdB bond formation 12.06.2.1 Ir-catalyzed CdH borylation 12.06.2.1.1

Ir-catalyzed non-directed CdH borylation

The access of aryl-, alkyl-boron reagents are difficult due to their multistep synthesis from halides, triflates or organomagnesium/ lithium derivatives. Direct borylation of alkyl or aryl counterparts provides an alternative process which thermodynamically and kinetically favorable. The most used borylating agents are HBPin and B2Pin2 (Pin ¼ pinacolate). The strong s-donor properties of the boryl group as well as the presence of an unoccupied pz-orbital on boron in a metal-boryl complex are the key factors in this chemistry. Ir-catalysts have shown remarkable development and selectivity for CdH borylation reactions.4 In 2005, Osuka and colleagues discovered that the treatment of catalytic amount of [Ir(cod)OMe]2 and 4,40 -di-tert-butyl-2,20 -bipyridyl (dtbpy) with bis(pinacolato) diborane (B2Pin2) in 1,4-dioxane resulted in unprecedented regioselectivity of b- over meso-borylation of porphyrins (Scheme 1).5

190

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00122-0

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

191

Scheme 1 Ir-catalyzed b-borylation of porphyrins.

These b-borylated porphyrins were synthetically important for the fabrication of multiporphyrin systems. Unfortunately, Zn-porphyrin was less soluble in dioxane resulted in poor reactivity. The methodology was applied to corrole,6 18-p-aromatic tetrapyrrolic macrocycles that contain a direct pyrrole–pyrrole linkage, that exhibit interesting optical properties, and are important for their metal coordination ability as ligands (Scheme 2). Corrole was successfully borylated at the 2-position.

Scheme 2 Ir-catalyzed site-selective borylation of carrole.

Later in the same year, Hartwig and the group explained the mechanism of Ir-catalyzed benzene borylation by identifying the catalyst resting state as [Ir(dtbpy)(COE)(Bpin)3] (COE ¼ cyclooctene). After dissociation of COE, the target CdH bond oxidatively adds to the active tris-Bpin complex [Ir(dtbpy)Bpin3], a 16-electron species, followed by reductive elimination of PhBPin. Another molecule of B2Pin2 restores the active catalyst (Scheme 3).7

192

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 3 Possible mechanism of Ir-catalyzed borylation reaction.

After unveiling the controlling factors for Ir-catalyzed borylation, the Hartwig group developed another reaction with catecholate-substituted diboron reagent B2cat2, with benzene in the presence of 2.5 mol% [Ir(COD)OMe]2 and 5 mol% dtbpy (Scheme 4).8

Scheme 4 Ir-catalyzed borylation with catecholate-substituted diboron.

Further studies showed that tris-Bcat complex was more stable at room temperature than its Bpin analog, thus the reaction is only effective above 50  C and gives the best result at 120  C. The steric influence of chelating diphosphinoethane ligands has a dramatic effect on the reactivity of trisboryl complexes with arenes (Scheme 5).9 Reaction with sterically less encumbered ligand dippe caused an increased yield of borylated compound shown by Smith, III.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

193

Scheme 5 Diphosphinoethane ligands to promote Ir-catalyzed borylation.

Contemporarily, Maleczka, Jr. & Smith, III reported Ir-catalyzed C7 borylation of unprotected indoles with pinacolborane (HBPin) at elevated temperatures (Scheme 6).10 However the 2-substituted indoles were used for this purpose to shift the regioselectivity completely towards C7 position. The mechanistic investigation revealed the coordination of the indole-N to Ir directs the CdH insertion to immediately adjacent C7 position which follows similar steps as discussed previously.

Scheme 6 Ir-catalyzed site-selective C7 borylation of indoles.

They extended the application of the methodology to functionalize substituted thiophenes at C5 postion.11 Similar transformation delivering C8 borylations of 7-deazapurines was delivered by Hocek group using this methodology (Scheme 7).12

Scheme 7 Ir-catalyzed site-selective C2 borylation of 7-deazapurines.

Marder explained that the Ir-catalyst borylates the ligand (dtbpy) present in stoichiometric amounts which not bound to the metal center. Thus nature of substrate specific reactions was explained by choosing 2-phenyl pyridine. 2.5 mol% of [Ir(cod) (m-OMe)]2 with 10 mol% of dtbpy in hexane delivered borylation at the 4- and 5-positions of the Py ring in preference to the Ph ring (Scheme 8).13 They were able to conclude that fine tuning of the substrate enables the formation of regioselective isomers such that ortho substitution to the N-atom is sufficient to inhibit N-coordination of substrate to the Ir center.

Scheme 8 Ir-catalyzed borylation of 2-phenyl substituted pyridines.

194

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Thus borylation of substrates with ortho-sterics requires different methodology. Apart from homogeneous catalysis, where the separation of catalysts and products is difficult, the application of heterogeneous catalysis finds a way for cleaner reaction methodology. To avail ortho-directed borylation, the Sawamura group developed Silica-SMAP, a silica-supported, caged, compact phosphine ligand which can lead to mono-phosphine-metal complexes (Scheme 9).14 The reaction of benzene with B2Pin2 in the presence of in situ formed Silica-SMAP-Ir(OMe)(cod) (0.5 mol%) provided mono-borylation product with very high efficiency.

Scheme 9 Heterogeneous catalysis with Silica-SMAP-Ir to achieve successful borylation.

A unique method to functionalize sterically and electronically unbiased indoles selectively at the C7 position was developed by the Hartwig group in 2010 (Scheme 10).15 They established a one-pot protocol for indole borylations by installation of the silyl group, directed borylation, and desilylation successively. A nice comparison can be drawn from the result of borylation of 3-phenylindole, which gives a mixture of minimum three products, while the borylation of 3-phenyl-N-diethylsilylindole formed only 7-boryl-3-phenylindole without borylation of the phenyl substituent.

Scheme 10 C7-borylation of indoles using in situ formed silyl directing group.

Based on this method, Sperry and coworkers streamlined the synthesis of antimicrobial indolequinones with and without C6 substituents (Scheme 11).16 Later in 2014, Hartwig and the group explored the scope and regeioselectivity of borylation reaction of various heteroarenes (Scheme 12).17 The results encompassing benzoxazoles, pyrimidines, as well as unprotected benzimidazoles, pyrazoles, and azaindoles motifs are the important backbone of medicinal importance.

Scheme 11 C7-borylation of indoles to indolequinones.

Scheme 12 Ir-catalyzed borylation of heterocycle derivatives.

196

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

The Ir-catalyzed CdH borylation of 2-substituted pyridines as substrates was shown by Marder and Steel (Scheme 13).18 The lower stoichiometrics (0.5 vs. 1.2 equiv.) use of borylating agent was found to give the mono-functionalized borylation product, however with lesser conversion.

Scheme 13 Ir-catalyzed borylation of substituted pyridines.

An extensive study on the reaction rates, efficiency and other parameters like boron reagent, ligand, order of addition, temperature, solvent effect was studied by Krska, Maleczka and Smith, III using a nondirected Ir-catalyzed borylation of arene deriavtives.19 Concise routes to verruculogen and fumitremorgin A, bioactive alkaloids, were streamlined applying the Ir-catalyzed CdH borylation of N-TIPS protected group enabled tryptophan as one of the important intermediate transformations.20 A further Cu-mediated oxidation led to desired precursor to reach the target alkaloids (Scheme 14).

Scheme 14 Ir-catalyzed borylation followed by one pot oxidation of substituted tryptophan derivatives.

Aryl- or alkylboron compounds are the intermediate to reach numerable value added functional groups. Marder and Steel showed a microwave assisted Ir-catalyzed borylation of arene rings followed by a Rh-catalyzed conjugate addition of the arylboronate to enones delivers either b-aryl-substituted ketones or the corresponding alcohols (Scheme 15).21

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

197

Scheme 15 Route to b-aryl-substituted ketones and alcohols via borylation.

The activation of aryl CdH bonds is often relatively easy compared to aliphatic CdH bonds. Moreover, in the competition of reactivity, primary CdH bonds often react preferentially resulting from steric accessibility compared to secondary CdH bonds. As the solution to the problem, Hartwig group developed an Ir–phenanthroline catalyst that enables the activation of methylene CdH bonds of heterocycles that are b to oxygen atoms (Scheme 16).22 Here CdH borylation of secondary CdH bonds in cyclic ethers was catalyzed by the tetramethylphenanthroline Me4phen (tmphen) ligand and (Z6-mes)IrBpin3 catalyst. Mechanistic studies revealed CdH cleavage to happen first, a to the cyclic ethers which eventually isomerizes to the b position.

Scheme 16 Borylation of secondary CdH bonds.

C(sp3)dH borylation of aliphatic substrates without strong directing groups like diisopropyl ether or cyclic ethers was shown to give enhanced yield in presence of catalytic amount of t-BuOK. The role of t-BuOK was supposed to be the improvement of the iridium complex structure via the deprotonation of the boron reagent (Scheme 17).23

198

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 17 Ir-catalyzed C(sp3)dH borylation with and without t-BuOK.

The application of the former protocol to avail the borylation of bromo-cyclopropanes was attempted by the Hartwig group and resulted in 68% yield in a 60:40 diastereomeric ratio. The modification with sterically encumbered ligand (2,9-dimethylphenanthroline (Me2phen)) enhanced the diastereoselectivity up to 97:3 (Scheme 18).24

Scheme 18 Ir-catalyzed C(sp3)dH borylation of cyclopropanes.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

199

A mechanistic investigation regarding the stability of the Ir catalyst explained that the reaction catalyzed by [Ir(COD)(OMe)]2 and tmphen or Me2phen yields substantially higher than those of reactions catalyzed by [Ir(COD)(OMe)]2 and dtbpy ligand.25 This reflects the higher stability of Ir- tmphen or Ir- Me2phen complex which is a direct result of its greater binding constant. A recent study by the Schley group was found to give superior reactivity for the borylation of unactivated alkanes (Scheme 19).26 They developed a highly efficient Ir-catalyzed C(sp3)dH borylation with the 2,20 -dipyridylarylmethane ligand. The ligand consists of a diimine backbone of typical dtbpy or Me4Phen ligands, while allowing for incorporation of substituents that project out of the N–M–N plane. A facial k3 binding mode upon cyclometallation was expected with Ir, which is a net five-electron donor analogous to the Cp ligand. Very recently, a detailed mechanistic DFT study done by Huang.27 They indicated the intermediacy of a borylated cyclometalated Ir(III) diboryl complex, generated by the association of the pendent aryl group. A C(sp2)dH activation of the pendent phenyl group to form borylated active ligand is necessary to get the cyclometalled Ir(III) complex. The CdH oxidative addition to this Ir(III) complex can give the seven-coordinated Ir(V) hydride intermediate which upon isomerization/C − B reductive elimination releases the desired product.

Scheme 19 Borylation of unactivated alkanes.

A contemporary study of Rh-catalyzed borylation of aliphatic CdH bonds will be discussed in a later section. Meanwhile Sawamura engineered a silica-supported heterogeneous monophosphine − Ir catalyst to functionalize the unactivated Cg to the pyridine nitrogen atom of 2-alkylpyridine derivatives using B2Pin2 (Scheme 20).28

200

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 20 Ligand Effects in Ir-Catalyzed Borylation of 2-Ethylpyridine.

A similar nondirected method was implemented on 3,5-disubstituted arene derivatives for the preparation of new, stable and versatile potassium aryltrifluoroborates bearing a pentafluorosulfonyl group as one of the substituents (Scheme 21).29 These meta-borylated compounds were further used as precursors of Suzuki-Miyaura coupling reactions.

Scheme 21 meta-Selective borylation of pentafluorosulfonyl group containing arene derivatives.

A mesoporous silica (SBA-15)-supported bipyridine-Ir complex was prepared by grafting of bipyridine onto the silica support, followed by complexation of an Ir(I)-precursor in the presence of HBpin and cyclooctene. 1.4 mol% of the foresaid catalyst was effective for the borylation of various arene derivatives.30 So far the regioselectivity of arenes and heteroaryls were predicted to be governed by the pKa of the CdH bond and dependent on the CdH dissociation energy and the stability of the forming IrdC bond. However various inconsistencies in selectivity and observed pKa value intrigued scientists to find the origin of selectivity. Houk employed the distortion/interaction model to investigate the origins of reactivity and selectivities for such reactions.31

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

201

Modification of silica supported Ir-catalyst formation to employ as the heterogeneous catalyst was done by Motokura and coworkers (Scheme 22).32 They developed a linker based ligand system which then forms the active It-catalyst and places it proximal to the substrate. The substrate (benzonitrile) is predicted to be fixed near the metal-catalyst via a hydrophilic interaction with the tertiary amide bound with the silica support via the SidOH of the silica base. The increase in the linker length of the ligand with the silica base reflected in the decrease in catalytic activity.

Scheme 22 Linker dependent heterogeneous catalysis using non-covalent interactions.

Interestingly, in 2015, the Hartwig group developed a nondirected CdH borylation of benzylic position of toluene (Scheme 23).33 They diverted the inherent arene selectivity of methylarenes towards the benzylic position using a silylborane as reagent, Et3SiBpin and an Ir-catalyst with a sterically hindered, electron-poor phenanthroline ligand. The protocol showed a good functional group tolerance as the arene-substituents. Unlike arene CdH bonds, the CdH oxidative addition to metal center was not the slowest step in the process of benzylic CdH borylation, but rather the isomerization prior to CdB reductive elimination.

Scheme 23 Comparative regioselectivity for benzylic borylation of methylarenes.

In 2015, Li and coworkers developed a different approach for the non-directed CdH borylation of aryl and hetero aryl systems with good regioselectivity (Scheme 24).34 They prepared a bidentate boryl anion as supporting ligand which is a symmetric dipyridinyl tetraaminodiborane and used it as a precursor for introducing double N,B-type boryl ligands onto Ir via BdB oxidative addition. This active catalyst was then used for CdH borylation.

202

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 24 N,B-type boryl ligands promoted CdH borylation reaction.

In 2016, Ozerov and the colleagues introduced a POCOP-type pincer complexes of Ir that promote the CdH borylation of non-directed arene derivatives (Scheme 25).35a The use of olefin to consume the H2 equivalents generated in the medium was assumed to increase the efficiency of the method. Although olefin hydroborylation was one of the competing side reactions, smaller olefins such as ethylene or 1-hexene were more advantageous to catalysis than sterically encumbered tert-butylethylene (TBE). Another important and interesting protocol was showed by Ozerov for catalytic CdH borylation of terminal alkynes. They introduces SiNN ligands for this purpose that combines amido, quinoline, and silyl donors to give rise to a structurally unique Ir-complex.35b,c

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

203

Scheme 25 POCOP and SiNN pincer complexes of Ir to promote CdH borylation.

12.06.2.1.2

Ir-catalyzed directed CdH borylation

The coordination of a pre-installed ligand can direct the metal at a certain distance to activate a particular CdH bond thus solving the selectivity issue. These are known as directing groups, which require a post-functionalization removal In 2008, Hartwig and the group developed efficient silyl directing groups (DG) to selectively functionalize the ortho-position of arene derivatives.36 They reported an Ir-catalyzed borylation at the CdH bond ortho to a hydrosilylmethyl, siloxide, or silylamine directing group. The DG first coordinates with the metal and forms 5–6 membered metallacycle after ortho-activation. The reactions were realized in one pot fashion via the in situ formed DG from free phenols and N-alkylanilines (Scheme 26). This kind of method avoids the installation of organolithium reagents to promote selective borylation via ortho-metalation.

204

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 26 Silyl-directed Ir-catalyzed borylation of phenols and N-alkylanilines.

The Hartwig group reported a benzylic methylene CdH bond activation protocol using previously existing robust methods.37 They implemented it to borylation of (2-propylphenyl)dimethylsilane, wherein the silane group directed selective methylene CdH activation(Scheme 27). DFT studies indicated that the propensity for CdH bond activation under this protocol to be in the order of benzylic C(sp3)dH > terminal alkyl C(sp3)dH > ortho C(sp2)dH of the aryl > secondary internal C(sp3)dH bonds.38

Scheme 27 Benzylic methylene CdH bonds borylation.

The reactivity of benzyl amines as the directing group for the Ir-catalyzed ortho-borylation, in presence of picolyl amine ligand was explained by Clark and group (Scheme 28).39

Scheme 28 Ir-catalyzed ortho-borylation of benzyl amines assisted by picolylamine as a ligand.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

205

In another example, ortho selective CdH borylations of arenes and alkenes were obtained with a NHBoc directing group, where an outer sphere hydrogen bonding of the NdH proton with the boryl ligand oxygen from tris-boryl complex was the stabilizing factor of the transition state (Scheme 29).40

Scheme 29 Outer sphere noncovalent interaction to favor CdH borylation reaction.

Further exploring the non-covalent interactions, the Kanai group illustrated the active role of Lewis acid-base pair system to direct the borylation at the ortho-position of aryl sulfides selectively (Scheme 30).41 In this case, the electron deficient Lewis acidic part of the ligand interacts with the Lewis basic substrate to anchor the Ir-metal at the desired position. The possible interaction is shown in the scheme.

Scheme 30 ortho-Selective CdH borylation controlled by Lewis acid-base interaction between a ligand and substrate.

Later, Kanai and Kuninobu developed Ir-catalyzed ortho-selective CdH borylation of thiomethyl group tagged phenol and aniline derivatives using similar kind of electron deficient bpy ligand (Scheme 31).42

206

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 31 Ir-catalyzed ortho-selective CdH borylation electron deficient bpy ligand.

Examples of sulfur-directed (a cyclic dithioacetal group), ligand-free CdH borylation,43 and S, Si-ligand assisted CdH borylation44 were developed by Li and co-workers realizing an excellent ortho-selectivity (Scheme 32).

Scheme 32 S-DG and S, Si-Ligand assisted borylation reaction.

Very recently in 2021, Chattopadhyay group replaced the monopolistic use of neutral bpy ligands by the judicious development of anionic IrdC(furyl) ligands (Scheme 33).45 The invention led to the functionalization of different rigid motifs that are unprecedented. Detailed mechanistic study showed the evidence of bis(boryl)dIr active complex with two vacant coordination site on the removal of COD. They employed this method for the selective borylation of aromatic to aliphatic systems. Examples are shown for the selective C(sp3)dH activation in presence of more reactive aromatic C(sp2)dH bonds.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

207

Scheme 33 Anionic IrdC(furyl) ligands assisted CdH borylation.

Kanai and Koninobu developed a very unique ligand system with an appropriate hydrogen donor fragment to establish a fine connection with the substrate (acceptor) via hydrogen bonding, thus placing the Ir in close proximity to the meta-CdH bond and controlling the regioselectivity (Scheme 34).46 They modified a bpy ligand with a pendent urea moiety, attached through a Ph linker. The possible intermediate is as shown in the scheme. The CdH borylation was accelerated by the urea unit-containing bpy-type ligand (Cy-Ubpy) compared to the case involving unsubstituted bpy ligand without the urea moiety.47 In 2019, Nakao and colleagues designed a bpy ligand bearing an alkylaluminum biphenoxide (LA) moiety (Scheme 35).48 They screened the following ligands for the meta-borylation of benzamides using IrdLA bifunctional catalysts.

Scheme 34 Regioselctive aromatic CdH borylation controlled by hydrogen bonding.

Scheme 35 Regioselctive aromatic CdH borylation controlled by Lewis acid ligands.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

209

Phipps and colleagues examined ion-pair interactions to control the regioselectivity of Ir-catalyzed CdH borylation reaction in arene systems (Scheme 36).49 They introduced an anionic counterpart in the bpy ligand and cationic counterpart in the substrate to establish an ion-pair interaction in them, by virtue of which the metal gets accurately placed to govern meta-selective borylation.

Scheme 36 Ion pair-directed regioselctive aromatic CdH borylation.

However, the poorer selectivity of non-cationic substrates were overcome in their next study,50 where single anionic bpy ligands could act as a hydrogen bond acceptor to promote meta-selective borylation of benzyl amine derivatives and a range of aromatic substrates bearing amide hydrogen bond donors (Scheme 37).

Scheme 37 Hydrogen bonding with anionic ligands to assist regioselctive aromatic CdH borylation.

At a similar time, the Chattopadhyay group reported ligand-enabled development of ortho and meta CdH borylation of aromatic aldehydes (Scheme 38).51 While, ortho-borylation was obtained using tert-butylamine as the traceless directing group, the meta-selective borylation was achieved due to the electrostatic interaction and a secondary interaction between the ligand of the catalyst and the substrate.

210

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 38 Ligand-enabled ortho and meta-CdH borylation of aromatic aldehydes.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

211

The steric influence was proved more pronounced than existing methods, when Itami and coworkers developed a special Ir-catalyst [Ir(cod)OH]2 with sterically encumbered phosphine based ligand (Xyl-MeO-BIPHEP) that disfavors the coordination and oxidative addition of meta-CdH bonds, hence reason for an exclusive distal (para) selectivity (Scheme 39).52 The current protocol was applicable for the late-stage functionalization of pharmaceutical molecules.

Scheme 39 Phosphine based ligand-enabled para CdH borylation of aromatic systems.

Other than phenyl silanes alkyl benzenes were found suitable for the mentioned transformation. In the mechanistic study, they showed that with the extent of increase in the steric bias on the silyl group reflects in the rise in para-selectivity, such as, SiH3 (and Me) < SiMe3 < Si(tdBu)3. On the other hand, a decrease in the para-selectivity obtained when an increased steric bulk was introduced by choosing bulkier 3,5-substituents to the phenyl rings of the diarylphosphino groups of the ligand.53 However, previously established Ir(III)/Ir(V) catalytic cycle was unfavored with bulky phosphine ligands due to considerable steric repulsion in the hepta-coordinated Ir(V) intermediate. The Ir(I)/Ir(III) catalytic cycle was invoked in this regard (Scheme 40),54 and proceeds as follows: (i) the oxidative addition of the CdH bond of the substrate to an active iridium(I) boryl complex; (ii) the reductive elimination of a CdB bond; (iii) the oxidative addition of B2pin2 to an iridium(I) hydride complex; and (iv) the reductive elimination of a BdH bond.

212

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 40 Ir(I)/Ir(III) catalytic cycle with sterically bulky ligands.

Following the achievement of para-selective borylation reaction using the sterically controlled ligand system, the Chattopadhyay group reported Ir-catalyzed para-CdH borylation of aromatic esters controlled by a noncovalent interaction between the substrate and a L-shaped ligand (Scheme 41). The ligand consisted of two parts, the first part is a bpy core to bind the Ir transition metal. The second part of the ligand contains a quinolone moiety where either the -OH group or the in situ generated OdM (M ¼ Li, Na, K) group of the ligand would recognize of the carbonyl oxygen atom of the aromatic ester substrate through the noncovalent interaction to facilitate the oxidative addition of Ir para to the ester.

Scheme 41 Ir-catalyzed para-CdH borylation of aromatic esters controlled by noncovalent interaction.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

213

In the same year, Nakao established a para-selective CdH borylation of benzamides and pyridines by cooperative Ir/Al catalysis (Scheme 42).55 They employed Ir-catalysis for the successful borylation process whereas Lewis acidic Al was used to hold the Lewis basic substrate via charge transfer complexation to govern the regioselectivity making the arene core more reactive. The steric repulsion between a ligand on Ir and LA would block the proximal and meta-positions and force the CdH borylation to proceed at the distal-position.

Scheme 42 para-Selective CdH borylation of benzamides and pyridines by cooperative Ir/Al catalysis.

In 2019, the Phipps group applied an ion-pair interaction combined with steric assistance to deliver para-selective borylation (Scheme 43).49 They proposed an alternative strategy with ion-pairing in which the counter ion contained in the substrate does not deliver the reactive catalyst, but remains unfunctionalized and bulky, acting as a “steric shield” to obstruct borylation at the meta-position, thereby resulting in para-selectivity with standard Ir-catalysts.

214

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 43 Ion-pair interaction combined with steric assistance to promote para-selective borylation.

Despite considerable development in the strategies to achieve proximal to distal CdH borylation, the enantioselective synthesis of the same is still elusive. In 2017, Hartwig and Shi group developed a set of Ir-catalyzed enantioselective borylations of aromatic CdH bonds using a chiral dinitrogen ligand to introduce point chirality by desymmetrization, that involves the formation of an IrdSi bond (Scheme 44).56

Scheme 44 Enantioselective borylation via desymmetrization.

Following the previous developments, Ke and Xu investigated the incorporation of a pendant chiral silyl or boryl moiety to assist in the creation of the desired chiral ligand (Scheme 45).57 They synthesized a chiral (S,S)-DPEN-derived bidentate boryl ligand to introduce desymmetrization in diarylmethylamines via Ir-catalyzed ortho-borylation. The formation of the chiral trisboryl Ir-complex with two available coordination sites that are capable of both being coordinated by a directing group and stereoselectively differentiating two identical prochiral C(sp2)dH bonds is the fundamental turn on for this methodology.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

215

Scheme 45 Enantioselective borylation via desymmetrization using N,B-type ligand.

Further investigation revealed that the chiral ligand bearing containing 3,5-(CF3)2C6H3 as Ar-group, was optimal in terms of selectivity (s ¼ 68), conversion (30%), and ee value (94%) of the kinetically resolved borylated product of racemic diarylmethylamine. Following this result, they achieved enantioselective C(sp3)dH borylation to chiral cyclopropylboronates which are versatile synthons.58 An unprecedented amide directed enantioselective (Scheme 46) Ir-catalyzed C(sp3)dH borylation of cyclopropanes was developed using modified chiral bidentate boryl ligands.

Scheme 46 Reaction generality of Ir-catalyzed enantioselective C(sp3)dH borylation of cyclopropanecarboxamides.

216

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Prior to this work, a method was developed by the Sawamura group to achieve enantioselective borylation of unactivated methylene C(sp3)dH bonds (g-to the directing hetero atom) in 2-alkylpyridines and 2-alkyl-1,3-azole derivatives using an Ir-BINOL-based chiral monophosphite catalyst system (Scheme 47).59 The generation of a monophosphite-Ir-tris(boryl) complex that provided a narrow chiral reaction pocket that was conceptually analogous to an enzyme active site with the multiple secondary attractive interactions between the substrate and the catalyst.

Scheme 47 Ir-catalyzed enantioselective C(sp3)dH borylation with chiral ligand.

Another example of the N,B-bidentate ligand skeleton containing a chiral pyridine moiety developed by the Li group to promote an enantioselective Ir-catalyzed desymmetrizing CdH borylation reaction of diaryl(2- pyridyl)methane compounds with up to 96% ee and 93% yield (Scheme 48).60

Scheme 48 N,B-bidentate ligand to promote an enantioselective borylation.

12.06.2.2 Rh-catalyzed CdH borylation The Hartwig group pioneered Rh-catalyzed CdH borylation with the terminal-selective CdH borylation of hydrocarbons (Scheme 49).61 They found the rhodium complex Cp Rh(Z4-C6Me6) (Cp ¼ C5Me5) catalyzes the reaction with high-yield under thermal conditions. While the most extensive development has been on Ir-catalyzed CdH borylation, Rh-catalysts are still relevant for some important conversions discussed below.

Scheme 49 Rh-catalyzed CdH borylation of unactivated hydrocarbons.

Sawamura used the Rh-phosphine catalysts (P/Rh 1:1), immobilized in a silica-supported system to deliver ortho-selective CdH borylation of 2-phenyl pyridines (Scheme 50).62

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

217

Scheme 50 Immobilized Rh-phosphine catalysts for ortho-selective CdH borylation.

The method was successful with amides, ureas and 2-aminopyridine derivatives for the direct C(sp3)dH borylation at the a position to the N atom, which gives the corresponding a-aminoalkylboronates (Scheme 51).63

Scheme 51 Immobilized Rh-phosphine catalysts for borylation of derivatives at the a position to the N atom.

An enantioselective version of the reaction was realized by the same group to access a-aminoboronic acids, isostructural to amino acids.64 The skeleton has received much attention from scientific community due its biomedical applications. They applied a coupling of chiral binol based monophosphate ligand (L, Scheme 47) with a homogeneous Rh-catalyst (Scheme 52), which previously was a success for enantioselective Ir-catalysis. On the other hand, a simple [Rh(OMe)(cod)]2 catalyst was successful in promoting ortho-borylation of 2-pyridones in a homogeneous environment.65

Scheme 52 Rh-catalyzed enantioseletive borylation.

12.06.2.3 Pd-catalyzed CdH borylation Borylation reaction with Ir-metal is a much explored topic, where development with other metals are still at its infancy. Often in a Pd-catalyzed reaction, CdB bonds are too much reactive to isolate as the desired product. However, in 2001 Miyaura66 described a Pd/C catalyzed benzylic CdH borylation of alkylbenzenes with B2pin2. Even reports of Pd-catalyzed borylation from aryl halides/ triflates are few,67,68 and direct CdH bond activation methods requires more amount of Pd catalyst as well as requires multistep procedure to reach aryl boranes from aryl halide as precursor.

218

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

In 2009, Suginome introduced a Pd-catalyzed reaction of isoindolines with HB(pin) that affords dehydrogenation followed by CdH borylation to deliver 1-borylisoindoles (Scheme 53).69

Scheme 53 Pd-catalyzed borylation reaction of isoindolines.

Yu reported a Pd-catalyzed oxidative ortho-borylation of N-arylbenzamides with a B2pin2 via a Pd(II)/Pd(0) catalytic cycle (Scheme 54).70 They developed an efficient directing group –CONHAr [Ar ¼ (4-CF3)C6F4] to produce selective ortho-borylation. A series of ligand screening revealed the crucial requirement of electron deficient dibenzylideneacetone (dba) ligand to increase the yield of the borylated product.

Scheme 54 Pd-catalyzed oxidative ortho-borylation of N-arylbenzamides.

A similar strategy when applied to benzanilides was found to give tetra-coordinated boron containing product, having an extra BdO bond with a fused ring formation.71 Shi introduced a method for unactivated primary C(sp3)dH bond activation followed by borylation based on a Pd0/PdII catalytic system (Scheme 55).72 A directing group assisted distal CdH bond activation has been adopted by the authors which led to g-borylated amino acid derivatives. The ligand iPr2S only is used to prevent the precipitation the Pd species and is not involved in the catalytic cycle. An alkaline environment is maintained to ensure the stability of CdB bond.

Scheme 55 Pd-catalyzed borylation of g-C(sp3)dH bonds.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

219

Right after this study Yu invented a protocol to activate the primary b-C(sp3)dH bond in carboxylic acid derivatives and secondary C(sp3)dH bonds in carbocyclic rings (Scheme 56).73 Thus from cyclopropane to cycloheptane acid derivatives can be borylated at the b-position. Use of pyridine or quinolone-based ligands found to give good results for this borylation reaction.

Scheme 56 Pd-catalyzed borylation of b-C(sp3)dH bonds.

An asymmetric version of this reaction was achieved by modifying the ligand system from monodentate quoinoline to bidentate and chiral acetyl protected aminoethyl quinoline (APAQ)74 right after their invention for enantioselective arylation reaction (Scheme 57).75

Scheme 57 Pd-catalyzed asymmetric borylation of b-C(sp3)dH bonds.

In 2015, Gong developed a Pd-catalyzed carbonyl allylation with simple olefins, which act directly as allylating reagents. The process involves a Pd(0)-catalyzed allylic CdH borylation first then allylic CdH activation reaction with aldehydes to generate homoallylic alcohols diastereoselectively, which could be accelerated by phosphoric acid.76 A similar allylic borylation of olefins was demonstrated by Szabo and Marder by using Pd-pincer complexes.77

12.06.2.4 Other metal catalyzed CdH borylation In 2016, Chirik demonstrated the use of CodPNP complex to deliver selective CdH borylation of heteroarenes such as furan, pyridine as well as simple arenes.78a In 2019, Chirik group showed a C(sp2)dH borylation of fluorinated arenes with B2Pin2, catalyzed by bis(phosphino)pyridine (iPrPNP) cobalt complexes.78b A strong ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal− carbon bonds, guided the total selectivity of borylation reaction for substituted fluoro-benzenes (Scheme 58).

220

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 58 Co-catalyzed borylation of heterocycles with PNP ligands.

a-Borylations of naphthalene-based aromatic compounds were developed by Kamei using a Ni-catalyst without directing groups.79 A N-heterocyclic carbene based Ni(II) complex found to promote C(sp2)dH borylation of arenes.80

12.06.3 Metal-catalyzed C-X (X ¼ cl, Br, I) bond formation 12.06.3.1 Pd-catalyzed CdH halogenation CdH halogenation reactions are very important in organic synthesis for their wide application as precursors of various feedstock materials. This section of the chapter discusses the transformation of CdH bonds to C-X (Cl, Br, I) bonds through CdH activation, mostly catalyzed by d block metal catalysts. This review covers the results that have been reported after 2005 and most of the directed pathways. While the C-X (Cl, Br, I) bond are easy to avail, to achieve CdF bond is difficult due to the absence of polarization required for reductive elimination. Sanford reported a general oxidative fluorination at Pd (II) center using electrophilic fluorinating agent, unlike established methods that used nucleophilic fluorinating agents (Scheme 59).81 They discovered N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate to be a highly effective F+ source upon microwave irradiation to yield benzylic CdF bond formation of 8-methylquinoline derivatives could be achieved with ortho-fluorination of 2-phenyl pyridines (F+ source ¼ 1-(chloromethyl)-4fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate).

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

221

Scheme 59 Palladium-catalyzed fluorination of 8-methylquinolines and 2-phenyl pyridines.

Following this work, Sanford reported another Pd-catalyzed ortho-halogenation of arenes with selectivity using NXS (X ¼ Cl, Br, I) as a halogenating agent (Scheme 60).82 While screening the halogenating agent, they found PhICl2 is behaving as a hyperactive chlorinating agent that in absence of Pd salt afforded a substrate controlled chlorinated product. It was found that meta-substituted arenes gave higher regioselectivity at the less hindered site over the substrates with no substitution. Not only aromatic C(sp2)dH bonds, terminal alkenes were convertible to halogenated alkenes under special condition. Other substrates like pyrrolidinones, keto-oximes were well tolerated under the protocol.

Scheme 60 Palladium-catalyzed halogenation of 2-phenyl pyridines.

In 2006, Shi showed a Pd-catalyzed ortho-halogenation of N-acetanilides, where the acetyl group served the purpose of directing the metal at the ortho-position to activate the corresponding CdH bond via insertion (Scheme 61).83 CuCl2 acted as the chlorinating reagent in toluene solvent to facilitate a CdCl reductive elimination. The major challenges remain during the chlorination of acetanilide is the competitive formation of para-chloroacetanilide as a result of Friedel-Crafts addition.82 The problem was solved in the presence of Pd-catalyst with increased electrophilicity. They mentioned the possibility of a catalytic pathway that may go through a Pd(IV) intermediate that reductively eliminates to afford the final product, although a mechanism involving Pd(0)dPd(II) catalytic cycle is equally probable in presence of Cu salts.

Scheme 61 Palladium-catalyzed ortho-chlorination of acetanilides.

In 2008, the Yu group reported the ortho-iodination of sodium and potassium carboxylates using catalytic Pd(OAc)2 and 1equiv. IOAc, (Sua’rez-type reagents) generated in situ from I2 and PhI(OAc)2, 1 equiv. each in DCE for 2 h at 80  C (Scheme 62).84 They

222

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

employed ammonium cations to get an exclusive mono-selectivity. During extensive screening of these salts, 1.5 equiv. Bu4NBr was found to improve the selectivity for mono-bromination product. The in situ generated IOAc reacts with Bu4NBr to form the known brominating reagent IBr,85 which could brominate the aryl palladium intermediate to give the brominated product and PdI2. These Pd(II)dI species are less unreactive towards further CdH activation, and thus selectively released the mono-halogenated derivatives of benzoic acid salts.

Scheme 62 Palladium-catalyzed ortho-iodination of benzoic acids with IOAc.

In 2009, the Dong group showed a Pd-catalyzed ortho-chlorination reaction of 2-phenyl pyridines with arylsulfonyl chlorides, in presence of catalytic Pd(CH3CN)2Cl2 and CuCl2 in DMF (Scheme 63).86 However in absence of 10 mol% Cu-salt these arylsulfonyl chlorides produced the corresponding ortho-sulfonyl variants.

Scheme 63 Palladium-catalyzed ortho-chlorination of 2-phenyl pyridines with arylsulfonyl chlorides.

In the same year Kakiuchi reported the ortho-chlorination of benzo[h]quinoline utilizing an electrochemical pathway (Scheme 64).87 They performed the reaction using 2 mol% PdCl2 in DMF (anode) under ambient atmosphere, and 2 M HCl (10 mL) (cathode) in an H-type divided cell with two platinum electrodes and an anion-exchange membrane at 90  C using 20 mA current. The HCl also acted as the electrolytic medium. The protocol established was suitable for other directing groups as well, For example pyrimidine and pyridine.

Scheme 64 Palladium-catalyzed regioselective chlorination of arenes by means of electrochemical oxidation.

In 2010, Xu reported a highly mono-selective Pd-catalyzed direct ortho-C-H halogenation of arylpyrimidines using commonly available calcium halides as halogenating agents and cupric trifluoroacetate as oxidant in the presence of air (Scheme 65).88 The pyrimidine directed the Pd to activate the ortho-C-H bond selectively. The protocol showed a good tolerance of substituents on the aryl ring for a good range of electron donating to electron withdrawing groups.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

223

Scheme 65 Palladium-catalyzed regioselective halogenation using calcium halides.

Bedford used 5 mol% of Pd(OAc)2 to deliver 2-brominated anilide in 95% yield with no para-bromo by-product in presence of N-bromosuccinimide (NBS) and 0.5 equivalents of PTSA additive at room temperature in toluene.89 While studying the mechanism, they isolated an unique Pd(I)dPd(II) organometallic p-arene complex, which demonstrated the potential role of CdH activation from Pd(I) (Scheme 66).

Scheme 66 Pd(I)dPd(II) organometallic p-arene complex.

In 2013, Punniyamurthy used a different directing group to serve similar Pd(II)-catalyzed ortho-selective halogenation of the N-aryl ring of N,1-diaryl-1H-tetrazol-5-amine using NBS as the brominating agent (Scheme 67).90 They assumed oxidative addition of NXS to the CdH activated Pd(II) complex to yield a Pd(IV) intermediate. Addition of trifluoromethyl sulfonic acid as an additive increased the yield of the brominated product, probably due to increased electrophilicity of Pd(II)-OTf vs Pd(II)-OAc favoring the CdH activation process.

Scheme 67 Pd(II)-catalyzed directed ortho-selective halogenation.

224

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

A catalytic (10 mol% Pd(OAc)2) room-temperature halogenation of N-tosylbenzamides was reported in 2014 by the Fabis group91 utilizing the wide range of in situ generated XOCOCF3 (Sua’rez-type reagents, when X ¼ Cl, Br. I) (Scheme 68).

Scheme 68 Pd(II)-catalyzed directed ortho-selective halogenation of N-tosylbenzamides.

The use of planar chiral derivatives of [2.2]paracyclophane ligands are quite important as organocatalysts in asymmetric synthesis and also polymer chemistry.92 However protocols to obtain enantiopure ortho-functionalized [2.2]paracyclophanes are limited. The combination of 20 mol% Pd(OAc)2, 20 mol% AgTFA in presence of 1.2 equiv. NXS (X ¼ Br, I) in DCE solvent provided the desired ortho-halogenated product of O-methyloxime derivatives of [2.2]paracyclophane (Scheme 69).93

Scheme 69 Pd(II)-catalyzed ortho-halogenation of O-methyloxime derivatives of [2.2]paracyclophane.

In 2014, the Chen group showed ortho-halogenation reactions of N-benzyl picolinamides using a unified set of reaction conditions featuring the use of K(Na)XO3 (X ¼ Cl, Br. I) and K2S2O8 (Scheme 70).94 They realized the need of Pd-catalyzed ortho-directed activation as the SEAr bromination of a simple N-benzyl picolinamide under the NBS mediated conditions in TFA/ DCM predominantly gave the nondirected bromination product. K(Na)XO3/K2S2O8-mediated halogenation reactions likely share a PdII/IV catalytic cycle.

Scheme 70 Pd(II)-catalyzed ortho-halogenation of N-benzyl picolinamide.

A similar picolinmide directed Pd-catalyzed halogenation of a-phenylglycine with NXS was reported to give di-halo substituted a-phenylglycines.95 Reports are available phenylglycinol substrates with similar picolinamide directing group to halogenate ortho/ gamma position of the arene96 with NXS (X ¼ I, Br) (Scheme 71).

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

225

Scheme 71 Pd-catalyzed directed dihalogenation.

Similar application of K2S2O8 oxidant was crucial for a Pd-catalyzed ortho-chlorination of aromatic ketones using NCS as the chlorine source (Scheme 72).97

Scheme 72 Pd-catalyzed ortho-chlorination of aromatic ketones.

In 2015, Purohit and co-workers showed that the [Pd(NHC)Cl2] complex of vitamin B1 furnishes a Pd(II)-catalyzed regioselective ortho-C–H chlorination/bromination of 1-aryl-3-methyl-1H-pyrazol-(4H)-ones via CdH bond activation in presence of NXS (X ¼ Cl,Br) and Ag2O as a terminal oxidant (Scheme 73).98 Control reactions without the catalyst led to mixture of ortho- and para-products proving the role of catalyst in controlling the selectivity.

Scheme 73 Pd-catalyzed ortho-halogenation using NHC adduct.

A Pd-catalyzed ortho-halogenation of mono-ortho substituted 2-arylbenzothiazole were reported by Patel and co-workers using NXS as the halogenating agent.99 Benzothiazole and quinoxaline group were used as an ortho-directing group through a PddN coordination in this case. The use of 0.5 equiv. PTSA was found to be beneficial for increased yield of the halogenated product. A similar study has shown by Moghaddam in case of N-arylcarbamates to furnish ortho halogenation in presence of similar reaction condition (Scheme 74).100

226

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 74 Pd-catalyzed ortho-halogenation of N-arylcarbamates.

A variety of directing groups were employed by Kapur to get various important halogenated feedstock chemicals.101 They have furnished ortho-halogenation of benzyl nitriles, aryl Weinreb amides, and anilides using a Pd-catalyzed transformation with NXS as the halogen source (Scheme 75).

Scheme 75 Halogenation of arenes with different directing group.

NXS being a versatile halogenating agent furnished a successful Pd-catalyzed ortho-halogenation of benzoxazinone, quinazolinone,102 and pyridazinedione103 reported by Dabiri (Scheme 76).

Scheme 76 Pd-catalyzed ortho-halogenation of benzoxazinone, quinazolinone.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

227

On a different note, Hierso and coworkers reported an unique di-aryltetrazine undergoing mono selective ortho-halogenation using 10 mol% [PdCl2] in HOAc at 120  C to afford the mono-halogenated tetrazine with 92% selectivity (X ¼ Cl) (Scheme 77).104 Excess equivalents of NXS were found to give tetra-halogenated tetrazine molecule. The reaction of tetrazines and 1 equiv. of N-fluorobenzenesulfonimide (NFSI) was conducted in nitromethane at 110 οC, using 10 mol% of [Pd(dba)2] over the span of 17 h. The monofluorinated product was isolated in 30% yield.

Scheme 77 Mono-selective ortho-halogenation of di-aryltetrazine.

In 2019, the Cai group reported an approach to prepare meta-nitrohalobenzenes via Pd-catalyzed ortho-halogenation using carboxylic acids as a traceless directing group with abundant NaX (X ¼ I, Br) under aerobic conditions (Scheme 78).105 K3PO4 (0.5 equiv.) as well as Bi(NO3)3
5H2O (2equiv.) were used as additives to deliver desired meta-nitroiodobenzene under oxygen atmosphere to regenerate the PdII/IV cycle. The use of Cu2O (1 equiv.) was essential for the decarboxylation of the benzoic acid derivative.

Scheme 78 Pd-catalyzed ortho-halogenation using carboxylic acids as traceless directing group.

Arene moieties like indolines and tetrahydroquinolines can be functionalized at C7 and C8 position respectively using pyrimidine as the DG, as shown by the Koley group (Scheme 79).106 They have established a Pd-catalyzed chlorination using NCS and bromination with N-bromopyrrolidinone. The use of stoichiometric CuO was beneficial for the protocol and supposed to furnish the inhibited SEAr reactions.

Scheme 79 Pd-catalyzed halogenation of indolines and tetrahydroquinolines.

228

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

In the same year, Li and Zhu reported the first use of a salen-based hyper-crosslinked polymer-supported Pd catalyst to carry out CdH halogenation (bromination and chlorination) (Scheme 80).107

Scheme 80 CdH halogenation catalyzed by poly-salen-Pd.

Very recently the Liu and Tong groups showed an asymmetric carbohalogenation of terminal alkenes via a general strategy that employs [Et3NH]+[BF4]− as an H-bond donor under a toluene/water/(CH2OH)2 biphasic system to efficiently promote C(sp3) dhalogen reductive elimination at low temperature (Scheme 81).108 An intramolecular halogen transfer is showed to be feasible under this protocol. As known to literature, C(sp3)dhalogen reductive elimination is an energy demanding process. The use of [Et3NH]+[BF4]− salt minimizes this energy barrier via H-boding interaction to facilitate the heterolytic dissociation of halogendPdIIdC(sp3) bonds.

Scheme 81 Hydrogen bonding assisted C-X reductive elimination.

12.06.3.2 Rh-catalyzed CdH halogenation In 2013, the Glorius group showed the very first instance of C-X bond formation using NXS halogen source in the presence of a [RhCp Cl2]2 catalyst and AgSbF6 oxidant with PivOH additive.109 The utility of the protocol over other Pd-catalyzed methods was its vast application with various directing group and functional group tolerance. A substituent-temperature correlation has been shown in the case of the bromination of benzamide derivatives and iodination of various directing group attached substrates. The method was compatible with variety of electron-rich and electron-poor groups such as ester, chloro, or methoxy substituents but also with other classes of arenes, such as secondary benzamides, acetamides, and phenylpyridines (Scheme 82).

Scheme 82 CdH halogenation catalyzed by [RhCp Cl2]2.

Following the previous report, a Rh(III)-catalyzed halogenation of vinylic CdH bonds was reported by Glorius group to deliver regioselective and stereoselective Z-haloacrylic acid derivatives.110 A combination of [RhCp Cl2]2 catalyst and AgSbF6 oxidant with PivOH additive produced a Z-selective iodination of amide-directed olefin derivatives with some percentage of di-halogenated products.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

229

From the vinylic CdH bond activation, the similar Rh catalyst and AgSbF6 combination furnished a successful orthohalogenation of 2-arylbenzo[d]thiazoles using NXS, (X ¼ Br and I) as halogen sources.111 The reaction mechanism was believed to proceed through the formation of active intermediate RhCp (SbF6)2 in presence of AgSbF6, which undergoes CdH activation via formation of an ortho-rhodacycle followed by the oxidative addition of NXS. Finally the formation of C-X bond occurs via reductive elimination. The [RhCp Cl2]2 catalyst was even effective to functionalize C8 position of quinoline N-oxides using the similar methodology (Scheme 83).112

Scheme 83 Rh-catalyzed ortho-halogenation of 2-arylbenzo[d]thiazoles.

In 2018, Xu and Pan demonstrated a regioselective method for the Rh-catalyzed direct CdH ortho-halogenation of anilines that involves a removable N-nitroso directing group (Scheme 84).113 However, they showed a solvent dependent selectivity to get the desired product at 30 οC. While tertiary butanol showed a high selectivity towards ortho-halogenated product, solvent system like DCE or MeOH provided para-functionalized product.

Scheme 84 Rh-catalyzed ortho-halogenation of anilines with N-nitroso directing group.

12.06.3.3 Cu-catalyzed CdH halogenation While Pd-catalyzed CdH activation is important due to its versatility, Cu is also noteworthy as one of the cheaper options. In 2006, the Yu group serendipitously discovered the ortho-chlorination of 2-phenyl pyridines having DCE as the chlorine source with 92% isolated yields, while doing a during a Cu(OAc)2 catalyzed acetoxylation reaction.114 It was believed that dichloroethylene was partially converted to Cl2C]CHCl and HCl that provided the Cl− anion source They reported 20 mol% of CuCl2 to be the best catalyst for the purpose. Interestingly, Daugulis reported a successful fluorination of b-sp2 CdH bonds of benzoic acid derivatives and g-sp2 CdH bonds of a,a-disubstituted benzylamine derivatives utilizing CuI as catalyst, AgF as fluoride source, and DMF, pyridine, or DMPU solvent at moderately elevated temperatures (Scheme 85).115 They postulated that reaction was proceeding through unusual Cu(III) intermediates, indicating that CdF reductive elimination from Cu(III) is possible given that aminoquinoline amides stabilize high oxidation states in transition metals.

Scheme 85 Cu-catalyzed fluorination of b-sp2 CdH bonds of benzoic acid.

230

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

In addition to this, Carretero introduced N-sulfonyl pyridine as a removable directing group scaffold that was able to direct CuCl2 catalyzed ortho-halogenation reaction using NXS as the halogen source, showing a good functional group tolerance.116 In 2013, Shen and co-workers reported a Cu-catalyzed protocol for the preparation of chloro- and bromoarenes via CdH bond activation. A good combination of 20 mol% Cu(NO3)2
3H2O, LiX (halogen source) and oxygen as the oxidant promoted the di-halogenation of 2-phenyl pyridine derivatives with very little mono-halogenated product.117 Switching the directing group or substrate to more rigid systems like quinolines or benzoquinone respectively delivered mono-halogenated product exclusively (Scheme 86). A good functional group tolerance has been shown in this report. Methods using 1 equiv. of CuX, 2 equiv. of NXS with acetic acid additive in MeCN solvent was also effective to limit the di-halogenation.118 The Han group reported this Cu-catalyzed method using 2-phenyl pyridines as the substrate. NXS is a versatile halogen source: Lianxun and Yingjie.reported that 5 mol% CuBF4(CH3CN)4 and 50 mol% benzoic acid catalyzed the ortho-halogenation of 2-phenyl pyridines with moderate mono:di selectivity.119

Scheme 86 Directing group dependent selectivity in Cu-catalyzed halogenation.

Another Copper-catalyzed ortho-halogenation of C(sp2)dH bonds has been achieved by a PIP directing group with NXS (X ¼ Cl, Br, I). The Shi group showed Zn(OAc)2 as an additive may play a role in activating the NBS reagent as a Lewis acid (Scheme 87).120

Scheme 87 PIP directed Cu-catalyzed ortho-halogenation of C(sp2)dH bonds.

Unlike the previous reports, Baidya reported an efficient Cu-catalyzed direct iodination and bromination of quinolines with a high selectivity at the C5-position based on chelation-assisted remote CdH bond functionalization (Scheme 88).121 The iodination was favored at the para-position of the amide unit which is a direct evidence of substrate controlling selectivity in this case. They employed Cu(OTf )2 (10 mol%), NXS (2 equiv.), Ag2CO3 (1 equiv.), and KI (30 mol%) for the reaction where Ag2CO3 was possibly acting as a base instead of an oxidant. Bao modified the condition by replacing the halogen source with stoichiometric KX and catalytic CuX2 catalyst and obviated the need of silver salt.122 An interesting result of b-halogenation of a-methylquinolines has been implemented by Chen using CuX and I2 as the halogenation source under different conditions.123

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

231

Scheme 88 Cu-catalyzed direct C5 halogenation of quinolines.

12.06.3.4 Other metal catalyzed CdH halogenation Along with Cu, CdH halogenation reactions were performed with other first row transition metals like Co and Ni. In 2014, the Glorius group demonstrated the first Co-catalyzed CdH halogenation reaction (Scheme 89).124 They performed selective ortho-iodination and bromination of arene derivatives with a pivalic acid DG as well as for N-alkylbenzamides to olefins using N-bromophthalimide (NBP) and NIS through Cp Co(III) catalyzed intermolecular formal SN-type reactions.

Scheme 89 Cp Co(III) catalyzed intermolecular formal SN-type reactions.

Following by this result, Cobalt-catalyzed CdH halogenation of biologically important 6-arylpurines was reported by Pawar under mild conditions with good functional group tolerance (Scheme 90).125

Scheme 90 Co-catalyzed CdH halogenation of biologically important 6-arylpurines.

In 2016, the Shi group showed the first example of Ni-catalyzed halogenation of (hetero)aryl CdH bonds with LiX, (X ¼ Br, I, Cl) using PIP as a removable directing group.126 They employed Ni(OTf )2 catalyst (10 mol%), THP (tetrahydropyrane) ligand (20 mol %), LiX (3 equiv.) as halogen source and KMnO4 oxidant in t-BuCN solvent at O2 atmosphere at 140 οC for a successful halogenation reaction. Reports with other metals as Mn127 and Fe128 are reported in the literature, but mostly via a radical mechanism, hence beyond the scope of this review.

232

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

12.06.4 Metal-catalyzed CdO bond formation 12.06.4.1 Pd-catalyzed CdH oxygenation 12.06.4.1.1

Pd-catalyzed CdH acetoxylation

Among the vast area of C-E bond formation, the occurrence of CdO bonds are diverse among the natural moieties, pharmaceuticals,129 agrochemicals.130 To mimic nature’s protocol organic chemists are continuously sketching out new methods to form CdO bond via metal-catalyzed CdH bond oxidation along with trapping molecular oxygen.131,132 Vast reports are available where PhI(OAc)2 is showed as the acetoxylating agent.133–135 Sanford group introduced peroxide based oxidant (Oxone and/or K2S2O8) in AcOH/Ac2O for ortho-acetoxylation of oxime ethers (Scheme 91).136 This oxime unit acts as the directing group in the system that first coordinates with the metal to activate the proximally available CdH bonds. They showed a solvent dependent alkoxylation of arene derivatives.

Scheme 91 Oxime-ethers to direct ortho-alkoxylation of C(sp2)dH bonds.

One of such example of ortho-directed acetoxylation of acetanilides was shown by Wang using acetic acid as the acetate source and K2S2O8 as the oxidant. The mechanism goes through a predictable fashion, where the acetanilide oxygen first get coordinated with the Pd(II) to form a chelate and thereby activating the ortho-C-H bond (Scheme 92).137 The resulting Pd(II) intermediate was oxidized by K2S2O8 in the presence of acetic acid to afford a hexacoordinated Pd(IV) intermediate, which then after reductive elimination released the acetoxylated product.

Scheme 92 Possible mechanism of Pd-catalyzed acetoxylation of acetanilides.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

233

In the same year, the Yu group explored a Pd-catalyzed oxazoline directed oxidation of unactivated methyl units using the peroxyester MeCOOOtBu as the stoichiometric oxidant and Ac2O as a promoter (Scheme 93).138 They next developed the diastereoselective oxidation of methyl groups using a chiral oxazoline, however, benzoyl or lauroyl peroxide were needed as the oxidant to get the diastereoselectivity up to 82%. Later they employed a similar protocol to avail the ortho-C-H acetoxylation of triflate protected phenethyl- and phenpropylamines with the same peroxyester.139

Scheme 93 Peroxyester-promoted Pd-catalyzed CdH oxidation directed by oxazolines.

The report of Pd-catalyzed regioselective acetoxylation are plenty. In 2007 Larock showed an 1,4dPd migration mechanism where the observed a conversion of aryl halides (1-bromo-8-methylnaphthalene) in to corresponding benzylic ester in presence of a base and Pd(OAc)2 catalyst (Scheme 94).140 Interestingly, reaction yield was very much sensitive on the reaction time and found to be the best with 6 h and diminished yield with increased reaction time.

Scheme 94 Regioselective acetoxylation of methylnaphthalene derivatives via 1,4dPd migration mechanism.

The dependence upon directing group to overcome the intrinsic electronic biases of a substrate is noteworthy. The Sanford group investigated a nice comparison of directing groups to show the relative rates of ortho-acetoxylation among them using catalytic Pd(OAc)2 and stoichiometric PhI(OAc)2 in polar protic AcOH, AcOH/Ac2O and nonpolar, non-protic benzene solvent systems (Scheme 95).141

234

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 95 Relative rates upon changing the directing group for ortho-acetoxylation of benzene.

Along this line, Xu and colleagues reported a modified reaction protocol to reduce the formation of di-acetoxylated products by employing 10 mol% Cu(OTFA)2 (Scheme 96).142

Scheme 96 Pd-catalyzed ortho-acetoxylation of 2-phenyl pyridines.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

235

Reports with TBHP as the oxidant is known in the literature when Pd-catalyzed hydroxylation was attempted on 2-phenyl pyridine derivatives.143 Contemporarily, through a mechanistic investigation Ritter showed a bimetallic Pd(II) complex of 10-chlorobenzo[h]quinolone could undergo simultaneous bimetallic oxidation in the presence of XeF2 and TMSOAc and subsequent bimetallic reductive elimination from the Pd(III)-complex to produce 10-acetoxybenzo[h]quinolone (Scheme 97).144

Scheme 97 Bimetallic Pd(II) complex to deliver regioselective acetoxylation through a bimetallic Pd(III) complex.

A similar Pd-dinuclear complex was efficient to achieve hydroxylation which is discussed later. In another example, Stahl and the group explored a new bidentate ligand 4,5-diazafluorenone (DAF) as an ancillary ligand to facilitate CdO bond formation from p-allyl-Pd(II) species (Scheme 98).145 Here the importance of benzoquinone (BQ) is shown to be essential as it can promote nucleophilic attack by acetate on a p-allyl-Pd(II) species followed by displacement of the allylic acetate product from Pd(0) to furnish reversible CdO bond formation, before final the regeneration of Pd(II).

Scheme 98 Pd-catalyzed allylic acetoxylation of CdH bonds.

Kwong explored indoles as the substrates to deliver a C3-oxygenation using catalytic Pd(OAc)2 and PhI(OAc)2 as the oxygen source.146 Shi and colleagues came up with a method for the direct ortho acyloxylation of aromatic CdH bonds of aryl oxime ethers with various carboxylic acids as the oxygen source. The use of stoichiometric PhI(OAc)2 was believed to serve as an oxidant (Scheme 99).147

Scheme 99 Pd-catalyzed ortho-acetoxylation of oxime ethers using carboxylic acid as the oxygen source.

Liu applied this method to benzene derivatives to promote non-directed CdO bond formation.148 Pd-catalyzed CdH acetoxylation reactions of 2-methoxyimino-2-aryl-acetates and acetamides were developed by Xiao in the year 2011.149 Mancheno and colleagues designed a modifiable sulfur derived directing group strategy to test the model regioselective ortho-acetoxylation and compared their rate of reactivity (Scheme 100).150 Where a higher stoichiometric amount of K2S2O8 make the sulfonyls working under the protocol.

236

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 100 Sulfonyl pyridine as the directing group for ortho-acetoxylation.

He presented a similar C-H-acetoxylation using a 2-pyridyloxy directing group to introduce a flexible chelation assisted CdH activation (Scheme 101).151

Scheme 101 Pyridyloxy directing group to deliver ortho-acetoxylation.

A subsequent study including the protection of acid groups with suitable directing group inhibited the formation of lactones but promoted selective ortho-acetoxylation of phenylacetic acids derivatives using oxone as the oxygen source (Scheme 102).152

Scheme 102 Pd-catalyzed ortho-acetoxylation of sulfimide protected phenyl acetic acids.

To overcome the dependence over the directing groups, Sanford and the group strategizes to activate benzene using a ligand promoted activation. They explored pyridine as a ligand for the Pd(II/IV)-catalyzed CdH acetoxylation of benzene with PhI(OAc)2. However the reaction with preformed [(pyr)2Pd(OAc)2] catalyst resulted in very poor yield of desired product under similar reaction condition hence inefficient. Electron deficient substrates like halo-benzenes mostly gave mono-acetoxylated product whereas ortho-dihalobenzenes yielded a:b 41:59 to 29:71 upon moving from Pd(OAc)2 to Pd(OAc)2/pyr (1:0.9) as the catalyst (Scheme 103).148

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

237

Scheme 103 Site selectivity of CdH acetoxylation as a function of catalyst and oxidant.

A follow up report showed that the combination of a sterically hindered oxygen source and catalytic acridine as the ligand gives rise to a different regio-isomer when acetoxylation was attempted with substituted nitrobenzenes (Scheme 104).153 Various other substituted benzenes underwent this protocol to give rise to selective acetoxylation through CdH activation.

Scheme 104 Ligand controlled regioselectivity in the presence of a sterically hindered oxygen source.

A single reaction is available where a S,O-ligand promoted the Pd-catalyzed nondirected acetoxylation of benzene (Scheme 105).154 However a modified application of nondirected acetoxylation of arenes using substituted picolinic acid has more scope towards its applicability and functional group tolerance.155

Scheme 105 Pd-catalyzed ligand assisted non-directed acetoxylation of benzene.

In 2013, Vedernikov reported oxidative CdH acetoxylation of 8-methylquinoline as a model substrate with O2 as oxidant from pre-derived Pd(II)-carboxylate catalysts. A comparative study among the catalysts is the topic of interest of this study (Scheme 106).156 The rate limiting trend is found to be dependent on the chelate ring size and the chelate ring strain of the catalytically active species.

238

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 106 Rate-limiting trend C(sp3)dH activation at Pd(II) center.

In 2014, an allylic CdH acetoxylation of N-heterocycle containing aryl-allyl motifs was demonstrated by Malik and colleagues in the presence of a Lewis acid counterpart to inhibit the side reactions occurring at the heterocycle site. Here oxidant carries out a nucleophilic attack on the Pd-p-allylic center. Proper tuning of the reaction conditions showed the regio-selective CdO bond formation to yield either linear or branched oxidation products. (Scheme 107).157

Scheme 107 Tuning between acetoxylation of internal or terminal CdH bonds.

As discussed in the earlier, the directed proximal CdO bond formation reports are many. Examples are available directing groups like oxobenzoxazine,158 2-aminopyrimidine,159 isoxazole,160 4,6-dimethoxy-1,3,5-triazin-2-yloxy161 carboxybenzyl group for benzyl amine 162 (Scheme 108). Transient directing groups like electron-deficient anthranilic acid for the ortho-hydroxylation of benzaldehyde derivatives using pTSA as the O-source.163

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

239

Scheme 108 Application of different directing groups.

Moving from proximal to further positions of arene system to get selective functionalization is difficult. The directing group strategy enables one to achieve site-selectivity. Various reports are established in this regard to understand the fine tuning of distance-geometry correlation within directing groups.164 In 2016, Maiti and colleagues represented a meta-selective CdO bond formation for benzylic derivatives (Scheme 109).165 They designed a perfect anchor that can direct the metal at the meta-position to activate the particular CdH bond in excess. A combination of catalytic Pd(OAc)2 with N-tert-butyloxycarbonyl-alanine ligand was optimal. While a judicial choice of PhI(TFA)2 was used for hydroxylation, PhI(OAc)2 resulted in successful acetoxylated product. The reaction takes place through a 12–13 membered transition state, stabilization of which during CdH activation is important. Mono-protected amino acid (MPAA) ligands help to stabilize the transition state by chelation as well as act as an internal base in the system to abstract the targeted H.

Scheme 109 Pd-catalyzed directed meta-acetoxylation of benzylic derivatives.

240

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

A different phosphonyl linked directed meta-hydroxylation and acetoxylation was reported by the same group for benzylic derivatives, highlighting the use of different MPAA ligands in each cases.166 In the same year, the Li group developed a meta-selective directing group to functionalize benzoic acid derivatives (Scheme 110),167 capitalizing as the similar strategy as Maiti.

Scheme 110 Pd-catalyzed directed meta-acetoxylation of benzoic acid derivatives.

Reaching out to the furthest position by designing a perfect para-directing group was first developed by the Maiti group.168 The reaction proceeds through a 17–18 membered transition state. The same methodology was applied by Yu to deliver successful paraacetoxylation. They enabled highly selective para-CdH acetoxylation of benzoic acid derivatives using a nitrile-based directing group to deliver the para-acetoxylated product (Scheme 111).169 The removal of the directing group leads to the para-hydroxy benzoic acid derivatives.

Scheme 111 Pd-catalyzed directed para-acetoxylation of benzoic acid derivatives.

In another example, a directing group installed a-selective hydroxylation of amide molecules was shown with similar key steps, however the ring size of transition state having organometallic connections is smaller in this case hence favorable (Scheme 112).170

Scheme 112 Directed a-hydroxylation of aliphatic acids.

In 2017 Shi reported g-selective CdO bond formation for free primary amines to release g-amino alcohols (Scheme 113).53

Scheme 113 Aliphatic CdH acetoxylation of functionalized primary amines.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation 12.06.4.1.2

241

Pd-catalyzed CdH hydroxylation

In 2009, Yu and the group explored molecular O2 as the oxygen source for the regioselective Pd-catalyzed ortho-hydroxylation of potassium benzoate salts to produce salicylic acids, which are important in securing the importance of them in the naturally occurring drugs. The protocol showed an excellent tolerance towards a good range of substituents from electron rich to electron withdrawing heterocycle systems (Scheme 114).171 However, 1-naphthoic acid was found to give decarboxylated naphthol as product. Recently, an extended modification to this work shows a well-designed ligand (Scheme 114) can diversify the application of the protocol. The method was superior to convert N-heterocyclic carboxylic acid to their corresponding hydroxylated analogs selectively at the ortho-position to carboxylic unit.172

Scheme 114 ortho-Hydroxylation of benzoic acid derivatives and its modified ligand enabled application for heterocycles.

The Ritter group developed a modified dinuclear Pd(II) catalyst to serve the a-hydroxylation of ketones to form tertiary alcohols by trapping molecular oxygen.(Scheme 115).173 The proposed mechanism suggests that the catalyst behaves as a dioxygenase and transfers oxygen from O2 for selective hydroxylation of ketones through bimetallic Pd(III) catalysis.

Scheme 115 Bimetallic Pd(II) complex to deliver a-hydroxylation of ketones.

242

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

In another report Jiao explained a ligand promoted Pd-catalyzed CdH hydroxylation of O-methyl oxime ethers using oxone as the oxidant (Scheme 116).174 The reaction believed to proceed through Pd(II)/ Pd(IV) catalytic cycle.

Scheme 116 Ligand assisted oxone promoted hydroxylation of oxime.

A R2(O)P-directed Pd(II)-catalyzed CdH hydroxylation was shown by Yang175,176 to deliver various substituted 2 -phosphorylbiphenyl-2-ol compounds (Scheme 117). The typical protocol was extendable to heteroarene systems for selective CdH activation. 0

Scheme 117 Phosphoryl directing group to deliver ortho-hydroxylation.

In 2012, Dong and colleagues demonstrated the ortho-hydroxylation of directed by native ketones to produce ortho-acylphenols (Scheme 118).177 Rao demonstrated that use of TFA/TFAA as the hydroxylating source could functionalize similar substrates at room temperature.178

Scheme 118 Ketones as the directing group for the ortho-hydroxylation.

In 2015, Chakraborti showed an unprecedented role of 1,4-dioxane as source of hydroxyl radical in the presence of oxone for the proximal hydroxylation of arene rings having 2-benzoxazolyl directing groups.179 Guin and colleagues reported a strategy for ortho-hydroxylation of 2-phenyl pyridines in the presence of Pd(CH3CN)2Cl2 catalyst and oxygen as the sole oxidant. The use of n-butyraldehyde makes this protocol unique, wherein aerobic oxidation coverts it in to n-butyric acid and produces an active acyl peroxo-radical intermediate to transfer the hydroxyl unit to the Pd center (Scheme 119).180 A similar methodology has been applied for the hydroxylation of arenes with Pd(II)/O2 using sulfoximine as the removable directing group.181

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

243

Scheme 119 n-Butyraldehyde to produce an active hydroxyl transfer reagent in presence of molecular oxygen.

12.06.4.1.3

Pd-catalyzed CdH lactonization

Another report of oxygenation comes as one of the examples of lactonization via C(sp3)dH activation of benzoic acid derivatives (Scheme 120).182 The carboxylic acid group acts as a native directing group to anchor the metal for successful ortho-metallation, in this case benzylic. The reaction made use of mono-N-protected amino acid ligand with catalytic Pd(OAc)2 to inhibit the formation of decarboxylated side product. N-acetyl protected ligand were optimal in this case. The increase of steric hindrance and electron deficiency of the protecting groups was found to be detrimental for the protocol.

Scheme 120 Ligand enabled lactonization of benzoic acid derivatives.

Shi showed a typical extension of this work during the formation of benzolactones from phenylacetic acid derivatives via C(sp2)dH activation (Scheme 121).183 A ligand free traditional approach led to the desired product.

244

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

Scheme 121 Lactonization of phenyl acetic acid derivatives.

A Pd-catalyzed cascade reaction of 4-hydroxycoumarins via CdH bond activation/CdO and CdC bond formations enables the synthesis of Coumestans (Scheme 122).184

Scheme 122 Pd-catalyzed CdH bond activation followed by CdC bond formation.

Recently, Jana and colleagues reported a Pd(II)/bis-sulfoxide-catalyzed intramolecular allylic acetoxylation of allyl ether, amine, and amino acids that generates lactones via allylic oxidation (Scheme 123).185 The predicted mechanism undergoes a Pd complex with carboxylate moiety followed by chain walking of Pd from the allylic to the vinylic position by double-bond isomerization. A subsequent intramolecular carboxypalladation activates the allylic position of the desired product.

Scheme 123 Pd(II)/bis-sulfoxide-catalyzed intramolecular allylic acetoxylation.

12.06.4.2 Other metals catalyzed CdO bond formation Moving to the other metals, Cu is also well precedent in literature to establish new CdE bond formations. Also the application of cheaper catalysts with mild reaction conditions are synthetically preferable. Martin and colleagues developed a Cu(OAc)2 catalyzed protocol to generate fused benzolactones, which are pharmaceutically relevant (Scheme 124).186 The use of benzoyl peroxide oxidant was optimal for the successful reaction which proceeds through the rise of a square-planar or square-pyramidal Cu(III) benzoate, this benzyloxy radical gets decarboxylated to give rise to benzene radical, subsequently either of these radicals abstract one hydrogen from the CudH complex causes to the formation of intramolecular CdO bond formation.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

245

Scheme 124 Cu-catalyzed CdH acetoxylation of 2-phenyl benzoic acid derivatives.

In the same year Patel showed an efficient Cu(I)-catalyzed (CuBr) synthesis of 3-aroylindoles from o-alkynylated N,N-dimethylamines via a sp3 CdH bond activation a to the nitrogen atom followed by an intramolecular nucleophilic attack with the alkyne using an aqueous solution of TBHP as the oxidant. This tandem process involves a new CdC and CdO bond formation (Scheme 125).187

Scheme 125 Cu-catalyzed tandem CdC and CdO bond formation.

In the following year, the Shi and Yu groups independently showed the Cu(II) ortho-hydroxylation of benzoic acid derivatives. The directing group used in each case was different. While Shi generated the hydroxylated product after hydrolysis of an acetoxylated product, Yu showed molecular O2 as an oxidant essential for the hydroxylation.188,189 In another example, Yu reported the viability

246

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

of electron deficient directing groups which can promote proximal hydroxylation in a dual Cu(II)/Cu(I) catalytic system with oxaziline ligands showing a range of functional group tolerance (Scheme 126).190

Scheme 126 Dual Cu(II)/Cu(I) catalytic system for CdO bond formation.

In 2018, another study showed copper-mediated regioselective CdH activation and CdO bond formation of naphthylamides with arylboronic acids using water as an oxygen source (Scheme 127).191

Scheme 127 H2O as the oxygen source.

This type of Cu-mediated protocol is also successful for activating aliphatic systems to establish new CdO bonds.192 Like Cu, Co-catalysts have been found to be effective in CdO bond formation. Co(II)-catalyzed intramolecular CdO bond formation via cross dehydrogenative coupling (CDC) of acids and C(sp3)dH bonds was developed by Liu and coworkers with by using oxygen as the terminal oxidant. The reaction goes through a SET mechanism and not usual CdH activation.193 Radical cyclizations to give lactones via photoredox and cobalt co-catalyzed reactions have been developed.194 However, a typical Co-catalyzed CdH activation was reported by Deb and coworkers to promote directed ortho-acetoxylation of benzoic acid derivatives using Mn(OAc)3.2H2O as the acetate source (Scheme 128).195

Scheme 128 Co-catalyzed ortho-acetoxylation using Mn(OAc)3•2H2O as the acetate source.

Co(acac)2 196 and CoBr2 197 have been shown to be competent to promote acetoxylation and lactone synthesis respectively. In 2017, Deb and coworkers developed a Ag- and Cu-free ([Cp Rh(MeCN)3](SbF6)2) catalyzed C7 acetoxylation reaction of indoles at near ambient temperature employing PIDA as an acetoxy source (Scheme 129).198 A pyrimidine group worked as the directing group. A similar transformation was amenable using [Cp RhCl2]2 as catalyst.199

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation

247

Scheme 129 Rh-catalyzed C7 acetoxylation reaction of indoles.

12.06.5 Conclusion Herein this chapter a comprehensive study of transition metal catalyzed CdH activation has been discussed. The efficiency of the metal catalyst to selectively activate a particular CdH bond under a ligand or directing group assisted scenario has been described in the realm of CdE bond formation encompassing borylation, halogenation and oxygenation.

Acknowledgment UGC India supported the scholarship to N.G. IIT Bombay provided the infrastructure.

References 1. Seyferth, D. Organometallics 2009, 28, 1598–1605. 2. Wakefield, B. J. The Chemistry of Organolithium Compounds; p 321. 3. (a) Dunina, V. V.; Zalevskaya, O. A.; Potapov, V. M. Russ. Chem. Rev. 1988, 57, 250; (b) Ryabov, A. D. Chem. ReV. 1990, 90, 403; (c) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698; (d) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105, 2527. 4. Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III Science 2002, 295, 305. 5. Hata, H.; Shinokubo, H.; Osuka, A. J. Am. Chem. Soc. 2005, 127, 8264. 6. Hiroto, S.; Shinokubo, H.; Osuka, A. Angew. Chem. Int. Ed. 2005, 44, 6763. 7. Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263. 8. Liskey, C. W.; Wei, C. S.; Pahls, D. R.; Hartwig, J. F. Chem Commun. 2009, 5603. 9. Chotana, G. A.; Vanchura, B. A., II; Tse, M. K.; Staples, R. J.; Maleczka, R. E., Jr.; Smith, M. R., III Chem. Commun. 2009, 5731. 10. Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr.; Smith, M. R., III J. Am. Chem. Soc. 2006, 128, 15552. 11. Chotana, G. A.; Kallepalli, V. A.; Maleczka, R. E., Jr.; Smith, M. R., III Tetrahedron. Lett. 2008, 64, 6103. 12. Kleˇcka, M.; Pohl, R.; Klepetarova, B.; Hocek, M. Org. Biomol. Chem. 2009, 7, 866. 13. Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.; Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angew. Chem. Int. Ed. 2006, 45, 489. 14. Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am. Chem. Soc. 2009, 131, 5058. 15. Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068. 16. Wang, C.; Sperry, J. J. Org. Chem. 2012, 77, 2584. 17. Larsen, M. A.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4287. 18. Sadler, S. A.; Tajuddin, H.; Mkhalid, I. A. I.; Batsanov, A. S.; Albesa-Jove, D.; Cheung, M. S.; Maxwell, A. C.; Shukla, L.; Roberts, B.; Blakemore, D. C.; Lin, Z.; Marder, T. B.; Steel, P. G. Org. Biomol. Chem. 2014, 12, 7318. 19. Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III J. Am. Chem. Soc. 2013, 135, 7572.

248 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L. R.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 10160. Tajuddin, H.; Shukla, L.; Maxwell, A. C.; Marder, T. B.; Steel, P. G. Org. Lett. 2010, 12, 5700. Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 12422. Ohmura, T.; Torigoe, T.; Suginome, M. Chem. Commun. 2014, 50, 6333. Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 3375. Oeschger, R. J.; Larsen, M. A.; Bismuto, A.; Hartwig, J. F. J. Am. Chem. Soc. 2019, 141, 16479. Jones, M. R.; Fast, C. D.; Schley, N. D. J. Am. Chem. Soc. 2020, 142, 6488. Zhang, M.; Wu, H.; Yang, J.; Huang, G. ACS Catal. 2021, 11, 4833. Kawamorita, S.; Murakami, R.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2013, 135, 2947. Joliton, A.; Carreira, E. M. Org. Lett. 2013, 15, 51473. Wu, F.; Feng, Y.; Jones, C. W. ACS Catal. 2014, 4, 1365. Green, A. G.; Liu, P.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 4575. Maeda, K.; Uemura, Y.; Chun, W.-J.; Satter, S. S.; Nakajima, K.; Manaka, Y.; Motokura, K. ACS Catal. 2020, 10, 14552. Larsen, M. A.; Wilson, C. V.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 8633. Wang, G.; Xu, L.; Li, P. J. Am. Chem. Soc. 2015, 137, 8058. a) Press, L. P.; Kosanovich, A. J.; McCulloch, B. J.; Ozerov, O. V. J. Am. Chem. Soc. 2016, 138, 9487; b) Lee, C.-I.; Zhou, J.; Ozerov, O. V. J. Am. Chem. Soc. 2013, 135, 3560; c) Zhou, J.; Lee, C.-I.; Ozerov, O. V. ACS Catal. 2018, 8, 536. Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534. Cho, S. H.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 8157. Patel, C.; Abraham, V.; Sunoj, R. B. Organometallics 2017, 36, 151. Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B. Org. Lett. 2012, 14, 3558. Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Maleczka, R. E., Jr.; Smith, M. R., III J. Am. Chem. Soc. 2012, 134, 11350. Li, H. L.; Kuninobu, Y.; Kanai, M. Angew. Chem. Int. Ed. 2017, 56, 1495. Li, H. L.; Kanai, M.; Kuninobu, Y. Org. Lett. 2017, 19, 5944. Liu, L.; Wang, G.; Jiao, J.; Li, P. Org. Lett. 2017, 19, 6132. Jiao, J.; Nie, W.; Song, P.; Li, P. Org. Biomol. Chem. 2021, 19, 355. Hoque, M. E.; Hassan, M. M. M.; Chattopadhyay, B. J. Am. Chem. Soc. 2021, 143, 5022. Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. Nat. Chem. 2015, 7, 712. Lu, X.; Yoshigoe, Y.; Ida, H.; Nishi, M.; Kanai, M.; Kuninobu, Y. ACS Catal. 2019, 9, 1705. Yang, L.; Uemura, N.; Nakao, Y. J. Am. Chem. Soc. 2019, 141, 7972. Mihai, M. T.; Williams, B. D.; Phipps, R. J. J. Am. Chem. Soc. 2019, 141, 15477. Davis, H. J.; Genov, G. R.; Phipps, R. J. Angew. Chem. Int. Ed. 2017, 56, 13351. Bisht, R.; Chattopadhyay, B. J. Am. Chem. Soc. 2016, 138, 84. Saito, Y.; Segawa, Y.; Itami, K. J. Am. Chem. Soc. 2015, 137, 5193. Segawa, Y.; Itami, K.; Musaev, D. G. ACS Catal. 2016, 6, 7536. Zou, L.; Bai, R.; Lan, Y. Organometallics 2017, 36, 2107. Yang, L.; Semba, K.; Nakao, Y. Angew. Chem. Int. Ed. 2017, 56, 4853. Su, B.; Zhou, T.-G.; Xu, P.-L.; Shi, Z.-J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2017, 56, 7205. Zou, X.; Zhao, H.; Li, Y.; Gao, Q.; Ke, Z.; Xu, S. J. Am. Chem. Soc. 2019, 141, 5334. Shi, Y.; Gao, Q.; Xu, S. J. Am. Chem. Soc. 2019, 141, 10599. Reyes, R. L.; Iwai, T.; Maeda, S.; Sawamura, M. J. Am. Chem. Soc. 2019, 141, 6817. Song, P.; Hu, L.; Yu, T.; Jiao, J.; He, Y.; Xu, L.; Li, P. ACS Catal. 2021, 11, 7339. Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995. Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2011, 133, 19310. Kawamorita, S.; Miyazaki, T.; Iwai, T.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2012, 134, 12924. Reyes, R. L.; Sato, M.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2020, 142, 589. Miura, W.; Hirano, K.; Miura, M. Org. Lett. 2016, 18, 3742. Tatsuo, I.; Kousaku, I.; Jun, T.; Norio, M. Chem. Lett. 2001, 30, 1082. Billingsley, K.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 5359. Billingsley, K.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589. Ohmura, T.; Kijima, A.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 6070. Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2012, 134, 134. Xiao, B.; Li, Y.-M.; Liu, Z.-J.; Yang, H.-Y.; Fu, Y. Chem. Commun. 2012, 48, 4854. Zhang, L.-S.; Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen, K.; Shi, Z. J. Angew. Chem., Int. Ed. 2014, 53, 3899. He, J.; Jiang, H.; Takise, R.; Zhu, R.-Y.; Chen, G.; Dai, H.-X.; Dhar, T. G. M.; Shi, J.; Zhang, H.; Cheng, P. T. W.; Yu, J. Q. Angew. Chem. Int. Ed. 2016, 55, 785. Shao, Q.; Wu, Q.; Yu, J. Q. J. Am. Chem. Soc. 2017, 139 (9), 3344. Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J. Q. Science 2016, 353, 1023. Tao, Z.-L.; Li, X. H.; Han, Z. Y.; Gong, L. Z. J. Am. Chem. Soc. 2015, 137, 4054. Mao, L.; Bertermann, R.; Rachor, S. G.; Szabo, K. J.; Marder, T. B. Org. Lett. 2017, 19, 6590. a Obligacion, J. V.; Semproni, S. P.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc. 2016, 138, 10645; b Pabst, T. P.; Obligacion, J. V.; Rochette, E.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc. 2019, 141, 15378. Kamei, T.; Nishino, S.; Yagi, A.; Segawa, Y.; Shimada, T. J. Org. Chem. 2019, 84, 14354. Das, A.; Hota, P. K.; Mandal, S. K. Organometallics 2019, 38, 3286. Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron Lett. 2006, 62, 11483. Wan, X.; Ma, Z.; Li, B.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416. Giri, R.; Maugel, N.; Yu, J. Q. Angew. Chem. Int. Ed. 2008, 47, 5215. Militzer, W. J. Am. Chem. Soc. 1938, 60, 256. Zhao, X.; Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466. Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato, M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009, 131, 11310. Song, B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal. 2010, 352, 329. Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Angew. Chem. Int. Ed. 2011, 123, 5638. Sadhu, P.; Alla, S. K.; Punniyamurthy, T. J. Org. Chem. 2013, 78, 6104.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163.

Peron, F.; Fossey, C.; Cailly, T.; Fabis, F.; Santos, J. S. O. Chem. Eur. J. 2014, 20, 7507. Bräse, S. In Asymmetric Synthesis with Chemical and Biological Methods; Enders, D., Jaeger, K.-E., Eds.; Wiley-VCH: Weinheim, Germany, 2007; p 196. Kramer, J. J. P.; Yildiz, C.; Nieger, M.; Bräse, S. Eur. J. Org. Chem. 2014, 2014, 1287. Lu, C.; Zhang, S. Y.; He, G.; Nack, W. A.; Chen, G. Tetrahedron Lett. 2014, 70, 4197. Zeng, W.; Nukeyeva, M.; Wang, Q.; Jiang, C. Org. Biomol. Chem. 2018, 16, 598. Singh, P.; Babu, S. A.; Aggarwal, Y.; Patel, P. Asian J. Org. Chem. 2021, 10, 180. Shan, G.; Huang, G. Y.; Rao, Y.; Zhang, H. Chin. Chem. Lett. 2015, 26, 1236. Purohit, V. B.; Karad, S. C.; Patel, K. H.; Raval, D. K. Catal. Sci. Technol. 2015, 5, 3113. Santra, S. K.; Banerjee, A.; Khatun, N.; Samanta, A.; Patel, B. K. RSC Adv. 2015, 5, 11960. Moghaddam, F. M.; Tavakoli, G.; Saeednia, B.; Langer, P.; Jafari, B. J. Org. Chem. 2016, 81, 3868. Das, R.; Kapur, M. J. Org. Chem. 2017, 82, 1114. Dabiri, M.; Lehi, N. F.; Movahed, S. K.; Khavasi, H. R. Org. Biomol. Chem. 2017, 15, 6264. Dabiri, M.; Lehi, N. F.; Osmani, C.; Movahed, S. K. Eur. J. Org. Chem. 2019, 2019, 7247. Testa, C.; Gigot, E.; Genc, S.; Decreau, R.; Roger, J.; Hierso, J. C. Angew. Chem. Int. Ed. 2016, 128, 5645. Fu, Z.; Jiang, Y.; Wang, S.; Guo, S.; Cai, H. Org. Lett. 2019, 21, 3003. Ahmad, A.; Dutta, H. S.; Kumar, M.; Khan, A. A.; Raziullah, ; Koley, D. Org. Lett. 2020, 22, 5870. Meng, D.; Bi, J.; Dong, Y.; Hao, B.; Qin, K.; Li, T.; Zhu, D. Chem. Commun. 2020, 56, 2889. Chen, X.; Zhao, J.; Dong, M.; Yang, N.; Wang, J.; Zhang, Y.; Liu, K.; Tong, X. J. Am. Chem. Soc. 2021, 143, 1924. Schroder, N.; Delord, J. W.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 8298. Kuhl, N.; Schroder, N.; Glorius, F. Org. Lett. 2013, 15, 3860. Ding, Q.; Zhou, X.; Pu, S.; Cao, B. Tetrahedron. 2015, 71, 2376. Dhiman, A. K.; Gupta, S. S.; Sharma, R.; Kumar, R.; Sharma, U. J. Org. Chem. 2019, 84, 12871. Peng, Q.; Hu, J.; Huo, J.; Yuan, H.; Xu, L.; Pan, X. Org. Biomol. Chem. 2018, 16, 4471. Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 6790. Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342. Urones, B.; Martinez, A. M.; Rodriguez, N.; Arrayas, R. G.; Carretero, J. C. Chem. Commun. 2013, 49, 11044. Mo, S.; Zhu, Y.; Shen, Z. Org. Biomol. Chem. 2013, 11, 2756. Du, Z. J.; Gao, L. X.; Lin, Y. J.; Han, F. S. ChemCatChem. 2014, 6, 123. Zhijun, D.; Lianxun, G.; Yingjie, L. Chem. Res. Chin. Univ. 2015, 31, 167. Li, B.; Liu, B.; Shi, B. F. Chem. Commun. 2015, 51, 5093. Sahoo, H.; Ramakrishna, I.; Baidya, M. ChemistrySelect 2016, 1, 1949. Zhang, S.; Ullah, A.; Yamamoto, Y.; Almansour, A. I.; Arumugam, N.; Kumar, R. S.; Bao, M. ChemistrySelect 2017, 2, 3414. Bi, W. Z.; Chen, Q.; Chen, X. L.; Wei, S. K.; Qu, L. B.; Liu, S. Y.; Zhao, Y. F. Tetrahedron Lett. 2018, 74, 1908. Yu, D. G.; Gensch, T.; Azambuja, F.d.; Cespedes, S. V.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17722. Pawar, A. B.; Lade, D. M. Org. Biomol. Chem. 2016, 14, 3275. Zhan, B.-B.; Liu, Y.-H.; Hu, F.; Shi, B.-F. Chem. Commun. 2016, 52, 4934. Liu, W.; Groves, J. T. Acc. Chem. Res. 2015, 48, 1727. Rana, S.; Biswas, J. P.; Sen, A.; Clemancey, M.; Blondin, G.; Latour, J.-M.; Rajaraman, G.; Maiti, D. Chem. Sci. 2018, 9, 7843. Li, J. J.; Johnson, D. S. Modern Drug Synthesis; Wiley2010. Muller, F. Agrochemicals; Wiley-VCH1999. Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400. Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912. Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141. Wang, G. W.; Yuan, T. T.; Wu, X. L. J. Am. Chem. Soc. 2008, 73, 4717. Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem. Int. Ed. 2005, 44, 7420. Vickers, C. J.; Mei, T. S.; Yu, J. Q. Org. Lett. 2010, 12, 2511. Kesharwani, T.; Larock, R. C. Tetrahedron Lett. 2007, 64, 6090. Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285. Zheng, X.; Song, B.; Xu, B. Eur. J. Org. Chem. 2010, 4376. Dong, J.; Liu, P.; Sun, P. J. Org. Chem. 2015, 80, 2925. Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116. Choy, P. Y.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2011, 76, 80. Sun, C. L.; Liu, J.; Wang, Y.; Zhou, X.; Li, B. J.; Shi, Z. J. Synlett. 2011, 7, 883. Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew. Chem. Int. Ed. 2011, 50, 9409. Wang, L.; Xia, X. D.; Guo, W.; Chen, J. R.; Xiao, W. J. Org. Biomol. Chem. 2011, 9, 6895. Richter, H.; Beckendorf, S.; Mancheño, O. G. Adv. Synth. Catal. 2011, 353, 295. Wang, L.; Pan, L.; Huang, Y.; Chen, Q.; He, M. Eur. J. Org. Chem. 2016, 2016, 3113. Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org. Lett. 2014, 16, 968. Cook, A. K.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2013, 15 (21), 5428. Naksomboon, K.; Valderas, C.; Gómez-Martínez, M.; Álvarez-Casao, Y.; Fernandez-Ibanez, M. A. ACS Catal. 2017, 7, 6342. Valderas, C.; Naksomboon, K.; Fernandez-Ibanez, M. A. ChemCatChem. 2016, 8, 3213. Wang, D.; Zavalij, P. Y.; Vedernikov, A. N. Organometallics 2013, 32, 4882. Malik, H. A.; Taylor, B. L. H.; Kerrigan, J. R.; Grob, J. E.; Houk, K. N.; Bois, J. D.; Hamann, L. G.; Patterson, A. W. Chem. Sci. 2014, 5, 2352. Bakthadoss, M.; Kumar, V. P.; Kumar, R.; Agarwal, V. Org. Biomol. Chem. 2019, 17, 4465. Zhao, J.; Huang, Y.; Feng, P. Organometallics 2019, 38, 2084. Guo, Y.; Wang, W.; Fe-Ji, Y. Adv. Synth. Catal. 2017, 359, 410. Peng, Z.; Yu, Z.; Li, T.; Li, N.; Wang, Y.; Song, L.; Jiang, C. Organometallics 2017, 36, 2826. Dai, C.; Liu, L.; Zhao, Y. Org. Chem. Front. 2020, 7, 1703. Chen, X. Y.; Ozturk, S.; Sorensen, E. J. Org. Lett. 2017, 19, 6280.

249

250 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199.

Direct C–E (E ¼ Boron, Halogen, Oxygen) Bond Formation Through C–H Activation Dutta, U.; Maiti, S.; Bhattacharya, T.; Maiti, D. Science 2021, 372. eabd5992. Maji, A.; Bhaskararao, B.; Singha, S.; Sunoj, R. B.; Maiti, D. Chem. Sci. 2016, 7, 3147. Bera, M.; Sahoo, S. K.; Maiti, D. ACS Catal. 2016, 6, 3575. Li, S.; Cai, L.; Ji, H.; Yang, L.; Li, G. Nat. Commun. 2016, 7, 10443. Bag, S.; Patra, T.; Modak, A.; Deb, A.; Maity, S.; Dutta, U.; Dey, A.; Kancherla, R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D. J. Am. Chem. Soc. 2015, 137, 11888. Li, M.; Shang, M.; Xu, H.; Wang, X.; Dai, H. X.; Yu, J. Q. Org. Lett. 2019, 21, 540. Wang, M.; Yang, Y.; Fan, Z.; Cheng, Z.; Zhu, W.; Zhang, A. Chem. Commun. 2015, 51, 3219. Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654. Li, Z.; Wang, Z.; Chekshin, N.; Qian, S.; Qiao, J. X.; Cheng, P. T.; Yeung, K. S.; Ewing, W. R.; Yu, J. Q. Science 2021, 372, 1452. Chuang, G. J.; Wang, W.; Lee, E.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 1760. Liang, Y.; Li, X.; Jiao, N. ACS Catal. 2015, 5, 6148. Zhang, H.-Y.; Yi, H.-M.; Wang, G.-W.; Yang, B.; Yang, S.-D. Org. Lett. 2013, 15, 6186. Zhang, H.; Hu, R. B.; Zhang, X. Y.; Li, S. X.; Yang, S. D. Chem. Commun. 2014, 50, 4686. Ren, Z.; Mo, F.; Dong, G. J. Am. Chem. Soc. 2012, 134, 16991. Rao, Y. Synlett 2013, 24, 2472. Seth, K.; Nautiyal, M.; Purohit, P.; Parikh, N.; Chakraborti, A. K. Chem. Commun. 2015, 51, 191. Das, P.; Saha, D.; Saha, D.; Guin, J. ACS Catal. 2016, 6, 6050. Das, P.; Guin, J. ChemCatChem 2018, 10, 2370. Novak, P.; Correa, A.; Donaire, J. G.; Martin, R. Angew. Chem. Int. Ed. 2011, 50, 12236. Yang, M.; Jiang, X.; Shi, W. J.; Zhu, Q. L.; Shi, Z. J. Org. Lett. 2013, 15, 690. Neog, K.; Borah, A.; Gogoi, P. J. Org. Chem. 2016, 81, 11971. Begam, H. M.; Samanta, K.; Jana, R. Org. Lett. 2020, 22, 7443. Donaire, J. G.; Martin, R. J. Am. Chem. Soc. 2013, 135, 9350. Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org. Lett. 2013, 15, 1802. Li, X.; Liu, Y.-H.; Gu, W.-J.; Li, B.; Chen, F.-J.; Shi, B.-F. Org. Lett. 2014, 16, 3904. Sun, S.-Z.; Shang, M.; Wang, H.-L.; Lin, H.-X.; Dai, H.-X.; Yu, J.-Q. J. Org. Chem. 2015, 80, 8843. Shang, M.; Shao, Q.; Sun, S.-Z.; Chen, Y.-Q.; Xu, H.; Dai, H.-X.; Yu, J.-Q. Chem. Sci. 2017, 8, 1469. Roy, S.; Pradhan, S.; Punniyamurthy, T. Chem. Commun. 2018, 54, 3899. Trammell, R.; D’Amore, L.; Cordova, A.; Polunin, P.; Xie, N.; Siegler, M. A.; Belanzoni, P.; Swart, M.; Garcia-Bosch, I. Inorg. Chem. 2019, 58, 7584. Shang, X. J.; Liu, Z. Q. Tetrahedron Lett. 2015, 56, 482. Zhang, M.; Ruzi, R.; Li, N.; Xie, J.; Zhu, C. Org. Chem. Front. 2018, 5, 749. Sarkar, W.; Bhowmik, A.; Mishra, A.; Vats, T. K.; Deb, I. Adv. Synth. Catal. 2018, 360, 3228. Gou, Q.; Tan, X.; Zhang, M.; Ran, M.; Yuan, T.; He, S.; Zhou, L.; Cao, T.; Luo, F. Org. Lett. 2020, 22, 1966. Hajipour, A. R.; Khorsandi, Z. Tetrahedron Lett. 2020, 61, 151396. Mishra, A.; Vats, T. K.; Nair, M. P.; Das, A.; Deb, I. J. Org. Chem. 2017, 82, 12406. Zhai, W.; Li, B.; Wang, B. ChemistrySelect. 2018, 3, 8035.

12.07

Synthetic Applications of Carbene and Nitrene CdH Insertion

Yannick Takinda Boni, Bo Wei, and Huw Madoc Lynn Davies, Department of Chemistry, Emory University, Atlanta, GA, United States © 2022 Elsevier Ltd. All rights reserved.

12.07.1 Introduction 12.07.2 Intermolecular rhodium(II) catalyzed carbene CdH insertion 12.07.2.1 Donor/acceptor carbenes 12.07.2.2 Early examples of Rh2(DOSP)4-catalyzed CdH functionalization 12.07.2.3 Combined CdH functionalization/Cope rearrangement 12.07.2.4 Catalyst-controlled CdH functionalization 12.07.2.4.1 Overview of chiral dirhodium catalysts 12.07.2.4.2 Catalyst-controlled selective reactions at unactivated CdH bonds 12.07.3 Intramolecular rhodium(II)-catalyzed carbene CdH insertion 12.07.3.1 Asymmetric intramolecular carbene CdH insertion reactions 12.07.4 Other metal catalysts for asymmetric carbene CdH insertion reactions 12.07.4.1 Chiral copper catalysts for asymmetric carbene CdH functionalization 12.07.4.2 Chiral rhodium catalysts for asymmetric carbene CdH functionalization 12.07.4.3 Chiral ruthenium catalysts for asymmetric carbene CdH functionalization 12.07.4.4 Chiral iridium catalysts for asymmetric carbene CdH functionalization 12.07.4.5 Chiral cobalt catalyst for asymmetric carbene CdH functionalization 12.07.5 Biocatalysts and metalloenzymes for asymmetric carbene CdH insertion reactions 12.07.6 Nitrene CdH insertion 12.07.6.1 Rhodium(II)-catalyzed nitrene CdH insertion 12.07.6.1.1 Intramolecular nitrene CdH insertion 12.07.6.1.2 Intermolecular nitrene CdH insertion 12.07.6.1.3 Enantioselective CdH amination 12.07.6.1.4 Applications in total synthesis 12.07.6.2 Manganese-catalyzed nitrene CdH insertion 12.07.6.3 Ruthenium-catalyzed nitrene CdH insertion 12.07.6.4 Copper-catalyzed nitrene CdH insertion 12.07.6.5 Silver-catalyzed nitrene CdH insertion 12.07.6.6 Gold-catalyzed CdH amination 12.07.6.7 Cobalt-catalyzed nitrene CdH insertion 12.07.6.8 Iron-catalyzed nitrene CdH insertion Acknowledgment References

251 252 252 254 255 257 257 260 267 267 271 271 272 273 273 274 275 276 276 277 277 279 280 280 281 282 284 285 285 286 287 287

12.07.1 Introduction CdH functionalization has developed into a powerful strategy for organic synthesis.1–12 The use of organometallic approaches has played a central role in these advances.13–18 The metal-catalyzed activation of CdH bonds has become a very effective transformation, especially when combined with the use of directing groups to ensure that specific CdH bonds are selectively functionalized.19,20 An alternative transition metal-induced approach is to use a group transfer reaction, in which a metal bound carbene (1) or nitrene (2) is inserted into the CdH bond (Scheme 1).21,22 The metal carbene and metal nitrene CdH insertions are catalytic processes and, in many instances, can be highly regio-, diastereo-, and enantioselective by utilizing appropriately designed chiral catalysts.23,24

Scheme 1 Metal carbene or metal nitrene CdH functionalization.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00157-8

251

252

Synthetic Applications of Carbene and Nitrene CdH Insertion

The intermolecular CdH insertion of metal carbenes has developed extensively since the edition of COMC (2007). Dirhodium(II) complexes have been the most effective catalysts, especially for enantioselective reactions. A major advance described in COMC (2007) was the development of donor/acceptor carbenes as the reactive intermediates for the CdH insertion reactions. They were found to still be sufficiently reactive to functionalize even unactivated CdH bonds. Due to the attenuating influence of the donor group, they were capable of highly site-selective and diastereoselective reactions of carefully selected substrates. Highly enantioselective reactions were also feasible but at that time most of the enantioselective examples were limited to a single catalyst. In the last decade, considerable advances have been made in the design of chiral catalysts with different steric demands to control the site selectivity, instead of just relying on specific features of the substrates to control whether a particular reaction is selective.25–27 An up-to-date overview, highlighting the most significant recent breakthroughs in the rhodium(II)-catalyzed intermolecular carbene CdH insertion chemistry is provided in Section 12.07.2. Due to the challenges associated with controlling site-selectivity in carbene-induced CdH functionalization, the intramolecular version of the reaction was the first to generate general prominence. The intermolecular reactions have been extensively applied in total synthesis and the broad utility of this chemistry was described in detail in COMC (1995), COMC (2007) and several other articles and reviews.1,3,5,7,9,10,12,28–34 In general, intramolecular reactions to form five-membered rings are preferred, but with appropriate substrates, it is possible to form either four- or six-membered rings. Traditionally, the standard precursors to the carbenes have been diazo compounds but in recent years several alternative carbene precursors have been introduced with great success. Intramolecular CdH functionalization by means of metal carbene-induced CdH insertion has been comprehensively reviewed in many excellent publications. Section 12.07.3 will focus primarily on recent advances of rhodium(II)-catalyzed intramolecular reactions and their application in synthesis. Since the edition of COMC (2007), the scope of metal nitrene CdH insertion has been widely explored.35–38 Various effective metal catalysts as well as novel methods for generation of the nitrene precursors have been reported.39–43 The recent developments of metal nitrene CdH insertion and their application to the synthesis of complex natural products are described in Section 12.07.6.

12.07.2 Intermolecular rhodium(II) catalyzed carbene CdH insertion 12.07.2.1 Donor/acceptor carbenes Intermolecular carbene functionalizations are challenging because the metal carbene needs to be sufficiently reactive to react with the CdH bonds but must still display good selectivity. Considerable progress has been made in this area, and several reviews have been reported on this topic.44,45 The first example of intermolecular CdH insertion of metal carbenes was reported by Scott and DeCicco in 1974.2 The carbene was formed from ethyl diazoacetate and CuSO4 and delivered the CdH insertion product with 9–24% yield. In 1981, Teyssie reported rhodium(II) trifluoroacetate, Rh2(TFA)4, as an effective catalyst in the CdH insertion of alkanes, generating the functionalized alkanes in 29–90% yield.13 A representative example is the reaction of 2-methylbutane (3) in Scheme 2. Four (4–7) of the five possible products are formed, indicating that the carbene from ethyl diazoacetate is not very selective.

Scheme 2 Early example of intermolecular carbene CdH insertion.

The generally accepted catalytic cycle for the CdH insertion is shown in Scheme 3.46–54 The first step of the reaction is extrusion of nitrogen from the diazo compound 8 to form the metal carbene intermediate 9. The rhodium carbene is considered to be highly electrophilic and is capable of reacting with unactivated CdH bonds. The CdH insertion is considered to be highly asynchronous, in which the carbene begins to abstract a hydride from the alkane leading to positive charge build-up at the carbon in the intermediate 10 before the CdH insertion is completed and the functionalized derivative 11 is formed. One of the intriguing aspects of this CdH functionalization process is that the rhodium(II) carbene complex is coordinatively saturated and so there is no direct interaction between the metal and the approaching substrate to help control the outcome of the reaction.

Synthetic Applications of Carbene and Nitrene CdH Insertion

253

Scheme 3 General mechanism of the carbene CdH insertion.

Over the last two decades, it has become readily apparent that the structure of the carbene has a dramatic influence on the outcome of the subsequent reactions.21,55,56 The early studies were primarily carried out on carbenes that were functionalized with electron withdrawing groups. These carbenes are now called acceptor carbenes (12) and acceptor/acceptor carbenes (13), depending on whether they have one or two electron withdrawing groups (Scheme 4). The electron withdrawing groups add to the inherent electrophilic character of these classes of carbenes, making them extremely reactive and relatively unselective. Hence a great deal of the early synthetically useful CdH insertion reactions were conducted using intramolecular reactions to help control the site selectivity of the process. A major breakthrough in the carbene CdH insertion reactions was the development of donor/acceptor carbenes (14). The presence of the electron withdrawing group ensures that these carbenes are still sufficiently reactive to functionalization unactivated CdH bonds, but the donor group modulates the electrophilicity of the carbene, leading to the possibility of achieving excellent regiocontrol even in the presence of a variety of functional groups.57

Scheme 4 Major classes of transient metal-carbene intermediates.

A particularly attractive feature of the donor/acceptor carbenes is the opportunity of highly enantioselective transformations using chiral dirhodium tetracarboxylate intermediates. Some of the early enantioselective intermolecular reactions are shown in Scheme 5. The rhodium(II) prolinate catalyst, Rh2(S-DOSP)4 (15) has been shown to be applicable to a wide range of enantioselective reactions of donor/acceptor carbenes, as illustrated in the cyclopropanation of styrene with the vinyldiazoacetate 16, to form the vinylcyclopropane 17 in 98% ee. Of particular relevance to this chapter is the reaction of the phenyldiazoacetate 18 with cyclohexane to form the CdH functionalization product 19 in 95% ee.

254

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 5 Seminal examples of Rh2(DOSP)4-catalyzed intermolecular reactions.

12.07.2.2 Early examples of Rh2(DOSP)4-catalyzed CdH functionalization In the 2007 edition of COMC, the Rh2(DOSP)4 (15)-catalyzed intermolecular CdH functionalization reactions were comprehensively reviewed. The reactions were shown to be highly effective with substrates that contained activated CdH bonds such as allylic and benzylic sites or sites adjacent to oxygen or nitrogen functionality. All of these sites can stabilize build-up of positive charge character during the CdH functionalization, which make them electronically favored sites for this chemistry. A few examples will be described here, illustrating how the carbene CdH insertion reactions can complement some of the classic disconnection strategies. A particularly effective system is The CdH insertion at a position adjacent to oxygen as illustrated in the reaction of tetraethoxysilane 20 with phenyldiazoacetate 18.58 The resulting b-alkoxycarboxylate 21 is formed with high levels of diastereoselectivity and enantioselectivity, and the overall transformation can be considered as a surrogate of the aldol reaction (Scheme 6).

Scheme 6 CdH functionalization as an aldol reaction equivalent.

CdH functionalization at acetal CdH bonds generates protected forms of b-ketoesters as illustrated in the Rh2(S-DOSP)4 (15)-catalyzed reaction of the allyl acetal 22 with the aryldiazoacetate 23 to form the ketal protected b-ketoester 24 (Scheme 7).59 Claisen condensation is the classic method to make b-ketoesters. However, the Claisen condensation products tend to racemize under the reaction conditions. The CdH insertion method provides an appealing approach because the ketal protection ensures that the product is readily isolated without epimerization.

Scheme 7 CdH functionalization as a Claisen condensation equivalent.

CdH functionalization at activated sites a-to-nitrogen provide b-amino esters, which are typically formed by means of a Mannich reaction. For example, the erythro product 26 is generated in good yield and with high levels of diastereo- and enantioselectivity from the Rh2(S-DOSP)4 (15)-catalyzed reaction of the phenyldiazoacetate 18 and N-Boc-pyrrolidine 25 (Scheme 8).60 When the reaction is extended to substituted pyrrolidine derivatives, kinetic resolution can be achieved with racemic substrates, whereas with chiral substrates, the site selectivity can be controlled depending on which enantiomer of the catalyst is used.

Synthetic Applications of Carbene and Nitrene CdH Insertion

255

Scheme 8 CdH functionalization as a Mannich reaction equivalent.

CdH functionalization at allylic sites generates g,d-unsaturated esters. One of the most established routes for the stereoselective synthesis of g,d-unsaturated esters is the Claisen rearrangement and thus, allylic CdH functionalization with donor/acceptor carbenes can be considered to be a surrogate for this classical reaction.61 A substrate that illustrates the subtleties of this transformation is a-pinene (27) as illustrated in Scheme 9. Both primary and secondary allylic sites are present in a-pinene (27) but under Rh2(DOSP)4 (15) catalysis, the reaction occurs exclusively at the methylene site. The gem-dimethyl functionality blocks one side of the methylene group and the reaction outcome depends on which enantiomer of the catalyst is used. The Rh2(S-DOSP)4 (15)-catalyzed reaction with the aryldiazoacetate 23 is the matched reaction and the CdH functionalization is high yielding and highly diastereoselective, favoring the formation of 28. In contrast, the Rh2(R-DOSP)4 (15)-catalyzed reaction proceeds in much lower yield, with a slight preference for the alternative diastereomer 29. The matched/mismatched nature of this reaction is further underscored with the Rh2(S-DOSP)4(15)-catalyzed reaction of racemic a-pinene, which results in kinetic resolution and the formation of 28 as the major diastereomer in 99% ee.

Scheme 9 CdH functionalization as a Claisen rearrangement equivalent.

12.07.2.3 Combined CdH functionalization/Cope rearrangement The attempted CdH functionalization of allylic substrates with vinyldiazoacetates results in an unexpected transformation as illustrated in Scheme 10 for the Rh2(S-DOSP)4 (15)-catalyzed reaction of vinyldiazoacetate 16 with cyclohexadiene 30.62,63 The product 31 is formed with very high level of asymmetric induction and would be consistent with a reaction proceeding by means of a CdH functionalization followed by a Cope rearrangement. However, the direct CdH functionalization product 32 is actually the thermodynamically favored product and on heating 31 cleanly converts to 32. Therefore, the reaction has been described as a “combined CdH functionalization/Cope rearrangement” (combined CdH/Cope) to differentiate it from a stepwise process involving 32 as an intermediate.

Scheme 10 Combined CdH functionalization/Cope rearrangement.

The seminal studies of the combined CdH/Cope were described in COMC (2007) and since then the topic has been extensively reviewed. Hence in this chapter, only a few representative examples will be illustrated. Many examples of the combined CdH/Cope proceed with extremely high levels of diastereo- and enantioselectivity as illustrated in Scheme 11.64 Compounds 33–35 are formed essentially as single diastereomers and many of the reactions proceed with 98% ee or higher.

256

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 11 Examples of combined CdH functionalization/Cope rearrangement reactions.

The stereochemistry observed in the combined CdH/Cope is consistent with a reaction proceeding the through a chair transition state as illustrated in Scheme 12. The reaction was first proposed to be an interrupted CdH functionalization process as illustrated with the generic allylic system 36 and the rhodium-bound vinylcarbene 37.65 The carbene CdH functionalization is considered to be a concerted asynchronous process, which is initiated by a partial hydride transfer event to form 38 but in this case continues with the Cope rearrangement to form 39 rather than the direct CdH functionalization. Computational interrogation of this proposed mechanism revealed that the hydride transfer reaction proceeds to completion to generate an allyl cation and a rhodium-bound allyl anion which rapidly undergoes the subsequent CdC bond formation before any bond rotation can occur.66

Scheme 12 Stereochemical outcome of the combined CdH functionalization/Cope rearrangement reaction.

In most cases, the relative stereochemistry of the combined CdH functionalization/Cope rearrangement is consistent with the reaction proceeding though a chair like transition state.64 However, it is possible to obtain a different stereochemical outcome as illustrated in the examples shown in Scheme 13.66 In the Rh2(S-PTAD)4 (42)-catalyzed reaction of the vinyldiazoacetate 40 with the cyclohexene derivative 41, the corresponding CdH/Cope product could then undergo a silica gel mediated desilylation followed by diazotization using p-ABSA to generate 43 as a single diastereomer in 89% ee. The formation of this product is

Scheme 13 Stereochemical outcome of the combined CdH functionalization/Cope rearrangement.

Synthetic Applications of Carbene and Nitrene CdH Insertion

257

consistent with the combined CdH functionalization/Cope rearrangement proceeding through a chair-like transition state 44.67 This ensures that the cyclohexene ring is pointing away from the surface of the catalyst. In contrast, the same sequence of reactions with 2-methyl substituted cyclopentyl silyl ether 45 is still highly diastereoselective but produces 46 in the opposite diastereomeric series to 43. In this case, the reaction is considered to proceed through the boat-like transition state 47. The smaller cyclopentyl ring can be accommodated pointing towards the catalyst, and this will ensure that the 2-methyl group is pointing away from the dirhodium scaffold. The combined CdH/Cope has been applied to the synthesis of a variety of natural products (Scheme 14).62 An impressive example is the stereodivergent reaction of the racemic dihydronaphthalene 48 with the vinyldiazoacetate 49, which has been applied to the synthesis of (−)-colombiasin A (51) and (+)-elisapterosin B (52).68 The dihydronaphthalene 48 is susceptible to both cyclopropanation and the combined CdH/Cope. When the reaction is catalyzed by Rh2(R-DOSP)4 (15), one enantiomer of 48 undergoes cyclopropanation, whereas the other enantiomer undergoes the combined CdH/Cope. After reduction of the alkene and ester of the combined CdH/Cope product, the alcohol 50 is obtained in 95% ee, in which three stereogenic centers are fixed. In alternative syntheses using more conventional chemistry, the control of the three stereogenic centers have been challenging but with the combined CdH/Cope they are all controlled in one step. The completion of the total synthesis of (−)-colombiasin A (51) and (+)-elisapterosin B (52) was achieved using well established literature procedures.

Scheme 14 Synthetic applications of the combined CdH functionalization/Cope rearrangement.

12.07.2.4 Catalyst-controlled CdH functionalization 12.07.2.4.1

Overview of chiral dirhodium catalysts

As illustrated in the examples discussed in Sections 12.07.2.2, the Rh2(DOSP)4 (15)-catalyzed enantioselective CdH functionalization with donor/acceptor carbenes is applicable to a wide range of substrates.25 Typically, reactions tend to preferentially occur at secondary CdH bonds and when the system is electronically activated (allylic, benzylic, a-to-oxygen or nitrogen), the reactions can be extremely site selective. By taking these general reactivity principles into consideration, a variety of effective substrates for the CdH functionalization have been identified.69 The next challenge, however, is to go beyond tailoring the substrates to suite one specific catalyst and instead, have a collection of catalysts to control the site selectivity at will. In the last decade, considerable progress has been made in designing sterically crowded catalysts to overcome the electronic preference for carbene CdH functionalization at the more highly substituted CdH bond.26,27,70–75 Some of the early studies applied rhodium(II), rhodium(III), copper, and rhodium porphyrin catalysts to influence the competition between steric and electronic effects to control site selectivity. A significant early example is the study described by Che in 2008, which showed that CdH functionalization at secondary and even primary sites of alkanes could be favored by employing bulky rhodium-porphyrin catalysts.76 However, the most broadly applicable catalysts for site-selective intermolecular CdH functionalization have been the chiral dirhodium tetracarboxylate catalysts of defined shape developed by the Davies group.27,72,77–81 One of the most intriguing aspects of the dirhodium tetracarboxylates is the possibility of generating high symmetry catalysts when four identical chiral ligands self-assemble around the dirhodium core (Scheme 15).26,82 The phenomenon was originally proposed to rationalize why Rh2(S-DOSP)4 (15) was capable of such high asymmetric induction.83 It was recognized that if a catalyst has a large group that does not align well at the periphery of the catalyst, then it would be forced to exist either on the top or the bottom faces of the complex. Only a certain number of permutations would be possible and some of these would be of high symmetry. The all up orientation 53 would be C4 symmetric, the up-down-up-down orientation 54 would be D2 symmetric, and the up-up-down-down orientation 55 would be C2 symmetric. Since then, a fourth high symmetry orientation has been recognized, an all-up orientation with p-stacking interactions between adjacent ligands (56), leading to a C2 symmetric structure. These high symmetry chiral catalysts limit the number of possible orientations for carbene binding to the rhodium, increasing the chance for a well-defined highly enantioselective catalyst.

258

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 15 High symmetry dirhodium tetracarboxylate complexes.

During the early development of Rh2(S-DOSP)4 (15), it was proposed this catalyst adopts a D2 symmetric structure and a simple model was developed that was highly predictive for the observed enantioselectivity and diastereoselectivity (Scheme 16).57 However, the D2 structure for Rh2(S-DOSP)4 (15) has not been confirmed experimentally. Since then, two other classes of chiral catalysts have been developed for the CdH functionalization chemistry. Through a combination of X-ray crystallographic and computational studies, these have been confirmed to adopt high symmetry structures. The structural aspects of these catalysts have been described in detail in a recent review,26 and so, only the key concepts will be described here.

Scheme 16 Predictive model for asymmetric induction with Rh2(S-DOSP)4 (15).

The phthalimido-based catalysts originally developed by Hashimoto84 and studied structurally by Fox,85,86 Charette87 and Davies83,88,89 have been shown to adopt an all-up orientation when derived from a bulky amino acid such as tert-butyl leucine or adamantyl leucine. Two catalysts of this class, Rh2(S-TCPTAD)4 (57)80 and Rh2(S-TPPTTL)4 (58)89 have had a large impact on intermolecular CdH functionalization (Scheme 17). They have been shown to adopt a C4 symmetric bowl-shaped structure. The catalysts are not sterically demanding at the carbene site and can allow tertiary CdH functionalization to occur, but the wall of the catalyst can influence what types of substrates would fit into the bowl. Rh2(S-TPPTTL)4 (58) has an additional subtle feature as all the 16 phenyl rings on the periphery of the bowl are tilted leading to the possibility of having propeller-like chirality superimposed on the C4 symmetric structure.

Synthetic Applications of Carbene and Nitrene CdH Insertion

259

Scheme 17 C4 symmetric catalysts derived from N-phthalimido amino acids.

The triarylcyclopropane carboxylate ligands (TPCP) have had a dramatic influence on site selective CdH functionalization because these catalysts are very bulky and can sterically overwhelm the electronic preference of the rhodium carbenes to react at tertiary CdH bonds.26 These catalysts can adopt three types of high symmetry orientations depending on the functionality of the C-1 aryl group (Scheme 18).82 If the C-1 aryl group is para-substituted the favored conformation for the catalyst is all up with p-stacking between the C-1 aryl groups, leading to a C2-symmetric structure. The most notable examples of this type of catalyst structures are Rh2(S-p-Br-TPCP)4 (59),77 Rh2(S-p-Ph-TPCP)4 (60)27 and Rh2(R-tris(p-tBuC6H4)TPCP)4 (61).90 If the aryl group is 3,5-disubstituted then it is impossible to have two adjacent ligands with 3,5-disubstituted phenyl groups pointing in the same direction. Hence the catalysts need to adopt and up-down-up-down arrangement, resulting in D2-symmetric structures. The most significant example of this type of structure is Rh2(R-3,5-di(p-tBuC6H4)TPCP)4 (62).78 Finally, if the C-1 aryl group has a 2-Cl substituent the catalysts adopt and all up arrangement leading to a C4-symmetric arrangement.79,91 Several members of the C4 symmetric class have been evaluated and they all display similar site selectivity. However, the 2-Cl-5-Br derivative, Rh2(S-2-Cl-5-BrTPCP)4 (63), is the one best suited for obtaining high levels of enantioselectivity.91–93

Scheme 18 C2, D2 and C4 symmetric catalysts derived from TPCP ligands.

260

Synthetic Applications of Carbene and Nitrene CdH Insertion

12.07.2.4.2

Catalyst-controlled selective reactions at unactivated CdH bonds

The early work on enantioselective intermolecular CdH functionalization reactions was primarily conducted with a single catalyst, Rh2(S-DOSP)4 (15).83 By judicious choice of substrates, site-selective transformations could be obtained. In general, Rh2(S-DOSP)4 (15) tended to react preferentially at secondary CdH bonds, due to a competing balance between electronic effects, which favor attack at tertiary CdH bonds best suites to stabilize positive charge build up at carbon during the CdH functionalization, and steric effects which led to preferred attack at the least crowded sites. Even though the secondary site was generally preferred, a few examples of reactions at primary sites were known in systems that were electronically activated, as well as reactions at relatively uncrowded tertiary sites, such as adamantane. Research over the past decade has focused on developing a series of sterically more crowded and rigid catalysts that would force the site selectivity away from the electronically preferred sites due to the steric interference. A review highlighting these accomplishments has recently been published,26 and in this section, the focus will be to illustrate with a few representative examples the key advances in site selectivity that has been obtained with these new catalysts. A major development in the area of catalyst control was the discovery that the dirhodium tetracarboxylate catalysts with the triarylcyclopropane carboxylate (TPCP) ligands were much more sterically demanding than Rh2(R-DOSP)4 (15).27,77,94 Competition reactions at activated benzylic sites illustrate this phenomenon (Scheme 19).27 The Rh2(R-DOSP)4 (15)-catalyzed reaction of the methyl p-aryldiazoacetate 64a with p-ethyltoluene gave the expected strong preference for reaction at the secondary CdH bond to form 65. However, when the same reaction was conducted using Rh2(R-p-Ph-TPCP)4 (60) the site selectivity changed dramatically and the primary CdH functionalization product 66 was favored by a 5:1 ratio. Further enhancement of the site selectivity to 13:1 was observed when the trichloroethyl ester of the aryldiazoacetate (64b) was used. Furthermore, the enantioselectivity for the formation of 66 improved to 99% ee.94 Similar enhanced primary site selectivity was observed at other activated sites such as allylic CdH bonds and methyl ethers.94 The use of the trihaloethyl esters instead of methyl esters was found to have a beneficial effect in many donor/acceptor carbene-induced CdH functionalization reactions, especially when unactivated hydrocarbons are used as substrates.

Scheme 19 Catalyst-controlled benzylic CdH functionalization.

Having established the steric influence of the Rh2(TPCP)4 catalysts, the influence of these catalysts on enantioselective CdH functionalization of unactivated hydrocarbon CdH bonds has been studied. The evaluation of the efficacy of these catalysts was conducted with pentane (67) as substrate, which in the reaction with the aryldiazoacetate 64b, could give rise to three regioisomers 68–70 (Scheme 20).78 Rh2(R-DOSP)4 (15) does preferentially react at methylene sites and actually does give good site selectivity for functionalization at C2 with some competing reaction at C3. The diastereoselectivity for 69 is low (3:1 d.r.) but the enantioselectivity is reasonable (82% ee). In order to have a truly effective system for functionalization at the most accessible methylene site (C2), the competing reaction at C3 methylene site needs to be avoided because many substrates would have multiple internal methylene sites. Rh2(R-p-Ph-TPCP)4 (60) is effective at blocking C3, but it is too crowded, resulting in a significant amount of the primary CdH functionalization product 68. After extensive optimization the D2 symmetric catalyst, Rh2(R-3,5-di(p-tBuC6H4) TPCP)4 (62),78 was identified as the best catalyst. It gave good selectivity for C2 over C1 (25:1 r.r.) and 69 was formed with excellent diastereoselectivity and enantioselectivity (20:1 d.r. and 99% ee). Good site selectivity was possible in the presence of substrates with functional groups as illustrated in the formation of the CdH functionalization products 71–73.

Synthetic Applications of Carbene and Nitrene CdH Insertion

261

Scheme 20 Rh2(R-3,5-di(p-tBuC6H4)TPCP)4-catalyzed CdH functionalization at the most sterically accessible secondary site.

Fairly soon thereafter, an even better catalyst Rh2(S-2-Cl-5-BrTPCP)4 (63) was identified for site selective CdH functionalization of the most accessible methylene site.91 A good example illustrating the type of selectivity that can be achieved is the reaction with the alkylbenzene derivative 74. Rh2(S-TCPTAD)4 (57) and Rh2(S-2-Cl-5-BrTPCP)4 (63) are both C4-symmetric bowl-shaped catalysts, but the structure of Rh2(S-TCPTAD)4 (57) is more open than Rh2(S-2-Cl-5-BrTPCP)4 (63) (Scheme 21). As a relatively uncrowded catalyst, Rh2(S-TCPTAD)4 (57) shows a strong preference for reaction at the electronically activated benzylic site to form 75, whereas Rh2(S-2-Cl-5-BrTPCP)4 (63) reverses the selectivity and strongly favors reactions at the most accessible methylene site to form 76. This type of site selectivity has been applied to the synthesis of the macrocyclic framework 80 of the cylindrocyclophane family of natural products (Scheme 22). An intermolecular CdH functionalization between 77 and 78 to form 79 in 91% ee is followed by an intramolecular CdH functionalization to generate the 7.7-paracyclophane 80 with four new stereocenters in >99% ee. The amplification of the enantioselectivity in the second CdH functionalization step is due to Horeau’s effect,95 in which the minor enantiomer of 79 would predominately form the diastereomer of 80.

Scheme 21 Rh2(S-2-Cl-5-BrTPCP)4 catalyzed selective functionalization of unactivated secondary CdH bonds.

Scheme 22 Enantioselective synthesis of cylindrocyclophane core by dirhodium catalyzed CdH functionalization.

262

Synthetic Applications of Carbene and Nitrene CdH Insertion

An even more impressive example of site selective CdH functionalization between different methylene sites, is the desymmetrization of alkylcyclohexanes. A specific example is the Rh2(S-TPPTTL)4 (58)-catalyzed reaction of 64b with tert-butylcyclohexane (81) (Scheme 23) to form the C3-functionalized product 82 in 95% ee.89 The reaction is highly regioselective favoring attack at the equatorial C3 position rather than equatorial C4 by a factor of >50:1. Desymmetrization of 81 occurs because the reaction at the equatorial C3 is favored by a factor of 11:1 over the equatorial C5. This high level of site selectivity is a characteristic of the Rh2(S-TPPTTL)4 (58)-catalyzed reaction. Computational studies and X-ray analyses suggested that the catalyst adopts a C4-symmetric structure, and the 16 phenyl groups at the periphery of the four phthalimido group are preferentially tilted in one way, leading to an induced helical chirality in the dirhodium complex.89 This helical chirality is considered to be a contributing factor for the high enantioselectivity exhibited by this catalyst. Furthermore, Rh2(S-TPPTTL)4 (58) is not considered to be a sterically demanding catalyst at the carbene center itself, but the wall of the catalyst can interfere with the approach of certain substrates. This can be seen in the models for the attack of cyclohexane at C3 (83) or C4 (84). When the carbene attacks C3 (83), the tert-butyl group is pointing out of the chiral pocket, whereas in the case of C4 attack (84) the tert-butyl group is pointing into the catalyst wall and so cannot be accommodated.

Scheme 23 Desymmetrization of tert-butylcyclohexane.

Catalyst-controlled CdH functionalization has been extended to achieve site selectivity at either tertiary or primary sites.26,59 A selective reaction at a tertiary site would require a relatively uncrowded catalyst, whereas reaction at a primary site would require a very crowded catalyst to overwhelm the electronic preference for reactions at tertiary and secondary sites. These catalysts were optimized on a deceptively simple system, 2-methylpentane (85), which contains tertiary, secondary and primary CdH bonds (Scheme 24).80,90 Only the most accessible sites are reactive, and so no reaction occurs at the C3-methylene of the gem-dimethyl sites, leading to three potential products, 86–88. As a point of reference one the best secondary selective catalysts, Rh2(R-3,5-di(p-tBuC6H4)TPCP)4 (62),78 has the expected preference for the methylene site (3 , 2 , 1 ratio of 7:75:18). The site selectivity is not as high as was observed in linear alkanes because there is a competing tertiary site and a slight steric interference by the C2-methyl group on the C4 methylene site. The best catalyst for tertiary selective reactions is Rh2(S-TCPTAD)4 (57), which gives a 3 , 2 ratio of 89:11 and no 1 product.80 The most effective sterically encumbered catalyst is Rh2(R-tris(p-tBuC6H4)TPCP)4 (61),90 which results in a strong preference for the functionalization of unactivated primary CdH bond (1 , 2 ratio of 84:16 and no 3 product).

Scheme 24 Site selective functionalization of 2-methylpentane (125).

Synthetic Applications of Carbene and Nitrene CdH Insertion

263

Even though the catalysts used in the optimization studies with 2-methylpentane do not give perfect control of site selectivity, the steric environment associated with more complex substrates enables highly site selective transformations to be feasible. This can be readily seen in the Rh2(S-tris(p-tBuC6H4)TPCP)4 (61)-catalyzed reaction with TBS protected (S)-2-methylbutanol 89 (Scheme 25).90 The tertiary site and the two methylene sites are a bit more crowded than they were in 2-methypentane (85). Hence, a very clean reaction is observed at the most accessible primary site to form (S, S) diastereoisomer 90. Furthermore, the catalyst control is clearly in evidence because when the (R) enantiomer of the catalyst 61 is used, the (S, R) diastereoisomer 91 is formed.

Scheme 25 Rh2(R-tris(p-tBuC6H4)TPCP)4 catalyzed selective functionalization of unactivated primary CdH bonds.

An example illustrating the exquisite site selectivity that can be achieved with the tertiary selective catalyst Rh2(S-TCPTAD)4 (57) is the reaction of the trifluoroethyl aryldiazoacetate 92 with cholesteryl acetate (93) (Scheme 26).80 Even though 93 has over 40 different CdH bonds, the reaction proceeds cleanly at the most accessible tertiary site to form 94 in 60% yield. No reaction is observed at any of the other tertiary CdH bonds nor the electronically activated allylic sites.

Scheme 26 Selective functionalization of cholesteryl acetate (133).

Having established a series of catalysts with different types of site selectivity, the CdH functionalization reactions have been applied to the synthesis of useful chiral derivatives. The CdH functionalization of cyclooctadiene (95) with aryldiazoacetate 96 has been used for the synthesis of chiral C2-symmetric COD ligands (Scheme 27).96 The optimum catalyst for these reactions is Rh2(S-2-Cl-5-BrTPCP)4 (63). When an excess of cyclooctadiene is used, the allylic CdH functionalized product 97 is obtained in 78% yield, >30:1 d.r. and 95% ee. Even more impressive is the double CdH functionalization that occurs using excess of the aryldiazoacetate 96, because the C2 symmetric product 98 is obtained in 6.8:1 d.r. and >99% ee.

264

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 27 Rh2(R-2-Cl-5-BrTPCP)4 catalyzed functionalization of cyclooctadiene.

Carbene-induced CdH functionalization can be used to generate chiral building blocks of pharmaceutical interest. Two classes of substrates illustrating the potential of this chemistry are the silacyclobutanes 9997 and the bicyclopentanes 10198 as illustrated in Scheme 28. The Rh2(S-TPPTTL)4 (58) catalyzed reaction of aryldiazoacetates with 99 resulted in clean formation of the C3 functionalized products 100 in 79–99% ee. In the case of bicyclopentanes 101, Rh2(R-TCPTAD)4 (57) was the optimum catalyst, resulting in the functionalization at the tertiary site to form 102 in 65–94% ee.

Scheme 28 Synthesis of pharmaceutically relevant chiral building blocks.

Catalyst-controlled site selectivity can be applied to the synthesis of pharmaceutical targets1,11,99 as illustrated in Scheme 29.92,93 Depending on which catalyst is used, different regioisomers of the products can be obtained. In the case of arylcyclobutane 103, when a relatively uncrowded catalyst such as Rh2(R-TCPTAD)4 (57) is used, the CdH functionalization preferentially occurs at the electronically activated tertiary site to form 104, but when the bulky catalyst Rh2(S-2-Cl-5-BrTPCP)4 (63) is used the reaction preferentially occurs at the C3 methylene site to form 105.92 Likewise in the case of the protected piperidine 106, the uncrowded catalyst Rh2(R-TCPTAD)4 (57) or Rh2(R-TPPTTL)4 (58) preferentially reacts at C2 a to nitrogen to form 107, but a bulky catalyst drives the reaction to C4 to form 108.93

Synthetic Applications of Carbene and Nitrene CdH Insertion

265

Scheme 29 Catalyst control in the synthesis of pharmaceutically relevant chiral building blocks.

The vast majority of enantioselective intermolecular CdH functionalizations has used diazo compounds as the carbene precursor. In an attempt to broaden the scope of carbenes, many efforts are being made to access alternative carbene precursors.100 The most prominent system to date has been N-sulfonyltriazoles 109 that were initially reported by Fokin.101 The corresponding metal-carbenes from these N-sulfonyltriazoles results from their in situ ring opening followed by trapping of the N-sulfonyliminodiazo intermediate by a transition metal catalyst. Fokin’s early reports demonstrated that N-sulfonyltriazoles 109 were effective carbene sources for the asymmetric CdH functionalization of certain hydrocarbons to form the sulfonylimines 111. The optimum catalyst for these reactions is Muller’s Rh2(S-NTTL)4 (110) (Scheme 30).102 However, extension of the CdH functionalization reaction to other substrates such as tetrahydrofuran failed. Lacour reported that instead, the ring expanded product 112 is observed presumably via the intermediacy of oxonium ylide 113 followed by a 2,3-sigmatropic rearrangement.103 It has been suggested that the broad functional group tolerance in the CdH functionalization reactions with aryldiazoacetates is because when the carbene interacts with weakly nucleophilic sites, the reactions are reversible but in the case of the N-sulfonyltriazoles the sulfonylimine group has a greater tendency than an ester to engage in further transformations once ylides are formed.104

Scheme 30 N-sulfonyltriazoles as carbene precursors for CdH functionalization.

266

Synthetic Applications of Carbene and Nitrene CdH Insertion

In recent years, Davies reported that the Rh2(S-NTTL)4 (110) catalyzed reaction of 4-aryl-N-sulfonyl-1,2,3-triazole (114) could be extended to the functionalization of allylic (115) and benzylic (117) C(sp3)dH bonds to form 116 and 118, respectively, as illustrated in Scheme 31.104 In systems with competing allylic or benzylic sites, the system showed modest preferential selectivity for tertiary sites. Harnessing the b-silicon effect, Davies reported in 2018 a site selective and enantioselective functionalization of the b-CdH bonds of silacycles (120) and linear silanes (122) using 1-sulfonyl-1,2,3-triazoles (119) as the corresponding carbene precursors, to form 121 or 123.105

Scheme 31 N-sulfonyltriazoles as carbene precursors for functionalization of activated CdH bonds.

Using the same Rh2(S-NTTL)4 (110) and 1-sulfonyl-1,2,3-trizoles (109) as carbene precursors, Davies and coworkers reported a one-pot asymmetric synthesis of b-arylpyrrolidines (125) through a catalytic enantioselective intermolecular allylic C(sp3)dH insertion of trans-alkenes (124) followed by a reduction, an ozonolysis, and then an in situ diversification of the generated cyclic hemiaminal to access a range of chiral pyrrolidines (125) (Scheme 32).106 Good yield (up to 66%) and stereoinduction (up to 92:8 d.r. and 98% ee) were achieved in the synthesis of these b-pyrrolidines. Early in 2020, Davies and coworkers also reported a site selective and stereoselective donor/acceptor dirhodium carbene insertion reaction at the distal allylic and benzylic C(sp3)dH bonds of allyl or benzyl silyl ethers.107 The silyl ethers (unlike cyclic alkyl ethers) did not undergo rhodium(II) carbene ylide formation but instead generated the desired CdH functionalization products. Rh2(S-NTTL)4 (110) in conjunction with 1-sulfonyl-1,2,3-triazoles (114) showed selectivity for the distal allylic CdH bond of cis-allyl silyl ethers (126) generating adduct 127 which is analogous to what would be obtained via an asymmetric vinylogous Michael addition reaction. The utility of the transformation was showcased in the asymmetric and rapid synthesis of a 3,4-disubstituted proline derivative (128).

Synthetic Applications of Carbene and Nitrene CdH Insertion

267

Scheme 32 Stereoselective synthesis of pyrrolidines.

In recent years, several examples of formal enantioselective CdH functionalization of aromatic rings have been reported, although these reactions do not proceed by a direct insertion into a CdH bond. Rovis108 and others109,110 have reported such transformations in recent years. In 2011 the Fox111 group reported a Rh2(S-NTTL)4 (110) catalyzed asymmetric intermolecular carbene CdH insertion at the C3 position of C2-substituted N-protected indoles (129) using a-alkyl-a-diazoesters (130) (Scheme 33). A mechanism based upon DFT calculations proposed that the formal CdH functionalization product 131 is formed from a Rh-ylide intermediate 132. Asymmetric induction was attributed to the approach of the indole from the si-face of the rhodium carbene with a subsequent aromatization and a stereoretentive protonation. A similar transformation has also been reported by Hashimoto and coworkers.112

Scheme 33 Formal CdH functionalization of indoles.

12.07.3 Intramolecular rhodium(II)-catalyzed carbene CdH insertion Intramolecular CdH insertions have been comprehensively explored in the area of metal carbene transformations.113 The reaction is an effective strategy to construct lactam, lactone, cyclopentanone, benzofuran, and benzopyran scaffolds with great selectivity. An overview of intramolecular carbene CdH insertion and their applications was presented in COMC 2007. Important advances afterwards have been reviewed comprehensively in several excellent publications.31,114–127 This section will highlight more recent progress and concentrate on examples of asymmetric intramolecular CdH insertion.

12.07.3.1 Asymmetric intramolecular carbene CdH insertion reactions Early intermolecular carbene CdH insertion reactions suffered from a lack of effective site- and stereoselectivity.13 Thus, intramolecular carbene transformations arose as a powerful strategy to circumvent this issue, allowing the construction of a variety of carbocyclic and heterocyclic derivatives.22,128–130 An early example is Taber’s Rh2(OAc)4-catalyzed reaction of the diazoacetoacetate

268

Synthetic Applications of Carbene and Nitrene CdH Insertion

133, leading to ready access of the fused cyclopentanone 134 (Scheme 34).131 Soon thereafter, chiral catalysts were developed to render the intramolecular CdH functionalization enantioselective.22,128,129 Hashimoto demonstrated that phthalimido catalysts were effective in enantioselective intermolecular reactions with acceptor/acceptor carbenes as illustrated in the Rh2(S-PTPA)4 (136)-catalyzed conversion of the diazoacetate acetate 135 to the cyclopentanone 137 in 80% ee.132 Doyle’s chiral dirhodium carboxamidate catalysts have proven over the years to be some of the most effective chiral catalysts for asymmetric intramolecular reactions with acceptor carbenes.133 The intramolecular reaction of the diazoacetate 138 to form a mixture of cis and trans isomers 141 and 142 is a good example of the type of stereocontrol that is possible.134 The Rh2(Oac)4-catalyzed reaction of 138 generated a 60:40 mixture of 142 and 141. When the chiral catalysts Rh2(5S-MEPY)4 (139) was used, the diastereoselectivity was greatly improved and 141 was formed in 86:14 d.r. and >99% ee. Even better diastereocontrol was obtained for the formation of 141 when Rh2(4S-MACIM)4 (140) was used as catalysts (99:1 d.r.), although the enantioselectivity was slightly lower (97% ee).

Scheme 34 Selected early intramolecular carbene CdH functionalizations.

In the late 1990s, it was discovered that rhodium(II)-stabilized donor/acceptor carbenes are able to effectively insert into CdH bonds adjacent to electron rich systems such as benzylic and a to heteroatoms.135 Using their dirhodium tetraprolinate catalyst Rh2(DOSP)4 (15), Davies and coworkers reported in 2001 a highly enantioselective carbene insertion into the methine a-to-oxygen (a-O) CdH bond of the ether 143 as a way to effectively and stereoselectively construct 2,3-disubstituted dihydrobenzofurans 144 (Scheme 35).136 Intramolecularly targeting CdH bonds that are both a-O and benzylic, Hashimoto137 and Davies88 later demonstrated the ability to efficiently access a second class of substituted dihydrobenzofurans by diastereoselective and

Scheme 35 Selected early examples of rhodium(II)tetracarboxylate intramolecular carbene CdH functionalization with donor/acceptor carbenes.

Synthetic Applications of Carbene and Nitrene CdH Insertion

269

enantioselective CdH functionalization at secondary sites. The optimum catalysts for this type of reaction is either Rh2(S-PTTL)4, (146) as illustrated in the example shown below, or Rh2(S-PTAD)4 (42). The Rh2(S-PTTL)4 (146)-catalyzed reaction of the aryldiazoacetate 145 preferentially forms the cis dihydrobenzofuran 147 in >99:1 favoring the cis isomer and 94% ee.137 Another approach for the enantioselective access of the dihydrobenzofurans has been the use of a combination of a chiral catalyst and a chiral auxiliary on the ester.138 The rapid access of chiral dihydrobenzofurans has shown great versatility and has been used as a key step in the synthesis of a variety of natural products.31,139,140 The asymmetric intramolecular carbene CdH insertion has been discussed in several reviews.22,128,129 The early work focused heavily on intramolecular reactions of acceptor and acceptor/acceptor carbenes. In general, the intramolecular CdH insertion reaction preferentially forms five-membered rings, but in certain systems, four and six-membered rings are preferentially formed. Several recent studies with donor/acceptor carbenes have resulted in the enantioselective formation of four membered rings. Davies and co-workers reported in 2014 that an ortho substituent on the aryl group of methyl aryldiazoacetates, such as 148, enhanced an intramolecular CdH functionalization over intermolecular reactions, resulting in the synthesis of cis-b-lactone 150 in a highly diastereoselective and enantioselective manner when Rh2(S-TCPTTL)4 (149) was used as catalyst (Scheme 36).120 In 2015 Doyle reported a highly selective and asymmetric intramolecular carbene CdH insertion reaction of enoldiazoacetamide 151 using Rh2(S-PTTL)4 (146) as catalyst to form the b-lactam 152 in 99% ee.125 Although the reaction appears like a direct CdH functionalization, it was proposed to proceed via the intermediacy of a donor-acceptor cyclopropene, which opened up to a dirhodium carbene intermediate before undergoing the intramolecular CdH functionalization event.

Scheme 36 Rhodium(II) tetracarboxylate-catalyzed four-membered ring formation by intramolecular reactions of donor/acceptor carbenes.

Alkylcarbenes are prone to 1, 2-hydride shifts but recent studies have shown impressive results in enantioselective intramolecular CdH functionalization with this class of carbene. Hashimoto and coworkers reported the synthesis of fused bicyclic ring systems via Rh2(S-PTTL)4 (146)-catalyzed intramolecular CdH insertion. A representative example is the desymmetrization of the cyclohexane derivative 153, which generated the bicyclic product 154, containing three new stereogenic centers, in 99% ee (Scheme 37).126

Scheme 37 Dirhodium catalyzed intramolecular a-alkyl-a-diazoacetate CdH functionalization.

270

Synthetic Applications of Carbene and Nitrene CdH Insertion

Donor and donor/donor carbenes tend to be less electrophilic than the carbenes containing acceptor groups.141–143 However, they are capable of diastereoselective and enantioselective intramolecular CdH functionalization reactions.124,144 Shaw and coworkers recently reported a highly enantioselective synthesis of a variety of dihydrobenzothiophenes and indanes (156), using Rh2(R-PTAD)4 (42)-catalyzed reactions of diaryldiazomethanes, generated in situ from the corresponding hydrazones 155 (Scheme 38).145

Scheme 38 Dirhodium catalyzed intramolecular CdH functionalization by mean of donor-donor diazo compounds.

Although seminal work on the application of enantioselective CdH insertion reactions for the synthesis of chiral 6-membered rings was reported by McKervey and Ye,23 examples of intramolecular CdH insertions to generate six-membered rings are relatively rare. Some classes of carbenes have recently been shown to be quite effective for the synthesis of tetrahydropyrans by means of a 1,5-intramolecular CdH insertion. Hashimoto has shown that the Rh2(S-PTTL)4 (146)-catalyzed reaction of the alkyldiazoacetate 157 generated the tetrahydropyran 158 with exceptional stereocontrol (>99:1 d.r. and 95% ee) (Scheme 39).124 Similarly, Shaw demonstrated that in situ oxidation of hydrazone 159 resulted in the corresponding diazo compound which then underwent a Rh2(R-PTAD)4 (42)-catalyzed intramolecular CdH functionalization to generate the isochroman 160 in >95:5 d.r. and 96% ee.146

Scheme 39 Rhodium(II) tetracarboxylate-catalyzed six-membered heterocycle ring formation by intramolecular asymmetric carbene CdH insertion.

Diazo compounds are the most widely used carbene precursors for intramolecular CdH functionalization, but alternative approaches can open up interesting synthetic opportunities. One such approach uses alkynes as the carbene precursor, which upon metal coordination are susceptible to nucleophilic attack, resulting in the formation of a metal carbene intermediate.110,114,147 A good example of the process is the Rh2(S-PTAD)4 (42)-catalyzed reaction of the enynones 161 reported by Zhu and coworkers (Scheme 40). The rhodium alkyne complexes 162 are trapped by the ester group to generate the furanyl carbenes 163, which then undergo the intramolecular functionalization of the benzylic CdH bonds to furnish the 2,3-disubstituted dihydroindole (164) or dihydrobenzofuran (165). The reaction can also be applied to the synthesis of tetrahydrofurans and pyrrolidines.148

Scheme 40 Dirhodium catalyzed intramolecular CdH functionalization by mean of donor-donor alkynyl carbenes.

Synthetic Applications of Carbene and Nitrene CdH Insertion

271

12.07.4 Other metal catalysts for asymmetric carbene CdH insertion reactions Although chiral dirhodium catalysts have dominated the area of asymmetric carbene CdH insertion reactions, they are certainly not the only metal catalysts for these transformations. Discussed in this section are chiral rhodium catalysts of different oxidation states as well as other chiral metal catalysts149,150 that have been demonstrated to be effective in asymmetric carbene CdH functionalization reactions.

12.07.4.1 Chiral copper catalysts for asymmetric carbene CdH functionalization Early literature reports of metal carbene transformations predominantly used copper complexes as the catalysts. However, the high electrophilicity of these copper complexes has limited their scope in terms of selectivity in asymmetric carbene transformations. Although many reports and reviews articles on copper-catalyzed carbene XdH (X ¼ O, N, S) insertion reactions exist,151 asymmetric carbene insertions into carbon-hydrogen (CdH) bonds are rather scarce. Chiral spirobox ligands as well as chiral bisoxazoline ligands have been extensively utilized in asymmetric copper catalyzed carbene transformations. Fraile and coworkers demonstrated the ability to achieve good levels of stereoinduction in the carbene CdH bond functionalization of cyclic ethers such as tetrahydrofuran using donor/acceptor diazo 18 and under the catalysis by the immobilized azabox-copper complex (170) on Laponite (Scheme 41).152

Scheme 41 Immobilized copper bisoxazoline catalyzed intermolecular carbene CdH insertion.

Using chiral bisoxazoline ligands, Maguire and coworkers reported an enantioselective copper-catalyzed intermolecular CdH functionalization reaction of a-diazo-b-keto-sulfones 171 as a way to access cyclopentanone 172 with high enantioselectivity (82% ee) (Scheme 42).153 Key to the success of the transformation was the use of chiral bisoxazoline ligand 173 along with NaBARF {BARF ¼ tetrakis[3,5-bis(trifluoromethyl)phenyl]borate}, to generate a cationic complex with a non-coordinating counterion, which improves the level of enantioselectivity in this intramolecular CdH functionalization.

Scheme 42 Copper bisoxazoline catalyzed intramolecular carbene CdH insertion.

Recently, the first example of a catalytic enantioselective formal C(sp)dC(sp3) cross-coupling carbene reaction was reported (Scheme 43) by Wang and coworkers.154 The reaction between N-tosylhydrazone 175 as the carbene precursor and trialkylsilylethyne 174, catalyzed by an in situ generated copper(I) complex with the chiral phosphoramidite ligand 177 achieved respectable levels of enantioinduction (83% ee) in the carbene C(sp)dH functionalization to generate the synthetically interesting functionalized alkyne 176.

Scheme 43 Copper phosphoramidite catalyzed intermolecular carbene CdH insertion.

272

Synthetic Applications of Carbene and Nitrene CdH Insertion

12.07.4.2 Chiral rhodium catalysts for asymmetric carbene CdH functionalization Rhodium(II) in dirhodium catalysts has been the go-to transition metal oxidation state especially for asymmetric carbene CdH functionalization reactions. Other oxidation states of are also viable alternatives for rhodium based chiral catalysts. Cramer reported a rhodium(III) catalyst capable of achieving highly enantioselective CdH functionalization reactions to access isoindolones (180) from arylhydroxamates (178) and weakly alkyl/acceptor diazo compounds (179) as carbene precursors (Scheme 44).155 Although the actual mechanism is yet to be determined, a plausible model through which the facial selectivity that leads to the chiral isoindolones was proposed. As can be seen in intermediate 181, the model showed that the large ester group of the diazo compound would steer away from the large hydroxamate-rhodium(III) cyclopentadienyl (Cp) complex thereby leading to the observed stereochemistry.

Scheme 44 Rhodium(III) catalyzed intermolecular carbene CdH insertion.

Using a transient rhodium(I) oxonium ylide intermediate (185), Wang et al. recently reported ortho-directed carbene CdH insertion reaction of unprotected phenols (182) using dialkyl diazomalonates (183) to efficiently access 2-benzofuranones (184), in which two equivalents of the carbene has been introduced (Scheme 45).156 The enantioselective version (up to 95% ee) of this transformation could be achieved using a chiral diene ligand, diisopropyl diazomalonate as the carbene precursor, nBu3BnNCl as an additive and cyclohexane as solvent. The proposed mechanism involves the oxonium ylide 185, which first form a directed ortho CdH functionalization product, which lactonizes to a benzofuran that undergoes a second CdH functionalization to generate 184.

Scheme 45 Rhodium(I) catalyzed double CdH functionalization.

Synthetic Applications of Carbene and Nitrene CdH Insertion

273

A highly asymmetric Rh(I)-catalyzed 3-C(sp3)dH functionalization of benzofuranone (186) using aryldiazoacetate (187) as the corresponding donor/acceptor carbene precursor was reported by Wang and coworkers157 The synthetic utility of this methodology was further demonstrated by diversifying the generated chiral benzofuranones (188) into enantiopure compounds with similarities to certain natural products scaffolds and drug candidates (Scheme 46).

Scheme 46 Rhodium(I) catalyzed CdH functionalization of a benzofuranone.

12.07.4.3 Chiral ruthenium catalysts for asymmetric carbene CdH functionalization Harnessing alpha-to-heteroatom CdH reactivity, Che and coworkers reported a chiral ruthenium catalyst [Ru(TPP)(CO)] (192) capable of efficiently catalyzing intramolecular asymmetric carbene CdH functionalization reactions. Favoring the cis isomer, a range of tetrahydrofurans (190) in >95:5 d.r. and pyrrolidines (191) in >99:1 d.r. could be accessed (Scheme 47).122 Carbenes in these transformations were derived from alkyl diazomethanes generated in situ from N-tosylhydrazones 189. Recently, Iwasa et al. reported a highly regio and enantioselective (90% ee) intramolecular carbene CdH insertion reaction of N-tert-butyl group of various diazoacetamides (193) using ruthenium(II) phenyl oxazolines (195) as chiral catalysts (Scheme 48).116

Scheme 47 Ruthenium catalyzed intramolecular carbene CdH insertion.

Scheme 48 Ruthenium(II) catalyzed intermolecular carbene CdH insertion.

12.07.4.4 Chiral iridium catalysts for asymmetric carbene CdH functionalization Reports of asymmetric carbene CdH insertion reactions by iridium catalysis are also uncommon, although Che and coworkers have reported intramolecular enantioselective CdH carbene insertion reactions to form chiral cyclobutanones (197) (Scheme 49). Key to the success of this transformation was the use of a chiral Iridium(III) complex of a D4-symmetric Halterman porphyrin ligand (198).158

274

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 49 Iridium catalyzed intramolecular carbene CdH insertion.

Intermolecular functionalization of electronically activated CdH bonds under the catalysis of these Iridium(III) Halterman complexes were also reported by Che. CdH functionalization of cyclohexadiene and tetrahydrofuran using aryldiazoacetates (199, 202) as the corresponding donor/acceptor carbenes under the catalysis of the iridium-porphyrin complex 200 were highly efficient with up to 98% ee and 97% ee, respectively (Scheme 50).

Scheme 50 Intramolecular iridium catalyzed intramolecular carbene CdH insertion.

Blakey, Sigman, Musaev, Davies, and coworkers have also reported an intermolecular enantioselective CdH functionalization with acceptor-only ethyl diazo ester (205) as carbene source using a new family of Ir(III)-bis(imidazolinyl)phenyl catalysts (206) (Scheme 51). The CdH functionalization proceeded selectively through the carbene insertion at the a-to-oxygen position of 204 to efficiently access 207 in 63% yield and 98:2 e.r.

Scheme 51 Intramolecular iridium catalyzed carbene CdH insertion.

12.07.4.5 Chiral cobalt catalyst for asymmetric carbene CdH functionalization Although many reports on the stereoselective preparation of tetrahydrofurans and pyrrolidines exist, reports of their sulfur counterparts are rather rare. Lawrence and Maguire recently reported a desymmetrization by asymmetric copper-catalyzed intramolecular CdH functionalization transformation by a-diazo-b-oxosulfones.159 Zhang and coworkers reported in 2015 a

Synthetic Applications of Carbene and Nitrene CdH Insertion

275

D2-symmetric Co(II)-based metalloradical catalyst (209) with amidoporphyrin as a supporting ligand.160 This Co(II) metalloradical catalyst was capable of affecting highly asymmetric intramolecular 1,5-CdH alkylation of acceptor/acceptor substituted diazo compounds of a-methoxycarbonyl-a-diazosulfones (208) providing 5-memebered sulfolane derivatives (210) in good yield (92% yield) and excellent stereoselectivity (92% ee) (Scheme 52).

Scheme 52 Intramolecular cobalt catalyzed carbene CdH insertion.

12.07.5 Biocatalysts and metalloenzymes for asymmetric carbene CdH insertion reactions Direct CdH bond transformations in biological systems are well documented.161–164 Inspired by transformations such as the direct cytochrome-450 (P450) mediated CdH hydroxylation reaction of certain biomolecules, organic chemists have sought to achieve a similar level of control for site- and stereoselectivity in CdH bond functionalization reactions using these biocatalysts in their native state or by engineering variants of the corresponding wild-type through directed evolution. Although a range of biocatalyst and metalloenzyme-catalyzed carbene and nitrene cyclopropanation and aziridination reactions have been reported, respectively, few reports of catalytic asymmetric carbene CdH insertion reactions by biocatalysts or metalloenzymes exist. The first example of C(sp3)dH bond transformation catalyzed by an artificial metalloenzyme was reported in 2013 by Hayashi and coworkers.164 In a 2016, Hartwig et al. reported a remarkable intramolecular unactivated and activated carbene C(sp3)dH insertion reaction using aryldiazoesters (211) as carbene precursors (Scheme 53).165 Key to the catalysis was the evolution of an iridium-porphyrin artificial metalloenzyme Ir(Me)-PIX CYP119 (212) which performed at up to 35,000 total turnover numbers (TON), 2550 hours−1 turnover frequency and, up to 98% enantiomeric excess to generate a range of dihydrobenzofuran derivatives (213). Using various mutants of Ir(Me)-mOCR-Myo (215), an artificial metalloenzyme, Hartwig and coworkers also demonstrated the ability to access a range of substituted dihydrobenzofurans (216) via an intramolecular carbene insertion into the CdH bonds of an ortho-alkoxy group of electron rich a-aryldiazoesters.165 Kinetic parameters of this transformation revealed an up to 7260 TON and up to 92:8 enantiomeric ratio.

Scheme 53 Asymmetric intramolecular iridium biocatalysts catalyzed CdH functionalization.

276

Synthetic Applications of Carbene and Nitrene CdH Insertion

Organofluorine compounds are highly privileged scaffolds, especially in medicinal chemistry, due to the fact that they can enhance stability, lipophilicity, and bioavailability.166 In a recent years, Arnold et al. reported an engineered cytochrome P411variant (219) obtained by directed evolution.167 This artificial iron-heme biocatalyst demonstrated remarkable capabilities in the functionalization of a-amino C(sp3)dH bonds of tertiary amines (217) using carbenes derived from a-trifluoroalkyl diazo compounds (218) (Scheme 54). The synthesis of the chiral fluoroalkyl motifs (220) could be achieved with up to 4070 total turnovers and 99% enantiomeric excess. Under the catalysis of a different P450 variant with an axially coordinated serine (223), Arnold and coworkers recently reported an asymmetric a-amino primary and secondary CdH insertion reaction of N-arylated pyrrolidines (221) using an a-diazo-g-lactone (222) as the corresponding carbene precursor to access chiral lactone motifs (224).168 The catalytic efficiency of the transformation was recorded at up to 4000 TON. The obtained chiral lactones with contiguous stereocenters could be accessed in up to 99:1 diastereomeric ratio and 99% enantiomeric excess.

Scheme 54 Iridium biocatalysts for enantioselective intermolecular CdH functionalization.

12.07.6 Nitrene CdH insertion Considerable advances in CdH amination protocols have been made in recent years.36,38,39,41,169–172 One of the most established methods is the CdH insertion chemistry of metal nitrenes.35,39,40,173,174 Metal nitrenes can react as either singlet or triplet nitrenes and this has a profound effect on the outcome of the reaction.42,175–177 Singlet-state metal nitrenes can undergo direct insertion into a CdH bond with retention of stereochemistry. Triplet-state metal nitrenes react with CdH bonds by abstracting hydrogen atoms, forming two separate radicals which then couple. The diradical processes tend not to be stereospecific.176,178,179 The considerable advances over the first 25 years of metal nitrene mediated amination of saturated CdH bonds pioneered in 1982 by Breslow and Gellman180 were reviewed in COMC 2007. Hence this overview will focus on the progress made since around 2007. Many different metal catalysts have been applied to the nitrene chemistry and the following section is organized according to which metal is used.

12.07.6.1 Rhodium(II)-catalyzed nitrene CdH insertion The most widely used class of catalysts for nitrene CdH insertions are the dirhodium tetracarboxylates.39,170,181 A general mechanism for the reaction is shown in Scheme 55.182–184 A suitable nitrene precursor is required, which will react with the catalyst to generate the rhodium(II) nitrene intermediate 228. The most widely used nitrene precursors are phenyliodinanes 227 and they are readily generated in situ from the reaction of the amine derivatives 225 with phenyliodonium dicarboxylate 226.170,185,186 In some instances azides can be used as the dirhodium nitrene precursor, and this process has been particularly effective with aryl azides.185,187 The nitrene then reacts with the appropriate substrate and undergoes the CdH functionalization to

Scheme 55 General mechanism for dirhodium-catalyzed CdH amination.

Synthetic Applications of Carbene and Nitrene CdH Insertion

277

form 229. As the in situ generation of the phenyliodinane is conducted under oxidative conditions, the dirhodium(II,II) is typically oxidized to the dirhodium(II,III) form, and it has been shown that the oxidized dirhodium complex is the active catalyst. Unlike the dirhodium-carbene chemistry, there is a much greater likelihood of a stepwise diradical process (231), occurring from the triple state of the dirhodium nitrene, competing with the concerted reaction (230) involving the singlet state of the carbene.

12.07.6.1.1

Intramolecular nitrene CdH insertion

The in-situ phenyliodinane generation protocol popularized by Du Bois and Che has been applied to a wide range of intramolecular reactions and these were discussed in COMC 2007.186 Hence only a few representative examples of intramolecular reactions will be described here (Scheme 56). A key component of this elegant protocol is to include base such as magnesium oxide to quench the acetic acid byproduct because otherwise the acetic acid would cause ligand exchange on the catalyst. A major advance was the development by the Du Bois group of the bridged dirhodium catalyst, Rh2(esp)2 (232).183 The tethered dicarboxylate ligands render the complex more robust than regular tetracarboxylate complexes, leading to overall better catalyst performance. Often, the nitrene is bound to an electron withdrawing substituent such as a sulfonyl (233 and 235)188,189 or carbonyl (237).190 The influence of Rh2(esp)2 is readily seen in the intramolecular reaction of 233 to form 234.188 Under rhodium(II) acetate catalysis the yield of 234 is only 20% but with Rh2(esp)2 the yield is 92%. Nitrenes with sulfonyl tethers tend to preferentially form six-membered rings as illustrated for 234 and 236,188,189 whereas in nitrenes with carbonyl tethers, typically form five member rings as seen in the formation of 238.190 When the nitrene substituent is an aryl group, aryl azides can be used as the dirhodium-nitrene precursor, as illustrated in the CdH amination with the aryl azide 239, which generates the tricyclic derivative 240.191

Scheme 56 Representative examples of intramolecular CdH amination.

12.07.6.1.2

Intermolecular nitrene CdH insertion

The dirhodium nitrene intermediates are highly reactive and one of the major challenges has been to find appropriate systems for highly site selective intermolecular reactions. In 2007, Du Bois demonstrated that the electron-deficient trichloroethylsulfamate (TcesNH2) (242) as the nitrene precursor and Rh2(esp)2 (232) as the catalyst were a good combination for benzylic amination as illustrated in the conversion of 241 to 243 (Scheme 57).183 A further synthetic advantage of this process is the facile regeneration of the amine from the trichloroethylsulfamate 243.

278

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 57 Benzylic CdH amination with TcesNH2.

Typically, CdH amination with dirhodium nitrenes is conducted with an excess of the CdH substrate. In the case of complex substrates, such an approach would not be practical, and hence, further refinements of the reaction conditions have been sought after. In 2013, Du Bois reported difluorophenoxysulfonamide (DfsNH2) (245) as a superior nitrene source for intermolecular CdH amination of 3 CdH bonds.192 The reaction could be conducted with the trapping agents as the limiting agent as illustrated in the conversion of 244 to 246 (Scheme 58). The reaction displayed high site selectivity even in the presence of multiple tertiary carbons in the substrate. Furthermore, the electron deficient nature of the sulfonamide enables mild deprotection by simply refluxing in aqueous CH3CN.

Scheme 58 Tertiary CdH amination with DfsNH2.

Further refinement of the intermolecular CdH amination was achieved by using phenyl sulfamate (247) as the nitrene source and pivalonitrile as the solvent (Scheme 59). Pivalonitrile is likely to coordinate to the open axial site of the dirhodium, enhancing the stability of the catalyst under the reaction conditions.193 This efficient intermolecular amination of C(sp3)—H bond method has been broadly applied to numerous pharmaceutical targets with excellent site selectivity as illustrated in the formation of 248–255. These examples demonstrate that good site selectivity is possible in complex substrates and that the chemistry is compatible with a variety of functional groups.

Scheme 59 CdH amination of pharmaceutically relevant substrates.

Synthetic Applications of Carbene and Nitrene CdH Insertion

12.07.6.1.3

279

Enantioselective CdH amination

In COMC 2007, chiral dirhodium catalysts for CdH amination reactions were not discussed but considerable advances have now been made in this area.37,39,194 The early reports using chiral catalysts tended to proceed with relatively low levels of enantioselectivity, but in 2006 Davies reported that Rh2(S-TCPTAD)4 (57) is as an effective chiral catalyst for both inter- and intramolecular CdH amination reactions.195 A representative example is the benzylic CdH amination of ethylbenzene to form 257 in 74% ee (Scheme 60).

Scheme 60 Rh2(S-TCPTAD)4-catalyzed enantioselective CdH amination.

As asymmetric inductions from using only a chiral catalyst was still relatively modest, Dauban explored enantioselective reactions using a combination of a chiral catalyst and an aminating agent (259) containing a chiral auxiliary.196 This tactic resulted in a considerable enhancement in the asymmetric induction (Scheme 61). The optimum catalyst was Rh2(S-NTTL)4 (110), originally developed by Müller. As illustrated in the reaction with indane (258), when the chiral catalysts and auxiliaries are matched, the asymmetric induction is very high and the amino indane 260 is formed in >99.5:0.5 d.e.

Scheme 61 Combination of chiral auxiliary and chiral catalyst for asymmetric CdH amination.

Another enantioselective catalyst for intramolecular CdH amination at benzylic and allylic sites is the carboxamidate derived catalyst Rh2(S-nap)4 (262).197 An intramolecular hydrogen bond between the tosylamine and the carbonyl rigidifies the ligand, and this is considered to be a key component behind why these catalysts are capable of very high levels of asymmetric induction, as illustrated in the conversion of the sulfinamine 261 to the cyclic product 263 in 99% ee (Scheme 62). Notably, with allylic substrates, Rh2(S-nap)4 (262) showed a greater preference for allylic CdH amination over aziridination, compared to the dirhodium tetracarboxylate catalysts.

Scheme 62 Rh2(S-nap)4-catalyzed enantioselective CdH amination.

280

Synthetic Applications of Carbene and Nitrene CdH Insertion

Lebel has published a series of papers describing the use of N-tosyloxycarbamates as the nitrene precursors.198,199 In 2011, she described an enantioselective intermolecular allylic CdH amination using a combination of phenyl-2,2,2-trichloroethylN-tosyloxycarbamate (265) as an aminating reagent with a chiral auxiliary and Rh2(S-Br-NTTL) (266) as the chiral catalyst (Scheme 63).199 As illustrated in the amination reaction of 264, the product 267 was formed with 11:1 d.r. No additional oxidant is required when using N-tosyloxycarbamates (265), which avoids potential side reactions. Furthermore, the free amine can be generated in high yield without degradation because the Ph-Troc protecting group in 267 is readily removed under mild conditions.

Scheme 63 CdH amination using N-tosyloxycarbamates.

12.07.6.1.4

Applications in total synthesis

The synthetic potential of nitrene CdH insertion has been demonstrated in elegant applications in total synthesis.200,201 The synthesis of (−)-tetrodotoxin, reported in 2003, includes both an intramolecular carbene CdH insertion as well as an intramolecular nitrene CdH insertion and was described in COMC 2007.202 Further examples of using nitrene CdH amination in total synthesis have been described. Intramolecular CdH amination has been applied to the total synthesis of another neurotoxin, (+)-saxitoxin (270) and the key CdH amination step is shown in Scheme 64. The early-stage conversion of 268 to 269 sets up a stereoselective arrangement of nitrogen and oxygen functionality at three contiguous stereocenters, which were then used to generate the dense heteroatom functionality in (+)-saxitoxin (270).202

Scheme 64 Total synthesis of (+)-saxitoxin.

12.07.6.2 Manganese-catalyzed nitrene CdH insertion In the pioneering studies by Breslow and Gellman, manganese porphyrins were shown to be effective catalysts for the CdH amination of cyclohexane.180 Subsequently, Mansuy and co-workers demonstrated that manganese porphyrins can catalyze amination of adamantane or allylic amination of alkenes in up to 70% yield.203 These early results used hypervalent iminoiodinanes as the nitrene precursor. Subsequently, Che demonstrated more practical procedures in which the iminoiodinanes were generated in situ using PhI(OAc)2 and NH2R (R ¼ Ts, Ns, and SO2Me).204 An electron-deficient Mn(III)-porphyrin catalyst was reported to catalyze amination of saturated CdH bonds with high turnover numbers, and these results were summarized in COMC 2007. One of the challenges of using porphyrin complexes is the synthesis of elaborate porphyrin ligands. Hence, efforts have been made to generate more accessible planar ligands.205,206 White and co-workers reported that the manganese tert-butylphthalocyanine complex ([Mn(tBuPc)]
SbF6) (274) was an effective catalyst as illustrated in the intramolecular amination of 271 to 273 in Scheme 65.207 The manganese catalysts had a distinctive reactivity profile compared to the dirhodium catalysts because in substrates where competing allylic CdH amination and aziridination could occur, the manganese catalyst strongly preferred CdH amination.207

Synthetic Applications of Carbene and Nitrene CdH Insertion

281

Scheme 65 Manganese-catalyzed intramolecular CdH amination.

In 2018, the same group reported that the more electron deficient manganese phthalocyanine catalyst, [Mn(III)(ClPc)] (276), was effective in late stage benzylic CdH amination of bioactive molecules and natural products, such as the amination of 275 to form 277 (Scheme 66).208 The system is selective at functionalizing benzylic CdH bonds even in the presence of other relatively active CdH bonds and showed good functional group compatibility with effective reactions occurring in substrates containing tertiary amine, pyridine or benzimidazole functionalities. Mechanistic studies indicated that the CdH bond cleavage proceeds via a stepwise CdH amination pathway with CdH cleavage as the rate-determining step. The electrophilic nature of metallonitrene intermediate favors reactions to occur at the more electron-rich benzylic site.

Scheme 66 Manganese-catalyzed intermolecular CdH amination.

12.07.6.3 Ruthenium-catalyzed nitrene CdH insertion Early studies from Cenini and Che demonstrated that ruthenium porphyrins were effective catalysts in allylic CdH amination.204,209–211 Most notable was the enantioselective intramolecular amination reported by Che in 2002.210 This work was discussed in detail in COMC 2007. Since then, efforts have been made to develop new ruthenium catalysts for CdH amination chemistry.209,212–215 In 2011, Du Bois developed a mixed-valent diruthenium (II/III) paddlewheel complex, Ru2(hp)4Cl (279), to catalyze intramolecular allylic CdH amination with sulfamate esters (Scheme 67).213 The reaction exhibited good selectivity to favor amination of allylic CdH bonds. Thus, the sulfamate 278 gave a strong preference for the allylic CdH amination product 280 over the aziridine 281.

Scheme 67 Ruthenium-catalyzed intermolecular CdH amination.

282

Synthetic Applications of Carbene and Nitrene CdH Insertion

In 2008, Blakey described a cationic ruthenium (II)-pybox catalyst (284) for intramolecular benzylic and allylic CdH amination with sulfamates (Scheme 68). Under ambient conditions, the catalyst showed good activity and high levels of enantioselectivity.212 The indole derivative 282 was readily converted to the cyclic product 283 in 92% ee. For the benzylic CdH amination, both electron-donating, electron-withdrawing, as well as ortho-substituents on the phenyl ring are tolerated. For allylic CdH amination, no competing aziridination product was observed, which demonstrated the remarkable chemoselectivity of the ruthenium (II)-pybox catalyst 284.

Scheme 68 Ruthenium-catalyzed enantioselective intramolecular CdH amination.

In 2013, Katsuki reported a chiral (salen) Ru(II) catalyst 287 which catalyzed enantioselective intermolecular C(sp3)—H amination utilizing SES azide (2-(trimethylsilyl)ethanesulfonyl azide) (286) as nitrene precursor (Scheme 69).214 While structurally simpler iridium-salen complexes were effective catalysts, the ruthenium complex 287 delivered the amine products with very high enantiocontrol as illustrated in the conversion of 285 to the amino product 288 in 99% ee.

Scheme 69 Ruthenium-catalyzed enantioselective intermolecular CdH amination.

12.07.6.4 Copper-catalyzed nitrene CdH insertion Copper complexes were some of the first catalysts to be extensively examined for group transfer reactions.42,216–223 Perez and co-workers have extensively studied the applications of copper complexes such as 290 with bulky electron-deficient homoscorpionate ligands (TpBr3Cu(NCMe)) (Scheme 70).216 An important breakthrough in this area, described in COMC 2007, was the demonstration that catalyst 290 was capable of intramolecular CdH amination of C(sp3)dH bonds to form amines such as 291–292, and functionalization of the C(sp2)dH bond of benzene to provide N-tosylaniline 293.

Scheme 70 Copper-catalyzed CdH amination.

Synthetic Applications of Carbene and Nitrene CdH Insertion

283

The Warren group has explored a number of novel copper complexes as potential catalysts for CdH amination.217–219,221 In 2008, they reported the reaction of [{(Cl2NN)Cu}2(m-benzene)] with the 1-adamantylazide to form the dicopper nitrene intermediates [[Cu]2(m-NAd)] (294),217 which reacts with unactivated C(sp3)dH bonds to deliver the corresponding amination products such as 295 under both stoichiometric and catalytic conditions (Scheme 71). The utilization of a tertiary organic azide generated N-functionalized secondary organic amines directly. Inspired by this precedent, in 2010, the same group investigated a new catalytic system (296) for intermolecular C(sp3)dH amination using primary and secondary unactivated alkyl amines.218 With the copper-amido complex 296 as nitrene precursor, the desired CdH aminated products were obtained in good yields. The method provided a valuable alternative avoiding requiring N-based electron-withdrawing activating groups.

Scheme 71 Novel copper complexes for CdH amination.

In 2014, Stavropoulos and co-workers developed a copper(I) catalyst 298 with a strongly Lewis basic guanidinato ligand to catalyze CdH amination of a broad scope of aliphatic hydrocarbons (Scheme 72).222 The C3-symmetric tripodal copper(I) complex was utilized to catalyze nitrene transfer from PhI]NR to deliver the CdH amination as well as olefin aziridination products. A detailed mechanistic investigation suggested that radicals are key intermediates and that the reaction follows the hydrogen atom abstraction (HAA)/rebound pathway to afford the desired products, although the active copper-nitrene species is still uncertain.

Scheme 72 Tripodal copper catalysts for CdH amination.

In 2012, Chan utilized Cu(OTf )2 (300) and 1,10-phenanthroline (1,10-phen) to catalyze allylic CdH amination of 2-alkyl substituted 1,3-dicarbonyl compounds to prepare a-acyl-b-amino acid, while increasing the equivalents of nitrene precursor, PhI] NTs, resulted in formation of aziridination product (Scheme 73).220 The enolic form of dicarbonyl substrate 299 generated in situ through coordination to the Lewis acid metal catalyst is the active intermediate that undergoes CdH amination. In most cases, the HAA/rebound pathway is favored in copper-catalyzed CdH amination reactions. However, the authors found that the reaction has a KIE value of 1.9, which suggested CdH bond cleavage might be the rate determining step, following a concerted asynchronous pathway to deliver the CdH amination products.

284

Synthetic Applications of Carbene and Nitrene CdH Insertion

Scheme 73 Synthesis of a-acyl-b-amino acids.

12.07.6.5 Silver-catalyzed nitrene CdH insertion In recent years a number of interesting silver catalysts have been developed for CdH amination reactions.224–233 Often these catalysts are silver dimers, which can have different properties from the monomeric species. In 2004, He and co-workers developed the novel disilver(I) complex 306 to catalyze intramolecular amination of saturated CdH bonds (Scheme 74).224 The dimeric silver(I) catalyst is generated in-situ and is capable of generating five- and six-membered-ring insertion products such as 303 and 305. The catalyst was not capable of effective intermolecular reactions, and so, a second dimeric silver complex 308 was developed and shown to catalyze intermolecular benzylic CdH amination.225

Scheme 74 Silver-catalyzed CdH amination.

Schomaker has also examined substituted phenanthroline ligands for silver catalysis and found there is a profound difference between the catalytic behavior of monomeric (313) or bis-ligated monomeric (314) silver complexes (Scheme 75).226,228,234–237 In particular, there is a distinct difference in the outcome of competing intramolecular CdH amination and aziridination. The coordination states of the ligand and the metal core could be tuned by simply changing the stoichiometry of the two species. When the silver/ligand ratio was 1:1.25, the aziridine 311 was mainly formed, whereas when the ratio was 1:3, allylic CdH amination to from 312 is strongly favored.226

Synthetic Applications of Carbene and Nitrene CdH Insertion

285

Scheme 75 Influence of ligand aggregation on CdH amination versus aziridination.

12.07.6.6 Gold-catalyzed CdH amination Gold complexes are also effective catalysts for CdH amination.238–241 A recent example described by Feng and Zhu showed that the gold-bipyridine complexes 315 catalyzed intermolecular benzylic CdH amination as illustrated for the formation of 316–318 (Scheme 76).240 The nitrene precursor in this case was N-bromosulfonamide formed in-situ from the sulfonamide and N-bromosuccinimide.

Scheme 76 Gold-catalyzed CdH amination.

12.07.6.7 Cobalt-catalyzed nitrene CdH insertion Cobalt catalysis has been popularized by Zhang and others in both carbene and nitrene group transfer reactions.242–252 In 2015, Blakey and MacBeth reported a novel cobalt(II) catalyst 320 bearing redox-active ligands (Scheme 77).245 The dinuclear cobalt(II) complex catalyzed intramolecular CdH amination to form indolines 319 from ortho-substituted aryl azides 321. The procedure is compatible with nucleophilic sites and can tolerate various heterocycles. It can also be employed to generate six-, and seven-membered rings.

Scheme 77 Cobalt-catalyzed CdH amination.

286

Synthetic Applications of Carbene and Nitrene CdH Insertion

12.07.6.8 Iron-catalyzed nitrene CdH insertion Advances in iron catalysis are of considerable interest because the metal is so abundant.253–258 Since the pioneering work of Breslow demonstrated that iron complexes can catalyze the intramolecular amination,180 iron catalysts have been widely investigated and notable advanced have been achieved. In 2012, White and co-workers revealed that Fe(III)-phthalocyaninato ([FePc]Cl, 323) favored the allylic CdH amination over the related aziridination and other CdH bonds (Scheme 78).253 For polyolefinic substrates, the site selectivity was controlled by tuning the electronic and steric character of the allylic position. It was proposed that the excellent selectivity was the result of a rapid radical rebound step that can suppress other possible side reactions of the diradical.

Scheme 78 Iron phthalocyanine-catalyzed CdH amination.

In 2013, Betley and coworkers developed an iron-dipyrrinato catalyst (326) capable of promoting a direct intramolecular CdH amination of aliphatic azides (325) to access substitute pyrrolidines (327) (Scheme 79).259 It was hypothesized that the transformation occurred in a three step process involving an initial iron oxidation by the alkyl azide substrate, an intramolecular H-atom abstraction to generate an alkyl radical, and a final step, a radical recombination is proposed to form the observed N-heterocycle product.

Scheme 79 Iron dipyrrinato catalyzed CdH amination.

A major recent accomplishment has been the application of directed evolution of heme enzymes to catalyze reactions not seen in nature.260–266 In 2017, the Arnold group reported an iron-containing enzymatic catalyst, Cytochrome P411CHA (330), generated after multiple cycles of directed evolution from cytochrome P450 monooxygenase. This enzymatic catalyst (330) was capable of CdH amination (Scheme 80).264 Most notably, the benzylamine products such as 331 with high enantioselectivity (>99% ee) and with low catalysts loadings. The highest catalyst turnover number was reported to be 1300, which is higher than what can currently be achieved using small metal or organo catalysts.

Scheme 80 Enzymatic CdH amination.

Synthetic Applications of Carbene and Nitrene CdH Insertion

287

In conclusion, transition metal catalyzed CdH functionalization by means of carbene and nitrene intermediates continues to expand in many different ways.267 The carbene system has the advantage of having two groups on the carbene, which can be tuned to obtain the right balance of sufficient reactivity to functionalize CdH bonds intermolecularly, while still being capable of highly site selective reactions without resorting to intramolecular reactions. The donor/acceptor carbenes have been particularly effective for catalyst controlled site selective CdH functionalization and the self-assembled dirhodium tetracarboxylates are well suited for this chemistry. Further catalyst design is a key element to refine the subtle control of the CdH functionalization chemistry and tremendous progress has been made in the last decade. Intramolecular nitrene insertion is a very useful transformation, but the intermolecular reaction is less developed because of the challenges of achieving highly selective transformations in complex systems. Considerable progress has been made in the design of new chiral catalysts and the spectacular results using engineered enzymes indicate that catalyst-controlled site-selective reactions of both carbenes and nitrenes is likely to become broadly applicable.

Acknowledgment The authors acknowledge funding of their work by the National Science Foundation (CHE-1956154 and the CCI Center for Selective C–H Functionalization (CHE-1700982)) and the National Institutes of Health (GM 099142).

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

Godula, K.; Sames, D. C-H Bond Functionalization in Complex Organic Synthesis. Science 2006, 312, 67–72. Scott, L. T.; DeCicco, G. J. Intermolecular Carbon-Hydrogen Insertion of Copper Carbenoids. J. Am. Chem. Soc. 1974, 96, 322–323. Gutekunst, W. R.; Baran, P. S. C–H Functionalization Logic in Total Synthesis. Chem. Soc. Rev. 2011, 40, 1976–1991. Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Innate and Guided C–H Functionalization Logic. Acc. Chem. Res. 2012, 45, 826–839. Abrams, D. J.; Provencher, P. A.; Sorensen, E. J. Recent Applications of C–H Functionalization in Complex Natural Product Synthesis. Chem. Soc. Rev. 2018, 47, 8925–8967. Bergman, R. G. C–H Activation. Nature 2007, 446, 391–394. McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent Developments in Natural Product Synthesis Using Metal-Catalysed C-H Bond Functionalisation. Chem. Soc. Rev. 2011, 40, 1885–1898. Newhouse, T.; Baran, P. S. If C-H Bonds Could Talk: Selective C-H Bond Oxidation. Angew. Chem. Int. Ed. 2011, 50, 3362–3374. Chen, D. Y.; Youn, S. W. C-H Activation: A Complementary Tool in the Total Synthesis of Complex Natural Products. Chem. A Eur. J. 2012, 18, 9452–9474. Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960–9009. Schçnherr, H.; Cernak, T. Profound Methyl Effects in Drug Discovery and a Call for New C-H Methylation Reactions. Angew. Chem. Int. Ed. 2013, 52, 12256–12267. Wencel-Delord, J.; Glorius, F. C-H Bond Activation Enables the Rapid Construction and Late-Stage Diversification of Functional Molecules. Nat. Chem. 2013, 5, 369–375. Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssié, P. Transition-Metal-Catalysed Reactions of Diazoesters. Insertion into C–H Bonds of Paraffins by Carbenoids. J. Chem. Soc. Chem. Commun. 1981, 688–689. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Catalytic Carbene Insertion into C–H Bonds. Chem. Rev. 2010, 110, 704–724. Sinha, S. K.; Guin, S.; Maiti, S.; Biswas, J. P.; Porey, S.; Maiti, D. Toolbox for Distal C–H Bond Functionalizations in Organic Molecules. Chem. Rev. 2021. https://doi.org/10. 1021/acs.chemrev.1c00220. Rej, S.; Ano, Y.; Chatani, N. Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds. Chem. Rev. 2020, 120, 1788–1887. Crabtree, R. H. Alkane C–H Activation and Functionalization With Homogeneous Transition Metal Catalysts: A Century Of Progress—A New Millennium in Prospect. J. Chem. Soc. Dalton Trans. 2001, 2437–2450. Labinger, J. A.; Bercaw, J. E. Understanding and Exploiting C–H Bond Activation. Nature 2002, 417, 507–514. Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788–802. Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous C–H Bond Functionalization: Challenges and Opportunities. ACS Cent. Sci. 2016, 2, 281–292. Berry, J. F. The Role of Three-Center/Four-Electron Bonds in Superelectrophilic Dirhodium Carbene and Nitrene Catalytic Intermediates. Dalton Trans. 2012, 41, 700–713. Davies, H. M. L.; Beckwith, R. E. J. Catalytic Enantioselective C-H Activation by Means of Metal-Carbenoid-Induced C-H Insertion. Chem. Rev. 2003, 103, 2861–2903. Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Roos, G. H. P. Asymmetric Synthesis in Carbon–Carbon Bond Forming Reactions of a-Diazoketones Catalysed by Homochiral Rhodium(II) Carboxylates. J. Chem. Soc. Chem. Commun. 1990, 361–362. Doyle, M. P. Catalytic Methods for Metal Carbene Transformations. Chem. Rev. 1986, 86, 919–939. Davies, H. M. L. Finding Opportunities from Surprises and Failures. Development of Rhodium-Stabilized Donor/Acceptor Carbenes and Their Application to Catalyst-Controlled C–H Functionalization. J. Org. Chem. 2019, 84, 12722–12745. Davies, H. M. L.; Liao, K. Dirhodium Tetracarboxylates as Catalysts for Selective Intermolecular C–H Functionalization. Nat. Rev. Chem. 2019, 3, 347–360. Qin, C.; Davies, H. M. L. Role of Sterically Demanding Chiral Dirhodium Catalysts in Site-Selective C-H Functionalization of Activated Primary C-H Bonds. J. Am. Chem. Soc. 2014, 136, 9792–9796. Bedell, T. A.; Hone, G. A.; Valette, D.; Yu, J. Q.; Davies, H. M. L.; Sorensen, E. J. Rapid Construction of a Benzo-Fused Indoxamycin Core Enabled by Site-Selective C-H Functionalizations. Angew. Chem. Int. Ed. 2016, 55, 8270–8274. Brady, P. B.; Bhat, V. Recent Applications of Rh- and Pd-Catalyzed C(sp3)-H Functionalization in Natural Product Total Synthesis. Eur. J. Org. Chem. 2017, 2017, 5179–5190. Rizzo, A.; Mayer, R. J.; Trauner, D. Biomimetic Approach Toward Enterocin and Deoxyenterocin. J. Org. Chem. 2019, 84, 1162–1175. Lombard, F. J.; Coster, M. J. Rhodium(II)-Catalysed Intramolecular C-H Insertion Alpha- to Oxygen: Reactivity, Selectivity and Applications to Natural Product Synthesis. Org. Biomol. Chem. 2015, 13, 6419–6431. Davies, H. M. L.; Doan, B. D. Total Synthesis of ()-Tremulenolide A and ()-Tremulenediol A via a Stereoselective Cyclopropanation/Cope Rearrangement Annulation Strategy. J. Org. Chem. 1998, 63, 657–660. Davies, H. M. L.; Ni, A. Enantioselective Synthesis of b-Amino Esters and Its Application to the Synthesis of the Enantiomers of the Antidepressant Venlafaxine. Chem. Commun. 2006, 3110-3112.

288

Synthetic Applications of Carbene and Nitrene CdH Insertion

34. Ibbeson, B. M.; Laraia, L.; Alza, E.; Connor, C. J. O.; Tan, Y. S.; Davies, H. M. L.; McKenzie, G.; Venkitaraman, A. R.; Spring, D. R. Diversity-Oriented Synthesis as a Tool for Identifying New Modulators of Mitosis. Nat. Commun. 2014, 5, 3155. 35. Collet, F.; Lescot, C.; Liang, C.; Dauba, P. Studies in Catalytic C–H Amination Involving Nitrene C–H Insertion. Dalton Trans. 2010, 39, 10401–10413. 36. Dequirez, G.; Pons, V.; Dauban, P. Nitrene Chemistry in Organic Synthesis: Still in Its Infancy?Angew. Chem. Int. Ed. 2012, 51, 7384–7395. 37. Hayashi, H.; Uchida, T. Nitrene Transfer Reactions for Asymmetric C-H Amination: Recent Development. Eur. J. Org. Chem. 2020, 2020, 909–916. 38. Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020, 120, 2613–2692. 39. Ju, M.; Schomaker, J. M. Nitrene Transfer Catalysts for Enantioselective C–N Bond Formation. Nat. Rev. Chem. 2021, 5, 580–594. 40. Noda, H.; Tang, X.; Shibasaki, M. Catalyst-Controlled Chemoselective Nitrene Transfers. Helv. Chim. Acta 2021, 104. 41. Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C-H Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017, 117, 9247–9301. 42. Carsch, K. M.; DiMucci, I. M.; Iovan, D. A.; Li, A.; Zheng, S.-L.; Titus, C. J.; Lee, S. J.; Irwin, K. D.; Nordlund, D.; Lancaster, K. M.; Betley, T. A. Synthesis of a Copper-Supported Triplet Nitrene Complex Pertinent to Copper-Catalyzed Amination. Science 2019, 365, 1138–1143. 43. Dong, Y.; Lund, C. J.; Porter, G. J.; Clarke, R. M.; Zheng, S. L.; Cundari, T. R.; Betley, T. A. Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands. J. Am. Chem. Soc. 2021, 143, 817–829. 44. Davies, H. M. L. Recent Advances in Catalytic Enantioselective Intermolecular C–H Functionalization. Angew. Chem. Int. Ed. 2006, 45, 6422–6425. 45. Davies, H. M. L.; Antoulinakis, E. G. Intermolecular Metal-Catalyzed Carbenoid Cyclopropanations. Org. React. 2004, 1–326. 46. Nakamura, E.; Yoshikai, N.; Yamanaka, M. Mechanism of C-H Bond Activation:C-C Bond Formation Reaction between Diazo Compound and Alkane Catalyzed by Dirhodium Tetracarboxylate. J. Am. Chem. Soc. 2002, 124, 7181–7192. 47. Yoshikai, N.; Nakamura, E. Theoretical Studies on Diastereo- and Enantioselective Rhodium-Catalyzed Cyclization of Diazo Compoundvia Intramolecular C–H Bond Insertion. Adv. Synth. Catal. 2003, 345, 1159–1171. 48. Wong, F. M.; Wang, J.; Hengge, A. C.; Wu, W. Mechanism of Rhodium-Catalyzed Carbene Formation from Diazo Compounds. Org. Lett. 2007, 9, 1663–1665. 49. Trindade, A. F.; Coelho, J. A. S.; Afonso, C. A. M.; Veiros, L. F.; Gois, P. M. P. Fine Tuning of Dirhodium(II) Complexes: Exploring the Axial Modification. ACS Catal. 2012, 2, 370–383. 50. Berry, J. F. Metal–Metal Multiple Bonded Intermediates in Catalysis. J. Chem. Sci. 2015, 127, 209–214. 51. Padwa, A.; Zou, Y. Solvent and Ligand Effects Associated with the Rh(II)-Catalyzed Reactions of Alpha-Diazo-Substituted Amido Esters. J. Org. Chem. 2015, 80, 1802–1808. 52. Werle, C.; Goddard, R.; Furstner, A. The First Crystal Structure of a Reactive Dirhodium Carbene Complex and a Versatile Method for the Preparation of Gold Carbenes by Rhodium-to-Gold Transmetalation. Angew. Chem. Int. Ed. 2015, 54, 15452–15456. 53. Liu, H.; Duan, J.-X.; Qu, D.; Guo, L.-P.; Xie, Z.-Z. Mechanistic Insights into Asymmetric C–H Insertion Cooperatively Catalyzed by a Dirhodium(II) Complex and Chiral Phosphoric Acid. Organometallics 2016, 35, 2003–2009. 54. Qi, X.; Li, Y.; Bai, R.; Lan, Y. Mechanism of Rhodium-Catalyzed C-H Functionalization: Advances in Theoretical Investigation. Acc. Chem. Res. 2017, 50, 2799–2808. 55. Kornecki, K. P.; Briones, J. F.; Boyarskikh, V.; Fullilove, F.; Autschbach, J.; Schrote, K. E.; Lancaster, K. M.; Davies, H. M. L.; Berry, J. F. Direct Spectroscopic Characterization of a Transitory Dirhodium Donor-Acceptor Carbene Complex. Science 2013, 342. 56. Morton, D.; Blakey, S. B. Expanding the Carbene C-H Insertion Toolbox. Chem. Cat. Chem. 2015, 7, 577–578. 57. Hansen, J.; Autschbach, J.; Davies, H. M. L. Computational Study on the Selectivity of Donor/Acceptor-Substituted Rhodium Carbenoids. J. Org. Chem. 2009, 74, 6555–6563. 58. Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin, Q. New Strategic Reactions for Organic Synthesis: Catalytic Asymmetric C–H Activation a to Oxygen as a Surrogate to the Aldol Reaction. J. Org. Chem. 2003, 68, 6126–6132. 59. Davies, H. M. L.; Yang, J.; Nikolai, J. Asymmetric C–H Insertion of Rh(II) Stabilized Carbenoids into Acetals: A C–H Activation Protocol as a Claisen Condensation Equivalent. J. Organomet. Chem. 2005, 690, 6111–6124. 60. Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. New Strategic Reactions for Organic Synthesis: Catalytic Asymmetric C–H Activation a to Nitrogen as a Surrogate for the Mannich Reaction. J. Am. Chem. Soc. 2003, 125, 6462–6468. 61. Davies, H. M. L.; Ren, P.; Jin, Q. Catalytic Asymmetric Allylic C–H Activation as a Surrogate of the Asymmetric Claisen Rearrangement. Org. Lett. 2001, 3, 3587–3590. 62. Davies, H. M. L.; Lian, Y. The Combined C-H Functionalization/Cope Rearrangement: Discovery and Applications in Organic Synthesis. Acc. Chem. Res. 2012, 45, 923–935. 63. Davies, H. M. L.; Stafford, D. G.; Hansen, T. Catalytic Asymmetric Synthesis of Diarylacetates and 4,4-Diarylbutanoates. A Formal Asymmetric Synthesis of (+)-Sertraline. Org. Lett. 1999, 1, 233–236. 64. Davies, H. M. L.; Lian, Y. The Combined C–H Functionalization: Cope Rearrangement-Discovery and Applications in Organic Synthesis. Acc. Chem. Res. 2021, 45, 923–935. 65. Hansen, J. H.; Gregg, T. M.; Ovalles, S. R.; Lian, Y.; Autschbach, J.; Davies, H. M. L. On the Mechanism and Selectivity of the Combined C-H Activation/Cope Rearrangement. J. Am. Chem. Soc. 2011, 133, 5076–5085. 66. Lian, Y.; Hardcastle, K. I.; Davies, H. M. L. Computationally Guided Stereocontrol of the Combined C-H Functionalization/Cope Rearrangement. Angew. Chem. Int. Ed. 2011, 50, 9370–9373. 67. Lian, Y.; Davies, H. M. L. Combined C-H Functionalization/Cope Rearrangement with Vinyl Ethers as a Surrogate for the Vinylogous Mukaiyama Aldol Reaction. J. Am. Chem. Soc. 2011, 133, 11940–11943. 68. Davies, H. M. L.; Dai, X.; Long, M. S. Combined C-H Activation/Cope Rearrangement as a Strategic Reaction in Organic Synthesis: Total Synthesis of (−)-Colombiasin a and (−)-Elisapterosin B. J. Am. Chem. Soc. 2006, 128, 2485–2490. 69. Bess, E. N.; Guptill, D. M.; Davies, H. M. L.; Sigman, M. S. Using IR Vibrations to Quantitatively Describe and Predict Site-Selectivity in Multivariate Rh-Catalyzed C-H Functionalization. Chem. Sci. 2015, 6, 3057–3062. 70. Adly, F. On the Structure of Chiral Dirhodium(II) Carboxylate Catalysts: Stereoselectivity Relevance and Insights. Catalysts 2017, 7, 347. 71. Collins, L. R.; van Gastel, M.; Neese, F.; Furstner, A. Enhanced Electrophilicity of Heterobimetallic Bi-Rh Paddlewheel Carbene Complexes: A Combined Experimental, Spectroscopic, and Computational Study. J. Am. Chem. Soc. 2018, 140, 13042–13055. 72. Ren, Z.; Sunderland, T. L.; Tortoreto, C.; Yang, T.; Berry, J. F.; Musaev, D. G.; Davies, H. M. L. Comparison of Reactivity and Enantioselectivity between Chiral Bimetallic Catalysts: Bismuth–Rhodium- and Dirhodium-Catalyzed Carbene Chemistry. ACS Catal. 2018, 8, 10676–10682. 73. McLarney, B. D.; Hanna, S.; Musaev, D. G.; France, S. Predictive Model for the [Rh2(esp)2]-Catalyzed Intermolecular C(sp3)–H Bond Insertion of b-Carbonyl Ester Carbenes: Interplay between Theory and Experiment. ACS Catal. 2019, 9, 4526–4538. 74. Szabo, M.; Kleineisel, M.; Nemeth, K.; Domjan, A.; Vass, E.; Szilvagyi, G. Twisted Paddlewheel Rhodium Complexes: Contribution of Central and Axial Chirality to ECD, VCD, and NMR Spectra. Chirality 2020, 32, 446–456. 75. Zhou, M.; Springborg, M. Theoretical Study of the Mechanism Behind the Site- and Enantio-Selectivity of C-H Functionalization Catalysed by Chiral Dirhodium Catalyst. Phys. Chem. Chem. Phys. 2020, 22, 9561–9572. 76. Thu, H. Y.; Tong, G. S.; Huang, J. S.; Chan, S. L.; Deng, Q. H.; Che, C. M. Highly Selective Metal Catalysts for Intermolecular Carbenoid Insertion into Primary C-H Bonds and Enantioselective C-C Bond Formation. Angew. Chem. Int. Ed. 2008, 47, 9747–9751. 77. Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.; Musaev, D. G.; Davies, H. M. L. D2-symmetric Dirhodium Catalyst Derived from a 1,2,2-Triarylcyclopropanecarboxylate Ligand: Design, Synthesis and Application. J. Am. Chem. Soc. 2011, 133, 19198–19204. 78. Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M. L. Site-Selective and Stereoselective Functionalization of Unactivated C-H Bonds. Nature 2016, 533, 230–234. 79. Liao, K.; Liu, W.; Niemeyer, Z. L.; Ren, Z.; Bacsa, J.; Musaev, D. G.; Sigman, M. S.; Davies, H. M. L. Site-Selective Carbene-Induced C–H Functionalization Catalyzed by Dirhodium Tetrakis(triarylcyclopropanecarboxylate) Complexes. ACS Catal. 2017, 8, 678–682.

Synthetic Applications of Carbene and Nitrene CdH Insertion

289

80. Liao, K.; Pickel, T. C.; Boyarskikh, V.; Bacsa, J.; Musaev, D. G.; Davies, H. M. L. Site-selective and Stereoselective Functionalization of Non-activated Tertiary C-H Bonds. Nature 2017, 551, 609–613. 81. Wertz, B.; Ren, Z.; Bacsa, J.; Musaev, D. G.; Davies, H. M. L. Comparison of 1,2-Diarylcyclopropanecarboxylates with 1,2,2-Triarylcyclopropanecarboxylates as Chiral Ligands for Dirhodium-Catalyzed Cyclopropanation and C–H Functionalization. J. Org. Chem. 2020, 85, 12199–12211. 82. Ren, Z.; Musaev, D. G.; Davies, H. M. L. Influence of Aryl Substituents on the Alignment of Ligands in the Dirhodium Tetrakis(1,2,2-Triarylcyclopropane-Carboxylate) Catalysts. Chem. Cat. Chem. 2021, 13, 174–179. 83. Davies, H. M. L.; Morton, D. D. Guiding Principles for Site Selective and Stereoselective Intermolecular C-H Functionalization by Donor/Acceptor Rhodium Carbenes. Chem. Soc. Rev. 2011, 40, 1857–1869. 84. Hashimoto, S.-I.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S. Enhancement of Enantioselectivlty in Intramolecular C-H Insertion Reactions of a-Diazo b-Keto Esters Catalyzed by Chiral Dlrhodlum(II) Carboxylates. Tetrahedron Lett. 1993, 34, 5109–5112. 85. DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. Chiral Crown Conformation of Rh2(S-PTTL)4-Enantioselective Cyclopropanation with a-Alkyl-a-Diazoesters. J. Am. Chem. Soc. 2009, 131, 7230–7231. 86. DeAngelis, A.; Boruta, D. T.; Lubin, J. B.; Plampin, J. N., 3rd; Yap, G. P.; Fox, J. M. The Chiral Crown Conformation in Paddlewheel Complexes. Chem. Commun. 2010, 46, 4541–4543. 87. Lindsay, V. N. G.; Lin, W.; Charette, A. B. Experimental Evidence for the All-Up Reactive Conformation of Chiral Rhodium(II) Carboxylate Catalysts-Enantioselective Synthesis of cis-Cyclopropane a-Amino Acids. J. Am. Chem. Soc. 2009, 131, 16383–16385. 88. Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Dirhodium Tetracarboxylate Derived from Adamantylglycine as a Chiral Catalyst for Carbenoid Reactions. Org. Lett. 2006, 8, 3437–3440. 89. Fu, J.; Ren, Z.; Bacsa, J.; Musaev, D. G.; Davies, H. M. L. Desymmetrization of Cyclohexanes by Site- and Stereoselective C–H Functionalization. Nature 2018, 564, 395–399. 90. Liao, K.; Yang, Y. F.; Li, Y.; Sanders, J. N.; Houk, K. N.; Musaev, D. G.; Davies, H. M. L. Design of Catalysts for Site-selective and Enantioselective Functionalization of Non-activated Primary C-H Bonds. Nat. Chem. 2018, 10, 1048–1055. 91. Liu, W.; Ren, Z.; Bosse, A. T.; Liao, K.; Goldstein, E. L.; Bacsa, J.; Musaev, D. G.; Stoltz, B. M.; Davies, H. M. L. Catalyst-Controlled Selective Functionalization of Unactivated C-H Bonds in the Presence of Electronically Activated C-H Bonds. J. Am. Chem. Soc. 2018, 140, 12247–12255. 92. Garlets, Z. J.; Wertz, B. D.; Liu, W.; Voight, E. A.; Davies, H. M. L. Regio- and Stereoselective Rhodium(II)-Catalyzed C-H Functionalization of Cyclobutanes. Chem 2020, 6, 304–313. 93. Liu, W.; Babl, T.; Rother, A.; Reiser, O.; Davies, H. M. L. Functionalization of Piperidine Derivatives for the Site-Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate. Chem. A Eur. J. 2020, 26, 4236–4241. 94. Guptill, D. M.; Davies, H. M. L. 2,2,2-Trichloroethyl Aryldiazoacetates as Robust Reagents for the Enantioselective C-H Functionalization of Methyl Ethers. J. Am. Chem. Soc. 2014, 136, 17718–17721. 95. Harned, A. M. From Determination of Enantiopurity to the Construction of Complex Molecules: The Horeau Principle and Its Application in Synthesis. Tetrahedron 2018, 74, 3797–3841. 96. Zhang, B.; Hollerbach, M. R.; Blakey, S. B.; Davies, H. M. L. C-H Functionalization Approach for the Synthesis of Chiral C2-Symmetric 1,5-Cyclooctadiene Ligands. Org. Lett. 2019, 21, 9864–9868. 97. Garlets, Z. J.; Hicks, E. F.; Fu, J.; Voight, E. A.; Davies, H. M. L. Regio- and Stereoselective Rhodium(II)-Catalyzed C-H Functionalization of Organosilanes by Donor/Acceptor Carbenes Derived from Aryldiazoacetates. Org. Lett. 2019, 21, 4910–4914. 98. Garlets, Z. J.; Sanders, J. N.; Malik, H.; Gampe, C.; Houk, K. N.; Davies, H. M. L. Enantioselective C–H Functionalization of Bicyclo[1.1.1]pentanes. Nat. Catal. 2020, 3, 351–357. 99. Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal Chemist’s Toolbox for Late Stage Functionalization of Drug-Like Molecules. Chem. Soc. Rev. 2016, 45, 546–576. 100. Davies, H. M. L.; Alford, J. S. Reactions of Metallocarbenes Derived From N-Sulfonyl-1,2,3-Triazoles. Chem. Soc. Rev. 2014, 43, 5151–5162. 101. Chuprakov, S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V. Catalytic Asymmetric C-H Insertions of Rhodium(II) Azavinyl Carbenes. J. Am. Chem. Soc. 2011, 133, 10352–10355. 102. Müller, P.; Allenbach, Y.; Robert, E. Rhodium(II)-Catalyzed Olefin Cyclopropanation with the Phenyliodonium Ylide Derived From Meldrum’s Acid. Tetrahedron Asymmetry 2003, 14, 779–785. 103. Medina, F.; Besnard, C.; Lacour, J. One-step Synthesis of Nitrogen-Containing Medium-Sized Rings via Alpha-Imino Diazo Intermediates. Org. Lett. 2014, 16, 3232–3235. 104. Kubiak, R. W., 2nd; Mighion, J. D.; Wilkerson-Hill, S. M.; Alford, J. S.; Yoshidomi, T.; Davies, H. M. L. Enantioselective Intermolecular C-H Functionalization of Allylic and Benzylic sp(3) C-H Bonds Using N-Sulfonyl-1,2,3-Triazoles. Org. Lett. 2016, 18, 3118–3121. 105. Garlets, Z. J.; Davies, H. M. L. Harnessing the Beta-Silicon Effect for Regioselective and Stereoselective Rhodium(II)-Catalyzed C-H Functionalization by Donor/Acceptor Carbenes Derived from 1-Sulfonyl-1,2,3-Triazoles. Org. Lett. 2018, 20, 2168–2171. 106. Kubiak, R. W.; 2nd; Davies, H. M. L., Rhodium-Catalyzed Intermolecular C-H Functionalization as a Key Step in the Synthesis of Complex Stereodefined Beta-Arylpyrrolidines. Org. Lett. 2018, 20, 3771–3775. 107. Vaitla, J.; Boni, Y. T.; Davies, H. M. L. Distal Allylic/Benzylic C-H Functionalization of Silyl Ethers Using Donor/Acceptor Rhodium(II) Carbenes. Angew. Chem. Int. Ed. 2020, 59, 7397–7402. 108. Hyster, T. K.; Ruhl, K. E.; Rovis, T. A Coupling of Benzamides and Donor/Acceptor Diazo Compounds to Form g-Lactams via Rh(III)-Catalyzed C–H Activation. J. Am. Chem. Soc. 2013, 135, 5364–5367. 109. Jha, N.; Singh, R. P.; Saxena, P.; Kapur, M. Iridium(III)-Catalyzed C(3)–H Alkylation of Isoquinolines via Metal Carbene Migratory Insertion. Org. Lett. 2021, 23, 8694–8698. 110. Dong, K.; Pei, C.; Zeng, Q.; Wei, H.; Doyle, M. P.; Xu, X. Selective C(sp3)–H Bond Insertion in Carbene/Alkyne Metathesis Reactions. Enantioselective Construction of Dihydroindoles. ACS Catal. 2018, 8, 9543–9549. 111. DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J. M. Rhodium(II)-Catalyzed Enantioselective C–H Functionalization of Indoles. J. Am. Chem. Soc. 2011, 133, 1650–1653. 112. Goto, T.; Natori, Y.; Takeda, K.; Nambu, H.; Hashimoto, S. Catalytic Enantioselective C–H Functionalization of Indoles with a-Diazopropionates Using Chiral Dirhodium(II) Carboxylates: Asymmetric Synthesis of the (+)-a-Methyl-3-Indolylacetic Acid Fragment of Acremoauxin A. Tetrahedron Asymmetry 2011, 22, 907–915. 113. Davies, H. M. L.; Morton, D.; et al. J. Org. Chem. 2016, 81, 343–350. 114. Pei, C.; Rong, G. W.; Yu, Z. X.; Xu, X. F. Copper-Catalyzed Intramolecular Annulation of Conjugated Enynones to Substituted 1H-Indenes and Mechanistic Studies. J. Org. Chem. 2018, 83, 13243–13255. 115. Solé, D.; Pérez-Janer, F.; Bennasar, M. L.; Fernández, I. Palladium Catalysis in the Intramolecular Carbene C-H Insertion of a-Diazo-a-(methoxycarbonyl)acetamides to Form b-Lactams. Eur. J. Org. Chem. 2018, 2018, 4446–4455. 116. Nakagawa, Y.; Chanthamath, S.; Liang, Y.; Shibatomi, K.; Iwasa, S. Regio- and Enantioselective Intramolecular Amide Carbene Insertion into Primary C-H Bonds Using Ru(II)-Pheox Catalyst. J. Org. Chem. 2019, 84, 2607–2618. 117. Doyle, M. P.; Ratnikov, M.; Liu, Y. Intramolecular Catalytic Asymmetric Carbon-Hydrogen Insertion Reactions. Synthetic Advantages in Total Synthesis in Comparison with Alternative Approaches. Org. Biomol. Chem. 2011, 9, 4007–4016. 118. Kaupang, A.; Bonge-Hansen, T. alpha-Bromodiazoacetamides—A New Class of Diazo Compounds for Catalyst-Free, Ambient Temperature Intramolecular C-H Insertion Reactions. Beilstein J. Org. Chem. 2013, 9, 1407–1413. 119. Wang, J.-C.; Zhang, Y.; Xu, Z.-J.; Lo, V. K.-Y.; Che, C.-M. Enantioselective Intramolecular Carbene C–H Insertion Catalyzed by a Chiral Iridium(III) Complex of D4-Symmetric Porphyrin Ligand. ACS Catal. 2013, 3, 1144–1148.

290

Synthetic Applications of Carbene and Nitrene CdH Insertion

120. Fu, L.; Wang, H.; Davies, H. M. L. Role of Ortho-substituents on Rhodium-Catalyzed Asymmetric Synthesis of Beta-Lactones by Intramolecular C-H Insertions of Aryldiazoacetates. Org. Lett. 2014, 16, 3036–3039. 121. Mo, S.; Li, X.; Xu, J. In Situ-Generated Iodonium Ylides as Safe Carbene Precursors for the Chemoselective Intramolecular Buchner Reaction. J. Org. Chem. 2014, 79, 9186–9195. 122. Reddy, A. R.; Zhou, C.-Y.; Guo, Z.; Wei, J.; Che, C.-M. Ruthenium-Porphyrin-Catalyzed Diastereoselective Intramolecular Alkyl Carbene Insertion into C-H Bonds of Alkyl Diazomethanes Generated In Situ From N-Tosylhydrazones. Angew. Chem. Int. Ed. 2014, 53, 14175–14180. 123. Soldi, C.; Lamb, K. N.; Squitieri, R. A.; Gonzalez-Lopez, M.; Di Maso, M. J.; Shaw, J. T. Enantioselective Intramolecular C-H Insertion Reactions of Donor-Donor Metal Carbenoids. J. Am. Chem. Soc. 2014, 136, 15142–15145. 124. Ito, M.; Kondo, Y.; Nambu, H.; Anada, M.; Takeda, K.; Hashimoto, S. Diastereo- and Enantioselective Intramolecular 1,6-C–H Insertion Reactions of a-Diazo Esters Catalyzed by Chiral Dirhodium(II) Carboxylates. Tetrahedron Lett. 2015, 56, 1397–1400. 125. Xu, X.; Deng, Y.; Yim, D. N.; Zavalij, P. Y.; Doyle, M. P. Enantioselective cis-Beta-Lactam Synthesis by Intramolecular C-H Functionalization From Enoldiazoacetamides and Derivative Donor-Acceptor Cyclopropenes. Chem. Sci. 2015, 6, 2196–2201. 126. Miyazawa, T.; Minami, K.; Ito, M.; Anada, M.; Matsunaga, S.; Hashimoto, S. Enantio-and Diastereoselective Desymmetrization of a-Alkyl-a-Diazoesters by Dirhodium(II)-Catalyzed Intramolecular C–H Insertion. Tetrahedron 2016, 72, 3939–3947. 127. Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu, S. Enantioselective Intramolecular C-H Insertion of Donor and Donor/Donor Carbenes by a Nondiazo Approach. Angew. Chem. Int. Ed. 2016, 55, 8452–8456. 128. Doyle, M. P.; Forbes, D. C. Recent Advances in Asymmetric Catalytic Metal Carbene Transformations. Chem. Rev. 1998, 98, 911–935. 129. Doyle, M. P.; Liu, Y.; Ratnikov, M. Catalytic, Asymmetric, Intramolecular Carbon-Hydrogen Insertion. Org. React. 2013, 80, 1–131. 130. Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. Electronic and Steric Control in Carbon-Hydrogen Insertion Reactions of Diazoacetoacetates Catalyzed by Dirhodium(II) Carboxylates and Carboxamides. J. Am. Chem. Soc. 2002, 115, 958–964. 131. Taber, D. F.; Ruckle, R. Cyclopentane Construction by Rh2(OAc)4-Mediated Intramolecular C-H Insertion—Steric and Electronic Effects. J. Am. Chem. Soc. 1986, 108, 7686–7693. 132. Hashimoto, S.-I.; Watanabe, N.; Anada, M.; Ikegami, S. Site- and Enantiocontrol in Intramolecular C-H Insertion Reactions of a-Diazo Carbonyl Compounds Catalyzed by Dirhodium(H) Carboxylates. J. Synth. Org. Chem. 1996, 54, 988–999. 133. Doyle, M. P. Perspective on Dirhodium Carboxamidates as Catalysts. J. Org. Chem. 2006, 71, 9253–9260. 134. Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A.; van Basten, A.; Mueller, P.; Polleux, P. Diastereocontrol for Highly Enantioselective Carbon-Hydrogen Insertion Reactions of Cycloalkyl Diazoacetates. J. Am. Chem. Soc. 1994, 116, 4507–4508. 135. Davies, H. M. L. Dirhodium Tetra(N-Arylsulfonylprolinates) as Chiral Catalysts for Asymmetric Transformations of Vinyl- and Aryldiazoacetates. Eur. J. Org. Chem. 1999, 1999, 2459–2469. 136. Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Asymmetric Intramolecular C-H Insertions of Aryldiazoacetates. Org. Lett. 2001, 3, 1475–1477. 137. Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. Enantio- and Diastereoselective Synthesis of cis-2-Aryl-3-Methoxycarbonyl-2,3-Dihydrobenzofurans via the Rh(II)-Catalyzed C-H Insertion Process. Org. Lett. 2002, 4, 3887–3890. 138. Kurosawa, W.; Kan, T.; Fukuyama, T. An Efficient Synthesis of Optically Active Trans-2-aryl-2,3-Dihydrobenzofuran-3-Carboxylic Acid Esters via C-H Insertion Reaction. Synlett 2003, 1028–1030. 139. Zhang, S. Y.; Zhang, F. M.; Tu, Y. Q. Direct sp3 alpha-C-H Activation and Functionalization of Alcohol and Ether. Chem. Soc. Rev. 2011, 40, 1937–1949. 140. Sultanova, R. M.; Khanova, M. D.; Zlotskii, S. S. The Insertion Reaction of Diazocarbonyl Compounds at C-H Bonds in the Synthesis of Biologically Active Nitrogen- and Oxygen-Containing Heterocycles. Chem. Heterocycl. Compd. 2015, 51, 775–784. 141. Zhu, D.; Chen, L. F.; Fan, H. L.; Yao, Q. L.; Zhu, S. F. Recent Progress on Donor and Donor-Donor Carbenes. Chem. Soc. Rev. 2020, 49, 908–950. 142. Shaw, J. T. C-H Insertion Reactions of Donor/Donor Carbenes: Inception, Investigation, and Insights. Synlett 2020, 31, 838–844. 143. Werlé, C.; Goddard, R.; Philipps, P.; Farès, C.; Fürstner, A. Structures of Reactive Donor/Acceptor and Donor/Donor Rhodium Carbenes in the Solid State and Their Implications for Catalysis. J. Am. Chem. Soc. 2016, 138, 3797–3805. 144. Lamb, K. N.; Squitieri, R. A.; Chintala, S. R.; Kwong, A. J.; Balmond, E. I.; Soldi, C.; Dmitrenko, O.; Castineira Reis, M.; Chung, R.; Addison, J. B.; Fettinger, J. C.; Hein, J. E.; Tantillo, D. J.; Fox, J. M.; Shaw, J. T. Synthesis of Benzodihydrofurans by Asymmetric C-H Insertion Reactions of Donor/Donor Rhodium Carbenes. Chem. A Eur. J. 2017, 23, 11843–11855. 145. Souza, L. W.; Squitieri, R. A.; Dimirjian, C. A.; Hodur, B. M.; Nickerson, L. A.; Penrod, C. N.; Cordova, J.; Fettinger, J. C.; Shaw, J. T. Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C-H Insertion of Donor/Donor Carbenes. Angew. Chem. Int. Ed. 2018, 57, 15213–15216. 146. Nickerson, L. A.; Bergstrom, B. D.; Gao, M.; Shiue, Y.-S.; Laconsay, C. J.; Culberson, M. R.; Knauss, W. A.; Fettinger, J. C.; Tantillo, D. J.; Shaw, J. T. Enantioselective Synthesis of Isochromans and Tetrahydroisoquinolines by C–H Insertion of Donor/Donor Carbenes. Chem. Sci. 2020, 11, 494–498. 147. Ma, J.; Jiang, H.; Zhu, S. NHC-AuCl/Selectfluor: A Highly Efficient Catalytic System for Carbene-Transfer Reactions. Org. Lett. 2014, 16, 4472–4475. 148. Hao, J.; Guo, X.; He, S.; Xu, Z.; Chen, L.; Li, Z.; Song, B.; Zuo, J.; Lin, Z.; Yang, W. Marine Furanocembranoids-Inspired Macrocycles Enabled by Pd-Catalyzed Unactivated C(sp3)-H Olefination Mediated by Donor/Donor Carbenes. Nat. Commun. 2021, 12, 1304. 149. Mbuvi, H. M.; Woo, L. K. Catalytic C-H Insertions Using Iron(III) Porphyrin Complexes. Organometallics 2008, 27, 637–645. 150. Empel, C.; Jana, S.; Koenigs, R. M. C-H Functionalization via Iron-Catalyzed Carbene-Transfer Reactions. Molecules 2020, 25. 151. Zhao, X.; Zhang, Y.; Wang, J. Recent Developments in Copper-Catalyzed Reactions of Diazo Compounds. Chem. Commun. 2012, 48, 10162–10173. 152. Fraile, J. M.; Lopez-Ram-de-Viu, P.; Mayoral, J. A.; Roldan, M.; Santafe-Valero, J. Enantioselective C-H Carbene Insertions with Homogeneous and Immobilized Copper Complexes. Org. Biomol. Chem. 2011, 9, 6075–6081. 153. Slattery, C. N.; Maguire, A. R. Asymmetric Copper-Catalysed Intramolecular C-H Insertion Reactions of Alpha-Diazo-Beta-Keto Sulfones. Org. Biomol. Chem. 2011, 9, 667–669. 154. Chu, W.-D.; Guo, F.; Yu, L.; Hong, J.; Liu, Q.; Mo, F.; Zhang, Y.; Wang, J. Cu(I)-Catalyzed Asymmetric Cross-Coupling of N-Tosylhydrazones and Trialkylsilylethynes: Enantioselective Construction of C(sp)-C(sp3) Bonds. Chin. J. Chem. 2018, 36, 217–222. 155. Ye, B.; Cramer, N. Asymmetric Synthesis of Isoindolones by Chiral Cyclopentadienyl-Rhodium(III)-Catalyzed C-H Functionalizations. Angew. Chem. Int. Ed. 2014, 53, 7896–7899. 156. Guo, R. T.; Zhang, Y. L.; Tian, J. J.; Zhu, K. Y.; Wang, X. C. Rhodium-Catalyzed ortho-Selective Carbene C-H Insertion of Unprotected Phenols Directed by a Transient Oxonium Ylide Intermediate. Org. Lett. 2020, 22, 908–913. 157. Liu, Y.; Zhou, C.; Xiong, M.; Jiang, J.; Wang, J. Asymmetric Rh(I)-Catalyzed Functionalization of the 3-C(sp(3))-H Bond of Benzofuranones with alpha-Diazoesters. Org. Lett. 2018, 20, 5889–5893. 158. Wang, J. C.; Xu, Z. J.; Guo, Z.; Deng, Q. H.; Zhou, C. Y.; Wan, X. L.; Che, C. M. Highly Enantioselective Intermolecular Carbene Insertion to C-H and Si-H Bonds Catalyzed by a Chiral Iridium(III) Complex of a D4-Symmetric Halterman Porphyrin Ligand. Chem. Commun. 2012, 48, 4299–4301. 159. Brouder, T. A.; Slattery, C. N.; Ford, A.; Khandavilli, U. B. R.; Skorˇepová, E.; Eccles, K. S.; Lusi, M.; Lawrence, S. E.; Maguire, A. R. Desymmetrization by Asymmetric Copper-Catalyzed Intramolecular C–H Insertion Reactions of a-Diazo-b-Oxosulfones. J. Org. Chem. 2019, 84, 7543–7563. 160. Cui, X.; Xu, X.; Jin, L. M.; Wojtas, L.; Zhang, X. P. Stereoselective Radical C-H Alkylation with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis. Chem. Sci. 2015, 6, 1219–1224. 161. Lewis, J. C. Artificial Metalloenzymes and Metallopeptide Catalysts for Organic Synthesis. ACS Catal. 2013, 3, 2954–2975. 162. Upp, D. M.; Lewis, J. C. Selective C-H Bond Functionalization Using Repurposed or Artificial Metalloenzymes. Curr. Opin. Chem. Biol. 2017, 37, 48–55.

Synthetic Applications of Carbene and Nitrene CdH Insertion

291

163. Damiano, C.; Sonzini, P.; Gallo, E. Iron Catalysts With N-Ligands for Carbene Transfer of Diazo Reagents. Chem. Soc. Rev. 2020, 49, 4867–4905. 164. Oohora, K.; Kihira, Y.; Mizohata, E.; Inoue, T.; Hayashi, T. C(sp3)-H Bond Hydroxylation Catalyzed by Myoglobin Reconstituted With Manganese Porphycene. J. Am. Chem. Soc. 2013, 135, 17282–17285. 165. Key, H. M.; Dydio, P.; Clark, D. S.; Hartwig, J. F. Abiological Catalysis by Artificial Haem Proteins Containing Noble Metals in Place of Iron. Nature 2016, 534, 534–537. 166. Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822–5880. 167. Zhang, J.; Huang, X.; Zhang, R. K.; Arnold, F. H. Enantiodivergent Alpha-Amino C-H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s. J. Am. Chem. Soc. 2019, 141, 9798–9802. 168. Zhou, A. Z.; Chen, K.; Arnold, F. H. Enzymatic Lactone-Carbene C–H Insertion to Build Contiguous Chiral Centers. ACS Catal. 2020, 10, 5393–5398. 169. Darses, B.; Rodrigues, R.; Neuville, L.; Mazurais, M.; Dauban, P. Transition Metal-Catalyzed Iodine(III)-Mediated Nitrene Transfer Reactions: Efficient Tools for Challenging Syntheses. Chem. Commun. 2017, 53, 493–508. 170. Du Bois, J. Rhodium-Catalyzed C-H Amination—An Enabling Method for Chemical Synthesis. Org. Process Res. Dev. 2011, 15, 758–762. 171. Liang, S.; Jensen, M. P. Half-Sandwich Scorpionates as Nitrene Transfer Catalysts. Organometallics 2012, 31, 8055–8058. 172. Zhang, Y.; Dong, X.; Wu, Y.; Li, G.; Lu, H. Visible-Light-Induced Intramolecular C(sp(2))-H Amination and Aziridination of Azidoformates via a Triplet Nitrene Pathway. Org. Lett. 2018, 20, 4838–4842. 173. Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed C(sp(3))-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem. Int. Ed. 2018, 57, 62–101. 174. Yuan, S.-W.; Han, H.; Li, Y.-L.; Wu, X.; Bao, X.; Gu, Z. Y.; Xia, J.-B. Intermolecular C-H Amidation of (Hetero)arenes to Produce Amides through Rhodium-Catalyzed Carbonylation of Nitrene Intermediates. Angew. Chem. Int. Ed. 2019, 58, 8887–8892. 175. Zhang, X.; Xu, H.; Liu, X.; Phillips, D. L.; Zhao, C. Mechanistic Insight into the Intramolecular Benzylic C-H Nitrene Insertion Catalyzed by Bimetallic Paddlewheel Complexes: Influence of the Metal Centers. Chem. A Eur. J. 2016, 22, 7288–7297. 176. Xu, H.; Zhang, X.; Ke, Z.; Zhao, C. A Theoretical Study of Dirhodium-Catalyzed Intramolecular Aliphatic C–H Bond Amination of Aryl Azides. RSC Adv. 2016, 6, 29045–29053. 177. Perry, R. H.; Cahill, T. J.; Roizen, J. L.; Du Bois, J.; Zare, R. N. Capturing Fleeting Intermediates in a Catalytic C-H Amination Reaction Cycle. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 18295–18299. 178. Zhang, X.; Xu, H.; Zhao, C. Mechanistic Investigation of Dirhodium-Catalyzed Intramolecular Allylic C-H Amination Versus Alkene Aziridination. J. Org. Chem. 2014, 79, 9799–9811. 179. Wentrup, C. Carbenes and Nitrenes: Recent Developments in Fundamental Chemistry. Angew. Chem. Int. Ed. 2018, 57, 11508–11521. 180. Breslow, R. G.; S. H., Tosylamidation of Cyclohexane by a Cytochrome P-450 Model. J. Chem. Soc. Chem. Commun. 1982; 1400–1401. 181. Deng, T.; Mazumdar, W.; Yoshinaga, Y.; Patel, P. B.; Malo, D.; Malo, T.; Wink, D. J.; Driver, T. G. Rh2(II)-Catalyzed Intermolecular N-Aryl Aziridination of Olefins Using Nonactivated N Atom Precursors. J. Am. Chem. Soc. 2021, 143, 19149–19159. 182. Williams Fiori, K.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. A Mechanistic Analysis of the Rh-Catalyzed Intramolecular C–H Amination Reaction. Tetrahedron 2009, 65, 3042–3051. 183. Fiori, K. W.; Du Bois, J. Catalytic Intermolecular Amination of C-H Bonds: Method Development and Mechanistic Insights. J. Am. Chem. Soc. 2007, 129, 562–568. 184. Wang, J.; Zheng, K.; Lin, B.; Weng, Y. A Comparative Study of Inter- and Intramolecular C–H Aminations: Mechanism and Site Selectivity. RSC Adv. 2017, 7, 34783–34794. 185. Müller, P.; Baud, C.; Naegeli, I. Rhodium(II)-Catalyzed Nitrene Transfer With Phenyliodonium Ylides. J. Phys. Org. Chem. 1998, 11, 597–601. 186. Espino, C. G.; Du Bois, J. A Rh-Catalyzed C-H Insertion Reaction for the Oxidative Conversion of Carbamates to Oxazolidinones. Angew. Chem. Int. Ed. 2001, 40, 598–600. 187. Kong, C.; Jana, N.; Jones, C.; Driver, T. G. Control of the Chemoselectivity of Metal N-Aryl Nitrene Reactivity: C-H Bond Amination versus Electrocyclization. J. Am. Chem. Soc. 2016, 138, 13271–13280. 188. Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. Expanding the Scope of C-H Amination through Catalyst Design. J. Am. Chem. Soc. 2004, 126. 189. Kurokawa, T.; Kim, M.; Du Bois, J. Synthesis of 1,3-Diamines Through Rhodium-Catalyzed C-H Insertion. Angew. Chem. Int. Ed. 2009, 48, 2777–2779. 190. Grigg, R. D.; Rigoli, J. W.; Pearce, S. D.; Schomaker, J. M. Synthesis of Propargylic and Allenic Carbamates via the C H Amination of Alkynes. Org. Lett. 2012, 14, 280–283. 191. Nguyen, Q.; Sun, K.; Driver, T. G. Rh2(II)-Catalyzed Intramolecular Aliphatic C-H Bond Amination Reactions Using Aryl Azides as the N-Atom Source. J. Am. Chem. Soc. 2012, 134, 7262–7265. 192. Roizen, J. L.; Zalatan, D. N.; Du Bois, J. Selective Intermolecular Amination of C-H Bonds at Tertiary Carbon Centers. Angew. Chem. Int. Ed. 2013, 52, 11343–11346. 193. Chiappini, N. D.; Mack, J. B. C.; Du Bois, J. Intermolecular C(sp(3))-H Amination of Complex Molecules. Angew. Chem. Int. Ed. 2018, 57, 4956–4959. 194. Müller, P.; Fruit, C. Enantioselective Catalytic Aziridinations and Asymmetric Nitrene Insertions into CH Bonds. Chem. Rev. 2003, 103, 2905–2920. 195. Reddy, R. P.; Davies, H. M. L. Dirhodium Tetracarboxylates Derived from Adamantylglycine as Chiral Catalysts for Enantioselective C-H Aminations. Org. Lett. 2006, 8, 5013–5016. 196. Liang, C.; Robert-Peillard, F.; Fruit, C.; Muller, P.; Dodd, R. H.; Dauban, P. Efficient Diastereoselective Intermolecular Rhodium-Catalyzed C-H Amination. Angew. Chem. Int. Ed. 2006, 45, 4641–4644. 197. Zalatan, D. N.; Du Bois, J. A Chiral Rhodium Carboxamidate Catalyst for Enantioselective C-H Amination. J. Am. Chem. Soc. 2008, 130, 9220–9221. 198. Lebel, H. L. N.; Huard, K.; Lectard, S. N-Tosyloxycarbamates as a Source of Metal Nitrenes: Rhodium-Catalyzed C-H Insertion and Aziridination Reactions. J. Am. Chem. Soc. 2005, 127, 14198–14199. 199. Lebel, H. S. C.; Leogane, O.; Trudel, C.; Parmentier, M. Stereoselective Rhodium-Catalyzed Amination of Alkenes. Org. Lett. 2011, 13, 5460–5463. 200. Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. Total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. J. Am. Chem. Soc. 2011, 133, 15797–15799. 201. Huters, A. D.; Styduhar, E. D.; Garg, N. K. Total syntheses of the elusive welwitindolinones with bicyclo[4.3.1] cores. Angew. Chem. Int. Ed. 2012, 51, 3758–3765. 202. Fleming, J. J.; McReynolds, M. D.; Du Bois, J. (+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis. J. Am. Chem. Soc. 2007, 129, 9964–9975. 203. Mahy, J. P.; Bedi, G.; Battioni, P.; Mansuy, D. Allylic Amination of Alkenes by Tosyliminoiodobenzene: Manganese Porphyrins as Suitable Catalysts. Tetrahedron Lett. 1988, 29, 1927–1930. 204. Yu, X.-Q. H.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Amidation of Saturated C–H Bonds Catalyzed by Electron-Deficient Ruthenium and Manganese Porphyrins. A Highly Catalytic Nitrogen Atom Transfer Process. Org. Lett. 2000, 2, 2233–2236. 205. Wang, J.; Zheng, K.; Li, T.; Zhan, X. Mechanism and Chemoselectivity of Mn-Catalyzed Intramolecular Nitrene Transfer Reaction: C–H Amination vs. C ¼ C Aziridination. Catalysts 2020, 10. 206. Singh, R.; Mukherjee, A. Metalloporphyrin Catalyzed C–H Amination. ACS Catal. 2019, 9, 3604–3617. 207. Paradine, S. M.; Griffin, J. R.; Zhao, J.; Petronico, A. L.; Miller, S. M.; Christina White, M. A Manganese Catalyst for Highly Reactive Yet Chemoselective Intramolecular C(sp(3))-H Amination. Nat. Chem. 2015, 7, 987–994. 208. Clark, J. R.; Feng, K.; Sookezian, A.; White, M. C. Manganese-Catalysed Benzylic C(sp(3))-H Amination for Late-Stage Functionalization. Nat. Chem. 2018, 10, 583–591. 209. Fantauzzi, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Casati, N.; Macchi, P.; Cenini, S. The Key Intermediate in the Amination of Saturated C-H Bonds: Synthesis, X-ray Characterization and Catalytic Activity of Ru(TPP)(NAr)(2) (Ar ¼ 3,5-(CF(3))(2)C(6)H(3)). Chem. Commun. 2009; 3952–3954. 210. Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M. Highly Diastereo- and Enantioselective Intramolecular Amidation of Saturated C—H Bonds Catalyzed by Ruthenium Porphyrins. Angew. Chem. Int. Ed. 2002, 41, 3465–3468. 211. Liu, Y.; Tse, C. W.; Lam, K. Y.; Chang, X. Y.; Guan, X.; Chao, M. Y.; Huang, J. S.; Che, C. M. Intramolecular Nitrene Insertion into Saturated C-H-Bond-Mediated C-N Bond Cleavage of a Coordinated NHC Ligand. Chem. A Eur. J. 2019, 25, 10828–10833. 212. Milczek, E.; Boudet, N.; Blakey, S. Enantioselective C-H amination using cationic ruthenium(II)-pybox catalysts. Angew. Chem. Int. Ed. 2008, 47, 6825–6828.

292

Synthetic Applications of Carbene and Nitrene CdH Insertion

213. Harvey, M. E.; Musaev, D. G.; Du Bois, J. A diruthenium catalyst for selective, intramolecular allylic C-H amination: reaction development and mechanistic insight gained through experiment and theory. J. Am. Chem. Soc. 2011, 133, 17207–17216. 214. Nishioka, Y.; Uchida, T.; Katsuki, T. Enantio- and regioselective intermolecular benzylic and allylic C-H bond amination. Angew. Chem. Int. Ed. 2013, 52, 1739–1742. 215. Zhang, X.; Lin, B.; Chen, J.; Chen, J.; Luo, Y.; Xia, Y. Synthesis of Sulfimides and N-Allyl-N-(thio)amides by Ru(II)-Catalyzed Nitrene Transfer Reactions of N-Acyloxyamides. Org. Lett. 2021, 23, 819–825. 216. Caballero, A.; Díaz-Requejo, M. M.; Belderraín, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. Highly Regioselective Functionalization of Aliphatic Carbon-Hydrogen Bonds with a Perbromohomoscorpionate Copper(I) Catalyst. J. Am. Chem. Soc. 2003, 125, 1446–1447. 217. Badiei, Y. M.; Dinescu, A.; Dai, X.; Palomino, R. M.; Heinemann, F. W.; Cundari, T. R.; Warren, T. H. Copper-nitrene complexes in catalytic C-H amination. Angew. Chem. Int. Ed. 2008, 47, 9961–9964. 218. Wiese, S.; Badiei, Y. M.; Gephart, R. T.; Mossin, S.; Varonka, M. S.; Melzer, M. M.; Meyer, K.; Cundari, T. R.; Warren, T. H. Catalytic C-H amination with unactivated amines through copper(II) amides. Angew. Chem. Int. Ed. 2010, 49, 8850–8855. 219. Gephart, R. T.; Warren, T. H. Copper-Catalyzed sp3 C–H Amination. Organometallics 2012, 31, 7728–7752. 220. Ton, T. M.; Tejo, C.; Tiong, D. L.; Chan, P. W. Copper(II) triflate catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds. J. Am. Chem. Soc. 2012, 134, 7344–7350. 221. Aguila, M. J.; Badiei, Y. M.; Warren, T. H. Mechanistic insights into C-H amination via dicopper nitrenes. J. Am. Chem. Soc. 2013, 135, 9399–9406. 222. Bagchi, V.; Paraskevopoulou, P.; Das, P.; Chi, L.; Wang, Q.; Choudhury, A.; Mathieson, J. S.; Cronin, L.; Pardue, D. B.; Cundari, T. R.; Mitrikas, G.; Sanakis, Y.; Stavropoulos, P. A versatile tripodal Cu(I) reagent for C-N bond construction via nitrene-transfer chemistry: catalytic perspectives and mechanistic insights on C-H aminations/amidinations and olefin aziridinations. J. Am. Chem. Soc. 2014, 136, 11362–11381. 223. Fauche, K.; Nauton, L.; Jouffret, L.; Cisnetti, F.; Gautier, A. A catalytic intramolecular nitrene insertion into a copper(i)-N-heterocyclic carbene bond yielding fused nitrogen heterocycles. Chem. Commun. 2017, 53, 2402–2405. 224. Cui, Y.; He, C. A Silver-Catalyzed Intramolecular Amidation of Saturated C–H Bonds. Angew. Chem. Int. Ed. 2004, 43, 4210–4212. 225. Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Silver-Catalyzed Intermolecular Amination of C–H Groups. Angew. Chem. Int. Ed. 2007, 46, 5184–5186. 226. Rigoli, J. W.; Weatherly, C. D.; Alderson, J. M.; Vo, B. T.; Schomaker, J. M. Tunable, chemoselective amination via silver catalysis. J. Am. Chem. Soc. 2013, 135, 17238–17241. 227. Alderson, J. M.; Phelps, A. M.; Scamp, R. J.; Dolan, N. S.; Schomaker, J. M. Ligand-controlled, tunable silver-catalyzed C-H amination. J. Am. Chem. Soc. 2014, 136, 16720–16723. 228. Alderson, J. M.; Corbin, J. R.; Schomaker, J. M. Tunable, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts. Acc. Chem. Res. 2017, 50, 2147–2158. 229. Ju, M.; Weatherly, C. D.; Guzei, I. A.; Schomaker, J. M. Chemo- and Enantioselective Intramolecular Silver-Catalyzed Aziridinations. Angew. Chem. Int. Ed. 2017, 56, 9944–9948. 230. Scamp, R. J.; Scheffer, B.; Schomaker, J. M. Regioselective differentiation of vicinal methylene C-H bonds enabled by silver-catalysed nitrene transfer. Chem. Commun. 2019, 55, 7362–7365. 231. Elkoush, T.; Mak, C. L.; Paley, D. W.; Campbell, M. G. Silver(II) and Silver(III) Intermediates in Alkene Aziridination with a Dinuclear Silver(I) Nitrene Transfer Catalyst. ACS Catal. 2020, 10, 4820–4826. 232. Maestre, L.; Dorel, R.; Pablo, O.; Escofet, I.; Sameera, W. M.; Alvarez, E.; Maseras, F.; Diaz-Requejo, M. M.; Echavarren, A. M.; Perez, P. J. Functional-Group-Tolerant, Silver-Catalyzed N-N Bond Formation by Nitrene Transfer to Amines. J. Am. Chem. Soc. 2017, 139, 2216–2223. 233. Scamp, R. J.; Rigoli, J. W.; Schomaker, J. M. Chemoselective silver-catalyzed nitrene insertion reactions. Pure Appl. Chem. 2014, 86, 381–393. 234. Dolan, N. S.; Scamp, R. J.; Yang, T.; Berry, J. F.; Schomaker, J. M. Catalyst-Controlled and Tunable, Chemoselective Silver-Catalyzed Intermolecular Nitrene Transfer: Experimental and Computational Studies. J. Am. Chem. Soc. 2016, 138, 14658–14667. 235. Weatherly, C.; Alderson, J. M.; Berry, J. F.; Hein, J. E.; Schomaker, J. M. Catalyst-Controlled Nitrene Transfer by Tuning Metal:Ligand Ratios: Insight into the Mechanisms of Chemoselectivity. Organometallics 2017, 36, 1649–1661. 236. Alderson, J. M.; Corbin, J. R.; Schomaker, J. M. Investigation of transition metal-catalyzed nitrene transfer reactions in water. Bioorg. Med. Chem. 2018, 26, 5270–5273. 237. Huang, M.; Corbin, J. R.; Dolan, N. S.; Fry, C. G.; Vinokur, A. I.; Guzei, I. A.; Schomaker, J. M. Synthesis, Characterization, and Variable-Temperature NMR Studies of Silver(I) Complexes for Selective Nitrene Transfer. Inorg. Chem. 2017, 56, 6725–6733. 238. Li, Z.; Capretto, D. A.; Rahaman, R. O.; He, C. Gold(III)-Catalyzed Nitrene Insertion into Aromatic and Benzylic C-H Groups. J. Am. Chem. Soc. 2007, 129, 12058–12059. 239. Li, C.; Zhang, L. Gold-Catalyzed Nitrene Transfer to Activated Alkynes: Formation of r,b-Unsaturated Amidines. Org. Lett. 2011, 13, 1738–1742. 240. Zhang, Y.; Feng, B.; Zhu, C. Au(III)-Catalyzed Intermolecular Amidation of Benzylic C-H Bonds. Org. Biomol. Chem. 2012, 10, 9137–9141. 241. Hou, K.; Qi, M.; Liu, J.; Bao, X.; Schaefer, H. F.; 3rd., Mechanistic Investigations of the AuCl3-Catalyzed Nitrene Insertion into an Aromatic C-H Bond of Mesitylene. J. Org. Chem. 2015, 80, 5795–5803. 242. Cenini, S.; Gallo, E.; Penoni, A.; Ragaini, F.; Tollari, S. Amination of Benzylic C–H Bonds by Aryl Azides Catalysed by CoII(porphyrin) Complexes. A New Reaction Leading to Secondary Amines and Imines. Chem. Commun. 2000; 2265–2266. 243. Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Gotti, C. L.; Lapadula, M.; Mangioni, E.; Cenini, S. Amination of Benzylic C-H Bonds by Arylazides Catalyzed by CoII  Porphyrin Complexes: A Synthetic and Mechanistic Study. Chem. A Eur. J. 2003, 9. 244. Lyaskovskyy, V.; Suarez, A. I.; Lu, H.; Jiang, H.; Zhang, X. P.; de Bruin, B. Mechanism of Cobalt(II) Porphyrin-Catalyzed C-H Amination with Organic Azides: Radical Nature and H-atom Abstraction Ability of the Key Cobalt(III)-Nitrene Intermediates. J. Am. Chem. Soc. 2011, 133, 12264–12273. 245. Villanueva, O.; Weldy, N. M.; Blakey, S. B.; MacBeth, C. E. Cobalt Catalyzed sp(3) C-H Amination Utilizing Aryl Azides. Chem. Sci. 2015, 6, 6672–6675. 246. Lee, J.; Kang, B.; Kim, D.; Lee, J.; Chang, S. Cobalt-Nitrenoid Insertion-Mediated Amidative Carbon Rearrangement via Alkyl-Walking on Arenes. J. Am. Chem. Soc. 2021, 143, 18406–18412. 247. Baek, Y.; Das, A.; Zheng, S. L.; Reibenspies, J. H.; Powers, D. C.; Betley, T. A. C-H Amination Mediated by Cobalt Organoazide Adducts and the Corresponding Cobalt Nitrenoid Intermediates. J. Am. Chem. Soc. 2020, 142, 11232–11243. 248. van Leest, N. P.; de Bruin, B. Revisiting the Electronic Structure of Cobalt Porphyrin Nitrene and Carbene Radicals with NEVPT2-CASSCF Calculations: Doublet versus Quartet Ground States. Inorg. Chem. 2021, 60, 8380–8387. 249. van Leest, N. P.; Tepaske, M. A.; Oudsen, J. H.; Venderbosch, B.; Rietdijk, N. R.; Siegler, M. A.; Tromp, M.; van der Vlugt, J. I.; de Bruin, B. Ligand Redox Noninnocence in [Co(III)(TAML)](0/-) Complexes Affects Nitrene Formation. J. Am. Chem. Soc. 2020, 142, 552–563. 250. van Leest, N. P.; Tepaske, M. A.; Venderbosch, B.; Oudsen, J.-P. H.; Tromp, M.; van der Vlugt, J. I.; de Bruin, B. Electronically Asynchronous Transition States for C–N Bond Formation by Electrophilic [CoIII(TAML)]-Nitrene Radical Complexes Involving Substrate-to-Ligand Single-Electron Transfer and a Cobalt-Centered Spin Shuttle. ACS Catal. 2020, 10, 7449–7463. 251. Jin, L. M.; Xu, X.; Lu, H.; Cui, X.; Wojtas, L.; Zhang, X. P. Effective Synthesis of Chiral N-Fluoroaryl Aziridines Through Enantioselective Aziridination of Alkenes with Fluoroaryl Azides. Angew. Chem. Int. Ed. 2013, 52, 5309–5313. 252. Dong, Y.; Clarke, R. M.; Porter, G. J.; Betley, T. A. Efficient C-H Amination Catalysis Using Nickel-Dipyrrin Complexes. J. Am. Chem. Soc. 2020, 142, 10996–11005. 253. Paradine, S. M.; White, M. C. Iron-Catalyzed Intramolecular Allylic C-H Amination. J. Am. Chem. Soc. 2012, 134, 2036–2039. 254. Legnani, L.; Morandi, B. Direct Catalytic Synthesis of Unprotected 2-Amino-1-Phenylethanols from Alkenes by Using Iron(II) Phthalocyanine. Angew. Chem. Int. Ed. 2016, 55, 2248–2251.

Synthetic Applications of Carbene and Nitrene CdH Insertion

293

255. Legnani, L.; Gabriele, P.-C.; Delcaillau, T.; Willems, S.; Morandi, B. Efficient Access to Unprotected Primary Amines by Iron-Catalyzed Aminochlorination of Alkenes. Science 2018, 362, 434–439. 256. Liu, W.; Zhong, D.; Yu, C. L.; Zhang, Y.; Wu, D.; Feng, Y. L.; Cong, H.; Lu, X.; Liu, W. B. Iron-Catalyzed Intramolecular Amination of Aliphatic C-H Bonds of Sulfamate Esters with High Reactivity and Chemoselectivity. Org. Lett. 2019, 21, 2673–2678. 257. Li, X.; Dong, L.; Liu, Y. Theoretical Study of Iron Porphyrin Nitrene: Formation Mechanism, Electronic Nature, and Intermolecular C-H Amination. Inorg. Chem. 2020, 59, 1622–1632. 258. Iovan, D. A.; Betley, T. A. Characterization of Iron-Imido Species Relevant for N-Group Transfer Chemistry. J. Am. Chem. Soc. 2016, 138, 1983–1993. 259. Hennessy, E. T.; Betley, T. A. Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C–H Bond Amination. Science 2013, 340, 591–595. 260. Yang, Y.; Arnold, F. H. Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer. Acc. Chem. Res. 2021, 54, 1209–1225. 261. Wang, J.; Gao, H.; Yang, L.; Gao, Y. Q. Role of Engineered Iron-haem Enzyme in Reactivity and Stereoselectivity of Intermolecular Benzylic C–H Bond Amination. ACS Catal. 2020, 10, 5318–5327. 262. Steck, V.; Kolev, J. N.; Ren, X.; Fasan, R. Mechanism-Guided Design and Discovery of Efficient Cytochrome P450-Derived C-H Amination Biocatalysts. J. Am. Chem. Soc. 2020, 142, 10343–10357. 263. Chen, K.; Arnold, F. H. Engineering New Catalytic Activities in Enzymes. Nat. Catal. 2020, 3, 203–213. 264. Prier, C. K.; Zhang, R. K.; Buller, A. R.; Brinkmann-Chen, S.; Arnold, F. H. Enantioselective, Intermolecular Benzylic C-H Amination Catalysed by an Engineered Iron-Haem Enzyme. Nat. Chem. 2017, 9, 629–634. 265. Farwell, C. C.; McIntosh, J. A.; Hyster, T. K.; Wang, Z. J.; Arnold, F. H. Enantioselective Imidation of Sulfides via Enzyme-Catalyzed Intermolecular Nitrogen-Atom Transfer. J. Am. Chem. Soc. 2014, 136, 8766–8771. 266. Chen, K.; Arnold, F. H. Engineering Cytochrome P450s for Enantioselective Cyclopropenation of Internal Alkynes. J. Am. Chem. Soc. 2020, 142, 6891–6895. 267. Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K. Total Synthesis of Oxidized Welwitindolinones and (-)-N-methylwelwitindolinone C Isonitrile. J. Am. Chem. Soc. 2012, 134, 1396–1399.

12.08

Metal-Catalyzed Amination: CdN Bond Formation

Alexander Haydla, Arne Geisslerb, and Dino Bertholdb, aChemical Process Development, Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim am Rhein, Germany; bInstitut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany © 2022 Elsevier Ltd. All rights reserved.

12.08.1 12.08.1.1 12.08.1.1.1 12.08.1.1.2 12.08.1.2 12.08.1.2.1 12.08.1.2.2 12.08.1.3 12.08.1.3.1 12.08.1.3.2 12.08.2 12.08.2.1 12.08.2.2 12.08.2.3 12.08.2.3.1 12.08.2.3.2 12.08.2.3.3 12.08.3 12.08.3.1 12.08.3.2 12.08.4 12.08.4.1 12.08.4.2 12.08.4.2.1 12.08.4.2.2 12.08.4.2.3 12.08.4.3 12.08.5 References

Amination of aliphatic Csp3dH bonds Csp3dH bond amination by catalyzed nitrene transfer reaction Racemic nitrene transfer reactions Enantioselective variants Csp3dH bond amination by SET photoredox catalysis and electrochemical oxidation Intramolecular amination Intermolecular amination Csp3dH bond amination by CdH activation Intramolecular amination Intermolecular CdH amination Allylic amination for the construction of Csp3dN bonds Introduction Asymmetric amination through allylic substitution Amination of alkynes and allenes Pd-catalyzed hydroamination of alkynes and allenes Rh-catalyzed hydroamination of alkynes and allenes Au-catalyzed hydroamination of alkynes and allenes Vinylic Csp2dN bond formation Transition metal catalyzed hydroamination of alkynes Vinylic amination by cross-coupling Aromatic Csp2dN bond formation The Ullmann-Goldberg reaction The Buchwald Hartwig amination Bulky biarylphosphine ligands Bisphosphine ligands Ni-catalyzed Buchwald-Hartwig amination The Chan-Lam amination Conclusion

294 294 295 296 298 298 299 300 300 302 303 303 303 306 306 306 308 309 310 313 315 315 318 320 321 322 322 325 325

Transition metal catalyzed carbon–nitrogen bond formations have been developed as fundamentally important reactions. CdN bonds are ubiquitously found in natural products, pharmaceuticals, agrochemicals and in recent products and intermediates of the chemical industry. This book chapter puts emphasis on recent state-of-the-art procedures and highlights achievements in the fields of aliphatic CdN bond formation including nitrene insertion reactions, allylic amination, hydroamination and CdN cross coupling reactions. This chapter has been clustered to the different types of reactions and references to literature from the last 20 years, specifically from 2000 to 2021.

12.08.1 Amination of aliphatic Csp3dH bonds Aliphatic Csp3dH bonds are ubiquitous in organic molecules. A functionalization of inert Csp3dH bonds offers the opportunity for direct introduction of functional groups into the desired compounds. However, their high stability and abundance in the molecule leads to a lack of selectivity, what makes them a challenging target for organic transformations. An increase in atom- and step-economy outweigh these complications, hence scientists have found several strategies to overcome these problems. Csp3dH bond amination may be clustered to three procedures, all relying on independent mechanisms1 (i) Nitrene insertion reactions, (ii) single electron transfer (SET) via radical intermediates and (iii) CdH activation amination.

12.08.1.1 Csp3dH bond amination by catalyzed nitrene transfer reaction Nitrenes (1), in close analogy to carbenes, show strong electrophilicity, partial biradical character and consequent instability in absence of stabilizing groups.2 The formation of nitrenes emanates in most cases from high-energy precursors, such as imidoiodanes, azides and tosyloxycarbamates and is often facilitated by a metal catalyst to form the metal-nitrene species [M] ¼ NR’ (2).3,4 Being highly energetic, metal-nitrene 2 shows unique reactivity enabling the reaction with inert Csp3dH bonds. Two main pathways are discussed to explain the outcome of this reaction according to mechanistic studies carried out by Warren (Scheme 1).5

294

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00091-3

Metal-Catalyzed Amination: CdN Bond Formation

295

Scheme 1 Proposed pathways for nitrene insertion reactions into CdH bonds.

While hydrogen atom abstraction (HAA) and consequent radical rebound of 3 is favored for biradical ground-state metal-nitrenes 2, singlet state nitrenes may also react in a concerted mechanism 4, where the nitrogen is directly inserted into the CdH bond.

12.08.1.1.1

Racemic nitrene transfer reactions

Pioneering work for nitrene insertion was reported in 1982 by Breslow and Gellmann, who applied a Mn- and Fe/tetraphenylporphyrine (TPP) catalyst for intermolecular tosylamidation of cyclohexanes.6 This protocol was later expanded by use of a [Rh(OAc)2]2 catalyst to perform a directed intramolecular tosylamidation in the benzylic position.7 Intermediately formed imidoiodanes are known to lack of stability, hence subsequently developed procedures take advantage of in-situ generated iodanes to serve as reactive interim compounds to undergo nitrene transfer reactions.8 Du Bois established a system based on the oxidant PhI(OAc)2 and employing different Rh-based catalysts for the synthesis of sulfamates,9 oxazilidinones,10 ureas11 and guanidines.11 They also introduced [Rh2(esp)2] as a powerful catalyst for nitrene insertion. The intramolecular addition of sulfamate 7 to form the cyclic sulfamate 8 was accomplished with as little as 0.15 mol % [Rh2(esp)2] in 96% yield, demonstrating its superiority to [Rh2(O2CtBu)4] (Scheme 2, top).11,12 Similarly, the cyclization of sulfamides 9 was found feasible (Scheme 2, bottom).13

Scheme 2 Rhodium catalyzed insertion of sulfamates 7 and sulfamides 9 into aliphatic Csp3dH bonds.

Electron-deficient substrates, such as 9 react stereospecifically to form six-membered sulfamide-bridged heterocycles 10 in excellent regio- and anti-diastereoselectivity as well as yields of up to 99% by requiring only 1 mol% of catalyst loading. Subsequent cleavage of the sulfamate allowed access to unprotected anti-1,3-diamines 11. Circumventing the undesired use of (super-)stoichiometric amounts of external oxidant, Lebel and co-workers observed that stable N-tosyloxycarbamates 12 are suitable precursors to form the reactive nitrene species, with the N–O-bond serving as internal oxidant for the nitrene formation.14,15 The reaction proceeded well at mild reaction conditions in an inter- and intramolecular fashion and resulted in an impressive stereospecific scope of different aliphatic and benzylic oxazolidinones 13, as well as N-Troc-protected amines 16 in good to excellent yields (Scheme 3, top).

296

Metal-Catalyzed Amination: CdN Bond Formation

Scheme 3 External oxidant-free Csp3dH amination with N-tosyloxyl carbamates 12 and 15 and azides 17.

In close analogy, organic azides were also found to work well in the nitrene transfer reaction.16,17 Inspired by Cenini’s earlier work,18–21 Warren found that CuI could catalyze nitrene transfer of 1-adamantylazides 17 to aliphatic-, allylic- and benzylic substrates 18 in excellent yields.22,23 In mechanistic studies a dicopper-nitrene species 20 was shown to be a key intermediate in the amination reaction. Notably, various other transition metals such as ruthenium,8,24–26 silver,27–29 iron,30–32 cobalt,33,34 manganese,35 and even enzymatic enabled reactions36 have been described to promote the above outlined nitrene insertion reactions.

12.08.1.1.2

Enantioselective variants

Early examples for asymmetric nitrene insertion, as very recently reviewed by Uchida and Hayashi,37 were found by Müller only short time after Breslow’s initial studies.38 This stereoselective nitrene insertion relied on a chirally enriched RhII-catalyst, but gave only moderate enantioselectivities. Selectivity was later significantly improved by Hashimoto, applying the electron-deficient chiral phthalimido-ligand 22 in the intermolecular enantioselective amination of indanes 23, to achieve enantioselectivites of up to 84% (Scheme 4, top).39

Scheme 4 Rh/Phthalimido catalysts 22 and 26 for intermolecular enantioselective CdH amination by nitrene insertion.

Metal-Catalyzed Amination: CdN Bond Formation

297

In close analogy to Hashimoto’s ligand 22, Dauban recently developed a perfluorinated phthalimido-ligand 26 that allowed stereoselective rhodium catalyzed nitrene insertion in benzylic position.40 High yields and consistent enantioselectivites, as well as a low catalyst loading, cheap oxidant and the possibility to cleave the sulfamate protective group under mild reaction conditions makes this method very appealing for late-stage modification (Scheme 4, bottom). In 2011, the Katsuki group reported on Ir-catalyzed intramolecular benzylic CdH amination (Scheme 5). The sterically encumbered BINOL-based salen complex 30 enabled the selective formation of different cyclic sultames 32 in yields of up to 90% and with ee’s of up to 93%.16,41 While yield and ee were consistent throughout the substrate scope, the regioselectivities were found to be difficult to control and resulted in mixtures of the five- and six-membered sultames 32 and 33. Taking advantage of this observation, this group later developed a Ru/salen system 34 that furnished excellent regioselectivity in the intermolecular Csp3dH bond amination in benzylic and allylic position.42

Scheme 5 Enantioselective intra- and intermolecular Csp3dH bond amination catalyzed by Ir- or Ru-salen catalysts.

A highlight in terms of enantioselectivity has been reported by Arnold in 2019.43 They employed a cytochrome P450 derived enzyme in the intramolecular amination of a variety of aliphatic, allylic and benzylic substrates 37 (Scheme 6). Amination of racemic substrates 39 involving a primary or tertiary Csp3dH bond is stereoconvergent and leads to a single enantiomer 40. The authors propose the nitrene-mediated insertion to proceed through a radical transition state 42, leading to desymmetrization of the target structure.

Scheme 6 Enzyme catalyzed enantioselective Csp3dH bond amination by Arnold.

In 2020, Bach and co-workers reported on an Ag-catalyzed enantioselective amination controlled by hydrogen bonding of pyridones and quinolones 41 achieving high enantioselectivities of up to 97% ee (Scheme 7).44,45

298

Metal-Catalyzed Amination: CdN Bond Formation

Scheme 7 Enantioselective amination of pyridones and quinolones 41 catalyzed by a Ag-catalyst.

Despite their high energetic character, insertion of nitrenes were successfully utilized in the total syntheses of (−)tetrodotoxine,46 (−)-agelastatin,47 (−)-N-methylwelwitindilinone,48 and various other complex natural products.49,50

12.08.1.2 Csp3dH bond amination by SET photoredox catalysis and electrochemical oxidation Photoredox catalysis has attracted significant attention in the recent years.51–54 Regarding the fields of CdN bond formation, several protocols for the amination of vinylic and aromatic Csp2dH bonds have been developed. Examples for photoredox catalyzed amination of unactivated Csp3dH bonds, as well as mechanistically related electrochemical aminations remain scarce, as they typically proceed through highly reactive radical intermediates.55 Since both photoredox- and electrochemical aminations proceed through similar SET processes and have similar scopes these topics are merged and outlined in the following section.

12.08.1.2.1

Intramolecular amination

From a mechanistic point of view, photoredox catalyzed reactions follow the pathway of a cross-dehydrogenative coupling (CDC).55 In 2016, Knowles56 and Rovis57 independently utilized the Hofmann-Löffler-Freytag (HLF) reaction58 and the 1,5hydrogen atom transfer (1,5-HAT) as key for a variety of photoredox catalyzed activations of Csp3dH bonds (Scheme 8, top).59 Here C-centered radicals with a photochemically generated N-radical, were scavenged with different unsaturated electrophiles. Inspired by these and other results60–63 Muniz reported on an iodine catalyzed mild CDC with different amides 47 (Scheme 8, bottom left).64 While the method has proven to be compatible for a large scope of substrates, halogenated aromatics for R2 tend to give lower yields due to overoxidation. The superiority of this method over earlier reports lies within the application of a free N–H-bond instead of pre-halogenated substrates as employed by others.65

Scheme 8 Cooperative photoredox catalysis as reported by Knowles, Rovis and Muniz, in contrast to Lei electrochemical oxidation approach for the amination of Csp3dH bonds.

Later, Lei investigated the electrochemical variant of this reaction (Scheme 8, bottom right).66 In an undivided cell, electro-oxidative Csp3dH bond amination provided the desired 2-aryl pyrrolidines, oxazolidines and imidazolines 50 in moderate to excellent yields of up to 98%. A drop in yield to 42% was observed for R2 containing 2 aliphatic Csp3dH groups.

Metal-Catalyzed Amination: CdN Bond Formation

299

In 2020 Nagib reported of a photocatalyzed stereoselective 1,5-HAT protocol for the synthesis of enantiomerically enriched b-amino alcohols 57 in benzylic, allylic and even 2 aliphatic positions from the corresponding alcohols 52 (Scheme 9).67 The iridium-based photosensitizer is complemented by the application of a chiral CuI-BOX catalyst, that allowed enantioselective cyclization of oxime imidate 52. The obtained chiral oxazolines 56 were subjected to acidic workup to yield the corresponding b-amino alcohols 57 in up to 99% yield with ee’s up to 98%.

Scheme 9 Nagib’s protocol for the enantioselective b-C-H amination of alcohols 57.

12.08.1.2.2

Intermolecular amination

In 2015 Pandey’s group reported on a visible light catalyzed intermolecular photoredox amination.68 More challenging N-nucleophiles, such as benzotriazoles and imidazoles 59 were found to react smoothly with different substituted 4-methoxy toluenes 58 (Scheme 10).69

Scheme 10 Pandey’s photoredox-catalyzed benzylic Csp3dH amination.

300

Metal-Catalyzed Amination: CdN Bond Formation

A mechanistic proposal by the authors envisioned the photocatalytic excitation of IrIII 62, followed by reduction of the oxidative quencher BrCCl3 (61) to generate a IrIV-complex 64. The latter then oxidizes the 4-methoxy toluene 58 generating a radical cation 65, which is subjected to H-atom abstraction providing the benzylic cation 66. Finally, the cation reacts with different N-heterocycles furnishing the desired products.

12.08.1.3 Csp3dH bond amination by CdH activation Directing groups facilitate the insertion of suitable transition metal catalysts in thus activated CdH bonds. The obtained covalent C–M bond can then undergo reaction with various functional groups.70,71 This upstream CdH bond cleavage differentiates the inner-sphere CdH activation mechanisms to the outer-sphere nitrene insertion mechanisms. Aside from structural prerequisites, directed CdH activation proofs to be a powerful reaction type for CdN bond-formation. The most challenging bond installed by this approach is the herein discussed formation of Csp3dN bonds.72

12.08.1.3.1

Intramolecular amination

In 2009, Glorius presented precedence for the viability of this transformation: PdII-catalyzed cyclization of N-acetyl-2-alkylanilines 67 provided dihydroindolines 68 in up to 83% yield (Scheme 11).73

Scheme 11 Glorius’ Csp3dH activation in the cyclization of alkylanilines 67 to dihydroindolines 68.

The scope of the reaction was limited to N-acetyl derivatives 67, arguably due to a fine equilibrium in steric and electronic properties. Two possible pathways were reasoned: After ligand exchange, the NdPd species 70 undergoes inserts into the activated CdH bond. Palladacycle 71 is either oxidized by Ag(OAc) to form PdIV-7274 followed by reductive elimination, or undergoes acetoxylation into 73, followed by subsequent nucleophilic substitution to give the desired protected dihydroindoline 74. The groups of Chen and Daugulis independently published a Pd(OAc)2-catalyzed intramolecular amination of Csp3dH bonds (Scheme 12).75,76 Both groups applied PhI(OAc)2 in toluene as the oxidant for the reoxidation of the active PdII-catalyst. Selective intramolecular g- or d-amination of 75 or 77 did yield the four- or five-membered N-heterocycles 76 and 78 stereospecifically.

Scheme 12 Picoline acetyl-assisted Csp3dH bond activation in the Pd-catalyzed intramolecular amination-cyclization.

Metal-Catalyzed Amination: CdN Bond Formation

301

Key to success was the 2-picoline acetyl-attachment (PA) as a directing group, earlier developed by Daugulis.77 Chen later introduced quinoline ligands as the N-protecting group to fulfill the same purpose.78 Inspired by these observations, Gaunt reported on the synthesis of aziridines 80 being accessed from a-methyl amines 79 by a palladium catalyzed reaction (Scheme 13).79 The desired aziridines 80 were generated under these reaction conditions without the necessity of an additional directing group.80 The highly strained aziridines 80 were used in subsequent ring opening reactions with different nucleophiles to generate a variety of b-substituted amines 81. Furthermore, carbonylation of the in-situ generated azirdines under CuII-catalysis enabled formylation to yield b-lactams 84.

Scheme 13 Aziridination reported by Gaunt and co-workers by activating an unactivated Csp3dH bond in b-position.

In 2017, Gaunt reported an enantioselective protocol of this reaction, employing a chiral BINOL phosphoric acid as a ligand to achieve ee’s of up to 94%.81 Following on the 2-picoline acetyl-based work of Chen and Daugulis, Wu devised a CdH activation procedure for the construction of highly strained aza-bicyclic derivatives 86.82 This method proved its usefulness in the synthesis of complex structures which were derived from (−)-cis-myrtanyl amine 87 (Scheme 14).83

Scheme 14 Wu’s g-selective CdH activation cyclization in the synthesis of highly strained aza-bicyclic structures.

The first enantioselective amidation of a methylene Csp3dH bond was accomplished by Shi utilizing a 2-pyridinylisopropyl (PIP) directed Pd-catalyzed CdH activation in presence of a chiral ligand L3 (Scheme 15).84 PIP-protected acetylamide 90 could be cyclized to the corresponding b-lactam 91 in the presence of a PdII/(S)-3,30 -dichlorobinol catalyst. A broad scope of substrates was aminated in the benzylic or 2 aliphatic position providing yields of up to 95% and ee’s of up to 95%. Notably, 2-fluoro-1-iodo-4-nitrobenzene is believed to serve as the oxidant to enhance both stereocontrol and selectivity of the reductive elimination.

302

Metal-Catalyzed Amination: CdN Bond Formation

Scheme 15 First Pd-catalyzed enantioselective intramolecular methylene Csp3dH activation amination.

The catalytic PdII/PdIV cycle is proposed to proceed through the cyclopalladium 92 being oxidized to the reactive PdIV-species 93 directly undergoing reductive elimination to favor CdN bond formation to the enantiomeric enriched lactam 91. Apart from well-studied Pd-catalyzed intramolecular CdH activations, other metals, such as Ni,85 Cu,86,87 Ag88 and Co89 were studied to some extent.

12.08.1.3.2

Intermolecular CdH amination

Intermolecular Csp3dH activation in the context of amination reactions is undeniably more challenging than its intramolecular variant. Firm directing groups typically must be employed in order to favor amination reactions over side reactions. Furthermore, differentiation of nitrene insertion versus CdH activation mechanisms becomes difficult since the underlying mechanisms can be complementary to each other. In 2006, Che and co-workers reported of the imine-N-oxide directed CdH activation in the presence of 4-chlorosulfonamides, providing the Csp3–amination product 95 in high yields for aliphatic and aromatic substrates (Scheme 16, left).90 The authors suggested two possible mechanistic pathways, both proceeding through an intermediate palladium-nitrene insertion step.

Scheme 16 Pd- or Ir-catalyzed intermolecular Csp3dH bond amination by CdH activation.

A significantly improvement of this transformation was published by Chang, employing an Ir-catalyst, allowing a selective coupling of sulfone and acetylazides 97 to primary aliphatic Csp3dH bonds (Scheme 16, right).91 Surprisingly, installing a branched protecting group on the ketoximine 99 allowed for selective amidation of the tert-butyl group and allowed the synthesis of 1,2-amino alcohols 100.92 Later, Liu developed an elaborated procedure bearing a directing group which may be easily cleaved under mild conditions.93

Metal-Catalyzed Amination: CdN Bond Formation

303

Morpholine-N-oxide 101 allows to avoid the stoichiometric use of oxidants and were reported Yu94 and Qin.95 Applying N-arylacetamides 102 and 103 as the directing group amination of Csp3dH bonds provided the b-amino carboxylic acid analogues 104 in high yields (Scheme 17).

Scheme 17 Morpholine-N-oxides as reagents in the intermolecular Csp3dH bond amination.

Recent examples for intermolecular CdH activation amination with more abundant alternatives such as Cu96 and Co97 are exemplarily for constant development in this field of research and provide a glimpse to the development of other useful methods.

12.08.2 Allylic amination for the construction of Csp3dN bonds 12.08.2.1 Introduction The importance of a-chiral amines and N-heterocycles in synthetic organic chemistry is best displayed by the large array of N-containing a-chiral molecules which can be found in nature, as well as in pharmaceutical industry. Encouraged by this aspect, many strategies for their asymmetric synthesis have been developed and among those, most prominently found as radical addition reactions, nucleophilic addition reactions, hydrogenation reactions of either imines or enamines and asymmetric reductive amination reactions.98 Particularly the asymmetric allylic substitution (AAS) with N-based nucleophiles has evolved strongly since its first reports to a general and elegant methodology for preparation of a-chiral allylic amines. This section highlights the asymmetric allylic amination of allylic substrates, and outlines procedures starting from other precursors, such as allenes and alkynes, leading to similar target molecules reported in the past years from 2000 until 2020.

12.08.2.2 Asymmetric amination through allylic substitution In their first reports on transition-metal catalyzed Csp3dN bond formation via allylic substitution, Trost and Tsuji particularly emphasized Pd-catalysts, featuring a broad scope of different electrophiles and nuclephiles.99–103 In recent years, many different types of catalysts have been identified and most interestingly IrI-catalysts proved to yield predominantly branched allylic amines rather than the linear amines typically obtained by Pd-catalyzed substitution reactions. A further push to the use of Ir-catalysts was given by the fact that the efficiency with regards to regio- and stereoselectivity could be tweaked by employing chiral phosphoramidite ligands, allowing for a broad range of other nucleophiles, in addition to amines and N-heterocycles. Herein, we outline some of the most recent highlights of IrI-phosphoramidite catalyzed allylic substitutions with amines, anilines and N-heterocycles. In the recent past, studies in the field of enantioselective allylic amination were carried out by Hartwig,104–106 Alexakis107 and Helmchen108 and the reported methods gave access to the branched products in both high yield and optical purity. Despite a large variety of compatible aromatic and aliphatic coupling partners, as well as various amines, at this point it is noteworthy to mention certain disadvantages of the catalyst applied in these substitution reactions. Alongside to its high sensitivity to elevated temperatures and high levels of oxygen, more importantly regioselectivities suffer when employing some challenging alkyl substituted starting materials. To overcome these issues, Helmchen108 and You109 developed a new generation of pre-catalysts that modified performance by change of the diene ligand employed in the reaction. Since then, several modified methods have been reported to give access to several new and widely applicable allylic amines (e.g. allylated amino acids, differently protected amines and amides).110–114 The utility of these reactions was later successfully exemplified as being applied in the total syntheses of several alkaloids (Scheme 18), such as (+)-angustureine (113) and (−)-cuspareine (114).115

304

Metal-Catalyzed Amination: CdN Bond Formation

Scheme 18 Overview on available methods for the intermolecular asymmetric allylation of amines and amides accessible by Ir-phosphoramidite systems and application in the synthesis of (+)-angustureine (113) and (−)-cuspareine (114).

The Helmchen group was also successful in developing an intramolecular asymmetric amination methodology by employing phosphoramidite ligand L5 to give access to linear allylic substrates.116,117 Employing related reaction conditions, Takahata was able to obtain synthetically expedient and substituted iminofuranes after starting from chiral, linear allylic carbonates (Scheme 19).118

Scheme 19 Intramolecular allylic substitution with benzylamine and an application of related reaction conditions for the synthesis of substituted pyrrolidines reported by Helmchen.

Of synthetic interest, direct allylic amination reaction with ammonia as suitable and cheap nucleophile can lead to allylic amines and also furnish unprotected amines, unlike typical procedures, which yield primarily protected amines or amides. Beside facing challenging issues such as low regioselectivities and overalkylation, the presence of free ammonia most typically leads to deactivation of the active catalyst. Carreira solved these problems by employing sulfamic acid as an ammonia surrogate, which allowed for asymmetric amination, starting from branched allylic alcohols and employing Carreira’s ligand L7.119 The first successful application of ammonia in an asymmetric allylic substitution reaction was reported by Hartwig and co-workers. Increasing the amount of ammonia to 100 equivalents led to selective formation of monoallylated amines (Scheme 20).120,121

Metal-Catalyzed Amination: CdN Bond Formation

305

Scheme 20 Carreira’s and Hartwig’s conditions for the enantioselective synthesis of unsubstituted allylic amines.

Aromatic N-heterocyclic moieties, such as pyrroles, imidazole and purines, are apparent in biologically active compounds as well as intermediates in natural product synthesis.122 Thus, asymmetric allylic substitution for the synthesis of a-chiral allylic N-heterocycles has been investigated by several groups. In 2009, Hartwig reported on regio- and enantioselective N-allylation reactions with imidazoles, benzimidazoles and purines, with preformed IrI-catalysts derived either from phosphoramidite ligand L4 or L6 (Scheme 21).123–128 The application of the utilized catalyst in the selective N-allylation of electron deficient indoles was achieved later providing an useful access to a-chiral, allylated indoles.129

Scheme 21 Ir-catalyzed N-allylation of imidazoles, benzimidazoles and purines.

Further asymmetric allylation of N-heterocycles was conducted by Zhao and You, applying sodium benzotriazolide salts and 2-pyridines as substrates, respectively. The amination with benzotriazoles is challenging since the equilibrium between the N1- and N2-tautomer of benzotriazole shifts readily in solution, resulting in low N1/N2 selectivity (Scheme 22, left).130,131

Scheme 22 Ir-catalyzed N-allylation with either sodium benzotriazolides (left) or 2-hydroxypyridines (right).

306

Metal-Catalyzed Amination: CdN Bond Formation

Next to various reports on asymmetric N-selective intramolecular allylation of electron deficient indoles131 You and co-workers subjected pyridine substrates linked to an allylic carbonate tether to an asymmetric allylic substitution reaction.132 Undergoing a dearomatization under mild reaction conditions, 2,3-dihydroindolizines could be obtained in high yields and enantioselectivities. The authors furthermore successfully expanded the nucleophilic scope with regards to pyrazines, quinolines and isoquinolines (Scheme 23). In addition to this, You reported on asymmetric allylic intramolecular dearomatizations of benzoxazoles, benzothiazoles and benzimidazoles, moreover broadening the scope of substrates for this kind of allylation.133–135

Scheme 23 Ir-catalyzed asymmetric allylic dearomatization of pyridines, pyrazines and quinolines.

12.08.2.3 Amination of alkynes and allenes The functionalization of alkynes and allenes by amination has grown into an important field of research over the last 30 years. The fact that no waste, such as by leaving groups is produced or that no reagents, such as oxidants and bases are required as additives, highlights the relevance of this new methodology, especially with focus on concepts of green chemistry136 and atom economy.137,138

12.08.2.3.1

Pd-catalyzed hydroamination of alkynes and allenes

At the beginning of the 1990s, Yamamoto was the trailblazer to develop various methodologies describing the addition of NdH pronucleophiles to alkynes and allenes. For this purpose, he used electrophilic palladium complexes, forming the desired allyl intermediate by hydrometallation. Noteworthy though, the intermolecular Pd-catalyzed addition of amines and amides to terminal allenes and alkynes typically results in selective access to the linear allylic product (Scheme 24).139,140

Scheme 24 Pd-catalyzed hydroamination of allenes and 1-phenyl-1-propyne toward linear allylic amines.

Conversely to the results of intermolecular addition reactions of amines to allenes, the first intramolecular hydroamination protocols of sultames with alkynes furnish branched allylic pyrrolidines and piperidines in moderate to high yields and enantioselectivities.140–142

12.08.2.3.2

Rh-catalyzed hydroamination of alkynes and allenes

As having outlined the synthetic importance of chiral allylic amines, amides and N-heterocycles, Breit and co-workers recently reported on various different transition metal based catalytic systems complementary to the already established Pd-based protocols

Metal-Catalyzed Amination: CdN Bond Formation

307

with respect to gaining access to chiral branched products. In this context, Werner’s discovery with respect to RhI complexes being capable of converting internal alkynes into allenes brought new concepts relying on Rhodium into the game (Scheme 25).143

Scheme 25 Werner’s observations that a RhI-catalyzed isomerization of 2-butyne to buta-1,2-diene, and subsequent acid-catalyzed conversion into a RhIII-complex might pave the way to new catalytic concepts giving access to branched allylic products.

In the past 10 years, this initial hypothesis on RhI-systems showing capability to provide branched chiral products was vindicated by Breit and various other groups by providing protocols for a broad scope of X–H pronucleophiles, moreover various N-heterocycles, employed as coupling partners.144–151 Specifically, the asymmetric addition of anilines, imidazoles, benzophenone imines and 4-pyridinones to allenes was accomplished by a catalytic system based on [{Rh(cod)Cl}2] and different Josiphos analogous ligands and moreover, these new methodologies proved to work well in the synthesis of two different alkaloids (+)-angustureine and (−)-cuspareine as key step (Scheme 26).152–157

Scheme 26 Intermolecular asymmetric hydroamination of allenes with various NdH pronucleophiles, catalyzed by a [{Rh(cod)Cl}2]/Josiphos based catalyst.

Furthermore, an asymmetric intramolecular hydroamination of allenes was developed, starting from sulfonamides as the corresponding nucleophiles and led to the desired chiral pyrrolidines and piperidines, which could were further derivatized within the synthesis of small natural products (Scheme 27).158

308

Metal-Catalyzed Amination: CdN Bond Formation

Scheme 27 Intramolecular asymmetric hydroamination of allenes catalyzed by a [{Rh(cod)Cl}2]/JoSPOphos based catalyst.

Interestingly, the asymmetric amination of different azoles with allenes and alkynes was accomplished by utilizing one single catalytic system consisting of [{Rh(cod)Cl}2] and JoSPOphos ligand J688–1 (L13). The synthesized allylated heterocycles could be obtained in high yields and enantioselectivities, and moreover in high regioselectivities, which are unprecedented to date in the literature (Scheme 28).159–163

Scheme 28 [{Rh(cod)Cl}2]/JoSPOphos based catalytic system as most efficient for asymmetric intramolecular allylation of pyrazoles, triazoles and tetrazoles.

12.08.2.3.3

Au-catalyzed hydroamination of alkynes and allenes

Amongside Pd- and Rh-based catalysts, other transition metals such as Au have been utilized as well for the amination of allenes to access allylic products.164–168 Specifically AuI-catalysts have been reported to lead to high branched regioselectivity and to provide high enantioselectivities for the addition of NdH pronucleophiles. It is noteworthy that Au-catalyzed reactions generally are restricted to amines and amides in an asymmetric hydroamination of internal allenes. This underlies a mechanism, different from those of Pd- and Rh reported earlier in this chapter, where an Au-vinyl intermediate enables the formation of the allylic product. Toste and Widenhoefer simultaneously reported on different approaches for the intramolecular enantioselective addition of amides to internal allenes that rely on chiral diphosphine BINOL-type ligands (Scheme 29).169–173

Metal-Catalyzed Amination: CdN Bond Formation

309

169

170

172

173

Scheme 29 Different approaches for the asymmetric intramolecular hydroamination of allenes. Various AuI/chiral diphosphine complexes lead to the desired branched products.

In 2012, Widenhoefer applied his catalytic system based on the (S)-DTBM-MeO-BIPHEP(AuCl)2 complex (174) to the asymmetric intermolecular hydroamination of internal, racemic allenes with amides. High regioselectivities were only observed for internal allenes with an arene-alkyl pattern (Scheme 30).174

174

Scheme 30 Widenhoefer’s catalyst proved to work well in the asymmetric intermolecular hydroamination of internal allenes.

12.08.3 Vinylic Csp2dN bond formation Vinylic CdN bonds are in most cases formed by either one out of two routes: (i) Formal hydroamination of an alkynes175–179 or (ii) Cross coupling of amines with olefinic halides or CdH bonds.180–183 Both reaction pathways have been realized in the past by developing taylor made catalytic systems, providing selectively access to these ubiquitous structural motifs (Scheme 31).184–191

Scheme 31 Schematic display of the pathways for imine/enamine synthesis via hydroamination of alkynes or cross-coupling.

310

Metal-Catalyzed Amination: CdN Bond Formation

12.08.3.1 Transition metal catalyzed hydroamination of alkynes Catalytic hydroamination of alkynes is an atom economic method with regards to the formation of enamines, imines and after subsequent reduction, amines. Different transition metal catalysts have been developed in the past for an applicable and efficient approach to access vinylic CdN bonds. Early examples on titanium catalyzed hydroamination of alkynes were reported by Doye,192–194 Odom195,196 and Beller.196,197 In 2009 Odom published a four component coupling of alkyne 187, arylamine 188 and two equivalents of isonitrile 189 to produce 2,3-diaminopyrroles 190 in 75–93% yield for terminal alkynes and lower yields for symmetric internal alkynes (Scheme 32, top).198 The employed Ti(NMe2)2(IndMe2)2 catalyst is accessible from commercially available Ti(NMe2)4 with 2,3-dimethylindole. Later Tonks employed Mountford’s titanium catalyst199,200 for the synthesis of pyrroles 193, starting from alkynes 191 and aryl diazenes 192 (Scheme 32, bottom).201 Employing unsymmetrically substituted alkynes in the reaction led to statistical mixtures of pyrroles 194 and 195. An improved protocol based on silyl-protected terminal alkynes allowed access to more structural diverse pyrroles, where the steric and electronic properties of the silyl group were shown to have a firmly directing impact in the reaction.202

198

201

Scheme 32 Odom’s cyclization titanium catalyzed four-component cyclization for the synthesis of 2,3-diaminopyrroles 190 (top); Tonk’s titanium catalyzed oxidative double amination reaction of alkynes in the synthesis of pyrroles 193 (bottom).

Regioselectivity in titanium catalyzed intermolecular hydroamination of alkynes is often challenging. Schafer addressed this problem with the development of a bis(amidate)bis(amido)titanium precatalyst (199).203 Addition of different primary amines 197 to terminal and internal alkynes 196, followed by a subsequent reduction, provided the desired amines 198 in excellent yields (Scheme 33, left).204–206 Application in the facile generation of aminoalcohols and a one-pot protocol for the synthesis of indoles 202 highlighted the synthetic value of this method. In 2016 a refined method involving Pd-catalyzed hydrogenation was reported to provide an average yield of 90%, hence qualifying for multigram scale reactions while avoiding column chromatography.207 Computational studies have deepened the insight into the catalytic potency of the precatalyst 199 and the metal/ligand interaction.208 Odom developed a heterogenous silica supported titanium catalyst for the hydroamination of alkynes (Scheme 33, top right).209 Different internal and terminal alkynes 204 were able to be successfully transformed into the corresponding Markovnikov imines 205. Noteworthy at this point is the sensitivity towards steric bulk on the imine leading to a decrease in selectivity. In 2019, this method was applied in a multicomponent reaction for the formation of a,b-unsaturated b-iminoamines 209 that has been already established earlier in homogenous catalysis (Scheme 33, bottom right).210,211 As a key-step the insertion of an isonitrile 208 into the cyclometallabutene 210 was constituted.

Metal-Catalyzed Amination: CdN Bond Formation

205

311

209

Scheme 33 Schafer’s titanium catalyzed hydroamination of alkynes (left); Odom’s heterogenous titanium catalyzed hydroamination of alkynes and multicomponent reaction with isonitriles (right).

In contrast to abundant titanium, gold-based catalysts usually outweigh commercial disadvantages with efficiency and low catalyst loadings of as little as 0.01 mol%, as it has been demonstrated by Tanaka in the Markovnikov selective hydroamination of terminal alkynes (Scheme 34, top left).212 Later, Che found a AuIII-porphyrin catalyst to enable a comparable hydroamination reaction (Scheme 34, bottom left)213 and Bertrand developed an AuI-NHC catalyst 220 for the hydroamination of alkynes 217 and allenes 221 with ammonia,214 leading to form different Markovnikov imines 218 and pyrroles 219 and allylamines 222 in moderate yield (Scheme 34, right). However, harsh reaction conditions, an excess of ammonia, as well as the tendency of overreaction generally limit the applicability of this method. Further modifications allowed for the introduction of primary and secondary amines,215 hydrazines216 and anilines.217,218

212

214

213

Scheme 34 Markovnikov selective AuI-catalyzed hydroamination of alkynes and allenes.

Hammond described the application of commercially available Au nanoparticles in an intermolecular hydroamination of terminal alkynes 223with anilines 224(Scheme 35, top).219 Corresponding amines 225 were synthesized by reduction with NaBH(OAc)3. Intramolecular hydroamination of 2-acetylene anilines 226 resulted in 2-substituted indoles 227. A similar system was shown earlier by Zhu to be driven using visible light.220 In 2019, Nolan reported on the development of a solvent-free AuI-catalyzed hydroamination of internal and terminal alkynes 228 with different N-heterocycles 229, such as (benzo)triazoles, imidazoles, 1,2 diazoles etc. (Scheme 35, bottom).221 With as little as 0.50 mol% catalyst, excellent yields of up to 96% were achieved favoring the (Z)-enamines (Z)-231. After subsequent Pd-catalyzed hydrogenation, secondary amines were obtained in moderate to excellent yields. On the base of their earlier studies,222,223 the authors proposed that the amphoteric catalyst serves on the one hand as a Lewis acidic activator for the alkyne and on the other hand as a Brønsted base for the deprotonation of the azole.

312

Metal-Catalyzed Amination: CdN Bond Formation

219

221

Scheme 35 Au-catalyzed hydroamination of alkynes with N-heterocycles (above). Hydroamination of alkynes applying Au-nanoparticles (bottom).

Other gold sources, such as gold-clusters in micelles,224 reusable AuI-catalysts225 and redox-active AuI-phosphite systems226 are further examples for the high versatility of gold-catalysts in the hydroamination of alkynes. Copper is known as a potent hydroamination catalyst despite competing side reactions. In 2015, Taillefer and Monnier reported the anti-Markovnikov selective addition of secondary amines to alkynes (Scheme 36).227,228 The outcome of the reaction is firmly driven by the catalyst and reaction conditions. While 15 mol% of CuCN led to the expected anti-Markovnikov amines 236 in moderate yield, conversely the use of CuCl resulted in the formation of substituted dienes 237, reflecting the high affinity of CuI towards the terminal selective coordination to alkynes. In both cases an excess of amine was an issue limiting applicability, which has been solved very recently by an intramolecular Cu/base catalyzed hydroamination.229 227,228

Scheme 36 Anti-Markovnikov copper catalyzed hydroamination of alkynes by Taillifer and Monnier.

Unsurprisingly, Pd was also found to be potent in the hydroamination of alkynes. In 2020, Pinter applied a Pd-catalyst with a proton shuttle 241 in the hydroamination of terminal alkynes with anilines (Scheme 37, left).230 Furthermore, Cao showed the potency of a recyclable PddNHC complex 245 in hydroamination that was used for Markovnikov selective amination of terminal alkynes with anilines (Scheme 37, right).231 In addition to the metals discussed herein, many other transition metals, such as Ag,232,233 Ru,234 Ir,235 Rh,236 Zr237 and Zn238 and are applicable in inter- and intramolecular alkyne hydroamination.

Metal-Catalyzed Amination: CdN Bond Formation

230

313

231

Scheme 37 Pd-catalyzed hydroamination of alkynes.

12.08.3.2 Vinylic amination by cross-coupling Subsequently after the discovery of the Buchwald-Hartwig amination of aryl halides (see Section 12.08.4.2), Voskoboynikov,239 Brace240 and Valdes241 reported on Pd-catalyzed aminations of vinyl bromides 247 and 253 and triflates 249 with secondary amines (Scheme 38). Valdes improved these methods to be also compatible with vinyl chlorides242 and primary amines.243

239

241

240

Scheme 38 Pd-catalyzed vinylic amination from vinyl bromides and triflates.

Soon after, Cu-based Ullmann systems were also found to be potent catalysts for vinylic amination reactions employing sulfoximines,244 hydrazines,245,246 amides,244,247–250 amino acids251 and secondary amines.252 An intramolecular highlight was reported by Li, employing a CuI/DMEDA catalytic system to overcome the high ring strain in the intramolecular amination of vinyl chlorides affording 2-alkylideneazetidines 256 in consistently excellent yields (Scheme 39, top).253 Subsequent oxidative cleavage led to pharmaceutical attractive b-lactams 257. The same catalytic system was also applied as a key-step in the total synthesis of Paliurine F 260 by Evano (Scheme 39, bottom).254 For this purpose, the Ullmann system allowed the intramolecular cross-coupling to generate 259 in excellent yield and with good functional group tolerance.

314

Metal-Catalyzed Amination: CdN Bond Formation

253

254

Scheme 39 Xi’s synthesis of azetidines and b-lactams 257 (top) and Cu-catalyzed cyclization in Evano’s total synthesis of Paliurine F 260 (bottom).

Pd-catalyzed aerobic oxidative aminations, generally known as aza-Wacker reactions,255 are capable of producing the desired enamines and imines directly from olefins and overcome the necessity of vinylic (pseudo)halides. Pioneering work in this field was conducted by Stahl in 2003, who developed the first aerobic intermolecular oxidative amination with aryl olefins.256 Extending the scope of this reaction, Ishii and Obora accomplished an oxidative addition of secondary aryl amines 261 to electron deficient olefins 262 yielding the desired (E)-configurated enamines 263 (Scheme 40, top left).257 Complementarily, Obora later published a protocol for the addition of bulky anilines 264 to acrylates and acryl nitriles 265 in favor of the (Z)-configurated enamines 266 in moderate to excellent yields (Scheme 40, top right).258,259 Very recently a thiocarbamate directed Cp CoIII-catalyzed CdH amidation was reported providing the desired enamides269 in up to 99% yield (Scheme 40, bottom).260

257

258

260

Scheme 40 Pd- and Co-catalyzed oxidative aminations of vinylic CdH bonds.

In 2011, Booker-Milburn reported a PdII-catalyzed heteroannulation of N-alkyoxybenzamides 270 to generate alkylidene isoindolinones 272 (Scheme 41, top left).261 E-selective CdH activation enabled a sequence of Heck and aza-Wacker reactions to provide the desired isoindolinones in up to 95% yield. Using a typical aza-Wacker system Zhang was furthermore able to synthesize isoquinolinones 274 (Scheme 41, bottom left).262 Notably, lacking copper in the reaction mixture led to the selective formation of dihydroisoindolinones 275.

Metal-Catalyzed Amination: CdN Bond Formation

261

262

315

263

265

Scheme 41 Pd-catalyzed oxidative intramolecular vinylic amination.

Sequential reactions with symmetric alkynes 277 were investigated by Zeng263,264 (Scheme 41, top right) and the synthesis of 3-arylindoles 281 from tosyl anilines 279 and styrenes 280 was shown by Jang (Scheme 41, bottom right).265

12.08.4 Aromatic Csp2dN bond formation 12.08.4.1 The Ullmann-Goldberg reaction In the beginning of the 20th century Ullmann described the coupling of aryl bromides in the presence of copper powder.266–268 Soon after these initial studies,269 Goldberg discovered the reaction of benzylamide with arylbromide to be catalyzed again by copper (Scheme 42).270 This transformation is entitled Goldberg reaction, as a variant of the Ullmann coupling for C-, N-, S-, and O-nucleophiles.271 Early examples of the Ullmann coupling required elevated temperatures, the use of polar solvents, strong bases and stoichiometric amounts of copper to maintain high yields. Milder methods, such as the Buchwald-Hartwig and Chan-Lam coupling reactions, are valuable alternatives and outlined in a later section. Constant effort of scientists in the development of the Ullmann-Goldberg reaction led to milder reaction conditions, tolerating a large variety of functional groups.269–276 Up to the present there are numerous examples, proving the utility of the Ullmann coupling in terms of yields, functional group tolerance and applicability in the synthesis of natural products277-282 and pharmaceuticals.283

Scheme 42 The two common mechanistic proposals for the key-steps in Ullmann couplings.

The Ullmann coupling is among the first examples of homogenous cross-coupling reactions. Compared to the mechanism of the related palladium catalyzed cross-coupling reactions,284 the mechanisms of Ullmann couplings are still elusive. Among the discussed mechanisms are the CuI/CuIII two-electron redox pathway (Scheme 42, top),285–288 which includes an oxidative addition and reductive elimination and the single-electron transfer (SET) mechanism (Scheme 42, bottom), that is characterized by occurring radical intermediates.289,290 Non-redox proposals, such as s-bond metathesis291–293 and p-bond complexation294–297 are also viable. Optimizing Ullmann coupling reactions is typically challenging because of its strong dependency on reaction parameters. Recent experiments showed to favor either the 2e−-redox-298–301 or the SET-pathway.302–304

316

Metal-Catalyzed Amination: CdN Bond Formation

While earlier studies suggested ligands to enhance solubility of the copper source,305 the application of 1,10-phenantroline (L14) was found to accelerate the coupling of secondary anilines with aryl iodides 306 and meant to be research subject for further investigations with regards to elucidate the reaction mechanism.307–310 Since then, other N,N-, N,O- and O,O-ligands were found to be effective in CdN bond formation (Scheme 43).273 Examples for procedures involving phosphanes311–313 and NHCligands314,315 are scarce, but have also proven effective.

Scheme 43 Representative examples of different ligands for the Goldberg reaction.

The electron-rich phenanthroline ligand L15 was developed by Buchwald and applied in the condensation of imidazoles and aryl bromides as well as steric demanding iodides 288with as little as 0.025 mol% Cu2O (Scheme 44, left).316–318 Inspired by Song’s biarylether synthesis,319 Shafir and Buchwald synthesized ligand L22.320 In combination with CuI the coupling of (hetero)aryl iodides with primary and cyclic secondary aliphatic amines at room temperature was achieved. A consecutive study revealed the high N- versus O-selectivity, enforced by diketone L22 (Scheme 44, right).321 321

Scheme 44 Buchwald’s ligands lead to low catalyst loadings and mild reaction conditions in the Goldberg reaction.

Saban conducted kinetic studies on the ligand acceleration of different ligands N,N-, N,O- and phosphine ligands revealing the kinetic superiority of 2,20 -bipyridyl and 4,40 -bipyridyl in the synthesis of tertiary tolylamines.322 This system later was applied by Koder in the synthesis of different Safranine derivatives 296, artificial electron transfer cofactors (Scheme 45).323,324

Scheme 45 Koder’s synthesis of different Safranines employing the Ullmann-Goldberg reaction.

Many of the systems used in Ullmann couplings are water- and air tolerant.325 Likewise, anilines can be directly prepared from aqueous ammonia and aryl iodides and bromides, as demonstrated by Taillefer applying commercial available Cu(acac)2 (Scheme 46, top left).326 By elevating the reaction temperature and using a mixture of H2O and NMP, Wolf achieved the same transformation without any ligand and broadening the scope to unreactive chlorides 298 (Scheme 46, bottom left).327,328

Metal-Catalyzed Amination: CdN Bond Formation

326

317

329

327

330

Scheme 46 Different methods for Ullmann-Goldberg amination of aryl halides with ammonia.

Furthermore, Ding developed N,O-ligand L26 for the synthesis of anilines 301 from the corresponding aryl iodides 299 in high yields at room temperature (Scheme 46, top right).329 A screening of different N-oxides revealed that 2-carboxylic acid-quinolineN-oxide (L20) is a suitable ligand for the aniline formation under mild conditions and excellent functional group tolerance (Scheme 46, bottom right).330 Derivating from the typical CuI-salts, Dai found a combination of Cu-powder and pyridine-N-oxides in water as catalytically active in Ullmann-Goldberg coupling.331 A CuII/tripyridine catalyst was found by Aberi to be a suitable catalyst for Ulmann-Goldberg coupling of N-heterocycles 302 with aryl chlorides, bromides and iodides 303 (Scheme 47, left).332 Photocatalytic versions of the Ullmann-Goldberg coupling that promote the radical pathway-mechanism, have recently been reported by Kobayashi, who used an IrI photocatalyst with CuI for the mild coupling of carbazoles 305 to aryl iodides 306 (Scheme 47, right).333,334 332

333

Scheme 47 Aberi’s CuII-catalyzed Goldberg-reaction and Kobayashi’s photoredox-catalyzed Goldberg-reaction.

Following up on their initial findings that ligating amino acids significantly accelerated the coupling reaction, Ma developed a useful procedures335 for the coupling of O-, C- and S-nucleophiles, as well as various N-nucleophiles, such as aliphatic and aromatic amines,336 N-containing heterocycles,337,338 guanidine nitrate,339 sodium azide,340 hydrazine,341 aqueous ammonia,341 carbamates342 and oxazilinones342 (Scheme 48).

Scheme 48 Scope of amino acid catalyzed Goldberg reaction.

318

Metal-Catalyzed Amination: CdN Bond Formation

Due to the robust and reliable nature of Ma’s CuI/amino acid catalytic system, it was for instance applied in the synthesis of GW876008 – a promising corticotropin releasing factor antagonist (Scheme 49).343 Applying Ma’s described procedure, 9.7 kg of GW876008 were prepared by GSK in 90% yield.

Scheme 49 Large scale synthesis of GW876008 by GSK for pharmaceutical purpose.

Besides the above-mentioned catalysts, oxalamide-based ligands were found to catalyze the Ullmann-Goldberg reaction exceptionally well. Catalyst loadings for the coupling of ammonia to aryliodides were decreased to 0.1 mol% Cu2O.344,345 Furthermore, challenging aryl chlorides 311 were found reactive with primary and secondary amines 312 catalyzed by bis(N-aryl) substituted oxalamides (Scheme 50).346,347 Later, amides,348 anilines,349 N-heterocycles350 and hydrazine351 were also applicable to these coupling conditions. 346

348

Scheme 50 Ullmann coupling of arylchlorides with amines and amides employing Ma’s oxalamides.

12.08.4.2 The Buchwald Hartwig amination Inspired by the pioneering work of Migita352 and Boger,353,354 Buchwald355,356 and Hartwig357,358 independently reported on the first Pd-catalyzed cross-coupling of aryl bromides with secondary amines in the presence of strong bases in 1995 (Scheme 51).

357

355

Scheme 51 First reports of Pd-catalyzed amination of arylbromides with secondary amines by Buchwald and Hartwig.

Emerging from these initial observations, a new and efficient approach for the synthesis of aromatic amines evolved providing access to highly valuable building blocks for organic synthesis.359–361 The value of this transformation is highlighted in its still growing number of publications in this field.362–368 The mechanism for the Pd-catalyzed amination of aryl halides was carefully elucidated by several groups357,369,370 A reevaluation of the mechanism by Buchwald, Hartwig and Blackmond was also reported for the Pd/BINAP catalyzed coupling of arylbromide 324 with secondary amines 326 in the presence of base (Scheme 52).372 They found that the catalytically active species [Pd(BINAP)] 323 is generated by [Pd(BINAP)2] 322, which is lying off cycle. Examination of the reaction rates have also

Metal-Catalyzed Amination: CdN Bond Formation

319

Scheme 52 Proposed mechanism for the Buchwald-Hartwig amination reaction.

shown that the oxidative addition of bromoarene occurs prior to the amination step. Reductive elimination of the low-valent alkylamido complex 327 gives the aromatic amine 328 as well as the free catalyst 323. A major side reaction is the b-H elimination in complex 327 resulting in the corresponding imine.373 The rate between b-H elimination and reductive elimination is largely determined by electronic properties found in the reactants. On the one hand, natural reactivity of electron deficient aryl halides and more nucleophilic amines suppress the b-H elimination,374 on the other hand, the steric bulk and electronic properties of the ligand disfavor said side reaction.375 Since the applied ligand has a tremendous influence on the selectivity and yield, a large variety of different phosphine ligands have been developed for Buchwald-Hartwig aminations. Their optimization for the individual need with different coupling partners enabled mild reaction conditions in comparison to previously mentioned Ullmann-Goldberg couplings (Scheme 53).355,371,376–385 The applied ligands can be roughly divided into bulky monophosphine and bisphosphine ligands, as well as a smaller group of NHC-ligands. Notably, bisarylmonophosphine ligands are listed according to their application in an user’s guide published by Buchwald.386,387

378

382

380 384

379

385

371

377

376

Scheme 53 Chronologic development of the ligand design for the Buchwald-Hartwig amination.373

381

383

320

Metal-Catalyzed Amination: CdN Bond Formation

12.08.4.2.1

Bulky biarylphosphine ligands

After initial success with DavePhos,378 Buchwald developed a large variety of bulky biaryl ligands. JohnPhos379 enabled the application of triflates as pseudohalides and the steric demanding XPhos allowed for hydroamination and amidation in water as solvent.388–390 Catalytic systems based on RuPhos and BrettPhos were shown to cover a large field of potential coupling partners (Scheme 54).384 384

Scheme 54 Some examples for the diversity available through Pd/RuPhos or BrettPhos cross coupling.

Buchwald later found tBuPhCPhos L32 to enable the challenging coupling of highly strained primary amines 334 with electron rich aryl chlorides 333 (Scheme 55, left).389,390 In 2018, AlPhos L33 was reported to promote the coupling of amines, anilines and amides 338 with (hetero)aryl halides and triflates 337 in the presence of the comparably mild base DBU (Scheme 55, right).391 389

391

Scheme 55 Functionalization of difficult substrates with the high performing tBuPhCPhos L32 and AlPhos L33.

tBuDavePhos (L34) allowed for cross-coupling of ammonia with different aryl halides 340 under high dilution.392 Good selectivities towards the monoarylated versus bisarylated product were observed (Scheme 56, bottom left). The sterically encumbered Me3(OMe)XPhos (L35) was found to further improve these results allowing to access more complex (hetero)arenes and suppressing bisarylation under non-high dilution conditions (Scheme 56, top left).393

Metal-Catalyzed Amination: CdN Bond Formation

321

393

394

392

Scheme 56 Pd-catalyzed coupling of ammonia with aryl halides and tosylates for the synthesis of anilines.

Stradiotto applied a P-bisadamantyl substituted air-stable P-N-ligand Mor-DalPhos (L36) for the chemoselective synthesis of anilines using minimal amounts of catalyst (Scheme 56, right).394 Similar results were obtained by Beller for stable NHC ligands, which may be reused and gave excellent results for sterically demanding aryl halides.395

12.08.4.2.2

Bisphosphine ligands

Concurrent to above mentioned ligands, bidentate bisphosphine ligands have been applied in the CdN cross-coupling as well. Hartwig was successfully using dppf as a ligand in combination with PdCl2 to couple primary and secondary amines to aryl bromides and iodides.374,396 At the same time Buchwald developed a method relying on rac-BINAP to couple aryl bromides with primary amines with as little as 0.05 mol% Pd2dba3 catalyst.376 These early innovations led to further investigations of related bisphosphine ligands featuring larger bite-angles. A combination of Pd(OAc)2 with DPEphos selectively catalyzed the coupling of sterically and electronically highly demanding substrates.377 Van Leeuven’s Xantphos, which is structurally related to DPEphos, was found to empower the reaction of ureas and amides with aryl bromides (Scheme 57, left).397–399 In 2018 Walsh reported NIXANTPHOS (L37)400 as an overall improved version of XantPhos,401 that allowed the coupling of non-activated aryl chlorides 346 with primary and hindered secondary amines 347 outperforming Xantphos (Scheme 57, right). 399

400

Scheme 57 Bisphosphine ligands in the Pd-catalyzed hydroamination of aryl bromides and chlorides.

The success of ferrocene ligands in Buchwald-Hartwig amination inspired Hartwig to apply bulky Josiphos ligands (Scheme 58, left). Due to its sterically encumbered, electronic-rich nature, Hartwig assumed this ligand would be successful at suppressing concurrent ligation by nitrogen containing moieties.402 After optimization of the reaction conditions, low catalyst loadings of up to 5 ppm Pd-precatalyst and Josiphos Ligand were required for the coupling of different primary amines 351 to pyridines, isoquinolines and other heterocycles 350 showing excellent functional group compatibility.403 Employing a Pd/Josiphos system, different ammonium salts 354 were successfully coupled with challenging (hetero)aryl chlorides 353 to form the corresponding anilines 355 (Scheme 58, right).404,405

322

Metal-Catalyzed Amination: CdN Bond Formation

403

405

Scheme 58 Hartwig’s amination of aryl chlorides with Josiphos J009 (L38).

12.08.4.2.3

Ni-catalyzed Buchwald-Hartwig amination

After Buchwald’s initial success with Ni0-catalyzed couplings,406 other groups joined the field of Ni-catalyzed Buchwald-Hartwig couplings. Yang applied Ni(PPh3)(1-naphthyl)Cl as the catalyst in the coupling of diaryl amines 357 to aryl halidess 356 (Scheme 59, left).407 As catalytic active species they proposed (PPh3)nNiIX (359) that consequently undergoes oxidative addition of Ar–X, ligand exchange with NaNAr2, and reductive elimination. 407

408

Scheme 59 Ni-catalyzed Buchwald-Hartwig amination by Yang (left) and Matsubara (right).

Matsubara reported on a bulky monovalent NHC/nickel catalyst 363 to promote the amination at lower temperatures with overall higher obtained yields (Scheme, right).408,409 Encumbering NHC ligands to give rise to even better yields, selective mono arylation products in case of anilines and a decent functional group tolerance.410 Most recently, Stradiotto found PAd2-DalPhos (L38) to be a suitable ligand for the cross-coupling of primary heteroarylamines and di(hetero)arylamines 365 to different aromatic chlorides 364 (Scheme 60).411 411

Scheme 60 Stradiotto’s bidentate PAd2-Dalphos (L38) in the Ni-catalyzed Buchwald-Hartwig amination.

12.08.4.3 The Chan-Lam amination In 1998, Chan, Evans and Lam reported on the first oxidative copper-catalyzed CdN and CdO cross coupling with arylboronic acids (Scheme 61).412–414 Since then this method attracted vivid attention and became one of the most well-known coupling reactions for the construction of CdN bonds.

Metal-Catalyzed Amination: CdN Bond Formation

323

412

413

414

Scheme 61 First CuII-catalyzed oxidative couplings of arylboronic acids with N-, and O-nucleophiles.

In contrast to other coupling reactions such as Ullmann and Buchwald-Hartwig couplings, the Chan-Lam coupling usually implies mild conditions and relies on less toxic boronic acids. The applied copper catalysts are abundant and cheap, making them an appealing synthetic option. Due to the nature of the reaction, often even requiring air as oxidant, the Chan-Lam coupling has proven to tolerate air and moisture. By now, the scope of the reaction includes NdH, OdH, SdH and even PdH pronucleophiles, though the NdH cross-coupling is arguably the most significant among these mentioned.415–421 Investigating the mechanism has proven to be rather difficult because of the instability of the copper intermediates and the complex interactions with the boronic acid. The clarification of the catalytic cycle is still subject of ongoing investigations.422 Stahl examined a plausible mechanism conducting kinetic and EPR studies on the Chan-Lam etherification of boronic ester with methanol,423,424 being later refined by Watson for amine coupling reactions with aryl boronic acids (Scheme 62).415,425 The copper acetate dimer 376 is proposed to be deprotonated to the mononuclear square planar CuII-catalyst 378. Lewis-pairing with hydroxy functions forms boronate ester/boronic acid 380. Transmetallation of the aryl-functionality to the copper-center furnishes 381 and is subsequently oxidized via disproportionation to generate CuIII-species 382, which finally undergoes reductive elimination to release aryl amine 383, as well as a CuI-species 384. The intermediate CuI-species may then be regenerated under oxidative conditions.

Scheme 62 Mechanistic proposal by Watson for the Chan-Lam coupling of aryl boronic acids with amines.

324

Metal-Catalyzed Amination: CdN Bond Formation

The original reported reaction protocols suffer from the (super)stoichiometric use of Cu-catalyst, the use of strong bases and prolonged reaction times. Since then many groups participated in this field of research to provide more general and applicable protocols for this type of transformation (Scheme 63).415

Scheme 63 Possible ways of tweaking and modifying the protocols of the Chan-Lam amination.

Aside from Cu(OAc)2 which is the most frequently used catalyst within Chan-Lam coupling reactions, other CuII-salts, such as Cu(OTf )2,426,427 Cu(acac)2,428 CuSO4,429 CuCl2427 and CuBr2430 were applied to some extent. CuI-halides431,432 and commercially available CuI-complexes422,433 were also observed to promote Chan-Lam amination, likely due to their ability to disproportionate to the active CuII-species.434 In recent publications the activity of Cu2(BDC)2(BPY)-MOF, a heterogeneous catalyst,435 and magnetic Cu@Fe3O4-TiO2-L-dopa436 combine new concepts with pre-existing Chan-Lam amination protocols. Electron-deficient aryl boronic acids were applicable in electrochemical437 and photoredox chemistry.438 As an alternative to copper, NiCl2 and Ni(OAc)2 were also found to act as potent precatalysts in Chan-Lam type coupling.439,440 The groups of Schaper427,441 and Peng442 were able to couple aryl boronic acids with aliphatic and aromatic amines as well as N-containing heterocycles at room temperature by employing low catalyst loadings of novel and very active Cu-complexes 388 and 392 (Scheme 64).

442

443

Scheme 64 Schaper’s and Peng’s ligand enabled Chan-Lam amination at room-temperature.

Oxidative turnover of the catalyst is usually accomplished by applying atmospheric oxygen within the reaction. However, the use of pure oxygen,443 peroxides430 and other oxidizing agents444 were found to significantly improve the yield in many cases. In industrial applications, aerobic conditions come along with obvious significant safety concerns. Thus, Brewer developed a large scale process under continuous flow using a 5% O2/N2-mixture as an oxidizing agent in the Chan-Lam coupling towards the active pharmaceutical ingredient 395 (Scheme 65).445

Metal-Catalyzed Amination: CdN Bond Formation

325

445

Scheme 65 Large-scale application of a controlled oxygen stream in Chan-Lam amination.

12.08.5 Conclusion CdN bond-forming reactions are a truly remarkable tool to built up complex scaffolds in a straightforward way. The rapidly increasing complexity of the structures of active pharmaceutical ingredients, and in light of the need to access them in a highly efficient and sustainable manner in the fewest possible number of steps, requires a highly versatile toolbox of key methodologies for CdN bond formation. The amination of aliphatic CdH bonds, particularly the chemistry of nitrenes, SET photoredox catalysis, electrochemical oxidation reactions and CdH activation reactions have fascinated organic chemists in the past few years. The high reactivity of activated nitrogen makes taming reactive intermediates for the service of chemical synthesis difficult. While the fields of CdH activation and nitrene insertion have already attracted the attention of a number of chemists in the past decade and resulted in a number of discoveries, the field of SET photoredox catalysis for CdN bond formation, and especially electrochemical oxidation reactions, remain to be more deeply explored. Nonetheless, the recent evolution in the fields of aliphatic CdH activation underscores the opportunity that reactivities may be controlled once being aware of the mechanisms being undergone. This understanding was highlighted in the light of the construction of allylic Csp3dN bonds as versatile building blocks for organic synthesis. Having identified the prevailing mechanism of the specific starting material used in this reaction in combination with the effective metal/ligand pair, allows for an efficient finetuning resulting in highest selectivities and yields. The widespread occurrence of anilines, amines, and ammonia in synthetic chemistry makes methods involving hydroamination and vinylic/aromatic CdH amination useful methods for both academic research and pharmaceutical/industrial process development. Specifically process robustness, operational simplicity, availability of the required starting materials, as well as accessibility to ligands and metal loadings are decisive factors for the rapid implementation of these methodologies. A growing interest in the development of first-row transition-metals might serve as low cost alternatives to precious metals such as Pd, conversely also the development of photochemical or electrochemical protocols are highly desired alternative reaction types being in current focus. Nonetheless, the importance of aminated building blocks together with the fundamental developments accomplished over the past years certainly hold potential for additional future industrial and academic applications.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117 (13), 9247–9301. Wentrup, C. Angew Chem. Int. Ed. 2018, 57 (36), 11508–11521. Berry, J. F. Comments Mod. Chem. A Comments Inorg. Chem. 2009, 30 (1-2), 28–66. Davies, H. M. L.; Manning, J. R. Nature 2008, 451 (7177), 417–424. Aguila, M. J. B.; Badiei, Y. M.; Warren, T. H. J. Am. Chem. Soc. 2013, 135 (25), 9399–9406. Breslow, R.; Gellman, S. H. Chem. Commun. 1982, 24, 1400. Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105 (22), 6728–6729. Yu, X. Q.; Huang, J. S.; Zhou, X. G.; Che, C. M. Org. Lett. 2000, 2 (15), 2233–2236. Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc 2001, 123 (28), 6935–6936. Espino, C. G.; Du Bois, J. Angew Chem. Int. Ed. 2001, 40 (3), 598–600. Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc 2004, 126 (47), 15378–15379. Du Bois, J. Org. Process. Res. Dev. 2011, 15 (4), 758–762. Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem. Int. Ed. 2009, 48 (15), 2777–2779. Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127 (41), 14198–14199. Huard, K.; Lebel, H. Chem. Eur. J. 2008, 14 (20), 6222–6230. Uchida, T.; Katsuki, T. Chem. Rec. 2014, 14 (1), 117–129. Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Chem. Commun. 2014, 50 (78), 11440–11453. Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Li Gotti, C.; Lapadula, M.; Mangioni, E.; Cenini, S. Chem. Eur. J. 2003, 9 (1), 249–259. Cenini, S.; Gallo, E.; Penoni, A.; Ragaini, F.; Tollari, S. Chem. Commun. 2000, 22, 2265–2266. Caselli, A.; Gallo, E.; Fantauzzi, S.; Morlacchi, S.; Ragaini, F.; Cenini, S. Eur. J. Inorg. Chem. 2008, 19, 3009–3019. Lyaskovskyy, V.; Suarez, A. I. O.; Lu, H.; Jiang, H.; Zhang, X. P.; de Bruin, B. J. Am. Chem. Soc. 2011, 133 (31), 12264–12273. Badiei, Y. M.; Dinescu, A.; Dai, X.; Palomino, R. M.; Heinemann, F. W.; Cundari, T. R.; Warren, T. H. Angew. Chem. Int. Ed. 2008, 47 (51), 9961–9964.

326

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95.

Metal-Catalyzed Amination: CdN Bond Formation

Gephart, R. T.; Warren, T. H. Organometallics 2012, 31 (22), 7728–7752. Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem. Int. Ed. 2008, 47 (36), 6825–6828. Fantauzzi, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Casati, N.; Macchi, P.; Cenini, S. Chem. Commun. 2009, 26, 3952–3954. Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc. Chem. Res. 2012, 45 (6), 911–922. Scamp, R. J.; Rigoli, J. W.; Schomaker, J. M. Pure Appl. Chem. 2014, 86 (3), 381–393. Huang, M.; Yang, T.; Paretsky, J. D.; Berry, J. F.; Schomaker, J. M. J. Am. Chem. Soc. 2017, 139 (48), 17376–17386. Alderson, J. M.; Corbin, J. R.; Schomaker, J. M. Acc. Chem. Res. 2017, 50 (9), 2147–2158. Das, S. K.; Roy, S.; Khatua, H.; Chattopadhyay, B. J. Am. Chem. Soc. 2020, 142 (38), 16211–16217. Zhang, L.; Deng, L. Chin. Sci. Bull. 2012, 57 (19), 2352–2360. Hennessy, E. T.; Liu, R. Y.; Iovan, D. A.; Duncan, R. A.; Betley, T. A. Chem. Sci. 2014, 5 (4), 1526–1532. Suarez, A. I. O.; Jiang, H.; Zhang, X. P.; de Bruin, B. Dalton Trans. 2011, 40 (21), 5697–5705. Baek, Y.; Das, A.; Zheng, S.-L.; Reibenspies, J. H.; Powers, D. C.; Betley, T. A. J. Am. Chem. Soc. 2020, 142 (25), 11232–11243. Zhang, J.; Hong Chan, P. W.; Che, C.-M. Tetrahedron Lett. 2005, 46 (32), 5403–5408. Singh, R.; Kolev, J. N.; Sutera, P. A.; Fasan, R. ACS Catal. 2015, 5 (3), 1685–1691. Hayashi, H.; Uchida, T. Eur. J. Org. Chem. 2020, 8, 909–916. Müller, P.; Baud, C.; Jacquier, Y.; Moran, M.; Ngeli, I. J. Phys. Org. Chem. 1996, 9 (6), 341–347. Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43 (52), 9561–9564. Nasrallah, A.; Lazib, Y.; Boquet, V.; Darses, B.; Dauban, P. Org. Process Res. Dev. 2020, 24 (5), 724–728. Ichinose, M.; Suematsu, H.; Yasutomi, Y.; Nishioka, Y.; Uchida, T.; Katsuki, T. Angew. Chem. Int. Ed. 2011, 50 (42), 9884–9887. Nishioka, Y.; Uchida, T.; Katsuki, T. Angew. Chem. Int. Ed. 2013, 52 (6), 1739–1742. Yang, Y.; Cho, I.; Qi, X.; Liu, P.; Arnold, F. H. Nat. Chem. 2019, 11 (11), 987–993. Annapureddy, R. R.; Jandl, C.; Bach, T. J. Am. Chem. Soc. 2020, 142 (16), 7374–7378. Huang, M.; Corbin, J. R.; Dolan, N. S.; Fry, C. G.; Vinokur, A. I.; Guzei, I. A.; Schomaker, J. M. Inorg. Chem. 2017, 56 (11), 6725–6733. Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125 (38), 11510–11511. Wehn, P. M.; Du Bois, J. Angew. Chem. Int. Ed. 2009, 48 (21), 3802–3805. Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134 (3), 1396–1399. Chiappini, N. D.; Mack, J. B. C.; Du Bois, J. Angew. Chem. Int. Ed. 2018, 57 (18), 4956–4959. Abrams, D. J.; Provencher, P. A.; Sorensen, E. J. Chem. Soc. Rev. 2018, 47 (23), 8925–8967. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113 (7), 5322–5363. Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81 (16), 6898–6926. Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116 (17), 10035–10074. Yoon, T. P. Acc. Chem. Res. 2016, 49 (10), 2307–2315. Zhao, Y.; Xia, W. Chem. Soc. Rev. 2018, 47 (8), 2591–2608. Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Nature 2016, 539 (7628), 268–271. Chu, J. C. K.; Rovis, T. Nature 2016, 539 (7628), 272–275. Wolff, M. E. Chem. Rev. 1963, 63 (1), 55–64. Zhang, D.; Wang, H.; Cheng, H.; Hernández, J. G.; Bolm, C. Adv. Synth. Catal. 2017, 359 (24), 4274–4277. Martínez, C.; Muñiz, K. Angew. Chem. Int. Ed. 2015, 54 (28), 8287–8291. O’Broin, C. Q.; Fernández, P.; Martínez, C.; Muñiz, K. Org. Lett. 2016, 18 (3), 436–439. Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A. Angew. Chem. Int. Ed. 2016, 55 (34), 9974–9978. Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. Synthesis 2018, 50 (8), 1569–1586. Becker, P.; Duhamel, T.; Stein, C. J.; Reiher, M.; Muñiz, K. Angew. Chem. Int. Ed. 2017, 56 (27), 8004–8008. Qin, Q.; Yu, S. Org. Lett. 2015, 17 (8), 1894–1897. Hu, X.; Zhang, G.; Bu, F.; Nie, L.; Lei, A. ACS Catal. 2018, 8 (10), 9370–9375. Nakafuku, K. M.; Zhang, Z.; Wappes, E. A.; Stateman, L. M.; Chen, A. D.; Nagib, D. A. Nat. Chem. 2020, 12 (8), 697–704. Pandey, G.; Laha, R. Angew. Chem. Int. Ed. 2015, 54 (49), 14875–14879. Pandey, G.; Laha, R.; Singh, D. J. Org. Chem. 2016, 81 (16), 7161–7171. Hazelard, D.; Nocquet, P.-A.; Compain, P. Org. Chem. Front. 2017, 4 (12), 2500–2521. Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900–2936. Basu, D.; Kumar, S.; Bandichhor, R. J. Chem. Sci. 2018, 130 (6). Neumann, J. J.; Rakshit, S.; Dröge, T.; Glorius, F. Angew. Chem. Int. Ed. 2009, 48 (37), 6892–6895. Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127 (37), 12790–12791. He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134 (1), 3–6. Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134 (1), 7–10. Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127 (38), 13154–13155. He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Angew. Chem. Int. Ed. 2013, 52 (42), 11124–11128. McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129–133. Smalley, A. P.; Gaunt, M. J. J. Am. Chem. Soc. 2015, 137 (33), 10632–10641. Smalley, A. P.; Cuthbertson, J. D.; Gaunt, M. J. J. Am. Chem. Soc. 2017, 139 (4), 1412–1415. Sun, W.-W.; Cao, P.; Mei, R.-Q.; Li, Y.; Ma, Y.-L.; Wu, B. Org. Lett. 2014, 16 (2), 480–483. Zhao, J.; Zhao, X.-J.; Cao, P.; Liu, J.-K.; Wu, B. Org. Lett. 2017, 19 (18), 4880–4883. Zhou, T.; Jiang, M.-X.; Yang, X.; Yue, Q.; Han, Y.-Q.; Ding, Y.; Shi, B.-F. Chin. J. Chem. 2020, 38 (3), 242–246. Wu, X.; Zhao, Y.; Ge, H. Chem. Eur. J. 2014, 20 (31), 9530–9533. Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem. Int. Ed. 2014, 53 (14), 3706–3710. Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Angew. Chem. Int. Ed 2014, 53 (13), 3496–3499. Yang, M.; Su, B.; Wang, Y.; Chen, K.; Jiang, X.; Zhang, Y.-F.; Zhang, X.-S.; Chen, G.; Cheng, Y.; Cao, Z.; Guo, Q.-Y.; Wang, L.; Shi, Z.-J. Nat. Commun. 2014, 5, 4707. Wu, X.; Yang, K.; Zhao, Y.; Sun, H.; Li, G.; Ge, H. Nat. Commun. 2015, 6, 6462. Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128 (28), 9048–9049. Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc. 2014, 136 (11), 4141–4144. Kang, T.; Kim, H.; Kim, J. G.; Chang, S. Chem. Commun. 2014, 50 (81), 12073–12075. Jin, L.; Zeng, X.; Li, S.; Hong, X.; Qiu, G.; Liu, P. Chem. Commun. 2017, 53 (28), 3986–3989. He, J.; Shigenari, T.; Yu, J.-Q. Angew. Chem Int. Ed. 2015, 54 (22), 6545–6549. Gou, Q.; Liu, G.; Liu, Z.-N.; Qin, J. Chem. Eur. J. 2015, 21 (44), 15491–15495.

Metal-Catalyzed Amination: CdN Bond Formation

96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167.

327

Min, Q.-Q.; Yang, J.-W.; Pang, M.-J.; Ao, G.-Z.; Liu, F. Org. Lett. 2020, 22 (7), 2828–2832. Liu, R.-H.; Shan, Q.-C.; Hu, X.-H.; Loh, T.-P. Chem. Commun. 2019, 55 (38), 5519–5522. Li, W., Zhang, X., Eds.; In Stereoselective Formation of Amines, Springer Berlin Heidelberg; Springer: Berlin, Heidelberg, 2014. Imprint. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944. Milhau, L.; Guiry, P. J. Top. Organomet. Chem. 2011, 38, 95–153. Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Chem. Rev. 2019, 119, 1855–1969. Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395–422. Trost, B. M. Org. Process Res. Dev. 2012, 16, 185–194. Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–15165. Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093–1096. Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797–4800. Tissot-Croset, K.; Polet, D.; Alexakis, A. A. Angew. Chem., Int. Ed. 2004, 43, 2426–2428. Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.; Helmchen, G. Angew. Chem., Int. Ed. 2008, 47, 7652–7655. Ye, K.-Y.; Zhao, Z.-A.; Lai, Z.-W.; Dai, L.-X.; You, S.-L. Synthesis 2013, 45, 2109–2114. Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int. Ed. 2006, 45, 5546–5549. Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen, G. Chem. Commun. 2005, 3541–3543. Weix, D. J.; Markovíc, D.; Ueda, M.; Hartwig, J. F. Org. Lett. 2009, 11, 2944–2947. Tosatti, P.; Horn, J.; Campbell, A. J.; House, D.; Nelson, A.; Marsden, S. P. Adv. Synth. Catal. 2010, 352, 3153–3157. Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 7094–7098. Satyanarayana, G.; Pflästerer, D.; Helmchen, G. Eur. J. Org. Chem. 2011, 34, 6877–6886. Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896–897. Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dübon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239–1242. Natori, Y.; Kikuchi, S.; Yoshimura, Y.; Kato, A.; Adachi, I.; Takahata, H. Heterocycles 2012, 86, 1401–1417. Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139–3143. Roggen, M.; Carreira, E. M. J. Am. Chem. Soc. 2010, 132, 11917–11919. Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11312–11313. Doule, J. A.; Mills, K. Heterocyclic Chemistry; Wiley: Chichester, 2010. chap. 32 and 33. Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and Society; Wiley: Chichester, 2011. chap. 10. Xiang, Y.; Hou, Z.; Zhang, Z. Chem. Biol. Drug Des. 2012, 79, 760–770. Turetsky, A.; Kim, E.; Kohler, R. H.; Miller, M. A.; Weissleder, R. Sci. Rep. 2014, 4, 1–7. Guzman-Perez, A.; Pfefferkorn, J. A.; Lee, E. C. Y.; Stevens, B. D.; Aspnes, G. E.; Bian, J.; Didiuk, M. T.; Filipski, K. J.; Moore, D.; Perreault, C.; Sammons, M. F.; Tu, M.; Brown, J.; Atkinson, K.; Litchfield, J.; Tan, B.; Samas, B.; Zavadoski, W. J.; Salatto, C. T.; Treadway, J. Bioorg. Med. Chem. Lett. 2013, 23, 3051–3058. Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. Lett. 2006, 14, 3987–4006. Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 8971–8983. Stanley, L. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2009, 48, 7841–7844. Zhang, M.; Guo, X.; Zheng, S.; Zhao, X. Tetrahedron Lett. 2012, 53, 6995–6998. Zhang, X.; Yang, Z.-P.; Huang, L.; You, S.-L. Angew. Chem., Int. Ed. 2015, 54, 1873–1876. Yang, Z.-P.; Wu, Q.-F.; You, S.-L. Angew. Chem., Int. Ed. 2014, 53, 6986–6989. Yang, Z.-P.; Wu, Q.-F.; Shao, W.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 15899–15906. Yang, Z.-P.; Jiang, R.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2018, 140, 3114–3119. Yang, Z.-P.; Wu, Q.-F.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 1530–1534. Noyori, R. Chem. Commun. 2005, 1807–1811. Trost, B. M. Science 1991, 254, 1471–1477. Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–281. Al-Masun, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1997, 38, 6071–6074. Patil, N. T.; Song, D.; Yamamoto, Y. Eur. J. Org. Chem. 2006, 2006 (18), 4211–4213. Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 1622–1623. Patil, N. T.; Lutete, L. M.; Shibuya, A.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270–4279. Wolf, J.; Werner, H. Organometallics 1987, 6, 1164–1169. Pritzius, A. B.; Breit, B. In Rhodium Catalysis in Organic Synthesis; Tanaka, K., Ed.; Wiley-VCH: Weinheim, 2019; pp 117–132, chap. 6. Haydl, A. M.; Breit, B.; Liang, T.; Krische, M. J. Angew. Chem., Int. Ed. 2017, 56, 11312–11325. Koschker, P.; Breit, B. Acc. Chem. Res. 2016, 49, 1524–1536. Chen, Q. A.; Chen, Z.; Dong, V. M. J. Am. Chem. Soc. 2015, 137, 8392–8395. Cruz, A.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 1029–1032. Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen, Z.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 10641–10644. Chen, Z.; Dong, V. M. Nature Commun. 2017, 8, 784–790. Davison, R. T.; Parker, P. D.; Hou, X.; Chung, C. P.; Augustine, S. A.; Dong, V. M. Angew. Chem., Int. Ed. 2021, 60, 4599–4603. Cooke, M. L.; Xu, K.; Breit, B. Angew. Chem., Int. Ed. 2012, 124, 11034–11037. Berthold, D.; Breit, B. Org. Lett. 2020, 22, 565–568. Xu, K.; Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2014, 53, 2162–2165. Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2017, 56, 1903–1907. Xu, K.; Wang, Y.-H.; Khakyzadeh, V.; Breit, B. Chem. Sci. 2016, 7, 3313–3316. Schmidt, J.; Li, C.; Breit, B. Chem. Eur. J. 2017, 23, 6531–6534. Berthold, D.; Geissler, A. G. A.; Giofré, S.; Breit, B. Angew. Chem., Int. Ed. 2019, 58, 9994–9997. Haydl, A. M.; Xu, K.; Breit, B. Angew. Chem., Int. Ed. 2015, 54, 7149–7153. Haydl, A. M.; Hilpert, L. J.; Breit, B. Chem. Eur. J. 2016, 22, 6547–6551. Xu, K.; Thieme, N.; Breit, B. Angew. Chem. Int. Ed. 2014, 53, 7268–7271. Berthold, D.; Breit, B. Org. Lett. 2018, 20, 598–601. Xu, K.; Raimondi, W.; Bury, T.; Breit, B. Chem. Commun. 2015, 51, 10861–10863. Muñoz, M. P. Chem. Soc. Rev. 2014, 43, 3164–3183. Hodjat-Kachani, H.; Perie, J. J.; Lattes, A. Chem. Lett. 1976, 5, 405–408. Trost, B. M.; Pinkerton, A. B.; Kreuzow, D. J. Am. Chem. Soc. 2000, 122, 12007–12008. Tsukako, A.; Oikawa, D.; Sakai, K.; Okamoto, S. Tetrahedron Lett. 2008, 49, 6529–6532.

328

168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240.

Metal-Catalyzed Amination: CdN Bond Formation

Jung, M. S.; Kim, W. S.; Shin, Y. H.; Jin, J. J.; Kim, Y. S.; Kang, E. J. Org. Lett. 2012, 14, 6262–6265. LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452–2453. Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148–14149. Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2007, 9, 2887–2889. LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.; Toste, F. D. Angew. Chem., Int. Ed. 2010, 49, 598–601. Li, H.; DuLee, S.; Widenhoefer, R. A. J. Organomet. Chem. 2011, 696, 316–320. Butler, K. L.; Traghi, M.; Widenhoefer, R. A. Angew. Chem. Int. Ed. 2012, 51, 5175–5178. Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36 (9), 1407–1420. Yim, J. C.-H.; Schafer, L. L. Eur. J. Org. Chem. 2014, 2014 (31), 6825–6840. Shi, S.-L.; Buchwald, S. L. Nat. Chem. 2015, 7 (1), 38–44. Pirnot, M. T.; Wang, Y.-M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2016, 55 (1), 48–57. Patel, M.; Saunthwal, R. K.; Verma, A. K. Acc. Chem. Res. 2017, 50 (2), 240–254. Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 8, 973–986. Wang, H.; Gao, X.; Lv, Z.; Abdelilah, T.; Lei, A. Chem. Rev. 2019, 119 (12), 6769–6787. Chemler, S. R.; Fuller, P. H. Chem. Soc. Rev. 2007, 36 (7), 1153–1160. Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132 (40), 14048–14051. Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. Synlett 2008, 2008 (20), 3157–3162. Heretsch, P.; Tzagkaroulaki, L.; Giannis, A. Angew. Chem Int. Ed. 2010, 49 (20), 3418–3427. Ogawa, S.; Iida, N.; Tokunaga, E.; Shiro, M.; Shibata, N. Chem. Eur. J. 2010, 16 (24), 7090–7095. Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132 (28), 9585–9587. Sirijindalert, T.; Hansuthirakul, K.; Rashatasakhon, P.; Sukwattanasinitt, M.; Ajavakom, A. Tetrahedron 2010, 66 (27-28), 5161–5167. Neumann, J. J.; Rakshit, S.; Dröge, T.; Würtz, S.; Glorius, F. Chem. Eur. J. 2011, 17 (26), 7298–7303. Shankaraiah, K.; Chandrasekhar, G.; Siva Nagi Reddy, K.; Sabitha, G. Tetrahedron Lett. 2015, 56 (6), 842–846. Holota, S.; Kryshchyshyn, A.; Derkach, H.; Trufin, Y.; Demchuk, I.; Gzella, A.; Grellier, P.; Lesyk, R. Bioorg. Chem. 2019, 86, 126–136. Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem. Int. Ed. 1999, 38 (22), 3389–3391. Pohlki, F.; Doye, S. Angew. Chem. Int. Ed 2001, 40 (12), 2305–2308. Heutling, A.; Pohlki, F.; Doye, S. Chem. Eur. J. 2004, 10 (12), 3059–3071. Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2002, 21 (23), 5148. Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6 (17), 2957–2960. Khedkar, V.; Tillack, A.; Beller, M. Org. Lett. 2003, 5 (25), 4767–4770. Barnea, E.; Majumder, S.; Staples, R. J.; Odom, A. L. Organometallics 2009, 28 (13), 3876–3881. Mountford, P. Chem. Commun. 1997, 22, 2127–2134. Blake, A. J.; Collier, P. E.; Dunn, S. C.; Li, W.-S.; Mountford, P.; Shishkin, O. V. J. Chem. Soc., Dalton Trans. 1997, (9), 1549–1558. Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Nat. Chem. 2016, 8 (1), 63–68. Chiu, H.-C.; Tonks, I. A. Angew. Chem. Int. Ed. 2018, 57 (21), 6090–6094. Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5 (24), 4733–4736. Zhang, Z.; Leitch, D. C.; Lu, M.; Patrick, B. O.; Schafer, L. L. Chem. Eur. J. 2007, 13 (7), 2012–2022. Yim, J. C.-H.; Bexrud, J. A.; Ayinla, R. O.; Leitch, D. C.; Schafer, L. L. J. Org. Chem. 2014, 79 (5), 2015–2028. Lui, E. K. J.; Brandt, J. W.; Schafer, L. L. J. Am. Chem. Soc. 2018, 140 (15), 4973–4976. Lui, E. K. J.; Schafer, L. L. Adv. Synth. Catal. 2016, 358 (5), 713–718. Hao, H.; Schafer, L. L. ACS Catal. 2020, 10 (13), 7100–7111. Aldrich, K. E.; Odom, A. L. Organometallics 2018, 37 (23), 4341–4349. Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125 (10), 2880–2881. Aldrich, K. E.; Odom, A. L. Dalton Trans. 2019, 48 (30), 11352–11360. Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5 (18), 3349–3352. Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8 (2), 325–328. Lavallo, V.; Frey, G. D.; Donnadieu, B.; Soleilhavoup, M.; Bertrand, G. Angew. Chem. Int. Ed. 2008, 47 (28), 5224–5228. Zeng, X.; Frey, G. D.; Kousar, S.; Bertrand, G. Chem. Eur. J. 2009, 15 (13), 3056–3060. Kinjo, R.; Donnadieu, B.; Bertrand, G. Angew. Chem. Int. Ed. 2011, 50 (24), 5560–5563. Hu, X.; Martin, D.; Bertrand, G. New J. Chem. 2016, 40 (7), 5993–5996. Zeng, X.; Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. J. Am. Chem. Soc. 2009, 131 (24), 8690–8696. Liang, S.; Hammond, L.; Xu, B.; Hammond, G. B. Adv. Synth. Catal. 2016, 358 (20), 3313–3318. Zhao, J.; Zheng, Z.; Bottle, S.; Chou, A.; Sarina, S.; Zhu, H. Chem. Commun. 2013, 49 (26), 2676–2678. Michon, C.; Gilbert, J.; Trivelli, X.; Nahra, F.; Cazin, C. S. J.; Agbossou-Niedercorn, F.; Nolan, S. P. Org. Biomol. Chem. 2019, 17 (15), 3805–3811. Veenboer, R. M. P.; Dupuy, S.; Nolan, S. P. ACS Catal. 2015, 5 (2), 1330–1334. Oonishi, Y.; Gómez-Suárez, A.; Martin, A. R.; Nolan, S. P. Angew. Chem. Int. Ed. 2013, 52 (37), 9767–9771. Lee, L.-C.; Zhao, Y. ACS Catal. 2014, 4 (2), 688–691. Leyva, A.; Corma, A. Adv. Synth. Catal. 2009, 351 (17), 2876–2886. Deck, E.; Wagner, H. E.; Paradies, J.; Breher, F. Chem. Commun. 2019, 55 (37), 5323–5326. Bahri, J.; Blieck, R.; Jamoussi, B.; Taillefer, M.; Monnier, F. Chem. Commun. 2015, 51 (56), 11210–11212. Bahri, J.; Jamoussi, B.; van der Lee, A.; Taillefer, M.; Monnier, F. Org. Lett. 2015, 17 (5), 1224–1227. Hojo, R.; Short, S.; Jha, M. J. Org. Chem. 2019, 84 (24), 16095–16104. Virant, M.; Mihelac, M.; Gazvoda, M.; Cotman, A. E.; Frantar, A.; Pinter, B.; Košmrlj, J. Org. Lett. 2020, 22 (6), 2157–2161. Chen, Q.; Lv, L.; Yu, M.; Shi, Y.; Li, Y.; Pang, G.; Cao, C. RSC Adv. 2013, 3, 18359–18366. Zhang, X.; Yang, B.; Li, G.; Shu, X.; Mungra, D.; Zhu, J. Synlett 2012, 23 (04), 622–626. Wong, V. H. L.; Hor, T. S. A.; Hii, K. K. M. Chem. Commun. 2013, 49 (81), 9272–9274. Uchimaru, Y. Chem. Commun. 1999, 12, 1133–1134. Lai, R.-Y.; Surekha, K.; Hayashi, A.; Ozawa, F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics 2007, 26 (4), 1062–1068. Fukumoto, Y.; Asai, H.; Shimizu, M.; Chatani, N. J. Am. Chem. Soc. 2007, 129 (45), 13792–13793. Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114 (5), 1708–1719. Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Chem. Sus. Chem. 2008, 1 (4), 333–338. Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya, I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, 4 (4), 623–626. Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43 (50), 9085–9088.

Metal-Catalyzed Amination: CdN Bond Formation

241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. 268. 269. 270. 271. 272. 273. 274. 275. 276. 277. 278. 279. 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310. 311. 312.

Barluenga, J.; Fernández, M. A.; Aznar, F.; Valdés, C. Chem. Commun. 2002, 20, 2362–2363. Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Commun. 2004, 12, 1400–1401. Barluenga, J.; Fernández, M. A.; Aznar, F.; Valdés, C. Chem. Eur. J. 2004, 10 (2), 494–507. Dehli, J.; Bolm, C. Adv. Synth. Catal. 2005, 347 (2-3), 239–242. Martín, R.; Rodríguez Rivero, M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45 (42), 7079–7082. Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9 (6), 973–976. Martín, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9 (17), 3379–3382. Jiang, B.; Tian, H.; Huang, Z.-G.; Xu, M. Org. Lett. 2008, 10 (13), 2737–2740. Lu, H.; Yuan, X.; Zhu, S.; Sun, C.; Li, C. J. Org. Chem. 2008, 73 (21), 8665–8668. Martín, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9 (26), 5521–5524. Cesati, R. R.; Dwyer, G.; Jones, R. C.; Hayes, M. P.; Yalamanchili, P.; Casebier, D. S. Org. Lett. 2007, 9 (26), 5617–5620. Wang, Y.; Liao, Q.; Xi, C. Org. Lett. 2010, 12 (13), 2951–2953. Lu, H.; Li, C. Org. Lett. 2006, 8 (23), 5365–5367. Toumi, M.; Couty, F.; Evano, G. Angew. Chem. Int. Ed. 2007, 46 (4), 572–575. Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46 (6), 1910–1923. Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125 (43), 12996–12997. Obora, Y.; Shimizu, Y.; Ishii, Y. Org. Lett. 2009, 11 (21), 5058–5061. Mizuta, Y.; Yasuda, K.; Obora, Y. J. Org. Chem. 2013, 78 (12), 6332–6337. Obora, Y.; Ishii, Y. Catalysts 2013, 3 (4), 794–810. Liang, Y.-R.; Si, X.-J.; Zhang, H.; Yang, D.; Niu, J.-L.; Song, M.-P. Eur. J. Org. Chem. 2021, 2021 (4), 694–700. Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13 (19), 5326–5329. Yang, G.; Zhang, W. Org. Lett. 2012, 14 (1), 268–271. Li, D.; Zeng, F. Org. Lett. 2017, 19 (24), 6498–6501. Yu, R.; Li, D.; Zeng, F. J. Org. Chem. 2018, 83 (1), 323–329. Youn, S. W.; Ko, T. Y.; Jang, Y. H. Angew. Chem. Int. Ed. 2017, 56 (23), 6636–6640. Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34 (2), 2174–2185. Ullmann, F. Eur. J. Org. Chem. 1907, 355 (3), 312–358. Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38 (2), 2211–2212. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36 (2), 2382–2384. Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39 (2), 1691–1692. Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48 (38), 6954–6971. Lindley, J. Tetrahedron 1984, 40 (9), 1433–1456. Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428–2439. Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248 (21-24), 2337–2364. Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Chem. Soc. Rev. 2014, 43 (10), 3525–3550. Lin, H.; Sun, D. Org. Prep. Proced. Int. 2013, 45 (5). Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 28, 4166–4175. Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108 (8), 3054–3131. Fischer, C.; Koenig, B. Beilstein J. Org. Chem. 2011, 7 (1), 59–74. Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42 (44), 5400–5449. Pant, P. L.; Shankarling, G. S. New J. Chem. 2018, 42 (16), 13212–13224. Zhao, R.; Dong, W.; Teng, J.; Wang, Z.; Wang, Y.; Yang, J.; Jia, Q.; Chu, C. Tetrahedron 2021, 79, 131858. Ma, D.; Jiang, Y. Chimia 2011, 65 (12), 914–918. Malinakova, H. C. Chem. Eur. J. 2004, 10 (11), 2636–2646. Cohen, T.; Cristea, I. J. Org. Chem. 1975, 40 (25), 3649–3651. Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98 (3), 748–753. Bethell, D.; Jenkins, I. L.; Quan, P. M. J. Chem. Soc., Perkin Trans. 1985, 2 (11), 1789. Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41 (11), 1450–1460. Arai, S.; Hida, M.; Yamagishi, T.; Ototake, S. BCSJ 1977, 50 (11), 2982–2985. Arai, S.; Hashimoto, Y.; Takayama, N.; Yamagishi, T.; Hida, M. BCSJ 1983, 56 (1), 238–243. Bacon, R. G. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1097. Bacon, R. G. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1108. Bacon, R. G. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1112. Weingarten, H. J. Org. Chem. 1964, 29 (12), 3624–3626. Weingarten, H. J. Org. Chem. 1964, 29 (4), 977–978. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120 (48), 12459–12467. Dargel, T. K.; Hertwig, R. H.; Koch, W. Mol. Phys. 1999, 96 (4), 583–591. Rovira, M.; Jašíková, L.; Andris, E.; Acuña-Parés, F.; Soler, M.; Güell, I.; Wang, M.-Z.; Gómez, L.; Luis, J. M.; Roithová, J.; Ribas, X. Chem. Commun. 2017, 53 (62), 8786–8789. Lo, Q. A.; Sale, D.; Braddock, D. C.; Davies, R. P. ACS Catal. 2018, 8 (1), 101–109. Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130 (30), 9971–9983. Tye, J. W.; Weng, Z.; Giri, R.; Hartwig, J. F. Angew. Chem. Int. Ed. 2010, 49 (12), 2185–2189. Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132 (17), 6205–6213. Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131 (1), 78–88. Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J. C. Science 2012, 338 (6107), 647–651. Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34 (6), 1007–1010. Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64 (2), 670–674. Tseng, C.-K.; Lee, C.-R.; Han, C.-C.; Shyu, S.-G. Chem. Eur. J. 2011, 17 (9), 2716–2723. Tseng, C.-K.; Tseng, M.-C.; Han, C.-C.; Shyu, S.-G. Chem. Commun. 2011, 47 (23), 6686–6688. Sung, S.; Braddock, D. C.; Armstrong, A.; Brennan, C.; Sale, D.; White, A. J. P.; Davies, R. P. Chem. Eur. J. 2015, 21 (19), 7179–7192. Moriwaki, K.; Satoh, K.; Takada, M.; Ishino, Y.; Ohno, T. Tetrahedron Lett. 2005, 46 (44), 7559–7562. Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3 (26), 4315–4317. Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett 2001, 42 (29), 4791–4793.

329

330

313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344. 345. 346. 347. 348. 349. 350. 351. 352. 353. 354. 355. 356. 357. 358. 359. 360. 361. 362. 363. 364. 365. 366. 367. 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381. 382. 383.

Metal-Catalyzed Amination: CdN Bond Formation

Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Chem. Commun. 2004, 17, 1994–1995. Tubaro, C.; Biffis, A.; Scattolin, E.; Basato, M. Tetrahedron 2008, 64 (19), 4187–4195. Biffis, A.; Tubaro, C.; Scattolin, E.; Basato, M.; Papini, G.; Santini, C.; Alvarez, E.; Conejero, S. Dalton Trans. 2009, 35, 7223–7229. Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72 (16), 6190–6199. Altman, R. A.; Buchwald, S. L. Nat. Protoc. 2007, 2 (10), 2474–2479. Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40 (14), 2657–2660. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4 (9), 1623–1626. Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128 (27), 8742–8743. Shafir, A.; Lichtor, P. A.; Buchwald, S. L. Am. Chem. Soc. 2007, 129 (12), 3490–3491. Manifar, T.; Rohani, S.; Bender, T. P.; Goodbrand, H. B.; Gaynor, R.; Saban, M. Ind. Eng. Chem. Res. 2005, 44 (4), 789–798. Raju, G.; Capo, J.; Lichtenstein, B. R.; Cerda, J. F.; Koder, R. L. Tetrahedron Lett. 2012, 53 (10), 1201–1203. Raju, G.; Singh, S.; Mutter, A. C.; Everson, B. H.; Cerda, J. F.; Koder, R. L. Tetrahedron Lett. 2014, 55 (15), 2487–2491. Larsson, P.-F.; Astvik, P.; Norrby, P.-O. Beilstein J. Org. Chem. 2012, 8, 1909–1915. Xia, N.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48 (2), 337–339. Xu, H.; Wolf, C. Chem. Commun. 2009, 21, 3035–3037. Xu, H.; Wolf, C. Chem. Commun. 2009, 13, 1715–1717. Wang, D.; Cai, Q.; Ding, K. Adv. Synth. Catal. 2009, 351 (11-12), 1722–1726. Zeng, X.; Huang, W.; Qiu, Y.; Jiang, S. Org. Biomol. Chem. 2011, 9 (24), 8224–8227. Wu, F.-T.; Yan, N.-N.; Liu, P.; Xie, J.-W.; Liu, Y.; Dai, B. Tetrahedron Lett. 2014, 55 (21), 3249–3251. Sharghi, H.; Saei, A. A.; Aberi, M. Chem. Select 2019, 4 (45), 13228–13234. Yoo, W.-J.; Tsukamoto, T.; Kobayashi, S. Org. Lett. 2015, 17 (14), 3640–3642. Singh, G.; Kumar, M.; Bhalla, V. Green Chem. 2018, 20 (23), 5346–5357. Cai, Q.; Zhou, W. Chin. J. Chem. 2020, 38 (8), 879–893. Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5 (14), 2453–2455. Ma, D.; Cai, Q. Synlett 2004, 1, 128–130. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70 (13), 5164–5173. Xing, H.; Zhang, Y.; Lai, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2012, 77 (12), 5449–5453. Zhu, W.; Ma, D. Chem. Commun. 2004, (7), 888–889. Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74 (12), 4542–4546. Li, J.; Zhang, Y.; Jiang, Y.; Ma, D. Tetrahedron Lett. 2012, 53 (31), 3981–3983. Ribecai, A.; Bacchi, S.; Delpogetto, M.; Guelfi, S.; Manzo, A. M.; Perboni, A.; Stabile, P.; Westerduin, P.; Hourdin, M.; Rossi, S.; Provera, S.; Turco, L. Org. Process. Res. Dev. 2010, 14 (4), 895–901. Gao, J.; Bhunia, S.; Wang, K.; Gan, L.; Xia, S.; Ma, D. Org. Lett. 2017, 19 (11), 2809–2812. Sherborne, G. J.; Adomeit, S.; Menzel, R.; Rabeah, J.; Brückner, A.; Fielding, M. R.; Willans, C. E.; Nguyen, B. N. Chem. Sci. 2017, 8 (10), 7203–7210. Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. J. Am. Chem. Soc. 2015, 137 (37), 11942–11945. Zhang, Y.; Yang, X.; Yao, Q.; Ma, D. Org. Lett. 2012, 14 (12), 3056–3059. De, S.; Yin, J.; Ma, D. Org. Lett. 2017, 19 (18), 4864–4867. Chen, Z.; Ma, D. Org. Lett. 2019, 21 (17), 6874–6878. Pawar, G. G.; Wu, H.; De, S.; Ma, D. Adv. Synth. Catal. 2017, 359 (10), 1631–1636. Kumar, S. V.; Ma, D. Chin. J. Chem. 2018, 36 (11), 1003–1006. Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 12 (6), 927–928. Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem. 1985, 50 (26), 5782–5789. Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1984, 25 (30), 3175–3178. Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1995, 34 (12), 1348–1350. Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116 (17), 7901–7902. Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36 (21), 3609–3612. Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116 (13), 5969–5970. Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37 (15), 2046–2067. Yaseneva, P.; Hodgson, P.; Zakrzewski, J.; Falß, S.; Meadows, R. E.; Lapkin, A. A. React. Chem. Eng. 2015, 1, 229–238. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576 (1), 125–146. Forero-Cortés, P. A.; Haydl, A. M. Org. Process. Res. Dev. 2019, 23 (8), 1478–1483. Dorel, R.; Grugel, C. P.; Haydl, A. M. Angew. Chem Int. Ed. 2019, 58 (48), 17118–17129. Lundgren, R. J.; Stradiotto, M. Chem. Eur. J. 2012, 18 (32), 9758–9769. Abaev, V. T.; Serdyuk, O. V. Russ. Chem. Rev. 2008, 77 (2), 177. Heravi, M. M.; Kheilkordi, Z.; Zadsirjan, V.; Heydari, M.; Malmir, M. J. Organomet. Chem. 2018, 861, 17–104. Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346 (13-15), 1599–1626. Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2012, 4 (3), 916–920. Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117 (19), 5373–5374. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc 1995, 117 (16), 4708–4709. Hartwig, J. F.; Richards, S.; Barañano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118 (15), 3626–3633. Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128 (11), 3584–3591. Berthold, D.; Haydl, A. M.; Leung, J. C.; Scholz, U.; Xiao, Q.; Zhu, Z. Recent Advances in the Synthesis of Arylamines in the Light of Application in Pharmaceutical and Chemical Industry. In Methodologies in Amine Synthesis: Challenges and Applications; Ricci, A., Bernardi, L., Eds.; Wiley, 2021; pp 377–444. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119 (35), 8232–8245. Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15 (12), 2755–2763. Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118 (30), 7215–7216. Sadighi, J. P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett. 1998, 39 (30), 5327–5330. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120 (37), 9722–9726. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65 (4), 1158–1174. Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1 (8), 1307–1309. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2 (8), 1101–1104. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125 (35), 10767. Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2005, 44 (9), 1371–1375.

Metal-Catalyzed Amination: CdN Bond Formation

384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408. 409. 410. 411. 412. 413. 414. 415. 416. 417. 418. 419. 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. 430. 431. 432. 433. 434. 435. 436. 437. 438. 439. 440. 441. 442. 443. 444. 445.

331

Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2010, 2 (1), 57–68. Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130 (41), 13552–13554. Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 2 (1), 27–50. Ingoglia, B. T.; Wagen, C. C.; Buchwald, S. L. Tetrahedron 2019, 75 (32), 4199–4211. Wagner, P.; Bollenbach, M.; Doebelin, C.; Bihel, F.; Bourguignon, J.-J.; Salomé, C.; Schmitt, M. Green Chem. 2014, 16 (9), 4170–4178. Ruiz-Castillo, P.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137 (8), 3085–3092. Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131 (22), 7532–7533. Dennis, J. M.; White, N. A.; Liu, R. Y.; Buchwald, S. L. J. Am. Chem. Soc. 2018, 140 (13), 4721–4725. Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129 (34), 10354–10355. Cheung, C. W.; Surry, D. S.; Buchwald, S. L. Org. Lett. 2013, 15 (14), 3734–3737. Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2010, 49 (24), 4071–4074. Dumrath, A.; Lübbe, C.; Neumann, H.; Jackstell, R.; Beller, M. Chem. Eur. J. 2011, 17 (35), 9599–9604. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118 (30), 7217–7218. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120 (29), 7369–7370. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124 (21), 6043–6048. Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001, 42 (26), 4381–4384. Mao, J.; Zhang, J.; Zhang, S.; Walsh, P. J. Dalton Trans. 2018, 47 (26), 8690–8696. van Leeuwen, P. W. N. M.; Kamer, P. C. J. Catal. Sci. Technol. 2017, 8 (1), 26–113. Hartwig, J. F. Acc. Chem. Res. 2008, 41 (11), 1534–1544. Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130 (20), 6586–6596. Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131 (31), 11049–11061. Green, R. A.; Hartwig, J. F. Org. Lett. 2014, 16 (17), 4388–4391. Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119 (26), 6054–6058. Gao, C.-Y.; Cao, X.; Yang, L.-M. Org. Biomol. Chem. 2009, 7 (19), 3922–3925. Nagao, S.; Matsumoto, T.; Koga, Y.; Matsubara, K. Chem. Lett. 2011, 40 (9), 1036–1038. Inatomi, T.; Fukahori, Y.; Yamada, Y.; Ishikawa, R.; Kanegawa, S.; Koga, Y.; Matsubara, K. Catal. Sci. Technol. 2019, 9 (8), 1784–1793. Nirmala, M.; Saranya, G.; Viswanathamurthi, P.; Bertani, R.; Sgarbossa, P.; Malecki, J. G. J. Org. Chem. 2017, 831, 1–10. Clark, J. S. K.; Ferguson, M. J.; McDonald, R.; Stradiotto, M. Angew. Chem. Int. Ed. 2019, 58 (19), 6391–6395. Chan, D. M.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39 (19), 2933–2936. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39 (19), 2937–2940. Lam, P. Y.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M.; Combs, A. Tetrahedron Lett. 1998, 39 (19), 2941–2944. West, M. J.; Fyfe, J. W. B.; Vantourout, J. C.; Watson, A. J. B. Chem. Rev. 2019, 119 (24), 12491–12523. Rao, S. K.; Wu, T.-S. Tetrahedron 2012, 68 (38), 7735–7754. Yousaf, M.; Zahoor, A. F.; Akhtar, R.; Ahmadm, M.; Naheed, S. Mol. Divers 2020, 24 (3), 821–839. Chen, J. Q.; Li, J. H.; Dong, Z.-B. Adv. Synth. Catal. 2020, 362 (16), 3311–3331. Qiao, J. X.; Lam, P. Y. S. Boronic Acids; John Wiley & Sons, Ltd, 2011; pp 315–361. Munir, I.; Zahoor, A. F.; Rasool, N.; Naqvi, S. A. R.; Zia, K. M.; Ahmad, R. Mol. Divers 2019, 23 (1), 215–259. Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 2011 (06), 829–856. Tromp, M.; van Strijdonck, G. P. F.; van Berkel, S. S.; van den Hoogenband, A.; Feiters, M. C.; de Bruin, B.; Fiddy, S. G.; van der Eerden, A. M. J.; van Bokhoven, J. A.; van Leeuwen, P. W. N. M.; Koningsberger, D. C. Organometallics 2010, 29 (14), 3085–3097. King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics 2012, 31 (22), 7948–7957. King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131 (14), 5044–5045. Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.; Watson, A. J. B. J. Am. Chem. Soc. 2017, 139 (13), 4769–4779. Zhang, L.; Zhang, G.; Zhang, M.; Cheng, J. J. Org. Chem. 2010, 75 (21), 7472–7474. Hardouin Duparc, V.; Bano, G. L.; Schaper, F. ACS Catalysis 2018, 8 (8), 7308–7325. Gavade, S.; Balaskar, R.; Mane, M.; Pabrekar, P. N.; Mane, D. Synth. Commun. 2012, 42 (11), 1704–1714. Bi, H.-Y.; Li, C.-J.; Wei, C.; Liang, C.; Mo, D.-L. Green Chem. 2020, 22 (17), 5815–5821. Gao, J.; Shao, Y.; Zhu, J.; Zhu, J.; Mao, H.; Wang, X.; Lv, X. J. Org. Chem. 2014, 79 (19), 9000–9008. Xue, J.-Y.; Li, J.-C.; Li, H.-X.; Li, H.-Y.; Lang, J.-P. Tetrahedron 2016, 72 (44), 7014–7020. Moon, S.-Y.; Nam, J.; Rathwell, K.; Kim, W.-S. Org. Lett. 2014, 16 (2), 338–341. Roy, S.; Sarma, M. J.; Kashyap, B.; Phukan, P. Chem. Commun. 2016, 52 (6), 1170–1173. Rosen, B. M.; Jiang, X.; Wilson, C. J.; Nguyen, N. H.; Monteiro, M. J.; Percec, V. J. Polym. Sci. A Polym. Chem. 2009, 47 (21), 5606–5628. Khosravi, A.; Mokhtari, J.; Naimi-Jamal, M. R.; Tahmasebi, S.; Panahi, L. RSC Adv. 2017, 7 (73), 46022–46027. Sharma, H.; Mahajan, H.; Jamwal, B.; Paul, S. Catal. Commun. 2018, 107, 68–73. Wexler, R. P.; Nuhant, P.; Senter, T. J.; Gale-Day, Z. J. Org. Lett. 2019, 21 (12), 4540–4543. Yoo, W.-J.; Tsukamoto, T.; Kobayashi, S. Angew. Chem. Int. Ed. 2015, 54 (22), 6587–6590. Raghuvanshi, D. S.; Gupta, A. K.; Singh, K. N. Org. Lett. 2012, 14 (17), 4326–4329. Keesara, S. Tetrahedron Lett. 2015, 56 (48), 6685–6688. Hardouin Duparc, V.; Schaper, F. Organometallics 2017, 36 (16), 3053–3060. Jia, X.; Peng, P. Org. Biomol. Chem. 2018, 16 (46), 8984–8988. Derosa, J.; O’Duill, M.; Holcomb, M.; Boulous, M. N.; Patman, R. L.; Wang, F.; Tran-Dubé, M.; McAlpine, I.; Engle, K. M. J. Org. Chem. 2018, 83 (7), 3417–3425. Chen, X.; Bian, Y.; Mo, B.; Sun, P.; Chen, C.; Peng, J. RSC Adv. 2020, 10 (42), 24830–24839. Campbell Brewer, A.; Hoffman, P. C.; Martinelli, J. R.; Kobierski, M. E.; Mullane, N.; Robbins, D. Org. Process Res. Dev. 2019, 23 (8), 1484–1498.

12.09

Synthetic Applications of CdC Bond Activation Reactions

Tao Xu, Molecular Synthesis Center & Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China © 2022 Elsevier Ltd. All rights reserved.

12.09.1 Introduction 12.09.2 C-C activation with (benzo)cyclobutenones in total synthesis 12.09.3 C-C activation with cyclobutanones in total synthesis 12.09.4 C-C activation with cyclobutanols and cyclopropanols in total synthesis 12.09.5 Conclusion Acknowledgments References

332 332 337 338 345 345 345

12.09.1 Introduction Transition metal (TM) catalyzed CdC activation has been established as one of the hot topics in modern synthetic communities. Through over 20 years’ effort from chemists around the world, we are now equipped with powerful methodologies to cleave various types of CdC sigma bonds. But it was not until the recent decade that it began to be applied in multistep total synthesis of complex molecules. In fact, there are many excellent reviews1–27 covering methodology development of TM catalyzed CdC bond activations compared to only two reviews28,29 focusing on CdC activation’s application in total synthesis. It is highly desirable to summarize a comprehensive overview on the latter topic, which is supposed to encourage future application in functional molecule and drug entity synthesis. There are two general modes of activation to cleave a CdC bond by TM catalysis that are summarized in Fig. 1. The first type is direct oxidative addition (Fig. 1A) of a CdC bond with low valent TM. The second type is through b-scission or b-carbon elimination (Fig. 1B). The challenges associated with oxidative addition of a CdC bond onto a transition metal are two-fold. First, the reductive elimination (reverse reaction of oxidative addition) is usually an exergonic reaction and thus thermodynamically favored, which makes the oxidative addition a sluggish process; more often than not, oxidative additions take place at high temperature or need other driving forces such as strain release and/or chelation assistance. Secondly, CdC bonds are typically immersed with neighboring carbon hydrogen bonds (CdH), thus posing a kinetic competition to CdC bond activation. In other words, when interacting with a transition metal, CdH bond activation would be much easier and faster than CdC bond activation due both to the abundance and the orbital trajectory of CdH bonds. The second mode of CdC activation, b-carbon elimination faces similar challenges to oxidative addition. Since it is primarily an intramolecular process, it does not involve the same kinetic barriers of carbon-carbon bond interaction with a transition metal. Furthermore, when acyclic substrates are employed a byproduct is generated alongside the elimination reaction. In this case, the b-carbon elimination process actually gains some entropy, which helps to lower the activation barrier. But, b-carbon elimination reactions are still thermodynamically disfavored, requiring relatively high temperatures and rely on ring-strain release. In this review, we’ll focus on examples using TM-catalyzed CdC cleavage (forming M-C bonds with the susceptible CdC bonds) as the key step in natural products synthesis. We are planning to classify the examples based on substrate type while following a chronological sequence.

12.09.2 C-C activation with (benzo)cyclobutenones in total synthesis In 1984, Liebeskind and South reported the total synthesis of racemic nanaomycin A (1),30 utilizing stoichiometric ClCo(PPh3)3 to reach a stable metallo compound, namely phthaloylcobalt(III) complex 6 via oxidative CdC bond activation with benzocyclobutendione 2 in a complete regioselective manner. The intramolecular migratory insertion of phthaloylcobalt(III) complex 6 with an alkyne would swiftly provide the benzoquinone fused pyrane skeleton (retrosynthesis, in Fig. 1).31 They started from simple THP masked propargyl alchol 3 by converting it into iodide 4 through several steps in an overall yield of 45% (synthetic route, Fig. 1). The CdC activation precursor 2 was obtained through condensing cyclobutenondione 5 with iodide 4 in a decent yield (77%). According to the authors, the stable cobalt(III) complex wouldn’t undergo migratory insertion into the alkyne unless it was activated by stoichiometric amount of silver salts, presumably by removing chloride from the cobalt center and revealing one empty site for coordination. So the phthaloylcobalt(III) complex 6, which was obtained by heating two equivalents of ClCo(PPh3)3 and compound 2 in benzene, was treated with five equivalents of AgBF4 and the macrocyclic benzofused quinone 7 was furnished in 76% yield. Thus, the oxidative CdC bond activation and subsequent migratory insertion into the internal alkyne were realized, albeit with a stoichiometric amount of cobalt (I) complexes. Since the authors used diastereomeric mixtures of 4, the mixed benzofused quinone 7 was reduced and hydrolyzed, during which the pyrane moiety was formed and provided tricyclic 8 and its epimer epi-8 in an 3:1 ratio with an overall 79% yield. The former was converted to nanaomycin A in 53% yield upon hydrolysis of the cyano group.

332

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00130-X

Synthetic Applications of CdC Bond Activation Reactions

333

Fig. 1 Two general modes of CdC activation with TMs.

While Liebeskind and coworkers unveiled strategic application of CdC activation as key step in complex natural product total synthesis, it was not until in 2014 the first catalytic diastereoselective example was reported by Xu and Dong.32 Cycloinumakiol was originally isolated from podocarpaceae, an evergreen plant that’s widely distributed in subtropical asia by Butler.33 It was believed that its unique polyfused tetracyclic skeleton accounted for the promising biological activities. However, as the only member of this family, which features an oxidation at the C20 carbon and forms a tetrahydrofuran moiety, also suggested its alternative biological synthetic pathway compared to other members in this family. Dong and Xu designed a retrosynthetic route (Fig. 2) based on their originally developed methodology, “Cut and Sew” (Fig. 3).34–37 The method relied on the built-in strain of benzocyclobutenone 9, which would undergo an oxidative addition with Rh(I) catalyst and yielded rhodacyclopentanone 10 in an regioselective manner. DFT calculations were carried out and elucidated the reason of regioselectivity.38,39 Rhodacyclopentanone 10 would furnish a polycyclic product 11 upon migratory insertion with the pendent olefin and the following reductive elimination. They designed a quite straightforward retrosynthesis based on this key transformation toward cycloinumakiol (retrosynthesis, Fig. 3), although trisubstituted olefin migratory insertion still posed a grand challenge in this synthesis. Their synthesis started from coupling between benzocyclobutenone (15, BCB) and alcohol 16 through Mitsunobu reaction in quite good yield (90%). The proposed key “Cut and Sew” transformation was realized using 5 mol% [Rh(CO)2Cl]2 and 20 mol% p-acidic P(C6F5)3. The desired tetracyclic core structure 17 was obtained in 66% yield. With this success, the C14 isopropyl group was regiospecifically introduced in three steps, namely bromination, Suzuki coupling and hydrogenation. The key advanced intermediate 13 was obtained in a 95% yield from bromide 18. The author proposed epimerization at C5 proved to be unviable after extensive trials. The strain of the tetracyclic rings was blamed for unfeasibility of epimerization. So the authors decided to take a detour of releasing the ring strain by olefin cleavage in 19, which was generated through reduction and dehydration from 13. Ozonolysis and DBU mediated epimerization at C5 afforded di-aldehyde 20 in 67% yield. McMurry coupling restored the tetracyclic ring skeleton with the desired C5 configuration and 21 was obtained in 66% yield. The proposed structure of cycloinumakiol 12 was yielded through hydrogenation and its structure was undisputedly verified by X-ray crystallography. Unfortunately, the synthetic sample’s NMR spectra didn’t match that of natural compounds, nor did its C5-epimers. Natural cycloinumakiol was finally reassigned as 19-hydroxyl totarol (see ref. 32 for detail) through X-ray crystallography. Although a proposed structure 12 and its epimer were synthesized in this report, it is still the first time that a catalytic carboacylation of alkenes is employed as the key step in constructing natural-product skeletons, allowing for investigation of whether a CdC activation strategy can streamline complex-molecule synthesis. Exploring the strategic use of benzocyclobutenone’s CdC activation continues to go further, with several recent total syntheses from Dong and Xu. In 2018, a Rh-catalyzed cascade reaction was developed achieving 2,3-substituted benzofuran derivatives, which is the core structure for viniferifuran and diptoindonesin G (Fig. 4).40 The Rh-catalyzed reaction took place via C1-C2 bond activation following the same doctrine of “Cut and Sew” from compound 22, achieving rhodacycle 23, which upon migratory insertion into a carbonyl bond led to tricyclic lactone 24. The resulting lactone 24 underwent a spontaneous aromatization through E1-type elimination. With this novel cascade transformation, they carried out a divergent synthesis toward C13-deoxy viniferifuran and diptoindonesin G based on a common intermediate. They started from a a-chloro ketone 26 and coupled it with benzocyclobutenone 15 to reach the CdC activation precursor 27 in 80% yield. The key carboacylation aromatization cascade reaction afforded 2,3-disubstituted benzofuran 28 in 83% yield with only 5 mol% Rh salt and 6 mol% dppf. The subsequent one carbon extrusion and functional group manipulation lead to the key common intermediate 30. Divergently, it was advanced to C13deoxy-viniferifuran 32 through Wittig reaction and global deprotection in 55% and 77% yield, respectively. On the other hand, the aldehyde 30 was converted to C13-deoxy diptoindonesin G through intramolecular Friedel–Crafts acylation and global demethylation in three steps.

334

Synthetic Applications of CdC Bond Activation Reactions

Fig. 2 Total synthesis of nanaomycin A.

In the same year, the linkage oxygen atom on the pendant chain was replaced with nitrogen and two similar methodologies were independently developed the Dong group41 and the Xu group42, respectively. In Dong’s work, they employed a chiral catalyst system to provided an indoline-like framework enantioselectively (Fig. 5). They applied it into the asymmetric total synthesis of (−)cycloclavine. The forward synthetic route was shown in Fig. 5. They commenced with benzocyclobutenone 36 and the desired asymmetric olefin carboacylation transformation afforded the tricyclic ketone 35 in 95% yield with overall 97% ee. This key reaction paved the way for the following investigation. A diazo transfer reaction with TsN3 provided diazo compound 37 in high yield (92%). According to the authors, they investigated the Rh(II)-catalyzed carbene cyclopropanation with allylic chloride and surprisingly, obtained 85% yield of 39 with decent diastereocontrol (dr ¼ 5.8:1). The following Staudinger reaction with azide 40 led to imine formation, which was reduced by NaBH3CN and subsequent methyl group introduction, ultimately afford (−)-cycloclavine 34 in 78% yield in an overall 10 steps from commercially available starting materials. In the same year of 2018, the Xu group developed an acrylamide tethered carboacylation transformation, enantioselectively yielding an oxindole moiety bearing a quaternary carbon center at the C3 position as well as forging a 3,4-fused oxindole framework (Fig. 6).42 In their report, Xu and coworkers tackle the challenging migratory insertion of trisubstituted olefins, taking advantage of activated electron-deficient acrylamides. Starting from compound 41, they achieved the polycyclic oxindole 43 via 42. Inspired by this success, they embarked on the journey of first total synthesis toward xylanigripones A. The key reaction precursor 45 was assembled through amide formation in 68% yield from compound 44 and aryl chloride. The desired “Cut and Sew” reaction was realized via CdC activation using only 2.5 mol% Rh and 3 mol% ligand. The reaction temperature could be lowered to 80  C and

Synthetic Applications of CdC Bond Activation Reactions

335

Fig. 3 Total synthesis of proposed cycloinumakiol and its C5-epimer by Dong and Xu.

achieved a 96% yield of 46. The pyridine ring was regioselectively introduced through a three-step sequence, culminating in the first total synthesis of xylanigripones A. These total synthesis vividly demonstrated that complex total synthesis can be streamlined, and in certain scenarios revolutionized, when considering CdC bond activation at the strategic planning stage. In 2020, Xu and coworkers achieved the concise total synthesis of galanthamine and lycoramine through CdC activation and late-stage CdH functionalization (Fig. 7).43 Based on their previous success with ether linkages, they explored the possibility of establishing consecutive stereocenters of the carbon framework of galanthame-type alkaloids through CdC activation. Their retrosynthesis relied on two key transformations, a Rh-catalyzed gram-scale CdC activation for the tetra-cyclic carbon framework and a regioselective Pd-catalyzed CdH activation for double bond introduction. Retrosynthetically, galanthamine (50) can be obtained through a regioselective Pd-catalyzed CdH activation from ketone 51. The nitrogen atom in 51 was postulated to be introduced by a Schmidt rearrangement from the tetracyclic intermediate 52, which possesses the A-B-C-D carbon framework of the target molecules. The tetracyclic ketone 52 can be reached through a Rh-catalyzed “cut and sew” annulation via CdC activation from benzocyclobutenone 53.

336

Synthetic Applications of CdC Bond Activation Reactions

Fig. 4 Total synthesis of deoxy viniferifuran and diptoindonesin G.

They commenced with preparation of benzylcyclobutenone 56. The [2+ 2] cycloaddition took place between the compound 54 and lithium enolate, satisfactorily affording benzocyclobutanol 55 in 64% yield on a deca-gram scale. Benzocyclobutenone 56 was accessed in 79% overall yield on a deca-gram scale through Dess-Martin oxidation followed by MOM removal under acidic conditions. A coupling between 56 and an a-bromo ketone, followed by Wittig olefination, provided the key CdC activation precursor 53 in 45% overall yield over two steps on a multi-gram scale. The carboacylation reaction proceeded with 5 mol% [Rh(CO)2Cl]2 and 22 mol% P(C6F5)3 giving rise to 57. The overall efficiency of this steps is quite high with 77% isolated yield on the gram scale, demonstrating practicality of the key CdC activation. The designed Schmidt rearrangement failed to provide the desired product. Likely, a Beckmann rearrangement yielded desired ring expanded amide 60 (63% yield), which was methylated providing the key diversifiable intermediate 61. It was converted to lycoramine (63) through consecutive double reduction using L-Selectride/LiAlH4 in 59% yield. In the meantime, the Pd-catalyzed regioselective CdH activation reaction using Stahl’s protocol, gave rise to unsaturated ketone 62 in 45% isolated yield, which was also reduced using the previously described conditions resulting in the total synthesis of galanthamine. The “Cut and Sew” strategy continues to be utilized as a key transformation in complex alkaloids’ total synthesis. Very recently, Dong and coworkers achieved the asymmetric total synthesis of (−)-thebainone A in 13 steps thanks to the strategic use of “cut and sew” reaction (Fig. 8). They screened a few conditions to enable the key transformation and found 4 mol% [Rh(cod)2]NTf2 and 4.8 mol% (R)-DTBM-segphos afforded the product in 76% yield and 94% ee from benzocyclobutenone analog 67. A two step

Synthetic Applications of CdC Bond Activation Reactions

337

Fig. 5 Asymmetric total synthesis of (−)-cycloclavine.

functional group adjustment gave rise to tetracycle 69, which upon pyrane ring opening and methylation led to bromide 70. The following transformation is a step efficient one pot reaction, in which they restored the glycol acetal moiety, introduced TsNMe via an SN2 reaction, and deprotected the acetyl group lead to 71 in 76% yield. Dehydration was mediated by Martin sulfurane and the following Ts deprotection was affected by sodium naphthalenide, yielding initially an N-centered radical, which added on to the olefin group leaving a benzylic radical that was further reduced and protonated to afford 72. Selective demethylation was rationalized by anti-bonding orbital availability and yielded 65 in good yield (87%). Finally, they used a similar dehydrogenation protocol developed by Stahl and coworkers to access (−)-thebainone A in 78% yield. In order to minimize the protecting group use, the authors also refined the steps from 66 to 72, demonstrating a protecting group free route.

12.09.3 C-C activation with cyclobutanones in total synthesis Compared to the numerous methodologies utilizing cyclobutanone as a starting material to achieve a CdC bond activation transformations, applications in total synthesis are extremely rare.44,45 In fact, there has been no total synthesis examples documented until very recently. In 2021, Dong and coworkers completed the first total synthesis of penicibilaenes using the “cut

338

Synthetic Applications of CdC Bond Activation Reactions

Fig. 6 First total synthesis of xylanigripones A.

and sew” strategy starting from cyclobutanones (Fig. 9).46 The sesquiterpene penicibilaenes A (73) and B (74) contain [3.3.1]-bridged and [4.3.0]-fused ring junctions, which nicely fit their “Cut and Sew” methodology developed earlier in 2014 based on a traceless directed [4 + 2] annulation.47,48 The retrosynthesis disconnected the bridged [3.3.1] ring system of 75 into cyclobutanone 76 with a pendent olefin. The forward synthesis commenced with a three-component reaction via cuprate (derived from 77) 1,4 addition to a propargylic ester (78), followed by SN2 reaction with 79. The overall efficiency of these transformations is quite good, obtaining key intermediate 76 in 50% yield from 80. Next, a series of directing pyridylamines and Lewis acids were screened for the directed “cut and sew” reaction. It was found that 3-isopropryl-2-amino pyridine and Zn(OTf )2 proved to be the best combination of additives. With 10 mol% [Rh(C2H4)2]Cl2 and 40 mol% P(3,5-C6H3(CF3)2)3 together with the additives aforementioned, precursor 76 was transformed to the tricyclo[6.3.1.01,5]dodecane skeleton 75 via a proposed transition state like 81 in moderate yield (48%). It was also demonstrated by the authors that the reaction could be operated on a gram scale without significant loss of efficiency (46% yield). Decarboxylation and dehydrogenation of 75 were affected through Barton and Grieco conditions, respectively, over 5 steps, giving rise to 83. 1,4-Conjugate borylation and oxidation installed a hydroxy group at the C4 position of 84 in moderate yield. Through chelation control, 1,2 addition using LaCl3 and MeMgBr delivered 1,3-diol as a single diastereomer in 88% yield, which was further oxidized by IBX to produce ketone 85. Desaturation with 86 and 1,4-Michael addition using Gilman’s reagent delivered 87 with good diastereoselective control but slightly low yield. Penicibilaenes A (73) was achieved upon diastereoselective reduction in an overall 13 steps. A further acylation of the resulting secondary alcohol furnished Penicibilaenes B (74).

12.09.4 C-C activation with cyclobutanols and cyclopropanols in total synthesis TM mediated b-carbon elimination with cyclobutanols, cyclopropanols, and with some less-strained tertiary alcohols was proven to be a useful strategy to cleave CdC bonds. However, its application in multi-step synthesis wasn’t reported until the late 1990s. Ihara and Nemoto reported a Pd(II)-catalyzed ring expansion reaction starting from olefinic cyclobutanol 88. The reaction proceeded through a quasi-semi pinacol type rearrangement, upon activation of the olefin with a Pd(II) catalyst.47 The Wacker type intermediate 90 was proposed via 89, which would undergo another migratory insertion with the other olefin, leading to the annulated product 91 upon b-H elimination (Fig. 10). The structural similarity between equilenin A and compound 91 led the authors to embark on the total synthesis of the former natural product.49 It took them four steps to synthesize moderately enantiopure (77% ee) cyclobutanone 96 from known aldehyde

Synthetic Applications of CdC Bond Activation Reactions

339

NM

Fig. 7 Total synthesis of galanthamine and lycoramine.

92. The key reaction included a (R,R)-(salen)Mn(III) catalyzed enantioselective epoxidation of the olefin 93, which underwent a spontaneous Meiwald rearrangement resulting in the formation of 96 in 55% yield. The CdC activation precursor 97 was accessed via a diastereoselective 1,2-addition with isopropenyl magnesium bromide. The key ring expansion took place with the presence of stoichiometric Pd(OAc)2. It was found by the authors that solvents played a pivotal role in controlling the production diastereoselectivity. HMPA and THF cosolvent proved to be the optimal combination and the tetracycle 98 was obtained in 44% yield as the major isomer (dr ¼ 2.7: 1). Three more steps to adjust the oxidation state as well as protecting removal led to total synthesis of (+)equilenin. In the same year, the authors completed another sesquiterpene natural product, ()-scirpene,50 using the same strategy in a more complex context (Fig. 10, bottom). The TBS-protected cyclobutanol 102 was obtained as a pair of diastereoisomers over five steps from tetrasubstituted olefin 100. Claisen rearrangement mediated by Hg(OAc)2, followed by a four-step sequence resulted in

340

Synthetic Applications of CdC Bond Activation Reactions

Fig. 8 Asymmetric total synthesis of (−)-thebainone A.

tertiary alcohol 104 in moderate overall yield. The tetrahydrofuran was formed via HCl (aq.) treatment and the CdC activation precursor 105 was yielded upon Swern oxidation and vinylMgBr addition. The key reaction was affected by activation with 1.2 equivalents of Pd(MeCN)2Cl2 together with other side products. The desired cyclopentenone 106 was achieved in 62% yield. The tricyclic core structure 108 was formed through a series of transformations. Finally, racemic scirpene could be obtained through deformylation and epoxidation in 35% yield. These synthetic efforts opened doors for strategic application of CdC activation as key steps in complex natural product synthesis starting from cyclobutanols. It also spurred further investigations from many other groups.45 Sarpong and coworkers conducted several total syntheses based on a pinene-type cyclobutanol’s CdC cleavage reaction (Fig. 11, upper).51,52 Their substrate cyclobutanol is located in a [3.1.1] bridged ring system, which was synthesized through a two step sequence from chiral (R)carvone. The chemoselective b-carbon elimination proceeded with catalytic amount of Rh(I) or Pd(II). The following event with C-M species can be either protonation or reductive elimination forming CdC bond depends on the catalyst used. Sarpong and coworkers applied this reaction into the total synthesis of (−)-xishacorene B in 2018 (Fig. 11, middle).53 5 mol% of Pd(PCy3)2 was used as catalyst for the key CdC activation and coupling cascade reaction. Pd(0) first underwent a oxidative addition into vinyl iodide 113 forming a Pd(II) intermediate, which coordinated with tertiary alcohol 111 through ligand exchange and affected the b-carbon elimination regioselectively to furnish desired product 114 in 88% yield upon reductive elimination. Hydrobromination of the trisubstituted olefin afforded bromide 115 as a pair of diastereomers. A radical mediated 1,4-conjugate addition resulted in the formation of the core [3.3.1] bicyclic structure 116. Subsequent oxidation state adjustment and diene side chain installation provided (−)-xiashacorene B (121). With this success, the authors’ group next aimed for the phomactin terpenoid family. The phomactin contains more than 20 family members and some of them displayed moderate inhibition against platelet-activating factor-induced platelet aggregation that embodies as new template to this class of activity. They share a core skeleton which contains a 6-6-5 tricyclic core and a macrocyclic tail-to-head linkage a carbon chain. These natural products pose great challenge to synthetic chemists ever since their debut in 1991.54,55 The Sarpong group focused on the densely functionalized 6-membered ring, which nicely fit their methodology listed in Fig. 11, top. They synthesized the CdC activation precursor 122 from (S)-carvone over 4 steps.56,57 The key reaction was driven by 10 mol% [Rh(cod)OH]2 and 20 mol% (S)-BINAP using MeOH as solvent. The reaction took place via an alkoxide Rh(I) mediated b-carbon

Synthetic Applications of CdC Bond Activation Reactions

341

Fig. 9 Total synthesis of penicibilaenes A and B.

elimination/protonation, affording sulfone 124 upon oxidation. The following exo olefin installation and allylic Riley oxidation gave rise to aldehyde 125, which coupled with vinyl iodide 126 via lithium-halogen exchange and 1,2-addition. The diastereoselectivity was poor but they carried on with both isomers. The macrocyclization was quite efficient, and led to a common advanced intermediate 129 in six steps. It was demonstrated by the authors that 129 can be used as a common intermediate to reach several members of phomactin family molecules. The well known phomactin A was obtained in four steps (Fig. 11, bottom). Cyclopropanols have also been demonstrated as viable starting materials in selective TM-catalyzed CdC bond cleavage reactions. Dai and coworkers reported a carbonylative spirolactonization initiated by cyclopropanol CdC activation catalyzed by Pd(II) in 2016 (Fig. 12, top).58 The spirolactonization relied on Pd(II) mediated b-carbon elimination followed by a CO insertion and reductive elimination to form the oxaspirolactone 135. The key precursor 139 was accessed by using a Kulinkovich reaction from 138, which itself was synthesized over six steps from a readily accessible pyrrole derivative 136. The overall efficiency is good and cyclopropanol 139 was obtained in 63% yield from 138. The key reaction was driven by 10 mol% freshly prepared [Pd(neocuproine)(m-OAc)]2(OTf )2 and stoichiometric benzoquinone under a carbon monoxide atmosphere. The reaction delivered the carbonylated oxaspirolactone 140 as a single diastereomer in 54% yield. It was noted that a slightly higher yield could be obtained by with a compensation of dr loss if an aged Pd catalyst was used. With 140 in hand, they carried on with an Eschenmoser protocol to introduce the exo-methylene group and used Ru(0) mediated olefin isomerization to obtain bisdehydrostemoninine

342

Synthetic Applications of CdC Bond Activation Reactions

Fig. 10 Total synthesis of (+)-equilenin and ()-scirpene.

(142) for the first time. Next, Vismer-Hacck reaction and Barbier alkylation gave rise to 144 in 42% yield together with its OH epimer. Lactonization and hydrogenation led to the total synthesis of bisdehydroneostemoninine 145 (Fig. 12, bottom).59 Compared to the aforementioned 3- and 4-membered cyclic alcohols, non-strained tertiary alcohols have also been used as substrates to engage in the CdC bond cleavage event, although examples are very rare. In fact, there are only two examples demonstrated by Gong and Yang toward the total synthesis of (−)-lingzhiol60 and sinensilactam A.61 Their strategy relied on a Rh-catalyzed cleavage of a 2O cycloheptanol/annulation cascade reaction. The mechanism of this cascade reaction, especially the CdC bond cleavage is still debated,62,63 but this novel transformation rendered the total synthesis in a highly concise and step-economic fashion. The first asymmetric total synthesis of (−)-lingzhiol based on a Rh-catalyzed [3 +2] cycloaddition Thus, besides cyclobutanols, cycloheptanols has also been proven to be a class of promising substrate for CdC bond cleavage (Fig. 13).

Synthetic Applications of CdC Bond Activation Reactions

Fig. 11 Total synthesis of xishacorene B and phomactin terpenoids.

343

Fig. 12 Total synthesis of bisdehydrostemoninine and its congener.

Fig. 13 Asymmetric total synthesis of (−)-lingzhiol.

Synthetic Applications of CdC Bond Activation Reactions

345

12.09.5 Conclusion TM-mediated CdC bond activation have been established as one of the important areas in modern organic synthesis from efforts made by chemists worldwide. It provides synthetic chemists novel perspectives when making retroanalysis; it offers alternative bond disconnections scenarios to medicinal chemists. Although CdC activation has come a long way since, it is not without drawbacks. Based on the total syntheses we summarized herein, it is not difficult to conclude that its application in complex molecules as well as medicinally important molecules remains elusive. Multistep syntheses that take more than 20 longest linear steps still require lower catalyst loading and higher efficiency for the overall CdC activation reaction. Last but not least, asymmetric TM-catalyzed CdC activation needs to be developed in a more practical manner. We foresee that it won’t be long before all the above-mentioned shortcomings will be overcome and CdC activation will evolve with the progress of ideal synthesis.

Acknowledgments We thank NSFC (No. 82122063, 81991522, 81973232), Shandong Science Fund for Distinguished Young Scholars (ZR2020JQ32), and the Fundamental Research Funds for the Central Universities (202041003) for financial support. Profs. G. Dong of UC and I. Tonks of UM are acknowledged for the kind discussion and invitation.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

Jones, W. D. Nature 1993, 364, 676–677. Murakami, M.; Ito, Y. Top. Organomet. Chem. 1999, 3, 97–129. Rybtchinski, B.; Milstein, D. Chem. Int. Ed. 1999, 38, 870–883. Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610–618. Satoh, T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1–20. Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566–1591. Ruhland, K. Eur. J. Org. Chem. 2012, 2683–2706. Korotvicka, A.; Necas, D.; Kotora, M. Curr. Org. Chem. 2012, 16, 1170–1214. Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem. Int. Ed. 2011, 50, 7740–7752. Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100–1105. Dong, G. C–C Bond Activation; Springer-Verlag: Berlin, 2014; vol. 346. Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410–9464. Murakami, M.; Ishida, N. Cleavage of Carbon–Carbon Single Bonds by Transition Metals; Wiley-VCH Verlag, 2015; p 1. Shaw, M. H.; Bower, J. F. Chem. Commun. 2016, 52, 10817–10829. Fumagalli, G.; Stanton, S.; Bower, J. F. Chem. Rev. 2017, 117, 9404–9432. Deng, L.; Dong, G. Trends Chem. 2020, 2, 183–198. Xia, Y.; Dong, G. Nat. Rev. Chem. 2020, 4, 600–614. Nakao, Y. Chem. Rev. 2021, 121, 327–344. McDonald, T. R.; Mills, L. R.; West, M. S.; Rousseaux, S. A. L. Chem. Rev. 2021, 121, 3–79. Sokolova, O. O.; Bower, J. F. Chem. Rev. 2021, 121, 80–109. Wang, J.; Blaszczyk, S. A.; Li, X.; Tang, W. Chem. Rev. 2021, 121, 110–139. Cohen, Y.; Cohen, A.; Marek, I. Chem. Rev. 2021, 121, 140–161. Vicente, R. Chem. Rev. 2021, 121, 162–226. Pirenne, V.; Muriel, B.; Waser, J. Chem. Rev. 2021, 121, 227–263. Murakami, M.; Ishida, N. Chem. Rev. 2021, 121, 264–299. Lutz, M. D. R.; Morandi, B. Chem. Rev. 2021, 121, 300–326. Bi, X.; Zhang, Q.; Gu, Z. Chin. J. Chem. 2020, 39, 1397–1412. Murakami, M.; Ishida, N. J. Am. Chem. Soc. 2016, 138, 13759–13769. Sarpong, R.; Wang, B.; Perea, M. A. Angew. Chem., Int. Ed. 2020, 59, 18898–18919. South, M. S.; Liebeskind, L. S. J. Am. Chem. Soc. 1984, 106, 4181–4185. Liebeskind, L. S.; Baysdon, S. L.; South, M. S. J. Am. Chem. Soc. 1980, 102, 7397–7398. Xu, T.; Dong, G. Angew. Chem. Int. Ed. 2014, 53, 10733. Devkota, K. P.; Ratnayake, R.; Colburn, N. H.; Wilson, J. A.; Hendrich, C. J.; McMahon, J. B.; Beutler, J. A. J. Nat. Prod. 2011, 74, 374. Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567–7571. Xu, T.; Ko, H. M.; Sagave, N. A.; Dong, G. J. Am. Chem. Soc. 2012, 134, 20005. Xu, T.; Savage, N. A.; Dong, G. Angew. Chem. Int. Ed. 1891, 2014, 53. Zhang, J.; Wang, X.; Xu, T. Nat. Commun. 2021, 12, 3022. Lu, G.; Fang, C.; Xu, T.; Dong, G.; Liu, P. J. Am. Chem. Soc. 2015, 137, 8274–8283. Wang, Y.; Qiu, B.; Hu, L.; Lu, G.; Xu, T. ACS Catal. 2021, 11, 9136–9142. Sun, T.; Zhang, Y.; Qiu, B.; Wang, Y.; Qin, Y.; Dong, G.; Xu, T. Angew. Chem. Int. Ed. 2018, 130, 2909. Deng, L.; Chen, M.; Dong, G. J. Am. Chem. Soc. 2018, 120, 9652–9658. Qiu, B.; Li, X.-T.; Zhang, J.-Y.; Zhan, J.-L.; Huang, S.-P.; Xu, T. Org. Lett. 2018, 20, 7689. Zhang, Y.; Shen, S.; Fang, H.; Xu, T. Org. Lett. 2020, 22, 1244–1248. Xia, Y.; Lu, G.; Liu, P.; Dong, G. Nature 2016, 539, 546–550. Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M. Org. Lett. 2006, 8, 3379–3381. Xue, Y.; Dong, G. J. Am. Chem. Soc. 2021, 143, 8272–8277. Ko, H. M.; Dong, G. Nat. Chem. 2014, 6, 739–744.

346

48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.

Synthetic Applications of CdC Bond Activation Reactions

Hou, S.-H.; Yu, X.; Zhang, R.; Deng, L.; Zhang, M.; Prichina, A. Y.; Dong, G. J. Am. Chem. Soc. 2020, 142, 13180–13189. Nemoto, H.; Yoshida, M.; Fukumoto, K.; Ihara, M. Tetrahedon Lett. 1999, 40, 907. Nemoto, H.; Takahashi, E.; Ihara, M. Org. Lett. 1999, 1, 517. Masarwa, A.; Weber, M.; Sarpong, R. J. Am. Chem. Soc. 2015, 137, 6327–6334. Weber, M.; Owens, K.; Masarwa, A.; Sarpong, R. Org. Lett. 2015, 17, 5432–5435. Kerschgens, I.; Rovira, A. R.; Sarpong, R. J. Am. Chem. Soc. 2018, 140, 9810–9813. Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463. Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda, K.; Hata, T. J. Org. Chem. 1994, 59, 564. Kuroda, Y.; Nicacio, K. J.; da Silva, I. A., Jr.; Leger, P. R.; Chang, S.; Gubiani, J. R.; Deflon, V. M.; Nagashima, N.; Rode, A.; Blackford, K.; Ferreira, A.; Sette, L.; Williams, D.; Andersen, R.; Jancar, S.; Berlinck, R.; Sarpong, R. Nat. Chem. 2018, 10, 938. Leger, P. R.; Kuroda, Y.; Chang, S.; Jurczyk, J.; Sarpong, R. J. Am. Chem. Soc. 2020, 142, 15536. Davis, D. C.; Walker, K. L.; Hu, C.; Zare, R. N.; Waymouth, R. M.; Dai, M. J. Am. Chem. Soc. 2016, 138, 10693–10699. Ma, K.; Yin, X.; Dai, M. Angew. Chem., Int. Ed. 2018, 57, 15209–15212. Long, R.; Huang, J.; Shao, W.; Liu, S.; Lan, Y.; Gong, J.; Yang, Z. Nat. Commun. 2014, 5, 5707. Shao, W.; Huang, J.; Guo, K.; Gong, J.; Yang, Z. Org. Lett. 2018, 20, 1857–1860. Qi, X.; Liu, S.; Zhang, T.; Long, R.; Huang, J.; Gong, J.; Yang, Z.; Lan, Y. J. Org. Chem. 2016, 81, 8306. Nemoto, H.; Miyata, J.; Yoshida, M.; Raku, N.; Fukumoto, K. J. Org. Chem. 1997, 62, 7850–7857.

12.10

Synthetic Applications of C–O and C–E Bond Activation Reactions

Mamoru Tobisua,b, Takuya Kodamaa,b, and Hayato Fujimotob, aDepartment of Applied Chemistry, Graduate School of Engineering and, Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives (ICS-OTRI), Osaka University, Suita, Osaka, Japan; bDepartment of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan © 2022 Elsevier Ltd. All rights reserved.

12.10.1 12.10.2 12.10.2.1 12.10.2.2 12.10.2.3 12.10.2.3.1 12.10.2.3.2 12.10.2.3.3 12.10.2.4 12.10.2.5 12.10.2.6 12.10.3 12.10.3.1 12.10.3.2 12.10.3.3 12.10.3.4 12.10.3.5 12.10.4 12.10.4.1 12.10.4.2 12.10.4.3 12.10.4.3.1 12.10.4.3.2 12.10.4.4 12.10.4.5 12.10.5 12.10.5.1 12.10.5.2 12.10.5.3 12.10.5.4 12.10.5.5 12.10.6 12.10.6.1 12.10.6.2 12.10.6.3 12.10.6.3.1 12.10.6.3.2 12.10.6.4 12.10.7 References

Introduction C–O bond activation Overview C(sp)–O bond activation C(aryl)–O bond activation Aryl esters and derivatives Aryl ethers Arenols C(alkenyl)–O bond activation C(acyl)–O bond activation C(sp3)–O bond activation C–S bond activation Overview C(sp)–S bond activation C(sp2)–S bond activation C(acyl)–S bond activation C(sp3)–S bond activation C–N bond activation Overview C(sp)–N bond activation C(aryl)–N bond activation The use of a directing group No directing group C(acyl)–N bond activation C(sp3)–N bond activation C–Si bond activation Overview C–Si bond activation of strained silacycles C(sp3)–Si bond activation C(sp2)–Si bond activation C(sp)–Si bond activation C–P bond activation Overview Phosphoniums Phosphines Intermolecular reactions Intramolecular cyclizations Phosphoric acid derivatives and phosphine oxides Conclusion and outlook

347 348 348 348 351 351 359 366 367 369 376 378 378 378 379 387 393 394 394 394 395 395 397 398 399 400 400 400 403 405 407 407 407 408 408 408 411 413 414 414

12.10.1 Introduction One of the notable features of transition metal complexes is their ability to activate otherwise unreactive chemical bonds. This feature allows transition metal complexes to serve as catalysts in an array of useful organic transformations that were classically unattainable. For example, Ar–X bonds had been thought to be unreactive, but the advent of transition metal complexes enabled them to be activated via oxidative addition, which led to the development of a series of catalytic reactions of aryl halides, such as cross-coupling reactions. If common but less reactive chemical bonds, such as C–O and C–N bonds, can be activated by transition metal complexes in a manner similar to Ar–X, it would undoubtedly enrich the methodological diversity of chemical transformations (Scheme 1).

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00089-5

347

348

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 1 Catalytic transformations initiated by the oxidative addition of C–E bonds.

Catalytic reactions that involve the activation of C–E bonds (E ¼ O, S, N, P and Si) that have appeared as of December of 2020 are reviewed in this chapter. C–E bond activation reactions mediated by a stoichiometric amount of a transition metal are not covered except when they are highly relevant to catalytic reactions. Catalytic reactions that involve the activation of C–E bonds not only via an oxidative addition mechanism but also via several other mechanisms are included as long as transition metal complexes play a pivotal role in the bond activation event. However, activation reactions by simple Lewis acid mechanisms without the formation of an intermediate bearing a carbon-metal bond is beyond the scope of this review. Structures and their abbreviations discussed in this section are summarized in Fig. 1.

12.10.2 C–O bond activation 12.10.2.1 Overview Aliphatic alcohols are one of the more widely occurring functional groups in organic synthesis and numerous methods have been developed for converting C(alkyl)–O bonds, for example via SN1 or SN2 reactions. In contrast, the conversion of C(aryl)–O bonds represents a far more difficult process, and methods for their conversion remain underdeveloped, although such methods would allow for the use of naturally abundant phenol derivatives as sustainable aromatic sources.1 Low valent transition metal complexes, such as Pd(0), can be used to activate C(aryl)–O bonds in phenols by oxidative addition after converting the phenolic hydroxy group into a better leaving group, such as a trifluoromethane sulfonate (triflate).2 However, the environmental advantage of using phenol starting materials is offset by the issue associated with the fluorine-containing wastes that are produced during the course of such reactions. The waste problem could be minimized by using nonfluorinated, less harmful leaving groups, such as acyloxy and methoxy groups. However, the bond dissociation energies of C(aryl)–O bonds in aryl esters and aryl ethers are significantly larger than those in aryl triflates, thereby posing a challenge to the activation and use C(aryl)–O bonds of aryl esters and ethers in catalytic reactions (Fig. 2). In fact, the common Pd(0)-based catalysts are incapable of mediating the oxidative addition of C(aryl)–O bonds of aryl esters and ethers. During the past decade, significant progress has been made in the development of catalysts that can be used to activate C(aryl)–O bonds in inert phenol derivatives, and such catalysts are now used in catalytic reactions, including cross-coupling reactions. The relative reactivity of C(aryl)–O bonds of phenol derivatives can be estimated quantitatively by comparing the calculated activation energies for the oxidative addition of a series of aryl electrophiles (Table 1).3 The activation barriers for the oxidative addition of phenyl acetate and anisole to Pd(PMe3) are higher than bromobenzene, a commonly used aryl electrophile, by 31–39 kcal/mol. These barriers are significantly decreased by switching the metal center to nickel. In fact, the vast majority of reactions involving the activation of C(aryl)–O bonds of inert phenol derivatives are catalyzed by nickel complexes. Once the oxidative addition of these phenol derivatives becomes viable, catalytic applications, for example to cross-coupling with various nucleophiles, is possible as is the case for the catalytic transformation of aryl halides. Comparative kinetic studies of the oxidative addition of a series of aryl electrophiles (Ar-X) to Ni(cod)(dppf ) indicate that the reaction rate decreases in the order of I > Br > Cl > OTs > OCO2Et > OTf > OCONEt2 > OSO2NMe2 > OCOtBu >> OMe, F.4 This chapter summarizes catalytic transformations of unactivated C–O bonds. The chapter is classified primarily by the hybridization states of the carbon attached to oxygen (i.e., C(aryl)–O, (alkenyl)–O, C(acyl)–O and C(sp3)–O bonds). Several reviews on catalytic transformations of unactivated C–O bonds have appeared recently.5

12.10.2.2 C(sp)–O bond activation Regarding the cleavage of C(sp)–O bonds, two catalytic reactions of cyanates were reported. Cp(CO)3MoMe was reported to mediate the reaction of cyanates with hydrosilane, leading to the formation of silyl cyanide via the cleavage of a O–CN

Synthetic Applications of C–O and C–E Bond Activation Reactions

Fig. 1 Structures and their abbreviations discussed in this chapter.

349

350

Synthetic Applications of C–O and C–E Bond Activation Reactions

Fig. 2 Phenolic electrophiles used in catalytic reactions.

Table 1

Calculated activation barriers of oxidative addition of phenolic electrophiles to Pd and Ni.

bond (Scheme 2).6 The results of DFT calculations indicate that the C(sp)–O bond is cleaved via the generation of a silylmolybdenum complex, followed by the insertion of a cyano group into a Mo–Si bond to form a Z2-imidato complex, and the subsequent deinsertion of silyl isocyanide. A relevant Z2-imidato complex of tungsten was characterized.

Scheme 2 Mo-catalyzed activation of C(sp)–O bond.

Synthetic Applications of C–O and C–E Bond Activation Reactions

351

The catalytic intramolecular insertion of an alkene into a C(sp)–O bond of a cyanate derivative was reported (Scheme 3).7 This reaction is catalyzed by the cooperative use of Pd(0)/Xantphos and BPh3. It was proposed that a cyano group coordinates to the BPh3 cocatalyst, facilitating the oxidative addition of a O–CN bond, as well as the reductive elimination of a C(sp3)–CN bond.

Scheme 3 Pd-catalyzed activation of C(sp)–O bond.

12.10.2.3 C(aryl)–O bond activation 12.10.2.3.1

Aryl esters and derivatives

In developing catalytic methods for aryl ester substrates, the selectivity between the cleavage of C(aryl)–O and C(acyl)–O bonds needs to be addressed (Fig. 3). In terms of bond dissociation energies, C(acyl)–O bonds (BDE: 80 kcal/mol) are more reactive than C(aryl)–O bonds (BDE: 106 kcal/mol), making C(aryl)–O bond transformations challenging.3 However, overall selectivity is determined by many other factors such as the reversibility of the C–O bond cleavage step and the relative rates of the subsequent reaction.3 The use of bulky acyl groups, such as a pivaloyl group, is also beneficial for achieving the selective transformation of C(aryl)–O bonds of aryl esters.

Fig. 3 C(aryl)-O cleavage vs C(acyl)-O cleavage.

A theoretical study3 of the Ni(0)/PCy3-catalyzed Suzuki-Miyaura type cross-coupling of aryl acetates revealed that the oxidative addition of a C(acyl)–O bond can occur reversibly with a relatively low barrier, but the subsequent transmetalation with phenylboronic acid is much less energetically favored (Scheme 4). In contrast, the oxidative addition of C(aryl)–O bonds can proceed irreversibly, and the subsequent transmetalation readily follows, which is in good agreement with reported experimental outcomes.

Scheme 4 C(aryl)-O cleavage vs C(acyl)-O cleavage.

Several metal complexes have been reported to mediate oxidative addition reactions of C(aryl)–O bonds of aromatic esters. The reaction of an aromatic ester with Ni(cod)2 and a bidentate phosphine ligand was reported to give an oxidative addition complex (Scheme 5).8a Although the use of PCy3 permits a more active nickel catalyst to be generated for C(aryl)–O bond activation, the corresponding oxidative addition complex is not isolable because of its lability. However, a bimetallic nickel complex, which is likely to be formed by the reaction of the putative oxidative addition complex with another Ni(PCy3) fragment, was isolated and characterized (Scheme 6).8b A rhodium complex ligated with a PNP pincer ligand was also reported to mediate the oxidative addition of a C(aryl)–O bond of phenyl pivalate and phenyl carbamate (Scheme 7).8c

352

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 5

Scheme 6

Scheme 7

Fig. 4 Calculated transition states for nickel-mediated C(aryl)–O bond activation.

Detailed mechanistic studies regarding the oxidative addition of C(aryl)–O bond of aryl esters using nickel complexes have been reported based on computational methods. When PCy3 is used as the ligand, oxidative addition to the nickel monophosphine species, rather than nickel bisphosphine species, is favored, since its vacant coordination site allows for an additional Ni–O interaction, which lowers the activation barrier for this process (A in Fig. 4).9b When a bidentate dcype ligand is involved, both the standard three-centered structure B9a and five-centered structure C9c,d were identified as viable transition states, depending on the calculation method used. The most widely used catalysts for transforming C(aryl)–O bonds of aryl ester derivatives are nickel complexes with a donating ligand. Many of the commonly known palladium-catalyzed reactions of aryl halides can be performed with aryl ester derivatives when the suitable nickel catalyst is used. Table 2 summarizes nickel-catalyzed cross-coupling of aryl ester derivatives with organometallic reagents. In 1992, Snieckus reported on a pioneering study of the cross-coupling of aryl carbamates using RMgX (R ¼ Ph, Me and Me3SiCH2) as a nucleophile, in which no external donor ligand is added (Entry 1).10a It was subsequently reported that the addition of a well-designed P,O-bidentate ligand can be used to generate a more active catalyst for this process, by allowing a magnesium ion to assist in the C–O bond activation (Entry 2).10b Both aryl (Entry 3)11a and alkylzinc (Entry 4)11b reagents can be cross-coupled with aryl esters using PCy3 and dcype, respectively, as the ligand. The Ni/PCy3 catalyst is also able to catalyze cross-coupling with an array of organoaluminum reagents (Entry 5).12 The Suzuki-Miyaura reaction is arguably recognized as the most useful cross-coupling reaction because the organoboron reagents are readily available, stable to moisture and oxygen and compatible with most of the common functional groups. Garg13b and Shi13c independently reported on the first Suzuki-Miyaura type cross-coupling of aryl esters using a Ni/PCy3 catalyst (Entries 6 and 7).14 Since then several catalysts have been reported to be useful for the Suzuki-Miyaura type coupling of phenyl ester derivatives. Although a slight modification in the reaction conditions was required depending on the protecting group of the boron reagents that are used, PCy3 was reported to be uniformly effective (Entries 6–12).9,14 Controlling the amount of water present in the reaction system is crucial for an efficient reaction, since H2O can react with a nickel complex to generate a catalytically inactive hydroxy-bridged nickel dimeric species.9b Therefore, the direct use of unprotected arylboronic acids is often not straightforward. The use of an NHC ligand [I(2-Ad)] was reported to be effective for both nonprotected and protected organoboron reagents (Entry 13).14i,j Aryl carbonates are also suitable substrates for nickel-catalyzed cross-coupling with organoboron reagents (Entries 10 and 14).14,15 Cross-coupling with alkylboron reagents was also possible

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 2 Nickel-catalyzed cross-coupling of aryl esters, carbamates and carbonates with organometallic nucleophiles.

353

354

Synthetic Applications of C–O and C–E Bond Activation Reactions

using a Ni/IPr catalyst (Entry 15).16 Organosilicon reagents represent another class of synthetically useful coupling partners, and an additional benefit would be expected because silicon is an earth-abundant element. However, there is only one successful example of the cross-coupling of inert phenol derivatives with organosilicon nucleophiles (Entry 16).17 Aryl carbamates can be coupled with arylsilanes under the influence of a combined nickel/copper catalyst system. The use of C-H bonds as coupling partners, in place of stoichiometric organometallic reagents, for cross-coupling reactions with aryl halides has emerged as some of the more powerful and greener alternatives to classical cross-coupling reactions. Therefore, it would become a widely applied method if inert phenol derivatives could be used instead of aryl halides in such C–H cross-coupling reactions. The nickel-catalyzed arylation of non-acidic arene C-H bonds with inert phenol derivatives has only been accomplished under intramolecular conditions. Thus, the reaction of a biaryl ether bearing an ortho pivaloxyl group can be cyclized to form a benzofuran derivative by a nickel catalyst (Scheme 8).18 The intermolecular cross-coupling of aryl esters with non-acidic C-H bonds has been accomplished via the use of cobalt or rhodium catalysts (vide infra).

Scheme 8

The cross-coupling of aryl esters and carbamates with relatively acidic C–H bonds are listed in Table 3. In 2012, Itami reported on the nickel/dcype-catalyzed cross-coupling of aryl pivalates with (benz)oxazoles, in which a C–H bond at the 2-position is selectively arylated (Entry 1).19 Other related heteroarenes, such as thiazoles and imidazoles also undergo 2-arylation under the

Table 3

Nickel-catalyzed cross-coupling of aryl esters and carbamates with C–H bonds.

Synthetic Applications of C–O and C–E Bond Activation Reactions

355

same conditions.19b Although p-extended aryl esters, such as naphthyl pivalates, can be efficiently cross-coupled, phenyl pivalates are much less reactive under these nickel/dcype-catalyzed conditions. This problem was solved by developing PS-dppbz, a new polymer-supported bisphosphine derivative, which can be used to promote the cross-coupling of phenyl pivalates with benzoxazoles.19c A C–H bond in penta- and tetrafluorobenzenes can also be coupled with aryl carbamates with the aid of a nickel/copper dual catalytic system, in which a perfluoroarylcopper species is proposed to be involved as the transient nucleophile (Entry 2).20 The same catalyst system is also effective for the Sonogashira-type coupling of aryl carbamates using triisopropylsilylacetylene (Entry 3).20 The a-arylation of ketones, esters and amides with aryl halides is a useful method for preparing a-aryl carbonyl compounds.23 A nickel catalyst ligated with a bisphosphine ligand dcypt permits aryl esters and carbamates to be used as arylating reagents in such a-arylation reactions (Entry 4).21b An enantioselective variant of this nickel-catalyzed a-arylation using aryl pivalates was accomplished by the use of a BINAP-type chiral ligand, thus allowing for the enantioselective construction of a quaternary stereogenic center (Entry 5).21c The Mizoroki-Heck reaction, in which aryl halides and alkenes are coupled via an insertion/b-hydrogen elimination sequence, is another class of C-H functionalization reactions. Aryl pivalate substrates can be used in Mizoroki-Heck type reactions in the presence of a nickel/dppf catalyst (Entry 6).22 Two other carbon–carbon bond formation reactions by the nickel-catalyzed reaction of phenyl ester derivatives using non-organometallic reagents that can serve as a carbanion equivalent were reported. One is the nickel-catalyzed cyanation of aryl pivalates and carbamates, in which aminoacetonitrile derivatives serve as a suitable cyano source (Scheme 9a).24a The other is the decarboxylative cross-coupling of naphthyl pivalates with perfluorobenzoic acid (Scheme 9b).24b

Scheme 9 Nickel-catalyzed cyanation and decarboxylative arylation of aryl pivalates.

The reductive cross-coupling of two different aryl electrophiles has gained significant attention as alternatives to the conventional cross-coupling of aryl halides with organometallic reagents, because the preparation of the organometallic reagents can be avoided.25 In these reactions, the differentiation of two aryl electrophiles is the key for achieving selective cross-coupling over the competing homocoupling process. In this context, the nickel-catalyzed reductive cross-coupling of naphthyl pivalates or carbamates with bromobenzenes was reported to proceed in the presence of metallic magnesium (Entry 1, Table 4).26 The nickel-catalyzed reductive carboxylation of aryl halides with CO2 has emerged as a powerful method for the synthesis of aromatic carboxylic acids.28 The key feature of the nickel system is the involvement of an in-situ generated Ar-Ni(I) species, which is capable of efficiently adding across CO2. Another advantage of a nickel catalyst is that naphthyl pivalates can be used in place of aryl halides (Entry 2).27a Isoelectronic alkyl isocyanates can also be coupled with naphthyl pivalates under similar conditions to form the corresponding amides (Entry 3).27b Recent progress in transition metal-catalyzed cross-coupling technology has allowed aryl halides to be coupled not only with carbon nucleophiles, but also with heteroatom-based nucleophiles, including amines, alcohols and related derivatives.29b,c Such carbon-heteroatom bond-forming reactions are also possible with aryl ester and carbamate substrates when a suitable nickel catalyst is used. For example, the amination of aryl pivalates or carbamates proceeds effectively in the presence of a Ni(cod)2/NHC catalyst (Table 5, Entry 1).30b,c The use of pivalates as a leaving group is essential for preventing undesired C(acyl)–O bond cleavage, which becomes a major pathway when aryl acetates and benzoates are used. Primary anilines can also be synthesized via the C–O bond activation of aryl esters and carbamates by amination using a benzophenone imine, followed by acid hydrolysis of the resulting imines (Entry 2).30d The introduction of other heteroatoms to phenyl ester derivatives was also reported. The borylation of inert phenol derivatives is reported to be catalyzed by a Ni/PCy3 system (Entry 3).31 In this reaction, the use of a neopentylglycolprotected diboron reagent, not the corresponding pinacol-protected derivative, is essential. The use of a silylboron reagent leads to

356

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 4

Table 5

Nickel-catalyzed reductive cross-coupling of aryl esters and carbamates with electrphiles.

Nickel-catalyzed cross-coupling of aryl esters and carbamates with heteroatom-based nucleophiles.

Synthetic Applications of C–O and C–E Bond Activation Reactions

357

the formation of a silylated product with the aid of combined nickel/copper catalytic system (Entry 4).32a An in situ generated silylcopper species was originally proposed to be an active nucleophile in this reaction. However, more recent studies suggest that the direct transmetallation from a silylborane reagent is also a viable pathway.8b Silylmagnesium bromides are also effective reagents for the nickel-catalyzed silylation of aryl carbamates (Entry 5).32b Carbon-phosphorus bond formation is possible by the cross-coupling of aryl esters with various organophosphorus reagents (Entry 6).34b The stannylation of aryl pivalates was also reported using a silylstannane reagent in conjunction with a nickel/dcype catalyst (Entry 7).33 Intramolecular C–N bond formation through the nickel-catalyzed decarboxylation of aryl carbamates was reported (Scheme 10).35 A polymer-supported bisphosphine PS-DPPBz serves as an effective ligand for this process. Unlike intermolecular amination,30 the addition of external aminating reagents is not needed, which allows a range of electrophilic functional groups, such as a formyl group, to be compatible.

Scheme 10 Nickel-catalyzed decarboxylative amination of aryl carbamates.

Ester and carbamate functionalities are common ortho directing groups in both transition metal catalyzed C–H activation and stoichiometric deprotonative metallation reactions. Methods for removing these directing groups are in demand, since this would allow the directing groups to serve as a traceless handle in arene functionalized reactions. An early example of the catalytic removal of a carbamate group was documented in the nickel-catalyzed Kumada-Tamao-Corriu type cross-coupling of aryl carbamates with isopropylmagnesium halide, which serves as a hydride donor via b-hydrogen elimination (Table 6, Entry 1).10a A more functional group tolerant protocol was developed for aryl pivalates36a and carbamates36b using hydrosilanes as a mild reducing agent, in which several functional groups that react with Grignard reagents, such as esters and amides, are compatible (Entries 2 and 3). Another functional group tolerant protocol was developed using HCO2Na as a reductant (Entry 4).36c Scheme 11 illustrates the synthetic application of nickel-catalyzed reductive removal of an acyloxy group. In the first step, a pivaloxy group activates the aromatic ring toward electrophilic bromination, and simultaneously directs bromination to occur at the para position. The robust nature of the pivaloxy group keeps it intact under Suzuki-Miyaura arylation at the bromide site. In the third step, the pivaloxy group functions as an ortho-director in palladium-catalyzed C–H bond arylation reaction. The pivaloxy group can finally be removed by a nickel-catalyzed reaction with hydrosilane. Thus, a pivaloxy group serves as a traceless handle in the regioselective functionalization of arenes. Catalytic transformations of C(aryl)–O bonds in aryl esters using metal catalysts other than nickel have also been reported, although the number of such examples are limited. Given that iron is an abundant, inexpensive and nontoxic element, iron catalysis

Table 6

Nickel-catalyzed reductive cleavage of aryl esters and carbamates.

358

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 11 Synthetic application of nickel-catalyzed removal of an acyloxy group.

Table 7

Iron-catalyzed cross-coupling of aryl esters and carbamates.

has attracted a great deal of interest in organic synthesis. In this context, the iron-catalyzed cross-coupling reactions of aryl halides has made a significant progress.37b–e However, only a few reports on the use of aryl ester derivatives in such iron-catalyzed reactions have appeared (Table 7). Cross-coupling with Grignard reagents was accomplished using a FeCl2/SIMes catalyst, which permitted the alkylation of naphthyl carbamates and alkenyl esters to occur (Entry 1).38a The addition of a catalytic amount of CH2Cl2 was subsequently reported to be effective for the cross-coupling of regular phenyl carbamates, although its role is not currently fully understood (Entry 2).38b The iron-catalyzed cross-coupling of naphthyl carbamate with arylsilane was reported to occur using CuF2 as a stoichiometric additive, although only one substrate set was included in this study (Entry 3).17 Iron-catalyzed silylation of aryl carbamates is also possible with a silyl nucleophile generated from silylborane and NaOMe (Entry 4).38c Ozerov reported that rhodium complexes with a pincer-type ligand can be used to mediate the oxidative addition of unactivated C(aryl)–O bond in aryl esters and carbamates (Scheme 7).8c The first catalytic reaction that involves the rhodium-mediated C(aryl)–O activation of unactivated phenol derivatives was reported for a borylation reaction with a diboron reagent, demonstrating that the use of a pincer-type ligand is not essential for this type of activation (Table 8, Entry 1).39a The rhodium-catalyzed Suzuki-Miyaura type reaction of aryl carbamates was also developed using a rhodium(I)/I(2-Ad) catalyst (Entry 2).39b Unlike the

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 8

359

Cobalt and rhodium-catalyzed cross-coupling of aryl esters and carbamates.

catalytic cycle involved in nickel-catalyzed reactions (Table 6), this rhodium-catalyzed cross-coupling presumably proceeds through the oxidative addition of C(aryl)–O bonds to an arylrhodium(I) species, which is initially generated by transmetallation between [RhCl(cod)]2 and arylboronic esters. In the nickel-catalyzed C–H/C–O coupling of unactivated phenol derivatives, the scope of the C-H bonds is limited to relatively acidic C–H bonds, such as those in azoles and pentafluoroarenes (Table 3). The cross-coupling of phenyl ester derivatives with non-acidic aromatic C–H bonds was made possible by using Group 9 metal catalysts. Co(acac)2/IMes can catalyze the cross-coupling of aryl carbamates with 2-phenylpyridine derivatives, in which an ortho C–H bond of a 2-phenylpyridine derivative is arylated (Entry 3).40 One limitation is the need to use stoichiometric amount of a Grignard reagent to promote the reaction. Arenes bearing an oxazoline directing group undergo directed ortho arylation with aryl carbamates in the presence of a rhodium(I) catalyst and an NHC ligand (Entry 4).41a Unlike the cobalt system (Entry 3), Grignard reagents are not required for this C–H/C–O coupling, thus allowing a range of functional groups to be compatible. Mechanistic studies revealed that the generation of a bis-NHC complex, Rh(I)(NHC)2, is essential for an efficient reaction. The rhodium-catalyzed C–O bond activation was further applied to alkynylation using propargylic alcohols (Entry 5)41b and reduction using isopropanol (Entry 6).41c The rhodium catalyst permits alcohol derivatives to be used as precursors of nucleophiles in cross-coupling, which renders rhodium catalysts distinct from nickel catalysts.

12.10.2.3.2

Aryl ethers

C(aryl)–O bonds of aryl ethers are much more inert and therefore more difficult to activate than those of the corresponding aryl ester derivatives (Table 1). Nevertheless, as early as 1979, Wenkert reported his pioneering work on the nickel-catalyzed cross-coupling of methoxyarenes with Grignard reagents (Scheme 12),42a,b although this intriguing reactivity of nickel complexes for activating ether C(aryl)–O bonds did not attract significant attention at that time.

Scheme 12 First catalytic reaction via the activation of C(aryl)–O bond of aryl ethers.

360

Synthetic Applications of C–O and C–E Bond Activation Reactions

During the past decade, significant progress has been made in the catalytic transformation of C(aryl)–O bonds of aryl ethers, most of which employ nickel-based catalysts. In contrast to the activation of aryl ester derivatives (Schemes 5 and 6), organometallic complexes that are directly related to nickel-catalyzed C(aryl)–O bond activation reactions of aryl ethers have not been reported, except for those involving pincer-type substrates,43b,c due, in part, to the facile b-hydrogen elimination of the postulated Ar–Ni–OMe species.44 The oxidative addition of the C(aryl)–O bond in non-pincer type aryl ethers was experimentally verified only with a ruthenium complex (Scheme 13).45a The possibility of oxidative addition to a Ru(II) complex was also proposed when RuH2(N2)2(PCy3)2 is used as a precursor.45b

Scheme 13 Ruthenium-mediated C(aryl)–O bond activation of aryl ether.

Computational studies indicate that several modes of C(aryl)–O bond activation are operative in the nickel-catalyzed cross-coupling of aryl methyl ethers, depending not only on the ligand being used but also on the nucleophile that is involved (Scheme 14). The classical oxidative addition through a three-centered transition state was proposed to be viable in Ni/ICy catalyzed cross-coupling with arylboronic esters (Scheme 14a).46 This oxidative addition process can be accelerated when Lewis acid additive/ reagents are used, by the coordination of a methoxy group to the Lewis acid (Scheme 14b).46 When stronger nucleophiles, such as organomagnesium, lithium or zinc reagents, are used, they can initially react with a nickel(0) catalyst to form an anionic nickelate species [i.e., R–Ni(0)−]. This nickelate complex subsequently attacks the ipso carbon of anisole with the metal derived from the nucleophile (i.e., Mg, Li, Zn or Al) being coordinated with a methoxy oxygen (a five-membered transition state, Scheme 14c).47 This mechanism is similar to concerted nucleophilic aromatic substitution reactions.48 A unique silylnickel(I)-mediated mechanism for

Scheme 14 Computed mechanisms for nickel-mediated C(aryl)–O bond activation.

Synthetic Applications of C–O and C–E Bond Activation Reactions

361

the reductive cleavage of methoxynaphthalene using a hydrosilane reagent was proposed.44 A silylnickel(I) species, generated by the comproportionation of an initially formed (silyl)Ni(II)H species, adds across naphthalene to form the dearomatized intermediate A, which collapses to a 2-naphthylnickel(I) intermediate via the concerted a-elimination of silyl methoxide (Scheme 14d). A similar mechanism was also proposed in the nickel-catalyzed silylation of methoxynaphthalene.49a In this reaction, a silicon nucleophile, which is generated by silylborane and KOtBu, initially reacts with Ni(0) to form an anionic silylnickelate species, which activates the C(aryl)–O bond of aryl ethers via the formation of an intermediate similar to A,49b while a classical three-centered oxidative addition mechanism was also proposed.49c In 2004, Dankwardt revisited the Wenkert reaction and developed modified nickel catalysts, in which alkylphosphines, such as PCy3, PiPr3, PPhCy2, and PPh2Cy, could be used as excellent ligands.50a A wide range of anisole derivatives, including those bearing an unprotected hydroxyl group, undergo cross-coupling with aryl Grignard reagents to form the corresponding biaryl derivatives. In addition to methyl ethers, ethyl, methoxymethyl, aryl and silyl ethers successfully participated in the C(aryl)–O bond cleavage. This report by Dankwardt stimulated additional studies of the nickel-catalyzed cross-coupling of aryl ethers with organometallic reagents (Table 9). Grignard reagents are the most reliable coupling partners in terms of the scope of both methoxyarene substrates Table 9

Nickel-catalyzed cross-coupling of aryl ethers with organometallic nucleophiles.

362

Synthetic Applications of C–O and C–E Bond Activation Reactions

and substituents that can be introduced. Regarding arylation reactions that use ArMgX, several ligands other than those mentioned above were reported to be effective (Entry 1).50b–g Alkylation without b-hydrogens (Entries 2 and 3)51 and alkynylation (Entry 4)52 are best performed with a nickel catalyst in conjunction with an ICy ligand. b-Hydrogen-containing alkyl Grignard reagents can be successfully cross-coupled with a range of anisole derivatives when a bidentate dcype ligand is used (Entry 5).53 In this alkylative cross-coupling, the addition of MgI2 accelerates the reaction. The nickel-catalyzed Suzuki-Miyaura cross-coupling of aryl ethers was accomplished using a Ni/PCy3 system (Entry 6).54a However, this catalyst system was limited to the cross-coupling of polyaromatic substrates such as methoxynaphthalene. This restriction was later overcome by using an Ni/ICy catalyst.54b Alkylative Suzuki-Miyaura cross-coupling was also possible with B-alkyl-9-BBN reagents using a Ni/dcype catalyst (Entry 7).54c The Lewis acidic nature of alkylboron reagents is likely to play a key role in the activation of C(aryl)–O bonds in methoxyarenes. Several other organometallic reagents, including organozinc (Entry 8),55 lithium (Entries 9 and 10),56 aluminum (Entries 11–13)12,57 and scandium (Entry 14),58 can also participate in the nickel-catalyzed cross-coupling of methoxyarenes. These cross-coupling reactions were successfully applied to the halogen-free synthesis of p-conjugated molecules52b and polymers.59a Regarding the alkoxy leaving group in these nickel-catalyzed cross-coupling, a methoxy group is the most synthetically useful in terms of availability and atom economy. However, other alkoxy groups, including longer chain alkoxy groups and a phenoxy group, can also serve as leaving groups. The ring-opening cross-coupling of dibenzofurane is also possible.59b Several nickel-catalyzed carbon–carbon bond forming reactions between aryl ethers and non-organometallic reagents have also been reported. Anisole derivatives can be cross-coupled with azoles using a nickel/carbodicarbene (CDC) catalyst (Scheme 15).60 Although the addition of a Grignard reagent as a stoichiometric base to deprotonate the C–H bond of azoles is required, the added Grignard reagent does not react with an anisole substrate.

Scheme 15 Nickel-catalyzed cross-coupling of anisole with azoles.

The reductive cross-coupling between methoxynaphthalene and bromobenzene is catalyzed by a Ni/ItBu system using metallic Mg as a stoichiometric reductant (Scheme 16).26 It was proposed that the reaction is not a simple consequence of the generation of a Grignard reagent and a subsequent Kumada-Tamao-Corriu type cross-coupling, based on the fact that PCy3, which is one of the most efficient ligands for cross-coupling reactions using Grignard reagents, is unable to promote this process.

Scheme 16 Nickel-catalyzed reductive cross-coupling of 2-methoxynaphthalene with bromobenzene.

The annulative cross-coupling of aryl ethers bearing an ortho carboxamide group with internal alkynes was reported to occur by nickel catalysis (Scheme 17).61 Unlike other C(aryl)–O bond activation reactions, an external s-donor ligand is not required, but a stoichiometric amount of LiOtBu is required. An ortho carboxamide group likely serves as a directing group, allowing for the activation of C–O bonds of phenyl ethers and carbamates under mild conditions.

Scheme 17 Nickel-catalyzed annulative coupling of 2-phenoxybenzamides with alkynes.

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 10

363

Nickel-catalyzed cross-coupling of methoxyarenes with heteroatom-based nucleophiles.

Carbon-heteroatom bond-forming cross-coupling reactions of aryl ether substrates are limited compared with those of aryl halides (Table 10). The amination of methoxyarenes was accomplished using a nickel/IPr catalyst (Entry 1).62a,b However, this amination method requires quite harsh reaction conditions (20 mol% catalyst, 5 equiv of amine, 6 equiv of NaOtBu, 120  C, 48 h) than are needed for the amination of aryl esters (see, Table 5, Entry 1). The corresponding siloxyarenes can be aminated under milder conditions (Entry 2).62b The borylation of methoxyarenes was reported to be catalyzed by a nickel/PCy3 system using a B2(nep)2 reagent (Entry 3).63 Interestingly, when the borylation of methoxyarenes is performed with a nickel/ICy catalyst using 0.8 equiv of a diboron reagent, the homocoupling of aryl ethers occurs (Scheme 18).64 The reaction presumably proceeds though the borylation of a methoxy group, followed by the Suzuki-Miyaura type cross-coupling of the resulting borylated product with the starting methoxyarene. The silylation of methoxyarenes takes place when a silyborane reagent along with KOtBu are used (Entry 4).49a The striking feature of this silylation reaction is that a difficult C(aryl)–O bond cleavage occurs in the absence of any strong s-donor ligands. An anionic silylnickel(0) ate complex was proposed to be responsible for this catalysis, but the mechanistic details of the activation of C(aryl)–O bond remains controversial.49b,c Hydrosilane can serve as a silylating reagent when siloxyarenes are used as substrates (Entry 5).65

Scheme 18 Nickel-catalyzed reductive homocoupling of aryl ethers.

The removal of alkoxy groups on an aromatic ring can be accomplished by the nickel-catalyzed reaction of aryl ethers in the presence of a suitable reducing agent (Table 11). Methods using hydrosilanes (Entries 1 and 2),36,44,66a hydrogen (Entry 3),66b and HCO2Na (Entry 4)36c have been established. When hydrosilanes are used, a unique mechanism that involves a silyl-Ni(I)-mediated C(aryl)–O bond cleavage was proposed (see Scheme 14d).49 Ti(OiPr)4 can also be used for the reductive cleavage of siloxyarenes (Entry 5).65 The C(aryl)–O bond in aryl ethers can be reductively cleaved even in the absence of an external reducing agent (Entry 6).66c The results of a labelling study revealed that the hydrogen delivered to the reduced product was primarily derived from the methoxy group of the substrate, indicating that the reaction proceeds through a b-hydrogen elimination from a nickel-alkoxide

364

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 11

Nickel-catalyzed reductive cleavage of aryl ethers.

Table 12 group.

Ruthenium-catalyzed transformation of C(aryl)–O bonds in aryl ethers bearing a directing

intermediate. The possible involvement of such a b-hydrogen elimination mechanism is also indicated in the reductive cleavage using external hydrogen source.43,66 The C(aryl)–O bond activation of aryl ethers can also be accomplished by metal catalysts other than Ni, including Ru, Cr and Rh. In 2004, Kakiuchi reported that anisoles bearing an ortho carbonyl group can be coupled with arylboronic esters in the presence of RuH2(CO)(PPh3)3 (Table 12, Entry 1).67a An ortho carbonyl moiety serves as a directing group to facilitate the oxidative addition of C–O bonds, which allows for the regioselective C–O bond cleavage of diaryl ethers or arenes bearing several methoxy groups. The intermediate complex formed by the oxidative addition of a C(aryl)–O bond to Ru(0) was isolated and characterized by X-ray

Synthetic Applications of C–O and C–E Bond Activation Reactions

365

crystallography when a substrate bearing an ortho aryloxy group was used (Scheme 13).45a A range of substituents, including aryl, alkenyl and alkyl groups, can be introduced using the corresponding organoboron reagent. Selectivity between mono/diarylation can be controlled by using the suitably modified ligand (Entries 2 and 3).67b,c Enantioselective biaryl coupling via this C(aryl)–OMe activation was also reported (Entry 4).67d RuH2(CO)(PPh3)3 can also serve as a powerful catalyst for use in directed ortho C-H bond activation reactions.68 Therefore, both ortho C–H and C–O bonds in aromatic ketones can be activated under such catalytic conditions. C–H bond activation is kinetically favored in this system, while C-O bond activation provides for a more thermodynamically stable complex.45a The tandem functionalization of C–H and C–O bonds is possible when the reaction is performed in the presence of alkenes and boronic esters (Scheme 19). The key to the chemoselectivity in this reaction is that a ruthenium-hydride intermediate can only react with alkenes, whereas boronic esters undergoes transmetallation only when a ruthenium-methoxide intermediate is produced. Theoretical studies regarding this selectivity issue in ruthenium-catalyzed directed C–H/C–O activation have also been reported.67e An amide (Entry 5)67f,g and ester (Entry 6)67h moiety can also serve as a directing group in this ruthenium-catalyzed ortho arylation of a C(aryl)–OMe bond, although their ability to promote the reaction is poorer than that for a ketone directing group. A methoxy group can be reductively removed when hydrosilane or DIBAL-His used instead of an arylboron reagent in such amide-directed reactions (Entry 7).67i These ruthenium-catalyzed C–O bond arylation reactions were successfully employed in the synthesis of polyaromatic compounds.67j–m

Scheme 19 Rhuthenium-catalyzed tandem C–H/C–O transformation.

Although the utility of organochromium(III) reagents in organic synthesis is well-recognized,69a chromium-catalyzed crosscoupling reactions remain underdeveloped,69b which is in sharp contrast to the tremendous success achieved for other first-row transition metals, such as Ni, Fe and Co, as alternatives to precious metals. It was reported that CrCl2 can be used to catalyze the Kumada-Tamao-Corriu type cross-coupling of anisole derivatives bearing a directing group (Scheme 20a).70a The optimal directing

Scheme 20 Chromium-catalyzed directed C(aryl)–O transformations of aryl ethers.

366

Synthetic Applications of C–O and C–E Bond Activation Reactions

group for this reaction is an imine moiety, which can subsequently be converted into a versatile formyl group upon hydrolysis. Both arylation and alkylation are possible using the corresponding Grignard reagents. Formal reductive cross-coupling using aryl bromides and a stoichiometric amount of metallic magnesium was also reported (Scheme 20b).70b The sequential substitution of ortho C–OMe and C–H bonds by different aryl groups was also demonstrated, in which the latter C–H arylation occurs when the reaction is carried out in the presence of a suitable oxidant (i.e., 1,2-dichloropropane) (Scheme 20c).70c Reductive cross-coupling between two inert phenol derivatives was accomplished by chromium catalysis (Scheme 20d).70d Anisoles bearing an imine directing group can be cross-coupled with aryl pivalates by a CrCl2/dtbpy catalyst using Mg as a stoichiometric reductant. There is one rhodium-catalyzed reaction that involves the C(aryl)–O bond of aryl ethers (Scheme 21a).71a 2-Aryloxybenzaldehydes can be converted into 2-hydroxybenzophenone derivatives via the cleavage of C(aryl)–O and aldehydic C–H bonds in the presence of a rhodium(I) catalyst and (tBuO)2. An iridium-catalyzed reductive cleavage of aryl ethers bearing a pyridine ring as an ortho directing group was reported (Scheme 21b).71b In this reaction, the addition of iPrOH significantly increased the yield of the reduction product, indicating that the added alcohol serves as the major sources of hydride.

Scheme 21 Rh and Ir-catalyzed C(aryl)–O bond cleavage reaction of aryl ethers.

12.10.2.3.3

Arenols

Although there have been significant advances in the cross-coupling of unactivated phenol derivatives, the ideal substrates are non-protected phenols themselves, in terms of availability and atom economy. However, a phenolic C(aryl)–O bond is among the most difficult to cleave, and the presence of a protic OH group is frequently detrimental to the efficiency of transition metal catalysis,9b both of which have hampered the direct use of phenols in cross-coupling reactions. Therefore, there are only sporadic reports on the direct catalytic transformation of phenol derivatives without them being converted into activated forms, such as triflates.72 Shi reported on the cross-coupling of naphthol derivatives with Grignard reagents (Table 13, Entry 1).73a In this reaction, magnesium naphthoate is initially generated, which then undergoes C(aryl)–O bond cleavage by a nickel complex. Although both

Table 13

Nickel-catalyzed transfromation of C(aryl)–O bonds of naphthols.

Synthetic Applications of C–O and C–E Bond Activation Reactions

367

arylation (Entry 1)73a and methylation (Entry 2)73b are possible for naphthols using a suitable ligand, phenols are unreactive under these conditions. A method for coupling naphthols with arylboroxine reagents was developed using a Ni/PCy3 catalyst and BEt3 as a stoichiometric promoter (Entry 3).73c Although the role of BEt3 is not currently clear, it can activate the borate intermediate as a Lewis acid toward C(aryl)–O bond activation. One isolated example, in which naphthol undergoes ipso borylation by a nickel-catalyzed reaction using a diboron reagent, was reported (Entry 4).73d Interestingly, de-hydroxylation becomes a major pathway rather than borylation, when the ligand is switched from I (1-Ad) to PCy3 (Entry 5).73e As discussed in Entry 1 of Table 4 and Scheme 16, the Ni/ItBu system can catalyze the reductive cross-coupling of aryl esters and ethers with aryl halides in the presence of metallic magnesium. This method was successfully applied to reactions of naphthols (Entry 6).26 The nickel-catalyzed hydrogenolysis of simple phenols using HSi(OMe)2Me has been reported (Scheme 22).73f This reaction proceeds through the silylation of phenol, followed by the reductive cleavage of the resulting silyl ether. A methoxy group is tolerated under these conditions, indicating that an OSi(OMe)2Me group is a better leaving group than a methoxy group under these conditions.

Scheme 22 Nickel-catalyzed reductive dehydroxylation of phenols with hydrosilane.

The iridium-catalyzed hydrogenolysis of C(aryl)-O bonds in phenols was reported (Scheme 23).73g Unlike nickel-catalyzed phenol activation, which requires O-activating reagents such as boron or silicon reagents (Table 13 and Scheme 22), no such additives are required in this reaction. Iridium complexes containing a hydroxycyclopentadienyl ligand specifically shows catalytic activity, which can be rationalized by the involvement of a metal-ligand cooperative hydrogen transfer mechanism. An OH group on the cyclopentadienyl ligand activates phenols by hydrogen bonding, which facilitates ipso substitution by the hydride on the iridium center.

Scheme 23 Iridium-catalyzed hydrogenolysis of phenols.

12.10.2.4 C(alkenyl)–O bond activation In 1979, Wenkert reported on the cross-coupling of alkenyl methyl ethers with Grignard reagents via the activation of C(alkenyl)–OMe bonds by using NiCl2(PPh3)2 as a catalyst precursor (Scheme 24).42a This reaction is recognized as the first catalytic transformation of inert C(sp2)–O bonds. Most of the nickel-catalyzed transformation of C(aryl)–O bonds described in the sections of C(aryl)–O bond activation can also be applied to the corresponding alkenyl esters74 and ethers.75 The nickel-catalyzed cross-coupling of C(alkenyl)–O bonds has been applied to the ring-opening coupling of furane derivatives.42,53,75 Iron-catalyzed cross-coupling of aryl ester derivatives (cf. Table 7) can also be effective for alkenyl ester derivatives.38,76 Cobalt catalysts can be used for the activation of C(alkenyl)–O bonds in alkenyl ester derivatives, allowing for directed C–H alkenylation (cf. Table 8, Entry 3)76c and cross-coupling with organozinc reagents.76d Chromium-catalyzed Kumada-Tamao-Corriu type cross-coupling of alkenyl esters has also been reported.76e Although palladium catalysts have not been used to activate inert C(aryl)–O bonds, the palladiumcatalyzed cross-coupling of alkenyl ester derivatives with Grignard76f and organoboron reagents76g has been developed.

368

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 24 Wenkert’s pioneering work on catalytic cross-coupling of C(alkenyl)–O bonds.

In these nickel and iron-catalyzed cross-coupling reactions of enol derivatives, a C(alkenyl)–O bond is activated by an oxidative addition mechanism (Scheme 25a). In this mechanistic regime, all of the elementary steps basically proceed with the configuration of the enol geometry being retained. Another mechanistic option appears to be involved in the cross-coupling of enol derivatives (Scheme 25b). A nucleophile initially attacks the metal catalyst to generate an anionic ate complex (or a neutral Nu–M species is generated when an MX type of catalyst precursor is used), which subsequently adds across the enol derivative to form an alkylmetal intermediate bearing an OR group at the b-position. The subsequent b-oxygen elimination provides a cross-coupling product. Because both the addition to enol derivatives and b-oxygen elimination normally occur in a syn fashion, the alkene configuration of the enol derivatives becomes inverted during the cross-coupling reaction. Therefore, in principle, the two mechanistic pathways shown in Scheme 25 can be discriminated by investigating the stereospecificity of the reaction using substituted enol derivatives. However, in reality, the determination of the stereospecificity of the reaction is often hampered by the low reactivity of the substituted enol derivatives as well as post isomerization of the alkene product under the catalytic conditions used. For example, in the rhodium77a,b and iron-catalyzed77c cross-coupling of vinyl ethers with ArMgX, an addition/elimination mechanism (i.e., Scheme 25b) is proposed. However, the net retention of the stereochemistry is observed for the reaction of a substituted enol ether substrate.

Scheme 25 Mechanism for C(alkenyl)–O bond cleavage in cross-coupling of enol derivatives with nucleophiles.

In the rhodium-catalyzed cross-coupling of vinyl acetates with ArB(OH)2, ipso-substitution78a,b and cine-substitution78c can be controlled by the choice of the ligand, which is thought to determine the mechanism involved (i.e., oxidative addition or addition/ elimination) (Scheme 26).

Scheme 26 Rh-catalyzed cross-coupling of alkenyl acetates with arylboronic acids.

The use of enol esters in ruthenium-catalyzed directed C–H alkenylation reactions was reported (Scheme 27).79a,b In this reaction, the C–O bond is proposed to be cleaved by b-oxygen elimination. A similar reaction is also catalyzed by a Rh(III) catalyst.79c

Synthetic Applications of C–O and C–E Bond Activation Reactions

369

Scheme 27 Ru-catalyzed cross-coupling of a C–H bond with alkenyl acetate.

A b-oxygen elimination mechanism is also involved in the nickel-catalyzed cleavage of a C(alkenyl)–O bond (Scheme 28).80 The nickel-catalyzed cycloisomerization of yne-enol derivatives was reported to result in the formation of benzofuran derivatives via the formal insertion of an alkyne moiety into a C(alkenyl)–O bond of an enol ether. Theoretical studies suggest that the reaction proceeds through an oxidative cyclization/b-oxygen elimination/reductive elimination pathway.

Scheme 28 Ru-catalyzed cross-coupling of a C–H bond with alkenyl acetate.

12.10.2.5 C(acyl)–O bond activation Although several catalytic C(acyl)–O bond cleavage reactions of acid anhydrides,81 activated esters (i.e., p-nitrophneyl esters),82 and esters having a directing group83 have been known for years, this section focuses on catalytic C(acyl)–O bond transformations of simple unactivated ester substrates. A seminal work by Yamamoto in 1976 demonstrated that phenyl propionate reacts with Ni(cod)(PPh3)2 to generate phenol, ethylene and Ni(CO)(PPh3)3 (Scheme 29).84a,b The formation of these compounds can be rationalized by the sequential oxidative addition of a C(acyl)–O bond to Ni(0), decarbonylation, b-hydrogen elimination, and reductive elimination.

Scheme 29 An early study of the Ni-mediated activation of a C(acyl)–O bond of a simple ester.

370

Synthetic Applications of C–O and C–E Bond Activation Reactions

The oxidative addition of a C(acyl)–O bond of aryl esters generates an acylmetal species, which can undergo decarbonylation to form an arylmetal complex (Scheme 30). Catalytic reactions triggered by the activation of a C(acyl)–O bond of an ester are classified into two major types.85 One is acylation via the formation of an acylmetal species, and the other is arylation via the formation of an arylmetal complex. In both cases, most of the reactions involve the use of relatively reactive phenyl esters (ArCO2Ph), and the activation of the corresponding methyl esters (ArCO2Me) is a more challenging issue. In the case of ArCO2Ph, the decarbonylation of the acylmetal complex proceeds with more difficulty than the oxidative addition a C(acyl)–OPh bond, and therefore decarbonylative arylation via arylmetal species generally requires harsher conditions (i.e., >150  C). Regarding metal catalysts, most of the reported reactions are mediated by both nickel and palladium complexes. This is in sharp contrast to the activation of C(aryl)–O bonds, in which palladium is unreactive.

Scheme 30 C(acyl)–O bond activation can be used for catalytic acylation and arylation.

Catalytic decarbonylative arylation of esters was first reported by Itami, who developed the nickel-catalyzed decarbonylative cross-coupling of heteroaryl esters with azoles (Scheme 31).86a,b In this reaction, a phenoxy carbonyl moiety serves as a leaving group.

Scheme 31 Nickel-catalyzed decarbonylative cross-coupling of phenyl esters with azoles.

Since this report, a number of nickel-catalyzed decarbonylative cross-coupling reactions of aryl esters have appeared (Tables 14 and 15). The Suzuki–Miyaura type reaction using phenyl esters can be catalyzed by a nickel/monophosphine system for reactions with aromatic boron reagents (Table 14, Entries 1 and 2)87a,b and by a nickel/bisphosphine system in the case of reactions with alkylboron reagents (Entry 4).87c,d Palladium-catalyzed methods were also reported for decarbonylative Suzuki-Miyaura reactions of phenyl esters, in which dcype serves as an effective ligand (Entries 3 and 5).87e,f An alkylation method using organozinc reagents was also reported (Entry 6).11b Organoaluminum reagents can be used in the nickel-catalyzed decarbonylative cross-coupling of phenyl and methyl esters (Entry 7).87g Nickel/dcype can catalyze the decarbonylative cyanation of phenyl esters using Zn(CN)2 (Entry 8).87h Both nickel (Entry 9)86b and palladium (Entry 10)88a can be used for the decarbonyaltive cross-coupling of phenyl esters with azole C–H bonds. Non-acidic C–H bonds can also be cross-coupled with phenyl esters via decarbonylation by palladium catalysis under an intramolecular setting (Entry 11).88b C–H bonds a to a carbonyl group (Entry 12)88c and those of terminal alkynes (Entry 13)88d can also participate in palladium-catalyzed decarbonylative cross-coupling with phenyl esters. Although the catalytic systems used in the reactions shown in Table 14 are similar to those used for the cross-coupling of aryl esters (Table 2), products that are produced by C(aryl)–O bond cleavage are not formed. This is presumably because C(acyl)–O bond cleavage is intrinsically preferred over the cleavage of C(aryl)–O bonds, particularly in the case of phenyl esters, unless steric bias is embedded in the substrates (i.e., pivalate esters).3,9 Carbon–heteroatom bond formation via the catalytic decarbonylative coupling of aryl esters was also reported. A nickelcatalyzed decarbonylative amination of phenyl esters with benzophenone imine provides primary anilines upon hydrolysis (Table 15, Entry 1).89a Substituted amino groups can be successfully introduced into phenyl esters using silylamines, the use of which allow the undesired direct amidation to be avoided (Entry 2).89b Decarbonylative C–O bond formation is also possible by the nickel-catalyzed reaction of aryl esters derived from azine carboxylic acids (Entry 3).89c In this reaction, C–O bond formation occurred intramolecularly by the decarbonylation of these esters without the need for adding an external alkoxide. Decarbonylative cross-coupling with thiols is also possible (Entry 4).89d Other heteroatoms, including phosphorus (Entry 5),89e boron (Entry 6),89f,g silicon (Entry 7),89g,h and stannane (Entry 8)89i can also be introduced to aryl esters by nickel-catalyzed decarboxylative crosscoupling. Unlike other reactions such as those shown in Tables 14 and 15, the stannylation can proceed with more challenging alkyl esters. The catalytic removal of a phenyl ester moiety is possible by decarbonylative reduction using a hydrosilane reagent (Entry 9).89j

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 14

Nickel-catalyzed decarbonylative cross-coupling of aromatic esters: C–C bond forming reactions.

371

372

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 15

Nickel-catalyzed decarbonylative cross-coupling of aromatic esters: C–heteroatom and C–H bond forming reactions.

Catalytic C(acyl)–O bond activation reactions that do not involve decarbonylation, i.e., catalytic acylation, have also been reported. Esters, especially phenyl esters, can undergo acyl substitution reactions with nucleophiles in the absence of a catalyst. However, the use of a catalyst allows for milder reactions and/or unique chemoselectivity. Catalytic acylation via the activation of a C(acyl)–O bond in aryl esters are basically limited to amidation or Suzuki-Miyaura type cross-coupling reactions (Table 16). Relatively reactive phenyl esters can be converted into amides by palladium catalysis under mild conditions (Entry 1).90a The amidation of less reactive methyl esters with aniline derivatives was catalyzed by a nickel/SIPr catalyst (Entry 2).90b This endergonic amidation process was made thermodynamically feasible by adding a stoichiometric amount of Al(OtBu)3, which stabilizes the amide product by complexation. This amidation was later accomplished without the need to use of a stoichiometric amount of a Lewis acid additive by nickel (Entry 3)90c,d and palladium (Entry 4)90e,f catalysts at elevated temperatures. Related amidation reactions using nitroarenes as an amine source are also possible with nickel (Entry 5)90g and chromium (Entry 6)90h catalysts in the presence of stoichiometric metallic reductant. The carbonyl-retentive Suzuki-Miuaura type cross-coupling of esters is limited to phenyl esters. Several palladium complexes can be used for cross-coupling with arylboronic acids (Entry 7).90,91 Alkylation with alkylboron reagents were achieved by both nickel (Entry 8)87c and palladium (Entry 9)87f catalysts. In both systems, it is possible to control whether acylative or decarbonylative cross-coupling occurs by the choice of an appropriate ligand (see Entries 4 and 5, Table 14). The acylated products can be further reduced when the catalytic reactions of esters are conducted under reducing

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 16

Nickel-catalyzed CO-retentive cross-coupling of esters.

373

374

Synthetic Applications of C–O and C–E Bond Activation Reactions

conditions. Ni/ICy-catalyzed reactions using hydrosilane can convert methyl esters to methylarenes (Entry 10).92 The palladium-catalyzed reaction of phenyl esters with hydrophosphine oxide in the presence of HCO2Na led to the formation of benzylic phosphine derivatives (Entry 11).93 In the reactions shown in Tables 14–16, esters can serve as either arylating or acylating reagents via C(acyl)–O bond cleavage. Phenyl esters can also function as a phonoxycarbonyl donor, and aryl halides can be phenoxycarbonylated in the presence of a Ni/ dcypt catalyst (Scheme 32).94a

Scheme 32 Nickel-catalyzed ester transfer reaction.

Transposition of an ester group to form a more thermodynamically stable isomer is also possible by a Pd/dcypt catalyst (Scheme 33).94b

Scheme 33 Palladium-catalyzed transposition of an ester group.

The acylmetal species, which is generated by the oxidative addition of a C(acyl)–O bond of an ester, can add across unsaturated bonds, and this process is used in catalytic cyclization reactions (Scheme 34). The nickel/PCy3-catalyzed reaction of cyclic esters derived from salicylic acids with alkynes affords chromone derivatives (Scheme 34a).95a This reaction involves the oxidative

Scheme 34 Nickel-catalyzed cyclization triggered by the oxidative addition of a C(acyl)–O bond in aryl esters.

Synthetic Applications of C–O and C–E Bond Activation Reactions

375

addition of a C(acyl)–O bond to form a seven-membered acylnickel intermediate, which undergoes ring contraction by loss of the ketone via b-oxygen elimination to give a five-membered nickelacycle. The resulting nickelacycle subsequently adds to an alkyne, thus affording a chromone product. The acylnickel species can also add across a pendant alkene to provide alkylnickel(OMe), which can be intercepted either by transmetallation with an arylboronic acid (Scheme 34b)95b or by reduction with a secondary benzylic alcohol (Scheme 34c).95b When an intramolecular alkyne is present in the substrate, a C(acyl)–O bond of esters can add to an alkyne to form benzofuran derivatives (Scheme 34d).95c In addition to the C(acyl)–O bond activation mechanism, a pathway initiated by oxidative cyclization is also considered to be possible (see, Scheme 28). a,b-Unsaturated phenyl esters are used in nickel-catalyzed reductive cycloaddition reactions with alkynes to form cyclopentenone derivatives via the loss of a OPh group (Scheme 35a, b)96a,b In these reactions, a five-membered nickelacycle, which is generated by the oxidative cyclization of an a,b-unsaturated phenyl ester and an alkyne, undergoes b-oxygen elimination to afford a ketene intermediate. The resulting alkenylnickel then attacks the carbonyl carbon of the ketene moiety to form an oxa-p-allyl complex (or nickel enolate), which then provides a cyclopentenone product upon protonation. A catalytic enantioselective variant using a chiral NHC ligand was also reported.96c This type of reductive cycloaddition was further applied to the three component coupling of a,b-unsaturated phenyl esters, alkynes and aldehydes (Scheme 35c).96d

Scheme 35 Nickel-catalyzed reductive cycloaddition of a,b-unsaturated esters.

C(acyl)–O bond cleavage reactions of esters via intramolecular acyl substitution by catalytically generated organometallic species were also reported. For example, an alkenyrhodium(I) species, which is generated by the addition of an arylrhodium(I) complex to an alkyne, can attack a pendant ester group to form a five or six-membered ring (Scheme 36).97a,b This type of cascade annulation involving the cleavage of a C(acyl)–O bond in esters is catalyzed not only by Rh(I),97c–g but also by Pd(II)97h and Ni(II).97i

Scheme 36 Catalytic C(acyl)–O bond cleavage via intramolecular acyl substitution by an organorhodium intermediate.

376

Synthetic Applications of C–O and C–E Bond Activation Reactions

12.10.2.6 C(sp3)–O bond activation The vast majority of catalytic C(sp3)–O bond activation reactions of esters and ethers are limited to allylic and benzylic substrates, which undergo a relatively facile oxidative addition of the C(sp3)–O bond driven by the formation of stable p-allyl or p-benzyl metal complexes.98 Most of the nickel-catalyzed reactions of aryl esters, carbamates and ethers that are listed in the section of C(aryl)–O bond activation are also applicable to the corresponding benzylic substrates,99 which are not discussed in this section. As an exception, the nickel-catalyzed deoxygenation of dibenzyl ethers is especially noteworthy, since no related transformation using biaryl ethers exists (Scheme 37).100 Strained C(sp3)–O bonds, including those of oxiranes and oxetanes, and C(sp3)–O bonds of acetals, which can be activated by a Lewis acid, are not discussed in this section. The focus of this section is the catalytic reactions involving the activation of non-allylic, non-benzylic, unactivated C(sp3)–O bonds.

Scheme 37 Nickel-catalyzed deoxygenation of dibenzyl ethers.

Some silymetal complexes (M–SiR3) can function as a metal anion (M–) and a Lewis acidic silylium ion (SiR+3), and the concerted action of these species allows for the cleavage of unactivated C(sp3)–O bonds. Murai reported on a series of Co-catalyzed reactions with ethers and esters with hydrosilanes and CO via the cleavage of a C(sp3)–O bond (Scheme 38).101a For example, the Co2(CO)8-catalyzed reaction of THF with hydrosilane and CO provides a ring-opened 5-siloxypentanal (Scheme 38a).101b,c The cleavage of a C(sp3)–O bond occurs by nucleophilic attack of Co(CO)–4 to a silylium-bound THF to generate an alkylcobalt intermediate, which then leads to the formation of an aldehyde product via CO insertion and reductive cleavage of the resulting acylcobalt species by hydrosilane. The aldehyde product can react further with hydrosilane and CO to form different products depending on the reaction conditions being used.101d–f This cobalt-based system can also be applied to the activation of C(sp3)–O bonds in aliphatic esters. The Co-catalyzed reaction of cyclohexyl acetate with hydrosilane and CO affords a silyl enol ether product with the incorporation of CO and hydrosilane (Scheme 38b).101g–i Lactones can also be converted to the corresponding ring-opened enol ether products in a similar manner via the cleavage of a C(sp3)–O bond, rather than a C(acyl)–O bond.

Scheme 38 Catalytic activation of unactivated C(sp3)–O bonds by Co2(CO)8/hydrosilane/CO system.

Silyiridium species can also cleave a C(sp3)–O bond of an alkyl ether via a silylium cation-mediated mechanism (Scheme 39). A cationic iridium(III) complex ligated with a pincer ligand (i.e., [Ir-1]) can catalyze the reductive cleavage of dialkyl ethers in the presence of hydrosilane as a reducing agent (Scheme 39a).102a This iridium/hydrosilane system was used for the reductive deoxygenation of glucose to hexanes.102b A cationic iridium(III) complex with PPh3 as ligands can also cleave alkyl ethers, and this catalyst is selective toward a Me–O bond compared with other C(alkyl)–O bonds (Scheme 39b).102c In the Iridium/PR3 system, the catalyst-controlled regioselective cleavage of C(alkyl)–O bonds in asymmetric dialkyl ether is possible (Scheme 39c).102d Another strategy for achieving a catalytic reaction that involves the cleavage of unactivated C(sp3)–O bonds involves b-oxygen elimination (Scheme 40). Alkyl ethers bearing a pyridine ring at the b-position can be arylated using an arylboron reagent in the presence of a ruthenium catalyst (Scheme 40a).103a This reaction proceeds through the formation of vinylpyridine via the loss of

Scheme 39 Catalytic activation of unactivated C(sp3)–O bonds in ethers by iridium/hydrosilane system.

Scheme 40 Catalytic cleavage of unactivated C(sp3)–O bonds via b-oxygen elimination.

378

Synthetic Applications of C–O and C–E Bond Activation Reactions

MeOH, followed by the ruthenium-catalyzed conjugate addition of an arylboron compound. The iron-catalyzed cross-coupling of homobenzylic ethers with alkyl Grignard reagents was also reported, in which a similar b-elimination mechanism with an intermediacy of a styrene derivative was proposed to be involved (Scheme 40b).103b Non-homobenzylic C(sp3)–O bonds can be cleaved by an iridium-pincer complex, possibly via the activation of a b-C–H bond, followed by b-oxygen elimination (Scheme 40c).103c The chelation-assisted activation of a C(sp3)–H bond by a Pd(II) complex104 can be combined with a subsequent b-oxygen elimination to form an Pd(II)-coordinated alkene, which is susceptible to attack by an exogenous nucleophile (Scheme 40d).103d,e

12.10.3 C–S bond activation 12.10.3.1 Overview Transition metal catalyzed C–S bond activation has been a subject of great attention over the decades. This section focuses on the catalytic activation of C–S bonds in organosulfur compounds including thioethers, thioesters, sulfoxides, and sulfones. Reactions that employ activated organosulfur compounds, such as sulfonyl chlorides, sulfonium or sulfoxonium salts, alkenyl thioethers, allyl thioethers, sulfonamides, sulfonyl chloride, triflyls, and thietanes, as starting materials are not covered. Reviews on stoichiometric105a and catalytic transformations of sulfonium salts105b are available. More comprehensive reviews on C–S bond activation have also been published.105c–g Most of the catalytic transformations that proceed via C–S bond activation involve the use of nickel, palladium, platinum, and rhodium complexes. The chapter is classified by the hybridization states of the carbon attached to sulfur (i.e., C(sp)–S, C(aryl)–S, C(acyl)–S and C(sp3)–S bonds).

12.10.3.2 C(sp)–S bond activation Although oxidative addition complexes of alkynyl thioether to ruthenium and the corresponding sulfoxide to a cobalt center have been isolated (Scheme 41),106b only a limited number of examples of catalytic alkynyl C(sp)–S bond activation reactions have been reported to date (Table 17). The carbothiolation of terminal alkynes via the C–S bond cleavage of alkynyl thioethers was achieved by palladium catalysis to afford the corresponding enyne thioethers (Entry 1).107 The sulfur-directed carbothiolation of terminal alkynes and allenes using alkynyl thiophenyl ethers bearing an ortho SPh group is catalyzed by a cationic rhodium complex (Entry 2).108 In this reaction, an intermediate complex generated by oxidative addition of the alkynyl thioether was isolated and characterized by X-ray crystallography.

Scheme 41 Oxidative addition of a C(sp)–S bond to metal complexes.

The palladium-catalyzed transformation of thiocyanates involving the activation of S–CN bonds has also been developed. Thiocyanates can serve as a cyanide source via the activation of the S–CN bond in the palladium-catalyzed oxidative cyanation of boronic acids in the presence of a stoichiometric amount of copper(I) thiophene-2-caboxylate (CuTC) (Scheme 42a).109 Palladium-catalyzed addition of thiocyanates across benzyne via S–CN bond activation was reported, leading to the formation of 1,2-thiobenzonitriles (Scheme 42b).110

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 17

379

Palladium or rhodium-catalyzed alkynylthiolation via C–S bond cleavage of thioalkynes.

Scheme 42 Palladium-catalyzed coupling involving the activation of S–CN bonds.

12.10.3.3 C(sp2)–S bond activation The oxidative addition of C(aryl)–S bonds to nickel and platinum has been extensively studied.105,111 The oxidative addition of a C–S bond in a diphenyl thioether to Ni(cod)2 was reported to proceed at room temperature, in which an isolable Ni(II) complex was generated by the addition of PEt3 (Scheme 43a).111a The use of a bidentate ligand dmpe enhanced the reaction rate. Nickel complexes ligated with an NHC ligand were also able to promote the oxidative addition of a C(aryl)–S bond in thioethers.111b The oxidative addition of diphenyl thioether to a platinum complex requires a higher reaction temperature than that required for Ni (Scheme 43b).111c The oxidative addition of aryl alkyl thioethers proceeds exclusively at a C(aryl)–S bond, rather than at a C(alkyl)–S bond.

Scheme 43 Representative examples of oxidative addition of aryl thioethers.

380

Synthetic Applications of C–O and C–E Bond Activation Reactions

When considering catalytic cross-coupling via C–S bond activation, the following difficulties need to be addressed: (1) Oxidative addition of the robust C–S bonds (2) Transmetallation via the cleavage of strong M–S bonds (3) Catalyst poisoning by anionic sulfur leaving groups that are generated in situ All of these difficulties were addressed, at least partially, by the use of highly reactive organometallic reagents, i.e., RMgX. From the late 1970s to early 1980s, pioneering works on the nickel-catalyzed Kumada–Tamao–Corriu type coupling of aryl thioethers via C(sp2)–S bond activation were independently reported by Wenkert, Takei, and Julia (Scheme 44).112,113 However, further developments on this type of reaction were not reported until the late 2000s, except for reactions in which specialized substrates, such as heteroarenes or substrates with directing groups were used.114

Scheme 44 Nickel-catalyzed Kumada–Tamao–Corriu type cross-coupling via C–S bond cleavage of aryl thioethers.

Following the pioneering works described above, a series of Kumada–Tamao–Corriu type coupling reactions were developed using aryl, alkyl and alkynyl Grignard reagents (Table 18, Entries 1–5).115–118 The use if Grignard reagents in the nickel-catalyzed dehydrogenative cross-coupling of alkyl aryl sulfides was also reported. In this reaction, the initial oxidative addition occurs at a C(aryl)–S bond, but a C–C bond is eventually formed via the formal cleavage of a C(alkyl)–S bond accompanied by dehydrogenation (Scheme 45).119 C–S bonds in thiophene derivatives120 or alkenyl thioethers121 could also be cross-coupled with Grignard reagents. Although the high reactivity of Grignard reagents enabled the smooth transformation of C–S bonds, the use of less reactive nucleophiles is desirable when applied to more elaborate functionalized substrates. To this end, Liebeskind reported on the development of Negishi-type cross-coupling of heteroaryl thioethers with organozinc reagents (Scheme 46a).122a The key to the success of this reaction is the use of a chelating leaving group, which facilitates the difficult oxidative addition and transmetallation processes by the coordination of the sulfur group to a Lewis acidic Zn(II) center. A series of directed Negishi type couplings were subsequently developed.122b–j The application to the cross-coupling of unactivated aryl thioethers bearing no directing group with organozinc reagents was achieved by the use of a Pd/NHC catalyst (Scheme 46b).123a,b Aryl sulfoxides could serve as a coupling partner for the cross-coupling with organozinc reagents by a nickel/NHC catalyzed method (Scheme 46c).123c Table 18

Transition metal-catalyzed cross-coupling of aryl thioethers with Grignard reagents.

Synthetic Applications of C–O and C–E Bond Activation Reactions

381

Scheme 45 Nickel-catalyzed alkenylative cross coupling reaction of aryl ether.

Scheme 46 Nickel-catalyzed Negishi-type cross-coupling of aryl thioethers.

The use of organoboron nucleophiles would be the most desirable from the viewpoint of functional group compatibility. However, such Suzuki–Miyaura type cross-coupling reactions of aryl thioethers are limited to heteroaryl substrates (Table 19) or substrates bearing a directing group (Table 20). The first example of the palladium-catalyzed Suzuki–Miyaura coupling of heteroaryl thioethers was accomplished with the aid of tris(2-furyl)phosphine (TFP) and a stoichiometric amount of copper(I) thiophene2-carboxylate (CuTC) (Table 19, Entry 1).124a It was proposed that the thiophilic Cu moiety polarizes the Pd–S bond formed by oxidative addition and the carboxylate moiety in CuTC nucleophilically activates boronic acid, allowing for a smooth transmetalation. A series of Suzuki–Miyaura type coupling reactions of heteroaryl thioethers and boronic acids was subsequently reported (Entry 2–4).124–127 The selective coupling of a thioether over a heteroaryl bromide moiety was achieved in the presence of CuTC.124b Replacing CuTC with a Ag2O mediator was reported to allow for efficient Suzuki–Miyaura type cross-coupling of tetrazine thioethers, the products of which serve as tools for chemical biology research (Entry 4).127 The directed group-assisted cross-coupling of aryl thioethers with boronic acids are summarized in Table 20. The rhodium-catalyzed directed cross-coupling of aryl thioethers with arylboron reagents was achieved with the aid of an acetyl directing

382

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 19

Palladium-catalyzed Suzuki–Miyaura coupling of heteroaryl thioethers.

Table 20

Transition metal-catalyzed directing group-assisted Suzuki–Miyaura coupling of aryl thioethers.

Synthetic Applications of C–O and C–E Bond Activation Reactions

383

group (Entries 1 and 2).128a,b It was proposed that the oxidative addition step was accelerated by the presence of a directing group. An ortho nitro group can also serve as a directing group for the palladium-catalyzed Suzuki-Miyaura type cross-coupling of thioethers with alkenylboronic acids (Entry 3).129 Migita–Kosugi–Stille type cross-coupling reactions of heteroaryl thioethers with aryl, heteroaryl, and alkenyl stannanes proceeds under palladium-catalyzed, copper(I)-mediated conditions (Scheme 47).124,130 In this type of reaction, copper(I) 3-methylsalicylate (CuMeSaI) was used as a copper(I) salt rather than CuTC.

Scheme 47 Palladium-catalyzed directed Migita–Kosugi–Stille coupling of heteroaryls.

The transition metal-catalyzed cross-coupling of aryl thioethers could be applied to the formation of carbon–heteroatom bonds (Table 21). The Buchwald–Hartwig type amination of aryl thioethers is possible when a Pd/NHC catalyst is used (Entry 1).131 Table 21

Transition metal-catalyzed cross-coupling of aryl thioethers with heteroatom-based nucleophiles.

384

Synthetic Applications of C–O and C–E Bond Activation Reactions

Aniline and alkylamine derivatives are applicable as a nitrogen source. Amination of aryl thioethers with secondary amines was achieved by nickel catalysis (Entry 2).132 The Pd/IPr catalytic system was successfully applied to the borylation of aryl thioethers using B2pin2 in the presence of an excess amount of LiHMDS (Entry 3).133a A similar Pd/IPr catalyst can borylate diaryl sulfoxides, in which both of the aryl groups are borylated (Scheme 48).133b A rhodium(I) complex in conjunction with PCy3 can be used to catalyze the borylation of aryl thioethers under base-free conditions (Entry 4).134 The introduction of a phosphorous-based substituent via the C–S bond cleavage of aryl sulfones and sulfoxides was developed with diaryl, dialkyl, or dialkoxyphosphine oxides (Entry 5).135 The use of thiols as a nucleophile in the Pd-catalyzed cross-coupling of aryl methyl thioethers or thiols in the presence of LiHMDS results in a C–S bond metathesis reaction (Entries 6 and 7).136

Scheme 48 Palladium-catalyzed dual borylation of diaryl sulfoxides.

Palladium-catalyzed intermolecular C–S/C–H coupling was also reported (Table 22). The C–H arylation reaction of azoles using aryl thioethers as an arylating reagent is catalyzed by a Pd/dcype system (Entry 1).137 Cross-coupling of aryl thioethers with a C–H bond in fluoroarenes was also reported via the use of a Pd catalyst and a suitable base (i.e., TMPZnCl
LiCl) (Entry 2).123b Pd/SIPr system could serve as a catalyst for a-arylation of ketimines via C–S/C–H bond cleavage (Entry 3).138 The Sonogashira-type coupling of aryl sulfoxides with terminal alkynes was also achieved by the Pd/SIPr catalytic system (Entry 4).139 C(aryl)–S bond-cleaving Sonogashira coupling was also reported for heteroaryl thioethers bearing OMe group at the ortho-position. An intramolecular C–S/ C–H coupling bond was also reported to proceed by Pd(II) catalysis (Scheme 49).140a This reaction is initiated by cyclopalladation, followed by reductive elimination to generate a sulfonium salt, which then undergoes C–S bond cleavage by the oxidative addition to palladium. A related intermolecular reductive coupling between diphenyl thioethers bearing an ortho-bromo group and an alkyne to afford benzothiophene derivatives was reported (Scheme 50).140b This reaction is also applicable to substrates bearing a SMe group, although a S–Me bond of the corresponding sulfonium intermediate is cleaved via an SN2 reaction by a base, not by a palladium catalyst.

Table 22

Transition metal-catalyzed cross-coupling of aryl thioethers with C–H bonds.

Synthetic Applications of C–O and C–E Bond Activation Reactions

385

Scheme 49 Palladium-catalyzed dibenzothiophene synthesis via C–S/C–H bond cleavage.

Scheme 50 Palladium-catalyzed synthesis of 2,3-disubstituted benzothiophenes via the annulation of aryl sulfides with alkynes.

Transition metal catalyzed insertion reactions into C(aryl)–S bonds have also been developed,141 although they are less common than cross-coupling type reactions. The transition metal-catalyzed insertion of carbon monoxide (CO) into a C–S bond of a thioether was reported to proceed by cobalt catalysis under somewhat harsh conditions (1000 atm of CO at 300  C, Scheme 51a).142 As a related work, the Co2(CO)8-catalyzed alkoxycarbonylation of thiophenols was also reported.143 The insertion of an isocyanide group into the C–S bond of heteroaryl thioethers was achieved by Pd(PPh3)4/dippf catalytic system to give thioester products via thioimidate intermediates.(Scheme 51b).144

386

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 51 Catalytic insertion of CO or isocyanide into a C(aryl)–S bond of aryl thioethers.

The insertion of alkynes into a C(aryl)–S bond of a thioether was also reported. Carbothiolation of terminal alkyne via C–S bond cleavage of a heteroaryl thioether was achieved by palladium catalysis to afford the corresponding alkenyl thioethers with complete regio- and stereoselectivities (Scheme 52a).145 The rhodium-catalyzed directed carbothiolation of terminal alkynes was achieved using aryl thioethers bearing an ortho ketone group (Scheme 52b).146 Insertion of alkynes into a C(alkenyl)–S bond of benzothiophenes is catalyzed by nickel, resulting in ring expansion of the thiophene skeleton to form thermally metastable benzothiepines (Scheme 52c).147

Scheme 52 Transition metal-catalyzed carbothiolations.

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 23

387

Transition metal-catalyzed desulfonative fragment coupling of sulfones.

Another class of transition metal-catalyzed C(aryl)–S bond cleavage reaction is the extrusion of SO2, namely, resulting in the desulfonative fragment coupling of sulfones, sulfonates, and sulfonamides (Table 23). Desulfonative fragment coupling was first reported using alkenyl thioethers by ruthenium catalysis to give the corresponding dienes (Entry 1).148 Desulfonative coupling of heteroaryl aryl thioethers was accomplished by a nickel/NHC catalytic system (Entry 2).149 Heteroaryl sulfonates (Entry 3) and sulfonamides (Entry 4) also undergo nickel/NHC catalyzed extrusion of SO2 to form C–O and C–N bonds, respectively.150

12.10.3.4 C(acyl)–S bond activation C(acyl)–S bonds of thioesters are relatively reactive compared to the corresponding C(acyl)–O bonds in esters, in terms of bond dissociation energies (CH3C(¼O)–OCH3: 100 kcal/mol; CH3C(¼O)–SC2H5: 76 kcal/mol).151 The oxidative addition of C(acyl)–S bonds to transition metal complexes has been studied.152 A thioester bearing an quinolinyl group oxidatively adds to Rh(PPh3)3Cl to form a Rh(III) complex, which was characterized as a dimeric form with loss of PPh3 (Scheme 53a).152a A similar oxidative addition complex of iron was also reported using a thioester bearing a PPh2 group at the ortho-position (Scheme 53b).152b Simpler thioesters with no directing group, i.e., MeC(¼O)SAr, can also react with [(dppe)Ni(cod)] to undergo C(acyl)–S bond oxidative addition, followed by decarbonylation, affording Me-Ni-SAr(dppe) (Scheme 53c).152c The oxidative addition of thioesters to a platinum complex was also reported (Scheme 53d).152d,e

Scheme 53 Oxidative addition of C(acyl)–S bonds to transition metals.

388

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 24

Transition metal-catalyzed acylative cross-coupling of thioesters with organozinc reagents.

C(acyl)–S bond cleavage by a homogeneous catalytic system was developed in the late 1990s.153 The transition metal-catalyzed acylative cross-coupling of aryl thioesters is possible with several organometallic nucleophiles, including organozinc (Table 24), organoboron (Table 25) and other (Table 26) reagents. Fukuyama reported on the first acylative cross-coupling of thioesters with aryl or alkenylzinc reagents in the presence of a PdCl2(PPh3)2 catalyst (Table 24, Entry 1).154 A series of palladium-catalyzed Negishi type cross-coupling reactions was subsequently reported (Entries 2 and 3).155,156 The enantioconvergent cross-coupling of thioesters with racemic benzylic organozinc reagents by a chiral palladium catalyst system was developed (Entry 4).157 Nickel (Entry 5)158 or cobalt (Entry 6)159 complexes could also serve as a catalyst for this type of reaction. Organoboron reagents can be coupled with thioesters using a Pd catalyst and a stoichiometric amount of CuTC (Table 25, Entries 1–3),160a–d as in the cross-coupling of heteroaryl thioethers (Table 19). The use of a stoichiometric copper salt can be avoided by employing a sulfur leaving group bearing an iodobutyl moiety, which allowed for the formation of cyclic sulfonium to facilitate the transmetallation with organoboron reagents without the aid of the copper mediator (Entry 4).160e Later, it was reported that copper alone can catalyze Suzuki–Miyaura type reactions when sulfur leaving groups bearing a directing group were used. Thioesters bearing an ortho amide group on the sulfur can be cross-coupled with organoboron reagents in the presence of a copper catalyst under aerobic conditions, which is proposed to permit copper thiolate species to react with excess organoboron reagents, realizing a turnover of the catalyst (Entry 5).161,162 Thioesters bearing an oxime ether moiety were also effective substrates for the copper-catalyzed Suzuki-Miyaura type reaction, in which the corresponding copper thiolate species can be converted to a catalytically active copper methoxide via loss of benzoisothiazole (Entry 6).163 The acylative Suzuki–Miyaura type coupling of thioesters was also reported to be catalyzed by a CuI/Ag2CO3 system (Entry 7).164 Cross-coupling of aryl thioesters with organoindium165 and organotin166 reagents are also known (Table 26).

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 25

Metal-catalyzed Suzuki–Miyaura coupling of thioesters.

Table 26

Transition metal-catalyzed cross-coupling of thioesters with other organometallic nucleophiles.

389

390

Synthetic Applications of C–O and C–E Bond Activation Reactions

Heteroatom-based nucleophiles can also be used in the acylative cross-coupling of thioesters via the activation of a C(acyl)–S bond. Rhodium-catalyzed acyl transfer reactions of thioesters with acid fluorides, polyfluoroarenes, diphosphine disulfide, and esters have been reported (Scheme 54).167 Aryl or alkyl thioacetates can serve as a SR source in the palladium-catalyzed thiolation of aryl bromides via decarbonylative C–S bond cleavage.168 The rhodium-catalyzed cross-coupling of aryl thioesters with B2pin2 results in decarbonylative C–B bond formation (Scheme 55).169a The oxidative addition of a C(acyl)–S bond of thioesters to the boryl rhodium species is proposed. Related decarbonylative borylation of alkenyl thioesters was also reported.169b

Scheme 54 Rhodium-catalyzed acyl transfer reaction.

Scheme 55 Rhodium-catalyzed decarboxylative borylation of thioesters.

A Pd(II) intermediate generated by the oxidative addition of a C(acyl)–S bond in thioesters can also be used in intramolecular C–H functionalization reactions. Oxidative C–H thioalkylation (Scheme 56a),170 Mizoroki-Heck type alkenylation (Scheme 56b),171 and acylation of an indole C–H bond (Scheme 56c)172 have been reported.

Synthetic Applications of C–O and C–E Bond Activation Reactions

391

Scheme 56 Palladium-catalyzed intramolecular C–S/C–H coupling of thioesters.

An oxidative addition complex of a C(acyl)–S bond in thioesters can also add across a terminal alkyne, resulting in a carbothiolation reaction (Scheme 57).173 A high regio- and stereoselectivity were observed, in which the bonding of a thiophenyl group to an internal carbon of the terminal alkyne is favored. Interestingly, the use of a Pt(PPh3)4 catalyst led the carbothiolation to involve decarbonylation (Scheme 58a).174a This method is applicable for use in reactions of activated internal alkynes with high regio- and stereoselectivity (Scheme 58b).174b

Scheme 57 Palladium-catalyzed carbothiolation of alkynes.

Scheme 58 Platinum-catalyzed decarboxylative carbothiolation of alkynes using thioesters.

Decarbonylative carbothiolation can be conducted with cyclic thioester substrates, resulting in a series of nickel-catalyzed decarbonylative cycloaddition reactions with external unsaturated molecules (Scheme 59).175 In the case of the cycloaddition of thiophthalic anhydrides with alkynes, three different types of cycloadducts, namely, thioisocoumarins, benzothiophenes, and thiochromone derivatives, were selectively produced depending on the nature of the phosphine ligand being used and the additive employed (Scheme 59b).175b Decarbonylative cycloaddition with methylene cyclopropanes has also been reported (Scheme 59c).175c

392

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 59 Metal-catalyzed decarboxylative cycloaddition of thioisathins or thiophthalic anhydrides.

When the reaction of thioesters is conducted in the absence of an external reagent, fragment coupling via the extrusion of CO can take place with the formation of a new C–S bond (Table 27).89,176 Early examples of the catalytic decarbonylation of thioesters were reported to be catalyzed by Pd(PCy3)2 (Entry 1)176a or mediated by NiCl2/PPh3 (Entry 2).176b Several other nickel or palladium-catalyzed decarbonylation reactions of thioesters have been extensively studied (Entries 3–7).89,176 When a-keto thioesters are used as substrates, selective mono- and di-decarbonylation are possible by the suitable choice of the ligand (Scheme 60).177

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 27

393

Transition metal-mediated or catalyzed decarbonylation of thioesters.

Scheme 60 Nickel-catalyzed ligand-controlled mono- and di-decarbonylation of a-keto thioesters.

12.10.3.5 C(sp3)–S bond activation Catalytic C(sp3)–S bond cleavage reactions are largely limited to reactions in which substrates containing allylic or benzylic C–S bonds are used, since they can be activated relatively easily because of the stability of the resulting p-allyl or p-benzyl intermediates.178 This section is focused on C(sp3)–S bond cleavage reactions of non-allylic, non-benzylic organosulfur substrates. The Fe(acac)3-catalyzed pyridine-directed coupling of thioethers or sulfones with ArMgBr was reported (Scheme 61).179 Rheniumcatalyzed carbothiolation via C(sp3)–S bond cleavage of a-thioketones was achieved with [ReH(CO)4]n (Scheme 62).180 This reaction is proposed to proceed via the oxidative addition of a C(sp3)–S bond to the rhenium center, the subsequent insertion of an alkyne, and double bond isomerization. The insertion of CO into an unactivated C(sp3)–S bond proceeds by cobalt catalysis under 1000 atm of CO at 300  C, in which dialkyl thioethers are converted into thioesters, albeit in very low (7%) yield (Scheme 63).142 In a related study, alkoxycarbonylation of alkylthiols by Co2(CO)8 was reported.143

Scheme 61 Iron-catalyzed directed cross-coupling of thioethers with arylmagnesium reagents.

394

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 62 Rhenium-catalyzed carbothiolation of alkynes with a-thioketones.

Scheme 63 Cobalt-catalyzed insertion CO into a C(sp3)–S bond of thioethers.

12.10.4 C–N bond activation 12.10.4.1 Overview In contrast to the pivotal importance of C–N bond formation reactions in organic synthesis, the reverse process, i.e., C–N bond cleavage reactions, is much less common. This is partly due to the fact that NR2 is a poorer leaving group and more sterically congested than OR. Nevertheless, considerable progress has recently been made in this area by taking advantage of transition metal catalysts. Although an array of nitrogen-containing compounds has been used in metal-catalyzed C–N bond cleavage reactions, this chapter will cover catalytic reactions involving the most common but unreactive derivatives, i.e., amines and amides. The C–N bond cleavage reactions of cationic compounds (i.e., diazonium, ammonium and pyridinium salts), hydrazines, nitro compounds, aminals, and strained cyclic amines (i.e., aziridine, 2H-azirines and azetitines) are not discussed. C–N bonds of allyl and benzylamine derivatives are also not covered in this chapter, because the chemistry of these compounds is more related to those involving p-allyl or p-benzylmetal complexes. Readers are encouraged to refer to relevant reviews that cover the activation of these compounds.181,182 From the mechanistic point of view, this chapter only deals with catalytic reactions, in which transition metal complexes directly participate in the C–N bond cleavage process, in most cases, via oxidative addition (Scheme 64a). C–N bond cleavage reactions under acidic conditions where the C–N bond is cleaved via the formation of ammonium salts (Scheme 64b), and those involving a sequence of amine dehydrogenation to form iminium salts or enamines, followed by hydrolysis (Scheme 64c) are not discussed in this chapter.181,182

Scheme 64 Representative mechanisms for C–N bond cleavage.

12.10.4.2 C(sp)–N bond activation Regarding the activation of C(sp)–N bonds, activated cyanamides, such as N-TsN(R)CN, have been reported to serve as cyanating reagents in the transition metal catalyzed cyanation of, for example, arylboronic acids183a and arene C–H bonds bearing a directing group,183b via a rhodium-catalyzed addition/b-nitrogen elimination mechanism. Regarding unactivated cyanamides, two types of catalytic reactions involving C(sp)–N bond activation have been reported. Similar to the reactions of cyanates (see Scheme 2), a Cp(CO)3MoMe complex can catalyze the silylation of cyanamides through the silylmetalation of a cyano group, followed by the deinsertion of silyl isocyanide (Scheme 65).184 A related 2-amidino iron complex was isolated and fully characterized.184a

Synthetic Applications of C–O and C–E Bond Activation Reactions

395

Scheme 65 Mo-catalyzed activation of C(sp)–N bonds.

Pd-catalyzed addition of the C(sp)–N bond of cyanamides to a tethered alkene can proceed by the use of a BR3 cocatalyst (Scheme 66a).185a,b A Pd(II) complex formed by the oxidative addition of a BPh3-activated cyanamide was isolated and characterized.185a A catalytic asymmetric variant was also demonstrated in which a chiral phosphine ligand was used instead of Xantphos.185a It should be noted that a similar transformation is catalyzed by Lewis acid alone, when N-Ts cyanmides are used.185c,d When cyanamides containing a pendant methylenecyclopropane, a C–O bond, rather than a C–N bond, is formed (Scheme 66b).185e

Scheme 66 Pd-catalyzed activation of C(sp)–N bond.

12.10.4.3 C(aryl)–N bond activation 12.10.4.3.1

The use of a directing group

The ruthenium-based catalyst system used for directed C–O bond activation reactions (see Table 12) has also been shown to be effective for the activation of C–N bonds (Table 28). Aniline derivatives bearing an ortho ketone or ester groups undergo Suzuki-Miyaura type coupling in the presence of a RuH2(CO)(PPh3)3 catalyst (Entry 1).186a–c Interestingly, not only N,N-disubstituted, but also N-monosubstituted amino groups and NH2 can serve as a leaving group. In the case of reactions involving substrates bearing an NH2 group, a chelated complex formed by the activation of a N–H bond was shown to be involved as an intermediate.186b,c An amide (Entry 2),186d pyridine (Entry 3)186e and imine (Entry 4)186f can also be used as a directing group. By performing the reaction under an atmosphere of CO, carbonylative cross-coupling is possible to afford benzophenone derivatives (Entry 5).186g When the ruthenium-catalyzed reactions of these aniline derivatives are conducted in the absence of other external reagents, the reductive cleavage of C–N bonds occurs via b-hydrogen elimination of an amide-ruthenium intermediate (Entry 6).186h The alkylation of C–N bonds takes place when the reaction is carried out in the presence of a terminal alkene (Table 28).186h

396

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 28

Ruthenium-catalyzed directed activation of C(aryl)–N bonds.

The chromium catalyst shown in Scheme 20 can also catalyze directed the Kumada-Tamao-Corriu type cross-coupling of aniline derivatives (Scheme 67a).187a The reductive cross-coupling of anilines bearing an imine directing group with aryl pivalates is also accomplished using a CrCl2/dtbpy system with Mg as a stoichiometric reductant (Scheme 67b).187b

Scheme 67 Cr-catalyzed activation of C(aryl)–N bond.

Synthetic Applications of C–O and C–E Bond Activation Reactions

397

Catalytic reactions in which N-heteroarenes function as a leaving group have also been reported. The nickel-catalyzed Suzuki-Miyaura coupling of purine deoxynucleosides bearing an imidazole at the 6-position proceed to afford arylated derivatives, which is possibly directed by nitrogen atoms in the purine ring (Scheme 68a).188 An unusual annulative oxidative coupling involving C(aryl)–N bond cleavage was also reported. The rhodium-catalyzed reaction of N-(2-pyridinyl)indole with propargyl alcohols results in the 1:2 coupling to form a pyrido[2,1-a]indole skeleton (Scheme 68b).188b Most interestingly, the C–N bond that connects the indole and pyridine rings and the C(aryl)–C(sp) bond in propargyl alcohols are cleaved during the course of the reaction. Although the mechanism for this intriguing transformation remains unclear, a cyclometallated complex formed by directed C–H bond activation at the 2-position of the indole is proposed to be an initial intermediate.

Scheme 68 Catalytic activation of C(aryl)–N bonds at the 2-position of a pyridine ring.

12.10.4.3.2

No directing group

Activation of unactivated C(aryl)–N bonds without the assistance of a directing group represents a daunting challenge and successful examples are extremely limited. In addition to the inherent low reactivity of C(aryl)–N bonds, a selectivity issue arises when considering the activation of aromatic amides. Analogous to the activation of esters (Fig. 3), aromatic amides bear two discrete C–N bonds, C(aryl)–N and C(acyl)–N bonds, and the latter is normally the more reactive of the two (see Section 12.10.4.4). Nevertheless, the use of a nickel catalyst ligated with a strong s-donor allows for the selective cleavage of a C(aryl)–N bond. The Ni/PCy3-catalyzed cross-coupling of Boc-protected naphthylamines with a Grignard reagent was developed (Scheme 69a).189a The use of a methoxycarbonyl-protected substrate significantly lowered the yield, suggesting that the steric protection by a Boc group is needed.

Scheme 69 Catalytic activation of C(aryl)–N bonds of aromatic amides without the aid of a directing group.

398

Synthetic Applications of C–O and C–E Bond Activation Reactions

When HB(pin) is used as a nucleophile, the reductive cleavage of a C(aryl)–N bond occurs (Scheme 69b).189b The use of a stronger s-donor ligand, IMesMe allows for the borylation of a C(aryl)–N bond in simpler acetamide derivatives (Scheme 69c).189b In these nickel-catalyzed activations of aromatic amide derivatives, the scope is basically limited to fused aromatic substrates, and regular N-acylated aniline derivatives are much less reactive. This reactivity trend is quite similar to that observed for nickel-catalyzed C(aryl)–O bond activation reactions.5f Suzuki-Miyaura type cross-coupling reactions in which aromatic amines are used as an electrophilic coupling partner was reported to be catalyzed in the presence of NiBr2/IMesMe catalyst and metallic Mg as a stoichiometric reductant (Scheme 70a).189c Oxidative addition by a Ni(I) species is proposed to be involved in the mechanism for the activation of C(aryl)–N bonds. The nickel-catalyzed borylation of aniline derivatives with B2(nep)2 was also developed, in which a Mg reductant is not required (Scheme 70b).189d

Scheme 70 Catalytic activation of C(aryl)–N bonds of aromatic amines without the aid of a directing group.

12.10.4.4 C(acyl)–N bond activation An amide bond is stabilized by nN ! p C¼O conjugation (Scheme 71a), which renders C(acyl)–N bonds significantly less reactive for oxidative addition to metal complexes than the corresponding C(acyl)–O bonds. Therefore, the catalytic transformations of C(acyl)–N bonds that have been reported to date are limited to those using activated amide substrates. To destabilize an amide bond, the introduction of an electron-withdrawing group at the amide nitrogen is often utilized, which disrupts the amide conjugation both electronically (by reducing the basicity of the nitrogen) and sterically (by increasing the twist angle around the C(acyl)–N bond) (Scheme 71b). Simple N,N-dimethylamides A are the least reactive among the amide derivatives, while N-phenylamides B have a lower activation barrier for rotation around the amide bond and exhibit some reactivity toward oxidative addition.190a N-Ts (C) and N-Boc (D) derivatives are reasonably reactive owing to the twisted nature (twist angle t  30 ), thereby decreasing the amide resonance.190a Among the most reactive amide derivatives are the N-acylated glutarimides (E), which have minimal amide resonance due to their large twist angle (t  90 ).190b Because of this ground-state destabilization, the electrophilicity of twisted amides C–E is estimated to lie between acid anhydrides and acid chlorides.190c Chelation assistance by the neighboring heteroatom in the activation of a C(acyl)–N bond has also been suggested to be another factor for the higher reactivity of twisted amides C–E.190d Based on the exceptionally high reactivity of these twisted amides, an array of acylative and decarbonylative cross-coupling reactions of twisted amides C–E that proceed via the cleavage of C(acyl)–N bonds have been developed.85,191 The major focus of this chapter, however, is on catalytic reactions in which unactivated amides A and B are used.

Scheme 71 Amide bond resonance and the order of reactivity of amide derivatives for transition metal catalyzed activation of a C(acyl)–N bond.

Synthetic Applications of C–O and C–E Bond Activation Reactions

399

Scheme 72 Ni-catalyzed cross-coupling of less activated amides.

The nickel-catalyzed conversion of N-phenylamides to esters using alcohols has been reported (Scheme 72a).192b,195f This amideto-ester transformation is thermodynamically favored only when an N-phenyl substituent is present (DG ¼ ca. −7 to −4 kcal/mol). The C(acyl)–N bond cleavage proceeds through oxidative addition to a Ni/SIPr complex. The acylative Suzuki-Miyaura type cross-coupling of N-phenylamides with alkylboron reagents catalyzed by a Ni/IPr catalyst was reported (Scheme 72b).193 This cross-coupling occurs specifically at an N-phenylamide moiety with esters and N-alkylamides remaining intact. The nickel-catalyzed decarbonylative fragment coupling of N-phenylamides has been reported (Scheme 73).194a This reaction proceeds only when the N-phenylamide moiety is located at the 2-position of azines. A similar Ni-catalyzed decarbonylation of arenecarboxamides was also reported for activated amides bearing azoles.194b

Scheme 73 Ni-catalyzed decarbonylation of pyridinylamides.

NH-amides undergo decarbamoylative arylation with azoles by palladium catalysis under oxidative conditions (Scheme 74).195 The reaction is proposed to proceed predominantly via C(acyl)–N bond cleavage, followed by decarbonylation, and the elimination of an isocyanate is involved as a minor pathway.

Scheme 74 Pd-catalyzed oxidative decarbamoylative arylation of azoles.

12.10.4.5 C(sp3)–N bond activation Catalytic reactions that involve the transition metal-mediated cleavage of an unactivated C(sp3)–N bonds remains underexplored. The palladium-catalyzed ring-opening reactions of cyclic amines have been reported (Scheme 75).196a The mechanism responsible for this intriguing process is proposed as follows. An aryl iodide bearing a cyclic amine moiety at the ortho position initially undergoes oxidative addition to Pd(0), followed by the insertion of an alkyne into an Ar–Pd bond to generate an alkenylpalladium(II) intermediate. The C(sp2)–Pd bond in this intermediate is located in close proximity to a C(sp3)–N bond of

400

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 75 Pd-catalyzed annulation of aryl halides with alkynes involving the ring-opening of cyclic amines via the cleavage of an unactivated C(sp3)–N bond.

a cyclic amine moiety of the substrate, allowing s-bond metathesis to occur between these two bonds. This process results in the construction of an indole ring with the concomitant formation of an alkyl–Pd(II)–I complex, followed by the reductive elimination of the alkyl iodide product under the catalytic conditions. When this reaction is conducted in the presence of an external secondary amine, the alkyl iodide product is aminated in tandem.196b 1,4-Dibromo-1,4-butadiene derivatives can also serve as substrates to afford the corresponding pyrrole products.196c

12.10.5 C–Si bond activation 12.10.5.1 Overview Given the fact that silicon is an earth-abundant element, it is important to develop the transformation of organosilicon compounds through C−Si bond activation, since such reactions have the potential use in the synthesis of new organosilanes via the formation of a C–M–Si intermediate. The C–Si bond activation through a transmetallation process is commonly observed in metal-catalyzed reactions such as Hiyama cross-coupling. Although this type of C–Si bond activation is of great value in organic synthesis, the silyl group serves as a leaving group and is not incorporated into the product. This type of the C–Si bond activation is not covered in this section, and a related review should be consulted.197 The focus of this section is on reactions that involve the formation of a new C–Si bond through C−Si bond activation. The chapter initially describes the catalytic C–Si bond activation reactions of strained silacycles, and the following sections are classified primarily based on the hybridization states of the carbon attached to silicon (i.e., C(sp3)–Si, C(sp2)–Si, and C(sp)–Si bonds). Several reviews on catalytic transformations of C–Si bonds have appeared.198

12.10.5.2 C–Si bond activation of strained silacycles Strained silacycles, such as silacyclopropanes and silacyclobutane, undergo oxidative addition to transition metal complexes driven by relieving the ring-strain. The resulting metalacycle intermediates can serve as a platform for ring expansion reactions via an insertion/reductive elimination process. Table 29 summarizes such transition metal-catalyzed insertion reactions of unsaturated molecules into strained silacycles. In 1975, Sakurai and Imai reported on the first palladium-catalyzed C–Si bond activation of silacyclobutane to form silacyclohexenes that proceeded via the insertion of an alkyne (Entry 1).199 Related alkyne insertions into silacyclobutane (Entry 2)200 and benzosilacyclobutene (Entry 3)201 were subsequently reported, in which the latter compound undergoes selective insertion into the C(sp2)–Si bond over C(sp3)–Si. The palladium-catalyzed asymmetric insertion of an alkyne into silacyclobutane (Entry 4)202 and benzosilacyclobutene (Entry 5)203 were also developed. The C–Si bond activation of more strained methylenesilacyclobutene derivatives was investigated (Entry 6).204 While there are two possible C(sp2)–Si bonds that could be cleaved in the substrate, the C–Si bond containing an exo alkene moiety is selectively cleaved to give a six-membered silacycle product. The palladium-catalyzed insertion of cyclopropene derivatives was also reported, in which the carbonyl group attached to cyclopropene is indispensable in terms of promoting the insertion reaction (Entry 7).205 Methylenesilacyclopropane is also applicable to this type of insertion reaction (Entry 8).206 The catalytic insertion of a carbonyl group is also possible. Silacyclobutanes reacts with acyl chlorides (Entry 9),207 and aldehydes (Entry 10)208 in the presence of Pd or Ni catalyst to form six-membered oxasilacycles. Conjugated enones can be inserted into the C–Si bond of silacyclobutanes to form eight-membered oxasilacycles (Entry 11).209 When terminal alkenes are used in nickel-catalyzed C–Si bond activation reactions of silacyclobutanes, ring-opening occurs, rather than the insertion reaction.210 The product is likely formed via the formation of a five-membered nickelacycle by oxidative addition of a C–Si bond, insertion of an alkene to generate a seven-membered nickelacycle intermediate, followed by b-hydrogen elimination and reductive elimination (Scheme 76).

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 29

Transition metal-catalyzed unsaturated bond insertion into strained silacycles.

401

402

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 76 Nickel-catalyzed ring-opening reactions of silacyclobutanes.

Scheme 77 Rhodium-catalyzed intramolecular annulation via C −Si and C −H bond activation.

The cleavage of C− Si and C −H bonds in silacyclobutanes takes place in the presence of a rhodium catalyst and has been applied to intramolecular annulation reactions (Scheme 77).211 This reaction is initiated by the oxidative addition of a C −Si bond to generate a silarhodacycle, which is then converted into silylrhodium(I) via b-H elimination and HX elimination. The silylrhodium species subsequently facilitates the oxidative addition of a nearby C − H bond with the formation of a six-membered rhodacycle. Ring closure by C− Si reductive elimination, followed by hydrometallation/protodemetallation leads to the formation of silafluorene derivatives. A palladium-catalyzed ring expansion reaction that involves both C–Si and C–C bond activation in silacyclobutane and cyclobutanone, respectively, was also reported (Scheme 78).212 This reaction is initiated by the oxidative addition of a C − Si bond to generate an silapalladacycle, which subsequently cleaves the nearby C −C bond of cyclobutanone via an additional oxidative addition to form a Pd(IV) intermediate. Sequential reductive elimination of the Pd(IV) intermediate gives a strain-relieved bicyclic product. This reaction can be viewed as the catalytic metathesis of C–Si and C–C bonds.

Scheme 78 Palladium-catalyzed C–Si and C–C bond exchange reactions.

This type of catalytic metathesis C–Si and C–C bonds can be accomplished in an intermolecular setting (Table 30). It was reported that a nickel-catalyzed reaction of benzosilacyclobutanes with cyclopropylidene acetate gives a seven-membered silacylcle (Entry 1).213 A palladium/isocyanide complex was reported to catalyze C–Si and C–C bond exchange between the silacyclobutane

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 30

403

Transition metal-catalyzed C–Si and C–C bond exchange reactions using silacyclobutane derivatives.

and the benzocyclobutenone (Entry 2).214 The palladacycle intermediate generated by the insertion of Pd(0) into the C(sp2)–Si bond of the benzocyclobutane was isolated, and the intermediate complex was shown to give the product by reacting with silacyclobutane. These results suggest that the C–C bond activation initially occurs. s-Bond exchange reactions between silacyclobutane derivatives and cyclopropenones in the presence of a Pd or Ni catalyst was also developed (Entries 3 and 4).215

12.10.5.3 C(sp3)–Si bond activation The C(sp3)–Si bond activation of acyclic organosilanes, which are much less reactive than strained silacycles, is a more challenging process. In 1994, Ojima reported on a pioneering reaction that involves C(sp3)–Si bond activation (Scheme 79).216 When the rhodium-catalyzed reaction of diyne with tBuMe2SiH under a CO atmosphere was examined in an attempt to develop a new silylformylation reaction, a silole derivative was unexpectedly obtained in 50% yield. This reaction involves the cleavage of one of the Me–Si bonds in the hydrosilane reagent.

Scheme 79 An early example of catalytic C(sp3)–Si bond activation.

404

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 80 Rhodium-catalyzed synthesis of benzosiloles by intermolecular annulation of 2-(trimethylsilyl)phenylboronic acid and alkynes.

The rhodium-catalyzed synthesis of benzosiloles by the coupling of 2-(trimethylsilyl)phenylboronic acid and internal alkynes through C(sp3)–Si bond activation was reported (Scheme 80).217 This reaction is initiated by the transmetallation of the starting boronic acid to generate an arylrhodium species. Subsequent alkyne insertion leads to the formation of an alkenylrhodium species. Cyclization occurs with the cleavage of a C(sp3)–Si bond. Regarding the substituents on the silyl group, not only a methyl but also ethyl and phenyl groups can be cleaved in this reaction. Computational studies indicate that the cleavage proceeds via an oxidative addition mechanism.218 This method is also applicable to the catalytic asymmetric synthesis of a chiral silole bearing a silicon-centered stereogenic center.219 The rhodium-catalyzed intermolecular cyclization of alkynes with disilane was also reported to afford fully substituted silole derivatives (Scheme 81).220

Scheme 81 Rhodium-catalyzed synthesis of siloles by intermolecular annulation of disilane and alkynes.

A palladium-catalyzed variant using the corresponding aryl halide substrates was also reported (Scheme 82). Intramolecular221 and intermolecular annulations with alkyne222 and benzyne223 are possible.

Scheme 82 Palladium-catalyzed synthesis of siloles through C(sp3)–Si bond activation.

The rhodium-catalyzed synthesis of heteroarene-fused silole derivatives was also developed by tandem cyclization of ortho-alkynylaniline derivatives, followed by cyclization via C(sp3)–Si bond activation (Scheme 83).224

Synthetic Applications of C–O and C–E Bond Activation Reactions

405

Scheme 83 Rhodium-catalyzed tandem cyclization through C(sp3)–Si bond activation.

The rhodium-catalyzed intramolecular cis-carbosilylation of alkynes was achieved. The normally difficult oxidative addition of a C(sp3)–Si bond is proposed to be facilitated by the pendant alkyne group, which can serve as a directing group (Scheme 84).225

Scheme 84 Rhodium-catalyzed carbosilylation of alkynes.

12.10.5.4 C(sp2)–Si bond activation As discussed in the above section, a C(sp3)–Si bond can be cleaved when the silyl group is located in close proximity to the organometallic intermediate that is involved in the catalytic reaction. There are also several such examples of C(sp2)–Si bond cleavage. A rhodium-catalyzed enantioselective transformation of cyclobutanol derivatives involves C(sp2)–Si bond cleavage when the substrate contains a silyl group at a suitable position (Scheme 85).226 The process is proposed to start with the b-carbon elimination of rhodium-alkoxide to generate a ring-opened alkylrhodium species. In this intermediate, the rhodium center is close to a C(sp2)–Si bond, thus allowing bond activation to occur. The C(sp2)–Si bond activation induces bond exchange between C(sp3)–Rh and C(sp2)–Si to form C(sp3)–Si and C(sp2)–Rh. The resulting arylrhodium species then attacks a pendant ketone to provide an indanol derivative.

Scheme 85 Rhodium-catalyzed transformation via the cleavage of C(sp2)–Si bond.

C(sp2)–Si bond cleavage has also been observed in the copper-catalyzed silacarboxylation of internal alkynes employing CO2 and silylborane (Scheme 86).227 The addition of a silylcopper complex to an alkyne, followed by the insertion of CO2 generates copper carboxylate. Subsequent s-bond metathesis of the O–Cu and the C–Si bonds then takes place with the final product being formed via the cleavage of a Ph–Si bond. A similar reaction with allenes was also reported.228

406

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 86 Copper-catalyzed silacarboxylation of alkynes via the cleavage of C(sp2)–Si bond.

The rhodium-catalyzed enantioselective ring opening of dinaphthosilole via the cleavage of C(sp2)–Si bond was reported (Scheme 87).229 It was proposed the oxidative addition of C(sp2)–Si to Rh(I) is promoted by the torsional strain of binaphthosilole, and that the less strained silafluorene fails to react under these conditions.

Scheme 87 Rhodium-catalyzed enantioselective ring opening acylation of dinaphthosilole.

In 1995, Narasaka reported on the palladium-catalyzed decarbonylation of a disilylketone through C(acyl)–Si bond cleavage (Scheme 88a).230 The postulated oxidative addition intermediate can be applied successfully to an addition reaction to an activated alkyne (Scheme 88b).

Scheme 88 Palladium-catalyzed decarbonylative transformation of disilylketone.

Synthetic Applications of C–O and C–E Bond Activation Reactions

407

Scheme 89 Nickel-catalyzed decarbonylation of acylsilanes.

Two catalytic methods have been developed for the nickel-catalyzed decarbonylation of acylsilanes (Scheme 89).231,232 The system using PBu3 as the ligand is effective for the decarbonylation of acylsilanes bearing SiPhMe2, while that using IPr or 1,10-phenanthroline can promote decarbonylation of TMS derivatives.

12.10.5.5 C(sp)–Si bond activation Compared to C(sp3)–Si and C(sp2)–Si bond activation, transition metal-catalyzed C(sp)–Si bond activation has been a less explored subject. In a stoichiometric example, the oxidative addition of a C(sp)–Si bond of an alkynylsilane to a Pt(0) complex was reported to proceed under thermal conditions (Scheme 90).233

Scheme 90 Stoichiometric C(sp)–Si bond activation of alkynylsilane.

Regarding catalytic reactions, rhodium-catalyzed intramolecular alkynylsilylation of alkynes via C(sp)–Si bond activation was reported (Scheme 91).234 As discussed in Scheme 84, the oxidative addition of an C(sp)–Si bond is facilitated by the precoordination of a pendant alkyne to the rhodium catalyst.

Scheme 91 Rhodium-catalyzed intramolecular alkynylsilylation of alkynes.

12.10.6 C–P bond activation 12.10.6.1 Overview Tertiary phosphines are essential components of transition metal catalysts in regulating the reactivity and selectivity of the catalytic reaction. In PAr3-ligated metal-catalyzed processes, C −P bond cleavage is frequently encountered as an undesired side reaction and it results in aryl group scrambling of PAr3. Several mechanisms for this C −P bond cleavage process have been proposed. One possible mechanism is the direct reversible oxidative addition of a C − P bond of the phosphine to a low-valent metal to form a P-bridged dimeric intermediate, wherein the Ar and m-P-bridging groups can be exchanged thereby allowing for bond exchange (Scheme 92).235 The C−P bond exchange reaction can also be mediated by an Ar −Pd −X species, through reductive elimination to form a phosphonium salt and Pd(0), followed by the oxidative addition of a C −P bond of the phosphonium to provide an exchanged product (Scheme 93).236

408

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 92 Metal-mediated C−P bond exchange through bridged phosphide intermediates.

Scheme 93 Palladium-mediated C−P bond exchange via phosphonium intermediates.

Inspired by an understanding of the C − P bond cleavage mechanism, elaborate catalytic reactions have been developed. This chapter summarizes catalytic transformations of C–P bonds. The chapter is classified primarily based on the oxidation states of the phosphine attached to carbon in the starting organophosphorus compound (i.e., phosphonium, phosphine, phosphonate, etc.). Several reviews on catalytic transformations of C–P bonds have appeared.237

12.10.6.2 Phosphoniums The oxidative addition of C−P bond of an arylphosphonium species generates an Ar–M species ligated with triarylphosphine. Therefore, it is possible to use a phosphonium salt as an electrophilic aryl source in various transition metal-catalyzed reactions, as is the case for aryl halides. Table 31 summarizes catalytic transformations of C–P bonds in phosphonium salts. The most widely used catalysts for transforming Ar–+PR3 bonds are palladium(0) complexes. In 1995, Yamamoto reported a pioneering study on the catalytic transformations of Ar–+PR3 bonds including hydrogenation, carbonylation, and olefination reactions (Entry 1–3).238 Palladium-catalyzed Suzuki–Miyaura and Sonogashira coupling reactions using quaternary phosphonium salts as an electrophile have been reported (Entry 4, 5).239 Characterization of the reaction intermediates for the reaction of PPh4Cl with Pd2(dba)3 by ESI-MS and X-ray crystallography clearly confirms that C–P bond cleavage occurs through the oxidative addition of quaternary phosphonium halides to palladium(0). Nickel-catalyzed Suzuki–Miyaura coupling using phosphonium-containing pyridine derivatives as an electrophile was also reported (Entry 6).240 The use of a cobalt catalyst allows for Negishi coupling between a pyridylphosphonium species and alkylzinc reagent to provide alkylated pyridine derivatives (Entry 7).241

12.10.6.3 Phosphines 12.10.6.3.1

Intermolecular reactions

Triarylphosphines are more readily available than the phosphonium salts. Several catalytic reactions that directly use triarylphosphines as aryl or phosphino group sources have been reported. The most widely used catalyst systems for transforming C–PR2 bonds are a palladium(II) complex in conjunction with a metal acetate, such as Cu(OAc)2 or Ag(OAc), as a stoichiometirc oxidant. It was proposed that the OAc ligand on a Pd(II) complex exchanges with an aryl group of the ligated PAr3 to generate an Ar–Pd(II)X species, which can then function as an arylating reagent.242 Table 32 summarizes the palladium-catalyzed transformation of C–PR2 bonds. The palladium-catalyzed oxidative Heck arylation of alkenes using triarylphosphine as an aryl source via C–P bond cleavage was reported (Entries 1243 and 2244). The palladium-catalyzed arylation of oxabenzonorbornadiene with tertiary phosphines was reported to afford 2-arylnaphthalenes via a sequence involving aryl-palladation of the alkene/b-oxygen elimination/dehydration (Entry 3).245 The palladium-catalyzed C–H arylation of heteroarenes using triarylphosphine as an aryl source is also possible (Entry 4).246 In this reaction, at least two aryl groups in one triarylphosphine can be transferred to the final product. Highly substituted naphthalene derivatives can be synthesized by the 1:2 annulative coupling of PAr3 with internal alkynes through C–H and C–P bond activation (Entry 5).247 A catalytic annulative coupling of PAr3, an alkyne and a primary amine was also developed, leading to the formation of indole derivatives through C–H and C–P bond activation (Entry 6).248 This reaction proceeds without the need for an excess amount of a metal oxidant, and the key to the success of the reaction is the use of 0.5 equiv of iodoanisole, which promotes the C–P bond activation process by generating Ar–Pd(II)–I. This is in sharp contrast to most arylation reactions using PAr3, in which a metal oxidant such as Ag(I) and Cu(II) is indispensable for the Pd(II)-promoted C–P bond activation.

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 31

409

Transition metal-catalyzed cross coupling via the cleavage of an Ar–+PR3 bond.

PAr3 can also serve as a reagent for transferring a phosphino group. The palladium-catalyzed phosphination of aryl triflates through the C–P bond activation of PAr3 was reported (Entry 7).249 This method was applied to the synthesis of some elaborate chiral phosphine ligands.250 The phosphination of haloarenes with PAr3 via C–P bond activation to afford a variety of triarylphosphines was also demonstrated (Entry 8).251 This catalytic phosphination reaction provides similar results even under solvent-free conditions.252 In all cases of phosphination reactions, the use of an excess amount of PAr3 was needed to drive the equilibrium of the exchange reaction to give the desired product. Nickel complexes are also used to activate the C–P bond of PAr3. For example, the nickel-catalyzed coupling of PAr3 with methylenecyclopropane derivatives gives a ring-opened product, in which an Ar–P bond formally adds across a C–C bond of a cyclopropane ring (Scheme 94).253 The C–C bond of the cyclopropane derivative undergoes oxidative addition to the in situ generated Ni(0) species to form a four-membered nickelacycle. Subsequent s-bond metathesis of the C–P bond and the Ni–C bond of nickelacycle takes place to form the final product.

410

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 32

Palladium-catalyzed transformations via the cleavage of C–PR2 bond.

Scheme 94 Nickel-catalyzed coupling of cyclopropane and triarylphosphine.

Synthetic Applications of C–O and C–E Bond Activation Reactions

12.10.6.3.2

411

Intramolecular cyclizations

Phosphole and its benzo-fused derivatives have recently attracted significant interest as promising organic materials due to their unique optical and electronic properties. Transition metal-catalyzed intramolecular cyclization involving C–P bond activation is a powerful approach for the synthesis of such phosphacycles. The intramolecular cyclization of biaryl phosphine through the C–H and C–P bond activation was reported (Scheme 95).254 This reaction proceeds through the formation of a cyclopalladated intermediate to give a dibenzophosphonium salt followed by oxidative addition of the C–P bond of the phosphonium to a palladium(0) species to afford dibenzophosphole. This method was used to synthesize the calix[4]arene-fused phospholes.255

Scheme 95 Palladium-catalyzed synthesis of dibenzophospholes via C–H and C–P bond activation.

Intramolecular cyclization through C–Br and C–P bond activation was also demonstrated (Scheme 96).256 In this reaction, a hydrosilane reductant was employed to regenerate the active Pd(0) species by reductively cleaving Ph–Pd–X to benzene and silyl bromide.

Scheme 96 Palladium-catalyzed synthesis of six-membered phosphacycles.

Palladium/copper-cocatalyzed intramolecular cyclizations using alkyne substituted triarylphosphine derivatives was reported (Scheme 97).257 It was proposed that the alkynyl group serves as a directing group in the oxidative addition to a C–P bond. Although Cu(I) is indispensable for the success of this cyclization, its role is unclear. This method was used to synthesize a calixarene-decorated benzophosphole.258

Scheme 97 Palladium/copper-catalyzed synthesis of benzophospholes.

The reversible nature of C–P bond metathesis limits the synthetic utility of the reaction (Schemes 92 and 93). The selective cross metathesis of two different phosphines poses a substantial challenge. Morandi136 and Tobisu259 independently reported on an intramolecular variant, which enables the palladium-catalyzed selective synthesis of dibenzophosphole derivatives from readily available bisphosphines (Table 33). This type of cyclization is also catalyzed by a nickel catalyst.260 Since a Ni(0) species generally undergoes oxidative addition more readily than Pd(0), this catalytic system displayed a superior activity towards electron-rich substrates and even more challenging C(sp3)–P bonds (Scheme 98). In these reactions, the formation of a phosphonium species is

412

Synthetic Applications of C–O and C–E Bond Activation Reactions

Table 33

Metal-catalyzed transformations that proceed via the cleavage of a C–PR2 bond.

Scheme 98 Nickel-catalyzed cyclization via the cleavage of C(sp3)–P bond.

essential for successful C–P bond cleavage. The addition of a catalytic amount of Ar–X promotes the C–P bond activation process by forming an Ar–M(II)–X complex. With regard to C(sp3)–P bond cleavage, a rhodium-catalyzed transformation of bisphosphine into unsymmetrical diphosphane was reported (Scheme 99).261 It was proposed that the reductive elimination of a P–P bond occurs to generate a diphosphirane intermediate. The strained C–P bond of the diphosphirane undergoes oxidative addition, followed by hydrogen migration to ultimately give the diphosphane product.

Scheme 99 Rhodium-catalyzed C(sp3)–P bond cleavage.

The nickel-catalyzed decarbonylation of acylphosphines through C–P bond cleavage was reported (Scheme 100).262 Various aryl or alkyl substituted acylphosphines, which can be prepared by the reaction of the corresponding acyl chloride and secondary phosphines, can participate in this reaction to afford the corresponding tertiary phosphines.

Scheme 100 Nickel-catalyzed decarbonylation of acylphosphine.

Synthetic Applications of C–O and C–E Bond Activation Reactions

413

12.10.6.4 Phosphoric acid derivatives and phosphine oxides The C(acyl)–P bond cleavage of acylphosphonates is involved in palladium-catalyzed decarbonylation (Scheme 101) and C–P bond exchange (Scheme 102)263 reactions. In both reactions, the oxidative addition of the C–P bond to the palladium(0) species is proposed.

Scheme 101 Palladium-catalyzed decarbonylation of acylphosphonates.

Scheme 102 Palladium-catalyzed C–P bond exchange reaction of acylphosphines.

The rhodium-catalyzed enantioselective annulative coupling of g-alkynylaldehydes with acylphosphonates was reported (Scheme 103).264 The g-Alkynylaldehyde reacts with the Rh(I) catalyst through oxidative cyclization, affording a oxarhodacyclopentene with the acyl phosphonate being chelated. It was proposed the s-bond metathesis of the C–P bond and the Rh–O bond of oxarhodacyclopentene intermediate takes place to form the final product.

Scheme 103 Rhodium-catalyzed enantioselective cyclization of g-alkynylaldehydes with acylphosphonates.

The palladium-catalyzed arylation of an alkene through the C–P bond activation of arylphosphonic acid was reported (Scheme 104).265 It was proposed that a fluoride anion coordinates to the arylphosphonic acid to form a five-coordinated phosphorane intermediate, which facilitates oxidative addition of the C–P bond.

Scheme 104 Palladium-catalyzed arylation of alkenes with arylphosphonic acids.

414

Synthetic Applications of C–O and C–E Bond Activation Reactions

Scheme 105 Chelation-assisted catalytic activation of a C–P(O) bond.

The chelation-assisted catalytic activation of the C–P bond in phosphine oxides was reported to be involved in the oxidative rearrangement of allenylphosphine oxide derivatives (Scheme 105).266

12.10.7 Conclusion and outlook This chapter provides an overview of the current state of our knowledge regarding the transition metal catalyzed transformation of unactivated C–O and related C–E (E ¼ S, N, Si and P) bonds. Since the pioneering work of Wenkert on the cross-coupling of methoxyarenes with Grignard reagents (Scheme 12), nickel complexes, in conjunction with strong s-donor ligands, have emerged as the most active catalysts available for mediating C(aryl)-O bond activation processes. Tremendous advancements have been made in the nickel-catalyzed cross-coupling reactions of unactivated phenol derivatives, including aryl ethers, esters and carbamates, allowing a range of nucleophiles, including organometallic reagents, heteroatom nucleophiles and even some C–H bonds, to be coupled. As a result, phenol derivatives have now become viable alternatives to aryl halides. From the mechanistic point of view, both experimental and theoretical findings revealed that the mode of activation by transition metals is not limited to classical oxidative addition, and that more diverse pathways can come into play (Scheme 14), which should be taken into consideration when designing a new catalytic transformations of phenol derivatives. The activation of inert C(sp3)–O bonds and C–OH bonds of phenols and alcohols remains a largely undeveloped area and the development of new catalysts that are capable of mediating oxidative addition of these C–O bonds is required. With the advantage of renewability and the less environmental impact of phenol and alcohol derivatives, they are now considered to be attractive feedstocks for use in the catalytic synthesis of a wide variety of organic compounds. Despite the significant advances that have been made over the past decade, the goal of realizing truly green processes has not yet been reached and additional breakthroughs in catalyst development will be essential. Regarding catalytic reactions involving the activation of C–E (E ¼ S, N, Si and P) bonds, the situation continues to be immature, primarily due to the lack of versatile catalysts for activating these bonds. Although several cross-coupling type reactions that proceed via the cleavage of C–E (E ¼ S, N, Si and P) bonds have been developed, their synthetic significance is much less than reactions that proceed via C–O bond activation, when the availability, atom economy and reactivity of these heteroatom-based leaving groups are taken into account. A more desired type of transformation is catalytic insertion into C–E bonds, which would allow heteroatom substituents to be incorporated into the products. To achieve this type of transformation, catalysts that can promote not only the oxidative addition of C–E bonds, but also the reductive elimination of new C–E bonds need to be created, and this largely remains as future challenges.

References 1. 2. 3. 4. 5.

6. 7. 8. 9.

Rappoport, Z. The Chemistry of Phenols; Wiley: Hoboken, 2003. Zhou, T.; Szostak, M. Catal. Sci. Techol. 2020, 10, 5702–5739. Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009, 131, 8815–8823. Bajo, S.; Laidlaw, G.; Kennedy, A. R.; Sproules, S.; Nelson, D. J. Organometallics 2017, 36, 1662–1672. (a) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–1416; (b) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem. Eur. J. 2011, 17, 1728–1759; (c) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013, 19–30; (d) Tobisu, M.; Chatani, N. Top. Organomet. Chem. 2013, 44, 35–53; (e) Cornella, J.; Zarate, C.; Martin, R. Chem. Soc. Rev. 2014, 43, 8081–8097; (f ) Tobisu, M.; Chatani, N. Acc. Chem. Res. 2015, 48, 1717–1726; (g) Tobisu, M.; Chatani, N. Nickel-Catalyzed Cross-Coupling Reactions of Unreactive Phenolic Electrophiles via C–O Bond Activation. In Ni- and Fe-Based Cross-Coupling Reactions; Correa, A., Ed.; Springer: Cham, 2017; pp 129–156; (h) Tobisu, M.; Chatani, N. Metal-Catalyzed Aromatic C–O Bond Activation/Transformation. In Organometallics for Green Catalysis. Topics in Organometallic Chemistry; Dixneuf, P. H., Soulé, J.-F., Eds.; Springer: Cham, 2018; vol. 63; pp 103–140; (i) Tobisu, M. C–O Bond Transformations. In Nickel Catalysis in Organic Synthesis: Methods and Reactions; Ogoshi, S., Ed.; Wiley-VCH: Weinheim, 2020; pp 123–150; (j) Qiu, Z.; Li, C.-J. Chem. Rev. 2020, 120, 10454–10515. Fukumoto, K.; Dahy, A. A.; Oya, T.; Hayasaka, K.; Itazaki, M.; Koga, N.; Nakazawa, H. Organometallics 2012, 31, 787–790. Koester, D. C.; Kobayashi, M.; Werz, D. B.; Nakao, Y. J. Am. Chem. Soc. 2012, 134, 6544–6547. (a) Muto, K.; Yamaguchi, J.; Lei, A.; Itami, K. J. Am. Chem. Soc. 2013, 135, 16384–16387; (b) Somerville, R. J.; Hale, L. V. A.; Gómez-Bengoa, E.; Burés, J.; Martin, R. J. Am. Chem. Soc. 2018, 140, 8771–8780; (c) Zhu, Y.; Smith, D. A.; Herbert, D. E.; Gatard, S.; Ozerov, O. V. Chem. Commun. 2012, 48, 218–220. (a) Hong, X.; Liang, Y.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 2017–2025; (b) Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352–6363; (c) Lu, Q.; Yu, H.; Fu, Y. J. Am. Chem. Soc. 2014, 136, 8252–8260; (d) Xu, H.; Muto, K.; Yamaguchi, J.; Zhao, C.; Itami, K.; Musaev, D. G. J. Am. Chem. Soc. 2014, 136, 14834–14844.

Synthetic Applications of C–O and C–E Bond Activation Reactions

415

10. (a) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. J. Org. Chem. 1992, 57, 4066–4068; (b) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc. 2009, 131, 9590–9599. 11. (a) Li, B.-J.; Li, Y.-Z.; Lu, X.-Y.; Liu, J.; Guan, B.-T.; Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 10124–10127; (b) Liu, X.; Jia, J.; Rueping, M. ACS Catal. 2017, 7, 4491–4496. 12. Ogawa, H.; Yang, Z.-K.; Minami, H.; Kojima, K.; Saito, T.; Wang, C.; Uchiyama, M. ACS Catal. 2017, 7, 3988–3994. 13. (a) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422–14423; (b) Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013, 15, 3950–3953; (c) Guan, B.-T.; Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 14468–14470. 14. (a) Xu, M.; Li, X.; Sun, Z.; Tu, T. Chem. Commun. 2013, 49, 11539–11541; (b) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022–4025; (c) Leowanawat, P.; Zhang, N.; Percec, V. J. Org. Chem. 2012, 77, 1018–1025; (d) Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748–17749; (e) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011, 76, 1507–1510; (f ) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc. 2009, 131, 17750–17752; (g) Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352; (h) Xu, L.; Li, B.-J.; Wu, Z.-H.; Lu, X.-Y.; Guan, B.-T.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Org. Lett. 2010, 12, 884; (i) Ohtsuki, A.; Yanagisawa, K.; Furukawa, T.; Tobisu, M.; Chatani, N. J. Org. Chem. 2016, 81, 9409–9414; (j) Ambre, R.; Wang, T.-H.; Xian, A.; Chen, Y.-S.; Liang, Y.-F.; Jurca, T.; Zhao, L.; Ong, T.-G. Chem. Eur. J. 2020, 26, 17021–17026. 15. Kuwano, R.; Shimizu, R. Chem. Lett. 2011, 40, 913–915. 16. Guo, L.; Hsiao, C.-C.; Yue, H.; Liu, X.; Rueping, M. ACS Catal. 2016, 6, 4438–4442. 17. Shi, W.-J.; Zhao, H.-W.; Wang, Y.; Cao, Z.-C.; Zhang, L.-S.; Yu, D.-G.; Shi, Z.-J. Adv. Synth. Catal. 2016, 358, 2410–2416. 18. Wang, J.; Ferguson, D. M.; Kalyani, D. Tetrahedron 2013, 69, 5780–5790. 19. (a) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 169–172; (b) Muto, K.; Hatakeyama, T.; Yamaguchi, J.; Itami, K. Chem. Sci. 2015, 6, 6792–6798; (c) Iwai, T.; Harada, T.; Shimada, H.; Asano, K.; Sawamura, M. ACS Catal. 2017, 7, 1681–1692. 20. Wang, Y.; Wu, S.-B.; Shi, W.-J.; Shi, Z.-J. Org. Lett. 2016, 18, 2548–2551. 21. (a) Takise, R.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem. Int. Ed. 2014, 53, 6791–6794; (b) Koch, E.; Takise, R.; Studer, A.; Yamaguchi, J.; Itami, K. Chem. Commun. 2015, 51, 855–857; (c) Cornella, J.; Jackson, E. P.; Martin, R. Angew. Chem. Int. Ed. 2015, 54, 4075–4078. 22. Ehle, A. R.; Zhou, Q.; Watson, M. P. Org. Lett. 2012, 14, 1202–1205. 23. Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082–1146. 24. (a) Takise, R.; Itami, K.; Yamaguchi, J. Org. Lett. 2016, 18, 4428–4431; (b) Chen, Q.; Wu, A.; Qin, S.; Zeng, M.; Le, Z.; Yan, Z.; Zhang, H. Adv. Synth. Catal. 2018, 360, 3239–3244. 25. Weix, D. J. Acc. Chem. Res. 2015, 48, 1767–1775. 26. Cao, Z.-C.; Luo, Q.-Y.; Shi, Z.-J. Org. Lett. 2016, 18, 5978–5981. 27. (a) Correa, A.; León, T.; Martin, R. J. Am. Chem. Soc. 2014, 136, 1062–1069; (b) Correa, A.; Martin, R. J. Am. Chem. Soc. 2014, 136, 7253–7256. 28. Fujihara, T.; Nogi, K.; Xu, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2012, 134, 9106–9109. 29. (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544; (b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338–6361; (c) Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564–12649. 30. (a) Shimasaki, T.; Tobisu, M.; Chatani, N. Angew. Chem. Int. Ed. 2010, 49, 2929–2932; (b) Mesganaw, T.; Silberstein, A. L.; Ramgren, S. D.; Nathel, N. F. F.; Hong, X.; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766–1771; (c) Hie, L.; Ramgren, S. D.; Mesganaw, T.; Garg, N. K. Org. Lett. 2012, 14, 4182–4185; (d) Yue, H.; Guo, L.; Liu, X.; Rueping, M. Org. Lett. 2017, 19, 1788–1791. 31. Huang, K.; Yu, D.-G.; Zheng, S.-F.; Wu, Z.-H.; Shi, Z.-J. Chem. Eur. J. 2011, 17, 786–791. 32. (a) Zarate, C.; Martin, R. J. Am. Chem. Soc. 2014, 136, 2236–2239; (b) Murugesan, V.; Balakrishnan, V.; Rasappan, R. J. Catal. 2019, 377, 293–298. 33. Gu, Y.; Martín, R. Angew. Chem. Int. Ed. 2017, 56, 3187–3190. 34. (a) Yang, J.; Chen, T.; Han, L.-B. J. Am. Chem. Soc. 2015, 137, 1782–1785; (b) Yang, J.; Xiao, J.; Chen, T.; Han, L.-B. J. Org. Chem. 2016, 81, 3911–3916. 35. Nishizawa, A.; Takahira, T.; Yasui, K.; Fujimoto, H.; Iwai, T.; Sawamura, M.; Chatani, N.; Tobisu, M. J. Am. Chem. Soc. 2019, 141, 7261–7265. 36. (a) Tobisu, M.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem. Commun. 2011, 47, 2946–2948; (b) Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012, 14, 2918–2921; (c) Xi, X.; Chen, T.; Zhang, J.-S.; Han, L.-B. Chem. Commun. 2018, 54, 1521–1524. 37. (a) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500–1511; (b) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293–1314; (c) Nakamura, E.; Hatakeyama, T.; Ito, S.; Ishizuka, K.; Ilies, L.; Nakamura, M. Org. React. 2013, 83, 1–210; (d) Shang, R.; Ilies, L.; Nakamura, E. Chem. Rev. 2017, 117, 9086–9139; (e) Rana, S.; Biswas, J. P.; Paul, S.; Paik, A.; Maiti, D. Chem. Soc. Rev. 2021, 50, 243–472. 38. (a) Li, B.-J.; Xu, L.; Wu, Z.-H.; Guan, B.-T.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J. J. Am. Chem. Soc. 2009, 131, 14656–14657; (b) Silberstein, A. L.; Ramgren, S. D.; Garg, N. K. Org. Lett. 2012, 14, 3796–3799; (c) Zhang, J.; Zhang, Y.; Geng, S.; Chen, S.; Liu, Z.; Zeng, X.; He, Y.; Feng, Z. Org. Lett. 2020, 22, 2669–2674. 39. (a) Kinuta, H.; Hasegawa, J.; Tobisu, M.; Chatani, N. Chem. Lett. 2015, 44, 366–368; (b) Nakamura, K.; Yasui, K.; Tobisu, M.; Chatani, N. Tetrahedron 2015, 71, 4484–4489. 40. Song, W.; Ackermann, L. Angew. Chem. Int. Ed. 2012, 51, 8251–8254. 41. (a) Tobisu, M.; Yasui, K.; Aihara, Y.; Chatani, N. Angew. Chem. Int. Ed. 2017, 56, 1877–1880; (b) Yasui, K.; Chatani, N.; Tobisu, M. Org. Lett. 2018, 20, 2108–2111; (c) Yasui, K.; Higashino, M.; Chatani, N.; Tobisu, M. Synlett 2017, 28, 2569–2572. 42. (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc. 1979, 101, 2246–2247; (b) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49, 4894–4899. 43. (a) van der Boom, M. E.; Liou, S. Y.; Ben-David, Y.; Vigalok, A.; Milstein, D. Angew. Chem. Int. Ed. 1997, 36, 625–626; (b) van der Boom, M. E.; Liou, S.-Y.; Ben-David, Y.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 1998, 120, 6531–6541; (c) Kelley, P.; Lin, S.; Edouard, G.; Day, M. W.; Agapie, T. J. Am. Chem. Soc. 2012, 134, 5480–5483. 44. Cornella, J.; Gómez-Bengoa, E.; Martin, R. J. Am. Chem. Soc. 2013, 135, 1997–2009. 45. (a) Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516–16517; (b) Lau, S.; Ward, B.; Zhou, X.; White, A. J. P.; Casely, I. J.; Macgregor, S. A.; Crimmin, M. R. Organometallics 2017, 36, 3654–3663. 46. Schwarzer, M. C.; Konno, R.; Hojo, T.; Ohtsuki, A.; Nakamura, K.; Yasutome, A.; Takahashi, H.; Shimasaki, T.; Tobisu, M.; Chatani, N.; Mori, S. J. Am. Chem. Soc. 2017, 139, 10347–10358. 47. (a) Ogawa, H.; Minami, H.; Ozaki, T.; Komagawa, S.; Wang, C.; Uchiyama, M. Chem. Eur. J. 2015, 21, 13904–13908; (b) Kojima, K.; Yang, Z.-K.; Wang, C.; Uchiyama, M. Chem. Pharm. Bull. 2017, 65, 862–868; (c) Uthayopas, C.; Surawatanawong, P. Dalton Trans. 2019, 48, 7817–7827. 48. Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba, S.; Murphy, J. A. Angew. Chem. Int. Ed. 2019, 58, 16368–16388. 49. (a) Zarate, C.; Nakajima, M.; Martin, R. J. Am. Chem. Soc. 2017, 139, 1191–1197; (b) Jain, P.; Pal, S.; Avasare, V. Organometallics 2018, 37, 1141–1149; (c) Wang, B.; Zhang, Q.; Jiang, J.; Yu, H.; Fu, Y. Chem. Eur. J. 2017, 23, 17249–17256. 50. (a) Dankwardt, J. W. Angew. Chem. Int. Ed 2004, 43, 2428–2432; (b) Xie, L.-G.; Wang, Z.-X. Chem. Eur. J. 2011, 17, 4972–4975; (c) Zhao, F.; Yu, D.-G.; Zhu, R.-Y.; Xi, Z.; Shi, Z. J. Chem. Lett. 2011, 40, 1001–1003; (d) Iglesias, M. J.; Prieto, A.; Nicasio, M. C. Org. Lett. 2012, 14, 4318–4321; (e) Zhang, J.; Xu, J.; Xu, Y.; Sun, H.; Shen, Q.; Zhang, Y. Organometallics 2015, 34, 5792–5800; (f ) Ghorai, D.; Loup, J.; Zanoni, G.; Ackermann, L. Synlett 2019, 30, 429–432; (g) Ambre, R.; Yang, H.; Chen, W.-C.; Yap, G. P. A.; Jurca, T.; Ong, T.-G. Eur. J. Inorg. Chem. 2019, 2019, 3511–3517. 51. (a) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 44, 1437–1439; (b) Tobisu, M.; Takahira, T.; Chatani, N. Org. Lett. 2015, 17, 4352–4355.

416

Synthetic Applications of C–O and C–E Bond Activation Reactions

52. (a) Tobisu, M.; Takahira, T.; Ohtsuki, A.; Chatani, N. Org. Lett. 2015, 17, 680–683; (b) Chen, X.-C.; Nishinaga, S.; Okuda, Y.; Zhao, J.-J.; Xu, J.; Mori, H.; Nishihara, Y. Org. Chem. Front. 2015, 2, 536–541. 53. Tobisu, M.; Takahira, T.; Morioka, T.; Chatani, N. J. Am. Chem. Soc. 2016, 138, 6711–6714. 54. (a) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem. Int. Ed. 2008, 47, 4866–4869; (b) Tobisu, M.; Yasutome, A.; Kinuta, H.; Nakamura, K.; Chatani, N. Org. Lett. 2014, 16, 5572–5575; (c) Guo, L.; Liu, X.; Baumann, C.; Rueping, M. Angew. Chem. Int. Ed. 2016, 55, 15415–15419. 55. Wang, C.; Ozaki, T.; Takita, R.; Uchiyama, M. Chem.-Eur. J. 2012, 18, 3482–3485. 56. (a) Leiendecker, M.; Hsiao, C.-C.; Guo, L.; Alandini, N.; Rueping, M. Angew. Chem. Int. Ed. 2014, 53, 12912–12915; (b) Heijnen, D.; Gualtierotti, J.-B.; Hornillos, V.; Feringa, B. L. Chem. Eur. J. 2016, 22, 3991–3995; (c) Yang, Z.-K.; Wang, D.-Y.; Minami, H.; Ogawa, H.; Ozaki, T.; Saito, T.; Miyamoto, K.; Wang, C.; Uchiyama, M. Chem.-Eur. J. 2016, 22, 15693–15699. 57. (a) Morioka, T.; Nishizawa, A.; Nakamura, K.; Tobisu, M.; Chatani, N. Chem. Lett. 2015, 44, 1729–1731; (b) Liu, X.; Hsiao, C.-C.; Kalvet, I.; Leiendecker, M.; Guo, L.; Schoenebeck, F.; Rueping, M. Angew. Chem. Int. Ed. 2016, 55, 6093–6098; (c) Liu, C.-Y.; Wititsuwannakul, T.; Hsieh, C.-H.; Tsai, C.-Y.; Wang, T.-H.; Ambre, R.; Chen, W.-C.; Surawatanawong, P.; Ong, T.-G. J. Chin. Chem. Soc. 2020, 67, 376–382. 58. Yan, X.; Yang, F.; Cai, G.; Meng, Q.; Li, X. Org. Lett. 2018, 20, 624–627. 59. (a) Yang, Z.-K.; Xu, N.-X.; Takita, R.; Muranaka, A.; Wang, C.; Uchiyama, M. Nat. Commun. 2018, 9, 1587–1593; (b) Kurata, Y.; Otsuka, S.; Fukui, N.; Nogi, K.; Yorimitsu, H.; Osuka, A. Org. Lett. 2017, 19, 1274–1277. 60. Wang, T.-H.; Ambre, R.; Wang, Q.; Lee, W.-C.; Wang, P.-C.; Liu, Y.; Zhao, L.; Ong, T.-G. ACS Catal. 2018, 8, 11368–11376. 61. Iyori, Y.; Ueno, R.; Morishige, A.; Chatani, N. Chem. Sci. 2021, 12, 1772–1777. 62. (a) Tobisu, M.; Shimasaki, T.; Chatani, N. Chem. Lett. 2009, 38, 710–711; (b) Tobisu, M.; Yasutome, A.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Tetrahedron 2012, 68, 5157–5161; (c) Wiensch, E. M.; Montgomery, J. Angew. Chem. Int. Ed. 2018, 57, 11045–11049. 63. Zarate, C.; Manzano, R.; Martin, R. J. Am. Chem. Soc. 2015, 137, 6754–6757. 64. Nakamura, K.; Tobisu, M.; Chatani, N. Org. Lett. 2015, 17, 6142–6145. 65. Wiensch, E. M.; Todd, D. P.; Montgomery, J. ACS Catal. 2017, 7, 5568–5571. 66. (a) Álvarez-Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132, 17352–17353; (b) Sergeev, A. G.; Hartwig, J. F. Science 2011, 332, 439–443; (c) Tobisu, M.; Morioka, T.; Ohtsuki, A.; Chatani, N. Chem. Sci. 2015, 6, 3410–3414; (d) Edouard, G. A.; Kelley, P.; Herbert, D. E.; Agapie, T. Organometallics 2015, 34, 5254–5277; (e) Saper, N. I.; Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 17667–17676. 67. (a) Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706–2707; (b) Hikaru, K.; Nana, A.; Takuya, K.; Fumitoshi, K. Angew. Chem. Int. Ed. 2015, 54, 9293–9297; (c) Kondo, H.; Kochi, T.; Kakiuchi, F. Org. Lett. 2017, 19, 794–797; (d) Kondo, H.; Kochi, T.; Kakiuchi, F. Chem. Eur. J. 2020, 26, 1737–1741; (e) Wang, Z.; Zhou, Y.; Lam, W. H.; Lin, Z. Organometallics 2017, 36, 2354–2363; (f ) Zhao, Y.; Snieckus, V. J. Am. Chem. Soc. 2014, 136, 11224–11227; (g) Zhao, Y.; Snieckus, V. Org. Lett. 2015, 17, 4674–4677; (h) Zhao, Y.; Snieckus, V. Chem. Commun. 2016, 52, 1681–1684; (i) Zhao, Y.; Snieckus, V. Org. Lett. 2018, 20, 2826–2830; (j) Matsumura, D.; Kitazawa, K.; Terai, S.; Kochi, T.; Ie, Y.; Nitani, M.; Aso, Y.; Kakiuchi, F. Org. Lett. 2012, 14, 3882–3885; (k) Suzuki, Y.; Yamada, K.; Watanabe, K.; Kochi, T.; Ie, Y.; Aso, Y.; Kakiuchi, F. Org. Lett. 2017, 19, 3791–3794; (l) Izumoto, A.; Kondo, H.; Kochi, T.; Kakiuchi, F. Synlett 2017, 28, 2609–2613; (m) da Frota, L. C. R. M.; Schneider, C.; de Amorim, M. B.; da Silva, A. J. M.; Snieckus, V. Synlett 2017, 28, 2587–2593. 68. Kakiuchi, F.; Kochi, T.; Murai, S. Synlett 2014, 25, 2390–2414. 69. (a) Fürstner, A. Chem. Rev. 1999, 99, 991–1046; (b) Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D.; Knochel, P. J. Am. Chem. Soc. 2013, 135, 15346–15349. 70. (a) Cong, X.; Tang, H.; Zeng, X. J. Am. Chem. Soc. 2015, 137, 14367–14372; (b) Tang, J.; Luo, M.; Zeng, X. Synlett 2017, 28, 2577–2580; (c) Rong, Z.; Luo, M.; Zeng, X. Org. Lett. 2019, 21, 6869–6873; (d) Tang, J.; Liu, L. L.; Yang, S.; Cong, X.; Luo, M.; Zeng, X. J. Am. Chem. Soc. 2020, 142, 7715–7720. 71. (a) Rao, H.; Li, C.-J. Angew. Chem. Int. Ed. 2011, 50, 8936–8939; (b) Hibe, Y.; Ebe, Y.; Nishimura, T.; Yorimitsu, H. Chem. Lett. 2017, 46, 953–955. 72. Liu, F.; Jiang, H.-J.; Zhou, Y.; Shi, Z.-J. Chin. J. Chem. 2020, 38, 855–863. 73. (a) Yu, D.-G.; Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-J. Angew. Chem. Int. Ed. 2010, 49, 4566–4570; (b) Shi, W. J.; Shi, Z. J. Chin. J. Chem. 2018, 36, 183–186; (c) Yu, D.-G.; Shi, Z.-J. Angew. Chem. Int. Ed. 2011, 50, 7097–7100; (d) Cao, Z.-C.; Luo, F.-X.; Shi, W.-J.; Shi, Z.-J. Org. Chem. Front. 2015, 2, 1505–1510; (e) Shi, W.-J.; Li, X.-L.; Li, Z.-W.; Shi, Z.-J. Org. Chem. Front. 2016, 3, 375–379; (f ) Ohgi, A.; Nakao, Y. Chem. Lett. 2016, 45, 45–47; (g) Kusumoto, S.; Nozaki, K. Nat. Commun. 2015, 6, 6296. 74. (a) Kocienski, P.; Dixon, N. Synlett 1989, 52–54; (b) Porée, F.-H.; Clavel, A.; Betzer, J.-F.; Pancrazi, A.; Ardisson, J. Tetrahedron Lett. 2003, 44, 7553–7556; (c) Sun, C. L.; Wang, Y.; Zhou, X.; Wu, Z. H.; Li, B.; Guan, B. T.; Shi, Z. J. Chem. Eur. J. 2010, 16, 5844–5847; (d) Meng, L.; Kamada, Y.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem. Int. Ed. 2013, 52, 10048–10051; (e) He, R.-D.; Li, C.-L.; Pan, Q.-Q.; Guo, P.; Liu, X.-Y.; Shu, X.-Z. J. Am. Chem. Soc. 2019, 141, 12481–12486. 75. (a) Hayashi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett. 1980, 21, 3915–3918; (b) Wadman, S.; Whitby, R.; Yeates, C.; Kocienski, P.; Cooper, K. J. Chem. Soc. Chem. Commun. 1987, 241–243; (c) Whitby, R.; Yeates, C.; Kocienski, P.; Costello, G. J. Chem. Soc. Chem. Commun. 1987, 429–430; (d) Ducoux, J.-P.; Le Ménez, P.; Kunesch, N.; Kunesch, G.; Wenkert, E. Tetrahedron 1992, 48, 6403–6412; (e) Tingoli, M.; Panunzi, B.; Santacroce, F. Tetrahedron Lett. 1999, 40, 9329–9332; (f ) Shimasaki, T.; Konno, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2009, 11, 4890–4892; (g) Cornella, J.; Martin, R. Org. Lett. 2013, 15, 6298–6301; (h) Ohtsuki, A.; Sakurai, S.; Tobisu, M.; Chatani, N. Chem. Lett. 2016, 45, 1277–1279; (i) Guo, L.; Leiendecker, M.; Hsiao, C.-C.; Baumann, C.; Rueping, M. Chem. Commun. 2015, 51, 1937–1940; (j) Ho, G.-M.; Sommer, H.; Marek, I. Org. Lett. 2019, 21, 2913–2917; (k) Saito, H.; Otsuka, S.; Nogi, K.; Yorimitsu, H. J. Am. Chem. Soc. 2016, 138, 15315–15318. 76. (a) Sun, C.-L.; Fürstner, A. Angew. Chem. Int. Ed. 2013, 52, 13071–13075; (b) Gärtner, D.; Stein, A. L.; Grupe, S.; Arp, J.; Jacobi von Wangelin, A. Angew. Chem. Int. Ed. 2015, 54, 10545–10549; (c) Moselage, M.; Sauermann, N.; Richter, S. C.; Ackermann, L. Angew. Chem. Int. Ed. 2015, 54, 6352–6355; (d) Li, J.; Knochel, P. Angew. Chem. Int. Ed. 2018, 57, 11436–11440; (e) Li, J.; Ren, Q.; Cheng, X.; Karaghiosoff, K.; Knochel, P. J. Am. Chem. Soc. 2019, 141, 18127–18135; (f ) Chen, Z.; So, C. M. Org. Lett. 2020, 22, 3879–3883; (g) Becica, J.; Heath, O. R. J.; Zheng, C. H. M.; Leitch, D. C. Angew. Chem. Int. Ed. 2020, 59, 17277–17281. 77. (a) Iwasaki, T.; Miyata, Y.; Akimoto, R.; Fujii, Y.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2014, 136, 9260–9263; (b) Itami, K.; Tanaka, S.; Sunahara, K.; Tatsuta, G.; Mori, A. Asian J. Org. Chem. 2015, 4, 477–481; (c) Iwasaki, T.; Akimoto, R.; Kuniyasu, H.; Kambe, N. Chem. Asian J. 2016, 11, 2834–2837. 78. (a) Yu, J.-Y.; Kuwano, R. Angew. Chem. Int. Ed. 2009, 48, 7217–7220; (b) Lee, H. W.; Kwong, F. Y. Synlett 2009, 3151–3154; (c) Yu, J.-Y.; Shimizu, R.; Kuwano, R. Angew. Chem. Int. Ed. 2010, 49, 6396–6399. 79. (a) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858–9859; (b) Ogiwara, Y.; Tamura, M.; Kochi, T.; Matsuura, Y.; Chatani, N.; Kakiuchi, F. Organometallics 2014, 33, 402–420; (c) Mei, S.-T.; Jiang, K.; Wang, N.-J.; Shuai, L.; Yuan, Y.; Wei, Y. Eur. J. Org. Chem. 2015, 2015, 6135–6140. 80. Ohno, S.; Qiu, J.; Miyazaki, R.; Aoyama, H.; Murai, K.; Hasegawa, J.-Y.; Arisawa, M. Org. Lett. 2019, 21, 8400–8403. 81. (a) Stephan, M. S.; Teunissen, A. J. J. M.; Verzijl, G. K. M.; de Vries, J. G. Angew. Chem. Int. Ed. 1998, 37, 662–664; (b) Gooßen, L. J.; Ghosh, K. Angew. Chem. Int. Ed. 2001, 40, 3458–3460; (c) Gooßen, L. J.; Paetzold, J. Angew. Chem. Int. Ed. 2004, 43, 1095–1098; (d) Jin, W.; Yu, Z.; He, W.; Ye, W.; Xiao, W.-J. Org. Lett. 2009, 11, 1317–1320. 82. Gooßen, L. J.; Paetzold, J. Angew. Chem. Int. Ed. 2002, 41, 1237–1241. 83. Lin, C.; Gao, F.; Shen, L. Adv. Synth. Catal. 2019, 361, 3915–3924. 84. (a) Ishizu, J.; Yamamoto, T.; Yamamoto, A. Chem. Lett. 1976, 5, 1091–1094; (b) Yamamoto, T.; Ishizu, J.; Kohara, T.; Komiya, S.; Yamamoto, A. J. Am. Chem. Soc. 1980, 102, 3758–3764. 85. Takise, R.; Muto, K.; Yamaguchi, J. Chem. Soc. Rev. 2017, 46, 5864–5888. 86. (a) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573–13576; (b) Kruckenberg, A.; Wadepohl, H.; Gade, L. H. Organometallics 2013, 32, 5153–5170. 87. (a) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508; (b) LaBerge, N. A.; Love, J. A. Eur. J. Org. Chem. 2015, 2015, 5546–5553; (c) Chatupheeraphat, A.; Liao, H.-H.; Srimontree, W.; Guo, L.; Minenkov, Y.; Poater, A.; Cavallo, L.; Rueping, M. J. Am. Chem. Soc. 2018, 140, 3724–3735; (d) Feng, B.; Yang, Y.;

Synthetic Applications of C–O and C–E Bond Activation Reactions

88.

89.

90.

91.

92. 93. 94. 95.

96.

97.

98. 99. 100. 101.

102.

103.

104. 105.

106. 107. 108. 109. 110. 111.

112.

113. 114.

115.

417

You, J. Chem. Sci. 2020, 11, 6031–6035; (e) Muto, K.; Hatakeyama, T.; Itami, K.; Yamaguchi, J. Org. Lett. 2016, 18, 5106–5109; (f ) Masson-Makdissi, J.; Vandavasi, J. K.; Newman, S. G. Org. Lett. 2018, 20, 4094–4098; (g) Okita, T.; Muto, K.; Yamaguchi, J. Org. Lett. 2018, 20, 3132–3135; (h) Chatupheeraphat, A.; Liao, H.-H.; Lee, S.-C.; Rueping, M. Org. Lett. 2017, 19, 4255–4258. (a) Matsushita, K.; Takise, R.; Hisada, T.; Suzuki, S.; Isshiki, R.; Itami, K.; Muto, K.; Yamaguchi, J. Chem. Asian J. 2018, 13, 2393–2396; (b) Okita, T.; Komatsuda, M.; Saito, A. N.; Hisada, T.; Takahara, T. T.; Nakayama, K. P.; Isshiki, R.; Takise, R.; Muto, K.; Yamaguchi, J. Asian J. Org. Chem. 2018, 7, 1358–1361; (c) Isshiki, R.; Takise, R.; Itami, K.; Muto, K.; Yamaguchi, J. Synlett 2017, 28, 2599–2603; (d) Okita, T.; Kumazawa, K.; Takise, R.; Muto, K.; Itami, K.; Yamaguchi, J. Chem. Lett. 2017, 46, 218–220. (a) Yue, H.; Guo, L.; Liao, H. H.; Cai, Y.; Zhu, C.; Rueping, M. Angew. Chem. Int. Ed. 2017, 56, 4282–4285; (b) Malapit, C. A.; Borrell, M.; Milbauer, M. W.; Brigham, C. E.; Sanford, M. S. J. Am. Chem. Soc. 2020, 142, 5918–5923; (c) Takise, R.; Isshiki, R.; Muto, K.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc. 2017, 139, 3340–3343; (d) Lee, S.C.; Liao, H.-H.; Chatupheeraphat, A.; Rueping, M. Chem. Eur. J. 2018, 24, 3608–3612; (e) Isshiki, R.; Muto, K.; Yamaguchi, J. Org. Lett. 2018, 20, 1150–1153; (f ) Guo, L.; Rueping, M. Chem. Eur. J. 2016, 22, 16787–16790; (g) Pu, X.; Hu, J.; Zhao, Y.; Shi, Z. ACS Catal. 2016, 6, 6692–6698; (h) Guo, L.; Chatupheeraphat, A.; Rueping, M. Angew. Chem. Int. Ed. 2016, 55, 11810–11813; (i) Yue, H.; Zhu, C.; Rueping, M. Org. Lett. 2018, 20, 385–388; (j) Yue, H.; Guo, L.; Lee, S. C.; Liu, X.; Rueping, M. Angew. Chem. Int. Ed. 2017, 56, 3972–3976. (a) Dardir, A. H.; Melvin, P. R.; Davis, R. M.; Hazari, N.; Mohadjer Beromi, M. J. Org. Chem. 2018, 83, 469–477; (b) Hie, L.; Nathel, N. F. F.; Hong, X.; Yang, Y. F.; Houk, K. N.; Garg, N. K. Angew. Chem. Int. Ed. 2016, 55, 2810–2814; (c) Ben Halima, T.; Masson-Makdissi, J.; Newman, S. G. Angew. Chem. Int. Ed. 2018, 57, 12925–12929; (d) Zheng, Y.-L.; Newman, S. G. ACS Catal. 2019, 9, 4426–4433; (e) Ben Halima, T.; Vandavasi, J. K.; Shkoor, M.; Newman, S. G. ACS Catal. 2017, 7, 2176–2180; (f ) Shi, S.; Szostak, M. Chem. Commun. 2017, 53, 10584–10587; (g) Cheung, C. W.; Ploeger, M. L.; Hu, X. Nat. Commun. 2017, 8, 14878; (h) Ling, L.; Chen, C.; Luo, M.; Zeng, X. Org. Lett. 2019, 21, 1912–1916. (a) Ben Halima, T.; Zhang, W.; Yalaoui, I.; Hong, X.; Yang, Y.-F.; Houk, K. N.; Newman, S. G. J. Am. Chem. Soc. 2017, 139, 1311–1318; (b) Lei, P.; Ling, Y.; An, J.; Nolan, S. P.; Szostak, M. Adv. Synth. Catal. 2019, 361, 5654–5660; (c) Lei, P.; Meng, G.; Shi, S.; Ling, Y.; An, J.; Szostak, R.; Szostak, M. Chem. Sci. 2017, 8, 6525–6530; (d) Shi, S.; Lei, P.; Szostak, M. Organometallics 2017, 36, 3784–3789; (e) Li, G.; Shi, S.; Lei, P.; Szostak, M. Adv. Synth. Catal. 2018, 360, 1538–1543; (f ) Zhou, T.; Li, G.; Nolan, S. P.; Szostak, M. Org. Lett. 2019, 21, 3304–3309. Cook, A.; Prakash, S.; Zheng, Y.-L.; Newman, S. G. J. Am. Chem. Soc. 2020, 142, 8109–8115. Kurosawa, M. B.; Isshiki, R.; Muto, K.; Yamaguchi, J. J. Am. Chem. Soc. 2020, 142, 7386–7392. (a) Isshiki, R.; Inayama, N.; Muto, K.; Yamaguchi, J. ACS Catal. 2020, 10, 3490–3494; (b) Matsushita, K.; Takise, R.; Muto, K.; Yamaguchi, J. Sci. Adv. 2020, 6, , eaba7614. (a) Ooguri, A.; Nakai, K.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009, 131, 13194–13195; (b) Zheng, Y.-L.; Newman, S. G. Angew. Chem. Int. Ed. 2019, 58, 18159–18164; (c) Doi, R.; Shimizu, K.; Ikemoto, Y.; Uchiyama, M.; Koshiba, M.; Furukawa, A.; Maenaka, K.; Watanabe, S.; Sato, Y. ChemCatChem 2021https://doi.org/ 10.1002/cctc.202001949. in press. (a) Ohashi, M.; Taniguchi, T.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 14900–14903; (b) Jenkins, A. D.; Herath, A.; Song, M.; Montgomery, J. J. Am. Chem. Soc. 2011, 133, 14460–14466; (c) Ahlin, J. S. E.; Donets, P. A.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 13229–13233; (d) Jenkins, A. D.; Robo, M. T.; Zimmerman, P. M.; Montgomery, J. J. Org. Chem. 2020, 85, 2956–2965. (a) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54–55; (b) Miura, T.; Sasaki, T.; Nakazawa, H.; Murakami, M. J. Am. Chem. Soc. 2005, 127, 1390–1391; (c) Matsuda, T.; Suda, Y.; Takahashi, A. Chem. Commun. 2012, 48, 2988–2990; (d) Matsuda, T.; Yasuoka, S.; Watanuki, S.; Fukuhara, K. Synlett 2015, 26, 1233–1237; (e) O’Brien, L.; Karad, S. N.; Lewis, W.; Lam, H. W. Chem. Commun. 2019, 55, 11366–11369; (f ) Selmani, A.; Darses, S. Org. Lett. 2019, 21, 8122–8126; (g) Chen, J.; Hayashi, T. Angew. Chem. Int. Ed. 2020, 59, 18510–18514; (h) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227–4230; (i) Karad, S. N.; Panchal, H.; Clarke, C.; Lewis, W.; Lam, H. W. Angew. Chem. Int. Ed. 2018, 57, 9122–9125. Trost, B. M.; Czabaniuk, L. C. Angew. Chem. Int. Ed. 2014, 53, 2826–2851. Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Acc. Chem. Res. 2015, 48, 2344–2353. Cao, Z.-C.; Shi, Z.-J. J. Am. Chem. Soc. 2017, 139, 6546–6549. (a) Chatani, N.; Murai, S. Synlett 1996, 7, 414–424; (b) Seki, Y.; Murai, S.; Yamamoto, I.; Sonoda, N. Angew. Chem. Int. Ed. 1977, 16, 789; (c) Murai, T.; Yasui, E.; Kato, S.; Hatayama, Y.; Suzuki, S.; Yamasaki, Y.; Sonoda, N.; Kurosawa, H.; Kawasaki, Y.; Murai, S. J. Am. Chem. Soc. 1989, 111, 7938–7946; (d) Seki, Y.; Murai, S.; Sonoda, N. Angew. Chem. Int. Ed. 1978, 17, 119–120; (e) Murai, T.; Kato, S.; Murai, S.; Hatayama, Y.; Sonoda, N. Tetrahedron Lett. 1985, 26, 2683–2684; (f ) Murai, T.; Hatayama, Y.; Murai, S.; Sonoda, N. Organometallics 1983, 2, 1883–1885; (g) Chatani, N.; Murai, S.; Sonoda, N. J. Am. Chem. Soc. 1983, 105, 1370–1372; (h) Chatani, N.; Fujii, S.; Yamasaki, Y.; Murai, S.; Sonoda, N. J. Am. Chem. Soc. 1986, 108, 7361–7373; (i) Chatani, N.; Fujii, S.; Kido, Y.; Nakayama, Y.; Kajikawa, Y.; Tokuhisa, H.; Fukumoto, Y.; Murai, S. Bull. Chem. Soc. Jpn. 2021, 94, 81–90. (a) Yang, J.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 2008, 130, 17509–17518; (b) McLaughlin, M. P.; Adduci, L. L.; Becker, J. J.; Gagné, M. R. J. Am. Chem. Soc. 2013, 135, 1225–1227; (c) Jones, C. A. H.; Schley, N. D. Org. Biomol. Chem. 2019, 17, 1744–1748; (d) Fast, C. D.; Jones, C. A. H.; Schley, N. D. ACS Catal. 2020, 10, 6450–6456. (a) Ogiwara, Y.; Kochi, T.; Kakiuchi, F. Org. Lett. 2011, 13, 3254–3257; (b) Luo, S.; Yu, D.-G.; Zhu, R.-Y.; Wang, X.; Wang, L.; Shi, Z.-J. Chem. Comm. 2013, 49, 7794–7796; (c) Haibach, M. C.; Lease, N.; Goldman, A. S. Angew. Chem. Int. Ed. 2014, 53, 10160–10163; (d) Tran, V. T.; Gurak, J. A.; Yang, K. S.; Engle, K. M. Nature Chem. 2018, 10, 1126–1133; (e) Guan, Q.; Lin, C.; Chen, S.; Gao, F.; Shen, L. Adv. Synth. Catal. 2020, 362, 5772–5776. Rej, S.; Ano, Y.; Chatani, N. Chem. Rev. 2020, 120, 1788–1887. (a) Wang, L.; He, W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599–621; (b) Yorimitsu, H. Chem. Rec. 2021, 21. https://doi.org/10.1002/tcr.202000172; (c) Modha, S. G.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2013, 42, 5042–5055; (d) Otsuka, S.; Nogi, K.; Yorimitsu, H. Top. Curr. Chem. 2018, 376, 13; (e) Pan, F.; Shi, Z.-J. ACS Catal. 2014, 4, 280–288; (f ) Lou, J.; Wang, Q.; Wu, P.; Wang, H.; Zhou, Y.-G.; Yu, Z. Chem. Soc. Rev. 2020, 49, 4307–4359; (g) Takahashi, F.; Nogi, K.; Yorimitsu, H. Phosphorus Sulfur Silicon Relat. Elem. 2019, 194, 742–745. (a) Alcalde, M. I.; Delgado, E.; Donnadieu, B.; Hernandez, E.; Martin, M. P.; Zamora, F. J. Organomet. Chem. 2004, 689, 552–556; (b) O’Connor, J. M.; Bunker, K. D.; Rheingold, A. L.; Zakharov, L. J. Am. Chem. Soc. 2005, 127, 4180–4181. Iwasaki, M.; Fujino, D.; Wada, T.; Kondoh, A.; Yorimitsu, H.; Oshima, K. Chem. Asian J. 2011, 6, 3190–3194. Shibata, T.; Mitake, A.; Akiyama, Y.; Kanyiva, K. S. Chem. Commun. 2017, 53, 9016–9019. Zhang, Z.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331–4333. Pawliczek, M.; Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, 17, 1716–1719. (a) Osakada, K.; Maeda, M.; Nakamura, Y.; Yamamoto, T.; Yamamoto, A. J. Chem. Soc. Chem. Commun. 1986, 22, 442–443; (b) Schaub, T.; Backes, M.; Plietzsch, O.; Radius, U. Dalton Trans. 2009, 38, 7071–7079; (c) Han, L.-B.; Choi, N.; Tanaka, M. J. Am. Chem. Soc. 1997, 119, 1795–1796; (d) Kundu, S.; Snyder, B. E. R.; Walsh, A. P.; Brennessel, W. W.; Jones, W. D. Polyhedron 2013, 58, 99–105. (a) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 20, 43–46; (b) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem. Lett. 1979, 8, 1447–1450; (c) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc. Chem. Commun. 1979, 15, 637–638; (d) Takei, H.; Sugimura, H.; Miura, M.; Okamura, H. Chem. Lett. 1980, 9, 1209–1212; (e) Okamura, H.; Takei, H. Tetrahedron Lett. 1979, 20, 3425–3428; (f ) Wenkert, E.; Fernandes, J. B.; Michelotti, E. L.; Swinndell, C. S. Synthesis 1983, 1983, 701–703. Fabre, J.-L.; Julia, M.; Verpeaux, J.-N. Tetrahedron Lett. 1982, 23, 2469–2472. (a) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J.-I. J. Am. Chem. Soc. 2004, 126, 11778–11779; (b) Itami, K.; Yamazaki, D.; Yoshida, J.-I. J. Am. Chem. Soc. 2004, 126, 15396–15397; (c) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem. 2009, 74, 6870–6873; (d) Eberhart, A. J.; Imbriglio, J. E.; Procter, D. J. Org. Lett. 2011, 13, 5882–5885; (e) Murakami, K.; Yorimitsu, H.; Osuka, A. Angew. Chem. Int. Ed. 2014, 53, 7510–7513. (a) Kanemura, S.; Kondoh, A.; Yorimitsu, H.; Oshima, K. Synthesis 2008, 2659–2664; (b) Baralle, A.; Yorimitsu, H.; Osuka, A. Chem. Eur. J. 2016, 22, 10768–10772.

418 116. 117. 118. 119. 120. 121. 122.

123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152.

153. 154. 155. 156. 157. 158. 159. 160.

161. 162. 163. 164. 165. 166.

Synthetic Applications of C–O and C–E Bond Activation Reactions Someya, C. I.; Weidauer, M.; Enthaler, S. Catal. Lett. 2013, 143, 424–431. Zhu, D.; Shi, L. Chem. Commun. 2018, 54, 9313–9316. Gehrtz, P. H.; Geiger, V.; Schmidt, T.; Sršan, L.; Fleischer, I. Org. Lett. 2019, 21, 50–55. Ishizuka, K.; Seike, H.; Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132, 13117–13119. (a) Tiecco, M.; Tingoli, M.; Wenkert, E. J. Org. Chem. 1985, 50, 3828–3831; (b) Hintermann, L.; Schmitz, M.; Chen, Y. Adv. Synth. Catal. 2010, 352, 2411–2415; (c) Shimada, T.; Cho, Y.-H.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396–13397. (a) Yang, Z.; Chen, X.; Kong, W.; Xia, S.; Zheng, R.; Luo, F.; Zhu, G. Org. Biomol. Chem. 2013, 11, 2175–2185; (b) Chen, J.; Chen, S.; Xu, X. H.; Tang, Z.; Au, C.-T.; Qiu, R. J. Org. Chem. 2016, 81, 3246–3255. (a) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 9449–9450; (b) Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett 2000, 905–907; (c) Ghosh, I.; Jacobi, P. A. J. Org. Chem. 2002, 67, 9304–9309; (d) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457–1459; (e) Metzger, A.; Melzig, L.; Despotopoulou, C.; Knochel, P. Org. Lett. 2009, 11, 4228–4231; (f ) Begouin, J.-M.; Rivard, M.; Gosmini, C. Chem. Commun. 2010, 46, 5972–5974; (g) Melzig, L.; Metzger, A.; Knochel, P. J. Org. Chem. 2010, 75, 2131–2133; (h) Kobatake, T.; Fujino, D.; Yoshida, S.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2010, 132, 11838–11840; (i) Melzig, L.; Metzger, A.; Knochel, P. Chem. Eur. J. 2011, 17, 2948–2956; (j) Ookubo, Y.; Wakamiya, A.; Yorimitsu, H.; Osuka, A. Chem. Eur. J. 2012, 18, 12690–12697. (a) Otsuka, S.; Fujino, D.; Murakami, K.; Yorimitsu, H.; Osuka, A. Chem. Eur. J. 2014, 20, 13146–13149; (b) Otsuka, S.; Yorimitsu, H.; Osuka, A. Chem. Eur. J. 2015, 21, 14703–14707; (c) Yamamoto, K.; Otsuka, S.; Nogi, K.; Yorimitsu, H. ACS COKatal. 2017, 7, 7623–7628. (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979–981; (b) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349–4352. Liu, J.; Liu, Y.; Du, W.; Dong, Y.; Liu, J.; Wang, M. J. Org. Chem. 2013, 78, 7293–7297. Li, J.; An, Y.; Li, J.; Yang, S.; Wu, W.; Jiang, H. Org. Chem. Front. 2017, 4, 1590–1594. Lambert, W. D.; Fang, Y.; Mahapatra, S.; Huang, Z.; Am Ende, C. W.; Fox, J. M. J. Am. Chem. Soc. 2019, 141, 17068–17074. (a) Hooper, J. F.; Young, R. D.; Pernik, I.; Weller, A. S.; Willis, M. C. Chem. Sci. 2013, 4, 1568–1572; (b) Pan, F.; Wang, H.; Shen, P.-X.; Zhao, J.; Shi, Z.-J. Chem. Sci. 2013, 4, 1573–1577. Creech, G. S.; Kwon, O. Chem. Sci. 2013, 4, 2670–2674. (a) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801–802; (b) Zhu, T.; Jiang, L.; Li, Y.; Xie, Z.; Li, Z.; Lv, L.; Chen, H.; Zhao, Z.; Jiang, L.; Tang, B. Z.; Huang, H. Angew. Chem. Int. Ed. 2019, 58, 5044–5048. (a) Sugahara, T.; Murakami, K.; Yorimitsu, H.; Osuka, A. Angew. Chem. Int. Ed. 2014, 53, 9329–9333; (b) Gao, K.; Yorimitsu, H.; Osuka, A. Eur. J. Org. Chem. 2015, 2015, 2678–2682. Bismuto, A.; Delcaillau, T.; Müller, P.; Morandi, B. ACS Catal. 2020, 10, 4630–4639. (a) Bhanuchandra, M.; Baralle, A.; Otsuka, S.; Nogi, K.; Yorimitsu, H.; Osuka, A. Org. Lett. 2016, 18, 2966–2969; (b) Saito, H.; Nogi, K.; Yorimitsu, H. Synthesis 2017, 49, 4769–4774. (a) Uetake, Y.; Niwa, T.; Hosoya, T. Org. Lett. 2016, 18, 2758–2761; (b) Uetake, Y.; Isoda, M.; Niwa, T.; Hosoya, T. Org. Lett. 2019, 21, 4933–4938. Yang, J.; Xiao, J.; Chen, T.; Yin, S.-F.; Han, L.-B. Chem. Commun. 2016, 52, 12233–12236. (a) Lian, Z.; Bhawal, B. N.; Yu, P.; Morandi, B. Science 2017, 356, 1059–1063; (b) Delcaillau, T.; Bismuto, A.; Lian, Z.; Morandi, B. Angew. Chem. Int. Ed. 2020, 59, 2110–2114. Zhu, F.; Wang, Z.-X. Org. Lett. 2015, 17, 1601–1604. Gao, K.; Yorimitsu, H.; Osuka, A. Angew. Chem. Int. Ed. 2016, 55, 4573–4576. Yoshida, Y.; Nogi, K.; Yorimitsu, H. Synlett 2017, 28, 2561–2564. (a) Tobisu, M.; Masuya, Y.; Baba, K.; Chatani, N. Chem. Sci. 2016, 7, 2587–2591; (b) Masuya, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2016, 18, 4312–4315. Nogi, K.; Yorimitsu, H. Chem. Asian J. 2020, 15, 441–449. Holmquist, H. E.; Carnahan, J. E. J. Org. Chem. 1960, 25, 2240–2242. (a) Shim, S. C.; Alper, H. J. Org. Chem. 1985, 50, 147–149; (b) Calet, S.; Alper, H.; Petrignani, J. F.; Arzoumanian, H. Organometallics 1987, 6, 1625–1628. Otsuka, S.; Nogi, K.; Yorimitsu, H. Angew. Chem. Int. Ed. 2018, 57, 6653–6657. Iwasaki, M.; Topolovcan, N.; Hu, H.; Nishimura, Y.; Gagnot, G.; Na Nakorn, R.; Yuvacharaskul, R.; Nakajima, K.; Nishihara, Y. Org. Lett. 2016, 18, 1642–1645. Hooper, J. F.; Chaplin, A. B.; Gonzalez-Rodriguez, C.; Thompson, A. L.; Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 2906–2909. Inami, T.; Takahashi, T.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2019, 141, 12541–12544. Kamigata, N.; Ozaki, J.; Kobayashi, M. J. Org. Chem. 1985, 50, 5045–5050. Takahashi, F.; Nogi, K.; Yorimitsu, H. Org. Lett. 2018, 20, 6601–6605. (a) Chen, X.; Xiao, X.; Sun, H.; Li, Y.; Cao, H.; Zhang, X.; Yang, S.; Lian, Z. Org. Lett. 2019, 21, 8879–8883; (b) Liu, J.; Jia, X.; Chen, X.; Sun, H.; Li, Y.; Kramer, S.; Lian, Z. J. Org. Chem. 2020, 85, 5702–5711. (a) Luo, Y. R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press LLC: Boca Raton, FL, 2003;; (b) Feng, Y.; Huang, H.; Liu, L.; Guo, Q.-X. Phys. Chem. Chem. Phys. 2003, 5, 685–690. (a) Shaver, A.; Uhm, H. L.; Singleton, E.; Liles, D. C. Inorg. Chem. 1989, 28, 847–851; (b) Royer, A. M.; Rauchfuss, T. B.; Gray, D. L. Organometallics 2009, 28, 3618–3620; (c) Ariyananda, P. W. G.; Kieber-Emmons, M. T.; Yap, G. P. A.; Riordan, C. G. Dalton Trans 2009, 38, 4359–4369; (d) Minami, Y.; Kato, T.; Kuniyasu, H.; Terao, J.; Kambe, N. Organometallics 2006, 25, 2949–2959; (e) Kundu, S.; Brennessel, W. W.; Jones, W. D. Organometallics 2011, 30, 5147–5154. (a) Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl. Chem. 2002, 74, 115–122; (b) Dubbaka, S. R.; Vogel, P. Angew. Chem. Int. Ed. 2005, 44, 7674–7684; (c) Prokopcová, H.; Kappe, C. O. Angew. Chem. Int. Ed. 2009, 48, 2276–2286; (d) Cheng, H.-G.; Chen, H.; Liu, Y.; Zhou, Q. H. Asian J. Org. Chem. 2018, 7, 490–508. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189–3192. Yoshida, S.; Yorimitsu, H.; Oshima, K. Org. Lett. 2009, 11, 2185–2188. Tang, S.-Q.; Bricard, J.; Schmitt, M.; Bihel, F. Org. Lett. 2019, 21, 844–848. Oost, R.; Misale, A.; Maulide, N. Angew. Chem. Int. Ed. 2016, 55, 4587–4590. Gehrtz, P. H.; Kathe, P.; Fleischer, I. Chem. Eur. J. 2018, 24, 8774–8778. Lutter, F. H.; Grokenberger, L.; Hofmayer, M. S.; Knochel, P. Chem. Sci. 2019, 10, 8241–8245. (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260–11261; (b) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554–3557; (c) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W. W.; Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 1132–1140; (d) Wang, X.; Wang, B.; Yin, X.; Yu, W.; Liao, Y.; Ye, J.; Wang, M.; Hu, L.; Liao, J. Angew. Chem. Int. Ed. 2019, 58, 12264–12270; (e) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2000, 2, 3229–3231. Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 15734–15735. Liebeskind, L. S.; Yang, H.; Li, H. Angew. Chem. Int. Ed. 2009, 48, 1417–1421. Zhang, Z.; Lindale, M. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2011, 133, 6403–6410. Ghosh, P.; Ganguly, B.; Perl, E.; Das, S. Tetrahedron Lett. 2017, 58, 2751–2756. Fausett, B. W.; Liebeskind, L. S. J. Org. Chem. 2005, 70, 4851–4853. Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 3033–3035.

Synthetic Applications of C–O and C–E Bond Activation Reactions

419

167. (a) Arisawa, M.; Yamada, T.; Yamaguchi, M. Tetrahedron Lett. 2010, 51, 6090–6092; (b) Arisawa, M.; Igarashi, Y.; Kobayashi, H.; Yamada, T.; Bando, K.; Ichikawa, T.; Yamaguchi, M. Tetrahedron 2011, 67, 7846–7859. 168. Park, N.; Park, K.; Jang, M.; Lee, S. J. Org. Chem. 2011, 76, 4371–4378. 169. (a) Ochiai, H.; Uetake, Y.; Niwa, T.; Hosoya, T. Angew. Chem. Int. Ed. 2017, 56, 2482–2486; (b) Niwa, T.; Ochiai, H.; Isoda, M.; Hosoya, T. Chem. Lett. 2017, 46, 1315–1318. 170. Chen, S.; Wang, M.; Jiang, X. Chin. J. Chem. 2018, 36, 921–924. 171. Thottumkara, A. P.; Kurokawa, T.; Bois, J. D. Chem. Sci. 2013, 4, 2686–2689. 172. Liu, M.; Liu, Y.-W.; Xu, H.; Dai, H.-X. Tetrahedron Lett. 2019, 60, 151061–151064. 173. Hua, R.; Takeda, H.; Onozawa, S.-Y.; Abe, Y.; Tanaka, M. J. Am. Chem. Soc. 2001, 123, 2899–2900. 174. (a) Sugoh, K.; Kuniyasu, H.; Sugae, T.; Ohtaka, A.; Takai, Y.; Tanaka, A.; Machino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123, 5108–5109; (b) Yamashita, F.; Kuniyasu, H.; Terao, J.; Kambe, N. Org. Lett. 2008, 10, 101–104. 175. (a) Inami, T.; Kurahashi, T.; Matsubara, S. Org. Lett. 2014, 16, 5660–5662; (b) Inami, T.; Baba, Y.; Kurahashi, T.; Matsubara, S. Org. Lett. 2011, 13, 1912–1915; (c) Inami, T.; Kurahashi, T.; Matsubara, S. Chem. Commun. 2011, 47, 9711–9713. 176. (a) Osakada, K.; Yamamoto, T.; Yamamoto, A. Tetrahedron Lett. 1987, 28, 6321–6324; (b) Wenkert, E.; Chianelli, D. J. Chem. Soc. Chem. Commun. 1991, 27, 627–628; (c) Kato, T.; Kuniyasu, H.; Kajiura, T.; Minami, Y.; Ohtaka, A.; Kinomoto, M.; Terao, J.; Kurosawa, H.; Kambe, N. Chem. Commun. 2006, 42, 868–870; (d) Ichiishi, N.; Malapit, C. A.; Woz´niak, L.; Sanford, M. S. Org. Lett. 2018, 20, 44–47; (e) Liu, C. W.; Szostak, M. Chem. Commun. 2018, 54, 2130–2133; (f ) Ishitobi, K.; Isshiki, R.; Asahara, K. K.; Lim, C.; Muto, K.; Yamaguchi, J. Chem. Lett. 2018, 47, 756–759. 177. Zheng, Z.-J.; Jiang, C.; Shao, P.-C.; Liu, W.-F.; Zhao, T.-T.; Xu, P.-F.; Wei, H. Chem. Commun. 2019, 55, 1907–1910. 178. (a) Luh, T.-Y. Pure Appl. Chem. 1996, 68, 105–112; (b) Luh, T.-Y. J. Organomet. Chem. 2002, 653, 209–214. 179. Denmark, S. E.; Cresswell, A. J. J. Org. Chem. 2013, 78, 12593–12628. 180. Nishi, M.; Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 6116–6118. 181. Ouyang, K.; Hao, W.; Zhang, W.-X.; Xi, Z. Chem. Rev. 2015, 115, 12045–12090. 182. (a) Wang, Q.; Su, Y.; Li, L.; Huang, H. Chem. Soc. Rev. 2016, 45, 1257–1272; (b) Garcı´a-Cárceles, J.; Bahou, K. A.; Bower, J. F. ACS Catal. 2020, 10, 12738–12759. 183. (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2011, 50, 519–522; (b) Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 10630–10633. 184. (a) Fukumoto, K.; Oya, T.; Itazaki, M.; Nakazawa, H. J. Am. Chem. Soc. 2009, 131, 38–39; (b) Dahy, A. A.; Koga, N.; Nakazawa, H. Organometallics 2013, 32, 2725–2735. 185. (a) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732–3735; (b) Pan, Z.; Wang, S.; Brethorst, J. T.; Douglas, C. J. J. Am. Chem. Soc. 2018, 140, 3331–3338; (c) Pan, Z.; Pound, S. M.; Rondla, N. R.; Douglas, C. J. Angew. Chem. Int. Ed. 2014, 53, 5170–5174; (d) Zhao, J.; Wang, G.; Li, S. Chem. Commun. 2015, 51, 15450–15453; (e) Yuan, Y.-C.; Yang, H.-B.; Tang, X.-Y.; Wei, Y.; Shi, M. Chem. Eur. J. 2016, 22, 5146–5150. 186. (a) Ueno, S.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 6098–6099; (b) Koreeda, T.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2009, 131, 7238–7239; (c) Koreeda, T.; Kochi, T.; Kakiuchi, F. Organometallics 2013, 32, 682–690; (d) Zhao, Y.; Snieckus, V. Org. Lett. 2014, 16, 3200–3203; (e) Xu, J.-X.; Zhao, F.; Franke, R.; Wu, X.F. Catal. Commun. 2020, 140, 106009; (f ) Zhao, Q.; Zhang, J.; Szostak, M. ACS Catal. 2019, 9, 8171–8177; (g) Xu, J.-X.; Zhao, F.; Yuan, Y.; Wu, X.-F. Org. Lett. 2020, 22, 2756–2760; (h) Koreeda, T.; Kochi, T.; Kakiuchi, F. J. Organomet. Chem. 2013, 741–742, 148–152. 187. (a) Cong, X.; Fan, F.; Ma, P.; Luo, M.; Chen, H.; Zeng, X. J. Am. Chem. Soc. 2017, 139, 15182–15190; (b) Tang, J.; Fan, F.; Cong, X.; Zhao, L.; Luo, M.; Zeng, X. J. Am. Chem. Soc. 2020, 142, 12834–12840. 188. (a) Liu, J.; Robins, M. J. Org. Lett. 2004, 6, 3421–3423; (b) Li, T.; Wang, Z.; Zhang, M.; Zhang, H.-J.; Wen, T.-B. Chem. Commun. 2015, 51, 6777–6780. 189. (a) Zhang, Z.-B.; Ji, C.-L.; Yang, C.; Chen, J.; Hong, X.; Xia, J.-B. Org. Lett. 2019, 21, 1226–1231; (b) Tobisu, M.; Nakamura, K.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 5587–5590; (c) Cao, Z.-C.; Xie, S.-J.; Fang, H.; Shi, Z.-J. J. Am. Chem. Soc. 2018, 140, 13575–13579; (d) Cao, Z.-C.; Li, X.-L.; Luo, Q.-Y.; Fang, H.; Shi, Z.-J. Org. Lett. 2018, 20, 1995–1998. 190. (a) Szostak, R.; Meng, G.; Szostak, M. J. Org. Chem. 2017, 82, 6373–6378; (b) Szostak, R.; Szostak, M. Org. Lett. 2018, 20, 1342–1345; (c) Ielo, L.; Pace, V.; Holzer, W.; Rahman, M. M.; Meng, G.; Szostak, R.; Szostak, M. Chem. Eur. J. 2020, 26, 16246–16250; (d) Wang, H.; Zhang, S.-Q.; Hong, X. Chem. Commun. 2019, 55, 11330–11341. 191. (a) Meng, G.; Shi, S.; Szostak, M. Synlett 2016, 27, 2530–2540; (b) Dander, J. E.; Garg, N. K. ACS Catal. 2017, 7, 1413–1423; (c) Adachi, S.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2018, 59, 1147–1158; (d) Meng, G.; Szostak, M. Eur. J. Org. Chem. 2018, 2018, 2352–2365; (e) Liu, C.; Szostak, M. Org. Biomol. Chem. 2018, 16, 7998–8010; (f ) Chaudhari, M. B.; Gnanaprakasam, B. Chem. Asian J. 2019, 14, 76–93. 192. (a) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y.-F.; Liu, P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79–83; (b) Dander, J. E.; Weires, N. A.; Garg, N. K. Org. Lett. 2016, 18, 3934–3936; (c) Weires, N. A.; Caspi, D. D.; Garg, N. K. ACS Catal. 2017, 7, 4381–4385. 193. Liu, X.; Hsiao, C.-C.; Guo, L.; Rueping, M. Org. Lett. 2018, 20, 2976–2979. 194. (a) Liu, X.; Yue, H.; Jia, J.; Guo, L.; Rueping, M. Chem. Eur J. 2017, 23, 11771–11775; (b) Morioka, T.; Nakatani, S.; Sakamoto, Y.; Kodama, T.; Ogoshi, S.; Chatani, N.; Tobisu, M. Chem. Sci. 2019, 10, 6666–6671. 195. Li, C.; Li, P.; Yang, J.; Wang, L. Chem. Commun. 2012, 48, 4214–4216. 196. (a) Hao, W.; Wei, J.; Geng, W.; Zhang, W.-X.; Xi, Z. Angew. Chem. Int. Ed. 2014, 53, 14533–14537; (b) Hao, W.; Geng, W.; Zhang, W.-X.; Xi, Z. Chem. Eur. J. 2014, 20, 2605–2612; (c) Geng, W.; Zhang, W.-X.; Hao, W.; Xi, Z. J. Am. Chem. Soc. 2012, 134, 20230–20233. 197. Nakao, Y.; Hiyama, T. Chem. Soc. Rev. 2011, 40, 4893–4901. 198. (a) Li, L.; Zhang, Y.; Gao, L.; Song, Z. Tetrahedron Lett. 2015, 56, 1466–1473; (b) Komiyama, T.; Minami, Y.; Hiyama, T. ACS Catal. 2017, 7, 631–651. 199. Sakurai, H.; Imai, T. Chem. Lett. 1975, 4, 891–894. 200. Takeyama, Y.; Nozaki, K.; Matsumoto, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 1461–1466. 201. Kende, A. S.; Mineur, C. M.; Lachicotte, R. J. Tetrahedron Lett. 1999, 40, 7901–7906. 202. Shintani, R.; Moriya, K.; Hayashi, T. Org. Lett. 2012, 14, 2902–2905. 203. Shintani, R.; Moriya, K.; Hayashi, T. J. Am. Chem. Soc. 2011, 133, 16440–16443. 204. Liu, J.; Sun, X.; Miyazaki, M.; Liu, L.; Wang, C.; Xi, Z. J. Org. Chem. 2007, 72, 3137–3140. 205. Wang, X.-B.; Zheng, Z.-J.; Xie, J.-L.; Gu, X.-W.; Mu, Q.-C.; Yin, G.-W.; Ye, F.; Xu, Z.; Xu, L.-W. Angew. Chem. Int. Ed. 2020, 59, 790–797. 206. Buchner, K. M.; Woerpel, K. A. Organometallics 2010, 29, 1661–1669. 207. Tanaka, Y.; Yamashita, H.; Tanaka, M. Organometallics 1996, 15, 1524–1526. 208. Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2006, 8, 483–485. 209. Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 2199–2201. 210. Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 6094–6095. 211. Zhang, Q.-W.; An, K.; Liu, L.-C.; Guo, S.; Jiang, C.; Guo, H.; He, W. Angew. Chem. Int. Ed. 2016, 55, 6319–6323. 212. Ishida, N.; Ikemoto, W.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 5912–5915. 213. Saito, S.; Yoshizawa, T.; Ishigami, S.; Yamasaki, R. Tetrahedron Lett. 2010, 51, 6028–6030. 214. Okumura, S.; Sun, F.; Ishida, N.; Murakami, M. J. Am. Chem. Soc. 2017, 139, 12414–12417. 215. Zhao, W.-T.; Gao, F.; Zhao, D. Angew. Chem. Int. Ed. 2018, 57, 6329–6332. 216. Ojima, I.; Fracchiolla, D. A.; Donovan, R. J.; Banerji, P. J. Org. Chem. 1994, 59, 7594–7595. 217. Tobisu, M.; Onoe, M.; Kita, Y.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 7506–7507. 218. (a) Yu, Z.; Lan, Y. J. Org. Chem. 2013, 78, 11501–11507; (b) Chen, W.-J.; Lin, Z. Dalton Trans. 2014, 43, 11138.

420 219. 220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251.

252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266.

Synthetic Applications of C–O and C–E Bond Activation Reactions Onoe, M.; Baba, K.; Kim, Y.; Kita, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2012, 134, 19477–19488. Matsuda, T.; Suda, Y.; Fujisaki, Y. Synlett 2011, 813–816. Liang, Y.; Zhang, S. G.; Xi, Z. F. J. Am. Chem. Soc. 2011, 133, 9204–9207. Liang, Y.; Geng, W. Z.; Wei, J. N. Angew. Chem. Int. Ed. 2012, 51, 1934–1937. Meng, T.; Ouyang, K.; Xi, Z. RSC Adv. 2013, 3, 14273–14276. Zhang, Q.-W.; An, K.; He, W. Angew. Chem. Int. Ed. 2014, 53, 5667–5671. Yang, Q.; Liu, L.; Chi, Y.; Hao, W.; Zhang, W.-X.; Xi, Z. Org. Chem. Front. 2018, 5, 860–863. Seiser, T.; Cramer, N. Angew. Chem. Int. Ed. 2010, 49, 10163–10167. Fujihara, T.; Tani, Y.; Semba, K.; Terao, J.; Tsuji, Y. Angew. Chem. Int. Ed. 2012, 51, 11487–11490. Tani, Y.; Yamaguchi, T.; Fujihara, T.; Terao, J.; Tsuji, Y. Chem. Lett. 2015, 44, 271–273. Feng, J.; Bi, X.; Xue, X.; Li, N.; Shi, L.; Gu, Z. Nat. Commun. 2020, 11, 4449. Sakurai, H.; Yamane, M.; Iwata, M.; Saito, N.; Narasaka, K. Chem. Lett. 1996, 25, 841–842. Srimontree, W.; Lakornwong, W.; Rueping, M. Org. Lett. 2019, 21, 9330–9333. Nakatani, S.; Ito, Y.; Sakurai, S.; Kodama, T.; Tobisu, M. J. Org. Chem. 2020, 85, 7588–7594. (a) Muller, C.; Lachicotte, R. J.; Jones, W. D. Organometallics 2002, 21, 1190–1196; (b) Okuda, Y.; Ishiguro, Y.; Mori, S.; Nakajima, K.; Nishihara, Y. Organometallics 2014, 33, 1878–1889. Shintani, R.; Kurata, H.; Nozaki, K. Chem. Commun. 2015, 51, 11378–11381. Abatjoglou, G.; Bryant, D. R. Organometallics 1984, 3, 932–934. (a) Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313–6315; (b) Herrmann, W. A.; Broßmer, C.; Priermeier, T.; Öfele, K. J. Organomet. Chem. 1994, 481, 97–108; (c) Morita, D. K.; Stille, J. K.; Norton, J. R. J. Am. Chem. Soc. 1995, 117, 8576–8581. (a) Wang, L.; Chen, H.; Duan, Z. Chem. Asian J. 2018, 13, 2164–2173; (b) Lee, Y. H.; Morandi, B. Coord. Chem. Rev. 2019, 386, 96–118. Sakamoto, M.; Shimizu, I.; Yamamoto, A. Chem. Lett. 1995, 24, 1101–1102. Hwang, L. K.; Na, Y.; Lee, J.; Do, Y.; Chang, S. Angew. Chem. Int. Ed. 2005, 44, 6166–6169. Zhang, X.; McNally, A. Angew. Chem. Int. Ed. 2017, 56, 9833–9836. Zhang, X.; McNally, A. ACS Catal. 2019, 9, 4862–4866. Kikukawa, K.; Takagi, M.; Matsuda, T. Bull. Chem. Soc. Jpn. 1979, 52, 1493–1497. Ma, M.-T.; Lu, J.-M. Tetrahedron 2013, 69, 2102–2106. Lu, D.-P.; Xu, Y.; Liu, W.-J.; Guo, L.-J.; Sun, X.-X. Helv. Chim. Acta 2015, 98, 116–122. Zhou, H.; Li, J.-X.; Yang, H.-M.; Xia, C.-G.; Jiang, G.-X. Org. Lett. 2015, 17, 4628–4631. Li, Z.-Y.; Zhou, H.-P.; Xu, J.-Y.; Wu, X.-M.; Yao, H.-Q. Tetrahedron 2013, 69, 3281–3286. Wu, Y.-T.; Huang, K.-H.; Shin, C.-C.; Wu, T.-C. Chem. Eur. J. 2008, 14, 6697–6703. Jafarpour, F.; Ghasemi, M.; Navid, H.; Safaie, N.; Rajai-Daryasarei, S.; Habibi, A.; Ferrier, R. C., Jr. Org. Lett. 2020, 22, 9556–9561. (a) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19, 2058–2060; (b) Kwong, F. Y.; Chan, K. S. Organometallics 2001, 20, 2570–2578. (a) Flanagan, S. P.; Goddard, R.; Guiry, P. J. Tetrahedron 2005, 61, 9808–9821; (b) Feng, J.; Dastgir, S.; Li, C.-J. Tetrahedron Lett. 2008, 49, 668–671. (a) Kwong, F. Y.; Chan, K. S. Chem. Commun. 2000, 1069–1070; (b) Kwong, F. Y.; Lai, C. W.; Tian, Y.; Chan, K. S. Tetrahedron Lett. 2000, 41, 10285–10289; (c) Kwong, F. Y.; Lai, C. W.; Yu, M.; Chan, K. S. Tetrahedron 2004, 60, 5635–5645; (d) Lai, C. W.; Kwong, F. Y.; Wang, Y. C.; Chan, K. S. Tetrahedron Lett. 2001, 42, 4883–4885; (e) Wang, Y. C.; Lai, C. W.; Kwong, F. Y.; Jia, W.; Chan, K. S. Tetrahedron 2004, 60, 9433–9439. (a) Kwong, F. Y.; Lai, C. W.; Chan, K. S. Tetrahedron Lett. 2002, 43, 3537–3539; (b) Kwong, F. Y.; Lai, C. W.; Yu, M.; Tian, Y.; Chan, K. S. Tetrahedron 2003, 59, 10295–10305. Cao, J.; Huang, X.; Wu, L. L. Chem. Commun. 2013, 49, 7747–7749. Baba, K.; Tobisu, M.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11892–11895. Elaieb, F.; Sémeril, D.; Matt, D.; Pfeffer, M.; Bouit, P.-A.; Hissler, M.; Gourlaouen, C.; Harrowfield, J. Dalton Trans. 2017, 46, 9833–9845. Baba, K.; Tobisu, M.; Chatani, N. Org. Lett. 2015, 17, 70–73. Zhou, Y.; Gan, Z.; Su, B.; Li, J.; Duan, Z.; Mathey, F. Org. Lett. 2015, 17, 5722–5724. Elaieb, F.; Hedhli, A.; Sémeril, D.; Matt, D.; Harrowfield, J. Eur. J. Org. Chem. 2016, 2016, 3103–3108. Baba, K.; Masuya, Y.; Chatani, N.; Tobisu, M. Chem. Lett. 2017, 46, 1296–1299. Fujimoto, H.; Kusano, M.; Kodama, T.; Tobisu, M. Org. Lett. 2019, 21, 4177–4181. Scheetz, P. M.; Glueck, D. S.; Rheingold, A. L. Organometallics 2017, 36, 3387–3397. Yu, R. R.; Chen, X. Y.; Martin, S. F.; Wang, Z. Q. Org. Lett. 2017, 19, 1808–1811. (a) Nakazawa, H.; Matsuoka, Y.; Yamaguchi, H.; Kuroiwa, T.; Miyoshi, K.; Yoneda, H. Organometallics 1989, 8, 2272–2274; (b) Nakazawa, H.; Matauoka, Y.; Nakagawa, I.; Miyoshi, K. Organometallics 1992, 11, 1385–1392. Masuda, K.; Sakiyama, N.; Tanaka, R.; Noguchi, K.; Tanaka, K. J. Am. Chem. Soc. 2011, 133, 6918–6921. Inoue, A.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 1484–1485. Zhu, J.; Mao, M.; Ji, H.-J.; Xu, J.-Y.; Wu, L. Org. Lett. 2017, 19, 1946–1949.

12.11

CdF Bond Activation Reactions

Kohei Fuchibe∗, Takeshi Fujita∗, and Junji Ichikawa, Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan © 2022 Elsevier Ltd. All rights reserved.

12.11.1 12.11.1.1 12.11.1.2 12.11.1.3 12.11.1.4 12.11.2 12.11.2.1 12.11.2.1.1 12.11.2.1.2 12.11.2.1.3 12.11.2.1.4 12.11.2.1.5 12.11.2.1.6 12.11.2.2 12.11.2.2.1 12.11.2.3 12.11.2.3.1 12.11.2.3.2 12.11.2.4 12.11.2.4.1 12.11.2.4.2 12.11.2.4.3 12.11.3 12.11.3.1 12.11.3.1.1 12.11.3.1.2 12.11.3.1.3 12.11.3.1.4 12.11.3.2 12.11.3.2.1 12.11.3.3 12.11.3.3.1 12.11.3.3.2 12.11.4 12.11.4.1 12.11.4.1.1 12.11.4.1.2 12.11.4.2 12.11.4.2.1 12.11.4.2.2 12.11.4.3 12.11.4.3.1 12.11.4.3.2 12.11.4.4 12.11.4.4.1 12.11.4.4.2 12.11.4.4.3 12.11.4.4.4 12.11.5 References

∗

Introduction and overview Introduction Overview of C(sp3)dF bond activation Overview of alkene C(sp2)dF bond activation Overview of arene C(sp2)dF bond activation Survey of C(sp3)dF bond activation 2005–mid 2021 Activation of allylic CdF bonds SN20 -type reaction Lewis acid-assisted SN20 -type reaction SN10 reaction Oxidative addition Electron transfer Addition–b-fluorine elimination Activation of propargylic CdF bonds Addition–b-fluorine elimination Activation of benzylic CdF bonds Metalation (oxidative addition and electron transfer) Fluoride abstraction Activation of alkyl CdF bonds SN2 reaction Addition–b-fluorine elimination Fluoride abstraction Survey of alkene C(sp2)dF bond activation 2005–mid-2021 Activation of vinylic CdF bonds SNV reaction Metalation (oxidative addition and electron transfer) Addition–b-fluorine elimination Addition–a-fluorine elimination Activation of allenylic CdF bonds Fluoride abstraction Activation of acyl CdF bonds Carbonyl-retentive coupling Decarbonylative coupling Survey of arene C(sp2)dF bond activation 2005–mid-2021 Activation of aromatic CdF bonds (1): Directed systems Metalation CdC and CdX bond formation Activation of aromatic CdF bonds (2): Nondirected systems with multiple fluorine atoms Metalation CdC and CdX bond formation Activation of aromatic CdF bonds (3): Nondirected systems with one fluorine atom Metalation CdC and CdX bond formation Activation of aromatic CdF bonds (4): Miscellaneous Carbene analog insertion Aryne formation SNAr reaction Fluoride abstraction Conclusions and perspectives

422 422 422 424 425 427 427 427 428 429 429 429 430 432 432 432 432 433 434 434 435 436 436 436 437 437 438 441 442 442 442 442 443 443 443 444 445 448 448 451 453 453 453 456 456 457 457 458 458 459

Contributed equally to the work.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00147-5

421

422

CdF Bond Activation Reactions

12.11.1 Introduction and overview 12.11.1.1 Introduction Fluorinated organic compounds have become indispensable in various fields, such as pharmaceutical, agrochemical, and materials science, because of the specific nature of the fluorine substituents. Thus, the development of effective methods for the synthesis of fluorinated compounds has attracted the attention of researchers. These compounds can be obtained via (I) carbon–fluorine (CdF) bond formation or (II) CdF bond cleavage. The latter approach sounds counterintuitive as a route to obtain fluorinated compounds; however, the situation has changed in recent years: as a result of the dramatic advancement in synthetic methodologies over the past decades, the trifluoromethyl, perfluoroalkyl, and polyfluoroaromatic compounds are now readily available as starting materials. Notably, these starting materials can be subjected to selective CdF bond activation, that is, selective CdF bond cleavage in combination with new carbon–carbon (CdC) and carbon–heteroatom (CdX) bond formation, which provides different synthetic approaches from those based on CdF bond formation. In addition, CdF bond activation reactions allow late-stage functionalization of stable CdF bonds in a complex molecule bearing reactive functional groups, providing an orthogonal approach to address the synthesis of complex molecules. The development of methods based on the transformation of CdF bonds has also enabled the degradation and upcycling of environment-polluting fluorinated compounds. Therefore, CdF bond activation has become a promising strategy for accessing a wide array of fluorinated compounds. Although CdF bonds are generally more difficult to transform than other carbon–halogen (CdI, CdBr, and CdCl) bonds due to their high bond dissociation energies, a remarkable development in this area has been achieved in the past two decades. This chapter discusses these advances on CdF bond activation reactions mediated by metals and metalloids. Herein, the term “CdF bond activation” is used in the broad sense to describe the process that involves both (a) the cleavage of CdF bonds and (b) the formation of new CdC bonds or CdX bonds, regardless of the order of these two events. With regard to the metal species, this chapter covers metals and metalloids of groups 13 and 14, in addition to d-block and f-block transition metals (groups 3–12). Particularly, among the elements of groups 13 and 14, boron, aluminum, silicon, and tin exhibit a high affinity for fluorine (fluorophilicity), which facilitates the CdF bond cleavage. CdF bond activation reactions reported between 2005 and mid 2021 are introduced in this chapter, occasionally referring to earlier works. Numerous comprehensive review articles on CdF bond activation have been published.1–23 In particular, excellent reviews regarding hydrodefluorination (HDF) reactions are available. However, the processes of HDF and defluorination via 1,2-elimination are not the focus of this review.24–26 Photoredox processes in which metal catalysts mediate electron transfer are also not included here.20 Section 12.11.1 describes the principal modes of CdF bond activation. Section 12.11.1.2 discusses the activation of C(sp3)dF bonds, such as allylic, propargylic, benzylic, and alkyl CdF bonds. Sections 12.11.1.3 and 12.11.1.4 cover the activation of C(sp2)dF bonds in alkenes and arenes, such as vinylic, allenylic, and aromatic CdF bonds. Acyl CdF bond activation is also included in Section 12.11.1.3. A comprehensive set of examples of CdF bond activation are provided in Sections 12.11.2–12.11.4, according to the classification of Sections 12.11.1.2–12.11.1.4. Section 12.11.5 presents forward-looking conclusions to promote further developments in this exiting field.

12.11.1.2 Overview of C(sp3)dF bond activation4,6,8,12–15,20,22 Due to the poor leaving group ability of fluorine, C(sp3)dF bonds rarely undergo nucleophilic substitution processes such as SN2 and SN1 reactions that are possible with other C(sp3)–halogen bonds. To activate the C(sp3)dF bonds, the following strategies have been conventionally adopted: (i) metalation (for alkyl CdF bonds; Scheme 1), (ii) addition–elimination (for allylic CdF bonds; Scheme 2), and (iii) fluoride abstraction (for alkyl and benzylic CdF bonds; Scheme 3).

Scheme 1 Type i: Metalation.

Scheme 2 Type ii: Addition–elimination (SN20 -type reaction).

Scheme 3 Type iii: Fluoride abstraction.

CdF Bond Activation Reactions

423

Since CdF bonds are stronger than CdCl, CdBr, and CdI bonds, the metalation of CdF bonds is difficult compared with that of other carbon–halogen bonds. Thus, the activation of alkyl CdF bonds via metalation (type i) requires highly reactive lithium biphenylide or activated magnesium to generate the corresponding carbanions, which are then trapped by electrophiles to form new bonds (Scheme 1). Meanwhile, the allylic CdF bond activation (type ii) is conventionally realized via an addition–elimination process in which a nucleophile attacks the terminal sp2 carbon to form an anionic intermediate that is stabilized by negative hyperconjugation and the inductive effect of fluorine atom. Subsequent b-fluorine elimination occurs, forming a CdC double bond. b-Fluorine elimination takes place intramolecularly, which guarantees that the cleavage of the CdF bond is entropically favorable and can proceed under mild conditions (SN20 -type reaction; Scheme 2). The alkyl CdF bond activation (type iii) is promoted by aluminum and silicon Lewis acids via carbocations stabilized by substituents, such as alkyl, aryl, and alkoxy groups (Scheme 3). Although the examples of types i and ii, which are mainly achieved by alkali and alkali earth metal species, are excluded from this chapter, type i may involve the oxidative addition of CdF bonds to transition metals, and the b-fluorine elimination in type ii constitutes a key elementary step in the CdF bond activation induced by transition metals. The type iii reactions are promoted by Lewis acidic metal species possessing a strong affinity for fluorine. Type i (metalation) of C(sp3)dF bond activation is achieved using transition metals. Early reports described the oxidative addition as a CdF bond cleavage step, which was promoted by electron-rich, low-valent transition metal species (Scheme 4). These processes enable the introduction of not only carbon but also heteroatom substituents by using the corresponding nucleophiles (R0 M0 ). In addition, low-valent transition metal species can reduce organic fluorides via a single electron transfer, which induces alkyl CdF bond cleavage, generating organic radicals or anions as synthetic intermediates for further bond formation (Scheme 5).

Scheme 4 Type i: Metalation (oxidative addition).

Scheme 5 Type i: Metalation (electron transfer).

In allylic fluorides, type ii activation (addition–elimination) is promoted by organo-transition-metal species. Similar to the aforementioned nucleophilic addition–elimination process of allylic fluorides (Scheme 2), when organometallic complexes (RMX) react with allylic fluorides, insertion into the CdC double bond occurs to form the intermediates, in which the fluorine is located on the b-carbon to the metal. Thus, the formed intermediates readily cause b-fluorine elimination that cleaves the CdF bond (Scheme 6). In addition, b-fluorine elimination can be combined with organometallic elementary processes other than insertion, including carbo(hetero)metalation and oxidative cyclization, thereby enabling efficient molecular transformations with new scaffolds. The strategy based on b-fluorine elimination involves the formation of a new bond, followed by the cleavage of a CdF bond, which is in sharp contrast with the order of the conventional strategy of oxidative addition, i.e., CdF bond cleavage followed by CdC bond formation (Scheme 4).

Scheme 6 Type ii: Addition–elimination (insertion–b-fluorine elimination).

The fluoride abstraction (type iii) for the activation of allylic, benzylic, and alkyl CdF bonds is achieved by using boron, aluminum, and silicon Lewis acid catalysts, which have a high affinity for fluorine. The Lewis acid-mediated fluoride abstraction results in the generation of carbocations that react with weak nucleophiles (Nu–Z), such as boron, aluminum, and silicon compounds (Scheme 7). For example, when using silylated nucleophiles, such as silyl enol ethers, the silicon atom in the nucleophiles effectively captures a fluoride ion to form fluorosilanes. Other weak nucleophiles, such as arenes and thiols, can also be used as nucleophiles. Organic boron, aluminum, and silicon compounds act as nucleophiles as well as Lewis acids (Scheme 7, right). Particularly, in the case of allylic and benzylic tri(di)fluorides, the selective substitution of one fluorine atom remains problematic as the substitution of the second and third fluorines becomes easier. In recent years, the development of methods for controlling the number of fluorine substituents to be transformed has enabled the synthesis of compounds with one or two remaining fluorines.

424

CdF Bond Activation Reactions

Scheme 7 Type iii: Fluoride abstraction (catalytic and stoichiometric processes).

12.11.1.3 Overview of alkene C(sp2)dF bond activation9,14,16,23 The methods for C(sp2)dF bond activation have some similarities to those for allylic C(sp3)dF bond activation (Scheme 2), since both approaches involve a nucleophilic addition–elimination process. While alkenes bearing fluorine substituents at the vinylic position are electron-deficient, the electron density on the carbon bearing the fluorine substituent further decreases due to the repulsion between the lone pair of the fluorine atom and the alkene p electrons. Thus, the attack of a nucleophile occurs on the fluorinated carbon, leading to the generation of b-fluorine-stabilized carbanions. Subsequent b-fluorine elimination results in formal nucleophilic substitution at the vinylic carbon via an addition–elimination mechanism (SNV reaction; Scheme 8).

Scheme 8 Type ii: Addition–elimination (SNV reaction).

The use of transition metals has expanded the variety of methodologies for C(sp2)dF bond activation. The catalytic application of these processes to organic synthesis, which was sporadically reported in the 1990s, underwent an explosive development since the 2010s. Consequently, the vinylic CdF bonds can be cleaved via the following reactions: (a) type i: metalation (oxidative addition; Scheme 9), (b) type i: metalation (electron transfer; Scheme 10), (c) type ii: addition–elimination (insertion–b-fluorine elimination; Scheme 11), and (d) type ii: addition–elimination (insertion–a-fluorine elimination; Scheme 12). As in the case of allylic CdF bonds, type i (a) is facilitated by the coordination of the CdC double bond to a metal center, and type ii (c) proceeds via an insertion/b-fluorine elimination sequence in an SNV fashion (Scheme 8). Meanwhile, type ii (d) is specific to the vinylic CdF bond activation promoted by transition metals, since it proceeds via a-fluorine elimination instead of via b-fluorine elimination. In organometallic intermediates bearing a fluorine atom on the carbon a to the metal, the metal induces the elimination of fluorine, followed by bond formation between the a-carbon and the organic group on the metal. The a-elimination processes proceed concertedly or through a stepwise sequence of carbenoid formation and 1,2-ligand migration (Scheme 12). Although catalytic reactions via a-fluorine elimination are still rarely reported, they have undergone a recent advance. These b- and a-fluorine eliminations for CdF bond cleavage can be preceded by not only insertion but also other organometallic elementary processes for CdC or CdX bond formation, which eventually enables type ii (addition–elimination) processes for CdF bond activation.

Scheme 9 Type i: (a) Metalation (oxidative addition).

Scheme 10 Type i: (b) Metalation (electron transfer).

Scheme 11 Type ii: (c) Addition–elimination (insertion–b-fluorine elimination).

Scheme 12 Type ii: (d) Addition–elimination (insertion–a-fluorine elimination).

CdF Bond Activation Reactions

425

In contrast with the allylic C(sp3)dF bond activation, the abstraction of fluoride in the vinylic CdF bond activation with Lewis acids (type iii: fluoride abstraction) is quite difficult. The removal of fluoride from vinylic fluorides results in the formation of unstable vinylic cations (Scheme 13), which renders these processes energetically disfavored and difficult to achieve.

Scheme 13 Vinylic fluoride abstraction (type iii).

12.11.1.4 Overview of arene C(sp2)dF bond activation2,3,7,10,11,23 Similarly to vinylic C(sp2)dF bonds (SNV reaction; Scheme 8), aromatic C(sp2)dF bonds can be transformed via addition–elimination. In this reaction, electron-deficient aryl fluorides are attacked by nucleophiles to form Meisenheimer complexes. Subsequent elimination of a fluoride ion results in the substitution of the aromatic fluorine (SNAr reaction; Scheme 14). Since the elimination leading to rearomatization is a facile process, the nucleophilic addition is the rate-determining step. The ipso carbons are more electron-deficient because of electron repulsion and the resulting Meisenheimer complexes are more stable, both of which are due to the presence of the fluorine substituent. Thus, aryl fluorides are the most reactive aryl halides toward the SNAr reaction.

Scheme 14 Type ii: Addition–elimination (SNAr reaction).

To realize the activation of aromatic CdF bonds with transition metal species, neither the aforementioned insertion/fluorine elimination sequence (Scheme 15, left) nor the fluoride abstraction leading to unstable aryl cations is applicable (Scheme 15, right). Contrarily, the oxidative addition (type i: metalation) in a SNAr fashion has been mostly employed (Scheme 16).

Scheme 15 Insertion (type ii); Aromatic fluoride abstraction (type iii).

Scheme 16 Type i: Metalation (oxidative addition).

Compared with other systems, the CdF bond activation in (hetero)aromatic systems promoted by transition metal complexes has been studied for many years. The metalation of aryl fluorides typically requires (I) the use of directing groups (DGs) and (II) additional fluorine substituents on the aromatic ring as an electron-withdrawing group (activating group). DGs were first introduced in coordination chemistry to compensate for the very low reactivity of CdF bonds. Lewis basic, coordinating sites in DGs bring the metal species closer to the target CdF bond via coordination (Scheme 17, Fig. 1). Then, the DG-promoted oxidative addition of the CdF bond to the metal center forms a carbon–metal (CdM) bond, which leads to further CdC or CdX bond formation (CdF bond activation) to afford the products while leaving the DGs unchanged. Besides the kinetically accelerating effect on the oxidative addition, DGs also facilitate the ortho-selective CdF bond cleavage when the substrates have fluorine atoms on the ortho, meta, and para positions.

Scheme 17 Type i: Directed metalation.

426

CdF Bond Activation Reactions

Fig. 1 Directing groups (DGs).

Fig. 2 Substrates for aromatic CdF bond activation.

The number of fluorine atoms on the aromatic ring is a dominant factor that affects the reactivity of (hetero)aromatic compounds. In general, since the basis of aromatic CdF bond activation is an SNAr process (Scheme 14), fully fluorinated (hetero)arenes such as perfluorobenzene and perfluoropyridine are the most reactive substrates. The reactivity of partially fluorinated (hetero)arenes such as pentafluorobenzene and 2,3,5,6-tetrafluoropyridine is moderate, and monofluorinated (hetero) arenes such as fluorobenzene are much less reactive. Among the monofluorinated (hetero)aromatic compounds, the reactivity difference between substrates with or without electron-withdrawing groups is very clear, with the former being more reactive and the latter less reactive (Fig. 2). The metalation of (hetero)aromatic CdF bonds with transition metal complexes is classified into three types (A–C), as presented in Scheme 18. Type A cleavage is an SNAr-like metalation typically conducted with anionic metal species, whereas type B and C cleavages are induced by neutral metal species. In the type B cleavage, electron-rich group 9 metals (typically, rhodium) bearing silyl/boryl groups approach the ipso carbon in a nucleophilic fashion. In the transition state, the Lewis acidic ligands induce the abstraction of fluoride to afford the corresponding metalated products (ligand-assisted metalation). The finding of the ligand-assisted CdF bond cleavage is one of the most important achievements in the last 15 years. Thus, the use of Lewis acidic ligands facilitates the metalation of fluoroarenes, leading to efficient synthetic reactions such as the rhodium-catalyzed borylation. In the type C cleavage, electron-rich group 10 metals (typically, nickel) undergo insertion into the CdF bond via a transition state involving migration of the fluorine to the metal center to complete the metalation (oxidative addition).

Scheme 18 Type A: SNAr-like metalation; Type B: Ligand-assisted metalation; Type C: Oxidative addition.

CdF Bond Activation Reactions

427

In the early stages of this chemistry, the CdF bond activation was investigated only in systems bearing DGs. The CdF bond cleavage was mainly studied from the viewpoint of coordination chemistry, and thus, only a limited number of stoichiometric CdC and CdX bond formations, such as methylation and borylation, were reported. Over the last 15 years, a remarkable progress in this field has led to the development of CdC/CdX bond formation reactions in the absence of DGs. Since the mid-2000s, the nondirected CdF bond activation in (hetero)arenes with multiple fluorines has been intensively investigated, leading to catalytic bond forming reactions, such as coupling reactions. The nondirected CdF bond activation of monofluorinated (hetero)arenes, some of which contain electron-withdrawing substituents that enhance their reactivity, was also developed in the 2010s. Since then, the catalytic CdF bond activation in nonactivated monofluoroarenes has become one of the most important topics in organic synthesis.

12.11.2 Survey of C(sp3)dF bond activation 2005–mid 2021 12.11.2.1 Activation of allylic CdF bonds Section 12.11.2.1 discusses CdF bond activation in allylic fluorides. This reaction can be classified as an SN20 -type reaction without Lewis acids (Section 12.11.2.1.1) and with Lewis acids (Section 12.11.2.1.2), an SN10 reaction (Section 12.11.2.1.3), metalation (oxidative addition and electron transfer) (Sections 12.11.2.1.4 and 12.11.2.1.5), or addition–b-fluorine elimination (Section 12.11.2.1.6).

12.11.2.1.1

SN20 -type reaction

Allylic fluorides undergo SN20 -type reactions via an addition–elimination process with transition metal species. In the presence of a catalytic amount of CuI, treatment of 2,2-difluorohomoallylic alcohols with organomagnesium reagents affords Z-monofluoroalkenes (Scheme 19).27,28 Furthermore, 2,20 -diceriobiaryls, derived from 2,20 dibromobiaryls, induce domino nucleophilic substitution (SN20 -type and SNV reaction) of 2-(trifluoromethyl)-1-alkenes, leading to the construction of seven-membered carbocycles (Scheme 20).29 The Cu-catalyzed Kinugasa reaction of propargylic fluorides with nitrones proceeds via allylic CdF bond activation (an intramolecular SN20 -type reaction) of difluorinated ketene intermediates to afford exo-alkylidene-b-lactams (Scheme 21).30

Scheme 19 Cu-catalyzed SN20 -type arylation and alkylation.

Scheme 20 Ce-mediated domino SN20 -type and SNV reaction.

Scheme 21 Cu-mediated defluorinative Kinugasa reaction.

The defluorinative borylation and silylation of allylic fluorides are achieved by using diboron and silylboron in combination with Cu catalysts, where borylcopper31–37 and silylcopper35,37,38 species are generated in situ, respectively (Scheme 22). The defluorinative borylation of 2-(trifluoromethyl)-1-alkenes is also promoted by an Fe39 or Co catalyst.40 By adding an alkyl iodide in a carbon dioxide atmosphere, the copper-catalyzed borylation allows for the introduction of an ester moiety on the carbon g to fluorine.41 Enantioselective alkylation is also possible using Cu(I) tetraalkylborate, generated in situ from alkylmagnesium reagents, a Cu(I) salt, and an arylboronate.42

428

CdF Bond Activation Reactions

Scheme 22 Cu-catalyzed SN20 -type borylation.

Additionally, the direct defluorinative borylation of CF3-alkenes is achieved via an addition–elimination process with a cyclic carbene-stabilized boryl anion to generate 3,3-difluoroallylic borane intermediates. These intermediates react in turn with aldehydes or ketones to provide 2,2-difluorohomoallylic alcohols (Scheme 23).43 Defluorinative silylation is also possible using silyl anions.44,45

Scheme 23 SN20 -type reaction with boryl anion.

12.11.2.1.2

Lewis acid-assisted SN20 -type reaction

The use of organoaluminum reagents enables SN20 -type reactions in allylic fluorides. The treatment of 2,2-difluorohomoallylic alcohols with trialkylaluminums affords 2-fluoroallylic alcohols with high diastereoselectivities (Scheme 24).46–50 In the generated alkoxyaluminum intermediates, one of the fluorines coordinates to the Al center. This coordination assists in the addition of an alkyl group and the elimination of fluorine simultaneously to afford the corresponding fluoroalkenes with a Z configuration. Additionally, azide51 and halogen substituents52 can be introduced by changing the substituent on the aluminum.

Scheme 24 Al-assisted SN20 -type alkylation.

Allylic CdF bond activation with Si reagents also affords substitution products in an enantioselective manner. In the presence of a catalytic amount of chiral (DHQD)2PHAL, racemic allylic fluorides undergo stereospecific defluorinative substitution with (trifluoromethyl)trimethylsilane (Me3SiCF3) or 2-[(trimethylsilyl)methyl]-2H-tetrazole. This subsequently affords substitution products with high enantiomeric excesses along with enantio-enriched substrates (Scheme 25).53–55 In these reactions, kinetic resolution occurs when (DHQD)2PHAL attacks the allylic fluorides in an SN20 -type manner after the coordination of the fluorine atom to the Si atom. The second SN20 reaction of the formed allylic ammonium salts with a nucleophilic group on Si results in formal SN2 products.

Scheme 25 Si-assisted stereospecific defluorinative substitution.

CdF Bond Activation Reactions

12.11.2.1.3

429

SN10 reaction

Currently, 2-trifluoromethyl-1-alkenes are popular substrates for allylic CdF bond activation. Among the CdF bonds, that of the trifluoromethyl (CF3) group is the most difficult to cleave because of the shielding effect of the three fluorine atoms. Moreover, the CdF bond in the CF3 group has the highest bond dissociation energy. Therefore, the allylic CdF bond activation of 3,3,3-trifluoroprop-1-ene has been difficult to achieve for a long time. The Friedel–Crafts-type alkylation without cleavage of the CdF bond is mainly promoted with AlCl356 or AlClnF3–n.57 However, when EtAlCl2 is used, the fluoride abstraction from 2-trifluoromethyl-1-alkenes efficiently proceeds to generate difluoroallylic cation intermediates. These intermediates undergo the Friedel–Crafts-type CdC bond formation with arenes to afford 3,3-difluoroallylic arenes (Scheme 26).58 This SN10 -type reaction via single CdF bond activation allows two fluorines to remain in the products. A similar defluorinative arylation of trifluoropropene proceeds with tri(isobutyl)aluminum and an in situ generated cationic zirconocene.59

Scheme 26 Al-assisted SN10 reaction via Friedel–Crafts-type CdC bond formation.

12.11.2.1.4

Oxidative addition

The defluorinative Tsuji–Trost reactions proceed via oxidative addition of allylic CdF bonds to transition metals. The oxidative addition of allylic monofluorides and difluorides to Pd60–65 and Pt66,67 generates p-allylmetal intermediates that undergo the addition of carbon and nitrogen nucleophiles to form CdC and CdN bonds, respectively (Schemes 27 and 28). The fluorine substituent selectively reacts in a substrate that has both fluorine and acetoxy substituents at allylic positions (Scheme 27).60

Scheme 27 Pd-catalyzed defluorinative Tsuji–Trost reaction with C-nucleophiles.

Scheme 28 Pd-catalyzed defluorinative Tsuji–Trost reaction with N-nucleophiles.

12.11.2.1.5

Electron transfer

The g,g-difluoro-a,b-unsaturated carbonyl compounds undergo stepwise two-electron transfer from organocuprates to generate fluorinated dienolate intermediates via the elimination of a fluoride ion (Scheme 29).68–74 Subsequent reactions with electrophiles allow the introduction of alkyl, benzylic, and allylic groups at the a-position of the carbonyl group. Treatment of CF3-bearing benzofulvenes with lanthanide metals generates e,e-difluorinated dienylmetal intermediates (Scheme 30).75,76 Depending on the metal used, 1,1- and 1,3-disubstituted indenes can be selectively produced by the reactions with aldehydes. The defluorinative intramolecular cyclization of the b-CF3-styrenes proceeds in the presence of low-valent niobium species to afford substituted indenes, where Nb carbenoids are proposed as the intermediates (Scheme 31).77

Scheme 29 Cu-mediated defluorinative alkylation via electron transfer.

430

CdF Bond Activation Reactions

Scheme 30 Dy- and La-mediated defluorinative hydroxyalkylation via electron transfer.

Scheme 31 Nb-catalyzed defluorinative cyclization via electron transfer.

12.11.2.1.6

Addition–b-fluorine elimination

The bond-forming addition processes of organometallics, such as (i) insertion (Section 12.11.2.1.6.1), (ii) oxidative cyclization (Section 12.11.2.1.6.2), and (iii) radical addition (Section 12.11.2.1.6.3), rationally precedes b-fluorine elimination and promotes allylic CdF bond activation under mild conditions. 12.11.2.1.6.1 Insertion The insertion of CdC double bonds of allylic fluorides into metal–carbon or metal–nitrogen bonds generates organometallic intermediates bearing fluorine on the carbon b to the metal that are ready to undergo b-fluorine elimination. For example, in the presence of a Pd catalyst, 2-(trifluoromethyl)allyl ketone oxime esters first undergo oxidative addition of the NdO bond to Pd (Scheme 32).78 The subsequent 5-endo insertion and b-fluorine elimination proceed to afford 1-pyrrolines bearing an exo-difluoromethylene moiety.

Scheme 32 Pd-catalyzed cyclization via an insertion/b-fluorine elimination sequence.

Arylmetals produced from boron compounds are also available for a fluoroalkene insertion/b-fluorine elimination sequence. The transmetalation of arylboronates with an Rh catalyst generates an arylrhodium species, to which insertion of a-(trifluoromethyl)styrenes followed by b-fluorine elimination affords the corresponding 1,1-difluoro-1-alkenes (Scheme 33).79,80 Asymmetric versions of this defluorinative arylation are effected by using chiral diene ligands.81,82

Scheme 33 Rh-catalyzed arylation via an insertion/b-fluorine elimination sequence.

Consecutive CdH and CdF bond activation allows for the allylation of indoles. After treatment with a Co catalyst, N-(pyridin2-yl)indoles undergo chelate-assisted CdH bond cleavage at the 2-position (Scheme 34).83,84 A subsequent insertion of perfluoroalkylated alkenes to the CodC bond, followed by b-fluorine elimination, affords 2-allylic indoles.83 Therefore, the selective allylic CdF bond activation of perfluoroalkylated alkenes is achieved. Similar reactions proceed with a Mn catalyst85 and a Co catalyst.

CdF Bond Activation Reactions

431

Scheme 34 Rh-catalyzed indolylation via an insertion/b-fluorine elimination sequence.

12.11.2.1.6.2 Oxidative cyclization Oxidative cyclization of two unsaturated compounds using transition metals generates metalacycles. These metalacycles can be followed by b-fluorine elimination. Ni-mediated oxidative cyclization between 2-trifluoromethyl-1-alkenes and alkynes generates nickelacyclopentenes bearing a CF3 group on the carbon a to the Ni.86–88 Therefore, b-fluorine elimination readily proceeds to generate difluorodienylnickel intermediates. A subsequent 5-endo insertion, followed by a second b-fluorine elimination, affords 2-fluorocylopenta-1,3-dienes. When a diboron is added, the produced nickel difluoride can be recycled by reduction (Scheme 35a).87 The use of a hydrosilane instead of a diboron promotes the ligand exchange of intermediary dienylnickel fluorides to afford 1,1-difluoro-1,3-dienes (Scheme 35b).88

Scheme 35 Ni-catalyzed coupling via an oxidative cyclization/b-fluorine elimination sequence.

12.11.2.1.6.3 Radical addition Radical addition can be combined with b-fluorine elimination to allow defluorinative alkylation. In the presence of a Ni catalyst and Zn powder, treatment of a-(trifluoromethyl)styrenes with alkyl halides affords difluoroalkenes via allylic CdF bond activation (Scheme 36).89,90 Nickelacyclopropanes (consisting of Ni(II)) are first generated from styrenes and a Ni(0) catalyst. Subsequent single-electron transfer from the nickelacyclopropanes to alkyl halides affords Ni(III)-based nickelacyclopropanes and alkyl radicals that are connected via radical ring opening. The formed Ni(II) species readily undergo b-fluorine elimination to afford the corresponding products. Additionally, alkyl radical sources such as N-hydroxyphthalimide esters,91 acetals,92 cyclobutanone oxime esters,93 aldehydes,94 alkenes,95 epoxides,96,97 and alkylpyridiniums98 can be applied to a Ni(Cr)-catalyzed radical addition/b-fluorine elimination sequence. Similar defluorinative alkylation proceeds by using Zn without any Ni catalysts (Scheme 37).99

Scheme 36 Ni-catalyzed alkylation via a radical addition/b-fluorine elimination sequence.

Scheme 37 Zn-mediated alkylation via a radical addition/b-fluorine elimination sequence.

432

CdF Bond Activation Reactions

12.11.2.2 Activation of propargylic CdF bonds Section 12.11.2.2 deals with CdF bond activation in propargylic fluorides. This is achieved via bond-forming processes such as (i) insertion and (ii) aminometalation, followed by b-fluorine elimination for CdF bond cleavage (Section 12.11.2.2.1).

12.11.2.2.1

Addition–b-fluorine elimination

Propargylic fluorides are subject to CdF bond activation via b-fluorine elimination in a manner similar to that of allylic fluorides. For example, the enantioselective synthesis of fluoroallenes is achieved via the insertion of propargylic fluorides into an organorhodium species, generated from organozinc reagents and an Rh catalyst, and the subsequent elimination of b-fluorine (Scheme 38).100

Scheme 38 Rh-catalyzed enantioselective alkylation via an insertion/b-fluorine elimination sequence.

Propargylic fluorides can be applied to the aforementioned method for consecutive CdH/CdF bond activation (Scheme 34).83 The chelate-assisted CdH bond cleavage of N-(methoxy)benzamides is achieved by an Rh catalyst to generate arylrhodium intermediates. These intermediates undergo the insertion of propargylic fluorides followed by b-fluorine elimination (Scheme 39).101 The repeated insertion and b-fluorine elimination sequence affords alkynylated isoindolinones. A similar consecutive CdH/CdF bond activation with propargylic fluorides is also achieved by Rh,102–105 Ir,106 and Ru catalysts.107

Scheme 39 Rh-catalyzed cyclization via an insertion/b-fluorine elimination sequence.

The Au-catalyzed synthesis of 3-fluoropyrroles is achieved using propargylic fluorides. N-Homopropargylic amides undergo Au-mediated aminometalation followed by a b-fluorine elimination/double bond migration or HF elimination/protodemetalation sequence (Scheme 40).108 Similarly, the Ag-109 and Au-catalyzed110 synthesis of 3-fluorofurans from propargylic fluorides is also possible.

Scheme 40 Au-catalyzed cyclization via an aminometalation/b-fluorine elimination sequence.

12.11.2.3 Activation of benzylic CdF bonds Section 12.11.2.3 deals with CdF bond activation in benzylic fluorides. This activation proceeds via metalation involving oxidative addition or electron transfer (Section 12.11.2.3.1) and via fluoride abstraction with B, Al, and Si reagents (Section 12.11.2.3.2).

12.11.2.3.1

Metalation (oxidative addition and electron transfer)

Benzylic fluorides undergo oxidative addition to Pd, generating a p-benzylpalladium species. As with allylic fluorides, defluorinative Tsuji–Trost-type sulfonylation, alkoxylation, and amination reactions proceed via the p-benzylpalladium intermediates generated from benzylic fluorides (Scheme 41).111 Notably, the defluorinative arylation of (trifluoromethyl)arenes is achieved with arylboronic acids (a single CdF bond activation, Scheme 42).112

CdF Bond Activation Reactions

433

Scheme 41 Pd-catalyzed defluorinative substitution with S-, O-, and N-nuleophiles via oxidative addition.

Scheme 42 Pd-catalyzed defluorinative arylation via oxidative addition.

Benzylic CdF bond activation is also effected via single-electron transfer from electron-rich metal species. Upon treatment with low-valent Nb species, generated from NbCl5 and LiAlH4, 2-arylated benzotrifluorides undergo defluorinative cyclization (presumably via niobium carbenoids) to afford fluorenes (Scheme 43).113 This protocol also produces indenes114 and N-fused indoles.115 Treatment of allylsilanes with CsF generates allylic silicates. This, in turn, induces radical cross-coupling via singleelectron transfer to (trifluoromethyl)arenes, leading to defluorinative allylation products (a single CdF bond activation, Scheme 44).116

Scheme 43 Nb-catalyzed defluorinative cyclization via electron transfer.

Scheme 44 Si-mediated defluorinative allylation via electron transfer.

12.11.2.3.2

Fluoride abstraction

Upon treatment with B, Al, and Si reagents, benzylic fluorides undergo SN2-type or SN1-type reactions. Al reagents can be used to substitute all of the fluorines in benzylic fluorides, affording alkylation, arylation, and chlorination products (Scheme 45).117–122 Defluorinative arylation, alkylation, allylation, acyloxylation, and halogenation are achieved similarly in the presence of Ti,123 Fe,124 Ga,125 Nb,126 and Ru catalysts.127

Scheme 45 Al-assisted defluorinative substitution.

434

CdF Bond Activation Reactions

The use of frustrated Lewis pairs enables the single CdF bond activation of benzylic fluorides. In the presence of a catalytic amount of B(C6F5)3, treatment of (trifluoromethyl)arenes with 2,4,6-triphenylpyridine (TPPy) and Me3SiNTf2 produces the corresponding pyridinium salts (Scheme 46).128 The further substitution of the formed salts with various nucleophiles leads to the introduction of oxygen, sulfur, nitrogen, and halogen functional groups. Starting from (difluoromethyl)arenes, the combination of B(C6F5)3 and tris(o-tolyl)phosphine similarly generates fluorobenzylic phosphonium salts. The Wittig reaction is then applied to afford fluorinated stilbenes (Scheme 47).129

Scheme 46 B-catalyzed formation of pyridinium salts and their further substitution.

Scheme 47 B-mediated formation of phosphonium salts and their Wittig reaction.

The single activation of benzylic CdF bonds is also achieved via intramolecular fluoride abstraction. Upon treatment with a trityl cation, (trifluoromethyl)arenes bearing a hydrosilyl group at the ortho position generate the corresponding difluorobenzyl cations via fluoride abstraction caused by the in situ generated silylium moiety (Scheme 48).130–132 The formed benzylic cations are trapped by nucleophiles such as allylsilanes,130 thiophenols,131 and chloride ions.132

Scheme 48 Silylium-mediated defluorinative allylation.

12.11.2.4 Activation of alkyl CdF bonds Section 12.11.2.4 contains CdF bond activation in alkyl fluorides. This is achieved via an SN2 reaction (Section 12.11.2.4.1), an addition–b-fluorine elimination (Section 12.11.2.4.2), and a fluoride abstraction (Section 12.11.2.4.3).

12.11.2.4.1

SN2 reaction

Although the defluorinative SN2 reaction is considered difficult due to the poor leaving group ability of fluorine, the SN2 reaction of alkyl fluorides is effected with transition metal ate complexes. 1-Fluorooctane undergoes the SN2 reaction with an alkylcobalt ate complex, generated from a t-BuMgCl reagent and a Co catalyst (Scheme 49).133 Deuterium-labeling experiments indicate that the substitution reaction proceeds via an SN2-type mechanism. The similar substitution of alkyl fluorides proceeds with in situgenerated organoiron (Scheme 50),134 organonickel,135,136 and organocopper complexes (Scheme 51).137–140

Scheme 49 Co-catalyzed SN2 alkylation.

CdF Bond Activation Reactions

435

Scheme 50 Fe-catalyzed arylation.

Scheme 51 Cu-catalyzed cyclopentadienylation.

12.11.2.4.2

Addition–b-fluorine elimination

Alkyl CdF bond activation is achieved via addition–b-fluorine elimination. Particularly, migratory insertion of fluorine-containing metal carbenoids is followed by b-fluorine elimination. Copper carbenoids bearing a CF3 ligand, generated from trimethyl (trifluoromethyl)silane and diazo compounds, undergo a migratory insertion and b-fluorine elimination sequence to afford 1,1-difluoro-1-alkenes (Scheme 52).141 Similarly, the treatment of trifluoromethyl ketone hydrazones with terminal alkynes affords difluorinated 1,3-enynes via identical CF3-bearing Cu carbenoids.142 Additionally, the defluorinative coupling of (trifluoromethyl) diazomethane with arylboronic acids affords b,b-difluorostyrenes via a boron-mediated 1,2-migration/b-fluorine elimination sequence (Scheme 53).143

Scheme 52 Cu-catalyzed alkenylation via a migratory insertion/b-fluorine elimination sequence.

Scheme 53 B-mediated alkenylation via a 1,2-migration/b-fluorine elimination sequence.

Trifluoromethyl ketones are attacked by borylcopper species, where CdB and OdCu bonds are formed (Scheme 54).144 Subsequent boron-mediated b-fluorine elimination generates difluorinated copper enolates. In turn, these enolates undergo aldol reactions with aldehydes to afford a,a-difluoro-b-hydroxyketones.

Scheme 54 Cu-catalyzed hydroxyalkylation via B-mediated b-fluorine elimination.

Oxidative addition of the CdC bond in strained gem-difluorocyclopropanes is readily promoted by Pd at the distal position to the difluoromethylene carbon, leading to the formation of difluorinated palladacyclobutanes (Scheme 55).145–151 Subsequent b-fluorine elimination generates p-allylpalladium species that undergo Tsuji–Trost-type reactions with carbon, nitrogen, and oxygen nucleophiles to afford substituted fluoroalkenes.145 The defluorinative arylation,146 alkenylation,147 benzylation,148 alkynylation,149 and the three-component coupling150,151 of gem-difluorocyclopropanes also proceed through an oxidative addition/b-fluorine elimination sequence.

436

CdF Bond Activation Reactions

Scheme 55 Pd-catalyzed ring-opening coupling via an oxidative addition/b-fluorine elimination sequence.

12.11.2.4.3

Fluoride abstraction

Similar to allylic and benzylic fluorides, the defluorinative substitution of alkyl fluorides is facilitated by using B, Al, and Si reagents. For example, the treatment of alkyl fluorides with Al reagents allows the introduction of alkyl, alkenyl, and alkynyl groups, as well as halogen, oxygen, selenium, tellurium, and nitrogen functional groups (Scheme 56).152 Alkylation,153 alkynylation,154 and arylation153,155,156 proceed in a similar manner, where Si reagents are used.

Scheme 56 Al-assisted defluorinative substitution.

O-(1,3-difluoropropan-2-yl)carbamates undergo alkyl CdF bond activation with N,O-bis(trimethylsilyl)acetamide (BSA), involving CdN bond formation, to afford 2-oxazolidinones (Scheme 57).157,158 Defluorinative CdN bond formation using alkyl fluorides is also achieved by a La complex.159

Scheme 57 Si-assisted defluorinative cyclization.

(Trifluoromethyl)cyclopropanes undergo Al-mediated fluoride abstraction, followed by ring-opening. Subsequent sulfanylation with thiols and thiocarboxylic acids affords the corresponding sulfides and thiocarboxylates, respectively (Scheme 58).160 The selective syntheses of both 2-fluorinated dihydrothiophens and 2,2-difluorinated tetrahydrothiophens are achieved via the nucleophilic 5-endo-trig cyclization of the obtained thiocarboxylates, depending on the reaction conditions. The method of a fluoride abstraction/ring-opening sequence for (trifluoromethyl)cyclopropanes is also applied to arylation.161

Scheme 58 Al-assisted defluorinative ring-opening sulfanylation and 5-endo-trig cyclization.

12.11.3 Survey of alkene C(sp2)dF bond activation 2005–mid-2021 12.11.3.1 Activation of vinylic CdF bonds Section 12.11.3.1 deals with CdF bond activation in vinylic fluorides. This reaction is classified into one of the following types: an SNV reaction (Section 12.11.3.1.1), metalation (oxidative addition and electron transfer) (Section 12.11.3.1.2), addition–b-fluorine elimination (Section 12.11.3.1.3), and addition–a-fluorine elimination (Section 12.11.3.1.4).

CdF Bond Activation Reactions

12.11.3.1.1

437

SNV reaction

Like allylic fluorides, the addition–elimination of vinylic fluorides is primarily achieved in reactions with nucleophiles. Recently, reactions with the nucleophiles of transition metal species have been reported. For example, when b,b-difluorostyrenes are treated with active methylene compounds in the presence of a Cu catalyst, an SNV reaction followed by HF elimination generates allene intermediates (Scheme 59).162 Subsequent cyclization is again promoted by the Cu catalyst to afford substituted furans. The defluorinative arylation (Scheme 60),163 borylation (Scheme 61),164–171 and silylation172 of vinylic fluorides are effected with aryl, boryl, and silyl Cu species. These species are derived from arylboron, diboron, and silylboron reagents, respectively. Additionally, the SNV reaction of tetrafluoroethylene with diethylzinc is known.173

Scheme 59 Cu-catalyzed cyclization via SNV reaction.

Scheme 60 Cu-mediated SNV arylation.

Scheme 61 Cu-catalyzed SNV borylation.

The reaction of 2-perfluorobutyl-1-tetralones with nitrogen-containing five-membered heterocycles proceeds in the presence of Cs2CO3 and a cobalt catalyst to afford pentafluoroethylated naphthofurans (Scheme 62).174,175 Density functional theory (DFT) calculations indicate that double HF elimination and an SNV reaction with N-nucleophiles form cobalt(II) phenoxides bearing vinylic fluorine. These compounds then undergo an intramolecular SNV reaction as the last step.

Scheme 62 Co-catalyzed cyclization via SNV reaction.

12.11.3.1.2

Metalation (oxidative addition and electron transfer)

The oxidative addition of vinylic CdF bonds is achieved by Ni and Pd catalysts. This process is utilized for the Negishi (Scheme 63),176,177 Suzuki–Miyaura (Scheme 64),178–181 Hiyama,182 and Sonogashira coupling reactions.183 Additionally, treatment of 3,3-difluoroacrylates with B2pin2 in the presence of a Pd catalyst affords 2,3-diflluoro-1,3-dienes through the reaction of borylated intermediates with difluoroacrylate substrates (Scheme 65).184

Scheme 63 Pd-catalyzed defluorinative Negishi coupling.

438

CdF Bond Activation Reactions

Scheme 64 Pd-catalyzed defluorinative Suzuki–Miyaura coupling.

Scheme 65 Pd-catalyzed self-coupling via defluorinative borylation.

1,1-Difluoro-1-alkenes, generated from CBrF2-bearing compounds, undergo single-electron transfer from CrCl2, producing fluorovinylchromium intermediates via the elimination of a fluoride ion (Scheme 66).185 Therefore, the defluorinative Nozaki–Hiyama–Kishi reaction proceeds with aldehydes to afford 2-fluoroallylic alcohols.

Scheme 66 Cr-mediated defluorinative Nozaki–Hiyama–Kishi reaction.

12.11.3.1.3

Addition–b-fluorine elimination

As with allylic fluorides, the CdF bond activation of vinylic fluorides can be achieved by a combination of elementary steps characteristic of organometallics with b-fluorine elimination. In the case of vinylic fluorides, the following addition processes are utilized as a step prior to b-fluorine elimination: (i) insertion (Section 12.11.3.1.3.1), (ii) carbo(hetero)metalation (Section 12.11.3.1.3.2), (iii) oxidative cyclization (Section 12.11.3.1.3.3), and (iv) radical addition (Section 12.11.3.1.3.4). 12.11.3.1.3.1 Insertion Pd-Catalyzed defluorinative cyclization proceeds with 3,3-difluoroallyl ketone oxime esters via a three-step sequence, consisting of oxidative addition of the NdO bond, 5-endo insertion into the NdPd bond, and b-fluorine elimination (Scheme 67)186 as with 2-(trifluoromethyl)allyl ketone oxime esters (Scheme 32).78 The CdPd bond of arylpalladiums (generated via oxidative addition187,188 or transmetalation189) also undergoes a fluoroalkene insertion/b-fluorine elimination sequence to afford fluorostilbenes starting from b,b-difluorostyrenes and arylboronic acids (Scheme 68). Similar reactions via a difluoroalkene insertion/b-fluorine elimination sequence have been reported, some of which involve the prior insertion of carbon monoxide (Scheme 69)190 or fluorine-free alkenes.191 Additionally, the insertion of fluoroalkenes into the RhdGe bond is used for vinylic CdF bond activation through an insertion/b-fluorine elimination sequence.192,193 Similar germylation is achieved by an aluminum catalyst.194

Scheme 67 Pd-catalyzed cyclization via an insertion/b-fluorine elimination sequence.

CdF Bond Activation Reactions

439

Scheme 68 Pd-catalyzed arylation via an insertion/b-fluorine elimination sequence.

Scheme 69 Pd- and Cu-catalyzed acylation via an insertion/b-fluorine elimination sequence.

Similar to allylic fluorides, consecutive CdH/CdF activation is possible for vinylic fluorides. For example, the CdH bond cleavage of N-(pyrimidin-2-yl)indoles with an Rh catalyst proceeds at the 2-position (Scheme 70).195–202 The insertion of 1,1-difluoro-1-alkenes into the formed CdRh bond, followed by b-fluorine elimination, affords 2-fluorovinylated indoles. The same type of domino CdH/CdF bond activation of vinylic fluorides has been achieved with Mn,203 Co,204 and Ru catalysts.205

Scheme 70 Rh-catalyzed indolylation via an insertion/b-fluorine elimination sequence.

Migratory insertion from fluorine-containing metal carbenoids also induces b-fluorine elimination. The Au carbenoids derived from diazo compounds undergo migratory insertion of fluorinated silyl enol ethers (Scheme 71).206 The subsequent b-fluorine elimination affords 2-alkene-1,4-diones.

Scheme 71 Au-catalyzed alkenylation via a migratory insertion/b-fluorine elimination sequence.

12.11.3.1.3.2 Carbo(hetero)metalation 1,1-Difluoro-1-alkenes can coordinate to cationic metal complexes, promoting the attack of weak nucleophiles. This type of carbo-, amino-, and oxymetalation, followed by b-fluorine elimination, enables vinylic CdF bond activation. A Pd-catalyzed carbometalation/b-fluorine elimination sequence affords fluorophenacenes (Scheme 72),207–211 whereas 2-fluoroindoles are successfully synthesized via an Ag-catalyzed aminometalation/b-fluorine elimination sequence (Scheme 73).212 Moreover, an In-catalyzed oxymetalation/b-fluorine elimination sequence leads to the synthesis of 3-fluoroisocoumarins (Scheme 74).213 In each case, a catalytic version is achieved by the addition of BF3
OEt2, N,O-bis(trimethylsilyl)acetamide (BSA), or ZnI2 as a scavenger of the liberated fluoride ion.

440

CdF Bond Activation Reactions

Scheme 72 Pd-catalyzed cyclization via a carbometalation/b-fluorine elimination sequence.

Scheme 73 Ag-catalyzed cyclization via an aminometalation/b-fluorine elimination sequence.

Scheme 74 In-catalyzed cyclization via an oxymetalation/b-fluorine elimination sequence.

12.11.3.1.3.3 Oxidative cyclization As with allylic fluorides, vinylic fluorides undergo metal-mediated oxidative cyclization followed by b-fluorine elimination. Ni-mediated oxidative cyclization between b,b-difluorostyrenes and alkynes generates nickelacyclopentenes. These are readily subject to b-fluorine elimination (Scheme 75).214 The catalytic synthesis of fluoro-1,3-dienes is achieved by the addition of a borate that serves as a hydrogen source and as a reductant. A 2,2-difluorovinylzinc complex, prepared from 1,1-difluoroethylene, undergoes Cu-catalyzed oxidative cyclization with organic azides (Scheme 76).215 4-Fluorotriazoles are synthesized via b-fluorine elimination and reductive elimination.

Scheme 75 Ni-catalyzed coupling via an oxidative cyclization/b-fluorine elimination sequence.

Scheme 76 Cu-catalyzed cyclization via an oxidative cyclization/b-fluorine elimination sequence.

12.11.3.1.3.4 Radical addition A radical addition/b-fluorine elimination sequence enables reductive couplings. In the Ni-catalyzed coupling of b,b-difluorostyrenes with alkyl halides, alkyl radicals, formed via the one-electron reduction of alkyl halides, add to the styrenes to produce fluorine-containing alkylnickel species suitable for b-fluorine elimination (Scheme 77).216 Similarly, Ni-catalyzed defluorinative benzylation,217 sulfanylation, and selenylation218 are also achieved. In addition, defluorinative alkylation proceeds by using Zn without any Ni catalysts.219 The hydrogen atom transfer from the in situ-generated iron hydride to the donor alkenes generates radical intermediates that react with b,b-difluorostyrenes to induce Fe-mediated b-fluorine elimination, leading to the synthesis of substituted fluoroalkenes (Scheme 78).220

CdF Bond Activation Reactions

441

Scheme 77 Ni-catalyzed alkylation via a radical addition/b-fluorine elimination sequence.

Scheme 78 Fe-catalyzed alkylation via a radical addition/b-fluorine elimination sequence.

12.11.3.1.4

Addition–a-fluorine elimination

Vinyl fluorides also undergo reactions involving a-fluorine elimination from metalacycle intermediates. The Ni-catalyzed oxidative cyclization of difluoro-1,6-enynes generates fluorinated nickelacyclopentenes, from which a-fluorine elimination is promoted by zinc reagents to afford fluorinated bicyclo[3.2.0]heptenes (Scheme 79).221 In the Ni-catalyzed reactions of 1,1-difluoroethylenes and alkynes, fluorinated nickelacycloheptadienes, generated via oxidative cyclization and insertion, undergo a-fluorine elimination to provide fluoroarenes (Scheme 80).222 The catalytic reactions are achieved by the addition of a borate as a fluoride scavenger. In addition, a nickelacycle derived from tetrafluoroethylene and styrene affords a difluorocyclobutene or a difluoro-1,3-diene with or without BF3
OEt2 via a-fluorine elimination, respectively (Scheme 81).223

Scheme 79 Ni-catalyzed cyclization via an oxidative cyclization/a-fluorine elimination sequence.

Scheme 80 Ni-catalyzed cyclization via an oxidative cyclization/a-fluorine elimination sequence.

Scheme 81 Ni-catalyzed coupling via an oxidative cyclization/a-fluorine elimination sequence.

442

CdF Bond Activation Reactions

12.11.3.2 Activation of allenylic CdF bonds Section 12.11.3.2 deals with CdF bond activation in allenylic fluorides, achieved via fluoride abstraction (Section 12.11.3.2.1).

12.11.3.2.1

Fluoride abstraction

The In-catalyzed defluorinative cyclization of 1,1-difluoroallenes proceeds via intramolecular carbometalation and fluoride abstraction, where allene C(sp2)dF bond activation is achieved. Due to the coordination of the more electron-rich CdC double bond in difluoroallenes to the In atom, a-fluorine-stabilized carbocation intermediates are generated (Scheme 82).224–226 A Friedel–Crafts-type CdC bond formation occurs, followed by fluoride abstraction and ring expansion. Subsequent dehydrogenation with DDQ affords fluorophenanthrenes. Similarly, a fluoropicene is successfully synthesized by repeating the ring extension cycle involving the difluoroallene preparation from fluoroarenes and another fluoroarene construction from the difluoroallenes (Scheme 83).227

Scheme 82 In-catalyzed cyclization via a carbometalation/fluoride abstraction sequence.

Scheme 83 Ring-extension cycle involving In-catalyzed defluorinative cyclization toward fluoropicene synthesis.

12.11.3.3 Activation of acyl CdF bonds After the Ni-catalyzed coupling of acyl fluorides with R2Zn (R ¼ aryl and alkyl) was discovered,228 acyl fluorides have emerged as substrates for CdF bond activation reactions with transition metal catalysts. Despite being rather stable, acyl fluorides are reactive toward oxidative addition, in which decarbonylation takes place or not (Sections 12.11.3.3.1 and 12.11.3.3.2) depends on the catalyst system.229 Reviews on the activation of acyl CdF bonds have recently appeared.230–233

12.11.3.3.1

Carbonyl-retentive coupling

Compared with decarbonylative reactions, reactions of acyl fluorides that proceed without decarbonylation are fewer in number. The majority of these reactions are conducted by Pd catalysts. Various acyl fluorides undergo Suzuki–Miyaura coupling with aryland alkenylboronic acids to afford the corresponding ketones (Scheme 84).234 Hiyama coupling with ArSiF3235 and CdF/CdH coupling with azoles (such as oxazoles, Scheme 85)236 are also known. The coupling of acyl fluorides with vinyl triflates237 and alkylpyridinium salts238 is performed by Ni/Mn systems to provide methods for vinyl and alkyl ketone syntheses.

Scheme 84 Pd-catalyzed carbonyl-retentive Suzuki–Miyaura coupling.

Scheme 85 Pd-catalyzed carbonyl-retentive CdF/CdH coupling with azoles.

CdF Bond Activation Reactions

443

Acyl fluorides act as acylating agents in the presence of Rh catalysts. Aromatic and aliphatic acyl fluorides react with various heteroatom reagents such as disulfides239 and diselenides240 in the presence of Rh(H)(PPh3)4 to afford the corresponding acylated products (Scheme 86).241–243

Scheme 86 Rh-catalyzed carbonyl-retentive coupling with disulfides and diselenides.

12.11.3.3.2

Decarbonylative coupling

Ni catalysts promote the decarbonylative reactions of acyl fluorides. In decarbonylative Suzuki–Miyaura coupling with boronic acids,244–246 PPh2Me is an efficient ligand for the promotion of decarbonylation (Scheme 87).247,248 Miyaura borylation proceeds in the presence of Ni catalysts to afford the corresponding arylboronates (Scheme 88).249,250 Additionally, Pd-catalyzed trifluoromethylation with CF3SiEt3251 and Ir-252/Rh-253catalyzed CdF/CdH coupling are achieved. Acyl fluorides undergo Ni-254catalyzed and Pd-catalyzed255 decarbonylative alkynylations with terminal alkynes and alkynylsilanes, respectively.

Scheme 87 Ni-catalyzed decarbonylative Suzuki–Miyaura coupling.

Scheme 88 Ni-catalyzed decarbonylative Miyaura borylation.

12.11.4 Survey of arene C(sp2)dF bond activation 2005–mid-2021 In a historical and synthetic context, Section 12.11.4 is composed of three parts: directed systems (Section 12.11.4.1), nondirected systems with multiple fluorine atoms (Section 12.11.4.2), and nondirected systems with one fluorine atom (Section 12.11.4.3). Each section involves both aspects of (i) CdF bond cleavage (coordination chemistry) and (ii) CdF bond activation (synthetic chemistry). Between 2005 and mid-2021, excellent review articles on aromatic CdF bond activation2,3,7,10,11,256–260 involving CdF/CdH selectivity issues have been published.261,262 In this section, the coupling reactions using organozinc reagents, Grignard reagents, organostannanes, and organosilanes are called Negishi coupling, Kumada coupling, Migita–Kosugi–Stille coupling,263,264 and Hiyama coupling, respectively, regardless of the catalyst metals.

12.11.4.1 Activation of aromatic CdF bonds (1): Directed systems The CdF bond cleavage of perfluorinated (hetero)arenes bearing directing groups (DGs) was discussed in COMC III.24 Although the use of DGs is disadvantageous from the viewpoint of organic synthesis, DGs still play an important role in coordination chemistry. Namely, DG-based complexation provides useful information such as mechanistic considerations on the oxidative addition of CdF bonds to transition metals. Most of the systems with DGs contain more than one fluorine atom on the aromatic rings. Examples of the monofluorinated systems that appeared recently are described in the last part of this Section 12.11.4.1. Although the nitrogen atom of perfluoropyridine sometimes coordinates to metal centers (e.g., Rh(I)265 and Ni(0)266) to function as DGs, perfluoropyridine undergoes not only ortho but also para metalation. Therefore, fluorinated pyridine derivatives are discussed as nondirected systems in the following Section 12.11.4.2.

444

CdF Bond Activation Reactions

12.11.4.1.1

Metalation

DG-promoted metalation (oxidative addition) results in the formation of metallacycles (cyclometalation). An azine (dC]NdN] Cd) derived from 2,6-difluorobenzaldehyde and hydrazine undergoes cyclometalation with an electron-rich Co(I) complex to afford a Co(III) complex via oxidative addition (Scheme 89).267 Interestingly, 2,6-difluorobenzophenone (bearing a ketone moiety as a DG) reacts with CoMe(PMe3)4 to afford a Co(III) complex (CdF bond cleavage product), whereas the corresponding imine affords a Co(I) complex (CdH bond cleavage product, Scheme 90).257 CdF bond cleavage with Fe(PMe3)4268,269 and with CpRh(PMe3)(ethylene) under UV irradiation270 are also known.

Scheme 89 Directed oxidative addition to Co(I) complexes.

Scheme 90 Directed CdF and CdH selective oxidative addition to Co(I) complexes.

The oxidative addition of 2,6-difluorobenzophenone imine to a Co(0) complex proceeds with a concomitant reduction by the released PMe3 to form a Co(I) complex, where the oxidation state of Co increases by one unit (Scheme 91).257 Fe(PMe3)4 undergoes a similar oxidative addition/reduction sequence with difluoroimines271 and difluoroketones.272 The phenylation of aryl–Co(I) with bromobenzene is also described (Scheme 114).

Scheme 91 Directed oxidative addition–reduction to Co(0) complexes.

A bimetallic Mg/Fe complex, XMgdFeCp(CO)2 (X ¼ diketiminate), undergoes nucleophilic metalation of pyridyl(pentafluoro) benzene (Scheme 92).273 DFT calculations indicate that the metalation proceeds through an SNAr-type mechanism and that the transition state involves a Mg-chelated structure.

Scheme 92 Para-selective metalation by bimetallic Mg(II)/Fe(0) complexes.

CdF Bond Activation Reactions

12.11.4.1.2

445

CdC and CdX bond formation

Over the 15 years covered in this article, CdC and CdX bond-forming reactions using DGs have been developed. These reactions are mainly performed by group 10 metal catalysts. 12.11.4.1.2.1 Alkylation and alkoxylation Upon treatment with Me2Zn in the presence of a Pt catalyst, ortho-fluorinated benzaldehyde derivatives bearing an imine moiety and electron-withdrawing groups afford methylation products (R]Me, Scheme 93).274–279 The use of Si(OMe)4 instead of Me2Zn leads to methoxylation products (R]OMe).280 Bromine substituents at the meta and para positions are less reactive than ortho fluorine substituents, whereas ortho chlorine substituents are more reactive than ortho fluorine substituents. The proposed catalytic cycle involves an oxidative addition/transmetalation/reductive elimination sequence to go through Pt(II)/Pt(IV) complexes.

Scheme 93 Directed methylation and methoxylation under Pt catalysis.

The methylation (Scheme 94) and benzylation of difluoro- and pentafluoroaldimines are also achieved with organozinc reagents (Negishi coupling) and Ni catalysts.281 The Ni-catalyzed system is more widely applicable than the Pt-catalyzed system because Pt-system requires electron-withdrawing substituents at the meta and para positions.

Scheme 94 Directed methylation under Ni catalysis.

12.11.4.1.2.2 Arylation, alkenylation, and borylation Suzuki–Miyaura coupling, Stille coupling, and amination of fluoro(nitro)benzenes bearing electron-withdrawing groups, such as cyano and formyl groups, were developed in the early stages of this chemistry.282,283 Fully fluorinated and partially fluorinated nitrobenzenes undergo Suzuki–Miyaura arylation and alkenylation in the presence of a Pd(PPh3)4 catalyst under microwave irradiation (Scheme 95).284,285 The nucleophilic behavior of Pd(0) in the oxidative addition step is supported by the effect of additional fluorine atoms upon reactivity.

Scheme 95 Directed arylation and alkenylation under Pd catalysis.

Ni(cod)2 catalyzes the Suzuki–Miyaura arylation of partially fluorinated benzenes bearing an imine moiety (Scheme 96).286 The synthesis of fluorinated terphenyls is also achieved by using 2,6-difluorinated imines and 3 equiv. of boronic acids. Ni(cod)2 also catalyzes the coupling of pyridyl group-bearing fluorobenzenes (120  C)287 and aminocarbonyl group-bearing fluorobenzenes (60  C)288 with boronic esters, of which the latter can be conducted at a lower temperature.

446

CdF Bond Activation Reactions

Scheme 96 Directed arylation under Ni catalysis.

In addition to group 10 metal complexes, a Ru(II) complex catalyzes DG-promoted arylation with boronic esters. 2,6-Difluoroacetophenone undergoes double arylation with ArBnep in the presence of vinylsilane and CsF.289 With the same catalyst system, 2-fluoroacetophenone undergoes CdH alkylation with trimethyl(vinyl)silane290 and CdF phenylation with a phenyl boronic ester, affording alkyl-substituted and aryl-substituted acetophenones (Scheme 97).

Scheme 97 Directed CdF arylation and CdH alkylation under Ru catalysis.

Miyaura borylation is the major route to boronic esters, which are important coupling partners for Suzuki–Miyaura coupling. Fluoro(pyridyl)benzenes undergo Miyaura borylation with B2pin2 in the presence of an Rh catalyst (Scheme 98).291 An Rh(III)/ Rh(V) catalytic cycle involving ligand-assisted CdF bond cleavage (Type B: Section 12.11.4.2.1.2) is proposed.

Scheme 98 Directed borylation under Rh catalysis.

Hydroxy, hydroxymethyl, and amino groups act as DGs in the arylation and alkenylation of fluoroarenes with Grignard reagents (Kumada coupling, Scheme 99).292 Of note, methoxylated fluoroarenes exhibit poor reactivity. The Co(acac)2-catalyzed coupling of acyl(fluoro)benzenes proceeds with (hetero)arylcuprates (Scheme 100).293,294

Scheme 99 Directed arylation and alkenylation under Pd catalysis.

Scheme 100 Directed (het)arylation under Co catalysis.

CdF Bond Activation Reactions

447

12.11.4.1.2.3 CdF/CdH coupling Fluoro(nitro)benzenes undergo coupling with terminal alkynes (Sonogashira coupling) in the presence of a Pd(PPh3)4 catalyst under microwave irradiation (Scheme 101).295 A Pd(MeCN)2Cl2 catalyst facilitates the CdF/CdH coupling of fluorinated pyridylbenzenes with oxazoles, thiazoles, and imidazoles, using LiOt-Bu as a base (Scheme 102).296

Scheme 101 Directed CdF/CdH coupling with alkynes under Pd catalysis.

Scheme 102 Directed CdF/CdH coupling with azoles under Pd catalysis.

12.11.4.1.2.4 Insertion Fluoro(nitro)benzenes, activated with electron-withdrawing groups, undergo DG-assisted alkenylation with hydrazones in the presence of a Pd catalyst (Scheme 103).297 The oxidative addition of fluoro(nitro)benzenes to Pd and the subsequent carbene transfer from the in situ-generated diazo compounds form the intermediary Pd(II) complexes. These complexes undergo migratory insertion, followed by b-hydrogen elimination, to afford the alkenylation products.

Scheme 103 Directed alkenylation with hydrazones under Pd catalysis.

2-Fluorobenzanilides react with alkynes in the presence of Ni(cod)2 catalyst to give lactams (Scheme 104).298 2-Fluorobenzamides, bearing a bidentate N-quinolylamide moiety, undergo double alkyne insertion leading to benzene ring formation (Scheme 105).299 Of note, DFT calculations indicate that the coordination of fluorine to the Li ion accelerates the oxidative addition step.

Scheme 104 Directed alkyne insertion for cyclization under Ni catalysis.

448

CdF Bond Activation Reactions

Scheme 105 Directed double alkyne insertion for cyclization under Ni catalysis.

12.11.4.2 Activation of aromatic CdF bonds (2): Nondirected systems with multiple fluorine atoms CdF bond activation in fluoroarene substrates without DGs is much more challenging than in those substrates with DGs. In this section, nondirected systems bearing multiple fluorine atoms are described. The representative substrates are perfluorobenzene and perfluorotoluene. Of note, the CdF bond activation reactions in partially fluorinated systems such as tetra- and trifluorobenzenes have increased over the past decade. As mentioned above, the CdF bond activation of fluorinated pyridines is discussed in this section. The ligand-assisted metalation of fluoroarenes by silyl- and boryl-complexes of the group 9 metals allows for catalytic borylation and etherification. The related phosphine-assisted aromatic CdF bond cleavages by the group 9300–302 and 10 metals266,303–305 are also described.306

12.11.4.2.1

Metalation

The metalation of (hetero)aromatic CdF bonds with transition metal complexes is classified into three types (A–C), as shown in Section 12.11.1.4 (Scheme 18). 12.11.4.2.1.1 SNAr-like metalation (type A) In addition to the anionic metal carbonyls such as CpFe(CO)−2 and Mn(CO)−5,307,308 a neutral Ir(I) complex, Cp Ir(CO)2, reacts with perfluorobenzonitrile in the presence of water or methanol to afford a metalocarboxylic acid or the corresponding metalocarboxylic ester, respectively (Scheme 106).309 Note that the reaction occurs at the position para to the CN group.

Scheme 106 SNAr-like metalation by Ir(I) complexes.

12.11.4.2.1.2 Ligand-assisted metalation (type B) The mechanistic insight into ligand-assisted metalation was gained by theoretical calculations (depicted in Fig. 3a). This mechanism can be interpreted as a counterpart of the concerted metalation–deprotonation mechanism,310 found in CdH bond activation (Fig. 3b). Electron-rich metal centers, typically bearing trialkylphosphines, approach fluoroarenes in a nucleophilic fashion. The Lewis acidic ligands, such as boryl and silyl groups, abstract a fluoride ion to facilitate both CdF bond cleavage and CdM bond formation without a change in the oxidation state of the metals. The ligand-assisted metalation of fluoroarenes with group 9 metals is distinct from the aforementioned oxidative addition/reduction sequence of the same metals that proceeds with an increase in the oxidation state. (A)

(B)

Fig. 3 (a) Ligand-assisted metalation in CdF bond activation; (b) Concerted metalation–deprotonation in CdH bond activation.

CdF Bond Activation Reactions

449

Perfluoropyridine undergoes metalation with a silyl–Rh(I) complex, Rh(SiPh3)(PMe3)3, to form ortho- and para-metalated pyridines (metal–fluorine exchange, 3:1 mixture) with the concomitant formation of fluorosilanes (Scheme 107), whereas 2,3,5,6-tetrafluoropyridine affords a roughly 1:1 mixture of ortho- and para-metalated pyridines via CdF and CdH bond activation, respectively.311 The formed metalated pyridines undergo borylation in the presence of B2cat2 to give pyridylboronates. UV irradiation of Rh[Si(OEt)3](CO)(L2) (L2 ¼ bidentate ligand) also facilitates the metalation of perfluorobenzene, perfluoropyridine, and partially fluorinated arenes, where CdH bonds are more reactive than CdF bonds.312 DFT calculations suggest that the metalation of perfluoroarenes with silyl–Rh(I) complexes proceeds in a concerted manner via a silyl-assisted mechanism, where the silyl group abstracts a fluoride ion to generate a fluorosilane (Fig. 4).313 By contrast, Rh(H)(PEt3)3 reacts with perfluoropyridine to afford the para-metalated product.314,315

Scheme 107 Silyl-assisted metalation by Rh(I) complexes and borylation.

Fig. 4 Transition state for silyl-assisted metalation by Rh(I) complexes.

A boryl–Rh(I) complex, Rh(Bpin)(PEt3)3, also promotes the CdF bond cleavage of perfluoropyridine to afford the ortho-metalated pyridine with the concomitant generation of FBpin. DFT calculations indicate that the reaction proceeds by a boryl-assisted mechanism, similar to the mechanism for the silyl–Rh(I) complex (Scheme 108).265 Rh(Bpin)(PEt3)3 reacts with perfluorobenzene and perfluorotoluene to form the corresponding metalated pentafluorobenzene and heptafluorotoluene, both of which are identified by NMR and X-ray diffraction analyses (Scheme 109).316 Rh(Bpin)(PEt3)3 functions as a catalyst for the borylation of perfluoropyridine and perfluorotoluene with B2pin2 (Scheme 119). Diaryl ether synthesis based on boryl-assisted metalation is known (Scheme 124).

Scheme 108 Boryl-assisted metalation of perfluoropyridine by Rh(I) complexes.

Scheme 109 Boryl-assisted metalation of perfluorobenzene and perfluorotoluene by Rh(I) complexes.

450

CdF Bond Activation Reactions

A germyl–Rh(I) complex, Rh(GePh3)(PEt3)3, reacts with perfluoropyridine, perfluorobenzene, and perfluorotoluene in a way similar to that of the silyl– and boryl–Rh(I) complexes.317 The CdH bonds in 2,3,5,6-tetrafluoropyridine and pentafluorobenzene react more readily than their CdF bonds. 12.11.4.2.1.3 Oxidative addition (type C) The oxidative addition of multiple fluorinated (hetero)arenes has been extensively studied on Ni(0) complexes,318 leading to coupling reactions of synthetic value. Among the Ni species, an NHCdNi(0) complex is electron-rich and ready to undergo oxidative addition with fully and partially fluorinated arenes, forming the corresponding Ni(II) complexes (Scheme 110).319,320 The same complex reacts with 1,2-difluorobenzene in a CdF bond-selective manner to afford a 2-fluorophenyl Ni(II) complex, where an NHC-assisted oxidative addition mechanism is also suggested.321 Regioselective oxidative addition of partially fluorinated benzenes can be achieved by using Me3Al–pyridine along with a Ni(PEt3)4 catalyst.322

Scheme 110 Oxidative addition to Ni(0) complexes.

In the case of transition metals such as Co and Ti, an oxidative addition/reduction sequence proceeds with an increase of oxidation state by one unit. For example, perfluorobenzene and perfluorotoluene undergo metalation with a Co(0) complex to afford Co(I) complexes (Scheme 111).323,324 Oxidative addition, followed by reduction with the released PMe3, accounts for the generation of fluoroaryl–Co(I) complexes.

Scheme 111 Oxidative addition–reduction to Co(0) complexes.

Another example of an oxidative addition/reduction sequence is a binuclear oxidative addition. A Ti(II)–bis(trimethylsilyl) acetylene complex promotes the oxidative addition of perfluoropyridine to form an ortho-metalated 2:1 (Ti/substrate) product (Scheme 112).325 This complex consists of two Ti(III) components, whose generation is ascribed to sequential oxidative addition and reduction with “Ti(II)Cp2,” while the same perfluoropyridine simply undergoes oxidative addition to the Zr(II) counterpart on its para position.326 The Ti(II)–bis(trimethylsilyl)acetylene complex reacts with CdF bonds selectively in the presence of CdH bonds. Binuclear oxidative addition to Co(I) diketiminate complexes (see Section 12.11.4.3.1)327,328and to Co(I)Cp half-sandwich complexes are also known.329

Scheme 112 Binuclear oxidative addition to Ti(II) complexes.

CdF Bond Activation Reactions

12.11.4.2.2

451

CdC and CdX bond formation

12.11.4.2.2.1 Alkylation and alkynylation Perfluoroarenes, such as perfluorobenzene, perfluorotoluene, and perfluoronaphthalene, undergo coupling with hydrazones derived from benzaldehydes in the presence of a RuCl2(cymene) catalyst to afford benzylated products (Scheme 113).330 A six-membered chair-like transition state is proposed. As a transition metal-free Sonogashira coupling, the reaction of fluoroarenes with terminal alkynes is promoted by Ca(OH)2 in the presence of Na/NaOMe/n-BuMgCl.331

Scheme 113 Ru-catalyzed benzylation with hydrazones.

12.11.4.2.2.2 Arylation A perfluoroaryl–Co(I) complex undergoes stoichiometric phenylation with bromobenzene (Scheme 114).323 Cross-coupling reactions of fully and partially fluorinated arenes have been primarily achieved by using group 10 metal catalysts. Suzuki–Miyaura arylation of fully fluorinated arenes takes place with arylboronic acids (Scheme 115)332 or boronates333 in the presence of NHC–Ni catalysts.

Scheme 114 Arylation of perfluoroaryl Co(I) complexes with bromobenzene.

Scheme 115 Ni-catalyzed arylation with arylboronic acids.

The coupling of perfluoroarenes and perfluoropyridine with diarylzinc reagents (Negishi coupling) is performed by a Pd(PCy3)2 catalyst (Scheme 116),334 where the addition of LiI is essential. Similar accelerating effects of Lewis acids (e.g., Li, Zr, and Mg ions) upon oxidative addition are known.287,335,336 [Ni(NHC)2]2(cod) catalyzed-Negishi coupling is also known.337

Scheme 116 Pd-catalyzed arylation with arylzinc reagents.

452

CdF Bond Activation Reactions

A [Ni(NHC)2]2(cod) catalyst facilitates the coupling of perfluoroarenes with aryl(trialkoxy)silanes (Hiyama coupling, Scheme 117).337 Etherification (methoxylation) proceeds when the reaction is performed in the presence of Me4NF.

Scheme 117 Ni-catalyzed phenylation and methoxylation with silanes.

12.11.4.2.2.3 Borylation At the early stage, borylation of perfluorobenzene was performed in a stoichiometric manner by the capture of the CdRh bond in a pentafluorophenyl Rh(I) complex.311 The system of B2pin2/Rh(Bpin)(PEt3)3 catalytically facilitates ortho-selective borylation of perfluoropyridine (Scheme 118),265 whereas the HBpin/Rh(H)(PEt3)3 system causes para-selective borylation.316 Note that review articles involving Rh-catalyzed and Ni-catalyzed borylation have been published.11,258

Scheme 118 Rh-catalyzed borylation.

An electron-rich Ni catalyst promotes the borylation of fully and partially fluorinated arenes with B2pin2 in the presence of fluoride ions to afford the corresponding arylboronates.338 A combination of Ni(IMes)2 with an Rh photocatalyst accelerates the reaction (Scheme 119).339 Energy transfer from the photo-excited Rh to the intermediary (IMes)2Ni(F)(Ar) removes one of the NHC ligands. This removal accelerates the rate-determining transmetalation step.

Scheme 119 Ni/Rh-catalyzed borylation.

12.11.4.2.2.4 Miscellaneous Carbyne complexes are potential intermediates for CdF bond activation. A Ti carbyne complex, generated in situ from the corresponding carbene complex, causes CdF bond cleavage and CdC bond formation in perfluorobenzene (Scheme 120) and perfluorotoluene.340

Scheme 120 CdF bond activation by Ti carbyne complexes.

CdF Bond Activation Reactions

453

12.11.4.3 Activation of aromatic CdF bonds (3): Nondirected systems with one fluorine atom The CdF bond activation of nonactivated monofluoroarenes is the most challenging task in this research area. Section 12.11.4.3 deals with CdF bond activation in monofluorinated aromatic systems without DGs. The substrates partly involve electron-withdrawing (activating) groups such as cyano and trifluoromethyl groups. The CdF bond activation of nonactivated monofluoroarenes has been intensively studied because of their synthetic importance. The appropriate ligand design and the use of Lewis acids are key points to compensate for the low reactivity of simple monofluoroarenes.

12.11.4.3.1

Metalation

Ir(III) and Rh(III) porphyrin complexes, M(L)(ttp)Cl, cause p-chlorophenylation with p-chlorofluorobenzene in a chemoselective manner (activated system, Scheme 121),341,342 The chemoselectivity is strongly affected by the reaction temperature and substrate concentration. An SNAr-like process by an in situ-generated anionic species, M(ttp)−, is proposed (type A). This system applies to other polyfluorinated benzenes (activated systems) and also to fluorobenzenes (nonactivated system).343

Scheme 121 SNAr-like metalation by Ir(III) and Rh(III) complexes.

Binuclear oxidative addition to a Co(diketiminate) complex327,328 promotes the CdF bond metalation of fluorobenzene (Scheme 122). Furthermore, aluminum-assisted metalation of fluoroarenes is effected with a bimetallic Rh/Al complex, where the in situ-generated magnesioarenes undergo coupling with various electrophiles (Scheme 133).344

Scheme 122 Binuclear oxidative addition to Co(I) complexes.

12.11.4.3.2

CdC and CdX bond formation

12.11.4.3.2.1 Activated monofluoroarenes Suzuki–Miyaura coupling of activated monofluoroarenes is achieved by using a Ni(cod)2 catalyst and ZrF4 (Scheme 123).287 On the basis of the correlation of product yields with the s−p values of the substituents in the fluoroarenes, charged intermediates or transition states are proposed for the oxidative addition step.

Scheme 123 Ni-catalyzed arylation.

454

CdF Bond Activation Reactions

Diaryl ether synthesis is facilitated by the [Ir(cod)Cl]2 complex on the basis of the boryl-assisted metalation (type B), where the stability of the BdF bond leads to CdF/CdCl and CdF/CdH selectivity in bond activation (Scheme 124).345 Note that fluorines located in the positions ortho or para to EWGs are reactive. Control experiments suggest that the oxygen source is water present in the system. In addition, the sulfanylation of monofluorinated arenes bearing a cyano or nitro group and partially fluorinated arenes is effected with diaryl or dialkyl disulfides in the presence of an RhH(PPh3)4 catalyst.346

Scheme 124 Ir-catalyzed etherification.

12.11.4.3.2.2 Nonactivated monofluoroarenes The CdC and CdX bond formation in nonactivated monofluoroarenes have been dominantly achieved by nucleophilic Ni(0) as catalysts (type C), while CpTiCl3-catalyzed alkylation,347 TaCl5-catalyzed alkylation,347 and CoCl2-catalyzed arylation348 are known. The overall strategy for the Ni-catalyzed reactions to compensate for the low reactivity of nonactivated monofluoroarenes first lists ligand design, where bidentate or pincer-type ligands are effective in stabilizing and increasing the nucleophilicity of catalyst metals. Second, the effects of Lewis acids must be considered. Fluorophilic Lewis acids (e.g., Li, Zr, and Ti) and counter cations of the coupling partners (typically, Mg) promote the abstraction of the fluorine in the transition state and accelerate the rate-determining oxidative addition step.336 There are a large number of known Ni-catalyzed coupling reactions of fluoroarenes with Grignard reagents (Kumada coupling, Scheme 125),349–359 most of which involve designer ligands.349,351–355,358,359 Aryl Grignard reagents are typical coupling partners, but even alkyl Grignard reagents bearing b-hydrogens are applicable in some reports.357,359 Coupling with (trimethylsilyl) methyllithium is also known.357

Scheme 125 Kumada arylation by Ni catalysts with designer ligands.

The Suzuki–Miyaura coupling of monofluoroarenes is achieved by Ni catalysts in the presence of ZrF4.287,360 The use of organoaluminum reagents, instead of boron reagents, also facilitates the coupling in the presence of a NiCl2(PCy3)2 catalyst (Scheme 126).361

Scheme 126 Ni-catalyzed arylation with organoaluminum reagents.

CdF Bond Activation Reactions

455

In addition to the alkylation of monofluoroarenes with R2Zn (Section 12.11.4.1.2.1),275,278,279,281 the Negishi coupling of fluoroarenes is performed with organozinc reagents (RZnX, Scheme 127).362 The reaction exhibits a broad scope; both electronrich/deficient fluoroarenes and (het)aryl/alkylzinc reagents are applicable.

Scheme 127 Pd-catalyzed Negishi (het)arylation.

Miyaura borylations proceed with Ni (Scheme 128),363 Ni/Cu,364 Fe, and Pd catalysts365 to afford the desired boronates. A CuCl(PCy3)2 catalyst also facilitates borylation with B2pin2, allowing for the transformation of di- and trifluorinated substrates to the corresponding di- and triborylated products.366

Scheme 128 Ni-catalyzed Miyaura borylation.

The coupling of monofluoroarenes with phenyl(trimethoxy)silane is achieved by a Ni(cod)2 catalyst (Hiyama coupling, Scheme 129).367 Sonogashira coupling with aryl- and (trimethylsilyl)alkynes proceeds by using a strong base, lithium hexamethyldisilazide, to afford disubstituted alkynes (Scheme 130).331,368 Ni catalysts facilitate the amination of fluoroarenes with secondary (Scheme 131)369 and primary amines.370 Amination with diarylamines is also possible.371

Scheme 129 Ni-catalyzed Hiyama phenylation.

Scheme 130 Pd-catalyzed Sonogashira alkynylation.

Scheme 131 Ni-catalyzed amination.

456

CdF Bond Activation Reactions

Monofluoroarenes undergo reductive coupling with benzylic chlorides in the presence of a Ni–NHC catalyst with the aid of magnesium metal as a reducing agent (Scheme 132).372,373

Scheme 132 Ni-catalyzed benzylation.

While Ni complexes catalyze cross-coupling reactions (as was discussed above), a bimetallic Rh/Al complex catalyzes the magnesiation of monofluoroarenes. The generated organomagnesium species reacts with CO2, D2O, and Weinreb amides to afford the carboxylation, deuteration, and acylation products, respectively (Scheme 133).344

Scheme 133 Coupling via Rh/Al complex-catalyzed magnesiation.

12.11.4.4 Activation of aromatic CdF bonds (4): Miscellaneous Section 12.11.4.4 describes reactions that are not classified into Sections 12.11.4.1–12.11.4.3. They primarily proceed via intermediates that do not contain transition dmetal–carbon bonds.

12.11.4.4.1

Carbene analog insertion

In addition to carbenes,17,374–377 silylenes (R2Si:) undergo insertion into the CdF bonds in perfluorobenzene to afford fluorinated arylsilanes (Scheme 134).378 Similar reactions of germylenes,379 stannylenes,379 and alumylenes (Scheme 135)380–382 are also known.

Scheme 134 Insertion of silylenes.

Scheme 135 Insertion of alumylenes.

CdF Bond Activation Reactions

12.11.4.4.2

457

Aryne formation

Fluorobenzenes are potential precursors for arynes as reactive intermediates in organic synthesis. The deprotonative zincation of fluoro[4]helicene,383 followed by the elimination of a fluoride ion, generates arynes. The Diels–Alder reactions of the arynes facilitate higher-order polycyclic aromatic hydrocarbon (PAH) synthesis (Scheme 136).226 A fluoroaryl–Co(I) complex, generated from perfluorotoluene via an oxidative addition/reduction sequence (Scheme 111), undergoes elimination to form an aryne–Co (I) complex with the concomitant generation of F2PMe3 (Scheme 137).323

Scheme 136 Zn-mediated aryne formation and Diels–Alder reaction.

Scheme 137 Formation of aryne–Co(0) complexes.

12.11.4.4.3

SNAr reaction

Fluoroarenes undergo SNAr reactions with alkoxysilanes (O), sulfanylsilanes (S), and aminosilanes (N) in the presence of an Au catalyst to afford the substitution products (Scheme 138).384 The amination of fluoroarenes can be conducted with a Mg diketiminate complex.385 Pentafluorobenzene undergoes CdF and CdH double arylsulfanylation with disulfides in the presence of CuBr (Scheme 139).386

Scheme 138 Au-catalyzed alkoxylation, sulfanylation, and amination.

Scheme 139 Cu-catalyzed CdF and CdH double sulfanylation.

458

CdF Bond Activation Reactions

12.11.4.4.4

Fluoride abstraction

Fluoride abstraction in fluoroarenes generates aryl cations. The instability of these cations is compensated by intramolecular trapping or by the cation-stabilizing effect. Si and Al Lewis acids promote fluoride abstraction to allow for the intramolecular CdF/CdH coupling of fluoroarenes. This provides synthetic routes for the formation of PAHs. Silyl cations, bearing a carborane as a weakly coordinating counter ion, facilitate intramolecular CdF/CdH coupling of p-conjugated fluoroarenes to afford the corresponding PAHs (Scheme 140).387 Treatment with g-alumina at 250  C also promotes a similar CdF/CdH coupling to afford the corresponding PAHs.388–390 Additionally, the silyl cations facilitate aryl–alkyl coupling and aryl–aryl coupling of 2-fluoro(trimethylsilyl)benzene with both alkanes and benzene (Scheme 141).391

Scheme 140 Intramolecular CdF/CdH coupling via fluoride abstraction.

Scheme 141 Intermolecular CdF/CdH coupling via fluoride abstraction.

12.11.5 Conclusions and perspectives Over the last two decades, metals and metalloids have promoted CdF bond activation, which has become one of the most efficient and applicable methods for the synthesis of fluorinated and fluorine-free compounds. Under mild conditions, various transformations of CdF bonds to new CdC and CdX bonds with enhanced functional group tolerance have been developed. Therefore, we can use these methods to synthesize pharmaceuticals, agrochemicals, and functional materials, particularly through late-stage functionalization of CdF bonds in complex molecules. The developed methods based on the transformation of CdF bonds also enable the upcycling of environment-polluting fluorinated compounds to provide much more valuable molecules, some of which are not otherwise accessible. Despite these advancements, future research on CdF bond activation should concentrate on the following: (1) Compared with the aromatic CdF bond activation, which has long been extensively studied, the activation of other C(sp2)dF bonds and C(sp3)dF bonds are relatively underdeveloped. Other than aromatic fluorides, a diverse array of substrates is expected to be employed. (2) Selective activation of the CF3 group to leave one or two fluorine atoms is still a difficult task.12 CdF bond activation in less reactive monofluorovinylic and trifluoroallylic systems, as opposed to difluorovinylic and difluoroallylic systems, continues to be accomplished, particularly via oxidative addition.112 (3) For CdF bond activation, a-/b-fluorine elimination should be preceded by organometallic elementary processes for CdC or CdX bond formation. To date, insertion, carbo(hetero)metalation, oxidative cyclization, and radical addition are mostly employed as elementary processes. Other processes in combination with fluorine elimination could develop novel CdF bond activation. In catalytic CdF bond activation, a-fluorine elimination should be more adopted.221–223 (4) To realize the activation of aromatic CdF bonds with transition metal species, the insertion/fluorine elimination sequence (Scheme 15, left) could pave the way. The fluoride abstraction from aromatic or vinylic fluorides resulting in the formation of unstable cations (Scheme 15, right391 or Scheme 13) is a significant challenge. (5) In aromatic CdF bond activation, two metalation methods, the ligand-assisted metalation and the oxidative addition/ reduction sequence (including the binuclear oxidative addition) should be more adopted. There are limited examples for specific transformation, although a wide range of scopes seems to be allowed. In this chapter, we reviewed CdF bond activation from the perspective of its reaction types: (i) metalation, (ii) addition–elimination, and (iii) fluoride abstraction. Hopefully, this review will lead to a better understanding of CdF bond activation and thus inspire further research on new methodologies in this exciting field.

CdF Bond Activation Reactions

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119–2183. Sun, A. D.; Love, J. A. Dalton Trans. 2010, 39, 10362–10374. Clot, E.; Eisenstein, O.; Jasim, N.; MacGregor, S. A.; McGrady, J. E.; Perutz, R. N. Acc. Chem. Res. 2011, 44, 333–348. Stahl, T.; Klare, H. F. T.; Oestreich, M. ACS Catal. 2013, 3, 1578–1587. Campbell, M. G.; Hoover, A. J.; Ritter, T. In Organometallic Fluorine Chemistry; Braun, T., Hughes, R. P., Eds.; Springer: Cham, 2015; vol. 52; pp 1–53. Unzner, T. A.; Magauer, T. Tetrahedron Lett. 2015, 56, 877–883. LaBerge, N. A.; Love, J. A. In Organometallic Fluorine Chemistry; Braun, T., Hughes, R. P., Eds.; Springer: Cham, 2015; vol. 52; pp 55–111. Shen, Q.; Huang, Y.-G.; Liu, C.; Xiao, J.-C.; Chen, Q.-Y.; Guo, Y. J. Fluorine Chem. 2015, 179, 14–22. Zhang, X.; Cao, S. Tetrahedron Lett. 2017, 58, 375–392. Pike, S. D.; Crimmin, M. R.; Chaplin, A. B. Chem. Commun. 2017, 53, 3615–3633. Chen, W.; Bakewell, C.; Crimmin, M. R. Synthesis 2017, 49, 810–821. Jaroschik, F. Chem. Eur. J. 2018, 24, 14572–14582. Hamel, J.-D.; Paquin, J.-F. Chem. Commun. 2018, 54, 10224–10239. Fujita, T.; Fuchibe, K.; Ichikawa, J. Angew. Chem. Int. Ed. 2019, 58, 390–402. Tian, F.; Yan, G.; Yu, J. Chem. Commun. 2019, 55, 13486–13505. Koley, S.; Altman, R. A. Isr. J. Chem. 2020, 60, 313–339. Pietrasiak, E.; Lee, E. Synlett 2020, 31, 1349–1360. Wang, M.; Shi, Z. Chem. Rev. 2020, 120, 7348–7398. Zhang, X.-J.; Cheng, Y.-M.; Zhao, X.-W.; Cao, Z.-Y.; Xiao, X.; Xu, Y. Org. Chem. Front. 2021, 8, 2315–2327. Yan, G.; Qiu, K.; Guo, M. Org. Chem. Front. 2021, 8, 3915–3942. Zhao, B.; Rogge, T.; Ackermann, L.; Shi, Z. Chem. Soc. Rev. 2021, 50, 8903–8953. Karimzadeh-Younjali, M.; Wendt, O. F. Helv. Chim. Acta 2021, 104, e2100114. Zhang, J.; Geng, S.; Feng, Z. Chem. Commun. 2021, 57, 11922–11934. Perutz, R. N.; Braun, T. In Comprehensive Organometallic Chemistry III; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier: Oxford, 2007; pp 725–758. Lentz, D.; Braun, T.; Kuehnel, M. F. Angew. Chem., Int. Ed. 2013, 52, 3328–3348. Hu, J.-Y.; Zhang, J.-L. In Organometallic Fluorine Chemistry; Braun, T., Hughes, R. P., Eds.; Springer: Cham, 2015; vol. 52; pp 143–196. Watanabe, D.; Koura, M.; Saito, A.; Yanai, H.; Nakamura, Y.; Okada, M.; Saito, A.; Taguchi, T. J. Fluorine Chem. 2011, 132, 327–338. Dai, W.; Lin, Y.; Wan, Y.; Cao, S. Org. Chem. Front. 2018, 5, 55–58. Fujita, T.; Takazawa, M.; Sugiyama, K.; Suzuki, N.; Ichikawa, J. Org. Lett. 2017, 19, 588–591. Nasr El Dine, A.; Grée, D.; Roisnel, T.; Caytan, E.; Hachem, A.; Grée, R. Eur. J. Org. Chem. 2016, 556–561. Corberán, R.; Mszar, N. W.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2011, 50, 7079–7082. Kojima, R.; Akiyama, S.; Ito, H. Angew. Chem. Int. Ed. 2018, 57, 7196–7199. Gao, P.; Yuan, C.; Zhao, Y.; Shi, Z. Chem 2018, 4, 2201–2211. Akiyama, S.; Kubota, K.; Mikus, M. S.; Paioti, P. H. S.; Romiti, F.; Liu, Q.; Zhou, Y.; Hoveyda, A. H.; Ito, H. Angew. Chem. Int. Ed. 2019, 58, 11998–12003. Paioti, P. H. S.; del Pozo, J.; Mikus, M. S.; Lee, J.; Koh, M. J.; Romiti, F.; Torker, S.; Hoveyda, A. H. J. Am. Chem. Soc. 2019, 141, 19917–19934. Akiyama, S.; Nomura, S.; Kubota, K.; Ito, H. J. Org. Chem. 2020, 85, 4172–4181. Butcher, T. W.; Yang, J. L.; Hartwig, J. F. Org. Lett. 2020, 22, 6805–6809. Gao, P.; Gao, L.; Xi, L.; Zhang, Z.; Li, S.; Shi, Z. Org. Chem. Front. 2020, 7, 2618–2627. Liu, Y.; Zhou, Y.; Zhao, Y.; Qu, J. Org. Lett. 2017, 19, 946–949. Liu, Y.; Li, C.; Liu, C.; He, J.; Zhao, X.; Cao, S. Tetrahedron Lett. 2020, 61, 151940. Yan, S.-S.; Wu, D.-S.; Ye, J. H.; Gong, L.; Zeng, X.; Ran, C.-K.; Gui, Y.-Y.; Li, J.; Yu, D.-G. ACS Catal. 2019, 9, 6987–6992. Wang, M.; Pu, X.; Zhao, Y.; Wang, P.; Li, Z.; Zhu, C.; Shi, Z. J. Am. Chem. Soc. 2018, 140, 9061–9065. Phillips, N. A.; Coates, G. J.; White, A. J. P.; Crimmin, M. R. Chem. Eur. J. 2020, 26, 5365–5368. Gao, P.; Wang, G.; Xi, L.; Wang, M.; Li, S.; Shi, Z. Chin. J. Chem. 2019, 37, 1009–1014. Coates, G.; Tan, H. Y.; Kalff, C.; White, A. J. P.; Crimmin, M. R. Angew. Chem., Int. Ed. 2019, 58, 12514–12518. Yanai, H.; Okada, H.; Sato, A.; Okada, M.; Taguchi, T. Tetrahedron Lett. 2011, 52, 2997–3000. Nakamura, Y.; Okada, M.; Koura, M.; Tojo, M.; Saito, A.; Sato, A.; Taguchi, T. J. Fluorine Chem. 2006, 127, 627–636. Okada, M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa, H.; Taguchi, T. Chem. Lett. 2002, 31, 28–29. Okada, M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa, H.; Taguchi, T. Tetrahedron Lett. 2002, 43, 5845–5847. Nakamura, Y.; Okada, M.; Sato, A.; Horikawa, H.; Koura, M.; Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 5741–5753. Sato, A.; Yanai, H.; Suzuki, D.; Okada, M.; Taguchi, T. Tetrahedron Lett. 2015, 56, 925–929. Liu, Z.; Tu, X.-S.; Guo, L.-T.; Wang, X.-C. Chem. Sci. 2020, 11, 11548–11553. Nishimine, T.; Fukushi, K.; Shibata, N.; Taira, H.; Tokunaga, E.; Yamano, A.; Shiro, M.; Shibata, N. Angew. Chem. Int. Ed. 2014, 53, 517–520. Nishimine, T.; Taira, H.; Mori, S.; Matsubara, O.; Tokunaga, E.; Akiyama, H.; Soloshonok, V. A.; Shibata, N. Chem. Commun. 2017, 53, 1128–1131. Nishimine, T.; Taira, H.; Tokunaga, E.; Shiro, M.; Shibata, N. Angew. Chem. Int. Ed. 2016, 55, 359–363. Kobayashi, Y.; Nagai, T.; Kumadaki, I.; Takahashi, M.; Yamauchi, T. Chem. Pharm. Bull. 1984, 32, 4382–4387. Calvo, B.; Wuttke, J.; Braun, T.; Kemnitz, E. ChemCatChem 2016, 8, 1945–1950. Fuchibe, K.; Hatta, H.; Oh, K.; Oki, R.; Ichikawa, J. Angew. Chem. Int. Ed. 2017, 56, 5890–5893. Lanzinger, D.; Höhlein, I. M.; Weiß, S. B.; Rieger, B. J. Organomet. Chem. 2015, 778, 21–28. Hazari, A.; Gouverneur, V.; Brown, J. B. Angew. Chem. Int. Ed. 2009, 48, 1296–1299. Pigeon, X.; Bergeron, M.; Barabé, F.; Dubé, P.; Paquin, J.-F. Angew. Chem. Int. Ed. 2010, 49, 1123–1127. Paquin, J.-F. Synlett 2011, 289–293. Hamel, J.-D.; Drouin, M.; Paquin, J.-F. J. Fluorine Chem. 2015, 174, 81–87. Drouin, M.; Paquin, J.-F. Tetrahedron 2018, 74, 6023–6032. Zeidan, N.; Zambri, M.; Unger, S.; Dank, C.; Torelli, A.; Mirabi, B.; Lautens, M. Org. Lett. 2020, 22, 3688–3691. Benedetto, E.; Keita, M.; Tredwell, M.; Hollingworth, C.; Brown, J. M.; Gouveneur, V. Organometallics 2012, 31, 1408–1416. Reddy, K. H. V.; Bédier, M.; Bouzbouz, S. Eur. J. Org. Chem. 2018, 1455–1459. Niida, A.; Mizumoto, M.; Narumi, T.; Inokuchi, E.; Oishi, S.; Ohno, H.; Otaka, A.; Kitaura, K.; Fujii, N. J. Org. Chem. 2006, 71, 4118–4129. Niida, A.; Tomita, K.; Mizumoto, M.; Tanigaki, H.; Terada, T.; Oishi, S.; Otaka, A.; Inui, K.; Fujii, N. Org. Lett. 2006, 8, 613–616. Narumi, T.; Niida, A.; Tomita, K.; Oishi, S.; Otaka, A.; Ohno, H.; Fujii, N. Chem. Commun. 2006, 4720–4722.

459

460

CdF Bond Activation Reactions

71. Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N. Tetrahedron 2008, 64, 4332–4346. 72. Oishi, S.; Kamitani, H.; Kodera, Y.; Watanabe, K.; Kobayashi, K.; Narumi, T.; Tomita, K.; Ohno, H.; Naito, T.; Kodama, E.; Matsuoka, M.; Fujii, N. Org. Biomol. Chem. 2009, 7, 2872–2877. 73. Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T. H.; Blais, V.; Guérin, B.; Gendron, L.; Dory, Y. L. ACS Chem. Neurosci. 2017, 8, 40–49. 74. Otaka, A.; Watanabe, H.; Yukimasa, A.; Oichi, S.; Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42, 5443–5446. 75. Kumar, T.; Massicot, F.; Harakat, D.; Chevreux, S.; Martinez, A.; Bordolinska, K.; Preethalayam, P.; Vasu, R. K.; Behr, J.-B.; Vasse, J.-L.; Jaroschik, F. Chem. Eur. J. 2017, 23, 16460–16465. 76. Kumar, T.; Yang, Y.; Sghaier, S.; Zaid, Y.; Le Goff, X. F.; Rousset, E.; Massicot, F.; Harakat, D.; Martinez, A.; Taillefer, M.; Maron, L.; Behr, J.-B.; Jaroschik, F. Chem. Eur. J. 2021, 27, 4016–4021. 77. Fuchibe, K.; Atobe, K.; Fujita, Y.; Mori, K.; Akiyama, T. Chem. Lett. 2010, 39, 867–869. 78. Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425–4427. 79. Miura, T.; Ito, Y.; Murakami, M. Chem. Lett. 2008, 37, 1006–1007. 80. Casalta, C.; Bouzbouz, S. Org. Lett. 2020, 22, 2359–2364. 81. Huang, Y.; Hayashi, T. J. Am. Chem. Soc. 2016, 138, 12340–12343. 82. Jang, Y. J.; Rose, D.; Mirabi, B.; Lautens, M. Angew. Chem. Int. Ed. 2018, 57, 16147–16151. 83. Zell, D.; Müller, V.; Dhawa, U.; Bursch, M.; Presa, R. R.; Grimme, S.; Ackermann, L. Chem. Eur. J. 2017, 23, 12145–12148. 84. Murakami, N.; Yoshida, M.; Yoshino, T.; Matsunaga, S. Chem. Pharm. Bull. 2018, 66, 51–54. 85. Zell, D.; Dhawa, U.; Müller, V.; Bursch, M.; Grimme, S.; Ackermann, L. ACS Catal. 2017, 7, 4209–4213. 86. Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J. Angew. Chem. Int. Ed. 2014, 53, 7564–7568. 87. Fujita, T.; Arita, T.; Ichitsuka, T.; Ichikawa, J. Dalton Trans. 2015, 44, 19460–19463. 88. Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal. 2015, 5, 5947–5950. 89. Lan, Y.; Yang, F.; Wang, C. ACS Catal. 2018, 8, 9245–9251. 90. Lin, Z.; Lan, Y.; Wang, C. Org. Lett. 2019, 21, 8316–8322. 91. Lu, X.; Wang, X.-X.; Gong, T.-J.; Pi, J.-J.; He, S.-J.; Fu, Y. Chem. Sci. 2019, 10, 809–814. 92. Lin, Z.; Lan, Y.; Wang, C. ACS Catal. 2019, 9, 775–780. 93. Ding, D.; Lan, Y.; Lin, Z.; Wang, C. Org. Lett. 2019, 21, 2723–2730. 94. Zhang, C.; Lin, Z.; Zhu, Y.; Wang, C. J. Am. Chem. Soc. 2021, 143, 11602–11610. 95. Chen, F.; Xu, X.; He, Y.; Huang, G.; Zhu, S. Angew. Chem. Int. Ed. 2020, 59, 5398–5402. 96. Lin, Z.; Lan, Y.; Wang, C. Org. Lett. 2020, 22, 3509–3514. 97. Lu, X.-Y.; Jiang, R.-C.; Li, J.-M.; Liu, C.-C.; Wang, Q.-Q.; Zhou, H.-P. Org. Biomol. Chem. 2020, 18, 3674–3678. 98. Jin, Y.; Wu, J.; Lin, Z.; Lan, Y.; Wang, C. Org. Lett. 2020, 22, 5347–5352. 99. Du, H.-W.; Chen, Y.; Sun, J.; Gao, Q.-S.; Wang, H.; Zhou, M.-D. Org. Lett. 2020, 22, 9342–9345. 100. Ng, J. S.; Hayashi, T. Angew. Chem. Int. Ed. 2021, 60, 20771–20775. 101. Wang, C.-Q.; Ye, L.; Feng, C.; Loh, T.-P. J. Am. Chem. Soc. 2017, 139, 1762–1765. 102. Li, T.; Zhou, C.; Yan, X.; Wang, J. Angew. Chem. Int. Ed. 2018, 57, 4048–4052. 103. Gao, H.; Lin, S.; Zhang, S.; Chen, W.; Liu, X.; Yang, G.; Lerner, R. A.; Xu, H.; Zhou, Z.; Yi, W. Angew. Chem. Int. Ed. 2021, 60, 1959–1966. 104. Zhong, X.; Lin, S.; Gao, H.; Liu, F.-X.; Zhou, Z.; Yi, W. Org. Lett. 2021, 23, 2285–2291. 105. Yang, J.; Shi, W.; Chen, W.; Gao, H.; Zhou, Z.; Yi, W. J. Org. Chem. 2021, 86, 9711–9722. 106. Romanov-Michailidis, F.; Ravetz, B. D.; Paley, D. W.; Rovis, T. J. Am. Chem. Soc. 2018, 140, 5370–5374. 107. Wu, M.; Wang, R.; Chen, F.; Chen, W.; Zhou, Z.; Yi, W. Org. Lett. 2020, 22, 7152–7157. 108. Surmont, R.; Verniest, G.; De Kimpe, N. Org. Lett. 2009, 11, 2920–2923. 109. Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2007, 72, 8559–8561. 110. Hamel, J.-D.; Paquin, J.-F. J. Fluorine Chem. 2018, 216, 11–23. 111. Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.; Gouverneur, V. Org. Lett. 2012, 14, 2754–2757. 112. Luo, Y.-C.; Tong, F.-F.; Zhang, Y.; He, C.-Y.; Zhang, X. J. Am. Chem. Soc. 2021, 143, 13971–13979. 113. Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2006, 128, 1434–1435. 114. Fuchibe, K.; Mitomi, K.; Akiyama, T. Chem. Lett. 2007, 36, 24–25. 115. Fuchibe, K.; Kaneko, T.; Mori, K.; Akiyama, T. Angew. Chem. Int. Ed. 2009, 48, 8070–8073. 116. Luo, C.; Bandar, J. S. J. Am. Chem. Soc. 2019, 141, 14120–14125. 117. Terao, J.; Nakamura, M.; Kambe, N. Chem. Commun. 2009, 6011–6013. 118. Gu, W.; Haneline, M. R.; Douvris, C.; Ozerov, O. V. J. Am. Chem. Soc. 2009, 131, 11203–11212. 119. Okamoto, A.; Kumeda, K.; Yonezawa, N. Chem. Lett. 2010, 39, 124–125. 120. Goh, K. K. K.; Sinha, A.; Fraser, C.; Young, R. D. RSC. Adv. 2016, 6, 42708–42712. 121. Ikeda, M.; Matsuzawa, T.; Morita, T.; Hosoya, T.; Yoshida, S. Chem. Eur. J. 2020, 26, 12333–12337. 122. Willcox, D. R.; Nichol, G. S.; Thomas, S. P. ACS Catal. 2021, 11, 3190–3197. 123. Yamada, T.; Saito, K.; Akiyama, T. Adv. Synth. Catal. 2016, 358, 62–66. 124. Dorian, A.; Landgreen, E. J.; Petras, H. R.; Shepherd, J. J.; Williams, F. J. Chem. Eur. J. 2021, 27, 10839–10843. 125. Dankert, F.; Deubner, H. L.; Müller, M.; Buchner, M. R.; Kraus, F.; von Hänisch, C. Z. Anorg. Allg. Chem. 2020, 646, 1501–1507. 126. Saito, K.; Umi, T.; Yamada, T.; Suga, T.; Akiyama, T. Org. Biomol. Chem. 2017, 15, 1767–1770. 127. Forster, F.; Metsänen, T. T.; Irran, E.; Hrobárik, P.; Oestreich, M. J. Am. Chem. Soc. 2017, 139, 16334–16342. 128. Mandal, D.; Gupta, R.; Jaiswal, A. K.; Young, R. D. J. Am. Chem. Soc. 2020, 142, 2572–2578. 129. Mandal, D.; Gupta, R.; Young, R. D. J. Am. Chem. Soc. 2018, 140, 10682–10686. 130. Yoshida, S.; Shimomori, K.; Kim, Y.; Hosoya, T. Angew. Chem. Int. Ed. 2016, 55, 10406–10409. 131. Kim, Y.; Kanemoto, K.; Shimomori, K.; Hosoya, T.; Yoshida, S. Chem. Eur. J. 2020, 26, 6136–6140. 132. Idogawa, R.; Kim, Y.; Shimomori, K.; Hosoya, T.; Yoshida, S. Org. Lett. 2020, 22, 9292–9297. 133. Iwasaki, T.; Takagawa, H.; Singh, S. P.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2013, 135, 9604–9607. 134. Mo, Z.; Zhang, Q.; Deng, L. Organometallics 2012, 31, 6518–6521. 135. Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem. Soc. 2005, 127, 3656–3657. 136. Terao, J.; Todo, H.; Watabe, H.; Ikumi, A.; Kambe, N. Angew. Chem. Int. Ed. 2004, 43, 6180–6182. 137. Sai, M.; Someya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 2545–2547. 138. Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem. Int. Ed. 2007, 46, 2086–2089. 139. Iwasaki, T.; Imanishi, R.; Shimizu, R.; Kuniyasu, H.; Terao, J.; Kambe, N. J. Org. Chem. 2014, 79, 8522–8532. 140. Iwasaki, T.; Shimizu, R.; Imanishi, R.; Kuniyasu, H.; Kambe, N. Angew. Chem. Int. Ed. 2015, 54, 9347–9350.

CdF Bond Activation Reactions

141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213.

Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2013, 135, 17302–17305. Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J. Org. Lett. 2015, 17, 2474–2477. Wu, G.; Deng, Y.; Wu, C.; Wang, X.; Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2014, 4477–4481. Doi, R.; Ohashi, M.; Ogoshi, S. Angew. Chem. Int. Ed. 2016, 55, 341–344. Xu, J.; Ahmed, E.-A.; Xiao, B.; Lu, Q.-Q.; Wang, Y.-L.; Yu, C.-G.; Fu, Y. Angew. Chem. Int. Ed. 2015, 54, 8231–8235. Ahmed, E.-A. M. A.; Suliman, A. M. Y.; Gong, T.-J.; Fu, Y. Org. Lett. 2019, 21, 5645–5649. Xiong, B.; Chen, X.; Liu, J.; Zhang, X.; Xia, Y.; Lian, Z. ACS Catal. 2021, 11, 11960–11965. Lv, L.; Li, C.-J. Angew. Chem. Int. Ed. 2021, 60, 13098–13104. Ahmed, E.-A. M. A.; Suliman, A. M. Y.; Gong, T.-J.; Fu, Y. Org. Lett. 2020, 22. 1414–1319. Suliman, A. M. Y.; Ahmed, E.-A. M. A.; Gong, T.-J.; Fu, Y. Org. Lett. 2021, 23, 3259–3263. Suliman, A. M. Y.; Ahmed, E.-A. M. A.; Gong, T.-J.; Fu, Y. Chem. Commun. 2021, 57, 6400–6403. Terao, J.; Begum, S. A.; Shinohara, Y.; Tomita, M.; Naitoh, Y.; Kambe, N. Chem. Commun. 2007, 855–857. Aoyama, M.; Hara, S. Tetrahedron 2009, 65, 3682–3687. Jaiswal, A. K.; Goh, K. K. K.; Sung, S.; Young, R. D. Org. Lett. 2017, 19, 1934–1937. Ali, M.; Liu, L.-P.; Hammond, G. B.; Xu, B. Tetrahedron Lett. 2009, 50, 4078–4080. Ahrens, M.; Scholz, G.; Braun, T.; Kemnitz, E. Angew. Chem. Int. Ed. 2013, 52, 5328–5332. Haufe, G.; Suzuki, S.; Yasui, H.; Terada, C.; Kitayama, T.; Shiro, M.; Shibata, N. Angew. Chem. Int. Ed. 2012, 51, 12275–12279. Tanaka, J.; Suzuki, S.; Tokunaga, E.; Haufe, G.; Shibata, N. Angew. Chem. Int. Ed. 2016, 55, 9432–9436. Janjetovic, M.; Träff, A. M.; Hilmersson, G. Chem. Eur. J. 2015, 21, 3772–3777. Fuchibe, K.; Fushihara, T.; Ichikawa, J. Org. Lett. 2020, 22, 2201–2205. Fuchibe, K.; Oki, R.; Hatta, H.; Ichikawa, J. Chem. Eur. J. 2018, 24, 17932–17935. Zhang, X.; Dai, W.; Wu, W.; Cao, S. Org. Lett. 2015, 17, 2708–2711. Kikushima, K.; Sakaguchi, H.; Saijo, H.; Ohashi, M.; Ogoshi, S. Chem. Lett. 2015, 44, 1019–1021. Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Org. Lett. 2017, 19, 3283–3286. Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.; Hosoya, T. J. Am. Chem. Soc. 2017, 139, 12855–12862. Tan, D.-H.; Lin, E.; Ji, W.-W.; Zeng, Y.-F.; Fan, W.-X.; Li, Q.; Gao, H.; Wang, H. Adv. Synth. Catal. 2018, 360, 1032–1037. Xie, S.-L.; Cui, X.-Y.; Gao, X.-T.; Zhou, F.; Wu, H.-H.; Zhou, J. Org. Chem. Front. 2019, 6, 3678–3682. Isoda, M.; Uetake, Y.; Takimoto, T.; Tsuda, J.; Hosoya, T. J. Org. Chem. 2021, 86, 1622–1632. Hu, J.; Han, X.; Yuan, Y.; Shi, Z. Angew. Chem. Int. Ed. 2017, 56, 13342–13346. Kojima, R.; Kubota, K.; Ito, H. Chem. Commun. 2017, 53, 10688–10691. Hu, J.; Zhao, Y.; Shi, Z. Nat. Catal. 2018, 1, 860–869. Sakaguchi, H.; Ohashi, M.; Ogoshi, S. Angew. Chem. Int. Ed. 2018, 57, 328–332. Ohashi, M.; Kamura, R.; Doi, R.; Ogoshi, S. Chem. Lett. 2013, 42, 933–935. Xie, T.; Wang, G.-Q.; Wang, Y.-W.; Rao, W.; Xu, H.; Li, S.; Shen, Z.-L.; Chu, X.-Q. iScience 2020, 23, 101259. Xie, T.; Zhang, Y.-W.; Liu, L.-L.; Shen, Z.-L.; Loh, T.-P.; Chu, X.-Q. Chem. Commun. 2018, 54, 12722–12725. Saeki, T.; Takashima, Y.; Tamao, K. Synlett 2005, 1771–1774. Ohashi, M.; Kambara, T.; Hatanaka, T.; Saijo, H.; Doi, R.; Ogoshi, S. Eur. J. Org. Chem. 2013, 443–447. Ohashi, M.; Saijo, H.; Shibata, M.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 3256–3259. He, X.-Y.; Zhang, X.-G. Org. Chem. Front. 2020, 7, 3174–3178. Wang, Y.; Qi, X.; Ma, Q.; Liu, P.; Tsui, G. C. ACS Catal. 2021, 11, 4799–4809. He, S.-Y.; Yan, X.-W.; Tu, H.-Y.; Zhang, X.-G. Org. Chem. Front. 2021, 8, 4746–4751. Saijo, H.; Sakaguchi, H.; Ohashi, M.; Ogoshi, S. Organometallics 2014, 33, 3669–3672. Ma, Q.; Wang, Y.; Tsui, G. C. Angew. Chem. Int. Ed. 2020, 59, 11293–11297. Wang, Y.; Ma, Q.; Tsui, G. C. Org. Lett. 2021, 23, 5241–5245. Nihei, T.; Yokotani, S.; Ishihara, T.; Konno, T. Chem. Commun. 2014, 50, 1543–1545. Sakoda, K.; Mihara, J.; Ichikawa, J. Chem. Commun. 2005, 4684–4686. Ichikawa, J.; Sakoda, K.; Mihara, J.; Ito, N. J. Fluorine Chem. 2006, 127, 489–504. Heitz, W.; Knebelkamp, A. Makromol. Chem. Rapid Commun. 1991, 12, 69–75. Thornbury, R. T.; Toste, F. D. Angew. Chem. Int. Ed. 2016, 55, 11629–11632. Wu, F.-P.; Yuan, Y.; Liu, J.; Wu, X.-F. Angew. Chem. Int. Ed. 2021, 60, 8818–8822. Ma, T.; Chen, Y.; Li, Y.; Ping, Y.; Kong, W. ACS Catal. 2019, 9, 9127–9133. Talavera, M.; Braun, T. Chem. Eur. J. 2021, 27, 11926–11934. Talavera, M.; Müller, R.; Ahrens, T.; von Hahmann, C. N.; Braun-Cula, B.; Kaupp, M.; Braun, T. Faraday Discuss. 2019, 220, 328–349. Meißner, G.; Kretschmar, K.; Braun, T.; Kemnitz, E. Angew. Chem. Int. Ed. 2017, 56, 16338–16341. Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. Liu, H.; Song, S.; Wang, C.-Q.; Feng, C.; Loh, T.-P. ChemSusChem 2017, 10, 58–61. Wu, J.-Q.; Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chen, Y.; Li, Q.; Li, X.; Wang, H. J. Am. Chem. Soc. 2017, 139, 3537–3545. Ji, W.-W.; Lin, E.; Li, Q.; Wang, H. Chem. Commun. 2017, 53, 5665–5668. Kong, L.; Liu, B.; Zhou, X.; Wang, F.; Li, X. Chem. Commun. 2017, 53, 10326–10329. Gong, T.-J.; Xu, M.-Y.; Yu, S.-H.; Yu, C.-G.; Su, W.; Lu, X.; Xiao, B.; Fu, Y. Org. Lett. 2018, 20, 570–573. Zhou, L.; Zhu, C.; Loh, T.-P.; Feng, C. Chem. Commun. 2018, 54, 5618–5621. Tian, M.; Yang, X.; Zhang, B.; Liu, B.; Li, X. Org. Chem. Front. 2018, 5, 3406–3409. Cai, S.-H.; Ye, L.; Wang, D.-X.; Wang, Y.-Q.; Lai, L.-J.; Zhu, C.; Feng, C.; Loh, T.-P. Chem. Commun. 2017, 53, 8731–8734. Kong, L.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 6320–6323. Li, N.; Chang, J.; Kong, L.; Li, X. Org. Chem. Front. 2018, 5, 1978–1982. Liao, F. M.; Cao, Z.-Y.; Yu, J.-S.; Zhou, J. Angew. Chem. Int. Ed. 2017, 56, 2459–2463. Fuchibe, K.; Morikawa, T.; Shigeno, K.; Fujita, T.; Ichikawa, J. Org. Lett. 2015, 17, 1126–1129. Fuchibe, K.; Morikawa, T.; Ueda, R.; Okauchi, T.; Ichikawa, J. J. Fluorine Chem. 2015, 179, 106–115. Fuchibe, K.; Shigeno, K.; Zhao, N.; Aihara, H.; Akisaka, R.; Morikawa, T.; Fujita, T.; Yamakawa, K.; Shimada, T.; Ichikawa, J. J. Fluorine Chem. 2017, 203, 173–184. Fuchibe, K.; Tsuda, N.; Shigeno, K.; Ichikawa, J. Heterocycles 2019, 99, 1196–1216. Yokota, M.; Fujita, D.; Ichikawa, J. Org. Lett. 2007, 9, 4639–4642. Fujita, T.; Watabe, Y.; Yamashita, S.; Tanabe, H.; Nojima, T.; Ichikawa, J. Chem. Lett. 2016, 45, 964–966. Yata, T.; Nishimoto, Y.; Chiba, K.; Yasuda, M. Chem. Eur. J. 2021, 27, 8288–8294.

461

462

214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. 268. 269. 270. 271. 272. 273. 274. 275. 276. 277. 278. 279. 280. 281. 282. 283. 284. 285. 286.

CdF Bond Activation Reactions

Watabe, Y.; Kanazawa, K.; Fujita, T.; Ichikawa, J. Synthesis 2017, 49, 3569–3575. Fujita, T.; Takeishi, M.; Ichikawa, J. Org. Lett. 2020, 22, 9253–9257. Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. J. Am. Chem. Soc. 2017, 139, 12632–12637. Zhou, L.; Chu, C.; Bi, P.; Feng, C. Chem. Sci. 2019, 10, 1144–1149. Li, J.; Rao, W.; Wang, S.-Y.; Li, S.-J. J. Org. Chem. 2019, 84, 11542–11552. Yu, L.; Tang, M.-L.; Si, C.-M.; Meng, Z.; Liang, Y.; Han, J.; Sun, X. Org. Lett. 2018, 20, 4579–4583. Yang, L.; Ji, W.-W.; Lin, E.; Li, J.-L.; Fan, W.-X.; Li, Q.; Wang, H. Org. Lett. 2018, 20, 1924–1927. Takachi, M.; Kita, Y.; Tobisu, M.; Fukumoto, Y.; Chatani, N. Angew. Chem. Int. Ed. 2010, 49, 8717–8720. Fujita, T.; Watabe, Y.; Ichitsuka, T.; Ichikawa, J. Chem. Eur. J. 2015, 21, 13225–13228. Ohashi, M.; Ueda, Y.; Ogoshi, S. Angew. Chem. Int. Ed. 2017, 56, 2435–2439. Fuchibe, K.; Mayumi, Y.; Zhao, N.; Watanabe, S.; Yokota, M.; Ichikawa, J. Angew. Chem. Int. Ed. 2015, 17, 2708–2711. Fuchibe, K.; Mayumi, Y.; Yokota, M.; Aihara, H.; Ichikawa, J. Bull. Chem. Soc. Jpn. 2014, 87, 942–949. Fuchibe, K.; Abe, M.; Idate, H.; Ichikawa, J. Chem. Asian J. 2020, 15, 1384–1392. Fuchibe, K.; Imaoka, H.; Ichikawa, J. Chem. Asian J. 2017, 12, 2359–2363. Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964–15965. Ogiwara, Y.; Sakurai, Y.; Hattori, H.; Sakai, N. Org. Lett. 2018, 20, 4204–4208. Blanchard, N.; Bizet, V. Angew. Chem. Int. Ed. 2019, 58, 6814–6817. Zhao, Q.; Szostak, M. ChemSusChem 2019, 12, 2983–2987. Ogiwara, Y.; Sakai, N. Angew. Chem. Int. Ed. 2020, 59, 574–594. Fu, L.; Chen, Q.; Nishihara, Y. Chem. Rec. 2021. https://doi.org/10.1002/tcr.202100053. Ogiwara, Y.; Sakino, D.; Sakurai, Y.; Sakai, N. Eur. J. Org. Chem. 2017, 4324–4327. Ogiwara, Y.; Maegawa, Y.; Sakino, D.; Sakai, N. Chem. Lett. 2016, 45, 790–792. Ogiwara, Y.; Iino, Y.; Sakai, N. Chem. Eur. J. 2019, 25, 6513–6516. Pan, F.-F.; Guo, P.; Li, C.-L.; Su, P.; Shu, X.-Z. Org. Lett. 2019, 21, 3701–3705. Wang, J.; Hoerrner, M. E.; Watson, M. P.; Weix, D. J. Angew. Chem. Int. Ed. 2020, 59, 13484–13489. Arisawa, M.; Yamada, T.; Yamaguchi, M. Tetrahedron Lett. 2010, 51, 6090–6092. Arisawa, M.; Suzuki, R.; Ohashi, K.; Yamaguchi, M.; Asian, J. Org. Chem. 2020, 9, 553–556. Arisawa, M.; Yamada, T.; Yamaguchi, M. Tetrahedron Lett. 2010, 51, 4957–4958. Arisawa, M.; Igarashi, Y.; Kobayashi, H.; Yamada, T.; Bando, K.; Ichikawa, T.; Yamaguchi, M. Tetrahedron 2011, 67, 7846–7859. Li, G.; Arisawa, M.; Yamaguchi, M.; Asian, J. Org. Chem. 2013, 2, 983–988. Malapit, C. A.; Bour, J. R.; Brigham, C. E.; Sanford, M. S. Nature 2018, 563, 100–104. Okuda, Y.; Xu, J.; Ishida, T.; Wang, C.-A.; Nishihara, Y. ACS Omega 2018, 3, 13129–13140. Fu, L.; Chen, Q.; Wang, Z.; Nishihara, Y. Org. Lett. 2020, 22, 2350–2353. Zhang, C.; Zhao, R.; Dagnaw, W. M.; Liu, Z.; Lu, Y.; Wang, Z.-X. J. Org. Chem. 2019, 84, 13983–13991. Feher, P. P.; Stirling, A. Organometallics 2020, 39, 2774–2783. Wang, Z.; Wang, X.; Nishihara, Y. Chem. Commun. 2018, s, 13969–13972. Malapit, C. A.; Bour, J. R.; Laursen, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2019, 141, 17322–17330. Keaveney, S. T.; Schoenebeck, F. Angew. Chem. Int. Ed. 2018, 57, 4073–4077. Sakurai, S.; Yoshida, T.; Tobisu, M. Chem. Lett. 2019, 48, 94–97. He, B.; Liu, X.; Li, H.; Zhang, X.; Ren, Y.; Su, W. Org. Lett. 2021, 23, 4191–4196. Chen, Q.; Fu, L.; You, J.; Nishihara, Y. Synlett 2021, 32, 1560–1564. Chen, Q.; Fu, L.; Nishihara, Y. Chem. Commun. 2020, 56, 7977–7980. Uneyama, K. Organofluorine Chemistry; Blackwell Publishing: Oxford, 2006; pp 223–336. Zheng, T.; Sun, H.; Ding, J.; Zhang, Y.; Li, X. J. Organomet. Chem. 2010, 695, 1873–1877. Braun, T.; Wehmeier, F. Eur. J. Inorg. Chem. 2011, 2011, 613–625. Thilgen, C. Angew. Chem. Int. Ed. 2012, 51, 7082–7084. Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Chem. Rev. 2015, 115, 931–972. Johnson, S. A.; Hatnean, J. A.; Doster, M. E. Prog. Inorg. Chem. 2012, 57, 255–352. Eisenstein, O.; Milani, J.; Perutz, R. N. Chem. Rev. 2017, 117, 8710–8753. Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 6, 301–302. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636–3638. Teltewskoi, M.; Panetier, J. A.; MacGregor, S. A.; Braun, T. Angew. Chem. Int. Ed. 2010, 49, 3947–3951. Nova, A.; Reinhold, M.; Perutz, R. N.; Macgregor, S. A.; McGrady, J. E. Organometallics 2010, 29, 1824–1831. Li, X.; Sun, H.; Yu, F.; Flörke, U.; Klein, H.-F. Organometallics 2006, 25, 4695–4697. Wang, L.; Sun, H.; Li, X. Eur. J. Inorg. Chem. 2015, 2015, 2732–2743. Wang, L.; Sun, H.; Li, X.; Fuhr, O.; Fenske, D. Dalton Trans. 2016, 45, 18133–18141. Procacci, B.; Blagg, R. J.; Perutz, R. N.; Rendón, N.; Whitwood, A. C. Organometallics 2014, 33, 45–52. Xu, X.; Sun, H.; Shi, Y.; Jia, J.; Li, X. Dalton Trans. 2011, 40, 7866–7872. Xu, X.; Jia, J.; Sun, H.; Liu, Y.; Xu, W.; Shi, Y.; Zhang, D.; Li, X. Dalton Trans. 2013, 42, 3417–3428. Garcon, M.; Bakewell, C.; White, A. J. P.; Crimmin, M. R. Chem. Commun. 2019, 55, 1805–1808. Crespo, M.; Martinez, M.; Sales, J. Organometallics 1993, 12, 4297–4304. Wang, T.; Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629–5631. Wang, T.; Love, J. A. Organometallics 2008, 27, 3290–3296. Buckley, H. L.; Sun, A. D.; Love, J. A. Organometallics 2009, 28, 6622–6624. Sun, A. D.; Love, J. A. J. Fluorine Chem. 2010, 131, 1237–1240. Keyes, L.; Sun, A. D.; Love, J. A. Eur. J. Org. Chem. 2011, 2011, 3985–3994. Buckley, H. L.; Wang, T.; Tran, O.; Love, J. A. Organometallics 2009, 28, 2356–2359. Yang, X.; Sun, H.; Zhang, S.; Li, X. J. Organomet. Chem. 2013, 723, 36–42. Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696–1697. Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578–579. Cargill, M. R.; Sandford, G.; Tadeusiak, A. J.; Yufit, D. S.; Howard, J. A. K.; Kilickiran, P.; Nelles, G. J. Org. Chem. 2010, 75, 5860–5866. Gadsby, J. M.; McPake, C. B.; Murray, C. B.; Sandford, G. J. Fluorine Chem. 2016, 181, 51–55. Sun, A. D.; Love, J. A. Org. Lett. 2011, 13, 2750–2753.

CdF Bond Activation Reactions

287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310. 311. 312. 313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344. 345. 346. 347. 348. 349. 350. 351. 352. 353. 354. 355. 356. 357. 358.

463

Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 19505–19511. Zhang, T.; Nohira, I.; Chatani, N. Org. Chem. Front. 2021, 8, 3783–3787. Kawamoto, K.; Kochi, T.; Sato, M.; Mizushima, E.; Kakiuchi, F. Tetrahedron Lett. 2011, 52, 5888–5890. Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516–16517. Guo, W.-H.; Min, Q.-Q.; Gu, J.-W.; Zhang, X. Angew. Chem. Int. Ed. 2015, 54, 9075–9078. Manabe, K.; Ishikawa, S. Synthesis 2008, 2645–2649. Korn, T. J.; Schade, M. A.; Wirth, S.; Knochel, P. Org. Lett. 2006, 8, 725–728. Korn, T. J.; Schade, M. A.; Cheemala, M. N.; Wirth, S.; Guevara, S. A.; Cahiez, G.; Knochel, P. Synthesis 2006, 3547–3574. Cargill, M. R.; Sandford, G.; Kilickiran, P.; Nelles, G. Tetrahedron 2013, 69, 512–516. Yu, D.; Lu, L.; Shen, Q. Org. Lett. 2013, 15, 940–943. Luo, H.; Wu, G.; Xu, S.; Wang, K.; Wu, C.; Zhang, Y.; Wang, J. Chem. Commun. 2015, 51, 13321–13323. Nohira, I.; Liu, S.; Bai, R.; Lan, Y.; Chatani, N. J. Am. Chem. Soc. 2020, 142, 17306–17311. Capdevila, L.; Meyer, T. H.; Roldan-Gomez, S.; Luis, J. M.; Ackermann, L.; Ribas, X. ACS Catal. 2019, 9, 11074–11081. Macgregor, S. A.; Roe, D. C.; Marshall, W. J.; Bloch, K. M.; Bakhmutov, V. I.; Grushin, V. V. J. Am. Chem. Soc. 2005, 127, 15304–15321. Macgregor, S. A.; Wondimagegn, T. Organometallics 2007, 26, 1143–1149. Erhardt, S.; Macgregor, S. A. J. Am. Chem. Soc. 2008, 130, 15490–15498. Jasim, N. A.; Perutz, R. N.; Whitwood, A. C.; Braun, T.; Izundu, J.; Neumann, B.; Rothfeld, S.; Stammler, H.-G. Organometallics 2004, 23, 6140–6149. Nova, A.; Erhardt, S.; Jasim, N. A.; Perutz, R. N.; Macgregor, S. A.; McGrady, J. E.; Whitwood, A. C. J. Am. Chem. Soc. 2008, 130, 15499–15511. Jiao, E.; Xia, F.; Zhu, H. Comput. Theor. Chem. 2011, 965, 92–100. Goodman, J.; Macgregor, S. A. Coord. Chem. Rev. 2010, 254, 1295–1306. King, R. B.; Bisnette, M. B. J. Organomet. Chem. 1964, 2, 38–43. Bruce, M. I.; Stone, F. G. A. Angew. Chem. Int. Ed. Engl. 1968, 7, 747–753. Chan, P. K.; Leong, W. K. Organometallics 2008, 27, 1247–1253. David, L.; Keith, F. Chem. Lett. 2010, 39, 1118–1126. Lindup, R. J.; Marder, T. B.; Perutz, R. N.; Whitwood, A. C. Chem. Commun. 2007, 3664–3666. Zamostna, L.; Sander, S.; Braun, T.; Laubenstein, R.; Braun, B.; Herrmann, R.; Klaering, P. Dalton Trans. 2015, 44, 9450–9469. Raza, A. L.; Panetier, J. A.; Teltewskoi, M.; MacGregor, S. A.; Braun, T. Organometallics 2013, 32, 3795–3807. Noveski, D.; Braun, T.; Neumann, B.; Stammler, A.; Stammler, H.-G. Dalton Trans. 2004, 4106–4119. Braun, T.; Noveski, D.; Ahijado, M.; Wehmeier, F. Dalton Trans. 2007, 3820–3825. Kallaene, S. I.; Teltewskoi, M.; Braun, T.; Braun, B. Organometallics 2015, 34, 1156–1169. Ahrens, T.; Ahrens, M.; Braun, T.; Braun, B.; Herrmann, R. Dalton Trans. 2016, 45, 4716–4728. Burling, S.; Elliott, P. I. P.; Jasim, N. A.; Lindup, R. J.; McKenna, J.; Perutz, R. N.; Archibald, S. J.; Whitwood, A. C. Dalton Trans. 2005, 3686–3695. Schaub, T.; Fischer, P.; Steffen, A.; Braun, T.; Radius, U.; Mix, A. J. Am. Chem. Soc. 2008, 130, 9304–9317. Schaub, T.; Fischer, P.; Meins, T.; Radius, U. Eur. J. Inorg. Chem. 2011, 2011, 3122–3126. Kuntze-Fechner, M. W.; Verplancke, H.; Tendera, L.; Diefenbach, M.; Krummenacher, I.; Braunschweig, H.; Marder, T. B.; Holthausen, M. C.; Radius, U. Chem. Sci. 2020, 11, 11009–11023. Baird, D. A.; Jamal, S.; Johnson, S. A. Organometallics 2017, 36, 1436–1446. Zheng, T.; Sun, H.; Chen, Y.; Li, X.; Durr, S.; Radius, U.; Harms, K. Organometallics 2009, 28, 5771–5776. Li, J.; Zheng, T.; Sun, H.; Xu, W.; Li, X. Dalton Trans. 2013, 42, 5740–5748. Piglosiewicz, I. M.; Kraft, S.; Beckhaus, R.; Haase, D.; Saak, W. Eur. J. Inorg. Chem. 2005, 2005, 938–945. Jäger-Fiedler, U.; Arndt, P.; Baumann, W.; Spannenberg, A.; Burlakov, V. V.; Rosenthal, U. Eur. J. Inorg. Chem. 2005, 2005, 2842–2849. Dugan, T. R.; Goldberg, J. M.; Brennessel, W. W.; Holland, P. L. Organometallics 2012, 31, 1349–1360. Dugan, T. R.; Sun, X.-R.; Rybak-Akimova, E. V.; Olatunji-Ojo, O.; Cundari, T. R.; Holland, P. L. J. Am. Chem. Soc. 2011, 133, 12418–12421. Ertler, D.; Kuntze-Fechner, M. W.; Duerr, S.; Lubitz, K.; Radius, U. New J. Chem. 2021, 45, 14999–15016. Cao, D.; Pan, P.; Zeng, H.; Li, C.-J. Chem. Commun. 2019, 55, 9323–9326. Jin, G.; Zhang, X.; Cao, S. Org. Lett. 2013, 15, 3114–3117. Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964–15965. Zhou, J.; Berthel, J. H. J.; Kuntze-Fechner, M. W.; Friedrich, A.; Marder, T. B.; Radius, U. J. Org. Chem. 2016, 81, 5789–5794. Ohashi, M.; Doi, R.; Ogoshi, S. Chem. Eur. J. 2014, 20, 2040–2048. Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem. Int. Ed. 2005, 44, 7216–7219. Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 17978–17979. Kuntze-Fechner, M. W.; Kerpen, C.; Schmidt, D.; Haering, M.; Radius, U. Eur. J. Inorg. Chem. 2019, 2019, 1767–1775. Zhou, J.; Kuntze-Fechner, M. W.; Bertermann, R.; Paul, U. S. D.; Berthel, J. H. J.; Friedrich, A.; Du, Z.; Marder, T. B.; Radius, U. J. Am. Chem. Soc. 2016, 138, 5250–5253. Tian, Y.-M.; Guo, X.-N.; Kuntze-Fechner, M. W.; Krummenacher, I.; Braunschweig, H.; Radius, U.; Steffen, A.; Marder, T. B. J. Am. Chem. Soc. 2018, 140, 17612–17623. Bailey, B. C.; Huffman, J. C.; Mindiola, D. J. J. Am. Chem. Soc. 2007, 129, 5302–5303. Qian, Y. Y.; Li, B. Z.; Chan, K. S. Organometallics 2013, 32, 1567–1570. Qian, Y. Y.; Lee, M. H.; Yang, W.; Chan, K. S. J. Organomet. Chem. 2015, 791, 82–89. Li, B. Z.; Qian, Y. Y.; Liu, J.; Chan, K. S. Organometallics 2014, 33, 7059–7068. Fujii, I.; Semba, K.; Li, Q.-Z.; Sakaki, S.; Nakao, Y. J. Am. Chem. Soc. 2020, 142, 11647–11652. Chen, J.; Zhao, K.; Ge, B.; Xu, C.; Wang, D.; Ding, Y. Chem. Asian J. 2015, 10, 468–473. Arisawa, M.; Suzuki, T.; Ishikawa, T.; Yamaguchi, M. J. Am. Chem. Soc. 2008, 130, 12214–12215. Guo, H.; Kong, F.; Kanno, K.-I.; He, J.; Nakajima, K.; Takahashi, T. Organometallics 2006, 25, 2045–2048. Wei, J.; Liu, K.-M.; Duan, X.-F. J. Org. Chem. 2017, 82, 1291–1300. Lu, Y.; Plocher, E.; Hu, Q.-S. Adv. Synth. Catal. 2006, 348, 841–845. Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 1437–1439. Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc. 2009, 131, 9590–9599. Xie, L.-G.; Wang, Z.-X. Chem. Eur. J. 2010, 16, 10332–10336. Ackermann, L.; Wechsler, C.; Kapdi, A. R.; Althammer, A. Synlett 2010, 294–298. Guo, W.-J.; Wang, Z.-X. J. Org. Chem. 2013, 78, 1054–1061. Wu, D.; Wang, Z.-X. Org. Biomol. Chem. 2014, 12, 6414–6424. Zhang, J.; Xu, J.; Xu, Y.; Sun, H.; Shen, Q.; Zhang, Y. Organometallics 2015, 34, 5792–5800. Ho, Y. A.; Leiendecker, M.; Liu, X.; Wang, C.; Alandini, N.; Rueping, M.; Rueping, M. Org. Lett. 2018, 20, 5644–5647. Kurisu, N.; Asano, E.; Hatayama, Y.; Kurihara, Y.; Hashimoto, T.; Funatsu, K.; Ueda, K.; Yamaguchi, Y. Eur. J. Inorg. Chem. 2019, 2019, 126–133.

464

359. 360. 361. 362. 363. 364. 365. 366. 367. 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. 390. 391.

CdF Bond Activation Reactions

Mueller, V.; Ghorai, D.; Capdevila, L.; Messinis, A. M.; Ribas, X.; Ackermann, L. Org. Lett. 2020, 22, 7034–7040. Malineni, J.; Jezorek, R. L.; Zhang, N.; Percec, V. Synthesis 2016, 48, 2795–2807. Ogawa, H.; Yang, Z.-K.; Minami, H.; Kojima, K.; Saito, T.; Wang, C.; Uchiyama, M. ACS Catal. 2017, 7, 3988–3994. Zhu, F.; Wang, Z.-X. J. Org. Chem. 2014, 79, 4285–4292. Liu, X.-W.; Echavarren, J.; Zarate, C.; Martin, R. J. Am. Chem. Soc. 2015, 137, 12470–12473. Niwa, T.; Ochiai, H.; Watanabe, Y.; Hosoya, T. J. Am. Chem. Soc. 2015, 137, 14313–14318. Zhao, X.; Wu, M.; Liu, Y.; Cao, S. Org. Lett. 2018, 20, 5564–5568. Niwa, T.; Ochiai, H.; Hosoya, T. ACS Catal. 2017, 7, 4535–4541. Jacobs, E.; Keaveney, S. T. ChemCatChem 2021, 13, 637–645. He, J.; Yang, K.; Zhao, J.; Cao, S. Org. Lett. 2019, 21, 9714–9718. Zhu, F.; Wang, Z.-X. Adv. Synth. Catal. 2013, 355, 3694–3702. Harada, T.; Ueda, Y.; Iwai, T.; Sawamura, M. Chem. Commun. 2018, 54, 1718–1721. Aoki, Y.; O’Brien, H. M.; Kawasaki, H.; Takaya, H.; Nakamura, M. Org. Lett. 2019, 21, 461–464. Zhang, J.; Lu, G.; Xu, J.; Sun, H.; Shen, Q. Org. Lett. 2016, 18, 2860–2863. Shen, Z.-W.; Meng, D.-D.; Imran, S.; Yan, C.-H.; Sun, H.-M. Organometallics 2020, 39, 3540–3545. Dewanji, A.; Mueck-Lichtenfeld, C.; Bergander, K.; Daniliuc, C. G.; Studer, A. Chem. Eur. J. 2015, 21, 12295–12298. Kim, Y.; Lee, E. Chem. Commun. 2016, 52, 10922–10925. Emerson-King, J.; Hauser, S. A.; Chaplin, A. B. Org. Biomol. Chem. 2017, 15, 787–789. Weidlich, F.; Esumi, N.; Chen, D.; Mueck-Lichtenfeld, C.; Zysman-Colman, E.; Studer, A. Adv. Synth. Catal. 2020, 362, 376–383. Jana, A.; Samuel, P. P.; Tavcar, G.; Roesky, H. W.; Schulzke, C. J. Am. Chem. Soc. 2010, 132, 10164–10170. Samuel, P. P.; Singh, A. P.; Sarish, S. P.; Matussek, J.; Objartel, I.; Roesky, H. W.; Stalke, D. Inorg. Chem. 2013, 52, 1544–1549. Crimmin, M. R.; Butler, M. J.; White, A. J. P. Chem. Commun. 2015, 51, 15994–15996. Kysliak, O.; Goerls, H.; Kretschmer, R. Chem. Commun. 2020, 56, 7865–7868. Rekhroukh, F.; Chen, W.; Brown, R. K.; White, A. J. P.; Crimmin, M. R. Chem. Sci. 2020, 11, 7842–7849. Uchiyama, M.; Kobayashi, Y.; Furuyama, T.; Nakamura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto, T.; Kondo, Y.; Morokuma, K. J. Am. Chem. Soc. 2008, 130, 472–480. Hu, J.-Y.; Zhang, J.; Wang, G.-X.; Sun, H.-L.; Zhang, J.-L. Inorg. Chem. 2016, 55, 2274–2283. Bole, L. J.; Davin, L.; Kennedy, A. R.; McLellan, R.; Hevia, E. Chem. Commun. 2019, 55, 4339–4342. Yu, C.; Zhang, C.; Shi, X. Eur. J. Org. Chem. 2012, 2012, 1953–1959. Allemann, O.; Duttwyler, S.; Romanato, P.; Baldridge, K. K.; Siegel, J. S. Science 2011, 332, 574–577. Amsharov, K. Y.; Kabdulov, M. A.; Jansen, M. Angew. Chem. Int. Ed. 2012, 51, 4594–4597. Suzuki, N.; Fujita, T.; Amsharov, K. Y.; Ichikawa, J. Chem. Commun. 2016, 52, 12948–12951. Papaianina, O.; Akhmetov, V. A.; Goryunkov, A. A.; Hampel, F.; Heinemann, F. W.; Amsharov, K. Y. Angew. Chem. Int. Ed. 2017, 56, 4834–4838. Shao, B.; Bagdasarian, A. L.; Popov, S.; Nelson, H. M. Science 2017, 355, 1403–1407.

12.12

Polymerization Reactions via Cross Coupling

Anthony J Varni, Manami Kawakami, Michael V Bautista, and Kevin JT Noonan, 4400 Fifth Ave, Pittsburgh, PA, United States © 2022 Elsevier Ltd. All rights reserved.

12.12.1 Introduction 467 12.12.1.1 Electrophilic and nucleophilic reactive groups 467 12.12.2 Organomagnesium, organozinc, and organolithium coupling (Kumada-Tamao, Negishi, and Murahashi reactions)468 12.12.2.1 General considerations 469 12.12.2.2 Chain-growth polymerization 470 12.12.2.2.1 Ligands and catalysts for chain-growth polymerization 471 12.12.2.2.2 Recent developments in chain-growth polymerization 472 12.12.2.3 Murahashi coupling 473 12.12.3 Organotin coupling (Stille-Migita-Kosuke reaction) 473 12.12.3.1 General considerations 474 12.12.3.2 AA/BB type coupling of organotin monomers 474 12.12.3.3 Recent developments in vinylene-based conjugated polymers 478 12.12.3.4 Polymerization of AB monomers 478 12.12.4 Organosilicon coupling (Hiyama-Denmark-Ito reaction) 479 12.12.5 Organoboron coupling (Suzuki-Miyaura reaction) 480 12.12.5.1 General considerations 480 12.12.5.2 Boron substituents 481 12.12.5.3 Polyphenylene derivatives synthesized from AA/BB monomers 481 12.12.5.4 Masked boronic acids in Suzuki-Miyaura cross-coupling polymerization 483 12.12.5.5 Chain-growth polymerization 483 12.12.6 Direct arylation polymerization (CdH activation) 485 12.12.6.1 General considerations 486 12.12.6.2 Selected examples of DArP 488 12.12.6.3 Chain-growth polymerization 489 12.12.7 Oxidative coupling (CdH activation) 490 12.12.7.1 General considerations 491 12.12.7.2 Glaser-Hay coupling 491 12.12.7.3 Oxidative polymerization of thiophene derivatives 492 12.12.8 Dehalogenative coupling (Yamamoto reaction) 493 12.12.9 Alkene coupling (Mizoroki-Heck reaction) 493 12.12.9.1 General considerations 495 12.12.9.2 Polymers synthesized via Mizoroki-Heck polycondensation 496 12.12.10 Alkyne coupling (Sonogashira-Hagihara reaction) 497 12.12.10.1 General considerations 498 12.12.10.2 Typical synthetic approach to PAEs 499 12.12.10.3 PAE variants synthesized using Sonogashira-Hagihara polymerization 500 12.12.10.4 Chain-growth polymerization for PAEs 501 12.12.11 Amine coupling (Buchwald-Hartwig amination reaction) 501 12.12.11.1 General considerations 502 12.12.11.2 AA/BB and AB approaches to polyarylamines 502 12.12.11.3 Dehalogenative polymerization to synthesize polyanilines 504 12.12.11.4 Polyanilines prepared by chain-growth polymerization 504 12.12.12 Conclusions 505 Acknowledgments 505 References 505

Nomenclature Polymers P3AT P3HT PANI

poly(3-alkylthiophene) poly(3-hexylthiophene) polyaniline

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00115-3

465

466

Polymerization Reactions via Cross Coupling

PF PPP

polyfluorene poly(para-phenylene)

Metal catalysts Pd(PPh3)4 Pd(PPh3)2Cl2 Pd(OAc)2 Pd2dba3 Pd-PEPPSI-IPr Pd-PEPPSI-IPent Pd(CH3CN)2Cl2 Pd[P(p-tolyl)3]3 Ni(PPh3)Cl2IPr

tetrakis(triphenylphosphine)palladium(0) bis(triphenylphosphine)palladium(II) dichloride palladium(II) acetate tris(dibenzylideneacetone)dipalladium(0) [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) bis(acetonitrile)dichloropalladium(II) tris(tri(o-tolyl)phosphine)palladium(0) [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]triphenylphosphine nickel(II) dichloride

Ancillary ligands AsPh3 Bpy t Bu-XPhos dppp dppe dppf IPr P(C6H4-o-Me)3 P(C6H4-o-NMe2)3 P(C6H4-p-OMe)3 PCy3 P(1-Ad)3 PPh3 P(o-tolyl)3 PtBu3 RuPhos SPhos

Triphenylarsine 2,2’-Bipyridine 2-di-tert-butylphosphino-20 ,40 ,60 -triisopropylbiphenyl 1,3-bis(diphenylphosphino)propane 1,2-bis(diphenylphosphino)ethane 1,1’-bis(diphenylphosphino)ferrocene 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene tris(2-methoxyphenyl)phosphine 2,2’,2’’-phosphinetriyltris(N,N-dimethylaniline) tris(4-methoxyphenyl)phosphine Tricyclohexylphosphine tris(1-adamantyl)phosphine Triphenylphosphine tri(o-tolyl)phosphine tri-tert-butylphosphine 2-dicyclohexylphosphino-20 ,60 -diisopropoxybiphenyl 2-dicyclohexylphosphino-20 ,60 -dimethoxybiphenyl

Solvents CHCl3 CH2Cl2 DMA DMF DMSO MeCN NMP THF

Chloroform Dichloromethane dimethylacetamide Dimethylformamide Dimethylsulfoxide Acetonitrile N-methylpyrrolidone Tetrahydrofuran

Miscellaneous reagents and terms BMIDA CTP

N-methyliminodiacetic acid boronate Catalyst-transfer polymerization

Polymerization Reactions via Cross Coupling

Ð DPn LDA Mn Mw nBuLi NDA NHC TBDMS

467

Dispersity Number-average degree of polymerization Lithium diisopropylamide Number-average molecular weight Weight-average degree of polymerization n-Butyllithium Neodecanoic acid N-heterocyclic carbene Tertbutyldimethylsilyl group

12.12.1 Introduction Cross-coupling polymerization involves formation of CdC or C-heteroatom bonds and has been used to efficiently prepare a wide range of macromolecules. p-Conjugated polymers are the most common products of these reactions, which are broadly defined as materials with an extended framework of alternating single and double (or triple) bonds. The unique photophysical and electronic properties of conjugated polymers has led to their exploration in solar harvesting,1,2 light emission,3–5 sensing,6–9 photocatalytic H2 generation,10 and as biomaterials (e.g. synthetic skin).11–13 The wide range of useful properties of these materials has been made possible by the advances in polymer synthesis over the past 40 years. To this end, this chapter is focused specifically on synthetic methods used for cross-coupling polymerization, with the bulk of the discussion focused around minimizing defects, controlling molecular weight, and expanding the types of functional groups and arenes that can be incorporated into conjugated polymers. Since the field of cross-coupling polymerization is extremely broad, only selected references will be discussed (a Web of Science search for “Conjugated Polymers” produced over 60,000 citations). For further reading, the Handbook of Conducting Polymers, serves as a comprehensive reference text on the subject.14,15 Several edited books have also appeared within the last ten years which serve as excellent resources on conjugated polymer synthesis.16–19 Ideally, the molecular weights would be discussed in an identical way throughout the chapter, but this is challenging as some references focus on either number-average or weight-average molecular weight (Mn and Mw). Additionally, some focus on number-average degree of polymerization (DPn) typically determined by end group analysis using NMR spectroscopy. Where possible, Mn values are discussed in the text and included in the figures, but in some instances other molecular weight descriptors are presented.

12.12.1.1 Electrophilic and nucleophilic reactive groups A cross-coupling polymerization brings together an electrophile (CdX bond) and a nucleophile (CdY bond) with release of a small molecule byproduct as the polymer is formed (XdY in Fig. 1). This reaction is classified as a polycondensation, and typically follows a step-growth mechanism with combination of bifunctional monomers (XdArdX and YdAr’dY) in the presence of a metal catalyst (Fig. 1, Top). This means pure monomers, strict stoichiometric control over the two bifunctional reagents, and highly chemoselective coupling processes are needed to produce high molecular weight materials.20 This approach enables precise control over the electronic properties of the polymer backbone through choice of arene building blocks in the reaction. AB type monomers with two different functional groups can also be polymerized (Fig. 1) which ensures the stoichiometry of reactive groups is controlled, but typically requires additional synthetic steps to install the two different functionalities on the monomer. A change from a step-growth to a chain-growth mechanism is possible with an AB monomer in the presence of an appropriate catalyst. The chain-growth process relies on catalyst complexation to the growing polymer chain during the reaction, which has been termed catalyst-transfer polymerization or CTP.21–28 CTP has some of the characteristics of a living polymerization including: linear increase of molecular weight with conversion, narrow molecular weight distributions, well defined end-groups, and reactive chain ends that can be used to synthesize block copolymers.21–28 CTP can be advantageous for building polymers that are difficult to make using step-growth techniques such as gradient and block copolymers, but the monomer scope of CTP is relatively narrow. The most common electrophilic reactive groups (CdX bonds) are bromides and iodides, as they can be activated using a wide range of metal catalysts. Iodoarenes are particularly attractive when milder polymerization conditions are desired (e.g. lower polymerization temperatures), with rapid activation of the weaker CdI bond. Chloroarenes find use in cross-coupling polymerizations, but often require higher temperatures or more active catalysts for efficient bond activation. Dehalogenation is a possible side reaction during polymerization and will deactivate the monomer/growing chain and limit the efficiency of the process. The chapter sections below are separated according to the nucleophilic coupling partners (Y groups in Fig. 1), and how each of these species have been employed in conjugated polymer synthesis.

468

Polymerization Reactions via Cross Coupling

Fig. 1 (Top) General scheme for polymer synthesis using an AA/BB or AB approach,where the hydrocarbon halide is defined as the electrophile (X) and the hydrocarbon −metal species (Y) is defined as the nucleophile. (Bottom) General catalytic cycle where M is a metal catalyst.

12.12.2 Organomagnesium, organozinc, and organolithium coupling (Kumada-Tamao, Negishi, and Murahashi reactions) Cross-coupling using organomagnesium, organozinc, and organolithium reagents has been used for the synthesis of a variety of conjugated polymers due the exceptional reactivity of these nucleophilic reagents. These types of polymerizations were explored as early as the late 1970s when Yamamoto reported the synthesis of polyphenylenes and polymethylene using organomagnesium reagents (Fig. 2).29–31 In the following 40 years, these polymerization strategies have played a key role in expanding the scope of conjugated polymer synthesis. They have served as the foundation for the development of chain-growth polycondensation of aromatics, which enables control over side chain regiochemistry in the polymer, as well as predictable molecular weights and narrow molecular weight distributions. In this section, early developments in Kumada-Tamao and Negishi polymerization will be discussed, followed by recent developments in chain-growth polymerization. Further details can be found in a series of reviews on the topic.23,28,32–34 Since these cross-couplings have been used extensively in polythiophene synthesis, several book chapters may also be of interest.35,36

Fig. 2 Early examples of Kumada-type polycondensation for synthesis of (A) polyphenylenes and (B) polymethylene.

Polymerization Reactions via Cross Coupling

469

12.12.2.1 General considerations The first reports on polythiophenes appeared in the early 1980s, starting from magnesium-activation of 2,5-dihalothiophenes, followed by polymerization using a nickel catalyst (Fig. 3A).37–39 The limited solubility of these unsubstituted polythiophenes prompted Elsenbaumer to attach alkyl side chains (Fig. 3B), which enabled the synthesis of polymers with moderate molecular weights (Mn’s ranging from 3 to 8 kg/mol).40 The authors noted that coupling occurred exclusively through the 2,5 positions of the thiophene ring, but the regiochemistry of the alkyl chains along the polymer backbone were random, likely due to polymerization of the two different regioisomers that can form from Mg activation of the 2,5-diiodo-3-alkylthiophene (2-iodo-3-alkyl-5iodomagnesiothiophene and 2-iodomagnesio-3-alkyl-5-iodothiophene).40,41 Regioirregular poly(3-alkylthiophenes) (irr-P3ATs) have varying arrangements of head-to-head (HH), head-to-tail (HT) and tailto-tail (TT) orientations of the alkyl side groups as shown in Fig. 4A. These irregularities can lead to steric conflicts between alkyl chains of neighboring repeat units as shown in Fig. 4B, which causes twisting of thiophenes along the inter-ring bond, and reduces p-orbital overlap along the polymer chain.35,36 Synthetic methods have been developed to minimize these irregularities and form polymers comprised of near exclusive HT couplings (Fig. 4C). McCullough and Rieke independently reported synthetic approaches to regioregular P3ATs (rr-P3AT) in the early 1990s (up to 98% HT couplings, Fig. 5A and B).42–45 In McCullough’s report, 2-bromo-3-hexylthiophene was treated with lithium diisopropylamide (LDA) at −78  C to selectively metalate the 5-position.42–44 Transmetalation with MgBr2
OEt2 then produced the desired 2-bromo-3-alkyl-5-bromomagnesiothiophene which could be polymerized using Ni(dppp)Cl2 to yield P3ATs with up to 98% regioregularity (Fig. 5A). An Mn ¼ 6.3 kg/mol was reported for poly(3-hexylthiophene) when polymerizing with 0.5 mol % of the nickel catalyst.44

(A)

(B)

Fig. 3 (A) Synthesis of polythiophene. (B) Synthesis of poly(3-alkylthiophenes) or P3ATs.

(A)

(B)

(C)

Fig. 4 (A) Regiochemical isomers for poly(3-alkylthiophenes). (B) Example of a irr-P3AT illustrating how regiodefects can lead to steric conflicts along the chain. (C) Example of rr-P3AT.

470

Polymerization Reactions via Cross Coupling

(A)

(B)

(C)

Fig. 5 (A) McCullough’s approach to P3AT synthesis from 2-bromo-3-alkylthiophene. (B) Rieke’s approach to P3ATs from 2,5-dibromo-3-alkylthiophene. (C) The Grignard Metathesis (GRIM) approach to P3ATs from 2,5-dibromo-3-alkylthiophene.

In 1992, Rieke reported that treatment of 2,5-dibromo-3-hexylthiophene with activated zinc affords monoorganozinc compounds quantitatively, with a 9:1 ratio of 2-bromo-3-hexyl-5-bromozinciothiophene and 2-bromozincio-3-hexyl-5bromothiophene. Polymerization of this isomeric mixture with Pd(PPh3)4 in refluxing THF afforded a regiorandom polymer, while polymerization under identical conditions with Ni(dppe)Cl2 produced rr-P3HT (>98% HT, Fig. 5B).45 The rr-P3HT was not completely soluble in THF, but the soluble fraction was fairly high molecular weight (Mw  15 kg/mol). In 1999, McCullough reported a similar strategy using organomagnesium activation.46 When 2,5-dibromo-3-dodecylthiophene is treated with methylmagnesium bromide, the formation of the 2-bromo-3-dodecyl-5-bromomagnesiothiophene isomer is favored, with a 4:1 mixture of regioisomers formed (Fig. 5C). Polymerization of this mixture with Ni(dppp)Cl2 produced the desired regioregular poly (3-dodecylthiophene) in good yield (60–70%) with high molecular weights (Mn ¼ 20–35 kg/mol, Ɖ ¼ 1.20–1.47). The minor regioisomer is relatively unreactive in the cross-coupling polymerization. This has been attributed to initiation and propagation steps being unfavorable with sterically hindered head-to-head (HH) intermediates.47,48 The work has since been expanded and a range of alkyl Grignards have been shown to be effective for 2,5-dihalothiophene activation.49 The versatility of these methods in creating well defined polymers with minimal defects as well as the simple synthesis, has led to their widespread utilization. Regioregular poly(1,4-arylene)s have also been prepared recently using this approach.50

12.12.2.2 Chain-growth polymerization The controlled chain-growth polymerization of 2-bromo-3-hexyl-5-chloromagnesiothiophene monomers was realized independently in 2004 by Yokozowa and McCullough.51–55 Linear molecular weight versus conversion plots provided strong evidence that these nickel-catalyzed polymerizations proceeded by a chain-growth rather than step-growth mechanism. These approaches enable the preparation of P3ATs with narrow molecular weight distributions (Đ  1.2–1.4), controllable Mn’s, and functional chain-ends by choice of quenching reagent.51–55 As these polymerizations can proceed where all monomer is consumed and the active metal catalyst at the polymer chain-end remains active, sequential addition can be used to prepare p-conjugated block copolymers.56–58 A p-complex is hypothesized to be the key intermediate in the chain-growth polymerization of AB-type aromatic monomers. The M(0) complex, which forms after each reductive elimination event in the catalytic cycle, binds to the growing chain as a ligand, and “walks” to the halogen chain-end where oxidative addition occurs (Fig. 6).59 The “ring-walking” and intramolecular oxidative addition event at the polymer chain end ensures the metal remains associated with the growing chain throughout the reaction. Kiriy and co-workers illustrated that the ring walking event was possible even if the monomer was comprised of multiple thiophene rings.60 Moreover, they demonstrated that bidirectional “ring-walking” was possible using dibromoarene initiators (Fig. 6).59 In 2018, McNeil and co-workers used MALDI-TOF analysis to examine ring-walking with Ni(dppp), Ni(IPr), and Pd(IPr) catalysts (IPr ¼ 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, as shown in Fig. 7).61 The choice of transition metal, ligand, and monomer all influenced propensity for ring-walking. For example, in polymerization of Kumada-type 3-alkylthiophene monomers, ring-walking was favorable for all three catalysts. In contrast, for a Kumada-type phenylene monomer, ring-walking was best promoted by the Ni(IPr) catalyst while Ni(dppp) was ineffective. While it was observed that the strongly s-donating NHC ligand

Polymerization Reactions via Cross Coupling

471

Fig. 6 Depiction of ring-walking by a nickel diphosphine catalyst, resulting in polymer growth on both sides of the dibromobenzene initiator.59 Reproduced with permission from the American Chemical Society.

Fig. 7 Examples of catalysts and ligands that have been used for Kumada, Negishi, and Murahashi type polycondensations.

effectively promoted ring-walking with two different monomers, reductive elimination of the ancillary ligand and polymer was also observed as a side reaction. An improved understanding of the factors which govern formation of the p-complex, its stability as well as possible side reactions during chain-growth polymerization are key to further expansion of this methodology. Computation has also been used to examine the metal p-complex and the role that both monomer and catalyst play in determining the strength of this interaction.62–70 The enhanced mechanistic understanding in chain-growth polymerization has recently led to the synthesis of monodisperse P3ATs. In 2019, Seferos and co-workers reported on a temperature cycling strategy to iteratively couple thiophene monomers and prepare monodisperse oligo-3-alkylthiophenes in one pot.71 An excess of 2-bromo-3-hexylthiophene in the presence of Ni(dppe) was cooled to −78  C and treated with 1 equiv. of lithium diisopropylamide (LDA) relative to catalyst. The highly reactive organolithium monomer makes transmetalation possible at cryogenic temperatures, but reductive elimination is not possible under these conditions. As such, the catalyst rests in the transmetalated state until the temperature is raised when reductive elimination and oxidative addition occur. At this point, the temperature of the reaction mixture can be returned to −78  C, and another equiv. of LDA is added to produce the organolithium monomer. This cycling process was repeated to create monodisperse octadecamers, at which point, the length of the chain began to cause solubility issues. Seferos and co-workers have also recently isolated “living” P3HT chains with a Ni(dppe) chain end to be used for further derivatization.72

12.12.2.2.1

Ligands and catalysts for chain-growth polymerization

Catalyst choice is particularly important in chain-growth polymerization as it governs the strength of the metal p-complex, as noted above.21,24,73 Some selected metal-ancillary ligand combinations that have been used in chain-growth polymerizations are shown in Fig. 7. The choice of metal center (e.g. nickel vs. palladium) and ancillary ligand are critically important, as these aspects control the steric and electronic features of the catalyst, and thus control chain-growth. It has even been shown that subtle changes in the catalyst structure can impact the rate limiting step in this reaction. For example, McNeil illustrated that the rate-determining step in Ni(dppe) catalyzed polymerizations of 1-bromo-2,5-bis(hexyloxy)-4-chloromagnesiobenzene and 2-bromo-3-hexyl-5chloromagnesiothiophene monomers is reductive elimination.74 This is in contrast to Ni(dppp) catalyzed polymerizations of the same monomers, in which transmetalation is the rate-limiting step.75 The different rate-limiting steps has been attributed to the different bite angles of the propyl and ethyl bridged diphosphines. Nickel catalysts produce highly rr-P3ATs from mixtures of regioisomers and are most common in Kumada and Negishi cross-coupling polymerization. Pd catalysts tend to produce irr-P3ATs with mixtures of regioisomers, as noted by Riecke.45 McNeil has shown that Pd-PEPPSI-IPr can bring about controlled polymerization of thiophene and phenylene type monomers,76 but the regioisomeric mixture of activated thiophene monomers were both consumed which produced irr-P3HT, as evidenced by 1H NMR spectroscopy of the final polymer. As such, it is important to consider the choice of starting monomer when using Pd catalysts in Kumuda and Negishi cross-coupling polymerization. Koeckelberghs has demonstrated that a RuPhos−Pd complex can produce chain-growth polymerization of both 3-alkylthiophene and 9,9-dioctylfluorene monomers (RuPhos ligand shown in Fig. 7).77 The iodo groups of 2-bromo-5-iodo-3-hexylthiophene and

472

Polymerization Reactions via Cross Coupling

2-bromo-7-iodo-9,9-dioctylfluorene were selectively activated using iPrMgCl
LiCl and nBui2PrMgLi at 40  C and −40  C, respectively. The activated Grignard monomers were transmetalated with dry ZnBr2, and polymerized with the RuPhosPd(Ar)Br catalyst and moreover, it was demonstrated that block copolymers of thiophene and fluorene could be synthesized starting from either monomer. This is advantageous since the formation of block copolymers from distinct monomers can often depend on the order of monomer addition, as has been shown with Ni catalysts previously.77–80 Catalyst initiation has also been an important aspect of conjugated polymer synthesis, as even single defects can impact properties and performance in devices.81 Specifically, reduction of a M(II) dihalide precatalyst such as Ni(dppp)Cl2 will produce a tail-to-tail (TT) defect within the polymer chain (Fig. 8A). As shown by Luscombe, this microstructural defect can be eliminated in Kumada coupling by using an externally initiated catalyst such as (dppp)Ni(Ar)X as shown in Fig. 8B.82 This family of catalysts enable precise control over end groups as well as evaluation of chain-end fidelity using 1H NMR spectroscopy. The active chain-end can also be terminated with other nucleophilic reagents to install functionality at the o chain-end for further post-polymerization modification.

12.12.2.2.2

Recent developments in chain-growth polymerization

The advances in polythiophene synthesis inspired work into the chain-growth polymerization of other heterocyclic and benzenoid monomers (Fig. 9). Poly(2,5-dialkoxy-p-phenylene)s,83 poly(N-alkylpyrrole)s,79 poly(3-alkylfuran)s,84 poly(3-alkylselenophene) s,85,86 and poly(3-alkyltellurophene)s87,88 have all been prepared from organomagnesium monomers with either Ni(dppp)Cl2 or Ni(dppe)Cl2. It is well recognized that heteroatom substitution in these polymers can be used to manipulate optical and electronic properties.89 It is important to note that chain-growth polymerization of novel aromatics can require optimization of side-chain length (and branching). This is exemplified by the work of the Seferos group in the synthesis of poly(3-alkyltellurophenes), where n-dodecyl

Fig. 8 (A) Initiation of MII dihalide precatalyst and the resulting tail-to-tail defect. (B) Initiation of an externally initiated MII species which eliminates the tail-to-tail defect.

Fig. 9 Various homopolymers that have been synthesized using Kumada-Tamao or Negishi cross-coupling polymerization.

Polymerization Reactions via Cross Coupling

473

side chains afforded more soluble polymers than the analogous n-hexyl side chains.87 The same group later demonstrated that use of a branched side-chain (3-ethylheptyl) leads to faster reaction kinetics, greater polymer solubility and improved control in polymerization.90 Poly(3-ethylheptyltellurophenes) were obtained with Mn’s near 25 kg/mol and narrow molecular weight distributions (1.2).90 Pammer and co-workers also demonstrated the importance of side chains in the synthesis of poly(thiazoles). Using alkyl chains (n-nonyl and n-tridecyl), Mn’s were limited to 3 kg/mol and below for this polymer.91 However, installation of bulky diisobutyloctadecylsilyl side chains afforded soluble polythiazoles with Mn’s exceeding 100 kg/mol.92,93 Monomers comprised of bicyclic and larger polycyclic p-systems have also been explored in Kumada coupling polymerization. In 2008, Rasmussen reported the synthesis of low band gap poly([3,4-b]pyrazine)s, reaching Mn’s  5 kg/mol in over 65% yield (using Ni(dppp)Cl2).94 Another fused ring system, cyclopentadithiophene, was polymerized by Koeckelberghs and co-workers with Mn’s near 31 kg/mol.80 Benzotriazole was successfully polymerized by the Seferos group using a nickel diimine catalyst, with Mn up to 32 kg/mol.63,95 The realization of chain-growth polymerization has allowed for the one-pot synthesis of numerous types of block copolymers, which can phase separate into well-defined nanostructures.96,97 Yokozawa illustrated that poly(para-phenylene)-block-poly (N-hexylpyrrole) can be obtained from sequential addition of the appropriate monomers as shown in Fig. 10A.79 Various block copolymers have been synthesized from aromatics such as thiophene, selenophene,98 cyclopentadithiophene,80 fluorene,99 and thieno[3,4-b]pyrazine using a similar approach (Fig. 10B).100 Chain growth polymerization also allows for more advanced polymer architectures and applications, such as the grafting of conjugated polymers from nanoparticles as reported by Kiriy (Fig. 10C).101

12.12.2.3 Murahashi coupling Murahashi cross-coupling polycondensation is less developed than Kumada and Negishi polycondensations, although a few interesting examples have been reported to date. In 2013, Mori used a nickel catalyst with an N-heterocyclic carbene ligand (IPr) to synthesize P3HT, PPPs, and P3HT-block-PPP (Fig. 11A).102 Mori also utilized the “halogen dance” rearrangement to convert a 2,5-dibromo-3-alkylthiophene monomer into a poly(3-hexyl-4-bromothiophene) using LDA to activate the monomer (Fig. 11B).103

12.12.3 Organotin coupling (Stille-Migita-Kosuke reaction) The Stille reaction is one of the most popular choices for the preparation of functional p-conjugated architectures as it enables cross-coupling of complex substrates.104 Organostannane coupling partners can be prepared in good yield from metalation and quenching reactions and they can be purified using column chromatography or distillation. Moreover, organostannanes are far less sensitive to air and moisture than many other nucleophilic coupling partners, so they can be handled under ambient conditions in the laboratory. While the Stille coupling method has many advantages, one drawback is the toxicity of organotin compounds. Below, some general features for this reaction are discussed, particularly in the context of making thiophene-based polymers. For further in-depth study, a comprehensive review,104 and book chapter105 have been published on the subject.

Fig. 10 (A) Use of chain growth polymerization to synthesize block copolymers, (B) block copolymers from sequential monomer addition and, (C) a P3HT functionalized nanoparticle (via grafting from approach).

474

Polymerization Reactions via Cross Coupling

(A)

(B)

Fig. 11 (A) Synthesis of P3HT and PPP by Murahashi polycondensation with NiCl2(PPh3)IPr. (B) Synthesis of poly(3-bromo-4-hexylthiophene) from 2,5-dibromo-3hexylthiophene. Deprotonation of 2,5-dibromo-3-hexylthiophene is followed by a rearrangement to form 2,4-dibromo-3-hexyl-5-lithiated thiophene, which is then polymerized with NiCl2(PPh3)IPr.

12.12.3.1 General considerations Stille cross-coupling polymerization is accomplished nearly exclusively with Pd catalysts. The most common precatalysts for this polymerization are Pd(PPh3)2Cl2 or Pd(PPh3)4. A Pd(0) source such as Pd2(dba)3 can also be used with added ancillary ligands. The choice of ligand in the Stille reaction is very important, as the donor power and steric properties of the ligand influence the cross-coupling reaction.106,107 Farina noted for example, that coupling iodobenzene and vinyl tributyltin was markedly faster when Pd2(dba)3 was paired with AsPh3 or tri(2-furyl)phosphine as compared to P(C6H4-p-OMe)3 or PPh3.107 Generally, weakly donating ancillary ligands tend to promote coupling of organostannanes more effectively than stronger s-donors. There are exceptions to this, as Fu and co-workers reported that the Pd(PtBu3)2 precatalyst can be used to efficiently couple aryl chlorides and aryl stannanes in good yield.108 Organ and co-workers have also demonstrated that the commercially available Pd-PEPPSI-IPent catalyst can promote effective coupling of aryl halides and aryl stannanes.109 The interplay between catalyst, additive, and solvent can be complex for coupling of organostannanes.110 Mechanistic investigations of the reaction have revealed that a wide range of additives can promote coupling in certain instances (CuI, CsF, NBu4F, Cs2CO3, etc).104 Various solvents can also be used in Stille coupling, such as benzene, toluene, xylene, mesitylene, chlorobenzene, THF, DMF, NMP, DMSO, 1,4-dioxane, and CHCl3. In polymerization, the choice of solvent is key for dissolution of the starting materials and growing chain, while also stabilizing the active catalyst. All of these factors must be balanced to prepare polymers with high molecular weight. Typically, electron-rich distannanes are combined with electron-deficient dihalides to synthesize conjugated polymers.104 Activation of the Caryl-X bond is typically more facile with electron deficient arenes, so the choice of arene bearing the halogens can be important. The transmetalation step may also be facilitated by electron-rich organotin compounds, which promote transfer of the organic moiety to the active catalyst. Symmetric AA and BB monomers are most common, as this avoids regioirregularities that can arise from unsymmetrical monomers.

12.12.3.2 AA/BB type coupling of organotin monomers The Stille reaction was used for the synthesis of polymers as early as 1980s with a number of major developments in the 1990s. In some of the first examples, Yu and co-workers developed a method to prepare an alternating thiophene-phenylene copolymer.106,111,112 The 2,5-tributylstannylthiophene monomer was prepared by dilithiation of thiophene using n-butyllithium (n-BuLi) followed by electrophilic quenching using tributyltin chloride. Pd(PPh3)2Cl2 was then used as the catalyst to copolymerize the distannylated thiophene with a 1,4-diiodobenzene derivative in refluxing THF. The choice of side chains on the benzene monomer were key to producing soluble polymer derivatives.111 The combination of 2,5-dihexadecyloxy-1,4-diiodobenzene with 2,5-bis(tributylstannyl)thiophene for example, produced a soluble polymer with an Mn ¼ 14 kg/mol. In 1995, Yu examined how catalyst loading, solvent and ligand impact coupling of 2,5-dioctyl-1,4-diiodobenzene and 2,5-bis(tributylstannyl)thiophene (Fig. 12).106 Copolymerizations with 1–5 mol % of the Pd (PPh3)2Cl2 revealed that the optimal loading was 2 mol %. The choice of solvent also had a marked impact on polymerization,106 with the highest Mn obtained in THF (21.7 kg/mol). This was attributed to the good solubility of the thiophene-phenylene alternating polymer in THF along with the stabilizing effect of THF on the active Pd catalyst for cross-coupling. The choice of ligand was also examined by conducting the copolymerization in THF at 80  C with AsPh3, tri(2-furyl)phosphine, P(o-tolyl)3, P(OPh)3 or PPh3, all paired with Pd2(dba)3. Generally, rate acceleration followed the trend AsPh3 > tri(2-furyl)phosphine > PPh3,106 which is similar to the results of Farina.107 The catalysts derived from P(o-tolyl)3 and P(OPh)3 were unstable after 24 h, limiting the molecular weight of the final

Polymerization Reactions via Cross Coupling

475

Fig. 12 Copolymerization of 2,5-dioctyl-1,4-diiodobenzene and 2,5-bis(tributylstannyl)thiophene.106

Fig. 13 (A) Copolymerization of perylene diimide and dithienothiophene using Pd(PPh3)4. (B) Copolymerization of naphthalene diimide and 2,5-trimethylstannylthiophene or 2,5-trimethylstannylselenophene using Pd2dba3 and P(o-tolyl)3.

thiophene-phenylene polymer. Altogether, this thorough study highlighted the importance of the reaction parameters for producing high molecular weight polymers using Stille cross-coupling polymerization. Since these initial studies, the utility of this reaction has been demonstrated with a wide range of different arenes and it arguably has the broadest substrate scope. Solvent choice is critically important to obtain high molecular weight polymers, ensuring the growing chain remains in solution over the course of the polymerization. Aromatic solvents such as chlorobenzene and toluene are sometimes preferred because the polycondensation reaction may require high temperature to ensure high conversion. For example, Marder and co-workers reported on the synthesis of a solution processible copolymer derived from perylene diimide and dithienothiophene using the Stille coupling polymerization (Fig. 13A).113 The polymer was prepared in toluene at 90  C using 2 mol % of Pd(PPh3)4 in 84% yield with a Mn of 10 kg/mol. This black-colored polymer was employed as the acceptor component in an all-polymer organic solar cell because of its high electron mobility, excellent thermal stability, and high electron affinity. Jenekhe and co-workers have synthesized naphthalene and perylene diimide based copolymers as the acceptor component in all-polymer solar cells using Stille coupling.114–119 In one of the early reports,114 they noted the copolymerization of a 1,8-dibromonapthalene diimide and 2,5-trimethylstannylthiophene could be accomplished in chlorobenzene under reflux for 72 h (Fig. 13B). The polymer was isolated in 82% yield as a dark reddish purple solid with an Mn ¼ 23.9 kg/mol.114 Jenekhe has prepared a range of different structural variants using this Stille approach where the diimide and heterocyclic ring can both be manipulated.115–119 McCulloch and co-workers illustrated that high temperatures and microwave heating can be used to promote Stille cross-coupling polymerization. They reported on a semicrystalline polythiophene that had high charge carrier mobility (0.2−0.6 cm2 V−1 s−1 under N2) in 2006.120 The polymer was prepared from the combination of 5,5’-dibromo-4,4’-didodecyl-2,2’-bithiophene and 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene using chlorobenzene as the solvent with P(o-tolyl)3 and Pd2(dba)3 to form the active catalyst (Fig. 14A).120 Polymerization was carried out under microwave heating at three successive temperatures (140  C for 2 min, 160  C for 2 min and 180  C for 10 min). The final poly(2,5-bis(3-alkylthiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT) was

476

Polymerization Reactions via Cross Coupling

(A)

(B)

Fig. 14 Thiophene-based polymers prepared using microwave heating.

Fig. 15 Examples of water-soluble conjugated polymers prepared using Stille coupling.

isolated in 90% yield with high molecular weight (Mn ¼ 29.6 kg/mol).120 Yan and co-workers used a similar approach with chlorobenzene as a solvent under microwave irradiation to prepare a benzothiadiazole-based copolymer with partially fluorinated thiophenes. The polymer was obtained in good yield (71%) with a Mn value of 28.2 kg/mol (Fig. 14B).121 Ramey, Schanze and Reynolds, reported on the copolymerization of a thiophene-phenylene copolymer bearing tertiary amines on the side chain as shown in Fig. 15A.122 The authors noted that higher molecular weights were difficult to obtain due to shorter chain length of the solubilizing groups, but an Mn ¼ 5.3 kg/mol was obtained in DMF at 70  C when the distannane monomer was added dropwise to the reaction.122 Quaternization of the amine groups was accomplished using dibromoethane over 5 days in THF, to afford an emissive water soluble polymer which was evaluated as the active component in a polymer light-emitting diode. Swager and co-workers demonstrated that a distannylated thiophene could be copolymerized with a phenyl-dipyridine trimer using Pd(PPh3)4 in DMSO (Fig. 15B).123,124 SOCl2 was then used for quaternization to form a water-soluble poly(pyridinium phenylene). While highly polar solvents such as DMF or DMSO may be useful when polar groups are present in the main chain or side chain, many conjugated polymers are poorly soluble in DMF alone. As DMF is known to accelerate the cross-coupling of stannanes and aryl halides, co-solvent systems have been employed to prepare conjugated polymers using Stille coupling. To this end, Fréchet and co-workers reported the synthesis of an ester-functionalized polythiophene prepared in toluene/DMF at 115  C (Fig. 16A).125 Yu and co-workers also synthesized a variety of different thiophene-based copolymers to be explored in organic solar cells using Pd(PPh3)4 in toluene/DMF at 120  C (Fig. 16B).126–128 In one example, they illustrated that random copolymers could be synthesized by incorporating two different dibrominated monomers into the reaction, and overall composition was controlled by feed ratio.126 It should be noted that high temperatures are not strictly required in Stille coupling as Marder and Reynolds reported on the copolymerization of a dithienopyrrole and a benzobisthiadiazole trimer in THF at reflux for 2 days.129 Inorganic salts such as LiCl or CuI can also be used to promote the Stille reaction. LiCl is known to enhance the coupling of electrophilic triflate coupling partners,130 and the overall impact of this additive is largely dependent on the reaction conditions

Polymerization Reactions via Cross Coupling

477

(A)

(B)

Fig. 16 (A) Example of Stille polycondensation performed in toluene with a polar co-solvent (DMF). (B) Other examples of polymers prepared using a co-solvent approach.

(A)

(B)

Fig. 17 (A) Polymerization of a diketopyrrolepyrrole-containing polymer (LiCl additive) (B) Polymerization of an anthracene-containing polymer (CuI additive).

(e.g. catalysts and solvents).131,132 As an example of a coupling reaction using LiCl, Yu and co-workers reported on the synthesis of photorefractive polymer containing pyrrole[3,4-c]pyrrole-1,3-dione-3,6-diyl units, where polymerization was conducted in 1,4-dioxane in the presence of Pd(PPh3)4 and LiCl (Fig. 17A).133 The authors noted the high reactivity of triflate electrophiles for polymerization in that work. Copper salts are also common additives in the Stille reaction. Liebeskind and Farina observed a more than 100 fold rate acceleration in the Stille reaction when a Cu(I) salt was added in combination with a strong electron donating ligand such as PPh3.134 The authors concluded that the copper salts acted as a scavenger of the free ligand, which was known to inhibit the Stille reaction.134 In addition to CuI, various copper(I) salts such as CuCl, CuBr, CuBr ∙Me2S, or copper(I) thiophene-2-carboxylate were reported to have the similar effect as additives in the Stille reaction.135–137

478

Polymerization Reactions via Cross Coupling

Interesting examples using copper salts as a co-catalyst were reported for the synthesis of a silyl-containing polymer.138,139 Ohshita and co-workers reported the synthesis of an anthracene-containing silane polymer using Pd(PPh3)4 and CuI (Fig. 17B).138 Although this polymer showed limited electroluminescence, the authors found that it could be applied as the hole-transporting material in double-layered electroluminescent devices.138

12.12.3.3 Recent developments in vinylene-based conjugated polymers Stille type polycondensation has also been used to incorporate vinylene groups into conjugated polymers, which can help reduce torsional strain between adjacent arenes, improving planarity and reducing the band gap.140 For example, in 2010 Bao demonstrated the copolymerization of 4,7-dibromobenzo[c][1,2,5]thiadiazole, trans-1,2-bis(tributylstannyl)ethylene, and either fluorene or cyclopentadithiophene was possible using Pd2(dba)3 and P(o-tolyl)3 (Fig. 18A).141 In another example by Venkataraman and Kumar in 2012, alkoxy functionalized benzothiadiazole was copolymerized with trans-1,2-bis(tributylstannyl)ethylene using Pd(PPh3)4, with an Mn ¼ 10.7 kg/mol (Fig. 18B).142 A similar polymer, with thiophene spacers between the thiadiazole and vinyl fragment, was reported by Wang and co-workers the year before (Fig. 18C).143 A more recent example, by Michinobu in 2019, detailed the design and synthesis of benzothiadiazole, vinylene, thiophene, and naphthalenediimide (NDI) containing polymers.144 Density functional theory calculations were used to design repeat units that were planarized by hydrogen-bonding interactions involving the vinylene unit, which led to improved properties over similar, previously synthesized materials (Fig. 19). The benzothiadiazole unit was fluorinated to promote HdF hydrogen bonding, while the carbonyl oxygen of the NDI unit was found to participate in a CdO hydrogen bonding interaction. This is a particularly interesting example of the state-of-the-art materials that can be reliably synthesized via Stille cross-coupling polycondensation.

12.12.3.4 Polymerization of AB monomers Moreau and co-workers had reported on the Stille coupling polymerization of 2-bromo-3-hexyl-5-tributystannylthiophene and produced extremely high molecular weight P3HT (Mn  140 kg/mol) using Pd2dba3/PPh3 as the catalyst (ratio of Pd: PPh3 ¼ 1:4).145 Noonan and co-workers expanded on this and reported on the chain-growth polymerization of 2-bromo-3hexyl-5-trimethylstannylthiophene with Pd-PEPPSI-IPr in the presence of CsF (Fig. 20).146 The chain growth mechanism was evidenced by a linear trend between molecular weight and monomer conversion, and a chain extension experiment demonstrated that the Pd catalyst remained active even after monomer was fully consumed. Mn could be modified by varying the monomer to catalyst ratio, reaching up to 73 kg/mol with dispersities around 1.5.

Fig. 18 Examples of copolymerization of trans-1,2-bis(tributylstannyl)ethylene with units such as fluorene (A), cyclopentadithiophene (A) and benzothiadiazole (A-C).

Polymerization Reactions via Cross Coupling

479

Fig. 19 Synthesis of a polymer with a donor-acceptor interaction between the vinylene unit and carbonyl group.

Fig. 20 Stille-type chain-growth polymerization using Pd-PEPPSI-IPr.

12.12.4 Organosilicon coupling (Hiyama-Denmark-Ito reaction) The natural abundance of silicon and its ubiquity as a protecting group in organic chemistry makes it of particular interest for use in cross-coupling. The stability of organosilicon compounds and their low-toxicity makes them attractive compared to the stannane reagents discussed above, but the Hiyama coupling is not commonly used in cross-coupling polymerization chemistry. Since Hiyama’s discovery of the coupling of aryl silanes,147 many advances have been made in the choice of organosilicon coupling partner,148–150 which will likely result in more extensive use of this method in polymer science in the future. Though this reaction is related to Stille coupling in that both employ Group 14 elements as the nucleophilic cross-coupling partner, silicon agents require activation to promote transfer of the organic group to the metal for eventual coupling.148–150 Ozawa and co-workers reported one of the first examples of Hiyama coupling polymerization in 2003 in an effort to prepare well defined trans and cis poly(p-phenylene vinylene) derivatives (Fig. 21).151 The authors used two different Ru-catalysts to hydrosilylate 1,4-diethynyl benzene. With RuHCl(CO)(PPh3)3, the disilylated E isomer was obtained selectively, while in the other case, the disilylated Z isomer was produced selectively (using RuCl2(CO)(PiPr3)2). These derivatives were then used as monomers in an AA/BB type polymerization with 2,5-dioctyloxy-1,4-diiodobenzene in THF using [PdCl(Z3-allyl)]2 and NBu4F
3H2O as the activator. The desired polymers were prepared nearly quantitatively though the molecular weights did not exceed 7 kg/mol. The polymerization of the E disilane proceeded as expected to afford the desired trans-PPV derivative, but polymerization of the Z-disilane afforded a cis/trans mixture for the final polymer. The authors concluded that the stereochemistry was most likely scrambled during the polymerization. Katayama and Ozawa did successfully prepare the cis-PPV derivative later, but using Suzuki-Miyaura coupling.152,153 Ozawa and co-workers also used a Hiyama coupling strategy to prepare an all trans poly(m-phenylenevinylene)s.154 2-(Hydroxymethyl)phenyl silanes (HOMSi) are also extremely convenient reagents for cross-coupling (Fig. 22).150 This type of reagent has been used in polymerization by Hiyama155 to promote coupling of fluorene and benzothiadiazole monomers (Mn  8 kg/mol, Đ ¼ 2.97). The use of such reagents in polymerization suggests many of the other organosilicon approaches to coupling should have potential for use in polymerization in the future.

480

Polymerization Reactions via Cross Coupling

Fig. 21 Preparation of trans and partially cis poly(p-phenylenevinylene) derivatives.

Fig. 22 Copolymerization of 4,7-dibromobenzo[c][1,2,5]thiadiazole with 2,7-HOMSi-9,9-dioctylfluorene to afford the poly(9,9- dioctylfluorene-cobenzothiadiazole) (F8BT).

12.12.5 Organoboron coupling (Suzuki-Miyaura reaction) The Suzuki-Miyaura coupling is one of the most popular cross-coupling reactions. Organoborons can be synthesized either by metalation and quenching with electrophiles, or by metal-catalyzed borylation of CaryldH and CaryldX bonds.156,157 Organoboron compounds are thermally and chemically stable in most instances, and can be purified by distillation or column chromatography. They can often be handled under ambient conditions in the laboratory.158 The Suzuki-Miyaura reaction can be carried out under mild conditions, it is exceptionally functional group tolerant, and the resultant boron byproducts are relatively non-toxic. Given all these advantages, it has been used extensively in the synthesis of conjugated polymers. For additional information on SuzukiMiyaura cross-coupling polymerization, a number of book chapters158,159 and reviews have been published.160

12.12.5.1 General considerations A wide range of catalysts and ligands have been used to in Suzuki polycondensation reactions. Novak has also demonstrated that polymerization can be accomplished by a metal catalyst without additional ligand in one instance.161 Coupling of boronic acids and esters typically requires addition of an inorganic base (e.g. K2CO3, K3PO4, Na2CO3, NaOH, CsF), and polymerizations are conducted in organic solvents such as THF, 2-MeTHF, dioxane, 1,2-dimethoxyethane and toluene. Addition of water is also necessary in these reactions to dissolve the base. In most cases, the reactions are biphasic, and the aqueous phase serves as a reservoir for the − OH or − F that promotes transmetalation.162–166 Side reactions are possible in Suzuki-Miyaura cross-coupling polymerization, but can be mostly avoided with appropriate choice of reaction conditions. Incorporation of phosphorus ligands into the polymer chain for example, has been reported in Suzuki polycondensation.167 Oxidative homocoupling of the boronate species is also possible, and O2 should be avoided to prevent this side reaction.158 Additionally, protodeboronation (hydrolysis of CdB bonds168,169) can lead to loss of the nucleophile in the reaction.

Polymerization Reactions via Cross Coupling

481

12.12.5.2 Boron substituents A wide array of organoboron cross-coupling partners can be used in Suzuki-Miyaura polymerization reactions. A few of the most common examples are shown in Fig. 23 which includes boronic acids, esters (e.g. Bpin and Bneop), borates and derivatives of N-methyliminodicarboxylic acid (BMIDA). The substituents on the 3-coordinate boron (OR or OH) groups impact the Lewis acidity and accessibility of the boron center and thus impact the rate of transmetalation. For example, it has been reported that 4-fluorophenylboronic acid couples 4.5 times faster than the related pinacol ester, and 4 times slower than the catechol derivative.165 Given this, choice of boronic acid or ester monomer is likely to lead to different rates of polymerization. Four-coordinate organoborates can also serve as a pre-activated coupling partner, as they can often transmetalate without the need for an inorganic base in the reaction mixture. The triolborates are shown as a representative class of this type of nucleophilic coupling partner.170 Other forms of 4-coordinate organoborons, such as the MIDA boronates, hydrolyze to the boronic acid under the alkaline conditions of the reaction.170

12.12.5.3 Polyphenylene derivatives synthesized from AA/BB monomers One of the the first reports of Suzuki-Miyaura coupling polymerization appeared in 1989 with the preparation of a poly(p-phenylene) (PPP).171 Schlüter and co-workers polymerized a dialkylbenzene AB type monomer using 0.5 mol% Pd(PPh3)4 to afford a poly(2,5-dihexyl-p-phenylene) with DPn  30 in nearly quantitative yield (Fig. 24). A follow-up report appeared a year later with the first AA/BB type polymerization to make PPPs with reduced side-chain density (Fig. 24).172 In that work, Schlüter and co-workers used a telomer approach to prepare PPPs with unsubstituted arenes along the backbone, by coupling oligomers using identical conditions to their first report. Vapor-pressure osmometry indicated the polymer had a DPn  37 (Mn ¼ 21 kg/mol) which was isolated in 85% yield. Schlüter and co-workers have also explored the impact of diiodo and dibromo monomers for synthesis of alkylated PPPs.173 Additionally, Holmes and Friend constructed PPPs with hexyloxy chains174 while Novak synthesized water-soluble PPPs with carboxylic acid side chains.175 In 2008, Goodson and co-workers published a study on reaction parameters and how these impact polymer molecular weights in Suzuki-Miyaura cross-coupling polymerization (Fig. 25).176 The first parameter tested was solvent, with 0.5 mol% of Pd2(dba)3,

Fig. 23 Various boron functionalities that have been used in Suzuki-Miyaura polycondensation.

Fig. 24 Early examples of Suzuki-Miyaura polycondensation reported by Schlüter for the synthesis of PPPs.171,172

Fig. 25 General scheme for Goodson’s 2008 investigation of various reaction parameters and their impacts on molecular weight using Suzuki-Miyaura coupling.176

482

Polymerization Reactions via Cross Coupling

1 mol% P(o-tolyl)3, and 3 M K3PO4 as the base. Several solvents were effective for achieving high molecular weight polymers including: CH2Cl2, THF, 1,4-dioxane and toluene. The combination of CH2Cl2 with 3 M K3PO4 produced the highest molecular weight material in this instance (Mn ¼ 63.6 kg/mol, Đ ¼ 2.8). Several electron-rich phosphines were screened, all of which promoted successful Suzuki-Miyaura polymerizations, though the molecular weights were not as high as those obtained with P(o-tolyl)3. Goodson and co-workers also noted that Pd(OAc)2 was a viable palladium source for these step-growth polymerizations. Tour and co-workers also utilized a Suzuki-Miyaura coupling approach to build imine-bridged ladder PPPs.177,178 The imine-bridge reduces steric conflicts normally present between ortho H’s from adjacent phenylene rings in PPPs. The precursor to the ladder polymer is synthesized by an AA/BB coupling of the boc-protected aniline bearing two boronic esters and a dihaloarene with two ketone groups (Fig. 26). The polymerization was carried out in DME/water at 85  C in the presence of Pd(dba)2, PPh3, and NaHCO3. The resultant polymer was obtained in 97% yield with an Mn of 28.4 kg/mol (Đ ¼ 3.70). Treatment of this polymer with CF3COOH, produced the imine-bridged PPP. FTIR ensured cyclization was quantitative, as no signals were observed that could be attributed to the ketone, carbamate and amine stretches from the precursor. Solution-cast films of the precursor in THF can be cleanly cyclized by suspension in anhydrous HCl/EtOAc followed by washing with Et3N/NaOH. Leclerc and co-workers demonstrated that carbazole copolymers can be synthesized effectively using Suzuki-Miyaura polymerization, and these derivatives were examined in field effect transistors and organic solar cells (Fig. 27).179 A series of copolymers were prepared from the combination of a carbazole-based monomer bearing two pinacol boronic ester groups and various dihalogenated trimers (Fig. 27). The trimers were comprised of a bicyclic repeat unit flanked with two halogenated thiophenes. The authors noted that higher molecular weights were obtained in copolymerizations with the bicyclics derived from benzene rather than the bicyclics bearing a pyridine ring. Polymers with Mn’s of 36 and 26 kg/mol were obtained when the Ar identity was benzothiadiazole and benzoxadiazole, respectively (Fig. 27). If the bicyclic arene was comprised of a pyridine, this could bind to the metal center and limit catalytic turnover. 1H NMR spectroscopy revealed regiorandom incorporation of the pyridine-type monomers in these systems. Mühlbacher, Scharber and Müllen reported on cyclopentadithiophene-benzothiadiazole copolymers for organic solar cells and field-effect transistors.180,181 The combination of dibromocylopentadithiophene with 2,1,3-benzothiadiazole-4,7-bis(boronic acid

Fig. 26 Suzuki-Miyaura polymerization and acidic deprotection/cyclization to prepare a ladder-type PPP derivative.

Fig. 27 Copolymerization of diborylated carbazole with various arene trimers.

Polymerization Reactions via Cross Coupling

483

Fig. 28 Pd(PPh3)4 catalyzed polycondensation of (A) cyclopentadithiophene and benzothiadiazole, and (B) fluorene with either pentacene or anthradithiophene.

pinacol ester) with Pd(PPh3)4 as the catalyst, produced a polymer with an Mn  10 kg/mol (Fig. 28A).180 Aliquat 336 was used as a phase-transfer catalyst to promote transfer of the − OH anion into the organic phase for catalytic turnover. In another example, Bao and co-workers prepared alternating copolymers of 9,9-dialkylfluorene with either pentacene or anthradithiophene (Fig. 28B).182 Pentacene presents quite a synthetic challenge given the low solubility of this polycyclic aromatic hydrocarbon. Triisopropylsilylethynyl-substituted pentacene and anthradithiophene were used in this copolymerization, as these substituted derivatives are soluble in a range of solvents.182 The materials were synthesized in good yield, with high molecular weights (36.4 kg/mol and 58.0 kg/mol, respectively) and could be blended with PCBM.182

12.12.5.4 Masked boronic acids in Suzuki-Miyaura cross-coupling polymerization While most boron moieties used in Suzuki-Miyaura polymerization are tricoordinate species, reports with masked boronates have also appeared to reduce active monomer concentration during polymerization and limit protodeboronation. For example, organotrifluoroborates, which are generally known to be isolable crystalline materials,183 were employed in polymerization by Nobile and co-workers in 2005 (Fig. 29A). In that report, fluorene vinylene copolymers were prepared by a cascade Suzuki-Heck polymerization in the presence of Pd(PPh3)4 (Fig. 29A).184 It gave the desired polymer (Mn of 8.3 kg/mol and Ð of 2.3) in 77% yield. Another modified boronate, BMIDA, was used by Ingleson and co-workers for the synthesis of several cyclopentadithiophene copolymers.185 BMIDA-functionalized cyclopentadithiophenes were copolymerized with a variety of dibrominated arenes (4,7-dibromo-5-fluorobenzothiadiazole is shown as a representative example in Fig. 29B). Excellent yields and relatively high molecular weights of the final polymers were obtained using Pd2(dba)3 with SPhos in the presence of KOH in THF/water at 55  C. Ingleson has also reported the polymerization of an AB type thiophene monomer functionalized with BMIDA using a similar approach (Fig. 29C).186 In that report, P3HT with an Mn ¼ 18.7 kg/mol was obtained in over 90% yield with K3PO4 as the base. Choi and co-workers have also reported the controlled polymerization of this thiophene-BMIDA monomer using a RuPhos − Pd catalyst.187,188 In that work, P3HT with an Mn ¼ 17.6 kg/mol (Đ ¼ 1.16) was obtained, and block copolymers could be synthesized by taking advantage of the reactivity differences between thienyl-BMIDA and thienyl-Bpin monomers.187,188

12.12.5.5 Chain-growth polymerization In 2007, Yokozawa and co-workers reported on one of the first Suzuki-Miyaura CTP reactions with a 9,9-dialkylfluorene monomer as shown in Fig. 30.189 The low Ð (1.33) and the linear dependence of Mn with conversion were indicative that the polymerization proceeded in a chain-growth fashion. Since then, alkyl and ester-functionalized polythiophenes,187,188,190–193 polyfluorenes,194–200

484

Polymerization Reactions via Cross Coupling

(A)

(B)

(C)

Fig. 29 (A) Copolymerization of a diborylated fluorene with potassium trifluoroborate. (B) Example of an AA/BB polycondensation using a BMIDA functionalized cyclopentadithiophene. (C-D) Thiophene-BMIDA monomers polymerized with Pd dialkylbiarylphosphines.

Fig. 30 Chain growth polymerization of an AB type fluorene monomer.189

ester-functionalized polyfurans,201 PPPs,202 poly(meta-phenylenes),203 poly(ortho, para-alternating-phenylenes),204 poly (benzo [1,2,3]triazoles),205 poly(3,6-phenanthrenes)206 and poly(phenylene-vinylenes) have been synthesized using Suzuki-Miyaura CTP (Fig. 31).208,209 The active catalyst in these reactions is usually a Ni or Pd complex with an electron-rich ligand such as a phosphine, diphosphine, or N-heterocyclic carbene. Fig. 31 highlights the homopolymers that have been prepared using chain-growth Suzuki-Miyaura polymerization, color coded with the successful metal ligand catalyst combination used to bring about crosscoupling. As noted in Section 12.12.2.2, the choice of ancillary ligand in these chain-growth reactions is very important as it impacts the steric and electronic properties of the metal catalyst and controls formation of the p-complex with the polymer. Both Pd and Ni catalysts have been explored in chain-growth polymerization of aromatic monomers using Suzuki-Miyaura coupling,207 both of which have their advantages. Generally, Pd catalysts are more common in this polymerization, as the advances in cross-coupling of small molecule substrates in the past 20 years can be used as a guide to help select ancillary ligands and precatalysts for the reaction. The most common catalyst system in Suzuki-Miyaura CTP is tBu3P− Pd, and a number of other electron-rich phosphines have been paired with Pd successfully (e.g. AmPhos, P(1-Ad)3, RuPhos, and SPhos).207 Producing high molecular weight materials using Suzuki-Miyaura CTP can sometimes be challenging. Several recent reports have appeared tackling this issue.194,210 Satoh demonstrated that polyfluorenes (PFs) could be prepared from a triolborate monomer using a tBu3P− Pd(Ar)Br precatalyst (Fig. 32).194 The authors demonstrated that PFs with very high molecular weights could be produced using this approach (Mn of 69.4 kg/mol). In addition, they illustrated that the triolborate monomer could be used in the synthesis of block and graft copolymers with various insulating polymers (e.g. polystyrene and polycaprolactone).194

Polymerization Reactions via Cross Coupling

485

Fig. 31 Ligand and polymer pairings for Suzuki-Miyaura CTP are indicated by the color coded boxes. Reproduced with permission from the Royal Society of Chemistry.207

Fig. 32 High molecular weight polyfluorene from polymerization of a triolborate monomer.

One of the major benefits of the triolborate monomer as compared to boronic acids and esters is the reduced water content needed, as this prevents aggregation or precipitation of the polymeric macroinitiators for block and graft synthesis. Kiriy and Voit have also illustrated that tBu3P− Pd can be used to prepare high molecular weight PFs. They noted in that work that under identical conditions, the combination of Pd(CH3CN)2Cl2 and PtBu3 was a superior catalyst to Pd(PPh3)4 and Pd[P(p-tolyl)3]3 in both AB and AA/BB type polymerizations.210 PFs up to 76.4 kg/mol were obtained from an AB pinacol boronic ester monomer with Na2CO3 as the base in THF, though controlling the molecular weight distribution was difficult at 0.2% catalyst loading.210

12.12.6 Direct arylation polymerization (CdH activation) While the cross-coupling methods discussed so far require a metal or metalloid transmetalating agent, direct arylation polymerization (DArP) allows for dehydrohalogenative cross-coupling of dihaloarenes and unsubstituted arenes (Fig. 33). In addition to enhanced atom economy and elimination of potentially toxic by-products, DArP offers broad functional group tolerance and can

486

Polymerization Reactions via Cross Coupling

Fig. 33 General scheme for an AA/BB direct arylation polymerization.

produce polymer materials with high molecular weights. As such, DArP has gained tremendous popularity in recent years as an alternative to the more traditional cross-coupling methods used to synthesize conjugated polymers. This section will aim to outline the distinctions and main considerations for DArP. A number of reviews have appeared recently on the subject.211–214

12.12.6.1 General considerations The key difference in DArP as compared to other coupling methods discussed above is the transmetalation step (Fig. 34). After oxidative addition, a base (either a carbonate or a carboxylate) exchanges with the halogen ligand on the metal center and facilitates activation of a CaryldH bond. This process is referred to as concerted metalation-deprotonation (CMD), and is typically energetically favored over other mechanistic possibilities for CdH activation (e.g. s-bond metathesis and Heck-type coupling).211,214–217 Base is necessary to neutralize the acid generated from the CdH activation and for the CMD event. The new CdC bond (Ar1dAr2) is then formed through reductive elimination. Generally, proton acidity determines the site of CdH activation. For example, in five-membered rings such as thiophenes, the a-position is favored for activation over the b-position (CMD activation energies are 25.6 kcal/mol and 29.9 kcal/mol, respectively).216 Despite differences in reactivity between multiple CdH bonds on a given arene, achieving perfect selectivity for the cross-coupling site can still be a considerable challenge. Activation of the b-position will result in a branching point or a bend in the chain, as shown in Fig. 35. Additionally, homocoupling events can lead to other types of irregularities, such as HH couplings. Altogether, minimization of defects remains a considerable challenge in DArP of thiophene-type monomers. Activation of the a and b-positions can be advantageous in some cases if the desired polymer structure is a highly branched or dendritic species. Luscombe

Fig. 34 Proposed mechanism for DArP, in which C-H activation occurs via a concerted-metalation deprotonation (CMD).

Fig. 35 Possible sites of C-H activation in 2-bromo-3-alkylthiophene are the a and b protons. Activation of the b positions will result in defects such as branch and bent points along the chain. HH alkyl groups can also arise from homocoupling defects.

Polymerization Reactions via Cross Coupling

487

and co-workers illustrated that base and ligand could be used to modify the degree of branching during synthesis of P3ATs via DArP, which resulted in control over morphology (i.e. linear vs globular) and viscosity.218 DArP is typically promoted with Pd(OAc)2, Pd2dba3 or the Herrmann-Beller catalyst ((trans-di(m-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)). Palladium precursors can be combined with phosphine ligands such as PCy3 P(C6H4-o-Me)3, and P(C6H4-o-NMe2)3. The identity of the phosphine ligand can play a particularly important role in CdH activation, which is the rate-determining step of direct arylation.215,219 While electron-poor phosphines tend to facilitate transmetalation, lowering the activation energy of this step can also decrease regioselectivity.220 DArP has been performed with catalyst loadings as low as 0.03%, which is promising when considering the economic viability of larger scale syntheses and mimizing metal impurities in the resulting materials. Initially, DArP was carried out only with added bases such as K2CO3, KOPiv, KOAc, Cs2CO3.211,214 This approach was effective for activating C-H bonds of electron-poor arenes, but was not suitable for synthesis of polymers from electron-rich arenes (e.g. thiophenes). Addition of a carboxylic acid, in addition to the base, results in marked improvement in polymerization of electron-rich arenes. This is due to the proton shuttling role of the carboxylic acid, which ultimately lowers the energy barrier for the CMD pathway. The identity of the carboxylic acid can also have a significant impact on the polymerization. Thompson for example, found that use of neodecanoic acid (NDA) suppressed activation of b-protons to a greater extent than pivalic acid (PivOH) in the synthesis of P3HT, which was attributed to NDA’s increased steric bulk (Fig. 36a–c).221,222 A subsequent report screened a larger scope of carboxylic acid additives for polymerization of 2-bromo-3-hexylthiophene. Interestingly, NDA and neotridecanoic acid performed the best, suggesting that the number of carbon atoms in the acid was the best predictor of regioselectivity, yield, and molecular weight.223 It is also worth noting that the larger carboxylic acids are used as a mixture of isomers (Fig. 36). A wide range of solvents have been used for DArP to date including: DMA, NMP, toluene, THF, 2-MeTHF, o-xylene, and dioxane.211,214 Ensuring the solvent is thoroughly dried has been shown to increase molecular weight, and other factors such as steric bulk must be considered when choosing amide solvents.224 Aromatic solvents may undergo CdH activation, creating increased opportunity for undesirable side reactions.224 Monomer concentration has also been reported as a key consideration in DArP. DPn has been noted in many instances to increase linearly with concentration, and is often optimal when monomer concentrations range from 0.1 to 0.5 M. One approach towards limiting b-defects includes the use of b-substituted arenes to block undesirable CdH activation. Comonomers that have desirable electronic properties such as 3,4-ethylenedioxythiophene (EDOT), thieno[3,4-c]pyrrole4,6-dione (TPD) and 4,40 -dialkyl-2,20 -bithiazole (BTz) serve as a few representative examples of this approach (Fig. 37A).214 Another interesting strategy is the use of a directing group, as shown in Fig. 37B. In this example, a 2-pyrimidinyl group was used by Kanbara to favor coupling at the a-positions of pyrrole via coordination to a Ru catalyst.225

Fig. 36 Depiction of the impact of carboxylic acid steric bulk on the tendency to form b -defects. Reproduced with permission from Elsevier.211

488

Polymerization Reactions via Cross Coupling

Fig. 37 Approaches to minimize b-defects. (A) Copolymerization of monomers with no b C-H bonds such as EDOT, BTz, and TPD and (B) Utilization of directing groups to activate specific C-H sites with the metal catalyst.

12.12.6.2 Selected examples of DArP 2-bromo-3-hexylthiophene is the most explored aromatic building block in DArP to date, as it provides a well-defined model system to better understand the reaction mechanism and optimize conditions. Several representative examples are shown in Fig. 38. In 2010, Takita and Ozawa reported the synthesis of P3HT using the Herrmann-Beller catalyst with P(C6H4-o-NMe2)3 and Cs2CO3 (Fig. 38A).226 After 24 h at 125  C in THF, an Mn of nearly 31 kg/mol was achieved, with excellent regioregularity (98%) and yield (99%). Fig. 38B shows an alternative approach towards highly regioregular P3HT, in which Thompson and co-workers used low catalyst loading (0.03%) to produce P3HT in high yield (91%), with an Mn  24 kg/mol and 96.5% HT couplings.227 The Pd(OAc)2 catalyst was used without additional phosphine in this case, and NDA was used as an additive. The authors noted that minimizing the required amount of Pd catalyst, as well as additives, is an important step towards making conjugated polymers more economically viable in the future. While many examples of DArP focus on P3ATs, the field has expanded to include more diverse aromatic monomers. AA/BB type polymerizations can be quite different depending on which arene is halogenated and which one is selected for C-H activation. For example, Farinola illustrated that the copolymerization of benzodithiophene, benzothiadiazole, and benzotriazole was more efficient when with CdH activation of the benzodithiophene monomer (Fig. 39).228 Kanbara229 and Ozawa230 have both reported on the copolymerization of 1,2,4,5-tetrafluorobenzene and 2,7-dibromo9,9-dioctyl-9H-fluorene. Ozawa obtained molecular weights of nearly 350 kg/mol using a combination of Pd2dba3-CHCl3, Cs2CO3, P(C6H4-o-OMe)3, and PivOH (Fig. 40A).230 Ozawa later demonstrated that using similar conditions to polymerize

(A)

(B)

Fig. 38 (A) DArP of 2-bromo-3-hexylthiophene using the Herrmann-Beller catalyst with P(C6H4-o-NMe2)3. (B) Phosphine-free DArP using Pd(OAc)2 with K2CO3 and NDA.

Fig. 39 Example of how the choice of which arene(s) are halogenated versus unsubstituted can play a role in polymerization.

Polymerization Reactions via Cross Coupling

489

Fig. 40 Selected examples of DArP with a range of monomers.

dibromodiketopyrrolepyrrole (DPP) and various thiophenes resulted in a high degree of homocoupling, branching, and crosslinking. However, addition of a second ligand, TMEDA, to the reaction mixture dramatically decreased the amount of defects, and yielded polymers of up to nearly 37 kg/mol (Fig. 40B).231 DPP has also been polymerized with other units such as benzotriazole.232,233 In another example, Scherf reported the polymerization of 4,4-bis(ethylhexyl)-4H-cyclopenta[2,1-b:3,4-b’]dithiophene and 4,7-dibromobenzo[c][1,2,5]thiadiazole using Pd(OAc)2 with K2CO3 in DMA, reaching molecular weights up to 40 kg/mol (Fig. 40C).234,235 Reynolds and co-workers reported DArP of phenylenedioxythiophene (PheDOT).236 PheDOT could be used as either the dihalogenated or unsubstituted monomer in copolymerization (Fig. 41A), and it was noted that both of these species were stable under ambient conditions for over one year. Copolymerization with dialkoxythiophenes using Pd(OAc)2, pivalic acid, K2CO3 in DMAc produced polymers with Mn ranging from 23 to 68 kg/mol (Fig. 41A). Jenekhe and Leclerc used Pd2(dba)3, pivalic acid, K2CO3 in chlorobenzene to synthesize poly[[N,N’-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5’(2,2’-bithiophene)] (PNDIOD-T2) (Fig. 41B).237 A relatively high Mn of 76 kg/mol was achieved, and the material slightly outperformed the commercially available analog N2200 (which is synthesized via Stille cross-coupling) in solar cells. An increasing number of reports have focused on improving the sustainability and practicality of conditions required for DARP.238–241 For example, Leclerc reported a biphasic water/toluene system for polymerization of various phenyl and thienyl type monomers.242 In addition to palladium catalyst, carboxylic acid, and base, water and a phase transfer agent were added to the reactions (Fig. 41C). Mn and yield under these conditions were comparable to anhydrous conditions, and it was found that the reaction was tolerant of air. Importantly, it was found that Pd(OAc)2 minimized defects more effectively than Pd(dppf )Cl2, as determined by analysis of the UV-Vis profiles of the synthesized copolymers. Overall, this robust protocol is an example of the promising steps being made towards more scalable reactions that do not require thoroughly dried solvents and reagents.

12.12.6.3 Chain-growth polymerization Although the majority of polymer syntheses via DArP proceed via a step-growth mechanism, chain-growth processes are of interest due to the increased control over molecular weight and dispersity. In 2018, Luscombe reported the first dual-catalytic Ag-Pd system

490

Polymerization Reactions via Cross Coupling

(A)

(B)

(C)

Fig. 41 (A) Copolymerization of PheDOT with other dialkoxythiophenes. (B) Synthesis of high molecular weight PNDIOD-T2. (C) DArP in a biphasic toluene/water solvent system, in which tetrabutylammonium chloride (TBAC) and K2CO3 were used as the phase transfer agent and base, respectively. Note that for the anhydrous conditions, tetrabutylammonium bromide (TBAB) was used as the phase transfer agent and Cs2CO3 the base.

for the direct arylation polymerization of 2-bromo-3-hexylthiophene (Fig. 42).243 Using PEPPSI-IPr and a silver carboxylate (AgNDA), chain-growth behavior was observed, and produced rr-P3HT with low dispersities (around 1.3). In addition to AgNDA, the presence of pyridine was key to achieve chain-growth behavior. This was attributed to the pyridine decreasing the average number of active Pd catalysts, slowing the overall reaction kinetics and allowing transmetalation of primarily Ag-activated monomers. While the AgNDA/pyridine system resulted in monomodal traces (as opposed to bimodal with just AgNDA), pyridine alone (i.e. no AgNDA) resulted in lower Mn. This was attributed to AgNDA’s hypothesized role in facilitating the C-H activation process.

12.12.7 Oxidative coupling (CdH activation) As shown in Fig. 43, it is possible to move away from the traditional cross-coupling methods typically employed in conjugated polymer synthesis and move to oxidative coupling reactions which require a transition metal catalyst and an oxidant. Though the

Polymerization Reactions via Cross Coupling

491

Fig. 42 Proposed mechanism of dual catalyzed Ag-Pd system for chain-growth synthesis of P3HT.

Fig. 43 Top – traditional cross-coupling reaction which involves a nucleophile and an electrophile. Bottom – Oxidative cross-coupling by activation of two C-H bonds.

benefit of this method is clear as pre-functionalization of the arene is not required and only “H2” is released, there are challenges with this coupling process for two nucleophiles. First, CaryldH activation is not always straightforward given the higher bond dissociation energy as compared to CdX and CdM bonds. Additionally, aromatic compounds often have multiple inequivalent CdH bonds, so the desired regioselective bond activation can be a challenging aspect of this chemistry. Oxidative coupling is ideal to build biaryl and polyaryl structures due to the simplicity of the overall process and the lower number of synthetic steps to form polymers. Several reviews have appeared on this subject. You and co-workers discussed efforts in oxidative coupling polymerization in their review in 2017,244 and Gobalasingham and Thompson reviewed advances in oxidative coupling polymerization in 2018.211

12.12.7.1 General considerations A range of metals have been employed in oxidative cross-coupling but, in polymerization, the typical metals are palladium and copper. The primary catalysts used to bring about polymerization are Pd(OAc)2 and/or Cu(OAc)2. In some cases, phosphine ligands have been used in the reaction, though it does not seem to be a strict requirement. There are quite a few choices for the solvent, oxidant and base in these reactions. Generally, researchers have employed screening approaches to identify the ideal choice of these three reaction components to maximize coupling efficiency, minimize polymer defects (arising from undesired CdH activation processes) and achieve high molecular weights. The solvent of choice is most often dimethylacetamide (DMA), which ensures the reaction can be completed at high temperature to facilitate the CdH activation reaction. Reports have appeared using other solvents such as CHCl3 or mixtures of 1,4-dioxane and DMSO. The oxidants range from molecular O2, to copper and silver salts (Cu(OAc)2 and AgOAc). Carbonate bases are used in most cases such as K2CO3, Ag2CO3 among others.211,244

12.12.7.2 Glaser-Hay coupling Oxidative coupling in polymerization has been in use for some time. The preparation of poly(2,6-dimethylphenylene oxide) was reported in 1959 by Hay and co-workers (typically called poly(phenylene oxide) or PPO).245,246 The oxidative coupling was

492

Polymerization Reactions via Cross Coupling

Fig. 44 Early examples of oxidative coupling. (A) Preparation of PPO via oxidation of 2,6-dimethylphenol. (B) preparation of poly(m-diethynylbenzene) from the 1,3-diethynylbenzene.

(A)

(B)

Fig. 45 (A) Copper catalyzed polymerization of 1,4-diethynyl-2,5-bis(decyloxy)benzene. (B) Modification on the Glaser-Hay coupling using conditions with similarities to the Sonogashira-Hagihara reaction (discussed in Section 12.12.10). Benzoquinone is the oxidant using this strategy.

accomplished with a Cu(I) catalyst, pyridine, and by passing O2 through the reaction solution at room temperature (Fig. 44A). This prompted Hay to evaluate the potential for the Cu(I) amine mixture in the coupling of acetylenes.247,248 This was a modification to the well known Glaser coupling, and Hay discovered that acetylene coupling could be accomplished in high yields in minutes with a Cu(I) salt dissolved in pyridine (now called Glaser-Hay coupling).247,248 Hay polymerized 1,3-diethynylbenzene in one of those first reports to make a tough, flexible poly(m-diethynylbenzene) film when solvent cast from nitrobenzene at 170  C (Fig. 44B).247 Poly(phenylenebutadiynylene)s or PPBs were synthesized using the Glaser-Hay approach by Shirakawa and co-workers in the late 1990s (Fig. 45A).249,250 The soluble polymers were fluorescent and semiconducting properties were observed upon doping with H2SO4. Lin and co-workers demonstrated a unique approach to PPB polymers by polymerization of 1,4-diethynyllbenzene on a Cu-functionalized mesoporous silica.251 In addition, Mecking and co-workers reported a method to synthesize fluorescent PPB nanoparticles using a variation of the Glaser-Hay coupling in miniemulsion.252 Recently, Dong, Hu, and co-workers have explored using the Glaser-Hay reaction to prepare poly(2,5-dihexyloxy-1,4-phenylenebutadiynylene) at an air/water interface.253 An alternative approach to PPBs was reported by Williams and Swager using Pd and Cu with benzoquinone as the oxidant (Fig. 45B). The mechanism of the reaction is different than the copper process, and the authors noted that random copolymerization of 1,4-diethynyl-2,5-bis(decyloxy)benzene and 1,4-diethynyl-2,5-bis(hexadecyloxy)benzene produced high molecular polymers (Mn ¼ 90 kg/mol, Đ ¼ 2.8).254 This synthetic approach was also used to build poly(iptycenebutadiynylene)s,255 and recently, a similar approach was used to make metal-containing PPBs.256

12.12.7.3 Oxidative polymerization of thiophene derivatives Thiophenes are excellent candidates for oxidative polymerization, as Mori reported on the preparation of bithiophenes using CdH activation via PdCl2(PhCN)2 with AgF as the oxidant in DMSO.257 Tsuchiya and co-workers were one of the first to look at this type of chemistry for polymerization with reports on P3HT and PEDOT (P3HT conditions shown in Fig. 46A).258 Though the polymerization was successful, high molecular weights and good yields were difficult to achieve, the regiochemistry of the alkyl groups was random along the backbone, and some undesirable activation of the 4-position of 3-hexylthiophene likely occurred. Thompson and coworkers demonstrated that thiophene-3-carboxylates were better suited for oxidative polymerization as they prepared high molecular weight poly(3-hexylesterthiophene) or P3HET using oxidative polymerization (Fig. 46B),259 and they incorporated hexylthiophene-3-carboxylate into random copolymers using oxidative polymerization.260 The directing power of the ester unit is thought to be key to improving the regioregularity and overall reactivity, as compared to the 3-hexylthiophene monomer. Another report recently expanded on the oxidative coupling approach to thiophene-based polymers, along with expansion to polyfurans and polyselenophenes .261 Collier and Reynolds illustrated that dialkylbiarylphosphine palladium

Polymerization Reactions via Cross Coupling

(A)

493

(B)

(C)

Fig. 46 (A) Catalytic oxidative polymerization of 3-hexylthiophene using palladium as the catalyst. The reaction is carried out in the presence of Cu(OAc)2, CF3CO2H and O2 as an oxidant. (B) Preparation of poly(3-hexylesterthiophene) using palladium-catalyzed oxidative coupling. The silver serves as the oxidant in this case. (C) Preparation of ProDOT via oxidative polymerization with a Pd catalyst and dialkylbiarylphosphine ligand.

catalysts could be used to promote oxidative polymerization of ProDOT very recently (Fig. 46C).262 The authors noted that use of Pd(OAc)2 paired with tBu-XPhos improved the polymer yield and molecular weight as compared to using Pd(OAc)2 alone as the catalyst (from 57% to 92% and Mn from 8.1 kg/mol to 12.5 kg/mol). Thiazole derivatives have been polymerized using the oxidative coupling approach.263,264 Trimer-type monomers were used, where substituted thiazoles flank an aryl spacer group as shown in Fig. 47.263,264 In the ester-functionalized thiazoles, silver was employed as the oxidant (Fig. 47A), while in the case of the alkylated thiazole derivatives, O2 was used as the oxidant (Fig. 47B). 5-alkyl[3,4-c]thienopyrrole-4,6-dione-based conjugated polymers have also been synthesized using oxidative coupling. Similar to the thiazole derivatives, a trimer monomer was employed to create equivalent reactive sites and ensure no defects along the backbone (Fig. 47C).265 Poly(benzimidazole)s (PBI) polymers were synthesized in 2014 using Cu(OAc)2, Ag2CO3 and O2 (Fig. 47D).266 These derivatives are quite interesting given that PBIs have been used extensively as membrane materials. Molecular weights ranging from 22.5 kg/mol (R ¼ C4H9) to 44.5 kg/mol (R ¼ C18H37) were obtained using this method. Bithiophenes and fluorinated biphenyls have also been explored in oxidative polymerization by Kanbara and Luscombe.267,268

12.12.8 Dehalogenative coupling (Yamamoto reaction) One other important type of polymerization reaction involves the direct coupling of halides, also known as the Yamamoto coupling. It is a simple, effective means to prepare conjugated polymers from readily accessible dihalide monomers. Ni(1,5-cyclooctadiene)2 (Ni(COD)2) with bipyridine (bpy) is commonly used to bring about polymerization, though nickel dihalides can also be used and reduced with Zn or Mg. This topic has been reviewed, and the reader is referred to these reports for a more in-depth description of the mechanism and types of polymers prepared using this reaction.269–271 A select few examples are shown in Fig. 48. The method is particularly well suited for polymerization of electron-poor aromatics as evidenced by the reports of poly(pyridine-2,5-diyl), poly(2,2’bipyridine-5,5’-diyl), poly(4,40 -dialkyl-2,20 -bithiazole-5,50 -diyl)s, and poly(quinoxaline-5,8-diyl)s.272–274 Many other types conjugated polymers have been prepared using this approach.269–271

12.12.9 Alkene coupling (Mizoroki-Heck reaction) Mizoroki-Heck coupling is a useful approach for constructing poly(arylene-vinylene)s (PAVs) by cross-coupling polymerization (Fig. 49). This reaction is exceptionally functional group tolerant and can be carried out under relatively mild conditions. The mechanism involves an olefin insertion and b-hydride elimination to produce alkene linkages along the polymer backbone (Fig. 49).

494

Polymerization Reactions via Cross Coupling

Fig. 47 Palladium-catalyzed oxidative polymerization of (A-B) thiazole derivatives and (C) thieno[3,4-c]pyrrole-4,6-dione derivatives. (D) Copper-catalyzed oxidative polymerization of benzobis(imidazoles).

Fig. 48 Selected examples of conjugated polymers prepared using dehalogenation polymerization.272–274

Polymerization Reactions via Cross Coupling

495

Fig. 49 (Top) General scheme for Mizoroki-Heck polycondensation of AA/BB and AB type monomers. (Bottom) General mechanism and commonly used reagents.

12.12.9.1 General considerations The synthesis of poly(p-phenylene-vinylene)s (PPVs) by Mizoroki-Heck polycondensation was first reported in the 1980s with p-bromostyrene, though the polymer had limited solubility.275 Since then, much work has been done to expand the reaction scope and refine reaction conditions. Mizoroki-Heck coupling is very reliable for forming trans linkages with few stereodefects276,277 and can be the only method to synthesize certain specialty PAVs as will be discussed below. The formation of 1,1-defects is a possibility when using the Mizoroki-Heck coupling (Fig. 50). As is this case for other polymer systems, defects can impact chain conformation, and therefore influence a material’s optoelectronic properties and solid-state organization. Heitz and co-workers have conducted in-depth model studies to illustrate how the choice of the electrophilic leaving groups, substituents on the arene, and choice of olefin influence the ratio of 1,2- vs 1,1-substitution.277,278 The most common catalyst system for this reaction is Pd(OAc)2 paired with the P(o-tolyl)3 ligand. While other phosphines such as PPh3 have been explored, they show inferior reactivity in many cases. Heck has illustrated that the rate of formation of 2-methylstyrene from 2-bromotoluene and ethylene is twice as fast using P(o-tolyl)3 in comparison to PPh3.279 Lastly, numerous amine bases have been used successfully for Mizoroki-Heck coupling, and the most common solvents are DMF or DMA.

Fig. 50 Defect possibility in formation of poly(para-phenylenevinylenes) using Mizoroki-Heck coupling.

496

Polymerization Reactions via Cross Coupling

Fig. 51 Example reaction conditions for Heck type polycondensations from (A) from dihaloarenes and divinylarenes (AA/BB type monomers) and (B) halovinylarenes (AB type monomer). (C) Synthesis of a regioregular poly(2-dodecyloxy-1,4-phenylenevinylene).

12.12.9.2 Polymers synthesized via Mizoroki-Heck polycondensation Mizoroki-Heck polycondensation using ethylene as the olefinic building block is attractive due to ethylene’s low cost.278,280 However, since the reaction proceeds by a step-growth mechanism, the stoichiometry of the gas must be strictly controlled. Given this, PPVs are often prepared through AA/BB coupling of dihalo- and divinylarenes. A dodecyloxy PPV derivative, for example, can be prepared in 87% yield after only 5 h, with an Mn value of 21.8 kg/mol (Fig. 51A).281 PPV polymers can also be prepared via AB polymerization of bromostyrene derivatives as shown in Fig. 51B.282 Although many monomers used to synthesize PPVs via Heck polycondensation have two solubilizing chains, it is also possible to polymerize monomers with only a single side chain. For example, Lahti and co-workers reported the synthesis of regioregular poly(2dodecyloxy-1,4-phenylenevinylene) using Pd(OAc)2, phosphine ligand, and tributylamine in DMF (Fig. 51C).283 The choice of phosphine ligand was found to make a significant difference in the resulting degree of polymerization, as PPh3 produced an Mn of only 0.5 kg/mol (Ɖ ¼ 2.0), while P(o-tolyl)3 produced an Mn of 8.2 kg/mol (Ɖ ¼ 2.9). The mild reaction conditions and broad functional group tolerance of Heck polycondensation have also led to the development of advanced functional materials. For example, in 1996 Yu and co-workers reported a PPV that included a bipyridine unit, which was used to incorporate a Ru complex into the polymer chain (Fig. 52A).284 This monomer was copolymerized with 1,4-bis(hexyloxy)-2,5-diiodobenzene and 1,4-divinylbenzene in varying ratios using Pd(OAc)2, P(o-tolyl)3 and tributylamine in DMF. Interestingly, polymerization of the bipyridinyl monomer without the Ru did not proceed, presumably due to coordination of the Pd catalyst. Yu and co-workers later showed that analogous polymers with Os complexes could also be synthesized,285 as well as Ru containing polymers with mixed ligands,286 both of which led to modified optoelectronic properties (Fig. 52B). Yu has also shown that, using similar reaction conditions, Heck polycondensation can be used to synthesize photorefractive PPVs containing metalloporphyrin complexes (Fig. 52C).287–289 Mizoroki-Heck polycondensation has also been used to synthesis dendritic PPVs. For example, Park and co-workers reported the polymerizations of both 1-bromo-3,5-divinylbenzene and 1-bromo-2,4-divinylbenzene using Pd(OAc)2 and P(o-tolyl)3.290 With the 1,2,4 substituted monomer, an Mn of 2.2 kg/mol (Ɖ ¼ 1.7) was achieved after 3 h, and 4.7 kg/mol (Ɖ ¼ 4.4) was achieved after 24 h (Fig. 53). The 1,3,5 substituted monomer was reported to have a higher Mn after 3 h, at 3.3 kg/mol.

Polymerization Reactions via Cross Coupling

497

(A)

(B)

(C)

Fig. 52 (A-B) Polymerization of Ru(bpy) complexes by Heck polycondensation. (C) Metalloporphyrin containing PPV synthesized by Heck polycondensation.

12.12.10

Alkyne coupling (Sonogashira-Hagihara reaction)

Sonogashira-Hagihara coupling is used to construct CdC bonds between sp2 and sp carbon centers as shown in the general scheme below (Fig. 54). A copper acetylide, formed from the combination of a terminal alkyne, amine and a copper source, serves as the nucleophilic coupling partner (Fig. 54). Poly(arylene ethynylene)s (PAEs), are the most common class of conjugated polymer prepared using this reaction (Fig. 54). These materials can be highly fluorescent, which has made them attractive in sensing applications.291,292 The reader is directed to reviews,293–295 a book,296 as well as a book chapter297 for in-depth descriptions of this vast research area.

498

Polymerization Reactions via Cross Coupling

Fig. 53 Dendritic PPVs prepared using a Heck polymerization strategy.

Fig. 54 (Top) Formation of poly(arylene ethylene) type polymers via cross-coupling of AA/BB type and AB type monomers. (Bottom) General mechanism of Sonogashira-Hagihara polycondensation, along with typical catalysts, bases, and copper source.

12.12.10.1

General considerations

PPh3-ligated palladium catalysts are commonly used to produce PAEs,293–295 and both Pd(PPh3)4 and Pd(PPh3)2Cl2 are often used as precatalysts. Dihalide salts such as Pd(PPh3)2Cl2 must undergo reduction prior to entering the catalytic cycle for polymerization. The reduction is accomplished with two equivalents of the nucleophilic coupling partner (copper acetylide), producing a diyne unit which will be incorporated into the polymer chain. A slight excess of the bisalkyne monomer can be used to compensate for the palladium reduction. Swager has also shown that a slight excess of the alkyne coupling partner is important to produce high molecular weights when using Pd(PPh3)4 as well.298 Recent reports describing the use of PtBu3-based catalysts for Sonogashira polymerization have appeared recently.299–301 CuI is used as the copper source in most instances for this type of polymerization. O2 and Cu2+ impurities can also result in alkyne-alkyne homocoupling, producing diyne defects within the polymer chain.248 The efficiency of Sonogashira-Hagihara coupling is highly dependent on the choice of amine, which can serve as the reaction solvent in some cases.293-295,302–304

Polymerization Reactions via Cross Coupling

499

Fig. 55 Side-chain regiochemistry possibilities. If R and R’ are the same, then polymers are all head-to-tail (ht). If R 6¼ R’, this can impact regularity along the chain.

In an AA/BB polymerization, when R groups are equivalent (R¼ R’ in Fig. 55), the symmetry ensures that no regiodefects arise. However inequivalent R groups on the same arene can lead to HT and HH linkages as shown in Fig. 55. Collard has demonstrated that differences in molecular assembly and electronic properties arise for regiorandom and regioregular poly(1,4-phenyleneethynylene)s (PPEs),305 indicating choice of monomer is important when two different substituents are present on the arene monomers.

12.12.10.2

Typical synthetic approach to PAEs

The most common synthetic strategy to prepare PAEs is shown in Fig. 56. A dihalide monomer is converted to a bisacetylene monomer with trimethylsilylacetylene in a Sonogashira-Hagihara reaction (Fig. 56A). The silyl groups are removed via deprotection, prior to reaction with Pd(PPh3)4 or Pd(PPh3)2Cl2 catalysts. The silyl groups can also be deprotected in situ during polymerization,306–308 which is advantageous as it is the rate-determining step, keeping the effective concentration of the active alkyne coupling partner low in the reaction mixture. This minimizes formation of diyne defects within the polymer chain.306 Interestingly, copper was not required for the coupling reaction in this instance.306 AB type monomers can be synthesized in a similar manner and subsequently polymerized (Fig. 56B). Acetylene gas has also been explored as a comonomer.309–311 This synthetic approach is quite powerful, as it removes the need for a coupling step to attach alkynes to the arene monomer. Bunz illustrated that this can be accomplished with very high DPs as is shown in Fig. 56C (DPn ¼ 259 with R ¼ 2-ethylhexyl).309 Recently, CaC2 was employed as a replacement for acetylene,312 and it requires no special setup since gaseous reagents are not used. A DPn ¼ 48 was obtained with octyloxy groups on the benzene

Fig. 56 Strategies for Sonogashira-Hagihara polymerization to prepare PAEs. For C, the amount of acetylene gas is normally measured, and the reactions are carried out with an atmosphere of acetylene (balloon).

500

Polymerization Reactions via Cross Coupling

Fig. 57 Left - In-situ deprotection of the TMS group to produce poly(meta-phenylene ethynylenes). The water in the reaction mixture is used to help facilitate silyl group deprotection. The reaction is conducted at room temperature (RT) or under microwave heating (MW). Right – reaction of 1,3-diiodobenzene derivative with trimethylsilylacetylene.

monomer, using palladium acetate (Pd(OAc)2) and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as the base (Fig. 56D). The same group also recently reported using a heterogeneous catalyst (Pd/CaCO3) for Sonogashira coupling to simplify polymer purification.313 Following the work of Heitz,306 Hecht reported on an AB’ or an AA/BB’ approach to poly(meta-phenylene ethynylene)s using in situ deprotection of the trimethylsilyl acetylene unit (Fig. 57).307 The polymerization could be accomplished from the AB monomer (left in Fig. 57), or by combination of the diiodoarene with TMS-acetylene under similar conditions (right in Fig. 57). Hecht illustrated that microwave heating could promote the reaction and prepared both meta and para-linked polymers using this approach.307,308 Ortho-phenylene ethynylenes have been synthesized using a similar silyl deprotection.314

12.12.10.3

PAE variants synthesized using Sonogashira-Hagihara polymerization

A wide range of arenes can be polymerized using Sonogashira-Hagihara coupling, ranging from simple aromatics and heteroaromatics, to more complicated polycyclic aromatic hydrocarbons and organometallic complexes (Fig. 58).293-295,302–304 Given the vast numbers of reports of Sonogashira-Hagihara, a few select examples are highlighted below in Fig. 58 to illustrate the structural versatility possible using this polymerization strategy. Iptycenes have been employed as a three-dimensional design element in a number of polymer materials.315 Swager and co-workers illustrated that iptycene-based PAEs could be synthesized, and that these bulky arene scaffolds afford excellent solution processability while preventing efficient p-stacking of the polymers in the solid.316,317 This prevented aggregation-induced fluorescence quenching, which is key for their use in sensing.

Fig. 58 Selected examples of polymers synthesized using the Sonogashira-Hagihara approach.

Polymerization Reactions via Cross Coupling

501

The Sonogashira-Hagihara reaction can often be conducted with metals or with a wide range of main group elements present in the monomer structure to afford hybrid organic-inorganic polymers. Salphen-based PAEs were developed in the early 2000s by MacLachlan and co-workers,318 and the zinc porphyrin PAEs prepared by Yamamoto (Fig. 58).319 Further discussions of some of the extensive work on organometallic PAEs can be found in reviews by Klemm and Yamamoto.303,304 In addition to metal-containing polymers, heteroatom containing PAEs also have benefits, such as the quinoxaline-based polymer described by Bunz and co-workers (Fig. 58).320 The review by Yamamoto thoroughly examines the different types of electron-acceptor based PAEs.304

12.12.10.4

Chain-growth polymerization for PAEs

In 2013, Bielawski was the first to describe chain-growth polymerization of an aryl ethynylene monomer (Fig. 59A).299 Monomers bearing an acetylene or a tributylstannylacetylene were used in the polymerization as shown in Fig. 59A. Polymerization with tBu3PPd(Ph)Br was effective in both cases, though improved yields and higher molecular weights were noted using the stannylated monomer. The authors noted the importance of additional PPh3 in the reaction mixture to ensure a chain-growth process. Bielawski expanded on this work, preparing both meta and para-phenylene polymers,300 and PPE-block-isocyanides have also been reported recently.300 Schanze and co-workers have explored water and alcohol soluble PAEs as sensors under aqueous conditions for amplified sensing of chemical and biological analytes.321–323 Recently they reported on PPEs prepared using chain-growth polymerization (Fig. 59B).301 The polymers bore pendent sulfonate ester groups that could be deprotected to form charged sulfonate groups.301 The authors prepared polymers using both step (AA/BB) and chain-growth (AB) approaches to explore how this impacts polymer properties. While they noted that that high molecular weight polymers could not be achieved via chain-growth, these derivatives had higher fluorescence quantum yields and better-resolved spectra, suggesting that the chains are comparatively defect-free relative to the step-growth samples.

12.12.11

Amine coupling (Buchwald-Hartwig amination reaction)

The cross-coupling of aryl halides and amines serves as a straightforward strategy to construct Csp2dN bonds. The coupling of secondary amines with aryl halides was first reported in 1995,324,325 with reports to make poly(arylamines) appearing not long after.326–329

Fig. 59 Strategies for chain-growth polymerization using Sonogashira-Hagihara coupling.

502

Polymerization Reactions via Cross Coupling

12.12.11.1

General considerations

Kanbara and co-workers copolymerized 1,3-dibromobenzene and 1,3-phenylenediamine using Pd2dba3 and BINAP, with NaOtBu as the base and toluene as the solvent as shown in Fig. 60A (yield ¼ 86%, Mn ¼ 20.1 kg/mol).327 Kanbara then reported a strategy to incorporate an azobenzene photoswitch into the poly(m-aniline) by a similar approach but with the PtBu3 ligand in place of BINAP (Fig. 60B).329 Generally, the phosphines employed in Buchwald-Hartwig amination polymerization include: BINAP, DPPF, PtBu3, and various dialkylbiarylphosphines. A non-nucleophilic bulky base is common in these reactions (e.g. NaOtBu or KOtBu). The solvent for polymerization can vary (e.g. toluene, THF, DMF), and the reaction is typically carried out at higher temperatures.

12.12.11.2

AA/BB and AB approaches to polyarylamines

330,331

Hartwig, Meyer332,333 and Buchwald334 reported on a series of polyanilines variants between 1998 and 2000. Hartwig and co-workers evaluated the choice of ligands for the amination of several aryl dihalides to form triarylamine polymers.330,331 The authors noted that P(C6H4-o-OMe)3 and PtBu3 led to quantitative amination. The authors also noted that competing cyclization was an issue limiting the polymer molecular weight, and oligomeric monomers were used to suppress this issue. Cyclic by-products could also be removed using column chromatography. Meyer and co-workers used Pd2dba3 and BINAP to build linear and hyperbranched poly(m-anilines) (Fig. 61A), though they noted some difficulties removing contaminants from the reaction (e.g. BINAP, salts).332 They also found that GPC estimation of molecular weight was different depending on the choice of mobile phase (NMP vs THF). GPC measurements in NMP routinely (A)

(B)

Fig. 60 Preparation of poly(m-anilines) using Buchwald-Hartwig amination.

Fig. 61 (A) Preparation of linear and hyperbranched m-polyanilines. (B) end capping strategy to prepare poly(triarylamines) from 4,4’-dibromo-1,1’-biphenyl and 4-octylaniline.

Polymerization Reactions via Cross Coupling

503

produced higher molecular weight estimates, which was attributed to the polyaniline chain being more extended (larger radius of gyration) in this solvent. The measured dispersity of the polymer is also much higher in this solvent, suggesting this may not be the best medium to solubilize these materials. Though molecular weight measurements in THF were lower, the authors concluded that these were more accurate estimates based on DPn predictions from elemental analysis. Kanbara recently noted that anisole was a better solvent for removing contaminants in polyanilines by Soxhlet extraction as compared to CHCl3.335 Moreover, they utilized an end capping strategy to prepare amine-based polymers with no Br or N-H endgroups (Fig. 61B).335 The Br and N-H termini can be problematic in amine-based polymers, as oxidation can result in side reactions with these functional groups present. Buchwald and co-workers reported on the synthesis of a p-polyaniline (PANI) derivative in 2000.334 They used a Boc-protected dimeric monomer to produce the desired polymer, as shown in Fig. 62. The authors noted that the most straightforward synthesis of the polymer would be from 1,4-dibromobenzene and 1,4-phenylenediamine, but this approach only produced low-molecular weight materials with poor solubility. In contrast, the dimer strategy as outlined in Fig. 62 afforded high molecular weight polymers in excellent yield (e.g., 1.0 M in THF with 1 mol% Pd, produced Boc-PANI with an Mn of 19.2 kg/mol in 96% yield). The Boc-PANI is soluble in common organic solvents and can be deprotected to form PANI using thermolysis or protonolysis. The authors noted that the monomer synthesis was straightforward, could be completed on large scale and did not require chromatographic purification steps. The dialkylbiarylphosphine ligand paired with Pd also served as a highly effective catalyst for the amination polymerization. This was one of the first reports using this important class of phosphine ligand in polymerization. Other reports have also appeared since then using Boc-protection approaches to polyaniline-type materials.333,337 Müllen reported on a series of aromatic poly(imino ketone)s (PIKs) using the Pd catalyzed amination of aryl halides. The structure resembles both a poly(arylene ether ketone)s (PEKs) and PANI (Fig. 63).336 In this sense, the polymer is a hybrid structure derived from these two polymer backbones and is of interest as a performance thermoplastic. In their work, the Pd precursor and ligand were kept the same (Pd2dba3 and BINAP), but they employed both dimethylacetamide (DMA) and diphenylsulfone (DPS) as the solvents. In the DMA case, the reaction was heated to 100  C for 4 h followed by heating to 165  C for 20 h. In DPS, the reaction was carried out at 165  C for 4 h and 200  C for 20 h. LiCl was also added to break up H-bonding interactions and chain aggregation. The polymer solubility depended on the solvent, the molecular weight, and choice of Ar unit (Fig. 63). Mn values ranged from 11.1 to 85.9 kg/mol while yields were typically >80%.

Fig. 62 Preparation of Boc-protected polyaniline (Boc-PANI).

Fig. 63 Hybrid polymers composed of poly(arylene ether ketone) (PEK) and polyaniline (PANI) like segments, prepared using Pd-catalyzed amination reactions.

504

Polymerization Reactions via Cross Coupling

Fig. 64 Microwave assisted polycondensation for synthesis of poly(triarylamine)s.

In 2007, Turner and co-workers developed a microwave heating route to polytriarylamines (Fig. 64).338 They noted that palladium-catalysed amination of 4,4’-dibromobiphenyl with 2,4-dimethylaniline is completed in 5 min when conducted at 100  C.338 They also discovered that prolonged heating under these conditions resulted in lower molecular weight polymers, presumably due to polymer degradation or depolymerization.338 End capping reactions were also carried out to remove bromo and NdH end groups. This approach was also used in 2008 to produce triarylamine polymers for OFETs,339 and more recently to prepare a variety of polytriarylamines.340

12.12.11.3

Dehalogenative polymerization to synthesize polyanilines

Yamamoto and co-workers employed a dehalogenative polycondensation approach to poly(arylamines) using a Ni(0) source.341 This strategy is attractive as noted in the above sections for the overall simplicity of the reaction. Interestingly, a phenyl and pyridyl group could be used in the coupling to make a polyphenylamine or a polypyridylamine (Fig. 65). The number-average molecular weights estimated by GPC versus polystyrene standards were lower than 7 kg/mol, but light scattering analysis of the pyridyl polymer indicated an Mw of 44 kg/mol in CHCl3.341 The larger Mw value by light scattering method as compared with that estimated from GPC method (Mw ¼ 16.4 kg/mol) suggested either an interaction of the polymer with the stationary phase during chromatography and/or partial aggregation of the polymer in the static solution used for the light scattering analysis.341

12.12.11.4

Polyanilines prepared by chain-growth polymerization

In 2019, Grisorio and Suranna reported the first example of a chain-growth polymerization to synthesize triarylamine polymers using an AB type monomer.342 The monomer was comprised of a 9,9-dialkylfluorene unit with a pendant diarylamine (Fig. 66). An externally initiated catalyst was used to bring about polymerization (tBu3PPd(Ph)I) with NaOtBu as the base in THF.

Fig. 65 Dehalogenative polycondensation approach to poly(arylamine) derivatives.

Fig. 66 Example of chain-growth polymerization of an AB-type monomer for preparation of a triarylamine-based polymer.

Polymerization Reactions via Cross Coupling

505

Polymerizations at 60  C produced polymer samples with high dispersities suggesting chain-transfer events were occurring. Lower reaction temperatures resulted in narrower molecular weight distributions while still ensuring the polymerization would proceed to high conversion. Reductive elimination was identified as the rate-determining step, and computational studies were used to better understand the elementary steps and transition states along the reaction coordinate.

12.12.12

Conclusions

Cross-coupling polymerization is a powerful tool to synthesize a wide variety of macromolecules. Over the past decade, there have been significant advances in catalyst development with an enhanced understanding of the key factors to optimize polymer synthesis. Moving forward, one can imagine a wide range of novel materials will be possible from further advances in polymer design and synthesis. The form and function of conjugated polymers are made possible by the diverse synthetic techniques described in the above sections. In the past ten years, efforts have trended towards more atom economical conjugated polymer synthesis, with direct arylation and oxidative coupling garnering a great deal of attention. Selective and efficient C-H activation remains a key aspect of this work, with many exciting advances to come.

Acknowledgments The authors are grateful to NSF for support of their work in synthetic polymerization techniques (CHE-1455136) and to the Army Research Office for supporting their work on sequence control in polymers (W911NF-16-1-0053). A. J. Varni performed a portion of their editing work under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. IM release number: LLNL-JRNL-829639.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

Brabec, C., Dyakonov, V., Scherf, U., Eds.; In Organic Photovoltaics: Materials, Device Physics, and Manufacturing Technologies; Wiley-VCH: Weinheim, Germany, 2008. Li, G.; Chang, W.-H.; Yang, Y. Nat. Rev. Mater. 2017, 2, 17043. Shinar, J., Ed.; In Organic Light-Emitting Devices: A Survey; Springer-Verlag: New York, NY, 2004. Grimsdale, A. C.; Leok Chan, K.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chem. Rev. 2009, 109, 897–1091. Mei, J.; Leung, N. L. C.; Kwok, R. T. K.; Lam, J. W. Y.; Tang, B. Z. Chem. Rev. 2015, 115, 11718–11940. Roberts, M. E.; Sokolov, A. N.; Bao, Z. J. Mater. Chem. 2009, 19, 3351–3363. Lin, P.; Yan, F. Adv. Mater. 2012, 24, 34–51. Someya, T.; Dodabalapur, A.; Huang, J.; See, K. C.; Katz, H. E. Adv. Mater. 2010, 22, 3799–3811. McQuade, D. T.; Pullen, A. E.; Swager, T. M. Chem. Rev. 2000, 100, 2537–2574. Zhang, G.; Lan, Z.-A.; Wang, X. Angew. Chem. Int. Ed. 2016, 55, 15712–15727. Hammock, M. L.; Chortos, A.; Tee, B. C.-K.; Tok, J. B.-H.; Bao, Z. Adv. Mater. 2013, 25, 5997–6037. Schwartz, G.; Tee, B. C.-K.; Mei, J.; Appleton, A. L.; Kim, D. H.; Wang, H.; Bao, Z. Nat. Commun. 1859, 2013, 4. Yang, J. C.; Mun, J.; Kwon, S. Y.; Park, S.; Bao, Z.; Park, S. Adv. Mater. 2019, 31, 1904765. Reynolds, J. R., Thompson, B. C., Skotheim, T. A., Eds.; In Handbook of Conducting Polymers Volume 1: Conjugated Polymers: Perspective, Theory, and New Materials; CRC Press: Boca Raton, FL, 2019. Reynolds, J. R., Thompson, B. C., Skotheim, T. A., Eds.; In Handbook of Conducting Polymers Volume 2: Conjugated Polymers: Properties, Processing and Applications; CRC Press: Boca Raton, FL, 2019. Leclerc, M., Morin, J.-F., Eds.; In Synthetic Methods for Conjugated Polymers and Carbon Materials; Wiley-VCH: Weinheim, Germany, 2017. Müllen, K., Reynolds, J. R., Masuda, T., Eds.; In Conjugated Polymers: A Practical Guide to Synthesis; Royal Society of Chemistry: Cambridge, UK, 2011. Leclerc, M., Morin, J.-F., Eds.; In Design and Synthesis of Conjugated Polymers; Wiley-VCH: Weinheim, Germany, 2010. Chujo, Y., Ed.; In Conjugated Polymer Synthesis: Methods and Reactions; Wiley-VCH: Weinheim, Germany, 2010. Odian, G. Principles of Polymerization, 4th edn.; Wiley-Interscience: Hoboken, NJ, 2004. Baker, M. A.; Tsai, C.-H.; Noonan, K. J. T. Chem.-Eur. J. 2018, 24, 13078–13088. Verheyen, L.; Leysen, P.; Van den Eede, M.-P.; Ceunen, W.; Hardeman, T.; Koeckelberghs, G. Polymer 2017, 108, 521–546. Yokozawa, T.; Ohta, Y. Chem. Rev. 2016, 116, 1950–1968. Leone, A. K.; McNeil, A. J. Acc. Chem. Res. 2016, 49, 2822–2831. Grisorio, R.; Suranna, G. P. Polym. Chem. 2015, 6, 7781–7795. Bryan, Z. J.; McNeil, A. J. Macromolecules 2013, 46, 8395–8405. Okamoto, K.; Luscombe, C. K. Polym. Chem. 2011, 2, 2424–2434. Yokozawa, T.; Yokoyama, A. Chem. Rev. 2009, 109, 5595–5619. Yamamoto, T.; Yamamoto, A. Chem. Lett. 1977, 353–356. Yamamoto, T.; Hayashi, Y.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1978, 51, 2091–2097. Yamamoto, T.; Sanechika, K.; Hayashi, Y.; Yamamoto, A. Polym. Sci. Part C: Polym. Lett. 1979, 17, 181–184. Kiriy, A.; Senkovskyy, V.; Sommer, M. Macromol. Rapid Commun. 2011, 32, 1503–1517. Geng, Y.; Huang, L.; Wu, S.; Wang, F. Sci. China Chem. 2010, 53, 1620–1633. Osaka, I.; McCullough, R. D. Acc. Chem. Res. 2008, 41, 1202–1214. Osaka, I.; McCullough, R. D. Regioregular and Regiosymmetric Polythiophenes. In Conjugated Polymer Synthesis: Methods and Reactions; Chujo, Y., Ed.; Wiley-VCH: Weinheim, Germany, 2010;; pp 59–90. McCullough, R. D. The Chemistry of Conducting Polythiophenes: From Synthesis to Self-Assembly to Intelligent Materials. In Handbook of Oligo- and Polythiophenes; Fichou, D., Ed.; Wiley-VCH: Weinheim, Germany, 1998.

506

37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105.

Polymerization Reactions via Cross Coupling

Yamamoto, T.; Sanechika, K.; Yamamoto, A. J. Polym. Sci. Part C: Polym. Lett. 1980, 18, 9–12. Lin, J. W.-P.; Dudek, L. P. J. Polym. Sci. Part A: Polym. Chem. 1980, 18, 2869–2873. Kobayashi, M.; Chen, J.; Chung, T.-C.; Moraes, F.; Heeger, A. J.; Wudl, F. Synth. Met. 1984, 9, 77–86. Jen, K. Y.; Miller, G. G.; Elsenbaumer, R. L. J. Chem. Soc. Chem. Commun. 1986, 1346–1347. Elsenbaumer, R. L.; Jen, K. Y.; Oboodi, R. Synth. Met. 1986, 15, 169–174. McCullough, R. D.; Lowe, R. D. J. Chem. Soc. Chem. Commun. 1992, 70–72. McCullough, R. D.; Lowe, R. D.; Jayaraman, M.; Ewbank, P. C.; Anderson, D. L.; Tristram-Nagle, S. Synth. Met. 1993, 55, 1198–1203. McCullough, R. D.; Lowe, R. D.; Jayaraman, M.; Anderson, D. L. J. Org. Chem. 1993, 58, 904–912. Chen, T. A.; Rieke, R. D. J. Am. Chem. Soc. 1992, 114, 10087–10088. Loewe, R. S.; Khersonsky, S. M.; McCullough, R. D. Adv. Mater. 1999, 11, 250–253. Bahri-Laleh, N.; Poater, A.; Cavallo, L.; Mirmohammadi, S. A. Dalton Trans. 2014, 43, 15143–15150. Tkachov, R.; Senkovskyy, V.; Komber, H.; Kiriy, A. Macromolecules 2011, 44, 2006–2015. Loewe, R. S.; Ewbank, P. C.; Liu, J.; Zhai, L.; McCullough, R. D. Macromolecules 2001, 34, 4324–4333. Shibuya, Y.; Nakagawa, N.; Miyagawa, N.; Suzuki, T.; Okano, K.; Mori, A. Angew. Chem. Int. Ed. 2019, 58, 9547–9550. Iovu, M. C.; Sheina, E. E.; Gil, R. R.; McCullough, R. D. Macromolecules 2005, 38, 8649–8656. Sheina, E. E.; Liu, J.; Iovu, M. C.; Laird, D. W.; McCullough, R. D. Macromolecules 2004, 37, 3526–3528. Miyakoshi, R.; Yokoyama, A.; Yokozawa, T. J. Am. Chem. Soc. 2005, 127, 17542–17547. Yokoyama, A.; Miyakoshi, R.; Yokozawa, T. Macromolecules 2004, 37, 1169–1171. Miyakoshi, R.; Yokoyama, A.; Yokozawa, T. Macromol. Rapid Commun. 2004, 25, 1663–1666. Scherf, U.; Gutacker, A.; Koenen, N. Acc. Chem. Res. 2008, 41, 1086–1097. Lee, Y.; Gomez, E. D. Macromolecules 2015, 48, 7385–7395. Yassar, A.; Miozzo, L.; Gironda, R.; Horowitz, G. Prog. Polym. Sci. 2013, 38, 791–844. Tkachov, R.; Senkovskyy, V.; Komber, H.; Sommer, J.-U.; Kiriy, A. J. Am. Chem. Soc. 2010, 132, 7803–7810. Beryozkina, T.; Senkovskyy, V.; Kaul, E.; Kiriy, A. Macromolecules 2008, 41, 7817–7823. Leone, A. K.; Goldberg, P. K.; McNeil, A. J. J. Am. Chem. Soc. 2018, 140, 7846–7850. He, W.; Patrick, B. O.; Kennepohl, P. Nat. Commun. 2018, 9, 3866. Bridges, C. R.; McCormick, T. M.; Gibson, G. L.; Hollinger, J.; Seferos, D. S. J. Am. Chem. Soc. 2013, 135, 13212–13219. Sontag, S. K.; Bilbrey, J. A.; Huddleston, N. E.; Sheppard, G. R.; Allen, W. D.; Locklin, J. J. Org. Chem. 2014, 79, 1836–1841. Mikami, K.; Nojima, M.; Masumoto, Y.; Mizukoshi, Y.; Takita, R.; Yokozawa, T.; Uchiyama, M. Polym. Chem. 2017, 8, 1708–1713. Zhang, T.-X.; Li, Z. Comput. Theor. Chem. 2013, 1016, 28–35. Kozuch, S.; Martin, J. M. L. Chem. Commun. 2011, 47, 4935–4937. McMullin, C. L.; Fey, N.; Harvey, J. N. Dalton Trans. 2014, 43, 13545–13556. Bilbrey, J. A.; Bootsma, A. N.; Bartlett, M. A.; Locklin, J.; Wheeler, S. E.; Allen, W. D. J. Chem. Theory Comput. 2017, 13, 1706–1711. Pollit, A. A.; Ye, S.; Seferos, D. S. Macromolecules 2020, 53, 138–148. McKeown, G. R.; Ye, S.; Cheng, S.; Seferos, D. S. J. Am. Chem. Soc. 2019, 141, 17053–17056. Ye, S.; Cheng, S.; Pollit, A. A.; Forbes, M. W.; Seferos, D. S. J. Am. Chem. Soc. 2020, 142, 11244–11251. Leone, A. K.; Mueller, E. A.; McNeil, A. J. J. Am. Chem. Soc. 2018, 140, 15126–15139. Lanni, E. L.; McNeil, A. J. J. Am. Chem. Soc. 2009, 131, 16573–16579. Lanni, E. L.; McNeil, A. J. Macromolecules 2010, 43, 8039–8044. Bryan, Z. J.; Smith, M. L.; McNeil, A. J. Macromol. Rapid Commun. 2012, 33, 842–847. Verswyvel, M.; Verstappen, P.; De Cremer, L.; Verbiest, T.; Koeckelberghs, G. J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 5339–5349. Wu, S.; Bu, L.; Huang, L.; Yu, X.; Han, Y.; Geng, Y.; Wang, F. Polymer 2009, 50, 6245–6251. Yokoyama, A.; Kato, A.; Miyakoshi, R.; Yokozawa, T. Macromolecules 2008, 41, 7271–7273. Willot, P.; Govaerts, S.; Koeckelberghs, G. Macromolecules 2013, 46, 8888–8895. Kohn, P.; Huettner, S.; Komber, H.; Senkovskyy, V.; Tkachov, R.; Kiriy, A.; Friend, R. H.; Steiner, U.; Huck, W. T. S.; Sommer, J.-U.; Sommer, M. J. Am. Chem. Soc. 2012, 134, 4790–4805. Bronstein, H. A.; Luscombe, C. K. J. Am. Chem. Soc. 2009, 131, 12894–12895. Miyakoshi, R.; Shimono, K.; Yokoyama, A.; Yokozawa, T. J. Am. Chem. Soc. 2006, 128, 16012–16013. Qiu, Y.; Fortney, A.; Tsai, C.-H.; Baker, M. A.; Gil, R. R.; Kowalewski, T.; Noonan, K. J. T. ACS Macro Lett. 2016, 5, 332–336. Heeney, M.; Zhang, W.; Crouch, D. J.; Chabinyc, M. L.; Gordeyev, S.; Hamilton, R.; Higgins, S. J.; McCulloch, I.; Skabara, P. J.; Sparrowe, D.; Tierney, S. Chem. Commun. 2007, 5061–5063. Fortney, A.; Tsai, C.-H.; Banerjee, M.; Yaron, D.; Kowalewski, T.; Noonan, K. J. T. Macromolecules 2018, 51, 9494–9501. Jahnke, A. A.; Djukic, B.; McCormick, T. M.; Domingo, E. B.; Hellmann, C.; Lee, Y.; Seferos, D. S. J. Am. Chem. Soc. 2013, 135, 951–954. Luppi, B. T.; McDonald, R.; Ferguson, M. J.; Sang, L.; Rivard, E. Chem. Commun. 2019, 55, 14218–14221. Jeffries-EL, M.; Kobilka, B. M.; Hale, B. J. Macromolecules 2014, 47, 7253–7271. Ye, S.; Steube, M.; Carrera, E. I.; Seferos, D. S. Macromolecules 2016, 49, 1704–1711. Pammer, F.; Passlack, U. ACS Macro Lett. 2014, 3, 170–174. Pammer, F.; Jäger, J.; Rudolf, B.; Sun, Y. Macromolecules 2014, 47, 5904–5912. Fujita, K.; Sumino, Y.; Ide, K.; Tamba, S.; Shono, K.; Shen, J.; Nishino, T.; Mori, A.; Yasuda, T. Macromolecules 2016, 49, 1259–1269. Wen, L.; Duck, B. C.; Dastoor, P. C.; Rasmussen, S. C. Macromolecules 2008, 41, 4576–4578. Pollit, A. A.; Obhi, N. K.; Lough, A. J.; Seferos, D. S. Polym. Chem. 2017, 8, 4108–4113. Hollinger, J.; Seferos, D. S. Macromolecules 2014, 47, 5002–5009. Segalman, R. A.; McCulloch, B.; Kirmayer, S.; Urban, J. J. Macromolecules 2009, 42, 9205–9216. Hollinger, J.; Jahnke, A. A.; Coombs, N.; Seferos, D. S. J. Am. Chem. Soc. 2010, 132, 8546–8547. Javier, A. E.; Varshney, S. R.; McCullough, R. D. Macromolecules 2010, 43, 3233–3237. Willot, P.; Moerman, D.; Leclère, P.; Lazzaroni, R.; Baeten, Y.; Van der Auweraer, M.; Koeckelberghs, G. Macromolecules 2014, 47, 6671–6678. Senkovskyy, V.; Tkachov, R.; Beryozkina, T.; Komber, H.; Oertel, U.; Horecha, M.; Bocharova, V.; Stamm, M.; Gevorgyan, S. A.; Krebs, F. C.; Kiriy, A. J. Am. Chem. Soc. 2009, 131, 16445–16453. Fuji, K.; Tamba, S.; Shono, K.; Sugie, A.; Mori, A. J. Am. Chem. Soc. 2013, 135, 12208–12211. Shono, K.; Sumino, Y.; Tanaka, S.; Tamba, S.; Mori, A. Org. Chem. Front. 2014, 1, 678–682. Carsten, B.; He, F.; Son, H. J.; Xu, T.; Yu, L. Chem. Rev. 2011, 111, 1493–1528. Zheng, T.; Schneider, A. M.; Yu, L. Stille Polycondensation: A Versatile Synthetic Approach to Functional Polymers. In Synthetic Methods for Conjugated Polymers and Carbon Materials; Leclerc, M., Morin, J.-F., Eds.; Wiley-VCH: Weinheim, Germany, 2017;; pp 1–58.

Polymerization Reactions via Cross Coupling

106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173.

507

Bao, Z.; Chan, W. K.; Yu, L. J. Am. Chem. Soc. 1995, 117, 12426–12435. Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595. Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343–6348. Dowlut, M.; Mallik, D.; Organ, M. G. Chem. Eur. J. 2010, 16, 4279–4283. Cordovilla, C.; Bartolomé, C.; Martínez-Ilarduya, J. M.; Espinet, P. ACS Catal. 2015, 5, 3040–3053. Bao, Z.; Chan, W.; Yu, L. Chem. Mater. 1993, 5, 2–3. Yu, L.; Bao, Z.; Cai, R. Angew. Chem. Int. Ed. 1993, 32, 1345–1347. Zhan, X.; Tan, Z.; Domercq, B.; An, Z.; Zhang, X.; Barlow, S.; Li, Y.; Zhu, D.; Kippelen, B.; Marder, S. R. J. Am. Chem. Soc. 2007, 129, 7246–7247. Earmme, T.; Hwang, Y.-J.; Murari, N. M.; Subramaniyan, S.; Jenekhe, S. A. J. Am. Chem. Soc. 2013, 135, 14960–14963. Earmme, T.; Hwang, Y.-J.; Subramaniyan, S.; Jenekhe, S. A. Adv. Mater. 2014, 26, 6080–6085. Kolhe, N. B.; Lee, H.; Kuzuhara, D.; Yoshimoto, N.; Koganezawa, T.; Jenekhe, S. A. Chem. Mater. 2018, 30, 6540–6548. Hwang, Y.-J.; Earmme, T.; Courtright, B. A. E.; Eberle, F. N.; Jenekhe, S. A. J. Am. Chem. Soc. 2015, 137, 4424–4434. Hwang, Y.-J.; Ren, G.; Murari, N. M.; Jenekhe, S. A. Macromolecules 2012, 45, 9056–9062. Hwang, Y.-J.; Murari, N. M.; Jenekhe, S. A. Polym. Chem. 2013, 4, 3187–3195. McCulloch, I.; Heeney, M.; Bailey, C.; Genevicius, K.; Macdonald, I.; Shkunov, M.; Sparrowe, D.; Tierney, S.; Wagner, R.; Zhang, W. M.; Chabinyc, M. L.; Kline, R. J.; McGehee, M. D.; Toney, M. F. Nat. Mater. 2006, 5, 328–333. Liu, Y.; Zhao, J.; Li, Z.; Mu, C.; Ma, W.; Hu, H.; Jiang, K.; Lin, H.; Ade, H.; Yan, H. Nat. Commun. 2014, 5, 8. Ramey, M. B.; Hiller, J. A.; Rubner, M. F.; Tan, C. Y.; Schanze, K. S.; Reynolds, J. R. Macromolecules 2005, 38, 234–243. Izuhara, D.; Swager, T. M. J. Am. Chem. Soc. 2009, 131, 17724–17725. Izuhara, D.; Swager, T. M. J. Mater. Chem. 2011, 21, 3579–3584. Murphy, A. R.; Liu, J.; Luscombe, C.; Kavulak, D.; Fréchet, J. M. J.; Kline, R. J.; McGehee, M. D. Chem. Mater. 2005, 17, 4892–4899. Liang, Y.; Xiao, S.; Feng, D.; Yu, L. J. Phys. Chem. C 2008, 112, 7866–7871. Liang, Y.; Feng, D.; Wu, Y.; Tsai, S.-T.; Li, G.; Ray, C.; Yu, L. J. Am. Chem. Soc. 2009, 131, 7792–7799. Liang, Y.; Feng, D.; Guo, J.; Szarko, J. M.; Ray, C.; Chen, L. X.; Yu, L. Macromolecules 2009, 42, 1091–1098. Steckler, T. T.; Zhang, X.; Hwang, J.; Honeyager, R.; Ohira, S.; Zhang, X.-H.; Grant, A.; Ellinger, S.; Odom, S. A.; Sweat, D.; Tanner, D. B.; Rinzler, A. G.; Barlow, S.; Brédas, J.L.; Kippelen, B.; Marder, S. R.; Reynolds, J. R. J. Am. Chem. Soc. 2009, 131, 2824–2826. Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508–523. Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem. 1993, 58, 5434–5444. Casado, A. L.; Espinet, P.; Gallego, A. M. J. Am. Chem. Soc. 2000, 122, 11771–11782. Chan, W.-K.; Chen, Y.; Peng, Z.; Yu, L. J. Am. Chem. Soc. 1993, 115, 11735–11743. Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905–5911. Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605. Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803–805. Aguilar-Aguilar, A.; Liebeskind, L. S.; Peña-Cabrera, E. J. Org. Chem. 2007, 72, 8539–8542. Ohshita, J.; Kangai, S.; Tada, Y.; Yoshida, H.; Sakamaki, K.; Kunai, A.; Kunugi, Y. J. Organomet. Chem. 2007, 692, 1020–1024. Ohshita, J.; Kimura, K.; Lee, K.-H.; Kunai, A.; Kwak, Y.-W.; Son, E.-C.; Kunugi, Y. J. Polym. Sci. Part A: Polym. Chem. 2007, 45, 4588–4596. Wang, Y.; Ma, J.; Jiang, Y. J. Phys. Chem. A 2005, 109, 7197–7206. Ko, S.; Mondal, R.; Risko, C.; Lee, J. K.; Hong, S.; McGehee, M. D.; Brédas, J. L.; Bao, Z. Macromolecules 2010, 43, 6685–6698. Nagarjuna, G.; Kokil, A.; Kumar, J.; Venkataraman, D. J. Mater. Chem. 2012, 22, 16091–16094. Qing, F.; Sun, Y.; Wang, X.; Li, N.; Li, Y.; Li, X.; Wang, H. Polym. Chem. 2011, 2, 2102–2106. Wang, Y.; Hasegawa, T.; Matsumoto, H.; Michinobu, T. J. Am. Chem. Soc. 2019, 141, 3566–3575. Lère-Porte, J.-P.; Moreau, J. J. E.; Torreilles, C. Eur. J. Org. Chem. 2001, 2001, 1249–1258. Qiu, Y.; Mohin, J.; Tsai, C.-H.; Tristram-Nagle, S.; Gil, R. R.; Kowalewski, T.; Noonan, K. J. T. Macromol. Rapid Commun. 2015, 36, 840–844. Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918–920. Nakao, Y.; Hiyama, T. Chem. Soc. Rev. 2011, 40, 4893–4901. Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486–1499. Hiyama, T.; Minami, Y.; Mori, A. Transition-Metal-Catalyzed Cross-Coupling of Organosilicon Compounds. In Organosilicon Chemistry; Hiyama, T., Oestreich, M., Eds.; WileyVCH: Weinheim, Germany, 2019;; pp 271–332. Katayama, H.; Nagao, M.; Moriguchi, R.; Ozawa, F. J. Organomet. Chem. 2003, 676, 49–54. Katayama, H.; Nagao, M.; Nishimura, T.; Matsui, Y.; Umeda, K.; Akamatsu, K.; Tsuruoka, T.; Nawafune, H.; Ozawa, F. J. Am. Chem. Soc. 2005, 127, 4350–4353. Katayama, H.; Nagao, M.; Nishimura, T.; Matsui, Y.; Fukuse, Y.; Wakioka, M.; Ozawa, F. Macromolecules 2006, 39, 2039–2048. Wakioka, M.; Ikegami, M.; Ozawa, F. Macromolecules 2010, 43, 6980–6985. Shimizu, K.; Minami, Y.; Nakao, Y.; Ohya, K.-i.; Ikehira, H.; Hiyama, T. Chem. Lett. 2012, 42, 45–47. Kubota, K.; Iwamoto, H.; Ito, H. Org. Biomol. Chem. 2017, 15, 285–300. Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931. Krishna, A.; Lunchev, A. V.; Grimsdale, A. C. Suzuki Polycondensation. In Synthetic Methods for Conjugated Polymers and Carbon Materials; Leclerc, M., Morin, J.-F., Eds.; Wiley-VCH: Weinheim, Germany, 2017;; pp 59–95. Sakamoto, J.; Rehahn, M.; Schlüter, D. Suzuki Polycondensation: A Powerful Tool for Polyarylene Synthesis. In Design and Synthesis of Conjugated Polymers; Leclerc, M., Morin, J.-F., Eds.; Wiley-VCH: WEinheim, Germany, 2010;; pp 45–90. Sakamoto, J.; Rehahn, M.; Wegner, G.; Schlüter, A. D. Macromol. Rapid Commun. 2009, 30, 653–687. Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034–5037. Amatore, C.; Jutand, A.; Le Duc, G. Angew. Chem. Int. Ed. 2012, 51, 1379–1382. Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J. 2011, 17, 2492–2503. Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116–2119. Thomas, A. A.; Zahrt, A. F.; Delaney, C. P.; Denmark, S. E. J. Am. Chem. Soc. 2018, 140, 4401–4416. Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329–332. Frahn, J.; Karakaya, B.; Schafer, A.; Schlüter, A. D. Tetrahedron 1997, 53, 15459–15467. Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2017, 139, 13156–13165. Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2016, 138, 9145–9157. Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Angew. Chem. Int. Ed. 2008, 47, 928–931. Rehahn, M.; Schlüter, A. D.; Wegner, G.; Feast, W. J. Polymer 1989, 30, 1060–1062. Rehahn, M.; Schlüter, A. D.; Wegner, G. Makromol. Chem. Macromol. Chem. Phys. 1990, 191, 1991–2003. Schlüter, S.; Frahn, J.; Karakaya, B.; Schlüter, A. D. Macromol. Chem. Phys. 2000, 201, 139–142.

508

174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245.

Polymerization Reactions via Cross Coupling

Jing, W. X.; Kraft, A.; Moratti, S. C.; Gruner, J.; Cacialli, F.; Hamer, P. J.; Holmes, A. B.; Friend, R. H. Synth. Met. 1994, 67, 161–163. Wallow, T. I.; Novak, B. M. J. Am. Chem. Soc. 1991, 113, 7411–7412. Murage, J.; Eddy, J. W.; Zimbalist, J. R.; McIntyre, T. B.; Wagner, Z. R.; Goodson, F. E. Macromolecules 2008, 41, 7330–7338. Tour, J. M.; Lamba, J. J. S. J. Am. Chem. Soc. 1993, 115, 4935–4936. Lamba, J. J. S.; Tour, J. M. J. Am. Chem. Soc. 1994, 116, 11723–11736. Blouin, N.; Michaud, A.; Gendron, D.; Wakim, S.; Blair, E.; Neagu-Plesu, R.; Belleêtte, M.; Durocher, G.; Tao, Y.; Leclerc, M. J. Am. Chem. Soc. 2008, 130, 732–742. Zhang, M.; Tsao, H. N.; Pisula, W.; Yang, C.; Mishra, A. K.; Müllen, K. J. Am. Chem. Soc. 2007, 129, 3472–3473. Mühlbacher, D.; Scharber, M.; Morana, M.; Zhu, Z.; Waller, D.; Gaudiana, R.; Brabec, C. Adv. Mater. 2006, 18, 2884–2889. Okamoto, T.; Jiang, Y.; Qu, F.; Mayer, A. C.; Parmer, J. E.; McGehee, M. D.; Bao, Z. Macromolecules 2008, 41, 6977–6980. Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286. Grisorio, R.; Mastrorilli, P.; Nobile, C. F.; Romanazzi, G.; Suranna, G. P. Tetrahedron Lett. 2005, 46, 2555–2558. Ayuso Carrillo, J.; Turner, M. L.; Ingleson, M. J. J. Am. Chem. Soc. 2016, 138, 13361–13368. Ayuso Carrillo, J.; Ingleson, M. J.; Turner, M. L. Macromolecules 2015, 48, 979–986. Seo, K.-B.; Lee, I.-H.; Lee, J.; Choi, I.; Choi, T.-L. J. Am. Chem. Soc. 2018, 140, 4335–4343. Lee, J.; Park, H.; Hwang, S.-H.; Lee, I.-H.; Choi, T.-L. Macromolecules 2020, 53, 3306–3314. Yokoyama, A.; Suzuki, H.; Kubota, Y.; Ohuchi, K.; Higashimura, H.; Yokozawa, T. J. Am. Chem. Soc. 2007, 129, 7236–7237. Baker, M. A.; Ayuso-Carrillo, J.; Koos, M. R. M.; MacMillan, S. N.; Varni, A. J.; Gil, R. R.; Noonan, K. J. T. Polym. J. 2020, 52, 83–92. Kosaka, K.; Uchida, T.; Mikami, K.; Ohta, Y.; Yokozawa, T. Macromolecules 2018, 51, 364–369. Baker, M. A.; Zahn, S. F.; Varni, A. J.; Tsai, C. H.; Noonan, K. J. T. Macromolecules 2018, 51, 5911–5917. Liversedge, I. A.; Higgins, S. J.; Giles, M.; Heeney, M.; McCulloch, I. Tetrahedron Lett. 2006, 47, 5143–5146. Kobayashi, S.; Fujiwara, K.; Jiang, D. H.; Yamamoto, T.; Tajima, K.; Yamamoto, Y.; Isono, T.; Satoh, T. Polym. Chem. 2020, 11, 6832–6839. Tokita, Y.; Sugawara, K.; Awayama, R.; Ohta, Y.; Yokozawa, T. J. Polym. Sci. Part A. Polym. Chem. 2019, 57, 2498–2504. Huber, S.; Mecking, S. Macromolecules 2019, 52, 5917–5924. Grisorio, R.; Suranna, G. P. ACS Macro Lett. 2017, 6, 1251–1256. Dong, J.; Guo, H.; Hu, Q. S. ACS Macro Lett. 2017, 6, 1301–1304. Zhang, Z.; Hu, P.; Li, X.; Zhan, H.; Cheng, Y. J. Polym. Sci. Part A: Polym. Chem. 2015, 53, 1457–1463. Zhang, H.-H.; Xing, C.-H.; Hu, Q.-S.; Hong, K. Macromolecules 2015, 48, 967–978. Varni, A. J.; Fortney, A.; Baker, M. A.; Worch, J. C.; Qin, Y. Y.; Yaron, D.; Bernhard, S.; Noonan, K. J. T.; Kowalewski, T. J. Am. Chem. Soc. 2019, 141, 8858–8867. Yokozawa, T.; Kohno, H.; Ohta, Y.; Yokoyama, A. Macromolecules 2010, 43, 7095–7100. Hohl, B.; Bertschi, L.; Zhang, X. Y.; Schlüter, A. D.; Sakamoto, J. Macromolecules 2012, 45, 5418–5426. Zhang, H.-H.; Zhu, Y.-X.; Wang, W.; Zhu, J.; Bonnesen, P. V.; Hong, K. Polym. Chem. 2018, 9, 3342–3346. Bautista, M. V.; Varni, A. J.; Ayuso-Carrillo, J.; Tsai, C. H.; Noonan, K. J. T. ACS Macro Lett. 2020, 9, 1357–1362. Verswyvel, M.; Hoebers, C.; De Winter, J.; Gerbaux, P.; Koeckelberghs, G. J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 5067–5074. Bautista, M. V.; Varni, A. J.; Ayuso-Carrillo, J.; Carson, M. C.; Noonan, K. J. T. Polym. Chem. 2021, 12, 1404–1414. Nojima, M.; Ohta, Y.; Yokozawa, T. J. Polym. Sci. Part A: Polym. Chem. 2014, 52, 2643–2653. Nojima, M.; Kamigawara, T.; Ohta, Y.; Yokozawa, T. J. Polym. Sci. Part A: Polym. Chem. 2019, 57, 297–304. Zhang, K.; Tkachov, R.; Ditte, K.; Kiriy, N.; Kiriy, A.; Voit, B. Macromol. Rapid Commun. 2020, 41. Gobalasingham, N. S.; Thompson, B. C. Prog. Polym. Sci. 2018, 83, 135–201. Pankow, R. M.; Thompson, B. C. Polym. Chem. 2020, 11, 630–640. Pouliot, J.-R.; Grenier, F.; Blaskovits, J. T.; Beaupré, S.; Leclerc, M. Chem. Rev. 2016, 116, 14225–14274. Bura, T.; Blaskovits, J. T.; Leclerc, M. J. Am. Chem. Soc. 2016, 138, 10056–10071. Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658–668. Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849. Gorelsky, S. I. Coord. Chem. Rev. 2013, 257, 153–164. Okamoto, K.; Housekeeper, J. B.; Michael, F. E.; Luscombe, C. K. Polym. Chem. 2013, 4, 3499–3506. Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64, 6015–6020. Xue, L.; Lin, Z. Chem. Soc. Rev. 2010, 39, 1692–1705. Rudenko, A. E.; Wiley, C. A.; Tannaci, J. F.; Thompson, B. C. J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 2660–2668. Rudenko, A. E.; Wiley, C. A.; Stone, S. M.; Tannaci, J. F.; Thompson, B. C. J. Polym. Sci. Part A: Polym. Chem. 2012, 50, 3691–3697. Rudenko, A. E.; Thompson, B. C. Macromolecules 2015, 48, 569–575. Rudenko, A. E.; Thompson, B. C. J. Polym. Sci. Part A: Polym. Chem. 2015, 53, 2494–2500. Lu, W.; Kuwabara, J.; Kanbara, T. Macromol. Rapid Commun. 2013, 34, 1151–1156. Wang, Q.; Takita, R.; Kikuzaki, Y.; Ozawa, F. J. Am. Chem. Soc. 2010, 132, 11420–11421. Rudenko, A. E.; Latif, A. A.; Thompson, B. C. J. Polym. Sci. Part A: Polym. Chem. 2015, 53, 1492–1499. Marzano, G.; Kotowski, D.; Babudri, F.; Musio, R.; Pellegrino, A.; Luzzati, S.; Po, R.; Farinola, G. M. Macromolecules 2015, 48, 7039–7048. Lu, W.; Kuwabara, J.; Kanbara, T. Macromolecules 2011, 44, 1252–1255. Wakioka, M.; Kitano, Y.; Ozawa, F. Macromolecules 2013, 46, 370–374. Wakioka, M.; Takahashi, R.; Ichihara, N.; Ozawa, F. Macromolecules 2017, 50, 927–934. Gruber, M.; Jung, S.-H.; Schott, S.; Venkateshvaran, D.; Kronemeijer, A. J.; Andreasen, J. W.; McNeill, C. R.; Wong, W. W. H.; Shahid, M.; Heeney, M.; Lee, J.-K.; Sirringhaus, H. Chem. Sci. 2015, 6, 6949–6960. Sonar, P.; Foong, T. R. B.; Dodabalapur, A. Phys. Chem. Chem. Phys. 2014, 16, 4275–4283. Kowalski, S.; Allard, S.; Scherf, U. ACS Macro Lett. 2012, 1, 465–468. Kowalski, S.; Allard, S.; Scherf, U. Macromol. Rapid Commun. 2015, 36, 1061–1068. Ponder, J. F.; Schmatz, B.; Hernandez, J. L.; Reynolds, J. R. J. Mater. Chem. C 2018, 6, 1064–1070. Robitaille, A.; Jenekhe, S. A.; Leclerc, M. Chem. Mater. 2018, 30, 5353–5361. Mainville, M.; Tremblay, V.; Fenniri, M. Z.; Laventure, A.; Farahat, M. E.; Ambrose, R.; Welch, G. C.; Hill, I. G.; Leclerc, M. Asian J. Org. Chem. 2020, 9, 1318–1325. Ichige, A.; Saito, H.; Kuwabara, J.; Yasuda, T.; Choi, J.-C.; Kanbara, T. Macromolecules 2018, 51, 6782–6788. Lin, Y.-J.; Sun, H.-S.; Yang, H.-R.; Lai, Y.-Y.; Hou, K.-Y.; Liu, Y.-H. Macromol. Rapid Commun. 2020, 41, 2000021. Pankow, R. M.; Ye, L.; Gobalasingham, N. S.; Salami, N.; Samal, S.; Thompson, B. C. Polym. Chem. 2018, 9, 3885–3892. Grenier, F.; Goudreau, K.; Leclerc, M. J. Am. Chem. Soc. 2017, 139, 2816–2824. Lee, J. A.; Luscombe, C. K. ACS Macro Lett. 2018, 7, 767–771. Yang, Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787–8863. Hay, A. S.; Blanchard, H. S.; Endres, G. F.; Eustance, J. W. J. Am. Chem. Soc. 1959, 81, 6335–6336.

Polymerization Reactions via Cross Coupling

246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. 268. 269. 270. 271. 272. 273. 274. 275. 276. 277. 278. 279. 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310. 311. 312. 313. 314.

509

Hay, A. S. Polym. Eng. Sci. 1976, 16, 1–10. Hay, A. S. J. Org. Chem. 1960, 25, 1275–1276. Hay, A. S. J. Org. Chem. 1962, 27, 3320–3321. Kijima, M.; Kinoshita, I.; Hattori, T.; Shirakawa, H. J. Mater. Chem. 1998, 8, 2165–2166. Kijima, M.; Kinoshita, I.; Hattori, T.; Shirakawa, H. Synth. Met. 1999, 100, 61–69. Lin, V. S.-Y.; Radu, D. R.; Han, M.-K.; Deng, W.; Kuroki, S.; Shanks, B. H.; Pruski, M. J. Am. Chem. Soc. 2002, 124, 9040–9041. Baier, M. C.; Huber, J.; Mecking, S. J. Am. Chem. Soc. 2009, 131, 14267–14273. Shu, Z.; Zhang, Q.; Zhang, P.; Qin, Z.; Liu, D.; Gao, X.; Guan, B.; Qi, H.; Xiao, M.; Wei, Z.; Dong, H.; Hu, W. Polym. Chem. 2020, 11, 1572–1579. Williams, V. E.; Swager, T. M. J. Polym. Sci. Part A: Polym. Chem. 2000, 38, 4669–4676. Zhao, D.; Swager, T. M. Macromolecules 2005, 38, 9377–9384. Ahmed, M. K.; Rahman, M. M.; Naher, M.; Mehdi, S. S.; Khan, A. R.; Khan, M. M. R.; Islam, S. M. S.; Younus, M.; Wedler, S.; Bagnich, S.; Hofmann, A.-L.; Rudnick, A.; Köhler, A. Macromol. Chem. Phys. 2019, 220, 1800494. Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074–5075. Tsuchiya, K.; Ogino, K. Polym. J. 2013, 45, 281–286. Gobalasingham, N. S.; Noh, S.; Thompson, B. C. Polym. Chem. 2016, 7, 1623–1631. Gobalasingham, N. S.; Pankow, R. M.; Thompson, B. C. Polym. Chem. 2017, 8, 1963–1971. Zhang, Q.; Chang, M.; Lu, Y.; Sun, Y.; Li, C.; Yang, X.; Zhang, M.; Chen, Y. Macromolecules 2018, 51, 379–388. Collier, G. S.; Reynolds, J. R. ACS Macro Lett. 2019, 8, 931–936. Zhang, Q.; Li, Y.; Lu, Y.; Zhang, H.; Li, M.; Yang, Y.; Wang, J.; Chen, Y.; Li, C. Polymer 2015, 68, 227–233. Guo, Q.; Wu, D.; You, J. ChemSusChem 2016, 9, 2765–2768. Zhang, Q.; Wan, X.; Lu, Y.; Li, Y.; Li, Y.; Li, C.; Wu, H.; Chen, Y. Chem. Commun. 2014, 50, 12497–12499. Huang, Q.; Qin, X.; Li, B.; Lan, J.; Guo, Q.; You, J. Chem. Commun. 2014, 50, 13739–13741. Aoki, H.; Saito, H.; Shimoyama, Y.; Kuwabara, J.; Yasuda, T.; Kanbara, T. ACS Macro Lett. 2018, 7, 90–94. Kang, L. J.; Xing, L.; Luscombe, C. K. Polym. Chem. 2019, 10, 486–493. Yamamoto, T. Bull. Chem. Soc. Jpn. 2010, 83, 431–455. Yamamoto, T.; Koizumi, T. Polymer 2007, 48, 5449–5472. Yamamoto, T. Synlett 2003, 425–450. Yamamoto, T.; Maruyama, T.; Zhou, Z.-H.; Ito, T.; Fukuda, T.; Yoneda, Y.; Begum, F.; Ikeda, T.; Sasaki, S. H. Takezoe, A. Fukuda, K. Kubota, J. Am. Chem. Soc. 1994, 116, 4832–4845. Yamamoto, T.; Sugiyama, K.; Kushida, T.; Inoue, T.; Kanbara, T. J. Am. Chem. Soc. 1996, 118, 3930–3937. Yamamoto, T.; Suganuma, H.; Maruyama, T.; Inoue, T.; Muramatsu, Y.; Arai, M.; Komarudin, D.; Ooba, N.; Tomaru, S.; Sasaki, S.; Kubota, K. Chem. Mater. 1997, 9, 1217–1225. Heitz, W.; Brugging, W.; Freund, L.; Gailberger, M.; Greiner, A.; Jung, H.; Kampschulte, U.; Niebner, N.; Osan, F.; Schmidt, H. W.; Wicker, M. Makromol. Chem. 1988, 189, 119–127. Hilberer, A.; Brouwer, H. J.; van der Scheer, B. J.; Wildeman, J.; Hadziioannou, G. Macromolecules 1995, 28, 4525–4529. Brenda, M.; Greiner, A.; Heitz, W. Makromol. Chem. 1990, 191, 1083–1100. Klingelhöfer, S.; Schellenberg, C.; Pommerehne, J.; Bässler, H.; Greiner, A.; Heitz, W. Macromol. Chem. Phys. 1997, 198, 1511–1530. Plevyak, J. E.; Heck, R. F. J. Org. Chem. 1978, 43, 2454–2456. Greiner, A.; Bolle, B.; Hesemann, P.; Oberski, J. M.; Sander, R. Macromol. Chem. Phys. 1996, 197, 113–134. Bao, Z.; Chen, Y.; Cai, R.; Yu, L. Macromolecules 1993, 26, 5281–5286. Huo, L.; Hou, J.; Zhou, Y.; Han, M.; Li, Y. J. Appl. Polym. Sci. 2008, 110, 1002–1008. Liu, Y.; Lahti, P. M.; La, F. Polymer 1998, 39, 5241–5244. Peng, Z.; Yu, L. J. Am. Chem. Soc. 1996, 118, 3777–3778. Peng, Z.; Gharavi, A. R.; Yu, L. J. Am. Chem. Soc. 1997, 119, 4622–4632. Wang, Q.; Yu, L. J. Am. Chem. Soc. 2000, 122, 11806–11811. Bao, Z.; Chen, Y.; Yu, L. Macromolecules 1994, 27, 4629–4631. You, W.; Wang, L.; Wang, Q.; Yu, L. Macromolecules 2002, 35, 4636–4645. Wang, Q.; Wang, L.; Yu, J.; Yu, L. Adv. Mater. 2000, 12, 974–978. Lim, S.-J.; Seok, D. Y.; An, B.-K.; Jung, S. D.; Park, S. Y. Macromolecules 2006, 39, 9–11. Thomas, S. W.; Joly, G. D.; Swager, T. M. Chem. Rev. 2007, 107, 1339–1386. Duarte, A.; Pu, K.-Y.; Liu, B.; Bazan, G. C. Chem. Mater. 2011, 23, 501–515. Giesa, R. J. Macromol. Sci. Part C 1996, 36, 631–670. Bunz, U. H. F. Chem. Rev. 2000, 100, 1605–1644. Bunz, U. H. F. Macromol. Rapid Commun. 2009, 30, 772–805. Weder, C., Ed.; In Poly(arylene ethynylene)s: From Synthesis to Application; Springer: Berlin, Heidelberg, 2005. VanVeller, B.; Swager, T. M. Poly(aryleneethynylene)s. In Design and Synthesis of Conjugated Polymers, Wiley-VCH: Weingheim, Germany, 2010;; pp 175–203. Zhou, Q.; Swager, T. M. J. Am. Chem. Soc. 1995, 117, 7017–7018. Kang, S.; Ono, R. J.; Bielawski, C. W. J. Am. Chem. Soc. 2013, 135, 4984–4987. Kang, S.; Todd, A. D.; Paul, A.; Lee, S. Y.; Bielawski, C. W. Macromolecules 2018, 51, 5972–5978. Jagadesan, P.; Schanze, K. S. Macromolecules 2019, 52, 3845–3851. Bunz, U. H. F. Adv. Polym. Sci. 2005, 177, 1–52. Klemm, E.; Pautzsch, T.; Blankenburg, L. Adv. Polym. Sci. 2005, 177, 53–90. Yamamoto, T.; Yamaguchi, I.; Yasuda, T. Adv. Polym. Sci. 2005, 177, 181–208. Nambiar, R.; Woody, K. B.; Ochocki, J. D.; Brizius, G. L.; Collard, D. M. Macromolecules 2009, 42, 43–51. Häger, H.; Heitz, W. Macromol. Chem. Phys. 1998, 199, 1821–1826. Khan, A.; Hecht, S. Chem. Commun. 2004, 300–301. Khan, A.; Müller, S.; Hecht, S. Chem. Commun. 2005, 584–586. Wilson, J. N.; Waybright, S. M.; McAlpine, K.; Bunz, U. H. F. Macromolecules 2002, 35, 3799–3800. Li, C.-J.; Slaven, W. T., IV; John, V. T.; Banerjee, S. Chem. Commun. 1997, 1569–1570. Li, C.-J.; Slaven, W. T., IV; Li, C.-J.; Chen, Y.-P.; John, V. T.; Rachakonda, S. H. Chem. Commun. 1998, 1351–1352. Thavornsin, N.; Sukwattanasinitt, M.; Wacharasindhu, S. Polym. Chem. 2014, 5, 48–52. Thavornsin, N.; Chamrasboon, P.; Kiatmongkolkul, P.; Sakthanasait, R.; Sukwattanasinitt, M.; Wacharasindhu, S. J. Polym. Sci. Part A: Polym. Chem. 2019, 57, 1556–1563. Khan, A.; Hecht, S. J. Polym. Sci. Part A: Polym. Chem. 2006, 44, 1619–1627.

510

315. 316. 317. 318. 319. 320. 321. 322. 323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342.

Polymerization Reactions via Cross Coupling

Swager, T. M. Acc. Chem. Res. 2008, 41, 1181–1189. Yang, J.-S.; Swager, T. M. J. Am. Chem. Soc. 1998, 120, 5321–5322. Yang, J.-S.; Swager, T. M. J. Am. Chem. Soc. 1998, 120, 11864–11873. Leung, A. C. W.; Chong, J. H.; Patrick, B. O.; MacLachlan, M. J. Macromolecules 2003, 36, 5051–5054. Yamamoto, T.; Fukushima, N.; Nakajima, H.; Maruyama, T.; Yamaguchi, I. Macromolecules 2000, 33, 5988–5994. Bangcuyo, C. G.; Ellsworth, J. M.; Evans, U.; Myrick, M. L.; Bunz, U. H. F. Macromolecules 2003, 36, 546–548. Harrison, B. S.; Ramey, M. B.; Reynolds, J. R.; Schanze, K. S. J. Am. Chem. Soc. 2000, 122, 8561–8562. Tan, C.; Pinto, M. R.; Schanze, K. S. Chem. Commun. 2002, 446–447. Yang, C. J.; Pinto, M.; Schanze, K.; Tan, W. Angew. Chem. Int. Ed. Engl. 2005, 44, 2572–2576. Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1348–1350. Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609–3612. Kanbara, T.; Honma, A.; Hasegawa, K. Chem. Lett. 1996, 25, 1135–1136. Kanbara, T.; Izumi, K.; Nakadani, Y.; Narise, T.; Hasegawa, K. Chem. Lett. 1997, 26, 1185–1186. Kanbara, T.; Izumi, K.; Narise, T.; Hasegawa, K. Polym. J. 1998, 30, 66–68. Kanbara, T.; Oshima, M.; Imayasu, T.; Hasegawa, K. Macromolecules 1998, 31, 8725–8730. Goodson, F. E.; Hartwig, J. F. Macromolecules 1998, 31, 1700–1703. Goodson, F. E.; Hauck, S. I.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 7527–7539. Spetseris, N.; Ward, R. E.; Meyer, T. Y. Macromolecules 1998, 31, 3158–3161. Ward, R. E.; Meyer, T. Y. Macromolecules 2003, 36, 4368–4373. Zhang, X.-X.; Sadighi, J. P.; Mackewitz, T. W.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 7606–7607. Kodama, S.; Kuwabara, J.; Jiang, X.; Fukushima, I.; Kanbara, T. ACS Appl. Polym. Mater. 2019, 1, 2083–2088. Al-Hussaini, A. S.; Klapper, M.; Pakula, T.; Müllen, K. Macromolecules 2004, 37, 8269–8277. Lee, C.-W.; Seo, Y.-H.; Lee, S.-H. Macromolecules 2004, 37, 4070–4074. Shen, I.-W.; McCairn, M. C.; Morrison, J. J.; Turner, M. L. Macromol. Rapid Commun. 2007, 28, 449–455. Horie, M.; Luo, Y.; Morrison, J. J.; Majewski, L. A.; Song, A.; Saunders, B. R.; Turner, M. L. J. Mater. Chem. 2008, 18, 5230–5236. Takase, N.; Kuwabara, J.; Choi, S. J.; Yasuda, T.; Han, L.; Kanbara, T. J. Polym. Sci. Part A: Polym. Chem. 2015, 53, 536–542. Horie, M.; Yamaguchi, I.; Yamamoto, T. Macromolecules 2006, 39, 7493–7501. Grisorio, R.; Suranna, G. P. Polym. Chem. 2019, 10, 1947–1955.