Comprehensive Organometallic Chemistry IV. Volume 13: Applications II. d- and f-Block Metal Complexes in Organic Synthesis - Part 2 [13] 9780128202067

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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 13

APPLICATIONS II. d- AND f-BLOCK METAL COMPLEXES IN ORGANIC SYNTHESIS - PART 2 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 13 Editor Biographies

vii

Contributors to Volume 13

xiii

Preface 13.01

xv

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

1

Graham E Dobereiner, Xumu Zhang, and Heng Wang

13.02

Hydrometallation of Organometallic Complexes

32

Jie Zhao and Baihua Ye

13.03

Metal-Catalyzed Aerobic Oxidation Reactions

75

Jessica M Hoover, Andreas Baur, and Jiaqi Liu

13.04

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

132

Lucas J Oxtoby, Alena M Vasquez, Taeho Kang, Zi-Qi Li, and Keary M Engle

13.05

Hydroformylation: Alternatives to Rh and Syn-gas

194

Minghao Wang, Alexander Lu, and Vy M Dong

13.06

Reactions of Ylides Generated from M]C Bonds

221

Shu-Sen Li, Zihao Fu, and Jianbo Wang

13.07

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

265

Quentin Michaudel, Samuel J Kempel, Ting-Wei Hsu, and Justine N deGruyter

13.08

Single-Electron Strategies in Organometallic Methods: Photoredox, Electrocatalysis, Radical Relay, and Beyond

339

Lu Song and Niankai Fu

13.09

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

404

Haobing Wang and Changle Chen

13.10

Polymerization of Epoxides

431

Donald J Darensbourg and Gulzar A Bhat

13.11

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

456

Thomas Scattolin and Steven P Nolan

13.12

High-Throughput Experimentation in Organometallic Chemistry and Catalysis

502

David C Leitch and Joseph Becica

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

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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

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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

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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.

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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 13 Andreas Baur C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, United States Joseph Becica Department of Chemistry, University of Victoria, Victoria, BC, Canada Gulzar A Bhat Texas A&M University, College Station, TX, United States Changle Chen Department of Polymer Science and Engineering, Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China Donald J Darensbourg Texas A&M University, College Station, TX, United States Justine N deGruyter Department of Chemistry, Texas A&M University, College Station, TX, United States Graham E Dobereiner Department of Chemistry, Temple University, Philadelphia, PA, United States Vy M Dong Department of Chemistry, University of California− Irvine, Irvine, CA, United States Keary M Engle Department of Chemistry, The Scripps Research Institute, La Jolla, CA, United States Niankai Fu Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China

Zihao Fu Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China Jessica M Hoover C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, United States Ting-Wei Hsu Department of Chemistry, Texas A&M University, College Station, TX, United States Taeho Kang Department of Chemistry, The Scripps Research Institute, La Jolla, CA, United States Samuel J Kempel Department of Chemistry, Texas A&M University, College Station, TX, United States David C Leitch Department of Chemistry, University of Victoria, Victoria, BC, Canada Shu-Sen Li Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China Zi-Qi Li Department of Chemistry, The Scripps Research Institute, La Jolla, CA, United States Jiaqi Liu C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, United States

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Contributors to Volume 13

Alexander Lu Department of Chemistry, University of California− Irvine, Irvine, CA, United States

Heng Wang Department of Chemistry, Temple University, Philadelphia, PA, United States

Quentin Michaudel Department of Chemistry, Texas A&M University, College Station, TX, United States

Jianbo Wang Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China

Steven P Nolan Department of Chemistry and Center for Sustainable Chemistry, Ghent University, Ghent, Belgium Lucas J Oxtoby Department of Chemistry, The Scripps Research Institute, La Jolla, CA, United States Thomas Scattolin Department of Chemistry and Center for Sustainable Chemistry, Ghent University, Ghent, Belgium Lu Song Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology of Ministry of Education, School of Chemistry, Beihang University, Beijing, China Alena M Vasquez Department of Chemistry, The Scripps Research Institute, La Jolla, CA, United States Haobing Wang School of Molecular Science and Engineering, South China Advanced Institute for Soft Matter Science and Technology, Guangdong Provincial Key Laboratory of Functional and Intelligent Hybrid Materials and Devices, South China University of Technology, Guangzhou, China

Minghao Wang Department of Chemistry, University of California − Irvine, Irvine, CA, United States Baihua Ye School of Physical Science and Technology, ShanghaiTech University, Shanghai, China Xumu Zhang Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China Jie Zhao Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 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

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13.01 Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation Graham E Dobereinera, Xumu Zhangb, and Heng Wanga, aDepartment of Chemistry, Temple University, Philadelphia, PA, United States; b Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China © 2022 Elsevier Ltd. All rights reserved.

13.01.1 13.01.2 13.01.2.1 13.01.2.1.1 13.01.2.1.2 13.01.2.1.3 13.01.2.1.4 13.01.2.2 13.01.2.2.1 13.01.2.2.2 13.01.2.3 13.01.2.4 13.01.2.5 13.01.3 13.01.3.1 13.01.3.1.1 13.01.3.1.2 13.01.3.1.3 13.01.3.2 13.01.3.3 13.01.3.3.1 13.01.3.3.2 13.01.3.4 13.01.4 References

Introduction Developing chiral phosphine ligands for olefin hydrogenation Functionalized olefin hydrogenation with Rh based catalyst History of developing chiral bisphosphine in Rh catalyst development Empirical ligand design in Rh catalyst development—Quadrant rule Empirical ligand design in Rh catalyst development—Backbone rigidity Mechanistic studies of Rh-catalyzed hydrogenation of functionalized alkenes Functionalized olefin hydrogenation with Ru-based catalysts Developing BINAP for Rh-catalyzed olefin hydrogenation BINAP in Ru-catalyzed olefin hydrogenation Unfunctionalized olefin hydrogenation with Ir based catalyst Olefin hydrogenation with Co based catalyst Olefin hydrogenation with Ni based catalyst Developing chiral phosphine ligands for ketone hydrogenation Ketone hydrogenation with Ru based catalysts Development of the BINAP-Ru catalyst for ketone hydrogenation Developing multidentate ligands for Ru-catalyzed transfer hydrogenation Developing pincer ligands for Ru-catalyzed ketone hydrogenation Ketone hydrogenation with Ir based catalysts Ketone hydrogenation with Fe based catalysts Ketone transfer hydrogenation with Fe based catalysts Ketone direct hydrogenation with Fe based catalyst Ketone hydrogenation with Mn based catalysts Conclusions and future directions

1 2 2 2 4 5 5 7 7 7 8 12 14 15 15 15 16 17 19 21 21 23 24 25 26

13.01.1 Introduction The homogeneous asymmetric hydrogenation of organic molecules is among the most effective synthetic protocols for producing optically active pharmaceuticals, agrochemicals, flavors and fragrances.1,2 Since the 1970s, tremendous efforts have resulted in efficient chiral ligands for controlling product stereoselectivity. The impact of this reaction on society was recognized through the  Noyori4 “for their work on chirally catalysed 2001 Nobel Prize in Chemistry, awarded to William S. Knowles3 and RyOji hydrogenation reactions.” It was Knowles who launched the field, using a chiral phosphine to achieve the Rh-catalyzed hydrogenation of dehydroamino acid.5 His successful employment of DIPAMP in production of L-DOPA inspired many others to further develop bisphosphine ligands 6 (Fig. 1). Since Knowles’ report in 1968,5 an enormous number of chiral ligands have been developed. Beyond Noyori’s BINAP,7 several other “privileged” chiral phosphine ligands, such as DIPAMP,6 DuPhos,7 JosiPhos,8 BisP ,9 TangPhos,10 and PHOX11 have been used widely to achieve efficient Ru, Rh and Ir hydrogenation catalysis with a wide variety of substrates. Chiral bisphosphines such as BPE12 and Binapine13 have worked well for emerging Co and Ni catalyzed reactions, while others work better for Mn and Fe catalysts. In this chapter, we chronicle the development of chiral bisphosphine and multidentate phosphine ligands for Rh, Ru, Ir, Fe, Co, and Mn hydrogenation catalysts, with an emphasis on the insights afforded by both empirical ligand screening and detailed mechanistic studies. We have chosen to tell this story through focusing on C]C and C]O hydrogenation reactions, as much of ligand design over the past 50 years has targeted hydrogenation of alkenes and carbonyls.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00110-4

1

2

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

COOH NHAc

AcO

COOH [(R,R)-DIPAMP-Rh(COD)]BF4 3 atm H2

COOH H3O

NHAc

AcO

OMe

NH2

HO

OMe

OH

96% ee, 98% yield S/C>10,000

L-DOPA

MeO P

P

OMe

(R, R)- DIPAMP 1975 Knowles

Fig. 1 Monsato’s process for producing L-DOPA.

13.01.2 Developing chiral phosphine ligands for olefin hydrogenation 13.01.2.1 Functionalized olefin hydrogenation with Rh based catalyst 13.01.2.1.1

History of developing chiral bisphosphine in Rh catalyst development

In production of chiral compounds, discarding 50% of a racemate can lead to significant amounts of waste, and so a stereoselective method can be an attractive alternative. Before the 1960s, chemists mostly relied on biochemical processes or laborious resolutions of racemic mixtures to make chiral molecules. With the invention of Wilkinson’s catalyst ([RhCl(PPh3)3]) in the 1960s,5 a well-characterized homogeneous hydrogenation catalyst became available, with good solubility in organic solvents and a reaction rate competitive with heterogeneous catalysts. The activity of RhCl(PPh3)3 offered an opportunity for asymmetric catalysis, since replacement of PPh3 with a chiral monophosphine14,15 formed a chiral environment. With this innovation, Knowles achieved an important milestone in the application of asymmetric catalysis, employing methylcyclohexyl-o-anisylphosphine (CAMP) in the hydrogenation of a L-DOPA precursor16 (Fig. 2). In the same period, Kagan reported the first chiral bisphosphine (DIOP), a scaffold with chiral elements shifted from the phosphorus atom to the carbon atoms nearby. Kagan and coworkers achieved 83% ee on hydrogenation of a dehydroamino acid.17 Kagan’s work inspired Knowles to develop a P-stereogenic chiral bisphosphine DIPAMP, used to achieve then-unprecedented levels of enantioselectivity: over 95% ee at producing L-DOPA 6 (Fig. 3). Within 5 years the protocol was successfully employed in the industrial production of L-DOPA, convincingly demonstrating the practical utility (and societal impact) of asymmetric catalysis. Knowles’ success stimulated ongoing development of bisphosphine ligands. A dizzying number of chiral bisphosphines have been subsequently synthesized and reported6–10,12,13,17–50 (Fig. 4). COOH

*

Rh(I)-ligand

NHAc

COOH

NHAc

H2

OMe

*

OMe

CH2CH(CH3)(Et) Ligand

P

P

*

P

Pr

CH2CH(CH3)(Et)

*

P

iPr

*

P

*

P

Ph

Cy

*

Cy

*

ee

1%

28 %

28 %

32 %

PAMP

CAMP

58 %

88 %

Fig. 2 Knowles’ early effort on asymmetric hydrogenation of a dehydroamino acid. From Knowles, W. S. Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem. Int. Ed. 2002, 41 (12), 1998–2007, 2002.

Fig. 3 Development of DIPAMP based on the inspiration from DIOP.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 4 Representative chiral bisphosphine ligands for asymmetric hydrogenation.

3

4

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

13.01.2.1.2

Empirical ligand design in Rh catalyst development—Quadrant rule

Knowles demonstrated a practical asymmetric hydrogenation more than 50 years ago—and yet the reaction’s full potential has not been completely realized. It remains difficult, if not impossible, to apply chiral hydrogenation catalysts in certain synthetic contexts. The challenge is often cast as one of chiral ligand design: How can we identify chiral bisphosphines for higher enantioselectivity, faster reaction rates, and larger turnover numbers—with broad applicability to myriad substrates? Few catalysts combine a wide substrate scope with high stereoselectivity, because effective stereoinduction depends on modest differences in energy between diastereomeric transition states (DDG{)—about 2–3 kcal/mol. Disruption of subtle interactions caused by a change in substrate can reduce or eliminate DDG{, with disastrous effects on stereoselectivity. Nonetheless, several ligands have found remarkably broad utility across multiple substrate classes. Here we shed some light on how empirical patterns have informed models in contemporary ligand development. The solid-state structure of a DIPAMP-Rh complex51 shows the ligand binding in a “side to face” manner to Rh. Looking at the Rh complex within the equatorial plane, across to the DIPAMP ligand, the two methoxy-substituted rings face the viewer, while the other two rings are on edge. By the “quadrant rule,” catalyst and substrate experience different steric pressures, depending on relative orientation as they encounter each other. With differences in steric effects on approach come diastereomeric transition states of different energies. Therefore, a C2-symmetric configuration can foster an asymmetric transformation. For DIPAMP, the phenyls that expose their sides have stronger repulsive interactions with a substrate’s substituents. Si and re face of the alkene thereby encounter different repulsion upon binding to the metal, and enantioselectivity is observed in catalysis (Fig. 5). The quadrant rule leads to useful empirical guidelines of ligand design: (1) C2-symmetric ligands can potentially lead to enantioselectivity; (2) increasing steric differentiation between the blocked quadrant and opened quadrant may improve enantioselectivity. In late 1990s, Imamoto developed BisP 9 and MiniPhos33 ligands which present t-butyl and methyl substituents in different quadrants (Fig. 6). This stark steric contrast yielded over 99.9% ee in hydrogenation of a-acetamidocinnamate (MAC).

OMe C P

Rh

H N

O

P

N H

C

COOMe

COOMe

O

= Blocked quadrant = Opened quadrant

MeO

Quadrant rule

“Side to face” manner

Fig. 5 Quadrant view of Rh-DIPAMP. From Knowles, W. S. Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem. Int. Ed. 2002, 41 (12), 1998–2007, 2006.

OMe

L

C P

S

Inspired Rh

P

P

C

Rh

S

MeO

Quadrant view of Rh-DIPAMP

COOMe

[Rh], MeOH 1-3 atm H2

NHAc

L

Rh

COOMe

[Rh]= 0.2 mol% [BisP*-Rh(NBD)]BF4: 99.9% ee [Rh]= 0.1 mol% [MiniPhos-Rh(COD)]SbF6: 99% ee

NHAc

CH3

P

H3C

Quadrant view of Rh-BisP*

Fig. 6 General ligand design strategy based on quadrant rule.

= Opened quadrant

General structure of Rh-Bisphosphine

CH3 P

= Blocked quadrant

P

P

Rh

= Blocked quadrant

P

H3C

Quadrant view of Rh-MiniPhos

= Opened quadrant

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

5

Fig. 7 C1-symmetric ligands in asymmetric hydrogenation. From Imamoto, T. Searching for Practically Useful P-Chirogenic Phosphine Ligands. Chem. Rec. 2016, 16 (6), 2659–2673, 2666.

Beyond the now-ubiquitous C2-symmetric model, a C1-symmetric quadrant rule has proven effective in ligand design as well. Here only one quadrant is opened, with the other three sterically encumbered. In 2004, Hoge and coworkers reported a C1-symmetric bisphosphine—Trichickenfootphos (TCFP),40 on which three quadrants are hindered (Fig. 7). Its cationic Rh complex achieved over 99% ee on hydrogenation of a-acetamido dehydroamino acid and was employed in the synthesis of a key intermediate to pregabalin. Ligands of a similar design, such as MaxPhos,43 MeO-POP,43 3H-BenzP ,41 3H-QuinoxP ,52 t Bu-WudaPhos53 and BulkyP 54 have yielded impressive selectivity in asymmetric hydrogenation.

13.01.2.1.3

Empirical ligand design in Rh catalyst development—Backbone rigidity

The quadrant rule helps chemists predict the geometry of chiral pockets, but strict adherence to the rule does not necessarily induce satisfactory enantioselectivity. For example, BPE12 was designed with a C2-symmetric quadrant environment, with the chiral phospholane group presenting stark differences between blocked and opened quadrants (Fig. 8). However, the flexible backbone of BPE results in a mixture of conformational isomers upon Rh binding.55 Only one of the equilibrium structures forms an effective chiral pocket according to molecule modeling. The solution to this problem is enhanced backbone rigidity: by introducing a more rigid aryl linker between two phosphines, DuPhos7 generally achieves better enantioselectivity than BPE in Rh-catalyzed asymmetric hydrogenation. Similar to BPE, the flexibility of DIOP17 may be responsible for its relatively poor effectiveness in asymmetric hydrogenation. In 1997, Zhang designed BICP30 by restricting the flexible backbone of DIOP (Fig. 8), 97% ee was achieved on hydrogenation of a-acetamidocinnamic acid. To further rigidify the backbone, the phosphino groups can instead be installed within the five-membered ring motif of BICP, as seen in the chiral phospholane bisphosphine TangPhos (Fig. 9).10 Imamoto56 similarly imagined the bis phospholane scaffold as a derivative of BisP .9 While the Imamoto group tried to synthesize the structure from a phosphine-borane synthon, the Zhang group started from a phosphine sulfide, which fortuitously could coordinate to the chiral auxiliary nBuLi/(−)-sparteine and predominantly deliver the desired C2 product. The Zhang group thereby managed to synthesize TangPhos, reporting it in 2002.10 TangPhos has been one of the most efficient chiral phosphine ligands in Rh-catalyzed asymmetric hydrogenation. For example, superior enantioselectivity and reactivity were observed in hydrogenation of dehydroamino acids and enamides.10 The success of TangPhos inspired the development of analogous bisphospholane ligands such as Binapine,13 DuanPhos,57 ZhangPhos,58 DisquareP ,59 WingPhos,60 BIPOP,44 BABIBOP50 (Fig. 10).

13.01.2.1.4

Mechanistic studies of Rh-catalyzed hydrogenation of functionalized alkenes

Halpern61 and Brown62 gained critical insights from studies of the mechanism of the Rh-DIPAMP system. According to the Halpern mechanism, the cationic [DIPAMP-Rh-NBD]+ (NBD ¼ 2,5-norbornadiene) precursor reacts with H2 very quickly, forming solvated [DIPAMP-Rh-S2]+. Upon substitution of solvent for alkene, a pair of diastereomers is formed. Subsequently, slow oxidative addition with H2, fast hydride insertion into alkene, and reductive elimination complete the cycle. At room temperature, oxidative addition with H2 is turnover limiting. Perhaps counterintuitively, the minor diastereomer formed from alkene binding is much more reactive

6

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 8 Backbone rigidity in chiral bisphosphine ligand design.

than the major one. According to experiment, the thermodynamic ratio of diastereomers is about 11:1, yet the minor diastereomer has a more than 500-fold higher reaction rate than the major isomer. The observed product ratio of 60:1 represents 96% ee, in agreement with Knowles’ report. Halpern therefore proposed that the enantioselectivity was determined by both the ratio of the diastereomeric adduct precursors and the relative reaction rates of these diastereomers—Curtin-Hammett kinetic regime (Fig. 11). In reflecting on Halpern’s mechanism, it is worth considering if an even higher selectivity (>99.9% ee) could be achieved. Can a minor diastereomeric intermediate have enough of a kinetic advantage to generate such high levels of selectivity? In 2000, the Imamoto group proposed that a Rh catalyst with an electron-rich bisphosphine ligand that went through a different pathway than Halpern’s mechanism (Fig. 12).63 In Imamoto’s mechanism, [BisP -Rh-NBD]BF4 reacts via hydrogenation to form solvated [BisP Rh-S2]BF4. Rather than react directly with alkene, solvated [BisP -Rh-S2]BF4 reacts first with H2 via oxidative addition. Alkene then coordinates to Rh by substitution of a solvent molecule, followed by fast hydride insertion, rearrangement, and reductive elimination to form product. Compared to Halpern’s mechanism, solvated [BisP -Rh-S2]BF4 reacts with H2 faster because electron-rich BisP lowers the energy barrier to oxidative addition. The two resulting Rh dihydride diastereomers (A/B ¼ 10:1) were observed below −90  C, and found to react with (Z)-a-acetamidocinnamate (MAC) in 3 min below −100  C. In comparison, independently prepared [BisP -Rh-MAC]BF4 species (formed in a 10:1 diastereomeric ratio) are far less reactive. Reaction of [BisP Rh-MAC]BF4 diastereomers with H2 requires over 1 h under −80  C achieving similar enantioselectivity (97% ee) to the Rh dihydride diastereomers (99% ee). Based on Imamoto’s mechanism, enantioselectivity is determined by the relative rate of formation of each [BisP -Rh(H)2(MAC)] diastereomer. The repulsion between bulky tert-butyl group and chelating ring results in that chelating ring preferring the opened quadrant.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

7

Imamoto's ligand design strategy based on BisP*

P

H

P

P

P P

P

H

BisP* Imamoto 1998

H P

BH3 P

H3 B

1. nBuLi/ (-)-sparteine 2. CuCl2

tBu

P

H

tBu

tBu

BH3

H P H3 B

P

H

tBu

tBu

BH3

Meso: 10% yield Zhang's ligand design strategy based on BICP Ph2P H

Ph2P H

H P

H PPh2

H PPh2

H

P

BICP Zhang 1997 H

1. nBuLi/ (-)-sparteine

S P

P

tBu

2. CuCl2

S tBu

H

H Si2Cl6

P

P

S

C2: meso= 83:17 20% yield Recrystallization

COOR

Ar

NHAc

NHAc

R Ar

H

P

tBu

Rh-TangPhos H2

Ar

Rh-TangPhos H2

R

88% yield Zhang 2002 TangPhos

COOR NHAc

NHAc Ar

> 99% ee 16 examples

97-99% ee 13 examples

Fig. 9 The design and synthesis of TangPhos.

13.01.2.2 Functionalized olefin hydrogenation with Ru-based catalysts 13.01.2.2.1

Developing BINAP for Rh-catalyzed olefin hydrogenation

P-stereogenic bisphosphines, while effective in stereoinduction, have a reputation for being difficult to prepare. Since stereochemistry at P is not required for hydrogenation stereoselectivity (e.g., DIOP, BICP; see Section 13.01.2.1.3) other frameworks based on a chiral backbone offer a compelling alternative. In 1974 Noyori and coworkers4 designed the axially chiral binaphthyl BINAP (Fig. 13), a ligand whose chirality could be inexpensively derived from natural chiral compounds. The ligand demonstrates atropisomerism where hindered rotation around the C(1)–C(10 ) bond forms an axis of chirality. Six years later, Noyori published the first work on asymmetric hydrogenation of a-(acylamino)acrylic acid derivatives with a Rh-BINAP catalyst.21 While up to 100% ee was achieved, the reaction is relatively slow. The observed hydrogenation enantioselectivity can be rationalized using the quadrant rule (Section 13.01.2.1.2) and Halpern’s mechanism (Section 13.01.2.1.4) (Fig. 13).

13.01.2.2.2

BINAP in Ru-catalyzed olefin hydrogenation

In 1986, Noyori employed BINAP in a Ru system, one of the earlier examples of a ruthenium-catalyzed asymmetric hydrogenation.64 As opposed to Rh and Ir, Ru is often proposed to maintain a +2 oxidation state throughout catalytic cycles.65 Noyori’s BINAP-Ru(II) dicarboxylate precatalyst is effective for a very wide scope of chelating olefins such as a,b-unsaturated carboxylic acids,66 dehydroamino acids,67 and allylic alcohols.68 Mechanistic study69 showed initial rapid exchange between the carboxylate ligand and the carboxylic acid substrate is followed by turnover limiting H2 activation (Fig. 14). A subsequent alkene insertion into Ru–H was proposed.69 The cycle continues with substitution of product for substrate.

8

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

tBu

P

H

P

P tBu

TangPhos Zhang, 2002

P H P

P

tBu

Binapine Zhang, 2003

tBu

DuanPhos Zhang, 2005

ZhangPhos Zhang, 2010 O HH O

H H P

H

HH

H H

P H P

O HH O

H H

P

P

P

P

P

P

tBu

R DiSquareP* Imamoto, 2004

P tBu

tBu

R

BIPOP Tang, 2010

Imamoto, 2004

tBu

WingPhos Tang, 2013

O R P P

tBu tBu

R O BABIBOP Tang, 2018

Fig. 10 Analogous chiral bisphosphine ligands of TangPhos family. From Imamoto, T. Searching for Practically Useful P-Chirogenic Phosphine Ligands. Chem. Rec. 2016, 16 (6), 2659–2673, 2665.

S

*

P MeO2C * P H Rh P H

O S NH Rh

H N

*

H H N CO2Me

CO2Me

H P

O

Ph

Ph O

ko.a.(major) r. d. s MeO2C

*

P P

Rh

ko.a.(Minor) >> ko.a.(major) (R)-Enantiomer (S)-Enantiomer: Major isomer

Ph

H Ph

Major diastereomer cycle Slow

COOMe

Curtin-Hammett regime 2S

NHAc

H N

CO2Me

HN

Ph O

*

P S Rh P S

Rh

Ph O

S= Solvent

P P

ko.a.(Minor) r. d. s

2S H Ph

Minor diastereomer cycle Fast

COOMe NHAc

H2

HN

S

2S

Ph O

MeO2C

H H N O

*

= DIPAMP

(R)-Enantiomer: Minor isomer S

H2

P P

P Rh P

Ph (S)-Enantiomer

HN S MeO2C Ph

*

H2

CO2Me P * H Rh P H

O Rh P

P S

H *

Fig. 11 Halpern’s mechanism for Rh-catalyzed asymmetric hydrogenation.

13.01.2.3 Unfunctionalized olefin hydrogenation with Ir based catalyst Functionalized olefin substrates were the initial focus of asymmetric hydrogenation, and the earliest success had been achieved with Rh catalysts. In this period, Ir was seldomly considered for catalytic reactions, as there was a belief that third row metals were unsuitable for catalytic reactions; the assumption was that oxidative addition would be too favorable and a thermodynamic sink would lead to insurmountable reaction barriers.70 Put another way, the higher M-L bond strength of Ir versus Rh analogs would lead

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

CH3

CH3 tBu

P

Pt Bu CH3

tBu

Rh

P

Pt Bu CH3 H

Rh

H2

P

Ph

Rh

NHAc

S

tBu

2S CH3

A/B=10:1

tBu

H

+

Pt Bu S CH3

Ph

P

Pt

H O

Rh

NH Ph

Bu CH3 O

Rh

Pt Bu S CH3 B

S

A H

H S

P

NH

-80 °C, 1 h SLOW

tBu

Rh

tBu CH3 O

OMe

COOMe S

P

CH3 S= Solvent

P

O Ph Rh

NHAc

CH3

CH3

P

H2

tBu

H

P

Ph

2S, H2

CH3

tBu

Ca. 10:1

COOMe

Ph

tBu

CH3

OMe O NH

O

9

OMe

H

COOMe -100 °C, < 3 min FAST

NHAc

CH3

S

tBu

CH3 tBu

P

P

P

P

H S

Rh

tBu CH3 O

H H

Ph R NH

Rh

tBu

R

S

CH3 O NH

R=COOMe Ph

R=COOMe

CH3 tBu

P S

P

H H

S

Rh

tBu

R

CH3 O

Ph NH H

R=COOMe

P

Rh

H3C X

CH3 P H

= Blocked quadrant = Opened quadrant = Chelating ring

Fig. 12 Imamoto’s mechanism for Rh-catalyzed asymmetric hydrogenation with electron rich bisphosphine ligands. From Imamoto, T. Searching for Practically Useful P-Chirogenic Phosphine Ligands. Chem. Rec. 2016, 16 (6), 2659–2673, 2670.

Fig. 13 Design of BINAP and application in Rh catalyzed asymmetric hydrogenation.

10

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 14 Mechanism of BINAP-Ru dicarboxylate catayzed olefin hydrogenation. From Ashby, M. T.; Halpern, J. Kinetics and Mechanism of Catalysis of the Asymmetric Hydrogenation of Alpha, Beta-Unsaturated Carboxylic Acids by Bis (Carboxylato){2, 20 -Bis (Diphenylphosphino)-1, 10 -Binaphthyl} Ruthenium (II),[RuII (BINAP)(O2CR) 2]. J. Am. Chem. Soc. 1991, 113 (2), 589–594, 592.

to intermediates too stable for efficient catalysis.71 Nonetheless, Crabtree found that [(COD)Ir(L)2]BF4 gave a high reaction rate in noncoordinating solvents such as CH2Cl2 (rather than the alcoholic solvents conventional in hydrogenation at that time).72 Subsequently, Crabtree73 developed the well-known [(COD)Ir(PCy3)(C6H5N)]PF6 achieving extraordinary activity for hydrogenation of olefins of many varieties—even tetra-substituted olefins. Even with a flurry of activity in asymmetric hydrogenation through the 1980s, it would take another decade before enantioselective hydrogenation of unfunctionalized olefins was realized. In 1997, Pfaltz and coworkers11 prepared the chiral chelating [P, N] ligand PHOX and formed a “Crabtree-like” [(COD)Ir(PHOX)]PF6 complex (Fig. 15). With 0.3 mol% of catalyst, up to 98% ee was achieved for asymmetric hydrogenation of unfunctionalized olefins under 10–50 bar of H2.74 A kinetic study showed a high initial rate but rapid catalyst deactivation,75 attributed to irreversible formation of hydride-bridged trinuclear Ir complexes.76,77 Attempts to increase catalytic efficiency by variation of solvents, hydrogen pressure or adding additives were all unsuccessful. However, an analog with the weakly coordinating anion BArF4 in place of PF6 offered higher turnover frequencies with reduced catalytic loading (as low as 0.02 mol%). A kinetic study78 with different anions reveals that with PF6 as counterion, shared that the reaction is first order with respect to olefin concentration, while a zero order reaction was seen with the BArF complex. The difference

X MeO

MeO [Ir], 50 bar H2, CH2Cl2 23 °C

O [Ir]=

(o-Tol)2P

Ir

N tBu

98% ee, 99% conversion

N

P

X

TOF(h-1)

Al(OC(CF3)3)4

5,000

BArF4

4,600

B(C6F5)4

3,900

PF6

1,700

BF4

300

SO3CF3

0

Ir N

H Ir P

Ir

P

N

Inactive species

Fig. 15 Ir-PHOX catalyzed ADH of unfunctionalized olefins. From Iridium-Catalyzed Asymmetric Hydrogenation of Olefins With Chiral N,P and C,N Ligands. Top. Organomet. Chem. 2011, 34, 31–76, 34.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

11

Fig. 16 Representative chiral [P, N] ligands for asymmetric hydrogenation.

can be explained by a formed tight counterion pair with PF6, or by coordination of PF6, inhibiting olefin coordination; weakly coordinating BArF in contrast doesn’t interfere with olefin coordination. Following Pfaltz’s report, various chiral PHOX ligands were subsequently developed (selected examples shown in Fig. 16).79–103 As for Rh catalysis, our rationalization of the relative selectivity of chiral Ir complexes has benefited from a deep understanding of mechanism. Unlike the Rh(I)/Rh(III) cycles typically proposed for Rh catalysis (Section 13.01.2.1.4), Ir(III)/Ir(V) cycles89,104–107 are currently favored for the PHOX-Ir system. But uncertainty remains regarding the elementary steps involved, and multiple mechanisms may be viable depending on substrate and conditions. Enantioselectivity can be predicted by Andersson’s model108 (Fig. 17) by considering olefin orientation in selectivity-determining migratory insertion (or metathesis, depending on the system studied). In the selectivity-determining step, the stereochemistry of the reacting Z2-H2 olefin complex places the olefin perpendicular to PHOX-Ir plane, with steric pressure dictating the favored structure. Olefin substituents are distinguished by a C1-PHOX-Ir quadrant model in the case of Andersson’s ligand.

12

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

z-axis H H N Ir

P H

H

H H

H2

N

S

R2

S

P Ir

H x-axis

H = Blocked quadrant

S

H H N Ir

P H

Migration insertion Pathway

N Ir

H

Metathesis Pathway

H

H

H

= Slightly blocked quadrant

H P

N Ir

= Opened quadrant

P H

Quadrant view of Ir-[P, N] complex

H

z-axis

z-axis

C2H6

R

R H N Ir H

P

RL

Rs

x-axis

Rs

RL

x-axis

H H

Proposed Ir(III)/Ir(V) cycle

Unfavored

Favored

Fig. 17 Proposed Ir(III)/Ir(V) cycle and enantioselective consideration. From Verendel, J. J.; Pamies, O.; Dieguez, M.; Andersson, P. G. Asymmetric Hydrogenation of Olefins Using Chiral Crabtree-Type Catalysts: Scope and Limitations. Chem. Rev. 2014, 114 (4), 2130–2169, 2134.

13.01.2.4 Olefin hydrogenation with Co based catalyst Precious metal catalysts dominated the first decades of asymmetric hydrogenation, perhaps because the earliest success was with Rh. Just as early assumptions had erroneously discounted third-row catalysts, first-row metals had been long assumed to be unsuitable for asymmetric hydrogenation for poor catalytic activities with respect to second-row metals. This, too, has been disproven, with extraordinary progress achieved in the last decade.109–112 In particular, complexes of Mn,113,114 Fe115,116 and Co117,118 have been extensively studied. Excellent enantioselectivity and, at times, comparable catalytic efficiency to precious metal complexes have been achieved. The renaissance of first-row metal chemistry is best exemplified by recent discovered Co catalysts for asymmetric hydrogenation.117–119 Here we find exciting prospects for unearthing new mechanistic paradigms and constructing novel ligand scaffolds—and of course, acknowledge the vastly higher natural abundance of Co versus Ir and Rh. Work in chiral Co catalysis had long failed to achieve the performance of precious metal complexes. For example, Schmidt and coworkers120 achieved modest stereoselectivity the reduction of methyl a-acetamidocinnamate using a combination of a Co(II) precursor and DIOP in the presence of NaBH4 (Fig. 18). In an major advance, Chirik, Tudge and coworkers121 reported a DuPhosCo(II)-dialkyl complex for asymmetric hydrogenation of dehydroamino carboxylates, a discovery enabled by high-throughput discoveries (Fig. 18, top). A respectable 93% ee and 99% conversion was achieved for 2-acetamido-3-phenylacrylate. A later study122 improved the reaction; precatalysts [Ph-BPE-Co(I)-Cl]2 and Ph-BPE-Co(0)-COD were each highly active toward dehydro-levetiracetam hydrogenation in methanol (Fig. 18, bottom), generating >97% ee with over 99% yield at only 0.5 mol% catalyst loading. More recently, Chirik123 and Zhang124 reported Co catalyzed hydrogenation of a, b-unsaturated carboxylic acid, achieving up to 99% ee and 1860 TON (Fig. 19). A two-electron mechanism, akin to those proposed for second and third-row complexes, can be envisioned for the Chirik system (Fig. 19). In a Co(0)/Co(II) cycle, (diphosphine)CoH2 would be an on-pathway species. A DFT study on the mechanism of (diphosphine)CoH2 suggests 1,2-alkene insertion and subsequent reductive elimination is a viable path to product.125 There is some experimental evidence for in situ formation of CoH2, but as of this writing, such a species remains unobserved. Precatalyst [Ph-BPE-Co(I)-Cl]2 disproportionates resulting in a Co(II) dihalide and a Co(0) complex122; the latter could undergo oxidative addition with H2 to form (diphosphine)CoH2. An analogous hydride could be formed via hydrogenolysis of iPr-DuPhos-Co(II)(CH2SiMe3)2; the byproduct, SiMe4, can indeed be observed in situ via NMR.126 A deactivating protonolysis seems possible in the protic media used for hydrogenation. Indeed, alcohols react with iPr-DuPhos-Co(II)-(CH2SiMe3)2 to form iPr-DuPhos-Co (II)-dialkoxides,127 while in methanol, subsequent dehydrogenation forms [iPr-DuPhos-Co(0)]2(m-CO)2. However, protonolysis does not lead to deactivation, as iPr-DuPhos-Co(II)-dialkoxide and [iPr-DuPhos-Co(0)]2(m-CO)2 are themselves competent for hydrogenation. Further study is needed to clarify the viable pathways to product, and a Co(0)/Co(II) cycle is only one possibility. Hopmann and coworkers identified a pathway for hydroxyl alkene hydrogenation via a metallacyclic species, on a pathway composed entirely of Co(II) intermediates.128

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 18 ADH of olefins with Co catalysts.

Fig. 19 Mechanism of hydrogenation of olefin with Co complexes.

13

14

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Asymmetric hydrogenation with Co is still in its infancy, and so the powerful quadrant-type models used to rationalize chiral ligand selectivity for Ir and Rh have not yet been adapted for Co. However, some progress has been made in considering the relative energies of stereoisomers formed upon substrate binding to Co. Chirik and coworkers,129,130 in reporting Co(I) diene and arene precatalysts for hydrogenation of methyl 2-acetamidoacrylate (MAA), prepared [iPr-DuPhos-Co(I)-(Z2,Z2-MAA)]+. The major, isolable pro-(R) isomer is in fact the opposite of the pro-(S) isomer that leads to observed product (>99% conversion). This finding supports a Curtin-Hammett kinetic regime, where substrate coordination is fast and reversible. Much like Halpern’s mechanism for the Rh congener (Section 13.01.2.2), the reaction rate of the minor isomer is apparently critical for determining reaction enantioselectivity.

13.01.2.5 Olefin hydrogenation with Ni based catalyst In contrast to Co, there are just a handful of reports of Ni asymmetric hydrogenation (Fig. 20). Zhou131,132 reported a transfer hydrogenation of enamides and a, b-unsaturated carboxylate esters using an in situ generated Ni catalyst and HCOOH/NEt3 as reductant. In 2016, Campeau and Chirik133 explored direct hydrogenation of a, b-unsaturated carboxylate esters, screening combinations of nickel precursors, halide additives and chiral bisphosphines (in all, 192 ligands were screened). Up to 95.6% ee can be achieved when both acetate and iodide were present, e.g., 5 mol% Ni(OAc)2 and 5 mol% Bu4NI. Zhang and coworkers134–138 discovered hydrogenation of conjugated alkenes with Ni(OAc)2/Binapine in 2017, reporting excellent enantioselectivity. The protocol can form a chiral quaternary carbon center through a desymmetrization reaction (see enone product, Fig. 20).139 Zhang and coworkers140 also reported successful hydrogenation of dehydroamino acid derivatives with a Ni/BIPHEP system. Mechanistic study of (racemic) Ni hydrogenation by Bouwman141 indicates that H2 is activated via heterolytic cleavage, with the assistance of acetate anion in during initiation of precatalyst (Fig. 21, left). The formed Ni(II) monohydride, now on-cycle, coordinates alkene and undergoes migratory insertion, followed by turnover-limiting hydrogenolysis to release product. Similarly, Campeau and Chirik133 identify heterolytic H2 cleavage as turnover-limiting. After the resting state complex [(Me-DuPhos)3Ni3(OAc)5I] activates H2 to generate a Ni–H intermediate, enantioselective conjugate addition forms a Ni enolate; protonation releases product. Chelating coordination of conjugated alkene is critical to achieve high enantioselectivity (Fig. 21, right).

Fig. 20 Olefin hydrogenation with Ni catalysts.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

P P

OAc

S

OAc

P

Ni OAc

P

S

15

[(S,S)-Me-DuPhos]3Ni3(OAc)5I

Ni OAc H2 H Ph

HOAc P P

R

OEt

O [Ni]

O

O

R

S Ni H

H

S

H2

OEt

Ph

HOAc [Ni]

M

O

R P P

R Ni S

H H

P P

M eO H H HOAc

eO

OH O

H [Ni]

Ni H Ph

S

Ph

COOEt

[Ni] EtO

Bouwman’s mechanistic proposal

H

O

Chirik’s mechanistic proposal

Fig. 21 Proposed mechanism for Ni catalyzed hydrogenation of olefins. From Nickel-Catalyzed Asymmetric Alkene Hydrogenation of a, b-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation. J. Am. Chem. Soc. 2016, 138 (10), 3562–3569, 3567; Kinetics of the Hydrogenation of 1-Octene Catalyzed by [Ni (o-MeO-dppp)(OAc) 2]. J. Mol. Catal. A Chem. 2001, 175 (1–2), 65–72, 71.

13.01.3 Developing chiral phosphine ligands for ketone hydrogenation Schrock and Osborn’s ketone hydrogenation142 came just a few years after Wilkinson’s5 olefin hydrogenation. And yet, chiral catalysts for stereoselective ketone hydrogenation took much longer to emerge and develop. The reactions share some superficial features, but the increased polarity of the C]O bond vs. C]C leads to different coordination behavior—and therefore, an entirely different set of catalyst-substrate interactions and elementary steps. Moreover, asymmetric ketone reduction using stoichiometric reagents had been attempted since the 1950s,143 and perhaps was seen as the most logical route to affording chiral alcohols. Noyori was one of the first to develop an efficient reagent for modifying lithium aluminum hydride (LAH) for asymmetric synthesis. The BINAL-H reagent, formed from chiral binaphthol (BINOL) and LAH in THF, was reported in 1979 for the asymmetric reduction of carbonyls.144 The binaphthyl C2 scaffold of BINOL—identified by Cram145 as a privileged scaffold for generating asymmetric environments—has the same spatial properties as BINAP,4 Noyori’s chiral ligand for Ru hydrogenation (Section 13.01.2.2.2). The extraordinary versatility of BINAP enabled Noyori to pioneer yet another field, asymmetric ketone hydrogenation.

13.01.3.1 Ketone hydrogenation with Ru based catalysts 13.01.3.1.1

Development of the BINAP-Ru catalyst for ketone hydrogenation

In the late 1980s, Noyori extended prior work on olefin hydrogenation (Section 13.01.2.2.2) to reductions of chelating ketones, utilizing a BINAP-Ru halide oligomer catalyst.146–148 A range of functionalized ketones are efficiently hydrogenated to corresponding chiral alcohols when chelating nitrogen or oxygen groups are adjacent to the carbonyl.4 A Ru-H formed via hydrogenolysis of Ru-Cl is proposed to be the active catalyst (Fig. 22).149–151 Solvated BINAP-RuCl2 oligomer is more efficient than BINAP-Ru carboxylate in ketone hydrogenation because the BINAP-RuCl2 precatalyst generates HCl upon activation, which facilitates Ru-H ketone insertion via acidic activation of C]O of ketone. Enantioselectivity is generated in the hydride transfer step, and the selectivity can be rationalized using the C2 quadrant model of BINAP-Ru in Fig. 23. Although effective for chelating ketones, ketones without an adjacent chelating group are inefficiently hydrogenated by BINAP-RuCl2 oligomer. In 1995, Noyori and coworkers152 synthesized a BINAP-RuCl2-diamine system through reaction of a chiral 1,2-diamine with BINAP-RuCl2 (Fig. 24). The resulting BINAP-RuCl2-diamine system catalyzes hydrogenation of acetophenone derivatives under low H2 pressure and at room temperature, with up to 99% ee and 5000 TON. Under 45 atm H2 at 30  C, up to 2,400,000 TON and 80% ee is achieved within 48 h.153 (Note that we focus on acetophenone in this chapter because it has become a benchmark for asymmetric hydrogenation, allowing for a comparison of selectivity and activity of catalysts in context.) An outer-sphere metal-ligand bifunctional mechanism has been proposed for the BINAP-Ru-diamine system.154–156 H2 activation occurs under basic conditions to form the trans-Ru dihydride active species. Ru–H and N–H transfer hydride and proton to C]O simultaneously via a six-membered cyclic transition state. In this geometry, the carbonyl C]O is aligned with the Ru–N bond. Enantioselectivity can therefore be achieved for acetophenones through differences in steric pressure as substrate engages the catalyst in the transition state (Fig. 25). The “NH effect” is the key feature for high efficiency in this system.157

16

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 22 Proposed mechanism for chelating ketone ADH by BINAP-Ru halide oligomer. From Asymmetric Catalysis: Science and Opportunities. Angew. Chem. Int. Ed. 2002, 41, 2008–2022, 2015.

P

Ru

OH O

P R

Quadrant view of Ru-(S)-BINAP

O OR’

Favored

OH R

’RO

Unfavored

Fig. 23 Quadrant view of enantioselectivity by Ru-(S)-BINAP.

OH

O 1 mol% KOtBu, 45 atm H2, 24-30 °C, 48 h S/C=2,400,000 Ar2 Cl P Ru P Ar2 Cl

H2 N

Ph

N H2

Ph

80% ee 100% yield

(S)-Tol-BINAP-RuCl2-(S,S)-DPEN Ar=4-Me-C6H4

Fig. 24 Hydrogenation of acetophenone by BINAP-Ru-diamine.

13.01.3.1.2

Developing multidentate ligands for Ru-catalyzed transfer hydrogenation

The BINAP-Ru-diamine system remains a state-of-the-art system for ketone asymmetric hydrogenations. But it does have limitations. Despite high reaction rate and high efficiency, enantioselectivity erodes when catalyst loading is low, probably due to diamine exchange with solvent or product.158 In late 1990s, Gao,159 Ikariya and Noyori160 prepared a tetradentate chiral P2N2 ligand; enhanced chelation should limit selectivity eroding ligand dissociation. The resulting (S, S)-trans-RuCl2-(P-NH-NH-P) achieves over 91% conversion and 97% ee in transfer hydrogenation of acetophenone (Fig. 26). Here we note that transfer hydrogenation of ketones is often explored in parallel with direct (H2) hydrogenation, and while mechanistic details and experimental conditions will vary, the same basic concepts in chiral ligand design apply to both reactions. Constraining the coordination environment around Ru appears to benefit reactivity—up to a point. In 2009, Mezzetti and coworkers161 went one step further than Noyori, preparing an even more constrained macrocyclic PNNP ligand. The corresponding Ru complex was evaluated in transfer hydrogenation of acetophenone. However, with 1 mol% of catalyst and 0.5 mol% of KOtBu at 60  C in iPrOH, 92% yield and only moderate enantioselectivity (30% ee) were achieved after 8 h (Fig. 27).

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

17

O

O Ph

H

H

O

H P H Ru P H

H

Ph

N

P Ru

N H

H

H Ph

N

P

Ph H

N H H

Ph H

Unfavored TS H Cl P

H

H

N

Ph

N

Ph

Ru P

Cl H

H P

KOtBu, H2

H

N

Ph

N

Ph

H

H

H

O

Ru

N

H

OH H

H

Ru P

C

H

[2+2] bifunctional mechanism “NH” effect

H Ph

N

P Ru P H2

N H H

Ph H

Fig. 25 Bifunctional mechanism of BINAP-Ru-diamine catalyzed ketone hydrogenation.

O

OH 0.5 mol% [Ru], 0.25 mol% KOtBu iPrOH,

45 °C, 7h 93% yield, 97% ee

H

Cl

H

N N Ru P P Ph2 Cl Ph2

[Ru]=

C

O

Ru

N

H

H

Proposed TS

Fig. 26 Ru-P2N2 catalyzed transfer hydrogenation of acetophenone.

O

OH 1 mol% [Ru], 0.5 mol% KOtBu iPrOH,

60 °C, 8h 92% yield, 30% ee Cl

[Ru]=

N N Ru P P Cl Ph Ph

Fig. 27 Transfer hydrogenation of acetophenone with Ru-PNNP complex.

13.01.3.1.3

Developing pincer ligands for Ru-catalyzed ketone hydrogenation

Although Noyori’s BINAP-RuCl2-diamine system has another limitation besides ligand dissociation: it is crowded at Ru, and bulky ketones can’t be efficiently hydrogenated. Compared to dicoordinate BINAP or diamine, a tricoordinate pincer ligand can provide a more stable coordination environment and a less crowded metal center. In 1996, Zhang162 developed Ru catalysts based on C2-symmetric ligand PNP 1 (48% ee for asymmetric transfer hydrogenation of acetophenone) and NPN ligand 2163 (72% conversion and 79% ee) while Togni164 reported chiral fac-Ru-PPP complex 3 (99% conversion and 71.7% ee). By 2003, Zheng had achieved selectivity approaching Noyori’s system; the Ru complex based on chiral PNO ligand 4165 reached 99% conversion and 92% ee, and the reaction of chiral PNP ligand 5166 was reported soon after (90% conversion, 80% ee; Fig. 28). By 2004, C1 pincer scaffolds began to rival the classic C2 structures in ketone hydrogenation (and transfer hydrogenation) reactions. Somanathan167 developed a chiral PNN ligand 6 (Fig. 29) based on chiral diamine motif; the in situ generated Ru/PNN

18

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 28 Representative Ru pincer complex in asymmetric transfer hydrogenation of acetophenone. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi: 10.1021/acs.chemrev.1c00075.

Fig. 29 Representative Ru pincer complex in ketone hydrogenation. Note that ligand 6 has been used in transfer hydrogenation, as well as direct hydrogenation as part of complex 7. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

19

achieved 99% ee for transfer hydrogenation of acetophenone. Employing a similar ligand design strategy, Clarke and coworkers168 synthesized mer-Ru-PNN complex 7, achieving 58% ee and 99% conversion in asymmetric direct (H2) hydrogenation of acetophenone. Note that pincer ligands need not be meridional to enforce stereoselectivity. Kitamura169 produced fac-Ru/PNN 9 and found a DMSO effect; by adding 140 mol% of DMSO, extraordinary yield (99%) and enantioselectivity (98% ee) were observed in the direct hydrogenation of a bulky b-keto ester. In 2015, Díaz and Castillón170 developed a C2-symmetric P-stereogenicly PNP-type ligand, forming highly reactive complex 8; 87% ee and 98% conversion were achieved in hydrogenation of acetophenone at −40  C under 30 atm H2.

13.01.3.2 Ketone hydrogenation with Ir based catalysts Compared to Ru, Ir catalyzed asymmetric transfer hydrogenation is less common. In 1995, Bianchini and Granziani171 reported the synthesis of fac-PNP-Ir dihydride (Fig. 30). Transfer hydrogenation of a, b-unsaturated ketone gave up to 54% ee and 97% conversion. In 2005, Abdur-Rashid172 developed a highly efficient PNP-Ir(III) complex 10, achieving 69% ee and 99% yield with 0.053 mol% catalyst loading and 0.053% KOtBu as activator. A mechanistic study on racemic catalyst173 supported Ir-H3 as the key active species. Similar to Noyori’s catalyst, a IrH/NH metal-ligand bifunctional mechanism was proposed. Ir catalyzed direct hydrogenation of ketones is more common. Zhou174 developed P-NH ligand 12 in 2011 and achieved 92% ee and 99% conversion in a 12/Ir-catalyzed hydrogenation of acetophenone (Fig. 31). Mechanistic study revealed the formation of Ir monohydride species when the ratio of ligand to Ir was 2:1. Based on this study Zhou developed tridentate SpiroPAP.175 Its corresponding Ir dihydride complex 11 achieved 99% conversion, 98% ee and an extraordinary 4,550,000 TON under mild conditions (1 mol% KOtBu, 10 atm H2, 25–30  C). Ir-SpiroPAP 11 is also effective with other ketones; 98% ee and 1000 TON are typical. Ir-H3 is believed to be the active species and once again, a six-membered cyclic transition state model—consistent with a IrH/NH bifunctional mechanism—rationalizes the stereochemistry of the transformation. Ir-SpiroPAP is representative of the stateof-the art in Ir hydrogenation of ketones, where TON above 1 million are increasingly commonplace. Ferrocene-based PNN ligands (Fig. 32) are a highly effective class of chiral scaffolds for ketone hydrogenation. In 2013, Chen and Zhang176 found in situ generated Ir/13 gave modest 77% ee and 99% conversion in acetophenone hydrogenation. Refinements by Hu177 led to 15, resulting in improved enantioselectivity (94% ee). In 2016, Zhang178 combined chiral ferrocene with an oxazolyl motif to form f-amphox 14. In situ complexation with [Ir(COD)Cl]2 generated a catalyst that achieves over 99.9% ee and

Fig. 30 Asymmetric transfer hydrogenation of simple ketone with representative Ir pincer complex. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Fig. 31 Developing SpiroPAP for Ir catalyzed ketone directed hydrogenation. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Fig. 32 Ferrocene and spiro-based PNN ligands for Ir hydrogenation of ketones. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

21

1,000,000 TON; moreover, the catalyst is stable in the freezer for months. Derivatives f-amphol 17,179 f-ampha 16180 and f-amphamide 18181 are all highly efficient. In 2018, Zhong182 developed ferrocene based PNN ligand 19; its corresponding Ir catalyst achieves 97.7% ee and 100,000 TON in acetophenone hydrogenation. In the same period, Ding183 developed spiro based chiral PNN ligand 20. The in situ generated Ir catalyst by complexation with [Ir(COD)Cl]2 achieved up to 98% ee and 1,000,000 TON. Although robust mechanistic data is not yet available, ferrocene-based and spiro-based PNN ligands can plausibly enforce stereochemistry in a manner akin to Ir-SpiroPAP (Fig. 31).

13.01.3.3 Ketone hydrogenation with Fe based catalysts As described in Section 13.01.2.4, first-row metal complexes are quickly becoming viable alternatives to conventional precious metal olefin hydrogenation catalysts. This trend is also apparent in ketone hydrogenation, although turnover numbers have not yet approached the 1,000,000 + benchmark seen for Ir. Much like Ru and Ir catalysts, Fe(II) based catalysts often contains strong field ligands, like phosphines and carbonyl ligands. Diamagnetic Fe(II) complexes undergo slower ligand substitution than paramagnetic complexes, making them more suitable for enantioselective transformations where ligand dissociation is a concern.184

13.01.3.3.1

Ketone transfer hydrogenation with Fe based catalysts

Morris initiated iron catalyst development after the study of Ru-PNNP185 and BINAP-RuCl2-diamine186–194 systems since early 2000s (Fig. 33). The first-generation Fe catalyst was designed based on an diiminophosphine P-N-N-P ligand. The [6,5,6]-P-N-N-P Fe(II) complex 21195 was synthesized via mixing free ligand with [Fe(H2O)6][BF4]2 in refluxing acetonitrile. This catalyst was evaluated for ketone hydrogenation, where up to 40% conversion and 27% ee were observed; there was no reactivity for transfer hydrogenation. The derivative carbonyl complex 22 is more active, with up to 61% ee and 99% conversion achieved. [6,5,6]-P-NN-P Fe(II) catalyst 22 have an induction period and need to be activated with base; these basic conditions form observable pentadentate ferraaziridine complex 23 and 24.196 But the mechanism of the catalyst is not immediately clear. IR and mass balance experiments suggests that 75% of iron is inactive, and Fe(0) nanoparticles may be formed. The flexibility of the six membered rings of [6,5,6]-P-N-N-P could be responsible for catalyst deactivation during catalysis, so a smaller [5,5,5]-P-N-N-P ligand (Fig. 34) was sought for increasing the rigidity of catalyst framework. A [5,5,5]-P-N-N-P Fe(II) O

OH [Fe], KOtBu Hydrogen source

2+

2+

2BF4

2BF4 N

N N N Fe P P Ph2 Ph2 N

N N Fe P P Ph2 CO Ph2

21 S/C/B(KOtBu)=225:1:15, iPrOH, 50 °C, 18 h 40% conversion, 27% ee

22 S/C/B(KOtBu)=200:1:8, iPrOH, 22 °C, 3.6 h 95% conversion, 61% ee + BF4

H

i Pr

Na O

N NH Fe P P Ph2 CO Ph2 23

2+ 2BF4 N N N Fe P P Ph2 CO Ph2 22

KOtBu

Exce

ss K O t Bu

H N N Fe P P Ph2 CO Ph2 24

Fig. 33 Ketone hydrogenation with Fe-PNNP complex. From Ligands for Iron-Based Homogeneous Catalysts for the Asymmetric Hydrogenation of Ketones and Imines. In Ligand Design in Metal Chemistry: Reactivity and Catalysis; 2016; pp 205–236, 219.

22

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

O Ph

+ Ph

Br

N

Fe

P Ph2

H BPh4

Ph

N

N Fe P P Ph2 Ph2 O

N iPrOH

P Ph2

H Ph

O

KO Pi r Bt u OH

O 25

Ph

Ph

N

N

H Fe P P Ph2 Ph2 O

t Bu H KO r O iP

Ph H

Ph

N

N Fe P P Ph2 Ph2 O

26

27

+ Ph

O

Ph

BF4 O

H

O

N

N Fe P P Ph2 Cl Ph2

OH Ph

Ph H Ph N

H

28

Fe

N P Ph2

P Ph

Ph

Ph Ph H

O Ph Ph H Ph H N Ph N Fe P P Ph2 Ph O

O Favored TS

Unfavored TS

Fig. 34 Mechanisms of Fe-PNNP and Fe-PN(H)NP complex. From Ligands for Iron-Based Homogeneous Catalysts for the Asymmetric Hydrogenation of Ketones and Imines. In Ligand Design in Metal Chemistry: Reactivity and Catalysis; 2016; pp 205–236, 227.

complex 25 was synthesized via multi-component template synthesis followed by a reaction with CO.197–199 Up to 3600 h−1 and 82% ee were achieved with this system, a significant improvement from the [6,5,6] catalyst. Mechanistic study200–202 suggests that an amido-enamido intermediate 26 is formed by reacting pre-catalyst with base. Subsequently, intermediate 26 is converted to a FeH/NH complex 27. The turnover limiting step is stepwise hydride transfer from Fe(II) to ketone substrate, followed by NH proton transfer and regeneration of the intermediate. Mechanistic study drove the effort to develop the third-generation catalyst, [5,5,5]-amino-enamidophosphine Fe(II) complex 28 (Fig. 35).203 Transfer hydrogenation of acetophenone derivatives gave up to 6100 TON and 98% ee. The mechanism is the same as the second-generation catalyst, now without an induction period. In 2014, Mezzetti and coworkers204,205 developed a isonitrile Fe(II) catalyst 30 with a chiral macrocyclic P-N-N-P ligand (Fig. 36). Up to 91% ee and 98% conversion were achieved. Preparing a chiral Fe(II) monohydride complex 31 achieved base-free transfer hydrogenation with up to 99% ee, quantitive conversion, and 9430 h−1 TOF.206–209

O

OH [Fe], KOtBu Hydrogen source

+ Ph

O

Ph

+ BF4

H

Ph

Br

Ph

BPh4

N

P P Ph2 Cl Ph2

N Fe P P Ph2 Ph2 O

28 S/C/B(KOtBu)=5000:1:8 iPrOH, 28 °C 82% conversion, 88% ee

29 S/C/B(KOtBu)=6000:1:8 iPrOH, 28-30 °C 2.0×104 h- TOF, 81% ee

N

Fe

N

Fig. 35 Transfer hydrogenation using Fe-PNNP and Fe-PN(H)NP complex.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

O

23

OH [Fe] Hydrogen source

+

2+ 2BF4 N P

Ph R

N

Fe P

BF4

H N

N

Ph N

P H

R

Ph

30 R=tBu S/C/B(NaOtBu)=100:1:4 iPrOH, 75 °C, 15 h 93% yield, 84% ee

Fe P

H

N N

R

Ph

31 R=CEt3 S/C=1000:1 iPrOH, 50 °C, 0.5 h 90% yield, 99% ee

Fig. 36 Transfer hydrogenation of acetophenone with macrocyclic Fe-PNNP and Fe-PN(H)N(H)P complex.

13.01.3.3.2

Ketone direct hydrogenation with Fe based catalyst

Fe(II) catalyst has shown good activity and enantioselectivity in transfer hydrogenation, but the reversible reaction can cause enantioselectivity erosion at extended reaction times. Motivated to develop an Fe catalyst for the (irreversible) direct hydrogenation, Morris and coworkers210 synthesized Fe(II)-PNP complex 32 via a template reaction (Fig. 37). The pre-catalyst was activated by 6 equivalents of LiAlH4 then with t-AmylOH to release an active Fe(II) alkoxide 33 (Fig. 38). Up to 85% ee and 5000 TON were achieved. A FeH/NH bifunctional mechanism was proposed combining experimental evidence and DFT studies. Inactive Fe(0) 34 was formed by reaction of Fe(II) alkoxide 33 with base in the absence of H2, limiting efficiency. In 2017, Morris developed the improved PNP-Fe(II) complex 36 (Fig. 37)211; up to 95% ee and 99% conversion was achieved for hydrogenation of acetophenone. As seen in the previous examples, N–H association with the ketone in the six-membered cyclic transition state forces substrate into one of two possible geometries; the diastereomer with lower steric pressure generates the observed product (Fig. 37, right). Other chiral PNP catalysts include Zirakzadeh’s212 ferrocene based PNP-Fe(II) complex 35 (Up to 81% ee and 96% conversion) and Mezzetti’s 213,214 chiral PNP-Fe(II) complex 38 (99% conversion and 42% ee) and analog 37 (44% ee and 99.7% conversion).

Fig. 37 Direct hydrogenation of simple ketone with representative Fe based pincer complex. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

24

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

Fig. 38 Mechanism of Fe-PNP complex catalyzed ketone direct hydrogenation reaction. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

13.01.3.4 Ketone hydrogenation with Mn based catalysts Mn catalysis is developing rapidly after the pioneering work of Beller in 2016.215,216 In 2017, Clarke217 developed fac-PNN-Mn(I) complex 39 achieving 70% ee for direct hydrogenation of acetophenone (Fig. 39). In 2020, Zhong218 developed chiral PNN ligand 42, which gave slightly improved enantioselectivity (73% ee and 99% conversion). Ding219 reported a lutidine based chiral PNN-Mn(I) complex 41 in 2019, which achieved 90% ee, 99% conversion; up to 9,800 TON was detected. Beller developed well-defined PNP-Mn(I) complex 40 in 2017.220 However, employing complex 40 in hydrogenation of the benchmark acetophenone substrate gave only 18% ee, while 83% ee was observed for cyclohexylethan-1-one. In 2019, Mezzetti 221 developed P-stereogenic PNP-Mn(I) complex 43, which gave 55% ee and 99% conversion with KH as activator (Fig. 39). Mechanistic study indicates a MnH/NH bifunctional mechanism, with H2 activation as the turnover determining step (Figure 40). Like Fe(II), DFT study reveals that hydride transfer for PNP-Mn is concerted, permitting a similar rationalization of stereoselectivity. Subsequently in 2020, Zhang222 developed PNP-Mn(I) 44 based on a rigid seven-membered P-N-Mn ring and a flexible five-membered P-N-Mn ring. 95% ee and 99% conversion were achieved for direct hydrogenation of acetophenone, and 2000 TON was observed.

Fig. 39 Direct hydrogenation of simple ketone with representative Mn pincer complexes. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

H N

H H

Br

CO

N

H2

P

tBu

tBu

Mn tBu

P

Mn

P

tBu

CO

CO

P

25

CO O

CO Ph

t

KO

Bu

43

N tBu

P

Mn CO

P

tBu

O

CO

Ph H H N tBu

OH

P

Mn CO

P tBu

CO

Ph

Fig. 40 Mechanism for Mn-PNP 43 catalyzed ketone direct hydrogenation. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Fig. 41 Transfer hydrogenation of simple ketones with representative Mn pincer complexes. From Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation. doi:10.1021/acs.chemrev.1c00075.

Mn based transfer hydrogenation has only recently been investigated. In 2017, Zirakzadeh and Kirchner223 developed PNP-Mn(I) 45; 85% ee and 95% conversion were achieved for transfer hydrogenation of acetophenone (Fig. 41). Subsequently, Morris 224 developed PNN-Mn(I) 46 and 47 in 2018; up to 42% ee and 99% conversion were achieved.

13.01.4 Conclusions and future directions Given the field’s incredible progress since Knowles, it is tempting to view asymmetric hydrogenation as a mature area—and even a solved problem. While the reality is more complicated, there are certain transformations where existing catalysts offer astounding efficiencies: above 1,000,000 turnover numbers (TON) and 99.9% ee. For example, synthetic chemists can choose from dozens of effective catalysts for hydrogenation of acetophenone or N-acylamino acrylates. Here, existing catalysts have set the bar very high for future entrants. In our view, the outstanding selectivity and reactivity for select compounds is the direct result of decades of tireless efforts (and a little luck) directed toward specific substrates. Of course, most have not received the same attention as acetophenone, and unfortunately advances do not often translate across multiple substrate classes. Privileged scaffolds like BINAP are “jack of all trades” options—a useful starting point but rarely the very best option for a given transformation. Empirical discovery remains an essential part of reaction optimization in asymmetric hydrogenation, and high throughput screening technology has eased the burden of this aspect of reaction exploration. The advent of new screening technology does not obviate the need for mechanistic study. While simple quadrant models for C2 and C1 scaffolds are incredibly useful mnemonics, they hide mechanistic complexity underneath. Steric pressure undoubtably influences efficiency of stereoinduction, but other ligand features can assist or hinder specific steps through dynamic behavior such as dissociation, conformational change, or reversible covalent reactivity. Such effects are often substrate or catalyst specific; any universal quadrant-like model will always be inadequate in these cases.

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Phosphine Ligand Development for Homogeneous Asymmetric Hydrogenation

As first row metals take center stage, new mechanistic insights will be needed to modify (or invent) new models for predicting ligand stereochemistry. Our mechanistic understanding has improved for Co and Fe, is still far behind Rh and Ir. Knowledge of oxidation states during catalysis is critical for understanding coordination environments, and thus essential for modeling chiral catalysts as they engage substrate. As new ligands are developed, we expect there will be a greater appreciation for the unique needs of 1st row metal catalysts relative to the 2nd and 3rd row. Strong field ligands that stabilize low spin configurations may be critical for Mn and Fe catalysts. Across the series, rigid geometries and/or noninnocent behavior could be essential to bring turnover numbers in the same order of magnitude as state-of-the-art Ru, Ir and Rh. Which ligand structure will emerge as the next “privileged” scaffold? Ter and tetradentate ligand scaffolds (including pincers) have great promise, but the recent achievements with bisphosphine Co and Ni catalysts show there are still opportunities for this classic chiral ligand motif. As the field continues to grow, we expect the boundless creativity of inorganic, organometallic and organic chemists will continue to unlock new classes of ligands for asymmetric hydrogenation.

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198. Sues, P. E.; Lough, A. J.; Morris, R. H. Stereoelectronic Factors in Iron Catalysis: Synthesis and Characterization of Aryl-Substituted Iron (II) Carbonyl P–N–N–P Complexes and Their Use in the Asymmetric Transfer Hydrogenation of Ketones. Organometallics 2011, 30 (16), 4418. 199. Mikhailine, A.; Lough, A. J.; Morris, R. H. Efficient Asymmetric Transfer Hydrogenation of Ketones Catalyzed by an Iron Complex Containing a P− N−N −P Tetradentate Ligand Formed by Template Synthesis. J. Am. Chem. Soc. 2009, 131 (4), 1394. 200. Lagaditis, P. O.; Lough, A. J.; Morris, R. H. Low-Valent ene–Amido Iron Complexes for the Asymmetric Transfer Hydrogenation of Acetophenone Without Base. J. Am. Chem. Soc. 2011, 133 (25), 9662. 201. Mikhailine, A. A.; Maishan, M. I.; Lough, A. J.; Morris, R. H. The Mechanism of Efficient Asymmetric Transfer Hydrogenation of Acetophenone Using an Iron (II) Complex Containing an (S, S)-Ph2PCH2CH]NCHPhCHPhN]CHCH2PPh2 Ligand: Partial Ligand Reduction Is the Key. J. 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Bigler, R.; Huber, R.; Stöckli, M.; Mezzetti, A. Iron (II)/(NH) 2P2 Macrocycles: Modular, Highly Enantioselective Transfer Hydrogenation Catalysts. ACS Catal. 2016, 6 (10), 6455. 208. Bigler, R.; Mezzetti, A. Highly Enantioselective Transfer Hydrogenation of Polar Double Bonds by Macrocyclic Iron (II)/(NH) 2P2 Catalysts. Org. Process Res. Dev. 2016, 20 (2), 253. 209. De Luca, L.; Mezzetti, A. Base-Free Asymmetric Transfer Hydrogenation of 1, 2-Di- and Monoketones Catalyzed by a (NH) 2P2-Macrocyclic Iron (II) Hydride. Angew. Chem. Int. Ed. 2017, 56 (39), 11949. 210. Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H. Iron(II) Complexes Containing Unsymmetrical P-N-P0 Pincer Ligands for the Catalytic Asymmetric Hydrogenation of Ketones and Imines. J. Am. Chem. Soc. 2014, 136 (4), 1367. 211. Smith, S. A. M.; Lagaditis, P. O.; Lupke, A.; Lough, A. J.; Morris, R. H. Unsymmetrical Iron P-NH-P0 Catalysts for the Asymmetric Pressure Hydrogenation of Aryl Ketones. Chemistry 2017, 23 (30), 7212. 212. Zirakzadeh, A.; Kirchner, K.; Roller, A.; Stöger, B.; Widhalm, M.; Morris, R. H. Iron(II) Complexes Containing Chiral Unsymmetrical PNP0 Pincer Ligands: Synthesis and Application in Asymmetric Hydrogenations. Organometallics 2016, 35 (21), 3781. 213. Huber, R.; Passera, A.; Gubler, E.; Mezzetti, A. P-Stereogenic PN(H)P Iron(II) Catalysts for the Asymmetric Hydrogenation of Ketones: The Importance of Non-Covalent Interactions in Rational Ligand Design by Computation. Adv. Synth. Catal. 2018, 360 (15), 2900. 214. Huber, R.; Passera, A.; Mezzetti, A. Iron(II)-Catalyzed Hydrogenation of Acetophenone With a Chiral, Pyridine-Based PNP Pincer Ligand: Support for an Outer-Sphere Mechanism. Organometallics 2018, 37 (3), 396. 215. Elangovan, S.; Garbe, M.; Jiao, H.; Spannenberg, A.; Junge, K.; Beller, M. Hydrogenation of Esters to Alcohols Catalyzed by Defined Manganese Pincer Complexes. Angew. Chem. 2016, 128 (49), 15590. 216. Elangovan, S.; Topf, C.; Fischer, S.; Jiao, H.; Spannenberg, A.; Baumann, W.; Ludwig, R.; Junge, K.; Beller, M. Selective Catalytic Hydrogenations of Nitriles, Ketones, and Aldehydes by Well-Defined Manganese Pincer Complexes. J. Am. Chem. Soc. 2016, 138 (28), 8809. 217. Widegren, M. B.; Harkness, G. J.; Slawin, A. M. Z.; Cordes, D. B.; Clarke, M. L. A Highly Active Manganese Catalyst for Enantioselective Ketone and Ester Hydrogenation. Angew. Chem. Int. Ed. Engl. 2017, 56 (21), 5825. 218. Ling, F.; Chen, J.; Nian, S.; Hou, H.; Yi, X.; Wu, F.; Xu, M.; Zhong, W. Manganese-Catalyzed Enantioselective Hydrogenation of Simple Ketones Using an Imidazole-Based Chiral PNN Tridentate Ligand. Synlett 2020, 31 (03), 285. 219. Zhang, L.; Tang, Y.; Han, Z.; Ding, K. Lutidine-Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones. Angew. Chem. Int. Ed. Engl. 2019, 58 (15), 4973. 220. Garbe, M.; Junge, K.; Walker, S.; Wei, Z.; Jiao, H.; Spannenberg, A.; Bachmann, S.; Scalone, M.; Beller, M. Manganese(I)-Catalyzed Enantioselective Hydrogenation of Ketones Using a Defined Chiral PNP Pincer Ligand. Angew. Chem. Int. Ed. Engl. 2017, 56 (37), 11237. 221. Passera, A.; Mezzetti, A. Mn(I) and Fe(II)/PN(H)P Catalysts for the Hydrogenation of Ketones: A Comparison by Experiment and Calculation. Adv. Synth. Catal. 2019, 361 (20), 4691. 222. Zeng, L.; Yang, H.; Zhao, M.; Wen, J.; Tucker, J. H. R.; Zhang, X. C1-Symmetric PNP Ligands for Manganese-Catalyzed Enantioselective Hydrogenation of Ketones: Reaction Scope and Enantioinduction Model. ACS Catal. 2020, 10 (23), 13794. 223. Zirakzadeh, A.; de Aguiar, S. R. M. M.; Stöger, B.; Widhalm, M.; Kirchner, K. Enantioselective Transfer Hydrogenation of Ketones Catalyzed by a Manganese Complex Containing an Unsymmetrical Chiral PNP0 Tridentate Ligand. ChemCatChem 2017, 9 (10), 1744. 224. Demmans, K. Z.; Olson, M. E.; Morris, R. H. Asymmetric Transfer Hydrogenation of Ketones With Well-Defined Manganese(I) PNN and PNNP Complexes. Organometallics 2018, 37 (24), 4608.

13.02

Hydrometallation of Organometallic Complexes

a

Jie Zhao and Baihua Yeb, aFeringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China; bSchool of Physical Science and Technology, ShanghaiTech University, Shanghai, China © 2022 Elsevier Ltd. All rights reserved.

13.02.1 Nickel 13.02.1.1 Ni-catalyzed hydrogenation 13.02.1.2 Ni-catalyzed hydrosilylation, hydroboration and hydroalumination 13.02.1.3 Ni-catalyzed hydrovinylation 13.02.1.4 Ni-catalyzed carbon-hydrogen functionalization 13.02.1.5 Ni-catalyzed hydrocarbonation 13.02.2 Copper 13.02.2.1 Cu-H catalyzed hydroamination 13.02.2.2 Cu-H catalyzed hydroalkylation 13.02.2.3 Cu-H catalyzed hydrosilylation and hydroboration 13.02.2.4 Cu-H catalyzed hydrocarbonylation 13.02.3 Cobalt 13.02.3.1 Co-catalyzed hydrosilylation 13.02.3.2 Co-catalyzed hydrogenation 13.02.3.3 Co-catalyzed isomerization of alkenes Acknowledgment References

32 32 34 40 44 46 49 50 54 58 60 63 63 67 69 71 71

The construction of carbon-carbon and heteroatom-carbon bonds is of great importance in the field of organic chemistry. Since the 19th century, the naissance of Grignard reactions using nucleophilic magnesium organo-reagents has bloomed a wide spectrum of chemical transformations, namely nucleophilic substitutions and additions to carbonyl components. Along with the development of stoichiometric reactions, catalysis enabled by various transition metal complexes with viable ligands plays a critical role. It is noteworthy that the reactivity of transition metal-carbon species as catalytic intermediates can often be modulated by an appropriate ligand, thus diversifying the operative modes of reactions and the types of formed products. In this context, generation of organometallic complexes to forge chemical bonds by catalysis represents great synthetic value in accord with the perspectives of atom and step-economies, and has therefore gained much attention for decades. Accessing transition metal-carbon (M-C) organometallic intermediates is of great importance in the frontier of organic catalysis. One of the most popular strategy exploited in classical cross-coupling reactions relies on oxidative addition of low valent metals into aromatic halide bonds, generating C-M-X species for downstream transmetallation or migratory insertion. Alternative elementary steps to generate M-C catalytically active species has been widely conceived to expand the diversity of catalysis. In this chapter, we focus on methodologies of relying on the addition of a transition metal-hydride (M-H) across an unsaturated coupling component to generate the M-C crucial intermediate. This strategy has become a versatile tool in the construction of carbonhydrogen, carbon-carbon and carbon-heteroatom bonds enabled by various transition metal catalysts. Accordingly, key advances of applying hydrometallation in catalysis are summarized and categorized by the choices of transition metals, namely nickel, copper, cobalt and iron. Comprehensive reviews on the hydrometallation of palladium1 and iridium2 can be found in the citations which have been thoroughly described.

13.02.1 Nickel 13.02.1.1 Ni-catalyzed hydrogenation Compared to successful applications of nickel catalysis in heterogeneous hydrogenation,3 exploration of Ni-catalyzed homogeneous reaction has gained relatively little attention. In 1998, Bouwman and coworkers4 reported a homogeneous hydrogenation of linear olefins catalyzed by a phosphine-ligated nickel complex under high hydrogen atmosphere (50 bar) (Scheme 1). Upon the introduction of an appropriate bidentate phosphine ligand to prevent the formation of colloidal Ni particles, the homogeneous Ni catalyst exhibits excellent reactivity with high turnover numbers up to 3000.5 In particular, the steric hindrance of the phosphine ligand has been stated to be crucial for the performance of catalysis. Further by the same group, kinetic studies of this phosphine ligated Ni-catalyzed hydrogenation have been performed to rationalize the catalytic cycle with the formation of mononuclear Ni-H active species.6

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Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00121-9

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33

Scheme 1 Ligand screening in Ni-catalyzed hydrogenation of oct-1-ene.

Alternatively, investigation of metal-ligand cooperativity through the heterolytic activation of dihydrogen to generate Ni-H intermediate has also been sought. Representatively, the use of diphosphane-borane ligand reported by Peters and coworker in 2012 realized the Ni-catalyzed hydrogenation of styrene under mild reaction conditions.7,8 According to the studied mechanism (Scheme 2), the Lewis acidic borane moiety of the employed tridentate ligand serves as hydride acceptor concurrent with 2-electron oxidative addition of proton to Ni(0). Contrary to this polarity inverted strategy, Ni(II) catalysts bearing pincer-type ligands with an amido moiety reported by Caulton and coworkers9 can also facilitate the heterolytic activation of H2 through the cooperative interaction between this d8 metal and the Lewis basic PNP ligand, enabling the formal addition of hydrogen as a hydride source to Ni metal.

Scheme 2 Ligand-metal cooperativity in catalytic hydrogenation of alkenes.

The aforementioned examples showcase evidence of forming mononuclear Ni intermediates in the process of Ni-catalyzed homogeneous hydrogenation. On the other hand, as illustrated in Scheme 3A, Driess and coworker have found that oxidative addition of H-H into a bis(N-heterocyclic silylene)xanthene Ni(0) catalyst affords a dihydrido H-Ni-H species in a reversible fashion of H2 activation.10 This work emphasizes high potential of the exploited catalyst in the hydrogenation of alkenes and showcases good functional group compatibility and mild reaction conditions (1 bar of H2). Additionally, tetrametallic base-metal M4N4 clusters as active catalysts for the hydrogenation of alkenes and alkynes, as demonstrated by Stryker and coworkers,11 feature high potential in this field (Scheme 3B).

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Hydrometallation of Organometallic Complexes

Scheme 3 Binuclear and tetrametallic cluster approaches in catalytic hydrogenation of alkenes and alkynes.

13.02.1.2 Ni-catalyzed hydrosilylation, hydroboration and hydroalumination In homogeneous hydrogenation, the protonation of an alkyl nickel intermediate derived from addition of Ni-H across alkenes is considered to be the terminal elementary step to turnover the Ni catalyst. Replacing this protonolysis by other elementary steps to complete the catalytic cycle can expand the diversity of reaction patterns, thus leveraging the potential of hydrometallation chemistry. In this respect, seminal research on Ni-catalyzed hydrosilylation, hydroboration and hydroalumination to forge C–Si, C–B and C–Al chemical bonds respectively are presented in the following section. Organosilanes often act as versatile building blocks owing to the rich chemistry of CdSi bond. Thus, transition metal catalyzed hydrosilylation has gained much interests for the purpose of synthesizing fine chemicals from the alkene feedstocks. In particular, platinum catalysts have been demonstrated to be capable of exhibiting excellent activity and selectivity in hydrosilylation.12 Alternatively, replacing this precious Pt metal by other more earth-abundant metal catalyst represents high value in terms of cost and sustainability. Herein, nickel metal is the choice. In 2005, Zargarian and coworkers13 reported a Markovnikov hydrosilylation of styrene catalyzed by indenyl phosphine nickel complex in the presence of PhSiH3. Addition of NaBPh4 as the initiator to generate a cationic Ni catalyst can be helpful to attain good reaction performance, while indenyl ligand with sterically different substituents did not affect the regioselectivity (Scheme 4).

Hydrometallation of Organometallic Complexes

35

Scheme 4 Indenyl-ligated Ni complex for catalytic hydrogenation hydrosilylation of styrenes.

In 2012, Valerga et al. demonstrated the hydrosilylation of styrenes catalyzed by a cationic allyl Ni catalyst complexed with a bidentate N-heterocyclic carbene ligand.14 As shown in Scheme 5A, moderate control of regioselectivity towards Markovnikov hydrosilylation was observed. Alternative allyl nickel catalyst bearing phosphine ligands reported by Valerga has also been sought showcasing moderate to good reactivity (Scheme 5B).15

Scheme 5 Cationic allyl Ni complexes for catalytic hydrogenation hydrosilylation of styrenes.

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Hydrometallation of Organometallic Complexes

In the same year, opposite to the fashion of Markovnikov addition, Gevorgyan and coworkers16 found that phosphine ligated nickel complex provides excellent regioselectivity towards anti-Markovnikov hydrosilylation by the use of monodentate Ph3P as the optimal ligand (Scheme 6A). Alternatively, Tilley and coworkers17 showcased also the viability of a Ni catalyst complexed with amido ligands in anti-Markovnikov hydrosilylation of 1-octene (Scheme 6B).

Scheme 6 Anti-Markovnikov hydrosilylation in the approaches of Gevorgyan and Tilley respectively.

In addition to the use of monodentate ligand, recently Hu and coworkers18 have applied a bis(amino)amide pincer ligand and developed a new Ni-catalyzed hydrosilylation of various functionalized alkenes with exclusive anti-Markovnikov selectivities (Scheme 7). In this work, broad scope of both terminal and internal alkenes has been achieved, and high functional group compatibilities can be attained. Moreover, authors highlighted both high turnover frequency and turnover number of the employed pincer Ni catalyst, highlighting the excellent synthetic potential of this approach.

Scheme 7 Pincer-Ni complexes for hydrosilylation of alkenes.

Hydrometallation of Organometallic Complexes

37

Other unsaturated coupling components such as allenes and alkynes have also been utilized in Ni-catalyzed hydrosilylation. In 2015, Montgomery and coworkers19 reported a highly stereo- and regio-selective hydrosilylation of 1,3-disubstituted allenes catalyzed by a nickel NHC catalyst (Scheme 8 left). In particular, modulation of the steric factor of the NHC ligand is essential, when the bulky IPr NHC ligand delivered dominantly Z alkenylsilane products in excellent yields. The same group has also studied the hydrosilylation of alkynes catalyzed by NHC-Ni complexes in the presence of Et3SiH yielding cis-addition adducts as the major products (Scheme 8 right).20 It is noteworthy that the reactions of various unsymmetrical alkynes are regioselective, since the Ni metal likely prefers to residue at the carbon either less sterically encumbered or adjacent to an aryl moiety.

Scheme 8 NHC-Ni catalyzed hydrosilylation of allenes and alkynes.

Having similar prospects of hydrosilylation, a number of syntheses of organoboranes enabled by transition metal catalyzed hydroboration of alkenes and alkynes has also been documented.21 Catecholborane has been extensively used as hydroborylating reagent in the early studies. For instance, Kabalka and coworkers developed a heterogeneous Ni-catalyzed hydroboration of alkenes in 1994.22 The active nickel catalyst was formed in situ by reducing NiI2 in the presence of lithium naphthalenide in ethereal solvents in prior to catalysis. Linear adducts through anti-Markovnikov hydroboration were dominantly formed under these reaction conditions. On the other hand, in order to establish a better user-friendly protocol, pinacolborane turns out to be an alternative hydroborylating reagent, which is less sensitive to air and moisture and can be possibly purified by flash chromatography on silica gel. In 1996, Srebnik and coworkers23 reported a NiCpPPh3Cl catalyzed homogeneous hydroboration in the presence of pinacolborane. In this case, anti-Markovnikov hydroboration of terminal alkenes and alkynes preferentially occurred. While most efforts were spent on the transformations of alkenes and alkynes, Morken and coworkers24 pioneered to explore a Ni-catalyzed 1,4-hydroboration of 1,3-dienes in both regio- and stereoselective fashions (Scheme 9). This catalysis enabled by phosphine ligated Ni catalyst was performed under very mild reaction conditions, affording the resulting stereodefined (Z)-allylborons which can be readily converted into the corresponding alcohols. In mechanism, authors suggested that the nickelacycle resulted from cycloaddition of 1,3-diene with Ni(0) reacts with PinBH to give the least hindered p-allyl nickel intermediate, which in turn gives the desired product upon reductive elimination. Based on these findings, the same group has successfully established a protocol of diastereoselective Ni-catalyzed 1,4-hydroboration of chiral dienols25 affording polyketide fragments upon oxidative workup.

38

Hydrometallation of Organometallic Complexes

Scheme 9 Ni-catalyzed 1,4-hydroboration.

Diborons can be also used as hydroborylating reagents instead of pinacolborane. In 2017, Ye and coworkers26 reported a base-free hydroboration catalyzed by a PtBu3-ligated Ni complex in the presence of pinacol diborane under alcoholic conditions (Scheme 10). Unsaturated substrates such as styrenes and other alkenes were feasible, affording the corresponding products in good to excellent yields with high preferences towards anti-Markovnikov addition. Alcoholic solvent is crucial, where the optimal alcohol MeOH serves as the proton source. In the mechanism, the authors suggested that oxidative addition of Ni(0) with B2Pin2 followed by migratory insertion of alkene generates an alkyl-Ni intermediate which further gives the desired product upon protonolysis.

Scheme 10 Base-free Ni-catalyzed hydroboration of alkenes.

Taking advantage of fine modulation of phosphine ligands, in 2017 Fu and coworkers27 reported a fascinating Ni-catalyzed 1,1-diboration of terminal alkenes (Scheme 11). Under basic conditions, introduction of PCy3 or Cy-XantPhos ligands led to the formation of 1,1-diborylalkanes from activated or non-activated olefins with highly chemo- and regio-selectivities. This protocol has a great tolerance of various functional groups, therefore allowing to expand scope to other more complex variants.

Hydrometallation of Organometallic Complexes

39

Scheme 11 Ni-catalyzed 1,1-diboration of terminal alkenes.

Ni-catalyzed Markovnikov-selective hydroboration of styrenes has been well developed. Contrary to the aforementioned existing methodologies, in 2016 Schomaker and coworkers28 discovered that heteroleptic N-heterocyclic carbene (NHC)−phosphine nickel complexes displayed distinct reactivity and selectivity and gave dominantly branched boronic esters (Scheme 12). Unfortunately, alkenes bearing heterocyclic components and polar substituents remains still challenging.

Scheme 12 Markovnikov-selective Ni-catalyzed hydroboration of styrenes.

In addition to hydroboration, in 2010 Hoveyda and coworkers29 pioneered the development of hydroalumination of internal terminal alkynes through nickel catalysis in the presence of diisobutylaluminum hydride (Scheme 13). The introduction of either monodentate or bidentate phosphine ligands control in the formation of which vinylaluminum isomers can be readily achieved. In practice, terminal alkynes bearing aryl and aliphatic substituents were feasible substrates. More importantly, commercially available Ni(PPh3)2Cl2 gave the b-vinylaluminum isomer whereas Ni(dppp)Cl2 provided the a-isomer, which has been utilized for downstream useful transformations such as asymmetric allylic alkylation, halogenations and boration.

40

Hydrometallation of Organometallic Complexes

Scheme 13 Site-selective hydroalumination catalyzed by phosphine-ligated Ni complexes.

13.02.1.3 Ni-catalyzed hydrovinylation Alkenes are some of the most abundant chemical feedstocks in the world. During the research of alkene polymerization, Ziegler and coworkers found that polymerization of ethylene could be interrupted by the presence of nickel in trace amounts, leading to the formation of 1-butene instead. This is called the “Nickel effect.”30,31 This dimerization of ethylene can be schematically represented by adding a hydrogen atom and a vinyl group across an alkenyl unit from two alkenes. This is a highly atom-economic and prominent reaction, delivering complex and potentially chiral molecules from simple starting materials.32 When two alkenyl coupling reagents become distinct, heterodimerization of two alkenes is termed as hydrovinylation (Scheme 14). Controlling its cross-selectivity as well as enantioselectivity becomes extremely important and challenging. The key to realize an asymmetric Ni-catalyzed hydrovinylation of alkenes has essentially relied on the use of an appropriate phosphine ligand. The employed nickel pre-catalyst is generally complexed with a monodentate phosphine ligand, and introduction of a weakly coordinating anion to form a cationic Ni complex is generally necessary. In the generally accepted mechanism, the phosphine ligated allyl Ni pre-catalyst is activated by the introduction of alkenes, generating cationic Ni-H intermediate for subsequent migratory insertion across alkenes. In this context, insertion across styrene derivatives as one of the coupling reagents is preferable owing to the stability of resulting Z3-intermediate. Further incorporation of another alkene followed by b-H elimination delivers the product and turnover the catalytic cycle. Over the decades, chemists have spent enormous efforts on the development of chiral versions of this powerful hydrovinylation. A family of appropriate and tunable chiral phosphine ligands was highly and urgently desired to unlock its potential in asymmetric catalysis. Meanwhile, minimizing potential side products derived from oligomerization and isomerization under more neutral reaction conditions have to be considered.

Hydrometallation of Organometallic Complexes

41

Scheme 14 Tentative mechanism of Ni-catalyzed hydrovinylation.

In the early stage of research, Wilke and coworkers33 realized a successful hydrovinylation of styrene and ethylene using dimeric azaphosphole (Scheme 15). In this case, (R)-3-phenyl-1-butene was isolated in excellent yield with 95% ee. Unfortunately, the structural modulation of this azaphosphole ligand was formidably challenging thus limiting further application of this powerful methodology. Therefore, much interests have been spent on discovering new phosphine ligands and exploring new protocols of asymmetric hydrovinylation.

Scheme 15 Azaphosphole ligand applied in the asymmetric Ni-catalyzed hydrovinylation.

In 1998, RajanBabu and coworkers34 reported a new protocol of asymmetric Ni-catalyzed heterodimerization of styrenes and ethylene based on the cooperation of weakly coordinating anion and MOP-type ligands containing labile coordinating elements (Scheme 16A). It is noteworthy that, the presence of the phosphine ligand stabilized the cationic Ni-H intermediate and the auxiliary ligation of MOP ligand has a strong impact on the induction of enantioselectivity. Under this developed system, products were generated in nearly quantitative yield with moderate to good enantioselectivities (up to 80% ee) when catalysis were conducted at low temperature. Later, the same group focused on the investigations of other new ligands as depicted in Scheme 16. Bidentate phospholane ligands didn’t give superior reaction outcome.35 On the other hand, a family of sugar-based monodentate

42

Hydrometallation of Organometallic Complexes

phosphinites featuring a tunable structure reported in 2002 has indeed bought new opportunities for the asymmetric catalysis.36 In parallel, Leitner et al. has discovered the privileged phosphonamidate ligands developed by Feringa and coworkers were amenable also to achieve high stereo-induction in asymmetric vinylation of styrenes (Scheme 16).37 In comparison, Leitner and Franciò has also developed a new class of NOBIN-based phosphoramidite and phosphorodiamidite ligands and successfully demonstrated their potential in catalysis.38 However, no suitable ligand candidate was found for the asymmetric hydrovinylation of a-substituted styrenes in the construction of quaternary stereogenic carbon center until RajanBabu et al. examined the class of chiral phosphoramidites in 2006.39 This particular ligand family gave desired products in high yields with excellent enantioselectivities despite with limited substrate scope of alkenes. Two years later, Zhou and coworkers have developed spiro phosphoramidite ligands for Ni-catalyzed enantioselective hydrovinylation of silyl-protected allylic alcohols (Scheme 16).40 Under optimized reaction conditions, a series of homoallylic alcohols bearing a quaternary chiral carbon had been readily synthesized with good to excellent enantioselectivities.

Scheme 16 Development of phosphorus ligands for asymmetric Ni-catalyzed hydrovinylation.

Regarding the regioselectivity of hydrovinylation described above, head-to-head or head-to-tail conjunctions of the different alkenes were often observed with cationic Ni-H catalysts complexed with phosphine ligands. Other pathways to forge the carboncarbon bond, especially in tail-to-tail fashion, have been scarcely reported. Since 2010, Ho and coworkers have conceived and reported a series of innovative works relying on the exploitation of an NHC as a ligand in the cationic Ni-H catalyzed intermolecular hydrovinylation (Scheme 17).41 Notably, this new catalytic protocol has fascinatingly offered new modes of catalysis in terms of reactivity as well as selectivity. For instance, cationic IPr-Ni-H complex was catalytically active in the intermolecular hydrovinylation of styrenes and a-olefins generating 1,10 -disubstituted alkenes via a tail-to-tail conjunction. In the proposed mechanism, initial migratory insertion of cationic NHC-Ni-H across styrene would deliver the stabilized benzylic Ni intermediate which in turn undergoes the subsequent insertion across another alkenyl reagent. At this stage, the steric bulk of NHC ligand has been demonstrated to be vital. The use of bulky IPr would enforce the tail-to-tail bond construction and also favor the formation of cross-coupling alkenes upon the final b-H elimination in the turnover of catalyst.

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43

Scheme 17 Cationic NHC-Ni catalyzed hydrovinylation.

In 2015, an asymmetric protocol of this NHC-Ni catalyzed tail-to-tail hydrovinylation was successfully established by the same group (Scheme 18).42 C2-symmetric NHC ligands derived from (1S,2S)-1,2-diphenyl-1,2-ethanediamine were effective for this purpose. The steric bulk and orientation of both N-aryl groups can apparently influence the reactivity. Upon successive modulation, ligands bearing a mono-o-Cy substituent on the Ar group were found to be optimal, and high selectivities in favor to monoene products which were generally in good yield with good to excellent enantioselectivities have been achieved. Ho et al. have also established protocols of distinct NHC-Ni catalyzed hydrovinylations using either vinyl ethers43 or vinyl silanes44 as coupling reagents in place of styrenes, accordingly leveraging the synthetic potential of hydrovinylation.

Scheme 18 Asymmetric cationic NHC-Ni catalyzed hydrovinylation.

In addition to intermolecular heterodimerization of alkenes, hydrovinylations of dienes, especially in asymmetric fashion, have also been conceived and investigated. For instance, RajanBabu et al. reported asymmetric hydrovinylation of 1,3-dienes using the azaphosphole ligated cationic Ni-complexe.45 In this study, controls of regioselectivity were excellent and chiral 1,4-dienes were obtained in high yields with up to >99% ee. Interestingly, Ho et al. reported that the replacement of phosphorus ligand by NHC as a

44

Hydrometallation of Organometallic Complexes

ligand induced distinct regioselectivity forming the 1,4-dienes through the conjunction with the tail-carbon of a-olefin.46 On the other hand, Leitner and coworkers have spent efforts on exploring asymmetric cycloisomerization of 1,6-dienes using the aforementioned cationic phosphine-ligated Ni-H complexes since 2005.47 This protocol gave a new avenue on the syntheses of carbo- and heterocycles. In particular, phosphoramidite ligands were found amenable giving products from diallylmalonate derivatives with moderate to good enantioselectivities. On the other hand, the azaphosphole developed by Wilke et al. was also promising, inducing superior stereo-inductions in certain applications of asymmetric cycloisomerization. Nearly a decade later, Zhou et al. have found spiro phosphoramidites as the promising ligands for asymmetric intramolecular hydroalkenylation of Nand O-tethered 1,6-dienes.48 This successful establishment of new asymmetric protocol has bought new opportunities on synthesizing chiral piperidines and tetrahydropyrans with excellent regioselectivities as well as stereoselectivities. Recently, competitive intramolecular cross-hydrovinylation of trienes has been sought by the group of Ho.49 The authors has observed that their catalytic NHC-Ni conditions can promote selectively ng-exo-trig cycloisomerization of 1,7-diene moiety generating a series of heterocyclic products.

13.02.1.4 Ni-catalyzed carbon-hydrogen functionalization Carbon-hydrogen bond functionalization has been recognized as a complementary tool to build up complex molecules from simple building blocks.50 Accordingly, the direct transformation of CdH bond into carbon-carbon and carbon-heteroatom bonds features definitely high synthetic value. Over the last two decades, exploration of C-H functionalizations relying on transition metal catalysis51 or even non-transition metal catalysis52 have been investigated. Numerous efforts have resulted in blooming a wide spectrum of innovative methodologies. Among the diverse strategies of C-H functionalization, the generation of the crucial Ni-H intermediate via two-electron oxidative addition of Ni(0) has been conceived and developed. Seminal works pioneered by Hiyama and coworkers53 have relied on the exploitation of nickel/Lewis acid (LA) catalysis for directly transforming CdH bonds of nitrogen containing heterocycles in couple with unsaturated reagents (Scheme 19). When AlMe3 as a Lewis acid and P(i-Pr)3-ligated Ni(0) catalyst were introduced, the CdH bond of N-methyl-2-pyridone at the C6-position was regio-specifically activated via oxidative addition of Ni(0) upon coordination to the AlMe3 co-catalyst at the Lewis basic carbonyl oxygen, forming the key Ni-H intermediate. Coordination of alkyne to the Ni center followed by migratory insertion of Ni-H across the alkyne delivers the Ni species which affords the cis-adduct upon reductive elimination and regenerates the initial catalyst. In the scope, coupling reagents such as internal alkynes, styrenes and 1,3-dienes were amenable to couple with a variety of heterocycles (pyridones, isoquinolone and uracil etc.), whereas intermolecular Ni/LA catalysis with unbiased terminal alkenes and alkynes failed. Interestingly, as reported by the same group in 2012, replacing P(i-Pr)3 by IPr as a ligand under the explored Ni/LA catalytic conditions has enabled the use of terminal or cyclic aliphatic olefins as coupling partners.54 Moreover, alkylation of CdH bond at C-2 position of 4-pyridone was also feasible under very similar reaction conditions.

Scheme 19 Nickel/Lewis acid (LA) catalysis developed by Hiyama et al. (MAD ¼ (2,6-tBu2-4-Me-C6H2O)2AlMe).

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45

Intramolecular cyclization of pyridones tethered with an alkenyl component via Ni/LA catalyzed C-H functionalization was also developed by Hiyama et al. proceeds preferentially in a exo-trig fashion. An alternative approach to control both exo and endo-cyclizations by simply the employed ligand was highly desired. In 2015, Cramer and coworkers reported a regiodivergent annulation of olefin tethered pyridones via Ni/LA catalysis (Scheme 20).55 In this case, both terminal and internal tethered alkenes were feasible. More importantly, exploiting alkyl phosphines and IPr ligands have selectively promoted exo- and endo-cyclization respectively, forming polycyclic heterocycles with quaternary carbon centers in good-to-excellent yields.

Scheme 20 Ligand modulated regiodivergent syntheses of functionalized heterocycles.

In addition to ligand-modulated cyclization, the same group has also developed the asymmetric Ni/LA-catalyzed hydrocarbamoylations of alkenes using diaminophosphine oxides as the chiral ligand (Scheme 21 left).56 Upon bimetallic activation with a SPO ligand, oxidative addition of the Ni(0) catalyst into the formyl CdH bond generates an Ni-H intermediate which subsequently undergoes migratory insertion of the tethered alkene to give a series of exocyclic amides with excellent enantioselectivities. C-H hydrocarbamoylation of substrates bearing two tethered olefins was also amenable, providing products with quaternary carbons with good-to-excellent diastereoselectivities and high level of enantioselectivities through desymmetrization. Recently, inspired by

Scheme 21 Asymmetric Ni/Al-catalyzed C-H functionalization of heterocycles reported by the groups of Cramer and Ye.

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this explored bimetallic activation catalysis, Ye and coworkers has discovered an alternative example of functionalizing the CdH bond of alkene-tethered imidazoles using Taddol-derived SPO ligands (Scheme 21 right). The forming cyclic products were obtained in exo-selectivity with excellent controls of stereoselectivites. Rather than achieving the aforementioned exo-control of cyclization, scarce precedents of preparing chiral functionalized pyridones has encouraged Cramer et al. to develop an enantioselective Ni-catalyzed endo-cyclization via C-H functionalization enabled by the use of steric demanding chiral carbene ligands (Scheme 22).57 Notably, based on Gawley’s carbene,57b efforts have been devoted to define the optimal chiral NHC ligand bearing an acenaphthene backbone with bulky chiral flanking aryl substituents. In scope, C-H functionalizations of pyridones and isoquinolones tethered with 1,10 -substituted or trisubstituted olefins were highly regioselective, yielding the corresponding cyclic products in good-to-excellent yields with up to 99:1 er. The asymmetric protocol was also applicable for the cases of uracil and 4-pyridone derivatives, keeping similar excellent reaction performances.

Scheme 22 Asymmetric endo-selective Ni/Al-catalyzed C-H functionalization of heterocycles reported by Cramer et al.

13.02.1.5 Ni-catalyzed hydrocarbonation Fixation of carbon dioxide as a carbon source represents as an urgent and highly valuable task in this century. Over the last decades, advances in the functionalizations of CO2 have been rapidly progressing and a wide spectrum of innovative methodologies have been established to implant this readily available inexpensive molecule into chemical feedstocks.58 Inspired by the Hoberg’s original work59 of Ni-mediated stoichiometric fixation of CO2 with alkenes, in 2008 Rovis and coworkers60 have developed a novel Ni-catalyzed reductive carboxylation of styrenes with CO2 in the presence of ZnEt2 as a reductant to supply the hydrogen source (Scheme 23). Upon workup of the reaction mixture, branched carboxylic acids were obtained in good-to-excellent yields in this approach. Noteworthy, a set of control experiments have been performed to support the tentative mechanism of this explored catalysis. In this regard, hydrometallation across styrenes is proposed to be more likely happened to deliver stabilized benzylic Ni-intermediate but not the Nickel metallacycle generated upon cycloisomerization of styrene and CO2. This crucial demonstration has triggered chemists to further expand other nickel catalysis for the fixation of CO2.

Scheme 23 Ni-catalyzed hydrocarbonation with CO2.

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47

In 2017, Martin and coworkers61 reported an innovative protocol of site-selective Ni-catalyzed carboxylation of aliphatic and aromatic olefins in the presence of CO2 and H2O (Scheme 24). Under reductive and mild reaction conditions, incorporation of CO2 with a variety of styrenes and diaryl substituted alkenes has been readily realized, showcasing high selectivities of addition at acarbons. On the other hand, this protocol has been also demonstrated to be viable for industrially relevant unactivated a-olefins. Upon migratory insertion of Ni-H across the alkene component, the dipyridyl-ligated Ni complex preferentially residues at the less hindered terminal carbon, thus generating linear carboxylic acids after catalysis. Notably, while internal acyclic aliphatic alkenes were introduced, carboxylation was solely occurred at the remote terminal carbon. In these cases, linear adducts were isolated as single regioisomers in acceptable yields. These results have revealed that iterative b-hydride elimination/migratory insertion events, termed as chain-walking, have occurred in the course of catalysis. In addition, this methodology emphasized the use of water as a hydride source to replace classical reductant such as organosilanes.

Scheme 24 Site-selective Ni-catalyzed carboxylation of aliphatic and aromatic olefins in the presence of CO2 and H2O.

On the basis of reversible addition of Ni-H intermediate across alkenes, other coupling reagents instead of carbon dioxide have also been rapidly investigated for the construction of carbon-carbon and carbon-heteroatom bonds.62 In particular, exposure of aryl or alkyl halides to Ni-C species upon migratory insertion of Ni-H into an olefin forging Csp2–Csp3 and Csp3–Csp3 bonds has become a novel and fascinating strategy in Ni catalysis under reductive reaction conditions. For instance, Zhu and coworkers has reported a protocol of reductive hydroalkylation of alkenes with aryl iodides relied on a Ni-H chainwalking strategy (Scheme 25 left).63 The use of a bidentate pyridyl ligand has resulted in the hydroalkylation occurring at the remote benzylic position, forming a variety of biologically relevant 1,10 -diarylalkanes in excellent yields with high regioselectivities. The tentative mechanism is expected to be initiated by the formation of a Ni-H species upon the introduction of polymethylhydrosiloxane (PMHS) as a hydride source. Subsequent iterative b-hydride elimination/migratory insertion of Ni-H into alkene would result in the formation of stabilized

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benzylic Ni intermediate. Further cross-coupling with Ar-I and reductive elimination of the resulting Ni(III) species would afford the branched biaryl products. On the other hand, replacing Ar-I by alkyl iodide under similar reaction conditions, the same group has developed a novel protocol of Ni-H catalyzed reductive relay hydroalkylation of alkenes using the optimal ligand (Scheme 25 right).64 The methodology can yield a variety of cross coupled aliphatic products with linear structures featuring excellent tolerance of functional group under mild reaction conditions.

Scheme 25 Ni-H catalyzed regioselective hydrocarbonation of alkenes with either aryl or alkyl iodides.

Ni-catalyzed hydrocarbonation has been rapidly advanced over the last decade. In similar to the Zhu’s approach, Hu and coworkers65 have demonstrated that the versatile boronic ester group can act as a directing group when installed in the alkenyl reagent (Scheme 26). The methodology provides the formation of an a-boryl organonickel intermediate via the chainwalking mechanism. Subsequently, both aryl and alkyl iodides were proven to be feasible in the cross-coupling events, affording branched products in good-to-excellent yields. High compatibility of functional groups and applications with complex bioactive molecules accordingly have been attained. Recently, the corresponding enantioselective protocol66 has been successfully established, further highlighting the synthetic potential of this protocol.

Scheme 26 Regioselective and enantioselective Ni-catalyzed hydrocarbonation of alkenes with organic halides.

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49

Applying heterocyclic pyrroline in catalytic hydrocarbonation has received interest since the functionalized pyrrolidine is a privileged scaffold of pharmaceuticals and natural products. Martin et al.67 have developed a protocol of Ni-catalyzed hydroalkylation of 3-pyrolline with a-haloboranes (Scheme 27). The more stabilized a-nitrogen organonickel intermediate enabled the selectivity of alkylation only at C2 position. Based on the corresponding mechanistic studies, the authors proposed two possible pathways, either the single-electron reduction of a-Cl boronic ester by Ni(0) followed by addition of boron-stabilized radical across alkene, or migratory insertion of Ni-H across alkene followed by oxidation to Ni(III) by a-Cl boronic ester. Eventually, structural confirmation of the obtained products indirectly supports the second pathway being more likely operated. On the other hand, Hu et al.68 have established an alternative regiodivergent approach in which the selectivity of Ni-catalyzed hydrocarbonation of 3-pyrrolines can be modulated simply by the ligands. These two seminal works definitely highlight the potential of nickel catalysis in which the outcome can be readily controlled by the employed ligand.

Scheme 27 Ni-catalyzed hydrocarbonation of pyrrolines.

13.02.2 Copper Copper catalysis has emerged as a powerful methodology in organic synthesis over decades.69 Together with the low toxicity and low cost of copper metal, the diversified reactivities of organocopper complexes have encouraged chemists to develop a wide spectrum of copper-mediated and copper-catalyzed organic transformations. For instance, the Lewis acidity of cationic organocopper complex allows it to promote asymmetric Cu-catalyzed Diels-Alder reactions.70 The soft nucleophilicity of C-Cu species emphasized in cuprate chemistry has made asymmetric Cu-catalyzed 1,4-addition viable.71 Utilizing single-electron-transfer technology of copper catalysis advances the investigations of dehydrogenative functionalization as well as aerobic oxidations of organic molecules.72–75 Recently, Cu-catalyzed cross-coupling reactions of aryl halides and a variety of nucleophiles represent tremendous synthetic values for both academia and industry.76 we encourage the reader to find the comprehensive reviews of these fascinating studies in the citations. Accordingly, these topics are not included in this sub-chapter. Since the renaissance of Stryker’s reagent as a phosphine-stabilized hexamer [(Ph3P)CuH]6, investigations of hydrocupration has unambiguously advanced the progress of copper catalysis and offered new perspectives of constructing chemical bonds. The crucial Cu-H intermediate which is considered as a soft and carbophilic nucleophile can be readily generated via s-bond metathesis in the presence of user-friendly organosilanes as mild hydride sources. Deutsch and Krause have reported a comprehensive review on Cu-H catalytic reaction, mainly for 1,2- and 1,4-additions.77 Therefore, we aim to scope the recent progress of hydrocupration chemistry and deliver a systematic summary of related studies which can be subdivided into several directions, namely Cu-H catalyzed hydroamination, hydroalkylation, hydrocarbonylation, hydrosilylation, hydroboration and hydroarylation of unsaturated organic molecules.

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13.02.2.1 Cu-H catalyzed hydroamination The amino functional group is common in pharmaceuticals, agro-chemicals and naturally occurring organic molecules. Considerable interests have been gained in developing diversified methodologies to access building blocks containing carbon-nitrogen motifs. In this context, hydroamination of alkenes represents a highly atom economic, fascinating but formidably challenging strategy.78–80 Over the decades, related metal-free or metal-catalyzed protocols have been increasingly established, often accompanied with harsh reaction conditions and issues of regioselectivity and enantioselectivity. Recently, hydroamination of alkenes powered by Cu-H catalysis via hydrocupration, pioneered by the groups of Buchwald and Miura, has become as an extremely versatile tool to synthesize chiral amines in highly regioselective and stereoselective fashions. In 2013, Buchwald and coworkers reported a highly enantio- and regioselective hydroamination of alkenes catalyzed by a Cu-H complex ligated with a SEGPHOS derivative (Scheme 28).81 Diethoxymethylsilane (DEMS) and esters of hydroxylamines were employed as the hydride and the electrophilic amine sources respectively in this case. The tentative mechanism is believed to start from the Z2-alkene coordination at Cu metal center and migratory insertion of Cu-H intermediate across the olefin. Subsequently, the crucial oxidative addition of the electrophilic hydroxylamine derivative followed by reductive elimination of the resulting Ni(III) species would deliver the optically active aliphatic amine. At the end, the active Ni-H catalyst can be readily regenerated by s-bond metathesis between Ni-O and Si-H of DEMS. In terms of scope, introduction of (R)-DTBM-SEGPHOS as the optimal chiral ligand enabled the asymmetric hydroamination of styrenes, giving benzylic amines in high yields (up to 99%) with excellent enantioselectivities. In addition, unreactive a-olefins were feasible, forming anti-Markovnikov products in spite of the challenging control of stereo-induction. In parallel as illustrated in Scheme 28, Miura and coworkers82 has independently developed a similar reaction conditions of Cu-H catalyzed asymmetric hydroamination of styrenes using bidentate Duphos and BPE derivatives as the viable chiral ligands. In this case, goodto-excellent enantiomeric excesses of the forming products were obtained. Eventually, Efforts by both groups of Buchwald and Miura have fascinatingly unlocked the potential of hydrocupration in catalysis.

Scheme 28 Asymmetric Cu-H catalyzed hydroamination of alkenes reported by the groups of Buchwald and Miura.

Hydrometallation of Organometallic Complexes

51

Upon those aforementioned seminal works, a variety of both alkenes and electrophilic hydroxylamine derivatives were examined to access various optically active amines through an intermolecular fashion.83 In 2015, Buchwald and coworkers reported an asymmetric synthesis of a-aminosilanes enabled by Cu-H catalysis (Scheme 29).84 Similar to the styrene examples, this catalytic hydroamination proceeds in an exclusive Markovnikov fashion. Upon the stereo-determining migratory insertion of Cu-H across vinyl silane, hyperconjugative stabilization of the forming alkyl-Cu intermediate by the adjacent silyl moiety would account for the preference of regioselectivity. Interestingly, mechanistic experiments indicated that no isomerization between (E)- and (Z)-vinyl silanes probably occurred, while the former isomer reacted faster. Together with high yielding and excellent controls of stereo-induction, this protocol of synthesizing amino acid bioisosteres shows its great promise for the interest of medicinal chemistry.

Scheme 29 Asymmetric Cu-H catalyzed hydroamination of vinyl silanes.

In addition to the application of vinyl silanes, Miura and coworkers have also sought to investigate Cu-H catalyzed hydroamination of vinyl borates (Scheme 30).85 In this case, installation of a dan boronic moiety in alkenes led to perfect control of regioselectivity, where the Cu resides at the carbon adjacent to boron upon migratory insertion. Notably, applications in scope showcase high compatibilities with a variety of functional groups, providing chiral a-boroamines with excellent enantiomeric excesses (up to 99:1 er).

Scheme 30 Asymmetric Cu-H catalyzed hydroamination of alkenyl dan boronates.

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Hydrometallation of Organometallic Complexes

Most successful examples in the early stage of investigations were limited to applications of activated alkenes in catalytic hydroamination. Alternatively, transforming unactivated internal olefins obtained from the petroleum processing will provide even higher synthetic utility of this approach. In 2015, Buchwald et al. have underlined the challenges arisen from the higher activation barrier with unactivated alkenes, and successfully developed a modified enantioselective protocol of synthesizing chiral amines bearing methyl-ethyl stereocenters (Scheme 31).86 Using DTBM-SEGPHOS derivative as the optimal ligand and trans-2-butene as the model alkene, the efficiency of catalysis was crucially improved through the chemical modulation of the electrophilic hydroxylamine ester reagent. Introduction of a more electron-rich substituent on the arene resulted in less pronounced reduction of the hydroxylamine as well as faster s-bond metathesis of Cu-O with organosilanes in the turnover of Cu-H catalyst. Finally, applying the optimal p-NEt2 substituted hydroxylamine derivatives has enabled the syntheses of trisubstituted enantioenriched amines from a variety of internal alkenes. Alternatively, the same group has used the same strategy and developed another protocol to access disubstituted chiral amines from monoalkyl hydroxylamine electrophiles.87 In this case, mechanistic studies revealed that appropriate modulation of the electrophile was essential to improve its tolerance with Cu-H intermediate. Recently, Buchwald et al. has discovered a complementary protocol of asymmetric Markovnikov hydroamination using 1,4,2-dioxazol-5-ones as a viable electrophilic amidating reagents.88

Scheme 31 Asymmetric Cu-H catalyzed hydroamination of unactivated internal alkenes.

In expansion of scope of asymmetric Cu-H catalyzed hydroamination, 1,1-disubstituted alkenes were also feasible, affording b-chiral amines in excellent yields with high enantiomeric excesses (Scheme 32).89 In this case, the Cu-H species preferentially inserts into the employed alkenes in an anti-Markovnikov fashion, presumably in minimizing unfavorable steric hindrance. Alternatively, Miura et al. reported the uses of oxa- and azabicyclic alkenes forming chiral oxa- and azanorbornenyl- and norbornanylamines.90 In this case, BPE ligand derivatives gave superior control of stereo-induction in comparison to the SEGPHOS family.

Hydrometallation of Organometallic Complexes

53

Scheme 32 Asymmetric Cu-H catalyzed hydroamination of 1,1-disubstituted alkenes.

The use of an unbiased alkene often led to mediocre control of regioselectivity in Cu-H catalyzed hydroamination, and thus has remained challenging. In 2016, Hartwig and coworkers conceived installing a directing group in close proximity to the olefinic component, thus promoting a regioselective migratory insertion of Cu-H (Scheme 33).91 Upon careful examination, benzoyl derivatives installed in the homoallylic positions were found to be the best candidates, resulting in regioselectivity ranging from 4:1 to >20:1. The family of SEGPHOS ligands was shown again to be the best choice in this type of chemistry, affording 1,3-aminoalcohol derivatives with excellent enantiomeric excesses.

Scheme 33 Asymmetric Cu-H catalyzed directed hydroamination of internal alkenes.

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Hydrometallation of Organometallic Complexes

In the same year, Buchwald et al. reported a fascinating strategy of Cu-H catalyzed reductive relay hydroamination of a variety of allylic alcohols, esters and ethers (Scheme 34).92 The key to this success relies on the b-alkoxide elimination that resulted after the migratory insertion of Cu-H across the alkene. Subsequent anti-Markovnikov hydroamination of the terminal alkene in the presence of electrophilic hydroxylamine reagent affords chiral amines bearing remote g- and d-stereogenic carbons.

Scheme 34 Asymmetric Cu-H catalyzed relay hydroamination of internal alkenes.

Apart from the application of alkenes in catalytic hydroamination, the same group has also established a complementary cascade strategy for accessing either regioisomeric defined enamides or aliphatic amines from a variety of alkynes (Scheme 35).93 In this case, additional subjection of alcohol as a proton source resulted in protonolysis of the vinylcuprate intermediate, forming a cis-alkene which was in turn transformed into the corresponding chiral amine via the developed Cu-H catalyzed hydroamination.

13.02.2.2 Cu-H catalyzed hydroalkylation Technology of hydrocupration has shown its great promise in hydroamination to construct carbon-nitrogen bonds. Other elementary steps rather than oxidative addition of electrophilic amine sources would offer opportunities of forging carbon-carbon or carbon-heteroatom bonds, especially in an enantioselective fashion.

Hydrometallation of Organometallic Complexes

55

Scheme 35 Cu-H catalyzed hydroamination of alkynes in access to either enamides or chiral amines.

In 2015, Buchwald and coworkers reported a highly diastereo- and enantioselective protocol for the Cu-H catalyzed intramolecular syntheses of functionalized chiral indolines (Scheme 36).94 cis-2,3-disubstitued indolines as the single diastereomers can be readily obtained from ortho-vinyl anilines and aldehydes. Crucially, the presence of alcohol in a stoichiometric amount facilitates the turnover of the Cu catalyst, where tBuOD was found to be optimal resulting from a additional deuterium isotope effect. On the

Scheme 36 Cu-H catalyzed intramolecular syntheses of functionalized indolines.

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basis of the nucleophilicity of the Cu-C species, an alternative cascade approach through hydrocupration of enynes and subsequent intermolecular nucleophilic addition into ketones has been conceived and developed (Scheme 37).95 The process allows the preparation of a variety of alcohols with complex structures containing adjacent tri- and tetrasubstituted stereogenic carbon centers. Moreover, combinations of diene-ketone, styrene-ketone and even enyne-thione were feasible, affording the corresponding alcohols and thiol in excellent enantiomeric excesses. Ge and coworkers have also discovered quinoline N-oxide derivatives as amenable electrophiles in the process of asymmetric Cu-H catalyzed hydroheteroarylation.96 The potential of this protocol is highlighted by the facile preparation of a variety of chiral nitrogen-containing heterocycles bearing a-stereogenic carbon centers under mild reaction conditions.

Scheme 37 Enantio- and diastereoselective Cu-H catalyzed syntheses of enantio-enriched complex alcohols.

Merging the classical process of Cu-catalyzed allylation with hydrocupration in an enantioselective fashion has also been demonstrated by Buchwald et al. (Scheme 38).97 This asymmetric protocol of Cu-H catalyzed hydroallylation provided a variety of b-chiral olefins from styrenes and allylic electrophiles. An alkoxide salt is required for the purpose of regenerating the active Cu-H catalyst upon s-bond metathesis of the forming Cu-OR with an organosilane. In scope, a range of vinyl arenes and vinyl heteroarenes were tolerated in the coupling with 2-substituted allylic electrophiles, affording the corresponding products in excellent yields with high enantioselectivities. In lieu of styrenes, Hoveyda and coworkers have demonstrated the viability of using vinyl borates in Cu-H catalyzed hydroallylation (Scheme 39).98 This protocol features the excellent controls of chemo-, diastereo- and enantioselectivities by employing a sulfonate-containing NHC ligand.

Hydrometallation of Organometallic Complexes

Scheme 38 Enantioselective Cu-H catalyzed hydroallylation of styrenes.

Scheme 39 Enantioselective Cu-H catalyzed hydroallylation of vinyl boronic esters.

57

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Hydrometallation of Organometallic Complexes

In 2017, Lalic et al. developed a IPr-Cu catalyzed hydroallylation of alkynes instead of alkenes (Scheme 40).99 This methodology was in complementary to the classical allylation using stochiometric alkenyl organometallic reagents. 1,4-dienes resulted from anti-Markovnikov hydroallylation were obtained in moderate-to-excellent yields. Moreover, functionalized internal alkynes bearing a heteroatom-containing moiety gave trisubstituted alkenes in highly regioselective fashions. By introducing cinnamoyl electrophiles, Zhang and coworkers have established an asymmetric route of synthesizing enantio-enriched 1,4-diene derivatives in the presence of sulfonate-containing NHC ligand.100 Eventually, excellent controls of regioselectivity as well as enantioselectivity have been realized under the asymmetric conditions. On the other hand, switching to the achiral IMes ligand favors SN2-type hydroallylation of alkynes, forming dominantly linear 1,4-dienes. In addition to hydroallylation, asymmetric Cu-H catalyzed hydroalkylation in an intramolecular fashion has also been sought.101 In this case, styrenes tethered with an alkyl halide moiety were the substrates in the scope, forming a variety of optically active cyclobutyl, cyclopentyl, indanyl and piperidinyl derivatives which are ubiquitous in biologically relevant molecules.

Scheme 40 NHC-bound Cu-H catalyzed syntheses of 1,4-dienes.

13.02.2.3 Cu-H catalyzed hydrosilylation and hydroboration Methodologies for constructing carbon-silicon and carbon-boron bonds which can be readily transformed downstream have received much interest and been widely investigated. Expansions of Cu-H catalysis to hydrosilylation and hydroboration have been sought. For instance, in 2017, Buchwald et al. established an asymmetric protocol of Markovnikov hydrosilylations of styrenes and vinyl heteroaromatics (Scheme 41).102 Reactions catalyzed by Cu-H complexed with chiral BPE ligand in the presence of the bench-stable Ph2SiH2 were performed giving desired products with good-to-excellent enantiomeric excesses. Mildness of this reaction conditions was attributed to the fact of having great compatibility with a range of heterocycles.

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59

Scheme 41 Enantioselective Cu-H catalyzed hydrosilylation of alkenes.

Regarding Cu-H catalyzed hydroboration, the classical borylating reagent pinacol borane (H-BPin) has been generally employed. Most examples are Markovnikov hydroboration of styrenes forming chiral benzylic borates.103,104 Otherwise, installation of a dan boronic moiety on alkenes can lead to preferential installation of copper at the carbon adjacent to boron.104 On the other hand, when unbiased 1,2-disubstituted alkenes were used, unselective hydrocupration were generally observed. Accordingly, Hartwig and coworkers have again exploited the strategy of weakly coordinating directing group and developed a regioselective and enantioselective Cu-H catalyzed hydroboration (Scheme 42).105,106 The resulting chiral secondary borates were obtained in moderate-to-good yields with excellent enantioselectivities (up to 99% ee), and DFT studies further demonstrated the origin of regioselectivity is attributed to the stabilization of C-Cu intermediate upon hydrocupration by the coordination of polar directing functional group to Cu metal center. Besides, catalytic hydroboration of 1,1-disubstituted alkenes have also been explored by Yun and coworkers, generating b-chiral alkyl pinacolboronates under mild reaction conditions.107

Scheme 42 Enantioselective Cu-H catalyzed directed hydroboration.

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Hydrometallation of Organometallic Complexes

In 2018, Hoveyda and coworkers have reported an alternative asymmetric Cu-H catalyzed hydroboration by replacing alkenes by 1,3-enynes (Scheme 43).108 Instead of forming propargylic borate, this interesting protocol dominantly afforded a variety of enantio-enriched allenyl-borates in moderate-to-good yields with excellent enantiomeric excesses. Chirality of the allenyl borate product can be completely retained or transferred in the course of post-functionalization under Suzuki −Miyaura cross-coupling reaction conditions and diastereoselective addition of aldehyde, respectively. Notably, authors have defined several factors of influencing the outcome of regio- and enantio-selectivities essentially by the electronic and steric alteration of the substrates. In general, (R,R)-phenyl-BPE bound Cu complex is the optimal catalyst to control the kinetic enantioselectivity. In addition to the aforementioned applications of alkenes and enynes, Cu-catalyzed hydroborations of alkynes have also been well studied. For instance, The groups of Cazin109 and Tsuji110,111 have independently investigated NHC-based Cu-H catalyzed regioselective protocols of generating functionalized multisubstituted olefins from internal alkynes. Steric modulations of the employed NHC carbene can particularly influence the reaction performance as well as regioselectivity. Notably, under the reaction conditions developed by Cazin, either protonolysis or trapping by an electrophilic alkyl halide upon hydrocupration across alkyne were viable to construct carbon-hydrogen or carbon-carbon bonds respectively.

Scheme 43 Enantioselective Cu-H catalyzed hydroboration of 1,3-enynes.

13.02.2.4 Cu-H catalyzed hydrocarbonylation Methodologies to access optically active ketones have gained much attention over the decades. Along with the rapid advances of Cu-H catalysis, Buchwald et al. reported a novel Cu-H catalysis for asymmetric reductive coupling of aryl alkenes and carboxylic anhydrides in an intermolecular fashion (Scheme 44).112 Here the catalytic cycle was proposed to commence with diastereoselective hydrocupration through addition of BPE derivative bound Cu-H complex across styrenes. The resulting nucleophilic C-Cu species would react with an appropriate carbonyl electrophile; hence the carboxylic anhydride was discovered to be the viable carbonyl surrogate. Upon control of reaction temperature, the forming enantio-enriched ketone can be further transformed into alcohols via reductions by Cu-H catalyst in a highly diastereoselective fashion.

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Scheme 44 Enantio- and diastereoselective Cu-H catalyzed hydrocarbonylation of styrenes.

Alternatively, Buchwald et al. reported a new protocol of asymmetric Cu-H catalyzed hydroacylation of styrenes using a,b-unsaturated carboxylic acids in the presence of organosilanes as reductants (Scheme 45).113 Chiral enol silyl ethers were observed after catalysis in this case. The operating mechanism of this hydroacylation still remains unclear. Nevertheless, authors have rationally proposed to commence with Cu-H catalyzed silylation of the conjugated carboxylic acid to form the corresponding silyl ester, which would be subjected into the reductive coupling with the Cu-C species upon asymmetric hydrocupration. In complement to the aforementioned application of symmetrical carboxylic anhydride, this methodology offers an avenue of synthesizing aliphatic chiral ketones in good yields with excellent enantiomeric excesses via Cu-H catalysis.

Scheme 45 Enantioselective Cu-H catalyzed hydroacylation of styrenes with conjugated carboxylic acids.

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Apart from this strategy of reductive Cu-H catalysis, Mankad and coworkers have also sought another alternative preparation of aliphatic ketones via IPr-Cu-H catalyzed carbonylative coupling of alkynes and aliphatic halides in the presence of pressured carbon monoxide atmosphere (Scheme 46).114 The catalytic process involves several crucial elementary steps1: anti-Markovnikov hydrocupration of terminal alkyne,2 formation of aliphatic acyl radical upon one-electron reduction of alkyl iodide and subsequent CO addition of the resulting alkyl radical,3 reductive elimination of Cu(III) intermediate,4 1,4-reduction of the resulting conjugated ketone to enol silyl ether. With respect to the scope, a range of functional groups can be tolerated, forming the unsymmetrical dialkyl ketone in good-to-excellent yields.

Scheme 46 Cu-catalyzed hydrocarbonylative coupling reaction to access dialkyl ketones.

Efforts have also been spent on investigating fixation of carbon dioxide via Cu-H catalysis. For example, Tsuji and coworkers reported NHC bound Cu-H catalyzed hydrocarboxylation of symmetrical and unsymmetrical alkynes under mild reaction conditions, producing a,b-unsaturated carboxylic acids in good yields.115 Recently, Yu and coworkers have discovered an enantioselective Cu-H catalyzed hydroxymethylation of styrenes and 1,3-dienes in the presence of CO2 atmosphere (Scheme 47).116 A wide variety of both important chiral homobenzylic alcohols and homoallylic alcohols were readily accessed under these reductive catalytic conditions. The yield and control of stereo-induction were excellent by the use of the (R)-DTBM-SEGPHOS-Cu catalyst. Notably, in the investigated mechanism as illustrated in Scheme 20, organosilane-mediated reduction of a chiral copper carboxylate, which would be formed via asymmetric hydrocupration and subsequent addition of CO2, would deliver the copper alkoxide prior to the turnover of Cu-H catalyst.

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Scheme 47 Asymmetric Cu-H catalyzed hydroxymethylation of dienes and styrenes.

13.02.3 Cobalt A wide spectrum of homogeneous catalysis involving the use of precious metals, namely rhodium, palladium and iridium et cetera, have been establishing in the frontier of organic chemistry. These methodologies have often offered new opportunities of accessing complex molecules from simple building blocks. On the other hand, exploration of catalysis with base-metals, for instance the cobalt as an electron-rich d9 metal,117 has been by far relatively much less advanced over the past decades in comparison to the noble metal catalysis. Nevertheless, several representatives of powerful Co-catalysis have been well established, for instance, the popular Fischer-Tropsch process for industrial manufacture of hydrocarbons, the regeneration of erythrocytes by cobalamin in human body as well as the Pauson-Khand cycloaddition. Today, the presence of multiple occurring oxidation states of cobalt including its sustainability and abundance has strongly encouraged chemists to continue exploring novel cobalt catalysis. Accordingly, the scope of this subchapter will be mainly focused on seminal discoveries of Co-catalyzed hydrosilylation, hydrogenation and isomerization of unsaturated organic reagents.

13.02.3.1 Co-catalyzed hydrosilylation Hydrosilylation of alkynes generates a variety of vinyl silanes as versatile building blocks in organic synthesis. Along with existing methodologies enabled by pronounced transition metal (Ru, Ni, Cu etc.) catalysis, studies on Co-catalyzed hydrosilylation have been increasingly reported, often showing high reactivities as well as excellent control of regioselectivities by the modulation of organic ligands. Representatively, the groups of Huang118 and Lu119 have independently developed two similar protocols of Co-catalyzed highly regioselective Markovnikov-hydrosilylation using tridentate PyBox and oxazoline iminopyridine (OIP) ligands respectively (Scheme 48). Both established reaction conditions provided a wide range of a-vinylsilanes from terminal alkynes in excellent yields with excellent compatibility of various functional groups. Internal alkynes were also feasible, while regioselectivities in the uses of unsymmetrical variants were likely dominated by the steric hindrance of the alkyne substituents. Notably, Co-catalyzed hydroboration of a-vinylsilanes has also been demonstrated, affording germinal borosilanes in mostly excellent yields. On the basis of the mechanistic studies, authors proposed the putative operation of catalysis proceeding through cis-migratory insertion of Co(I)-Si intermediate across the terminal alkynes followed by protonolysis of vinyl Co(I) specie in the presence of Ph2SiH2. Together with low catalyst loading and mild reaction conditions, these two seminal reports have successfully highlighted the potential of Co(I) catalysis. Recently, Huang et al. reported an asymmetric version of this Co-catalyzed Markovnikov hydrosilylation, in which the chiral PyBox ligand derivative with (R)-hydroxyethyl moiety was optimal (Scheme 49). Having the reaction conditions established, hydrosilylation of both terminal and internal alkynes provided the desired silicon-stereogenic a-vinylsilanes with high enantiomeric excesses.120

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Scheme 48 Co-catalyzed highly regioselective Markovnikov-hydrosilylation of terminal alkynes and catalytic hydroboration of the forming a-vinylsilanes.

Scheme 49 Asymmetric Co-catalyzed Markovnikov hydrosilylation of alkynes. (MTBE ¼ methyl tert-butyl ether).

Next, anti-Markovnikov Co-catalyzed hydrosilylation of terminal alkynes has been realized, and relied on the ligand modifications to be successful. In this context, Huang and coworkers have found that phosphine-iminopyridine ligands are optimal for the generation of a variety of (Z)-b-vinylsilanes which can be readily transformed into (Z)-alkenes under Hiyama-Denmark cross-coupling reaction conditions (Scheme 50).121 In the proposed mechanism, origins of both regio- and stereoselectivity in favor of the anti-Markovnikov product with cis-configuration have been explained by the isomerization of the vinyl-Co intermediate in minimization of steric repulsions between the silyl groups and Co surroundings. Alternatively, a Co complex with a pyridine-2,6-diimine (PDI) ligand reported by Ge and coworkers exhibited the same trend of selectivity in hydrosilylation of terminal alkynes, forming alkyl and aryl substituted (Z)-b-vinylsilanes in excellent yields.122 Interestingly, replacing PDI with dpephos as a bidentate phosphine ligand led to the formation of (E)-b-vinylsilanes in another work of Ge et al.123 The observation of different stereoselectivity in this case can be plausibly explained by the distinct operating mechanism, which commences with migratory insertion of Co-H across the alkyne but not the Co-Si.

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Scheme 50 Co catalyzed syntheses of (Z)-b-vinylsilanes.

Besides, identical formation of (E)-b-vinylsilanes can be also realized by the use of three-coordinate cobalt(I) complex [Co(IAd) (PPh3)(CH2TMS)] as the catalyst in the report of Deng et al.124 In this case, in situ formation of Co-Si and no isomerization of vinyl-Co intermediate were postulated. In addition to most examples relied on the use of terminal alkynes, regioselective Co-catalyzed hydrosilylation of internal alkynes was feasible, however steric differentiation of both two substituents125 or installation of heteroatom126 as a directing element were essential. In addition to alkynes, Co-catalyzed hydrosilylation of alkenes has also been conceived and developed. Controlling the regioselectivity (i.e., linear vs. branched silanes) as well as the enantioselectivity of the branched adduct were the major challenges. In 2016, Huang et al. developed a Co-catalyzed Markovnikov hydrosilylation of a-olefins with the use of iPr-substituted phosphine-iminopyridine (iPr-PCNN) as the optimal ligand (Scheme 51).127 In highlight, this protocol provided excellent compatibility with a wide range of functional groups including amines, esters, ethers and amides. In parallel, Lu and coworkers have developed an asymmetric protocol of Co-catalyzed Markovnikov hydrosilylation.128 The chiral OIP ligand illustrated in Scheme 4 gave excellent control of stereo-induction in general. Together with the successful scope, this Co catalyst featured with both high TON and TOF have given a promising perspective for industrial application.

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Scheme 51 Racemic and enantioselective approaches of Co-catalyzed Markovnikov hydrosilylation of a-olefins reported by the groups of Huang and Lu respectively.

Alternatively, Ge and coworkers have established another phosphine ligand involved protocol in which the regioselectivity of hydrosilylation can be simply controlled by the modulation of the employed ligands (Scheme 52).129 In this case, Xantphos ligand gave branched organosilanes whereas dppf ligand led to the linear variants. Mechanistic studies suggested that the cobalt/bisphosphine system operated via the Chalk-Harrod pathway130 involving the formation of Co-H intermediates for subsequent migratory insertion across styrenes. Additionally, NHC bound Co catalyst reported by Deng et al.131 as well as b-diketiminate Co complex reported by Weix and Holland132 also exhibited very high reactivity, dominantly affording linear organosilanes in good yields. In addition to the scope of a-olefins, Lee and coworker disclosed a Co-catalyzed anti-Markovnikov hydrosilylation of vinylsilanes.133 Fine modulation of (aminomethyl)pyridine ligand derivatives led to high conversions with low catalyst loading (0.25 mol%). RajanBabu and coworkers reported that a (i-PrPDI)CoCl2 catalyst gave exclusively linear 1,3-dienes resulting from anti-Markovnikov hydrosilylation of 1,3-dienes.134 Also, cascade hydrosilylation-cyclization of 1,6-Enynes catalyzed by iminopyridine cobalt complexes has been established by Lu et al.135

Scheme 52 Ligand controlled regioselective Co-catalyzed hydrosilylation of styrenes.

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13.02.3.2 Co-catalyzed hydrogenation Transition metal catalyzed hydrogenation, especially in an asymmetric fashion, has become a robust and well-established technology accessing a wide spectrum of chiral biologically relevant molecules and industrial fine-chemicals.136 Over the past decades, organometallic complexes consisting of noble metals such as Rh, Pd, Ir and Ru have been commonly applied in this field. On the other hand, replacement with a sustainable and abundant base-metal, particularly important for asymmetric hydrogenation, has been gaining more and more consideration today. In 1989, Pfaltz and coworkers reported the use of chiral C2-symmetric ligands featuring the structure of semicorrins for Co-catalyzed asymmetric hydrogenation of a,b-unsaturated carboxylates.137 Control of enantioselectivity in this case was excellent, however, the use of NaBH4 as a H source would certainly limit the compatibility of functional groups. In 1992, Iglesias et al.138 reported an enantiopure 2-aminocarbonylpyrrolide cobalt(I) complex was proven active in asymmetric hydrogenation of ethyl-a-benzoylaminocinnamate by dihydrogen. Moderate enantiomeric excess (74% ee) of the corresponding product was obtained displaying the promising prospects of Co catalysts in this field. Since the last decade, the group of Chirik has spent considerable efforts on discovering new avenues of asymmetric Co-catalyzed hydrogenation of alkenes (Scheme 53). In this context, discovery of an appropriate ligand is of great importance. Eventually, under H2 atmosphere, enantiopure C1-symmetrical bis(imino)pyridine cobalt complexes exhibited good reactivity for asymmetric hydrogenation of a-substituted styrene derivatives, affording the corresponding products in good-to-excellent enantioselectivities.139 Further fine modulations of this class of ligand enabled a successful application of benzo-fused 5-, 6- and 7-membered alkenes in Co-catalyzed asymmetric hydrogenation.140 Alternatively, bis(arylimidazol-2-ylidene)pyridine based catalytic system exhibiting excellent reactivities with a wide range of multisubstituted cyclic and acyclic olefins.141

Scheme 53 Co-catalyzed hydrogenation of alkenes reported by the group of Chirik.

In addition to the Co(I) catalysis studied by Chirik et al., Hanson and coworkers have examined a Co(II) complex ligated with the tridentate bis[2-(dicyclohexylphosphino)ethyl]amine ligand in hydrogenation of alkenes, aldehydes, ketones, and imines.142 In this case, the odd-electron Co catalyst displayed excellent reactivity. On the other hand, Lu and coworkers have sought an alternative cascade strategy involving enantiopure OIP-Co(I)-catalyzed asymmetric Markovnikov hydrosilylation—hydrogenation of terminal alkynes in the presence of Ph2SiH2 as a limiting reagent under an atmosphere of dihydrogen (Scheme 54).143 The same group has also demonstrated again this class of chiral OIP-Co complex was suitable in asymmetric hydrogenation of 1,10 -diaryl alkenes, forming enantiomeric enriched 1,1-diarylethenes as privileged scaffolds existed in biologically active molecules.144

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Scheme 54 Enantiopure OIP-Co(I)-catalyzed asymmetric hydrogenation.

All these existing methodologies required synthetic efforts on the preparation of the Co precatalyst in prior to reaction. Therefore, a combinatory and practical approach to access requisite active Co catalyst was highly desired, and phosphine based catalytic systems turned out to be the variant. Chirik et al. has discovered that bidentate phosphine ligated Co complexes were active for the hydrogenation of geminal and 1,2-disubstituted alkenes.145 On the basis of this finding, the same group has successfully developed a high-throughput strategy to rapidly evaluate a large library of chiral phosphine ligands for Co-catalyzed asymmetric hydrogenation of enamide and stilbene derivatives (Scheme 55).146 Excellent reaction performance with high levels of enantioselectivities has highlighted the industrial potential of this approach. In 2018, Chirik et al. has disclosed another approach of Co-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction in conjunction with the high-throughput technology (Scheme 55).147 Elemental zinc as a one-electron reductant was used to activate the Co(II) dichloride precatalyst complexes with various chiral phosphine ligand. Representatively, scaled up enantioselective preparation (200 g) of the epilepsy medication levetiracetam was successfully achieved with only 0.08 mol% catalyst loading under protic reaction conditions in this case. All these exciting advances eventually have laid the cornerstone for frontier cobalt asymmetric catalysis.

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Scheme 55 Asymmetric high-throughput Co-catalyzed asymmetric hydrogenation

13.02.3.3 Co-catalyzed isomerization of alkenes The alkenyl functional group is widespread in the structural scaffold of organic molecules including pharmaceuticals, fine-chemicals and synthetic intermediates etc. A number of synthetic methodologies to access them have been well established to date. In particular, access of thermodynamically less stable (Z)-alkenes represents still as a formidable challenge. Most existing methodologies deliver the (E)-isomers since the selectivity was often dominated by the thermodynamic issue. In the advance of Co catalysis, catalytic hydrogenation of alkynes to access isomeric alkenes in a stereoselective fashion represents as an important technology. In 2016, Liu and coworkers have reported a ligand-controlled stereodivergent hydrogenation of internal alkynes to Z- and E-alkenes (Scheme 56).148 In the presence of ammonia borane as a hydrogen source, the bulkier PNP-Co complex gave Z-stilbene, whereas the less bulky NNP-Co complex delivered the E-isomer exclusively in the hydrogenation of diphenylacetylene. Mechanistic studies have revealed that isomerization of the kinetic Z-product into the more thermodynamically stable E-isomer occurred via alkyl mechanism149 when the less steric demanding NNP ligand was employed. This fascinating work was also highlighted by the wide scope, high tolerance of functional groups as well as the high reactivity with low catalyst loading.

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Scheme 56 Ligand-controlled stereodivergent hydrogenation of internal alkynes and isomerization of (Z)-alkenes.

In addition to catalytic hydrogenation of alkynes, Co-catalyzed olefin isomerization of alkenes has also been considered as an important and atom-economic strategy. In 2014, the groups of Weix and Holland elaborated a protocol of catalytic isomerization of terminal alkenes into Z-internal isomers by a bulky high-spin b-diketiminate Cobalt(II) complex.150 As depicted in Scheme 57 left, authors have proposed the alkyl mechanism149 in the course of isomerization of 1-hexene as a model substrate. This catalysis involves an iterative migratory insertion and b-H elimination. The rationale of regioselectivity and stereoselectivity of alkene isomerization was suggested by a steric model which showcases a square-planar transition state of b-H elimination and the steric encumbrance of the ligand enforces the formation of the Z-isomer as a kinetic product. In 2018, the groups of Jiao and Liu have established an another important protocol for Co-catalyzed regioselective olefin isomerization of complex molecules featuring an exocyclic olefinic component.149 As depicted in Scheme 57 right, the superior class of NNP pincer Co complexes exhibited excellent reactivities as well as high kinetic control of regioselectivity in the scope of catalytic isomerization of various 1,10 -alkenes. In highlight, this protocol has shown its great promise of Co-catalyzed alkene isomerization in natural product synthesis. Beyond the scope of hydrosilylation, hydrogenation and isomerization of unsaturated chemicals, Co-H catalysis has also been advanced in the hydrovinylation of dienes pioneered by the groups of Rajanbabu,151 Vogt152,153 and Schmalz.154 In addition to the scope of Co-H catalysis, enormous efforts have also been spent on the catalysis of iron as a base-metal which is one of the most abundant and environmentally friendly metal on earth.155 A wide spectrum of organic transformations such as additions, cycloadditions, oxidations, reductions and polymerizations etc. enabled by iron catalysis have been well established.156–160 Along with the rapid advances of Co-H catalysis over the last decades, organometallic Fe-H catalyzed hydrogenation,161–166 hydrosilylation,167–176 hydroboration,177–187 reduction188 and hydromagnesation189–192 of unsaturated chemicals have also been elaborated. The related processes of catalysis displayed often comparable or even superior reaction outcomes than those obtained from Co-H catalysis.193 In similar to the strategies established in the cases of Co catalysis, fine modulation of organic ligands plays crucial roles on controlling regio-, enantio-, chemo- and stereoselectivities. Readers are encouraged to see details in exploration of Fe catalyzed functionalizations of alkenes and alkynes citied in the related references. Overall, having all these amazing works established, efforts spent on the exploration of cobalt and iron catalysis has definitely bought completely new perspectives for the fruitful future of base-metal catalysis.

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Scheme 57 Co-catalyzed kinetic isomerization of alkenes.

Acknowledgment J.Z. acknowledges support from the Shanghai Municipal Science and Technology Major Project (2018SHZDZX03) and the Program of Introducing Talents of Discipline to Universities (B16017). B. Y. thanks the startup fund as a financial support from ShanghaiTech University.

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Hydrometallation of Organometallic Complexes 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. 168.

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13.03

Metal-Catalyzed Aerobic Oxidation Reactions

Jessica M Hoover, Andreas Baur, and Jiaqi Liu, C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, United States © 2022 Elsevier Ltd. All rights reserved.

13.03.1 13.03.2 13.03.2.1 13.03.2.1.1 13.03.2.1.2 13.03.2.2 13.03.2.2.1 13.03.2.2.2 13.03.2.3 13.03.2.3.1 13.03.2.3.2 13.03.3 13.03.3.1 13.03.3.1.1 13.03.3.1.2 13.03.3.1.3 13.03.3.1.4 13.03.3.2 13.03.3.2.1 13.03.3.2.2 13.03.3.3 13.03.3.3.1 13.03.3.3.2 13.03.4 13.03.4.1 13.03.4.1.1 13.03.4.1.2 13.03.4.1.3 13.03.4.2 13.03.4.2.1 13.03.4.2.2 13.03.4.3 13.03.4.3.1 13.03.4.3.2 13.03.5 References

Introduction Oxygenation reactions Cobalt catalysts for oxygenation reactions Alkane oxygenation Phenol oxygenation Copper catalysts for oxygenation reactions Alkane oxygenation Phenol oxygenation Other catalysts for oxygenation reactions Alkane oxygenation Arene oxygenation Dehydrogenation reactions Palladium catalysts for dehydrogenation reactions Basic mechanistic considerations Alcohol oxidation Amine oxidation Alkane dehydrogenation Copper catalysts for dehydrogenation reactions Alcohol oxidation Amine dehydrogenation Other catalysts for dehydrogenation reactions Alcohol oxidation Amine oxidation Dehydrogenative coupling reactions Palladium catalysts for dehydrogenative coupling reactions Oxidative couplings of alkenes Oxidative couplings of arenes Allylic functionalization Copper catalysts for dehydrogenative coupling reactions Oxidative coupling of arenes Oxidative coupling of alkanes Other catalysts for dehydrogenative coupling reactions Alkene and alkyne oxidation and oxidative coupling Arene coupling Conclusions

75 75 76 76 79 81 81 85 87 87 88 88 88 89 90 95 96 98 98 104 106 106 108 110 110 110 114 116 118 118 122 123 123 125 125 126

13.03.1 Introduction The use of O2 as a terminal oxidant for chemical transformations has both economic and environmental advantages over traditional oxidants, due to its low cost and the formation of water and hydrogen peroxide as byproducts. Large scale industrial use of O2 requires high temperature and pressure conditions that are not typically amenable to fine chemical synthesis. The extension of aerobic oxidation reactions to small molecule targets requires methods that provide high efficiency and selectivity under relatively mild conditions. This chapter covers the recent developments in homogeneous transition-metal catalyzed aerobic oxidation reactions of small molecules with an emphasis on reaction mechanisms as a framework for further synthetic advances in this area. The chapter is organized into three sections including oxygenation, dehydrogenation, and dehydrogenative coupling reactions. Each section discusses the most prominent catalytic systems and highlights key mechanistic insights that have led to improvements in synthetic utility, selectivity and scope. Select examples are included to illustrate the state of the art and remaining challenges in the field.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00097-4

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Metal-Catalyzed Aerobic Oxidation Reactions

13.03.2 Oxygenation reactions In oxygenation reactions, one or both oxygen atoms of O2 are incorporated into the product. The most prominent oxygenation reactions are those of CdH bonds and this section will describe the oxygenation reactions of alkanes and phenols by the most established catalyst systems based on cobalt and copper. Other catalytic systems have been developed, including those based on iron, vanadium, palladium and even nickel, and a selection of these reactions will also be presented. Although alkene oxygenation reactions are established,1–4 they are of limited synthetic utility due to challenges associated with selectivity as a mixture of alcohol, ketone and epoxide products are formed.

13.03.2.1 Cobalt catalysts for oxygenation reactions 13.03.2.1.1

Alkane oxygenation

Some of the largest scale oxidation reactions performed in industry rely on radical-chain autoxidation processes catalyzed by cobalt.5 For example, the synthesis of terephthalic acid from para-xylene in the Mid-Century process uses a Co(OAc)2/Mn(OAc)2/ HBr catalyst system,6,7 while catalytic CoX2 salts are used to generate a mixture of cyclohexanone and cyclohexanol, known as KA oil, from the oxidation of cyclohexane (Scheme 1).8,9 In contrast, the application of these and related methods are less common in the smaller scale synthesis of pharmaceuticals or other complex molecules. CH3

CH3

Mid-Century Process Co(OAc) 2/Mn(OAc) 2/HBr

O

OH

O

OH

air (23-26 atm) 170-230 °C

O CoX 2 air (10 atm) 140-165 °C

OH

KA Oil

Scheme 1 Cobalt-catalyzed oxygenations of para-xylene and cyclohexane.

The most prominent examples of cobalt-catalyzed aerobic oxygenation reactions utilize the N-hydroxyphthalimide (NHPI) cocatalyst reported by Ishii in 1996.10 This Co/NHPI catalyst system accomplishes the oxygenation of benzylic and aliphatic hydrocarbons to alcohols, ketones, and carboxylic acids, depending upon the substrate.10–12 While select activated substrates such as fluorene undergo oxidation to ketones in the absence of a metal cocatalyst, these oxidations are enhanced by the presence of CoII salts.12,13 Other less-activated substrates, such as linear alkanes and toluenes, require the presence of cobalt. In these reactions, the phthalimido-N-oxyl radical (PINO) is generated in situ from NHPI and O2, as indicated by EPR experiments and stoichiometric control reactions.10 Cobalt(II) salts have been shown to accelerate formation of the PINO radical suggesting that a CoIII-peroxo species may form and facilitate the generation of the PINO radical.12,14 The PINO radical abstracts a hydrogen atom from the substrate to generate the corresponding alkyl radical which is then oxygenated by O2 to yield peroxy radicals, which decompose into the oxygenated products (Scheme 2). O N O

CoIIIOOH or CoIIIOH

CoII, O2

CoIII OO or CoIII O O CoIII

PINO•

O

H Ar

O N OH NHPI

O

Scheme 2 General pathway for the Co/NHPI-catalyzed aerobic CdH oxygenation reactions.

Ar

O2

O Ar

O

O Ar

Metal-Catalyzed Aerobic Oxidation Reactions

77

The formation of ketones from the peroxy radical was originally believed to result from Russell termination, accounting for the formation of both ketone and alcohol products (Scheme 3A). Nolte and co-workers, however, showed that while at early reaction times both ketone and alcohol are present in the oxidation of ethylbenzene, at longer reaction times, the ketone forms preferentially.15 A polar transition state model involving PINO based HAA of both the alkane and the alcohol CdH bonds was proposed to account for the preferential formation of the ketone product (Scheme 3B). This model supports more rapid oxidation of the alcohol over the ketone, due to stabilization of the positive charge on the benzylic position by the benzylic OH group. This model also accounts for the increase in reaction rate when NHPI derivatives bearing electron-withdrawing substituents are used, as well as the faster reaction rates of electron-rich benzylic substrates seen by Ishii.10 This polar transition state may also be related to the challenges associated with the oxidation of heteroaromatic substrates, as seen later in this section.

(A)

(B)

Scheme 3 Proposed pathways for the formation of ketones from peroxy radical and PINO•.

Because these reactions follow a radical oxygenation pathway, the oxidation of a wide variety of substrate classes is possible. Cyclic and linear alkanes, as well as alkylbenzenes, are oxidized to the ketone, however overoxidation to the dicarboxylic acid does occur (Scheme 4). Oxidation at the more substituted position is favored, which is especially apparent in the oxidation of linear alkanes which give mixtures of secondary alcohols and ketones preferentially over the corresponding aldehydes and carboxylic acids. For example, the oxidation of n-octane yields 2-, 3-, and 4-octanols as well as octanones. O Co/NHPI/O2

CO2H CO2H O

Co/NHPI/O2

Co/NHPI/O2

octanols

octanones

O Co/NHPI/O2

OH

Scheme 4 Select examples of Co/NHPI-catalyzed CdH oxygenation reactions.

The applications and extensions of the Co/NHPI catalyst system have been limited due, in part, to the propensity of the radical reaction to generate mixtures of oxygenated products. Reactions of select substrate classes in which a single reaction product forms, however, have seen further development, in particular the benzylic oxygenation reactions. As an example, Patil and co-workers have developed phase transfer conditions using DDAB as a phase transfer catalyst to enable the recovery and reuse of the Co/NHPI/ DDAB catalyst system in an effort to extend the benzylic oxygenation of ethylbenzene to larger scale industrial applications (DDABdi-n-decyl-methyl ammonium bromide).16 Additional efforts have focused on coaxing improved selectivity from the reactions. In the oxygenation reactions of methylarenes, oxidation of the aldehyde occurs easily and overoxidation to the carboxylic acid is common, often leading to mixtures of products. Pappo and co-workers have used 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as the reaction solvent to provide high selectivity for the aldehyde (Scheme 5).17 The strong hydrogen bonds formed between HFIP and the aldehyde deactivate the aldehyde toward further hydrogen atom abstraction (HAA) and prevent overoxidation.

78

Metal-Catalyzed Aerobic Oxidation Reactions

NHPI (5-20 mol%) Co(OAc) 2 4H2O (2 mol%) HFIP (0.5 M), O 2 (1 atm), rt

R

O R

H 20 examples 65-99% conversions 88-99% selectivities

Scheme 5 Co/NHPI-catalyzed oxygenation of toluenes to yield the corresponding aldehydes.

An alternative strategy to achieve selectivity is the use of a covalently bound NHPI derivative to enable a directed CdH abstraction.18 This approach provides good regioselectivity for oxygenation at the g-position (or the d-position depending on the substrate) and it shows tolerance for functional groups that are traditionally problematic for Co/NHPI oxidation protocols such as electron-rich heteroarenes, haloarenes, alkenes, and alkynes, among others (Scheme 6). Ketone or alcohol products are formed depending on the substrate. For the oxidation of tertiary CdH bonds, Me2S was included to avoid the formation of byproducts resulting from the CdC bond cleavage of hydroperoxide intermediates (Scheme 6, Conditions B). Removal of the directing group can be accomplished with LiAlH4 to give the corresponding 1,3-diol product. This strategy was also applied to the synthesis of nitrate esters with the inclusion of NaNO2 in the reaction mixture.19

O N OH F 3C O directing activator

R

Cond itions A: Co(OAc) 2 (5 mol%) Mn(OAc) 3 2 H2O (5 mol%) O2 (1 atm), TFE (0.1 M) Conditions B: Co(OAc) 2 (1 mol%) Me2S (1.2 equiv) O2 (1 atm), TFE (0.1 M)

O N OH [O] F 3C O

R

22 examples 19-93% yields

[O] = O or OH

Scheme 6 Co-catalyzed CdH oxygenation using an intramolecular directing activator. Modified from Ozawa, J.; Tashiro, M.; Ni, J.; Oisaki, K.; Kanai, M. Chem. Sci. 2016, 7, 1904. doi:10.1039/C5SC04476F. Reproduced by permission of The Royal Society of Chemistry.

There has also been much interest in extending the Co/NHPI-catalyzed methods to the oxygenation of heterobenzylic CdH bonds. The oxidation of heterobenzylic substrates is particularly challenging because the heteroarene deactivates the CdH bonds. In addition, the coordination of the heteroatoms to cobalt may be problematic and the formation of heterooxides, such as nitroxide and sulfoxide species, has been suggested to hinder benzylic oxygenation.15 The oxygenation of 3-methylpyridines20 and methylquinolines21 can be achieved to yield the corresponding carboxylic acids (Scheme 7). Although small amounts of the aldehyde products are formed (1–2%), these reactions are highly selective for formation of the carboxylic acid (32–93%). Both reactions require the inclusion of CoII salts and Mn(OAc)2 for efficient oxidation to occur. In the case of pyridines, the inclusion of Mn(OAc)2 led to increased yields and accelerated reaction rates in the oxidation of 3-methylpyridine and Mn(OAc)2 was required for the oxidation of 4-methylpyridine. Alternatively, when both 3- and 4-methylpyridines were included together in a single reaction mixture, oxidation of the 4-methylpyridine occurred efficiently in the absence of Mn(OAc)2, suggestive of the presence of 3-ArCH2OO and 3-ArCH2O radical intermediates that serve as chain transfer agents to generate the 4-ArCH2 radical. To accomplish the oxidation of methylquinolines, the addition of NO2 to the previously reported conditions was crucial. In these reactions the quinoline is believed to coordinate cobalt and hinder the formation of the PINO radical by Co/O2; NO2 aids the formation of PINO from NHPI by acting as a hydrogen atom abstractor.

N

CH3

O2

NHPI (10 mol%) Co(OAc) 2 (2 mol%) Mn(OAc) 2 (0.1 mol%) NO2 (0 or 10 mol%) AcOH, 100 °C

O N

OH

7 examples 32-93% yields

Scheme 7 Co(OAc)2/Mn(OAc)2/NHPI-catalyzed oxygenation of methylpyridines and methylquinolines.

Stahl and co-workers have further improved the Co/NHPI system to enable the efficient oxygenation of heterobenzylic compounds with pharmaceutical relevance (Scheme 8).22 The authors found the nature of the cobalt counteranion to be important for catalysis, with Co(OAc)2 (1 mol%) giving the highest yields when paired with NHPI (20 mol%) in butyl acetate at 90–100  C under 1 atm O2. For challenging substrates, such as sulfur-containing heterocycles, alternative conditions employing a pyridine cosolvent gave improved yields due to the role of pyridine as a ligand to attenuate side reactions by cobalt. Heterocycle chelation to cobalt remains a challenge in this system and for select substrates cobalt-free electrochemical conditions were employed.

(Het)Ar

1 mol% Co(OAc)2 • 4H2O O 20 mol% NHPI 15 examples R BuOAc, 90-100 °C, 1 atm O R 48-95% yields 2 (Het)Ar

Scheme 8 Co/NHPI-catalyzed aerobic oxygenation of heterobenzylic compounds.

Metal-Catalyzed Aerobic Oxidation Reactions

79

Although some efforts have been made to render the Co/NHPI catalyst systems enantioselective, they have been met with limited success. For example, Shen and Tan applied chiral anthrone-derived analogues of NHPI to the oxidation of benzylic compounds (Scheme 9). Unfortunately, mixtures of ketone and alcohol products were obtained and low enantioselectivities were observed in all cases (4–13% ee).23

OH

O +

50% (13% ee)

30% O

OH + 42% (4% ee) O

conditions: O N OH O OH Cl

35%

O O

(10 mol%)

Cl Co(OAc) 2 (5 mol%) O2 (1 atm) CH3CN, 60 °C

48% (8% ee) Scheme 9 Enantioselective CdH oxygenation reactions catalyzed by Co/NHPI.

A small number of cobalt-catalyzed benzylic oxygenation reactions that proceed in the absence of NHPI have also been developed. Cobalt(II) phthalocyanine24 and tetraphenylporphyrin (TPP) complexes25 have been reported for the oxygenation of benzylic CdH bonds. These reactions are proposed to proceed through a pathway involving direct activation of O2 by the cobalt complex and HAA by a superoxocobalt(III) species.

13.03.2.1.2

Phenol oxygenation

In 1967 Geursen and co-worker26 reported the first reaction of a bis(salicylidene)ethylenediiminocobalt(II) (salcomine) as a homogeneous catalyst for the oxidation of phenols with molecular oxygen in chloroform or methanol with the addition of anhydrous magnesium sulfate (Scheme 10). In 1984, Martell and co-workers27 reported Co(TPP) complexes to be active for the oxidation of 2,6-di-tert-butylphenol to form 2,6-di-tert-butyl-para-benzoquinone as the major product. Thesee30,28 and related30 reactions are proposed to proceed through a pathway that features the formation of a phenoxyl radical which is then either oxidized by the CodO2 species to form the benzoquinone, or dimerizes to form the diphenoquinone (Scheme 10).

Scheme 10 Aerobic oxygenation of phenols catalyzed by salcomine and Co(TPP) complexes.

Although a number of developments have been made toward improved cobalt catalysts for phenol oxidation reactions,31,32 the majority of recent work has focused on application of these catalyst systems to the selective oxidative degradation of lignin-related molecules to value-added products (Fig. 1).

80

Metal-Catalyzed Aerobic Oxidation Reactions

O H3CO OCH3 H3CO OH

OH

OH

p-hydroxyphenyl (H)

OCH3

guaiacyl (G)

O

O HO

OH

OH

syringyl (S) H3CO

OCH3 O

H3CO

O

OH OH

HO O

OH

O H3CO

OCH 3 O

O OH

Fig. 1 Partial structure of lignin illustrating the p-hydroxyphenyl (H), guaiacyl (G), and syringyl (S) components. Modified from Magallanes, G.; Kärkäs, M. D.; Bosque, I.; Lee, S.; Maldonado, S.; Stephenson, C. R. J. ACS Catal. 2019, 9, 2252–2260. https://pubs.acs.org/doi/10.1021/acscatal.8b04172. Copyright 2019 American Chemical Society.

Early work from Bozell and co-workers established the oxidation of para-substituted phenols, such as syringyl alcohol, as models for lignin33 (Scheme 11). Cobalt-salen catalysts (5 mol%) effectively oxidize a series of para-substituted phenols to the corresponding quinones in yields ranging from 11% to 90% under 50 psi O2 at room temperature in methanol. Complexes bearing an amine or pyridine in the axial coordination site were less effective catalysts due to the inability to bind substrate and O2 simultaneously. The reaction mechanism is analogous to those described above with initial formation of a phenoxyl radical that is trapped by O2 or a CodO2 species. Here, subsequent elimination of formaldehdye generates the quinone product. Two methoxy substituents on the substrate were necessary for efficient oxidation (Scheme 11, R1 ¼ OMe). In the absence of electron-donating substituents, initial formation of the phenoxyl radical becomes challenging due to the polar character developed in the transition state for hydrogen atom abstraction (HAA) (as shown in Scheme 3 for the oxidation of alkanes and alcohols). Electron-donating groups also facilitate the initial oxidation by lowering the bond dissociation energy (BDE) of the OdH bond. The rate of initial HAA determines the overall success of the transformation. When slow HAA occurs, an irreversible background oxidation of the catalyst by O2 occurs in methanol and deactivates the catalyst, although this oxidation can be slowed by using dichloromethane as the solvent.

Scheme 11 Co-salen catalyzed oxidation of substituted phenols.

Metal-Catalyzed Aerobic Oxidation Reactions

81

Bozell and co-worker addressed the lower yielding conversion of mono-methoxy phenols by studying the effects of added imidazoles and 4-substituted pyridines on the reactivity of their catalytic systems.34 The addition of monodentate nitrogencontaining bases has been shown to increase the binding of molecular oxygen,35 but also slow the oxidation of phenols as described above. In this study, the typical reaction conditions consist of 10 mol% cobalt catalyst under 60 psi dioxygen in methanol or dichloromethane with 1 equivalent of added base (Scheme 11B). Under these conditions, the oxidation of syringyl alcohol increased with the donor ability of the imidazole and the pKa of the conjugate acid. Sterically more hindered imidazoles reduced the yield, which was rationalized by a distortion of the complex and shifting of the equilibrium to disfavor the Co-superoxo complex. While these catalyst systems enable efficient oxidation of syringyl alcohol, the corresponding oxidation of guaiacyl and p-hydroxyphenyl lignin models is more challenging. In a follow-up study Bozell and co-worker36 designed ligands bearing a sterically hindered pendant base (Scheme 11C), to enable the efficient oxidation of various monomeric and dimeric syringyl and guaiacyl subunit lignin models in good yields. Further studies from the same authors37 used DFT studies to explore the differing effects of pyridines and related bases on the oxidations of syringyl (S), guaiacyl (G) and p-hydroxybenzyl (H) alcohols. While the oxidation of S proceeds efficiently (99% yield) with Co(salen) in the presence of coordinated pyridine, G and H are not oxidized under these conditions. The calculations showed that these differences arise from issues during the catalyst regeneration steps.

13.03.2.2 Copper catalysts for oxygenation reactions Although the interest of the chemical community in copper systems that catalyze aerobic oxygenase-type reactions is fairly recent, the copper-mediated oxygenation of organic molecules is a common process in biological systems. Copper-containing monooxygenase enzymes incorporate one oxygen atom from dioxygen into their substrates whereas the second oxygen becomes reduced to water (Scheme 12A).38 Dopamine b-monooxygenase (DbM) hydroxylates the benzylic position in dopamine to form norepinephrine while tyrosinase catalyzes the ortho-hydroxylation of monophenols and the oxidation of diphenols to ortho-quinones (Scheme 12B). The tyrosinase active site contains a bis-m-oxo dicopper core while DbM contains a noncoupled dinuclear active site. Mechanistic studies of DbM support that oxygen binding forms a Cu(II)-OO− intermediate which undergoes HAA with the substrate. The resulting radical is oxygenated to form the alcohol, although the specific steps of this transformation are still debated.39 Inspiration has been drawn from these enzymatic systems leading to a large body of reports on the chemistry of related CudO2 complexes.38 Biomimetic catalytic systems that can oxidize strong CdH bonds with dioxygen, however, are rare and their reactions are usually performed at low temperatures due to the instability of the oxygen complexes. SMet

(A) Dopamine β-Monooxygenase

OH

NH3

NH3

DβM

HO OH

H2O

O2

HO

NH2

OH

O

NH2

Tyr

HO O2

HO H2O

NHis

CuMII

OH

(B) Tyrosinase

O O

O

NHis

O

CuHI

NHis NHis DβM Active Site

NHis

NHis NHis

O

NHis

O CuII

CuII

NHis

O

NHis NHis

Tyrosinase Active Site

Scheme 12 CdH oxygenation reactions mediated by Cu-containing dopamine b-monooxygenase and tyrosinase enzymes.

13.03.2.2.1

Alkane oxygenation

Despite the efficiency of copper-based enzymatic systems in achieving the direct oxygenation of CdH bonds, small molecule systems have proven to be less successful.40 Challenges arise in controlling the degree of the oxidation particularly in the oxygenation of aliphatic CdH bonds. The oxidation products contain weaker CdH bonds than the starting alkanes41 facilitating further oxidation and giving rise to acid, aldehyde and alcohol products in these reactions. The copper-catalyzed oxygenation of Csp3dH bonds can proceed through two mechanisms, the first involving direct hydrogen atom abstraction (HAA) of the alkane CdH bond, and the second proceeding through deprotonation followed by single-electron oxidation. While initial deprotonation typically requires an activated CdH bond, HAA can occur with simple alkanes. In the late 1990s, Murahashi and co-workers reported that CuCl2 (0.0025 mol%) can facilitate the oxygenation of cyclohexane in the presence of 18-crown-6 and acetaldehyde under an atmosphere of O2 (Scheme 13).42 The mechanism is not fully elucidated, but is believed to involve a Cu-catalyzed reaction of the acetaldehyde with O2 to generate a peroxyacid. The peroxyacid reacts with copper to generate an active oxometal species (either CuIIIdO or CuIV]O) that abstracts a H-atom from the substrate. The same authors later reported a related catalyst system employing Cu(OAc)2 in acetonitrile and dichloromethane with an O2/N2 mixture (1:8, 9 atm total) for the oxidation of ethylbenzene, tetraline, and indane. Here, selectivity is poor and the benzylic alcohol is obtained alongside the ketone product.43

82

Metal-Catalyzed Aerobic Oxidation Reactions

CuCl2, 18-crown-6 (0.0025 mol%) O2 (1 atm), CH3CHO CH2Cl2, 70 °C

OH

O +

10 %

61 %

O O Cu O OH2 O O

O

Cl Cl

Cu Cl

Cl Cl

Cl Cu

Cl Cl

O OH2 O Cu O O O

O

Scheme 13 CuCl2-catalyzed aerobic oxygenation of cyclohexane.

Building on this early work from Murahashi, a number of researchers have developed catalyst systems for the oxidation of simple alkane systems, such as cyclohexane44,45 and benzylic substrates.46–49 In general, however, copper-catalyzed alkane oxygenation reactions are typically limited to simple and symmetrical hydrocarbons due to a lack of selectivity in oxidation. In an effort to achieve site selectivity, some researchers have employed directing groups. For example, Schönecker and co-workers developed the selective hydroxylation of steroids with O2 through the use of pyridylmethyl- and pyridylethylamine directing groups (Scheme 14).50,51 This conformationally restricted bidentate ligand at the 17-position of the steroid leads to regio- and stereospecific g-hydroxylation of the nonactivated CH2 group. The reaction is proposed to proceed through a pathway in which a Cu2O2 species is responsible for HAA. Consistent with this proposal, the bis(m-hydroxy)dicopper(II) complex was isolated and characterized crystallographically. The high stereoselectivity of the system is inherent in the steroid structure and the seven-membered ring transition state that places the g-C—H in the same plane as the directing group N atoms.52 These studies laid the groundwork for further developments in the directed CdH hydroxylation catalyzed by copper, such as the selective CdH oxygenation of steroids reported by Baran and co-workers.53 This group used a 3-methyl-2-pyridylethanamine directing group and a CuII salt paired with sodium ascorbate as a reducing agent to improve the reaction yields (40–94% yields) and extended the protocol to a wider scope of substrates, highlighted with the synthesis of polyoxypregnane natural products.

Scheme 14 Cu-mediated selective hydroxylation of steroids.

Chiba and co-workers reported the directed benzylic oxygenation of carbonitriles using Cu(OAc)2 (10 mol%) in DMF under 1 atm O2 at 80  C.54 The addition of Grignard reagents to carbonitriles forms imine intermediates that then undergo benzylic CdH oxygenation to yield diketones or the 1H-isoindol-1-ol products (Scheme 15). This reaction proceeds via an iminyl copper intermediate and labelling experiments confirmed that both incorporated oxygen atoms arise from O2. R CN

Ar-MgBr Et2O, 60 °C then MeOH

R

NH

Cu(OAc) 2 (10 mol%) Ar DMF, 80 °C, O2 (1 atm)

R

O

O Ar

or

R

OH N

29 examples Ar 49-91% yields

Scheme 15 Cu-catalyzed directed benzylic oxygenation of carbonitriles.

In a related system, Lei, Zhuo and co-workers used ethyl chloroacetate as an activating group to generate N-heterocyclic ketones from pyridines as well as quinolines, benzoquinolines, quinoxalines, benzimidazoles, and benzothiazoles.55 Notably, this method also enables the oxidation of 3-alkylpyridines, which are unsuccessful substrates in other systems described later in this section. The full catalyst system includes CuCl2
2H2O (10 mol%) with ethyl chloroacetate under 1 atm O2, in DMF at 130  C (Scheme 16). Ethyl chloroacetate acts as an activator to generate the alkyl pyridinium salt, in a fashion similar to the formation of pyridinium salts in the acidic systems described below. The use of 18O2 in the oxidation of 4-ethylpyridine led to the 18O-labeled product in 75% yield and EPR spectroscopy confirmed the presence of organic radicals during the reaction. These experiments led to a mechanistic proposal involving N-alkylation of the heterocyclic nitrogen with ethyl chloroacetate to activate the benzylic methylene toward HAA and oxygenation by CuII. The resulting benzylic radical combines with O2 to form a peroxide intermediate that undergoes dehydration and copper-induced reduction to form the ketone product.

Metal-Catalyzed Aerobic Oxidation Reactions

O

CuCl2•2H2O (10 mol%) ClCH2CO2Et (1 equiv) O2 (1 atm), DMF, 130 °C

N

22 examples 30-92% yields N

O N CO2Et

O

O2

CuII Cl-

83

Cl-

N CO2Et

Cl-

N CO2Et

Scheme 16 Cu-catalyzed oxygenation of ethylpyridine with ethyl chloroacetate as an activator.

Finally, Chiba and co-workers reported the oxidation of alkylindole and pyrrole substrates using CuBrSMe2 (15 mol%) with DABCO (1 equiv) in DMSO under 1 atm O2 at 100  C (Scheme 17, DABCO ¼ 1,4-diazabicyclo[2.2.2]octane).56 Labelling studies with 18O2 indicated incorporation of oxygen atoms from O2 and the authors proposed a reaction pathway involving initial HAA, followed by a one-electron oxidation of indole to form the radical cation intermediate. O R N Me

CuBr•SMe2 (15 mol%) DABCO (1 equiv) DMSO, O2 (1 atm)

R N Me

13 examples 22-93% yields

Scheme 17 Cu-catalyzed oxygenation of alkylindoles.

While the direct hydrogen atom abstraction of CdH bonds requires simple substrates or directing groups to achieve selectivity, activated substrates bearing acidic benzylic CdH bonds afford more selective oxygenation. Oxidation of these substrates often proceeds via initial deprotonation, followed by single-electron oxidation to form a radical intermediate that then reacts with O2. However, given the nature of the initial deprotonation, these reactions are limited in scope to activated substrates. para-Nitrotoluene bears acidic methyl CdH bonds (pKa ¼ 20.4 in DMSO,57 23.5 in H2O58) that can undergo oxygenation via deprotonation. For example, She and co-workers reported a copper phthalocyanine catalyst (0.13 mol%) paired with sodium hydroxide under 2 MPa of oxygen to enable the benzylic oxygenation of nitrotoluene to nitrobenzoic acid as the major product (Scheme 18).59 Later developments by Shan and co-workers extended the method to the use of an ionic liquid solvent [omim][BF4] (omim ¼ 1-octyl-3-methylimidazolinium) allowing for recycling of the catalyst.60

Scheme 18 Cu-phthalocyanine catalyzed aerobic oxygenation of para-nitrotoluene.

The oxygenation of doubly benzylic positions also proceeds efficiently under basic conditions. For example, early work from Allara reported the facile oxygenation of fluorene by Cu(OBz)(OMe) (5 mol%) with a triethylenetetramine (11 mol%) ligand in a pyridine:methanol (5:1) solvent mixture at 1950 Torr O2 (Scheme 19).61 This reaction proceeds under mild conditions in minutes to yield the fluorenone product with high selectivities over bifluorenyl (200:1), the homocoupling product. The author proposed a base-catalyzed mechanism for the oxidation based on earlier proposals by Russell and co-workers62 as well as reaction kinetics and KIE measurements (kH/KD ¼ 9.0). Initial deprotonation of the benzylic position generates the fluorenyl anion which then complexes with CuII and undergoes electron transfer with O2 to generate the corresponding radical intermediate. Selectivity for oxygenation in these reactions arises from the trapping of the anion with Cu, which remains associated with the fluorenyl radical, limiting radical homocoupling pathways.

84

Metal-Catalyzed Aerobic Oxidation Reactions

O

Cu(OBz)(O Me) (5 mol%) triethylenetetramine (11 mol%) 5:1 pyridine:MeOH O2 (1950 torr), rt

+

200 : 1 Scheme 19 Cu-catalyzed oxygenation of fluorene.

Activated substrates can also be oxidized in the absence of strongly basic conditions. A serendipitous discovery by the Maes group led to a CuI (10 mol%)/AcOH (10 mol%) catalyst system for the oxygenation of aryl(di)azinylmethanes with 1 atm O2 in DMSO at 100  C (Scheme 20).63 The inclusion of AcOH was crucial for oxidation and later studies revealed the acid promotes tautomerization to the enamine.64 The enamine tautomer reacts with CuII formed in situ, to form a new CuIIdC bond. The resulting intermediate then reacts with O2 to generate a CuIII-superoxide species that undergoes rapid rearrangement to form the organoperoxide intermediate. Finally, deprotonation of the benzylic position generates the product. Both mononuclear and dinuclear catalyst species were shown to be involved in product formation, although the mononuclear catalysts are more active. This study also enabled the correlation of imine-enamine tautomerization equilibrium constants of the substrates with the yields of the ketone products obtained, ultimately allowing prediction of how readily a substrate will be oxidized based on the Keq values.

N

CuII Ph NH

O

CuI (10 mol%), AcOH (10 mol%) O2 (1 atm), DMSO, 100 °C

Ph

CuII -H+

N

O

O

Ph O2

Ph N CuII O O

CuIII Ph -H+

N

Ph H

Scheme 20 Cu-catalyzed oxygenation of aryl(di)azinylmethanes via an enamine intermediate.

In 2017, the Maes group applied this catalyst system to the oxidation of benzylpyridine-N-oxides.65 The N-oxide moiety serves to activate the benzylic position toward oxidation while also enabling subsequent pyridine functionalization. Removal of the activating N-oxide can be accomplished by deoxygenation with PCl3, and this overall strategy was applied to the formal synthesis of acrivastine from 2-picoline-N-oxide (Scheme 21).

Scheme 21 Cu-catalyzed oxygenation of 2-picoline-N-oxide to access acrivastine.

Sato and Itoh reported a similar protocol using CuCl2
2H2O as the catalyst in DMSO with 1 atm O2 at 100  C for the oxidation of methylpyridines to the corresponding aldehydes (Scheme 22).66 The effective oxidation of 2- and 4-picoline and the inactivity of 3-picoline suggests a tautomerization pathway involving protonation of the pyridine by in situ formed HCl. This pathway is also supported with control experiments using either anhydrous CuCl2 or the inclusion of triethylamine, both of which supress the catalytic reaction. Furthermore, reaction with CuCl2/D2O under anaerobic conditions leads to deuterium incorporation (73%) in the methyl group. Although the tautomerization pathway provides high selectivity in these oxidation reactions, it also introduces an inherent substrate limitation with the requirement for benzyl heterocycles with a nitrogen in the a- or g-position.

R N

CH3 CuCl2•2H2O (10 mol%) O2 (1 atm), DMF, 100 °C

Scheme 22 Cu-catalyzed oxygenation of methylpyridines to yield aldehydes.

R N

O

7 examples H 24-96 % yields

Metal-Catalyzed Aerobic Oxidation Reactions

85

Oxygenation adjacent to carbonyls and imines also proceeds efficiently under copper catalysis. Kumar and co-workers have shown the oxygenation of (hetero)aryl acetimidates to yield aryl-a-ketoesters67 as well as the oxygenation of benzylimidates to generate a-ketoamides (Scheme 23).68 Both reactions employ Cu(OAc)2 and undergo benzylic oxygenation by O2. Although the imine CdN bond is cleaved under these conditions, the C(imine)dC bond remains intact.

OEt R

NH

O

Cu(OAc) 2 (2 equiv) O2 (1 atm), DMF, 80 °C

R

O

NH2 20 examples 36-85% yield

Scheme 23 Cu-catalyzed oxygenation of (hetero)aryl acetimidates to yield aryl-a-ketoesters.

The a-oxygenation of carbonyl compounds, however, often proceeds with cleavage of the C(acyl)dC bond. A copper-catalyzed aerobic oxidative esterification of ketones occurs by CdC bond cleavage.69 The system employs a CuBr catalyst (10 mol%) and either a pyridine (2 equiv) or BF3
Et2O (1 equiv) additive in PhCl at 130  C under open air conditions (Scheme 24). The reaction tolerates alcohols and chiral alcohols are coupled with retention of stereochemistry. The same authors also reported the related ring-opening CdC cleavage of ketones with amines.70 More recently Beng and co-workers described the hydroxylation of dihydroisoquinolines in a regio- and diastereoselective fashion using CuF2 (5 mol%) and Cs2CO3 (1.1 equiv) in 2-MeTHF, at room temperature under 1 atm O2.71 O Ar

n alkyl

+

HOR CuBr (10 mol%), py (2 equiv) PhCl, 130 °C, open air

O Ar

O

R

14 examples 30-90% yields

Scheme 24 Cu-catalyzed aerobic oxidative esterification of ketones.

In 2016, Schoenebeck revealed the origin of the selectivity.72 Using a combined experimental and computational approach, the group identified an a-peroxy ketone as a shared intermediate in both the hydroxylation and CdC cleavage pathways. In the presence of hppH or PPh3 the a-peroxy ketone is reduced to yield the alcohol product (hppH ¼ 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a]pyrimidine). In the absence of a reductant, the a-peroxy ketone intermediate undergoes cleavage to form the a-oxy radical, and subsequent CdC cleavage leads to the product (Scheme 25).

Scheme 25 Selective oxidative cleavage of ketones to yield the hydroxylation products in the presence of hppH and the CdC cleavage products in the presence of DBU.

13.03.2.2.2

Phenol oxygenation

Despite the interest in oxygenation reactions catalyzed by enzymatic systems, few synthetic systems have been designed that enable the efficient and selective oxygenation of phenols. Early work focused on the development of catalytic enzymatic models, with the majority of these systems providing low conversions of a limited substrate scope. Réglier and co-workers reported the first example in the early 1990s using BiPh(impy)2 (L1) as a ligand to coordinate two copper centers (Scheme 26).73 The resulting binuclear complex was capable of the conversion of 2,4-di-tert-butylphenol (DTBP) with a turnover of 16 in dichloromethane in the presence of triethylamine.

Scheme 26 Chelating ligands applied to the selective Cu-catalyzed oxygenation of phenols.

86

Metal-Catalyzed Aerobic Oxidation Reactions

Building on this prior work, Tuczek and co-workers have made substantial contributions in this area. In 2010, they reported the oxidation of DTBP using a mononuclear copper complex bearing a simple bidentate ligand (L2).74 Oxidation of DTBP with the complex [CuI(L2)(DTBP)]PF6 (2 mol%) provided 48% conversion after 1 day generating a product mixture consisting of 3,5-ditert-butylcatechol (DTBC, 3% yield), 3,5-di-tert-butyl-ortho-quinone (DTBQ, 15% yield), and the corresponding biphenol (30% yield). In their following studies, the same group prepared related complexes to explore the importance of tethered ligands (L3) to generate binuclear complexes,75 the influence of steric and electronic effects of the phenol and ligand (L4),76 and the role of ligand hemilability (L5) in these oxidation reactions.77,78 These designs allowed for the isolation and characterization of key intermediates, including the phenolato and catecholato intermediates. They also revealed increased reactivity with 4-methoxyphenol, consistent with the reactivity expected for an electrophilic copper-peroxo system. In 2013, Stack, Herres-Pawlis and co-workers used Tp analogs (Tp ¼ trispyrazolylborate, L6) to generate a bis-m-peroxo complex at low temperatures.79 This species reacted with a broad scope of para-substituted phenolates at −78  C to provide the catechol products in excellent yields (Scheme 27). Catalytic hydroxylations could be performed at room temperature in CH2Cl2 in the presence of Et3N. Kinetic data showed a first order dependence on [copper complex] and [phenolate] supporting a pre-equilibrium binding event and a rate-limiting oxidation. A rate-limiting CdH cleavage step was excluded on the basis of KIE studies (kH/kD ¼ 1.2  0.2). Hammett studies showed a negative correlation with s+p (r ¼ − 0.99) consistent with the proposed electrophilic aromatic substitution mechanism.

Scheme 27 Oxygenation of para-substituted phenolates by a well-defined copper bis-m-peroxo complex. Modified from Hoffmann, A.; Citek, C.; Binder, S.; Goos, A.; Rübhausen, M.; Troeppner, O.; Ivanovic-Burmazovic, I.; Wasinger, E. C.; Stack, T. D. P.; Herres-Pawlis, S., Angew. Chem. Int. Ed. 2013, 52 (20), 5398–5401. doi:10.1002/anie.201301249. Copyright 2013, with permission from John Wiley and Sons.

Although limited in scope and yield, the systems described above laid the groundwork for the development of Cu catalysts for more efficient oxygenation reactions. Most studies seeking to apply these complexes to small molecule synthesis focus on the oxidation of 2,3,5-trimethoxyphenol,80 because the corresponding quinone is a key intermediate in the synthesis of Vitamin E. Other researchers have harnessed the catechol intermediate to access more complex heterocyclic products. For example, Herres-Pawlis and co-workers81 prepared a guanidine-containing bis(m-oxo) complex that demonstrated good catalytic activity in the oxidation of a broad scope of phenolic substrates. The catechol intermediate was trapped with 1,2-phenylenediamine to yield the corresponding phenazines in moderate yields (Scheme 28).

OH R

X

Cu catalyst (4 mol%) NEt3 (2 equiv) R THF, -90 °C

O X

N

NH2

O rt

NH2

N N R

11 examples 19-32% yields

X X = C, N

N N N

Cu

O O

Cu

N

2 PF 6

N N

N

Scheme 28 Cu-catalyzed oxygenation of phenols and trapping with 1,2-phenylenediamine to yield phenazines.

Lumb and co-workers82 applied a biomimetic strategy to the synthesis of polyfunctional indoles starting from the N- and O-protected tyrosine, Boc-Tyr-OMe. The catalytic system consists of a previously reported83,84 combination of [Cu(CH3CN)4] PF6 paired with N,N0 -di-tert-butylethylenediamine (DBED) as a ligand and allows access to C-5 substituted indoles. The reaction proceeds in two steps, first an oxidation which forms a coupled ortho-quinone (Q1) in 90–95% yield (Scheme 29), followed by a second step, in which acidic conditions yield the substituted indoles in moderate yields. The reaction was effective for a variety of primary and secondary alcohols including allylic, propargylic and benzylic alcohols. The same authors later applied a biomimetic strategy to the total synthesis of (S,S)-tetramethylmagnolamine.85 The key catalytic step involves oxygenation of a pendant phenol, followed by CdO coupling.

Metal-Catalyzed Aerobic Oxidation Reactions

OH

MeO2C O2 (1 atm) Cu(CH3CN) 4(PF 6) (4 mol%)

NHBoc

NHtBu DBED (5 mol%)

R1

O O BocHN

tBuHN

BocHN

R2 O R2OH (10 equiv) H2SO 4 (4 equiv) CH2Cl2 (0.5 M) O rt, 1 h BocHN

O

O OH

H N

15 examples 26-75% yields

R1

R1

R1

Q1

R2 O

87

Scheme 29 Cu-catalyzed CdH oxygenation and coupling of a tyrosine derivative to access substituted indoles.

13.03.2.3 Other catalysts for oxygenation reactions 13.03.2.3.1

Alkane oxygenation

Catalysts other than those based on cobalt and copper have also been applied to aerobic oxygenation reactions,86–90 the most prominent of which is iron.91 A series of non-heme iron complexes have been shown to catalyze the oxygenation of ethylbenzene under 1 atm of O2, although low yields are obtained and alcohol byproducts are also formed.92 Similarly, the oxidation of alkylbenzenes to ketones is catalyzed by Fe(TPP)Cl (5 mol%) with chloramine-T (1 mmol) under 1 atm O2 in MeCN.93 Iron salts, such as Fe(NO3)3
9H2O, have also been paired with NHPI for the oxygenation of benzylic methylene compounds under 1 atm O2 at room temperature (Scheme 30).94 Under these conditions substrates bearing electron-donating groups are oxidized most rapidly and the proposed pathway involves HAA by PINO to generate the benzylic radical. The aryl(di)azinylmethane systems explored by Maes and co-workers under cobalt catalysis can also undergo oxidation by iron. The optimized conditions consist of FeCl2
4H2O (10 mol%) with acetic acid as an additive under 1 atm O2 in DMSO at 100  C or 130  C (Scheme 31).63 Kappe and co-workers have devised a continuous flow system for the related catalytic oxidation of 2-benzylpyridines with FeCl3 (5 mol%).95 Flow photochemical systems have also been designed using a riboflavintetraacetate photocatalyst paired with Fe(ClO4)2 (5 mol%) for the oxidation of benzylic substrates (Scheme 32).96 In this and related reactions,97–99 HAA of the benzylic CdH occurs by photoactivated riboflavintetraacetate (RFT) assisted by iron. The resulting radical reacts with singlet oxygen to yield the ketone product.

Scheme 30 Fe/NHPI catalyzed oxygenation of benzylic methylene compounds to yield ketones.

R

N

O

FeCl 2•4H2O (10 mol%) AcOH (1 equiv) DMSO, O2, 100°C

N

R

7 examples 59-85% yields

Scheme 31 Fe-catalyzed oxygenation of aryl(di)azinylmethanes.

R1

R2

RFT (10 mol%) Fe(ClO4) 2 (5 mol%) 50 °C, UV (106 W)

R N

O R 2 15 examples 17-79% yields

R1

N

O NH

N RFT O

Scheme 32 Fe-catalyzed photochemical continuous flow oxidation of benzylic compounds.

Xiao and coworkers reported the oxidation of substituted tetrahydrofurans, isochromans, and phthalans to the corresponding lactones (Scheme 33).100 Although this is not an asymmetric reaction, they employed a chiral PyBisulidine ligand paired with Fe(OTf )2 introducing the possibility for future chiral oxygenation reactions with iron. tBu

R2 R1

Fe(OTf) 2-ligand (5.65 x 10-3 mmol) O2 (1 atm), THF, 60 °C O

R2

23 examples O 8-67% yields

R1 O

tBu

O2S

SO 2

N

N

N NH

HN

ligand

Scheme 33 Fe-catalyzed oxygenation of isochromans to yield lactones.

88

Metal-Catalyzed Aerobic Oxidation Reactions

San Martin, Domínguez and co-workers have developed Pd complexes bearing pincer ligands for the oxygenation of benzylic compounds.101,102 These catalysts are selective toward formation of the ketone and operate efficiently at low catalyst loadings (0.1 mol%) and low pressures of O2 (1 atm O2 or air).

13.03.2.3.2

Arene oxygenation

Despite the prevalence of enzymatic and small molecule catalyst systems capable of the oxygenation of phenols, oxygenation reactions of other arene CdH bonds are quite rare. One remarkable oxygenation of an aromatic CdH bond by Pd was reported by Yu and co-workers. Using Pd(OAc)2 (10 mol%) paired with benzoquinone (BQ, 1 equiv) and KOAc (2 equiv) under 1 atm O2 in DMA, the authors enabled the ortho-hydroxylation of simple benzoic acids. Labelling studies showed the incorporated oxygen to arise from O2 (Scheme 34).103

O R

OH

Pd(OAc) 2 (10 mol%) KOAc (2 equiv), BQ (1 equiv) O2 (1 atm), DMA, 115°C

O R

OH

18 examples 48-82% yields

OH

Scheme 34 Pd-catalyzed aerobic ortho-hydroxylation of benzoic acids.

13.03.3 Dehydrogenation reactions This section will detail formal dehydrogenation reactions in which a saturated substrate is oxidized to form a new C]O, C]N, or C]C double bond. The most prominent of the aerobic dehydrogenation reactions are alcohol oxidation reactions. Catalyst systems based on Pd and Cu have become some of the most well-understood and powerful catalyst systems available for the aerobic oxidation of alcohols and amines and we focus this section on these systems. Co, Ru and V catalyst systems are also studied and are included below as well.

13.03.3.1 Palladium catalysts for dehydrogenation reactions Pd-catalyzed aerobic oxidation reactions date back to the 1950s with the discovery of the Wacker process for the production of acetaldehyde from ethylene and water. In this reaction, the reoxidation of Pd by O2 is mediated by copper. In 1967 Lloyd showed that Pd alone is capable of the catalytic aerobic oxidation of alcohols indicating that the direct oxidation of Pd0 by O2 is possible.104 In the mid-1990s, Larock and Heimstra developed Pd catalyst systems for the oxidation of alcohols in DMSO.105,106 These conditions proved to be general across diverse reaction classes leading to the development of a wide variety of Pd-catalyzed aerobic transformations. These reactions all follow the same general mechanistic framework consisting of substrate oxidation by PdII and reoxidation of the resulting Pd0 to PdII by O2 (Scheme 35). The intermediacy of Pd0 in these systems often leads to aggregation and decomposition into inactive Pd black making the facile reoxidation of Pd0 crucial for catalyst lifetime and efficiency.

Scheme 35 General mechanistic framework for Pd-catalyzed aerobic oxidation reactions. Modified from Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S. Chem. Rev. 2018, 118, 2636–2679. https://doi.org/10.1021/acs.chemrev.7b00334. Copyright 2018 American Chemical Society.

Metal-Catalyzed Aerobic Oxidation Reactions

13.03.3.1.1

89

Basic mechanistic considerations

For aerobic oxidations like alcohol oxidations, Wacker-type oxidations, and oxidative Heck reactions the product forming step proceeds via b-hydride elimination and the concurrent formation of a PdII-hydride species. The reaction of the PdII-hydride with O2, either directly or via a Pd0 intermediate, provides the turnover required for catalysis. There are three major pathways that are possible to achieve this turnover: H-atom abstraction (HAA),107 HX reductive elimination (HXRE), and [H-L]+ reductive elimination (HLRE).108 In contrast to HAA, the HXRE and HLRE processes proceed through a Pd0 species (Scheme 36).109

cheme 36 Pathways for the catalytic turnover of PdII-hydride with O2. Modified from Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S. Chem. Rev. 2018, 118, 2636–2679. https://doi.org/10.1021/acs.chemrev.7b00334. Copyright 2018 American Chemical Society.

The reaction of Pd complexes with O2 is difficult to study under catalytic conditions because it is often kinetically invisible due to turnover-limiting substrate oxidation. Consequently, our understanding of the reoxidation of Pd species by O2 is derived from the study of well-defined Pd complexes and DFT calculations. Simple Pd(OAc)2/py systems are common catalysts in aerobic oxidation reactions, and (py)Pd(H)(k2-OAc) was used by Goddard110 and Stahl111 as a model to computationally explore the reaction of Pd with O2. The results favor a HXRE pathway that features the formation of a three-coordinate transition state for reductive elimination of AcOH to form Pd0. The authors propose that this pathway is universal for all PdII-hydride species bearing monodentate L-type (e.g., py) and basic (e.g., acetate) ligands or base additives. In contrast, DFT studies using common bidentate nitrogen-based ligands, such as (−)-sparteine, phenanthroline, bipyridine and pyridine-oxazoline, support a HLRE pathway in which the ligand dissociates from the Pd center forming a zwitterionic Pd0 species.108 In the presence of exogenous 3o amine or by replacing the chloride with a carboxylate ligand the HXRE pathway is strongly favored.110 These studies support the formation of Pd0 species as key intermediates in the catalytic turnover of relevant aerobic reactions. The oxidation of Pd0 with O2 is thought to proceed through a PdII-peroxo intermediate which consequently forms hydrogen peroxide following reaction with Brønsted acids (Scheme 37). This mechanistic model was supported by Stahl and co-workers,112 who demonstrated the rapid formation of (bc)PdII(Z2-O2) from a Pd0-dba precursor and dioxygen (bc ¼ bathocuproine, 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline). DFT studies using a Pd0-ethylenediamine model system supported a two-step protonolysis of the Pd-peroxo intermediate that was found to be dependent on the identity of the ancillary ligand.108 When IMes ligands were used the Pd-hydroperoxy intermediate could be isolated and characterized (IMes ¼ 1,3-bis(2,4,6-trimethylphenyl) imidazoline-2-ylidene).113

O2

LnPd0

LnPdII

Ph N

O O

OOH Ln PdII

X

HX

Ln PdII

X Ph

CH3 Ph

Pd

Ph

O O

N

O CH3

H2O2

X

CH3 N

dry O2 (1 atm), rt CH2Cl2, 30 min

Pd

N Ph

HX

CH3 (bc)Pd(O2) 70% yield

N Ar Ar N O AcOH, rt dry O2 (1 atm) Ar Pd Pd toluene, -78°C Ar O N Ar Ar N Ar N N Ar

N

N

Ar = 2,4,6-trimethylphenyl

Scheme 37 Isolated PdII-peroxo and -hydroperoxy intermediates.

(IMes) 2Pd(O2) 97% yield

Ar

N

N

Ar

AcO Pd OOH Ar

N

N

Ar

(IMes) 2Pd(OAc)(OOH) 65% yield

90

Metal-Catalyzed Aerobic Oxidation Reactions

13.03.3.1.2

Alcohol oxidation

The first example of a Pd-catalyzed aerobic alcohol oxidation reaction was reported by Moiseev in 1963 and employed cocatalytic CuCl2.114 Significant advances have followed. Most notable are the removal of CuCl2104,115 and the use of DMSO and basic additives to improve reaction rates and yields.105,106,116,117 The most significant advances in developing synthetically attractive Pd-catalyst systems for the aerobic oxidation of alcohols, however, have come from the mechanistic studies of some of these early systems. These systems all follow the same basic mechanism comprised of alcohol oxidation by PdII and reoxidation of Pd0 by O2 (Scheme 35). In the alcohol oxidation sequence, deprotonation of a Pd-coordinated alcohol generates a Pd-alkoxide intermediate that undergoes b-hydride elimination to form the corresponding ketone or aldehyde product (Scheme 38). The different catalyst systems vary in the use of supporting ligands to accelerate the reoxidation step and to tune the b-hydride elimination step.

β-hydride elimination

deprotonation LnPdII X 2

R

OH

LnPdII

-HX

X O

LnPdII O

R R

reductive elimination X Pd0 H -HX

H

Scheme 38 General pathway for the Pd-catalyzed aerobic oxidation of alcohols.

Early mechanistic work by Stahl and co-workers probed the Pd-catalyzed aerobic alcohol oxidation developed by Larock and found the DMSO solvent to have both advantageous and deleterious effects on the reaction.118 Kinetic data indicated the turnover-limiting step to be oxidation of Pd by O2, with a competitive binuclear decomposition pathway to form Pd metal under standard catalytic conditions. Later studies showed that this O2 dependence observed at high catalyst loadings is a mass-transfer limitation.119 In this catalyst system, the slow mass transfer of O2 into solution arises from the low solubility of O2 in DMSO and leads to increased catalyst decomposition because the Pd0 resting state has more time to aggregate leading to Pd black formation. DMSO, however, is a crucial solvent for stabilizing the Pd0 intermediates.120 Given the importance of DMSO in stabilizing Pd0 by ligation, the development of improved systems using a variety of supporting ligands followed. Two key classes are those involving N-based ligands and N-heterocyclic carbene (NHC) ligands (Scheme 39).

OH R1

O

Pd catalyst / ligand

R2

O2

Pd(OAc) 2 / DMSO N N Pd(OAc) 2 / pyridine Ar Ar Pd OAc AcO PdX 2 / NEt3 OAc (X = OAc, Cl)

R1

R'

R

R2

R' N

N Pd

R

AcO OAc R = H, Me R' = Ph, H, C6H4SO 3Na

O N N Pd Cl Cl

Pd

N

AcO 2

Scheme 39 Most prominent catalysts for the Pd-catalyzed aerobic oxidation of alcohols. Reprinted with permission from Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348–4355. https://doi.org/10.1021/ja057914b. Copyright 2006 American Chemical Society.

The Pd(OAc)2/py catalyst system developed by Uemura and co-workers is the first Pd catalyst system for aerobic alcohol oxidation reactions to employ nitrogen-based ligands (py ¼ pyridine).116,117 An empirical approach established an ideal py loading of 4:1 py:Pd. Mechanistic studies by Stahl and co-workers120 revealed that this ideal pyridine loading results from a need to balance the catalyst turnover rate with the catalyst stability. More specifically, the py ligand serves to accelerate catalyst reoxidation, but hinders the alcohol oxidation sequence. In contrast to the Pd/DMSO system described above, the Pd/py catalyst system exhibits turnover-limiting alcohol oxidation by PdII, indicated by a saturation dependence on both [catalyst] and [alcohol] as well as primary kinetic isotope effects of 1.3 and 1.8 (at [alcohol] ¼ 0.10 and 1.0 M) when PhCD2OH is employed. Under these conditions pyridine accelerates the oxidation of Pd0 by O2 leading to a PdII resting state. This change in turnover-limiting step minimizes catalyst decomposition which only becomes problematic at high Pd loadings. The catalyst resting state was shown by 1H NMR spectroscopy to be a mixture of (py)2Pd(OAc)2 and the alcohol adduct of this complex, which is suggested to be a hydrogen bonded species as shown in Scheme 40. The alcohol oxidation sequence is inhibited at pyridine loadings greater than 1 equivalent per Pd because the b-hydride elimination step is expected to occur from a three-coordinate intermediate. Dissociation of py from the alkoxide intermediate prior to b-hydride elimination is consistent with the positive slope of the Hammett correlation of para-substituted pyridines.

Metal-Catalyzed Aerobic Oxidation Reactions

R

OH

CH2R O

H

Pd(OAc) 2 (5 mol%)

py AcO Pd OCH2R py

-HOAc py O AcO Pd O CH3 py

R

pyridine (20 mol%) O2 (700 torr) toluene, 4 hrs, 80 °C -py

91

O

py AcO Pd OCH2R

(AcO)Pd(py)(H ) + R

O

Scheme 40 Proposed pathway for substrate oxidation in the Pd(OAc)2/py-catalyzed aerobic alcohol oxidation reaction.

In 2013, Emmert and co-workers121 evaluated a series of substituted pyridine ligands for the Pd-catalyzed alcohol oxidation in order to identify a system that enables the use of 1 atm air as the sole oxidant while avoiding the formation of Pd black. As described above, reactions conducted under an O2 atmosphere showed high reaction rates with electron-withdrawing groups on the pyridine. In contrast, Emmert and co-coworkers found that under an air atmosphere electron-donating groups in the para-position of the pyridine provided superior yields. These data highlight the importance of the pyridine ligand in facilitating Pd0 reoxidation when the reaction is conducted under air. The authors also observed a rate enhancement when pivalate was used in place of acetate. This improvement was attributed to the increased basicity of pivalate which accelerates deprotonation. In addition, the increased steric bulk favors dissociation to generate the unsaturated Pd intermediate required for b-hydride elimination. The optimal catalyst systems identified in these studies consists of low loadings of Pd(OPiv)2 (2 mol%) paired with 4-dimethylaminopyridine (DMAP, 4 mol%) and a PivOH (0.5 equiv) additive in toluene under an atmosphere of air (Scheme 41). Under these conditions high yields were obtained for the oxidation of both primary and secondary benzylic and aliphatic alcohols without any observable decomposition of Pd0.

OH R1

R2

pyr (4 mol%) Pd(OPiv) 2 (2 mol%) PivOH (0.5 equiv) toluene, air, 100 °C

O R1

R2

OCH3

12 examples 69-99% yields pyr = DMAP

pyr =

CF 3 N

N

N

N

2h 24 h

19% 25%

28% 40%

65% 93%

49% 99%

tBu

N(CH3) 2

Scheme 41 Influence of pyridine substituents on the Pd(OPiv)2/pyr-catalyzed alcohol oxidation under an air atmosphere.

Bidentate ligands with ortho-substituents are known to promote aerobic alcohol oxidation reactions. Neocuproine-ligated Pd catalysts can achieve reactivity under room temperature conditions and provide selective oxidation of a,o-diols to lactones and the oxidation of secondary alcohols in vicinal diols and carbohydrates (Scheme 42).122 Despite the advantages of these catalyst systems, the neocuproine ligand undergoes oxidative degradation leading to catalyst decomposition and limiting the overall efficiency and practicality of these reactions. Recently, Waymouth and co-workers identified this oxidative degradation pathway to occur though a radical autoxidation process that begins with hydrogen atom abstraction (HAA) of the benzylic CdH bond (Scheme 43A).123 This finding was supported by the improved yields obtained when the deuterated neocuproine ligand was used, and when ethylbenzene was included in the reaction mixture. In the case of ethyl benzene, oxidation occurs to form 1-phenethyl hydroperoxide which acts as a sacrificial hydrogen atom donor and slows ligand oxidation.

O [(neocuproine)Pd(OAc) 2](OTf) 2 (10 mol%) CH3CN / H2O (9:1), 25 °C, air or O2 R2 R1 R2

OH R1

O

O R1

OH R2

9 examples 70-99% yields Scheme 42 Pd/neocuproine-catalyzed selective aerobic oxidation of polyols.

O X X=O 65% yield NBoc 76% yield

92

Metal-Catalyzed Aerobic Oxidation Reactions

Scheme 43 (A) Pathway for oxidative degradation of the neocuproine ligand and (B) role of styrene in attenuating the degradation.

The authors also identified styrene to be an effective additive to prevent catalyst decomposition. Pd-catalyzed alcohol oxidation reactions typically proceed via reductive elimination of HX from the Pd-hydride intermediate, followed by reoxidation of the resulting Pd0 species by O2. The intermediacy of Pd0 in this pathway introduces the opportunity for catalyst decomposition via aggregation and formation of Pd black. In the presence of styrene, however, isotopic labelling studies indicate that alkene insertion into PddH occurs and subsequent reaction with O2 generates 1-phenethyl hydroperoxide while bypassing Pd0 in the regeneration of the active PdII catalyst (Scheme 43B). These findings led to new catalytic conditions employing low Pd loadings (0.25–1.5 mol%) with a phenol (0.5 equiv) or styrene (1.5–3.5 equiv) additive in MeCN at 60  C under 1 atm of O2. These conditions provide a more than 10-fold improvement in turnover numbers and enable the efficient and selective oxidation of a small series of diols (Scheme 44). Although the separation of styrene oligomers may be problematic in some cases, this recent report highlights new strategies to avoid catalyst deactivation in these Pd-catalyzed aerobic alcohol oxidation reactions. 0.4 mol% Pd styrene (1.5 equiv) ambient air Ph OH 1:1 MeCN/EtPh, rt 5 mmol OH

OH OH O

1.5 mol% Pd styrene (3.5 equiv) bubbling air MeCN, 50 °C

OH BocN

OH 72 % O O O 59%

12.5 mmol OH

O Ph

1.25 mol% Pd styrene (3.5 equiv) bubbling air MeCN, 50 °C

20 mmol

O O BocN 54%

Scheme 44 Aerobic Pd-catalyzed oxidation of diols with styrene as an additive.

Sigman and co-workers developed a related system employing triethylamine (Et3N) in place of pyridine.124 This system efficiently oxidizes both primary and secondary benzylic and aliphatic alcohols to the corresponding aldehydes and ketones under milder conditions and at room temperature (Scheme 45). Allylic alcohols, however, are ineffective substrates because the resulting a,b-unsaturated carbonyl compounds ligate to Pd and inhibit catalysis. For example, the oxidation of 2-decanol is completely inhibited by the addition of cinnamaldehyde. Similarly, substrates bearing ortho-coordinating groups, such as methoxy and a,b-unsaturated carbonyls, are not tolerated by this catalyst. Mechanistic studies125 showed that the replacement of py with Et3N leads to a change in the catalyst resting state. In the case of py, the resting state consists of (py)2Pd(OAc)2 and the corresponding alcohol-bound adduct (Scheme 40, above). Because the b-hydride elimination proceeds more rapidly through a three-coordinate intermediate, a pyridine ligand must dissociate prior to b-hydride elimination. When Et3N is used, however, a pre-equilibrium binding of amine exists between Pd(OAc)2, Pd(OAc)2(Et3N) and Pd(OAc)2(Et3N)2 as determined by 1H NMR

Metal-Catalyzed Aerobic Oxidation Reactions

93

analysis of reaction mixtures. Calculations show the mono-Et3N species to be the dominant species in solution under typical catalytic conditions indicating that dissociation of amine is not required for alcohol to bind or for b-hydride elimination to proceed. This equilibrium mixture leads to a lower barrier to b-hydride elimination and a turnover-limiting deprotonation of the alcohol adduct. Pd(OAc) 2 (3 mol%), Et3N (6 mol%) THF (15%) in toluene, 25 °C R' 3 Å MS, O2 (1 atm)

OH R

O R

R'

17 exmaples 30-97% yields

Scheme 45 Pd(OAc)2/Et3N-catalyzed aerobic oxidation of alcohols.

The finding that nitrogen-based ligands both accelerate catalysis and extend the scope of reactivity laid the foundation for the development of enantioselective variants of these Pd-catalyzed alcohol oxidation reactions. Most prominent are the Pd/ (−)-sparteine catalyst systems developed independently by Sigman126 and Stoltz127 for the oxidative kinetic resolution of racemic secondary alcohols and the oxidative desymmetrization of meso-diols. Early systems employed (−)-sparteine with a PdII precatalyst to achieve the oxidation of benzylic alcohols with enantioselectivities of up to 99% (and ranging from 66% to 99% ee). Under these conditions, electron-donating substituents on the arene provided higher enantioselectivities than those bearing electron-withdrawing groups (Scheme 46).

Scheme 46 Oxidative kinetic resolution of benzylic alcohols by Pd/(−)-sparteine. Data from Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475–7476.

The use of tert-butyl alcohol (tBuOH) as the solvent enables the efficient oxidation of a broad scope of benzylic, allylic and aliphatic alcohols, presumably due to the enhanced ability of tBuOH to stabilize cationic intermediates (Scheme 47).128 Overall, the optimal conditions for this oxidative kinetic resolution were 5 mol% of Pd[(−)-sparteine)]Cl2, 20 mol% of (−)-sparteine, and 0.25 M alcohol in tert-butyl alcohol with crushed activated molecular sieves (3 A˚ ) at 65  C under a balloon pressure of O2. This kinetic resolution is an attractive route to access enantioenriched alcohols from readily available racemic sources. Unfortunately, a number of substrates are inefficient under these conditions including those bearing esters, alkynes, ketones and trifluoromethyl groups. These alcohols undergo low conversions, consistent with observations by Uemura and co-workers that chelating substrates inhibit catalysis and those bearing trifluoromethyl groups are generally challenging oxidation substrates. Additionally, a large size differentiation between the two alcohol substituents is required for high selectivity. OH R2 R1

Pd[(-)-sparteine]Cl2 (5 mol%) (-)-sparteine (20 mol%) tBuOH, 65°C, O2, 20 h

OH R2 R1

O + R1

R2

18 examples 14-90% yields 1-99.8% ee

Scheme 47 Oxidative kinetic resolution of benzylic alcohols by Pd/(−)-sparteine in tert-butanol.

Although these systems were originally designed to employ (−)-sparteine as a chiral ligand, mechanistic studies129 have revealed the importance of sparteine as a chiral Brønsted base in an asymmetric deprotonation step. The isolation and use of the well-defined complex Pd[(–)-sparteine)]Cl2 demonstrated this complex to be catalytically competent only in the presence of added cocatalytic (−)-sparteine indicating the need for additional base under these catalytic conditions. This reaction features a change in the turnover-limiting step upon increasing [(−)-sparteine]. At low [(−)-sparteine] deprotonation is enantiodetermining (and rate determining) while at high [(−)-sparteine] b-hydride elimination is enantiodetermining (and rate determining) and the difference in stability of two diastereomeric alkoxide intermediates contributes to the overall reaction selectivity (Scheme 48). Because under high [(−)-sparteine] conditions, the chiral sparteine is acting as a Brønsted base that is not involved in asymmetric induction, an alternative achiral base, such as sodium carbonate, could be used to achieve similar yields and selectivities.130

94

Metal-Catalyzed Aerobic Oxidation Reactions

rate and enantiodetermining rate and enantiodetermining at low [(-)-sparteine] at high [(-)-sparteine] OH -CI-

N N Pd Cl Cl

N N Pd Cl

+CI-

R

R'

OH R

+ B: , -BH+ + BH+, -B:

N N Pd H Cl O R

R'

N

N Pd Cl O R

R'

O R

R'

N N Pd Cl H

R'

Scheme 48 Proposed pathway for the substrate oxidation in the Pd/(−)-sparteine catalyzed alcohol oxidation. Modified from Mueller, J. A.; Cowell, A.; Chandler, B. D.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 14817–14824. https://doi.org/10.1021/ja053195p. Copyright 2005 American Chemical Society.

Further mechanistic work by Sigman and co-workers in 2005131 showed that high concentrations of (−)-sparteine inhibit alcohol oxidation. In this reaction, the alcohol binding equilibrium is rapid and the Pd-alkoxide intermediate is not observable. Under these conditions, the rate of reprotonation of the Pd-alkoxide by sparteineH+ is increased and the overall reaction is slowed. Thus, this reaction is under Curtin-Hammett control and the relative rates of b-hydride elimination and alkoxide reprotonation by (−)-sparteine give rise to the observed selectivities. One significant drawback to this Pd/(−)-sparteine system described above is that only a single antipode of the ligand is available and the ligand supply is unreliable which limits the pool of structures accessible using this methodology. The finding that sparteine is required not only as a ligand, but also as an exogenous base to conduct deprotonation of the alcohol led to the use of chiral bases paired with achiral supporting ligands as a more attractive protocol for a kinetic resolution. N-Heterocyclic carbene ligands were selected for their strong s-donor properties and their anticipated ability to stabilize the three-coordinate intermediate required for b-hydride elimination (Scheme 49).132 Pairing (NHC)Pd complexes with sparteine as a chiral base132,133 led to the kinetic resolution of a small set of benzylic alcohols. Enantioselectivities of up to 96% ee could be obtained. In these reactions, the b-hydride elimination is turnover-limiting based on the observed first-order dependencies on [(NHC)Pd(OAc)2(H2O)] and [alcohol] as well as an unusually large KIE (6.8  0.7) and a negative r value of −0.48 obtained from a Hammett correlation.134 The change in turnover-limiting step as compared to the systems featuring N-based ligands is attributed to the inclusion of acetic acid. Acetic acid is responsible for accelerating the protonation of the palladium-peroxo species, which then reforms (NHC)Pd(OAc)2 and generates 1 equiv. of H2O2. With the faster protonation step, b-hydride elimination becomes the sole turnover-limiting step. This small change to the reaction conditions has a significant influence on the synthetic utility of the reaction because with slower catalyst decomposition, air can now be used in place of O2.

Ar N OH R1

R2

[(NHC)PdCl2]2 (1.5 mol%) (-)-sparteine (15 mol%)

O R1

3 Å MS, DCE, O2, 65°C

R2

5 examples 36-65% conv 35-96% ee

N Ar

AcO Pd O

R2 H R1 Ar = 2,5-di iPr phenyl 3-coordinate Pd(NHC) intermediate

Scheme 49 (NHC)Pd/(−)-sparteine-catalyzed oxidative kinetic resolution of alcohols.

Unfortunately, the PddNHC catalyst conditions are limited in scope. For example, the oxidation of aliphatic substrates led to autoxidation of the resulting aldehydes and catalyst inhibition, and so required more dilute reaction conditions (0.125 M) and replacement of HOAc with Bu4NOAc in order to obtain good yields of the corresponding aldehydes. Because these PddNHC systems are efficient catalysts only for the oxidation of benzylic and allylic alcohols, they have seen limited applications. They have, however served as a platform for the development of new axially chiral bis(NHC) ligands. In 2007, Shi and co-workers reported the axially chiral PddNHC complex derived from optically active 1,1-binaphthalenyl-2,20 -diamine (BINAM) for the kinetic resolution of secondary benzylic alcohols (Scheme 50).135

OH R1

R2

PdII (NHC) (10 mol%) Cs2CO3 (0.5 equiv), MS, O2 toluene, 80 °C

OH R1

R2

O R1

Scheme 50 Pd(NHC)-catalyzed oxidative kinetic resolution of benzyl alcohols.

R2

22 examples 60-82% conversions 63-99% ee

N

N Pd

N

N

I I

Metal-Catalyzed Aerobic Oxidation Reactions

95

More recently, Zhang and co-workers have designed a new chiral bis(NHC) ligand based on the 1,10 -spirobiindane scaffold. Pairing this ligand with Pd in the presence of Cs2CO3 under 1 atm O2 results in the kinetic resolution of secondary alcohols with good enantioselectivities (Scheme 51).136

PdII (NHC) (10 mol%) O2 (1 atm) Cs2CO3 (0.5 equiv) R toluene, 80 °C

OH Ar

OH Ar

O

R

Ar

9 examples 8-63% conv. R 5-99% ee

N

N N Me

N

Pd I

I

Me

Scheme 51 Pd(NHC)-catalyzed oxidative kinetic resolution of benzyl alcohols.

13.03.3.1.3

Amine oxidation

Despite the prevalence of Pd catalysts for the aerobic oxidation of alcohols discussed above, and the applications of Pd catalysis to aerobic cross-coupling reactions described below (Section 13.03.4.1), there are relatively few examples of the Pd-catalyzed aerobic oxidation of amines to imines and nitriles. This may be due, in part, to the coordinating ability of amines which hinder catalysis by Pd and other 2nd and 3rd row transition metals. Nevertheless, some recent developments in this area have been made. In 2006, Guo and co-workers137 developed the first palladium-catalyzed aerobic oxidation of amines. While the Pd(OAc)2/py conditions developed by Uemura were initially explored, these conditions were effective for only N-phenylbenzylamine, while benzylamine and N-methylbenzylamine remained unreactive. The authors found replacement of py with PPh3 enabled the oxidation of ArCH2NHPh, ArCH2NHOMe, and ArCH2NHMs to the corresponding imines in high yields (Scheme 52, Ms ¼ methanesulfonyl). The optimized system consists of 5 mol% PdCl2 and 10 mol% PPh3 in the presence of stoichiometric sodium acetate and 3 A˚ molecular sieves in DMF under 1 atm of O2 at 80  C. Amides, N-phenylalkylamines, and N-alkylbenzylamines were not oxidized under these conditions. The authors attributed this lack of reactivity to the lower barriers for b-hydride elimination calculated for the N-phenylamines as compared to those for the N-alkylamines.

N H

R1

R2

PdCl2 (5 mol%) ligand, 3Å MS NaOAc (1 equiv), DMF O2 (1 atm), 80 °C, 14 h

R1

for R1 = R2 = H ligand = py (20 mol%) Et3N (20 mol%) PPh3 (10 mol%)

R 2 15 examples 25-95% yields

N

65% 74% 96%

Scheme 52 PdCl2/L-catalyzed aerobic oxidation of amines to imines. Data from Wang, J.-R.; Fu, Y.; Zhang, B.-B.; Cui, X.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2006, 47, 8293–8297.

Landaeta and co-workers138 developed a related phosphite based catalyst system that is active toward the oxidative coupling of benzylamines to the corresponding N-benzylidenebenzylamines (Scheme 53). The palladium tris(quinoline-9-yl)phosphite complex, [Pd{P(Oquin)3}Cl2], provides yields up to 99% and TONs up to 230 for the oxidative homocoupling of a small series of benzylamines under neat conditions under 30 psi air. The cross-coupling of benzylamine with anilines, however, showed poor selectivity for the asymmetric imines.

[Pd] =

2

R2 R1

R2 R2

[Pd] (1 mol%)

NH2 air (30 psi), 60 °C, 6 h

R1

N

R1

Scheme 53 Pd-catalyzed aerobic oxidative coupling of primary amines to imines.

homocoupling 6 examples 28-99% yields cross-coupling 11 examples 0-36% yields

N N

O O O P Cl Pd Cl N

96

Metal-Catalyzed Aerobic Oxidation Reactions

In an alternative approach, Che and co-workers have found PdII-porphyrin complexes139 and related tetradentate PdII species140 to act as photocatalysts in the conversion of secondary benzylic amines to their corresponding imines (Scheme 54). These complexes have high emission quantum yields in solution at room temperature and long lifetimes of the triplet excited states. The authors propose the photoinduced oxidation to proceed through photochemically generated singlet oxygen.

N H

R1

C6F 5

R2

Pd complex MeCN, O2, light

N

R1

R2

C6F 5

N

N

N Pd N N

N C6F 5

C6F 5

O

Pd(F 20TPP) 0.005 mol% λ > 400 nm yields 98-99%

Pd

N

0.05 mol% λ > 350 nm yields 96-99%

Scheme 54 Pd-catalyzed photocatalytic aerobic oxidation of amines to imine. Data from To, W.-P.; Liu, Y.; Lau, T.-C.; Che, C.-M. Chem. A Eur. J. 2013, 19, 5654–5664.

Finally, Wu and co-workers141 leveraged the palladium-catalyzed oxidation of tertiary amines for the synthesis of H-pyrazolo [5,1-a]-isoquinolines. In this reaction, PdBr2 catalyzes the aerobic oxidation of the tertiary amine to the iminium ion. After tautomerization, the resulting enamine couples with isoquinolinium-2-yl amides to form the cyclized isoquinoline products. The reaction proceeded with 5 mol% PdBr2 in DMF at 65  C in air in good to excellent yields (Scheme 55).

N

NHTs

R 2N R1

R2

Ph

R1

R2

AgOTf (10 mol%) PdBr2 (5 mol%) DMF, air, 65 °C 8-12 h

N

R1

R2

PdII O2

R

R N R1

+ R 2 -H

R

R N R1

28 examples 41-92% yields

Ph N

R 2N

N

R2

NHTs Ph

product

Scheme 55 Pd-catalyzed aerobic oxidation of tertiary amines to access H-pyrazolo[5,1-a]-isoquinolines. Modified from Sheng, J.; Guo, Y.; Wu, J. Tetrahedron 2013, 69 (31), 6495–6499. Copyright 2013, with permission from Elsevier.

13.03.3.1.4

Alkane dehydrogenation

Recently, synthetic advances in the Pd-catalyzed aerobic dehydrogenation of alkanes to form C]C bonds have been made. Activated substrates, like cyclohexanone, have shown the most successes. Muzart and co-workers reported the first example of the Pd-catalyzed aerobic oxidation of cyclohexenone to phenol, albeit with low yields and long reaction times (1–13 days).142 Stahl and co-workers continued to develop these oxidative dehydrogenation reactions and identified efficient conditions for the high yielding synthesis of substituted phenols. The selective oxidation to cyclohexenones can be accomplished with Pd(TFA)2 (5 mol%) and DMSO (10 mol%) as a ligand in acetic acid under 1 atm O2 at 80  C for 12 h (Scheme 56).143 This system enables the oxidation of a variety of cyclic ketones to the corresponding enones in good yields and with high selectivities. In contrast, the complete oxidation of cyclohexanone to phenol occurs when 2-(N,N-dimethylamino)pyridine (2-Me2Npy) is used as a ligand with TsOH as an additive in DMSO (Scheme 57). 144 The inclusion of 4,5-diazafluorenone as a ligand allowed for further extension of this reaction to the dehydrogenation of benzyl acetone derivatives.145,146

Metal-Catalyzed Aerobic Oxidation Reactions

O

R

O

Pd(T FA) 2 (5 mol%) DMSO (10 mol%) n

97

AcOH, O2 (1 atm), 80 °C,

n = 0, 1, 2

R

n

16 examples 54-94% yields

n = 0, 1, 2

Scheme 56 Pd(TFA)2-catalyzed aerobic oxidation of cyclohexanones to cyclohexenones.

O R

Pd(T FA) 2 (5 mol%) 2-Me2Npy (10 mol%)

OH

R TsOH (20 mol%) DMSO, O2 (1 atm), 80 °C

N

17 examples 57-95 % yields

NMe2

2-Me2Npy

Scheme 57 Pd(TFA)2/2-Me2Npy/TsOH-catalyzed oxidation of cyclohexanones to phenols.

The origin of the chemoselectivity for cyclohexenone or phenol products arises from the relative rates of the two oxidations.147 The two reactions are catalyzed by different species. The initial oxidation of cyclohexanone to cyclohexenone is catalyzed by homogeneous Pd, while the subsequent oxidation to phenol is catalyzed by Pd nanoparticles. The Pd(TFA)2/2-Me2Npy/TsOH catalyst oxidizes cyclohexenone to phenol more rapidly than cyclohexanone to cyclohexenone giving rise to the phenol products. In contrast, Pd(DMSO)2(TFA)2 oxidizes cyclohexanone much more rapidly than cyclohexenone allowing for selective conversion to the cyclohexenone products without overoxidation to the phenols (Scheme 58). O

molecular PdII k1

O

soluble nanoparticles k2

OH

catalyst

k1 (h -1)

k2 (h -1)

k1/k2

Pd(DMSO) 2(T FA) 2 Pd(T FA) 2/2-Me2Npy/TsOH

0.19 0.008

0.0057 0.14

33 0.61

Scheme 58 Relative rates of oxidation of cyclohexanone and cyclohexenone under varying Pd-catalyzed conditions. Modified from Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci. 2012, 3, 887–891. doi:10.1039/C1SC00724F. Reproduced by permission of The Royal Society of Chemistry.

Kinetic studies on the oxidation of cyclohexanone by the Pd(TFA)2/2-Me2Npy/TsOH catalyst system provided details on the oxidation of cyclohexanone to cyclohexenone catalyzed by homogeneous Pd.147 This reaction shows a first order dependence on [cyclohexanone] and [Pd(DMSO)2(TFA)2] with little effect arising from changes in [DMSO] or pO2. In the absence of DMSO, however, rapid catalyst decomposition is observed. These data combined with a KIE of 2.9 ( 0.27) for cleavage of the a-C-H suggest turnover-limiting CdH activation. The CdH activation step is suggested to proceed with assistance of the trifluoroacetate ligand through a 5-coordinate concerted metalation-deprotonation (CMD) pathway. The proposed mechanism features turnover-limitation activation of the a-C-H bond from a coordinated cyclohexanone, followed by b-hydride elimination to form the cyclohexenone product. The resulting PdII-hydride undergoes reductive elimination of trifluoroacetic acid and reaction with O2 to regenerate the PdII catalyst, in a fashion analogous to the pathway operative for alcohol oxidation reactions (Scheme 59). In contrast, the oxidation of cyclohexenone to phenol by the same Pd(TFA)2/2-Me2Npy/TsOH catalyst system shows an induction period and a sigmoidal time course that correspond to the formation of catalytically active soluble Pd nanoparticles and inactive Pd-black. DMSO is found to have a strong inhibitory effect on the rate of oxidation of cyclohexenone in the form of both a slower reaction rate and an increased induction period and this is attributed to the stabilizing effects of DMSO coordination to Pd0. The 2-Me2Npy and TsOH additives are suggested to form the ammonium salt which aids in the generation and stabilization of Pd nanoparticles.

98

Metal-Catalyzed Aerobic Oxidation Reactions

H2 O 2 (1/2 O2 + H2O)

O PdII (DMSO) 2(T FA) 2

2 CF 3COOH

reversible binding

k-1

O DMSO Pd O DMSO

k1 α-H activation turn-over limiting

O TFA DMSO PdII TFA DMSO k2

O2

CF 3COOH

O DMSO PdII TFA DMSO

DMSO Pd0 DMSO

O CF 3COOH

β-H elimination (fast)

H DMSO PdII TFA DMSO

Scheme 59 Proposed pathway for the Pd(TFA)2/2-Me2Npy/TsOH-catalyzed oxidation of cyclohexanone to cyclohexenone. Reprinted with permission from Pun, D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8213–8221. doi:10.1021/ja403165u. Copyright 2013 American Chemical Society.

In 2008, Bercaw reported that a related catalyst system will oxidize cyclohexene to benzene, albeit in low yields (25%) (Scheme 60).148 Mechanistic experiments suggest the reaction to be homogeneously catalyzed, in contrast to the disproportionation reactions of cyclohexene catalyzed by heterogeneous Pd.149 Linear alkenes are not competent substrates for dehydrogenation and the reaction is only effective for the oxidation of cyclohexene and tetralin.150 Low turnover numbers and catalyst decomposition are also observed. Despite the limitations of this system, it illustrates the potential to use O2 as the terminal oxidant in alkane dehydrogenation reactions. Pd(O 2CCF 3) 2 (5 mol%) acetone, rt, O 2 (1 atm) 25% yield Scheme 60 Pd-catalyzed oxidation of cyclohexene to yield benzene.

Building on this work, Stahl and co-workers reported the Pd-catalyzed oxidation of cyclohexenes to arenes.151 The catalyst system employs Pd(TFA)2 (5 mol%) with sodium anthraquinone-2-sulfonate (AMS, 20 mol%) as a cocatalyst in chlorobenzene under 1 atm O2 at 110  C. The AMS additive is believed to prevent disproportionation pathways152 allowing for the oxidation of a variety of cyclohexenes bearing aromatic, alkyl, ester, ketone and imide functionalities (Scheme 61).

R

Pd(T FA) 2 (5 mol%) AMS (20 mol%) MgSO 4, PhCl 1M O2 (1 atm), 110 °C

O R

SO 3Na

18 examples 62-99% yields O

AMS

Scheme 61 Pd/AMS-catalyzed oxidation of cyclohexenes to yield arenes.

13.03.3.2 Copper catalysts for dehydrogenation reactions 13.03.3.2.1

Alcohol oxidation

Despite significant early advances with noble metal catalysts such as Pd and Ru for alcohol oxidation reactions, these systems are often limited in functional group compatibility due to coordination of heterocycles and related functionality (N-, O-, S-containing functional groups). To overcome this challenge, first-row transition metal catalyst systems with weaker metal-ligand bonds have been explored. In particular, copper catalysts paired with redox-active cofactors have seen much attention and development. These systems have employed varied cofactors but the most prominent, and those that will be discussed below, include nitroxyl radicals and azodicarboxylates. These reactions offer the advantage of improved functional group tolerance as well as milder reaction conditions and often the ability to use air instead of pure O2.

Metal-Catalyzed Aerobic Oxidation Reactions

99

Although early copper-catalyst systems for aerobic alcohol oxidation were developed independently of the biochemical systems,153,154 researchers soon identified similarities to enzymatic systems, such as galactose oxidase (GO), that accomplish the same transformation.38,155 Galactose oxidase catalyzes the two-electron oxidation of primary alcohols to aldehydes, and at a much slower rate, aldehydes to carboxylates using dioxygen while forming hydrogen peroxide. The active site contains a single CuII center, in addition to a redox-active cysteine-linked tyrosine (Tyr272) radical center (Scheme 62).156 The overall mechanism features separate oxidation and reduction steps occurring in a ping-pong fashion. Tyr495 deprotonates the alcohol group whereas Tyr272 performs HAA on the pro-S hydrogen atom of galactose.156

OH

OH

OH

O HO

OH

OH

GOase

O2

O O

HO

OH

OH

H 2O 2

Tyr272 Tyr495

OH NHis NHis

CuII

O

S Cys H

O

GO active site

R H

tBu

N N O Cu O SPh

tBu

PhS Stack model complex

Scheme 62 The aerobic oxidation of galactose catalyzed by galactose oxidase (GO) and a related Cu-salen model complex.

Consequently, biomimetic models of GO have been developed157 and systems like GO have sparked interest in the use of redox-active ligands in copper catalysis.158 For instance, Stack and co-workers employed a salen ligand bearing a binaphthyl backbone in which the phenol of the salen ligand functions as the tyrosine-like hydrogen atom abstractor (Scheme 62).159,160 The thioether moiety of this salen ligand models the cysteine-bound tyrosine residue that bears the radical and the complex is EPR silent at room temperature, consistent with the spectrum of the enzyme. While an elegant model of the enzymatic system, synthetically, the catalyst system is limited to the oxidation of only activated benzylic or allylic alcohols. The structure of galactose oxidase and in particular the pairing of a copper center with a redox-active ligand or co-catalyst which enables a hydrogen atom abstraction of the alcohol, have been compared to catalytic systems for alcohol oxidation that use copper with redox-active cofactors such as TEMPO and azodicarboxylates.161 The first catalyst system of this type, reported by Semmelhack and co-workers in 1984, employed CuCl with TEMPO in DMF for the oxidation of a small scope of primary alcohols to aldehdyes.154 The subsequent developments by the groups of Sheldon162,163 and Koskinen164 introduced a 2,20 -bipyridine (bpy) ligand, tert-butoxide base and a CuII precatalyst. With these modifications, the reactivity of the system could be extended to aliphatic alcohols. In the following years, a large number of related systems were developed that employ alternative ligands, solvents, and bases,165,166 yet the oxidation of aliphatic alcohols beyond octanol remained challenging and the synthetic utility of these systems remained limited. In 2011, Stahl and co-workers reported a related Cu/TEMPO system that operates efficiently in open air, under mild conditions for a broad scope of alcohols and with high selectivity.167 The development of this system arose from the exploration of the most common Cu/cofactor systems, including both CuI and CuII precatalysts, TEMPO and DBAD cofactors, as well as strong and weak bases. The authors identified the combination of [Cu(CH3CN)4](OTf )/bpy with NMI (N-methylimidazole) and TEMPO in CH3CN to achieve the mild and selective oxidation of a broad scope of alcohols. A full mechanistic study including reaction kinetics, UV-visible and EPR time course experiments, and KIE and Hammett studies led to the mechanism shown in Scheme 63.168,169 The reaction proceeds through a two-stage mechanism including distinct substrate oxidation and catalyst oxidation sequences. In this mechanism, the resting state and turnover-limiting steps differ for benzylic and aliphatic alcohols. In the case of benzylic alcohols, in which the alcohol oxidation steps are rapid, the oxidation of CuI/TEMPOH by O2 is turnover-limiting. In the case of aliphatic alcohols, which undergo slower oxidation, both the substrate oxidation and catalyst oxidation steps contribute to the overall reaction rate. A follow-up study by the same authors addressed the unique efficiency of this Cu/TEMPO/NMI catalyst system when compared with other related Cu/cofactor/base systems.170 The high reactivity is attributed to the interrelationship of the base and copper oxidation state in generating the key copper-alkoxide intermediate. In the case of CuI salts, a highly basic CuII-hydroxide is generated in situ from CuI and O2. The CuII sources, however, require stronger bases to access the same intermediate.

100

Metal-Catalyzed Aerobic Oxidation Reactions

[Cu(MeCN) 4]OTf (5 mol%) bpy (5 mol%), TEMPO (5 mol%) NMI (10 mol%), CH3CN, rt, air

R

HO

O

R

27 examples R 25-99% yields

Catalyst Oxidation

Substrate Oxidation R’2NO-H

O

1/2 O2

LnCuI

R’2NO H H Ln CuII O

1/2 [LnCuII]2(O 2)

R

R’2NO-H H2 O R

HO

LnCuII OH

R’2NO

Scheme 63 Conditions and proposed pathway for the (bpy)CuI/NMI/TEMPO-catalyzed aerobic oxidation of alcohols. Reprinted with permission from Ryland, B. L.; McCann, S. D.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136, 12166–12173. doi:10.1021/ja5070137. Copyright 2014 American Chemical Society.

In these aerobic Cu/nitroxyl-catalyzed reactions, O2 oxidizes CuI and TEMPOH to CuII and TEMPO. The CuII/TEMPO pair are then responsible for the alcohol oxidation. The nature of this step and how TEMPO and Cu work in concert to facilitate the alcohol oxidation was the subject of some debate in the literature. Common proposals171–173 relate Cu/TEMPO systems to galactose oxidase through a shared hydrogen atom transfer to the TEMPO or phenoxyl radical. Recent combined experimental and computational studies by Stahl and co-workers169 have shown that this step instead proceeds via a concerted hydrogen transfer via a 6-membered ring transition state (Scheme 64). In these studies HAA by a radical intermediate was excluded with cyclopropyl carbinol derivates which underwent smooth oxidation to the corresponding aldehydes without the formation of any ring opening products. Computational evidence instead supported a two-electron Oppenauer-like pathway in which the hydrogen transfers from the alkoxide ligand to an Z1-coordinated nitroxyl.

O Ln CuII

R H H

O Ln Cu

O NR 2

O

R H

R Ln CuII O

H

H

+

NR 2

HO NR 2 I

Scheme 64 Proposed concerted hydrogen transfer pathway for substrate oxidation in the Cu /TEMPO catalyzed aerobic oxidation of alcohols. Modified from Ryland, B. L.; McCann, S. D.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136, 12166–12173. https://doi.org/10.1021/ja5070137. Copyright 2014 American Chemical Society.

The sterically bulky nature of TEMPO imparts the selectivity for the oxidation of primary alcohols over secondary. While this chemoselectivity is attractive in many cases, the need for a universally efficient catalyst system is also important. The replacement of TEMPO with the sterically less encumbered nitroxyl radical ABNO (ABNO ¼ 9-azabicyclo[3.3.1]nonane N-oxyl, Scheme 65) enables the efficient oxidation of a broad scope of primary and secondary alcohols with equal efficiency.174 The more electron-rich methoxy-substituted ligand MeObpy was found to accelerate the reaction (MeObpy ¼ 4, 40 -dimethoxy-2,20 -bipyridine, Scheme 65). A selection of nitroxyl radicals were explored for their reactivity and it was found that the redox potential and steric

OH R1

R2

[Cu(MeCN) 4] (OTf) (5 mol%), nitroxyl (1 mol%) MeObpy (5 mol%), NMI (10 mol%) MeCN, rt, ambient air

N

O

AZADO 188 mV Relative Rate = 1.9

N

O R1

O

ABNO 200 mV 1.9

R2

N O• TEMPO 239 mV 1.0

Scheme 65 Influence of the nitroxyl radical in the (MeObpy)CuI/nitroxyl-catalyzed aerobic oxidation of alcohols.

nitroxyl = ABNO 37 examples 77-98% yields

Metal-Catalyzed Aerobic Oxidation Reactions

101

environment influence the reaction rate. Both ABNO (E1/2 ¼ 200 mV vs Fc/Fc+ in MeCN) and AZADO (E1/2 ¼ 188 mV vs Fc/Fc+ in MeCN)175 were found to provide significant rate enhancements relative to TEMPO (E1/2 ¼ 239 mV vs Fc/Fc+ in MeCN).174 Under these conditions, aliphatic alcohols displayed a linear reaction time course indicating a zero-order dependence on the catalyst concentration. Thus, the loading of the ABNO cocatalyst could be reduced to 1 mol% without any significant influence on the reaction rates or product yields. The activity of Cu/ABNO and selectivity of Cu/TEMPO systems enable the efficient and selective oxidation of alcohols to lactones (Scheme 66).176 Here, the identity of the nitroxyl cocatalyst can be used to tune the chemo- and regioselectivity of the oxidation of unsymmetrical diols. As an example, the Cu/ABNO catalyst system shows greater reactivity due to its smaller steric profile, and is most effective for the oxidative cyclization of symmetrical diols. In contrast, TEMPO provides more selective oxidative cyclization reactions favoring oxidation of a 1 alcohol in preference over 2 alcohols, as well as the ability to distinguish sterics more remote from the alcohol.

OH OH BocHN

[Cu(CH3CN) 4]OTf (5 mol%), bpy (5 mol%) O O NMI (10 mol%), MeCN, rt, open air Nitroxyl (1 mol%) BocHN nitroxyl = ABNO 33 % nitroxyl = TEMPO 82 %

O

O BocHN

67 % 18 %

Scheme 66 Cu/nitroxyl-catalyzed selective oxidative cyclization of diols to lactones.

The challenging oxidation of amino alcohols can be achieved using a (bpy)CuCl/AZADO catalyst system (10 mol%) with DMAP (20 mol%) in acetonitrile at room temperature under open air conditions.177 Similarly, oxidation of alcohols bearing oxidizable thioether groups are selectively oxidized to the corresponding alcohols with a similar (bpy)CuCl/AZADO catalyst system.178 Cu/ nitroxyl systems also catalyze the conversion of alcohols and amines to amides.179,180 This transformation is particularly challenging due to the competitive amine oxidation to generate imines or nitriles and condensation of amines with aldehyde intermediates to form imines or enamines. In contrast, Cu/nitroxyl catalyst systems are tolerant of primary amines and the less sterically demanding ABNO enables the efficient oxidation of the bulky hemiaminal intermediate (Scheme 67). Han and co-workers, applied a CuI/DABCO/4-OH-TEMPO catalyst system to the oxidation of primary benzylic alcohols for subsequent coupling with aldehydes to yield 2-substituted quinazolines.181

R1

OH

HN

tBu

H3CO

CuI/ligand = CuI tBu N

R1

R3

OCH3 N

HN

R2 R3

H3CO

N R3

R 2 65 examples 38-99 %yields

OCH3 CH3 N N

N

Cu/nitroxyl O2

O R1

[Cu(MeCN) 4]OTf

CuCl

N

OH

CuI/ligand (5 mol%) ABNO (3 mol%) solvent (0.2 M), O2 (1 atm)

R2

R1 HN

OH

R2 R3

R1

N

N

N

O

CuCl or CuCN N N N

N R3

R2

Cu/nitroxy O2

O R1

N R3

R2

Scheme 67 CuI/ABNO-catalyzed aerobic oxidative coupling of alcohols and amines to yield amides. Modified from Zultanski, S. L.; Zhao, J.; Stahl, S. S. J. Am. Chem. Soc. 2016, 138, 6416–6419. https://doi.org/10.1021/jacs.6b03931. Copyright 2016 American Chemical Society.

A number of natural product and pharmaceutical syntheses have leveraged the efficient and selective oxidation of Cu/nitroxyl catalysts including the synthesis of an LSD1 inhibitor (Scheme 68).182

102

Metal-Catalyzed Aerobic Oxidation Reactions

CuI (6 mol%), bpy (6 mol%) CO2tBu TEMPO (5 mol%), NMI (9 mol%) O 0.55 M in sulfolane, 55 °C bubbling air (350 mL/min)

HO N

Ph

N H

CO2tBu N

CO2H

SO 3H H2 O

N GSK2879552 LSD1 inhibitor

SO 3H

Scheme 68 Application of the (bpy)CuI/TEMPO catalyst system to the synthesis of an LSDI inhibitor.

Finally, these Cu/nitroxyl catalyst systems have also been further developed for industrial applications. A scalable continuous-flow process employing the early Cu/TEMPO system was reported, in which a dilute oxygen source (9% O2 in N2) was used to accomplish the quantitative oxidation of primary alcohols in 5–45 min on scales of 100 g.183 Similarly, improvement of the Cu/ABNO catalyst system enabled both batch (>50 g scale) and flow methods (9 mmol).184 Both protocols benefit from the use of CuI as the precatalyst as well as reduced ABNO loadings below 0.3 mol%, and the elimination of the MeObpy ligand. Although the selectivity and efficiency of these Cu/nitroxy methods are attractive, TEMPO and the more specialized ABNO nitroxyl radicals are often the most expensive component of these catalyst mixtures. The design of recyclable and recoverable nitroxyl derivatives such as Si-ABNO185 and TEMPO derivatives bearing ionic liquid tags186 have been used to address this challenge. There has also been interest in identifying systems capable of oxidizing alcohols in the absence of redox mediators as an alternative to copper catalyst systems bearing nitroxyl or azodicarboxylate cofactors. These systems are typically limited to the oxidation of activated alcohols, however, recent developments by Lumb and co-workers have identified conditions that avoid the need for an additional cocatalyst.187 Use of [Cu(CH3CN)3]PF6 (5 mol%) with a DBED ligand (5 mol%) and DMAP as a basic additive (20 mol%) in dichloromethane at room temperature under 1 atm O2 enables the oxidation of primary and secondary benzylic and aliphatic alcohols, with preferential oxidation of secondary alcohols over primary (DBED ¼ N,N0 -di-tert-butylethylenediamine) (Scheme 69). Mechanistic studies conducted in collaboration with Stahl and co-workers identified an initial burst phase during which the DBED ligand undergoes oxygenation by Cu/O2 to yield the corresponding hydroxylamine in an oxidative self-processing event.188 Further oxidation by CuI and O2 generates the nitroxyl radical which functions in concert with CuII to oxidize the alcohol according to the mechanism described above. This system highlights the ability to access efficient nitroxyl cocatalysts from inexpensive amine precursors.

R

tBu

N H

H N DBED

tBu

[Cu(MeCN) 4]PF 6 (5 mol%) DBED (5 mol%) OH DMAP (5 mol%), 4Å MS DCM, O2 (1 atm), rt.

Cu/O2

tBu

N OH

H N

R

O

L CuI, O2 tBu N tBu n O

H N

tBu + LnCuII OH

Scheme 69 Cu-catalyzed aerobic oxidation of alcohols via in-situ oxygenation of amine to nitroxyl.

In 1996 Markó and co-workers reported an aerobic copper-catalyzed alcohol oxidation reaction employing a CuCl/phen catalyst and azo compounds (DBAD) or hydrazines (DBADH2) as the cocatalyst (DBAD ¼ di-tert-butylazodicarboxylate).189 Here, the azodicarboxylate acts in concert with the copper catalyst to enable the hydrogen atom abstraction of the copper alkoxide intermediate. Superstoichiometric amounts of K2CO3 are required as a dehydrating agent, but could be reduced if fluorobenzene is used as the solvent (Scheme 70).190 This catalyst system enables the oxidation of both primary and secondary alcohols to the corresponding aldehydes and ketones. Functionality such as heterocycles, amines and alkenes are all tolerated and the stereochemistry of a-stereocenters is preserved.

Metal-Catalyzed Aerobic Oxidation Reactions

103

Scheme 70 Conditions and proposed mechanism of the Cu/DBAD catalyzed aerobic oxidation of alcohols. Reprinted with permission from McCann, S. D.; Stahl, S. S. J. Am. Chem. Soc. 2016, 138, 199–206. https://doi.org/10.1021/jacs.5b09940. Copyright 2016 American Chemical Society.

The mechanism originally proposed by Markó and co-workers was based on the pathways of hemocyanins and tyrosinases and featured oxidation of Cu by O2 to generate a m2-peroxide intermediate. Homolytic cleavage of the OdO bond generates a copper-oxyl that initiates an intramolecular hydrogen atom abstraction of the bound alkoxide ligand. Unfortunately, this mechanism does not account for the poor reactivity observed for allylic alcohols nor the catalyst deactivation that occurs in the presence of aliphatic alcohols. Furthermore, the authors found that the hydrazine (DBADH2) led to both increased reaction rates and improved product yields, while acyl analogs are ineffective co-catalysts. In a revised mechanism they propose that the oxyl radical instead abstracts the hydrogen atom from the coordinated hydrazide ligand to generate a copper-hydroxide with a bound azo ligand. Ligand exchange generates the copper-alkoxide which undergoes hydrogen abstraction by the azo ligand, instead of the originally proposed oxyl radical in an Oppenaur-type pathway. This mechanistic proposal is reminiscient of the copper/nitroxyl systems described above and accounts for the improved reaction efficiency when the hydrazine is employed, because this enables formation of the basic copper hydroxide. Unfortunately, the reactivity of aliphatic alcohols and the requirement for excess DEAD remain unaccounted for with this reaction description. Additional experiments revealed formation of the carbonate as a byproduct resulting from acylation of the aldehyde by DEAD. The use of bulkier azo compounds such as DBAD enables efficient oxidation of both primary and secondary aliphatic alcohols with only catalytic loadings (5 mol%) of the azo compound.191 A thorough mechanistic follow-up study by Stahl and co-workers revealed that the catalytic pathway for this Cu/DBAD system is mechanistically distinct from the Cu/nitroxyl catalyst systems.192 Kinetic and spectroscopic studies revealed unexpected two-phase kinetics in which an initial burst phase generates the active catalyst followed by steady-state catalysis (Scheme 70). The steady state catalysis involves two interdependent catalytic cycles, one in which DBAD mediates two-electron oxidation of the alcohol and the other involving alcohol oxidation by CuII without the involvement of DBAD. The burst phase of the reaction was identified by in situ IR spectroscopy and is associated with the reduction of DBAD to form DBADH2. During this catalyst activation step, ketone product is formed rapidly although no O2 is consumed. Here, DBAD acts as the stoichiometric oxidant. During steady-state catalysis, DBADH2 is the only form of the cocatalyst present and steady-state turnover consists of a copper-only oxidation of the alcohol without the assistance of DBAD or DBADH2. The CuI formed from this

104

Metal-Catalyzed Aerobic Oxidation Reactions

pathway then enters a second catalytic cycle in which oxidation by O2 generates CuII, which then acts in concert with DBAD to oxidize the alcohol through the Oppenaur-type pathway originally proposed. Finally, the resulting CuII-hydroxide re-enters the slow copper-only oxidation pathway to continue the bicycle. This second cycle is fast and does not contribute to the overall reaction rate law. This two-cycle mechanism accounts for the 2:1 product-to-O2 stoichiometry as well as the observed kinetic dependencies. The surprising aspect of this cycle is the lack of cooperativity between Cu and DBAD. In these systems, the alcohol oxidation step catalyzed by CuII/DBAD leads to two-electron reduction of the DBAD with no change in the oxidation state of CuII. In contrast, in the Cu/TEMPO catalytic systems, the alcohol oxidation step results in one-electron reduction of TEMPO alongside a one-electron reduction of CuII to CuI.

13.03.3.2.2

Amine dehydrogenation

Relative to the oxidation of alcohols, the copper-catalyzed aerobic amine oxidation reactions are underdeveloped. Although amine oxidase enzymes enable the selective oxidation of amines,193 small molecule catalyst systems often give rise to a larger array of products, including imines, amides, nitriles, amine oxides, oximes and azo compounds. Here, we focus on the dehydrogenation reactions of amines to imines and nitriles, in direct analogy to the aerobic alcohol oxidation reactions. Building on the copper-catalyst systems for alcohol oxidation reactions, a number of related protocols have been developed for the aerobic oxidation of amines to nitriles and imines. Early work by Capdevielle showed CuCl to be an effective catalyst for the oxidation of primary amines in pyridine solvent in the presence of 4 A˚ molecular sieves at 60  C under an atmosphere of O2.194,195 These conditions provided access to nitriles in high yields (96–99%) but with low turnover numbers (5.5). In 2003, Uemura and co-workers replaced the pyridine solvent with toluene to achieve improved yields and turnover numbers with the use of CuCl2 for benzylamines (TON up to 60) and CuCl for aliphatic amines and secondary amines (TON up to 45, Scheme 71).196 In these reactions, the benzonitrile and the N-benzylidenebenzylamine coupling product were obtained in 75% and 25% yields respectively. Reaction kinetics revealed a first-order dependence on [amine] and a KIE value of kH/kD ¼ 1.25  0.1. These data, combined with the rate acceleration observed with benzylamines as compared to alkylamines, suggest oxidation of the coordinated amine to the aminium radical to be turnover-limiting. In the follow-up study by Uemura,196 reactions employing galvinoxyl as a radical scavenger show complete selectivity for the N-benzylidenebenzylamine product (84%), consistent with formation of the nitrile through the aminium radical intermediate. The N-benzylidenebenzylamine product presumably arises from b-hydride elimination from a copper-amido intermediate.

R

R

NH2

NH2 CuII

CuCl (10 mol%) toluene, 3Å MS 80 °C, O2 (1 atm)

-CuI

R

NH2

CuII(oxo) -CuI, -2H+

N R

R

N

R

2 CuII -2 CuI -2 H+ R

NH

aminium

Scheme 71 CuCl-catalyzed aerobic oxidation of benzylamines to nitriles and imines.

A number of improvements on these catalytic systems followed. In 2011, Adimurthy and co-workers reported that air could be used in place of O2 for the oxidation of a small series of benzylamines to the corresponding N-benzylidenebenzylamine products using a CuCl (5 mol%) catalyst under neat reaction conditions at 100  C.197 The inclusion of anilines allowed the synthesis of unsymmetrically substituted imines. Most recently, Arndtsen and Lumb reported a novel approach for amine oxidation inspired by biological systems to employ the amine substrate as the ligand.198 The catalyst system uses 5 mol% CuI with 3 A˚ MS in acetonitrile at room temperature and is efficient for the oxidation of both benzylic and aliphatic amines. The most noteworthy feature of this catalyst system is the ability to obtain either imine or nitrile by simply changing the copper counteranion. The use of CuPF6 affords the imine while CuI generates the nitrile (Scheme 72). Consistent with earlier systems, the authors propose a rate-limiting substrate coordination step based on KIE values of 1 obtained from independent rate measurements, and values of kH/kD ¼ 2.6  0.28 and 1.9  0.15 for the intermolecular competition experiments. Dehydrogenation of the Cu-amido intermediate generates a CuI-imine complex. This intermediate can either undergo nucleophilic attack by another equivalent of amine to form the imine or oxidation to form the nitrile. The authors attribute formation of imine from CuPF6 to the greater electrophilicity of the complex, while the more tightly bound iodide provides a more electron-rich intermediate that is more susceptible to oxidation, and thus nitrile formation.

Metal-Catalyzed Aerobic Oxidation Reactions

25 examples 43-96% yields R

CuI (5 mol%) O2 (1 atm) 3Å MS, MeCN

N

R

NH2

CuPF 6 (5 mol%) O2 (1 atm) 3Å MS, MeCN

R

N

N

O2 R

R

N Cu N H2

X=I electron rich oxidation

R H Cu N

O2

8 examples 53-76% yields

-NH3

-H2O O O Cu

R

105

R X = PF6 electrophilic complex nucleophilic attack

NH R

Scheme 72 Counteranion-dependent selective aerobic oxidation of amines to yield nitriles and imines. Modified from Xu, B.; Hartigan, E. M.; Feula, G.; Huang, Z.; Lumb, J.-P.; Arndtsen, B. Angew. Chem. Int. Ed. 2016, 55 (51), 15802–15806. Copyright 2016, with permission from John Wiley and Sons.

The Cu/nitroxyl catalyst systems have also been extended to the oxidation of amines. In 2012 and 2013, the groups of Kanai, Xu, Stahl, and Yu independently developed Cu/nitroxyl-catalyzed protocols for the oxidation of amines. Kanai’s system199 employed a newly developed ketoABNO nitroxyl that is more oxidizing than both TEMPO and ABNO, enabling the oxidation of a large scope of amines to the corresponding imines in high yields (Scheme 73). Xu’s system used a (bpy)CuI/TEMPO catalyst system to afford high yields of imine products at room temperature under open air conditions.200

Ph

NH2

Ph

N

Ph or Ph

imine Kanai CuBr ketoABNO

N

nitrile Xu (bpy)CuI TEMPO

Stahl (tBu2bpy)CuI ABNO

O N

O 16 examples 72-99% yields

N O• 19 examples 37-97% yields

N

O

23 examples 47-98% yields

Scheme 73 CuI/nitroxyl-catalyzed aerobic oxidation of amines to yield imines and nitriles.

In contrast to the imine syntheses described above, Stahl and co-workers reported conditions for the selective oxidation of primary amines to nitriles (Scheme 73).201 The optimized conditions demonstrated oxidation of a wide scope of aromatic and aliphatic amines and are based on a CuI/tBu2bpy/ABNO catalyst system (5 mol%) with DMAP (10 mol%) under 1 atm O2 in acetonitrile. The high selectivity for nitrile over imine was attributed to the nature of the solvent and nitroxyl radical; ketoABNO was an ineffective cocatalyst under the reported reaction conditions. Similar to the related alcohol oxidation reactions, this catalyst system is inhibited by phenols and is ineffective for the oxidation of homobenzylic amines. Mechanistic investigations revealed a first order dependence on pO2, a small KIE (kH/kD ¼ 1.19  0.02) and no significant effects of benzylamine substituents on the reaction rates, indicative of turnover-limiting catalyst oxidation. These data combined with the existing mechanistic understanding of related alcohol oxidation reactions supported a two-stage mechanism with a turnover-limiting catalyst oxidation step and a rapid substrate oxidation sequence. A related Cu/TEMPO catalyst system has recently been applied to the dehydrogenative aromatization of pyrrolidines by Hu and co-workers (Scheme 74).202 The use of CuCl (10 mol%) and cocatalytic TEMPO (30 mol%) in dimethyl carbonate at 80  C under an atmosphere of air affords the substituted pyrroles in good yields. The reaction is proposed to proceed through an initial oxidation to the imine. Although the reaction requires an ester in the 2-position, it represents a unique example of a copper-catalyzed dehydrogenative aromatization reaction. A similar Cu/DBAD catalyst system has been shown to be active for the dehydrogenative aromatization of 1,2,3,4-tetrahdyroquinolines.203

Scheme 74 Cu/TEMPO-catalyzed dehydrogenative aromatization of pyrrolidines.

106

Metal-Catalyzed Aerobic Oxidation Reactions

13.03.3.3 Other catalysts for dehydrogenation reactions 13.03.3.3.1

Alcohol oxidation

Despite some early successes in the development of Ru-catalyzed aerobic alcohol oxidation reactions, these catalyst systems have seen less recent interest than their Pd and Cu counterparts, in part, because these methods are often limited to the oxidation of activated benzylic substrates. Early work from Ishii and co-workers reported the aerobic oxidation of primary alcohols by Ru(PPh3)3Cl2 (10 mol%) paired with hydroquinone as a cocatalyst (10 mol%) under 1 atm O2 in trifluorotoluene at 60  C.204 This work built on prior findings from Bäckvall and co-workers,205 while enabling oxidation of a broader scope of alcohols including the preferential oxidation of primary alcohols in the presence of secondary alcohols. Shortly after, Sheldon developed the [Ru(PPh3)3Cl2]/TEMPO catalyst system for the oxidation of primary and secondary allylic, benzylic and aliphatic alcohols.206,207 Although a fairly general catalyst system, it is ineffective for the oxidation of substrates bearing heterocycles. Chang and co-workers reported the use of the [RuCl2(p-cymene)]2 catalyst (5 mol%) with Cs2CO3 for the oxidation of benzylic and allylic alcohols.208 The reaction is believed to proceed through b-hydride elimination of a ruthenium-alkoxide intermediate, although the role of the Cs2CO3 and its unique efficacy as a base was unclear. Based on the Ru-catalyzed acceptorless dehydrogenation of alcohols reported by Hong209 and prior work by Bäckvall,210 Maiti, Lahini and co-workers reported the use of RuH(CO)Cl(PPh3)3 (2 mol%) for the additive-free oxidation of benzylic alcohols in the presence of 1 atm O2 at 90  C in toluene (Scheme 75).211 Heterobenzylic alcohols are also efficiently oxidized to the corresponding aldehyde and ketone products. The reaction is proposed to proceed through a RuIV-oxo intermediate that undergoes hydride transfer from the alcohol to generate the carbonyl on the basis of KIE experiments (kH/kD ¼ 6.73) and a Hammett r value of −0.815 for the oxidation of differently substituted benzyl alcohols. OH R1

R2

O

[RuH(CO)Cl(PPh 3) 3] (2-5 mol%) O2 (1 atm), PhCH3, 90 °C, 18 h 4 Å MS (200 mg), 0.25 M

R1

R2

41 examples 40 - 95 % yields

Scheme 75 Ru-catalyzed aerobic oxidation of alcohols.

While a number of groups have reported Ru catalysts with varying ligand structures for the aerobic alcohol oxidation (Fig. 2),212–215 some of the more synthetically interesting advances are related to the Ru-salen complexes of Katsuki and co-workers (Scheme 76). In contrast to the hydride-transfer pathways described above, the Ru-salen catalyzed alcohol oxidation reactions proceed through a hydrogen atom abstraction (HAA) pathway. These catalysts enable the additive-free oxidation of unprotected diols with high chemoselectivity for the primary alcohol even in the presence of activated secondary alcohols.216,217 In these systems, the selectivity is sterically induced and the ligands are typically decorated with methyl groups to enhance such

Fig. 2 Selected Ru catalyst systems developed for the aerobic oxidation of alcohols.

Scheme 76 Ru-salen-catalyzed aerobic oxidation of alcohols.

Metal-Catalyzed Aerobic Oxidation Reactions

107

selectivity. On the basis of reaction kinetics and KIE measurements, the authors proposed a pathway involving hydrogen atom transfer from the a-position of the alcohol to the ligand phenoxyl radical (Scheme 76). Chiral salen ligands have also been applied to the oxidative desymmetrization of meso-diols with enantioselectivities up to 93% ee218 and the oxidative kinetic resolution of secondary alcohols with enantioselectivities up to 99% ee.219 Early discoveries of vanadium-catalyzed aerobic alcohol oxidation reactions uncovered catalyst systems such as ammonium metavanadate, NH4VO3, in aqueous acidic media that proceed via one-electron redox pathways.220–222 In contrast, Uemura and co-workers reported a catalyst system based on VO(acac)2 complexes that was proposed to proceed through a two-electron pathway involving the intermediacy of a vanadium(V)-alkoxide intermediate that undergoes hydride transfer from the alcohol to the vanadyl oxygen. This proposal was based on radical trap experiments, which showed no inhibition of product formation, and EPR experiments that revealed the disappearance of vanadium(IV) under catalytic conditions.223 In 2009, Hanson and co-workers further supported a two-electron pathway and the intermediacy of VV with stoichiometric studies of a dipicolinate vanadium(V)-oxo complex, (dipic)VV(O)(Hpin) (Scheme 77, H2dipic ¼ dipicolinic acid, Hpin ¼ pinacolate).224 Upon heating in pyridine-d5, oxidation of pinacol to acetone occurs along with formation of a VIII m-oxo dimer, supporting the possible involvement of VIII species in aerobic oxidation reactions. Further mechanistic studies225,226 revealed a pathway featuring rate-limiting deprotonation of the a-CdH bond by pyridine. More basic pyridines and electron-withdrawing substituents on the dipicolinate ligand accelerate the alcohol oxidation. These discoveries led to the development of a catalytic systems based on the 8-quinolinate (HQ) complex, (HQ)2VV(O)(OiPr), that facilitates the oxidation of benzylic, allylic, and propargylic alcohols under an air atmosphere.227 This catalyst system was also applied to the oxidation of lignin model compounds228 and shown to give products and selectivities different from those reported by Toste and co-workers (Scheme 78).229 The Toste catalyst proceeds through a radical pathway involving initial benzylic CdH activation followed by cleavage of the CdO bond. In contrast, the quinolinate complex does not cleave the benzylic CdH bond and instead breaks the C-phenyl bond, likely through involvement of a phenoxy radical intermediate, highlighting the ability to control product selectivity with catalyst design in these aerobic oxidation reactions. A handful of related vanadium catalyst systems have been reported for the aerobic oxidation of alcohols through singleelectron230,231 or two-electron pathways,232,233 yet these systems are often applicable only to specific alcohol substrates.

Scheme 77 Aerobic oxidation of bound pinacol to acetone in a dipicolinate vanadium(V)-oxo complex supporting VIII intermediates in alcohol oxidation reactions.

O N O H3CO HO OCH3

V

O

OMe O

N

tBu

OCH3

tBu

air, 80 °C Toste

V

N OH

OH +

O

H3CO

O

HO

OH OCH3

O OiPr

O

OCH3

NEt3 (10 mol%) air, 80 °C Hanson

H3CO

O

O + H

O

O

OCH3

OCH3

Scheme 78 Selective oxidation of lignin model compounds to yield CdC and CdO cleavage products.

The Co/NHPI and Co-salen catalysts described above for oxygenation reactions (Section 13.03.2.1), are also competent catalysts for the oxidation of alcohols.12 In 2002 Minisci reported the aerobic oxidation of primary benzylic alcohols to benzaldehydes using Co(OAc)2 (10 mol%) with NHPI (5 mol%) and meta-chlorobenzoic acid (0.5 equiv) in acetonitrile with 1 atm O2.234 The selectivity for formation of the aldehyde over the benzoic acid originates from a polar effect stabilizing the partial positive charge on the reactive CH in the HAA transition state. The polar effect explains the higher HAA reactivity of the alcohol vs. the aldehyde (as discussed in Section 13.03.2.1.1 and Scheme 3) because the BDE of the alcohol and the aldehyde are comparable (87 kcal/mol). In contrast, primary aliphatic alcohols are oxidized to the carboxylic acids under these conditions since the BDE of the alcohol is much stronger (by 8–10 kcal/mol) than that of the aldehyde, and so the aldehydes are readily oxidized under these conditions.

108

Metal-Catalyzed Aerobic Oxidation Reactions

13.03.3.3.2

Amine oxidation

In 2017, Ray and co-workers developed a pair of ruthenium catalysts that enable catalyst-controlled selective oxidation of amines to either the imine or the nitrile, depending on the ligand used.235 The catalysts are ruthenium hydride complexes bearing either a BIAN (bis(aryl)acenaphthenequinonediimine) or phenanthroline ligand, paired with TEMPO as a cocatalyst in toluene under 1 atm O2 at 90  C or 110  C. Under these conditions, the more p-acidic ligand BIAN-containing complex produces nitriles from primary amines whereas the phenanthroline complex forms the coupled imine products (Scheme 79).

21 examples 44 - 98 % yields R C N

[Ru] (2 mol%) TEMPO (20 mol%) O2 (1 atm), 90 °C, 20 h

R

NH2

[Ru] (2 mol%) TEMPO (30 mol%) O2 (1 atm), 110 °C, 24 h

Ar PPh 3 N H II Ru CO N PPh 3 Ar Ar = 4-OMe-C6H4 [Ru II (OMe-BIAN)(PPh 3) 2(CO)(H )]ClO4

H OC

PPh 3 Ru II PPh 3

R

N

R

14 examples 50 - 97 % yields

N N

[Ru II (phen)(PPh 3) 2(CO)(H )]ClO4

Scheme 79 Selective aerobic oxidation of primary amines catalyzed by Ru/TEMPO/L to yield nitriles (L ¼ BIAN) or imines (L ¼ phen).

Albrecht and co-workers236 prepared a series of ruthenium complexes bearing differently substituted pyridyl-triazolium ligands with the goal of electronically modulating the metal center through the ligand. The model reaction consisted of the oxidation of 4-methylbenzylamine to the corresponding nitrile in 1,2-dichlorobenzene with 5 mol% [Ru] at 150  C. No significant influence of the pyridyl substituent was observed, however substituents on the triazolylidene moiety had a significant influence on catalytic activity, with electron-donating groups providing faster reaction rates. Reaction time course data indicated the formation of the aldimine intermediate to be reversible and the addition of ammonia was shown to shift the imine-amine equilibrium to the primary amine favoring formation of the nitrile product. A thermally induced activation of the ruthenium complexes was also apparent when reactions were monitored by 1H NMR spectroscopy. The ruthenium-bound cymene NMR signals disappeared within 2 h, suggesting dissociation of the cymene ligand. A cymene-free precatalyst was synthesized and shown to be more active, leading to complete oxidation of amine to nitrile within 20 min (Scheme 80).

NH2

Ru catalyst (5 mol%) + NH3 1,2-dichlorobenzene (6 mL) O (1 atm), 150 °C 2

N

85-86% yields

OTf Ru R'' R'

N

MeCN NCMe MeCN Ru NCMe N N N N

Cl

N N N

R

> 99% conversion in 3 h

(OTf) 2

> 99% conversion in 10 min

Scheme 80 Ru/pyridyl-triazolium-catalyzed aerobic oxidation of primary amines to nitriles.

Ruthenium catalysts have also been applied to the visible-light mediated dehydrogenation of amines under aerobic conditions which proceeds through initial oxidation of the amine to the aminium radical cation.237 Finally, the dehydrogenations of tetrahydroisoquinolines238 and imidazolines239 to generate the corresponding heteroarenes have been accomplished under aerobic conditions with ruthenium catalysts. The single-electron oxidation pathways promoted by vanadium oxo species described above, has recently been extended to the dehydrogenation of N-heterocycles in water (Scheme 81).240 Although only illustrated for a small number of 1,2,3,4-tetrahydroquinoline and 2-methylpiperidine substrates, this reaction represents this first example of a vanadium catalyzed aerobic dehydrogenation of CdN and CdC bonds.

X R1

X

X X = C, N

R2

[V] (10 mol%) O2 (1 atm) H2O, 60 °C

X R1

Scheme 81 V-catalyzed aerobic dehydrogenation of N-heterocycles.

X

X

R2

8 examples 57-100 % yields

tBu

tBu N O V O O tBu O OH

Metal-Catalyzed Aerobic Oxidation Reactions

109

Despite early successes applying cobalt-salen complexes to the aerobic oxidation of amines to imines,241 there are few examples of cobalt catalysts that enable these transformations. In 2018, the Elias group developed a protocol for the oxidative coupling of aromatic, heteroaromatic and aliphatic amines to imines using water as solvent and air as oxidant.242 The optimized reaction conditions feature a CoII(bpb) catalyst (0.75 mol%) and achieve turnover numbers of up to 128 (Scheme 82). In addition, the catalyst can be recycled up to five times with only a slight reduction in activity (from 96% to 85%). Excellent yields are obtained for the oxidation of a large scope of (hetero)aromatic amines, while aliphatic amines provide moderate yields.

R2 R1

NH2

Co(bpb) (0.75 mol%) H2O, air, 35-40 °C

R2 R2 R1

N

30 examples R 1 50-95% yields

O

R 1 = (hetero)aromatic,aliphatic R 2 = H, Me

NH HN N

O

N bpb

Scheme 82 Co-catalyzed oxidative coupling of primary amines to yield imines.

Cobalt-salen complexes and quinones have been used extensively as a cocatalyst to facilitate the activation of O2. These cocatalytic methods are reminiscent of biological systems that feature multiple coupled redox systems to avoid high-energy reoxidation pathways for the metal catalyst (Scheme 83). O SubOx

Co-salophen

Mn

+ 2 HX

O 2 + 2 H+

O Q OH

SubH2

Co-salophenox

Mn+2X 2

2 H2O

OH H2Q

Scheme 83 General pathway for the aerobic oxidation reactions employing Co-salophen/quinone co-catalysts.

In 2016 Stahl and Hammes-Schiffer243 explored the mechanism of the oxidation of para-hydroquinone (H2Q) by cobaltsalophen. Reaction kinetics showed a first order dependence on [Co(salophen)], and a saturation dependence on pO2 and [H2Q]. When a mixture of MeOH and MeOD was used, a KIE of 4.0  0.5 was obtained, consistent with turnover-limiting hydrogen atom transfer. Monitoring the addition of O2 to CoII-salophen by EPR and UV-visible spectroscopy showed formation of a CoIII-superoxide species. The same species was observed by EPR under catalytic conditions. These data combined led to the key mechanistic steps shown in Scheme 84. The first hydrogen atom transfer (HAT) occurs to form the semiquinone and CodOOH intermediates. A subsequent PCET step is turnover-limiting and results in the formation of quinone and CoII-H2O2. A second oxidation of catechol to quinone occurs from the CoII-H2O2 species, but these steps are rapid and kinetically invisible. Of particular importance is the finding that partially reduced oxygen intermediates, such as superoxide or hydrogen peroxide, do not build up under these conditions. This is attributed to the role of hydroquinones in intercepting these reactive oxygen species, ultimately giving rise to the high selectivity often observed in oxidation reactions employing a Co/BQ system.

Scheme 84 Proposed pathway for the aerobic oxidation of para-hydroquinone by Co-salophen.

The Bäckvall group has developed a Ru/Co/quinone catalyst system for the oxidation of amines to ketimines and aldimines.244 The optimized system uses a dimeric Ru-carbonyl complex (2 mol%), 2,6-dimethoxy-1,4-benzoquinone (20 mol%) and a Co-salen complex (2 mol%) in toluene under a stream of air (Scheme 85). Based on previous studies, the dimeric Ru complex is proposed to dissociate into an active monomeric catalyst form in the presence of amines. The resulting Ru-amido complex undergoes b-hydride elimination to form the imine product. The Ru-hydride complex is then reoxidized by 2,6-dimethoxy-1,4-benzoquinone.

110

Metal-Catalyzed Aerobic Oxidation Reactions

Scheme 85 Ru/Co/quinone-catalyzed oxidation of amines to ketimines.

Stahl and co-worker improved upon a recently reported phd/ZnI2/PPTS system by employing a Ru catalyst and replacing the I−/I−3 redox system245 with Co(salophen) (phd ¼ 1.10-phenanthroline-5,6-dione, PPTS ¼ para-toluenesulfonate).246 The optimized reaction operates at room temperature and open to ambient air to convert secondary tetrahydroquinolines to quinoline derivatives in good yields (Scheme 86).

R

N H

[Ru(phd) 3](PF 6) 2 (2.5 mol%) Co(sa lophen) (5 mol%) MeCN, rt, ambient air

2+ R

N

17 examples 59-99% yields

(phd) 2Ru

N

O

N

O

Scheme 86 Ru/Co(salophen)-catalyzed aerobic oxidation of tetrahydroisoquinolines.

13.03.4 Dehydrogenative coupling reactions A dehydrogenative coupling reaction is the oxidative coupling of two nucleophilic coupling partners (CdH or NudH).247–249 In this section we focus on the CdC bond forming reactions as well as oxidative coupling reactions of CdH bonds with various nucleophiles (NuH), in particular O and N nucleophiles. Palladium has a rich history of aerobic oxidative coupling reactions, such as the Wacker oxidation and oxidative Heck reactions, and has continued to be an efficient catalyst for a wide array of oxidative coupling reactions. In recent years, copper has evolved as a dynamic catalyst for various oxidative coupling reactions owing to its ability to facilitate both one- and two-electron processes.250 Palladium and copper systems are the focus of this section, although recent developments with other metals, such as Rh, Ru, and Fe, are also highlighted.

13.03.4.1 Palladium catalysts for dehydrogenative coupling reactions 13.03.4.1.1

Oxidative couplings of alkenes

Palladium-catalyzed aerobic oxidative coupling reactions date to the 1950s and the development of the Wacker reaction to produce acetaldehyde from ethylene and oxygen under palladium catalysis.251 The classical Wacker reaction uses PdCl2 as the catalyst precursor in the presence of stoichiometric CuCl2 and air. A simplified mechanism involves coordination of ethylene to Pd followed by the attack of water on the coordinated alkene, deprotonation, and finally the formation of acetaldehyde and Pd0. Catalytic turnover is achieved by the oxidation of Pd0 to PdII by CuCl2 which forms CuCl. Dioxygen is the terminal oxidant for the reoxidation of CuCl to CuCl2. In the absence of CuCl2 the reoxidation of Pd0 to PdII is slow and results in the loss of catalytically active Pd due to the formation of palladium metal. Direct dioxygen-coupled systems were developed in the early to mid-2000s by Sheldon,252 Sigman,253 and Kaneda.254 Each of these systems employed a chelating N-based ligand or the use of a polar coordinating solvent to aid the reoxidation of Pd0 to PdII. Although landmark systems, these protocols are all limited to the oxidation of terminal aliphatic alkenes to ketones. The ability to oxidize styrenes, or to achieve selectivity for aldehyde products are ongoing challenges and recent efforts toward these goals are described below. In 2017, Muldoon and co-workers developed an efficient catalytic system for the aerobic Wacker-type oxidation of styrenes to ketones using a well-defined PdII complex, [(PNO)Pd(NCMe)2](OTf )2.255 Low catalyst loadings (1 mol%) can be used along with low O2 to N2 ratios (O2/N2 ¼ 8:92, 40 bar) (Scheme 87). An array of functional groups including ethers, acetoxy groups, halogens, and nitro groups were well tolerated.

R

[(PNO)Pd(NCMe) 2][OTf] 2 (1 mol%) MeOH (5 mL), H2O (0.5 mL) R O2/N2 (8:92) 40 bar, 27 °C

O

(OTf) 2

O 16 examples 54-86% yields

N

N Pd

MeCN

NCMe

[(PNO)Pd(NCMe) 2](OTf) 2 Scheme 87 Pd-catalyzed aerobic Wacker-type oxidation of styrenes to ketones.

Metal-Catalyzed Aerobic Oxidation Reactions

111

Typical Wacker-Tsuji oxidations are conducted in wet DMF affording ketone products from attack of water on the more substituted alkene carbon. Although anti-Markovnikov selectivity for the aldehyde product has been achieved in select cases256–259 the selectivity in these systems is substrate controlled. There is much interest in the development of methods capable of catalyst-controlled selectivity favoring aldehyde formation. Building on prior work from Feringa,260 Grubbs and co-workers identified an aldehyde-selective Wacker-type oxidation of alkenes.261 The optimized system features the use of AgNO2 (6 mol%) and CuCl2 (12 mol%) as co-catalysts with a [PdCl2(PhCN)2] catalyst (12 mol%) in a tert-butanol and nitromethane solvent mixture under 1 atm dioxygen at room temperature (Scheme 88). The reaction tolerated nitro, ester, ether, and carboxylic acid functionalities that were positioned 2–8 carbons away from the alkene to minimize substrate directing effects. Aldehyde yields were synthetically useful and ranged from 45% to 70%.

R

[PdCl2(PhCN) 2] (12 mol%) CuCl2 (12 mol%), AgNO2 (6 mol%) tBuOH/MeNO (15:1), O , rt 2 2

R

O

11 examples 45-70% yields

Scheme 88 Pd-catalyzed aldehyde-selective Wacker-type oxidation of alkenes.

Kang and co-workers identified a catalyst system with solvent-controlled selectivity for the formation of aldehyde or ketone products.262 When Pd(PhCN)2Cl2 (20 mol%) is paired with cocatalytic tBuONO (20 mol%) in tert-butanol, aldehyde products are obtained. In contrast, ethanol solvent with 2 equivalents of water affords the ketone product (Scheme 89). The authors propose that the selectivity for aldehydes arises from the larger tert-butanol molecule from the solvent preferentially attacking the terminal carbon of the PdII-bound alkene.

Scheme 89 Solvent-dependent selectivity in the Pd-catalyzed oxidation of alkenes. Modified from Hu, K.-F.; Ning, X.-S.; Qu, J.-P.; Kang, Y.-B. J. Org. Chem. 2018, 83, 11327–11332. https://doi.org/10.1021/acs.joc.8b01547. Copyright 2018 American Chemical Society.

The selective oxidation of internal alkenes remains a challenge in this area, however Kaneda and co-workers have made significant advances toward this end.263–265 Their copper-free catalyst system employs PdCl2 (10 mol%) with TsOH (0.4 equiv) in DMA and MeOH at 80  C under 6 atm O2 for the efficient and selective oxidation of a broad scope of alkenes, including simple linear alkenes, cyclic alkenes, and those bearing electron-withdrawing groups. Reduced yields are observed in the presence of CuCl2, suggesting that the copper salts that facilitate reoxidation of Pd0 to PdII under typical conditions inhibit the oxidation of internal olefins. The copper-free conditions, however, require a higher pressure of O2. The system developed by Kang described above (Scheme 89) is also capable of achieving the oxidation of internal olefins with high regioselectivity under 1 atm O2.262 Alkyl and aryl substituted alkenes bearing phenylether, phthalimide, sulfonamide, ester and carbonate moieties were converted to the corresponding substituted ketones in good yields and with regioselectivities ranging from 5:1 to greater than 20:1. The reaction could also be extended to simple cyclic and linear alkenes, as well as cholesterol 18 analogues. The addition of H18 O incorporation (54%) into the product, suggesting solvent to be the 2 O to the reaction resulted in source of the oxygen atom. The regioselectivity of the reaction is proposed to arise from nucleophilic attack of the tert-butanol solvent on the less sterically hindered carbon of the PdII-bound alkene, as described above. Control experiments indicate that the cocatalytic tBuONO releases nitric oxide NO which is oxidized by O2 to form NO2. The NO2 is responsible for the reoxidation of Pd0 to PdII enabling efficient catalysis with a lower pressure of O2. Oxidative amination reactions, or “aza-Wacker” reactions, are the oxidative couplings of amines with alkenes to generate enamine products. Although seemingly straightforward, these reactions suffer from challenges associated with the strong coordinating ability of amines to PdII. Early developments involved the use of sulfonamides, ureas, or other less basic nitrogen nucleophiles as well as tethered substrates for intramolecular cyclization reactions.266 A number of groups have leveraged the intramolecular aza-Wacker reaction for the synthesis of N-heterocycles and annulation reactions.267–270 Of particular interest here are the enantioselective variants. Aza-Wacker reactions proceed through aminopalladation of a PdII-amidate-alkene intermediate (Scheme 90, Step 3) followed by product-forming b-hydride elimination (Step 4).271 The aminopalladation step can occur through a formal migratory insertion, providing cis-aminopalladation, or nucleophilic attack of the amine onto the coordinated alkene, yielding trans-aminopalladation (Scheme 91).

112

Metal-Catalyzed Aerobic Oxidation Reactions

Scheme 90 Proposed pathway for the Pd-catalyzed intramolecular aerobic oxidative amination of aminoalkenes. Reprinted with permission from Ye, X., Liu, G.; Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011, 76, 1031–1044. doi:10.1021/jo102338a. Copyright 2011 American Chemical Society.

(A ) cis-aminopalladation

LnPd NR’2 R

(B ) trans-aminopalladation

LnPd LnPd

NR’2 R

R

NR’2

L Cl

PdII

Cl

L

R

Cl

PdII

Cl

R NHR'2

NHR'2

Scheme 91 Possible cis- and trans-aminopalladation events in the Pd-catalyzed oxidative amination of alkenes.

The stereochemistry of the aminopalladation step is of particular importance in the development of enantioselective amination reactions. The use of cleverly designed stereochemical probes has shown that most common Pd catalyst systems, such as Pd(OAc)2/ DMSO, Pd(OAc)2/py, and Pd(O2CCF3)2/py all proceed through a cis-aminopalladation event (Scheme 92).272

Scheme 92 The use of stereochemical probes indicates cis-aminopalladation under most Pd-catalyzed oxidative amination conditions. Reprinted with permission from Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. doi:10.1021/ja070424u. Copyright 2007 American Chemical Society.

Metal-Catalyzed Aerobic Oxidation Reactions

113

A particularly surprising result revealed that the conditions developed for the enantioselective synthesis of pyrrolidines using the chiral pyridine-oxazoline (pyrox) ligand (Scheme 93),273 favor a trans-aminopalladation pathway although both pathways are operative.274 It was also shown that the trans-aminopalladation occurs with greater enantioselectivity and that the preference for this pathway is enforced by the pyrox ligand.

Scheme 93 Pd/pyrox-catalyzed enantioselective intramolecular oxidative amination.

In a related study, Stahl and co-workers275 explored the role of ligands in the Pd-catalyzed aerobic aza-Wacker reaction. The comparison of reactivity of several chelating N-based ligands demonstrated that traditional bidentate ligands, such as 9,10-phenanthroline (phen), strongly inhibited catalytic activity, while the diazafluorenone (DAF) ligand was superior to pyridine. Additionally, all ligands studied except for DAF showed an inhibitory effect at high ligand concentrations. The unique activity of DAF arises from an interconversion between k2 and k1 coordination modes that provides access to an open coordination site at the PdII center to facilitate the turnover-limiting alkene insertion step (Scheme 94). The correlation between the nucleopalladation event and the stereoselectivity of the overall transformation and the role of ligand lability in accelerating aminopalladation have significant implications for the development of enantioselective aza-Wacker reactions. In recent years, several groups have reported the design of new chiral ligands for related reactions.276,277

N H

Ts

Pd(OAc) 2 (5 mol%) DAF (5 mol%)

Ts N

Ts

toluene, 50 °C, O 2 (1 atm)

AcO

N

O

N Pd N

97% yield

Scheme 94 Pd/DAF-catalyzed aerobic intramolecular oxidative amination reaction.

For example, in 2012 Zhang and co-workers used a Pd(O2CCF3)2/iPr-pyrox catalyst system to access to chiral isoindolines in good yields and selectivities (Scheme 95).278 More recently, Zhang and Yang used the related tBu-pyrox ligand for the asymmetric cyclization of N-tosyl-hydrazines to yield chiral pyrazolines.279 Zhu and co-workers280 reported an enantioselective desymmetrizative cyclization reaction using a Pd(CPA)2(MeCN)2/pyrox-system for the synthesis of enantioenriched cis-3a-substituted tetrahydroindoles from cyclohexa-1,4-dienes (CPA ¼ chiral phosphoric acid). Good yields (49–93%) and high enantioselectivities (81–95%) were obtained for a series of dienes containing aryl bromides as well as standard hydroxy and amino protecting groups. The authors applied this methodology to a concise and divergent total synthesis of (−)-mesembrane and (+)-crinane. O NHR

Pd(O 2CCF 3) 2 (5 mol%) iPr-pyrox (7.5 mol%) O2 (1 atm) MeCN, 60 °C

O NR

14 examples 33-99% yields 57-99% ee

O N

N

iPr-pyrox

R = OBn, OMe Scheme 95 Pd/iPr-pyrox catalyzed enantioselective oxidative amination of alkenes to yield isoindolines.

The oxidative coupling of alkenes with arenes also has a long history beginning with the Pd-catalyzed coupling reactions of arylboronic acids reported by Uemura and Cho in the mid-1990s.281 More recent advances in this area have focused on the direct coupling of alkenes with arene CdH bonds. Unfortunately, these reactions are often plagued by a narrow substrate scope and poor regioselectivity. Some of the most significant recent advances to overcome these challenges have come from Yu and co-workers who identified amino acids as ligands to afford high site-selectivity. Phenylacetic acids can be coupled with alkenes under catalysis by Pd(OAc)2 (5 mol%) and benzoquinone (BQ, 5 mol%) with KHCO3 (2 equiv) in tert-amyl alcohol under 1 atm O2 at 85  C (Scheme 96).282,283 Later work enabled the sequential coupling with multiple alkenes to provide the selectively multi-substituted arenes284 as well as the olefination of diphenylacetic acids.285

114

Metal-Catalyzed Aerobic Oxidation Reactions

R2 R3 OH R1

H

+

O

R4

Pd(OAc) 2 (5 mol%) Ac-Ile-OH (10 mol%), KHCO3 (2 equiv) t-amyl alcohol, 85 °C, O2 (1 atm)

R2 R3 O

CO2H 24 examples 16-98% yields R4

R1

O NH OH

Ac-Ile-OH

Scheme 96 Pd/Ac-Ile-OH-catalyzed oxidative CdH alkenylation.

Recent efforts have also focused on the development of asymmetric oxidative Heck reactions.286 Challenges in obtaining high enantioselectivities are often attributed to the need for polar solvents which may encourage ligand dissociation during the insertion step, leading to reduced enantioselectivities. Jung and co-workers have shown an enantioselective intermolecular coupling of alkenes with arylboronic acids to proceed in high yields (67–79%) and with good selectivities (62–75% ee) by employing a Pd(tBupyrox) complex (Scheme 97).287 The use of SPINOL-derived phosphoramidate ligands was recently applied by Bower and co-workers to the enantioselective synthesis of pyrrolidines and piperidines through an aza-Heck cyclization reaction.288

Ar B(OH) 2 +

Pd(tBu-pyrox)(O Ac) 2 (5 mol%) O2 (1 atm), DMF, rt R

* Ar

R

8 examples 67-79% yields 62-75% ee

O

N N

Pd OAc Pd(tBu-pyrox)(OAc) 2 AcO

Scheme 97 Pd-catalyzed enantioselective coupling of alkenes with arylboronic acids.

An additional variation of the oxidative Heck reaction is the decarboxylative coupling of benzoic acids with alkenes. This reaction pattern was reported by Su and co-workers to be catalyzed by Pd(OAc)2 (10 mol%) with DMSO (5%) in DMF under 1 atm O2 at 120  C.289 The reaction is effective for the coupling of electron-rich (hetero)aromatic acids with electron-deficient alkenes (Scheme 98). The coupling of electron-deficient benzoates can be accomplished using an SiPr ligand and basic additive (SiPr ¼ 1,3-bis(2,6-diisopropylphenyl)imidazolidine). R1 O R2

OH

+

R4

R3

Pd(OAc) 2 (10 mol%) 5% DMSO in DMF O2 (1 atm), 120 °C

R1 R4 R2

R3

28 examples 23-94% yields

Scheme 98 Pd-catalyzed decarboxylative alkenylation.

13.03.4.1.2

Oxidative couplings of arenes

Early developments in the Pd-catalyzed oxidative coupling of arenes came from Davidson and Triggs in the mid-1960s using stoichiometric PdCl2 to achieve the homocoupling of benzene and toluene.290 Further work extended the chemistry to catalytic protocols using O2 as the terminal oxidant.291,292 The poor regioselectivity and potential for overoxidation and oligomerization have hampered the more rapid development and the widespread use of these reactions. The dimerization of dimethyl-o-phthalate, however, has received attention for its high regioselectivity and has been applied to the commercial synthesis of Upilex®, a polyimide film.293 Stahl and co-workers proposed a streamlined alternative synthesis of Upilex® based on the homocoupling of o-xylene with Pd(OAC)2, 2-fluoropyridine (2Fpy) as ligand and CuII(OTf )2 as a cocatalyst (Scheme 99).294 When considering biaryl formation, the reaction can undergo sequential CdH activation and transmetalation steps at a single Pd center through a monometallic pathway, or parallel CdH activation events can occur at distinct Pd centers followed by a bimetallic transmetalation step (Scheme 100). Mechanistic studies of this system295 revealed a second-order dependence on [Pd] at low [Pd], and a first-order dependence at high [Pd], and a very large KIE value (kH/kD ¼ 24  2), both consistent with a bimetallic mechanism with rate-limiting transmetalation at low [Pd] and rate-limiting CdH activation at high [Pd]. The Cu(OTf )2 cocatalyst included in this Pd-catalyzed biaryl coupling provides a significant rate enhancement (more than 45-fold) and was originally expected to function as an oxidant or redox-active cocatalyst. Further investigation revealed that the triflate anion is the source of rate acceleration.296 In the presence of triflate ions (OTf−), (2Fpy)2Pd(OAc)(OTf ) is formed and shows increased activity toward CdH activation, thus accelerating the overall catalytic reaction.

H

Pd(OAc) 2 (0.1 mol%), Cu(OTf) 2 (0.1 mol%) 2-fluoropyridine (0.2 mol%), CF3CO2H (0.13 mol%) O2 (1 atm), AcOH, 80 °C

Scheme 99 Pd-catalyzed aerobic oxidative homocoupling of o-xylene.

+ 83% yield

11% yield

Metal-Catalyzed Aerobic Oxidation Reactions

115

R H LnPdIIX 2

R LnPdII

H X

X

- LnPdX 2

H R’ LnPdII X 2

LnPdII

H X

R LnPdII R’

X R’

C-H Activation rate-limiting at high [Pd]

Transmetalation rate-limiting at low [Pd]

Scheme 100 Possible mononuclear CdH activation pathway and dinuclear transmetalation pathway to access the PdII-biaryl intermediate. Modified from Wang, D.; Izawa, Y.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136 (28), 9914–9917. https://pubs.acs.org/doi/10.1021/ja505405u. Copyright 2014 American Chemical Society.

De Vos and co-workers297 recently explored the homocoupling of benzene to biphenyl catalyzed by Pd(OAc)2 in the presence of TfOH in AcOH, to establish the role of acetate ions. A combination of kinetic isotope effect and hydrogen-deuterium exchange studies, as well as the investigation of the reactivity of proposed palladium-aryl intermediates identified a monometallic pathway with two distinct CdH activation steps (Scheme 101). The first CdH activation step is a concerted metalation-deprotonation (CMD) reaction mediated by a coordinated acetate ligand, in which donation from the acetate ligand to the Pd center disfavors an electrophilic aromatic substitution pathway. The CdH activation results in loss of acetic acid and generates an electrophilic Pd species which then undergoes a second CdH activation step following an electrophilic aromatic substitution pathway step. These disparate CdH activation steps are similar to those observed in Pd-catalyzed cross-coupling reactions of two distinct aryl coupling partners.

+ 0.5 O 2

2

(T fO)Pd

O O

CH3

active complex

Pd(OAc) 2 (0.0056 mmol) TfOH (0.0112 mmol) AcOH (0.12 mmol) in benzene (0.94 mL) 120 °C, 3 h, O 2 (16 bar)

(T fO)Pd CMD

+ H2O TOF = 21.5

(T fO)Pd O

OH CH3

+ H3C

O

SEAr OH

Pd + TfO- + H+

Scheme 101 Pd-catalyzed oxidative cross-coupling of (hetero)arenes. Modified from Beckers, I.; Henrion, M.; De Vos, D. E., ChemCatChem 2020, 12 (1), 90–94. https://doi.org/10.1002/cctc.201901238. Copyright 2019, with permission from John Wiley and Sons.

The ability to achieve chemoselectivity for the unsymmetrical biaryl product, as well as regioselectivity are recurring challenges in the oxidative coupling of arenes. Fagnou and co-workers illustrated chemoselectivity in the cross-coupling of indoles and arenes when Cu(OAc)2 is used as the oxidant.298 Studies by DeBoef and co-workers showed that similar chemoselectivity can be achieved using O2 as an oxidant. For example, the selective coupling of benzofurans with benzene proceeds under catalysis by Pd(OAc)2 (10 mol%) and HPMV in AcOH under 3 atm O2 (HPMV ¼ heteropolymolybdovanadic acid H4PMo11VO40).299 Similarly, Zhang and co-workers have leveraged electron-deficient polyfluoroarenes to accomplish the selective cross-coupling with electron-rich (hetero)arenes (Scheme 102).300

Scheme 102 Pd-catalyzed oxidative cross-coupling of (hetero)arenes.

Work from Fagnou and co-workers revealed an elegant oxidant-controlled regioselectivity for coupling at either the C2 or C3 position of indole.301 Achieving high selectivity in aerobic methods, however, requires the identification of catalysts capable of controlling the selectivity. Catalyst-controlled regioselectivity has been demonstrated in the cross-coupling of indoles with benzene.302 The use of Pd(O2CCF3)2 (5 mol%) with a 9,9-dimethyl-4,5-diazafluorene ligand (DMeF, 5 mol%) favors coupling at the C3 position while Pd(OPiv)2 (5 mol%) and 4,5-diazafluorenone (DAF, 5 mol%) favor the C2 coupling product (Scheme 103).

116

Metal-Catalyzed Aerobic Oxidation Reactions

N R R = Piv, SO 2Ph

Pd catalyst (5 mol%) ligand (5 mol%) C6H6/acid (10:1) O2 (1 atm) 120 °C

N R

N R favored with Pd(OPiv) 2/DAF O

N

N DAF

favored with Pd(T FA) 2/DMeF

N N DMeF

Scheme 103 Ligand-controlled selectivity in the Pd-catalyzed aerobic oxidative coupling of indole at the C2 and C3 positions.

Chelating directing groups within the substrate can also be used to achieve high regioselectivity, such as in the amide-directed CdH arylation of N-acetanilides reported by Shi and co-workers303 and the ortho-arylation of anilides developed by Buchwald and co-workers (Scheme 104).304

R2

NHR 1 H

H R3 4-11 equiv

Pd(OAc) 2 (5 -10 mol%) DMSO (10-20 mol%)

R2

NHR 1

O2 (1 atm) TFA, 80-100 °C

18 examples 59-94% yields R3

Scheme 104 Pd-catalyzed oxidative ortho-arylation of anilides.

The direct CdH functionalization of arenes to form CdN and CdO bonds has also been of recent interest. While a handful of these reactions have been reported in recent years, the majority are intramolecular cyclization reactions. Stahl and co-workers have used the Pd(OAc)2/DAF catalyst system to enable the aerobic cyclization of N-benzenesulfonyl-2-aminobiphenyl to access carbazole (Scheme 105),305 while ligand-free conditions enable the synthesis of indole-2-carboxylate derivatives (Scheme 106).306

Pd(OAc) 2 (1 mol%) 4,5-diazafluorenone (1 mol%) NHSO 2Ph glycolic acid (2 equiv) H 1,4-dioxane, O2 (1 atm), 80 °C

NSO 2Ph

80 % yield Scheme 105 Pd/DAF-catalyzed intramolecular oxidative CdH amination.

Scheme 106 Pd-catalyzed intramolecular oxidative CdH amidation.

13.03.4.1.3

Allylic functionalization

Pd-catalyzed allylic functionalization reactions typically employ benzoquinone (BQ) oxidants,307,308 however Stahl and co-workers reported the use of DAF as a ligand to enable the aerobic allylic CdH acetoxylation reaction.309 In these reactions, CdH activation of a Pd-alkene complex forms a Pd-p-allyl intermediate that is attacked by the nucleophilic coupling partner to generate product and Pd0. The reoxidation of Pd occurs by the terminal oxidant, BQ or O2. The authors hypothesized that benzoquinone is responsible for more than the reoxidation of Pd0 to PdII and that it also acts as a ligand to promote the nucleophilic attack on the Pd-p-allyl intermediate. During the development of aerobic conditions, the group identified the DAF ligand to be crucial for successful catalysis. In-depth mechanistic studies310,311 identified two kinetic phases in the reaction. First, an initial burst phase is characterized by an unusual DAF-bridged PdI species and a rate-determining allylic CdH activation step. During the following steady-state turnover (Scheme 107), a PdII-p-allyl species is identified as the resting state. Reversible reductive elimination forms the product and Pd0, which is trapped in a turnover-limiting reoxidation step. This slow reductive elimination when DAF is used is in contrast to the BQ-catalyzed conditions in which reductive elimination is rapid and facilitated by BQ coordination, highlighting the important role

Metal-Catalyzed Aerobic Oxidation Reactions

117

of BQ and DAF in facilitating nucleophilic attack. In a follow up study,312 a Pd2(dba)3 precatalyst was employed to expand the scope of carboxylic acid coupling partners (Scheme 108). The inclusion of a quinone cocatalyst led to more efficient catalysis, consistent with the mechanistic findings.

Pd(OAc) 2/DAF (5 mol%) NaOAc (0.2 equiv) Ph dioxane/AcOH (3:1) O2 (1 atm), 60 °C

Ph

OAc

R

H2O2

Pd(OAc) 2/DAF

R

Pd(OAc) 2/DAF

2 HOAc N N

O2

Pd

O O

HOAc

(DAF)Pd 0

R R

OAc Pd

(DAF)PdOAc -DAF +DAF

R

2

OAc

Scheme 107 Conditions and mechanism of the Pd/DAF-catalyzed allylic acetoxylation reaction. Reprinted with permission from Jaworski, J. N.; Kozack, C. V.; Tereniak, S. J.; Knapp, S. M. M.; Landis, C. R.; Miller, J. T.; Stahl, S. S. J. Am. Chem. Soc. 2019, 141, 10462–10474. https://doi.org/10.1021/jacs.9b04699. Copyright 2019 American Chemical Society.

+

O HO

Pd2(dba) 3 (2.5 mol%), Fe(Pc) (0.5 mol%) DAF (5 mol%), Me2BQ (10 mol%) DCE (1 mL), 60 °C, O2 (1 atm) R

O O

R

19 examples 30-92% yields

Scheme 108 Pd/DAF catalyzed allylic acetoxylation reaction.

Aerobic variants of allylic functionalization have also been applied to the formation of CdN and CdC bonds. Building on prior work by Liu and co-workers,313 the White group314 used a bis-sulfoxide ligand paired with a Co-salophen cocatalyst to facilitate the amidation of linear alkenes at 45  C under 1 atm O2 (Scheme 109). Under related conditions, Shi and co-workers accomplished the allylic alkylation using diketone coupling partners (Scheme 110).315

Scheme 109 Pd-catalyzed oxidative amidation of alkenes.

O

H Ar

O

Ph

Me H

Pd(OAc) 2 Ph S S Ph O O (10 mol%) BQ (1.3 equiv), O2 balloon Ar toluene, 60 °C

Scheme 110 Pd-catalyzed oxidative allylic alkylation of alkenes.

Me O Ph

O

10 examples 4-88% yields

118

Metal-Catalyzed Aerobic Oxidation Reactions

13.03.4.2 Copper catalysts for dehydrogenative coupling reactions Copper-catalyzed CdH coupling reactions have a long history originating with the observation by Glaser and co-workers of the homocoupling of CuI-phenylacetylide under aerobic conditions.316,317 Significant advances followed in the development of catalytic oxidative coupling reactions of alkynes318,319 with a particular interest in the resulting 1,3-diynes for applications in materials chemistry. Copper-catalyzed CdH coupling reactions under aerobic conditions became of interest in the early-2000s, with Yu’s report of the CdH activation of phenyl pyridines320 and Stahl’s work exploring the amidation of terminal alkynes to synthesize ynamides.321 Following this time, the field has exploded with the rapid development of copper-catalyzed methods for the aerobic oxidative couplings of a wide variety of coupling partners. In particular, the copper-catalyzed CdH coupling reactions of arenes have gained increasing popularity recently as a means to access functionalized arenes with relevance to biologically active and pharmaceutically relevant structures. A number of reviews have provided thorough accounts of the history and development of related CdC, CdO and CdN coupling reactions.322–330 Here, we focus on the mechanistic understanding of the systems that have enabled key advances in these protocols, as well as some of the most recent developments and applications of these reactions.

13.03.4.2.1

Oxidative coupling of arenes

Seminal work by Chan, Evans and Lam in the late-1990s described the stoichiometric coupling of amines and alcohols with boronic acids, now known as the Chan-Evans-Lam (CEL) reaction.331–333 The classical CEL reaction is performed stoichiometrically with the most common conditions using Cu(OAc)2 with Et3N in dichloromethane with O2 as the oxidant at room temperature. A ground-breaking advance came from Collman and co-workers in the early 2000s when they identified conditions using catalytic loadings of [Cu(OH)
TMEDA]2Cl2.334,335 The reaction is mild, simple and inexpensive, yet the Chan-Lam coupling reaction has a reputation of being capricious with small changes in substrates often leading to low yields or reaction failures. Detailed mechanistic studies by several research groups have addressed these challenges. Early mechanistic models by Chan, Lam, and Evans332,333 suggested the intermediacy of a CuIII species that undergoes reductive elimination to form product as shown in Scheme 111. Further work by Stahl and co-workers showed the oxidative coupling of tolylboronic acid and methanol to be mediated by 2 equivalents of CuII.336,337 Kinetic studies supported a turnover-limiting transmetalation of the aryl group from boron to CuII based on a saturation dependence on [boronic ester], a half-order dependence on [Cu] and no dependence on pO2. Electron-rich arylboronic acids showed faster reaction rates consistent with turnover-limiting transmetalation and EPR studies identified a pair of CuII resting states that exist in equilibrium and were assigned as adducts of the arylboronic ester with copper.

Scheme 111 Proposed pathway for the Cu-catalyzed aerobic coupling of aryl boronic esters with methanol. Reprinted with permission from King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045. https://doi.org/10.1021/ja9006657. Copyright 2019 American Chemical Society.

Building on the work by Stahl, Watson and co-workers338 sought to address two long-standing limitations in CEL reactions: the efficient coupling of aryl amines and the use of pinacol boronic esters. Using a combination of kinetics, EPR and UV-visible spectroscopies, and the preparation and study of copper(II) complexes the authors found that alkyl amines denucleate better than aryl amines. Pinacol ester substrates are problematic due to the liberation of pinacol which traps CuII in the form of a CuIIbis(pinacol) complex. A protocol to enable the efficient coupling of arylamines with pinacol boronic esters resulted, and features the addition of boric acid to capture liberated pinacol and the use of 2 equivalents of amine (Scheme 112). This methodology was also applied to etherification and thiolation reactions.

Metal-Catalyzed Aerobic Oxidation Reactions

Bpin R

Cu(OAc) 2 (20 mol%), B(OH) 3 (2 equiv)

+ NHR 2

1 equiv

MeCN, 4Å MS, 80 °C, O2

2 equiv

119

NR 1R 2 51 examples 52-94% yields

R

Scheme 112 Chan-Evans-Lam reaction conditions for the coupling of pinacol boronic esters with arylamines.

In a beautiful study by Schaper and co-workers339 the mechanistic findings from the previous two decades were used to design a ligand with a pendant coordinating group to bind boron and facilitate transmetalation. The authors developed a CuII-pyridyliminoarylsulfonate complex that eliminates the need for acetate and other additives to activate the boronic acid. The system proved to be powerful and straightforward affording efficient catalysis under mild reaction conditions while minimizing the formation of protodeborylation and homocoupling side products. The reaction showed a wide scope of amine coupling partners including primary and secondary amines, anilines, aminophenol, imidazole, pyrazole and phenyltetrazole (Scheme 113).

N Cu OTf

N

O S O O 2.5 mol% rt or 50 °C, MeOH

R 2N H + (HO) 2B Ph 1-1.5 equiv HN

R 2N Ph

30 examples 15-100% yields

Ph

R

Ph N R R

R

Ph N X X X R

Ph N H R

X R = H, Me, iPr R = Me, Ph, nBu X = halide, alkoxyl, alcohol, piperidyl

R = Me, nOct, Ph

R = H or Me X = N or H

Scheme 113 CuII-pyridyliminosulfonate catalyzed aerobic amination of phenyl boronic acid.

Finally, in an industrial application by Eli Lilly, Brewer and co-workers designed a continuous flow catalytic Chan-Evans-Lam coupling to produce a key intermediate en route to an active pharmaceutical ingredient. The coupling was conducted on a 75 kg scale to give the target compound in 69% yield and 99.6% purity (Scheme 114).340 Safety concerns of using O2 in large scale reactions were addressed with the adaptation to a continuous flow system. Cu(OAc) 2 (12.5 mol%) 2,2'-bipyridine (18.75 mol%) valeric acid (25 mol%) iPr2NEt (1.5 equiv) THF/DMSO (1:1) 5% O2/N2 (300 psi) 90 °C

O N

NH

O Cl

HO

B

OH

N

O N

N

O Cl

N

69% yield 99.6 % purity

Scheme 114 Industrial application of the Chan-Evans-Lam coupling reaction.

Of particular current interest is the extension of the Chan-Evans-Lam reaction to the couplings of heteroaromatic amines341–343 and related coupling partners (Scheme 115).344 The resulting structures are common scaffolds in a wide array of biologically active molecules, and Cham-Evans-Lam coupling reactions can enable late stage functionalization or provide direct access to key (HO) 2B Ar

HetAr H H N N

H N

S Ar

Dong and coworkers

N

Ar

N N Ar

Das and coworkers

Cu(OAc) 2•H2O (5 mol%) Cu(OAc) 2 (20 mol%) bpy (20 mol%) bpy (10 mol%) Cs2CO3 (2 equiv) DMF/H2O (1:3), air, 80 °C DMF, air, 60 °C 17 examples 28-95 %

ArHet

26 examples 65-87 %

N

N

N

R

N Ar

Das and coworkers Krasavin and coworkers Cu(OAc) 2 (20 mol%) Cs2CO3 (3 equiv) DMF, air, 120 °C

Cu(OAc) 2 (1.5 equiv) K2CO3 (7.5 equiv) DMSO, open air, rt

28 examples 70-91 %

24 examples 29-87 %

Scheme 115 Cu-catalyzed aerobic oxidative coupling reactions of aryl boronic acids with heteroaromatic coupling partners.

120

Metal-Catalyzed Aerobic Oxidation Reactions

intermediates. This approach has been applied by Moody and co-workers345 to the late-stage functionalization and diversification of a key reactive intermediate toward the synthesis of integrin antagonists allowing for the installation of a diverse array of pyrazole, imidazole, piperidine, and morpholine structures, although often in low yields (Scheme 116).

N N Boc

H N O

1. Cu(OAc) 2 (1 equiv) B(OH) 3 (2 equiv) MeCN, 3 Å MS, 70 °C 2. TFA, DCM, rt

CO2t-Bu + H NR2 BO O

N H

H N

N O

CO2H

34 examples 11-37% yields

NR2

Scheme 116 Application of the Chan-Evans-Lam coupling to the synthesis of integrin antagonists.

Advances in the development and mechanistic understanding of the Chan-Evans-Lam reaction provided a foundation for the design of copper catalyst systems capable of the direct functionalization of arene CdH bonds. Yu and co-workers reported the CdH acetoxylation and chlorination of phenylpyridines in the pioneering example of a copper-catalyzed aerobic CdH functionalization reaction.320 Electron-withdrawing groups in the substrate decreased reaction rates and biphenyl was not reactive, suggesting that the pyridyl moiety is essential for the coordination to copper. These reactions were proposed to proceed via a mechanism involving single-electron transfer (SET) from CuII to the phenyl ring, on the basis of a negligible KIE. Building on this work, researchers have identified methods for the analogous coupling reactions with a number of nucleophiles including acyl chlorides,346 anhydrides,347 amines348,349 and amides350 (Scheme 117). These synthetic advances have been surveyed in recent reviews351,352 and here we focus again on the mechanistic framework identified for these reactions and the recent protocols that have derived from them.

N

Nu-

Cu(OAc) 2 , O2

N Nu

H H OH Cl

H SPh Cl

TMSCN

H NHTs I2

O R

O O

H NHPh

O R

R1 O

Cl

N H

R2

Ar

Scheme 117 Cu-catalyzed aerobic CdH functionalization reactions of 2-phenylpyridine.

The 8-aminoquinoline directing group pioneered by Daugulis and co-workers353 has received considerable attention for its ability to enable the CdH functionalization of benzamide substrates.354 Stahl, Ertem and co-workers showed that aerobic functionalization of these substrates by Cu can proceed through either a single-electron transfer (SET) mechanism or a concerted metalation deprotonation (CMD) mechanism depending on the reaction conditions used.355 The authors explored the chlorination and methoxylation reactions and found that under basic conditions, an organometallic CMD pathway dominates giving rise to functionalization of the benzamide ring, while under acidic conditions, an SET pathway leads to functionalization of the quinoline (Scheme 118). An SET pathway is enabled due to the presence of CuCl2, which is more oxidizing than the corresponding Cucarbonate species present under basic conditions. The SET pathway shows no KIE, while the organometallic CdH activation displays a KIE value of kH/kD ¼ 5.7  0.8 suggestive of a concerted metalation deprotonation (CMD). The carbonate is responsible for the CdH activation by the CMD pathway, while also stabilizing CuII and CuIII intermediates.

Scheme 118 Condition-dependent selectivity in the aerobic Cu-catalyzed CdH functionalization of N-(8-quinolinyl)benzamide through concerted metalation deprotonation (CMD) or single-electron transfer (SET) pathways.

Metal-Catalyzed Aerobic Oxidation Reactions

121

Evidence supporting the intermediacy of organometallic copper(III) species was established in earlier studies of macrocyclic copper complexes developed by Stahl and Ribas.356 The CuIII complex was prepared and shown to be active in both catalytic and stoichiometric methoxylation reactions. The formation of CuIII during catalysis was evidenced by UV-visible and gas uptake experiments (Scheme 119). 2+ (ClO4) 2

CuIII NH

N

MeOH

NH

N

OMe

CuI(ClO4)

NH

HClO4

N

Scheme 119 Stoichiometric methoxylation of the organometallic copper(III) species supported by a macrocyclic ligand.

Recent work applied the copper-catalyzed CdH functionalization reactions to new substrates and directing groups including tetrahydropyrimidines357 indolines,358 picolinamide,359 and arenes bearing N-aminopyridinium ylides.360 Furthermore, these CdH functionalization reactions have been extended to a variety of cyclization and annulation protocols to generate a diverse array of heterocycles361–364 and spirocyclic compounds (Scheme 120, DMB ¼ 2,4-dimethoxybenzyl).365,366

H

MeO

H

CO2Et

N DMB

Cu(OAc) 2•H2O (5 mol%)

MeO

mesitylene, 165 °C, air

CO2Et O N DMB

Me N 5 steps

MeO N

O

Scheme 120 Cu-catalyzed aerobic CdH cyclization to access the corresponding spirocyclic product. Modified from Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2010, 12, 3446–3449. https://doi.org/10.1021/ol1012668. Copyright 2010 American Chemical Society.

Finally, there has been much interest in developing CdH functionalization reactions that avoid the need for directing groups. While few of these reactions employ O2 as the terminal oxidant, a handful of notable examples exist. In general, these reactions require electron-deficient (hetero)arenes, such as fluorinated benzenes or benzoxazoles as the coupling partners. For example, Miura reported the alkynylation of perfluoroarenes,367,368 Schreiber developed an amidation of benzoxazoles,369 Miura disclosed the alkynylation of oxazoles,370 and Daugulis reported the homocoupling of fluorinated arenes.371 The homocoupling of activated arenes is a special class of CdH functionalization reactions and a number of groups have reported the synthesis of biaryls via direct biaryl coupling. Kozlowski and co-workers developed the aerobic enantioselective oxidative biaryl coupling reaction of substituted 2-naphthol derivatives to form binaphthyls using a 1,5-diaza-cis-decalin (DCD) copper catalyst (Scheme 121).372 The group applied this chemistry to the preparation of chiral binaphthyl polymers373 and the total synthesis of the perylenequinone hypocrellin A374 and the bisanthraquinone (S)-bisoranjidiol.375 Either (DCD)CuII or (DCD) CuII(OH)I can be used as the catalyst precursor and both showed an initial kinetic burst phase. Mechanistic studies376 showed that (DCD)CuII is converted to (DCD)CuII(OH)I under aerobic conditions. Further studies suggested a catalyst “self-processing” event during which oxygenase activity of the catalyst with the 2-naphthol (NapH) substrate generates a quinone cofactor NapHox and the active species [(DCD)CuI(NapHox)]+, although the precise identity of NapHox was not determined. O OMe OH H H OH

H N III N Cu (10 mol%) OH

ClCH2CH2Cl/MeCN 40 °C, O 2 (1 atm)

OMe O Scheme 121 Cu-catalyzed enantioselective oxidative homocoupling of 2-naphthols.

O OMe OH OH OMe O 85%, 93% ee

122

Metal-Catalyzed Aerobic Oxidation Reactions

Decarboxylative coupling reactions have gained recent interest as a strategy to generate functionalized arenes while avoiding the need for prefunctionalization or the site selectivity challenges associated with CdH functionalization reactions. While the majority of oxidative decarboxylative coupling reactions employ silver salts as terminal oxidants, there are a handful of systems that are capable of utilizing O2 including arylation,377,378 amidation,379 etherification,380 and thiolation reactions381 (Scheme 122).

Scheme 122 Cu-catalyzed aerobic oxidative decarboxylative coupling reactions.

Hoover and co-workersconducted a thorough mechanistic study of decarboxylative thiolation reactions of benzoic acids using a CuI/phen catalyst system in DMSO.382 In these reactions diphenyldisulfide (PhSSPh), which is formed from oxidation of thiophenol (PhSH) by O2 in the presence of Cu, was identified as the active thiolating species. From the synthesis and reactivity of four well-defined copper complexes it was concluded that CuI-carboxylates are more likely intermediates than their CuII counterparts. Reactions of the CuII-carboxylates with PhSSPh show an induction period consistent with in situ reduction to CuI which was observed using UV-Visible spectroscopy. The reaction showed a first-order dependence on [CuI] and [2-nitrobenzoic acid] as well as a zero-order dependence on [PhSSPh] and pO2, suggesting decarboxylation of the CuI-carboxylate to be the turnover-limiting step. The authors proposed a reaction mechanism in which O2 is responsible both for the generation of PhSSPh and for enabling oxidation and catalytic turnover of a catalytically inactive CuI-thiolate species (Scheme 123).

O

SH HO

O2N

O

N N

CuI

O O2N

CuI (10 mol%) Phen (12 mol%) K2CO3 (1 equiv)

S

DMSO, 140 °C 4Å MS, O2 (1 atm)

O2N

N -CO2

N

O2N

N

PhSSPh

CuI -

S

N

CuI SPh

O2

O2N

Scheme 123 Reaction conditions and proposed pathway for the aerobic Cu-catalyzed decarboxylative thiolation reaction.

13.03.4.2.2

Oxidative coupling of alkanes

The copper-catalyzed oxidative coupling of alkanes bearing activated CdH bonds, such as those adjacent to alkenes, arenes, carbonyls and amines has been developed.383–385 The subset of these coupling reactions that utilize O2 as the oxidant is limited and the most prominent reactions are those of tetrahydroisoquinolines (THIQ) and related substrates. In 2007, Li and co-workers reported the coupling of isoquinolines with nitroalkanes.386 The optimized reaction conditions employ CuBr (5 mol%) under 1 atm O2 at 60  C in water to furnish the substituted products in good yields (Scheme 124). The authors propose the reaction to proceed through initial amine dehydrogenation to form the iminium cation, followed by a copper-catalyzed Henry-type addition of the nitroalkane to yield the product.

N

NO2 Ph

H

R

CuBr (5 mol%) O2 (1 atm), 60 °C, H2O

Scheme 124 Cu-catalyzed oxidative coupling of tetrahydroisoquinoline with nitroalkanes.

N R

Ph

NO2

8 examples 30-95 % yields

Metal-Catalyzed Aerobic Oxidation Reactions

123

The Klubmann group has contributed significant insight into the initial oxidation of N-aryltetrahydroisoquinolines.387,388 The accepted reaction pathway involves the formation of an iminium ion intermediate which subsequentially reacts with nucleophiles. Several pathways were suggested in the past for the formation of the iminium ions, including electron transfer (ET), hydrogen atom transfer (HAT), proton transfer (PT), and proton-coupled electron transfer (PCET). Hammett competition experiments revealed a negative correlation with s+ (r¼1.9), indicating a strong electronic effect of substituents. KIE measurements (kH/kD ¼ 1.3) supported a product-controlling ET mechanism (Scheme 125). Building on this work, the Engeser group investigated the reaction of tetrahydroisoquinolines with diethyl zinc using ESI-MS with a coupled electrochemical flow cell (EC/MS).389 Using this method the authors were able to detect the transient iminium radical intermediate. Monitoring of the reaction indicated that the formation of the electrophilic iminium ion is slow while the Cu-independent coupling with the diethyl zinc is fast. Engeser also evaluated N-protecting groups other than N-phenyl and found that Boc, Cbz, and tosyl protected tetrahydroisoquinolines have redox potentials too high to enable oxidation by the CuCl2/O2 system (Boc ¼ N-butyloxycarbonyl, Cbz ¼ N-carbobenzyloxy). The authors proposed the use of stronger oxidants in these reactions.

N

+ Nu

Cu catalyst, O2

N

Ph

Ph

Nu

II SET Cu X 2 -CuIX

X N

Ph

NuX

CuX 2 N

-CuX, HX

Ph

Scheme 125 Proposed pathway for the Cu-catalyzed aerobic oxidative coupling of tetrahydroisoquinolines.

Several related reactions have been developed for the couplings of CdH bonds adjacent to carbonyls. Pan and co-workers390 reported an a-oxyacylation of ketones using CuI (20 mol%) and DMAP (50 mol%) in DMSO at 110  C under air (DMAP ¼ N,N0 -dimethylaminopyridine, Scheme 126). The acid scope includes substituted benzoic acids, cinnamic acids and some aliphatic acids with yields ranging from 35% to 90%. Reactions of aliphatic and cinnamic acids required the addition of 20 mol% CuI to suppress the decomposition of the propiophenone starting material to benzoic acid. The ketone scope was limited to arylketones bearing ethyl, propyl, and butyl acyls. The reaction was suppressed by the addition of TEMPO or the exclusion of O2. Based on their results and literature precedent the authors propose a reaction pathway analogous to that described for THIQ described above. The reaction begins with the formation of an a-carbonyl radical through the oxidation of the ketone by Cu/O2. Subsequent oxidation generates a cationic intermediate which undergoes nucleophilic attack to generate the coupled products.

O

O R

OH

CuI (20 mol%) DMAP (50 mol%) DMSO, 110°C, air

O R

O

14 examples 35-90 % yields

O Scheme 126 Cu-catalyzed aerobic CdH acylation.

13.03.4.3 Other catalysts for dehydrogenative coupling reactions 13.03.4.3.1

Alkene and alkyne oxidation and oxidative coupling

Han and co-workers developed a Wacker-type oxidation of alkenes to ketones using an iron catalyst and ambient air.391,392 The optimized system uses 10 mol% FeCl2 and polymethylhydroxosiloxane (PMHS, 3 equiv) as a reductant in ethanol at 80  C under an air atmosphere and oxidizes internal alkenes with exceptional functional-group tolerance (Scheme 127). Alkenes bearing boronic acids, silanes, alcohols, aldehydes, esters, acids and halides were all converted to the corresponding ketones in good to excellent yields. The reaction was also applied to the late-stage oxidation of natural products and pharmaceutically relevant structures with quinine, steroid, and carbohydrate scaffolds. The authors proposed a reaction pathway involving insertion of the alkene to an FeIII-hydride species. The resulting Fe-alkyl intermediate reacts with O2 to form an alkyl radical, which is oxygenated to form the ketone product. This type of pathway is quite different from those of Pd and Cu catalysts which have discrete product oxidation and catalyst reoxidation steps. Here, Fe and O2 act in concert to enable substrate oxidation while turnover is achieved by reduction of an FeIII-OH species with silane.

124

Metal-Catalyzed Aerobic Oxidation Reactions

F

R1

Fe catalyst reductant air or O2

R2

O R2

R1

FeCl2 (10 mol%) PMHS (3 equiv) EtOH, rt - 80 °C, air 41 examples 31-95 % yields

FePcF16 (5 mol%) Et3SiH (2 equiv) EtOH, rt, O2 (1 atm) 17 examples 30-95 % yields

F

F

F

F

F

N F

N

Fe N

N

F

F

N

N N

F

N

F F

F

F

F F

FePcF16

Scheme 127 Fe-catalyzed oxidation of alkenes to yield ketones.

Knölker and co-worker393 developed a related conversion of alkenes to ketones with good functional group tolerance using a hexadecafluorinated iron-phthalocyanine complex and stoichiometric amounts of triethylsilane (Et3SiH) under an oxygen atmosphere at room temperature (Scheme 127). The use of Et3SiD as the reductant formed the deuterium-incorporated ketone in 97% yield and no product was formed in the absence of oxygen. The group proposed a mechanism similar to that described by Han and co-workers391,392 in which the alkene reacts with an FeIII-hydride intermediate to form an Fe-alkyl species that reacts with O2 via a radical pathway to form the ketone. In 2019, Han and co-workers394 developed a nickel-catalyzed Wacker-type oxidation featuring a chain-walking mechanism to form aromatic ketones from remote alkenes under ambient air using PMHS as a hydride source (Scheme 128). The reaction tolerates a broad scope of functionality including halogens, cyano groups and trifluoromethyl substitution. The method was also applied to the late-stage modification of steroid and glucoside derivatives. The authors propose that the reaction proceeds under the formation of a Ni-hydride species that undergoes hydrometallation and b-elimination in a chain-walking process until the benzylic Ni-alkyl species is formed. Reaction of this intermediate with O2 generates the thermodynamically favored benzyl radical which reacts with a Ni-peroxo species to form the ketone. The authors were able to verify the benzyl radical with inclusion of galvinoxyl and the detection of the corresponding galvinoxyl adduct through ESI-MS. Furthermore, when the reaction was conducted under nitrogen the internal intermediates arising from the chain-walking sequence were detected.

n

R

FG

NiBr2 (5 mol%) neocuproine (6 mol%) PMHS (3 equiv.), rt EtOH, air

O n

R

FG

36 examples 60-96% yields

Scheme 128 Ni-catalyzed oxidation of internal alkenes to yield ketones.

More recently, the Gunnoe group explored the Rh-catalyzed aerobic alkenylation of arenes using either copper co-oxidants (Scheme 129)395 or O2-only conditions (Scheme 130).396 A broader scope of styrenes and arenes could be coupled under the Cu-containing conditions. These conditions employ [Rh(m-OAc)(Z2-C2H4)2]2 as the catalyst and the authors speculated that the acetate group might facilitate CdH activation via a concerted metalation deprotonation (CMD) mechanism. Under the O2-only conditions, RhCl3
3H2O is used as the catalyst to couple ethylene with arenes to yield styrenes. Here, kinetic studies showed a first order dependence on pO2 indicating a kinetically relevant oxidation step. In the proposed catalytic cycle, benzene activation proceeds through a CMD step followed by ethylene insertion and b-hydride elimination. The rate-limiting oxidation step involves a Rh-hydroperoxide intermediate that is protonated to regenerate the rhodium catalyst with the formation of hydrogen peroxide. These O2-only conditions show reduced linear:branched selectivity with substituted alkenes as compared to the Cu-containing conditions, which is explained through the reaction kinetics. The rate-limiting reoxidation allows for alkene isomerization to occur prior to oxidation, while when Cu is present, the oxidation step is rapid and alkene insertion become turnover-limiting providing a linear:branched selectivity that arises from the selectivity of the insertion step.

R

+

Ar

[Rh( μ-OAc)( η2-C2H4) 2]2 (0.25 mol%) Cu(OPiv) (160 equiv), HOPiv (800 equiv) air (15 psig), N2 (60 psig), 165 °C

R

Ar 44 examples 21-91% yields

Scheme 129 Rh-catalyzed aerobic oxidative coupling of arenes with alkenes.

+

RhCl 3•3H2O (0.112 mM) AcOH (1 mL), 150 °C, air (1 atm) 1,031 turnovers

Scheme 130 Rh-catalyzed oxidative coupling of benzene and ethylene under air.

Metal-Catalyzed Aerobic Oxidation Reactions

13.03.4.3.2

125

Arene coupling

In 2010, Katsuki and co-workers reported the enantioselective cross-coupling of naphthols catalyzed by chiral Fe-salan complexes at 60  C under an air atmosphere (Scheme 131).397 Electronic differentiation of the two naphthols is required to favor the cross-coupled product over the homocoupled product. The reaction begins with the formation of Fe-naphtholate intermediates, followed by oxidation. Here, oxidation is favored for the more electron-rich of the two naphtholate complexes. Then the more acidic naphthol binds and coupling follows to generate the resulting cross-coupled product.

Ph EDG OH +

EDG 4 mol% [Fe(μ-OH) 2(sa lan) 2]

OH OH

toluene, air, 60 °C

OH

Ph

NH HN 13 examples 36-70% yields 60 - 95% ee

O O PhPh

EWG

EWG

salan Scheme 131 Fe-salan catalyzed enantioselective cross-coupling of naphthols.

Following the development of the iron- and copper-catalyzed372 couplings of naphthols, Kozlowski and co-workers investigated the asymmetric oxidative coupling of phenols, dihydroxyarenes, and 2-hydroxycarbazoles catalyzed by vanadium.398 The authors reported a thorough optimization of the vanadium complex in terms of conversion, oxidizing power, regioselectivity and enantioselectivity, ultimately using a monomeric VV-oxo complex (Scheme 132). Mechanistic studies indicate a radical process with the active VV species exhibiting a VV/VIV redox couple. A non-linear effect of the enantiomeric excess of the product in relation to the enantiomeric excess of the catalyst supported the formation of a dimeric cluster during the reaction. The inclusion of acetic acid accelerates the reaction due to the formation of an active acetate-bridged dimer. DFT studies using a truncated catalyst system identified the CdC bond formation as the rate-limiting step with selectivity arising from greater torsional strain in the transition structure corresponding to the minor enantiomer.

V catalyst (20 mol%)

R OH

R OH

toluene, O 2, 60 °C

OH

16 examples 12-100% yields 0-99% ee

O2N

R

tBu N O O O V O tBu OMe V catalyst

Scheme 132 V-catalyzed enantioselective oxidative homocoupling of phenols.

More recently, Pappo and co-workers have designed a Co-salen catalyst system that enables the selective cross-coupling of naphthols with phenols at room temperature under open air conditions in HFIP solvent (Scheme 133).399 The selectivity of the system arises from a reaction pathway similar to that observed in the Fe systems described above in which the more electron-rich naphthol first coordinates to cobalt, and then undergoes coupling with a phenoxyl radical to form the coupled product.

Ph R

OH

+ MeO

Co-salen (1 mol%]) air, HFIP, rt OH

R

MeO

Ph

N

19 examples Br OH 40-89% yields OH

N CoII O O tBu

Br

tBu

Co-salen

Scheme 133 Co-salen-catalyzed cross-coupling of naphthols with phenols.

13.03.5 Conclusions In summary, we have highlighted the recent advances in the transition-metal catalyzed aerobic oxidation reactions of organic molecules. In general, the field has been dominated by Pd and Cu catalysts. Mechanistic insight into the roles of ligands and additives has provided a framework for the development of catalytic methods that show high reactivity and selectivity. The field is currently experiencing a shift toward the use of first-row transition-metal catalysts and a similar mechanistic understanding will likely be important to guide the development of these catalyst systems.

126

Metal-Catalyzed Aerobic Oxidation Reactions

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13.04 Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics Lucas J Oxtoby, Alena M Vasquez, Taeho Kang, Zi-Qi Li, and Keary M Engle, Department of Chemistry, The Scripps Research Institute, La Jolla, CA, United States © 2022 Elsevier Ltd. All rights reserved.

13.04.1 13.04.2 13.04.2.1 13.04.2.2 13.04.2.3 13.04.2.4 13.04.2.5 13.04.3 13.04.3.1 13.04.3.2 13.04.3.3 13.04.3.4 13.04.3.5 13.04.4 13.04.4.1 13.04.4.2 13.04.4.3 13.04.4.4 13.04.4.5 13.04.4.5.1 13.04.4.5.2 13.04.5 13.04.5.1 13.04.5.2 13.04.5.3 13.04.5.4 13.04.6 13.04.6.1 13.04.6.1.1 13.04.6.1.2 13.04.6.1.3 13.04.6.1.4 13.04.6.1.5 13.04.6.1.6 13.04.6.1.7 13.04.6.1.8 13.04.6.2 13.04.6.2.1 13.04.6.2.2 13.04.6.2.3 13.04.6.2.4 13.04.6.3 13.04.6.3.1 13.04.6.3.2 13.04.7 13.04.7.1 13.04.7.2 13.04.7.3 13.04.7.4 13.04.8 13.04.8.1 13.04.8.2 13.04.8.3

132

Introduction Dicarbofunctionalization Overview Dicarbofunctionalization of alkynes Dicarbofunctionalization of allenes Dicarbofunctionalization of 1,3-dienes Dicarbofunctionalization of alkenes Diamination Overview Diamination of alkenes Diamination of 1,3-dienes Diamination of alkynes Diamination of allenes Dioxygenation Overview Alkyne dioxygenation Dioxygenation of allenes Dioxygenation of 1,3-dienes Dioxygenation of alkenes Syn-dioxygenation of alkenes Anti-dioxygenation of alkenes Homo/heterodihalogenation reactions Overview Homo/heterodihalogenation of alkenes Homo/heterodihalogenation of allenes Homo/heterodihalogenation of alkynes Aminooxygenation Aminooxygenation of alkenes Palladium-catalyzed Rhodium-catalyzed Copper-catalyzed Platinum-catalyzed Iron-catalyzed Gold-catalyzed Manganese-catalyzed Iridium-catalyzed Aminooxygenation of alkynes Ruthenium-catalyzed Gold-catalyzed Copper-catalyzed Iron-catalyzed Aminooxygenation of allenes Rhodium-catalyzed Copper-mediated Carboamination Carboamination of alkynes Carboamination of allenes Carboamination of 1,3-butadienes Carboamination of alkenes Carbohalogenation Carbohalogenation via reductive elimination from Pd(II) Carbohalogenation via reductive elimination from high valent metals Carbohalogenation via nickel catalysis

Comprehensive Organometallic Chemistry IV

133 134 134 134 135 136 138 140 140 140 144 145 146 146 146 147 152 152 153 153 159 160 160 161 163 163 163 163 164 165 165 168 168 169 169 169 169 169 170 170 171 171 171 172 172 172 173 174 175 177 177 179 181

https://doi.org/10.1016/B978-0-12-820206-7.00096-2

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.9 Aminohalogenation 13.04.9.1 Aminohalogenation via palladium catalysis 13.04.9.2 Iron-catalyzed aminohalogenation 13.04.9.3 Aminohalogenation via gold catalysis 13.04.9.4 Aminohalogenation via high-valent copper catalysis 13.04.10 Oxyhalogenation 13.04.11 Carbooxygenation 13.04.11.1 Palladium-catalyzed 13.04.11.2 Gold-catalyzed 13.04.12 Conclusion and outlook Acknowledgment References

133

182 182 184 185 185 185 186 186 187 187 187 187

13.04.1 Introduction The difunctionalization of unsaturated organics is a powerful bond-forming strategy in organic chemistry. Installing combinations of amino-, oxo-, carbo-, and halo-groups across a carbon–carbon double or triple bond allows for rapid build-up of molecular complexity in an expedient manner. To accomplish this, transition-metal catalysis has often been employed as it enables the transformations to proceed in a highly selective and efficient fashion. A brief overview of the contents covered in this chapter is given here. In some instances, the reader is directed to reviews on topics that have been previously covered elsewhere. This chapter focuses on reactions of the general type depicted in Fig. 1, where the transition metal mediates the addition of the “X” and “Y” coupling partners across a double or triple bond. Reactions in which the transition metal plays an ancillary role (not adding across or binding to the unsaturated species), such as simply generating an initial radical species, are not covered. Additionally, reactions involving the addition of a single atom, including cyclopropanation, epoxidation, and aziridination, have been reviewed elsewhere1–3 and are not covered in this chapter except for instances involving a tandem process that results in net difunctionalization. The scope of transition metal catalysts and coupling partners that are covered within is depicted in Fig. 2. While different selectivity challenges are present for different types of substrates (alkenes vs. dienes vs. allenes vs. alkynes), some general strategies frequently arise across substrate and coupling partner classes. These include, but are not limited to, the examples depicted in Fig. 3.

Fig. 1 Overview of reaction types covered in this chapter.

Fig. 2 Heatmap of metals and coupling partners covered in this review.

134

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mechanism-based strategies covered in this chapter [M]

DG

[M]

R

[M]

R

[M] X substrate hapticity

X directing group coordination

[M]

X

L L

R' ligand design

X radicalrebound

X

R intramolecular tethering

Fig. 3 Overview of mechanism-based strategies covered in this chapter.

Given the expansive scope of the topic, the material in this chapter is not intended to be comprehensive in nature; instead, the chapter is written with the goal of showcasing a general landscape of the topics covered within. Representative examples have been chosen in order to highlight the state of the art and draw attention to outstanding challenges and limitations of current methods.

13.04.2 Dicarbofunctionalization 13.04.2.1 Overview Dicarbofunctionalization of unsaturated organics is a powerful strategy for forming multiple CdC bonds, the most common skeletal linkages in organic molecules, in a single operation.4,5 Inspired by classical transition-metal-catalyzed cross-coupling reactions, various two- and three-component reactions that install two different carbogenic groups across alkynes, allenes, 1,3-dienes, and alkenes have been developed using different transition metal catalysts and coupling partners. This section will focus primarily on dicarbofunctionalization reactions in which the transition metal is directly involved in the carbon–carbon bond-forming step(s). Systems where the transition metal acts as a Lewis acid to promote conjugate additions, cycloadditions, or related reactions have been covered elsewhere and will not be discussed here.6

13.04.2.2 Dicarbofunctionalization of alkynes Early research on transition-metal-catalyzed dicarbofunctionalization focused on two-component reactions, including those where intramolecular cyclization enables control of chemo- and regioselectivity. As a representative example, in 1989 Grigg developed a regioselective alkyne dicarbofunctionalization system in which an aryl iodide substrate containing a tethered alkyne reacts with an organozinc/tin reagent under palladium catalysis (Eqs. 1 and 2).7,8 The reaction mechanism involves oxidative addition of the palladium(0) catalyst to the C(aryl)dI bond followed by intramolecular 1,2-migratory insertion. The thusly generated alkenylpalladium(II) intermediate undergoes transmetalation with the organometallic nucleophile, and finally reductive elimination gives the desired product.

ð1Þ

ð2Þ

The first example of transition-metal-catalyzed three-component dicarbofunctionalization of alkynes was described by Larock in 2003.9,10 The Pd-catalyzed dicarbofunctionalization of alkynes proceeds in the presence of an arylboronic acid, an alkenyl/aryl iodide, and base, giving the corresponding tetrasubstituted olefins in a regio- and stereoselective manner (Fig. 4). The proposed catalytic cycle involves oxidative addition of the aryl iodide to palladium(0) to furnish a Pd(II)dAr intermediate, Heck-type syn-migratory insertion of the alkyne, transmetalation of the arylboronic acid, and reductive elimination. The regio- and stereoselectivity are determined in the syn-migratory insertion step, in which the aryl group preferentially adds to the less hindered and/or more electron-rich carbon of the alkyne. Beyond arylboronic acids, electron-deficient alkenes or styrenes can function as coupling partners and generate 1,3-butadiene products via a Heck-like manifold (Eq. 3).11,12 In addition, nickel-catalyzed alkyne dicarbofunctionalization using aryl Grignard reagents and aryl halides was studied, with the proposed mechanism involving rapid insertion of the Grignard reagents into the alkyne followed by cross-coupling of the in situ generated alkenyl–metal intermediate with an aryl–nickel species (Eq. 4).13

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

135

Fig. 4 Proposed mechanism for palladium-catalyzed three-component dicarbofunctionalization of alkynes. Adapted from Zhou, C. X.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5(9), 1579–1582.

ð3Þ

ð4Þ

More recently, three-component reactions using terminal alkynes and alkyl halide electrophiles under palladium or nickel catalysis have been reported (Eq. 5).14,15 Various mechanistic experiments shed light on the radical-based mechanism initiated by the corresponding transition metal catalyst prior to cross-coupling of the alkenylmetal species with arylboronic acid.

ð5Þ Recently, Morandi and coworkers reported the first example of intermolecular carboformylation (Eq. 6).16 Using aryl chlorides as both a carbon electrophile and CO source in tandem with hydrosilane and a palladium catalyst, a variety of alkynes readily undergo stereoselective carboformylation. The authors additionally report an extension of the reaction to the chemodivergent formation of three other carbonyl derivatives (forming the corresponding hydroformylation, carboacylation, and hydroacylation products).

ð6Þ

13.04.2.3 Dicarbofunctionalization of allenes The initial example of dicarbofunctionalization of allenes was also reported by Grigg.17,18 Applying the same concept described above for the tethered alkyne, 1,2-dicarbofunctionalization of an aryl iodide substrate tethered allenes was developed using arylboron reagents under palladium catalysis (Eq. 7).

136

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Fig. 5 Proposed mechanism for palladium-catalyzed three-component dicarbofunctionalization of allenes. Adapted from Huang, T. H.; Chang, H. M.; Wu, M. Y.; Cheng, C. H. J. Org. Chem. 2002, 67(1), 99–105.

ð7Þ

The Pd-catalyzed three-component reaction of an allene, an aryl/alkenyl halide, and an arylboronic acid was reported in 2002.19 The organopalladium intermediate generated upon oxidative addition of the organohalide to the Pd(0) catalyst can rapidly insert into the allene to give a p-allylpalladium intermediate (Fig. 5). The p-allylpalladium complex is resistant to b-hydride elimination and reacts as an electrophile with the arylboronic acid nucleophile. The E-isomer was observed as the major product, and its formation was rationalized by faster transmetalation/reductive elimination steps compared to cis/trans-isomerization of the p-allylpalladium species. Indeed, the E/Z ratio of the product decreased when s-donor phosphorus ligands that promote cis/trans isomerization were added. A similar transformation using nickel catalyst and zirconium nucleophile has also been demonstrated.20 As mentioned above, the allyl moiety of a p-allylpalladium complex is generally electrophilic, but it can be converted into a nucleophile via small modifications to the reaction conditions. In one approach, the p-allypalladium complexes can undergo transmetalation with electropositive indium to give nucleophilic allylindium species which can further react with aldehydes or imines (Eq. 8).21,22 In a second approach, strong s-donor ligands such as tri(tert-butyl)phosphine can donate electron density to the metal to such an extent that the p-allylpalladium complex is rendered nucleophilic and is able to engage carbonyl or imine electrophiles (Eq. 9).23

ð8Þ

ð9Þ

13.04.2.4 Dicarbofunctionalization of 1,3-dienes 1,3-Diene substrates offer advantages in dicarbofunctionalization compared with nonconjugated alkenes since the initial CdC bond-forming step generates a versatile, stabilized p-allylmetal intermediate. By taking advantage of this phenomenon, Larock developed two-component annulation reactions between ambiphilic aryl iodides containing a tethered malonate nucleophile and various 1,3-dienes (Eqs. 10 and 11).24,25 The proposed mechanism involves intermolecular 1,2-migratory insertion of an arylpalladium(II) species followed by intramolecular Tsuji–Trost-type addition of the carbon nucleophile to the p-allylpalladium intermediate.

ð10Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

137

ð11Þ

In 2003, the first cobalt-catalyzed three-component dicarbofunctionalization reaction of 1,3-dienes was reported (Eq. 12).26 An alkyl halide and a silylmethylmagnesium chloride Grignard reagent were used as coupling partners, and the use of 1,6-bis (diphenylphosphino)hexane (dpph) as a ligand on cobalt was essential for the reaction. Mechanistic studies were consistent with a pathway in which an alkyl radical is generated by single-electron transfer from low-valent cobalt to the alkyl halide. Next, the alkyl radical adds to the 1,3-diene to furnish an allyl radical that recombines with the cobalt catalyst to give a p-allylcobalt intermediate. Transmetalation and reductive elimination then yield the 1,2-carbodifunctionalizated product. Only one year later, a threecomponent coupling reaction involving a similar combination of reagents under nickel catalysis was reported (Eq. 13).27 Several control experiments support an open-shell mechanism, analogous to the cobalt-catalyzed reaction; however, in this case with nickel as the catalyst 1,4-difunctionalizated products were obtained.

ð12Þ

ð13Þ

More recently, palladium-catalyzed three-component dicarbofunctionalization reactions of 1,3-dienes using alkenyl triflates and arylboronic acids have been demonstrated by Sigman (Fig. 6).28,29 Alkenyl triflates were selected specifically to facilitate Heck-type insertion into the 1,3-diene rather than the common and otherwise facile Suzuki–Miyaura coupling process. In addition, undesired b-hydride elimination is suppressed by the formation of the relatively stable p-allylpalladium intermediate. Indeed, the authors found that use of a terminal alkene in place of the 1,3-diene results in formation of 1,1-disubstituted products, which presumably arise from a sequence of migratory insertion of the alkenylpalladium species, rapid b-hydride elimination, re-insertion to generate a p-allyl species, transmetalation, and reductive elimination. In 2014, diarylation of 1,3-dienes using aryldiazonium electrophiles was achieved (Eq. 14).30,31 ð14Þ Enantioselective palladium-catalyzed 1,2-dicarbofunctionalization of 1,3-dienes was reported in 2015 (Eq. 15).31,32 A chiral phosphoramidite ligand was found to be optimal in terms of yield and enantioselectivity. With aryl iodides as the electrophilic component and sodium malonates as the nucleophilic component, the reaction proceeds via Heck-type insertion of an arylpalladium species, followed by asymmetric allylic alkylation.

ð15Þ

R OTf

+

+

R'

Ar

B(OH)2

Pd2(dba)3 (3 mol%)

Ar R

R' 1,2-product

(R = alkenyl)

R OTf

+

+

Ar

B(OH)2

Pd2(dba)3 (3 mol%)

R

Ar 1,4-product

(R = alkenyl)

Fig. 6 1,2-difunctionalization vs. 1,4-difunctionalization selectivity in the palladium-catalyzed reaction of dienes. Adapted from Liao, L. Y.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133(15), 5784–5787.

138

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.2.5 Dicarbofunctionalization of alkenes Despite the many successes described above in developing dicarbofunctionalization reactions of alkynes, allenes, and 1,3-dienes, analogous reactions with simple alkenes are comparatively more challenging for several interrelated reasons. First, the rate of the migratory insertion step with alkenes is slower than with alkynes and allenes due to their weaker coordination affinity with transition metals. In addition, b-hydride elimination of the alkylmetal intermediate that is generated upon migratory insertion into the alkene is fast compared with b-hydride elimination from a p-allylmetal species formed from allenes or dienes. For these reasons, early examples of dicarbofunctionalization of alkenes generally employed electronically activated conjugated alkenes, such as styrenes or acrylates, or substrates in which one of the coupling partners is intramolecularly tethered to the alkene. Based on Grigg’s initial achievement using an alkene tethered to the aryl iodide under palladium catalysis (Eq. 16), many different two-component dicarbofunctionalization reactions have been developed using various combinations of coupling partners and transition metals.17,32–34 Such reaction have even been rendered enantioselective through use of an appropriate chiral ligand. For example, Fu reported asymmetric coupling between an arylboron nucleophile containing a tethered alkene and an alkyl halide (Eq. 17).35

ð16Þ

ð17Þ

In 2016, Baran reported one of the first examples of 1,2-dicarbofunctionalization of alkenes under nickel catalysis, in which a tertiary redox-active ester (an alkyl radical precursor) and a phenylzinc reagent are added across an acrylate (Eq. 18).36 Mechanistically, a tertiary alkyl radical is generated via single-electron transfer from an in situ generated phenylnickel(I) species to the redox-active ester, followed by decarboxylation. This tertiary radical adds to the b-position of benzyl acrylate in a Giese-type fashion. The resulting a-carbon-centered radial recombines with the phenylnickel(II) species, and reductive elimination from the Ni(III)(Ph) (Alkyl) intermediate gives the 1,2-dicarbofunctionalized product. Using similar conjugated alkenes containing electronwithdrawing groups as well as allyl alcohol derivatives, Nevado demonstrated reductive 1,2-arylalkylation reaction with a nickel catalyst (Eq. 19).37 A tertiary alkyl iodide was employed as a radical precursor and tetrakis(dimethylamino)ethylene (TDAE) was used as a reductant to turnover the catalytic cycle. More recently, Nevado further extended the substrate scope to unactivated alkenes through tuning the reaction conditions (Eq. 20).38

ð18Þ

ð19Þ

ð20Þ

Palladium-catalyzed 1,2-dicarbofunctionalization of styrenes was reported in 2017 (Eq. 21). Using a similar approach to the aforementioned 1,3-diene chemistry, alkenyl triflates and arylboronic acids could be used as coupling partners to functionalize a wide range of styrenes.39 In 2018, Giri and Brown reported 1,2-dicarbofunctionalization reactions of styrenes under nickel catalysis.40,41 Giri employed tertiary alkyl halides and arylzinc reagents for 1,2-alkylarylation of styrenes (Eq. 22). Mechanistic experiments showed that excess arylzinc reagent reduces the Ni(II) precatalyst to Ni(0) to initiate the reaction. Brown demonstrated a 1,2-diarylation of terminal or internal styrenes using aryl bromides and arylboronic esters (Eq. 23). B2pin2 was used for the reduction of Ni(II) to Ni(0), and a syn-migratory insertion mechanism was supported by the generation of a single diastereomer when internal alkenes were used as substrates.

139

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð21Þ

ð22Þ

ð23Þ Radical-type copper-catalyzed 1,2-dicarbofunctionalization of styrenes has also been extensively studied.42–45 In terms of representative examples, Liu reported enantioselective trifluoromethylcyanation and trifluoromethylarylation reactions under copper catalysis (Eqs. 24 and 25).42,43 In both reactions, Togni’s electrophilic trifluoromethylating reagent was employed as the trifluoromethyl radical source, and chiral bisoxazoline ligands were used to achieve stereoinduction in the radical trapping process. TMSCN and arylboronic acid served as nucleophilic coupling partners to give trifluoromethylcyanated and trifluoromethylarylated products, respectively.

ð24Þ

ð25Þ

For non-conjugated alkenes, directing group strategies have been employed to control regio- and diastereoselectivity as well as suppress undesired b-hydride elimination. In 2016, Engle reported a palladium-catalyzed dicarbofunctionalization of non-conjugated alkenes using an 8-aminoquinoline directing group (Eq. 26).46 This strongly coordinating directing group stabilizes the putative nucleopalladated intermediate and enables dicarbofunctionalization with aryl/alkenyl iodides via a Pd(II)/Pd(IV) cycle. Using the same directing group, nickel-catalyzed 1,2-diarylation and 1,2-dialkylation reactions have been reported using organohalides and organozinc reagents.47,48 In 2018, Giri demonstrated that an imine could direct 1,2-diarylation under nickel catalysis; after acidic workup, the corresponding diarylated ketone products were obtained (Eq. 27).49 In the same year, Zhao reported nickel-catalyzed dicarbofunctionalization reaction using the 2-aminopyrimidine directing group (Eq. 28).50 Interestingly, the regioselectivity of the reaction depended on the electrophile employed. Specifically, use of an aryl iodide electrophile exclusively delivered the 1,3-difunctionalized product, whereas alkenyl and alkynyl bromides gave 1,2-difunctionalized product with the opposite regioselectivity. Zhao propose that the origin of these reactivity patterns is faster b-hydride elimination and reinsertion steps for aryl electrophiles, which results in 1,3-difunctionalized products. In addition, Zhao proposes that lower migratory insertion rates of alkynylnickel species compared with arylnickel species results in the inversed 2,1-difunctionalized product in the case of alkyl bromide electrophiles. O O

N

N H

R

O

Pd(OAc)2 (5 mol%) +

R''

X

+

R'

H K2CO3

R'' = aryl, alkenyl, alkynyl X = Br or I

carbon nucleophile

N

N H

R'' R R'

via:

N N

Pd L R

ð26Þ

ð27Þ

140

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð28Þ In 2018, Engle developed a 1,2-diarylation reaction of non-conjugated alkenes containing native monodentate amide functional groups instead of the previously employed bidentate 8-aminoquinoline directing auxiliary (Eq. 29).51 Using a nickel(0) precatalyst in conjunction with an electron-deficient olefin ligand (dimethyl fumarate (dmfu)), aryl iodides and arylboronic esters could be incorporated. Experimental and computational studies revealed that the dmfu ligand accelerates the reductive elimination step. Using this native directing group strategy, carboxylic acids, N-heterocycles, and sulfonamides could be employed in various dicarbofunctionalization reactions.52–54

ð29Þ Directing group strategies have also been leveraged in enantioselective three-component dicarbofunctionalization reactions of non-conjugated alkenes involving addition of C-centered radicals and enantioselective radical capture.55–58 For example, Chu reported reductive, asymmetric 1,2-alkylarylation reactions of non-conjugated alkenyl esters using a nickel catalyst and a chiral bisoxazoline (BiOx) ligand (Eq. 30). Control experiments pointed to a radical-based reaction mechanism and the essential role of the ester directing group for high yields and enantioselectivity.

ð30Þ

13.04.3 Diamination 13.04.3.1 Overview Vicinal diamines are important substructures found in a variety of biologically active molecules, including the penicillins (a well-known type of antibiotic), eloxatin (an anti-cancer drug), and biotin (also known as vitamin H or vitamin B7). However, unlike the analogous dihydroxylation and aminohydroxylation reactions, 1,2-diamination reactions of CdC p-bonds are far less established.59 Several mechanistically distinct approaches have been pursued towards this challenging transformation. Early reports by Barluenga and co-workers showed that thallium60 and mercury61,62 can promote alkene diamination with aniline as the nitrogen source. Diamination using bis-imido-osmium was reported in 1977 in analogy to the reactivity of OsO4 (as exemplified in the Sharpless dihydroxylation).63 A nucleometalation/oxidation/reductive elimination approach has also been developed, using a combination of a palladium catalysts and stoichiometric oxidant. Related radical-based pathways have been developed, primarily using copper catalysts. Rhodium–nitrenoid-mediated aziridine formation, followed by nucleophilic ring opening is another useful method of generating vicinal diamines in a stereospecific fashion. In general, unimolecular diamination and two-component reactions between an alkene/yne and a suitable diamine reagent have been the most extensively studied, while fully intermolecular (three-component) reactions remain scarce.

13.04.3.2 Diamination of alkenes The 1,2-diamination of alkenes using a stoichiometric bis-imido-osmium reagent was reported by the Sharpless group in 1977.59 Both electronic and steric variables affect the relative reactivity of alkenes with activated alkenes, such as fumarates, being the most reactive substrates, while (Z)-internal alkenes and trisubstituted alkenes are least reactive. The first diastereoselective osmiummediated diamination was achieved by using an a,b-unsaturated ester substrate bearing a menthol-derived auxiliary (Fig. 7).64,65 Later on, the same group reported the chiral-Lewis-acid-assisted asymmetric diamination of acrylamides bearing an oxazolidinone group. A Ti-TADDOL complex was found to be the most effective for promoting the reaction (Eq. 31).66,67 Although catalytic versions of both osmium-catalyzed dihydroxylation and aminooxygenation have been achieved, the catalytic diamination of alkenes with osmium has not yet been developed.68

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

141

Fig. 7 1,2-diamination of alkenes using a stoichiometric bis-imido-osmium reagent. Adapted from Chong, A. O.; Oshima, K.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99(10), 3420–3426; Muniz, K.; Nieger, M. Synlett 2003, (2), 211–214; Muniz, K.; Nieger, M.; Mansikkamaki, H. Angew. Chem. Int. Ed. 2003, 42(48), 5958–5961.

ð31Þ

Palladium-catalyzed intramolecular diamination of alkenes with a tethered diurea motif was achieved in 2005 by Muñiz and co-workers (Eq. 32).69 Detailed mechanistic studies led the authors to propose the formation of a Pd(IV) intermediate resulting from a syn-aminopalladation/oxidation sequence (Fig. 8).70,71 A analogous transformation using a guanidine moiety was achieved using a more practical copper-based oxidant (Eq. 33).72,73

ð32Þ

ð33Þ

Interestingly, with an alkenyl sulfamide substrate, use of a palladium catalyst only offered the corresponding aminooxygenated product, while a nickel catalyst led to the diaminated product (Eq. 34).74 When an electrophilic nitrogen source (NFSI) was used as oxidant, two-component diamination was observed.75–77 Using a chiral quinox ligand, Michael and co-workers were able to render this transformation highly enantioselective (Eq. 35).78 In their efforts to generalize this transformation to a three-component 1,2-diamination with unactivated alkenes, Muñiz and co-workers found that saccharin79,80 and phathalimide81 could serve as privileged nucleophiles under the action of a palladium catalyst and the proper oxidants.

Fig. 8 Proposed mechanism for palladium-catalyzed intramolecular diamination of alkenes with a tethered diurea.

142

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð34Þ

ð35Þ

Intermolecular diamination of olefins via NdN bond activation of di-tert-butyldiaziridinone and derivatives thereof has been achieved using palladium and copper catalysts.82 A wide variety of imidazolindinones, cyclic guanidines, cyclic sulfonamides, imidazolinones and indolines can be obtained. Mechanistically speaking, palladium-catalyzed reactions are likely initiated by the oxidative addition of Pd(0) to the NdN bond, giving a four-membered Pd(II) intermediate. With Cu(I) catalysts, on the other hand, after oxidative addition, there is likely a rapid interconversion between the four-membered Cu(III) species and the Cu(II) nitrogen-centered radical species. Palladium-catalyzed diamination of terminal alkenes using di-tert-butyldiaziridinone occurred at the allylic and homoallylic CdH sites rather than at the alkene.83 An asymmetric version of this reaction was achieved using a phosphoramidite ligand (Fig. 9, right)84 It is likely that the reaction proceeds through an in situ-generated 1,3-diene intermediate. Interestingly, when di-tert-butylthiadiaziridine 1,1-dioxide was used as the nitrogen source, a dehydrogenative diamination took place at the terminal position (Fig. 9, left).85

ð36Þ

ð37Þ

ð38Þ

A sequential diamination/dehydrogenation process was observed when monosubstituted olefins were treated with di-tertbutyldiaziridinone under copper catalysis (Eq. 36).86 When 1,1-disubstituted olefins were tested, dehydrogenation was not observed.87 Similarly, when monosubstituted olefins were treated with diamine reagents in the presence of a copper catalyst, cyclic sulfamides (Eq. 37) and guanidines (Eq. 38) were obtained in good yields.88,89

ð39Þ

Fig. 9 Selectivity in the palladium-catalyzed diamination of terminal alkenes. Adapted from Du, H. F.; Zhao, B. G.; Shi, Y. J. Am. Chem. Soc. 2008, 130(27), 8590; Wang, B.; Du, H. F.; Shi, Y. Angew. Chem. Int. Ed. 2008, 47(43), 8224–8227.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

143

ð40Þ

ð41Þ

ð42Þ

ð43Þ

In addition to the examples above that rely on two-electron pathways, various radical-based approaches to diamination have also been developed using transition metal catalysts. Nitrogen-centered radicals readily undergo 5-exo-trig cyclization onto a pendant alkene giving a primary carbon-centered radical that can then be trapped by another nitrogen reagent, giving the corresponding diaminated product. The formation of a copper(III) intermediate was proposed to be a crucial step in the catalytic cycle. Well studied nitrogen-centered radical precursors include oximes (Eq. 39),90 oxime esters (Eq. 40),91 carbamates (Eq. 41),92 and ketohydrozones (Eq. 42).93 Using azidoiodinane94 or NdO reagent95 as trapping reagent, Wang and co-workers achieved diamination via aminocyclization under copper catalysis (Eq. 43).

ð44Þ

ð45Þ

ð46Þ

ð47Þ

Azido groups are versatile amine precursors that possess diverse reactivity. As such, alkene diazidation reactions have received significant attention. Using azidoiodine(III) compounds, the Greaney96 and Loh groups97 independently developed coppercatalyzed methods for 1,2-diazidation of styrenes (Eq. 44). Using an iron catalyst bearing a tridentate PyBOX ligand, Xu and co-workers extended alkene diazidation to a broader scope of alkenes, including aliphatic alkenes and 1,3-dienes (Eq. 45).98,99 An enantioselective synthesis of Oseltamivir Phosphate (Tamiflu) was achieved via this approach.100 Using TMSN3 as the azide source,

144

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Bao and co-workers developed a copper-catalyzed ligand-free 1,2-diazidation reaction under aqueous conditions (Eq. 46).101 A manganese-catalyzed electrochemical 1,2-diazidation reaction was developed by Lin and co-workers with NaN3 as the azide source (Eq. 47).102

ð48Þ

ð49Þ

Metal–nitrenoid species react with unactivated alkenes to form aziridines, which can undergo subsequent nucleophilic ring opening with nitrogen-based nucleophiles to bring about formal diamination. Du Bois and co-workers developed a method for facile aziridination using a dirhodium-based catalyst and hypervalent iodine oxidants that react with the amine nucleophile to generate the corresponding iminoiodinane. When a bifunctional nitrogen source was used, a two-component aziridination/nucleophilic ring opening tandem process takes place (Eq. 48).103 Hydroxylamine derivatives are also effective nitrenoid precursors with various metal catalysts (Eq. 49). With an exogenous nitrogen nucleophile, a three-component diamination reaction was achieved.104 Interestingly, Rovis and co-workers reported a regiodivergent iridium-catalyzed diamination of alkenyl N-pivaloylhydroxamates, which lead to g- or d-lactams under solvent and catalyst control (Fig. 10).105

O

O

O [Cp*IrCl2]2 (2.5 mol%) NH HNRR' (1.2 eq.), HFIP NRR'

N H

OPiv

[Cp*IrCl2]2 (2.5 mol%)

NH

HNRR' (1.2 eq.), 2 M KHCO3/TFE (1:1) NRR'

Fig. 10 Regiodivergent iridium-catalyzed diamination of alkenyl N-pivaloylhydroxamates. Adapted from Conway, J. H.; Rovis, T. J. Am. Chem. Soc. 2018, 140(1), 135–138.

13.04.3.3 Diamination of 1,3-dienes

ð50Þ

ð51Þ

ð52Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

145

ð53Þ

In 2005, Lloyd-Jones and Booker-Milburn reported the diamination of 1,3-dienes with ureas under palladium(II) catalysis (Eq. 50).106 The reaction occurred at the less-substituted of the two alkenes with up to 95% regioselectivity. When R1 6¼ H, the regioselectivity varies from 77% to 90%. As introduced above, di-tert-butyldiaziridinone is highly effective for the diamination of 1,3-dienes at the internal position, as reported by Shi.107 A detailed mechanistic study based on NMR monitoring and reaction kinetics revealed that the reaction proceeds through oxidative addition of the NdN bond, migratory insertion, and subsequent CdN reductive elimination from the p-allyl palladium complex.108 An enantioselective version of the transformation was achieved using a chiral phosphoramidite ligand (Eq. 51).109 Further studies showed that an N-heterocyclic-carbene–Pd(0) complex can also catalyze this transformation, albeit with modest enantioselectivity (62–78% ee) (Eq. 52).110,111 The enantioselective synthesis of cyclic sulfamides has also been reported using a phosphoramidite ligand with products being obtained in 66–98% yield and 90–93% ee (Eq. 53).112

ð54Þ

ð55Þ

In contrast to the palladium-catalyzed reactions described above, copper-catalyzed diamination of 1,3-dienes likely proceeds through a radical mechanism. With CuCl as catalyst and P(OPh)3 as ligand, the diamination reaction with di-tertbutyldiaziridinone as the diamine source occurred at the terminal alkene (Fig. 11, right).113 An asymmetric version of this reaction was achieved in 55–93% yield and 23–74% ee with DTBM-SEGPHOS ligand (Eq. 54).114 When a chiral Cu(I) phosphate catalyst was used in combination with a tri(2-naphthyl)phosphine ligand, the same transformation was achieved in 45–77% yield and 49–61% ee (Eq. 55).115 In contrast, when CuBr was used as catalyst in chloroform solvent, reversed regioselectivity was observed, and diamination of the internal alkene took place in 81–99% yield (Fig. 11, left).116 Similarly, regiodivergent diamination of 1,3-dienes with di-tert-butylthiadiaziridine-1,1-dioxide was achieved under catalyst and ligand control.117 The change in selectivity likely arises from two distinct mechanisms involving Cu(II) or Cu(III) species.118

Fig. 11 Selectivity in copper-catalyzed diamination of 1,3-dienes. Adapted from Yuan, W. C.; Du, H. F.; Zhao, B. G.; Shi, Y. A. Org. Lett. 2007, 9(13), 2589–2591.

13.04.3.4 Diamination of alkynes

ð56Þ

146

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð57Þ

Polyheterocycles with a 3-aminoindole moiety are found in many natural products and bioactive synthetic compounds; however, traditional synthetic routes often involve multiple steps.119 A one-pot synthesis through an intramolecular diamination of alkynes is thus synthetically appealing. As an extension of to their work in the palladium-catalyzed diamination of alkenes, Muñiz group reported the first example of such transformation for alkynes (Eq. 56).120 Later on, several successful examples were reported for the synthesis of tricyclic121 and tetracyclic122–125 heterocycles (Eq. 57).

ð58Þ

ð59Þ

ð60Þ

The copper-catalyzed oxidative diamination of alkynes with various diamine coupling partners can afford a variety of azaheterocycles under aerobic conditions (Eqs. 58 and 59). Use of o-phenylenediamine, amidines, and 2-aminopyridine derivatives furnished quinoxalines,126 imidazoles,127 and imidazopyridines, respectively.128–130 The cycloaddition between alkynes and azides to furnish 1,2,3-triazoles can be viewed as an example of alkyne 1,2-diamination. While this reaction can be performed thermally, the process is not widely used due to the high temperature required and poor regioselectivity (1,4- vs. 1,5-additions). Various transition metals have been found to catalyze this process and allow for control of regioselectivity. The copper-catalyzed variant, which is 1,4-selective, has seen broad application due to its robustness, scope, and chemo-orthogonality, becoming synonymous with the concept of “click chemistry.”131 For example, in the initial disclosure by Sharpless and Fokin, the reaction between phenyl propargyl ether and benzylazide in the presence of 5 mol% sodium ascorbate in aqueous solution at room temperature furnished the 1,4-disubstituted triazole product in 91% yield (Eq. 60).

13.04.3.5 Diamination of allenes A gold-catalyzed intramolecular dihydroamination reaction of N-d- and N-g-allenyl ureas has been reported.132 The corresponding bicyclic imidazolindin-2-ones were obtained in good yield and high diastereoselectivity.

13.04.4 Dioxygenation 13.04.4.1 Overview Several transition-metal-catalyzed methods for dioxygenation of alkynes to afford 1,2-diketones have been reported. Due to the wealth of literature on stoichiometric dioxygenation using ruthenium, this chapter will only cover catalytic methods and stoichiometric examples that illustrate unique or challenging substrate classes. Similarly, representative examples of gold-catalyzed dioxygenation of alkynes are presented, but the reader is directed to a number of recent reviews on the subject for additional information.133–136 Allenes have not been extensively studied as substrates in metal-mediated dioxygenation due to the unpredictable and often unselective reaction profiles (i.e., 1,2- vs. 2,3-dioxygenation). Nevertheless, there are a few osmium-,137,138 copper-,139 and tungsten-based140 methods for dioxygenation that have been described. Palladium-catalyzed 1,4-dioxygenation of 1,3-dienes is well known, and there are a number of reviews on the subject.141,142 Osmium-based methods for syn-dioxygenation of alkenes (Fig. 12), such as the Milas dihydroxylation, the Upjohn dihydroxylation, the Sharpless asymmetric dihydroxylation, and subsequent variants, have received extensive attention and will therefore not be covered in this section. The reader is directed to a review on those topics.143

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

147

Fig. 12 Osmium-based methods for syn-dioxygenation not covered in this chapter.

13.04.4.2 Alkyne dioxygenation Manganese-mediated dioxygenation of alkynes to generate 1,2-diketones has been known since at least 1888.144 In aqueous solution, neutral or basic pH is necessary to prevent oxidative cleavage.145 To date, no catalytic methods have been developed to perform alkyne dioxygenation with manganese. To bring about the synthesis of sugar-derived 1,2-diketones, Zhao developed a one-pot method involving palladium/ copper-catalyzed Sonogashira coupling of heteroaryl iodides to sugar-containing alkynes followed by dioxygenation with permanganate.146 This protocol is tolerant of cyclic and acyclic sugars and a variety of heteroaryl iodides. Use of a tetraalkylammonium phase transfer salt allows the reaction to be performed in organic solvents (Eq. 61).

ð61Þ

Tandem decarboxylative cross-coupling/dioxygenation of alkynyl acids and arylboronic acids has been developed using Mn(III).146 This protocol is compatible with electron-rich and -poor aryl-substituted alkynylcarboxylic acids, but is not tolerant of alkylboron coupling partners (Eq. 62).

ð62Þ

Some of the earliest work examining catalytic dioxygenation of alkynes was performed with tungsten. Tomaseli reported the conversion of terminal alkynes into a-oxo aldehydes with catalytic sodium tungstate dihydrate in combination with hydrogen peroxide (Eq. 63).147 Soon after, Ishii developed a method for the conversion of internal alkynes to 1,2-diketones using peroxotungstophosphate (PCWP) and hydrogen peroxide (Eq. 64).140

ð63Þ

ð64Þ

ð65Þ

ð66Þ

148

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð67Þ

In 2000, Li reported a cis-dioxoruthemium(IV) complex capable of reacting in a stoichiometric fashion with alkynes via [3 +2] cycloaddition to furnish ruthenate esters that upon hydrolysis yield 1,2-diketones (Eq. 65).148 This complex is capable of oxidizing diaryl-, dialkyl-, and mixed alkyl/aryl alkynes. Later, Zhao developed a catalytic method using 5 mol% of RuO2
3H2O to generate a-keto-imides via the dioxygenation of ynamides (Eq. 66).149 This protocol is compatible with aryl- and alkyl-substituted ynamides. In 2010, Wan utilized [Ru(cymene)Cl2]2 to perform alkyne dioxygenation using part per million catalyst loadings with t-BuOOH as oxidant (Eq. 67).150 Wan expanded on this methodology to employ Oxone® as an oxidant and demonstrated a one-pot procedure to synthesize quinoxalines (Eq. 68).151 Through use of RuCl3
3H2O, Fischmeister was able to incorporate NaOCl as an oxidant, although this protocol is incompatible with dialkyl alkynes (Eq. 69).152 In 2010, Bera incorporated the usage of NHC ligands to promote oxidation of alkenes and alkynes.153 The authors tested three different alkynes, which were oxidized in 96–100% yield (Eq. 70).

ð68Þ

ð69Þ

ð70Þ

Gold catalysis has been used extensively to dioxygenate alkynes to afford 1,2-diketones and a-hydroxy ketones. Representative examples are covered within, but the reader is directed to a number of recent reviews on the subject for additional information.133–136 A general catalytic cycle for gold-catalyzed alkyne dioxygenation is illustrated in Fig. 13, in which gold coordinates the alkyne and activates it as a p-Lewis acid; oxyauration takes place to ultimately give an a-oxo gold carbene (generally viewed as a Fisher-type carbene), which then reacts further with an oxygen atom transfer reagent or alternatively, with a different type nucleophile to furnish 1,2-difunctionalized products.

Fig. 13 General mechanism of gold-catalyzed alkyne dioxygenation.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

149

Li discovered in 2011 that diphenyl sulfoxide in the presence of Au(I) and Ag(I) can oxidize alkynes to 1,2-diketones and a-keto-imides (Eq. 71).154 While yields are good for the substates reported, no alkyl-substituted alkynes are described. In later literature, pyridine-N-oxides were identified as the oxidant of choice, and Kukushkin used 2,5-dichloro-pyridine-N-oxide to synthesize 1,2,3-tricarbonyls.155 A variety of aryl-substituted alkynyl esters and amides are tolerated under these conditions (Eq. 72). a-Alkoxyketones can also be synthesized from terminal alkynes using Au(I) and pyridine-N-oxides (Eqs. 73 and 74).156,157 Intramolecular methods have been developed with terminal alkynes to synthesize dihydrofuran-3-ones (Eq. 75)158 and oxetan-3-ones (Eq. 76).159

ð71Þ

ð72Þ

ð73Þ

ð74Þ

ð75Þ

ð76Þ

The gold-catalyzed Mannich-type addition of 3-butynol to nitrones has been rendered enantioselective by use of chiral phosphoric acids, allowing for the synthesis of b-amino-dihydrofuran-3-ones in up to 95% ee (Fig. 14).160 A number of methods for dioxygenation of alkynes to generate 1,2-diketones using Pd(II) and DMSO have been developed,161–164 some of which use a copper cocatalyst with O2 as the terminal oxidant, reminiscent of the Wacker process.163,164 These methods are summarized in Eqs. (77–79). A tandem Sonogashira/dioxygenation protocol has also been developed (Eq. 80).164 In contrast to other methods, alkyl alkynes and other electron-rich alkynes are tolerated due to the low oxidation potential of palladium, which make it a poor catalyst for facilitating oxidative cleavage.

Fig. 14 Gold-catalyzed Mannich-type addition of 3-butynol to nitrones. Adapted from Wei, H.; Bao, M.; Dong, K.; Qiu, L.; Wu, B.; Hu, W.; Xu, X. Angew. Chem. Int. Ed. 2018, 57(52), 17200–17204.

150

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð77Þ

ð78Þ

ð79Þ

ð80Þ

Under aerobic conditions, Kim developed an iron-catalyzed dioxygenation of aryl alkynes and compared H2O2 and t-BuOOH as oxidants.165 They found that while both could competently promote the dioxygenation of alkynes, H2O2 was more effective and more generally applicable with their catalyst (Eq. 81). FeCl3 and DMAP was shown by Enthaler to dioxygenate diaryl-substituted alkynes to produce 1,2-diketones (Eq. 82).166 Without DMAP at elevated temperature, only oxidative cleavage was observed. Sreedhar was able to effect 1,2-ketoacetoxylation of terminal alkynes using Fe(II) and PhI(OAc)2 as oxidant.167 This method is compatible with both alkyl- and aryl-substituted alkynes (Eq. 83).

ð81Þ

ð82Þ

ð83Þ

Methylrhenium trioxide was shown to catalyze dioxygenation of alkynes with H2O2 to afford 1,2-diketones in 1995.168 This protocol was efficient with both aryl- and alkyl-substituted alkynes using only 10 mol% catalyst, but as the alkynes become more electron-rich, oxidative cleavage predominates (Eqs. 84 and 85).

ð84Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

151

ð85Þ

Cationic copper activated by Selectfluor allows for the synthesis of 1,2-diketones from alkynes and water using Selectfluor as the terminal oxidant.169 While the method was able to oxidize a range of aryl alkynes and ynamides, dialkyl- and diester-substituted alkynes were not competent in this reaction (Eq. 86). A Sonogashira-type decarboxylative coupling reaction has been developed under copper catalysis.170 In this method, aryl iodides undergo decarboxylative cross coupling with aryl-substituted alkynylcarboxylic acids to afford internal alkynes which are oxidized in situ to the corresponding 1,2-diketone (Eq. 87). Sing expanded on this work by adding aryl diazines to the compatible collection of coupling partners (Eq. 88).171

ð86Þ

ð87Þ

ð88Þ

Li has developed a method for oxidation of diphenylacetylene in 78% yield via a Co(II) catalytic system (Eq. 89).172 While not strictly necessary, the rate of reaction is greatly increased by the addition of a Mn(II) co-catalyst. When applied to other alkynes, oxidative cleavage was the major product in all cases.

ð89Þ

ð90Þ

Vishwakarma and Bharate developed a cobalt-catalyzed cross-coupling/dioxygenation tandem process to convert alkynes to 1,2-diketones.173 This protocol combines aryl hydrazines and alkynes under cobalt catalysis, utilizing air as an oxidant (Eq. 90). The authors are able to dioxygenate a variety of substrates. With the addition of aldehydes to the reaction mixture, highly substituted imidazoles can be synthesized directly, enabling rapid synthesis of platelet aggregator Trifenagrel (Fig. 15).

Fig. 15 Synthesis of Trifenagrel enabled by cobalt-catalyzed dioxygenation of alkynes. Adapted from Bharate, J. B.; Abbat, S.; Sharma, R.; Bharatam, P. V.; Vishwakarma, R. A.; Bharate, S. B. Org. Biomol. Chem. 2015, 13(18), 5235–5242.

152

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.4.3 Dioxygenation of allenes

ð91Þ

ð92Þ

In a proof-of-concept study, Cazes and coworkers realized the OsO4-catalyzed dihydroxylation of allenes with NMO as oxidant (Eq. 91).137 This study examined a variety of allenes and found unpredictable regioselectivity. Recognizing the exceptional regioselectivity in the special case of aryl-substituted allenes, this process was later rendered enantioselective using AD-mix by Redd in 2004, but exact conditions were not disclosed (Eq. 92).138 It was shown that electron-rich aryl groups performed best, both in terms of yield and ee.

ð93Þ

PCWP-mediated dioxygenation of a variety of allenes was found to take place in the presence of an alcoholic solvent, furnishing the products with modest selectivity (Eq. 93).

ð94Þ

ð95Þ

In 2015, Chemler reported the intramolecular dioxygenation of allenols using stoichiometric copper.139 Using this method, alkenyl carboxylate esters are synthesized with excellent regioselectivity and diastereoselectivity (Eqs. 94 and 95).

13.04.4.4 Dioxygenation of 1,3-dienes Mechanistically, the palladium-catalyzed 1,4-dioxygenation of 1,3-dienes begins with Pd(II) coordinating the diene, which triggers syn-nucleopalladation.135,174 The resulting p-allylpalladium intermediate can undergo one of two fates depending on the reaction conditions. Without chloride in the system, the X-type ligand on palladium is acetate and this species undergoes stereoretentive reductive elimination to furnish syn-products. With chloride in the system, the X-type ligand on palladium is chloride, and therefore acetate performs a stereoinvertive SN2-type reductive elimination to furnish anti-products. In both cases, the resulting Pd(0) species is reoxidized to Pd(II) by benzoquinone to close the cycle (Fig. 16).

ð96Þ

An early example of this catalytic process was the dioxygenation of 1,3-cyclohexadiene when treated with catalytic Pd(OAc)2 and p-benzoquinone in acetic acid (Eq. 95).175 The relative stereochemistry of the product could be controlled through the presence or absence of chloride as explained above (Fig. 17).176,177 In alcoholic solvents, analogous 1,4-dialkoxylation of 1,3-dienes can also be achieved (Eq. 96).178 This mode of reactivity can be coupled with an intramolecular nucleopalladation process to form cyclic structures (Eq. 97).179,180 This methodology has been applied in the total synthesis of the muscle relaxer paeonilactone A.181

ð97Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

153

Fig. 16 General mechanism of palladium-catalyzed 1,3-diene dioxygenation.

Fig. 17 Stereoselectivity in the palladium-catalyzed diacetoxylation of 1,3-cyclohexadiene. Adapted from Grennberg, H.; Gogoll, A.; Baeckvall, J. E. J. Org. Chem. 1991, 56(20), 5808–5811; Baeckvall, J. E.; Nystroem, J. E.; Nordberg, R. E. J. Am. Chem. Soc. 1985, 107(12), 3676–3686.

ð98Þ

Diene deoxygenation with other metals remains largely unexplored, and 1,2-selective catalytic systems are lacking.

13.04.4.5 Dioxygenation of alkenes 13.04.4.5.1

Syn-dioxygenation of alkenes

Beyond osmium, one of the most commonly used metals to promote syn-dioxygenation of alkenes is ruthenium.182,183 RuO4 behaves similarly to OsO4, and the same stereochemical models developed by Kishi may be applied to ruthenium.184 This group-8 metal has a high oxidation potential, and it is often difficult to prevent overoxidation of the alkene. Ruthenium dioxygenation proceeds through the simplified mechanism illustrated in Fig. 18 where RuO4 reacts with the alkene through a [3 +2] cycloaddition. The resulting ruthenate ester intermediate is then oxidized and hydrolyzed to furnish the dihydroxylated product.

Fig. 18 General mechanism for ruthenium-catalyzed dioxygenation of alkenes.

154

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

The first RuO4-catalyzed dioxygenation was described by Shing, and due to its short reaction times was dubbed “flash dihydroxylation”.185 This method proved to be successful for the oxidation of olefins that are known to be less reactive in OsO4-catalyzed dihydroxylations, such as 1,2-diesters (Eq. 99). Under the initially developed conditions high catalyst loading was used, and prolonged reaction times led to overoxidation and oxidative cleavage. It was determined that hydrolysis of the intermediate ruthenate ester is the rate-limiting step,183,186 and based on this mechanistic hypothesis an improved protocol was developed using catalytic H2SO4.183 This modification allowed the catalyst loading to be reduced to 0.5 mol%, but the issue of over-oxidation persisted (Eq. 100). This point was addressed by replacing H2SO4 with CeCl3, a redox-active Lewis acid that forms Ce(IV)-periodato species when mixed with NaIO4.186–188 These Ce(IV)-periodato complexes feature a higher redox potential than most common reoxidants, a moderate pH value, and a low tendency to catalyze glycol cleavage, thereby broadening the substrate scope (Eqs. 101 and 102). By replacing the acid additive with Oxone® and sodium bicarbonate, highly regioselective ketohydroxylation can be achieved, with the hydroxyl group introduced closest to the most electron-withdrawing substituent.189–191

ð99Þ

ð100Þ

ð101Þ

ð102Þ

A number of tandem olefin metathesis/dioxygenation reactions have been developed using NaIO4 and Lewis acid additives to generate RuO4 in situ from Grubbs I or II catalysts.192,193 Blechert et al. performed intramolecular ring-closing metathesis on various substrates using Grubbs I; subsequent removal of DCM and addition of EtOAc/MeCN, NaIO4, and YbCl3 furnished dihydroxylated carbo- and heterocycles (Eq. 103).192 The authors also applied this methodology to alkene cross-metathesis using Hoveyda–Grubbs II (Eq. 104). Snapper and coworkers later improved this protocol by replacing YbCl3 with CeCl3
7H2O, which improved the operational simplicity in that removal of DCM was no longer required.193

ð103Þ

ð104Þ To perform diastereoselective ruthenium-catalyzed dioxygenation, a chiral auxiliary approach has been pursued, as first reported by Wong in 1999.194 This protocol utilized Oppolzer’s (S)-sultam auxiliary to promote dihydroxylation of a,b-unsaturated amides in good yields, albeit with variable dr (Eqs. 105–107). This family of auxiliaries has also been applied to the asymmetric tandem cross metathesis/dioxygenation sequence as reported by Plietker.195 A variety of alkene cross-metathesis partners could be paired with chiral a,b-unsaturated amides, providing syn-diols in moderate yields and high dr (Eqs. 108 and 109).

ð105Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

155

ð106Þ

ð107Þ

ð108Þ

ð109Þ

Manganese is also frequently used to promote alkene dioxygenation, and methods can be classified as homogenous stoichiometric, heterogenous stoichiometric (not discussed in this chapter), or homogenous catalytic. Oxidation with stoichiometric potassium permanganate (KMnO4) has been extensively studied, and several reviews and book chapters have been published on this subject.142,196,197 Reactions are typically run under aqueous conditions to solubilize the potassium permanganate, and the pH of the solution is important for reactivity, with alkaline conditions promoting dihydroxylation, neutral or slightly basic conditions promoting ketohydroxylation, and acidic conditions promoting oxidative cleavage. This latter point is in direct contrast to the ruthenium-based methods described above. A general mechanism is shown in Eq. (110).198–203 ð110Þ First generation dioxygenation with permanganate was run in water to solubilize the permanganate ion (Eqs. 111–113), but these methods had limited scope. It had been shown that permanganate and tetraalkyl ammonium salts form tight ion pairs in non-polar solvents. This observation was applied to develop water-free conditions for manganese-mediated dioxygenation, thereby expanding the scope of this process. Representative examples are shown in Eqs. (114) and (115).200,201 Chiral phase transfer catalysts combined with KMnO4 are able to promote enantioselective dihydroxylation and ketohydroxylation of a,b-unsaturated carbonyls (Eqs. 116 and 117).202,203

ð111Þ

ð112Þ

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Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð113Þ

ð114Þ

ð115Þ

ð116Þ

ð117Þ

The first homogeneous manganese-catalyzed alkene dihydroxylation process was reported by Feringa in 2002 using [Mn2O3(tmtacn)2]2+ in the presence of glyoxylic acid methyl ester methyl hemiacetal (GMHA) with H2O2 as oxidant.25 The addition of the carbonyl additive suppresses H2O2 decomposition and allows for the catalytic dihydroxylation of unactivated alkenes. In all cases, however, epoxidation was a highly competitive process (Fig. 19). By further optimizing the additive and using 2,6-dichlorobenzoic acid, Feringa was able to suppress epoxide formation and facilitate dihydroxylation.204 Subsequent mechanistic studies revealed that the active catalyst is the carboxylate-bridged dimer, and this insight was leveraged to develop a new manganese catalyst.205,206 This new catalyst used N-acetyl-protected D-phenylglycine as a chiral bridging ligand to promote dihydroxylation of 2,2-dimethylchromene in up to 54% ee (Eq. 118).206 Prior to 2010, there were no examples of manganese-catalyzed dihydroxylation of electron-deficient olefins, at which point Feringa and Browne addressed this problem through a combination Mn(II), pyridine-2-carboxylic acid, and base in acetone.207 This protocol quantitatively dihydroxylates highly electron-deficient alkenes, but formation of epoxidized byproducts becomes more prominent with increasingly electron-rich alkenes (Eqs. 119 and 120). Developing a universal method for manganese-catalyzed dioxygenation that is compatible with a broad array of alkenes possessing different substituents and substitution patterns remains an outstanding challenge.

ð118Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

157

Fig. 19 Manganese-catalyzed dihydroxylation of cyclooctene. Adapted from Mizutani, K.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5(21), 3959–3961; de Boer, J. W.; Brinksma, J.; Browne, W. R.; Meetsma, A.; Alsters, P. L.; Hage, R.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127(22), 7990–7991.

ð119Þ

ð120Þ

Dongare and coworkers reported the first example of molybdenum-catalyzed syn-dioxygenation (Eq. 121).208 The mechanism of this transformation is presumed to proceed similarly to the mechanisms of osmium- and ruthenium-catalyzed dioxygenation. In 1988, Davidson reported on technetium-mediated dioxygenation in which oxotechnetium diolates are generated and subsequently hydrolyzed (Eq. 122).209 The spent metal salts can be filtered off to isolate pure diols. ð121Þ

ð122Þ

Non-heme iron-catalyzed cis-dioxygenation of alkenes was first reported in 1999, with the dihydroxylation of cyclooctene giving up to 22% yield.210 Early iron-mediated syn-dioxygenation methods, despite being rendered enantioselective,211 were prone to catalyst deactivation and could not operate under substrate-limiting conditions. For the purposes of this section, only those methods that operate under substrate-limiting conditions will be discussed, and the reader is directed to a number of reviews on prior work in this area.212,213 Iron-mediated dioxygenation did not reach synthetically useful yields until 2010 with Che’s use of a macrocyclictetraaza-Fe(III)-complex [Fe(Cl)2(LN4Me2)]+ with Oxone® as oxidant.214 This protocol is compatible with activated and unactivated alkenes and proceeds with minimal overoxidation (Fig. 20). By modifying a common ligand scaffold, [Fe(tpa)] (tpa ¼ tris(2-pyridylmethyl)amine), through the addition of triisopropylsilyl (TIPS) groups at the 5-positions of the three pyridine rings, Costas was able to increase catalyst performance and enlist H2O2 as oxidant (Fig. 21).215 This catalyst also proved competent

Fig. 20 Iron-catalyzed dihydroxylation using Oxone as an oxidant. Adapted from Chow, T. W.-S.; Wong, E. L.-M.; Guo, Z.; Liu, Y.; Huang, J.-S.; Che, C.-M. J. Am. Chem. Soc. 2010, 132(38), 13229–13239.

158

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Fig. 21 Iron-catalyzed dihydroxylation using hydrogen peroxide as an oxidant. Adapted from Borrell, M.; Costas, M. J. Am. Chem. Soc. 2017, 139(36), 12821–12829.

in the green solvent mixture of 1:1 propylene carbonate (PC)/ethyl acetate and can be generated in situ.216 In the presence of multiple alkenes, Costas’s iron catalyst will selectively dioxygenate the most electron-rich alkene. Proof-of-concept studies on enantioselective iron-mediated syn-dioxygenation were carried out by Que and colleagues in 2001.211 The authors were able to dihydroxylate trans-2-octene in 2.3% yield and 82% ee using ligands derived from chiral diamines. While all other substrates proceeded in poor yield and variable enantiomeric excess (0–78%), this report laid the foundation for future work by the Que and Che groups (Fig. 22). The second-generation ligand from Que’s group modified the diamine backbone to improve enantioselectivity across most substrates, but this method still suffered from low yields.217 The third-generation ligand reported by Che returned to the cyclohexyl backbone and replaced the methylpyridines with quinolines.218,219 These modifications brought about even further improvements in yield and ee for activated and unactivated alkenes, but the reaction still behaved unpredictably. The fourth-generation system by Che modified the backbone and was able to reliably promote enantioselective dioxygenation on a,b-unsaturated amides and esters in good yield and with high ee.220 In recent years, palladium has emerged as a highly effective catalyst for alkene dioxygenation, with the majority of dioxygenation protocols involving a Pd(II)/Pd(IV) p-Lewis acid activation mechanism. Sigman described dioxygenation of ortho-hydroxystyrenes via a Pd(II)/Pd(0) redox couple, with products formed in good yield and moderate dr (Eq. 123).221 This chemistry is facilitated by the o-hydroxy group as it stabilizes the nucleopalladated intermediate by coordinating to the palladium center, preventing b-hydride elimination, and allowing for the formation of an o-quinone methide upon reductive elimination, which can subsequently be attacked by the alcohol to furnish dioxygenated products.222

ð123Þ

Dong developed a cationic Pd(II)/Pd(IV) system capable of dioxygenating a variety of styrene derivates.223 Use of acetate as the nucleophile allows for subsequent intramolecular CdO cyclization to form an acetoxonium intermediate that can then be opened with water or acetate to generate the dioxygenated product (Eq. 124). Grubbs expanded this methodology to include unactivated alkenes using catalytic nitrite as oxidant,224 and Shi developed a bis-NHC-Pd(II) catalyst to dioxygenate styrenes and includes one example of an unactivated alkene with PhI(OAc)2 as oxidant.225 Jiang was able to perform diacetoxylation of both activated and unactivated alkenes by also using a Pd(II)/Pd(IV) system where O2 served as oxidant (Eq. 125).226 They found that the addition of KI improved reaction yield, rationalizing its beneficial effect by proposing that it may help promote oxidation of palladium. This chemistry is performed in an autoclave under high pressure, which led Jung to devise a method of diacetoxylation using peracetic acid as oxidant under ambient conditions (Eq. 126).227 Mechanistically, Dong proposes an anti-nucleopalladation followed by

Fig. 22 Ligand scaffolds designed by the Que and Che groups. Adapted from Costas, M.; Tipton, A. K.; Chen, K.; Jo, D.-H.; Que, L. J. Am. Chem. Soc. 2001, 123(27), 6722–6723; Suzuki, K.; Oldenburg, P. D.; Que Jr, L. Angew. Chem. Int. Ed. 2008, 47(10), 1887–1889; Chow, T. W.-S.; Liu, Y.; Che, C.-M. Chem. Commun. 2011, 47(40), 11204–11206; Zang, C.; Liu, Y.; Xu, Z.-J.; Tse, C.-W.; Guan, X.; Wei, J.; Huang, J.-S.; Che, C.-M. Angew. Chem. Int. Ed. 2016, 55(35), 10253–10257. Wei, J.; Wu, L.; Wang, H.-X.; Zhang, X.; Tse, C.-W.; Zhou, C.-Y.; Huang, J.-S.; Che, C.-M. Angew. Chem. Int. Ed. 2020, 59(38), 16250–16250.

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159

Fig. 23 Mechanistic proposals for syn-selective palladium-catalyzed dioxygenation. Data from Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130(10), 2962–2964; Wang, W.; Wang, F.; Shi, M. Organometallics 2010, 29(4), 928–933; Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131(11), 3846–3847.

reductive acetate cyclization while Jiang and Jung propose syn-nucleopalladation followed by direct reductive elimination to explain the syn-dioxygenation selectivity (Fig. 23). Palladium can also promote keto-hydroxylation of activated and unactivated terminal alkenes using H2O2 as the sole oxidant and source of both oxygen atoms (Eq. 127).228

ð124Þ

ð125Þ

ð126Þ

ð127Þ A chiral auxiliary approach has also been applied to the palladium-catalyzed diastereoselective dioxygenation of alkenes.229 Menthone derivates substituted at the isopropyl group were able to afford syn-dibenzoylated products with high dr (Eq. 128). In this system, the oxime serves as a chiral directing group by binding to palladium to influence the stereochemistry of the reaction. The authors propose that the mechanism could involve either an anti-oxypalladation/SN2-type reductive elimination sequence or a syn-oxypalladation/stereoretentive reductive elimination sequence, to afford syn-1,2-dioxygenated products.

ð128Þ

13.04.4.5.2

Anti-dioxygenation of alkenes

While syn-dioxygenation of alkenes has received significant attention, transition-metal-catalyzed anti-dioxygenation remains comparatively underdeveloped due to the wealth of literature on metal-free approaches based on epoxide ring opening.230 Early work in transition-metal-catalyzed processes focused on tungsten,231,232 vanadium,233,234 and rhenium235,236 based systems with hydrogen peroxide as the oxidizing agent to furnish diols (Eq. 129). ð129Þ

160

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Later reactions with manganese237 and copper238 afforded dioxygenated products using air as the terminal oxidant. Intramolecular anti-dioxygenation of alkenyl oximes has been examined in the context of oxazoline synthesis under manganese,237 palladium,239 and cobalt240 catalysis (Eq. 130). ð130Þ While highly enantioselective methods for anti-dioxygenation are rare, a method using molybdenum has been developed for allylic alcohols that delivers the resulting 1,2,3-triol in up to 96% ee of the (Eq. 131).241 This system proceeds through enantioselective epoxidation followed by in situ, regioselective ring opening by peroxide to furnish the corresponding triol after reduction. The authors propose that both of these steps are facilitated by molybdenum as no ring opening is observed when a pre-synthesized epoxide is exposed to standard reaction conditions without the molybdenum catalyst.

ð131Þ

13.04.5 Homo/heterodihalogenation reactions 13.04.5.1 Overview The growing number of natural products containing halogen atoms, especially at stereogenic centers, has underscored the critical role of these “salt-producing” elements. The ocean is replete with both chlorine and bromine, which are the 3rd and 8th most abundant elements in sea water, respectively; indeed, marine life continues to be a rich source of halogenated natural products, with the library of characterized chlorine- and bromine-containing bioactive natural products expanding with every passing year. These chemical structures have placed a spotlight on reactions capable of introducing halogen atoms in a controlled and predictable fashion, and transition metals have continued an important role in defining the state of the art in this area. Reactions between diatomic halogen molecules and alkenes are classical synthetic transformations covered early on in chemical education. They typically involve a mechanism of haliranium formation followed by halide-mediated nucleophilic ring opening, which results in an overall anti addition process. While these reactions are highly robust, they are not without their limitations. In this context, introduction of transition-metal mediators has allowed for chemists to employ less toxic and more operationally convenient halogen atom sources and to gain selectivity control in various aspect of the reaction. In particular, the stereoselectivity of the vicinal dihalogenation reaction can be compromised due to various issues (Fig. 24)242: (1) regioselectivity of the nucleophilic trapping, (2) potential alkene to alkene haliranium ion transfer induced racemization, (3) the extent of halogen atom bridging. Additionally, the ability to employ nucleophilic halide anions as the halogen atom source offers both operational advantages and some distinct opportunities in controlling the stereoselectivity (Fig. 25): (A) Instead of forming haliranium ion with an electrophilic X+, the alkene substrates could form a p-complex or -iranium ion with electrophilic metal or main group element. Then either outer sphere syn-addition or inner sphere anti-addition of a halide ion proceeds. Finally, a formal reductive elimination via either retentive or inversive pathways gave the dihalogenation product. (B) The mechanism may proceed through a concerted group

Fig. 24 Overview of complications frequently encountered in dihalogenation reactions. Adapted from Angew. Chem. Int. Ed. 2015, 54(52), 15642–15682.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

161

Fig. 25 Stereochemical pathways in transition-metal catalyzed dihalogenation. Adapted from Angew. Chem. Int. Ed. 2015, 54(52), 15642–15682.

transfer of two halogen atoms via a 5-membered transition state. Metal centers such as antimony and molybdenum are often proposed to go through this pathway. (C) A halogen atom transfer gives rise to a b-halo radical intermediate, which further lead to the dihalogenation products. Low valent metals, such as manganese, copper and ruthenium, are considered to react through this pathway.

13.04.5.2 Homo/heterodihalogenation of alkenes The dichlorination of alkenes with stoichiometric metal chlorides has been extensively studied since the 1970s. Depending on the nature of the metal, different mechanisms lead to different stereochemical outcomes. By using SbCl5 or MoCl5 as chlorinating agent, Uemura and co-workers were able to develop the syn-stereoselective dichlorination (Fig. 26). When SbCl5 was used, 96% combined yield and 82:18 syn/anti ratio was observed,243–247 while MoCl5 provides a lower yield of 85%.248,249 Notably, in these reports all yields are reported with respect to MCl5, as unproductive alkene polymerization took place. A monomeric 5-membered concerted halogen transfer mechanism was proposed to explain the unique synstereoselectivity. Meanwhile, the lower syn/anti selectivity in the case of the SbCl5-mediated system was proposed to arise from the larger contribution of an alternative ion pair ([SbCl4]+[SbCl6]−) mechanism. The gas phase reaction of solid-supported CuCl2 with alkenes at high temperatures, known as the “oxylchlorination” process,250,251 contributes to the current industrial synthesis of dichloroethane. The solution-phase dichlorination of alkenes with stoichiometric CuCl2 proceeds with moderate anti/syn selectivity, (Fig. 27).252–254 A b-chloroalkyl radical or a b-chloroalkyl cation intermediate might explain the diminished selectivity. In contrast, the analogous dibromination with CuBr2 in MeCN or alcohol solvents predominantly proceeds in an anti-addition fashion, consistent with either a bromonium intermediate or an antibromometallation/stereoretentive CdBr reductive elimination sequence (Fig. 28).255

Fig. 26 Stereoselectivity in antimony- or molybdenum-catalyzed alkene dihalogenation. Adapted from Uemura, S.; Sasaki, O.; Okano, M. J. Chem. Soc. Chem. Commun. 1971, (18), 1064; Uemura, S.; Onoe, A.; Okano, M. Bull. Chem. Soc. Jpn. 1974, 47(3), 692–697; Heasley, V. L.; Rold, K. D.; Titterington, D. R.; Leach, C. T.; Gipe, B. T.; Mckee, D. B.; Heasley; Akiyama, F.; Horie, T.; Matsuda, M. Bull. Chem. Soc. Jpn. 1973, 46(6), 1888–1890; Vignes, R. P.; Hamer, J. J. Org. Chem. 1974, 39(6), 849–851; Uemura, S.; Onoe, A.; Okano, M. Bull. Chem. Soc. Jpn. 1974, 47(12), 3121–3124; Sanfilippo, J.; Sowinski, A. F.; Romano, L. J. J. Am. Chem. Soc. 1975, 97(6), 1599–1600.

162

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Fig. 27 Stereoselectivity in the copper-catalyzed dichlorination of alkenes. Adapted from Koyano, T. Bull. Chem. Soc. Jpn. 1970, 43(5), 1439; Koyano, T. Bull. Chem. Soc. Jpn. 1970, 43(11), 3501; Koyano, T.; Watanabe, O. Bull. Chem. Soc. Jpn. 1971, 44(5), 1378.

Fig. 28 Stereoselectivity in the copper-catalyzed dibromination of alkenes. Adapted from Koyano, T. Bul. Chem. Soc. Jpn. 1971, 44(4), 1158–1160.

ð132Þ

The combination of stoichiometric KMnO4 and BnNEt3Cl, known as Markό’s reagent, gives rise to anti-stereoselective dichlorination reactions with chloride-based promoters such as chlorotrimethylsilane or oxalyl chloride (Fig. 29).256,257 This reaction is proposed to take place via an in situ generated Cl−3 species. As a mechanistic departure from this Mn(VII)-mediated reactivity, Mn(III) and Mn(IV) can undergo successive chlorine atom transfer through a b-chloroalkyl radical intermediate (Eq. 132).258–261 A catalytic version of this transformation was achieved using stoichiometric NaClO2 as a re-oxidant. Recently, an electrocatalytic strategy was employed for manganese-catalyzed dichlorination using MgCl2 as the chlorine source.262 Additionally, a photoredox ligand-metal charge transfer strategy was employed in the copper-catalyzed dichlorination of alkenes. The mild conditions could be ascribed to the facile generation of a chlorine radical induced by light.263

ð133Þ

ð134Þ

A landmark achievement in enantioselective dihalogenation was established by Burns and coworkers using a chiral titanium– TADDOL promoter (Eq. 133). In the initial report, the authors used a latent bromine source, diethyl dibromomalonate, which is activated upon coordination of the chiral titanium promoter, vastly diminishing the racemic background reaction. Coordination of the hydroxyl directing group from the allyl alcohol substrate then facilitates intramolecular Br+ transfer and trapping.264 The author ascribed the high selectivity to the octahedral coordination geometry. In later work, a more selective tridentate chiral Schiff base diol was developed (Eq. 134). When monodentate NBS was used as bromine source together with stoichiometric ClTi(Oi-Pr)3, a six-coordinate geometry could be maintained around the titanium center, thus giving the asymmetric bromochlorination reaction in high regio- and stereoselectivity.265 Accordingly, a series of asymmetric dehalogenations and related reactions were achieved using this strategy, enabling access to a variety of halogenated marine natural products.266

Fig. 29 Stereoselectivity in the manganese-catalyzed dichlorination of alkenes. Adapted from Markó, I. E.; Richardson, P. F. Tetrahedron Lett. 1991, 32(15), 1831–1834; Markó, I. E.; Richardson, P. R.; Bailey, M.; Maguire, A. R.; Coughlan, N. Tetrahedron Lett. 1997, 38(13), 2339–2342.

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163

13.04.5.3 Homo/heterodihalogenation of allenes Manganese-mediated vicinal dihalogenation of allenes was achieved by Boyes and co-workers using Markό’s reagent.267 Dihalogenation of other polyunsaturated compounds has also been investigated using different mechanistic approaches. Although palladium-mediated chloropalladation and CdCl bond reductive elimination have both been reported, no examples of palladium-catalyzed dihalogenation of alkenes have been described. This is because the resulting b-haloalkylpalladium intermediate that is formed upon halometallation is highly unstable due to the facile nature of the reverse b-halide elimination process. Alternatively, the p-allyl intermediate that is formed through chloropalladation of an allene moiety is sufficiently stable and resistant to b-halide elimination. Using this approach, Bäckvall and Jonasson reported a stepwise vicinal-dichlorination in which an alkene was combined with PdCl2(PhCN)2 followed by treatment with p-benzoquinone and LiCl in AcOH. Catalytic dibromination of allenes was also achieved. The greater nucleophilicity of bromide ion compared to chloride prevented the competing reaction between unreacted allene and the p-allyl intermediate (Fig. 30).268

Fig. 30 Palladium-catalyzed dihalogenation of allenes. Adapted from Bäckvall, J.-E.; Jonasson, C. Tetrahedron Lett. 1997, 38(2), 291–294.

13.04.5.4 Homo/heterodihalogenation of alkynes

ð135Þ

The electrophilic addition of diatomic halogen molecules to alkynes is a traditional method for generating (E)-dihaloalkenes. However, the lack of chemoselectivity and the use of hazardous diatomic halogens is problematic for many applications. Plausible alternative reagents (or reagent combinations), such as N-bromosuccinimide, KBr/Selectfluor, KBr/diacetoxyiodobenzene, or HBr/TBHP, suffer from variable stereoselectivity as well as low functional group tolerance.269 The dichlorination and dibromination of alkynes with CuCl2 or CuBr2 in MeCN as solvent were studied by Uemura and co-workers (Eq. 135).270,271 Under kinetic control, the (E:Z) ratio of the products from internal 1-aryl-2-alkylalkynes decreased markedly when the alkyl group was varied from primary to secondary and tertiary. With (3,3-dimethyl-but-1-ynyl)-benzene, reversed selectivity was observed for both chlorination and bromination reactions. Reaction kinetics revealed that this reaction likely proceeds via a positively charged transition state, with the positive charge build up on the carbon atom adjacent to the phenyl ring. Stereospecific diiodination of acetylenes was also achieved with CuI2 and molecular I2.272

ð136Þ

Heterodihalogenation of alkynes was reported using different combinations of electrophilic and nucleophilic halogen elements. The chloroiodination of phenyl acetylenes were achieved by using the combination of molecular iodine and nucleophilic CuCl2 (Eq. 136).273 The high stereospecificity of this reaction may arise from electronic properties of the iodonium intermediate, where iodine has a stronger bond with the b-carbon. Partial positive charge at the a-carbon could be stabilized by forming delocalized p bond with the phenyl ring. A silver-assisted bromofluorination was achieved using NBS and AgF as electrophile and nucleophile, respectively.274

13.04.6 Aminooxygenation 13.04.6.1 Aminooxygenation of alkenes Osmium-based methods for aminooxygenation of alkenes (Eq. 137), such as the Sharpless asymmetric aminohydroxylation, and subsequent variants, have received extensive attention and will therefore not be covered in this section. The reader is directed to a number of reviews on the subject.275–277 ð137Þ

164

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.6.1.1

Palladium-catalyzed

The first palladium-mediated aminooxygenation of alkenes was reported by Bäckvall in 1975.278 This early report featured a stepwise procedure, involving initial coordination of the alkene to Pd(II), followed by addition of the appropriate amine to the resultant p-alkene–palladium(II) complex, and finally oxidation of the nucleopalladated species with Pb(OAc)4 (Eq. 138). This type of transformation was then rendered catalytic in 2005 by Sorensen; alkenyl nosylsulfonamides were found to undergo a sequence of intramolecular aminopalladation, oxidation from Pd(II) to Pd(IV) with PhI(OAc)2, and CdO reductive elimination (Eq. 139).279 The authors found (E)-alkenes resulted in syn-diastereomers while (Z)-alkenes lead to the corresponding anti-diastereomers, suggesting that the initial aminopalladation step takes place in an anti-fashion. The first fully intermolecular (three-component) palladium-catalyzed aminooxygenation procedure was reported by Stahl in 2006.280 In the initial report, the method was only compatible with phthalimide as the nucleophile and an allyl alcohol derivative as the substrate (Eq. 140), although this was expanded in later work to include more diverse alkenes through the use of catalytic tert-butylcatechol.281 Ureas282 and carbamates283 have also been shown to competent in intramolecular ring-closing aminooxygenation (Fig. 31). While these methods use strong oxidants such as PhI(OAc)2 and H2O2, Engle was able to develop an 8-amidoquinoline-directed aminooxygenation procedure using O2 as the oxidant.284 This method is compatible with phthalimide and derivatives thereof, a-substituted terminal alkenyl amides, and an internal alkenyl amide (Eq. 141). ð138Þ

ð139Þ

ð140Þ

ð141Þ

Controlling 1,2- vs. 1,4-selectivity in the aminooxygenation of 1,3-dienes can be achieved by using ortho-amino-phenols, 1,2-aminoalcohols, and a-amino acids, as these bis-nucleophilic coupling partners preferentially react to furnish the six-membered heteroannulated products. This strategy has been used with palladium to perform 1,2-aminooxygenation of conjugated dienes. Zhang observed that with 1,2-amino alcohols, the solvent identity affects the regioselectivity of this process, with MeCN providing 1,2-aminooxygenation and DMSO providing 1,2-oxyamination,285 while a-amino acids preferentially undergo 1,2-aminooxygenation (Figs. 32 and 33).286 They also found that adding 2-5-dimethylbenzoquinone as a co-oxidant in

Fig. 31 Intramolecular palladium-catalyzed aminooxygenation of ureas and carbamates. Adapted from Rao, W.-H.; Yin, X.-S.; Shi, B.-F. Org. Lett. 2015, 17(15), 3758–3761; Zhu, H.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136(5), 1766–1769.

Fig. 32 Palladium-catalyzed 1,2-aminooxygenation vs. 1,2-oxyamination of 1,3-dienes. Adapted from Wen, K.; Wu, Z.; Huang, B.; Ling, Z.; Gridnev, I. D.; Zhang, W. Org. Lett. 2018, 20(6), 1608–1612.

Fig. 33 Palladium-catalyzed 1,2-aminoxygenation of a-amino acids derivatives. Adapted from Wen, K.; Wu, Z.; Chen, B.; Chen, J.; Zhang, W. Org. Biomol. Chem. 2018, 16(31), 5618–5625.

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165

DMSO gave higher yields than using O2 alone. Han and Gong observed that with an appropriate chiral py-BOX ligand, the regioselectivity could be controlled and the transformation could be rendered enantioselective (Eq. 142).287

ð142Þ

13.04.6.1.2

Rhodium-catalyzed

Rhodium-mediated aminooxygenation of alkenes involves a mechanistic paradigm of either metallonitrenoid formation, followed by aziridination and oxygen nucleophile mediated ring opening, or carbocation formation followed by nucleophilic quenching of the carbocation. The first example of rhodium-catalyzed intramolecular, two-component-aminooxygenation was developed by Rojas in 2002.288 This protocol, while limited in scope, was used in the synthesis of amidoglycols, providing good yields and excellent b:a selectivity (Eq. 143). Intermolecular methods for aminooxygenation have also been developed using rhodium catalysis,.289,290 Dauban reported the first method in 2014 through the use of [Rh2(esp)2], tosyl amine, PhI(OAc)2, and acetic acid (Eq. 144).289 A variety of styrenes and aliphatic alkenes underwent aminooxygenation in good yields and with high regioselectivity. Zhong was able to extend this methodology for use in aqueous media with a PBS buffer (Eq. 145).290 Rhodium-mediated aminooxygenation has also been used to synthesize a-amino-dihydrofurans via the intramolecular cyclization of N-tosyl O,o-unsaturated alkoxyamines (Eq. 146).291

ð143Þ

ð144Þ

ð145Þ

ð146Þ

A regiodivergent method for aminooxygenation of 1,3-dienes was developed under rhodium catalysis.292 Castillion realized 1,2-functionalization using [Rh2(OAc)4]/PhI(OPiv)2 and 1,4-functionalization using [Rh2(OPiv)4]/PhI(OAc)2 (Fig. 34). The authors propose that selectivity is controlled based on the metal that is coordinated to the aziridine nitrogen during nucleophilic ring opening. With Rh2(OAc)4, rhodium coordinates to the aziridine, whereas with Rh2(OPiv)4, bulky nature of the OPiv ligands prevent it from coordinating; instead, the smaller magnesium ion coordinates to the amide nitrogen and directs the nucleophile to attack the alkene terminus (Fig. 35).

13.04.6.1.3

Copper-catalyzed

Copper-mediated aminooxygenation has been widely studied, and this work can be divided into four general types: (1) radical-based aminocyclization, (2) aziridine-based aminooxygenation, (3) intermolecular aminooxygenation, and (4) oxycylization. 13.04.6.1.3.1 Radical mediated aminocyclization A variety of intramolecular aminooxygenation methods have been developed that are proposed to proceed through Cu(I)/Cu(III) or Cu(I)/Cu(II) cycles involving radical intermediates. In 2008, Chemler developed an enantioselective aminocyclization through use of a chiral BOX ligand.293 This method uses TEMPO as the oxygen source and is compatible with alkenes containing tethered

166

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Fig. 34 Intramolecular 1,2- and 1,4-aminoxygenation of dienes using rhodium catalysis. Adapted from Guasch, J.; Díaz, Y.; Matheu, M. I.; Castillón, S. Chem. Commun. 2014, 50(55), 7344–7347.

Fig. 35 Mechanistic rationale for regioselectivity in rhodium-catalyzed aminooxygenation of dienes. Adapted from Guasch, J.; Díaz, Y.; Matheu, M. I.; Castillón, S. Chem. Commun. 2014, 50(55), 7344–7347.

anilines and similar substrates. This mode of reactivity was later expanded to include N-sulfonyl-O-butenyl hydroxylamines294 and alkenyl imines295 as alkene substrates (Eqs. 147 and 148) and PhI(OAc)2 (Eq. 149),296 carboxylic acids (Eq. 150)297 and O2 (Eq. 151)298 as the oxygen atom sources.

ð147Þ

ð148Þ

ð149Þ

ð150Þ

ð151Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

167

13.04.6.1.3.2 Aziridine-based aminooxygenation Aminooxygenation can also proceed via the intermediacy of aziridines using sulfonyl-protected amines (Eq. 152).299,300

ð152Þ

13.04.6.1.3.3 Intermolecular aminooxygenation Many activated and a few unactivated alkenes have been shown to undergo copper-catalyzed intermolecular aminooxygenation using N-sulfonyl oxaziridines301–303 and N-acyloxyamines.304 Yoon first developed this approach with styrenes and unactivated alkenes in 2007301 and later expanded the scope to include additional conjugated alkenes in 2008303 (Eq. 153). For terminal 1,3-dienes, good to excellent selectivity for the 1,2-product is observed. This process was rendered enantioselective for styrenes through use of a chiral BOX ligand (Eq. 154).303 The intermolecular aminooxygenation of a,b-unsaturated ketones has also been developed using N-acyloxyamines with complete regioselectivity to form the a-alcohol (Eq. 155).304

ð153Þ

ð154Þ

ð155Þ

A three-component copper-catalyzed 1,2-aminooxygenation reaction of 1,3-dienes was reported by Wang in 2019.305 This method is highly compatible with terminal dienes that are sterically or electronically differentiated, but low diastereoselectivity is observed with all internal dienes and many unactivated terminal dienes (Eq. 156). The authors do not propose a mechanism to account for the selectivity of this transformation; nevertheless, a radical trapping experiment with BHT was performed, and BHT adducts from reaction with the diene and with the NdO reagent were observed, suggesting a radical pathway may be operative.

ð156Þ

13.04.6.1.3.4 Oxycyclization The first intramolecular oxyamination was developed by Chemler in 2012 using stoichiometric copper.306 This method involves the cyclization of b-hydroxy-N-allylsulfonamides to provide substituted morpholine products (Eq. 157). Later, Wang developed a method for the oxyamination of b,g-unsaturated aryl oximes with TMS-azide to afford isooxazoline products.307 This work was later expanded by Yu to incorporate simple amines as nucleophiles (Eq. 158).304 Alkenyl carboxylic acids have proven competent substrates in oxycyclization processes, as developed by Buchwald,308 Lei309 (Eq. 159), and Wang310 (Eq. 160), with each report incorporating new nitrogen sources, alkenyl acids, and oxidants.

ð157Þ

ð158Þ

168

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð159Þ

ð160Þ

13.04.6.1.4

Platinum-catalyzed

A single report of platinum-catalyzed aminooxygenation of alkenes was described by the Muñiz group in 2009.311 In this protocol, alkyl ureas undergo intramolecular cyclization to afford aminooxygenated products in good yields (Eq. 161). In terms of scope, the method tolerates alkyl branching off of the tethering atoms, and in addition to monosubstituted terminal alkenes, one example of a 1,1-disubstituted alkene is reported.

ð161Þ

13.04.6.1.5

Iron-catalyzed

Yoon developed an iron-catalyzed protocol for aminooxygenation.312 In this method, sulfonyl-oxaziridines serve as the source of both nitrogen and oxygen (Eq. 162), providing the opposite regioselectivity compared to Yoon’s copper-based system (Eq. 153). This transformation was later rendered enantioselective through use of a chiral BOX ligand, but this protocol is only compatible with conjugated alkenes (Eq. 163).313 The diastereoselective intramolecular aminooxygenation of alkene-containing hydroxylamines was developed by Xu in 2013314 and later expanded on by Berhal and Prestat315 (Eq. 164). This method is stereoconvergent, meaning that both (E)- and (Z)-olefins lead to the same major diastereomer (with the same ee and dr) (Eq. 165). Later, an intermolecular version of this chemistry was developed (Eq. 166).316 When used with electronically or sterically differentiated 1,3-dienes, the products were observed as single regioisomers.

ð162Þ

ð163Þ

ð164Þ

ð165Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

169

ð166Þ

13.04.6.1.6

Gold-catalyzed

While there exists a large body of literature on gold-catalyzed aminooxygenation of alkynes, only one example of gold-catalyzed alkene aminooxygenation has been reported to date. Nevado described the aminooxygenation of alkenyl sulfonamides with water or alcohol as the oxygen nucleophile with Selectfluor as the oxidant (Eq. 167).317 Typically, these conditions favor formation of the 6-membered ring but vary considerably based on substrate. Deuterium labeling studies revealed that (E)-alkenes provide trans products and (Z)-alkenes provide cis products, consistent with an anti-aminoauration step.

ð167Þ

13.04.6.1.7

Manganese-catalyzed

Jiao has reported the only example of manganese-catalyzed hydroxyazidation of alkenes, a transformation that possesses remarkable efficiency and scope.318 This method is compatible with styrenes, aliphatic alkenes, and a,b-unsaturated carbonyls using TMSN3 as nucleophile and air as oxidant (Fig. 36). In the case of vinylbenzoic acids, lactonization occurs to produce substituted endoperoxides. Aryl-substituted terminal 1,3-dienes underwent 1,2-aminooxygenation in high yields and regioselectivity.

13.04.6.1.8

Iridium-catalyzed

Iridium is able to promote the oxyamination of unactivated alkenes to provide g-lactams, g-lactones, and d-lactams, as described by Rovis (Fig. 37).319 The authors found that the regioselectivity could be inverted by altering the structure of the iridium catalyst and the identity of the base.

13.04.6.2 Aminooxygenation of alkynes 13.04.6.2.1

Ruthenium-catalyzed

A number of 1,4-benzoxazine derivatives can be synthesized via the ruthenium-catalyzed annulation of 1,2-aminophenol analogues and symmetrical internal alkynes (Eq. 168).320

ð168Þ

Fig. 36 Manganese-catalyzed hydroxyazidation of alkenes. Adapted from Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.; Jiao, N. J. Am. Chem. Soc. 2015, 137(18), 6059–6066.

Fig. 37 Iridium-catalyzed synthesis of g-lactams, g-lactones, and d-lactams from unactivated tethered alkenes. Adapted from Lei, H.; Conway, J. H.; Cook, C. C.; Rovis, T. J. Am. Chem. Soc. 2019, 141(30), 11864–11869.

170

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.6.2.2

Gold-catalyzed

Mechanistically, gold-mediated alkyne aminooxygenation is similar to gold-mediated alkyne dioxygenation. Hence, the reader is directed to that section for further details. A regiodivergent gold-catalyzed aminooxygenation of aminoalkynes was reported using gold catalysis.321 The authors found that the combination of JohnPhosAuSbF6 and nitrones resulted in 1,2-oxyamination, while IPrAuCl/AgNTf2 and nitrosoarenes resulted in 1,2-aminooxygenation (Fig. 38). The products could be isolated directly or reduced in situ. Later, methods were developed for the synthesis of pyrrolidine-3-ones322 and 3-oxyindoles323 using intermolecular gold-catalyzed oxidation followed by annulation (Eqs. 169 and 170). These methods use pyridine-N-oxides as oxidants and phosphines as ligands. In the case of enantioenriched chiral homopropargyl amines, aminooxygenation occurred without erosion of ee for most substrates. A gold-catalyzed 6-endo-dig azide-yne cyclization/OdH insertion cascade reaction of azide-containing alkynes with alcohols was reported by Xu in 2020.324 This method is compatible with a range of alkyl- and aryl-substituted alkynes in good yields (Eq. 171).

ð169Þ

ð170Þ

ð171Þ

ð172Þ

13.04.6.2.3

Copper-catalyzed

Stoichiometric copper has been used to synthesize ionic pyridinium-oxazole-dyads (PODs) for use in mitochondrial imaging (Eq. 173).325 A method to access these PODs had previously been developed using catalytic Au(I) and Selectfluor, but this approach was incompatible with electron-rich aromatic rings due to formation of large amounts of fluorinated byproducts in these cases (Eq. 172).326

ð173Þ

Fig. 38 Gold-catalyzed 1,2-aminooxygenation and 1,2-oxyamination of aminoalkynes. Adapted from Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad, S. N.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133(39), 15372–15375.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.6.2.4

171

Iron-catalyzed

An Fe(III)-catalyzed aminooxygenation protocol has been developed for the synthesis of imidazo[1,2-a[pyridines]].327 In this method, 2-aminopyridines are first condensed with alkynyl aldehydes to generate imines that then undergo subsequent iron-mediated aminocyclization followed by CdO bond forming using air as the terminal oxidant (Fig. 39). This chemistry is compatible with a variety of pyridines and (hetero)aryl aldehydes; additionally, one example of an alkyl-substituted alkyne is included.

13.04.6.3 Aminooxygenation of allenes 13.04.6.3.1

Rhodium-catalyzed

The aminooxygenation of allenes containing tethered sulfonamides with nitrones was developed by Blakey in 2011.328 Mechanistically, this transformation is proposed to proceed through rhodium–nitrene addition to the allene, which generates an allylic cation. This rearranges to an iminocyclopropane which can then react with the nitrone. Subsequent trapping of the oxyanion provides the corresponding aminooxygenated products in moderate yields (Fig. 40). Schomaker has reported related transformations in which analogous methylene aziridines are generated and can then react with oxygen nucleophiles in either stepwise manner329 or in a one-pot procedure (Eqs. 174 and 175).330

ð174Þ

ð175Þ

Fig. 39 Iron-catalyzed synthesis of imidazo[1,2-a[pyridines]] via aminooxygenation of alkynes. Adapted from Chen, Z.; Liu, B.; Liang, P.; Yang, Z.; Ye, M. Tetrahedron Lett. 2018, 59(7), 667–670.

Fig. 40 Proposed mechanism for Rhodium-catalyzed intramolecular aminooxygenation of allenes. Adapted from Stoll, A. H.; Blakey, S. B. Chem. Sci. 2011, 2(1), 112–116.

172

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Fig. 41 Copper-mediated aminooxygenation of allenes. Adapted from Casavant, B. J.; Khoder, Z. M.; Berhane, I. A.; Chemler, S. R. Org. Lett. 2015, 17(24), 5958–5961.

13.04.6.3.2

Copper-mediated

The only example of copper-mediated aminooxygenation of allenes was described by Chemler in 2015.139 This reaction requires stoichiometric copper and provides access to substituted heterocycles in good yields and with high diastereoselectivity (Fig. 41).

13.04.7 Carboamination Carboamination reactions convert a CdC p-bond into one new CdN bond and one new CdC bond. In the past few decades, many different types of carboamination reactions have been developed using an array of carbon and nitrogen coupling partners and various transition-metal catalysts. Based on the advances, carboamination has emerged as an increasingly powerful transformation in modern synthetic chemistry, especially for synthesizing azaheterocycles and structurally complex amines.

13.04.7.1 Carboamination of alkynes Transition-metal-catalyzed carboamination of alkynes was pioneered by Bergman in 2004 (Fig. 42).331,332 Using an imidozirconium complex as the catalyst, the carbon–nitrogen double bond of an aldimine substrate is cleaved, and the resulting benzylidene and imido fragments are added across an internal alkyne, giving a conjugated imine product. In the proposed mechanism, the reaction proceeds through a six-membered metallacycle intermediate generated from insertion of the electron-deficient imine into the azazirconacyclobutene catalyst. This metallacycle complex undergoes retro-[4 +2] cycloaddition to afford the corresponding product and an imidozirconium species. Then, the catalyst can be regenerated by [2 +2] cycloaddition between the alkyne and the imidozirconium species. A similar carboamination reaction catalyzed by a cationic titanium catalyst was also reported in following year by Mindiola.333,334 In 2016, the first three-component, titanium-catalyzed oxidative carboamination of alkynes was reported by Tonks (Eq. 176).335 Using alkenes and diazenes as coupling partners, either a,g-unsaturated imine or a-(iminomethyl)cyclopropanes were afforded. A series of mechanistic studies supported the proposal that each of these products is generated from a common azatitanacyclohexene intermediate that is formed during the Ti(II)/Ti(IV) catalytic cycle. From the azatitanacyclohexene intermediate, b-elimination followed by reductive elimination leads to formation of the unsaturated imine product. On the other hand, a,g-reductive coupling from this intermediate gives corresponding cyclopropane product.

Fig. 42 Proposed mechanism for zirconium-catalyzed carboamination of alkynes. Adapted from Ruck, R. T.; Zuckerman, R. L.; Krska, S. W.; Bergman, R. G. Angew. Chem. Int. Ed. Engl. 2004, 43(40), 5372–5374.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

173

ð176Þ Numerous late transition metals, such as palladium, nickel, and copper, have also been employed for heteroannulation of alkynes.336–342 For example, Larock reported what has become a widely used and venerable method for indole synthesis via palladium-catalyzed heteroannulation of alkynes with o-iodoanilines (Eq. 177).343 More recently, nickel-catalyzed carboamination of alkynes with N-aryl phthalimides was reported in 2008 (Eq. 178).338 In this reaction. the electron-rich trimethylphosphine ligand is essential for achieving challenging CdN oxidative addition of the nickel catalyst into the imide, giving the six-membered nickelacycle intermediate. Sequential decarbonylation, alkyne insertion, and reductive elimination from this intermediate provide the desired isoquinolone product. Only one year later, decarboxylative carboamination of alkynes was also developed under similar reaction conditions.339

ð177Þ

ð178Þ

13.04.7.2 Carboamination of allenes Most examples of transition-metal-catalyzed allene carboamination involve intramolecular aminocyclization of a tethered nitrogen nucleophile onto a pendant allene.342 The first example of intramolecular carboamination of allenes was reported in 1993 by Gallagher (Eq. 179).343 Using a palladium catalyst and an aryl iodide as the electrophile, allene substrates containing pendant protected secondary amines underwent cyclization to afford pyrrolidine products. Mechanistically, the reaction was proposed to involve Heck-type insertion of an arylpalladium species into the allene, followed by intramolecular aminocyclization onto the resultant p-allylpalladium intermediate. When aminoallenes containing a shorter tether with one fewer carbon atom were employed under similar reaction condition, either a four-membered ring or six-membered ring was obtained from the common p-allylpalladium intermediate (Eq. 180).344 The regioisomeric product ratio between these two products was highly affected by the substituents, coupling partners, and reaction time. In particular, shorter reaction time delivered the kinetically favored four-membered azetidine products, while longer reaction time gave the thermodynamically preferred six-membered ring product. Beyond these examples, numerous related allene carboamination reactions using different nitrogen nucleophiles, electrophiles and transition-metal catalysts have been reported.342,345

ð179Þ

ð180Þ

In 2014, the copper-catalyzed enantioselective carboamination of allenes was reported (Eq. 181).346 Using a copper catalyst with chiral (S,S)-Ph-BPE as ligand, allenyl anilide substrates and carbonyl electrophiles were found to react to deliver 2-(2-hydroxyethyl) indole scaffolds in an enantioselective manner. The proposed catalytic cycle begins with intramolecular amido-cupration to generate a chiral allylcopper species, which then reacts with the carbonyl electrophile to effect asymmetric allylation, thereby furnishing the desired indole product.

174

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð181Þ

13.04.7.3 Carboamination of 1,3-butadienes Heteroannulation of 1,3-butadiene with o-iodoanilines was first disclosed by Dieck in 1983 and then extended to a variety of other heterocyclic systems by Larock.347,348 More recently, enantioselective heteroannulation of 1,3-dienes has been reported using a palladium catalyst bearing a chiral phosphoramidite ligand (Eq. 182).349 The proposed mechanism involves the migratory insertion of an ortho-aminoarylpalladium(II) species into the 1,3-diene followed by intramolecular nucleophilic attack of the nitrogen nucleophile. Additionally, it has been found that ortho-aminoarylpalladium(II) species of this type can also be accessed from simple aniline substrates via carbonyl-directed CdH activation.350,351

ð182Þ 352

The first three-component carboamination of 1,3-dienes was reported in 2019. Using a Weinreb amide directing group, Rh(III) catalyzed C(aryl)dH activation takes place, followed by insertion into the 1,3-diene to give the putative p-allylrhodium intermediate. This intermediate reacts further with the electrophilic dioxazolone to trigger CdN bond formation (Eq. 183). The overall sequence yields the 1,4-carboaminated, (E)-configured allylic amine product with high selectivity under mild reaction conditions.

ð183Þ

Beyond reactions involving closed-shell classical organometallic 1,2-migratory insertion into 1,3-dienes, three-component carboamination can also be achieved via carbon-centered radical addition processes. This mode of reactivity is exemplified in the photoinduced palladium-catalyzed three-component coupling between an alkyl iodide, a secondary amine, and 1,3-dienes reported in 2020 (Eq. 184).353 Various mechanistic experiments indicate that the mechanism involves generation of a carbon-centered radical from a single-electron transfer process between the photoexcited Pd(0) catalyst and the alkyl iodide. Addition of the alkyl radical to the diene and combination with Pd(I) gives a p-allylpalladium(II) species. Then, the amine nucleophile attacks the p-allylpalladium species to yield the 1,2-carboamination product. In the same year, Glorius employed N-hydroxyphthalimide esters as bifunctional regents to effect carboamination of 1,3-dienes (Eq. 185).354 In the proposed catalytic cycle, an alkyl radical is generated after single-electron transfer from the metal to the N-hydroxyphthalimide ester, followed by decarboxylation. The thusly generated carbon-centered radical engages the 1,3-dienes and forms a p-allylpalladium(II) intermediate that is trapped by phthalimide.

ð184Þ

ð185Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

175

13.04.7.4 Carboamination of alkenes The carboamination of alkenes has been most thoroughly studied in the context of two-component reactions. A series of palladium(0)-catalyzed cyclization reactions between alkenes containing tethered nitrogen nucleophiles and aryl (pseudo)halides have been extensively investigated by Wolfe and others (Fig. 43).355 These reactions are initiated via oxidative addition of the aryl (pseudo)halide to the palladium(0) catalyst, and the resulting arylpalladium(II) intermediate undergoes ligand exchange to furnish a palladium–amido species. Then, intramolecular syn-aminopalladation into the alkene followed by CdC reductive elimination delivers the desired carboamination product. This catalytic system is assisted by specially designed phosphine ligands. For example, enantioselective aminocyclization was enabled by using chiral (R)-Siphos-PE ligand.356 Applying an analogous reaction mechanism, enantioselective carboamination between an aryl triflate bearing a tethered alkene and a free amine has also been demonstrated by Wolfe (Eq. 186).357 Bower reported a Narasaka–Heck-type umpolung carboamination using an alkene substrate tethered to an electrophilic nitrogen source, which upon cyclization is able to couple with a carbon nucleophile (Eq. 187).358,359 In 2009, Michael reported an intramolecular carboamination using nucleophilic arenes instead of aryl halides as a carbon source.360 In the presence N-fluorobenzenesulfonimide (NFSI), an alkylpalladium(II) intermediate was able to be oxidized to an alkylpalladium(IV) species that is capable of activating a C(aryl)dH bond; C(sp3)dC(Ar) reductive elimination then affords the desired carboaminated product (Eq. 188). Unlike the previous Pd(0)/Pd(II) catalytic involving syn-aminopalladation mechanism, in this case a Pd(II)/Pd(IV) catalytic cycle was proposed.76,360

ð186Þ

ð187Þ

ð188Þ

A significant advance in intermolecular two-component carboamination was reported by Rovis in 2015 using rhodium as a catalyst (Eq. 189).361 By using an N-enoxyphthalimide as both the nitrogen and carbon source, 1,2-syn-carboamination of electronically activated alkenes was demonstrated.

Fig. 43 Proposed mechanism for the palladium-catalyzed intramolecular carboamination of alkenes. Adapted from Garlets, Z. J.; White, D. R.; Wolfe, J. P. Asian J Org. Chem. 2017, 6(6), 636–653.

176

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð189Þ Due to difficulties stemming from competitive two-component coupling, b-hydride elimination and controlling regiochemistry, three-component carboamination thus far have been largely limited to specific alkene classes such as electronically activated alkenes or directing group tethered alkenes. For example, a radical carboamination strategy has been an extensively studied for the vicinal-carboamination of styrenes, which benefit from radical stabilization effect.362 In particular, copper catalysts or transitionmetal-based photoredox catalysts are widely used in this field. Successful coupling partner combinations include nitrogen radical source/carbon nucleophile or carbon radical source/nitrogen nucleophile. For instance, copper-catalyzed three-component enantioselective 1,2-carboamination of styrenes was reported in 2017 (Eq. 190).363,364 A nitrogen-centered radical generated from N-fluorobenzenesulfonimide (NFSI) adds to the styrene, and the resulting benzylic radical stereoselectively combines with a Cu(II)dCN intermediate to afford the enantioenriched 1,2-carboaminated product. On the other hand, carbon-centered radical initiated 1,2-carboamination has also been reported.365 Employing alkyl iodide as a carbon radical source and free amine under blue LED irradiated condition, a Cu(I)/Cu(III) catalytic cycle gives the desired carboaminated product (Eq. 191).

ð190Þ

ð191Þ In 2017, Engle reported a three-component 1,2-carboamination of unactivated alkenes using a directing auxiliary strategy (Eq. 192).366 The 8-aminoquinoline directing group was used to control regioselectivity of aminopalladation and stabilize the resulting alkylpalladium(II) intermediate to prevent b-hydride elimination. Mechanistic studies suggested a pathway involving oxidative addition of the organoiodide (RdI) electrophile to the alkylpalladium(II) to generated a Pd(IV)(Alkyl)(R) species. In addition, reaction kinetics and computational studies were consistent with the CdC reductive elimination step from the Pd(IV) center as the turnover-limiting step. An umpolung nickel-catalyzed 1,2-carboamination reaction was also reported by Engle using the same 8-aminoquinoline directing group (Eq. 193).367 Using electrophilic aminating reagent and organozinc reagent as coupling partners, a wide range of b- and g-amino acid derivatives were afforded. O O

N

R'''

N H

+

R'

N

R''

Pd(OAc)2 (10 mol%) +

R

I KHCO3

H

R

O

N

N R'''

N H R'

N

via:

N

Pd L

R''

R'''

R' N R''

R = Ar, alkenyl

ð192Þ

O

N

N H

R'''

+

R'

N

R''

O

Ni(cod)2 (15 mol%) +

R ZnX

OBz

N

N H

R'

N

OM

R'' R''' R

via:

N N

Ni L/X R'''

R

R = Ar, alkyl

ð193Þ In 2015 Liu and coworkers reported the first example of an intermolecular aminocarbonylation reaction. The authors propose that using a hypervalent iodine reagent accelerates intermolecular aminopalladation of alkene substrates allowing for facile access to b-amino acid derivatives (Eq. 194).368 The proposed mechanism includes syn-aminopalladation of alkenes followed by CO insertion and nucleophilic attack of carboxylate to deliver the anhydride product, which could undergo alcoholysis to ester.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

1) Pd(O2CCF3)2 (10 mol%), CO (1 atm), R''

+

O

O

NRZ

2) MeOH, 1h, rt

O

NRZ

NHRZ PhI(O2CR')2 (2 eq.), MeCN/toluene

O

R''

3) TMSCHN2, 3h, rt

MeO

177

R''

ð194Þ

13.04.8 Carbohalogenation 13.04.8.1 Carbohalogenation via reductive elimination from Pd(II) To date, most examples of alkene/alkyne carbohalogenation proceeding via a Pd(0)/Pd(II) cycle have been intramolecular, with intermolecular examples being limited to norbornene. These reactions proceed through the general mechanism depicted in Fig. 44 in which reversible oxidative addition of an aryl halide to Pd(0) is followed by carbopalladation to afford an alkylpalladium(II) species that cannot undergo b-hydride elimination. Subsequent C(sp3)dX reductive elimination affords the cyclized product and regenerates the Pd(0) catalyst. This approach is exceedingly atom-economical, with all of the atoms in the starting material being incorporated into the product. In 2011, Newman and Lautens reported the first example of this methodology using alkene-tethered aryl iodides treated with Pd(Q-Phos)2 at elevated temperatures to give carboiodinated products in good to excellent yields (Eq. 195).369 A bulky phosphine ligand was found to be crucial for reactivity, which is common for reductive eliminations of this type.370 Lautens and coworkers later improved this methodology by developing a process involving tandem Pd-catalyzed halogen exchange with potassium iodide, which expanded the scope to include aryl bromide precursors.371 This strategy was further extended to facilitate domino processes for the synthesis of lactams from the corresponding aryl bromide or iodide (Eq. 196).

ð195Þ

ð196Þ

Lautens and coworkers next reported the highly diastereoselective synthesis of isochromans (Eq. 197) and chromans (Eq. 198).372 This report marked the first example of nitrogen-containing heteroaryl compounds undergoing a carboiodination process. Triethylamine was determined to be a necessary additive that dramatically increased yield at the expense of reaction rate; however, the origin of this effect has not been determined.

ð197Þ

ð198Þ

Lautens et al. subsequently reported the synthesis of indene products prepared through a domino approach from o-isoprenyl iodobenzenes and internal alkynes (Eq. 199)373 as well as the intramolecular carboiodination reactions of various classes of diiodinated substrates (Eq. 200).374 Owing to the reversibility of the oxidative addition step, the CdI bond in the product remains intact under the reaction conditions; however, the authors were also successful in developing a chemoselective intramolecular

Fig. 44 General mechanism for carbohalogenation proceeding via a Pd(0)/Pd(II) cycle.

178

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

carboiodination/intermolecular Heck reaction (Eq. 201). In situ 1H NMR studies suggested that the two processes occur simultaneously and not sequentially.374

ð199Þ

ð200Þ

ð201Þ

Tong and co-workers reported the cyclization of (Z)-1-iodo-1,6-dienes using the relatively less bulky dppf (1,10 -Bis (diphenylphosphino)ferrocene) ligand (Eq. 202).375 Using (S)-BINAP as a ligand allowed for the preparation of a tetrahydropyridine product with 56% ee, but in only 10% yield. Tong’s group later reported a similar method for the synthesis of dihydropyrroles.376

ð202Þ

Lautens and coworkers found that alkenyl halides could be prepared according to their previously developed strategies (Eq. 203).377 In this case, both use of the Q-Phos ligand and the presence of a sterically bulky R0 substituent were crucial for formation of the product (presumably because the combined steric encumbrance helps to facilitate reductive elimination). Both syn- and antiaddition products were formed in this reaction, but the syn-addition products could be isomerized to the anti-addition products in the presence of the catalyst at elevated temperatures. Notably, this marks a rare example of aryl chloride precursors acting as viable substrates for this type of process.

ð203Þ

Lautens and coworkers found that using enantioenriched N-allyl carboxamides in the cyclization reactions afforded the corresponding benzo-fused g-lactams in good to excellent yields with high levels of enantiocontrol (Eq. 204).378 Few of the previously discussed carbohalogenation reactions have been rendered enantioselective, with most reports only proving moderately successful. For instance, using chiral Josiphos ligand SL-J002-1 afforded the corresponding product in high ee with a poor yield (Eq. 205), while synthesis of a lactam using chiral Walphos ligand SL-W001-1 proceeded with a moderate yield but significantly poorer enantioselectivity (Eq. 206).379 The recent highly enantioselective carboiodination reactions reported by Li and Xiang (Eq. 207) represent one of the only examples of this type of process generating products in good yields with high enantioselectivity.380

ð204Þ

ð205Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

179

ð206Þ

ð207Þ Recently, Tong and coworkers reported the asymmetric cyclization of (Z)-1-iodo-1,6-dienes and (Z)-1-bromo-1,6-dienes (Eq. 208).381 The method uses [Et3NH]+[BF4]− as an H-bond donor under a toluene/water/(CH2OH)2 biphasic system and proceeds with moderate to good yields and good to excellent enantioselectivity. Mechanistic studies suggest that [Et3NH]+[BF4]− facilitates the heterolytic dissociation of halogen–PdII bonds via hydrogen-bonding interactions, reducing the energy barrier of C(sp3)–halogen reductive elimination.

ð208Þ

In 2019 Lee and Morandi disclosed an intermolecular palladium-catalyzed addition reaction to alkynes for the stereoselective synthesis of functionalized tetrasubstituted alkenyl iodides (Eq. 209).382 While typical intermolecular strategies for alkyne carboiodination proceed via a carbometallation followed by interception with an external halide source, this marks the first example that follows the atom-economical incorporation of the starting material halide into the products. Notably, the reaction relies on the rarely employed electron-deficient dArFpe ligand.

ð209Þ

13.04.8.2 Carbohalogenation via reductive elimination from high valent metals Advances in strategies for C(sp3)dX reductive elimination from high valent metal species under mild conditions have facilitated the development of several new approaches to alkene/alkyne carbohalogenation, including products formed from kinetically difficult CdF bond formation. These reactions follow the general mechanisms outlined in Fig. 45. Following nucleometallation (via a Heck-type pathway), the alkylmetal intermediate can be intercepted with electrophilic halogenation reagents or nucleophilic halogen sources combined with an oxidant to form a high-valent intermediate complex, which readily undergoes reductive elimination to give the newly formed CdX bond. Achieving high levels of pathway selectivity (favoring 1,2- vs. 1,1-carbohalogenation pathways, b-hydride elimination, or other side reactions) can be challenging. In efforts focused on intramolecular methods, selectivity typically arises from conformational restrictions. For intermolecular couplings, the selective formation of either 1,1- or 1,2-carbohalogenated products is typically accomplished with electronic control (where regioselectivity is governed by substrate electronics, exemplified by p-benzyl-stabilized intermediates) or directing groups (where selectivity is governed by substrate directivity), respectively. A stoichiometric example of an intramolecular fluorocyclization of polyenes using an electrophilic Pt(II) complex was reported by Gagne and coworkers in 2013.383 XeF2 served as both the fluorinating reagent and oxidant and moderate enantioselectivity could be achieved in the presence of (S)-xylyl-phanephos (Eq. 210).

ð210Þ

180

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Fig. 45 Mechanistic pathways in alkene carbohalogenation proceeding via high valent metal intermediates (top) and strategies previously employed for controlling regioselectivity (bottom).

Fig. 46 Palladium-catalyzed 1,1- and 1,2-arylchlorination and arylbromination. Adapted from Kalyani, D.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130(7), 2150–2151; Kalyani, D.; Satterfield, A. D.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132(24), 8419–8427.

Despite being first reported by Heck in 1968 (albeit with limited synthetic utility owing to modest substrate scope, competing b-hydride elimination/olefin dissociation, and the requirement for aryl mercury reagents)384 intermolecular carbohalogenation achieved via high-valent metal complexes remained relatively unexplored until pioneering work by Sanford and coworkers. This work demonstrated synthetically relevant methodologies for the intermolecular carbohalogenation of alkenes and identified conditions for 1,1- and 1,2-arylchlorination385 as well as 1,1- and 1,2-arylbromination.386 The authors were able to tune selectivity by modifying the relative rates of four elementary steps in the mechanism: olefin insertion, b-hydride elimination, olefin dissociation, and oxidative functionalization. This was achieved through judicious choice of oxidant and solvent (Fig. 46). In 2014, Talbot, McKenna, and Toste reported a palladium-catalyzed amide-directed arylfluorination of styrenyl substrates.387 The three-component coupling using Selectfluor, arylboronic acid, and styrenyl substrate was able to produce chiral benzylic fluorides in generally good yield with moderate to high ee (Eq. 211). The authors note that in the absence of a coordinating ligand only Heck product was formed. Solvent selection was of vital importance, as no product was formed in DMF, THF, MeCN, or EtOAc. Water increased the rate of the reaction, and addition of an organic phosphate phase transfer catalyst to the biphasic mixture reduced byproducts. The addition of tert-butylcatechol was posited to prevent polymerization of starting material and negate any radical pathways. A closely related variant of this method has been developed by Chen and coworkers to expand the substrate scope to include internal enamides.388

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

181

ð211Þ

Toste and coworkers subsequently developed conditions for the 1,1-arylfluorination of aminoalkene substrates.389 Because the protected allylamines cannot serve as a suitable directing group (to stabilize the alkylpalladium intermediate and prevent b-hydride elimination and subsequent reinsertion), the 1,1-arylfluorination pathway is favored. Using a chiral Box ligand facilitated the asymmetric reaction with moderate to good enantioselectivity (Eq. 212). Toste later reported conditions that expanded the reaction scope to include a,b-unsaturated carbonyl derivatives.390

ð212Þ

Recently, Engle and coworkers reported the palladium-catalyzed three-component coupling of alkenylbenzaldehydes, arylboronic acids, and N-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate facilitated by a transient directing group (TDG) (Eq. 213).391 The method allows for the formation of vicinal stereocenters with excellent regio-, diastereo-, and enantioselectivities. Notably, both quaternary carbon–aryl and carbon–fluorine bonds were accessible.

ð213Þ

13.04.8.3 Carbohalogenation via nickel catalysis In the past few years, nickel-catalyzed processes for the carbohalogenation of alkenes/alkynes have appeared in the literature. Lautens and coworkers have developed a number of nickel-catalyzed methods for some of the same substrates that were previously explored in palladium-catalyzed processes. They reported the first intramolecular Ni-catalyzed halogenation from aryl iodide or bromide starting materials in 2018 (Eq. 214).392 Subsequently, they were able to expand the substrate scope to include carbamoyl chloride starting materials (Eq. 215).393

ð214Þ

ð215Þ

Lautens and coworkers have also developed Ni-catalyzed carboiodination reactions that do not require a metal based reducing agent such as manganese. Through utilization of a phosphite ligand on nickel, the authors were able to develop a dearomative carboiodination reaction of indoles394 as well as a diastereoselective carboiodination to synthesize six-membered nitrogen-based heterocycles (Eq. 216).395 This was further extended to the synthesis of carbocyclic ring systems (Eq. 217).396

ð216Þ

ð217Þ

182

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Kurahashi and Matsubara have disclosed conditions for the intermolecular carboiodination397 and carbobromination of internal alkynes (Eq. 218).398 To overcome the limitations associated with the typically disfavored reductive elimination of a carbon– bromine bond from Ni(II), the authors targeted a reductive elimination process from the corresponding Ni(III) species. Mechanistic studies provided evidence supporting the proposed Ni(I)/Ni(III) catalytic cycle.

ð218Þ

13.04.9 Aminohalogenation 13.04.9.1 Aminohalogenation via palladium catalysis In 2004, Liu and Chemler independently reported examples of palladium-catalyzed intramolecular 1,2-aminohalogenation using copper salts as both the stoichiometric oxidant and the halide source. Liu’s report detailed the cyclization of N-tosylcarbamates and ureas, a substrate class that was a able to undergo highly regio- and diastereoselective aminohalogenation reactions (Eq. 219).399

ð219Þ

Chemler’s conditions were similar but did not employ LiX as additive. Using N-tosylpentene and N-tosyl-2-allylaniline as substrates, Chemler and coworkers observed a mixture of regioisomers (Eq. 220).400 In these cases, the author’s attributed the formation of piperidine side products to endo-selective aminopalladation and subsequent oxidative halogenation. Other possibilities discussed included initial exo-selective aminopalladation followed by aziridinium ion formation, and subsequent intermolecular nucleophilic attack by halide.

ð220Þ

An exo-selective intramolecular 1,2-aminochlorination of amides and carbamates was reported by Michael and co-workers in 2008.401 Using N-chlorosuccinimide as both the oxidant and halogen source, the cyclized products were obtained in good to excellent yield (Eq. 221).

ð221Þ

In 2009, Liu and co-workers reported an endo-selective intramolecular 1,2-aminofluorination of g-pentenylsulfonamides for the synthesis of piperidines (Fig. 47).402 A variety of b-fluoropiperidines were prepared in good to excellent yields. This same catalytic system was also later applied in the synthesis of fluorinated cyclic sulfonamids.403 Based on the results of deuterium labeling studies, the authors propose that the reaction proceeds through anti-aminopalladation, oxidation of the resulting alkylpalladium(II) species to an alkylpalladium(IV) intermediate, and then CdF bond formation through reductive elimination (either inner-sphere (favored) or SN2-like displacement). Additional mechanistic studies suggested that the aminopalladation step is reversible, and that oxidation of the corresponding secondary alkylpalladium(II) species is much faster than oxidation of the alternative primary alkylpalladium(II) species (due to the Pd(II) center being more electron-rich). To overcome this influence and obtain the opposite regioselectivity, the authors later installed a chelating directing group (C(O)NR2) on nitrogen.404 Both monofluoromethylated pyrrolidines and imidazolines were obtained in moderate to good yields. In 2010 Liu and co-workers reported an intermolecular 1,2-aminofluorination of styrenes using NFSI as the fluorine source and oxidant (Eq. 222).405 The authors propose a mechanism involving in situ reduction of the Pd(II) precatalyst to a Pd(0) species that is then oxidized to a Pd(II) with NFSI (Fig. 48). This intermediate then undergoes fluoropalladation and subsequent CdN reductive elimination to form the final product. This was supported by characterization (19F NMR, 1H NMR and MS) of a Pd(II)–fluoride complex generated from the oxidation of Pd(0) by NFSI. Liu and co-workers also extended this methodology to endo-selective synthesis of fluoro-substituted pyrrolidines from b-alkenyl styrenes (Eq. 223).406

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

183

Fig. 47 Proposed mechanistic rationale for the outcome of palladium-catalyzed intramolecular aminofluorination. Adapted from Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131(45), 16354–16355; Cheng, J.; Chen, P.; Liu, G. Chin. J. Catal. 2015, 36(1), 40–47.; Wu, T.; Cheng, J.; Chen, P.; Liu, G. Chem. Commun. 2013, 49(77), 8707.

Fig. 48 Proposed fluoropalladation mechanism for palladium-catalyzed 1,2-aminofluorination. Adapted from Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132(9), 2856–2857.

ð222Þ

ð223Þ

Most recently, Liu and coworkers disclosed the first example of asymmetric 1,2-aminofluorination of unactivated alkenes to synthesize b-fluoropiperidines using chiral quinoline-oxazolines (Quox) ligands (Eq. 224).407 The products are obtained in good yields and with excellent enantioselectivity. The authors found that in addition to the chiral ligand, both Et4NF
3HF and CsOCF3 were crucial additives for obtaining high enantioselectivity.

184

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

ð224Þ

13.04.9.2 Iron-catalyzed aminohalogenation Bach and coworkers first reported iron-catalyzed intramolecular aminochlorination of alkenes and alkynes using tethered azides in 2000.408,409 In the presence of TMSCl, both alkenes and alkynes were readily converted to the corresponding chlorooxazolidinones and chlorooxazolidines, respectively (Fig. 49).410 While the reaction proceeds with good yields and selectivity, the use of azides inherently limits its synthetic utility. Xu and coworkers disclosed the first iron-catalyzed intramolecular aminofluorination of styrenes in 2014,411 followed shortly after by a more general intermolecular version in 2016412 using Et3N
3HF and XtalFluor-E as the fluorine source (Eq. 225). Mechanistic studies suggest that the reaction proceeds through an iron-nitrenoid intermediate that forms a carbon radical species after cycloamination. This radical undergoes a single electron transfer–mediated oxidation of a carbon-centered radical to a carbocation that subsequently reacts to form the fluorinated product. In addition to styrenes, unactivated alkenes, ene-yne, and a-methylstyrene substrates were competent coupling partners in the intermolecular reaction.

ð225Þ In 2018, Morandi and coworkers reported an iron-catalyzed aminochlorination reaction to access primary amines under operationally simple conditions (Eq. 226).413 The reaction proceeds with excellent anti-Markovnikov regioselectivity using a hydroxylamine derivative and sodium chloride as the respective nitrogen and chlorine sources. The synthetically useful 2-chloroalkylamine products can be easily diversified to access linear or branched aliphatic amines, aziridines, aminonitriles, azido amines, and homoallylic amines.

ð226Þ

Mechanistic studies suggest that unlike previous iron-catalyzed aminohalogenation approaches (proceeding through single electron transfer–mediated oxidation of a carbon-centered radical to a carbocation), this reaction undergoes chlorine atom transfer from the amine-bound iron(III) complex to form the desired product and regenerate the iron(II) catalyst (Fig. 50). This allows a much broader scope, avoiding limitations that arise when nonbenzylic radicals are generated as intermediates in the carbocation pathway.

Fig. 49 Iron-catalyzed intramolecular aminochlorination of alkenes and alkynes. Adapted from Xu, T.; Qiu, S.; Liu, G. Chin. J. Chem. 2011, 29(12), 2785–2790.

Fig. 50 Mechanistic pathways for iron-catalyzed aminohalogenation reactions.

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

185

13.04.9.3 Aminohalogenation via gold catalysis In 2011 Xu and co-workers reported the synthesis of fluorinated pyrazoles via intramolecular 1,2-aminofluorination of alkynes under Au(I) catalysis in the presence of Selectfluor (Eq. 227).414 A variety of fluorinated pyrazoles were synthesized in moderate to good yield at room temperature; however, the reaction utility was somewhat diminished by formation of competing hydroamination byproducts.

ð227Þ

In 2013 Wu and coworkers reported the intramolecular 1,2-aminofluorination of alkynes to synthesize fluorinated imidazoles (Eq. 228).415 The reaction proceeds via aminoauration of the propargyl amidine followed by oxidative fluorination to give an alkenyl fluoride, which is aromatized to afford the final product.

ð228Þ

13.04.9.4 Aminohalogenation via high-valent copper catalysis In 2019 Fu and coworkers reported the copper-catalyzed intermolecular aminative difunctionalization of unactivated alkenes with N-halodialkylamines as the terminal dialkylamino source (Eq. 229).416 The authors found that a directing bidentate auxiliary was crucial for reactivity, with computational studies suggesting it promotes the migratory insertion into the aminyl radical–metal complex and stabilizes the resulting high-valent copper intermediate (allowing for reductive elimination or ligand exchange followed by reductive elimination). The reaction was able to be furnish the corresponding aminochlorination and aminobromination products in good to excellent yields with excellent diastereoselectivity.

ð229Þ

13.04.10

Oxyhalogenation

Building on their work in aminofluorination, Liu and coworkers were able to successfully extend their methodology to allow for both inter- and intramolecular 1,2-oxyfluorination (Fig. 51). The authors found that high yields were obtained when the carboxylic acid derivative was a weak nucleophile, but maintained high acidity, such as in the case of CF3CO2H and CCl3CO2H.417 While the fluoroesterification products derived from trichloroacetic acid were stable enough for isolation, the authors found it necessary to immediately hydrolyze the products from coupling with trifluoroacetic acid. As in their related work on aminohalogenation, the reaction is proposed to proceed through oxidation of Pd(0) to a Pd(II)–fluoride complex by NFSI, followed by fluoropalladation with the alkene. Liu and coworkers also extended this strategy to the intramolecular synthesis of fluorinated tetrahydrofuran derivatives.418 Recently, Yang and coworkers reported similar conditions for application specifically to gem-difluoroalkene substrates.419

Fig. 51 Palladium-catalyzed inter- and intramolecular 1,2-oxyfluorination. Adapted from Peng, H.; Yuan, Z.; Wang, H.-y.; Guo, Y.-l.; Liu, G. Chem. Sci. 2013, 4(8); Yuan, Z.; Peng, H.; Liu, G. Chin. J. Chem. 2013, 31(7), 908–914.

186

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

Zhu and coworkers disclosed an intramolecular 1,2-oxychlorination and 1,2-oxybromination of alkenyl oximes that involves O-cyclization of the oxime. Under palladium catalysis the reaction affords a wide range of chlorinated and brominated isoxazolines in moderate to good yield (Eq. 230).420

ð230Þ In 2010 Nevado and coworkers reported the oxyfluorination of alkynes under gold catalysis (Eq. 231).421 Interestingly, either a-fluoro acetals or a-fluoro ketones could be obtained simply by extending the reaction time from 2 to 17 h.

ð231Þ

13.04.11

Carbooxygenation

13.04.11.1

Palladium-catalyzed

1,1-Carbooxygenation of alkenes was first reported in the 1980s,422 but the chemoselectivity of methods reported was poor until Moran and coworkers disclosed a palladium-catalyzed carbooxygenation of a,b-unsaturated esters using hypervalent iodine reagents in 2009 (Eq. 232).423 In 2011 Sanford and coworkers reported a Pd-catalyzed 1,1-aryloxygenation of unactivated terminal alkenes using aryl stannanes as coupling partners with hypervalent iodine oxidants (Eq. 233).424

ð232Þ

ð233Þ

Recently, Baik, Hong, and coworkers reported a palladium-catalyzed 1,1-aryloxygenation of unactivated alkenes in the presence of an aminoquinolinamide directing group (Eq. 234). In the presence of a cationic Pd(II) catalyst, an internal oxygen nucleophile and an external carbon nucleophile react to generate the corresponding five- and six-membered quaternary cyclic ether/lactone products in low to moderate yields.425 To date, 1,1-aryloxygenation of alkenes remains the only reported variation of transition-metal catalyzed carbooxygenation.

ð234Þ

Wolfe an coworkers have reported a variety of palladium-catalyzed difunctionalization reactions of alkenes bearing tethered aryl or alkenyl triflate electrophiles and exogenous nucleophiles,426 including the synthesis of carbocycles using alcohols and phenols (Eq. 235).427 The reaction generates substituted indanyl or alkylidenecyclopentyl ethers in good yields with excellent diastereoselectivity. Mechanistically, the reaction proceeds via intermolecular capture of the intermediate [Pd(II)–alkene]+[OTf]− complex by the alcohol/phenol nucleophile.

ð235Þ

Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics

13.04.11.2

187

Gold-catalyzed

In 2010 Toste and coworkers reported a gold-catalyzed three-component coupling of alkenes, alcohols, and arylboronic acids (Eq. 236).428 The resultant oxyarylation products are formed. Additionally, the authors found that carboxylic acids and water were also competent nucleophiles. ð236Þ In 2012 Wolfe and coworkers reported an intermolecular gold(I)-catalyzed alkyne carboalkoxylation reaction (Eq. 237).429 The three-component coupling allows for the synthesis of b-alkoxy ketones in moderate to good yield.

ð237Þ

In 2017 Russell and coworkers reported a gold-catalyzed oxidative oxyarylation of ethylene (Eq. 238).430 The gold catalyst facilitates the coupling of aryl silanes and alcohols to ethylene, in one of the rare examples of catalytic difunctionalization of the feedstock chemical.

ð238Þ

13.04.12

Conclusion and outlook

Homogeneous transition-metal-mediated and -catalyzed carbon–carbon p-bond functionalization plays a unique, important, and growing role in contemporary organic synthesis. In this chapter, we have sought to highlight the breadth of transformations, catalytic manifolds, and selectivity control strategies that have been used in the difunctionalization of unsaturated organic compounds. While a great deal of progress has been made, lingering challenges in the field include: (1) further development of classically challenging three-component couplings, (2) realization of methods to access all possible regio- and stereochemical outcomes in a predictable manner from common building blocks, and (3) expansion of substrate and coupling partners scope, particularly with respect to alkene substitution pattern. Recent parallel and complementary achievements in biocatalysis,431 electrochemistry/ electrocatalysis,432,433 photocatalysis/photoredox catalysis,434 and radical chemistry435–437 foreshadow a bright future where alkenes and alkynes can be viewed as universal functional group progenitors.

Acknowledgment Financial support was provided by the National Institutes of Health (5R35GM125052-05). We are also grateful for predoctoral fellowships from the National Science Foundation (L.J.O., DGE-184247; A.M.V., DGE-1842471), Kwanjeong Educational Foundation (T.K.), and Bristol Myers Squibb (Z.-Q.L.)

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Metal-Mediated and Catalyzed Difunctionalization of Unsaturated Organics 377. 378. 379. 380. 381. 382. 383. 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.

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13.05

Hydroformylation: Alternatives to Rh and Syn-gas

Minghao Wang, Alexander Lu, and Vy M Dong, Department of Chemistry, University of California −Irvine, Irvine, CA, United States © 2022 Elsevier Ltd. All rights reserved.

13.05.1 13.05.2 13.05.2.1 13.05.2.2 13.05.2.2.1 13.05.2.2.2 13.05.2.2.3 13.05.3 13.05.3.1 13.05.3.2 13.05.3.3 13.05.3.3.1 13.05.3.3.2 13.05.3.4 13.05.4 13.05.5 13.05.6 13.05.6.1 13.05.6.2 13.05.6.3 13.05.6.3.1 13.05.6.3.2 13.05.6.3.3 13.05.7 References

Introduction Monometallic hydroformylation with syn-gas Brief introduction of rhodium catalysts Alternative metal catalysts Cobalt catalysts Ruthenium catalysts Iron catalysts Metal catalyzed hydroformylation with syn-gas surrogates Carbon dioxide Alcohol Aldehyde Formaldehyde Transfer hydroformylation Formic acid Bimetallic hydroformylation Asymmetric hydroformylation Applications of hydroformylation Tandem hydroformylation Hydroformylation in natural product synthesis Heterogeneous hydroformylation Inorganic oxides Transition metal modified zeolite catalyst system Single atom catalysts for hydroformylation Summary

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13.05.1 Introduction The hydroformylation of alkenes, also known as the oxo process, produces more than 10 million tons of aldehydes each year. This classic transformation involves the addition of a formyl group and hydride across alkenes using syn-gas (CO and H2) Scheme 1. Depending on the position of the new carbon-formyl bond, hydroformylation results in either linear or branched aldehydes. Such aldehydes are used en route to make industrial products (e.g., detergents, polymeric materials, and dyes). Yamashita and Nozaki wrote a comprehensive chapter titled “hydroformylation, other hydrocarbonylations, and oxidative alkoxycarbonylations” for the previous book edition in 2007.1 It describes the history of hydroformylation and relevant advances in Rh catalysts. We refer the reader to this previous review for excellent background regarding this topic. In this follow up chapter, we focus on describing alternatives to Rh-catalysis, including the use of Co, Ru, and Fe catalysts. In addition, we summarize efforts developing alternatives to syn-gas, including the use of CO2, alcohols, aldehydes, and formic acid. To conclude, we highlight a few advances that feature the use of Rh-catalyzed hydroformylation in asymmetric catalysis, cascade reactions, and natural product synthesis.

Scheme 1 Hydroformylation of alkenes.

13.05.2 Monometallic hydroformylation with syn-gas 13.05.2.1 Brief introduction of rhodium catalysts Since the discovery of [RhCl(PPh3)3] in 1965 by Wilkinson and co-workers, Rh catalysts have been widely applied for hydroformylation due to the low pressure (10–60 bar) and temperature (80–135  C) required, as well as the catalysts’ high chemoselectivity for hydroformylation over hydrogenation. These catalysts also promote high linear to branched selectivity (l:b selectivity).2,3 Wilkinson studied the mechanism of Rh-catalyzed hydroformylation using syn-gas and proposed the following catalytic cycle Scheme 2. The elementary steps include olefin coordination to unsaturated Rh-species I, olefin insertion into the RhdH bond to afford either a linear or branched rhodium alkyl intermediate III, CO coordination to form coordinatively saturated catalyst IV,

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Scheme 2 Wilkinson mechanism for Rh hydroformylation.

migratory insertion of the alkyl group to the carbonyl ligand to form acyl complex V, oxidative addition of dihydrogen to afford acyldihydridorhodium VI, and reductive elimination to furnish the aldehyde. Further studies have illustrated the role of phosphine ligands in improving catalytic efficiency. Phosphine ligands are strong s-donating ligands that can improve p-backbonding from the Rh-center to the carbonyl ligands; the stronger MdCO bond reduces the CO pressure required to stabilize the catalyst.4 The increased electron density on the metal center also leads to a more polarized MdH bond and decreases its acidity, both factors which can affect the regioselectivity of hydrometallation.3 Wilkinson’s mechanistic proposal sets the stage for further studies in monometallic systems using other transition metals.

13.05.2.2 Alternative metal catalysts Aside from its use in industrial chemical production, Rh is used in the automotive industry.5–7 The price of Rh is high and volatile due to demand, and the world’s consumption of rhodium is unsustainable given that Rh is a precious metal. The facile dissociation of monodentate phosphines on Rh catalysts requires excess phosphine ligands to maintain regioselectivity, which increases the cost and represents another drawback. These factors have motivated chemists to find alternative metals that are less expensive and more sustainable. Roughly, the order of reactivity for unmodified metal carbonyl complexes are Rh  Co > Ir, Ru > Os > Pt > Pd  Fe > Ni.5,6,8,9 Despite their native reactivity, researchers have shown that other metals (e.g., Co, Ru, Fe) have potential as catalysts for hydroformylation through ligand tuning.10 In the following section, we describe monometallic hydroformylation using alternative metals and syn-gas, as well as advantages of these alternative metals.

13.05.2.2.1

Cobalt catalysts

While rhodium has been the most widely used metal in hydroformylation, the discovery of hydroformylation started with cobalt. Otto Roelen generated aldehydes and diethylketone from ethylene in a Co-catalyzed Fischer-Tropsch reaction. Roelen observed that aldehyde formation was dependent on the pressure of syn-gas and found that HCo(CO)4 was the catalyst responsible for the transformation.11 Heck and Breslow proposed a mechanism for this Co catalyst Scheme 3.12 In the proposed Heck-Breslow mechanism, coordinatively unsaturated Co species I is first generated from the dissociation of a CO ligand from HCo(CO)4. Coordination and insertion of an olefin leads to intermediate III. Insertion into the carbonyl leads to complex IV, which releases the aldehyde product after the addition of H2.

Scheme 3 Heck-Breslow mechanism for Co-catalyzed hydroformylation.

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In the 1950s, the Shell Development modified the catalyst by adding tri-n-butylphosphine ligands for the Co catalyst.13 The Co2(CO)8 precursor decomposes to cobalt metal without high pressures of syn-gas. The ligand modification stabilizes the Co catalyst and enables hydroformylation to be carried out under lower pressures (under 35 bar). Additionally, the phosphine ligands improve the hydrogenation activity of the Co catalyst, allowing aldehyde to undergo a subsequent hydrogenation to generate detergent alcohols.14 While these Co catalysts represent the first generation of industrial formylation catalysts, they were eventually replaced by Rh-phosphine catalysts that displayed improved reactivity and selectivity at lower pressures.15 Most recently, Stanley and co-workers reported a cationic CoII hydroformylation catalyst that is more active than the traditional neutral CoI catalysts and showed reactivity that almost parallels Rh catalysts Scheme 4A.16 Low l:b selectivity is observed with linear

Scheme 4 Co-bisphosphine complexes catalyzing hydroformylation reactions.

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terminal alkene substrates due to the high alkene isomerization activity of the catalyst. In contrast, alkenes with branched alkyl substituents, difficult substrates for traditional Rh catalysts, undergo hydroformylation with cationic CoII catalysts under lower pressures of syn-gas Scheme 4B. Stanley proposes the following mechanism Scheme 4C. Cationic Co complex I undergoes association with CO ligands to furnish active catalyst III. The coordination of a third CO ligand to form an octahedral 19e− complex is crucial for improving reactivity. This binding weakens all the metal-ligand bonds to help dissociate the equatorial CO ligand. This provides a coordination site for the incoming olefin. Alkene coordination gives intermediate IV, and sequential insertions into the Co–H and carbonyl furnishes metal-acyl complex VI. Since the formation of a CoIV species is unlikely, the authors propose a heterolytic cleavage of H2 through complex VII to form the formyl CdH bond. The authors believe that the cationic charge localized on the Co center helps accommodate a donating bisphosphine ligand, accelerating the reaction. The cationic charge offsets the electron density provided by the phosphines, weakening p-backbonding and allowing ligands to be more susceptible to dissociation. Through the design of a cationic CoII bisphosphine system, the efficiency of Co hydroformylation catalysts is greatly improved. Computational studies from the Wang group sheds further insight on how the cationic nature of the Co catalyst affects the transition states of the proposed elementary steps.17 The Chirik group reported syntheses of Co complexes that could be possible intermediates for Co-catalyzed hydroformylation Scheme 4D.18 While Co analogs of Rh asymmetric hydrogenation catalysts have shown promising reactivity, the Co(iPr-DuPhos) complex synthesized by the Chirik group did not show any catalytic hydroformylation activity. Stoichiometric studies on the Co(iPr-DuPhos) complex highlight the feasibility of the catalytic hydroformylation. Addition of Grignard reagent and CO to the starting Co(iPr-DuPhos) complex leads to an isolable Co-acyl complex. Treatment of this Co-acyl complex with H2 gas leads to the formation of hydrocinnamaldehyde and the corresponding Co–H complex. The fundamental studies on these Co-bisphosphine complexes pave the way for improved Co hydroformylation catalysts.

13.05.2.2.2

Ruthenium catalysts

While Wilkinson and co-workers studied the high reactivity of Rh catalysts, they also discovered the hydroformylation activity of the ruthenium complex [Ru(CO)3(PPh3)2].19 The Ru catalyst enabled the hydroformylation of 1-pentene to the corresponding aldehyde with a yield of 83% Scheme 5A. Following Wilkinson’s initial discovery, Schulz performed a comparison study and concluded that Ru catalysts are moderately reactive and chemoselective in comparison to Rh and Co catalysts.20 The high stability of carbonylruthenium species decreased the pressure needed for oxidative addition of H2, providing a key benefit for using ruthenium. They noticed that the Ru catalyst efficiently catalyzes hydrogenations, which can lead to alcohols (from aldehydes) and alkanes (from alkenes) as byproducts.21 The hydrogenation reactivity with ruthenium was exploited in tandem hydroformylation/reduction chemistry, which will be discussed in more detail (vide infra).

Scheme 5 Ru-catalyzed hydroformylation.

A subsequent investigation on the catalytic activity of [Ru(CO)3(PPh3)2] in hydroformylation was carried out by Wilkinson and co-workers in 1976.22 They propose the following mechanism related to the Rh and Co catalysts Scheme 5B: the active catalyst II is generated from the oxidative addition of H2 with complex I. Coordination of the alkene and its subsequent insertion into the Ru–H furnishes IV. Migratory insertion of the alkyl group into the carbonyl leads to intermediate V. The transfer of a second hydrogen atom results in the formation of the desired product and regenerates the starting complex I. Oxidative addition with H2 to I is proposed to be the rate determining step, since the reaction rate increases with higher H2 pressure and decreases with additional PPh3 and CO.

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A more recent Ru-catalyzed hydroformylation was developed by the Nozaki group in 2012.23 As mentioned above, traditional ruthenium hydroformylation catalysts involve dihydridoruthenium(II) [LnRuII(H)2] as the active catalyst, which can also promote hydrogenation Scheme 5C. To eliminate the side reactivity of this intermediate and improve the ruthenium efficiency, the authors designed a [CpRuII] catalyst by replacing one hydride with a pentamethylcyclopentadienyl anion. They expected that this modified catalyst would be ineffective for alkene hydrogenation because the Ru center lacks the additional hydride. This new Ru catalyst enables linear selective hydroformylation of terminal alkenes with one of the highest linear selectivities reported in ruthenium catalysts (l:b  20:1). They isolated the active catalyst species [Cp Ru(Xantphos)H], providing support for their initial hypothesis. The authors proposed that an open coordination site was achieved either by slippage of Cp from Z5 to Z3 coordination or by dissociation of one phosphine of the bisphosphine ligand. Higher linear selectivity is observed when bulkier bidentate phosphine ligands are used due to unfavorable steric interactions for the branched pathway. The [Cp Ru] complexes developed by Nozaki and co-workers show great potential given their high selectivity and availability.24 Notably, Ru is about seven times more abundant than Rh and costs only 4% of the price.25

13.05.2.2.3

Iron catalysts

As an earth abundant metal, Fe is regarded as a cheap and ideal alternative to precious metal catalysts. The major challenges for using first row metals include overcoming poor selectivity and functional group tolerance, as well as controlling their propensity for single electron chemistry. The first example of Fe-catalyzed hydroformylation was reported by Reppe and Vetter.26 Using [Fe(CO)5] and syn-gas generated in situ by the water gas shift reaction, ethylene was converted to propanol under 100–200 bar of CO pressure. Most of the reported Fe catalysts showed limitations including a need for high syn-gas pressure, limited substrate scope, and low catalyst efficiency. Chikkali and co-workers developed an Fe-catalyzed hydroformylation of alkenes that operates under mild conditions Scheme 6A.27 Hydroformylation of alkenes was achieved at 10–30 bar syn-gas pressure and temperatures below 100  C. Aliphatic and aromatic alkenes are suitable substrates under these conditions. Experimental investigations and computational studies identify the dihydride iron species [H2Fe(CO)2(PPh3)2] as the active catalyst species. Cyclic voltammetry confirms that an Fe0/FeII redox cycle is operative, and control experiments with radical scavengers exclude the possibility of a radical pathway. The authors propose a catalytic cycle similar to that of Wilkinson’s Ru-catalyst Scheme 6B. The catalyst precursor [HFe(CO)4][PPN] forms active catalyst II in the presence of PPh3 and syn-gas. Coordination of the olefin furnishes complex III, and subsequent hydrometallation leads to intermediate IV. Migratory insertion of the alkyl group into the carbonyl gives intermediate V. The addition of H2 releases the aldehyde product and regenerates active catalyst II. Active catalyst II was characterized in situ from reacting known complex I with H2 at 60  C.

Scheme 6 Fe-catalyzed hydroformylation of alkenes.

13.05.3 Metal catalyzed hydroformylation with syn-gas surrogates It is estimated that more than 10 million tons of oxo products are produced every year via hydroformylation on alkene substrates.5 The involvement of syn-gas is essential in industrial processes. However, syn-gas presents a challenge when carrying out hydroformylation in organic and medicinal chemistry research laboratories. Carbon monoxide is toxic and harmful to the environment. Furthermore, the use of syn-gas at high pressure (5–80 bar) and temperature (60–120  C) over long reaction times (12–36 h) requires specialized equipment and additional laboratory safety precautions. Many research projects have provided syn-gas

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alternatives for less toxic and more user-friendly transformations. Potential syn-gas surrogates for hydroformylation have been investigated, including carbon dioxide, alcohols, formaldehyde, and formic acid. Some of these methods provide milder reaction conditions and better regioselectivities.

13.05.3.1 Carbon dioxide CO is currently obtained from fossil fuels, and its toxicity introduces additional safety and environmental concerns. These concerns have led chemists to investigate the replacement of CO with CO2 as a C1 source. There is already a strong interest in reducing CO2 by homogenous catalysis to generate organic products such as formic acid, methanol, and methane.28 Additions of organometallics into CO2 to furnish carboxylic acid derivatives directly has also been investigated.29 The direct use of CO2 as the carbonyl source in alkene carbonylation reactions is less explored but may allow for new applications. In 2000, Sasaki and co-workers achieved a metal-catalyzed hydroformylation using CO2 as the carbonyl source.30 In the presence of LiCl and a Ru catalyst, the hydroformylation of cyclohexene was found to provide the hydroxymethylation product with a yield of 88% at 140  C Scheme 7. This product arises from the hydrogenation of the aldehyde intermediate. This tandem hydroformylation/ reduction sequence is comparable to other metal-catalyzed systems traditionally carried out with syn-gas.

Scheme 7 Sasaki’s condition for using CO2 as a CO substitute.

Two possible pathways for generating the aldehyde intermediate were proposed Scheme 8.31 Path A involves hydroformylation of alkene with the CO formed in situ from the hydrogenation of CO2, while Path B involves the hydrocarboxylation of alkene with CO2. Mechanistic studies rule out the second pathway because no formation of the corresponding carboxylic acid is observed. The detection of CO in the reaction headspace further supports path A.

Scheme 8 Possible pathways for using CO2 as CO source in hydroformylation.

Mechanistic investigations by Sasaki illustrate the role of the salt additive. The hydrogenation rate of CO2 to CO increases proportionally with the proton affinity of the halide additive, with chloride being the fastest.32 Lithium halide salts are the most effective additive since Li+ ions are more soluble than Na+ and K+ ions in N-methyl-2-pyrrolidone (NMP) solution.33 Further studies suggest that the salt additives help stabilize ruthenium clusters, preventing decomposition and release of the carbonyl ligands. Based on these results, the authors propose the following mechanism for the transformation Scheme 9A.33 The overall transformation has three main steps: hydrogenation of CO2 to CO, alkene hydroformylation, and hydrogenation of the aldehyde to an alcohol. The hydrogenation of CO2 begins with the Cl− doubly deprotonating complex I to give intermediate II. This intermediate coordinates with CO2 to form complex III and reacts with HCl to reduce CO2, forming complex IV. The addition of H2 releases CO and regenerates the catalyst. The subsequent hydroformylation and hydrogenation can be catalyzed by either the [RuCl3(CO)3]− or [Ru4(CO)12]4− complex Scheme 9B.

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Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 9 Mechanism of tandem hydroformylation/reduction with CO2.

The Beller group subsequently reported a phosphite ligand (L6) modified Ru catalyst, where they achieved the overall hydroxymethylation transformation of alkenes with CO2 under milder conditions. In contrast to Sasaki’s work, the formation of CO from CO2 proceeds through a reverse water gas shift reaction (RWGS), where CO2 and H2 are converted to CO and H2O Scheme 10.34 A potential issue of Sasaki’s CO2 mediated hydroformylation is competitive reactivity between hydroformylation and hydrogenation of the alkene substrates. Beller’s new protocol lowers the catalyst loading and improves selectivity for alcohol products over alkene hydrogenation side products. Preliminary mechanistic investigations into the active catalyst suggest that the ligand improves the hydroformylation step rather than the reverse water gas shift reaction.

Scheme 10 Hydroxymethylation of olefins using a phosphite-ligand modified ruthenium catalyst system.

In 2014, Dupont and co-workers developed a Ru-catalyzed hydroformylation using CO2 as the CO source in the presence of ionic liquids Scheme 11.35 Previously, the Vogt group showed that imidazolium ionic liquids (ILs) with acidic protons such as 1-butyl-3-methylimidazolium (BMI) could improve Rh-catalyzed hydroaminomethylation by converting Rh–H to the more activated [Rh(H)2]+.36 Dupont and co-workers designed Ru-catalyzed hydroformylation conditions with CO2 using [BMI
Cl] salt hoping to improve the reactivity of Ru–H in the same way. When using [BMMI
Cl] instead of [BMI
Cl], lower yields are observed, presumably due to the lack of the acidic imidazolium CdH bond. However, reactivity with [BMMI
Cl] can be restored by adding an acid additive such as H3PO4. NMR studies and isotope labeling with 13C provides evidence that [BMI
Cl] becomes a carbene ligand for Ru3(CO)12. The Dupont group believes that the Ru carbene complexes can help promote the reverse water gas shift reaction, since headspace analysis by gas chromatography with a thermal conductivity detector (GC-TCD) shows the presence of CO. Although [BMMI
Cl] lacks the acidic imidazolium CdH bond, it can still act as a carbene ligand by binding through abnormal binding modes.37

Scheme 11 Ru-catalyzed hydroformylation/hydrogenation using different ionic liquids.

Hydroformylation: Alternatives to Rh and Syn-gas

201

In most tandem reductive transformations of olefins in the presence of CO2, alcohols are usually obtained. The aldehyde products of hydroformylation are difficult to isolate given the high reaction temperatures and hydrogenation ability of Ru and Rh catalysts. Xia and Ding addressed this challenge by developing a highly efficient Rh catalyst with phosphoramidite ligand L7 for the selective hydroformylation of olefins to aldehydes without overreduction to the corresponding alcohols.38 Based on mechanistic studies, CO2 and PMHS [poly(methylhydrosiloxane)] are used to generate CO Scheme 12. This is followed by a Rh-catalyzed hydroformylation. Aldehydes generated by hydroformylation are not further reduced to the alcohol since PHMS reacts with the excess CO2 instead. Although a chiral bisphosphine ligand is used for this transformation, the major product of hydroformylation is the achiral linear aldehyde (l:b ¼ 89:11).

Scheme 12 Highly efficient Rh-catalyzed hydroformylation using CO2 with no formation of alcohol.

Hydroformylations where CO is replaced by CO2 requires the catalyst to carry out two processes: hydrogenation of CO2 to form CO in situ and metal catalyzed hydroformylation of alkene substrates. Ru catalysts generally catalyze a subsequent hydrogenation of the aldehyde products to form primary alcohols, although some Rh catalysts do not catalyze this third process. Using CO2 for hydroformylation chemistry helps circumvent strict storage and transportation requirements for CO due to its toxicity. Developing hydroformylations with CO2 warrants further investigation, as swapping CO for CO2 in industrial processes can provide environmental and economic benefits.

13.05.3.2 Alcohol While CO2 is a less toxic alternative to CO for hydroformylation, using high pressures of H2 and CO2 gas still requires specialized equipment. A complementary approach to hydroformylation that addresses this issue is developing a liquid reagent that can generate CO and H2 in situ. After syn-gas is generated from the liquid reagent, subsequent hydroformylation can be carried out on alkene substrates. Alcohols are an ideal reagent candidate, since syn-gas can be released from alcohols through a tandem sequence of dehydrogenation and decarbonylation Scheme 13A.

Scheme 13 Ir-catalyzed dehydrogenative decarbonylation.

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Hydroformylation: Alternatives to Rh and Syn-gas

Dehydrogenation of alcohols generates the corresponding carbonyl species and H2. Decarbonylation of aldehydes or ketones generates the corresponding saturated hydrocarbon species and releases CO.39,40 Initially, dehydrogenation and decarbonylation were rarely coupled in catalysis since dehydrogenation catalysts are often inhibited by the CO released from decarbonylation.41 Based on mechanistic studies of alcohol dehydrogenation and aldehyde decarbonylation,42 Olsen and Madsen proposed that the dehydrogenative decarbonylation of primary alcohols to the corresponding hydrocarbons could be carried out with Ir catalysts Scheme 13B.40 Madsen’s dehydrogenative decarbonylation method was achieved with an active catalyst generated from [Ir(coe)2Cl]2 (coe ¼ cyclooctene) and racemic 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl (rac-BINAP) in a solution mixture of mesitylene and water. Addition of catalytic lithium chloride improves the catalyst turnover. The authors observe decent yields with a wide variety of primary alcohols, including substrates bearing ethers, esters, imides, and aryl halides. The reaction proceeds even without the flow of N2 gas, since the reaction is similarly efficient when carried out in a sealed system where the evolved syn-gas is captured and quantified using a water-filled burette. Based on the observed results, the authors propose the following mechanism Scheme 13C. The Ir monomer I is the proposed active catalyst, which oxidatively adds into the alcohol OdH bond to generate II. Subsequent b-H elimination affords the octahedral Ir-dihydride III. Dissociation of the aldehyde to form IV is facilitated by destabilization from having trans hydride ligands. Reductive elimination to release hydrogen from the Ir catalyst and regenerate I is favored due to the increase in entropy. The decarbonylation cycle starts with oxidative addition of I into the aldehyde CdH bond to form II0 . Complex II0 undergoes deinsertion of CO to generate octahedral complex III0 . Reductive elimination affords the decarbonylated product, and dissociation of CO regenerates catalyst I. By measuring the reaction mixture composition over time, the authors concluded that the dehydrogenation and decarbonylation cycles operate independently. An alternative pathway to explain the formation of alkane is possible, where b-H elimination forms an alkene after CO deinsertion, and the alkene undergoes hydrogenation. However, additional isotope-labeling experiments excluded the possibility of this pathway. Sadow and co-workers developed a photocatalytic variant of the tandem dehydrogenation/decarbonylation reaction Scheme 14.43 [ToMRh(CO)2] is a photocatalyst that can efficiently convert primary alcohols into hydrocarbons. Compatible functional groups include silyl, ether, and aryl fluoride groups. However, nitro groups, aryl chlorides, and esters are not tolerated. A small amount of the corresponding aldehyde intermediate was detected by 1H NMR and GC/MS analysis, suggesting that dehydrogenation and the formation of aldehyde is the first step of the tandem sequence. In the absence of light, there is no conversion of either the aldehyde or alcohol, confirming a fully photocatalytic mechanism. Further mechanistic studies suggest that CO dissociation through photolysis is essential for both alcohol dehydrogenation and aldehyde activation, and that aldehydes are more reactive than the corresponding alcohols. The reaction does not require N2 flow to remove the liberated gasses, though the reaction does proceed slower under higher pressures of CO (5 atm). While the works of Madsen and Sadow highlight the feasibility of using alcohols as syn-gas sources, additional reaction setup engineering is required to apply these syn-gas surrogates in actual hydroformylations.

Scheme 14 Photocatalytic deoxygenation reaction through a tandem dehydrogenation/decarbonylation.

These dehydrogenation/decarbonylation reactions are new pathways for transforming alcohols. They can become a useful tool in organic synthesis for various hydrocarbonylations of alkenes. While transformations that decompose alcohols to release syn-gas have been developed, there remains the challenge of combining the syn-gas releasing reaction with the syn-gas consuming hydroformylation reaction in the same reaction vessel. An alternative strategy devised by chemists is to conduct the two transformations separately in two separate reaction vessels which are connected to allow the flow of syn-gas from one vessel to another. The two-chamber setup for ex situ generation of CO for chemical transformations has already been developed by the Skrydstrup group and applied in various carbonylation reactions.31 A connected two-chamber reaction setup enables the use of alcohols as syn-gas sources for hydroformylation. Having two different chambers allows one catalyst to generate syn-gas while another catalyst carries out hydroformylation. The Skrydstrup group demonstrated the feasibility of ex situ generation of a reagent gas in a two-chamber system, where CO is generated in one chamber to carry out a carbonylative amination in the second chamber Scheme 15A.44 Andersson and co-workers applied the two-chamber setup strategy hydroformylation using polyols.45 In the first chamber, biomass derived polyols like sorbitol and glycerol are converted to syn-gas by an Ir catalyst. Hydroformylation of alkenes under ambient reaction conditions occurred in the second chamber with Wilkinson’s catalyst Scheme 15B. The method represents a sustainable complement to traditional hydroformylation, generating syn-gas from abundant biomass and circumventing the use of pressurized gas cylinders. The Madsen group developed a similar reaction for the hydroformylation of styrene Scheme 15C.46 They examined a variety of alcohols and diols as syn-gas sources and profiled the overall pressure of syn-gas in the reaction system. They found hexane-1,6-diol to be the optimal syn-gas source, with the second chamber generating mixtures of branched and linear hydroformylation products with good yields.

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203

Scheme 15 Transfer of H2 and CO from polyols to alkenes.

In both reaction setups, a cold-finger condenser fitted over the syn-gas generating chamber prevents the migration of solvent due to the harsh reaction conditions. Following their initial Ir-catalyzed dehydrogenative decarbonylation, Madsen and co-workers developed a ruthenium catalyzed protocol for the dehydrogenative decarbonylation of primary alcohols.47 Using Ru(cod)Cl2 in conjunction with sterically hindered monodentate P(o-tolyl)3 ligand, syn-gas is released from both benzylic and non-benzylic primary alcohols. Aldehyde intermediates are observed during the reaction process, suggesting that the ruthenium complex catalyzes separate dehydrogenation and decarbonylation cycles. In general, alcohols can be used as syn-gas surrogates and applied in various hydrocarbonylation chemistry including hydroformylation. The overall transformation is achieved through a tandem dehydrogenative decarbonylation and a subsequent hydroformylation. Two-chamber setups are used to separate the gas-releasing and gas-consuming chemistry, affording good conversions. Polyols are noteworthy syn-gas surrogates, since they demonstrate that renewable biomass can be transformed into value-added products.

13.05.3.3 Aldehyde 13.05.3.3.1

Formaldehyde

Despite being the product of hydroformylation, aldehydes can also serve as syn-gas surrogates for hydroformylation via metal-catalyzed decarbonylation reactions to release CO and H2. The overall transformation is isodesmic, achieving the transfer of formyl groups to alkenes through the reversible nature of hydroformylation catalytic cycles. The hydroformylation of alkenes using the simplest aldehyde, formaldehyde, as a syn-gas surrogate is the most well studied. Two possible pathways are proposed for the hydroformylation alkenes with formaldehyde Scheme 16A.28b Starting from the

Scheme 16 Reaction pathway for the activation of formaldehyde.

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Hydroformylation: Alternatives to Rh and Syn-gas

formyl-metal complex, the decarbonylation pathway releases syn-gas, where the generated syn-gas participates in a subsequent hydroformylation reaction. From the same formyl-metal complex, an olefin insertion pathway is possible with olefin insertion and reductive elimination to afford the hydroformylation product. One benefit for using formaldehyde as a syn-gas surrogate is that it can be used as either an aqueous solution (formalin) or as a solid polymer (paraformaldehyde), thus eliminating the need for high pressure equipment. Okano and co-workers were the first to successfully use formaldehyde as a syn-gas surrogate in the hydroformylation reaction of alkenes Scheme 16B.48 By using [RhH2(O2COH)(P(iPr)3)2] without additional ligands, alkene substrates are successfully transformed to corresponding aldehydes using formaldehyde. For example, 1-hexene is converted to the corresponding aldehyde with moderate yield (67%). The reaction takes place at 120  C in a sealed stainless steel autoclave. Only a small amount of the alcohol is produced through hydrogenation of the generated aldehyde. Seok and co-workers later reported a hydroformylation of olefins with paraformaldehyde using Rh catalysts with phosphine ligands. The reactions can be carried out under an inert atmosphere or a reduced pressure of syn-gas Scheme 17A.49 Using [RhHCO(PPh3)3] with excess PPh3, high linear selectivity (l:b  20:1) is observed with allyl alcohol, a substrate containing an oxygen atom b to the double bond. Additional pressure of syn-gas in the reaction vessel deteriorated the linear selectivity. To explain the regioselectivity and understand the mechanism, in situ IR experiments and variable-temperature NMR studies were conducted. The authors observe a signal at 1604 cm−1 from in situ IR, which is attributed to the formation of an intermediate where the formyl ligand is coordinated to metal center.

Scheme 17 Linear aldehyde selectivity through metallacycle formation.

The following mechanism was proposed based on the spectroscopic evidence Scheme 17B. Allyl alcohol first coordinates to the Rh catalyst. Formaldehyde undergoes oxidative addition with Rh to afford a formyl-Rh-hydride species. Subsequent insertion of the alkene affords a metallacyclic compound. Either five- or four-membered metallacycles are possible. A key observation from NMR studies suggests that the b oxygen participates to form a thermodynamically stable five-membered metallacycle. The observed linear selectivity can be explained by the thermodynamic stability of five-membered metallacycle compared to the less stable four-membered metallacycle. Reductive elimination with the formyl ligand affords aldehyde products and regenerates the active Rh species. Morimoto and co-workers reported another highly linear selective hydroformylation of terminal alkenes using formaldehyde as a syn-gas surrogate Scheme 18.50 Previously reported hydroformylation conditions using formaldehyde use a single catalyst for both generating syn-gas and subsequent hydroformylation. The authors sought to develop two discrete catalysts to catalyze one process each, since the demands for hydroformylation catalytic reactivity are reversed for each process. To simultaneously generate two types of Rh catalysts in one reaction system, Morimoto proposed that the two different Rh species could be generated in situ by adding two different bisphosphine ligands. The optimal catalyst system is with [Rh(cod)Cl]2 as the catalyst precursor with a mixture of BIPHEP and NiXantphos ligands. [Rh(Cl)BIPHEP]2 is effective for formaldehyde decomposition, while [Rh(cod)(NiXantphos) Cl] carries out highly regioselective hydroformylation. The simultaneous use of two bisphosphine ligands to separately catalyze the decarbonylation and the hydroformylation contributes to the high regioselectivity (l:b up to 98:2) and reactivity (up to 95% yield). The substrate scope demonstrates that functionalized alkenes with ether, ester, siloxy, and phthaloyl groups are tolerated in the system. Both formalin and paraformaldehyde are used, with higher conversion observed with formalin.

Hydroformylation: Alternatives to Rh and Syn-gas

205

Scheme 18 Highly linear selective hydroformylation with formaldehyde.

Shortly afterwards, Taddei and co-workers developed a microwave-assisted hydroformylation reaction based on Morimoto’s two catalyst strategy Scheme 19A.51 The authors believed that Morimoto’s hydroformylation conditions could be sped up under dielectric microwave heating, and they used a domino hydroformylation of b,g-unsaturated amides with formaldehyde to test their hypothesis. They achieve comparable yields to the Morimoto conditions in a fraction of the time when subjecting their specific chiral substrate to microwave dielectric heating. Using BIPHEP and NiXantphos as mixed ligands with formalin in toluene at 90  C affords the desired heterocycle with good yield.

Scheme 19 Improving the reactivity of hydroformylation with formaldehyde.

Börner and co-workers published a Rh(dppp)-catalyzed hydroformylation of alkenes with formalin as the syn-gas source Scheme 19B.52 Börner and co-workers observed that the addition of 10 bar H2 significantly improves the conversion, yields, and regioselectivities of the reaction. The additional H2 promotes hydrogenolysis of the Rh-acyl complex, leading to higher TON and TOF. The Clarke and Morimoto groups independently reported asymmetric hydroformylation protocols with formaldehyde Scheme 20.53,54 In both studies, Clarke and Morimoto illustrate that a highly stereoselective hydroformylation of substituted alkene substrates could be achieved under mild reaction conditions. Through ligand screening, both groups determined that Ph-BPE (L10) is the optimal ligand, although different Rh sources were used. The Clarke group highlighted the hydroformylation of various cis-stilbenes and cyclic alkenes, while the Morimoto group focused on the hydroformylation of styrene derivatives. The Morimoto group synthesized various pharmaceutical precursors to demonstrate the synthetic utility of asymmetric hydroformylation. Mechanistic investigations support Rh(Ph-BPE) catalyzing both the decarbonylative degradation of formaldehyde and the subsequent hydroformylation of vinylarenes. The enantioselective transformations achieved by Clarke and Morimoto provide a useful protocol for asymmetric hydroformylation that does not require high-pressure equipment.

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Scheme 20 Enantioselective Rh(I)-catalyzed hydroformylation using formaldehyde.

For all of the screened ligands other than Ph-BPE, the Clarke group observed low yields of aldehyde product for the asymmetric hydroformylation of cis-stilbene with formaldehyde.55 The authors suggest that some of the catalysts could not survive the high reaction temperatures and decompose prior to hydroformylation. Other catalysts might not produce sufficient syn-gas, or they may be inactive at low syn-gas pressures. To fully understand the scope of Rh(Ph-BPE) catalyst, the authors screened unsymmetrical cisstilbenes. They discovered that Rh(Ph-BPE) promotes formaldehyde decomposition and affords decent conversion, but it is not the optimal ligand for hydroformylation due to low regioselectivity and enantioselectivity. To address this, the Clarke group established dual catalytic conditions that uses the decarbonylating ability of Rh(Ph-BPE) as well as the selective hydroformylating ability of another chiral ligand to achieve both optimal conversion and regioselectivity Scheme 21. In this dual catalytic system, Ph-BPE is used in combination with [Rh(cod)Cl]2 to decompose paraformaldehyde, while the selective hydroformylation is entirely controlled by another chiral ligand pre-mixed with [Rh(acac)(CO)2]. The asymmetric hydroformylation of allylbenzene was used to evaluate the dual catalytic protocol. (S,S)-Ph-BPE is gives poor selectivity for asymmetric hydroformylation when it is used as the only ligand. [Rh(acac)(CO)2] mixed with BOBPHOS ligand (L11) shows better selectivity for the hydroformylation, with the enantiomer of BOBPHOS ligand determining the enantiomer of the product.

Scheme 21 Dual catalyst hydroformylation using formaldehyde.

In the examples discussed above, formaldehyde shows its unique advantages in serving as a syn-gas surrogate. In order to take full advantage of the tandem in situ decarbonylative degradation and subsequent hydroformylation, dual catalytic reaction conditions were developed. Approaches to dual catalyst systems involve either using mixtures of ligands with a single metal or using mixtures of two pre-complexed catalysts. These conditions facilitate highly regioselective or enantioselective transformations. Using formaldehyde to generate low pressures of syn-gas still enables hydroformylation with perfect atom economy, while minimizing exposure to hazardous gasses in laboratory settings.

13.05.3.3.2

Transfer hydroformylation

While formaldehyde is a convenient syn-gas source for mild and selective hydroformylation, aliphatic aldehydes bearing bhydrogen atoms were also postulated to be potential syn-gas surrogates Scheme 22A. In 1990, Watanabe and co-workers observed

t-

Transfer hydroformylation using an aliphatic aldehyde.

Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 22

207

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Hydroformylation: Alternatives to Rh and Syn-gas

he transfer formylation of benzaldehyde and cyclohexene to benzene and cyclohexanecarbaldehyde in some of their Ru-catalyzed hydroacylation reactions.56 A dehydroformylation mechanism was proposed via a dihydrido ruthenium intermediate to explain this reactivity Scheme 22B. The observation indicates the possibility of using aliphatic aldehyde as a syn-gas surrogate for a tandem degradation and hydroformylation reaction. The net transformation involves a formyl group transfer from the aldehyde to olefin acceptor, generating a new olefin and aldehyde. Brookhart and Lenges later reported a Rh-catalyzed aldehyde isomerization, which demonstrates the feasibility of using saturated aliphatic aldehydes as substitutes for syn-gas.57 While conducting the intermolecular hydroacylation using their Co catalyst [Cp Co(olefin)2], the linear n-butyraldehyde converts into the branched isomer during the reaction, suggesting reversible insertion and b-H elimination prior to the reductive elimination step Scheme 22C. Changing the catalyst to a Rh center from Co should increase energy barrier for the reductive elimination, allowing for increased reversibility and aldehyde isomerization. As expected, the alkyl aldehydes undergo isomerization in the presence of [Cp Rh(olefin)2] catalysts. Additionally, formyl groups can transfer between two different alkenes under the Rh-catalyzed conditions. For example, one equivalent of syn-gas is transferred from isovaleraldehyde to 3,3-dimethyl-1-butene, generating the corresponding linear aldehyde and 2-methylpropene Scheme 22D. This result introduces an interesting catalytic process that interconverts linear and branched alkyl aldehydes to alter the l: b ratio of aldehydes formed from hydroformylation reactions. Dong and co-workers envisioned that a Rh-catalyzed transfer hydroformylation strategy could be achieved by coupling dehydroformylation of an aldehyde substrate with the concomitant hydroformylation of a strained olefin acceptor Scheme 23A.58 Initial optimization studies with different Rh-complexes show that typical counterions like BF4−, Cl− and I− lacked reactivity or catalyzed undesired decarbonylation reactions. Significant improvements in reactivity and selectivity are achieved when using more basic counterions, particularly with benzoate counterions such as 3-methoxybenzoic acid (3-OMeBzOH). Studies regarding the olefin acceptor demonstrate the importance of ring strain. Acceptors with high ring strain such as norbornadiene enable highly selective transfer hydroformylation under mild conditions (catalyst loadings as low as 0.5 mol%, mild reaction temperatures of 40  C). The reactivity can be explained by the thermodynamic driving force provided by the release of ring strain in the olefin acceptors. A variety of Lewis basic functional groups are tolerated in the reaction, such as ethers, esters, amines, phthalimides, and indoles. The catalytic cycle is proposed based on mechanistic investigations Scheme 23B. The neutral Rh-complex activates the aldehyde CdH bond to generate an acyl-RhIII-hydride intermediate. The benzoate counterion then undergoes reductive elimination with the hydride to furnish acyl-RhI, generating an equivalent of acid. Deinsertion of CO and b-hydride elimination affords a Rh-hydridocarbonyl species. Olefin exchange with norbornadiene occurrs, followed by hydroformylation to release the ring strain of the olefin acceptor. The combined effects of the benzoate counterion and wide bite-angle Xantphos ligand help promote b-hydride elimination to achieve the unique reactivity. The benzoate counterion acts as a proton shuttle during the reaction to prevent full decomposition of the aldehyde to syn-gas. Transfer hydroformylation has potential application in editing the carbon skeleton of complex molecules, as evidenced when Dong and co-workers accomplished a three-step transformation of (+)-yohimbine to (+)-yohimbenone using transfer hydroformylation as a means of dehydroformylation.59 In 2019, You and co-workers applied the concept of transfer hydroformylation towards the Rh-catalyzed hydroformylation of alkynes to the corresponding a,b-unsaturated aldehydes Scheme 24.60 The mechanism of this method proceeds similarly to the previous transfer hydroformylation. Rather than using strained olefins as sacrificial acceptors, You hydroformylates a broad range of alkynes into the corresponding a,b-unsaturated aldehyde using accessible and inexpensive n-butyraldehyde as a sacrificial formyl and hydride donor. The transformation proceeds with excellent chemo-, regio-, and diastereoselectivity. The exclusive formation of (E)-a,b-unsaturated aldehydes is attributed through cis hydrometallation and subsequent carbonylation. Formation of side products such as saturated aldehydes and hydrogenated products is suppressed by the high chemoselectivity of the catalyst. Through the development of transfer hydroformylation reactions, aldehydes are suitable syn-gas sources for hydroformylation. The development of transfer hydroformylation catalysis enriches the content of this traditional field and brought up new ways of generating and transferring formyl groups into the alkene substrates. In addition, these studies inspired a new field of catalysis, shuttle catalysis, where group transfer enables the use of new alternatives to reagents that are toxic or difficult to handle.61

Rh-catalyzed transfer hydroformylation using norbornadiene acceptors.

Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 23

209

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Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 24 Rh-catalyzed transfer hydroformylation of alkynes.

13.05.3.4 Formic acid An important bulk chemical, formic acid (HCOOH) has a high CO content of 60.9 wt% as well as a high H2 content of 4.4 wt%. It is considered as an efficient carrier to transport H2 or CO, depending on the decomposition pathway to liberate gas. Formic acid decomposes to H2 and CO2 under dehydrogenative conditions, while it decomposes to CO and H2O under decarbonylative conditions Scheme 25A. Since formic acid can release both H2 and CO depending on the decomposition conditions, it has the potential to be a syn-gas surrogate. While there are several transformations that take advantage of the release of CO from formic acid, formic acid is used primarily as a H2 source for hydroformylation, requiring additional CO gas for hydroformylation.62

Scheme 25 Proposed formic acid as syn-gas surrogate.

Shi and co-workers reported the first hydroformylation method of alkenes using a mixture of formic acid and acetic anhydride as a syn-gas surrogate Scheme 26A. The Pd catalyst bearing a 1,3-bis(diphenylphosphino)propane (dppp) ligand favors linear aldehydes over branched aldehydes in up to 93% yield with >20:1 regioselectivity.63 This hydroformylation was inspired by the authors’ previous Pd-catalyzed hydrocarboxylation of olefins using a mixture of formic acid and Ac2O.64 The authors envisioned formation of Pd-H intermediate II following the release of CO2 from key Pd complex I. Subsequent reductive elimination would afford the corresponding hydroformylation product in the absence of either CO or H2 Scheme 25B. The addition of the dppp ligand (L13) improves the regioselectivity and reactivity. In their proposed mechanism, Pd catalyst I oxidatively adds into the HCOOAc that is formed in situ to furnish intermediate II. Deinsertion of CO forms complex III, and migratory insertion by the olefin forms complex IV. Migratory insertion into the carbonyl furnishes intermediate V. Iodide mediates ligand exchange, eventually leading to key Pd-complex VII. Extrusion of CO2 forms VIII, which reductively eliminates to provide the desired aldehyde. Control experiments show that the addition of iodide is essential for facilitating exchange of acetate for formate. However, the excessive addition of iodide relative to Pd is detrimental since iodide begins to occupy the coordination sites. The authors postulate that the unique bite angle of dppp favors the CO2 release over the reductive elimination, thus favoring the formation of the aldehyde over the corresponding carboxylic acid Scheme 26.

Hydroformylation: Alternatives to Rh and Syn-gas

211

Scheme 26 Pd-catalyzed hydroformylation using formic acid.

Recently, Liu and co-workers published a hydroformylation of olefins with formic acid under Xantphos modified Rh-catalyzed conditions,65 where formic acid acts as both the H2 and CO donor Scheme 26C. The decomposition rate of CO and H2 from formic acid is slow, so prolonged reaction times were used to solve the issue. The overall conversion of the olefin substrates is high (92–98%) with excellent chemoselectivity converting to the target aldehydes (93–97%). In situ FT-IR and high pressure 1H NMR were used by the authors to elucidate the mechanism for hydroformylating olefins with formic acid. Although the use of formic acid as a syn-gas surrogate in the hydroformylation reactions is less well-studied than other surrogates, the unique reactivity of formic acid has shown interesting applications in serving as a CO source or H2 source in various carbonylation reactions, including hydroformylation.

13.05.4 Bimetallic hydroformylation Most hydroformylation catalysts in industrial processes are monometallic catalysts of Rh or other transition metals. Bimetallic and cluster catalysts for hydroformylation are less studied and applied due to their lower reactivity and regioselectivity. However, recent advances have produced bimetallic catalysts possessing unique catalytic properties that are competitive with monometallic catalysts. Stanley and co-workers reported a high regioselective and reactive homobimetallic hydroformylation catalyst Scheme 27A.66 A mixture of racemic and meso diastereomers of an electron-rich tetraphosphine ligand (L14) bridges and chelates both metal centers. Control experiments using each ligand stereoisomer individually show that the racemic ligated Rh-bimetallic complex has higher reactivity and linear regioselectivity than the meso ligated complex. The authors propose a mechanism involving a bimetallic cooperativity between bridged Rh centers during an intramolecular hydride transfer Scheme 27B. The first steps in the proposed mechanism for the bimetallic catalyst are similar to that of monometallic Rh/PPh3 catalysts. Addition of syn-gas to the Rh complex leads to intermediate II. Insertion of an alkene furnishes intermediate IV, and subsequent insertion into the carbonyl forms acyl-metal intermediate V. Diverging from the monometallic system, this bimetallic catalyst undergoes an intramolecular hydride transfer between the two Rh-centers, forming complex VI before elimination to furnish the aldehyde product. The bimetallic conditions show improved reactivity than the corresponding monometallic catalyst. The oxidative addition of H2 is less favored than coordination with CO when electron donating ligands are coordinated, and the bimetallic catalyst avoids this process by

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Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 27 High regioselective and reactive homobimetallic Rh-Rh hydroformylation catalyst.

undergoing intramolecular hydride transfer instead. The lower activity of meso ligand catalyst arises from an increased barrier for hydride transfer due to steric interactions. Molecular dynamic minimization modeling was used to analyze the binding orientation of the olefin in intermediate III. For the binding orientation that leads to branched products, the modeling predicts unfavorable steric interactions the olefin and the phosphine substituents. These predicted steric interactions help explain the excellent regioselectivity. Recently, Dydio and co-workers reported another highly selective and reactive bimetallic catalyst that features a unique PdI–PdI intermediate Scheme 28A.67 A halide-assisted hydroformylation is proposed, beginning with the activation of the Xanthos-PdI2 complex using H2 to form active catalyst II. Subsequent olefin insertion into the Pd–H affords a cationic alkyl-Pd intermediate III. Insertion into CO affords a cationic Pd-acyl intermediate IV, which undergoes a binuclear elimination through transition state V to furnish the aldehyde product and generate bimetallic complex VI. The halide ligands assist the final elimination step. A subsequent reaction with H2 and acid regenerates the Pd-hydride species for the catalytic cycle. A wide functional group tolerance is observed, and the insights on halide ligand assistance provides insights on further Pd catalyst design strategies. Although the bimetallic catalyzed hydroformylation reactions are not as common as their monometallic counterparts, the existing examples of bimetallic hydroformylation indicate interesting reactivities. These bimetallic catalysts highlight the importance of ligand design in the development of highly reactive and regioselective catalysts.

Hydroformylation: Alternatives to Rh and Syn-gas

213

Scheme 28 High regioselective and reactive homobimetallic Pd-Pd hydroformylation catalyst.

13.05.5 Asymmetric hydroformylation A longstanding barrier in achieving asymmetric hydroformylation of terminal olefins is regioselectivity, given that linear hydroformylation products are typically achiral.68 The Tan and Breit groups addressed this issue through reversible covalent bonds to ligands. The Breit group’s strategy employs methyl diphenylphosphinite as a transient directing group in the reaction Scheme 29. Hydroxyl group bearing substrates undergo transesterification with the phosphinite to catalytically install the directing group. Subsequent hydroformylation yields lactols derived from the branched aldehyde products with excellent regioselectivity.69,70 The Tan group developed phosphorus-based ligands termed “scaffolding ligands” (L15–17).71 These scaffolding ligands contain a carbon atom in the orthoformate oxidation state which could form reversible covalent bonds with heteroatoms Scheme 30. The scaffolding ligand proves versatile, extending regioselective hydroformylation to alcohol72 and sulfonamide directing groups.73 Substrates containing internal alkenes are also reactive towards hydroformylation, and the regioselectivity of hydroformylation is ligand controlled.74 A second generation of scaffolding ligand enables the asymmetric hydroformylation of allyl anilines with excellent yields and enantioselectivities.75

Scheme 29 Breit’s catalytic methyl diphenylphosphinite directing group.

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Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 30 Tan’s scaffolding ligands control the regioselectivity through reversible covalent bonds.

Selective asymmetric hydroformylation has also been achieved with a variety of other substrates. Activated olefins are electronically biased towards giving branched hydroformylation products. The Stahl and Landis groups disclosed a highly selective hydroformylation of enamides with excellent yields (up to 99%) and selectivities (b:l ¼ 27:1, 86% ee) using their bisdiazaphos ligand (L18) Scheme 31A.76 The Xuphos ligands (L19), a family of ligands inspired from the bisdiazaphos ligands, can hydroformylate styrene derivatives in an asymmetric fashion Scheme 31B.77 Heterocyclic alkenes, such thiophene78 and indole,79 also yield hydroformylated products with Binaphos (L20) and Yanphos (L21) ligands, respectively Scheme 31C and D. Additional branched-selective hydroformylation substrates include vinyl acetates.80 Other strategies for achieving selective asymmetric hydroformylation include using 1,1-disubstituted olefins to generate stereocenters from linear hydroformylation81 and desymmetrizing symmetrical substrates.82 For a more complete review on the new ligands developed for asymmetric hydroformylation, we refer the readers to these reviews by Dong83 and Zhang.84

13.05.6 Applications of hydroformylation 13.05.6.1 Tandem hydroformylation Due to the high reactivity of aldehydes in the presence of metal catalysts, a variety of tandem hydroformylation methods have been developed, where the generated aldehyde can be further transformed into various functional groups. These tandem transformations enable a wider application of hydroformylation. Herein we include some tandem catalysis examples of hydroformylation.

Hydroformylation: Alternatives to Rh and Syn-gas

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Scheme 31 Asymmetric hydroformylation of activated alkenes.

The Nozaki group reported a tandem hydroformylation/hydrogenation of alkenes using either a Rh/Ru dual catalytic system or a single Ru catalyst Scheme 32.85 While single catalysts can carry out both reactions, they generally give alkane side products or mixtures of linear and branched products. By using a dual catalyst system, catalysts can be optimized for their specific roles. The orthogonality of Rh-catalyzed hydroformylation and Ru-catalyzed hydrogenation in Nozaki’s dual catalytic system is demonstrated through control experiments monitored via real-time IR spectroscopy. Shvo catalyst can catalyze both the hydroformylation and the subsequent hydrogenation, although it is less efficient at hydroformylation. The reaction using Shvo catalyst was also followed by real-time IR and 31P NMR spectroscopies. Shvo catalyst is more reactive than traditional Ru catalysts because it is robust even under CO pressure. Regardless of the catalyst system used, the tandem hydroformylation/hydrogenation affords linear alcohol with high regioselectivity.

Scheme 32 Tandem hydroformylation/hydrogenation of alkenes.

Landis and Wong published a sequential asymmetric hydroformylation/olefination sequence that could be conducted in a single flask in an iterative fashion Scheme 33.86 This method provides a unique way of synthesizing oligomers containing multiple

216 Hydroformylation: Alternatives to Rh and Syn-gas

Scheme 33

Iterative asymmetric hydroformylation/Wittig olefination.

Hydroformylation: Alternatives to Rh and Syn-gas

217

stereocenters introduced by a single loading of chiral catalyst. As mentioned previously, the Rh/bis(diazaphospholane) catalyst is highly reactive and selective. A significant finding was the dependence of regioselectivity on temperature and pressure.87 The catalyst could select for either the branched or linear hydroformylation products based on the reaction conditions. The aldehyde products can undergo a subsequent Witting olefination to furnish alkene products. More recently, Clarke and co-workers developed a diastereoselective and branched-selective tandem hydroformylationcyclization reaction.88 Starting from acyclic precursors, Rh(BOBPHOS) catalysts can carry out hydroformylation on the terminal olefins with good stereoselectivities. Subsequent cyclization through hemiacetal/hemiaminal formation furnishes functionalized six-membered heterocycles. Oxidation or hydrogenation can convert the products into other heterocycles for further transformations or synthetic applications Scheme 34. In general, reactivity of the aldehyde products enables it to act as an intermediate in several tandem catalytic methodologies. These tandem transformations not only broaden the application of hydroformylation, but also provide insights for the development of new and efficient transformations.

Scheme 34 Tandem hydroformylation-hemiacetal formation.

13.05.6.2 Hydroformylation in natural product synthesis While the initially harsh conditions of hydroformylation are suitable for industrial purposes, the development of milder and more efficient conditions has made the transformation more appealing towards organic research labs and target-oriented synthesis. Hydroformylation forges a new CdC bond and installs an aldehyde functional group. As demonstrated by the tandem hydroformylation transformations, the diverse reactivity of the aldehyde functional group makes hydroformylation a useful transformation for accessing reactive synthetic intermediates. A noteworthy example of hydroformylation in natural product synthesis was carried out by Leighton and co-workers, where a tandem intramolecular silylformylation-allylsilylation of alkenes iteratively synthesizes polyketide fragements.89 This method was eventually used in the synthesis of a polyketide natural product, zincophorin methyl ester Scheme 35.90 We refer readers to Bates’ and Kasinathan’s book chapter focused on hydroformylation in natural product synthesis for a more comprehensive overview for this topic.91

Scheme 35 Leighton’s total synthesis using hydroformylation.

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Hydroformylation: Alternatives to Rh and Syn-gas

13.05.6.3 Heterogeneous hydroformylation In the above sections, the chemistry discussed are homogeneous catalytic hydroformylation reactions. While there are a variety of efficient and interesting homogeneous transformations, there are still some issues in large scale industrial applications. For example, homogenous catalysts incur additional costs to separate and recover from the reaction mixture. Although immobilization of the catalyst can address this problem of separation, the deactivation and denaturation of the catalyst can still cause issues. Heterogeneous catalysis can potentially address this challenge. The following is a brief introduction of the main types of heterogeneous catalytic hydroformylation catalysts.

13.05.6.3.1

Inorganic oxides

A variety of inorganic oxides are used as supports for heterogeneous catalytic hydroformylation, including SiO2 and Al2O3. These inorganic oxides can be doped with metals such as Rh to catalyze hydroformylation. Rh/SiO2 is one of the most reactive heterogeneous catalysts. Ichikawa and co-workers92 studied the effects on activity by adding additional reaction components. They used an Zn-Rh/SiO2 catalyst to catalyze the hydroformylation reaction of ethylene. Compared with Rh/SiO2, the addition of Zn significantly inhibits hydrogenation side reactions and promoted hydroformylation. In addition to Zn, other metal ions have also been incorporated, such as Mn, Zr, and Ti. Through chemical adsorption studies and IR spectroscopy, they verified that the auxiliary agents are located on the surface of the Rh particles. The auxiliary metals block adsorption sites, preventing the dissociative adsorption of syn-gas while promoting CO insertion. Kobayashi and co-workers93 reported that supported Pd catalyzes the hydroformylation of ethylene. The Pd/SiO2 catalyst has almost similar catalytic activity as Rh/SiO2. Ichikawa and Sachtler94 further explored the effect of sulfur on the reaction activity. They found that adding H2S decreases the adsorption of CO, though not to the same degree as Zn additives. Chuang notes that H2S does not hinder the Rh/SiO2 catalyst, and it can increase the activity of Ni/ SiO2.95

13.05.6.3.2

Transition metal modified zeolite catalyst system

The pore channels of zeolites are special molecular reactors. Its shape-selective characteristics can greatly affect the selectivity of the hydroformylation reaction. Takahashi and Kobayashi jointly explored the hydroformylation reaction of ethylene and propylene on a Rh-Y zeolite catalyst.96 The activity of Rh-Y zeolite can be maintained for up to 1 month. Through studies regarding the concentration of Rh, they concluded that the Rh is distributed mainly at the entrance to the pores. The Rh on the outer surface is active in catalyzing the hydroformylation of ethylene and propylene, but the Rh distributed in the pores could not catalyze the hydroformylation of propylene. This observation explains the relationship between the size of olefin molecules to catalytic activity. The research of heterogeneous hydroformylation with transition-metal modified zeolites has mainly focused on zeolite Y, although zeolites A and X have been studied as well.97

13.05.6.3.3

Single atom catalysts for hydroformylation

The zeolite supported Rh formed through ion exchange technically fits the definition of a single atom catalyst (SAC).98 SACs are an emerging class of heterogenous catalysts that disperse single metal atoms throughout the support. The isolation of the individual metal atoms maximizes their efficiency, bridging the gap between homogenous and heterogenous catalysis. The Zhang group deposited Rh atoms on a ZnO nanowire (ZnO-nw) Scheme 36A.99 For the hydroformylation of styrene, they obtain higher turnover numbers (TON) for their Rh1/ZnO-nw catalyst compared to traditional homogenous catalysts like RhCl(PPh3)3. The same group later deposited Rh atoms on CeO2 supports and found that this SAC could catalyze low pressure water gas shift reactions Scheme 36B.100 This enabled them to replace the H2 in syn-gas with H2O. Finally, in a recent report from the Chen group, they immobilized Rh atoms with PNP ligands on a nanocrystal diamond (ND) Scheme 36C.101 The phosphine ligands and ND support enables branched selective hydroformylation of styrene (b:l ¼ 13.1:1). Recent advances in SAC have given rise to hydroformylation catalysts that leverage the benefits of both homogenous and heterogenous catalysis.

Scheme 36 Single atom Rh catalysts can use various solid supports.

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219

13.05.7 Summary In this article, we present the readers a discussion on the more recent development of hydroformylation using alternative metals to Rh, syn-gas surrogates, bimetallic catalysts and asymmetric catalysis. We also highlight applications of hydroformylations in tandem catalysis, natural product synthesis and heterogeneous system. A traditionally industrial scale process, hydroformylation has been optimized to be a milder and more efficient transformation that can be widely used in research laboratories, and it remains a valuable transformation that continues to evolve.

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13.06

Reactions of Ylides Generated from M]C Bonds

Shu-Sen Li, Zihao Fu, and Jianbo Wang, Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China © 2022 Elsevier Ltd. All rights reserved.

13.06.1 13.06.2 13.06.2.1 13.06.2.2 13.06.2.3 13.06.2.4 13.06.2.5 13.06.3 13.06.3.1 13.06.3.2 13.06.3.3 13.06.3.4 13.06.3.4.1 13.06.3.4.2 13.06.3.4.3 13.06.3.5 13.06.4 13.06.4.1 13.06.4.2 13.06.4.3 13.06.4.4 13.06.4.5 13.06.4.6 13.06.5 13.06.6 13.06.7 References

Introduction Formation of oxygen ylide from metal carbene complexes and subsequent reactions [2,3]-Sigmatropic rearrangements [1,2]-Stevens rearrangement Trapping of the oxonium ylide Miscellaneous reactions of oxonium ylides 1,3-Dipolar cycloaddition of carbonyl ylide Formation of sulfur ylide from metal carbene complexes and subsequent reactions [2,3]-Sigmatropic rearrangements [1,2]-Stevens rearrangement S-H insertion Trapping of the sulfonium ylide Electrophilic trapping of the sulfonium ylide Nucleophilic trapping of the sulfonium ylide Miscellaneous applications of sulfonium ylides 1,3-Dipolar cycloadditions of thiocarbonyl ylide Formation of nitrogen ylide from metal carbene complexes and subsequent reactions [2,3]-Sigmatropic rearrangements [1,2]-Stevens rearrangement Formal N-H insertions through ammonium ylide Trapping of the ammonium ylide The reaction of azirinium ylide and pyrazolium ylide 1,3-Dipolar cycloadditions of azomethine and pyridinium ylide Ylide generation from other heteroatoms and subsequent reactions Reaction of metal complexed nitrene with Lewis base Conclusion

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13.06.1 Introduction In situ generated metal carbene or metal nitrene species have proven to be among the most valuable intermediates in organic synthesis, showing abundant transformations including the reactions between electrophilic metal carbene (nitrene) and nucleophilic heteroatoms which offer convenient approaches to access ylide intermediates (Scheme 1).1 This strategy avoids both the pre-preparation of onium salts and the use of stoichiometric bases. Also, such method of ylide formation makes it possible to control the reactivity and selectivity (chemo-, regio-, and stereoselectivity) by modulating properties of the catalysts (both metal salts and ligands). Thus, the ylide formation and subsequent transformations have found prominent applications in both organic synthesis methodology and total synthesis and are still of great interests.

Comprehensive Organometallic Chemistry IV

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Reactions of Ylides Generated from M]C Bonds

Scheme 1 Ylide generation from metal carbene and subsequent transformations.

Heteroatoms that can function as Lewis bases are amenable to ylide formation with their non-bonding lone-pair electrons, including O, S, N, Se and halogens. The generated ylide intermediates are usually highly active and undergo various subsequent transformations, which have found applications in constructing complex molecules. The transformations of ylide intermediates are diverse, typically including: [2,3]-sigmatropic rearrangement, [1,2]-Stevens rearrangement, X-H insertion, trapping reaction of ylide with nucleophile or electrophile, 1,3-dipolar cycloaddition of the carbonyl ylide or azomethine ylide, and some other reactions (Scheme 1). We have reviewed the same topic in this book series in 2007,2 yet the past more than 10 years have witnessed great advances in this area. Thus, we have deemed it is necessary to summarize these new developments to give the readers some insights for further development and application of those transformations. Since in recent years the related topic has also been reviewed elsewhere,1g,3–15 this article will focus on the new reactions, new developments in selected transformations (especially in enantioselective transformation), and new applications of those reactions in the synthesis of complex molecules.

13.06.2 Formation of oxygen ylide from metal carbene complexes and subsequent reactions The oxygen atom in ethers is a weak-to-moderate Lewis base. Nevertheless, a highly reactive metal carbene complex can interact with the oxygen to generate an oxonium ylide and subsequently goes through [2,3]-sigmatropic rearrangement, [1,2]-Stevens rearrangement, 1,3-dipolar cycloaddition and other types of ylide reactions (Scheme 2).

Scheme 2 Oxygen ylides generation and subsequent transformations.

13.06.2.1 [2,3]-Sigmatropic rearrangements [2,3]-Sigmatropic rearrangement of the ylide intermediate is one of the most remarkable bond reorganizations in organic reaction, and has unique utility in organic synthesis for its high efficiency of CdC bond formation with high diastereo- and enantioselectivity (Scheme 3).

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Scheme 3 [2,3]-Rearrangement of ylides generated from diazo compounds.

Transition-metal-catalyzed [2,3]-sigmatropic rearrangement of oxonium ylides provides an efficient strategy for ring-expansion. For example, Quinn and co-workers demonstrated Cu-catalyzed ylide formation and [2,3]-sigmatropic rearrangement of trans-divinyl epoxide 1 and diazoacetates to provide cis-dihydropyran 2 with high diastereoselectivity (Scheme 4).16

Scheme 4 Cu-Catalyzed [2,3]-sigmatropic rearrangement of vinyl epoxide.

In another example, chiral Rh(II)-catalyzed asymmetric intramolecular [2,3]-sigmatropic rearrangement of oxonium ylides was reported by Hashimoto and co-workers. The product 3 was obtained in 72% yield and 93% ee (Scheme 5).17

Scheme 5 Rh(II)-Catalyzed asymmetric [2,3]-sigmatropic rearrangement.

Davies and co-workers reported the generation of oxonium ylide from allylic or propargylic alcohols. The reaction with racemic secondary or tertiary allylic alcohols gave [2,3]-rearrangement products effectively with high chemo- and enantioselectivity, instead of the O-H insertion products (Scheme 6A).18 Intermolecular oxonium ylide [2,3]-sigmatropic rearrangement between diazo compounds and chiral allylic alcohols (Scheme 6B)19 or tertiary propargylic alcohols (Scheme 6C)20 were explored by the same group, which produced homoallylic alcohols containing vicinal stereocenters as well as a-hydroxy allenes with high diastereo- and enantioselectivity.

Scheme 6 Rh(II)-Catalyzed asymmetric [2,3]-sigmatropic rearrangement of diazo compounds with allylic and propargylic alcohols.

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The Davies group also applied their methodology to the stereoselective synthesis of functionalized cyclopentanes from vinyldiazoacetates 4 and allyl alcohols 5 through a cascade reaction, which started with [2,3]-rearrangement of oxonium ylide to form 6, followed by oxy-Cope rearrangement, enol-ketone tautomerization to form 7 and eventually intramolecular carbonyl-ene reaction to give the product 8 (Scheme 7A).21,22 Using enantiomerically pure allylic alcohols and a matched chiral Rh(II) catalyst higher enantioselectivity could be obtained than using racemic allylic alcohols. Moreover, poly-substituted cyclohexanes containing four stereocenters were synthesized through the same strategy (Scheme 7B).23

Scheme 7 Rh(II)-Catalyzed domino sequence for asymmetric synthesis of cyclopentanes

Prabhu and co-workers reported gold-catalyzed [2,3]-sigmatropic rearrangement between diazo compounds and primary allylic alcohols. The tertiary alcohol product 9 could be obtained selectively over O-H insertion and other byproducts under mild, open-air conditions (Scheme 8).24

Scheme 8 Gold-catalyzed [2,3]-sigmatropic rearrangement with diazo compounds and primary allylic alcohols.

Oxonium ylide generated from non-diazo carbene precursors was also reported to go through [2,3]-sigmatropic rearrangement. Boyer demonstrated that 1-sulfonyl-1,2,3-triazoles 10 could be adopted as a carbene precursor to afford oxonium ylides, which further undergo intramolecular sigmatropic rearrangement to give substituted heterocycles 11 and 12 (Scheme 9).25,26

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Scheme 9 [2,3]-Rearrangement adopting triazoles as carbene precursors.

Yang and Tang showed that a-oxo gold carbenes generated from alkynes could undergo intramolecular oxonium ylide formation and [2,3]-sigmatropic rearrangement, allowing the rapid access of highly functionalized dihydrofuran-3-ones 13 (Scheme 10).27

Scheme 10 Gold-catalyzed intramolecular rearrangement with alkynes as carbene precursors.

13.06.2.2 [1,2]-Stevens rearrangement Another important type of ylide reaction is the [1,2]-shift, which is also known as Stevens rearrangement (Scheme 11). Compared to the symmetry-allowed [2,3]-sigmatropic rearrangement, concerted [1,2]-shift is an orbital symmetry-forbidden process. Thus, [1,2]-shift is commonly considered occurring stepwise via radical pair intermediates.28

Scheme 11 [1,2]-Shift reaction of the ylide generated from diazo compound.

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The [1,2]-shift is an efficient process for the synthesis of heterocyclic compounds. For example, Krasavin and co-workers reported a Rh(II)-catalyzed [1,2]-Stevens rearrangement of a-diazo homophthalimides 14 and cyclic ethers, leading to spirocyclic products 15 (Scheme 12).29

Scheme 12 Rh(II)-Catalyzed spirocyclization of a-diazo homophthalimides with cyclic ethers.

Beller and co-workers demonstrated a tandem alkoxylation/acetalization reaction of diazo compounds and trimethyl orthoformates yielding a tertiary a-alkoxy-b-oxo-ester 16 without enantiomeric excess. No cross-over product was observed, which indicated that this reaction might proceed via a concerted pathway (Scheme 13).30

Scheme 13 [1,2]-Stevens rearrangement of trimethyl orthoformates.

Similar to [2,3]-sigmatropic rearrangements, gold carbenes generated from alkynes could go through [1,2]-Stevens rearrangement as well. Li and co-workers developed a mild approach to synthesize cyclobutanones from homopropargylic ether. The a-oxo gold carbene 17 was proposed to be the intermediate, which reacted with the ethereal oxygen in an intramolecular manner to generate oxonium ylide 18, followed by [1,2]-shift to produce the cis-cyclobutanones 19 (Scheme 14).31

Scheme 14 Gold-catalyzed [1,2]-Stevens rearrangement with alkynes as carbenoid precursors.

In addition to transition-metal catalyzed reactions, photochemical excitation of diaryldiazomethane32 and donor/acceptor diazo compounds33 led to oxonium ylide formation and Stevens rearrangement. When donor/acceptor diazo compounds 20 were used, substituted tetrahydrofurans 21 were produced with high diastereoselectivity (Scheme 15).33

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Scheme 15 Photochemical [1,2]-Stevens rearrangement of oxonium ylides.

13.06.2.3 Trapping of the oxonium ylide A significant recent development of ylide chemistry is trapping the in situ generated ylides with electrophiles.1g Since the first such type of Rh(II)-catalyzed reaction was reported by Hu and co-workers in 2005 (Scheme 16A),34 various electrophiles including carbonyl compounds,34–46 imines,47–51 and Michael acceptors52–59 were proved to be capable to trap oxonium ylides. The reaction pathway of this type of transition-metal-catalyzed multi-component reactions involves oxonium ylide generation with diazo compounds and alcohol, followed by tandem addition to electrophiles containing unsaturated bonds. This type of reactions

Scheme 16 Electrophilic trapping of oxonium ylides.

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provides a novel approach for the efficient construction of poly-functional molecules with high yields and stereoselectivity. Mechanistic experiments provided the evidence to support the existence of oxonium intermediates 22 and 23.60 It is noteworthy that the conventional O-H insertion is suppressed (Scheme 16B). Besides commonly used Rh(II), Cu(I) complex36 and InBr337 were also proved to be effective catalysts in these multi-component reactions. A dual-metal cooperative catalysis strategy was achieved to control35 or switch43 the diastereoselectivity (Scheme 17). Asymmetric three-component reactions of diazoesters, alcohols and imines were developed with cooperative catalysts of Rh(II) and chiral Brønsted acid 24 (Scheme 18).47 The chiral Brønsted acid played important roles in both activating imine group and accelerating proton transfer. A broad scope of hydroxyl-group-containing compounds including alcohols, water48,49 and carboxyl acids50 were demonstrated to convert into oxonium ylides with diazo compounds, followed by trapping with imines.49,51

Scheme 17 Diastereoselective dual-metal catalyzed three-component reaction of diazoesters, alcohols and carbonyl compounds.

Scheme 18 Asymmetric trapping of oxonium ylides with imines.

Tandem process involving trapped oxonium ylides provides a highly effective synthetic route to heterocycles. The Hu group reported tandem cyclization/three-component reactions of 2-alkynylarylaldimines with diazo compounds and water or alcohols to afford 1,2-dihydroisoquinoline derivatives.61 Afterwards, the same group demonstrated enantioselective cascade reactions combining trapping oxonium ylides and subsequent Michael addition/SN2 cyclization/amide formation (Scheme 19).51,62

Scheme 19 Tandem process involving trapping oxonium ylides with imines.

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Enantioselective three-component reaction of diazo compounds with water and a,b-unsaturated 2-acyl imidazoles synthesized g-hydroxyketone derivatives under a Rh-Zn cooperative catalytic system (Scheme 20A).53 A cascade multicomponent reaction of diazoesters, benzyl alcohol and 2-formyl chalcones was developed through trapping oxonium ylide and successive aldol-type process, and diastereoselectively yielded functionalized 1-indanols (Scheme 20B).56

Scheme 20 Enantioselective and diastereoselective trapping of oxonium ylides with Michael acceptors.

Recently, the Hu group reported a Rh(II)/chiral Brønsted acid co-catalyzed enantioselective reaction via trapping of oxonium ylides with 3-hydroxyisoindolinones by a formal SN1 pathway (Scheme 21).63 This reaction constructed two contiguous chiral quaternary stereocenters containing an isoindolin-1-one moiety with good yields and high enantioselectivities.

Scheme 21 Trapping oxonium ylides via a formal SN1 pathway.

13.06.2.4 Miscellaneous reactions of oxonium ylides In addition to [2,3]-sigmatropic rearrangement, [1,2]-shift and ylide trapping reactions mentioned above, oxonium ylides may undergo other reactions. For example, oxonium ylides have been reported to go through macrocyclization reactions with cyclic ethers. Lacour and co-workers firstly reported Rh(II)-catalyzed synthesis of functionalized polyether macrocycles with diazoesters and dioxane, tetrahydropyran or tetrahydrofuran. The reaction mechanism was proposed to involve the generation of oxonium ylides 28 and the dimerization through synchronous intermolecular nucleophilic attacks of the enolate onto the electrophilic oxonium a-carbon (Scheme 22).64

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Scheme 22 Rh(II)-catalyzed macrocyclization of diazoesters and dioxane.

Rh(II) or Ru(II)-catalyzed ring-expansion reactions of diazo compounds with oxaheterocycles65–69 were also developed by the Lacour group. In addition, Kitamura and co-workers found that Pd(OAc)2 was an efficient catalyst for the macrocyclization of 1,2-diazonaphthoquinones 29 and cyclic ethers leading to the synthesis of protected 1,2-naphthalenediols (Scheme 23).70

Scheme 23 Pd-catalyzed macrocyclization of 1,2-diazonaphthoquinones with cyclic ethers.

Yin and co-workers disclosed a protocol for three-component reactions of diazoesters, cyclic ethers and weak nucleophiles. These reactions involved metal-free oxonium ylide formation with subsequent ring-opening nucleophilic attack (Scheme 24).71

Scheme 24 Metal-free three-component reaction of diazoesters, cyclic ethers and nucleophiles.

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The Hu group and Zhang group reported Pd- or Au-catalyzed formal [4 + 1] cycloadditions of diazoesters and propargyl alcohols, respectively, generating 2,5-dihydrofurans in both cases (Scheme 25).72,73 The metal catalysts not only catalyzed the formation of the protic oxonium ylides, but also activated the alkyne moiety in these processes.

Scheme 25 Formal [4 + 1] cycloaddition of diazoesters and propargyl alcohols.

13.06.2.5 1,3-Dipolar cycloaddition of carbonyl ylide The oxygen lone-pair electrons in a carbonyl group can react with the electron-deficient carbenic carbon of a metal carbene complex to generate the carbonyl ylide. Unlike an oxonium ylide, a positive charge in such a carbonyl ylide is mainly localized at the carbonyl carbon. Consequently, carbonyl ylides behave like 1,3-dipolar species. Carbonyl ylides possess versatile reactivities, among which the 1,3-dipolar cycloaddition is the most common and important reaction (Scheme 26).

Scheme 26 1,3-Dipolar cycloaddition of carbonyl ylide.

Rh (II) catalyzed carbonyl ylide formation and subsequent dipolar cycloadditions have been extensively studied and broadly utilized. Besides C]C bonds,74 various unsaturated bonds, including C^C,75,76C]O,77–79 C]N,80–82 N]N and N]O bonds83 have been reported to undergo [3 + 2] cycloadditions with carbonyl ylides to give oxygen-bridged bicyclic products (Scheme 27).

Scheme 27 Examples of carbonyl ylide cycloaddition with various dipolarophiles.

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Asymmetric cycloaddition of carbonyl ylides84 has been attained mostly by chiral Rh(II) catalysts (Scheme 28A).85 Interestingly, Suga and co-workers achieved significant enantioselectivity in 1,3-dipolar cycloadditions by using an achiral Rh(II) catalyst and chiral Lewis acid generated from Sc(III) and a chiral Pybox ligand (Scheme 28B).86–89 Another efficient strategy was cycloaddition to dipolarophiles bearing chiral sulfinyl groups as the chiral auxiliaries. In such case almost complete enantioselectivity was observed (Scheme 28C).90

Scheme 28 Asymmetric carbonyl ylide cycloadditions.

In addition to the diazo compounds, carbonyl ylides generated from alkynes could undergo 1,3-dipolar cycloadditions to afford oxa-heterocyclic compounds. Iwasawa and co-workers reported the reaction of acyclic g,d-ynone 30 and alkenes with catalytic PtCl2 to give the cycloaddition product 31 in good yield (Scheme 29).91 The enantioselective and diastereoselective version of this reaction were achieved by the same group.92,93 Furthermore, it was noteworthy that the carbonyl ylides generated from benzylic epoxides by photoredox catalysis could also undergo 1,3-dipolar cycloadditions, although in this case carbene is not involved as reactive intermediate (Scheme 30).94

Scheme 29 Cycloaddition of carbonyl ylides derived from ynones.

Scheme 30 Cycloaddition of carbonyl ylides generated by photoredox catalysis.

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The Fox group and other groups developed three-component carbonyl ylide cycloadditions by utilizing diazo compounds, aldehydes and dipolarophiles in a one-pot process. The scope of the Rh(II)-catalyzed transformation has been widely explored including various dipolarophiles (Scheme 31).95 Moreover, Zhao and Chen reported Ag(I)-catalyzed three-component 1,3-dipolar cycloaddition of diazoesters, aldehydes and a,b-unsaturated carbonyl compounds.96

Scheme 31 Three-component cycloaddition with various dipolarophiles.

13.06.3 Formation of sulfur ylide from metal carbene complexes and subsequent reactions Similar to the oxygen atom, the sulfur atom in sulfide, thiol, and thiocarbonyl compound can act as nucleophiles to attack metal carbene centers, forming sulfur ylides that can subsequently undergo sigmatropic rearrangement reactions, S-H insertions, 1,3-dipolar cycloadditions and other reactions (Scheme 32). A range of transition metals, such as Cu(I), Rh(II), Ag(I), Ru(II), Fe, Au(I/III), Pt(II) and Ni(II), were proven to be proper catalysts for such cascade transformations. Apart from commonly used diazo compounds, hydrazones, cyclopropenes, and alkynes are also viable carbene precursors.

Scheme 32 Sulfur ylides generation and subsequent transformations.

Different from the corresponding oxygen ylides, most sulfur ylides could be formed intermolecularly due to the higher nucleophilicity of sulfur atom, making it easier to access the ylide species. While most oxygen ylides are transformed via metal-associated intermediates, the sulfur ylides generally undergo transformations via free ylide intermediates, probably because of their higher stability. However, such property makes it challenging to control the stereoselectivity of the related reactions.

13.06.3.1 [2,3]-Sigmatropic rearrangements Sulfonium ylides bearing allyl, propargyl, allenyl or benzyl groups on sulfur atom, smoothly undergo [2,3]-sigmatropic rearrangement reactions. While the reactions have been known as Doyle-Kirmse reaction for long time, in recent years new types and enantioselective versions of [2,3]-sigmatropic rearrangement reactions with sulfonium ylides have appeared in the literature and those new developments will be discussed in detail. The diversity of carbene precursors,97–103 metal catalysts104–110 and reaction conditions111 were proven to be viable in the Doyle-Kirmse reaction, and they will be summarized fist.

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Apart from diazo compounds, N-tosylhydrazones98 and pre-prepared or in situ formed 1,2,3-triazoles,99,100 which are surrogates of diazo compounds, can interact with Rh(II) to form metal carbenes. Ylide formation with sulfides and subsequent rearrangement finally afforded the products effectively (Scheme 33A and B). Furthermore, Zhang102 and Davies101,103,104

Scheme 33 Various carbene precursors for sulfonium ylide formations/rearrangements.

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demonstrated that the a-oxo gold or platinum carbenes generated from alkynes could react with allylic sulfides to give sulfonium ylides, which further underwent [2,3]-sigmatropic rearrangements to afford the corresponding products with good yields. Both terminal alkynes and internal ynamides are viable reaction partners, and the pattern of metal carbene formation as well as the ylide formation can be in both intra- and intermolecular manners (Scheme 33C). Wang and co-workers also discovered that cyclopropenes could act as a carbene precursors to participate in similar transformations (Scheme 33D).105 It is apparent that the diversification of carbene precursors would enhance the applications of carbene-based ylide reactions in chemical bond formations. Nevertheless, the most used reaction partners are still the diazocarbonyl compounds. For the catalysts, while a series of transition metals can affect the carbene formations and subsequent rearrangements, Cu(I) and Rh(II) complexes are the most common catalysts used in carbene transfer reactions. As shown in Scheme 34, in addition to Cu(I) and Rh(II) complexes, Ru(II),106 Ag(I),107 Fe,108–110 and Au(I)111 with proper ligands are viable catalysts for catalytic Doyle-Kirmse reaction of sulfonium ylides. The diversity of catalysts makes it possible to acquire various reactivity and selectivity. For example, while the products of [2,3]-sigmatropic rearrangement of sulfonium ylide generated from propargyl sulfide are easy to further cyclize under Ru(II) catalysis, affording furan derivatives (Scheme 34A),106 the similar rearrangement products obtained under other metal catalysts such as Rh(II), Cu(I) and Ag(I) will not be affected (Scheme 34B). Several groups have shown that iron catalysts are capable of accelerating related reactions; these reactions could be performed “on-water,”109,110 and even showed higher efficiency than cobalt and rhodium when using in situ generated volatile diazo compounds (Scheme 34C, D and E).109 Notably, the first example of [2,3]-sigmatropic rearrangement of sulfur ylides carried out in water had been disclosed earlier by Wang and co-workers.112 More recently, Koenigs group reported that Au(I) complex is an efficient catalyst for Doyle-Kirmse reaction (Scheme 34F).111

Scheme 34 The catalysts for sulfonium ylide formation/rearrangement.

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The chemoselectivity in the Doyle-Kirmse reaction was investigated; the tendency of preferential [2,3]-sigmatropic rearrangement has the following order: propargyl sulfide > allyl sulfide > allenyl sulfide.113 As expected, when the sulfide bears oxathiolane group, only sulfonium ylide formed,114 suggesting that sulfonium ylides are easier to form than oxonium ylides. The enantioselective version of Doyle-Kirmse reaction is of great interests yet very challenging, because free ylides generally are involved in the rearrangement step. To realize this target, chiral sulfur stereocenters in the sulfonium ylide need to be constructed. Up to now, only three examples have been reported. In 2005, Wang attained high stereoselectivity with a double asymmetric induction strategy by involving a chiral auxiliary in the substrates (Scheme 35A).115 More recently, a significant breakthrough in asymmetric Doyle–Kirmse reaction was again made by Wang and co-workers,116 where employing trifluoromethyl sulfides is the key for achieving high enantioselectivities (Scheme 35B). This transformation provides a unique and highly enantioselective method for the construction of C(sp3)–SCF3 bonds. The mechanistic studies show that this rearrangement proceeds via a free ylide process and the electronic repulsion between the trifluoromethyl group and the ligand plays an important role in chiral induction. Later, Feng and coworkers designed an auxiliary-promoted strategy to obtain high enantioselectivities in the same rearrangement process, in which a pyrazole group is involved to form a “temporary chiral auxiliary” with chiral Ni(II) complex to guarantee the high enantioselectivity. Meanwhile, the Ni(II) catalyst was effective for the generation of metal carbene and then the sulfonium ylide (Scheme 35C).117

Scheme 35 Stereoselective Doyle-Kirmse reactions.

The thia-Sommelet-Hauser reaction is a unique [2,3]-sigmatropic rearrangement of sulfonium ylides, in which an aromatic ring is involved. While the classic thia-Sommelet-Hauser reactions were performed with stoichiometric base, Wang and co-workers developed a catalytic version of thia-Sommelet-Hauser rearrangement through Rh(II)-catalyzed carbene transfer reaction (Scheme 36A).118 Compared with typical Doyle-Kirmse reaction, additional steps such as [1,3]-proton transfer, and an energy-demanding dearomatization/re-aromatization are involved. Later, the same group disclosed another thia-Sommelet-Hauser rearrangement, a facile and efficient approach to 3-arylthio-1,3-disubstituted-oxindoles (Scheme 36B).119

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Scheme 36 Catalytic thia-Sommelet-Hauser rearrangement.

Later, various catalysts120 and substrates121,122 were explored to expand the scope of this catalytic Sommelet-Hauser rearrangement. In 2017, Pan established a hemin-catalyzed system for this rearrangement reaction, in which water was adopted as the solvent to promote the target transformation.120 Recently, Koenigs reported a Rh(II)-catalyzed same rearrangement reactions of benzyl sulfides, where a 2-pyridyl group was tolerated.122 In these sigmatropic rearrangements, chemoselectivity depends on both electronic nature of substrate and type of the solvent, which will be discussed in the section of [1,2]-sigmatropic rearrangement. Notably, catalytic Sommelet-Hauser rearrangement of sulfonium ylides has a multi-step reaction mechanism involving metal carbene formation, proton transfer and energy-demanding dearomatization (Scheme 35A), which increases the complication of this reaction, it is thus anticipated that asymmetric control of this reaction is very challenging. Based on the high interest upon asymmetric [2,3]-sigmatropic rearrangements, Wang and co-workers recently reported a Cu(I)/chiral bisoxazoline-catalyzed enantioselective Sommelet-Hauser rearrangement (Scheme 37A).123 With a modified bisoxazoline ligand, moderate to high

Scheme 37 Enantioselective Sommelet-Hauser rearrangements.

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enantioselectivity was attained. The mechanism of this reaction was studied in detail and indicated that this rearrangement again involves a free ylide process and water is beneficial for this reaction by forming a favorable six-membered cyclic transition state in [1,3]-proton transfer step. Kinetics studies indicate that the reaction of the diazo substrate and the Cu(I) catalyst to form Cu(I) carbene is likely the rate-limiting step and sulfide can act as a bidentate ligand to poison the catalyst, thus suppressed the decomposition of diazo compounds. As expected, in the sigmatropic rearrangements, Doyle-Kirmse reaction was proven to be more facile than Sommelet-Hauser rearrangement.117,122 On the other hand, Feng described a Ni(II)/N,N0 -dioxide complex-catalyzed [2,3]-Stevens and Sommelet-Hauser rearrangements. In the latter case, the pyrazole group was assembled to the diazo substrates for complexation with the chiral catalyst. Moderately good enantioselectivity was obtained in this case (Scheme 37B).124 Apart from hydrocarbons, other unsaturated double bond such as those in carbonyl125 and imine126 compounds were disclosed by Anbarasan and co-workers to be viable motifs that could participate in [2,3]-sigmatropic rearrangement of sulfonium ylides. Those oxa- or aza-[2,3]-sigmatropic rearrangements offer unique methods for the synthesis of vinylogous carbonates or N, N-disubstituted enamides in good yields (Scheme 38).

Scheme 38 Other motifs participating in [2,3]-sigmatropic rearrangement of sulfonium ylides.

[2,3]-Sigmatropic rearrangement reactions of sulfonium ylides have found applications in the synthesis of complex compounds in the past years. One example was reported by Crich and co-workers who modified amino acid and peptide with this type of rearrangement. While this reaction was not compatible with the tryptophan, diverse functional groups could be selectively introduced to cysteine residues regardless of other possible side reactions such as N-H insertions (Scheme 39).127

Scheme 39 [2,3]-Sigmatropic rearrangements as tool for amino acid and peptide modification.

As mentioned above,106 the Doyle-Kirmse reaction of sulfonium ylides generated from propargyl sulfide gives the products with an allenyl motif which is usually reactive under proper conditions, thus allowing the development of tandem catalytic transformations. In this context, Wang and co-workers demonstrated that the cascade reactions including [2,3]-sigmatropic rearrangement of sulfonium ylide, 1,4 migration of the sulfonyl group and generation of Ru(II) carbene intermediates, and subsequent cyclization could afford the multi-substituted furan products (Scheme 40).128 Notably, this cascade reaction could also be catalyzed with only Ru(II) catalyst, albeit giving the furan products in slightly diminished yields.

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Scheme 40 [2,3]-Sigmatropic rearrangements followed by cyclization to give multi-substituted furans.

Other cascade reactions were also designed for the construction of complex molecules. With bis-diazolactams, Padwa and co-workers reported that the Doyle-Kirmse reaction could be paired with subsequent carbonyl ylide formation and intramolecular cycloaddition to give polycyclic N-heterocycle 41, forming three new rings in a single operation with excellent diastereoselectivity (Scheme 41).129

Scheme 41 [2,3]-Sigmatropic rearrangements in polycyclic N-heterocycle synthesis.

13.06.3.2 [1,2]-Stevens rearrangement With proper substrates and conditions, the Stevens rearrangement of sulfonium ylide can also occur, featuring substituent migration from the sulfonium center to the anionic carbon center; as a result, it offers a unique method for carbene insertion into CdS120,122,130–140 or NdS141 bonds. Since 2005, the thia-Stevens rearrangements have been significantly developed and have also found some applications. The [1,2]-migration of sulfonium ylide could be used as a unique method for ring expansion.129–135 For example, a macrocyclic ring expansion through a double Stevens rearrangement was reported by Diver and co-workers to synthesize new benzimidazolidinone cyclophanes 42 (Scheme 42A).130 In another example Zakarian and co-workers developed an approach to the central thiolane subunit of Nuphar sesquiterpene thioalkaloids 43 with [1,2]-migration of sulfonium ylide (Scheme 42B).137 When the ylides derive from intramolecular carbenes and sulfides, subsequent Stevens rearrangement will give cyclized compounds. Muthusamy and co-workers utilized such transformations to construct sulfur-containing macrocycles, giving high yields and diastereoselectivities.138,139 In 2017, West and co-workers reported a stereoselective approach to functionalized medium-sized cyclic ethers through Stevens rearrangement of sulfonium ylides generated from readily accessible mixed

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Scheme 42 Stevens rearrangement as tool for ring expansion.

monothioacetals.140 With downstream transformations, the Stevens [1,2]-shift could act as the key step for an enantioselective formal synthesis of (+)-laurencin. It is worth noting that the stereochemical configuration of the anomeric carbon retained after the rearrangement (Scheme 43).

Scheme 43 Application of Stevens rearrangement in formal synthesis of (+)-laurencin.

Reasonably, it was anticipated that stereoselective Stevens rearrangements, especially enantioselective versions, are difficult to realize due to the stepwise mechanism via radical or ionic intermediates. Nevertheless, Tang and co-workers developed the first enantioselective [1,2]-Stevens rearrangement under copper/bisoxazoline complex catalysis, providing optically active 1,4-oxathianes with moderate to high enantioselectivities (Scheme 44).135 For rationalizing such unexpected enantioselectivity, the malonate motif was supposed to coordinate to chiral Cu(I) center to guide the asymmetric induction .

Scheme 44 Enantioselective Stevens rearrangement.

The chemoselectivity in rearrangements of sulfonium ylide was also studied. When more than one type of rearrangement is possible, the chemoselectivity was found to be related with electronic nature of substrate and reaction conditions. Pan and co-workers reported that strong electron-withdrawing groups at para-position on the benzyl motif significantly promote the Sommelet-Hauser rearrangement, while others prefer the [1,2]-Stevens migration. That could be reasonably contributed to higher reactivity of nucleophilic dearomatization step with electro-poor benzenes. Protic solvent was also found to be favorable for [2,3]-rearrangement (Scheme 45A).120 Additionally, Koenigs demonstrated that [1,2]-Stevens rearrangement occurs with THF as the

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Scheme 45 The chemoselectivity in rearrangements of sulfonium ylide.

solvent, while EtOAc prefers Sommelet–Hauser rearrangement. Yet when the pyridyl in sulfide is replaced with benzyl, only Stevens rearrangement can occur, which is probably due to the lack of electro-withdrawing group to promote the [1,3]-proton transfer involved in Sommelet-Hauser rearrangement (Scheme 45B).122 The [1,2]-Stevens rearrangement can also lead to formal N-S insertion. In this context, Koenigs and co-workers reported a Rh(II)-catalyzed [1,2]-rearrangement of sulfonium ylide, where the N-containing group prefer to migrate over the aryl group, forming CdS and CdN bonds. This selective rearrangement is probably attributed to the weaker bond of NdS as compared with the corresponding CdS bond (Scheme 46).141

Scheme 46 N-S insertion via Stevens rearrangement of sulfonium ylide.

13.06.3.3 S-H insertion Similar to the reaction with alcohols, the sulfonium ylides generated from thiols and metal carbenes can undergo S-H insertion to give thioetheral products, which may undergo various subsequent transformations, such as oxidation and hydrogenolysis. Compared to alcohols, thiols have higher coordination ability to metal center and thus may depress the reactivity of the catalysts, making S-H insertions a challenging topic. Since the first example was disclosed in 1952,142 the S-H insertion reaction have attained significant developments and this research topic has been reviewed by several groups1f,143,144; thus only recent advances will be discussed in this section. In addition to the conventional Cu(I)142 and Rh(II),145 other catalysts, such as Ru,146 Ir147 and biocatalyst148 were also proven to be capable of catalyzing S-H insertion reactions via carbene transfer reactions. Recent efforts have been made to design highly reactive metal catalyst,149 to extend the substrates scope,150–152 to develop efficient non-precious metal catalysts with broad scope,153,154 and ultimately to develop asymmetric catalysis.155,156 For example, Che and co-workers designed bis(NHC)ruthenium(II)–porphyrin complexes which have high catalytic activity toward X-H (including S-H) insertion due to the

242

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strong s-donor ability of axial NHC ligands in stabilizing the trans M ¼ CRR0 motif.149 Gouverneur and co-workers described copper-catalyzed S-H insertions of 2,2,2-trifluorodiazoethane and 1-aryl 2,2,2-trifluorodiazoethanes, giving broad fluorine-containing products with moderate to high yields.151 Simple metal salt, such as Fe(OTf )2,154 was proven to be viable catalyst in S-H insertion reactions, affording a wide range of a-thioester products in high yield. Among these advances, asymmetric S-H insertions are of great interests yet very challenging. Apart from catalyst poisoning, sulfonium ylides often undergo transformations via free ylides because of their high stability. Regardless the tremendous efforts devoted to this topic, only low enantioselectivities (up to 23% ee) could be achieved before 2009.157–159 In 2009, Zhou and co-workers made a breakthrough in this field. They reported a Cu(I)/spiro bisoxazoline complex-catalyzed enantioselective S-H insertion, giving moderately high enantioselectivities (Scheme 47A).155 Later, the same group developed a highly enantioselective S-H insertion under the cooperative catalysis of achiral Rh(II) and chiral spiro phosphoric acids (Scheme 47B).156 This asymmetric S-H insertion offers an efficient approach to (S)-Thiomandelate and (S)-Eflucimibe (Scheme 47C). Mechanistic study with DFT calculations indicated that the proton shift step is the enantio-determining step, and the chiral phosphoric acid acted as a chiral proton shuttle in this step, thus governing the asymmetric induction.

Scheme 47 Asymmetric S-H insertions.

13.06.3.4 Trapping of the sulfonium ylide Because of the zwitterionic nature, sulfonium ylide can also act as a nucleophile or electrophile to be trapped by ether electrophilic or nucleophilic reaction partner. The trapping reactions give opportunities to construct new bonds which are different from rearrangements and S-H insertions.

Reactions of Ylides Generated from M]C Bonds

13.06.3.4.1

243

Electrophilic trapping of the sulfonium ylide

Besides proton, which traps the sulfonium ylide in S-H insertions, other electrophiles can also act as trapping partner. Hu and co-workers have shown that imines,160 Michael acceptors,161 and ketones162 are viable electrophilic trapping partners. When electrophiles are activated by Brønsted (Scheme 48A and C) or Lewis (Scheme 48B) acids, the anion in the sulfonium ylide can attack the unsaturated bond to afford addition products. Trapping processes were proven to be more favorable than 1,3-proton shift which would give S-H insertion products. Using chiral acids, high diastereoselectivity and enantioselectivity were obtained in the addition step.

Scheme 48 Electrophilic trapping of thiol derived ylides with various partners.

When sulfides rather than thiols react with metal carbenes, the generated ylides can also be trapped by proton or other electrophiles, followed by CdS bond breaking (Scheme 49A). Koenigs163 and Pan164,165 successively reported the dealkylative intercepted sigmatropic rearrangement reactions (Scheme 49B and C). These reactions offer a unique approach to novel thioethers. Additionally, the chemoselectivity between such transformations and rearrangements was influenced by the diazo compounds and sulfides. Wang and Zhao also described a related domino reaction in which the sulfonium ylide was trapped by a ketone group, with subsequent transformations to afford poly-substituted thiophenes (Scheme 49D).166

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Reactions of Ylides Generated from M]C Bonds

Scheme 49 Electrophilic trapping reactions of sulfides derived ylides.

13.06.3.4.2

Nucleophilic trapping of the sulfonium ylide

Under proper conditions, the sulfonium behaves as an electrophile and will be attack by nucleophiles. For example, the nucleophilic trapping of sulfonium ylide was applied as a key step for total synthesis of unsymmetrically oxidized nuphar thioalkaloids, with (−)-6-hydroxythionuphlutine being synthesized for the first time (Scheme 50).167

Scheme 50 The application of nucleophilic trapping of sulfonium ylide in total synthesis.

Reactions of Ylides Generated from M]C Bonds

13.06.3.4.3

245

Miscellaneous applications of sulfonium ylides

In addition to the above-mentioned reaction types, the sulfonium ylides can also be involved in other transformations. As a recent example, Wan and co-workers reported an efficient glycosylation which involved sequential Rh(II)-catalyzed sulfonium ylide formation, Brønsted acid-catalyzed sulfonium ion generation, oxocarbenium ion formation and subsequent nucleophilic attack (Scheme 51).168 This method features low catalyst loading, mild reaction conditions, and broad scope, making it potentially applicable in the studies of carbohydrate chemistry.

Scheme 51 The application of sulfonium ylide in glycosylation.

13.06.3.5 1,3-Dipolar cycloadditions of thiocarbonyl ylide Compared with carbonyl ylides, the carbene transfer reactions are less utilized to form thiocarbonyl ylides, probably arising from the high coordinative ability of the thiocarbonyl to the metal centers, thus making catalyst poisoning. To date, only highly active Rh(II) catalysts are capable of thiocarbonyl ylide formation. In 2012, Palomo and co-workers reported the thiocarbonyl ylide derived from Rh(II) carbene and subsequent 1,3-dipolar cycloaddition in the synthesis of thiiranes.169 DFT calculation supports the mechanism that involves the thiocarbonyl ylide formation, [3 + 2] cycloaddition to afford tricyclic adduct 53, and subsequent ring-opening sequence to give final thiiranes 54 with high stereoselectivity (Scheme 52).

Scheme 52 1,3-Dipolar cycloaddition of thiocarbonyl ylide formation.

13.06.4 Formation of nitrogen ylide from metal carbene complexes and subsequent reactions Nitrogen atoms in amine or imine groups also have the ability to act as nucleophilic site to attack metal carbene centers, forming nitrogen ylides. The subsequent transformations commonly include sigmatropic rearrangement reactions, N-H insertions, 1,3-dipolar cycloadditions and other miscellaneous reactions (Scheme 53).

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Reactions of Ylides Generated from M]C Bonds

Scheme 53 Nitrogen ylides generation and subsequent transformations.

13.06.4.1 [2,3]-Sigmatropic rearrangements Compared with oxonium and sulfonium ylides, the generation of ammonium ylides via metal carbenes and subsequent [2,3]-sigmatropic rearrangements were less developed and barely applied in organic synthesis. The most commonly practiced method to synthesize ammonium ylides for rearrangement is still the base-induced process. As the related reactions have been reviewed in the previous edition of this book, this section will only focus on some important recent advances. Metal carbene-induced [2,3]-sigmatropic rearrangement of ammonium ylides have found application in the construction of complex structures. For example, Schomaker and co-workers described a Rh(II)-catalyzed [3 + 1] ring expansion of strained bicyclic methylene aziridines to afford poly-substituted methylene azetidines with excellent regio- and stereoselectivity (Scheme 54A).170 Experimental and computational studies strongly support that the reaction proceed via a concerted, asynchronous [2,3]-sigmatropic rearrangement,171 thus making this process stereospecific (Scheme 54B).

Scheme 54 [2,3]-Sigmatropic rearrangement of aziridinium ylides.

The catalytic Sommelet-Hauser rearrangement of ammonium ylide is a unique transformation. Recently, Gu and co-worked disclosed a copper-catalyzed Sommelet-Hauser dearomatization, where ammonium ylide was formed between a copper carbene and dihydrophenanthridine 55. This reaction offers an efficient method to construct spiroindoline compounds 56 bearing adjacent quaternary and tertiary carbon centers (Scheme 55A).172 Notably, only single isomer was obtained and higher temperature prefers the [1,2]-Stevens rearrangement (Scheme 55B). Mechanistic studies indicated that the torsional strain in the biaryl substrate is beneficial for the reaction.

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247

Scheme 55 Metal carbene-induced Sommelet-Hauser rearrangement of ammonium ylide.

13.06.4.2 [1,2]-Stevens rearrangement The [1,2]-migration of ammonium ylides offers an efficient approach for CdN bond formation, in particular for ring expansion. For the migratory groups, in additional to the benzyl groups which are most commonly observed, other alkyl groups can also migrate. Besides, some functional groups are known to be capable of migration, featuring carbene insertions into amine CdN, amide CdN, as well as CdO bonds. West and co-workers have constructed functionalized pyrrolidines via [1,2]-migration of azetidinium ylides.173,174 In one example, complete selectivity for ring expansion was obtained; neither the migration of other exocyclic groups such as benzyl and allyl on the azetidinium nitrogen nor [2,3]-sigmatropic rearrangements on these motifs were observed (Scheme 56A).174 Lacour and co-workers described a Rh(II)-catalyzed ring expansion of methano-bridged Tröger bases 58 with diazo compounds, yielding highly enantioenriched ethano-bridged Tröger derivatives 59 with much higher configurational stability than the substrates.175 This transformation proceeded via ammonium ylide formation and subsequent [1,2]-Stevens shift with high regio- and stereoselectivity (Scheme 56B). Later, they extended the scope with a CuTc catalyst.176 Recently they utilized the same strategy to synthesize polycyclic indoline-benzodiazepines with N-sulfonyl 1,2,3-triazoles as carbene precursor. However, only racemic products were obtained when enantiopure substrates were used, which could be attributed to the initial ring-opening and subsequent reversible Mannich reaction.177

Scheme 56 Other alkyl groups involved in [1,2]-migration of ammonium ylide.

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Reactions of Ylides Generated from M]C Bonds

The acyl group has also been proven to be viable migrating group. Nemoto and Hamada disclosed a novel method to construct various nitrogen-bridged bicyclic compounds 60 via Rh-catalyzed carbene insertion into CdN bond of amide.178 The experimental and calculational studies support the mechanism that involves ammonium ylide formation and subsequent [1,2]-migration of acyl group, and the latter step proceeds via a concerted addition/elimination process (Scheme 57A). Soon afterwards, the catalyst with copper salt at very low loading was reported by the same authors to be efficient for amide insertion, producing functionalized azapolycyclic rings.179 Recently, they utilized this strategy as one of the key steps to synthesize enantioenriched 61, which is an intermediate for the synthesis of (+)-catharanthine (Scheme 57B).180

Scheme 57 Acyl groups involved in [1,2]-migration of ammonium ylide.

Interestingly, Xu and co-workers recently reported a Rh(II)-catalyzed nitrene alkyne metathesis for carbene formation, followed by ammonium ylide formation and amide CdN bond insertion through [1,2]-acyl migration. This cascade reaction offers an efficient approach to a wide variety of tricyclic 3-iminoindolines 62 in good to excellent yields (Scheme 58).181 It is worth noting that both the acyl and ester groups could migrate rather than other groups such as benzyl, allyl, and propargyl, and no [2,3]-rearrangements were mentioned.

Scheme 58 Nitrene alkyne metathesis for carbene formation/[1,2]-acyl migration.

Reactions of Ylides Generated from M]C Bonds

249

The oxygen-containing group attached to ammonium can also migrate, resulting in formal N-O insertions. Davies and co-workers reported that nitrogen ylides could be formed by the reaction of isoxazoles 63 and Rh(II) carbenes, which further underwent ring expansion to afford 2H-1,3oxazines 64 (Scheme 59A).182 Soon after, they utilized this insertion reaction with vinyldiazo compounds to synthesize functionalized pyridines, which were formed through a reaction sequence involving rearrangement, tautomerization, and oxidation.183 While the insertion was proposed to go through [1,2]-migration (Scheme 59A, path A), experimental and theoretical studies indicated a ring-open rearrangement/6p-cyclization mechanism of the ylide (Scheme 59A, path B).184 Doyle and co-workers reported a N-O insertion of hydroxylamine. With TBSO substituted vinyldiazoacetate 65 and nitrones 66 as substrate, they constructed multi-functionalized 3-hydroxypyrroles 67 via one-pot cascade process involving Mannich addition, carbene and ylide formation, N-OTBS insertion, and acid-promoted aromatization (Scheme 59B).185

Scheme 59 Oxygen-containing groups involved in [1,2]-migration of ammonium ylide.

13.06.4.3 Formal N-H insertions through ammonium ylide Nitrogen-containing molecules, such as a-amino carbonyl compounds and N-heterocycles, are important bioactive compounds precursors. Metal-catalyzed carbene N-H insertions represent a versatile approach to these compounds. Like S-H insertion reactions, NH motifs also have strong coordinating ability, which leads to catalyst poisoning and thus makes it difficult to achieve high reactivity and selectivity. In the past two decades, enormous efforts have been dedicated to explore various metal catalysts, which are effective for high reactivity toward different substrates and for high enantioselectivities. In particular, the enantioselective carbene insertion into NdH bonds attracted great attentions and significant advances in this field have been made. In addition to the common Cu(I), Rh(II), other transition metals, such as Ru,186,187 Au,188 Fe,189–191 Ir,192–194 Pd195 complexes as well as hemin196 have shown the ability to catalyze carbene insert into N-H bonds. Various metal catalysts bring more opportunities to achieve high reactivity and selectivity for N-H insertions. For example, using water as the solvent, Sivasankar and co-workers found that [(COD)IrCl]2 is most efficient for acceptor/acceptor carbene insertions, while Pd2dba3 and AgOTf have higher reactivity for donor/acceptor and donor/donor carbenes, respectively.194 Enantioselective N-H insertions offer an attractive method to construct various chiral centers bearing CdN bonds. There are three possible pathways may access the insertion products, as shown in Scheme 60. When the proton shift proceeds based on a metal-associated ylide (path A), the asymmetric induction can be governed by a chiral ligand on metal catalyst, and thus high enantioselectivity may be achieved. However, if the ylide has high stability, the free ylide will form (path B), which is disfavored for chiral induction. Additionally, if a chiral proton shuttle, which can assist the proton transfer process, is involved, the asymmetric control may become effective (path C).

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Reactions of Ylides Generated from M]C Bonds

Scheme 60 Three possible pathways leading to insertion products.

The first asymmetric N-H insertion was reported by McKervey and co-workers in an intramolecular form, where chiral Rh(II) carboxylates were used to afford pipecolic acid derivatives with up to 45% ee.197 Later, Jørgensen and co-workers studied the intermolecular insertion of carbene into NdH bonds, but only up to 48% ee was obtained.198 It was not until 2007 that the first highly enantioselective N-H insertion reaction was reported by Zhou and co-workers.199 Using the copper/spiro bisoxazoline ligand as the catalyst, the a-amino acid derivatives were obtained with high yields and excellent enantioselectivities (Scheme 61). However, only diazopropionates and primary anilines are viable substrates for high enantioselectivity. This insertion reaction is considered to occur through path A in Scheme 60.

Scheme 61 The First highly enantioselective N-H insertion reaction.

Subsequently, plenty of catalytic systems were developed to expand the scope of the substrates and enrich the diversity of the products. In the same year, Fu and co-workers reported another example carbene N-H insertion with high enantioselectivity, where a-aryl diazoesters and carbamates were employed as the substrates (Scheme 62A).200 Feng and Liu developed an alternative catalytic system with chiral Cu(I)/69 catalyst. In this reaction primary amines afford high enantioselectivities, however, secondary amines only gave low to moderate enantioselectivity (Scheme 62B).201 Nevertheless, these were the best results for secondary amines until then.

Reactions of Ylides Generated from M]C Bonds

251

Scheme 62 Various catalytic systems for N-H insertion of aromatic amines/amides.

Moreover, an alternative strategy was explored to achieve symmetric carbene insertion into NdH bonds. Saito and co-workers reported a N-H insertion cooperatively-catalyzed by Rh(II) carboxylate and cinchona alkaloid. Only up to 71% ee was obtained.202 Soon later, Zhou and Zhu reported a highly enantioselective example using similar strategy, where Rh(II) complex and chiral SPA (spiro phosphoric acids) 70 were involved (Scheme 62C).203 In these cases, the stereoselectivity is control by chiral proton shuttles (Scheme 60, path C).

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Reactions of Ylides Generated from M]C Bonds

Until then, the asymmetric N-H insertions highly depends on the substrates, and only two types of a-diazo compounds, namely a-aryl diazoacetates and a-diazopropionates, could be obtained in high yields and enantioselectivities. In 2012, Zhou and Zhu extended the scope of diazo compounds to a-alkyl diazoacetates using Cu(I)/(Sa,S,S)-49 complex as the catalyst, affording the corresponding a-amino acid derivatives in high yields and enantioselectivities (Scheme 62D).204 The same authors also realized an asymmetric N-H insertion reaction of a-diazoketones, which is considered challenging due to the high stability of the relevant free ylide attached by strong electron-withdrawing carbonyl motif.205 Using the cooperative catalyst system of Rh(II) carboxylates and chiral SPA, they could resolve this problem and excellent enantioselectivities could be obtained. Furthermore, the same cooperative catalyst strategy was also proven to be applicable to vinyldiazoacetates.206 A copper/(Sa,S,S)-49 complex-catalyzed intramolecular NdH bonds insertion reaction was also developed, providing a unique approach to 2-carboxytetrahydroquinolines with high enantioselectivities.207 It is worth noting that Pd(0), with chiral guanidine derivatives 71 as ligand, was proven to be capable of catalyzing asymmetric N-H insertions.208 As the first example, the secondary amines, which might generate more stable ylides and would be disfavored for asymmetric control, were used as viable substrates to achieve high enantioselectivities (Scheme 62E). Vranken and co-workers described a Pd(II)/PyBOX-catalyzed N-H insertion reaction with C3-substituted indoles or carbazoles as substrates with moderate to high enantioselectivities. However, the secondary aliphatic amines are inefficient substrates for chiral control in this reaction.209 Although a great variety of advances have been obtained, the N-H insertions were confined to amides as well as aromatic amines (Schemes 61 and 62). This is attributed to the high coordinating ability and high basicity of the aliphatic amines, which results in catalyst poisoning and products racemization. Recently, Zhou and Zhu solved this problem by using cooperatively catalytic strategy with an achiral copper complex Tp Cu and chiral amino-thiourea 72.210 Through the coordination with the sterically encumbered homoscorpionate ligand, the poisoning of the copper center by amines could be avoided. On the other hand, the proton transfer process was promoted by chiral amino-thiourea catalyst. Thus, both high reactivity and enantioselectivity could be achieved over a wide range of diazo ester and primary/secondary aliphatic amine substrates (Scheme 63).

Scheme 63 Highly enantioselective carbene insertion into NdH bonds of aliphatic amines.

13.06.4.4 Trapping of the ammonium ylide When ammonium ylides are trapped by other electrophilic partners instead of proton, a variety of different transformations are possible, expanding the capability for constructing complex compounds. Since the first example of such transformation was disclosed in 2003,211 the ammonium ylide trapping reactions have extensively explored. The initial development was focused on the extension of the type of electrophiles, and a series of electrophiles with polarized double bonds, such as C]O, C]N, C]C and N]N, were proven to be viable trapping partners (Scheme 64).1g Later, various catalytic systems were disclosed to further extend the scope and realize the high stereoselectivity. Moreover, in addition to the commonly used Rh(II) catalysts different transition-metal catalysts have been explored with proper ligands, including Fe(I),212–214 Ru(II),215 Rh(I),216 Pd,217,218 and Ag(I).219 Those transition-metal catalysts were also proven to be capable catalysts, showing high reactivity and selectivity.

Scheme 64 Trapping of the ammonium ylide with various electrophiles.

Reactions of Ylides Generated from M]C Bonds

253

Considering the related topics have been reviewed1g and the reaction types are similar with oxonium/sulfonium ylides, in this section only some selected examples, in particular the enantioselective transformations, will be discussed in detail. In the Rh(II)-catalyzed ammonium ylide trapping reactions, previous studies indicated that only less basic amines such as aromatic amines, carbamates, phosphoramidates were used to avoid catalyst poisoning. To extend the scope of amine, Hu and co-workers employed Fe(TPP)Cl (TPP: tetraphenylporphyrin) as the catalyst, and aliphatic amines could be utilized in such reactions (Scheme 65A).212 The same catalyst was also capable of catalyzing similar reaction starting from ammonia, producing unprotected primary amines under mild reaction conditions (Scheme 65B).213 However, the stereoselectivity of this catalyst is unsatisfactory (Scheme 65A and B). Palladium also showed high reactivity to some new types of electrophile. In 2017, Hu et al. disclosed a Pd(II)-catalyzed ammonium ylide trapping reaction with N-alkylquinolinium salts, featuring high regioselectivities and giving multi-functional bridged tetrahydroquinoline and dihydroquinoline derivatives with excellent yields (Scheme 65C).217

Scheme 65 Examples of ammonium ylide trapping with electrophiles.

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Reactions of Ylides Generated from M]C Bonds

Additionally, nonpolar alkenes were proven to be viable electrophiles when a Pd(II) salt was employed as the catalyst, affording a variety of tri- and tetra-substituted indolines with good yield and high diastereoselectivity. Experimental and DFT studies revealed that the ylide trapping proceeded via metallo-ene-type reaction (Scheme 65D).218 Asymmetric versions of the ammonium ylide reactions are highly desirable, because they can offer convenient approach toward various complex structures with chiral centers bearing CdN bonds. Two strategies, namely cooperative catalysis with achiral metal/ chiral organo-catalysts and single chiral metal catalyst-controlled process, were explored. In 2011, Hu and co-workers reported the enantioselective trapping process of ammonium ylide by using a cooperative catalytic system with an achiral Rh(II) and chiral phosphoric acids. This reaction afforded both syn- and anti a-substituted a,b-diamino acid derivatives with high diastereo-, and enantioselectivity (Scheme 66A).220 Later, the same strategy comprising of an achiral Ru(II) and a chiral phosphoric acid was utilized to accomplish an enantioselective four-component reaction. With high chemoselectivity, arylamine and benzyl carbamate in situ generated iminium and ylide respectively. Upon the ylide trapping, an aza-Michael reaction was followed to afford enantioenriched 1,3,4-tetrasubstituted tetrahydroquinolines bearing quaternary stereogenic carbons in high diastereo- and enantioselectivity (Scheme 66B).215 Very recently, Hu and co-workers developed an asymmetric trapping reaction with fluoroalkyl-substituted diazo compounds as carbene precursors.214 Thus diverse fluoroalkyl-containing chiral syn-diamines were obtained with high stereoselectivities. Noteworthily, while the reaction with Rh(II) catalyst gave no desired products, the FeTPPCl exhibited high efficiency (Scheme 66C).

Scheme 66 Selected examples for synergetic asymmetric catalysis of ammonium ylide trapping.

Besides cooperative catalytic systems, which were mainly applied to the reaction where imines acted as the electrophile, chiral metal complexes are also capable of asymmetric control through metal-associated ylides. The competing free ylide process makes this strategy challenging. In 2012, Che and co-workers reported a chiral Rh(II)-catalyzed asymmetric three-component coupling reaction of anilines, a-diazophosphonates, and electron-deficient aldehydes, giving of a-amino-b-hydroxyphosphonates with moderate to high enantioselectivities (Scheme 67A).221 Remarkably, Hu and co-workers developed a chiral Rh(I)-diene-catalyzed trapping reaction.216 In this transformation, Rh(I)-associated ammonium ylides were formed, followed by Michael additions to b-nitroacrylates. This reaction affords an approach toward polyfunctional amino succinic acid derivatives with high stereoselectivities (Scheme 67B). Recently, Zhang and Sun described another interesting example.222 When 2-O-substituted pyridines were employed as the substrates, pyridinium ylides could be formed, which further underwent 1,4-acyl migration via intramolecular trapping reaction of ylide, affording the dearomatized N-substituted 2-pyridones bearing quaternary stereogenic centers in high enantioselectivity (Scheme 67C).

Scheme 67 Selected examples of chiral metal complex-controlled asymmetric catalysis via ammonium ylide trapping.

In addition to ammonium and pyridinium ylides, nitrile ylide can also be formed and some trapping reactions have been reported.223–226 The nitrile ylide can undergo both nucleophilic and electrophilic trapping reactions. For example, Liu and co-workers found that the nitrile ylide could be generated from gold carbene and a cyano group, and the ylide could be trapped by a nucleophilic N-oxide. Upon subsequent transformation, N-containing seven-membered rings were constructed (Scheme 68A).224 The nitrile ylide can also be trapped by electrophiles, for example, Ma and co-workers reported a

Scheme 68 Nitrile ylides formation and subsequent trapping reactions.

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Reactions of Ylides Generated from M]C Bonds

three-component reaction involving CF3CHN2, nitriles, and aldehydes.225 Through ylide formation and subsequent tapping reaction, CF3-substituted oxazolines could be obtained in moderate to high yields with excellent diastereoselectivity (Scheme 68B). From mechanistic point of view, this reaction follows stepwise [3 + 2] cycloaddition. Such type of reaction will be discussed in Section 13.06.4.6.

13.06.4.5 The reaction of azirinium ylide and pyrazolium ylide The nitrogen ylides can also undergo other transformations, among them the reaction of the azirinium ylide generated from azirines and diazo compounds and subsequent cyclization have developed as an efficient way for ring expansion. For example, Novikov and co-workers provided a unique approach to 2H-1,4-oxazines using 2H-azirines as the substrates.226,227 Mechanistic studies suggest that the reaction follows a sequence comprising azirinium ylide formation, ring-opening, and subsequent 1,6-electrocyclization (Scheme 69A). Also, a pyrazolium ylide could undergo similar tautomerization followed by 1,6-cyclization, affording a unique approach to 1,2-dihydropyrimidines.228 This reaction features the first carbene insertion into a NdN bond (Scheme 69B).

Scheme 69 The reactions involving azirinium ylide or pyrazolium ylide.

13.06.4.6 1,3-Dipolar cycloadditions of azomethine and pyridinium ylide Similar to the carbonyl and thiocarbonyl ylides, the corresponding azomethine or pyridinium ylides generated from imines or pyridines can also participate in cycloaddition reactions via synergistic or stepwise mechanisms. Various transition metal catalysts are able to catalyze the formation of metal carbenes and the subsequent generation these ylides. Che and co-workers reported the ruthenium porphyrin-catalyzed three-component reaction of a-diazo esters, N-benzylidene imines and alkenes, or alkynes, or azodicarboxylates to give the corresponding highly substituted pyrrolidines, pyrrolines, or 1,2,4-triazolidines with moderate diastereoselectivity (Scheme 70A).229,230 Copper was also a capable catalyst in such type of transformations.231,232 Shin and co-workers reported an internal redox/dipolar cycloaddition sequence, where the azomethine ylides were generated from gold carbenes (Scheme 70B).233

Reactions of Ylides Generated from M]C Bonds

257

Scheme 70 Azomethine ylide formations and subsequent cycloadditions.

Pyridinium ylides, which are similar to azomethine ylides, are also capable of undergoing cycloaddition.234 In 2016, Dowden and co-workers accomplished a development of the multi-component reactions of pyridinium ylides generated from metal carbenes.235 With commercially available Fe(III) or Cu(I) complexes as the catalysts，the cycloaddition of pyridines, diazo compounds, and electrophilic alkenes occurred smoothly to afford the tetrahydroindolizidines with high yields and diastereoselectivity (Scheme 71). Later, the scope of the substrates was further extended, and the benzimidazolium N-ylide generated from benzimidazole and iron carbene was also found to undergo cycloaddition.236–239 Notably, the first asymmetric cycloaddition of pyridinium ylide was achieved by Feng and co-workers employing an iron(III)/chiral N,N0 -dioxide-scandium(III) cooperatively catalytic system.240 Various tetrahydroindolizidines were obtained through this method with good to excellent diastereo- and enantioselectivities.

Scheme 71 Pyridinium ylide formations and subsequent cycloadditions.

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Reactions of Ylides Generated from M]C Bonds

13.06.5 Ylide generation from other heteroatoms and subsequent reactions Over the past two decades, some advances have been made in the generations and transformations of other heteroatom ylides in addition to oxygen, sulfur, and nitrogen. In particular, the reaction of selenium and halonium ylides has been explored. Koenigs and co-workers have recently reported systematic studies on the reaction of selenium ylides generated from Rh(II) carbene.241 Depending on the structure of the substrates, various rearrangements, including Doyle-Kirmse reaction, Sommelet-Hauser rearrangement, and [1,2]-Stevens rearrangement, could smoothly with Rh(II) catalysis (Scheme 72A). Moreover, an asymmetric Doyle-Kirmse reaction of selenium ylides was reported very recently by Feng and co-workers.242 With a chiral N,N0 -dioxide/ cobalt(ΙΙ) complex as the catalyst, various selenides bearing quaternary stereocenters were obtained in high yields and enantioselectivities (Scheme 72B). Notably, the pyrazole motif in the diazo substrate is necessary for achieving high reactivity and selectivity. Additionally, a formal carbene insertion into SedSe bond was reported by employing diazoesters and diselenides as the substrates under Rh(II) catalysis.243

Scheme 72 Doyle-Kirmse reactions of selenium ylides.

Halonium ylides can also be generated via the interaction between halides with metal carbenes. The subsequent transformations such as [2,3]/[1,2]-sigmatropic rearrangements and CdX bond insertions are possible to occur. As for the catalysts, in addition to the commonly utilized Rh(II) and Cu(I) complexes, other transition-metals such as Ag(I)244 and Ru(II),245 were proven to be capable of catalyzing the generation of halonium ylides from carbene precursors. Remarkably, Tambar and co-workers developed a ligand-controlled [2,3]- and [1,2]-rearrangements of iodonium ylides.246 Mechanistic studies indicated that the formal [2,3]-sigmatropic rearrangement occurred through a concerted charge-induced process, while [1,2]-rearrangement proceeded via a stepwise oxidative addition/reductive elimination approach (Scheme 73A). Later, the same group accomplished an asymmetric [2,3]-rearrangement of iodonium, giving the highly transformable iodoester products with high diastereoselectivity and enantioselectivity (Scheme 73B).247 As the iodide center in the iodonium ylide intermediate does not possess chirality, this asymmetric rearrangement must go through a metal-associated ylide species.

Reactions of Ylides Generated from M]C Bonds

259

Scheme 73 Rearrangement reactions of iodonium ylides.

C-X insertions can also occur through halonium ylides. For instance, Lovely described a silver-catalyzed related transformation. While some common halogenated solvents could act as substrates to give C-X insertion products, the halogenoalkanes underwent net additions of H-X to the carbene (Scheme 74).248

Scheme 74 Insertion reactions of halonium ylides.

Other miscellaneous transformations were also reported.249–251 For example, Li and co-workers developed a novel approach to highly functionalized 4-bromo-1,2-dihydroisoquinolines; a bromonium ylide generated by intramolecular attack of the benzyl bromide to the a-imino rhodium carbene is the key intermediate (Scheme 75).251

Scheme 75 Other transformations of halonium ylides.

260

Reactions of Ylides Generated from M]C Bonds

13.06.6 Reaction of metal complexed nitrene with Lewis base As mentioned in the third edition of this book series, metal nitrene may also form ylides with Lewis base, and subsequent [2,3]-sigmatropic rearrangements may occur. Compared with the ylides derived from metal carbene, the formation and reaction of ylides derived from metal nitrene were less developed in the last 10 years, probably because the lower electrophilicity of the metal nitrene and the low activation barrier for the competing C-H insertion reaction.252 In addition to the [2,3]-sigmatropic rearrangement, [1,2]-Stevens rearrangement of ammonium ylides is also possible,252–254 leading to the formal insertion of nitrenes into the CdN bonds. These transformations are similar to ylides generated from metal carbenes.

13.06.7 Conclusion The past decades have witnessed significant development in the generation and transformation of ylides derived from metal carbene and nitrene. As showed above, a variety of metal complexes were explored as capable catalysts in various reactions, such as sigmatropic rearrangements, X-H insertions, trapping reactions, 1,3-dipolar cycloadditions, and other miscellaneous reactions. High reactivity and high selectivity could be achieved. Especially, great advances have been achieved in enantioselective transformations. Two strategies including chiral metal complex-controlled process and synergistic catalytic process were developed to construct chiral heteroatom-containing molecules such as amino acids. These transformations have also found their applications in the synthesis of nature products and functional molecules. Despite the significant developments been made, some challenges remain to be addressed. First, the ammonium ylides applied in organic synthesis are still commonly generated via base-induced approach, because the metal catalyst-mediated process via metal carbenes are easily suppressed by coordination of the nitrogen atom to metal centers, and thus high temperature are often necessary for the rearrangement reactions of ammonium which makes it difficult to realize asymmetric catalysis. Second, except X-H insertions and trapping reactions, the strategies for enantioselective rearrangements of ylides strongly depend on the substrates. General methods for highly enantioselective reactions are still not available. Finally, novel applications of ylides under metal catalysis are expected in the future; for example, these reactions of ylides can be possibly designed to synthesize polymers with novel structures.

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13.07

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Quentin Michaudel, Samuel J Kempel, Ting-Wei Hsu, and Justine N deGruyter, Department of Chemistry, Texas A&M University, College Station, TX, United States © 2022 Elsevier Ltd. All rights reserved.

13.07.1 Introduction 13.07.1.1 Olefin metathesis 13.07.1.2 Alkene stereoselectivity in olefin metathesis 13.07.2 Catalyst design 13.07.2.1 Mo and W catalysts 13.07.2.1.1 Early studies with Mo bisalkoxide complexes 13.07.2.1.2 Early studies with Mo diolate catalysts 13.07.2.1.3 Mo and W monoaryloxide pyrrolide (MAP) complexes 13.07.2.1.4 Stereoretentive Mo catalysts 13.07.2.1.5 Mo and W NHC Imido Alkylidenes 13.07.2.2 Ru catalysts 13.07.2.2.1 Early discovery: cis selectivity in alternating copolymerization 13.07.2.2.2 Cyclometalated Z-selective Ru catalysts 13.07.2.2.3 Monothiolate catalysts 13.07.2.2.4 Stereoretentive dithiolate catalysts 13.07.3 Summary Acknowledgment References

265 265 266 268 268 268 269 269 298 304 305 305 307 317 319 335 335 335

13.07.1 Introduction 13.07.1.1 Olefin metathesis Over the last few decades, olefin metathesis has emerged as one of the most powerful methods to create carbon–carbon double bonds.1–3 The abundance of suitable starting materials; the consistency, efficiency, and predictability of the reaction itself; and the versatility of products are among the oft-cited reasons for its enduring popularity. While organic chemistry per se has benefited most, the impact of this invention is undeniably sweeping: A cursory search of the Web of Science database returns more than 10,000 results across a range of fields, including polymer and materials sciences (Fig. 1). In further testament to the importance of this work, the 2005 Nobel Prize in Chemistry was awarded to Robert H. Grubbs and Richard R. Schrock for their pioneering efforts in the development of olefin metathesis catalysts and to Yves Chauvin for elucidation of the reaction mechanism.4–6 Some of the earliest example of olefin metathesis are found in industrial processes that relied on heterogenous Rh and Mo catalysts—for example, the Phillips Triolefin Process (Olefin Conversion Technology), which interconverts propylene with ethylene and 2-butene.7 With the development of homogeneous catalysts came improved reactivity, stability, and functional group tolerance, followed quickly by applications to the synthesis of fine chemicals, including complex natural products, medicinal compounds, and intricate polymeric structures. Much of this catalyst craftsmanship can be attributed to a thorough understanding of the reaction mechanism. The Chauvin mechanism8 involves the [2 + 2] cycloaddition of an alkene and a transition metal alkylidene, which leads to formation of a metallacyclobutane intermediate (Scheme 1). Retro [2 + 2] then produces either the original species or a new alkylidene and alkene pair. Repetition of these two steps allows the formation of the cross-metathesis product. This foundational mechanism sets the stage for a variety of processes, including ring-opening cross-metathesis (ROCM),9 ringclosing metathesis (RCM),10 cross metathesis (CM),11 and ethenolysis12 (Fig. 2). Beyond small molecules, ring-opening metathesis polymerization (ROMP),13 acyclic diene metathesis (ADMET) polymerization,14 and entropy-driven ROMP (ED-ROMP)15 have found extensive use in the synthesis of macromolecules. With respect to reaction thermodynamics, olefin metathesis with unstrained alkenes is governed by the change in Gibbs free energy, DG ¼ DH–TDS, where the change of entropy dominates minor variations in enthalpy.16,17 For example, CM, RCM, and ADMET are driven by the release and removal of ethylene or propylene gas. In ED-ROMP,15 the increased conformational freedom of the polymer, relative to that of the macrocyclic monomer, enables access to polymers of high molar mass. In contrast, ROCM and ROMP processes of strained alkenes see enthalpic gains drive the reaction forward. For example, norbornene, the archetypical ROMP monomer, exhibits a high ring strain, which allows efficient polymerization with a variety of catalysts leading to the formation of the well-studied polynorbornene (Scheme 2). For a comprehensive overview of olefin metathesis and its applications, we direct readers to the numerous reviews18–22 and books16,17 written on the topic, as well as more recent accounts.23–26 This chapter will focus instead on burgeoning efforts toward development of catalysts that permit stereochemical control of the alkene formed in the metathesis process.27–32 Specifically, the

Comprehensive Organometallic Chemistry IV

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Fig. 1 Results of a topic search for “olefin metathesis” on Web of Science. The query returned 11,779 results, organized here by categories as a treemap. Only categories accounting for more than 1% of total publications are shown. Retrieved on May 31, 2021.

Scheme 1 Foundational mechanism of olefin metathesis.

advances of the field since the prior publication of a dedicated book chapter33 will be covered in detail, as well as the numerous applications of these catalysts to ROMP. While some sp3 carbon-generating asymmetric olefin metathesis processes are discussed in the context of the design of Z-selective catalysts, an exhaustive review of these transformations is beyond the scope of this account. A discussion of polymer tacticity—the relative stereochemistry of adjacent asymmetric groups in a macromolecule—will be included for ROMP processes when reported in the primary literature, as it has a profound influence on the thermal and mechanical properties of a polymer.34

13.07.1.2 Alkene stereoselectivity in olefin metathesis The ability to precisely control and predict alkene stereochemistry is critical in organic synthesis.35 The spatial arrangement, physical properties, and bioactivity of a given molecule are subject to tremendous influence by the stereochemistry of the alkenes.36 Moreover, the products of diastereospecific transformations of alkenes (e.g., epoxidation, difunctionalization, pericyclic reactions) depend on the geometry of the starting olefin.37 Likewise, the properties of polymers such as melting and glass transition

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

267

Fig. 2 Typical olefin metathesis processes.

Scheme 2 Generic ring-opening metathesis polymerization of norbornene.

temperatures have been shown to be dramatically altered by the content of cis (Z) or trans (E) double bonds.38–40 It has also been long known that the physical properties of alkene-containing conjugated polymers are impacted by the configuration of the repeating olefin subunits. For example, the photoluminescence of polyphenylacetylenes (PPAs) varies with the content of cis olefins.41 Similarly, the shape of PPAs is dictated by the configuration of the alkenes: trans-rich polymers exhibit a flat structure, while the cis-rich variants prefer to adopt a helical structure minimizing steric interactions.42 Careful examination of the Chauvin mechanism reveals the stereoselectivity (or lack thereof ) in metathesis processes. The reversibility of the cycloaddition and cycloreversion steps (Scheme 3) leads to equilibration between the E (trans) and Z (cis) stereoisomers. Early homogenous catalysts typically favor the thermodynamic product, which is often the E olefin, irrespective of the olefin configuration in the starting material. However, even minor energy differences between the resultant isomers may result

R1 [M]

R2

[M] R1 R2

[M]

+ R1

R2

Scheme 3 Thermal equilibrium in olefin metathesis that leads to alkene isomerization.

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in an unexpected mixture of products including, in rare instances, one in which the Z product prevails. To circumvent thermodynamic constraints, several families of kinetically stereoselective catalysts have been developed in the last decade.27–32 The first part of this chapter will focus on the design and optimization of stereoselective Mo and W catalysts, and applications thereof. The second part will examine Ru catalysts, including a discussion on Z selectivity vs stereoretention. Examples of CM, ROCM, RCM, and ROMP will be surveyed across the full chapter.

13.07.2 Catalyst design 13.07.2.1 Mo and W catalysts 13.07.2.1.1

Early studies with Mo bisalkoxide complexes

Examples of Z selectivity with well-defined Mo and W catalysts were first reported in the 1990s. The polymerization of 2,3-bis(trifluoromethyl)norbornadiene with Mo alkoxide initiator Mo-1 provided the corresponding polynorbornadiene with >98% cis content as reported by Gibson (Scheme 4).43 Prior to this report, Mo and W catalysts comprising tert-butoxide anionic

Scheme 4 Mechanism for the cis vs trans selectivity with bisalkoxide Mo alkylidenes. R0 ¼ alkylidene ligand, P ¼ polymer.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

269

ligands (Mo-2) were found to produce preferentially trans linkages during polymerizations of 2,3-disubstituted norbornadienes.44 This opposite selectivity between hexafluoro-tert-butoxide and tert-butoxide ligands—in conjunction with rapid ligand exchange between the initiator complexes—was exploited through addition of the monomer to varied mixture of Mo-1 and Mo-2 initiators to produce mixed cis and trans linkages. While these findings represented a significant step toward stereoselective olefin metathesis, the origin of the selectivity remained unclear until Schrock and coworkers performed extensive mechanistic investigations.45,46 Through rigorous 1H NMR experimentation and characterization, the authors discovered that Mo alkoxides interconvert between two rotamers, designated syn or anti based on the orientation of the alkylidene relative to the phenylimido ligand, with syn pointing toward and anti pointing away. In the case of Mo-1, the rate of interconversion is negligible compared to the rate of propagation during ROMP. Moreover, the hexafluoro-tert-butoxide Mo initiator is typically synthesized in the syn form, wherein the syn olefin addition furnishes a cis vinylene linkage. Conversely, the rapid interconversion between syn and anti isomers in the tert-butoxide Mo initiator leads to trans linkages, which arise from an energetically-favorable olefin addition to the anti form. This addition creates a syn alkylidene with a trans olefin linkage that rapidly interconverts to the anti alkylidene before subsequent olefin addition (Scheme 4). This process repeats throughout propagation, leading to the formation of polymers with a high trans content.

13.07.2.1.2

Early studies with Mo diolate catalysts

Another family of Mo complexes that demonstrated high cis selectivity in ROMP early on was synthesized using racemic or enantiomerically pure chelating diolate ligands.47 The bidentate C2 symmetric diolate ligands were designed to produce isotactic polymers by favoring olefin addition to the same enantiotopic face of the M]C bond in each step.48 This enantiomorphic site control over the chain growth indeed led to the formation of highly cis and isotactic polymers from chiral norbornadiene ester monomers and catalysts Mo-3 or Mo-4 (Scheme 5).49 Of note, the incorporation of stereogenic centers into the norbornadiene structure facilitated the determination of the tacticity of the resulting polymer through 1H and 13C NMR experimentation.

Scheme 5 ROMP of chiral norbornadienes with diolate complexes Mo-3 and Mo-4.

13.07.2.1.3

Mo and W monoaryloxide pyrrolide (MAP) complexes

13.07.2.1.3.1 Catalyst design and mechanism During the synthetic campaign to access enantiopure quebrachamine, diolate catalysts were found to result in low enantioselectivity during a key RCM step.50,51 Hoveyda, Schrock, and coworkers began the search for a catalyst that would deliver the desired product in high yields and enantioselectivities. Guided by theoretical investigations from Eisenstein,52,53 the authors targeted stereogenicat-metal Mo complexes with a donor and an acceptor ligand to maximize olefin binding through electronic dissymmetry. Conceptually, the donor ligand should lead to the distortion of the Mo complex, which would then provide a ligation site for the olefin. The acceptor ligand, on the other hand, would preserve the electrophilicity of the metal center, priming it for olefin attack. To minimize electronic repulsion, the donor ligand should occupy an apical position, and thereby a trans approach by the olefin (Scheme 6). Following olefin coordination and [2 + 2] cycloaddition, the same electronic dissymmetry should distort the trigonal bipyramidal complex, making cycloreversion more energetically favorable.

270

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 6 Electronic effects of donor and acceptor ligands on Mo-catalyzed olefin metathesis.

However, when these design principles were tested with a hexafluoro-tert-butoxide ligand as the acceptor and 2,5-dimethylpyrrolide as the donor, the RCM of 1 proceeded rapidly, but poor enantioselectivities were observed (Scheme 7). The enantioselective indiscrimination prompted exchange of the acceptor ligand in favor of a chiral alcohol—specifically, a monoprotected binaphthol ligand. Through reaction of monoprotected alcohol 3 with bispyrrolide complex Mo-6,54,55 the desired monoaryloxide pyrrolide (MAP) catalyst (Mo-7 and Mo-8) could be formed with high conversions and diastereoselectivity (Scheme 8). Partially hydrogenated derivatives Mo-9 and Mo-10 were also obtained through this strategy, giving higher enantioselectivities than their unsaturated counterparts. Importantly, Mo-10 afforded the desired (+)-quebrachamine precursor 2 in high yield (83%) and enantioselectivity (95% ee) (Scheme 9).51

Scheme 7 RCM of 1 with Mo-5 does not exhibit enantioselectivity.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

271

Scheme 8 Synthesis of MAP complexes Mo-7–10 from Mo-6a or Mo-6b.

Scheme 9 Synthesis of intermediate 2 en route to (+)-quebrachamine through enantioselective RCM of 1 with Mo-10.

The high enantioselectivities of these stereogenic-at-metal catalysts prompted further investigation of their catalytic activity and mechanism, including studies into their viability as Z-selective catalysts. Z-selective olefin metathesis had long remained a grand challenge; previous iterations of Mo and W catalysts offered few advancements in the area. While diolate catalysts exhibited high enantioselectivities in choice transformations, they still delivered either mixtures of E and Z olefins or almost exclusively E alkenes.56 Formation of the Z product required an all-cis metallacyclobutane, and the size of the diolate ligand alone was presumed to be an insufficient enforcer of syn addition of the olefin substrate to the alkylidene. However, with stereogenic-at-metal complexes, it was postulated that the size difference between the rotating (about the Mo–O bond) aryloxide ligand and the smaller imido ligand would render formation of the all-cis metallacyclobutane more energetically favorable (Scheme 10). Indeed, a MAP-based Mo catalyst with a monoprotected binaphthol ligand (Mo-11) was found to catalyze the Z-selective ROCM between styrene and unsaturated bicyclic compound 4 with remarkably high Z:E ratios (Scheme 11).57 The process also returned near-perfect enantioselectivities, with enantiomeric ratios reaching 99:1 while maintaining high Z:E ratios (>98:2). The impressive Z selectivity of Mo-11 was largely attributed to a steric model in which the rotating aryloxide ligand prohibits both anti addition of the alkene

272

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 10 Steric effects of imido and aryloxide ligands that lead to cis selectivity with Mo MAP complexes.

Scheme 11 ROCM of 4 with styrene catalyzed by Mo-11.

and interconversion of the alkylidene to the anti form, while the relatively small adamantyl ligand easily accommodates the all-cis metallacyclobutane to afford the Z olefin upon cycloreversion (Scheme 10). Notably, these catalysts boast increased efficiency over hexafluoro-tert-butoxide- and biphenolate-based catalysts, as well as a marked increase in stability—both attractive features that, in part, account for their wide-spread adoption.48 The high selectivity of Mo-11 and structurally similar catalysts was predicted to extend to other olefin metathesis processes, including ROMP, self-metathesis, and CM. On reaction of 5,6-dicarboxymethyl norbornadiene with hexaisopropyl terphenoxide analogs Mo-12 and Mo-13, a 99% cis, syndiotactic polymer was furnished—the first time a cis, syndiotactic polymer was accessed through olefin metathesis (Scheme 12). This unique microstructure was made possible through the fluxional nature of the chiral metal center throughout the course of the polymerization. Through electronic effects, the monomer adds trans to the pyrrolide in a syn fashion with substituents of both the alkene and the alkylidene pointing toward the imido ligand. Following cycloreversion of the molybdacyclobutane, the stereochemistry of the metal center inverts (Scheme 13). The next monomer to undergo a syn addition to the propagating alkylidene then adds to the opposite face relative to the first monomer, leading to the observed syndiotacticity.58 This stereogenic-at-metal control differs significantly from the chain-end and enantiomorphic site control models with C2 symmetric and hexafluoro-tert-butoxide based Mo catalysts.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 12 All-cis polymers obtained via ROMP of cyclic alkenes catalyzed by Mo-12 and Mo-13.

Scheme 13 Mechanism of the formation of syndiotactic microstructures from ROMP catalyzed by MAP complexes.

273

274

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

In addition to the formation of cis, syndiotactic poly(2,3-dicarboxymethylnorbornadiene), polymerization of cyclooctene and cyclooctadiene with Mo-12 led to >99% cis polycyclooctadiene and polycyclooctene (Scheme 12). Mo-12 was found to catalyze the CM between internal olefins (Z)-4-octene and (Z)-3-hexene (Scheme 14). However, the reaction was notably slow, reaching only 50% conversion after 8 h at 22  C. The reaction rate was ascribed to the undesirable steric crowding of the all-cis metallacyclobutane. On the other hand, the homocoupling of terminal alkenes catalyzed by Mo and W MAP catalysts displayed not only high Z selectivity, but also high efficiency.59 The increased reaction rates were partially credited to the decreased steric bulk of the metallacyclobutane relative to the cross coupling of internal alkenes. The extensive catalyst screening reported revealed that the size of the imido group had a diminished impact with regard to the Z selectivity of terminal olefin homocoupling. The selectivity model proposed by Schrock and Hoveyda posited that the terminal olefin adds to the syn alkylidene trans to the pyrrolide, similar to previously reported examples.57,58 In the case of terminal olefins, however, the large aryloxide is critical to ensuring the olefin substituent is oriented in the same direction as the alkylidene substituent to form the desired Z alkene (Scheme 15). Indeed, this model is borne out by the excellent Z selectivities observed on reaction of various substrates—including esters, boronic ester, and protected amines—to W MAP catalysts at elevated temperatures (80–120  C) and extended times. The resultant internal olefin product is achieved in moderate-to-high yields.

Scheme 14 (Z)-Selective CM of (Z)-4-octene and (Z)-3-hexene catalyzed by Mo-12.

Scheme 15 Mechanism for cis-selective CM catalyzed by MAP complexes.

13.07.2.1.3.2 Molybdacyclobutane and tungstacyclobutane MAP complexes Unsubstituted tungstacyclobutane W-1 was found to catalyze the Z-selective homocoupling of several terminal alkenes to form the corresponding Z internal olefins in good yields with selectivities ranging from 81% to >99% (Table 1).60 Notably, the catalyst also tolerated E-1,5-undecadiene—which features both a terminal and E alkene—to give the E,Z,E product, a transformation hitherto unreported in the literature. In the case of 1-hexene, W-1 was far more efficient and selective than the related alkylidene complex, W2 (Scheme 16). Conveniently, tungstacyclobutane W-1 is also more readily isolable, more crystalline, and exhibits higher reactivity than W-2. These results align with previous reports on molybdacyclobutane and other tungstacyclobutanes and their substituted alkylidene analogues.61 The rare Z-selective homocoupling of 1,3-dienes can be catalyzed efficiently in high yields and Z:E ratios by molybdacyclobutane catalyst Mo-14 and W-1.62 Importantly, Mo vinylalkylidenes—a species required for the homocoupling of 1,3-dienes—were also accessible. With this proof-of-concept established, E-1,3-dienes were coupled in up to 98% yield and > 98% Z selectivity at room temperature (Scheme 17).

Table 1

Substrate

Homodimerization of Terminal Alkenes with W-1.

Product

a

60% yield.

Scheme 16 cis-Selective homocoupling of 1-hexene by W-2.

Time

Conversion (%)

Z (%)

4h

74

>99

4d

89

>99

2d

45

>99

24 h

35

97

4h

45

81

2.5 h

61

92

8h

60a

92

276

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 17 Formation of a E,Z,E-triene from diene homocoupling catalyzed by Mo-14.

Several natural products were targeted to test the tolerance and capabilities of these catalysts (Scheme 18). Epilachnene, an amine-containing macrocycle,63 was formed in 70% yield with 91% Z selectivity by Mo-15 and in 82% yield with 91% Z selectivity by tungstacyclobutane W-3 through Z-selective RCM of diene 6.64 Previous syntheses required amine protection and installation of

Scheme 18 Z-selective macrocyclic RCM catalyzed by Mo-15 and W-3.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

277

methylated alkyne groups—both unproductive steps that were entirely avoided in this route.65 Macrocyclic yuzu lactone and ambrettolide were also synthesized through Z-selective RCM with Mo-15 and W-3 in moderate yields and high Z purity. These and other natural products explorations revealed that more flexible diene systems appear to require the more active Mo-15. Conversely, W-3 is better suited for rigid diene systems, as well as for products that are particularly susceptible to the postpolymerization isomerization that is anticipated with Mo-15. 13.07.2.1.3.3 W oxo MAP catalysts While Mo MAP catalysts have excellent activity and Z selectivity, the Z to E isomerization of the product observed over longer reaction times was problematic. Similarly, W MAP catalysts displayed high Z selectivity and desirable activity, but it was hypothesized that catalyst performance could be further improved through a more electrophilic W metal center and a greater size disparity between the aryloxide and imido ligands. One strategy, reported by Schrock and Hoveyda, was to leverage the high activity of tungsten oxo complexes.66 The authors proposed that the smaller oxo ligand confers higher selectivity by creating a larger space for the all-cis tungstacyclobutane, as compared to the larger imido aryl groups in previously reported MAP catalysts. Polymerization of 2,3-dicarboxymethylnorbornadiene was much slower with W-4 than with W-5, on the order of several hours vs minutes. Additionally, the propagation rate with W-4 was slower than initiation, which likely impeded the living character of the ROMP polymerization. Higher selectivity was also observed with phosphine-coordinated W-5, providing a polynorbornadiene derivative with >99% cis double bonds and 98% syndiotactic (Scheme 19). The increased steric crowding of W-4 was implicated in the slower polymerization and poorer selectivities observed. Similarly, the homocoupling of terminal olefins proceeded well with W-5, delivering the internal olefin products within 6 h with no apparent E olefin present, as exemplified by the homocoupling of allylbenzene in Scheme 19.

Scheme 19 ROMP of 2,3-dicarboxymethylnorbornadiene and homodimerization of allyl benzene catalyzed by oxo complex W-5.

The homocoupling of terminal olefins using W-5 saw marked improvements over previously reported phenylimido W MAP catalysts.59–60 DFT calculations predicted key differences between the imido and W oxo complexes. Critically, the oxo ligand renders the metal center more electron deficient and therefore more electrophilic. However, the relative strength of the M]C bond raises the energy barrier for the [2 + 2] cycloaddition en route to the requisite metallacyclobutane; the cycloaddition and cycloreversion steps are both presumed to be higher energy as compared to the imido analog. Nonetheless, the increased efficiency of the oxo catalyst becomes apparent when considering the turnstile rearrangement undergone by the oxo tungstacyclobutane to go from the more unfavorable trigonal bipyramidal geometry to the relatively lower energy square bipyramidal geometry. This square bipyramidal oxo tungstacyclobutane is far less likely to undergo b-H elimination followed by ethylene coordination and insertion. This pathway is often attributed to catalyst decomposition and is frequently observed with the imido variant. These calculations help rationalize the positive attributes of oxo complexes, while also explaining the observed limitations.67 Oxo W complexes W-6 and W-7 readily polymerize monomers that were previously deemed unreactive toward common ROMP catalysts or had not been polymerized in a stereoregular manner.68 For example, norbornadiene derivatives 7a–d (Table 2)—monomers

278

Table 2

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design Polymerization of monomers 7–9 with either W-6 or W-7.

Monomer

Catalyst (mol%)

Polymer (olefin configuration, tacticity)

7a (R ¼ CO2Me) 7b (R ¼ CO2Menthyl) 7c (R ¼ CF3) 7d (R ¼ CN) 8a (R ¼ CO2Me) 8b (R ¼ CO2Decyl) 8c (R ¼ CO2Menthyl) 9a (X ¼ CMe2) 9b (X ¼ O)

W-6 (1%) W-7 (1%) W-6 (1%) W-6 (1%) W-6 (2%) W-6 (2%) W-6 (2%) W-6 (2%) W-6 (2%)

cis, n.d. cis, isotactic cis, n.d. cis, atactic cis, n.d. cis, n.d. cis, syndiotactic cis, n.d. cis, n.d.

of significant interest for their potential as precursors of conjugated materials through ROMP followed by thermal isomerization (Scheme 20)69—were polymerized by W-6 or W-7. Although polymers with cis linkages and high tacticity were obtained with all monomers (except dicyano derivative 7d), the specific tacticity could not be determined for most. Only in the case of dimentholate derivative 7b was the tacticity assigned as isotactic (Table 2). Importantly, the ROMP of 7b with phenylpropylidene W-7 required the addition of B(C6F5)3, a Lewis acid. Similarly, trifluoromethyl derivative 7c was polymerized by tert-butyl alkylidene oxo complex W-6 with two equivalents of B(C6F5)3 to provide a polymer with unassignable tacticity. This critical additive is thought to bind to the oxo ligand, leading to increased electrophilicity of the metal center, thereby increasing catalyst reactivity toward olefins. The catalysts were then tested against 7-oxanorbornadiene (8a–c) and benzene-fused (9a and 9b) monomers to give highly cis polymers of which, only poly-8c could have its tacticity determined as syndiotactic.

Scheme 20 Thermal isomerization of a polynorbornadiene-type polymer to afford a conjugated material.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

279

13.07.2.1.3.4 Cross metathesis with Mo and W MAP catalysts Efficient access to Z alkene-containing small molecules remained a nontrivial challenge in organic chemistry for many years. Many of the common olefination methods produced difficult-to-separate by-products, required challenging functional group installations, or lacked control over stereoselectivity. To address this challenge, Schrock and Hoveyda reported the CM between enol ethers and terminal alkenes catalyzed by Mo-16 in high Z selectivity (Table 3).70 Among the wide scope of tolerated substrates were amines, esters, and secondary amides. These alkenes could be coupled with excess amounts of enol ethers butyl vinyl ether or paramethoxy benzene vinyl ether in yields up to 97% and Z:E ratios >98:2. The excess of enol ether coupling partner was required Table 3

Substrates

Cross metathesis of terminal alkenes with Mo-15 and Mo 16.

Catalyst (mol%)

Product

Yield (%)

Z (%)

Mo-16 (2.5%)

68

98

Mo-16 (2.5%)

77

94

Mo-16 (2.5%)

51

>98

Mo-16 (2.5%)

73

98

Mo-16 (1.2%)

57

>98

Mo-16 (1.2%)

70

>98

Mo-16 (5.0%)

59

>98

Mo-16 (5.0%)

75

>98

(Continued )

280

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Table 3 Substrates

(Continued) Catalyst (mol%)

Product

Yield (%)

Z (%)

Mo-15 (3.0%)

93

96

Mo-15 (3.0%)

97

93

Mo-15 (5.0%)

63

96

Mo-15 (5.0%)

65

97

to stabilize the Mo methylidene intermediate by generating a stabilized ether alkylidene. This method was further extended to the synthesis of anti-oxidant plasmalogen phospholipid, C18 (plasm)-16:0 (PC), the Z isomer of which has greater antioxidant activity relative to the E analog.71 The ability of Mo-15 to tolerate allylic amides also permitted the streamlined synthesis of a synthetic intermediate en route to antitumor agent KRN7000, thereby decreasing the number of synthetic steps by nearly half .72 Both of these examples demonstrate the tremendous potential of catalytic Z-selective CM as a tool for medicinal and synthetic organic chemists. The creative implementation of Z selective metathesis methods continued into the early 2010s. (Pinacolato)allylboron and (pinacolato)alkenylboron—common substrates in the ubiquitous Suzuki-Miyaura cross-coupling reaction—were some of the most desirable targets of these investigations.73,74 Z-selective CM between 1-decene and (pinacolato)allylboron was successfully carried out using W-8 and the resulting unstable olefin intermediate was oxidized to the corresponding allylic alcohol with H2O2. The final product was obtained in 65% yield with 95% Z selectivity (Scheme 21).75 Importantly, this was the first example of a Z-selective CM reported with a W catalyst. However, for the CM of more sterically demanding (pinacolato)vinylboron substrates, Mo-15 was found

Scheme 21 Z-selective CM of 1-decene and (pinacolato)allylboron with W-8 followed by oxidation to the corresponding allylic alcohol.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design Table 4

Substrate

281

Z-selective CM between (pinacolato)alkenylboron and styrene derivatives using Mo-15.

Product

Yield (%)

Z (%)

69

95

69

93

93

95

n.d.

n.d.

73

96

to be more efficient (Table 4). Notably, alkenyl boron 10 was synthesized using Mo-15 and converted to anticancer agent combretastatin A-4 through Suzuki-Miyaura coupling with 2-methoxy-4-bromophenol, thereby demonstrating the relevance of this protocol to palladium-catalyzed cross-coupling reactions. The unique disconnections offered by Z-selective CM were put on display in the synthesis of disorazole C1,76 a campaign in which two fragments of the molecule were accessed separately, then brought together through stereoretentive Suzuki-Miyaura cross-coupling aided by Z-selective CM (Scheme 22).77 Alkenyl boron 11 could be prepared using Mo-16 with perfect Z selectivity and no competitive RCM product detected, presumably due to the excess of boron reagent. Alkenyl iodide 12 was then obtained through treatment of 11 with iodine, followed by TMS deprotection. The formation of 14 was effected through esterification of hydrolyzed 13 with alcohol 12. The Z boronic ester was installed using Mo-17 in 91% yield and > 98:2 Z:E selectivity. Suzuki-Miyaura intermolecular cross coupling of 15 afforded the macrocycle in 60% yield and subsequent deprotection gave disorazole C1. This synthesis highlights the ability of Z-selective catalysts to significantly reduce the number of synthetic steps when thoughtfully applied (Scheme 22).

282

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 22 Application of Z-selective CM with Mo-16 and Mo-17 toward the synthesis of natural product disorazole C1.

The challenging synthesis of (+)-neopeltolide78 showcased an elegant combinatorial metathesis approach.79 This strategy combined macrocyclic RCM, catalytic Z-selective CM, and ROCM80 at different stages of the route (Scheme 23).79 A key step in the synthesis of the macrolactone fragment 17 from diene 16 was a macrocyclic ring closing metathesis with pentafluoroimido Mo18, which delivered unsaturated lactone 17 in 89% yield and > 98:2 Z:E selectivity. Lactone 17 was then converted to the desired fragment through syn palladium-catalyzed hydrogenation with H2 gas. Z-selective CM was featured in the synthesis of the oxazole

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

283

Scheme 23 (Top) Z-Selective RCM of 16 with Mo-18 (middle) CM between (pinacolato)alkenylboron and 18 catalyzed by Mo-15 (bottom) fragments 17 and 19 of natural product (+)-neopeltolide.

fragment, as adamantylimido Mo-15 catalyzed the CM of allyl carbamate 18 and (pinacolato)alkenylboron in 86% yield and >98:2 Z:E selectivity. Notably, completion of the synthetic sequence required the use of a stereoretentive Ru catalyst in order to forge the final Z olefin (see Section 13.07.2.2.4.1). Achieving linear (Z)-a,b-unsaturated esters through CM poses several synthetic challenges. First, formation of the desired metallacyclobutane requires an electronically mismatched approach of the substrate and the catalyst. Indeed, the electron-deficient b carbon of the conjugated ester needs to engage with the electrophilic metal center, and the electron-rich a carbon with the similarly electron-rich alkylidene carbon. A second challenge is coordination of the ester oxygen to the oxophilic metal center, which would slow down reaction rates. Initial catalyst screening revealed that Mo-16 can deliver a,b-unsaturated tert-butyl ester 20 in 55% yield and

284

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

92:8 Z:E selectivity, outperforming the selectivity of the other catalysts tested (Mo-19 and Mo−20), albeit with diminished yield (Scheme 24).81 The increased selectivity and lower yield were attributed to the bulky aryloxide ligand, since steric crowding disfavors anti olefin addition while also hampering catalytic activity. To further elucidate the origin of the low conversions observed with Mo-16, a 1:1 mixture of 2-ethylhexylacrylate and Mo-16 was studied. Indirect X-ray characterization with the closely related alkylidene complex and analysis of the 1H NMR spectra indicated that the alkylidene had adopted an anti conformation in which the carbonyl oxygen was coordinating to the metal center (Mo-21) (Scheme 24). Guided by this discovery, subsequent reactions were run in acetonitrile, which successfully outcompeted carbonyl oxygen coordination and allowed the CM of tert-butyl acrylate and several

F Me

F

F

F

F

Me

Me N N

Mo

Me

Me

Me N

Ph

Me

O

N Me

Me

Mo

Me Me O Me Me

Me

Mo-19

Ph

Me Me

Mo-20 [Mo] cat. (5.0 mol%)

C8H17

+

CO2

tBu

C8H17

ambient pressure, C6H6, 22 oC, 4 h Mo-16: 55% yield, 92:8 Z:E Mo-19: 90% yield, 6:94 Z:E Mo-20: 83% yield, 58:42 Z:E

20

Me O O

Et nBu

Me Me N

Mo-16 (1 equiv) N

C6D6, 22

CO2tBu

Me

oC

Mo

H

Br O

O

O Br

nBu

TBSO Et

Mo-21 Mo-15 (5.0 mol%) C8H17

+

CO2tBu

C8H17

100 torr, C6D6, 22

oC,

15 min

CO2tBu

76% yield, 93:7 Z:E Scheme 24 (Top) Comparison of Mo catalysts in the CM of 1-decene with tert-butyl acrylate; (middle) carbonyl chelation that inhibits the activity of Mo catalysts; and (bottom) Z-selective of an a,b,g,d-unsaturated ester catalyzed by Mo-15.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

285

terminal olefins in good yields and high Z:E ratios. Interestingly, linear E,Z-dienoates could be isolated upon reaction of an a,b,g,d-unsaturated ester and 1-decene with 5 mol% of Mo-15 (Scheme 24). The terminal olefin 1-decene could be coupled to a variety of silyl enol ethers leading to alkene-containing silyl ethers or allyl alcohols (after protodesilylation) in high Z selectivity and yields (Table 5).82 Of note, the CM only tolerated highly congested alkynes as shown in the last entry of Table 5, presumably because of undesired side reactions caused by alkyne metathesis. To illustrate applications to natural product synthesis, propargyl allyl silyl ethers were coupled with 1-decene in high Z selectivity. This reactivity was expanded to natural products falcarindiol and trocheliophorolide C in high Z selectivity (92% Z and 91% Z, respectively). Table 5

Substrate

Z-selective CM between silyl ethers and 1-decene using Mo-15.

Product

Yield (%)

Z (%)

68

>98

64

>98

60

>98

76

90

n.d.

n.d.

13.07.2.1.3.5 Z-selective macrocyclic ring-closing metathesis Extension of Z-selective olefin metathesis methods to RCM has been exhibited through the stereoselective synthesis of epothilone C and nakadomarin A, two compounds whose bioactivity is correlated to high Z purity.83 While pharmaceutical applications of epothilone A have been limited by its instability in animal cells,84 nakadomarin A remains actively studied for its cytotoxicity

286

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

toward lymphoma cells and antimicrobial activity.85 Previously reported syntheses of epothilone C relied on macrocyclic RCM with non-stereoselective Ru and Mo catalysts which (as expected) provided low Z:E ratios.86–87 Similarly, RCM with Mo-1 or non-stereoselective Grubbs 1st generation catalyst (Ru-1, see Scheme 50) to produce a key intermediate in the total synthesis of nakadomarin A also favored the E isomer.83 Only on use of Z-selective catalyst W-8 were both compounds accessed in high Z purity. For epothilone C, key intermediate 22 could be synthesized in high yields from diene 21 through exposure to modest loadings of W-8 (3–10%, Scheme 25) under a light vacuum.83 Additionally, the extreme dilution factor in previously reported syntheses—required to prevent oligomerization through ADMET oligomerization—was deemed unnecessary, with substrate concentrations of up to 0.05 M being tolerated. Intermediate 22 could then be converted to epothilone C on treatment with HF-pyridine. For nakadomarin A, W-8 readily converted diene 23 to intermediate 24 in 90% yield with 97:3 Z:E selectivity (Scheme 26). Nakadomarin A was then synthesized in 6 steps from intermediate 24. In an alternative approach, nakadomarin A was also formed through the late-stage Z selective macrocyclic RCM of 25 with W-8 (5.0 mol%) in 63% yield with an impressive 94% Z selectivity (Scheme 26). Notably, the same reaction using non-stereoselective Grubbs 1st generation catalyst (Ru-1, see scheme 50) required higher catalyst loadings (20 mol% vs 5 mol%), elevated reaction temperatures (40  C vs 22  C), and extremely dilute conditions (0.2 mM vs 1.0 mM) while resulting in lower Z selectivity (63% Z).88

Scheme 25 Formation of intermediate 22 en route to epothilone C in high Z-selectivity through RCM of 21 with W-8.

Scheme 26 The RCM approach using W-8 delivered nakadomarin A directly or through intermediate 25.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

287

Pentafluoroimido-based Mo-2289 was used in the Z-selective RCM of a disubstituted alkene and a terminal alkene to form epothilone D, a precursor to epothilone B, following deprotection of a tert-butyl dimethyl silyl group (Scheme 27).90 The pentafluoroimido ligand was sufficiently electron-withdrawing to enhance the electrophilicity of the Mo center toward olefin coordination while maintaining a small enough steric influence to accommodate a trisubstituted metallacyclobutane. Minimal steric interactions in the metallacyclobutane formation also helped lower the energy barrier to cycloreversion, thereby increasing the rate of RCM. Using Mo-22, precursor 27 could be cyclized from diene 26 in 82% yield with 91% Z selectivity.

Scheme 27 Z-selective RCM catalyzed by bisalkoxide Mo-22 afforded macrocycle 27 through the challenging formation of a trisubstituted alkene.

Macrocyclic Z-selective RCM was also employed in the synthesis of macrocyclic Z-, Z,E-, and E,Z-conjugated esters (Scheme 28).91 14–24-membered Z-enoate macrocycles were accessed through RCM with Mo-20 in yields ranging from 43% to

Scheme 28 Macrocyclic Z-selective RCM of a,b- or a,b,g,d-unsaturated esters.

288

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

70%. Macrocyclic E,Z-enoates were also competent, producing 15-,16-,18-, and 19-membered rings with good yields (50–71%) and high Z:E ratios (generally >98:2). Similarly, Z,E-dienoates were accessed in yields of 75% and 57% for 18-membered and 19-membered rings, respectively. Included in the substrate scope was an intermediate in the total synthesis of (+)-aspicilin. 13.07.2.1.3.6 Ethenolysis catalyzed by Mo and W MAP catalysts In 2011, Hoveyda, Schrock and coworkers predicted that catalyst Mo-15 would selectively react with Z alkenes during ethenolysis, just as it preferentially forms Z alkenes during CM and homocoupling of terminal olefins.92 To this end, Mo-15 was mixed with a mixture of (E)- and (Z)-4-octene (4:1) in C6D6 with ethylene (20 atm, Scheme 29). The reaction mixture produced E-4-octene (>98%) in 79% yield, as well as 1-pentene, which was easily removed from the final product. With these results in hand, the authors targeted a multistep sequence in which CM-unselective Mo-1 was used in the homocoupling of terminal olefins to give products with mixed E:Z ratios. By exposing the product to ethylene and Mo-15, the stereoisomerically pure E olefin could be isolated, indicating an efficient route to synthetically relevant E alkenes.

Scheme 29 Z-Selective ethenolysis of a mixture of (E)- and (Z)-4-octene with Mo-15.

13.07.2.1.3.7 Ring-opening cross metathesis Z-selective enantioselective ROCM with Mo-15 successfully formed Z alkenes from strained cyclic alkenes and alkyl or aryl vinyl ethers in high enantiomeric purity (Table 6).80 Cyclobutenes, oxabicycles, azabicycles, and cyclopropenes all reacted quickly in the neat with Mo-15 in the presence of an enol ether. Subsequent functionalization could be performed through ester hydrolysis, Diels-Alder cycloadditions, and epoxidation, establishing Z-selective enantioselective ROCM as an exciting approach to the synthesis of biologically active compounds and natural products.

Table 6

Z-selective ROCM using Mo-15.

Substrates

Product

Yield (%)

Z (%)

90

92

90

96

90

94

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design Table 6

289

(Continued) Substrates

Product

Yield (%)

Z (%)

90

92

61

84

73

98

79

>98

71

>98

PMP ¼ p-methoxyphenyl.

13.07.2.1.3.8 Tacticity and E/Z-stereoselectivity in ROMP with MAP catalysts The observed stereochemical inversion of the metal center during Mo and W MAP-catalyzed ROMP was exploited to achieve polymerization of rac-endo,exo-2,3-dicarboxymethylnorbornene (28) using Mo-23 to afford a cis, syndiotactic polymer (Scheme 30) with alternating enantiomeric subunits. The alternating structure originates from one enantiomer reacting preferentially with one of the chiral metal centers formed during forward metathesis. Following addition of this monomer to the propagating chain, the metal center inverts, thereby allowing the other enantiomer to add to the chain and form the alternating polymer structure. However, the reaction of enantiopure (+)-28 with the same catalyst provided a polymer with no apparent long-range order.93 In contrast, polymerization of (+)-28 with diolate Mo-24—a catalyst expected to exhibit enantiomorphic site control—provided the cis, isotactic polymer (Scheme 30). Additionally, cis, syndiotactic, alternating structures could also be produced from the ROMP of racemic 1-methyl-2,3-dicarbomethoxy-7-oxanorbornadiene (29) and racemic endo,exo-2,3-dicyanonorbornene 30 with Mo-23 (Scheme 30). These findings illustrate the versatility of Mo MAP catalysts in the production of polymers with various microstructures.

290

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 30 ROMP of enantiopure or racemic monomers with control over tacticity through catalyst selection.

As the polymerization of both enantiomerically pure and racemic disubstituted norbornenes was expanded to diverse MAP catalyst architectures, it was discovered that some catalysts produced trans, isotactic errors.94 While most of these errors constituted a small portion of the polymer, the polymerization of (+)-28 with Mo-25 produced a 92% trans, isotactic polymer. Formation of this unique microstructure was attributed to rearrangement of the metallacyclobutane following monomer addition to the syn alkylidene from an anti approach. The resultant metallacyclobutane is presumably very high in energy due to steric clashes between the monomer and aryloxide ligand. This sterically congested intermediate then undergoes a turnstile rearrangement characterized by the inversion of positions a and a0 . Upon cycloreversion, the trans olefin is formed, but unlike the polymerization of rac-28, the metal stereochemistry is retained. This retention allows the monomer to add from the same side as the previous monomer, leading to isotactic polymers (Scheme 31).

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

291

Scheme 31 Proposed mechanism of trans, isotactic polymer formation with a MAP complex.

In contrast to typical Mo MAP catalysts, decafluoroterphenoxide catalyst Mo-26 produced cis, isotactic poly-2,3dicarboxymethylnorbornadiene, a microstructure that was previously inaccessible with MAP catalysts (Scheme 32).95 This same result was obtained when employing Mo-27, suggesting that the fluorinated imido ligand is not solely responsible for the observed

Scheme 32 ROMP of 2,3-dicarboxymethyl norbornadiene with fluorinated Mo MAP complexes.

292

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

tacticity. Possible explanations for this unique reactivity could stem from disproportionation of Mo-26 to form catalytically active bisalkoxide Mo-28, or from a turnstile rearrangement of the metallacyclobutane similar to the one described for Mo-25 (Scheme 31).94 To further explore the stereoregularity of Mo and W catalysts, the polymerization of enantiopure monomer (S)-31 with a variety of Mo and W catalysts—including MAP, bisalkoxide, and oxo MAP complexes—was studied (Scheme 33).96 When reacted

Scheme 33 ROMP of (S)-31 with MAP and diolate catalysts.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

293

with (S)-31, most MAP catalysts provided poly-(S)-31 with high content of cis double bonds and a syndiotactic structure, except for Mo-25 which was nonselective and produced an atactic polymer. As observed in other ROMP processes, diolate catalysts Mo-33 and W-12 delivered on the other hand, cis, isotactic poly-(S)-31. In contrast to the polymerization of rac-28 with Mo-23,93 ROMP of rac31 with Mo-31 and W-9 showed poor syndioselectivity for the alternating polymer, thereby highlighting the subtle energetic requirements of catalysts and monomers necessary to obtain perfect control over stereochemistry, tacticity, and sequence. The scope of syndiotactic or isotactic polymers accessible through catalyst control was further explored with the ROMP of norbornene and endo,anti-tetracyclodecene (32) using MAP and diolate catalysts (Scheme 34).97 The latter were found to be competent in the formation of cis, isotactic polynorbornene and poly-32 with the exception of W-13 that led to cis, atactic polynorbornene. MAP catalysts afforded syndiotactic polynorbornene with high cis olefin contents, but lower cis- and syndioselectivity for 32, with Mo-38 and W-15 leading to atactic poly-32. This observed trend—i.e., biphenolate catalysts producing cis, isotactic polymers and MAP catalysts producing cis, syndiotactic polymers—was found to hold true in the ROMP of endo-dicyclopentadiene.98 Interestingly, addition of chain-transfer agent 1-hexene, which allows for lower catalyst loading, is not deleterious to the cis selectivity in these polymerizations and neither is the presence of a coordinating solvent, such as THF, that stabilizes the catalyst in solution.

Scheme 34 ROMP of 32 with MAP and diolate catalysts.

294

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 34—Cont’d

The reactivity of Vince lactams (33a–d) toward stereoselective ROMP was also tested with several catalysts, including Ru, Mo, and W alkylidenes.99 Cyclometalated Ru-13 (see Section 13.07.2.2.2.5) catalyzed the polymerization of enantiomerically pure, unprotected amide (+)-33a to form a syndiotactic polymer with 95% cis double bond content. Polymerization of protected lactams 33b–c with diolate catalyst Mo-35, MAP catalysts W-15 and W-18, and diolate catalyst W-13 led to high cis polymers (>98%) in most cases with either isotactic (diolate catalysts) or syndiotactic (MAP catalysts) structures (Scheme 35).

Scheme 35 ROMP of vince lactam and vince lactam derivatives with W-18.

While racemic mixtures of 2,3-disubstituted norbornenes readily form alternating enantiomer polymer structures on ROMP with W and Mo MAP catalysts, two different enantiopure monomers can also undergo alternating polymerization.100 For example, ROMP of (2R,3R)-dicarboxymethyl norbornene and (2S,3S)-dicarboxyethyl norbornene with Mo-32 delivered poly-(2R,3R)-dicarboxymethyl norbornene-alt-(2S,3S)-dicarboxyethyl norbornene (Scheme 36). The polymer was assigned as 94% cis, syndiotactic with a small

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

295

Scheme 36 ROMP of chiral norbornene derivatives with Mo-31 or Mo-32 to form polymers with alternating chiral monomers in the repeat unity.

defect purported to be trans, isotactic dyads of (2R,3R)-dicarboxymethyl norbornene, (2R,3R)-dicarboxymethyl norbornene and (2S,3S)-dicarboxyethyl norbornene, (2S,3S)-dicarboxyethyl norbornene. Similarly, ROMP with Mo-31 afforded alternating polymers of two different enantiomerically pure endo-2-substituted norbornenes (34 and 35) (Scheme 36).101 In both examples, the propagation proceeds through reaction of the catalyst with either the R or S monomer, which causes an inversion of chirality that preferentially reacts with the opposite enantiomer, thereby creating a cis, syndiotactic, alternating polymer. Notably, W catalysts were largely ineffective at producing these alternating polymers. ROMP of 3-substituted cyclooctenes occurred on exposure to Mo-38 or W-17 with cis, head-to-tail selectivity (Scheme 37).102 Steric effects help rationalize the slow polymerization of 3-hexylcyclooctene, as compared to 3-phenylcyclooctene, which itself was slower than 3-methylcyclooctene. These differences in rate were attributed to steric interactions in the propagating polymer. DFT calculations also revealed that the 3-methyl group of the cyclooctene monomer lies closer to the propagating polymer chain than the alkylidene, in what was deemed a proximal approach (Fig. 3).103 Calculations suggested that the distal approach, which would place the cyclooctene substituent closer to the alkylidene after cycloreversion, causes significant steric clash between the substituent and the alkylidene alkyl groups in the metallacyclobutane.

Scheme 37 ROMP of 3-substituted cyclooctenes with Mo-38.

Fig. 3 A comparison of the proximal vs distal approach of 3-methylcyclooctene to W-17.

296

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

ROMP of endo-N-aryl pyrrolidine-fused norbornene 36 with Ru-1 afforded all-trans poly-36, a reaction that was exploited in the synthesis of a ladderphane polymer with ferrocene linkers connecting the polynorbornene chains (Scheme 38).104 Due to steric interactions between Mo-39 and the endo-N-aryl pyrrolidine in 36, the ROMP reaction was predicted to provide cis, isotactic poly36.105 Specifically, the bulky N-aryl pyrrolidine was expected to point away from the phenyl imido ligand of Mo-39, while the aryloxide would disfavor anti addition of the monomer to the syn alkylidene, in favor of cis, isotactic poly-36. As expected, all-cis, isotactic poly-36 was isolated upon ROMP of 36 with Mo-39 in dichloromethane at room temperature over 2 h (Scheme 38). High molar masses could be reached due to the living character of the polymerization. To form the ladderphanes, 36 was converted to 37, which bears a ferrocene linker. All-cis, isotactic ladderphanes could then be produced through Mo-39-catalyzed ROMP of 37

Scheme 38 (Top) ROMP of 36 with Ru-1 and Mo-39 (bottom) cis-selective ROMP of ferrocene-linked 37.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

297

(Scheme 38). Unfortunately, scanning tunneling microscopy (STM) images of ladderphanes poly-37 indicated that the morphology of the isolated products showed few differences from the all-trans congeners. Analogous to 36, cyclobutene-fused pyrrolidine could be polymerized through ROMP with diolate catalyst Mo-37 (Scheme 39).106 Differences in chain stiffness between Z and E polymers can be identified through functionalization of poly-38 and norbornene-fused poly-39 with a porphyrin chromophore.107 Electron paramagnetic resonance (EPR) and UV–visible absorption spectroscopies revealed that porphyrin substituents are more closely packed when poly-38 and poly-39 possess a high cis content, relative to the trans counterparts produced using Grubbs 1st generation catalyst Ru-1 (see Scheme 50). This example highlights the ability of Z-selective catalysts to control polymer morphology and physical properties.

Scheme 39 ROMP of porphyrin-substituted 38 and 39 with Mo-37.

The potential influence of cis and trans configurations within the polymer backbone was further illustrated in the synthesis of a mucin mimic (Scheme 40).108 Synthetic mucin holds great importance and potential in the study of the microbiome.109 To access this polymer, N-hydroxy succinimide-functionalized norbornene 40 was polymerized through ROMP with either Ru-4 (see Scheme 50) or W-19, which provided trans and cis poly-40, respectively. Postpolymerization functionalization with modified galactose afforded poly-40. The all-cis polymers were observed to bind to cholera toxin efficiently and displayed excellent solubility in aqueous media—a welcomed departure from the poor solubility of the high trans analog. The improved performance of the all-cis polymer was attributed to the predominance of cis linkages, which lead to a morphology that mimics the structure of natural mucin.

Scheme 40 Cis-selective ROMP of 40 with W-19 and post-polymerization modification to afford a mucin mimic polymer.

298

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

13.07.2.1.4

Stereoretentive Mo catalysts

The synthesis of alkenyl halides through catalytic CM long remained a significant challenge in the field. These high-value compounds are featured heavily in agrochemicals and pharmaceuticals, creating demand for an efficient, selective synthesis. Unfortunately, common Ru carbenes decompose quickly on reaction with vinyl or alkenyl halides.110–112 Following an exhaustive catalyst screening process, Hoveyda and Schrock found that Mo-40 effectively catalyzes the coupling of (Z)-1,2-dichloroethene and 8-bromo-1-octene to give alkenyl halide 41 in 75% yield and > 98:2 Z:E ratio (Scheme 41).113 Notably, this CM constituted an example of stereoretentive olefin metathesis with a Mo alkylidene, as the configuration of (Z)-1,2-dichloroethene was preserved in the final product. This stereoretentive process was found to be remarkably general, forming a variety of alkenyl halides in good yields and high Z purity, including compounds containing internal olefins, phthalimides, esters, silanes, tin, esters, epoxides, silyl ethers, alkynes, heteroaromatics, and thiols. In addition to (Z)-1,2-dichloroethylene, 1,2-dibromoethene was also used as a CM partner to form alkenyl bromides in high Z purity and good yields, albeit in lower selectivity than what was observed with alkenyl chlorides. The lower selectivity is likely due to the low stereopurity of commercially available (Z)-1,2-dibromoethene (64:36 Z:E) (Scheme 41). Presumably, during the CM process, the E-1,2-dibromoethene present in the reaction mixture reacts with the alkylidene to form a metallacyclobutane that leads to trans products. Stereoretentive behavior in Mo and W catalysts is not uncommon. Early, ill-defined catalysts tended to form higher Z content olefins at low conversions when reacted with cis alkenes before equilibrating to the more traditionally observed high E purity products.114–123

Scheme 41 Synthesis of Z-alkenyl halides through CM with Mo-40.

The inherent challenges of handling (Z)-1,2-difluoroethene, such as its volatility and explosiveness, discouraged its use in this method in favor of Z-1-bromo-2-fluoroethene (Scheme 41, bottom). Despite the possibility of competitive side reactions, steric and electronic arguments were made for the regioselectivity observed in the formation of high Z purity alkenyl fluorides. On analysis of potential steric interactions, the size difference between the bromide and fluoride becomes all the more pronounced—were the fluoride analog to approach the alkylidene group in a manner similar to I (Fig. 4), the alkylidene group and bromide would be subject to significant steric clash. Moreover, in the 1H NMR spectrum, the olefin HBr sits further upfield than HF, indicating that the fluoride-bound carbon is far more electron deficient than the other. This suggests that the bromide-bound carbon is more likely to attack the electrophilic Mo metal (pathway II vs I). Experimentally, these arguments are borne out by the number of alkenyl fluorides that were formed in good yields and in high Z:E ratios (Scheme 41).

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

299

Fig. 4 Potential approaches of Z-1-bromo-2-fluoroethene and catalyst Mo-40.

In Z-selective processes,113 Z (cis) alkenes are kinetically favored through catalyst control that offset the otherwise thermodynamic preference for E (trans) alkenes. However, for some alkenes such as alkenyl halides, the Z isomer is actually more stable than its E counterpart.124 Consequently, E alkenyl halides are often the more challenging isomers to prepare through typical Mo or W metathesis. Capitalizing on the stereoretention provided by alkylidene Mo-41, Schrock and Hoveyda reported the CM of terminal olefins and E-1,2-dichloroethene leading to E alkenyl chlorides in high yields and E selectivities (Table 7).125 A key modification of

Table 7

R

E-Selective CM of terminal alkenes and (E)-1,2-dichlorethene through stereoretention.

Product

Yield (%)

E (%)

93

93

80

92

(Continued )

300

Table 7 R

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design (Continued) Product

Yield (%)

E (%)

65

>98

54

>98

60

>98

69

>98

75

>98

59

>98

61

>98

80

>98

62

>98

85

>98

69

>98

78

74

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

301

the catalyst structure was crucial to these results: rather than ortho substituents on the aryloxide ring, a meta aryloxide was incorporated instead—a group that was thought to limit steric clashes between the b-substituent on the metallacyclobutane and the aryloxide while still effecting sufficient steric shielding for catalyst stability. The size of the terminal alkene also plays a role with unhindered, aliphatic alkenes leading to poor selectivities (74:26 E:Z ratio with (Z)-8-bromo-1-chlorooct-1-ene). The poor selectivity was credited to product isomerization over time to the thermodynamic product (Z alkene). Additionally, E alkenyl fluorides could be produced in the CM of terminal alkenes and (E)-1-chloro-2-fluoroethene (Scheme 42).

Scheme 42 Kinetically E-selective CM with Mo-40.

Schrock, Hoveyda, and coworkers also evaluated the use of stereoretentive olefin metathesis for E-selective macrocyclic RCM.126 Stereoretentive RCM requires at least one alkene site to bear the stereochemical information necessary for high selectivity, so several functional groups were installed to assess their compatibility in the synthesis of a E-macrocyclic lactone (Scheme 43). Terminal diene 42a led to the desired macrocycle with high yield, but poor E-selectivity with catalyst Mo-41. Contrary to the success of alkenyl chlorides in previous stereoretentive processes,113,125 42b led to low conversions attributed to the lack of stability of the chloroalkylidene. The poor applicability in RCM of alkenyl chlorides was attributed to high dilution required for the transformation, a factor that greatly increases the odds of catalyst decomposition prior to productive reaction. With a balance of reactivity and stability, vinyl boronate 42c was converted to the macrocycle in 44% yield and in a 96:4 E:Z ratio. The increased stability of the (pinacolato)boryl alkylidenes is known to lower reactivity while also carrying out CM efficiently.77,127 After identifying a suitable E-1,2-disubstitued alkene for RCM, the method was applied to number of macrocycles of varying sizes with high yields and E selectivities.

Scheme 43 E-selective RCM of 42 with Mo-41.

Through investigations of catalytic intermediates in the CM of alkenyl halides, Hoveyda and Schrock discovered that treating Mo-32 with pyridine during exposure to dibromoethylene forms a bromo Mo complex.128 This led to further studies toward development of chloro–Mo complex Mo-42, which successfully carried out the ROCM of cyclooctene and (Z)-1,2-dichloroethene to give 43 in a > 98:2 Z,Z:E,Z ratio (Scheme 44).129 The substrate scope was expanded to include Z-1,2-disubstituted olefins with (Z)-1,2-dichloroethene, and demonstrated efficient coupling between (Z)-methoxy-b-methylstyrene, a Boc-protected indole, a 1,3-disubstituted olefin and (Z)-1,2-dichloroethene to give the corresponding alkenyl chlorides in high yields (80–83%) and > 98:2 Z:E ratios (Table 8).128 The use of Z-1,2-disubstituted olefins prevented formation of a Mo-42 methylidene complex that was previously shown to decompose rapidly. Finally, (Z)-1,2-dibromoethene was coupled to methyl oleate in the presence of Mo-42 to provide ester alkenyl bromide 44 in 90% yield and 45 in 85% yield and > 98:2 Z:E ratios (Scheme 45).

302

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 44 ROCM of cyclooctene with (Z)-1,2-dichloroethene catalyzed by Mo-42 with high Z,Z selectivity. Table 8

R

Stereoretentive CM of 1,2-disubstituted olefins and (Z)-1,2-dichloroethene.

Product

Yield (%)

Z:E

80

>98:2

83

>98:2

83

>98:2

Scheme 45 Synthesis of 44 and 45 via CM of methyl oleate and (Z)-1,2-dibromoethene catalyzed by Mo-42.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

303

Efficient methods of installing a trifluoromethyl substituent are highly sought after in both pharmaceutical and agrochemical fields. The wide availability of Z-1,1,1,4,4,4-hexafluoro-2-butene made it an attractive option for the installation of trifluoromethyl substituents through CM. While Mo-42 catalyzed CM between methyl oleate and Z-1,1,1,4,4,4-hexafluoro-2-butene in high selectivity, poor yields necessitated modification of the catalyst to increase its stability and steric congestion. This prompted development of tert-butyl imido catalyst Mo-43, which readily catalyzed CM between Z-1,1,1,4,4,4-hexafluoro-2-butene and methyl oleate to provide the ester-containing trifluoromethyl olefin in 95% yield and > 98:2 Z:E selectivity (Scheme 46). A broad scope of Z-1,2-disubstituted olefins were tolerated, highlighting the excellent functional group tolerance of the catalyst and the ability of this procedure to aid in the synthesis of trifluoromethyl analogs of drug candidates and important agrochemicals. The activity and selectivity of Mo-43 was examined through DFT calculations. The authors concluded that the aryloxide exerts steric pressure on the metallacyclobutane intermediate to a greater extent in MAP catalysts as compared to Mo-43. In addition to the reduced steric effects from the chloro ligand, the electron withdrawing halide increases the Lewis acidity of Mo, rendering it more susceptible to olefin attack. Later reports indicated that functional group tolerance could be improved by treating an alcohol- or carboxylic acid-containing substrate with a borane for 15 min to form a boronate in situ before reaction with the catalyst and desired olefin metathesis partner.130

Scheme 46 Formation of trifluoromethyl-containing Z-alkenes from commercially available Z-1,1,1,4,4,4-hexafluro-2-butene.

Stereoretentive olefin metathesis with Mo and W catalysts is possible not only with 1,2-disubstituted olefins, but also trisubstituted olefins.131 Here, Z or E trisubstituted olefins react efficiently with (Z)-1,2-dichloroethene, (Z)-1-bromo-2-fluoroethene, and 1,2-dialkylolefins. Note that the stereochemistry of the trisubstituted alkene is critical, as it is retained through the cross-metathesis process. This particular example relied on stereoretentive Suzuki-Miyaura cross coupling to produce the substrates in high stereochemical purity before the desired CM (Scheme 47). Because the Z-trisubstituted alkenes require a fully eclipsed cyclobutene with the

Scheme 47 Trisubstituted alkenyl halides with high E- or Z-selectivity catalyzed by Mo-41 and Mo-40, respectively.

304

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Fig. 5 E vs Z pathways with trisubstituted metallacyclobutanes and stereoretentive Mo-40.

large R group interacting with the other two metallacyclobutane substituents, lower Z selectivities were observed compared to the E substrates (Fig. 5). For the CM between a Z-trisubstituted alkene and a 1,2-disubstituted olefin, the enhanced reactivity of Mo-44 was required to facilitate formation of the corresponding Z-trisubstituted olefin product (Scheme 48).

Scheme 48 Alkyl-substituted trisubstituted E-olefins through CM with Mo-44.

The Z-selective CM between acrylonitrile and terminal alkenes was readily catalyzed by Mo-40.132 A broad array of alkenyl nitriles could be formed in high yields and Z selectivities, though substrate limitations were noted; styrene derivatives, allyl (pinacolato) boron, electron-withdrawing groups, and bulky substrates all saw an adverse effect on yield. These limitations were addressed through use of chloride-based Mo-42 and maleonitrile through stereoretentive olefin metathesis. With this stereoretentive modification, many of the previously incompatible substrates were found to work well, and E alkenes could also be formed in great yields and selectivities.

13.07.2.1.5

Mo and W NHC Imido Alkylidenes

A new family of Mo and W stereoselective catalysts featuring an N-heterocyclic carbene (NHC) ligand has recently emerged.133,134 While many of these catalysts tend to favor the formation of thermodynamically favorable trans linkages in ROMP, a cationic O-chelated catalyst (Mo-45) furnished a 93% cis, 85% syndiotactic polynorbornene that was proposed to follow a similar mechanism to stereogenic-at-metal MAP catalysts (Scheme 49).135 Yet, in the case of NHC Mo catalysts, the cis/trans selectivity was found to heavily rely upon the rate differences between apparent polymerization rate and syn/anti interconversion of a alkylidene. If the ratio between apparent polymerization rate to interconversion rate is high, cis polymers are formed and if the ratio is low, trans polymers are formed. Later studies found that selectivity could also be correlated to the buried volume of the

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

305

Scheme 49 Stereoselective ROMP of Norbornene with Mo-45, Z-selective ROCM of endo, endo-dicarboxymethyl norbornene, and steric model rationalizing influence of imido aryl substituents on E- vs. Z-selectivity.

imido ligand with higher buried volumes associated with increased selectivity towards the formation of trans, isotactic polymers that are difficult to prepare with Mo and W MAP catalysts, but more easily accessible with NHC Mo and W imido alkylidenes.136 In small molecule studies, catalyst design and substrate-catalyst interactions dictated E/Z selectivity.137 For instance, the ROCM between endo, endo-dicarboxymethyl norbornene and a number of terminal alkenes delivered the product in high cis content. This high Z-selectivity may, in part, be attributed to low steric influence of the 3,5-dimethyl substituents on the imido aryl ligand that allows both substituents of the metallacyclobutane to point towards the imido aryl group. In contrast, catalysts installed with a 2-tert-butyl group on the imido aryl ligand likely forced the substituent in the b position away from it, leading to high E selectivity. In addition to steric effects, flexible, unhindered ethers such as allyl ethyl ether was found to lead to diminished Z-selectivity with Mo-46 in the ROCM of endo, endo-dicarboxymethyl norbornene, contradicting the steric model proposed (Scheme 49). The result was attributed to chelation of the oxygen to metal center apical to the imido aryl group, which is only possible through a metallacyclobutane that produces E alkenes.

13.07.2.2 Ru catalysts 13.07.2.2.1

Early discovery: cis selectivity in alternating copolymerization

Common ROMP initiators—for example, those based on Grubbs (Ru-1, 2 and 5) or Hoveyda-Grubbs (Ru-3 and 4) scaffolds (Scheme 50), typically afford polymers with almost exclusively trans (or E) alkenes.138–145

306

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 50 Typical olefin metathesis ruthenium catalysts: Ru-1–5.

Few cis-generating transformations have been reported,146–147 with even fewer that result in primarily cis junctions.148–149 The slower development of Z-selective Ru catalysts, relative to their Mo or W counterparts (vide supra), was originally ascribed to the low calculated barriers of rotation for common Ru carbenes that fail to sustain the steric compression required for stereocontrol.150–151 However, the 2000s marked isolation of Ru catalysts that produced copolymers with unusually high cis content. For example, Wang and coworkers reported a phosphine-based Ru-carbene optimized to catalyze the alternating copolymerization of norbornene and cyclooctene.152 The copolymer was comprised of 90% trans olefins, which prompted the investigation of the role of the X ligand on the stereoselectivity of the process. The authors found that replacing the chloride ligand with large sulfonates improved the cis-to-trans ratio to about 1:1 (Scheme 51).153 Here, we see a few competing behaviors: The introduction of a bulky sulfonate (denoted in blue) forces the propagating polymer to turn away from it. However, p-complexation of the olefin to the metal center trans to the phosphine ligand and subsequent formation of a metallacyclobutane requires a compromise between (a) the steric repulsion of the cycloolefin and the sulfonate and (b) the steric interaction between the all-cis substituents in the metallacyclobutane structure. The stronger of these two interactions will determine the stereochemical outcome and formation of a cis or trans alkene via path 1 or 2. (Scheme 51).

Scheme 51 Copolymerization of norbornene and cyclooctene with Ru-6 and Ru-7.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

307

Interestingly, a variety of other catalytic systems developed for the alternating copolymerization of norbornene and cyclooctene around that time also demonstrated modest Z selectivity, up to 75%. In contrast to Chen’s complexes, these catalysts were derived from the Grubbs 2nd generation scaffold, which is characterized by a N-heterocyclic carbene (NHC) as the L ligand.154,155 A Ru-based NHC-arene system demonstrated Z selectivity up to 81% in a ROMP of norbornene but at very low conversion (17%).156 Grubbs and coworkers have reported similar cis content for sulfonate- and phosphate-substituted NHC-based catalysts as well.157

13.07.2.2.2

Cyclometalated Z-selective Ru catalysts

13.07.2.2.2.1 Catalyst structure and mechanism Directional binding of the olefin plays a critical role in determining the stereochemical outcome. Dichlororuthenium catalysts (I)—including Ru-1–5—favor a bottom-bound olefin addition (II) in which the olefin is bound trans to the ancillary ligand (L), as opposed to a side-bound approach (III) in which the olefin is bound cis (Scheme 52).25 The resulting bottom-bound metallacyclobutane was found to be highly dynamic following separate studies by Grubbs158,159 and Piers, who first reported the observation of a 14-electron ruthenacyclobutane.160 In the bottom-bound approach, formation of a ruthenacycle with anti substituents (IV), which leads to E alkenes, is sterically favored over the syn arrangement (V), which results in Z alkenes. Consequently, E olefins are both thermodynamically and kinetically favored with typical dichlororuthenium catalysts.29

bottom-bound approach

L Ru

favored R2

sidebound approach

disfavored L Ru

R2 Scheme 52 Different olefin approach to the ruthenium alkylidene leading to diastereomeric ruthenacyclobutanes.

Several rationalizations for the observed energetic bias toward the side-bound mechanism exist: electronic repulsion between the syn X ligands, build-up of a high dipole moment, and steric repulsion between L and ruthenacyclobutane substituents (Scheme 53).161 As such, modification of the X ligands has been vigorously pursued by several groups to disrupt the classic bottom-bound path and favor the formation of Z alkenes.

L

L X

X

Ru

X

Ru

R1 R1

R2 X

R2

from ‘bottom-bound’ approach Scheme 53 Electronic effect on the conformation of ruthenacyclobutane.

from ‘side-bound’ approach

electron repulsion

308

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Following moderately successful attempts to increase Z selectivity through substitution of a chloride ligand by a large sulfonate or phosphane,157 Grubbs and coworkers investigated the replacement of the chloride by a pivalate group instead. However, treatment of complex Ru-8 with silver pivalate unexpectedly led to the formation of cyclometalated Ru-10, which was not only metathetically active but also provided the highest observed Z selectivity for the homopolymerization of several terminal alkenes, including 47.162 The structure of this unusual catalyst is characterized by a chelating NHC ligand derived from intramolecular C–H bond activation of an N-adamantyl substituent, and a bidentate ligand that was optimized for activity and Z selectivity. Substitution of the carboxylate ligand with a nitrato group (Scheme 54, Ru-12) improved the stability of the catalyst, the Z selectivity (>90%), and the turn-over number (TON) for homodimerization reactions.163 Subsequent DFT calculations suggests that the side-bound mechanism remains operational with the nitrato ligand.164 Of note, Grubbs, Houk, and coworkers reverted to the pivalate ligand for the preparation of sterically demanding cyclometalated Ru catalysts for the challenging CM between terminal alkenes and acrylamides.165 Finally, exchanging the mesityl substituent for a bulkier N-2,6-diisopropylphenyl group (DIPP) resulted in even greater Z selectivity, with catalyst Ru-13 exhibiting >98% Z selectivity in similar homodimerization reactions.166 The activity of nitrato-based catalysts was also remarkably improved and catalyst loadings as low as 0.01 mol% were reported. Table 9 summarizes the improvement of yield and Z selectivity when used for the homodimerization of 47.163,166 Additional variations of the ligands were investigated but catalysts Ru-12 and Ru-13 typically afforded the best yields and stereoselectivity, so were used in subsequent synthetic applications.27 Notably, Ru-12 is already commercially available.

Scheme 54 Synthesis of Z-selective Ru-12 and Ru-13 with a cyclometalated NHC.

Table 9

Homodimerization of 47 with catalysts Ru-10, Ru-12 and Ru-13.

Ru-cat

Time (h)

Z (%)

Yield (%)

Ru-10 Ru-12 Ru-13

12 12 6

90 91 >95

13 85 >95

Houk and Grubbs performed density functional theory (DFT) calculations to help elucidate the origins of the observed selectivity.167 Interestingly, their results revealed that the cyclometalated NHC architecture actually favors a side-bound mechanism, which was attributed to two factors: steric effects and d-orbital backdonation. Investigations into the former indicate that steric compression in the [2 + 2] transition state accounts for the orientation preference. As depicted in Scheme 55, the bottom-bound complex I sees adverse van der Waals interactions between the adamantyl group and the metallacycle protons. In contrast, the side-bound variant II positions the metallacyclobutane anti to the adamantyl group, thereby reducing steric clash. This side-bound preference is reinforced by the use of NHC and alkylidene ligands, both of which are strong s-donors and p-acceptors. As such, the Ru-NHC p orbital is preferentially positioned coplanar to the Ru-alkylidene bond. In the side-bound complex, two discrete Ru d orbitals backbond to NHC and alkylidene p orbitals, respectively. The bottom-bound complex instead relies on a single Ru d orbital for backdonation to both acceptor ligands,150,168,169 resulting in weaker contributions and a destabilized complex.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

309

Scheme 55 Steric and stereoelectronic effects at play in bottom- and side-bound mechanisms.

In the side-bound approach, the non-chelating N-aryl NHC substituent lays directly over the forming ruthenacyclobutane (Scheme 56). With both substituents pointing away from the N-aryl group, the syn-metallacycle is then favored over the antimetallacycle, which suffers steric clash between one ruthenacycle substituent and the NHC aryl group.170 The energy difference between the transition states leads to a predominance of Z-olefin products. This model also rationalizes the improved Z selectivity observed when the mesityl group is replaced by the bulkier DIPP substituent on the NHC.

Scheme 56 Z- vs E-selectivity models for cyclometalated Ru catalysts.

310

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

13.07.2.2.2.2 Cross metathesis with Z-selective cyclometalated Ru catalysts As discussed above, catalysts Ru-10–13 were first optimized for homodimerization reactions with terminal alkenes containing a variety of R substituents. For example, homodimerization of substrates using Ru-12 was achieved in high yields and impressive Z selectivity (Table 10).163 Functional groups such as alcohols, amines, esters, and ethers were tolerated, but substrates containing allylic substituents (e.g., 3-methyl-1-hexene) and those with a pendent carboxylic acid (e.g., 4-pentenoic acid) could not be homodimerized. CM of two distinct terminal olefins was also attempted with these catalysts. This transformation requires prudent selection of the reactant olefins and ratios thereof, lest a statistical mixture of products (two homodimers and the desired cross-product) be returned. Attempts to cross allyl benzene and (Z)-1,4-diacetoxybutene, for example, found that 5 mol% of catalyst Ru-10 affords the desired product at 50% conversion and 86% Z selectivity in THF at slightly elevated temperatures (Table 11).163 Use of catalyst Ru-12, however, allowed for a much lower catalyst loading (1 mol%) and resulted in improved conversion and Z selectivity. Table 10

Homodimerization of terminal alkenes with catalyst Ru-12.

Substrate

Table 11

Product

Yield (%)

Z (%)

91

92

83

92

67

81

CM of allyl benzene and (Z)-1,4-diacetoxybutene with Ru-10 and Ru-12.

Catalyst

Loading (mol%)

Time (h)

Conv. to 48 (%)

Z (%)

Conv. to 49 (%)

Z (%)

Ru-10 Ru-12

5 1

6 9

50 58

86 91

19 28

>95 >95

Significant steric and electronic differences between the two olefin reactants bode well for cross-reactivity.171 However, in cases with similar olefin dispositions, an excess of one starting olefin and an increase in catalyst loading are required to facilitate the desired transformation. In one example, nine Z-olefin-bearing pest control agents were targeted for synthesis by Grubbs and coworkers. The authors reported that, at room temperature, low catalysts loadings (Ru-12, 1 mol%) resulted in moderate to good yield and high Z selectivity (76–88%) as exemplified by pheromone 50 in Scheme 57.172 In separate studies, insect pheromone derivative 52 was prepared via CM of acetate 51 and 1-hexene.163,166 A comparison of catalysts Ru-12 and Ru-13 revealed that the bulky N-DIPP ligand of Ru-13 promotes near-perfect Z selectivity with a lower catalyst loading and only a minor reduction in yield. Finally, the Z cross-product of olefins 53 and 1-dodecene could be selected for when using catalyst Ru-13,27 an impressive outcome considering the propensity of allyl-substituted terminal olefin starting materials to undergo E-selective CM. As expected, catalyst Ru12 could not completely overcome the substrate preference for E-olefin formation and provided a diminished Z selectivity.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

311

Scheme 57 Examples of Z-selective CM using Ru-12 and Ru-13.

This catalyst system was then used to target synthetic intermediate 55 en route to mytilipin A (Scheme 58).172,173 Vanderwal and coworkers reported that—despite the complexity of the substituted vinyl epoxide and terminal olefin starting materials—high Z selectivity could be achieved in decorated systems, albeit in moderate yield.

Scheme 58 Z-selective CM with Ru-12 as key step in the synthesis of natural product mytilipin A.

Additional studies revealed that CM attempts with two internal olefins were essentially ineffective, likely due to the energetically disfavored formation of trisubstituted metallacyclobutane intermediates within an already congested steric environment.27,174 This could be circumvented through the addition of ethylene, which induces the transient formation of methylidene intermediates.174 Interestingly, internal E olefins were unreactive with this family of cyclometalated catalysts, even in the presence of ethylene. Capitalizing on this apparent lack of reactivity, the chemoselective coupling was exploited to prepare 56 in 68% yield and 88% Z selectivity using catalyst Ru-12 (Scheme 59), leaving the internal E olefin intact.175 Similarly, 1,1-disubstituted terminal olefins and Z-a,b-unsaturated esters remained untouched in the reactions, forming 57 and 58, respectively.176 Finally, conditions were optimized for the Z-selective CM of conjugated 3E-1,3-dienes using catalyst Ru-13. Impressively, only 1.5 equivalent of the diene relative to the terminal alkene were required. DFT calculation suggests that Ru-13 reacts first with the diene to form a Ru vinylcarbene, which subsequently reacts with the terminal olefin selectively.177 (E,Z)-9,11-dodecadienyl acetate (59) was synthesized in 56% yield and > 95% Z selectivity using this method.

312

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 59 Chemoselective CM with Z-selective Ru-12 and Ru-13.

13.07.2.2.2.3 Ethenolysis with Z-selective cyclometalated Ru catalysts Ethenolysis—the reverse process of CM between two terminal olefins—proceeds through the same metallacyclobutane intermediates found in the forward reaction; Ru catalysts with cyclometalated NHCs are therefore expected to discriminate between E and Z isomers. Indeed, Ru-12 was found to catalyze the selective ethenolysis of Z olefins in the presence of E olefins: Z olefins were converted to terminal olefins, while E olefins remained intact.92 In one example, a mixture of E/Z isomers of diacetate 60 containing 80% of E isomer was exposed to catalyst Ru-12 under 5 atm of ethylene at 35  C. Ethenolysis of the minor Z isomer allowed the isolation of the E isomer 61 with a 95% isomeric purity after removal of terminal alkene as the side-product by flash column chromatography (Scheme 60).174 This enrichment strategy was broadly applicable to a variety of E alkenes bearing various functional groups, including alcohols, esters, amines, and ketones. It also proved efficient with a E:Z mixture of macrocycles.178 As a result, Z-selective ethenolysis now constitutes an indirect method to access E alkenes.

Scheme 60 Ethenolysis of a mixture of E- and Z-60 with ethylene and Ru-12.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

313

13.07.2.2.2.4 Ring-closing metathesis with Z-selective cyclometalated Ru catalysts RCM is often used in the synthesis of macrocycles,179–182 but medium-to-large ring systems are generally returned as a mixture of E and Z isomers on reaction with typical Ru carbenes; the product distribution reflects the thermodynamic landscape of the reaction. For example, RCM of 62 with Grubbs 2nd generation catalyst Ru-2 led to a mixture of E and Z isomers (92% E isomer) (Scheme 61).183 The invention of catalysts Ru-10–13 provided an opportunity to examine whether kinetic control can overcome the selectivity observed in traditional RCM catalysis. Impressively, 14-membered 63 was obtained in 58% yield and 85% Z selectivity using catalyst Ru-12 at 60  C under static vacuum (20 mTorr).178 Similarly, 20-membered 64 was obtained in 75% yield and 95% Z selectivity. These RCM conditions provided a formal synthesis of the cytotoxic alkaloid motuporamine C. Compound 65 was produced in 30% yield and 84% selectivity using catalyst Ru-12. This intercepted intermediate had been previously attained either through a two-step ring-closing alkyne metathesis followed by Lindlar hydrogenation184 or by standard RCM, which necessitated a painstaking purification of the isomeric mixture via radial chromatography.185

Scheme 61 Examples of Z-selective RCM with Ru-12.

In another example, stapled peptide 66 was obtained through resin-bound RCM catalyzed by Ru-12 or Ru-13 (Scheme 62).186 CM between peptidic fragments was also reported in the same communication, highlighting the functional group tolerance of the catalyst and potential for applications toward the synthesis of druglike biomolecules.

Scheme 62 Application of Z-selective RCM in the synthesis of druglike biomolecules.

13.07.2.2.2.5 Ring-opening cross metathesis with Z-selective cyclometalated Ru catalysts ROCM is a useful synthetic tool to access molecules with multiple stereocenters. Grubbs and coworkers demonstrated that ROCM between a norbornene derivative and a conjugated 3E-1,3-diene led to highly substituted cyclopentane derivative 67 in over 95% yield and over 95% Z selectivity (Scheme 63).177 ROCM of cyclobutene and 3E-1,3-diene led to 68 with similar yield and stereoselectivity.

314

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 63 Examples of Z-selective ROCM with Ru-12.

An asymmetric ROCM variant was also developed by the same group. Homochiral catalyst Ru-12 was first prepared from complex Ru-14 via a two-step sequence involving resolution of the initial racemate though chromatographic separation of the diastereomeric pair of compounds Ru-15 (Scheme 64).187

Scheme 64 Synthesis of homochiral cyclometalated catalyst Ru-12 .

Complex Ru-12, which is stereogenic at the Ru, was subsequently used for a variety of asymmetric ROCM (Table 12). For example, the ring opening of norbornene derivatives using homochiral catalyst Ru-12 in combination with allyl acetate allowed the formation of substituted cyclopentane with high Z selectivity (70–98%) and modest-to-high enantioselectivity (ee: 60–95%).187 Overall, the stereocontrol offered by this catalytic transformation is likely to appeal to the synthetic community. 13.07.2.2.2.6 Ring-opening metathesis polymerization with Z-selective cyclometalated Ru catalysts The advent of the cyclometalated Ru catalysts brought about considerable improvement of Z selectivity in ROMP processes. Polymerization of norbornene in THF using racemic catalyst Ru-12 at room temperature afforded polynorbornene in 94% isolated yield with 88% cis double bonds.188 The authors found that low temperatures (−20  C) prior to catalyst addition increased the selectivity to 96% (Table 13). While the cis content of the resulting alkenes varied by monomer, 80% and 91% were obtained for the oxanorbornene derivatives depicted in Table 13. Though norbornadiene afforded a slightly lower cis content (75%), 98% Z) (Scheme 72).161 High TONs (up to 43,000) were obtained for both catalysts at low catalyst loading, highlighting the longevity of the active Ru-species. Interestingly, catecholate Ru-28 with two oxygens in place of the sulfur atoms resulted in similar activity but no or modest Z selectivity (Scheme 72). This head-to-head comparison emphasizes the importance of careful catalyst design and the incredible influence of small electronic, and therefore geometric, variabilities in catalyst structure.

320

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 72 ROMP of norbornene and cyclooctadiene with Ru-26–28.

ROCM of strained alkenes with an excess of styrene or vinylcyclohexane (20 equivalents) afforded the ring-opened products in good-to-excellent yields (59–92%) and high Z stereoselectivities (>93% in every example) (Table 15).

Table 15

Stereoretentive ROCM of strained alkenes with terminal alkenes and Ru-27.

Substrate

Product

Yield (%)

Z (%)

75

98

59

>98

92

97

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design Table 15

321

(Continued) Substrate

Product

Yield (%)

Z (%)

75

98

93

96

82

98

61

>98

63

97

Ru-27 was also evaluated in the more challenging CM of (Z)-2-butene-1,4-diol and allylbenzene.198 Catalyst Ru-27 furnished the desired product in high Z selectivity (98:2 Z/E), but poor yield (42%, Scheme 73). Migratory insertion of the propagating

Scheme 73 Impact of the substituents on the dithiolate ligand on the stereoretentive CM between allyl benzene and (Z)-2-butene-1,4-diol using catalysts Ru-29–32.

322

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

carbene into the Ru–sulfur bond trans to the NHC was proposed to lead to catalyst decomposition (Scheme 74). To prevent the 1,2-shift, systematic structural modifications of the dithiolate ligands, guided by computation, were undertaken. The S–Ru bonds were strengthened by introducing electron-withdrawing groups in the ligand, thereby decreasing the electron density on the sulfur atoms. All four modified Ru-alkylidenes (Ru-29–Ru-32) provided similar Z selectivity and slightly improved yield as compared to parent catalyst Ru-27 (Scheme 73).

Scheme 74 1,2-shift mechanism leads to presumably catalytically inactive species.

Derived from the commercially available 3,6-dichloro-1,2-benzenedithiol, dichloro congener Ru-29 was selected to survey the scope of the CM reaction (Table 16).198 Z-2-butene-1,4-diol was found to engage with a variety of coupling partners, including protected alcohols, a nonproteinogenic amino acid, carbonyl compounds, and styrene. The reaction was also found to proceed Table 16

Substrate

Stereoretentive CM between terminal alkenes and (Z)-2-butene-1,4-diol.

Product

Yield (%)

Z (%)

65

93

73

98

80

94

70

96

56

96

53

94

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

323

between commercially valuable oleyl alcohol and oleic acid in a stereoretentive manner to afford high-value products.199 While the Z-selective metathesis process using cyclometalated Ru catalysts suffers some functional group limitation (see Section 13.07.2.2.2), Ru-29 was found to work well in the presence of particularly sensitive moieties, including allylic alcohols, carboxylic acids, and aldehydes. Notably, only two equivalents of (Z)-2-butene-1,4-diol were required to effect CM in good yields, despite possible homodimerization pathways. In a final testament to the broad applicability of this process, catalyst Ru-29 was critical in achieving a stereoselective synthesis of an intermediate toward cytotoxic natural products (+)-neopeltolide,78 and leucascandrolide A (Scheme 75). Remarkably, the other key fragment required for the synthesis of (+)-neopeltolide was prepared via two Mo-catalyzed Z-selective metathesis processes (ROCM and RCM, see Scheme 23), which highlights the synthetic potential of stereoselective olefin metathesis.79

Scheme 75 The application of stereoretentive CM toward the synthesis of natural products leucascandrolide A and (+)-neopeltolide.

Stoltz, Grubbs, and coworkers also reported an elegant synthesis of D12-prostaglandin J natural products using catalyst Ru-29 for the key installation of the side chain containing a Z alkene (Scheme 76).200

Scheme 76 The application of stereoretentive CM toward the synthesis of prostaglandin D12-PGJ2.

324

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

A slight drawback to this impressive reactivity was the strict inert conditions required for the isolation and utilization of Ru-29. In answer to this challenge, Mauduit and coworkers reported an in situ synthesis of Ru-29 through reaction of 2nd generation Hoveyda-Grubbs catalyst Ru-4 with a premixed diethyl zinc and 3,6-dichloro-1,2-benzenedithiol solution (Scheme 77).201 Ru-29 was then added to a solution of the desired alkene reactants in order to effect the CM of various terminal alkenes with (Z)-2butene-1,4-diol or the diacetate congener (Table 17). The functional group tolerance of Ru-29 was left unchanged, though the excess zinc chloride and zinc catechothiolate did result in a minor decrease in yields. Finally, a highly Z-selective catalyst with a dicarbadodecaborane (12)-1,2-dithiolate ligand was prepared by Wang and coworkers shortly after and provided high yields for ROMP and ROCM, but low yields for CM.202

Scheme 77 Stereoretentive CM between a terminal alkene and a cis alkene with in-situ generated catalyst Ru-29.

Table 17

CM of terminal alkenes and (Z)-2-butene derivatives with Ru-29 generated in situ.

Substrates

Product

Yield (%)

Z (%)

64

>98

55

>98

62

98

58

98

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design Table 17

325

(Continued) Substrates

Product

Yield (%)

Z (%)

64

>98

64

>98

28

95

63

96

53

98

Finally, in 2019, Hoveyda and coworkers reported the synthesis of Ru-33, a catalyst that is characterized by an unsaturated NHC ligand (Scheme 78).203 DFT calculations predicted that this catalyst would be more reactive due to increased accessibility of the olefin coordination site and weaker trans influence on the ruthenacycle. Moreover, it was expected to be less prone to b-hydride elimination, so less susceptible to common decomposition pathways. Ru-33 was found to efficiently catalyze the demanding CM of terminal alkenes and a,b-unsaturated carbonyl compounds, including esters, amides, and Weinreb amides with high Z selectivity.

Scheme 78 The stereoretentive CM of terminal alkenes and a,b-unsaturated carbonyl compounds was enabled by a dithiolate catalyst containing an unsaturated NHC ligand (Ru-33).

326

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

13.07.2.2.4.2 Mechanism and stereoretention Further study of Ru-29 by Materia Inc. and Grubbs and coworkers provided key insights into the unique mechanism of this family of catalysts. While the self-metathesis of (Z)-71 generated (Z)-72 in high Z-selectivity (97% Z) as anticipated, the self-metathesis of (E)-71 generated (E)-72 with a 5:95 Z/E ratio (Table 18).204 This finding was the first report of a kinetically controlled E-selective metathesis with a Ru catalyst. Table 18

Stereoretentive self-metathesis of E- or Z-71 with Ru-29.

Substrate

Product distribution (yield%, Z/E)

Z-71 E-71

71

72

73

50, 97/3 54, 4/96

25, 97/3 23, 5/95

25 (n.d.) 23 (n.d.)

Since the stereochemistry of the olefin is preserved during the metathesis process, this class of Ru-catalysts was dubbed “stereoretentive.” As shown in Scheme 79, the retention is largely attributed to cis-chelating catechothiolate ligand, which compels a side-bound mechanism, and the steric influence of the NHC on the a positions of the metallacyclobutane. The resulting pocket is then available for alternative approach by both cis and trans olefins, respectively. Z/Cis olefins add to the catalyst such that all substituents are pointed away from the NHC ligand. In contrast, addition of E/trans olefins forces the a metallacyclobutane substituents away from the NHC ligand and the remaining substituent settles in the b position. This Pederson/Grubbs steric model204 is supported by computational studies by Houk and Liu.205

cis-selectivity model Me

Me N Me

N

Me

Me

Me

Me

N Me

Me

Me

Me

S

Ru

N

Ru

S

Me

S S

favored

disfavored trans-selectivity model Me

Me N Me

Me

Me Ru

S S

favored Scheme 79 Stereoselectivity model with dithiolate catalysts.

Me

Me

N

N Me

Me

N Me

Me Ru

S S

disfavored

Me

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

327

13.07.2.2.4.3 E selectivity The previous model also rationalizes the lower reactivity of E substrates relative to Z substrates, as even the favored transmetallacycle suffers steric hindrance. To increase the reactivity of E substrates, a series of catalysts (Ru-34–37) were synthesized with smaller ortho-substituents on the N-aryls flanking the NHC ligand.204 Indeed, the reactivity of (E)-4-octene in CM was found to increase as the ortho-substituent size decreased (Scheme 80), while maintaining exceptional selectivity (>99:1 E/Z). Interestingly, the opposite trend was observed in presence of (Z)-4-octene.

Scheme 80 Optimization of the stereoretentive CM between 1-decene and (E)-4-octene through catalyst design: The role of the aryl substituents on the NHC.

While modification of the NHC aryl substituents saw a notable improvement in yields with E olefins, results remained modest compared to that of Z olefins, likely due to the slow reactivity of E olefins. Indeed, these catalysts are prone to decomposition over time, a path presumably caused by the formation of unstable Ru methylidene species (see Section 13.07.2.2.2.4) and subsequent insertion of the ruthenium sulfur bond (similar to Scheme 73). 1H NMR studies confirmed poor catalyst initiation as the culprit,206 and a new series of catalysts were designed to improve initiation. Substitution of the 2-isopropoxybenzylidene ligand with a 3-phenyl-2-isopropoxybenzylidene ligand was undertaken,206 a modification that is known to increase initiation rates of Ru metathesis catalysts.207–210 CM of (E)-1,4-diacetoxy-2-butene and (E)-4-octene was attempted with catalysts Ru-37–40 (Scheme 81). All catalysts provided high stereoselectivity of products (>99% E), while Ru-37 and Ru-39 demonstrated increased activity and faster reaction times. An impressive 83% yield was obtained in only 1 h with Ru-39—a marked improvement on the days-long reaction time needed for parent catalyst Ru-29. This catalyst series however provided only marginal improvements with the more reactive Z substrates. Finally, an increase in steric bulk on the dithiolate ligand was attempted with another set of catalysts, but this strategy did not yield significant improvements with E substrates.211

328

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

Scheme 81 Optimization of the stereoretentive CM between (E)-1,4-diacetoxy-2-butene and (E)-4-octene through catalyst design: Increasing the rate of initiation through modification of the alkylidene ligand.

13.07.2.2.4.4 Methylene capping strategy Catechothiolate Ru species (e.g., Ru-29) generally boast a higher functional group compatibility than the Z-selective cyclometalated catalyst scaffold (e.g., Ru-12). However, they typically struggle with CM of terminal alkenes due to the formation of unstable Ru methylidenes (vide infra)198; these intermediates are known to undergo 1,2-shift of the sulfide trans to the NHC to the carbene carbon, thereby forming an effectively inert catalyst. In fact, there are very few examples of terminal alkene competence in the reaction—In these cases, the olefin partners are either highly reactive (e.g., strained bicyclic alkene) or rely on H-bonding between (Z)-2-butene-1,4-diol and the sulfide ligands to minimize methylidene formation.198 In response to this limitation, Hoveyda and coworkers proposed a methylene capping strategy (Scheme 82).212 By using a large excess of (Z)-2-butene (I), the starting terminal alkenes were capped in situ to form II and III. Removal of volatiles I and IV, followed by addition of a second portion of catalyst Ru29, enabled separation of the desired Z cross-coupled product from homodimeric side products through chromatographic purification.

Scheme 82 Hoveyda’s methylene capping strategy to allow stereoretentive CM of terminal alkenes.

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design

329

Hoveyda and coworkers first applied the methylene capping strategy to cross-metathesis reactions with nearly 20 examples isolated in modest-to-good yields and excellent stereoisomeric purity (Table 19).212 To ensure high conversion in cross-metathesis reactions, a 1:3 ratio of substrates was used. Practitioners should note that (1) the two substrates must be of significantly different polarity to achieve ready column chromatographic separation and (2) sterically hindered olefins are not tolerated. Additionally, Table 19

CM of methylene-capped terminal alkenes with Ru-29.

Coupling partners (R1/R2)

Product

Yield (%)

Z (%)

56

95

74

97

80

97

63

97

64

98

51

>98

25a

>98

58

96

(Continued )

330

Table 19

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design (Continued) Coupling partners (R1/R2)

Product

Yield (%)

Z (%)

56

95

70

98

a

25% conversion using a 20 mol% loading of Ru-29 at 22  C for 32 h.

styrene derivatives could not be capped in situ due to the far too rapid formation of the methylidene complex and stilbene side products. Replacement of styrenes with (Z)-b-methylstyrene derivatives allowed for successful reaction with a methyl ester (Table 19). By contrast, Hoveyda noted that carboxylic acids are not suitable cross-metathesis partners with (Z)-b-methylstyrene substrates. The authors reasoned that with sluggish substrates, the protonation and loss of the catechothiolate ligand by Brønsted acid is a faster process, and leads to catalyst degradation. It should be noted that stereoretentive CM and RCM with (E)-2-butene as capping reagent were also reported, however, these reactions required a significantly higher catalyst loading (10.0–12.5 mol%).212 Macrocyclic ring-closing metathesis (RCM) with (Z)-butene was also explored, affording 14–21-membered macrocycles in good yield and high stereoretention such as the 16-membered macrocycle depicted in Table 19. Hoveyda and coworkers also investigated the use of Ru dithiolate catalysts for the synthesis of Z or E trisubstituted allylic alcohols.213 Catalyst Ru-35 (Scheme 80), which bears smaller N-aryl substituents on the NHC, was found more reactive than Ru29—an observation that aligns with the side-bound mechanism depicted in Schemes 53 and 55 and the formation of highly congested ruthenacycles. The in situ methylene capping strategy with 1,1-disubstituted allylic alcohols and terminal alkene returned the desired CM products in good yield; impressive retention of stereochemistry was also observed, regardless of allylic alcohol configuration (Table 20). Additionally, the authors confirmed that the prevailing notion of allylic oxygen activation extends to Table 20

CM of Methylene-Capped Terminal Alkenes and Trisubstituted Alkenes with Ru-35.

Coupling partners

Product

Yield (%)

Z (%)

58

>98

75

>98

E vs Z Selectivity in Olefin Metathesis Through Catalyst Design Table 20

331

(Continued) Coupling partners

Product

Yield (%)

Z (%)

58

>98

77

>98

50

>98

52

2

77

4200 kg mol−1). Copolymerization of ethylene with methyl 10-undecenoate was also accessible, although with a low comonomer incorporation (Fig. 6).

13.09.4.2 Phosphine-sulfonate catalysts (Drent-type) In 2002, Drent and co-workers reported another major advance in this field,110 where they showed that some phosphine-sulfonate palladium catalysts (Drent catalyst, F7–1) can mediate ethylene-alkyl acrylate copolymerization. In contrast to the Brookhart catalyst, highly linear copolymers with acrylate units inserted in the main-chain were generated (Fig. 7A). Their unique properties, especially their ability to produce linear copolymers with in-chain comonomer incorporation, have triggered tremendous research interest.111–137 It was found that Drent-type phosphine-sulfonate palladium catalysts could copolymerize ethylene with very wide range of polar monomers types, including acrylic acid and other comonomer (Scheme 3). Remarkably, the Mecking group reported the first example of insertion copolymerization of ethylene with vinyl chloride (VC) using phosphine-sulfonate palladium catalysts (F7–2). They found that after the 2,1-insertion of VC, ethylene insertion resulting in monochlorinated polyethylene is competitive to chain walking to produce chlorine-containing copolymers, albeit with relatively low activities and low copolymer molecular weights.128 Nozaki and co-workers showed that the copolymer molecular weights could be significantly increased using a Men(menthyl) substituent on a phosphine-sulfonate ligand (F7–3).129 They showed that a carbene precursor (dimethyl diazomalonate) could act as an efficient chain-transfer agent in the ethylene copolymerization reactions, leading to polar group-functionalized PEs bearing chains capped with carbene species (Fig. 7B).130 Mecking and co-workers showed that the cyclopolymerization of some non-conjugated divinyl comonomers could promote chain propagation and suppress b-hydride elimination, thereby generating copolymers with cyclic units and high copolymer molecular weights (Fig. 7C and D).131,132 Mecking and co-workers also reported an interesting system, in which a phosphine-sulfonate palladium catalyzed copolymerization of ethylene with 2-vinylfuran to generate a a,o-di-furan telechelic polyethylene (Fig. 7E).133 Chen and co-workers showed that the polymerization properties of phosphine-sulfonate palladium and nickel catalysts (F7–5, F7–6) can be improved by the introduction of a polyethylene glycol unit.134 This beneficial effect is most significant in ethylene copolymerization with polar monomers bearing hydrogen-bond-donating abilities. The Chen group also reported a direct and tandem strategy to realize ethylene copolymerization with various 1,2-disubstituted ethylenes (Fig. 7F). This work is a step forward in terms of expanding the substrate scope for transition metal catalyzed ethylene copolymerization with complex polar-functionalized comonomers.135 Recently, the Chen group reported that bioresourced eugenol and related comonomers were incorporated into polyolefins through palladium F7–7 catalyzed copolymerization and terpolymerization reactions to generate high-molecular-weight catechol-functionalized polyolefins.136 The introduction of different metal ions induces efficient interactions with the incorporated catechol groups, leading to enhanced mechanical properties, self-healing properties, improved surface properties, adhesion properties, and compatibilizing properties (Fig. 7G). Inspired by the great success of Drent type palladium catalysts, the utilization of low-cost nickel phosphine-sulfonate catalysts to address the polar monomer problem becomes another fascinating challenge in this field. However, the phosphine-sulfonate nickel complexes showed undesirable reactivities when used for copolymerization of ethylene with polar monomers.138 By modifying the substituents bonded to the P-atom, nickel complexes F8–1 and F8–2 bearing various ligands have been reported (Fig. 8).139–146

416

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

Fig. 6 Selected a-diimine nickel complexes for ethylene copolymerization of ethylene with polar monomers.

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

417

Fig. 7 Selected phosphine-sulfonate palladium catalysts (Drent type) for ethylene copolymerization of ethylene with polar monomers.

Chen and co-workers reported the design and synthesis of high-performing phosphine-sulfonate nickel catalysts by installing biaryl substituents on the phosphorous atom and substituents on the ortho-position of the sulfonate group (F8–3).147 These complexes worked as single-component catalysts and copolymerized ethylene with allyl monomers, norbornene derivatives, vinyl trialkoxysilane and monomer with spacers between polar functional groups and double bonds. Phosphine-sulfonate nickel catalysts were designed to investigate the electronic effects at the P-aryl groups and the ligand backbone on catalytic performance. Fundamental polar comonomer methyl acrylate and vinyl acetate were attempted in ethylene copolymerization using these nickel catalysts but failed.

418

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

Fig. 8 Selected phosphine-sulfonate Nickel catalysts (Drent type) for ethylene copolymerization of ethylene with polar monomers.

13.09.4.3 Catalysts beyond Brookhart and Drent systems Recently, many research efforts have been directed toward the development of palladium and nickel catalysts bearing ligands other than the Brookhart and Drent frameworks. In 2012, Nozaki and co-workers reported the synthesis and polymerization studies of cationic bisphosphine monoxide palladium complexes (F9–1), where highly linear polyethylene was generated for ethylene homopolymerization. Moreover, these palladium complexes can mediate efficient copolymerization of ethylene with various fundamental polar monomers (MA etc.) to afford highly linear copolymers at moderate activities (0.3–7.6 kg mol−1 h−1).148 Functionalized polyethylene with moderate comonomer incorporation (0.7–4.1 mol%) and relatively low copolymer molecular weights (Mn up to 9300) have been produced. The catalyst performance was found to be sensitive to ligand substitutions,149 and electron-donating R2 groups led to better catalytic performance. The authors proposed that the nonsymmetric strong/weak s-donor ligand framework is crucial for the success of this system. These studies demonstrated the first catalyst system other than the Drent catalyst that can catalyze the copolymerization of ethylene with various fundamental polar monomers to generate linear copolymers. By contrast, the nickel complexes based on the same type ligands have only been reported to oligomerize ethylene.150 In 2014, Jordan and co-workers prepared several cationic phosphine-diethyl phosphonate palladium catalysts (F9–2),151 and showed that they were highly active in ethylene polymerization. These palladium complexes mediated copolymerization of ethylene with methyl acrylate or acrylic acid at moderate activities (1.2–150 kg mol−1 h−1), producing copolymers with very low molecular weights (Mn up 99%).185 Recently, Marks and co-workers reported the synthesis of polar functionalized isotactic and syndiotactic polypropylenes (PPs) by direct copolymerization of propylene and bulky amino–olefins (AO, CH2]CHd(CH2)xNnPr2, x ¼ 2, 3, 6) by using the borate-activated pre-catalysts rac-[Me2Si(indenyl)2]ZrMe2 and [Me2C-(Cp)(fluorenyl)]ZrMe2 (F11–1: SBIZrMe2 and F11–2, FluZrMe2, Fig. 11),186 respectively. Polymerization activities at 25  C are as high as 4208 and 535 kg mol−1 h−1 atm−1 with AO incorporation up to 4.0 mol% and 1.6 mol%, respectively. Remarkably, compared with propylene homopolymerization, the direct amino-olefin copolymerization with propylene significantly enhances stereo-control for both isotactic (mmmm: 59.5% to 91.0%) and syndiotactic (rrrr: 66.3% to 81.3%) copolymer products.

422

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

Fig. 10 Post-metallocene Hafnium catalyst for functional isotactic polypropylene.

Fig. 11 Metallocene zirconium catalysts for functional isotactic polypropylene.

13.09.5.2 Ni and Pd catalysts The development of late-transition metal complexes with high regio- and stereo-selectivity toward propylene (co)polymerization is particular challenging due to their tendency to undergo chain walking processes. The first report in the copolymerization of propylene with polar monomer came from Brookhart, who used cationic palladium complexes bearing a-diimine ligands to successfully incorporate either MA or fluorinated octyl acrylate into the resultant copolymer.78 The amorphous polymers formed were highly branched and contained chain straightened units due to the formal 1,3 insertion of propylene. MA was found to insert in a 2,1 mode and was mainly located at the branch ends, indicating that its insertion was followed by chain termination or chain

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

423

walking. To overcome this issue, in 2014, the Nozaki group investigated the copolymerization of propylene with methyl acrylate (MA) using Pd/imidazolidine −quinolinolate (IzQO) precatalyst (F12–1), which generated a regio-regular polymer, but the system featuring an IzQO ligand did not display any stereoselectivity, leading to the formation of atactic functional polypropylene.154 Coates and co-worker synthesized highly isotactic polypropylene using a Brookhart type catalyst under very low reaction temperature (−78  C), which rendered the polar commoner incorporation unfeasible.187 In 2016, the Nozaki group examined the effect of altering the bulky substituents of the phosphine −sulfonate (PS) ligand in their corresponding palladium complexes (F12–2).188 With the introduction of two menthyl groups on the phosphorus atom, (F12–2), regiocontrolled polypropylene was obtained with a moderate isotacticity up to [mm] ¼ 0.57. A further difference between two Pd catalysts F12–1 and F12–2 was found in the insertion mode of MA: the Pd/IzQO system inserted in a 1,2 fashion, while in the Pd/PS system a 2,1 insertion was observed. Recently, the same group has developed two classes of asymmetric bidentate ligands, each containing a stereogenic phosphorus atom.189 Using a rapid synthetic protocol, a family of Pd/BPMO and Pd/PS catalysts were screened. The highest isotacticity value among late transition metal catalysts was found using the Pd/BPMO system (F12–3, [mm] ¼ up to 0.75), while the Pd/PS system was also moderately stereoselective (F12–4, [mm] ¼ up to 0.67). Both systems were also able to copolymerize propylene with polar allyl comonomers while maintaining their stereoselectivity. It is of interest that the copolymerization reactions using the Pd/BPMO precatalyst F12–3 in fact displayed a greater stereoselectivity than the homopolymerized counterpart. This “comonomer enhanced stereocontrol” was also noted recently by Marks in Zr-catalyzed copolymerization reactions.185 The Nozaki group also developed earth-abundant nickel catalysts for the copolymerization of propylene with polar monomers, which would be especially desired for industrial applications.190 The well-defined nickel precatalysts F12–5 and F12–6, which bear an alkylphosphine-phenolate (PO) ligand, were not able to impart any stereoregularity within the resulting polymer (values of [mm] < 0.20 were obtained). To improve the stereocontrol of the system, a precatalyst bearing a ligand with chiral menthyl groups on its phosphine moiety (F12–7) was synthesized. This allowed for the generation of moderately isotactic polymers and copolymers ([mm] values of up to 0.61) due to increased enantiomorphic site control at a practical temperature of 50  C. A nickel complex F12–8 bearing a bisphosphine monoxide (BPMO) ligand in combination with MMAO was also applicable for the copolymerization of propylene with allyl acetate, although the copolymerization suffered from poor activity and low comonomer incorporation ( 99%), sequence-controlled copolymerization of prochiral polar and non-polar olefins, but also the first example of co-stereospecific alternating copolymerization of any prochiral monomer pairs with distinctly different functionalities, efficiently affording a new family of functionalized polyolefins with precise controlled sequences, unprecedented regio- and stereochemistry as well as improved thermal and surface properties.

424

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

Fig. 12 Palladium and Nickel catalysts for functional isotactic polypropylene.

Polybutadiene and polyisoprene have excellent properties such as high elasticity, good flexibility, low rolling resistance and easy processing, and are widely used in the preparation of tires, gaskets and other materials. Introduction of functional groups such as carboxyl, hydroxyl and silicon groups in the rubber to improve its surface properties such as permeability, wettability, and adhesion are very necessary to reduce the phase separation caused by blending and improve the performance of the material. In 2016, the Mecking group reported that the cationic nickel complex [(mesitylene)Ni-(allyl)+][BArF−4] (F14–1, Fig. 14A) enables the effective copolymerization of butadiene (BD) with alkoxysilyl functionalized dienes with high activity to produce stereoregular functionalized poly-BDs ( 94% 1,4-cis units) with high molecular weights.197 Due to the extraordinary functional group tolerance of F14–1, this approach extends to providing access to highly stereoregular heteroatom (B, N, P, and S) containing poly(dienes) by coordination insertion copolymerization. Remarkably, most of the functional comonomers used are effectively incorporated into the formed polymers, even at low comonomer and high butadiene concentrations. In 2017, the same group investigated the relationship between the different functional groups, linker lengths and polymerization rate constants, monomer reactivity ratios in copolymerizations of BD and polar functionalized dienes catalyzed by F14–1. Although certain linker lengths lead to an unprecedented preference for the incorporation of the polar functionalized diene, all obtained copolymers are stereoregular. Interestingly,

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

425

Fig. 13 Rare-earth catalysts for stereoregular functional polystyrene.

the interaction between the metal center and the polar moieties including PhS- or even PhNH- groups led to favorable copolymerization parameters (during the copolymerization, the comonomer is consumed faster than the butadiene).198 They suggest that this remarkable behavior results from a k-X assisted pre-coordination of the functional group to the metal center based on kinetic NMR experiments with various comonomers and model compounds. This is of significance, as it allows for high percentages of incorporation and complete consumption of the more expensive comonomers. Some functional group tolerance was also reported with a more industrially relevant, Neodymium based Ziegler − Natta system.199 The copolymerizations of butadiene with tertiary amine- and thioether-containing monomers could also be achieved with high efficiency and yielded high-molecular weight polymers with high stereoselectivity. Cui and co-workers demonstrated the efficient cis-1,4 selective copolymerizations of butadiene (BD) with unprotected polar methylthio- and p-tolylthio-functionalized a-olefins by using the thiophene-fused cyclopentadienyl scandium complex F14–2 (Fig. 14B).200 The substituents of the functional a-olefins are critical to govern the performances of the

426

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

Fig. 14 Transition metal catalysts for stereoselective copolymerization of 1,3-dienes with polar monomers.

copolymerizations and the microstructures of the resultant copolymers. The copolymerization of polar 4-methylthio-1-butene (MTB) and BD resulted in both high syndioselectivity and cis-1,4 selectivity. The strong polar MTB coordination −insertion afforded di-block copolymers. By contrast, the copolymerization of 4-(p-tolylthio)-1-butene (pTTB) and BD is more controllable, displaying high activity and syndioselectivity albeit with slightly lowered cis-1,4 selectivity. The incorporation ratios of pTTB in the resultant copolymers could be precisely controlled by monomer feed ratio, suggesting a random microstructure. The Cui group also reported a unprecedented highly cis-1,4 selective (>99%) coordination–insertion polymerization of the polar monomer 2-(4-methoxyphenyl)-1,3-butadiene (2-MOPB) using a b-diketiminato yttrium bis(alkyl) complex F14–3 to afford a hydrophilic plastic polymer P(2MOPB) (Fig. 14C).201 The copolymerization of polar 2-MOPB and isoprene has also been successfully realized to produce a type of highly functionalized cis-1,4 polyisoprene with a wide range of polar monomer contents (8.2%–88.5%) by regulating the monomer feed ratio.

Transition Metal-Catalyzed Copolymerization of Olefins With Polar Functional Monomers

427

13.09.7 Conclusions The incorporation of even small amounts of polar functional groups into polyolefins could significantly improve their surface properties (paintability, printability, etc.) toughness, adhesion, barrier properties, miscibility with other polymers, and rheological properties. The recent advances in this chapter demonstrated the creation of functional polyolefins with enhanced surface and mechanical properties, leading to the formation of useful materials such as thermoplastic elastomers with self-healing and other interesting properties.62,63,136,202 A further advantage is the improved prospect of controlled polymer degradation following the oleolefin’s useful lifecycle if the polyolefin materials contains polar functionalities because of the incorporation of heteroatoms.203–206 Recent advances in transition metal-catalyzed copolymerization of olefins with polar comonomers have demonstrate potentials for the synthesis of various functionalized polyolefins that are inaccessible via other polymerization methods. These advances would trigger future investigations to extend the scope of polar monomers and to explore new type of polymer structures and compositions. Despite these great advances, current catalysts still need to overcome some critical issues before they meet the actual requirements for practical applications, such as activity, incorporation efficiency, controllability over the structure and unclear structure-property relationship. The cost of catalysts and renewability of the feedstocks for the comonomers should also be considered for the sustainable development.

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13.10

Polymerization of Epoxides

Donald J Darensbourg and Gulzar A Bhat, Texas A&M University, College Station, TX, United States © 2022 Elsevier Ltd. All rights reserved.

13.10.1 13.10.2 13.10.2.1 13.10.2.1.1 13.10.2.2 13.10.3 13.10.3.1 13.10.3.2 13.10.4 13.10.4.1 13.10.4.2 13.10.4.2.1 13.10.4.2.2 13.10.4.2.3 13.10.5 13.10.5.1 13.10.5.2 13.10.5.3 13.10.6 13.10.7 13.10.7.1 13.10.7.2 13.10.8 References

Introduction Homopolymerization of epoxides Mechanistic aspects Ionic polymerizations Catalysts for epoxide polymerization Alternating copolymerization of epoxides and carbon monoxide Catalysts for the coupling of epoxides and CO to poly(3-hydroxyalkanoate)s Mechanistic aspects of epoxide/CO polymerization reactions Alternating copolymerization of epoxides and carbon dioxide Mechanistic aspects of CO2/epoxide copolymerization processes Improvement in catalysts Mono-metallic catalysts Bimetallic catalysts Organocatalysts Block copolymers of epoxides/CO2 and other monomers Sequential monomer addition Chain-transfer polymerization Kinetic controlled polymerization Alternating copolymerization of epoxides and anhydrides Alternating copolymerization of epoxides and COS or CS2 Epoxides and CS2 Epoxide and COS Conclusions and outlook

431 432 433 434 434 437 438 439 440 440 441 441 442 445 446 446 447 448 449 450 450 451 453 453

13.10.1 Introduction Epoxides are three-membered cyclic ethers, also known as oxiranes, which are highly important building blocks in organic synthesis. This mainly results from their intrinsically polar bonds and ring strain. For example, epoxides are valuable intermediates in drug design, serving in medicinal chemistry where they react with nucleophiles in ring-opening process to afford new CdC, CdO and CdN bonds.1 More recently, using well-defined metal catalysts, epoxides have been employed in alkene isomerization strategies for accessing trans alkenes from cis alkenes (or vice-versa) by way of stereoretentive epoxidation subsequent to stereoinvertive deoxygenation.2 Similarly, these useful building blocks have been utilized for the synthesis of b-amino alcohols via nucleophilic ring-opening of trans-2,3- disubstituted epoxides or aldol products by regioselective carbonylation of 2,2-disubstituted epoxides.3,4 Polymerization of alkylene oxides, most commonly ethylene oxide (EO), propylene oxide (PO), and butylene oxide (BO) monomers, can be achieved by three different pathways: (i) base-initiated, (ii) acid-initiated, and (iii) coordination polymerization (Scheme 1). The release of ring-strain from the ring-opening of the epoxides is the driving force for polymerization.5 The ring-strain energy in epoxides has been experimentally quantified by measured heat of combustion data coupled with calculated bond energies to be 114.1 kj/mol.6 Hence this strain energy is similar to that of cyclopropane. The annual global production of ethylene oxide and propylene oxide is approximately 30 and 9 million metric tons respectively, with a sizable portion of this being employed in synthesizing polyether polyols for making polyurethanes. Additionally, a large quantity of ethylene oxide is polymerized to polyethylene glycols (PEG), polymers of EO with molecular weight below 30,000 g/mol which are utilized in pharmaceutical and medical applications due to their high aqueous solubility.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00123-2

431

432

Polymerization of Epoxides

O

PEO/PEG n

O

O

O

EO

PO

BO

PPO

O n O n

PBO

Scheme 1 Homopolymerization of epoxides.

In the following sections we will summarize the recent results over the last two decades for the homopolymerization of epoxides, and more importantly, the alternating copolymerization and terpolymerization of epoxides with CO2 and its sulfur congeners, COS and CS2, as well as with other monomers such as cyclic acid anhydrides. Particular focus will include catalyst development, both metallic and metal-free, for regio- and stereo-regular polymer preparations. Special attention will be paid to the progress in synthetic methodology for providing block polymers leading to functional polymeric materials for use in various applications.

13.10.2 Homopolymerization of epoxides When considering the polymerization of propylene oxide or other unsymmetrically substituted epoxides, ring-opening by way of CdO bond cleavage can lead to three regioisomers resulting from the coupling of two repetitive monomers. These are as shown below in Fig. 1. This similarly is true if following epoxide ring opening CO or CO2 addition occurs. Dependent on the nature of the epoxide, catalyst, and reaction conditions, it is possible to provide regio-regular or regio-irregular polymers. The issue of stereoregularity can be illustrated by again considering propylene oxide or similar unsymmetrically substituted epoxides. For symmetrically substituted cis-epoxides, e.g., representative, 2,3-dimethylepoxide or cyclohexene oxide, stereoregularities are as listed below. This is shown in Fig. 2. The homopolymerization of some ubiquitous epoxide monomers, including EO, PO, and epichlorohydrin (ECH), afford a variety of important industrial products. These encompass materials for coatings, surfactants, and polyols for manufacturing urethane foams and other applications, as mentioned earlier, these processes are commonly carried out by anionic and cationic pathways involving alkali metal alkoxides, or Lewis acids such as BF3 or AlCl3 in presence of protic cocatalysts. However in general, these processes lead to low molecular weight polymers with high polydispersities along with a lack of regio-and stereo-regularities. Controlled polymerization reactions are best achieved employing coordinative anionic initiators which provide very clean and highly active processes. This latter process pathway involves substrate monomer activation by binding to the electrophilic metal center. For example, Inoue and coworkers described an aluminum-porphyrin complex for the polymerization of epoxides which

Fig. 1 Regioregularities in the homopolymerization of epoxides.

Polymerization of Epoxides

O

or

R

O

R

R

O

O

or

or

R

R

O

S

O

meso-diads

O

tacticity of these polymers is isotactic

R

O

S

O

O

or

S

n

S

O

S

n

S

R

R

R

O

433

O

R

racemic-diads

O

tacticity of these polymers is syndiotactic

or

S

or

S

O

O

R R

S

R R

S

O

R R

O

S

S

O

O

or

S S

or

s s

n

n

O

O

S S

O

meso-diads isotactic

R R

O

racemic-diads syndiotactic

Fig. 2 Stereoregularities in the homopolymerization of epoxides.

possesses several of the characteristic of living polymerization reactions.7,8 These researchers developed the reaction mechanism for polymerizing epoxides which involves the addition of a protic source to the metal catalyst which leads to chain transfer reactions. They referred to this process as immortal polymerization (Scheme 2).

O (por)Al-OR

(por)Al-OR, + H O

, + R OH

n O

(por)Al O

n OR

x

OR

por = porphyrin

O (por)Al O

, x OR + H

O

degree of polymerization (Dp)

O x

(por)Al O

OR

x OR

+H

O

x OR

,

O

O Dp =

O

(por)Al-OR + R,OH

Dp = (por)Al-OR

NOTE: all equilbria (chain transfer) are rapid and reversible

Living polymerization

Immortal polymerization

Scheme 2 Immortal polymerization of epoxides.

13.10.2.1 Mechanistic aspects At this point it is useful to outline in limited detail the mechanistic pathways involved in the preparation of aliphatic polyethers via ionic polymerization processes. The polymerization reactions of cyclic ethers involve breaking of a CdO bond and the formation of a CdO bond, hence, DH reaction  zero. Ring strain of the cyclic ethers drives the polymerization process, with ring size of x ¼ 3 and 4 having higher ring strain (Eq. 1).

O

I x

O

O

x n

, I = initiator

ð1Þ

434

Polymerization of Epoxides

13.10.2.1.1

Ionic polymerizations

13.10.2.1.1.1 Cationic initiators Classical cationic initiators are Lewis acids, e.g., BF3, AlCl3, TiCl4 or SnCl4. Others are strong acids such as H2SO4 or HClO4. Mechanism

O

O

H O

H

H

O

O

O

HO

O

O

Polyether

O

In a similar process where the proton is replaced by a Lewis acid (LA),

LA O

LA O

O

Polyether

O

O

For cationic processes, termination can occur via rearrangement as depicted below.

H R

O

R

nO

O

nO

+

H

13.10.2.1.1.2 Anionic initiators Typically, highly basic alkali metal alkoxides are employed as initiators. Mechanism

O O RO

O

Polyether

RO For anionic processes, there is no inherent termination step. To terminate polymerization, the addition of a reagent to cap the chain end with a non-reactive functional group is required.

13.10.2.2 Catalysts for epoxide polymerization As alluded to earlier, these ionic polymerization processes generally lead to poor control of molecular weight and polydispersity, whereas, metal complexes can polymerize epoxides via well-controlled living pathways. However, metal-free catalysts are desirable from both an economic and toxicity standpoint. Nevertheless, some of the most robust organocatalysts are not efficient at polymerizing epoxides, e.g., nitrogen bases such as 4-dimethylaminopyridine (DMAP) or 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU). Importantly, the activity of these nitrogen bases toward the effective polymerization of epoxides can be enhanced in the presence of a cocatalyst. This dual catalysis approach is illustrated in Scheme 3, where the Lewis acid can be metal-free or metal based, and is reminiscent of that applied by Bourissou and coworkers for lactone polymerization.9 In addition, this procedure can inhibit the undesirable side-reaction involving the polymer chain-end abstracting of a proton from the epoxide monomer (Eq. 2)

Polymerization of Epoxides

435

LA n PO

O

O

organobase

polyether

LA zwitterionic species

organobase Scheme 3 Dual catalysis approach to polymerization of epoxides.

P

O

+ H H

O

P

O

OH +

ð2Þ

H

Employing this technique, Naumann and coworkers have utilized N-heterocyclic olefins (NHOs) and magnesium bis(hexamethyldisilazide) (Mg(HMDS) to polymerize propylene oxide to prepare very high molecular weight polymers with modest polydispersities.10 Initially these researchers performed a polymerization reaction of propylene oxide at ambient temperature in the presence of 1 and Mg(HMDS)2 at a 1/LA/PO of 1:5:1000. Under these conditions the polymerization went to completion in only 5 min to afford a polymer with a Mn of 61,000 and Đ of 1.47. In order to better assess reaction behavior with changes in catalyst loading, the process was retarded by lowering the temperature to −36  C. As anticipated, the reaction was much slower yet still well-controlled, affording a polyether with molecular weight over 500,000 and Đ of 1.24 for a 1/LA/PO of 1:5:1000 over 3 days. Overall, the polymerization process was dependent on the proportion of Mg(HMDS)2 in relation to NHO and PO. Probes of the reaction pathway by 1H NMR revealed a 1:1 mixture of Mg(HMDS)2 and PO exhibited significantly shifted methylene and methine resonances of the monomer, indicative of a LA/PO adduct, A, with activation of PO followed by NHO ring-opening to afford the zwitterion B (Scheme 4). The zwitterion in B is stabilized by interaction with the magnesium Lewis acid salt. The slow formation of B was evident as seen by an induction period in all polymerization reactions. Needless to say, no polymerization of PO occurred in the lone presence of NHO or LA. The zwitterionic polymerization mechanism was further confirmed by MALDI-ToF analysis of a low molecular weight polymer which clearly displayed NHO derived end group. Similar observations were noted using other NHOs and BO or AGE (allyl glycidyl ether) with the addition of Mg(HMDS)2.

Mg Mg(HMDS)2 N

N

O

N O

PO

N N

1

N

A

nPO

Polyether

Mg

B

Scheme 4 Polymerization of Propylene Oxide via NHO/Mg (HMDS)2.

Naumann, along with his coworker Vogler, have also shown that triethyl borane (Et3B) can serve in a similar but metal-free manner to Mg(HMDS)2 to activate epoxide monomers for ring-opening by various organocatalysts, such as NHOs and nitrogen bases (Fig. 3).11 These organobase/Et3B polymerization reactions of PO were examined in the presence of PEG (8 k) to provide amphiphilic triblock copolyethers as seen in Eq. (3). This process in terms of conversion times and degree of polymerization was significantly better than that noted for conventional anionic polymerization processes. Fig. 4 illustrates the rate enhancement for NHO 1 with varying equivalents of triethyl borane. In all instances, high molecular weight polymers were obtained with very low polydispersities. Similar results were observed employing the organobases 3–7. It is noteworthy that in the presence of Et3B not only is PO polymerization accelerated, but the occurrence of side reactions is greatly reduced.

436

Polymerization of Epoxides

N

N

N

3

2

1

N

N

N

N

N

4

N N N

N

N N

N 7

N 6 DMAP

5 DBU

DABCO

Fig. 3 Organobases for epoxide polymerization.

Fig. 4 Polymerization rates for PO as function of organobase 1 as a function of [Et3B]. From Vogler, C.; Naumann, S. A Simplified Approach for the Metal-Free Polymerization of Propylene Oxide. RSC Adv. 2020, 10, 43389–43393.

O HO-PEG-OH

PO organobase Et3B, 50-80 C solvent-free

amphiphillic triblock copolyether H

O

O n/2

O

O m

H

ð3Þ

n/2

Although amorphous atactic poly(propylene oxide) has numerous important commercial usages, there is a need for the availability of isotactic semi-crystalline poly(propylene oxide) with its enhanced properties for other applications. Inspired by the early work of Jacobson and coworkers on the asymmetric ring-opening of epoxides,12 Coates and coworkers have utilized a bimetallic chromium catalyst to address this issue.13 Using dinuclear complexes of chromium as shown in Fig. 5, these researchers have prepared high molecular weight isotactic poly(propylene oxide)s from racemic-PO with narrow polydispersities via kinetic resolution. For example, in the presence of these bimetallic catalysts along with [PPN]Cl, [PPN]+ ¼ [Ph3PdN]PPh3]+, at 22  C isotactic polymers with molecular weights of 36–68 kDa and Đ of 1.30 were synthesized with excellent stereocontrol. For catalysts with n ¼ 5–6, krel

Polymerization of Epoxides

(R)

(R)

O R

+

N

O S

Cr

N

O

O Cl O

tBu

tBu

(R)

(R)

N

O

O

O

22 οC [PPN]Cl

N

O

O Cl O

n-Cl(n = 4-7)

tBu

Cr

tBu

437

O

+

n

tBu

tBu

Fig. 5 Bimetallic chromium catalysts for PO isotactic polymerization via kinetic resolution.

R

P O

O

Cr

Cr

~6Å Optimal M-M seperation Fig. 6 Metal -metal separation for excellent stereocontrol of PO polymerization.

increased from 42 to 59, decreasing again to 40 for n ¼ 7. Hence there is an optimal CrdCr distance of 6 A˚ as depicted in Fig. 6. It should be noted that the monometallic version of these catalysts was not effective for polymerizing PO. In this study these authors also reported on the use of the chain-transfer agents (CTA) 1, 6-hexanediol with bimetallic (salen) CrOAc catalysts using the [PPN]OAc initiator. Similarly, low polydispersity and isotactic (polypropylene oxide) was produced, with molecular weights decreasing with the [CTA] added. More comprehensive mechanistic aspects of isotactic poly(propylene oxide) (iPPO) formation utilizing bimetallic (salen)CrOAc catalysts in the presence of water and 1,2-propanediol as CTAs have recently been described.14 These studies have identified the induction period noted when employing tethered bimetallic chromium complexes as catalysts for the synthesis of iPPO. Furthermore, it was demonstrated that eliminating water and vicinal diols as CTAs resulted in no induction period. Prior results from these researchers using related bimetallic cobalt and chromium catalyst systems were shown to be less effective at producing (polypropylene oxide) with good control of molecular weight and enantioselectivity.15–17 Relevant to potentially important applications of iPPO, various stereoregular forms of the isotactic polyether were shown to be photodegradable, with Mn decreasing from 93 to 21 kDa following continuous exposure to UVA light (365 nm) over a 30-day period.18 This led the researchers to suggest that iPPO might be a suitable replacement for nylon-6,6 with little long term environmental negative effects.

13.10.3 Alternating copolymerization of epoxides and carbon monoxide Since the last edition of this compendium there has been much attention centered on the coupling of CO and epoxides to provide biodegradable poly(3-hydroxyalkanoate)s (PHAs). Although, there are credible reports of the direct coupling of CO and epoxides to provide these polyesters involving a Co2(CO)8/3-hydroxypyridine catalyst system, this process generally results in low monomer conversion and low molecular weight copolymers.19–21 The synthetic approach utilized for the production of high molecular weight polymers involves in a one-pot first carbonylation of epoxides to cyclic carboxylic esters (lactones), followed by ring-opening polymerization of the b-lactones (Scheme 5).

O O

Direct

+

R

cat

CO

O

R O O

Indirect

+

CO

O

cat 1

R

Scheme 5 Pathways for the formation of PHAs from epoxides and CO.

R

n O

R

cat 2 O

n

438

Polymerization of Epoxides

13.10.3.1 Catalysts for the coupling of epoxides and CO to poly(3-hydroxyalkanoate)s Alper and coworkers, using the Co2(CO)8/3-hydroxy pyridine catalyst system previously reported by Drent and Kragtwijk to afford b-butyrolactone, found it to produce predominantly poly(3-hydroxybutyrate).19,22 This result was later verified by Rieger and coworkers by kinetic studies using in-situ infrared spectroscopy to monitor the reaction’s progress.20,21,23 Nevertheless, Alper developed a related catalyst system for synthesizing a large variety of lactone products (Scheme 6).

Co2(CO)8

OH diglyme @ 80 oC

N

[PPN][Co(CO)4] BF3•Et2O DME or THF @ 80 oC Alper catalyst system

Drent catalyst system Scheme 6 Catalysts employed for coupling of CO and epoxides to form polyesters.

Since these early studies on the direct production of PHAs from CO and epoxides, the focus has been synthesizing these copolymers via the intermediacy of b-lactones. In 2010, Dunn and Coates utilized a carbonylation catalyst accompanied by a polymerization catalyst for the preparation of poly(3-hydroxybutyrate)(P3HB), with the catalyst systems shown in Scheme 7 being the most effective.24 Earlier studies from this research group have shown these catalysts to be active for the two individual steps in Scheme 5, suggesting a one-pot synthesis of P3HBs might be feasible using this approach.25,26 Under the reaction conditions of 50  C in THF at a CO pressure of 5.7 MPa, the molecular weight of the copolymer increased linearly with conversion and Đ remained narrow. High molecular weight isotactic P3HB was synthesized from (R)-PO and CO resulting in a semicrystalline material with all the stereocenters being in the (R) configuration. Confirmation of the copolymer being formed via a two-step pathway was demonstrated by in situ infrared spectroscopy. In related studies, Bildstein and coworkers have reported on chiral indole-imino chromium (III) complexes along with Co(CO)−4 as catalysts for the coupling of rac-PO and CO to afford modestly enantioenriched b-butyrolactone.27

O

+ CO

R

Carbonylation catalyst O Ar N

Ar

Al N Ar

R O

n

Polymerization catalyst

[Co(CO)4]

iPr

OiPr iPr Zn

N N

O

carbonylation catalyst polymerization catalyst

N Ar

iPr

N iPr

Ar = 4-Cl phenyl

O

Scheme 7 Multicatalytic approach for the synthesis of poly(3-hydroxybutyrate).

Recently Yoon and coworkers have addressed the issue of product separation and recycling of homogeneous catalyst systems by employing a heterogeneous [bpy-CTF-Al(OTf )2][Co(CO)4] catalyst for preparing b-butyrolactone from PO and CO, where bpy-CTF is a bipyridine based covalent triazine framework.28 In a related study, Nozaki and coworkers have described the use of an acetyl cobalt complex for the copolymerization of oxetane and CO to afford polymers containing both ether and ester units.29 The reaction pathway was thought to proceed via the intermediacy of a g-lactone.

Polymerization of Epoxides

439

13.10.3.2 Mechanistic aspects of epoxide/CO polymerization reactions Prior to covering the mechanistic details of the copolymerization reactions of epoxides and CO, it is worthy of note that in the early organometallic literature Heck reported various epoxides including EO, PO and cyclohexene oxide (CHO) react with HCo(CO)4 in the presence of CO to afford in excellent yields stable b-hydroxyacyl cobalt tetracarbonyls (Fig. 7).30 These cobalt complexes were isolated as their mono-triphenyl phosphine derivatives, and no copolymer products were identified in these reactions. For the direct coupling of CO and PO to produce PHB mediated by pyridine, the following mechanism is proposed supported via in-situ infrared monitoring of the reaction (Scheme 8A). Coates and coworkers have performed detailed mechanistic studies on the formation of b-lactones from CO and epoxides employing the [(salph)Al(THF)2][Co(CO)4] catalyst system. Specifically, the

OH CH3CHCH2Co(CO)4 Fig. 7 3-Hyroxybutyrate derivative of cobalt tetracarbonyl produced from PO and CO.

Scheme 8 Mechanistic pathways for: (A) Direct alternating copolymerization of CO and epoxides in the presence of pyridine. (B and C). Indirect via coupling of CO and epoxides to b-lactones, followed by ring-opening of lactone to polyester.

440

Polymerization of Epoxides

carbonylation of 1,2-epoxide butane to b-valerolactone was investigated kinetically and shown to be first-order in the aluminum complex and independent of the epoxide/CO concentrations. The particulars of their findings are shown in the mechanistic cycle in Scheme 8B. Earlier studies from this research group have defined the ring-opening polymerization of lactones to proceed via a coordination insertion mechanism (Scheme 8C).

13.10.4 Alternating copolymerization of epoxides and carbon dioxide Among the chemical processes currently under investigation for the incorporation of the greenhouse gas, carbon dioxide, are nonreductive pathways for the production of polycarbonates and cyclic carbonates derived from the coupling of CO2 and epoxides.31–39 The major application of these aliphatic polycarbonates are primarily limited to low-molecular weight polyols to serve as replacement for polyethers used in polyurethane synthesis.40,41 More recently, there have been significant advances in the production of functionalized aliphatic polycarbonates for a wide variety of potential applications.42,43 The late Professor Shohei Inoue and his coworkers pioneered the area of epoxide and CO2 copolymerization in 1969.44,45 This research group utilized a heterogeneous catalyst based on diethylzinc and water for the copolymerization of CO2 and propylene oxide. Since the active catalyst in this study was poorly defined, no definitive mechanistic aspects of this process were attainable. Nevertheless, the polymerization reaction was badly controlled with broad molecular weight distributions, as well as numerous ether linkages in the copolymer chains. The first single site catalyst, an aluminum porphyrin complex coupled with a quaternary organic salt or triphenylphosphine, was reported by Inoue and coworkers, and was shown to provide completely alternating copolymers with low polydispersities.46 However, these catalysts were of low activity. Since this initial single-site catalyst study, numerous more active metal catalyst systems have been reported. These include, zinc phenoxides,47,48 b-diiminate zinc alkoxides,49 metalloporphyrins,50,51 metal-salen or -salan complexes,52–54 and bimetallic macrocyclic derivatives.55 More recently, metal-free catalyst systems have been utilized to synthesis the alternating copolymerization of CO2 and epoxides.56 This compilation will examine the role of these catalyst systems in the completely alternating copolymerization reactions of epoxides and CO2, as well as advances made to greatly enhance the effectiveness of these catalyst networks. In general, the above catalysts behave as living polymerization processes. That is, polymerization reactions with no termination step, where molecular weight of the polymer is linearly related to the percent conversion of monomers, or the number of polymer chains are the same as the number of initiators.57 However, in the copolymerization of CO2 and epoxides there is a disconnect between the theoretical molecular weights and the experimentally determined values. This discrepancy is due to trace quantities of protic impurities in the reactions, primarily adventitious water. Indeed, upon meticulous drying of the reagents in the polymerization process, agreement between the theoretical and observed molecular weights is better achieved.58 Alternatively, control of molecular weights is better achieved by knowing the quantity of protic additives, aka chain-transfer agents (CTAs). As previously discussed for epoxide polymerizations (Scheme 2), an immortal polymerization process occurs in this instance as well. As will be shown, this pathway (also referred to as chain-transfer polymerization) provides a very useful methodology for synthesizing CO2-based block polymers which can be functionalized for various applications (vide infra).

13.10.4.1 Mechanistic aspects of CO2/epoxide copolymerization processes One of the undesirable side reactions which can occur during the synthesis of copolymers from epoxides and CO2 is the production of cyclic five-membered organic carbonates. These cyclic products are provided by a backbiting process, and its preference is dependent on the catalyst, epoxide, and reaction temperature. Similarly, in general the avoidance of ether domains in the polymers is beneficial, except in the instance of PO or EO and CO2 produced polyols for urethane synthesis.59 The accepted mechanistic pathway for the mono-metal catalyzed copolymer formation is depicted below in Scheme 9, where several of these features are common to many catalyst systems. Most of these catalysts operate in the absence of added organic solvents, thereby, making the processes more sustainable.

Polymerization of Epoxides

X M

+

O

X M

X

X M

fast initiation X

O

O X

CO2

CO2 O

O

X M

Polycarbonate

441

rds

X M O

O

O

fast CO2 insertion without prior coordination and independent of [CO2] above 1.0 MPa generally little to no consecutive epoxide ring-opening

O O O

X O X

O O

O

+ X

backbiting cyclic carbonate formation enhanced at high temperature can occur from growing anionic polymer chain as well

Scheme 9 Mechanistic Aspects of the CO2/Epoxide Copolymerization Reaction Utilizing a (Salen)MX/PPNX Catalyst System.

13.10.4.2 Improvement in catalysts Following the initial introduction of single-site catalysts, advances have been made to these systems to enhance catalytic activity and durability, as well as product and stereo-selectivities. This progress has been achieved in several of the catalyst categories which will be individually illustrated in the sections below.

13.10.4.2.1

Mono-metallic catalysts

As mentioned earlier, the Coates and Lu groups have synthesized poly(propylene carbonate)s using (salen)CoIIIX complexes in the presence of onium salts at ambient temperature.58,60 However, at higher reaction temperature this catalytic system leads to an increase in cyclic carbonate product for PO and other aliphatic epoxides. A significant enhancement in catalytic activity at higher temperatures without loss in polymer selectivity of these catalysts has been achieved employing second generation systems which contain the anion initiator attached to the ancillary ligand. Several of these catalysts are illustrated in Fig. 8.61–64 Similar modifications to (salen)CrX and (porphyrin)AlX catalysts have also been reported.65,66 In a ground breaking report, Nozaki and coworkers introduced the addition of aminated arms appended to the salen ligand of cobalt(III) to provide a pathway for proton shuffle between the amine and free copolymer chains. This reversible process provides for controlling chain transfer reactions thereby maintaining 96% selectivity for copolymer production even at 60  C. Inspired by this ligand design, Lee and coworkers synthesized cobalt salen complexes with quaternary ammonium salts bound at the 5-positions. These catalysts were similarly shown to be selective for copolymers at temperatures as high as 90  C and can operate at very low catalyst loadings (e.g., 0.002 mol%), which is 10 times less than the binary (salen)CoX/onium salt systems. Utilizing related catalytic systems featuring an appended bulky amine or quaternary ammonium salt at the 3-position of the salen ligand, Lu and coworkers have provided catalysts capable of enhancing polymer selectivity and activity at temperatures as high as 100  C. This behavior is ascribed to the dissociated growing anionic polymer chain during chain propagation (as shown in Scheme 9) being electrostatically attracted to the catalyst center, thereby, retarding back-biting to cyclic carbonates. A detailed kinetic study of the coupling of CO2 and epoxides for the selectivity of product formation catalyzed by binary and bifunctional catalysts has been described by Lu and coworkers.67 As part of their conclusions, there is a significant increase in the energy of activation for cyclic carbonate production vs that of copolymer in proceeding from binary to bifunctional cobalt(III) catalysts. Additionally, these substituents on the salen ligands of cobalt(III) complexes somehow are stabilizing toward reduction to cobalt(II). In another innovation to the very useful (salen)CoX catalyst system, Nozaki and coworkers have added piperidinyl arms to the 5-positions of the salen ligand while retaining t-butyl substituents in the 3-positions to afford stereo gradient poly(propylene carbonate)s from rac-PO and CO2.68

442

Polymerization of Epoxides

Fig. 8 Metal salen catalysts, first generation (binary) followed by improvements with tethered cocatalysts (referred to as bifunctional) where the later are highly selective for copolymer at elevated temperatures. TOF ¼ turnover frequency.

13.10.4.2.2

Bimetallic catalysts

In Coates and coworkers early investigation of b-diiminate zinc(II) derivatives, they were able to demonstrate via kinetic studies that the most active form of the complexes was a weakly associated dimeric species.69 Consistent with these initial studies, Nozaki and coworkers have employed bimetallic cobalt-salen complexes to illustrate that the copolymerization of propylene oxide and CO2 proceeds by a bimetallic mechanism in the absence of added onium salt cocatalysts.70 That is, based on catalyst dilution rate measurements the bimetallic catalyst remained effective as its concentration was lowered, whereas, its monometallic analog becomes ineffective with a reduction in catalyst loading. However, in the presence of onium salts the bimetallic catalyst displayed monometallic behavior. There was a strong dependence on the linker distance in the bimetallic catalyst, where the (R, R)-(S, S) complex with four methylene units shown in Fig. 9 was most effective.

Polymerization of Epoxides

N

O

N

O

tBu

O tBu

O X

N

R

Co O

N Co

O

O

tBu

443

tBu

tBu

O X

tBu

Fig. 9 Dinuclear cobalt catalyst, R0 ¼ −(CH2)4 −.

N N

Co O

R

O

X

R

X O O

tBu

tBu

Co N

N

R = H or Me X = 2,4- dinitrophenoxide

Fig. 10 Biphenol-linked dinuclear Co(III) catalysts for enantioselectivity control.

In more recent investigations, Lu and coworkers have utilized enantiopure bimetallic cobalt complexes to provide high activity and enantioselectivity for the asymmetric copolymerization of meso-epoxides with CO2 (Eq. 4).71,72 For example, the chiral cobalt(III) complexes (S, S, S, S) where R¼H or Me and X¼2,4-dinitrophenoxide (Fig. 10) in the presence of two equivalents of PPNX were shown in reactions of cyclohexene oxide and CO2 to provide high molecular weight polycarbonates selectively with % ee values greater than 99% (S,S).

O R

S +

CO2

chiral catalyst

O S

O S

O

isotactic polycarbonate

ð4Þ

Williams and coworkers have pioneered studies of dinuclear macrocycle diphenolate tetraamine complexes as stand alone catalysts for the copolymerization of epoxides and CO2. Originally the dizinc complex in Fig. 11 was shown to be among the first catalyst to exhibit modest activity at 0.1 MPa CO2 pressure, with a ToF of 25 h−1 at 100  C.73 This ligand system containing other dimetals was thereafter shown to display similar catalytic activity at 0.1 MPa CO2 pressure, e.g., dimagnesium, dicobalt(II) and diiron(III), where the ToF for Co(II) was enhanced to 161 h−1 at 80  C.74–76 Exhaustive investigation of this copolymerization process by William’s research team have concluded it to involve a chain shuttling mechanism, where the growing polymer chain migrates between metal centers following monomer insertion.77 As might be anticipated, since different metals may be favored for distinct roles in the copolymerization process, it was of considerable interest to investigate mixed metal dinuclear catalysts. Indeed, heterodinuclear Zn(II)Mg(II) catalysts displayed greater catalytic activities than their homodinuclear analogs, thereby suggestive of catalytic synergy.78,79 A mechanistic study of the heterodinuclear Mg(II)Co(II) catalyst for the copolymerization of cyclohexene oxide and CO2 was performed on this catalyst for

444

Polymerization of Epoxides

H

H N

N

O

Zn Zn N X O XN H

H

X = OAc

Fig. 11 Williams Zn(II)2 catalyst.

comparison with their homodinuclear analogs.80 This study showed the greater efficiency of the mixed metal system vs their homodinuclear analogs was due to a lowering of the entropy of activation of the diMg(II) catalyst, and a reduction in the enthalpy of activation of the diCo(II) catalyst. That is, the epoxide is better activated (more strongly coordinated to Mg(II)), while the Co(II) carbonate chain lower the barrier for ring-opening of the epoxide. Carbon dioxide insertion into the newly formed magnesium alkoxide bond and shuttling the anionic polymer chain to the cobalt center followed by epoxide binding to Mg(II) continues the polymer propagation steps. This is illustrated in Scheme 10, where M1 ¼ cobalt and M2 ¼ magnesium.

M1

M2 O O

OP O CO2

M1

M2

O

O

O

O

M1

M2

O

O O

O

O O

OP

O PO Scheme 10 Chain shuttling mechanism for CHO/CO2 copolymerization by a Co(II)Mg(II) catalyst.

M1 = Co(II) M2 = Mg(II)

Polymerization of Epoxides

13.10.4.2.3

445

Organocatalysts

Presently, several studies are being published describing the use of organocatalysts, for the copolymerization of CO2 and epoxides. These catalytic processes are carried out much like the dual catalyst approach presented earlier for the homopolymerization of epoxides to polyethers. Gnanou, Feng and coworkers have synthesized well-defined alternating copolymers of CO2 and PO or cyclohexene oxide (CHO) utilizing triethyl borane as the Lewis acid for activating epoxides along with onium halides or alkoxides to initiate the copolymerization process (Scheme 11).56 For example, reactions performed in THF solvent displayed good reactivity at modest pressures of carbon dioxide (PO: ToF 35 h−1@ 60  C, 0.1 mol%, 1.0 MPa with 85% copolymer selectivity, and CHO: ToF 89 h−1@ 80  C, 0.1 mol%, 1.0 MPa with 99% copolymer selectivity).

O

BEt3 O R1

R2

PPNCl

O

+ BEt3 R1

Cl R1

R2

CHO: R1/R2 =

O R2

BEt3 CO 2

Cl

epoxide

O

O

O BEt3 Polycarbonates

R1

R2 R1

R2

(CH2)4

PO: R1 = H, R2 = CH3

Scheme 11 Copolymerization of CO2 and epoxides using metal-free catalyst system.

Further studies of the mechanistic aspects of this trialkylborane organocatalyzed copolymerization process via DFT computations revealed that the barrier for CHO was slightly lower than PO, consistent with experimental observations.81 Both processes proceed with a lower transition state involving two triethyl borane molecules as depicted in Fig. 12. Well-defined polyols and block copolymers resulting from this organocatalyzed process will be described in a latter section of this compendium.82,83 These researchers have also reported the use of triisobutylaluminum to effectively remove any trace water from CO2 to provide monomodal ultrahigh molecular weight copolymers from CO2 and PO or CHO.84

O B

O O O C O B

O O C O B

VS

Cl

Cl lower

Fig. 12 Transition states for chain-growth in the triethyl borane catalyzed PO/CO2 reaction.

In a subsequent publication, Wu and coworkers employed a bifunctional organoboron catalyst (Fig. 13) to demonstrate the organocatalyzed copolymerization reaction of CO2 and CHO to be easily scalable to the kilogram level, exhibiting enhanced activity at 150  C with a ToF of 4900 h−1 at 1.5 MPa CO2 pressure.85 The rate-determining step of this process was shown by computational studies to involve a boron activated epoxide undergoing ring-opening by the growing polymer chain interacting with the boron-tethered ammonium ion (Fig. 14). This is very similar to what was proposed for the enhanced reactivity and selectivity of the bifunctional metal catalyzed copolymerization processes.35

X n

R3N ethanol, 95 °C

R N R n R X

R

9-BBN THF, 60 °C

Fig. 13 Synthesis of bifunctional catalyst, optimum n value of five. 9-BBN ¼ 9-borabicyclo- [3.3.1]− nonane.

B

n N RX R

446

Polymerization of Epoxides

Fig. 14 Transition-state for bifunctional catalyzed CHO/CO2 copolymerization.

Importantly, the utilization of organocatalyzed copolymerization of epoxides and CO2 are suggested to eliminate the need for polymer purification to remove metal residues, the latter which results in polymer coloration and decomposition issues.

13.10.5 Block copolymers of epoxides/CO2 and other monomers In order to expand the applicability of polycarbonates derived from CO2 and epoxides, it will be necessary to develop synthetic routes for the production of designer block copolymers.43 Presently there are three proven methods for achieving this goal: (a) sequential monomer addition, (b) chain-transfer polymerization, sometimes requiring additional catalysts, and (c) kinetic control polymerization. Examples of these processes are illustrated below. It should be noted here parenthetically that terpolymerization of different epoxides simultaneously with CO2 can lead to various polymer structures and properties, depending on epoxide reactivity (binding and ring-opening), catalytic system, and reaction conditions (temperature and monomer feed).86

13.10.5.1 Sequential monomer addition In several of the catalytic system described, following complete consumption of the initially copolymerized epoxide, addition of a second epoxide can lead to a block sequence. This usually requires the addition of a solvent for the original reaction to proceed to 100% conversion, or alternatively the first epoxide monomer can be removed prior to addition of the second epoxide. An early demonstration of this approach by Nozaki and coworkers involved the copolymerization of PO and CO2 in the presence of a (salen)Co(III) catalyst in 1,2-dimethoxyethane to 100% conversion, followed by the addition of 1-hexene oxide leading to polypropylene carbonate-b-poly hexene carbonate (PPC-b-PHC), Fig. 15.61 Numerous similar studies have been reported utilizing various catalyst systems and epoxide monomers.87–89 Of course, this procedure is not limited to the sequential addition of only two epoxide monomers, but can be replicated several times to synthesize more complex block polycarbonates.90 Williams and coworkers have reported the synthesis of a polycaprolactone (PCL) and poly(cyclohexene carbonate) block polymers using a dizinc complex which serves as an effective catalyst for both ROP of lactones and copolymerization of epoxides and CO2.91 The diblock copolymers were produced in a two-step, one-pot sequence where both lactone and epoxide monomers are simultaneously present in the reaction mixture. CHO initially reacts with a zinc bound carboxylate to afford a zinc alkoxide which catalyzes the ROP of CL. Upon completion of PCL formation, addition of CO2 results in copolymerization of CHO and CO2, resulting in PCL-b-PCHC production. On the other hand, if CO2 is present initially, following formation of PCHC and replacement of CO2 with nitrogen, the second block PCL is afforded. The use of this innovative switchable catalysis pathway for the synthesis of block copolymers has been extended to include the preparation of poly(PCHC-b-e-decalactone-b-PCHC) with varying degrees of the CO2-derived component using a heterodinuclear Zn(II)Mg(II) catalyst. In this manner, ABA triblock polymers were synthesized with promising thermal and mechanical properties for applications covering a wide range of material requirements.92 In related studies involving epoxides as comonomers not incorporating CO2, yet probably amenable to doing so using this catalytic pathway, Diaconescu and coworkers have pioneered the use of redox switchable catalysts for the copolymerization of CHO and L-lactide or b-butrolactone.93 Specifically, these researchers initially employed the zirconium alkoxide complex, (salfan)Zr (OtBu)2 to prepare diblock PLA/CHO copolymers, where the reduced form of the catalyst was active for polymerizing LA and the

O O O Fig. 15 PPC- b- PHC, a diblock polycarbonate.

O

n

Bu O

O m

Polymerization of Epoxides

447

tBu

tBu

N Fe

O Zr

N

OtBu

OtBu O tBu

catalyst

tBu

Fig. 16 Reduced form of catalyst for redox-switchable polymerization process.

oxidized form was active for polymerizing CHO (Fig. 16). Other related metal catalyst systems have been utilized to synthesize diblock polymers containing CHO and lactides or lactones using ferrocene derivatives, generally employing ferrocenium tetrakis(3,5-bis-(trifluoromethyl)phenyl)borate (FcBArF) for chemically oxidizing the complexes for the ROP of CHO.94–96 Similarly, Byers and coworkers have used an iron complex which undergoes oxidation state change between iron(II) and iron(III) to serve as a redox-switchable polymerization catalyst for copolymerizing CHO and lactides using the chemical reductant cobaltocene (Cp2Co).97 Alternatively, these researchers have employed an electrochemical method for switching the ROP of lactide and CHO.98 In other studies of interest, Wu and coworkers have discovered a new type of polymeric material, poly(cyclohexene carbonate)b-poly(N-isopropylacrylamine) (PCHC-b-PNIPAM), which was synthesized using a bifunctional b-diiminate zinc catalyst containing a reversible addition-fragmentation chain-transfer (RAFT ) agent.99 This agent acts as an initiator for the copolymerization of CHO and CO2 followed by the homopolymerization of the vinyl monomer upon addition of a radial initiator. In this manner, several diblock polymers have been prepared, including PCHC-b-PS and PCHC- b- PMMA.100

13.10.5.2 Chain-transfer polymerization An extremely convenient method for producing di-or tri-block polymers derived from epoxides and CO2 involves the addition of water as a chain-transfer agent (CTA) during the copolymerization of epoxides and CO2. This process is particularly effective for triblock polymer formation if the reaction is initiated by a hydrolyzable group e.g., CF3CO−2 (Scheme 12). For example, Williams and coworkers were first to utilize their dizinc complex containing two trifluoro acetates in the presence of a small quantity of water to completely copolymerize CHO and CO2 to provide the telechelic polymer OH-PCHC-OH.101 Upon addition of yttrium amide and lactide to this macrodiol, ROP afforded PLA-b-PCHC-b-PLA (PLA¼polylactic acid). Similarly, in an analogous approach in the absence and presence of water, Wu and coworkers first produced PSC from styrene oxide and CO2 to give PSC-OH and HO-PSC-OH respectively.102 These end-capped hydroxyl groups can then serve as macro-initiators in the presence of DBU to afford PSC- b- PLA and PLA- b- PSC- b-PLA.

O O

+ CO2

O

M X O

M

O

X

O

H2O

M OH + HO

n O

O HO

O

CO2

O O

OH n

M

O

O

O

Telechelic polycarbonate (Dominant polymer if X is hydrolyzable) Scheme 12 Immortal polymerization of Epoxide and CO2.

OH n

O

O

X n

448

Polymerization of Epoxides

The above procedure is readily adaptable for the synthesis of other triblock polymers upon addition of an alternate epoxide,103 cyclic ester,104 or cyclic phosphate105 monomers. For example the ABA triblock copolymers poly(allylglycidyl ether carbonate)b -PPC- b- PAGEC, PCL- b- PCHC- b- PCL, and polyphosphoester-b-PPC-b-polyphosphoester (PPE-b-PPC-b-PPE) have been prepared using this strategy. Relevant to this methodology, incorporation of epoxides with vinyl substituents, such as AGE can be functionalized by thiol-ene click chemistry to provide micelles in aqueous solution.103 Alternatively, polymers bearing hydroxyl chain ends can be fed into a CO2/epoxide copolymerization as a macromolecular chain-transfer agent for the preparation of diblock copolymers. In this manner, Wu and coworkers have reported a new type of diblock material, PS -b- PPC, by the reaction shown in Eq. (5) using a binary (salen)Co(III)/PPNCl catalyst.106 Other polymers similarly prepared include the use of poly(ethylene oxide)107 and polyolefins108 as macro-CTAs. More recently, functionalized CTAs such as protic ionic liquids and metal carbonyl containing diols or dicarboxylic acids have been employed in this manner to prepare di- and tri-block copolymers.109–112

OH m

m

O

O

O

Catalyst

O

O n ð5Þ

+ CO2

13.10.5.3 Kinetic controlled polymerization Kinetic controlled polymerization of a mixture of monomers by a single active catalyst for all monomers presence in the mixture presents a challenging opportunity for the synthesis of block polymers. Nevertheless, this has been achieved by Coates and coworkers for the formation of poly(ester-b-carbonate) diblock copolymers via a one-step, one-pot process catalyzed by a b-diiminate zinc catalyst (Scheme 13).113 This was feasible because the rate of ring-opening of DGA by A was much faster in the polyester formation cycle than CO2 insertion into the metal alkoxide polycarbonate cycle. In situ infrared spectroscopy clearly demonstrated that the anhydride was completely consumed prior to the initiation of polycarbonate formation. Other diblock terpolymers were prepared by an analogous procedure involving CHO, succinic anhydride and CO2, and the functionalizable vinyl cyclohexene oxide, DGA and CO2. Similar kinetically controlled terpolymerization process to afford diblock copolymers have been reported for various other metal catalysts, including chromium(III),114–117 cobalt(III),117,118 aluminum(III),117 di-Mg(II) and di-Zn(II) complexes.119

O

Et O

CHO + O O O DGA + CO2

NC iPr

Et N O Zn O N

O

O

O

O O

iPr

O O

O m

n

Diblock Terpolymer

R O O

[Zn]

O A

Scheme 13 Terpolymerization of epoxide, anhydride and CO2.

More recently, a Lewis-pair organocatalyst has been employed for a one-pot synthesis of diblock copolymers from a mixture of epoxides, anhydrides, and CO2.120 In a one-step route, the diblock terpolymers were obtained with very little tapering. On the other hand, sequential copolymerization of anhydride and epoxides followed by the addition of CO2 afforded a well-defined diblock copolymers.

Polymerization of Epoxides

449

13.10.6 Alternating copolymerization of epoxides and anhydrides Coates, Tolman and coworkers have investigated the alternating copolymerization of epoxides and cyclic anhydrides via kinetic studies and DFT calculations utilizing a binary (salph)AlCl/PPNCl catalyst system (Scheme 14).121 First-order and zero-order dependence was noted on the [epoxide] and [anhydride], respectively. Therefore, epoxide binding at the aluminum center is fast relative to rate-determining epoxide ring-opening by the cocatalyst-associated carboxylate growing polymer chain. DFT computations were supportive of this mechanistic interpretation.

(salph)AlCl

N

N Al

O

tBu

O

BO

Cl

tBu

+ O

PPNCl, 50

O

tBu

O

tBu οC

O

O O n

O

CPMA

O Scheme 14 Alternating copolymerization of epoxides and cyclic anhydrides. From Lidston, C. A.; Abel, B. A.; Coates, G. W., Bifunctional Catalysis Prevents Inhibition in Reversible-Deactivation Ring-Opening Copolymerizations of Epoxides and Cyclic Anhydrides. J. Am. Chem. Soc. 2020, 142, 20161–20169.

As has been noted in epoxide/CO2 copolymerization processes utilizing binary metal catalyst systems, retardation of the epoxide/anhydride copolymerization rates, with an enhancement of side reaction rates, were observed at low catalyst loading. In the former instance, this behavior was shown to be overcome by replacing binary metal catalyst systems with bifunctional analogs.61 Hence, Coates and coworkers designed an easily synthesized bifunctional catalyst for the epoxide/cyclic anhydride alternating ring-opening polymerization process.122 This was accomplished using a modular approach for tethering various amino-cyclopropenium cocatalysts to the diamine backbone of the salen ligand. The result was that the bifunctional catalyst provided high polymerization rates at low catalyst loading ( 0.025 mol%) and prevented transesterification side reactions (Scheme 15). This catalyst system was further shown to avoid inhibition in reversible-deactivation chain transfer in these ring-opening polymerization reactions.123

Scheme 15 Alternating copolymerization of epoxides and cyclic anhydrides by binary and bifunctional catalysts.

450

Polymerization of Epoxides

Williams and coworkers have reported the synthesis of triblock polyester thermoplastic elastomers by first preparing a dihydroxyl telechelic poly (e-decalactone) (PDL, soft-block) using a Zn(II)Mg(II) catalyst in a one pot procedure.124 Upon addition of cyclohexene oxide and phthalic anhydride, ROP provided the polyester (PE, hard-block) end-blocks. These polyester hard-blocks polymer were shown to exhibit wider operating temperature ranges, as well as higher upper service temperatures than their PLA-based analogs. Alternatively, a PDL -b- PCHPE- b- PDL triblock polymers were readily synthesized using ortho-vanillin derived Al(III) and Co(III) catalyst systems.125 This switchable catalysis was carried out in a one-pot method, where the ring- opening copolymerization of epoxide/anhydride is much faster than the ROP of the lactone. Both catalysts displayed tolerance for low catalyst loadings and showed high catalyst activity at 100  C, resulting in triblock polyesters of high molar mass (Mn ¼ 6–57 kg/mol). Comparable catalytic studies involving heterodinuclear catalysts of Zn(II) or Mg(II) coupled with Na(I), Ca(II) or Cd(II) displayed reduced activity for the phthalic anhydride/cyclohexene oxide ring-opening copolymerization process relative to their di- Zn(II) or Mg(II) homodinuclear counterparts.126 This illustrates the lack of synergy provided by heterodinuclear catalysts in this instance.

13.10.7 Alternating copolymerization of epoxides and COS or CS2 Comparative to CO2-based polycarbonates derived from the alternating copolymerization of CO2 and epoxides, the introduction of sulfur atoms into the copolymer backbone via copolymerization of epoxides and COS or CS2 imparts them with attractive features such as optical and thermal properties, chemical resistance, and the ability to sequester heavy metals.127

13.10.7.1 Epoxides and CS2 Early studies of these sulfur congeners of carbon dioxide with epoxides involved copolymerization reactions of carbon disulfide with propylene oxide. That is, Zhang and coworkers employed a ZndCo(III) DMC (double metal cyanide) complex at temperatures 80–130  C for the copolymerization of CS2 and PO to provide low molecular weight (1.2–5.4 kg mol−1), rather broad PDI (1.24–3.50) copolymers with complex random structure sequence (Fig. 17).128 The predominate sequence contained the dSd (CO)dO structural unit, however other structural sequences were present in significant quantities, indicative of much atom exchange during the copolymerization process (Scheme 16).

N

N N

C C Co C C N N C N C

N

N

CA(H2O)

N

Zn

C N C C C Co

OH(Cl)

C C N N

Fig. 17 Proposed coordination around the zinc site in the [Zn]m[Co(CN)6]n DMC heterogeneous catalyst.

X

X O

Catalyst + S C S

X

X

n

X

m +

X = O, S O/S Scrambling Scheme 16 O/S scrambling during the copolymerization of epoxides with CS2.

X

X

Polymerization of Epoxides

451

This initial study was followed by the copolymerization of cyclohexene oxide and CS2 using a very effective (salen)CrCl/PPNCl homogeneous catalyst for the coupling of CHO and CO2.129 Even at 50  C this catalytic system produced copolymers which indicated significant O/S exchange processes had occurred. Furthermore, at 60  C the major product was the cyclic materials with varying sulfur content. The polymer selectivity and yield was optimized at a CHO/CS2 of 1.0 and 50  C. The analogous reaction of CHO and CO2 had been shown to display little tendency for producing the cyclic carbonate product at 80  C due to the ring-strain of trans-5 and 6 membered rings. However, introduction of the larger sulfur atom(s) considerably relieves the strain. Darensbourg and coworkers also examined the copolymerization of another alicyclic epoxide, cyclopentene oxide (CPO), with CS2 in the presence of a (salen)CrX/PPNX catalyst system.130 As noted for CHO, equivalent quantities of CS2 and CPO afforded the best selectivity and yield of polymeric products. Of the 12 cyclic cyclopentene [thio] carbonates possibly produced from the coupling reaction, eight were observed. Interestingly, cyclopentene sulfide was observed as a side product of the copolymerization process, and was shown to be unreactive with CO2 or CS2 under the reaction conditions. Mechanistic aspects of the atom scrambling process were investigated, nevertheless, this process remains poorly understood.

13.10.7.2 Epoxide and COS Presently, much attention is focused on the investigation of a wide range of epoxides with carbonyl sulfide (COS) employing a variety of metal- and organo-catalysts. Noted below in Fig. 18 the regioselectivity of the copolymerization of COS with monosubstituted epoxides are the four possible diads; T-H, H-T, T-T, H-H, whereas the first two are equivalent sequences for the polycarbonates (Fig. 1).

O O O

+

COS

S

CH3

CH3 cyclic product

monothiocarbonate

S

O

CH3

O O

S O

CH3

n

Tail-to-head

S

O

n

CH3

O H3C

S

+

O

O

S

O

CH3 O

n

Head-to-tail

Fig. 18 Regiochemistry possibilities for the copolymerization of COS and PO.

The first reported study involving COS and an epoxide was that of CHO and COS using the ZndCo(III) DMC complex depicted in Fig. 17.131 The afforded poly(cyclohexene monothiocarbonate) had a degree of alternating copolymer of 93% with a Đ ¼ 1.6–2.1. When the reaction was carried out in tetrahydrofuran at 110  C there was little oxygen/sulfur exchange, with only 2% carbonate linkages being observed. Furthermore, unlike the copolymer produced from CS2, the obtained poly(cyclohexene monothiocarbonate) was highly transparent and colorless when purified. In a subsequent study involving the copolymerization of styrene oxide and COS, the chain growth process was shown to be regioselective at the alpha carbon center.132 Hence, chain propagation is driven by the electron withdrawing effect of the phenyl substituent of the epoxide. On the contrary, when the monosubstituted epoxide contains an electron-donating substituent such as methyl group, the anionic sulfur chain-end attacks the less sterically encumbered beta carbon center to yield selectively a tail-to-head sequence.133,134 Most copolymerization processes involving COS and epoxides have utilized homogeneous chromium (III) binary or bifunctional complexes (Fig. 19). However, organocatalysts are also very effective at catalyzing this process.135 Scheme 17 illustrates the reaction pathway to producing copolymers involving either metal or borane centered Lewis acids for epoxide activation. In this manner, COS and PO were copolymerized by a metal-free Lewis pair catalysts to produce poly(monothiocarbonate) with >99% T-H content of high molecular weight (up to 92.5 kg mol−1) with low PDIs in the absence of O/S exchange reactions.

452

Polymerization of Epoxides

R1

R2

N

N

N N Cl N

R

Cr tBu

O tBu

R

tBu

Cr

tBu

O Cl

R

N

N

N Cr

O

tBu

O X

tBu

R

tBu

N

(Salen)CrCl

(tmtaa)CrCl

N N

Ph Ph Ph P N P Ph Cl Ph Ph

Cocatalysts

H N

N

Bi-functional (salen)CrCl

N

PPNCl

TBD

Fig. 19 Common chromium (III) complexes used in the copolymerization of COS and epoxides.

LA O

LA

LB

O

LB O

S C O LA LA = (salen)Cr(III)

S (ii)

LB

O (C2H5)3B

LB = (i) DBU or TBD (ii) Quaternary ammonium( phosphonium) salt Scheme 17 COS/PO copolymerization catalyzed by metal complexes or boranes as Lewis acids.

Numerous epoxide monomers have been copolymerized with COS to yield alternating, high molecular weight poly(monothiocarbonate)s with polymer selectivity >99% and low Đ values in the absence of O/S exchange. These copolymerization reactions have utilized the catalysts shown in Fig. 19 and have included the epoxides listed in Fig. 20. This subject has recently been extensively reviewed by Zhang and coworkers.136

O

O

O

O

O Cl

O

O Ph

O

O

O Ph

Fig. 20 Some of the epoxides successfully copolymerized with COS.

O

Ph

Polymerization of Epoxides

453

Most recently, the synthesis of terpolymers from CHO, CO2 and COS utilizing a dinuclear aluminum catalyst have afforded CO2-based polycarbonates with sulfur atoms randomly dispersed throughout the polymer’s backbone.137 The sulfur content of the polymers could be tuned by varying the CO2 pressure at a constant ratio of CHO to COS. These polymeric materials were shown to possess both high refractive indices, as well as high Abbe numbers (approximate measure of dispersion). This is rarely observed, since there is a general trade-off tendency between these two properties in optical polymers. At this point it is fitting to note that terpolymerization processes in general can represent a strategy for modification of the topological structures of CO2-based polycarbonates to provide polymeric materials with desirable properties, i.e., thermal, optical, ductile vs brittle, etc.

13.10.8 Conclusions and outlook In the past decade impressive advances have been made in the development of well-defined metal catalysts for the homopolymerization of epoxides and the co- and terpolymerization of epoxides with carbon dioxide and its sulfur analogs, as well as cyclic anhydrides. More recent studies for the copolymerization of epoxides and CO2 have lead to the effective evolution of organocatalysts for these reactions, notably organoboron derivatives. These later pathways involving the elimination of metal contaminants in the resulting polymers are particularly important for the production of polymeric materials for applications in biomedical and microelectronic areas. Currently, there is a good understanding of copolymerization reactions of epoxides and carbon monoxide to provide polyesters via the intermediacy of preformed lactones. However, an area where future advances are warranted is to develop catalytic systems which proceed directly to polyesters. Some recent, modest success using this approach has been achieved utilizing organoboron catalysts.138 The use of metal catalysts for the copolymerization and terpolymerization of epoxides and CO2 is well-understood from both synthetic and mechanistic viewpoints, with these aspects being somewhat lacking in the case of organocatalytic systems. Although, presently large scale production of polycarbonates derived from CO2 and ethylene oxide and propylene oxide have commercial value in the synthesis of polyurethanes, other CO2-based polycarbonates have not thus far lead to industrial utilization. However, significant advances in the preparation of block polymers from these monomers provide a platform for the production of a diverse variety of polymeric materials for wide scale use in a range of applications, such as drug delivery, lithography, and microelectronics. Important to this effort are current research studies aimed at better understanding sequence control for the synthesis of polymers containing ether, ester and carbonate linkages.139

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Polymerization of Epoxides

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13.11 Reaction Parameterization as a Tool for Development in Organometallic Catalysis Thomas Scattolin and Steven P Nolan, Department of Chemistry and Center for Sustainable Chemistry, Ghent University, Ghent, Belgium © 2022 Elsevier Ltd. All rights reserved.

13.11.1 13.11.2 13.11.3 13.11.3.1 13.11.3.2 13.11.3.3 13.11.3.4 13.11.3.5 13.11.4 13.11.4.1 13.11.4.2 13.11.4.3 13.11.5 13.11.5.1 13.11.5.2 13.11.5.3 13.11.5.4 13.11.5.5 13.11.5.6 13.11.5.7 Acknowledgment References

Introduction Conventional ligand classification Quantifying ligand electronic properties Tolman electronic parameter (TEP) Ligand electrochemical parameter (LEP) Computed electronic parameter (CEP), molecular electrostatic potential (MESP) and metal-ligand electronic parameter (MLEP) Huynh electronic parameter (HEP) NMR spectroscopy of selenoureas or carbene-phosphinidene adducts and 1J(C-H) coupling constants of azolium salts Descriptors for ligand steric properties Tolman cone angle and the bite angle Percent buried volume Topographic steric maps Analysis of catalyst performance based on parameterization of ancillary ligands Catalytic trends of transition metal complexes bearing monodentate phosphines Parameterization of transition metal complexes bearing monodentate phosphines Catalytic trends of transition metal complexes bearing diphosphines Parameterization of transition metal complexes bearing diphosphines Catalytic trends of transition metal complexes bearing NHC ligands Catalytic trends of transition metal complexes bearing other ligands Parameterization of transition metal complexes bearing other ligands

456 456 461 461 464 466 468 473 475 475 476 482 484 484 486 489 489 491 495 497 498 498

13.11.1 Introduction In coordination and organometallic chemistry the term ligand is commonly used for ions and organic or main group molecules that bind to metal centers to form the corresponding complexes. The nature of the ligand can modulate both the electronic characteristics of the metal center and the steric environment of the coordination sphere, heavily influencing the structure and reactivity of the metal complex. For these reasons, many research groups have focused on the development of models and parameters that permit to explain the extent and type of influence that the main categories of ligands exert on the reactivity as well as on the catalytic and biological properties of metal complexes. In this respect, the growing understanding of the stereoelectronic characteristics of ligands and the nature of the metaldligand bond have enabled chemists to discover new and improved metal-catalyzed reactions for the synthesis of a wide range of organic compounds of pharmaceutical interest or as materials for next generation technological devices (e.g., Organic Light Emitting Diodes, OLEDs). Moreover, the appropriate choice of ligands has allowed for the isolation and study of key intermediates for important catalytic reactions, offering valuable information on how to improve these processes both in terms of yield and operating conditions that can guarantee greater environmental sustainability.1 In this chapter, after a brief summary on the conventional classification of ligands, we propose an overview of the most commonly used parameters for ligand design and how these descriptors represent a powerful tool for interpreting and sometimes predicting the efficiency of homogeneous catalysts.

13.11.2 Conventional ligand classification According to Crystal Field Theory (CFT)2 and Ligand Field Theory (LFT),3 developed by Bethe and van Vleck in the 1930s and by Griffith and Orgel in the 1950s, respectively, ligands often play a decisive role on the geometry and electronic configuration of transition metal complexes. Depending on the type of effect on the energy of the d orbitals of the metal, ligands are traditionally classified as weak- and strong-field ligands. In particular, using octahedral complexes as a model, p-donating ligands such as halides and alkoxides behave as weak-field ligands as they reduce the energetic difference between the t2g and eg orbitals (DO). The reduced energy gap favors high-spin configurations (Fig. 1). Conversely, p-acceptor ligands such as imines, bypyridines, CO and CN− act as strong-field ligands by increasing the energy gap between the t2g and eg orbitals, favoring low-spin configurations (Fig. 1).

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https://doi.org/10.1016/B978-0-12-820206-7.00088-3

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Fig. 1 Strong-field and weak-field ligands in octahedral complexes and spectrochemical series.

Using appropriate spectroscopic methods, it is possible to determine the DO and then order the ligands in the well-known spectrochemical series (Fig. 1).2 In this regard, it must be remembered that this ranking remains substantially unaltered if we consider tetrahedral or trigonal bipyramidal complexes. As previously stated, the ligand field strength can also affect the geometry of transition metal complexes. The typical case is represented by tetracoordinate complexes with first-row transition metals, in which strong-field ligands favor the formation of 2− square planar species (e.g., Ni(CN)2− 4 ), whereas weak-field ligands favor the tetrahedral geometry (e.g., NiCl4 ). Another traditional way to classify ligands is based on the type of electronic pairs used for the formation of the metaldligand bond. According to the Covalent Bond classification, neutral two electron donor species and anionic two electron donor species (or single electron donors) are cataloged as L-type and X-type ligands, respectively.4 Using this formalism, carbenes and phosphines are then considered L-type ligands whereas halides, alkoxides and alkyl/aryl groups are considered X-type ligands. Electron-poor compounds such as neutral boron-based species (e.g., BH3, BX3 and BR3) are called Z-type ligands (or zero-electron donors) by virtue of their ability to act as Lewis acids toward the metal center, receiving electron density through the formation of the covalent bond. Numerous ligands can be described as a combination of L and X character, oftentimes resulting from the analysis of the X-ray structures of the corresponding complexes. In this respect, Z3-allyls, Z5-cyclopentadienyls and Z6-arenes are classified as LX, L2X and L3-type ligands, respectively (Fig. 2). If the same atom behaves as both L-type and X-type donor, the metaldligand bond can be formally considered as a double bond. In this context, some amide and alkoxide species bind to the metal center as LX-type ligands. Depending on the symmetry of the orbital used by the ligand to donate electron density to the metal center, it is possible to divide them into s- and p-donor ligands.

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Fig. 2 Representation of L, X, Z, LX, L2X and L3-type ligands (top) and differences between s- or p-donor and p-acceptor ligands (bottom).

As we will see in detail in the following paragraphs, the strength of this interaction depends not only on the stereoelectronic characteristics of the ligand but also on the nature of the metal and its oxidation state. As a matter of fact, it is important to remember that ligands possessing empty p or p orbitals, in the presence of an electron-rich metal center, can act as p-acids, draining electronic density from the metal and strengthening this MdL bond. This important phenomenon is known as p-backdonation (Fig. 2). The strength of the metaldligand bond often heavily affects the reactivity of the complex under examination. A classic example is represented by the ligand substitution reactions in square planar d8 complexes. The presence of strong s-donor or p-acceptor ligands in trans position with respect to the ligand that undergoes the substitution reaction considerably increases the rate of this process. This kinetic effect is known as the trans effect (Fig. 3).5 A crucial role in homogeneous catalysis as well as in biochemistry and material sciences is played by polydentate ligands. These species have two or more donor atoms which act as an anchor point for one or more metal centers. In this context, the most frequently used species are the chelating ligands since, due to the chelate effect,6 they increase the stability of the complex and at the same time allow to modulate the coordination environment by acting on the type of donor atoms, the linker between the donor atoms and wingtype groups. The use of chelating ligands allowed the synthesis of a large number of complexes that have good stability under catalytic conditions7 or in the biological environment in the case of metallodrugs.8 An important parameter that characterizes the chelating ligands is the bite angle, which represents the angle between the two donor atoms and the metal.9 This parameter can be experimentally determined from X-ray diffraction data as well as simulated by molecular mechanics calculations.10

Fig. 3 Example of trans-effect in substitution reactions.

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Table 1

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Influence of bite angle of diphosphine ligands in the hydroformylation of 1-Octene (octane/Rh = 674, ligand/Rh = 2.2, [Rh] = 1.78 mM)

. Ligand

Calculated bite angle ( )

Normal/branched aldehydes

TOF (s−1)

DPEphos Thixantphos Xantphos BISBI

102.2 109.4 111.7 122.6

6.7 41 53.5 80.5

250 445 800 850

From Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081–3089

As we will see in detail in the section dedicated to diphosphine ligands, the bite angle often has a profound effect on the reactivity of complexes used as homogeneous catalysts. One of the classical cases deals with the increase in reactivity of Rh(I) hydroformylation catalysts using diphosphine ligands with high bite angle values (Table 1).11 Within the macro-category of chelating ligands, the pincer-ligands are particulary worthy of mention. These involve three adjacent donor atoms and ensure high stability of the corresponding complexes by virtue of their rigid structure and strong binding. Although a wide range of pincer ligands combining B, C, N, O, Si and P donor groups are known, one of the most used motif consists of two lateral L-type ligands (e.g., phosphines) and a central cyclometallated aryl group (Fig. 4).12 In order to obtain polydentate ligands that can easily liberate at least one coordination site, the use of polydentate ligands that contain both strong and

Fig. 4 Example of a Co(II) Pincer complex and its reactivity toward NO (top). Example of an enantiomeric hydrovinylation with a chiral hemilabile P,O ligand (bottom).

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weak donor groups is extremely important. These hemilabile polydentate ligands ensure good stability of their derivatives and at the same time enable the coordination and activation in solution of a substrate of interest. For example, it is well-estabilished that hydrovinylation processes can occur with surprisingly high enantiomeric excesses when chiral hemilabile P,O ligands are employed (Fig. 4).13 A fundamental distinction that is made every time the reactivity and the catalytic or biological properties of a given complex are examined is that between ancillary and reactive ligands. Reactive ligands undergo dissociation or irreversible transformations when the complex interacts with a given substrate. Conversely, ancillary ligands (or supporting ligands) modulate the reactivity of the complex both from the steric and electronic point of view without undergoing dissociation or irreversible transformations. Classical examples of supporting ligands are tertiary phosphines and N-heterocyclic carbenes which, by virtue of their soft character (see Pearson Acid and Bases Concept14), form very strong bonds with most common transition metals used in homogeneous catalysis, especially with those in relatively low oxidation states (e.g., Pd(0)/Pd(II), Rh(I), Ru(II) Au(I) and Cu(I)). It is important to remember that the same ligand can act as an ancillary ligand or as a reactive ligand depending on the nature of the substrate interacting with the complex. For example, the behavior of Pd(II)-Z3-allyl, palladacyclopentadienyl and Pd(0)-Z2-olefin complexes in the presence of different substrates is presented in Fig. 5. It is worth mentioning that these organometallic fragments have been studied both for the synthesis of well-defined homogeneous catalysts15 and for the design of new promising anticancer agents.16 As highlighted in Fig. 5, the allyl fragment acts as an ancillary ligand in the reaction of complex 1 with triphenylphosphine (displacement of the labile pyridine arm) to form complex 1a.17 Conversely, the allyl fragment acts as a reactive ligand if the same complex is reacted with piperidine in the presence of a stabilizing olefin such as dimethyl fumarate (dmfu) yielding complex 1b (N-allylation process).17 Similarly, the olefin and palladacyclopentadienyl fragments in 3 and 2, respectively, can also act as reactive or ancillary ligands according to the reactions reported in Fig. 5.18 We next focus on the broad category of ancillary ligands, examining in detail how their stereoelectronic characteristics can be determined experimentally and/or by theoretical calculations and how these features have a fundamental influence on the catalytic activity of the corresponding metal complexes.

Fig. 5 Influnce of substrates in the ancillary and reactive ligands definition.

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

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13.11.3 Quantifying ligand electronic properties As already stated in the introductory sections (Sections 13.11.1 and 13.11.2), the electronic features of the ancillary ligands present on a given metal complex heavily influence its electronic structure, geometry, reactivity and consequently its catalytic and/or biological properties. In contrast to steric effects, which can be intuitively and qualitatively estimated by the Lewis formula or by the three-dimensional representation of the ligand within the complex by simple theoretical calculations or by X-ray diffraction data, electronic effects are often very difficult to predict as it is necessary to take into account the inductive and mesomeric effects of the various substituents bound to the donor atom. These effects can be synergistic or, very frequently, antagonistic making it very difficult to define which effects are predominant. For all these reasons, in order to quantify the donating and/or accepting abilities of the ancillary ligands most commonly used in organometallic chemistry and in homogeneous catalysis, several parameters have been developed.

13.11.3.1 Tolman electronic parameter (TEP) From a historical perspective, the most commonly used descriptor to define the electronic characteristics of an ancillary ligand is the Tolman Electronic Parameter (TEP).19 In his seminal work, published in 1970, Chadwick Tolman proposed to quantify the electronic effects of the ligand of interest (L) by experimentally determining the value of the A1 carbonyl IR stretching frequency for the tetrahedral complex [Ni(CO)3L], which is typically obtained by reacting the precursor [Ni(CO)4] with one equivalent of the ligand in tetrahydrofuran at room temperature. This parameter, originally developed for tertiary phosphine ligands, is correlated to the electron density on the metal center. In particular, the introduction of ligands that increase the electron density on the metal entails a strengthening of the metaldcarbon bond by p-backdonation on the p -CO antibonding orbital and a consequent decrease in the carbondoxygen bond order. Conversely, if the ligand depletes the metal center of electron density, there will be a smaller degree of p-backdonation and a strengthening of the carbondoxygen bond. Hence, strongly electron-donor ligands exhibit lower TEP values than electron-acceptor ligands. As for the phosphine ligands, which have been and continue to be extensively studied and employed for the preparation of a wide range of efficient homogenous catalysts,20 the TEP values increase starting from the highly electron-donating trialkylphophines (e.g., PCy3) through triarylphosphines (e.g., PPh3) and phosphites (e.g., P(OEt)3) to PF3 (see Table 2).21 It is worth mentioning that the TEP value for the free CO is 2143 cm−1. It is important to remember that one of the first systematic studies concerning the synthesis and spectroscopic characterization of metal-carbonyl complexes bearing phosphine ligands was published by Strohmeier and colleagues in the late 1960s.22 In their work, in addition to the already mentioned nickel complexes [Ni(CO)3(PR3)], also [Mn(CO)2(Cp)(PR3)], [V(CO)3(Cp)(PR3)] and [Fe(CO)4(PR3)], regardless of the coordination geometry, showed a lowering of IR frequencies of carbonyl ligands in the presence of more electron-donating phosphines. The idea of correlating the donor-acceptor properties of ligands to the IR frequencies of carbonyl groups in [Ni(CO)3(L)] complexes was exploited almost 30 years later by some research groups, which experimentally determined the TEP values for some 20 N-heterocyclic carbenes (NHCs).23 This fascinating class of ancillary ligands has become extremely popular in the last 20 years by virtue of their ability to strongly stabilize most late transition metals but also main group centers. These metal-NHC complexes are currently used and studied in various fields such as homogeneous/heterogeneous catalysis,24 medicinal chemistry25 and material sciences.26 Their good stability to air and moisture has allowed these compounds to become viable alternatives to phosphine derivatives and so much more. All of these attractive properties have stimulated researchers to develop different synthetic strategies for their preparation.27 In this context, the most intriguing, modern and above all sustainable approach concerns the direct reaction of the azolium salt and the metal precursor of interest in the presence of weak bases such as potassium carbonate, sodium acetate or triethylamine in extremely mild conditions and using technical grade green solvents (e.g., acetone, ethyl acetate and ethanol).27,28 This approach, known as weak-base route, allows to synthesize in a Table 2 IR stretching frequencies (TEP) of the carbonyl ligands in [Ni(CO)3L] complexes bearing phosphine ligands.21,22 Phosphine ligand

TEP (cm−1)

PCy3 PiPr3 PnBu3 PEt3 PMe3 PBn3 PPh3 P(OEt)3 P(OMe)3 P(OPh)3 PPhCl2 PCl3 P(CF3)3 PF3

2060 2062 2064 2066 2066 2068 2070 2077 2080 2087 2092 2103 2107 2110

From Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081–3089

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

single step, with high atom efficiency and under air the complexes of interest in high yields and purity. Some of these can be used to directly determine electronic parameters (see below). The weak-base approach has so far been very successful only for the synthesis of some limited categories of Late Transition metal-NHC complexes. For this reason, the classical transmetallation29 and free carbene30 routes are still widely used. The latter involves the preparation of the free carbene ligand which is then reacted, in a successive step or in situ, with the metal precursor of interest. The seminal work of Arduengo30 from the early 1990s showed how some of the NHC ligands are sufficient stable even in solution, by virtue of the p-donation of the nitrogens on the empty p orbital of the carbene carbon and the high steric hindrance that can be achieved by appropriately choosing the R substituents present on the nitrogen atoms. In some of the first published articles on the subject, the synthesis and spectroscopic data of [Ni(CO)3(NHC)] complexes were reported.31,32 Although the IR spectra have sometimes been recorded in different solvents (e.g., hexane and THF), it is certainly possible to state that these ancillary ligands are generally more electron-donors than classical tertiary phosphines. As a matter of fact, the TEP values shown in Fig. 6 are decidedly lower than those determined for the analogous phosphine complexes. These data are the result of the studies conducted by Nolan and co-workers on the well-known IPr, SIPr, IMes, SIMes, ICy, IPent, IHept, INon and on Marko-type ligands (IPr and IPr OMe).33–37 An important observation concerns the lower TEP values of unsaturated NHCs compared to saturated congeners. Although saturated NHCs are more efficient s-donors,38 they tend to more efficiently promote the p-backdonation from the metal center than their unsaturated analogs. It is precisely the greater backdonation that contributes to making the TEP values of saturated NHCs higher. Furthermore, in Fig. 6 it is also possible to observe how the NHCs bearing alkyl groups (e.g., ICy) are slightly more electron-donors than those containing aryl groups (e.g., IPr).

Fig. 6 TEP (cm−1) of some NHCs determined from the corresponding [Ni(CO)3L] complexes.31–37

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

463

Fig. 7 Synthetic routes to [Ir(NHC)(CO)2Cl] complexes.39–41

The major drawback of the classical method to determine the TEP concerns the difficulty or impossibility of isolating nickel complexes with NHC ligands other than those mentioned so far (see Fig. 6). An emblematic case concerns the IAd and ItBu ligands, which lead to the formation of the [Ni(CO)2(NHC)] species compared to the classic tricarbonyl ones.33 Although these compounds are interesting and convey the idea of the high steric hindrance of these ligands, they are not suitable for the determination of TEPs. Moreover, the high toxicity of Ni(0)-carbonyl precursors, and their difficulty in being manipulated, have prompted some research groups to turn to iridium and rhodium derivatives which are decidedly less toxic, more accessible and easier to prepare. As for the iridium complexes, those with the general formula [Ir(NHC)(CO)2Cl] have been extensively studied and then taken as a model. In this respect, starting from the work of Crabtree and co-workers in 2003,39 these Ir(I) complexes have been synthesized with a wide range of different NHC ligands according to the synthetic approaches illustrated in Fig. 7. By far the most used strategy concerns the preparation, by means of the aformentioned free-NHC, transmetallation and weak-base routes, of [Ir(NHC)(COD)Cl] species and their subsequent exposure to an atmosphere of carbon monoxide. A variant on the theme is represented by the use of the dimeric precursor [Ir(CO)2Cl]2. The final [Ir(NHC)(CO)2Cl] complexes present a cis geometry and what is conventionally determined, unlike the tetrahedral nickel complexes, is the average of the two carbonyl stretching vibrations. In the same way, numerous complexes of this type have also been prepared using phosphine ligands.42 From the spectroscopic data of the phosphine complexes [Ir(PR3)(CO)2Cl] it was possible to confirm a linear correlation between the average value of the carbonyl bands frequencies and the TEP determined from the [Ni(CO)3(PR3)] species (Eq. 1).39 h i ~ AV ðIrÞ + 593 cm −1 TEPphosphine ¼ 0:722
V (1) Until 2008, this equation was also used to determine the TEP values of NHC ligands. In this respect, the works published by Crabtree and Glorius on the electronic properties of abnormally (via C5) vs normally (via C1) bound imidazolylidenes and bisoxazoline-based (IBiox) NHCs, are particularly worthy of mention.43,44 In particular, it was observed that the abnormal imidazolylidenes are significantly more electron-donating than the normal imidazolylidenes.43 Within this context, as reported by Bertrand and co-workers in 2005, another class of carbenes significantly more electron-donor than the normally bound imidazolylidenes is represented by the cyclic (alkyl)(amino) carbenes (CAACs).45 The studies conducted by Plenio in 2007, however, showed that Eq. (1), despite being valid for phosphine ligands, it does not correctly describe complexes bearing NHC ligands.46 This evidence is attributable to the greater electron-donor character of NHCs compared to phosphines which makes their TEP values not predictable from Eq. (1). Nolan proposed a new equation that is in good agreement with the data for the most commonly used N-heterocyclic carbenes (Eq. 2).47 h i ~ AV ðIrÞ + 336:2 cm −1 TEPNHC ¼ 0:8475
V (2) This equation is therefore currently used to calculate the TEP of NHC ligands starting from [Ir(NHC)(CO)2Cl] complexes. In 2009, Plenio and Wolf were the first to propose the use of Rh(I) complexes of the type [Rh(NHC)(CO)2Cl] as probes to measure the TEP values of carbene ligands.48 In this case, the authors proposed, by means of a linear regression, an equation that ~ CO frequency with that determined for the of Ir(I) counterparts (Eq. 3). correlated the average V h i h i ~ AV ðIrÞ ¼ 0:8695
V ~ AV ðRhÞ + 250:7 cm −1 V (3) ~ AV(Ir) has been calculated from this equation, it is possible to use Eq. (2) proposed above to obtain the TEP of the Once the V carbene ligand of interest. In this respect, a comparison between the Rh(I) and Ir(I) methods to determine the TEP values for some of the NHCs investigated is presented in Fig. 8. The use of Rh(I) complexes as probes, by virtue of their good stability to air and moisture, has become by far the most popular method to first determine the electronic characteristics of a NHC ligand. However, this approach, similarly to Ni(II)- and Ir(I)-based systems, has severe limitations and disadvantages. First of all, being methods that are based on FT-IR spectroscopy, they refer to bands rather than peaks and have limited resolutions (ca. 2 cm−1) both in the solid state and in solution, which often produce

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Fig. 8 Examples of IR stretching frequencies of the carbonyl ligands in [Ir(NHC)(CO)2Cl] and [Rh(NHC)(CO)2Cl] complexes bearing NHC ligands and their calculated TEP values (in DCM).39–48

broadening of the observed signals. Another severe limitation concerns the well-known dependence, for the same carbene ligand, between the vibration frequency of the carbonyls and the type of halogen on the metal center. This evidence is known as the halido effect and for this reason it was decided to carry out the measurements strictly with chloride as a supporting ligand.49 A very important aspect concerns the type of spectrometer used and the sample preparation method (e.g., KBr pellets, neat with ATR technology, Nujol suspensions or in solution). The typical case concerns the measurements carried out in solution. They can only be compared with each other if the same solvent is used (typically dichloromethane). Both TEP and Rh/Ir variants involve the use of toxic compounds such as Ni(CO)4 or carbon monoxide. A conceptual problem in the use of the TEP concerns the fact that this parameter does not provide for the separation of donor and acceptor contributions. As a matter of fact, it examines the amount of p-backdonation from the metal center to the carbonyl ligands, which is strictly influenced by the donor/acceptor power of the ligand L. For ligands such as phosphines, in which the s-donor and p-acceptor characters are usually inversely proportional, the TEP represents a good overall indicator of their electronic properties. Conversely, for ligands in which this inverse proportionality is not respected, the lack of separation of donor and acceptor contributions makes TEP values more difficult to interpret and often can provide misleading information. Finally, the most important failure of TEP and the other carbonyl-based methods concerns the impossibility of estimating the electronic characteristics for most of Werner-type ligands. For example, it is well known that pyridines and amines do not react with [Ni(CO)4]. For all these reasons, although TEP still remains a parameter widely used by the scientific community, other spectroscopic, computational and electrochemical methods have been developed in order to replace and/or complete the information that can be obtained from carbonyl-based systems.

13.11.3.2 Ligand electrochemical parameter (LEP) In the early 1990s, Lever introduced a new electronic descriptor, known as the Ligand Electrochemical Parameter (LEP), which correlates the donating power of a ligand to the redox potential of the corresponding transition metal complexes. In this respect, the most commonly used redox couple is Ru(II)/Ru(III).50,51 This parameter has been widely used to estimate the electronic properties of Werner-type ligands (mainly O, N, S, halido and pseudohalido donors) which, as previously stated, cannot often be determined with the TEP and other carbonyl-based methods. Conversely, electrochemical studies and the corresponding experimental LEP values are less frequent for N-heterocyclic carbene and phosphine ligands. The LEP (V) values that are determined from the

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465

electrochemical potentials of a certain redox couple according to Eq. (4), although are not a direct measure of ligand donor strength, reveal the ability of a ligand to stabilize a metal in a certain oxidation state. Therefore, ligands with low LEP values tend to better stabilize the higher oxidation state of the metal than ligands with higher LEP values. Eq. (4) shows the parameters Sm and Im which depend on the metal center (e.g., Sm ¼ 0.97 and Im ¼ 0.04 for the Ru(II)/Ru(III) couple), the redox potential E and the sum of the LEP parameters that characterize each ligand present in the complex.50,51 X  E ¼ Sm
LEPðLÞ + Im (4) For example, the calculated LEP values for some of the most commonly encountered ligands in coordination and organometallic chemistry are reported in Table 3. One of the few experimental studies concerning the determination of LEP for NHC ligands was conducted by Albrecht and colleagues in 2006.52 In this study, a general LEP value of 0.29 was determined for imidazolin-2-ylidenes, with the assumption that there is no influence of the substituents on the nitrogen atoms. These data were determined for the Fe(II)/Fe(III) couple in complexes of the type [Fe(NHC)(CO)2(Cp)]+. The fact that the observed LEP value is very similar to that of pyridine can be explained by the significant p-backdonation from electron rich Fe(II) centers to the NHCs. Apart from Albrecht’s work, there are few examples of LEP values determined specifically for NHC ligands. Conversely, a number of studies have been reported that focus on the electrochemical potentials (E1/2) of ruthenium and Ir(I)/Rh(I) complexes of the type [M(NHC)(COD)Cl] (M ¼ Rh, Ir).48,53,54 Fig. 9 shows some of the redox potentials obtained in dichloromethane, with tetrabutylammonium hexafluorophosphate as electrolyte, for [Rh(NHC)(COD)Cl] complexes.48 With the same approach as for the LEP parameter, more strongly donating ligands lead to lower E1/2 redox potential values. One of the main drawbacks of the LEP parameter concerns the possibility of studying only complexes that exhibit reversible or quasi-reversible redox processes. Furthermore, those complexes that decompose during measurement as well as those complexes that contain non-innocent ligands, which significantly interfere with the redox process involving the metal center of interest are particularly difficult to study.

Table 3

LEP (V) values for some common ligands.50,51

Ligand

LEP (V)

Ligand

LEP (V)

1.9 0.99 0.8 0.68 0.53 0.39 0.25 0.07 0.04

CN Br− Cl− I− F− OH− NO− H− SiMe−3

0.02 −0.22 −0.24 −0.24 −0.42 −0.59 −0.75 −0.76 −0.90

+

NO CO Z2-H2 s-N2 CH2 PPh3 NMe3 NH3 H2O

−

Fig. 9 Examples of E1/2 (V) of [Rh(NHC)(COD)Cl] complexes in CH2Cl2 with Bu4NPF6 as electrolyte.48

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

These reasons, combined with the often poor availability of electrochemical setups compared to the use of spectroscopic techniques (e.g., NMR and IR), justify the rare use of redox potentials as a tool to determine the electronic properties of the ancillary ligands most commonly used in organometallic chemistry and homogeneous catalysis, yet this we feel is about to change as these devices are now being popularised.

13.11.3.3 Computed electronic parameter (CEP), molecular electrostatic potential (MESP) and metal-ligand electronic parameter (MLEP) In the previous sections, we have discussed in detail the TEP and LEP parameters, which are used in organometallic and coordination chemistry, respectively. These descriptors have been presented up to now as experimental measures starting from transition metal complexes synthesized in the laboratory. However, almost parallel to the experimental measurements, theoretical models have been developed, based mainly on quantum chemical methods, in order to simulate the experimental data and therefore predict those data not yet obtained in the laboratory, often due to poor stability or to difficulty of isolation for some metal complexes. In their seminal work, Clot and co-workers performed DFT (B3PW91) calculations to predict the A1n(CO) vibration of [Ni(CO)3L] complexes for a wide range of ligands.55 This theoretical descriptor, known as Computed Electronic Parameter (CEP), proved to correlate well with the experimental TEPs, LEPs and sm (Hammett) constants. In Table 4, we report the CEPs and the corresponding TEP, LEP and sm values for some of the studied ligands. For example, from a regression analysis, the following correlation (Eq. 5) was determined between the TEP and CEP values (cm−1) for the most common phosphine ligands: TEP ¼ 0:9572
CEP + 4:081

(5)

Similarly, a linear correlation between CEP (cm ) and LEP (V) was determined for many of the examined ligands. This relationship (Eq. 6) was obtained by excluding hydride and nitrosyl ligands from linear regression.55 −1

LEP ¼ 0:001246
CEP − 26:619

(6)

Finally, in the same article the correlations between Hammett constants (sm) and CEPs, TEPs and LEPs were determined (Eqs. 7–9). With this approach it is possible to exploit the Hammet constants of several ligands in order to obtain information on the IR spectra and on the electrochemical behavior of the corresponding metal complexes. sm ¼ 0:01008
CEP − 20:934

(7)

sm ¼ 0:01053
TEP − 20:977

(8)

sm ¼ 0:819
LEP + 0:602

(9)

It is surprising to note a good correlation (R ¼ 0.97) between CEP and sm, since the determination of the latter does not involve the presence of the metal center. In summary, from the CEP values reported in Table 4, it can be seen that the net donor character of a ligand strongly depends on its charge. Anionic ligands are in fact much better donors than neutral ones, which in turn are better donors than cationic ones. Among the neutral ligands, the least donating is CO, followed by fluorides of Group 15 (BiF3, AsF3, SbF3 and PF3), Z2-H2, amines (e.g., NMe3), phosphines (e.g., PMe3) and NHC ligands (e.g., IMe and SIMe). Therefore, the greater net donor character of NHCs compared to the most common phosphines is also confirmed by computational methods. In 2009, Gusev, using a MPW1PW91 functional, ranked a large number of two electron donor ligands based on: (1) calculated carbonyl stretching frequencies and CO distances in [Ni(CO)3L], [Ir(L)(CO)2Cl] or [Ir(L)(CO)(Cp)] complexes; (2) enthalpies in ligand exchange reactions; (3) Z2-bond enthalpies and bond distances in [Ir(L)(Cp)(Z2-C2H4)] or [Ir(L)(Cp)(H2)] species.56 In the same year, Gusev reported the calculation of carbonyl stretching frequencies in [Ni(CO)3L] complexes for 76 different NHCs and their correlation with two important calculated parameters such as the CO elimination enthalpies, DH (kcal
mol−1) and Ni-C distances (A˚ ) in the final [Ni(CO)2(NHC)] derivatives (see Fig. 10).57 In all cases examined so far, despite the theoretical values of the CO stretching frequencies differing from those measured experimentally, it should be emphasized that an excellent correlation between experimental data and the calculated values is found. Table 4

CEP (cm−1), LEP (V), sm and TEP (cm−1) values for some common ligands.55

Ligand

CEP (cm−1)

TEP (cm−1)

LEP (V)

sm

Ligand

CEP (cm−1)

TEP (cm−1)

LEP (V)

sm

NO+ CO BiF3 AsF3 SbF3 PF3 Z2-H2 s-N2 H2O P(OMe)3 PH3

2287.4 2210.6 2207.3 2205.1 2202.9 2201.2 2192.4 2185.8 2174.4 2171.3 2170.8

2193.5 2120.0 2116.8 2114.7 2112.6 2110.8 2102.6 2096.3 2085.3 2079.5 2083.2

1.9 0.99 0.89 0.86 0.83 0.81 0.80 0.68 0.04 0.42 0.43

2.12 1.35 1.32 1.30 1.27 1.26 1.17 1.10 0.99 0.96 0.95

NH3 SMe2 NMe3 PMe3 IMe SIMe Cl− CN− OH− H− t-Bu−

2161.8 2161.3 2155.9 2152.4 2142.1 2137.6 2120.8 2115.0 2091.9 2074.3 2062.8

2073.3 2072.8 2067.6 2064.1 2054.4 2050.1 2034.0 2028.5 2006.4 1989.5 1978.5

0.07 0.31 0.25 0.33 0.08 0.02 −0.24 0.02 −0.59 −0.76 −0.90

0.86 1.00 0.80 0.74 0.66 0.62 0.37 0.56 0.12 0.00 −0.10

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467

Fig. 10 TEP, DH and repulsivness (r ¼ 10(3.493-dNi-C) of some NHC ligands.57

Therefore, the trend that is provided by the theoretical calculations can be exploited as a tool to choose the most suitable NHC ligand for a given catalytic process, before testing the ligand itself or the corresponding metal complex as organocatalyst and well-defined organometallic catalyst, respectively. An appealing variant to the study of the electronic properties of a ligand starting from its metal complexes (e.g., [Ni(CO)3L]) is represented by the calculation of the well-known Molecular Electrostatic Potential (MESP). This approach is decidedly less expensive in terms of computing power and time as it takes into account the free ligand, without involving the presence of the metal center. Suresh and Mathew calculated the electrostatic potential for a wide range of phosphine and NHC ligands.58 This potential was then correlated to extremely important properties in organocatalysis and organometallic chemistry such as basicity/nucleophilicity and the nature and strength of the bond that the ligand will form with a specific metal center. Furthermore, the electrostatic potential (VC) is in excellent correlation with the TEP of these categories of ancillary ligands. In the case of NHCs, linear regression led to the following correlation (Eq. 10) between VC and TEP: TEP ¼ 0:43335
VC + 6072:9

(10)

Another interesting electronic parameter has been recently developed by Cremer and co-workers and is based on the metal-ligand local stretching force constant.59 This descriptor, known as the Metal-Ligand Electronic Parameter (MLEP), was introduced in order to estimate the strength of the metaldligand bond. This aspect was in fact taken marginally into consideration by the classical TEP, in which the primary goal was to categorize the ligands based on their net donor character. In the case of MLEP, the authors found a good correlation between the local CO and Ni-L stretching frequencies and the electronic features of the vibrating bonds and therefore of the strength of the metal-CO and metal-L bonds, for 181 [Ni(CO)3L] complexes.59 The main difference between TEP (or its computational equivalent, CEP) and MLEP is the use by the latter of local vibrational modes instead of normal vibrational

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

modes. Normal vibrational modes have the big disadvantage of always being contaminated by coupling frequencies. With the MLEP model, it is possible to easily and successfully convert the local Ni-L stretching force constant into the relative bond strength order (BSO). In particular, by using Ni(CO)4 as a reference, it is possible to divide NidL bonds into very weak, weak, normal, strong and very strong bonds. As it is well known, the strength of the NidL bond depends on the s-donor, p-donor and/or p-acceptor character of the ligand and on the steric interaction of the latter with the Ni(CO)3 fragment. The steric L-Ni(CO)3 interaction does not require a second parameter in the case of the MLEP, unlike the TEP which normally uses the cone angle of L as an additional parameter. However, if desired, the local C-Ni-L bending force constant can be exploited to separate steric effects from other electronic interactions. Data collected for 181 different [Ni(CO)3L] complexes showed average BSO values that follow the order: bismuthines < amines < stibines < arsines < phosphines (see Table 5). This trend is obviously attributable to the increasing s-donor and p-acceptor power of the above mentioned ligands. As for the NHC ligands, they exhibit a BSO in the range 0.57–0.67, which means they bind more firmly to the metal center than phosphine ligands (see Table 5). The excellent potential of MLEP, which is summarized in a recent review,60 must, however, deal with the fact that, similar to all computational methods, it should be validated by experiments. Unfortunately, as some Ni-L stretching frequencies are in the far-infrared range, they are measurable only with advanced spectroscopic techniques such as depolarized Raman scattering or the terahertz spectroscopy. Although these techniques are of growing interest, they have not yet reached such importance as to make them readily available in most chemical research laboratories. Much more available in this sense are the classical FT-IR spectrometers, for the measurement of TEP and analogs, and NMR spectrometers.

13.11.3.4 Huynh electronic parameter (HEP) The limits highlighted by electrochemical and carbonyl-based methods which, as described above, often make it difficult to verify the reliability of the electronic parameters calculated using quantum chemical approaches, have prompted many researchers to turn to other types of techniques and parameters. For this purpose, in 2009 Huynh and co-workers have developed a new methodology to evaluate the electronic properties of both Werner-type and organometallic ligands.61 The new parameter introduced by the authors, which is known as Huynh Electronic Parameter (HEP), corresponds to the 13C NMR signal (ppm) ascribable to the carbenic carbon of iPr2-bimy (iPr2-bimy ¼ 1,3-diisopropylbenzimidazolin-2-ylidene) in the complexes of general formula trans[PdBr2(iPr2-bimy)L]. Since the backdonation from the Lewis acidic Pd(II) center is negligible, this parameter essentially measures the s-donor capacity of a given ligand. In particular, strong s-donor ligands result in high HEP values (ppm) compared to weakly s-donors. This trend is due to the fact that strong donors in the trans position to iPr2-bimy weaken the metaldcarbene bond, in accordance with the concept of the trans influence. The labilization of the metaldcarbene bond increase the “free-carbene” like character of the coordinated iPr2-bimy and a downfield shift is observed. The synthesis of trans-[PdBr2(iPr2-bimy)L] complexes is generally carried out by reacting two equivalents of the ligand of interest (L) with the dimeric species [PdBr2(iPr2-bimy)]2 (see Fig. 11).62 With this type of approach, complexes containing ligands such as acetonitrile, bromide and triphenylphosphine were initially synthesized and studied.61–63 Later, these studies were extended to other phosphines and other categories of ligands such as imidazoles, pyridines, anilines, triazoles, isocyanides and NHCs.61,62 In this respect, we report in Table 6 some HEP values determined for the categories of ligands mentioned above. From the data reported in Table 6, N-donor ligands are the weakest among the ligands considered. For these ligands, as already discussed in the previous sections, the TEP value cannot be experimentally determined as they are not able to replace one of the carbonyl ligands of [Ni(CO)4]. Table 5 Ni-L distances (A˚ ), local mode stretching force constants k (mdyn
A˚ −1), local mode stretching frequencies o (cm−1) and bond strength orders (BSO) for some [Ni(CO)3L] complexes.59 Ligand

˚) Ni-L (A

k (mdyn ˚A−1)

o (cm−1)

BSO

Ligand

˚) Ni-L (A

k (mdyn ˚A−1)

o (cm−1)

BSO

H2O BiH3 BiMe3 NMe3 NH3 Z2-H2 s-N2 SbH3 ClSbMe3 AsH3 PH3

2.386 2.745 2.712 2.204 2.165 1.684 1.984 2.566 2.391 2.553 2.391 2.264

0.151 0.359 0.445 0.546 0.628 0.633 0.646 0.702 0.732 0.787 0.794 0.896

142.9 116.0 129.1 286.7 307.4 742.9 311.8 174.4 238.8 184.7 203.0 274.6

0.075 0.175 0.216 0.265 0.304 0.306 0.312 0.339 0.353 0.379 0.382 0.431

AsMe3 PPh3 PMe3 OH− SIMe IMe H− CO CMe2 CS CH2 NO+

2.372 2.274 2.253 2.024 2.018 2.008 1.579 2.981 1.888 1.814 1.829 1.680

0.954 0.989 1.069 1.192 1.201 1.253 1.401 1.705 1.895 2.242 2.600 3.745

222.6 288.4 299.8 401.8 452.8 462.6 1549.2 480.5 568.9 618.7 666.3 750.8

0.458 0.475 0.512 0.570 0.575 0.599 0.669 0.811 0.900 1.062 1.229 1.759

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469

Fig. 11 Synthesis of trans-[PdBr2(iPr2-bimy)L] complexes as probes for HEP determination. Table 6

HEP (ppm) for some of the tested ligands (measured in CDCl3).62

Ligand

HEP (ppm)

CH3CN Pyridine Xyl-NH2 Imidazole Br− CN-Cy PPh3 PCy3 IMesBr IMes SIMes

157.4 160.0 160.1 161.4 165.6 169.1 173.1 176.4 175.6 177.2 177.6

The determination of the HEP is therefore one of the few ways, together with the pKb values, that allows us to estimate the electronic features of this popular category of ancillary ligands. Examining the approach more closely, it is clear from Table 6 and Fig. 12 that the most labile ligand is acetonitrile and that it is possible to effectively modulate the s-donor strength of N-heterocycles by varying the type of heterocyclic ring and the type of substituents present in the backbone. Taking the imidazole, 1-methylimidazole and 1-phenylimidazole as examples (see Fig. 12), the inductive effect of methyl group with respect to H and

Fig. 12 HEP (ppm) for some N-donor ligands (measured in CDCl3).62

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Ph makes 1-methylimidazole a stronger s-donor (HEP ¼ 161.6 ppm) than imidazole and 1-phenylimidazole (HEP ¼ 161.4 and 161.2 ppm, respectively). As for the phosphine ligands, the HEP values reported in Table 6 confirm their marked s-donor character. In this respect, an important aspect concerning phosphines is their tendency to form cis-[PdBr2(iPr2-bimy)(PR3)] species rather than the desired trans[PdBr2(iPr2-bimy)(PR3)] derivatives.63,64 Therefore, it is crucial to record the 13C NMR spectra before the kinetic product trans-[PdBr2(iPr2-bimy)(PR3)] evolves to the thermodynamic product of cis configuration. If the isomerization process is very rapid, it is necessary to label the carbene carbon and rapidly record the 13C NMR spectrum.61 The method does have disadvantages for such systems as rapid data acquisition is required immediately after synthesis. Returning to the HEP values for the phosphine ligands reported in Table 6 and Fig. 13, the greater donor character of the alkyl phosphines compared to the aryl congeners is evident, similarly to what was observed with the TEP. In Fig. 13 are also reported the HEP values for a class of particularly electron-rich phosphines that presents azolin-2-ylidenamino substituents at the phosphorus atom.65 These values are between 180 and 187 ppm, and are comparable with the strongest s-donor NHC ligands such as non-classical NHCs. The NHCs are the class of ligands where the Huynh Electronic Parameter (HEP) has been the most successful. As a matter of fact, this descriptor makes it possible to enhance the differences between the different NHCs and to exclude the contribution of p-backdonation which in the case of TEP made it difficult to establish a true scale of the donor power of this important class of ancillary ligands.49 The trans-[PdBr2(iPr2-bimy)(NHC)] complexes probes, which are generally synthesized by the free-NHC and transmetallation routes, highlighted the greater donor character of saturated NHCs compared to the unsaturated congeners (e.g., SIMes (HEP ¼ 177.6 ppm) vs IMes (HEP ¼ 177.2 ppm)). Fig. 14 shows an overview of the HEP values for classical NHCs, in which the presence of electron-donor/electron-withdrawing groups on the backbone or the presence of condensed rings (e.g., benzymidazol-2-ylidenes) heavily affects the donor character of these ligands. As already mentioned above, a class of carbene ligands which are particularly s-donors is represented by the so-called non-classical NHCs. As shown in Fig. 15, with the exception of 3-benzylbenzothiazolin-2-ylidenes (HEP ¼ 176.4 ppm),66 they are all stronger donors than the classical NHCs. To overcome the poor stability of some palladium complexes bearing certain ligands or the formation of cis/trans mixtures, the Au(I) complexes of general formula [Au(iPr2-bimy)(L)] (if L is a X-type ligand) and [Au(iPr2-bimy)(L)]X (if L is a L-type ligand), have been developed as alternative and powerful probes.66 To make this variant very convenient is the excellent correlation that was observed between the chemical shifts of the iPr2-bimy carbene carbon obtained in the palladium and gold complexes containing the same ligand L. This linear correlation, verified for a wide range of ligands, is reported as Eq. (11).66

Fig. 13 HEP (ppm) for some P-donor ligands (measured in CDCl3).62

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

471

Fig. 14 HEP (ppm) for some classical NHC ligands (measured in CDCl3).62

Fig. 15 HEP (ppm) for some non-classical NHC ligands (measured in CDCl3).62

HEP ¼ 1:19
dAu − 45:0

(11)

Taking advantage of this approach, the HEP values for a library of 14 Acyclic Diamino Carbenes (ADCs), which were synthesized by reacting Au(I)-NHC (NHC ¼ iPr2-bimy) complexes bearing isocyanide ligands with different secondary amines, have been determined very recently.67 From the 13Ccarbene NMR signals and the corresponding HEP values (see Fig. 16) it is possible to state that ADCs are stronger donors than classical and expanded-ring NHCs but weaker donors than non-classical NHCs. The gold variant also allowed to indirectly determine the HEP value for anionic ligands such as acetate, chloride, iodide and acetylides, given their low propensity to form palladium complexes in a pure form.66,68,69 In this respect, we present in Table 7 the calculated HEP for these ligand types. Very recently, Huynh and colleagues determined the HEP values also for pnictogen and chalcogen donor ligands that had not been examined thus far (e.g., phosphites, AsPh3, SbPh3, DMS, THT and PNO).70 For some of these the trans-cis isomerization of the corresponding palladium complexes has been observed and studied. The characteristic of some of these ligands to prefer the formation of cis-[PdBr2(iPr2-bimy)(L)] complexes had already been observed for phosphine ligands and is called transphobia. Furthermore, in the same paper the influence of different substituents present in ortho, meta or para position on the donor capacity of pyridine ligands (remote substituent effect) was estimated and correlated to the Hammett constant. Finally, a broad class of ligands that has not been taken into consideration by carbonyl-based and electrochemical approaches, despite their fundamental importance in coordination and organometallic chemistry, is represented by the bidentate ligand class. These undoubtedly present a greater degree of complexity than monodentate ligands, given their ability to chelate the metal if they have two strong coordinating atoms or to act as hemilabile ligands. In this respect, Huynh and co-workers have developed an evolution of the HEP, called HEP2, which allows to estimate the electronic features of neutral cis-chelating and symmetrical bidentate ligands such as 1,2-diimines and dicarbenes.71 This study, which was then extended to unsymmetrical N,N0 -donors, was conducted by synthesizing and recording the 13C NMR spectra of complexes of the type [PdBr(iPr2-bimy)(L2)]PF6. Fig. 17 shows the

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Fig. 16 HEP (ppm) for some non-classical NHC ligands (measured in CDCl3).62

Table 7

HEP (ppm) for some anionic ligands (measured in CDCl3).66,68,69

Ligand

HEP (ppm)

OAc− Cl− Br− I− Py-CC− Ph-CC−

170.2 175.8 180.0 186.4 192.1 192.5

Fig. 17 HEP (ppm) for some N,N- and diNHC bidentate ligands (measured in CDCl3).62

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

473

values of HEP2 for some of the N,N0 -donors and dicarbene ligands examined by the authors, in which it is possible to observe a significant influence of the backbone, the lateral substituents and of the type of ring (for cyclic compounds) on the s-donor character of bidentate ligands. In summary, the advantages of 13C NMR-based methods consist first of all in the use of low toxicity compounds, which are easy to prepare and generally air- and moisture stable. With this approach, it is possible to determine the s-donor strength for a wide range of Werner-type and organometallic ligands with a small margin of error (ca. 0.02 ppm) and recovering the sample (by evaporation of the solvent) at the end of the analysis. The main disadvantage concerns the analysis time, which strongly depends on the solubility of the compound in CDCl3. Thus, poorly soluble compounds require a few hours or overnight 13C NMR measurements to correctly detect the signal of interest. When the classical trans-[PdBr2(iPr2-bimy)(L)] complexes are used, it must be remembered that some compounds tend to isomerize to the corresponding cis isomers, sometimes making it difficult or impossible to experimentally determine the HEP value. This latter aspect has in most cases been solved by using alternative [Au(iPr2-bimy)(L)] or [Au(iPr2-bimy)(L)]X probes.

13.11.3.5 NMR spectroscopy of selenoureas or carbene-phosphinidene adducts and 1J(C-H) coupling constants of azolium salts In 2013, Ganter and Bertrand proposed the use of selenoureas and carbene-phosphinidene adduct, as probes for the evaluation of p-accepting character of NHC ligands.72,73 These adducts, which are synthesized via the synthetic routes proposed in Fig. 18, can be represented with two different resonance structures. The zwitterionic form A, which is predominant for weak p-acceptor NHCs, involves an upfield shift of the 31P or 77Se NMR signal. Conversely, in the presence of good p-acceptor NHCs, the neutral form B becomes predominant and the detected downfield shift of the 31P or 77Se NMR signal can be associated to the formal C]P or C] Se double bond.

Fig. 18 Synthetic routes to selenoureas and carbene-phosphinidene adducts and their resonance structures.

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Fig. 19

77

Se and 31P NMR chemical shifts of some seleoureas and carbene-phosphinidene adducts (in acetone-d6 and benzene-d6, respectively).72,73

The chemical shifts values obtained from the 31P or 77Se NMR experiments are reported in Fig. 19 and highlight that saturated NHCs are decidedly better p-acceptors than their unsaturated counterparts (es. IMes vs SIMes) as already mentioned in the previous sections. It is also evident that the presence of electron-withdrawing groups increases the p-acceptor character of the NHC ligand (e.g., compound OAC). Morever, the presence in the Cyclic Alkyl Amino Carbenes (CAACs) of a single nitrogen atom adjacent to the carbene carbon efficiently promotes the p-backdonation from the phosphorus or selenium atom to the carbene carbon, making this category of ligands strong p-acceptors. In 2020, Nolan and co-workers completed the 77Se NMR scale with NHC ligands that had not yet been considered (e.g., IAd and Me 74 IPr ). In this work, the possibility of synthesizing selenoureas and their sulfur or tellurium counterparts, taking advantage of the weak base approach, was demonstrated. Furthermore, the authors studied in detail the coordination chemistry of chalcogenoureas with metals of Group 11, obtaining also in this case a trend of the p-acceptor capacity of the ligands based on the 77Se NMR chemical shifts (Fig. 20). Finally, the most recent and appealing method for evaluating the electronic properties of NHC ligands was initially proposed by Ganter in 2015 and subsequently simplified and extended by Szostak in 2019.75,76 This method is based on the good correlation between the s-donor capacity of an NHC ligand and the 1J(C-H) coupling constant of the carbene carbon in the starting azolium salt. The azolium salts precursors can be considered as “complexes” in which the coordinated proton acts as a Lewis acid. In this respect, the empirical correlation between the 1J(C-H) coupling constant and the s-character of a certain carbon is well known.77 This empirical correlation is expressed by the generic formula 1J(C-H)¼500 s, where s varies from 0.25 to 0.33 to 0.5 and represents the hybridizations sp3, sp2 and sp, respectively.78 Thus, higher 1J(C-H) coupling constant of the carbene carbon in the starting azolium salt correspond to an increase in the s-character of the CdH bond and therefore to a poorer s-donating NHC ligand. Such 1J(C-H) coupling constants can be determined by recording non-decoupled 13C NMR spectra75 or, as recently reported by Szostak and co-workers, by simple 1H NMR spectra of the azolium salt.76 In order to rigorously compare the different carbene ligands it is necessary to record the spectra in the same solvent (DMO-d6) and with the same counterion (chloride). Since some chloride salts are not easily available it is possible to determine the 1J(C-H) coupling

Fig. 20

77

Se chemical shifts of some coordinated seleoureas (in CDCl3).74

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

475

Fig. 21 1J(C-H) coupling constants of some NHC precursors (in DMO-d6). From Meng, G.; Kakalis, L.; Nolan, S. P.; Szostak, M. Tetrahedron Lett. 2019, 60, 378–381.

constants using counterions other than chloride (e.g., BF4, PF6). It has in fact been demonstrated by the authors that the counterion effect is negligible (ca. 0.23 Hz). Another very important aspect is that the 1J(C-H) is independent of the sample concentration. Thus, in Fig. 21 we present the 1J(C-H) coupling constants obtained from the 13C satellites of 1H NMR spectra (or from non-decoupled 13C NMR spectra) for some of the tested NHC ligands. The 1J(C-H) reported in Fig. 21 show values ranging from 183 (strong s-donor NHCs) to 229 Hz (poor s-donor NHCs). This new unified scale highlights the same trends observed in the case of the Huynh Electronic Parameter (HEP), in which is evident the greater s-donor character of saturated NHCs compared to the unsaturated counterparts and the strong s-donor power of ADC and CAAC ligands. The advantage of this approach, compared to HEP, is the possibility of directly using the azolium salts as probe and carrying out the measurement in a few seconds/min, by virtue of the higher sensitivity of 1H vs 13C NMR spectroscopy. The drawback of this method is that it is only applicable to NHC ligands, but extensions to other ligands is surely forthcoming.

13.11.4 Descriptors for ligand steric properties After discussing the most important experimental and theoretical methods that are commonly used for the determination of the electronic features of ancillary ligands, it is now appropriate to report an overview of the various descriptors that can be used to describe the steric hindrance brought about by these ligands around the metal center. After all, to be true to the general statement that “all is a fine balance of sterics and electronic effects,” one must discuss sterics. As already mentioned in the introduction, it is often difficult to separate electronic from steric effects since, according to Crystal Field and Ligand Field Theories, the electronic nature of a certain ligand can heavily influence the geometry of a complex. However, starting from the late 1970s, increasingly accurate descriptors were introduced to estimate the steric properties of spectator ligands most commonly used in homogeneous catalysis.

13.11.4.1 Tolman cone angle and the bite angle In his seminal work, Tolman proposed to measure the size of a ligand by the cone angle y.21 This parameter, initially conceived for phosphine ligands, can be defined as the angle whose vertex is the metal center and which includes the van der Waal’s surfaces of all ligand atoms over all rotational orientations using a standard M-L distance of 228 pm in [Ni(CO)3L] complexes (Fig. 22).

Fig. 22 Representation of the Tolman cone angle y for a generic monodentate phosphine.

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Table 8

Cone angles for a selection of phosphine ligands.21

Phosphine Ligand

Cone angle y/

PMe3 PEt3 P(n-Bu)3 PPh3 P(i-Pr)3 P(t-Bu)3 P(t-Bu)3 P(o-Tol)3 PMes3

118 132 132 145 160 182 182 194 212

For this purpose, the cone angle values reported in the literature are the result of geometrical calculations based on simple space-filling models (CPK).79 In this respect, Table 8 summarizes the cone angles for some of the phosphine ligands examined. The cone angle is widely used, in combination with the electronic parameter TEP, to correlate the catalytic activity of an organometallic compound with the nature of the spectator ligand. In particular, as we will see in the last part of this chapter, it can be considered in all respects as an important tool to fine tune the catalytic activity of phosphine-bearing complexes. Although the cone angle concept could be applied in theory to any ligand, it should be noted that it is difficult to determine or gives meaningless results for ligands other than phosphines. Ligands such as N-heterocyclic carbenes (NHCs), biarylphophines (Buchwald-type ligands) and other bidentate ligands fail to be characterised meaningfully using the cone angle concept. For example, bidentate ligands can be easily described using the concept of bite angle developed by van Leeuwen.10 This parameter, as already mentioned in one of the introductory paragraphs, represents the angle between the two donor atoms and the metal and it is usually determined by means of X-ray diffraction data or molecular mechanics calculations.9,10 In this respect, Fig. 23 shows the bite angle values for some important bidentate ligands used in organometallic and coordination chemistry. The natural bite angle that characterizes a certain bidentate ligand usually changes during the catalytic cycle or during the biological activity performed by the bidentate ligand bearing metal complex. Therefore, It is important to distinguish bidentate ligands not only on the basis of their bite angle but also to take into account their structural flexibility. In this respect, Casey and Whiteker introduced the concept of “flexibility range,” that is the range of bite angles that is accessible, within 3 kcal mol−1, by a certain ligand.81 With regard to N-heterocyclic carbene ligands, given their high and growing importance in homogeneous catalysis, as well as in other strategic fields, they served as cue for the development of new steric descriptors that were subsequently successfully applied to other categories of ligands. As mentioned above, such monodentate ligands, as well as N-, S- and O- donor ligands, are difficult to describe from the steric point of view with the Tolman cone angle. More general steric descriptors were proposed in the late 1970s by Charton and Verloop.82–84 These are based on the determination of the rotational barriers of a given molecule in correlation with a Taft-type equation and on the theoretical calculation of the total volume occupied by a molecule, respectively. Although these two models are more general than the Tolman cone angle, they have received a great attention mainly in the field of organic drug design. Conversely, these methods have been scarcely used to simulate the metal-ligand interaction that is the basis of coordination and organometallic chemistry.

13.11.4.2 Percent buried volume The percent buried volume (% Vbur), which was introduced by Nolan and Cavallo in 2003, is currently one of the most important descriptors used to quantify the steric properties of any given ligand.85 This parameter is defined as the percentage of a sphere around the metal center occupied by the ligand of interest. This sphere has a radius of 3.5 A˚ and the metal-ligand distance is usually fixed at 2.00 or 2.28 A˚ , often omitting hydrogen atoms from the calculations (Fig. 24). The use of these fixed values, along with the use of scaled Bondi radii for the atomic radii of different atoms, is strongly recommended in order to uniformly compare the new data with those already present in the literature. Moreover, the %Vbur values reported in most of the papers and specialized reviews were calculated starting from crystallographic data and in particular from CIF files with an R factor less than 7%. The SambVca tool, a free online web-based program, is now the most straightforward and simple method for determining the % Vbur for a given ligand.86 This software also provides steric maps, which will be described in detail in the next section, and per-quadrant measurements of the buried volume. This last aspect is very important in the case of simulations involving non-symmetrical ligands. Although the Percent Buried Volume was originally proposed for NHC ligands, it can be applied to any monodentate or polydentate ligand. The versatility of the model is its strength and is responsible for its ever growing use. As a matter of fact, the %Vbur does not have particular requirements related to the symmetry of the ligand, unlike the Tolman cone angle. For example, the %Vbur was widely used to study the properties and catalytic activity of several metal complexes bearing symmetrical and unsymmetrycal phosphines (e.g., Buchwald-type ligands).87

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Fig. 23 Average Bite angles b for some bidentate ligands.80

Fig. 24 Representation of the %Vbur for a generic NHC ligand.

477

478

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Table 9

%Vbur and Tolman cone angles for some phosphine ligands.87,88

Ligand

Cone angle ( )

%Vbur (2.00 ˚A)

%Vbur (2.28 ˚A)

PMe3 PEt3 PnBu3 PPh3 PiPr3 PCy3 P(SiMe)3 PtBu3 P(C6F5)3 PMes3 P(OPh)3

118 132 132 145 160 170 178 182 184 212 128

26.1 32.7 30.4 34.5 37.6 37.1 37.9 42.4 42.6 53.1 35.4

22.2 27.8 25.9 29.6 32.3 31.8 34.0 26.7 37.3 47.6 30.7

As for the phosphine ligands, since only very rare examples of X-ray structures of complexes of the type [Ni(CO)3(PR3)] are reported in the literature, a good estimate of the %Vbur can be initially made considering the crystal structures of phosphines themselves.88 In this respect, by placing the coordinates of the atoms contained in the phosphine ligand in the SambVca software and fixing a hypothetical metal-P distance of 2.00 or 2.28 A˚ , it is possible to obtain the desired ligand %Vbur. Table 9 shows the calculated %Vbur and Tolman cone angles for some monodentate phosphines.87 An excellent correlation between these two parameters has been observed, demonstrating the possibility of using the buried volume as a substitute for the cone angle. Although the %Vbur values calculated for the free phosphine ligands show a clear trend regarding their steric hindrance, it is necessary to compare these results with those that can be obtained from the crystallographic data of metal-phosphine complexes. A category of complexes of which a large number of crystallographic data are available are the Au(I) complexes of the type [Au(PR3)Cl].89 This category of compounds is particularly suitable for this purpose due to the low steric influence of the chloride ligand. Also in this case it is possible to observe an excellent correlation between the cone angle and the %Vbur. Phosphites are an exception, since their steric hindrance is decidedly underestimated in the calculation of the Tolman cone angle (Table 10). To demonstrate the low steric influence of the chloride ligand in the determination of the buried volume of phosphines, the same procedure was carried out keeping the phosphine ligand constant (e.g., PPh3) and varying the type of auxiliary ligand. As expected, the %Vbur values determined for the different complexes [Au(PPh3)X] (X ¼ Cl, Br, I, Me, CF3, CN, OAc, OTf, N3, SCN, etc.) fall within a narrow 2% range.87 Conversely, the non-negligible influence of the type of metal center, the coordination geometry and of the other spectator ligands on the buried volume of some phosphines taken as models (e.g., PtBu) has been demonstrated (Table 11).87b This evidence therefore justifies the choice of gold(I) chloride complexes as an ideal probe. As already mentioned above, the buried volume offers the important possibility of determining the steric properties even of non-symmetrical ligands. In this context, the steric hindrance around the metal center of an important class of asymmetric ligands such as biaryldialkyl phosphines (Buchwald-type ligands) has been successfully studied.87b It is worth mentioning that the quantification of the steric properties of this versatile class of ligands, widely used in several Pd-catalyzed C-C, C-N and C-O couplings,91 had never been reported before the advent of the buried volume parameter. The existing models were simply ineffective toward this end. Table 12 gathers the %Vbur for the most popular Buchwald-type ligands and their corresponding Tolman cone angle. As for the diphosphine ligands, unlike the Tolman cone angle, it is possible to insert the entire ligand in the calculations. Thus, the percent buried volume values are available for the most widely used diphosphine ligands in organometallic chemistry and homogeneous catalysis and were determined using [(diphosphine)(AuCl)2] or [Pd(diphosphine)Cl2] complexes as probes (Table 13).87b In particular, it was noted that the Pd(II) complexes are more appropriate for the correct simulation of this class

Table 10

% Vbur and cone angles for some phosphine ligands using [Au(PR3)Cl].87,89

Complex

Cone angle ( )

%Vbur (2.00 ˚A)

%Vbur (2.28 ˚A)

[Au(PMe3)Cl] [Au(PEt3)Cl] [Au(PPh3)Cl] [Au(P(NMe2)3)Cl] [Au(PiPr3)Cl] [Au(PCy3)Cl] [Au(PtBu3)Cl] [Au(PMes3)Cl] [Au(P(OMe)3)Cl] [Au(P(OPh)3)Cl]

118 132 145 157 160 170 182 212 107 128

27.3 31.7 34.8 36.9 39.1 38.8 43.9 50.5 30.8 36.5

23.3 27.1 29.9 31.9 24.0 33.4 38.1 45.0 26.4 31.9

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Table 11

% Vbur of PtBu3 calculated for different metal-complexes.87b,89h,90

Complex

%Vbur (2.00 ˚A)

%Vbur (2.28 ˚A)

[Au(PtBu3)Cl] [Al(PtBu3)H3] [Hg(PtBu3)(OAc)2] [Ni(PtBu3)Br3] [Pd(PtBu3)2] [Pd(PtBu3)BrPh] [Pt(PtBu3)(dvtms)] [Ir(PtBu3)(CO)2Cl] [Fe(PtBu3)(CO)4] [Ru(PtBu3)(CO)2(OAc)]2 [W(PtBu3)(CO)5]

43.9 43.4 45.3 41.9 42.5 43.2 40.7 41.7 40.7 40.9 40.6

38.1 37.6 39.5 36.3 36.8 37.4 35.1 36.0 35.1 35.2 34.9

Table 12

% Vbur and cone angles for some Buchwald-type phosphines in [Au(L)Cl] complexes.87b,92

. Complex

Cone angle ( )

%Vbur (2.00 ˚A)

%Vbur (2.28 ˚A)

[Au(PCy2Ph)Cl] [Au(MePhos)Cl] [Au(SPhos)Cl] [Au(JohnPhos)Cl] [Au(XPhos)Cl]

159 238 240 246 256

38.0 53.6 53.7 55.5 57.4

32.7 49.3 49.7 50.9 53.1

Table 13

% Vbur for some diphosphine ligands in digold(I) and palladium(II) complexes.87b,93

Complex

%Vbur (2.00 ˚A)

Complex

%Vbur (2.00 ˚A)

[(dppm)(AuCl)2] [(dppe)(AuCl)2] [(dppp)(AuCl)2] [(dppb)(AuCl)2] [(XantPhos)(AuCl)2] [(dppf )(AuCl)2] [(BINAP)(AuCl)2]

44.2 34.2 41.2 35.8 46.8 38.7 57.9

[Pd(dppm)Cl2] [Pd(dppe)Cl2] [Pd(dppp)Cl2] [Pd(dppb)Cl2] [Pd(XantPhos)Cl2] [Pd(dppf )Cl2] [Pd(BINAP)Cl2]

47.0 51.4 52.2 53.8 54.4 55.5 55.6

479

480

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

of ligands, highlighting, for example, the increase in steric hindrance according to the (CH2)n bridge length. On the contrary, digold (I) complexes, by virtue of the presence of two metal centers and therefore of the need to divide the ligand into two parts and then calculate the average steric hindrance, sometimes provides results that are not supported by predictions and/or experimental evidence. As mentioned above, the percent buried volume was initially conceived to describe the steric properties of N-heterocyclic carbene ligands in view of the failures of the cone angle model. The first NHC ligands that were considered were the classical imidazol-2-ylidenes, imidazolin-2-ylidenes and their ring-expanded analogs, using [Au(NHC)Cl] complexes as the standard organometallic system.87b In Fig. 25, it can be observed that rigid NHCs such as IPr undergo negligible changes in the buried

Fig. 25 % Vbur for some classical NHCs in [Au(NHC)Cl] complexes.87

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

481

volume if methyl groups or chlorine atoms are installed in the backbone (%Vbur at 2.00 A˚ : IPr ¼ 45.4 vs IPrCl ¼ 44.9 vs IPrMe ¼ 44.4). Conversely, more flexible ligands such as IIPr undergo significant changes in %Vbur if the hydrogens of the backbone are replaced with methyl groups (%Vbur at 2.00 A˚ : IIPr ¼ 27.5 vs IiPrMe ¼ 38.5). Morever, the saturation of the imidazolium ring or the transition to 6- and 7-membered rings leads to an increase of the steric demand (%Vbur at 2.00 A˚ : IPr ¼ 45.4 vs SIPr ¼ 47.0 vs THP-Dipp ¼ 50.9 vs THD-Dipp ¼ 52.7). Considering the influence of substituents on the nitrogen atoms, it should be noted that aryl groups make the carbene ligand much more rigid than alkyl groups (e.g., IPr vs IiPr). In particular, the most effective strategy to significantly modify the steric hindrance of rigid NHC ligands with N-aryl groups is to vary the nature of the substituents present in the ortho aryl positions (e.g., IMes vs IPr ). For NHC ligands with N-alkyl groups, it is possible to tune the buried volume by acting on the number of substituents on the ipso carbon. It is in fact known that the flexibility of the ligand increases as the number of substituents in this position increases (e.g., IMe vs ItBu). To complete the discussion on NHC ligands, Fig. 26 shows the percent buried volumes for some non-classical NHC ligands. Some of these have a high steric hindrance due to the important rigidity of the ring or, as in the case of CAACs, to the replacement of one of the two nitrogen atoms with an sp3 carbon. CAAC ligands, as well as other non-classical NHCs reported in Fig. 26, are asymmetrical and therefore, for a more appropriate steric analysis, it is necessary to resort to the per-quadrant measurements of the buried volume or to the steric maps, which will be discussed next. In addition to phosphines and NHCs, the buried volume approach is applicable in principle to all classes of ligands. For instance, in 2012, Odom and collaborators determined the %Vbur for a large number of anionic ligands (e.g., halides, triflate, cyanide and alkoxides) using [N  Cr(NiPr2)2(X)] complexes as standard probes.94 The values reported by the authors follow, in the case of halides, the trend given by their ionic radius: I− > Br− > Cl− > F− (see Table 14). It should be remembered that [N  Cr(NiPr2)2(X)] complexes were used by the same authors to estimate the donor character of the anionic ligands reported in Table 14. The determination of the rate of diisopropylamido rotation, which was measured using Spin Saturation Transfer (SST) in the 1H NMR, allowed Odom and co-workers to obtain the amido rotational barrier by means of the Eyring equation.94 This rotational barrier (kcal mol−1) represents the Ligand Donor Parameter (LDP) due to its good correlation with the donor capacity of the investigated anionic ligands (see Table 15).

Fig. 26 % Vbur for some non-classical NHCs in [Au(NHC)Cl] complexes.87

Table 14

%Vbur for some anionic ligands in [N  Cr(NiPr2)2(X)] complexes.94

Anionic ligand

%Vbur (2.00 ˚A)

Anionic ligand

%Vbur (2.00 ˚A)

NiPr−2 carbazolyl NMe−2 OTf− PhS− PhCO−2 NO−3

29.1 25.0 22.4 21.6 21.2 19.7 19.7

I− PhO− BnO− Br− Cl− CN− F−

19.2 18.6 18.5 18.1 16.8 16.7 11.9

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Table 15

LDP for some anionic ligands in [N  Cr(NiPr2)2(X)] complexes.94

Anionic ligand

LDP (kcal mol−1)

Anionic ligand

LDP (kcal mol−1)

NMe−2 NiPr−2 BnO− carbazolyl PhO− F− NO−3

9.34  0.32 11.12  0.23 11.15  0.23 12.04  0.25 12.38  0.25 13.39  0.27 14.15  0.29

PhS− CN− PhCO−2 Cl− Br− OTf− I−

14.22  0.27 14.40  0.27 14.45  0.28 15.05  0.29 15.45  0.30 15.75  0.29 15.80  0.30

From Denny, J. A.; Darensbourg, M. Y. Coord. Chem. Rev. 2016, 324, 82–89.

Table 16 % Vbur for some metallodithiolates ligands in tungsten carbonyl complexes (bme-daco ¼ N, N0 -bis-mercaptoethylene-1,5-diazacyclooctane; bme -daco ¼ N,N0 -bis(2-mercapto-2-methylpropylene)1,5-diazacyclooctane; bme-dach ¼ N,N0 -bis-mercaptoethylene-1,4-diazacycloheptane).95,96

. Metallodithiolato ligand

Complex

%Vbur (2.00 ˚A)

Ni(bme-daco) Ni(bme -daco) Ni(bme -daco) Ni(bme-dach) Co(NO)(bme-dach) Fe(NO)(bme-dach) ZnCl(bme-dach)

[W(CO)4(LL)] [W(CO)5(L)] [W(CO)4(LL)] [W(CO)4(LL)] [W(CO)4(LL)] [W(CO)4(LL)] [W(CO)4(LL)]

31.6 22.3 35.6 32.5 33.0 33.8 33.8

In particular, low values of Ligand Donor Parameter (LDP) correspond to a greater donor capacity of the ligand of interest. More recently, Darensbourg and co-authors published a review that analyzes in detail the electronic and steric properties of metallodithiolates.95 This category of ligands has an interesting coordination chemistry with different transition metals. Making use of the SambVca software, the buried volumes for some metallodithiolates in tungsten carbonyl complexes were determined (Table 16). In summary, the percent buried volume is an excellent tool for evaluating the steric hindrance of a given ligand around the metal center. However, like all methods, it has limitations that must be taken into consideration whenever this approach is used. The correct calculation of the buried volume requires the use of very accurate crystallographic data, or alternatively accurate DFT calculations. For a correct comparison between different ligands, especially the more flexible ones, it is necessary to consider the same metal center, geometry and ancillary ligands. Finally, since this descriptor is represented by a single number, it does not provide a complete and optimal representation of the steric hindrance, especially for asymmetric ligands. To partially overcome this issue, it is necessary to resort to per-quadrant analysis of the buried volume and steric mapping discussed next is a great vsualisation tool for steric analysis.

13.11.4.3 Topographic steric maps In 2010, Cavallo and co-workers introduced the concept of topographic steric maps as a powerful tool to represent and visualize, with the same philosophy of physical maps in geography, the steric profile of ligands around a metal center.86,97 This tool was created in order to visualize and study in detail the catalytic pocket which represents, in analogy with the lock and-key model proposed by Fischer for enzymatic catalysis, the space accessible by the substrates in close proximity to the metal. This approach represents a simpler and more quantitative appreciation of the space occupied by the ligands compared to the classical wireframe or space-filling Corey-Pauling-Koltun (CPK) models (Fig. 27). As illustrated in Fig. 27, topographic steric maps are usually divided into quadrants and via colored contours, which vary from dark red to deep blue depending on the steric hindrance of the ligands above and below the plane identified by the metal center. This approach allows not only to identify the bulkiest and less bulky areas about the metal, but above all, it helps to define the

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483

Fig. 27 Wireframe, Space-filling CPK and topograpraphic steric maps for a Ruthenium Metathesis Catalyst bearing a N-trifluoromethyl NHC ligand.98

features of the catalytic pocket. This is especially useful in the field of asymmetric catalysis, in order to rationalize substrate preferred route of approach to the metal.86 For these unique features, steric maps have been widely used to study transition metal complexes bearing asymmetrical NHC or phosphine ligands. In this context, an example of the utility of this method is clearly visible in Fig. 28, in which two NHC ligands with very similar percent buried volumes were compared. Although they have the same percent buried volume, which is calculated from [Au(NHC)Cl] complexes, it is very clear from the picture that the space is occupied very differently by the two ligands. If we consider the left hemisphere, the ligand 4 concentrates its bulk in the north-west quadrant whereas ligand 5 is more hindered in the south-west quadrant. Therefore, for the gold complex bearing ligand 4, possible substrates might approach from the south-east and/or south-west quadrants, since the northern hemisphere is particularly hindered.

Fig. 28 Topographic steric maps of two NHC ligands with identical percent buried volumes.99

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

Conversely, the gold complex bearing ligand 5 makes it possible to approach substrates that are willing to occupy two diametrically opposite quadrants (north-west and south-east). As mentioned in the buried volume section, topographic steric maps can be easily obtained using the SambVca 2.1 software, which simultaneously provides the per-quadrant percent buried volume.86 It is noteworthy that steric maps are not limited to the study of metal complexes to be used as homogeneous catalysts, but can be successfully used to characterize and visualize the catalytic pocket of natural or artificial metalloenzymes as recently reported by several authors.100 Like all electronic and steric descriptors, topographic steric maps also have some limitations. In particular, in addition to requiring very accurate DFT calculations or crystallographic data, it is good to remember that steric maps refer to the solid-state conformation of the metal complex or metalloenzyme of interest. This intrinsic limit does not have major repercussions on the steric analysis of compounds containing particularly rigid ancillary ligands. Conversely, it represents a severe limitation when analyzing compounds containing ancillary ligands sufficiently flexible to modify their arrangement around the metal center. Hence, although they can be a powerful tool for visualizing and characterizing the catalytic pocket of a given metal complex, they should be analyzed with caution when dealing with more flexible ligands.

13.11.5 Analysis of catalyst performance based on parameterization of ancillary ligands In this closing section, we report some concrete examples on the use of the different steric and electronic parameters to rationalize and sometimes predict the catalytic activity of transition metal complexes. In particular, we will focus on the numerous strategies that are currently available to chemists to appropriately choose the combination of ligands and organometallic fragments in order to obtain an efficient homogeneous catalyst.

13.11.5.1 Catalytic trends of transition metal complexes bearing monodentate phosphines The ubiquitous use of phosphine ligands in homogeneous catalysis has always been a test case for synthetic catalyst design practitioners. The tools described above could assist in selecting/designing steric and electronic properties to shape a catalyst architecture to result in high catalyst activity by design. Among the most used phosphine ligands in catalysis are the biaryldialkylphosphines developed by Buchwald, which have proven to be particularly beneficial in palladium-catalyzed coupling reactions as well as in gold(I) catalysis by virtue of their unique architecture and stereoelectronic properties.101 Buchwald-type phosphines have been designed to be electron-rich, sterically demanding and therefore able to stabilize low-coordinate as well as cationic complexes, which are the most common active species in Pd- and Au-catalyzed reactions (Fig. 29). In particular, the presence of secondary interactions between the metal center and the p-system of the lateral arene appear to stabilize and further protect the catalytically active species.102 In gold(I)-catalyzed processes such as the hydroamination of alkynes, the high donor property of Buchwald-type ligands favors the proto-deauration reaction, which is a key step along the catalytic cycle. The biaryl moiety allows to increase the stability of the catalyst and the intermediate cationic species.103

Fig. 29 Examples of Buchwald-type phosphines and putative catalytically active species.

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Fig. 30 Structure, TEP (cm−1) and %Vbur of YPhos ligands.104

Among the numerous articles that have appeared in the literature concerning the interdependence of the s-donor ability of phosphine ligands and their catalytic activity of their transition metal complexes, we present a recent study conducted by Gessner and co-workers on mono- and diylide-substituted phosphines (YPhos).104 This class of ligands, similar to Buchwald-type phosphines, was synthesized in 2018 and 2019 and successfully applied to palladium catalyzed a-arylations and Buchwald-Hartwing aminations as well as in gold catalyzed hydroamination reactions.105 In a 2019 report, six different YPhos ligands were considered, whose steric and electronic characteristics are shown in Fig. 30.104 In particular, the TEP values, indirectly determined using the carbonyl stretching frequencies of [Rh(L)(acac)(CO)] or [Ir(L) (CO)2Cl] complexes showed the following s-donor capacity trend: 6 < 7 < 8 < 9 < 10 < 11. These ligands are therefore strong s-donors, with TEP values comparable to the most donating alkyl phosphines (TEP (11) ¼ 2054.7 cm−1 vs TEP (PtBu3) ¼ 2056.1 cm−1). This marked s-donor trait combined with their extremely high steric hindrance (44 < %Vbur < 63), makes YPhos ligands an attractive alternative to Buchwald-type phosphines. With the aim of optimise and understand the catalytic activity of the [Au(YPhos)Cl] complexes in the hydroamination of phenylacetylene with aniline, using NaBArF4 as a halide abstractor at low catalyst loading (0.1 mol%), a strong correlation between the initial reaction rates and the TEP values of the monoylide-substituted phosphines used (ligands 6, 8 and 10) was observed. This correlation, which has also been highlighted between TEP and reaction yields, is essentially attributable to the greater efficiency in promoting the proto-deauration step. For these three ligands, it was possible to reach complete conversion at room temperature after 3 or 24–48 h using 0.5 and 0.1 mol% as catalyst loading, respectively (Fig. 31).

Fig. 31 Hydroamination of phenylacetylene with aniline catalyzed by gold(I) complexes bearing monoylide-substituted phosphines (6, 8 and 10).104

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

These results are very interesting since normally harsher conditions as well as higher catalyst loadings are required for this reaction.106 However, the same trend (catalytic activity vs TEP) cannot also be extended to the more electron-rich diylide phosphines (ligands 7, 9 and 11). For the latter, the greater s-donation is in fact hampered by the high steric congestion which actually hinders the entire process. In order to obtain reaction rates and yields comparable to the same process catalyzed by gold(I) complexes bearing monoylide phosphine ligands, it is necessary to increase the temperature from RT to 50  C.104 It therefore appears clear how it is sometimes possible to qualitatively and quantitatively rationalize the catalytic activity data on the basis of two simple parameters such as TEP and the percent buried volume. In order to design an efficient hydroamination catalyst, a correct combination of s-donor strength and steric hindrance is needed.

13.11.5.2 Parameterization of transition metal complexes bearing monodentate phosphines In 2019, Jover and Cirera, with the aim of calculating by MM/DFT methods the Tolman cone angles (yO, yL and yT) for 119 phosphine ligands in octahedral [Ir(CO)2Cl3(L)], linear [Au(L)Cl] and tetrahedral [Ni(CO)3(L)] complexes, observed a relatively good correlation between the tetrahedral cone angle (yT) and the corresponding percent buried volumes (%Vbur).107 Interestingly, in the same contribution, the authors, examining the Suzuki-Miyaura coupling between bromobenzene and phenylboronic acid, used a multi-linear regression model to determine the correlation between the computed reaction barriers (in kcal mol−1) and stereoelectronics parameters such as the tetrahedral cone angle (yT) and HOMO (EHOMO) or LUMO (ELUMO) energies (both in Hartrees) of the free phosphine ligands. It is noteworthy that EHOMO and ELUMO, which are, respectively, a measure of the electron s-donation and p-acceptance ability of the phosphine, have been extracted from the monodentate phosphine Ligand Knowledge Base (LKB-P).108 Gratifingly, with this multilinear regression approach, it was possible to establish a mathematical correlation for each of the three key steps of the Suzuki-Miyaura coupling: oxidative addition, transmetalation and reductive elimination (see Fig. 32). An appealing and powerful approach for the parameterization of phosphine ligands in homogeneous catalysis was proposed by Sigman and co-authors in 2016 and consists in the use of regressions involving several electronic and steric descriptors.109 In fact, it is reasonable that in order to study in detail the intrinsic complexity of the most important catalytic processes, in which multiple equivalents of ligand, pre-equilibrium bindings, multiple mechanistic steps and competitive reactions are involved, it is necessary to take into consideration numerous parameters in order to attempt to rationalize the system of interest. These multivariable methods are obviously less intuitive than those presented so far, in which the influence of only one or two ligand descriptors (e.g., TEP and % Vbur) on the efficiency of the catalyst was analyzed. The multivariable methods require the creation of very large libraries, known as Ligand Knowledge Bases (LKB-P), which were implemented by Fey and other authors in the last decade and contain a large number of ligands for each category (348 in total) and, for each ligand, several steric and electronic descriptors (28 in total).110 In brief, the LKB uses a standard DFT approach to optimise the free ligand and its metal complexes. From these simulations it is possible to obtain numerous steric and electronic parameters and, the resulting database, is then analyzed with a statistical data projection approach (Principal Component Analysis, PCA) to reduce the dimensionality and facilitate visualization.

Fig. 32 Computational analysis of key steps of Suzuki-Miyaura coupling of bromobenzene and their energy barriers.

Reaction Parameterization as a Tool for Development in Organometallic Catalysis

487

This is possible because many descriptors are highly correlated, as they are obtained from the same ligand in different environments. In this way we achieve a new set of uncorrelated variables (Principal Components, PCs) by linear combination of the original descriptors. Plots of PCs allow the generation of so-called maps of chemical space. Since the multivariable methods require a huge amount of data to be applied, good computing power and some experience in order to interpret the output in a meanful way from a statistical perspective are required. These methods are more widespread in industry, where an enormous amount of data relating to the optimization of a given process is available, compared to academic environments where smaller data sets are generated. Despite these obvious limitations, the works published by Sigman and colleagues offers interesting examples and insights that are particularly noteworthy.109 In one of these reports, the authors considered 26 different monodentate phosphine ligands belonging to four broad classes: triarylphosphines, trialkylphopshines, mixed phosphines and Buchwald-type phosphines (see Table 17). For each ligand, the structure of the several possible conformers was studied and optimized and, at the end of this process, the two isomers with the smallest and largest cone angle, calculated using the Solid-G program,109 were selected. For each of the two conformers of a given ligand, the infrared spectra were then computed, from which the symmetric stretch and bend of the three PdC bonds were extrapolated as parameters. Taking into account also the corresponding phosphine oxides, which can be considered as surrogates of the metal-phosphine complexes, it was possible to obtain a further parameter, namely the stretching frequency of the P]O bond. As a further spectroscopic parameter, the 31P chemical shift of each phosphine, the 31P chemical shift of the corresponding phosphine-selenide adduct and the 1JPdSe coupling constant were examined. The values obtained for the different parameters mentioned above suggest that there is no general trend that simply correlates two or more of these parameters for all the 26 phosphines examined. It therefore appears clear how essential it is to include all parameters and determine the contribution that each of them has on the entire process through a multilinear regression. The authors attempted to rationalize the experimental results obtained in the cross-coupling reaction between 2-methyl phenylboronic acid and 4-chlorophenyl trifluoromethanesulfonate (Fig. 33), catalyzed by Pd2(dba)3 (1.5 mol%) in the presence of different phosphine ligands ([PR3] ¼ (3 mol%)).109,111 Specifically, it was observed that PtBu3 promotes the selective oxidative addition of the aryl chloride, which leads to a mixture of coupling products (C/D) of about 99:1, whereas using PCy3 as phosphine, a C/D mixture of about 1:20 was observed, indicating a quasi-selective oxidative addition of the aryl triflate. This result is far from obvious, since the bulkiness and the s-donor capacity are very similar for these two alkylphosphines. Detailed computational studies reported by Schoenebeck and Houk have highlighted, as a possible cause of the opposite selectivity imparted by these two phosphines, the preference of PtBu3 to form the monoligated palladium complex (PtBu3)Pd as a catalytically active species whereas tricyclohexylphosphine favors the formation of bis-ligated palladium complex [Pd(PCy3)2].112 This type of computational study, besides being expensive in terms of computation time required, involves the intimate mechanism of the reaction, often requiring experimental tests to be considered reliable (e.g., kinetic studies and isolation of one or more reaction intermediates) and are obviously not extendible to reactions with completely different mechanisms. Furthermore, the presence of at least two different reaction pathways becomes problematic for those ligands that do not show a marked selectivity in the formation of one of the products. The method proposed by Sigman simulates, by means of the various descriptors that can be

Table 17

Classes of phosphines studied by Sigman and co-workers.109

26 Phosphine ligands studied Triarylphosphines

Trialkylphosphines

Mixed phosphines

Buchwald-type phosphines

PPh3 P(o-OMePh)3 P(p-OMePh)3 P(p-FPh)3 P(o-Tol)3 P(m-Tol)3 P(p-Tol)3

PEt3 PiPr3 PnBu3 PtBu3 PBn3 PCy3 PCyp3

PMe2Ph PMePh2 PEtPh2 PtBu2Ph PtBuPh2 PCy2(o-Tol) PCy2(p-NMe2Ph)

JohnPhos CyJohnPhos SPhos RuPhos XPhos

Fig. 33 Suzuki-Miyaura coupling between 2-methyl phenylboronic acid and 4-chlorophenyl trifluoromethanesulfonate.109,111

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Reaction Parameterization as a Tool for Development in Organometallic Catalysis

associated to a given phosphine ligand, the energy preferences (DDG+), which have been experimentally determined using the final ratio between the two different coupling products and considering the Hammett-Curtin equation DDG+ ¼ 0.001986
298.15
ln([C]/ [D]).109 Taking advantage of a multistep approach that involved the use of 45 different descriptors for each ligand, subsequently reduced to less than 10 descriptors, and linear regressions gradually refined, obtained by varying the terms of the equation once inserted in the initial model other ligands as a validation set, the authors found a general equation that predicts the reaction outcomes with good accuracy and which consists of 5 parameters and 6 terms (Eq. 12).109       DDG + ¼ 0:12 − 0:76
P − CbendingðnÞ + 0:57
P − CbendingðiÞ + 0:79
31 PPR3
P − CbendingðnÞ − 1:49 31  31  31  PSe¼PR3
y (12) PSe¼PR3
P − CbendingðiÞ + 0:85
PSe¼PR3
P − CbendingðnÞ + 0:35

This model served as a starting point to carry out further studies on the mechanism of this reaction using both theoretical DFT calculations and cyclic voltammetry measurements. Moreover, the same multivariable approach has allowed to obtain two decidedly simpler equations than Eq. (12), which are valid if we separate the Buchwald-type ligands and the phosphines with a Tolman cone angle (y) lower than that of triphenylphosphine (Eq. 13) from those with a high cone angle (Eq. 14).       DDG + ¼ 0:56 − 0:24
31 PSe¼PR3 − 0:32
ðJP − Se Þ + 0:14
P − CbendingðnÞ + 0:20
31 PSe¼PR3
y (13)   DDG + ¼ − 0:103
31 PSe¼PR3 + 7:136 (14) Another interesting and recent example of a multivariable approach to predict the reaction outcome of organic transformations catalyzed by metal-complexes bearing monodentate phosphine ligands was reported in 2017 by Doyle and Wu.113a In their contribution, a new class of alkyl aryl-phosphines has been developed which, by virtue of their remote steric hindrance which is provided by bulky groups at the 3,5-positions in the aryl moieties, are able to confer a high catalytic activity in Ni-catalyzed Suzuki cross-coupling of benzylic acetals. The key role of the remote steric hindrance, which represents a fairly new and unexplored concept in catalysis, has been demonstrated by the modeling and parameterization of this cross-coupling reaction. As can be seen in Fig. 34, the yields obtained when using both small and bulky phosphines are very low. On the other hand, if bulky substituents are installed in a remote position (e.g. ligands 12, 13 and 14) yields between 67% and 78% are obtained. This is due to the smaller atomic size of nickel compared to palladium, resulting in a shorter metal-P distances. It therefore appears intuitive that if bulkier phosphines are used, the approach of the substrate to the metal center is dramatically hindered. Conversely, if phosphines with bulky groups in remote positions are employed, there is the double result of allowing the substrate

Fig. 34 Performances of some Ni-catalysts for Suzuki cross-coupling of benzylic acetals.

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489

to approach the nickel center and inhibiting, via remote steric hindrance, the coordination of multiple ligands that would trigger classical bimetallic deactivation mechanisms. The parameterization of the ligands by means of a linear regression model made it possible to obtain an equation that correlated the yield of the process with an appropriate combination of three steric parameters such as the Tolman cone angle (y), the percent buried volume (%Vbur) and the minimum electrostatic potential Vmin (Eq. 15).113a Yield ¼ 0:24 + 0:82
y − 0:67
ð%Vbur Þ − 0:084
ðVmin Þ − 0:534
y
ðVmin Þ

(15)

Since the percent buried volume describes the bulkiness in the proximity of the metal center whereas the Tolman cone angle is sensitive to ligand size at a distance, in order to have a high remote steric hindrance, it is necessary to consider those ligands that have high y and low %Vbur. The high cone angle and low buried volume that characterizes the alkyl aryl-phosphines proposed by Doyle and Wu, help rationalize the high yields obtained in the Ni-catalyzed coupling represented in Fig. 33. The same authors verified the efficiency of these ligands and the reliability of the proposed mathematical model, taking into consideration a wide range of acetals and aryl boronic derivatives. The approach appears to yield general conclusions and can be extended to a series of substrates. Moreover, some recent developments of the machine learning approach in this field have recently been published by Doyle and co-workers, demonstrating the effectiveness of statistical models in predicting the final outcome of a catalytic process.113b,c

13.11.5.3 Catalytic trends of transition metal complexes bearing diphosphines As already mentioned in Section 13.11.2, the great importance of diphosphine ligands in homogeneous catalysis has prompted chemists to find criteria to modulate their stereoelectronic characteristics in order to obtain high yields and selectivity in various catalytic processes. In this context, by far the most used descriptor for diphosphine ligands is the bite angle. Among the many examples that can be found in the literature, we have decided to report in Fig. 35 some model C-C and C-N cross-coupling reactions catalyzed by transition metal complexes in the presence of diphosphine ligands.79 The first reaction reported in Fig. 35, which involves the C-C coupling between bromobenzene and sec-butylmagnesium chloride, was studied by Hayashi and Kranenburg and showed, as reported in Table 18 (Entry 1), an increase in the reaction yield with increasing bite angles (positive bite angle effect).114 For the Heck arylation of 5-hexen-2-one with 1-bromo-4-fluorobenzene, a strong dependence on the regioselectivity of the process was noted as a function of the type of diphosphine ligand used (Entries 2–3 of Fig. 35 and Table 18).115 In particular, the use of phosphines with high bite angles (e.g., dppf or Xantphos) favors the formation of the product 17 (positive bite angle effect) whereas phosphines with a lower bite angle (e.g., dppp) favor the g-phenylated g,d-unsaturated ketone 16 (negative bite angle effect). Among the examples of C-N couplings, the diarylation of urea (Entry 6) is particularly noteworthy since, as observed by Beletskaya and co-workers, it proceeds with high yields only with the wide bite angle ligand XantPhos (positive bite angle effect).116 Conversely, in the synthesis of alkylaryl amine 21 (Entry 7), Hartwig and Hamann observed an increase in the reaction yield with the decrease of the bite angle of the diphosphine used (negative bite angle effect).117 A possible explanation provided by the authors deals with the probable dissociation of one of the two phosphorus arms for high bite angle ligands. Thus, the resulting three-coordinate species efficiently promotes b-hydrogen elimination rather than the desired reductive elimination. Similarly to what has been seen for monodentate phosphines, dozens of descriptors have also been proposed for the diphosphine ligands in the attempt to apply multidimensional analyses that can explain and potentially predict the catalytic trends for reported reactions.110 In addition to the bite angle, other steric parameters useful for this purpose are the percent buried volume and the solid cone angle. In this context, for example, the activation barrier of nickel-catalyzed coupling of carbon dioxide and ethene was calculated and correlated, by means of a multilinear regression, to the percent buried volume of the 12 different diphosphines and the Mulliken charge in the Ni atom (Fig. 36).118

13.11.5.4 Parameterization of transition metal complexes bearing diphosphines The extension of the Ligand Knowledge Base approach also to diphosphine ligands (LKB-PP) constitutes a database where one can extract the desired descriptors for use in a given reaction and includes more than 320 different diphosphines.110 Some examples of the descriptors contained in this library are reported in Table 19 and have allowed to explain and in a few cases predict some characteristics of systems involving diphosphine ligands. Girolami and Frenking have successfully analyzed the characteristics of the bonds in nickel dihydride complexes in relation to their decomposition energy.119 However, unlike monodentate phosphines, the difficulty in finding simple multivariate models that are able to simulate and predict the catalytic trends, observed, for example, in palladium-catalyzed amine arylation reactions with diphosphine ligands, is a limitation.

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Fig. 35 Examples of C-C and C-N cross coupling catalyzed by Pd complexes in the presence of diphosphine ligands.79

Table 18 Entry

1 2 3 4 5 6 7

Effect of diphosphine ligands on yields in the reactions reported in Fig. 34.79,114–117 Product

15 16 17 18 19 20 21

Diphosphine ligands and isolated yields (%)

Bite angle effect

dppp

BINAP

dppf

DPEPhos

XantPhos

43 86 14 56 12 / /

/ 37 63 88 73 17 91

95 26 74 54 45 22 52

98 / / / / 17 11

41 23 77 46 74 89 47

Positive Negative Positive Negative Positive Positive Negative

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491

Fig. 36 Nickel-catalyzed coupling of carbon dioxide and ethene.118

Table 19

Examples of descriptors used for diphosphine ligands in LKB calculations.110

Parameter

Derivation

He8_wedge

Interaction energy between the free diphosphine ligand and wedge of 8 He atoms (P atoms in fixed position and fixed P-X distance of 2.28 Ǻ) Energy of highest occupied orbital (truncated ligand LP1, LP2) Energy of lowes unoccupied orbital (truncated ligand LP1, LP2) Proton affinity for the truncated ligand (PA ¼ E(LP1)-E([LP1-H]+)) Average Zn-Cl distance (Ǻ) in a Zn(PP)Cl2 complex Bond energy dissociation of the ligand from the metal centre in Zn(PP)Cl2 Bite angle in a Zn(PP)Cl2 complex NBO charge on ZnCl2 fragment Bond energy dissociation of the ligand from the metal centre in Pd(PP)Cl2 Average Zn-Cl distance (Ǻ) in a Pd(PP)Cl2 complex Bite angle in a Pd(PP)Cl2 complex NBO charge on PdCl2 fragment

EHOMO_P1, EHOMO_P2 ELUMO_P1, ELUMO_P2 PAP1, PAP2 Zn-Cl BE(Zn) P1-Zn-P2 Q(Zn) BE(Pd) Zn-Cl P1-Pd-P2 Q(Zn)

13.11.5.5 Catalytic trends of transition metal complexes bearing NHC ligands The use of electronic and steric descriptors has allowed several authors to rationalize the performances of well-defined metal-NHC catalysts for a wide range of important organic transformations. A first example in this context concerns the C-H activation and deuteration of primary sulfonamides catalyzed by [Ir(COD)(NHC)Cl] complexes.120 For this reaction, Tuttle and Kerr demonstrated the possibility of combining the Tolman Electronic Parameter (TEP) and the percent buried volume (%Vbur) to explain the observed catalytic trend and therefore to identify the ideal species to promote the process. The deuteration percentages shown in Fig. 37 suggested that this process is favored by catalysts bearing bulky NHCs and in particular those with percent buried volume greater than 33%. The high steric hindrance might favor the reductive elimination step and therefore the overall process. Moreover, if we compare NHC ligands with similar steric demand such as IMes and IMesMe, it should be noted that the reaction is favored by more electron rich ligands (TEP ¼ 2049.6 and 2046.7 cm−1, respectively).

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Fig. 37 Deuteration of primary sulfonamides catalyzed by [Ir(COD)(NHC)Cl] complexes.

Among the different complexes tested, the most efficient one is [Ir(COD)(IMesMe)Cl], which was then used by the authors as a model catalyst for the transformation of a wide range of primary sulfonamides, thus demonstrating the general validity of the process. In this context, its utility in labeling more complex substrates such as Celecoxib and Mavacoxib, which are COX-2 inhibitors commercialized by Pfizer, was demonstrated. Finally, the authors carried out some detailed mechanistic studies and proposed a catalytic cycle that is most in agreement with the experimental evidence. In 2006, Sigman and co-workers reported the influence of steric parameters in the reaction between [Ni(NHC)(Z3-allyl)Cl] pre-catalysts and oxygen.121 Complexes bearing bulky NHC ligands such as ItBu and IAd are stable in solution for at least 48 h whereas less bulky analogs, such as IMe, ICy and IMes, undergo oxidation to the corresponding [Ni(NHC)(m-OH)Cl]2 dimers in a few seconds/min, using benzene or THF as solvents (Fig. 38). It is therefore possible to establish a qualitative scale of reactivity of the starting allyl complexes based on the percent buried volume values of the carbene ligands anchored to them. The role of the NHC ligand is to block one or both of the empty axial sites above and below the square plane configuration. A strong correlation was found between the reactivity of these complexes with the conformational freedom about the nickel-NHC bond. Thus, complexes with hindered rotation are stable to oxygen while species with free rotation or with intermediate conformational freedom react with oxygen. This observation is consistent with a mechanism requiring the adoption of a nonplanar geometry about the metal center as a requirement for reaction with O2.

Fig. 38 Oxidation of [Ni(NHC)(Z3-allyl)Cl] pre-catalysts.

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493

Fig. 39 Photoredox oxidative addition of L-Au-Cl complexes (L ¼ PR3 or NHC) with aryl-diazonium salts to the corresponding (C,N)-cyclometallated Au(III) species.

In 2016, Glorius and colleagues, with the aim of studying in detail the oxidative addition promoted by photoredox catalysts between aryl-diazonium salts bearing a pendant pyridine moiety and L-Au-Cl complexes (L ¼ PR3 or NHC) to afford the corresponding (C,N)-cyclometallated Au(III) complexes, observed that the process occurs efficiently for both phosphine and carbene ligands with little influence of their electronic properties.122 Conversely, a strong dependence on the steric hindrance in the starting Au(I) complexes was observed and in particular a decrease in the reaction yield was correlated with an increase in steric demand (Fig. 39). This evidence explains the poor efficiency of complexes bearing ligands with %Vbur > 44 that were reported by the same group in 2013.123 The mechanistic hypothesis that was proposed suggests that the oxidation of the starting gold(I) complexes occurs by a photogenerated aryl radical to the corresponding gold(II) complexes which then evolves into a cyclometallated gold(III) species.122 Another interesting category of reactions in which both steric and electronic parameters have been taken into consideration is represented by palladium-catalyzed cross couplings. In particular, in the last two decades, among the numerous palladium compounds studied for this purpose, [Pd(NHC)(Z3-allyl or cinnamyl)Cl] complexes have played a crucial role.124 With the aim of studying the coupling of two aryl groups and in particular those that lead to the formation of tetra-substituted biaryl compounds, Nolan and co-workers found that the most efficient well-defined Pd(II)-allyl (or cinnamyl) precatalysts present bulky and electron-rich ligands.125 In particular, they have demonstrated the high catalytic activity, even under very mild conditions, of [Pd(IPr )(Z3-cinnamyl)Cl] (Fig. 40).126 The ligand IPr , in addition to having a high steric hindrance, similar to IPent, more efficiently promotes the coupling between the two aryl units due to its good flexibility, which allows it to adapt its shape to the surrounding environment. Nolan and colleagues used both %Vbur and steric maps to explain the observed catalytic trends for Pd(II)-cinnamyl complexes. The result of this study is that the good flexibility and above all the high steric demand of IPr compared to all the other NHCs studied (e.g., IPr, SIPr, IPent and anti-(2,7)-SICyoctNap) makes this ligand the best for this process.

Fig. 40 Synthesis of tetra-substituted biaryl compounds catalyzed by [Pd(IPr )(Z3-cinnamyl)Cl].

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Furthermore, the steric map calculated for [Pd(IPr )(Z3-cinnamyl)Cl] reveals two particularly congested quadrants and the other two with a sufficiently low steric hindrance to allow the approach of the substrates and therefore the resulting C-C coupling. The intermediate species [Pd(IPr )(Ar1)(Ar2)], by virtue of the high congestion of the other two quadrants, is then particularly prone to the reductive elimination of the desired tetra-substituted biaryl compound (Ar1-Ar2). About the use of steric maps to describe the bulkiness of metal-NHC complexes, other processes where this approach has been used as a powerful tool to explain catalytic trends are particularly worthy of mention. A first interesting example concerns the Pd(II)-catalyzed a-arylation of ketones with aryl chlorides.127 This type of reaction, similarly to C-C cross couplings, can be promoted by Pd(II)-allyl complexes bearing NHC ligands. In particular, Bertrand and colleagues used the concept of steric maps to design a well-defined Pd(II)-allyl precatalyst bearing a six-membered cyclic(alkyl)amino carbene (CAAC-6) capable of catalyzing a-arylation of ketones with both hindered and less hindered aryl chlorides.127 In an earlier work, the palladium complexes bearing five-membered CAACs (CAAC-5) were able to promote this process only with unhindered aryl chlorides such as chlorobenzene and that this reaction is more efficient with the bulkier complex 22 compared to complex 23 (yields: 100% and 11%, respectively). Given the failure of the reaction, for both complexes, with the bulkier 2-chloro-m-xylene, the authors thought that the more electron-rich six-membered cyclic (alkyl) aminocarbene (CAAC-6) reported in Fig. 41 (complex 24), which has both a high steric hindrance and greater flexibility, could be an ideal candidate for this reaction.

Fig. 41 a-Arylation of ketones catalyzed by Pd(II)-allyl complexes bearing CAAC-5 and CAAC-6 ligands. Adapted from Falivene, L.; Cao, Z.; Petta, A.; Serra, L.; Poater, A.; Oliva, R.; Scarano, V.; Cavallo, L. Nat. Chem. 2019, 11, 872–879.

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Indeed, complex 24 was shown to catalyze both the reaction with chlorobenzene (yield: 99%) and that with 2-chloro-m-xylene (yield: 86%). A further explanation of this catalytic trend is in the smaller hindrance of complex 24 along the north to south axis compared to complex 22. This favors the approach and consequent coupling of the two organic substrates. A really appealing field of application for steric maps is the study of enantioselective processes. In this context, the use of chiral NHCs for a wide range of organic transformations, and in particular in hydrogenation reactions, is well known.128 Although many chiral ligands are added to the reaction environment to form the catalytically active species in situ, some examples of well-defined chiral complexes are, however, known. Lautens and co-workers reported the structure and use of [Rh(IBiox(−)-mentlyl)(CO)2Cl], which has proven particularly efficient as a catalyst for the enantioselective hydroarylation of alkenes using boronic acid substrates (Fig. 42).129 If we analyze the steric maps of this complex and its non-chiral analog [Rh(IBioxMe4)(CO)2Cl],130 it is clear that in the latter there is very little difference in terms of steric hindrance in the various quadrants. Conversely, in the chiral complex [Rh(IBIox(−)-mentlyl)(CO)2Cl] it is possible to identify a very specific catalytic pocket, which therefore orients both the entry of the substrate and the stereochemistry of the final product.

13.11.5.6 Catalytic trends of transition metal complexes bearing other ligands For ancillary ligands other than phosphines and N-heterocyclic carbenes, numerous reports have appeared that correlate steric and electronic characteristics, using some of the various descriptors listed above, and the observed catalytic trends. An interesting example concerns the asymmetric addition of phenylboronic acids to 2-cyclohexenone catalyzed by rhodium complexes bearing chelating S,S ligands.97 This type of reaction occurs with high enantiomeric excesses (ee > 90%) with both rhodium complexes examined (complexes 25 and 26 in Fig. 43).

Fig. 42 Enantioselective hydroarylation of alkenes using boronic acid substrates and catalyzed by [Rh(IBiox(−)-mentlyl)(CO)2Cl].

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Fig. 43 Asymmetric addition of phenylboronic acids to 2-cyclohexenone catalyzed by rhodium complexes bearing chelating S,S ligands. Adapted from Poater, A.; Ragone, F.; Mariz, R.; Dorta, R.; Cavallo, L. Chem. Eur. J. 2010, 16, 14348–14353.

Although the performance of complex 25 is in accordance with the specific catalytic pockets that are identifiable from the corresponding steric map, the very high enantioselective induction obtained by the small and upward-oriented S]O moieties of complex 26 is surprising. To explain this outcome, Poater and Cavallo performed the characterization, by means of DFT calculations, of the catalytic pockets present in the two different complexes. This in-depth steric analysis confirmed the high asymmetry of the catalytic pocket of complex 25 whereas it highlighted a decidedly flatter catalytic pocket for complex 26. It is therefore evident that the high enantioselectivity imparted by 26 is not attributable only by examining its steric characteristics. In this context, the analysis of the catalytic pocket using electrostatic potential maps has shown an exactly opposite trend compared to the steric type analysis. It is possible to note a substantially flat electrostatic map for complex 25 while a high electronic asymmetry is visible in complex 26. This last datum therefore explains that both complexes are efficient enantioselective catalysts while showing in one case a marked steric asymmetry and in the other case an electronic asymmetry of the catalytic pocket.

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497

13.11.5.7 Parameterization of transition metal complexes bearing other ligands As far as multidimensional approaches are concerned, a noteworthy example was reported by Du Bois and Sigman in 2014 for the model complex [Rh2(esp)2] (esp ¼ a, a, a0 , a0 -tetramethyl-1,3-benzenedipropionic acid).131 In this report, the authors studied the steric and electronic parameters that explain the catalytic trend observed in the Rh-catalyzed C-H amination of isoamylbenzenes with a wide range of sulfamate esters (Fig. 44). In particular, in addition to the optimization of the reaction conditions and detailed mechanistic studies, it was possible to obtain a correlation between the selectivity of the process, expressed as DDG+ between the benzyl and tertiary products, and the ~ CO), the intensity of O − S − N asymmetric combination of three parameters: the calculated carbonyl stretching frequency (V 131 stretching (IOSN) and the Hammett parameter (sm) of the sulfamate ester (Eq. 16). ~ CO
sm + 0:17
V ~ CO + 0:26
IOSN DDG + ¼ − 0:01 − 0:86
sm − 0:11
V

(16)

This model, in addition to describing fairly well the substrates initially examined, allowed the development of a novel sulfamate ester (compound 27 in Fig. 43) which provided the highest benzylic-to-tertiary site selectivity (94:10) so far observed for this type of reaction. In 2015, Copéret prepared a wide range of silica-supported tungsten imido-alkylidene complexes bearing different L ancillary ligands (OtBuF9, OtBuF6, OSi(OtBu)3 and Me2Py) and NAr groups (NArIPr, NArF5, NArCF3 and NArCl).132 The authors investigated their catalytic activity toward self-metathesis of cis-4-nonene and observed the best performance with NAr and L ligands with opposing electronic properties (push-pull effect), as reported in Fig. 45. A multivariant linear regression analysis provided a quantitative relationship between the steric and electronic influences of NAr and L, and the activity of these supported metathesis catalysts. In particular, the authors determined an equation that correlates the Turn Over Frequency (TOF) with stereoelectronic parameters derived from the parent organic molecules HL and ArNH2. The result of this regression, reported in Eq. (17), showed that the model is composed of two interactive terms: the NBO charge of the ArNH2 nitrogen (NBON,ArNH2) combined with a steric term, Sterimol B5 of HL (B5,HL), and the same NBO charge combined with the pKa of HL (pKa,HL).   TOF ¼ 53:8 + 16:6
ðNBON, ArNH2 Þ
ðB5, HL Þ + 33:6
ðNBON, ArNH2 Þ
pka, HL (17) It is worth mentioning that the NBO charge on the ArNH2 nitrogen is intimately linked to the pKa of anilines and was obtained through the classical natural population analysis. This descriptor is also an index of the donating ability of the amido nitrogen toward the tungsten metal center. At the same time, the dipole that has formed between the metal center and the alkylidene carbon is stabilized by the electron-withdrawing character of the L ligand, which is quantified in the model by the parameter pka,HL. From the experimental data and the regression, it is evident that the best catalyst contains the most electron-rich NArIPr group and the more acidic L ligand OtBuF9 (pka tBuF9OH ¼ 4.91). Other examples of multidimensional analysis in asymmetric catalysis were summarized and explained in detail by Sigman and co-workers in 2016.133 This approach, as we have explained above for phosphine ligands, presents the severe limitation of correlating many parameters, some of which are not easy to interpret and obtain, and above all it cannot be extended to even very similar reactions. The correlation and the number of parameters in fact change from case to case and requires iterative processes to achieve the final output. Although this technique is time consuming and decidedly not intuitive for classical organometallic

Fig. 44 Rh-catalyzed C-H amination of isoamylbenzenes with sulfamate esters.

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Fig. 45 Self-metathesis of cis-4-nonene catalyzed by silica-supported tungsten imido-alkylidene complexes bearing different L and NAr fragments.

chemists, it has allowed in some cases to simulate and predict surprisingly well the enantiomeric excess of important reactions such as the peptide-catalyzed desymmetrization of bisphenols, the rhodium-catalyzed asymmetric hydrogenations of ketones and Pd-catalyzed Heck cross-coupling reactions.133 The parametrization of ligand properties is a tool to understand and ultimately predict the reactivity. One can see from the short account of the evolution of such descriptors that we have come a long way, yet much remains to be done to fully understand the latest descriptors and, of course, to come up with even more powerful ones.

Acknowledgment The UGent BOF (starting and project grants to S.P.N.) and the Moonshot project D2M are gratefully acknowledged for support.

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13.12 High-Throughput Experimentation in Organometallic Chemistry and Catalysis David C Leitch and Joseph Becica, Department of Chemistry, University of Victoria, Victoria, BC, Canada © 2022 Elsevier Ltd. All rights reserved.

13.12.1 Introduction 13.12.1.1 Purpose and scope of this chapter 13.12.1.2 Additional reviews and resources 13.12.2 Tools and techniques 13.12.2.1 Experimental design 13.12.2.2 Array set up and dispensing 13.12.2.3 Reaction execution 13.12.2.4 High-throughput analysis 13.12.2.5 Data interrogation 13.12.3 Specific applications in catalysis 13.12.3.1 CdH bond formation: Asymmetric hydrogenation 13.12.3.2 CdC bond formation: Suzuki-Miyaura cross-coupling 13.12.3.3 CdC bond formation: Negishi and Kumada-Corriu couplings 13.12.3.4 CdC bond formation: Cross-electrophile couplings 13.12.3.5 CdC bond formation: Mizoroki-Heck coupling 13.12.3.6 CdC bond formation: Sonogashira coupling 13.12.3.7 CdC bond formation: C-H arylation 13.12.3.8 CdC bond formation: Allylation 13.12.3.9 CdC bond formation: Carbonylative coupling 13.12.3.10 CdC bond formation: Alkene metathesis 13.12.3.11 CdC bond formation: Alkene polymerization and selective oligomerization 13.12.3.12 CdC bond formation: Other reactions 13.12.3.13 CdN bond formation: Buchwald-Hartwig and Ullmann-Goldberg coupling 13.12.3.14 CdN bond formation: Chan-Lam and other oxidative couplings 13.12.3.15 CdN bond formation: Hydroamination 13.12.3.16 CdN bond formation: Other reactions 13.12.3.17 CdO bond formation: Hydroxylation/etherification 13.12.3.18 CdO bond formation: Other reactions 13.12.3.19 CdB bond formation: Miyaura borylation 13.12.3.20 CdB bond formation: C–H borylation 13.12.3.21 Other reactions 13.12.4 Conclusions and future trends Acknowledgment References

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13.12.1 Introduction Every synthetic chemist has, at some point, been confronted with the same general problem: how do I know that my chemistry is optimized? How can I be sure that the current experimental conditions provide the best results, be it in terms of chemical yield, selectivity, generality, or the realization of a fundamentally new chemical transformation? At its core, this is a many-variable problem with myriad possible solutions; however, the resources (i.e., time and material) available to deploy on any particular problem necessarily limits the space that can be explored. While this challenge is common to all varieties of synthetic chemistry, it is especially relevant in the context of catalysis. In general, the number of possible variables and the corresponding range of settings for those variables increases substantially in catalytic reaction systems. Furthermore, subtle changes can (and often do) have dramatic and unexpected effects on the outcome of catalytic reactions. This is just as true of the catalyst itself, where a small change to a structural feature can significantly enhance or diminish activity or selectivity, as it is for the other reaction conditions, where a change of solvent or base can similarly alter the reaction course. Faced with this fundamental and prevailing challenge, most synthetic chemists are trained to treat each variable or factor individually, in a so-called One Factor at a Time (OFAT) or One Variable at a Time (OVAT) exploration of the reaction landscape (Fig. 1, left). This intuitive method has the experimenter hold all but one factor constant in order to isolate the effect of the varied factor. An organometallic-relevant example is given here for the Pd-catalyzed carbonylation of an electron-deficient Ar-Cl, where the first factor screened is ligand identity under otherwise identical reaction conditions (entries 1–16).1 Iterative optimization of each

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Fig. 1 An example of OFAT (left) versus multivariate experimentation (right) in the optimization of a Pd-catalyzed carbonylation reaction. By screening phosphine ligands using only DIPEA and ACN in the OFAT approach, many other successful catalyst systems are missed. Performing a high-throughput screen in a 96-well array enables all of the variable combinations to be explored. From Allen, C.L.; Leitch, D.C.; Anson, M.S.; Zajac, M.A. Nat. Catal. 2019, 2, 2–4.

factor in turn—the solvent, reagents, temperature, concentrations, etc.—will ultimately reveal an “optimal” set of conditions (here entries 16–21, exploring solvent and base). Not only is this technique intuitive and satisfying, it typically requires only a modest number of individual experiments to complete. Unfortunately, it is also likely to miss critical information about the reaction system; namely, any significant interactions between variables. This often leads to optimization toward a local maximum, rather than a more global maximum, and also obscures important aspects of the underlying chemistry. In the example of Fig. 1, OFAT optimization leads to 81% yield using the conditions in entry 16. An alternative approach is multivariate experimentation, where many factors are changed simultaneously (Fig. 1, right). This is a common and powerful method for understanding and optimizing complex systems using statistical techniques such as Design of Experiments2–5 and multivariate regression.6–8 While discrete reaction variables (time, temperature, concentration) are easily handled by such techniques, synthetic chemists are also concerned with understanding and optimizing categorical variables (identities of catalyst, solvent, reagents). Achieving sufficient experimental coverage of these categorical factors in a multivariate experimental design requires running a lot of individual experiments: a modest set of 16 catalysts, 3 bases, and 2 solvents for the example in Fig. 1 results in 96 combinations. Upon performing all of these individual experiments, it is clear that many promising reaction conditions and catalysts were missed in the initial OFAT design. Even a mostly OFAT exploration of a large catalyst library—such as for an asymmetric hydrogenation—will result in dozens, if not hundreds of potential experiments. Performing such large sets of reactions in a timely and consistent manner is the hallmark of high-throughput experimentation (HTE). HTE necessarily requires miniaturization and automation of key operations; hence, much effort has been expended in designing and creating new tools and equipment for this purpose. But it also requires the experimenter to “think in arrays” when designing new experiments, rather than relying only on OFAT designs. For applications in synthetic chemistry, both aspects—the tools and the mindset—are critical for success in HTE. HTE, like all experimental techniques, is a means to an end. For organometallic chemistry and catalysis, often that end is an optimized chemical reaction (or at least the beginnings of one) or identification of a suitable catalyst. As the tools and technique develop further, synthetic chemists are starting to use HTE to address different and more varied research questions. While HTE

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contributes significantly to the direct optimization of a catalyzed reaction, catalysis enabled by HTE methods can impact chemical discovery and process development in many other ways. The same HTE methods used to highly optimize a single chemical reaction are being used to discover new chemical reactions,9–11 expand the scope or robustness of known chemical reactions,12–14 and to lay the data foundation for predictive models of chemical reactivity.7,15

13.12.1.1 Purpose and scope of this chapter Since the previous version of this Chapter in COMC-III, published in 2007,16 there has been even wider adoption and exploitation of HTE methods in organometallic chemistry and catalysis research. This includes expanded use within industrial research labs, most notably in the pharmaceutical industry, as well as the establishment of academic centers dedicated to HTE. The tools themselves have gotten more sophisticated, including those enabling experimental design, set-up, execution, analysis, and data curation. The scope of chemical problems addressed by HTE techniques has also grown, with increasingly complex experimental designs being deployed against increasingly complex target reactions and products. This aspect of pushing the boundaries of HTE in catalysis is currently being driven in large part by applications in pharmaceutical research and development, as well as in collaborations between academic and industrial research labs.17 HTE is also extensively used for many applications within synthesis and catalysis beyond organometallic chemistry. These include reactions involving heterogeneous catalysts,18 enzyme catalysts,19 Lewis or Bronsted acid catalysts,20 photocatalysts,21 or no catalyst.22 In preparing this Chapter, we have defined HTE as any form of parallel experimentation performed simultaneously (or in rapid succession) on small scale that is designed to study the effects of changing variables on organometallic reactivity. Therefore, we will not cover HTE as applied to heterogeneous catalysis (except in a few exceptional cases where there are clear organometallic insights), enzymatic catalysis, or non-organometallic aspects of reaction/process optimization. We also have excluded most examples of combinatorial synthesis involving standard catalytic conditions, since these aim to prepare libraries of compounds rather than study catalysis (though there are exceptional examples covered that do both). While we endeavor to highlight as many examples as possible, we devote more discussion to examples offering insights that would be difficult or impossible to realize without a high-throughput approach. Finally, to ensure continuity from the previous volume, we cover the published literature from 2006 until late 2020. In presenting a comprehensive overview of HTE in organometallic chemistry over the past 15 years, this Chapter has two major purposes: to outline the principles, tools, and techniques relevant to conducting HTE with organometallic systems; and to provide a descriptive overview of key examples from the published literature where HTE has been applied in organometallic catalysis. By combining coverage of these two aspects of HTE, we hope to not only give the reader an appreciation for the current state-ofthe-art, but to show researchers that are new to the area both the power and accessibility of the technique. Section 13.12.2 takes a “workflow” based approach to describing the tools and techniques needed for successful implementation of HTE. We outline the hardware and software required to perform HTE on organometallic systems within the context of a general experimental workflow; this is based on published accounts and the authors’ prior experience. The information in Section 13.12.2 serves as a general roadmap for researchers seeking to build their own HTE platform, and also provides context for the remaining content. Section 13.12.3 covers specific examples of HTE drawn from a broad range of reactions, categorized by the type of bond formation and sub-divided according to specific reaction class (often a named-reaction). The examples within each sub-division are chosen to highlight: (1) what reaction classes are prevalent in the chemical industry; (2) how investigation of exemplar reactions is carried out using HTE; (3) what fundamental insights into organometallic chemistry are obtained in the process; (4) how combining HTE and mechanistic experiments lead to greater insights and more robust chemical processes; and (5) new organometallic reactions unveiled by HTE. Finally, Section 13.12.4 concludes with a forward-looking view of HTE in organometallic chemistry, seeking to envisage what advances the next 10–15 years will bring.

13.12.1.2 Additional reviews and resources There are a plethora of review articles published since 2006 that cover many aspects of HTE in organometallic chemistry and catalysis. In addition to the prior version of this Chapter from COMC-III,16 several reviews, perspectives, and accounts have appeared that focus on specific industries, such as commodity chemicals/materials23 and pharmaceuticals.22,24–28 Other reviews take a more practical bent, with an intent to show others how to carry out HTE in their own laboratories1,29 including how to assemble a suitable ligand library.30 There are also perspectives on HTE in academia.31–34 Other highly pertinent reviews are more focused on specific reaction classes, but do address aspects of HTE. As is clear from the distribution of HTE examples throughout this Chapter, several important reaction classes from an HTE perspective are alkene polymerization,35,36 asymmetric hydrogenation37–42 and cross-coupling.43

13.12.2 Tools and techniques Performing HTE in any discipline is often associated with sophisticated automation equipment, including custom-built robotics, operated by a dedicated technical staff. This leads to a perceived high-bar for entry that excludes smaller research operations such as start-up companies and academic groups. This perception is reinforced by the fact that many high-throughput-based experimental

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studies are reported by industrial R&D labs at relatively large companies. These operations are able to acquire, operate, and maintain the capital- and resource-intensive equipment that tends to be synonymous with HTE. The two sectors that have historically driven HTE innovation for synthetic chemistry are petrochemicals—specifically polyolefin synthesis—and pharmaceuticals—especially process research and development. Many of the most important tools and techniques were developed by these various industrial laboratories in collaboration with companies that specialize in scientific equipment. In addition to industrial research involving HTE, many academic institutions have adopted a center-based model to establish HTE platforms for synthetic chemistry research. These include (but are not limited to) the Center for Catalysis Research and Innovation at the University of Ottawa,31,34,44 the High Throughput Experimentation Center at the University of Pennsylvania,45–47 the Catalyst Development and Discovery Laboratory at Cornell University,48 the Catalysis Research Laboratory (CaRLa) at the University of Heidelberg,33 the Center for Catalysis and Chemical Synthesis at the California Institute of Technology,49–51 the Merck Catalysis Center at Princeton University,10,52 and the KAUST Catalysis Center at King Abdullah University of Science and Technology.53 These centers have made HTE more accessible to academic research labs, leading not only to new discoveries, but also the opportunity for students and postdoctoral researchers to learn HTE workflows and principles. Notably, nearly all of these centers specifically refer to catalysis in their names. In academia, as in industry, the major application of HTE in synthetic chemistry is in catalysis research. While the large industrial lab model and the academic center model are certainly successful and perhaps most visible, there is a growing recognition that investing millions of dollars in capital investment and hiring dedicated staff are not necessary to achieve HTE capabilities for synthetic chemistry. More important is establishing a suitable workflow, enabled by the right tools, to perform array-based experimentation. Performing thousands of highly-repetitive individual experiments requires a very different platform than performing hypothesis-driven array experiments that each contain dozens of individual reactions. The following sections will discuss the various tools and techniques that are currently used, at varying degrees of sophistication (and cost), for each step of a general high-throughput workflow (Fig. 2). These levels are “Essential” (intended as economical and widely available), “Preferred” (to provide versatility in the types of chemistry under investigation), and “Advanced” (high-end equipment, miniaturization, and maximum utility). Our hope is to not only give the reader an understanding of these tools and techniques, but also to provide a roadmap for almost any synthetic chemistry research group to incorporate aspects of HTE into their own work.

13.12.2.1 Experimental design The most important aspect of successful HTE is experimental design. It does one no good to perform thousands of aimless experiments, or to collect huge amounts of unreliable or inconsistent data. Fortunately, this aspect of HTE has a very low barrier to entry from a cost/capability perspective, though it does require chemistry researchers to change their mindset away from OFAT designs and toward multivariate designs. Many HTE practitioners (the authors included) maintain that HTE is more about this mindset than the tools themselves. A well-designed series of high-throughput experiments carried out with simple, manual tools will likely yield greater insight than a poorly-designed but highly automated version. In terms of specific tools used for experimental design, there are many pieces of software available. As an “Essential” option that is widely-available and (reasonably) user-friendly, Excel (and/or related spreadsheet applications) can handle automated stoichiometry calculations, providing a simple means of designing and documenting an array experiment. Excel-based templates, often coupled with electronic notebooks, are a low-barrier approach that is within the means of every synthetic laboratory. Some groups may adopt “Preferred” chemistry-specific experimental design options, such as Unchained Laboratories Library Studio (familiar to all those who have used Symyx/Freeslate/Unchained equipment), that are more task-specific. Finally, there are many “Advanced” applications for more sophisticated experimental designs. Several statistical packages focused on Design of Experiments are

Fig. 2 A general high-throughput experimental workflow, with three levels of equipment sophistication. An “essential” equipment build makes HTE accessible to nearly any laboratory.1

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available, including JMP, Design Expert, Modde and others, all of which are no doubt familiar to process chemists. Finally, there are also many general and powerful statistics packages and mathematics applications to enable complex experimental designs and data analyzes that rely on parameterization (vide infra). For HTE applied to organometallic catalysis, there is one specific aspect of experimental design that is critical: the method of generating and/or activating the catalyst. HTE designs will most frequently employ some form of in situ catalyst generation. One approach is the activation of a “single-component” precatalyst—where the ancillary ligand is already metallated—with an appropriate reagent or co-catalyst; this is most familiar in the context of alkene polymerization or alkene metathesis, both of which rely on well-defined organometallic precatalysts, but is also increasingly employed in cross-coupling catalysis.54–58 These experimental designs depend on the availability of precatalyst libraries, each member of which must be synthesized, isolated, and purified before being used. For experimental designs focused more on other reaction variables, using single-component precatalysts is an excellent way to simplify material dispensing. Another approach to catalyst generation is to use a combination of a metal precursor and “free” ligand to achieve in situ metallation; this is frequently used in catalysis for organic synthesis, even in a non-HTE context. One well-known example of this approach is in cross-coupling catalysis, where a relatively simple Pd or Ni source (e.g., Pd(OAc)2, Ni(COD)2, etc.) is combined with a phosphine or carbene ligand to create an active catalyst within the reaction mixture; another is in asymmetric hydrogenation, where a library of chiral ligands will be combined with an appropriate organometallic precursor (e.g., [Ir(COD)Cl]2, [Rh(nbd)2] [BF4], etc.). While this approach can introduce a creeping doubt in the mind of an organometallic chemist—Are we sure the ligand is metallated? What else could be happening?50—in many cases it is far more practical and operationally convenient, especially when sifting through large numbers of possible catalysts. Assembling and maintaining a large library of potentially sensitive organometallic complexes as precatalysts is impractical, while assembling and maintaining libraries of ligands and metal precursors is not only easier, but also enables far greater diversity through combinatorial experimental designs. For HTE in organometallic chemistry, having access to a sufficiently diverse ligand library30 is one of the most important aspects of successful experimental designs. In situ catalyst assembly also introduces an additional set of variables to study. Metal-to-ligand stoichiometric ratios, order-of-addition, and differential metallation/activation reactivity based on the identity of the metal precursor can all impact the outcome of a reaction. To address this last point, several groups have developed new organometallic complexes for in situ catalyst assembly, particularly those based on Ni (Fig. 3). One key example is (TMEDA)Ni(o-tolyl)Cl, which was simultaneously reported by Doyle59 and Magano and Monfette.60 The latter authors, part of process development at Pfizer, explicitly state that compatibility with HTE dispensing protocols was a motivation for the development of this Ni source. More recently, Cornella and coworkers reported an air-stable Ni(0) complex based on fluorinated stilbene ligands,61 and a collaboration between the Engle group and BristolMyers-Squibb process chemistry repurposed an already-reported Ni(0) quinone complex as a bench-stable precursor for cross-coupling catalysis.62 In terms of addressing specific research questions with HTE, there are a large number of possible approaches to experimental design. Here, we provide examples in three general categories: (1) optimization; (2) reaction scope and/or robustness; and (3) reaction discovery. This is not an exhaustive categorization of HTE designs, but it does capture the majority of HTE work in organometallic chemistry. HTE for optimization, including catalyst discovery, is perhaps the most familiar form of the technique; accordingly, it is used in the vast majority of specific examples covered in Section 13.12.3. These types of designs can take the form of a “full-factorial” (terminology from Design of Experiments), wherein all of the variable combinations are run; the carbonylation design from Section 13.12.1 is representative of this approach. An alternative is a large OFAT design that explores a ligand library under a single set of reaction conditions; this approach is very common in asymmetric hydrogenation (Section 13.12.3.1). A typical workflow is to carry out successive, hypothesis-driven optimization screens that build on the information gained from each screen until the target outcome (yield, productivity, selectivity) is reached. One major challenge in HTE design for catalysis is the prevalence of categorical variables. While continuous variables such as time, temperature, absolute and relative concentrations, and others can be modeled quantitatively using statistical or kinetic approaches, often the main variables of interest are the specific identities of substrate, catalyst, ligand, solvent, additive, etc. Converting these categorical variables into sets of numerical parameters can help both with experimental design and subsequent data analysis (Section 13.12.2.5). As an exemplar of this approach for organometallic chemistry, Fey and coworkers are developing a

Fig. 3 Ni sources for in situ catalyst assembly.59–62

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Fig. 4 Principal component analysis of the Ligand Knowledge Base—Phosphines (LKB–P), providing a quantitative measure of structural and electronic diversity based on computed parameters. Reprinted with permission from Jover, J.; Fey, N.; Harvey, J. N.; Lloyd-Jones, G. C.; Orpen, A. G.; Owen-Smith, G. J. J.; Murray, P.; Hose, D. R. J.; Osborne, R.; Purdie, M. Organometallics 2010, 29, 6245–6258. Copyright 2010 American Chemical Society.

universal Ligand Knowledge Base of computed parameters for a wide variety of different ligand types (Fig. 4).63,64 Mapping the diversity of a particular ligand or catalyst library using Principal Component Analysis (PCA) provides an excellent starting point for selecting a diverse screening array, as well as informing iterative optimizations and understanding catalyst activity.65 Parameterization is also a powerful means to quantitatively define structural diversity in substrate libraries. From an experimental design standpoint, this can reveal areas of chemical space that are unexplored by current synthetic methods. Researchers at Merck have introduced the concept of “chemistry informer libraries” as a means to more fully explore the chemical space inhabited by pharmaceutically-relevant molecules.66 As shown in Fig. 5, a PCA plot of physicochemical properties for marketed drug molecules and a representative selection of metal-catalyzed cross-coupling products reveals a significant disconnect in molecular complexity. The authors propose the use of higher-complexity substrate libraries as a means to test and optimize catalytic methods for synthesis of correspondingly complex products, and demonstrate this approach for several metal-catalyzed C-C, C–B and C–N cross-coupling reactions. Often, even with HTE tools at one’s disposal, the experimental space to be covered is simply too large to be practically evaluated. In 2015 Moran and coworkers devised a deconvolution approach to reducing the experimental load in multivariate optimization/ catalyst discovery, using a metal-catalyzed C–H arylation as one of the case-studies (Fig. 6). The authors designed a series of small array experiments (25 experiments total) to explore a large reaction space (324 experiments possible) by using pools of the different metal precursors and ligands. Successive expansion of the successful catalyst pools led to discovery of high yielding and selective reaction conditions for the target arylation. While this initial demonstration of the approach does not necessarily rely on HTE (since only 25 individual experiments were required), one could envision a similar approach applied to reducing experimental arrays that are thousands or tens of thousands of entries down to only a few 96-well plates. The aims of an HTE design for reaction scope and/or robustness are distinct from those focused on optimization. In this second category of experimental design, HTE is used to map the reactivity of a transformation with respect to the reactant structures, or potentially incompatible additives, under a smaller number of overall reaction conditions. This is an especially useful approach to rapidly explore the generality and robustness of a newly developed reaction, or a new set of reaction conditions for an existing transformation. There are several examples of substrate reactivity maps generated by HTE in Section 13.12.3, including examples of “parallel-in-parallel” screening, where both optimization and reaction scope are investigated simultaneously. In 2013, Collins and Glorius introduced the concept of a “robustness screen” as a means to rapidly explore the functional group compatibility of a given transformation.12 These experimental designs involve adding a library of additives containing potentially reactive functional groups to a specific set of established reaction conditions. The screening array is then evaluated for both yield of desired product, and quantity of each additive remaining. Thus, the screen will not only identify inhibitory functional groups, but also the chemoselectivity of the transformation. Effectively, this is an array-based version of classic inhibitor experiments (such as addition of radical traps as mechanistic probes).13 In the original report, the authors used a prototype Buchwald-Hartwig C–N coupling as a test case, evaluating 33 different additives; since then, hundreds of examples of robustness screening for reaction exploration have been reported. Notably, robustness screening is particularly suited to HTE, as demonstrated by Richardson et al.67 Using arrays of 47 additives plus one control reaction, the authors evaluated 69 different reaction conditions in an exhaustive set of 3312 experiments (Fig. 7). The resulting reactivity map enabled identification of reaction conditions that are successful even in the presence of reactive functional groups, and also provides a method to specifically optimize reaction conditions for chemoselectivity.

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Fig. 5 Principal component analysis of calculated physicochemical properties for cross-coupling products from the literature (red and blue dots) and all marketed small-molecule Active Pharmaceutical Ingredients (gray). Properties in boxes B-E are the largest contributors to PC1 and PC2. Reproduced from Kutchukian, P.S.; Dropinski, J.F.; Dykstra, K.D.; Li, B.; DiRocco, D.A.; Streckfuss, E.C.; Campeau, L.-C.; Cernak, T.; Vachal, P.; Davies, I.W.; Krska, S.W.; Dreher, S.D. Chem. Sci. 2016, 7, 2604–2613, published by The Royal Society of Chemistry.

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Fig. 6 Deconvolution as an approach to reducing experimental load in multivariate screening by Moran and coworkers. Reproduced from Wolf, E.; Richmond, E.; Moran, J. Chem. Sci. 2015, 6, 2501–2505, published by The Royal Society of Chemistry.

One caveat about this technique is that while it captures intermolecular functional group compatibility, it does not give information about how functional groups on the substrates themselves might influence reactivity via steric and/or electronic effects. HTE designs for reaction discovery are less commonly reported than those for optimization or reaction scope. Both optimization and scope evaluation have well-defined goals, whereas reaction discovery is inherently exploratory. In 2011, McNally, Prier, and MacMillan described the concept of “accelerated serendipity” to scan for new reactivity.10 The authors used a pool of 19 potential substrates with different functional groups, and generated a matrix of all pairwise combinations to give 190 different possible reactions. By applying this substrate array to a variety of reaction conditions using transition metal catalysis and photoredox catalysis, the authors “re-discovered” three known transformations (Au-catalyzed indole alkylation by styrene, FeCl3-mediated Glaser homocoupling of phenylacetylene, and Ru3(CO)12-mediated carbonylative esterification of styrene with MeOH), and discovered one powerful new photoredox transformation: a-arylation of aliphatic amines. A contemporaneous and related account by Robbins and Hartwig also used substrate pools to discover new reactivity.9 In contrast to the substrate-pairing approach, these authors subjected the entire 17 substrate pool to 384 different reaction conditions. In this way, a broader range of catalysts (16 different metal precursors) and ligands (24) can be evaluated without increasing the experimental load—performing this array with substrate pairs would require almost 73,000 runs! This pooling approach does pose an analytical challenge, where many different reactions can occur simultaneously in each well. GCMS analysis enabled differentiation based on product mass; however, in one case identification of the reactive partners required deconvolution by split-pool methods (analogous to that subsequently used by Moran and coworkers for catalyst deconvolution68). By using this multidimensional approach, Robbins and Hartwig identified new catalyst systems for alkyne hydroarylation using either arylboronic acids or aryl halides (Ni-catalysis), and alkyne hydroamination (Cu-catalysis). Taran and coworkers used a similar experimental design, involving pools of potential substrates, but employed an immunoassay in lieu of chromatographic analysis to rapidly determine successful coupling reactions.69 In addition to identifying many known processes, these authors report two new Cu-catalyzed reactions involving thiourea substrates. The challenges in analysis and deconvolution encountered during these initial efforts led Troshin and Hartwig to develop a modified approach—“snap deconvolution”—to remove the need for subsequent split-pool experiments or bespoke assays.11 By designing the substrate arrays in triplicate, with three pools containing the same functional groups but distinct molecular weights, an automated analysis of raw GCMS data can reveal that a specific reaction has occurred on the basis of the three diagnostic product molecular weights. This approach successfully identified numerous reaction products from known catalytic processes, as well as a new reaction: Ni-catalyzed hydroallylation of alkynes.

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Fig. 7 An HTE robustness screening approach to developing chemoselective C–N coupling conditions. Yields in parentheses are average values for the pictured cross-coupling. Reprinted with permission from Richardson, J.; Ruble, J.C.; Love, E.A.; Berritt, S. J. Org. Chem. 2017, 82, 3741–3750. Copyright 2017 American Chemical Society.

13.12.2.2 Array set up and dispensing Once a design for a high-throughput experiment is established, the material components of the array need to be dispensed into dozens-to-hundreds of individual experiments. Additionally, the miniaturization of each experiment means that very small quantities are needed, especially for the catalyst components (often 1 mg). This poses a significant challenge for HTE applied to organometallic chemistry and catalysis. This aspect of HTE is often addressed through a combination of equipment capabilities and experimental design considerations. The typical plates used for HTE in (for example) molecular biology are plastic, and therefore incompatible with most organic solvents. This is especially true at the elevated temperatures required for many catalytic reactions. Instead, small (0.25–1 mL capacity) glass vials arrayed in aluminum (or another heat-conductive material) blocks are used for parallel reaction screening. These vials can be individually sealed using crimp-caps common to HPLC/GC vials, or the plate itself can be sealed using a screwed-down lid. The simplest approach to dispensing materials to these vial-based arrays is to use stock solutions of each component. Ideally, every material needed for the array—substrates, reagents, catalyst and ligand—should either be soluble in the reaction solvent(s), or be liquids themselves. Readily available single or multichannel pipettors are an economical option for manual dispensing, removing the need for robotic platforms; this also makes dispensing under inert atmosphere straightforward. Of course, this

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idealized scenario of perfect solubility is rarely realized in practice. Differential solubilities of components such as metal precursors can be handled by first dispensing solutions of these precursors using a different solvent, followed by evaporation. The remaining components can then be dispensed as needed. Solvent evaporation from a plate can be achieved passively, or by using a centrifugal evaporator (some of which are small enough to be housed inside gloveboxes), or by passing streams of an inert gas into each vial. Still, many critical reaction components will not be soluble in any appropriate solvent. Of particular relevance to organometallic catalysis are inorganic bases. These reagents are mainstays of cross-coupling reactions, which are some of the most heavily screened transformations. A simple approach is to dispense these materials as fine slurries in the reaction solvent, though the accuracy of the quantity added is obviously sacrificed. Another method is to simply design-out these insoluble reaction components. Several research groups, including those of Buchwald,70 Newman,71 and Carrow,72 as well as groups at Merck73 and BMS74 have studied the use of soluble weak bases for C–N coupling. In addition to affording greater functional group compatibility and reaction scalability, these conditions also enable easier HTE dispensing. The Merck group in particular used soluble phosphazene “super-bases” to enable further miniaturization of reaction screening down to nanomole scale in 1536 well plates.14,75 The chemistry explored using this technique will be discussed in detail in Section 13.12.3.13, but the dispensing specifics are relevant here. In order to accurately dose nanoliters of stock solutions to high-density 1536 well plates, Buitrago-Santanilla et al. used a Mosquito automated liquid handler to accurately transfer and mix solutions from a 384-well source plate to the 1536-well reaction plate (Fig. 8). The use of soluble superbases and single-component Pd precatalysts not only enabled completely homogeneous stock solutions and reaction mixtures, but also room temperature catalysis using DMSO solvent. These latter aspects are critical to the success of this initial demonstration, since the reaction plates were plastic. Subsequent developments at Merck expanded the scope of chemistry amenable to this high-density platform using a combination of glass microplates, liquid-handlers capable of using more volatile solvents, and acoustically-mixed stable slurries of solid reagents.75 While liquid/slurry handling techniques are powerful enablers of HTE, they are still somewhat limiting in terms of material amenability. Many varieties of automated solid-dosing equipment are available that can directly and quantitatively dispense solid materials to reaction vials. Just as liquids have different physical properties that affect dispensing (volatility, viscosity, surface tension), solids can range from free-flowing and crystalline to waxy and amorphous. The sheer variety of solid properties encountered in organic synthesis means there is no universal system able to reliably and accurately dispense all materials. A cross-company Enabling Technologies Consortium from the pharmaceutical sector studied all of the commercial systems available in 2018. They reported an extensive comparison of the capabilities, strengths, and weaknesses of each option under a variety of conditions relevant to HTE.76 However, even with the most sophisticated automated solid handling system, there is a lower limit to the quantities amenable to solid dosing. While accurate liquid dispensing down to the nanoliter is possible, weighing submilligram quantities (especially in an inert atmosphere glovebox) is far more difficult. Researchers at Abbvie devised an ingenious solution to this problem by using inert glass beads as a solid diluent.77 Using acoustic mixing to evenly coat a variety of materials onto spherical glass beads at 1–20% by weight, the researchers effectively generated a diverse library of immobilized catalysts, reagents, and substrates. The consistent density and flow properties of the newly dubbed ChemBeads enabled seamless solid dispensing of nanograms of material using automation, or even with 3D-printed calibrated plastic scoops.

13.12.2.3 Reaction execution Once all of the materials are dispensed, each reaction within the plate must be heated and mixed for the appropriate length of time. One of the most important aspects of a high-throughput screen is ensuring consistency in temperature and agitation across all members of the array; this is not as straightforward as it may seem. While smaller arrays of experiments can be conducted using standard laboratory stirrer hotplates, larger arrays of 48 or 96 vials will not be adequately mixed. This can lead to reaction performance depending just as much on the position of the vial (center or edge) as the reaction components! For most chemistry, “tumble” stirring achieved by using a cylindrical rare-earth magnet combined with fitted heatblocks achieve excellent consistency in temperature and agitation across all positions of a 96 well plate (Fig. 9).78 The use of reactive gasses—H2, CO, ethylene, etc.—in high-throughput experiments is another important challenge. Some of the most commonly investigated reactions using HTE fall into this category, including asymmetric hydrogenation and olefin polymerization. As a result, many plate-based reactor solutions have been developed. For array-based hydrogenation, Merck and Symyx pioneered the use of “clamshell” like reactors that enclose the reaction plate within a sealed and pressurized chamber (Fig. 10).39 A variety of reactor types akin to this are available, and either fit within standard-footprint heating/stirring elements, or are standalone units with heating/stirring integrated with gas delivery into one system. Specialized designs are able to miniaturize the reaction vessels even further, enabling parallel reaction screening on higher density arrays (Fig. 11).79 While minimizing the size of each individual reaction in a high-throughput array is paramount in areas such as pharmaceutical R&D, where the available quantity of the complex substrates under investigation can be extremely small, this does introduce problems in achieving efficient mixing. This issue is exacerbated in gas/liquid reactions, where mixing and mass-transfer are often major contributors to reaction rate and selectivity. HTE applied to alkene polymerization/oligomerization often tries to strike a balance between small-scale operation and proper temperature and stir rate control. A typical solution to this is to use “parallel pressure reactors” (PPRs), which are banks of medium-scale reaction vessels equipped with individual overhead stirrers. Busico et al. describes a sophisticated but representative system that contains 48 individual pressure reactors (6 banks of 8-pot PPRs) that produce material for downstream high-throughput analytics (Fig. 12).80 This type of system is certainly more space and resource intensive than a small plate-based reactor; however, the conditions required for successful and reproducible alkene polymerization

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Fig. 8 Nanoscale HTE using high-density liquid dosing to 384 and 1536 well-plates. From Santanilla, A.B.; Regalado, E.L.; Pereira, T.; Shevlin, M.; Bateman, K.; Campeau, L.-C.; Schneeweis, J.; Berritt, S.; Shi, Z.-C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C.J.; Vachal, P.; Davies, I.W.; Cernak, T.; Dreher, S.D. Science 2015, 347 (6217), 49–53.

screening clearly warrant this approach. PPR-type reactors have also been used in pharmaceutical R&D, generally for more in-depth reaction profiling that requires the higher level of control afforded by these systems.4,81 One of the most challenging aspects of performing HTE for organometallic chemistry is generating and subsequently using temperature sensitive reagents. This is critical for a number of cross-coupling strategies, such as Negishi and Kumada-Corriu couplings (Section 13.12.3.3), as well as stoichiometric organometallic chemistry, such as the use of organolithium reagents. Maintaining low temperature under inert atmosphere, especially while generating and manipulating solutions of organometallic compounds in an array-based format requires specialized equipment. Merck has described an automated platform and workflow to

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Fig. 9 Rare-earth magnetic tumble stirrer with independent heat control across three plate positions for executing high-throughput screens.

Fig. 10 Plate-based “clamshell” reactor for use with a 96 well array. Reprinted with permission from Shultz, C.S.; Krska, S.W. Acc. Chem. Res. 2007, 40, 1320–1326. Copyright 2007 American Chemical Society.

achieve this (Fig. 13), through integration of an automated liquid handler, a recirculating chiller, and mixing by tumble stirring.82 The system was validated via array-based heterocycle metallation by Knochel-Hauser bases and subsequent quenching by I2. Generally, HTE in organometallic chemistry is based on taking batch experiments and running them in parallel—from 8 PPR runs to 1536 simultaneous C–N couplings. In 2018, a group at Pfizer reported a complementary flow-based system for achieving high-throughput screening in series.83 This platform, built from a combination of HPLC parts (Fig. 14), automates nearly the entire screening process including in-line analytics by LCMS. Each individual reaction can be performed on nanoscale in flow, providing an alternate means to the aforementioned Merck nanoscale system to achieve further miniaturization. This team was able to perform >5000 Suzuki cross-coupling reactions to build a comprehensive map of the reaction landscape (more details are in Section 13.12.3.2).

13.12.2.4 High-throughput analysis While all aspects of an HTE workflow are important, rapid and accurate quantitative analysis of the individual experiments within an array is perhaps the most important.84,85 By far the most common approach is to use rapid analytical chromatography to separate, identify, and quantify reaction products. Either gas chromatography (GC) or (ultra) high performance liquid

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Fig. 11 Custom 384-well array pressure reactor. Reprinted with permission from Allwardt, A.; Holzmüller-Laue, S.; Wendler, C.; Stoll, N. Catal. Today 2008, 137, 11–16. Copyright 2008 Elsevier.

Fig. 12 Integrated system for HTE applied to polymerization. Reprinted with permission from Busico, V.; Cipullo, R.; Mingione, A.; Rongo, L. Ind. Eng. Chem. Res. 2016, 55, 2686–2695. Copyright 2016 American Chemical Society.

chromatography (UPLC or HPLC) methods are employed depending on the nature of the reactants/products, with quantitative analysis done by flame ionization detection (GC) or UV absorbance (U/HPLC), and identification achieved by in-line mass spectrometry (MS). These methods use existing automation for sample handling/injection, achieve rapid separation (especially for UPLC) and operate with very small quantities of analyte, enabling the sort of miniaturization described in previous sections.86 Techniques such as MISER (multiple injections in a single experimental run)87 chromatography and strategic use of sample pooling enables even faster and more efficient analysis.

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Fig. 13 HTE platform for automated generation of temperature sensitive organometallic reagents. Reproduced from Boga, S.B.; Christensen, M.; Perrotto, N.; Krska, S.W.; Dreher, S.; Tudge, M.T.; Ashley, E.R.; Poirier, M.; Reibarkh, M.; Liu, Y.; Streckfuss, E.; Campeau, L.-C.; Ruck, R.T.; Davies, I.W.; Vachal, P. React. Chem. Eng. 2017, 2, 446–450, published by The Royal Society of Chemistry.

Fig. 14 An integrated flow-based nanoscale reaction screening and analysis platform. From Perera, D.; Tucker, J.W.; Brahmbhatt, S.; Helal, C.J.; Chong, A.; Farrell, W.; Richardson, P.; Sach, N.W. Science 2018, 359, 429–434.

Many traditional means of monitoring the extent of organic chemistry reactions, such as TLC and NMR spectroscopy, do not initially appear compatible with large experimental arrays. Researchers have nevertheless used these simple but powerful techniques in high-throughput analysis. Grela and coworkers made ingenous use of preparative TLC plates to conduct rapid screening of alkene metathesis catalysts.88 The plate was used both as reactor, with the metathesis occurring within each TLC “spot,” and for analysis, with the metathesis product clearly separated upon plate development. While not quantitative, the output provides a low-barrier method for rapid screening (Fig. 15). Cipullo and coworkers also utilize high-throughput 13C NMR spectroscopy for analysis of polypropylene products with respect to quantification of regioerrors.89 Colorimetric assays are another powerful means of analyzing array-based experiments. While these assays can take time to create for each individual case, they are operationally simple and extremely rapid once developed. Berkowitz and coworkers used a coupled enzymatic reporter system (alcohol oxidase and peroxidase) in a biphasic reaction mixture to assay for methanol produced as a byproduct of a catalytic cyclization reaction.90 Enzymatic oxidation of a water-soluble dye produces a colored radical cation, indicating the reaction has proceeded (Fig. 16). In related work, a series of high-throughput colorimetric assays for organometallic catalysis has been developed by Lee and coworkers.91–95 These systems rely on colorimetric sensors for halide ions, which are the byproducts of cross-coupling reactions. In one example, an Hg(II) complex of 4-(2-pyridylazo)resorcinol is used to detect halide ions, with the red color of the Hg complex converting to yellow in the presence of soluble halides (Fig. 17).93 Plate-reader-equipped UV/Vis absorbance spectrometers can also enable quantitative analysis of colorimetric assays, further increasing their power. Related fluorometric methods have also been used to analyze catalysis screens.96–98

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Fig. 15 HTE by TLC: rapid screening of alkene metathesis catalysts for dimerization of methyl 9-decenoate using preparative TLC plates as both reactor and analysis method. From Cabrera, J.; Padilla, R.; Dehn, R.; Deuerlein, S.; Gułajski, Ł.; Chomiszczak, E.; Teles, J.H.; Limbach, M.; Grela, K. Adv. Synth. Catal. 2012, 354, 1043–1051.

Fig. 16 Enzymatic colorimetric assay for the halocyclization reaction shown. From Friest, J.A.; Broussy, S.; Chung, W.J.; Berkowitz, D.B. Angew. Chem. Int. Ed. 2011, 50, 8895–8899.

As high-throughput experimentation approaches in organometallic chemistry and catalysis are driven to further miniaturization and array density, many high-throughput analysis techniques actually become too slow and cumbersome. The aforementioned nanoscale screening performed by Merck relied initially on MISER chromatography to quantitatively analyze 1536 individual reactions.14,87 Further developments at Merck in expanding the scope of chemistry also explored MALDI-MS as an alternative analysis technique capable of analyzing multiple samples per second.75 By using an appropriate internal standard to normalize product response, the Merck team validated this approach relative to more standard UPLC methods. The authors recently published a practical guide to achieving this manner of high-throughput analysis.99 Other rapid MS-based techniques are being developed, such as desorption electrospray ionization (DESI-MS).100–102

13.12.2.5 Data interrogation Once analysis of the high-throughput experiment is complete, all that remains is what to do with the resulting data. Depending on the aim of the experiment, a simple analysis based on hit identification may be appropriate, or else a more sophisticated quantitative analysis of the entire dataset may be performed. The experimental design approach used (Section 13.12.2.1) will inform the level of analysis needed, such as arrays designed specifically for Design of Experiment analysis,2–4 or the generation of linear free energy relationships informed by molecular parameterization and multivariate regression.6,8 A particularly powerful approach with enormous potential is the combination of high-throughput experimental methods with “big data” analysis methods such as machine learning.15 A recent example of this in the context of organometallic chemistry is a report from a Merck/Princeton

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Fig. 17 Colorimetric assay for Pd-catalyzed C–H arylation based on an Hg(II) complex. Adapted with permission from Eom, M.S.; Noh, J.; Kim, H.-S.; Yoo, S.; Han, M.S.; Lee, S. Org. Lett. 2016, 18, 1720–1723. Copyright 2016 American Chemical Society.

collaboration on developing predictive models for C–N cross-coupling chemistry.7,103,104 This team performed nanoscale high-throughput experimentation to generate a large, consistent reactivity data set inspired by the Collins-Glorius robustness screen.12 This experimental foundation enabled generation of a highly correlative model for predicting reaction yield based on a variety of molecular parameters by using a Random Forest algorithm.

13.12.3 Specific applications in catalysis Since the previous incarnation of this chapter appeared in 2007, there has been a marked shift in the published literature with respect to the application of HTE in organometallic chemistry. More and more studies are being reported by the pharmaceutical sector, particularly in process chemistry, while there are comparatively fewer being reported by the commodity and polymer chemistry industries. Note well that this is necessarily an “outsider’s view” of the prevalence of HTE, based only on published studies; the internal use of HTE on proprietary activities is undoubtedly as strong as ever in all industrial R&D sectors. This shift in focus of published studies is also reflected in the types of reactions under investigation. Many more examples of cross-coupling catalysis have been reported in the past 15 years, with C–C and C–N coupling being among the most frequent transformations investigated by HTE. Another important trend is that more and more academic research labs are using HTE for reaction optimization, exploration, and discovery; this shift is also having an influence on the number and type of HTE applications in catalysis. As mentioned above, the high prevalence of HTE in industrial R&D labs means that our view of HTE adoption and applications is skewed by what is available in the published literature—certainly the “iceberg” metaphor is applicable to the HTE accounts that are in view versus those that are “below the surface.” In 2019, a group of researchers representing seven large pharmaceutical companies and two academic HTE centers published a review that summarized the current state-of-play for HTE at their respective institutions.22 In addition to six illuminating case-studies, the authors provide a glimpse into the demand for various transformations from internal projects. As shown in Fig. 18, organometallic catalysis comprises nearly half of all HTE projects, with C–C and C–N cross coupling being most prevalent; the other major uses are in biocatalysis, isolation/purification screening (e.g., crystallization), non-catalytic reactions (e.g., amide coupling), and heterogeneous catalysis (e.g., hydrogenation). Notably, asymmetric hydrogenation is much less prevalent than may be expected based on its relative contribution to the published literature. The following sections describe published accounts of HTE used in organometallic chemistry and catalysis research, categorized by reaction type. Every effort has been made to be comprehensive in terms of the cited literature; however, occasionally HTE techniques are used but not explicitly mentioned in publications, especially if HTE was used to generate preliminary data that is not included in the experimental details or supporting information.

13.12.3.1 CdH bond formation: Asymmetric hydrogenation The asymmetric hydrogenation of alkenes using a chiral catalyst and dihydrogen is an important methodology in chemical synthesis, particularly when applied toward the synthesis of complex targets in the pharmaceutical and agrochemical sectors.

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Fig. 18 Prevalence (% of total) of HTE campaigns by screen type at seven large pharmaceutical process chemistry R&D departments in 2018. Organometallic catalysis represents nearly half of all chemistry screened. From Mennen, S.M.; Alhambra, C.; Allen, C.L.; Barberis, M.; Berritt, S.; Brandt, T.A.; Campbell, A.D.; Castañón, J.; Cherney, A.H.; Christensen, M.; Damon, D.B.; Eugenio de Diego, J.; García-Cerrada, S.; García-Losada, P.; Haro, R.; Janey, J.; Leitch, D.C.; Li, L.; Liu, F.; Lobben, P.C.; MacMillan, D.W.C.; Magano, J.; McInturff, E.; Monfette, S.; Post, R.J.; Schultz, D.; Sitter, B.J.; Stevens, J.M.; Strambeanu, I.I.; Twilton, J.; Wang, K.; Zajac, M.A. Org. Process Res. Dev. 2019, 23, 1213–1242.

One of the key challenges in developing efficient and selective asymmetric hydrogenation methods is that few chiral ligands have general applicability; in other words, complex substrates often require very particular (and unpredictable) ligand structures. Therefore, exploration of large chiral ligand libraries is often necessary, as both catalyst activity and enantioselectivity must be optimized. HTE is therefore a go-to technique for this purpose.37–42 The ever-increasing complexity of drug development and agrochemical candidates means the pool of chiral catalysts needs to constantly expand to address new and difficult transformations for which there is little to no literature precedent. One important trend to note: increasingly, pharmaceutical development is turning to alternative means of setting stereochemistry via reduction of C]X or C]C bonds, particularly with enzymatic catalysis. While some of these enzymatic transformations (e.g., C]O reduction) are becoming mature, others (C]N and C]C reduction) are still being developed for practical applications. Organometallic and enzymatic approaches to enantioselective reduction will undoubtedly continue to be complementary methods. HTE has impacted many industrially relevant asymmetric hydrogenations reactions over the past 15 years. Perhaps one of the best-known examples is in the synthesis of Sitagliptin, a DPP-4 inhibitor for the treatment of Type 2 diabetes.105 A second generation route to Sitagliptin was necessary for large scale (>100 kg) syntheses for safety and clinical studies. Asymmetric hydrogenation of a primary enamine is a key step in this improved route. Notably, this approach bypasses several problematic reactions in the earlier synthesis, including a Mitsunobu reaction. HTE was critical for the rapid identification of a suitable catalyst ([Rh(COD)Cl]2/JosiPhos), especially in light of the minimal literature precedent for this type of asymmetric hydrogenation (Eq. 1).

ð1Þ

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Source: Hansen, K.B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E.J.J.; Armstrong, J.D. Highly Efficient Asymmetric Synthesis of Sitagliptin. J. Am. Chem. Soc. 2009, 131(25), 8798–8804. Another example is the application of HTE to develop asymmetric transfer hydrogenation in the synthesis of (R)-fluoxetine and (S)-duloxetine. Here, Ru and Rh based catalysts were identified using a series of amino-acid based ligands.106 The asymmetric hydrogenation of an imine en route to MK-8742, an N55a antagonist, was also enabled by HTE. In this case, Wills-type tethered TsDPEN-Ru catalysts were shown to outperform Rh and Ir catalysts.107 Other notable examples include the hydrogenation of an intermediate benzodiazepine en route to BET inhibitor BAY1238097,108 and the Ru-catalyzed hydrogenation of an enamide en route to TAK-828F.109 The synthesis of solifenacin, a urinary anti-spasmodic, represents another example in which asymmetric hydrogenation has streamlined preparation of an active pharmaceutical ingredient; HTE played a key role in the optimization.110 The initial route to solifenacin employed an achiral reduction of the parent tetrahydroisoquinoline, followed by a diastereoselective chiral salt resolution, and separation of the diastereomers by chiral HPLC. A direct asymmetric hydrogenation was attempted to streamline the synthesis, and avoid installation/removal of a protecting group and purification by chromatography. Initial results from extensive high-throughput screens revealed that [Ir(COD)Cl]2 and (R)-BINAP enable high conversion of substrate, but only moderate enantioselectivity (50–70% ee). A broader screen of chiral phosphine ligands identified (R)-PPhos as providing slightly better enantioselectivity (80% ee), though this was still not suitable for the route. To further enhance the stereochemical purity of the final product, a variety of additives (chosen based on literature precedent) were screened in high-throughput manner. These included halide salts (KI, NBu4I, NBu4Br, NaI, MgI2), acids (TsOH, HCl, HBF4, H3PO4, AcOH) and bases (amines). The addition of either H3PO4 or KI resulted in high enantioselectivies (>94% ee). Subsequent solvent screening established a mixture of aqueous H3PO4 and toluene as the optimal system. Tuning of the reaction temperature, time, and pressure for large scale reactions enabled increase of the substrate to catalyst ratio (S/C) to 1275:1, giving the product in 94% ee with >99% conversion (Eq. 2).

ð2Þ

Source: Ružic, M.; Pecavar, A.; Prudic, D.; Kralj, D.; Scriban, C.; Zanotti-Gerosa, A. The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin. Org. Process Res. Dev. 2012, 16(7), 1293–1300. Aliskiren is an oral renin inhibitor for lowering blood pressure developed by Novartis. A key stereocenter in the final molecule is formed by the asymmetric hydrogenation of an a,b-unsaturated carboxylic acid.111 HTE campaigns were used to find a cost-effective method for this hydrogenation step. In particular, this work displays the utility of in situ derived ligand libraries and mixed ligand screening enabled by HTE. Phosphoramidites are a powerful class of chiral ligands that are amenable to modular library synthesis.38,112 Applying this instant ligand library113 approach to preliminary screens identified Rh(COD)2BF4 with phosphoramidite ligands as active for the reduction, albeit with poor enantioselectivity. The best ligand identified for the transformation contains the 3,30 -dimethylbinaphthyl framework. At this point, the authors proposed that the reaction failed in part due to the poor sigma donicity of the phosphoramidite, and hypothesized that the addition of more electron rich phosphines could accelerate the oxidative addition of H2. To this end, a mixed ligand screen was performed using a single phosphoramidite ligand (MonoPhos), as well as a variety of phosphine and nitrogen ligands and other additives. Simple phosphines, such as PPh3, P(p-tol)3, and P(p-OMePh)3, were the only additives shown to dramatically accelerate the reaction, leading to full conversion with reasonable enantioselectivity; for example, the hydrogenation with Rh(COD)2BF4, 2 equiv. MonoPhos, and 1 equiv. P(p-tol)3 results in 75% ee. Tuning of solvent, phosphoramidite (L) and Rh:L:PPh3 ratio enabled reproducibly high enantioselectivity (>90% ee) (Eq. 3). The optimal Rh:L:PPh3 ratio is found to be 1:2:1, with high L equiv. reducing conversion and high PPh3 equiv. reducing enantioselectivity.

ð3Þ

Source: Lefort, L.; Boogers, J.A.F.; deVries, A.H.M.; deVries, J.G. High Throughput Screening of Monophos Instant Ligand Library Leads to a Ton-Scale Asymmetric Hydrogenation Process. Top Catal 2006, 40(1), 185–191. Kluwer, Reek and coworkers describe an analogous mixed ligand screening approach to the discovery and optimization of an enantioselective imine hydrogenation catalyst.114 By evaluating targeted mixed ligand combinations from a 22-member ligand library in successive screening rounds, the authors increased the enantioselectivity from 51% ee to 96% ee while increasing the S/C ratio from 25:1 to 200:1. Here again, the key to high enantioselectivity is the combination of a chiral monodentate phosphine with an achiral monodentate phosphine (Eq. 4).

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ð4Þ

Source: Kluwer, A.M.; Detz, R.J.; Abiri, Z.; van der Burg, A.M.; Reek, J.N.H. Evolutionary Catalyst Screening: Iridium-Catalyzed Imine Hydrogenation. Adv. Synth. Catal. 2012, 354(1), 89–95. The synthesis of an 11B-HSD-1 inhibitor for the treatment of Type 2 diabetes is a case where creating a new ligand family was required to develop a highly active and selective catalyst.115 The initial route to the tricyclic chiral indenopiperidine core of the drug candidate required a Pd-catalyzed cyanation with Zn(CN)2 and a late-stage chiral resolution. Due to these problematic steps, as well as an overall lengthy synthetic sequence, stereoselective hydrogenation of the parent indenopyridinium was pursued to support Phase 3 clinical trials. The planned synthesis posed several challenges: in addition to achieving high stereoselectivity, the catalyst needed to be reactive enough to add three equivalents of H2 across the pyridinium moiety, but not reduce the nitrile group. Extensive HTE revealed that heterogeneous catalysts reduced both the pyridinium and the nitrile, Rh catalysts with bisphosphines or phosphoramidites were not reactive enough to hydrogenate the pyridinium, and Noyori-type Ru catalysts generally provided poor enantioselectivity. In contrast, Ir-based catalysts did provide the desired product in 60–80% yield with up to 45% ee; however, reducing the catalyst loading to 0.2 mol% Ir led to dramatically diminished yield. Boehringer Ingelheim’s BoQPhos ligand family based on the dihydrobenzoxaphosphole structure was explored as an alternative. The modularity of this ligand class enabled generation of a structurally diverse library informed by rational catalyst design principles. A screen of this ligand library at 0.2 mol% Ir loading revealed MeO-BoQPhos as the most successful, providing the desired product in 97% yield with acceptable enantioselectivity (85:15 er) (Eq. 5). Isolation of the D-DBTA salt of the product enabled a significant upgrade to stereochemical purity (67% yield, >99.75:0.25 er).

ð5Þ

Source: Wei, X.; Qu, B.; Zeng, X.; Savoie, J.; Fandrick, K.R.; Desrosiers, J.-N.; Tcyrulnikov, S.; Marsini, M.A.; Buono, F.G.; Li, Z.; Yang, B.-S.; Tang, W.; Haddad, N.; Gutierrez, O.; Wang, J.; Lee, H.; Ma, S.; Campbell, S.; Lorenz, J.C.; Eckhardt, M.; Himmelsbach, F.; Peters, S.; Patel, N.D.; Tan, Z.; Yee, N.K.; Song, J.J.; Roschangar, F.; Kozlowski, M.C.; Senanayake, C.H. Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11b-HSD-1 Inhibitor. J. Am. Chem. Soc. 2016, 138(47), 15473–15481. While catalysts based on platinum-group transition metals (Rh, Ir, and Ru) still dominate in enantioselective hydrogenation applications, the high cost of both the metals and the chiral ancillary ligands have spurred research efforts to discover suitable effective earth-abundant metal catalysts. The Chirik group, in collaboration with Merck, have used HTE to assess the viability of multiple first-row transition metal systems for asymmetric hydrogenation, including Fe,116,117 Co,116,118,119 and Ni.120 In the development of a Ni-based catalyst,120 Ni(OAc)2 was used as the metal source along with 192 chiral bidentate phosphines for the hydrogenation of an a,b-unsaturated ester. In general, the results were not satisfactory, though Me-DuPhos as the ligand gave the hydrogenation product with 44% conversion and 83% ee. Follow-up screening identified both halide and acetate additives as promoting higher reactivity and selectivity; for example, the addition of NBu4I resulted in 100% conversion and 93% ee (Eq. 6). Isolation of potential catalyst intermediates found that (MeDuPhos)Ni(I)2 is catalytically inactive and substitutionally labile, either dissociating phosphine or forming [(MeDuPhos)2Ni(I)][I] in equilibrium. To determine the catalyst resting state, the authors applied HTE to the method of continuous variation, constructing Job plots to relate the Ni(OAc)2/MeDuPhos/NBu4I stoichiometry. From these experiments, the highest catalyst activity is observed with a Ni:I ratio of 3:1, potentially indicating a trimeric catalyst resting state, proposed to be (MeDuPhos)3Ni3(OAc)5I. In support of this proposal, a non-linear effect (% ee product versus % ee catalyst) of the asymmetric catalysis was also observed.

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ð6Þ

Source: Shevlin, M.; Friedfeld, M.R.; Sheng, H.; Pierson, N.A.; Hoyt, J.M.; Campeau, L.-C.; Chirik, P.J. Nickel-Catalyzed Asymmetric Alkene Hydrogenation of a,b-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation. J. Am. Chem. Soc. 2016, 138(10), 3562–3569. The Chirik group has also developed asymmetric hydrogenation catalysts using Co; however, these systems suffer from significant drawbacks, including the need for preformed transition metal complexes, rigorous exclusion of air and moisture, and use of pyrophoric activators (such as LiCH2SiMe3).118 In collaboration with Merck, the Chirik group employed HTE to extensively screen reaction conditions for Co-catalyzed hydrogenations to overcome these challenges in pursuit of practically-applicable systems.119 Initial screening focused on using simple starting materials: CoCl2 as the metal source, MeOH as solvent (desirable due to H2 solubility), and metal powders as reductants. Zn powder was found to be an excellent activator in concert with MeOH, generally outperforming LiCH2SiMe3. About 200 chiral ligands were screened using these conditions in the hydrogenation of the a,b-unsaturated amide precursor to levetiracetam (Fig. 19). Out of these ligands, Ph-BPE and iPr-DuPhos both provided excellent yield and selectivity. Levetiracetam was isolated on 200 mg scale with 0.08 mol% CoCl2 ∙ 6H2O and 0.084 mol% (R,R)-Ph-BPE in 97% yield and 98.2% ee. Mechanistic studies indicate that the success of the discovered catalyst is due to the conservation of Co-phosphine coordination throughout catalysis. CoCl2 complexes are challenging to employ in catalysts due to their substitutional lability, tending to dissociate the phosphine in solvents such as MeOH. However, isolation of key reduced intermediates indicated that the phosphine ligand does not readily dissociate from CoI and Co0. The importance of solvent is also noted, as MeOH also appears to accelerate Zn-mediated reduction to access the catalytically active Co species. Bergens and coworkers used HTE to identify suitable Ru catalysts for a hydrogenative dynamic kinetic resolution (DKR) of amides.121 Selective hydrogenolysis of racemic a-amidoethers to b-hydroxyethers with epimerization of the starting material under basic conditions enables this DKR. Initial results indicate that Ru(H)2((R)-BINAP)((R,R)-dpen) (2 mol%) (dpen ¼ 2,3-diphenyl1,4-diaminoethane) promotes the hydrogenolysis of a piperidinyl amide in the presence of KOtBu (30 mol%) and 4 atm H2 in THF at 0  C, providing the alcohol product in 100% conversion and 60% ee. To optimize for selectivity, HTE was used to evaluate 96 different catalysts with variation of the P and N ligands (mixtures of N-N and P-P ligands employed, as well as P-N, P-N-P, and P-N-N-P ligands). Rather than using isolated precatalysts for every reaction, the authors pre-mixed [(allyl)Ru(NCMe)2(COD)][BF4] with the required ligand(s) for 30 mins at 60  C before addition of the remaining reagents and pressurization with H2. Several catalyst mixtures were successful, while enantioselectivities were suboptimal; for example, the catalyst ((S,S)-Skewphos)Ru(H)2((R, R)-dpen), provided 100% conversion but only 25–29% ee. Further optimization of the base revealed that NaOiPr/iPrOH (2.5 equiv./2 equiv.) dramatically improved enantioselectivity to >90% ee (Eq. 7).

Fig. 19 HTE-driven discovery of Co-catalyzed enamine hydrogenation and application to the synthesis of levetiracetam. From Friedfeld, M.R.; Zhong, H.; Ruck, R.T.; Shevlin, M.; Chirik, P.J. Science 2018, 360, 888–893.

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ð7Þ

Source: Rasu, L.; John, J.M.; Stephenson, E.; Endean, R.; Kalapugama, S.; Clément, R.; Bergens, S.H. Highly Enantioselective Hydrogenation of Amides via Dynamic Kinetic Resolution Under Low Pressure and Room Temperature. J. Am. Chem. Soc. 2017, 139(8), 3065–3071. Other examples of HTE applied to asymmetric hydrogenations include the use of an instant ligand library113 for the synthesis of b2-amino acids122 and enamides,123 the development of ferrocenyl-based bisphosphines for asymmetric hydrogenation of alkenes and ketones,124 Cu-mediated methods for the hydrogenation of ketones,125 among others.126–128

13.12.3.2 CdC bond formation: Suzuki-Miyaura cross-coupling The Suzuki-Miyaura reaction—the coupling of organohalide electrophiles with organoboronic acid nucleophiles—is one of the most broadly applied cross-coupling reactions, particularly in pharmaceutical syntheses. As is typical for many cross-coupling reactions (and indeed, many catalytic reactions in general), multivariate optimization is often required to identify the best set of reactions conditions; therefore, HTE is a common method to tackle this problem. An exemplar of this approach was reported in 2013 by Schmink and Tudge at Merck, who sought to optimize the synthesis of diarylmethanes via Suzuki-Miyaura coupling.129 Exploring a 384-condition array comprised of 8 Pd-precatalysts, 4 bases, 6 solvents, and two reactions temperatures via HTE enabled a thorough mapping of the reaction landscape, identifying myriad sets of conditions for the targeted coupling reaction (Fig. 20). Notably, this array perfectly illustrates the complex interactions between catalyst, solvent, and base with respect to reaction success—aspects of this reaction that would be opaque to an OFAT optimization. Researchers at Merck developed a regioselective Suzuki-Miyaura coupling on a multiple-halogenated naphthyridone, where HTE found that Pd2(dba)3 ∙ CHCl3, IMes ∙HCl or P(o-OMePh)3 as ligand, and K3PO4 in DMF to be the optimal reaction and catalyst conditions for high regioselectivity.130 A selective PI3K inhibitor developed by Pfizer involved a Suzuki-Miyaura coupling upon the multiply-substituted iodothiophene core, dehalogenation of which was found to be a considerable side-reaction. Extensive

Fig. 20 HTE approach to multivariate optimization of the pictured Suzuki-Miyaura coupling across 384 conditions. Blue spots: 35  C; red spots: 50  C. Spot size is proportional to solution yield. From Schmink, J.R.; Tudge, M.T. Tetrahedron Lett. 2013, 54, 15–20.

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screening using HTE focused on finding scalable conditions which minimized formation of the des-iodo thiophene byproduct; Pd(PtBu3)2 and CsF as base, in a solvent mixture of dioxane/toluene/H2O were found to provide optimal conditions.131 Boehringer Ingolheim’s BI-DIME class of chiral phosphine ligands were found by HTE to provide high diastereoselectivity in a Suzuki-Miyaura coupling to form the precursor to an atropisomeric HIV integrase inhibitor.132 Another example of an atropselective Suzuki-Miyaura coupling includes the synthesis of a BTK enzyme inhibitor developed by Bristol-Myers Squibb, used against various cancer targets (Eq. 8).133

ð8Þ

Source: Beutner, G.; Carrasquillo, R.; Geng, P.; Hsiao, Y.; Huang, E.C.; Janey, J.; Katipally, K.; Kolotuchin, S.; La Porte, T.; Lee, A.; Lobben, P.; Lora-Gonzalez, F.; Mack, B.; Mudryk, B.; Qiu, Y.; Qian, X.; Ramirez, A.; Razler, T. M.; Rosner, T.; Shi, Z.; Simmons, E.; Stevens, J.; Wang, J.; Wei, C.; Wisniewski, S. R.; Zhu, Y. Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes. Org. Lett. 2018, 20(13), 3736–3740. A stereoselective Suzuki-Miyaura coupling was also developed by Merck using HTE to find catalysts for the arylation of a tetrasubstituted (Z)-alkene substrate, which is derived via tosylation of the corresponding enolate.127 A similar scenario was explored by Genentech and Roche, where a stereoselective Suzuki-Miyaura coupling using a tetrasubstituted alkenyl tosylate was necessary. In this case, HTE revealed PdCl2(XantPhos) to be the best precatalyst for the transformation.134,135 The industrial manufacturing route to savolitinib, a c-Met inhibitor developed by AstraZeneca, involves a Suzuki-Miyaura coupling with several problematic features. The use of a CH3CN/H2O solvent mixture produced a hydrated form of the product which was a gelatinous solid and difficult to filter and contained residual Pd. Furthermore, the ligand previously found optimal, 3-(di-tert-butylphosphonium)propanesulfonate (DTBPPS), has limited commercial availability on large scale. HTE was employed to find alternative protocols suitable for industrial-scale syntheses that would address these complications. As a result, a new system was developed using PdCl2(AmPhos)2, K2CO3, and sec-butanol/H2O (1:1) as the solvent, which yielded a more desirable crystal form of the cross-coupling product.136 Other uses of HTE in the context of Suzuki-Miyaura couplings involve the incorporation of fluorinated functionality by cross-coupling methods,137,138 as well as in development of one-pot tandem Suzuki/Heck reactions for the preparation of 1,2-diarylated alkenes.44 One of the industrial case studies reported in the aforementioned cross-industry perspective from 2019 is the development of a complex Suzuki-Miyaura coupling during the synthesis of a PCSK9 inhibitor developed by Pfizer for the treatment of LDLC.22 Aside from the presence of multiple heterocycles in the target, two other problematic features of the coupling were the formation of several byproducts, including decomposition of the boronic ester (oxidation and homocoupling) and cleavage of the N-alkyltetrazole. The latter side-pathway necessitated the use of a weak base, among which CsF was found to be most successful. HTE was instrumental in improving the medicinal chemistry route under tight deadlines, given the low yield (36%) and need for column chromatography in the discovery route. A preliminary screen used 24 different Pd precatalysts and 3 solvents (toluene/H2O (9:1 v/v), dioxane/H2O (9:1 v/v), MeTHF/H2O (9:1 v/v)). Successful trials were evaluated on the basis of providing high conversion of the boronic ester with minimal byproduct formation: PdCl2(DCyPF), PdCl2(DPEPhos), PdCl2(DPPF), and Pd(PCy3)2 were found to meet these requirements, and toluene/H2O was found to be the best solvent mixture. A second screen uses a broad range of solvents with these four precatalysts and found that PdCl2(DCyPF) with toluene solvent and Pd(PCy3)2 with either DME, tAmOH, or IPA (isopropyl acetate) as solvent were the best options. While PdCl2(DCyPF) is a more practical choice due to its ease of handling versus Pd0, this precatalyst performed poorly (30–40% conversion) during large scale reactions with mechanical stirring, likely due to insufficient reduction under biphasic conditions. Despite the oxygen sensitivity of Pd(PCy3)2, this precatalyst was able to provide 92–94% isolated yield for multikilogram quantities of the product with minimal byproduct formation (Eq. 9).

ð9Þ

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Source: Mennen, S.M.; Alhambra, C.; Allen, C.L.; Barberis, M.; Berritt, S.; Brandt, T.A.; Campbell, A.D.; Castañón, J.; Cherney, A.H.; Christensen, M.; Damon, D.B.; Eugenio de Diego, J.; García-Cerrada, S.; García-Losada, P.; Haro, R.; Janey, J.; Leitch, D.C.; Li, L.; Liu, F.; Lobben, P.C.; MacMillan, D.W.C.; Magano, J.; McInturff, E.; Monfette, S.; Post, R.J.; Schultz, D.; Sitter, B.J.; Stevens, J.M.; Strambeanu, I.I.; Twilton, J.; Wang, K.; Zajac, M.A. The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future. Org. Process Res. Dev. 2019, 23(6), 1213–1242. A stereospecific Suzuki-Miyaura coupling was optimized by HTE in the development of BMS-978587, an IDO-enzyme inhibitor with potential application as anti-cancer treatment.139 A redesign of the initial medicinal chemistry route was required to enable scale-up. By performing the key Suzuki coupling later in the synthetic sequence, several improvements could be made: installing the urea moiety earlier in the route gives crystalline intermediates (rather than viscous oils that are difficult to isolate); using iodocyclopropanecarboxylic acid instead of the analogous methyl ester removes ester formation and saponification steps; and performing the nitro group hydrogenation earlier reduces the risk of handling multiple potentially genotoxic intermediates. As a trade-off, these aspects significantly increase the complexity of the Suzuki coupling. For the envisioned coupling, an initial HTE ligand screen using Pd(OAc)2 as precatalyst found only three ligands provided significant conversion: DTBPF, CataCXium POMetB, and P(o-tol)3, although the hits with P(o-tol)3 were very poor in comparison to the other two systems. Extensive screening was performed to optimize the reaction with DTBPF and CataCXium POMetB; however, due to the limited commercial availability of these ligands on large scale, the process chemistry team focused on improving the yield of the reaction catalyzed by Pd(OAc)2/ P(o-tol)3. Further optimization via HTE revealed that the solvent/base combination of THF/NaOH does provide the desired product in 80% HPLC yield, albeit along with the formation of numerous byproducts (dehalogenation, homocoupling of boronic acid, boronic acid oxidation). These impurities were removed by EtOH(aq)/heptane phase separation under basic conditions. Further purifications involved MTBE/aqueous acid treatment followed by activated charcoal and Silia Met5-thiol. The final product obtained in 60% yield, >99% purity (Eq. 10).

ð10Þ

Source: Maity, P.; Reddy, V.V.R.; Mohan, J.; Korapati, S.; Narayana, H.; Cherupally, N.; Chandrasekaran, S.; Ramachandran, R.; Sfouggatakis, C.; Eastgate, M.D.; Simmons, E.M.; Vaidyanathan, R. Development of a Scalable Synthesis of BMS-978587 Featuring a Stereospecific Suzuki Coupling of a Cyclopropane Carboxylic Acid. Org. Process Res. Dev. 2018, 22(7), 888–897. Several systems have been developed to use HTE in continuous flow to evaluate a large volume of reactions and continuous variables in the Suzuki-Miyaura reaction.83,140 The system designed by Pfizer, described in Section 13.12.2.3, was used to explore the coupling of a quinoline with an indazole through numerous Pd-mediated routes. Over 7000 reaction variable permutations could be evaluated in a relatively short amount of time using this method, providing an incredibly granular view of the entire coupling system as a function of every variable. Csp2–Csp3 cross-couplings can also be achieved by Suzuki-Miyaura reactions, though they are considerably more challenging. One such example is the coupling of secondary alkyltrifluoroborates (RBF3K) with aryl halides, developed by Molander and Dreher.141 This variant of the Suzuki-Miyaura reaction is more amenable to alkylboron nucleophiles. The advantage of RBF3K reagents versus alkylboronic acids is their ability to more readily undergo transmetalation, and reduced proclivity toward protodeboronation. Microscale HTE optimization found Pd(OAc)2, CataCXium A (n-BuPAd2) with Cs2CO3 in toluene as the highest yielding reaction system screened. A notable limitation of Pd catalysis is the difficulty in carrying-out couplings with alkyl halide substrates; Chirik and coworkers recently described a Co-catalyzed Csp2–Csp3 coupling of arylboronate esters with alkyl bromides, where HTE was used to discover that [(DMCyDA)CoBr2] (DMCyDA ¼ N,N0 -dimethylcyclohexyl-1,2-diamine), KOMe, in DMA (60  C) is effective for this coupling reaction.142

13.12.3.3 CdC bond formation: Negishi and Kumada-Corriu couplings While organoboron substrates are ubiquitous in cross-coupling due to the general ease of Suzuki-Miyaura coupling, use of more reactive organometallic nucleophiles, including those based on Zn (Negishi coupling) and Mg (Kumada coupling), is advantageous in certain circumstances. A considerable challenge to Negishi and Kumada-Corriu couplings arises from generation of the organometallic coupling partner (RMgX, RZnX, or RLi); in particular, assessing the metalation step in a high-throughput manner is challenging due to the necessity of cryogenic conditions, and handling/dispensing organometallic bases can provide an additional challenge. Scientists at Gilead established non-cryogenic (0  C) conditions for the metalation of oxazole using the Hauser base TMPZnCl (TMP ¼ tetramethylpiperidinyl) to enable HTE screens of the subsequent Negishi coupling.143 Similarly, scientists at Merck developed the aforementioned automated platform to evaluate the selectivity of metalation conditions in high-throughput fashion using TMPMCl (M ¼ Zn or Mg) for base and temperature screening with automated dispensing, agitation, cooling, and quenching (Section 13.12.2.3).82 A successful development from an academic/industrial collaboration between Merck and the Knochel group is the use of air stable organozinc pivalate (RZnOPiv) reagents for use in Negishi couplings.144 This study demonstrates that RZnOPiv reagents are convenient for HTE optimization and library synthesis, finding that XPhos Pd G3 is the best catalyst screened for a variety of Negishi couplings of complex, “drug-like” coupling partners (Fig. 21).

High-Throughput Experimentation in Organometallic Chemistry and Catalysis

Catalyst PEPPSI-iPr XPhos-Pd-G3 QPhos-Pd-G3 NiXantPhos-Pd-G3

1 81 66 49 45

2 0 0 0 0

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4 67 75 80 84

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Aryl Halide X3 + Zincate: 7 8 9 10 11 12 39 70 29 33 83 0 46 41 32 16 5 0 18 57 32 21 33 0 14 40 27 11 62 0

Zincate 16 + Aryl Halide: Catalyst X1 X2 X3 X4 X5 X6 X7 X8 X9 X10 X11 X12 PEPPSI-iPr 0 0 6 15 0 8 0 0 3 0 0 0 XPhos-Pd-G3 0 46 40 59 13 60 0 0 42 0 0 13 QPhos-Pd-G3 0 19 18 25 3 23 0 0 23 0 0 9 NiXantPhos-Pd-G3 0 19 12 11 0 31 0 0 0 0 0 0

525

13 14 15 16 17 10 0 7 6 1 4 0 29 40 92 17 43 49 18 52 13 12 0 12 95

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Fig. 21 High-throughput exploration of “drug-like” aryl halide coupling partners with bench-stable zinc pivalates (THF, 50  C, 18 h). Values are solution yields obtained by HPLC analysis using product standards. From Greshock, T.J.; Moore, K.P.; McClain, R.T.; Bellomo, A.; Chung, C.K.; Dreher, S.D.; Kutchukian, P.S.; Peng, Z.; Davies, I.W.; Vachal, P.; Ellwart, M.; Manolikakes, S.M.; Knochel, P.; Nantermet, P.G. Angew. Chem. Int. Ed. 2016, 55, 13714–13718.

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Other applications of HTE for these coupling reactions include a report by Merck for the reaction of allylmagnesium bromide with 4-bromoisoindoline. This Kumada reaction was developed to synthesize 4-allylisoindoline, an intermediate toward the synthesis of an unspecified active pharmaceutical ingredient. HTE was used to identify the combination of Pd(OAc)2 (0.5 mol%) and NpPtBu2 ∙ HBF4 (1 mol%) as an effective catalyst system (Np ¼ neopentyl).145 Another study from Newman and coworkers describes use of HTE to perform a Collins/Glorius additive screen to demonstrate the high relative chemoselectivity of a Pd(OAc)2/ SPhos catalyst for Kumada-Corriu couplings.146 Finally, scientists at Amgen developed a Negishi reaction of 2-pyridyl halides with isopropylzinc chloride, using HTE to simultaneously evaluate three Pd catalysts with a scope of heteroaryl halides.147 In this work, XantPhos Pd G3 was identified as particularly successful in obtaining coupling products in high branched:linear ratio.

13.12.3.4 CdC bond formation: Cross-electrophile couplings An emerging class of cross-coupling reactions involve two electrophile substrates and a reductant—cross-electrophile couplings—which are typically catalyzed by Ni catalysts. A collaborative effort from the Weix group and Pfizer has approached the problem of scope in Ni-catalyzed cross-electrophile coupling by using HTE to identify new ligand structures. This effort was in pursuit of more active catalysts as well as extending the reaction scope to more complex medicinally-relevant structures.148 One challenge of this reaction class is limited knowledge about ligand design features; typically, simple bipyridines are used, such as 4,40 dimethoxybipyridine. Drawing from the diverse Pfizer compound library (2.8 million compounds), structure searches were performed to identify promising potential nitrogen-based ligands to test, narrowing down the list to 82 compounds (mostly substituted heterocycles). The cross-electrophile reaction was performed in a high-throughput manner using NiCl2(dme) (5 mol%), ligand (5 mol%), NaI (0.25 equiv.), reductant (2 equiv.), and trifluoroacetic acid (TFA, 0.1 equiv.), in DMA (Fig. 22). Dispensing of the solid reductant to the HTE reaction arrays was done by creating a “stock slurry,” where a known mass and particle size of metal reductant was suspended in DMA. This suspension was rapidly agitated using magnetic stirring to create a roughly uniform slurry, which was dispensed to reaction vials using a syringe. A number of the non-conventional ligands discovered in this screening campaign are successful in promoting complex coupling reactions in good yields, exceeding the activity and generality of standard bipyridine based catalysts. The successful ligand structures all featured 2-amidylpyridine functionality; further optimization found 2,6-diamidylpyridine (A15 in Fig. 22) to be the most general ligand. Hughes and Fier subsequently used an HTE approach to discover conditions for a related cross-electrophile coupling between alkyl sulfones and aryl halides.149 Exploring a selection of multidentate nitrogen ligands inspired by the aforementioned Weix/

Fig. 22 Ligands screened for Ni-catalyzed cross-electrophile coupling derived from Pfizer compound library. From Hansen, E.C.; Pedro, D.J.; Wotal, A.C.; Gower, N.J.; Nelson, J.D.; Caron, S.; Weix, D.J. Nat. Chem. 2016, 8, 1126–1130.

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527

Pfizer work again revealed a 2,6-diamidylpyridine to be the optimal ligand. Taking a 10% yield hit from HTE through several rounds of optimization led to identification of NiBr2 as the catalyst, Zn as reductant, and dimethyl isosorbide (DMI) as a particularly effective solvent (Eq. 11).

ð11Þ

Source: Hughes, J.M.E.; Fier, P.S. Desulfonylative Arylation of Redox-Active Alkyl Sulfones with Aryl Bromides. Org. Lett. 2019, 21(14), 5650–5654. As an alternative to using stoichiometric reductants, tandem photocatalytic variants of Ni-catalyzed cross-electrophile couplings have emerged that use light as a driving force for the reaction. Researchers at Idorsia Pharmaceuticals Ltd. used a high-throughput approach to optimize a dual tandem Ir (photoredox) and Ni (organometallic) catalytic coupling reaction for the decarboxylative arylation of aliphatic amines150 based on seminal work from Doyle and MacMillan.52 By using pre-dosed reaction vials acquired from HepatoChem Inc., the authors arrived at a combination of [Ir(dtbbpy)(ppy)2]PF6 (photocatalyst) and DBU (soluble base) in conjunction with (dtbbpy)NiCl2 as the optimal system. Notably, this is different than the initially reported reaction conditions, but is consistent with a parallel optimization carried out by researchers at Janssen, also with an eye toward continuous flow operation.151 A recent and comprehensive study by scientists at AbbVie employed HTE to rapidly compare and contrast seven different methods of Csp2–Csp3 couplings in parallel, with an eye toward evaluating these systems from a medicinal chemistry perspective.152 The systems investigated include palladium catalyzed methods for the coupling of heteroaryl bromides with alkyl trifluoroborate (BF3K) salts or alkyl MIDA boronates (Suzuki-Miyaura), or alkyl zinc reagents (Negishi), as well as nickel catalyzed methods using alkyl bromides (cross-electrophile), or alkyl BF3K salts (Suzuki-Miyaura), or alkyl carboxylate acids or bromides in the presence of photosensitizers and visible light (photoredox cross-electrophile) (Fig. 23). Representative aryl halide cores are screened in parallel

Fig. 23 Parallel-in-parallel evaluation of seven different approaches to Csp2-Csp3 cross-coupling. Reprinted with permission from Dombrowski A.W.; Gesmundo, N.J.; Aguirre, A.L.; Sarris, K.A.; Young, J.M.; Bogdan, A.R.; Martin, M.C.; Gedeon, S.; Wang, Y. ACS Med. Chem. Lett. 2020, 11, 597–604. Copyright 2020 American Chemical Society.

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with medicinally relevant alkyl coupling partners. The most successful reaction evaluated in the Pd-catalyzed Negishi reaction, where all of the alkyl coupling partners were successful; however, this reaction class relies on the availability of the required alkylzinc reagent. Additionally, Pd-catalyzed couplings with alkyl BF3K salts, which have complementary diversity profile versus alkylzinc reagents, provided good yields across numerous substrate combinations. Ni-catalyzed photoredox mediated cross-electrophile couplings performed generally well, but had a more limited scope. Other methods evaluated were less successful.

13.12.3.5 CdC bond formation: Mizoroki-Heck coupling The Mizoroki-Heck reaction—the alkenylation of aryl halides catalyzed by Pd—is generally regarded as a “mature” coupling reaction, having been developed and widely applied for decades. In spite of this, complex molecular structures are still challenging to construct by Heck-type reactions when standard conditions fail. In one such example, the Mizoroki-Heck reaction was considered as a potential route to rosuvastatin, but required considerable optimization to arrive at suitable conditions. As a result of this project, scientists at AstraZeneca established a generic protocol of first-pass conditions for screening of Mizoroki-Heck reactions that are applicable to a range of coupling partners (Fig. 24).153 In one screen, 13 structurally simple aryl bromides are reacted with styrene using one set of reaction conditions based on a protocol developed by Fu154 (Cy2NMe as base, tetrabutylammonium chloride (10 mol%) as an additive, DMAc as solvent, 80  C) and 10 different Pd catalysts (Pd/C, Pd(PPh3)4, PdCl2(P(o-tol)3)2, Pd(OAc)2, PdCl2(dppe), PdCl2(dippf ), [Pd(PtBu3)Br]2, Pd(PtBu3)2, PdCl2(dtbpf )). While catalysts based on PtBu3 are the most versatile, other catalysts including PdCl2(P(o-tol)3)2 and PdCl2(dtbpf ) result in high conversion for a number of substrates. Even simple Pd/C or Pd(OAc)2 in the absence of phosphine ligands work well for several substrates. The screen was repeated with various substituted acrylates, where the “optimal” catalyst, Pd(PtBu3)2, was found to be less reliable. As an alternative, PdCl2(dtbpf ) offers good reactivity for a variety of substrate combinations. The synthesis of TAK-828F features a substituted 2-vinylpyridine as an early intermediate. In the initial synthesis, this intermediate was constructed using the parent 2-chloropyridine and potassium vinyltrifluoroborate in a Suzuki-Miyaura-type reaction. However, concerns about the release of fluoride on large scale prompted scientists at Takeda to consider alternative routes to the vinylpyridine. Despite little literature precedent, a Mizoroki-Heck reaction using ethylene gas was pursued.109 Screening a variety of Pd sources (20 mol%) and ligands (40 mol%), using ethylene (3 MPa), NEt3 (3 equiv.), and LiCl additive (3 equiv.) in DMF revealed that most systems promote the desired coupling, but generally form a considerable quantity of unidentified byproducts. Ultimately, selective conditions were developed using PdCl2 at lower catalyst loading (5 mol%), DPEPhos as ligand, and with LiCl and phenothiazine additives (Eq. 12). Another example of HTE screening of the Mizoroki-Heck reaction finds that the terphenylphosphine Cy Phine is a suitable ligand for couplings with a variety of unusual alkenes.155

ð12Þ

Ar-Br, R = Catalyst Pd/C Pd(PPh3)4

H

4-Me

4-OMe

4-CN

n/a 60

14 26

n/a 15

100 11

4-C(O)Me 2-OMe

2-Et

2-CHO 2-CO2Me

100 34

n/a 0

0 0

0 0

2-CN

3-OMe

3-CN

3-OH

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n/a 0

50 6

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Pd[P(o-tol) 3]2Cl 2

0

n/a

15

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99

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99

99

99

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0

67

0

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100

0

12

0

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4

Pd(dppe)Cl 2

0

88

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13

0

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66

14

0

Pd(dppb)Cl 2

0

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30

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3

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Pd(dippf)Cl 2

30

n/a

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99

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Pd[P(t Bu) 3]2

99

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99

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79

99

Fig. 24 First-pass Mizoroki-Heck screen developed at AstraZeneca. Values represent yields determined by HPLC analysis using a product standard. From Murray, P.M.; Bower, J.F.; Cox, D.K.; Galbraith, E.K.; Parker, J.S.; Sweeney, J.B. Org. Process Res. Dev. 2013, 17, 397–405.

High-Throughput Experimentation in Organometallic Chemistry and Catalysis

529

Source: Tsuruoka, R.; Yoshikawa, N.; Konishi, T.; Yamano, M. Asymmetric Synthesis of a 5,6,7,8-Tetrahydro-1,6-Naphthyridine Scaffold Leading to Potent Retinoid-Related Orphan Receptor Gt Inverse Agonist TAK-828F. J. Org. Chem. 2020, 85(16), 10797–10805. An example of an atypical application of Heck couplings come from a collaboration between the Schindler group and Merck, aimed at developing a methodology to access tricyclic spirolactones using an intramolecular variant of the Mizoroki-Heck reaction.156 Initial results showed that the cyclization of a relatively simple vinyl bromide substrate occurs with Pd(PPh3)4 (20 mol%) and Ag2CO3 (2 equiv.) in DMA at 130  C, providing 66% yield of the desired spirocyclic product. Notably, high temperatures and the use of a Ag base were found critical to a high yielding reaction. Unfortunately, these conditions did not enable the spirocyclization of a more densely substituted substrate in reasonable yields. Therefore, HTE was used to find conditions amenable for spirocyclization of more complex substrates by evaluating a broad scope of ligands and solvent/base combinations for different electrophile types (i.e., vinyl bromide vs. vinyl triflate). Multivariate screening of the less thermally sensitive vinyl bromide found that the combination of [Pd(allyl)Cl]2 as precatalyst and DMA as solvent provided the best results, with several triarylphosphines consistently providing the highest yields. Next, optimization of the base and Ag additive in the spirocyclization (Eq. 13) used [Pd(allyl)Cl]2 (5 mol%), four triarylphosphine ligands (20 mol%), base (2 equiv.), AgOTs (1.1 equiv.) in DMA (0.01 M) at 120  C. The screen identified tris(2-methyl-5-trifluoromethyl)phosphine and pentamethylpyridine as the optimal ligand and base respectively, providing the desired product in 91% solution yield.

ð13Þ

Source: Annand, J.R.; Riehl, P.S.; Schultz, D.M.; Schindler, C.S. High-Throughput Approach toward the Development of a Mizoroki–Heck Reaction to Access Tricyclic Spirolactones. J. Org. Chem. 2020, 85(14), 9071–9079. The discovery of new reaction classes has also been enabled by HTE. A particularly relevant example from the Newman group describes a Mizoroki-Heck-inspired method for deriving ketones from aryl halides and aldehydes.157,158 Here, it was postulated that the Mizoroki-Heck mechanism, which operates through the carbopalladation of an alkene by a Pd(aryl) intermediate followed by b-hydride elimination, may also operate with aldehydes as the unsaturated coupling partner. Microscale (30 mmol) multivariate screens focused on broad evaluation of reaction parameters (32 ligands, 4 bases, 4 solvents, 8 aryl electrophiles, both Pd and Ni precatalysts), with 672 possible permutations evaluated. The optimal results were found with Ni catalysts: phenyl triflate and benzaldehyde form the benzophenone in 97% solution yield using Ni(cod)2 (10 mol%), triphos (12 mol%), tetramethylpiperidine (TMP, 1 equiv.), toluene, 110  C (Eq. 14). Notably, Pd catalysts were found to be totally ineffective for the reaction, and aryl triflate (rather than halide) electrophiles are essential.

ð14Þ

Source: Vandavasi, J.K.; Hua, X.; Halima, H.B.; Newman, S.G. A Nickel-Catalyzed Carbonyl-Heck Reaction. Angew. Chem. Int. Ed. 2017, 56(48), 15441–15445.

13.12.3.6 CdC bond formation: Sonogashira coupling Sonogashira couplings synthesize substituted phenylacetylenes from terminal alkynes and a Pd catalyst. Typical reaction conditions tend to be fairly simple, utilizing catalyst precursors such as PdCl2(PPh3)2 and a Cu cocatalyst (typically CuI); however, more complex examples can require more sophisticated screening protocols. For example, development of the high potency FLT-3 inhibitor HSN608 by Thompson and coworkers required the discovery of more active catalysts for a complex Sonogashira coupling, as well as DOE study for optimization of continuous variables for a telescoped process for sequential amide coupling and Sonogashira reaction under continuous flow conditions.159 A thorough study from Plenio utilized HTE to determine kinetic and thermodynamic parameters for >500 Sonogashira couplings performed under different reaction conditions (Fig. 25), finding that a catalyst’s competency for the coupling correlates roughly with the cone angle of the ligand (the best results use PAdtBu2 as a sterically hindered ligand), and with the electron deficiency of the aryl halide coupling partner.160

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High-Throughput Experimentation in Organometallic Chemistry and Catalysis

Fig. 25 HTE kinetic evaluation of 17 phosphines and 20 aryl bromides for Sonogashira coupling. Vertical axis is rate constant of the coupling in units h−1. From an der Heiden, M.R.; Plenio, H.; Immel, S.; Burello, E.; Rothenberg, G.; Hoefsloot, H.C.J. Chem. A Eur. J. 2008, 14, 2857–2866.

13.12.3.7 CdC bond formation: C-H arylation C-H arylation is a broad class of cross-coupling reactions in which substrates with relatively reactive (generally acidic) CdH bonds are the nucleophilic coupling partner. In this respect, Sonogashira coupling (Section 13.12.3.6) is a specific class of CH arylation. Another specific class of C-H arylation is “direct arylation,” where an aromatic or heteroaromatic nucleophile with a reactive CdH bond is coupled to an aryl halide. The C–H can be cleaved by a concerted-metalation-deprotonation type mechanism,161,162 which is assisted by basic ligands on the transition metal, or by directed C–H activation. An example of the latter is a reaction developed at Bristol-Myers Squibb for the synthesis of BMS-919373, in which 2-pyridylmethylamine moiety present in the target molecule itself is used as a directing group for Pd-catalyzed C–H arylation.163 HTE was used to develop suitable reaction conditions: Pd(OAc)2 (5 mol%) and KOAc (3 equiv.) in neat iodobenzene (0.1 M) at 118  C, which provides the arylation product in good solution yields (Eq. 15). Notably, high-throughput screening indicated that the presence of any ligand (phosphine, pyridine, or phosphite) leads to inhibition of catalysis.

ð15Þ

Source: Wisniewski, S.R.; Stevens, J.M.; Yu, M.; Fraunhoffer, K.J.; Romero, E.O.; Savage, S.A. Utilizing Native Directing Groups: Synthesis of a Selective IKur Inhibitor, BMS-919373, via a Regioselective C–H Arylation. J. Org. Chem. 2019, 84(8), 4704–4714. A study from Kappe and coworkers focused on developing C–H arylations with base-metal catalysts under high pressure and temperature. These researchers developed an HTE platform using silicon carbide ceramic plates to enable high reaction temperature homogeneity, which is a necessity for parallel screening at high temperatures.164 An array of base-metal catalysts (Co, Ni, Fe, Cr, Cu, Mn) were evaluated for their competency to undergo the reaction of 4-bromoanisole with benzene in the presence of LiHMDS at 160  C. Co catalysts were the most successful, with CoIII(acac)3 being the best precursor, while Cu or Ni salts promoted C–N coupling of the aryl halide with LiHMDS. Further optimization indicated Co(acac)3 (5 mol%), LiHMDS (2 equiv.) and a temperature of 200  C provided the highest activity and selectivity.

High-Throughput Experimentation in Organometallic Chemistry and Catalysis

531

Fig. 26 Ligand and base screening for Ni-catalyzed C–H arylation. Values represent yields determined by HPLC analysis using a product standard. Reprinted with permission from Larson, H.; Schultz, D.; Kalyani, D. J. Org. Chem. 2019, 84, 13092–13103. Copyright 2020 American Chemical Society.

Another study in base-metal C–H arylation, by Schultz, Kalyani, and coworkers, describes the development of Ni catalysts for the direct arylation of medicinally relevant heterocycles (Fig. 26).165 HTE identified Ni(COD)2 and either dcype or NiXantphos as suitable ligands for the reaction, while the identity of the base was dependent on substrate choice. The phosphazene base P2Et afforded the most general reactivity. A recent study from researchers at Biogen used HTE to explore a 112-member ligand library for the transannular C–H arylation of a series of pharmaceutically-relevant nitrogen-containing (bi)cyclic building blocks. The relatively simple 6-methylpicolinic acid was found to be effective in combination with Pd(OAc)2, enabling synthesis of many diversified heterocyclic scaffolds.166 In addition to direct arylation, a distinct class of C–H arylation reactions is deprotonative cross-coupling. Here, the nucleophilic substrate can form an enolate or other stabilized anion under strongly basic conditions. A number of reports in this area have been published by Dreher and Walsh, where HTE is applied to discover reaction conditions for a variety of C–H arylation reactions. A representative example includes the arylation of diarylmethanes,45 where an extensive screen of 112 phosphine ligands, 12 Pd sources, 4 solvents, a variety of reagent stoichiometries, and a range of temperatures were evaluated for the reaction of diphenylmethane with 1-bromo-4-tert-butylbenzene. KHMDS was identified as the only suitable base and only one ligand (NiXantphos) provided a good solution yield of the desired product. Multivariate screening established Pd(OAc)2 (5 mol%), NiXantphos (7.5 mol%), and KHMDS (3 equiv.) in CPME with a slight excess of diphenylmethane (1.2 equiv. to the aryl halide) as optimal (>95% isolated yield). In an effort to expand the scope of this coupling, attempts were made to find alternative bases that could be used in the reaction. A screen of additives, again enabled by HTE, found that the addition of 15-crown-5 enabled high yielding synthesis of triarylmethanes when LiHMDS or NaHMDS was used as base (Eq. 16).46 Related protocols discovered conditions to arylate other C–H acidic substrates, such as benzylphosphine oxides,167 sulfoxides,168 a,b-unsaturated imines,169 and cyclopropylnitriles.170,171

ð16Þ

Source: Bellomo, A.; Zhang, J.; Trongsiriwat, N.; Walsh, P.J. Additive Effects on Palladium-Catalyzed Deprotonative-Cross-Coupling Processes (DCCP) of Sp3 C–H Bonds in Diarylmethanes. Chem. Sci. 2013, 4(2), 849–857.

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13.12.3.8 CdC bond formation: Allylation Pd-catalyzed allylation is another well-studied transformation, and takes advantage of the propensity of allylic electrophiles to readily undergo oxidative addition to Pd(0). Subsequent nucleophilic attack at the Pd-allyl ligand enables CdX bond formation with a variety of nucleophiles. In 2007, Reek and coworkers explored the SUPRAphos class of chiral ligands to develop a kinetic resolution through Pd-catalyzed allylation.172 These ligands are composed of a chiral phosphite tethered to a Zn-porphyrin; this species can then be modified through coordination of a second fragment to Zn, providing a tunable binding pocket in a manner convenient for HTE. Screening 64 ligand combinations resulted in an optimal S value of 12 for the resolution of rac-1acetoxycyclohex-2-ene with dimethylmalonate. Walsh and coworkers investigated a variation of the Tsuji-Trost reaction in which allyl carboxylates are cross-coupled with Cr-bound alkylbenzenes in the presence of Pd catalysts173 HTE focused on screening Pd precursors, phosphine ligands, and bases: Pd(COD)Cl2, XantPhos, and LiHMDS were found to be successful, and further optimization found that an additional base, NEt3, promoted high yields of the cross-coupling reaction. Stoltz and coworkers developed an intramolecular, asymmetric, decarboxylative allylic alkylation reaction catalyzed by Pd. Screening via HTE identified (S)-tBuPHOX as the optimal phosphine ligand, giving the highest yield and enantioselectivity, and also revealed solvent effects on the reactivity (Fig. 27).174 Ooi and coworkers developed a Pd-catalyzed allylic alkylation reaction in which ion-paired cationic phosphines and chiral phosphonic acids were screened using HTE.175 Berkowitz and coworkers used reporting enzymes to visualize HTE screens of a transition-metal catalyzed sequential allylic alkylation/halometalation—as described previously in Section 13.12.2.4—finding both Rh and Pd catalysts suitable for the transformation in the presence of Li salts.90 Finally, Anslyn and Krische reported an optical assay for enantiomeric excess determination, which enabled rapid analysis of HTE screens for Ir-catalyzed allylic alkylation.176

13.12.3.9 CdC bond formation: Carbonylative coupling Pd-catalyzed carbonylation reactions are a mass-efficient method of synthesizing aryl carboxylic acid derivatives. Researchers at Merck used HTE to develop a carbonylative coupling involving benzenesulfonate electrophiles. This group found that the combination of Pd(OAc)2, JosiPhos, and NaOAc is competent for the carbonylation of aryl fluorobenzenesulfonates to esters under CO atmosphere (90 psi) in EtOH solvent at 135  C.177 A report from Pfizer describes the use of HTE to develop an aminocarbonylation of aryl tosylates with t-butylamine and CO (130 psi), using Pd(OAc)2 and dcyhpe ∙2HBF4 (1,2-dicyclohexylphosphinoethane HBF4 salt) in DMF at 120  C.178 Schunk and coworkers evaluated the effect of continuous variables on the carbonylation of polyols by HTE.179 A recent example of carbonylation methods developed by HTE was reported by a group at GSK, which focused on practical synthesis of a,b-unsaturated g-ketoesters.81 To bypass oxidative or reductive routes to these building blocks, a Pd-catalyzed carbonylative strategy to assemble the methyl ester was instead pursued, starting from the corresponding b-chloro enones. HTE was used to develop a catalytic method for the transformation, despite little literature precedent for carbonylation of vinyl chlorides in this manner. Parallel-in-parallel HTE screening found that while many conditions furnished simple derivatives, more sterically encumbered substrates requires the use of PMetBu2 as the phosphine (Fig. 28). Further optimization resulted in the following general conditions: PdCl2(NCCH3)2 (2 mol%), PMetBu2 ∙ HBF4, (4 mol%), CO (60–70 psig), NEt3 (1.5 equiv.) using toluene/ CH3CN (5:2) solvent at 80  C for 18 h. A variety of enone esters can be prepared in this manner, with 20 examples reported on a 1 mmol scale (44–87% yield). Similar conditions using PtBu3 instead of PMetBu2 were used to prepare one of these examples in 90% isolated yield on a 60 g scale with 0.5 mol% Pd.

13.12.3.10

CdC bond formation: Alkene metathesis

Advances in alkene metathesis have been enabled by HTE in a number of cases. Grubbs and coworkers used HTE to evaluate a catalyst library, and in doing so discovered novel backbone-substituted NHC ligands for Ru-catalyzed ring closing metathesis (RCM). These ligands improved catalyst lifetimes by mitigating decomposition pathways.49 Fogg and coworkers developed a quenching system for a Ru-catalyzed RCM to enable an HTE study of this reaction where reaction time could be evaluated as a critical continuous variable.180 As described in Section 13.12.2.4, Grela, Limbach and coworkers performed alkene metathesis reactions on thin-layer chromatography (TLC) plates, using the silica-lined plate as both a reaction vessel and solid support for the catalyst.88 Performing reactions in this manner allowed rapid identification of successful catalysts for both intermolecular cross-metathesis and ring-opening metathesis polymerization, though catalyst stability on the silica gel is one complication of this method. Researchers at Dow endeavored to use simple W salts (WEX4, E ¼ oxo or imido, X ¼ Br or Cl) as catalyst precursors for HTE screening purposes. Through the screening of the combination of these precursors, a variety of ligands, and alkylaluminum activators, catalysts were identified which exceeded the activity of preformed Grubbs and Schrock type catalysts.181 Fedorov and coworkers used HTE to discover a highly active catalyst for the Ru-catalyzed ethenolysis of maleate esters to acrylate esters.182 Finally, Han and coworkers used an alkene appended with pyrenyl groups as a fluorescent tag for screening both catalysts and reaction conditions for cross-metathesis and ring-closing metathesis. A quantitative ratiometric method was devised to measure substrate consumption that closely matched values obtained by traditional means (e.g., GC-FID).183 Grazoprevir, synthesized by Merck, is an example of a pharmaceutical application of alkene metathesis where RCM was used to form the compound’s macrocyclic core (Fig. 29).184 Based on the observation that the formation of the macrocyclized product was

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Fig. 27 Screen of PHOX-type ligands for enantioselectivity in Pd-catalyzed allylation. Reproduced with permission from McDougal, N.T.; Virgil, S.C.; Stoltz, B.M. Synlett 2010, 2010, 1712–1716. Copyright 2010 Georg Thieme Verlag KG.

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Fig. 28 Parallel-in-parallel screening for the discovery of generally-applicable carbonylation conditions for the esterification of b-chloroenones. Reprinted with permission from Kaplan, J.M.; Hruszkewycz, D.P.; Strambeanu, I.I.; Nunn, C.J.; VanGelder, K.F.; Dunn, A.L.; Wozniak, D.I.; Dobereiner, G.E.; Leitch, D.C. Organometallics 2019, 38, 85–96. Copyright 2019 American Chemical Society.

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Fig. 29 Macrocyclic core of Grazoprevir formed by alkene metathesis (top); Ru-catalyzed ring-closing metathesis with new Ru complexes featuring quinoxaline-appended alkylidenes. From Williams, M.J.; Kong, J.; Chung, C.K.; Brunskill, A.; Campeau, L.-C.; McLaughlin, M. Org. Lett. 2016, 18, 1952–1955.

dependent on the chain length of the respective diene precursor, it was proposed that the quinoxaline moiety formed a metallacycle with the Ru catalyst that was necessary for activity. This proposal was confirmed by the synthesis of a library of Ru catalysts with a quinoxaline-appended alkylidene ligand, which demonstrated improved activity in ring-closing metathesis. Subsequent HTE identified cocatalytic Brønsted and Lewis acids that were able to boost catalytic activity of these quinoxaline-based Ru catalysts. The value of HTE methods for evaluating structure-activity relationships using libraries of alkene metathesis catalysts has been demonstrated by the groups of Copéret and Sigman. By correlating experimental data to computational catalyst parameters using multivariate modeling, reactivity can be better understood as a function of catalyst and ligand structure. In one study, Grubbs-type Ru catalysts for alkene metathesis were explored for ethenolysis of cycloalkenes to acyclic a,o-dienes.185 Selectivity in this reaction is difficult to achieve due to the propensity for Grubbs-type catalysts to be highly active for ring-opening metathesis polymerization (ROMP). While numerous highly active and selective Grubbs type catalysts have been developed for a wide variety of metathesis reactions, there is little understanding of properties of the ancillary ligands which determine the activity of the catalyst. To ascertain rational ligand design principles, 29 different catalysts—general structure of (NHC)Ru(Cl)2(]CHPh)(PCy3) (NHC ¼ N-heterocyclic carbene)—were evaluated in the reaction of ethylene with cycloctene to form 1,9-decadiene (Fig. 30).

Fig. 30 Comparison of selectivity and activity for ethenolysis of cyclooctene (1) to 1,9-decadiene (2). Reprinted with permission from Engl, P.S.; Santiago, C.B.; Gordon, C.P.; Liao, W.-C.; Fedorov, A.; Copéret, C.; Sigman, M.S.; Togni, A. J. Am. Chem. Soc. 2017, 139, 13117–13125. Copyright 2017 American Chemical Society.

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The reactions were performed with 210 ppm of the respective catalyst injected as a toluene solution into 0.95 mL neat cyclooctene, followed by pressurization with 10 bar ethylene, and monitored by GC-FID and gas uptake at different timepoints. Visualizing the data in the form of conversion-selectivity plots, two clusters of catalysts can be identified: one cluster has good conversion and selectivity for 1,9-decadiene, and the other shows good conversion and selectivity for polycyclooctene via ROMP. Interestingly, the former group of catalysts all feature NHCs with a N-trifluoromethyl moiety, whereas the latter group of catalysts are more prototypical NHCs with symmetric N,N-diaryl substituents. Molecular parameters found to be influential are the percent buried volume (%Vbur) of the NHC ligand, and the syy component of the isotropic 77Se chemical shift of the respective [Se(NHC)] complexes. The syy is defined as the shielding tensor along the SedC bond axis, and reflects the multiple bonding interactions of this bond. Deshielding of syy therefore indicates increased p-bonding as a result of donation of an occupied pSe orbital into the p orbital of the NHC ligand. Multivariate modeling indicates a correlation between catalyst selectivity for forming 1,9-decadiene and deshielding of syy in the corresponding [Se(NHC)] complex. Therefore, N-trifluoromethyl groups are understood to have increased p-accepting capacity in comparison to prototypical NHCs, as well as a smaller steric profile. Both of these features explain the improved selectivity according to the developed model. In a second study, a collaborative effort from Fedorov, Sigman, and Copéret used HTE to evaluate Mo-based catalysts for alkene metathesis, and develop correlations between experimental results and molecular parameters of the ancillary ligands (Fig. 31).186 In particular, despite significant recent advances in identifying highly active and selective catalyst structures, rational design principles for these complexes remain elusive and unpredictable. This work focused on developing quantitative insights into ligand effects for Mo catalysis and lead to rational catalyst design principles for both activity and catalyst longevity. These researchers used high throughput experimentation to evaluate the homodimerization of 1-nonene, assisted by automated liquid dispensing under inert atmosphere. Two Mo precatalysts based on the general structure (py)Mo(]NR)(]CCMe2Ph) (R ¼ 2,6-dimethylphenyl or 2,6-diisopropylphenyl) were combined with a library of 35 different substituted phenol ligands in both 1:1 and 1:2 Mo:L ratios. In situ catalyst formation was performed for 3 h in toluene at 27  C before injection into the catalytic reaction mixture containing 1-nonene. The metathesis reaction itself was evaluated by GC to determine initial turnover frequency (TOFin) at 6 mins and turnover number at 72 mins (defined as “TON1h”). These data points are selected as metrics to evaluate catalyst activity and degree of deactivation, respectively. Various computed electronic and steric parameters of the phenol ligands were subject to both univariate and multivariate regression analysis to identify key parameters that influence the observed reactivity. From the correlations, trends within two groups of phenol ligands were identified: phenols with ortho-aryl substituents, and those without. By multivariate analysis, two key steric features which model attractive and repulsive non-covalent interactions (NCIs) are found to influence TOFin. In the case of phenol ligands with ortho-aryl substituents, TOFin is correlated to attractive NCIs, whereas for phenol ligands without ortho-aryl substituents, TOFin is correlated to repulsive NCIs. Similar conclusions were made for analogous SiO2-supported Mo catalysts for alkene metathesis.187

13.12.3.11

CdC bond formation: Alkene polymerization and selective oligomerization

Historically, alkene polymerization (and oligomerization) research has been a major driver of innovation in HTE as applied to organometallic chemistry. Exploring large catalyst libraries and navigating complex multivariate reaction landscapes are hallmarks of alkene polymerization just as they are for every catalytic reaction. One of the best examples of catalyst discovery and optimization enabled by HTE is the development of post-metallocene group 4 systems for high-temperature synthesis of isotactic polypropylene (iPP). In 2006, researchers at Dow, Symyx, and Università di Napoli Federico II reported HTE screening of structurally diverse pyridyl-amine proligands in combination with HfBn4 and Hf(NMe2)4, generating the metallated complexes via in situ protonolysis.188 Rapid evaluation of this catalyst library identified candidates capable of forming iPP that possessed an aryl group adjacent to the neutral pyridine donor (Fig. 32, left). Subsequent synthesis and characterization of the complexes revealed an unexpected metallation of this pendent aryl group. Not only is this ligand binding mode unanticipated, but subsequent studies of catalyst activation and speciation revealed that monomer can insert into the Hf-aryl bond to modify the catalyst structure during catalysis,189 leading to changes in molecular weight distribution of the resulting polymers. Subsequent work reported by LaPointe and coworkers, then at Symyx, expanded the set of ligands and catalysts based on this general framework.190 An HTE-enabled exploration of catalyst identity and reaction conditions combined with synthetic organometallic chemistry pointed toward the beneficial effect of expanding the metallacyclic framework from a 5,5-system to a 5,6-system by using benzofuran or benzothiophene pendent arenes, resulting in catalysts with high activity and stereoselectivity, even at 110  C (Fig. 32, right). A recent study of this expanded metallacycle catalyst class by Voskoboynikov, Hagadorn, and coworkers explored the insertion of various small unsaturated molecules into the Hf–aryl bond to create families of new, ligand-modified catalysts; these catalysts were then evaluated in parallel high-throughput screening for polymerization activity.191 The authors suggest that this “late-stage modification” of catalysts in situ is a possible avenue to accelerate catalyst discovery efforts. Another significant breakthrough in polymerization catalysis enabled by HTE is the development of chain shuttling polymerization.192 Also in 2006, researchers at Dow disclosed a ternary catalyst system to create alkene block copolymers. By combining two ethylene polymerization catalysts that exhibit different degrees of linear a-olefin (LAO) co-monomer incorporation, “hard” (low/no co-monomer) and “soft” (high co-monomer) blocks can be generated. Crucial to the realization of this concept is the inclusion of an appropriate chain shuttling agent (CSA). Not only do the two polymerization catalysts need to be compatible—operating successfully under the same conditions without mutual inhibition or annihilation—but each catalyst also needs to be compatible with the CSA. By devising a primary/secondary screening approach, >1600 individual polymerization experiments were conducted

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Fig. 31 (A) Proposed mechanism of Mo-catalyzed alkene metathesis. (B) Homodimerization of 1-nonene. (C) Library of phenol ligands for Mo catalysts. (D) TON and TOF frequency data. Reprinted with permission from Ferreira, M.A.B.; De Jesus Silva, J.; Grosslight, S.; Fedorov, A.; Sigman, M.S.; Copéret, C. J. Am. Chem. Soc. 2019, 141, 10788–10800. Copyright 2017 American Chemical Society.

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Fig. 32 Exemplar post-metallocene catalysts identified by HTE.

in 3 weeks to identify suitable ternary systems. The combination of a Zr-bis(phenoxyimine) catalyst for “hard” ethylene polymerization with a Hf-pyridylamido catalyst for ethylene/1-octene copolymerization and ZnEt2 as the CSA successfully generated the desired block co-polymer (Fig. 33). Subsequent studies on this chain shuttling polymerization system by Cipullo and coworkers used an HTE approach to map the complex multivariate reaction space of the Dow system.193 By collecting a large dataset of polymer properties under myriad conditions, the authors were able to model the kinetics of this complex catalytic system, and thereby closely approximate the commercially-relevant conditions for producing the Infuse brand of materials. In a related study, Tonks and coworkers evaluated group 10 ethylene polymerization catalysts in combination with a variety of main group CSAs. While most combinations did not exhibit evidence of chain shuttling, Ni-a-diimine catalysts do undergo chain transfer with ZnEt2, with rates dependent on the sterics of the diimine ligand, the strength of the ZndC bond, and ethylene pressure.65,194 More traditional metallocene-based catalysts have also been explored by HTE. In 2009, Pérez and coworkers reported an HTE evaluation of supported zirconocene catalysts for ethylene/LAO co-polymerization.195 More recently, O’Hare and coworkers studied a series of 9 supported-zirconocene catalysts for the production of polyethylene waxes (Mn < 10 kg mol−1). The addition of H2 to ethylene polymerization generally reduces the molecular weight of the resulting polymers, though reduction of catalyst activity under these conditions can be problematic. The silyl-bridged ansa-metallocenes under investigation here were able to retain acceptable activity in the presence of H2, as well as exhibiting excellent stability over time.196 A compelling series of studies on propylene polymerization with ansa-zirconocene catalysts by Ehm, Uborsky, Cipullo and coworkers has established robust and predictive models that correlates catalyst structure with the resulting polymer properties.197–201 In 2018, an HTE-enabled study of 18 exemplar catalysts (Fig. 34) for polypropylene production demonstrated that stereoselectivity (for iPP), regioselectivity, and polymer molecular weight are all correlated to catalyst structure.197 Not only are these three attributes correlated, but stereoselectivity can be quantitatively predicted using only a single steric parameter: the percent buried volume (%VBur)202 of the Zr center (Fig. 35). Based on these insights, the authors designed catalyst M19 (Fig. 34), intended to exhibit higher stereoselectivity; this prediction was borne out by experiment, with M19 resulting in the highest stereoselectivity in the series. This team expanded the scope of this study in a follow-up report that doubles the number of catalysts under investigation, further refines the stereoselectivity model, and introduces additional models for regioselectivity and molecular weight using a series of steric parameters.198 Using this quantitative structure-reactivity relationship, new catalyst candidates were designed computationally and tested for performance across the three criteria. These new catalysts exhibited excellent performance as predicted by the model. An analogous study with a set of 21 catalysts was performed at higher temperature,199 revealing subtle but important changes to the important model parameters, particularly for stereoselectivity: while the initial model only requires a single steric term, at higher temperature a two term correlation involving %Vbur and the NPA charge at Zr resulted in a more robust correlation. Finally, this team also used this approach to study ethylene/LAO co-polymerization in a set of 40 catalysts.200 A single steric parameter, describing the “openness” of the open quadrants of the metallocene, predicts the propensity for co-monomer incorporation; unfortunately, modulation of this parameter through structural modifications is difficult. The combined insights stemming from these studies cannot be overstated, and would not be possible without the use of HTE. A closely related catalytic reaction—selective ethylene oligomerization—has also been studied through HTE approaches. An early example of this from 2008 by Delaude and coworkers describes the evaluation of iminophosphorane complexes of Ni, Fe, Pd, and Cu for the production of LAOs from ethylene.203 While activity (measured by ethylene consumption) was not significantly affected by any of the reaction variables, selectivity toward 1-hexene varied substantially, with the Pd variant exhibiting a 93% mol/mol selectivity for the desired LAO. More recently, a team from Dow led by Rosen and Klosin reported a high-throughput approach to identifying new ligands for Cr-catalyzed ethylene oligomerization, specifically for high 1-octene selectivity. Scanning a library of >50 bidentate phosphines, including several validation experiments using ligands with known activity, revealed the classic asymmetric hydrogenation ligand MeDuPhos generates a highly active catalyst with good selectivity for 1-octene (50% wt/wt).204 Further study of the influence of ligand structure within the DuPhos ligand class via HTE revealed differential activity as well as selectivity for 1-hexene versus 1-octene. EtDuPhos exhibited extremely high activity for ethylene

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Fig. 33 HTE-enabled discovery of a ternary catalyst system for chain shuttling polymerization. From Arriola, D.J.; Carnahan, E.M.; Hustad, P.D.; Kuhlman, R.L.; Wenzel, T.T. Science 2006, 312, 714–719.

Fig. 34 Set of catalysts (M1-18) used to develop a quantitative structure-selectivity relationship for propylene polymerization stereoselectivity, and new highly selective catalyst (M19) designed based on these data. Reprinted with permission from Ehm, C.; Vittoria, A.; Goryunov, G.P.; Kulyabin, P.S.; Budzelaar, P.H.M.; Voskoboynikov, A.Z.; Busico, V.; Uborsky, D.V.; Cipullo, R. Macromolecules 2018, 51, 8073–8083. Copyright 2018 American Chemical Society.

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Fig. 35 Plot of relative free energy for stereocontrol in propylene polymerization using M1-18 versus percent buried volume (%VBur).202 This single parameter gives a remarkably good fit. Reprinted with permission from Ehm, C.; Vittoria, A.; Goryunov, G.P.; Kulyabin, P.S.; Budzelaar, P.H.M.; Voskoboynikov, A.Z.; Busico, V.; Uborsky, D.V.; Cipullo, R. Macromolecules 2018, 51, 8073–8083. Copyright 2018 American Chemical Society.

consumption (106 g gCr−1 h−1) and selectivity for 1-hexene, whereas the less active MeDuPhos catalyst was the most selective for 1-octene production.205 The authors remark that many other phospholane-based ligands are likely to be active for Cr-catalyzed selective ethylene oligomerization. While outside the scope of this review, HTE has also been employed in the study of heterogeneous Ziegler-Natta type polymerization using analogous experimental techniques.80,89,206,207

13.12.3.12

CdC bond formation: Other reactions

In addition to the specific categories covered in the preceding sections, there are several examples of less conventional CdC bond forming reactions studied by HTE methods. Schmink and Krska developed a Pd-catalyzed CdC bond-forming cross coupling reaction using acylsilanes and aryl halides as coupling partners. HTE identified phosphites, such as P(OEt)3, as successful ligands for the transformation, although further optimization found the Pd catalysts with the 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa6-phosphaadamantane ligand as more long-lived catalysts.208 Simmons and coworkers at Bristol-Myers Squibb developed an asymmetric conjugate addition reaction of cyclohexanone with isopropenylboronic acid derivates suitable for large-scale synthesis. HTE identified [Rh(COD)2]BF4 with (R)-DTBM-SEGPHOS to be the best catalyst (Eq. 17).209 Pericàs and coworkers used HTE to discover tandem Cu/photoredox catalysts for the decarboxylative hydroxylation of alkynes.210

ð17Þ

Source: Simmons, E.M.; Mudryk, B.; Lee, A.G.; Qiu, Y.; Razler, T.M.; Hsiao, Y. Org. Process Res. Dev. 2017, 21, 1659–1667.

13.12.3.13

CdN bond formation: Buchwald-Hartwig and Ullmann-Goldberg coupling

High throughput experimentation techniques have been widely used in the discovery of novel molecules for medicinal chemistry applications, where C–N coupling is often applied to generate diverse libraries of nitrogen-substituted compounds for biological study. The Buchwald-Hartwig reaction catalyzed by palladium is one of the most common methods of C–N coupling. Researchers at Merck used this as a prototype transformation to develop nanoscale HTE methods (described in Section 13.12.2.2) to meet the demands of medicinal chemistry efforts.14,75 Many aspects of catalytic C–N coupling reactions needed to be redesigned to enable this advance. For example, Buchwald-Hartwig reactions typically require the use of heterogeneous bases that are insoluble in most

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organic solvents. While heterogeneous reactions are easily performed on microscale in 1 mL vials assisted by tumble stirring, higher throughput experiments which employ 1536-well plates place additional demands. The small reaction volumes (10 mL) require non-volatile solvents (such as DMSO) that are compatible with the reaction plate material; furthermore, solution agitation by magnetic stirring is not possible, and heating the reaction mixtures is also not possible if using a plastic wellplate. Initial efforts to explore Buchwald-Hartwig reactions on nanoscale focused on identifying suitable soluble organic bases, as well as reactions that can operate at room temperature. The coupling of 3-bromopyridine with various nucleophiles was explored as a test reaction. The components explored include third-generation Buchwald precatalysts with eight different ligands, six different solvents, and four organic superbases (DBU, BTMG, MTBD, and the phosphazene P2Et).73 This multivariate experiment was run at room temperature using 10 mmol of the aryl halide with 5 mol% of the respective catalyst at 0.1 M concentration. In particular, couplings using the phosphazene base P2Et were broadly successful across the range of solvents when tBuBrettPhos and tBuXPhos precatalysts were used, with many substrates giving >90–100% conversion. The results were validated on larger scale; for example, the reaction of 3-bromopyridine (200 mmol) with a secondary amine (300 mmol) and P2Et (400 mmol) using 1 mol% tBuXPhos Pd G3 in DMSO (0.2 M) at room temperature provides the C–N coupling product in 99% solution yield. These unprecedented reaction conditions were applied to nanoscale screening chemistry in 1536-well plates to perform a broad parallel screen of densely functionalized coupling partners simultaneously using multivariate optimization and Design of Experiments to establish scale-up conditions.14 A thorough exploration of C–N coupling using Cu, Pd, Ir, and Ru catalysts also formed the basis of a follow-up study on expanding the scope of nanomole-scale screening previously discussed in Sections 13.12.2.2 and 13.12.2.4.75 Newman and coworkers used HTE to develop conditions for Pd-catalyzed C–N coupling reactions that could be performed in continuous flow reactors. Similar to the aforementioned nanoscale chemistry, continuous flow chemistry is also enabled by homogeneous reaction conditions. By evaluating and optimizing a number of reaction variables, these researchers enabled the use of DBU as a soluble base (and ionic liquid DBU ∙ HX byproduct) in combination with simple phosphine ligands for CdN coupling reactions.71 Recently, Cernak and Buchwald reported that oxidative addition complexes (OAC) of tBuXPhosPd, derived from [tBuXPhosPd]2(COD) and structurally complex aryl halides, are generally stable and isolable. Nanoscale reaction screening using HTE methods demonstrated that the N-arylation of certain complex, medicinally-relevant aryl halides was more successful using stoichiometric OACs as reagents, rather than catalytic conditions. This concept was also amenable to other Pd-mediated reaction classes, as it was demonstrated that stoichiometric OAC-mediated Negishi, Suzuki-Miyaura, Sonogashira reactions, among others, were more successful in the screening context than when catalytic Pd conditions were used.211 Despite significant effort over the past 20 years, methodology gaps remain in Buchwald-Hartwig reactions. Certain classes of nitrogen nucleophiles and heterocyclic aryl halides perform poorly using canonical catalysts for C–N coupling. In addition, sterically hindered coupling partners can also be challenging to combine.212 Dobereiner, Leitch, and coworkers reported Pd catalysts able to perform the N-arylation of secondary sulfonamides with (hetero)aryl halides, both of which are particularly challenging substrates for C–N coupling.213 HTE was used to perform a broad screen of C–N couplings using weakly nucleophilic amide-type substrates and Pd catalysts. From these preliminary screens, JackiePhos214 and tBuBippyPhos215 were found to provide moderate yields for select substrate combinations. Following up on these results, commercially available variants of these ligands were evaluated in a 96-well plate screen in which two aryl halides were reacted with the simple secondary sulfonamides. Various Pd precursors, solvents, and bases were selected, with [Pd(crotyl)Cl]2, K2CO3, and CPME identified as the best combination of reagents. Select results from the screen show that all the ligands, when high catalyst loadings were applied (10 mol% Pd, 10 mol % L) were able to promote the coupling of N-phenylsulfonamide with 4-methyl bromobenzoate under these conditions in high assay yield; however, an analogous heteroaromatic product could only be prepared in reasonable yields using BippyPhos-type ligands. Upon further optimization of the catalytic reaction, which focused on reducing the catalyst loading practical levels (0.5–2 mol% Pd), only AdBippyPhos216 as the ligand enabled high yields. A subsequent study explored the substrate scope of the catalyst in a high-throughput fashion by performing a parallel screen of 24 heteroaryl halides and 12 sulfonamides. Out of these substrate combinations, >70 novel tertiary sulfonamides were identified by LCMS in reasonable solution yield, and selected examples were isolated on 0.2 mmol scale (Fig. 36). Another example of sulfonamide N-arylation includes work from AbbVie, where a new, modular family of ligands based on the phosphorinane structure was found to be successful for C–N couplings with sulfonamides. HTE was used to optimize catalyst conditions and explore reaction scope.217 The incorporation of heteroaromatic groups by Buchwald-Hartwig couplings remains challenging. To support a lead optimization program, scientists at Merck opted to explore the coupling of five-membered heteroaromatic electrophiles with piperidines, a substrate combination which has been identified as particularly challenging.218 HTE was employed to perform a broad screen of precatalysts in an effort to develop this coupling. The reaction of a representative piperidine and bromopyrazole was performed with 39 Pd catalysts using NaOtBu and THF at 50  C. Notably, only the precatalyst Pd-PEPPSI-IPent219 was able to promote the coupling in reasonable assay yield. Subsequent optimization found that NaOtBu/THF was a preferred solvent/base combination versus others screened, but also that Pd-PEPPSI-IPentCl performs the coupling significantly faster.220 Parallel screens using the optimized conditions of 4 mol% Pd-PEPPSI IPentCl, NaOtBu and THF at 40  C were conducted to explore the substrate scope with respect to both nucleophile and heteroaryl halide, with numerous complex compounds identified on microscale. Using this catalyst, 21 complex heteroarylpiperidines were then prepared on 1 mmol scale in isolated yields 31–97%. Elbasvir is an inhibitor of the HS5A protein developed my Merck as a potential treatment for the hepatitis C virus, and contains a complex heterocycle core composed of a benzoxazino-indole featuring a chiral hemiaminal. Chiral hemiaminals have been prepared in the literature by asymmetric addition to imines; however, this reaction has limited generally, leading scientists at

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Fig. 36 Reaction scope exploration via HTE for C–N coupling with sulfonamides. Values in table are approximate yields based on relative HPLC peak areas. Reprinted with permission from Becica, J.; Hruszkewycz, D.P.; Steves, J.E.; Elward, J.M.; Leitch, D.C.; Dobereiner, G.E. Org. Lett. 2019, 21, 8981–8986. Copyright 2019 American Chemical Society.

Merck to develop a novel approach to the chiral heterocyclic core by an asymmetric Pd-catalyzed intramolecular C–N coupling.221 High-throughput experimentation was employed to find suitable catalytic conditions and a chiral ligand to support the coupling reaction: Pd(OAc)2 or Pd2(dba)3 (10 mol%) were screened with a library of chiral phosphines (11 mol%) using a K3PO4 (7.5 equiv.) in toluene (0.03 M) in 55  C (18 h). A variety of conditions were found to promote the cross-coupling reaction in good yields and enantioselectivities; however, a striking observation was made with respect to the success of the Pd precatalyst. Catalysts formed from Pd2(dba)3 are significantly less effective than the analogous catalysts derived from Pd(OAc)2. The results are depicted in Fig. 37, where enantiomeric excess is plotted against conversion for a variety of Pd catalysts. It was postulated that in situ phosphine monoxidation could be responsible for these observations, where the bisphosphine mono-oxide is the actual ligand for the active catalyst. Reduction of Pd(OAc)2 in the presence of phosphines, bases, and water is known to proceed with concomitant phosphine oxidation in some cases.222–225 This hypothesis was confirmed by using isolated phosphine mono-oxides in combination with Pd2(dba)3 or Pd(OAc)2 as the precatalyst. Good yields and enantioselectivities were observed using either Pd source, with the best ligand being (R,R)-QuinoxP mono-oxide. Further experimentation demonstrated that the desired Pd/L species forms reproducibly when in situ catalyst formation is conducted between Pd(OAc)2 and (R,R)-QuinoxP. Spectroscopic experiments indicate rapid formation of the (R,R)-QuinoxP mono-oxide under catalytically relevant conditions, obviating the need to isolate the bisphosphine mono-oxide.226 As an alternative to Pd-catalyzed C–N coupling, Cu-mediated methods, sometimes referred to as the Ullmann-Goldberg reaction, are often used for aryl iodide or bromide substrates. One example of a pharmaceutical application of an Ullmann-Goldberg is in the synthesis of niraparib, a poly(ADP-ribose)polymerase inhibitor developed by Merck. Cu catalysts were explored by HTE to determine the feasibility of regioselective N-arylation of an indazole en route to niraparib. Good regioselectivity was observed with a model indazole containing a tert-butylamide substituent as a blocking group. Screening identified CuBr2 and DMCyDA (N,N0 -dimethylcyclohexyl-1,2-diamine) as a suitable regioselective catalyst, using polar solvents such as DMAc or DMSO.227 A study from Cook and Shekhar employed HTE to find Cu catalysts amenable to sterically hindered substrates, such as a-branched amines, in Ullmann-Goldberg type reactions. A broad ligand screen was performed using potential N and O-ligands sourced from AbbVie’s compound library, which uncovered a substituted pyrrole that promoted the reaction of ortho-substituted aryl iodides with bulky amines.228

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Fig. 37 High-throughput screening data for enantioselective Pd-catalyzed imine arylation revealing the activity and selectivity of phosphine oxide ligands. Reprinted with permission from Li, H.; Belyk, K.M.; Yin, J.; Chen, Q.; Hyde, A.; Ji, Y.; Oliver, S.; Tudge, M.T.; Campeau, L.-C.; Campos, K.R. J. Am. Chem. Soc. 2015, 137, 13728–13731. Copyright 2015 American Chemical Society.

13.12.3.14

CdN bond formation: Chan-Lam and other oxidative couplings

As an alternative to redox-neutral C–N couplings, which typically require high temperature and/or expensive Pd/ligand combinations, oxidative C–N coupling can often be achieved under mild conditions with simple Cu-based catalysts. One powerful iteration of this approach is the Chan-Lam reaction (or Chan-Evans-Lam reaction, when including both C–N and C–O coupling variants).229–231 In 2018, scientists at GSK and the University of Strathclyde reported a general method for the arylation of weakly nucleophilic sulfonamides,232 which are discussed in Section 13.12.3.13 as challenging substrates in Pd-catalyzed C–N coupling.213 HTE was integral to the identification of conditions that enabled use of both arylboronic acids and the corresponding pinacol esters (Fig. 38). While the former were found to work under several sets of conditions, the latter required a very specific combination of the cationic Cu(I) source [Cu(MeCN)4]PF6 and K3PO4 as the base. A team at GSK led by Leitch and Kowalski exploited this manner of Chan-Lam arylation in the synthesis of GSK8175, a clinical candidate NS5B inhibitor.233 A key step in the synthesis is formation of an N,N-diarylsulfonamide with multiple points of halogenation; thus, the synthesis required an orthogonal C–N coupling method to typical Pd or Cu catalyzed arylation. Preliminary high-throughput screening identified similar conditions to those from Fig. 38: cationic Cu sources Cu(CH3CN)4X (X ¼ OTf or PF6) and amine bases were the best performing, giving as high as 60% conversion on this scale. Upon further optimization, a catalyst mixture of CuCl, CuCl2, and KPF6 as a halide abstractor was chosen based on the high cost and poor availability of Cu(CH3CN)4PF6 on large scale. Ultimately, this oxidative C–N coupling provided the desired product in 62% isolated yield on a 35 g scale (Eq. 18).

ð18Þ

Source: Arrington, K.; Barcan, G.A.; Calandra, N.A.; Erickson, G.A.; Li, L.; Liu, L.; Nilson, M.G.; Strambeanu, I.I.; VanGelder, K.F.; Woodard, J.L.; Xie, S.; Allen, C.L.; Kowalski, J.A.; Leitch, D.C. Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis. J. Org. Chem. 2019, 84(8), 4680–4694.

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Fig. 38 Plate heatmap for the Chan-Lam coupling between N-phenylmethanesulfonamide and either phenylboronic acid or the corresponding pinacol ester. Color is proportional to solution yield obtained by HPLC analysis using a product standard; red ¼ 0%, yellow ¼ 50%, green ¼ 100%. Reprinted with permission from Vantourout, J.C.; Li, L.; Bendito-Moll, E.; Chabbra, S.; Arrington, K.; Bode, B.E.; Isidro-Llobet, A.; Kowalski, J.A.; Nilson, M.G.; Wheelhouse, K.M.P.; Woodard, J.L.; Xie, S.; Leitch, D.C.; Watson, A.J.B. ACS Catal. 2018, 8, 9560–9566. Copyright 2015 American Chemical Society.

Chan-Lam coupling has also been explored for pharmaceutical library synthesis as a late-stage modification method.234 Researchers at GSK and the University of Nottingham used conditions previously developed by Watson and coworkers235 to elaborate a scaffold relevant to aVb6 integrin inhibitors. As part of their report, the authors provide a qualitative map of successful and unsuccessful coupling partners. Finally, another academic/industrial collaboration involving GSK and the University of Strathclyde utilized HTE to develop a Cu-catalyzed intramolecular oxidative C–H amination for the synthesis of 2-aminobenzimidazoles from N-arylguanidines.236 Simultaneous interrogation of Cu source, solvent, and acid or base additives revealed that the enolate derived from ethyl acetoacetate is an effective ligand. The optimized conditions were used in the key step to prepare emedastine, a marketed antihistamine.

13.12.3.15

CdN bond formation: Hydroamination

Hydroamination is an atom-efficient method for forming CdN bonds from amines and CdC unsaturations. Key applications of hydroamination include the generation chiral amines by asymmetric variants, and the synthesis of N-heterocycles. HTE has been used to identify Rh and Ir catalysts based on diazabutadiene ligands for high yielding intramolecular hydroamination of acetylenes to indoles.237,238 Robbins and Hartwig’s multidimensional, HTE reaction discovery approach (previously discussed in Section 13.12.2.1) identified new hydroamination conditions for the reaction of anilines and alkynes using CuCl (25 mol%) in THF at 100  C.9 More recently, a collaboration between the Hull group and Merck utilized HTE to develop catalysts for the asymmetric hydroamination of allylamines using Rh catalysts.239 A representative allylamine and morpholine (1.2 equiv.) were screened for hydroamination reactivity using 10 mol% [Rh(nbd)2]BF4 (nbd ¼ norbornadiene) and 10 mol% chiral ligand in dioxane (0.1 M) at 60  C. 288 chiral bidentate ligands were evaluated, with only nine providing any observable product. The best results were obtained using the biphenyl-based bis[(difuryl)phosphine], where the hydroamination product was produced in 63% solution yield and 99:1 er. Using this discovered catalyst, 26 chiral diamines are synthesized on larger scale (0.2 mmol) in good yields (41%–91%) and high enantioselectivity or diastereoselectivity.

ð19Þ

Source: Vanable, E.P.; Kennemur, J.L.; Joyce, L.A.; Ruck, R.T.; Schultz, D.M.; Hull, K.L. Rhodium-Catalyzed Asymmetric Hydroamination of Allyl Amines. J. Am. Chem. Soc. 2019, 141(2), 739–742.

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CdN bond formation: Other reactions

The synthesis of N-heterocycles has also employed transition-metal catalysts for C–N coupling. One such example, from Merck, demonstrates the utility of HTE in the synthesis of the pyrimidinone fragment of an HIV integrase inhibitor. The intramolecular Michael addition of an N-hydroxyamidine was surveyed using a broad screen of 475 reaction conditions using transition metal salts, or other additives such as phosphines or amines. From this screen, it was found that a number of catalysts can mediate the transformation, with CuBr2 or CuCl2 in combination with phenanthroline as optimal.240 A related example of HTE-assisted discoveries in this area is the Ni(COD)2/XantPhos-catalyzed synthesis of quinazolinediones from isatoic anhydrides and isocyanates from scientists at BMS.241 As many of the resulting products are chiral (due to atropisomerism), the authors also explored the use of chiral ligands, achieving up to 65% ee with the SIPHOX chelating phosphine oxazoline.

13.12.3.17

CdO bond formation: Hydroxylation/etherification

CdO bond formation is typically achieved with nucleophilic substitution, including classic reactions such as the Williamson ether synthesis, nucleophilic aromatic substitution, the Mitsunobu reaction, and others. Transition metal catalyzed alternatives for C–O coupling are sometimes advantageous, despite the increased difficulty of this transformation relative to a corresponding C–N coupling. In one example, a potential drug candidate developed by BMS required process improvements to enable scale-up for a toxicology study.242 The original discovery route to the compound used a Mitsunobu reaction to forge a key ether linkage; however, this reaction suffered from practical drawbacks. In particular, chromatography was required to remove byproducts, including the alkene from elimination of the secondary alcohol and triphenylphosphine oxide. To circumvent these issues, a Pd-catalyzed C–O coupling was considered as a substitute. Initial experiments revealed a number of side reactions prevalent under Pd-catalysis: dechlorination of the pyridine ring, epimerization or oxidation of the alcohol, debromination and hydroxylation of the Ar–Br, and coupling between the Ar–OH byproduct and the Ar–Br substrate to generate a diaryl ether. A ligand screen was performed using HTE to identify a system for selective C–O coupling. AdBippyPhos, RockPhos, and tBuBrettPhos, were identified, with AdBippyphos giving the best results. In addition, HTE optimization revealed that K3PO4 is optimal as the base, and that the particle size of the base is important for reactivity; jet-milled K3PO4 provides the best results. Further optimization provided a process to isolate the desired product in 35% yield with exceptional purity (Eq. 20).

ð20Þ

Source: Young, I.S.; Simmons, E.M.; Fenster, M.D.B.; Zhu, J.J.; Katipally, K.R. Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step. Org. Process Res. Dev. 2018, 22(5), 585–594. While select Pd catalysts have been employed in the hydroxylation of aryl halides using hydroxide as the nucleophile, a significant challenge of this reaction arises when using substrates which contain base-sensitive functionality. To this end, scientists at Merck evaluated novel catalysts for hydroxylation using hydroxide surrogates; in particular, benzaldehyde oxime.243 This nucleophile undergoes C–O coupling with aryl halides via Pd catalysis, and subsequent hydrolysis of the functionalized oxime liberates the desired phenol; however, the high cost of the associated catalyst components for this reaction prompted researchers to find alternative methods to complement the Pd-catalyzed method. Turning to Cu catalysts, an aryl halide containing a base-sensitive ester and an epimerizable stereocenter was evaluated via HTE in combination with benzaldehyde oxime using CuI (5 mol%), a variety of ligands, and Cs2CO3 in DMSO at 80  C. Given limited precedent for the transformation, a library of nitrogen-containing compounds from the Merck compound library were screened as potential ligands for the coupling reaction. This initial screen identified oxamides as an active ligand class. Following up on this observation, these researchers prepared a library of oxamides in a modular fashion from oxalyl chloride or methyl oxalylacetate and corresponding amines. Parallel synthesis methods were used to generate 96 novel oxamide ligands, purified by mass-directed HPLC, which were then evaluated for the CuI-catalyzed hydroxylation reaction. The oxazoline-containing ligand L1 provides 61% yield with 11% diarylether formation (Fig. 39). Modifications to the ligand structure focused on increasing stability of the oxamide during the catalytic reaction conditions, and identifying structural features that lead to a more active and selective catalyst. Iterative structural optimization led to oxamide L4, which provides 94% yield of the desired product with minimal (76  C), 1,3-propanediol was added to generate the bis(propanediol)boronic acid, which is less susceptible to decomposition. Presumably, the mass balance of the overall borylation can be improved by reducing the degree of decomposition of B2(OH)4. Fifteen aryl halides of varying properties (electron rich, electron poor, sterically hindered, heterocyclic, different leaving groups) were subject to this standard 24-well plate to indicate a range of activities for different catalyst components (Fig. 40). To demonstrate the utility of the developed reaction conditions, a large scale (10 g) coupling of 3-bromo-2-methylaniline with B2(OH)4 (1.2 equiv.) is performed using Ni(NO3)2 ∙6H2O (0.1 mol%), CyJohnPhos (0.55 mol %), DIPEA (2.0 equiv.), MeOH (20 vol) to obtain 80% yield of the desired boronic acid product after 16 h of reaction at 20  C. The BMS team subsequently reported on general Pd- and Ni-based systems for borylation involving B2(OH)4.252 Among the myriad studies conducted is a robustness screen conducted using HTE, revealing that the (AmPhos)2PdCl2 catalyst exhibits the greatest additive tolerance of the three systems under investigation. The NS5B inhibitor GSK8175 (also discussed in Section 13.12.3.14) developed by GlaxoSmithKline contains a boronic acid moiety in the final product, which is introduced by a late stage Miyaura borylation.233 The reaction required selective borylation of a sterically hindered aryl bromide over the less sterically hindered aryl chloride. The presence of a methoxymethyl (MOM) protecting group proximal to the aryl bromide precursor was deemed necessary in the medicinal chemistry route to GSK8175, though use of MOMCl was not feasible upon scale-up due to toxicity concerns. A broad ligand screen enabled by HTE was conducted with 48 ligands and four alternative protecting groups: Ac, Piv, TBS, tetrahydropyran (THP), using KOAc and toluene as a single solvent/ base combination. Fortunately, the best results are observed with THP, an easily introduced and removed protecting group (Fig. 41). In most reactions, debromination of the aryl halide is a major byproduct, although dechlorination was not observed. A follow-up

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Fig. 41 Parallel-in-parallel screening to identify an appropriate catalyst/substrate combination for Miyaura borylation en route to GSK8175. Size of the circles corresponds to % product; color corresponds to % debromination (red, 100% debromo; yellow, 25% debromo; green, 0% debromo). Reprinted with permission from Arrington, K.; Barcan, G.A.; Calandra, N.A.; Erickson, G.A.; Li, L.; Liu, L.; Nilson, M.G.; Strambeanu, I.I.; VanGelder, K.F.; Woodard, J.L.; Xie, S.; Allen, C.L.; Kowalski, J.A.; Leitch, D.C. J. Org. Chem. 2019, 84, 4680–4694. Copyright 2019 American Chemical Society.

screen evaluated 33 monodentate phosphines with different solvent/base combinations using the THP protected substrate. Moderately hindered alkyldiphenylphosphines were determined to be the best ligand class, which simultaneously maximized product yield and minimized hydrodehalogenation of the parent aryl bromide. Upon scale-up, the reaction with KOAc/toluene suffered from a variable reaction rate, which was traced to the particle size of the KOAc base. Milling KOAc on large scale was impractical due to its hygroscopicity; therefore, a mixture of K2CO3 (325 mesh) and pivalic acid was used to generate KOPiv in situ as a more soluble base, leading to a >10-fold rate increase. Subsequently, scientists at AstraZeneca used HTE to independently discover the benefits of pivalate bases in the Miyaura borylation, and applied these conditions to the preparation of verinurad.253

13.12.3.20

CdB bond formation: C–H borylation

Ir-catalyzed C–H borylation, largely developed by the groups of Smith254 and Hartwig,255 is an atom-economical alternative to prepare functionalized aryl boronate esters. The success of this C–H functionalization methodology is in part to due to predictable selectivity of arene C–H activation, which is largely governed by steric factors, providing complementary arene substitution patterns to that of electrophilic aromatic substitution. Indeed, Ir-catalyzed C–H borylation is amenable to in late-stage functionalization efforts application to drug discovery.256 Despite the broad applicability of C–H borylation, there appears to be little flexibility with respect to the nature of the catalyst and reaction conditions, which can be problematic as it remains unintuitive how to troubleshoot catalyst design challenges for difficult substrates. The Smith group, in collaboration with Merck, therefore embarked on a systematic mechanistic study enabled by HTE to evaluate the role of synergistic substrate-dependent variables which influence C–H borylation performance.257 Factors studied include order of reagent addition, catalyst derivation method, solvent, temperature, and whether the reaction is performed in an open or closed system, among others (Fig. 42). For example, for room temperature borylations the order of addition is critical for reaction success: borylations using [Ir(COD)Cl]2 and HBpin require that the borane be added to the reaction mixture before the dipyridyl ligand. Additionally, HTE revealed that a broad range of solvents, including polar solvents, are compatible with C–H borylation, and that low catalyst loadings can be achieved for in situ catalyst generation by increasing the ligand-to-metal ratio. The groups of Smith and Mindiola discovered an Ir catalyst for the C–H borylation of methane, enabled by a high-pressure, high-throughput reactor for screening. Systematic evaluation of Ir precursor and catalyst loading, polypyridine ligands, and solvents was performed.258 Borylation activity was observed, albeit in low yield, using B2pin2 as the borylation reagent, various

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Fig. 42 Effect of order of reagent addition as a function of catalyst and borylating reagent on Ir-catalyzed C–H borylation of arenes. Values/circle sizes represent yields determined by HPLC analysis using product standard. Reprinted with permission from Preshlock, S.M.; Ghaffari, B.; Maligres, P.E.; Krska, S.W.; Maleczka, R.E.; Smith, M.R. J. Am. Chem. Soc. 2013, 135, 7572–7582. Copyright 2013 American Chemical Society.

phenanthroline ligands, and either [Ir(COD)(OMe)]2 or (MesH)Ir(Bpin)3 at 120  C and 2068 kPa CH4. Based on a DFT study of the potential energy surface for the proposed mechanism, it was postulated that a more polarizable ligand would help promote the presumed turnover-limiting step, the oxidative addition of CH4 to Ir(III). Therefore, a second screen of reaction conditions was performed using phosphorus ligands, of which dmpe (1,2-bis(dimethylphosphino)ethane) provided the best results, with as high as 52% yield of CH3Bpin observed with a 3.1:1 ratio of CH3Bpin:H2C(Bpin)2 (0.5 mol% [Ir(COD)Cl2], 1 mol% dmpe, cyclohexane, 150  C, 3447 kPa CH4). A subsequent study focused on evaluating continuous variables (concentration of catalyst and B2pin2) using the dmpe-based catalyst in two solvents (cyclooctane and decalin).259 Additionally, the well-defined precatalyst (dmpe)Ir (COD)Cl was used. Here, it was found that catalysts with TON as high as 170 could be obtained, with relatively high conversion and selectivity for the monoborylated product (Fig. 43).

Fig. 43 Ir-catalyzed C–H borylation of methane.258 From Ahn, S.; Sorsche, D.; Berritt, S.; Gau, M.R.; Mindiola, D.J.; Baik, M.-H. ACS Catal. 2018, 8, 10021–10031.

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13.12.3.21

Other reactions

Coates, Cramer, Tolman, and coworkers employed HTE using a broad screen of transition metal catalysts and ligands for the decarboxylation of carboxylic acids to alkenes, finding Ni catalysts with simple phosphines to be successful.48 Hall and coworkers developed a Cu-catalyzed conjugate borylation of substituted cyclobutenones to prepare enantiomeric cyclobutanes. HTE focused on screening a broad library of chiral ligands with Cu precursors, finding only a few successful catalyst combinations. In particular, the highest enantioselectivity was found using (2S,4S)-2,4-bis(diphenylphosphino)pentane as ligand.260 Finally, Molander and coworkers used HTE to develop a tandem Ni/photoredox catalyzed CdS bond formation reaction of aryl halides with sulfonate salts.261

13.12.4 Conclusions and future trends High-throughput experimentation is a mindset more than a collection of tools or techniques. Continuing a trend notes in the prior version of this Chapter in COMC-III,16 HTE is clearly moving beyond simply “fishing” for hits in a sea of chemical reaction space. Significant strides have been made in all areas of the high-throughput workflow, as noted in Section 13.12.2. Advances in equipment, including automated material handling, reactor design, and high-throughput analytics, go hand-in-hand with advances in experimental design and data interrogation. Experimental designs focused on understanding reactivity in a quantitative way, as well as innovative approaches to new reaction discovery, are making HTE an indispensable technique for advancing our knowledge of organometallic chemistry and catalysis. And further decreases to feasible reaction volumes and corresponding increases in array density and analytical throughput will open new windows into chemical reactivity on a much grander scale, enabling a holistic view of aspects like reaction mechanisms and structure-reactivity relationships. In the past 15 years, it is clear that HTE uptake has exploded in organic synthesis, especially as applied to pharmaceutical discovery and development chemistry. In Fig. 44, we compare the number of reviewed HTE examples in COMC-III (50 in 10 years) versus the present review in COMC-IV (150 in 15 years). Collectively, cross-coupling (C–C, C–N, C–O, and C–B) has overtaken alkene polymerization and asymmetric hydrogenation as the major application (at least in the published literature). The breadth of transformations under study has also increased substantially, with many important transformations including cross-electrophile coupling, carbonylative coupling, and catalytic borylation absent from the examples in COMC-III, but comprising a sizable number of examples herein. We can forecast several trends with respect to the organometallic and catalytic chemistry that will be investigated by HTE in the coming years. There is likely to be a reduced emphasis on asymmetric hydrogenation, despite its current status as the most commonly pursued application of HTE. This will be due to continuing moves toward enzymatic catalysis for many of the

Fig. 44 Breakdown of HTE examples in COMC-III (1995–2005)16 and COMC-IV (2006–2020) by selected reaction classes.

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enantioselective reductions currently achieved through organometallic catalysis. This is not at all to suggest asymmetric hydrogenation with transition metal catalysts will disappear! Simply that it will continue to be used strategically as a complementary approach to other methods of setting absolute stereochemistry. Cross-coupling catalysis will continue to be a major application, with greater emphasis placed on non-precious metals. In addition, parallel-in-parallel screening approaches will push the boundaries of molecular complexity achieved through cross-coupling, and enable discovery of new reactivity toward more sustainable building blocks (e.g., biomass derived oxygenates as electrophiles) and more complex three-dimensional molecular architectures. The ability to collect far more data than ever before coupled with increasingly powerful approaches in predictive analytics will also enable comprehensive and holistic quantitative maps of chemical reactivity to be generated. These will power the next generation of AI-enabled synthesis, giving robots the opportunity to (indirectly) learn physical organic and organometallic principles. As we go forward, our job is clear: to build and maintain these robots. Humor aside, the ability to draw multivariate correlations between molecular structure and reactivity across a wide swath of chemical space will greatly expand our knowledge base in organometallic chemistry and catalysis, leading to more impactful discoveries and uncovering previously hidden phenomenon. Finally, a trend that is already in motion is to bring HTE principles into the teaching laboratory.47,262 Training the next generation of scientists to be mentally and technically prepared to tackle multivariate problems using HTE will ensure this important approach to experimentation continues to result in greater innovation and understanding.

Acknowledgment We acknowledge with respect the Lekwungen peoples on whose traditional territory the University stands and the Songhees, Esquimalt and WSÁNEĆ peoples whose historical relationships with the land continue to this day. We also gratefully acknowledge research support from the University of Victoria, the Natural Sciences and Engineering Research Council of Canada, and the New Frontiers in Research Fund.

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