Comprehensive Organometallic Chemistry IV. Volume 11: Applications I. Main Group Complexes in Organic Synthesis [11] 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 11

APPLICATIONS I. MAIN GROUP COMPLEXES IN ORGANIC SYNTHESIS VOLUME EDITOR

DAVID J. LIPTROT University of Bath, Bath, United Kingdom

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 11 Editor Biographies

vii

Contributors to Volume 11

xiii

Preface 11.01

xv

Overview and Introduction

1

David J Liptrot

11.02

Lithium Complexes in Organic Synthesis

2

R Luisi, L Degennaro, and M Colella

11.03

Sodium and Potassium Complexes in Organic Synthesis

57

Derek Yiren Ong, Jia Hao Pang, and Shunsuke Chiba

11.04

Magnesium Complexes in Organic Synthesis

78

Ankur, Suban Kundu, Sumanta Banerjee, and Ajay Venugopal

11.05

Calcium, Strontium and Barium Complexes in Organic Synthesis

104

Yann Sarazin and Peter M Chapple

11.06

Zinc Reagents in Organic Synthesis

193

Eszter Fazekas, Phoebe A Lowy, Maisarah Abdul Rahman, and Jennifer A Garden

11.07

Boron Complexes in Organic Synthesis

305

Eva M Israel, James WB Fyfe, and Allan JB Watson

11.08

Aluminum Complexes in Organic Synthesis

335

Dragoslav Vidovic

11.09

Gallium and Indium Complexes in Organic Synthesis

382

Manoj K Gupta, Monika, and Sharol Sebastian

11.10

Silicon and Germanium Complexes in Organic Synthesis

469

David J Liptrot

11.11

Tin and Lead in Organic Synthesis

470

Terrance J Hadlington

11.12

Antimony and Bismuth Complexes in Organic Synthesis

503

Saurabh S Chitnis and Toren Hynes

11.13

Selenium and Tellurium Complexes in Organic Synthesis

536

Claudio Santi and Cecilia Scimmi

11.14

Frustrated Lewis Pairs in Organic Synthesis

563

Matthew J Heard, Katarina Stefkova, Yara van Ingen, and Rebecca L Melen

11.15

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

606

Xiang-Yu Zhang and Bing-Tao Guan

11.16

Main Group Complexes in Polymer Synthesis

626

David J Liptrot and Laura E English

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.

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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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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 11 Ankur School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, ThiruvananthapuraÅm, India Sumanta Banerjee School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, ThiruvananthapuraÅm, India Peter M Chapple Institut des Sciences Chimiques de Rennes—UMR 6226 CNRS—Université de Rennes 1, Rennes Cedex, France Shunsuke Chiba Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore Saurabh S Chitnis Chemistry Department, Dalhousie University, Halifax, NS, Canada M Colella Department of Pharmacy—Drug Sciences, University of Bari “A. Moro”, Italy L Degennaro Department of Pharmacy—Drug Sciences, University of Bari “A. Moro”, Italy Laura E English Department of Chemistry, University of Bath, Bath, United Kingdom; Centre for Sustainable and Circular Technologies, University of Bath, Bath, United Kingdom Eszter Fazekas EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom James WB Fyfe EaStCHEM, University of St Andrews, North Haugh, St Andrews, United Kingdom

Jennifer A Garden EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom Bing-Tao Guan Department of Chemistry, Fudan University, Shanghai, China Manoj K Gupta Department of Chemistry, School of Basic Sciences, Central University of Haryana, Mahendegarh, Haryana, India Terrance J Hadlington Department of Chemistry, Technical University Munich, Munich, Germany Matthew J Heard Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Cardiff, United Kingdom Toren Hynes Chemistry Department, Dalhousie University, Halifax, NS, Canada Yara van Ingen Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Cardiff, United Kingdom Eva M Israel EaStCHEM, University of St Andrews, North Haugh, St Andrews, United Kingdom Suban Kundu School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, ThiruvananthapuraÅm, India David J Liptrot Department of Chemistry, University of Bath, Bath, United Kingdom; Centre for Sustainable and Circular Technologies, University of Bath, Bath, United Kingdom Phoebe A Lowy EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom

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Contributors to Volume 11

R Luisi Department of Pharmacy—Drug Sciences, University of Bari “A. Moro”, Italy Rebecca L Melen Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Cardiff, United Kingdom Monika Department of Chemistry, School of Basic Sciences, Central University of Haryana, Mahendegarh, Haryana, India Derek Yiren Ong Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore Jia Hao Pang Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore Maisarah Abdul Rahman EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom Claudio Santi Group of Catalysis Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy Yann Sarazin Institut des Sciences Chimiques de Rennes—UMR 6226 CNRS—Université de Rennes 1, Rennes Cedex, France

Cecilia Scimmi Group of Catalysis Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy Sharol Sebastian Department of Chemistry, School of Basic Sciences, Central University of Haryana, Mahendegarh, Haryana, India Katarina Stefkova Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Cardiff, United Kingdom Ajay Venugopal School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, ThiruvananthapuraÅm, India Dragoslav Vidovic School of Chemistry, Monash University, Clayton, VIC, Australia Allan JB Watson EaStCHEM, University of St Andrews, North Haugh, St Andrews, United Kingdom Xiang-Yu Zhang College of Chemistry and Chemical Engineering, China West Normal University, Nanchong, 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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11.01

Overview and Introduction

David J Liptrot, Department of Chemistry, University of Bath, Bath, United Kingdom © 2022 Elsevier Ltd. All rights reserved.

Main group chemistry continues to grow in prominence and is ever a source of interesting and exciting new reactivity, with profound implications for organic chemistry. Main group organometallic complexes have held an enduring popularity in stoichiometric organic transformations, and still lie at the heart of many C–C bond forming and functional group transforming steps. This reactivity has achieved a level of maturity and the metals of the s- and p-blocks feature in almost every organic synthetic route, as they did when this volume was last issued. Since then, however, main group organometallic chemistry has undergone two quiet revolutions; the explosion of main group catalysis, and the accessibility of main group compounds with variable oxidation states. The former has been driven by the growing recognition that Earth-abundant elements have much to offer the field of organic transformations as catalytic reagents in their own right. The latter reflects the increasingly complex range of main group systems that are now available as a result of fundamental explorations of main group reactivity since the mid-20th century. These two exciting concepts are, unsurprisingly, a significant focus of work in this section. The volume comprises 15 chapters each focused on a single, or small group of elements followed by three concept chapters. Chapters 11.02 and 11.03 open the discussion focused on the s-block and concern the alkali metals. In Chapter 11.02, Luisi, Degennaro and Colella provide an excellent overview of the ever-important role of lithium organometallics in organic transformation, opening with a comprehensive summary of the synthesis of a range of organolithium reagents, with a particular focus on those bearing heteroatoms that predispose them to useful reactivity. They then provide a summary of reactivity that these reagents allow access to in organic synthesis. Final, practical methodologies such as use of lithium reagents in the flow are overviewed. Chapter 11.03 concerns the heavier congeners of the alkali metals, and in this work Ong, Pang and Chiba introduce another important advance in main group chemistry, synergistic systems from mixed metals. They thus discuss the growing importance of mixed and monometallic sodium and potassium reagents, particularly in their most widespread use; metalation of high pKa reagents. They also briefly touch on the utility of such compounds in catalytic hydroamination. Chapters 11.04 and 11.05 complete this s-block focus by discussing the alkaline earths, and Chapter 11.06 continues the theme of divalent metals, considering the chemistry of zinc. In Chapter 11.04, Ankur, Kundu, Banerjee and Venugopal give a contemporary account of magnesium, with special focus on its applications in catalytic transformations. This theme of catalysis is then elucidated by Chapple and Sarazin whose provision of a thorough consideration of the huge advances in heavier alkaline earth chemistry in organic transformations constitutes Chapter 11.05. Chapter 11.06, from Fazekas, Lowy, Abdul Rahman and Garden, gives a wide-ranging account of the uses of zinc ranging from stoichiometric exploitation of its organometallics in a range of productive C–C coupling steps; to the reducing ability of zinc hydrides; to examples of transformations centered on zinc catalysis. The authors also expand the theme of bimetallic systems, where zinc continues to show its quality. Chapters 11.07–11.09 bring us to the p-block and concern the chemistry of group 13. In Chapter 11.07, Watson, Israel and Fyfe discuss boron complexes. Once again, catalysis is a theme and the utility of boron as a stoichiometric reagent in cross coupling, as well as in boronic acid catalysis is considered. Beyond this, exciting progress in metal-free boron centered reactivity are considered and finally the burgeoning field of boryl anions is assessed. Vidovic follows, in Chapter 11.08, with an extensive work on aluminum complexes. An enormous range of transformations, relying on catalytic aluminum species, are considered and the chapter ends with a provocative summary of the importance of intricate mechanistic understanding on aluminum chemistry. The chemistry of the triels is closed out by Gupta, Monika and Sebastian in Chapter 11.09 which concerns gallium and indium. These utility reagents for organic transformations are assessed in a comprehensive fashion with discussion of both their application as stoichiometric metal reagents, and their uses in a number of redox active processes proves a very appropriate introduction to the chemistry of the heaver p-block where variable oxidation states become a trend. In Chapter 11.11, Hadlington provides an overview of exciting developments in the fields of tin and lead chemistry where the generation of unprecedented low-valent compounds is exploited in the reduction of a wide range of organic substrates. Whilst in the case of tetrels, these are confined to a stoichiometric regime, Chitnis and Hynes show that this limitation can be overcome by application of the heavier pnictogens. In Chapter 11.12, they survey organoantimony and organobismuth chemistry across a range of oxidation states. They then provide an exciting overview of the increasing recognition that reversible two-electron redox steps at these metals bring catalytic manifolds previously confined to the d-block into the realm of contemporary main group chemistry. Santi and Scimmi close out this adventure in the main group and, in Chapter 11.13, provide an update on heavy chalcogen chemistry focused on that of selenium and tellurium. They overview selenium reagents with a particular focus on reaction strategies, and a number of recently accessed selenides. They continue the catalytic theme by accounting for redox-switching steps available at these centers. After these considerations of complexes confined to groups of, or single elements, there are three chapters discussing concepts which span the entire main group. In Chapter 11.14, Heard, Stefkova, van Ingen and Melen summarize the significant advances made in organic synthesis thanks to the powerful concept of frustrated Lewis pairs. In Chapter 11.15, Zhang and Guan provide a conceptual framework to pull together the repeated theme of bimetallic systems which ripples through this volume. In this, they summarize possible origins of synergistic effects in multimetallic main group compounds and give a brief overview of some systems exemplifying these important effects. Finally, the work closes with a very brief overview of the significant and ongoing contributions of main group chemistry to polymer science; in Chapter 11.16, English and Liptrot overview main group initiators for ring-opening polymerization and for polymer degradation.

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11.02

Lithium Complexes in Organic Synthesis

R Luisi, L Degennaro, and M Colella, Department of Pharmacy—Drug Sciences, University of Bari “A. Moro”, Italy © 2022 Elsevier Ltd. All rights reserved.

11.02.1 11.02.2 11.02.3 11.02.4 11.02.4.1 11.02.4.2 11.02.4.3 11.02.4.4 11.02.4.5 11.02.4.6 11.02.5 11.02.5.1 11.02.5.2 11.02.5.3 11.02.6 11.02.6.1 11.02.6.2 11.02.6.3 11.02.7 11.02.8 References

Introduction Preparation of lithium reagents Reactivity of lithium reagents Functionalized lithium complexes in synthesis Use of oxygen-bearing lithium compounds in synthesis Use of nitrogen-bearing lithium compounds in synthesis Use of sulfur-bearing lithium compounds in synthesis Use of phosphorous-bearing lithium compounds in synthesis Use of boron-bearing lithium compounds in synthesis Use of halogen-bearing lithium compounds in synthesis Special lithium complexes Carbamoyllithiums Strained lithium compounds Secondary lithium compounds Diverse reactions of lithium compounds Rearrangements and migrations Directed lithiations Cross couplings with lithium compounds Flow technology and flash chemistry with lithium compounds Conclusions

2 2 4 4 4 8 14 16 18 21 25 25 27 29 30 30 37 42 47 50 50

11.02.1 Introduction Organolithium compounds, first reported by Wilhelm Schlenk more than a century ago (1917),1 are still considered very useful reagents for the selective construction of CdC and CdX bonds.2 The advent of sophisticated analytical techniques, and the introduction of new technology, brought about relevant knowledge on their structural features,3,4 and important progress in the preparation and use of new functionalized lithium compounds. In contrast to their well-known reactivity, and air- and moisture-sensitivity, nowadays handling and using lithium compounds is common practice in modern laboratories,5,6 and this allowed the exploration of new reactions under reaction conditions impracticable in the past. Recent developments in this field span from the employment of new green and renewable solvents to the use of enabling technology. Here, we report progress made in the last 15 years with the use of lithium compounds in modern synthesis. Because the use of such organometallic compounds is widely practiced, comprehensive coverage of the literature would have been impossible, thus a selection of synthetically relevant organolithium complexes is described. Moreover, structural aspects of lithium compounds will not be emphasized here.7

11.02.2 Preparation of lithium reagents Organolithium compounds can be prepared by using the following four approaches. In particular, organolithium compounds can be generated by: (1) Reduction of organic halides with lithium metal Organolithium compounds, including those which are commercially available, can be prepared by reductive lithiation of alkyl halides with lithium metal. The substrates of choice for the reaction with lithium metal must be alkyl chlorides, rather than alkyl iodides or bromides that more easily undergo Wurtz reaction leading to RdR coupled products affecting the yields in organolithiums (Scheme 1).

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Scheme 1

(2) Exchange reactions from halides or other organometallics The halogen-lithium exchange reaction discovered by Gilman and Wittig is generally used to generate vinyl-, aryl-, and heteroaryllithium compounds. The halogen-lithium exchange reaction involving alkyl substrates (preferentially iodides and bromides) is an equilibrium shifted towards the most stable and less basic organometallic species. The exchange reaction is accelerated in coordinating solvents and may be an extremely fast reaction even at very low temperatures (99:1

chiral crown ether L

O

O O 3

O

Scheme 42 Asymmetrical 1,4-addition of carboxamides to a,b-unsaturated carboxamides.

O O

74

Sodium and Potassium Complexes in Organic Synthesis

Knochel recently achieved the sodiation of substituted acrylonitriles, alkyenyl sulfides and acrylates in continuous flow utilizing NaDA in dimethylethylamine (DMEA) or sodium tetramethylpiperidide ∙ TMEDA in hexane (Scheme 43).95 The sodiated organometallic species could be trapped with various electrophiles, efficiently providing the corresponding functionalized cinnamonitriles, alkenyl sulfides and acrylates.

Flow

Batch

NaDA in EtNMe2 (1.2 equiv)

10 mL/min tR = 0.12 s Temp = -78 °C

Ph Ph

Ph

Na

Ph • •

CN

N

OH

CN O

Na

Br

CN E/Z = >99/1 (1 equiv)

Br

95% E/Z = >99/1

H (1.5 equiv)

Scheme 43 Sodiation of various substituted acrylonitriles, alkyenyl sulfides and acrylates.

11.03.4 Hydroamination of alkenes García-Álvarez and Hevia reported hydroamination of styrenes using a catalytic amount of alkylsodium as a base initiator (Scheme 44A).96 Interestingly, Strohmann reported that the use of potassium amide (generated from KH and piperidine) in the presence of potassium tert-butoxide does not give any reaction (Scheme 44B),97 whereas hydroamination could proceed using the metal amide generated from Lochmann-Schlosser bases (n-BuLi/t-BuOK) (Scheme 44C).97 This observation again showcased the synergistic effect between lithium and potassium in the Lochmann-Schlosser bases that enabled the transformation. These two separate reports suggested that the potassium amides are not nucleophilic enough to perform hydroamination while sodium amides are capable. (A)

R N

+

Ph

H

NaCH2SiMe3 (5 mol%) R

Ph

THF-d8, 10 min

O Ph

N

Ph

N

Ph

(B)

R

NBz2 72%

87%

80%

R N

KOt-Bu Ph H N

K N

KH –78 °C to rt THF

Ph

no reaction

–78 °C to rt

(C)

H N

1) KOt-Bu, n-BuLi –78 °C 2)

Ph Ph –78 °C to rt

Ph Ph

N 85%

Scheme 44 Hydroamination of styrene using alkali metals amides.

Chiba reported an intramolecular hydroamination of g,d-unsaturated ketoximes catalyzed by tripotassium phosphate for construction of 5-membered cyclic nitrones (Scheme 45A).98 The computational studies revealed the importance of the potassium cation, which could efficiently facilitate the stepwise hydroamination involving nucleophilic amination of the alkene and ensuing

Sodium and Potassium Complexes in Organic Synthesis

75

(A) Ph HO

N

K Ph

K3PO4 (0.1 equiv) PhCl, 120 °C

Ph N

O

R

R

O

Ph Ph

96%

O

Ph

91%

O 98%

Ph N

N

N

Me

Ph N

N

R

O

O

O

N 89%

(B) Ph

Ph

Ph

H

N

KOt-Bu (1 equiv) o-xylene 135 °C, 2 h

Me Me

N

+ N K N

N

Ph

Ph Ph

Ph N

Ph

Ph Me Me

Me Me 94% (cis/trans = 4.5:1)

Scheme 45 Hydroamination of alkenyl oximes and hydrazones.

protonation of the resulting organopotassium intermediate. This hydroamination is in contrast with the typical retro-Cope-type hydroamination of alkenyl oximes, which proceeds under a concerted pericyclic mechanism.99 Similarly, the intramolecular hydroamination of alkenyl hydrazones could be mediated by potassium tert-butoxide, providing pyrrolidines (Scheme 45B).100

11.03.5 Conclusion This review discussed the latest development on chemistry of organosodium/potassium reagents in terms of their generation, reactivity, and applications in chemical synthesis. The structural elucidations of the exotic yet attractively reactive organosodium and potassium species allowed for design and implementation of their synthetic applications, especially deprotonative metalations. Employment of continuous flow technologies has expanded the synthetic scope in leveraging of organosodium/potassium reagents for development of novel molecular transformations, which are hitherto difficult to be practiced in conventional batch processes. It is our strong belief that application of organosodium and potassium reagents to exploit novel and sustainable synthetic transformations continues to flourish and thus enhance our synthetic capability.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Wardell, J. L. In Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; pp 43–120. Wakefield, B. J. In Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; pp 1–110. Mordini, A. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier: Oxford, 1995; pp 93–128. Mordini, A. In Comprehensive Organometallic Chemistry III; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier: Oxford, 2007; pp 3–30. Morton, A. A.; Brown, M. L.; Magat, E. J. Am. Chem. Soc. 1947, 69, 161–167. Morton, A. A.; Claff, C. E.; Collins, F. W. J. Org. Chem. 1955, 20, 428–439. Morton, A. A.; Eisenmann, J. L. J. Org. Chem. 1958, 23, 1469–1474. Morton, A. A.; Marsh, F. D.; Coombs, R. D.; Lyons, A. L.; Penner, S. E.; Ramsden, H. E.; Baker, V. B.; Little, E. L.; Letsinger, R. L. J. Am. Chem. Soc. 1950, 72, 3785–3792. Morton, A. A. Ind. Eng. Chem. 1950, 42, 1488–1496. Morton, A. A.; Holden, M. E. T. J. Am. Chem. Soc. 1947, 69, 1675–1681. Morton, A. A.; Finnegan, R. A. J. Polym. Sci. 1959, 38, 19–32. Schlosser, M. J. Organomet. Chem. 1967, 8, 9–16. Schlosser, M. Pure Appl. Chem. 1988, 60, 1627–1634. Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376–393. Schlosser, M. In Modern Synthetic Methods; Scheffold, R., Ed.; Helvetica Chimica Acta/VCH Verlagsgesellschaft/VCH Publishers: Basel/Weinheim/New York, 1992; vol. 6; pp 227–271. 16. Schlosser, M. In Organometallics in Synthesis: A Manual; Schlosser, M., Ed.; John Wiley & Sons: Chichester, 2001; pp 1–352.

76 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89.

Sodium and Potassium Complexes in Organic Synthesis Kawa, H.; Manley, B. C.; Lagow, R. J. Polyhedron 1988, 7, 2023–2025. Li, M. Y.; San Filippo, J. Organometallics 1983, 2, 554–555. Finnegan, R. A.; Kutta, H. W. J. Org. Chem. 1965, 30, 4138–4144. Chisholm, M. H.; Drake, S. R.; Naiini, A. A.; Streib, W. E. Polyhedron 1991, 10, 337–345. Pi, R.; Bauer, W.; Brix, B.; Schade, C.; von Ragué Schleyer, P. J. Organomet. Chem. 1986, 306, C1–C4. Lochmann, L.; Lím, D. J. Organomet. Chem. 1971, 28, 153–158. Lochmann, L.; Pospíšil, J.; Lím, D. Tetrahedron Lett. 1966, 7, 257–262. Reich, H. J. Chem. Rev. 2013, 113, 7130–7178. Harrison-Marchand, A.; Mongin, F. Chem. Rev. 2013, 113, 7470–7562. Mulvey, R. E. Acc. Chem. Res. 2009, 42, 743–755. Robertson, S. D.; Uzelac, M.; Mulvey, R. E. Chem. Rev. 2019, 119, 8332–8405. Unkelbach, C.; O’Shea, D. F.; Strohmann, C. Angew. Chem. Int. Ed. 2014, 53, 553–556. Benrath, P.; Kaiser, M.; Limbach, T.; Mondeshki, M.; Klett, J. Angew. Chem. Int. Ed. 2016, 55, 10886–10889. Jennewein, B.; Kimpel, S.; Thalheim, D.; Klett, J. Chem. A Eur. J. 2018, 24, 7605–7609. Morton, A. A.; Davidson, J. B.; Newey, H. A. J. Am. Chem. Soc. 1942, 64, 2240–2242. Wurtz, A. Justus Liebigs Ann. Chem. 1855, 96, 364–375. Lehmann, R.; Schlosser, M. Tetrahedron Lett. 1984, 25, 745–748. Mulvey, R. E.; Robertson, S. D. Angew. Chem. Int. Ed. 2013, 52, 11470–11487. Armstrong, D. R.; Kennedy, A. R.; Mulvey, R. E.; Robertson, S. D. Chem. A Eur. J. 2011, 17, 8820–8831. McLellan, R.; Uzelac, M.; Bole, L. J.; Gil-Negrete, J. M.; Armstrong, D. R.; Kennedy, A. R.; Mulvey, R. E.; Hevia, E. Synthesis 2019, 51, 1207–1215. Asako, S.; Kodera, M.; Nakajima, H.; Takai, K. Adv. Synth. Catal. 2019, 361, 3120–3123. Armstrong, D. R.; Graham, D. V.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T. Chem. A Eur. J. 2008, 14, 8025–8034. Hamell, M.; Levine, R. J. Org. Chem. 1950, 15, 162–168. Haynes, W. M. CRC Handbook of Chemistry and Physics; CRC Press, 2014. Martin, G.; Rentsch, L.; Höck, M.; Bertau, M. Energy Storage Mater. 2017, 6, 171–179. Raynolds, S.; Levine, R. J. Am. Chem. Soc. 1960, 82, 472–475. Lochmann, L.; Trekoval, J. J. Organomet. Chem. 1979, 179, 123–132. Barr, D.; Dawson, A. J.; Wakefield, B. J. J. Chem. Soc. Chem. Commun. 1992, 204. Ma, Y.; Algera, R. F.; Collum, D. B. J. Org. Chem. 2016, 81, 11312–11315. Algera, R. F.; Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2017, 139, 7921–7930. Ma, Y.; Algera, R. F.; Woltornist, R. A.; Collum, D. B. J. Org. Chem. 2019, 84, 10860–10869. Clegg, W.; Kleditzsch, S.; Mulvey, R. E.; O’Shaughnessy, P. J. Organomet. Chem. 1998, 558, 193–196. Bergman, R. G.; Schlenk, W. J. Justus Liebigs Ann. Chem. 1928, 463, 98–227. Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552–560. Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356–363. Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306–312. Snieckus, V. Chem. Rev. 1990, 90, 879–933. Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43, 2206–2225. Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F. Chem. A Eur. J. 1999, 5, 2055–2068. Cotter, J.; Hogan, A.-M. L.; O’Shea, D. F. Org. Lett. 2007, 9, 1493–1496. Tricotet, T.; Fleming, P.; Cotter, J.; Hogan, A.-M. L.; Strohmann, C.; Gessner, V. H.; O’Shea, D. F. J. Am. Chem. Soc. 2009, 131, 3142–3143. Bao, W.; Kossen, H.; Schneider, U. J. Am. Chem. Soc. 2017, 139, 4362–4365. Bowden, K.; Cook, R. S. J. Chem. Soc. Perkin Trans. 1972, 2, 1407–1411. Algera, R. F.; Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2017, 139, 11544–11549. Gissot, A.; Becht, J.-M.; Desmurs, J. R.; Pévère, V.; Wagner, A.; Mioskowski, C. Angew. Chem. Int. Ed. 2002, 41, 340–343. Garden, J. A.; Armstrong, D. R.; Clegg, W.; García-Alvarez, J.; Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; Robertson, S. D.; Russo, L. Organometallics 2013, 32, 5481–5490. Martínez-Martínez, A. J.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T. Science 2014, 346, 834–837. Algera, R. F.; Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2017, 139, 15197–15204. Asako, S.; Nakajima, H.; Takai, K. Nat. Catal. 2019, 2, 297–303. Ma, Y.; Woltornist, R. A.; Algera, R. F.; Collum, D. B. J. Org. Chem. 2019, 84, 9051–9057. Riggs, J. C.; Singh, K. J.; Yun, M.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 13709–13717. Too, P. C.; Chan, G. H.; Tnay, Y. L.; Hirao, H.; Chiba, S. Angew. Chem. Int. Ed. 2016, 55, 3719–3723. Hong, Z.; Ong, D. Y.; Muduli, S. K.; Too, P. C.; Chan, G. H.; Tnay, Y. L.; Chiba, S.; Nishiyama, Y.; Hirao, H.; Soo, H. S. Chem. A Eur. J. 2016, 22, 7108–7114. Ong, D. Y.; Tejo, C.; Xu, K.; Hirao, H.; Chiba, S. Angew. Chem. Int. Ed. 2017, 56, 1840–1844. Huang, Y.; Chan, G. H.; Chiba, S. Angew. Chem. Int. Ed. 2017, 56, 6544–6547. Kaga, A.; Hayashi, H.; Hakamata, H.; Oi, M.; Uchiyama, M.; Takita, R.; Chiba, S. Angew. Chem. Int. Ed. 2017, 56, 11807–11811. Tejo, C.; Pang, J. H.; Ong, D. Y.; Oi, M.; Uchiyama, M.; Takita, R.; Chiba, S. Chem. Commun. 2018, 54, 1782–1785. Chan, G. H.; Ong, D. Y.; Yen, Z.; Chiba, S. Helv. Chim. Acta 2018, 101, e1800049. Pang, J. H.; Kaga, A.; Chiba, S. Chem. Commun. 2018, 54, 10324–10327. Pang, J. H.; Kaga, A.; Roediger, S.; Lin, M. H.; Chiba, S. Asian J. Org. Chem. 2019, 8, 1058–1060. Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796–11893. Weidmann, N.; Ketels, M.; Knochel, P. Angew. Chem. Int. Ed. 2018, 57, 10748–10751. Harenberg, J. H.; Weidmann, N.; Knochel, P. Angew. Chem. Int. Ed. 2020, 59, 12321–12325. Fleming, P.; O’Shea, D. F. J. Am. Chem. Soc. 2011, 133, 1698–1701. Manvar, A.; Fleming, P.; O’Shea, D. F. J. Org. Chem. 2015, 80, 8727–8738. Suzuki, H.; Igarashi, R.; Yamashita, Y.; Kobayashi, S. Angew. Chem. Int. Ed. 2017, 56, 4520–4524. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463. Yamashita, Y.; Suzuki, H.; Sato, I.; Hirata, T.; Kobayashi, S. Angew. Chem. Int. Ed. 2018, 57, 6896–6900. Rayaroth, A.; Singh, R. K.; Kalyanakrishnan, A. V.; Hari, K.; Kaliyamoorthy, A. Org. Biomol. Chem. 2020, 18, 3354–3359. Liu, Y.-F.; Zheng, L.; Zhai, D.-D.; Zhang, X.-Y.; Guan, B.-T. Org. Lett. 2019, 21, 5351–5356. Zhai, D.-D.; Zhang, X.-Y.; Liu, Y.-F.; Zheng, L.; Guan, B.-T. Angew. Chem. Int. Ed. 2018, 57, 1650–1653. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511. Zhou, Y.; Keresztes, I.; MacMillan, S. N.; Collum, D. B. J. Am. Chem. Soc. 2019, 141, 16865–16876.

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Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel, P. Org. Lett. 2000, 2, 3285–3287. Yamashita, Y.; Igarashi, R.; Suzuki, H.; Kobayashi, S. Org. Biomol. Chem. 2018, 16, 5969–5972. Barham, J. P.; Tamaoki, S.; Egami, H.; Ohneda, N.; Okamoto, T.; Odajima, H.; Hamashima, Y. Org. Biomol. Chem. 2018, 16, 7568–7573. Barham, J. P.; Fouquet, T. N. J.; Norikane, Y. Org. Biomol. Chem. 2020, 18, 2063–2075. Suzuki, H.; Sato, I.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2015, 137, 4336–4339. Harenberg, J. H.; Weidmann, N.; Karaghiosoff, K.; Knochel, P. Angew. Chem. Int. Ed. 2021, 60, 731–735. Mulks, F. F.; Bole, L. J.; Davin, L.; Hernán-Gómez, A.; Kennedy, A.; García-Álvarez, J.; Hevia, E. Angew. Chem. Int. Ed. 2020, 59, 19021–19026. Seymen, A.; Opper, U.; Voß, A.; Brieger, L.; Otte, F.; Unkelbach, C.; O’Shea, D. F.; Strohmann, C. Angew. Chem. Int. Ed. 2020, 59, 22500–22504. Peng, X.; Tong, B. M. K.; Hirao, H.; Chiba, S. Angew. Chem. Int. Ed. 2014, 53, 1959–1962. Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243–269. Kaga, A.; Peng, X.; Hirao, H.; Chiba, S. Chem. A Eur. J. 2015, 21, 19112–19118.

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11.04

Magnesium Complexes in Organic Synthesis

Ankur, Suban Kundu, Sumanta Banerjee, and Ajay Venugopal, School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, ThiruvananthapuraÅm, India © 2022 Elsevier Ltd. All rights reserved.

11.04.1 11.04.2 11.04.2.1 11.04.2.2 11.04.2.3 11.04.2.4 11.04.3 11.04.3.1 11.04.3.2 11.04.3.3 11.04.3.4 11.04.3.5 11.04.3.6 11.04.4 11.04.5 References

Introduction Stoichiometric reactions Reactions with carbon monoxide Reaction with carbon dioxide Transformations using Mg(I)dMg(I) compounds Reactions with isocyanate Catalytic reactions Hydrogenation Hydroboration Hydrosilylation Hydrostannylation Dehydrocoupling Hydroamination Ring-opening polymerization Conclusions

78 78 78 79 79 80 80 80 81 89 92 93 93 96 102 102

11.04.1 Introduction Magnesium compounds have found immense applications in preparative chemistry. Organomagnesium halides are indispensable in academic laboratories and industrial applications to reduce organic compounds through CdC coupling. Salts of magnesium are used in organic transformations like the synthesis of heterocyclic ring systems, condensation reactions and selective functionalizations.1 Use of chiral ligands in magnesium compounds have resulted in their application in a wide range of enantioselective synthesis.2 Emergence of low valent Mg(I)dMg(I) compounds at the beginning of the 21st century have opened up the possibility of employing these compounds in reductive coupling reactions.3–5 The earlier version of this chapter published in Comprehensive Organometallic Chemistry IV in 2007 by Knochel and co-workers exhaustively described the use of Grignard reagents in organic synthesis.6 Other recent reviews published in this area discuss the role of magnesium salts in organic synthesis and enantioselective reactions.2,7,8 Noting this precedence, we present here organic transformations where new magnesium compounds have been involved. The reactions are broadly divided into stoichiometric and catalytic transformations.

11.04.2 Stoichiometric reactions 11.04.2.1 Reactions with carbon monoxide Carbon monoxide is a major C1-precursor in the chemical industry from which organic compounds are synthesized. While transition metal-catalyzed CO transformations are well established, there are limited examples of C^O activation by s-block metal compounds (Scheme 1). Hill and co-workers reported the reduction of carbon monoxide using beta-diketiminate magnesium hydride, [{(DipNacnac)MgH}2], (DipNacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6).11 The reaction begins with the reduction of two CO molecules by the hydride ligands followed by the CdC coupling of the reduced CO units leading to an enedialato species (Scheme 1, A). Similar observation has been made by Jones and co-workers who started with the low-valent Mg(I)dMg(I) dimer [{(Dip/DepNacnac) Mg}2] (DipNacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6; DepNacnac ¼ [(DepNCMe)2CH]−,Dep ¼ C6H3Et2-2,6) and hydrogenated it to a hydride compound [{(Dip/DepNacnac)MgH}2] using 1,3-cyclohexadiene.9 The resulting magnesium hydride [{(Dip/DepNacnac)MgH}2] converted CO to an enedialato species (A). Very recently, Jones and co-workers have reported the intriguing formation of benzenehexolate moiety (Scheme 1, B) which resulted from hexamerization of CO in the presence of Mg(I)dMg(I) dimer and catalytic amounts of Mo(CO)6.10 Notably, the reaction does not proceed in the absence of the magnesium compound.

Scheme 1 Reactions of carbon monoxide with magnesium reagents. L ¼ Dip/DepNacnac.9,10

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11.04.2.2 Reaction with carbon dioxide Functionalization of carbon dioxide into value-added chemicals is an important area of research in today’s world. Stoichiometric reactions of magnesium compounds with CO2 can be broadly classified as presented in Scheme 2. Grignard reagents (RMgX) and dialkylmagnesium (R2Mg) are known to reduce CO2 to corresponding carboxylates (Scheme 2, C) which eventually can be hydrolyzed to obtain the corresponding carboxylic acids.6 These reactions proceed via the addition of the polar MgdC bond across C]O in CO2. Parkin and co-workers reported [3-HB(3-tBuPz)3]MgCH3 and showed the addition of methyl moiety to carbon dioxide.12 Similar reactivity was shown using the cationic Me6TREN-Mg-Bu complex.13 Addition of CO2 across MgdN bonds in magnesium amides result in the corresponding carbamates (Scheme 2, D).14 Beckert reported CO2 fixation using oxalic amidinato magnesium compounds, which resulted in the formation of a carbamate complex. These magnesium carbamates are further known to displace isocyanates (Scheme 2, E).15 Venugopal and co-workers have made a similar observation using [(Me6TREN)Mg (N(SiMe3)2]+.16 Budzelaar reported the reaction of magnesium bis(hexamethyldisilazane) with CO2, which results in the formation of trimethylsilylisonitrile.17 Magnesium (I) compounds have been demonstrated to reductively couple CO2 to oxalate species in a low yielding reaction (Scheme 2, F).18,19

Scheme 2 Reduction of carbon dioxide using magnesium reagents.6,12–19

11.04.2.3 Transformations using Mg(I)dMg(I) compounds Development of LMg(I)dMg(I)L compounds by Jones and co-workers has led them to explore the reactivity of these low-valent compounds in the reduction of organic molecules.3–5,20 Though such reduction processes have been previously performed using conventional reducing agents like alkali metals, zinc and copper, employment of a hydrocarbon soluble reducing agent such as LMg(I)dMg(I)L makes the reduction more effective and facile.3,20 LMg(I)dMg(I)L reduces benzophenone to the corresponding secondary alcohol through a radical pathway (Scheme 3). Cyclooctatetraene and anthracene are reduced to their corresponding

Scheme 3 Reduction of unsaturated organic molecules using Mg(I) reagent.3–5,20–23

80

Magnesium Complexes in Organic Synthesis

di-anions(Scheme 3).21 Reaction between tert-butyl isocyanate and LMg(I)dMg(I)L leads to CdC coupling, resulting in an oxamide complex formation (Scheme 3).22 In a similar manner, azobenzene is reduced to an azaallyl species and azides are reduced to hexazenediide species via NdN bond formation (Scheme 3).23

11.04.2.4 Reactions with isocyanate Hill and co-workers reported the synthesis of bis(imidazolidine-2,4-dione)s using di-n-butyl magnesium in stoichiometric amount. Bis(imidazolidine-2,4-dione)s were synthesized from isocyanate and acetylene derivatives. The reaction proceeds by deprotonation of acetylene derivative, forming magnesium acetylide derivative. The resulting magnesium acetylide then adds on to the isocyanate derivative forming 1 which then undergoes intramolecular cyclization reaction forming imidazolidine-2,4-dione derivative.2 Compound 2 further reacts with two equivalents of isocyanate resulting in 3 and subsequently undergoes intramolecular cyclization reaction forming the bis(imidazolidine-2,4-dione)s (Scheme 4).24

Scheme 4 Synthesis of bis(imidazolidine-2,4-dione)s using di-n-butylmagnesium.24

11.04.3 Catalytic reactions 11.04.3.1 Hydrogenation Hydrogenation of unsaturated bonds using finely powdered nickel is known since late 19th century, pioneered by Sabatier. In recent years, alkaline earth metal compounds have been explored as potential hydrogenation catalysts.25 Harder and co-workers have shown magnesium catalyzed hydrogenation of aldimines using magnesium hexamethyldisilazane.26 The reaction proceeds at 80  C when pressurized with H2 at 6 bar. Involvement of a metal hydride intermediate is proposed by theoretical studies (Scheme 5). The reaction between magnesium hexamethyldisilazane and hydrogen gives rise to an amido-hydridomagnesium species, which serves as the active catalyst. Aldimines coordinate to the amido-hydridomagnesium species and subsequently undergoes hydride insertion. The magnesium amide intermediate of the reduced aldimine then reacts with a molecule of hydrogen through s-bond metathesis forming the respective amine and regenerating the active catalyst. Harder and co-workers also explored other alkaline earth metal amides for alkene hydrogenation. Heavier alkaline metal compounds exhibited efficient catalytic activity for alkene hydrogenation as compared to magnesium compounds.27,28

Magnesium Complexes in Organic Synthesis

81

Scheme 5 Catalytic hydrogenation of aldimines.26

11.04.3.2 Hydroboration The reduction of unsaturated organic substrates through catalytic hydroboration has been widely explored in the last decade.29–34 It is a highly selective and non-hazardous method to access boro-esters and organoboron compounds. Due to the ease of handling and cost-effectiveness, sodium borohydride (NaBH4) is one of the reagents of choice for an organic chemist for hydroboration. However, NaBH4 is not the perfect candidate concerning selectivity and atom efficiency. In order to overcome these problems, different metal complexes were investigated for their catalytic efficiency. The first metal-catalyzed hydroboration was demonstrated using Wilkinson’s catalyst.35 Over the years, several magnesium complexes have been synthesized, which can perform catalytic hydroboration of organic substrates (Table 1).36–56 Catalytic hydroboration can be divided into three categories based on the active species catalyzing the reaction. The first method is metal hydride mediated hydroboration, where a magnesium hydride species is generated in situ via the action of hydridoborane and acts as the primary reducing species (Scheme 6). The second method can be described as Lewis acid mediated hydroboration where a Lewis acidic magnesium species boosts the hydridic nature of the hydridoborane (Scheme 6). The third route involves a Lewis base mediated hydroboration in which the Lewis base binds to the boron center and activates the BdH bond for reduction of organic substrates (Scheme 6).

Scheme 6 Types of active catalyst for hydroboration of organic substrates.

82

Table 1 S. no. 1

Magnesium Complexes in Organic Synthesis Magnesium catalysts for the hydroboration of unsaturated organic molecules. Magnesium catalyst Dip

[( Nacnac)MgH]2

Organic substrates undergoing hydroboration

Ref. no.

Carbon dioxide, aldehydes, ketones, imines, pyridines, nitriles, isonitriles

36–43

Esters, amides

44,45

Dip ¼ C6H3Pri2-2,6 2

ToMMgMe

ToM ¼ tris(4,4-dimethyl-2-oxazolinyl)phenylborate 3

[Mg(THF)6][HBPh3]2

Carbon dioxide, aldehydes, ketones, imines, pyridines, nitriles, isonitriles, carbodiimide

46

4

Mg(Me3TACD-AliBu3)H

Ketones, pyridines, nitriles, imines, amides

47

5

[(DipPh2PN)MgH]4

Ketones, pyridine

48

Dip ¼ C6H3Pri2-2,6

(Continued)

Table 1 S. no.

Magnesium catalyst

Organic substrates undergoing hydroboration

Ref. no.

6

Mg{N(SiMe3)2}2 LMgN(SiMe3)2
THF L ¼ ArNC(NiPr2)NAr; Ar ¼ 2,6-Me2-C6H3 dipp LMgN(SiMe3)2
THF dip L ¼ ArNC(NiPr2)NAr; Ar ¼ 2,6-iPr2-C6H3

Esters

49

7

[(Dip,MesNacnac)Mg]2

Aldehydes, ketones, nitriles, alkynes

50,51

Dip

Nacnac ¼ [(DipNCMe)2CH]−; Dip ¼ C6H3Pri2-2,6; Mes ¼ 2,4,6-Me3C6H2 Unsymmetrical magnesium(I) compound 7

BINOL-Mg

Ketones

52

8

Bu2Mg

Alkynes, organic carbonates, carbamates, epoxides

53–56

Hill and co-workers pioneered the work on magnesium-mediated catalytic hydroboration.31 They have extensively studied catalytic hydroboration of CO2, aldehydes, ketones, imines, pyridine, nitriles, isonitriles, and heterocumelenes.36–42 They have explored mechanistic aspects of pyridine and CO2 hydroboration in detail. In both the cases, LMgH, the catalytically active species, is generated by the s-bond metathesis between [(DipNacnac)MgnBu], DipNacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6 and HBpin (Scheme 7). In the case of pyridine, 1,2-dihydropyridine derivative is obtained as the reduced product.41 Catalytic CO2 reduction requires the presence of an additional Lewis acid, tris-(pentafluoro)phenylborane (B(C6F5)3) and proceeds to give a mixture of formate, actetal and methoxy species.42

84

Magnesium Complexes in Organic Synthesis

Scheme 7 General catalytic cycle for hydroboration of unsaturated organic molecules using [(DipNacnac)MgnBu].36–42

Sadow and co-workers were the first to report the catalytic hydroboration of esters and amides using ToMMgMe [ToM ¼ tris(4,4dimethyl-2-oxazolinyl)phenylborate] complex (Scheme 8). Hydroboration catalyzed by ToMMgMe was performed under ambient conditions and showed tolerance toward cyano, nitro, azo and aryl bromide functionalities. It is noteworthy that the reaction pathway described here doesn’t involve a metal hydride species and the resting state of the catalyst is a magnesium alkoxide species.44,45 Okuda and co-workers showed a non-metal hydride mediated hydroboration of organic substrate by using [Mg(THF)6] [HBPh3]2 complex. The authors have speculated that the dicationic magnesium species plays a role in activating the unsaturated organic substrates.46

Scheme 8 Hydroboration of esters and amides using ToMMgMe as catalyst.44,45

Magnesium Complexes in Organic Synthesis

85

Enantioselectivity was achieved by Rueping and co-workers when they investigated the hydroboration of ketones using a chiral BINOL-Mg, [BINOL ¼ {1,10 -binaphthalene}-2,20 -diol] complex.52 The catalysis does not involve a metal hydride species and can achieve enantiomeric excess up to 86%. The mechanism proposed by the authors is based on the DFT calculations (Scheme 9).52 According to the calculations, the reaction proceeds via the formation of a ketone adduct of BINOL-Mg complex. In the next step, pinacolborane’s oxygen moiety binds to the magnesium center, and the BdH bond gets activated. Subsequently, hydride adds onto the carbonyl carbon with the formation of the boronic ester.

Scheme 9 Enantioselective reduction of aldehydes and ketones.52

Rueping and co-workers reported alkyne hydroboration using di-n-butylmagnesium. The reaction shows high selectivity for Eisomers, and a maximum yield of 85% was achieved. Although the completion time of the reaction was relatively long (18 h) as compared to other catalysts, this is the first example of hydroboration by an inexpensive and readily available reagent.53 The catalytic cycle is shown in Scheme 10. The reaction proceeds via the formation of hydridobutylmagnesium (BuMgH) species which adds onto the alkyne, forming vinylmagnesium species. The vinyl-Mg species then reacts with a pinacolborane molecule, thereby regenerating butylmagnesium hydride and forming vinyl borane.

86

Magnesium Complexes in Organic Synthesis

Scheme 10 Alkyne hydroboration catalyzed by di-n-butylmagnesium.53

The reduction of organic carbonates yields methanol and diols. However, it is a challenging process owing to the stability of organic carbonates. Magnesium catalyzed hydroboration of organic carbonates was first reported by Rueping and co-workers using di-n-butylmagnesium. Hydroboration is observed to be faster with cyclic carbonates as compared to linear carbonates. Mechanistic investigations have revealed a hydride mechanism which is generated by the reaction between di-n-butylmagnesium and pinacolborane. Three-step sequential reduction occurs where in the cyclic carbonate is initially reduced to an organoformate species. It is further reduced to formaldehyde and diboroester. In the last step, formaldehyde is reduced to methoxyboroester (Scheme 11).54

Scheme 11 Di-n-butylmagnesium catalyzed hydroboration of organic carbonates.54

Magnesium Complexes in Organic Synthesis

87

Rueping and co-workers have also reported the hydroboration of cyclic and linear carbamates using di-n-butylmagnesium forming N-methylated amines.55 The reaction mechanism is similar to as discussed in Scheme 11, where an active hydrido-butylmagnesium species is generated. In a three-step sequential reduction, an N-methylated amine product is obtained (Scheme 12). Ma and co-workers reported the hydroboration of organic carbonates using low-valent magnesium(I) complex [(XylNacnac)Mg]2, (XylNacnac ¼ [(DipNCMe)2CH]−, Xyl ¼ C6H3(CH3)2-2,6).51 The reaction was performed under solvent-free conditions, and a maximum yield of 99% is achieved in 6 h.

Scheme 12 Di-n-butylmagnesium catalyzed hydroboration of cyclic and linear carbamates.55

Regio-divergent hydroboration of epoxides using di-n-butylmagnesium and magnesium bis(trifluoromethylsulfonamide) [Mg(NTf )2] is demonstrated by Rueping and co-workers.56 In the case of MgBu2, branched alcohol is obtained as the hydroborated product. On the other hand, Mg(NTf )2 leads to a linear alcohol derivative. The regio-divergence observed in the hydroboration catalyzed by MgBu2 occurs via Mg-H pathway while reactions catalyzed by Mg(NTf )2 follow a non-hydride mechanism, where the epoxide gets converted to an aldehyde by 1,2 hydride transfer reaction. The resulting aldehyde then undergoes reduction, which is catalyzed by Mg(NTf )2 through metal-ligand cooperative HBpin activation (Scheme 13).

Scheme 13 Regio-divergent hydroboration of epoxides catalyzed by di-n-butylmagnesium and magnesium bis(trifluoromethylsulfonamide) [Mg(NTf )2].56

88

Magnesium Complexes in Organic Synthesis

Hill and co-workers reported the hydroboration of isocyanate using [(DipNacnac)MgBu], (DipNacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6) as catalyst with a maximum conversion of 90% in 24 h.43 The mechanism of the reaction is proposed by computational investigations as well as control reactions. In the first step, the butylmagnesium species reacts with pinacolborane, forming hydridomagnesium species which then adds on to the carbon center of the isocyanate functionality. Through a three-step sequential reduction, a secondary amine derivative is formed as the final reduced product (Scheme 14).

Scheme 14 Catalytic hydroboration of isocyanate.43

Hill and co-workers reported the hydroboration of carbodiimide using [(DipNacnac)MgBu], (DipNacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6) as a pre catalyst. The carbodiimides are converted to borylated formamidine products. The catalyst is efficient for sterically unhindered carbodiimides with a maximum conversion of 90% in 15 h. The catalytic reactions were performed at elevated temperatures between 60 –80  C with a catalyst loading of 10 mol% for all substrates (Scheme 15).40 Okuda and co-workers reported the hydroboration of N,N-diisopropyl carbodiimide using [Mg(THF)6][HBPh3] as catalyst. Contrary to Hill’s catalyst which selectively reduced corbodiimide to formamidine derivative, [Mg(THF)6][HBPh3] did not show selective reduction and lead to the complete reduction of carbodiimide to amides (Scheme 15).46

Scheme 15 Hydroboration of carbodiimide catalyzed by [(DipNacnac)MgBu] and [Mg(THF)6][HBPh3].40,46

Magnesium Complexes in Organic Synthesis

89

11.04.3.3 Hydrosilylation Unlike catalytic hydroboration, magnesium catalyzed hydrosilylation reactions have not been studied extensively (Table 2). One of the significant challenges with the magnesium compounds is the activation of Si―H bonds. This has been circumvented by introducing Lewis acids additives like B(C6F5)3, capable of activating Si―H bonds. The first reported magnesium catalyzed hydrosilylation was shown by Sadow and co-workers using ToMMgHB(C6F5)3 complex. Catalytic amounts of the complex were sufficient in selective 1,4-hydrosilylation of a,b-unsaturated esters (Scheme 16).57

Scheme 16 Hydrosilylation of a,b-unsaturated esters catalyzed by ToMMgHB(C6F5)3.57

Hill and co-workers reported the carbon monoxide reduction as well as its catalytic hydrosilylation by [{(DipNacnac)MgH}2], ( Nacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6).11 The reaction proceeds by the hydride insertion to the carbon monoxide molecule, forming magnesium formyl species which then reacts with a molecule of phenylsilane forming silanecarbaldehyde species and regenerating the catalyst. The silanecarbaldehyde undergoes further reduction forming alkoxymagnesium species, which subsequently gets reduced to 1,3-diphenyldisiloxane (Scheme 17). Dip

Scheme 17 [{(DipNacnac)MgH}2] catalyzed hydrosilylation of carbon monoxide.11

Parkin and co-workers reported for the first time that [TismiPrBenz]MgH in combination with B(C6F5)3 can effectively hydrosilylate CO2 by a hydride source (R3SiH) to afford the bis(silyl)acetal [H2C(OSiR3)2] and sequentially CH4 where R3SiH ¼ PhSiH3, Et3SiH, and Ph3SiH.58 The reaction proceed at room temperature and can be controlled to obtain different reduction products as shown in Scheme 15. Interestingly, the reducing agent also plays an essential role in controlling the reduction product. Carbon dioxide was found to be reduced to methane when phenylsilane (PhSiH3) was used as the reducing agent, whereas the use of triphenylsilane (Ph3SiH) gave bis(silyl)acetal, H2C(OSiPh3)2 as the final product. The addition of Lewis acidic B(C6F5)3 to hydridomagnesium complex [TismiPr Benz]MgH results in the abstraction of the hydride, thereby forming [{TismiPr Benz}Mg] [HB(C6F5)3]. Carbon dioxide then inserts itself into the ionic salt forming a formatoborate complex [TismiPr Benz]-Mg{OC(H)OB (C6F5)}. In the subsequent step, oxygen atom on the formatoborate complex attacks the activated silane and forms silylformate with the regeneration of the magnesium hydridoborane complex. The reduction of carbon dioxide to methane follows the same catalytic cycle as mentioned above with stepwise reduction of silylformate species to bis(silyl)acetal followed by reduction to methoxysilane (Scheme 18).

90

Magnesium Complexes in Organic Synthesis

Scheme 18 Catalytic hydrosilylation of CO2 leading to silane derivatives of formate, acetal and methoxy and methane.58

Hill and co-workers reported the stoichiometric reduction and catalytic hydrosilylation of alkene using [{(DipNacnac)MgH}2], ( Nacnac ¼ [(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6).59 The reaction was carried out at 80  C, resulting in the formation of butylmagnesium species. When [{(DipNacnac)MgH}2], was treated with 1,5-hexadiene, the 5-exo-trig cyclization product was observed. To see a similar cyclization reaction with other dienes, 1,7-octadiene was used and no 7-exo-trig or 8-endo-trig ring closure was observed, instead, a magnesio-oct-7-en-1-yl species and dimagnesio-octane-1,4-diide were observed (Scheme 19). Dip

Scheme 19 Stoichiometric reduction of dienes by [{(DipNacnac)MgH}2].59

The reaction mechanism was proposed through computational analysis, and it was found that reaction proceeds via the addition of C]C to the magnesium hydride dimer, and upon addition of the first alkene molecule, the magnesium hydride alkyl dimer breaks into monomeric hydrido and alkyl magnesium species. In the second step, the formed monomeric hydridomagnesium species reacts with a second molecule of alkene generating alkylmagnesium species. The catalyst is regenerated by SidH/MgdC bond metathesis (Scheme 20).59

Scheme 20 Catalytic reduction of alkenes by [{(DipNacnac)MgH}2].59

Magnesium Complexes in Organic Synthesis

91

Crimmin and co-workers reported catalytic hydrosilylation of alkylidene cyclopropane. The reaction resulted in the formation of a ring-opened reduced product.60 The formed alkenemagnesium species reacts with phenylsilane and undergoes MgdC/SidH bond metathesis regenerating the metal hydride complex and forming alkenesilane species. Along with the linear alkenesilane species, cyclosilane is also observed as a minor product in the reaction which is formed by the intramolecular hydrosilylation of C] C in alkene silane (Scheme 21).

Scheme 21 Catalytic hydrosilylation of alkylidene cyclopropane.60 Table 2 S. no. 1.

Magnesium catalysts for hydrosilylation of unsaturated organic molecules. Magnesium catalyst M

To MgHB(C6F5)3

Organic substrates undergoing hydrosilylation

Reference no.

a,b-Unsaturated esters

57

Carbon dioxide

58

(ToM ¼ tris(4,4-dimethyl-2-oxazolinyl)phenylborate 2.

[TismiPr-Benz]MgH

[TismiPr-Benz] ¼ Tris{(1-isoprpylbenzimiazole-2-yl)dimethylsilyl}methyl (Continued )

92

Table 2

Magnesium Complexes in Organic Synthesis (Continued)

S. no.

Magnesium catalyst

Organic substrates undergoing hydrosilylation

Reference no.

3.

[(DipNacnac)MgH]2

Alkenes

11,18,59,60

Ketones

61

(DipNacnac][(DipNCMe)2CH]−, Dip ¼ C6H3Pri2-2,6) 4.

Na[LMgLNa]

L ¼ (E)-2,4-di-tert-butyl-6-(((2,4,6-tri-tert-butylphenyl)imino)methyl)phenoxide

11.04.3.4 Hydrostannylation Hydrostannylation is an important route to obtain organotin compounds. It also finds application in the reduction of olefinic bonds. Palladium(0) is a commonly used catalyst for the hydrostannylation of alkenes and alkynes. In search for inexpensive catalysts, Rueping and co-workers have used di-n-butylmagnesium for the hydrostannylation of alkynes to obtain Z-isomers of the resulting alkenes selectively.62 The mechanism follows a non-hydridic pathway. It is proposed that the reaction is catalyzed by the Lewis acidic magnesium center, which activates either the hydride on Bu3SnH or the carbon-carbon triple bond (Scheme 22).

Scheme 22 Di-n-butylmagnesium catalyzed hydrostannylation of alkynes.62

Magnesium Complexes in Organic Synthesis

93

11.04.3.5 Dehydrocoupling Parkin and co-workers reported alkyne-silane dehydocoupling reaction catalyzed by [TismiPr Benz]MgH/Me complexes.63 When an equimolar amount of [TismiPrBenz]MgH/Me and phenylacetylene are reacted together and elimination of CH4/H2 takes place, forming magnesium alkyne complex. When this magnesium alkyne complex is treated with one equivalent of phenylsilane it results in [TismiPrBenz]MgH and phenyl(phenylethynyl)silane (Scheme 23).

Scheme 23 [TismiPr Benz]MgH/Me catalyzed alkyne silane dehydocoupling.63

Pucheault and co-workers reported the alkyne-borane dehydrocoupling reaction catalyzed by simple phenylmagnesium bromide. In this reaction, diidopropylaminoborane is treated with an alkyne with 5 mol% catalyst loading, and methyl tert-butyl ether is used as the solvent with a maximum yield of 98%.64

11.04.3.6 Hydroamination Hydroamination is an atom economical method to produce amines and imines as well as heterocycles. Group 2 element compounds, particularly magnesium compounds, are studied as catalysts for hydroamination reaction (Table 3). Hill and co-workers reported the intramolecular hydroamination of primary and secondary amines using [(DipNacnac)MgMe], DipNacnac][(DipNCMe)2CH]−; Dip ¼ C6H3Pri2-2,6 (Scheme 24).65 The reaction begins with the protonation of [(DipNacnac)MgMe] resulting in an amidomagnesium complex. The nitrogen on the amidomagnesium complex attacks the unsaturated bond on the

Scheme 24 Intramolecular hydroamination catalyzed by (DipNacnac)MgMe
(THF).65

94

Magnesium Complexes in Organic Synthesis

alkyl moiety forming the cyclic amidomagnesium species. In the last step, the cyclic amidomagnesium species undergoes protonolysis by the unreacted amine forming cyclic amine and regenerating the amidomagnesium complex. The amidomagnesium complex formed in the catalytic cycle acts as the active catalyst in the reaction. Hultzsch and co-workers reported enantioselective hydroamination catalyzed by chiral (R,R) phenoxyamine magnesium complex.71 The catalyst showed exceptional efficiency with enantiomeric excess up to 90% for intramolecular hydroamination reaction and catalyzed intermolecular hydroamination reaction between vinyl arenes and primary/secondary amines (Scheme 25). The catalyst follows the same mechanistic pathway as shown above in Hill’s (DipNacnac)MgMe complex.

Scheme 25 Enantioselective hydroamination catalyzed by a chiral magnesium catalyst.71

Sadow and co-workers found that ToMMgMe (ToM ¼ tris(4,4-dimethyl-2-oxazolinyl)phenylborate), mentioned in the Section 11.04.3.2 (Hydroboration), can be used in catalytic hydroamination reactions.67 The mechanism proposed by Sadow involves two amine substrates attached to the magnesium center compared to one amine substrate suggested by Hill (Scheme 26).

Scheme 26 Intramolecular hydroamination catalyzed by ToMMgMe.67

Table 3

Magnesium catalysts for hydroamination.

S. no.

Magnesium catalyst

Reference no.

1.

(DipNacnac)MgMe
(THF)

65

Dip

Nacnac][(DipNCMe)2CH]−; Dip ¼ C6H3Pri2-2,6

2.

[Dipp-BIAN]MgCH(SiMe3)2

66

3.

BIAN ¼ bis(imino)acenaphthene; Dipp ¼ C6H3Pri2-2,6 ToMMgMe

67

ToM ¼ tris(4,4-dimethyl-2-oxazolinyl)phenylborate 4.

ToTMgMe

68

ToT− ¼ Tris(4S-tert-butyl-2-oxazolinyl)phenylborate 5.

L2MgiPr

69

L2 ¼ 4-tert-butyl-6-(triphenylsilyl)-[bis((3-(dimethylamino)propyl)amino)methyl]phenoxyl (Continued )

96

Table 3

Magnesium Complexes in Organic Synthesis (Continued)

S. no.

Magnesium catalyst

Reference no.

6.

[ONN]MgCH2Ph

70

[ONN] ¼ 4-tBu-2-(CH2NMeCH2CH2NMe2)-6-(SiPh3)C6H2O− 7.

[ONN]MgCH2Ph

71

8.

[ONN] ¼ 4-(tert-butyl)-2-((((1R,2R)-2-(dimethylamino)cyclohexyl)(methyl)amino)methyl)-6-(triphenylsilyl)phenol [DippNBN]Mg
(THF)3

72

Dipp

NBN ¼ HB[N(2,6-iPr2-C6H3)]2

9.

[Mg{h5-C5H3-1,3-(CH2CH2NiPr2)(SiMe2NPh2)}][BPh4]

73

11.04.4 Ring-opening polymerization Ring-opening polymerization (ROP) of cyclic ethers and esters has gained popularity because of the versatile usage of the derived polymers as drug delivery agents and biodegradable thermoplastic. While the electrophilic compounds of group 3 and 4 and the rare-earth elements have been extensively studied for these polymerizations, main-group Lewis acids have also shown significant

Magnesium Complexes in Organic Synthesis

97

Scheme 27 General ring-opening polymerization pathway.74

activity. In general, these polymerization reactions can proceed via two pathways (Scheme 27). Pathway I involves the transfer of metal-bound nucleophilic alkyl or amide ligand to the monomers. Pathway II involves ring-opening and propagation through the formation of a cationic intermediate. [(Et2O)3MgBu][B(C6F5)4], and [(Et2O)3MgN(SiMe3)2][B(C6F5)4] show high catalytic efficiency and follow both pathway I and II.74 Hetero-scorpionate stabilized alkylmagnesium complexes developed by Solera and co-workers present an excellent example of ROP of cyclic esters via alkyl transfer pathway.75 Cationic magnesium complexes are promising initiators for the ring-opening polymerization reactions. Hayes and co-workers reported the first such cationic magnesium complex 4,6-bis(diphenylphosphino) dibenzofuran butylmagnesium. The compound catalyzed ring-opening polymerization of e-caprolactone. The reaction proceeds via coordination of cationic magnesium center to carbonyl oxygen of caprolactone. The addition of alkyl moiety on magnesium center occurs, leading to the ring opening of the carprolactone ring.76 Another cationic magnesium complex [{ONN}Mg][H2N {B(C6F5)3}2] ({ONN} ¼ 2,4-di-tert-butyl-6-{[(20 -dimethylaminoethyl)-methylamino]methyl}phenolate) reported by Carpentier and co-workers showed polymerization of trimethylene carbonate (Scheme 28).77

Scheme 28 Ring-opening polymerization of trimethylene carbonate catalyzed by [{ONN}Mg][H2N{B(C6F5)3}2].77

Another class of complexes that finds use in ring-opening polymerization is magnesium alkoxides. They can be prepared by treating respective alkyl complexes of magnesium with an appropriate alcohol. An example of one such complex is Mg(OR)2(THF)2, which is synthesized by the reaction of n-butyl-sec-butylmagnesium with two equivalents of HOR (HOR ¼ ditert-butylphenylmethanol, HOCtBu2Ph). The synthesized magnesium dialkoxide was further used for the ring-opening co-polymerization of lactides, cyclohexane oxides (CHO) with cyclic anhydrides, limonene oxide with phthalic anhydride and dihydrocoumarin (Scheme 29).78

98

Magnesium Complexes in Organic Synthesis

Scheme 29 Ring-opening co-polymerization catalyzed by Mg(OCtBu2Ph)2(THF)2.78

Trinuclear and tetranuclear aggregates of magnesium alkoxide supported by bulky phenolate ligand are used for ring-opening polymerization. These aggregates are synthesized using 2,6-di-tert-butylphenol (HL1): DMEA (2-N,N-dimethylaminoethanol): MgnBu2 in toluene at room temperature.79 These magnesium alkoxides have been further used to polymerize L-lactides (Scheme 30).

Scheme 30 Ring-opening polymerization of L-lactides catalyzed by [DMEA]Mg(OAr).79

Heterobimetallic Mg/Al cooperativity has been illustrated by Wu and co-workers utilizing [(LAl)MgOBn]2 and [(LAl)Mg(OC2H4OCH3)]2 complexes where L]N1,N1,N2,N2-tetrakis(2-hydroxy-3,5-dimethylbenzyl)-1,2-ethanediamine} in the polymerization L-lactides (Scheme 31).80

Scheme 31 Ring-opening polymerization of lactides catalyzed by [(LAl)MgOBn]2.80

Carbon dioxide polymerization reactions derive significance due to the availability as a raw material in the chemical industry. In 2012, Williams and co-workers reported a dimagnesium complex which has shown to be an efficient catalyst for the co-polymerization of cyclohexane oxide and carbon dioxide (Scheme 32; Table 4).81

Magnesium Complexes in Organic Synthesis

99

Scheme 32 Ring-opening polymerization catalyzed by Di-Mg alkoxide macrocycle.81

Table 4

Magnesium catalysts for ring-opening polymerization.

S. no.

Magnesium catalyst

Organic substrate

Reference no.

1.

[(Et2O)3MgnBu][B(C6F5)4]

Epoxides, e-caprolactone

74

Cyclic esters

75

[(Et2O)3MgN(SiMe3)2][B(C6F5)4]

2.

[Tbpamd]MgR [Pbpamd]Mg

Tbpamd ¼ N-ethyl-tert-N0 -butylbis(3,5-dimethylpyrazol-1-yl)acetamidinate; Pbpamd ¼ N,N0 diisopropylbis(3,5-dimethylpyrazol-1-yl)acetamidinate R ¼ C3H5, tBu, CH2SiMe3 (Continued )

100

Table 4

Magnesium Complexes in Organic Synthesis (Continued)

S. no.

Magnesium catalyst

Organic substrate

Reference no.

3.

[{NNO}Mg] [H2N{B(C6F5)3}2]

Trimethylene carbonate

77

Copolymerization

78

L-Lactides

79

Lactides

80

NNO− ¼ 2,4-di-tert-butyl-6-[{(20 -dimethylaminoethyl)methylamino}methyl]phenolate 4.

Mg(OCtBu2Ph)2(THF)2

HOCtBu2Ph ¼ di-tert-butylphenylmethanol 5.

[DMEA]Mg(OAr)

OAr ¼ 2,6-di-tertbutylphenolate, DMEA ¼ 2-N,N-dimethylaminoethanol (Clustered compound) 6.

[(LAl)MgOBn]2

Magnesium Complexes in Organic Synthesis

Table 4 S. no.

(Continued) Magnesium catalyst

Organic substrate

Reference no.

e-Caprolactone

76

L ¼ N1,N1,N2,N2-tetrakis(2-hydroxy-3,5-dimethylbenzyl)-1,2-ethanediamine 7

101

[LMgnBu][B(C6F5)4]

L ¼ 4,6-bis(diphenylphosphino)dibenzofuran 8

[Me2NCH2CH2N{CH2-3,5-But2-C6H2OH-2}2]Mg

e-Caprolactone

82

9

Dimagnesium alkoxide macrocycle

Co-polymerization of CO2 and epoxides

81

102

Magnesium Complexes in Organic Synthesis

11.04.5 Conclusions Organomagnesium halides continue to be indispensable reagents in organic transformations. Magnesium, an earth-abundant, inexpensive, and environmentally friendly element, has attracted immense interest to be employed in catalytic reactions in the 21st century. Isolation of molecular magnesium alkyls and hydrides facilitated catalytic reduction of unsaturated bonds. Neutral and monoanionic ligands are used to tune the reactivity of MgdC, and MgdH bonds. Monomeric magnesium compounds have been used as model compounds to elucidate catalytic cycles in the reduction of unsaturated bonds. Theoretical investigations have strengthened the hypothesis predicted by experiments. The synthesis of Mg(I) compounds have resulted in their use in stoichiometric reduction of CO and CO2. A recent report by Jones and co-workers involving Mg(I)/Mg(II) redox couple for the reversible addition of diphenylethylene83 will open up new avenues in the chemistry of organomagnesium compounds and their potential applications as mimics to transition metal compounds.

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P.; Mahon, M. F. Angew. Chem. Int. Ed. 2015, 54 (34), 10009–10011. Han, R.; Looney, A.; Parkin, G. J. Am. Chem. Soc. 1989, 111 (18), 7276–7278. Banerjee, S.; Ankur, ; Andrews, A.; Venugopal, A. Chem. Commun. 2018, 54, 5788–5791. Yang, K. C. Organometallics 2001, 20 (1), 126–137. Ruben, M.; Walther, D.; Knake, R.; Görls, H.; Beckert, R. Eur. J. Inorg. Chem. 2000, 1055–1064. Banerjee, S.; Ankur, ; Andrews, A. P.; Varghese, B.; Venugopal, A. Dalton Trans. 2019, 48 (21), 7313–7319. Phull, H.; Alberti, D.; Korobkov, I.; Gambarotta, S.; Budzelaar, P. H. M. Angew. Chem. Int. Ed. 2006, 45, 5331–5334. Lalrempuia, R.; Stasch, A.; Stasch, A.; Jones, C. Chem. Sci. 2013, 4, 4383–4388. Kefalidis, C. E.; Stasch, A.; Jones, C.; Maron, L. Chem. Commun. 2014, 50, 12318–12321. Hicks, J.; Juckel, M.; Paparo, A.; Dange, D.; Jones, C. Organometallics 2018, 37 (24), 4810–4813. Jones, C.; McDyre, L.; Murphy, D. M.; Stasch, A. Chem. Commun. 2010, 46, 1511–1513. Ma, M.; Stasch, A.; Jones, C. Chem. Eur. J. 2012, 18, 10669–10676. Bonyhady, S. J.; Green, S. P.; Jones, C.; Nembenna, S.; Stasch, A. Angew. Chem. Int. Ed. 2009, 48, 2973–2977. Hill, M. S.; Liptrot, D. J.; Mahon, M. F. Angew. Chem. Int. Ed. 2013, 52 (20), 5364–5367. Bauer, H.; Harder, S. Early Main Group Metal Catalyzed Hydrogenation. In Early Main Group Metal Catalysis, John Wiley & Sons, 2020; pp 175–199. Bauer, H.; Alonso, M.; Färber, C.; Elsen, H.; Pahl, J.; Causero, A.; Ballmann, G.; De Proft, F.; Harder, S. Nat. Catal. 2018, 1, 40–47. Bauer, H.; Thum, K.; Alonso, M.; Fischer, C.; Harder, S. Angew. Chem. Int. Ed. 2019, 131 (13), 4292–4297. Martin, J.; Knüpfer, C.; Eyselein, J.; Färber, C.; Grams, S.; Langer, J.; Thum, K.; Wiesinger, M.; Harder, S. Angew. Chem. Int. Ed. 2020, 59, 9102–9112. Sadow, A. D. Alkali and Alkaline Earth Element-Catalyzed Hydroboration Reactions. In Early Main Group Metal Catalysis, John Wiley & Sons, 2020; pp 201–224. Shegavi, M. L.; Bose, S. K. Catal. Sci. Technol. 2019, 9 (13), 3307–3336. Hill, M. S.; Liptrot, D. J.; Weetman, C. Chem. Soc. Rev. 2016, 45, 972–988. Rochat, R.; Lopez, M. J.; Tsurugi, H.; Mashima, K. ChemCatChem 2016, 8 (1), 10–20. Chong, C. C.; Kinjo, R. ACS Catal. 2015, 5 (6), 3238–3259. Revunova, K.; Nikonov, G. I. Dalton Trans. 2015, 44 (3), 840–866. Kono, H.; Ito, K.; Nagai, Y. Chem. Lett. 1975, 4 (10), 1095–1096. Arrowsmith, M.; Hadlington, T. J.; Hill, M. S.; Kociok-Köhn, G. Chem. Commun. 2012, 48, 4567–4569. Arrowsmith, M.; Hill, M. S.; Kociok-Köhn, G. Chem. Eur. J. 2013, 19 (8), 2776–2783. Weetman, C.; Anker, M. D.; Arrowsmith, M.; Hill, M. S.; Kociok-Köhn, G.; Liptrot, D. J.; Mahon, M. F. Chem. Sci. 2016, 7, 628–641. Weetman, C.; Hill, M. S.; Mahon, M. F. Chem. Commun. 2015, 51, 14477–14480. Weetman, C.; Hill, M. S.; Mahon, M. F. Chem. Eur. J. 2016, 22 (21), 7158–7162. Arrowsmith, M.; Hill, M. S.; Hadlington, T.; Kociok-Köhn, G.; Weetman, C. Organometallics 2011, 21, 5556–5559. Anker, M. D.; Arrowsmith, M.; Bellham, P.; Hill, M. S.; Kociok-Köhn, G.; Liptrot, D. J.; Mahon, M. F.; Weetman, C. Chem. Sci. 2014, 5, 2826–2830. Yang, Y.; Anker, M. D.; Fang, J.; Mahon, M. F.; Maron, L.; Weetman, C.; Hill, M. S. Chem. Sci. 2017, 8 (5), 3529–3537. Mukherjee, D.; Ellern, A.; Sadow, A. D. Chem. Sci. 2014, 5, 959–964. Lampland, N. L.; Hovey, M.; Mukherjee, D.; Sadow, A. D. ACS Catal. 2015, 5 (7), 4219–4226. Mukherjee, D.; Shirase, S.; Spaniol, T. P.; Mashima, K.; Okuda, J. Chem. Commun. 2016, 52 (89), 13155–13158. Schnitzler, S.; Spaniol, T. P.; Okuda, J. Inorg. Chem. 2016, 55 (24), 12997–13006. Fohlmeister, L.; Stasch, A. Chem. Eur. J. 2016, 22 (29), 10235–10246. Barman, M. K.; Baishya, A.; Nembenna, S. Dalton Trans. 2017, 46, 4152–4156. Li, J.; Luo, M.; Sheng, X.; Hua, H.; Yao, W.; Pullarkat, S. A.; Xu, L.; Ma, M. Org. Chem. Front. 2018, 5, 3538–3547. Cao, X.; Wang, W.; Lu, K.; Yao, W.; Xue, F.; Ma, M. Dalton Trans. 2020, 49 (9), 2776–2780. Falconnet, A.; Magre, M.; Maity, B.; Cavallo, L.; Rueping, M. Angew. Chem. Int. Ed. 2019, 58 (49), 17567–17571. Magre, M.; Maity, B.; Falconnet, A.; Cavallo, L.; Rueping, M. Angew. Chem. Int. Ed. 2019, 58 (21), 7025–7029.

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54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.

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Szewczyk, M.; Magre, M.; Zubar, V.; Rueping, M. ACS Catal. 2019, 9 (12), 11634–11639. Magre, M.; Szewczyk, M.; Rueping, M. Org. Lett. 2020, 22 (8), 3209–3214. Magre, M.; Paffenholz, E.; Maity, B.; Cavallo, L.; Rueping, M. J. Am. Chem. Soc. 2020, 142 (33), 14286–14294. Lampland, N. L.; Pindwal, A.; Neal, S. R.; Schlauderaff, S.; Ellern, A.; Sadow, A. D. Chem. Sci. 2015, 6, 6901–6907. Rauch, M.; Parkin, G. J. Am. Chem. Soc. 2017, 139 (50), 18162–18165. Garcia, L.; Dinoi, C.; Mahon, M. F.; Maron, L.; Hill, M. S. Chem. Sci. 2019, 10, 8108–8118. Kong, R. Y.; Crimmin, M. R. J. Am. Chem. Soc. 2020, 142 (28), 11967–11971. Ma, M.; Shen, X.; Wang, W.; Li, J.; Yao, W.; Zhu, L. Eur. J. Inorg. Chem. 2016, 31, 5057–5062. Magre, M.; Szewczyk, M.; Rueping, M. Org. Lett. 2020, 22 (4), 1594–1598. Rauch, M.; Roberts, R. C.; Parkin, G. Inorg. Chim. Acta 2019, 494, 271–279. Birepinte, M.; Liautard, V.; Chabaud, L.; Pucheault, M. Chem. A Eur. J. 2020, 26 (15), 3236–3240. Crimmin, M. R.; Arrowsmith, M.; Barrett, A. G. M.; Casely, I. J.; Hill, M. S.; Procopiou, P. A. J. Am. Chem. Soc. 2009, 131 (28), 9670–9685. Arrowsmith, M.; Hill, M. S.; Kociok-Köhn, G. Organometallics 2014, 33 (1), 206–216. Dunne, J. F.; Fulton, D. B.; Ellern, A.; Sadow, A. D. J. Am. Chem. Soc. 2010, 132 (50), 17680–17683. Neal, S. R.; Ellern, A.; Sadow, A. D. J. Organomet. Chem. 2011, 696 (1), 228–234. Zhang, X.; Emge, T. J.; Hultzsch, K. C. Organometallics 2010, 29 (22), 5871–5877. Zhang, X.; Tobisch, S.; Hultzsch, K. C. Chem. Eur. J. 2015, 21 (21), 7841–7857. Zhang, X.; Emge, T. J.; Hultzsch, K. C. Angew. Chem. Int. Ed. 2012, 51 (2), 394–398. Freitag, B.; Fischer, C. A.; Penafiel, J.; Ballmann, G.; Elsen, H.; Färber, C.; Piesik, D. F.; Harder, S. Dalton Trans. 2017, 46, 11192–11200. Gallegos, C.; Camacho, R.; Valiente, M.; Cuenca, T.; Cano, J. Catal. Sci. Technol. 2016, 6, 5134–5143. Sarazin, Y.; Schormann, M.; Bochmann, M. Organometallics 2004, 23 (13), 3296–3302. Sánchez-Barba, L. F.; Garcés, A.; Fajardo, M.; Alonso-Moreno, C.; Fernández-Baeza, J.; Otero, A.; Antiñolo, A.; Tejeda, J.; Lara-Sánchez, A.; López-Solera, M. I. Organometallics 2007, 26 (25), 6403–6411. Ireland, B. J.; Wheaton, C. A.; Hayes, P. G. Organometallics 2010, 29 (5), 1079–1084. Brignou, P.; Guillaume, S. M.; Roisnel, T.; Bourissou, D.; Carpentier, J. F. Chem. Eur. J. 2012, 18 (30), 9360–9370. Wannipurage, D.; Hollingsworth, T. S.; Santulli, F.; Cozzolino, M.; Lamberti, M.; Groysman, S.; Mazzeo, M. Dalton Trans. 2020, 49, 2715–2723. Gao, Y.; Dai, Z.; Zhang, J.; Ma, X.; Tang, N.; Wu, J. Inorg. Chem. 2014, 53 (2), 716–726. Jian, C.; Zhang, J.; Dai, Z.; Gao, Y.; Tang, N.; Wu, J. Eur. J. Inorg. Chem. 2013, 20, 3533–3541. Kember, M. R.; Williams, C. K. J. Am. Chem. Soc. 2012, 134 (38), 15676–15679. Sarazin, Y.; Howard, R. H.; Hughes, D. L.; Humphrey, S. M.; Bochmann, M. J. Chem. Soc. Dalton Trans. 2006, 340–350. Boutland, A. J.; Carroll, A.; Alvarez Lamsfus, C.; Stasch, A.; Maron, L.; Jones, C. J. Am. Chem. Soc. 2017, 139 (50), 18190–18193.

11.05

Calcium, Strontium and Barium Complexes in Organic Synthesis

Yann Sarazin and Peter M Chapple, Institut des Sciences Chimiques de Rennes—UMR 6226 CNRS—Université de Rennes 1, Rennes Cedex, France. © 2022 Elsevier Ltd. All rights reserved.

11.05.1 11.05.1.1 11.05.1.2 11.05.1.3 11.05.1.4 11.05.2 11.05.2.1 11.05.2.2 11.05.2.3 11.05.2.3.1 11.05.2.3.2 11.05.2.3.3 11.05.2.3.4 11.05.3 11.05.3.1 11.05.3.2 11.05.3.3 11.05.3.4 11.05.3.4.1 11.05.3.4.2 11.05.4 11.05.4.1 11.05.4.2 11.05.4.3 11.05.4.4 11.05.4.4.1 11.05.4.4.2 11.05.4.4.3 11.05.5 11.05.5.1 11.05.5.1.1 11.05.5.1.2 11.05.5.2 11.05.6 11.05.6.1 11.05.6.1.1 11.05.6.1.2 11.05.6.1.3 11.05.6.2 11.05.6.2.1 11.05.6.2.2 11.05.6.2.3 11.05.6.3 11.05.6.3.1 11.05.6.3.2 11.05.6.3.3 11.05.6.3.4 11.05.7 11.05.7.1 11.05.7.2 11.05.7.3 11.05.7.3.1 11.05.7.3.2

104

Alkaline-earth metal catalysis: An introduction General background The Schlenk equilibrium: Problems and solutions Historical developments Principles of Ae-mediated catalysis Hydroamination of unsaturated carbon-carbon bonds Intramolecular hydroamination reactions Asymmetric intramolecular hydroamination reactions Intermolecular hydroamination reactions Intermolecular hydroamination of alkenes Intermolecular hydroamination of carbodiimides and isocyanates Intermolecular hydroamination of alkynes Intermolecular hydroamination of diynes Hydrophosphination and related catalysis Intermolecular hydrophosphination of alkenes Intermolecular hydrophosphination of alkynes Hydrophosphination of carbodiimides Hydrophosphorylation and hydrophosphonylation catalysis Hydrophosphorylation of alkynes Hydrophosphonylation of aldehydes and ketones Other hydrofunctionalization reactions with pre-polarized E—H substrates Hydroalkoxylation of alkynyl and allenyl alcohols Hydroacetylenation of carbodiimides and related reactions Hydroboration catalysis Hydrosilylation catalysis Hydrosilylation of alkenes Hydrosilylation of ketones Hydrosilylation of imines Hydrogenation catalysis Hydrogenation of alkenes Hydrogenation of activated alkenes Hydrogenation of unactivated alkenes Hydrogenation of imines Dehydrocoupling catalysis Dehydrocoupling of amines and boranes Synthesis of asymmetrical diaminoboranes Dehydrocoupling of dimethylamine-borane and tert-butylamine-borane Dehydrocoupling of amines and boranes Heterodehydrocoupling of amines and silanes Catalyzed NH/HSi heterodehydrocouplings for the formation of mono- and disilazanes Formation of cyclic disilazanes Catalyzed NH/HSi dehydropolymerizations Other alkaline-earth catalyzed heterodehydrocouplings Dehydrocouplings of silanes and alcohols Dehydrocouplings of silanes and borinic acids Dehydrocouplings of silanes and silanols Dehydrogenative silylation of activated CdH bonds Miscellaneous catalyzed reactions with reactive [Ae]-X (pre)catalysts Dimerization of aldehydes—Tishchenko reaction Trimerization of isocyanates Alkylation reactions Dimerization of terminal alkynes Alkylation of aromatic rings

Comprehensive Organometallic Chemistry IV

106 106 107 108 109 111 112 115 117 117 118 120 120 122 123 126 127 128 128 128 128 128 130 130 131 131 133 134 134 135 135 135 142 144 144 145 146 147 148 149 151 152 153 153 156 158 158 159 159 160 160 160 161

https://doi.org/10.1016/B978-0-12-820206-7.00069-X

Calcium, Strontium and Barium Complexes in Organic Synthesis

11.05.7.3.3 Alkylation of alkylpyridines 11.05.7.4 Catalyzed H/D exchange 11.05.7.5 Polymerization of ethylene 11.05.7.6 Reduction of carbon-oxygen unsaturated compounds 11.05.7.7 Redistribution and cross-coupling of arylsilanes 11.05.7.8 Reactions other than hydrofunctionalizations and dehydrocouplings 11.05.7.8.1 Desilacoupling of silaboranes and amines 11.05.7.8.2 Cyanosilylation of carbonyls 11.05.7.8.3 Alumination of Csp2 dH bonds 11.05.8 Alkaline-earth mediated Lewis-acid catalysis 11.05.8.1 Introduction 11.05.8.1.1 Lewis acidity of the group 2 metal cations 11.05.8.1.2 Measuring Lewis acidity 11.05.8.2 Lewis acid catalyzed transformations: CdC bond forming reactions 11.05.8.2.1 Mannich reactions 11.05.8.2.2 Cycloaddition reactions 11.05.8.2.3 Chiral 1,4-addition reactions 11.05.8.2.4 Hydroarylation of alkenes 11.05.8.2.5 Heterofunctionalization of alkenes 11.05.8.2.6 Cyclic rearrangements 11.05.8.2.7 Ca2+-catalyzed dehydroxylation reactions 11.05.9 In lieu of a conclusion Acknowledgments References

Abbreviations Ad Ae AN BDE BDI BDIDiPP BINOL Bn Boc Box CN Cy dabco DiPeP DiPP dme DPE dr DXE Ea ee eq Et FIA FLP Fmoc GEI HBCat HBPin Hex hfip

Adamantyl Alkaline earth Acceptor number Bond dissociation energy b-Diketiminato CH{C(Me)N-DiPP}2− 1,10 -bi-2-Naphthol Benzyl tert-Butoxycarbonyl Bis(oxazoline) Coordination number Cyclohexyl 1,4-Diazabicyclo[2.2.2]octane 2,6-Diisopentylphenyl 2,6-Diisopropylphenyl Dimethoxyethane 1,1-Diphenylethylene Diastereomeric ratio Dixylylethylene Activation energy Enantiomeric excess Equivalent Ethyl Fluoride ion affinity Frustrated Lewis pair Fluorenylmethyloxycarbonyl Global electrophilicity index Catecholborane Pinacolborane Hexyl Hexafluoroisopropanol

105

162 163 165 166 167 169 169 169 170 171 171 171 172 172 172 175 176 178 181 182 185 187 188 188

106

Calcium, Strontium and Barium Complexes in Organic Synthesis

HIE hmpa HOMO i Pr KIE L LA LUMO Me Mes MS Naph n Bu NHC NTf OS OTf Ph PyBox S rionic t Bu thf thp TM TON TOF tmeda Tf2NH TfOH Ts ΧP XRD 1,4-CHD 9-BBN

Hydrogen isotope exchange Hexamethylphosphoramide Highest occupied molecular orbital Isopropyl Kinetic isotope effect Monoanionic ligand Lewis acid Lowest unoccupied molecular orbital Methyl Mesityl Molecular sieves Naphtyl Butyl N-heterocyclic carbene Triflimidate Oxidation state Triflate Phenyl Pyridine-based bi(oxazoline) Solvent molecule Effective ionic radius tert-Butyl Tetrahydrofuran Tetrahydropyran Transition metal Turnover number Turnover frequency Tetramethylethylenediamine Triflimide Triflic acid Tosyl Pauling electronegativity X-ray diffraction 1,4-Cyclohexadiene 9-Borabicyclo[3.3.1]nonane

11.05.1 Alkaline-earth metal catalysis: An introduction The present article is a survey of the recent accounts of alkaline-earth mediated homogeneous catalysis applied to organic transformations relevant to small molecules. The literature for Ae-promoted polymerization catalysis, reviewed elsewhere in this volume, is not discussed here. Nota bene: Unless otherwise stated, hereafter Ae stands for the three large alkaline-earth metals Ca, Sr and Ba.

11.05.1.1 General background Catalysis is a key contributor to the chemical industry. It is estimated that about 90% of all chemical processes are catalyzed, and catalysis is thought to contribute to 30–40% of the world’s GDP. By far and large, industrial homogeneous catalysis has, until recently, revolved around the utilization of precious transition metals such as rhodium, palladium, iridium and platinum. However, these metals are both scarce and expensive (costs in USD per ozt as of April 2021: Rh, 28,500; Pd, 2650; Ir, 6250; Pt, 1200); market prices can also be unstable and fluctuate with worldwide availability. Since the beginning of this century, main group metal catalysis has begun to appear as a viable response to these limitations. Molecular, soluble catalysts built around the abundant and cheap metals of the s- and p-blocks of the Periodic Table are now involved in a myriad of transformations. Group 13 metals (Al, Ga, In and Tl)1 and, to a lesser extent, tin2,3 and other group 14 metals,4 have long been known to generate useful reagents and catalytic systems for organic chemistry; a detailed survey can be found in this volume. Early main group metals, that is, alkali and alkaline-earth metals, are a comparatively recent addition to the set of tools applied in molecular catalysis.5 The input of alkali metals and magnesium, the smallest of the synthetically relevant alkaline earths, is comprehensively surveyed in relevant chapters of the present volume; this includes the synergic multimetallic systems. The applications of the heavier alkaline earths—calcium, strontium and

Calcium, Strontium and Barium Complexes in Organic Synthesis

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barium—in organic chemistry are covered in this article; it encompasses the literature of the past 15 years. For the interested reader, the first reviews on homogeneous catalysis mediated by calcium6 and, more generally, large alkaline-earth metals,7 were released only in 2010; the initial insight into the area was covered in more detail in book chapters published in the following years.8–10 The large alkaline earths (]Ae) calcium, strontium and barium are both abundant (calcium, the 5th most common element, accounts for 3.39 wt% of the Earth crust) and affordable. Their toxicity is limited, although barium can even in small doses induce hypokalemia by blocking transmembrane potassium channels; yet, it is not carcinogenic and does not bioaccumulate.11,12 These metals are characterized by their large ionic radii (effective rionic for a coordination number of 6: Ca2+, 1.00 Ǻ: Sr2+, 1.18 Ǻ: Ba2+, 1.35 Ǻ)13 and high electropositivity (Pauling electronegativity ΧP: Ca, 1.00; Sr, 0.95; Ba, 0.89; see Fig. 1). They are highly polarizable, and generate ionic complexes with ns2 (n-1)d0 outer electronic configurations where non-directional bonding is dictated by electrostatic considerations. Except for two notable examples of Ca(I) compounds,14,15 Ca, Sr and Ba generate redox-inert complexes with the metal in the +II oxidation state. They do not undergo oxidative addition—reductive elimination processes that are more typical of middle to late transition metals, which, as detailed below, bears implications on the mechanisms of Ae-mediated chemical processes. These features are similar to those of the lanthanide elements, and the analogy between Ae and lanthanide elements has indeed been drawn on multiple occasions.10,16 In particular, it is this analogy which prompted the seminal investigations in the potential reactivity and catalytic behavior of molecular Ae complexes. Yet, the two families of elements display substantial differences that go beyond the presence of core f-electrons for the lanthanides: whereas the 4f-elements are characterized by a small reduction of their size upon increasing atomic number due to the lanthanide contraction (rionic for CN ¼ 6: Ce3+, 1.01 Ǻ; Lu3+, 0.86 Ǻ), the ionic radius of alkaline earths increases dramatically upon descending group 2 from Mg2+ (0.72 Ǻ) to Ba2+ (1.35 Ǻ). Similarly, the electronegativity of the element increases substantially from Ba to Mg (ΧP ¼ 0.89 and 1.31, respectively) whereas the fluctuation is more modest for the lanthanides, with ΧP confined between 1.10 (La) and 1.27 (Lu). The comparatively high electronegativity of magnesium confers a certain covalent character to the bonding in Mg complexes, which makes this metal stand apart from the other Ae elements. Beyond this peculiarity, the large variations of size and electronegativity across the other large Ae metals entails much more diverse and less predictable reactivity patterns than for the lanthanide counterparts. For example, ligand exchange in solution, a significant issue for the alkaline earths, is relatively innocuous for the lanthanides, and constitutes another difference between the two families of these hard and oxophilic elements.

11.05.1.2 The Schlenk equilibrium: Problems and solutions Ligand redistribution in solution, also named Schlenk equilibrium after the dynamic ligand exchange that characterizes Grignard reagents RMgX and lead to the formation of homoleptic species MgR2 and MgX2,17 affects all alkaline earths. The properties of the metal, in particular the increasing ionic bonding and metal size, make it a much greater problem upon descending group 2, as metal-to-ligand bonds become weaker and ligand lability is amplified accordingly. Hence, for heteroleptic complexes LAeX, ligand exchange often leads to the formation of new AeL2 and AeX2 species (Fig. 2) in proportions that vary both with the nature of the monoanionic ligands L− and X−, and with the reaction conditions (temperature, concentration, nature of the solvent). It can result in the formation of polymeric aggregates or cluster compounds with low solubility. Although ill-defined mixtures may still be able to mediate catalytic transformations, control over the reaction will be altered or even entirely suppressed. Beyond catalyst speciation, such mixtures effectively prohibit accurate mechanistic and kinetic analysis of the operating systems. This is particularly irksome for enantioselective reactions and for living polymerizations, where control of the reaction parameters by a carefully designed coordination sphere around the metal is critical. The difficulty associated to ligand scrambling is perhaps best exemplified with the archetypal nitrogen-based b-diketiminate ligand CH{C(Me)N-DiPP}2− (DiPP ¼ 2,6-diisopropylphenyl), hereafter abbreviated as BDIDiPP. This ligand has been used with great effect to suppress ligand redistribution for calcium (and magnesium) chemistry, allowing access to many unprecedented and exciting compounds.18–21 Nonetheless, it is unable to stabilize heteroleptic strontium or barium complexes, as they have been shown to redistribute to equilibrium mixtures with the corresponding homoleptic species (Fig. 3).22 The use of a specifically designed bulky, monoanionic and multidentate ancillary ligand L− in heteroleptic complexes LAeX∙(S)n, where X− is a reactive coligand and S is a coordinated solvent molecule (e.g., thf, Et2O, tmeda, etc.), has overall proved a successful strategy to overcome ligand reshuffling in Ae chemistry.23–26 Such ligands kinetically stabilize the heteroleptic complexes by taking advantage of steric

Fig. 1 Main physical properties of the large alkaline earths calcium, strontium and barium.

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Fig. 2 General ligand exchange (“Schlenk equilibrium”) in alkaline-earth complexes.

Fig. 3 Schlenk equilibria with BDI-ligated Ae complexes for Ae ¼ Ca, Sr and Ba.

and/or electronic factors and, in some cases, structural rigidity.27 The use of a judicious ancillary ligand enables control of the first coordination sphere around the metal; it enhances catalyst properties and lifetime, and generally improves the solubility of the relevant metal species in a given catalytic manifold. The chemistry of barium is particularly representative of the benefits gained through sophisticated ligand design; ligands with tailored properties have allowed access to a plethora of heteroleptic complexes that feature unique bonds to a negatively charged reactive group such as (Me3Si)2N−, (Me3Si)2CH−, Ph2P− or H−.28 Beyond the construction of sterically shielding and electronically stabilizing ligands, intramolecular secondary interactions are also a valuable synthetic tool that helps obtain Ae complexes.29 A number of stable heteroleptic complexes, some of them devoid of bulky multidentate ligands, were for instance generated thanks to the presence of intramolecular Ae ⋯ H–Si,27,30–32 Ae ⋯ F33,34 or Ae ⋯ C(p)35,36 interactions.

11.05.1.3 Historical developments For a long time, development of the molecular chemistry of the alkaline earths was impeded by the high air-sensitivity and reactivity of Ae complexes, and was therefore lagging well behind the chemistry of their lighter congener magnesium. However, the synthetic organometallic chemistry of Ca, Sr and Ba took a decisive turn in the 1990s when the stable s-bonded amide and alkyl precursors [Ae{E(SiMe3)2}2
(thf )2] became available (Ae ¼ Ca, Sr, Ba; E ¼ N, CH).37–39 A range of amide and cyclopentadienyl Ae complexes were also synthesized and were reviewed on several occasions,40–44 but reactivity features were seldom explored until the mid2000s. One of the reasons behind this is that heteroleptic Ae complexes bearing a single cyclopentadienyl-type ligand were often found to be prone to ligand scrambling. Although simple amido complexes of the type [Ae{N(SiMe3)2}2]2 and the related thf adducts [Ae{N(SiMe3)2}2
(thf )2] are very conveniently synthesized37,38 and are sometimes seen to act as competent precatalysts, but on the whole, simple AeX2 species are often polymeric and insoluble in hydrocarbons; this is typically the case for Ae alkoxides. Heteroleptic complexes LAeX (often found as solvated species) bearing two different monoanionic ligands, a bulky and commonly multidentate ancillary ligand L− and a reactive (nucleophilic or basic) group X−, have become the quintessential examples of Ae molecular precatalysts. The bulky ligand L− is installed onto the metal to provide stability to the complex and to improve its solubility in non-polar solvents. The efforts paid into the development of increasingly sophisticated ancillary ligands have with time allowed for the synthesis of stable and soluble Ae-amides, alkyls, alkoxides and even hydrides, with all of these species being relevant to Ae-mediated catalysis. The seminal breakthrough came from the group of M. Chisholm, when they reported in 2003 that heteroleptic b-diketiminate (1) and (pyrazolyl)borate calcium complexes were very efficient precatalysts for the stereocontrolled ring-opening polymerization of lactide (Fig. 4).45,46 Shortly afterwards, Hill and co-workers demonstrated that 1 could also be used very effectively to catalyze the intramolecular hydroamination of aminoalkenes.47 Although interesting results had been obtained earlier in Ae-mediated catalysis, notably for polymerization reactions, these results convincingly showed the advantages of using a bulky ancillary to stabilize the catalytically active species in a given reaction manifold.

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Fig. 4 Alkaline-earth ring-opening polymerization45,46 and hydroamination47 precatalysts.

11.05.1.4 Principles of Ae-mediated catalysis In the past 20 years, the bulk of newly prepared Ae complexes were designed to be catalysts or precatalysts in reactions as varied as olefin hydrofunctionalization, E-H/E0 -H heterodehydrocouplings, and polymerizations. The reactivity of alkaline-earth metals being restricted to redox-neutral pathways, an Ae complex that contains a polarized Aed+dXd– bond where X is a reactive group, can only engage in two fundamental elementary steps (Fig. 5), that is: (1) the [2s-2s] exchange of electronic density during s-bond metathesis with a polarized d-YdZd+ bond, which advances through a highly organized and polarized 4-membered transition state to return the newly-formed AedY and XdZ bonds, and (2) the insertion of a polarized, unsaturated d-Y]Zd+ bond into the Aed+dXd– bond to yield the Ae-Y-Z-X sequence. The catalytic manifolds of Ae-catalyzed reactions can typically be deconvoluted in a succession of these two key elementary processes, as simply depicted in Figs. 6 and 7. In a preliminary off-cycle step, the precatalyst LAeX reacts with a polarized substrate to generate the catalytically active species LAeY. The reactivity of the AedY bond is rationalized by the electronegativity difference between the Ae metal and the more electronegative Y atom(s) (where Y ¼ H or a p-block element, e.g., C, N, O or P), in a way that the d+ AedYd– s bond is always polarized negatively towards the Y atom. Although the charge distribution within the AedY bond is always relative and depends on the identity of the Y substituent, the reactivity with another s-bonded, polarized substrate d–H-Zd+ is limited by the polarized nature of this interaction to a s-bond metathesis (Fig. 6).48,49 The outcome of the reaction is imposed by

Fig. 5 The two elementary steps (with illustrative examples) in the reactivity of alkaline-earth metals: s-bond metathesis and insertion of unsaturated bond. DiPP ¼ 2,6-iPr2-C6H3.

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Fig. 6 Common mechanism for Ae-catalyzed heterodehydrocouplings, illustrated with the coupling of Ph3SiH and HNEt2. L ¼ ligand.

the polarization of the d+AedYd– bond, as the more electronegative hydride in the polarized d–H-Zd+ substrate will take the position a to barium in the pertaining 4-membered transition state. In heterodehydrocoupling catalysis, the combination of both “protic” and “hydridic” s-bond metathesis steps for the dehydrocoupling of d+H-Yd− and d–H-Zd+ pre-polarized substrates (e.g., HNEt2 and HSiPh3, respectively) has been used to build various types of YdZ bonds between p-block heteroelements upon release of dihydrogen. Except for the specific example of hydrogenation reactions where the ability of Ae metal to trigger polarization of H2 will be critical, this type of reactivity is, for now, essentially limited to pre-polarized protic or hydridic element-to-hydrogen bonds. Depending on the identity and intrinsic reactivity of the pair of substrates H-Y and H-Z, the catalytic cycle for dehydrocoupling catalysis can be accessed via two different ways from the precatalyst LAeX. The d+AedYd– bond of the catalytically active species can also induce polarized insertion into multiply bonded substrates, such as ketones, imines, alkenes and alkynes (Fig. 7), as for instance in hydrofunctionalization reactions. Whether the reaction occurs is influenced by the thermodynamics of the relative energy of all broken and formed bonds. However, the kinetic feasibility of any given transformation relies on the substrates ability to stabilize the charge separation induced in the 4-membered transition state. Again, an element of directionality is conferred from the metal: in pre-polarized substrates, e.g., ketones or imines, the more electronegative heteroatom will pre-coordinate to the alkaline earth and will as a result occupy the position a to the metal in the four-membered transition state. This sequence will control the regiochemistry of the whole insertive process. In contrast, for non-polar unsaturated bonds such as alkenes and alkynes, polarization of the p-electrons is induced by the d+Ae-Yd– unit itself; one often speaks in this case of “metal-induced polarization,” a key step in the hydrofunctionalization of unsaturated C]C and C^C bonds.50 The precise operating manifold will be dictated by the polarization of the H-Y between the hydrogen atom and the heteroelement within the substrate. With a d–HdYd+ bond negatively polarized towards hydrogen, as for instance, with hydrosilanes in hydrosilylation reactions, the species responsible for catalytic turnovers is a metal-hydride (Fig. 7, bottom). In the opposite scenario of a d+HdYd– bond negatively polarized towards the heteroatom Y, as in the hydroamination or hydrophosphination of olefins, the catalytically active species will feature a d+AedYd– polarized bond (Fig. 7, top). Beyond the hydrofunctionalization of alkenes and alkynes, the chain-growth polymerizations of unsaturated monomers such as olefins and cyclic esters catalyzed by Ae metals may also advance through iterative insertive pathways. Conceptually, the specificity of these metal-promoted polymerizations resides in the fact that the product of each insertion step, i.e., the growing polymer chain, uniquely remains bound to the metal for the entire duration of the chain extension.

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Fig. 7 Classical stepwise insertive mechanisms for Ae-catalyzed hydrofunctionalizations for substrates containing protic (top) or hydridic (bottom) H atoms.

11.05.2 Hydroamination of unsaturated carbon-carbon bonds The majority of Ae-promoted homogeneous catalysis since 2005 has focused on the hydrofunctionalization of unsaturated bonds. The intramolecular hydroamination of aminoalkenes (also referred to as cyclohydroamination) and its intermolecular version between a primary/secondary amine and an alkene have in particular attracted the largest share of the attention in the years following the initial communication by Hill and co-workers.47 The hydroamination of alkenes is essentially thermoneutral, but it is entropically disfavored, while the electrostatic repulsion between a nitrogen atom and an electron-rich alkene renders the direct nucleophilic attack difficult. The utilization of well-defined molecular catalysts allows for more facile reactions, and has opened access to a range of amine products with original regio- and, in some cases, enantioselectivity. Alkaline-earth complexes are a small contribution to the extensive toolbox of metal-based hydroamination (pre)catalysts, but they can be singled out for their remarkable combination of selectivity and high reaction rates.

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11.05.2.1 Intramolecular hydroamination reactions The first example of Ae-mediated intramolecular hydroamination of aminoalkenes was reported in 2005 by Hill and co-workers,47 who showed that the heteroleptic [{BDIDiPP}CaN(SiMe3)2
(thf )] calcium complex (1) promoted the ring-closure of aminoalkenes to yield a range of substituted pyrrolidines and piperidines (Fig. 8, n ¼ 1 and 2). The formation of azepanes (n ¼ 3) could not be achieved with calcium complexes and was only observed with magnesium analogues. Their initial study was complemented by a set of stoichiometric reactions and by the preparation of model compounds aimed at delineating the nature of the operative mechanism,51–53 and by a more comprehensive survey that explored both substrate scope and kinetic and mechanistic aspects of the catalyzed process.50,54 Beyond 1, the investigations were also extended to the utilization of the bis(amide) and bis(alkyl) complexes [Ca{N(SiMe3)2}2
(thf )2], [Ca{N(SiMe3)2}2]2 and [Ca{CH(SiMe3)2}2
(thf )2], and to their heavier Sr and Ba congeners. Catalysis proceeded under mild conditions, with relatively low catalyst loading and short reaction times except for the most reluctant substrates. Reaction rates were found to be at least competitive with those reported earlier by Marks and co-workers with benchmark lanthanide precatalysts in the 1990s.55 Ring closure followed Baldwin’s guidelines (cyclisation rates: 5 > 6 > 7-membered rings), with the formation of pyrrolidines (near-complete conversion within minutes with a catalyst loading of 2–10 mol% at room temperature) being substantially faster than that of piperidines. Positive Thorpe-Ingold effects were very noticeable, with the presence of geminal alkyl/aryl substituents in b position to the amine facilitating alkene coordination onto the metal center through the formation of favorable conformations in the transition state; this effect was particularly notable for Ph substituents. The inclusion of substituents onto the nitrogen atom or the C]C double were shown to severely reduce reaction rates for N-substitution (R1) or internal C-atom (R5) of the C]C double bond, whereas cyclization was entirely prohibited with internal alkenes. The catalyzed cyclization of 1-amino-1-phenyl-4-pentene and 2-amino-5-hexene, that is, substrates with substituents in a to the nitrogen atom (R2), proceeded with good diastereoselectivity, affording the trans-pyrrolidines with diastereoisomeric excesses of 90% and 78%, respectively. However, reactions with prochirality in the b position (R3 and R4) did not exhibit any diastereoselectivity. For all its merits, precatalyst 1 was still somewhat hampered by its propensity to decompose through Schlenk equilibrium at high temperatures, and its inability to mediate the formation of seven-member azepanes or the cyclization of internal alkenes. Comparison of the reaction rates and observed yields indicated that for identical ligand environments, calcium precatalysts outclassed their strontium analogues, while barium was the least efficient of the three metals. Stoichiometric studies (Fig. 9) showed that although fast, the reaction between 1 and benzylamine is equilibrated (DH ¼ −12.3 kcal mol−1, DS ¼ −32.1 cal mol−1, DG 298 ¼ −2.7 kcal mol−1).52 With other, comparatively less acidic amines such as t BuNH2 and CyNH2, transamination did not occur. Instead, these amines were found to displace thf from the metal center and generate an amine adduct. This finding was consistent with the necessity for amine coordination onto the metal during catalysis, and was also in agreement with the observed catalyst inhibition by both substrate and product during catalysis. In a similar study, the reaction of the strontium complex [{BDIDiPP}SrN(SiMe3)2
(thf )] (2) in benzene-d6 with the model substrate

Fig. 8 Observed trends in the intramolecular hydroamination of aminoalkenes catalyzed by [{BDIDiPP}CaN(SiMe3)2
(thf )] (1) and [Ae{E(SiMe3)2}2
(thf )2] complexes (Ae ¼ Ca, Sr, Ba; E ¼ CH, N).

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Fig. 9 Transaminative protonolysis with [{BDIDiPP}AeN(SiMe3)2
(thf )] precatalysts (Ae ¼ Ca, 1; Sr, 2).

2-methoxyethylamine corroborated these results.54 It led to the formation of an equilibrated mixture between the starting materials, the intermediate adduct [{BDIDiPP}SrN(SiMe3)2
(MeOCH2CH2NH2)] (which could be isolated by crystallization), and the dimeric product of transamination [{BDIDiPP}SrN(H)CH2CH2OMe]2. By contrast, the equimolar reaction of 1 with 2-methoxyethylamine was found to quantitatively generate [{BDIDiPP}CaN(H)CH2CH2OMe]2,51 which was consistent with the superiority of the calcium precatalyst 1 over its strontium derivative 2 for catalysis. Catalyst activation with much more basic Ae-alkyl precursors was found to be irreversible and to provide overall more effective catalytic systems. Kinetic analysis pointed to a rate law that showed first order dependence upon catalyst concentration consistent with a monometallic active species, and first order dependence upon [substrate]. It also highlighted catalyst inhibition by the product and by the substrate, in particular with an inverse dependence in the initial substrate concentration [substrate]0. Unsurprisingly, the presence of thf was also found to considerably reduce reaction rates, due to competitive coordination onto the metal center. Deuterium labeling experiments highlighted the existence of a short-lived metal-alkyl intermediate within the catalytic manifold, produced upon insertion of the unsaturated C]C double bond into the CadN bond and then irreversibly cleaved upon reaction with an incoming substrate molecule that releases the final product and regenerates the catalytically active metal-amide species. Overall, reaction rates and catalytic turnover were found to be impeded by the coordination of Lewis bases (substrate, product, thf ), dimerization of the complex to form a catalytically inactive species, and gradual decomposition through ligand scrambling at elevated temperatures. Based on these observations, the stepwise mechanism is depicted in Fig. 10 as initially proposed by Hill and co-workers. Further kinetic studies of the cyclization of the benchmark (1-allylcyclohexyl)methanamine (that is, n ¼ 1, R1 ¼ R2 ¼ R5 ¼ H and R3, R4 ¼ Cy in Fig. 8) catalyzed by the unsolvated [Ae{N(SiMe3)2}2]2 for Ae ¼ Ca and Sr confirmed that reactions rates decreased with increasing [substrate]0. Eyring analysis provided the activation parameters, which showed that the observed increase of activation enthalpies as metal size increased was compensated by a favorable entropy of activation, the latter being a result of a decrease of the charge-to-size ratio and a less constrained geometry in the transition state. A substantial kinetic isotope effect was detected when deuterated amines were used (kH/kD ¼ 3.4–3.5). This KIE appeared to be unreconcilable with the initially proposed stepwise mechanistic pathway. Instead, it was suggested to reflect a rate-limiting step consisting of a non-insertive concerted proton transfer leading to ring-closure in a single step (Fig. 11). Such concerted mechanism involving a six-centered transition state was consistent with a similar proposal made by Sadow and co-workers for their magnesium-mediated intramolecular hydroamination reactions, where the precatalyst was a tris(oxazolinyl)phenylborate magnesium methyl.56 A subsequent detailed DFT investigation of the mechanism of Sadow’s magnesium-catalyzed hydroaminations, carried out by Tobisch, is relevant to the discussion on calcium-promoted catalysis.57 Both the regular s-insertive and the six-centered non-insertive pathways were found to be kinetically viable, and fully agreed with the experimental data. However, the transition state for the rate-limiting step for the insertive manifold (consisting of the aminolysis of the transient MgdC bond) was calculated

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Fig. 10 Proposed stepwise mechanism for the hydroamination of aminoalkenes catalyzed by 1.

Fig. 11 Refined non-insertive six-centered concerted transition state for intramolecular hydroaminations catalyzed by 1.

to be 5.0 kcal mol−1 lower in energy than that for the concerted mechanism, and hence for this case of magnesium-catalyzed hydroamination, the classical mechanism seems to be clearly prevailing. This study was not extended to reactions catalyzed by 1, and therefore the question as to the exact nature of the operating mechanism with this calcium precatalyst is still unresolved. Following the landmark studies by Hill and co-workers, a number of other calcium and strontium precatalysts were disclosed for the intramolecular hydroamination of aminoalkenes (Fig. 12). They were most commonly stabilized by nitrogen-ligands, e.g., the bulky triazenides 3–4,58 the aminotroponiminates 5–6,59,60 the iminoanilides Ae-amides (7–9) and alkyls (10−12).27,61,62 and the bis(imino)pyrrolides 7–8.63 The attempt to utilize bis(imino)acenaphthene to generate Ae-alkyls precatalysts resulted in the formation of 15 and 16 through dearomatization of the ligand backbone; these precatalysts proved remarkably robust against Schlenk redistribution.64 Some systems also incorporated oxygen-based ligands, such as the Ae-phenoxides 17–19.61 The zwitterionic bis(imisazolin-2-ylidene)borate 20–21 displayed excellent reaction rates, outperforming 1 by some margin in the case of 21; interestingly, this strontium precatalyst was more efficient than its calcium counterpart, and both enabled the cyclisation of 2-methyl-6,6-diphenylazepane.65 Overall, the observed catalyst behaviors and reaction rates were similar to those observed with

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Fig. 12 Selected precatalysts for the intramolecular hydroamination of aminoalkenes.

1 and 2. With some exceptions, for the same supporting ligand framework, cyclization rates were generally found to decrease upon descending group 2, with calcium often giving the best results: Ca > Sr > Ba. The amido precatalysts 7 and 8 supported by a comparatively rigid iminoanilide ligand proved superior to their b-diketiminato analogues 1 and 2.62 This trend was rationalized by the observation that no decomposition of 7 and 8 via ligand redistribution was detected under the chosen experimental conditions, in contrast to 1 and 2. The alkyl precatalysts (10–12) provided much greater reactions rates than their amido counterparts (7–9) in the cyclization of 1-amino-2,2-dimethyl-pent-4-ene,62 due to their greater basicity and ability to produce irreversibly the catalytically active Ae-amidoalkene species. Accordingly, the Gibbs energy of activation determined by Eyring analysis for the barium-alkyl 12 was lower than that for 9 (DG{ ¼ 21.1(2) and 23.8(3) kcal mol−1, respectively). A moderate kinetic isotope effect was measured when N-deuterated aminoalkene was used (kH/kD ¼ 2.6(4)), and the kinetic rate law showed a first-order dependence upon both [catalyst] and [aminoalkene]. Based on these data, Sarazin and co-workers proposed a six-centered non-insertive concerted mechanism as the prevailing pathway for intramolecular hydroamination catalyzed by the barium complexes 9 and 12, in agreement with the mechanism previously proposed by Hill for his calcium catalyst (see Fig. 11).54,62 A thorough computational assessment of the two possible alternative mechanisms (stepwise s-insertive vs. concerted protonassisted) for the intramolecular hydroamination of aminoalkenes catalyzed by 7–9 was performed.66 This DFT study supported a prevalent mechanistic pathway consisting of (i) a stepwise insertive route, with a catalytically active Ae-amidoalkene that undergoes reversible s-insertive NdC bond-forming ring-closure, followed by (ii) a rate-limiting, irreversible s-bond aminolysis between the newly formed AedC bond in the Ae-alkyl intermediate and an incoming aminoalkene (Fig. 13). The DFT-derived mechanism was compatible with the experimental data. Rate-determining aminolysis was consistent with the observed kinetic isotope effect, and the DFT-computed energy barrier also agreed with the data obtained from kinetic analysis.62 The reactivity trend Ba < Sr < Ca observed in intramolecular hydroaminations catalyzed by 7–9 was rationalized as being the outcome of increasingly favorable metal-aminoalkene interactions when the metal was more compact, since regardless of its size (Ca < Sr < Ba), the metal center was found to be equally accessible and the approach of the substrate was not sterically hindered.

11.05.2.2 Asymmetric intramolecular hydroamination reactions Because complexes of the large alkaline earths are easily prone to ligand scrambling, Ae-based precatalysts for asymmetric hydroaminations are rare, and the overall performances of such complexes have been unimpressive. By contrast, a small number of very selective (ees up to 92%) magnesium precatalysts have been described, where the metal is encapsulated by a rigid aminophenolate.67,68 The first attempt to achieve the asymmetric intramolecular hydroamination reactions came from the group of Harder, who used the enantiopure calcium bis(oxazoline)-amide [{(S)-Ph-BOX}CaN(SiMe3)2
(thf )2] (22, Fig. 14) but despite achieving high substrate conversions, they only observed low ees (5–10%).69 The diamido calcium precatalyst 23 gave slightly higher ees

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Fig. 13 Prevailing stepwise s-insertive pathway for the hydroamination of aminoalkenes catalyzed by 7–9 derived from experimental and DFT investigations.

Fig. 14 Calcium precatalysts for the asymmetric intramolecular hydroamination of aminoalkenes.

(up to 26%), but the reactions required several days to partly convert 10 equivalents of 1-amino-2,2-R2-pent-4-ene (R ¼ Me or Ph).70 The utilization of chiral calcium-bis(imidazoline) complexes did not provide any improvement,71 but tangibly better results (ees up to 50%, reaction time 24 h) were achieved by using bis(oxazolinylphenyl) ligands (24).72 High reaction rates (full conversion in 5 min) but low ees (16%) were observed when the tris(oxazolinyl)borato calcium complex 25 was used.73 Generally, all attempts to obtain ees in the upper ranges were thwarted by the participation of the calcium complexes in ligand-redistribution processes; to alleviate this issue, the attempt to use a calcium complex supported by axially chiral dianionic (R)-(+)-2,20 diamino-1,10 -binaphthyls only led to similar ees, up to 57%.74 No asymmetric cyclohydroamination was reported for Sr or Ba precatalysts.

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11.05.2.3 Intermolecular hydroamination reactions The intermolecular hydroamination of unsaturated CdC bonds is entropically more demanding than its intramolecular version. The observed reactions rates are considerably slower, and, with Ae catalysts, it is, for now, restricted to activated alkenes (i.e., styrene derivatives and conjugated double bonds) and alkynes. Accordingly, fewer investigations have been led in the area of intermolecular Ae-mediated hydroamination. It is likely to remain so until the current deadlock concerning the elusive functionalization of non-activated alkenes, necessary to expand the scope and utility of this catalysis, is broken.

11.05.2.3.1

Intermolecular hydroamination of alkenes

Hill and co-workers first showed that the bis(amido) and bis(alkyl) complexes [Ae{N(SiMe3)2}2]2 and [Ae{CH(SiMe3)2}2
(thf )2] (Ae ¼ Ca, Sr, Ba) efficiently catalyzed the hydroamination of vinylarenes and conjugated dienes with a wide range of cyclic or acyclic amines such as pyrrolidine, piperidine, benzylamine and tert-butylamine.75,76 Later, the iminoanilide complexes 7–12 also emerged as highly competent catalysts, providing the highest reactions rates measured for these reactions.27,62 The reactions proceeded under mild conditions (room temperature to 60  C, low catalyst loading) with excellent regiospecificity, affording exclusively the anti-Markovnikov addition products (Fig. 15). The general mechanism is presumed to follow the main guidelines displayed in Fig. 7 for substrates with a protic hydrogen atom. The entry into the catalytic cycle is achieved through quantitative and irreversible (for Ae-alkyl) or equilibrated (for Ae-amide) protonolysis between the precatalyst and the reactive amine substrate. The regioselective outcome of the catalytic event is dictated by the relative distribution of charges along the AedN and C]C bonds, as the positioning of the unsaturated substrate with respect to the metal is governed by the intrinsic polarity of these two bonds. In the case of vinylarenes, the aromatic ring will stabilize the incipient negative charge on the C atom in the position a to the ring, hence promoting the exclusive formation of the anti-Markovnikov addition product. Accordingly, reaction rates were substantially enhanced when electron-withdrawing groups (F, CF3) were introduced in para position to the vinylic moiety as a result of transition state lower in energy compared to benchmark styrene (R ¼ H), whereas inversely, the kinetics were much slower when electron-donating groups (OMe < tBu < Me) were added instead. In all cases, Ae-alkyl precatalysts that irreversibly entered the reaction manifold displayed much greater efficacy than their amido analogues, for which activation was reversible. Kinetic analysis of the [Ae{N(SiMe3)2}2]2 precatalysts showed that hydroamination rates were in the order Ba  Ca < Sr.75,76 The low ability of this barium system to catalyze the reaction was attributed to its large and diffuse nature, and its resulting inability to sufficiently polarize the incoming C]C unsaturated bond in order to enable its insertion into the prepolarized BadNamide bond. The kinetic rate law that was established and given is Eq. (1) shows a second-order dependence in [catalyst] that was hypothesized to be the consequence of the dimeric nature of the catalyst. Rate ¼ k ½catalystŠ2 ½amineŠ1 ½alkeneŠ1

(1)

A strong kinetic isotope effect was detected when N-deuterated amines were utilized, which led the authors to propose a catalytic manifold consisting of a six-centered transition state with concerted H-assisted bond-breaking and bond-forming processes, reminiscent of that suggested for intramolecular hydroaminations (see Fig. 11). Kinetic investigations of the intermolecular hydroamination of vinylarenes and pyrrolidine catalyzed by 7–9 provided different conclusions.27,62 The barium precatalyst provided by far the highest reactions rates, and rate dependence varied with Ca < Sr < Ba. A very strong kinetic isotope effect was measured for N-deuterated pyrrolidine (kH/kD ¼ 6.8 at 40  C and 7.3 at 60  C), whereas the kinetic rate late given in Eq. (2) showed a partial first-order dependence in the concentrations of each of the components in the system. Rate ¼ k ½catalystŠ1 ½amineŠ1 ½alkeneŠ1

Fig. 15 Ae-catalyzed intermolecular hydroamination of activated alkenes. Only the formation of anti-Markovnikov products is observed.

(2)

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Fig. 16 Transition state in the initially proposed non-insertive mechanism for the hydroamination of vinylarenes and amines catalyzed by iminoanilide precatalysts 7–9.

The activation parameters obtained by Eyring analysis (DH{ ¼ 18.3 kcal mol−1, DS{ ¼ −13.1 cal mol−1, DG{298 ¼ 22.2 kcal mol−1) showed the reaction to be kinetically affordable in the chosen temperature range (25–60  C). Again, a non-insertive proton-assisted mechanism consistent with the experimental and kinetic data was proposed as being the prevailing mechanism (Fig. 16). Yet, a comprehensive computational analysis of the two plausible mechanisms for the hydroamination of vinylarene catalyzed by 7–9 showed that the kinetically prevailing mechanism most likely consisted of a stepwise s-insertive pathway (with a corresponding transition state 4.2 kcal mol−1 lower than for the proton-assisted mechanism, Fig. 17), with fast and reversible migratory C]C bond insertion into the suitably polarized Ae-Npyrrolide s bond.77 This insertion was found to occur with 2,1-regiospecificity through a highly polarized four-center transition state, followed by irreversible intramolecular aminolysis of the AedC bond in the alkaline-earth alkyl intermediate. The experimentally observed Ca < Sr < Ba trend was rationalized as being the outcome of weaker AedNpyrolide bonds along with decreased steric protection of the metal center by the iminoanilide ligand as group 2 is descended. Intermolecular hydroamination reactions are more sluggish than their intramolecular version, generally requiring more forceful conditions (higher temperature, longer reaction times and greater metal loading). This was illustrated by the one-pot domino intramolecular and intermolecular hydroamination that combined styrene and 1-amino-2,2-dimethyl-pent-4-ene to selectively yield 2,4,4-trimethyl-1-phenethylpyrrolidine when catalyzed by the barium precatalyst 9 (Fig. 18). Because the observed rate dependence on metal identity are opposite for the intramolecular (Ba < Sr < Ca) and intermolecular (Ca < Sr < Ba) hydroaminations, careful examination of the performances for each precatalyst is a requisite to obtain chemospecific reactions.62

11.05.2.3.2

Intermolecular hydroamination of carbodiimides and isocyanates

Heterocumulenes such as carbodiimides78 and isocyanates79 were found to be suitable substrates for intermolecular hydroaminations with aromatic amines, yielding respectively guanidines and ureas in controlled fashion (Fig. 19). With 2–6 mol% catalyst loading and in the temperature range 25–80  C, the reaction catalyzed by 1 or the amido precatalysts [Ae{N(SiMe3)2}2
(thf )n] (Ae ¼ Ca, Sr, Ba; n ¼ 0, 2) proceeded with rates greater than those observed with alkenes. The rates were heavily influenced by the nature of the metal (Ba < Sr < Ca), with the barium systems being poorly efficient, likely as a result of the formation of insoluble and inactive polynuclear species. Product formation was greatly affected by substitution on both the amine and the carbodiimide (tBu < iPr < Cy). Although high yields could be achieved (reaching sometimes over 90%), the reactions were never quantitative. The formation of stable guanidinate or ureate resting states, in concentrations that increased as the substrates were gradually consumed, was presumed to inhibit full conversion to the products. Substrate scope was limited to aromatic amines. Aliphatic amines were insufficiently acidic to allow for the aminolysis re-activation of these resting states. The isolation of catalytically active homoleptic guanidinate and heteroleptic ureate complexes, achieved through stoichiometric reactions,80 agreed with reaction manifolds advancing via s-insertive pathways.

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Fig. 17 DFT analysis of the rival mechanistic pathways for the hydroamination of styrene with pyrrolidine catalyzed by 9, showing the s-stepwise insertive route (green) to be kinetically favored over the more energetically demanding concerted route (red). Modified from Tobisch, S. Intermolecular Hydroamination of Vinylarenes by Iminoanilide Alkaline-Earth Catalysts: A Computational Scrutiny of Mechanistic Pathways, Chem. Eur. J. 2014, 20, 8988–9001.

Fig. 18 Domino intra- and intermolecular hydroamination of styrene with aminoalkenes.

Fig. 19 Hydroamination of carbodiimides and isocyanates catalyzed by 1 or [Ae{N(SiMe3)2}2
(thf )n].

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11.05.2.3.3

Intermolecular hydroamination of alkynes

The hydroamination of alkynes can be catalyzed by Ae precatalysts, often yielding alkenylamines as mixtures of E and Z isomers.76 [Sr{CH(SiMe3)2}2
(thf )2] mediated the quantitative hydroamination of diphenylacetylene (phenylacetylene could not be used on account of the acidity of the terminal C-H hydrogen) with piperidine in thf within 2 h at 60  C (Fig. 20). It outperformed its calcium analogue [Ca{CH(SiMe3)2}2
(thf )2] and, even more so, the unsolvated Sr-amide derivative [Sr{N(SiMe3)2}2]2. The reaction was found to be very solvent dependent, with thf affording greater E/Z selectivity (91:9) than hydrocarbons (ca. 60:40). Other ethers (dioxane, 2-Me-thf, dme) did not afford any conversion.

11.05.2.3.4

Intermolecular hydroamination of diynes

Westerhausen and co-workers have explored the hydroamination of diynes with secondary amines. The reaction can be catalyzed by alkaline-earth complexes, often as ate salts obtained upon mixing with alkali species. For instance, neither KNPh2 nor Ca(NPh2)2 catalyze the addition of HNPh2 onto diphenylbutadiyne, but the reaction proceeds when the ate heterobimetallic [K2Ca(NPh2)4] is used instead.81 Replacement of an aromatic group by an alkyl one in the amine results in increased reaction rates, due to the enhanced basicity of the resulting amide. Quantitative addition of HNPhiPr onto diphenylbutadiyne is catalyzed within 1 h by 5 mol% of [K2Ca(NPh2)4] at 65  C in thf (Fig. 21). Starting from the ubiquitous heterobimetallic [K2Ca{N(H)DiPP}4], a typical catalytic manifold starting with a preliminary aminolysis and leading to the E and Z isomers is proposed in Fig. 22; the exact identity of the active species remains unknown. The second triple bond in diphenylbutadiyne is less reactive than the first one. Hence, the unsolvated and pre-isolated [K2Ca {N(H)Dipp}4]82 readily catalyzed the hydroamination of diphenylbutadiyne with N-methyl-anilines in thf at room temperature, regioselectively yielding (N-methyl)-(N-aryl)-1,4-diphenylbut-1-ene-3-yne-1-ylamine within a few hours as a mixture of E/ Z isomers. However, hydroamination of the second unsaturated bond required extended reaction times and could only be achieved with N-methyl-aniline and N-methyl-4-fluoroaniline; a mixture of E,E-, E,Z- and Z,Z-isomers was obtained (Fig. 23).83 The elegant attempt to exploit the difference in reactivity between the two triple bonds in diphenylbutadiyne using 1,2-dianilinoethane for the production of a cyclic butadiene through consecutive inter- and intramolecular hydroaminations led to the unexpected formation of acyclic enyne derivatives (Fig. 24). A mixture of E,E-, E,Z- and Z,Z-isomers was again generated within a few hours using the combined action of [K2{1,2-(PhN)2-C2H4}
(thf )3] and [Ca2{1,2-(PhN)2-C2H4}2
(thf )5] (with a K/Ca ratio of 2:1).84 The formation of the entropically favored cyclic butadiene was never detected. By contrast, the use of primary amines for the double hydroamination of diynes allows for the formation of cyclic products. Hence, the addition of substituted aniline onto diphenylbutadiyne is efficiently catalyzed by [K2Ca{N(H)DiPP}4].85 With 10 mol% of catalyst in refluxing thf, the expected N-aryl-2,5-diphenylpyrroles were obtained in high yields after 6 days, independently of the identity of the N-aryl group (Fig. 25). However, entirely different products were formed if the reactions were performed at room temperature, due to the low reactivity of the second CdC triple bond and kinetically competitive C-H activation processes for orthoC-H positions of the N-aryl moieties. Hence, quinolines with annelated cycloheptatriene rings were obtained with p-tBu-aniline. If the ortho positions on the N-aryl substrate were blocked by methyl substituents (e.g., with mesityl), a substituted cycloheptatriene formed instead. Utilization of the bulkier 2,6-diisopropylaniline led to the formation of a very unusual, strained tetracyclic product.86 Several plausible mechanisms were proposed to explain the formation of the different observed products; that leading to the substituted pyrroles is depicted in Fig. 26, but accurate catalyst speciation could not be accomplished. On the whole, the reactivity of the amines in the hydroamination of diynes increased with diphenylamine < N-alkylaniline < dialkylamine < aniline.

Fig. 20 Hydroamination of alkynes.

Fig. 21 Hydroamination of diphenylbutadiyne with the calciates [K2Ca(NRPh)4] in thf.

Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 22 Proposed mechanistic pathway to the hydroamination of diphenylbutadiyne.

Fig. 23 Hydroamination of diphenylbutadiyne with the isolated calciate [K2Ca(NHPh)4].

Fig. 24 Double Hydroamination of 1,2-dianilinoethane and diphenylbutadiyne.

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Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 25 Hydroamination of diphenylbutadiyne with substituted anilines, showing the influence of substrate and reaction conditions.

It is also clear that the synergistic effect of the combined potassium and calcium anilido salts to generate a heterobimetallic active species was necessary to achieve high turnovers and acceptable reactions rates, as each component taken on its own failed to deliver equally satisfactory results.

11.05.3 Hydrophosphination and related catalysis The creation of CdP bonds through metal-mediated catalysis has been attracting interest for over 30 years because it allows for the convenient formation of valuable phosphines and related P-containing molecules. P-hydroelementations are split into three categories that are defined by the number of oxygen atoms contained in the P-substrate that is going to be added to the C^C, C]C, C]O or C]N unsaturated bonds. Hydrophosphination (also called hydrophosphanylation) involves a phosphine HPR2. Hydrophosphinylation (for HP(O)(R)2 and HP(O)(OR)R0 , one and two oxygen atoms, respectively; the name hydrophosphorylation is also often used for HP(O)(R)2) and hydrophosphonylation (for HP(O)(OR)2, three oxygen atoms) are the two other sets of reactions. On the whole, the attention has mostly focused on hydrophosphination reactions. Although lanthanidocenes built on trivalent rare earths are known to catalyze the intramolecular hydrophosphination of phosphinoalkenes and phosphinoalkynes to yield cyclic phosphines, they have failed to promote the equivalent intermolecular reactions.87,88 However, in 2003 a ytterbium(II) system was shown to enable the addition of diphenylphosphine onto alkynes.89 The analogy between Yb(II) and Ca, combined to the fact that calcium and larger Ae complexes competently catalyzed intermolecular hydroamination reactions, naturally prompted exploration in the area of Ae-mediated intermolecular hydrophosphinations. The seminal report of a discrete Ae catalyst by Hill and co-workers dates back to 2007.90 It was followed by a series of contributions from the group of Westerhausen for the alkaline-earth

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Fig. 26 Proposed operative mechanism for the formation of substituted formation of 2,5-diphenyl-pyrroles catalyzed by K/Ca heterobimetallic precatalysts.

promoted hydrophosphination of alkynes and diynes, and by other studies dealing with the hydrophosphination of activated alkenes and heterocumulenes catalyzed by Ae complexes. A handful of other contributions disclosed Ca, Sr and Ba precatalysts to promote the hydrophosphonylation of non-activated alkenes, aldehydes and ketones.

11.05.3.1 Intermolecular hydrophosphination of alkenes A number of alkaline-earth complexes have been disclosed for the hydrophosphination of activated arenes, such as vinylarenes and conjugated dienes. To date, there is no example of successful catalysis with non-activated alkenes, e.g., 1-hexene. The P-substrates that are employed are mostly limited to benchmark secondary phosphines (HPPh2 and, to a lesser extent, HPCy2) and, in some cases, the primary phosphine PhPH2. The reactions afford the products of anti-Markovnikov addition with excellent regioselectivity (Fig. 27). Intermolecular hydrophosphinations are more sluggish than the hydroamination version, and require more forcing conditions. Depending on its identity and overall efficiency, precatalyst loading typically range between 2 and 10 mol%, with temperatures generally between 25  C and 80  C. Reactions can be run in C6D6 or, to improve reaction rates, in neat substrates. A selection of alkaline-earth precatalysts that have been used for the hydrophosphination of alkenes is listed in Fig. 28. Some of the different ligands that have been implemented with mitigated success include b-diketiminates,90 variously substituted iminoanilides27,62,91,92 and amidinates,93–95 NHC-stabilized amides,96 benhydryls,97 phenolates27,62,98 and fluoroalkoxides.32 By and large, most of the effective precatalysts to date are hence supported by sterically shielding nitrogen-based ligands. The majority of systems have been built around calcium, although there is now abundant evidence that reaction rates increase from calcium to strontium and, even more so, to barium. In 2007, Hill and co-workers first reported on the intermolecular hydrophosphination of activated alkenes with HPPh2, catalyzed by the b-diketiminate calcium precursor 1 or by its phosphido analog, [{BDIDiPP}CaPPh2
(thf )] (26) under relatively

Fig. 27 Ae-catalyzed intermolecular hydrophosphination of alkenes.

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Fig. 28 Selected alkaline-earth precatalysts for the intermolecular hydrophosphination of alkenes.

mild conditions (10 mol%, 25–75  C, 13–24 h in C6D6).90 Compound 26 was obtained by slow protonolysis between 1 and HPPh2. The role of the supporting ligand in this catalysis is crucial. For instance, [Ca{N(SiMe3)2}2
(thf )2]2 (10 mol%) was a poor precatalyst in comparison with 1, needing 36 h at 75  C to achieve near-quantitative conversion of the substrates. It was found to be plagued by the formation of the bis(phosphido) complex [Ca(PPh2)2
(thf )4], a yellow solid very poorly soluble in hydrocarbons. Compound 26, shown to be the likely active catalyst, slowly degraded in solution to generate a mixture of [{BDIDiPP}2Ca] and [Ca(PPh2)2
(thf )4], thereby limiting the catalytic efficiency of the system. Precatalyst 1 also catalyzed the addition of diphenylphosphine onto isoprene and 1,3-cyclohexadiene, but not on more hindered alkenes such as 1,1-diphenylethene or a-methylstyrene. With the more electrophilic 2-vinylpyridine, 1 and 26 did not give hydrophosphination products, but instead catalyzed the formation of phosphine-capped poly(2-vinylpyridine). The hydrophosphination of alkenes catalyzed by 1 and 26 was assumed to proceed via a s-insertive pathway, with coordination and regiospecific 2,1-insertion of the polarized C]C bond into the CadP bond, followed by protonolysis of the resulting Ca-alkyl intermediate by an incoming HPPh2 molecule. The observed 2,1-regiospecificity was thought to lower the energy of the transition state traversed in the insertion step, presumed to be rate-limiting, by better stabilization of the developing negative charge on the carbon atom in a position to the aromatic ring (Fig. 29). Potential stabilizing interactions between the p cloud of the aromatic ring and the electron-deficient metal center may also be a favorable factor encouraging the observed 2,1-insertion. Some years later, the family of homologous heteroleptic precursors 7–12 were also shown to catalyze the hydrophosphination of vinylarenes and dienes, with reaction rates and substrate conversions that increased very substantially with metal size (Ca < Sr < Ba); the barium catalysts 9 and 12 still range among the most active systems for these reactions.27,62 At about the same time, the calcium precursor [{2-NC(Ph)-NArC6H4CHNAr}CaN(SiMe3)2
(thf )] (27) supported by an imino-amidinate catalyzed the anti-Markovnikov addition of HPPh2 onto styrene and p-Me-styrene.91 It also catalyzed the regioselective 1,4-addition of HPPh2 to isoprene, 2,3-Me2-1,3-butadiene and myrcene. The 1,4-regioselectivity of the addition catalyzed by 27 is different from that observed with 1, which, with conjugated dienes, mostly generated the products of 1,2-addition. Besides, in contrast with 1, precatalyst 27 was also reported to convert hindered substrates such as a-methylstyrene and cis-stilbene. However, in these cases, the reactions required more forcing conditions than for styrene and p-Me-styrene. The suite of phenolato precatalysts 17–19 and 39–40 were globally less efficient than precursors bearing nitrogen-based ligands, although again, rate dependence increased according to Ca < Sr < Ba.

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125

Fig. 29 Proposed mechanism for the hydrophosphination of alkenes catalyzed by 1 and 26.

Despite substantial efforts paid into the design of sophisticated ancillary ligand aimed at improving catalyst lifetime and solubility, on the whole few breakthroughs in the area of Ae-catalyzed alkene hydrophosphination were disclosed following the initial reports. In typical reactions, 2–10 mol% of the precatalyst was required to achieve complete conversion, at temperature that were often in the range 60–75  C. Reactions required hours or days in C6D6, although in the best cases they could be shortened to 3–15 min when performed in neat substrates.27,62 The TONs remained limited to a few hundred at best, with corresponding TOF values between a few dozens to a few hundred turnovers per hour. The utilization of chiral benzamidinato ligands did not bring any added value, as the addition of diphenylphosphine onto styrene was still found to ensue via 2,1-insertion, forming the anti-Markovnikov product devoid of chiral carbon atom; yet, it further confirmed the Ca < Sr < Ba trend in hydrophosphination catalysis.99 The question of the mechanisms at work in alkaline-earth catalyzed alkene hydrophosphination was probed experimentally by Sarazin and co-workers with their suite of Ae iminoanilides 7–12.27,62 The amido barium precatalyst 9 (2 mol%) quantitatively converted styrene and diphenylphosphine to the anti-Markovnikov product PhCH2CH2PPh2 within 15 min at 60  C in neat substrates, with a corresponding TOF value of 192 molsubst (molBa h)−1. The reaction with HPCy2 was slower (42% conversion under the same conditions). The more basic alkyl precursors 10–12 were tangibly more active than their amido counterparts 7–9, as full conversion with 12 was achieved within 3 min (TOF > 1000 molsubst (molBa h)−1), presumably as the result of irreversible vs. reversible formation of the catalytically competent species. Kinetic analysis was performed with the amido systems 7–9 for the benchmark addition of HPPh2 onto styrene. Electron-withdrawing substituents in para position of the aromatic ring in p-X-C6H4-CH]CH2 vinylarenes led to sizably higher reaction rates, whereas electron-donating groups lowered the reaction kinetics (OMe < tBu < Me < H < Cl < CF3). The kinetic rate law (Eq. 3) showed first order dependence in both [catalyst] and [styrene], while it was independent from [HPPh2]. Rate ¼ k ½catalystŠ1 ½styreneŠ1 ½diphenylphosphineŠ0

(3)

Eyring analysis corroborated the rate trend Ca < Sr < Ba. Taken collectively, these experimental data were consistent a stepwise pathway progressing through a turnover-limiting insertion of the C]C double bond into the AedP bond, as proposed by Hill for catalysis mediated by 1 (see Fig. 29); the two systems were assumed to follow a similar mechanistic pathway. The mechanism of the hydrophosphination of styrene with diphenylphosphine catalyzed by [{HC(C(Me)NPh)2}CaPPh2], i.e., a simplified version of 1, was explored to a considerable length by DFT computations.100 The investigations revealed that insertion of the C]C bond did not follow the traditional route, and the calculations hence contradicted the assumption of a stepwise, insertive reaction manifold suggested by the groups of Hill90 and Sarazin.62 By contrast with the intermolecular hydroamination mechanism, it was found that the prevailing mechanism implicated an unusual outer sphere, conjugative addition. The pertaining computed free energy profile displayed in Fig. 30 shows the initial insertion of the alkene to constitute the rate-limiting step and,

126

Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 30 DFT-computed free energy profile for the prevailing mechanism in the hydrophosphination of styrene with diphenylphosphine catalyzed by [{HC(C(Me) NPh)2}CaPPh2]. All energies in kcal mol−1. Modified from Ward, B. J.; Hunt, P. A. Hydrophosphination of Styrene and Polymerization of Vinylpyridine: A Computational Investigation of Calcium-Catalyzed Reactions and the Role of Fluxional Noncovalent Interactions, ACS Catal. 2017, 7, 459–468.

with DG{ ¼ 18.2 kcal mol−1, to be kinetically accessible. In this mechanistic scenario, there is no direct interaction between the metal center and the C]C double bond. The aromatic ring of the vinylarene moiety was identified to hold a key role. In this scenario, the multiple Ca⋯ Cp and CH⋯ Cp secondary interactions govern the modes of coordination of the substrates and products onto the metal. Moreover, the vinylarene aromatic ring counterbalances unfavorable charge localization in the transition state. Beyond the initial discoveries and enthusiastic reports, the main achievements in recent years dealt with the broadening of the substrate scope, mostly with amidine-amidopyridinato calcium complexes. The very first report of the hydrophosphination of the non-activated 1-nonene with PhPH2 or HPPh2 catalyzed by complexes 30 and 31 was particularly exciting,94 although the reaction remained very sluggish (2 mol% Ca, 40 h, 70  C, ca. 25% conversion). Yet, despite the very small number of systems capable of catalyzing the hydrophosphination of non-activated alkenes,101–104 no further work has capitalized on these promising initial results. The primary phenylphosphine PhPH2 has been used in reactions with vinylarene in ratios that varied from 1:1 to 1:2. Because primary phosphines are more reactive than secondary ones, the reactions were generally chemoselective, and afforded accordingly the products of single or double hydrophosphinations, respectively PhCH2CH2P(H)Ph and PhP(CH2CH2Ph)2 in the case of styrene, with excellent selectivity.94–98 Other phosphines that have been used successfully include MesPH2 and 2-PH2-pyridine. However, the utilization of amidine-amidopyridinates has surprisingly been limited -for now- to calcium, and has not been extended to the more efficient metals strontium and barium.

11.05.3.2 Intermolecular hydrophosphination of alkynes A number of calcium complexes have been reported to catalyze the addition of diphenylphosphine onto alkynes. Despite being insoluble in hydrocarbons, the calcium bis(phosphide) [Ca(PPh2)2
(thf )4] dissolves in ethers. It was found to catalyze (Ca ¼ 6 mol%)

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127

Fig. 31 Alkaline-earth catalyzed hydrophosphination of alkynes.

the hydrophosphination of diphenylethyne (25  C) or 1-phenylpropyne (85  C) with HPPh2, providing selectively the Z isomer in the latter case (Fig. 31).105,106 Precatalysts 1 and 27 were also ale to allow for the hydrophosphination of diphenylacetylene, although unexpectedly, the distribution between E and Z isomers depended on the nature of the supporting ligand framework.90,91 Under forcing conditions (2 mol%, 60  C, 70 h; 84% conversion), the amidinato precursor 34 led to a 58:42 mixture of E and Z isomers after catalyzing the addition of phenylphosphine on diphenylacetylene.93 The calcium bis(phosphide) [Ca(PPh2)2
(thf )4] also catalyzed the addition of diphenylphosphine onto substituted 1,3-diynes RdC^CdC^CdR (R ¼ Me, Mes, tBu, Ph and SiMe3).106 Double addition to 1,4-disubsituted dienes was systematically observed, but the distribution of regio and configuration isomers was found to be heavily dependent upon the identity of the substituents on the diyne. Product identification was ensured through X-ray diffraction analysis of the crystallized dienes. In the simplest cases for R ¼ Me and Mes, 1,4-bis(diphenylphosphanyl)buta-1,3-dienes formed exclusively through consecutive syn-additions, but a mixture of E,E, E,Z and Z,Z stereoisomers was obtained (Fig. 32).

11.05.3.3 Hydrophosphination of carbodiimides The addition of diphenylphosphine onto carbodiimides, yielding phosphaguanidines, was catalyzed by the amido complexes [Ae {N(SiMe3)2}2
(thf )2] and the solvent-free [Ca{N(SiMe3)2}2]2, with activities which increased upon descending group 2 (Ae ¼ Ca < Sr < Ba).107 On the other hand, the heteroleptic precursor 1 was far less efficient. Catalysis with the bis(amide)s in C6D6 was facile, occurring at room temperature with typical precatalyst loading of 1.5–2.0 mol%. Reaction times ranged between 15 min and, for the most reluctant substrates, 28 h. Substrate scope was explored, and the reaction was seen to proceed more slowly

Fig. 32 Alkaline-earth catalyzed hydrophosphination of substituted butadiynes.

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Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 33 Alkaline-earth catalyzed hydrophosphination of carbodiimides.

as sterically demanding N-substituents were introduced in the carbodiimide (Fig. 33). The addition of HPCy2 onto carbodiimides could not be achieved under the same experimental conditions, which was assumed to be the outcome of its low acidity compared to HPPh2. [Ca(PPh2)2
(thf )4] was elsewhere shown to react with diisopropyl- and dicyclohexylcarbodiimides, yielding [Ca{RNC(PPh2)NR}2
(thf )2] (R ¼ iPr, Cy).108 However, both phosphaguanidinato complexes were only poorly active in the hydrophosphination of carbodiimides and diphenylphosphine.

11.05.3.4 Hydrophosphorylation and hydrophosphonylation catalysis 11.05.3.4.1

Hydrophosphorylation of alkynes

The amido precursors [Ae{N(SiMe3)2}2
(thf )2] were used to catalyze the hydrophosphorylation of phenylacetylene with phosphine oxides (Pudovik reaction, Fig. 34).109 Ae-di(aryl)phosphinites [Ae(OPAr)2
(thf )x] were presumed to be the catalytically active species. Catalytic activity increased drastically with metal size (Ca  Sr  Ba), with calcium being inactive under the chosen experimental conditions (5 mol% precatalyst, room temperature, 1 h in thf ) and barium being both very fast and selective. For diarylphosphine oxides, Ar2P(O)H (Ar ¼ Ph, Mes), the reactions yielded E/Z isomeric mixtures of phenylethenyl-di(aryl)phosphine oxides, with barium giving a 22:1 selectivity in favor of the E isomer. The operative mechanism was proposed to involve insertion of the C^C bond into the AedP bond in the postulated [Ae(OPAr)2
(thf )x] active species. The hydrophosphorylation of diynes with diphenylphosphine oxide was also catalyzed by [Ca(PPh2)2
(thf )4].110 Products formation depended heavily on the substitution of 1,3-butadiyne (Fig. 34), with diphenyl- and di(tert-butyl)butadiyne yielding respectively 1,4-diphenyl-1,3-butadiene-2,3-bis(diphenylphosphine oxide) and 2,2,7,7-tetramethyl-4-octyne-3,6-bis(diphenylphosphine oxide). [Ca(PPh2)2
(thf )4] was also an effective precatalyst for the hydrophosphorylation of isocyanates and isothiocyanates (5 mol% precatalyst, thf, room temperature, 12–48 h), affording N-alkyl and N-aryl substituted diphenylphosphorylformamides and -thioformamides respectively, of the type Ph2P(]O)dC(]E)dN(H)R (E ¼ O, R ¼ iPr, tBu, Cy, Ph, 4-Br-C6H4, C6H2-2,4,6-Me3 and Naph) (E ¼ S, R ¼ iPr, Cy, Ph and 4-Me-C6H4).111 Product isolation was ensured by recrystallisation, which enabled easy characterization but led to limited isolated yields.

11.05.3.4.2

Hydrophosphonylation of aldehydes and ketones

The bis(amides) [Ae{N(SiMe3)2}2
(thf )2] are extremely effective precatalysts for the addition of dialkylphosphites HP(]O) (OR)2 onto aldehydes and ketones to produce tertiary or quaternary phosphonates, respectively (Fig. 35).112 No stereoselectivity was observed. The catalytic activity in neat substrates increased according to Ca < Sr < Ba. With aldehydes, full conversion was achieved within minutes at room temperature, using a precatalyst loading as small as 0.02 mol%. With the less electrophilic −1 ketones, TOF values as high as 1200–1500 molsubst mol−1 were reached. The reaction was sensitive to steric demands on the Ae min substrates, e.g., the activity dropped upon introduction of large substituents in ortho position of the aromatic ring of arylketones. However, reaction rates were largely unaffected by the addition of electron-donating/withdrawing group on the substrates. No proposal was made as to a potential catalytic mechanism.

11.05.4 Other hydrofunctionalization reactions with pre-polarized E—H substrates 11.05.4.1 Hydroalkoxylation of alkynyl and allenyl alcohols Some years after their investigations in alkaline-earth-mediated intramolecular hydroamination catalysis, Hill and co-workers revealed that homoleptic [Ae{N(SiMe3)2}2]2 amido complexes were also competent precatalysts for the regioselective intramolecular hydroalkoxylation of alkynyl and allenyl alcohols, yielding 5- and 6-membered enol ethers.113 Typical reactions were carried out in C6D6 at 60–120  C with 5 mol% precatalyst. Substrate scope was probed to a great extent, and showed that in most cases, ring-closure for alkynylalcohols returned mixtures of the endo- and exocyclic enol ethers (Fig. 36). This distribution of products was rationalized as the outcome of isomerization of the alkynylalkoxide (initially formed upon alcoholysis of the Ae-amide bond) into the pertaining allenylalkoxide. Cyclization rates were much greater for allenylalcohols than for their alkynyl counterparts, while terminal alkynylalcohols were found to lead to ring-closure much more rapidly than internal alkynes. Ring-closure proceeded

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129

Fig. 34 Alkaline-earth catalyzed hydrophosphorylation of alkynes, diynes and iso- and isothio-cyanates.

Fig. 35 Alkaline-earth catalyzed hydrophosphonylation of ketones and aldehydes.

Fig. 36 Proposed mechanism for the alkaline-earth catalyzed ring-closing intramolecular hydroalkoxylation of alkynylalcohols. Modified from Brinkmann, C.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A.; Reid, S. Alkaline Earth Catalysis of Alkynyl Alcohol Hydroalkoxylation/Cyclization, Organometallics 2012, 31, 7287–7297.

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following Baldwin’s guidelines, with a pronounced Thorpe-Ingold effect. The established kinetic rate law indicated catalyst inhibition upon increasing [substrate], suggesting that rate-limiting insertion of the unsaturated CdC bond into the AedO bond required the dissociation of coordinated substrate molecules away from the metal center.

11.05.4.2 Hydroacetylenation of carbodiimides and related reactions In 2008, Hill and co-workers utilized the heteroleptic b-diketiminato calcium precatalyst 1 to catalyze the hydroacetylenation of carbodiimides, using phenylacetylene and 1,3-diisopropylcarbodiimide as the benchmark substrates to produce the corresponding propargyl amidine. In what was the first example of Ae-mediated CdC bond formation,114 catalysis took place with 5 mol% catalyst at 80  C for 14 h, but afford only moderate substrate conversion (isolated yield 59%). However, the supporting bdiketiminate ligand was found to be protonolyzed with the relatively acidic phenylacetylene, making catalyst speciation very difficult. A following study showed that [Ca{N(SiMe3)2}2
(thf )2] and even more so [Sr{N(SiMe3)2}2
(thf )2] were more competent precatalysts. The strontium derivative in particular converted a broad range of acetylenic substrates to substituted propargyl amidines under overall relatively forcing conditions (2.5–10 mol%, 12–48 h, 60–100  C; Fig. 37).115 Reactions rates slowed as steric demands on both the carbodiimide and acetylene derivatives increased. In very elegant studies, the Hill group used its experience in alkaline-earth catalyzed heterofunctionalizations to generate highly functionalized cyclic molecules. Using commercially available terminal alkynes and heterocumulenes, they assembled a suite of sophisticated imidazolidin-2-ones, imidazolidin-2-thiones, N,N0 -(5-benzylidene-imidazolidin-2,4-ylidene)diamines and 1,3-thiazolidin-2-thiones through a succession of 100% atom-efficient steps.116,117 The reactions first involve the formation of propargyl amidines, which once formed enter cyclisation reactions through addition of the isocyanate and isothiocyanate. This reactivity was rationalized to occur through a well-defined sequence of heterocumulene hydroacetylenation and alkyne hydroamidation. The simple [Ae{N(SiMe3)2}2
(thf )2] performed smoothly (loading 0.5–5.0 mol%), but required vastly different reactions conditions depending upon substrate selection. The rate and regioselectivity of the cyclisation reactions were found to be heavily dependent upon the nature of the metal. As an illustration, the one-pot sequential synthesis of imidazolidin-2-ones starting from arylacetylenes, isocyanates and carbodiimides could be deconvoluted into four consecutive Ae-promoted heterofunctionalization steps: (i) hydroacetylenation of carbodiimides, (ii) intermolecular isocyanate hydroamination, (iii) ring-closing intramolecular hydroamination of the resulting alkynylurea giving mixture of E and Z isomers for the exocyclic C]C double bond, and (iv) tautomerization into the thermodynamically more stable product (Fig. 38).

11.05.4.3 Hydroboration catalysis Unlike magnesium which has proved fairly competent in the catalysis of hydroboration reactions,118 the large alkaline earths have seldom been used for hydroboration catalysis. A possible justification may be that in a first report of hydroboration of 1,1-diphenylethylene (DPE) with catecholborane (HBCat), the dimeric calcium hydride [{BDIDiPP}CaH
(thf )]2 (45), [Ca[2Me2N-a-Me3Si-benzyl)2
(thf )2] (46) and [{BDIDiPP}Ca(9-BBN)
(thf )] (47) were all found to decompose HBCat into B2H6 and B2Cat3.119 In this so-called Trojan Horse process, the product that formed was not the expected Ph2CHCH2Bcat ensuing from Ca-catalyzed hydroboration of DPE, but (Ph2CHCH2)3B coming from the reaction of B2H6.

Fig. 37 Alkaline-earth catalyzed hydroacetylenation of carbodiimides.

Fig. 38 Sequential alkaline-earth catalyzed formation of substituted imidazolidin-2-ones.

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Ketone hydroboration has met with mitigated success. The four calcium amidinates [{tBuAmDIPP}CaI
(thf )2]2 (48), [{tBuAmDIPP} Ca
(C6H6)]+[B(C6F5)4]− (49), [{tBuAmDIPP}CaN(SiMe3)2
(Et2O)] (50) and [{tBuAmDIPP}Ca(m-H)]2 (51) were found to catalyze the addition of ketones and aldehydes with HBPin.120 The catalytic activity (typical precatalyst loading 0.5–3.0 mol%, 10–300 min at −1 25  C; TOF ca. 10–600 molsubst mol−1 Ca h ) was heavily dependent upon the identity of the anion, and increased in the order − − − − I < B(C6F5)4 < N(SiMe3)2 < H . Calcium hydrides were supposed to be operating in the case of the best systems 50 and 51, assumed to involve a classical insertive pathway (Fig. 39). No enantioselectivity was mentioned in the case of prochiral substrates. Catalyst loading could be decreased to as low as 0.05 mol% for the hydroboration of cyclohexanone. Finally, it was shown the structurally characterized tris(pentafluorophenyl)hydroborate [{BDIDiPP}CaHB(C6F5)3
(thf )] (52) could catalyze the reductive hydroboration of CO2 to generate the methanol equivalent CH3OBPin, along with the by-product O(BPin)2.121 However, the reactions were extremely slow, required 10 mol% of precatalyst and 4 days at 60  C in thf to achieve full conversion. A multi-step mechanistic pathway was formulated (Fig. 40), and was supported by the isolation of several intermediates, notably a boryl formate HC(]O)OBPin and the bis(boryl)acetal CH2(OBPin)2.

11.05.4.4 Hydrosilylation catalysis A number of examples of alkaline-earth catalyzed hydrosilylation reactions, for the addition of hydrosilanes across CdC, CdO and CdN unsaturated bonds, have been described. Like hydroborations, Ae-mediated hydrosilylation reactions rely on polarized d+ Ae-Hd– hydridic species that will often evolve through a s-insertive pathway.

11.05.4.4.1

Hydrosilylation of alkenes

The group of Harder provided in 2006 the first example of calcium- and strontium-catalyzed hydrosilylation of alkenes, using diphenylethylene (a non-polymerizable substrate) and PhSiH2R (R ¼ H, Me, Ph) hydrosilanes as the benchmark substrates (Fig. 41). The reactions were catalyzed by the Ae-benzyls [Ae(DMAT)2
(thf )2] under mild conditions (0.5–2.5 mol% precatalyst, 25–50  C) and afforded quantitative conversions and excellent regioselectivity (Ae ¼ Ca, 53; Sr, 54; DMAT ¼ 2-dimethylamino-2-trimethylsilylbenzyl).122

Fig. 39 Alkaline-earth catalyzed hydroboration of ketones and aldehydes.

Fig. 40 Proposed mechanistic pathway for the Ca-catalyzed reductive hydroboration of CO2.

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Fig. 41 Alkaline-earth catalyzed hydrosilylation of C¼C bonds.]

In apolar solvents such as benzene, the branched Markovnikov product was formed with strict selectively (a regioselectivity that transition metals rarely enable), whereas in thf only the linear anti-Markovnikov product was generated. The strontium precatalyst 54 proved an order of magnitude more efficient that its calcium congener 53. Beyond diphenylethylene, conversion of a-methyl-styrene and styrene also returned the branched products. Notably, the hydrosilylation of styrene was extremely facile, proceeding at 25  C with 0.5 mol% of precatalyst, without detectable formation of polystyrene. The monosilylation of cyclohexa1,3-diene could be achieved selectively. The catalytically active species was deduced to be a series of hydride-rich clusters. The changing regioselectivity of the reaction with the nature of the solvent made it difficult to propose a mechanistic pathway with good confidence. Subsequent studies showed that the molecular hydride [{BDIDiPP}CaH
(thf )]2 (45) was an equally competent hydrosilylation precatalyst, yielding exclusively the Markovnikov product regardless of the solvent upon hydrosilylation of DPE with PhSiH3,123 while the calcium complexes 53 or [Ca{N(SiMe3)2}2
(thf )2] could be grafted onto dehydroxylated silica to generate heterogeneous catalysts that displayed the same selectivity as 53.124 The group of Okuda also reported on some pertinent alkene hydrosilylation catalysts. In 2012, they revealed that the cationic hydrido cluster of composition [{Me3TACD}3Ca3(m3-H)2][Ph3SiH2] (55), where {Me3TACD}− is a macrocyclic ligand derived from the polyamine 1,4,7-trimethyl-1,4,7,10-tetraazacyclododecane (aka {Me3TACD}H), effectively catalyzed the addition of Ph2SiH2 onto diphenylethylene at 25  C (18 h, 5 mol% precatalyst).125 Only the formation of the anti-Markovnikov addition product could be detected. Several years later, the Okuda group improved on their original results when they showed that the dinuclear hydrido dication [(Me4TACD)2Ca2(m-H)2(thf )][B(C6H3-3,5-Me2)4]2 (56) was a highly versatile and efficacious catalyst.126 It allowed for the functionalization of vinylarene and, remarkably, ethylene and non-activated a-olefins (Fig. 42). The overall suitability of the system was established in the hydrosilylation of ethylene (1 bar) with a variety of hydrosilanes, which proceeded under mild conditions (2.5 mol% precatalyst, 70  C, 15–60 min in thf-d8). The selectivity was poor with arylhydrosilanes due to a kinetically competitive process of aryl exchange, but in contrast, the selectivity was excellent with alkylhydrosilanes. Higher a-olefins such as 1-octene and 1-hexene were hydrosilylated at 70  C in 24 h at 70  C, to give the anti-Markovnikov products with good regioselectivity; depending on the stoichiometry and the hydrosilane, secondary or tertiary silanes were obtained, but no reaction occurred with the tertiary products or Et3SiH. Hydrosilylation did not occur for internal alkenes. The hydrosilylation of vinylarenes (styrene, a-methyl-styrene, diphenylethylene, cis- and trans-stilbene) also took place at 70  C (0.5–48 h) and returned the Markovnikov addition products; reactions were faster with arylsilanes than with alkylsilanes, but selectivity was in this case again limited by aryl scrambling. Overall, using nOctSiH3 as the benchmark hydrosilane, the following order of reactivity was evidenced: ethylene > styrene >1-octene. The mechanism was not fully ascertained. Yet, the gathered experimental data was consistent with a scenario where the cation [CaH]+ produced an alkyl calcium complex as the result of hydrometallation of the olefin, followed by s-bond metathesis with the incoming hydrosilane to yield the hydrosilylated product and regenerate the catalytically active cation [CaH]+. The nuclearity of the species responsible for catalytic turnovers was not determined. The calcium bis(silanide) [Ca(SiPh3)2
(thf )4] (57; 2.5 mol%) was also shown to catalyze the anti-Markovnikov addition of arylsilanes onto diphenylethylene and a-methyl-styrene.127 Reactions occurred slowly at 60–100  C in thf-d8 (2–62 h), with a rate dependence followed the trend PhSiH3 > Ph2SiH2 > Ph3SiH. Under the same experimental conditions, styrene was found to be polymerized while 1-octene did not react. A number or mechanistic proposals have been made to account for the varying regioselectivity of the alkaline-earth catalyzed hydrosilylation of olefins. They consider solvent effects, with polar solvent likely to encourage the formation of ionic species and

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Fig. 42 Hydrosilylation of alkenes catalyzed by the calcium cationic complex [(Me4TACD)2Ca2(m-H)2(thf )][B(C6H3-3,5-Me2)4]2 (56).

allow for the switch of regioselectivity observed with 53 in thf or benzene. The fact that cationic hydrides (56) and silanides (57) mediate the formation of opposite regioisomers in the hydrosilylation of a-substituted styrenes is an element in these proposals. However, the debate is still open, and the exact nature of the prevailing mechanisms remains unclear. The input of DFT calculations would undeniably be helpful in this ongoing discussion.

11.05.4.4.2

Hydrosilylation of ketones

The calcium-catalyzed hydrosilylation of ketones was reported in 2008. The Ca-hydride 45 and the dibenzyl 53 were shown to enable the addition of PhSiH3 onto benzophenone and enolizable ketones, e.g., acetone, acetophenone, cyclohexanone, dibenzylketone and 2-adamantone.128 Catalysis took place at 50  C in benzene, with 1.25 mol% precatalyst. Regardless of the ratio between substrates, the reactions consistently yielded the disiloxanes PhSiH(OR)2 as the result of the activation of two SidH bonds, indicating that the intermediate PhSiH2(OR), i.e., the product of monocoupling, was more reactive than the initial substrate PhSiH3. In contrast, the formation of the tricoupled product PhSi(OR)3 could barely be detected. Stoichiometric reactions between 45 and ketones were not selective towards the formation of a Ca-alkoxide, as a-deprotonation also systematically led to the formation of sizeable quantities of Ca-enolates. Yet, enolization hardly occurred under catalytic conditions. Although a Ca-mediated hydrosilylation “hydride” reaction manifold involving the addition of calcium hydride to the ketone could not be ruled out (Fig. 43), the overall excellent alkoxy/enolate ratio in the hydrosilylation products suggested a different route. Consistent with experimental observations and stoichiometric reactivity, an “ion pair” mechanism was proposed instead. It implicates a hypervalent five-coordinate silicon intermediate, and a concerted step where the hydride atom is transferred from

Fig. 43 Potential mechanisms for the calcium-catalyzed hydrosilylation of ketones.

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the silicon atom to the ketone (Fig. 43). The two rival mechanisms could potentially be intertwined, and possibly competing, through the occurrence of a hypervalent alkoxysilicate intermediate.

11.05.4.4.3

Hydrosilylation of imines

The Harder group reported the first example of alkaline-earth catalysis for the hydrosilylation of imines in 2019.129 The benzyl complexes 53 and 54 and the Ae-amides [Ae{N(SiMe3)2}2]2 (Ae ¼ Ca, Sr, Ba) were found to catalyze the addition of PhSiH3 onto eight different aldimines R1C(H)]N-R2 and one ketimine R1R2C]N-R3 (1–5 mol% precatalyst, C6D6, 25–60  C, 5 min to 24 h depending on substrate). The amides were less active than the benzyl complexes, and the activity increased with metal size according to Ca < Sr < Ba. The best system, utilizing precatalyst 54 (2.5 mol%), gave quantitative conversion within 5 min at room temperature. The fastest rates were measured for imines with N-alkyl and C-aryl substituents, as in PhC(H)]NtBu. Variation of substituents (H, Me, Cl, MeO) in the para position of the aromatic ring indicated adequate functional group tolerance. Kinetic rates with tBuC(H)]NtBu or PhC(H)]NPh were much lower. An insertive mechanism involving a catalytically active metal hydride was proposed (Fig. 44). The proposed mechanism was supported by stoichiometric reactions and by the successful isolation of reaction intermediates. It was corroborated by DFT computations based of the simple CaH2 model, which indicated a rate-limiting conversion of calcium-amide intermediate into the catalytically active hydride. In this scenario, a N-aryl group stabilizes the intermediate Ca-amide through resonance and reduces its nucleophilicity, thereby decreasing reaction rates. The hydrosilylation of pyridine, quinoline and isoquinoline is catalyzed but the calcium hydride 45 and by [Ca{N(SiMe3)2}2
(thf )2].130 High and selective conversion to the 1,2-dihydropyridine and 1,2-dihydroquinoline silanes was observed under mild conditions (5 mol% precatalyst, 25–60  C, 24 h in C6D6). Catalysis was possible due to the fact that the dearomatized product resulting from hydride reduction of pyridine through 1,2-insertion into the CadH bond of 45 was stable. Remarkably, the product of 1,4-reduction could not be detected. An insertive mechanism involving a Ca-hydride active species and a pentavalent hydrosilicate intermediate was invoked (Fig. 45).

11.05.5 Hydrogenation catalysis Despite traditionally being dominated by heterogeneous catalytic systems, homogeneous hydrogenation catalysis has evolved significantly over the past 60 years. Early work was centered on transition metal (TM) catalysts, such as Wilkinson’s catalyst [RhCl(PPh3)3], Schrock-type catalysts such as [Rh{norbornadiene}(PPh3)][PF6], and Crabtree’s [Ir{1,5-cyclooctadiene}(PCy3) (py)][PF6].131–133 The desire for catalytic hydrogenation without expensive transition metals initiated the development of a range of frustrated Lewis pairs and hydrogenation catalysts using earth-abundant metals. Although alkene hydrogenation based on TM catalysts indicated that d ! p back-bonding was essential for alkene activation, the development s-block metal hydrogenation catalysts has shown that this is not a strict requirement.

Fig. 44 Alkaline-earth catalyzed hydrosilylation of imines.

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Fig. 45 Calcium-catalyzed 1,2-selective hydrosilylation of pyridine and quinolines.

11.05.5.1 Hydrogenation of alkenes 11.05.5.1.1

Hydrogenation of activated alkenes

The first use of an alkaline-earth catalyst for the hydrogenation catalysis was that of Slaugh in 1967, who reported the partial hydrogenation of 1,3-pentadiene using [MgH2] in a heterogeneous system at high temperature and pressure (186  C, 900–1500 psi).134 Following up on the isolation of the soluble calcium-hydride [{BDIDiPP}CaH
(thf )] (45),19 the first mention of homogeneous alkene hydrogenation catalysis with large alkaline earths was reported in 2008, using activated alkenes as substrates.135 Complexes 45, [Ca(DMAT)2
(thf )2] (53) and [Sr(DMAT)2
(thf )2] (54) mediated the hydrogenation of styrene to ethylbenzene or DPE to diphenylethane at 20–60  C (Fig. 46). Although full conversions of styrene were achieved using either 45 or 53 after 15 h, up to 19% styrene oligomers were also formed, indicating that styrene polymerization was competitive with hydrogenation. A catalytic cycle involving Ae-hydrides active species was formulated; it was supported by characterization of the intermediates. In the case of 53 and 54, an off-cycle initiation step generates the hydride. It followed by a regiospecific s-bond metathesis generating the branched insertion product; hydride transfer occurs exclusively to the terminal carbon, due to the low stability of the alternatively generated primary alkyl species. The secondary alkyl intermediate then undergoes another s-bond-metathesis, giving the hydrogenated product and regenerating the hydride catalyst. In the case of styrene, higher H2 pressures accelerated the reaction, resulting in a lower percentage of oligomers from the competing styrene polymerization. The hydrogenation of myrcene catalyzed by 45 gave a mixture of three partially hydrogenated isomers. Only the conjugated double bonds were hydrogenated, indicating that the catalytic system was limited to activated alkenes.

11.05.5.1.2

Hydrogenation of unactivated alkenes

More than 10 years after the first isolation of 45, the thf-free calcium hydride complex, [{BDIDiPP}Ca(m-H)]2 (58) was unveiled.18 This complex was shown to be a significantly stronger Lewis acid than 45, capable of undergoing s-insertion with 1-hexene or ethylene to generate the corresponding alkyl-bridged dimers.136 Complex 58 is also able to catalyze the hydrogenation of unactivated alkenes with good conversions (Fig. 47). However, reaction conditions, and in particular temperature and solvent identity, had to be carefully controlled, due to the propensity for ligand-redistribution to the catalytically inactive bis-ligated species [{BDIDiPP}2Ca] and nucleophilic attack of the reaction solvent at higher temperatures. Under such mild conditions (10 mol% catalyst, C6D6, 25  C, 2 bar H2, 7–21 d), long reaction times and slow turnovers only were observed. Okuda’s calcium hydrides [{Me3TACD}3Ca3(m3-H)2][Ph3SiH2] (55), [(Me4TACD)2Ca2(m-H)3][SiPh3] (59) and [(Me4TACD)2Ca2(m-H)2][B(C6H4-4-tBu)4]2 (60) were utilized for the hydrogenation of alkenes.125,137,138 Although complex 55 was capable of hydrogenating DPE under very mild conditions (60  C, 1 bar), the reaction was slow, taking 13 days to reach full conversion with high precatalyst loading (19 mol%, Fig. 48). Complex 61, generated from 1 equivalent of 59 with DPE, was significantly faster in the hydrogenation of DPE, fully converting the substrate within 24 h at 60  C under a 1 bar pressure of H2,

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Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 46 Hydrogenation of DPE, styrene and myrcene catalyzed by [{BDIDiPP}CaH(thf )] (45), [Ca(DMAT)2(thf )2] (53) and [Sr(DMAT)2(thf )2] (54), with the proposed catalytic cycle.

Fig. 47 Hydrogenation of alkenes catalyzed by [{BDIDiPP}Ca(m-H)]2 (58).

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137

Fig. 48 Hydrogenation of alkenes catalyzed by (MexTACD)-supported calcium hydrides.

although the catalyst loading was not reported.137 The dicationic complex 60 was an even better catalyst, fully converting DPE to the corresponding alkane at 25  C within 6 h (1 bar H2).138 The difference in activity between MexTACD-supported complexes was attributed to their solubility, with the compounds bearing the neutral (Me4TACD) ligand (60 and 61) dissolving fully in thf, whereas 55, bearing the monoanionic (Me3TACD)− was only partly soluble. Crucially, complex 60 also showed good catalytic behavior towards unactivated alkenes, fully or partially hydrogenating 4-vinylcyclohex-1-ene, hexa-1,5-diene and trimethyl(vinyl) silane, although these substrates required slightly forcing conditions (5 mol% precatalyst, 60  C). It was assumed that the dipositive charge on the metal in 60 was key for the activation of the olefins, as the less electro-deficient calcium center in 61 led to poorer catalytic activity. As the nucleophilicity of the hydrides is lower in the dications, it feels legitimate to consider that electrophilic alkene activation prevails over hydride nucleophilicity in catalysis promoted by these systems. Hydrides of the heavier alkaline earths have also been used in hydrogenation catalysis. The first isolated heteroleptic barium hydride complex [{TpAd,iPr}Ba(m-H)]2 (62), reported by Cheng in 2017, catalyzed the hydrogenation of DPE under moderate conditions (2.5–5.0 mol% cat., 12 h, 6 bar H2) (Fig. 49).139,140 Changing the reaction solvent from benzene to thf increased the rate of the reaction, but also generated small amounts of 1,1,3,3-tetraphenylbutane, a product presumably formed upon insertion of a second equivalent of DPE occurs prior to the s-bond metathesis with H2 that regenerates the hydride catalytic species. In 2020, Cheng and co-workers also reported the hydrogenation of a range of activated and unactivated alkenes using a calcium precatalyst supported by the same heteroscorpionate ligand, [(TpAd,iPr)Ca(p-CH2C6H4Me)(thp)] (63).141 This complex fully converted a range of activated and unactivated alkenes under moderate temperature and pressure (40  C, 10 atm H2), including DPE, 1,2-diphenylethylene, Me3SiCH]CH2, 1-hexene, pent-4-en-1-ylbenzene, and even cyclohexene and norbornene with longer reaction times. The precatalyst also hydrogenated reluctant substrates such as internal alkenes, achieving 90% conversion of 2-octene to octane after 72 h (Fig. 49).141 The heteroleptic Ae-hydrido complexes [(CpAr)Ae(m-H)(S)]2 bearing a sterically demanding cyclopentadienyl ligand (Ae ¼ Ca, 64; Sr, 65; Ba, 66; {CpAr}− ¼ {(3,5-iPrC6H3)5C5}−; S ¼ thf or dabco) have also been used to catalyze the hydrogenation of DPE with H2 under mild conditions (Fig. 49).142 Hydrogenation rates were found to increase with metal size (Ca < Sr < Ba). The barium catalyst 66 could fully hydrogenate 1,1,2-triphenylethylene under mild conditions with a 5 mol% catalyst loading, and could even partially hydrogenate 1,1,2,2-tetraphenylethylene after 24 h.142 1-Hexene was fully converted to hexane within 10 h by both 65 and 66.

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Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 49 Selected data for alkene hydrogenation with Cheng’s heteroleptic calcium, strontium and barium hydrido catalysts.

The extreme steric bulk of the ancillary ligands in complexes 62 and 66 highlight the amount of kinetic stabilization required to suppress ligand redistribution of barium complexes in solution. To alleviate the issue of ligand scrambling, Harder and co-workers reported in 2018 the efficient hydrogenation of a range of substrates using the simple amides [Ae{N(SiMe3)2}2]2 as precatalysts.143 Activity increased with metal size, although all of the catalysts converted activated alkenes within 30 min at 120  C (H2 ¼ 6 bar). Interestingly, if thf was added to the reaction medium, catalytic activity ceased, regardless of the precatalyst used. This contrasts with heteroleptic precatalysts such as 62 and 65 and alkyl precatalysts such as 53 and 54, which displayed faster conversion when thf was used instead of benzene as the reaction solvent. Another positive feature of the [Ae{N(SiMe3)2}2]2 catalytic systems was that in the case of styrene, competing polymerization of the substrate was not observed at all, indicating that the rate of s-bond metathesis between H2 and the Ae-alkyl species generated during the catalytic cycle was significantly faster than the competing insertion of another molecule of styrene (see Fig. 46). Hydrogenolysis of the metal amide precursor was presumed to produce the Ae-hydrido catalytically active species, with a mechanistic pathway implicating a s-insertion of the coordinated olefin into the Ae-to-H bond. Although hydrogenolysis of the resulting Ae-alkyl intermediate regenerates in one step the active species, the suggestion was made that the Ae-alkyl species could be protonated by the stoichiometric equivalent of Brønsted acidic HN(SiMe3)2 (pKa ¼ 25.8, pKa of H2  49) liberated in the reaction medium during catalyst initiation.144,145 This protonation regenerates the precatalyst [Ae {N(SiMe3)2}2]2, which can then undergo another hydrogenolysis with H2 to re-enter the catalytic manifold (Fig. 50).

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Fig. 50 Alkene hydrogenation catalyzed by [Ae{N(SiMe3)2}2]2 complexes.

When excess amine was added to the reaction medium, conversion was slowed significantly. This was rationalized as the consequence of shifting the equilibrium back towards the homoleptic complex [Ae{N(SiMe3)2}2]2, thus decreasing the amount of the presumed catalytic species, thought to be an aggregated [{N(SiMe3)2}Ae(H)]n species, in solution. Several such multimetallic species have been isolated.146 The most active precatalyst, [Ba{N(SiMe3)2}2]2, was capable of fully converting a range of vinylarenes within an hour (6 bar H2, 120  C) including para-methoxy-styrene, DPE, a-methyl-styrene and 1,2-diphenylethylene. 1,1,2-Triphenylethylene and tetraphenylethylene were not used as substrates, so direct comparison cannot be made with the heteroleptic Ba-hydrides 62 and 66. Unlike 60 and 63, [Ba{N(SiMe3)2}2]2 could only partially hydrogenate 1-hexene, due to competing isomerization to 2-hexene, which itself could not be hydrogenated. However, [Ba{N(SiMe3)2}2]2 could hydrogenate other relatively unactivated alkenes such as Me3SiCH]CH2 (30 min), norbornene (10 h), and norbornadiene (24 h, although a distribution of three products was obtained). These results considered collectively demonstrate that there is no universal best hydrogenation catalyst, and that different catalysts may be suitable for different substrates. The Harder group further elaborated on alkene hydrogenation by using the bulkier ligand systems [Ae{N(SiiPr3)2}2] (67–69) and [Ae{N(SiiPr3)(DiPP)}2] (70–72).147,148 The catalytic activity increased from Ca to Ba, while the [Ae{N(SiiPr3)2}2] precatalysts outperformed their [Ae{N(SiiPr3)(DiPP)}2] relatives. Notably, complexes 67–69 were capable of partially hydrogenating aromatic ring systems such as anthracene, naphthalene and even benzene (Fig. 51). Complexes 67–69 all hydrogenated 1-hexene under moderate conditions (6 bar H2, 120  C), with no observable isomerization to 2-hexene. In contrast, precatalysts 70–72 gave mixtures of hexane and 2-hexene. Dimerization of SiMe3CH]CH2 and a-methylstyrene when using the most active catalyst, 69, was an issue. The authors suggested dimerization resulted from the significantly slower rate of amine deprotonation in the reaction manifold, as HN(SiiPr3)2 is less acidic than HN(SiMe3)2 (see Fig. 50), making a second insertion more rate competitive. Dimerization could be avoided by lowering the reaction temperature, but this also entailed longer reaction times to reach full conversions. A range of internal alkenes including cyclohexene, 4-vinylcyclohex-1-ene and 3-hexene were all fully hydrogenated by 69 (Fig. 51).

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Fig. 51 Selected data for the hydrogenation of alkenes catalyzed by 67–72.

In 2021, Harder reported the hydrogenation of both activated and unactivated alkenes using “activated” metallic barium (i.e., Ba0) deposited as a thin film under high vacuum.149 The thin-film vapor deposition was deemed to be an essential part of the catalyst synthesis, as various other attempts to activate metallic barium, such as dissolution in liquid ammonia, the use of freshly cut barium under an inert atmosphere, or the direct use of [BaH2]n dried under high vacuum (200  C, 1  10−2 mbar) all resulted in species that were completely inactive in alkene hydrogenation. Two different catalytic cycles were for the hydrogenation with Ba0 were proposed. The first, based on a metal hydride system, uses BaH2 as the catalytic species, formed from the oxidative addition of Ba0 with H2 (Fig. 52A). Alkene insertion into the BadH bond followed by hydrogenolysis regenerates the catalyst. The second,

Fig. 52 Possible catalytic pathways for the hydrogenation of alkenes using activated Ba0.

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based on a Ba0 catalytic species, implicates oxidative addition with the substrate, followed by sequential s-bond metathesis steps and reductive elimination to regenerate Ba0 (Fig. 52B). The reductive elimination of H2 from [BaH2] starts occurring at 330  C. However, it has been shown that a decrease of particle size decreases this onset temperature, which has been reported down to 100  C.150–152 Mercury poisoning experiments provided some evidence that a heterogeneous reaction mechanism was in play. It was also suggested that the true catalytic system could be a composite of these two mechanisms, i.e., a system where alkenes are activated by Ba0 to allow s-bond metathesis with a [BaH2] catalyst. The catalytic pathway was probed by DFT calculations, which hinted at a catalytic manifold where Ba0 activates the substrate (benzene) into a boat conformation with partial Ba2+-1,3-cyclohexadiene2− character. Although the computations were only indicative of a possible catalytic pathway due to the difficulties associated with heterogenous reaction mechanisms, the data suggested a clear accelerating effect for hydrogenation with Ba0 compared to hydrogenation with [BaH2] as the sole species. A broad range of substrates were investigated, including acetylenes, unactivated internal alkenes such as 3-hexene, 4-vinylcyclohex-1-ene and 1,1,2,2-tetraphenylethylene. All were fully hydrogenated using moderate conditions (12 bar H2, 120  C, 10 mol% catalyst) (Fig. 53). Under more forcing conditions (50 bar H2, 140–150  C) a range of aromatic substrates including benzene, pyridine and isoquinoline could be hydrogenated within 96 h. The ability of the Ba0 system to hydrogenate heteroatom-containing substrates contrasts with the aforementioned [Ba{N(SiiPr3)2}2] (69) which failed to hydrogenate them, likely due to deleterious coordination of the substrates onto the Lewis-acidic metal center that inhibited catalytic turnover. Although the activation of H2 is the common hydride source in most alkaline-earth mediated hydrogenation reactions, it is not the only available source. Transfer hydrogenation of alkenes using 1,4-cyclohexadiene (1,4-CHD) as the H source has also been reported (Fig. 54).153 Although transfer-hydrogenation is not as atom efficient as conventional H2 hydrogenation due to the formation of a tandem coproduct, the ability to avoid high-pressure gas setups can be desirable both for safety reasons and for some sensitive substrates, where harsher reaction conditions may lead to undesirable reaction pathways. The alkene transfer hydrogenation was reliant on catalyst choice. Hence, the Ae amides [Ae{N(SiMe3)2}2]2 successfully hydrogenated a range of vinylarenes under mild conditions, whereas the calcium alkyl [Ca(DMAT)2(thf )2] (53) generated only polystyrene, and the heteroleptic precatalyst [{BDIDiPP}CaN(SiMe3)2] (73) gave a mixture of the two products The best catalysts for the transfer hydrogenation were therefore found to be [Ae{N(SiMe3)2}2]2, for which activity increased with metal size. A range of activated vinylarenes were hydrogenated, including DPE, 1,2-DPE, Me3SiCH]CH2 and 2,3,4,5-tetrahydro-1,10 -biphenyl. Poorly activated alkenes such as cyclohexene and 4-vinylcyclohex-1-ene were only partially hydrogenated under moderate conditions (120  C, 24 h, 5 equivalents of CHD) with the most active system, [Ba{N(SiMe3)2}2]2. The catalytic pathway for the hydrogenation of styrene with [Ca{N(SiMe3)2}2]2 was investigated by DFT. The result indicated initial deprotonation of CHD by the amide precatalyst, generating what the authors described as a labile hydride Meisenheimer complex. Hydride transfer to the metal in this Meisenheimer intermediate generates a heteroleptic calcium hydride, that then undergoes an insertion reaction with styrene to generate a metal-alkyl species (Fig. 54). In the final step, protonolysis with the fleeting amine HN(SiMe3)2 reconstructs the homoleptic amido precursor. The energy barrier for the polymerization of styrene was calculated to be 4.3 kcal mol−1 higher than the protonolysis with HN(SiMe3)2, indicating that polymerization may only take place when HN(SiMe3)2 is not present in solution.

Fig. 53 Selected results for the Ba0-catalyzed hydrogenation of unactivated alkenes.

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Fig. 54 Alkaline-earth catalyzed transfer hydrogenation of activated and unactivated alkenes.

11.05.5.2 Hydrogenation of imines The hydrogenation of imines using the heteroleptic alkaline-earth precatalysts [Ae{N(SiMe3)2}2]2 was demonstrated in 2018.154 The results were said to be unexpected, as in the proposed catalytic cycle (Fig. 55), the final s-bond metathesis step between the product of imine insertion and H2 was deemed to be very unfavorable. This was due to the metal-amide intermediate being a significantly weaker Brønsted base relative to the metal-alkyl species seen in olefin hydrogenation. As such, it is conceivable to envisage a catalytic cycle where similarly to the aforementioned hydrogenation of alkenes using [Ae{N(SiMe3)2}2]2, the small amount of protonated HN(SiMe3)2 present in the reaction mixture is deprotonated by the metal-amide insertion product. However, against this hypothesis, when the precatalyst was changed from [Ae{N(SiMe3)2}2]2 to the alkyl complex [Ca(DMAT)2(thf )2] (53)

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Fig. 55 Proposed catalytic cycle for the alkaline-earth catalyzed hydrogenation of imines.

which generates the poorly acidic alkane {DMAT}-H after initial protonolysis, catalytic imine hydrogenation was fast and quantitative conversions were observed. The reaction rates of the precatalysts increased with metal size (Ca < Sr < Ba). Unexpectedly, the bis-thf adduct [Ba{N(SiMe3)2}2(thf )2] showed greater activity than its unsolvated congener [Ba{N(SiMe3)2}2]2. Nonetheless, when the reaction solvent was changed from benzene to thf, conversion was inhibited, most likely because of saturation of the coordination sphere by thf molecules. Substrate scope was limited to aldimines; however, a range of various alkyl and aryl substitutions were possible. DFT calculations on imine hydrogenation were also completed, in which three different catalytic pathways were investigated: a classical Ae-hydride catalytic cycle, a route involving a bifunctional catalyst, and a last scenario which avoided the formation of a high energy metal-hydride intermediate. It emerged from the theoretical study that the conventional Ae-hydride mechanism was the likely prevailing mechanism. The turnover-limiting step was identified as the deprotonation of H2 (Fig. 55). In 2020, the hydrogenation of imines using alkaline-earth alanates was described.155 The homoleptic alkaline-earth complexes [Ca{AlH4}2(thf )4]2 (74), [Sr{AlH4}2(thf )5] (75) and the heteroleptic complex [{BDIDiPP}Ca(AlH4)(thf )2] (76) were all characterized in solution and in the solid-state by single-crystal X-ray diffraction. They displayed either H3Al-(m-H)-Ae or/and H2Al(m-H)2-Ae bridging motifs in the solid state (Fig. 56). The complexes were all competent catalysts in the hydrogenation of imines. As per the earlier hydrogenation of imines, the activity of the catalyst increased with metal size. The heteroleptic complex 76 seemed to display improved activity compared to 74 and 75. Only a limited range of substrates were investigated. However, these did include a ketimine, signifying an improvement of scope on the earlier reported imine hydrogenation catalyzed by [Ae {N(SiMe3)2}2]2.154 The number of catalytic turnovers increased with temperature. The pressure of dihydrogen only slightly effected the catalysis, as lowering it to 1 bar only resulted in a slight loss of conversion. In a subsequent extension of the scope of alkaline-earth catalyzed imine hydrogenation, the aforementioned Ba0 catalytic system (see Fig. 52) also proved excellent for imine (and pyridine) hydrogenation,149 fully converting aldimines and ketimines to the corresponding amines with molar loadings up to 10% under moderate conditions (12 bar H2, 120  C; Fig. 56).

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Fig. 56 Imine hydrogenation catalyzed by alkaline-earth alanates and by the Ba0 catalytic system.

11.05.6 Dehydrocoupling catalysis Catalyzed dehydrocoupling reactions allows for the formation of EdE0 bonds between two main group elements from E-H and E0 -H substrates. The reactions are clean, and proceed through the loss of dihydrogen which makes them entropically favorable. Homodehydrocouplings are these reactions which enable the formation of apolar EdE bonds, i.e., E ¼ E0 such as in the coupling of silanes or stannanes. The more diverse and widespread heterodehydrocouplings build a polarized EdE0 bond between two different elements, and have attracted considerable attention in recent years. The coupling of ditopic substrates that contain two EdH/E0 dH bonds is particularly attractive, as it allows for the construction of polymers through dehydropolymerisations. The polarization of d+ EdHd− and d−E0 dHd+ bonds (hydridic and protic substrates, respectively) is often critical in catalyzed heterodehydrocoupling reactions, as it heavily weighs on the nature of the mechanisms at work in the pertaining catalytic cycles leading to the creation of d+ EdEd− bonds. The feasibility of a specific coupling also relies on the specific thermodynamics of the reaction, as the net energy gain upon creation of EdE0 and HdH bonds must outweigh the energy required to break the EdH and E0 dH bonds. It can be anticipated using bond dissociation energies (BDE), with the formation of H2 already releasing a substantial 104 kcal mol−1. Alkaline-earth complexes have not been used to mediate homodehydrocoupling reactions. On the other hand, they have proved particularly competent precatalysts for the controlled formation of NdB, NdSi and SidO bonds (Fig. 57).

11.05.6.1 Dehydrocoupling of amines and boranes The coupling of amines and boranes that generates dimeric aminoboranes and borazines (respective BDE: N-H, 81 kcal mol−1; B-H: 83 kcal mol−1; B-N, 90 kcal mol−1) has attracted substantial attention, triggered by the fact that ammonia borane H3N-BH3 (19.6 wt % H-content) is a potential material for the storage of dihydrogen.156 With group 2 metals, catalysis for the dehydrocoupling of amines and boranes has essentially focused on magnesium and calcium; surprisingly, strontium and barium have seldom been looked at. The Harder group investigated in 2008 the decomposition of the calcium amidoborane [{BDIDiPP}CaNH2BH3(thf )2] as a preliminary step towards the development of hydrogen-storage materials (Fig. 58).157 This initial studies was followed by other stoichiometric and subcatalytic reactions.158,159 On the whole, the complexes [{BDIDiPP}CaN(H)RBH3(thf )n] (n ¼ 1–2; R ¼ H, 77; Me, 78; iPr, 79) thermally decomposed to afford B-N coupling and concomitant loss of H2. This process yielded the dinuclear complexes [({BDIDiPP}Ca(thf ))2{RN-BH-NR-BH3}] bridged by the dianion {RN-BH-NR-BH3}2−. Thermal decomposition required increasing temperature as the steric bulk around the nitrogen atom became greater. Using the sterically demanding [{BDIDiPP}CaN(H)DiPPBH3(thf )] (80), the monomeric borylamide [{BDIDiPP}Ca{NDiPPdBH2}(thf )] incorporating the monoanionic fragment {H2B]NDiPP}− was isolated.

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Fig. 57 Generic representation of homo- and heterodehydrocoupling reactions.

Fig. 58 Synthesis and thermal decomposition of calcium amidoboranes.

11.05.6.1.1

Synthesis of asymmetrical diaminoboranes

The calcium bis(amide) [Ca{N(SiMe3)2}2]2 (2.5 mol%) was shown to catalyze the formation of asymmetrical diaminoboranes by selective heterodehydrocoupling of amines HNR1R2 and amine-boranes H3B-N(H)R3R4 (Fig. 59).160 The reaction was generally selective and ensued via successive couplings. The chemoselectivity was governed by the relative difference of Lewis basicity between the two amines. Asymmetrical diaminoboranes were obtained when one of the amines was clearly more basic than the other, as otherwise mixtures of symmetrical and asymmetrical products were generated as a result of an off-cycle equilibrium between HNR1R2 + H3B-N(H)R3R4 and HNR3R4 + H3B-N(H)R1R2. A multi-step catalytic manifold relying on a calcium-hydride active species was proposed. Postulating that the Lewis basicity of HNR1R2 is lower than that of HNR3R4, the Ca-hydride first reacts with the amine-borane H3B-N(H)R3R4 through aminolysis to generate a metallated amido borane. This transient species then expulses the intermediate aminoborane H2B]NR3R4 through a b-hydride elimination, a process which also regenerates the hydrido active species. At this stage, the metal-hydride enters a second cycle where it reacts in a protonolysis reaction with the more (Lewis) acidic amine HNR1R2 to yield the amido Ca-NR1R2. This intermediate then intercepts the floating H2B]NR3R4 to produce a metal-bound diamidoborate, which releases the final diaminoboranes through b-hydride elimination.

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Fig. 59 Calcium-earth catalyzed synthesis of diaminoboranes and proposed reaction manifold.

11.05.6.1.2

Dehydrocoupling of dimethylamine-borane and tert-butylamine-borane

The catalyzed dehydrocoupling of dimethylamine-borane Me2NH-BH3 has been attracting attention both as a dihydrogen storage material and as a field of debated mechanistic investigations. A number of metal-based systems are known to mediate the formation of the cyclic dimer c-(Me2NBH2)2 with minimal formation of the bis(dimethylamino)borane by-product, (Me2N)2BH. In a contribution focusing mostly on the related magnesium chemistry, Hill reported that treatment of the calcium complex 1 with Me2NH-BH3 afforded [{BDIDiPP}Ca{NMe2BH3}∙(thf )] (81). This thermally stable complex was characterized by X-ray diffraction analysis and NMR spectroscopy in C6D6.161 Heating a solution of 81 for 4 h at 80  C in C6D6 led to the formation of small quantities of the unsaturated Me2N]BH2 along with the calcium hydride 45. The authors suggested that 81 was prone to a thermally induced b-hydride elimination/intramolecular s-bond metathesis process. Following this discovery, it was found that both 1 and [Ca{CH(SiMe3)2}2(thf )2] reacted with Me2NH-BH3 to afford the dimer c-(Me2NBH2)2 under catalytic conditions. The experimental observations (in particular spectroscopic detection of H2B]NMe2) and distribution of products were reminiscent of those made for related magnesium catalysts. Both systems were postulated to follow a similar mechanistic pathway involving successive b- and d-hydride elimination and insertion steps (Fig. 60); the magnesium system was more active than its thermally-triggered calcium counterpart.

Fig. 60 Initial mechanistic proposal for the calcium-catalyzed dehydrocoupling of Me2NH-BH3.

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A DFT investigation of the coupling of dimethylamine-borane by 81 suggested instead that due to the large size of the Ca2+ cation (in contrast with magnesium), the relative instability of the calcium-hydride intermediate precluded the thermally-induced d-hydride elimination.162 The authors proposed instead an alternative concerted proton-assisted pathway, where an incoming dimethylamine-borane molecule enables the formation of the cyclic product without recourse to a putative calcium-hydride. In this mechanism, the additional Me2NH-BH3 molecule displaces thf from 81 (a mandatory step as thf was found to inhibit catalytic turnovers), and intermolecular elimination of H2 occurs by interaction of the N-H proton of the dimethylamine-borane molecule and a b-hydride of the ligated amidoborane. This results in the release of the aminoborane Me2N]BH2 while the thf-free amidoborane catalyst is regenerated. Coordination of another molecule of dimethylamine-borane restarts the catalytic cycle. Hill and co-workers then re-explored their original mechanism, and showed that the reaction of 81 with Me2NH-BH3 led to the formation of [{BDIDiPP}Ca{Me2N-BH2-NMe2-BH3}] through loss of dihydrogen.163 The same reaction with deuterated Me2ND-BH3 and Me2NH-BD3 indicated that the formation of this complex proceeded in both cases with a non-negligible KIE (1.4 and 1.6, respectively). Consistent with these findings, Hill proposed a refined dimethylamine-borane assisted mechanism involving solely 81 and [{BDIDiPP}Ca{Me2N-BH2-NMe2-BH3}] as the metallated catalyst and intermediate, respectively (Fig. 61). The b- and d-elimination steps inducing the formation of the cyclic dimer c-(Me2NBH2)2 were both suggested to take place through NH-assisted release of H2 and without participation of any Ca-hydride or aminoborane Me2N]BH2 species. In a separate investigation, the Hill group also reported on the stoichiometric and catalytic reactivity of the calcium amide 1 with tert-butylamine-borane, tBuNH2-BH3.164 Catalysis towards the formation of the trisubstituted borazine occurred very slowly (20% conversion after 138 h at 60  C in toluene, 5 mol% precatalyst), and was accompanied by significant catalyst decomposition resulting in the formation of the catalytically inactive [Ca(BH4)2]n. Product distribution was poorly controlled, as the formation of by-products in substantial amounts was detected (Fig. 62). The formation of borazine was assumed to be the outcome of ring-expansion from the spectroscopically detected dimer c-(tBuN(H)BH2)2. Although some of the experimental observations were similar to those for the coupling of dimethylamine-borane, a clear mechanistic pathway accounting for the formation of the borazine and the different by-products could not be formulated.

11.05.6.1.3

Dehydrocoupling of amines and boranes

Early work by Hill and co-workers showed that the calcium amide [{BDIDiPP}CaNPh2(thf )] (82) reacted stoichiometrically with the 9-BBN dimer in toluene at 25  C to give cleanly the isolated calcium borohydride 83 along with formation of an aminoborane (Fig. 63).165 The same group exploited this knowledge to investigate the alkaline-earth catalyzed coupling of amines and monohydroboranes.166 A range of primary/secondary amines and anilines along with 9-BBN and pinacolborane were selected as typical substrates (Fig. 63), and 1 was used as the precatalyst (10 mol%). Conversion to the corresponding aminoboranes and aminodi(borane)s took place under mild conditions (25–60  C in C6D6). The weaker Lewis acid HBPin was found to give noticeably higher reaction rates (generally less than 1 h) than 9-BBN (ca. 12–144 h). With primary amines R’NH2, monocoupling to R2B-NHR0 was selectively achieved during equimolar reactions with both 9-BBN and HBPin. However, with a twofold excess of the borane, catalytic production of the aminodi(borane)s R’N(BR2)2 could only be achieved for aliphatic amines and with HBPin, and required extended reaction times (ca. 24 h). For these catalyzed dehydrocoupling reactions, the calcium precatalyst 1 proved inferior to its magnesium congener, and the ensuing detailed study focused solely on the smaller metal. The mechanism of the calcium-promoted catalysis was not ascertained, and there is no evidence that the convincing mechanistic scenario established for magnesium could be confidently extrapolated to calcium.

Fig. 61 Proton-assisted mechanism for the calcium-catalyzed dehydrocoupling of dimethylamine-borane and formation of c-(Me2NBH2)2.

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Fig. 62 Calcium-catalyzed dehydrocoupling of BuNH2-BH3.

Fig. 63 Calcium catalyzed dehydrocoupling of amines and boranes.

11.05.6.2 Heterodehydrocoupling of amines and silanes The construction of NdSi bonds through the atom-efficient catalyzed dehydrocoupling of primary or secondary amines with hydrosilanes yields silazanes. These compounds are routinely employed as ligands in in coordination chemistry,167 as bases,168 silylating agents169 or protecting groups for amines, indoles and anilines, making their clean synthesis a desirable synthetic aim.170 In addition, oligo- and polysilazanes are used as precursors to Si3N4 ceramics.171 Alkaline-earth catalysis has proved particularly effective in the selective dehydrocouplings of hydrosilanes with amines, hydrazines or ammonia. In the past decade, a detailed exploration of substrate scope and operating mechanism in the formation of mono- or disilazanes has paved the way for more ambitious applications in the area of polymer synthesis.

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Catalyzed NH/HSi heterodehydrocouplings for the formation of mono- and disilazanes

A small number of well-defined alkaline-earth precatalysts have been utilized to mediate the dehydrocoupling of amines with silanes, leading to a range of products with high reaction rates and selectivity. The reaction outcome is heavily influenced by steric and electronic factors, but can be orientated favorably with the choice of an adequate precatalyst (Fig. 64). Chemoselectivity, i.e., the ability to direct and control the number of created NdSi bonds starting with substrates containing more than one Si-H or one N-H, was a key factor in the efforts paid to extend substrate scope. 11.05.6.2.1.1 Catalyst selection and substrate scope Harder first mentioned in 2007 that the calcium dibenzyl 53 and the solvated azametallacyclopropane [Ca(Z2-Ph2CNPh)(hmpa)] (84) could be used as competent precatalysts for the coupling of primary and secondary amines with the tertiary silane Ph3SiH.172 The reactions proceeded smoothly at 20  C in thf, with 3–10 mol% of precatalyst. Although substrate scope was limited, it appeared that alkylamines were more reactive than anilines, even if the introduction of cumbersome tertiary alkyl substituents led to a decrease of reaction rates. A small selection of Ca, Sr and Ba precatalysts that included the amido and alkyl complexes [Ae {E(SiMe3)2}2(thf )2] (E ¼ N, CH), and [Ae{N(SiMe3)2}2]2 as well as the Ae-iminoanilides 7–9 and 10–12 were subsequently reported by the groups of Hill173 and Sarazin174,175 to successfully allow for the coupling of a broad suite of substrates. Although the benchmark substrates for the evaluation of catalyst performance were pyrrolidine and triphenylsilane, substrate scope was extended to a very large selection of amines and hydrosilanes (Fig. 65). Catalysis generally occurred in the temperature range 25–60  C in C6D6, and quantitative conversions were observed typically within 1–2 h using 5 mol% precatalyst. Simple silanes like PhSiH3, Ph2SiH2 and PhSiH3 were found to be very easily coupled with primary and secondary amines, e.g., EtNH2, HNCy2, BnNH2, pyrrolidine, piperidine, tBuNH2 and DiPPNH2. The coupling of a,o-dihydrosilanes or a,o-diamines was also shown to be possible. Importantly, the chemoselectivity of the reactions was excellent in the cases of primary amines and primary or secondary silanes, that is, the number of NdSi bonds created during the catalytic process could be adjusted and controlled by appropriate choice of the ratio between the two substrates. The reactions were fast and the catalysts were highly active; in these cases where chemoselectivity was sought, judicious choice of the precatalyst to favor selectivity over reaction rates was a key factor, e.g., by preferring the Ba-amide 9 over the more active Ba-alkyl 12. Several main conclusions emerged from catalyst and substrate screening by Hill and Sarazin.173–175 Regarding the substrates, reactions rates were reduced with increasing substitution of the amine or the silane; in particular, Ph3SiH was significantly less reactive than Ph2SiH2 and PhSiH3. The reaction kinetics were found to increase for more nucleophilic amines (alkylamines > anilines), whereas the reactions were faster when the silane was more electrophilic. Several trends for catalyst selection were also reported. Regardless of the identity of the supporting ligands in a homologous series of Ae precatalysts, the catalytic activity increases in the order Ca < Sr < Ba; the Ba precatalysts afforded unmatched TOF values that could be in excess of 3600 molsubst −1 mol−1 Ba h . The bis-amido complexes [Ae{E(SiMe3)2}2(thf )2] (E ¼ N, CH) and [Ae{N(SiMe3)2}2]2 were more effective than their heteroleptic counterparts 9 and 12. Uncharacteristically, the presence of coordinated thf molecules in the bis-amido precatalysts [Ae {N(SiMe3)2}2(thf )2] did not influence the overall catalytic efficiency, as they were found to be equally competent as their unsolvated congeners [Ae{N(SiMe3)2}2]2. Moreover, the alkyl complexes were tangibly more efficient than their amido analogs, an observation rationalized by the fact that the formation of the catalytically active species by aminolysis is irreversible with the former while it is an equilibrium for the latter. It resulted from this screening that the barium alkyl [Ba{CH(SiMe3)2}2(thf )2], a compound reasonably easy to synthesize under crystalline form,176 was the precatalyst of choice for the heterodehydrocoupling of amines and silanes. The NHC-supported calcium bis(alkyl) complex [Ca{CH(SiMe3)2}2(IiPr2Me2)2] (85), where IiPr2Me2 is the N-heterocyclic carbene 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene, displayed high activity and excellent chemoselectivity in the catalyzed coupling reactions of hindered amines and silanes, including with tBuNH2 and DiPPNH2, which were earlier found to be among the least reactive substrates.177 The authors also achieved the moderately enantioselective coupling of (Naph)(Ph)SiH2 and BnNH2 (ee up to 26%) by combining a chiral NHC ligand and the calcium bis(alkyl) precursor. These results further highlighted the close relationship between metal size and catalytic performance in Ae-promoted dehydrocoupling reactions. Taken collectively,173–176 the experimental observations suggested that the overall efficiency (both in terms of reaction rates and selectivity) was a composite of two key factors: accessibility of the metal center, and reactivity (often linked to the strength) of the pertaining polarized Ae-to-heteroelement bonds.

Fig. 64 Alkaline-earth catalyzed NH/HSi heterodehydrocoupling.

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Fig. 65 Selected data for the barium-catalyzed heterodehydrocoupling of amines with silanes.

11.05.6.2.1.2 Mechanistic insight The mechanism of Ae-mediated amine-silane dehydrocoupling was probed by kinetic and computational analyzes. Hill showed that the kinetic rate laws given in Eqs. (4) and (5) for the coupling of Et2NH and Ph2SiH2 catalyzed by the solvent-free [Ae {N(SiMe3)2}2]2 (Ae ¼ Ca or Sr) unexpectedly depended on the identity of the metal.173

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Rate ¼ kCa ½Ca1 ½Et2 NH1 ½Ph2 SiH2 0

(4)

Rate ¼ kSr ½Sr2 ½Et2 NH1 ½Ph2 SiH2 1

(5)

The partial kinetic order of 1 in [catalyst] suggested a monometallic active species in the turnover-limiting step, while for strontium, the partial order of 2 was seen as the expression of a dinuclear active species. Dimerization for strontium was rationalized as being the outcome of its greater size and resulting affinity for higher coordination numbers, often with bridging ligands. Unexpectedly in the light of other comprehensive data,174,175,178,179 the strontium precursor was less active than its calcium analog, which was hypothesized to be the outcome of this dimerization process. The zero-order dependence in [Ph2SiH2] agreed with a rate-determining aminolysis step in the case of calcium. With strontium, the first-order dependence in both [Et2NH] and [Ph2SiH2] was said to be consistent with a concerted, proton-assisted b-hydride transfer. The mechanisms of the dehydrocoupling of pyrrolidine and Ph3SiH catalyzed by 9 was probed in detail by Sarazin and co-workers by combination of synthetic, kinetic and computational investigations.174,175 The substrates and precatalyst were selected to enable convenient monitoring of kinetics by NMR spectroscopy. The catalytically active species was inferred to consist of an iminoanilide-supported Ae-pyrrolide. This working hypothesis agreed with the fact the bis(silanide) precursors [Ae(SiPh3)2(thf )3] were found to be inactive, whereas the performances of pre-isolated Sr-iminoanilide [{N^N}Sr{N(CH2)4} (NH(CH2)4)] (where {N^N}− ¼ {DiPPN(o-C6H4)C(H)]NDiPP}−) matched those of 8. Kinetic analysis allowed for the determination of the kinetic rate law given in Eq. (6): Rate ¼ k ½91 ½pyrrolidine0 ½Ph3 SiH1

(6)

By contrast with other systems, the kinetic rate law with 9 is independent from the concentration in amine. Hammett analysis was performed on the coupling of pyrrolidine with para-substituted triarylsilanes Ph2(p-X-C6H4)SiH substrates, with X chosen among Me, OMe, F and CF3. Electron-withdrawing p-substituents were found to increase substantially the reaction rate (r ¼ 2.0), suggesting they helped stabilize an incipient negative charge in the transition state. Kinetic measurements with Si-deuterated silane and N-deuterated pyrrolidine indicated a maximal kinetic isotopic effect with the silane (kSiH/kSiD ¼ 4.7), whereas none was found for the amine (kNH/kND ¼ 1.0). Both the kinetic rate law and KIE pointed at a rate-limiting step involving SidH bond breaking and without direct participation of pyrrolidine. The activation parameters DH{ ¼ 15.6(23) kcal mol−1 and DS{ ¼ −13.3(7.5) cal mol−1 K−1 (DG{ ¼ 19.6(1) kcal mol−1 at 298 K) were estimated by Eyring analysis. The negative value of DS{, diagnostic of an associative mechanism, was much smaller than those mentioned for the bis(amido) Ca and Sr precatalysts.173 This was thought to be the consequence of the larger radius of the Ba2+ cation, leading to a less constrained arrangement about the metal in the turnover-limiting step. A detailed computational analysis for the cross-dehydrocoupling of pyrrolidine and Ph3SiH catalyzed by 9 was performed to determine the prevailing mechanistic pathway (Fig. 66). A s-bond breaking metathesis route was found to be energetically non-competitive. Instead, the DFT analysis provided compelling evidence that the coupling progressed via a stepwise mechanism involving first NdSi bond forming through nucleophilic attack of the catalytically competent Ba-pyrrolide onto the incoming silane, followed by rate-limiting b-hydride elimination liberating the silazane. The Ba-hydride intermediate formed then further reacts with pyrrolidine to regenerate the Ba-pyrrolide upon dehydrogenative aminolysis. The proposed catalytic manifold was fully consistent with the experimental observations and with the kinetic analysis. The potential involvement of a Ba-silanide was shown to be energetically prohibited, consistent with the observation that [Ae]–SiPh3 precursors did not show any catalytic ability. The experimentally-determined reactivity trend Ca < Sr < Ba was rationalized by DFT calculations as the outcome of the greater accessibility of the metal center and decreasing Ae-Npyrrolide bond strength upon descending group 2.

11.05.6.2.2

Formation of cyclic disilazanes

The chemoselectivity observed in the alkaline-earth catalyzed formation of regular silazanes allowed for the multi-step synthesis of tailor-made disilazanes and cyclic disilazanes through iterative dehydrocoupling steps (Fig. 67).178 Starting from Ph3SiH, the barium precatalyst [Ba{CH(SiMe3)2}2(thf )2] was used to produce Ph3SiN(Bn)SiPh2NHBn by a smooth succession of quantitative and fully chemoselective NH/HSi dehydrocouplings between BnNH2 and Ph3SiH or Ph2SiH2 (20–60  C, 0.25–1.0 mol% precatalyst, 1–2 h). Substrate scope was extended to other silanes, e.g., Ph2(p-CF3-C6H4)SiH, and to different amines, notably 2,4,6-Me3-C6H2-CH2NH2 and 1,4-(CH2NH2)2C6H4. Further attempts at chain extension by dehydrocoupling of Ph2SiH2 with Ph3SiN(Bn)SiPh2NHBn failed. It afforded instead the cyclic disilazane c-(Ph2Si-NBn)2 following a very unusual cyclisation process and concomitant elimination of C6H6; the gradual and quantitative formation of benzene could be visualized by NMR spectroscopy. Identification of c-(Ph2Si-NBn)2 was confirmed by X-ray diffraction analysis (all synthetic intermediates were also analyzed by XRD and by NMR spectroscopy) and by independent barium-catalyzed dehydrocoupling of Ph2SiH2 with the diaminosilane Ph2Si(NHBn)2. The selective elimination of trifluoromethylbenzene was favored over that of benzene when Ph2(p-CF3-C6H4)SiH was used as the starting material hinted at a mechanism involving a silicate intermediate, where the negative charge was stabilized by the electron-withdrawing group in para position of the aromatic ring. The pertaining mechanism for the cyclisation of Ph3SiN(Bn)SiPh2NHBn under catalytic conditions was delineated by a comprehensive combination of experimental and DFT investigations. Stoichiometric treatment of [Ba{CH(SiMe3)2}2(thf )2] with Ph3SiN(Bn)SiPh2NHBn afforded the reactive [Ba{N(Bn)SiPh2N(Bn)SiPh3}2], which was authenticated by NMR in C6D6. From this point, in a stepwise process, intramolecular nucleophilic attack of the metal-bound N-amide atom onto the terminal silicon atom was proposed to generate a five-coordinate silicate (Fig. 68). This step is followed by a rate-determining C6H5-transfer

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Fig. 66 Prevailing mechanistic pathway for the alkaline-earth catalyzed dehydrocoupling of amines and silanes, with [{N^N}AeN(CH2)4] (Ae ¼ Ca, Sr, Ba) as the catalytically active species and triphenylsilane and pyrrolidine substrates; {N^N}− ¼ {DiPPN(o-C6H4)C(H)¼DiPP}–.] Modified from Bellini, C.; Carpentier, J.-F.; Tobisch, S.; Sarazin, Y. Barium-Mediated Cross-Dehydrocoupling of Hydrosilanes with Amines: A Theoretical and Experimental Approach, Angew. Chem. Int. Ed. 2015, 54, 7679–7683.

to barium, which assembles the cyclic product c-(Ph2Si-NBn)2 and produces a [Ba]–Ph intermediate. The catalytic manifold is completed by aminolysis of this transient barium species to regenerate [Ba]-N(Bn)SiPh2N(Bn)SiPh3. DFT computations revealed that the irreversible production of c-(Ph2Si-NBn)2 through this stepwise pathway, traversing a pentavalent silicate transition state, was much more kinetically affordable (DG{ ¼ 26.2 kcal mol−1) than an alternative, kinetically prohibited s-metathesis pathway (DG{ ¼ 48.2 kcal mol−1).

11.05.6.2.3

Catalyzed NH/HSi dehydropolymerizations

The well-understood barium dehydrocoupling precatalyst [Ba{CH(SiMe3)2}2(thf )2] also proved very effective for the controlled production of polycarbosilazanes from difunctional amines and silanes.179 The rapid and controlled syntheses of either linear or cyclic polymers by dehydropolymerization of p-xylylenediamine (1,4-(CH2NH2)2-C6H4) and Ph2SiH2 were achieved within 10–60 min at 25–60  C with 1 mol% precatalyst (Fig. 69). The estimated molecular weights of the resulting polycarbosilazanes ranged between 1000 and 10,000 g mol−1, depending on the initial NH/HSi feed ratio. The experimental number-average degree of polymerization agreed with its theoretical value calculated using Carothers’ equation.180 Analysis of these polymers by 1H, 29Si and 13 C NMR spectroscopy showed that exclusive formation of cyclic polymers was achieved during reactions performed with

Calcium, Strontium and Barium Complexes in Organic Synthesis

153

Fig. 67 Barium-catalyzed synthesis of the cyclodisilazane c-(Ph2Si-NBn)2.

equimolar amounts of Ph2SiH2 and p-xylylenediamine, whereas linear materials were selectively obtained with excellent control of the chain-end when one of the comonomers was used in excess. The mechanism of the iterated catalytic event leading to the creation of multiple NdSi bonds along the macromolecules was inferred to be similar to that described for the coupling of amines with silanes (see Fig. 66). However, it was not specified whether monomer diffusion and potentially impeded access to the metal center impacted the overall polymerization kinetics. In a further development, Hill and Manners used [Ba{N(SiMe3)2}2(thf )2] to catalyze the synthesis of ferrocenecontaining polycarbosilazanes.181 The barium precursor catalyzed the coupling of the hydrosilane [CpFe(CpSiPhH2)] with 1,4-(CH2NH2)2C6H4 to give polycarbosilazanes with dangling ferrocene groups (Fig. 70). Well-defined polycarbosilazanes with ferrocene contained within the polymer backbone were prepared by dehydrocoupling of [Fe(Cp(SiPhH2))2] and [Fe(Cp(SiMe2H))2] with 1,4-(H(Me)-NCH2)2C6H4 and 1,4-(CH2NH2)2C6H4, respectively. The materials were subjected to electrochemical studies and proved to be promising precursors to magnetic iron-containing ceramics. This dehydrocoupling strategy could also be applied to the synthesis of monomeric Fe-containing silanes with by mono- and decoupling BnNH2, e.g., for the preparation of [CpFe{CpSiPhN(H)Bn}2] and related compounds.

11.05.6.3 Other alkaline-earth catalyzed heterodehydrocouplings Beyond the dehydrocouplings of amine-boranes and amines with silanes, the two sets of reactions which have attracted the lion’s share of the attention, alkaline-earth complexes have demonstrated their ability to catalyze several other heterodehydrocoupling reactions, displaying a unique combination of high selectivity and rates. The atom-efficient creation of SidO bonds has been particularly scrutinized, as polysiloxanes are main materials, with the extremely robust SidOdSi unit resulting in excellent thermal and chemical stability.

11.05.6.3.1

Dehydrocouplings of silanes and alcohols

The compounds [Ae{N(SiMe3)2}2(thf )2] and [Ae{CH(SiMe3)2}2(thf )2] (Ae ¼ Ca, Sr, Ba) were found to be convenient precatalysts for the dehydrocoupling of silanes and alcohols (HexOH, nBuOH, iPrOH, tBuOH, DiPPOH, Ph3COH; Fig. 71).182 Primary, secondary, and tertiary alcohols were efficiently coupled to PhSiH3 or Ph2SiH2. The catalyzed reactions were typically performed in C6D6, using 0.5–5.0 mol% precatalyst in the temperature range 25–60  C. As commonly encountered for the coupling of amines and silanes,174,175 turnover frequencies increased very substantially with metal size (Ca < Sr < Ba). Chemoselectivity enabled the construction of mono-, di- or tri-substituted silylethers, depending on reaction conditions. Tertiary silanes were less reactive, requiring barium precatalysts. The ferrocenylsilylether [CpFe(C5H4SiPh(OBn)2] was obtained upon coupling of ferrocenylsilane [CpFe(C5H4SiPhH2)] with benzyl alcohol. Stoichiometric experiments were consistent with the participation of Ae-alkoxide and Ae-hydride species to the reaction manifold. Mechanistic experiments suggested a complex manifold with dimeric or possibly polynuclear active species. Kinetics depended on the identities and concentrations of the precatalyst and of each substrate. In the coupling of tBuOH and PhSiH2, [Ba{N(SiMe3)2}2(thf )2] was found by kinetic analysis to display an apparent first-order dependence in both [silane] and [alcohol]. In a way recalling the syntheses of ferrocene-containing polycarbosilazanes,181 barium catalysis allowed for the synthesis of poly- and oligosilylethers that

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Fig. 68 Proposed mechanism for the barium-catalyzed ring-closure of Ph3SiN(Bn)SiPh2NHBn.

Fig. 69 Barium-catalyzed dehydropolymerization of 1,4-(CH2NH2)2C6H4 and Ph2SiH2, yielding cyclic or linear polycarbosilazanes.

Calcium, Strontium and Barium Complexes in Organic Synthesis

Fig. 70 Barium-catalyzed syntheses of selected ferrocene-containing polycarbosilazanes by dehydrocoupling of amines and silanes.

Fig. 71 Alkaline-earth catalyzed dehydrocoupling of silanes and alcohols towards the synthesis of ferrocene-containing polysilylethers.

155

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Calcium, Strontium and Barium Complexes in Organic Synthesis

contained ferrocenes either as dangling groups or within the main chain. The molecular weight of the macromolecules reached over 20,000 g mol−1. Cyclic voltammetry investigations showed the iron centers displayed reversible redox behavior. Thermal analysis indicated these materials constituted viable precursors to magnetic ceramic materials.

11.05.6.3.2

Dehydrocouplings of silanes and borinic acids

The alkaline-earth boryloxides [Ae(OBR2)2(thf )x] and [AeN(SiMe3)2(OBR2)(thf )x] can be conveniently synthesized for Ae ¼ Ca, Sr, Ba upon reaction of [Ae{N(SiMe3)2}2(thf )2] and [Ae{CH(SiMe3)2}2(thf )2] with borinic acids R2BOH upon appropriate adjustment of the stoichiometry.183 The syntheses were limited to using boronic acids with sterically demanding substituents on the boron atom (e.g., R ¼ CH(SiMe3)3, 2,4,6-iPr3-C6H2, 2,4,6-(CF3)3-C6H2), presumably so that the metal center in these low coordinate Ae complexes is sufficiently shielded. The coupling of the hindered borinic acid {(Me3Si)2CH}2BOH and silanes was competently catalyzed by the amides [Ae{N(SiMe3)2}2(thf )x] (Ae ¼ Ca, Sr, Ba; x ¼ 0 or 2), or by the barium boryloxides [Ba(OB {CH(SiMe3)2}2)2(thf )x] with x ¼ 0 (86, a two-coordinate monomer with loose intra- and intermolecular Ba⋯ HdC interactions in the solid-state) or 2 (87), and by [Ba{m-N(SiMe3)2}(OB{CH(SiMe3)2}2)]2 (88).184,185 Catalysis occurred smoothly at 60  C in C6D6, with 1–2 mol% precatalyst (Fig. 72). For a homologous suite of precursors, reaction rates increased with metal size, Ca < Sr < Ba. Substrate scope could be extended to para-substituted phenylsilane, butylsilane and tris(isopropoxy)silane. However, no turnover occurred with Ph2SiH2 or with less encumbered borinic acids, thus limiting somewhat the scope of the reaction. The coupling of {2,4,6-(CF3)3-C6H2}2BOH and (2,4,6-iPr3-C6H2)2BOH with PhSiH3 using the most active barium precatalysts required more forcing conditions ([SiH]0/[BOH]0/[Ba]0 ¼ 10:10:1, 24 h, 60  C), and only reached moderate conversions. Regardless of precatalyst selection, reaction conditions and initial borinic acid-to-silane ratio, excellent chemoselectivity towards the production of the secondary products PhSi(H)2OB{CH(SiMe3)2}2, PhSi(H)2OB(2,4,6-iPr3-C6H2)2 and PhSi(H)2OB{2,4,6-(CF3)3-C6H2}2 was achieved, without detectable formation of tertiary or quaternary silanes. No conclusive explanation was provided to account for the greater reactivity of {(Me3Si)2CH}2BOH with respect to (2,4,6-iPr3-C6H2)2BOH and {2,4,6-(CF3)3-C6H2}2BOH. It was tentatively proposed to reflect greater nucleophilicity of the O atoms in {(Me3Si)2CH}2BOH/{(Me3Si)2CH}2BO− than in the aromatic substrates. Another possibility was that the boryloxides (2,4,6-iPr3-C6H2)2BO− and {2,4,6-(CF3)3-C6H2}2BO− that were shown to induce multiple stabilizing Ba⋯FdC and Ba⋯C(p) secondary interactions in the molecular solid-state,183 entailed the formation of barium species of limited reactivity in the reaction manifold.

Fig. 72 Alkaline-earth catalyzed dehydrocoupling of PhSiH3 and borinic acids.

Calcium, Strontium and Barium Complexes in Organic Synthesis

157

The barium-catalyzed coupling of PhSiH3 with {(Me3Si)2CH}2BOH was kinetically investigated. The apparent rate constants measured in C6D6 for [Ba{N(SiMe3)2}2(thf )2] and 86–87 were commensurate, suggesting that a bis(boryloxide) was the likely active species in the catalytic cycle. Kinetic analysis for [Ba{N(SiMe3)2}2(thf )2] and 88 provided the rate laws given in Eqs. (7) and (8), respectively, showing zero-order dependence in [borinic acid] and first-order dependence in [PhSiH3].   (7) Rate ¼ k BafNðSiMe3 2 g2  ðthf Þ2 2 ½borinic acid 0 ½PhSiH3 1 Rate ¼ k‘½881 ½borinic acid 0 ½PhSiH3 1

(8)

The unusual second-order in [precatalyst] for the monomeric [Ba{N(SiMe3)2}2(thf )2] implicated dimerization of a metallic species to produce a bimetallic transition state in the rate-limiting step. This working hypothesis was corroborated by first-order dependence in [88], a precatalyst that exists as an amide-bridged dimer. It was also supported by an initial DFT study which showed that any Ba-amide or Ba-boryloxide precatalyst was very likely to eventually dimerize as [Ba(OB{CH(SiMe3)2}2)2]2 (862) in the presence of excess borinic acid. Eyring analysis showed the reaction is kinetically facile, i.e., DG{ ¼ 16.4(5) kcal mol−1 at 25  C with the precatalyst [Ba{N(SiMe3)2}2(thf )2]. Hammett analysis showed the inclusion of electron-withdrawing groups in para-substituted arylsilanes p-X-C6H4-SiH3 in the coupling with {(Me3Si)2CH}2BOH catalyzed by [Ba{N(SiMe3)2}2(thf )x] was beneficial to reaction rates (r ¼ 2.03(9)), consistent with a mechanism involving the accumulation of a negative charge on the silicon atom in the turnover-limiting step. The prevailing mechanism for barium catalysis was determined by DFT calculations. Complex 862 was referred to as the zero-point energy for the mechanistic pathway depicted in Fig. 73. The proposed catalytic cycle starts with the nucleophilic attack of one of the oxygen atoms of on PhSiH3. The resulting intermediate presents a negatively charged

Fig. 73 Mechanistic pathway for the barium-catalyzed coupling of {(Me3Si)2CH}2BOH with PhSiH3. Modified from Le Coz, E.; Zhang, Z.; Roisnel, T.; Cavallo, L.; Falivene, L.; Carpentier, J.-F.; Sarazin, Y.: Barium-Catalysed Dehydrocoupling of Hydrosilanes and Borinic Acids: A Mechanistic Insight, Chem. Eur. J. 2020, 26, 3535–3544.

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pentasilicate and evolves readily to a more stable intermediate through replacement of the bridging oxygen with the Si-H moiety. This step is required to facilitate the following H-transfer affording a bridged Ba-hydride with release of PhSi(H)2OB{CH (SiMe3)2}2. Protonolysis of the Ba-hydride intermediate with an additional {(Me3Si)2CH}2BOH that coordinates to barium promotes the release of H2 and regenerates the dimeric catalyst. Overall, the proposed dominant stepwise pathway was found to be kinetically ruled by the initial nucleophilic attack of barium boryloxide onto the incoming silane, and was in full agreement with all experimental observations.

11.05.6.3.3

Dehydrocouplings of silanes and silanols

Metal-based catalysts, and a fortiori alkaline-earth ones, have seldom been implemented in the controlled production of siloxanes, despite the commercial importance of oligo- and polysiloxanes. Asymmetric R3Si-O-SiR0 3 siloxanes can be prepared by conventional condensations involving a silanol (with a base) or a metal silanolate and a halosilane R3SiX, but these protocols have low atom efficiency, often generating large amounts of by-products. The homoleptic barium amide [Ba{N(SiMe3)2}2]2 and the well-defined dimeric siloxides [Ba2{m-OSi(SiMe3)3}3{OSi(SiMe3)3}] (89) and [Ba{m-OSi(SiMe3)3}{N(SiMe3)2}]2 (90) were shown to promote the formation of asymmetric siloxanes R3Si-O-SiR0 3 through the first reported case of main group metal-mediated, atom-efficient dehydrocoupling of silanols and hydrosilanes (Fig. 74).186 The formation of Ph2(H)SiOSi(SiMe3)3 upon coupling of Ph2SiH2 with (Me3Si)3SiOH took place within 4 h with 2 mol% precatalyst in C6D6, generally at 30  C. PhSiH3 was dehydrocoupled with similar efficacy to tBu3SiOH to return PhSi(H)2OSitBu3. The coupling of (p-X-C6H4) SiH3 (X ¼ MeO, Me, H, F) with (Me3Si)3SiOH was quantitative and chemoselective; traces of (p-X-C6H4)H3−nSi{OSi(SiMe3)3}n (n ¼ 2 or 3) could not be detected. In addition, when using PhSiH3, the mono-coupled Ph(H)2SiOSi(SiMe3)3 was still the only product regardless of reaction conditions and substrate ratio. The reactivity of the hydrosilanes overall decreased with increasing substitution: ArSiH3 > Ar2SiH2 > nBuSiH3 > > Ar3SiH, Et2SiH2, Et3SiH. Couplings with Ph3SiOH were more sluggish and less selective than those starting from (Me3Si)3SiOH and tBu3SiOH. All homoleptic Ae-amides [Ae{N(SiMe3)2}2]2 were found to catalyze the benchmark coupling of Ph2SiH2 and (Me3Si)3SiOH, and kinetic analysis indicated that the rates increased when descending group 2, Ca < Sr < Ba. The reaction kinetics were zero-order in [(Me3Si)3SiOH] and first-order in [Ph2SiH2] The dependence in [catalyst] could not be ascertained, likely due to the observed catalyst inhibition by the silanol. Hammett analysis showed that the rates increased with electron-withdrawing groups in para position of the aryl-substituted (p-X-C6H4)SiH3 (X ¼ MeO < Me < H < F). The available kinetic data agreed with a mechanism involving nucleophilic attack of the Ba-bound O-siloxide atom onto the hydrosilane in a scenario recalling that seen in the barium-catalyzed formation of silazanes174,175 and borasiloxanes,184,185 but no reaction manifold was conjectured in the absence of supporting computational analysis.

11.05.6.3.4

Dehydrogenative silylation of activated CdH bonds

Alkynylsilanes can be synthesized by stoichiometric reactions between metal alkynides and chlorosilanes. However, an atom-efficient halogen-free and metal-poor route is more desirable. The Harder group showed the dehydrogenative silylation of 1-hexyne with Ph3SiH was catalyzed by the azametallacyclopropane [Ca(Z2-Ph2CNPh)(hmpa)] (84).172 The product nBu-C^C-SiPh3 could be isolated in yields over 80% after 17 h (thf, 20  C). However, despite quantitative conversions, the coupling with secondary silane PhMeSiH2 systematically returned a mixture of mono- and dialkynylated silanes, that is, nBu-C^C-Si(H)PhMe and (nBu-C^C)2SiPhMe, respectively. Cheng and co-workers have confirmed the calcium-catalyzed regioselective C-H silylation of a wide range of alkoxy-substituted benzene derivatives (e.g., anisoles, Fig. 75) with primary hydrosilanes.187 This dehydrogenative, atom-efficient process affords silyl-substituted aromatic ethers without recourse of a hydrogen acceptor. The reactions were mediated by the calcium benzyl [(TpAd,iPr)Ca(p-CH2C6H4Me)(thp)] (63; TpAd,iPr ¼ hydrotris(3-adamantyl-5-isopropylpyrazolyl)borate). Good functional group tolerance was evidenced through detailed examination of the substrate scope. The silylation of anisole derivatives without

Fig. 74 Barium-catalyzed dehydrocoupling of silanols and silane towards the formation of asymmetric siloxanes.

Calcium, Strontium and Barium Complexes in Organic Synthesis

159

Fig. 75 Calcium-catalyzed dehydrogenative C-H silylation of substituted anisoles.

ortho-substituent exclusively occurred at the ortho-sp2 CdH bond, yielding the pertaining ortho-silylated anisoles. With 2-methylanisole, silylation occurred solely on one of the benzylic sp3 CdH bonds. The products of di- or tricoupling at silicon were not detected. Complexes such as the isolated and structurally characterized [(TpAd,iPr)Ca(o-MeO-m-Br-C6H3)] and [(TpAd,iPr)Ca(o-Me-OCH2C6H4)] were proposed as likely intermediates in the catalytic manifold. The catalytic silylation of o-deuterated 4-methyl-anisole with HexSiH3 indicated a strong kinetic isotope effect (kH/kD ¼ 2.45), suggesting CdH bond breaking occurred in the rate-limiting step. A path involving pre-coordination of the anisole onto the known calcium hydride [(TpAd,iPr)CaH(thp)] was hypothesized, but it was not supported by further experimental of theoretical data.

11.05.7 Miscellaneous catalyzed reactions with reactive [Ae]-X (pre)catalysts A number of pertinent alkaline-earth catalyzed reactions that are mechanistically different from those described in the preceding sections have been reported. These are collated here and discussed in the light of the available mechanistic information, where possible in link with related Ae-mediated catalyzed elementary steps or more complex processes.

11.05.7.1 Dimerization of aldehydes—Tishchenko reaction Hill and co-workers reported in 2007 on the alkaline-earth catalyzed Tishchenko reaction, i.e., the dimerization of aromatic and aliphatic aldehydes into the corresponding carboxylic esters (Fig. 76).188 Catalyst activity decreased with increasing metal size in the series [Ae{N(SiMe3)2}2]2 (Ba < Sr < Ca), with calcium providing the highest turnovers (1–5 mol% precatalyst, C6D6, 20  C). The catalyzed process involved hydride transfer between two molecules of the substrate. The quenching of the dimerization with

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Fig. 76 Alkaline-earth catalyzed Tishchenko dimerization of aldehydes, with proposed mechanism.

benzaldehyde in its early stage indicated the formation of a calcium-alkoxide intermediate, assumed to be generated through Meerwein-Ponndorf-Verley reduction of the aldehyde along with concomitant release of a stoichiometric equivalent of benzamide. Once formed, the Ae-alkoxide was thought to react with a second aldehyde via insertion into the AedO bond, thus generating a metallated acetal derivative. This intermediate further reacted with an additional molecule of aldehyde in six-center concerted step to produce the final ester product and regenerate the Ae-alkoxide active species.

11.05.7.2 Trimerization of isocyanates The Harder group demonstrated that the congested calcium methanediide 91 catalyzed the cyclotrimerization of isocyanates to isocyanurates (Fig. 77).189 The conversion of phenyl isocyanate was facile (1 mol% precatalyst, 3 h at 20  C in thf-d8) although the reaction was very sluggish for cyclohexyl isocyanate (5 mol% precatalyst, 50  C, 1 week). The poor reactivity of the latter substrate allowed for the isolation of the double insertion product 92, which was not stable in solution. It instead decomposed to give the mono insertion product and release an equivalent of cyclohexyl isocyanate, which was then found to trimerize to the isocyanurate.

11.05.7.3 Alkylation reactions 11.05.7.3.1

Dimerization of terminal alkynes

Further elaborating on their initial observation that a side-on (p-type) electrostatic interaction in asymmetric b-diketiminato calcium-acetylide dimers allowed for an effective dissipation of negative charge over both acetylide carbon centers,190 Hill revealed

Fig. 77 Calcium-catalyzed trimerization of isocyanates.

Calcium, Strontium and Barium Complexes in Organic Synthesis

161

Fig. 78 Alkaline-earth catalyzed dimerization of donor-functionalized terminal alkynes.

that the precursors [Ae{E(SiMe3)2}2(thf )2] (Ae ¼ Ca, Sr; E ¼ N, CH) and complexes 1 and 3 mediated the head-to-head dimerization of ether-functionalized terminal alkynes.191,192 Reactions were limited to a single turnover with the homoleptic complexes, but the heteroleptic 1 and 3 enabled for catalytic dimerization (5 mol% precatalyst in toluene/thf mixtures, 48–72 h at 100  C). Propargyl ethers and amines were dimerized to a mixture of E and Z isomers of 2,3,4-hexatriene (Fig. 78). By contrast, for aryl- and silyl-substituted acetylenes, mixtures of the thermodynamically favored (E) and (Z)-enynes were obtained, although the reactions required more drastic conditions. For ether- or amine-functionalized acetylenes, the selectivity towards the hexatrienes was imputed to the presence of the donor group. Coordination of the heteroatom to the metal center reduced repulsion between the two a-carbanions, and encouraged an intramolecular proton transfer from the propargylic carbon atom to the hexatriene with concomitant intermolecular deprotonation of two O-coordinated acetylenic substrates. This concerted process was corroborated by experiments run with deuterated acetylenes, where deuterium transfer to the terminal methylene unit in the product was detected (Fig. 78).

11.05.7.3.2

Alkylation of aromatic rings

In a groundbreaking contribution, the Hill group demonstrated that the unsolvated dimeric calcium-hydride [{BDIDiPP} Ca(m-H)]2 (58) reacted at 25  C with n-alkenes to generate well-defined calcium alkyls.18 These complexes further reacted quantitatively at 60  C with protio or deuterio benzene through nucleophilic substitution of an aromatic CdD/H bond to give the n-alkyl benzenes (e.g., ethyl-, nbutyl- and nhexylbenzene) and return a calcium deuteride dimer (Fig. 79). A single alkylation of the aromatic ring was observed, while a second alkylation step giving di(n-alkyl) benzene derivatives was not mentioned. Alkylation of n-alkyl benzene is almost certainly kinetically prohibited with respect to benzene, due to the presence of the n-alkyl substituent that will disfavor nucleophilic substitution through destabilization of the corresponding Meisenheimer intermediate. Density functional theory calculations highlighted a Meisenheimer complex in the CdH activation transition state. Although the process

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Fig. 79 Formation of n-alkyl benzenes by reaction of a calcium/strontium n-alkyls and benzene. The product is formed by nucleophilic substitution traversing a Meisenheimer intermediate.

was essentially stoichiometric, regeneration of the starting 58 upon release of the n-alkyl benzenes suggested that it held the potential to be transformed into a catalytic reaction in the presence of excess n-alkenes. In a further development, Harder later showed that the same reactivity could be extended to the solvent-free strontium hydride [{BDIDiPeP}Sr(m-H)]2 (93), using the highly congested b-diketiminato ligand {BDIDiPeP}, where DiPeP is the particularly bulky 2,6-diisopentylphenyl substituent.193

11.05.7.3.3

Alkylation of alkylpyridines

The dinuclear calcium hydride 45 was shown to react with 2,6-lutidine in thf to yield the calcium alkyl 94 through selective dehydrogenative C-H activation (Fig. 80).194 The observed stoichiometric benzylic C-H activation was elaborated into a catalytic functionalization of 2,6-lutidine and other 2,6-disubstituted pyridine derivatives. Coupling with vinylarenes, conjugated dienes and non-activated alkenes (including internal ones, e.g., norbornene) catalyzed by 45 took place to create CdC bonds and afford alkylated pyridines. Although the reactions required forcing conditions (5 mol% precatalyst 4, 120  C in toluene, 12–72 h), good selectivity was observed, and the products of double benzylic alkylation were not detected. Reaction with ethyl-substituted pyridines showed that alkylation selectively occurred once in a position. Hammett analysis confirmed that reaction rates increased significantly with electron-withdrawing groups in para position of substituted styrene (r ¼ 4.53). Complex 94 displayed the same overall catalytic performance as 45, showing that it was a likely intermediate in the corresponding catalytic cycle. A strong kinetic isotope effect was observed when 2,6-(CD3)2-pyridine was employed (kH/kD ¼ 4.96), hinting that CdH bond activation was a key component in the rate-determining step. A mechanism was proposed, where insertion of the C]C unsaturation into the CadC bond of 94 was thought to assemble into a metallacycle. This intermediate is protonolyzed with another 2,6-lutidine molecule to form the alkylation product and regenerate the catalyst. For aromatic olefins, 2,1-insertion was assumed to stabilize of the calcium center through favorable Ca. . .C(p) interactions, affording the linear anti-Markovnikov alkylation product. Conversely, 1,2-insertion forming the branched Markovnikov products was said to be preferred for aliphatic olefins in order to minimize steric repulsion with the metal.

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Fig. 80 Calcium-catalyzed alkylation of 2,6-lutidine with alkenes, with the proposed mechanism.

11.05.7.4 Catalyzed H/D exchange Deuterium or tritium-labeled compounds find widespread use throughout many scientific disciplines, though are primarily used for NMR spectroscopy, kinetic studies and as molecular markers in chemistry, biology and physics.195,196 The development of high-performance mass-spectrometry (MS) and liquid chromatography-mass spectrometry (LC-MS) techniques has further increased demand for deuterated molecules. The introduction of deuterium into organic molecules is generally achieved in two ways. The first, classical synthesis from commercially available deuterated compounds can be synthetically challenging, as well as time- and resource-consuming. The second, hydrogen-deuterium exchange/hydrogen-isotope exchange (HIE), is normally carried out directly on the non-deuterated target molecule, potentially saving considerable time and effort from a synthetic standpoint, as well as significantly increasing atom efficiency. Traditional catalytic approaches to HIE have required transition metal catalysts, often based on precious metals, and require harsh reaction conditions that often give poor selectivity.197 Recently, a range of direct HIE reactions using alkaline-earth hydrides have been reported for the aryl and alkyl substrates. In 2017, the HIE between the calcium hydride [(Me4TACD)2Ca2(m-H)2][B(C6H4-4-tBu)4]2 (60) and D2 was described, catalytically generating HD from an equal molar mixture of H2 and D2.138 The reaction reached the equilibrium point within 5 min at 25  C with a 5% molar loading of 60. Alternatively, when 60 was treated with pure HD under the same conditions, statistical amounts of H2 and D2 were observable by NMR spectroscopy. The HIE of the strontium hydride [(Me3TACD)3Sr3H2][SiPh3] (95) with D2 was also reported.198 Treatment of 95 with D2 generated the deuterated derivative 95-D2. The HIE was proposed to proceed via a multi-step mechanism involving a hypervalent silicate (Fig. 81), in which the cation initially reacts with D2 to generate an unstable neutral strontium hydride/deuteride and DSiPh3. The unstable intermediate subsequently rearranges via hydride/deuteride transfer to generate another cationic hydride cluster with a hypervalent silicate counterion. This species is also unstable, and undergoes reductive elimination to either generate a benzene species PhHxD1−x or hydrogen species HxD2−x and the corresponding cationic Sr cluster. This process continues, to generate the cation [(Me3TACD)3SrD2]+ and various phenylsilanide anions. The proposed mechanism was supported by attached DFT calculations.

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Fig. 81 Proposed mechanism for deuteration and anion degradation of [(Me3TACD)3Sr3H2][SiPh3] in the presence of H2/D2.

HIE between the strontium hydride complex [{BDIDiPeP}Sr(m-H)]2 (93) and deuterated benzene upon heating to 60  C was also demonstrated (Fig. 82).193 When the same complex was exposed to D2 (1.5 bar), the deuterated compound 93-D2 and HD were generated within 2 h at 20  C, with no evidence of complex decomposition. Indeed, when 93 was used catalytically (5 mol%, 60  C, 1.5 bar D2) in benzene, benzene was converted to C6H5D with a 12% yield after 5 days. This assumed only mono-deuteration took place, a hypothesis made as distinguishing C6H5D from other deuterated benzenes by 2H NMR spectroscopy proved difficult. The mechanism for the exchange was suggested to occur via nucleophilic aromatic substitution between an activated benzene molecule and the hydride complex, generating a Meisenheimer-type cyclohexadienyl anion (Fig. 82).

Fig. 82 Hydrogen-isotope exchange reactions with the strontium hydride [{BDIDiPeP}Sr(m-H)]2 (93). DiPeP ¼ 2,6-diisopentylphenyl.

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Fig. 83 Hydrogen-isotope exchange between protio or deuterio benzene with H2 or D2 using alkaline-earth amide precatalysts.

Harder extended this work in 2020, reporting the catalytic HIE of a range of aromatic complexes using the homoleptic alkaline earth amide complexes [Ae{N(SiMe3)2}2]2, [Ae{N(SiiPr3)2}2] (67–69) and [Ae{N(SiiPr3)(DiPP)}2] (70–72) as (pre)catalysts (Fig. 83).199 Reaction rates increased according to Ca < Sr < Ba, an observation rationalized by the greater ionic character and weaker AedN bonding in the heavier Ae complexes. The catalytic activity of [Ba{N(SiiPr3)2}2] (69) was also superior to that of [Ba{N(SiiPr3)(DiPP)}2] (72) and [Ba{N(SiMe3)2}2]2, which was ascribed to the increased steric bulk of the {N(SiiPr3)2}2}− ligand, thus generating smaller and more active aggregates of the presumed true catalytic species [{SiiPr3)2N}Ba(H)]. The chosen deuterium source for the catalysis was C6D6, to allow for in situ reaction monitoring. The conditions for the HIE were found to be extremely important, as under harsher conditions (140  C, 50 bar H2), the most active (pre)catalyst, 69, would hydrogenate the solvent to cyclohexane. The reverse reaction, where D2 is used as the deuterium source and benzene as the reaction solvent, occurs 1.5–2 times faster, due to the kinetic isotope effect. The extent of deuterium incorporation was investigated for a range of substituted arenes. Alkyl substituted benzene gave moderate substitutions for hydrogens on the a-carbon (up to 42% for ethylbenzene), but no substitution of b-hydrogens. Interestingly, under longer reaction times, the initially high a-D content in alkylbenzenes decreases, while the overall percentage of deuteration of the molecule increases. Precatalyst 69 could not facilitate the HIE with unactivated (sp3)-CdH bonds, however it could achieve the HIE of a range of (sp3)-SidH bonds with D2. DFT calculations indicated a nucleophilic aromatic substitution mechanism via a Meisenheimer anion was favorable over a deprotonation/protonation mechanism. This analysis was substantiated by experimental evidence, in particular as a deprotonation/protonation mechanism would be expected to generate HD; yet, this gaseous co-product that was not detected when deuterated benzene was used as the deuterium source in reactions without H2. A similar HIE exchange was reported with the solvent-free calcium hydride [{BDIDiPP}Ca(m-H)]2 (58).200 In an attempt to replicate the HIE reaction reported in Fig. 82, a solution of 58 in C6D6 was heated to 60  C for 12 h (Fig. 84). 1H NMR analysis of the resulting suspension only had identifiable [Ca{BDIDiPP}2] resonances, indicating kinetic ligand redistribution. Instead, after keeping a solution of 58 for 21 days at room temperature, a new unresolved set of {BDIDiPP}− resonances grew in at the expense of the starting material, while the hydride signal broadened into an unresolved 1:2:1 triplet. This was attributed to deuterium incorporation generating the previously reported 58-D1.18 The observed reactivity was not elaborated into a given catalytic process.

11.05.7.5 Polymerization of ethylene Like most main group elements, Ziegler-Natta polymerization of a-olefins is certainly a field where alkaline-earth metals have not (yet?) been efficient. Alkaline-earth complexes have been found to catalyze the polymerization of styrenes, as hinted at elsewhere in

Fig. 84 Decomposition and deuteration reactions for [{BDIDiPP}Ca(m-H)]2 (58).

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this article. However, with a-olefins, they do not display equal proficiency as other oxophilic metals such as lanthanides and group 4 transition metals, and also do not compete with the more functional group-tolerant late transition metals (e.g., Ni, Pd). Yet, a note of optimism came from recent results by the Harder and Hill groups. As discussed in Section 11.05.7.3.2, the heteroleptic strontium hydride [{BDIDiPeP}Sr(m-H)]2 (93) reacts with alkenes to generate strontium alkyls that lead to the nucleophilic alkylation of benzene.193 The Sr-ethyl complex [{BDIDiPeP}Sr(m-CH2CH3)]2 (96) was obtained within minutes by treatment of 93 with ethylene in C6D6 at 20  C and 1 bar pressure. Complex 96 further reacted by ethylene through iterative s-insertions to give Sr-butyl, Sr-hexyl and higher oligomers. However, chain growth in this process akin to the well-known aluminum-mediated Aufbau reaction was hampered by the propensity of strontium-alkyl species derived from 93 to react with C6D6 and yield n-alkylated benzene derivatives. Nonetheless, the isolation of small quantities of insoluble, higher molecular weight material was detected; GC-MS analysis indicated the formation of linear alkanes and low molecular weight oligomers (C2H4)nH2 with n ¼ 5–15. Of note, the calcium analogue [{BDIDiPP}Ca(m-CH2CH3)]2 did not polymerize ethylene,18 suggesting that the higher polarity of the metal-to-carbon in 96 was key to the ability to catalyze the polymerization of apolar ethylene. Although these results are only preliminary, they suggest that strongly polarized alkaline-earth alkyls offer the prospect to be elaborated into more effective a-olefin polymerization catalysts. The choice of comparatively more polarized higher a-olefinic substrates, and the utilization of toluene as a non-reactive, non-coordinating solvent, appear to be reasonable options in this direction.

11.05.7.6 Reduction of carbon-oxygen unsaturated compounds Alkaline-earth complexes have met limited success in catalysis towards the reduction of unsaturated CdO bonds. In a remarkable synthetic contribution, the highly Lewis acidic ansa-arene dicationic strontium complex [(DXE)Sr(1,2-F2-C6H4)2] [Al{OC(CF3)3}4]2 (97; DXE ¼ dixylylethylene) was reported to catalyze the reduction of CO2 into CH4, using triethylsilane as the hydrogen source (Fig. 85).201 The reaction with a 0.6 mol% catalyst loading was slow, requiring 14 days to reach 24% conversion of the silane. A scenario involving sequential reaction with Et3SiH and release of hexaethyldisiloxane was tentatively proposed, but further mechanistic studies were not conducted. The ability of the calcium hydride [{BDIDiPP}CaH(thf )]2 (45) to catalyze the reduction of carbon monoxide with phenylsilane was examined.202 Like its lighter magnesium derivative,203 complex 45 was found to react with CO (1 atm) at room temperature to generate a cis-ethenediolate dianion 98 (Fig. 86), although the CdC bond formation was not a catalytic process. Yet, the reaction of CO and PhSiH3 catalyzed by 45 at room temperature in toluene-d8 gave the methylene silyl ether PhH2SiOCH2SiPhH2 within 60 min. Unlike the corresponding reaction with the magnesium catalyst, the formation of the fully reduced silane PhSiMeH2 could not be enforced with 45. Based on thorough DFT calculations and experimental data, the reactions were proposed to involve the formation of a Ca-formyl intermediates (Fig. 86). When reacted with primary calcium-amides, insertion of CO in the CadN bond with concomitant migration of hydrogen from nitrogen to carbon was observed, giving well defined di- or trinuclear calcium formamidates (Fig. 86). In stoichiometric studies,

Fig. 85 Postulated pathway for the reductive hydrosilylation of CO2 into CH4 catalyzed by 97.

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Fig. 86 Calcium-catalyzed reduction of carbon monoxide: (A) stoichiometric formation of dianionic ethenediolate from the hydride 45; (B) proposed mechanism for the reduction with phenylsilane catalyzed by 45; (C) reaction with calcium-amides and pinacolborane forming methylamines.

further reduction of these intermediates with pinacolborane led to the formation of the resultant N-borylated methylamines. The proposed multi-stem mechanism, starting with the generation of amidatohydridoborate, was reminiscent of that established for the deoxygenative hydroboration of isocyanates catalyzed by a magnesium hydride precatalyst.204 The attempts to elaborate this stoichiometric reactivity into a more complex catalytic manifold for the utilization of CO as a C1 synthon towards the production of methylamines were hampered by competitive calcium-catalyzed dehydrocoupling of the amines with pinacolborane, and by the limited solubility of CO under the chosen experimental conditions (1 atm).

11.05.7.7 Redistribution and cross-coupling of arylsilanes Owing to the main importance of hydrosilanes in many facets of synthetic chemistry, it is not surprising that catalysts have been developed to enable the controlled redistribution of hydrosilanes in order to diversify the range of potentially usable compounds. The asymmetric b-diketiminato calcium alkyl complex 99, which reacted cleanly with an equivalent amount of PhSiH3 to form the

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Fig. 87 Calcium-catalyzed redistribution (A) and cross-coupling (B) of arylsilanes.

dimeric hydrido compound 100, was shown to catalyze the selective redistribution of ArSiH3 or Ar(alkyl)SiH2 to Ar3SiH and SiH4 or Ar2(alkyl)SiH and alkylSiH3, respectively (Fig. 87).205 It also allowed for the controlled cross-coupling between the electron-withdrawing substituted Ar(alkyl)SiH2 and the electron-donating substituted Ar0 (alkyl)SiH2, producing ArAr0 (alkyl)SiH in good yields. The reactions took place within 20–180 min in C6D6, using 0.5–2.0 mol% precatalyst in the temperature range 37–50  C. A broad range of aryl-functionalized substrates were utilized, and the redistributions remained highly selective. Cross-coupling reactions proved challenging, as the heterocoupled products were contaminated by the presence of variable amounts of homocoupled redistribution by-products. Experimental and theoretical studies (DFT) indicated that the catalytically active species was a calcium-hydride complex, e.g., 100 or a related compound. The inferred reaction manifold for the redistribution of PhSiMeH2 (Fig. 88) was found to be kinetically very affordable. It is initiated by the formation of the calcium-hydride upon reaction of the alkyl precatalyst with PhMeSiH2. The concerted formation of a transient Ca-phenyl intermediate through a four-membered transition state with H/Ph exchange then ensues. A second, rate-limiting s-bond metathesis between this intermediate with a second PhSiMeH2 equivalent regenerates the Ca-hydride while also releasing the final product of redistribution, Ph2SiMeH. A similar study revealed that the tris(pyrazolyl)hydroborate barium benzyl [{TpAd,iPr}Ba(CH2C6H4-o-NMe2)]206 derived from the hydrido parent 62 also competently catalyzed the homo- and cross-coupling of aryl and benzyl primary silanes to secondary silanes.207 High conversions and generally excellent selectivity towards the secondary silanes were achieved, both for homo- and cross-couplings, under mild conditions (precatalyst loading 5 mol% in C6D6, 25  C).

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Fig. 88 Proposed mechanism for the calcium-catalyzed redistribution of arylsilanes.

The ability to catalyze the controlled formation of new suites of arylsilanes is certainly an exciting result as it broadens the scope of potential substrates for the many reactions relying on the participations of hydrosilanes. However, it may be possible that this reactivity also sometimes proves troublesome in alkaline-earth catalyzed reactions involving the transformation of arylsilanes. One notable such reaction is the heterodehydrocoupling of amines and silanes (see Section 11.05.6.2). In such cases, it is important that the catalyst and reaction conditions are chosen appropriately so that arylsilane redistribution does not become kinetically competitive with the targeted catalyzed reaction.

11.05.7.8 Reactions other than hydrofunctionalizations and dehydrocouplings 11.05.7.8.1

Desilacoupling of silaboranes and amines

The fragility of the BdSi bond (BDE ¼ 76 kcal mol−1) was exploited by the Hill group. They reported on the desilacoupling of the commercially available silaborane PinB-SiMe2Ph with a variety of primary and secondary amines catalyzed by [Ae{N(SiMe3)2}2(thf )2], with formation of the corresponding aminoboranes through creation of a BdN bond (BDE bond: 90 kcal mol−1) accompanied by PhMe2SiH as the sole coproduct (Fig. 89).208 In C6D6, these reactions were complete within 24 h at room temperature with 5 mol% precatalyst. Secondary amines were overall more reactive than primary ones; while both aliphatic and aromatic amines could be used as coupling partners. The reaction rate increased with metal size (Mg < Ca < Sr). This catalyzed procedure provided the first example for the coupling of two heteroelements E and E’ that was not dependent of the concomitant production of dihydrogen.

11.05.7.8.2

Cyanosilylation of carbonyls

The addition of Me3SiCN onto pre-polarized aromatic aldehydes and ketones ArC(]O)R giving cyanohydrin derivatives was proved to be catalyzed by the amidinato calcium iodide 101 (Fig. 90).209 These cyanosilylation reactions afforded high substrate conversion at room temperature in toluene within 30 min, using a 2 mol% metal loading, and without the need for any additional co-catalyst.210 A very broad range of carbonyl substrates was used, demonstrating excellent tolerance towards functional groups. Based on experimental and theoretical investigations, the authors concluded that the mechanism at work did not obey a classical s-insertive pathway, because neither the substrates nor the precatalyst possess any reactive Ca-H or E-H site. Instead, they proposed a more unusual outer-sphere scenario where polarization of the SidCN bond by coordination onto the Lewis acidic metal facilitated the nucleophilic attack by the carbonyl.

Fig. 89 Alkaline-earth catalyzed coupling of silaboranes and primary/secondary amines.

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Fig. 90 Calcium-catalyzed cyanosilylation of carbonyls with Me3SiCN.

11.05.7.8.3

Alumination of Csp2 dH bonds

Simple, selective and efficient CdH bond activation has long been one of the most desirable goals in both organic and inorganic chemistry. The ability to directly activate and functionalize CdH bonds allows unnecessary functionalization and derivatization steps to be avoided, increasing stepwise, atom and (potentially) energy efficiency.211 Although a vast number of metal and organic complexes and materials have been reported to catalyze various CdH bond activations, there has only been one select example of Ae-mediated CdH bond activation, that of an arene CdH bond activation with an Al(I) complex reported in 2019.212 The catalysis was discovered serendipitously. In an attempt to generate a CadAl bond, 2 equivalents of the aluminum(I) complex [{BDIDiPP}Al] (102) were reacted with [{BDIDiPP}Ca(m-H)]2 (58) in benzene (Fig. 91). However, instead of generating the desired heterobimetallic complex, the oxidative addition product, [{BDIDiPP}Al(H)(Ph)], was generated within 1 h at room temperature via cleavage of a Csp2dH bond. Subsequent investigations showed the process was catalytic, and that the reaction could proceed to full conversion at room temperature using down to a 5% molar loading of 58. If the reaction solvent was changed to toluene, activation of the ortho

Fig. 91 Reactions of the aluminum(I) complex [{BDIDiPP}Al] (102) with benzene and toluene catalyzed by the calcium hydride [{BDIDiPP}Ca(m-H)]2 (58).

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and meta hydrogen atoms was achieved in a 1:9 ratio. p-Xylene could also be activated; however, the reaction was slightly slower, only reaching 73% conversion after 8 h. The observed stoichiometric reactivity (in terms of reagents) catalyzed by 58 could not be upgraded in a “true” catalytic reaction, i.e., with multiple calcium-mediated turnovers. When the catalyst 58 was replaced by the amido complex [{BDIDiPP}CaN(SiMe3)2] (73), no oxidative addition was observed, even when the solution was heated to 60  C, indicating the hydride functionality plays a vital role in the reaction. Regeneration of the [{BDIDiPP}Al] starting material could be achieved using stoichiometric equivalents of iodine followed by reduction with potassium (Fig. 91). DFT calculations suggested that the most likely reaction pathway proceeded via direct oxidative addition, initiated by the formation of a the weakly bound CadAl complex [{BDIDiPP}Al(H)-Ca{BDIDiPP}] in equilibrium with the bridged [{BDIDiPP}Al(m-H)Ca{BDIDiPP}]. Yet, the computations could not entirely rule out other competitive mechanisms based on Meisenheimer or anti-aromatic C6H2− 6 intermediates. Attempts to establish which of the catalyst 58 or the aromatic substrate was the source of hydride in the product by D-labeling experiments proved inconclusive.

11.05.8 Alkaline-earth mediated Lewis-acid catalysis A number of pertinent alkaline-earth catalyzed reactions that are mechanistically different from those described in the preceding sections have been reported. These are collated here and discussed in the light of the available mechanistic information, where possible in link with related Ae-mediated catalyzed elementary steps or more complex processes. The section encompasses a range of CdC, CdN and CdO bond forming reactions catalyzed by compounds based on calcium, strontium and barium via Lewis-acid catalysis. Although it attempts to give a detailed overview on some of the most recent chemistry from this growing field, the reader is also directed to a range of other publications and monographs specializing on this growing field.213–217

11.05.8.1 Introduction 11.05.8.1.1

Lewis acidity of the group 2 metal cations

Broadly defined, a Lewis acid is any compound that possesses an empty orbital capable of accepting electron density (a lone pair from another atom) from a donor molecule, the Lewis base. There are six main recognized types of Lewis acid (Fig. 92). The redox chemistry of group 2 Lewis acids is quite simple in comparison to their transition-metal (TM) counterparts. Their lack of valence d electrons results in an almost exclusive +2 oxidation state (OS), meaning that the alkaline-earth metals do not undergo any of the catalytic redox reactivity seen with transition metals. In this +2 oxidation state, their shell-like LUMO is made up of superimposed s orbitals that are not easily accessible and cannot accept or donate electron density from the Lewis base. By contrast, although TM Lewis-acid/Lewis base interactions are primarily s-donor interactions from the base to the metal, the ability of the metal to accept of donate electron density through its d-orbitals heavily influences the nature and subsequent reactivity of the Lewis adduct. The relative strength of the s interaction between the Lewis base and the alkaline-earth Lewis acid is dictated by two chief factors: the charge, and the ionic radius of the metal cation. Although the oxidation state of the alkaline-earth metal cations is consistent down the periodic table, the decreasing electronegativity and increasing ionic radii of the dications result in a decreasing charge density from Mg to Ba, with the consequence that for most purposes, group 2 Lewis acid catalysis is dominated by Mg2+ and Ca2+ compounds.

Fig. 92 The six different types of Lewis acids often discussed.

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11.05.8.1.2

Measuring Lewis acidity

By the definition of Lewis acidity given above, one could believe that quantifying Lewis acidity is a simple task. However, differences with the steric and electronic nature of the complementary Lewis base can create difficulties. As such, several classification methods have been developed to assist the prediction of Lewis acidity. There are four commonly employed procedures for the quantification of Lewis acidity: 1. The Gutmann-Beckett method, which correlates Gutmann’s Acceptor Number (AN) with a change in the 31P NMR chemical shift of Et3P]O upon adduct formation.218,219 2. The Childs protocol uses a crotonaldehyde to form a complex in a similar method to the Gutmann-Beckett.220 The change in chemical shift of the hydrogen atom in g position is used as a gage to measure relative Lewis acidity. 3. The Fluoride ion affinity (FIA), a computational method based on ab initio calculations originally at the MP2/PDZ level of theory.221 4. The global electrophilicity index (GEI) is a quantitative and base-independent metric of Lewis acidity and is a measure of the ability of a molecule to take up electrons, based on chemical potential and chemical hardness, where hardness is defined as the resistance to deformation or change.222,223 It is relatively easy to calculate, requiring only the optimized HOMO and LUMO molecular orbitals of the Lewis acid in question.

11.05.8.2 Lewis acid catalyzed transformations: CdC bond forming reactions 11.05.8.2.1

Mannich reactions

Alkaline-earth amides and alkoxides have been used in stereoselective Mannich-type addition reactions between sulfonylimidates and secondary Boc-protected aldimines (1:1.5 ratio), exhibiting good stereocontrol based on reaction solvent (Fig. 93).224 The magnesium alkoxide [Mg{OtBu}2] had the best activity for anti-addition, with yields up to 99% and moderate stereoselectivity,

Fig. 93 Alkaline-earth catalyzed Mannich-type addition reactions of sulfonylimidates.

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giving up to a 4:96 syn/anti product ratio when reactions were carried out in DMF. When the reaction solvent was changed to thf, the catalyst [Sr{N(SiMe3)2}2]2 in conjunction with a Schiff-type ligand gave yields of up to 99% and moderate stereoselectivity for syn-addition, with up to a 93:7 syn/anti product ratio. In a similar system, high enantioselectivity was achieved using [Sr{OiPr}2]n and a bis(sulfonamide) chiral ligand with a diphenylethylenediamine backbone.225 Similar Mannich-type reactions have also been described, including the highly diastereoselective addition of N-Boc-amides to N-diphenylphosphinoyl imines, followed by a Boc migration in the presence of a [Ba{OtBu}2]n/[20 -methoxybiphenyl-2-ol] catalytic system.226,227 Chiral Schiff-base ligands have also been used in alkaline-earth catalyzed Mannich-type addition reactions of a methyla-isothiocyanato ester (Fig. 94).228 The use of [Mg{nBu}2] as a catalyst favored the syn addition with 80–95% ee and 90:10–93:7 dr (syn/anti), while [Sr{OiPr}2]n was found to favor anti addition with 84–97% ee and 17:83–4:96 dr (syn/anti). A range of substrates were investigated, primarily aryl or heteroaryl methyl ketimines, with both diastereomers being accessible by switching the metal source. Asymmetric Mannich-type reactions between N-Boc imines and 1,3-dicarbonyl substrates have be investigated using complexes bearing a chiral phosphate ligand based on a BINOL backbone (Fig. 95).229,230 The catalytic system was especially efficient for 1,3-dicarbonyl compounds with poorly acidic a-protons, such as b-ketoesters and thiomalonates. This work was extended to include pyrone and 1,3- diketones as carbonyl sources (Fig. 96).231 The most active catalytic species was observed to be the Ca-BINOL phenolate complex with tris-2,4,6-triisopropyl-phenyl groups as the R moiety at the 3 and 30 positions of the aryl backbone. Chiral barium catalysts, bearing optically pure (S)-BINOL or another optically pure (S)-aryldiol (shown in Fig. 97) have been shown to catalyze the Mannich-type reaction between b,g-unsaturated esters and N-diphenylphosphinoyl imines.232 The assumed catalytic species, the Ba phenolate, is generated in situ from [Ba{OiPr}2]n and the appropriate optically pure diol. The reaction had good enantioselectivity, generating the a,b-unsaturated ester with ees of up to 88%. As per all of the previously mentioned Mannich-type reactions, the catalysis proceeds via a s-bond metathesis step between the precatalyst (in this case a barium phenolate) and the carbonyl of the substrate, followed by insertion of the imine and formation of the carbon-carbon bond.

Fig. 94 Asymmetric alkaline-earth catalyzed Mannich-type addition reactions with methyl-a-isothiocyanato esters.

Fig. 95 Chiral Ae-phosphate catalyzed asymmetric Mannich reactions.

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Fig. 96 Chiral Ca-phosphate catalyzed asymmetric Mannich reactions of substituted pyrones.

Fig. 97 Chiral barium-aryloxide-catalyzed Mannich reactions of b,g-unsaturated esters with imines, with the postulated catalytic cycle.

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11.05.8.2.2

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Cycloaddition reactions

Cycloadditions have long been a favorite topic of investigations for synthetic chemists. They allow for the convenient synthesis of highly functionalized, complex ring systems, with good stereochemical control over the product formation. A number of alkaline-earth catalytic systems have displayed good efficacy in these processes.233 11.05.8.2.2.1 [3 + 2] cycloadditions Kobayashi and co-workers investigated alkaline-earth catalyzed [3 + 2] cycloadditions of Schiff bases derived from glycine with b-substituted a, b-unsaturated esters such as methyl crotonate.234 These reactions were catalyzed by a chiral [Ca{OiPr}2]n/bis(oxazoline) system and generated chiral pyrrolidine derivatives in high yields with excellent enantioselectivity (Fig. 98).235,236 When aldimines were used opposed to a secondary arylketimine, the substrates were less stable, possibly due to tautomerization leading to the formation of enamines. Moreover, the secondary arylketimine likely forms a more stable carbocation, thus moving the equilibrium to favor the formation of cyclic adducts and also inducing better enantioselectivity. A range of substrates derived from other a-amino acids including alanine, methionine, leucine, and serine derivatives were also used. In these systems, an heteroleptic alkoxo catalyst bearing a chelating bis(oxazolinato) ligand is produced in situ via deprotonation of the proligand by [Ca{OiPr}2]n. In the proposed catalytic cycle (Fig. 99), the substrate derived from an amino-acid is deprotonated. The resulting enolate acts as a nucleophile in the nucleophilic attack onto the a,b-unsaturated carbonyl substrate, which itself has had its electrophilicity increased through coordination to the metal. Cyclization followed by pronation generates the pyrrolidine product, with the stereochemistry being induced by the chirality of the Ca-coordinated ancillary ligand. Further investigations showed that using a stronger Brønsted base such as the calcium hexamethyldisilazide [Ca{N(SiMe3)2}2]2 as a precatalyst could also be successful in these types of reactions. The bulky silazide group offers the added advantage of increased solubility in many organic solvents, overall making the corresponding complexes better suited to organic synthesis.233,236,237 11.05.8.2.2.2 [4 + 2] cycloadditions Lewis-acid catalyzed Diels-Alder reactions have been frequently reviewed.238 Chiral calcium phosphate complexes catalyzed the [4 + 2] cycloaddition between 3-siloxydiene and an activated alkene, giving the desired cyclic product in moderate yields and enantioselectivity (ee up to 55%) (Fig. 100).239 Similar reactions between heteroatom-containing a-ketoesters and siloxydienes gave the desired 6-membered heteroatom rings in high yields with excellent ees up to 99%.240 Oxo-Diels-Alder reactions between heterodienes and vinyl ethers have also been reported, generating chiral dihydropyran-fused indole molecules in good yields with excellent enantioselectivity (up to 99% ee). In these reactions, both oxygen atoms on the carbonyl of the Boc group and in the vinyl

Fig. 98 [3 + 2] cycloaddition reactions catalyzed by [Ca(OiPr)2]n/bis(oxazoline) systems.

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Fig. 99 Proposed catalytic cycle for the [3 + 2] cycloaddition between an a-amino ester aldimine and tert-butyl-acrylate catalyzed by the system [Ca(OiPr)2]n/ bis(oxazoline).

ether chelate with the calcium of the chiral phosphate catalyst to form a 6-coordinate transition-state that heavily favors endo selectivity for the hetero-Diels-Alder product.241 An enantioselective Diels-Alder reaction has also been reported with a chiral Ba catalyst (Fig. 100).242 The catalyst, proposed to be a trimeric cluster in solution, was generated in situ from a chiral diol and [Ba{OiPr}2]n. The one-pot synthesis of dihydropyrrolo[1,2-a]quinolines has been reported using calcium trifluoromethanesulfonimide [Ca{NTf2}2] as the catalyst. The proposed mechanism for the cascade reaction starts with a [4 + 2] cycloaddition (Fig. 101).243 The solely syn products are generated from an inverse electron demand [4 + 2] aza-Diels-Alder cycloaddition, followed by a further [3 + 2] cyclization with a suitable activated alkyne. The difference in regioselectivity between benzo[b]furan and 2,3-dihydrofuran was ascribed to the different identity of the most nucleophilic carbon between the two substrates. Tricyclic azepines have also been synthesized from ynones and amidines using a [4 + 2] cycloaddition strategy, catalyzed by calcium triflate, while a [5 + 2] cycloaddition strategy using this same catalyst has been used to synthesize cyclohepta[b]indole derivatives from alkylidene b-ketoesters and olefins.244,245

11.05.8.2.3

Chiral 1,4-addition reactions

The heavy alkaline-earth metals have been used as Lewis-acid catalysts in a plethora of enantioselective 1,4-addition reactions. Early examples of enantioselective calcium-catalyzed 1,4-addition reactions include the reaction between malonates and b-ketoesters with a,b-unsaturated carbonyl compounds.244–248 The Kobayashi group reported the enantioselective 1,4-addition reaction between Schiff bases of an a-aminoether with system (see a,b-unsaturated carbonyl compounds, using the aforementioned [Ca{OiPr}2]n/bis(oxazoline) 234,235 Section 11.05.7.2.2.1). The system generated the desired 1,4-addition products in quantitative yields with excellent enantioselectivity, up to 99% (Fig. 102). The same system was used to extend the substrate scope to b-substituted a,b-unsaturated carbonyl compounds, while a range of neutral pyridine-based bi(oxazolinato) ligands (PyBox) were used in asymmetric Michael reactions between dimethyl malonate and a,b-unsaturated carbonyl compounds (Fig. 102).249–251 In 2009 Kobayashi et al. used a chiral calcium-PyBox aryloxide system for the enantioselective 1,4-addition of malonates with nitroalkenes, obtaining quantitative yields and ees up to 96% (Fig. 102).252 It was also found that the same PyBox ligand could be used with CaCl2 and triethylamine in a system for the 1,4-addition of malonates by nitroalkenes (Fig. 102).253,254 This study described the first example of a calcium chloride being used in Lewis-acid catalyzed enantioselective additions; the reactions could be carried out in heterogeneous conditions in a continuous flow reactor, leading to turn over numbers up to 25-fold greater than the earlier reported homogeneous chiral calcium-PyBox aryloxide system.254 Due to the relative abundancy, stability and non-toxic nature of CaCl2, its use with a chiral ligand in continuous flow processes is currently a research area of great interest, as has been shown by its use in the synthesis of (R)-Rolipram.255

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Fig. 100 [4 + 2] cycloadditions catalyzed by chiral calcium-phosphate and barium-alkoxide catalysts.

Chiral strontium and barium catalysts have also been used as catalysts in 1,4-addition reactions. A chiral strontium bis(amide), generated from [Sr{OiPr}2]n and the parent chiral diamine, gave good yields and excellent enantioselectivity for the reaction of aromatic enones (chalcones) with malonates (Fig. 103).256 When a catalytic species synthesized from [Sr{N(SiMe3)2}2]2 and the same proligand was subjected to identical reaction conditions, turnovers were improved from the isopropoxide catalyst.257 A chiral barium catalyst, synthesized from [Ba{N(SiMe3)2}2]2 and a silyl-functionalized BINOL derivative, was used for the 1,4-addition of

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Fig. 101 One-pot synthesis of dihydropyrrolo[1,2-a]quinolines mediated by [Ca{NTf2}2].

chalcones with indoles (Fig. 103).258 The desired functionalized indole was obtained in near quantitative yields with excellent enantioselectivity, giving with the (S) enantiomer quasi exclusively. Interestingly, if the metal source was switched to [Ca{N(SiMe3)2}2]2 and conventional BINOL was used as the proligand, the opposite enantiomer (R) of the indole was obtained, though with only a low ee of 33%. Enantioselective a-protonations have also been reported using chiral calcium catalysts. These reactions occur via enolate formation followed by nucleophilic attack on a a,b-unsaturated carbonyl compound. Assuming either the enolate or a,b-unsaturated carbonyl substrate are substituted at an a position, a chiral center can be created.259–262 A calcium-PyBox system has been used to catalyze the reaction between dibenzyl malonate and an a,b-unsaturated amide with an a aryl or alkyl group, giving high yields and high ees up to 96% (Fig. 104).259 Alternatively, the reaction between a-aryl functionalized indoles and a methyl-vinyl ketone has been catalyzed by a chiral calcium-phosphate complex with high yields and ees (Fig. 104).260 Similar reactions for azalactones and indoles are also known.261,262 The addition reaction between basic primary amines and maleimides catalyzed by a chiral calcium-phosphate complex was also reported (Fig. 104).263 Although these reactions do not proceed via enolate formation, they nicely exemplify asymmetric conjugate additions where a Lewis-base acts as a nucleophile in the presence of a relatively strong Lewis acid.

11.05.8.2.4

Hydroarylation of alkenes

The functionalization of olefins catalyzed by alkaline-earth Lewis-acid is considered a difficult reaction, primarily due to the lack of an electronegative heteroatom with a free electron pair that can interact with the electropositive Ae-metal center. However, a smattering of examples of alkaline-earth promoted olefin functionalization exist. The calcium-catalyzed hydroarylation of alkenes using a [Ca{NTf2}2]/[Bu4N][PF6] binary system was reported in 2010.264 Although triflimide (Tf2NH) is a weaker Brønsted acid than triflic acid (TfOH), metal triflimidates are stronger Lewis-acids than metal triflates, due to the greater delocalization of the negative charge and the larger volume.265,266 The system was limited to the addition electron-rich aromatic substrates across both activated and unactivated alkenes, including aliphatic alkenes (Fig. 105). Notably, the reaction exclusively generates the Markovnikov addition product, which contrasts to other alkaline-earth catalyzed hydroelementation reactions. The reaction had good functional group tolerance, proceeding smoothly under mild conditions (2.5 mol% catalyst) in the presence of halides, furans and thiophenes. No mechanism for the reaction was proposed, but it was noted that both [Bu4N][PF6] and trace water were needed for the catalysis to occur. It was hence suggested that the reaction ensues via a carbinol intermediate, though such species could not be detected. Related work has found that [Ca{NTf2}2]/[Bu4N][PF6] catalytic system can functionalize electron-rich arenes with a

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Fig. 102 Enantioselective 1,4-addition reactions with calcium-based catalytic systems.

variety of alcohols, including secondary and tertiary benzylic alcohols, as well as propargylic and allylic alcohols.267 In these reactions, it was presumed that the system forms a more reactive charge-separated [Ca{NTf2}][PF6] salt for which some spectroscopic evidence has been provided. The substrate scope of hydroarylation of alkenes was extended for the same [Ca{NTf2}2]/[Bu4N] [PF6] catalytic system by using hexafluoroisopropanol (hfip) as a solvent (Fig. 105).268 Styrenes with strongly election withdrawing substituents were utilized as electrophiles, including various fluorinated as well as SF5- and CN-containing vinylarenes. Halobenzenes, m-xylene, benzene or naphthalene were used as nucleophiles. The Markovnikov products of addition were obtained exclusively. The mechanism of the hydroarylation in hfip was probed by DFT calculations. The data suggested that the initial step is a proton transfer from an hfip molecule activated by the Lewis acid [Ca{NTf2}]+ to the vinylarene molecule, hence producing a carbocation and a calcium-hexafluoroisopropoxide. The nucleophilic arene then undergoes addition on the carbocation to generate a Wheland intermediate. This intermediate is then deprotonated by NTf−2 ligand, a step that releases the final Markovnikov addition product. Finally, deprotonation of the Tf2NH ligand by the calcium-hexafluoroisopropoxide regenerates the catalyst.

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Fig. 103 1,4-Addition-reactions catalyzed by strontium and barium catalytic systems.

Fig. 104 a-Protonations catalyzed by calcium Pybox and BINOL-based phosphate systems.

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Fig. 105 Hydroarylation of alkenes with the [Ca{NTf2}2]/[Bu4N][PF6] binary catalytic system.

Anilines have also been alkylated in the ortho position using highly deactivated alkenes and vinylarenes, using the same [Ca {NTf2}2]/[Bu4N][PF6]/hfip catalytic system (Fig. 106).269 The Lewis-acid [Ca{NTf2}2] was not pivotal in the catalytic process; the use of other Lewis-acids including [Ba{OTf}2] and HNTf2 also worked well, though the [Ca{NTf2}2]/[Bu4N][PF6]/hfip system gave the best outcome. Only the Markovnikov products were obtained. The alkylation of a large number of anilines with electron-poor alkenes (for instance p-CN-styrene) was investigated, with ortho-alkylation occurring preferentially. Exceptions included carbazole (ortho/para alkylation ratio of 67:33) and triarylamines, which gave the para-alkylated products, which the authors ascribed to the difference of pKa of their conjugate acids (pKa Ph3NH+ ¼ −3.9, Ph2NH2+ ¼ 0.8, PhNH3+ ¼ 4.6).270 The para-substituted products presumably formed via protonation of the alkene by Ph3NH+, leading to an electrophilic aromatic substitution reaction. When electron-rich alkenes were used, e.g., 1,1-diphenylethylene, a- and b-methyl-styrenes, 4-methoxystyrene, 4-aminostyrene, (E)-1phenyl-1,3-butadiene or acenaphthylene, para-alkylation of the aniline was obtained exclusively, in moderate to high yields (68–93%). The reaction pathway was probed by DFT calculations, using [Ca{NTf2}][PF6] salt as the likely metal species formed in the reaction medium. A reaction mechanism where two hfip molecules were acting in tandem with one [Ca{NTf2}+] cation as the catalytic species, and traversing a Wheland intermediate, was suggested (Fig. 106).

11.05.8.2.5

Heterofunctionalization of alkenes

Other related Ca2+-mediated heterofunctionalizations of alkenes, such as hydroalkoxylation, hydroamidation or hydroacyloxylation have also reported.271–273 The hydroalkoxylation reaction, a ring-closing intramolecular process catalyzed by [Ca{NTf2}2]/ [Bu4N][PF6], exclusively generated the Markovnikov product, and occurred at room temperature (Fig. 107). Formation of the pyran or furan was shown to be governed by angle of compression effects induced by the substituents in the a-position from the alcohol functional group. A wide range of aryl of alkyl substrates were investigated and with overall excellent yields. The intramolecular hydroamidation of unactivated alkenes using the three-component [Ca{NTf2}2]/[Bu4N][PF6]/hfip catalytic system also proceeded exclusively to generate the Markovnikov products (Fig. 107). DFT calculations showed the [{NTf2}Ca(hfip)n]+ moiety, generated in situ in the reaction medium, could activate the amide at a basic site of the {NTf2}− ligand and the alkene with one acidic hfip proton.272 A wide range of substrates were investigated, with the formation of the Markovnikov pyridinyl or pyrrolidinyl products occurring in excellent yields. The same study also reported the intermolecular hydroamidation of electronically deactivated styrenes using p-toluenesulfonamide. The cyclizing intramolecular hydroacyloxylation of unactivated alkenes has also been reported using the same catalytic system (Fig. 107).273

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Fig. 106 Ortho-alkylation of anilines by the [Ca{NTf2}2]/[Bu4N][PF6]/hfip catalytic system, with the proposed catalytic cycle.

11.05.8.2.6

Cyclic rearrangements

11.05.8.2.6.1 Nazarov cyclisation In 2014, the calcium-catalyzed Nazarov electrocyclization using the [Ca{NTf2}2]/[Bu4N][PF6] catalytic system was described.274 This 4p conrotatory ring closure is used to generate cyclopentanone compounds.275–277 A range of substrates were investigated, which included electron rich and electron poor aryl and alkyl substituted species (Fig. 108). The cyclizations gave generally good yields (74–99%). The reactions showed good selectivity, favoring formation of the trans product with diastereomeric ratios in the range 92:8 to 98:2. The beneficial role in this cyclisation of the counter-ion PF−6, thought to exacerbate the Lewis acidity of the metal cation for instance by comparison with BF4− or I−, was specifically highlighted.

11.05.8.2.6.2 Aza-Piancatelli cyclization The Aza-Piancatelli cyclization has also been reported to be catalyzed by the three-component [Ca{NTf2}2]/[Bu4N][PF6]/hfip system.278–280 This reaction consists of the transformation of 2-furylcarbinols into 4-aminocyclopentenones when anilines are

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(A)

(B)

(C)

Fig. 107 [Ca{NTf2}2]/[Bu4N][PF6] catalytic system (loading 5 mol%) for the ring-closing hydroalkoxylation (A) hydroamidation (with hfip; B) and hydroacyloxylation (with hfip; C) of alkenes.

Fig. 108 Calcium-catalyzed intramolecular Nazarov cyclization.

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(A)

(B)

(C)

(D)

Fig. 109 Calcium-catalyzed Aza-Piancatelli reaction: (A) simplified reaction pathway; (B) reactions in nitromethane; (C) reaction in hfip; (D) Aza-Piancatelli reaction—Michael addition sequence.

employed as nucleophiles. The reaction is a development from the Piancatelli rearrangement, which is mostly used for the synthesis of prostaglandin derivatives or other natural products.213,220,281,282 The Aza-Piancatelli cyclization proceeds via Lewis-acid catalyzed formation of an oxonium ion, which undergoes nucleophilic addition with the aniline, followed by a 4p-conrotatory electrocyclization (Fig. 109A). The process has been implemented both for regular Aza-Piancatelli reactions279,280 and successive sequences of Aza-Piancatelli and Michael addition.278 Early work on this reaction used the catalytic calcium Lewis-acid system [Ca{NTf2}2]/[Bu4N][PF6] in nitromethane (Fig. 109B).279 The reaction was later developed using hfip as a solvent, which both increased the reactivity and allowed for a widening of the substrate scope (Fig. 109C).280 As per the other systems using the [Ca{NTf2}2]/[Bu4N][PF6]/hfip catalytic system, the primary reactivity is derived from the Lewis-acidity of hfip, which is enhanced

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by in situ generated [Ca{NTf2}][PF6]. This was highlighted by the fact that some of the Aza-Piancatelli reactions could proceed only in the presence of hfip with catalytic HNTf2, although higher yields were obtained with the [Ca{NTf2}2]/[Bu4N][PF6]/hfip system. More recently, the reaction has been used to synthesize natural products (Fig. 109D).278 Finally, in another sequential process, the Aza-Piancatelli reaction of propargylic amines, extended by a copper(II)-catalyzed hydroamination reaction, was used to generate substituted cyclopenta[b]pyrroles in a one-pot protocol (not shown).282–284

11.05.8.2.7

Ca2+-catalyzed dehydroxylation reactions

Alcohols are among the most common groups of organic chemistry. As such, reactions that allow direct functionalization of alcohol-containing substrates are highly desirable, especially if these reactions also have good chemoselectivity and stereoselectivity. However, due to the poor nature of the OH− anion as a leaving group, hydroxyls often have to be substituted or transformed into halides, carboxylates or carbonates prior to subsequent derivatization.213 Perhaps surprisingly, Ca2+ is almost unparalleled in its high proficiency for dihydroxylation of alcohols at room temperature. A general reaction manifold is sketched in Fig. 110. The initial reactivity between a L2Ca species and an alcohol results in a s-bond metathesis step induced by the polarization of the Ca2+ cation; a second alcohol moiety may assist in the stabilization of the transition state. The resulting L− R+ moiety reacts with a nucleophile to generate the desired Nu-R compound and a protonated ligand species, which reacts slowly with the poorly soluble heteroleptic calcium hydroxide species to regenerate the catalyst L2Ca. The ligand L− used in these reactions is usually {NTf2}− which is capable of readily stabilizing the negative charge through extensive delocalization. As a carbocation R+ plays a role in the proposed mechanism, the regular constraints of carbocation formation dictate the substrate scope available for the reaction. Several reactions making use of the binary [Ca{NTf2}2]/[Bu4N][PF6] catalytic system were described. The seminal work of calcium Lewis acid catalyzed dehydroxylation of electron-rich arenes with alcohols was reported by Niggemann in 2010 to give the corresponding substituted aryl products (Fig. 111A).267 The substrate scope of the reaction was later extended to include anilines, carbamates, sulfonamides and propargyl alcohols tethered to b-ketoesters, before a microwave-assisted nitrile variation of the Ritter reaction was also developed (Fig. 111B).285,286 The dehydroxylation strategy using has also been used with an oxime to generate amides via a Beckmann rearrangement.287 Alkylation has also been achieved using unsaturated silicon and boron compounds as sources of nucleophilic carbon (Fig. 111C).288,289 The diastereoselective formation of highly substituted indanes and tetralines, from diastereomeric mixtures of alcohols, has been reported through a strategy that exploits a Wagner-Meerwein hydride shift (Fig. 111D).290 In a somewhat similar reaction, a vinyl cation tethered to an olefin has been used to generate diastereoselective bicyclic amines via a dynamic multicomponent reaction291; the process relied on the high Lewis-acidity of the Ca2+ cation for the generation of the most thermodynamically stable amine product. In another multicomponent reaction catalyzed by [Ca{OTf}2]/[Bu4N][PF6], a sequence starting with enolization of a cyclic diketone followed by addition to a dehydroxylated propargylic alcohol and concluding with a Michael cyclization was used to generate highly substituted furans (Fig. 112).292 A similar dihydroxylation-addition-cyclization process has also been used for the synthesis of other substituted furans and pyrans.293,294 Allenyl cations accessed as a mesomeric form of propargylic carbocations have also been used in cycloisomerizations. These reactions mimic the chemistry coinage metals for the construction of a range of valuable products.295 The seminal work was the cycloisomerization of an enynol to generate substituted cyclopropanes using [Ca{NTf2}2]/[Bu4N][X] as the catalytic system, where X− was the PF6− or SbF6− anion (Fig. 113).296 The proposed mechanism, which was supported with DFT calculations, suggested an initial dehydroxylation step followed by a cascading range of CdC bond forming steps and a cyclization. Other Ca-catalyzed allenyl-cyclopropyl rearrangements have also have also been studied.297

Fig. 110 Proposed mechanistic pathway for the calcium-catalyzed dihydroxylation of alcohols.

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(A)

(B)

(C)

(D)

Fig. 111 Selected dehydroxylation reactions catalyzed by the binary [Ca{NTf2}2]/[Bu4N][PF6] system (5 mol% of each component). (A) Arylation of alcohols. (B) Microwave-assisted Ritter reaction. (C) Alkenylation of allyl alcohols. (D) Stereo-redistributing diastereoselective synthesis of indanes.

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Fig. 112 Multistep synthesis of functionalized furans catalyzed by [Ca{OTf}2]/[Bu4N][PF6].

Fig. 113 Cycloisomerization of an enynol and formation cyclopropanes using [Ca{NTf2}2]/[Bu4N][X].

11.05.9 In lieu of a conclusion The past 20 years have taught us that far from being simple and intricate derivatives of magnesium, unable to compete with other systems for metal-promoted homogeneous catalysis, the large alkaline-earth metals calcium, strontium and barium can be used to assemble competent catalysts and precatalysts for a growing array of organic transformations. Beyond the simple derivatization of the behavior observed with their lanthanoid cousins, the large alkaline earths have been used to catalyze new, original reactions. Along the way, several paradigms have been broken. The efforts paid to elucidate mechanistic pathways by combining experimental and theoretical (DFT) studies have shown that the initially conceptualized reaction pathways, such as those depicted in Figs. 6 and 7, are often over-simplistic, if not plainly wrong. In short, the three heavy alkaline earths display a reactivity of their own, and this is a very positive omen indeed. Far from being a mature field, Ae-mediated catalysis is on a fast-rising curve. We can expect it to grow much beyond the initial hydrofunctionalization and dehydrocoupling catalysis that were abundantly investigated in the early years.

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Quite the contrary, the story is still very fresh, many exciting catalyzed reactions lie ahead, and the scope of alkaline earth catalysis now appears to be limited only by the imagination of the synthetic chemists astute enough to tackle this field. It is undeniable that some inspiration may be gained from the much more developed chemistry of magnesium and that of the lanthanides. But beyond this, exciting discoveries disclosed in recent years, such as the calcium-catalyzed non-dehydrogenative desilacoupling of silaboranes and amines,208 or the alkylation of aromatic rings18,193 show that boundaries need not be set. The field does face ongoing challenges; catalyst loadings required for many catalytic systems are often significantly higher than for similar transition metal or organo-catalyzed transformations, hampering the commercial development of industrial processes based on this chemistry. Asymmetric alkaline-earth catalysis is another area where major improvements are required. However, the impressive molecular reactivity exhibited by unusual alkaline-earth complexes will likely lead to further development in the future. Many potential milestones still lie ahead, and the very first Ca(I)-Ca(I) complex is certainly one of many valid entry points in this respect.15 Barium is a metal that is certainly difficult to tame and therefore it has perhaps been less investigated than its lighter congeners, but recent experience has shown that the efforts are often highly rewarding.28 These countless challenges and opportunities are now well recognized by the community of organometallic chemists, and the growing number of groups across the world that design and implement alkaline-earth complexes for organic synthesis is a very positive sign of the vitality of the field. May it continue!

Acknowledgments Y. S. thanks the Centre National de la recherche Scientifique (CNRS) for support.

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11.06

Zinc Reagents in Organic Synthesis

Eszter Fazekasa, Phoebe A Lowya, Maisarah Abdul Rahmana, and Jennifer A Garden, EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom © 2022 Elsevier Ltd. All rights reserved.

11.06.1 11.06.2 11.06.2.1 11.06.2.1.1 11.06.2.1.2 11.06.2.1.3 11.06.2.1.4 11.06.2.2 11.06.2.2.1 11.06.2.2.2 11.06.3 11.06.3.1 11.06.3.2 11.06.3.2.1 11.06.3.2.2 11.06.3.2.3 11.06.3.2.4 11.06.3.3 11.06.3.4 11.06.3.5 11.06.3.6 11.06.3.7 11.06.3.8 11.06.3.9 11.06.4 11.06.4.1 11.06.4.2 11.06.4.3 11.06.4.4 11.06.4.5 11.06.4.6 11.06.5 11.06.5.1 11.06.5.2 11.06.5.3 11.06.5.4 11.06.5.5 11.06.6 11.06.6.1 11.06.6.2 11.06.6.3 11.06.6.4 11.06.6.5 11.06.7 11.06.7.1 11.06.7.2 11.06.7.3 11.06.7.4 11.06.7.5 11.06.7.6 11.06.7.7

Introduction Preparation of organozinc compounds Synthetic routes to prepare homometallic zinc reagents Direct insertion of zinc into metal-halogen bonds Advances in directed metalation Transmetalation routes to prepare organozinc complexes Metal-halogen exchange routes to organozinc reagents Preparation of heterometallic compounds Co-complexation preparation routes toward heterometallic zincates Formation of heterometallic complexes via trans-metal trapping Applications of organozinc reagents in addition reactions Overview Addition to carbonyl compounds Alkylation of carbonyl compounds Alkenylation (vinylation) of carbonyls Alkynylation of carbonyls Arylation of carbonyls Conjugate 1,4-addition to a,b-unsaturated compounds Addition to carbon dioxide Addition to imines Addition to oxabicyclic alkenes Chelation-controlled additions Tandem reactions using organozinc reagents Summary Applications of organozinc reagents in substitution reactions Overview Asymmetric allylic substitutions Alkylations Alkenylation reactions Αrylation reactions Summary Application of organozinc reagents in cross-coupling reactions Overview Negishi cross-coupling reactions Synthesis of functionalized ketones Barbier reactions Summary Catalytic applications using organozinc reagents Overview Hydrosilylation and dehydrogenative silylation Zinc-catalyzed hydroboration and borylation reactions Zinc-catalyzed hydroamination reactions Summary Reactivity of molecular zinc hydrides Overview Insertion of unsaturated substrates into ZndH bonds Hydrosilylation reactions Dehydrocoupling of alcohols and silanes Borylation and hydroboration of terminal alkynes Hydrogenation of imines Summary

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a

Represents equal author contribution.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00090-1

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Zinc Reagents in Organic Synthesis

11.06.8 Reactivity and applications of N-heterocyclic carbene zinc complexes 11.06.8.1 Overview 11.06.8.2 Hydrosilylation of CO2 using NHC-Zn-alkyl complexes 11.06.8.3 Hydroamination of carbodiimides using NHC-Zn-bis(amide) complexes 11.06.8.4 Chiral NHC-Zn-alkyl catalysts for enantioselective allylic alkylations 11.06.8.5 Summary 11.06.9 Organozinc pivalates as enhanced air- and moisture-stability reagents 11.06.9.1 Overview 11.06.9.2 The application of zinc-pivalates in cross-coupling reactions 11.06.9.3 Application of organozinc pivalates in acylations, allylations and carbocuprations 11.06.9.4 Summary 11.06.10 Reactivity of heterometallic organozinc compounds 11.06.10.1 Overview 11.06.10.2 Deprotonative metalation 11.06.10.3 Metal-halogen exchange using heterometallic zincate reagents 11.06.10.4 Addition reactions 11.06.10.5 Silylzincation reactions 11.06.10.6 Cross-coupling reactions 11.06.10.7 Summary 11.06.11 Conclusions Acknowledgments References

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11.06.1 Introduction Zinc is a metal with a dual identity due to its position in the periodic table. Whilst generally classed as a main group metal on account of its 4s2 3d10 electronic configuration, zinc is situated in the d-block, and thus forms a bridge between main group and transition metal chemistry. Organozinc reagents have, therefore, been used in stoichiometric transformations typically dominated by polar main group organometallics (such as metal-halogen exchange and deprotonative metalation), as well as catalytic transformations traditionally mediated by transition metal catalysts (such as hydrosilylation). Organozinc reagents are attractive alternatives to polar main group organometallics such as organolithium and Grignard reagents, due to the lower polarity (and thus reactivity) of the ZndC bond.1 This lower reactivity leads to improved functional group tolerance and can avoid the need for economically and energetically costly cryogenic conditions that are typically required for highly polar organometallic bases. Unlike lithium and magnesium, zinc possesses low-lying p-orbitals, which facilitate the participation of ZndC bonds in transition metal catalysis. Combined with the low cost and low toxicity of zinc, these features make organozinc reagents attractive polyfunctional reagents which have been extensively used in CdC bond forming reactions and enable the synthesis of complex organic molecules. There has been an explosion of zinc chemistry over the past 15 years, in both stoichiometric and catalytic regimes, and this chapter presents some of the key developments during this period. Advances in the preparation of homo- and hetero-metallic organozinc reagents are showcased in Section 11.06.2, while Sections 11.06.3–11.06.10 focus on reactivity studies. Traditional organozinc compounds, such as dialkylzinc and organozinc halide compounds, have long been cornerstone reagents of addition, substitution and Negishi cross-coupling reactions. Sections 11.06.3–11.06.5 describe reactivity improvements in these fields, organized by the type of reaction and with a particular focus on the functionalization of novel substrates and the use of new ligands. While organozinc reagents have generally been used as a stoichiometric source of nucleophiles, organozinc catalysts have also been developed and exciting advances in this field are described in Section 11.06.6. Sections 11.06.7–11.06.10 focus on emerging classes of zinc reagents, such as hydrides, carbenes, pivalates and heterometallic zincates. These compounds are discussed in separate sections to draw particular attention to their unique reactivities in reactions both including and beyond classical addition, substitution and cross-coupling chemistry.

11.06.2 Preparation of organozinc compounds Organozinc reagents have revolutionized many fields of research, including total synthesis, catalysis and polymerization chemistry. Over the past 15 years, a broad variety of new homo- and hetero-metallic zinc complexes have been synthesized, with most homometallic complexes produced through direct insertion, direct metalation, metal-halogen exchange or transmetalation reactions, and with most heterometallic complexes synthesized via co-complexation reactions. This section reviews recent advances in each of these preparation methods.

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195

11.06.2.1 Synthetic routes to prepare homometallic zinc reagents A wide range of organozinc reagents can be synthesized from different zinc precursors (Scheme 1). When starting with zinc metal, oxidative addition of Zn into a carbon-halide bond can generate organozinc halides. From zinc halides, transmetalation can transfer an organo-group from a more electropositive metal such as lithium to zinc, driven by the thermodynamically favorable formation of lithium halides as well as ZndC bonds with greater covalency. Once formed, organozinc reagents can be further derivatized through direct metalation (deprotonation of a more acidic organic substrate) or metal-halogen exchange (conversion of a carbon-halide bond to a carbon-metal bond). While these different routes each have associated advantages and disadvantages, synthetic strides have been made in each area over the past 15 years. Perhaps most notably, the use of salt additives has facilitated the preparation of organozinc compounds for each of these routes, by helping to solubilize reagents and/or products as well as lower the energy of some key transition states (vide infra). The presence of salts has also been shown to influence the subsequent reactivity of organozinc reagents, leading to activity enhancements in many cases. The use of salts is an important factor to consider when selecting a preparation route, as residual salts can play either a “Jekyll” or a “Hyde” role and may be beneficial or detrimental in subsequent reactions.2–4

Scheme 1 Synthetic routes to homometallic organozinc complexes.

11.06.2.1.1

Direct insertion of zinc into metal-halogen bonds

Direct insertion of Zn into a CdI bond provides a useful and atom efficient method of generating organozinc iodides. However, this preparative route often requires demanding conditions such as the use of activated Rieke zinc (prepared by reducing zinc halides with an alkali metal), highly polar solvents (e.g. hexamethylphosphoramide, dimethylformamide or dimethylsulfoxide) and/or the use of stabilizing ortho-substituents (e.g. CO2Me, CN, Br or CF3) at high temperatures. The high activity of Rieke zinc can be exploited in direct insertion into more challenging CdBr bonds (vs CdI), yet the activity of this zinc source decreases over time, which is a drawback.1,5 In 2006, Knochel and co-workers reported a practical method of preparing organozinc reagents from commercially available zinc dust in THF, with LiCl accelerating the insertion of Zn into a C-halogen bond.6 For example, adding LiCl (1.5 equiv.) to the reaction between iodobenzene and zinc dust increased the conversion from 5% after 24 h, to quantitative conversion after 7 h (Scheme 2). LiCl was proposed to facilitate zinc insertion by solubilizing the arylzinc halide (RZnX) product through the formation of Li+[ZnRXCl]− species, thus avoiding deactivation of the metal surface. This proposal has since been supported by fluorescence microscopy studies on zinc insertion into fluorophore-tagged organohalides, which show that the zinc surface is not evenly active and that LiCl removes the organic material from the most reactive locations, thus freshly exposing active Zn sites for subsequent insertion reactions.7,8 Mixed-metal species of formula Li+[ZnRXCl]− have since been detected by ESI-MS, with DFT calculations showing that these species are very favorable and provide a strong driving force for the insertion reaction.9,10 Modelling of the reaction pathway of Zn insertion into aryl bromides suggests that LiCl acts as both a Lewis acid (Li) and a Lewis base (Cl) to provide steric and electronic stabilization of the zinc insertion transition state via the formation of a 5-membered (CPhdZndCldLidBr) ring. Subsequent studies have shown that LiCl, LiBr and LiI additives can all boost zinc insertion into (2iodoethyl)benzene, by solubilizing the organozinc halide products formed. In contrast, LiF and LiOTf neither efficiently solubilized the product nor noticeably improved the reaction yield.11

Scheme 2 LiCl-accelerated direct insertion of Zn into iodobenzene.6

The use of LiCl as an activity booster has proven to be a versatile methodology that can be used for zinc insertion into a range of aryl iodides (including those with amide, ester, formyl and nitrile substituents) and heteroaryl iodides (including substituted pyrimidine iodides).12 Organobromides can also be activated using Zn/LiCl, including aryl, alkenyl, acetylenic and heteroaryl

196

Zinc Reagents in Organic Synthesis

bromides such as 3-bromopyridine, 3-bromoquinoline and 4-bromoisoquinoline.6,13–15 Zinc insertion into alkyl bromides such as 2-bromoadamantane can also be mediated by LiCl.6,16 With aryl polybromides and iodides, regioselective directed ortho-insertion occurs, with directing metalation groups (such as carbamates, esters, ethers or ketones) stabilizing the formation of adjacent CdZn bonds.17,18 For example, the reaction of ethyl-2,3,5-triiodobenzoate with pre-activated zinc dust and LiCl in THF at 0  C gave the ortho-zinc product (Scheme 3), whereas the same conditions but without LiCl gave no zinc insertion, and the use of increased temperatures led to unselective reactivity. Where there are equivalent CdBr and CdI bonds, such as in 4-bromophenyliodide, Zn insertion occurred only into the CdI bond (reflecting the greater bond strength of CdBr vs CdI).6 Interestingly, the direct insertion of Zn can provide a contradictory and complementary regioselectivity to Mg (Scheme 4). With di- or tri-bromo aromatics featuring a directing metalation group (OTs, OPiv, OAc or OBoc), directed ortho-insertion of Zn regioselectively occurred (Scheme 4, left). In contrast, Mg inserted into the least sterically hindered para-BrdC bond (Scheme 4, right). This difference was attributed to the stronger reducing power of Mg, which circumvents the need for ortho-coordination, unlike Zn where the directing metalation group facilitates reactivity at the ortho-position. Subsequent transmetalation of the organomagnesium compound with ZnCl2 offers a route to prepare para-arylzinc species, thus enabling selective preparation of the ortho- or para-arylzinc halides depending on the synthetic route selected.18

Scheme 3 Regioselective directed ortho-insertion of Zn into activated C-halogen bonds, accelerated by LiCl additives.17

Scheme 4 Ortho- or para-regioselectivity of zinc or magnesium insertion into di- or tri-bromo aromatics.18

Direct insertion of Zn into CdCl bonds provides a greater challenge on account of the greater CdCl bond strength (vs CdBr and CdI). However, direct zinc insertion into di- and tri-substituted allylic chlorides was successfully performed using Zn dust (5 equiv.) and LiCl (1.2 equiv.) in THF solvent. The metalated products could undergo subsequent addition to aldehydes or ketones to generate homoallylic alcohols with remarkable regioselectivity and diastereoselectivity.19 Interestingly, sterically hindered allyl chlorides featuring a bulky SiMe3 substituent at the 2-position could also undergo direct insertion of Zn in the presence of LiCl. Using a mixture of trimethylsilyl substituted allyl chlorides generated the allylic zinc chloride in 78% yield (Scheme 5).20 Mediated by LiCl, zinc insertion into organo-pseudohalides, such as allylic phosphonates, aryl triflates and vinyl triflates, has also been achieved.14,19

Scheme 5 Direct insertion of Zn into sterically hindered allyl chlorides.20

The catalytic use of CoCl2 and Xantphos can further accelerate Zn insertion mediated by LiCl in THF.21 For example, reaction of 4-iodoanisole with Zn (1.5 equiv.) and LiCl (1 equiv.) for 16 h at 20  C gave anisole in just 9% yield after quenching with HCl (Scheme 6). The addition of CoCl2/Xantphos (5 mol% of each) dramatically increased the yield, generating anisole in 97% yield which suggests that almost quantitative conversion to (4-OMedC6H4)ZnI occurred prior to acidic work up. This methodology was successfully applied to a broad range of aryl iodides, bromides and chlorides, as well as heteroaryl bromides and chlorides. Alternative cobalt and lithium salts (e.g. CoBr2, CoI2, Co(acac)2 or Co(acac)3; LiBr or LiI) also accelerated the reaction, which was proposed to proceed via reduction of Co(II) by Zn, followed by oxidative addition of the organohalide and transmetalation to form the organozinc halide.

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197

Scheme 6 Direct insertion of Zn into 1-iodoanisole.21

11.06.2.1.2

Advances in directed metalation

Directed metalation, where a relatively unreactive CdH bond is converted to a more polar and more reactive C-metal unit, is an important route to prepare organometallic reagents. While this class of reaction is typically performed using organolithium and organomagnesium reagents as Brønsted bases, these highly polar reagents often require careful control over the reaction conditions and display limited functional group tolerance. Moreover, some lithiated or magnesiated heterocycles can undergo subsequent ring-opening reactions. In contrast, organozinc reagents display enhanced functional group compatibility but are generally slow and sluggish to react. Some of these challenges have been overcome using heterometallic bases (refer to Section 11.06.10 for details). However, the use of inorganic salts has also helped to boost the Brønsted basicity of organozinc reagents toward organic substrates.2 For example, TMP2Zn
2MgCl2
2LiCl (TMP ¼ 2,2,6,6-tetramethylpiperidide) has been successfully exploited as a mild base for the direct zincation of aryl and heterocyclic substrates.22 Prepared through the transmetalation of TMPMgCl
LiCl with ZnCl2 in a 2:1 ratio in THF at room temperature, TMP2Zn
2MgCl2
2LiCl is proposed to contain MgCl2 and LiCl salts that enhance both the solubility and the reactivity of TMP2Zn toward aromatic substrates (Scheme 7). This base combines high reactivity with excellent functional group tolerance, and can be used to metalate arenes and heterocycles bearing sensitive aldehyde and nitro functional groups, as well as heterocycles that are prone to ring-opening such as 2-phenyl-1,3,4-oxadiazole and N-tosyl-1,2,4-triazole. This methodology has since been expanded to the metalation of 3,6-dichloropyridazine, which can undergo sequential zincation and electrophilic quenching to generate mono- and bis-functionalized products (Scheme 8).23 In contrast to organolithium and organomagnesium reagents, which generally require cryogenic conditions, TMP2Zn
2MgCl2
2LiCl can often be used at ambient temperatures.22 Using this base and microwave irradiation, zincation of a range of polyfunctional aromatic and heteroaromatic substrates was also reported at elevated temperatures (60–120  C), including substrates with sensitive cyano, ester and ketone functionalities.24 Metalations using TMP2Zn
2MgCl2
2LiCl have since been scaled-up to multi-gram scale syntheses while maintaining good yields.25

Scheme 7 Preparation of TMP2Zn
2MgCl2
2LiCl and subsequent reactivity toward sensitive azole derivatives.22

Scheme 8 Zincation and electrophilic quenching of 3,6-dichloropyridazine.23

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Zinc Reagents in Organic Synthesis

The related amido-base, [tBu(iPr)N]2Zn
2MgCl2
2LiCl, was generated as a lower cost alternative to TMP2Zn
2MgCl2
2LiCl through the transmetalation of [tBu(iPr)N]MgCl
LiCl with ZnCl2 (0.5 equiv.).26 By using [tBu(iPr)N]2Zn
2MgCl2
2LiCl, 2-phenyl-1,3,4-oxadiazole was successfully metalated without subsequent ring-opening reactions (as is typically observed using organolithium or organomagnesium bases). This base was also used for the metalation of other sensitive substrates, including quinoxaline, 6-nitrobenzothiazole, and aromatic substrates featuring aldehyde, cyano and halogen substituents. While [tBu(iPr)N]2Zn
2MgCl2
2LiCl displayed similar metalation times and reaction yields to its TMP analogue, the substrate scope was smaller, as the enhanced nucleophilicity of amide [tBu(iPr)N] vs TMP facilitated the formation of amides from reaction with ester-substituted substrates under microwave conditions. Compared to TMP2Zn
2MgCl2
2LiCl, bimetallic TMPZnCl
LiCl was shown to be a mild and (chemo)selective base for the direct zincation of arenes and heteroarenes, with LiCl proposed to play a solubility enhancing role.27 Initially, this base was prepared via lithiation of TMPH using BuLi, followed by transmetalation with ZnCl2. Whilst high yielding, this protocol requires the use of dry ZnCl2 along with pyrophoric organolithium reagents, which limits the range of suitable solvents. Subsequent studies showed that Zn dust could be directly inserted into the NdCl bond of TMPCl in the presence of LiCl (where TMPCl was generated through chlorination of TMPH by treatment with NCS or an aqueous bleach solution (13% aq NaOCl)).28 Brønsted basic TMPZnCl
LiCl was successfully used to metalate chloro- or bromo-substituted pyrazines, pyridazines and pyrimidines. With dibromodiazine substrates, the metalated products displayed enhanced stability compared to those obtained using more active bases such as TMP2Zn
2MgCl2
2LiCl and TMPMgCl
LiCl, which can decompose these heterocyclic bromides.28 TMPZnCl
LiCl can also be used to metalate substrates featuring sensitive functional groups (such as aldehydes and nitro groups) and electron poor (hetero)arenes such as 2-chloro-3-nitropyridine (Scheme 9), as well as unsaturated nitroolefins, trifluoromethyl ketones and nitriles.27,29

Scheme 9 Zincation of 2-chloro-3-nitropyridine.27

In some cases, TMPZnCl ∙ LiCl and TMP2Zn∙ 2MgCl2 ∙2LiCl can give different metalation products, for example, upon reaction with chromone (Scheme 10).30 DFT calculations indicate that the C2-position of chromone is the most acidic, yet the strongest Lewis base is the carbonyl oxygen which provides a docking site for metal coordination. With TMPZnCl ∙ LiCl, Zn coordinates to the carbonyl group and metalation is directed at the C3-position through a complex induced proximity effect. The presence of MgCl2 (in TMP2Zn ∙2MgCl2 ∙ 2LiCl) switches the regioselectivity from C3-metalation to C2-metalation, which was attributed to Lewis acid coordination of MgCl2 at the carbonyl oxygen. In the presence of MgCl2, TMP2Zn coordinates to the heterocycle heteroatom, and thus deprotonates the C2-position. By including or excluding MgCl2, the regioselectivity can thus be controlled to generate 2- or 3-substituted chromones respectively, after electrophilic quenching or cross-coupling. Similarly, 2,3-disubstituted chromones can be prepared through sequential metalation/cross-coupling sequences using TMP2Zn∙ 2MgCl2 ∙ 2LiCl (C2functionalization) followed by TMPZnCl ∙LiCl (C3-functionalization). The mechanistic role of MgCl2 as a Lewis acid was further supported by adding 1 equivalent of MgCl2 to TMPZnCl ∙LiCl and chromone, which gave the C2-metalation product. An alternative Lewis acid, BF3 ∙ OEt2, showed a similar effect. With N-methylquinolone, C2-metalation also occurred with TMP2Zn∙ 2MgCl2 ∙ 2LiCl, whereas TMPZnCl ∙ LiCl gave C3-metalation (Scheme 10), while with thiochromone, DFT calculations indicated a much greater difference in acidity for the C2- and C3-protons. Due to the strong thermodynamic preference for C2-metalation, reaction with TMPZnCl ∙ LiCl in THF solvent generated a mixture of C2- and C3-metalated products, while the use of TMP2Zn∙2MgCl2 ∙ 2LiCl led to decomposition of thiochromone. However, regioselective C2-metalation could be achieved by switching the solvent to a less polar THF/Et2O combination (2:1 ratio), which may influence TMPZnCl complexation at the sulfur atom. Thus, the synthesis of 2,3-disubstituted thiochromones could be achieved through the sequential metalation and electrophilic quenching using TMPZnCl ∙ LiCl. In a similar vein, Lewis acidic BF3 ∙ OEt2 has also been used to change the metalation regioselectivity for pyridine substrates.31,32 For example, 3-cyanopyridine can be selectively metalated at the 2-position through reaction with TMP2Zn∙ 2MgCl2 ∙ 2LiCl, whereas pre-complexation of 3-cyanopyridine with BF3 ∙ OEt2 switched the regioselectivity to generate the 3,4-substituted product, as evidenced by subsequent Negishi cross-coupling reactions.32

Scheme 10 Regioselective zincation of chromone (Y ¼ O) or N-methylquinolone (Y ¼ NMe) in the absence (top) or presence (bottom) of MgCl2.30

Zinc Reagents in Organic Synthesis

11.06.2.1.3

199

Transmetalation routes to prepare organozinc complexes

Organozinc reagents can be prepared from highly reactive organolithium and organomagnesium precursors via transmetalation with a zinc halide salt.33 This approach has been used to prepare a broad range of organozinc reagents, with recent examples including the first bisdisilenylzinc compound [Zn{Si(Tip)]Si(Tip)2}2] (where Tip ¼ 2,4,6-iPr3C6H2), a-chloro-b,bdifluoroethenylzinc [CF2]CClZnCl] and bulky diorganozinc reagents such as [Zn(2,4,6-tBu3C6H2)2], as well as borylzinc and (diborylmethyl)zinc compounds.34–39 Organozinc compounds are useful synthons to prepare other organometallic compounds through reduction with a highly reactive metal (e.g. cesium), or transmetalation with a less electronegative metal compound including many transition metal halides (a key step in catalytic cross-coupling transformations, see Section 11.06.5).36,40 When prepared via transmetalation from an organolithium reagent, the organozinc products display better thermal stability than their organolithium precursors. With in situ transmetalations, the order of addition of the Li and Zn reagents can be key; in some cases, changing the order of addition can change the regioselectivity of the reaction.41 For example, deprotonating 2,4-dichlorobenzonitrile with TMPZnCl ∙ LiCl generated the thermodynamic C3-metalation product, as determined by iodine quenching (Scheme 11, right). In contrast, adding the more potent base LiTMP to 2,4-dichlorobenzonitrile in the presence of ZnCl2
2LiCl generated the kinetic metalation product, with directed ortho-metalation (DoM) occurring adjacent to the cyano group (Scheme 11, left). The rate of reaction of LiTMP with the substrate was shown to be faster than that of LiTMP with ZnCl2 to generate TMPZnCl ∙ LiCl. Following metalation with LiTMP, transmetalation with ZnCl2 occurred to generate a more stable product. Controlling the regioselectivity through altering the order of addition has enabled the preparation of some previously inaccessible organozinc species, including those based on arenes, pyridine, thiophene and furan scaffolds.

Scheme 11 Transmetalation of 2,4-dichlorobenzonitrile followed by iodine quenching.41

Whilst the direct insertion of zinc into a carbon-halogen bond provides an atom efficient route to prepare organozinc reagents, direct insertion of magnesium followed by transmetalation with ZnCl2 can offer faster reactivity, avoid the need for elevated temperatures and, in some cases, allows access to complementary regioisomers of the organozinc products (refer to Section 11.06.2.1.1, Scheme 4 for details).18,42–44 This approach often exploits the use of LiCl (which is proposed to activate the magnesium surface), as well as ZnCl2 (which traps the highly reactive organomagnesium product via transmetalation to form the more stable organozinc species).44 For example, reaction of 4-fluorobenzyl chloride with Mg (2.5 equiv.), ZnCl2 (1.1 equiv.) and LiCl (1.25 equiv.) gave the corresponding benzylzinc chloride after 45 min at 25  C, whereas the use of Zn (2 equiv.) and LiCl (2 equiv.) required 24 h at 25  C.42 Both organozinc halide and diorganozinc compounds can be prepared using this Mg/LiCl/ ZnCl2 metalation strategy, which has been applied to functionalized aromatic and heteroaromatic bromides, alkylzinc bromides and benzylic chlorides,18,42–44 with some studies suggesting that C60 can catalyze this reaction.45 While the exact nature of the co-complexes formed remains somewhat ambiguous, the presence of MgCl2 and LiCl salts can boost the reactivity of organozinc reagents toward subsequent addition reactions.44 For example, the presence of MgCl2 accelerated the addition of alkylzinc bromide [C(Me)2(CN)(CH2)4ZnBr] to trifluoromethyl phenyl ketone, reducing the reaction time from 48 h (77% yield without MgCl2) to just 6 h (76% yield with MgCl2) at 25  C in THF solvent (see Sections 11.06.3.4 and 11.06.10.4 for further examples). Deprotonation of heterocyclic substrates using TMP2Mg ∙ 2LiCl in the presence of ZnCl2 gave excellent yields of functionalized products upon subsequent cross-coupling or electrophilic quenching.46 Mechanistic studies suggested that Zn plays a dual role, first acting as a Lewis acid to form a pre-complex with heterocyclic substrates such as (functionalized) quinoxalines, pyrazines and pyrimidines, which facilitates deprotonation (Scheme 12). After deprotonation by TMP2Mg∙ 2LiCl, rapid Mg/Zn transmetalation occurs to trap the metalated intermediate as a more stabilized organozinc product. This methodology can overcome problematic decomposition of magnesiated heterocycles, enabling sensitive aromatics and heterocycles to be metalated at ambient temperature. For example, in the absence of ZnCl2, the metalation and iodine quenching of quinoxaline gave only traces of the desired iodinated product, whereas the homo-coupled product was observed in 34% yield. In contrast, treatment of the heterocycle with ZnCl2, followed by the slow addition of TMP2Mg ∙2LiCl, generated the desired quinoxalyl iodide in 94% yield after iodine quenching.

200

Zinc Reagents in Organic Synthesis

Scheme 12 Mg/Zn deprotonation/transmetalation of quinoxaline and subsequent iodine quenching.2,46

Heteroleptic diorganozinc reagents of formula ArZnEt can be prepared through transmetalation between Et2Zn and aryl boronic acids [ArB(OH)2] or aryl boroxines (Ar3B3O3). However, reactivity studies suggest that this formula may be oversimplistic, as PhZnEt prepared through Zn/B transmetalation routes gave higher yields in the arylation of benzyl halides compared to PhZnEt prepared from Ph2Zn and Et2Zn.47 This observation suggests that other species in the B/Zn mixture can influence the activity. 11B NMR spectroscopic studies suggested that PhB(OH)2 and Et2Zn react to give solvent dependent mixtures that included BEt3, BEt2Ph and BEtPh2 in toluene. Similar NMR resonances were also observed when using triphenylboroxine as the boron source. In THF, several boron-containing compounds were detected, which were assigned as RB(OY)2 (where R ¼ Et or Ph and OY could be OH, or OZnR), Et2B(OY) and a tetraborate anion. In glyme solvent, peaks corresponding to all five borate [BPh4-nEtn]− anions were observed (where n ¼ 0–4), counterbalanced by a solvated [ZnR]+ cation. These studies emphasize that transmetalation provides a useful preparation route for organozinc reagents, where the complex mixtures formed may play a beneficial (or detrimental) role in subsequent reactions.

11.06.2.1.4

Metal-halogen exchange routes to organozinc reagents

The preparation of organozinc reagents featuring sensitive functional groups such as aldehydes, esters, isothiocyanates, ketones and nitro groups has been facilitated by mild zinc-halogen exchange reactions starting from dialkylzinc precursors.48 Recent advances have included the synthesis of fluorinated organozinc reagents and new methods of boosting the metal-halogen exchange activity of dialkylzinc reagents by using transition metal salt catalysts or forming lithium zincates (refer to Section 11.06.9 for further details). Fluorinated diiodoalkanes can react with diethylzinc reagents in the presence of a Lewis base such as acetonitrile, to generate di-zinc reagents corresponding to the formula [(MeCN)2Zn((CF2)n)2Zn(MeCN)2] (where n ¼ 3, 4, and 6, Scheme 13).49,50 These di-zinc species can undergo transmetalation reactions to generate metallacycles, such as [(MeCN)2Ni(CF2)4], through reaction with [(dme)NiBr2] in MeCN solvent (where dme is dimethoxyethane). Alternatively, these fluorinated di-zinc reagents can be used as synthetic precursors to prepare fused fluorinated ring systems, through zinc/iodine exchange reactions with diiodo(hetero)arenes in the presence of a copper catalyst. Expanding on this work, zinc-iodine exchange between difluoroiodomethane, Et2Zn (0.5 equiv.) and DMPU (N,N0 -dimethylpropyleneurea) generated dialkylzinc [(DMPU)2Zn(CF2H)2] in 94% yield, which was stable and isolable under inert conditions.51 Designed for fluoromethylation reactions, [(DMPU)2Zn(CF2H)2] underwent nickel-catalyzed zinc-halogen (or pseudo-halogen) exchange with aryl bromides, iodides or aryl triflates, to generate a series of difluoromethylated (hetero)arenes under mild conditions (15 mol% [(dppf )Ni(COD)] in DMSO at room temperature for 24 h, where dppf is 1,10 -bis(diphenylphosphino)ferrocene). This methodology successfully difluoromethylated a broad range of (hetero)aryl halides, including those based on pyridine, furan and thiophene scaffolds with sensitive electron withdrawing groups (aldehyde, ester, ketone and nitrile). However, the reaction was sensitive to electron-donating groups, with alkyl and ether substituents yielding little to no product. Zinc-iodine exchange has since been applied to the coupling of fluorinated iodoalkenes/arenes with aryliodides, mediated by Et2Zn (1.5 equiv.), to generate a series of coupled bis-aryl and alkene-aryl products.52,53

Scheme 13 Reaction of fluorinated diiodoalkanes with diethylzinc (L ¼ MeCN).49

Zinc Reagents in Organic Synthesis

201

Zinc-halogen exchange of iPrZnI with (bromodifluoromethyl)trimethylsilane (Me3SiCF2Br), in the presence of a [(dppe)CoBr2] catalyst (where dppe is 1,2-bis(diphenylphosphino)ethane), generated the fluorinated alkylzinc complex (F2(Me3Si)C)ZnBr in 88% yield (Scheme 14).54,55 This route was a significant improvement over the direct insertion route (from Zn dust and F2(Me3Si)Br), which led to homo-coupling of the zinc species, that is, formation of (F2(Me3Si)CdC(SiMe3)F2). The key feature of (F2(Me3Si)C) ZnBr is the ZndCF2dSi unit, which can act as the source of a CF2 dianion. By exploiting the different nucleophilicities of the ZndC and SidC bonds through step-wise coupling with two different C-electrophiles (an allylic halide for ZndC and an aldehyde for SidC), (F2(Me3Si)C)ZnBr can be used to generate products featuring a difluoromethylene fragment.

Scheme 14 Synthesis of fluorinated alkylzinc species through zinc-halogen exchange.48,54

The preparation of polyfunctional bis-arylzinc reagents has been achieved via zinc-iodine exchange catalyzed by lithium acetylacetonate [Li(acac)] salts. This methodology tolerates a range of sensitive functional groups such as aldehydes, esters, ethers, isothiocyanates, ketones and nitriles.56 Combining functionalized aryliodides with iPr2Zn or sBu2Zn and Li(acac) (10 mol%) in a Et2O:NMP solvent system generated the bis-arylzinc species (Scheme 15, top), which could be subsequently functionalized via electrophilic trapping. The acetyl acetonate anion is proposed to coordinate to Zn to form a tetracoordinate zincate species with enhanced reactivity compared to the dialkylzinc reagent, which can subsequently undergo metal-halogen exchange to generate the bis-arylzinc product and regenerate the Li(acac) catalyst (Scheme 15).48,56,57

Scheme 15 Preparation of bis-arylzinc reagents catalyzed by Li(acac) salts and the proposed mechanism.48

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Zinc Reagents in Organic Synthesis

Transition metal salts can also be used to catalyze zinc/halogen exchange reactions.48,58 Aryl chlorides are more challenging metal-halogen exchange substrates than the bromide and iodide analogues, on account of the greater CdCl bond strength. Combining the magnesium triorganozincate (4-Me2NC6H4)2Zn(iPr)MgCl with iron(III) or cobalt(II) catalysts enabled zinc/ chlorine exchange reactions to occur with aryl, heteroaryl and alkyl chlorides, including primary, secondary and tertiary alkyl chlorides. Sensitive ester and nitrile functional groups were also tolerated. For example, reaction of substituted 2-chlorothiophene with (4-Me2NC6H4)2Zn(iPr)MgCl (2 equiv.) in the presence of 10% Fe(acac)3 and 20% 4-fluorostyrene generated organometallic zinc species under mild conditions (THF, 25  C, 16 h, Scheme 16). Subsequent electrophilic quenching of the thiophene-zinc product with pivaloyl chloride (3 equiv.), in the presence of 20% CuCN ∙2LiCl, generated the acylated thiophene with an isolated yield of 62%. Notably, substrates bearing more than one chloro-group, such as 2,5-dichlorothiophene and 1,3,5-trichlorobenzene underwent selective mono-metal/halogen exchange. Alkyl chlorides, such as ethyl 4-chlorobutanoate, benzyl-protected 6-chlorohexanol and cholesteryl chloride, could also be successfully metalated, including more challenging tertiary alkyl chlorides such as 1-chloroadamantane.

Scheme 16 Zinc/halogen exchange and electrophilic quenching of thiophene derivatives.58

While the Fe(III)-catalyzed methodology worked well for alkyl chlorides, some aryl chlorides and chloro-substituted N-heterocycles performed better in the presence of Co(acac)2 catalysts using a modified magnesium zincate prepared from 4,40 oxybis(3-iodo-1-methylbenzene) (Scheme 17).58 For example, chloro-substituted pyrazolopyridine derivatives were converted to the iodo-substituted analogues using 4 equivalents of zincate and 20% Co(acac)2, followed by quenching with iodine (65% yield).

Scheme 17 Cobalt-catalyzed zinc/halogen exchange of heterocyclic chlorides.58

11.06.2.2 Preparation of heterometallic compounds Heterometallic organozinc complexes often display enhanced activities and selectivities compared to their homometallic analogues. The majority of heterometallic reagents are prepared via co-complexation reactions, although trans-metal trapping has recently emerged as an alternative preparation route. Once formed, heterometallic species can be derivatized through a wide variety of reactions, including deprotonation, metal-halogen exchange and addition reactions. These different modes of reactivity are detailed in Section 11.06.10.

11.06.2.2.1

Co-complexation preparation routes toward heterometallic zincates

A library of heterometallic zinc complexes have been prepared through co-complexation, where two monometallic compounds are combined to form a larger molecular structure (Scheme 18, top). The majority of heterometallic zinc complexes synthesized through this route have been alkali metal zincate species, formed by combining a diorganozinc reagent with an organoalkali metal reagent (typically LiR, NaR or KR where R is an alkyl/amido/alkoxo unit).59,63,64 Here, the “ate” suffix refers to the anionic formulation of zinc, as the anionic ligands are typically transferred from the alkali metal to the softer, more carbophilic zinc center. These anions can either be completely transferred to form solvent separated ion pair structures, or can bridge between the two

Zinc Reagents in Organic Synthesis

203

metals to form contacted ion pairs (Scheme 18). The resultant structure often depends on the solvent and heterometal stoichiometry, as well as the nature of the Lewis donor solvent. Using one equivalent of the organoalkali metal reagent typically forms a complex of formula [AM]+[ZnR3]− (AM ¼ alkali metal), termed a lower order zincate, where the zinc bears a monoanionic charge. Alternatively, two equivalents of the organoalkali metal reagent typically form higher order zincates, ([AM+])2[ZnR4]2−. Many higher order zincates adopt the Weiss motif, a commonly observed solid-state structural motif featuring a contacted ion pair with a central [ZnR4]2− unit.59 However, it is worth noting that the solution-state chemistry is often more complex than the solid-state structure, as dynamic equilibria between lower order and higher order species as well as homometallic compounds can occur in solution.

(A)

(B)

Scheme 18 (A) Formation of metal zincates,59 (B) common structural motifs for alkali metal zincates formed by co-complexation routes, where D ¼ Lewis donor solvent, R ¼ bridging alkyl/amido/alkoxo, R0 ¼ terminal alkyl/amido/alkoxo.60–62

A variety of homoleptic alkali metal zincate reagents have been prepared via co-complexation of organoalkali metal (AMR) and diorganozinc reagents (ZnR2), including NaZnEt3, LiZnMe3, LiZntBu3, and Li2ZntBu4.60–62 Heteroleptic alkali metal amidozincates have also been prepared, many of which include the sterically bulky amide tetramethylpiperidide (TMP), such as [LiZn(TMP)tBu2] and [(TMEDA)Na(m-tBu)(m-TMP)Zn(tBu)] (where TMEDA ¼ tetramethylethylenediamine).65,66 Such co-complexation methodologies are very versatile, and have been extended to a broad variety of alkali/alkaline earth metals (e.g. Li, Na, K and Mg) and amides such as dimethylpiperidide (DMP), hexamethyldisilazide (HMDS) and diisopropylamide (DA).59,67–71 Although co-complexation is a versatile route to prepare both lower and higher order zincates, the reaction is not always straightforward. For example, combining TMEDA, Zn(CH2SiMe3)2 and phenyllithium in a 1:1:1 ratio did not give the expected heteroleptic co-complex [(TMEDA)LiZn(Ph)(CH2SiMe3)2]. Instead, disproportionation occurred to yield homoleptic alkylzincate [(TMEDA)LiZn(CH2SiMe3)3].72 Deviation from the common lower order and higher order zincate motifs can also be observed, for example, when using the multidentate amide, 2,20 -dipyridylamide (dpa). Transamination of [(TMEDA)Na(m-tBu)(m-TMP)Zn(tBu)] with 2,20 dipyridylamine (dpaH) generated a complex that appears to be a disodium zincate, [(TMEDA)2Na2(dpa)2ZntBu2]. However, this complex can perhaps be better described as a co-complex between dimeric TMEDA-chelated sodium amide and di-tert-butylzinc, where the sodium metalloligand datively coordinates to the neutral zinc fragment through two ZndN(pyridyl) bonds (Scheme 19).73

Scheme 19 Synthesis and structure of the co-complex formed between dimeric TMEDA-chelated sodium amide and di-tert-butylzinc.73

204

Zinc Reagents in Organic Synthesis

11.06.2.2.2

Formation of heterometallic complexes via trans-metal trapping

More recently, another preparative method toward zincate reagents has emerged, based on partial transmetalation and coined as trans-metal trapping by Mulvey and co-workers. While transmetalation involves anion transfer from an electropositive metal such as lithium to a softer, less reactive metal such as zinc (vide supra), recent studies have shown that complete transmetalation does not always occur. Instead, partial metathesis can occur to form a heterometallic complex (Scheme 20).74 Unlike transmetalation, the metal that performed the initial deprotonation is not fully released, and so the product formed is heterometallic rather than homometallic.74–76

Scheme 20 The relationship between trans-metal-trapping and transmetalation.74

For example, a fluorinated b-aminoimine compound was deprotonated using nBuLi, and subsequently reacted with ZnBr2 or ZnI2 to generate the heterometallic lithium zincates [HC(CMeNAr)2]Zn(Br)2Li(Et2O)2 and [HC(CMeNAr)2]Zn(I)2Li(Et2O)2, respectively (where Ar is 2,6-F2C6H3). Transmetalation from Li to Zn occurs, as the LidN bonds are replaced by ZndN bonds, yet the LiBr product formed remains coordinated via two bridging halide atoms (Scheme 21). In a similar vein, combining alkali metal dipp-dabqdi compounds with ZnCl2 (dipp-dabqdiH2 ¼ 2,5-diamino-1,4-benzoquinonediimine) produced a series of alkali metal zincates: [(THF)3Li(m-Cl)ClZn(m-dipp-dabqdi)ZnCl(m-Cl)Li(THF)3]; [(Et2O)2Li(m-Cl)ClZn(m-dipp-dabqdi)ZnCl(m-Cl)Li(Et2O)2]; and [(Et2O)2Na-(m-Cl)2Zn(m-dipp-dabqdi)Zn(m-Cl)2Na(Et2O)2].78 While still an emerging area, these studies hint that many reactions that were previously assumed to operate via transmetalation may actually involve heterometallic structures.74–76

Scheme 21 Preparation of heterometallic LidZn complex via trans-metal trapping.59,77

11.06.3 Applications of organozinc reagents in addition reactions 11.06.3.1 Overview Organozinc reagents have been well-explored as a source of nucleophiles in addition reactions, as well as in substitution and cross-coupling chemistry (Sections 11.06.4 and 11.06.5). Compared to highly polar organolithium and Grignard reagents, organozinc reagents are slow to add to electrophilic substrates due to the covalent, relatively non-polar nature of the ZndC bond, and thus require activation via a catalyst.79 However, as a consequence of this moderate reactivity (and relatively low cost), organozinc reagents are privileged reactants in asymmetric syntheses, generally providing higher stereo- and enantioselectivities and tolerating a larger variety of reactive functional groups. Using high purity dialkylzinc reagents is crucial, as Lewis acidic Li and Mg salt impurities formed during their preparation can exert a significant and sometimes detrimental effect on the enantioselectivity.

11.06.3.2 Addition to carbonyl compounds Nucleophilic addition of organozinc reagents to carbonyl compounds is one of the most relevant methodologies for CdC bond formation, used to prepare important molecular building blocks in pharmaceuticals and agrochemistry.80 The asymmetric alkylation, alkenylation, alkynylation and arylation of aldehydes or ketones generates chiral secondary or tertiary alcohols, where stereocontrol is typically introduced by a chiral ligand. The past 15 years have seen a rapid expansion of the chiral catalysts and synthetic methods available.

Zinc Reagents in Organic Synthesis

11.06.3.2.1

205

Alkylation of carbonyl compounds

For decades, chiral amino alcohol and hydroxyamide-based ligands have been used as catalysts for the addition of organozinc reagents to carbonyl compounds.81 More recent examples include the application of a b-hydroxyamide ligand (derived from (1S,2R)-(+)-norephedrine and furoic acid) in the ethylation of benzaldehydes and heteroaryl carbonyl compounds at 0  C in toluene (Scheme 22).82 The reactions were investigated in the presence and absence of a Ti(OiPr)4 promoter. In both cases, similarly high yields (95%) and enantioselectivities (ee < 99.8%) were achieved, indicating that the hydroxyamide ligand alone exerts excellent activity and selectivity. The proposed mechanism involves a ligated Zn-monoalkyl species coordinating to a diethylzinc unit through the alkoxide moiety (Scheme 23).82 Subsequent coordination and nucleophilic attack of an aldehyde substrate (on the re-face) yields the chiral Zn-alkoxide, which is converted to the corresponding alcohol during the workup.

Scheme 22 Addition of diethylzinc to benzaldehydes using a b-hydroxyamide ligand.82

Scheme 23 Proposed catalytic cycle for the addition of diethylzinc to benzaldehyde using an amino alcohol ligand.82

Enantioselective addition of dialkylzinc reagents to aromatic aldehydes was also achieved using a series of structurally flexible bis(amino amide) ligands as catalysts (Scheme 24). The chiral benzyl- or naphthylalcohol products were obtained with high yields (60–90%) and excellent enantioselectivities (ee < 99%).83 DFT studies revealed that an anti-trans transition state provides the S enantiomer of the product (Scheme 24, bottom), while the R enantiomer could form via syn-trans or anti-cis pathways (the syn-cis transition state is sterically disfavored).

206

Zinc Reagents in Organic Synthesis

Scheme 24 Enantioselective addition of Et2Zn to aromatic aldehydes catalyzed by bis(amino amide) ligands and the representation of relevant transition states.83

The uncatalyzed alkylation of a-ketoesters with dimethylzinc was shown to be relatively rapid compared to aldehydes and ketones. As a-ketoesters can act as chelating ligands to activate the alkylzinc reagent, competing ligand-free, non-enantioselective background reactions may occur (refer to Section 11.06.3.2.3 for further details). These background reactions may be overcome by using strongly electron-donating ligands. However, overshooting the electron-donating effect could decrease the Lewis acidity of Zn and thus disfavor coordination and activation of the carbonyl unit toward nucleophilic attack. Mandelamides proved to be excellent ligands for the asymmetric methylation of a-ketoesters, affording chiral a-hydroxyesters with good yields and enantioselectivities (ee < 90%) at mild temperatures (Scheme 25).84

Scheme 25 Methylation of a-ketoesters using dimethylzinc and a mandelamide ligand.84

Chiral ligands derived from inexpensive, naturally occurring chiral backbones have also been used, such as methionine-derived N-ferrocenylmethylazetidin-2-yl(diphenyl)methanol and camphor-based tertiary-amido isoborneol derivatives.85–87 Both of these ligand systems were employed in the addition of dialkylzinc reagents to aldehydes providing excellent enantioselectivities (ee < 99%). Ligands with non-natural chiral backbones, including ferrocenyl substituted aziridinylmethanols (FAM)s88 and derivatives of atropisomeric 1,10 -bi-2-naphthol (BINOL) were also successfully applied.89

11.06.3.2.2

Alkenylation (vinylation) of carbonyls

The addition of vinylzinc reagents to carbonyls furnishes chiral allylic alcohols, which are valuable and versatile synthetic building blocks as the double bond (adjacent to a stereogenic center) can undergo a variety of transformations. The classical method of in situ hydrozirconation with subsequent zirconium–zinc transmetalation has been used to generate vinylzinc reagents since the 1990s. More recently, the vinylation of various carbonyl compounds was studied using Ti(OiPr)4 as a promotor along with valine-derived b-aminothiol ligands (Scheme 26).90 The high efficiency of this system (compared to amino alcohol ligands) was attributed to the superior affinity of thiols to coordinate to zinc (vs zirconium) without detrimentally reducing the Lewis acidity of Zn (due to the poorer electron-donor ability of thiols), thus maintaining efficient carbonyl coordination.80 This methodology was used to functionalize a broad range of aldehydes and ketones with good yields (98:2 >98:2 96:4 >98:2

Reproduced from Ref. Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464–3471 with permission from ACS.

Scheme 109

430

Gallium and Indium Complexes in Organic Synthesis

Table 25 Indium-catalyzed diastereoselective coupling of chiral imino ester with allylic bromide.

Reproduced from Ref. Min, Q.-Q.; He, C.-Y.; Zhou, H.; Zhang, X. Chem. Commun. 2010, 46, 8029–8031 with permission from RSC.

An excellent procedure to access chiral homoallylic amines in a one-step protocol was reported via allylation of aldehydes with (S)-N-tert-butanesulfinamide and tetraethoxytitanium.192 Similarly, addition of NaBr as additive has been explored; such reactions went well in water with improved yields and high diastereoselectivities.193 Later Foubelo, Yus, and Das used novel compounds with heterocyclic moieties and developed new natural products (Schemes 110 and 111).194–201 Furthermore, Sirvent et al. extended this strategy and achieved excellent stereocontrol using substrate N-tert-butanesulfinyl ketimines.202 Recently, Taddei and co-workers prepared homoallylic amines with great stereocontrol by using chiral 1-amino-2-indanol during allylation of imines (Scheme 112).203 In addition to further elaboration of this work, hydroformylative cyclohydrocarbonylation was employed with a rhodium catalyst to prepare various substituted piperidines and indolizines with the great enantiocontrol. Using indium as a mediater, (R)-N-benzyl-2,3-O-isopropylideneglyceraldimine underwent allylation with 4-bromo-1,1,1-trifluoro-2-butene in good yield (Scheme 113).204 Another representative example facilitated by indium was intramolecular allylation of substituted imines

Scheme 110

Scheme 111

Gallium and Indium Complexes in Organic Synthesis

431

Scheme 112

Scheme 113

having lactone unit with allylindium reagents in MeOH (Scheme 114).205 Cook’s group utilized allylated chiral hydrazones as starting material which underwent intramolecular allylation in good yields (Scheme 115).109

Scheme 114

Scheme 115

432

Gallium and Indium Complexes in Organic Synthesis

11.09.5.1.2.3 Enantioselectivity in imines The enantioselective allylation of imines is receiving enormous attention.206 Asymmetric allylation with some chiral auxiliaries has already been discussed herein, however, it was noticed that a minute quantity of chiral catalyst in indium-mediated reactions can generate compounds with chiral behavior facilitating its synthetic applicability. Therefore, attempts were made to work with (+)-cinchonine in allylation of imines (Scheme 116).207 It was noteworthy that when 2,20 -binaphthol (BINOL) was used, indium-mediated allylation of hydrazone went effectively, affording several homoallylic amines. This reaction was made more efficient by another chiral catalyst such as sulfone BINOL (Scheme 117).208 Later, a novel chiral catalyst was developed comprising sulfinamide and urea moieties which was used in acylhydrazones allylation, which effectively improved yields in good quantity (Scheme 118).209

Scheme 116

Scheme 117

Gallium and Indium Complexes in Organic Synthesis

433

Scheme 118

Kim and Jang discovered an allylation method where asymmetric induction in benzohydrazones was observed via a chiral protonated ligand in methanol (Scheme 119).210 Singaram continued this work with the same idea by using chiral amino alcohols.173,174 In order to meet the demands of enantiopure medicinal compounds211 various new biologically active heterocycles were prepared. Some additives specially amino acids played an important role in intramolecular allylation assisted by indium206 where N-Boc-glycine (Boc-Gly-OH) emerged as a promising additive in the allylation of isatins.212 3-Allyl-3-aminooxindoles were prepared when ketimines underwent allylation in the presence of an imidazolylpyridine ligand with high enantioselectivities (up to 97%ee) (Scheme 120).213 A unique method was developed for the preparation of a-allyl-a-aryl amino esters in desirable yields and high enantioselectivity where acyclic a-ketiminoesters were allylated efficiently. The allylation reaction was performed with indium halides and BOX-type ligands. The transformation of the products into a-substituted proline derivatives was later achieved with high optical activity (Scheme 121).214

Scheme 119

434

Gallium and Indium Complexes in Organic Synthesis

Scheme 120

Scheme 121

11.09.5.2 Propargylation and allenylation reactions Allenyl alcohols were prepared by reacting derivatives of 4-bromo-2-butyn-1-ol with 2,3-O-isopropylidene-D-glyceraldehyde via indium, LiI and THF under ultrasonication (Scheme 122).215 A selective and easy method was implemented by another group who prepared bryostatin.216 Similarly, Loh and Huang designed a route to 1-substituted-3-methylene-5-yn-1-ols in which aldehydes reacted with propargyl bromide using indium halides (Scheme 123).217 Another instance was seen where isatins were propargylated in DMF or THF gave mixture of allenyl and homopropargyl alcohols.131,218 On further amplifications, the same protocol was successfully employed for the preparation of diverse functionalized spirocyclic oxindoles.219,220 Interestingly, a series of 3-methyl cyclopentenones was obtained by reacting b-bromovinylaldehydes with propargyl bromide in DMF catalyzed by indium (Scheme 124).221 Samanta, Kar and Sarkar used b-furyl-a,b-unsaturated aldehydes as substrates and afforded hydroxyphenanthrenes after a multistep pathway reactions (Table 26).222

Gallium and Indium Complexes in Organic Synthesis

Scheme 122

Scheme 123

Scheme 124

435

436

Gallium and Indium Complexes in Organic Synthesis

Table 26

Propargylation and of aromatic aldehydes.

Reproduced from Ref. Samanta, K.; Kar, G. K.; Sarkar, A. K. Tetrahedron Lett. 2012, 53, 1376–1379 with permission from Elsevier.

Further works on allenylation were validated by taking substrates processing an aldehyde unit and propargyl bromide (Scheme 125).223 Along these another synthesis using indium was carried out for accessing (−)-cinchonidine224–226 and (1S,2R)(+)-2-amino-1,2-diphenylethanol.173–175 Singaram and co-workers showed improved enantioselective propargylation with the chiral (+)-2-amino-1,2-diphenylethanol ligand (Scheme 126).227 Pulukuri and Chakraborty developed another process using (R)-Garner aldehyde, affording the corresponding product with excellent diastereoselectivity (Scheme 127). The homopropargyl alcohol obtained was further used in preparing rhizopodin.228 Moreover, benign conditions were used where aryl nitrile underwent allenylation to afford 5-methylisoxazole (Scheme 128).229 Additionally, Jin and Xu further introduced a method for an indium promoted diastereoselective controlled reaction of (S)-N-tert-butanesulfinyl imino ester with propargyl halides resulting in a-allenylglycines (Scheme 129).230

Scheme 125

Gallium and Indium Complexes in Organic Synthesis

Scheme 126

Scheme 127

Scheme 128

Scheme 129

437

438

Gallium and Indium Complexes in Organic Synthesis

Lee et al. found that a substoichiometric amount of indium was sufficient to carry allenylation of [3R(10 R,4R)]-(+)-4-acetoxy-3[1 -(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone with propargyl bromides to afford 4-allenyl-2-azetidinones (Scheme 130).231 The construction of dihydrocycloocta[b]-indole moieties was reported by performing the reaction of 2-allyl-3-iodoindoles with propargylbromides (Scheme 131).232 Later, Qing and his team applied novel synthetic procedures to many compounds with gem-difluoro units.233 Lee and co-workers allenylated carbonyls with g-vinyl propargyl bromide and prepared vinyl allenols (Scheme 132).234 Another allenylation reaction was reported using ethyl 4-bromobutynoate which gave corresponding a-hydroxyalkyl allenyl esters (Scheme 133).235 0

Scheme 130

Scheme 131

Scheme 132

Scheme 133

Gallium and Indium Complexes in Organic Synthesis

439

Interestingly, indolizines were prepared by using 2-pyridyl triflates or iodides and allene intermediates generated in situ then subjected to subsequent cross-coupling and cycloisomerization (Table 27).236 Lee et al., accomplished a methodology for preparation of an organoindium reagent by allenylmethyl bromide and indium.237 Similarly, an indium promoted pathway was developed to isolate 3-(1,3-butadien-2-yl)-3-hydroxy-1-methylindolin-2-one from isatin and 1,4-dibromo-2-butyne (Scheme 134).131 Coupling of 4-acetoxy-2-azetidinones and organoindium reagents produced azetidinones containing a 1,3-butadienyl-2-yl unit (Scheme 135).238 An organoindium reagent acting as 3,6-dianion of 1,2-hexadien-4-yne couples with carbonyl compounds to afford product comprising allenyne and diol moieties (Scheme 136).239 Later, with the help of indium as catalyst various electrophiles were used in designing products with propargyl and allenyl units, e.g. 1,2-dicarbonyls240–243 b-chloro vinylaldehyde,244 acetals and ketals,245 phenacyl bromide,134 a-diazoketone133 glycals,246 a-imino ethyl esters,108 imino isatins,113 epoxides,247 quinolinium and isoquinolinium salts,246,248 organosilyl chlorides,249 thiocyanates,250 hydroxyphthalides,110 and several others,251 were reported. An excellent method of preparing syn-homopropargylic alcohols was discovered using In(I) salts and nickel with good yields.252 Table 27

Propargylation involving Pd-catalyzed cross-coupling and cycloisomerization.

Reproduced from Ref. Kim, H.; Lee, K.; Kim, S.; Lee, P. H. Chem. Commun. 2010, 46, 6341–6343 with permission from RSC.

440

Gallium and Indium Complexes in Organic Synthesis

Scheme 134

Scheme 135

Scheme 136

11.09.5.3 Additions to alkenes and alkynes Ordinarily, 1,2-addition products could be formed when an allylindium species are added to an a,b-unsaturated ketones and aldehydes. Interestingly, a,b-unsaturated ketones with a methylene cyclopropane moiety, produced variety of products with different allylindium species (Scheme 137).253 A new compound, 4-allyl-2-amino-4H-chromene-3-carbonitrile was prepared from salicylaldehyde, malononitrile and several allyl bromides in aqueous medium mediated by indium (Scheme 138).254 Further studies showed even cyclopropylindium intermediate could be trapped with the aid of an allyl source to afford functionalized cis-diallylcyclopropanes (Scheme 139).255 Another instance of indium promoted allylation was developed wherein an allyl bromide bound with a terminal alkyne underwent allylation-cyclization and form five membered compounds.256 Further many works were observed on addition of allylindium species to various derivatives allenyne 1,6-diols.257 It was noticed that the same reaction with gold as catalyst, dienyne 1,6-diols convert to trisubstituted furans.258

Scheme 137

Gallium and Indium Complexes in Organic Synthesis

441

Scheme 138

Scheme 139

Among the most widely used methods for alkynylation, indium(III) salts provide an efficient route to activate terminal alkynes. An efficient In(III)-catalyzed process for the alkynylation of carbonyls was developed by Shibasaki and co-workers (Table 28).7 When phenylacetylene was introduced to imines in presence of InCl3 and copper as catalyst the rate of reaction was increased significantly (Scheme 140).259 Surprisingly, it was found that high enantioselectivity could also be produced with (R)-BINOL having less enantiopurity.260 Various catalytic methods have been designed for alkynylation of imines and nitrones.261 Further it was found that imines can be generated directly262 from carbonyl compounds and amines (Scheme 141).263 Subsequently, an asymmetric alkynylation of aldehydes was reported employing (R)-BINOL (Scheme 142).264

Table 28

InBr3-catalyzed alkynylation of aldehydes.

Entry

R1

R2 (2 equiv.)

Time (h)

Yield (%)

1 2 3 4 5a 6 7 8 9 10 11 12a

Ph o-MeC6H4 m-OMeC6H4 o-FC6H4 p-FC6H4 o-ClC6H4 o-CF3C6H4 o-CF3C6H4 o-NO2C6H4 Naphthyl 3-Formylthiophene Cyclohexyl

Ph Ph Ph Ph Ph Ph Ph (CH2)2Ph Ph Ph Ph Ph

44 48 44 24 22 5 10 42 10 24 48 10

73 88 63 86 73 93 98 75 99 82 62 84

a DME was used as solvent (5.0 M). Reproduced from Ref. Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org. Lett. 2005, 7, 1363–1366 with permission from ACS.

Scheme 140

442

Gallium and Indium Complexes in Organic Synthesis

Scheme 141

Scheme 142

It was noticed that indium (III) triflate when compared to other metal catalyst afforded better yields.265 In(III) salts form enolates and addition reaction between dicarbonyls and alkynes successfully yields terminal olefins (Scheme 143). But it was noticed that substrate 1-iodoalkynes yielded specifically syn products.266 Moreover, Curran and co-workers extended this methodology, to include substrates such as malonate derivatives along with low boiling-point terminal alkynes.267 The Nakamura group observed asymmetric addition between enamines and terminal alkynes leading to products with high enantioselectivity (Scheme 144).268 Pronin et al. presented an easy method in which silyl enolates underwent addition to terminal alkynes.269 An efficient catalyst In(NTf2)3 was used in the Friedel–Crafts alkynylation of indoles (Scheme 145).270 Prajapati and his group reported hydroamination reaction of phenylacetylene with anilines yielding imines. When the reaction was run for longer duration with surplus terminal alkyne subsequent hydroalkylation was observed (Scheme 146).93 Additionally, hydrothiolation of terminal alkynes was found to give heteroaromatic thiols.271 Generally, internal alkynes showed less reactivity, but when 1-bromoalkynes were used with heteroaromatic thiols, these produced Z-alkenes predominantly.272

Scheme 143

Scheme 144

Gallium and Indium Complexes in Organic Synthesis

443

Scheme 145

Scheme 146

11.09.5.4 Indium based carbo- and heterocyclization reactions Indium (III) catalysts can readily tolerate heteroatoms and therefore assist as convenient substitutes to other metals in cyclization reactions. Additionally, indium (III) salts have the capability to stimulate a number of reaction components and at the same time allowing possibilities for designing multicomponent reactions, permitting various practical synthesis of carbo- and heterocyclic products.

11.09.5.4.1

Carbocyclization

The Conia-ene reaction was observed when 1,3-dicarbonyl compounds underwent both intra- and intermolecular addition with alkynes forming many useful carbo- and heterocycles.273 Nakamura also noticed the intramolecular Conia-ene reaction with indium (III) salts (Scheme 147).274 When In(NTf2)3 was used, substrates such as o-alkynyl-b-keto esters scaffolded the formation of six to fifteen-membered compounds. Further, this strategy was followed in synthesizing ()-muscone (Scheme 148).274a The same group performed another intermolecular double Conia-ene cyclization with b-keto esters and a,o-diynes producing some interesting cyclic and spirocyclic systems (Scheme 149).274c Meanwhile another intramolecular cyclization in acetylenic malonic esters was investigated.275 Using this strategy syntheses of novel compounds such as (−)-salinosporamide A, (+)-neooxazolomycin and (−)-cinatrin C1 were developed.275c Additionally, a simultaneous intermolecular addition-cyclization was observed between propargyl alcohols and ethenedicarboxylates.276

Scheme 147

444

Gallium and Indium Complexes in Organic Synthesis

Scheme 148

Scheme 149

An excellent method was established to synthesize exomethylene cyclopentane derivatives by reacting functionalized aldehydes and alkynes.277 It was noted that with reaction conditions comprising amines with InCl3 (both 20 mol%) the cyclization reaction went effectively in DCE (Table 29). Further, the same group tried a new asymmetric modification for this conversion.277c In(OTf )3 was also used to design highly substituted aryl phenanthrenyl selenides.278 A complete study was done on annulation of substituted arylindoles by propargyl ethers using In(ONf )3 as catalyst (Scheme 150).279 Yet another approach was developed in which allenic alcohols having propargyl moiety to afforded benzene derivatives through rearrangement (Scheme 151).280 Xu et al. discussed cyclization in alkynes to afford 1,3,5-trisubstituted benzenes.281 Another example of an In(III)-mediated carbocylization was reported including an alkene and ynamide moiety.282

Gallium and Indium Complexes in Organic Synthesis

Table 29

445

Cyclization reaction involving chiral primary amines with the indium(III)-based metallo-organocatalytic system.

Amine

Solvent

Temp ( C)

t (h)

Yield (%)

ee (S/R)

(S)-A (S)-A (S)-A (S)-A (R)-A (R)-A (R)-A (R)-A

DCE DCE DCE Toluene CH2Cl2 Et2O THF Dioxane

100 60 20 20 20 20 20 20

3 4 40 45 40 23 28 67

92 92 87 30 27 41 68 83

59:41 63:37 68:32 55:45 38:62 41:59 35:65 32:68

Reproduced from Ref. (a) Montaignac, B.; Vitale, M. R.; Michelet, V.; Ratovelomanana-Vidal, V. Org. Lett. 2010, 12, 2582–2585; (b) Montaignac, B.; Vitale, M. R.; Ratovelomanana-Vidal, V.; Michelet, V. J. Org. Chem. 2010, 75, 8322–8325; (c) Praveen, C.; Montaignac, B.; Vitale, M. R.; Ratovelomanana-Vidal, V.; Michelet, V. Chem. Cat. Chem. 2013, 5, 2395–2404 with permission from Wiley.

Scheme 150

Scheme 151

Further, Prajapati and his group reported a subsequential addition, hydroarylation and decarboxylation when dicarbonyls and terminal alkynes were reacted resulting in b,b-disubstituted indanones (Scheme 152).283 Later, Srinivasan and his group discovered a strategy to synthesize functionalized naphthyl ketones and other 1,2-dihydronaphthalenes.284 Another methodology was developed to design complex carbopolycycles by Corey and co-workers (Scheme 153).285 A cascade cyclization reaction was reported forming a series of oxatricyclic compounds by the use of Chan’s diene and keto-alkynal using In(OTf )3 as catalyst.286 A fine catalytic procedure was developed for the synthesis of oxazolines from oxetanes using In(OTf )3.287 Another excellent demonstration to synthesize tetrahydro-1H pyrrolo[2,1-a]isoindolone-1,1-dicarboxylate with high regioselectivity was presented by Archana and her team (Scheme 154).288

446

Gallium and Indium Complexes in Organic Synthesis

Scheme 152

Scheme 153

Scheme 154

11.09.5.4.2

Heterocyclization of oxygen based functional groups

Indium(III) has an excellent ability in activating heteroatom functionalities and alkyne groups making it as an exceptional catalyst in designing several heterocycles. In this application, various functionalized tetrahydrofurans have been designed using p-toluene sulfonic acid as a cocatalyst (Scheme 155).289 An excellent method to design substituted furans was developed by Connell and Kang where rearrangement was noticed in acetylenic epoxides (Scheme 156).290 Nakamura et al. introduced a proficient cycloisomerization reaction for synthesizing some functionalized furans with a-propargyl-b-keto esters in decent yields (Scheme 157).291

Scheme 155

Gallium and Indium Complexes in Organic Synthesis

447

Scheme 156

Scheme 157

Furthermore, the Sestelo group established hydroarylation of aryl propargyl ethers catalyzed by InI3.292 Moreover, computational study was carried out by Lee293 supporting a mechanism involving a 6-endo-dig cyclization mechanism carried out by an InI3 active catalyst (Scheme 158).292a,293 Another example was reported which utilized an intramolecular hydroarylation reaction which was sequentially followed by a Pd-catalyzed cross-coupling reaction.292b Moreover, a smart methodology was designed using alkynyl enones, amines and aldehydes assisted by indium bromide affording several fused furan moieties (Scheme 159).294 Balalaie and his group295 developed an effective protocol for synthesizing pyranoquinoline with high proficiency via an InCl3 catalyzed activation of alkyne which afterwards undergoes a 6-exo-dig cyclization, resulting in a fused pyran ring in good yield (Scheme 160).

Scheme 158

Scheme 159

Scheme 160

448

Gallium and Indium Complexes in Organic Synthesis

11.09.5.4.3

Heterocyclization of nitrogen based functional groups

Nitrogen based heterocycles can be efficiently synthesized by addition of nitrogen based functional moieties to alkynes. A broad and simple method for preparing indole and quinoline derivatives were developed with 2-ethynylanilines and indium bromide by Konakahara and co-workers (Scheme 161).296 Similarly, Nakamura and his group developed an interesting method for synthesizing sulfonyl-substituted indoles through cyclization of 2-alkynyl-anilides using indium bromide as catalyst (Scheme 162).297 Another example of simultaneous addition-cyclization was observed between 2-(1-alkynyl)arylaldimines and 2-(1-alkynyl)arylaldehydes affording 1,2-dihydroisoquinolines (Scheme 163).298 Furthermore, same strategy was applied on 2-(1-alkynyl)arylaldehydes for designing 1H-isochromenes.298b

Scheme 161

Scheme 162

Scheme 163

Another representative example was developed for preparing heteroaromatic compounds with the aid of alkynylbenzaldehydes and alkynylanilines (Scheme 164).299 Singh and his group reported an interesting method for designing functionalized quinolines from 2-aminoaryl ketones.300 Recently, novel derivatives of 3-amino-2-benzoyl-1-aryl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione and 3-amino-2-benzoyl-1-aryl-1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives were reported by Jeong and his group.301 An excellent cycloisomerization reaction was utilized for synthesizing functionalized pyrroles by performing the reaction of a-propargyl-b-keto esters with imine equivalents as discussed by Nakamura and his group (Scheme 165).293

Gallium and Indium Complexes in Organic Synthesis

449

Scheme 164

Scheme 165

11.09.5.5 Coupling reactions Lee and his group used b-bromostyrene, which undergoes intramolecular cross coupling with allyl halides to afford coupled products with excellent stereocontrol but g-regioselectivity (Scheme 166).302 Cross-coupling was successfully achieved by using indium (20 mol%) and manganese (3 equiv.) with adequate efficiency.303 Rather than an organohalide, allyl carbonate also acted as electrophilic coupling moiety wherein, under Pd catalysis with allylindium sesquihalide, dienes were produced (Scheme 167).304 Aryl triflates were cross coupled with allylmetallic reagents affording product in high yields (Table 30).305 Furthermore, reactions could also proceed without any catalyst by the use of benzyl and cinnamyl bromides resulting in good yields.306

Scheme 166

Scheme 167

450

Gallium and Indium Complexes in Organic Synthesis

Table 30

Cross coupling of aryl triflates with allylmetallic reagents.

Solvent

M

Reaction temperature ( C)/time (h)

Yield (%)

Yield (%)

Yield (%)

DMF DMF THF DMF DMF

In In In SnBu3 9-BBN

100/4 65/24 Reflux/24 65/24 65/24

A 60 50 40 60 0

B 20 5 5 0 0

C 0 0 0 25 80

Reproduced from Ref. Dai, Q.; Xie, X.; Xu, S.; Ma, D.; Tang, S.; She, X. Org. Lett. 2011, 13, 2302–2305 with permission from ACS.

Another representative example utilized (Z)- and (E)-alkenyl iodides with organoindium reagents in the presence of Pd(dppf ) Cl2, resulting in (Z)- and (E)-alkenes (Scheme 168).307 For instance, triorganoindium reagents cross-coupled with racemic secondary benzyl bromides with high enantioselectivity (Scheme 169).308 Liebeskind and co-workers reported a palladium catalyzed cross-coupling between R3In and thiol esters under palladium catalysis to afford ketones (Scheme 170).309 More recently, Giri and his team observed catalysis by copper and performed cross-coupling between triarylindium reagents and aryl halides.310

Scheme 168

Scheme 169

Gallium and Indium Complexes in Organic Synthesis

451

Scheme 170

Minehan’s group designed several functionalized carbohydrates under palladium catalysis (Scheme 171).311 Another example reported was total synthesis of proansamitocin and its derivatives using palladium catalyzed coupling using trialkynylindium312 and trivinylindium313 reagents. Another unprecedented reaction with triorganoindium reagents afforded derivatives of 5-bromo-2-chloropyrimidine via palladium catalysis.314 In recent times, cross-couplings in N-benzyl-2,4,5-triiodoimidazole moiety was seen which led to mono-coupled products with good yields (Scheme 172).315 By the use of two different triorganoindium reagents, the unsymmetrical transformation of 3,4-dichloromaleimide into 3,4-disubstituted maleimide via palladium-catalyzed cross-coupling was observed (Scheme 173).316 Furthermore various substituted polyaromatic compounds were produced by coupling tri(1- or 2-naphthyl)indium and aryl halides via a palladium catalyst.317 Another representative example was demonstrated between chromenes and 1,3-dicarbonyls in DDQ and In(OTf )3 (Scheme 174).318 Recently, an excellent coupling reaction with substituted carboxylic acids was developed using InI3–TMDS (1,1,3,3-tetramethyldisiloxane) to afford unsymmetrical dialkyl sulfides.319 A simple In(III)-catalyzed plan was executed to couple propargylamine and N-fluorobenzenesulfonimide to yield allenylsulfonamide and enaminonesulfonamide (Scheme 175).320 A unique rearrangement was seen during the cross coupling of bromoalkynes and allylsilanes to afford 1,4-enynes.321 Recently, Feng et al., developed a unique method involving cross dehydrogenative coupling of 3,6-dihydro-2H-pyrans with 1,3-dicarbonyls with aryl moieties.322

(A)

(B)

Scheme 171

452

Gallium and Indium Complexes in Organic Synthesis

Scheme 172

Scheme 173

Scheme 174

Gallium and Indium Complexes in Organic Synthesis

453

Scheme 175

11.09.5.6 Reduction reactions 11.09.5.6.1

Reduction of carbonyl compounds and their derivatives

A unique methodology was developed where two carboxylic acids under a reducing system result in ester derivatives in presence of InBr3 and sulfuric acid (Scheme 176)323 Another reaction between 1,1,3,3-tetramethyldisiloxane and trimethylbromosilane in presence of InBr3 led to reductive bromination of carboxylic acids in excellent yields (Scheme 177).324 Pinacol coupling products were observed during reduction of benzophenones, benzaldehydes and acetophenones in presence of InCl3–aluminum in aqueous ethanol at 80  C.325 Another reduction strategy with substrates such as esters and thiols used an excellent reducing system of 1,1,3,3-tetramethyldisiloxane or PhSiH3 and afforded unsymmetrical sulphides (Scheme 178).326 Direct etherification was made possible by using various aliphatic carboxylic acids and alcohols via an excellent reducing system composed of InBr3 and PMHS in a one-pot procedure (Table 31).327 Moreover, derivatives of 1,3-dithiolane or 1,3-dithiane via InI3-1,1,3,3-tetramethyldisiloxane were designed from substituted acids and finally afforded aldehydes.328

Scheme 176

Scheme 177

Scheme 178

454

Gallium and Indium Complexes in Organic Synthesis

Table 31

Synthesis of ethers from various carboxylic acids and alcohols.

Yi

Reproduced from Ref. Sakai, N.; Usui, Y.; Moriya, T.; Ikeda, R.; Konakahara, T. Eur. J. Org. Chem. 2012, 24, 4603–4608 with permission from Wiley.

A procedure where carboxylic acids are transformed into aldehydes via InI3 was developed by Sakai and his group (Scheme 179).329 An excellent reduction strategy to convert secondary amides to secondary amines using InI3 and 1,1,3, 3-tetramethyldisiloxane was reported.330 Another method was developed wherein various aliphatic, cyclic and aromatic amines were alkylated via InBr3-PhSiH3 affording tertiary amines in high yileds.331 Sakai and his team reported reduction of various substituted esters with iodine and 1,1,3,3-tetramethyldisiloxane in presence of 5 mol% indium bromide (Scheme 180).332

Scheme 179

Scheme 180

Gallium and Indium Complexes in Organic Synthesis

11.09.5.6.2

455

Reduction of nitrogen-, oxygen- and other heteroatom containing functional groups

An interesting investigation of reductive heterocyclization in nitroarenes with specific moieties at the ortho position in the presence of InI/MeOH was presented (Scheme 181).333 A unique method was reported in which substrate comprising epoxides and a radical-stabilizing group underwent deoxygenation in presence of indium/indium chloride in alcohol (Scheme 182).334 Saavedra et al. described a unique InCl3–NaBH4 reduction system which converts aromatic and aliphatic nitriles into primary amines.335 Furthermore, substituted nitrobenzenes underwent a selective reduction with the help of InI3-1,1,3,3-tetramethyldisiloxane to afford corresponding aniline derivatives (Scheme 183).336 Another reliable example in which reductive alkylation of indoles was observed with carbonyls as substrates lead to wide range of alkylindoles (Scheme 184).337

Scheme 181

Scheme 182

Scheme 183

Scheme 184

An excellent one pot preparation of aromatic amines from nitroarenes bearing an aliphatic ester via InCl3/(EtO)3SiH-based reducing system were reported in high yields (Scheme 185).338 Sakai and his group synthesized various dithioacetal and diselenoacetal derivatives through an indium-catalyzed reductive insertion of an orthoester into diaryl/dialkyl disulfides or diselenide bonds (Scheme 186).339 Sakai et al. demonstrated single step conversion nitrobenzenes to azobenzenes via an excellent reducing system using In(OTf )3 and Et3SiH.340

456

Gallium and Indium Complexes in Organic Synthesis

Scheme 185

Scheme 186

11.09.5.7 Annulation reactions A sole annulation reaction was achieved using 2-arylindoles and propargyl ethers via In(ONf )3 forming two successive carbon-carbon bonds, which can be further utilized in preparing substituted arylannulated[a]carbazoles (Scheme 187).341 A novel [1+ n] annulation reaction was carried out using b-ketoesters and 1,6-diynes to afford five to seven membered heterocyclic and spirocyclic structures (Scheme 188).342 Different aryl- and heteroaryl[b]carbazoles were prepared from indoles and ethyl(2ethynylaryl)methyl carbonates with different heteroaryl moieties.343 Another unique reaction was performed between derivatives of indoles and propargyl ethers affording substituted arylannulated[c]carbazoles (Scheme 189).344

Scheme 187

Tanwar and his group carried out annulation between 2-aminobenzophenone and ethyl acetoacetate under different metal Lewis acid catalysts. They reported that In(OTf )3 proved an excellent reagent affording the Friedländer product. Further they carried out the reaction between 2-aminoarylketones and several carbonyl compounds resulting in quinolines in high yields

Gallium and Indium Complexes in Organic Synthesis

457

Scheme 188

Scheme 189

Scheme 190

(Scheme 190).345 A unique strategy was developed for designing indolo[3,2-b]quinolones by performing the annulation between o-acylanilines and alkoxyheteroarenes. The heteroaryl[b]quinolones obtained were further transformed into cryptolepine derivatives.346 Luo and his group reported an excellent an annulation reaction with 2,3-disubstituted indoles and o-aminobenzyl alcohols aided by In(OTf )3 in dichloroethane affording bridged polycyclic indoline alkaloid skeletons (Scheme 191).347 Makhanya and his group synthesized fused indolo-pyrazoles using [3 +2] annulation reaction in a single pot system. Further they were screened for antifungal activity and surprisingly they also showed high potency against Saccharomyces cerevisiae.348 Another representative example using indium promoted annulation afforded spiro[indoline-3,40 -thiopyran]-2-ones (Scheme 192).349

Scheme 191

458

Gallium and Indium Complexes in Organic Synthesis

Scheme 192

11.09.5.8 Cycloaddition reactions using indium(III) salts An interesting azidation reaction with In (III) salts was performed with dialkyl acetal derivatives and trimethylsilyl azide. Furthermore, sequential azidation-cycloaddition reaction was observed in derivatives of alkynyl acetals to afford cyclic triazolo compounds which can be further recognized as aza-sugar analogues.350 A unique In(III) promoted Diels–Alder reaction was performed with alkynes and N-aryl trifluoroethylimine to obtain 2-trifluoromethyl-4-aryl quinolones (Scheme 193).351 A stereo based hetero Diels–Alder was performed with a chiral ligand in the presence of In(OTf )3 to give b-methoxy-g-methyl a,bunsaturated-d-lactones (Scheme 194).352 A new methodology was developed for isolating ()-lycoposerramine T, ()-serratine and ()-lycopoclavamine B in which the functionalized octahydroindane skeleton was created by carrying out a cycloaddition of an R-alkynylcyclopentenone with further stereo controlled incorporation of a hydroxyl group.353

Scheme 193

Scheme 194

A efficient catalysis by indium halide was observed during the cycloaddition of 1,2-cyclopropanated pyranoses and various aldehydes resulting in functionalized carbohydrates (Scheme 195).354 Another representative example was noticed between 3-butyliminomethyl-2-aryl-1H-indoles and p-benzoquinone affording products in good yields.355 An excellent protocol was developed for the preparation of cyclobutenone by the [2 +2] cycloaddition of allylsilanes and alkynones mediated by indium bromide (Scheme 196).356 Another indium catalyzed reaction involving 1,3-dipolarcycloaddition reaction was reported for isolating 5-[2-(1,2,4-triazol-3-yl)hydrazinyl]-1,2,4-triazin-6-ones while performing the reaction between hydrazonoyl

Gallium and Indium Complexes in Organic Synthesis

459

Scheme 195

Scheme 196

hydrochlorides and N,N0 -bis(trimethylsilyl)carbodiimide (Scheme 197).357 In recent times, Cao and colleagues reported an intramolecular cycloaddition reaction of N-sulfonylaziridines with indoles resulting in tetracyclic pyrroloindole skeletons found in several natural products with attractive biological features (Scheme 198).358 An easy and excellent procedure for preparing derivatives of tetrahydrocyclohepta[b]indoles was developed by [5 +2] cycloaddition of an unsaturated ester to an alkyne mediated by InI3.359

Scheme 197

Scheme 198

11.09.5.9 Reactions involving transition metals and chalcogens A unique protocol was implemented for the synthesis of diorganyl selenides via an indium(III) catalyzed process aided by zinc metal in a one pot manner (Scheme 199)360 Another efficient method to design functionalized carbocyclic moieties via palladium and InI promoted allylation reactions of 4-acetoxy-2-azetidinone has been developed with high regio- and stereoselectivity (Scheme 200)361 In recent times a consecutive conversion by indium-catalyzed Friedel–Crafts addition followed by a rhodium-catalyzed dehydrogenative cyclization affording Y-amino alcohol ended finally in designing the central tricyclic core of isatisine A.362

460

Gallium and Indium Complexes in Organic Synthesis

Scheme 199

Scheme 200

A efficient Indium(III)-catalyzed preparation of thioethers by performing the reaction between aromatic aldehydes and elemental sulfur was developed by Miyazaki et al. (Scheme 201).363 A special method was developed wherein direct transformation of dibenzyl ethers to dibenzyl sulfide via elemental sulfur was observed (Scheme 202).364 An easy preparation of thiolactones from lactones was reported using disilathiane.365 Further thiolactones and selenolactones could also be prepared using sulfur and selenium with indium chloride-PhSiH3 as a reducing system with good yields.366

Scheme 201

Scheme 202

11.09.6 Miscellaneous reactions 11.09.6.1 Cycloisomerization reactions The cycloisomerization reaction catalyzed by indium(III) salts of o-alkynyl-b-ketoesters proved an effectual way for synthesis of medium to large-sized rings (Scheme 203)274a A unique cycloisomerization protocol was developed for designing various benzo-fused heteroaromatic compounds by cyclopropene-3,3-dicarbonyls.367 Kwon and his team reported an indium catalyzed synthesis of phenanthrenes through 6-exo-dig-cycloisomerization (Scheme 204).368 Another example of indium(III) mediated cycloisomerization of polyyne-type aryl propargyl ethers for developing fused chromenes was developed.369

Scheme 203

Gallium and Indium Complexes in Organic Synthesis

461

Scheme 204

11.09.6.2 Glycosylation reactions An effective method of synthesizing glycosides was designed by the activation of N-phenyltrifluoroacetimidate or thioglycosides via indium(III) salts in combination with PhIO or halogenated reagents.370 Another work was reported in which bromo sugars were allowed to react with benzyl glycolate resulting in O and S-glycosylation.371 A unique work discussed O-glycosylation of nucleoside hydroxyls mediated by indium(III) salts.372 A special glycosylation procedure has been developed successfully by using indium(III) salts and performing a Koenigs-Knorr synthesis by activating hydroxyl groups.373

11.09.6.3 Hydroarylation reactions A unique intramolecular hydroarylation was carried out for designing tetralin and chromene derivatives through In(III) catalysis in comparison to a Ru-catalyzed alternative (Scheme 205).374 An effective protocol was designed for preparing 2,3diarylnaphthofurans through subsequent hydroarylation and Heck oxyarylation with the aid of In(OTf )3 in a one pot manner (Scheme 206).375 Another efficient method was discussed for synthesizing benzo-fused quinolones by carrying out the reaction between phenylacetylenes and naphthylamines (Scheme 207).376

Scheme 205

Scheme 206

Scheme 207

462

Gallium and Indium Complexes in Organic Synthesis

11.09.6.4 Silylation reactions An effective strategy was developed for designing silyl ethers with a hydrosilane via indium(III) bromide of various alcohols and oximes.377 Another simple protocol was catalyzed by indium(III) chloride wherein 1,4-hydrosilylation of a,b-enone esters took place by the use of triethylsilane and trifluoroacetic acid (Scheme 208)378 Another example of hydrosilylation was observed with terminal alkynes and aromatic amines using indium(III) bromide resulted in secondary amines in good yields.379 An well-organized plan to isolate tetralin derivatives was developed by carrying the reaction using 3-benzoylpropionic acids under indium(III) catalysis (Scheme 209).380

Scheme 208

Scheme 209

11.09.6.5 Redox-active reactions A successful oxidative study was carried out by reactions of carbene analogue of indium complex [In{N(Dipp)-C(Me)}2CH] (Dipp ¼ 2,6-iPr2C6H3) wherein the iminoenamine ligand reacted with In(I), [K{N(SiMe3)2}] to give the corresponding complex which on further reaction with alkyl halides to produce oxidative products [InRI{N(Dipp)C(Me)}2CH] (Scheme 210).381

Scheme 210

11.09.7 Conclusion The rapid advancement of indium and gallium complexes in organic synthesis have aroused the interest of organic chemists toward development of several organoindium and organogallium reagents toward various organic transformations. Within past two decades, the preparation and applications of indium and gallium complexes in organic synthesis have seen leaps and jumps. The

Gallium and Indium Complexes in Organic Synthesis

463

exceptional behavior of these complexes favors substrates possessing sensitive functional groups to be used as such without any modifications thus employing an efficient and economical synthesis. Organoindium and organogallium reagents have been found extremely useful in the synthesis of many natural products and complex moieties involving chemoselectivity. The highly versatile nature of gallium and indium complexes along with a potential substitute to other Lewis acid catalyst ensure a broader application of these reagents in organic synthesis, as well as in other areas.

Acknowledgments We are thankful to Dr. Prakash Kanoo, CUH, for his thoughtful suggestion. Monika and SS thank CSIR and UGC, New Delhi (India) respectively for the awards of research fellowship.

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Angew. Chem. Int. Ed. 2005, 44, 1336–1340. Tsuji, H.; Tanaka, I.; Endo, K.; Yamagata, K.-i.; Nakamura, M.; Nakamura, E. Org. Lett. 2009, 11, 1845–1847. Nagase, Y.; Miyamura, T.; Inoue, K.; Tsuchimoto, T. Chem. Lett. 2013, 42, 1170–1172. Nagase, Y.; Shirai, H.; Kaneko, M.; Shirakawa, E.; Tsuchimoto, T. Org. Biomol. Chem. 2013, 11, 1456–1459. Tanwar, B.; Kumar, D.; Kumar, A.; Ansari, I. M.; Qadri, M. M.; Vaja, M. D.; Singh, M.; Chakraborti, A. K. New J. Chem. 2015, 39, 9824–9833. Yonekura, K.; Shinoda, M.; Yonekura, Y.; Tsuchimoto, T. Molecules 2018, 23, 838–855. Luo, M.; Chen, J.; Yu, L.; Wei, W. Eur. J. Org. Chem. 2017, 2652–2660. Makhanya, T. R.; Gengan, R. M.; Kasumbwe, K. ChemistrySelect 2020, 5, 2756–2762. Hao, Y.; Gong, Y.; Cao, Z.; Zhou, Y.; Zhou, J. Chin. Chem. Lett. 2020, 31, 681–684. Yanai, H.; Taguchi, T. Tetrahedron Lett. 2005, 46, 8639–8643. Xie, H.; Zhu, J.; Chen, Z.; Li, S.; Wu, Y. Synlett 2010, 17, 2659–2663. Lin, L.; Kuang, Y.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 3868–3871. Zaimoku, H.; Nishide, H.; Nishibata, A.; Goto, N.; Taniguchi, T.; Ishibashi, H. Org. Lett. 2013, 15, 2140–2143. Ma, X.; Tang, Q.; Ke, J.; Yang, X.; Zhang, J.; Shao, H. Org. Lett. 2013, 15, 5170–5173. Gupta, R.; Jain, A.; Madan, Y. J. Heterocyclic Chem. 2013, 50, 1342–1345. Okamoto, K.; Shimbayashi, T.; Tamura, E.; Ohe, K. Org. Lett. 2015, 17, 5843–5845. Tsai, S.-E.; Yen, W.-P.; Li, Y.-T.; Hu, Y.-T.; Tseng, C.-C.; Wong, F. F. Asian J. Org. Chem. 2017, 6, 1470–1475. Cao, B.; Wei, Y.; Shi, M. Org. Chem. Front. 2018, 5, 423–427. Takeda, T.; Harada, S.; Okabe, A.; Nishida, A. J. Org. Chem. 2018, 83, 11541–11551. Braga, A. L.; Schneider, P. H.; Paixao, M. W.; Deobald, A. M. Tetrahedron Lett. 2006, 47, 7195–7198. Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 1293–1295. Patel, P.; Reddy, N. B.; Ramana, C. V. Tetrahedron 2014, 70, 510–516. Miyazaki, T.; Nishino, K.; Konakahara, T.; Sakai, N. Phosphorus Sulfur Silicon Relat. Elem. 2015, 190, 1378–1379. Sakai, N.; Takada, K.; Katayama, M.; Ogiwara, Y. Chem. Lett. 2018, 47, 791–793. Ogiwara, Y.; Takano, K.; Horikawa, S.; Sakai, N. Molecules 2018, 23, 1339–1349. Sakai, N.; Horikawa, S.; Ogiwara, Y. Synthesis 2018, 50, 565–574. Phun, L. H.; Aponte-Guzman, J.; France, S. Angew. Chem. Int. Ed. 2012, 51, 3198–3202. Kwon, Y.; Cho, H.; Kim, S. Org. Lett. 2013, 15, 920–923. Alonso-Maranon, L.; Sarandeses, L. A.; Martinez, M. M.; Pérez, S. J. Org. Chem. Front. 2018, 5, 2308–2312. Salmasan, R. M.; Manabe, Y.; Kitawaki, Y.; Chang, T.-C.; Fukase, K. Chem. Lett. 2014, 43, 956–958. Chandra, S.; Yadav, R. N.; Paniagua, A. B.; Bimal, K. Tetrahedron Lett. 2016, 57, 1425–1429. Zhang, Y.; Knapp, S. J. Org. Chem. 2016, 81, 2228–2242. Li, C.; Liang, H.; Zhang, Z.-X.; Wang, Z.; Yu, L.; Liu, H.; An, F.; Wang, S.; Ma, L.; Xue, W. Tetrahedron 2018, 74, 3963–3970. Xie, K.; Wang, S.; Li, P.; Li, X.; Yang, Z.; An, X.; Guo, C.-C.; Tan, Z. Tetrahedron Lett. 2010, 15, 4466–4469. Rao, V. K.; Shelke, G. M.; Tiwari, R.; Parang, K.; Kumar, A. Org. Lett. 2013, 15, 2190–2193. Rajesh, N.; Sarma, R.; Prajapati, D. Synlett 2014, 25, 1448–1452. Sridhar, M.; Raveendra, J.; Ramanaiah, B. C.; Narsaiah, C. Tetrahedron Lett. 2011, 52, 5980–5982. Xing, P.; Zang, W.; Huang, Z.-G.; Zhan, Y.-X.; Zhu, C.-J.; Jiang, B. Synlett 2012, 23, 2269–2273. Sakai, N.; Takahashi, N.; Ogiwara, Y. Eur. J. Org. Chem. 2014, 5078–5082. Sakai, N.; Kobayashi, T.; Ogiwara, Y. Chem. Lett. 2015, 44, 1503–1505. Hill, M. S.; Hitchcock, P. B.; Pongtavornpinyo, R. Inorg. Chem. 2007, 46, 3783–3788.

11.10

Silicon and Germanium Complexes in Organic Synthesis

David J Liptrot, Department of Chemistry, University of Bath, Bath, United Kingdom © 2022 Elsevier Ltd. All rights reserved.

Due to reasons beyond the editors’ control, the intended authors of the revised chapter on Silicon, with additional content regarding Germanium, were not able to complete it. Instead, the editors have provided a short list of important recent reviews in the area and the chapter “Silicon” from Comprehensive Organometallic Chemistry III, Volume 9. Applications I: Main Group Compounds in Organic Synthesis, has been included. Selected reviews and monographs: Organosilicon Compounds; Lee, V. Y., Ed. Academic Press, 2017. Fleming, I. Ed. Science of Synthesis; Thieme: Stuttgart, 2001; Vol. 4. Hydrosilylation. In Advances In Silicon Science; Marciniec, B., Ed.; Madsons, J., Series Ed. Springer: Dordrecht, 2009. Nakao, Y.; Hiyama, T., Chem. Soc. Rev. 2011, 40, 4893–4901. Hartwig, J. F., Acc. Chem. Res. 2012, 45 (6), 864–873. Functional Molecular Silicon Compounds I. Structure and Bonding vol. 155, Scheschkewitz, D., Ed. Springer: Cham, 2013. Korch, K. M.; Watson, D. A. Chem. Rev. 2019, 119 (13), 8192–8228. Klare, H. F. T.; Albers, L.; Süsse, L.; Keess, S.; Müller, T.; Oestreich, M. Chem. Rev. 2021, 121 (10), 5889–5985. Thomas, E. J.; Moloney, M. G. Eds. Science of Synthesis; Thieme: Stuttgart, 2002; Vol 5. Hanusch, F.; Groll, L.; Inoue, S. Chem. Sci. 2021, 12, 2001–2015. Roy, M. M. D.; Omaña, A. A.; Wilson, A. S. S.; Hill, M. S.; Aldridge, S.; Rivard, E. Chem. Rev. 2021, 121 (20), 12784–12965.

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11.11

Tin and Lead in Organic Synthesis

Terrance J Hadlington, Department of Chemistry, Technical University Munich, Munich, Germany © 2022 Elsevier Ltd. All rights reserved.

11.11.1 11.11.2 11.11.2.1 11.11.3 11.11.3.1 11.11.3.1.1 11.11.3.1.2 11.11.3.1.3 11.11.3.1.4 11.11.3.2 11.11.3.2.1 11.11.3.2.2 11.11.3.2.3 11.11.3.2.4 11.11.3.2.5 11.11.3.3 11.11.3.3.1 11.11.3.3.2 References

Introduction ‘Classical’ tin chemistry and toxicity Progress regarding polymer-supported tin reagents Progress in low-valent lead and tin chemistry Tin(I) and lead(I) dimers (distannynes and diplumbynes) Alkenes Unsaturated nitrogen-nitrogen bonds Isocyanides Dihydrogen Monomeric tin(II) and lead(II) species (stannylenes and plumbylenes) Early work Frontier orbitals Oxidative addition and reductive elimination reactions of stannylenes and plumbylenes Insertion reactions of stannylenes and plumbylenes Catalysis promoted by stannylenes Dimeric tin(II) and lead(II) species (distannenes and plumbenes) Alkynes Phosphalkynes

470 470 471 473 473 474 476 477 478 480 481 481 482 485 492 498 498 499 500

11.11.1 Introduction Classically, the chemistry of tin and lead has been dominated by the organostannanes and plumbanes, with the former playing a prominent historical role in organometallic chemistry. Initially endeavors were largely concerned with the direct synthesis of stannanes and plumbanes employing a number of now common strategies,1 initiated by Frankland in 1849,2 and rapidly expanded on in the early 20th century.3,4 From the mid-20th century, organostannanes in particular played a pivotal role in organic and organometallic synthesis, for example in hydrostannylation,5 radical initiated processes (viz Bu3SnH),6,7 and catalyzed coupling reactions (viz the Stille coupling),8–10 to name but a few. Toxic tin-derived radical initiators, notably Bu3SnH, have largely been superseded by an array of photo-initiators.11 Indeed, given this toxicity of organotin reagents, considerable efforts have focused on developing a range of protocols reducing tin contamination in reaction products,12 in order to maintain the broad utility of tin compounds in organic synthesis. These ‘classical’ examples of tin chemistry have long sat at the heart of organometallic chemistry, and indeed aided in fueling the resurgence in this field in the mid-1900s. It seems fitting, then, that ‘modern’ tin chemistry has had a similar effect on the organometallic community: the new renaissance in main-group chemistry revolved around low-valent tin chemistry, and to a lesser degree lead, with the discovery of heavier alkene analogues,13–15 heavier tetrylenes, heavier alkynes (and related reduced radical species),16–18 and hydrido-tetrylenes,19 and is now broadly encompassed by fascinating chemistry from throughout the sand p-blocks.20–23 Due to the ambiphilic nature of the majority of the above described group 14 compound classes, they are typically highly reactive toward a variety of organic substrates; a number of multiply-bonded species readily undergo cycloaddition reactions with unsaturated organics, sometimes reversibly, whilst facile bond activations in small molecules such as ammonia and dihydrogen are now known for a number of low-valent tin compounds. A selection of such complexes have even been employed as efficient catalysts for organic transformations. This article, therefore, will focus mainly on developments in the reactivity of these remarkable low-valent tin and lead compounds toward organic small molecules, and related chemical processes. This aims to highlight the importance of this field in moving toward achieving challenging organic transformations catalyzed by abundant, low-cost main group elements, which is too often a synthetic challenge reserved for the transition metals. Notably, this field was in its infancy at the publication of the previous compendium of COMC, making this a particularly poignant, and indeed necessary summary.

11.11.2 ‘Classical’ tin chemistry and toxicity The broadly developed concepts using SnIV reagents in organic synthesis have seen little further development since the previous volume of this book, largely due to moves away from organotin reagents and their inherent toxicity. It should be noted that this applies most prominently to a specific class of reagents, the triorganylstannanes (R3SnH), which have LD50 values of 0.7 (R ¼ Me),

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0.3 (R ¼ Et), and 0.5 (R ¼ Bu) mmol kg−1 for rats.24,25 Nevertheless, due to the incredible utility of Bu3SnH as a radical initiator this simple molecule truly monopolized this facet of chemical synthesis for quite some time.26,27 It took until chemists learned to harness the power of photons in visible light to promote similar chemistry that organyl-tin compounds could be broadly circumvented,28,29 despite earlier efforts to employ less toxic stannanes such as (Me3Si)3SnH.30 Still, despite the prominence of photo chemistry, the broad substrate tolerance and thus applicability of organostannanes has driven the search for ‘green’ tin chemistry. This has taken on many forms,12 notable examples being partitioning through phase separation or chromatography,31,32 in situ regeneration of catalytic quantities of stannane,33,34 implementation of stannanes on solid inorganic matrices,35,36 and utilization of ionic liquids as reaction media.37 Still, few developments in these areas have been forthcoming within the last 15 years, and so will not be discussed in further depth here. Polymer supported tin reagents, however, have seen some key developments leading to recyclable tin reagents, and deserve a brief discussion.

11.11.2.1 Progress regarding polymer-supported tin reagents A key development in tin chemistry has centered on the removal of trace amounts of organostannane reagents from product mixtures. As in heterogeneous catalysis, employment of solid-supported reagents ideally leads to easy separation of these reagents from reaction mixtures, allowing for both recyclability and reduced or negligible contamination. The most successful method for achieving this with tin reagents has been grafting of stannanes onto both soluble and insoluble organic polymers. Most often, this methodology involves the tethering of di-n-butyl stannane to a polymer support through a 4-carbon chain, so as to best mimic the cornerstone of organostannane chemistry, tri-n-butylstannane.38 The synthesis of polymer-bound stannanes is ordinarily achieved through two methods, either copolymerization of a stannane-functionalized monomer with a second monomer, or tethering of the stannane to a preformed polymer (Scheme 1). This has allowed for the synthesis of soluble stannylated polymers, for example polystyrene derivatives, which benefit from routine solution-state analyses such as NMR.39,40 Generally, however, due to drawbacks in the synthesis of useful examples of soluble stannylated polymeric materials, the use of insoluble

Scheme 1 Representation for synthetic pathways to polymer-supported stannanes.

stannylated polymers has been a much more central focus in this area.12 Stannylated polymers, both soluble and insoluble, have been employed primarily in halo-destannylation, allylation, and Stille coupling reactions, with the vast majority of reports regarding this chemistry being seen before 2005.12 More recent notable advances will be briefly discussed here. A soluble norbornene-derived polymeric system was developed by Espinetand co-workers, through the copolymerization of norbornene with (norborn-4-yl)(chloro)dibutylstannane, the chloride being readily substituted by a range of organic groups in the formed polymers.41,42 These have been successfully employed in the Stille reaction (Scheme 2), and markedly in the tandem ‘double Stille reaction’ for the coupling of alkynylstannanes with allylic halides, leading to trienynes (Scheme 3).42 Related soluble fluorene-derived stannylated polymers have also been reported by same group, which can be successfully employed in the Stille reaction.43 The main pitfall of these systems, the solubility of the polymers requiring a precipitation step to allow for efficient separation (Scheme 2), was later overcome with the synthesis of less soluble norbornadiene-derived stannylated polymers.44 This allowed for batch-synthesis via the Stille coupling reaction, utilizing a column packed with the polymer material, which could be efficiently regenerated between runs. Further, the proficiency of the system remained consistent after multiple runs, and tin contamination was reportedly low, between 15 and 50 ppm.

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Scheme 2 Steps required in the use and recycling of soluble poly(norbornadiene) supported organostannanes for the Stille coupling reaction.

Scheme 3 The ‘double Stille reaction’ of alkenyl halides with polymer supported alkynylstannanes, leading to trienynes.

Quintard and co-workers have reported on the straight-forward functionalization of a number of insoluble polymer supports, such a polyethylene and Amberlite resins, leading to supported aryl, allyl, and vinyl stannanes which can be reproducibly reused in cross-coupling catalyzes, with 10–30 ppm of residual tin in the isolated products.45–47 The use of HRMAS (High Resolution Magic-Angle Spinning) NMR here also gave good insight into the formulation of tin sites in these materials. A number of grafted organotin species have been reported as efficient supported catalysts in their own right. Building on earlier work,48,49 Biesemans and co-workers have shown that undecyltin trichloride supported on cross-linked polystyrene (Scheme 4) is in fact a more efficient catalyst for transesterification than the related homogenous catalyst (i.e. RSnCl3).50

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Scheme 4 The use of polymer supported trichlorostannane as a catalyst for transesterification and ROP of e-caprolactone.

The same group reported on the synthesis of well-defined cross-linked polystyrene-supported (dialkyl)(dichloro)stannane and (dialkyl)(chloro)stannoxane catalysts, which were active for both transesterification and ring opening polymerization (ROP) of e-caprolactone.51,52 The latter material showed good efficiencies in the ROP process, although tin leaching leading to residual tin levels >100 ppm were observed.52 Later results using the undecyl tin trichloride catalyst described above allowed for shorter reaction times and led to lower tin leaching, ranging from 10 to 50 ppm, with lower values for shorted reaction times.53 Given that the main drawback of utilizing organostannanes in synthesis is the high toxicity of these species, efficient methods to reduce tin residues in products is paramount to maintain the utility of these previously indispensable compounds. The described developments in polymer-supported stannanes in synthesis shows that this method is beneficial not only for the reduction of residual tin, but also in the broader context of recyclability. As such, these findings can and have been applied across a range of sub-disciplines, so as to aid in the ‘greening up’ of countless homogenous processes.

11.11.3 Progress in low-valent lead and tin chemistry The historical importance of Sn(IV) compounds in organic synthesis cannot be overstated. This now extremely well understood discipline of chemistry, however, has diminished in popularity considerably due to the discussed issue of toxicity in organostannanes. The reactive utility of low-valent tin compounds on the other hand has risen to prominence only in the last two decades. This has shone a light on a new facet of chemistry for this element, with an overarching theme of the activation of small (organic) molecules. These processes deviate considerably from earlier tin chemistry, and begin to mimic processes often related with transition metals. These bond activation processes, therefore, are central to the functionalization of organic substrates, and move toward the key goal of catalysis utilizing low-cost, highly abundant elements. Related lead chemistry is somewhat more challenging given the propensity for low-valent lead compounds to disproportionate to metallic lead. Nevertheless, some highly interesting chemistry is observed here, too. Given that the discipline of low-valent tin and lead chemistry is in its early stages, and so wider applications have not yet been developed, the tin contamination and toxicity of these complexes has not been critically assessed. It is likely, though, that such complexes will not be a toxicological threat given their ready oxidation to insoluble inorganic species under aerobic conditions. It is therefore envisaged that low-valent tin chemistry poses much less of an issue than organyl tin(IV) reagents. As such, low-valent tin, and to a lesser degree, lead chemistry is still a burgeoning field.

11.11.3.1 Tin(I) and lead(I) dimers (distannynes and diplumbynes) The distannynes and diplumbynes (e.g. compounds 1 and 2, Fig. 1) represent a class of compounds that are often described as heavier analogues of alkynes, and were only realized as stable crystalline species in 2002 and 2000, respectively.16,54,55 Reactivity studies involving these compound classes have therefore been fervent over the last two decades. Due in large to factors culminating in the inert pair effect, such as reduced or negligible sp hybridization with increasing quantum number,56–58 these heavier species differ significantly from classical alkynes in that the E-E bond order (E ¼ Sn or Pb) can deviate considerably toward one, typically with non-bonding electron density and vacant orbitals residing at the E centers leading to a trans-bent structure in these compounds.59,60 Because of this, these heavier alkyne analogues present reactivity patterns far from those exhibited by alkynes.61 These center on the facile activation of organic substrates, in some cases reversibly. Such processes are implicit in the broader field of organic synthesis, and will be focused on here.

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Fig. 1 Molecular structures of the first reported distannyne, 1, and a related diplumbyne 2, which is structurally similar to the first reported example. Dip ¼ 2,6-iPr2-C6H3.

Fig. 2 The frontier orbital interactions allowing for the cycloaddition of ethylene with a 1,2-diaryl tin(I) dimer.

11.11.3.1.1

Alkenes

The cycloaddition chemistry of CdC multiple bonds holds a well-established position in organic chemistry, rooted in the Woodward-Hoffman rules.62,63 The heavier alkynes, however, have only been studied in this regard relatively recently. Bulky 1,2-diaryldistannynes (e.g. 1) readily undergo [2 + 2 + 2] cycloaddition reactions with unactivated alkenes such as ethylene, without the need for heating, light, or an external catalyst. This, of course, contrasts with common CdC triple bonded species, and is viable due to the perturbed multiple bonding in heavier alkyne analogues leading to highly reactive frontier orbitals (Fig. 2).64 The products of these reactions, for example 3, maintain single SndSn bonds, forming highly strained bicyclic systems which can in fact liberate the free alkene to regenerate the distannyne starting material upon mild heating or application of vacuum (Scheme 5). Mechanistically, this process differs from that for the cycloaddition of ‘all carbon’ systems, the frontier orbitals of which are of p (HOMO) and p (LUMO) symmetry. For the heavier alkynes, the frontier orbitals hold p (HOMO) and n+ (LUMO) symmetry.65 This bears some similarity to the orbitals involved in the classical Dewar-Chatt-Duncanson model for transition metal-alkene binding, and essentially allows the LUMO of the heavier alkyne analogues to directly interact with the HOMO of the inbound alkene (Fig. 2). The most feasible mechanism for the overall reaction is a sequential double [2 + 1] cycloaddition of the alkene substrate at each Sn center, each addition being followed by ring expansion (Scheme 5). Such a mechanism was found to be feasible for closely related Si and Ge systems computationally.66,67

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Scheme 5 The reversible addition of ethylene to the distannyne 1, generating the bicyclic tin alkyl complex 3.

Conversely to the above, distannyne 1 undergoes a CdH activation reaction with cyclopentadiene, rather than the expected cycloaddition process, to eventually form the (aryl)(cyclopentadienyl)stannylene 4 (Scheme 6). This is hypothesized to proceed through CdH activation across the SndSn bond, followed by dissociation of the formed asymmetrical distannene into the finally observed product and (aryl)(hydrido)stannylene, the latter of which deprotonates CpH to complete the formation of 4.68 This latter point was corroborated by the addition of isolated (aryl)(hydrido)stannylene (vide infra) to CpH, which cleanly formed the expected species with loss of dihydrogen.69

Scheme 6 The reaction of distannyne 1 with cyclopentadiene, with mechanistic details involving 1,2-CH addition and CdH activation by a tin(II) hydride.

The 1,2-aryldistannynes were also found to readily reduce cyclooctatetraene through complete SndSn bond cleavage, in the formation of the aromatized sandwich complex, 5 (Scheme 7). This differs from the above described reversible addition of alkenes to aryldistannynes due both to the irreversible nature of this reaction, and the formal 2-electron reduction of the organic subsrate.70

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Scheme 7 The reduction of cyclooctatetraene with distannyne 1, leading to the inverse sandwich complex 5.

11.11.3.1.2

Unsaturated nitrogen-nitrogen bonds

The 1,2-diaryldistannynes also readily undergo reaction with unsaturated nitrogen compounds, specifically organic diazo and azide species. In a similar process to that for CdC unsaturates, distannyne 1 reacts with azobenzene via [2 + 2] cycloaddition and complete SndSn bond cleavage, to form the N,N0 -distannenyl hydrazine derivative, 6 (Scheme 8).71 The same distannyne also reacts with Me3Si-N3 to yield a unique distannenyl-imide 7, again in complete cleavage of SndSn interactions, and loss of N2. This is in notable contrast to related chemistry for digermynes, which form cyclic [Ge2N2] diradicals by reacting with two equivalents of the azide compound. These high-yielding reactions give some insight into the potential use of low-valent tin species in the construction of poly-stannylenes, which may otherwise be challenging to access through conventional methods.

Scheme 8 The reaction of distannyne 1 with azobenzene to form to the distannenyl hydrazine 6, and with trimethylsilylazide to form the distannenyl amide 7.

The above reactions also contrast with the reaction of 1,2-diaryldiplumbyne (8) with Me3Si-N3, which did not lead to a N-containing compound, but rather to a plumbylplumbylene in which CdH bonds of two flanking iPr groups have been activated (Scheme 9).72 Whilst this isomeric form of a diplumbene is highly interesting, the mechanism for its formation is unknown, but perhaps proceeds through a radical pathway initiated by the azide compound.

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Scheme 9 The double CdH bond activation observed upon reaction of diplumbyne 8 with trimethylsilyl azide, in forming plumbylplumbylene 9. Trip ¼ 2,4,6-iPr3C6H2.

11.11.3.1.3

Isocyanides

Given the availability of the LUMO in singly-bonded distannynes, caused by reduced sp-hybridization for the heavier group 14 elements, they can readily bind organic Lewis bases such as isocyanides. Power and co-workers have shown that 1 reversibly reacts with RNC (Scheme 10; R ¼ Mes (10) or tBu (11); Mes ¼ 2,4,6-Me3C6H2).73 Satisfyingly, a 1:1 mixture of green 1 and MesNC: remains green at ambient temperature, but becomes deep red when cooled to −40  C due to the formation of adduct 10. Warming again restores the green color of 1. This reversible phenomenon allowed for a van ‘t Hoff analysis giving the binding energy of RNC: to 1, with values of DHassn ¼ 25(3) kJ mol−1 (R ¼ tBu) and DHassn ¼ 127(4) kJ mol−1 (R ¼ Mes). Related reactivity of amido distannyne 12 toward tBuNC: lead to clean adduct formation (13), but no signs of reversibility (Scheme 11).74 It should also be noted that the outcome of the same reaction for the amido digermyne, 14, with tBuNC: led to a CdC coupled product, 15, indicative of a greater reductive capacity for the digermyne when compared to the tin analogue.

Scheme 10 The reversible addition of isocyanides to 1,2-diaryl distannyne 1.

Scheme 11 The addition of tert-butyl isocyanide to singly-bonded 1,2-bisamido distannyne 12, and a comparison with the divergent reactivity with the closely related 1,2-amido digermyne 14.

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These potentially highly conjugated systems are analogous to presently unknown carbon-based 1,2-diketenimines (Scheme 11). Given the synthetic prominence of ketenimines in synthetic organic chemistry in recent years,75,76 the isolation of the described heavier derivatives could lead to interesting synthetic protocols for metal-containing conjugated organic systems.

11.11.3.1.4

Dihydrogen

An incredibly important discovery in bond activation processes which have key implications in organic synthesis is the activation of H2 by SnI species. Indeed, in recent years it has been found that a number of low-valent main-group compounds can promote the activation of H2, due to narrow energy gaps for the frontier orbitals in a number of these compounds.77–81 The first discovery of a tin compound that could achieve this reaction came from Power and co-workers, who showed that 1,2-diarylddistannyne 1 can activate H2 at ambient pressure and temperature, affording exclusively a tin(II) hydride species (Scheme 12).82 This breakthrough is particularly poignant given that we now know such tin hydride complexes can further react with alkenes, catalyst free, hinting toward a method for efficient group 14 catalyzed hydrogenation reactions. Since this time, further examples of SnI species which can achieve this H2 activation reaction have been forthcoming, namely from Jones and co-workers, employing bulky amide ligands in distannyne 12 and hydride product 24 (Scheme 13),74 and further examples from Power and co-workers (Scheme 12),83 including the use of a mixed-valence octanuclear cluster 25,84 which liberates elemental tin in the reaction with H2 to form tetrameric tin(II) hydride 26 (Scheme 14). Notably, this octanuclear cluster also reacts with ethylene, irreversibly, again in the liberation of elemental tin to form and organotin(II) tetramer, with all tin centers bridged by ethyl groups.

Scheme 12 The addition of dihydrogen to the distannynes 1 and 16–19, generating bridged hydride complexes 20–23, or stannyl stannylene 24.

Scheme 13 The activation of H2 by a 1,2-bisamido distannyne, yielding dimeric hydride complex 24 which exists in a monomer-dimer equilibrium in solution at ambient temperature.

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Scheme 14 H2 activation by an octanuclear tin cluster, forming the tetrameric tin(II) hydride complex 26.

More recently, it was shown by Power et al. that under certain conditions, the activation of H2 by 1,2-diaryldistannynes is reversible,85 which has implications in catalysis as well as in hydrogen storage chemistry.86 The in-depth study of the equilibrium between hydride 20 and distannyne 1 suggests that the hydride is strongly favored, indicated by the Keq (2.33  10−4) and DG0 (5.86 kcal mol−1), with H2 elimination prominently observed at 80  C. Given these remarkable findings, it is not surprising that the mechanism of the H2 activation process has been fervently studied. The mechanism and kinetics of the reaction of H2 with distannynes has been studied in some depth, the former through computational methods. It was originally suggested that H2 activation proceeded initially at a single tin center, through interaction with the HOMO (of p symmetry) and the LUMO (vacant non-bonding orbital, or n+ symmetry).82 It was later found that a closely related but distinct ‘first approach’ is more likely, with one H-atom bridging the two Sn centers of the dimer (Fig. 3).87 This leads to the mono-hydride-bridged tin(II) dimer, which rearranges to the doubly hydride-bridged or stannyl-stannylene isomers, depending on ligand sterics. This reaction proceeds no further, and is in contrast to the activation of H2 by the related 1,2-diaryldigermyne, thus highlighting key disparities in the chemistry of these fascinating low-valent complexes. The employment of low-valent tin hydride species, including in catalysis, will be discussed within this article. Related H2 activation chemistry, or rather elimination chemistry, is also known for lead. The first synthetic protocol for accessing a lead(I) dimer, namely 8, was reportedly via a closely related lead(II) hydride complex, which it was postulated released

Fig. 3 Orbital interactions involved in the activation of H2 by a distannyne.

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dihydrogen in forming the lead(I) dimer.54 This was later corroborated by the successful synthesis of the thermally labile lead(II) hydride compound whose original synthesis generated the lead(I) species. Using a facile s-bond metathesis method, lead hydride 28 could readily be prepared at −40  C from (aryl)(alkyl)plumbylene 27 (Scheme 15).88 The formation of 28 was clear given its markedly low-field resonance in its solution state 1H NMR spectrum (d ¼ 35.61 ppm), with clear 207Pb satellites. Pure samples of hydride 28 release H2 over the course of hours in the formation of the known diplumbyne 8, corroborating the earlier hypothesis of Power and co-workers. Two further examples of bulky aryl-lead hydride complexes, 31 and 32, have since been reported by Power and co-workers through reaction of the (aryl)(chloro)plumbylene precursors 29 and 30 with di-isobutyl aluminum hydride (Scheme 15), which were also found to eliminate H2 at ambient temperature in solution.89 In the case of 32, this cleanly formed the diplumbyne derivative 2, with a rate constant of 1.2  10−3 M h−1. The monomeric lead(II) hydride complex 33 can be readily accessed through cleavage of dimeric 28 with a small N-heterocyclic carbene.88

Scheme 15 Synthesis of dimeric lead(II) hydride complexes 28, 31, and 32, cleavage of 28 with an NHC to yield monomeric lead(II) hydride 33, and loss of H2 from diplumbynes to yield diplumbynes 2 and 8.

11.11.3.2 Monomeric tin(II) and lead(II) species (stannylenes and plumbylenes) These compounds, often referred to as heavy carbene analogues despite the first examples being isolated some time before the carbon analogues, display a range of reactivities pertaining to organic synthesis, in stoichiometric bond activations operating via metathesis processes and oxidative addition/reductive elimination type reactivity.19 The former metathesis-type reactivity has been extended to a number of catalytic regimes for organic synthesis, whilst the latter oxidative addition/reductive elimination chemistry draws direct analogies with ‘precious’ transition metal catalysis. It is therefore not surprising that tetrylenes have seen considerable attention in recent years. The reactivity patterns of tetrylenes can be understood through consideration of the frontier orbitals of these species, namely a high s-character lone electron pair (HOMO) and a vacant p-orbital (LUMO; Fig. 4). The degree of sp-hybridization decreases with atomic number, concomitant with an increase in the HOMO-LUMO gap for the group 14 elements. As such, the relative stability of the +2 oxidation state increases down the group, leading to the so-called ‘inert-pair effect’. These factors are important for

Fig. 4 Frontier orbitals of singlet tetrylenes. E ¼ Si-Pb.

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mechanistic aspects of the reactivity of stannylenes and plumbylenes in bond-cleavage processes (viz metathesis and oxidative addition) and bond-forming processes (viz metathesis and reductive elimination). Here, the reactivity of stannylenes and plumbylenes in a range of processes that relate to organic synthesis will be discussed, so as to highlight key steps forward that have been made in this area in recent years, and to further stimulate interest in this new facet of chemistry moving toward transition metal mimicking main group catalysis.

11.11.3.2.1

Early work

The first structurally authenticated examples of two-coordinate plumbylenes and stannylenes were reported by Lappert and co-workers as early as 1973,90,91 some years before the isolation of the famed Arduengo N-heterocyclic carbene.92,93 The closely related dicyclopentadienyl stannylene and plumbylene, which can be considered as higher coordinate tetrylenes, were reported some years earlier by E. O. Fischer.94,95 The tin derivative was shown to readily cleave the CdI bonds in methyl iodide and 1,2-diiodoethane, as well as diphenyl disulphide.96,97 Notably, the former reaction was postulated to occur through a radical mechanism, given that it only occurs when conducted in daylight. A number of oxidative addition processes of activated bonds at the SnII center in stable stannylenes were described by Lappert in the 1970s and 1980s, examples of which are given in Scheme 16.98,99 Although only ‘reactive’ X-X0 bonds were studied in this context, these investigations displayed the potential for main group compounds to achieve a process that is typically the realm of transition metals. As a side note, the described addition of alkyl halides is not so far removed from the formation of phosphonium cations through the addition of alkyl halides to phosphines.100 Nevertheless, these early experiments not only give facile access to functionalized SnIV compounds, but also pave the way for the concept of main group catalysis involving oxidative addition/reductive elimination at a main group center. This concept is rather prominent for heavier group 14 elements given their ability to access both +2 and + 4 oxidation states. That being said, similar reactions to those described above involving the plumbylene analogues tended to yield the lead(II) halide species, thought to come about due to the reluctance of lead to exist in the +4 oxidation state. The electronic nature of both Sn and Pb could allow for processes leading to efficient catalytic regimes, which are of course indispensable in organic synthesis. Aspects surrounding this topic will be discussed here.

Scheme 16 Some example of oxidative addition reactions of stannylenes reported by Lappert and co-workers.

11.11.3.2.2

Frontier orbitals

The frontier orbitals of EII elements are key to understanding bond activation and possible catalysis involving these centers. Our grasp of this has progressed significantly over the last two decades. The HOMO and LUMO of the singlet tetrylenes, i.e. the most stable electronic ground state for essentially all isolable stannylenes and plumbylenes,101 comprise a lone electron pair and a vacant p-orbital, respectively. The s-character and non-bonding nature of the former increases on descending the group, hence the prominence of lead complexes in the +2 oxidation state. The frontier orbitals of tetrylenes allow them to activate small-molecules in a manner similar to transition metals, typically through donation of HOMO electron density to an anti-bonding orbital of the incoming substrate, and concomitant acceptance of electron density from a bonding orbital of the incoming molecule into the LUMO. Transition metals achieve this with d-orbitals, the symmetry of which can be compared with the described tetrylene HOMO and LUMO. This comparison is depicted with the activation of H2 in Fig. 5. The HOMO-LUMO gap plays a key role here too, where a smaller gap translates to a greater reactive capacity. A number of studies in recent years have shown the effects of ligand type on the HOMO-LUMO gap of tetrylenes, suggesting that tailor-made ligands can lead to desired/directed bond activation properties for a given tetrylene.19 Further, the effect of ancillary neutral donor ligands on

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(A)

(B)

Fig. 5 Comparison of the orbitals involved in the activation of dihydrogen by (A) a singlet tetrylene (E ¼ Si-Pb) and (B) a transition metal center (right).

the reductive elimination process in tetryl compounds, to form tetrylenes, gives a further point of design for the development of catalysts built on group 14 elements, operating via transition metal like catalytic mechanisms. Complimentary to these studies, the individual steps required for such a catalytic cycle have been well documented over the last decade, giving considerable promise to this area of research.

11.11.3.2.3

Oxidative addition and reductive elimination reactions of stannylenes and plumbylenes

The addition and elimination of unactivated bonds (e.g. HdH, NdH, SidH, and CdH bonds) at an element center are key reactions in catalytic processes. As described above, a number of early examples indicated that oxidative addition of reactive polar bonds (e.g. carbon-halogen bonds) is possible at SnII centers, whilst generally speaking PbII, in plumbocene, is observed to react with related bonds to yield only ligand-exchanged PbII products.102 Evidence for such processes occurring through oxidative addition/reductive elimination came from the elimination of ethylene from Cp2PbMe2.103 A series of results involving exchange reactions at Cp2Sn, resulting exclusively in SnII, have also been postulated to occur through oxidative addition/reductive elimination, but mechanistic insight was not given. Stannylenes have now displayed the ability to activate a range of typically unreactive bonds, leading to a now well understood reactive process for these compounds, and taking this chemistry closer to transition-metal like catalytic processes. The initial report of this reactivity came from Power, in the activation of H2 and NH3 by a bis(aryl)stannylene, 34 (Scheme 17).104 These were early examples of the clean activation of dihydrogen and ammonia by a molecular main group compound, and particularly prominent in that the main group center in this case (i.e. Sn), maintained its oxidation state of +2. Specifically, heating a sample of 34 to 70  C for 1 h under an atmosphere of H2 led to complete conversion to the SnII hydride complex, 20, and free arene (i.e. protonated ligand). A similar reaction is seen when 34 reacts with NH3, forming the (aryl)(amido) stannylene complex 35, again with arene elimination. Whilst computational evaluation of this reaction has not been forthcoming, making it challenging to consider whether an addition/elimination or concerted s-metathesis route is at play here, the complementary reactions for the GeII system lead to GeIV compounds through oxidative addition,105 perhaps indicating that a similar initial step also occurs for the SnII systems described here. It was also demonstrated that utilizing a less sterically encumbered bis(aryl)stannylene (Scheme 17) prevented any reaction with H2,

Scheme 17 Oxidative addition/reductive elimination reactions of bis(aryl) stannylene 34 with dihydrogen and ammonia, leading to the tin(II) amide and hydride complexes 35 and 20.

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which suggests that elimination of the arene ligand in the bulkier system is driven by steric pressure, an effect which also has precedent in transition metal systems,106 and, more recently, has even been demonstrated for carbene systems.107 In a set of reactions that are particularly relevant to catalysis, it was shown that (amido)(alkyl)stannylenes, generated through the stoichiometric hydrostannylation of unactivated alkenes by a tin(II) hydride complex (vide infra), reacted with bulky alcohols through the elimination of the protonated alkane and the formation of (amido)(alkoxy)stannylenes (Scheme 18).108 Whilst only stoichiometric, this stands as the initial example of a full cycle of a hypothetical catalytic process. That is, the tin(II) hydride 24 can be generated by the reaction of pinacol borane (HBpin) with (amido)(alkoxy)stannylenes 36 and 37, hence the overall reaction described above can be seen as the transfer hydrogenation of alkenes by the ROH/HBpin couple. Due to the Lewis basic nature of the alcohol substrates, the alkane elimination step likely proceeds via s-metathesis, rather than the addition/elimination process hypothesized by Power for H2 activation/arene formation discussed above.

Scheme 18 The reaction of tin(II) alkyl 38 with alcohols in the elimination of alkanes, forming tin(II) alkoxide complexes 36 and 37, and a hypothetical cycle for the transfer hydrogenation of ethylene with the HBpin/HOR0 couple.

Evidence for such an addition/elimination mechanism taking place with Lewis basic substrates was recently forthcoming. The bis(boryl)stannylene 39, due to the strongly s-electron-donating capacity of the boryl substituent, has an amplified bond activation capacity due to the contracted HOMO-LUMO gap in this compound (that is, the s electron-donation destabilizes the HOMO).109 Stannylene 39 thus has the capacity to readily activate dihydrogen at ambient temperature and pressure, yielding the dihydrostannane 40, with no sign of ligand elimination (Scheme 19). This is in contrast to the (amido)(boryl)stannylene 48 (Scheme 21), which, due to the HOMO stabilizing p-electron donation capacity of the amide ligand, has an increased HOMO-LUMO gap relative to 39. Bis(boryl)stannylene 39 also readily cleaves the BdH and SidH bonds in parent borane and silane, to yield 41 and 42 respectively (Scheme 19). Markedly, 39 also cleaves H2O and NH3 to yield stannane products 43 (H2O) and 44 (NH3), with the formal stannylene-ammonia adduct, 39
NH3 also isolated prior to NdH bond activation (Scheme 20). The product amido

Scheme 19 The reaction of bis(boryl)stannylene 39 with dihydrogen and hydridic substrates.

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Scheme 20 Adduct formation, oxidative addition, and reductive elimination reactions of ammonia and water with bis(boryl)stannylene 39, leading to ammonia adduct 39
NH3, stannane species 43 and 44, and ultimately borane species 45–47, and reduced tin species/tin metal.

Scheme 21

The reaction of (amido)(boryl)stannylene 48 with ammonia, leading to amide ligand elimination and formation of the bridged amido stannylene 49.

stannane 44 was found to decompose over the course of 4 days, yielding amido borane 45 and borane 46, with liberation of unidentified ‘reduced tin species’. Similar observations were made for hydroxy stannane 43 after heating in hexane. It was further observed that the (amido)(boryl)stannylene 48 reacts with ammonia through amido ligand elimination, yielding the novel NH2-bridged (amido)(boryl)stannylene 49 (Scheme 21). This series of adduct formation, oxidative addition, and reductive elimination is an impressive and poignant demonstration of the potential for heavier group 14 centers to break and make bonds in organic species through mechanisms that would typically be considered the realm of transition metals. Whilst tetrylenes are known to oxidatively cleave a variety of bonds, as discussed above, stoichiometric and well-defined reductive elimination reactions are much less common. In this light, is has been shown that stannanes bearing bulky aryl ligands, for examples 50, are capable of the reductive elimination of H2.110 In the context of catalysis this is an important development, given that the generated tin(II) hydride species are highly reactive, for example undergoing spontaneous insertion reactions with unactivated alkenes (vide infra). These hydrogen elimination reactions are base induced, all involving nitrogen bases (Scheme 22). Remarkably, depending on the nitrogen base which is employed, the level of reduction and the final coordination number at tin can be selectively varied, defined in Scheme 22 as pathways A, B, and C. It should be noted that carbenes can affect similar results, but in the elimination of oxidized carbene-H2 by products,111,112 and therefore do not formally represent H2 elimination.

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Scheme 22 Base (D) dependent H2 elimination reactions from the stannane 50, leading to distannane (pathway A), bridged stannylene/stannyl stannylene (pathway B), or base-stabilized monomeric hydrido stannylene (pathway C), promoted by nitrogen bases. All reactions were conducted in C6D6, with conversions and conditions given below the respective base.

11.11.3.2.4

Insertion reactions of stannylenes and plumbylenes

A key step in the functionalization of unsaturated molecules at a catalytically active center is the insertion reaction, a prominent example being hydrometallation (i.e. the insertion into a metal-hydrogen bond). A number of such processes which can pertain to catalysis and organic functionalization are known for tin, and one or two for lead. Fulton and co-workers reported that alkoxy stannylenes 51–53 undergo a reversible insertion reaction with CO2 in the formation of stannylene carbonate species 54–56 (Scheme 23).113 Tin(II) carbonates are surprisingly rare, and the described insertion reactions could pave the way for alcohol/CO2 functionalization at tin. The mechanism proceeds initially via nucleophilic attack of the C-atom of the incoming CO2 molecule by the alkoxide O center, followed by migration of the tin to an O atom of the CO2 molecule. This process is near thermoneutral, with DG values between 0 and 1.1 kcal mol−1 for the substituents studied, in keeping with the observed reversibility of these reactions.

Scheme 23 The reversible insertion of carbon dioxide into the SndO bond of tin(II) alkoxides 51–53, forming tin(II) carbonates 54–56.

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Since the isolation of the NacNac-stabilized monomeric tin(II) hydride system 57, Roesky and co-workers have reported on a number of hydrostannylation reactions with this species involving alkyne, aldehyde, ketone, and carbodimine substrates leading to compounds 58–69 (Scheme 24), as well as CO2 in the formation of tin(II) formate 71 (Scheme 25).114 Hydride 57 reacts with activated aldehydes and ketones at ambient temperature, whilst less polarized dialkyl ketones required more forcing conditions.115,116 Further, employing fluorinated aromatic aldehydes and ketones led in some cases to CdF bond activation and exchange, forming tin(II) fluoride compound 70.117 Only activated alkynes could be successfully hydrostannylated, albeit at ambient temperature.116 This allowed for the isolation of four examples of vinyl stannylenes. These results are significant given two points: (i) catalyzed hydrostannylation of alkynes has held precedent for more than 50 years; the described examples were the first operating in the absence of a catalyst, and (ii) as described above, these insertion reactions represent a key step in a tin-based catalytic cycle.

Scheme 24 The reactivity of tin(II) hydride 57 with a variety of unsaturated CdO, CdN, and CdC bonds.

Scheme 25 CO2 insertion reaction of 57, and subsequent generation of deuterated methanol through sequential reactions with ammonia borane and D2O.

It was also shown that hydride compound 57 readily inserts CO2, in the formation of the tin(II) formate 71 (Scheme 25).115 The further reaction of the formate complex with ammonia borane generated deuterated methanol after quenching the reaction mixture with D2O, with some mechanistic insight coming from a later publication by Driess and co-workers, involving a related GeII

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hydride.118 This therefore stands as a promising early example for the fixation and utilization of CO2 mediated by a main group center, which has since been expanded toward efficient catalytic regimes (vide infra). It has been postulated that low coordination numbers at a hydrido tetrylene center should increase its reactive capacity by freeing frontier orbitals and reducing steric congestion. The amido tin(II) hydride 24, reported by Jones and co-workers,74 which incorporates the extremely bulky amide ligand L{ (L{ ¼ [(iPr3Si)(Ar{)N]−; Ar{ ¼ 2,6-(Ph2CH)2-4-iPr-C6H2), exists as a hydridebridged dimer in the solid state, but forms a monomeric, two coordinate hydride species in solution.119 As a result, in solution 24 is considerably more reactive than any previously reported tin hydride compounds. Both unactivated terminal and internal alkenes are hydrostannylated at ambient temperature essentially immediately upon substrate addition, forming monomeric (alkyl)(amido) stannylenes 72–75 (Scheme 26).108 Moreover, the insertion reaction is reversible for cyclic alkenes, the reverse reaction proceeding through b-hydride elimination. This was made particularly clear by the addition of an excess of cyclopentene to a pure sample of the cyclopentyl stannylene 74, preventing the reverse (i.e. b-hydride elimination) reaction. Removal of the cyclopentene and dissolution of the stannylene led to rapid formation of small amounts of the tin(II) hydride starting material and related decomposition products. The calculated reaction trajectory involves a concerted one step mechanism, whereby a 4-membered transition state is formed, leading directly to the insertion product (Fig. 6).120 This contrasts with related SiII hydride chemistry, where initial alkene

Scheme 26 The insertion of reactions of unactivated alkenes with amido tin(II) hydride complex 24.

Fig. 6 The calculated reaction coordinate for the hydrostannylation of cyclopentene with (Me2N)SnH.

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addition leads to a [2 + 1] cycloaddition yielding a silirane, followed by a ring-opening hydride migration, generating the SiII alkyl compound.121 This is likely due to the increased stability of the +2 oxidation state, relative to the +4 oxidation state, for Sn when compared with Si. The energetic profile for this reaction of tin(II) hydride with cyclopentene, calculated using the dimethylamide ligand rather than the bulky L{, gave a barrier of 18.0 kcal mol−1 and a DG of −9.0 kcal mol−1, which are concordant with the observed reversibility of the hydrostannylation reaction at ambient temperature.120 This pseudo-two coordinate tin(II) hydride also rapidly reacts with aldehydes, ketones, alkynes, and CO2, to yield tin(II) alkoxides,122 vinyl,108 and formate compounds,123 all in essentially quantitative yield (Scheme 27). This is particularly important for SndO species given that 24 is synthesized through the metathesis reaction of tin(II) tert-butoxide complex 36 with HBpin, giving a clear pathway for hydroboration catalysis.

Scheme 27 The insertion chemistry of tin(II) hydride 24 toward aldehydes, ketones, alkynes, and CO2.

Power and co-workers have reported a number of interesting bond functionalization reactions involving terphenyl tin(II) hydride systems. An initial report described the formation of an (aryl)(cyclopentadienyl)stannylene, 4, in the reaction of cyclopentadiene with the distannyne 1 (Scheme 28). Though not initially involving the hydride compound 20, the reaction proceeds through CdH bond activation of the diene, generating 20 and 4. The hydride compound 20 then deprotonates the diene, generating a further equivalent of 4 and dihydrogen.

Scheme 28 Deprotonation of cyclopentadiene by tin(II) hydride 20.

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Reaction of tin(II) hydride complexes 20 and 80 with two equivalents of tert-butyl-ethylene led to the uncatalyzed hydrostannylation reaction, yielding the distannene products, 81 and 82, which it is suggested exists in a monomer-dimer equilibrium in solution (Scheme 29).124 Addition of a single equivalent of the same alkene gave differing results depending on slight differences in terphenyl ligand, yielding either stannyl stannylene 83, or the novel hydride bridged bis-stannylene 84 (Scheme 29). Contrasting results are also observed for these two ligand systems in the reaction of their tin(II) hydride compounds with ethylene (Scheme 30).

Scheme 29 Reactions of aryl tin(II) hydride complexes with tert-butyl ethylene.

Scheme 30 Reactions of aryl tin(II) hydride complexes with ethylene.

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For 80, the addition of excess ethylene leads to insertion of ethylene into both SndH bonds, forming an alkyl stannylene with highly dynamic behavior: when crystallized at ambient temperature the symmetrical diethyl distannene 85 was isolated, whilst recrystallization at −20  C led to the unsymmetrical stannyl stannylene isomer, 86, through migration of one ethyl group to the adjacent tin center. Addition of excess ethylene to tin(II) hydride 20 gave a surprisingly different result, in the formation of the ethyl-bridged bis-stannane 87, arising from initial SndH bond insertion leading to the expected 1,2-diethyldistannene, which exists in a monomer-dimer equilibrium in solution. The (aryl)(ethyl)stannylene then undergoes a [1 + 2] cycloaddition with ethylene, leading to a series of CdH activation and bond migration steps, finally forming 87. The two discussed terphenyl tin(II) hydride complexes also readily undergo insertion reactions with the bicyclic alkenes, norbornene and norbornadiene (Scheme 31).125 In the former case, the norbornyl stannylenes 88 and 89 are cleanly formed, with no evidence for the formation of distannene products either in solution of the solid state. Reaction with norbornadiene also leads to the insertion products, giving similar monomeric products 90 and 91. However over time or with heating, these rearrange to nortricyclyl stannylenes, 92 and 93, in essentially quantitative yield. The formation of these tricyclic species arises from an initial b-hydride elimination reaction, reforming norbornadiene and the tin(II) hydride complexes. The thermodynamically preferred reaction pathway then ensues, involving an endo-syn addition of the SndH moiety to the norbornadiene substrate. This leads to bond rearrangement, and formation of the observed tricyclic products.

Scheme 31 The reactions tin(II) hydride complexes 20 and 80 with norbornene and norbornadiene.

The described set of reactions is gives both further evidence for the synthetic capacity of tin(II) hydrides in uncatalyzed bond functionalization processes, as well as revealing the fluctional nature of structural aspects of these species, and some unexpected reactive process which we can aim to better understand and directly employ in the future. Related to the described hydride insertion reactions, the bis(aryl)stannylenes 34 and 94 undergo an insertion reaction with ethylene, with the C2 unit inserting into one aryl tin-carbon bond (Scheme 32).126 Only one insertion event was observed, forming novel (aryl)(alkyl)stannylenes 96 and 97, after heating reaction mixtures to 60  C under an atmosphere of ethylene for 12 h. Under these conditions, no further reaction was observed. The observed insertion reactions differ from reactions typically observed

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Scheme 32 The insertion of ethylene into the aryl CdSn bond of bis(aryl) stannylenes, yielding (aryl)(alkyl)stannylenes 96 and 97.

between reactive tetrylenes and ethylene, which tend to yield [2 + 1] cycloaddition products.127–130 Such a reaction between 34 and ethylene, which has the ethylene unit approach the [CdSndC] fragment in a symmetrical fashion, was found to be energetically disfavored by 10 kcal mol−1. Conversely, approach of ethylene essentially parallel to one aryl CdSn bond, leading to the insertion product, is favored by 34.8 kcal mol−1. That the insertion product does not further react with ethylene is directly correlated with the change in HOMO-LUMO gap upon forming the (aryl)(alkyl)stannylene. This was shown through UV/vis analysis of stannylenes 34 and 96 (i.e. before and after ethylene insertion), the value for the former indicating a narrower HOMO-LUMO separation for 34 (612 nm) relative to 96 (489 nm). Further, the bis(aryl) stannylene 95, which bears less bulky ligands than the stannylenes discussed above, was found to be unreactive toward ethylene. This stannylene has a narrower HOMO-LUMO gap than bis(aryl) stannylenes 34 and 96, as indicated by UV/vis spectroscopy (553 nm), adding some weight to this hypothesis. Nevertheless, the insertion of ethylene in the SndC bond of stannylenes draws similarities with this key insertion step in both olefin functionalization and olefin polymerization. The development of low-valent group 14 element complexes which can catalyze this latter reaction would be a very exciting development for polymer chemistry and main group chemistry alike. Bis(aryl)stannylene 34 has also shown the capacity to activate the CdH bonds of methylated aromatics, namely toluene, xylene, and mesitylene, under relatively mild conditions (Scheme 33).131 Rather than insertion products typically observed for tetrylenes, the metathesis products were observed in all cases, with the elimination of ‘ArH’, maintaining the +2 oxidation state at tin in the formation of novel (aryl)(benzyl)stannylenes, 98–100, which exist as distannenes in the solid state. The mechanism for these reactions involves formation of the radical pair [LSn%] and [L%], which opens a new avenue for reactive tetrylene chemistry in bond activation and functionalization. It is also worth noting that in all cases yields were good, despite such radical pathways often leading to uncontrolled reactions, giving further utility to the described process.

Scheme 33 The radical pathway leading to CdH bond functionalization of toluene by bis(aryl)stannylene 34.

One example of the reactivity of the lead(II) hydride 28 has been reported, namely the insertion of phenyl acetylene and 1,1-dimethylallene into the PbdH bond, forming compounds 101 and 102 (Scheme 34).132 These reactions proceed rapidly at ambient temperature, leading to the monomeric vinyl and allyl plumbylenes, respectively, in high isolated yields. These are the first examples of hydroplumbylation which proceed in the absence of a catalyst or initiator, and, as with the described tin(II) hydride chemistry, could pave the way for group 14 catalyzed CdC bond functionalization catalysis.

Scheme 34 The hydroplumbylation of phenylacetylene and dimethylketene with lead(II) hydride 28.

11.11.3.2.5

Catalysis promoted by stannylenes

The utilization of cheap, abundant elements in homogenous catalysis is a central topic in chemistry today. Catalysis is incredibly important in the industrial synthesis of fine chemicals. Still, the majority of catalysts employed in this setting rely on high-cost, often toxic heavier transition metals. The elements of the s- and p-blocks typically satisfy the desired characteristics to overcome these issues, and have been prevalent in a range of catalytic processes over the last decade.19,133,134 The past 6 years have seen major steps forward regarding the utilization of heavier group 14 elements in catalysis,19 leading on from the stoichiometric processes which have been described in this article. Prior to any reports of catalysis involving the heavier tetrylenes, an in-depth computational investigation into the germanium(II) hydride catalyzed hydrosilylation of unsaturated CdO bonds suggested that such catalysis should be possible, in this case utilizing a highly active silane, namely F3SiH.135 These results spurred on investigations into realizing such catalytic regimes employing heavier group 14 elements. The first report of a well-defined catalytic process involving tin(II) was the hydroboration of aldehydes and ketones with pinacol borane (HBpin).122 This reaction had previously been described for a handful of transition metals (e.g. Rh,136,137 Mo,138 and Ti139–141), and also for the s-block metal Mg.142 Since the initial report of the SnII catalyzed process described herein, further developments have been made in applying a broader range of main group catalysts in this process. The amido tin(II) hydride complex 24 readily hydrostannylates aldehydes and ketones, yielding amido-alkoxy stannylenes. Addition of HBpin to solutions of these stannylenes leads to regeneration of the hydride catalyst, and formation of boronate esters (Scheme 35, Fig. 7).122 In all cases the tin catalyzed reactions were complete in considerably shorter times than the related

Scheme 35 Catalytic cycle with intermediates for the hydroboration of ketones and aldehydes with tin(II) precatalyst 36.

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Fig. 7 The scope of the hydroboration of unsaturated CdO bonds catalyzed by 36. Percentage yields given below substrates, with turn over frequencies (TOFs) in parentheses (h−1).

germanium system. Further, it was observed that the catalyst resting state was the alkoxy stannylene species, which is beneficial on the grounds that tin(II) hydride complex 24 is thermally unstable, which would lead to catalyst deactivation over time were this the favored resting state. The turn over frequencies (TOFs) of the tin catalyzed reactions were in some cases extremely high (e.g. >13,000 h−1), and in fact at that time of publication were higher than any other reported values for alternative catalysts. Rates of reaction were more effected by sterics of substrates, rather than electronics, with the hydroboration of bulky benzophenone (TOF ¼ 80 h−1) proceeding considerably more slowly than acetophenone (TOF ¼ 800 h−1), at 0.5 mol% catalyst loading. Selectivity of the reaction was also briefly screened. The double hydroboration of benzil was seen to rapidly proceed, in the formation of the di-boron ester, whilst the carbonyl moiety of cyclohexenone was selectively hydroborated, leaving the alkene fragment intact. Essentially no cis-/trans-selectivity was observed in the hydroboration of 2-methylcyclohexanone, indicating that ligand modifications would be required to impart any form of diastereoselectivity. An initial rates kinetic analysis for the hydroboration of 4-ethylbenzophenone using the closely related germanium system showed first-order dependence in HBpin and catalyst, and zeroth-order dependence in ketone, indicating that the rate determining step in the cycle is regeneration of the hydride from the germanium alkoxide intermediate. This corroborates that the catalyst resting state is indeed the germanium/tin alkoxide intermediates. Further analysis through computational methods shed further light on this. Overall, a favorable reaction profile for the suggested inner sphere mechanism was found, proceeding through an initial attack of the ketone oxygen at the tin center of the hydride catalyst (Scheme 35). This is followed by a 4-membered transition state, and hydride transfer to the ketone carbon in forming the tin alkoxide resting state. Subsequent reaction with HBpin also proceeds

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Tin and Lead in Organic Synthesis

through a 4-membered transition state, generating the tin hydride catalyst and the boronate ester. Notably, the calculated energetic barrier to the ketone insertion product is 5.6 kcal mol−1 smaller than that for boron ester formation and catalyst regeneration, in line with the observed rate determining step and catalyst resting states. It should be noted here that in an attempt to conduct catalysis utilizing phosphine-stabilized stannylene 103 through a dual-center bond activation mechanism that was corroborated for the germanium counterpart, the known SnII hydride complex 80 was formed, which was found to catalyze the hydroboration of aldehydes and ketones (Scheme 36).143 However, further details of this catalysis were not reported.

Scheme 36 The metathesis reaction of (phosphinomethyl)stannylene 103 leading to tin(II) hydride 80.

The heavy nitrile 104, which can be described as a tin(II) phosphinidene complex, is also capable of catalyzing the hydroboration of aldehydes and ketones with HBpin (Scheme 27, Table 1).144 Good reaction rates were observed for both benzaldehyde (>99% conversion, 15 min, 0.1 mol% catalyst) and benzophenone (>99%, 2.5 h, 2 mol% catalyst). This reaction perhaps proceeds through a mechanism similar to that pursued above. Whilst no computational study was presented, it was shown that 104 reversibly reacts with diphenylketene to yield the 4-membered cycloaddition product 105 (Scheme 37). One could envisage a similar activation of other carbonyl substrates, activating them and allowing for hydroboration with HBpin. Such a dual-center mechanism may therefore warrant further attention regarding bond functionalization catalysis.

Table 1

The hydroboration of aldehydes and ketones, catalyzed by heavy nitrile derivative 104.

Loading (mol%)

R

R0

Time (h)

Yield (%)

0.05 0.1 0.1 0.05 0.5

Ph Ph p-MeOPh Ph Ph

H H H Me Ph

99 >99

Scheme 37 The reversible reaction of diphenylketene with heavy nitrile 104.

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495

A contrasting outer-sphere mechanism for the hydroboration of aldehydes has also been reported for N-heterocyclic stannylene 106 (Table 2).145 In this case HBpin is ‘activated’ through coordination of both O centers to a stannylene’s Sn center (Scheme 38). The incoming aldehyde then bonds at boron, forming a 4-membered transition state, leading to hydride transfer and finally to liberation of the hydroborated reaction product. Interestingly, rates for the hydroboration of benzaldehyde by 106 were much lower than for the hydride system 24, with 91% conversion observed after 4 h at 1 mol% catalyst loading (viz >99% conversion after 2.5 h Table 2

The hydroboration of aldehydes catalyzed by N-heterocyclic stannylene 106.

Loading (mol%)

R

Time (h)

Yield (%)

0.5 1 2 2 5 2 2 2 2 2 2 2 2 2 2 2 2

Ph Ph Ph Ph Ph o-BrPh m-BrPh p-BrPh m-MeOPh p-NCPh p-FPh p-O2NPh p-MePh o-HOPh Napth 2-Furan 2dPhd1dC(O)H

4 4 4 6 4 4 4 4 4 4 4 4 4 4 4 4 4

26 91 80 87 82 76 85 82 66 97 87 88 77 97 77 66 49

Scheme 38 The proposed mechanism and energetic profile for the hydroboration of benzaldehyde by N-heterocyclic stannylene 106.

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Tin and Lead in Organic Synthesis

at 0.05 mol% catalyst loading for 24). The sluggishness of this reaction can be linked with the calculated reaction profile of this process. The bis-adduct of HBpin sits at −9.0 kcal mol−1 relative to free HBpin and stannylene 106. However, the adduct of the hydroborated product is considerably more stable, at −48.1 kcal mol−1. Given the vast excess of the hydroborated product in the reaction mixture, the catalyst is most likely to be consumed in this resting state, hampering efficient catalysis. Stannylene 106 was also found to catalyze the cyanosilylation of aldehydes through a similar outer-sphere mechanism involving one equivalent of the catalyst (Table 3). That is, the cyano-trimethylsilane reactant binds the Sn center of the catalyst forming an adduct complex, allowing for nucleophilic attack of the aldehyde O center at the SiMe3 fragment. Following insertion the adduct of the cyano-silylated product is formed, with an energy gain of 17.1 kcal mol−1. The hydroboration of carbonyl compounds with pseudo-monomeric hydrido stannylene 24 was later extended to the hydroboration of carbon dioxide (Table 4).123 This reaction has seen considerable interest in recent years, due to the environmental implications of excess carbon dioxide in our atmosphere, and thus the benefits of utilizing this gas as a C1 feedstock. The tin(II) hydride 24 works as an extremely active catalyst for the hydroboration of CO2 to methanol equivalents, employing HBpin or HBcat as the borane. At low catalyst loadings of 1 mol%, TOFs of 14.5 h−1 were reported for the reduction using HBpin, with impressive TOFs of up to 1188 h−1 reported for the more reactive HBcat, competing with known Nobel metal catalysts. In all cases the sole by-products are the bis(borate)ethers, catBOR and pinBOR.

Table 3

The cyanosilylation of aldehydes catalyzed by N-heterocyclic stannylene 106.

Loading (mol%)

R

Time (h)

Yield (%)

0.5 1 1 2 5 1 1 1 1 1 1 1 1 1 1 1 1

Ph Ph Ph Ph Ph o-BrPh m-BrPh p-BrPh m-MeOPh p-NCPh p-FPh p-O2NPh p-MePh o-Xyl Napth 2-Furan 2dPhd1dC(O)H

2 1 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1

28 81 86 79 75 50 71 80 99 95 60 60 84 45 99 37 72

Table 4

Reduction of CO2 to methanol equivalents with secondary boranes, catalyzed by tin(II) hydride 24.a

Loading (mol%)

BR2

Time (h)

Yield (%)

TOF (h−1)

10 1 1

Bpin Bpin Bcat

1.2 6.6 0.08

>99 >99 >99

8 14.5 1188

a

All reactions performed in D6-benzene at 20  C under  2 bar of CO2 using 1 equiv. of HBpin.

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497

Stoichiometric reactivity studies, alongside computational investigations, allowed for some degree of elucidation of the mechanism for this rather complicated process (Scheme 39). The first step is the insertion of CO2 into the SndH bond of the catalyst, leading to the tin(II) formate derivative 79. This compound does not react with excess CO2, but rapidly reacts with one equivalent of HBpin to form the tin(II) borate ester 107, with presumed loss of a formaldehyde equivalent from intermediary (stannenyl)(borato)acetal 107. 108 further reacts with HBpin to regenerate the catalyst starting material, 24, through a s-metathesis mechanism. This could suggest that the liberated formaldehyde reacts with the hydride catalyst to generate tin(II) methoxide complex 109, which then undergoes a further reaction with borane to again regenerate the hydride catalyst and the final product, MeOBpin.

Scheme 39 The plausible catalytic cycle (Cycle A) for the reduction of CO2 to methanol equivalents with secondary boranes, catalyzed by tin(II) hydride 24, involving spontaneous formaldehyde loss and reduction.

The above process, whereby formaldehyde is eliminated upon reaction of tin(II) formate 79 with HBpin, represents the key step in one possible catalytic cycle (Cycle A, Scheme 39). This cycle and a second alternative cycle (Cycle B, Scheme 40) were investigated by computational means, to determine which is most likely at play in the active catalytic regime. In the second possible mechanism,

Scheme 40 The second plausible catalytic cycle (Cycle B) for the reduction of CO2 to methanol equivalents with secondary boranes, catalyzed by tin(II) hydride 24.

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Tin and Lead in Organic Synthesis

the formate complex 79 reacts with HBpin to form the (stannenyl)(borato)acetal complex 107. This can eliminate formaldehyde as described above, whilst it can also undergo a metathesis reaction with a further equivalent of HBpin to form the bis(borato)acetal 110. This then reacts with the catalyst, 24, to yield the tin(II) borate ester 108, and MeOBpin. The reaction of 108 with HBpin regenerates the active hydride catalyst and forms the by product, pinBOBpin. The rate limiting step for Cycle A is the elimination of formaldehyde from 107, whilst that for Cycle B is the reaction of the hydride 24 with bis(borato) acetal 110. Comparing the calculated enthalpies for these two processes for the germanium catalyzed system (36.7 and 36.0 kcal mol−1, respectively) would suggest that both mechanisms are at play in the catalytic regime. Although less intensive methods were used, calculated barriers for the tin catalyzed process were similar. Notably, whilst monitoring catalytic reactions through NMR spectrometry considerable amounts of the acetal (pinBCH2)2O could be observed, which is only present in Cycle B. This was taken as evidence for this cycle providing a larger contribution to the catalytic process.

11.11.3.3 Dimeric tin(II) and lead(II) species (distannenes and plumbenes) Despite considerable efforts toward the reactivity of Si and Ge analogues of alkenes (ditetrylenes), which can affect activation and functionalization of a range of unsaturated substrates, little work in this area has been forthcoming for tin and lead. What has been studied centers around cycloaddition chemistry, which will briefly be summarized here.

11.11.3.3.1

Alkynes

Initial efforts toward this end involved Lappert’s distannene, 111, which exists in equilibrium with the monomeric stannylene 112 in solution. The addition of a strained alkynyl-thiepin to the equilibrium mixture of 111 and 112 did not lead to the stanna-cyclobutene as perhaps expected. This rather led to [2 + 1] cycloaddition with 112, forming monomeric stannacyclopropene 113 (Scheme 41).146 Conversely, the monomeric stannylene 114 reacts with the same strained alkyne in the formation of 1,2-distannacyclobut-3-ene 115, presumed to be through an initial [2 + 1] cycloaddition, followed by insertion of the stannylene into on SndC bond of the stannacyclopropene (Scheme 42).147 Interestingly, Lappert’s distannene/stannylene reacts with cyclooctyne also in the formation of the 1,2-distannacyclobut-3-ene derivative 115, hypothesized to occur through the same initial [2 + 1] cycloaddition/SndC bond insertion process described above (Scheme 41).148

Scheme 41 Reactions of bis(alkyl)stannylene with alkynes, leading to stannacyclopropene 113 and 1,2-distannacyclobut-3-ene 116.

Scheme 42 Reaction of stannylene 114 with a strained alkyne, forming 1,2-distannacyclobut-3-ene 115.

Tin and Lead in Organic Synthesis

499

The first proposed formal [2 + 2] cycloaddition reaction of a SndSn double bond required the thermal fragmentation of a cyclotristannane into the distannene and stannylene fragments, the former of which undergoes the targeted [2 + 2] cycloaddition reaction.149 It was not until later, however, that the distannene 117 bearing a persistent SndSn double bond was reported by Apeloig and co-workers, which readily undergoes formal [2 + 2] cycloaddition with phenylacetylene to form a 1,2-distannacyclobut-3-ene derivative, 118, related to those described above (Scheme 43).150

Scheme 43 Reaction of persistent distannene 117 with phenylacetylene.

Again more recently, this chemistry was expanded by Wesemann and co-workers, who investigated the reactivity of a selection of tethered distannenes/bis(stannylenes) with terminal alkynes (Scheme 44).151 They found that a range of distannenes tethered through the aromatic backbones naphthalene, acenaphthene, and xanthene, readily undergo [2 + 2] cycloaddition with phenyl acetylene and trimethylsilyl acetylene. Further, depending on the backbone/alkyne combination, this reaction is reversible. A van ‘t Hoff analysis of the elimination of trimethylsilyl acetylene from the acenaphthene-tethered distannene gave a DG of dissociation of 14.8 kJ mol−1, and is therefore endergonic. It was thus suggested that the ready isolation of the alkyne adducts is driven by their low solubility relative to the stating materials.

Scheme 44 The reactions of alkynes with tethered distannenes, leading to a range of 1,2-distannacyclobut-3-enes.

11.11.3.3.2

Phosphalkynes

Related cycloaddition chemistry is known for distannenes with phosphalkynes. An early example employing distannene 111 and tBu-phosphalkyne gave similar results to the addition of all-carbon alkynes, forming the phosphadistannacyclobutene 119 (Scheme 45).152 This was expanded upon much more recently by Jones and co-workers, who demonstrated that the addition of four equivalents of Me-C^P to the distannenes 111 and 120 leads to the unexpected coupling of the four phosphlkyne units to form polycyclic compounds 121 and 122 (Scheme 43).153

500

Tin and Lead in Organic Synthesis

Scheme 45 Reactions of distannenes with phosphalkynes.

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In Organophosphorus Chemistry: From Molecules to Applications; Iaroshenko, V., Ed.; Wiley-VCH: Weinheim, Germany, 2019;; pp 59–112. Mizuhata, Y.; Sasamori, T.; Tokitoh, N. Chem. Rev. 2009, 109, 3479–3511. Holliday, A. K.; Makin, P. H.; Puddephatt, R. J. J. Chem. Soc. Dalton Trans. 1976, 435–438. Fritz, H. P.; Schwarzhans, K. E. Chem. Ber. 1964, 97, 1390–1397. Peng, Y.; Ellis, B. D.; Wang, X.; Power, P. P. J. Am. Chem. Soc. 2008, 130, 12268–12269. Peng, Y.; Guo, J.-D.; Ellis, B. D.; Zhu, Z.; Fettinger, J. C.; Nagase, S.; Power, P. P. J. Am. Chem. Soc. 2009, 131, 16272–16282. Mann, G.; Shelby, Q.; Roy, A. H.; Hartwig, J. F. Organometallics 2003, 22, 2775–2789. Tolentino, D. R.; Neale, S. E.; Isaac, C. J.; Macgregor, S. A.; Whittlesey, M. K.; Jazzar, R.; Bertrand, G. J. Am. Chem. Soc. 2019, 141, 9823–9826. Hadlington, T. J.; Hermann, M.; Frenking, G.; Jones, C. Chem. Sci. 2015, 6, 7249–7257.

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109. Protchenko, A. V.; Bates, J. I.; Saleh, L. M. A.; Blake, M. P.; Schwarz, A. D.; Kolychev, E. L.; Thompson, A. L.; Jones, C.; Mountford, P.; Aldridge, S. J. Am. Chem. Soc. 2016, 138, 4555–4564. 110. Sindlinger, C. P.; Stasch, A.; Bettinger, H. F.; Wesemann, L. Chem. Sci. 2015, 6, 4737–4751. 111. Sindlinger, C. P.; Wesemann, L. Chem. Sci. 2014, 5, 2739–2746. 112. Maudrich, J.-J.; Sindlinger, C. P.; Aicher, F. S. W.; Eichele, K.; Schubert, H.; Wesemann, L. Chem. A Eur. J. 2017, 23, 2192–2200. 113. Ferro, L.; Hitchcock, P. B.; Coles, M. P.; Cox, H.; Fulton, J. R. Inorg. Chem. 2011, 50, 1879–1888. 114. Mandal, S. K.; Roesky, H. W. Acc. Chem. Res. 2012, 45, 298–307. 115. Jana, A.; Roesky, H. W.; Schulzke, C.; Döring, A. Angew. Chem. Int. Ed. 2009, 48, 1106–1109. 116. Jana, A.; Roesky, H. W.; Schulzke, C. Inorg. Chem. 2009, 48, 9543–9548. 117. Jana, A.; Roesky, H. W.; Schulzke, C.; Samuel, P. P. Organometallics 2010, 29, 4837–4841. 118. Tan, G.; Wang, W.; Blom, B.; Driess, M. Dalton Trans. 2014, 43, 6006–6011. 119. Hadlington, T. J.; Hermann, M.; Li, J.; Frenking, G.; Jones, C. Angew. Chem. Int. Ed. 2013, 52, 10199–10203. 120. Zhao, L.; Hermann, M.; Jones, C.; Frenking, G. Chem. A Eur. J. 2016, 22, 11728–11735. 121. Rodriguez, R.; Gau, D.; Contie, Y.; Kato, T.; Saffon-Merceron, N.; Baceiredo, A. Angew. Chem. Int. Ed. 2011, 50, 11492–11495. 122. Hadlington, T. J.; Hermann, M.; Frenking, G.; Jones, C. J. Am. Chem. Soc. 2014, 136, 3028–3031. 123. Hadlington, T. J.; Kefalidis, C. E.; Maron, L.; Jones, C. ACS Catal. 2017, 7, 1853–1859. 124. Wang, S.; McCrea-Hendrick, M. L.; Weinstein, C. M.; Caputo, C. A.; Hoppe, E.; Fettinger, J. C.; Olmstead, M. M.; Power, P. P. J. Am. Chem. Soc. 2017, 139, 6586–6595. 125. Wang, S.; McCrea-Hendrick, M. L.; Weinstein, C. M.; Caputo, C. A.; Hoppe, E.; Fettinger, J. C.; Olmstead, M. M.; Power, P. P. J. Am. Chem. Soc. 2017, 139, 6596–6604. 126. Yi Lai, T.; Gu, J.-D.; Fettinger, J. C.; Nagase, S.; Power, P. P. Chem. Commun. 2019, 55, 405–407. 127. Ohgaki, H.; Kabe, Y.; Ando, W. Organometallics 1995, 14, 2139–2141. 128. Rodriguez, R.; Gau, D.; Kato, T.; Saffon-Merceron, N.; De Cózar, A.; Cossío, F. P.; Baceiredo, A. Angew. Chem. Int. Ed. 2011, 50, 10414–10416. 129. Lips, F.; Fettinger, J. C.; Mansikkamäki, A.; Tuononen, H. M.; Power, P. P. J. Am. Chem. Soc. 2014, 136, 634–637. 130. Gullett, K. L.; Yi Lai, T.; Chen, C.-Y.; Fettinger, J. C.; Power, P. P. Organometallics 2019, 38, 1425–1428. 131. Yi Lai, T.; Fettinger, J. C.; Power, P. P. J. Am. Chem. Soc. 2018, 140, 5674–5677. 132. Weiß, S.; Schubert, H.; Wesemann, L. Chem. Commun. 2019, 55, 10238–10240. 133. Hill, M. S.; Liptrot, D. J.; Weetman, C. Chem. Soc. Rev. 2016, 45, 972–988. 134. Weetman, C.; Inoue, S. ChemCatChem 2018, 10, 4213–4228. 135. Takagi, N.; Sakaki, S. J. Am. Chem. Soc. 2013, 135, 8955–8965. 136. Fu, G. C.; Evans, D. A. J. Org. Chem. 1990, 55, 5678–5680. 137. Koren-Selfridge, L.; Query, I. P.; Hanson, J. A.; Isley, N. A.; Guzei, I. A.; Clark, T. B. Organometallics 2010, 29, 3896. 138. Khalimon, A. Y.; Farha, P.; Kuzmina, L. G.; Nikonov, G. I. Chem. Commun. 2012, 48, 455–457. 139. Oluyadi, A. A.; Ma, S.; Muhoro, C. N. Organometallics 2013, 32, 70. 140. Almqvist, F.; Torstensson, L.; Gudmundsson, A.; Frejd, T. Angew. Chem. Int. Ed. 1997, 36, 376. 141. Giffels, G.; Dreisbach, C.; Kragl, U.; Weigerding, M.; Waldmann, H.; Wandrey, C. Angew. Chem. Int. Ed. 1995, 34, 2005–2006. 142. Arrowsmith, M.; Hadlington, T. J.; Hill, M. S.; Kociok-Köhn, G. Chem. Commun. 2012, 48, 4567–4569. 143. Schneider, J.; Sindlinger, C. P.; Freitag, S. M.; Schubert, H.; Wesemann, L. Angew. Chem. Int. Ed. 2017, 56, 333–337. 144. Nesterov, V.; Baierl, R.; Hanusch, F.; Espinosa-Ferao, A.; Inoue, S. J. Am. Chem. Soc. 2019, 141, 14576–14580. 145. Dasgupta, R.; Das, S.; Hiwase, S.; Pati, S. K.; Khan, S. Organometallics 2019, 38, 1429–1435. 146. Sita, L. R.; Bickerstaff, R. D. J. Am. Chem. Soc. 1988, 110, 5208–5209. 147. Krebs, A.; Jacobsen-Bauer, A.; Haupt, E.; Veith, M.; Huch, V. Angew. Chem. Int. Ed. 1989, 28, 603–604. 148. Sita, L. R.; Kinoshita, I.; Lee, S. P. Organometallics 1990, 9, 1644–1650. 149. Weidenbruch, M.; Schafer, A.; Kilian, H.; Pohl, S.; Saak, W.; Marsmann, H. Chem. Ber. 1992, 125, 563–566. 150. Lee, V. Y.; Fukawa, T.; Nakamoto, M.; Sekiguchi, A.; Tumanskii, B. L.; Karni, M.; Apeloig, Y. J. Am. Chem. Soc. 2006, 128, 11643–11651. 151. Schneider, J.; Henning, J.; Edrich, J.; Schubert, H.; Wesemann, L. Inorg. Chem. 2015, 54, 6020–6027. 152. Cowley, A. H.; Hall, S. W.; Nunn, C. M.; Power, J. M. Angew. Chem. Int. Ed. 1998, 27, 838–839. 153. Jones, C.; Schulten, C.; Stasch, A. Inorg. Chem. 2008, 47, 1273–1278.

11.12

Antimony and Bismuth Complexes in Organic Synthesis

Saurabh S Chitnis and Toren Hynes, Chemistry Department, Dalhousie University, Halifax, NS, Canada © 2022 Elsevier Ltd. All rights reserved.

11.12.1 Introduction 11.12.2 Antimony in organic synthesis 11.12.2.1 Organoantimony(I) compounds 11.12.2.2 Organoantimony(II) compounds 11.12.2.3 Organoantimony(III) compounds 11.12.2.3.1 CdC Bond forming reactions 11.12.2.3.2 C-X bond forming reactions (X ¼ O, N) 11.12.2.3.3 Reactions involving transition metals 11.12.2.3.4 Multicomponent reactions 11.12.2.3.5 Oxidations 11.12.2.3.6 Reductions 11.12.2.4 Organoantimony(V) compounds 11.12.2.4.1 CdCd bond forming reactions 11.12.2.4.2 C-X bond formation (X ¼ O, N, S, P) 11.12.2.4.3 Oxidations 11.12.2.4.4 Reductions 11.12.3 Bismuth in organic synthesis 11.12.3.1 Organobismuth(I) compounds 11.12.3.2 Organobismuth(II) compounds 11.12.3.2.1 Ring opening 11.12.3.2.2 Olefin radical polymerization 11.12.3.2.3 Intramolecular CdC coupling 11.12.3.2.4 Intermolecular CdC coupling 11.12.3.3 Organobismuth(III) compounds 11.12.3.3.1 CdC bond forming reactions 11.12.3.3.2 C-X (X ¼ O, N, S) bond forming reactions 11.12.3.3.3 Reactions involving transition metals 11.12.3.3.4 Multi-component reactions 11.12.3.3.5 Oxidations 11.12.3.3.6 Reductions 11.12.3.4 Organobismuth(V) compounds 11.12.3.4.1 Stoichiometric C-C/N/O bond formation 11.12.3.4.2 Catalytic CdC/N/O bond formation Acknowledgment References

503 504 504 504 505 505 508 509 510 511 512 512 512 514 516 517 518 518 519 519 519 520 520 520 520 523 525 526 528 529 530 530 531 532 532

11.12.1 Introduction Antimony and bismuth are the heaviest members of group 15 of the periodic table and exhibit chemistry that is in stark contrast to their lighter congeners. The confluence of large atomic radii, high polarizability, and low electronegativity result in behavior reminiscent of many transition metal elements (Table 1). Furthermore, the ability to tune this behavior through a rich coordination chemistry is particularly relevant in the context of functional properties such as catalysis. Despite their potentially unique reactivity, research into the organometallic chemistry of these elements has been hampered due to the inability to assay them by NMR spectroscopy (c.f. organophosphorus chemistry) and due to the labile nature of the respective M-C bonds. Nevertheless, significant advances in crystallographic methods, together with a recognition that M-C bond metastability can be exploited for catalysis, have reinvigorated this field in recent years. In light of the above, the emphasis of this chapter is primarily on recent (since 2004) advances in the catalytic chemistry of organoantimony and organobismuth compounds. Due to their widespread usage, the binary halides or pseudohalides of these metals are also included. The following sections are divided by the oxidation state of the metal – albeit some crossover is inevitable when redox reactions are involved – and then by the type of reaction. Due to space limitations, a comprehensive description of reactivity, selectivity, and mechanism is impossible and the interested reader is therefore referred to the primary references for more details. A number of excellent review articles discussing the structure and reactivity of antimony and bismuth compounds also provide a more comprehensive understanding of this fascinating field of chemistry.2–10

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00025-1

503

504

Table 1

Antimony and Bismuth Complexes in Organic Synthesis

Elemental properties of Sb and Bi.

Property

Sb

Bi

Atom Number Atomic Weight Melting point ( C) First Ionization Potential (eV) Allred-Rochow Electronegativity Ionic Radius (A˚ ) Covalent Radius (A˚ ) Bond Dissociation Energy (E-C, kJ mol−1)1

51 121.757 630.7 8.64 1.82 0.90(3+), 0.74 (5+) 1.41 (3+) 268

83 208.980 271.4 7.287 1.67 1.17(3+), 0.90 (5+) 1.52(3+) 194

11.12.2 Antimony in organic synthesis 11.12.2.1 Organoantimony(I) compounds The +1 oxidation state is common in multi-metallic compounds, as seen from the extensive chemistry of catenated cyclostibanes or distibenes, including their incorporation into polymers.3,11 Monometallic Sb(I) compounds have also been proposed as transient intermediates.12–17 The successful isolation of well-defined molecular, monomeric Sb(I) compounds (known as stibinidenes) was reported in 2010 and relied upon the use of a planar NdCdN chelating ligand to provide steric shielding.18 These Sb(I) compound were subject to irreversible oxidation in the presence of dichalcogenides19 or alkynes,20 and reversible oxidation in the presence of the electronically activated C]C double bonds in N-alkyl/aryl imides (Eq. 1).21 Resonance-stabilized Sb(I) compounds have also been reported (Eqs. 2, 3) and, in some instances, found to exhibit reversible dimerization as a function of temperature.22,23 The organo-reactivity of such liminal stibinidenes remains to be examined.

ð1Þ

ð2Þ

ð3Þ

11.12.2.2 Organoantimony(II) compounds Very few isolable stibinyl radicals are known due to their tendency to dimerize to give distibines, R2Sb-SbR2.24–27 Recently, stibinyl radicals were proposed as transient reaction intermediates in the addition of SbdH bonds to alkynes giving Z-alkenes (Eq. 4).28 Although the radical itself could not be isolated due to a high rate of dimerization, its presence was supported by kinetic studies, solvent studies, and computational modelling.28,29 Transient stibinyl radicals have also been used to mediate the polymerization of alkenes (Eq. 5). In this context, the metalloradical behaves as both an initiator and as a metathesis agent that rapidly swaps on-metal and off-metal chains, enabling all chains to grow at a similar rate, resulting in low polydispersities.30

ð4Þ

Antimony and Bismuth Complexes in Organic Synthesis

505

ð5Þ

11.12.2.3 Organoantimony(III) compounds Antimony halides and pseudohalides are Lewis acidic by virtue of a low-lying Sb-X s antibonding orbital. Stable adducts of neutral antimony(III) centers with a variety of s- and p-donor ligands are known.31–44 The ready commercial availability, good solubility and stability of antimony(III) halides and pseudohalides makes them convenient Lewis acids in a broad range of reactions.

11.12.2.3.1

CdC Bond forming reactions

11.12.2.3.1.1 Indole additions SbCl3 catalyzes the condensation of indoles and aldehydes or ketones to yield bis(indolyl) methanes (Eq. 6). Electron whatdrawing groups on the carbonyl aromatic rings were found to accelerate the reaction, suggesting catalyst coordination to the indole rather than the carbonyl.45 Followup studies revealed that antimony(III) sulfate was an equally competent catalyst for these additions and overcomes the hydrolytic sensitivity of SbCl3 (Eq. 7).46 With Sb2(SO4)3 as the catalyst, reactions could be conducted at ambient temperature in methanol as the solvent. Interestingly, the use of a,b-unsaturated ketones as substrates led to formation of the 1,4-addition product giving 3-indolyl ketones (Eq. 8). The analogous addition to triazolyl-substituted a,b-unsaturated ketones can also be achieved with SbCl3 at elevated temperatures in MeCN (Eq. 9).47

ð6Þ

ð7Þ

ð8Þ

ð9Þ

11.12.2.3.1.2 Nucleophilic allylations Elemental antimony is known to mediate stoichiometric addition of allylbromides with carbonyl electrophiles in aqueous media (Eq. 10), with computational modelling suggesting the intermediacy of Sb(III) species and a six-membered transition state

506

Antimony and Bismuth Complexes in Organic Synthesis

(Eq. 11).48 The provenance of the elemental antimony has a significant influence on the reaction outcome, with the best result being obtained when Sb(III) halides are freshly reduced by NaBH4 prior to the reaction with the aldehyde an allyl bromide. In a related variant, the need for NaBH4 reduction can be eliminated by the use of KF as an additive and ultrasound irradiation, which presumable aids in the disintegration of oxide surface coatings to expose fresh metal. Thus, nucleophilic allylation of aldehydes and ketones was achieved in MeOH with a tenfold reduction in reaction times (Eq. 12).49 Recently, the use of tetraallyltin compounds for nucleophilic allylations as aldehydes has been developed with the use of an air and moisture stable CdNdC chelated antimony(III) triflate (Eq. 13).50 Although requiring more synthetic work than simple antimony(III) halides/pseudohalides, the organoantimony catalyst shows low loadings (80% ee) point to a crucial on-cycle role for a dioxobipyridine-bismuth complex and suggests Bronsted acid catalysis is not likely. A model for the active catalyst was proposed based on the seven-coordinate (at metal), pentagonal-bipyramidal, structure of a 1:1 adduct between the chiral dioxobipyridine ligand and BiBr3 determined through single-crystal X-ray diffraction. A more general, albeit achiral, variant of the reaction has been developed which tolerates a wide range of aldehydes and silyl-enolate equivalents and can be carried out in an ionic liquid as the solvent (Eqs. 92, 93).187 When trimethylsiloxy-substituted furans are used as the silyl-enolate, high diastereoselectivity (up to 98:2) is observed in the corresponding furanones, albeit the reactions must be performed at low temperatures (Eq. 94).188 As before, a broad range of aldehydes and enolates could be tolerated.

ð91Þ

ð92Þ

ð93Þ

ð94Þ

11.12.3.3.1.3 Nucleophilic allylations Aldehydes react smoothly with allylstannanes in the presence of Bi(OTf )3 under microwave irradiation to produce secondary alcohols (Eq. 95).189 The asymmetric variant of the reaction employed a bulky triol ligand (Eq. 96).190 The identity of the active catalyst was established by a combination of NMR spectroscopic and mass spectrometric experiments. Up to two equivalents of the ligand were detected in the coordination sphere of the metal, implying a hypervalent metal center. Aminosulfone electrophiles can be allylated (a variant of the Sakurai reaction) with allylsilanes with catalytic amounts of Bi(OTf )3.191 Allylation of aryl or alkyl substituted propargylic alcohols with allyltrimethylsilane has been reported in the presence of catalytic amounts of BiCl3 without the need for excluding air or moisture (Eq. 97).192 While electron-rich or moderately electron-poor substrates were tolerated, cyano-substituted electron deficient substrates showed poor yields. Although detailed mechanistic studies were not undertaken, the reaction is envisioned to proceed through a propargylic cation intermediate.

Antimony and Bismuth Complexes in Organic Synthesis

523

ð95Þ

ð96Þ

ð97Þ

11.12.3.3.2

C-X (X ¼ O, N, S) bond forming reactions

Simple Bi(III) Lewis acids catalyze a variety of carbon-heteroatom bond forming reactions. For example, BiCl3 (Eq. 98) and Bi(OTf )3 (Eq. 99) perform well as a catalyst for C-X (X ¼ O, N, S) couplings involving propargylic or allyl alcohols and nucleophiles such as alcohols, sulfides, aryl amides, aryl sulfonamides, carbamates, or carboxamides.192,193

ð98Þ

ð99Þ

The intramolecular dehydrative ring-closure of cyclopropyl carbinols is catalyzed by Bi(OTf )3 providing access to butyrolactone derivatives via a carbocationic intermediate that undergoes rearrangement (Eq. 100).194 Interestingly, HOTf also proved competent in this process suggesting Bronsted acid catalysis could be operative, but the more convenient handling of solid Bi(OTf )3 compared to HOTf makes the metal salt the preferred choice. Lighter metal triflates showed significantly lower conversion under similar conditions. Bi(OTf )3 also catalyzes the dehydrative etherification and thioetherification of phenyl hydroxy groups (Eq. 101).195 Surprisingly, the reaction does not work with leaving groups besides OH−, such as triflate, iodides, cyanides, or acetates are present in the electrophile. When allylthiols are used as nucleophiles, the initial dehydrative thioetherification is followed by a Claisen rearrangement and hydrothiolation of the resulting alkene to give a five-membered (Eq. 102). This cascade reaction exploits the dual capability of bismuth Lewis acids to behave as s (thioetherification) and p (hydrothiolation) electrophile.

ð100Þ

ð101Þ

524

Antimony and Bismuth Complexes in Organic Synthesis

ð102Þ

A related Bi(OTf )3 catalyzed cascade reaction is the one-pot, intermolecular nucleophilic substitution followed by CdO bond forming intramolecular hydroalkoxylation of alkene functionalized aldehydes to give complex tetrahydrofurans (Eq. 103).196 While the first step proceeds between −78  C and 0  C, heating the reaction mixture to 80  C triggers the second step in the cascade to ultimately yield the tetrahydrofuran. Mechanistic studies revealed the intermediacy of both TMSOTf and HOTf in the reaction mixture. Dihydropyrans are also readily accessible via substrate modification using Bi(OTf )3 as the catalyst (Eq. 104).197 ð103Þ

ð104Þ

The addition of BidS bonds across the triple bond in benzynes has been reported as a tandem, non-classical way of making BidC and CdS bonds (Eq. 105).198 A diverse range of 1,2-silyltriflate substituted arene substrates undergo activation by CsF to generate the benzynes, which smoothly insert into the BidS bonds of monosulfides (e.g. R2Bi-SR’) or disulfides (RBi(SR)2) to give the corresponding diaryl thioethers. Interestingly, the intramolecular version of the process was used to develop a new synthetic route to dibenzothiophenes.

ð105Þ

Organobismuth(III) compounds stabilized by a naphthalenediamine ligands and a labile dimethylamino group act as sources of amide nucleophiles in a range of addition reactions. For example, addition of the BidN bond across the unsaturated motifs in aldehydes, ketones, alkenes, alkynes, carbodiimides, and isocyanates has been reported (Eqs. 106–108).199,200 Interestingly, substitution occurs exclusively through the dimethylamino group rather than the naphthalene diamine ligand, which may be a consequence of chelate stabilization or sterical hindrance by the bulky trimethylsilyl group.

ð106Þ

ð107Þ

Antimony and Bismuth Complexes in Organic Synthesis

525

ð108Þ

There is significant interest in the development of Bi(III) Lewis acids as alternative to toxic tin alkoxide catalysts in the ring opening polymerization (ROP) of lactide to give biodegradable polymers. The salen class of ligands has been explored in this context, yielding the first bismuth catalyst for the single site ROP of lactide monomers.201 Although the low moisture tolerance of the acid renders is unsuitable in the present form, it provides a compelling proof of principle for the potential replacement of tin catalysts with bismuth in this important industrial reaction. Bi(OTf )3 also proved competent in the ROP of trimethylene carbonate to give high molecular weight polycarbonates (Eq. 109).202 Here too, the reaction is effective in the presence of HOTf, but more convenient to perform given the greater ease of handling inherent to Bi(OTf )3. Ligand bound complexes of bismuth cations featuring weakly coordinating anions (e.g. B(C6F5)4) are potent catalysts for the polymerization of cyclic ethers such as THF to give polyethers.203,204

ð109Þ

11.12.3.3.3

Reactions involving transition metals

Due to the polar nature of BidC bonds and the low toxicity of the metal in comparison with other organometallics, arylbismuthanes have been used as environmentally and biologically benign sources of aryl anions. Exploiting this property, the palladium catalyzed CdC cross-coupling of bromopyridines with arylbismuthanes was developed as a modular route to functionalized pyridines (Eq. 110).205 Moderate to good yields are observed irrespective of whether the aryl nucleophile is added to the ortho, meta, or para positions. Double arylation to achieve challenging 2,6-disubstituted pyridines featuring either symmetric or asymmetric substitution was also reported (Eqs. 111, 112). In all cases, 5–10% of biaryl coupling product was also observed.

ð110Þ

ð111Þ

ð112Þ

This reactivity mode has been extended to copper catalysis and other electrophiles such as halopyrazines, halopyrimidines, halopyridazines, and haloaryls.206–208 As new applications of such triarylbismuthanes have developed, so too have new routes been investigated to prepare them in reproducible and high-yield manner. In particular, the synthesis of asymmetrically substituted triarylbismuthanes is challenged by scrambling reactions and a recent investigation of different synthetic conditions highlighted the importance of low reaction concentrations and bismuth tosylates or iodides as halide precursors for avoiding dismutation at the metal.209 Moving beyond arylbismuth compounds, the use of trialkylbismuth compounds in cross-coupling has also been debuted. Notably, tricyclopropylbismuthane was found to be a competent equivalent of the cyclopropyl anion in the palladium catalyzed cyclopropanation of aryl halides and triflates (Eq. 113).210 The trialkyl bismuthane could also be used as a nucleophilic partner in the copper-catalyzed cyclopropanation of cyclic amides.211

526

Antimony and Bismuth Complexes in Organic Synthesis

ð113Þ

Besides CdC couplings, a broad range of intermolecular hydroamination reactions between dienes and carbamates, sulfonamides, or carboxamides are catalyzed by a combination of Bi(OTf )3 and Cu(CH3CN)4PF6 (Eq. 114).212 The p-acidity of the bismuth salt appears to drive reactivity in these systems by generation of allyl cations, as supported by detection of polyolefins when the nucleophilic substrates are absent. The addition of the copper salt suppresses the polymerization pathway.

ð114Þ

11.12.3.3.4

Multi-component reactions

The three-component Mannich reaction between aldehydes, anilines, and ketones giving b-amino ketones is catalyzed by hydrated Bi(OTf )3 under aqueous conditions (Eq. 115).213,214 In a related variant, with the reaction performed in THF instead of water, the ketone can be replaced by a silyl ketene acetal to furnish the corresponding b-amino esters in up to 90% yields (Eq. 116).213,215 Although electron-rich, electron-poor, and conjugated arylaldehydes were tolerated, the reaction showed poor conversion for aliphatic aldehydes. No evidence of aldol product formation was detected under the studied conditions. A recent improvement upon this procedure is the use of ultrasonication to reduce the reaction time in aqueoue media.216

ð115Þ

ð116Þ

An organometallic Bi(III) complex featuring intramolecular amine coordination also catalyzes this reaction (Eq. 117).217 A marked increase in activity was observed upon boosting the metal electrophilicity by replacement of the counterion with the [BF4]− or perfluoroalkanesulfonate pseudohalides. The related derivative featuring intramolecular thioether coordination, was found higher yields and distereoselectivity for this reaction in contrast to Bi(OTf )3 or the amine-coordinated variant (Eq. 118).217,218 Both hypercoordinate compounds were found to be air and moisture stable, which bodes well for their wider adoption.

ð117Þ

ð118Þ

The one-pot, three-component, synthesis of homoallyl ethers or acetates from aldehydes, orthoformates, and allylsilanes is accomplished by catalytic Bi(OTf )3 (Eqs. 119, 120).219 Performing the reaction stepwise indicated that the first step is reaction of the aldehyde and orthoformate to give a metastable acetal, which undergoes allylation in the presence of the allyltrimethylsilane (Eq. 121). In contrast, the allylation of the aldehyde under these conditions was very slow, suggesting it was not the first step. Replacement of the orthoformates by anilines and of the allylsilane by allylstannane enables the formation of homoallylic amines in the presence of Bi(NO3)3•(H2O)5 (Eq. 122).220 Interestingly, despite the hydrated nature of the catalyst, the reaction

Antimony and Bismuth Complexes in Organic Synthesis

527

does not proceed under aqueous conditions. The bismuth catalyst shows shorter reaction times and ambient reaction conditions compared to transition metal salts that catalyze this reaction.

ð119Þ

ð120Þ

ð121Þ

ð122Þ

Carbometallation of alkynes is an atom-efficient route to reactive alkenyl-metal compounds. In this context, BiBr3 participates in a very unusual carbo-bismuthination reaction with alkynes in the presence of silylacetals (Eq. 123).221 The reaction shows a remarkable sensitivity to the choice of Bi(III) salts and no product was obtained when the reaction was attempted with BiF3, BiCl3, BiI3, or Bi(OTf )3. Mechanistic studies suggest coordination of BiBr3 to the alkyne, which activates the latter to nucleophilic attack by the silylacetal in an anti fashion (Eq. 124). This proposal is supported by the exclusive E-stereochemistry of carbobismuthination. Oxidation of the metallated product with iodine or disulfides provide convenient access to iodoalkenes and thioalkenes respectively. Carbobismuthination could also be coupled with Pd catalyzed cross-coupling of the in-situ generated alkenyl-bismuth product with acid chlorides to access highly functionalized enones (Eq. 125).

ð123Þ

ð124Þ

528

Antimony and Bismuth Complexes in Organic Synthesis

ð125Þ

Bi(OTf )3 catalyzes the three-component C-C/C-N coupling of indoles, a-bromoacetaldehyde, and ketones to yield heavily functionalized carbazoles (Eq. 126).222 Tetracyclic carbazoles are accessible when cyclic ketones are employed. The use of 1,3-dicarbonyls gives 3-acetylcarbazole derivatives. Mechanistic studies implicate the Bi(OTf )3 catalyzed dehydrobrominative coupling of the a-bromoacetaldehyde and indole as the first step. The liberated HBr converts the acetal to the aldehyde and furthermore stabilizes the enol tautomer of the ketone. Coupling of this enol with the aldehyde and ring closure yields the carbazole.

ð126Þ

11.12.3.3.5

Oxidations

The bismuth catalyzed oxidation of methylarenes to benzoic acids (or ketones) is effected by Bi(OTf )3 in the presence of tBuOOH under aqueous conditions (Eq. 127).223 Although Bi(V) species are potent oxidants, mechanistic studies suggest that the metal salt activates the peroxide toward oxidative reactions rather than itself serving as a redox catalyst undergoing Bi(III/V) cycling. A mechanism involving radical intermediates was proposed and subsequently corroborated by radical clock experiments.224 Interestingly, the reaction can also be performed by metallic bismuth, which presumably undergoes in situ oxidation to a Bi(III) salt in the presence of the peroxide. Several Bi(III) salts were also found to be effective catalysts for allylic oxidation using peroxides, enabling the formation of enones.225 Given that these reactions typically require toxic chromate salts, the development of safer bismuth alternatives represents an important step forward. Primary and secondary alcohols can be oxidized to aldehydes and ketones, respectively, by the combination of catalytic amounts of BiBr3 and nitric acid under air (Eqs. 128, 129).226 The protocol bypasses the need for pure oxygen, which is common in such oxidations. Based on the observation that the reaction also requires water to proceed and that trace amounts of bromination products were also observed, a mechanism involving trace amount of Br2 and BiOBr as intermediates is proposed (Eq. 130).

ð127Þ

ð128Þ

ð129Þ

ð130Þ

Antimony and Bismuth Complexes in Organic Synthesis

529

An interesting variant of the above reactivity is the amino-oxygenation of propargyl amidines under oxygen to yield aldehyde functionalized imidazoles (Eq. 131).227 Among a broad range of bismuth salts tested, including some Bi(V) derivatives, BiCl3 was found to be the most effective catalyst. However to improve yields beyond 50%, the addition of 3 equivalents of phenol was found to be necessary. Presumably, this enables the in situ formation of Bi(OPh)3, which serves as the catalyst. Decarboxylation of the products was also achieved by KOtBu to yield the free imidazole.

ð131Þ

11.12.3.3.6

Reductions

The reductive diarylation of imines has been reported using Bi2(SO4)3 as the catalyst under ambient conditions (Eq. 132).228 The use of Me3SiCl as an additive was found to be essential for achieving high yields, although the precise role of the chlorosilane was not delineated. The reaction shows excellent scope, tolerating a broad range of aromatic and aliphatic N-tosylamines, as well as anisole, phenol, and thioanisole derived arenes as the nucleophiles with yields in the 70–99% range.

ð132Þ

The Bi(OTf )3 mediated catalytic reduction of ketones and aldehydes in the presence of Et3SiH has been investigated (Eq. 133).229 Interestingly, instead of giving the hydrosilylation products, these reactions selectively primarily give the dialkylethers. Mechanistic considerations suggest that the siloxycarbenium ion generated in the initial stages of the reaction has a sufficiently high lifetime that it undergoes addition to a second carbonyl equivalent instead of hydride abstraction from [HBi(OTf )3]− anion. In contrast, the combination of B(C6F5)3 and Et3SiH in this reaction yields hydrosilylation products, presumably due to more rapid hydride transfer from the sterically encumbered boron atom. Interestingly, when the Bi(OTf )3 mediated reduction is attempted with toluene as the solvent, a significant amount of solvent benzylation product is also observed due to competitive Friedel-Crafts addition of the toluene to the in situ generated siloxycarbenium ion.

ð133Þ

Solvent dependent outcomes are also observed in the Bi(OTf )3•(H2O)x mediated catalytic reduction of tertiary alcohols (Eqs. 134, 135).230 In dichloromethane, the alcohols are dehydrated to the terminal olefins but in nitromethane dehydration is followed by dimerization (Eq. 136).

ð134Þ

ð135Þ

530

Antimony and Bismuth Complexes in Organic Synthesis

ð136Þ

A tris-pyrazolylborate bound Bi dication is able to effect the catalytic hydrosilylation of alkenes and alkynes without forming carbocation rearrangement byproducts (Eq. 137).231 Independent reaction of the dication with Et3SiH showed decomposition with elimination of Bi(0), suggesting hydride transfer and subsequent reductive elimination. Thus the mechanism of hydrosilylation is likely similar to that of other main group Lewis acids (e.g. hydride abstraction from Et3SiH) and it is unclear whether the bismuth dication is a true catalyst or an initiator for the highly effective silylium catalyzed hydrosilylation of alkenes. The hydrosilylation of ketones and aldehydes is also catalyzed by an intramolecularly stabilized bismuth dication (Eq. 138).232 Notably, unlike the case of Bi(OTf )3, dialkyl ether formation is not observed in this system, which may be due to a mechanistically different pathway. Consistently, formation of an adduct between the bismuth dication and benzaldehyde (rather than Et3SiH, as postulated for Bi(OTf )3) could be experimentally verified through crystallographic characterization of a reaction intermediate.

ð137Þ

ð138Þ

11.12.3.4 Organobismuth(V) compounds Bi(V) compounds are both strong Lewis acids and potent oxidizers.144 Both electronic features have been harnessed for organic synthesis in stoichiometric and catalytic contexts.

11.12.3.4.1

Stoichiometric C-C/N/O bond formation

Triarylbismuth diacetates undergo metathetical exchange of an acetate with a phenoxy group. Subsequent reductive coupling between the phenoxy group and one of the aryl substituent at the metal could be exploited for the synthesis of benzopyran derivatives in good yields (Eq. 139).233 Triarylbismuth(V) dichlorides and diacetates could be used as stoichiometric CdC bond forming arylation reactions which eliminate HX and the diarylbismuth(III) (pseudo)halide as the reduction product.234 Introduction of a Cu(II) additive further unlocked CdN and CdO bond forming arylations of amines, azobenzenes and phenols starting from arylbismuth(V) salts (Eqs. 140–142).234–237 The oxidative CdC coupling of lithium enolates to give 1,3-diketones is accomplished by triarylbismuth(V) salts, presumably with the intermediacy of the triarylbismuth(V) di-enolates, which undergo reductive elimination (Eq. 141).238

ð139Þ

ð140Þ

Antimony and Bismuth Complexes in Organic Synthesis

531

ð141Þ

ð142Þ

11.12.3.4.2

Catalytic CdC/N/O bond formation

Besides stoichiometric reaction, new catalytic protocols involving Bi(V) compounds have also emerged. A unique application of triarylbismuth(V) ditriflates in this context involves activation of thioglycosides to enable glycosidation reactions with alcohols, giving oligosaccharides (Eq. 143).239 In contrast to previous promoters, the bismuth(V) salt is readily accessible and indefinitely air, light and moisture stable. Triarylbismuth(V) perfluoroalkylphosphinates have been recognized as competent Lewis acid catalysts for Friedel Crafts acylation and Diels-Alder reactions.240 These derivatives also exhibit good air and moisture stability and reaction yields are high when performed without an inert atmosphere.

ð143Þ

Inclusion of a Bi(V) center within a cyclic framework lends it greater chelate stability, unlocking catalytic applications. For example, an O


Bi intramolecularly stabilized Bi(III) pseudohalides undergoes sequential transmetallation with a boronic acid, oxidation, and reductive elimination in the presence of O-nucleophiles to yield ortho CdC coupled products (Eq. 144).241 As the chelating biaryl substituent is robust across this reaction coordinate, the reduced Bi(III) product to be recycled following anion exchange. Kinetic labelling studies suggest that electrophilic aromatic substitution in the coordination sphere of the metal is responsible for the final CdC bond forming step. A related derivative featuring N


Bi intramolecular coordination participates in a true one-pot catalytic cycle featuring Bi(V) intermediates active in the fluorination of arylboronic esters (Eq. 145).242 A Bi(III) bismuthenium tetrafluoroborate undergoes transmetallation with arylboronic esters to in situ generate a Bi(III) aryl species. The latter is oxidized to Bi(V) with a fluoropyridinium tetrafluoroborate salt to yield a pyridine stabilized arylfluorobismuthonium(V) cation, which undergoes reductive elimination of a fluoroarene to regenerate the bismuthium terafluoroborate. When a source of triflate or nonaflate ions is present (e.g. NaOTf or NaONf ), the pyridine stabilized arylfluorobismuthonium(V) cation is neutralized to the neutral pentavalent triflato/nonaflato complex.243 Reductive elimination then yields aryl triflates/nonaflates instead of a fluoroarenes.

ð144Þ

ð145Þ

532

Antimony and Bismuth Complexes in Organic Synthesis

Acknowledgment Saurabh S. Chitnis and Toren Hynes acknowledge generous financial support from the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, and Dalhousie University.

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11.13

Selenium and Tellurium Complexes in Organic Synthesis

Claudio Santi and Cecilia Scimmi, Group of Catalysis Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy © 2022 Elsevier Ltd. All rights reserved.

11.13.1 11.13.1.1 11.13.2 11.13.2.1 11.13.2.2 11.13.2.3 11.13.2.4 11.13.2.5 11.13.2.6 11.13.2.6.1 11.13.2.6.2 11.13.3 11.13.4 References

General introduction Electrophilic selenium and tellurium reagents Nucleophilic selenium and tellurium reagents Cadmium Lanthanum Indium Samarium Tin Zinc Synthesis and reactivity of [RSeZnSeR] generated by oxidative insertion of elemental zinc into the SedSe bond Synthesis and reactivity of bench stable zinc selenolates (Santi’s reagents) New insights in organoselenium and organotellurium catalysts Conclusion

536 536 542 542 542 543 544 544 545 545 552 558 560 561

11.13.1 General introduction The chemistry of organoselenium compounds has been recognized as an important tool both in synthetic and medicinal chemistry.1 Even if in the past its development was slowed down by several concerns related to the toxicity and the potentially harmful environmental impact, nowadays several synthetically relevant organoselenium reagents can be used in efficient and selective transformations, evidencing, in some cases, a plethora of advantages over other commonly used reagents.2 The first relevant organic application dates back to 19703 and in the last decades several synthetic transformations attracted the interest of organic chemists for their unique chemo-, regio- and stereoselectivity as well as for the possibility of being realized under particularly mild conditions. Among these reactions we can mention electrophilic and nucleophilic selenenylations, cyclofunctionalizations, selenoxide and selenone elimination or substitution, 2,3-sigmatropic rearrangements and many others. A particular emphasis in the past has been devoted to the use of organoselenium reagents as catalysts in one-pot selenenylationdeselenenylations,4 biomimetic oxidations5 and as chiral reagents or ligands in metal mediated reactions.6,7 In 2009 the use of selenium catalyst was proposed for the first time as a convenient strategy to address the requirement of “green chemistry”8 and in the following years a number of new green protocols based on organoselenium reagents appeared in the literature and were further collected in a review article.9 In the recent past several synthetic strategies were revised in ameliorative manner thanks to the use of several enabling technologies, such as photochemistry, electrochemistry, microwave, ultrasound and flow chemistry. In this chapter some selected relevant developments in the field of electrophilic and nucleophilic chemistry of selenium and tellurium reagents will be discussed considering that several aspects have been already included in review articles and book chapters10–12 covering large part of the scientific production subsequent to the comprehensive chapter reported by Wirth in 2007.13 A comprehensive attention will be dedicated to the reactions involving selenium and tellurium metal complexes, that have recently found applications in a number of nucleophilic chalcogenation(s) and are the main focus of this work.

11.13.1.1 Electrophilic selenium and tellurium reagents The preparation of electrophilic selenium reagent and their application in selenenylation reactions is the most studied aspect of organoselenium chemistry. Some reagents such as PhSeCl, PhSeBr and PhSe-phthalimide are commercially available and can be used in electrophilic addition to multiple bonds directly or after transformation into derivatives having an anion stabilized by resonance, or the presence of strong EdX bonds (triflate, hexafluorophosphate, hexafluoroborate), less prone to act as a competitive nucleophile.14 Several strategies were used to prepare electrophilic selenium reagents in situ starting from the corresponding and easily accessible diselenides through the cleavage of the SedSe bond that can be achieved using electrochemical activation15 or using different mild oxidants, such as Oxone®,16 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),17 hypervalent iodine reagents,18 ammonium persulfate,19,20 m-chloroperbenzoic acid,21 KNO3,22 Ce(NH4)2(NO2)6,23 and Mn(OAc)2.24 Electrophilic selenenylation reactions are regio- and stereoselective addition processes in which the nucleophilic attach of a multiple bond to the electron poor selenium atom leads the formation of a seleniranium ion intermediate which is subsequently quenched by the anti-addition of a nucleophile which could be an external nucleophile, usually the solvent, or an internal nucleophile. This latter class of reactions is particularly interesting because represent an efficient and convenient strategy for the synthesis of several classes of functionalized heterocycles (Scheme 1).25

536

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00082-2

Selenium and Tellurium Complexes in Organic Synthesis

537

H Nu

Nu

R Se X R’’

’R

H

’R

R’’

’R R-SeX

’R R

Se

X

NuH

Nu

Nu R’’

’R

SeR

’R SeR

Scheme 1

In 2016 it was reported that N-phenyl selenosaccharin 2 can be easily obtained by the reaction of silver saccharin 1 and the commercially available phenyl selenium chloride or bromide in dichloromethane at room temperature (Scheme 2). The resulting electrophilic selenium reagent 2 has been used for the methoxyselenenylation of a series of linear and cyclic olefins affording in dichloromethane at room temperature, the corresponding a-methoxy phenylselenides in yields ranging from 56% to 93%. More interestingly N-phenyl selenosaccharin 2 was used in the very efficient cyclofunctionalization of the alkenol 3 and the alkenoic acid 5 into the corresponding tetrahydrofuran 4 and the lactone 6, respectively (Scheme 2A and B). In addition, the applicability of 2 has also been demonstrated in rare examples of electrophilic aliphatic CdH activation of ketones 7 and aldehydes 9 as described in Scheme 2C and D for the synthesis of the a-phenylseleno indanone 8 and the a-selenenylated heptanal 10 in good yields when reacted at room temperature for 20 h.26

(A)

(B)

(C)

(D)

Scheme 2

538

Selenium and Tellurium Complexes in Organic Synthesis

In the last decade molecular Iodine (I2) emerged as an interesting agent for the in situ generation of the electrophilic species RSeI, starting from the corresponding diselenide (RSeSeR), in which the anion counterpart has a scarce nucleophilicity. Yan et al. reported the iodine activated reaction of alkenes with diselenides under mild reaction conditions in MeCN/H2O to afford b-hydroxy selenides in good to excellent yields and high regioselectivity.27 Furthermore, after the addition reaction the resulting hydroiodic acid (HI) can be easily re-oxidized to molecular I2, enabling the use of the halogen as a catalyst in the presence of a milder second stoichiometric oxidant. As an example, in 2012 Wirth et al. reported a nice example of carbon-carbon bond formation using 20 mol% of iodine and diphenyl diselenide to catalyze the formation of 13 starting from an excess of styrene 11. In the proposed mechanism the olefin acts both as substrate for the formation of the intermediate seleniranium ion (not shown in the scheme) and as a nucleophile in 1,2-dichloromethane at 70  C. The authors proposed the intermediate formation of an iodine derivative (12) that lead the final product by elimination. The moderately higher yields with respect to the stoichiometry can be explained supposing an air mediated re-oxidation of HI to molecular iodine accounting for both the long reaction time and the moderate yields (Scheme 3).28

Scheme 3

Wey and co-workers reported an interesting and simple protocol for the synthesis of 3-sulfenyl-indoles in dimethyl carbonate, using an equivalent amount of DMSO as stoichiometric oxidant and molecular iodine (I2) as catalyst29 and, similarly, I2 and DMSO were used for the preparation of 3-sulfenyl-indoles by using aryl sodium sulfinates as an organosulfur source.30 Braga et al. strongly improved this catalytic protocol optimizing a very efficient solvent and metal free methodology in which the reaction was strongly accelerated by microwave irradiation affording the target compounds in almost quantitative yields within very short reaction time (5–10 min). Using this procedure, the synthesis of 3-selenenenyl-indoles (16) from variously decorated indoles (14) and diorganyl diselenides (15) was reported. The authors discussed 18 examples demonstrating a good efficiency for aryl diselenides and NH or NMe indoles whereas benzyl or alkyl diselenides as well as N-Boc or N-Ts indoles afforded the corresponding selenenenyl-indole in traces or low yield. From a mechanistic point of view, iodine reacts with the diselenide 15 affording the in situ formation of the electrophilic reagent (R000 SeI) which promotes the aromatic substitution on 14 affording the selenenylated indole 16 and a molecule of HI that is oxidized by the DMSO to I2 that continue the catalytic cycle (Scheme 4).31

R’’’SeSeR’’’

15

R’’’SeI I2 MW 100W, 50°C 5 min

H2 O +

R R’ N 14 R’’

S

SeR’’’

HI

O S

R R’ N 16 R’’

R = H, Me, OMe, Br, COOMe R’ = H, Ph R’’ = H, Me Ph, -Boc, -Ts R’’’= Ph, p-Me-C6H4, p-Cl-C6H4, p-OMe-C6H4, m-CF3-C6H4, -Bn, -nBu Scheme 4

Selenium and Tellurium Complexes in Organic Synthesis

539

The same protocol was also used for the versatile electrophilic alkoxyselenenylation of styrene and very interestingly for the cyclofunctionalization of 3 and 5 affording, in 10 minutes, the formation of 4 and 6 in 81% and 95% yield, respectively. As an example of the broad applicability of the method the authors described the cyclofunctionalization of C-allyl lawsone 17 and lapachol 19 affording in good yields the cyclic derivatives arising from a 5-exo-trig 18 or a 6-endo-trig 20 cyclization reaction, respectively (Scheme 5).32

Scheme 5

Similarly, the selenoalkoxylation of variously substituted alkenes was reported for the synthesis of a-alkoxyl selenides using iodine as catalyst and hydrogen peroxide as stoichiometric oxidant. The reaction is accelerated by visible light irradiation and air has been proposed as an additional oxidant to achieve the full consumption of alkenes and diselenides.33 More recently, the commercially available hypervalent iodine derivative PhIO has been described for the activation of a three-component coupling of olefins, diselenide and a nucleophile (water, alcohol, phenol, carboxylic acid, or amine) for the synthesis of b-functionalized selenoderivatives. The reaction involves the transient formation of an electrophilic species, most reasonably a seleninic acid or the corresponding anhydride leading to the intermediate formation of a seleniranium ion, accounting for the high chemo-, regio- and stereoselectivity reported in a massive number of examples. The procedure is characterized by mild conditions, easy operation and excellent functional group tolerance, and is thus particularly suitable for the late-stage functionalization of complex molecules of biological relevance. Some selected example (21–26) and the proposed mechanism are summarized in Scheme 6.34 Oxone® is currently emerging as a cheap, readily available and environmentally benign oxidant.15 It is a stable and easily handle triple salt (2KHSO5
KHSO4
K2SO4) in which the active oxidant is the potassium peroxymonosulfate (HOOSO3K). In recent years it has been used for the in situ generation of selenium-centered electrophiles by the oxidative cleavage of the SedSe bond starting from different diselenides in the selenomethoxylation of aryl substituted olefins.35

540

Selenium and Tellurium Complexes in Organic Synthesis

ArSeO HO Ph I SeAr Ph I SeAr

ArSeSeAr + PhIO

PhI ArSeOH Nu-H

ArSeOSeAr

SeAr

SeAr Nu Nu = HO- ; RO- ; RNH- ; RC(O)OO MeO

O

O

SePh

O

Se

SePh O

21 (74%)

OH

Se

OH

OH

22 (92%)

23 (84%)

Se

O

Se

O

HN O

24 (66%)

25 (68%)

Cl

26 (73%)

Scheme 6

Very interestingly, different aryl and heteroaryl diselenides were activated toward the electrophilic aromatic substitution of imidazothiazoles 27, imidazopyridines 29 and pyrazoles 31 affording the corresponding selenides 28, 30 and 32 in moderate to excellent yields. It was also demonstrated that the process can be efficiently activated by the use of ultrasound irradiation, in the place of the conventional heating to 50–60  C, resulting in a strong rate acceleration and, consequently, a reduction of the reaction time (Scheme 7).36

))), rt, 30 min

28 (80-99%)

’R N

S N ’R N

SeR

N H 32 (60-96%)

R’’

R’’ N H 31

50°, 4h

RSeSeR + Oxone MeCN

60°, 2h

60°, 2h

N

N N

R’

30 SeR (76-83%)

R’’ N

S ’R

R’

R’’

N 28

N 29

Scheme 7

N 27

’R

SeR

(15-95%)

Selenium and Tellurium Complexes in Organic Synthesis

541

Oxone® has been also used to activate diselenides toward the electrophilic cyclization of ortho-functionalized chalcogenoalkynes 3337 to afford the corresponding 2,3-bis-chalcogenyl-benzo[b]chalcogenophenes 34 and in the sequential intramolecular cyclization of methyl 2-(organyl-1,3-diynyl)benzoate 35, with the formation of 5H-selenopheno[3,2-c]isochromen-5-ones 36, in both cases with yields ranging from poor to excellent as reported in Scheme 8.38

Ch’R’

Ch-Alkyl SeR Ch’R’ Ch 34 (42-95%)

COOMe ’’R

Ch = S, Se Ch’ = O, S, Se 33 reflux, up to 7h

R’ RSeSeR + Oxone EtOH

O

35

O SeR

reflux, up to 2,5 h ’’R 36 Se (40-86%)

R’

Scheme 8

In a similar way the same authors also reported the electrophilic cyclization of a,b-alkynyl hydrazones, into 4-organoselanyl-1H-pyrazoles39 that can be also obtained through a multicomponent reaction between a hydrazine, an 1,3-diketone and a diorganyl diselenide, in the presence of Oxone® and AcOH at 50  C.40 Applications of tellurium electrophiles in organic synthesis are quite limited and some were recently reviewed.41 TeCl4 has been reported as a convenient bis-electrophile in the reaction with dienes42 and alkynes. In this latter case It can promote double-electrophilic cyclization of the sulfide 37 in 1,2-dichloroenthane (DCE) at 60  C affording the telluride 39 through the intermediate formation of 38, which was not isolated but reduced by treatment with Na2S2O3 during the workup.43 Using a similar reactivity symmetric (40b) and non-symmetric (40a) butadiynes can be converted into several different heteroacenes by treatment with chalcogen centered electrophilic TeCl4 (see as an example 41a–b) and/or SeCl2 (see an example 42) (Scheme 9A and B).43

(A)

(B)

(C)

Scheme 9

542

Selenium and Tellurium Complexes in Organic Synthesis

4-Trimethylsilylmethyl-3-butyn-2-one (43) and tellurium tetrachloride or tetrabromide react affording the 1,1-dihalotelluracyclopentenones 42a and 42b, respectively in good yields from which the tellurium can be reduced to 43a and 43b by treatment with aqueous Na2S2O3 (Scheme 9C).44 Furthermore, benzotellurandiazoles (47) were prepared by Garrett et al.45 starting from 1,2-phenylenediamines (46) and tellurium tetrachloride that replaced the SeO2, previously reported by Cozzolino et al.46 for the synthesis of the corresponding selenium derivative 48 (Scheme 10).

Scheme 10

11.13.2 Nucleophilic selenium and tellurium reagents Beside the electrophilic reagents the use of selenolates represent a convenient and common alternative for the introduction of organoselenium moieties into suitably functionalized organic substrates. The higher nucleophilicity of selenols and selenolates with respect to the corresponding thiol/thiolates is a consequence of the higher polarizability of the selenium atom that, in association with its low ionization potential, lead them to be considered good soft nucleophiles according to the hard-soft theory. All these characteristics can be used in the formation of carbon-selenium bonds enabling further transformations considering that selenium can be easily removed by elimination and/or substitution reactions.47 Nucleophilic selenolates are often generated in situ by reduction of the selenium–selenium bond in diselenides, or by the insertion of elemental selenium into organometallic species, such as Grignard reagents or organolithium derivatives.12,48,49 Some different low valent metals were used for the reductive SedSe bond cleavage of diselenides and are discussed here.

11.13.2.1 Cadmium Elemental cadmium (produced in situ by reduction of CdCl2-H2O with powdered samarium in DMF-H2O or THF-H2O) has been reported by Zheng et al. in a study of aqueous organometallic reactions. It was reported that the formed Cd(0) promotes the reaction between allyl bromides or a-bromocarboxylates with aromatic and/or aliphatic diorganodiselenides in a mixture of DMF and water affording the corresponding allyl selenides or a-selenocarboxylates, respectively in good to excellent yields. The oxidative insertion of the Cd(0) into the SedSe bond affords reasonably the nucleophilic selenenylating species [RSedCddSeR] enabling the nucleophilic substitution of the bromine atom from the substrates.50

11.13.2.2 Lanthanum Diphenyl diselenide after activation with elemental lanthanum and a catalytic amount of iodine reacts with two equivalents of alkyl iodides (49a), bromides (49b) and chlorides (49c) to afford the corresponding alkyl phenyl selenides 50 in moderate to good yields (selected examples are shown in Scheme 11). In the case of primary alkyl chlorides and secondary alkyl iodides, the low yields can

Scheme 11

Selenium and Tellurium Complexes in Organic Synthesis

543

be improved by the addition of TMEDA or HMPA, and, based on experimental evidence, it was suggested that the reaction does not involve a radical pathway but instead an in situ generated lanthanum phenylselenolate intermediate. The same reaction can be used to activate also the TedTe bond of diphenyl ditelluride affording the alkyl phenyl telluride 51 in excellent yields.51

11.13.2.3 Indium Allyl and propargyl bromides can be selenenylated by reaction with diorganyl diselenides in the presence of indium metal in aqueous media without any additional of activation. The corresponding allylic and propargyl selenides can be obtained in moderate to good yields also when the reactions were carried out under non-inert atmospheres. Very interestingly the reactions showed a rate acceleration when performed in a mixture of THF and water with respect to fully organic media.52 Similarly, Ranu et al. reported that indium(I) iodide can be used to perform the same reaction in dichloromethane at room temperature evidencing a good structural and functional group tolerance. They proposed a bis(phenylseleno)-iodo-indium(III) as the key intermediate in the formation of the carbon-selenium bond.53 Both In(0) and In(I) were used by Braga for the synthesis of b-chalcogen amides through the ring-opening reactions of 2-oxazolines, a convenient strategy that offers the possibility of using inexpensive and easily available starting materials with a large possibility of structural diversification avoiding the need for N-protection/deprotection steps.54,55 These conversions suffer of long reaction times (24 h) and harsh reaction conditions (1,4-dioxane at reflux), drawbacks that were recently addressed by Galeto et al. using microwave irradiation in ethylene glycol in the presence of stoichiometric amount of elemental indium and molecular iodine. A single electron transfer from indium to iodine leads the generation of indium(I) iodide, which in turn is involved in an oxidative insertion at the SedSe bond of the diselenide affording the reactive bis(organylseleno)iodo indium(III) 53. This intermediate acts as Lewis acid and reacts with the oxazoline 52 affording the proposed 54 that spontaneously can collapse into the final b-chalcogen amides 55 with a preservation of the stereochemistry of the starting (S)-2-oxazolines 52. In all the cases the desired selenides (see 55a–i) were obtained in good yields after 20 min of microwave irradiation at 50 W and 150  C (Scheme 12).56

RSeSeR + In0 + 0.5 I2

RSe R1 R 2

I

R3 52

N H

SePh

55a (79%)

Ph

O

HO-CH2CH2-OH MW, 50W, 150° 20 min

SePh

N H

Se

Ph

55f (62%) Scheme 12

R2 R1 SeR

N H 55

Ph SePh

N H

Ph

O

Ph

O

SePh

N H

Se

55g (79%)

Ph F

SePh

N H

55e (68%)

O N H

Ph

55d (55%)

55c (83%)

55b (62%)

Ph

R3

54

O N H

O

R3

O

O Ph

SeR In I SeR

N

O

O Ph

R1 R2

53

N O

(III)

In SeR

O N H

Se

55h (48%)

F3C

Ph

N H

Se

55i (44%)

544

Selenium and Tellurium Complexes in Organic Synthesis

11.13.2.4 Samarium In 1990 Fukuzawa et al. reported that allyl selenides can be prepared starting from the corresponding acetates in the presence of samarium(II) diiodide and palladium as a catalyst. The reaction proceed in good yields in THF at room temperature for 2 h and the initial formation of a p-allyl palladium complex was speculated.57 Selenolates can be prepared also starting from diselenides by treatment with elemental samarium and zinc chloride in aqueous medium58,59 or elemental samarium and a catalytic amount of potassium iodide60 and in turn used in different nucleophilic substitutions. A series of variously decorated Baylis-Hillman adducts 56 were stereoselectively selenenylated using different diselenides activated by elemental samarium and TMSCl. The reaction may involve a silyl enolate intermediate 58, as product of a Michael-type addition of the nucleophilic selenium species 57 to the Baylis-Hillman adducts 56, leading to the one-pot formation only of the Z-isomers of the selenides 59, in all the cases in very good yields (59a–f Scheme 13).61

RSeSeR + Sm/TMSCl

COOMe R1

RSeSiMe3 57 THF, rt

MeO

OSiMe3 R1

RSe

OH 56

COOMe RSe R1

OH

59

58

COOMe Se

COOMe

COOMe Se

Se

O 59a (90%)

59b (92%)

COOMe Se

59d (97%)

59c (89%)

COOMe Se

59e (89%)

COOMe Se

59f (85%)

Scheme 13

11.13.2.5 Tin Like indium and samarium tin has also been used for the synthesis of allyl and propargyl selenides starting from the corresponding allyl and propargyl bromides and diselenides in aqueous media (THF/H2O).62 Similarly allyl, propargyl, benzyl, and alkynyl bromides reacts with diorganodiselenides by activation with SnCl2 in the presence of a catalytic amount of CuCl2.The corresponding selenides were obtained in good to excellent yields at room temperature in THF and the authors suggested the formation of an unprecedented dicopper-(selenophenyl) intermediate as the active selenenylating species.63 Dialkyl tin chlorides 60 reacts with two equivalents of sodium 2-pyridyl selenolates 61 to afford the air stable diorganotin selenolate complexes 62 that, via further reaction with an equivalent of 60, can be transformed into the chloro-complexes 63 (Scheme 14). Some of these complexes have been used for the preparation of tin selenide nanomaterials and for the deposition of SnSe thin films.64

Selenium and Tellurium Complexes in Organic Synthesis

545

Scheme 14

11.13.2.6 Zinc 11.13.2.6.1

Synthesis and reactivity of [RSeZnSeR] generated by oxidative insertion of elemental zinc into the SedSe bond

11.13.2.6.1.1 Oxidative insertion catalyzed by Lewis acids Among all the metal selenolates that were prepared and used in organic synthesis, zinc derivatives have been the most widely investigated. The use of this metal for the reduction of dichalcogenides bond to afford the in situ formation of a [RSeZnSeR] reagent was initially reported, in combination with some Lewis acids, such as aluminum chloride (AlCl3),65,66 zirconium tetrachloride (ZrCl4),67 RuCl368 and TiCl4.69 The Zn/AlCl3 mixture reported for the first time by Movassagh afford the reduction of diphenyl diselenide only using a large excess of both the zinc (4.6 equivalents) and the Lewis acid (2.0 equivalents) at 65  C in DMF or in refluxing MeCN. This methodology was applied to the synthesis of selenol esters starting from the corresponding acyl chlorides65 and for the synthesis of selenocabamates 65 starting from isocyanates 64, a reaction in which the AlCl3 plays a double role in the in situ formation of the nucleophilic reagent [RSeZnSeR] as well as in the coordination of the oxygen atom of the isocyanate, with the consequent activation of the group toward the nucleophilic attack of the selenolate. As reported in Scheme 15 better results were obtained for aryl diselenides in comparison with the benzyl analogues.70

Scheme 15

An equimolar mixture of diphenyldiselenide and zinc-powder in the presence of a catalytic amount of ZnCl2 generates the nucleophilic selenenylating reagent in situ that can be efficiently used for the preparation of 1,2-trans-selenoglycosides 67 and 69 by the reaction with glycosyl bromides 66 and 68 (2.0 equiv). This protocol resulted to be particularly versatile and structurally tolerant, representing a good strategy to synthesize seleno- and thio-sugars. As a further application, shown in Scheme 16, is the conversion of the chloro derivative 70 into the selenoglycoside of the sialic acid 71.71

546

Selenium and Tellurium Complexes in Organic Synthesis

PhSeSePh + Zn + ZnCl2 cat MeCN, 70°C AcO

AcO AcO AcO AcO

[PhSeZnSePh]

O Br

AcO AcO AcO

66 AcO AcO

O SePh

67 (92%)

AcO AcO

[PhSeZnSePh]

O

AcO AcO

AcO AcO

O SePh

Br 68 AcO

OAc O

AcO O AcHN AcO 70

69 (90%) OMe

AcO [PhSeZnSePh]

Cl

OAc O

AcO O AcHN AcO

OMe SePh

71 (50%)

Scheme 16

Indium(III)72 and ruthenium(III)67 halides were demonstrated to be efficient catalysts for the synthesis unsymmetrical diorganyl selenides by the reactions of diselenides with organic halides including unreactive bromides and chlorides in the presence of zinc. The first step of the reaction was proposed to be the formation of the zinc complex [RSeZnSeR] that is subsequently subjected to a metal exchange that activates the selenium atom toward a coupling reaction with benzylic (or allylic), and aliphatic halides to afford the corresponding unsymmetrical selenides 72, 73 in good yields with limited dependence on the identity of the halogen used on the catalyst but not on the substrate (74 and 75) (Scheme 17). These bimetallic systems demonstrated their efficiency providing a cleaner and faster strategy for the synthesis of the target compounds in comparison with the direct use of zinc selenates. RuCl3 was used also to activate a seleno-Michael reaction between three different zinc selenates [PhSeZnSePh], [BnSeZnSeBn], [4-ClC6H5SeZnSe4-ClC6H5] and conjugated esters, ketones, aldehydes and nitriles in aqueous media (MeCN/H2O 4:1).73 A very efficient and practical method for CdSe coupling of diaryl diselenides with alkyl halides was reported in 2017 by Chen et al. using a new heterogeneous ruthenium catalyst easily available in a two-step procedure starting from cheap and commercially available reagents. For the preparation of the MCM-41-2N-RuCl3 complex the mesoporous silicate MCM-41 is functionalized with 3-(2-aminoethylamino)propyl moiety that acts as a N,N-bidentate center for the coordination of the Ruthenium.

Selenium and Tellurium Complexes in Organic Synthesis

RSeSeR + Zn

547

RSeZnSeR DMF 100°C ZnX2

(RSe)2MX

MX3 RSeR’

R’X

(RSe)MX2 R’X

RSeR’

M = In, Ru ; X = Cl, Br R= Ph, PhCH2 , alkyl selected examples

Se

Se

72

73

M = In 58% M = Ru 98%

M = In 57% M = Ru 82%

PhSe

Se 74

M = In; X = Cl 89% M = In; X = Br 85% M = In; X = I 90%

C11H23

C6H13

75 M = Ru; X = Cl 0% M = Ru; X = Br 85% M = Ru; X = I 75%

Scheme 17

This catalyst for the coupling reaction afforded unsymmetrical diorganyl selenides in good to excellent yields starting from alkyl iodides, bromides and chlorides, and it was demonstrated that it could be recovered by filtration and reused for eight subsequent cycles without loss of efficiency (Scheme 18).74

548

Selenium and Tellurium Complexes in Organic Synthesis

Scheme 18

11.13.2.6.1.2 Oxidative insertion using a recyclable biphasic acidic system A very simple and efficient method to promote the oxidative insertion of elemental zinc into SedSe and TedTe bonds was introduced by our group using, as reaction medium, an acidic biphasic system composed by the same volume of organic solvent (diethyl ether or ethyl acetate) and a 10% aqueous solution of hydrochloric acid. In this system the dichalcogenide is dissolved in the organic phase and, in the presence of elemental zinc, it is rapidly reduced affording a zinc chalcogenate that can be used to perform a series of nucleophilic chalcogenations in situ (Fig. 1). The main advantages of this protocol are represented by the possibility of performing the reaction in a closed vial, avoiding any drawbacks connected with the chalcogenols’ odor, as well as their tendency to be rapidly oxidized back to the diselenide by air exposure. Furthermore, this methodology is characterized by a very simple workup consisting of the separation of the organic layers containing the target compound(s) that, in most cases, do not require any further purification. Starting from diphenyl diselenides it was demonstrated that the acidic conditions lead to the formation of benzene selenol that can be isolated by the in vacuo evaporation of the organic solvent after the separation and drying of the organic layer. This procedure was initially applied to the synthesis of different selenides and b-hydroxy selenides using as electrophiles alkyl halides and epoxides, respectively. In the last case an high regioselectivity was observed according to the ring opening reaction of epoxide under acidic conditions.75 One year later Braga et al. demonstrated that the same acidic biphasic system can be applied to the ring opening reaction of unprotected aziridines (76), an interesting strategy for the synthesis of chiral b-seleno amines (78a, 78c–i) and chiral b-telluro amines (78b).

Fig. 1 Oxidative zinc insertion in a biphasic acidic system.

The reaction proceeds through the protonated intermediate 77 that is stereo- and regioselectively opened by the chalcogenates which attack the less hindered aziridine carbon with a complete retention of configuration at the preformed chiral center, affording the target compounds 78 in enantiomerically pure form. The versatility of the protocol is clearly demonstrated by the molecular diversity that can be introduced both in the substrate and in the reagent as evidenced by some selected examples reported in Scheme 19. The best yields were obtained using aromatic diselenides bearing electron-withdrawing substituents.76

Selenium and Tellurium Complexes in Organic Synthesis

549

Scheme 19

Slightly adjusted conditions of this protocol were found to be an elective method for the preparation of a series of N-protected selenocysteine derivatives as building block in the synthesis of peptides. The reaction conditions for the cleavage of the SedSe bond were optimized according to the lability of the protecting group at the nitrogen atom, 1M HCl were used for N-Boc derivatives (79) and 3 M for the N-Fmoc ones (80). After the reduction the selenolates were reacted with the appropriate electrophile affording in good yields the Se-Meb (81,82), Se-Mob (83,84), and SedBz (85,86), derivatives.77 The same author in a different paper reported the use of the biphasic system for the introduction of TFA-labile protective groups on the selenium atom (Scheme 20). In particular the synthesis of new compounds, Fmoc-Sec(Trt)-OH (87) and Fmoc-Sec(Xan)-OH (88) were reported as useful and practical alternatives to the traditional derivatives. Compound 88 showed a higher bench-stability with respect to the trityl derivative 87, which is prone to slow detritylation when at temperature higher than −20  C78 (Scheme 20).

550

Selenium and Tellurium Complexes in Organic Synthesis

Scheme 20

Another synthetic application of this protocol has been, surprisingly, for the nucleophilic selenenylation of acyl chlorides in the synthesis of selenol esters. For these substrates the procedure lacks general applicability, it failed in the case of styryl and benzyl derivatives as well as in all of the cases of substrates containing functional groups sensitive to reductive conditions (e.g. -NO2) but afforded better results respect to the use of THF as the sole solvent. In this latter case tetrahydrofuran proved to be reactive, undergoing a non-selective ring opening reaction.2 The hydroselenenylation of alkynes represents a convenient and direct method for the preparation of vinyl selenides. The first example was reported by Sharpless using of an in situ generated boron complex.79 The addition of PhSeH to alkynes is very slow but strongly regio- and stereoselective leading the formation of the Z-anti-Markovnikov isomer. High temperature can be used to accelerate the reaction that, at room temperature, require several days with deleterious effects on the selectivity of the reaction.80 Using zinc selenolates generated in the biphasic system, the hydroselenenylation reaction of alkynes (89) can be easily performed affording the corresponding vinyl selenides (90) in excellent yields. The reaction is regiospecific and affords, in all the cases, the Z-isomer as the major reaction product. The stereoselectivity is only slightly affected by steric hindrance and by the electron density of the selenenylating reagents (compare examples a, b, c in Scheme 21A). Interestingly the reuse of the aqueous reaction medium as well as of the unreacted zinc has been demonstrated and applied to the gram scale synthesis of 90 in five subsequent cycle without need of any further purification a with an overall yield of 95%.81

Selenium and Tellurium Complexes in Organic Synthesis

551

(A)

(B)

Scheme 21

A similar protocol was also attempted starting from ditellurides but, even if the discoloration evidenced the reduction of the TedTe bond no evidence of reaction of the alkyne was observed. This is unsurprising as this transformation generally requires more forcing conditions and longer reaction times.82 Barros et al. reported that hydrochalcogenation of propargylic acid (91) and esters (92) can be effected using diaryl diselenides and diaryl or dialkyl ditellurides as sources of zinc selenolates or zinc tellurolates generated in situ in the presence of elemental zinc under basic conditions. The reactions required activation at 100  C for 24 h affording in all the cases the Z-isomer as major reaction product. In the hydroselenenylation reaction of propargyl esters afforded better yield in comparison to the corresponding acid (94 vs 93) while diphenyl ditellurides afforded the target compounds in good yields for both substrates (95 vs 96). Interestingly dialkyl ditellurides afforded stereospecific formation of the Z-isomers (Z)-97 and (Z)-98 as the unique reaction product starting from 91 and 92, respectively.83 (Scheme 21B). Very recently we reported a further application of the recyclable biphasic system for the functionalization of organic substrates thought a seleno-Michael type reaction. Beside diphenyl diselenide, 1,2-bis(3-phenylpropyl)diselenide and protected selenocystine were also used as sources for the in situ generation of the selenenylating reagents that were reacted with alkenes (99) activated by variety of electron-withdrawing groups (ketones, aldehydes, esters, amides, and acids), affording the corresponding selenenylation product in moderate (100e), fair (100b) and good (100a,c,d) yields, depending on the electron withdrawing group. Some limitations were reported for vinyl sulfones, a,b-unsaturated nitriles, and chalcones that proved unstable under the applied conditions.84 In Scheme 22 selected examples are reported to demonstrate that stereoselectivity could be moderately controlled both by the substrate (101!102 and 103!104) and by the selenenylating reagent (105! 106).

552

Selenium and Tellurium Complexes in Organic Synthesis

Scheme 22

11.13.2.6.2

Synthesis and reactivity of bench stable zinc selenolates (Santi’s reagents)

In 2008 we reported that the oxidative insertion of zinc into the Se-halogen bond of commercially available electrophilic species, such as PhSeCl (107) and PhSeBr (109), affords the bench stable solid compounds namely PhSeZnCl (108) and PhSeZnBr (110), respectively. The umpolung of the selenium atom is obtained in refluxing THF until the discoloration of the solution indicates the full reduction and the formation of the selenolate.85 These reagents are currently named as Santi’s reagents86,87 and the PhSeZnCl, that is stable under ambient condition for several months, is currently the unique commercially available nucleophilic selenenylating reagent. These reagents showed a straightforward reactivity in on-water conditions and the nucleophilic substitutions on primary (111) and secondary (113) alkyl halides is principally affected by the steric hindrance at the carbon attached by the selenium atom, affording selenides 112 and 114 in 95% and 60% yield, respectively. This suggests that a SN2 mechanism is involved dispelling a radical pathway (Scheme 23).85

Scheme 23

Selenium and Tellurium Complexes in Organic Synthesis

553

Nucleophilic substitution at a sp2 carbon bearing, as a leaving group, a halogen atom proved particularly difficult in the case of aryl halides and only strongly activated substrates, such as, 2,4-dinitro-bromobenzenene afforded the desired diarylselenide in moderate yield (50%).85 Some years before our isolation of 108 Xu et al., proposed the intermediate formation of an Ar0 SeZnCl from the reaction of ArMgBr with ZnCl2 and, subsequently, with grey selenium in THF. After the complete consumption of the selenium the addition of a series of diaryliodonium salts and HMPA afforded a small library of unsymmetrically substituted diaryl selenides (ArSeAr0 ) in moderate yields indicating the presence of a nucleophilic selenium reagent.88 The nucleophilic substitution of halogens at the vinylic position affording the corresponding vinyl selenides proved to be much more efficient with good stereoselectivity. It was demonstrated that when the olefin has non-coordinating functional groups (e.g. 115) the reaction proceeds with stereochemical retention affording E-116 from E-115 and Z116 from Z-115. In contrast, when the olefin is conjugated with a keto group, as a consequence of an oxygen zinc coordination proposed from DFT theoretical calculations, both the E-isomers E-117 and Z-117 afforded the same product Z-118. Very interestingly a vinylic nucleophilic substitution can be efficiently performed also starting from 4-chlorocoumarin 119 to afford the corresponding phenylseleno derivative 120. In all the cases the reaction is accelerated in water suspension, reaching good or excellent yields after 2 h.85 Churchill and coworkers reported some elegant applications of the brominated Santi’s reagent (PhSeZnBr, 110) in the synthesis of phenyl-selenium-substituted coumarin as probe for the selective and rapid detection of the glutathione over other free thiol like cysteines (122, 124, 126, Scheme 24). These dual emission double activated probes, are selective for glutathione (GSH) in the red region and for cysteine/homocysteine (Cys/Hcy) in the green region and were developed for biomedical purposes.89,90 PhSeZnCl (108) has been further used to perform Michael-type addition reactions starting from conjugated alkenes and alkynes under neutral and mild conditions affording, in good yields, b-seleno-carbonyl compounds and vinyl selenides, these latter with a very good stereoselectivity in favor of the (Z) isomer. While addition to propargyl substrates showed a great rate acceleration in onwater conditions, the same effect was not observed for the addition to conjugated olefins.91 A further interesting application of this class of nucleophilic selenenylating reagents was reported in the synthesis of selenoesters 128 starting from the corresponding acyl-halides 127 according to an acyl nucleophilic substitution. Braga and coworker described that aryl diselenides react with zinc in ionic liquids under microwave irradiations generating the complex [ArSeZnSeAr] that, after the reaction with an acyl halide produces an equivalent of ArSeZndX, responsible for the consumption of a second equivalent of substrate.92 In the same period we reported that PhSeZnCl 108 and the corresponding bromide 110 can be directly used in water at room temperature affording good yields after 3 h. In general better conversion was observed when 110 was the selenenylating agent.

554

Selenium and Tellurium Complexes in Organic Synthesis

Scheme 24

The preference of the selenenylation over the hydrolysis was attributed to a coordination of the zinc with the oxygen of the acyl chloride that activates the C]O bond bringing the selenium atom close to the electrophilic carbon. Some representative examples of the selenoesters (128a–i) prepared according to this procedure are reported in Scheme 25.93

Selenium and Tellurium Complexes in Organic Synthesis

555

Scheme 25

Another bench stable form of zinc selenate (132) can be prepared from the reaction of selenophenol 129 with Zn[N(SiMe3)2]2 in toluene to afford 130 that is subsequently stabilized by the complexation with the bidentate diamine 131 (N,N,N0 ,N0 -tetramethylethylenediamine) (Scheme 26).94,95 The resulting complex 132 was applied to the synthesis of selenoesters showing a higher reactivity when compared to 108 and 110 even if slightly reduced respect to freshly prepared 130. Thanks to its stability it was reported to be possible to setup a one-pot synthesis and chromatographic purification by passing the substrate through a column filled with silica and 132, skipping any intermediate workup.96

Scheme 26

A widely reported application of Santi’s reagents is the ring opening reaction of epoxides and aziridines. In the seminal publication85 together with the synthesis of PhSeZnCl (108) and PhSeZnBr (110) it was reported that epoxides can be easily transformed into the corresponding b-hydroxyselenides, according to an highly stereoselective mechanism in which the zinc acts as

556

Selenium and Tellurium Complexes in Organic Synthesis

a Lewis acid activating the epoxide and generating an incipient carbocation as clearly evidenced by the reaction of the styrene oxide 133 with the selenolate 108. The epoxide is quantitatively transformed into the pair of regioisomers 134 and 135 in a ratio of 80:20 (in water) or 88:12 (in THF) demonstrating that the electronically controlled path is largely favored over the sterically controlled one, and evidencing a strong rate acceleration in on-water conditions (2 h vs 24 h). When the substrate is not able to stabilize the incipient carbocation (e.g. 136) the sterically favored isomer (137) is the unique product obtained using 108 as nucleophile (Scheme 27A and B). Braga and coworkers reported that N-tosyl aziridines are similarly opened using PSeZnBr (110) but the reaction require harsher conditions and 138 was transformed into 139 using a ionic liquid as reaction medium at 90  C.97 (Scheme 27C).

(A)

(B)

(C)

Scheme 27

The high selectivity of this reaction was used by Jastrzebska et al. to prepare a small library of selenosteroids endowed with an interesting antibiofilm activity against bacteria and fungi. In particular it was reported that scaffolds having an epoxide in C5dC6 (140) are selectively selenenylated in C-6 only when the epoxide is a [140 (5a,6a)], while the E-isomer b [140 (5b,6b)] resulted completely unreactive. Similarly, the geometry of the epoxide in C1dC2 related to that of the hydroxyl group in C3 strongly affected the regiochemistry of the ring opening reaction. The steroidal scaffold is selenenylated in C-2 starting from 142 (1a-2a-3b) and in C1 starting from 144 (1b-2b-3a) affording selenides 143 and 145, respectively98 (Scheme 28).

Selenium and Tellurium Complexes in Organic Synthesis

557

Scheme 28

Further examples are reported in a recent study on the total synthesis of idesolide as well as in the synthesis of polymers with high refractive index (Scheme 29).

Scheme 29

558

Selenium and Tellurium Complexes in Organic Synthesis

It was reported that epoxide 146 can be converted into the corresponding b-seleno alcohol 147 using PhSeZnCl (108) in water. The yield is particularly low (12%) but other general protocols for the in situ preparation of the nucleophilic selenenylating reagent (PhSeSePh, NaBH4/EtOH) failed affording to a mixture of unidentified compounds.99 More recently the use of Santi’s reagent was described for the post-synthetic modification of a poly(glycidylmethacrylate) polymer 148 to prepare a series of new selenenylated materials (149) characterized by an adjustable refractive index and Abbe’s number dependent on the selenium concentration.87,100

11.13.3 New insights in organoselenium and organotellurium catalysts Organoselenium catalysts were widely used in organic synthesis, essentially following two main different strategies: in the first one (Scheme 30 left side) the selenium is used as an electrophile in a one-pot selenenylation-deselenenylation reaction in the presence of an excess of oxidant. Starting from a diselenide the initial oxidation of the SedSe bond generates in situ the electrophilic reagent that, by the addition to a CdC double (or triple) bond in the presence of an external or internal nucleophile, leads to a selenide intermediate. This latter is subjected to a further oxidation that transforms the organoselenium moiety into a good leaving group which can be eliminated or, in few cases, substituted, according to the reaction conditions and the thermodynamic stability of the target compound. From this latter step the electrophilic species is regenerated enabling the use of the selenium source in catalytic amounts. Several examples were reported by Tiecco et al. and were collected in a number of review articles.9–13,101

”R H

H

+ NuH

R’

RSeSeR (NH4)S2O8

RSeSeR H2O2

RSeOSO3H

RSeO3H

Substrate Substrate - [O]

”R H Nu

SeR H

RSeO2H

R’

H2O

”R (NH4)S2O8

”R H Nu

OSO3H Se-R H

H Nu

H

H2O 2

R’ or

R’

”R H Nu

H Nu R’

Scheme 30

In a different way, following a biomimetic mechanism summarized in the right part of Scheme 30, organoselenium compounds can be used as catalysts in oxygen transfer reactions from a peroxide to a nucleophilic substrate. According this mechanism epoxides, diols, carboxylic acids, esters, lactones and cyclic ethers were successfully prepared, in most cases using water as the reaction medium.102 The mechanism proposed in the oxidation of a C]C bond is the initial formation of an epoxide103 that can be the reaction product or, in the presence of an external or internal nucleophile, can be ring-opened to afford diols104 or cyclic ethers and esters.105 A peroxyseleninic species was initially proposed as the actual oxidizing reagent but most recently Back et al. reported a very elegant demonstration of the role of SeVI species in the olefin epoxidation. According to these recent findings an unprecedently reported peroxyselenonic acid is proposed as the actual oxidant.106

Selenium and Tellurium Complexes in Organic Synthesis

559

An attractive development of this class of oxidation reactions was obtained using both flow chemistry and biphasic reaction systems. In particular the efficiency and the sustainability of the oxacyclization reactions can be increased by the use of an integrated flow process assisted by in-line workup and purification (Scheme 31A). (A)

solution A EtOAc

0.1mL/min O

OH

0.3M solution B H2O/Acetone

PhSeO2H (0.09M) H2O2 (1.5M) HCOOH (10 mol%)

OH

v = 10mL

150

BPR

O

0.1mL/min 25°C 50'

O 151 (90%)

(B)

solution A EtOAc

R

S

R'

0.5 M 152

V = 2mL BPR

solution B H 2O

solution A EtOAc

H2O2 SeO2 1.0 M 0.05 M

R

S

R'

6 examples 74-99% yields

153

Flow rate 0.1mL/min

R'

0.5 M 152

V = 2mL BPR

solution B H 2O

R

O S

H2O2 SeO2 5.0 M 0.05 M

Flow rate 0.2mL/min

O O S R R'

6 examples 99% yields

154

Scheme 31

Under these conditions, the synthesis of 13 substrates was optimized reducing the reaction time from 8 h to 50 min and obtaining, in all the cases, excellent results in terms of yields and stereoselectivity. For the synthesis of 3-g-butyrolactone (151), we demonstrated an easy and fast scale-up processing 22 mmol of starting material 150 with an overall productivity of 6 g d−1 of the lactone 151 in high purity without human intervention both in the workup as well as in the purification.107 Similarly, using SeO2 as the most atom economical Se-based pre-catalyst at room temperature with hydrogen peroxide as green oxidant it was realized also the oxidation of thiols (152) into the corresponding sulfoxide (153) or sulfones (154). The chemoselective formation of 153 or 154 can be achieved simply changing the concentration of the H2O2 and the flow rate affording almost quantitative yields for a small set of examples (Scheme 31B).108 Recently Tanini et al. reported the selenium mediated oxidation of anilines in aqueous conditions. When the reaction is performed in the presence of a catalytic amount of diphenyl diselenide or benzenseleninic acid the oxidation affords selectively the formation of the corresponding nitroarenes while in the presence of sodium selenite or SeO2 the main product is an azoxyarene. Differently from the above reported mechanism elucidated by Back et al. the authors demonstrated here the direct involvement of a SeIV species as the actual catalyst in water, highlighting the multifaced nature of organoselenium catalysts.109 Organotellurium compounds supported on an ionic liquid (155) were reported as recyclable catalysts in the photoactivated oxidation of thiols (156) to afford the corresponding disulfides (157) by using the atmospheric oxygen as mild and friendly oxidant. The irradiation with a 500-W halogen lamp in the presence of Rose Bengal afford almost quantitative yields of the target 157 for five subsequent runs as reported in Scheme 32. The scope was explored for 10 differently functionalized aliphatic and aromatic thiols affording the corresponding disulfides in good yields, ranging from 71% to 100%. About the mechanism the authors speculated the formation of a telluroxide intermediate, but no spectroscopic evidence of this species was indeed reported.110

560

Selenium and Tellurium Complexes in Organic Synthesis

Scheme 32

Deoximation reaction is a quite interesting transformation in organic synthesis. Oximes are stable and easily synthesized from carbonyl compounds and for this reason this reaction can be used in protection-deprotection step during chemical manipulation of carbonyl containing derivatives. Organoselenium and organotellurium catalyst were used to promote this reaction in the presence of an oxidant. Dibenzyl diselenide in the presence of hydrogen peroxide at 60  C promoted the deoximation of 158 in 24 h affording the benzophenone 159 in 81%yield (Scheme 33A).111

Scheme 33

Considering the lower TedTe bond energy respect that of SedSe one (149 kJ/mol vs. 192KJ/mol) ditellurides resulted to be more easily activable and able to promote the conversion of 158 into using milder oxidation condition: oxygen at 60  C or oxygen under blue Led irradiation (Scheme 33B and C, respectively).112,113

11.13.4 Conclusion In this chapter we summarized some of the most recent and relevant developments in the chemistry of organoselenium and organotellurium reagents. In particular we focused our attention into the new insights in the field of electrophilic nucleophilic and catalytic reactions highlighting the general applicability, the mild reaction conditions generally required and the chemo, regio and stereoselctivity. Metalloorganic complexes are mainly related to the nucleophilic selenium and tellurium reagents and among different metals, zinc is the most studied and the most interesting from a synthetic point of view. In particular, some zinc selenolates showed a surprising stability (enabling the possibility of a commercialization) and an unprecedent reactivity in water (replacing classical volatile organic solvents with a recyclable cheap and safe reaction medium). In the field of the catalytic reactions, the bioinspired use of selenium in some oxygen transfer reactions offer novel and green protocols for the preparation of several classes of oxygenated compounds (epoxides, diols, lactones, carboxylic acids, nitroarenes, et cetera). Under these conditions’ mild oxidants like hydrogen peroxide or oxygen can be used and the application of some enabling technologies should further increase the overall sustainability of these reactions.

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561

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64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113.

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Lakouraj, M. M.; Movassagh, B.; Fadaei, Z. Monatsh. Chem. 2002, 133, 1085–1088. Movassagh, B.; Lakouraj, M. M.; Fadaei, Z. J. Chem. Res. (S) 2001, 22–23. Tian, F. S.; Zhu, Y. M.; Zhang, S. L.; Wang, Y. L. J. Chem. Res. (S) 2002, 11, 582–583. Movassagh, B.; Tatar, A. Synlett 2007, 12, 1954–1956. Zhou, L.-H.; Zhang, Y.-M. Synth. Commun. 1999, 29, 533–540. Movassagh, B.; Moradi, M. Chin. Chem. Lett. 2013, 24, 192–194. Mukherjee, C.; Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006, 47, 441–445. Braga, A. L.; Schneider, P. H.; Paixão, M. W.; Deobald, A. M. Tetrahedron Lett. 2006, 47, 7195–7198. Zhao, X.; Yu, Z.; Yan, S.; Wu, S.; Liu, R.; He, W.; Wang, L. J. Org. Chem. 2005, 70, 7338–7341. Chen, Q.; Wang, P.; Yan, T.; Cai, M. J. Organomet. Chem. 2017, 840, 38–46. Santi, C.; Santoro, S.; Testaferri, L.; Tiecco, M. Synlett 2008, 1471–1474. Braga, A. L.; Schwab, R. S.; Alberto, E. E.; Salman, S. M.; Vargas, J.; Azeredo, J. B. Tetrahedron Lett. 2009, 50, 2309–2311. Flemer, S. Protein Pept. Lett. 2014, 21, 1257–1264. Flemer, S., Jr. J. Pept. Sci. 2015, 21, 53–59. Bellino, G.; Scisciani, M.; Vargas, J. P.; Sancineto, L.; Bagnoli, L.; Marini, L.; Lüdtke, D. S.; Lenardão, E. J. Santi, C. J. Chem. 2016, 1–8. Comasseto, J. V.; Ferreira, J. T. B. J. Organomet. Chem. 1981, 216, 287–294. Tidei, C.; Sancineto, L.; Bagnoli, L.; Battistelli, B.; Marini, F.; Santi, C. Eur. J. Org. Chem. 2014, 5968–5975. Vieira, M. L.; Zinn, F. K.; Comasseto, J. V. J. Braz. Chem. Soc. 2001, 12, 586–596. Nunes, V. L.; de Oliveira, I. C.; do Rego Barros, O. S. Eur. J. Org. Chem. 2014, 1525–1530. Nacca, F. G.; Monti, B.; Lenardão, E. J.; Evans, P.; Santi, C. Molecules 2020, 25, 2018. Santi, C.; Santoro, S.; Battistelli, B.; Testaferri, L.; Tiecco, M. Eur. J. Org. Chem. 2008, 5387–5390. Perin, G.; Alves, D.; Jacob, R. G.; Barcellos, A. M.; Soares, L. K.; Lenardão, E. J. ChemistrySelect 2016, 1, 205–258. Eom, T.; Khan, A. Chem. Commun. 2020, 56, 14271–14274. Xu, X. H.; Liu, W. Q. Chin. Chem. Lett. 2002, 13, 283. Kim, Y.; Mulay, S. V.; Choi, M.; Yu, S. B.; Jon, S.; Churchill, D. G. Chem. Sci. 2015, 6, 5435–5439. Mulay, S. V.; Kim, Y.; Choi, M.; Lee, D. Y.; Choi, J.; Lee, Y.; Jon, S.; Churchill, D. G. Anal. Chem. 2018, 90, 2648–2654. Battistelli, B.; Testaferri, L.; Tiecco, M.; Santi, C. Eur. J. Org. Chem. 1848–1851, 2011. Godoi, M.; Ricardo, E. W.; Botteselle, G. V.; Galetto, F. Z.; Azeredo, J. B.; Braga, A. L. Green Chem. 2012, 14, 456–460. Santi, C.; Battistelli, B.; Testaferri, L.; Tiecco, M. Green Chem. 2012, 14, 1277–1280. Bochmann, B.; Bwembya, G.; Webb, K. J. Inorg. Synth. 1997, 31, 19–23. Jun, Y.; Koo, J.-E.; Cheon, J. Chem. Commun. 2000, 1243–1244. Sancineto, L.; Pinto Vargas, J.; Monti, B.; Arca, M.; Lippolis, V.; Perin, G.; Lenardao, E. J.; Santi, C. Molecules 2017, 22, 953–966. Salman, S.; Schwab, R.; Alberto, E.; Vargas, J.; Dornelles, L.; Rodrigues, O. E. D.; Braga, A. L. Synlett 2011, 1, 69–72. Jastrzebska, I.; Mellea, S.; Salerno, V.; Grzes, P. A.; Siergiejczyk, L.; Niemirowicz-Laskowska, K.; Bucki, R.; Monti, B.; Santi, C. Int. J. Mol. Sci. 2019, 20, 2121–2134. Nagasawa, T.; Shimada, N.; Torihata, M.; Kuwahara, S. Tetrahedron 2010, 66, 4965–4969. Jiang, H.; Pan, X.; Li, N.; Zhang, Z.; Zhu, J.; Zhu, X. React. Funct. Polym. 2017, 111, 1–6. Santi, C.; Tidei, C. Electrophilic selenium/tellurium reagents: Reactivity and their contribution to Green Chemistry. In The Chemistry of Organic Selenium and Tellurium Compounds; Rappoport, Z., Ed.; John Wiley & Sons, Ltd: Chichester, UK, 2013; vol. 4. Singh, F. V.; Wirth, T. Cat. Sci. Technol. 2019, 9, 1073–1091. Santi, C.; Jacob, R. G.; Monti, B.; Bagnoli, L.; Sancineto, L.; Lenardão, E. J. Molecules 2016, 21, 1482. Back, T. G. Curr. Green Chem. 2016, 3, 76–91. Santoro, S.; Santi, C.; Sabatini, M.; Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2008, 350, 2881–2884. Sancineto, L.; Mangiavacchi, F.; Tidei, C.; Bagnoli, L.; Marini, F.; Scianowski, J.; Gioiello, A.; Santi, C.; Asian, J. Org. Chem. 2017, 6, 988–992. Sands, K. N.; Mendoza Rengifo, E.; George, G. N.; Pickering, I. J.; Gelfand, B. S.; Back, T. G. Angew. Chem. Int. Ed. 2020, 59, 4283–4287. Cerra, B.; Mangiavacchi, F.; Santi, C.; Lozza, A. M.; Gioiello, A. React. Chem. Eng. 2017, 2, 467–471. Mangiavacchi, F.; Crociani, L.; Sancineto, L.; Marini, F.; Santi, C. Molecules 2020, 25, 2711. Tanini, D.; Dalia, C.; Capperucci, A. Green Chem. 2021, 23, 5680–5686. Mihoya, A.; Koguchi, S.; Shibuya, Y.; Mimura, M.; Oba, M. Catalysts 2020, 10, 398. Jing, X.; Yuan, D.; Yu, L. Adv. Synth. Catal. 2017, 359, 1194–1201. Deng, X.; Cao, H.; Chen, C.; Zhou, H.; Yu, L. Sci. Bull. 2019, 64, 1280–1284. Deng, X.; Qian, R.; Zhou, H.; Yu, L. Chin. Chem. Lett. 2021, 32, 1029–1032.

11.14

Frustrated Lewis Pairs in Organic Synthesis

Matthew J Heard, Katarina Stefkova, Yara van Ingen, and Rebecca L Melen, Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Cardiff, United Kingdom © 2022 Elsevier Ltd. All rights reserved.

11.14.1 11.14.2 11.14.2.1 11.14.2.2 11.14.3 11.14.4 11.14.4.1 11.14.4.2 11.14.4.3 11.14.5 11.14.5.1 11.14.5.2 11.14.5.3 11.14.5.4 11.14.6 11.14.6.1 11.14.7 References

Introduction to frustrated Lewis pairs (FLPs) FLP-mediated catalytic hydrogenation Early examples of FLP-mediated hydrogenation Substrates which are the Lewis Basic component of FLPs Air and moisture stable frustrated Lewis pairs Asymmetric catalysts Enantioselective reduction of CdN multiple bonds and silyl enols Hydrosilylation Asymmetric FLP-mediated hydrosilylation Other FLP-mediated organic transformations FLP-mediated hydroamination FLP-mediated direct Mannich-type reactions FLP-mediated C-H borylation FLP-mediated cyclization reactions Frustrated radical pairs in organic synthesis FRP-mediated CdC bond formations Summary and outlook

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11.14.1 Introduction to frustrated Lewis pairs (FLPs) Typically, the combination of a Lewis acid with a Lewis base results in the lone pair of electrons from the base being donated into the empty p-orbital of the acid forming a Lewis adduct (Fig. 1, top). However, in some circumstances the Lewis acid and base are segregated, usually by steric demands, and the adduct is unable to form, this leads to the formation of a frustrated Lewis pair (FLP) (Fig. 1, bottom). As an adduct has not formed, FLPs preserve the individual reactivity of the Lewis acid and base centers and participate in reactions which Lewis adducts are unable to. The term frustrated Lewis pair was not introduced until the 2000s by Stephan, however unpredicted reactivity of Lewis acids and bases, that could retrospectively be classified as FLP-like can be found as far back as 1942.2–5 Piers discovered in 1996 that the hydrosilylation of carbonyls with triphenylsilane could be achieved using tris(pentafluorophenyl)borane [B(C6F5)3] as an efficient catalyst.6 The mechanism for this reaction however was not fully determined for an additional 12 years.7 Stephan’s pivotal discovery of 2006, in which the first metal-free reversible activation of dihydrogen was reported (Scheme 1), gave the first use of the term “frustrated Lewis pair” and kickstarted the use of FLPs as catalysts.4 The phosphinoborane displayed large steric bulk around both the Lewis acidic and basic sites, and was capable of reversibly activating dihydrogen under mild conditions.4 Since the discovery of hydrogen activation by FLPs, there has been widespread interest in their application, initially towards small molecule activation and subsequently towards catalysis and their use in organic synthesis. Since Stephan’s seminal work of 2006, the scope of small molecule activation by FLPs has been broadened to include CO2, NO2, SO2 and alkenes among others.8–11 This book article intends to explore both the catalytic and stoichiometric applications of frustrated Lewis pairs within organic synthesis.

Comprehensive Organometallic Chemistry IV

https://doi.org/10.1016/B978-0-12-820206-7.00041-X

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Fig. 1 Formation of Lewis adducts (top) and frustrated Lewis pairs (bottom).1

Scheme 1 First example of reversible activation of dihydrogen by a non-metal complex.4

11.14.2 FLP-mediated catalytic hydrogenation Across both academia and industry, a fundamental process is the catalytic reduction of unsaturated compounds with dihydrogen, with an estimated 20% of all synthetic products utilizing catalytic hydrogenation at one stage of their development.12 A large majority of these catalysts contain a transition-metal center, whose d-orbitals are integral to the reduction process. Dihydrogen donates its electron density from the filled s-orbital into an empty d-orbital on the transition metal, concurrently electron density from a filled d-orbital is donated into the empty s∗-orbital of dihydrogen (Fig. 2). frustrated Lewis pairs employ a different process for the activation of hydrogen, with the basic component being an electron donor into the empty s∗-orbital of dihydrogen and the acidic counterpart acting as an electron acceptor from the filled s-orbital of dihydrogen (Fig. 3).

Fig. 2 Activation of H2 by metals.

Fig. 3 Activation of H2 by FLPs.

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Historically transition metal catalysts have been at the forefront of hydrogen reduction, with examples of main-group metals being scarcer.13 The fundamental discovery of frustrated Lewis pairs has opened the field to a whole new chapter of research.

11.14.2.1 Early examples of FLP-mediated hydrogenation Stephan’s discovery that frustrated Lewis pairs could reversibly activate dihydrogen has led to the exploration of a new area within the field of metal-free catalysis.4 Shortly after this Stephan, among other researchers, noticed the connection between the FLP’s capability for reversible dihydrogen activation and the capacity to reduce catalytically a wide variety of polar substrates. Confirmation of this capacity, was quickly shown by Stephan with the first example of FLP catalyzed hydrogenation (Scheme 2).14 A small substrate scope of 11 sterically demanding imines, protected nitriles and un-activated aziridines were reduced catalytically by two intramolecular FLPs (1) and (2), in poor to excellent yields.14

Scheme 2 The first report of FLP catalyzed hydrogenation with intramolecular FLPs (1) and (2).14

After running NMR scale reactions as well as stoichiometric reactions between FLPs (1) and (2) and a range of imines, a mechanism for these reductions was proposed (Scheme 3).14 Initially protonation of the imine to the iminium salt occurs by the phosphonium borate zwitterion, followed by nucleophilic attack from the borohydride anion affording the amine, after hydride transfer. Finally, the reduced amine dissociates from the boron atom and the liberated phosphine-borane can react with H2 to reform the phosphonium borate.14

Scheme 3 Catalytic cycle for imine reduction.14

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An important element of the mechanism is the dissociation of the amine from the borane, so the phosphine-borane can react with H2 to regenerate the catalyst. The inclusion of sterically bulky substituents on the substrate can encourage dissociation of the amine, due to the formation of an unfavorably tight adduct, thus speeding the catalytic reduction. It was also found that elevated temperatures of 80–120  C additionally promote dissociation of the amine, and hence speed the reduction and catalyst reformation.14 In the case of some substrates, such as PhCH2N]CPh(H), the amine-borane adduct formed inhibits reduction and thus only allows stoichiometric reduction to occur. The previously mentioned elevated temperature caused no dissociation of the adduct and a different tactic was required. The nitrogen lone pair of the amine was coordinated to the stronger Lewis acid B(C6F5)3, freeing the phosphine-borane which could then complete the catalytic cycle, and provided the amine-B(C6F5)3 adduct in moderate yields.14 The use of B(C6F5)3 to complete the catalytic cycle resulted in a change to the observed mechanism. The B(C6F5)3 activates the imine-borane adduct and the imine carbon atom of this adduct undergoes nucleophilic attack from the borohydride component of FLPs (1) or (2). This is then followed by proton transfer from the phosphonium center to the amido borate anion intermediate, completing the reduction (Scheme 4).14

Scheme 4 Catalytic cycle for the BCF protected imine reduction.14

Stephan’s demonstration that FLPs were capable of being catalytic systems for the H2 reduction of imines, nitriles, and aziridines, was a fundamental step forward for the field of metal-free catalysis.14 Subsequently Erker et al. reported an intramolecular FLP, phosphonium borate (3), capable of the reduction of five bulky imines in good to excellent yields, but importantly under ambient conditions—an improvement upon the elevated conditions required by Stephan for efficient reduction.14,15 Erker’s FLP was additionally the first FLP capable of enamine reduction at room temperature (Scheme 5).15

Scheme 5 FLP catalyzed reduction of imines by (3).15

Repo followed the work of Stephan and Erker, with his “molecular tweezer,” a linked amine-borane FLP (4), which could reduce imines that previous FLPs had been uncapable of (Scheme 6).14–16 Repo’s molecular tweezer (4) was shown to reduce eight imines, at low catalytic loadings, achieving almost quantitative NMR yields for most of the substrates under the relatively mild conditions of reflux in toluene under 2 bar of H2.16

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Scheme 6 Imine reduction catalyzed by an intramolecular FLP (4).16

Intentions to expand the functional group tolerability of catalytic reduction by Soós, led to the design of some modified FLP systems. The successful Lewis acid B(C6F5)3 was adjusted with a mesitylene substituent replacing one of the perfluorinated aryl groups on the borane, increasing the steric bulk around the boron center and preventing unwanted reactivity between the FLP and olefin functionalities in most examples.17 Soós then screened the combination of Lewis acid B(C6F5)2Mes with a variety of nitrogen-based Lewis bases for the reduction of an imine. Finding that 1,4-diazabicyclo[2.2.2]octane (5) (DABCO) and quinuclidine (6) combined with B(C6F5)2Mes were the most efficient FLPs, with (5) notably operating efficiently under ambient conditions.17 These novel FLP systems were employed for the reduction of seven imines with poor to excellent yields observed (Scheme 7) and achieved the reduction of difficult substrates [I] and [II]. With compound [I], the FLP systems left the allyl and unactivated olefin groups alone and solely reduced the imine group. Conversely with crotyl imine [II] both the imine and olefin groups were reduced, and lower yields were observed for the B(C6F5)2Mes/DABCO (5) FLP.17

Scheme 7 Catalytic reduction by B(C6F5)2Mes/(5) and B(C6F5)2Mes/(6) FLP systems.17

These early examples of metal free hydrogenation demonstrate that FLP catalyst systems could become common place catalytic tools for both academic and industry settings, replacing the expensive precious-metal catalysts commonly used and offering a cheaper, more environmentally friendly alternative. However, for this overhaul of the catalysts currently used, the FLP systems would need to be more robust to a wider range of functional groups on substrates and potentially air and moisture stable compounds themselves.

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Frustrated Lewis Pairs in Organic Synthesis

11.14.2.2 Substrates which are the Lewis Basic component of FLPs Shortly after Stephan coined the term “frustrated Lewis pairs”, Stephan and Klankermayer concurrently demonstrated that there was no need for an external base in an FLP-mediated reduction, and that a basic substrate would also function as the basic element of an FLP.18,19 Both used B(C6F5)3 (7) for the reduction of imines, with Stephan focussing on functional group tolerance using a set of optimized conditions, whilst Klankermayer investigated reaction optimization, exploring time, H2 pressure, temperature and catalyst loading (Scheme 8).18,19

Scheme 8 Catalytic reduction of imines where the imine acts as both substrate and basic component of FLP.18,19

Stephan explored this idea further for the reduction of a protected aziridine, to form the corresponding amine with a 95% yield and attempted the reduction of protected nitriles (Scheme 9). The reduction of the protected nitriles was unsuccessful, as they were not sufficiently basic to remove the proton from the activated H2, however the inclusion of an external base led to these reductions being successful with very high yields.19

Scheme 9 Catalytic reduction of aziridine and nitriles with B(C6F5)3.19

In 2010, Stephan further explored the “base-less” B(C6F5)3 reactions, reporting the reduction of five N-heterocycles including some substituted quinolines (Scheme 10) in good to excellent yields.20 They subsequently showed that B(C6F5)3 was a suitable catalyst for the reduction of indole derivatives to their respective dihydroindoles.21 However in order to achieve an acceptable level of reactivity, the reduction of the indole derivatives required much harsher conditions of 80  C and 103 bar H2 in comparison to the imine and other N-heterocycle reductions.19–21 The B(C6F5)3-mediated reduction of diimines and pyridines was also achieved under the slightly less harsh conditions of 4 bar of H2 and 120  C, with the FLP system selectively reducing the imine functionality on pyridine derivatives (Scheme 11).21

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Scheme 10 Catalytic reduction of N-heterocycles with B(C6F5)3.20

Scheme 11 Catalytic reduction of indoles, pyridine derivatives, and diimines.21

Oestreich used catalytic amounts of B(C6F5)3 for the reduction of protected oximes to hydroxylamines, observing good to excellent yields over 14 examples (Scheme 12).22 Steric bulk was found to be key to these reductions however, with the reduction of unprotected or less sterically hindered protected oximes being unsuccessful. Additionally, the reaction was found to be chemoselective, with reduction occurring exclusively for the C]N bond and no splitting of the NdO bond.22

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Frustrated Lewis Pairs in Organic Synthesis

Scheme 12 Chemoselective reduction of protected oximes with catalytic B(C6F5)3.22

Du focussed on the formation of a range of piperidines through the reduction of pyridines using a borane catalyst and reasonably harsh conditions of 100  C and 50 bar pressure of H2 (Scheme 13). The catalyst was formed by an in situ hydroboration reaction between alkene (8) and Piers’ borane [HB(C6F5)2] and was found to be stereoselective, forming the cis isomers in up to 99:1 d.r. and with isolated yields up to 99% being reported.23 Du used this technique as part of the synthesis of anti-HIV drug, isosolenopsin A.

Scheme 13 Catalytic reduction of pyridines with Piers’ borane and 8.23

11.14.3 Air and moisture stable frustrated Lewis pairs Whilst B(C6F5)3 has been shown to be a good Lewis acid and has seen widespread use as part of an FLP catalyst system, one fundamental problem with it is its moisture sensitivity. The boron atom is very oxophilic and when exposed to water a strong adduct is formed, with the oxygen lone pair donating into the empty p-orbital of the boron. This filled p-orbital prevents the FLP catalyst system forming and irreversibly stops the borane from being able to act as a catalyst.24 Prevention of this waterB(C6F5)3 adduct from forming can be achieved by increasing the steric shielding around the boron Lewis acidic center, protecting it from any water molecules. One technique to accomplish this is replacing the fluorinated aryl rings around the borane with heavier, bulkier halogens. The problem with altering the halogen substitution pattern is that it can have drastic effects upon the Lewis acidity of the triarylborane and subsequently affect the catalytic activity.25 Through the inclusion of chlorine atoms on the ortho position of a single aryl ring within triarylboranes (9) and (10), Soós aimed to develop FLP catalysts which were moisture and functional group tolerant and bench stable, thus making the reduction of carbonyls more accessible (Scheme 14).26 The incorporation of these chlorine atoms had the effect of increasing the steric bulk around the boron center, hence providing more moisture tolerance, however this did not lower the Lewis acidity significantly

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Scheme 14 Moisture tolerant FLPs (9) and (10) for carbonyl reduction.26

enough that activation of dihydrogen was prevented. Tetrahydrofuran (THF), a weakly coordinating ethereal solvent, was also key for the completion of a moisture tolerant FLP system, as it did not inhibit hydrogenation by formation of hydrogen bonds with water, as stronger Lewis bases are known to do. With this moisture tolerant FLP system, Soós was able to easily reduce 10 carbonyls, including both electron-rich and electron-deficient benzaldehydes, without the need for air-sensitive techniques.26 Subsequently Soós utilized the water tolerant borane (9) for the reductive etherification of aldehydes, ketones, and acetals, again without the need for air-sensitive techniques (Scheme 15).27 For the reduction of acetals into ethers, THF was used as both the basic component of the FLP and as the solvent. For these reactions, the reduced oxophilicity of the borane compared to B(C6F5)3 was key, as the catalytic activity was unhindered by the alcohol by-product or by the ether formed binding irreversibly to the boron center. The reductive etherification of 15 acetals was shown, with the good to excellent yields observed and high functional group tolerance.27

Scheme 15 FLP catalyzed reductive etherification of acetals (top), aldehydes, and ketones (bottom).27

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Frustrated Lewis Pairs in Organic Synthesis

This technique was then explored for the reductive etherification of aldehydes and ketones, however these reactions required three equivalents of an ortho-ester or an alcohol, which functioned as an alkylating agent. Varying yields were observed for the conversion of a wide scope of carbonyls into their respective ethers, and the yields were found to be substantially reduced, when the alkylating agent was an alcohol. This was because of competing reductions of the carbonyls into alcohols.27 “Auto-tandem” catalysis, where FLP catalyzed hydrogenation and FLP-assisted Brønsted-Lowry acid catalysis work concurrently is how the reductive etherification of carbonyls has been classified to work (Scheme 16).27 Initially, an FLP forms between the borane and THF, with subsequent H2 activation then generating H[THF]+ and borohydride H[BAr3]− (Scheme 16, A). The Brønsted-Lowry acidic H[THF]+ then protonates the oxygen of the carbonyl, activating it which promotes the attack from the alkylating agent, R3OH (Scheme 16, B). The acetal intermediate is generated after the loss of water and a proton (Scheme 16, C), with the released proton then capable of acidifying another THF molecule, which then protonates the acetal (Scheme 16, D). The oxocarbenium cation (Scheme 16, E) is a temporary intermediate formed after the loss of one of the R3OH groups, which is easily reduced by the borohydride H[BAr3]− to form the desired ether product (Scheme 16, F).27

Scheme 16 “Auto-tandem” mechanism of reductive etherification of acetals, aldehydes and ketones.27

Following on from Soós’ work on the reductive etherification of carbonyls using the very moisture tolerant boranes (9) and (10), Ogoshi explored the FLP-mediated reductive alkylation of amines with carbonyls and dihydrogen, utilizing borane (10) (Scheme 17). Owing to the fact that the only by-product of the secondary amine formation is water, the moisture tolerant borane (9) was fundamental to the success of the reaction. This was evident after other boranes including B(C6F5)3 were explored, these reactions only led to the formation of the imine intermediate. The reductive alkylation was unable to occur, due to the catalysts being deactivated by the water by-product.28

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Scheme 17 FLP catalyzed reductive alkylation of amines with carbonyls to form secondary amines, isoindolinones, and 3-aminophthalic anhydrides.28

The FLP system consisted of a low catalytic loading of the borane (10) (5 mol%) combined with THF, which acted as both base and reaction medium. The addition of 4 A˚ molecular sieves, as a drying agent, resulted in significantly increased product yields and reduced reaction times. With these reaction conditions in place, a large substrate scope of 34 secondary amines were formed in very high yields, demonstrating a large functional group tolerance towards bulky hydroxyl and carboxyl groups (Scheme 17). The functional group tolerance was observed to be limited when the reductive alkylation of aniline with 4-(dimethylamino) benzaldehyde was explored. Here the secondary amino group led to FLP-mediated hydrogenation and subsequent reduction to form the N,N-dimethyl-p-toluidine instead. Additionally selective choice of reagents in combination with harsher reaction conditions allowed the FLP system to catalyze intramolecular cyclization reactions to form 3-aminophthalic anhydrides and isoindolinones in high yields (Scheme 17).28 Similarly, to the mechanism for reductive etherification, the mechanism for the reductive alkylation involved a combination of two tandem catalytic cycles combining FLP-mediated reductive alkylation and Lewis acid catalyzed intramolecular amidation (Scheme 18). The first catalytic cycle was proposed to be exclusively Lewis acid catalysis, with the borane coordinating to and activating the carbonyl substrate in typical fashion (Scheme 18, A). Subsequent nucleophilic attack of the activated carbonyl by the amine, resulted in the generation of the imine intermediate and H2O (Scheme 18, B). The imine was then involved in the second catalytic cycle, FLP-mediated reduction. Here the THF solvent participated as the Lewis basic component of the FLP, which first underwent the heterolytic cleavage of H2, which was subsequently used to reduce the imine into the desired amine (Scheme 18, C, D).28

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Frustrated Lewis Pairs in Organic Synthesis

Scheme 18 Mechanism of FLP catalyzed reductive alkylation of amines with carbonyls to form secondary amines.28

Ashley utilized the softer p-block element tin, as opposed to boron, to demonstrate a different approach to the increasingly conventional FLP chemistry, preparing stannylium salt iPr3SnOTf (11) (Scheme 19).29 The cation of this salt, [iPr3Sn]+, is an isolobal equivalent of triarylborane, with the bulky alkyl groups surrounding the tin center, preventing the triflate counterion from interaction and hence creating an electrophilic moiety acidic enough to act as a Lewis acid in an FLP system.29 Ashley combined the Lewis acid (11) with a range of bases for the reduction of four carbonyls and six imines under mild conditions and crucially without the necessity for air sensitive techniques. They found that the product yields were strongly dependent on the base used and that most reactions had the highest yield when collidine (2,4,6-trimethylpyridine) was the base.29

Scheme 19

i

Pr3SnOTf (11) catalyzed reduction of carbonyls and imines.29

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Encouraged by the previous research into the use of iPr3SnOTf (11) as a catalyst for the reduction of carbonyls and imines (Scheme 19)29, Ashley explored the use of iPr3SnOTf for the reductive amination of carbonyls (Scheme 20). iPr3SnOTf was found to be capable of catalyzing the reductive amination of 17 carbonyls into their respective secondary amines, in good to excellent yields. The catalyst (11) exhibited tolerance towards bulky electron-withdrawing and electron-donating groups on the carbonyls and for most reactions the substrates acted as the Lewis basic component of the FLP. However, collidine (12) was added as an external base to aid the reactivity of more difficult substrates. In the cases where there was a lower amine yield, this was explained by the competing direct reduction of the carbonyl into its respective alcohol.30

Scheme 20

i

Pr3SnOTf catalyzed reductive alkylation of amines with carbonyls to form secondary amines.30

11.14.4 Asymmetric catalysts As many biologically active compounds only function as a single enantiomer, there is thus a large interest in enantioselective synthesis, with asymmetric catalysts being of great importance to the synthetic chemist. Typically, enantioselective catalysts often use transition metals where attaching chiral ligands onto the metal center can be achieved with relative ease. However, recently there have been a growing number of frustrated Lewis pair systems that can assist enantioselective transformations. This section shall explore some of these transformations, starting with enantioselective reductions.

11.14.4.1 Enantioselective reduction of CdN multiple bonds and silyl enols In 2008, Klankermayer was the first to show that FLPs were capable of enantioselective reduction, when a chiral borane catalyst was prepared which was able to asymmetrically reduce imines. The borane (13) was formed after the natural product (+)-a-pinene underwent hydroboration using Piers’ borane. Full conversion of the imine substrate into the secondary amine with 13% e.e. was achieved by using 10 mol% of catalyst (13), and heating to 65  C with 20 bar of H2 (Scheme 21).18

Scheme 21 First report of FLP-mediated enantioselective reduction of imines.18

Klankermayer made a large improvement upon this in 2010, when Piers’ borane was again utilized for the hydroboration of another natural product, (1R)-(+)-camphor, to form a chiral borane. This borane was then combined with PtBu3 to form the FLP system (14), which was employed for the reduction of a scope of pro-chiral ketimines to their respective secondary amines in good to excellent yields (Scheme 22). The improvement was the higher enantioselective reductions of up to 83% e.e. that were observed with the reduced catalytic loading of 5 mol% of (14).31

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Frustrated Lewis Pairs in Organic Synthesis

Scheme 22 Enantioselective reduction of imines with an intermolecular FLP system containing a camphor-based borane (14).31

Further development of FLP (14), led to the formation of an intramolecular variant, in which the (1R)-(+)-camphor had a phosphine group attached prior to hydroboration by Piers’ borane, to create the intramolecular chiral FLP (15). Chiral FLP (15) was then used to achieve the highly enantioselective reduction of a range of imines with a variety of aryl substituents, exhibiting good tolerance to bulky substrates whilst maintaining the high enantioselectivity of up to 76% e.e. (Scheme 23). In addition, Klankermayer found that catalyst (15) had high recyclability, achieving reproducible conversion (>99%) and enantioselectivity (76% ee) over four concurrent experiments, validating the stability and effectiveness of catalyst (15).32

Scheme 23 Enantioselective reduction of imines with an intramolecular FLP system containing a camphor-based borane.32

In 2011, Stephan attempted using B(C6F5)3 for the diastereoselective reduction of chiral ketimines, which was met with limited success (Scheme 24). A correlation between the distance from the imine’s chiral center to the unsaturated carbon center and the extent of diastereoselectivity was observed. For instance both the camphor [I] and menthone [II] based imines were reduced with good yields and diastereoselectivity under the conditions used, but the phenethylamine derivative [III] was not, with much lower diastereoselectivity observed (Scheme 24).33

Frustrated Lewis Pairs in Organic Synthesis

577

Scheme 24 Diastereoselective reduction of chiral ketimines with B(C6F5)3.33

Repo also explored the enantioselective reduction of imines, developing a chiral version (16) of his previously explored “molecular tweezer” FLP (4) (Fig. 4).16,34 This new asymmetric FLP (16) was observed to have high air- and moisture-stability, however the enantioselectivity observed for the reduction of imines was limited, with the highest reported e.e. being 37%.34

Fig. 4 Chiral variant of FLP “molecular tweezers”.34

A different approach for asymmetric reduction was explored by Du, who reacted chiral dienes or diynes with Piers’ borane, to form catalytically active bisboranes. With this strategy the chirality of the bisborane catalyst comes from the attached ligand, however the desired effect on the reduction is still observed.35–38 Diene (17) (Scheme 25) was first used for asymmetric reduction, being reacted with Piers’ borane to form the desired catalytically active chiral bisborane in situ. This was then used for the reduction of a range of ketimines into their respective secondary amines, with both high enantioselectivities and yields noted at room temperature (74–89% ee, 63–99%). In addition, these reactions were observed to tolerate a variety of functional groups on the phenyl substituent, including an alkyne moiety, [I], which was unaffected by the reduction (Scheme 25).35

Scheme 25 Chiral reduction of ketimines with bisborane based upon diene (17).35

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Frustrated Lewis Pairs in Organic Synthesis

Using this strategy of synthesizing chiral bisboranes in situ from a chiral diene and Piers’ borane via hydroboration, Du developed a subsequent catalyst based on chiral diene (18) with its aryl rings modified (Scheme 26). This was combined with an equal amount of PtBu3 to aid in the asymmetric reduction of silyl enol ethers back to their respective chiral alcohols. This system was an improvement, as the catalyst was able to reduce the substrates in very high yields (up to 99%) and very high e.e. (up to 99%).36

Scheme 26 Chiral reduction of silyl enol ethers with bisborane based upon diene (18).36

In order to develop an enantioselective catalyst for the asymmetric reduction of quinoxalines (Scheme 27), Du utilized a more electron deficient diene (19), in combination with Piers’ borane, to develop a capable chiral diphenyl bisborane in situ. For these reductions, the quinoxaline was capable of being the Lewis base, and so the frustrated Lewis pair was formed in situ from the substrate and the bisborane catalyst and led to the enantiopure reduction of 14 quinoxalines at room temperature. The tetrahydroquinoxaline products were found to be highly cis-selective (up to 99:1 d.r.) and very enantioselective (67–96% ee), making this catalyst very efficient.37

Scheme 27 Chiral reduction of ketimines with a bisborane based upon diene (19).37

Furthering this strategy to develop bisboranes in situ for chiral reduction, has led to Du more recently exploring the use of a naphthyl-derived diyne ligand (20) (Scheme 28). The chiral borane formed after hydroboration with Piers’ borane was found to have increased rigidity, due to the structural changes, which also made it predisposed to electronic tuning by adjustment to the naphthyl ring. For the catalytic reduction of an array of silyl enol ethers, Du employed this chiral bisborane in combination with PtBu3, using the previously optimized conditions.37 This led to the formation of the desired optically active alcohols in up to 99% yield and up to 99% ee.38

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Scheme 28 Chiral reduction of silyl enol ethers with bisborane based upon diyne (20).38

Building on the work of Du, Repo developed a binaphthyl-linked aminoborane (21) in 2015 (Scheme 29). He demonstrated that this intramolecular FLP could facilitate the asymmetric reduction of six imines and impressively the asymmetric reduction of enamines, the first example of a chiral FLP capable of this. Repo’s binaphthyl-linked aminoborane was capable of reducing a range of N-aryl and N-alkyl imines under mild conditions, even exhibiting tolerance to imines with non-bulky N-substituents like imine [I]. In light of the strong B-N adducts that often form between small imines and FLP systems, leading to irreversible deactivation of the catalyst, it is impressive that Repo’s binaphthyl FLP system can tolerate smaller N-substituted imines. The yields and e.e.s of the reductions of the differently substituted imines did vary however, with the bulkier imines having much higher yields and e.e.s of up to 92% and 83% respectively, compared to the significantly reduced N-alkyl imines which exhibited e.e.s of up to 34%. For the asymmetric reduction of enamines, Repo’s intramolecular FLP showed remarkable results for both symmetric and asymmetric enamines, with isolated yields of up to 99% and 99% e.e. of the reduced products.39

Scheme 29 Chiral reduction of imines and enamines.39

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Frustrated Lewis Pairs in Organic Synthesis

11.14.4.2 Hydrosilylation Hydrosilylation is the process of attaching synthetically useful silanes onto unsaturated bonds like carbonyls (Scheme 30).40 Typically, like many transformations, this installation of the silane group is achieved using platinum-based catalysts like Karstedt’s catalyst or Speier’s catalyst. As these catalysts are transition metal based, they are thus unsustainable, and so there has been a pursuit from many research groups to discover sustainable, more environmentally friendly alternatives utilizing earth abundant metals or main group elements.40 This research has shown that FLP systems are capable of being used for hydrosilylation and further advancements have led to enantioselective catalysts.

Scheme 30 Hydrosilylation of a carbonyl.40

11.14.4.3 Asymmetric FLP-mediated hydrosilylation In 2008, Oestreich demonstrated that asymmetric FLP-mediated hydrosilylation was possible using chiral silane (SiR)-(22) and B(C6F5)3 as part of a mechanistic study.7 The hydrosilylation of acetophenone to form a scalemic mixture of hydrosilane (SiR, R)(22) with a d.r. ratio of 74:26 was achieved using a combination of (SiR)-(22) and 5 mol% of B(C6F5)3. The alcohol [I] was isolated in good yield and e.e. (68%, 38% respectively) after the racemization-free reductive cleavage of hydrosilane (22) (Scheme 31).7

Scheme 31 First example of FLP-mediated asymmetric hydrosilylation.7

Subsequently Oestreich explored the asymmetric hydrosilylation of a series of six acyclic methyl ketones, using a racemic mixture of silane (22) and B(C6F5)3 (Scheme 32).41 These reactions were undertaken in toluene at room temperature and proceeded with excellent yields of up to 87% and good diastereoselective ratios of up to 81:19. Curiously when the asymmetric hydrosilylation of cyclic ketones [I] and [II] was explored the reactions were slow and the diastereoselective ratios were reduced, when compared to the acyclic ketones. Oestreich also applied the same conditions to the hydrosilylation of imines, which led to racemic mixtures of products albeit with good conversions.41

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Scheme 32 Asymmetric hydrosilylation of prochiral ketones.41

The inconsistency in stereochemical outcome has been attributed to a difference in hydride transfer pathways (Fig. 5). For the hydrosilylation of carbonyls, the hydride transfer was capable of conveying chirality at the silylated carbonyl (Fig. 5A). However for the hydrosilylation of imines, the hydride transfer occurred at the borane-activated imine (Fig. 5B) at a different stage of the reaction pathway where there was no effect upon stereoselectivity, as the silylated iminium ion intermediate (Fig. 5C) was too sterically hindered for hydride transfer to occur.41

Fig. 5 Origin of stereochemical outcomes in the hydrosilylation of ketones and imines.41

Klankermayer was the first to accomplish highly enantioselective hydrosilylation of imines in 2012. A small scope of six acyclic N-aryl imines were hydrosilylated and reduced, using chiral camphor-based boranes (14) and (23) in low catalytic loadings at room temperature, achieving good to excellent yields of the amine products in high enantioselective ratios of up to 87% (Scheme 33). However, the reduction of more sterically encumbered imines such as 2-methyl-N-(1-phenylethylidene)aniline [III] led to negligible conversion, as did the reduction of imines with electron withdrawing groups on the para position of their aryl rings [I], which led to a low yield but high e.e. of the respective amine.42

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Frustrated Lewis Pairs in Organic Synthesis

Scheme 33 First FLP-mediated enantioselective reduction of imines.42

Oestreich developed (S)-(24)∙THF, the THF adduct of a chiral analog of B(C6F5)3, to further explore asymmetric hydrosilylation reactions. Borane (24) has fewer pentafluorophenyl groups when compared to B(C6F5)3, lowering the Lewis acidity, however the inclusion of the BINOL-like ligand gives the molecule axial chirality (Scheme 34). At first Oestreich asymmetrically hydrosilylated and reduced a small scope of four imines using Me2PhSiH as the hydride source. Noting that the (S)-borane favorably catalyzed conversion of the imines into their respective (S)-amines, with a moderate overall e.e. of 30–41%. Curiously additional exploration

Scheme 34 Tuneable FLP-mediated asymmetric hydrosilylation.43

Frustrated Lewis Pairs in Organic Synthesis

583

showed that the use of axial chiral silanes (S)-(25) or (R)-(25) as the hydride source led to the amine product of the same enantiomer being preferentially formed, as opposed to the (S)-amine that was formed when (S)-(24)∙THF was the catalyst with a racemic silane.43 Later, using in situ 1H NMR spectroscopic studies, Oestreich was able to determine the hydride transfer pathway for (S)-(24)
THF catalyzed imine hydrosilylation. They observed an equimolar ratio of free amine [I] and silylated enamine [II] intermediates during hydrosilylation, alongside the anticipated silylated iminium ion intermediate [III] (Fig. 6). The formation of these additional unanticipated intermediates implied that alternative competing reaction pathways with different enantioselective determining steps were also occurring. This would enhance the probability of the formation of a racemic silyl imine, in spite of the use of chiral borane (24).44

Fig. 6 Intermediates observed during the (S)-(24)
THF catalyzed imine hydrosilylation reaction.44

They proposed a mechanism wherein the borane catalyst initially activated the hydrosilane (Scheme 35, A), which then reacted with an imine to form the silyliminium ion and its counter borohydride ion (Scheme 35, (E)-B or (Z)-B), with the silyliminium ion having inverted stereochemistry with respect to the imine starting material. Subsequent hydride attack by the borohydride on both silyliminium ions (Scheme 35, (E)-B and (Z)-B) led to the formation of the relevant silylamine product (Scheme 35, C) via loss of the borane.44 Oestreich also discovered that two additional mechanisms were happening concurrently. Deprotonation of the silyliminium ion (Scheme 35, (E)-B or (Z)-B) by unreacted imines produced the silylated enamine [II], found in the initial 1H NMR experiments. These silylated enamines were then capable of forming the racemised silylamine product (Scheme 35, D) via CdN bond rotation of the enamine intermediates.44 The other potential mechanism is the attack at the a-position of the silyliminium ion by a second equivalent of (E)-imine to form an ion pair via loss of hydrosilane (Scheme 35, (E)-E). (Note: the mechanism (Scheme 35, (E)-B) can occur with either (E)-B and (Z)-B, however only (E)-B has been depicted for clarity in the scheme). Subsequent reduction of the iminium cation (Scheme 35, (E)-E) formed amine [I], the other intermediate discovered by the 1H NMR study. Amine [I] was then subsequently re-exposed to an equivalent of hydrosilane, forming an ammonium ion and borohydride counterion pair (Scheme 35, F), consequently the silylated enamine [II] deprotonated the ammonium species (Scheme 35, F) to form the silyliminium ion (Scheme 35, (Z)-B). The silylamine (Scheme 35, C) was then formed after hydride attack on the silyliminium by the borohydride.44

Scheme 35 Mechanism of imine hydrosilylation catalyzed by (S)-(24)
THF.44

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Frustrated Lewis Pairs in Organic Synthesis

To achieve enantioselective hydrosilylation of carbonyls, Oestreich synthesized (S)-(26)∙DMS, an analog of (S)-(24)∙THF, which also contained axial chirality. However, the additional installation of phenyl groups at the 3 and 30 positions of the binaphthyl rings led to extra steric bulk around the boron center, which prevented THF from coordinating and hence dimethyl sulfide (DMS) was utilized as a smaller Lewis base.45 Oestreich then explored the hydrosilylation of acetophenone, using a range of hydrosilanes and the new catalyst (S)-(26)∙DMS, to find optimal hydrosilylation conditions. The found the larger monohydrosilanes to be less reactive, which was recognized as the effect of their steric hinderance. In contrast more compact trihydrosilanes like PhSiH3 and MesSiH3, exhibited quantitative reduction with up to 87% e.e.45 Using the optimized conditions of a low catalytic loading of (S)(26)∙DMS (2.4 mol%) and 3 equivalents of PhSiH3, a scope of 16 acetophenone compounds were asymmetrically reduced (Scheme 36). It was found that the electronic effects of the groups on the aryl rings influenced the rate of the reactions and the e. e.s. of the products. With strongly electron withdrawing groups leading to a lower reaction rate but yielding the corresponding alcohol in reasonable yield but good e.e. This is in contrast to acetophenones with electron donating groups which were fully reduced to their respective alcohols much faster, but in significantly lower e.e.s. Furthermore, Oestreich found that the reduction of sterically hindered acetophenone derivatives had both low reactivity and enantioselectivity.45

Scheme 36 (S)-(26)
DMS-mediated hydrosilylation of acetophenones.45

The formation of chiral bisboranes via the hydroboration of binaphthyl-based dienes by Piers’ borane and their subsequent use as catalysts for asymmetric hydrogenations by Du has previously been mentioned.35–38 In 2015, Du explored the use of these catalysts for asymmetric hydrosilylations (Scheme 37), assessing a selection of chiral bisboranes to determine the most optimal for imine hydrosilylation. Finding that the bisborane formed from diene (18) was the best, Du proceeded to utilize this for the enantioselective hydrosilylation of 18 imines, which were effectively reduced to their respective amines in excellent yields and pleasing e.e.s of up to 82%.46 Curiously there was no need for an external Lewis base in these reactions, unlike Klankermayer’s chiral boranes (14) and (15) whose imine reductions were racemic without one.42,46

Scheme 37 Asymmetric hydrosilylation catalyzed by a chiral bisborane.46

Frustrated Lewis Pairs in Organic Synthesis

585

In 2019, Du combined the chiral bisborane derived from diene (18) with PtBu3 to form an FLP capable of the asymmetric hydrosilylation of acetophenone derivatives finding optimal conditions of 5 mol% of the chiral FLP with 1.2 equivalents of PhSiH2. This led to the reduction of a range of 27 ketones in very high yields of up to 99% and impressive e.e.s of up to 97% (Scheme 38).47

Scheme 38 FLP-mediated asymmetric hydrosilylation of acetophenones by a chiral bisborane.47

Rosenberg was the first to achieve FLP-mediated diastereoselective hydrosilyation when B(C6F5)3 was combined with different hydrosilanes for the hydrosilylation and bishydrosilyation of a-diketones. Curiously, it was found that the steric bulk of the hydrosilane determined the relative stereochemistry of the products formed. For example, the meso products were almost selectively formed (up to 96% d.e.) when less sterically bulky hydrosilanes like Me3SiH were used. In contrast, when bulkier hydrosilanes such as Ph3SiH were employed in the reaction, the dl products were almost selectively formed (up to 92% d.e.) (Scheme 39).48

Scheme 39 FLP-mediated diastereoselective hydrosilylation of a-diketones.48

In 2016, Du exhibited another example of diastereoselective hydrosilylation of 1,2-dicarbonyls, employing a bisborane derived from diyne (27). This bisborane was used in combination with three equivalents of PhMe2SiH for the hydrosilylation of a scope of 20 1,2-dicarbonyls, reducing them to the optically active a-hydroxy ketones and a-hydroxy esters in yields of up to 98% and e.e.s of up to 99% (Scheme 40). The reduction of smaller substrates proved to be a limitation, for example the hydrosilylation and reduction of acetophenone led to 1-phenylethanol being formed in a yield of 95%, but an e.e. of only 42%.49

Scheme 40 FLP-mediated enantioselective hydrosilylation of 1,2-dicarbonyl compounds.49

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Frustrated Lewis Pairs in Organic Synthesis

11.14.5 Other FLP-mediated organic transformations So far, this article has looked at the early examples of the uses of FLPs as catalysts, the development of air and moisture stable FLPs, and the ability of FLPs to catalyze the reduction of a range of substrates asymmetrically. Most of these examples have been exploring the reduction of polar substrates, this next section shall explore some of the other organic reactions which FLPs are capable of catalyzing.

11.14.5.1 FLP-mediated hydroamination In 2013, Stephan was the first to modify B(C6F5)3 to be used as a catalyst for hydroamination, successfully forming 14 enamines in high yields of up to 84% after the 1,2-addition of a secondary amine to an alkyne with 10 mol% of B(C6F5)3 as catalyst (Scheme 41). The most efficient conditions for the reaction involved the slow addition of the alkyne to the reaction mixture and low temperatures, which increased the yield of product in some cases. Encouraged by the FLP-like nature of these reactions, and the fact that the reduction of substrates by FLPs was well explored, Stephan also reported two examples of a tandem hydroamination/ hydrogenation reactions to form tertiary amines directly in good yield of up to 77% (Scheme 41).50

Scheme 41 B(C6F5)3 mediated hydroamination of terminal alkynes and B(C6F5)3 mediated tandem hydroamination/hydrogenation of alkynes.50

The reactions were proposed to be FLP-like mechanistically, due to the observed enamine products from Markovnikov addition, and it was suggested that the amine substrate could act as the basic component of the FLP (Scheme 42, A). The mechanism was suggested to start with adduct formation between the terminal alkyne carbon and the Lewis acidic boron. This made the alkyne susceptible to nucleophilic attack from the amine to form the Zwitterion intermediate (Scheme 42, B), with the alkyne activated between the boron and nitrogen centers. Finally, 1,3-hydrogen transfer on the intermediate led to the enamine product and regenerated the B(C6F5)3 catalyst (Scheme 42).50

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587

Scheme 42 Mechanism of B(C6F5)3 mediated hydroamination of terminal alkynes.50

In 2015, Stephan further explored the B(C6F5)3 catalyzed hydroamination reactions, reporting the procedure capable of intramolecular tandem hydroamination/hydrogenation reactions for the formation of cyclic amines.51 Using similar conditions as for the intermolecular reactions, seven substrates formed their corresponding N-heterocycles in yields of up to 89% (Scheme 43).50,51 These reaction conditions allowed for the formation of five, six and seven-membered heterocycles, however the formation of aziridines from N-propynyl-substituted anilines proved to be a limitation (Scheme 43).51

Scheme 43 B(C6F5)3 mediated intramolecular tandem hydroamination/hydrogenation of alkynes.51

Paradies explored the synthesis of indoles by intramolecular hydroamination using Lewis acidic boranes in 2017. The authors found that B(C6F5)3 could successfully catalyze the reaction, but that weakly acidic boranes like B(2,6-F2C6H3)3 or B(2,4,6-F3C6H2)3 were unable to achieve the same results. Paradies reported the formation of six indoles, formed via 5-endo-dig cyclizations of the intramolecular substrates, in high yields of up to 92% (Scheme 44). Two limits to the procedure were observed, finding that substrates with reduced nucleophilicity of the nitrogen atom led to no reaction, and that some adducts formed between the substrate and B(C6F5)3 and led to no desired indole, despite efforts to promote reactivity by raising the reaction temperature.52

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Frustrated Lewis Pairs in Organic Synthesis

Scheme 44 B(C6F5)3 catalyzed indole synthesis through intramolecular hydroamination.52

11.14.5.2 FLP-mediated direct Mannich-type reactions Direct Mannich-type reactions represent highly important CdC bond forming transformations in organic synthesis, as they are widely used for the preparation of biologically compelling aminocarbonyl moieties from the carbonyls and imines. Such reactions are usually mediated by a co-catalytic system, consisting of Lewis acidic and Brønsted basic sites. However, due to the possibility of unwanted acid-base adduct formation and thus suppression of the catalyst’s activity, most of the catalysts used can only possess mildly acidic and basic sites. This mostly limits the use of the direct Mannich-type reactions towards the carbonyl pronucleophiles possessing highly acidic protons, such as 1,3-dicarbonyls, or carbonyl moieties which are additionally activated by adjacent electron withdrawing substituents.53 To broaden such limiting carbonyl substrate range, Wasa et al. introduced a metal-free catalytic protocol for the direct Mannich-type reactions, which utilized an unconventional FLP system, composed of the strong bulky Lewis acid, B(C6F5)3 and a hindered Brønsted base, 1,2,2,6,6-pentamethylpiperidine (PMP), (28) (Scheme 45). Thus, the possible adduct formation and catalyst deactivation was prevented by the steric hindrance between the two catalysts.54 Various cyclic and acyclic ketones were successfully subjected towards the direct Mannich-type reaction with Boc-protected imine by applying 10 mol % of B(C6F5)3 and 20 mol% of PMP catalytic loadings, which resulted in the formation of six corresponding a-amino-carbonyls in good to excellent yields (48–98%) (Scheme 45). Moreover, in the case of cyclic ketones, the reactions were highly diastereoselective, with observed d.r.s of up to 20:1 (anti:syn). However, the yields were drastically decreased below 20% in presence of ketones, bearing ester, amide, or thioester moieties. Furthermore, when N-tosyl protected imines were subjected towards the transformation, the obtained yields were rather poor. Nevertheless, the inclusion of a softer Lewis acid co-catalyst, such as CuOTf, whose role was to activate the less reactive aldimines, rendered the reactions an increased yield, from 18% to 98% in the case of [III].54

Scheme 45 Direct Mannich-type reactions of ketones with imines using B(C6F5)3 and (28) as an FLP system.54

Frustrated Lewis Pairs in Organic Synthesis

589

Additionally, an iminoester with a chiral sulfinamide auxillary was also subjected towards the direct Mannich-type reactions with eight different carbonyl pronucleophiles (Scheme 46). Though the reactions showed to be highly diastereoselective, with reported d.r.s. up to >20:1 (anti:syn), the corresponding a-aminoesters were formed in quite moderate yields (32–70%).54

Scheme 46 Direct Mannich-type reactions of ketones with chiral iminoesters using B(C6F5)3 and (28).54

Based on the observations from the experimental studies, a catalytic cycle for such FLP-catalyzed direct Mannich reactions was proposed, which starts with the initial activation of the carbonyl pronucleophile by the Lewis acidic B(C6F5)3. This renders the proton at a-C position to be more acidic, which is then consequently abstracted by the Brønsted base (Scheme 47, A), leading to the formation of enolate and the ammonium ion (Scheme 47, B). The cation, now itself serving as the Brønsted acid, further activates the imine substrate, which then undergoes a nucleophilic attack by the enolate (Scheme 47, C), leading to the formation of the a-amino ester (Scheme 47, D) and at the same time, the regeneration of the catalytic system.54

Scheme 47 Proposed catalytic cycle of FLP-mediated direct Mannich-type.54

Not long after, FLP-catalyzed enantioselective direct Mannich reactions were also developed by using a chiral, boron-based Lewis acid. The chirality was introduced via binaphthyl framework ligands, bearing different substitutions at 3,30 -positions, such as 4-trifluoromethyl-substituted arenes (29) or phenyl groups (30). A series of aryl ketones with N-Boc protected imines underwent the asymmetric Mannich reactions, using 10 mol% of (29) or (30) and 20 mol% of PMP (28), achieving good to excellent yields of up to 99%, with excellent e.r.s of up to 98:2 and d.r.s of up to >20:1 (anti/syn) (Scheme 48). Moreover, differently protected imines were also subjected towards CdC bond forming reactions, from which N-Cbz benzaldimine derivative [II] yielded the corresponding product in almost quantitative yield of 99%, e.r. of 97:3, and with excellent d.r.s of 20:1 (anti/syn). Interestingly, the diastereomeric ratios were significantly decreased (3:1 anti/syn) with N-tosyl protected imine [III], suggesting that the already established hydrogen bonding between the ammonium ion and N-Boc or N-Cbz groups plays an important role in stereoselective CdC bond formation (Scheme 48, A).55

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Frustrated Lewis Pairs in Organic Synthesis

Scheme 48 Enantioselective direct Mannich-type reactions of ketones with imines using chiral boron-based Lewis acids.55

More recently, frustrated Lewis acid/Brønsted base chemistry was further extended towards the asymmetric vinylogous direct Mannich reactions, in which a,b-unsaturated carbonyls served as the pronucleophiles. For such reactions to occur, a strong chiral fused bicyclic bisborane (31) was required to activate the less acidic proton at g-position of the carbonyl. Initially, 32 a,b-unsaturated ketones were reacted with Boc-protected imines, by using 5 mol% of (31) and 20 mol% of N-methylpiperidine (32) as the catalytic system, with the reactions carried out in trifluorotoluene at 10  C for 24 h (Scheme 49). Overall, the reactions were shown to be high yielding, with both excellent diastereoselectivity (up to >20:1) and enantioselectivity (up to 96% e.e.) observed for the variously substituted a,b-unsaturated ketones. Though, poorer diastereomeric ratios were obtained with ketones bearing cyclopropyl groups [I] (2.9:1 d.r.) or no substitution [II] at all (1.7:1 d.r.) at the a-position. Moreover, when less acidic a,b-unsaturated carbonyls, such as esters and amides, were subjected towards the transformation, no reaction was observed, showing the given protocol was limited towards the more acidic ketones. Lastly, 13 different aldimines were subjected towards the asymmetric transformations, which were all compatible with the reaction conditions, yielding the products in high yields (70–96%) with great observed d.r.s of up to 13:1 and enantioselectivities (86–96% e.e.s). However, no products were observed when aliphatic imines were reacted with the a,b-unsaturated ketone. It is also noteworthy that no a-addition products were observed in the given protocol. This suggested that the bulky chiral bisborane Lewis acid catalyst was successfully blocking the a-position of the carbonyls, thus preventing the formation of unwanted by-products.56

Scheme 49 Enantioselective direct Mannich-type reactions of a,b-unsaturated ketones with imines using bisborane (31) as a source of chirality.56

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591

The FLP chemistry was also utilized in a direct a-amination of the carbonyl compounds, in which the dialkyl azodicarboxylates represented the amination reagents. Fifteen various pronucleophiles were showed to undergo high yielding a-aminations (35–98%), including ketones, esters, amides, and thioesters (Scheme 50).57 As for the catalytic system, 5–20 mol% of B(C6F5)3 was used as Lewis acid in combination with various bulky amines, as Brønsted bases, depending on the acidity of the substrates. As such, ketones, lactones and thioesters could all undergo amination reactions with 10 or 20 mol% of PMP (28), whereas 20 mol% of the stronger Barton’s base (33) was required for the deprotonation of amides.57

Scheme 50 FLP-mediated direct a-amination of carbonyls with dialkyl azodicarboxylates.57

This protocol was also rendered enantioselective, with the chirality being introduced to the amine base. The amine bases are usually more easily prepared from the commercial chiral amines, as they are more easily stored and handled when compared to the chiral borane-based Lewis acids. During the screening of various chiral bases, chiral amines with single chiral C-N stereogenic centers, such as (34), were capable of forming only one hydrogen bond with the electrophile (Scheme 51), which eventually led to an inferior directing-ability, thus resulting in low observed e.r. of 50:50. However, chiral amines with two CdN stereogenic centers exhibited higher enantioselectivities, as these promoted dual hydrogen bonding between the base and the electrophile. As such, when N-trifluoroacetyl-substituted amine (35) was used in the aminations of cyclic ketones, the chiral products were obtained in good to excellent e.r.s, ranging between 68:32 and 99:1 (Scheme 51). Moreover, the enantioselectivity and overall yields were also shown to be temperature dependent, with the lower temperature of −46  C being an optimal condition to obtain the best possible results.57

Scheme 51 Enantioselective direct a-amination of carbonyls with dialkyl azodicarboxylates using chiral Brønsted base (35) with B(C6F5)3.57

Wasa et al. also reported a convenient, diastereoselective and enantioselective preparation of a-substituted amines from N-alkyl amines and a,b-unsaturated carbonyls, using the cooperative catalysis of non-chiral B(C6F5)3 and chiral Lewis acids. The design strategy in the catalytic system consisted of an initial B(C6F5)3-mediated hydride abstraction from the a-carbon of the amine,

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resulting in the formation of an iminium cation and the borohydride anion (Scheme 52, A). Simultaneously, the chiral Lewis acid (M-L∗) activates the carbonyl moiety (Scheme 52, B), which upon the nucleophilic attack by the formed borohydride, transforms into the chiral enolate (Scheme 52, C). Subsequently, the iminium cation is attacked by the chiral enolate, furnishing the new CdC bonded product (Scheme 52, D) and thus closing the catalytic cycle. Hence, this strategy differed significantly from the “direct” Mannich type reactions mentioned previously. In those, the imines had already been prepared and only the enolates were generated in situ, which eventually resulted in some scope limitations, mainly with the less acidic substrates such thioesters or amides.58

Scheme 52 Proposed catalytic cycle for enantioselective a-amination of unsaturated carbonyls using the cooperative catalysis of non-chiral B(C6F5)3 and chiral Lewis acid (M–L∗).58

Initially, B(C6F5)3 alone was screened as a catalyst for such transformations, thus it served to activate both amine and the carbonyl substrates. 20 examples of a-substituted amines were reported in good to excellent yields (50–99%) and in moderate diastereomeric ratios of up to 10:1 (anti/syn) (Scheme 53). For the enantioselective transformations, an appropriate chiral Lewis acid

Scheme 53 Enantioselective a-amination of unsaturated carbonyls catalyzed by a cooperation of Lewis acids.58

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was screened and Mg(OTf )2 was chosen as a co-catalyst with chirality introduced by the bis-oxazoline ligand, 2,6-bis((S)-4-(3chlorophenyl)-4,5-dihydrooxazol-2-yl)pyridine (36). However, initial observed enantiomeric ratios were quite poor, which was mainly attributed to the fact that Mg(OTf )2 is functionally similar towards B(C6F5)3, thus there was less control over which Lewis acid activates which substrate. Hence, to improve the enantioselectivity, the Michael acceptor substrates had to possess geminal substitution alpha to the amine to create steric hindrance, making the carbonyl substrate rather selective towards the smaller chiral Lewis acid (Scheme 53, A). This hypothesis was later confirmed as 3-acryloyl-4,4-dimethyloxazolidin-2-one (37) did not undergo the reaction when only B(C6F5)3 as a catalyst was present, however when the chiral Lewis acid was added, the reaction proceeded and furnished the corresponding a-substituted amine in 88% yield, with high e.r.s for each diastereoisomer of 97:3 for anti and 98:2 for syn. Subsequently, two N-acryloyl oxazolidinones were reacted with various N-alkyl amines, which resulted in the formation of nine a-substituted amines in excellent e.r.s of up to 99:1, though d.r.s remained quite moderate.58

11.14.5.3 FLP-mediated C-H borylation Fontaine explored FLP catalyzed C-H activation and borylation of heteroarenes in 2015, designing intramolecular FLP (38) intentionally to achieve this (Scheme 54). The Lewis acidic boron center was positioned to be within range of the nucleophilic carbon on the heteroarene to promote good reactivity. In addition to prevent the possibility of dimerization, after proton abstraction from the heteroarene, the Lewis basic nitrogen center was surrounded by large steric bulk. Catalyst (38) was found to exist in an equilibria between its monomeric and dimeric forms when in solution.59

Scheme 54 FLP-mediated borylation of heteroarenes.59

With the specifically designed catalyst (38), Fontaine was able to borylate a scope of 14 heterocycles containing oxygen, nitrogen, and sulfur atoms successfully achieving yields of up to 98% (Scheme 54). It was found that the regioselectivity of the borylation was highly dependent on the identity of substrate. For example, 1-methylpyyrole was the first substrate explored and borylation yielded the 2 and 3-borylated products, [I] and [II], in a 93:7 ratio. The addition of bulkier N-protecting groups to pyrrole, for instance trimethyl silyl (TMS), [III], and triisopropyl silyl ether (TIPS), enabled borylation to occur selectively at the 3 position. In contrast the phenyl protecting group reduced this selectivity and led to a 3:2 ratio of products, [IV] and [V].59 In contrast to the N-protected pyrroles, it was found that the majority of electron-rich furans favored borylation exclusively at the C2 position, giving high to excellent yields of the 2-borylated products. However not all substrates were as easily compliant with 3-bromofuran requiring

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harsher conditions of increased temperature, reaction time and catalyst loading in order for borylation to occur. In addition, whilst the yield of borylated products was good under these conditions, the regioselectivity was drastically reduced, forming [VII] and [VIII] in a 10:9 ratio. Contrary to the furans, it was found that only electrophilic thiophenes were susceptible to borylation. The reactivity of 3,4-ethylenedioxythiophene is of note, depending on the stoichiometry of HBPin used, either the monoborylated product was formed in 87% yield or the diborylated products in 92% yield, [IX].59 A combination of kinetic studies and DFT allowed Fontaine to elucidate the mechanism for the borylation of 1-methylpyrrole, which begins with the splitting of FLP dimer (38) to form the active catalyst (39) in its monomeric form. The rate-determining step of the cycle follows, in which the CdH bond of the 1-methylpyrrole is activated by (39) in a four-membered transition state (Scheme 55, A), to form the zwitterionic intermediate, (Scheme 55, B). Loss of H2 from the zwitterion in B leads to the formation of a transient borohydride species (Scheme 55, C), which then undergoes s-bond metathesis with HBPin, via another four-membered transition state (Scheme 55, D), to give the desired borylated product, [I], and regenerate the active catalyst (39). A comparison of the activation energy levels for reaction at C2 vs. C3, found the activation at C2 to be marginally more accessible (0.4 kcal mol−1), explaining the formation of the two regioisomers and the preference for C2.59

Scheme 55 Mechanism of FLP-mediated borylation of heteroarenes with calculated bond energies, DG273K (DH273K), given for each structure in kcal mol−1.59

In 2016, Fontaine improved upon catalyst (39), by developing a moisture and oxygen stable precatalyst (40), allowing the FLP catalyzed borylation reaction to occur without the need for air-sensitive techniques (Scheme 56). The comparable catalytic ability of (40) to (38) was shown in a small scope of six heterocycles, achieving yields of up to 96%. Remarkably the only difference in precatalyst (40) was the substitution of the fluoroborate salt to replace the dihydroborane in (38). Furthermore, HBPin was capable of deprotecting (40) to the active catalyst (38), rendering there no need for further reagents, and thus allowing FLP catalyzed borylation of heteroarenes to occur on the bench.60

Scheme 56 FLP-mediated borylation of heteroarenes with a bench stable precatalyst.60

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Subsequently Repo found that the C-H activation of heteroarenes could be catalyzed by 2-aminophenylboranes, which had optimal geometry for reactivity between the Lewis acidic and basic centers due to the rigid phenyl bridge. Repo found that the Lewis acidity of the boron center, and basicity of the nitrogen center contributed more to the reactivity of the catalyst than the substituents at these sites, in addition the steric factors also affected reactivity.61 In 2017, Fontaine applied Repo’s observations to explore alternative amine groups that could be incorporated into catalyst (38), aiming to replace the TMP unit with a less expensive, higher yielding alternative. Fontaine explored more accessible, less sterically hindered amines, attaching piperidine, diethylamine and dimethylamine to (38) in place of the bulkier TMP unit. This change of amine moiety led to a significant increase in reactivity, with the smaller FLPs being reported as up to 15 times more reactive than (38). Further investigation by DFT and kinetic studies attributed this change in reactivity to the rate determining step of the mechanism shifting. In (38) the rate determining step was found to be the C-H activation, however for the modified catalysts with the smaller amines, the slowest step of the mechanism was found to be the initial dimer dissociation, explaining the observed increase in reactivity.62

11.14.5.4 FLP-mediated cyclization reactions Cyclization reactions using FLPs in stoichiometric amounts are well reported in the literature. For instance, in 2010 Stephan demonstrated the formation of zwitterionic nitrogen containing heterocycles by the intramolecular cyclization of an amine with a terminal alkene, using stoichiometric amounts of B(C6F5)3 (Scheme 57, [I]).63 This is similar to earlier work of the internal cyclization of unsaturated aliphatic phosphines to form zwitterionic phosphorus heterocycles, which again used stoichiometric amounts of B(C6F5)3 (Scheme 57, [II]).64 More recently in 2013, Stephan achieved the formation of methylene-oxazolines from propargyl amides, which again utilized stoichiometric amounts of B(C6F5)3 (Scheme 57, [III]).65 However this led to the question of whether FLPs could be used catalytically for these cyclization reactions, which this next section shall discuss briefly.

Scheme 57 Examples of stoichiometric FLP-mediated cyclizations.63–65

Interestingly, for the cyclization reactions of the N-H propargyl amides to form the methylene-oxazolines, it was observed that the products with an aryl substituent would isomerize into oxazoles, a key component found in many anti-bacterial and anti-fungal agents.65 Stephan explored a scope of 16 propargyl amides, all of which were reported to cyclize, however only a few of these products were then isomerized into the desired oxazole (Scheme 58). The technique to encourage isomerisation necessitated heating to 45  C over an additional four-day period, and after this only one of the four oxazoles was isolated in a moderate yield of 60%, [I].65

Scheme 58 Stoichiometric B(C6F5)3 mediated cyclization and subsequent isomerization of propargyl amides.65

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Frustrated Lewis Pairs in Organic Synthesis

Due to the strength of the dative N !B bond within the oxazole product, this cyclization/isomerization reaction was initially believed to be unable to be catalyzed by B(C6F5)3. However, increasing the steric bulk within the propargyl amide, by the inclusion of an adamantyl group allowed the Lewis acid to be released. Stephan reported that from the respective adamantyl propargyl amide, using 10 mol% of B(C6F5)3 and the harsh conditions of 100  C, that oxazole [I] was formed in an impressive 83% yield (Scheme 59). This was the first example of boron catalyzed cyclization of propargyl amides.65

Scheme 59 Catalytic B(C6F5)3 mediated cyclization and subsequent isomerization of propargyl amides.65

In 2016, Paradies demonstrated that FLPs could catalyze the cycloisomerization of 1,5-enynes.66 Initially, stoichiometric amounts of B(C6F5)3 were combined with the 1,5-enyne, to show that a 5-endo-dig cyclization reaction was occurring to form the cyclized product (Scheme 60, C). DFT studies allowed the authors to propose that the alkyne was activated by the borane to generate a reactive carbocation, which was then attacked by the attached double bond resulting in an intramolecular cyclization, which occurred to generate the zwitterion intermediate, (Scheme 60, A). Rearrangement of this intermediate by a combination of 1,1-carboboration and a 1,2-hydride shift gave intermediate (Scheme 60, B). A subsequent 1,3-borane shift produced the desired cyclized product (Scheme 60, C).66

Scheme 60 Synthesis of 5-endo-dig cyclized product from 1,5-enyne and B(C6F5)3.66

The inclusion of a phosphine Lewis base prevented the 1,1-carboboration from occurring in the cycloisomerization reaction and led to the base abstracting a proton from carbocation in (Scheme 61, A) to form the stable onium borate intermediate (Scheme 61, B). This intermediate B was in equilibrium with the addition product (Scheme 61, C), however it was found that heating this compound to 90  C resulted in protodeborylation to form the desired cycloisomerized compound D and regenerate the FLP, giving proof of the FLP catalyzed cycloisomerization (Scheme 61).66

Scheme 61 Mechanism of FLP-mediated cycloisomerization of 1,5-enynes.66

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A small scope of seven substituted enynes were successfully cycloisomerized using 20 mol% of the FLP and heating to 90  C, with NMR yields of up to 98% (Scheme 62). Paradies noted that the electronic nature of the substituents on the alkyne had an effect on the yield of cyclized product, with electron donating groups leading to an increase and electron withdrawing groups and thiophenes (Scheme 62, [III]) resulting in a decrease. Paradies also explored the exchange of the phenyl core for heterocyclic furanyl or thiophenyl groups, however these cyclization reactions were unsuccessful, which was attributed to the greater distance between the alkene and alkyne groups.66

Scheme 62 FLP-mediated cycloisomerization of 1,5-enynes.66

A large range of pharmaceutical drugs, pesticides and photovoltaic cells contain a 3,4,5-triaryl-1,2,4-triazole moiety within the compounds, making this an important structure to be able to synthesize. Unfortunately, many of the syntheses of these compounds are limited by a narrow functional group tolerance or require large excess of reagents, making discovery of alternative routes desirable. In 2019, Maji showed that the reaction between N-tosylhydrazones and anilines to form 3,4,5-triaryl-1,2,4-triazoles could be catalyzed by B(C6F5)3, which was found to have a dual-role within this one-pot metal-free reaction (Scheme 63).67

Scheme 63 B(C6F5)3-mediated synthesis of 3,4,5-triaryl-1,2,4-triazoles.67

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Frustrated Lewis Pairs in Organic Synthesis

The reaction between two equivalents of hydrazone and one of amine, catalyzed by 5 mol% B(C6F5)3, led to the formation of symmetrical 1,2,4-triazoles in yields of up to 87%. Maji extended the reaction scope to explore the synthesis of asymmetrical 1,2,4-triazoles, simply by reacting two different hydrazones under the same conditions to form the asymmetrical product in high yields. However, it was found that these two different hydrazones needed to have varying electronic properties in their aryl groups to avoid a 1:1:1 ratio of symmetrical and asymmetrical products from forming.67 Maji was able to determine, through the collective use of experimental and computational data, the mechanism for this reaction and thus discover that B(C6F5)3 functioned as a Lewis acid catalyst in one stage and additionally as the Lewis acidic part of an FLP in another stage. Initially, the Lewis acidic boron center of B(C6F5)3 formed an adduct with the sp2-hybridized nitrogen of the N-tosylhydrazone, activating the C]N double bond (Scheme 64, A). After the coordination of aniline, [I], to this activated adduct to form a zwitterion, the rate-determining step of the reaction, an intramolecular hydride transfer from N3 to N1 could occur to generate an adduct intermediate (Scheme 64, B). This subsequently reacted with the second equivalent of the hydrazone to generate the unstable intermediate (Scheme 64, C) by releasing the NH2Ts component. Owing to its unstable nature, intermediate C then readily cyclized to give a heterocycle (Scheme 64, D), by the dissociation of the boron-N1 bond and following protonation of N4. This led to the intramolecular nucleophilic attack of N2 on N1 forming the new NdN bond and closing the heterocycle with the simultaneous loss of an additional NH2Ts. After forming heterocycle D, B(C6F5)3 took on its second role in the mechanism, as part of an FLP catalyst, to enable the dehydrogenative aromatization of intermediate D to give the desired triazole product, [II] and the zwitterion FLP by-product (Scheme 64, E). This FLP then liberated H2 to give the aniline and regenerate the borane catalyst.67

Scheme 64 Mechanism of FLP-mediated synthesis of 3,4,5-triaryl-1,2,4-triazoles.67

The FLP-catalyzed cyclization reactions have also been rendered asymmetric by Wasa and co-workers, who reported the enantioselective Conia-ene type cyclization of alkynyl ketones to furnish cyclopentenes (Scheme 65). Such enantioselective cycloaddition reactions were cooperatively catalyzed by the Lewis acid B(C6F5)3 and the Brønsted base PMP (28), whilst the chirality was introduced via an additional use of the chiral Lewis acid co-catalyst, ZnI2 with bis-oxazoline ligand (41). The explanation behind this choice for the chiral “softer” Lewis acid was dictated by intended role for each Lewis acid. The more oxophilic organoborane catalyst would therefore activate the carbonyl, whereas the chiral Lewis acid would rather activate the alkyne moiety.68

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Scheme 65 FLP-mediated enantioselective Conia-ene type cyclization of alkynyl ketones.68

The authors showed that a variety of internal alkynes underwent the cyclizations, yielding the corresponding cyclopentenes in excellent yields of up to 98% with excellent e.r.s (up to 97:3) (Scheme 65), even in the presence of carboxylic ester or alkene functional groups, making the reported protocol quite chemoselective. Moreover, differently substituted alkyls and aryls near the ketone moiety were subjected to the cyclization reaction, mostly showing satisfactory yields and e.r.s. The indanone derivative proved problematic, and was not cyclized when using the bulkier PMP base. However, when the less sterically hindered piperidine base (32) was used, the corresponding cyclopentene was obtained in 98% yield and 99:1 e.r. Moreover, when a tetralone derivative was cyclized using the less bulky Brønsted base (32), the cyclized product [II] was formed in the lower yield of 20%, albeit in high e.r. (98:2). Presumably, such low obtained yield was due to the severe steric repulsion between the n-propyl substituent and the tetralone ring, as when n-propyl group [II] was exchanged for methyl [III], the corresponding cyclopentenyl product was obtained in 73% yield.68 The proposed catalytic cycle of the presented enantioselective Conia-ene type cyclization is initiated with activation of the carbonyl moiety by B(C6F5)3 and simultaneously the chiral Lewis co-catalyst activating the alkyne functionality (Scheme 66, A). Such carbonyl activation generates a more acidic proton at a-position, which enables the N-alkyl amine Brønsted base 28 to abstract the acidic proton, thus resulting in the formation of the enolate and the iminium cation (Scheme 66, B). The enolate then serves as a nucleophile, which attacks the activated alkyne moiety via enantio-determining 5-endo-dig cyclization, eventually resulting in the formation of a carbocycle (Scheme 66, C). A subsequent protonation of the intermediate (Scheme 66, C) by the ammonium cation then produces the final cyclopentenyl product (Scheme 65, D), whilst the catalysts are regenerated.68

Scheme 66 Proposed catalytic cycle for FLP-mediated enantioselective Conia-ene type cyclization of alkynyl ketones.68

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Frustrated Lewis Pairs in Organic Synthesis

11.14.6 Frustrated radical pairs in organic synthesis As indicated in the previous sections, frustrated Lewis pairs have found many applications in catalysis and, as they continuously show new reactivities, they have become an exciting alternative towards the transition metals in organic synthesis. Since their discovery, it was suggested that the activation of small molecules by frustrated Lewis pairs undergoes solely via heterolytic bond cleavage (Scheme 67, A). However, recently it has been suggested that certain Lewis acid/Lewis base pairs can activate the substrates in homolytic fashion instead (Scheme 67, B).

Scheme 67 Two possible pathways for FLP-mediated small molecule activation.

For instance, in 2013 Stephan et al. reported the formation of frustrated radical pairs (FRPs) composed of tBu3P/Al(C6F5)3 and nitrous oxide (Scheme 68, A).69 Following mechanistic studies they also proposed that the Mes3P/E(C6F5)3 (E ¼ Al; B) FLP system underwent single electron transfer (SET) reactions with substrates, such as tetrachloro-1,4-benzoquinone (42) (Scheme 68, B) and Ph3SnH (Scheme 68, C). Interestingly, when tBu3P/B(C6F5)3 FLP was subjected towards the reaction with Ph3SnH, the product of the heterolytic cleavage [tBu3P-SnPh3]+ [HB(C6F5)3]− was observed instead (Scheme 68, D).70 Nevertheless, several examples of FLP-mediated SET reactions have been reported, whilst activating small molecules, including NO,71 H272 and (PhCOO)273 and their electron paramagnetic resonance (EPR) studies have been recently reviewed.74 Hence, in the following section only the utilization of FRPs for the CdC bond formations will be discussed further.

Scheme 68 Reported FLP systems also capable forming FRPs.69,70

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11.14.6.1 FRP-mediated CdC bond formations The first report of the potential application of FRPs in organic synthesis was disclosed by Melen et al. In the study, FLP systems, consisting of B(C6F5)3 and various phosphine-based Lewis bases, were reacted with diaryl ester (43). Whilst most of the FLP systems gave expected heterolytic product, a phosphonium borate (Scheme 69, A), when Mes3P was used as a Lewis base, a different reactivity was observed, in which a homocoupled benzhydryl and the salt (Scheme 69, B) were obtained as sole products. Such results suggested that Mes3P/B(C6F5)3 cleaved the Csp3 – O bond via a SET pathway, which was subsequently confirmed byEPR spectroscopy. A distinctive doublet signal was observed in the EPR spectrum, which was later attributed to the [Mes3P]+
radical.75

Scheme 69 FLP-mediated cleavage of diaryl ester (43) resulting in heterolytic (A) or homolytic (B) product.75

Subsequently, the FRP system identified was utilized for the C–H activation of styrenes, which resulted in the formation of b-functionalized olefins (Scheme 70). Interestingly, the initial optimization reactions revealed that an excess of the styrene (5 eq.) as well as the use of coordinating solvent, such as tetrahydrofuran, were necessary in order to maximize the obtained yields of the desired olefinic products. Overall, 35 different examples of b-functionalized olefins were presented with the obtained yields ranging from 30% to 85%. The reaction protocol was compatible with electron withdrawing and electron donating substituents on the aryl rings of esters and styrenes. Moreover, alkyl functionalities on the styrene, such as cyclohexyl, [II], were tolerated, albeit lower overall yields were observed due to the formation of Z/E isomers in up to a 6:1 ratio.75

Scheme 70 FRP-mediated CdC bond coupling of styrenes with diarylesters.75

Based on the conducted experimental, EPR, and DFT studies, a reaction mechanism for the reported FRP-mediated C–H activation was proposed. The formation of FRPs (Scheme 71, A) is promoted by the initial dissociation of B(C6F5)3
THF adduct, which is also considered to be in equilibrium with FLP and FRP. The [B(C6F5)3]-. radical then facilitates homolytic Csp3 – O bond cleavage (Scheme 71, B), resulting in the expulsion of borate adduct (44) and the formation of benzylic radical, which further undergoes an addition reaction with styrene (Scheme 71, C). This produces a tertiary carbon radical intermediate, which is then subjected towards the hydride abstraction by [Mes3P]+. (Scheme 71, D), resulting in the expulsion of a phosphonium cation, and the formation of the final b-functionalized olefin (Scheme 71, E).75

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Scheme 71 Proposed mechanism for FRP-mediated CdC bond coupling of styrenes with diaryl esters.75

In a subsequent publication, Melen et al. demonstrated the efficacy of the same FLP in the functionalization of terminal alkynes through Csp3 – Csp coupling with the same aryl esters. Although radical species could be observed by EPR spectroscopy, DFT studies found that a diamagnetic pathway was most likely. However, calculations showed that a low-energy single-electron pathway could operate depending upon the substrates.76 Another example of FRP-mediated CdC bond formation has been presented by Ooi et al. B(C6F5)3 and various N, N-dialkylanilines were shown to undergo SET processes, proceeding via the formation of electron donor-acceptor (EDA) complexes, in which the boron-based Lewis acid served as a p-acceptor and the Lewis base acted as the p-donor (Scheme 72). Interestingly, the reaction conditions, required for the formation of a-aminoalkyl radical cation, were dependent on the aniline Lewis base. Whilst the trimethylsilyl derivative (45) could form the radical under dark conditions, a dimethyl derivative (46) required a visible light irradiation. The formation of the radical species was confirmed byEPR spectroscopy as well as by UV-vis absorption spectroscopy.77

Scheme 72 Formation of a-aminoalkyl radical under various reaction conditions.

Subsequently, two trimethylsilyl derivatives were reacted with an excess of electron-deficient alkene, methyl vinyl ketone, which served as a radical acceptor in the presence of 10 mol% B(C6F5)3. Such reaction indeed afforded the desired radical addition product, though the obtained yields were moderate (31–66%). The lower yields were attributed to the presence of enolate intermediate (48), formed upon the desilylation of the cationic radical species and a subsequent one electron reduction by B(C6F5)3–% (Scheme 73, A). Hence, MeOH, serving both as TMS trapping agent and a proton source, was used in the solvent system 1:10 MeOH: Et2O, which drastically improved the obtained yields from 66% to 92%.

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Scheme 73 FRP-mediated CdC bond coupling of N,N-dialkylamines with methyl vinyl ketone.

Moreover, various derivatives of N-aryltetrahydroisoquinolines were reacted with a, b-unsaturated ketones under visible-light in MeCN (Scheme 74). Both electron donating and electron withdrawing substituents at the para position on the phenyl ring were tolerated, however when the ortho-tolyl group was investigated, no reaction occurred, which was rationalized by the absence of formation of EDA complexes due to sterics. Further limitations of the reported protocol included the use of less reactive electron acceptors, such as styrene or methyl acrylate (49), which did not undergo the reactions at all.77

Scheme 74 CdC bond coupling of N-aryltetrahydroisoquinolines with unsaturated ketones under visible light.77

11.14.7 Summary and outlook This article has explored the catalytic and stoichiometric uses of frustrated Lewis pairs focusing on their application within organic synthesis. FLPs have been shown to be viable alternatives to precious metal catalysts, for both simpler catalytic reduction as well as more complex organic transformations such as the direct Mannich-type reactions and cyclizations. With such a growth in the field over the last 15 years, including explorations of air and moisture stable FLPs, we predict that many more organic transformations will be catalyzed by FLPs, which will become more commonplace within organic synthesis.

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Stephan, D. W. Org. Biomol. Chem. 2012, 10 (30), 5740–5746. Wittig, G.; Benz, E. Chem. Ber. 1959, 92 (9), 1999–2013. Tochtermann, W. Angew. Chem. Int. Ed. 1966, 5 (4), 351–371. Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W. Science 2006, 314 (5802), 1124–1126. Brown, H. C.; Schlesinger, H. I.; Cardon, S. Z. J. Am. Chem. Soc. 1942, 64 (2), 325–329. Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118 (39), 9440–9441. Rendler, S.; Oestreich, M. Angew. Chem. Int. Ed. 2008, 47 (32), 5997–6000. Stephan, D. W. Dalton Trans. 2009, 9226 (17), 3129–3136. Fontaine, F. G.; Courtemanche, M. A.; Légaré, M. A.; Rochette, É. Coord. Chem. Rev. 2017, 334, 124–135. Stephan, D. W.; Erker, G. Chem. Sci. 2014, 5 (7), 2625–2641. Welz, E.; Krummenacher, I.; Engels, B.; Braunschweig, H. Science 2018, 359, 896–900. Nerozzi, F. Platin. Met. Rev. 2012, 56 (4), 236–241. Aldridge, S.; Downs, A. J. Chem. Rev. 2001, 101 (11), 3305–3365. Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. 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Soc. 2013, 135 (35), 12968–12971. Fasano, V.; Ingleson, M. J. Synthesis 2018, 50 (9), 1783–1795. Carden, J. L.; Dasgupta, A.; Melen, R. L. Chem. Soc. Rev. 2020, 49 (6), 1706–1725. Gyömöre, Á.; Bakos, M.; Földes, T.; Pápai, I.; Domján, A.; Soós, T. ACS Catal. 2015, 5 (9), 5366–5372. Bakos, M.; Gyömöre, Á.; Domján, A.; Soós, T. Angew. Chem. Int. Ed. 2017, 56 (19), 5217–5221. Hoshimoto, Y.; Kinoshita, T.; Hazra, S.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2018, 140 (23), 7292–7300. Scott, D. J.; Phillips, N. A.; Sapsford, J. S.; Deacy, A. C.; Fuchter, M. J.; Ashley, A. E. Angew. Chem. Int. Ed. 2016, 55 (47), 14738–14742. Sapsford, J. S.; Scott, D. J.; Allcock, N. J.; Fuchter, M. J.; Tighe, C. J.; Ashley, A. E. Adv. Synth. Catal. 2018, 360 (6), 1066–1071. Chen, D.; Wang, Y.; Klankermayer, J. Angew. Chem. Int. Ed. 2010, 49 (49), 9475–9478. Ghattas, G.; Chen, D.; Pan, F.; Klankermayer, J. Dalton Trans. 2012, 41 (30), 9026–9028. Heiden, Z. M.; Stephan, D. W. Chem. Commun. 2011, 47 (20), 5729–5731. Sumerin, V.; Chernichenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.; Repo, T. Adv. Synth. Catal. 2011, 353 (11 −12), 2093–2110. Liu, Y.; Du, H. J. Am. Chem. Soc. 2013, 135 (18), 6810–6813. Wei, S.; Du, H. J. Am. Chem. Soc. 2014, 136 (35), 12261–12264. Zhang, Z.; Du, H. Angew. Chem. Int. Ed. 2015, 54 (2), 623–626. Ren, X.; Li, G.; Wei, S.; Du, H. Org. Lett. 2015, 17 (4), 990–993. Lindqvist, M.; Borre, K.; Axenov, K.; Kótai, B.; Nieger, M.; Leskelä, M.; Pápai, I.; Repo, T. J. Am. Chem. Soc. 2015, 137 (12), 4038–4041. Obligacion, J. V.; Chirik, P. J. Nat. Rev. Chem. 2018, 2 (5), 15–34. Hog, D. T.; Oestreich, M. Eur. J. Org. Chem. 2009, 29, 5047–5056. Chen, D.; Leich, V.; Pan, F.; Klankermayer, J. Chem. A Eur. J. 2012, 18 (17), 5184–5187. Mewald, M.; Oestreich, M. Chem. A Eur. J. 2012, 18 (44), 14079–14084. Hermeke, J.; Mewald, M.; Oestreich, M. J. Am. Chem. Soc. 2013, 135 (46), 17537–17546. Süsse, L.; Hermeke, J.; Oestreich, M. J. Am. Chem. Soc. 2016, 138 (22), 6940–6943. Zhu, X.; Du, H. Org. Biomol. Chem. 2015, 13 (4), 1013–1016. Liu, X.; Wang, Q.; Han, C.; Feng, X.; Du, H. Chin. J. Chem. 2019, 37 (7), 663–666. Skjel, M. K.; Houghton, A. Y.; Kirby, A. E.; Harrison, D. J.; McDonald, R.; Rosenberg, L. Org. Lett. 2010, 12 (2), 376–379. Ren, X.; Du, H. J. Am. Chem. Soc. 2016, 138 (3), 810–813. Mahdi, T.; Stephan, D. W. Angew. Chem. Int. Ed. 2013, 52 (47), 12418–12421. Mahdi, T.; Stephan, D. W. Chem. A Eur. J. 2015, 21 (31), 11134–11142. Tussing, S.; Ohland, M.; Wicker, G.; Flörke, U.; Paradies, J. Dalton Trans. 2017, 46 (5), 1539–1545. Trost, B. M.; Bartlett, M. J. Acc. Chem. Res. 2015, 48 (3), 688–701. Chan, J. Z.; Yao, W.; Hastings, B. T.; Lok, C. K.; Wasa, M. Angew. Chem. Int. Ed. 2016, 55 (44), 13877–13881. Shang, M.; Cao, M.; Wang, Q.; Wasa, M. Angew. Chem. Int. Ed. 2017, 56 (43), 13338–13341. Tian, J.-J.; Liu, N.; Liu, Q.-F.; Sun, W.; Wang, X.-C. J. Am. Chem. Soc. 2021, 143 (8), 3054–3059. Shang, M.; Wang, X.; Koo, S. M.; Youn, J.; Chan, J. Z.; Yao, W.; Hastings, B. T.; Wasa, M. J. Am. Chem. Soc. 2017, 139 (1), 95–98. Shang, M.; Chan, J. Z.; Cao, M.; Chang, Y.; Wang, Q.; Cook, B.; Torker, S.; Wasa, M. J. Am. Chem. Soc. 2018, 140 (33), 10593–10601. Légaré, M. A.; Courtemanche, M. A.; Rochette, É.; Fontaine, F. G. Science 2015, 349 (6247), 513–516. Légaré, M. A.; Rochette, É.; Légaré Lavergne, J.; Bouchard, N.; Fontaine, F. G. Chem. Commun. 2016, 52 (31), 5387–5390. Chernichenko, K.; Lindqvist, M.; Kótai, B.; Nieger, M.; Sorochkina, K.; Pápai, I.; Repo, T. J. Am. Chem. Soc. 2016, 138 (14), 4860–4868. Légaré Lavergne, J.; Jayaraman, A.; Misal Castro, L. C.; Rochette, É.; Fontaine, F. G. J. Am. Chem. Soc. 2017, 139 (41), 14714–14723. Voss, T.; Chen, C.; Kehr, G.; Nauha, E.; Erker, G.; Stephan, D. W. Chem. A Eur. J. 2010, 16 (10), 3005–3008. McCahill, J. S. J.; Welch, G. C.; Stephan, D. W. Angew. Chem. Int. Ed. 2007, 46 (26), 4968–4971. Melen, R. L.; Hansmann, M. M.; Lough, A. J.; Hashmi, A. S. K.; Stephan, D. W. Chem. A Eur. J. 2013, 19 (36), 11928–11938. Tamke, S.; Qu, Z. W.; Sitte, N. A.; Flörke, U.; Grimme, S.; Paradies, J. Angew. Chem. Int. Ed. 2016, 55 (13), 4336–4339. Guru, M. M.; De, S.; Dutta, S.; Koley, D.; Maji, B. Chem. Sci. 2019, 10 (34), 7964–7974. Cao, M.; Yesilcimen, A.; Wasa, M. J. Am. Chem. Soc. 2019, 141 (10), 4199–4203. Ménard, G.; Hatnean, J. A.; Cowley, H. J.; Lough, A. J.; Rawson, J. M.; Stephan, D. W. J. Am. Chem. Soc. 2013, 135 (17), 6446–6449.

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11.15 Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis Xiang-Yu Zhanga and Bing-Tao Guanb, aCollege of Chemistry and Chemical Engineering, China West Normal University, Nanchong, China; b Department of Chemistry, Fudan University, Shanghai, China © 2022 Elsevier Ltd. All rights reserved.

11.15.1 Introduction 11.15.2 General properties 11.15.2.1 Enhanced reactivity 11.15.2.2 Enhanced stability 11.15.2.3 Enhanced solubility 11.15.2.4 Cooperative activation 11.15.2.5 Structural templating 11.15.3 Nucleophilic addition reactions 11.15.4 Deprotonative metalation reactions 11.15.5 Catalytic enantioselective reactions 11.15.6 Catalytic hydroamination reactions 11.15.7 Catalytic hydroboration reactions 11.15.8 Catalytic hydrogenation reactions 11.15.9 Catalytic CdC bond formation reactions 11.15.10 Conclusion and outlook Acknowledgments References

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11.15.1 Introduction The concept of “synergy” is not simply “working together” or “cooperating,” but is the benefit that results when two or more variables combine to achieve something neither one could have achieved on its own. Thus, the synergistic effect illustrates the phenomena that the whole being greater than the sum of its parts, simply “1 + 1 > 2.” In organometallic chemistry, the synergistic effect has been used to describe the facts that mixing two organometallic reagents can lead to a new species bringing properties distinct from those of each component. Another term closely associated with synergistic effect of main group organometallic complexes is “ate complex.” As early as the 1950s, the Nobel laureate Wittig coined the term “ate” to refer to the bimetal combinations containing a metal as part of a complex anion. Several other related terms include “mixed complexes,” “bimetallic superbases,” “aggregates,” and so on. In the two huge reviews in 2013, Mongin and Harrison-Marchand suggested naming the dipolar organometallic aggregates as “Mixed AggregAtes” (MAAs).1 These complexes were widely used in metal-halogen exchange, nucleophilic addition, deprotonative metalation, catalytic hydroamination and catalytic hydrogenation reactions, and displayed enhanced reactivities and better selectivities with respect to their monometallic cousins. The synergistic effects in these reactions are easy to find and define; the truth behind the phenomena, however, is much harder to elucidate than expected. There are several excellent reviews about ate complexes and their deprotonative metalation reactions.1,2 From an inorganic-organometallic-structural perspective, Mulvey recently published a detailed review about the synergistic effects in polar main group organometallic chemistry.3 A perspective article by Hevia published very recently provided an overview on cooperative catalysis and their applications.4 To avoid unnecessary repetition, this present review will thus only focus on the essence of the synergistic effects, a mission made more challenging by the different modes of reactivity described by this concept, and the changing mechanistic rationales for such effects over the decades. As a chapter in Comprehensive Organometallic Chemistry, this review will try to present the highlights in the development of ate complexes and provide an overview about the understanding of the synergistic effects that could be a stepping stone for readers to explore in more depth. Furthermore, treatments of specific mixed-metal systems are addressed in Chapters 2 and 5 of this volume.

11.15.2 General properties Even though various combinations of organometallic compounds generate innumerable ate complexes, most of them share formally similar structures: the less electronegative metal cation and the anion part composing the more electronegative metal and the ligands around it. One of the most special features of the ate complexes is that different ate complexes may be formed from the same components simply with different ratio of the two organometallic compounds. As early as 1966, Brown and co-workers established the formation of rapidly equilibrating ate complexes with several distinct stoichiometries of LiR and MR2 (R ¼ Me or Ph, M ¼ Mg or Zn) by detailed 1H and 7Li NMR studies.5 The ate complexes from the same components with different ratios displayed

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Scheme 1 Typical ate complexes and general synergistic effects.

different reactivity in some specific reactions (see Sections 11.15.3). In addition to the typical heterobimetallic ate complexes, the homoaggregates and the ate complexes bearing bridging anion ligands between metals also display similar properties (Scheme 1). The Lewis acidity of the cationic metal and the nucleophilicity and basicity of the anion ligands define the basic functions of the ate complexes. A number of conceptual perspectives as to the origins of synergistic effects have been put forward, and are summarized here (Scheme 1). In a given system, it is often not possible to attribute a specific performance of an ate complex to a single synergistic effect, and in fact a “synergy of synergistic effects” is most probably often operant. Nevertheless, these concepts are useful to both rationalize observed reactivities, and to guide the design of new synergistic systems.

11.15.2.1 Enhanced reactivity When Wittig made the lithium triphenylzincate “LiZnPh3” and the analogous magnesium species “LiMgPh3” by direct combination of their homometallic component compounds in 1951, he noticed the unique reactivity of the phenyl anion ligands and rationalized that in terms of an anionic activation: the negative charge activated all of the ligands surrounding the metal “anionically” through an inductive effect (Scheme 2).6 Tochtermann later in 1966 emphasized this basic concept in a review: as a counterpart to cationic activation in onium-complexes, anionic activation of ligands in ate complexes may facilitate the removal of a ligand as an anion or may lead to an increase in the mobility of hydrogen as hydride on a carbon near the central atom.2d The basicity of the anion ligands could be greatly enhanced as the widely used example of Lochmann-Schlosser superbase: the binary mixture of n-butyllithium and potassium t-butoxide (LIC-KOR).7 This system has been designated as a “superbase” due to its enhanced reactivity of the mixture compared to its component n-butyllithium. In sharp contrast to the reactivity of n-BuLi or t-BuOK, the combined ate complex LIC-KOR could easily deprotonate toluene to afford potassium benzyl.

 Scheme 2 Enhanced nucleophilicity and basicity of an ate complex.

As summarized above, and exemplified in Scheme 2, bimetallic systems often show enhanced reactivity with C—H bonds and electrophiles acquiring significantly greater basicity or nucleophilicity in synergistic systems. This is, however, a simplification; in many cases, bimetallic systems show enhanced but specific reactivity where selectivity is acquired. Examples of such effects can be found in Sections 11.15.3 and 11.15.4. This enhanced reactivity has also had impacts in the field of catalysis by facilitating the reactivity of substrates previously constrained to transition metal catalysts, such as H2 (see Section 11.15.8). Interestingly, there are also some other examples displaying deactivated reactivity of the ate complexes, which could be considered as reflecting enhanced stability.

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11.15.2.2 Enhanced stability Bimetallic systems also often show enhanced stability, rendering them attractive alternatives to highly reactive organolithium reagents, for example, which are profoundly air and moisture sensitive, and often demand energy intensive cryogenic conditions. For example, the complexes made from phenyl lithium or alkyl lithium and lithium bromide could safely be exposed to air, illustrating its considerable stability compared to organolithium compounds.8 As well as effects on the stability of reactants, synergistic effects can also facilitate the formation of otherwise inaccessible synthons by providing subtle control of the thermodynamics of these systems, taming reactants prone to spontaneous decomposition. This is exemplified by the concept of “Cleave-and-Capture” reactivity, where highly reactive fragments are trapped as guests in supramolecular organometallic arrays.9 For example, butyl lithium is generally unstable in tetrahydrofuran due to a-deprotonation and subsequent decomposition of the thermodynamically instable carbanion intermediate. With NadZn ate complex as a base, the deprotonation of tetrahydrofuran took place smoothly to afford a thermodynamically stable carbanion ate complex (Scheme 3). The extraordinary deprotonation ability of an ate complex is not merely promoted by its enhanced basicity. Many ate complexes do not display significantly greater basicity than their compounds, but the deprotonation of some compounds does proceed smoothly. The enhanced stability of the product carbanion complexes could be the key to achieve the deprotonation process with “less basic” compounds. A related concept, “Trans-Metal Trapping,” has extended this to a wide range of otherwise unavailable heterocycle deprotonations where the resultant anions are trapped in ate complexes developed via “frustrated” transmetallations.10

 Scheme 3 Enhanced stability of a NadZn ate complex.

11.15.2.3 Enhanced solubility The enhanced solubility of the ate complexes in organic solutions with respect to its components is very common and always regarded as a reliable indication of the formation of an ate complex. As an early observation, Coates in 1968 found that dimethyl magnesium dissolved better in ether solutions when treated with n-butyllithium.11 Lithium chloride, as an additive, could enhance the solubility of the organomagnesium compounds in their “ate complexes form,” which could be a key factor behind the success of “turbo Grignard reagents.”12 Lithium hydride ((LiH)ꝏ) as an inorganic compound exists in a saline structure like NaCl. The saline structure and its high lattice energy result in the poor solubility in organic solvent and thus this material is essentially inert towards many organic compounds. While LiAlH4, as a commercially available and highly versatile reagent, is well dissolved in several ethereal solvents and is widely used in organic synthesis. The bimetallic compound displays greater solubility than LiH and easier handling and enhanced stability with respect to its aluminum component AlH3 (Scheme 4).

Scheme 4 Enhanced solubility of bimetallic LiAlH4 than saline (LiH)1.

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For another example, Slootweg and Uhl achieved activation of stable saline alkali metal hydrides MH (M ¼ Li, Na, and K) by P/Al-based frustrated Lewis pair (FLP) to afford soluble adducts. The Na-containing adduct smoothly underwent the reaction with chlorotriphenylsilane to afford triphenylsilane with release of NaCl. This reaction between NaH and chlorotriphenylsilane could achieved catalytically with the FLP (10 mol%) as catalyst to give the triphenylsilane in 76% yield. The blank reaction without FLP catalyst proved to be much less effective, suggesting the essential role of the FLP phase-transfer catalyst and synergistic effect of donor and acceptor sites of FLP to dissolve the saline metal hydrides.13 Furthermore, the enhanced solubility of the hydride ate complexes could be a crucial factor for their catalytic activity (see Section 11.15.7).

11.15.2.4 Cooperative activation As an indivisible part of the bimetallic complexes, the less electronegative metal cation does not simply work as a counterion to balance the charge. The Lewis acidity of the cationic metal plays a crucial role for the structure and reactivity of the bimetallic complexes. The intimate association of, for example, a Lewis acidic Li atom with a nucleophilic phenyl substituent bonded to magnesium as shown in Scheme 2 can itself lead to enhanced reactivity, displaying a cationic activation through the inductive effect. The cation M


C p interactions can have profound effects upon the pKa of arene protons rendering otherwise inert substrates amenable to deprotonation (Scheme 5, see Section 11.15.4). The coordination of the metal with a C]C double bond could possibly enhance the electrophilicity of an alkene to facilitate the further insertion reactions (Scheme 5, see Section 11.15.7). Beyond enhancements in reactivity, the coordination of a bimetallic complex with a C]O bond could alter the reaction pathway to afford products distinct from traditional addition products (see Section 11.15.3). The provision of a Lewis acidic “docking site” in a system can allow exquisite control of onward reactivity resulting in unprecedented regioselectivities (see Section 11.15.4).

Scheme 5 Cooperative activation via M


p interactions, AM ¼ alkali metal, M ¼ alkaline earth.

11.15.2.5 Structural templating The source of these enhanced reactivities and solubilities can clearly be attributed to structural changes induced in bimetallic systems. Often these systems are highly dynamic, and clear structural data regarding active species can only be achieved with extensive, careful work. Nevertheless, a number of such studies have been reported and the preeminent class of these are the “inverse crown” systems described by Mulvey and co-workers. In these, and related cases, the synergistic reactivity of the systems can be rationally correlated with their structures, conferring unusual selectivity and reactivity as discussed in Section 11.15.4. For the example of toluene, deprotonation usually takes place on the benzylic CdH bonds to afford benzyl anion. When a sodium magnesium bimetallic complex as a base was used in the deprotonation of toluene, the well-formed ring template of this complex selectively achieved the 2,5-deprotonation of toluene (Scheme 6).14 Another striking example of the structural effects of bimetallic systems is the ability to generate robust single stereoisomers of catalysts via secondary interactions between counterions and ate complexes (see Section 11.15.5).

Scheme 6 Templating deprotonation of toluene with a NadMg bimetallic complex.

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Having summarized some possible synergistic effects, we will describe a number of specific examples of reactivity that is predicated on, or exemplifies unique aspects of such effects.

11.15.3 Nucleophilic addition reactions Commonly used organometallic reagents such as RLi and RMgX, although established to exist in aggregated forms, are usually considered as monometallic compounds (i.e. are not generally considered to belong to the class of multimetallic compounds). Bimetallic or multimetallic compounds, bearing two or more carbon-metal bonds in close proximity in one same molecule, display novel reactivities and possible synergistic effects. In 2001, Xi and co-workers found that the reactions between substituted 1,4-dilithio-1,3-butadienes and benzaldehyde did not give the diol products as expected, but afforded cyclopentadiene derivatives.15 They further carried out the reactions between dilithio reagents with various ketones and aldehydes to give substituted cyclopentadiene products. They then proposed a mechanism as shown in Scheme 7: once one of the two alkenyllithium moieties reacts with the carbonyl group to form a lithium alkoxide intermediate, the remaining alkenyllithium moiety undergoes an intramolecular attack to give cyclopentadiene derivatives. The dilithio reagents were further allowed to react with various unsaturated substrates, such as CO, CO2, and nitriles to yield a wide variety of cyclic compounds with diversified structures.16 This work demonstrated that the dilithio reagents display unique reactivity and could work as useful building blocks in organic synthesis. Xi and co-workers gradually recognized that the cooperative effect between the two CdLi moieties and the butadienyl bridge is essential for their unique reactivity. In 2010, they successfully characterized the dilithio compounds with X-ray diffraction analysis. The dilithio compounds were revealed to exist as their dimer or trimer aggregate structures bridging with carbanion ligands.17 The spatial proximity of the two CdLi moieties could be the key factor of the synergistic effect (referred to as a “cooperative effect” by Xi).

Scheme 7 A unique reactivity of dilithio reagents.

The lithium TMP-zincate “LiZnBut2(TMP)” developed by Kondo and Uchiyama exhibited high levels of chemo- and regioselectivity in aromatic deprotonation reactions.18 The TMEDA adduct of the analogous sodium TMP-zincate was then synthesized, and its crystal structure was determined to have a Na


Me agostic contact as the second bridging interaction other than the TMP anion.19 Mulvey found this complex underwent the 1,6-addition reaction with benzophenone selectively to afford an enolate anion complex.20 Compared with the reactant alkyl sodium zincate complex, the enolate O-bound anion occupies the second bridge position vacated by But ligand. Structural analysis reveals the retention of the connectivity with the remaining backbone of the structure. Given that the homonuclear But2Zn is essentially inert towards benzophenone, the 1,6-addition reaction with benzophenone suggests the synergistic effect of the sodium zincate complex (Scheme 8). Similarly, the neutral arylzinc compound Ph2Zn

Scheme 8 1,6-Addition of a LidZn ate complex to benzophenone.

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itself is unable to transfer its phenyl groups to acridine. The lithium zincate complexes LiZnPh3 and Li2ZnPh4, however, were found to chemoselectively arylate acridine at the 9 position (Scheme 9).21 The enhanced nucleophilicity of higher-order lithium zincate Li2ZnPh4 over its triorgano analogue LiZnPh3 was found, that could easily be explained by its stronger anionic activation effect.

Scheme 9 1,4-Addition of LidZn ate complexes to acridine.

11.15.4 Deprotonative metalation reactions Metalation, an exchange process of metal cations with protons or halogens on organic compounds, produces reactive metallic intermediates, which can be transformed to versatile organic compounds (Scheme 10). Strong basic lithium reagents such as n-BuLi are often applied to the metalation process, but generally demand low reaction temperatures. Besides, the functional group tolerance of this process is very limited. In contrast, ate complexes generated by mixing two organometallic reagents show better selectivity and functional group tolerance under ambient conditions.

Scheme 10 Stoichiometric metalation reaction and transformation.

As mentioned in the general properties of ate complexes, LIC-KOR (the combined ate complex of n-BuLi and t-BuOK) can achieve selective aromatic metalation of toluene derivatives.22 Generally, the binary mixture LIC-KOR exhibits reactivity between that of n-BuLi and n-BuK, which means the enhanced reactivity compared to that of n-BuLi. In 2014, Strohmann and co-workers explored mechanism of deprotonative process of benzene and toluene by n-BuLi/t-BuOK mixed metal reagent: the metalation of benzene afforded a new phenyl KdLi ate complex [(PhK)4(PhLi)(t-BuOLi)(THF)6(C6H6)2] (A) smoothly; metalation of toluene gave the benzylic deprotonation product BnK (B).22c Interestingly, the mixed metal complex A can also act as a “superbase” to deprotonate toluene and produce BnK (B). A possible mechanism was revealed where the benzylic metalation of toluene was effected by two alkali metals as a synergistic hard-soft partnership: potassium (soft) coordinates with and activates the phenyl ring, and the strong basic alkyllithium (hard) deprotonates the benzylic CdH bond of toluene (Scheme 11).

Scheme 11 Synergistic metalation of benzene and toluene with LIC-KOR.

Schlosser compared deprotonative (metal/hydrogen exchange) reactions of 2-m-anisyl-N-pivaloylethylamine with either t-BuLi, n-BuLi or LIC-KOR (Scheme 12). t-BuLi effected the deprotonation of the benzylic CdH bond. Ordinary butyllithium preferred to abstract the proton from the aromatic position ortho to both substitutes. The LIC-KOR, however, reacted with the substrate at extremely different position which is adjacent to the methoxyl group but distant from the alkyl sidechain. The ate complex LIC-KOR displayed not only the enhanced basicity but also the distinct regioselectivity, suggesting the unique synergistic effect of two alkali metals.23

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Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

Scheme 12 Different metalation selectivity of LIC-KOR from simple alkyllithiums.

Alkali-alkaline metal ate complexes were widely applied for selective aryl metalation reactions. As early as the 1990s, Mulvey and co-workers realized metalation of the 1,4-position of benzene and 2,5-position of toluene with the mixed sodium-magnesium reagent “NaMg(n-Bu)(TMP)2” at room temperature, affording the inverse crown ate complexes with a 12-membered (R2N)6Na4Mg2 dicationic ring and a benzene/toluene dianion center.14 As a normal metalation would take place at the benzylic CdH bond of toluene to produce a benzylic anion, this novel ortho-meta-metalation was attributed to a special ring template effect.24 Selective metalation of Group 8 metallocenes also proceeds via a similar process: reaction of sodium butyl, magnesium dibutyl and 3 equiv. of diisopropylamide could afford an ate complex “NaMg(NiPr2)3,” which deprotonates 1,10 ,3,30 -positions of metallocenes (Cp2M, M ¼ Fe, Ru, and Os) (Scheme 14). Three metalation products existed inverse crown structures: a [(NaNMgN)4]4+ cation forms the 16-membered host ring with a guest anion [M(C5H3)2]4− as a center.25 In 2014, they further extended the substrates to naphthalene, anisole, amides and N,N-dialkylanilines to afford various inverse crown systems (Scheme 13).26 The concept of template metalation is elaborated through the characterization of both deprotonative organometallic intermediates and electrophilically quenched products.27 This unique template metalation process not only breaks the dogma of ortho metalation, creating new deprotonation selectivity, but also delivers a protocol for synthesis of difunctionalized arene derivatives.

Scheme 13 Inverse crown complexes synthesized by a mixed NadMg complex.

The Mulvey group, in 2005, synthesized and characterized a TMEDA coordinated NadMg butyl amido ate complex, which was used for the selective meta-deprotonation of toluene at room temperature.28 The structure analysis of the product indicates the direct replacement of a butyl group by an aryl group, while the amide groups are retained unchanged. It is generally difficult for alkali metal reagents to deprotonate toluene at the meta-position, showing the advantages of bimetallic systems. Density functional theory (DFT) calculations suggests that the Na


C p-interaction of toluene in the meta deprotonation product is most stable in the possible deprotonation products (Scheme 15).

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

613

Scheme 14 Selective metalation of metallocenes by NaMg(N(i-Pr)2)3.

Scheme 15 Selective deprotonation of toluene and relative energies.

In the two processes above, arenes could be coordinated and preactivated by the Lewis acidic sodium cation of the ate complex by M


C(arene) p-interaction, and then the highly active butyl group connected to magnesium deprotonates CdH bonds of arenes, realizing the bimetallic synergistic deprotonative metalation process. It is worth noting that benzene without activating or directing substitutions is generally difficult to be deprotonated due to its low acidity (pKa  43). The single components of ate complexes like alkali metal butyls accomplish the deprotonation process of toluene via formation of the stabilized benzylic anion PhCH−2 preferentially under harsh conditions, and magnesium compounds could not realize this process because of its low bond polarity and weak basicity. In contrast, the ate complexes realize the processes effectively and selectively under mild conditions. Such different performance of multimetallic and monometallic system in arene deprotonation reactions possibly due to disparate nature of the metal nodes and the product stabilization by 2-fold s- and p-bonds of the ate complexes, which hints at the alkali-alkaline bimetallic synergistic effect. In 2007, Naka, Uchiyama and Wheatley designed, synthesized and characterized a new LidAl ate complex [(i-Bu)3Al(TMP)Li].29 This ate complex was an effective and regioselective alumination reagent for a variety of aromatic compounds and functionalized allylic compounds and delivered multi-substituted aromatic and allylic compounds (Scheme 16a and b). DFT calculations on [Me3Al(Me2N)LiOMe2] as metalation reagent and anisole as substrate showed Lewis acidic Li+ cation facilitated “molecular recognition” by acting as a binding position for electronegative groups, coordinating with the OMe group, which directed ortho aromatic CdH bond deprotonation by the amide connected to aluminum. Furthermore, FT-IR, NMR, and X-ray diffraction analyses also proved that the directed ortho-metalation (DoM) was induced by LidAl bimetallic synergistic effect and aluminum amide was the deprotonating group (Scheme 16c). In 2014, Mulvey, Ramsay and co-workers studied this metalation process of anisole with experimental methods and calculations in detail, showing that the ate complex [(i-Bu)3Al(TMP)Li] has four structures in THF, and structure-defined [(i-Bu)3Al(TMP)Li] itself could not mediate the ortho-directed metalation of anisole.30 In contrast to previous investigations, they proposed a new process for this “black box chemistry”: only the lithium amide LiTMP was capable of metallating anisole but in low yield; the lithiated anisole intermediate was quickly trapped by an alkylaluminium species (termed as trans-metal-trapping), which continuously drives on the reaction to afford “aluminated” anisole in a high yield.

614

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

(A)

(B)

(C)

Scheme 16 Selective metalation of aromatic and allylic compounds by LidAl ate complexes.

Kondo and co-workers reported alkali metal-mediated zincation reactions of arenes in 1999.31 In this work, the ate complex [LiZnTMP(t-Bu)2] was used for directed metalation of arenes, and the metalation products could produce multi-substituted arene derivatives by cross-coupling reactions or nucleophilic reactions. Various substrates including carbonates, aryl nitriles, pyridines, furans and thiophenes undergoes the deprotonative metalation with this lithium zincate complex (Scheme 17).

Scheme 17 Directed ortho-metalation of arenes by [LiZnTMP(t-Bu)2].

In 2003, Mulvey group treated KHMDS and Zn(HMDS)2 in excess toluene to achieve the benzylic deprotonation reaction, affording the KdZn ate complex [KZn(HMDS)2(CH2Ph)]1 (Scheme 18).32 In contrast, KHMDS and Zn(HMDS)2 alone could not realize this process. They proposed that the reaction between KHMDS and Zn(HMDS)2 delivered ate complex “KZn(HMDS)3,” one amide of which deprotonated the benzylic C(sp3)dH bond of toluene and afforded [KZn(HMDS)2(CH2Ph)]1. However, the magnesium analogue KMg(HMDS)3 only gave the solvent coordinated product {[K(toluene)2]+[Mg(HMDS)3]−}1 in toluene, not the corresponding toluene deprotonation product, suggesting the metal center of the ate complexes has significant influence in synergistic metalation.33

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

615

Scheme 18 Synergistic benzylic metalation of toluene by a KdZn ate complex and the comparison with its magnesium analogue.

In 2005, a new amide (TMP) and alkyl (t-Bu) bridged NadZn ate complex [Na(m-t-Bu)(m-TMP)Zn(t-Bu)
TMEDA] was synthesized by Mulvey and co-workers, which metalated the benzene C(sp2)dH bond at room temperature to give [Na(m-t-Bu) (m-Ph)Zn(t-Bu)
TMEDA] (Scheme 19a).34 In this reaction, a tert-butyl group was replaced by a phenyl group, and the amide remained. A DFT calculation study suggested a tert-butyl group deprotonating the aryl CdH bond requested less energy, consistent with the experiment results. Single component Zn(t-Bu)2 or NaTMP could not realize this metalation process, indicating obvious synergistic effect of the ate complex. Similarly, [Na(m-t-Bu)(m-TMP)Zn(t-Bu)
TMEDA] could also synergistically deprotonate meta-position of N,N-dimethylaniline35 and 1,4-position of benzene.36 In addition, Mulvey and co-workers also reported directed ortho-metalation of tetrahydrofuran (or tetrahydropyran) by [(TMEDA)Na(m-TMP)(m-CH2TMS) Zn(CH2TMS)], affording an ate complex containing a tetrahydrofuran (or tetrahydropyran) anion group.9a These results were quite different from alkali metal reagents, which consistently led to ring-opening of tetrahydrofuran (Scheme 19b and c).

(A)

(B)

(C)

Scheme 19 Synergistic metalation of benzene and THF by NadZn ate complex.

616

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

Knochel and co-workers utilized a series of “turbo” reagents such as [TMPMgCl
LiCl], [i-PrMgCl
LiCl], [TMPZnCl
LiCl], and [TMP2Zn
2MgCl2
2LiCl] in the chemoselective metalation of aryl (or heteroaryl) CdH or CdX bond. The metalation intermediates were widely used in the synthesis of various substituted arenes.2b,37 Mild conditions, high selectivity and good functional group tolerance of metalation reactions made this method attractive for the synthesis of arene derivatives (Scheme 20). Extra addition of lithium salts is the main reason for divergent reactivity of these turbo reagents compared to traditional organometallic reagents like Grignard reagents, which may be because of enhanced Lewis acidity, formation of cationic centers and/or activation of the substrates.

Scheme 20 Selective metalation of isoquinoline by “turbo” reagents.

Quite different from Lochmann-Schlosser superbase (n-BuLi + t-BuOK), these amide magnesiates, aluminates, and zincates actually did not have obviously reactive anion ligands. Yet the efficient and selective deprotonation reactions of these ate complexes revealed their enhanced basicity. Mulvey, in a review in 2006, summarized three key aspects of the synergic effects of the ate complexes in the deprotonative metalation reactions: 1, the intimate contact between the two metals through bridging ligands; 2, the coordination of the substrate with the alkali metal through M


p interaction or agnostic interactions; 3, the alkali-metal-mediated metalation takes place and gives the deprotonation complexes with lower entropy.3a Given the synergistic effects, the ate complexes, regardless of their components, could achieve the deprotonative metalations selectively under mild conditions, providing powerful and versatile tools in organic synthesis.

11.15.5 Catalytic enantioselective reactions Shibasaki and co-workers have reported a series of enantioselective reactions, including Michael addition, aldol condensation and hydrophosphination reactions, catalyzed by chiral BINOL supported alkali metal-rare earth metal ate complexes.38 In 1993, they reported the LidLa ate complex (R)-LLB catalyzed the reactions between nitromethanes and aldehydes. The reactions afforded alcohols enantioselectively with ee values up to 97%.38a In 1997, they further achieved enantioselective aldol reaction by using the (R)-LLB catalyst (Scheme 21). The reaction had wide substrate scope, including various alkyl/aryl aldehydes/ketones.38b In addition, catalytic amounts of alkali metal amides (like KHMDS) added to this reaction could enhance the catalytic activity to achieve high yields and better enantioselectivity. Generally, simple BINOL could not provide a chiral environment good enough for an enantioselective transformation. That is also the reason that many chemists took a lot effort for the modification of BINOL at the 3,30 -positions and 6,60 -positions to tune its steric and/or electronic properties. Shibasaki’s binol/La catalyst skillfully used the bridging coordination of the phenol anion to lithium and lanthanum to construct three BINOL moieties around the lanthanum metal center. Two of the BINOL moieties together with the lithium cation built an excellent chiral environment for the catalytic enantioselective reactions.

Li O O Li O La O O O Li (R)-LLB

Scheme 21 BINOL supported LidLa ate complex for catalytic enantioselective aldol reactions.

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

617

11.15.6 Catalytic hydroamination reactions From 2012 to 2018, Westerhausen and co-workers investigated a new KdCa amide ate complex {K2Ca[N(H)Dipp]4}1, in catalytic hydroamination of diphenyl diacetylene and aryl amines.39 CaI2 was allowed to react with excess potassium 2,6-diisopropylphenylamide and afforded {K2Ca[N(H)Dipp]4}1, which could effectively catalyze intermolecular hydroamination of diphenyl diacetylene and 2,6-diisopropylaniline and give tetracyclic compounds.39b In 2018, using the ate complex as catalyst they achieved hydroamination of diphenyl diacetylene and 1,2-bis(anilino)ethane.39d Controlling the ratio of alkyne and amine, mono- and di-hydroamination products could be obtained (Scheme 22).

iPr iPr NH

* Pri

Dipp NH

Ca

HN Dipp

NH

K

iPr

K HN Dipp

Pri

Dipp NH

Ca

HN iPr

N Dipp H

∞

Scheme 22 {K2Ca[N(H)Dipp]4}1 catalyzed hydroamination of diacetylene with anilines.

In 2013, Hevia and co-workers reported [NaMg(CH2TMS)3] catalyzed hydroamination of isocyanates by diarylamines to afford urea derivatives (Scheme 23a).40 Most substrates smoothly underwent the hydroamination reactions and gave corresponding products. However, when using 2,20 -dipyridylamine, the yield significantly decreased, which could be due to the coordination of pyridine to Na+ and influence of isocyanate coordination, indicating the essential role of the alkali metal center. In 2016, they also achieved hydroamination of carbodiimides by primary amines to afford guanidinates (Scheme 23b).41 A synergistic double Lewis acid-Lewis base activation of the NadMg complex is proposed for these catalytic processes: the cationic Lewis acid sodium center enables activation of the electrophilic isocyanate or carbodiimide substrates by coordination, facilitating their approach to the reactive Lewis base bound to the magnesium center and promoting the hydroamination reactions. (A)

(B)

Scheme 23 [NaMg(CH2TMS)3] catalyzed hydroamination of isocyanates and carbodiimides.

In 2019, the Hevia group reported [AMMgR3] (AM ¼ Li, Na, K, R ¼ CH2TMS) catalyzed hydroamination of alkynes and piperidine to afford mixed E- and Z-products, where C6D6 was the most suitable solvent (Scheme 24a).42 The ate complexes [(donor)2AM2MgR4] (AM ¼ Li, Na, donor ¼ TMEDA; AM ¼ K, donor ¼ PMDETA) were also applied to catalytic hydroamination of 1,2-diphenylacetylene and secondary cyclic amines, and the K2dMg complex was the most effective in both yield and E/Z selectivity. When 18-crown-6 was added to the K2dMg catalyst, the yield of hydroamination product was dramatically decreased, suggesting the essential role of potassium for catalysis. In addition, [(PMDETA)2K2MgR4] could also effectively catalyze the

618

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

(A)

(B)

Scheme 24 Magnesiate complexes catalyzed hydroamination of alkynes and styrene.

hydroamination of styrene and piperidine (Scheme 24b). The authors also indicated the alkali metal in the ate complex can act as Lewis acid site and active the unsaturated substrates, accelerating nucleophilic process of the anion groups connected to magnesium (Lewis base site) to the substrates. The results above suggested the synergistic effect of ate catalysts in the catalytic hydroamination reactions.

11.15.7 Catalytic hydroboration reactions Three LidAl hydride ate complexes were shown to catalyze hydroboration of unsaturated compounds by Mulvey and co-workers in 2018 (Scheme 25).43 In these reactions, the corresponding neutral aluminum alkyls or amides were compared with the ate complexes, and these ate complexes were obviously better for most unsaturated substrates, suggesting the synergistic effect of Li

Scheme 25 LidAl hydride ate complexes catalyzed hydroboration of carbonyl compounds.

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

619

and Al. For substrates, besides easily reactive aldehydes and ketones, more challenging imines and alkynes can also undergo the hydroboration reactions. The proposed mechanism suggested that the TMP group in the ate complex can deprotonate the NdH of the imine to produce intermediate I. Lithium in the intermediate may control different molecular charge distribution from the monometallic aluminum hydride, which clearly facilitates the hydroboration step. In the same year, they further reported LidAl diamide ate complexes catalyzed hydroboration of aldehydes and ketones.44 In 2016, Okuda and co-workers synthesized and characterized three alkali metal hydridotriphenylborates [(L)AM][HBPh3] (AM ¼ Li, Na, K, L ¼ Me6TREN) and these complexes could catalyze hydroboration by HBpin of a series of carbonyl compounds including aldehydes, ketones and even CO2 (Scheme 26).45 The lithium complex showed high TOF of 17 s−1. Hydroboration of CO2 afforded formoxylborane HCO2Bpin without any over-reduction product. The high activity of these reactions was due to the combination of the Lewis acidic alkali metal and the hydride borate, which is synergistic effect of alkali metals and boron. (A)

(B)

C)

Scheme 26 Borohydride complexes catalyzed hydroboration of carbonyl compounds.

11.15.8 Catalytic hydrogenation reactions LiAlH4, a commercially available LidAl hydride ate complex, in itself could achieve catalytic hydrogenation reactions. For example, Slaugh reported LiAlH4 catalyzed hydrogenation of alkenes and alkynes in 1966.46 Though the hydrogenation required harsh conditions and produced low conversions, a LidAl bimetallic mechanism was proposed. In 2018, Harder and co-workers achieved LiAlH4 catalyzed hydrogenation of imines. Influences of temperature, solvent, H2 pressure, catalyst and substrate scope were discussed in detail.47 A plausible mechanism was proposed on the basis of the experimental research and DFT calculations (Scheme 27). The direct addition of LiAlH4 to the imine generated a dihydride intermediate LiAlH2[N(t-Bu)CH2Ph]2. The coordination of the imine with the lithium cation could facilitate the further addition reaction to afford the Al[N]3LiH, could heterolyse H2 to close the catalytic cycle.

Scheme 27 LiAlH4 catalyzed hydrogenation of imines and the proposed mechanism.

620

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

In 2019, we synthesized a KdY benzyl ate complex [KY(HMDS)3Bn] by mixing Y(HMDS)3, BnK and 2 equiv. THF in toluene. The benzyl ate complex underwent peripheral deprotonation to produce a cyclometalated complex or hydrogenation to afford a hydride ate complex. The latter hydride ate complex features a (KH)2 structure protected by two yttrium amide complexes. The synergistic effect between potassium hydride and the amide ligand enables the complex to deprotonate a methyl CdH bond. The cyclometalated complex and the hydride ate complex could also interconvert reciprocally by addition or removing H2, which constituted a reversible H2 activation process (Scheme 28). Through this process, the KdY hydride ate complex could efficiently catalyze hydrogenation of alkenes, alkynes and imines under mild conditions. The reaction between 1,1-diphenylethylene and the KdY hydride ate complex afforded the hydrogenation product and the KdY cyclometalated complex, indicating that the peripheral deprotonation took place before hydrogenation, and the KdY cyclometalated complex acted as an essential intermediate.48

(A)

(B)

(C)

Scheme 28 Reversible H2 activation by KdY ate complexes.

In hydrogenation reactions, alkali metal hydrides show poorer activity than molecular alkaline-earth metal hydrides because of their saline structures (MH)1 and large lattice energies. In 2020, we further reported the efficient hydrogenation of various styrenes and a-alkenes with the combined catalysts of KH and alkaline-earth amides [Ca(HMDS)2
(THF)2 or Mg(HMDS)2
Et2O]. Hydrogenation reactions reported by Harder and co-workers with simple alkaline-earth metal amide catalysts showed much better activity of barium amide compared to its magnesium and calcium homologues. In contrast, the combined catalysts showed much better activity than their components, suggesting the obvious synergistic effect. Initial mechanistic research revealed a degradation and activation effect of the alkaline-earth metal amides on saline (KH)1 (Scheme 29).49 As we mentioned in the general properties part, the enhanced solubility of the ate complexes was commonly detected in their preparation. Considering the saline structure and poor reactivity of the hydrides of s-block metals (MH)1 and (MH2)1, the formation of the ate complexes not only provides enhanced solubility but also facilitates kinetic reactivity.

Scheme 29 Combined KH/Alkaline-earth metal catalysts for hydrogenation of alkenes.

11.15.9 Catalytic CdC bond formation reactions The potassium yttrium ate complex as a catalyst was also applied in the reaction between 2-ethylpyridine and styrene, and the catalytic alkylation product was obtained in a good yield of 86%. Either the yttrium amide and or potassium benzyl individually failed to catalyze the desired reaction. The synergistic effect was also found on the combination of potassium benzyl and magnesium amide or zinc amide, suggesting that the unique and general catalytic activity of the ate complexes (Scheme 30). Finally, the potassium amide itself could serve as an efficient catalyst for the benzylic CdH bond addition of various alkyl pyridines to styrenes.50

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

621

Scheme 30 Catalytic benzylic CdH addition of 2-ethyl pyridine to styrene.

In contrast to the deprotonation discussed earlier, potassium amide actually failed to undergo the deprotonation of 2-methyl pyridine. The possible intermediate potassium picoline 1 h-K was prepared via the deprotonation of 2-methyl pyridine with LIC-KOR. The acid-base reaction between potassium picoline and hexamethyldisilazane (HMDS) immediately produced 2-methyl pyridine and KHMDS, revealing the alkylpyridine and potassium amide as the thermodynamic stable side in the deprotonation equilibrium (Scheme 31a). We further compared the catalytic activity of the potassium picoline and potassium amide in the alkylation of 2-methyl pyridine with styrene. The potassium alkyl catalyst quickly consumed most of the styrene and 2-methylpyridine but only produced the alkylation products in a low yield of 20% (Scheme 31b). The potassium amide catalyst slowly but smoothly and selectively converted the reagents to the alkylation product (Scheme 31c).

Scheme 31 Deprotonative alkylation of 2-picoline with potassium alkyl and potassium amide.

Based on these observations, we proposed a possible mechanistic process composed of kinetic deprotonation of alkyl pyridine, insertion or addition to styrene and the protonation of the potassium alkyl intermediate (Scheme 32). The relative weak base potassium amide, which introduces a deprotonation equilibrium, is the key for the excellent reactivity and selectivity in this kinetic deprotonative functionalization reaction.51 Although potassium amide served as the efficient catalyst, we could not exclude the possibility that KHMDS worked in its ate complex form. Credence is lent to this proposal as the alkali metal amides usually exist as dimeric structures through the strong bridging coordination of the amide anions.

622

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

Scheme 32 A possible mechanism via kinetic deprotonative functionalization.

We soon found some hints in the catalytic a-alkylation reaction of benzyl sulfides and 1,3-dithianes with styrenes.52 Similar with the catalytic alkylation of alkylpyridine, potassium amide failed to deprotonate benzyl phenyl sulfide but formed a deprotonative equilibrium. Removing the volatiles from the reaction mixture of KHMDS and benzyl phenyl sulfide, however, generated a red oil, which was later proved to be the mixture of KHMDS and the deprotonation intermediate. We have made great efforts to crystallographically characterize this material but unfortunately failed. However, the 1H-DOSY NMR spectrum was performed and suggested that the KHMDS species and K-1a (Scheme 33) species did belong to the same molecule as an ate complex. The deprotonation of sulfide with LIC-KOR in n-hexane gave an orange precipitate, which failed to catalyze the alkylation reaction. Once treated with KHMDS, the undissolved orange solid was dissolved in Et2O and afforded a red solution of the ate complex (K-1a
KHMDS), which could successfully catalyze the alkylation reaction and might be the true catalyst. Ar +

H

Ar’

Ph 3aa

SPh Ph path A

Ar’

53 examples up to 99% yield

DOSY 1H NMR

H 1a

-9.5 -9.4

H N

Me3Si K-3aa • KHMDS

Ph

2 KHMDS

RS

Et2O, 40 ºC, 22 h

SPh H

H

-9.3

SiMe3

1a

-9.2 -9.1

path B

K-1a • KHMDS

-9.0

KHMDS

K-1a species

3aa

logD/(m2/s)

RS

Ar

KHMDS (10 mol %)

-8.9 -8.8 -8.7

Ph 2a

-8.6 9.0

7.5

6.0

4.5 3.0 H/ppm

1.5

0.0

Scheme 33 KHMDS catalyzed alkylation of benzyl phenyl sulfides.

On the basis of the above-described results, we propose the reaction pathway, similar to the catalytic alkylation of alkylpyridines, but featuring the dimeric potassium amide catalyst (Scheme 34). One of the two KHMDSs undergoes the coordination and deprotonation with benzyl phenyl sulfide to afford an alkyl potassium intermediate K-1a, which would intermediately coordinate with another KHMDS to form the ate complex as the true catalyst to complete the catalytic cycle.

Scheme 34 [KZn(HMDS)2Bn] catalyzed benzylic CdH bond addition of diarylmethanes to styrenes.

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

623

To further probe the catalytic activity of ate complexes, we turned to a well-defined KdZn ate complex [KZn(HMDS)2Bn] which was previously synthesized by Mulvey via the deprotonation of toluene with KZn(HMDS)3.32 Through the combination of potassium benzyl and zinc amide, we could achieve the synthesis of the potassium zincate complex directly and efficiently. This potassium zincate complex displayed excellent catalytic activity in the benzylic C(sp3)dH bond addition of diarylmethanes to styrenes (Scheme 34).53 Compared with the direct benzyl C(sp3)dH functionalization of diarylmethanes in the present of stoichiometric strong bases or oxidants, this work provided an effective, atom-economic and practical approach for synthesis diarylmethane derivatives. Preliminary mechanism research suggested the diarylmethane benzyl C(sp3)dH bond was deprotonated by the benzyl ate complex to afford the diarylmethyl ate complex as the true catalyst. The further insertion of styrene and deprotonation of diarylmethane generated the product and completed the catalytic cycle. In the same year, Kobayashi and co-workers realized the mixed t-BuOK/LiTMP catalyzed benzyl C(sp3)dH bond addition of substituted toluenes to imines or alkenes under mild conditions (Scheme 35). On account of the very weak acidity of toluene benzyl CdH bonds, simple bases including t-BuOK and LiTMP could not individually achieve this catalytic addition process compared with the mixed base t-BuOK/LiTMP, indicating the bimetallic synergistic effect.54 Variable substituted toluenes smoothly underwent the mixed base-catalyzed direct addition to N-p-methoxycumylimines at −40  C or stilbenes at above 0  C. When ethyl or isopropyl groups were located on the para-position of toluene, only the CdH bonds of methyl groups were activated and reacted with imines to afford the addition products. Catalytic addition of ethylbenzene to imines gave syn-adduct as a main product. The results above demonstrate the dramatic regio- and diastereo-selectivities of the mixed base-catalyzed addition reactions without extra ligands. In addition, the asymmetric addition was also revealed using a chiral potassium amide generated from KCH2SiMe3 and a chiral diamine with the enantioselectivity of 56% ee. A plausible mechanism was proposed (Scheme 35). Firstly, the strong mixed base M-TMP (M: Li and K mixture) was generated from t-BuOK/LiTMP mixture, then M-TMP deprotonates toluene benzylic C(sp3)dH bond to afford benzylic metal intermediate. After insertion of imines or alkenes, the “product base” can be formed, which undergoes deprotonation of (H)TMP or toluene to give the addition product.

Scheme 35 t-BuOK/LiTMP catalyzed benzyl CdH bond addition of toluenes to imines or alkenes.

11.15.10

Conclusion and outlook

In summary, the synergistic effects of multimetallic main group complexes are essential in organic synthesis and widely applied in stoichiometric and catalytic reactions. As discussed previously, the synergistic effects are not supernatural phenomena beyond our understanding. When a transition metal meets a ligand, the newly generated complex usually displays distinct reactivities and selectivities. This is generally viewed as unsurprising as the structural details and their consequent relationships with activity are reasonably deduced. For the ate complexes, the lack of structural characterization remains a great challenge to understand the structure-activity relationship. Dipolar organometallic compounds generally interact each other via bridged coordination to form

624

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis

multimetallic ate complexes and even polymeric structures through infinite repeated aggregations. The mix of two organometallic compounds and substrates leads to many possibilities. Considering of the broad choice of organometallic compounds, the combinations could provide almost limitless possibilities. The nuanced grasp of solution behavior demanded by the complexity of the ate complexes also brings some barriers on the way. When two organometallic compounds are mixed and endowed with synergistic effects, the two compounds were not simply “mixed” but undergo a chemical transformation to afford a new complex. The newly formed complex has a distinct, although not always fully elucidated, structure from its components, and naturally displays different reactivity. This can be regarded as the consequence of the synergistic effects. In this review, we outline several representative synergistic effects: Lewis acidity of the cation, enhanced reactivity of the anion ligand, enhanced stability and solubility, cooperative activation, template effects and so on. We would like to emphasize the coordination from a polar main group metal organometallic compound to a reactive organometallic species. This coordination provides a protection effect to the reactive species to form an ate complex bearing interesting thermodynamic stability and kinetic reactivity, which can play a crucial role in selective catalytic transformations. With the development of main group organometallic chemistry, chemists are getting better understandings about the structure of the ate complexes and the synergistic effects. We believe that in the near future the synergistic effects could be well-controlled, rationally designed and applied in more catalytic transformations. As Mulvey pondered in a review,3c a “Pairiodic Table of Element Pairs” in the future could probably provide a better guide, which definitely demands more efforts and patience.

Acknowledgments We gratefully acknowledge the generous start-up financial support from Fudan University and the support from the National Natural Science Foundation of Tianjin (No. 19JCYBJC20100). We gratefully thank Dr. David J. Liptrot (University of Bath) and Prof. Zhenfeng Xi (Peking University) for their constructive discussions about “synergistic effects.” We acknowledge Dr. David J. Liptrot for his kind modification and proof-reading of this review.

References 1. (a) Harrison-Marchand, A.; Mongin, F. Chem. Rev. 2013, 113, 7470–7562; (b) Mongin, F.; Harrison-Marchand, A. Chem. Rev. 2013, 113, 7563–7727. 2. (a) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802–3824; (b) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 9794–9824; (c) Chevallier, F.; Mongin, F.; Takita, R.; Uchiyama, M. In Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds; Mortier, J., Ed.; John Wiley & Sons Inc., 2015; pp 777–812; (d) Tochtermann, W. Angew. Chem., Int. Ed. 1966, 5, 351–371; (e) Weiss, E. Angew. Chem., Int. Ed. 1993, 32, 1501–1523 3. (a) Mulvey, R. E. Organometallics 2006, 25, 1060–1075; (b) Mulvey, R. E. Acc. Chem. Res. 2009, 42, 743–755; (c) Robertson, S. D.; Uzelac, M.; Mulvey, R. E. Chem. Rev. 2019, 119, 8332–8405. 4. Gil-Negrete, J. M.; Hevia, E. Chem. Sci. 2021, 12, 1982–1992. 5. (a) Seitz, L. M.; Brown, T. L. J. Am. Chem. Soc. 1966, 88, 4140–4147; (b) Seitz, L. M.; Brown, T. L. J. Am. Chem. Soc. 1967, 89, 1602–1607. 6. (a) Wittig, G.; Meyer, F. J.; Lange, G. Justus Liebigs Ann. Chem. 1951, 571, 167–201; (b) Wittig, G. Angew. Chem. 1958, 70, 65–71. 7. (a) Lochmann, L.; Pospíšil, J.; Lím, D. Tetrahedron Lett. 1966, 7, 257–262; (b) Lochmann, L.; Janata, M. Open Chem. 2014, 12, 537–548. 8. Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436–4437. 9. (a) Kennedy, A. R.; Klett, J.; Mulvey, R. E.; Wright, D. S. Science 2009, 326, 706–708; (b) Mulvey, R. E.; Blair, V. L.; Clegg, W.; Kennedy, A. R.; Klett, J.; Russo, L. Nat. Chem. 2010, 2, 588–591. 10. Uzelac, M.; Mulvey, R. E. Chem. Eur. J. 2018, 24, 7786–7793. 11. Coates, G. E.; Heslop, J. A. J. Chem. Soc. A 1968, 514–518. 12. (a) Li-Yuan Bao, R.; Zhao, R.; Shi, L. Chem. Commun. 2015, 51, 6884–6900; (b) Ziegler, D. S.; Wei, B.; Knochel, P. Chem. Eur. J. 2019, 25, 2695–2703. 13. Appelt, C.; Slootweg, J. C.; Lammertsma, K.; Uhl, W. Angew. Chem., Int. Ed. 2012, 51, 5911–5914. 14. Armstrong, D. R.; Kennedy, A. R.; Mulvey, R. E.; Rowlings, R. B. Angew. Chem., Int. Ed. 1999, 38, 131–133. 15. Xi, Z.; Song, Q.; Chen, J.; Guan, H.; Li, P. Angew. Chem., Int. Ed. 2001, 40, 1913–1916. 16. (a) Xi, Z. Eur. J. Org. Chem. 2004, 2004, 2773–2781; (b) Xi, Z. Acc. Chem. Res. 2010, 43, 1342–1351. 17. Liu, L.; Zhang, W.; Luo, Q.; Li, H.; Xi, Z. Organometallics 2010, 29, 278–281. 18. (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539–3540; (b) Imahori, T.; Uchiyama, M.; Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450–2451; (c) Uchiyama, M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514–8515. 19. Andrikopoulos, P. C.; Armstrong, D. R.; Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. J. Am. Chem. Soc. 2005, 127, 6184–6185. 20. Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. J. Am. Chem. Soc. 2005, 127, 13106–13107. 21. Hernán-Gómez, A.; Herd, E.; Uzelac, M.; Cadenbach, T.; Kennedy, A. R.; Borilovic, I.; Aromί, G.; Hevia, E. Organometallics 2015, 34, 2614–2623. 22. (a) Fleming, P.; O’Shea, D. F. J. Am. Chem. Soc. 2011, 133, 1698–1701; (b) Blangetti, M.; Müller-Bunz, H.; O’Shea, D. F. Chem. Commun. 2013, 49, 6125–6127; (c) Unkelbach, C.; O’Shea, D. F.; Strohmann, C. Angew. Chem., Int. Ed. 2014, 53, 553–556. 23. Schlosser, M.; Simig, G. Tetrahedron Lett. 1991, 32, 1965–1966. 24. Mulvey, R. E. Chem. Commun. 2001, 1049–1056. 25. Andrikopoulos, P. C.; Armstrong, D. R.; Clegg, W.; Gilfillan, C. J.; Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T.; Parkinson, J. A.; Tooke, D. M. J. Am. Chem. Soc. 2004, 126, 11612–11620. 26. Martínez-Martínez, A. J.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T. Science 2014, 346, 834–837. 27. Martínez-Martínez, A. J.; Justice, S.; Fleming, B. J.; Kennedy, A. R.; Oswald, I. D. H.; O’Hara, C. T. Sci. Adv. 2017, 3, e1700832. 28. Andrikopoulos, P. C.; Armstrong, D. R.; Graham, D. V.; Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T.; Talmard, C. Angew. Chem., Int. Ed. 2005, 44, 3459–3462. 29. Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley, A. E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc. 2007, 129, 1921–1930. 30. Armstrong, D. R.; Crosbie, E.; Hevia, E.; Mulvey, R. E.; Ramsay, D. L.; Robertson, S. D. Chem. Sci. 2014, 5, 3031–3045.

Synergistic Effects of Multimetallic Main Group Complexes in Organic Synthesis 31. 32. 33. 34. 35. 36. 37. 38. 39.

40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.

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Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539–3540. Clegg, W.; Forbes, G. C.; Kennedy, A. R.; Mulvey, R. E.; Liddle, S. T. Chem. Commun. 2003, 406–407. Forbes, G. C.; Kennedy, A. R.; Mulvey, R. E.; Roberts, B. A.; Rowlings, R. B. Organometallics 2002, 21, 5115–5121. Andrikopoulos, P. C.; Armstrong, D. R.; Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. J. Am. Chem. Soc. 2005, 127, 6184–6185. Hevia, E.; Kennedy, A. R.; McCall, M. D. Dalton Trans. 2012, 41, 98–103. Armstrong, D. R.; Clegg, W.; Dale, S. H.; Graham, D. V.; Hevia, E.; Hogg, L. M.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. Chem. Commun. 2007, 598–600. (a) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7681–7684; (b) Klier, L.; Ziegler, D. S.; Rahimoff, R.; Mosrin, M.; Knochel, P. Org. Process Res. Dev. 2017, 21, 660–663; (c) Ziegler, D. S.; Karaghiosoff, K.; Knochel, P. Angew. Chem., Int. Ed. 2018, 57, 6701–6704. (a) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372–10373; (b) Hultzsch, K. C.; Spaniol, T. P.; Okuda, J. Organometallics 1997, 16, 4845–4856; (c) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117–1127. (a) Glock, C.; Görls, H.; Westerhausen, M. Chem. Commun. 2012, 48, 7094–7096; (b) Glock, C.; Younis, F. M.; Ziemann, S.; Görls, H.; Imhof, W.; Krieck, S.; Westerhausen, M. Organometallics 2013, 32, 2649–2660; (c) Younis, F. M.; Krieck, S.; Görls, H.; Westerhausen, M. Dalton Trans. 2016, 45, 6241–6250; (d) Ziemann, S.; Krieck, S.; Görls, H.; Westerhausen, M. Organometallics 2018, 37, 924–933. Hernán-Gómez, A.; Bradley, T. D.; Kennedy, A. R.; Livingstone, Z.; Robertson, S. D.; Hevia, E. Chem. Commun. 2013, 49, 8659–8661. De Tullio, M.; Hernán-Gómez, A.; Livingstone, Z.; Clegg, W.; Kennedy, A. R.; Harrington, R. W.; Antiñolo, A.; Martínez, A.; Carrillo-Hermosilla, F.; Hevia, E. Chem. Eur. J. 2016, 22, 17646–17656. Davin, L.; Hernán-Gómez, A.; McLaughlin, C.; Kennedy, A. R.; McLellan, R.; Hevia, E. Dalton Trans. 2019, 48, 8122–8130. Pollard, V. A.; Fuentes, M.Á.; Kennedy, A. R.; McLellan, R.; Mulvey, R. E. Angew. Chem., Int. Ed. 2018, 57, 10651–10655. Pollard, V. A.; Orr, S. A.; McLellan, R.; Kennedy, A. R.; Hevia, E.; Mulvey, R. E. Chem. Commun. 2018, 54, 1233–1236. Mukherjee, D.; Osseili, H.; Spaniol, T. P.; Okuda, J. J. Am. Chem. Soc. 2016, 138, 10790–10793. Slaugh, L. H. Tetrahedron 1966, 22, 1741–1746. Elsen, H.; Färber, C.; Ballmann, G.; Harder, S. Angew. Chem., Int. Ed. 2018, 57, 7156–7160. Zhai, D.; Du, H.; Zhang, X.; Liu, Y.; Guan, B. ACS Catal. 2019, 9, 8766–8771. Zhang, X.; Du, H.; Zhai, D.; Guan, B. Org. Chem. Front. 2020, 7, 1991–1996. Zhai, D.; Zhang, X.; Liu, Y.; Zheng, L.; Guan, B. Angew. Chem., Int. Ed. 2018, 57, 1650–1653. Guan, B.; Shi, Z. Sci. Sin. Chim. 2021, 51, 201–212. Liu, Y.; Zheng, L.; Zhai, D.; Zhang, X.; Guan, B. Org. Lett. 2019, 21, 5351–5356. Liu, Y.; Zhai, D.; Zhang, X.; Guan, B. Angew. Chem., Int. Ed. 2018, 57, 8245–8249. Yamashita, Y.; Suzuki, H.; Sato, I.; Hirata, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2018, 57, 6896–6900.

11.16

Main Group Complexes in Polymer Synthesis

David J Liptrota,b and Laura E Englisha,b, aDepartment of Chemistry, University of Bath, Bath, United Kingdom; bCentre for Sustainable and Circular Technologies, University of Bath, Bath, United Kingdom © 2022 Elsevier Ltd. All rights reserved.

11.16.1 Scope 11.16.2 Introduction 11.16.3 Ring opening polymerization 11.16.3.1 Mechanisms 11.16.3.1.1 Cationic ROP mechanism 11.16.3.1.2 Activated monomer mechanism 11.16.3.1.3 Coordination-insertion ROP mechanism 11.16.3.1.4 Nucleophilic activation mechanism 11.16.3.1.5 Anionic ROP 11.16.4 Polymers accessible by main group catalyzed ROP 11.16.4.1 Polymers derived from cyclic ethers and thioethers 11.16.4.1.1 Polyethers derived from epoxides, O(CH2CHR) 11.16.4.1.2 Higher polyethers derived from cyclic esters, O(CH2)n (n ¼ 3, 4) 11.16.4.1.3 Polymers derived from thioethers 11.16.4.2 Polymers derived from cyclic esters, thioesters, and amides 11.16.4.2.1 Polymers derived from lactones 11.16.4.2.2 Polymers derived from thiolactones 11.16.4.2.3 Polymers derived from lactams 11.16.4.3 Polymers derived from cyclic carbonates and thiocarbonates 11.16.4.3.1 Polymers derived from cyclic carbonates 11.16.4.3.2 Polymers derived from cyclic thiocarbonates 11.16.5 Ring-opening copolymerization mediated by main group complexes 11.16.5.1 Epoxide/Anhydride ROCOP 11.16.5.2 Epoxide/Heterocumulene ROCOP 11.16.6 Chemical polymer recycling 11.16.6.1 Chemical depolymerization of PLA 11.16.6.2 Chemical degradation of PLA 11.16.6.3 Depolymerization of other polyesters 11.16.7 Conclusion Acknowledgments References

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11.16.1 Scope Owing to issues beyond the editors’ control, the commissioned chapter “Main Group Complexes in Polymer Synthesis” was not received. As a consequence, this short perspective is offered as an alternative. Whilst provision of a comprehensive work on this broad topic was, thus, not possible, this chapter is instead designed to be a primer which overviews classes of catalyst and polymer, summarizes mechanistic considerations and provides resources for further exploration of the topic, with reference to appropriate reviews of each component of the chapter where possible.

11.16.2 Introduction Main group compounds have been fundamental to polymer synthesis since its very early days. Transition metal olefin polymerization catalysts are often reliant on the activation/cocatalytic activity of aluminum complexes such as Al(C2H5)3, or materials such as methylaluminoxane. Remarkable work from Jordan and co-workers in the late 1990s showed that judicious complex design could obviate the need for a d-block metal component in this reactivity,1 and correspondingly, this chapter will focus on purely main group systems for polymerization, which has a history dating back to the 19th century. Many commercial polymers are generated with the aid of main group compounds, especially polyesters such as polyethylene terephthalate, which is generated through the use of antimony trioxide, Sb2O3, catalysis.2 Since the mid-20th century there has been an explosion in polyester synthesis catalyzed by s- and p-block derived catalysts and, in the last two decades, a particular focus on sustainable, renewable, biofeedstock-derived or carbon dioxide incorporating polymer systems. This chapter will address a number of these polymers, in

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each case providing a discussion of proposed mechanisms of their production and a brief summary of catalytic systems applied in their synthesis. Finally, a discussion of polyester degradation mediated by main group catalysts will be included; this important mechanistic step constitutes a new and growing area of research and is essential to the integration of renewable polymers in a circular economy.

11.16.3 Ring opening polymerization Polyesters are predominantly produced by either the direct polycondensation of corresponding carboxylic acids or the ring-opening polymerization (ROP) of cyclic esters, e.g., lactide, the cyclic dimer of lactic acid (Fig. 1). Polycondensation often results in the production of low molecular weight polymers3 which must then be reacted with chain coupling agents to produce the often more desirable high molecular weight product.4 Water, produced in the condensation reaction, can attack the growing polymer chain and cause degradation, as well as diluting the mixture as the reaction progresses meaning the polymer chains are less likely to couple. This reduction in concentration can also cause “back-biting,” the active end of a growing polymer chain attacking the chain itself rather than a new monomer, leading to cyclic by-products.5 Chemists have thus increasingly focused on the use of the strained cyclic esters as the starting material for the production of many polyesters and related compounds, eliminating the issues caused by the production of water during the polymerization. Many of these contributions have relied on main group catalysis, and its applications in polymer chemistry and will be discussed below.

11.16.3.1 Mechanisms Since the mid-20th century, extensive mechanistic work on ROP has revealed a number of mechanisms by which the reaction can proceed. Many of these mechanisms are not relevant to main group systems.6 Of those relevant to main group initiators, the interplay of thermodynamics and kinetics results in the possibility that one or a number of these mechanisms can be operant in the formation of a given polymer dependent on conditions and the identity of the initiator. Furthermore, in a given system extensive kinetic analysis is required to know which mechanism dominates with any degree of certainty, thus the mechanisms are summarized below followed by a discussion of polymers including an overview of which polymerization mechanism is most commonly followed. This should not be treated as a prescriptive discussion as precise mechanistic understanding is a continuing area of interest.

11.16.3.1.1

Cationic ROP mechanism

In the presence of an appropriate reagent, cationic ROP (CROP) occurs where a Lewis- or Brønsted acid, or a reactive electrophile such as an alkylating agent, results in the generation of a cation via activation of a Lewis basic group in a cyclic monomer, followed by ring opening to generate a cation (Fig. 2). This can act as a Lewis acid to another equivalent of monomer and leads to polymer propagation.

Mw = 1000 - 10,000 g/mol depolymerizaƟon

Mw > 100,000 g/mol Fig. 1 Routes to some cyclic monomers and polyesters.

Fig. 2 Cationic ROP mechanism for an epoxide.

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11.16.3.1.2

Activated monomer mechanism

The ROP of cyclic monomers, closely related to Brønsted acid or alkylating agent initiated cationic ROP, can proceed via the activated monomer mechanism (Fig. 3), generally observed for Lewis acidic initiators which lack a labile alkoxide ligand and thus require an excipient co-initiator.7 Coordination of the Lewis basic groups on the ring to the metal center, followed by attack of an excipient alcohol co-initiator opens the lactide ring to generate a linear chain. Propagation occurs by attack on the activated monomer by the heteroatom terminus of the growing polymer chain.8 As the catalyst does not remain attached to the growing polymer chain during the propagation steps, the activated monomer mechanism also lends itself towards “immortal” polymerizations.9

11.16.3.1.3

Coordination-insertion ROP mechanism

Alternatively, the coordination-insertion mechanism (Fig. 4), first reported in 1988 by Kricheldorf and co-workers, can operate.10 This process is generally proposed for initiators comprising a Lewis acidic metal center bonded to a labile alkoxide ligand.11 Activation of the heteroatom groups of the cyclic monomer via coordination to the metal center predisposes them to attack by the labile alkoxide. The resulting tetrahedral intermediate (Fig. 4, Intermediate A) then collapses, opening the ring to form a linear chain which remains coordinated to the metal center. The chain then proceeds to act as the labile nucleophile in subsequent propagation steps until the polymerization is terminated, often by addition of a proton source. The coordination-insertion mechanism lends itself to “living” polymerizations12,13 which produce polymers with high molecular weights and narrow molecular weight distributions, characteristics that are desirable in commercial polymers. “Immortal” polymerizations, with increased production per catalyst center, can be achieved with the addition of an alcohol co-initiator, which participates in chain transfer reactions with the growing polymer chain coordinated to the metal catalyst.13 The resulting metal alkoxide can then activate and ring-open another monomer to start a new polymer chain, increasing the productivity. A consequence of this is that the molecular weight of the polymers produced is linked to the amount of alcohol added, rather than the amount of catalyst. Molecular weight distributions can also be affected, with narrow distributions requiring the rate of chain transfer to exceed that of propagation.9

11.16.3.1.4

Nucleophilic activation mechanism

Alternatively, a nucleophilic activation mechanism13 can operate which involves the attack of a nucleophilic catalyst on a carbonyl carbon forming a zwitterionic intermediate. This collapses to open the heterocyclic ring (Fig. 5) and produce a zwitterionic chain with the now positively charged nucleophile attached to one end and a negatively charged heteroatom at the other, which deprotonates an alcohol co-initiator. The resulting alkoxide can then attack the growing chain, displacing the nucleophile and allowing it to activate another monomer. This is generally restricted to organocatalysis and will not be discussed further.

Fig. 3 Mechanism of activated monomer ring-opening polymerization.

H+ Fig. 4 Coordination-insertion mechanism of ring opening polymerization for the example of lactide.

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Fig. 5 Mechanism of nucleophilic activation ring-opening polymerization.

11.16.3.1.5

Anionic ROP

A closely related mechanism is anionic ring opening polymerization (AROP), where the nucleophilic catalyst is an anionic species derived from the growing polymer chain. In the case of main group complexes, these species form via the attack of anion contained in a ionic complex with a main group counterion such as a group 1 metal. Attack of the anion in the first instance ring opens the monomer to generate an anion terminated polymer chain with the charge balanced by a main group counterion. This resultant anion is active towards nucleophilic attack on additional monomer resulting in chain growth (Fig. 6).

11.16.4 Polymers accessible by main group catalyzed ROP A wide swathe of cyclic monomers are amenable to ROP by main group complexes, ranging from unsubstituted 3-membered rings which generate correspondingly simple polymers to chiral molecules which can generate polymers with complex microstructures and tacticities. Below is a selection of cyclic molecules, or compound classes, generally amenable to ROP which have been reported to be initiated by main group complexes. A brief discussion of tacticity and microstructure is provided where relevant and feasible, and a non-comprehensive summary of main group initiators is provided.

11.16.4.1 Polymers derived from cyclic ethers and thioethers A number of polymers have been derived from simple cyclic heteroatom containing species (Fig. 7).

11.16.4.1.1

Polyethers derived from epoxides, O(CH2CHR)

Epoxide ring opening polymerization results in materials with a huge range of uses in medicine, biology, fast-moving consumer products and numerous industrial processes.14 The simplest polymer derived from the parent epoxide, polyethylene glycol (PEG), is most widely used in these applications. Whilst PEG can be readily generated via condensation polymerization initiated by a diverse range of organic and inorganic compounds, higher molecular weight polymers, called poly(ethylene oxide), often rely on ROP of the parent epoxide.15 Early forays in this direction were made by Wurtz, who reported that both alkali metal hydroxides and zinc chloride could generate a material that was most likely polymeric from ethylene oxide in the mid-19th century.16 Given the huge number of applications this material has, research has been extensive and a full treatment is beyond the scope of this work, but a

NH NH

Fig. 6 Anionic ring opening polymerization of e-caprolactam.

Fig. 7 An overview of monomeric cyclic ethers that can be subjected to ROP.

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number of excellent reviews are available.15,17–19 Nevertheless, a number of significant main group compounds have been reported as initiators for the ROP of ethylene oxide. AROP is widely reported with alkali metal alkoxides,20,21 hydrides,22 amides and carbohydryls.17 Alongside these, trialkylaluminum species,23 aluminum alkoxides,24,25 and alkali metal aluminates of the form Na [AliBu4],26 have also been investigated. Commercial processes are reported to exploit alkaline earth carbonates,27 and calcium amides,28 possibly via a coordination polymerization mechanism. Aluminum alkoxides25 and alkyls, as well as zinc and magnesium dialkyls have been reported to generate high molecular weight polymer,29 and coordination polymerization has been proposed as a mechanism for both these, and related mixtures such as group 1 alkoxide/aluminum alkyl30,31 and ZnCl2/AlOiPr3.24 In some cases, activated monomer mechanisms have been proposed especially for alkali metal alkoxide/trialkylaluminum systems.18 CROP was initially considered to be disfavoured by side reactions leading to low-molecular weight and contaminated polymers.15 Subsequent work with boron and aluminum Lewis acids32,33 indicated this was not the case, and productive polymerizations were viable by CROP of epoxides. Substituted epoxides have also been investigated, albeit less intensively than the widely-used parent. The methyl-substituted analog of PEG, polypropylene glycol, can be generated under similar conditions however the unsymmetrical monomer leads to the possibility of a range of tacticities based on the regiochemistry of the ring opening and competing elimination reactions often hinder access to higher molecular weights.29 Under standard AROP conditions, polypropylene glycol is formed as the atactic polymer. Recently, activated monomer approaches have been applied to provide access to higher molecular weights and greater control of tacticity, notably applying aluminum co-initiators.18,30 Alongside these, a range of alkoxides have been applied to provide the nucleophilic fragment in this mechanism including systems derived from Grignard reagents when the formation of a mixed metal aluminum/magnesium system was proposed.34 Substitution of the epoxide with longer chains has also been explored providing access to poly(butylene oxide), although complexity in monomer synthesis has hindered wider exploration of this chemistry.15,18 Alongside these, fused alicyclic epoxides such as cyclohexene oxide and its derivatives have been polymerized generally by the application of aluminum-centered Lewis acids,35–37 which have been comprehensively reviewed,38 although focus on this substrate have more widely applied it in ROCOP (vide infra). Functionalised epoxides can also be polymerized by main group initiators, such as zinc pyrrolidides,39 with significant complexity added by the nature of the side chains, especially if they are reactive,19,40 and access to unique mechanisms such as zwitterionic ROP opened by the presence of such functional groups.41

11.16.4.1.2

Higher polyethers derived from cyclic esters, O(CH2)n (n ¼ 3, 4)

Poly(oxetanes), the C3 homologs of polyethylene oxides have been reported via the CROP of oxetanes which proceed via the generation of an appropriate oxonium ion via activation of the monomer. Whilst the simplest route to provide such an ion is via the action of a strong Brønsted acid on the monomer, the first report of oxetane ring opening applied a main group system for this polymerization; BF3
OEt2.42 In these cases, coordination of the cyclic oxygen to the Lewis acidic boron center results in a formal oxonium ion, thus predisposing the 4-membered ring to nucleophilic attack. Extension of the Lewis acid catalyst to other main group species such as aluminum alkoxides has also been explored.43 This has been far more widely explored than AROP, which seems to be isolated to reports of KOtBu44 or NaH45 initiators at elevated temperatures. CROP has been applied to the generation of the C4 homolog, poly(tetrahydrofuran), from THF which finds use in elastic fibers and has been extensively reviewed owing to its commercial significance.46 Polyethers containing additional cyclic O-linkages, polyacetals, have also been reported as substrates for main group mediated ROP (Fig. 8). 1,3-Dioxolane can be readily synthesized from ethylene glycol and formaldehyde, both of which can be derived from sustainable feedstocks. Work on main group mediated polymerization with a wide range of main group systems indicated that GaCl3, SnCl4 and SbCl5 were active alone, whilst indium(III) halides and ZnCl2 catalyzed ROP only in the presence of methoxymethyl halides, with polymerization approximating a CROP mechanism, albeit with extensive studies showing a more complex reaction pathway.47

11.16.4.1.3

Polymers derived from thioethers

Application of sulfur analogs of oxy-centered functional groups in ROP has potential to yield polymers with profoundly different properties to their oxygen congeners, and has been reviewed.48 The sulfur analogs of epoxides and oxetanes, thiiranes and thietanes respectively, have also been subjected to ROP, although such reports are far more limited. CROP is severely limited by side-reactions, although these have been carefully applied to yield highly branched systems.49 Early work on thiiranes showed them to be prone to ROP, which was reviewed in 1966.50 A number of main group nucleophiles have been applied such as Grignard reagents,51 alkali metal and alkaline earth alkoxides, thiolates52,53 and naphthalenides.54 Ethyl lithium at −78  C in THF, additionally, was found to ring open 3- and 4-membered saturated sulfur heterocycles to generate linear polymers, presumably via AROP, whereas higher homologs were found to be inert to these conditions.55 Larger rings with higher sulfur content, related to acetals, can be polymerized via CROP initiated by boron trifluoride.56

Fig. 8 Acetal ROP catalyzed by an indium halide complex.

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11.16.4.2 Polymers derived from cyclic esters, thioesters, and amides A number of polymers have been derived from systems containing the RC(]O)XR (X ¼ O, NH, S) moiety. (Fig. 9).

11.16.4.2.1

Polymers derived from lactones

Aliphatic polyesters are attractive polymers with often renewable sources or interesting biocompatible or degradable properties. Particular focus has fallen on 4-membered lactones such as b-propiolactone and b-butyrolactone, with the latter showing significant effects originating from its chiral nature. Alongside these, the 7-membered e-caprolactone has drawn significant focus owing to its use in a diverse range of applications from packaging to tissue engineering. Lactone ring opening mediated by NaH was reported in 1958,57 and since then a huge range of initiators have been applied to generate polyesters. Catalysts based on aluminum,58,59 tin,60,61 zinc,62–64 indium65 have been reported. Related “metal-free” species have also been investigated, with a particularly notable recent example of poly(b-hydroxybutyrate) generation from b-butyrolactone which relied on a bifunctional organoboron catalyst. Extensive work into this reaction provided a plausible mechanism where the coordination of monomer to the boron center activated it towards attack by the growing polymer chain which was intimately associated with a cationic nitrogen fragment of the catalyst species. Whilst this mechanism resembles the coordination-insertion mechanism discussed above, it is unique in the spatial separation of the nucleophilic alkoxide chain from the monomer-activating Lewis acid fragment.66 e-Caprolactone ROP has been extensively reviewed67 Extensive mechanistic work into simple aluminum compounds has been undertaken59,68–75 and provided insight to facilitate the design of active aluminates.76–78 Aluminum catalysts with porphyrin79 Schiff-base72,80,81 and phenoxyimine ligands82 have been reported. From the s-block, compounds of potassium83 sodium84,85 and group 2 have been explored. The latter in the form of magnesium ligated by heteroscorpionate86 and phenoxide87,88 ligands, calcium as amides89 and alkoxides90 and strontium as an amino alkoxide.91 Related group 12 systems relying on zinc, with comparative work on magnesium92,93 as well as other zinc94 systems have been reported. From the p-block, tin systems have been reported.72,95 11.16.4.2.1.1 Poly(lactic acid) Poly(lactic acid) (PLA) has seen growing focus as a possible sustainable polymer, and consequently interest in its synthesis via ROP of the lactide dimer, available from non-food crop sources, remains high. The tacticity of PLA has profound consequences for its physical properties, and thus the applications for which it is appropriate, and a brief discussion of these factors follows. There are three possible stereoisomers of lactide (Fig. 10). L-Lactide is the result of coupling two molecules of L-lactic acid, D-lactide is the result of coupling two molecules of D-lactic acid, with a 50:50 mixture of L- and D-lactide making rac-lactide. In contrast, the coupling of one molecule of L- and D-lactic acid generates meso-lactide.96 An early report of ROP of lactide was reported by Carothers et al. In this report lactide was heated to 250–275  C resulting in a resinous mass with an apparent molecular weight of around 3000 g/mol. In the same report, the presence of potassium carbonate was noted to decrease temperature needed for the polymerization, to around 140–150  C, demonstrating the first example of main group catalyzed ROP of lactide.97 Since then there has been much more research into the catalyzed ROP of lactide,98 with a variety of transition metal, main group metal and metal free catalysts having been explored.13,99

Fig. 9 An overview of monomeric cyclic carboxylic acid derivatives that can be subjected to ROP.

½-lactide

Fig. 10 Stereoisomers of lactide.

—-lactide

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Poly(lactic acid) (PLA) is a polyester comprising lactic acid repeat units (Fig. 11). Over the last 20 years there has been significant interest in PLA as it can be derived from renewable resources and is both biodegradable and biocompatible.100,101 The chiral nature of the lactide polymer results in a polymer produced can have a number of tacticities with correspondingly distinct thermal properties; notably the melting temperature (Tm) and the glass transition temperature (Tg) (Fig. 12).102 Isotactic PLLA and PDLA both have Tm ¼ 180  C and Tg ¼ 60  C and are crystalline polymers. Both the Tm and Tg of isotactic PLA can be increased by copolymerization of the two isotactic forms in a block fashion. This results in a polymer chain of PLLA joined to a chain of PDLA, with Tm  230  C and Tg ¼ 65–72  C.7 Atactic PLA results from a random ordering of S and R chiral methine centers along the polymer chain resulting in a polymer that is amorphous, with no determinable Tm, and Tg ¼ 45–55  C. The heterotactic configuration of PLA arises from an alternating—RRSS—structure along the polymer chain. This results in an amorphous polymer with a Tg < 45  C. Syndiotactic PLA is polymer made up of alternating S and R chiral methine centers along the polymer chain. The resulting semi-crystalline polymer has Tg ¼ 34  C and Tm ¼ 152  C.7 Commercial PLA is produced using tin(II) bis(2-ethylhexanoate), also known as tin(II) octanoate, as the catalyst alongside an alcohol co-initiator, generally benzyl alcohol. The reaction proceeds continuously, in flow under neat conditions, with catalyst loadings as low as 1%, at temperatures greater than 120  C to produce high molecular weight PLA (970 kg/mol)13 in quantities of 150,000 t/year as of 2015.103 However there are issues relating to potential toxicity of the catalyst remaining in the polymer104 and with the lack of stereocontrol over the polymer produced.13 Due to these issues, other catalysts have been explored that could be less toxic, more active or more selective than tin(II) octanoate. Alongside transition metals, a range of main group metal based catalysts have been reported for lactide polymerization. Aluminum tri-isopropoxide has been shown to polymerize lactide at 70  C, but required extended reaction times and induced significant transesterification resulting in a lower molecular weight polymer.105 Aluminum alkoxides with ancillary ligands have been explored, such as salen or N,N0 -bis(o-hydroxybenzyl)-1,2-diaminoethane (salan) type ligands. Salen aluminum pre-catalysts have been shown to polymerize lactide to 94% conversion in 1.3 h producing isotactic PLA with a narrow polydispersity.106 Salan aluminum pre-catalysts are also active for the production of isotactic PLA to a high conversion and with narrow polydispersities, but in longer time frames (>20 h).107 Zinc catalysts have also been observed to be highly active for the polymerization of lactide. Zinc(II) alkoxides supported by aryl substituted b-diketiminate (BDI) ligands can polymerize lactide to high conversion at room temperature in times ranging from 3 min to 10 h, dependant on the steric demand and electronic of the ligand aryl rings.108,109 Zinc alkoxides bearing mono- and bis-diaminoethyl-phenolate ligands are also extremely active,110 with kinetic studies of the monodiaminoethyl-phenolate complex showing the polymerization to occur five times faster than the best BDI supported zinc catalyst.111 Alkaline earth based catalysts have also been explored for the polymerization of lactide due to their low cost and low toxicity.112 Magnesium silylamido complexes are highly active, producing high molecular weight PLA (>100 kg/mol) at room temperature in 15 min with low catalyst loadings (0.01 mol%).113 b-Diketiminate supported magnesium systems including alkoxides have been reported to polymerize lactide to 100% conversion in 2 min at room temperature, although the polymer produced is stereo-irregular and with a broad polydispersity.108 Calcium BDI complexes are less active, requiring 2 h to reach 90% conversion of lactide at room temperature.114 Calcium 2,6-tert-butyl-4-methylphenol complexes are much more active, reaching 83% conversion in 1 min at room temperature compared to 15% in 60 min for the analogous magnesium complex. While complexes of the larger group 2 metals have also been explored, they are somewhat less active than magnesium and calcium,

Fig. 11 Structure of PLA.

Fig. 12 Possible stereochemical configurations of PLA.

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needing extended reaction times to produce PLA with broad polydispersities.91,115,116 Other main group metal based catalysts involving groups 13 and 14 are less known but also active for lactide polymerization. A dialkyl gallium NHC complex was observed to polymerize lactide at −20  C, reaching 97% conversion in 20 min.117 Indium trichloride, when combined with benzyl alcohol and triethylamine, catalyzes the production of heterotactic PLA at room temperature, reaching 96% conversion in 2.5 h.118 Germanium(IV) amide complexes are also highly active, polymerizing lactide to 96% conversion in 2 min, although with broad polydispersities.119 Some unusual sources of main group complexes have also been applied to PLA polymerization.120 Lewis acid-base pairs have also proven active.121

11.16.4.2.2

Polymers derived from thiolactones

Thiolactones show significantly reduced polymerizability compared to their oxygen congeners, nevertheless they have unusual and attractive properties that have made their polymerization desirable, and led to a number of excellent reviews.48,122–124 An early report applied potassium tert-butoxide as a catalyst in this ROP, albeit requiring harsh conditions (17 h. at 155  C).125 Optimisation of the initiator provided more favorable conditions, investigations into n-BuLi, triethylaluminum and potassium carbonate revealing that these could provide appreciable conversions at room temperature, albeit over extended timeframes (40 h).126 Subsequent studies have further optimized these conditions, focussing on s-block alkyls and alkoxides, although the vast majority of work in this field has focussed on bio- and organocatalysis and will not be discussed here. Thionocaprolactone has also been subjected to ROP initiated by both BF3
OEt2 via CROP127 and s-block alkyl and alkoxides via AROP128 yielding predominantly thioester products in both cases despite the RC(]S)OR moiety present in the starting material.

11.16.4.2.3

Polymers derived from lactams

Polylactams are a widely applied class of polymers,129 the most notable of which is nylon 6, a polymer derived from 7-membered e-caprolactam.130 A number of excellent reviews on this topic are available131,132 Whilst thermolytic ring opening polymerization in the presence of small amounts of water and acid catalyst is widely used as a route to this species, a number of main group initiator-centered approaches have also been reported.133 Such methods are attractive for complex processing methods they facilitate.134 Of these, the most widely applied is the use of sodium caprolactamate,135 which is both commercial and readily generated from the action of strong sodium bases upon caprolactam. Related alkali metal,136,137 magnesium,138 and aluminum species135 have also been reported and, in some cases, commercialized, and can be generated in a similar fashion based on the widespread availability of highly basic aluminum and magnesium alkyls. Similar systems have also been reported to initiate the ROP of 4- and 5-membered cyclic amides, and related bicyclic systems.129

11.16.4.3 Polymers derived from cyclic carbonates and thiocarbonates A number of polymers have been derived from cyclic carbonate derivatives. (Fig. 13).

11.16.4.3.1

Polymers derived from cyclic carbonates

Whilst ROCOP can give access to polycarbonates (vide infra), the synthesis of aliphatic polycarbonates by ROP of cyclic carbonates has been widely applied to the generation of these systems which are attractive due to their high biocompatibility and biodegradability. An excellent recent review has covered these properties, and synthetic approaches definitively.139 Ring opening polymerization has increasingly emerged as a preferred approach to these polymers with high molecular weight and dispersity control, especially in contrast to traditional polycondensation approaches. Initial work reported the potassium carbonate catalyzed ROP of such compounds as early as the 1930s.140,141 More recently, AROP of cyclic carbonates has been achieved with alkali metal alkoxides,142–145 alkyls,142,145,146 and carboxylates.147 Coordination-insertion ROP mediated by tin(II), tin(IV), aluminum, and zinc has also been reported. BF3
OEt2was proposed to catalyze the reaction via CROP.145,148–150 These approaches have been applied principally to 6-membered carbonates such as trimethylene carbonate, and its derivatives although some exploration of 5-, 7- and 8-membered, bicyclic, spiro and heteroatom-containing rings has occurred.

11.16.4.3.2

Polymers derived from cyclic thiocarbonates

Cyclic thiocarbonates have also been explored in ROP, albeit far less extensively than their all-oxygen congeners. 1,3-Dioxane2-thione, containing an exocyclic carbon-sulfur double bond could be polymerized with BF3
OEt2, Sn(IV) precursors and alkali metal alkyls and alkoxides. Whilst CROP, which was proposed to occur with borane and tin initiators provided poly(mercaptopropanol carbonate) which retained the exocyclic C]S moiety, AROP with group 1 initiators gave poly(trimethylene thiocarbonate) containing main-chain C-S linkages.151 This latter species could also be generated by ROP of 1,3-oxathian-2-one, possessing a RC(]O)SR functionality, initiated by potassium tert-butoxide.152 This approach has been extended to substituted, 5- and 7-membered and spiro precursors via CROP with BF3
OEt2153–158 and AROP with alkali metal alkyls and alkoxides.159,160

Fig. 13 An schematic of monomeric cyclic carbonates that can be subjected to ROP.

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Main Group Complexes in Polymer Synthesis

11.16.5 Ring-opening copolymerization mediated by main group complexes Beyond polymerization of single precursors, the desire to provide functional polymers with well-defined physical characteristics and properties has resulted in an enormous demand for the generation of copolymers, wherein mixtures of monomers can provide a range of copolymer microstructures with correspondingly tuneable properties. Whilst these extensive investigations are well beyond the scope of this chapter, the field of chemoselective ring-opening copolymerization (ROCOP) demands discussion. In this methodology, mixtures of cyclic and/or unsaturated acyclic monomers are copolymerized in a highly selective fashion to yield alternating copolymers. In many cases, the copolymers themselves would be inaccessible from starting cyclic monomers, or the inclusion of attractive feedstocks such as CO2 renders this approach significant, and has resulted in extensive reviews.161–166

11.16.5.1 Epoxide/Anhydride ROCOP Copolymerization of cyclic anhydrides with epoxides gives access to polyesters (Fig. 14), often with highly unusual structures that would be synthetically challenging with the use of single-source precursors. Main group chemistry has contributed extensively to this transformation, and has been reviewed.166,167 In recent years, salen supported aluminum centers,168–174 Lewis acidic zinc dialkyls and diaryls,175 dinuclear magnesium and zinc complexes,176–179 alkali metal carbonates,180 and organoboron systems181 have all been reported to mediate this reaction.

11.16.5.2 Epoxide/Heterocumulene ROCOP In the main group, the largest area of study by far has been the generation of polycarbonates via copolymerization of epoxides with CO2 (Fig. 15). Early reports of this work focussed on zinc182,183 and aluminum chemistry.184 The former achieved maturity in the early 21st century, and has been comprehensively reviewed.185 Subsequent to this review, a range of bimetallic zinc catalysts were reported,186–192 alongside monomeric BDI-supported zinc systems.193,194 Binuclear magnesium systems were also reported,195 and shown, alongside their zinc analogs, to tolerate even captured carbon dioxide from power station wastestreams.196 Heterodinuclear zinc/magnesium systems were then explored.197,198 Recently, much work has focussed on intricately designed199,200 or extremely simple boron systems.201,202 Alongside epoxides, 4-membered cyclic ethers have also been investigated. Copolymerization of oxetane and carbon dioxide can be mediated by aluminum complexes,203 organotin halides204,205 and boron centered Lewis acids.206 Beyond CO2 copolymerization, additional heterocumulenes have been applied in ROCOP, and an extensive, excellent review was recently published by Williams and co-workers.166 One of the earliest reports of this, and ROCOP in general, was copolymerization of isocyanates with ethylene oxide, mediated by triethylaluminum in the presence and absence of water.207,208 Subsequently, the capacity of diethylzinc/electron donor systems to copolymerize carbon disulfide with propylene oxide was reported.209 More recently, this has been extended to lithium tert-butoxide, albeit with unselective thio(ester) linkage formation.210,211

11.16.6 Chemical polymer recycling Once a product made from polymer has been used for its intended purpose, there are a variety of options for disposal of the plastic with numerous associated issues.212–219 An alternative to mechanical recycling of polymers is chemical recycling which has been widely reviewed,220–222 by which the polymer is broken down into molecules that can be either directly repolymerized to form virgin material, converted into molecules that can be processed then repolymerized or used as value added chemicals in other ways.223–225 Two such approaches, using PLA as an example, are depolymerization and degradation (Fig. 16), with depolymerization producing lactic acid and degradation producing lactate esters.7,226

Fig. 14 ROCOP of epoxides with anhydrides to yield polycarbonates.

Fig. 15 ROCOP of epoxides with CO2 to yield polycarbonates.

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Fig. 16 Depiction of degradation and depolymerization of PLA and poly(tetramethyl glycolide).

11.16.6.1 Chemical depolymerization of PLA Depolymerization of PLA via hydrolysis of the polymer chain is traditionally performed at high temperatures, with the addition of an inorganic catalyst.227 The reaction occurs by random scission of the ester linkages in the polymer as a result of water diffusion,225,228 producing oligomers with carboxylic end groups that can further catalyze the reaction until only lactic acid and water are present.229 Coszach et al. have shown that the chemical depolymerization can occur with or without the presence of a Lewis acidic catalyst and in the presence of a base, all at 120–140  C under increased pressure in up to 24 h.230 Other methods have shown that in the absence of a catalyst, much higher temperatures or much longer reaction times are needed to achieve complete degradation. Tsuji and co-workers reported that the hydrolysis of blended PDLA/PLLA films with a water to PLA ratio of 20:1 takes longer than 30 months to degrade at 37  C at a constant pH,231 but that at temperatures above the Tm of the polymer the degradation time is reduced to within 5–10 min.232 However, this increased temperature can lead to racemisation and degradation of the lactic acid product.233 Increasing the water to PLA ratio can increase the rate of depolymerization, but this leads to a more dilute product requiring more purification steps.234 Ohara and co-workers found that by using microwave heating at 170  C the ratio of water to PLA could be decreased to 1:3 to produce a product that is 45 wt% lactic acid rather than the 6 wt% that is produced at the higher 20:1 ratio.235 At a water to PLA ratio of 1:3 microwave heating was also observed to decrease the time required to reach the 45 wt% solution of lactic acid from 800 h to 120 h.

11.16.6.2 Chemical degradation of PLA Chemical degradation of PLA, generally via alcoholysis, involving the attack of an alcohol on the polymer chain produces lactate esters. As with the polymerization of lactide, the mechanism by which the degradation proceeds is dependent on the type of catalyst used.236,237 When a Lewis acidic catalyst is used, the mechanism is thought to involve the coordination of the polymer chain to the Lewis acidic center (Fig. 17).237 This is followed by the attack of the alcohol at the activated carbonyl, to cleave the polymer chain in a transesterification type reaction. Subsequent coordination and attack sequences break down the polymer chain until no further transesterification reactions can occur. In the case of nucleophilic catalytic systems (Fig. 18), as seen with some organocatalysts, the nucleophilic catalyst attacks a carbonyl carbon along the polymer chain, resulting in cleavage of the acyl CdO bond producing an anionic species bearing an O− end group and a cationic species bearing the now positively charged nucleophilic catalyst bonded to the carbonyl carbon. The added alcohol then attacks the carbonyl carbon adjacent to the nucleophile, releasing it, and protonates the anionic species producing two shorter polymer chains. This then repeats until subsequent reactions can no longer occur and the polymer is broken down to the alkyl lactate species.236 As with the polymerization of lactic acid, the degradation of PLA can be catalyzed by tin(II) octanoate. Coszach and Willocq hold a patent in which PLA is degraded to ethyl lactate in the presence of ethanol and 1 wt% tin(II) octanoate.238 The reaction proceeds to 93% conversion in 30 h at 120  C, after which time the product is then cyclised to produce lactide in high yields of greater than 95%. The closely related poly(tetramethyl glycolide), which is fully methylated at the b-carbon, could also be degraded, but remarkably to the cyclic dimer, tetramethyl glycolide, which can be subjected to ROP to return the polymer in a truly circular approach.239 However, the toxicity issues relating to tin compounds are still present, and as such, other catalysts for the degradation of PLA have been explored. Magnesium based catalysts are known to be active catalysts for the alcoholysis of PLA.240 Magnesium metal, used in 1 mol% loadings alongside 2 equivalents of methanol catalyzed the degradation of PLA to methyl lactate, proceeding to 88% conversion in 1.5 h at 200  C. Dibutylmagnesium has also been used, producing isobutyl lactate with a conversion of 89% in 2 h at 200  C with 1 mol% catalyst loading and 2 equivalents of isobutanol.241 Potassium fluoride has been used in the methanolysis of PLA, with the reaction proceeding to 98% conversion in 10 min, with 5 mol% catalyst loading and 23.1 equivalents of methanol at 180  C.242

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Main Group Complexes in Polymer Synthesis

Fig. 17 Mechanism for the metal catalyzed chemical degradation of PLA.

Fig. 18 Mechanism for the nucleophilic degradation of PLA.

A range of zinc(II) complexes are also known to be active catalysts for the alcoholysis of PLA.240 Zinc(II) acetate has been reported to degrade PLA in different alcohols, proceeding to 70% conversion in methanol and 21% conversion in ethanol, both in 16 h at the boiling point of the alcohol.243 Zinc(II) catalysts bearing NO and NNO type Schiff base ligands can catalyze the methanolysis of PLA with conversions ranging from 63% in 30 min at 130  C to 100% conversion in the same time at 50  C with 7 equivalents of methanol and catalyst loadings of 8 and 4 wt% respectively.244,245

11.16.6.3 Depolymerization of other polyesters Simple metal salts have been investigated for the depolymerization of polyesters with C3, C4 and C6 chains, i.e., poly(3-hydroxybutyrate), poly(4-hydroxybutyrate) and poly(caprolactone), and can either reduce the unzipping temperature to yield the respective monomers or be applied in transesterification. Sodium, calcium, zinc, tin and aluminum systems showed distinct activity and selectivity for each of the polymers.246 Dialkyl tin(IV) systems were also explored for poly(3-hydroxybutyrate) depolymerization yielding cyclic oligomers.247 Tin(II) octanoate has also been explored in poly(carboxyvalerolactone) depolymerization to yield the cyclic monomer, which can be repolymerized by ring-opening transesterification polymerization.248 Polycarbonates derived from ROCOP can be returned to relevant cyclic monomers, and/or CO2 via the action of strong bases such as sodium hexamethyldisilazide249 or to the cyclic monomers alone with B(C6F5)3.201 Zinc triflate has been shown to act to depolymerize polytetrahydrofuran to THF.250 Reversible polymerization of 2,3-dihydro-5H-1,4-benzodioxepin-5-one with aluminum salen systems was shown to be subject to an equilibrium, returning to monomer at reduced monomer concentration.251

11.16.7 Conclusion In conclusion, main group catalysts have been fundamental to ROP approaches since their earliest days. Work which began as simple phenomenological reports of the ability to generate polymer gave way, in the middle of the 20th century, to intensive mechanistic studies. These studies have allowed the chemists of the 21st century to begin to design polymer systems with exquisite molecular control. These systems show enhanced capacity to generate polymers with desirable microstructures, or to derive polymers from sustainable resources. The inclusion of main group catalysts for chemical recycling of polymers shows that main group mediated reactivity continues to have much to offer to the field of polymer science as we move away from a linear, waste producing economic model.

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Acknowledgments DJL thanks the Royal Society for the support of a University Research Fellowship. We would like to thank the Engineering and Physical Sciences Research Council for funding (EP/L016354/1) for a PhD studentship for LEE.

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