Organic Synthesis Using Transition Metals

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Organic Synthesis Using Transition Metals

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Organic Synthesis Using Transition Metals Second Edition

RODERICK BATES Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore

A John Wiley & Sons, Ltd., Publication

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This edition ﬁrst published 2012 © 2012 John Wiley & Sons, Ltd First Edition published in 2000 Registered ofﬁce John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom

For details of our global editorial ofﬁces, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identiﬁed as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and speciﬁcally disclaim all warranties, including without limitation any implied warranties of ﬁtness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modiﬁcations, changes in governmental regulations, and the constant ﬂow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data Bates, Roderick. Organic synthesis using transition metals / Roderick Bates. – 2nd ed. p. cm. Includes bibliographical references and index. ISBN 978-1-119-97894-7 (hardback) – ISBN 978-1-119-97893-0 (paper) 1. Transition metals. 2. Organic compounds–Synthesis. I. Title. QD172.T6B383 2012 547’.056–dc23 2012003765 A catalogue record for this book is available from the British Library. HB ISBN: 9781119978947 PB ISBN: 9781119978930 Typeset in 10/12pt Times by Aptara Inc., New Delhi, India

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The cover shows the X-ray crystallographic structure of stemoamide, a stemona natural product, determined by Dr. Li Yongxin in the X-Ray Crystallography Laboratory of the Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore. Syntheses of Steoamide can be found in chapter 4, scheme 44 and chapter 8, scheme 112.

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Contents

About the Author

xiii

Preface

xv

1 Introduction 1.1 The Basics 1.2 The Basic Structural Types 1.2.1 Phosphines 1.2.2 Phosphites 1.2.3 N-Heterocyclic Carbenes 1.2.4 Other Ligands 1.2.5 Quantifying Ligand Effects 1.2.6 Heterogeneous Catalysis 1.3 Just How Many Ligands Can Fit around a Metal Atom? 1.3.1 Method 1: Covalent 1.3.2 Method 2: Ionic 1.3.3 Examples 1.4 Mechanism and the Basic Reaction Steps 1.4.1 Coordination and Dissociation 1.4.2 Oxidative Addition and Reductive Elimination 1.4.3 Transmetallation 1.4.4 Alkene and Alkyne Insertion 1.4.5 CO Insertion 1.4.6 ␤-Hydride Elimination 1.4.7 Oxidative Cyclization 1.5 Catalysis References

1 2 2 5 8 9 10 10 10 10 11 11 12 13 13 15 15 15 16 16 17 17 19

2 Coupling Reactions 2.1 Carbon–Carbon Bond Formation 2.1.1 The Main-Group Metal, M 2.1.2 Limitation 2.1.3 Reactivity of the Leaving Group 2.1.4 Selectivity 2.1.4.1 Selectivity Based on Halogen Reactivity 2.1.4.2 Steric Hindrance 2.1.4.3 Electronic Effects 2.2 Lithium and Magnesium: Kumada Coupling 2.3 Zinc: The Negishi Reaction 2.4 Aluminium and Zirconium

21 21 22 23 23 25 25 25 26 27 32 35

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2.5

Tin: The Stille Reaction 2.5.1 Vinyl Stannanes 2.5.2 Aryl and Heteroaryl Stannanes 2.5.3 The Intramolecular Stille Reaction 2.5.4 Coupling of Acid Chlorides 2.5.5 Stille Coupling of Triﬂates 2.5.6 Stille Coupling of Alkyl Halides 2.5.7 Stille Reaction Troubleshooting 2.6 Boron: The Suzuki Reaction 2.6.1 Alkenyl Borane Coupling Reactions 2.6.2 Alkyl Borane Coupling Reactions 2.6.3 Aryl Borane Coupling Reactions 2.6.4 Suzuki Coupling of Alkyl Halides 2.7 Silicon: The Hiyama Reaction 2.8 Copper: The Sonogashira Reaction 2.9 Other Metals 2.10 Homocoupling 2.11 Enolate and Phenoxide Coupling 2.12 Heteroatom Coupling 2.12.1 Palladium-Catalysed Synthesis of Amine Derivatives 2.12.2 Palladium-Catalysed Synthesis of Ethers 2.12.3 Ullmann Coupling 2.12.4 Formation of Other C–X bonds References

37 41 42 42 42 44 44 44 46 48 50 52 56 57 61 67 67 69 70 72 76 78 81 82

3 C–H Activation 3.1 Arenes and Heteroarenes 3.1.1 Fujiwara–Heck Reaction 3.1.2 Biaryl Coupling 3.2 Aldehydes 3.3 Borylation and Silylation 3.4 Allylic Functionalization 3.5 Unfunctionalized C–H Bonds 3.5.1 Carbon–Heteroatom Bond Formation 3.5.2 Carbon–Carbon Bond Formation References

89 91 91 93 100 102 103 105 105 109 115

4 Carbonylation 4.1 Carbonylative Coupling Reactions: Synthesis of Carbonyl Derivatives 4.2 Carbonylative Coupling Reactions: Synthesis of Carboxylic Acid Derivatives 4.3 Carbonylation of Alkenes and Alkynes 4.3.1 The Carbonylative Heck Reaction 4.3.2 Other Carbonylation Reactions of Allenes and Alkynes 4.4 Hydroformylation 4.4.1 Directed Hydroformylation 4.4.2 Asymmetric Hydroformylation

117 117 122 127 127 129 130 135 138

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4.5

Stoichiometric Carbonylation Using Carbonyl Complexes 4.5.1 Iron and Cobalt Carbonyl Anions 4.5.2 Ferrilactones and Ferrilactams 4.5.3 Molybdenum and Tungsten Carbonyls 4.6 Carboxylation 4.7 Decarbonylation and Decarboxylation References

139 139 142 145 146 148 150

5 Alkene and Alkyne Insertion Reactions 5.1 The Heck Reaction 5.1.1 The Organic Halide 5.1.2 Leaving Groups 5.1.3 Catalysts, Ligands and Reagents 5.1.4 The Alkene: Scope and Reactivity 5.1.5 The Alkene: Regio- and Stereoselectivity 5.1.6 Cyclic Alkenes 5.1.7 Isomerization 5.1.8 The Intramolecular Heck Reaction 5.1.9 The Asymmetric Heck Reaction 5.1.10 Tandem Reactions 5.1.10.1 Alkynes 5.1.10.2 Trisubstituted Alkenes 5.1.10.3 Rigid Alkenes 5.1.11 Heck-Like Reactions of Organometallics 5.2 Insertion Reactions Involving Zirconium and Titanium 5.2.1 Hydrozirconation and Carbozirconation 5.2.2 Alkene and Alkyne Complexes 5.2.3 Zirconium-Mediated Carbomagnesiation 5.2.4 The Kulinkovich Reaction References

153 153 153 155 158 159 160 161 162 163 164 169 169 171 172 174 175 175 177 182 185 188

6 Electrophilic Alkene and Alkyne Complexes 6.1 Electrophilic Palladium Complexes 6.1.1 Tandem Reactions Involving CO or Alkene Insertion 6.1.2 Tandem Reactions with Oxidative Addition 6.2 Other Metals: Silver, Gold, Platinum and Rare Earths 6.2.1 Reactions of Alkenes 6.2.2 Reactions of Allenes 6.2.3 Reactions of Alkynes 6.2.4 The Hashmi Phenol Synthesis 6.2.5 Ene–Yne Cyclization 6.3 Iron 6.3.1 Fp Complexes of Alkenes 6.3.2 Fp Complexes of Alkynes 6.3.3 Alkylation of Allyl Fp Complexes and Formal Cycloadditions 6.4 Cobaloxime ␲-Cations References

191 191 198 207 210 210 213 216 223 225 229 229 234 234 235 237

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7 Reactions of Alkyne Complexes 7.1 Alkyne Cobalt Complexes 7.2 Propargyl Cations: The Nicholas Reaction 7.3 The Pauson–Khand Reaction 7.3.1 Asymmetric Pauson–Khand Reaction 7.3.2 The Hetero-Pauson–Khand Reaction 7.4 Synthesis Using Multiple Cobalt Reactions References

241 241 244 246 248 249 250 251

8 Carbene Complexes 8.1 Fischer Carbenes 8.1.1 Demetallation 8.1.2 The D¨otz Reaction 8.1.3 Not the D¨otz Reaction 8.1.4 Fischer Carbene Photochemistry 8.2 Vinylidene Complexes 8.3 Metathesis Reactions Involving Carbene Complexes 8.3.1 Tebbe’s Reagent 8.3.2 Alkene (Oleﬁn) Metathesis 8.3.3 Ring-Closing Metathesis 8.3.4 Cross-Metathesis 8.3.5 Ring-Opening Metathesis 8.3.6 Asymmetric Metathesis 8.3.7 Ene–Yne Metathesis 8.3.8 Ene–Yne–Ene Metathesis 8.3.9 Tandem Reactions 8.3.10 Metathesis Side Reactions 8.4 Carbyne Complexes 8.4.1 Alkyne Metathesis 8.5 Carbene Complexes from Diazo Compounds 8.5.1 Nucleophilic Trapping 8.5.2 C–H Insertion Reactions of Carbene Complexes 8.5.3 C–H Insertion Reactions of Nitrene Complexes References

253 253 258 258 263 267 269 273 274 278 279 291 296 297 300 303 306 306 310 310 312 313 315 316 319

9 ␩3 - or ␲-Allyl Complexes 9.1 Stoichiometric Reactions of ␲-Allyl Complexes 9.2 Catalysis: Mostly Palladium 9.2.1 Regioselectivity 9.2.2 Internal versus Terminal Attack 9.2.3 Stereoselectivity 9.2.4 Asymmetric Allylation 9.2.5 Synthesis Using Palladium Allyl Chemistry 9.2.6 Base-Free Allylation 9.2.7 Allylation with Decarboxylation 9.2.8 Allyl as a Protecting Group 9.2.9 Other Routes to ␩3 - or ␲-Allyl Palladium Complexes 9.3 Propargyl Compounds References

325 325 328 331 333 335 337 341 343 347 350 352 357 357

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10 Diene, Dienyl and Arene Complexes 10.1 ␩4 -Diene Complexes 10.1.1 Electrophilic Attack 10.1.2 Nucleophilic Attack 10.1.3 Deprotonation 10.2 ␩5 -Dienyl Complexes 10.2.1 Nucleophilic Attack 10.3 ␩6 -Arene Complexes 10.3.1 Nucleophilic Attack 10.3.2 Deprotonation 10.4 ␩2 -Arene Complexes References

361 361 364 366 370 371 372 377 380 385 387 389

11 Cycloaddition and Cycloisomerization Reactions 11.1 Formal Six-Electron, Six-Atom Cycloadditions 11.1.1 The [4 + 2] Cycloaddition 11.1.2 The [2 + 2 + 2] Cycloaddition 11.2 Cycloadditions Involving Fewer than Six Atoms 11.2.1 Four-Membered Rings 11.2.2 Five-Membered Rings through TMM Methods 11.2.3 Other Five-Membered Ring Formations 11.3 Cycloadditions Involving More than Six Atoms 11.3.1 The [5 + 2] Cycloaddition 11.3.2 The [4 + 4] Cycloaddition 11.3.3 The [6 + 2] and [6 + 4] Cycloadditions 11.4 Isomerization 11.5 Cycloisomerization and Related Reactions References

391 391 391 394 402 402 402 405 407 407 410 411 414 415 426

Abbreviations

431

Index of Principle Transition Metal Catalysts and Reagents

433

Index

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About the Author

Roderick Bates received his PhD at Imperial College, London with Professor Steven Ley, using organoiron complexes for organic synthesis. After a postdoctoral stint at Colorado State University with Professor L. S. Hegedus working on chromium carbenes, he moved to the University of North Texas as an Assistant Professor and began independent research, working on palladium catalysed coupling reactions, organocobalt chemistry and applications of allenes. After some years spent in Thailand at Chulalongkorn University and the Chulabhorn Research Institute and a short stay in the ill-fated Department of Chemistry at Exeter, he joined Nanyang Technological University in Singapore as a pioneer member of the brand-new Division of Chemistry and Biological Chemistry. He is currently an Associate Professor and has research interests in the use of transition metals in natural product synthesis, and stereocontrol in alkaloid chemistry.

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Preface

The gradual realization that complexes of transition metals have a place in organic synthesis has caused a quiet revolution. Organic chemists have used certain transition metal substances, such as palladium on carbon and OsO4 , for many years. These kinds of reactions are not the subject of this book, as they appear in every standard text. The aim of this book is to provide an outline of the principle reactions of transition metal complexes that are used in organic synthesis, both catalytic and stoichiometric, with examples to show how they can be applied, and sufﬁcient mechanistic information to allow them to be understood. The examples of syntheses are intended to place them in the context of the entire synthesis where space permits, so a great deal of non-transition metal chemistry can also be found in these pages. The molecular targets include natural products, novel structures and molecules of industrial, especially pharmaceutical, interest. The scale of the reaction for some of these molecules is indicated to show that these reactions are of more than just academic interest. Tremendous progress has been made since the ﬁrst edition of this work. The introduction of new ligands (“designer ligands”) has hugely expanded the scope of coupling reactions and is starting to impact other areas, while the introduction of NHC ligands has opened new possibilities in reactions of many types, from coupling to metathesis. Ten years ago, this ﬁeld of chemistry was dominated by palladium; now other metals, once neglected, have become ﬁrmly established. In particular, the organic chemistry of gold has become a major area. Metathesis chemistry has gone from strength to strength. An old but also once neglected area, the activation of C-H bonds by transition metals, has achieved huge prominence and has earned itself its own chapter. Two more general trends have emerged. One is that the emphasis on catalytic reactions, rather than stoichiometric reactions has increased. While it is undeniable that catalytic reactions are the ones that will be used in industry, the stoichiometric chemistry of transition metal complexes can still provide transformations that are both elegant and interesting and, hence, retain their place. The other is the much greater acceptance of transition metal mediated reactions in the mainstream of organic synthesis. In the ﬁrst edition, most syntheses might feature a single such transformation; it is now increasingly common for syntheses to include multiple, different transition metal mediated reactions. The different aspects of such syntheses can be found in various chapters of this text. Roderick Bates January 2012

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1 Introduction At irregular intervals, it is announced that organic synthesis is dead, that it is a completed science, that all possible molecules can be made by the application of existing methodology, and that there are no new reactions or methods to discover – everything worth doing has been done. And yet new molecular structures come up to challenge the imagination, most often from nature, and new challenges arise from the demands of society and industry, usually to be more selective, to be more efﬁcient and to be more green. The tremendous progress that has been made in the last few decades, including the hectic period since the ﬁrst edition of this work appeared, is more than ample to prove the prophecies of doom to be wrong. The art and science of organic synthesis continues to make progress as the new challenges are met. While much of the limelight has been taken up by the expansion of the once small and neglected ﬁeld of asymmetric organocatalysis, huge progress has also been made in the use of transition metals. The academic and practical signiﬁcance of this area can be seen by a glance at the list of Nobel prizes for chemistry (even if not all of the laureates had intended to contribute to organic synthesis): Sabatier, shared with Grignard (1912), Ziegler1 and Natta2 (1963), Wilkinson3 and Fischer4 (1973), Sharpless,5 Noyori6 and Knowles7 (2001), Grubbs, Schrock8 and Chauvin9 (2005) and, most recently, Heck, Negishi10 and Suzuki11 (2010). Advances in the area have not been uniform. With the challenge of greenness, atom economy and sustainability, the most progress has been made in the area of catalysis.12 Progress in the use of stoichiometric transition-metal reagents and with transition-metal complex intermediates has lagged, while progress in catalysis has surged ahead. Four areas of transition-metal chemistry have been at the forefront of recent progress. One is the tremendous advances and applications made in the area of alkene metathesis chemistry and its spin-off ﬁelds. What was once a mainstay of the petrochemical industry, but a curiosity to synthetic organic chemistry has become a standard method for carbon–carbon bond formation. New metathesis catalysts continue to open up new possibilities. The second, not unrelated, area is the development of new ligands. At one time, except for asymmetric catalysis, triphenylphosphine was the option as a ligand, with a small number of variants available. Driven by the demand for greater efﬁciency and wider substrate scope, a myriad of complex ligands is now available. While their initial impact was upon coupling reactions, their inﬂuence is spreading to other areas. The emergence of the N-heterocyclic carbene ligands has provided a second stimulus in this area and opened up further opportunities. In addition to more ligands, a greater number of the transition metals are ﬁnding applications in organic synthesis. While palladium probably remains the most widely used metal, its “market share” has shrunk, with the increasing use other metals. Most notable is the glittering rise of gold and gold catalysis. The ﬁnal area had been present in the literature for decades but only took off recently.

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals

This is the area of C–H activation, based upon the realization that C–H bonds are not passive spectators, but, with the ability of transition metals to insert into them under mild conditions, are potent functional groups. This is an area of science that is very much alive and moving forwards. Transition-metal chemistry is not only used for academic purposes, but also in the ﬁne chemicals industry. The reader will ﬁnd references to these real-life applications in the appropriate chapters.

1.1

The Basics

Why? What is special about the transition metals and the chemistry that we can do using them? What makes metals such as palladium, iron and nickel different from metals such as sodium, magnesium and lithium? The answer lies in the availability of d-orbitals, ﬁlled or empty, that have energy suitable for interaction with a wide variety of functional groups of organic compounds. In an important example, transition metals can interact with alkenes. In ordinary organic chemistry, simple alkenes are relatively unreactive, being ignored by almost all bases and nucleophiles, requiring a reactive radical or a strong electrophile or oxidizing agent, such as bromine, ozone or osmium tetroxide (watch out – osmium is a transition metal!). But they coordinate to transition metals and their reactivity changes. An important molecule that has almost no “ordinary” organic chemistry is CO. It is ignored by metal ions such as Na+ and Mg2+ , but forms complexes with almost all transition metals and is ubiquitous in transition-metal chemistry. The reactions of CO, catalysed by transition metals, has made it a fundamental C1 building block for both complex molecules and bulk chemicals. Organometallic chemistry begins with the work of Frankland in the 1840s who made the ﬁrst organozinc compounds. Grignard’s work with organomagnesium compounds rapidly became part of the standard repertoire of organic chemists, and remains there today. The pathway for transition metals was not so smooth and took much longer. Indeed, it followed two tracks. One track was in industry, where the understandable objective is a proﬁtable process even if there is no understanding of what is happening in the mechanistic “black box”. This track produced alkene metathesis and hydroformylation. The other track was in academia, restrained by the need to understand. Alongside the isolation of then unexplainable complexes, such as an ethylene complex of platinum by Danish apothecary Zeise,13 one of the starting points is with Ludwig Mond in the late nineteenth century.14 He serendipitously discovered Ni(CO)4 – an amazing compound in that it is a gas under normal conditions, yet is made from so-solid metallic nickel. In terms of using transition metals for synthetic chemistry, a great advance was by Sabatier at the end of the nineteenth century who showed that ﬁnely divided metals such as nickel, palladium or platinum could catalyse the hydrogenation of alkenes. This discovery rapidly led to the manufacture of margarine, for instance. A real turning point was with the determination of the structure of ferrocene by Wilkinson – many decades after Mond. This gave chemists a stable organometallic compound to study and understand. Aided by advances in instrumentation, it was in this period that chemists were able to study organotransition-metal complexes thoroughly and understand the ground rules of their reactivity. Thus, the use of transition metals enables the organic chemist to do reactions that are difﬁcult or, more often, impossible otherwise, opening up new synthetic pathways and selectivities. Transition-metal organometallics do this through a different set of rules. To understand what is done and what can be done, it is important to be familiar with these rules.

1.2

The Basic Structural Types

While some of the structures found look similar to those formed by s-block and p-block metals, many do not. Many organometallic complexes are classiﬁed by the number of contiguous atoms, usually carbon atoms, but

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Introduction

3

O M R

M

M

η1-vinyl

η1-alkyl

M

η1-alkynyl

M η1-aryl

R

η1-acyl

M

M

M •

carbene

carbyne

vinylidene

Figure 1.1 η1 -Complexes.

M

M

Figure 1.2 η2 -Alkene complex.

not always, bound to the metal. This number is known as the hapticity or hapto number. As this is symbolized as a superscript with the Greek letter “eta”, ␩, it is sometimes called the eta number. ␩1 -Complexes contain a metal–carbon single bond (Figure 1.1). The organic group may be alkyl, vinyl, alkynyl, aryl or acyl. With the exception of the acyl complexes, there are analogous compounds of more familiar metals, such as magnesium and zinc. It is also possible to have complexes with metal–carbon double and triple bonds; these are known as carbenes and carbines. Cumulenes are also known, such as in vinylidene complexes. ␩2 -Complexes do not have analogues amongst the main group metals. They are formed by the interaction of the metal with the ␲-orbitals of alkenes and alkynes (Figure 1.2). They may also be drawn as their metallacyclopropane resonance structures, although this representation is less frequently used. The ﬁrst such complex, isolated in the early nineteenth century, is the platinum-ethylene complex known as Ziese’s salt (Figure 1.3).15 The reason for the ability of transition metals to bind to alkenes (and alkynes) lies in the fact that electrons can be donated in both directions, resulting in a synergistic effect (Figure 1.4). The ␲ * -orbital of the alkene can accept electrons from ﬁlled d-orbitals on the metal, while the ﬁlled ␲-orbital of the alkene can donate back to empty metal orbitals. This is known as the Chatt—Dewar—Duncanson model.16 ␩3 -Allyl complexes, also known as ␲-allyl complexes, have three atoms bonded to the metal (Figure 1.5). They are frequently in equilibrium with the corresponding ␩1 -allyl complex. H(1) H(2)

C(1) CI(2)

Cl Pt Cl Cl

P1

CI(1)

C(2) H(3)

CI(3) H(4)

Figure 1.3 Zeise’s salt. Reprinted with permission from Love, R. A.; Koetzle, T. F. et al. Inorg. Chem. 1975, 14, c 1975 American Chemical Society. 2653.

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Organic Synthesis Using Transition Metals M M

electron donation from electron donation from filled metal d-orbital to alkene π orbital metal alkene π* orbital empty metal orbital

Figure 1.4 The Chatt–Dewar–Duncanson model.

M

M

Figure 1.5 The η3 –η1 equilibrium in allyl complexes.

M η4-diene

M η5-dienyl

Fe M M η5-cyclopentadienyl (Cp) ferrocene, Cp2Fe η6-arene

Figure 1.6 η4 , η5 and η6 -complexes.

␩4 -diene, ␩5 -dienyl and ␩6 -arene complexes have four, ﬁve or six atoms bonded to the metal (Figure 1.6). The chemistry of these complexes is explored in Chapter 10. Amongst the ␩5 -dienyl complexes, the best known is the ␩5 -cyclopentadienyl ligand. Such is its ubiquity, that it has its own symbol: Cp. The best known of the cyclopentadienyl compounds is ferrocene (Cp2 Fe) with two Cp rings, the original sandwich compound. The permethyl derivative, pentamethylcyclopentadienyl, is known as Cp* . The most important class of ␩6 complexes by far is the ␩6 -arene complexes in which a metal is coordinated to the face of a benzene derivative through the ␲-system. ␩7 -Complexes are unusual in synthesis: an example may be found in Chapter 11. In all of these complexes, the carbon atoms are coplanar, with the metal occupying one face. A ligand of special importance is carbon monoxide. The reactivity of CO is a key difference between transition-metal chemistry and classical organic chemistry. Several of the transition metals, such as Mond’s nickel, can even form complexes with only CO. The HOMO of CO is its ␴ * -orbital, concentrated on the carbon atom, hence CO is most commonly bonded to the metal via its carbon atom. Backbonding then occurs with electron donation from metal d-orbitals into the LUMO of carbon monoxide which is the ␲ * -orbital (Figure 1.7). This is the case for the simple metal carbonyls including Ni(CO)4 , Fe(CO)5 and Cr(CO)6 . M

M

C O

electron donation from filled metal d-orbital to CO π* orbital

C O

electron donation from CO σ* orbital metal empty metal orbital

O OC C CO OC Co Co CO C OC CO O

Figure 1.7 Carbonyl complexes.

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Introduction

5

Carbon monoxide may also be a bridging ligand between two metal atoms. Some of the CO ligands in the complexes Fe2 (CO)9 , Co2 (CO)8 and Fe3 (CO)12 can behave in this way. Heteroatoms may also be ligands. These include oxygen, nitrogen, sulfur and halogen atoms. Some of these, such as oxygen, may form double bonds to the metal, as in OsO4 . A variety of nitrogen species may complex to the metal including the rather special case of the nitrosyl ligand, NO+ , which can replace CO. 1.2.1

Phosphines

The most widely employed heteroatom ligands are the phosphines. Although they are largely spectators and do not participate directly in bond formation (and when they do, the result is often highly undesirable), they are not innocent bystanders. The size and electronic nature of the three groups attached to phosphorus have a profound effect on the course of the reaction and may make the difference between success and failure. An example is with the Grubbs catalyst (Chapter 8). The bis(triphenylphosphine) complex is of little use. The bis(tricyclohexylphosphine) complex is Nobel-prize winning. Triphenylphosphine 1.1 has always been the most commonly used ligand, due to cost, availability, ease of handling and habit. While triphenylphosphine 1.1 remains commonly used, it no longer has its old ubiquity. An entire ﬁeld of research, which might be termed “ligand engineering”, has grown up, centred on the design of new ligands with tailor-made electronic and steric properties (Figure 1.8). In a great many of the early applications of transition metals to organic synthesis, triphenylphosphine was used almost exclusively. An early exception is the use of a modiﬁed version, tri-o-tolylphosphine 1.2, in Heck reactions.17 This was done to suppress quaternization of the phosphine by adding steric hindrance, though its success may actually be due to formation of Herrmann’s catalyst in situ.18 Addition of one or more sulfonate groups to the phenyl rings gives water-soluble analogues, such as 1.3. Triphenylphosphine has also been modiﬁed by changing the donor atom. Both triphenylarsine 1.4 and triphenylstibine 1.5 have been employed. Changing the phenyl groups to furyl groups giving the more electron-rich tri-(2-furyl)phosphine 1.6 can also be beneﬁcial. Alternatively, adding ﬂuorine atoms gives an electron-poor ligand in tris(pentaﬂuorophenyl)phosphine 1.7. One or more of

Me Ph

Ph

Ph P Ph 1.1

Ph As Ph 1.4

n-Bu P n-Bu

n-Bu

1.9

SO3- Na+

P

P Me

Me 1.3

1.2

Ph

Ph Sb Ph 1.5

t-Bu

O O

P t-Bu

t-Bu t-Bu

1.10

C6F5

O

P

1.6

P Me

t-Bu

1.11

t-Bu

P

C F P 6 5 C6F5 1.7

P 1.8

t-Bu Pt-Bu2

Me Me Me

1.12

Figure 1.8 Phosphine ligands.

1.13

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Organic Synthesis Using Transition Metals

the aryl groups attached to phosphorus may be changed to alkyl groups. Tri(cyclohexyl)phosphine 1.8 has found considerable application from being both more electron rich and more bulky than its aromatic analogue, triphenylphosphine. The related tricyclopentylphosphine is also known. Acyclic alkyl groups have also been used. Tri-n-butylphosphine 1.9 is readily available and used in organic procedures, such as Staudinger reactions and Wittig reactions, but is relatively uncommon as a ligand. In contrast, tri-t-butylphosphine 1.10, has proved to be valuable. Its bulk promotes ligand dissociation and, hence, catalytic reactivity. As you can have too much of a good thing, the less-hindered di(t-butyl)methylphosphine 1.11 is also available. The neopentyl group and binaphthyl groups has also been used to replace one of the t-butyl groups. The binaphthyl modiﬁcation 1.13 is known as Trixiephos. A disadvantage of using alkyl phosphines is their air sensitivity. All phosphines can be oxidized to the corresponding phosphine oxides, but this tendency is more pronounced with alkyl phosphines. A solution is to store and handle them as a salt, such as the tetraﬂuoroborate salt.19 If a small amount of a base is added to the reaction mixture, and many reaction mixtures already contain a base, then the phosphine is liberated in situ. The focus of development of more sophisticated ligands has mainly been concerned with replacing one of the groups on phosphorus with a biphenyl group (Figure 1.9). Johnphos 1.14 and its dicyclohexyl analogue 1.15 contain the unadorned biphenyl moiety. Addition of ortho-substituents to the second phenyl group changes the steric and electronic properties, as in Sphos 1.16 and the closely related Ruphos 1.17, both with alkoxy substituents. Mephos 1.18 and Xphos 1.19 have different alkyl substituents. Davephos 1.20 and its t-butyl analogue 1.21 possess a potentially chelating amino group. More highly substituted ligands, such as Brettphos 1.22 and Jackiephos 1.23, have also been developed. Qphos 1.24, with a highly substituted ferrocene moiety, can also be considered in this class of ligands. The popularity of the biphenyl moiety in many ligands is not a mere result of adding bulk. The second aryl ring, twisted at an angle to its partner, may affect the metal directly by coordination, as in the cationic gold complex (Figure 1.10).20 The X-ray structure (anionic counter ion not shown) clearly shows the proximity of the second ring to the metal atom.

Pt-Bu2

1.14 Johnphos PCy2

H3C 1.18 Mephos

PCy2 OMe

PCy2

1.15 Cy-Johnphos

MeO 1.16 Sphos

i -PrO 1.17 Ruphos

PCy2

PCy2 i-Pr

i -Pr 1.19 Xphos

PCy2 Oi -Pr

Me2N 1.20 Davephos

Pt-Bu2

Me2N 1.21 t-Bu Davephos

OMe

Pt-Bu2

PAr 2 i-Pr

Fe 1.22 Brettphos: Ar = Cy 1.23 Jackiephos: Ar = (m-CF3)2C6H3

MeO i -Pr

Ph Ph Ph

Ph Ph

1.24 Qphos

Figure 1.9 Phosphine ligands with a biphenyl motif.

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Introduction C4

C3 C2 C1

C5 C6

7

C12 C11 C10 C7 C9

C8

P1 Au1

P Au N C Me t-Bu t-Bu 1.25

N1 C1A C2A

2b

Figure 1.10 A gold(I) biphenylphosphine complex. Reprinted with permission from Herrero-Gomez, E.; Nieto´ c 2006 Wiley-VCH Verlag GmbH & Co. KGaA. Oberhuber, C. et al. Angew. Chem., Int. Ed. 2006, 45, 5455.

Bidentate phosphines have been used for many years (Figure 1.11). They provide the complex with greater stability because, for complete ligand dissociation, two metal–phosphine bonds must be broken, rather than one. Simple bidentate ligands consist of two diphenylphosphino units linked by an alkyl chain or group (1.26–1.30). More complex ligands use more elaborate linkers. Bis(diphenylphosphino)ferrocene, with a ferrocenyl linker, has proved to be a useful ligand. Most other linkers are based upon aromatic motifs. BINAP 1.33, most often employed as a chiral ligand for asymmetric catalysis, has sometimes been used. Xantphos 1.34 and DPEphos 1.35 form a special subset of bidentate ligands. In square planar complexes, such as complexes with palladium(II), due to the geometrical demands of the linker, the two phosphines are capable of being trans.21 The other bidentate ligands tend to be cis.

Ph2P

PPh2

1.26 dppm Ph2P

PPh2

Ph2P

1.27 dppe (diphos)

PPh2 1.29 dppp

PMe2

Me2P

1.28 dmpe PPh2

Ph2P 1.30 dppb

PPh2

PPh2 Fe

PPh2

PPh2

1.31 dppbz

1.32 dppf

Ph2P PPh2 PPh2

1.33 BINAP

PPh2

Ph2P

PPh2

O

O

1.34 Xantphos

1.35 DPEphos

Figure 1.11

Bidentate phosphines.

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Organic Synthesis Using Transition Metals

PPh2 PPh2

1.36 (S)-BINAP

Ph2P Ph2P

p-tol2P p-tol2P

Ph2P Ph2P

1.38 (R)-TolBINAP

1.37 (R)-BINAP Me

OMe P

Ph2P

PPh2

Ph2P

PPh2

Me Me

P Ph

P

1.41 skewphos

1.40 chiraphos

Me 1.42 Me-DUPHOS

Figure 1.12

1.39 H8-BINAP MeO P Ph

1.43 DIPAMP

Chiral phosphine ligands.

The list given above is just a small selection of the ligands reported, and a tiny selection of the ligands that are possible. The use of chiral phosphines has been the principle way to achieve asymmetric reactions in organometallic chemistry. A small selection of the huge number of chiral phosphines reported so far is presented in Figure 1.12. While chiral monodentate species have been used, most of the ligands are bidentate. Their designs can be divided into three groups. One group has the chirality present in the chain that links the two phosphorus atoms. Many of these are axially chiral. The two enantiomers of BINAP, 1.36/1.37, are the ﬁrst in this group, and many derivatives and modiﬁcations of BINAP have been reported. Others, such as chiraphos 1.40 and skewphos 1.41 have stereogenic carbon atoms in the chain. A second group, represented here by Me-DUPHOS 1.42 has the chirality in the phosphorus substituents, rather than the chain. A third and rarer group exploits the chirality of the phosphorus atom. DIPAMP 1.43, the ﬁrst effective ligand for asymmetric hydrogenation, is in this group. Applications of asymmetric catalysis are included in several chapters. For a deeper discussion, the reader is referred to more specialized textbooks.22

1.2.2

Phosphites

Phosphites are closely related to phosphines, but have P–O bonds in place of P–C bonds (Figure 1.13). While they have been found to be useful ligands in certain reactions (see Section 4.4 and Sections 11.1.1 and 11.2.2), they have not been subject to the same widespread use or development as phosphines.

EtO

OEt P OEt

1.44 triethylphosphite

i-PrO

Oi -Pr P Oi -Pr

1.45 tri-iso-propylphosphite

Figure 1.13

Phosphites.

PhO

OPh P OPh

1.46 triphenylphosphite

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Introduction

1.2.3

9

N-Heterocyclic Carbenes

Carbene complexes have been known since the 1960s. Their chemistry revolves around the reactions of the carbene moiety (Chapter 8). The isolation of the ﬁrst stable carbene by Arduengo,23 and the realization that such carbenes could function as useful ligands for transition metals, in a similar way to phosphines, opened up a new chapter in organometallic chemistry.24,25 Arduengo’s ﬁrst stable carbenes were formed by the deprotonation of imidazolium salts (Schemes 1.1 and 1.2). The carbene carbon is built into a stabilizing nitrogen heterocycle. The stabilization is principally electronic, by the two nitrogen atoms. The N-substituents provide steric stabilization that is not, however, essential.26 They are, therefore, referred to as N-heterocyclic carbenes or NHCs. The many NHC ligands that have followed have largely been variations on Arduengo’s original (Figure 1.14). The N-mesityl, rather than N-admantyl, has been commonly used, although families of N-alkyl carbenes have been produced. The double bond in the N-heterocycle may be absent, as in the Grubbs second-generation catalyst (Chapter 8). The heterocycle may also be varied, as in TPT 1.50. Numerous more complex carbenes, including chelating bis-carbenes, have also been synthesized.

H NaH N

N

N

N IAd

Scheme 1.1

Me Me

H

Me

Me

N

Me

Me KOt-Bu

Me N

N

Me

Me

Me

Me

N

IMes

Me

Scheme 1.2

Me

Me

Me

Me

Me

Me Me N

Me

N

N

Me

Me

Me

1.47 IMes Me

Me N

Me 1.48 SIMes

Me

Me

Ph N

N

N Ph N

Ph Me Cl

Cl

Me

1.49 ClIMes

Figure 1.14

N

1.50 TPT

R N

N R

1.51 IAd R = Adamantyl Cy 1.52 ICy Me 1.53 IMe i -Pr 1.54 IiPr t-Bu 1.55 ItBu

N-heterocyclic carbene (NHC) ligands.

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Organic Synthesis Using Transition Metals Table 1.1 Cone angles

R Mθ

R R

1.2.4

Ligand

Cone angle, θ

PH3

87°

P(OEt)3

109°

PPhMe2

122°

Pn-Bu3

132°

PPh3

145°

PCy3

170°

Pt-Bu3

182°

P(mesityl)3

212°

Other Ligands

Many other species have been employed as ligands, including amines and nitrogen heterocycles, sulﬁdes and sulfoxides, halides, alkoxides and nitriles. Dienes, such as 1,5-cyclooctadiene, are commonly used as ligands. 1.2.5

Quantifying Ligand Effects

The two principle effects of the ligand are electronic and steric.27 The concept of cone angle is used to describe the size of a ligand (Table 1.1). It is the angle of a cone that has its point at the metal and just contains the phosphine ligand. As this angle will vary depending on the metal–ligand bond length, the standard is taken as the nickel tricarbonyl derivative, (OC)3 NiL. Is cone angle still adequate to describe the increasingly complex phosphine ligands, and the new NHC ligands that are far from cone shaped? New quantiﬁers are being proposed.28 1.2.6

Heterogeneous Catalysis

The vast majority of the transition-metal catalysed reactions in this book use transition-metal species that are soluble in the reaction medium. These are often well-deﬁned and characterized complexes. It does not have to be this way. Sources of transition metals that are insoluble in the reaction medium, especially heterogeneous sources of palladium, can be very effective. Palladium on inert supports, such as carbon, has been employed for many decades for hydrogenation reactions. They can also be employed for carbon–carbon bond-forming reactions.29 Other heterogeneous sources, such as perovskites, which are better known as components of car exhaust systems, have also been used. Catalysts of this type may act as sources of palladium, releasing palladium as complexes or nanoparticles into the reaction medium, then reclaiming it.30 Often, these systems leave less residual metal contamination in the ﬁnal product and, therefore, are particularly useful industrially.

1.3

Just How Many Ligands Can Fit around a Metal Atom?

This is a fairly easy question to answer. If we think about elements such as carbon, nitrogen and oxygen, we know that their valency can be explained by the importance of ﬁlling the outer valence

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Introduction

11

shell with eight electrons and obtaining an inert-gas conﬁguration. As they have to ﬁll up an s orbital and three p orbitals, this means acquiring eight electrons, including the electrons that they already possess. Transition metals have to ﬁll an s orbital, three p orbitals and ﬁve d orbitals. This requires eighteen electrons. This is the eighteen-electron rule. These electrons must either belong to the metal atom already or must be supplied by the ligand. We must also adjust for the charge. There are two methods for adding up electrons, both are based on counting the electrons contributed to the complex from the metal and the ligands. The methods have been referred to as the “covalent” and “ionic” methods as they differ in the notional origin of the electrons.31 It has to be clearly understood that this is the notional origin, not the actual origin. A hydride ligand is assigned as bringing 1 or 2 electrons to the complex respectively, whether its actual origin was from LiAlH4 , H2 or HCl. The same answer is obtained whichever method is used. The important thing is to not get the two methods mixed up! Examples of both methods are given in Figures 1.15–1.18. 1.3.1

Method 1: Covalent

Electrons from the metal: This is equal to its group number. Just count from the far left-hand column (group 1) of the periodic table (Table 1.2). Electrons from the ligands: this depends, naturally on the ligands. For hydrocarbon ligands, the number is equal to the hapto number. Single-bonded ligands (hydride, halide etc) count as 1 (although a bridging halide counts as 2 – a lone-pair donor), while carbenes and carbynes count as 2 and 3, respectively. Lone-pair donors, such as phosphines and CO, count as 2. Charge: electrons have a negative charge. A positive charge on your complex means a missing electron, so subtract one. A negative charge means an extra electron, so add one.

1.3.2

Method 2: Ionic

Electrons from the metal: ﬁrst, the oxidation state of the metal must be assigned. Oxidation state is a formalism, but a useful formalism. The assignment can be done by the notional stripping off of ligands to reveal a notional metal ion. Ligands that are donors of pairs of electrons, or multiple pairs of electrons are removed with their pair(s) of electrons and do not effect the charge of the metal. Examples include alkenes, dienes and arenes (all of which have an even hapto number), CO, phosphines and carbenes. Ligands with a sigma bond are stripped off as anions even if this makes no chemical sense. Examples are alkyl, allyl, dienyl and even acyl ligands (all of which have an odd hapto number), hydride, halide and carbynes. The number of electrons contributed by the metal is then its group number (count from the far left-hand column (group 1) of the periodic table) minus the oxidation state. This is also the number of d electrons, dx . This number is useful for comparing metals with different oxidation states across groups of the periodic table. Table 1.2 Transition metals and numbers of electrons 3

4

5

6

7

8

9

10

11

Sc Y La

Ti Zr Hf

V Nb Ta

Cr Mo W

Mn Tc Re

Fe Ru Os

Co Rh Ir

Ni Pd Pt

Cu Ag Au

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Organic Synthesis Using Transition Metals

Electrons from the ligands: The number of electrons supplied by a ligand is related to how the ligand was notionally stripped off above. Hydrocarbon ligands with even hapto numbers were stripped off as neutral molecules, so the number of electrons donated is equal to their hapto number. Hydrocarbon ligands with odd hapto numbers were stripped off as anions, so the number of electrons donated is equal to their hapto number plus one. Thus, an allyl group is a donor of four electrons. Lone-pair donors donate two electrons; sigma-bonded ligands stripped off as anions also donate two electrons. Charge: The assignment of the oxidation state has already taken the charge into account, so there is no further adjustment.

1.3.3

Examples

The rule is often broken. d8 -Complexes of metals towards the right-hand side of the d-block often form stable square-planar complexes, such as (Ph3 P)2 PdCl2 . Bulky ligands may prevent a complex reaching 18 electrons: palladium forms an eighteen-electron complex with triphenylphosphine to give the popular catalyst (Ph3 P)4 Pd, but only a fourteen-electron complex with the bulkier tri(t-butyl)phosphine, (t-Bu3 P)2 Pd. Complexes with fewer than 18 electrons are not impossible; it is just that they tend to be less stable. What is important to remember is that stable complexes are unreactive. To get them to participate in chemistry, it is usually ﬁrst necessary to get them away from their stable state (meaning, in most cases, 18 electrons) by forcing them to dissociate a ligand. Example 1: Cp(Ph3P)CoMe2 Cp Co Me Me Ph3P

Cp + Ph3P + Co3+ + 2 Me

Oxidation state = +3 Method 1 Ligands: Cp = Ph3P = Me = 2 x 1 = Metal: Co = Charge = 0 Total =

5 2 2 9 0 18

Method 2 Ligands: Cp– = Ph3P = Me– = 2 x 2 = Metal: Co(+3) = Total =

6 2 4 6 __ 18

Figure 1.15 Example 2: O Mn(CO)4

O Mn(CO)4

O

+ Mn + 4 CO

Oxidation state = +1 Method 1 Method 2 Ligands: 4 x CO = 4 x 2 = Ligands: 4 x CO = 4 x 2 = 8 ketone lone pair = ketone lone pair = 2 1 η1-aryl = η1-aryl = 7 Metal: Mn = Metal: Mn(+1) = 0 Charge = 18 Total = Total =

Figure 1.16

8 2 2 6 __ 18

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Introduction

13

Example 3: (C6H6)(C4H6)(C3H5)Mo+ PF6-

+

+

Mo

+ Mo2+

Oxidation state = +2 Method 1 Ligands: η6-C6H6 = η4-C4H6 = η3-allyl = Metal: Mo = Charge = +1 Total =

6 4 3 6 -1 18

Method 2 Ligands: η6-C6H6 = η4-C4H6 = η3-allyl = Metal: Mo(+2) = Total =

6 4 4 4 __ 18

Figure 1.17 Example 4: NaCo(CO)4 Co(CO)4

Co + 4 CO

Oxidation state = -1 Method 1 Ligands: 4 x CO = 4 x 2 = 8 9 Metal: Co = +1 Charge = –1 18 Total =

Method 2 Ligands: 4 x CO = 4 x 2 = Metal: Co(–1) = Total =

8 10 __ 18

Figure 1.18

1.4 Mechanism and the Basic Reaction Steps To adapt the well-known phrase of Lord Rutherford, organic chemistry without mechanism is just stamp collecting. Mechanisms have been proposed for all of the major reactions catalysed or mediated by transition metals and used in organic synthesis. In many cases, the proposed mechanisms are supported by sound and thorough studies. In other cases, this is not so. The reader should approach any published mechanism (including those in this book) with caution. Unless the mechanism is backed up by the proper experiments such as kinetics and isotopic labeling, it should be regarded as speculative and fully open to reinterpretation. Nevertheless, thinking about mechanisms is one of the most valuable activities and an excellent source of new ideas. Mechanisms for reactions catalysed or mediated by transition metals are multistep. While the overall result can be complex and bewildering, the individual steps are taken from a quite small and relatively simple list. Some of these are common to “classical” organic chemistry; others are speciﬁc to the transition metals. While the basic reactions such as nucleophilic and electrophilic attack do operate, the presence of transition metals means that another set of basic reaction steps also operate. Combinations of these steps give us the overall reactions that we use. 1.4.1

Coordination and Dissociation

The most fundamental step is the simple coordination and dissociation of ligands (Scheme 1.3). This is important because a stable complex cannot coordinate the substrate, but must ﬁrst dissociate a ligand. Although some ligands are sufﬁciently labile to dissociate under mild conditions, in other cases it is necessary to use heat or light to achieve this. Often, reaction conditions are dictated by this initial dissociation.

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Organic Synthesis Using Transition Metals co ordination M + L

ML dissociation

Scheme 1.3

The equilibrium between the coordinated and dissociated species may be driven towards the dissociated side, to generate the more reactive complex, by the addition of a second metal ion (Scheme 1.4). The purpose of the second ion is to absorb the dissociated ligand, thus driving the equilibrium according to le Chatelier’s principle. In the case of phosphine ligands, this can be done using copper(I) salts (see Section 2.5.7). In the case of chloride ligands, this can be done, effectively irreversibly, but the addition of silver(I) salts (see Section 6.2 and Section 11.3.1). In this latter situation, what is achieved is the exchange of the chloride for a more labile anionic ligand, often triﬂate, but also perchlorate, tetraﬂuoroborate and hexaﬂuoroantimonate. + CuX

LnM PPh3

LnM Cl

+ AgOTf

LnM

+ Ph3PCuX

LnM OTf

+ AgC l

Scheme 1.4

Dissociation may also be made easier by replacing a strongly bound ligand with a weakly bound ligand in a separate step (Scheme 1.5). This can be achieved by destruction of a ligand. This is often done by oxidation of a CO ligand to CO2 using an amine oxide. The vacant site is then taken up by the more labile amine ligand. Another strategy is to substitute a less-labile ligand for a more-labile ligand in a separate step, so that the substrate avoids the more brutal conditions required for dissociation. LnM CO

Mo(CO)6

Me3N O

hν, MeCN

LnM NMe3

+ CO2

Mo(CO)3(NCMe)3

Scheme 1.5

Exchange of ligands may also be employed to modify the reactivity of a complex. Substitution of CO by NO+ will make a complex much more electrophilic (see Scheme 10.19). Substitution of CO by PPh3 will achieve the opposite. Complexation can also raise stereochemical issues. When a ␲-system is involved, the metal may attach to either face (Scheme 1.6). Selectivity is often observed, and can be exploited. The selectivity may be due to steric effects or neighbouring group effects.32 SiMe3

Cr(CO)6

(OC)3Cr

SiMe3

OTHP

Cr(CO)6

(OC)3Cr

OTHP

Scheme 1.6

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Introduction

1.4.2

15

Oxidative Addition and Reductive Elimination

Oxidative addition is the most important method for the formation of a metal–carbon single bond, although it is not limited to just this. In oxidative addition, a transition-metal fragment, which must have less than eighteen electrons, inserts into the X Y bond, and the oxidation state of the metal increases by 2 (Scheme 1.7). Usually X is an organic group and Y is a leaving group, such as a halide. There are, however, many other possibilities, including the simple one where both X and Y are hydrogen. The reverse process is reductive elimination in which the metal fragment is expelled by formation of an X Y bond, and the oxidation state of the metal drops by 2. oxidative addition M + X-Y

reductive elimination

X M Y

Scheme 1.7

1.4.3

Transmetallation

Oxidative addition is often followed by transmetallation in which an organic group on a second metal, usually a main group metal, is transferred in exchange for a group such as a halide (Scheme 1.8). This is another important method for formation of a transition metal–carbon bond. There is no change in oxidation state. M1 X

X M2

transmetallation M1 R

R M2

Scheme 1.8

1.4.4

Alkene and Alkyne Insertion

A fundamental process for coordinated alkenes and alkynes is insertion (also called migratory insertion), usually into a metal–carbon or metal–hydrogen bond (Scheme 1.9). This is a stereospeciﬁcally syn process, so insertion of alkynes results in cis-vinyl complexes. There is no change of oxidation state. M R

M R

insertion

insertion

M

M

R R

Scheme 1.9

The insertion of ethylene into a carbon–cobalt bond was carefully studied as part of work on the mechanism of Ziegler–Natta polymerization (Scheme 1.10).33

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Organic Synthesis Using Transition Metals Cp Co Me Me Ph3P

Cp + CH4 +

Co

Me

Ph3P

Scheme 1.10

1.4.5

CO insertion

Similarly, CO insertion (or migratory insertion) is the fundamental transformation of the CO ligand. It is a reversible process and an equilibrium will exist between the ␩1 -alkyl and ␩1 -acyl complexes (Scheme 1.11). This insertion is not observed for the formation of formyl ligands (R = H), owing to the low thermodynamic stability of the formyl group. R M C O

O

insertion M

R

Scheme 1.11

1.4.6

␤-Hydride Elimination

For alkyl transition-metal complexes, ␤-hydride elimination is a signiﬁcant process and many alkyl organometallics are unstable because of this facile transformation. It is the reverse of an alkene-insertion process (Scheme 1.12). As with insertion, there is no change in oxidation state. While the initial product is a ␩2 -complex, it is frequently followed by dissociation to give the free alkene. Stereochemically, it is also a syn process and, thus, quite unlike the familiar E2 reaction in classical organic chemistry. If there is no ␤-hydrogen available, then ␤-hydride elimination is (almost) impossible. ␩1 -Acyl, aryl and vinyl complexes do not undergo this reaction. The reaction is impossible for alkyl complexes possessing no ␤-hydrogens at all, such as neopentyl derivatives (Figure 1.19). ␤-Hydrogens may also be unavailable for geometrical reasons. In the norbornyl complex, Ha is unavailable as the rigidity of the bicyclic structure prevents a syn relationship with the metal. Hb is unavailable, as elimination would produce a structure in breach of Bredt’s rule. The same is true if the metal is at the bridgehead position of a norbornane structure, as in the stable tetranorbornyl derivative of cobalt (Figure 1.20).34 . Complexes that are unable to undergo ␤-hydride elimination for these reasons are sometimes referred to as ␤-blocked. β-hydride

M

H elimination

M

H

Scheme 1.12

M Hb neopentyl

R M Ha

M

norbornyl

Figure 1.19 β-Blocked complexes. Reprinted with permission from Byrne, E. K.; Theopold, K. H. J. Am. Chem. C 1989 American Chemical Society. Soc. 1989, 111, 3887.

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Introduction

17

C3

C13A

C12A C2 C4A

C16A C14A

C11A C5A

C17A

C1

C4

C15A

C12

C13

C5 Co

C11 C15

C14

C17

C16

C6 C10A

C7

C10

C9A C8 C9

Figure 1.20 A norbornyl cobalt complex. Reprinted with permission from Byrne, E. K.; Theopold, K. H. J. Am. Chem. Soc. 1989, 111, 3887. Copyright 1989 American Chemical Society.

1.4.7

Oxidative Cyclization

Oxidative cyclization (or oxidative coupling) is also a key reaction of alkene complexes, giving rise to metallacycles (Scheme 1.13). The oxidation state of the metal increases by 2.

M

oxidative cyclization

M

Scheme 1.13

1.5 Catalysis A catalyst is a substance that, when present in a reaction, increases the rate without itself being consumed.35 However, the catalyst cannot change the ⌬ G or ⌬ H of the reaction, or the position of an equilibrium; the change of rate is due to lowering of the activation energy. Most of the reactions catalysed by transition metals cannot occur in the absence of the catalyst. Transition-metal catalysts therefore increase the rate from zero, by opening up new molecular pathways. This is unlike many catalysts in classical organic chemistry. For instance, the formation of esters by the reaction of a carboxylic acid and an alcohol does proceed, albeit at a snail’s pace, even in the absence of a strong acid. The phenomenon of catalysis was discovered (amongst others) by D¨obereiner, a Chemist in the German city of Jena, in 1823.36 He found that when a jet of hydrogen

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Organic Synthesis Using Transition Metals pre-catalyst product C

starting material A

catalyst

another intermediate

by-product X

Figure 1.21

intermediate

starting material B

A catalytic cycle.

gas (generated by the reaction between zinc and sulfuric acid) played upon a piece of platinum foil in air, the gas immediately ignited even though no ﬂame was present. This discovery not only provided the world’s ﬁrst lighter, but also introduced the concept of catalysis, a term coined by the great Swedish chemist, Berzelius.37 Catalysis has become increasingly important. Many organometallic processes – though not all – are catalytic. Catalysis reduces waste and reduces cost. Ideally, the loading of the catalyst should be as low as possible. Many reactions employed in academic labs are run at 5 mol%. It seems likely that these could work at much lower loadings. While low catalyst loading is obviously desirable, it must be remembered that there is nothing in the deﬁnition of a catalyst about the loading. Thus, a material used in excess can still be a catalyst. Whatever the loading, the test as to whether something is acting as a catalyst is to draw the mechanism as a catalytic cycle (Figure 1.21). If the cycle brings the species back to where it started, then the reaction is catalytic. The term catalyst is widely used. It is often applied to molecules that are not the catalyst, but a precursor for the catalyst. These should be termed “pre-catalysts”. This is particularly the case is industrial processes. A combination of metal salts, reagents, ligands and supports are combined in a reactor. Somehow, they combine in situ to generate the catalyst. Due to this combination process, some reactions may have an induction period. The activity of the catalyst is an important issue. While the reactivity can be judged empirically by looking at the reaction conditions, temperature, concentration, pressure if a gas is involved, for catalysts, the loading is an important factor. In academic laboratories, it is common practice to employ 5 or 10 mol% as a standard loading. In academic research, cost of chemicals and waste disposal is often less of an issue, and the cost of a catalyst is of lesser importance when the investigator is ﬁfteen steps into a thirty-step sequence! An additional factor is that many academic reactions are run on milligrammes of substrate, and measuring anything less than 5 mol% of catalyst is very difﬁcult. The situation is quite different in industry. Catalyst loading must be reduced to reduce the cost of the process, to reduce the cost of waste disposal and to minimize the amount of residual metal that may contaminate the ﬁnal product. In this age, it is time for all academic labs to address the issue of catalyst loading to train students to think in this way for green and costeffective chemistry. So how do we measure the activity of the catalyst? This is usually discussed as the turnover number (TON), a concept adapted from enzymology. For mechanistic studies in organometallic chemistry, the turnover number is the number of times the catalyst can go around the catalytic cycle before becoming deactivated.38

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Introduction

19

In practice, for organic synthesis, the limit is often when the substrate is consumed, even if the catalyst is still active. Hence, for practical purposes, TON quoted will be calculated based upon the number of moles of product formed divided by the number of moles of catalyst employed, so a reaction proceeding in 80% chemical yield with 5 mol% of a catalyst will have a turnover number of 80/5 = 16.39 TOF is the turnover number per unit time.

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

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

26. 27. 28. 29. 30. 31. 32. 33.

Ziegler, K. Angew. Chem. 1964, 76, 545. Natta, G. Angew. Chem. 1964, 76, 553. Wilkinson, G. Angew. Chem. 1974, 86, 664. Fischer, E. O. Angew. Chem. 1974, 86, 651. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1999. Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748. Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3741. Negishi, E.-i. Angew. Chem., Int. Ed. 2011, 50, 6738. Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723. Trost, B. M. Pure Appl. Chem. 1992, 64, 315; Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. Thayer, J. S. J. Chem. Ed. 1969, 46, 442. The structure was determined by neutron diffraction (Love, R. A.; Koetzle, T. F. et al. Inorg. Chem. 1975, 14, 2653) following earlier X-ray work (Wunderlich, J. A.; Mellor, D. P. Acta Cryst. 1954, 7, 130; 1955, 8, 57). Abel, E. Chemistry in Britain 1989, 25, 1014. Zeise, W. C. Ann. Phys. 1827, 85, 632. As applied to Zeise’s salt: Chatt, J.; Duncanson, L. A. J. Chem. Soc. 1953, 2939. Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941. Herrmann, W. A.; Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295. Herrero-G´omez, E.; Nieto-Oberhuber, C. et al. Angew. Chem., Int. Ed. 2006, 45, 5455. Guari, Y.; van Strijdonck, G. P. F. et al. Chem. Eur. J. 2002, 4, 2229; Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. Caprio, V.; Williams, J. M. J. Catalysis in Asymmetric Synthesis, 2nd edn, John Wiley and Sons, Chichester, 2009. Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361. D´ıez-Gonz´alez, S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. Although the free carbene ligands were not isolated until the work of Arduengo, their complexes had been prepared ¨ as long ago as 1968: Ofele, K. J. Organometal. Chem. 1968, 12, P42; Wanzlick, H.-W.; Sch¨onherr, H.-J. Angew. Chem., Int. Ed. 1968, 7, 141. Arduengo, A. J.; Dias, H. V. R. et al. J. Am. Chem. Soc. 1991, 113, 361. Tolman, C. A. Chem. Rev. 1977, 77, 313. W¨urtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523; Diebolt, O.; Fortman, G. C. et al. Organometallics 2011, 30, 1668. Seki, M. Synthesis 2006, 2975. Andrews, S. P.; Stephan, A. F. et al. Adv. Synth. Catal. 2005, 347, 647. Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, John Wiley and Sons, 5th edn, Chichester, 2009. Butensch¨on, H. Synlett 1999, 680. Evitt, E. R.; Bergman, R. G. J. Am. Chem. Soc. 1979, 101, 3973.

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34. Bower, B. K.; Tennent, H. G. J. Am. Chem. Soc. 1972, 94, 2512; Byrne, E. K.; Theopold, K. H. J. Am. Chem. Soc. 1989, 111, 3887. 35. The term “catalytic amount” is widely used and understood, even though the deﬁnition of a catalyst does not refer to any amount of material. 36. Hoffmann, R. American Scientist 1998, 86, 326. 37. Berzelius provided a more elegant deﬁnition: “to awaken afﬁnities, which are asleep at a particular temperature, by their mere presence and not by their own afﬁnities”. For a historical discussion, see Roberts, M. W. Catalysis Lett. 2000, 67, 1. 38. Rothenberg, G. in “Kirk-Othmer Encyclopedia of Chemical Technology” John Wiley and Sons, Chichester, 2010, 1. 39. For a discussion of turnover number and palladium catalysis, see Farina, V. Adv. Synth. Catal. 2004, 346, 1553.

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2 Coupling Reactions 2.1 Carbon–Carbon Bond Formation The coupling of an organometallic and an organic halide should be a useful way of forming a C–C single bond. The reaction is, however, not general, but restricted to special cases. Grignard reagents will react efﬁciently with some halides, such as allyl halides, while copper reagents can be used in this type of reaction with a wider range of substrates. Even so, that range is not great and copper reagents are thermally unstable, as well as sensitive to air and moisture. A useful method would not require special conditions, be quite general and use easily prepared starting materials. This can be done with transition-metal catalysis (Scheme 2.1). By far the most widely used metal is palladium, but other metals, especially nickel and, more recently, iron, have also been employed.1 The main variables to consider are the “R” and “R ” groups that can be employed, the main group metals “M” that can be used, the nature of the leaving group “X” and the identity and quantity of the ligand “L”. The basic mechanism for palladium-catalysed coupling is a simple combination of oxidative addition, transmetallation and reductive elimination (Scheme 2.2). A coordinatively unsaturated palladium(0) complex 2.1, which is the catalytic species, is generated from an 18-electron palladium(0) complex by reversible ligand dissociation. Alternatively, it can be generated by reduction of a palladium(II) complex. Both the L4 Pd and the L2 PdX2 should be regarded as “pre-catalysts”. The catalyst or pre-catalyst complex may be assembled in situ from a mixture of a palladium source, such as a palladium(II) salt, Pd2 (dba)3 or even, in a few cases, palladium on carbon, and the ligand. This avoids the need to preform a palladium complex. If a palladium(II) pre-catalyst is employed, then there must be a reduction step prior to the start of the catalytic process. This has sometimes been done by the addition of a reducing agent, but more commonly, the palladium(II) is reduced by homocoupling of the organometallic partner, RM (Scheme 2.3). This homocoupling reaction is of occasional synthetic use itself (see Section 2.10). So how do we know which catalyst to employ? It is determined by looking for precedent and by doing experiments. Key variables are the ligand to metal ratio, and the identity of the ligand. Historically, Ph3 P has been the most widely used, but that doesn’t mean it is best (although it is cheapest). A less widely explored variable is the metal.

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals Pd cat. R M

R'

R R'

X

M X

Scheme 2.1 L4Pd

L2PdX2

±2L

reduction L2Pd 2.1

R R' reductive elimination

R'X oxidative addition

R' L2Pd 2.3

R' L2Pd

R

2.2

X

R M

M X

transmetallation

Scheme 2.2 L2Pd(II)X2 + 2RM

L2Pd(0) + R2 + 2MX 2.1

Scheme 2.3

2.1.1

The Main-Group Metal, M

A wide variety of main group metals, M, have been employed (Scheme 2.4). In terms of the main group metal, M, reactivity follows electropositivity. When highly electropositive metals such as lithium and magnesium are employed, transmetallation can be expected to be fast, but problems of low functional-group tolerance as well as air and moisture sensitivity arise. Less-reactive metals are more often employed: lithium and magnesium (Kumada or Corriu–Kumada reaction), zinc (Negishi reaction), aluminium, zirconium, tin (Stille coupling),

R Li R Cu

R MgBr

R SiR"3

R ZnBr

R R'

R AlR"2

R BR"2 R Snn-Bu3

R ZrClCp2

X R'; catalyst

Scheme 2.4

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Coupling Reactions

23

boron (Suzuki or Suzuki–Miyaura reaction) and silicon (Hiyama reaction) are the principal ones. Copper(I) derivatives of alkynes, generated in situ, are important coupling partners (Sonogashira reaction). A number of other metals have also been surveyed, but have yet to achieve signiﬁcant use in synthesis. The uses of these different metals are discussed later in this chapter. Each has their own advantages and disadvantages.2 2.1.2

Limitation

The most signiﬁcant limitation has been the difﬁculty of using alkyl halides: R’X, where R’ is a simple alkyl group. The coupling of alkyl halides posed a considerable challenge. While the synthetic importance of such a process is unquestionable, the ease with which ␤-hydride elimination from the ␩1 -intermediate 2.2a occurred (Scheme 2.5), presented great difﬁculties. In addition, alkyl halides are more reluctant to undergo oxidative addition than vinyl or aryl halides. A number of solutions to the problem gradually emerged, based upon either substrate structure or ligand choice.3 Examples may be found in the following sections speciﬁc to each reaction type. R'

β-hydride

elimination

L2Pd

H L2Pd

H X 2.2a

L2Pd

R'

+

X

+

HX

Scheme 2.5

2.1.3

Reactivity of the Leaving Group

The group X, which may be termed as a “leaving group” is most often a halogen. The order of reactivity is, generally, X = I ⬎ Br Cl, the same order as for nucleophilic substitution. Organoﬂuorine derivatives do not couple under normal circumstances. It is, therefore, commonly found that coupling reactions proceed much more easily with the more reactive iodo or bromo derivatives, rather than the chloro derivatives. This is, however, not universally true because it depends on which step in the mechanism is the rate-determining step.4 It will be true if oxidative addition is the rate determining step. Oxidative addition to iodides has been shown to be faster. A study of the Stille coupling of 2-halo pyridines 2.4, however, found the opposite order of reactivity (Table 2.1).5 In the time that it took for coupling of 2-chloropyridine to go to 75% completion, the same reaction with 2-iodopyridine had only progressed half as far. It was found that addition of lithium chloride to the reaction mixture with 2-iodopyridine enhanced reactivity. The added halide actually makes Table 2.1

N 2.4

X

+ Bu Sn 3

X

Conversion at 1440 min.

I

36%

Cl

75%

I, with added LiCl

100%

O 2.5

(Ph3P)2PdCl2 N 2.6

O

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Organic Synthesis Using Transition Metals OH

OTf Tf2O, base 2.7

2.8

Scheme 2.6 OTf

O Tf2O, base 2.9

2.10

Scheme 2.7

the rate of coupling of the iodide faster than that of the chloride. This indicates a second effect, believed to be the formation of more reactive anionic chloropalladium(0) complexes. Historically, the low reactivity of most aryl and vinyl chlorides in coupling reactions meant that such substrates were only used in special cases. As chlorides are cheaper than bromides and iodides, overcoming this obstacle became an important goal. The key was in the ligand. More reactive complexes, which are capable of catalyzing this reaction, can be generated by employing specialist ligands. The usefulness of halogens is often limited by difﬁculties in preparing the desired aryl and alkenyl halides. In addition, lack of reactivity can also be a problem. Alternatives to halides have been developed. The most widely used is the triﬂate group, that can be easily prepared from phenols for the coupling of aryl groups (Scheme 2.6), or from carbonyl compounds for the coupling of alkenyl groups (Scheme 2.7). Triﬂates can be somewhat unstable. Other sulfonates, such as mesylates6 and tosylates, can be used in some circumstances. Not only do these sulfonates tend to be more stable, they are also cheaper. Phosphate derivates are another alternative.7 Diazonium salts have also been used.8 These salts have the advantage of high reactivity, but the disadvantage of low stability. Thiol derivatives, especially thioesters, have also been successfully coupled.9

MgBr

dpppNiCl2

+ O 2.12

2.11

X 2.13 X = OH

(CF3CO)2O, LiBr

2.14 X = Br

1. Mg, Et2O 2.

(Ph3P)2NiCl2

OH

O 2.16 1. (CF3CO)2O, LiBr 2. Mg, Et2O; O CuI 3. Ac2O, py

OAc 2.17

Scheme 2.8

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Coupling Reactions

25

Under some circumstances, even ethers can be coupled. Dihydrofuran and dihydropyran were employed in a synthesis of a pheromone 2.17 of Pectinophora gossypiella, the pink bollworm (Scheme 2.8).10 The pheromone is exclusively the Z isomer at the 7,8-alkene, but a 1:1 E/Z mixture at the 11,12-alkene. Coupling of dihydrofuran 2.12 with n-butylmagnesium bromide 2.11 using dpppNiCl2 as the catalyst resulted in coupling with loss of alkene stereochemistry, while coupling of the subsequent Grignard reagent with dihydropyran using (Ph3 P)2 NiCl2 as the catalyst resulted in complete retention of alkene stereochemistry yielding, after chain extension with oxetane and acetylation, the desired pheromone mixture 2.17.

2.1.4

Selectivity

Achieving selective coupling at one position in a molecule, while leaving another potentially reactive position untouched is synthetically important. There are several ways to achieve this goal.11 One is to use several different halogens or other leaving groups and exploit the inherent reactivity difference. Another is to employ the same halogen in several sites, but exploit electronic or steric factors.

2.1.4.1

Selectivity Based upon Halogen Reactivity

Given the usual order of reactivity amongst the halogens, I ⬎ Br Cl, it is often possible to achieve selective coupling at the position of one halogen in the presence of a less-reactive halogen.12 Arene 2.18 underwent selective Sonogashira coupling at only the bromine-substituted position (Scheme 2.9). This selectivity has been exploited in a synthesis of terprenin 2.26, an immunosuppressant compound (Scheme 2.10).13 The iodobromide 2.20 underwent selective Suzuki coupling with one boronic acid 2.21 at the iodo position, then a second boronic acid 2.23 at the bromo position. This two-step process could be carried out in one pot. The unusual catechol protecting group was not wasted, but converted into a prenyl ether at the end of the synthesis by hydrolysis and a Wittig reaction. For synthetic purposes, it would often be more efﬁcient to introduce the same halogen by a single doublehalogenation step, then exploit reactivity differences due to position. Factors that affect this form of regioselectivity would be steric hindrance, coordination and electronics.

2.1.4.2

Steric Hindrance

The steric environment around X is also important. Reaction tends to be favoured at the less-hindered position, other factors being equal, as in the coupling reactions of gem-dihalides 2.27 (Scheme 2.11)14 and 2.30 (Scheme 2.12).15 An application of this selectivity can be found in Scheme 2.48.

F 3C

Br

SiMe3 Pd(PPh3)4, CuI, Et3N

SiMe3 F3C

Cl

Cl

2 .1 8

2.19

Scheme 2.9

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Organic Synthesis Using Transition Metals OMe Br

2.21 O Pd2(dba)3, Na2CO3 OMe

I

MeO

OMe

O

(HO)2B

OH 2.20

O

Br MeO

OH

O 2.22

OMe

OMe (HO)2B

OH O

HO

2.23

Pd(PPh 3)4

MeO

OH 2.24

H3O

O OMe

OMe HO

O

CHO

Ph3P OMe

MeO

OH

OH HO

2.25

O MeO

OH 2.26

OH

Scheme 2.10

Cl

Ph

dppbPdCl2 ClMg

Cl 2.27

S

Ph

S

Cl

2.28

2.29

Scheme 2.11 TBSO Cl 2.30

1. Me2Zn, (dpephos)PdCl2 2. PhMgBr, (Cy3P)2Pd

Cl

TBSO Me 2.31

Ph

Scheme 2.12

2.1.4.3

Electronic Effects

Coupling reactions often appear to be favoured at the more electron-poor halogenated position. One reason can be that oxidative addition is favoured at such sites.16 This is because oxidative addition involves donation of electron density from the low-valent metal to the substrate, a process made easier by the presence of suitably placed electron-withdrawing groups. This has been systematically studied for the Sonogashira reaction for a series of nitrogen substituted arenes (Scheme 2.13).17 For the nitro compound 2.32, para-coupling is favoured over meta. Ortho-coupling is also (in 2.34) favoured over meta, but the para-coupling is thirty times faster. The ortho and para positions are the more electron poor. For the anilines (Scheme 2.14), meta-coupling is favoured in both cases, as the meta position is the least electron rich, but they are still less reactive than the nitro compounds. The reaction times for the anilines were longer than for the nitro compounds, even at reﬂux.

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Coupling Reactions O2N

Br 2.32 Br

O2N

n-C5H11 2.33 Br

H

n-C5H11 Pd(PPh3)4, CuBr, NEt3, RT

O2N

27

O2N Br

Br

Br 2.35

2.34 n-C5H11

Scheme 2.13 H2N

H2N

Br

2.36

Br

H2N Br

Br

H

n-C5H11 2.37 Pd(PPh3)4, CuBr, NEt3, reflux H2N

n-C5H11

Br

Br

2.38

2.39

n-C5H11

Scheme 2.14 Br

Br Br

CO2Me O 2.40

SnBu3 (Ph3P)4Pd O

CO2Me

2.41 Me

Me Me4Sn [(o-tol)3P]4Pd O

CO2Me

2.42

1. NaOH 2. Cu,Δ

O 2.43

Scheme 2.15

The dibromofuran 2.40 was subjected to a sequence of Stille coupling reactions, the second one requiring a more robust catalyst, leading to rosefuran 2.43 after hydrolysis and copper-catalysed thermal decarboxylation (Scheme 2.15).18 A quite different synthesis of rosefuran may be found in Scheme 11.48. In other cases, the reason for the selectivity may not be primarily electronic, but a coordination effect. This may be the case in a synthesis of Ailanthoidol using the Sonogashira reaction (see Scheme 2.115).

2.2 Lithium and Magnesium: Kumada Coupling When organolithium or Grignard reagents are coupled, the reaction is known as the Kumada reaction, or Kumada–Corriu reaction (Schemes 2.16 and 2.17).19 Functional-group tolerance is often low, as organolithium and magnesium reagents show high reactivity to a wide range of functional groups. If, however, the catalyst

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Organic Synthesis Using Transition Metals NMe2

NMe2

n-BuLi ortho-metallation

Br

Ph

NMe2

(Ph3P)4Pd

Ph

Li

2.44

2.46

2.45

Scheme 2.16 EtMgBr Pd(PPh3)4 n-C6H13

I

n-C6H13 Et 2.48

2.47

Scheme 2.17 Br PhMgBr dpppNiCl2

Br2, NaOAc, AcOH

N N

N N

N N

2.50

2.49

Ph

2.51

Scheme 2.18

Br

S 2.52

Br

+

BrMg

S

NiCl2, dppbenz

S

S S

2.53

2.54

Scheme 2.19

is sufﬁciently reactive that coupling is fast, surprisingly good functional-group tolerance can be achieved. Nevertheless, this reaction is most often used for the synthesis of molecules with little functionality. With vinyl halides, alkene geometry is retained. A nickel-catalysed coupling of a Grignard reagent with a bromopyrazole 2.50 was employed as the last step in a synthesis of withasomnine 2.51 (Scheme 2.18).20 Nickel catalysis was also employed to make terthiophene on a 700 g scale (Scheme 2.19).21 The Kumada reaction was employed for the synthesis of dendralenes, cross-conjugated alkenes, which show interesting reactivity (Scheme 2.20).22 The products even include the labile [3]dendralene 2.56 which has a half-life of just 10 h at 25 ◦ C. A Kumada allylation gave the desired isoindoline 2.59 on a multigramme scale (69.5g as its HCl salt) accompanied by small amounts of the isomerization product 2.61 (Scheme 2.21). Transition-metal catalysed isomerization is discussed in Section 11.4. Formation of this by-product could be minimized by correct choice of ligand and the metal:ligand ratio.23 Kumada coupling reactions of alkyl chlorides, possessing ␤-hydrogens also proceed using palladium catalysis in the presence of either electron-rich phosphines24 and NHC ligands (Scheme 2.22).25 Simple dienes, such as butadiene, may also act as useful ligands in promoting coupling of this sort (Schemes 2.23 and 2.24).26 This form of catalysis shows a surprising preference for primary alkyl halides over aryl halides. Grignard reagents are also formed during addition of nucleophiles, with magnesium counter ions, to benzynes. A Grignard reagent, generated in this way, was employed in a synthesis of Dictyodendrin A.27 Given the array of aryl groups in this telomerase inhibitor natural product, it is no surprise that palladiumcatalysed coupling was also used later in the synthesis (Schemes 2.25 and 2.26).

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Br dpppNiCl2 2.56

Cl Cl dpppNiCl2

MgCl Br

Cl

2.55

Cl

2.58

dppeNiCl2 2.57

Scheme 2.20 MgCl Npt-Bu2P, Pd(OAc)2

HN

+

HN

2.59 Br

HN 2.61

2.60

Scheme 2.21 Pd(OAc)2, PCy3 , NMP or IMesPd.Naphthoquinone

BrMg Cl

+

2.62

2.64

2.63

Scheme 2.22 NiCl2 OTs

Ph

+

EtMgBr

Ph 2.66

2.65

Scheme 2.23 NiCl2 Br Br

+ n-PrMgBr Br

2.67

Scheme 2.24 HO

Suzuki OSO3 NH

MeO2C N

thermal nitrene chemistry

OH

benzyne trappingKumada coupling HO OH

2.69

HO

Scheme 2.25

29

2.68

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Organic Synthesis Using Transition Metals OMe

OMe

Br

BocHN

Br

TMP2Mg.2LiBr

Br

BocN

OMe

Br

N OMe Boc MgTMP 2.72

OMe

2.70

2.71

MeO

Br

I OMe CuI, (Ph3P)4Pd

MeO

N Boc

OMe

1. Me3SiOTf 2. DDQ 3. p-MeOC6H4(CH2)2Br, KOH 4. p-MeOC6H4CHBrCO2Me, AgOTf

2.73 OMe MeO

MeO Ot-Bu 1. pinBBpin, dppfPdCl2, KOAc Ot-Bu 2.

Br MeO2C N

N3

OMe

N3 MeO2C N

2.75

OMe

I dppfPdCl2, NaOH

MeO

MeO OMe

MeO

OMe

2.74

MeO

HO

OSO3 1. Δ 2. Cl3CCH2SO3Cl, DABCO 3. BCl3, Bu4NI 4. Zn, NH4HCO2

NH

MeO2C N

OH

HO OH HO

Scheme 2.26

2.69

2.76

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Coupling Reactions

31

The benzyne intermediate 2.71 was generated by elimination of HBr from dibromo arene 2.70 using the magnesium derivative of tetramethylpiperidine, and trapped in an intramolecular fashion by a nearby carbamate anion. Under carefully developed conditions, coupling of the Grignard reagent 2.72, generated in situ, with an added aryl iodide was possible. Success required the addition of a copper(I) salt, indicating that the active species might be an aryl copper. After installation of two more side chains and oxidative conversion of the indoline to an indole, the arene 2.74 with the remaining bromide, was converted to a pinacolatoborane, and then Suzuki-coupled to an additional, highly functionalized aryl group with iodide 2.75. Thermal ring closure formed the carbazole group, and a series of functional group transformations yielded the natural product 2.69. The coupling reactions of Grignard reagents may also be promoted by the addition of zinc halides, possibly generating organozinc reagents in situ (Scheme 2.27).28 Br +

MgBr

Pd(OAc)2, Pt -Bu3, ZnBr2 CN

CN 2.78

2.77

Scheme 2.27

Grignard reagents have been coupled with organic halides using metals other than palladium and nickel. While various metals or metal combinations have been tested, such as a manganese–copper mixed system,29 iron has been found to be of particular use. In addition, iron, compared to palladium, is very much cheaper and less toxic. While the iron-catalysed coupling of Grignard reagents was reported as long ago as 1971,30 most of the development of this reaction is more recent.31 Simple iron salts and complex can catalyse the coupling of a variety of Grignard reagents with aryl, vinyl and alkyl halides (Schemes 2.28–2.31).32 Due to the potency of the catalytic system, surprising functional-group tolerance is possible. Br

Ph

+

Fe(dbm)3

PhMgBr

Ph

Ph 2.80

2.79 O

O

dbm = Ph

Ph

Scheme 2.28 O

O I +

MeMgBr

Me

Fe(acac)3

2.81

2.82

Scheme 2.29 CO2Me + n-C9H19MgBr

Cl

CO2Me

Fe(acac)3 n-C9H19

2. 83

2 .8 4

Scheme 2.30

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Organic Synthesis Using Transition Metals OAc

OAc

N O

Cl

N

AcO

OAc

+ n-C14H29MgBr N

N O

Fe(acac) 3

N AcO

n-C14H29

N OAc

N

N

2.86

2.85

Scheme 2.31

2.3

Zinc: The Negishi Reaction

When organozinc reagents, usually organozinc halides, undergo coupling, the reaction is known as the Negishi reaction.33 Greater functional-group tolerance than in the Kumada reaction is displayed, due to the lower reactivity of zinc reagents. Nevertheless, some functional groups cannot be present, and the reagents are still air and water sensitive. Zinc reagents often made from Mg or Li reagents, so the same problem of lack of tolerance in that partner can be found. Zinc reagents can also be generated directly from organic halides by treatment with metallic zinc (as Frankland did back in the 1840s) and modern techniques have made this easier.34 This route can avoid some of the tolerance problems. Direct generation of an organozinc from an alkyl iodide 2.87, in the presence of an alkyl chloride, was used in the synthesis of insect pheromone 2.90 (Scheme 2.32).35 1. act. Zn 2. 2.88 I (Ph3P)4Pd

Cl

I

X

2.87 2.89 X = Cl NaOAc 2.90 X = OAc

Scheme 2.32

One particular aspect of this chemistry is in the preparation of zinc homoenolates prepared from ␤-iodoesters (Scheme 2.33).36 This chemistry becomes particularly signiﬁcant with ␤-iodoesters 2.95 derived from the amino acid serine 2.94. These are useful for the synthesis of novel amino acids by Negishi coupling with aryl and acyl halides (Scheme 2.34).37 Coupling of a complex peptidyl aryl iodide 2.98 with a zinc reagent 2.99 of this type was a late step in a synthesis of a cyclic tripeptide and aminopeptidase inhibitor OF494-III 2.100 (Scheme 2.35).38

n-Bu I

CO2Et Zn(Cu) 2.91

IZn

CO2Et 2.92

OTf

(Ph3P)4Pd

n-Bu

CO2Et 2.93

Scheme 2.33

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Coupling Reactions NH3

HO

NHBoc

I

Zn/Cu, )))

NHBoc

IZn

CO2Bn

CO2 2.94

CO2Bn

2.95

COCl O (Ph3P)2PdCl2

33

2.96

NHBoc

O

O CO2Bn 2.97

Scheme 2.34

OMe

OMe O

O

CbzHN

ZnI CO2t-Bu Pd2dba3, P(o-tol)3

I

HN BocHN

CO2Me

CbzHN

HN

t-BuO2C

O

2.98

BocHN

CO2Me O

2.99 CONH2

CONH2 OMe O

1. 2. 3. 4.

CF3CO2H HATU, i-Pr2NEt LiOH H2, Pd/C

NH2 NH O 2.100

HN

CO2H O

CONH2

Scheme 2.35

Zinc reagents may also be prepared by deprotonation of the substrate with a strong lithium base to form the organolithium reagent, followed by transmetallation with a zinc salt, such as zinc chloride. This strategy will work well for substrates that can be cleanly and selectively deprotonated. One example is provided by furan 2.101, which is quite easily converted into the ␣-zinc derivative 2.102. (Scheme 2.36).39 Ethyl vinyl ether 2.104 is another good substrate (Scheme 2.37).40 In addition, after coupling, the substituted vinyl ether 2.106 may be hydrolysed to give a ketone 2.107. Zinc reagents may also be prepared by transmetallation from other organometallic derivatives. Treatment of Grignard reagents with zinc salts, gives zinc reagents, which may undergo coupling. In this way, the zinc reagent 2.109 could be prepared from the alkyl bromide 2.108 and coupled to give supellapyrone 2.110, a cockroach sex pheromone (Scheme 2.38).41 The cyclopropyl tin reagent 2.111 may be converted to the lithium reagent, and then the zinc reagent, which could be coupled to a vinyl iodide (Scheme 2.39).42

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Organic Synthesis Using Transition Metals

Br

1. n-BuLi 2. ZnCl2 O

ZnCl

O

2.101

Br (Ph3P)4Pd

O

O

2.10 2

2.10 3

Scheme 2.36

I OEt

1. t-BuLi 2. ZnCl2

MeO2C (Ph3P)2PdCl2

OEt ZnCl

2.104

2.105 O

OEt H3O+

MeO2C

MeO2C 2.106

2.107

Scheme 2.37

Br

1. Mg 2. ZnCl2

ZnX

2.108

Br

2.109

O

O

O dppfPdCl2

O 2.110

Scheme 2.38

TBSO

SnBu3

1. n-BuLi 2. ZnCl2 3. I Pd(PPh3)4

OTBS

2.111

TBSO

OTBS 2.112

Scheme 2.39

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Coupling Reactions Ph

Ph

Et2Zn, LiI, Ni(acac) 2

Ph via

Br 2.113

35

[Ni] 2.115

2.114

Scheme 2.40 (n-C5H11)2Zn, Ni(acac)2 F3C S

S

2.117

I

S

2.116

S 2.118

Scheme 2.41 Br + Ts

N

Ni(COD)2, L

IZn

Ts

2.119

N 2.120

L=

O

N

N s-Bu

O

N 2.121

s-Bu

Scheme 2.42

During studies of organozinc chemistry with nickel catalysis, it was found that the presence of a nearby functional group capable of coordinating nickel could prevent ␤-hydride elimination and permit successful coupling of alkyl halides (Scheme 2.40).43 The functional groups involved include alkenes, both simple and substituted, amides, ketones, and dithiolanes. The addition of electron-poor ligands improved the reaction, particularly p- or m-triﬂuoromethylstyrene 2.117,44 or p-ﬂuorostyrene (Scheme 2.41).45 Secondary alkyl halides can also undergo coupling with zinc reagents using the bidentate pybox ligand 2.121 (Scheme 2.42).46

2.4 Aluminium and Zirconium Derivatives of these two metals are of interest as they can be generated by hydrometallation, a process analogous to hydroboration. Treatment of alkynes with DIBAL gives a vinyl aluminium reagent 2.122. These can be coupled with organic halides in the presence of a palladium or nickel catalyst (Scheme 2.43). While this works well for terminal alkynes, the coupling with derivatives of internal alkynes is slow due to steric hindrance. The coupling reaction can be speeded up by employing a zinc halide additive, which acts as a second metallic catalyst (Scheme 2.44). This has been termed “bimetallic” catalysis. In this case, the rate acceleration and concomitant yield improvement is due to transmetallation: the vinyl group is transferred to zinc and the resulting zinc reagent 2.126 is more reactive towards transmetallation. Vinyl aluminium reagents 2.128 prepared by the hydroalumination of propargylic alcohols 2.127 can also undergo coupling (Scheme 2.45).47 This chemistry has been employed on a multigramme scale for the

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Organic Synthesis Using Transition Metals Br

DIBAL n-Bu

H

Ni(PPh3)4

Ali-Bu2

n-Bu

n-Bu

2.122

2.123

Scheme 2.43 Me

Me Pd(PPh3)4 ZnCl2

Ali-Bu2

DIBAL Et

Et Et

via

I Et

Et 2.125 88% in 1 hr with ZnCl2 0% in absence of ZnCl2

Et 2.124

Ali-Bu2

ZnCl + i-Bu2AlCl

+ ZnCl2 Et Et 2.124

Et

Et 2.126

Scheme 2.44 OH 1. LiAlH4 OH 2. EtOAc

2.127

I O Al EtO OEt

CO2Me Pd2dba3, Ph3As

2.128

2.129

CO2Me

Scheme 2.45

synthesis of a drug candidate 2.135,48 using a sequence of a Suzuki coupling with heterogeneous catalysis and a Sonogashira reaction to construct the propargylic alcohol substrate 2.133 (Scheme 2.46). Addition of a zinc salt and the use of the PEPPSI catalyst were found to be important for the ﬁnal coupling. Di(cyclopentadienyl)zirconium hydrochloride, “Schwartz’s reagent”, hydrochloride allows hydrozirconation. The resulting vinyl zirconium species 2.137 behave similarly to the vinylalanes, and undergo coupling in a similar manner (Scheme 2.47). A sequence of zirconation reactions was employed to synthesize the side chains of the mycolactones (Scheme 2.48).49 Hydrozirconation, followed by iodinolysis, gave the trans-iodoalkene 2.139, which was then subjected to Negishi coupling with a zinc acetylide. Unlike in the Sonogashira coupling (Section 2.8), coupling at both termini of the alkyne is not observed. Carbozirconation of intermediate 2.140, using the reagent derived from trimethylaluminium and zirconocene chloride, again followed by iodinolysis and Negishi coupling, gave a dienyne 2.141. A third iteration yielded the left-hand fragment, iodotrienyne 2.142. In the right-hand triol fragment, the methyl group of the trisubstituted alkene is cis to the main chain of the molecule and, consequently, a different strategy had to be employed to make it. This was done by taking advantage of the higher reactivity of the trans halogen in the 1,1-dihaloalkene 2.144 (see Section 2.1.4.2).

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Coupling Reactions Br B(OH)2 O 2.130

I

Br Pd/C, PPh3, n-Bu4NBr, Na 2CO3 O

2.131

OH

2.132

OH

Pd(OAc)2, PPh3, DMPU

O Al RO OR

Red-Al® O

37

2.133

2.134

O OH

Br ZnCl2, PEPPSI

S

S O

2.135

Scheme 2.46 Cl Et

Et

ZrCp2

Cp2ZrHCl Et

2.136

Br MeO2C ZnCl2, (Ph3P)4Pd

Et 2.137

Et MeO2C

Et

2.138

Scheme 2.47

Thus, sequential Negishi coupling reactions of an alkyne and dimethylzinc delivered the desired stereoisomer 2.145. Hydrozirconation-iodinolysis of alkyne 2.145 installed an iodide and allowed coupling with the lefthand fragment 2.143. After the Negishi coupling of the two fragments, selective deprotection and oxidation gave the desired carboxylic acid 2.148 with six stereodeﬁned alkenes, which corresponds to mycolactone B. A Negishi coupling of a vinyl zirconium species 2.150 was one of a series of coupling reactions in syntheses of cis and trans bupleurynol 2.156 (Scheme 2.49).50 The vinyl zirconium species was coupled with a vinyl bromide 2.153 that was the product of a Negishi coupling of a 1,2-dihaloalkene 2.151 with a diynyl zinc reagent 2.152. After desilylation, the syntheses were completed by Sonogashira reactions with either cis or trans 3-iodoallyl alcohol. As the molecule could be brought through the entire sequence without isolation, the residual palladium from the earlier couplings served to catalyse the ﬁnal coupling, and no extra needed to be added.

2.5 Tin: The Stille Reaction Coupling of organotin reagents is known as Stille coupling.51 There is now enormous functional-group tolerance. Tin reagents are stable to many common reagents, as well as water and air. They do tend to be unstable to strong electrophiles, such as strong acids and halogens, and to some oxidizing agents. The low reactivity of organotin reagents makes the Stille reaction ideal for the synthesis of highly functionalized

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Organic Synthesis Using Transition Metals

HO

1. Cp2ZrCl2, DIBAL 2. I2 HO

Br I

Br 2.144 TBSO

2.139 Zn 2 (dpephos)PdCl2

OMOM

1. BrZn SiMe3 (dpephos)PdCl2 2. Me2Zn, (t-Bu3P)2Pd 3. MeOH, K2CO3

HO 2.140

1. Cp2ZrCl2, Me3Al 2. I2

OMOM I

HO 2.141

Zn 2 (dpephos)PdCl2

OTBS

2.145

TBSO

OTBS

1. Cp2ZrCl2, DIBAL 2. I2

HO 2.142

OMOM

1. Cp2ZrCl2, Me3Al 2. I2 3. TBSCl, C3N2H4 TBSO

I

I

2.146

TBSO

OTBS

2.143 1. t-BuLi 2. ZnBr2 (dpephos)PdCl2 OMOM TBSO 2.147

TBSO

OTBS

1. TBAF 2. Dess-Martin 3. NaClO2, Na2HPO4 OMOM HO2C 2.148

TBSO

OTBS

Scheme 2.48

molecules. For instance, the vinyl bromide 2.157 was coupled with an aryl tin reagent with retention of stereochemistry (Scheme 2.50).52 The substrate contains an enol ester, an alkene, a ketone and a nitro group. This tremendous substrate tolerance is very signiﬁcant for natural-product synthesis. In a synthesis of rapamycin 2.160, a double Stille coupling was used to close the macrocycle in the last step after all of the deprotections had been carried out (Scheme 2.51).53 Other “no protecting group” Stille couplings are in syntheses of manumycin 2.163 (Scheme 2.52)54 and indanomycin (Scheme 2.53).55 One advantage of organotin reagents is that they can be easily puriﬁed by chromatography or distillation. Another advantage is the number of methods that can be used to make them. Simple organotin reagents are often made by the reaction of organolithium reagents or Grignard reagents with tin halides (Scheme 2.54). The reverse, the addition of a tin nucleophile to an organic electrophile, can also be used (Scheme 2.55). Tin reagents can also be prepared by the addition of tin radicals to multiple bonds (Scheme 2.56). The palladium-catalysed coupling of organic halides or their equivalent with distannanes is a mild method

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I

Br 2.149

+ ClZn

SiMe3 2.152

2.151 (Ph3P)4Pd

Cp2ZrHCl

SiMe3 ZrClCp2 Br

2.150

2.153

(PhCN)2PdCl2 SiMe3

2.154 1. TBAF 2. I OH CuI, i-PrNH2 OH 2.156

Scheme 2.49 NO2

O O Br

NO2

O

Me3SnPh, (Ph3P)2PdCl2,CHCl3, Δ

O

O

O Ph 2.157

2.158

Scheme 2.50

O H OH OMe O H O

I I O

O

O

H

OMe

OH O

OH

OMe

O OH H OMe O H O

2.159 Snn-Bu3 n-Bu3Sn (MeCN)2PdCl2, i-Pr2NEt

O

O O

OH O OMe 2.160

Scheme 2.51

39

H

OMe OH

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Organic Synthesis Using Transition Metals O O

O

H N (Ph3P)2PdCl2, DIBAL

O 2.161

HO

H N

O

O HO

Snn-Bu3

2.163 O

H N

Br O 2.162

HO

Scheme 2.52

O O H H CO2H Et

N H H

n-Bu3Sn

I

2.164

Pd(PPh3)4 DMF O

2.165 H

Et

N H H

O H H CO2H Et H

2.166

Et

Scheme 2.53

n-Bu3SnR

RLi + n-Bu3SnCl

Scheme 2.54

O n-Bu3SnLi

OH

+ R

H

R

Snn-Bu3

Scheme 2.55

n-BuSn3H AIBN, Δ OH

n-Bu3Sn

Scheme 2.56

H N

OH

O HO

O

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Coupling Reactions Pd(0)

RX + Me6Sn2

41

RSnMe3

Scheme 2.57 1. NaCNBH3, TiCl 4 2. DCC, CuCl

CO2Et

AcO O

Ot-Bu

CO2Et

AcO

2.167

OTIPS O

1. L-selectride, Ph2NTf2 2. Me6Sn2, (Ph3P)4Pd, LiCl

1. DIBAL 2. TIPSCl, TMG 3. CrO3, acetone

Ot-Bu

OTIPS Me3Sn

Ot-Bu

Ot-Bu

2.168

2.169

Scheme 2.58

for their synthesis (Scheme 2.57). This last method was used to form vinyl stannane 2.169 for carbonylative coupling, as part of a synthesis of strychnine (Scheme 2.58; see Scheme 4.12 and Scheme 9.53 for earlier and later parts of this synthesis).56 Tin has a valency of four, so there must be four “R” groups. Typically, only one R group transfers. Unless the “R” group is something cheap and readily available, such as methyl, then three of the group must be non-transferring dummies. Tri-n-butyltin derivatives, n-Bu3 SnR, where R is aryl, vinyl or alkynyl, are often used. The n-Bu group usually transfers more slowly than aryl, vinyl or alkynyl groups, although, sometimes, the product is contaminated by butyl transfer products. Trimethyltin derivatives, Me3 SnR, can also be used. They are more reactive, but more expensive. The removal of the tin by-product can be a problem. While trimethyltin halide by-products can be removed by aqueous extraction, tri-n-butyl tin by-products remain in the organic phase and their removal can be troublesome. Treatment with potassium ﬂuoride to convert them to an insoluble polymer,57 or the use of silica gel impregnated with either KF58 or K2 CO3 ,59 is the best method of removal. However they are removed, the toxicity of organotin compounds presents a serious problem, and, if the products are being used in biological assays, any organotin contaminants can give erroneous results. 2.5.1

Vinyl Stannanes

The coupling of vinyl stannanes with vinyl halides is a useful route for making dienes, as, in general, the stereochemistry of the double bonds of the coupling partners is retained. This property of the reaction was exploited in a synthesis of coriolic acid (Scheme 2.59).60 n-Bu3Sn 2.170

n-C5H11

+

HO2C I

OH

2.171

(MeCN)2PdCl2 HO2C

2.172 HO

Scheme 2.59

n-C5H11

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Organic Synthesis Using Transition Metals CO2Me

H

Br N

N OTBDPS

O

H

N

Boc

CO2Me

SnBu3 (Ph3P)4Pd

N

Boc

OTBDPS OTBDPS 2.174

TBDPSO 2.173

Scheme 2.60 1. O O

Br S (Ph3P)4Pd, DMF, 100 °C 2. aq. HCl

O

1. n-BuLi 2. Me3SnCl

O

S

N

SnMe3 2.176

S

2.175

BocHN

S

S 2.177

Scheme 2.61 N I S Cl

N

M

Pd(PPh3)4

N

N

2.178

N S

2.179

Cl

N 2.180

Scheme 2.62

A tandem Stille–Diels–Alder reaction to form tricycle 2.174 from vinyl bromide 2.173 was used in a manzamine synthesis (Scheme 2.60).61 Another aspect of this synthesis is discussed in Scheme 8.66. 2.5.2

Aryl and Heteroaryl Stannanes

The Stille reaction is a robust choice for the synthesis of biaryls, including heteroaryl systems (Scheme 2.61).62 Despite trying Suzuki, Hiyama and Kumada couplings and others, only Stille coupling (M = n-Bu3 Sn) proved reliable on a large scale (302 g) for the synthesis of a heteroaryl-substituted imidazole 2.180, needed for the synthesis of an angiogenesis inhibitor (Scheme 2.62).63 2.5.3

The Intramolecular Stille Reaction

Intramolecular Stille couplings have been employed for ring formation, especially macrocycles. A macrocyclic Stille coupling was employed close to the end of a synthesis of sarain A 2.182 to form a 14-membered ring (Scheme 2.63).64 The natural product displays an interesting amine–aldehyde interaction. 2.5.4

Coupling of Acid Chlorides

Acid chlorides may also be used as substrates. Oxidative addition generates an acyl palladium(II) complex that may decarbonylate leading to by-products. This may be avoided by running the reaction under an atmosphere

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Coupling Reactions

1. (Ph3P)4Pd, LiCl 2. DIBAL I 3. Dess-Martin 4. HF.pyridine

O N

N

43

CHO N

N

OTES

OH

PMBO

HO

2.181

SnBu3

2.182

Scheme 2.63 O

CO2Bn

O 2.183

2.185

1. KOH 2. TBDPSCl, C3H4N2 3. (COCl)2

n-Bu3SnH, AIBN

O n-Bu3Sn

Cl TBDPSO 2.184

CO2Bn

2.186 CO, BnPd(PPh3)2Cl O CO2Bn

TBDPSO

2.187

Scheme 2.64 O

O Cl O O

O CO, BnPd(PPh3)2Cl

O

O

O

Snn-Bu3 2.188

2.189 O

Scheme 2.65

of CO.65 Le Chatelier’s principle then operates to disfavour decarbonylation. This method was used in a synthesis of a pyrenophorin precursor 2.187 (Scheme 2.64).66 Another approach to the same natural product, pyrenophorin 2.189, is to carry out a dimerization by the Stille coupling of a stannane containing an acid chloride 2.188 (Scheme 2.65).67 The fact that these two functional groups can be in the same molecule illustrates further the functional group tolerance of the Stille reaction. Once again, decarbonylation is prevented by the use of a CO atmosphere. A corollary of this is that if a Stille coupling of a vinyl or aryl halide is carried out under an atmosphere of CO, then a ketone will be produced. This is discussed in Section 4.1.

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Organic Synthesis Using Transition Metals Tf2O, py 2.190

N H

O

N

OTf

2.191

Me3Sn Pd(PPh3)4, LiCl 2.192

N

O 2.193

O

O O

Scheme 2.66 L L Pd R' OTf

LiCl

L L Pd R' Cl

Scheme 2.67

2.5.5

Stille Coupling of Triﬂates

The triﬂate leaving group was introduced to coupling reactions as an alterative to halogens. They are particularly useful when there is no simple way to prepare the required halide partner. Aryl triﬂates can be prepared from phenols and pyridyl triﬂates can be prepared from pyridones.68 This transformation is usually achieved using triﬂic anhydride and an amine base. The coupling of a triﬂate 2.191, derived from quinolone 2.190, with stannane 2.192 was used in a short synthesis of dubamine 2.193 (Scheme 2.66). The inclusion of lithium chloride is important. This is almost always required when triﬂates are used. It is believed that transmetallation is more favourable with a chloropalladium intermediate, generated in situ by ligand exchange, than a palladium triﬂate (Scheme 2.67). Vinyl triﬂates can be prepared from ketones by formation of the enolate, followed by quenching with a suitable reagent. Triﬂic anhydride can be used, but triﬂamide reagents, ArNTf2 , often give better results.69 When unsymmetrical ketones are used as the starting material, the use of the kinetic enolate or thermodynamic enolate can result in the formation of either isomer of the triﬂate, 2.194 or 2.196 (Scheme 2.68). Each undergoes coupling without isomerization, giving the two isomers of the diene 2.195 or 2.197. 2.5.6

Stille Coupling of Alkyl Halides

Stille coupling of alkyl halides with alkenyl stannanes can be achieved using electron-rich alkyl phosphines ligands, combined with the addition of a ﬂuoride source as a nucleophilic promoter (Scheme 2.69).70 This probably works by generating a “stannate” complex 2.201 that participates in transmetallation more readily than the original stannane, in a similar manner to the addition of Lewis bases to Suzuki reactions (Section 2.6). 2.5.7

Stille Reaction Troubleshooting

There are various occasions when the Stille reaction gives low yields, gives no product or requires unacceptably harsh reaction conditions. In addition to the use of sophisticated phosphine ligands, various techniques have been developed to boost rates and yields.71 One technique is to add a copper salt72 or silver salt73 co-catalyst. Copper(I) iodide is often used. These additives can give a signiﬁcant rate enhancement (Table 2.2).74

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Coupling Reactions

45

SiMe3 SiMe3 Me3Sn Pd(PPh3)4, LiCl

OTf 1. LDA 2. Tf 2NPh 2.194

O

2.195 SiMe3

1. L-selectride 2. Tf 2NPh

SiMe3 Me3Sn Pd(PPh3)4, LiCl

OTf

1. i-Pr2NMgBr 2. Tf 2NPh

2.197

2.196

O

Scheme 2.68 O O

Br [(allyl)PdCl]2, (t-Bu)2MeP, Me4NF

2.198 +

Ph

O O

Ph

2.200

n-Bu3Sn 2.199 Ph n-Bu3Sn

F

2.201

Scheme 2.69 Table 2.2 Effect of additives on stille coupling

+ PhBr N

Snn-Bu3

dppbPdCl2, additive N

Ph

Additive

Yield

Time

none

47%

4h

Ag2O

48%

80 min

CuO

82%

80 min

The main role of these additives is to regulate the phosphine concentration by reversible coordination (see Scheme 1.4).75 Several important steps in the mechanism are inhibited by excess phosphine, yet, if the phosphine concentration falls too low, the catalyst may decompose. Ligands other than triphenylphosphine have also been used. A simple change to the more electron rich tri(2-furyl)phosphine 1.6 or triphenylarsine 1.4 can have a dramatic effect (Table 2.3).

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Organic Synthesis Using Transition Metals Table 2.3 Effect of ligands on stille coupling

+ I

2.6

Pd2dba3, L Snn-Bu3 THF, 50 °C

L

Relative rate

Yield

PPh3

1

15%

P(2-Fu) 3

105

95%

AsPh3

1100

95%

Boron: The Suzuki Reaction

The coupling of boron compounds is known as Suzuki coupling.76 The Suzuki reaction has two distinct advantages over Stille coupling: easier removal of the boron by-products and lower toxicity of the boroncontaining compounds, compared to their tin counterparts. Like the Stille coupling, there is enormous functional-group tolerance, and the borane reagents are often air and water stable. A huge number are commercially available. There is a problem is low reactivity of neutral boron compounds. By themselves, they do not participate in coupling reactions. A Lewis base must be added to the reaction mixture to act as a nucleophilic promoter by generating an “ate”-complex (Scheme 2.70). In early work, these Lewis bases were relatively strong bases such as ethoxide and hydroxide. Gradually, milder bases, such as carbonate and phosphate, were introduced, allowing better functional-group tolerance. An alternative is to use a pre-prepared stable “ate” complex, so that no Lewis base needs to be added to the mixture. One simple example is the tetraphenylborate ion, as in NaBPh4 , which can acts as a phenyl transfer agent. A wide range of palladium catalysts have been used. While complexes with simple phosphines, such as triphenylphosphine, work well in many cases, the use of more sophisticated ligands is required in more difﬁcult cases including the coupling of unactivated aryl chlorides.77 Boranes are generally made either by hydroboration (for alkyl and vinyl derivatives) or from organolithium reagents or Grignard reagents (for aryl derivatives). Some borane derivatives can be made by the coupling of diboranes 2.203 with aryl halides by the Miyaura borylation (Scheme 2.71).78 This reaction employs a palladium catalyst, which is reduced to palladium(0) in situ, and requires the presence of acetate. The role of acetate is to participate in a ligand exchange at palladium on the initial oxidative addition product 2.205, displacing halide, and making the transmetallation process with the diborane more favourable. Nickel catalysis can also be used.79 Boranes may also be prepared through C–H activation methods, discussed in Chapter 3, and by crossmetathesis with vinyl boranes (Scheme 8.97). The additional groups on the boron atom, X, are non-transferrable. These groups are often either alkyl groups or alkoxy groups. The choice of groups may be initially determined by the means by which the boron compound is synthesized (see below). As the identity of the X groups has a very signiﬁcant effect on reactivity, they may subsequently be changed by substitution to give the optimum borane-coupling partner. X

X B R

+ Y

X unreactive

Scheme 2.70

B R X Y "ate"complex reactive

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Coupling Reactions CO2Me

O

O

+

O

O

Br 2.202

CO2Me

dppfPdCl2, KOAc

B B

pinB 2.204

2.203 = pinB Bpin dppfPd(0)

Ar Bpin

47

Ar X oxidative addition

reductive elimination

Ar

Ar dppfPd

2.207 dppfPd

2.205 X

Bpin

OAc ligand exchange

pinBOAc Ar

transmetallation

X

dppfPd pinB Bpin

OAc 2.206

Scheme 2.71 HO B(OH)2

O

-2H2O

+

B O

HO 2.209

2.208

2.210 =

Bpin

Scheme 2.72

N

O B O N

Me 2.211

Cl O O

Pd2dba3, XPhos, Cu(OAc)2, K2CO3

+

N

CN 2.212

CN 2.213

Scheme 2.73

Boronic acids are one of the most readily available kinds of boron reagent for the Suzuki coupling. They are, however, complicated by the fact that they are often in equilibrium with their anhydrides, the boroxines. In addition, the boronic acids can have a tendency to undergo protio-deboration, resulting in shortened shelf lives and the need to employ excess boronic acid in the coupling reaction. Esters of boronic acids, especially the pinacol esters 2.210, are widely used and can be easily prepared from the boronic acid (Scheme 2.72).80 The mixed anhydrides 2.211 formed with N-methyliminodiacetic acid can either couple directly, or, under the usual mildly basic aqueous conditions undergo slow hydrolysis to release boronic acids, which undergo coupling (Scheme 2.73).81 This is very advantageous for unstable boronic acids.

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Organic Synthesis Using Transition Metals R

OH B OH

KHF2

R

2.214

F B F F

K

2.215

Scheme 2.74 1. Py.BH3, I2 2. KHF2, MeOH BF3 K 2.216

2.217

Scheme 2.75 N + Cl 2.218

N H

KF3B

Pd(OAc)2, RuPhos, Na2CO3

N H

N 2.220

2.219

Scheme 2.76

Another solution is to employ triﬂuoroborate salts 2.215, which can be prepared from the boronic acid by treatment with potassium hydrogen ﬂuoride (Scheme 2.74). They can also be prepared from alkyl boranes in a similar way (Scheme 2.75).82 These stable salts can be efﬁciently employed in Suzuki coupling reactions (Scheme 2.76).83 One application is in the synthesis of the unusual amino acid, trityrosine 2.226 (Scheme 2.77).84 In this synthesis an aryl diiodide 2.222 was coupled with a triﬂuoroborate salt 2.224 that had been formed by Miyaura borylation of iodide 2.223 followed by KHF2 treatment. Global debenzylation of coupling product 2.225 gave the product 2.226. Another example of the use of a triﬂuoroborate salt can be found in Scheme 2.88. The installation of a vinyl group by Suzuki coupling presents a particular problem because vinyl boronic acid is unstable, readily undergoing polymerization. In a study of vinylation in order to make a polymer precursor, the vinyl triﬂuoroborate salt was found to be effective, giving the cleanest product 2.228 on a 72 g scale (Scheme 2.78).85 2.6.1

Alkenyl Borane Coupling Reactions

Alkenyl boranes are most commonly prepared by the cis-hydroboration of alkynes using catechol borane (Scheme 2.79). The resulting catechol boranes may be directly coupled, or hydrolysed to the boronic acid, prior to coupling. This method was employed in the stereospeciﬁc construction of a silyl diene in a synthesis of chlorotricholide (Scheme 2.80). The boronic acid partner 2.233 was prepared by hydroboration and hydrolysis. The vinyl iodide was 2.235 prepared by hydroalumination-iodination. The silyl group was included in order to boost stereoselectivity in the later Diels–Alder reaction, but also served to facilitate the synthesis of the vinyl iodide coupling partner.86 The Suzuki coupling yielded the diene 2.236 with retention of the stereochemistry of both alkenes. Thallium hydroxide was employed as the Lewis base. Thallium-containing Lewis bases have been found to be advantageous in a number of cases, but the toxicity of thallium is a serious concern. Similarly, Suzuki coupling of a vinyl boronic acid was employed for formation of a diene 2.238 in a synthesis of dictyostatin (Scheme 2.81).87

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Coupling Reactions CbzHN

CbzHN

CO2Bn I2, Ag2SO4

HO

I

I

2.223

CO2Bn

2.224

BnO

NHCbz

NH2

CO2Bn CbzHN

CO2Bn

CO2H H2N

CO2H

H2N

CO2H

H2, Pd/C THF, MeOH, H 2O

BnO HO BnO

2.225

dppfPdCl2, K2CO3

2.222

1. pinBBpin, CO2Bn dppfPdCl2, CbzHN K2CO3 K F3B 2. KHF 2

CbzHN

BnO

I HO

2.221

CO2Bn

HO HO HO

CbzHN

CO2Bn

2.226

Scheme 2.77

BF3 K Pd(OAc)2, PPh3, K2CO3, NaOAc

Br

2.227

OH

S O O

2.228

S O O

Scheme 2.78

O n-Bu

+

H B n-Bu

O

2.230

2.229

Br N Pd(PPh3)4 NaOEt

O B

n-Bu

N 2.231

Scheme 2.79

O

OH

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Organic Synthesis Using Transition Metals Me3Si HO

OMe 2.232

OMOM 2.234

O 1. HB

1. DIBAL 2. NIS

O 2. H 2O HO

OMe

I

B(OH)2 2.233

OMe

Me3Si

OMOM 2.235

OMe

(Ph3P)4Pd TlOH OMe

HO Me3Si

OMOM

OMe

2.236

Scheme 2.80 O 1. HB O TBSO TBSO

2. I CO2Et (Ph3P)4Pd, NaOH

CO2Et TBSO TBSO 2.238

2.237

Scheme 2.81

A Suzuki coupling was the key step in a synthesis of the iconic molecule, quinine 2.244, serving to connect the two halves of the molecule together (Scheme 2.82).88 The vinyl boronate 2.240 was prepared in an unusual fashion, by a modiﬁed Takai reaction from the aldehyde 2.239. Suzuki coupling with the bromoquinoline 2.241 was unsuccessful until SPhos 1.16 was employed as a catalyst. Stereoselective epoxidation of the internal alkene of the Suzuki product 2.242 was then achieved indirectly using a Sharpless protocol89 via dihydroxylation. Deprotection of the nitrogen atom was achieved, again, in an unusual way, by treatment with a strong Lewis acid. On heating, the quinuclidine core could then form by nucleophilic attack of the now-free nitrogen on the near terminus of the epoxide 2.243. The related natural product, quinidine 2.245, could also be synthesized by changing the reagent for dihydroxylation from ADmix-␤ to ADmix-␣.

2.6.2

Alkyl Borane Coupling Reactions

The coupling of alkyl boranes with a wide variety of halides is a ﬂexible route for carbon–carbon bond formation. The borane partners are usually prepared using 9-BBN that is both highly selective for borylation at the terminal position of an alkene, and highly selective for the less-hindered alkene (Scheme 2.83). The coupling was used to form a trans alkene in a synthesis of brevicomin 2.253 (Scheme 2.84).90 After coupling, asymmetric dihydroxylation of the coupling product 2.251 and acetal exchange completed the synthesis.

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Coupling Reactions Br NCbz NCbz (pin)BCHCl2, CrCl2, LiI O

B O

MeO N 2.241 Pd(OAc)2, SPhos, K3PO4

O

2.239

2.240 NCbz

NCbz 1. ADmix- β, MeSO2NH2 2. (MeO)3CMe, PPTS 3. AcBr

MeO N

O

MeO N

2.242

OMe

1. Et2AlCl 2. microwave

2.243

OMe N

OH N

OH N

N

2.244

2.245

Scheme 2.82 PhS B

9-BBN

2.246

Pd(PPh3)4 K3PO4

Br

2.247

2.248

Scheme 2.83 O

9-BBN

O

O

2.249 Br Pd(PPh3)4, NaOH

O

B

2.250

O

OsO4, K3Fe(CN)6, (DHQD)2PHAL

O 2.251

O

O

OH

O

H3O+ O

2.252

SPh

OH

Scheme 2.84

2.253

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Organic Synthesis Using Transition Metals O

BnO

H O

O

BnO

OTBS

2.254

9-BBN O

BnO

B

BnO

(PhO)2P

O

Ph O 2.256 H 1. KHMDS 2. (PhO) 2POCl H O O O

O

OTBS

2.255

2.257

dppfPdCl2, NaHCO3 BnO

H O

O

Ph

O H

O Ph O

BnO

H

BnO BnO

O

H

H

O TBS

H O

H 2.258

OAc Me3Al OAc H

O

H EtO2S 2.259

H

BnO BnO

O F

H

H G

O Me H 2.260

H O H

OAc OAc H

Scheme 2.85

A Suzuki coupling was employed to connect the F and H rings of the marine polyether toxin Gambierol (Scheme 2.85).91 The borane component 2.255 was prepared by hydroboration of an exocyclic enol ether 2.254, while the other partner was an enol phosphate 2.257, prepared by enolate chemistry. Coupling of these two fragments to give enol ether 2.258 proceeded even at room temperature. Manipulation of the functional and protecting groups then allowed formation of the in-between G ring, with installation of the angular methyl group by sulfone displacement. 2.6.3

Aryl Borane Coupling Reactions

The Suzuki coupling of aryl boronic acids is a widely used method for the synthesis of functionalized arenes, including biaryls (Scheme 2.86).92 ortho-Metallation can be an effective method for introduction of the boronic acid group. O O Br

1. n-BuLi 2. B(OMe) 3 3. HO i-Pr2N

O 2.261

B(OH)2 i-Pr2N

NEt2

O

Pd(PPh3)4, Na2CO3

O

N

O

i-Pr2N O 2.263

2.262

Scheme 2.86

N

NEt2

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Coupling Reactions Br Br

53

H AgOAc Br

H

H

MeO2CHN 2.264 NHCO2Me

2.265 Pd(PPh3)4 Na2CO3

Br Li

O

1. B(OMe) 3 2. HO -

B(OH)2

O

N MeO2C

2.268

O

O 2.266

2.267 1. H 2, Pd/C 2. POCl 3 3. LiAlH 4

O O

N MeO2C 2.269

γ-lycorane

O N

O 2.270

Scheme 2.87

The coupling of a vinyl boronic acid 2.267, prepared via the organolithium, with a vinyl bromide 2.268 was a key step in an elegant synthesis of ␥ -lycorane 2.270 (Scheme 2.87).93 The vinyl bromide partner 2.268 was prepared from a dibromocyclopropane 2.264 by electrocyclic ring opening of a cyclopropyl cation with intramolecular nucleophilic trapping. The methoxycarbonyl protecting group then supplied the additional carbon atom to close the ﬁnal ring through a Bischler–Napieralski reaction, followed by carbonyl excision. Another synthesis of ␥ -lycorane can be found in Scheme 9.78. An example of the use of the Suzuki coupling of an aryl triﬂuoroborate salt in alkaloid synthesis can be found in a synthesis of ipalbidine 2.277 (Scheme 2.88).94 The starting material was prepared by a tandem deprotection-6-endo cyclization of a propargylic ketone 2.271. Coupling of a p-methoxyphenyl triﬂuoroborate salt 2.274 could then be achieved by a Suzuki reaction after electrophilic iodination. Alternatively, this could be done directly by C–H activation (see Scheme 3.21). After conversion of the ␣,␤-unsaturated ketone to a vinyl triﬂate 2.275, Negishi coupling to install a methyl group, followed by a ﬁnal deprotection, gave the natural product 2.277. An aryl boronate ester 2.279 was coupled with a heterocyclic bromide 2.278 to make a specialized kinase inhibitor 2.280 on a scale of 1.88 kg (Scheme 2.89).95 The inertness of the aryl ﬂuorides is as expected in this example. Boron derivatives of heteroarenes are also viable partners. A Suzuki reaction of a vinyl triﬂate 2.282, prepared by enantioselective enolate formation, with a benzothiophenyl boronic acid 2.283 was used to prepare 12.75 kg of a tropane derivative 2.284 (as its tartrate salt) as a drug candidate (Scheme 2.90).96 In many examples the catalyst employed is tetrakis(triphenylphosphine)palladium(0) and this is satisfactory in many cases, but may fail when challenged by a difﬁcult coupling, such as between sterically hindered substrates, or substrates with a chlorine leaving group. Such challenging couplings can be successful using specialized ligands. The use of tri-t-butylphosphine as the ligand and cesium carbonate as the base is effective for the coupling of aryl chlorides.97 NHC ligands also contribute to highly active catalysts (Scheme 2.91),98 and nickel NHC complexes have also been used.99 A catalyst system employing SPhos 1.16 was capable

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Organic Synthesis Using Transition Metals H O N Boc 2.271

H

O 1. NaI, HCO 2H 2. K 2CO3, MeOH

N

BF3 K 2.274 Pd(OAc)2, S-Phos

O

1. L-selectride 2. Cl

H

2.275 H

Me

N

1. MeZnBr, (Ph 3P)4Pd 2. BBr 3

2.276

MeO

NTf2

N

H N

2.273

N

MeO TfO

N

I

2.272

MeO

H

O

I2, DMAP

2.277

HO

Scheme 2.88

Br N F

N

N Me F

H N

O Pd(PPh3)4, NaHCO3

2.278 +

N N

F

N Me F

O

B O

H N

O

O 2.280

O 2.279

Scheme 2.89

1. Ph NMe

O

N Li

Ph LiCl NMe

2. PhNTf 2

2.281

2.282

(HO)2B S 2.283 Pd(PPh3)4, LiCl, K3PO4

NMe S 2.284 90% ee

Scheme 2.90

OTf

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Coupling Reactions

Me

Me Cl

2.285

55

IPrPd(crotyl)Cl, KOt-Bu

(HO)2B

Me

Me

2.286

2.287

Scheme 2.91 Me Me

Me Br

Me Me Pd2(dba)3, SPhos, K3PO4

(HO)2B

Me

Me

Me

2.288

Me Me 2.290

2.289

Scheme 2.92 t-Bu t-Bu

Br

t-Bu Pd2(dba)3, SPhos, K3PO4

(HO)2B

t-Bu

t-Bu 2.291

2.293 Me

2.292

Me

Scheme 2.93 O

O O

O

O

O O B(OH)2 Pd(OAc) 2, SPhos, K2CO3

Br MeO

O MeO

OMe

OMe OMe

OMe 2.294

2.295

Scheme 2.94

of forming an all-ortho substituted biphenyl (Scheme 2.92).100 When the system was too challenging, by introducing ortho t-butyl groups, C–H activation occurred leading to coupling on a substituent, rather than the ring (Scheme 2.93). The remarkable feature of this reaction is that the SPhos–palladium complex was sufﬁciently reactive to undergo oxidative addition in such a crowded environment, although the subsequent transmetallation was too slow, allowing the C–H activation process to intervene. The use of SPhos as the ligand allowed the Suzuki coupling of the highly hindered aryl bromide 2.294 in a synthesis of all of the diastereoisomers of eupomatilone 2.295 (Scheme 2.94).101 Qphos 1.24 has been found to be an effective ligand (Scheme 2.95),102 while Herrmann’s catalyst (Scheme 5.17) is also effective for reluctant substrates.103 ortho-Palladated phosphites have shown exceptional activity.104 Heterogeneous catalysts, including perovskites, have also been used in Suzuki coupling reactions (Scheme 2.96).105

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Organic Synthesis Using Transition Metals Cl

Cl Br

Pd2(dba)3, QPhos, K3PO4

(HO)2B

Cl 2.296

Me

Cl Me 2.298

2.297

Scheme 2.95 MeO MeO

LaFe0.57Co0.38Pd0.05O3 (perovskite) K2CO3, aq. i-PrOH MeO

+ (HO) B 2

Br

2.301

2.300

2.299

MeO

Scheme 2.96

B

OBn

n-C6H13I, (Ph3P)4Pd, K3PO4

OBn

2.302

2.303

Scheme 2.97 Ni(cod)2, KOt-Bu Ph Ph B(OH)2

+

Br

N

F3C

OTBS 2.304

CF3

N OTBS 2.306

2.305

Scheme 2.98 B(OH)2

O + O 2.307

Pd(OAc)2, (t-Bu)2MeP, KOt-Bu

O O

Br 2.308

2.309

Scheme 2.99

2.6.4

Suzuki Coupling of Alkyl Halides

Organoborane compounds have also been successfully coupled to alkyl halides. This can be done for alkyl iodides using a simple catalyst system consisting of (Ph3 P)4 Pd (Scheme 2.97),106 or, for alkyl bromides, with a nickel catalyst with a bidentate nitrogen ligand (Scheme 2.98).107 Taking advantage of the more rapid oxidative addition of alkyl halides to palladium complexes with electron-rich phosphine ligands, the Suzuki coupling of alkyl bromides with boronic acids has been achieved (Scheme 2.99).108 ␤-Hydride elimination is sufﬁciently slow that the oxidative addition product 2.310 could be isolated and characterized by X-ray crystallography (Figure 2.1). 9-BBN derivatives, on the other hand, require a different catalyst system.109

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Coupling Reactions

57

P(t-Bu)2Me Ph Pd Br Me(t-Bu)2P

P(2) P(1)

Pd(1) Br(1)

2.310

Figure 2.1 An alkylpalladium(II) complex. Reprinted with permission from Kirchhoff, J. H.; Netherton, M. R. c 2002 American Chemical Society. et al. J. Am. Chem. Soc. 2002, 124, 13662.

2.7 Silicon: The Hiyama Reaction The coupling of silicon derivatives is known as Hiyama coupling.110 The use of silicon derivatives has two practical beneﬁts: silanes are often cheap, and the silicon-containing by-products are almost completely nontoxic. Nevertheless, the Hiyama reaction has seen much less use than some of the other coupling reactions. This is likely to be due to the quite harsh conditions originally required. The same issue of low reactivity is observed with silicon as with boron. As with Suzuki coupling, it is solved by addition of a Lewis base as an activating reagent, commonly a ﬂuoride source due to the high afﬁnity of this anion for silicon (Scheme 2.100).111 The role of the Lewis base is to form a hypervalent silicon “ate” complex 2.313, which is more reactive towards transmetallation than the parent, neutral silane. Even so, simple silanes still tend to have low reactivity and need quite forcing conditions for coupling. The scope of the reaction may be widened if some of the alkyl “dummy” groups on silicon are changed to electronegative atoms, such as ﬂuorine (Scheme 2.101)112 and oxygen (Scheme 2.102).113 Preformed “ate” complexes 2.321 can also be used (Scheme 2.103).114 The importance of the use of a Lewis-basic activating reagent is demonstrated in a synthesis of nitidine 2.328 (Scheme 2.104).115 Without the activating reagent, the carbon–silicon bond of a vinyl silane 2.324 proved to be inert, and a Heck reaction with aryl iodide 2.326 occurred. A second aryl group could then be introduced by Hiyama coupling with iodide 2.326 in the presence of an activator. A particularly noteworthy variant of the Hiyama coupling is the Denmark modiﬁcation.116 Silacyclobutanes 2.329 were found to be excellent partners in the reaction with enhanced reactivity (Scheme 2.105).117 This effect was found not to be due to the strain of the four-membered ring directly, but due to the rapid ring opening to give silanols 2.333 and disiloxanes 2.334 that were the active and competent coupling partners. I

SiMe3 [(allyl)PdCl]2, (Et2N)3S Me2SiF3

2.311

2.312

Me Me Si F Me 2.313

Scheme 2.100 [(allyl)PdCl]2, (Et2N)3S Me2SiF3

I SiMe2F 2.314

+

n-Bu 2.315

Scheme 2.101

2.316

n-Bu

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Organic Synthesis Using Transition Metals O OMe

O OMe

Si(OEt)3 + MeO

OMe

Pd(OAc)2, PPh3, TBAF OMe 2.319 OMe

OMe 2.318

Br 2.317

MeO

Scheme 2.102

OTf

Pd(OAc)2, PPh3, TBAF

O O Si O O

+ OMe 2.320

OMe

2.321

2.322

Scheme 2.103 MeO

OMe O O

I

MeO

(EtO)Me2Si 2.324 (Ph3P)2PdCl2, Et3N

O O

(EtO)Me2Si

2.323

2.325 MeO

MeO

OMe

OMe

I 2.326

MeO CO2Me [(allyl)PdCl]2, (EtO)3P, TBAF

O MeO MeO

O CO2Me 2.327 O

MeO MeO

O NMe 2.328

Scheme 2.104

Consideration of the mechanism led to the development of a ﬂuoride-free system, activated by a mild Brønsted base, such as Me3 SiOK or hydrated Cs2 CO3 , rather than a Lewis base (Scheme 2.106).118 The base functions by deprotonating the silanol 2.335 (or generating a silanol by cleaving the disiloxane). The siloxide 2.337 changes the game. Rather than be converted into an “ate” complex, ligand exchange occurs at palladium, forming a siloxide–palladium complex 2.338, followed by facile intramolecular transmetallation.119 Given that a different mechanism operates in the case of silanols, selective coupling of a silanol in the presence of a silane derivative can be achieved by judicious choice of activator (Scheme 2.107).120 In the

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Coupling Reactions O

O Si

n-C5H11

Pd(dba)2, TBAF.3H 2O

+ Me

n-C5H11

I 2.330

2.329

2.331

n-Pr Si Me X

n-C5H11

H OH

Me Si

n-C5H11

OH

2.333 n-C5H11

2.332 "ate" complex X = F, OH

n-Pr Me Me n-Pr Si Si O n-C5H11 2.334

Scheme 2.105

Ar'

SiMe2OH + 2.335

Br

Pd(0), base

Ar

Ar'

L2Pd(0) Ar'

Br

Ar

Ar

oxidative additon

reductive elimination

Ar

Ar 2.339

Ar

L2Pd

2.336

Ar'

L2Pd

O Me Si Me Ar' 2.337 ligand exchange

Ar

intramolecular transmetallation

Me O Si Ar' Me

SiMe2OH 2.335 base

Br

L2Pd (Me2SiO)n

Ar'

Br

2.338

Scheme 2.106

SiMe2OH

BnMe2Si

I OTHP NaH, Pd2(dba)3.CHCl3

BnMe2Si

OTHP 2.341

2.340 I EtO2C Pd(dba)2, TBAF

EtO2C

Scheme 2.107

OTHP 2.342

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Organic Synthesis Using Transition Metals H Si(OEt)3 Pd(dba)2, Johnphos, i-Pr2NEt or [Rh(COD)(NCMe)2]BF4, Et3N

MeO

MeO

X

2.343 X = Br, I

Si(OEt)3 2.344

1. Mg 2. Si(OEt) 4 or SiCl4; EtOH

Scheme 2.108

presence of a base, the silanol of diene 2.340 undergoes coupling; use of ﬂuoride in the second step then allows coupling of the silane moiety to give tetraene 2.342. The required silanes can be formed by the reaction of organolithium species or Grignard reagents with silicon electrophiles,121 but also by palladium-122 and rhodium-catalysed123 coupling reactions (Scheme 2.108). In addition to these methods, platinum-catalysed hydrosilation of alkynes can be an effective method for the formation of vinyl silanes. Coupling of a vinyl silane 2.346, made by hydrosilylation, with a crowded aryl iodide 2.347 was a key step in a synthesis of an HMG-CoA reductase inhibitor, NK-104 (Scheme 2.109) 2.349.124 Complex vinyl silanes may also be formed from simpler vinyl silanes by metathesis reactions. A ring closing metathesis (Section 8.3.3) to form a silicon heterocycle 2.351, with a necessarily cis alkene was employed in a synthesis of brasilenyne 2.354 (Scheme 2.110).125 The RCM was followed by an intramolecular Hiyama

O

O CO2t-Bu F

2.345 HSiMe2Cl (t-Bu3P)Pt(dvds) O

[(allyl)PdCl]2, TBAF

I

O

+

ClMe2Si

N CO2t-Bu

2.347

2.346 F

F OH O

O

CF3CO2H O CO2t-Bu

N 2.348

N 2.349

Scheme 2.109

O

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Coupling Reactions

I Me Si O Me

Schrock's catalyst

O Et

2.350

I Me Si O Me 2.351

OPMB

[(allyl)PdCl]2, TBAF

O

HO O

Et

61

PMBO

Et

2.352

OPMB

Sii-Pr3 1. TBSOTf, py 2. DDQ, H2O 3. Dess-Martin

1.i-Pr 3Si 2. TBAF 3. Oct3P, CCl4

TBSO O O

Li

Cl

Et

2.353

O

Et

2.354

Scheme 2.110

EtO2C

Br 2.355

+

(MeO)3Si

PdBr2, (t-Bu)2MeP, EtO C 2 TBAF

2.356

2.357

Scheme 2.111

coupling reaction. Subsequent functional group manipulation allowed introduction of the cis-enyne by a Peterson oleﬁnation. Alkyl bromides and iodides can participate in Hiyama coupling reactions when bulky alkyl phosphine ligands are employed (Scheme 2.111).126 The reaction can even works at room temperature.

2.8 Copper: The Sonogashira Reaction It was demonstrated long ago that heating copper acetylides with aryl halides leads to a coupling reaction. This is known as the Castro-Stephens reaction.127 Its use was limited due to the high temperatures typically used and the need to handle stoichiometric amounts of potentially explosive copper acetylides. It was also found that the same reaction could be achieved using the terminal alkynes themselves with a palladium catalyst, but still requiring some heating, in a process that looks in its overall result like the alkyne version of a Heck reaction.128 The same overall result can be achieved by using both metals, and now usually proceeds without the need for heat.129 The ingenious combination of copper(I) and palladium(0) as co-catalysts is known as the Sonogashira reaction,130–132 and is one of the mildest ways to make a carbon–carbon bond (Scheme 2.112). It is unlike the coupling reactions described above as the organometallic species is generated in situ, rather than pre-prepared; it is, however, limited to alkyne couplings. The mechanism is believed to involve two catalytic cycles. The C–C bond formation occurs in a palladium cycle, while a copper cycle generates the copper acetylide for transmetallation. A singular feature of the Sonogashira reaction is the wide range of solvents that have been used, from benzene and toluene, to DMF and water. Even vodka has been used.133 The mild nature of the Sonogashira reaction makes it a singularly useful carbon–carbon bond-formation reaction. The enyne natural product,

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Organic Synthesis Using Transition Metals R'X

R

+ H

R

Pd(0), Cu(I), Et3N

L2Pd

R' reductive elimination

R

R'

R'X oxidative addition

R' L2Pd R' L2Pd

R

X

transmetallation CuX

H

R

Cu

R

Et3NH X

Et3N

Scheme 2.112 I +

OH

2.358

(PhCN)2PdCl2 CuI, pyrrolidine

2.359

X 1. TsCl, Et 3N 2. MeHN(CH 2)2NMe2

2.360 X = OH 2.361 X = NMe(CH2)2NMe2

Scheme 2.113 (Ph3P)2PdCl2, CuI, Et2NH N

N

Br

N 2.363

2.362

Scheme 2.114

Clathculin B 2.361, could be assembled in an efﬁcient and straightforward manner by coupling iodide 2.358 with alkyne 2.359 (Scheme 2.113).134 If acetylene itself is used in a Sonogashira reaction, then symmetrical disubstituted alkynes are generally formed (Scheme 2.114).130 Monocoupling of acetylene, or unsymmetrical decoupling, is usually achieved with trimethylsilylacetylene, employing the TMS group to protect one terminus of the alkyne. Several Sonogashira reactions were employed in a synthesis of Ailanthoidol 2.368 (Scheme 2.115), one employing TMS acetylene, taking advantage of the facile cyclization of o-alkynyl phenols to benzofurans.135 In practice, the ﬁnal cyclization of alkyne 2.367 could be carried out in tandem with a deprotection step to give Ailanthoidol 2.368

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Coupling Reactions I OMe

1. SiMe3 (Ph3P)4Pd, CuI, Et3N MsO 2. K 2CO3, MeOH

MsO

OH

OMe MsO

2.366 OMe (Ph3P)4Pd, CuI, Et3N

Br 2 . 3 64

63

2.365

H

OMe MsO

OH

KOH, EtOH, Δ

OH

HO O MeO

MsO

2.368

2.367

OMe

OMe

Scheme 2.115

O

1. LDA 2. N

2.369

O I

2.371

1. OTf NTf2

SiMe3 (Ph3P)4Pd, CuI, Et3N 2. K 2CO3, MeOH

2.370 O

(Ph P2PdCl2, O CuI,3 i-Pr 2NH 2.372 OTBS

O 2.373 OTBS O

1. H 2SiF6 2. AcOH, DCC

O 2.374

OAc

Scheme 2.116

directly. 3-Methylbutyn-3-ol is a cheaper alternative to trimethylsilylacetylene, but requires more strongly basic conditions for releasing the alkyne.136 Trimethylsilylacetylene was used in sequential Sonogashira reactions to synthesize tricholomenyn A 2.364 (Scheme 2.116).137 The ﬁrst Sonogashira reaction was with a vinyl triﬂate 2.370; after desilylation, an ␣-iodoenone 2.372, derived from benzoquinone, could be coupled. A change from a TBS protecting group to an acetate group completed the synthesis. The challenge of the synthesis of the ene-diyene natural products was one of the factors that brought the Sonogashira reaction to prominence. Three Sonogashira reactions were used in a synthesis of the core of the esperamycin/calichemicin anti-tumour agents (Scheme 2.117).138 Two were employed in sequence to add two alkynes onto cis-1,2-dichloroethylene 2.375 to form the ene-diyne 2.376. Due to the sensitivity of propiolaldehyde, its diethyl acetal was employed. After hydrolysis of the acetal, a diene unit was installed.

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Organic Synthesis Using Transition Metals 1. Cl

Sit-BuPh2 (Ph3P)4Pd, CuI, n-PrNH2 2. CH(OEt)2 (Ph3P)4Pd, CuI, n-PrNH2

Sit-BuPh2

1. H 3O+ 2. Li

Sit-BuPh2 OMe

Cl 2.375

CH(OEt)2

2.376

OMe

2.377 OH

1. TBAF 2. CO2Me I (Ph3P)4Pd, CuI, Et3N

CO2Me

H CO2Me

Δ

OMe OMe

OTBS

OR 2.378 R = H

2.380

2.379 R = TBS

Scheme 2.117

Br +

MeO

Ph

(MeCN)2PdCl2, (t-Bu)3P, CuI, Et 3N

MeO

2.381

Ph 2.382

Scheme 2.118 OMe Cl

Ph (MeCN)2PdCl2, L, Cs2CO3, CH3CN

2.383

OMe L=

Ph

PCy2 i-Pr

i-Pr

2.384 i-Pr

2.385

Scheme 2.119 MeO2C

OMe OTs

Ph (MeCN)2PdCl2, L, Cs2CO3, CH3CN

MeO2C Ph MeO2C

MeO2C 2.386

2.387

Scheme 2.120

After desilylation of the other alkyne, a third Sonogashira reaction added an electron-poor alkene to give a tetraene 2.378, setting the stage for an intramolecular Diels–Alder reaction. Another approach to the ene-diynes using the Sonogashira reaction can be found in Scheme 7.8. Tri-t-butyl phosphine can be more effective in the coupling of reluctant aryl bromides (Scheme 2.118).139 Bulky electron-rich biaryl phosphine ligands, such as 2.385, can also promote the Sonogashira reaction of “difﬁcult” aryl chlorides (Scheme 2.119).140 Interestingly, in this case, the presence of copper(I) salts inhibited the reaction, and the copper-free version provided better yields. Aryl tosylates, easily prepared from phenols, also couple under these conditions (Scheme 2.120).

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Coupling Reactions

HO

Br

n-Bu [(allyl)PdCl]2, IAd or ItBu, K2CO3, CuI

65

HO

2.388

2.389

n-Bu

Scheme 2.121 OTHP

CO2Me

CO2Me

1. H 2, Pd/C 2. MeOH, H +

Pd/C, CuI, K2CO3 N

N Cl 2.390

OTHP

2.391

OH CO2Me 1. NaCNBH 3, H+ 2. LiAlH 4

CO2Me MsCl, Et3N N

N

OH

2.392

H N

2.393

2.394

Scheme 2.122

Br

Br N

ArB(OH)2, (Ph3P)2PdCl2, Na2CO3

NH2

Ar

Ar

Ar

Ar

MsCl, Et3N N

1. t-BuONO, CH 2I2, I2 2. CH2OH (Ph3P)2PdCl2, CuI, Et3N

N NH2 2.396

2.395 Ar

Ar

OH

Ar = p-MeOC6H4

N

2.397

2.398

Scheme 2.123

Sonogashira coupling reactions of primary alkyl halides have been reported.141 The key to this was the use of an NHC ligand with bulky alkyl groups on the two nitrogen atoms (Scheme 2.121) IAd 1.51 and ItBu 1.55. This reaction is an alternative to the classical alkylation of acetylides ions with alkyl halides, with the advantage that base-sensitive functionality is tolerated. Heterogeneous sources of palladium have also been employed for the Sonogashira reaction, and these can outperform the standard homogeneous catalysts in some cases. Palladium on carbon is the most common heterogeneous source of palladium,142 but others sources, including perovskites,143 have also been used. A Sonogashira coupling of a chloropyridine 2.390 using a heterogeneous catalyst was a key step in a synthesis of the indolizidine alkaloid, tashiromine 2.394 (Scheme 2.122).144 After alkyne reduction and removal of the THP protecting group, activation of the alcohol 2.392 as a mesylate led directly to the bicyclic pyridinium ion 2.393. Stereoelectronically controlled reduction of this ion, followed by reduction of the ester, gave tashiromine 2.394. The indolizidinium alkaloid, ﬁscuseptine 2.398, was made in a similar way, using two Suzuki couplings and a Sonogashira reaction (Scheme 2.123).145

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Organic Synthesis Using Transition Metals O +

Ph

Cl

Ph

(Ph3P)2PdCl2, CuI, Et3N

O Ph

2.399

Ph

2.400

Scheme 2.124

O + SEt MeO

Ph

dppfPdCl 2, CuI, P(2-Fu)3

2.401

O

MeO

2.402

Ph

Scheme 2.125

OEt 2.404 OEt (Ph3P)2PdCl2, CuI, Et3N

OEt Me OEt 2.405

Me

I 2.403

OEt 1.

OEt 2.406 OEt

Me

(Ph3P)2PdCl2, CuI, Et3N 2. H 3O+

CO2Et 2.407

Scheme 2.126

The Sonogashira reaction can also be used to prepare diynes from terminal alkynes and haloalkynes. This coupling is, however, a known reaction, the Cadiot–Chodkiewitz reaction, using only copper(I). The reaction may proceed better under Sonogashira conditions in some cases.146 Acid chlorides couple with alkynes under Sonogashira conditions to give alkynyl ketones 2.400 (Scheme 2.124).147 This is most efﬁcient with aryl or ␣,␤-unsaturated acid chlorides. Acid chlorides of simple aliphatic acids will tend to decompose via ketenes under Sonogashira conditions. Thioesters, on the other hand, show no such tendency. A wide range may be coupled with alkynes using palladium catalysis (Scheme 2.125).148 In contrast to the usual Sonogashira procedure, an excess of the copper(I) salt is required, probably because it becomes bound to the thiol released. Certain alkynes may not be suitable for the Sonogashira reaction. The highly sensitive ethoxyacetylene often fails, and use of its tin or zinc derivatives may be better.149 Alkynes conjugated to electron-withdrawing groups are frequently not effective partners, and a protected form may be required (Scheme 2.126), or the corresponding Negishi or Stille reactions may have to be used.150 Thus, propiolaldehyde is better replaced by its acetal 2.404, and propiolate esters are better replaced by the ortho-ester 2.406. A common by-product in the Sonogashira reaction is the homo-coupled diyne (Scheme 2.127). This is usually due to the presence of O2 . This is a long-known copper-catalysed reaction called Glaser coupling, which is a form of homo-coupling (Section 2.10).151 Palladium may also catalyse this reaction.

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Coupling Reactions HO

CuX, O2

HO

67

OH

2.408

Scheme 2.127 I O

O In, CuI, LiCl EtO

InX2 N

EtO

Br

Pd(Ph3)4, LiCl EtO

2.409

2.408

O

2.410

N

Scheme 2.128 MeO

FF Ge

n-C8F17

Br

CF3

+ OMe

2.411

CF3

(MeCN)2PdCl2, P(o-tol)3

2.412 CF3

2.413 CF3

Scheme 2.129

S 2.414

Br

+ Bi

OEt 3

Pd(OAc) 2, Ph3P, K3PO4

S

OEt

2.416

2.415

Scheme 2.130

2.9 Other Metals A range of other metals has been investigated as the source of one of the coupling fragments, such as indium (Scheme 2.128),152 germanium (Scheme 2.129)153 and bismuth (Scheme 2.130).154 Despite their potential, none of these has yet gained widespread use.

2.10 Homocoupling Homocoupling155 can involve either two organic halides (or their equivalent) or two organometallic compounds (Scheme 2.131). Palladium is often employed for this transformation. Neither reaction is of itself catalytic, but each can be rendered catalytic by the inclusion of either a reducing agent or an oxidizing agent. For the homocoupling of halides, there is a net oxidation of the metal. Either a stoichiometric amount of a low-valent transition-metal complex must be used as a reagent, or a reducing agent must be included. Zinc is frequently used,156 and this can be promoted by ultrasound.157 The reaction can also be achieved electrochemically.158 In some cases, it may not be entirely clear what is responsible for the reduction (Scheme 2.132).159 Distannanes compounds, such as hexa-n-butylditin, have also been used. In this case, it is also possible that one molecule of halide couples with the distannane to give a tetraorganotin derivative, which then undergoes a Stille coupling in situ.

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Organic Synthesis Using Transition Metals 2 RX

2 RM

R R Pd(0)

R R Pd(II)

Pd(II)

reducing agent

Pd(0)

oxidising agent

Scheme 2.131 Tr

Pd(PPh3)4, Et3N, DMF

N

Tr

I N

N

N N

2 . 417

Tr

N

2.41 8

Scheme 2.132

I

I

(Ph3P)4Pd, Cu dust

+ NO2 2.419

O 2.420

H2, Pd/C

O NO2

N H 2.422

2.421

Scheme 2.133 MOMO I

O

I

1. Ni(PPh3)4, DMF HO 2. H3O+ HO

O

MOMO 2.423

2.424

Scheme 2.134

Although it may seem that homocoupling should only be useful for the synthesis of symmetrical products, useable yields of unsymmetrical products have been obtained.160 For instance, o-halonitrobenzenes 2.419 can be selectively coupled with ␣-haloenones 2.420 in the presence of copper dust (Scheme 2.133).161 Hydrogenation of the coupling product provides a short synthesis of indoles 2.422. Stoichiometric quantities of nickel complexes have been used to achieve the homocoupling of aryl iodides. When the reaction is intramolecular, as in the synthesis of alnuson 2.424 (Scheme 2.134), good yields of unsymmetrical coupling products could be obtained.162 The homocoupling of organostannanes is known and a convenient oxidizing agent for the palladium catalyst is atmospheric oxygen. The process is usually regarded as a synthetic problem, rather than a synthetic possibility. It is responsible, in many cases, for the pre-reduction of palladium(II) complexes to active palladium(0) complexes when they are used as the pre-catalyst in coupling reactions. The homocoupling of boronic acids is also known.163 The homocoupling of alkynes, the Glaser reaction, is mentioned in Section 2.8.

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Coupling Reactions i-Pr

69

i-Pr (Ph3P)4Pd, KOt-Bu

I 2.425

O

2.426 O

i-Pr

i-Pr I

LnPd(0)

2.425 t-BuO

2.426 O

O

oxidative addition and deprotonation t-BuOH i-Pr

i-Pr LnPd

Pd Ln 2.428

O

palladation

I O 2.427

Scheme 2.135

Br

O

(Ph3P)2PdCl2, CsCO3

2.479

O

2.480

Scheme 2.136

2.11 Enolate and Phenoxide Coupling The palladium-catalysed coupling of enolates with aryl and vinyl halides is a useful carbon–carbon bondforming method (Scheme 2.135).164 A suitably strong base must be included in the reaction mixture in order to generate the enolate. Potassium or sodium t-butoxide is often used.165,166 Other bases, such as caesium carbonate, have also be used (Scheme 2.136).167 With the more acidic active methylene compounds, such as malonate esters, even weaker bases can be used. A mechanism can be drawn involving oxidative addition of the palladium(0) catalyst to generate an organopalladium(II) intermediate 2.427. The enolate can then be C-palladated, followed by reductive elimination. This area of coupling chemistry has also beneﬁted from the introduction of new ligands to replace triphenyphosphine. Both bidentate ligands (Scheme 2.137)168 and biaryl ligands (Schemes 2.138 and 2.139)169 can impart improved reactivity to the catalysts. An intramolecular enolate arylation of ketone 2.490 was employed in a synthesis of lennoxamine 2.492 and related alkaloids (Scheme 2.140).170 The carbonyl group, having served the purpose of activating the ␣-protons in ketone 2.490, was subsequently removed by a double reduction sequence, including a Kursanov-Parnes reaction.

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Organic Synthesis Using Transition Metals Pd(dba)2, BINAP or dppf NaOt-Bu

Br N Me 2.481

O N Me 2.482

O

Scheme 2.137 CO2Et EtO2C

CO2Et +

Cl

O

Pd2(dba)3, QPhos, K3PO4

O

O

CO2Et

O 2.483

2.484

Scheme 2.138 CO2Et

CO2Et Pd(OAc)2, L NaOt-Bu

O + 2.485

Br

O

L = 1.18

PCy2 Me

2.487

2.486

Scheme 2.139

Changing the enolate counter ion can also be beneﬁcial. Reformatsky reagents 2.494 are zinc enolates, generated indirectly. These reagents can couple with aryl halides using either palladium or nickel catalysis (Scheme 2.141).171 This may also be considered as a variant of Negishi coupling (Section 2.3). In many cases, the arylation of an enolate forms a new stereogenic centre. The use of chiral ligands for the catalyst can result in enantioselectivity (Scheme 2.142).172 Asymmetric arylation is less challenging when a quaternary stereogenic centre is being generated, as the product cannot epimerize under the reaction conditions. Nevertheless, asymmetric arylation to generate less-substituted centres is possible (Scheme 2.143).173 The use of silyl enol ethers as enolate precursors allowed the avoidance of strongly basic conditions. A hard but mildly basic nucleophile, acetate, was included to liberate the enolate. Phenoxides may be considered an extreme form of enolates, with the “ene” component buried in an aromatic ␲-system, although their coupling reaction can also be considered to be related to C–H activation (Chapter 3). Phenoxides can be coupled with vinyl halides both intra- and intermolecularly (Scheme 2.144).174

2.12 Heteroatom Coupling A heteroatom nucleophile may be coupled to an organic halide or its equivalent using transition-metal catalysis in the same way that a main-group organometallic species can be coupled (Scheme 2.145).175 The leaving group (X) is often a bromide, but may also be an iodide. Chlorides have been extensively studied and work well with the right choice of ligand. Sulfonate derivatives may also be used in place of halide. This reaction has been most intensively studied for reactions of nitrogen nucleophiles. Other nucleophiles used include

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Coupling Reactions O NH O

O

O

2.488 O + ClOC OMe Br

NaHCO3

Pd2(dba)3.CHCl3, BINAP, KOt -Bu

N O Br

2.490 O

OMe OMe

OMe 2.489

O

O

1. NaBH4 2. Et3SiH, BF3.OEt3

O N

O N

O

O O

OMe

OMe 2.491

2.492

OMe

OMe

Scheme 2.140 Br +

BrZn

CO2Et

(Ph3P)4Ni

CO2Et

MeO

MeO 2.493

2.495

2.494

Scheme 2.141 O

O Me PhBr, NaOt-Bu, Ni(COD)2, L 2.496

Ph Me

N

OMe MeO

L = MeO Ph2P

2.497 92% e.e.

N

OMe

PPh2 2.498

Scheme 2.142 OTf S 2.499

CO2Me

2-Naph

OSiMe3

(TMEDA)PdMe2, LiOAc, L Ot-Bu

+

CO2Me S

Me

L=

CO2Me

2.501 96% e.e.

2.500

2.502

Scheme 2.143 OH

OH I

Pd(OAc)2, (o-tol)3P, Cs2CO3 O

O 2.503

2.504

Scheme 2.144

O PCy2

71

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Organic Synthesis Using Transition Metals X + RYH

Pd catalyst, ligand, base

YR

Scheme 2.145 Br

Br

OTBDPS I

OTBDPS

Pd2(dba)3 BINAP, NaOt -Bu

+ HN

N

N3 2.505

2.506

2. 507

N3

Scheme 2.146 Cl + n-Bu2NH

Pd(dba)2, Qphos, K3PO4

Nn-Bu2 MeO2C

MeO2C 2. 5 08

2.509

Scheme 2.147 TIPSO

TIPSO H

Pd(OAc)2 BINAP, Cs 2CO3

HN OTf

H N

2 . 510

2.511

Scheme 2.148

alcohols and phenols, thiols and phosphines. The base varies largely with the acidity of the coupling partner, (RYH). Halide ions may be used as the nucleophiles to change one leaving group into another; cyanide, which is a pseudohalide can be used; hydride sources can be used to remove a functional group. The organic group involved is most often aryl. While there had been early reports of heteroatom coupling,176 and success with the t-Bu3 P ligand, a major advance was the use of bidentate phosphine ligands such as BINAP and dppf.177 This was followed later by the use of monodentate phosphine ligands containing a biaryl moiety. A base is also required in the reaction mixture. The bases employed range from very strong bases such as LHMDS, through alkoxide bases, including NaOt-Bu and KOt-Bu, to milder bases such as NaOH, Cs2 CO3 , K2 CO3 and even K3 PO4 . 2.12.1

Palladium-Catalysed Synthesis of Amine Derivatives

The coupling of amines has been extensively studied using both bidentate ligands (Scheme 2.146)178 and monodentate ligands with a biaryl moiety, such as QPhos 1.24 (Scheme 2.147).179 An intramolecular version was employed as part of a synthesis of the mitomycin ring system 2.511 (Scheme 2.148).180 The intramolecular coupling of anilines was used for the synthesis of heterobenzazepines 2.513 on a 127 mmole scale (Scheme 2.149).181 An amine-coupling reaction of chloride 2.514 was carried out on a kilo scale in the synthesis of CP 529,414 (Torcetrapib) 2.518 (Scheme 2.150), which was hoped to become an LDL-reducing drug.182

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Coupling Reactions

Br

S

Pd2(dba)3, Pt-Bu3, NaOt-Bu, K2CO3

S H2N

73

N H 2 .513

Cl

2. 51 2

Cl

Scheme 2.149

F3C

Pd(OAc)2, Davephos, Cs2CO3

CN + Cl

H2N

2.514

2.515 O

CO2Me

F3C N H

N H

N H

Et

O N H

2.516

HN

CN

Et

F3C

1. H3O+ 2. CbzCl, LiOt-Bu

F3C

4, MgCl2 OBn 1. NaBH 2. H+

Et

1. EtOCOCl, py 2. m-(F3C)2C6H3CH2Br, KOt-Bu

F3C

CF3

N

CO2Me

F 3C

Et

2.517

2.518

Et N CO2Et

Scheme 2.150

The coupling of 2-chloroaniline 2.520 with 2-bromostyrene 2.519 using the ligand Brettphos 1.22 showed the expected selectivity for coupling at the bromo position (Scheme 2.151). The product could be converted to three different heterocyclic systems by palladium catalysis according to the ligand employed.183 Use of Davephos 1.20 as the ligand resulted in formation of the benzodiazepine 2.522 by an apparent endo-Heck reaction, while use of tri(t-butyl)phosphine 1.10 gave the acridine 2.523 via an exo-Heck reaction. In contrast, using Trixiephos 1.13, the vinyl group was ignored and the carbazole 2.524 was produced by C–H activation. A very wide range of nitrogen derivatives has been employed.184 Common ones include amides (Scheme 2.152),185 sulfonamides, carbamates (Scheme 2.153), including cyclic carbamates (Scheme 2.154)186 and ureas (Scheme 2.155).187 Reactions may be not only intermolecular, but also intramolecular (Scheme 2.156).188 N-Heterocycles may also be arylated.189 A double coupling of methane sulfonamide was used to prepare dofetilide 2.538, an antiarrhythmic agent (Scheme 2.157).190 Mesylates have also been a substrate for coupling (Scheme 2.158).191 As these N-acyl and N-sulfonyl derivatives tend to be more acidic than simple amines, weaker bases tend to be employed. More exotic derivatives of nitrogen, including sulfoximines (Scheme 2.159),192 hydrazines (Scheme 2.160)193 and guanidines194 can also be coupled. The intramolecular coupling of a ␤-lactam was employed in the synthesis of carbapenems 2.548 (Scheme 2.161).195 An important objective has been the development of “ammonia surrogates”, molecules that can be coupled to yield primary amines. One way is to use secondary amines bearing groups such as allyl (Scheme 2.162)

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Organic Synthesis Using Transition Metals NH2 Cl + Br 2.519

2.520 Pd2(dba)3, Brettphos NaOt-Bu Me

Pd2(dba)3, Davephos NaOt-Bu

Pd2(dba)3, t-Bu3P NaOt-Bu NH

N H

N Cl

2.521

2.522

2.523 Pd2(dba)3, Trixiephos NaOt-Bu

N H 2.524

Scheme 2.151

O NC

Br

+

H2N

O Pd(OAc)2 Ph XantPhos, Cs2CO3

Ph NC

N H 2.526

2.525

Scheme 2.152

O

O Br + H N 2

Ot-Bu

Pd2(dba)3 t-Bu3P, NaOPh

Ot-Bu

N H 2.528

2.527

Scheme 2.153

Cl +

F3C 2.529

HN O

O

Pd2(dba)3 Johnphos, Cs2CO3 F3C

2.530

Scheme 2.154

N 2.531

O

O

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Coupling Reactions MeO

Br

+ HN

Pd2(dba)3, Xantphos, MeO Cs2CO3

NH

OMe N

O 2.534

O 2.533

2.532

N

Scheme 2.155 NHAc Pd(OAc)2, DPEphos, Cs2CO3 N Ac

Br 2.536

2.535

Scheme 2.156 Cl O

MeSO2NH2, K2CO3 [(allyl)PdCl]2, t-BuXPhos

N Me

Cl

O

2.537

NHSO2Me

N Me

MeO2SHN

2.538

Scheme 2.157 O O

Me Pd(OAc)2, t-BuBrettphos, Cs2CO3, aq, t-BuOH

H2N

O

O

O

O

N H 2.541

OMs 2.539

2.540

Scheme 2.158 Br

MeO

O

O Pd(OAc) 2 BINAP, Cs2CO3 S Br + Me HN p -Tol 2.542

2.543

N 2.544

Scheme 2.159

N AcHN

Pd(OAc)2 DPEPhos, Cs2CO3

N

Br

2.545

2.546

Scheme 2.160

N Ac

Me S p -Tol

Me

75

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Organic Synthesis Using Transition Metals TBSO

TBSO

H H NH Br

O

H H

Pd(OAc)2 DPEphos, K2CO3 CO2Et

N O

2.547

2.548

CO2Et

Scheme 2.161 NH2 dppfPdCl2, NaOt-Bu

N

N N H

Br 2.549

N

Pd/C, MsOH, EtOH

2.550

NH2 2.551

Scheme 2.162 I

Ph + HN

Pd2(dba)3, BINAP, NaOt-Bu, 18-Crown-6

Ph

Br 2 . 552

N Ph

Br

2 . 55 3

Ph

2 . 554 NH2

H3O+ Br 2.555

Scheme 2.163

and benzyl that can be easily cleaved after coupling.196 The imine of benzophenone 2.553 has been found to be useful despite the poor atom economy (Scheme 2.163). After coupling, the N-aryl imine 2.554 may be converted to the aniline 2.555 by a number of methods including acidic hydrolysis, catalytic hydrogenation or exchange with hydroxylamine.197 Triﬂates can also be used as the substrate for this coupling reaction.198 Benzophenone imine 2.553 has been used for the synthesis of a 5-HT1F receptor agonist 2.562 (Scheme 2.164) to aminate chloropyridine 2.560.199 This synthesis included the use of an intramolecular Heck reaction (Section 5.1.8) of iodopyridine 2.558 to form the furano ring. Like the use of the imine as an ammonia surrogate, the hydrazone of benzophenone can be used as a hydrazine surrogate (Scheme 2.165).200 The coupling product 2.564 may be diverted directly into a Fischer indole synthesis via hydrazone exchange with an added ketone. This pathway gives an indole 2.565 with a free N–H. Alternatively, the available nitrogen atom may be alkylated or coupled a second time, and then diverted into a Fisher indole synthesis. In this way, indoles with no nitrogen substituent, or an N-alkylated indole 2.566 or an N-arylated indole 2.567 can be formed.

2.12.2

Palladium-Catalysed Synthesis of Ethers

Systems similar to those used for the formation of C–N bonds can also be applied to the formation of C–O bonds.201 The oxygen system is less reactive, with reductive elimination being slower, which explains why alkoxide bases can be employed for C–N bond formation. Both alcohols202 and phenols (Scheme 2.166)203 can be the substrates. Intramolecular reactions (Scheme 2.167) are possible.204

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Coupling Reactions Cl

N

I Cl

N

I

Pd(OAc)2, Na2CO3

DEAD, PPh3

OH 2.556 +

O

CO2Me

2.558 HO

CO2Me 2.557

Cl

NMe2 CO2Me 1. Me3Al, Me2NH 2. LiAlH4

N

Cl

N

O

O 2.560

2.559 NMe2 H2N

1. Ph2C=NH Pd2(dba)3, BINAP, NaOt-Bu 2. H3O+

NMe2

F H N

p-FC6H4COCl, py

N

N

O

O 2.561

O

2.562

Scheme 2.164 Ph

Ph2C=NNH, Pd(OAc)2, Xantphos, NaOt-Bu Br

N H 2.564

2.563

R2

O

Ph

R2 H+

R1

N

1. LDA; RX 2. O + R2 H R1 R2

R1 N 2.565 H

1. Pd, L, base, ArX 2 O R1

R2 H+ R2

R1

R1

N 2.566 R

N 2.567 Ar

Scheme 2.165 Br

NaOPh, Pd(dba)2, L

NC

P(C6H4p-CF3)2

OPh L=

Fe

NC

P(C6H4p-CF3)2 2.569

2.568

2.570

Scheme 2.166 OH

Pd2(dba)3, QPhos NaOt-Bu O 2.571

Br 2.570

Scheme 2.167

77

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Organic Synthesis Using Transition Metals Br

O

HO Cu(OTf)2, Cs2CO3

+

EtO2C

EtO2C 2.572

2.574

2.573

Scheme 2.168 Et2N

O

Et2N I

HO

O O

(CH3CN)4CuPF6, Cs2CO3

+

OMe 2.575

OMe 2.577

2.576

Scheme 2.169

OH CuI, 1,10-phen Cs2CO3

I

O OMe

OMe 2.579

2.578

Scheme 2.170

I

CuBr, phosphazene base

HS +

MeO

Cl

MeO

Cl 2.580

S

2.582

2.581

Scheme 2.171

SH

+

I

CuI, n-Bu4NBr, NaOH

S

Cl 2.583

Cl 2.585

2.584

Scheme 2.172

2.12.3

Ullmann Coupling

Over a century ago, Ullmann reported coupling reactions catalysed by metallic copper.205,206 The harsh conditions typically involved limited its applicability, but Ullmann’s work ultimately stimulated the search for milder conditions using copper catalysis. Both copper(I) and copper(II) salts can catalyse the coupling of aryl halides with a range of heteroatom nucleophiles, including phenols (Scheme 2.168, 2.169),207 alcohols (Scheme 2.170),208 thiols (Scheme 2.171, 2.172),209 amines (Scheme 2.173),210 anilines (Scheme 2.174)211 and N-heterocycles (Scheme 2.175, 2.176).212,213

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Coupling Reactions

O +

NH

O

CuI, K3PO4, HO(CH2)2OH

I

2.586

79

N

2.588

2.587

Scheme 2.173 MeO2C NH2

MeO2C

(Ph3P)3CuBr, Cs2CO3

I +

2.589

H N

2.590

2.587

Scheme 2.174 N N

Br

Cu(OTf)2, 1,10-phen Cs2CO3

+ HN 2.591

N

2.593

2.592

Scheme 2.175

I

N

CuI, K3PO4, L

+ N H

L= MeHN

NHt-Boc

2.594

2.596

2.595

NHt-Boc

NHMe

2.597

Scheme 2.176 HO

NH2

I + 2.599

2.598 CuI, picolinic acid, K3PO4, DMSO O F

NH2

A=

F

palladacycle A, NaOt-Bu H HO N

NH2 Pd Brettphos Cl

F 2.600

2.601

Scheme 2.177

While the copper-catalysed Ullmann reaction seems to have the same substrates and products as the palladium-catalysed heteroatom coupling (Section 2.12.1), there are differences. Interesting selectivity can be achieved by switching between the two systems (Scheme 2.177). Aminophenol 2.598 can give either O-arylation product 2.600 or the N-arylation product 2.601 according to the conditions and catalysts chosen.214

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Organic Synthesis Using Transition Metals

Copper-mediated arylation of various nucleophilic groups, including phenols, anilines and thiophenols, with boronic acids has been reported by several groups (Scheme 2.178).215 As an organometallic species is used as the aryl donor, the copper(II) acts as a net oxidant, and must be used stoichiometrically. Inclusion of an oxidant, such as molecular oxygen as in the Wacker reaction (Section 6.1) can allow a system that is catalytic in copper.216 Aryl triﬂuoroborates have also been used as the aryl donor.217 The coupling reaction may be either intermolecular, as for a synthesis of an intermediate in a synthesis of thyroxine 2.605 (Scheme 2.179),218 or intramolecular, as in a synthesis of a metalloproteinase inhibitor 2.607 (Scheme 2.180) (for a different approach to related peptides, see Scheme 10.47).219 It is notable in the thyroxine synthesis that the two iodine substituents of coupling substrate 2.602 are not affected and no Suzuki products are formed in the absence of palladium.

XH

(HO)2B

X

Cu(OAc)2, Et3N

+

Scheme 2.178

I OH

AcHN

(HO)2B +

EtO2C

I

OMe 2.603

2.602 I Cu(OAc)2, Et3N

O

AcHN EtO2C

I

OMe

O

I

2.604 I 1. HI, AcOH 2. I2, EtNH2

H 2N HO2C

I 2.605

OH I

Scheme 2.179

OH O

B(OH)2 Cu(OAc)2, Et3N

O t-BuO2C

N H

CONHMe

O t-BuO2C

N H

CONHMe

2.607

2.606

Scheme 2.180

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Coupling Reactions OTf

Sn-Bu

n-BuSH, KOt-Bu Pd(OAc)2, tol-BINAP

2.608

81

2.609

Scheme 2.181

HS I

CO2Me

CO2Me

Me

S

Me (Ph3P)4, Et3N

2.610

N H

2.611

N H

Scheme 2.182

2.12.4

Formation of Other C–X bonds

Thiols have been employed as nucleophiles in palladium-catalysed coupling reactions (Scheme 2.181). An aryl thioether could be formed from an aryl triﬂate using a strong base, a bidentate ligand and a nonpolar solvent to suppress competitive triﬂate decomposition.220 An intramolecular thiol coupling with an iodoindole was a key step in a synthesis of chuangxinmycin (Scheme 2.182).221 Carbon–phosphorus bonds may also be formed.222 Chemists at Merck developed a synthesis of either enantiomer of the valuable ligand BINAP 1.33 from the more easily resolved BINOL 2.612, using a triﬂate–phosphine coupling reaction (Scheme 2.183).223 They reasoned that nickel catalysis would be more effective as this metal is harder than palladium and, therefore, less susceptible to catalyst poisoning by the product. BINAP 1.33 could be obtained with no loss of chirality. They also reported a resolution procedure for BINOL 2.612.224 Triarylphosphines can add an additional aryl group to form tetraarylphosphonium salts 2.613 by reaction with an aryl halide and a transition-metal catalyst (Scheme 2.184).225 This is one cause of ligand destruction during coupling and Heck reactions.226

OH dppeNiCl2, Ph2PH DABCO, DMF OH

2.612

PPh2 PPh2

1.33

Scheme 2.183

Ph3P +

PhBr

NiBr2

Ph4P Br 2.613

Scheme 2.184

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Organic Synthesis Using Transition Metals Cl

Ph

Ni(COD)2, NaI, DMF

I

Ph

2.614

2.615

Scheme 2.185 Br NaCN, 15-Crown-5, (Ph3P)4Pd

Ph 2.616

CN

Ph 2.617

Scheme 2.186

H

2.618 X = OTf

H H

H

2.619 X = H

Pd(OAc)2, PPh3, n-Bu3N, HCO2H

X

Scheme 2.187

The transition-metal-catalysed exchange of halogen atoms may also be viewed as a heteroatom coupling reaction. It is particularly useful for the conversion of the cheaper and more available chloro compounds to the more reactive iodo compounds. Nickel catalysis may be used (Scheme 2.185).227 Cyanide can also be coupled (Scheme 2.186).228 The use of hydride sources, such as formate or tri-n-butyltinhydride is a method of removing functionality (Scheme 2.187).229 The mechanism of formate reduction is illustrated in Scheme 5.50.

References 1. Care must be taken in evaluating claims of activity for many metals, as traces of other metals may be the responsible catalyst: Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586; Bedford, R. B.; Nakamura, M. et al. Tetrahedron Lett. 2009, 50, 6110. 2. For a rare comparative study of different metals, see Negishi, E.-i.; Takahashi, T. et al. J. Am. Chem. Soc. 1987, 109, 2393. 3. (a) Kambe, N.; Iwasaki, T.; Terao, J. Chem. Soc. Rev. 2011, 40, 4937; (b) Frisch, A. C.; Beller, M. Angew. Chemie, Int. Ed. 2005, 44, 674; (c) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525. 4. Similarly this order of reactivity is not usually observed in nucleophilic aromatic substitution reactions as loss of the leaving group is usually not the r.d.s. 5. Verbeeck, S.; Meyers, C. et al. Chem. Eur. J. 2010, 16, 12831. 6. So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963. 7. Sellars, J. D.; Steel, P. G. Chem. Soc. Rev. 2011, 40, 5170. 8. Roglans, A.; Pla-Quintana, A.; Moreno-Ma˜nas, M. Chem. Rev. 2006, 106, 4622. 9. Fukuyama, T.; Tokuyama, H. Aldrich. Acta 2004, 37, 87. 10. Frankland, E. Justus Liebigs Ann. Chem. 1849, 71, 171. 11. Rossi, R.; Bellina, F. Org. Prep. Proc. Int. 1997, 27, 139. 12. Fenwick, A. E. Tetrahedron Lett. 1993, 34, 1815. 13. Kawada, K.; Arimura, A. et al. Angew. Chem., Int. Ed. Engl. 1998, 37, 973. 14. Minato, A.; Suzuki, K.; Tamao, T. J. Am. Chem. Soc. 1987, 109, 1257. 15. Reiser, O. Angew. Chem., Int. Ed. 2006, 45, 2838.

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Coupling Reactions 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

33. 34. 35. 36. 37. 38. 39. 40.

41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

83

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Organic Synthesis Using Transition Metals Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115, 9293. Leibner, J. E.; Jacobus, J. J. Org. Chem. 1979, 44, 449. Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968. Harrowven, D. C.; Curran, D. P. et al. Chem. Commun. 2010, 46, 6335. Stille, J. K.; Sweet, M. P. Tetrahedron Lett. 1989, 30, 3645. Humphrey, J. M.; Liao, Y. et al. J. Am. Chem. Soc. 2002, 124, 8584. Yang, Y.; H¨ornfeldt, A.-B.; Gronowitz, S. Synthesis 1989, 130. Ragan, J. A.; Raggon, J. W. et al. Org. Process Res. Dev. 2003, 7, 676. Garg, N. K.; Hiebert, S.; Overman, L. E. Angew. Chem., Int. Ed. 2006, 45, 2912. Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634. The earlier procedure called for dry air: Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129. Labadie, J. W.; Stille, J. K. Tetrahedron Lett. 1983, 24, 4283. (a) Baldwin, J. E.; Adlington, R. M.; Ramcharitar, S. H. J. Chem. Soc., Perkin Trans I 1991, 940; (b) Baldwin, J. E.; Adlington, R. M.; Ramcharitar, S. H. Synlett 1992, 875. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478. (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033; (b) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979; (c) Comins, D. L.; Dehgani, A. Org. Synth. 1995, 74, 77. Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. Farina, V. Pure Appl. Chem. 1996, 68, 73. For the synthesis of hindered bi- and terphenyls, see Sa´a, J. N.; Martorell, G. J. Org. Chem. 1993, 58, 1963. Malm, J.; Bj¨ork, P. et al. Tetrahedron Lett. 1992, 33, 2199. Gronowitz, S.; Bj¨ork, P. et al. J. Organomet. Chem. 1993, 460, 127. Farina, V.; Kapadia, S. et al. J. Org. Chem. 1994, 59, 5905. Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437; for reviews, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Bellina, F.; Carpita, A.; Rossi, R. Synthesis, 2004, 2419. Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. Ishiyama, T.; Murate, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (a) Wilson, D. A.; Wilson, C. J. et al. Org. Lett. 2008, 10, 4879; (b) Moldoveanu, C.; Wilson, D. A. et al. Org. Lett. 2009, 11, 4974. Brown, H. C.; Bhat, N. G.; Somayaji, V. Organometallics 1983, 2, 1311. Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766. Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74, 973. Skaff, O.; Joliffe, K. A.; Hutton, C. A. J. Org. Chem. 2005, 70, 7353. Grosjean, C.; Henderson, A. P. et al. Org. Proc. Res. Dev. 2009, 13, 434. Roush, W. R.; Kageyama, M. et al. J. Org. Chem. 1991, 56, 1192. J¨agel, J.; Maier, M. Synlett 2006, 693. Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706. Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515. Soderquist, J. A.; Rane, A. M. Tetrahedron Lett. 1993, 34, 5031. Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000, 41, 8371. Further examples can be found in Sasaki, M.; Fuwa, H. et al. Org. Lett. 1999, 1, 1075. Sharp, M. J..; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997. Banwell, M. G.; Wu, A. W. J. Chem. Soc., Perkin Trans. I 1994, 2671. Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6019. Milburn, R. R.; Thiel, O. R. et al. Org. Process Res. Dev. 2011, 15, 31. Malmgren, H.; Cotton, H. et al. Org. Process Res. Dev. 2011, 15, 408. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387. (a) Marion, N.; Navarro, O. et al. J. Am. Chem. Soc. 2006, 128, 4101; (b) W¨urtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523 Ritleng, V.; Oertel, A. M.; Chetcuti, Dalton Trans. 2010, 39, 8153.

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Coupling Reactions 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141.

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Barder, T. E.; Walker, S. D. et al. J. Am. Chem. Soc. 2005, 127, 4685. Yu, S. H.; Ferguson, M. J. et al. J. Am. Chem. Soc. 2005, 127, 12808. Kataoka, N.; Shelby, Q. et al. J. Org. Chem. 2002, 67, 5553. Beller, M. Fischer, H. et al. Angew. Chem. Int. Ed. 1995, 34, 1848. Bedford, R. B.; Hazelwood, S. L. et al. Dalton Trans. 2003, 4164. Smith, M. D.; Stephan, A. F. et al. Chem. Commun. 2003, 2652. Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 21, 691. Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. Kirchhoff, J. H.; Netherton, M. R. et al. J. Am. Chem. Soc. 2002, 124, 13662. Netherton, M. R.; Dai, C. et al. J. Am. Chem. Soc. 2001, 123, 10099. (a) Nakao, Y.; Hiyama, T. Chem Soc. Rev. 2011, 40, 4893; (b) Denmark, S. E.; Liu, J. H.-C. Angew. Chem., Int. Ed. 2010, 49, 2978. Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1989, 54, 268. Seganish, W. M.; Handy, C. J.; DeShong, P. J. Org. Chem. 2005, 70 8948. Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137. Minami, T.; Nishimoto, A.; Hanaoka, M. Tetrahedron Lett. 1995, 36, 9505. (a) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486; (b) Denmark, S. E.; Ober, M. H. Aldrich. Acta 2003, 36, 75. Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821. (a) Denmark, S. E.; Ober, M. H. Org. Lett. 2003, 5, 1357; (b) Denmark, S. E.; Ober, M. H. Adv. Synth. Catal. 2004, 346, 1703; (c) Denmark, S. E.; Wang, Z. Org. Synth. 2004, 81, 42. Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876. (a) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971; (b) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, 127, 8004. Manoso, A. S.; Ahn, C. et al. J. Org. Chem. 2004, 69, 8305. Manoso, A. S.; Ahn, C. et al. J. Org. Chem. 2004, 69, 8305. Murata, M.; Ishijura, M. et al. Org. Lett. 2002, 4, 1843. Kyoko, T.; Tatsuya, M. et al. Tetrahedron Lett. 1993, 34, 8263. Denmark, S. E.; Yang, S. M. J. Am. Chem. Soc. 2004, 126, 12432. Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. Owsley, D. C.; Castro, C. E. Org. Synth. 1988, Coll. Vol. VI, 916. (a) Cassar, L. J. Organometal. Chem. 1975, 93, 253; (b) Dieck, H. A.; Heck, R. F. J. Organometal. Chem. 1975, 93, 259. Other “copper-free” methods have also been reported: Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467; (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. (a) Chinchilla, R.; N´ajera, C. Chem. Soc. Rev. 2011, 40, 5084; (b) Chinchilla, R.; N´ajera, C. Chem. Rev. 2007, 107, 874; (c) Rossi, R.; Carpita, A.; Bellini, F. Org. Prep. Proc. Int. 1995, 129. For a discussion of other metals in the Sonogashira reaction see, Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954. Chem. Eng. News, April 15th, 1996, p. 34. Hoye, R. C.; Anderson, G. L. et al. J. Org. Chem. 2010, 75, 7400. Bates, R.W. Rama-Devi, T. Synlett, 1995, 1151. (a) Sabourin, E. T.; Onopenko, A. J. Org. Chem. 1983, 48, 5135; (b) Melissaris, A. P.; Litt, M. H. J. Org. Chem. 1992, 57, 6998. Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582. Schreiber, S. L.; Kiessling, L. L. J. Am. Chem. Soc. 1988, 110, 631. Hundertmark, T.; Littke, A. F. et al. Org. Lett. 2000, 2, 1729. Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993. Echhardt, M. E.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.

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Bleicher, L.; Cosford, N.D.P. Synlett, 1995, 1115. Lohmann, S.; Andrews, S. P. et al. Synthesis 2005, 1291. Bates, R. W.; Boonsombat, J. J. Chem. Soc., Perkin Trans I 2001, 654. Bracher, F.; Daab, J. Eur. J. Org. Chem. 2002, 2288. Alami, A.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763. Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis, 1977, 777. Tokuyama, H.; Tohru, M. et al. Synlett 2003, 1512. Sakamoto, T.; Yasuhara, A. et al. Chem. Pharm. Bull. 1994, 42, 2032. Sakamoto, T.; Shiga, F. et al. Synthesis 1992, 746. (a) Siemsen, P.; Livingston, R. P.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632; (b) Takahashi, A.; Endo, T.; Nozoe, S. Chem. Pharm. Bull. 1992, 40, 3181. (a) Shen, Z.-L.; Lai, Y.-C. et al. Org. Lett. 2011, 13, 422; (b) Shen, Z.-L.; Goh, K. K. K. et al. Chem. Commun. 2011, 47, 4778. Spivey, A. C.; Tseng, C.-C. et al. Chem. Commun. 2007, 2926. (a) Ducoux, J.-P.; Le M´eneuz et al. Tetrahedron 1992, 48, 6403; (b) Rao, M. L. N.; Banerjee, D.; Dhanorkar, R. J. Synlett 2011, 1324. Stefani, H. A.; Guarezemini, A. S.; Cella, R. Tetrahedron 2010, 66, 7871. (a) Jutland, A.; Mosleh, A. Synlett, 1993, 568; (b) Takagi, K.; Hayama, N.; Sasaki, K. Bull. Chem. Soc. Jpn. 1984, 57, 1887. Yamashita, J.; Inoue, Y. et al. Chem. Lett. 1986, 407. Jutland, A.; Negri, S.; Mosleh, A. J. Chem. Soc., Chem. Commun. 1992, 1729. Cliff, M. D.; Pyne, S. G. Synthesis, 1994, 681. Ross Kelly, T.; Lang, F. Tetrahedron Lett. 1995, 36, 5319. Banwell, M. G.; Kelly, B. D. et al. Org. Lett. 2003, 5, 2497. Semmelhack, M. F.; Helquist, P. et al. J. Am. Chem. Soc. 1981, 103, 6460. Moreno-Ma˜nas, M.; P´erez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346. Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. Piers, E.; Renaud, J.; Rettig, S. J. Synthesis 1998, 590. Shaugnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546. (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581; (b) Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett. 1997, 38, 7577; (c) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355. see reference 167. (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541; (b) Fox, J. M.; Huang, X. et al. J. Am. Chem. Soc. 2000, 122, 1360. Honda, T.; Sakamaki, Y. Tetrahedron Lett. 2005, 46, 6823. Fauvarque, J. F.; Jutland, A. J. Organometallic Chem. 1979, 177, 273. Chen, G.; Kwong, F. Y. et al. Chem. Commun. 2006, 1413. Huang, Z.; Liu, Z.; Zhou, J. J. Am. Chem. Soc. 2011, 133, 15882. (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H. Tetrahedron Lett. 1997, 38, 6379; (b) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2. (a) Jiang, L.; Buchwald, S. L. in Metal-Catalysed Cross-Coupling Reactions (Eds: de Meijere, A.; Diederich, F.), Wiley-VCH, Weinheim, 1998; (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; (c) Hartwig, J. F. in Modern Arene Chemistry (Ed: Didier, A.), Wiley-VCH, Weinheim, 2002, pp. 107–168; (d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; (e) Prim, D.; Campagne, J. M. et al. Tetrahedron 2002, 58, 2041; (f) Frost, C. G.; Mendoca, P. J. Chem. Soc., Perkin Trans I 1998, 2615. For an industrial perspective, see Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599. Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927. (a) Wolfe, J. P. et al. Acc. Chem. Res. 1998, 31, 805; (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 853. Lee, S.; Lee, W.-M.; Sulikowski, G. A. J. Org. Chem. 1997, 9, 64, 4224. Kataoka, N.; Shelby, Q. et al. J. Org. Chem. 2002, 67, 5553.

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176. 177. 178. 179.

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Coleman, R. S.; Chen, W. Org. Lett. 2001, 3, 1141. Margolis, B. J.; Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003, 68, 644. Damon, D. B.; Dugger, R. W. et al. Org. Proc. Res. Dev. 2006, 10, 472. Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14048. Hartwig, J. F.; Kawatsura, M. et al. J. Org. Chem. 1999, 64, 5575. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. Ghosh, A.; Sieser, J. E. et al. Org. Lett. 2003, 5, 2207. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. Mann, G.; Hartwig, J. F. et al. J. Am. Chem. Soc. 1998, 120, 827 Rosen, B. R.; Ruble, J. C. et al. Org. Lett. 2011, 13, 2564. Dooleweerdt, K.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2010, 12, 2350. Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169. Zhu, Y.-M.; Kiryu, Y.; Katayama, H. Tetrahedron Lett. 2002, 43, 3577. Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133. (a) Kozama, Y.; Mori, M. J. Org. Chem. 2003, 68, 3064; (b) Kozama, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 111. Jaime-Figueroa, S.; Liu, Y. et al. Tetrahedron Lett. 1998, 39, 1313. ˚ Wolfe, J. P.; Ahman, J. et al. Tetrahedron Lett. 1997, 38, 6367. ˚ Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363. Mathes, B. M.; Filla, S. A. Tetrahedron Lett. 2003, 44, 725. Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251. Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912. (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109; (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395. Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005. Shelby, Q.; Kataoka, N. et al. J. Am. Chem. Soc. 2000, 122, 10718. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389; (b) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389. (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (a) Marcoux, J. F.; Doyle, S. Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539; (b) Kalinin, A. V.; Bower, J. F. et al. J. Org. Chem. 1999, 64, 2986. (a) Wolter, M.; Nordmann, G. et al. Org. Lett. 2002, 4, 973; (b) Chang, J. W. W.; Chee, S. et al. Tetrahedron Lett. 2008, 49, 2018. (a) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803; (b) Buranaprasertsuk, P.; Chang, J. W. W. et al. Tetrahedron Lett. 2008, 49, 2023. Kwong; F. Y.; Klapars; A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. Gujadhur, R. K.; Venkataraman, D. Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791. Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657. Antila, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423. (a) Chan, D. M. T.; Monaco, K. L. et al. Tetrahedron Lett. 1998, 39, 2933; (b) Lam, P. Y. S.; Clark, C. G. et al. Tetrahedron Lett. 1998, 39, 2941. Lam, P. Y. S.; Vincent, G. et al. Tetrahedron Lett. 2001, 42, 633. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381. Evans, D.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937. Decicco, C. P.; Sing, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029. Zheng, N.; McWilliams, J. C. et al. J. Org. Chem. 1998, 63, 9606. Kato, K.; Ono, M.; Akita, H. Tetrahedron Lett. 1997, 38, 1805; for another example, see Abbas, S.; Hayes, C. J. Synlett 1999, 1124. Tappe, F. M. J.; Trepohl, V. T.; Oestrich, M. Synthesis 2010, 3037.

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Cai, D.; Payack, J. F. et al. J. Org. Chem. 1994, 59, 7108. Cai, D.; Hughes, D. L. et al. Tetrahedron Lett. 1995, 36, 7991. Hirusawa, Y.; Oku, M.; Yamamoto, K. Bull. Chem. Soc. Japan 1957, 30, 667. Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941. Hooijdink, M. C. J. M.; Peters, T. H. A. et al. Synth. Commun. 1994, 24, 1261. (a) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049; (b)Yamamura, K.; Murahashi, S. I. Tetrahedron Lett. 1977, 18, 4429. 229. Cacchi, S.; Morera, E.; Ortar, G. Org. Synth. 1993, Coll. Vol. VIII, 126; see also Org. Synth. 2011, 88, 260.

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3 C–H Activation Much of organic chemistry is based on the manipulation of reactive functional groups, and much of organic synthesis is about introducing, exploiting and removing these groups, or protecting them when their reactivity becomes a liability. With very few exemptions, all organic compounds have C–H bonds, but these are rarely used in organic synthesis unless activated in some way by a nearby functional group. Carbonyl groups, and other electron-withdrawing groups activate the ␣-protons towards bases, while alkenes activate the allylic protons to radical abstraction. Similarly, many of the reactions mediated by transition metals involve functional groups, such as organic halides or alkenes. C–H activation involves the formation of a carbon–transition-metal bond, most often a carbon–metal single bond, from a carbon–hydrogen bond.1 The carbon–metal bond can then be employed in bond-forming reactions with other molecules or functional groups, or even by reaction with a second carbon–hydrogen bond. The term C–H activation should be reserved for reactions that are initiated by the breaking of the C–H bond by the metal complex. Reactions, such as the Heck reaction (Chapter 5), in which the C–H bond is broken late in the mechanism are not considered within this topic. Efforts at C–H activation can be divided into three broad categories. The ﬁrst involves C–H bonds of arenes, heteroarenes and comparable alkenes. In many cases, the formation of the carbon–metal bond may be viewed as an electrophilic substitution reaction (Scheme 3.1), following the same pathway as metallation by main-group metals such as mercury, thallium and lead, as well as classical reactions such as bromination and nitration. This is not, however, always the case. The second category is C–H functionalization in the allylic position. It is based upon coordination of the alkene to the metal to form an ␩2 -complex, followed by oxidative addition to the allylic C–H bond to produce an ␩3 -allyl complex (Scheme 3.2). The third category is the most challenging: C–H activation at an unfunctionalized position, especially at sp3 -hybridized carbon atoms (Scheme 3.3). Clearly, most organic molecules have a large number of such C–H bonds. The problem is regioselectivity. The solution is coordination. A metal complex becomes coordinated to a functional group, Y, often nitrogen or oxygen containing, in the molecule, and is directed to a nearby C–H bond. The formation of the metal–carbon bond can be through oxidative addition, followed by loss of HX by reductive elimination, or by sigma-bond metathesis. This mechanism can also operate in aromatic molecules. A functional group capable of coordinating a metal complex can direct oxidative addition to an ortho C–H bond. A carbonyl or carboxylic group is often involved. Such complexes, including the manganese complex 3.2, have been isolated2 and can undergo further reactions (Scheme 3.4).3

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals M (n-1)+ H - H+

Mn+

M(n-1)+

Scheme 3.1 H

- H+

Mn+

M(n-1)+

Scheme 3.2

oxidative addition

Y

H

Y

Y Mn+ H X

- HX

Y Mn+

H Mn+ X

- HX Y Mn+ H X sigma bond metathesis

Scheme 3.3 CO2Me BnMn(CO) 5 N

N Me 3.1

O

Mn(CO) 4 MeO 2C O

Me 3.2

CO2Me N Me

OH 3.3

CO2Me

Scheme 3.4

Following the formation of the organometallic species by whichever method, further chemistry is usually through the familiar processes, such as reductive elimination or alkene insertion. Another route for formation of carbon–carbon bonds is by C–H activation by reaction with a second molecule of substrate. Alternatively, a carbon–heteroatom bond may be formed (Scheme 3.5). These could be bonds to electronegative atoms, such as oxygen, nitrogen and halogens, or electropositive atoms, such as boron or silicon, which are useful for further transformations. In many cases, the net result is net reduction of the metal of the catalyst. To maintain the catalytic cycle, an oxidant must be added. Candidates are salts of copper(II), benzoquinone (BQ), peroxides and oxygen itself. Using transition-metal catalysts for C–C bond forming at carbons bearing acidic protons, such as the position ␣- to a carbonyl group is discussed in Section 2.11, as the C–H bond is activated by its position, and not primarily by the metal. The coupling of terminal alkynes, the Sonogashira reaction, is also discussed in Section 2.8. The use of carbene and nitrene complexes for bond formation through C–H activation is a well-established process. This is discussed in Section 8.5.2.

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C–H Activation

91

R H C-H activation R' M' coupling R M

R R'

second C-H activation

R' alkene insertion R

R R

heteroatom bond formation R X

R'

Scheme 3.5

Another classiﬁcation of C–H activation methods is as “inner-sphere” and “outer-sphere” mechanisms. Inner-sphere mechanisms can be deﬁned as those that involve the formation of a carbon–metal bond from a C–H bond, while outer-sphere mechanisms involve the cleavage of a C–H bond by a metal-containing species to generate a reactive intermediate, but without a metal–carbon bond. A disadvantage of this classiﬁcation is that it assumes that the mechanism is known! The reactions discussed in this chapter would be considered inner-sphere. Reactions such as the Fenton reaction would be considered outer-sphere. A grey area is likely to exist between the two mechanisms. Another disadvantage of this classiﬁcation is that the term “inner-sphere” mechanism tells us nothing about the mechanism beyond the formation of a metal–carbon bond! An additional, and practical, classiﬁcation is between reactions that convert a C–H bond into a new functional group, which is useful for further bond formation, and reactions that convert a C–H bond directly into a new C–C bond. The latter are obviously more efﬁcient, but may not always be practical in every circumstance.

3.1 Arenes and Heteroarenes 3.1.1

Fujiwara–Heck Reaction

An important route for the C–H activation of arenes and heteroarenes is through electrophilic metallation of an aromatic ring, followed by reaction with an alkene. There are numerous simple examples with arenes and heteroarenes reacting with alkenes under palladium catalysis.4 This has been referred to as the dehydrogenative Heck reaction and the oxidative Heck reaction, as well as the Fujiwara reaction, or Fujiwara–Heck reaction. Both benzene 3.4 and its derivatives (Schemes 3.6 and 3.7)5,6 and heteroarenes (Schemes 3.8 and 3.9)7,8 can be used. While the reaction has been carried out with a stoichiometric amount of palladium, catalytic processes, with an added oxidant are widespread.

CO2n-Bu 3.4

CO2n-Bu

Pd(OAc)2, O2

3.5

3.6

Scheme 3.6

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Organic Synthesis Using Transition Metals CO2Et CO2H Pd(OAc)2, BQ, KHCO3, O2

MeO

MeO

CO2H 3.8

3.7

CO2Et

Scheme 3.7 CO2Et Pd(OAc)2, PhCO3t-Bu CO2Et

O

O 3.9

3.10

Scheme 3.8 CO2n-Bu CO2n-Bu Pd(OAc)2, Cu(OAc)2 3.11

N H

3.12

N H

Scheme 3.9

NH 3.13

3.14

NMe2

O

CO2Et

CO2Et Pd(OAc)2, TsOH, BQ, Ac 2O

C-H activation

N CONMe2

nucleophilic attack [Pd]

[Pd]

CO2Et

O N H 3.15

NH

NMe2 O CO2Et

insertion NH O

η →η 1

NMe2

3.17

3

[Pd]

NMe2 3.16

Scheme 3.10

As with the classical Heck reaction (Section 9.2.9), if a diene is employed, the ␩1 -palladium intermediate 3.16 generated by CH activation and insertion can become a ␩3 -complex 3.17 and be trapped by a nucleophile (Scheme 3.10) to give a heterocycle 3.14.9 A pioneering application of C–H activation to natural-product synthesis is in a synthesis of ibogamine 3.24 (Scheme 3.11).10 An asymmetric Diels–Alder reaction set up the chirality. The chirality was controlled by the use of a chiral auxiliary on the diene 3.18. Reductive amination then connected the Diels–Alder product 3.19 to an indole moiety. Palladium-catalysed cyclization then generated the bicyclic alkene 3.23. In this reaction,

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C–H Activation

Ph O

OMe O

Ph

OMe

O

O CHO

CHO BF3.OEt2

3.18

Et

Ph O

Et

93

NH2

3.20

NaBH4

N H

3.19

OMe O

(Ph3P)4Pd

(Ph3P)2Pd

N H

Et

3.21

NH

N H

NH

3.22

Et (Ph3P)2PdCl2, AgBF4; then NaBH4, MeOH

HN

N

N 3.23

3.24

Et

N H

Et

Scheme 3.11

an intermediate ␩3 -allyl palladium complex 3.22 (see Section 9.2) is generated with the chiral auxiliary left over from the Diels–Alder reaction acting as a leaving group. Treatment of the bicyclic alkene 3.23 with a stoichiometric amount of a palladium(II) complex, activated by silver(I), gave a ␩1 -alkyl palladium complex, which was reduced, without isolation, to give the natural product, by treatment with sodium borohydride to give the alkaloid 3.24. ␤-Hydride elimination cannot occur, as there is no ␤-hydrogen suitably placed stereochemically. It could be argued that the cyclization does not proceed by C–H activation, but by formation of an electrophilic ␩2 -complex 3.25, which is then attacked by the electron-rich indole (pathway 1). If this were the case, a distereoisomeric ␩1 -complex 3.26, with palladium trans to the indole would be involved, whereas, by the C–H activation mechanism (pathway 2), the palladium and the indole in the intermediate 3.30 would have the cis relationship, resulting from alkene insertion. As the C–Pd bond is converted to a C–H bond, the same ﬁnal product is obtained. The C–H activation mechanism of pathway 2 was demonstrated by using NaBD4 to introduce deuterium, in place of hydrogen (Scheme 3.12). The product 3.31 was found to have D cis to the indole. This synthesis involves net reduction of palladium in a stepwise process. Hence, it is necessarily stoichiometric in palladium. A catalytic method for vinylation of indoles employing a pyridine ligand 3.33 has been reported in which oxygen is employed to reoxidize the palladium (Scheme 3.13).11 In sharp contrast, a platinum-catalysed version of the cyclization does proceed by nucleophilic attack of the indole onto an ␩2 -alkene–metal complex, and not by C–H activation (Scheme 6.58).12 Again, this was shown by deuterium labeling. 3.1.2

Biaryl Coupling

C–H activation of arenes can also be used to couple two arenes together. A straightforward intramolecular biaryl formation is found in a synthesis of neocryptolepine 3.38 (Scheme 3.14).13 C–H activation was

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Organic Synthesis Using Transition Metals

HN

- H+

N

N

N

Et

N H

[Pd] 3.25

Et

Et

N H

[Pd] 3.26 trans

D 3.27

pathway 2

HN

HN N

-

H+

Et L2PdCl

N LnPdCl

Et

3.28

3.29

D N

[Pd] N Et

N H

Et

N H

3.30 cis

3.31

Scheme 3.12

Pd(OAc)2, O2 N Me

CO2Et N

3.33 N Me

3.32

3.34

Scheme 3.13

employed to from the C–C bond linking the two aryl units, while straightforward substitution was used to form the C–N bond. The 2,3-dihaloquinoline 3.35 was quaternized with the highly reactive methyl triﬂate. Displacement of the chloride in the 2-position then formed the C–N bond. Palladium catalysis was used to form the C–C bond linking the two aryl units. The coupling of the two aryl units is likely to proceed by oxidative addition of palladium to the carbon-bromine bond, C–H activation by electrophilic addition of the palladium(II) complex to the second aromatic ring, and reductive elimination (Scheme 3.15). Two indoles were coupled in a synthesis of N-methylarcyriacyanin A 3.12, a slime mould alkaloid (Scheme 3.16).14 The same natural product could also be synthesized in a shorter sequence using a double indole coupling, although in modest yield (Scheme 3.17). In an intermolecular reaction, pentamethylation of a ferrocenylphosphine 3.15 was observed using palladium catalysis, giving the useful ligand Qphos 1.24 (Scheme 3.18).15 A synthesis of the biaryl moiety and the seven-membered ring core 3.16 of allocolchicine employed a C–H activation reaction as part of the intramolecular biaryl formation (Scheme 3.19).16 The starting material was prepared by the acid chloride variant of the Sonogashira reaction (Section 2.8), coupling alkyne 3.17 with acid chloride 3.18. Asymmetric reduction of the ketone 3.19, protection of the alcohol and reduction of the alkyne gave the substrate 3.20 for CH activation. Diimide, generated in situ, was employed for the alkyne reduction to avoid potential problems of over reduction. C–H activation and biaryl formation was then

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1. H 2N 2. DBU

Br

Br MeOTf N 3.36 Me

Cl

N 3.35

Br

Cl

(Ph3P)2PdCl2, NaOAc, DMA

N

N Me

N

N Me

3.37

3.38

Scheme 3.14

Br PdLn N N 3.38 Me reductive elimination

N N 3.37 Me oxidative addition

Ln Pd N Me

PdLnBr H

N

N Me

3.10

C-H activation

AcOH + Br

N 3.39

AcO

Scheme 3.15 Me N

O

O

O

Me N

Pd(OAc)2, NH dppp, Et 3N

O

NH N

N TfO Boc

Boc 3.12

3.11

Scheme 3.16

O

Me N

O

O Br

N Boc 3.13

Pd(OAc)2, PPh3, Et3N

NH

3.14

Scheme 3.17

95

O

NH N

Br

Me N

Boc 3.12

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Organic Synthesis Using Transition Metals Pt-Bu2

Pt-Bu2 PhCl, NaOt-Bu, Pd(OAc)2

Fe

Fe

Ph Ph Ph

Ph Ph

3.15

1.24

Scheme 3.18 Sonogashira reaction MeO NHAc MeO MeO C-H activation and coupling

3.16 O

O MeO

MeO (Ph3P)2PdCl2, CuI, Et3N

Cl

+ MeO

Br MeO

Br MeO MeO

3.18

3.17

3. 19

OMOM 1. (S )-pinene, 9-BBN 2. NaH, MOMCl 3. H2NNHTs, AcONa

MeO

Pd(OAc)2, K2CO3, Davephos 1.20, Δ

MeO MeO

MeO OMOM MeO

Br 3.20

1. HCl, MeOH 2. Zn(N3)2.Py2, DIAD, PPh3

MeO N3 MeO

MeO

MeO

3 . 21

3.22 MeO

1. LiAlH4, THF 2. Ac2O, Et3N, DMAP

NHAc MeO MeO

3.16

Scheme 3.19

achieved using a palladium catalyst with the Davephos ligand 1.20. Other ligands were much less effective. The synthesis could then be completed by deprotection of the alcohol and installation of the nitrogen as an azide in a Mitsunobu reaction, followed by reduction and acetylation. Two C–H catalytic activation reactions were employed in a synthesis of rhazinal 3.23 (Scheme 3.20).17 The starting material was prepared from a readily available aldehyde 3.24. An aldol reaction installed a methylene group ␣ to the carbonyl. This was followed by addition of methyl lithium and a Johnson–Claisen rearrangment

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C–H Activation CHO N CH activation and Fujiwara-Heck

CH activation and coupling Et

3.23 NH

O O OTBDPS

CH2O, EtCO 2H, pyrrolidine

O OTBDPS

3.24

3.25 OH

MeLi

CH3C(OEt)3 H+

OTBDPS

OTBDPS EtO2C

3.26

1. TBAF 2. TsCl, py

N K

OTs EtO2C

N EtO2C

3.28

CHO N

N

Pd(OAc)2, t-BuOOH

3.27

3.29 1. Crabtree's catalyst, H2 2. LiOH 3. H2N

POCl3, DMF I 3.30

CO2Et

3.31

CHO

CO2Et CHO

N

N

Pd(OAc)2, K2CO3 Davephos

NaHMDS, MOMCl Et NH

Et

I

N

O 3.33

3.32 CHO

CHO N

N BCl3

Et

Et

O

N MOM 3.34

NH O 3.23

Scheme 3.20

O

MOM I

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Organic Synthesis Using Transition Metals

H

O

BF3 K

MeO

O

Pd(OAc) 2, Cu(OAc)2, K2CO3 t-BuOH, AcOH, DMSO

N 3.35

N 3.36

MeO O [Pd(II)]

H

H N 3.37

Scheme 3.21

set up a trisubstituted alkene 3.27. Conversion of the protected alcohol to a tosylate then allowed N-alkylation of pyrrole. Treatment of this alkylated pyrrole 3.29 with palladium(II) acetate resulted in ring closure by a Fujiwara–Heck reaction with the ␤-hydride elimination step moving the double bond to form a vinyl group. As the ␤-hydride elimination generates palladium(0), an oxidant, t-butyl hydroperoxide, was included to reoxidize it. A short series of functional group interconversions, Vilsmeier–Haack formylation, selective hydrogenation of the vinyl group, ester hydrolysis and coupling with o-iodoaniline using the Mukaiyama reagent, set the stage for the second C–H activation, involving pyrrole 3.32. The C–H activation reaction, with a free N–H, failed. Therefore, the amide was protected as its MOM derivative 3.33. This compound underwent cyclization on treatment with a palladium catalyst in the presence of Davephos 1.20. Removal of the MOM group completed the synthesis. An example of activation of a C–H bond of an alkene by initial electrophilic attack by palladium(II) can be found in a synthesis of ipalbidine (Scheme 3.21).18 The carbon ␣- to the ketone of enaminone 3.35 is nucleophilic. Treatment of the enaminone with palladium(II) and a boron reagent, with a copper salt present to reoxidize the palladium, resulted in the coupled product 3.36, via the ␩1 -palladium complex 3.37. Further aspects of this synthesis can be found in Scheme 2.88. Not all C–H activation reactions amongst arenes can proceed by this mechanism. This is particularly true for electron poor heterocycles, such as pyridines and oxazines. These heterocycles undergo electrophilic substitution with great reluctance, yet coupling reactions through C–H activation are known. The coupling is often ␣- to the coordinating heteroatom. Pyridines and quinolines, usually extremely bad substrates for electrophilic attack, undergo ␣-arylation on treatment with a rhodium catalyst and an aryl halide (Scheme 3.22),19 or ␣-alkylation with an alkene (Scheme 3.23).20 A mechanism has been proposed involving coordination to the ring nitrogen atom giving a ␴-complex 3.43 and bringing the metal in for oxidative addition to an adjacent C–H bond (Scheme 3.24). The ␣-metallated heterocycle 3.44, which may be in equilibrium with its carbene tautomer 3.45, undergoes reductive elimination of HX, opening up a vacant site for oxidative addition of the aryl bromide. Product formation is completed by reductive elimination.

[RhCl(CO)2]2, Δ

+ N 3.38

Br

N 3.39

3.40

Scheme 3.22

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C–H Activation

99

[RhCl(coe)2]2, Cy3P.HCl, Δ

+ N

N

3.41

3.42

Scheme 3.23 Cl (OC)2Rh

Cl

Rh(CO)2

N CO 3.38

X Rh CO N

3.43 X = Cl or Br

CO Ar

N

OC

CO Rh N X H

Br Rh CO

OC

CO H Rh N X

3.44

3.45

3.40

HX OC

CO Rh N Br Ar

OC

CO Rh N

3.47

3.46

ArBr

Scheme 3.24

A similar mechanism may operate in related reactions, such as a vinylation of azoles 3.48 using an economical cobalt catalyst (Scheme 3.25), generated in situ,21,22 as well as a ruthenium-catalysed carbonylative coupling of imidazoles 3.50 (Scheme 3.26).23 An extension of this concept is the coupling of two molecules by double C–H activation; two hydrocarbons coupling with formal elimination of H2 .24 This is possible under the right circumstances. Thiophenyl and other heteroaryl derivatives of caffeine 3.54 could be produced in this way (Scheme 3.27).25 The reaction shows surprising selectivity for the coupling of the two different heterocycles over dimerization of either Pr

N + O

CoBr2, DPEphos, Me3SiCH2MgCl

O

Pr

3.48

3.49

Scheme 3.25

Pr

N Pr

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Organic Synthesis Using Transition Metals Ph

Ph O

O

Ru3(CO)12, CO, Δ

N

+

O

O N

N 3.51

3.50

N

O

3.52

Scheme 3.26

Me N OHC

O NMe

+ S

N

3.53

3.54

N Me

Me N

Pd(OAc)2, Cu(OAc)2, py

O

N

S

OHC

3.55

O NMe N Me

O

reductive elimination

Pd(OAc)2 C-H activation

OHC

S

PdOAc

C-H activation - AcOH

Me N Pd N S

3.56

O NMe N Me

O

3.57

CHO

Scheme 3.27

one. The mechanism appears to go through electrophilic attack of palladium(II) on the heterocycle to give a thiophenyl palladium(II) complex 3.56, which then preferentially reacts with a molecule of caffeine, perhaps due to a coordination effect. An electrophilic ﬂuorinating agent 3.60 was employed as the oxidant to coupling benzamides 3.58 with unactivated arenes (Scheme 3.28).26

3.2

Aldehydes

Transition metals, especially rhodium(I) will undergo oxidative addition to the C–H bond of an aldehyde. While this can result in decarbonylation (Section 4.7), alkene insertion can occur.27 In an intramolecular

ArHN

ArHN

Me

O

Pd(OAc) 2, [O]

+

Me

N

[O] =

Me Me

OTf

3.60 F

O

3.58

F

3.59

F

CF3

Ar = F F

Scheme 3.28

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C–H Activation

101

O CHO

Rh(dppe)2 ClO4

3.61

3.62

Scheme 3.29

O H

O [Rh(S,S-Meduphos)(acetone) 2] PF6

3.64

3.63

Scheme 3.30

OHC

3.65

O H

H Rh(dppe)2OTf H

3.66

H

Scheme 3.31

CHO

Rh(dppe)2ClO4

MeO2C

MeO2C MeO2C

MeO2C

H

O

H 3.67

H

OH

H 3.68

3.69

Scheme 3.32

sense, this leads to a cyclic ketone 3.62 (Scheme 3.29).28 The reaction is more efﬁcient using cationic rhodium complexes with bidentate ligands,29 although other metals, such as cobalt30 can also be employed. Replacement of the phosphine ligands with chiral ligands can result in the formation of a new stereogenic centre in an asymmetric cyclization (Scheme 3.30).31 Variations on the theme include the use of vinylcyclopropanes 3.65 (compare Scheme 11.48 and others in Chapter 11) for the synthesis of eight-membered rings 3.66 (Scheme 3.31),32 and polyene substrates, as in a synthesis of epiglobulol 3.69 (Scheme 3.32).33 Intramolecular reactions with both alkenes and alkynes can also be achieved under correctly chosen conditions, especially when the aldehyde contains a second donor atom that can chelate the rhodium, as in the ␤-thioaldehyde 3.70 (Scheme 3.33).34 Ruthenium catalysts have been used with dienes (Scheme 3.34).35

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Organic Synthesis Using Transition Metals CO2Me [Rh(COD)Cl]2, CHO dpephos, AgClO4 MeS

MeS

O CO2Me

3.70

3.71

Scheme 3.33

OHC

O

Ru(COD)(cot), PPh3

O O

3.73

3.72

Scheme 3.34 Bpin

[RhCl(COD)]2 HBpin 3.74

3.75

Scheme 3.35

3.3

Borylation and Silylation

A number of systems have been developed for the functionalization of C–H bonds by their conversion into carbon–boron36 or carbon–silicon bonds.37 The substrates can be alkenes (Scheme 3.35),38 arenes (Schemes 3.36–3.38),39 heteroarenes (Schemes 3.39–3.41)40 and even alkanes (Scheme 3.42).41 With arenes, the electronic properties of the aromatic ring do not always seem to control the regioselectivity, as mixtures of isomers are often formed. Methyl-substituted aromatics may be borylated on the side chain depending on the choice of catalyst.42 The products, especially the C–B compounds, are useful for subsequent transformations. The C–B bond of arylboranes may also be oxidized to give a phenol.43 A one-pot ␤-selective borylation-Suzuki coupling was

Cp*Rh(η4-C6Me6) MeO B2pin2

MeO

Bpin MeO

Bpin

MeO Bpin

3.76

3.77

3.78

3.79

0.3:2.6:1

Scheme 3.36 Me

RhCl(Pi-Pr 3)2(N2)2 HBpin

Me Bpin

Me 3.80

3.81

Scheme 3.37

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C–H Activation F

F (Ind)Ir(COD), dppe HBpin F

F

103

3.82

Bpin 3.83

Scheme 3.38 Et3SiH [(COD)Ir(OMe)2 ] 2, dtbpy, norbornene

t-Bu SiEt3 N H

N H 3.84

t-Bu

dtbpy = N

3.85

N 3.86

Scheme 3.39

N H

CO2Me

[Ir(COD)(OMe)]2 dtbpy, B2pin2

pinB

3.87

N H

CO2Me

3 .8 8

Scheme 3.40 Cl N H

[Ir(COD)(OMe)]2 Cl CO2Et dtbpy, B2pin2

CO2Et pinB 3.90

3.89

N H

Scheme 3.41 CH3 Cp*Re(CO)3 or [Cp*RuCl2]2 B2pin2 3.91

Bpin

3.92

Scheme 3.42

employed in a synthesis of rhazinicine (Scheme 3.43).44 The N-protected, ␣-silyl pyrrole 3.93 was borylated using an iridium catalyst; the ␤-borylated product 3.94 was then coupled with an iodoarene in a one pot operation. The Boc group was then exchanged for a more elaborate side chain. A second CH activation event, a Fujiwara–Heck reaction, could then follow at the remaining free ␣-position, the other being blocked by silicon, to give alkene 3.97. Reduction, removal of the ester and silyl substituents, and closure of the nine-membered ring completed the synthesis.

3.4 Allylic Functionalization ␲-Allyl palladium complexes may be prepared from alkenes. The resulting complexes are electrophilic (Chapter 9). Nucleophilic attack results in the formation of a functionalized alkene, while the

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Organic Synthesis Using Transition Metals

O B O [Ir(cod)Cl]2, dtbpy, B2pin2 Me3Si 3.93

N Boc

I Me3Si 3.94

NO2 Me3Si 3.95

Me3Si

Me3Si

Pd(O2CCF3), t-BuOOBz

N CO2TSE

3.96 O

CO2TSE

NO2

N Boc

NO2

N Boc

NO2

Pd(OAc)2, K3PO4, SPhos 1.16

1. H 2, Pd/C 2. AlCl 3 3. Mukaiyama's reagent, Et3N

N

NH

O

N

3.97

3.98

Scheme 3.43

PdCl2, AcOH, MnO2, BQ 3.99

OAc 3.100

Scheme 3.44

palladium is reduced to palladium(0). As with ␩2 -alkene complexes (Chapter 6), the process can be made catalytic by the inclusion of an oxidizing agent. An example is the use of a carboxylate ion as the nucleophile,45 giving an alternative to singlet oxygen and selenium dioxide for allylic oxidation (Scheme 3.44). The most ambitious application of this chemistry is in the ring closure to form 6-deoxyerythronolide B 3.104 (Scheme 3.45).46 Macrolides are most commonly prepared by lactonization of a hydroxy acid, so there is a need to carry the hydroxy functional group through the synthesis. The allylic CH activation method avoids this need, requiring just an alkene. Controlled by the conformation of the substrate, allylic oxidation of the precursor 3.101 provided a single diastereoisomer of the macrolide 3.103. A bis-sulfoxide 3.102 was found to be the optimum ligand for palladium. The macrolide 3.103 could be converted to 6-deoxyerythronolide B 3.104 by simultaneous reduction of the alkene and the PMP acetal, selective oxidation of one hydroxyl group, and acetonide removal.

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C–H Activation PMP H

PMP H

O Pd(OAc)2, BQ O O

HO2C

105

O

Ph S S Ph O O 3.102

O O

O

O

O

3.101

O

3.103 O

1. H 2, Pd(OH)2 2. TPAP, NMO 3. H 3O+

OH O O

OH OH

3.104

Scheme 3.45

Pd(OAc)2, BQ, (salen)CrCl, TsNHCO2Me

O O OBn 3.105

Ph S S Ph O O 3.102

O O OBn 3.106

N Ts

CO2Me

Scheme 3.46

Nitrogen nucleophiles, provided that they are resistant to oxidation, can be employed for C–N bond formation (Scheme 3.46).47

3.5 Unfunctionalized C–H Bonds 3.5.1

Carbon–Heteroatom Bond Formation

The fact that palladium, directed by a coordinating group in the molecule, can oxidatively add to a nearby C–H bond has been known for a long time. Nitrogen derivatives, such as oximes, have been found to be effective coordinating groups (Scheme 3.47). For instance, treatment of the oxime 3.107 of phenyl t-butyl ketone gave the stable palladacycle 3.108 as its chloride–bridged dimer.48 This chemistry was applied to a steroidal system allowing functionalization of one of the methyl groups ␣ to the oxime of steroid 3.109 (Scheme 3.48).49 The diastereoselectivity must arise from the conformation of the molecule: only the equatorial methyl group is close enough to the oxime. The palladacycle was isolated as its monomeric PPh3 complex 3.110. Treatment of this complex with elemental iodine gave the iodo derivative 3.111. Surprisingly, oxidation of the analogous complex with mcpba gave the chloro derivative (Scheme 3.49). This may be an oxidatively induced reductive elimination.

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Organic Synthesis Using Transition Metals OH N

Ph

Na2PdCl4, NaOAc

OH Cl N Pd

Ph

H

2

3.107

3.108

Scheme 3.47

HO

1. Na 2PdCl4, NaOAc 2. PPh 3 N

HO

N Cl(Ph3P)Pd H

3.110

3.109

I2

HO

N I

3.111

Scheme 3.48

HO

HO

N 1. PdCl 2, NaOAc 2. mcpba

N

Cl 3.113

3.112

Scheme 3.49

Versions of this chemistry that results in formation of carbon–oxygen and carbon–nitrogen and carbon–halogen bonds, and are also catalytic in palladium have been developed (Scheme 3.50). The choice of an appropriate oxidizing agent is key to the success of the chemistry. Iodosobenzene diacetate has been found to be very effective for adding an acetate group. It has been proposed that this is by oxidation of the C–H activation intermediate from a palladium(II) complex 3.117 to a palladium(IV) complex 3.118, which triggers reductive elimination, giving the ortho-acetoxylated product 3.115. The acetoxylation reaction can be applied to aryl (Scheme 3.51),50 benzylic (Scheme 3.52)51 and aliphatic C–H bonds (Schemes 3.53 and 3.54).52,53

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C–H Activation PhI(OAc)2, Pd(OAc)2

N 3.114

N AcO 3.115

Pd(OAc)2

N 3.115 AcO

N 3.114 coordination

reductive elimination

3.118

N IV Pd L OAc AcO OAc

N 3.116 Pd(OAc)2 CH activation

PhI oxidation

HOAc

N II Pd L OAc 3.117

PhI(OAc)2

Scheme 3.50

NO2

NO2

Pd(OAc) 2, PhI(OAc) 2 N 3.119

N 3.120

AcO

Scheme 3.51

Pd(OAc)2, PhI(OAc) 2 N

N CH3

3.121

3.122

AcO

Scheme 3.52

MeO

MeO

N

N

Pd(OAc)2, PhI(OAc)2 3.124

3.123

Scheme 3.53

OAc

107

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Organic Synthesis Using Transition Metals O

O

O N O

O Pd(OAc)2, t-BuOOH, Ac2O, Mn(OAc) 2

N H

H

N O

N H OAc

H

N 3.125

N

3.126

Scheme 3.54 CH3

N CH3

Pd(OAc)2, NCS

3.128

Cl

CH3

Pd(OAc)2, NBS N

N 3.127 Pd(OAc)2; NIS or PhI(OAc)2, I2

3.129 Br

CH3

N

3.130 I

Scheme 3.55

Br

NOMe

Pd(OAc) 2, Oxone, MeOH

Br

NOMe OMe

3.131

3.132

Scheme 3.56 I CO2H

CO2H Pd(OAc)2, IOAc

MeO2C

MeO2C 3 . 13 3

I 3. 13 4

Scheme 3.57

Use of other nucleophiles in the presence of an oxidant can install other functionality (Scheme 3.55).54 While N-halosuccinimides are very effective, other systems, such as iodosobenzene diacetate–halide mixtures, or copper(II) halide55 salts can be employed. The powerful oxidant oxone can also be used in combination with alcohols, to give ethers (Scheme 3.56).56 Iodine acetate has been used for C–H activation directed by carboxylic acids (Scheme 3.57).57 The heteroatom may also be supplied intramolecularly (Scheme 3.58).58 The use of palladium catalysis can also override the inherent regioselectivity of an arene substrate (Scheme 3.59).

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C–H Activation

109

O CO2H

K2PtCl4, CuCl2

O

3 .1 3 3

3 . 13 4

Scheme 3.58

NOMe Br NBS no Pd NOMe

MeO 3.135

MeO 3.136

Br

Pd(OAc)2, NBS

NOMe

MeO 3.137

Scheme 3.59

3.5.2

Carbon–Carbon Bond Formation

An example of the use of this kind of C–H activation, combined with C–C bond formation, rather than C-heteroatom formation, can be found in a synthesis of the core of teleocidin 3.138, using an imine as the coordinating group to direct palladation (Scheme 3.60).59 Of the four key bond-forming events, three involve palladium, and two involve the activation of unfunctionalized C–H bonds. Treatment of the imine 3.139 with palladium(II) chloride results in activation of one of the C–H bonds of the t-butyl group. Treatment of the palladacycle 3.140 with a vinyl boronic acid 3.141 results in coupling. This step is analogous to the bond forming process of the Suzuki reaction and presumably proceeds in the same way: transmetallation and reductive elimination. This results in net reduction of palladium. Silver oxide may act as a halophilic Lewis acid, abstracting the chloride from the palladium to facilitate transmetallation. Treatment of the coupling product 3.143 with a strong acid results in an intramolecular Friedel–Crafts reaction. A second C–H activation reaction was used to form the lactam, employing the same imine as the coordinating group. Treatment of the bicyclic compound 3.144 under the same palladation conditions resulted in activation of one of the C–H bonds of the methyl groups, with fair selectivity for the desired diastereoisomer. This selectivity is, perhaps, due to the bulk of the i-propyl group controlling the conformation of the ring, and putting one of the two methyl groups into closer proximity to the palladium. This time, the palladacycle 3.145 was carbonylated in the presence of methanol to give an ester 3.146. This was not isolated, as the reaction mixture was subjected to the conditions for imine hydrolysis. With the amine exposed, cyclization occurred to give the lactam 3.147. N-Alkylation, to install a 2-bromoallyl unit, and O-deprotection, then allowed the ﬁnal palladium-catalysed step, a phenol o-alkylation (see Section 2.11), to complete the synthesis. Catalytic carbon–carbon bond formation has been achieved using boron derivatives but requires the right choice of oxidant, otherwise homocoupling of the added organometallic (Section 2.10) may occur. Benzoquinone (BQ) has been found to be effective, combined with direction of CH activation by pyridine (Scheme 3.61),60 by carboxylates (Scheme 3.62)61 and by hydroxamic acids.62 Air has been used as the

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Pd catalysed o-alkylation

Friedel-Crafts

OMe

N O 3.138 C-H activation and coupling

C-H activation and CO insertion OMe

OMe

PdCl2, NaOAc

N O Me

H

B(OH)2

OMe

OMe

Ag2O 3.141

N Pd O Cl Me

3.139

3.140

OMe

OMe OMe N Pd O Me

OMe reductive elimination

N

H O Me

3.142

OMe

3.143

OMe OMe

OMe PdCl2, NaOAc

N

CO, MeOH

N Pd

O Me 3.144

O Cl Me

OMe

3.145

OMe OMe SiO2, CHCl3

N O Me 3.146

MeO2C

O 3.147 OH

Br 1.

NH

OH Br

Br Pd(OAc)2, Pt-Bu3, Cs2CO3

N

KOt-Bu 2. BBr3

N

O

O

3.148

3.149

Scheme 3.60

110

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C–H Activation B(OH)2 Pd(OAc)2, Ag2O, BQ, air

N

111

N

3.150

3.151

Scheme 3.61 Ph

B O

O Pd(OAc)2, BQ, Ag2CO3, K2HPO4 Ph CO2H

CO2H 3.152

3.153 Ph

I

Pd(OAc)2, Ag2CO3, K2HPO4, NaOAc

Scheme 3.62

+

Pd(OAc) 2, KOAc

I

3.154

3.156

3.155

Scheme 3.63 H3CO I O

CH3

Pd(OAc) 2, K2CO3, n-Bu4NBr O H3CO

3.157

3.158

Scheme 3.64

oxidant in some cases. The use of an aryl halide, rather than an aryl boronate means that the oxidizing agent can be omitted (Scheme 3.62). Intramolecular C–H activation by ␩1 -organopalladium complexes, often generated in situ as reactive intermediates, can lead to surprising, but useful cyclic structures (Schemes 3.63, 3.64).63 Even benzocyclobutenes may be formed in this way, despite the ring strain.64 Benzocyclobutenes are valuable intermediates in synthesis because they undergo thermal electrocyclic ring opening to o-xylylenes, which may be trapped in Diels–Alder reactions (see Scheme 11.16 for another example),65 or by electrocyclic ring closure. The alkaloid coralydine 3.166 was synthesized using this chemistry (Scheme 3.65).66 The ester-substituted benzocyclobutene 3.160 was prepared by CH activation of ester 3.159. The ester could then be converted to an amine 3.161 by Curtius rearrangement. Condensation with aldehyde 3.162 gave an imine 3.163 which, upon thermolysis, underwent 4-electron electrocyclic ring opening, followed by electrocyclic 6-electron ring closing of the intermediate

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Organic Synthesis Using Transition Metals CO2Me Pd2dba3, t-Bu3P, K2CO3 Br

Me CO2Me 1. NaOH 2. (PhO) 2P(O)N3

MeO MeO

3.159

3.160

OTBS OMe

Me NH2 aldehyde 3.162 -H2O

MeO

Me N

MeO

MeO

OMe

Δ

MeO 3.163

3.161

Me

Me MeO

N

MeO

OTBS

N

OTBS

MeO

MeO OMe

3.164

3.165

OMe

OMe OMe

Me MeO 1. NaBH 4 2. TBAF 3. HBF 4; DIAD, PPh 3

OTBS

N

MeO

OHC

3.162

H

OMe

OMe

3.166

OMe

OMe

Scheme 3.65

N 3.167

CO2Et Pd(OAc)2, H4[PMo11VO 40], NaOAc, O 2

N

N 3.168 CO2Et

CO2Et

3.169

Scheme 3.66

o-xylylene 3.164. Stereoselective reduction of the ring-closure product, imine 3.165, followed by deprotection and ring closure under Mitsunobu conditions gave the natural product 3.166. The lone pair of pyridine can be employed to direct C–H activation for C–C bond formation. If the palladium intermediate is intercepted in a Fujiwara–Heck reaction, the oleﬁnation product 3.168 undergoes conjugate addition of the pyridine nitrogen to the newly formed alkene giving a pyridinium ion product 3.169 (Scheme 3.66).67 Amide carbonyl groups can also direct. Again, conjugate addition to the newly formed alkene 3.172 is often observed if the directing group is also a potential nucleophile (Schemes 3.67 and 3.68).68,69 Intramolecular alkene insertion can be used to create useful cyclic structures (Scheme 3.69).70 Carbonyl groups on aryl rings can also direct CH activation to the neighbouring position. Rhodium catalysts have also been found to be effective (Schemes 3.70 and 3.71).71,72

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C–H Activation CO2Bn Pd(OAc)2, LiCl, Cu(OAc)2, AgOAc

NHC6F5 O 3.170

NHC6F5 O 3.171

[Pd] O

O NHC6F5

BnO2C

N C6F5

3.172

3.173

CO2Bn

Scheme 3.67 O

O CO2t-Bu MeO NHTs Pd(OAc) , Bphen, O 2 2

MeO

MeO

N Ts CO2t-Bu

MeO 3.175

3.174

Scheme 3.68 TBSO

TBSO

TBSO

[Ir(COE)2Cl]2, IPr

+ N

N O

N O

O 3.176

3.178

3.177

Scheme 3.69 OEt

OEt

CO2Et [Cp*RhCl2]2, O AgSbF6, Cu(OAc)2

O CO2Et

3.179

3.180

Scheme 3.70 NMe2 O

O

NMe2

CO2Et (Cp*RhCl2)2, AgSbF6, Cu(OAc) 2

3.181

O

CO2Et

3.182

Scheme 3.71

O

113

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Organic Synthesis Using Transition Metals

O

O

Si(OEt)3 RuH2(CO)(PPh3)3, Δ S

S 3.183

Si(OEt)3 3.184

Scheme 3.72

R

N S O O

CO2Me (MeCN)2PdCl2, Cu(OAc)2 N R=H

N S O O

CO2Me N

3.186

3.185

Mg MeOH

Zn, NH4Cl

CO2Me

N H

CO2Me

N H

3.187

3.188

Scheme 3.73

N S O 3.189 O

N

CO2Me

CO2Me (MeCN)2PdCl2 Cu(OAc)2

N S O 3.190 O

N

Pd(OAc)2 (1.2 eq) PdX N 2-PySO2

N SO22-Py

3.192

N S O O

N

3.191

Scheme 3.74

A related reaction using a ruthenium catalyst proceeded with reductive elimination to form a carbon–hydrogen bond, giving the product of alkylation 3.184, rather than alkenylation, with a saturated side chain. This means that there was no net reduction, so no oxidant was needed (Scheme 3.72).73 If the substrate does not possess an appropriate directing group, one may be attached by a temporary linker. The 2-pyridyl sulfonyl group is a useful directing group for C–H activation. The pyrrole derivative 3.185 gave the ␣-alkenylation product 3.186. In the pyrrole series, an N-pyridyl sulfonyl group did not change the inherent regioselectivity, which is naturally ␣, but did have a signiﬁcant activating effect: the corresponding N-tosyl derivative gave almost no product under the same conditions (Scheme 3.73).74 Consistent with electrophilic palladation, existing substituents exert a distinct effect on the reaction rate. Thus, the pyrrole derivative with

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C–H Activation

115

an electron-donating methyl group (R = Me) reacted 14.3 times faster than the corresponding ester (R = CO2 Me). The pyridylsulfonyl group could be removed under mildly reducing conditions to give the vinylated pyrrole 3.187; more strongly reducing conditions also reduced the alkene, to give the alkyl pyrrole 3.188. In the indole series, the N-pyridylsulfonyl indole 3.189 gave the product of C2 vinylation 3.190, rather than the typical C3 vinylation, showing that the coordination effect of the pyridine can overwhelm the normal indole reactivity (Scheme 3.74). The reaction presumably proceeds via a chelated palladium intermediate 3.192.75 Interestingly, an indole dimer 3.191 is produced in the absence of an added alkene, showing that the palladium(II) intermediate is capable of attacking a second molecule of the substrate.

References 1. (a) Godula, K.; Sames, D. Science 2006, 312, 67; (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (c) Campeau, L.-C.; Stuart, R.; Fagnou, K. Aldrich. Acta 2007, 40, 35; (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173; (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2009, 110, 624; (f) Jazzar, R.; Hitce, J. et al. Chem. Eur. J. 2010, 16, 2654; (g) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885; (h) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902. 2. Robinson, N. P.; Main, L.; Nicholson, B. K. J. Organomet. Chem. 1988, 349, 209. 3. Depree, G. L.; Main, L. et al. J. Organomet. Chem. 2006, 691, 667. 4. Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. 5. Dams, M.; De Vos, D. E. et al. Angew. Chem., Int. Ed. 2003, 42, 3512. 6. Wang, D.-H.; Engle, K. M. et al. Science 2010, 327, 315. 7. Tsuji, J.; Nagashima, H. Tetrahedron 1984, 40, 2699. 8. Grimster, N. P.; Gauntlett, C. et al. Angew. Chem., Int. Ed. 2005, 44, 3125. 9. Houlden, C. E.; Bailey, C. D. J. Am. Chem. Soc. 2008, 130, 10066. 10. Trost, B. M.; Godleski, S. A.; Gen´et, J. P. J. Am. Chem. Soc. 1978, 100, 3930. 11. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. 12. Liu, C.; Han, X. et al. J. Am. Chem. Soc. 2004, 126, 3700. 13. Hostyn, S.; Tehrani, K. A. et al. Tetrahedron 2011, 67, 655. 14. Brenner, M.; Mayer, G. et al. Chem. Eur. J. 1997, 3, 70. 15. Shelbu, Q.; Kataoka, N. et al. J. Am. Chem. Soc. 2000, 122, 10718. 16. LeBlanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849. 17. Bowie, A. L.; Trauner, D. J. Org. Chem. 2009, 74, 1581. For early work by the same group in a synthesis of Rhazinilam, see Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7, 5207. 18. Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6019. 19. Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2010, 75, 7863. 20. Lewis, C. J.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332. 21. Ding, Z.; Yoshikai, N. Org. Lett. 2011, 12, 4180. 22. Yoshikai, N. Synlett 2011, 1047. 23. Chatani, N.; Fukuyama, T. et al. J. Am. Chem. Soc. 1996, 118, 493. 24. Han, W.; Oﬁal, A. R. Synlett 2011, 1951. 25. Xi, P.; Yang, F. et al. J. Am. Chem. Soc. 2010, 132, 1822. 26. Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 13864. 27. Willis, M. C. Chem. Rev. 2010, 110, 725. 28. (a) Lochow, C. F.; Miller, R. G. J. Am. Chem. Soc. 1976, 98, 1281; (b) Gable, K. P.; Benz, G. A. Tetrahedron Lett. 1991, 32, 3473. 29. Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 936. 30. Vinogradov, M. G.; Tuzikov, A. B. et al. J. Organomet. Chem. 1988, 348, 123. 31. Barnhart, R. W.; McMorran, D. A.; Bosnich, B. Chem. Commun. 1997, 589. 32. Aloise, A. D.; Layton, M. E.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 12610.

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33. Oonishi, Y.; Taniuchi, A. et al. Tetrahedron Lett. 2006, 47, 5617. 34. Moxham, G. L.; Randell-Sly, H. E. et al. Angew Chem., Int. Ed. 2006, 45, 7618. 35. (a) Kondo, T.; Hiraishi, N. et al. Organometallics 1998, 17, 2131; (b) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14120. 36. Mkhalid, I. A. I.; Barnard, J. H. et al. Chem. Rev. 2010, 110, 890. 37. Lu, B.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 7508. 38. Murata, M.; Watanabe, S.; Masuda, Y. Tetrahedron Lett. 1999, 40, 2585. 39. (a) Chen, H.; Schlecht, S. et al. Science 2000, 287, 1995; (b) Cho, J.-Y.; Iverson, C. N., Smith III, M. R. J. Am. Chem. Soc. 2000, 122, 12868; (c) Nguyen, P.; Blom, H. P. et al. J. Am. Chem. Soc. 1993, 115, 9329. 40. Ishiyama, T.; Takagi, J. et al. Adv. Synth. Catal. 2003, 345, 1103. 41. (a) Chen, H.; Hartwig, J. F. Angew. Chem., Int. Ed. 1999, 38, 3391; (b) Murphy, J. M.; Lawrence, J. D. et al. J. Am. Chem. Soc. 2006, 128, 13684. 42. (a) Shimida, S.; Batsanov, A. S. et al. Angew. Chem., Int. Ed. 2001, 40, 2168; (b) Ishiyama, T.; Ishida, K. et al. Chem. Lett. 2001, 30, 1082. 43. Maleczka Jr., R. E.; Shi, F. et al. J. Am. Chem. Soc. 2003, 125, 7792. 44. Beck, E. M.; Hately, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004. ˚ 45. Heumann, A.; Akermark, B. Org. Syn. 1990, 137. 46. Stang, E. M.; White, M. C. Nat. Chem. 2009, 1, 547. 47. (a) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316; (b) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11701. 48. Constable, A. G.; McDonald, W. S. et al. J. Chem. Soc., Chem. Commun. 1978, 1061. 49. Carr, K.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1984, 1227. 50. Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. 51. Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. 52. Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. 53. Subba Reddy, B. V.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. 54. Kalyani, D.; Dick, A. R. et al. Tetrahedron 2006, 62, 11483. 55. Wan, X.; Ma, Z. et al. J. Am. Chem. Soc. 2006, 128, 7416. 56. Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141. 57. Mei, T. S.; Giri, R. et al. Angew. Chem., Int. Ed. 2008, 47, 5215. 58. Lee, J. M.; Chang, S. Tetrahedron Lett. 2006, 47, 1375. 59. Dangel, B. D.; Godula, K. et al. J. Am. Chem. Soc. 2002, 124, 11856. 60. Chen, X.; Goohue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. 61. Giri, R.; Maugel, N. et al. J. Am. Chem. Soc. 2007, 129, 3510. 62. Wang, D.-H.; Wasa, M. et al. J. Am. Chem. Soc. 2008, 130, 7190. 63. (a) Catellani, M.; Motti, E. et al. Chem. Commun. 2000, 2003; (b) Dyker, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103. 64. Chaumontet, M.; Piccardi, R. et al. J. Am. Chem. Soc. 2008, 130, 15157. 65. Chaumontet, M.; Retailleau, P.; Baudoin, O. J. Org. Chem. 2009, 74, 1774. 66. Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew. Chem., Int. Ed. 2009, 48, 179. 67. Stowers, K. J.; Firtner, K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. 68. Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. 69. Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214. 70. DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556. 71. Feng, C.; Loh, T. P. Chem. Commun. 2011, 47, 10458. 72. Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13, 2372. 73. (a) Murai, S.; Kakiuchi, F. et al. Nature 1993, 366, 529; (b) Murai, S.; Chatani, N.; Kakiuchi, F. Pure Appl. Chem. 1997, 69, 589. 74. Garc´ıa-Rubia, A.; Urones, B. et al. Chem., Euro. J. 2010, 16, 9676. 75. Garc´ıa-Rubia, A.; Array´as, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 6511.

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4 Carbonylation Carbon monoxide, with the use of transition-metal catalysis, has become a valuable C1 building block.1 Carbonylation is one method of intercepting the palladium intermediates generated by oxidative addition.2 If the reaction is run under at atmosphere of carbon monoxide, then the palladium intermediate may undergo CO insertion, generating an ␩1 -acyl complex, before any other reagent (Scheme 4.1). Whether it will do so in useful quantities is a question of kinetics: will the rate of CO insertion be faster than the rates of the other possible processes? The reactivity of the other reagents may be reduced by careful choice of functionality, or their concentration may be reduced by slow addition, perhaps by use of a syringe pump. The rate of reactions involving carbon monoxide may be increased by the use of higher pressures. While many reactions proceed satisfactorily at atmospheric pressure, other reactions require increased pressures. Pressures up to 100 psi may be safely attained in good quality, heavy-wall glass vessels, ﬁtted with a pressure head and safety release valve, and operated behind a safety shield. Much higher pressures may be achieved using steel autoclaves.*

4.1 Carbonylative Coupling Reactions: Synthesis of Carbonyl Derivatives Can we intercept the acyl intermediate with a main-group organometallic, or other carbon nucleophile? This could be a useful synthesis of ketones (Scheme 4.2).3 How would the mechanism work? It would require coordination and insertion of CO before reductive elimination (Scheme 4.3). As reductive elimination is usually fast, CO must be involved before transmetallation. Ketone production will be favoured over direct coupling if the rate of CO insertion is faster than the rate of transmetallation of L2 PdR’X. We can make CO chemistry faster by increasing the pressure; we can make transmetallation slower by using a less-reactive organometallic, and also by slow addition, to get the right kinetics. Although slow transmetallation is favoured by the use of less electropositive metals, M, such as tin, boron and silicon, a wide range of organometallics have been employed too. In addition to tin (Schemes 4.4 and 4.5)4,5 , boron (Scheme 4.6)6 and silicon (Scheme 4.7),7 examples include aluminium (Scheme 4.8)8 and zinc (Scheme 4.9)9 .

∗ WARNING Carbon monoxide is highly toxic. All reactions using this gas should be carried out in an efﬁcient fume cupboard. Reactions

under pressure should be carried out behind additional safety shielding. Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals O

± CO

L2Pd

R X

R PdL2X

oxidative addition

R

PdL2X increase CO pressure to favour this pathway

add reagent slowly to reduce this rate by-products

carbonyl products

Scheme 4.1 O

Pd cat. R M

+ CO +

R'

X

M X

R'

R

Scheme 4.2 O R R' reductive elimination

R'X

L2Pd

oxidative addition

O L2Pd

R' L2Pd

R'

X

R M X transmetallation R M

CO coordination and insertion

O R'

L2Pd X

Scheme 4.3 EtO2C

Br

Ph4Sn, PhPd(PPh3)2I, CO

Ph

EtO 2C

4.1

4.2

O

Scheme 4.4 O OTf

O

O n-Bu3Sn (Ph3P)4Pd, LiCl, CO

O

4.3

O

4.4

OMe

Scheme 4.5

OMe

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Carbonylation Me I

Me

PEPPSI-IPr CO, Cs 2CO3

+ (HO)2B

119

O

Me

Me

4.5

4.6

Scheme 4.6

I S 4.7

SiF2Et

CHO

+

O

[η3-(C3H5)PdCl]2, KF, CO

CHO S

4.8

4.9

Scheme 4.7 I O i-Bu2AlCl

OMe Ali-Bu2 (MeCN) PdCl , CO 2 2

PhLi

OMe 4.10

4.11

Scheme 4.8

OTf

O

Ph2Zn, CO, NiCl2, MgBr2, L

MeO Ph

OMe

L= N

4.12

4.13

N 4.14

Scheme 4.9

A route to ﬂavonones 4.16 involves the carbonylative coupling of alkynes to o-iodophenols or their corresponding acetates 4.15, with in situ cyclization (Scheme 4.10).10 The carbonylative coupling of an alkynyl zinc reagent 4.18 with a highly substituted, electron-rich aryl iodide 4.17 was used in a short synthesis of luteolin 4.20, a ﬂavanoid natural product (Scheme 4.11). After the coupling, employing the PEPPSI catalyst, selective ortho-deprotection and 6-endo cyclization yielded the natural product.11 A carbonylative coupling of an aryl iodide 4.21 and a stannane 4.22 was employed in a synthesis of strychnine 4.24 (Scheme 4.12).12 Further steps employed in the synthesis of the stannane 4.22 can be found in Chapter 2, Scheme 2.58 and Chapter 9, Scheme 9.53. Carbonylative coupling was employed twice in a synthesis of capnellene 4.25 (Scheme 4.13) using an iterative sequence to establish multiple fused cyclpentane rings.13 Carbonylative coupling of a vinyl triﬂate 4.26 with vinyl stannane 4.27 gave divinyl ketone 4.28. Such compounds are substrates for Nazarov cyclization, a reaction promoted by the presence of the silyl group. Desilylation during the Nazarov reaction generates the cyclopentenone 4.29. Reduction of the alkene and formation of a new vinyl triﬂate 4.30 by sulfonylation of a

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Organic Synthesis Using Transition Metals Ph (Ph3P)2PdCl2, CO, (H2N)C=S, Et2NH, DBU

I AcO

O

Ph

O

HO

Ph

4.15

O 4.16

Scheme 4.10 MeO

BrZn I

MeO

OMe

+

OMe

OMe

4.17 MeO

PEPPSI, CO, LiBr, PPh 3

4.18

O

MeO

O

1. BBr 3 OMe 2. Cs 2CO3 MeO

OMe

MeO

OMe

O

OMe 4.19

OMe

4.20

Scheme 4.11 MeN

NMe N

Ot-Bu +

I

OTIPS

Me3Sn

4.21

4.22 Pd2dba3, Ph3As CO (50 psi), LiCl NMP N

MeN

Ot-Bu

NMe N

H

O

N

OTIPS O

H HO

4.24

4.23

Scheme 4.12

lithium enolate allows the carbonylative-coupling – Nazarov – hydrogenation sequence to be repeated to give the tricycle 4.32 via enone 4.31. Finally, a Wittig reaction yielded the natural product 4.25. Quite different syntheses of capnellene can be found in Chapter 5, Scheme 5.40 and Chapter 8, Schemes 8.58–8.60. A carbonylative coupling of a vinyl derivative was employed in a synthesis of cylindricine C 4.33 (Scheme 4.14).14 In this case, the double Michael acceptor ability of the product was exploited to generate the tricyclic product, following protecting group manipulation and installation of nitrogen in the form of azide. Another synthesis of this molecule can be found in Scheme 11.89.

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Carbonylation HH

*

*

bonds formed by Navarov reactions carbon atoms derived from CO

* H 4.25

O

Me3Sn

OTf

(Ph3P)4Pd, LiCl, CO

+

BF3.OEt2

SiMe3 4.27

4.26 O

H

H

1. H2, Pd/C 2. LDA, Tf2NPh

Me3Sn

OTf

4.27

4.29

SiMe3

(Ph3P)4Pd, LiCl, CO

4.30

O

H

SiMe3

4.28

O

HH

1. BF3.OEt2 2. H2, Pd/C

HH

Ph3P CH2

SiMe3

H 4.32

4.31

H 4.25

Scheme 4.13 n-C6H13 O H

n-C6H13 N

O

double aza-Michael

NH2 OPG

OH

4.33

4.34

carbonylative coupling

OTf R

CO

4.35

4.36 O

OTf

n-C6H13 1. (MeCN) PdCl , aq. MeOH 2 2 2. TBSCl, Et3N, DMAP 3. MsCl, Et3N 4. NaN3, DMF

n-C6H13

Me3Sn (Ph3P)4Pd, LiCl THF, CO, Δ O 4.35

n-C6H13

M

O O

4.37

O

n-C6H13 O

N3 OTBS

1. CrCl2, H3O+ 2. TBAF

4.38

O H

n-C6H13 N

OH 4.33

Scheme 4.14

121

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Organic Synthesis Using Transition Metals I

CHO Pd(PPh3)4, n-Bu3SnH, CO

CO2CH3

CO2CH3

4.39

4.40

Scheme 4.15

OAc

1.

OAc I n-Bu3SnH, CO, (Ph3P)4Pd

I

I

OH

(Ph3P)4Pd, CuI, Et3N 2. LiOH CHO 4.43

CHO 4.42

4.41

Scheme 4.16

If a hydride source is employed in place of a main-group organometallic, the same process can also be used to make aldehydes in a formylation reaction (Scheme 4.15). Hydride sources include Bu3 SnH15 and poly(methylhydrosiloxane).16 A regioselective formylation of a diiodide 4.41, followed by Sonogashira coupling, was used in a synthesis of Eutypine 4.43, a fungal phytotoxin (Scheme 4.16).17

4.2

Carbonylative Coupling Reactions: Synthesis of Carboxylic Acid Derivatives

The acyl palladium intermediate may also be trapped by heteroatom nucleophiles (Schemes 4.17 and 4.18), such as alcohols18 and amines19 as part of the catalytic process, to give esters (Scheme 4.19) and amides (Scheme 4.20), respectively. Less commonly used nucleophiles include water, to give carboxylic acids,20 carboxylate salts, to give anhydrides, and ketones, via their enol form, to give enol esters. Metal carbonyl complexes may be used as both the source of CO and as the catalyst for the reaction (Scheme 4.21).21 The nucleophile is often used in large excess and, especially in the case of simple nucleophiles such as methanol and ethanol, is often used as the solvent. Nevertheless, efﬁcient acylation reactions can be achieved with much smaller quantities of the nucleophile in an inert solvent. Intramolecular reactions are particularly useful to prepare both lactams (Scheme 4.22)22 and lactones (Schemes 4.23 and 4.24).23 The carbonylation O R

R'OH

RX

LnPd(0), CO, base

OR'

O R

O

H2O

PdLnX

R R'NH2

O R

Scheme 4.17

OH

NHR'

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Carbonylation

123

O R Nuc reductive elimination

RX oxidative addition

L2Pd

R

O L2Pd

L2Pd

R Nuc

CO coordination and insertion

O

base.HX NucH base

X

L2Pd

R X

Scheme 4.18 O Pd(OAc)2, CO, n-Bu3N, n-BuOH

I MeO

On-Bu 4.45

4.44

Scheme 4.19 O Br

PhNH2, (Ph3P)2PdBr2, n-Bu3N, CO

N H N

N

4.47

4.46

Scheme 4.20 O BnNH2, n-Bu3N, Mo(CO)6, Δ

NHBn

S

4.49

Br S

O 4.48 aq. NH 3, Mo(CO)6, Δ

S

NH2 4.50

Scheme 4.21

reaction is not limited to the formation of medium-sized rings, both macrocycles and four-membered rings, such as the ␣-methylene-␤-lactam 4.52, can also be formed. Palladium-catalysed carbonylation of an iodoallylic alcohol, stereoselectively formed from the propargylic alcohol 4.57 through organoaluminium chemistry, was employed to form the base sensitive butenolide moiety of parviﬂorin 4.62 in a two-directional synthesis (Scheme 4.25).24,25 After oxidative removal of the protecting group-linker and a Swern oxidation, a vinyl iodide was installed in a Takai reaction. This allowed completion of the carbon skeleton of the target molecule by a Sonongashira reaction between alkyne 4.60 and iodide

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Organic Synthesis Using Transition Metals O

Br NHBn

Pd(OAc)2, PPh3, CO N 4.52 Bn

4.51

Scheme 4.22

Br O

(Ph3P)2PdCl2, K2CO3, CO O

OH 4.53

4.54

Scheme 4.23

MeO

MeO MeO

OH (Ph3P)2PdCl2, K2CO3, CO

MeO O

I 4.55

4.56

O

Scheme 4.24

4.59, perhaps the mildest way of forming a carbon–carbon bond (Chapter 2, Section 2.8). The synthesis was completed by selective reduction of the alkynes and disubstituted alkenes of Sonogashira product 4.61 using Wilkinson’s catalyst, and deprotection. Under special conditions, double carbonylation can be achieved (Scheme 4.26),26 although this is rarely observed. It appears to be favoured by the correct choice of nucleophile and phosphine ligands and, of course, high CO pressures. Useful precursors for agrochemicals were obtained by either single or double alkoxycarbonylation of a dichloropyridine 4.65 (Scheme 4.27).27 Either product, 4.66 or 4.67, could be obtained by the choice of the reaction temperature, on a 120 g scale. For single carbonylation, the expected selectivity (see Chapter 2, Section 2.1.4) for greater reactivity ␣ to the pyridine nitrogen giving ester 4.67 was found. In the preparation of a platelet aggregation inhibitor 4.71 on a scale of 123.9 kg, both the bromide 4.69a and the iodide 4.69b could be coupled with the piperidine 4.70 in the presence of carbon monoxide to introduce the desired amide linkage (Scheme 4.28).28 While the bromide 4.69a required somewhat speciﬁc conditions for good yields, the carbonylative coupling of the iodide 4.69b did not. Heterocycles may also be carbonylated, to give either ring-expanded heterocycles, or ring-opened products.29 These include epoxides (Scheme 4.29), aziridines (Scheme 4.30),30 oxetanes (Scheme 4.31)31 and azetidines (Scheme 4.32).32 The cobalt-catalysed carbonylation of epoxides provides a short route to ␤-hydroxyesters 4.73 (Scheme 4.29).33 These useful synthetic building blocks are often obtained in enantiomerically enriched form by the asymmetric reduction of ␤-ketoesters.34 As many epoxides are readily available in very high e.e., the carbonylation chemistry provides a useful alternative route. Unstrained heterocycles may also be carbonylated, although, owing to the absence of ring strain, which provides a powerful driving force, more vigorous conditions may be required.

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Carbonylation OH

O TBDPSO

TBDPSO O

O

O

1. Red-Al® 2. I2 3. (Ph3P)2PdCl2, CO, K2CO3

O

O

TBDPSO

TBDPSO 4.57

OH

1. Ce(NH4)2(NO3)6 2. (COCl)2, DMSO, Et 3N 3. CHI3, CrCl2

O

4.58 O

O

O

TBDPSO I 4.59 O

HO

TBDPSO H O H H O H

4.60, (Ph3P)2PdCl2, Et3N, CuI

O

1. (Ph3P)3RhCl, H2 2. HCl, MeOH n-C7H15 4.61

HO O HO

O

HO

HO H O H H O H HO

H O H H O H

4.62 HO

n-C10H21

Scheme 4.25

O I

Et2NH, CO (10 atm), Et3N, (MePh2P)2PdCl2

NEt2 O 4.64

4.63

Scheme 4.26

4.60

n-C7H15

125

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Organic Synthesis Using Transition Metals F3C

CO2Et at 150 °C

F3C

Pd(OAc)2, dppf, CO, NaOAc, EtOH

Cl

N

CO2Et

N

Cl

4.66 F3C

4.65

Cl at 80 °C CO2Et

N 4.67

Scheme 4.27 Me

n-Bu4N Br3 or ICl.py

N O N H 4.68

Me X

N O N H

CO2Me

CO2Me

X = Br 4.69a X = I 4.69b O NH

CbzN

Me N

N

4.70 Pd(OAc)2, PPh3, CO

O N H

CbzN

CO2Me

4.71

Scheme 4.28

BnO

Co2(CO)8, CO, MeOH

O

OH CO2Me

BnO

4.72

4.73

Scheme 4.29 Bn N

1. LiI 2. Ni(CO) 4

Me

Bn

O N

Me

4.74

4.75

Scheme 4.30

O Me

Me

Co2(CO)8, Ru3(CO)12, CO

O Me

Ph 4.76

Scheme 4.31

O

Me Ph 4.77

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Carbonylation H

127

H Co2(CO)8, CO

N

O N H Me 4.79

Me

H 4.78

Scheme 4.32

4.3 Carbonylation of Alkenes and Alkynes 4.3.1

The Carbonylative Heck Reaction

It is possible to intercept acyl palladium complexes by alkene insertion (Scheme 4.33). This may be considered as a carbonylative version of the Heck reaction (Chapter 5), and it requires that the initially formed ␩1 -palladium complex insert CO ﬁrst, and the alkene second, prior to ␤-hydride elimination. Once achieved, this would, in terms of synthesis, be somewhat equivalent to a Friedel–Crafts reaction of alkenes, but under mild conditions. One factor in the successful realization of this concept is the correct choice of alkene. Five-membered rings, including cyclopentene and dihydrofuran 4.81 are good substrates under “standard” conditions (Scheme

O

LnPd

Ph X + CO +

R

Ph

Et3NH I Et3N L I Pd L H L

R

PhX L2Pd

reductive elimination

coordination

Ph oxidative addition L2Pd X ligand exchange

CO

L Ph

OC O L Ph

R

Pd H

O Ph

I

H

Pd L

β-hydride elimination; dissociation PdLI η1

R

X

CO insertion

O Ph coordination LPd

insertion

O

L I Pd Ph

Scheme 4.33

η2

R

X R

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Organic Synthesis Using Transition Metals Me

PdCl2, PPh3, Et3N, CO (5 atm)

+ Me

I 4.80

O

Me Me

O O

4.81

4.82

Scheme 4.34 MeO2C

[(cinnamyl)PdCl]2, MeO2C L = 4.89, Et3N, CO (5 bar)

+ Br 4.83

O

4.84

4.85

Scheme 4.35 [(cinnamyl)PdCl]2, EtO L = 4.89, Et3N, CO (5 bar)

EtO +

On-Bu

Br 4.86

On-Bu O

4.87

4.88

Scheme 4.36

4.34).35 With other alkenes, including styrene 4.84, enol ethers 4.87 and acrylates, success was only obtained by switching to a sophisticated phosphine ligand 4.89 (Schemes 4.35 and 4.36).36 N N i-Pr

Pi-Ad2 i-Pr 4.89

The intermolecular version of the reaction can also be effective, and, under the right conditions, can give good yields even when the substrate, such as iodide 4.90, is capable of ␤-hydride elimination (Scheme 4.37).37 Curiously, the intramolecular carbonylative Heck reaction of styrene 4.03 proceeded with net reduction of the alkene (Scheme 4.38).38 Multiple insertions are possible. Systems have been designed that involve two alkene insertions and three carbon monoxide insertions, which proceed in good yield, such as the conversion of 4.95 to 4.96 (Scheme 4.39).39 The efﬁciency of the reaction is notable, as the tandem sequence can go astray at various points (Scheme 4.40). Several intermediates are capable of undergoing ␤-hydride elimination (4.99, 4.101) or direct alkene insertion (4.97, 4.99), but do not: CO insertion occurs instead. The high CO pressure (40 atm) is likely to be responsible in part for this selectivity. O (Ph3P)4Pd, i-Pr2NEt, CO (50 atm)

O

H

H

+

I H 4.91

4.90

Scheme 4.37

H 4.92

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Carbonylation MeO

MeO

Pd(OAc) 2, py, n-Bu4NCl, CO

MeO

129

MeO

I

O 4.93

4.94

Scheme 4.38 O I

H

(Ph3P)2PdCl2, MeOH, Et3N, CO

O

MeO

MeO

4.95

4.96

CO2Me

Scheme 4.39 O I

PdLnI

PdLn

PdLnI CO insertion

oxidative addition MeO

MeO

4.95

4.97

MeO 4.98

O

O PdLnI

alkene insertion MeO O

MeO O

H

MeO

PdLnI

CO insertion

4.99

O PdLnI

O O O

MeO 4.102

alkene insertion

4.100

H

CO insertion

4.101

O

H

MeOH

O MeO

PdLnI

CO2Me

4.96

Scheme 4.40 PdCl2, CuCl2, NaOAc, CO, MeOH

PhO

CO2Me PhO

4.103

4.104

Scheme 4.41

4.3.2

Other Carbonylation Reactions of Allenes and Alkynes

Terminal alkynes 4.103 may be converted in propiolic esters 4.104 under conditions that look very like a Wacker oxidation (see Chapter 6, Section 6.1) (Scheme 4.41).40 The reaction is likely to proceed via the copper(I) acetylide. This is a mild alternative to the classical method of employing a strong base and quenching the acetylide anion with a chloroformate.

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Organic Synthesis Using Transition Metals H

OH

O

PdCl2, SnCl2, n-Bu3P, CO

O H 4.106

4.105 H O H 4.106

OH

PdCl2

O

4.105 CO

HCl O

H O

O O H 4.108

PdX

PdX 4.107 insertion

Scheme 4.42

Me

Me

Me OHC

Ru3(CO)12, Et3N

SnCl2, NaI, H2O, DMF HO Br

O •

4.109

4.110

O

4.111

Scheme 4.43

Alkynols 4.105 may be cyclized to ␣-methylene lactones 4.106 using palladium-catalysed carbonylation (Scheme 4.42).41 The reaction is proposed to proceed via formation of an acyl palladium species 4.107, which undergoes intramolecular alkyne insertion. Protonolysis of the carbon–palladium bond of the vinyl complex 4.108 yields the product. Allenols may be carbonylated under quite different conditions. Using Ru3 (CO)12 as the catalyst, unsaturated lactones can be synthesized efﬁciently.42 The reaction may also be extended to lactams.43 This cyclization, combined with an intramolecular propargylic Barbier reaction has been used in syntheses of mintlactone 4.111 from allenol 4.110 (Scheme 4.43)44 and its diastereoisomer, isomintlactone,45 as well as the stemona alkaloid, stemoamide 4.115 from allenol 4.113 (Scheme 4.44),46 and in the skeleton of stenine.47 A different synthesis of stemoamide can be found in Chapter 8, Scheme 8.112.

4.4

Hydroformylation

Hydroformylation is the addition of one molecule of hydrogen and one of carbon monoxide across an alkene to generate an aldehyde (Scheme 4.45). Unsymmetrically substituted alkenes can give mixtures of linear and branched aldehydes, 4.116 and 4.117. Hydroformylation was discovered in the 1930s and rapidly

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Carbonylation

Br

In, THF, AcOH

O

N

• H

HO 4.112

N

H

O

O

Ru3(CO)12, Et3N CO (100 psi)

4.113

CHO

O

O

N

131

NiCl2, NaBH4, MeOH, -30 °C

H O O

4.114

H

O

N

4.115

Scheme 4.44 CHO

H2, CO, catalyst R

CHO

R

+

4.116 linear

R 4.117 branched

HRhL2(CO)2 H O

± CO

reductive elimination

4.122

O

HRhL2(CO)

coordination

Rh(CO)L2 HH

4.118 H

H2

Rh(CO)L2 insertion

oxidative addition Rh(CO)L2

Rh(CO)L2

4.121 O CO insertion

4.119

CO coordination Rh(CO)2L2 4.120

Scheme 4.45

developed as an industrial process using initially ill-deﬁned cobalt catalysts. Mechanistic studies came much later with the work of Heck48 and Wilkinson. The latter also introduced rhodium catalysis, which works under much milder conditions. Applications to the synthesis of complex organic molecules came even later.49 The mechanism of hydroformylation is believed to be largely the same whether cobalt or rhodium is used. The mechanism involves coordination of the substrate alkene to a rhodium hydride complex, insertion of the alkene to form alkyl rhodium complexes 4.119 and 4.120, followed by CO insertion to convert them to an acyl rhodium complex 4.121. Oxidative addition of hydrogen and reductive elimination then gives the product and regenerates the initial rhodium hydride. If the insertion reaction proceeds with the opposite regiochemistry to put the rhodium at the internal, more hindered position, then the branched isomer 4.117 is formed (Scheme 4.46).

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Organic Synthesis Using Transition Metals insertion Rh(CO)L2

H

H Rh(CO)L2

O 4.116 linear

4.120

4.119

rotation

insertion H

Rh(CO)L2

CHO

Rh(CO)L2

4.117 branched

4.123

Scheme 4.46 OTBS OBn

Rh(acac)(CO)2, Ph(OPh)3, CO, H 2

OTBS OHC

OBn

4.124

4.125

Scheme 4.47 O TBSO

OH

TBSO 1. [Rh(OAc) 2]2, CO, H 2 2. PCC

BnO

O

BnO

OMe

OMe

TBSO

4.126

TBSO

4.127

Scheme 4.48 t-Bu

t-Bu O

O

(acac)Rh(CO)2, PPh3 CO, H 2

O

O CHO

BnO

BnO 4.128

4.129

Scheme 4.49

The linear/branched ratio has been a key issue, and considerable effort has been put into optimizing the selectivity. Alkenes with alkyl substituents tend to favour formation of the linear isomer 4.116. This property was employed in a synthesis of the C1–C13 fragment of the cytotoxic marine natural product, dolabelide (Scheme 4.47),50 and to form a key lactone 4.127 in a synthesis of carbomycin B (Scheme 4.48).51 Enol ethers have also been used as the substrate to create ␤-functionalized aldehydes (Scheme 4.49).52 The proportion of linear isomer may be increased by varying the ligands: biphephos 4.130, a chelating bisphosphite, appears to be the ligand of choice, giving very high linear/branched ratios under quite mild conditions.53 Styrenes, on the other hand, tend to give the branched isomer (Scheme 4.50),54 unless they have an ␣-substituent. Hydroformylation of norbornene raises the question of stereoselectivity (Scheme 4.51). High selectivity for the exo-isomer can be obtained, although, on a large scale (11 kg), the product was isolated as the sodium salt of the corresponding carboxylic acid.55 The exo-selectivity is useful, as the more conventional Diels–Alder route would favour the endo-isomer.

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Carbonylation MeO

OMe

t-Bu

t-Bu O P O O

O O P O

133

4.130

CHO Rh(I), H2, CO 4.132

4.131

Scheme 4.50 1. Rh(acac)(CO) 2, dppf, CO, H 2 2. NaClO 2, TEMPO 3. NaOMe

CO2Na

4.133

4.134

Scheme 4.51 Ph

H2, CO, [Rh(cod)Cl]2 NH

Ph

Ph

Pn-Bu3

CHO

Ph

-H2O

4.136

4.135

Ph

Ph N

Ph

H2

Ph

4.137

N 4.138

Scheme 4.52

The metal present can also catalyse other reactions, giving rise to tandem processes. If hydroformylation is carried out in the presence of a secondary amine, the aldehyde 4.136 produced by hydroformylation will condense to give an enamine 4.137, which will be hydrogenated (but not hydroformylated) under the reaction conditions to give a tertiary amine 4.138 (Scheme 4.52).56 This chemistry can be extended to dienes to give N-heterocycles of various kinds (Schemes 4.53 and 4.54).57 On the other hand, if an amine, protected by an electron-withdrawing group, is suitably placed within the molecule, tandem hydroformylation-condensation occurs without alkene reduction. Depending on the reaction conditions, either an N,O-acetal 4.145 (Scheme 4.55)58 or an enamide 4.148 (Scheme 4.56) derivative may be obtained. Each of these can be useful synthetic intermediates for the stereocontrolled formation of piperidines. Dihydroxylation of enamide 4.148 lead to a short synthesis as epi-pseudoconhydrine 4.151.59

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Organic Synthesis Using Transition Metals [Rh(cod)Cl]2, CO, H2, i-PrNH2

+

4.139

4.140

N i-Pr

O

4.141

Scheme 4.53

Ph

[Rh(cod)Cl]2, CO, H2, i-PrNH2

Ph N i-Pr

4.142

4.143

Scheme 4.54

CO2Me NHt-Boc

Rh(acac)(CO)2, BIPHEPHOS 4.130, EtOH, CO, H2

4.144

n-BuCu, BF3.OEt2

n-Bu

EtO

N CO2Me t-Boc 4.145

CO2Me N t-Boc 4.146

Scheme 4.55

TsNH

Rh2(OAc)4, P(OPh)3 or biphephos CO, H2

n-Pr

OH Ts

N

OsO4, NMO

1. Ac 2O, Et3N 2. CF3CO2H, Et3SiH

4.148 Ts

OAc

N

OH

N

n-Pr

n-Pr 4.147

Ts

4.149

1. K2CO3, MeOH 2. Mg, MeOH, )))

HN n-Pr

n-Pr 4.150

Scheme 4.56

4.151

OH

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Carbonylation

135

MeO

MeO MeO

Rh(acac)(CO)2, BIPHEPHOS 4.130, CO, H2, H+

H N O

MeO HO -H2O N O

4.152 MeO

4.153

MeO

MeO

MeO LiAlH4, Et3NHCl N

N

O 4.154

4.155

Scheme 4.57

N H

H2, Pd(OH)2

N3

N

Rh(acac)(CO)2, BIPHEPHOS 4.130, CO, H2, H+

N 4.156

N3 N 4.157

CHO

1. CF3CO2H 2. HCHO, HCO2H

4.158

N Me N

4.159

Scheme 4.58

The hemi-aminal or enamide intermediates can also be used for C–C bond formation, via iminium ion intermediates, as in a short synthesis of crispine 4.155 (Scheme 4.57).60 Hydroformylation can be highly tolerant of functional groups. An azide, normally highly reactive towards transition metals, can survive. This property has been exploited in a synthesis of the pyridine alkaloids anabasine 4.158 and nicotine 4.159 from the same hydroformylation reaction (Scheme 4.58).61 Another approach to both of these alkaloids can be found in Chapter 8, Schemes 8.76 and 8.77. Double hydroformylation of the azido diene 4.160 gave the bis-aldehyde 4.161 (Scheme 4.59). Tandem azide reduction and double reductive amination then gave the indolizidine alkaloid, lupinine 4.162.62

4.4.1

Directed Hydroformylation

The typical regioselectivity of hydroformylation can be perturbed if the substrate contains a good ligand for rhodium. If the substrate is an aliphatic alkene, the ligand can then direct rhodium to the internal position. Nitrogen derivatives are often capable of doing this: hydroformylation of 4-pentenamide 4.163 yielded dihydropyridone 4.164 due to coordination of the carbonyl oxygen to rhodium (Scheme 4.60),63 while an amine derivative 4.166 underwent a tandem hydroformylation–condensation–hydrogenation sequence to give a piperidine 4.169 (Scheme 4.61).64

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Organic Synthesis Using Transition Metals OTBS

Rh(acac)(CO)2, BIPHEPHOS 4.130, H2, CO

OTBS OHC

N3 4.160

CHO N3 4.161

OH 1. H 2, Pd(OH)2 2. TBAF N 4.162

Scheme 4.59

NH2

Rh4(CO)12, CO, H2 O N H 4.164

O 4.163

via (CO)xHyRh

O

NH2

4.165

Scheme 4.60

NHBn

(Ph3P)3RhH(CO) CO, H 2

4.166 -H2O

CHO NHBn 4.167

Bn N

H2

4.168

Bn N

4.169

Scheme 4.61

Oxygen atoms, such as in an alcohol, are not sufﬁciently good ligands to have this effect. The best ligands are phosphorus based, but this atom is almost never required in the ﬁnal product of the synthesis. The solution is to attach the phosphorus ligand, “L” to the alcohol in the substrate by a temporary tether that may be subsequently cleaved (Scheme 4.62). The reaction can proceed with useful diastereoselectivity and regioselectivity and, when allylic alcohols are the substrate, this represents an alternative to aldol chemistry. The directing effect can also involve stereochemical issues (Schemes 4.63–4.65).65–67 While this strategy achieves the objective, two steps are added: attachment and removal of the temporary ligand. A shorter process is to introduce a reagent to the hydroformylation mixture that will attach and detach itself in situ (Scheme 4.66). Provided that the rate of hydrofomylation of the attached form 4.171 of the substrate is much faster than that of the detached form 4.170, then an efﬁcient process will be achieved. As the temporary directing group is likely to also accelerate coordination to rhodium, this rate enhancement is to be expected. Several systems have been developed to put this into practice (Schemes 4.67 and 4.68).68,69

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Carbonylation L HO

L LnRhH

O

4.172

4.171

4.170 L H2, CO

RhLn

O

CHO

CHO cleave O-L bond

O

HO

4.173

4.174

Scheme 4.62

OP(OEt)2

[Rh(OAc)2]2 CO, H 2

OP(OEt)2 CHO

OH LiAlH4

4.176

4.175

OH 4.177

Scheme 4.63

O

O

PPh2 (acac)Rh(CO) 2 P(OPh)3, CO, H 2

Ph

PPh2 O

O

Ph

CHO 4.179

4.178

Scheme 4.64

P

P

(acac)Rh(CO)2, CO, H2

O

O CHO 4.181

4.180

Scheme 4.65

137

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Organic Synthesis Using Transition Metals OH

slow linear hydroformylation

HO

HO

O

CHO

4.183

4.182

4.170 ±L L

L

fast directed hydroformylation

O

CHO

4.171

CHO

±L

O

HO

4.173

4.174

Scheme 4.66

Me N

OH

Oi-Pr P Ph

Ph 4.184

OH

1. Rh(acac)(CO)2, TsOH, CO, H2 2. NaClO2

4.185

CO2H Ph 4.186

Me N O

via 4.187

Ph

P Ph

Scheme 4.67

F3C

O O S N H CF3

4.188

Me N P Ph

Rh(acac)(CO)2, Oi-Pr TsOH, CO, H2

4.189

F3C

O O S N H CF3

CHO

4.190

Scheme 4.68

4.4.2

Asymmetric Hydroformylation

Branched hydroformylation introduces a new stereogenic centre and, therefore, there is the opportunity to control the new centre by the use of chiral ligands. An early application of this concept is in an industrial synthesis of the anti-inﬂammatory drug, naproxen 4.193 from the corresponding styrene (Scheme 4.69).70 The ligand for the hydroformylation reaction, chiraphite 4.194, consisted of two bulky phosphates linked by a chiral tether. Many other chiral ligands have been developed.71 A problem with generating aldehydes with an ␣-chiral centre is their facile racemization via their enol or enolate form. One solution to this problem is to protect the product as its acetal 4.195 in situ (Scheme 4.70).72

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Carbonylation

139

CHO H2, CO, acacRh(CO) 2, L* MeO

MeO 4.191

4.192 CO2H

KMnO4 MeO 4.193

t-Bu

t-Bu

O

MeO

P O

L*= 4.194

O

O

O

OMe

P O

t-Bu t-Bu MeO

OMe

Scheme 4.69 EtO

OEt

Cat., H2, CO, SnCl2, HC(OEt)3 MeO

MeO 4.191

4.195 Ph2P Cat. = 4.196

Cl2 Pt PPh2

N t-Boc

Scheme 4.70

4.5 Stoichiometric Carbonylation using Carbonyl Complexes 4.5.1

Iron and Cobalt Carbonyl Anions

Iron pentacarbonyl can be reduced by various reagents, such as sodium amalgam, to generate the anion Fe(CO)4 2− 4.197. Its sodium salt, known as Collman’s reagent, is commercially available as a complex with 1,4-dioxane.73 This material is pyrophoric and must be handled under an inert atmosphere. The potassium salt can also be prepared.74 The dianion acts as a nucleophile and participates in various SN 2 reactions (Scheme 4.71). Tight ion pairing has been demonstrated and, as a consequence, reaction rates are markedly higher in polar solvents, which break up the ion pairs and free the anion. N-Methyl pyrrolidine has been widely used. Additionally, the tetracarbonylferrate dianion is quite basic, so, in line with this familiar situation with less-exotic nucleophiles, efﬁcient alkylation reactions appear to be limited to primary halides and secondary tosylates; other substrates give the products of elimination. The initial products of nucleophilic substitution, alkyl tetracarbonyl iron monoanions 4.198, are generally not isolated. Addition of another ligand, typically CO or triphenylphosphine, results in CO insertion to give the acyl complex anion 4.199. This can be further

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Organic Synthesis Using Transition Metals Fe(CO)5

2 e-

Fe(CO)42- R X 4.197

R Fe(CO)4 4.198 L = CO, PPh 3

O

O R'

R

Fe(CO)4 R' 4.200

R Fe(CO)4 4.199

O R

R

R

H

Br2, MeOH

O2 O

O

H

I

O OH

R

OMe

R'

Scheme 4.71 Br

H

K2Fe(CO)4 NMP

O H

Br

4.202

4.201

Scheme 4.72 1. K2Fe(CO)4 2. Br 4.203

O NaOH

O 4.204

O

4.205

O

Scheme 4.73

alkylated, a reaction that is followed by reductive elimination to generate a ketone. A notable example is the conversion of the dihalide 4.201 to the cyclic ketone 4.202 (Scheme 4.72). Other carbonyl and carboxylic derivatives can also be formed: protonolysis of the acyl anion complex gives an aldehyde, oxidation can give either a carboxylic acid or an ester. Another useful reaction of these complexes is alkene insertion. This works well with electron-poor alkenes and may be drawn as a Michael addition. One application is in the synthesis of the perfumery compound, cis-jasmone 4.205 (Scheme 4.73).75 The initial acyl iron complex reacted with methyl vinyl ketone to give a 1,4-diketone 4.204, which underwent a subsequent intramolecular aldol reaction on treatment with a base. Intramolecular insertion of simple alkenes is possible (Scheme 4.74). While this is potentially a powerful cyclization method, it has seen little application beyond a synthesis of aphidicolin 4.209 (Scheme 4.75),76 and appears to be limited to a small group of alkenes, such as monosubstituted alkenes and cyclopentenes.77 Cobalt forms a tetracarbonyl anion 4.211 by treatment of dicobalt octacarbonyl 4.210 with sodium amalgam or sodium hydroxide (Scheme 4.76).78 In accord with the eighteen-electron rule, this species is a monoanion. It is much less nucleophilic and less basic than Collman’s reagent 4.197. Indeed, the conjugate acid, HCo(CO)4

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Carbonylation

141

Na2Fe(CO)4, THF, Δ; then AcOH OTs

O

4.206

4.207

Scheme 4.74

O

TsO

H O

H O

Na2Fe(CO) 4

H O

4.208

H O

4.209

Scheme 4.75

Co2(CO)8 4.210 Na(Hg) or NaOH NaCo(CO)4 4.211

MeI

O Me Co(CO)4

CO Me Co(CO)4 4.213

4.212 ROH

RNH2

O Me

O OR

Me

NHR

Scheme 4.76

is regarded as a strong acid, similar to HCl. The best alkylating agents are reactive ones, such as methyl iodide and MOM chloride. The resulting alkyl cobalt complexes 4.212 have been isolated, but are quite unstable. The reactions are typically carried out under CO, resulting in immediate insertion to give the more stable, but air-sensitive, acyl complexes 4.213. Alcoholysis of these complexes gives esters, and the reaction with amines gives amides.79 Addition of a 1,3-diene to a solution of the acyltetracarbonylcobalt complex 4.213 results in insertion, with formation of an ␩3 -allyl complex 4.214 (Scheme 4.77); acylation occurring at the less-hindered terminus of the diene.80 In the presence of a base, the allyl complex undergoes elimination to give an acyl diene 4.215. As the allyl complex is electrophilic, it can also be attacked by some nucleophiles, such as malonate anions and nitronates (see Chapter 9, Section 9.1).81 Allenes can be used in place of the 1,3-diene (Scheme 4.78). The reaction is especially useful in an intramolecular sense.82 The products are useful Michael acceptors.83 Other anionic acyl complexes include those generated by addition of organolithium agents to Ni(CO)4 and the cobalt complex, Co(NO)(CO)2 (PPh3 ).84

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Organic Synthesis Using Transition Metals O Me

O

Co(CO)4 4.213

Co(CO)3

Me 4.214 Et3N

CH2NO2

O

O

Me

Me 4.215

NO2

4.216

Scheme 4.77 O

O

1. •

NHTs

Me 2. Et 3N

O

Co(CO)4 NHTs Co(CO)3

4.217

4.218

N Ts

4.219

Scheme 4.78 O

O (OC)3Fe

4.220

O

Fe 2(CO)9 4.222 HO

OH 4.221

Scheme 4.79 OH

Fe 2(CO)9 (OC)3Fe

OH 4.223

4.224

O O

Scheme 4.80

4.5.2

Ferrilactones and Ferrilactams

Treatment of vinyl epoxides 4.220 with metal-carbonyl complexes yields cyclic lactone complexes, which incorporate an allyl ligand derived from epoxide opening (Scheme 4.79).85 The most widely used are the ferrilactones 4.222, prepared using either iron pentacarbonyl or diiron nonacarbonyl.86 These complexes may also be prepared from other starting materials, such as diols 4.22187 and derivatives.88 The particular advantage of the epoxide route is that the preparation of the vinyl epoxide starting materials can be done through the Sharpless asymmetric epoxidation of allylic alcohols. In this way, the complexes can be prepared with very high enantiomeric excess. An advantage of the diol route is that it also allows access to the isomeric series of complexes 4.224, “isoferrilactones”, in which the methylene-oxy bridge is attached to the central carbon of the allyl unit, rather than a terminal carbon (Scheme 4.80).

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Carbonylation O

143

O

(OC)3Fe O

RNH2, ZnCl2.TMEDA

4.225

R N

Fe(CO) 3

4.226

Scheme 4.81 O (OC)3Fe X 4.227

CO, Δ

(OC)4Fe

X

4.228 O

X 4.229

O

Ce(IV) O X

X = O, NR

X O

4.231

4.230

Scheme 4.82

The corresponding nitrogen derivatives, termed ferrilactams 4.226, can be prepared from vinyl aziridines or by treatment of the corresponding ferrilactone 4.225 with an amine and a Lewis acid (Scheme 4.81). The transformation proceeds with allylic migration, indicating that nucleophilic attack on the allyl group occurs as part of the mechanism of this transformation. There are two important reactions for decomplexation (Scheme 4.82). High-pressure carbonylation results in reductive elimination, perhaps via the ␩1 -complex 4.228, to give a six-membered ring lactone or lactam 4.229. In the kinetic product 4.229, the double bond is out of conjugation, but may move into conjugation, an isomerization catalysed by iron carbonyl byproducts, to give the thermodynamic product 4.230. In contrast, oxidative decomplexation with cerium(IV) results in reductive elimination in a different sense, to give a four-membered ring, a ␤-lactone or ␤-lactam 4.231. This is an example of an oxidatively induced reductive elimination. One application of the carbonylation of these complexes is in the synthesis of the spiroketal fragment of the avermectins (Scheme 4.83).89 The vinyl epoxide 4.234 for ferrilactone formation was synthesized starting from leucine 4.232. This amino acid may be decarboxylated to give the volatile (S)-2-methylbutyraldehyde. Extension of this aldehyde to an allylic alcohol 4.233 allowed Sharpless epoxidation. The epoxide could then be converted to a vinyl epoxide 4.234 and, thence, to the desired ferrilactone 4.235. High-pressure carbonylation gave the desired trans-isomer of the lactone 4.236 as the major product. After conversion to a sulfone 4.237, this fragment could be coupled with epoxide fragment 4.238 and formation of the spiroketal 4.239 could be completed by a selenium-induced cyclization, giving the Northern hemisphere of the potent anthelmintic Avermectin B1a.90 The oxidative decomplexation chemistry has been employed for the synthesis of both ␤-lactones91 and ␤-lactams, such as the thienamycin precursor 4.242 (Scheme 4.84).92 With the isomeric series of complexes, both decomplexation methods yield the same product, the ﬁvemembered ring, as the two termini of the allyl group are equivalent (Scheme 4.85). The isoferrilactam 4.244,

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Organic Synthesis Using Transition Metals NH2

1. t-BuOOH, Ti(Oi-Pr) 4, (-)-DET 2. DMSO, (COCl)2, Et3N 3. Ph3P=CH2

1. Ninhydrin HO 2. Ph3P=C(Me)CO2Et 3. DIBAL

HO2C 4.232

4.233 O Fe2(CO)9

O

O

4.234

O

4.235

PhSO2

O

1. H2, PtO2 2. DIBAL 3. PhSO2H

CO, Δ

(OC)3Fe

O

H

4.236

1. BuLi, epoxide 4.238, TBDPSO BF3.OEt2 2. PhSeCl, MeOH 3. oxidation

H

O O

H

OH 4.239

4.237

OTBS

TBDPSO

O 4.238

Scheme 4.83 MeO

OMe Ce(IV)

N

N

Ph

(OC)3Fe

O O

OH

OMe 1. O 3 2. K-Selectride OMe 3. Na, NH 3(l)

OMe OMe NH

Ph

O

4.241

4.240

4.242

Scheme 4.84

O

H N

Fe2(CO)9, ))) H O

4.243

Fe(CO)3 CO, Δ or Ce(IV) O N 4.244

H N

O

4.245 1. H2, Pd/C 2. LiAlH4

BH3.THF then H2O2, NaOH HO H

H N

4.246

Scheme 4.85

N 4.247

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Carbonylation O

O (OC)3Fe O

(OC)3Fe O O

4.248 disfavoured

O

Snn-Bu3 O

145

(OC)3Fe HO

BF3

4.249 favoured

O

4.250

Scheme 4.86

O

1. CpMo(CO) 3 2. Al 2O3

Cl OH

O Cp(OC)2Mo

4.251

4.252

Scheme 4.87

1. H + 2. ROH

CO2R

Cp(OC)2W Cp(OC)2W

4.253

4.254

Scheme 4.88

prepared from the readily available cyclic carbonate 4.243, could be either oxidized or carbonylated to give the bicyclic lactam 4.245 with an exo-cyclic methylene group.93 This could then be converted to the pyrrolizidine alkaloid, isoretronecanol 4.246, by hydroboration, and to heliotridane 4.247 by reduction. The tricarbonyl iron moiety also affects nearby functional groups. This is a steric effect resulting from the bulk of the organometallic moiety.94 A ketone functional group, adjacent to the ␩3 -allyl unit, is forced to exist as a single rotamer 4.249, a fact that can be veriﬁed by spectroscopic and X-ray methods. One face of the ketone is then blocked by the iron carbonyl moiety, leaving only the other face free for addition of a wide range of nucleophiles (Scheme 4.86). A similar effect is observed for ferrilactams.95

4.5.3

Molybdenum and Tungsten Carbonyls

␩ -Allyl molybdenum and tungsten complexes, 4.252 and 4.254, may be formed in a carbonylation reaction starting from propargylic derivatives (Schemes 4.87 and 4.88).96,97 Ligand exchange at the metal of the ␩3 -allyl complexes generates complex 4.257 that can act as nucleophiles towards aldehydes.98 This reaction has been used in a synthesis of avenaciolide 4.258 and isoavenaciolide (Scheme 4.89).99 Related ␩1 -propargylic tungsten complexes 4.259 have been found to be sufﬁciently nucleophilic, with Lewis acid assistance, to attack aldehydes in an intramolecular fashion (Scheme 4.90).100 The initial cyclisation products, believed to be ␩2 -allene complexes 4.260, cyclize to ␩1 -complexes 4.261, which can be oxidatively carbonylated to esters 4.262. 3

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Organic Synthesis Using Transition Metals O

OH

1. CpW(CO) 3 + CO2Et 2. H CO2Et

Cl

O CO2Et CO2Et

Cp(OC)2W 4.256

4.255 O

O CO2Et

1. NO BF 4 2. NaI

CO2Et Cp

O 1. n-C8H17CHO 2. MgCl 2, Δ

H

H

W

I NO

O

O

n-C8H17

4.257

4.258

Scheme 4.89 O Cp(OC)3W

O

BF3.OEt2

O

O

O

Cp(OC)3W •

H

O 4.259 O O

4.260 O

(NH4)2Ce(NO3)6 MeOH, CO

O MeO2C

Cp(OC)3W O

O 4.262

4.261

Scheme 4.90

4.6

Carboxylation

Carbon dioxide, unlike carbon monoxide, has found little use in transition-metal-catalysed reactions. Nickel appears to have a particular afﬁnity for CO2 . In the presence of low-valent nickel, 1,3-dienes 4.263 react with CO2 to give nickelalactones 4.264, which can undergo a number of decomplexation reactions (Scheme 4.91).101 Bis-dienes 4.265 can undergo a double functionalization reaction with CO2 and an organozinc reagent in the presence of a nickel catalyst (Scheme 4.92).102 One diene moiety becomes carboxylated, the other can be alkylated or partially reduced, depending upon the zinc reagent employed. Chiral ligands can also be employed in this reaction.103 Alkynes and CO2 can also couple in the presence of low valent nickel to give a nickelalactone 4.268 which can be treated with acid or reacted with an organozinc reagent (Scheme 4.93).104 This useful method for the formation of trisubstituted alkenes has been employed in a synthesis of erythrocarine 4.275 (Scheme 4.94).105 After stereoselective formation of the trisubstituted alkene 4.272 by LNi O CO2, Ni(COD)2, TMEDA

4.263

O 4.264

Scheme 4.91

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Carbonylation H TsN

1. Ni(COD) 2, PPh3, CO2, R2Zn 2. CH 2N2

TsN

CO2Me

H

R = Et

4.266

R = Me

H

4.265

CO2Me

TsN

Me H 4.267

Scheme 4.92

Ph

H3O+

CO2, Ni(COD)2, DBU

Ph O

Ph

LNi O

CO2H 4.269

Me2Zn

Ph

CO2H

4.268 Me 4.270

Scheme 4.93

NHt-Boc 1. CO2, Ni(COD)2, DBU SiMe3 2. ClZn 3. CH2N2

O O

NHt-Boc

O 4.271

4.272 1.

O O 4.273

1. CF3CO2H SiMe3 2. Δ 3. TBAF

O

MeO2C

O K2CO3 NH 2. LiAlH4 O 3. (COCl)2, DMSO, Et3N 4. MgBr 4.274 5. Ac 2O, DMAP

O 1. Grubbs I 2. K2CO3, MeOH

CO2Me

Br

N

O HO

4.275

Scheme 4.94

N

OAc

147

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Organic Synthesis Using Transition Metals Ph Ph

Ph Ph

+ (Ph3P)3RhCl CHO

+ (Ph3P)2Rh(CO)Cl 4.278

4.277

4.276

Scheme 4.95 (Ph3P)3RhCl ± PPh3 H R O

H Cl Rh(PPh3)2

(Ph3P)2RhCl

R

R

oxidative addition

O R H

reductive elimination

4.279

H Cl Rh(PPh3)2 CO 4.280

+ (Ph3P)2Rh(CO)Cl 4.278

Scheme 4.96 Me

Me CHO (Ph3P)3RhCl

4.281 CHO

4.282

Scheme 4.97

nickel-mediated carboxylation, an intramolecular aza-Michael addition, followed by installation of additional alkenes, allowed an ene–yne–ene metathesis process for the formation of the remaining two rings (Chapter 8, Section 8.3.8). The participation of CO2 in formal [2 + 2 + 2] cycloadditions can be found in Chapter 11, Section 11.1.2.

4.7

Decarbonylation and Decarboxylation

Aldehydes can be decarbonylated by treatment with one equivalent Wilkinson’s “catalyst”, (Ph3 P)3 RhCl (Scheme 4.95).106 The reaction is not catalytic, except at very high temperatures,107 because the rhodium is converted to a stable monocarbonyl complex 4.278. This can be converted back to the “catalyst” in a separate step.108 In some cases, the reaction can be made catalytic by the addition of diphenylphosphoryl azide.109 The use of other ligands for rhodium, especially dppp 1.29, can allow catalytic reactions, although strong heating is still required.110 For an example, see Chapter 8, Scheme 8.106. The mechanism involves oxidative addition of rhodium to the C–H bond of the aldehyde, decarbonylation and reductive elimination (Scheme 4.96). The reaction has a wide scope, and decarbonylation works for alkyl, vinyl and aryl aldehydes, including dialdehydes (Scheme 4.97).111 Reducing sugars, which are masked aldehydes, can also be decarbonylated. Unless there is steric hindrance, the reaction will often proceed at room temperature. In the case of hindered aldehydes, it may be advantageous to employ rhodium complexes with less-bulky ligands (Scheme 4.98).112

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Carbonylation

O

O O

O O

149

O

(Ph2MeP)3RhCl

O

O O

CHO

O

4.283

4.284

Scheme 4.98

O

(Ph3P)2Ni(CO)2, Δ -CO, -CO2

O

O

4.285

4.286

Scheme 4.99

O

O

O Ni(cod)2, bipy -CO

I

N Ni

O

O

MnI2

CO2H

N

4.287

4.288

4.289

Scheme 4.100

Ph2Zn O

O

Ni(cod)2, O neocuproine, dppb -CO 4.290

N Ni

O

O F

Ph

CO2H

N 4.291

4.292

Scheme 4.101

In the presence of alkenes, the reaction may follow a different course, involving alkene insertion after oxidative addition, rather than decarbonylation. This is discussed in Chapter 3, Section 3.2 as a form of CH activation. A number of other carbonyl compounds can also be decarboxylated, including cyclic anhydrides. Catalysed by nickel, this reaction is a decarbonylation–decarboxylation leading to an alkene (Scheme 4.99).113 Under milder conditions, and with the right choice of ligands, nickelacycles 4.288 can be isolated that may correspond to intermediates in the decarbonylation–decarboxylation reaction, and are related to carboxylation products (see Scheme 4.93).114 The alkyl carbon–nickel bond in these complexes can be intercepted by both alkyl halides (Scheme 4.100),115 and organometallic species (Scheme 4.101).116

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References 1. Modern Carbonylation Methods, Koll´ar, L. (Ed.), Wiley, Chichester, 2008; Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation, Plenum, New York and London, 1993. 2. (a) Brennf¨uhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int., Ed. 2009, 48, 4114; (b) Brennf¨uhrer, A.; Neumann, H.; Beller, M. ChemCatChem 2009, 1, 28; (c) Barnard, C. F. J. Organometallics 2008, 27, 5402. 3. Wu, X. F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986. 4. Tanaka, M. Tetrahedron Lett. 1979, 20, 2601. 5. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110, 1557. 6. O’Keefe, B. M.; Simmons, N.; Martin, S. F. Org. Lett. 2008, 10, 5301. 7. Hatanaka, Y.; Fukushima, S.; Hiyama, T. Tetrahedron Lett. 1992, 48, 2113. 8. Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P. Tetrahedron Lett. 1985, 26, 4819. 9. Wang, Q.; Chen, C. Tetrahedron Lett. 2008, 49, 2916. 10. Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765. 11. O’Keefe, B. M.; Simmons, N.; Martin, S. F. Tetrahedron 2011, 67, 4344. 12. Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115, 9293. 13. Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 7500. 14. Molander, G. A.; R¨onn, M. J. Org. Chem. 1999, 64, 5183. 15. Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452. 16. Pri-Bar, I.; Buchman, O. J. Org. Chem. 1984, 49, 4009. 17. Bates, R. W.; Gabel, C. J. et al. Tetrahedron 1995, 51, 8199. 18. Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327. 19. Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3319. 20. (a) Cassar, L.; Fo`a, M.; Gardano, A. J. Organometallic Chem. 1976, 121, C55; (b) Bumagin, N. A.; Nikitin, K. V.; Beletskaya, I. P. J. Organometallic Chem. 1988, 358, 563. Uncommon on a small scale. It is used on a multimillion tonne scale in the Monsanto acetic acid process and its descendant, the Cativa process, to make acetic acid. 21. (a) Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 3017; (b) Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 8410; (c) Ren, W.; Emi, A.; Yamane, M. Synthesis 2011, 2303. 22. Mori, M.; Chiba, K. et al. Tetrahedron 1985, 41, 375; 387. 23. (a) Hoye, T. R.; Humpal, P. E. et al. Tetrahedron Lett. 1994, 35, 7517; (b) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193. 24. Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801. 25. For the 2-directional approach to synthesis, see: (a) Magnuson, S. R. Tetrahedron 1995, 51, 2167; Poss, C. S.; (b) Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9. 26. Ozawa, F.; Soyama, H. et al. J. Am. Chem. Soc. 1985, 107, 3235. 27. Crettaz, R.; Waser, J.; Bessard, Y. Org. Process Res. Dev. 2001, 5, 572. 28. Etridge, S. K.; Hayes, J. F. et al. Org. Process Res. Dev. 1999, 3, 60. 29. (a) Church, T. L.; Getzler, Y. D. Y. L. et al. Chem. Commun. 2007, 657; (b) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414; (c) Alper, H. Aldrich. Acta 1991, 24, 3. 30. Chamchaang, W.; Pinhas, A. R. J. Org. Chem. 1990, 55, 2943. 31. Wang, M. D.; Calet, S.; Alper, H. J. Org. Chem. 1989, 54, 21. 32. Roberto, D.; Alper, H. J. Am. Chem. Soc. 1989, 111, 7539. 33. (a) Denmark, S. E.; Ahmad, M. J. Org. Chem. 2007, 72, 9630; (b) Hinterding, K.; Jacobsen, E. N. J. Org. Chem. 1999, 64, 2164. 34. Genˆet, J. P.; Ratovelomanana-Vidal, V. et al. Tetrahedron Letters 1995, 36, 4801. 35. Satoh, T.; Itaya, T. et al. J. Org. Chem. 1995, 60, 7267. 36. Wu, X.-F.; Neumann, H. et al. J. Am. Chem. Soc. 2010, 132, 14596. 37. Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010, 132, 12823. 38. Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804. 39. C´operet, C.; Ma, S.; Negishi, E.-i. Angew. Chem., Int. Ed. Engl. 1996, 35, 2125.

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151

40. Tsuji, J.; Takahashi, M.; Takahashi, T. Tetrahedron Lett. 1980, 21, 849. 41. Murray, T. F.; Samsel, E. G. et al. J. Am. Chem. Soc. 1981, 103, 7520. 42. (a) Yoneda, E.; Zhang, S.-W. et al. Tetrahedron Lett. 2001, 42, 5459. (b) Yoneda, E.; Kaneko, T. et al. Org. Lett. 2000, 2, 441. 43. Kang, S. K.; Kim, K. J. et al Org. Lett. 2001, 3, 2851. 44. Bates, R. W.; Sridhar, S. J. Org. Chem. 2008, 73, 8104. 45. Tsubuki, M.; Takahashi, K.; Honda, T. J. Org. Chem. 2009, 74, 1422. 46. (a) Bates, R. W.; Sridhar, S. Synlett 2009, 1979; see also (b) Wang, Y.; Zhu, L. et al. Angew. Chem., Int. Ed. 2011, 50, 2787. 47. Bates, R. W.; Sridhar, S. J. Org. Chem., 2011, 76, 5026. 48. Heck, R. F.; Breslow, D. S. J. Am. Chem. Soc. 1961, 83, 4023. 49. (a) Clarke, M. L. Curr. Org. Chem. 2005, 9, 701; (b) Breit, B.; Seiche, W. Synthesis 2001, 1. 50. Keck, G. E.; McLaws, M. D. Tetrahedron Lett. 2005, 46, 4911. 51. Wuts, P. G. M.; Bigelow, S. S. J. Org. Chem. 1988, 53, 5023. For a related hydroformylation to give a lactol in a synthesis of leucoscandrolide, see Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894. 52. Leighton, J. L.; O’Neil, D. N. J. Am. Chem. Soc. 1997, 119, 11118. 53. Billig, E.; Abatjoglu, A. G.; Bryant, D. R. U. S. Patent, 1988, 4769 498. 54. Kwok, T. J.; Wink, D. J. Organometallics, 1993, 12, 1954. 55. Gu, J.; Storz, T. et al. Org. Process Res. Dev. 2011, 15, 942. 56. Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915. 57. Kranemann, C. L.; Kitsos-Rzychon, B. E.; Eilbracht, P. Tetrahedron 1999, 55, 4721. 58. Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60, 7078; for further examples, see Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999. 59. Bates, R. W.; Kasinathan, S.; Straub, B. F. J. Org. Chem. 2011, 76, 6844. 60. Chiou, W.-H.; Lin, G.-H. et al. Org. Lett. 2009, 11, 2659. 61. Spangenberg, T.; Breit, B.; Mann, A. Org. Lett. 2009, 11, 261. 62. Airiau, E.; Spangenberg, T. et al. Org. Lett. 2010, 12, 528. 63. Ojima, I.; Korda, A.; Shay, W. R. J. Org. Chem. 1991, 56, 2024. 64. Zhang, Z.; Ojima, I. J. Organomet. Chem. 1983, 454, 281. 65. (a) Jackson, W. R.; Perlmutter, P, Tasdelen, E. E. J. Chem. Soc., Chem. Commun. 1990, 763; (b) Jackson, W. R.; Moffat, M. R. et al. Aust. J. Chem. 1992, 45, 823. 66. Briet, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2835. 67. Krauss, I. J.; Wang, C. C.-Y.; Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 11514. 68. Sun, X.; Frimpong, K.; Tan, K. L. J. Am. Chem. Soc. 2010, 132, 11841. 69. Worthy, A. D.; Gagnon, M. M. et al. Org. Lett. 2009, 11, 2764. 70. Babin, J. E.; Whiteker, G. T. (Union Carbide) WO 93/03839. 71. (a) Klosin, J.; Landis, C. R. Acc. Chem. Res. 2007, 40, 1251; (b) Di´eguez, M.; P´amies, O.; Caver, C. Tetrahedon Asym. 2004, 15, 2113; (c) Wang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 19080. 72. Stille, J. K.; Su, H. et al. Organometallics 1991, 10, 1183. 73. Collman, J. P. Acc. Chem. Res. 1975, 342. 74. Gladysz, J. A.; Tam, W. J. Org. Chem. 1978, 43, 2279. 75. Yamashita, M.; Tashika, H.; Uchida, M. Bull. Chem. Soc. Jpn. 1992, 65, 1257. 76. McMurray, J. E.; Andrus, A. et al. J. Am. Chem. Soc. 1979, 101, 1330. 77. McMurray, J. E.; Andrus, A. Tetrahedron Lett. 1980, 21, 4687. 78. (a) Hieber, W.; Sedlmeier, J.; Abeck, W. Chem. Ber. 1953, 86, 700; (b) Egdell, W. F.; Lyford IV, J. Inorg. Chem. 1970, 9, 1932. 79. Heck, R. F.; Breslow, D. S. J. Am. Chem. Soc. 1963, 85, 2779. 80. Heck, R. F. J. Am. Chem. Soc. 1963, 85, 3383. 81. (a) Hegedus, L. S.; Inoue, Y.; J. Am. Chem. Soc. 1982, 104, 4917; (b) Hegedus, L. S. Perry, R. J. J. Org. Chem. 1984, 49, 2570.

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82. (a) Bates, R.W.; Rama-Devi, T.; Ko, H.-H. Tetrahedron, 1995, 51, 12939; (b) Bates, R.W.; Satchareon, V. Synlett, 2001, 532. 83. Bates, R.W.; Kongsaeree, P. Synlett, 1999, 1307. 84. Hegedus, L. S.; Perry, R. J. J. Org. Chem. 1985, 50, 4955. 85. Aumann, R.; Ring, H. et al. Chem. Ber. 1979, 112, 3644. 86. (a) Ley, S. V. Phil. Trans. R. Soc. Lond. A 1988, 326, 633; (b) Ley, S. V.; Cox, L. R.; Meek, G. Chem. Rev. 1996, 96, 423. 87. Bates, R. W.; Diez-Martin, D. et al. Tetrahedron 1990, 46, 4063. 88. Caruso, M.; Knight, J. G.; Ley, S. V. Synlett 1990, 224. 89. Ley, S. V.; Armstrong, A. et al. J. Chem. Soc., Perkin Trans 1 1991, 667. 90. see also: (a) Diez-Martin, D.; Kotecha, N. R. et al. Synlett 1992, 392; (b) Diez-Martin, D.; Grice, P. et al. Synlett 1990, 326; (c) Kotecha, N. R.; Ley, S. V. Synlett 1992, 395. 91. (a) Bates, R. W.; Fernandez-Moro, R.; Ley, S. V. Tetrahedron Lett. 1991, 32, 2651; (b) Bates, R. W.; Fernandez-Moro, R.; Ley, S. V. Tetrahedron 1991, 47, 9929. 92. Hodgson, S. T.; Hollinshead, D. M. et al. J. Chem. Soc., Perkin Trans 1 1985, 2375. 93. Knight, J. G.; Ley, S. V. Tetrahedron Lett. 1991, 32, 7119. 94. Cox, L. R.; Ley, S. V. Chem. Soc. Rev. 1998, 27, 301 95. Ley, S. V.; Middleton, B. J. Chem. Soc., Chem. Commun. 1998, 1995. 96. Bancuni, J.; Giuleri, F. J. Organomet. Chem. 1979, 165, C28. 97. Shiu, L. H.; Wang, S.-L. et al. J. Chem. Soc., Chem. Commun. 1997, 2055. 98. Compare to Faller, J.; Linebarrier, D. J. J. Am. Chem. Soc. 1989, 111, 1937. 99. Narkunan, K.; Liu, R.-S. J. Chem. Soc., Chem. Commun. 1998, 1521; see also Shieh, S.-J.; Liu, R.-S. Tetrahedron Lett. 1997, 38, 5209. 100. Shieh, S.-J.; Tang, T.-C. et al. J. Org. Chem. 1996, 61, 3245. 101. Walther, D.; Dinjus, E. et al. J. Organomet. Chem. 1985, 286, 103. 102. Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2002, 124, 10008. 103. Takimoto, M.; Nakamura, Y. et al. J. Am. Chem. Soc. 2004, 126, 5956. 104. Takimoto, M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3, 3345. 105. Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2003, 5, 2323. 106. Tsuji, J.; Ohno, K. Synthesis 1969, 157. 107. Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99. 108. Geoffroy, G. A.; Denton, D. A. et al. Inorg. Chem. 1976, 15, 2382. 109. O’Connor, J. M.; Ma, J. J. Org. Chem. 1992, 57, 5075. 110. Kreis, M.; Palmelund, A. et al. Adv. Synth. Catal. 2006, 348, 2148. 111. McCague, R.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Perkin Trans. I 1984, 165. 112. Ward, D. J.; Szarket, W. A.; Jones, J. K. N. Chem. Ind. 1975, 97, 2563. 113. (a) Trost, B. M.; Chen, F. Tetrahedron Lett. 1971, 28, 2603; (b) Dauben, W. G.; Rivers, G. T. et al. J. Org. Chem. 1976, 41, 887; (c) Grunewald, G. L.; Davis, D. P. J. Org. Chem. 1978, 43, 3074. 114. (a) Uhlig, V. E.; Fehske, G. et al. Anorg. Allg. Chem. 1980, 465; (b) Sano, K.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. Japan 1984, 57, 2741. 115. Sch¨onecker, B.; Walther, D. et al. Tetrahedron 1990, 30, 1257. 116. O’Brien, E. M.; Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2003, 125, 10498.

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5 Alkene and Alkyne Insertion Reactions 5.1 The Heck Reaction The Heck reaction (or Mizoroki–Heck reaction) is an alkene transformation involving the insertion of an alkene into a carbon–palladium single bond (Scheme 5.1).1 The alkene employed is often electron poor, but this is not a requirement. In synthetic planning, it is an alternative for the Wittig reaction in some cases, but uses a starting material with one carbon fewer. While the original Heck reaction appears to be a simple, but useful, transformation, it has become a powerful synthetic reaction. The mechanism involves oxidative addition of the halide 5.1 to the palladium(0) species to generate an organopalladium(II) intermediate 5.4. Alkene coordination and insertion generates a new organopalladium(II) intermediate 5.7 which undergoes ␤-hydride elimination. The product 5.3 dissociates from the palladium, leaving a palladium(II) hydrohalide 5.10 that reacts with the base to regenerate the palladium(0) catalytic species. Ligand association and dissociation occurs at a number of points in the mechanism. Consequently, the amount of ligand, which is usually a phosphine, is a key variable. Excess ligand inhibits, and even shuts down, the reaction as the operation of Le Chatelier’s principle prevents the formation of any sufﬁcient concentration of an active, coordinatively unsaturated, palladium species. Conversely, if too little ligand is present, the palladium may become totally uncoordinated. In this case, the palladium usually deposits itself in metallic form on the inner surface of the ﬂask as a palladium mirror and is catalytically inactive. A ﬁxed rule for the ligand:catalyst ratio cannot be given and this must be determined empirically. In general, when the substrate is an iodide, less ligand is required as the liberated iodide can act as a ligand. The solvent may also act as a ligand. Solvents such as toluene are very poor ligands, while acetonitrile is a good ligand. The amount of added phosphine ligand required will, therefore, differ according to solvent properties. 5.1.1

The Organic Halide

Iodobenzene is the example given above. For the organic part, aryl, including heteroaryl,2 and vinyl groups can be used (Schemes 5.2–5.4). The reaction between 3-bromopyridine and the N-phthaloyl substituted alkene allowed a short synthesis of nornicotine (Scheme 5.5). Alkynyl halides have been infrequently employed.3 If an alkyl group is used, oxidative addition is slow and ␤-hydride elimination will occur, as in coupling reactions. Steric hindrance around the halide will slow the reaction down. The presence of a good donor group, such as a carboxylic acid, in the ortho position of an aryl halide will also inhibit the Heck reaction, as chelation of the palladium will block coordination of the alkene substrate.4 Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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I

+

CO2Me

5.1

Pd catalysis base CO2Me

5.2

5.3 (Ph3P)4Pd Et3NH I

Et3N L I 5.10 Pd L H

PhI

±2L L2Pd

reductive elimination

oxidative addition

Ph 5.4

L2Pd I

L

dissociation L

coordination Ph

5.9 Ph

CO2Me

Pd H

L

I

LPd

5.5 I

coordination dissociation L I Pd H L I Ph Pd CO2Me β-hydride Ph insertion η2 elimination CO2Me PdLI η2 5.8 H 5.6 Ph CO2Me 1 η 5.7

5.3

CO2Me 5.2

Scheme 5.1 CO2Me Pd(OAc)2, P(o-tol)3, Et3N

Br

CO2H 5.11

CO2Me

CO2H 5.12

Scheme 5.2 Br

CO2Me Pd(OAc)2, n-Bu3N

5.13

CO2Me 5.14

Scheme 5.3

S 5.15

Br

Pd(OAc) 2, P(o-tol)3, Et3N

+

S N

N 5.16

5.17

Scheme 5.4

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Alkene and Alkyne Insertion Reactions

Br

1. H 2NNH2 NPhth 2. Hg(OAc) 2, 3. NaBH 4

NPhth Pd(OAc)2, P(o-tol)3, Et3N

N

N H N

N 5.19

5.18

155

5.20

Scheme 5.5 OH

OAc

1. NaH Br 2. AcCl, Et 3N

I

I

5.21

5.22 OH

1.

CO2Me Pd(OAc)2, (o-tol)3P, Et 3N 2. MeOH, K 2CO3

5.23 MeO2C

Scheme 5.6

The electronic nature of the organic halide is important. For reactions with electron-poor alkenes, best yields and rates are obtained with electron-poor arenes. Phenolic halides, for instance, can be so electron rich, that they give no products. They must ﬁrst be converted into a less electron rich derivative, such as an acetate, as in a short synthesis of Plicatin B 5.23 from p-iodophenol 5.21 (Scheme 5.6).5 5.1.2

Leaving Groups

The reactivity of the organic halide varies with the identity of the halide. The order is I ⬎ Br ⬎⬎ Cl. The reactivity is sufﬁciently different that, as with coupling reactions (Section 2.1.4), a Heck reaction may be selectively carried out at one centre, with nothing happening at the second less-reactive centre (Scheme 5.7).6 A further example that exploits the differential reactivity may be found in Schemes 6.17 and 6.18. A variety of other leaving groups have been employed, especially triﬂates. There is an unusual mechanistic consequence in their reactions.7 In the basic Heck mechanism given above (Scheme 5.1), ligand dissociation is required prior to alkene coordination, in order to generate a palladium complex 5.5 with a vacant site for alkene coordination. While this is most commonly the dissociation of a phosphine ligand, if an organic triﬂate is the substrate, then the triﬂate anion may dissociate (Scheme 5.8). A vacant site is then opened up

CH3

CO2Me

Br

Pd(OAc)2, base, CH3CN

CH3

Ph

Br Br

Br

CH3 Ph

Pd(OAc) 2, base, CH3CN

Ph

I 5.24

CO2Me

5 . 25

Scheme 5.7

CO2Me

5. 2 6

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Organic Synthesis Using Transition Metals L

R

L

L

± OTf

Pd

R

L

Cl

Pd L

OTf

L

±L

R Pd

Cl

L

5.28 cationic 3coordinate species

5.27

R Pd

Cl 5.30 neutral 3coordinate species

5.29

Scheme 5.8 CO2Et OTf (Ph3P)2PdCl2, LiCl, Et3N

N

CO2Et N

5.31

5.32

Scheme 5.9 SO3

SO3

NaNO2, AcOH

NH3

SO3

CF3 Pd2(dba)3

N2

CF3

5.34

5.33

5.35 N N O O O S N N OMe N H H

SO3

H2, charcoal

5.36

CF3

5.37

CF3

Scheme 5.10

on palladium, without phosphine loss. The palladium 5.28 is now cationic and, therefore, reacts faster with electron rich, rather than electron-poor alkenes. For Heck reactions of electron-poor alkenes with triﬂate substrates, the reaction rate can be increased by the addition of lithium chloride (Scheme 5.9).8 The chloride ion replaces the triﬂate on palladium, thus returning the system to the “normal” situation, with subsequent phosphine loss to generate the vacant site. Diazonium salts have also been used.9 While the disadvantage of using these salts is their low stability, their advantage is their high reactivity. In some cases, they may also give better selectivity.10 A Heck reaction involving a diazonium salt 5.34 was used for the synthesis of a herbicide, prosulfuron 5.37 (Scheme 5.10).11 If a Heck reaction of an aryl halide had been chosen, the readily available sulfanilic acid 5.33 would be the logical starting material, but would have required an additional Sandmeyer step. An interesting feature of this synthesis is that, simply by addition of charcoal after the Heck reaction, the palladium could also serve to reduce the alkene 5.35 formed. Diazonium salts were also used in the synthesis of all stereoisomers of centrolobine (Scheme 5.11).12 After formation of a dihydropyran by RCM-alkene isomerization (see Section 8.3.10), a Heck reaction with the p-methoxyphenyl diazonium salt 5.40 occurred trans to the side chain, with the expected alkene migration (Section 5.1.6). Hydrogenation of the alkene 5.41, followed by deprotection using ﬂuoride gave the unnatural diastereoisomer 5.43, while deprotection under acidic conditions gave the natural product 5.42.

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Alkene and Alkyne Insertion Reactions TBSO

157

TBSO O

O

Grubbs I, NaOH, i-PrOH, Δ 5.39

5.38 N2

OMe 5.40

TBSO

OMe O

Pd(OAc)2, NaOAc 5.41

HCl, MeOH HO

OMe

TBAF HO

OMe

O

O

5.42

5.43

Scheme 5.11

O Cl

CO2Et Pd(OAc)2, n-Bu3N

CO2Et

100 °C 5.45

5.44 O PdLnCl

via

-CO

PdLnCl 5.47

5.46

Scheme 5.12

O Cl

Cl Cl Pd(OAc) ,BnNMe2 2 50 °C

Cl 5.48

Cl + Cl

Cl

Cl 5 . 49

Cl

5 . 50

Scheme 5.13

Unlike aryl chlorides, acyl chlorides are quite reactive, although not often used.13 Oxidative addition of palladium(0) to the acid chloride 5.44 generates an acyl palladium(II) complex 5.46 (Scheme 5.12). This may undergo decarbonylation or not prior to alkene insertion depending on the reaction conditions, and the substrate structure (Schemes 5.13 and 5.14).13,14 Acid chlorides are more reactive than aryl bromides and selective coupling at the two positions of p-bromobenzoyl chloride 5.53 with different alkenes is possible (Scheme 5.15).15

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Organic Synthesis Using Transition Metals O

O On-Bu Pd(OAc)2, Et3N

Cl O

On-Bu O 5.52

50 °C 5.51

Scheme 5.14 O CO2Et Cl Pd(OAc)2, R3N Br

- CO

5.53

CO2Et Br

5.54

CN (Ar3P)2Pd(OAc)2, R 3N

CO2Et NC

5.55

Scheme 5.15 X R Pd L L 5.4

+

Ag

R Pd L L 5.56

+

AgX

Scheme 5.16

5.1.3

Catalysts, Ligands and Reagents

Heck reactions are often carried out using palladium(0) complexes. Tetrakis(triphenylphosphine)palladium(0) is frequently used, but does not allow the chemist to vary either the identity of the ligand, or the ligand:palladium ratio. A more convenient mixture is to use the air-stable palladium(0) dibenzylideneacetone complex with the added ligands of choice. It is, however, not necessary to use a palladium(0) pre-catalyst. Palladium(II) salts, especially the more soluble palladium(II) acetate, are often used, with added phosphines. The palladium(II) salts are reduced to palladium(0) in situ. For organic halide substrates, monodentate phosphines are usually preferred because bidentate phosphines do not allow the partial dissociation step to generate the active site on palladium. However, in the presence of a silver salt, bidentate phosphines can be used, as the ligand lost in step 2 of the mechanism will be the halide (Scheme 5.16). Triﬂates may dissociate without such assistance (see Scheme 5.9), as this anion is a poor ligand for palladium, also allowing the use of bidentate phosphines. The most commonly used ligand is PPh3 . The ratio of ligand to palladium is of great importance. Too much ligand will inhibit the reaction (due to Le Chatelier’s principle). If too little ligand is present, the catalyst may decompose to give a palladium mirror. As iodide (if an aryl iodide is employed) and coordinating solvents such as acetonitrile, are used, then the amount of phosphine can be reduced even to zero. Several catalysts have been developed that allow efﬁcient Heck reactions of reluctant substrates under reasonable conditions and with high turnover numbers. One such catalyst is Herrmann’s catalyst 5.58,16 a palladacycle derived from (o-tol)3 P 5.57 (Schemes 5.17 and 5.18). Palladium complexes with t-Bu3 P also provide highly active catalysts (Scheme 5.19).17

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159

Me O P + Pd(OAc)2

(o-tol)2P

3

Pd O

O P(o-tol)2 Pd O

Me 5.58 Me

5.57

Scheme 5.17 Cl

CO2n-Bu

CO2n-Bu 5.58, NaOAc, Δ

OHC

OHC 5.59

5.60

Scheme 5.18 Cl +

CO2Me

CO2Me

Pd2dba3, t-Bu3P, Cy2NMe 5.62

5.61

Scheme 5.19

For the base, triethylamine or inorganic carbonates are most commonly used. Other bases, such as sodium acetate and pempidine (1,2,2,6,6-pentamethylpiperidine) have also been used. When silver salts are added, the counter ion is sometimes used as a base, such as in silver carbonate and silver phosphate. An interesting set of conditions are the Jeffrey conditions, using a polar solvent and a quaternary ammonium salt (Table 5.1).18 Detailed investigations have shown that the correct choice of ammonium salt and addition of a small amount of water can be critical. Under the right conditions, many Heck reactions can run at or near room temperature. The main effect is due to the cation of the phase-transfer catalyst, not the anion, and the effect was most marked when inorganic bases were used. The phase-transfer catalyst may facilitate the ﬁnal step of the Heck mechanism. 5.1.4

The Alkene: Scope and Reactivity

The reaction is greatly affected by steric hindrance. The reactivity of the alkene decreases with its degree of substitution. Ethylene is a good partner in Heck reactions,19 but infrequently used. The Heck reaction of a pyridyl halide 5.63 with ethylene was employed on a 5.4 kg scale for the preparation of a pharmaceutical intermediate 5.64 (Scheme 5.20).20 Table 5.1 Jeffrey Conditions for the Heck Reaction Additive

PhI +

CO2Me

Pd(OAc)2, PPh3, K2CO3, CH3CN

Ph

CO2Me

Yield (%)

none

15

n-Bu4 NCl.xH2O

97

n-Bu4 NCl anhydrous

15

n-Bu4 NCl + 10% H2 O

96

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Organic Synthesis Using Transition Metals (50 psi) Pd(OAc)2, Et3N, P(o-tol)3, BINAP

Br AcHN

N

AcHN

N 5.64

5.63

Scheme 5.20 PhI, Et3N, Pd(OAc)2, PPh3

CO2Me Ph 5.66

5.65

5.67

Ph

β-hydride elimination

insertion

ring opening PdLnI

MeO2C

ILnPd Ph

Ph 5.68

5.69

Scheme 5.21

Monosubstituted alkenes are also good partners. Disubstituted alkenes are distinctly less reactive and trisubstituted alkenes are usually limited to intramolecular reactions. A very special case of a tetrasubstituted alkene is cyclopropylidene cyclopropane 5.65 (Scheme 5.21).21 Due to the special chemistry associated with strained rings, ring opening and ␤-hydride elimination follows insertion to give a diene 5.66, which may be trapped in a Diels–Alder reaction.

5.1.5

The Alkene: Regio- and Stereoselectivity

In principle, in the insertion step, two products are possible. With electron-poor alkenes, the palladium almost invariably becomes attached to the ␣-carbon while the new C–C bond is formed at the ␤-carbon. With electron-rich alkenes, such as enol ethers, either ␣- or ␤-arylation may be observed, to yield either a 1,1-disubstituted alkene or a 1,2-disubstituted alkene (Scheme 5.22). The ligands can play an important role in determining this selectivity.22 Use of bidentate ligands strongly favours the ␣-product 5.71 that, on hydrolysis, yields a ketone 5.73.23 This reaction is an alternative to a carbonylative coupling reaction (Section 4.1). The leaving group also has an effect: when the bromide was used in place of the triﬂate 5.70, a mixture of the ␣- and ␤-adducts was obtained. However, use of the bromide in the presence of a silver salt, resulted, again, in exclusive ␣-addition. Monosubstituted alkenes such as acrylates usually give the trans isomer. In a synthesis of an angiogenesis inhibitor 5.75, use of the Heck reaction to install a trans alkene proved to be higher yielding than routes employing Suzuki and Sonogashira reactions (Scheme 5.23).24 In addition, the Heck process generated signiﬁcantly less waste. Selectivity for formation of the desired 1,2-disubstituted alkene, rather than the 1,1-disubstituted alkene was dependent on the N-protection, with the bulky bis-Boc protection giving the optimum result. This chemistry was employed to make 91.6 kg of alkene 5.75 as the HCl salt after double deprotection.

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161

On-Bu On-Bu

OTf +

On-Bu

Pd(OAc)2, L, Et3N, DMF 5.71

5.70

H3

5.72 O+

L = PPh3 63:37 dppe >99:1

O

5.73

Scheme 5.22

N

N

O HN I

N N

O

1. (Boc)2N Pd2dba3, Et3N 2. HCl

HN N

H 3N Cl 5.74

N

5.75

Scheme 5.23

With 1,2-disubstituted alkenes, such as methyl crotonate 5.76, the stereochemistry of the product can be predicted by close examination of the ␤-hydride elimination step (Scheme 5.24). Inversion of alkene stereochemistry is the result. This is because both insertion and ␤-hydride elimination are syn processes. Insertion delivers the ␩1 -intermediate 5.78 in a conformation in which ␤-hydride elimination cannot occur because the palladium and the ␤-H are not syn. A rotation is required to bring a hydrogen atom syn to palladium; the rotation causes the methyl group and the ester group to become cis in the product 5.80. This effect has been used in a clever synthesis of butenolides 5.83 (Scheme 5.25).25 Heck reaction of the trans-4-alkoxycrotonate 5.81 resulted in the expected inversion of alkene stereochemistry, allowing lactonization on deprotection. The alkene inversion, in an intramolecular Heck reaction, is also apparent in an approach to vitamin D compounds (Scheme 5.26).26 5.1.6

Cyclic Alkenes

This is an interesting group of alkenes to use as the ring prevents the rotation step that follows insertion (Scheme 5.27). ␤-Hydride elimination then involves a hydrogen atom that was originally allylic rather than vinylic, resulting in net migration of the alkene. This reaction has been used in a synthesis of indole derivatives 5.93, using the Heck reaction between a protected o-iodoaniline 5.90 with a dihydrofuran 5.91 (Scheme 5.28).

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Organic Synthesis Using Transition Metals

Me

X R Pd L

X R Pd L coordination

CO2Me

H Me

5.76

CO2Me H

insertion (syn)

H

and dissociation

Me R

CO Me H 2 5.78

β-hydride elimination R

PdLX

PdLX

H Me

5.77

rotation (120°)

R

CO2Me H 5.79

CO2Me Me 5.80

Scheme 5.24

Pd(OAc)2, Bu4NCl, NaHCO3 THPO

I

CO2Me

CO2Me

5.81

5.82

THPO

MeOH, H+ 5.83

O

O

Scheme 5.25 EtO2C

Br

Pd(OAc)2, PPh3, K2CO3, CH3CN

EtO2C TBSO

OTBS

TBSO

5.84

OTBS 5.85

Scheme 5.26 L Ar PdLX

5.86

X

Pd Ar

insertion

L X Pd β-hydride H H Ar H elimination

5.87

5.88

Ar

5.89

Scheme 5.27

5.1.7

Isomerization

The use of cyclic alkenes is not the only instance in which the alkene does not reappear in its original location. Double-bond isomerization can occur in other instances when alternative ␤-hydride-elimination pathways are available. A particularly useful one is when allyl alcohols are employed as the substrate (Scheme 5.29). After insertion, ␤-Hydride elimination gives an enol 5.97, which will tautomerize to a ketone 5.95.27

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Alkene and Alkyne Insertion Reactions I +

MeO

NHCO2Et 5.90

O

OMe

163

Pd(OAc)2, i-Pr2NEt BnNEt3+ Cl-

5.91 OMe CO2Me

O

CF3CO2H

OMe NHCO2Et

N CO2Et

5.92

5.93

Scheme 5.28 PhI, Et3N, Pd(OAc)2, CH3CN

OH

O

Ph

5.94

5.95 tautomerism

insertion

Ph

PdLnI OH

β-hydride elimination

Ph

5.96

OH 5.97

Scheme 5.29 O Pd(OAc) 2, OH P(o-tol)3, n-Bu3N

Br + N 5.98

OH

OH N

5. 99

5.100

Scheme 5.30

This chemistry was employed on a 200 g scale to prepare a functionalized pyridyl ketone 5.100, an intermediate in a drug candidate synthesis (Scheme 5.30).28 The choice of base proved to be the key to minimizing formation of the regular Heck product. 5.1.8

The Intramolecular Heck Reaction

The intramolecular Heck reaction is a powerful method for ring formation.29 Depending on the substrate structure, the question of exo- or endo-ring formation may need to be addressed (Scheme 5.31). In principle, intramolecular alkene insertion can yield either the exo-product 5.101 or the endo-product 5.103. Generally, the exo-product 5.101 is obtained. Two Heck reactions, the ﬁrst intramolecular in an exo- sense, the second intermolecular, were used to prepare an intermediate 5.105 for a prostaglandin receptor antagonist on a 2.17 kg scale (Scheme 5.32).30 An intramolecular Heck reaction of a vinyl triﬂate 5.106 with an exo-ring closure was employed to form an eight-membered ring in a synthesis of taxol (Scheme 5.33).31

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Organic Synthesis Using Transition Metals PdLnX PdLnX

exo

5.101

PdLnX

endo

5.102

5.103

Scheme 5.31 F

1. Pd(OAc) 2, P(o -tol) 3, Et3N F 2. Pd(OAc) 2, P(o-tol)3, CO2H

Br

Br

N H

N H 5.105

5.104

CO2H

Scheme 5.32 TfO

OTBS

OTBS (Ph3P)4Pd, K2CO3

O O

O

H

O OBn

H O OBn

O

5.106

O

O

5.107

Scheme 5.33

An intramolecular Heck reaction was employed in a synthesis of morphine 5.113 (Scheme 5.34).32 An azadecalin 5.108 was treated with a palladium catalyst to generate a fourth ring 5.109 by formation of a quaternary centre through a Heck reaction in the exo-mode. After debenzylation under Lewis-acidic conditions, epoxidation of the alkene 5.109 and in situ ring opening established the ﬁnal ring. Oxidation of the alcohol 5.111 and a one-pot removal of the nitrogen-protecting group and reductive amination gave dihydrocodeinone 5.112, which could be converted to morphine 5.113 through a known sequence.33 5.1.9

The Asymmetric Heck Reaction

Although the Heck reaction mainly involves the formation of bonds between sp2 -hybridized carbon atoms, there are asymmetric versions.34 One approach is to capture the chirality of the insertion intermediate by ensuring the ␤-hydride elimination either occurs away from the site of the original alkene (Scheme 5.35), or is pre-empted by a different step such as another insertion in a tandem process. Another approach is to provide a symmetrical substrate with two enantiotopic alkenes (Scheme 5.36), an approach also used in metathesis chemistry (Section 8.3.6). In all of these reactions, the source of chirality is from the employment of chiral ligands for the palladium catalyst, often chelating bisphosphines. The asymmetric Heck reaction is often carried out in the presence of silver salts, implying the formation of a cationic palladium intermediate (Section 5.1.3); triﬂate substrates would be expected to also proceed in this way. There are also examples of Heck reactions carried out without silver, implying that a neutral palladium

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165

OMe OMe OBn

(Ph3P)2Pd(O2CCF3), pempidine, Δ

OBn

I DBS

N

DBS

5.108

OH N

O

N 5.109 OMe

OMe

DBS

1. BF3, EtSH 2. ArCO3H, H+

1. TPAP, NMO 2. H2, H2CO, Pd(OH)2

O OH

N

DBS

5.110

5.111 OMe

OH

O O

OOH

MeN

DBS =

NO2

MeN Ar =

5.113

5.112

O 2N

Scheme 5.34 OTf Pd(OAc)2, Et3N, (S,S)-DIOP

Pd(OAc)2, Et3N, (R,R)-DIOP O

5.114

O

O

5.115

5.116

Scheme 5.35 MeO2C

CO2Me

Pd(OAc)2, Ag2CO3, (S)-BINAP

Pd(OAc)2, Ag2CO3, (R)-BINAP

CO2Me

I H 5.117

H 5. 118

5.119

Scheme 5.36

intermediate is involved. Both the e.e. and the sense of stereochemical induction can be different depending on the conditions (Scheme 5.37).35 The enantiotopic alkene approach was used in a synthesis of vernolepin 5.128, with ␤-hydride elimination proceeding away from the original alkene site, leading to a ketone 5.124 after tautomerization (Scheme 5.38).36 After a series of functional group interconversions and protecting group manipulation steps, a known37 intermediate 5.127 for vernolepin could be synthesized. When taken through to the end, this work also served to determine the absolute stereochemistry of this natural product.

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Organic Synthesis Using Transition Metals Me N

O

Pd2(dba)3, (R)-BINAP, Ag3PO4

O O

Me

5.120 71% e.e.

Pd2(dba)3, (R)-BINAP, pempidine

N

O I

O

Me N

O

O O O

5.121

5.122 66% e.e.e

Scheme 5.37 1. HO(CH 2)2OH, H+ OPiv 2. LiAlH 4 3. PDC 4. NaClO 2, Na2HPO4 5. CH 2N2

OPiv

OTf

HO

Pd2(dba)3, (R)-BINAP, K 2CO3 O

H

5.123 CO2Me

CO2Me 1. CrO 3, DMP 2. NaBH 4, CeCl3

O O

5.124 1. AcOH, DEAD, PPh 3 2. LiOH 3. Ac 2O, NaOAc

OH

O O

H

H

5.125

5.126 O O

OH

O O

O

H 5.127

H 5.128

O O

Scheme 5.38 OAc OTf

H

H Me

Me 5.129

OAc

Pd(OAc)2, (S)-BINAP, Bu4NOAc

5. 13 0

Pd(BINAP)

Me 5 .1 3 1

Scheme 5.39

A variant on this approach is to incorporate the enantiotopic alkenes into a ﬁve-membered ring such as a cyclopentadiene. ␤-Hydride elimination is then obviated, as a ␩3 -allyl complex 5.130 is formed after insertion, which may be intercepted by an added nucleophile, such as acetate (Scheme 5.39). Other nucleophiles, including carbon nucleophiles can also be used to intercept the ␩3 -allyl intermediate (see Section 9.2.9). This chemistry was used in a synthesis of capnellene 5.137 (Scheme 5.40).38 The ␩3 -allyl intermediate 5.130 was intercepted with a functionalized malonate nucleophile 5.132. The malonate was used to construct the third ﬁve-membered ring of the natural product: while one ester group was removed by Krapcho

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Alkene and Alkyne Insertion Reactions EtO2C EtO2C H

OTf + Me

[Pd(allyl)Cl]2, (S)-BINAP, NaBr

EtO2C EtO2C

5.129

OTBDPS

OTBDPS 5.132

5.133

Me

O2CPh

O2CPh OTBDPS

1. LiCl, H 2O, DMSO, Δ 2. DIBAL 3. PhCOCl, DMAP, py

167

H

I

1. TBAF 2. MsCl, Et 3N 3. NaI

H

Me 5.134

Me 5.135

OH 1. n-Bu3SnH, AIBN 2. NaOH 3. Et 2Zn, CH2I2

1. H 2, PtO2 2. o-(O2N)C6H4SeCN, Bu3P 3. H 2O2, K2CO3

HH

Me

H

HH

Me

5.136

H

5.137

Scheme 5.40

decarboxylation, the other was taken through a number of steps to become an exocyclic methylene group. The three-carbon side chain on the malonate 5.135 was used to form the ﬁve-membered ring by a 5exo-trig free-radical ring closure. The gem-dimethyl structure was formed by cyclopropanation and hydrogenation of the resulting cyclopropane. Other syntheses of capnellene may be found in Scheme 4.13 and Schemes 8.58–8.60. The single-alkene approach was employed in a synthesis of physostigmine 5.144 (Scheme 5.41), a powerful acetylcholine esterase inhibitor from the African calabar bean.39 The closely related alkaloid, physovenine MeO

I

OTIPS +

NHMe

MeO

HO2C 5.139

5.138

I

BOP, Et 3N

1. Pd 2(dba)3.CHCl3, (S)-BINAP, pempidine MeO 2. aq. HCl

5.140 CHO O

5.141

N Me

OTIPS

N Me

1. MeNH 2 MeO 2. LiAlH4

NMe N H Me 5.142

1. LiAlH4 2. BBr 3 2. NaH; MeNCO MeNHCO2

O

O

1. BBr 3 2. Na; MeNCO MeNHCO2

NMe

N H Me 5.143

Scheme 5.41

N H Me 5.144

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Organic Synthesis Using Transition Metals

5.143, could also be prepared by a modiﬁcation of the post-Heck sequence. While the right-hand ring of the molecule was constructed by a condensation reaction, the central ring was formed by an asymmetric Heck reaction of iodide 5.140, forming a challenging quaternary centre in the process. In this Heck reaction, it was found that the Z-isomer of the alkene 5.140 underwent the Heck reaction with good e.e. under either neutral conditions or with an added silver reagent. Both sets of conditions gave the same sense of enantioselectivity. The E-isomer underwent Heck cyclization with lower e.e., and with the two sets of conditions giving opposite stereochemical outcomes. The same strategy was used for the synthesis of the more complex, polycyclic alkaloids quadrigemine C and psycholeine (Scheme 5.42).40 A double Stille coupling between diiodide 5.145 and stannane 5.146 was

I

H H Me N N

TfO

Bn N

Snn-Bu3 Pd2(dba)3.CHCl3, (2-Fu)3P, CuI O

I

NMeTs

5.146

N N H H Me 5.145

TfO

TfO

Bn N

NMeTs

O N Bn

H H Me N N

O NMeTs H H Me N N

Pd(OAc)2, (R)-Tol-BINAP pempidine

1. H 2, Pd(OH)2 2. Na, NH 3(l)

N N H H Me

Bn N O

N N H H Me NMeTs O 5.148

N Bn

NMeTs

5.147 Me H H N N

Me N H NH MeN

H H Me N N

N

H 3O +

N N H H Me N N H H Me

H N

H HN H N Me

5.149

Scheme 5.42

NMe 5.150

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169

followed by a double asymmetric Heck reaction to give the desired polycycle 5.148, accompanied by a small amount of its meso isomer. Deprotection and cyclization gave quadrigemine 5.149, which could be converted to psycholeine 5.150 by treatment with acid. 5.1.10

Tandem Reactions

In some cases, after insertion, no ␤-hydrogen is available and the ␩1 -intermediate is stable. This situation arises with alkynes, which undergo insertion to yield vinyl organometallic species. The situation also arises with certain trisubstituted alkenes when insertion gives rise to a ␤-blocked, neopentyl-like intermediate. With constrained hydrocarbons, such as norbornene, where Bredt’s rule may operate, stable ␩1 -intermediates can also form (see Figure 1.19).41 In these cases, the reaction will therefore stop unless a reagent is present to intercept the intermediate. This allows the chemist the chance to design tandem processes. 5.1.10.1

Alkynes

In iodide 5.151, intramolecular insertion of the alkyne is favoured over intramolecular alkene insertion (Scheme 5.43).42 The alkyne insertion generates a stable ␩1 -intermediate 5.152, which undergoes a second insertion, now intermolecular, and the normal Heck pathway then leads to a stereodeﬁned diene 5.153. In contrast, when the related iodide 5.154 was subjected to palladium-catalysed crosscoupling, either the direct coupling product 5.155 or the tandem alkyne insertion-coupling product 5.157 could be obtained (Scheme 5.44).43 Which product was obtained depended on whether alkyne insertion or transmetallation was kinetically favoured. With more reactive organometallics, such as zinc reagents, direct coupling was the preferred pathway. Less-reactive organometallics, including zirconium, tin and boron reagents, led to formation of the tandem product. Aluminium reagents, having intermediate reactivity, gave mixtures.

CO2Me (Ph3P)4Pd, Et3N

I

L2IPd 5.151

5.152

MeO2C

5.153

Scheme 5.43

I 5.154 RM, (Ph3P)4Pd

R 5.155

5.157 L2IPd

Scheme 5.44

5.156

R

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Organic Synthesis Using Transition Metals Br

OH

(Ph3P)2PdCl2, Br CuI, Et2NH

OH 1. PBr 3 2. o-iodophenol, K2CO3

I 5.159

5.158 (HO)2B

Br

NO2

O I

Br

O

5.161 Pd(OAc)2, Na2CO3

5.160

5.162

Br

PdLnI

O 5.163 X = NO2

coupling

1. Pt/C/S, H 2 2. HCl 5.164 X = NH3 Cl

X

Scheme 5.45

A tandem alkene insertion–Suzuki coupling was used to synthesize an intermediate 5.164 for a hormone receptor modulator on a 302 g scale (Scheme 5.45).44 The starting material 5.160 was prepared by a selective Sonogashira coupling, followed by installation of an iodoaryl moiety. The tandem alkene insertion–Suzuki coupling also proceeded selectively: oxidative addition at the iodide site, followed by alkyne insertion and coupling with the boronic acid 5.161 gave the tandem product 5.163 via the ␩1 -intermediate 5.162 After the coupling, the nitro group could be chemoselectively reduced using hydrogenation over a sulﬁded platinum on carbon catalyst. A Heck-type ring closure, using formate as the reducing agent was used to form a ﬁve-membered ring and a stereodeﬁned exo-cyclic alkene in a synthesis of streptazolin 5.166 (Scheme 5.46).45 Another synthesis of this natural product may be found in Scheme 11.87. The mechanism of reduction by formate is shown in Scheme 5.50. Careful design of the substrate allows multiple bond formation in a single reaction. In the multiply unsaturated iodide 5.167, after oxidative addition, two alkyne insertions occur, followed by an alkene insertion (Scheme 5.47).46 This insertion generates a neopentyl complex, which undergoes a second alkene insertion. The sequence is terminated by an eventual ␤-hydride elimination giving the steroid-like 5.168.

Br N

H

OTBS

1. Pd(OAc)2, Ph3P, NaOCHO 2. TBAF

OH N

O

O

H

O

O 5.165

5.166

Scheme 5.46

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Alkene and Alkyne Insertion Reactions

171

(Ph3P)4Pd, Et3N

EtO2C EtO2C

EtO2C EtO2C

I

5.167

5.168

Scheme 5.47

If a suitably placed nucleophilic atom is present, it can coordinate to the palladium atom after insertion to give a cyclic intermediate 5.174.47 This can be followed by reductive elimination to give a useful synthesis of indoles 5.170, known as the Larock indole synthesis (Scheme 5.48),48 and other heterocycles (Scheme 5.49).49 5.1.10.2

Trisubstituted Alkenes

Trisubstituted alkenes are usually poor substrates for Heck chemistry, and must almost always be used in an intramolecular way. Treatment of the phenolic ether 5.177 with a palladium catalyst resulted in oxidative addition and insertion, leading to a stable ␩1 -intermediate 5.179 as it has no available ␤-hydrogen

I +

Me

Pd(OAc)2, PPh3, LiCl, KOAc

Me

Ph

Ph

NHAc

5.170

5.169

reductive elimination

Me

N Ac

oxidative addition

I

LnPd

Ph N 5.170 Ac

Me PdLnI

Ph N Ac

PdLn

NHAc

5.171

Me

5.174

HI

NHAc 5.169

coordination

coordination

Me

Me Ph

5.173

PdLnI NH insertion Ac

Scheme 5.48

Ph PdLnI NHAc

5.172

Ph

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Organic Synthesis Using Transition Metals

I

CO2Et Ph

Pd(OAc)2, PPh3, LiCl, KOAc

EtO2C + NHAc

N

Ph

5.175

Ac

5.176

Scheme 5.49

BnO I

BnO

OSEM

OSEM

(MeCN)2PdCl2, NaOCHO, DMF O

O

O

O 5.178

5.177

oxidative addition, insertion BnO SEMLPdI O O 5.179

O

reductive elimination H BnO SEM LPd O O

O O

O HCO2

O

H

O BnO SEM LPd O O O 5.180

-CO2

O 5.181

O

O

Scheme 5.50

(Scheme 5.50).50 The reaction was run in the presence of formate, which acts as a reducing agent. Formate delivers hydride to the palladium, by exchanging with the iodide and undergoing decarboxylation. Reductive elimination then gave the product 5.178.

5.1.10.3

Rigid Alkenes

The rigid structure of norbornene 5.182 prevents ␤-hydride elimination after insertion. The insertion product can be intercepted by various means including formate reduction,51 further alkene insertion,52 coupling,53 or CH activation (Scheme 5.51).54 A synthesis of epibatidine 5.192 rests on ␤-hydride elimination being prevented by Bredt’s rule and the rigidity of the norbornane system (Scheme 5.52).55 An azanorbornene 5.188 reacted with an iodopyridine 5.189 using a palladium catalyst in the presence of formate ions. The stable ␩1 -intermediate 5.190 was reduced by formate to give the functionalized heterocycle 5.191 that could be deprotected to give the natural product 5.192. Heck reactions and coupling reactions may be combined into tandem processes (Scheme 5.53). Often the coupling proceeds ﬁrst as transmetallation is usually faster than insertion. This is the case in the conversion

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Alkene and Alkyne Insertion Reactions

173

Ph

Ph

Br (R)-BINAP, HCO2H, Et3N

Br Ph (Ph3P)4Pd, KOAc

Ph 5.183

5.185 5.182

n-C5H11

PdL nBr

Br

n-C5H11 Br (Ph3P)4Pd, KOAc

5.184 (Ph3P)4Pd, KOAc

5.186

n-C5H11 5.187

Scheme 5.51

Cl

MeO2C N

(Ph3P)2PdCl2 HCO2N 5.189

I

MeO2C N PdLI H

5.188 MeO2C N

Cl N

5.190 Cl

Cl HBr, AcOH

HN N

N 5.191

5.192

Scheme 5.52

I

I

ClZn (Ph3P)2PdCl2

5.193

5.194

Scheme 5.53

of diiodide 5.193 to the tetracycle 5.194, in which Negishi coupling is followed by an intramolecular Heck reaction. A tandem double Heck reaction was employed to build the steroid ring system from dibromide 5.196 and alkene 5.195 (Scheme 5.54).56 The ﬁrst Heck reaction involves the vinyl bromide and results in alkene migration giving intermediate 5.197 in preparation for the second Heck reaction, involving the aryl bromide.

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Organic Synthesis Using Transition Metals Ot-Bu Ot-Bu Br +

Br Herrmann's cat. 5.58 n-Bu4NOAc

Br

H

H 5.195

5.196

5.197 Ot-Bu H H

H 5.198

Scheme 5.54

5.1.11

Heck-Like Reactions of Organometallics

Early versions of the Heck reaction employed organomercury compounds rather than organic halides.57 This process results in net reduction of palladium, so a stoichiometric amount was used. Other organometallic species may be used in place of organomercury compounds, such as boronic acids 5.199. In the presence of an oxidant, a catalytic process is possible, delivering Heck-like products (Scheme 5.55).58 While this reaction offers an alternative to the standard Heck reaction, under other conditions, the pathway diverges giving a different product. The rhodium-catalysed addition of boron derivatives to enones involves protonation of the ﬁnal intermediate, rather than ␤-hydride elimination, leading to saturated products 5.202, 5.205 (Schemes 5.56 and 5.57).59,60 The reaction, therefore, is more like a Michael addition in terms of the products formed, than a Heck reaction. As the reaction of a ␤-substituted enone generates a new stereogenic centre, considerable efforts have been invested into developing the asymmetric version. Unsurprisingly, chiral phosphines have been used successfully (Scheme 5.58).61 Surprisingly, chiral dienes 5.209 have also proved highly effective as ligands (Scheme 5.59).62

O

B(OH)2

CO2n-Bu Pd(OAc) 2, Cu(OAc) 2, LiOAc

O

CO2n-Bu

O O

5.199

5.200

Scheme 5.55 O

O

B(OH)2 acacRh(CO)2, dppb, H 2O 5.201

5.202

Scheme 5.56

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Alkene and Alkyne Insertion Reactions O

175

O

F3B acacRh(CO)2, dppb, H 2O

+ S 5.203

S

5.205

5.204

Scheme 5.57

O

PhB(OH)2, acacRh(CH2CH2)2, (S)-BINAP, H2O

O

Ph 5.206

5.203 PhBF3 K, (COD)2RhPF6, (S)-BINAP, H2O

Scheme 5.58 i-Pr B(OH)2 + 5.201

O

O

[RhCl(CH2CH2)2]2, L*, KOH

i-Pr 5.207

5.208 Bn

L*= Bn

5.209

Scheme 5.59

5.2 Insertion Reactions Involving Zirconium and Titanium 5.2.1

Hydrozirconation and Carbozirconation

In a reaction that parallels hydroboration, alkenes and alkynes undergo insertion into the metal–hydrogen bond of Schwartz’s reagent, zirconocene hydrochloride, generating alkyl zirconium complexes 5.211 (Scheme 5.60).63 The reaction occurs at room temperature. As with hydroboration, for terminal alkenes, the hydrogen becomes attached to the internal position and the metal at the terminal position. Unlike hydroboration (except when it is carried out under extreme conditions), internal alkenes give the same product as terminal alkenes. This is because a series of rapid ␤-hydride elimination–reinsertion reactions occur after formation of the initial addition product 5.210, allowing the zirconium to migrate to the terminal position.64 The importance of the reaction rests upon the reactivity of the resulting alkyl and alkenyl zirconium complexes. While the complexes are comparatively stable in air, the carbon–zirconium bond may be cleaved by simple electrophiles such as bromine and iodine, as well as by acid chlorides,65 and by oxidation with peroxide reagents (Scheme 5.60).66 Epoxide opening can be achieved intramolecularly and with Lewis-acid assistance (Scheme 5.61).67 Carbonylation is also possible: the resulting acyl zirconium complexes 5.216 may be protonated to give aldehydes 5.217, or oxidized in the presence of either water or an alcohol to give a carboxylic acid 5.219 or an ester 5.218, respectively (Scheme 5.62).68

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Organic Synthesis Using Transition Metals n-C8H17Cl PhICl2 n-C8H17Br

Br2 Cp2ZrHCl

Cl Cp2Zr

I2 5.211

n-C8H17I

t-BuOOH n-C8H17OH CH3COCl

Cl

O

Cp2Zr Cp2ZrHCl

n-C8H17

CH3

5.210

Scheme 5.60

O

O

Cp2ZrHCl

BnO

BF3.OEt2

BnO

5.212

5.213

Cp2Zr

5.214 Cl

Scheme 5.61

Cl Cp2Zr 5.215 CO Cl Cp2Zr O

5.216 H2O2

H+ Br2, MeOH

H O

HO O

5.217

5.219

MeO O

5.218

Scheme 5.62

BnO OH

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177

Me H2O Me

Cp2ZrCl2, Me3Al Ph

Ph

5.220

Ph 5.222

AlMe2 5.221

Me

I2

I

Ph 5.223

Scheme 5.63

Insertion of alkynes can also be used to form a carbon–carbon bond at the same time as the carbon–zirconium bond.69 This process, carbometallation, is useful for the stereospeciﬁc construction of trisubstituted alkenes (Scheme 5.63). The active reagent is formed by mixing zirconocene dichloride and trimethylaluminium. Both metals are required for the reaction to proceed. The vinyl organometallic 5.221 produced may be subjected to protonolysis or halogenation. An application with iodination can be found in Scheme 8.121. Transmetallation of the organic group from zirconium to another metal opens up possibilities. The palladium-catalysed coupling reactions can be found in Section 2.4. Addition of dimethyl cuprate results in transmetallation to copper. The resulting cuprate then displays typical cuprate reactivity, such as addition to enones.70 More economically, small amounts of copper can catalytically activate the zirconium complex towards this kind of chemistry, although the precise mechanism is unclear.71 Additions to enones can also be achieved directly using nickel catalysis (Scheme 5.64).72 Transmetallation to zinc has also been demonstrated.73 5.2.2

Alkene and Alkyne Complexes

The organometallic fragments titanocene, Cp2 Ti, and zirconcene, Cp2 Zr, have found an important role in synthesis.74 Unfortunately, being 14-electron species, they are highly unstable and tend to attack themselves. To use them it is necessary to supply at least one other ligand to maintain some stability. 1-Butene is a convenient ligand, as it is generated when the metallocene fragments are generated by treatment of the stable and commercially available metallocene dichlorides 5.227 with butyl lithium (Scheme 5.65). Addition of the substrate then results in displacement of the 1-butene. Alternatively, titanocene and zirconocene may be generated by reduction of the dichlorides in the presence of the substrate, as long as the substrate is stable to the reduction conditions.75 Addition of a diene 5.231 to these reagents results in the formation of a metallacycle 5.232 (Scheme 5.66). The carbon–zirconium bonds can then be cleaved by electrophilic or oxidizing agents. If the reaction is intramolecular, a reasonable degree of control of the new stereogenic centres is possible. The insertion can, however, be reversible. The stereochemistry of the product therefore depends on the reaction time and temperature, longer times yielding thermodynamically more stable complexes.76,77 RO O t-Bu 5.224

Cp2ZrHCl

t-Bu

RO O

ZrClCp2 Ni(acac)2, DIBAL t-Bu 5.22 5

Scheme 5.64

5 .226

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Organic Synthesis Using Transition Metals

Cp2Zr

Cl 2 n-BuLi

β -hydride elimination

n-Bu Cp2Zr n-Bu

Cl 5.227

5.228 Cp2Zr

-butane Cp2Zr H n-Bu 5.229

5. 2 3 0

Scheme 5.65 H Cp2ZrCl2, n-BuLi

ZrCp2 5.232

5.231

H

1. O2 2. H3O+

H

5.233

H

OH

OH

cis:trans 22 h, RT, 75:25 RT, then 75 °C 1:99

Scheme 5.66 Et

H

PhCOCl, CuCl, LiCl

ZrCp2 Et

Et

Ph O

Et

H 5.234

5.235

Cp2ClZr cyclisation

I2 Et

Ph O

Et 5.236

I

Et

H Ph

Et

H 5.237

Scheme 5.67

The metallacycles can also be used for carbon–carbon bond-forming reactions (Scheme 5.67). Transmetallation with cuprates, or the use of catalysis by copper(I) salts allows reaction with a variety of electrophiles. With an acid chloride, reaction occurs at one of the carbon–zirconium bonds of the metallacycle 5.234. This leaves the second carbon–zirconium bond of the acylated product 5.235 available for further chemistry by, for instance, halogenation,78 or back attack onto the ketone.79 More elaborate multiple component couplings can also be achieved (Scheme 5.68).80 Another approach to using zirconium is to remember that it has only sixteen electrons and can, therefore, be attacked by electrophiles (Scheme 5.69). Addition of the anion prepared by deprotonation of allyl chloride results in addition to zirconium, followed by an alkyl migration with loss of chloride, resulting in the formation

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Alkene and Alkyne Insertion Reactions

179

O Cp2ZrCl2

1. 2 EtMgBr 2. n-PrC≡Cn-Pr

ZrCp2

CuCl.2LiCl

n-Pr n-Pr 5.238

5.227

O ZrCp2

n-Pr n-Pr 5.239

xs NBS

1. n-Bu4NCl 2. PhCHO 3. H +

O

O OH

Br

Ph

Br

n-Pr

n-Pr

n-Pr

Br

n-Pr

5.240

5.241

Scheme 5.68

of an allyl complex 5.245. Complexes of this type are nucleophilic and further reactions are possible. The allyl complex can be trapped with aldehydes, as well as other electrophiles.81 The insertion of alkenes and alkynes with the alkyne complex generates metallocyclopentenes and metallocycopentadienes 5.247 (Scheme 5.70). The metal–carbon bonds in these complexes are quite polar and may be cleaved by a variety of electrophiles, including acids, halogens and molecular oxygen. Addition of reagents such as sulfur and phosphorus chlorides yields various unusual and interesting heterocycles. An alternative route to alkyne complexes avoids the intermediacy of the metallocenes and allows formation of complexes of unstable alkynes, such as benzyne and cyclohexyne. Treatment of Cp2 ZrMeCl with an aryl or vinyl lithium gives the expected aryl (or vinyl) complex 5.250 (Scheme 5.71).82 Mild heating then causes loss of methane and formation of the ␩2 -alkyne complex 5.251, which can also be drawn as its metallacyclopropane resonance structure 5.252. These complexes become sufﬁciently stable to be isolated if an additional ligand, such as trimethylphosphine, is added, giving the adduct 5.253. Analysis of the structures Cl

H ZrCp2

H

Li H

H 5.242

Cl

H

Zr Cp Cp

ZrCp2 H

5.243 H

η1 → η 3 ZrCp2

1. RCHO, BF3.OEt2 2. NaHCO3

5.244 H

R Me H 5.246

H 5.245

Scheme 5.69

OH

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Organic Synthesis Using Transition Metals

Cp2Zr

Cl 1. 2 n-BuLi 2. Cl

PhPCl2

Zr2Cp

5.227

PhP

5.247

5.248

Scheme 5.70 Me

Li

Cp2Zr

Me

H -CH 4

Cp2Zr Cl

5.250

5.249

PMe3

Cp2Zr

Cp2Zr

Cp2Zr Me3P

5.251

5.252

5.253

Scheme 5.71

by X-ray crystallography (Figure 5.1) has shown that the metallacyclopropene resonance structure is the more important, indicating substantial metal to ligand backbonding.83 Once the complexes have been prepared, they can undergo a further insertion reaction with an added alkene, diene84 or alkyne, or with a host of multiply bonded species including nitriles and ketones (Scheme 5.72). The direction of insertion in substituted complexes appears to be sterically controlled.

P

C11 C6

C10

Zr C9 C7 C8

Figure 5.1 Complex 5.253. Reprinted with permission from Buchwald, S. L.; Watson, B. T. J. Am. Chem. Soc. C 1986 American Chemical Society. 1986, 108, 7411.

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Alkene and Alkyne Insertion Reactions

Cp2Zr

Cp Zr

Cp

CH3CN

181

H3O+

N

O

5.254

5.255

5.256

Scheme 5.72

Applying this chemistry to N-allyl anilines has been a fruitful route to indoles and indolines (Scheme 5.73).85 N,N-Diallyl o-bromoaniline 5.257 was converted to a benzyne complex 5.258 by treatment with t-butyllithium and Cp2 ZrMeCl. Immediate intramolecular insertion generated a zirconacycle 5.259. The carbon–zirconium bonds could then be cleaved by double iodination: the two iodides that resulted were distinctly different. After a change of nitrogen-protecting group, the alkyl iodide was eliminated to give the exo-methylene heterocycle 5.261. Electrophilic bromination then gave a bromomethyl indole 5.262. SN 2 displacement of the bromide and Suzuki coupling of the iodide gave a known precursor 5.263 of the Clavicipitic acids. The pharmacaphore 5.270 of CC1065 has also been prepared by exploiting the differential reactivity of the two halogen atoms, introduced after a remarkable regioselective insertion reaction involving the zirconium complex derived from aryl bromide 5.265 (Scheme 5.74).86 In this case, while the alkyl iodide of diiodide 5.266 underwent nucleophilic substitution leading to an acetate, the aryl iodide was employed in an intramolecular Heck reaction to close the second ﬁve-membered ring giving the indoline 5.269. The exo-methylene compound 5.271, generated in a similar way, could also be used in ene reactions (Scheme 5.75).87 Such a reaction with Eschenmoser’s salt gave a dimethyl amine 5.272. Monodemethylation, von Braun style, was followed by an intramolecular palladium-catalysed heteroatom coupling. The tricycle 5.274 was converted to dehydrobufotenine 5.275, a toad poison.88 Cp2Zr

ZrCp2

Br

1. t-BuLi 2. Cp 2ZrMeCl

insertion

N

N

N

5.258

5.257 I

5.259 I

I

I

1. EtOCOCl, NaI 2. DBU

2 I2

NBS

N

5.261

5.260 1. MeO2C

CO2Me

CO2Me

2. B(O2C6H4) Pd(OAc)2, PPh3, K2CO3

CO2Me

5.263

Br

N CO2Et

Scheme 5.73

N CO2Et

5.262

N CO2Et

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Organic Synthesis Using Transition Metals

Br NO2 H2N OMe

1. H 2, Pt 2. PhSO 2Cl, py 3. NBS Br 4. base

N N PhSO2

5.264

SO2Ph 1. t-BuLi; Cp ZrMeCl 2 2. I 2

OMe 5.265

X

OAc (Ph3P)4Pd, Et3N

N SO2Ph

I

N SO2Ph

5.266 X = I aq. Ag 2O

N PhSO2

OMe

Ac2O

N PhSO2

5.267 X = OH

OMe

5.268 X = OAc

5.269

N H N H

5.270

O

Scheme 5.74

5.2.3

Zirconium-Mediated Carbomagnesiation

When allylic alcohol derivatives 5.276 are employed in a catalytic system, a carbomagnesiation reaction results, giving a Grignard reagent, 5.277 or 5.278, as the product (Scheme 5.76).89 This can be quenched with an electrophile, for instance, oxidation gives an alcohol, 5.279 or 5.280. The reaction is diastereoselective, with the diastereoselectivity depending on whether a free alcohol (R = H) or an ether (R = Me) is used as the substrate. Asymmetric carbomagnesiation has been achieved using heterocyclic alkenes and zirconocene complexes 5.283 as catalysts, in which the cyclopentadienyl groups are part of a chiral bridged

I

NMe2

I NMe2

MeO

MeO

OCOCl 1. 2. EtOH

H N 5.271 CO2Et

I

N 5.272 CO2Et

NHMe (Ph3P)4Pd, K2CO3, Δ

MeO

5.273

Cl

N CO2Et

MeN MeO

5.274

Scheme 5.75

1. BBr 3 2. MeI N CO2Et

Me2N MeO N H 5.275

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Alkene and Alkyne Insertion Reactions EtMgCl, Cp2ZrCl2

OR

OMgCl

OMe MgCl

5.276

5.277

183

MgCl 5.278

Et R=H

Et R = Me

B(OMe)3; H 2O2 or O2 OH

OH OH

OH

Et

5.279

Et

5.280

Scheme 5.76

bis-indenyl-based structure (ethylene-1,2-bis(␩5 -4,5,6,7-tetrahydro-1-indenyl, EBTHI) (Scheme 5.77).90 This reaction is proposed to proceed by formation of a zirconocycle 5.284. The zirconacycle is cleaved by the Grignard reagent, and this is followed by ring opening of the oxygen heterocycle, and regeneration of the catalytic species 5.287. The products are useful building blocks for the synthesis of more complex molecules. Both the diastereoselective and the enantioselective reactions were combined in a synthesis of ﬂuviricin B1 5.288, an antifungal and anti-inﬂuenza agent (Scheme 5.78).91 Of the two fragments required for the formation of the macrocycle,

EtMgCl, catalyst O 5.281

Et pre-catalyst = 5.282

ZrCl2 (EBTHI)ZrCl2 5.283

OH

H

O 5.281

H

EtMgCl

Zr O 5.284

Zr

O

Cl EtMgCl Cl

Zr Zr

5.287

H

5.285

5.283 Et OMgCl

OH 5.282

Et

Zr

Et

H 5.286

Scheme 5.77

MgCl

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Organic Synthesis Using Transition Metals OH NH2

RCM, then hydrogenation

O

OH O

O

Et acylation

OH

glycosylation Et

Et

HN

5.288

Et

CO2H

H2N 5.290

5.289

OH O

5.281

5.292

EtMgBr (S )-(EBTHI)ZrBINOL

EtMgCl, Cp2ZrCl2 OMgCl

Et OH

MgCl

5.291

5.293

1. n-PrMgBr, Cp 2TiCl 2 2. Br (Ph3P)2NiCl2 3. TPAP, NMO

Et Ts N 1. CuI 2. TBSOTf, Et 3N 3. Na, NH3(l) OTBS

Et

NH2

CO2H 5.289

5.294

Et

1. DCC, HOBT 2. HF O 3. F AgClO4, SnCl2 AcO Et

OAc NHCOCF3 5.295

Et

H N O

O

O

5.296 AcO

OAc NHCOCF3

1. Schrock's catalyst 2. H2, Pd/C 3. H2NNH2

OH NH2 O

OH O

O

Et HN

Scheme 5.78

Et 5.288

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Alkene and Alkyne Insertion Reactions

185

the simpler fragment 5.289 was formed by enantioselective magnesiation-ring opening of dihydrofuran 5.281 to give alcohol 5.291 (Scheme 5.77). Alcohol 5.291 was then chain-lengthened by titanium-catalysed hydromagnesiation, followed by Kumada coupling (Section 2.2) with vinyl bromide. The primary alcohol was then oxidized to the carboxylic acid 5.289. The other fragment 5.290 was prepared by diastereoselective carbomagnesiation. The Grignard reagent 5.293 generated was used in a ring opening of N-tosylaziridine. Protecting-group manipulation yielded the amine 5.294, which was coupled with the ﬁrst fragment 5.289 to give an amide. It was found that the best sequence was to carry out glycosylation with the amino sugar derivative 5.295 prior to ring-closing metathesis using Schrock’s catalyst (Figure 8.3). Reduction of the alkene, with diastereoselectivity provided by the macrocycle conformation, and global deprotection provided the natural product 5.288. 5.2.4

The Kulinkovich Reaction

When a titanacyclopropane 5.300, generated from the reaction of titanium tetraisopropoxide with two equivalents of a Grignard reagent is treated with an ester 5.297, once again, insertion takes place. The resulting metallacycle 5.301 is unstable, and loses the ester alkoxy group to form a new carbonyl group 5.302 coordinated to the titanium. The system is now set up for intramolecular nucleophilic attack to form a cyclopropyl alkoxide 5.303 coordinated to titanium. As the alkoxide 5.304 may be displaced from the titanium by additional Grignard reagent, the reaction becomes catalytic in titanium. The cyclopropanol product 5.298 is then obtained upon work-up. This process is known as the Kulinkovich reaction (Scheme 5.79).92

R

(i-PrO)4Ti, EtMgBr

O

OMe

R HO 5.298

5.297 (i-PrO)4Ti R

R

work up

HO 5.298

2 EtMgBr

BrMg O 5.304

Et (i-PrO)2Ti

2 EtMgBr

Et 5.299 R (i-PrO)2Ti

(i-PrO)2Ti O MeO 5.303

(i-PrO)2Ti 5.300 R O OMe 5.297

intramolecular nucleophilic attack δ-

(i-PrO)2Ti

(i-PrO)2Ti MeO O

O R

R 5.301

5.302

Scheme 5.79

OMe

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Organic Synthesis Using Transition Metals MgBr (i-PrO)3TiCl

O OMe

HO

5.306

5.305

Scheme 5.80 (i-PrO)4Ti or (i-OPr)3TiCl 2 n-BuMgBr +

(i-PrO)2Ti

CO2Me 5.308 alkene exchange

5.307

+

(i-PrO)2Ti

CO2Me

OH

intramolecular Kulinkovich reaction

5.309

5.310

Scheme 5.81

The reaction may be extended to higher Grignard reagents by the use of the more reactive chlorotitanium tri-iso-propoxide, allowing the synthesis of more highly substituted cyclopropanols 5.306 with the two alkyl groups cis (Scheme 5.80).93 It has also been found that the primary Kulinkovich intermediate, the titanacyclopropane 5.300, can exchange with added alkenes. This allows the use of alkenes that are not compatible with Grignard chemistry, including ester-containing alkenes 5.308 that permit an intramolecular Kulinkovich reaction giving bicyclic cyclopropanols 5.310 (Scheme 5.81).94 Amides can also be employed as substrates.95 The mechanism in this case is subtly different to the mechanism involving the ester (Schemes 5.82–5.84). If the mechanism were the same, the amino group would be eliminated and the same product would be obtained. Instead, as with the LiAlH4 reduction of amides, the oxo group is eliminated, and the amino group is retained in the product, which is an amino cyclopropane 5.313. As with the esters, intramolecular Kulinkovich reactions are also possible (Schemes 5.85 and 5.86).96 One application of these highly electron rich cyclopropanols is in their ring opening.97 This property was exploited in an approach to benzospiroketals (Scheme 5.87).98 Kulinkovich reaction of the styrene 5.325 R

(i-PrO)2Ti O 5. 312

(i-PrO)2Ti O 5.311

R

R

NR'2

NR'2

5.3 13

NR'2

ester-like pathway - not followed

(i-PrO)2Ti R NR'2 O 5.314

Scheme 5.82

R HO 5.315

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Alkene and Alkyne Insertion Reactions O N

EtMgBr, Ti( i-OPr)4

O

N

O

H 5.316

5.317

Scheme 5.83 MgBr + N Me

Ti(i-OPr)4

OTIPS

N Me

O 5.318

5.319

OTIPS 5.320

Scheme 5.84 H

MgBr

O

NEt2

Ti(i-OPr)4

NEt2 5.321

5.322

Scheme 5.85

Me Bn

MgBr

O

Ti(i-OPr)4

N

Me

H

Bn N 5.324

5 . 323

Scheme 5.86 EtOCH2O

EtOCH2O O +

OBn

MeO

MgBr Ti(i-OPr)4

5.326

5.325

OBn OH 5.327

HO EtOCH2O H

EtOCH2O

HO , Δ

O OBn

OBn O 5.328

5.329 O

H2, Pd/C, HCl

O

5.330

Scheme 5.87

187

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Organic Synthesis Using Transition Metals O

TBSO TBSO

Ti(Oi-Pr)4, EtMgBr

OEt

TBSO TBSO

5.331

OH

5.332

1. MsCl, Et 3N 2. MgBr2 TBSO TBSO 5.333

Br

Scheme 5.88

with ester 5.326 gave the cyclopropanol 5.327, which underwent ring opening on heating with aqueous base. Given the high ␲-character of the cyclopropane C–C bonds, cyclopropanols may be viewed as homo-enols, making this conversion to the ketone analogous to enol–ketone tautomerism. Upon double deprotection, the spiroketal 5.330 was obtained. The ester Kulinkovich reaction was used to prepare a key allylic bromide 5.333 in a synthesis of neolaulimalide and isolaulimalide (Scheme 5.88).99 The cyclopropanol 5.332 produced by the Kulinkovich reaction of ester 5.331, as its mesylate, was subjected to ring opening with magnesium bromide. This is likely to involve electrocyclic ring opening of the cyclopropyl carbocation, followed by bromide trapping.

References 1. (a) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379; (b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2; (c) Heck, R. F. Organic Reactions 1982, 27, 345; (d) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427. 2. Franck, W. C.; Kim, Y. C.; Heck, R. F. J. Org. Chem. 1978, 43, 2947. 3. Jeffrey, T. Synthesis 1987, 70. 4. Patel, B. A.; Ziegler, C. B. et al. J. Org. Chem. 1977, 42, 3903. 5. Bates, R. W.; Gabel, C. J. Tetrahedron Lett. 1993, 34, 3547. 6. Tao, W.; Nesbitt. S.; Heck, R. F. J. Org. Chem. 1990, 55, 63. 7. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. 8. Draper, T. L.; Bailey, T. R. Synlett 1995, 157. 9. (a) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem. 2011, 1403; (b) Roglans, A.; Pla-Quintana, A.; Moreno-Ma˜nas, M. Chem. Rev. 2006, 106, 4622. 10. Werner, E. W.; Sigman, M. S. J. Org. Chem. 2011, 133, 9692. 11. Baumeister, P., Meyer, W. et al. Chimia 1997, 51, 144. 12. Schmidt, B.; H¨olter, F. Chem. Eur. J. 2009, 15, 11948; see also Schmidt, B.; H¨olter, F. et al. J. Org. Chem. 2011, 76, 3357. 13. (a) Spencer, A. J. Organomet. Chem. 1983, 247, 117; (b) Blaser, H. U.; Spencer, A. J. Organomet. Chem. 1982, 233, 267. 14. (a) Andersson, C.-M.; Hallberg, A. J. Org. Chem. 1988, 53, 4257; (b) Andersson, C.-M.; Hallberg, A. J. Tetrahedron Lett. 1987, 28, 4215. 15. Spencer, A. J. Organomet. Chem. 1984, 265, 323 16. Herrmann, W. A.; Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844. 17. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295. 18. Ref 5 Jeffrey, T. Tetrahedron 1996, 52, 10113. 19. Plevyak, J. E.; Heck, R. F. J. Org. Chem. 1978, 43, 2454. 20. Raggon, J. W.; Snyder, W. M. Org. Process Res. Dev. 2002, 6, 67.

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Alkene and Alkyne Insertion Reactions

189

21. Bl¨ase, S.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 2545. 22. Cabri, W.; Candiani, I. et al. J. Org. Chem. 1992, 57, 1481. 23. (a) Cabri, W.; Candiani, I. et al. J. Org. Chem. 1992, 57, 1481; (b) Cabri, W.; Candiani, I. et al. J. Org. Chem. 1992, 57, 3558. 24. Brown Ripin, D. H.; Bourassa, D. E. et al. Org. Process Res. Dev. 2005, 9, 440. 25. Ciattini, P. G.; Ortar, G. Synthesis 1986, 70. 26. Nagasawa, K.; Zako, Y. et al. Tetrahedron Lett. 1991, 32, 4937. 27. (a) Buntin, S. A.; Heck, R. F. Org. Synth. 1990, Coll. Vol. VI, 361; (b) Malponder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265. 28. Ainge, D.; Vaz, L.-M. Org. Process Res. Dev. 2002, 6, 811. 29. Thomas, S. E.; Middleton, R. J. Contemp. Org. Syn. 1996, 3, 447. 30. Zagar, S.; Tokar, C. et al. Org. Process Res. Dev. 2007, 11, 747. 31. Masters, J. J.; Link, J. T. et al. Angew. Chem., Int. Ed. Engl. 1995, 34, 1723. 32. Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028. 33. Rice, K. C. J. Org. Chem. 1980, 45, 3135. 34. (a) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533; (b) Guiry, P. J.; Kiely, D. Curr. Org. Chem. 2004, 8, 781; (c) Shibasaki, M.; Vogl, E. M. J. Organomet. Chem. 1999, 576, 1; (d) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371. 35. Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571. 36. (a) Kondo, K.; Sodeoka, M. et al. Synthesis 1993, 920; (b) Ohrai, K.; Kondo, K. et al. J. Am. Chem. Soc. 1994, 116, 11737. 37. Danishefsky, S.; Schuda, P. F. et al. J. Am. Chem. Soc. 1977, 99, 6066. 38. Ohshima, T.; Kagechika, K. et al. J. Am. Chem. Soc. 1996, 118, 7108. 39. (a) Ashimori, A.; Matsuura, T. et al. J. Org. Chem. 1993, 58, 6949; (b) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. 40. Lebsack, A. D.; Link, J. T. et al. J. Am. Chem. Soc. 2002, 124, 9008. 41. Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1983, 250, 509. 42. Zhang, Y.; Negishi, E.-i. J. Am. Chem. Soc. 1989, 111, 3454. 43. Negishi, E.-i.; Noda, Y. et al. Tetrahedron Lett. 1990, 31, 4393. 44. Richey, R. N.; Yu, H. Org. Process Res. Dev. 2009, 13, 315. 45. Huang, S.; Comins, D. L. Chem. Commun. 2000, 569. 46. (a) Zhang, Y.; Wu, G. et al. J. Am. Chem. Soc. 1990, 112, 8590; (b) Zhang, Y.; Negishi, E.-i. J. Am. Chem. Soc. 1989, 111, 3454. 47. Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652 48. Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689 49. Larock, R. C.; Yum, E. K. et al. J. Org. Chem. 1995, 60, 3270 50. Hoffmann, H. M. R.; Schmidt, B.; Wolff, S. Tetrahedron 1989, 45, 6113. 51. Ozawa, F.; Kobatake, Y. et al. J. Chem. Soc., Chem. Commun. 1994, 1323. 52. Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1982, 240, 311. 53. Catellani, M.; Chiusoli, G. P. Tetrahedron Lett. 1982, 23, 4517. 54. Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1982, 233, C21. 55. (a) Clayton, S. C.; Regan, A. C. Tetrahedron Lett. 1993, 34, 7493; (b) Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 804. 56. Tietze, L. F.; N¨obel, T. et al. Angew. Chem., Int. Ed. Engl. 1996, 35, 2259. 57. Heck R. F. J. Am. Chem. Soc. 1968, 90, 5518. 58. Karimi, B.; Behzadnia, H. et al. Synthesis 2010, 1399. 59. Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169. 60. (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229; (b) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1, 1683. 61. (a) Takaya, Y.; Ogasawara, M. et al. J. Am. Chem. Soc. 1998, 120, 5579; (b) Pucheault, M.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002, 3552.

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190 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.

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Organic Synthesis Using Transition Metals Shintani, R.; Hayashi, T. Aldrich. Acta 2009, 42, 31. Buchwald, S. L.; LaMaine, S. J. Org. Synth. 1992, 71, 77. Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. See reference 64. Blackburn, T. A.; Labinger, J. A.; Schwartz, J. Tetrahedron Lett. 1975, 16, 3041. Harada, S.; Kowase, N. et al. Tetrahedron 1998, 54, 753. Bertelo, C. A.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 228. (a) Van Horn, D. E.; Negishi, E.-i. J. Am. Chem. Soc. 1978, 100, 2252; (b) Negishi, E.-i.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985, 107, 6639. Lipshutz, B. H.; Keil, R. J. Am. Chem. Soc. 1992, 114, 7919. (a) Wipf, P. G., Xu, W. Tetrahedron 1994, 50, 1935; (b) Wipf, P. G., Xu, W. Pure Appl. Chem. 1997, 69, 639; for a general discussion of transmetallation, see Wipf, P. G. Synthesis 1993, 537. (a) Loots, M. J., Schwartz, J. J. Am. Chem. Soc. 1977, 99, 8045; (b) Schwartz, J.; Loots, M. J., Kosugi, H. J. Am. Chem. Soc. 1980, 102, 1333; (c) Sun, R. C.; Okabe, M. Org. Synth. 1992, 71, 83. Wipf, P. G., Xu, W. Org. Synth. 1995, 74, 205. (a) Buchwald, S. L.; Nielsen, R. B. Chem. Rev. 1988, 88, 8047; (b) Broene, R. D.; Buchwald, S. L. Science 1993, 261, 1696; (c) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. Miura, K.; Funatsu, M. et al. Tetrahedron Lett. 1996, 37, 9059. Taber, D. F.; Louey, J. P. Tetrahedron 1995, 51, 4495. Taber, D. F.; Louey, J. P. et al. J. Am. Chem. Soc. 1994, 116, 9457. Takahashi, T.; Sun, W.-H. et al. Tetrahedron 1998, 54, 715. Takahasi, T.; Kotora, M.; Xi, Z. J. Chem. Soc., Chem. Commun. 1995, 1503. Lipschuta, B. H.; Segi, M. Tetrahedron 1995, 51, 4407. (a) Luker, T.; Whitby, R. J. Tetrahedron Lett. 1995, 36, 4109; (b) Fillery, S. F.; Gordon, G. J. et al. Pure Appl. Chem. 1997, 69, 633. Buchwald, S. L.; Lum, R. T. et al. J. Am. Chem. Soc. 1989, 111, 9113. Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am. Chem. Soc. 1986, 108, 7411. Negishi, E.-I.; Miller, S. R. J. Org. Chem. 1989, 54, 6014. Tidwell, J. H.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164. Tietze, L. F.; Buhr, W. Angew. Chem., Int. Ed. 1995, 34, 1366. Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797. Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028. Houri, A. F.; Didiuk, M. T. et al. J. Am. Chem. Soc. 1993, 115, 6614. (a) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6997; (b) Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1262. Xu, Z.; Johannes, C. W. et al. J. Am. Chem. Soc. 1997, 119, 10302. (a) Kulinkovich, O. G.; Sviridov, S. V. et al. Zh. Org. Khim. 1989, 25, 2244; (b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis, 1991, 234; (c) Breit, B. J. Prakt. Chem. 2000, 342, 211. Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116, 9345. (a) Kasatkin, A.; Nakagawa, T. et al. J. Am. Chem. Soc. 1995, 117, 3881; (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198. (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 413; (b) Cha, J. K.; Lee, J. J. Org. Chem. 1997, 62, 1584. Madelaine, C.; Buzas, A. K. et al. Tetrahedron Lett. 2009, 50, 5367. Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597. Haym, I.; Brimble, M. Synlett 2009, 2315. Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701.

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6 Electrophilic Alkene and Alkyne Complexes Simple, isolated alkenes are relatively unreactive. They do react with radicals or powerful electrophiles, such as strong acids, halogens, ozone and carbocations, but do not typically react with weak electrophiles, such as alkyl halides. They do not react with nucleophiles, unless they bear an electron-withdrawing group. If an alkene is coordinated to a transition metal in a high oxidation state, however, then ligand to metal electron donation makes the alkene electrophilic and susceptible to nucleophilic attack. Extensive stoichiometric studies have been carried out with iron complexes (Section 6.3); both catalytic and stoichiometric work with palladium (Section 6.1). Recently, other metals, such as gold, silver and platinum, have gained in prominence (Section 6.2). In some cases, isolable ␩2 -complexes, with the metal coordinated to one face of the alkene ␲-system are used (Figure 6.1). More often, the alkene complexes are intermediates in catalytic processes. The product of nucleophilic attack on an ␩2 -alkene complex is an ␩1 -complex (Scheme 6.1). Both alkynes (Scheme 6.2) and allenes (Scheme 6.3) can be activated towards nucleophilic attack in a similar way. In the case of allenes, the mechanism may not be a straightforward attack on a ␩2 -complex: a ␩1 -coordinated allyl cation has been proposed. Nevertheless, both pathways would lead to the same ␩1 -vinyl intermediate. Such intermediates, in rare cases, have been isolated.1 The same types of products may also be formed through another mechanism involving insertion of the alkene, alkyne or allene into a metal–nucleophile bond. The usefulness of these processes in organic synthesis depends upon what is made of the resulting ␩1 -complexes. In some cases, they proceed with typical organometallic reactions such as alkene insertion, thereby creating a tandem process, or ␤-hydride elimination. In other cases, the C–M bond is cleaved by protonolysis, or reaction with another electrophile.

6.1 Electrophilic Palladium Complexes Nucleophilic attack on alkene-palladium(II) complexes became commercially important when the Wacker process was developed.2 In this process, ethylene is converted to acetaldehyde (Scheme 6.4). This involves coordination of ethylene to palladium.3 The oxygen atom, which comes from water, may then become attached to carbon in one of two different ways. Direct nucleophilic attack on one carbon atom of the ␩2 -ethylene complex 6.1 by water can form an ␩1 -complex 6.3. Alternatively, ligand exchange at palladium, with water replacing chloride, can be followed by insertion of the coordinated ethylene into the palladium–oxygen bond to give the same ␩1 -complex 6.3, via the hydroxy complex 6.2. Which of these two variants of the mechanism Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals

Fe - Cα = 2.09 (2) Å

C

Cα

Cβ

CO CO

1.34 (2)

1.42 (2)

O

Cp

Fe - Cβ = 2.32 (2) Å

Fe

Fe OMe

C

C

O C

Figure 6.1 An iron-alkene complex. Reprinted with permission from Chang, T. C. T. et al. J. Am. Chem. Soc., c 1981 American Chemical Society. 1981, 103 (24), pp 7361–7362

Nuc M

Nuc

+

M

Scheme 6.1

Nuc M

Nuc

M+

Scheme 6.2

Nuc •

M

•

Nuc

M+ M Nuc

Scheme 6.3

operates appears to depend on the concentration of the different ligands available to palladium: the latter is likely to operate under the conditions employed in the industrial process. ␤-Hydride elimination then gives an ␩2 -enol complex 6.4. Reinsertion generates an isomeric ␩1 -complex 6.5, which undergoes a second ␤-hydride elimination to give acetaldehyde. The reductive elimination of HCl has, at this point, reduced the palladium to zero, so the process is not catalytic. Copper salts are included: copper(II) oxidizes Pd(0) to Pd(II), but is reduced to copper(I). The reaction is run in the presence of air. Oxygen from air re-oxidizes the copper(I) to copper(II) in the second catalytic cycle. The chemistry of the Wacker reaction is not limited to ethylene, but may be extended to a wide range of alkenes, and is useful throughout organic synthesis.4 For the synthesis of complex molecules, the Wacker

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Electrophilic Alkene and Alkyne Complexes 1 2

+

O

PdCl2, CuCl2, H2O

O2

193

H 1 2

O2 + 2H+

H2O 2 Cu+

2 Cu2+

coordination PdCl2

HCl Pd(0)

reductive elimination

H2O

re-oxidation

PdCl2 6.1

PdHCl 6.6

O H

ligand exchange

H 2O

HCl

nucleophilic attack

β-hydride

HCl

elimination

Cl

Pd

OH 6.2

O H

insertion

ClPd 6.5 insertion

OH ClPdH 6.4

OH

ClPd 6.3

β-hydride

elimination

Scheme 6.4 Ts N

PdCl2, CuCl, aq. DMF, O2

Ts N

O

6.8

6.7

Scheme 6.5 PdCl2, CuCl, aq. DMF, O2

O

KOH

CHO 6.9

CHO 6.10

O 6.11

Scheme 6.6

oxidation is useful for converting terminal alkenes to methyl ketones, as in a synthesis of anatoxin (Scheme 6.5).5 As attack by water is charge controlled, the more substituted carbon is oxidized. The reaction is highly chemoselective. Even an aldehyde may be present. In the example shown (Scheme 6.6), the Wacker product 6.10 can then be used in an intramolecular Aldol reaction to give cyclopentenone 6.11.6 The reaction is sensitive to steric effects. Terminal alkenes are by far the most reactive, and, therefore, excellent selectivity for the least hindered alkene is usually obtained (Schemes 6.7 and 6.8). This is because more substituted alkenes bind less strongly to Pd(II).7,8

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Organic Synthesis Using Transition Metals PdCl2, CuCl2, aq. DMF, O2

NHBoc

NHBoc

6.12

O

6.13

Scheme 6.7

H

O

H

PdCl2, CuCl, aq. DMF, O2

H

H

H 6.15

H 6.14

Scheme 6.8 OH OH

O

PdCl2, CuCl2, DMF, O2 O

6.16

H+

6.17

O OH OH

Cl2Pd

O O HO

6.18

ClPd 6.23 6.21

H+

β -hydride elimination ClPd 6.19

O HO

Cl2Pd O 6.20 HO

6.22

O HO

Scheme 6.9 PdCl2, CuCl2, THF, O2 OH

O O OBn

OH OBn

6.24

6.25

Scheme 6.10

Nucleophiles other than water may be used. If an alcohol is used as the nucleophile, the initial product is an enol ether, which can then add a second alcohol molecule to form a ketal (Scheme 6.9). This reaction has often been used effectively in an intramolecular sense to form bicyclic acetals: unsaturated diols cyclize to ketals. The formation of the second C–O bond may be either H+ catalysed, via oxonium ion 6.21, or Pd(II) catalysed via ␩2 -complex 6.22 and ␩1 -complex 6.23. This reaction has been employed in a synthesis of frontalin 6.179 and in a synthesis of saliniketals A and B by cyclization of diol 6.24 (Scheme 6.10).10

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Electrophilic Alkene and Alkyne Complexes

CO2Me

195

O

Na2PdCl4, t-BuOOH, AcOH

CO2Me

Scheme 6.11

CO2Me

MeOH, O2, Cu, FeCl3, Na2PdCl4 MeO

CO2Me

MeO 6.26

Scheme 6.12 MeO O

Li

O

OMe • LiBr

•

OH

OH 6.28

6.27

O

(MeCN)2PdCl2, BQ, H2O

6.29

O 6.30

Scheme 6.13 PdCl2 PdCl2 NH2

N H2

6.31

6.32

Scheme 6.14

Electron-poor alkenes can also participate in the Wacker oxidation. Now, the role of the palladium is to enhance the natural electrophilicity of the alkene (Scheme 6.11).11 In addition, the regioselectivity of the reaction is controlled by the electron-withdrawing group. Once again, alternative nucleophiles may be employed. The use of an alcohol, in place of water, leads to acetal formation. The scalability of the reaction is illustrated by formation of acetal 6.26 on a 200 g scale (Scheme 6.12).12 In this case, a third catalyst, Fe(III), was included to improve the efﬁciency of the catalyst re-oxidation. The reaction may also be intramolecular. The allenic ether 6.28 was subjected to Wacker conditions, employing benzoquinone as the oxidant, on a multigramme scale (Scheme 6.13).13 The palladium could catalyse both the hydrolysis of the allenic ether to enone 6.29 and the 6-endo cyclization to the tetrahydropyran 6.30. In contrast, use of Brønsted acids to catalyse the cyclization of the isolated enone resulted in partial epimerization.14 Other nucleophilic atoms, such as nitrogen, may also be used, but it is necessary to be careful about the nitrogen substitution.15 If the nitrogen atom is too good a donor, as in amine 6.31, it will simply bind to Pd giving an inactive chelate 6.32 (Scheme 6.14). Less-nucleophilic nitrogen atoms are required, such as in sulfonamide 6.33 and aniline 6.35, where the electron density on the nitrogen atom is moderated either by the electron-withdrawing tosyl group, or by conjugation with the benzene ring (Schemes 6.15 and 6.16). In both cases it can be noted that the alkene formed by ␤-hydride elimination migrates into a more stable position under the reaction conditions. This method of making indoles has been used in a synthesis of the methyl ester of Clavicipitic acid 6.37.16 Palladium catalysis was employed for many key steps (Scheme 6.17). Heck reactions were planned to add

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Organic Synthesis Using Transition Metals (MeCN)2PdCl2, LiCl, benzoquinone 6.33

N 6.34 Ts

NHTs

Scheme 6.15 (MeCN)2PdCl2, LiCl, benzoquinone

N H

NH2 6.35

6.36

Scheme 6.16 nuc. addition to alkene AcHN H N

Heck reaction 6.37

CO2Me

X2

N H

CO2Me

HO

Heck reaction, then reduction of alkene

6.38

X1

N H

X2

X2

NO2

NH2 6.39

6.40

Scheme 6.17

two alkenes to a dihalogenated indole 6.38, where X1 and X2 are halogens showing different reactivity. The indole 6.38 would be made from a vinyl aniline 6.39, which would be derived form a substituted toluene 6.40. The synthesis started with 2-bromo-5-nitrotoluene 6.40 (X2 = Br) (Scheme 6.18). Benzylic bromination and SN 2 displacement of the bromide gave a phosphonium salt 6.41. A Wittig reaction could then be carried out under mild conditions, because the salt is activated by the ortho-nitro group. The nitro group was then reduced and the resulting amine was tosylated. The vinyl aniline derivative 6.39 was then cyclized to an indole 6.43 using palladium catalysis, with benzoquinone to reoxidize the palladium(0) to palladium(II). With the indole in hand, the second halogen could then be introduced, which was done via an organomercury intermediate. Indoles usually react with electrophiles at the 3-position. Two regioselective selective Heck reactions were then carried out on the dihalogenated indole 6.38 (X1 = I, X2 = Br). The ﬁrst, with a dehydroalanine derivative, functionalized the 3-position of the indole, due to the higher reactivity of iodide. The second installed a tertiary alcohol substituted alkene at the 4-position. Further treatment of the double Heck product 6.44 with a palladium(II) salt gave the tricyclic structure 6.47. No oxidizing agent was needed because the palladium eliminates as (formally) PdClOH, via ␩2 -complex 6.45 and ␩1 -complex 6.46, and, therefore, does not end up as Pd(0). However, the authors found that this step does not actually need Pd – just H+ will work, perhaps via an allylic carbocation. Double deprotection and alkene reduction was then carried out photochemically in one pot to complete the synthesis.

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Electrophilic Alkene and Alkyne Complexes Br 1. Br2, CCl4 2. PPh3

Br

Br PPh3

NO2

CH2O, Et3N NO2

NO2

6.40

6.41

1) Fe, HOAc 2) TsCl, py

Br

6.42 Br

Pd(MeCN)2Cl2 BQ

1) Hg(OAc)2 2) I2

NHTs 6.39

Br

I

N Ts

197

6.43

AcHN 1)

CO2Me Pd(OAc)2, Et3N

2) HO

Pd(OAc)2, Et3N

N Ts

OH CO2Me (MeCN)2PdCl2

AcHN

N 6.44 Ts

6.38 OH AcHN

HO

CO2Me

Ac N

CO2Me

ClPd

Cl2Pd

N Ts

6.45

N Ts

6.46

Ac N

CO2Me

H N

CO2Me

NaBH4, Na2CO3, hν N 6.47 Ts

N H

6.37

Scheme 6.18

The metal-catalysed cyclization of o-alkynyl anilines to indoles and o-alkynylphenols to benzofurans has been studied (Scheme 6.19).17 It is a useful method because the starting materials are readily available by Sonogashira reactions (Section 2.8). Cyclization followed by protonolysis of the ␩1 -intermediate 6.51 gives the heterocycle. As protonolysis regenerates a palladium(II) species, no added oxidant is required. In some cases, protonolysis is slow, and the reaction must be carried out in acidic conditions.18 In terms of synthetic planning, it must be noted that a transition-metal catalyst is not required for this cyclization. o-Alkynylamines can be cyclized to indoles under basic conditions, especially if the nitrogen atom has an electron-withdrawing substituent to lower the pKa . Just such a base-catalysed cyclization was employed in a synthesis of goniomitine (Scheme 6.20),19 after a Sonogashira reaction was employed to synthesize the substrate. Similarly, benzofurans are easily prepared by base catalysed cyclization as in a synthesis of Ailanthoidol (Scheme 2.115). The transition-metal catalysed cyclization is of particular importance when

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Organic Synthesis Using Transition Metals R PdCl2

R

X = O, NR'

X

XH 6.48

6.49

R

PdCl2 R X 6.49 protonolysis

coordination

XH 6.48

HCl Cl2Pd

PdCl

R

R X

XH

6.51

6.50 nucleophilic attack

Scheme 6.19 MeO2C Et NaOEt, Δ NHCO2Et 6.52

N 6.53

O

Et

Scheme 6.20

base-sensitive functionality is present, or when the ␩1 -intermediate 6.51 is intercepted to functionalize C3 in a tandem process (Section 6.1.1). 6.1.1

Tandem Reactions Involving CO or Alkene Insertion

Wacker-type chemistry can be combined with other aspects of palladium chemistry to create tandem reactions. For instance, the ␩1 -intermediate can be intercepted by carbon monoxide giving ester products. This chemistry has been found to be useful in the formation of tetrahydrofurans and tetrahydropyrans as the stereochemistry of the newly formed ring is usually controlled quite well (Scheme 6.21).20 For tetrahydrofuran formation, the substituent in the allylic position seems to have the most stereochemical-directing effect (Scheme 6.22).21,22 For tetrahydropyran formation, the 2,6-cis isomer, with both ␣-substituents equatorial, is favoured. If a disubstituted alkene is used, an additional chiral centre is created, and the two geometrical isomers of the alkene starting material give different diastereoisomers of the product (Scheme 6.23). The stereochemistry is consistent with nucleophilic attack trans to palladium, followed by CO insertion with retention. For most substrates, cyclization is found to be exo, but there are exceptions (Scheme 6.24). The stereochemical control can be particularly good for the formation of tetrahydropyrans. Examples include use in the synthesis of cyanolide (Scheme 6.25)23 and polycavernoside (Scheme 6.26).24 A further example can be found in Scheme 8.24.

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Electrophilic Alkene and Alkyne Complexes (MeCN)2PdCl2, CuCl2, CO, MeOH

87:13 O

OH 6.54

6.55

O

CO2Me

6.56

CO2Me

L nPdCl2

CO2Me

6.55/6

O

OH 6.54 coordination

MeOH

PdCl2 O 6.59

OH PdCl

O

6.57

nucleophilic attack

CO insertion CO

O 6.58

PdCl

Scheme 6.21

i-Pr

i-Pr PdCl2, CuCl2, CO, MeOH O 6.61

OH 6.60

CO2Me

Scheme 6.22

PdCl2, CuCl2 MeOH, CO

i-Bu

i-Bu

O H H CO2Me 6.63

i-Bu

O H H CO2Me 6.65

OH 6.62 PdCl2, CuCl2 MeOH, CO

i-Bu OH 6.64

Scheme 6.23

199

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Organic Synthesis Using Transition Metals

CO2Me

PdCl2, CuCl2, CO, MeOH O

OH 6.66

6.67

Scheme 6.24 OH PMPO

OH

OH

PdCl2, CuCl2, MeCN, MeOH, CO

PMPO H

6.68

CO2Me

O

H 6.69

Scheme 6.25 OTIPS OH

OTIPS

BnO

Pd(OAc)2 MeCN, MeOH, CO BnO

CO2Me

O

H

H 6.71

6.70

Scheme 6.26 PdCl2, CuCl2, CO, NaOAc

Ph

H O Ph

OH OH 6.72

O O H

H

PdCl2

Ph

6.73

OH Ph

OH OH

O CO

H

H O

PdCl

OH Ph O H PdCl

Scheme 6.27

The methanol can be replaced by another alcohol, especially if this second attack is also intramolecular. The product of the cyclization of an unsaturated diol 6.72 will then be a lactone 6.73 (Scheme 6.27).25 This reaction has been used to synthesize goniofufurone 6.74, starting from a known glucose derivative 6.76 (Scheme 6.28).26 Oxidative cleavage of the free diol, followed by Grignard addition proceeded with useful diastereoselectivity to give alcohol 6.77. After adjustment of the protecting groups, a Wittig reaction installed the alkene 6.79, ready for the palladium-catalysed carbonylative cyclization, which gave the bicyclic lactone 6.80. The synthesis was completed by debenzylation. Cyclocarbonylation of the monoprotected diol 6.81 gave a carboxylic acid 6.82 with complete stereocontrol (Scheme 6.29).27 This acid could be converted to the natural product, diospongin A 6.83, by Stille coupling

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Electrophilic Alkene and Alkyne Complexes HO

H

Ph HO

nucleophilic attack O H carbonylation H 6.74

HO HO

HO Ph

HO HO

O

O

6.75

HO

H

O

1. NaIO 4 2. PhMgBr

O

H

Ph

O

HO

H

O

Ph

O

O 6.77

OH Ph3P CH2

BnO BnO

PdCl2, CuCl2, NaOAc, CO, MeOH

Ph BnO

HO HO 6.79

OH 6.78

BnO

H

HO

O H

Ph

H O 6.80

BnO

1. BnBr, NaH 2. H 3O+

O

HO

6.76 BnO

HO

H

Ph

H2, Pd/C O

HO

O H O H 6.74

O

Scheme 6.28 OTBDPS OH OTBDPS

PdCl2, CuCl2, NaOAc, H2O, CO

Ph

Ph 6.81

O 6.82

CO2H

1. (COCl)2 2. n-Bu3SnPh, Pd(dba)2 3. TBAF OH OH OH

(PhCN)2PdCl2, n-Bu3SnPh

O

Ph

Ph 6.84

PdCl2, CuCl2, NaOAc, MeOH, CO

OH

O OH O

+ Ph

O 6.85

O 6.83

CO2Me

CO2Me

Ph 6.86

Scheme 6.29

Ph

201

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Organic Synthesis Using Transition Metals

Pd(OAc) 2 (1.1 eq.)

OH OTBS

O H H OTBS

6.87

6.88

Scheme 6.30 OEt HO

O + EtO

n-C5H11 Pd(OAc)2 NaOAc

+

n-C5H11

O TBSO

6.89

TBSO

6.90

1. (S)-BINAL 2. H3O+ 3. Ph3P

O

6.91

HO CO2H CO2

n-C5H11 HO

OH

6.92

Scheme 6.31 EtO

OEt

EtO HO

Pd(OAc)2

O

O

PdOAc insertion

6.93 TBSO

TBSO

6.89

n-C5H11

6.94

PdOAc 6.95

TBSO

OEt

OEt

O

O

β-hydride PdOAc elimination n-C5H11

O 6.90 insertion TBSO

O 6.96

n-C5H11 TBSO

O 6.91

Scheme 6.32

(Section 2.5). In contrast, the unprotected diol 6.84 gave a mixture of products, including a bis-carbonylation product 6.86. The diol 6.84 could, however, be cyclized directly to diospongin A 6.83 by treatment with a stoichiometric amount of a palladium(II) complex and a phenyl tin reagent. Another synthesis of this natural product may be found in Scheme 8.93. The ␩1 -palladium intermediate may be intercepted in other way. If additional alkenes are present, then a series of insertion reactions can occur. Alternatively, if a ␤-hydrogen is present, ␤-hydride elimination may occur to give an alkene (Scheme 6.30), a reaction used in the cyclization of alkene 6.87 as part of studies towards tetronasin.28 A three-component coupling involving three alkenes was employed using a stoichiometric amount of palladium to generate a bicyclic acetal 6.91, which could be converted to an epimer of the prostaglandin, PGF2 ␣ (Scheme 6.31).29 The three-component coupling involves nucleophilic attack of the alcohol 6.89 onto an ethyl vinyl ether–palladium complex 6.93, intramolecular alkene insertion, intermolecular insertion of

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Electrophilic Alkene and Alkyne Complexes

203

n-BuO On-Bu OH

PdOAc

O

Pd(OAc)2 TBSO

TBSO

6.98

6.97 On-Bu O

insertion

β-hydride elimination

On-Bu O

TBSO TBSO 6.99

AcOPd

6.100

Scheme 6.33 NHCO2Me

PdCl2, CuCl2, CO, MeOH

6.101

NCO2Me

6.102

1. HBr 2. Boc 2O

NBoc

CO2Me

CO2Me

6.103

Scheme 6.34

Ph

OMe HNPhth, (MeCN)2PdCl2, PhI(OAc)2

6.104

OAc Ph

OMe NPhth 6.105

Scheme 6.35

alkene 6.90 and, ﬁnally, ␤-hydride elimination (Scheme 6.32). The non-occurrence of ␤-hydride elimination from ␩1 -intermediate 6.94 after the nucleophilic attack step may be attributed to rapid intramolecular insertion of the second alkene; non-occurrence of ␤-hydride elimination from ␩1 -intermediate 6.95 after the ﬁrst alkene insertion is due to the absence of any ␤-hydrogen atoms with the correct syn stereochemical arrangement. A similar, but shorter sequence was employed in a synthesis of dihydroxanthatin, with the addition of a copper(II) salt to make the process catalytic in palladium (Scheme 6.33).30 The ␤-hydride elimination terminates a sequence that includes a nucleophilic attack and an intramolecular insertion. The alkene insertion from the ﬁrst ␩1 -complex 6.98 to the second ␩1 -complex 6.99 proceeds with very high diastereoselectivity. Further aspects of this synthesis, employing metathesis chemistry, can be found in Scheme 8.113. Other nucleophiles can also be used to attack the ␩2 -alkene palladium complexes. For instance, a nitrogen nucleophile was used in a transannular reaction to give a known precursor 6.103 to ferruginine (Scheme 6.34).31 The anti-stereochemistry in the nucleophilic attack is translated into the trans disposition of the nitrogen and ester groups in the product. Under oxidative conditions, double additions to alkenes can be achieved. Treatment of alkene 6.104 with phthalimide in the presence of a palladium catalyst, as well as iodosobenzene diacetate as both an oxidizing agent and as an acetate source, gave a 1,2-difunctionalized product 6.105 (Scheme 6.35).32 The reaction is believed to proceed through a Pd(IV) intermediate. Intramolecular difunctionalization has also been reported (Schemes 6.36 and 6.37).33,34

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Organic Synthesis Using Transition Metals HNPhth, Pd(OAc)2, AgBF4, PhI(OAc)2

HO

O PhthN

6.106

6.107

Scheme 6.36 O

NHTs O

Pd(OAc)2, PhI(OAc) 2, Me4NCl, NaOAc

NH

N

6.108

NTs

6.109

Scheme 6.37 R

PdCl2, Et3N R

NEt3 Pd Cl

6.110

NEt3 CO2Me CO2Me CO2Me

CO2Me R

CO2Me

→ RT

CO2Me CO

R

CO2Me

R

PdLnCl 6.111

6.112

PdLnCl 6.109

H2 CO2Me R

CO2Me O

ArSnMe3

ArSnMe3

CO2Me 6.113

CO2Me R

CO2Me Ar

6.114

CO2Me R

CO2Me O 6.115 OMe

CO2Me R

CO2Me O 6.116 Ar

Scheme 6.38

Using carbon nucleophiles in these schemes is complicated by the fact that the nucleophiles themselves are often susceptible to oxidation. The most general system is a stepwise process that is stoichiometric in palladium (Scheme 6.38).35 The alkene is ﬁrst complexed to palladium in the presence of triethylamine, which acts as a ligand. Addition of a stabilized carbanion nucleophile to the ␩2 -complex 6.110 results in the formation of a ␩1 -complex 6.111. Complexes of this type are stable at –20 ◦ C. At higher temperatures, ␤-hydride elimination occurs to give the alkene 6.112. Alternatively, other reagents may be added to intercept the complex and make extra use of the expensive palladium atom. Hydrogenation yields the alkane 6.113, while addition of a tin reagent results in Stille coupling product 6.114. Addition of CO and an alcohol gives an ester 6.115;36 addition of a tin reagent and CO results in a ketone 6.116.37 Both of the carbonylation reactions proceed via the ␩1 -acyl complex 6.109.

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Electrophilic Alkene and Alkyne Complexes OH

1. PdCl2, Et3N 2. Nuc 6.124 2. CO 3. Me2C=CHSnMe3

O Ph (PhO)2CO, NaH

HN

N

O

Ph

(OC)5Cr

Ph 6.117

Ph 6.118

Ph

Ph O

Ph O

O

N

CO2Et 6.119

O

Ph HO

1. CF3CO2H 2. Δ, -CO2 3. NaBH4, CeCl3

CO2t-Bu

N

O

1. LiOH CO2Et 2. PPh3, (t-BuO2CN)2

6.120

Ph O

Ph

N

O

1. EtOH, KCN 2. O3; Me2S, NaBH4 3. TBSCl, imid. 4. MsCl, Et3N, 5. NaN3

O O 6.121

HO

205

O

Ph TBSO

N

N3

O CO2Et

1. LiOH 2. EtO2COCl, Et3N 3. RNH2 6.125 4. HF 5. H2, Pd/C

6.122

NH2 O

H2N

Ph

N H

Me N

CO2Et CO2H

Nuc =

6.123

CO2t-Bu 6.124

RNH2 =

H2N

Me N

CO2Bn

6.125

Scheme 6.39

Consistent with the Wacker process, ethylene and monosubstituted alkenes give the best results. Alkenes bearing heteroatoms can also be good substrates. Stabilized nucleophiles such as malonates are preferred; simple enolates and the anions derived from nitriles can be used but require HMPA as a co-solvent. This reaction has been used in a synthesis of the antibiotic negamycin 6.123 (Scheme 6.39).38 The starting alkene 6.118, bearing a chiral auxiliary, was prepared by chromium carbene chemistry (Section 8.1.1) as attempted cyclization of the amino carbene 6.117 resulted in elimination of chromium to give the vinyl oxazolidinone 6.118 (compare to Scheme 8.14).39 Reaction of the alkene with the anion of unsymmetrical malonate 6.124 followed by the carbonylative Stille conditions gave the enone 6.119, as a single stereoisomer other than at the inconsequential malonate centre, as a result of a four-component coupling. Decarboxylation and reduction gave the alcohol 6.120 with very good diastereoselectivity on reduction, but as the undesired anti-isomer. This was corrected by a Mitsunobu reaction forming lactone 6.121. The Mitsunobu reaction had to be intramolecular, as intermolecular attempts were complicated by the allylic nature of the substrate 6.120. Reopening of the lactone and oxidative cleavage of the alkene allowed introduction of the additional nitrogen functionality as azide 6.122. After ester hydrolysis, this could be coupled with the substituted hydrazine 6.125. Catalytic hydrogenation, including a combined debenzylation, chiral auxiliary removal and azide reduction, gave the natural product 6.123. A 6-endo cyclization of an indole derivative is one example of a cyclization involving a carbon nucleophile that is catalytic (Scheme 6.40).40

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Organic Synthesis Using Transition Metals CO2Me

Et PdCl2, CuCl2, MeOH, CO

N H

N H

Et

6.126

6.127

Scheme 6.40 CO2Et CO2Et PdCl2, CuCl2

Ph

Ph 6.129

N Ms

NHMs

CO2Me

PdCl2, CuCl2, K2CO3, CO, MeOH

6.128

Ph N 6.130 Ms

Scheme 6.41 •

TsHN

PdCl2, CuCl2, CO, MeOH N Ts

6.131

CO2Me

6.132

Scheme 6.42 OH • 6.133

1. PdCl 2, CuCl2, CO, MeOH 2. NaOH O

CO2H

6.134

Scheme 6.43

The synthesis of indoles and benzofurans by the palladium-catalysed cyclization of o-alkynyl anilines and phenols can also form part of tandem processes through interception of the ␩1 -intermediate (Scheme 6.41). Inclusion of an alkene results in a Heck process, giving 3-vinylated indoles 6.129.41 As the ␤-hydride elimination step causes reduction of the palladium(II) to palladium(0), an oxidizing agent, such as copper(II) must be included to maintain catalysis. The intermediate may also be intercepted by alkoxycarbonylation, giving an ester 6.130.42 Again an oxidant is needed. Alkoxycarbonylation is also a useful method for allene cyclization (Schemes 6.42).43,44 This reaction has been employed in a synthesis of rhopaloic acid by cyclization of allene 6.133 (Scheme 6.43).45

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Electrophilic Alkene and Alkyne Complexes

207

RX, Pd(0), base

YH

Y R

R

R X

LnPd(0)

Y reductive elimination

oxidative addition

LnPd

YH

R LnPd X

Y

base

R

Y

nucleophilic attack

L

X R Pd

coordination

Y

Heck pathway

R

YH

Scheme 6.44 Ph CO2Me

PhI, KOt-Bu, Pd(dppe)

CO2Me

MeO2C MeO2C

6. 13 5

6.136

Scheme 6.45

6.1.2

Tandem Reactions with Oxidative Addition

Another tandem possibility is to use oxidative addition to generate the palladium(II) species that initiates cyclization (Scheme 6.44). The result is formation of both a C–C bond and a bond between an alkene carbon and a heteroatom. The C–C bond is formed by reductive elimination that generates a palladium(0) species. This is then returned to the palladium(II) state by oxidative addition, hence no added oxidant is required. The reaction has often been used in an intramolecular fashion to ensure regioselectivity. If the nucleophilic attack is slow, a by-product may occur, which is the Heck product arising from alkene insertion. Alkynes may also be used as substrates. This chemistry can be used in a number of ways, for instance, the combination of a malonate 6.135 with an unsaturated side chain and an aryl halide yields a substituted cyclopentane 6.136 (Scheme 6.45).46 Alkynes have been widely employed as the ␲-component, with both N-nucleophiles (Scheme 6.46)47 and O-nucleophiles (Scheme 6.47)48 to give a variety of heterocycles. An application of particular importance has been in the synthesis of indoles 6.142 by the cyclization of o-alkynyl aniline 6.141 derivatives (Scheme 6.48).49 The system may be extended to the synthesis of 3-acyl indoles 6.144 by the inclusion

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Organic Synthesis Using Transition Metals H

Ph 1. n-BuLi 2. PhI, Pd(OAc) 2, PPh3

N Ts H 6.138

TsHN 6.137

Scheme 6.46 H

1. n-BuLi Ph 2. PhI, Pd(OAc) 2, PPh3 O

HO

H 6.140

6. 1 39

Scheme 6.47 OMe

(Ph3P)2PdCl2, K2CO3 OMe

N 6.143 COCF3

+

OMe

O NHCOCF3

I

6.141

6.142

(Ph3P)2PdCl2, CO,K 2CO3

6.144 N COCF3

Scheme 6.48

Ph

• (Ph3P)4Pd

+ OH 6.145

OCO2Me 6.146

Ph O 6. 147

Scheme 6.49

of CO, allowing a three-component coupling reaction.50 Propargyl derivatives can also induce cyclization (Scheme 6.49).51 An important stereochemical study illustrates how the mechanism can depend on the ligation state of the palladium.52 In a doubly intramolecular process, different diastereoisomers were formed depending on the ligand employed (Scheme 6.50). The stereochemical results can be explained by the ligation state of the palladium (Scheme 6.51). It appears likely that the monodentate tricyclohexylphosphine 1.8 allows

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Electrophilic Alkene and Alkyne Complexes

Pd(0), PCy3, NaOt-Bu

209

O 6.151 >20:1 dr

Br HO 6.147

Pd(0), dppbz, NaOt-Bu O 6.152 15:1 dr

Scheme 6.50

Br Pd(0), PCy3, NaOt-Bu

6.147

HO

Pd(0), dppbz, NaOt-Bu

Ph2P

Cy3P O Pd

Pd PPh2

6.153

O

6.155 anti-attack

insertion

PdL

6.154

Pd O Cy3P

O 6.156 reductive elimination

reductive elimination

6.151

O

6.152

O

Scheme 6.51

coordination of both the alkene and the alkoxide to palladium after oxidative addition, giving a complex 6.153. Insertion of the alkene into the C–Pd bond, gives an alkoxy palladium complex 6.154, which undergoes reductive elimination to form the C–O bond. These are all syn processes, so isomer 6.151 is formed. On the other hand, the bidentate phosphine, dppbz 1.31, may block O–Pd coordination, so that complex 6.155 is formed and only anti-attack of the alkoxide can occur, leading to the other diastereoisomer 6.152.

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Organic Synthesis Using Transition Metals HO

Cl

O

Cl

Ph3PAuCl, AgOTf 6.157

Scheme 6.52 OMe AuCl3, CuCl2, MeOH, Δ

n-C6H13

n-C6H13 6.158

Scheme 6.53 Ph3PAuCl, AgOTf

Me N 6.159 Ts

NHTs 6.35

Scheme 6.54

6.2

Other Metals: Silver, Gold, Platinum and Rare Earths

Silver, gold,53 and platinum coordinate well to C–C ␲-bonds and activate them to nucleophilic attack. Numerous examples have appeared over the last few years and asymmetric versions have also been reported.54 The reactions encompass not only heteroatom nucleophiles, but also carbon nucleophiles.55 When gold chloride catalysts are used, they are often accompanied by silver salts, typically AgOTf, AgBF4 or AgSbF6 . The purpose of the silver salt is to effect counter ion exchange of the chloride from the gold complex with the more-labile ion of the silver salt (see Scheme 1.4), to give a more reactive gold complex. Reactive but air-stable gold complexes with the weakly coordinating triﬂamide counter ion, LAuNTf2 (L = phosphine or NHC), can be prepared in a separate step and used in catalysis without the addition of silver salts.56 6.2.1

Reactions of Alkenes

Alkenes tend to be the least-reactive class of substrates, requiring more forcing conditions and nonpolar solvents. Nucleophilic attack generates a ␩1 -alkyl gold species. These show little or no tendency to undergo ␤-hydride elimination. Instead, protonolysis of the carbon–gold bond is observed, regenerating the catalyst and resulting in net addition of HX across the alkene. As with the chemistry of the palladium catalysts, nucleophilic attack tends to be at the more-substituted terminus of the alkene. Both oxygen (Schemes 6.52 and 6.53)57,58 and nitrogen (Schemes 6.54 and 6.55)59,60 nucleophiles can be used. Dienes may be employed as substrates (Scheme 6.56).61 Platinum catalysis, especially with platinum triﬂate, has also been used (Scheme 6.57).62 Unlike palladium chemistry, ␤-hydride elimination of the ␩1 -intermediate is not observed. Instead, protonolysis of the carbon–metal bond is observed, giving overall addition without change of the metal oxidation state. The difference is particularly apparent in the cyclization of o-allylaniline (Scheme 6.54) that gives the indoline 6.159 with gold(I) catalysis. In contrast, the same substrate, with palladium catalysis with an added oxidant, gives the indole (Scheme 6.16). Electron-rich heteroaromatics may also act as the nucleophile (Scheme 6.58).63 The platinum-catalysed cyclization of indole 6.165 proceeds through intramolecular attack of the heterocycle on the ␩2 -complex

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Electrophilic Alkene and Alkyne Complexes

biph(t-Bu)2PAuCl, AgOTf

CbzHN Ph Ph 6.160

Cbz N Me Ph Ph 6.161

Scheme 6.55 H

SO2Ph N

Ph3PAuCl, AgOTf NHSO2Ph

HPh Ph

Ph Ph 6.162

6.163

Scheme 6.56 TsNH2 CODPtCl2, AgOTf

NHTs

6.164

Scheme 6.57

CO2Me

H CO2Me CO2Me

H

PtCl2

CO2Me N Me

N Me

6.165

6.166

H CO2Me CO2Me

H

CO2Me CO2Me

N Me 6.166 protonolysis H

PtCl2

N Me 6.165 coordination

ClPt H

Cl2Pt

H CO2Me CO2Me

CO2Me N Me

N Me 6.169 H

CO2Me

nucleophilic attack

ClPt H

6.167

H

N Me

H CO2Me CO2Me 6.168

Scheme 6.58

211

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Organic Synthesis Using Transition Metals Cat., 10 °C S Et

S

NH2 Et

6.170 H

Cat., 60 °C

HN 6.171

H Ni(R)

N

N

Et

S

6.172

i-Pr

N

n-C7H15

Cat. = 6.174

6.173

Sc N(SiMe3)2 N

i-Pr

Scheme 6.59

F N +

TsSO2HN

(HO)2B

N

6.177 dppm(AuBr)2

F

Cl

NTs F

6.176

6.175

6.178

Scheme 6.60 O

+ MeOH N + O

6.179

M

F N

O

N

6.177 Ph3PAuCl

Cl

N MeO O

6.180

M = SiMe3, B(OH)2

Scheme 6.61

6.167, followed by protonolysis of the carbon–platinum bond of ␩1 -complex 6.169. This reaction may be contrasted with the related palladium-catalysed cyclization, which proceeds through CH activation (Scheme 3.11). Amino complexes of rare-earth elements can undergo intramolecular alkene insertion rather than alkene activation followed by nucleophilic attack (Scheme 6.59). Treatment of the amino diene 6.170 with a scandium complex 6.174 resulted in insertion of one double bond to give a cis-pyrrolidine 6.171.64 Raising the reaction temperature then caused insertion of the second alkene to give the pyrrolizidine 6.172. The thiophene group had been chosen to activate the ﬁrst alkene: it also serves as a surrogate alkyl group, and the synthesis was completed by desulfurization-reduction. The product is the alkaloid, xenovenine 6.173 (see Schemes 6.65 and 6.74 for related syntheses, and Scheme 9.46 for a different approach.) The ␩1 -organogold intermediate generated by the nucleophilic attack may undergo other reactions rather than just protonolysis. Coupling with boronic acids and other main-group organometallics has been demonstrated (Schemes 6.60 and 6.61). The addition of selectﬂuor 6.177 was an essential additive. This reagent functions as both an oxidizing agent to convert the gold(I) catalyst to gold(III), and as a ﬂuoride source to activate the boronic acid or silane.65,66

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Electrophilic Alkene and Alkyne Complexes Mn+

Mn+ •

213

•

XH Mn-1+

XH

H+ X

X

Scheme 6.62

HO

AgBF4

•

O

6.181

6.182

Scheme 6.63 OAc AcO

HO

H • NH

1. Ph 3PAuCl, AgBF4 2. LiAlH4

H

OH

N

O 6.183

6.184

Scheme 6.64 O •

HON

n-C5H11

Ag(I)

n-C5H11

N O

6.185

6.186 1. CrO 3 2. (HSCH 2)2 3. Ni(R)

H H n-C5H11

N O O

H2, Pd/C

HO

N

H N n-C7H15

n-C7H15 6.187

6.188

6.189

Scheme 6.65

6.2.2

Reactions of Allenes

When allenes are employed, the result is an ␩1 -vinyl organometallic complex. These often undergo in situ protonolysis of the carbon–metal bond to give a simple double bond (Scheme 6.62).67 The reaction can occur in both the endo- mode (as shown) or the exo- mode, with a wide variety of nucleophilic groups, including alcohols (Scheme 6.63),68 sulfonamides,69 amides and oximes.70 The cyclization of allenic amides was employed in a synthesis of ent-retronecine 6.184 and other pyrrolizidine alkaloids (Scheme 6.64).71 The substrate, lactam 6.183, was prepared from malic acid using iminium ion chemistry. The Oxime cyclization reaction gave a nitrone 6.186, which could be employed in a subsequent 1,3-dipolar cycloaddition (Scheme 6.65). This sequence was used in a synthesis of xenovenine 6.189, a component of an ant venom. The cycloadduct of the nitrone 61.86 with methyl vinyl ketone was subjected to catalytic hydrogenation, which

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Organic Synthesis Using Transition Metals

O

•

O

O

Ph3PAuCl

O O

OH 6.190

6.191

1. MeOH, H + 2. DMP 3. Ph 3P=CH2

OH O 6.192

Scheme 6.66 Et Et OH

Ph

Ph • 6.193

O 6.194

LAuCl, AgOTf CbzNH2

NHCbz 6.195

Scheme 6.67

resulted in a tandem process including alkene reduction, N–O bond cleavage and reductive amination, to give pyrrolizidine 6.188. Removal of the hydroxy group produced by N–O bond cleavage completed the synthesis. See Schemes 6.59, 6.73 and 9.46 for other routes to this alkaloid. The cyclization of a chiral allenic alcohol was employed in a synthesis of bejarol 6.192, with the allene chirality relayed into the product (Scheme 6.66).72 While intramolecular reactions are undoubtedly favoured, intermolecular reactions have also been developed (Scheme 6.67).73 The silver-catalysed cyclization of an allenic hydroxylamine was used to form a syn-aminoalcohol derivative in a synthesis of sedinine 6.202 (Scheme 6.68).74 Cyclization of allene 6.196 with silver triﬂate gave predominantly the cis-isoxazolidine 6.197, with the selectivity dependent on the counter ion. Ring opening and reclosing gave a cyclic N,O-acetal 6.199, conformationally predisposed towards the following RCM due to the steric demand of the Boc group. Ring opening of the N,O-acetal 6.299, formed by RCM, via stereoselective trapping of the associated iminium ion and a pair of reduction reactions yielded the natural product 6.202. The silver-catalysed cyclization of allenic ketones has been extensively used for the synthesis of furanoid natural products. An example is the cyclization of allene 6.203 to furan 6.204 in the synthesis of kallolide (Scheme 6.69).75 The reaction of allenic ketones 6.205 with a gold(III) catalyst proved to give a much faster reaction than with silver catalysts, to give substituted furans, 6.206 and 6.207 (Scheme 6.70).76 In the products, a second molecule of the substrate adds to the initial product, to give 2,5-disubstituted furan. Interestingly, palladium(II) catalysis, also slower than gold catalysis, gives the isomeric series of products 6.208. The cyclization of an allenic carbamate 6.209 was employed in a formal synthesis of swainsonine (Scheme 6.71).77 The stereoselectivity of the cyclization was completely controlled by the adjacent silyloxy group. Further steps in this synthesis can be found in Scheme 9.71. Tandem cyclization processes involving epoxides have also been described (Scheme 6.72).78

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Electrophilic Alkene and Alkyne Complexes

• AgOTf N Me

ONHt-Boc

Me

1. Mo(CO)6, H2O t-Boc 2.(MeO) HC(CH ) Br, H + 2 2 3 3. KOt-Bu, THF

O

Me

6.197

6.196 N

t-Boc Me

O

Me

6.199 HO

O N H H t-Boc

Ph

OSiMe3 Ph SnCl4

N O H 6.200

1. (R )-CBS, BH3.SMe2 2. AlH 3

OH 6.198

H

Grubbs I, CH2Cl2

t-Boc

NHt-Boc

HO

OH H

6.201

N H Me

Ph

6.202

Scheme 6.68

DPSO

OCOPh AgNO3

•

DPSO

6.203

OCOPh

O

O 6.204

Scheme 6.69 AuCl 3 R

+

R

O

• O 6.205

R

R

O

6.206

O

6.207 O R

(MeCN)2PdCl2 R

O 6.208

Scheme 6.70 TBSO TBSO •

t-BocHN

AuCl 3, CaCO3, MeCN, CH2Cl2

Nt-Boc

6.209

6.210 TBSO

1. CF 3CO2H 2. AlocCl, Na 2CO3 N

O O

Scheme 6.71

6.211

215

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Organic Synthesis Using Transition Metals

•

MeO2C CO2Me

Me

O

OH (PhO)3PAuCl, AgOTf

MeO2C CO2Me

H

6. 21 2

O

Me O H

6.213

Scheme 6.72

Cp*2LaCH(SiMe3)2 6.215 n-C5H11

n-C5H11

N H 6.216

• 6.214

NH2 H N Me2Si

SmN(SiMe3)2

N t-Bu

n-C5H11

6.218

6.217

H2, Pd(OH)2/C H N n-C7H15 6.189

Scheme 6.73

The amino derivatives of rare-earth metals follow a distinct mechanism involving direct insertion of the allene or alkene into the metal-nitrogen bond (Scheme 6.73).79 With the less-reactive lanthanum complex 6.215, amine 6.214 underwent insertion of only the allene, giving a pyrrolidine product 6.216 as the trans isomer. On the other hand, using the more-reactive samarium complex 6.217, tandem allene and alkene insertion occurred giving, after hydrogenation, the pyrrolizidine alkaloid, xenovenine 6.189. A closely related synthesis of this alkaloid is in Scheme 6.59. Other syntheses may be found in Scheme 6.65, and Scheme 9.46.

6.2.3

Reactions of Alkynes

Nucleophilic addition to alkynes is promoted by a number of metal catalysts. One of the simplest catalysts is silver nitrate, which can be more effective when absorbed onto silica gel.80 Treatment of alkynyl alcohols 6.190 with this reagent is a useful route to furans, as the exo-cyclic double bond, under the reaction conditions, migrates to the endo-cyclic position (Scheme 6.74). In the cyclization of N-propargyl amides, whether the exo-cyclic double bond of the initial product migrates into the ring or not could be controlled by the choice of catalyst (Scheme 6.75). The same substrate 6.193, with a gold(III) catalyst gave the oxazole 6.194 after double-bond migration.81 With the milder gold(I) triﬂamide

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Electrophilic Alkene and Alkyne Complexes

AgNO3

n-C7H15 n-C5H11 6.190

n-C7H15

HO

217

n-C5H11

O

6.191

n-C5H11

O

n-C7H15

6.192

Scheme 6.74

O N

AuCl3

S

O

6.194

N H

S

O Ph3PAuNTf 2

6.193

N S

6.155

Scheme 6.75 F F

F F

F

AuCl3, CH3CN

Ar TsHN

Ar

R

N Ts

6.156

R 6.157

Ar

N Ts

R 6.158

Scheme 6.76 n-C11H23 NH2 6.159

NaAuCl 4 N H

n-C11H23 6.160

N

n-C11H23

6.161

Scheme 6.77

catalyst, migration was not observed, giving the exo-cyclic isomer 6.155. The reactive exo-cyclic double bond opens up synthetic possibilities to introduce further functionality. Alternatively, cyclization can be followed by elimination to give the aromatic heterocycle (Scheme 6.76). With two ﬂuorine substituents in the starting material 6.156, only one is eliminated from intermediate 6.157, leading to a 3-ﬂuoropyrrole 6.158.82 In a pioneering example, an amino alkyne 6.159 cyclized in the presence of a gold(III) salt to give an unstable exo-cyclic enamine 6.160, which tautomerized to the tetrahydropyridine 6.161, a component of an ant venom (Scheme 6.77).83

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Organic Synthesis Using Transition Metals O PtCl2, THF, H2O O 6.162

6.163

6.164

Scheme 6.78 O OEt

PtCl2, THF, H2O 6.165

OEt

OEt 6.166

88:12

O 6.167

Scheme 6.79 MeOH, PtCl2, Na2SO4 MeO OMe 6.168

6.169

Scheme 6.80 OH OH t-Bu2(o-biph)AuCl, AgOTf

HO 6.170

O O

6.171

Scheme 6.81

Alkynes often give the product of the addition of two nucleophiles, which may be the same, or different species.84 Platinum(II) chloride has been found to be a useful catalyst for the hydration of alkynes to give ketones, avoiding the use of mercury, the classical catalyst for this reaction (Scheme 6.78).85 With simple, unsymmetrical alkynes, regioselectivity is poor, but the presence of a substituent can bias the regioselectivity strongly in favour of one isomer (Scheme 6.79).86 Replacement of water by simple alcohols leads to ketals (Scheme 6.80).87 The mechanism for ketal formation must involve attack by one molecule of alcohol to form a vinyl ether, followed by a second attack. The ﬁrst attack clearly involves nucleophilic attack on an ␩2 -platinum complex to give a vinyl ether. In principle, the second attack may be also platinum catalysed, or catalysed by traces of Brønsted acids present. A similar situation occurs in Wacker chemistry (Scheme 6.9). In this case, it was found that adding a bulky base, 2,6-di-t-butylpyridine, did not suppress the reaction. This fact indicates that the second step is also platinum catalysed. Both gold (I)88 and platinum(IV)89 have also been used in the synthesis of cyclic ketals (Schemes 6.81 and 6.82), while gold catalysis converted propargylic alcohol into a cyclic bis-acetal 6.174 (Scheme 6.83).90 Other nucleophiles, or combinations of nucleophiles, can also be employed in double additions (Scheme 6.84).91 Electron-rich heterocycles can also participate in such reactions. This is mechanistically distinct from C–H activation (Chapter 3) as it is more closely related to an electrophilic attack on the pyrrole (Scheme 6.85).92 A number of catalysts have been employed for the addition of carboxylates to alkynes (Scheme 6.86). For additions to terminal alkynes, addition can be to either the internal and terminal carbon, depending on the catalyst.93–95

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Electrophilic Alkene and Alkyne Complexes MeO2C

OH MeO2C OH

O

PtCl4, THF

N Ts

O N Ts

6.172

6.173

Scheme 6.82

OH

Ph3PAuMe, MeOH

MeO

O O

OMe

6.174

Scheme 6.83

O NH2

CO2H

+

PtCl2 or PtCl4 or Ph3PAuCl, AgOTf

N

NH2 6.175

6.176

N Me H

Scheme 6.84

NH2

+

OH

PtCl2

N

N N Me

6.177

Scheme 6.85

PhCO2H [(i-PrPh)RuCl2]2, P(2-Fu)3

R PhCO2

R

6.180 PhCO2

6.179 PhCO2H, [Rh(cod)Cl]2

R 6.181

N PPh2

Scheme 6.86

6.178

219

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Organic Synthesis Using Transition Metals

CO2H EtO2C EtO2C

EtO2C (Ph3P)AuCl, AgSbF6

O

O

EtO2C H

6 . 18 2

6.183

Scheme 6.87 OMe OMe Ph3PAuNTf2

O H

OH 6.184

H

6.185

Scheme 6.88

+ 6.186

CO2Et

PtCl2, AgOTf CO2Et 6.188

6.187

Scheme 6.89 MeO

AuL+

MeO

MeO

O 6.189

MeO

MeO

O

AuL

MeO

6.190

O 6.191 H+

MeO MeO

MeO O

6.193 5-exo product

•

MeO

O 6.192

AuL

MeO MeO

O

6.194 6-endo product

Scheme 6.90

Tandem cyclization reactions to form polycyclic structures have also been reported (Schemes 6.87 and 6.88).96 Some of these reactions can strongly resemble the polyene cyclizations that lead to steroids.97 Further ene–yne reactions can be found in Section 6.2.5. Alkynes can also be activated to attack by carbon nucleophiles. Examples include the reaction between propiolate esters 6.187 and arenes (Scheme 6.89).98 In intramolecular reactions, both exo- and endo-mode cyclizations may be observed. In a study of chromene formation, endo-cyclization giving the chromene 6.194 was generally the preferred pathway; the observation of the 5-exo product 6.193 was attributed to fragmentation of the organogold intermediate 6.191 prior to protonation, to give an allenic intermediate 6.192, followed by cyclization (Scheme 6.90).99

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Electrophilic Alkene and Alkyne Complexes

221

Li O I

O

+

OTBS

TBSO 6.195

6.196

6.197 O

1. TBAF 2. PCC

LAuNCCH3 SbF6

O

O

O

6.198

6.199 O

1. MeMgBr, CuBr.SMe 2, Me3SiCl 2. TBAF 3. Me3SiOTf, Et3N; IBX

L = Johnphos 1.14

O 6.200

Scheme 6.91

An intramolecular version of this reaction, employing a furan as the nucleophile with an acetylenic ketone as the acceptor was employed in a short synthesis of crassifolone 6.200 (Scheme 6.91).100 The cyclization substrate 6.198 was synthesized using standard chemistry and cyclized on treatment with a cationic gold catalyst. The product 6.199 could be converted to the natural product by conjugate addition of a Grignard reagent to form the quaternary centre, followed by oxidative introduction of an alkene. A synthesis of tylophorine 6.207 used an electron-rich arene as the carbon nucleophile (Scheme 6.92).101 The substrate was constructed by a sequence of two Suzuki couplings (Section 2.6), ﬁrst an aryl–aryl coupling between iodide 6.201 and boronic acid 6.202, then an aryl–alkyne coupling, using an alkyne boronate 6.204 derived from proline. Platinum-catalysed cyclization generated the pyrrolidine 6.206, and the synthesis was completed by a one-pot deprotection-Pictet–Spengler reaction. A silyl enol ether was employed as the nucleophile in a synthesis of lycopladine A 6.211 (Scheme 6.93).102 Gold-catalysed cyclization onto an iodoalkyne 6.208 gave a vinyl iodide 6.209 then allowed a Suzuki coupling to install an ␣,␤-unsaturated imine. After coupling, the imine 6.210 underwent an electrocyclic ring closure to form the pyridine ring of the natural product. Another synthesis of this alkaloid is presented in Scheme 9.62. Cyclization can proceed with cleavage of the carbon–metal bond by an electrophilic group released from the ﬁrst step, rather than protonolysis, though it is not clear exactly how the group transfer occurs. Treatment of the ethoxyethyl ether 6.212 with a platinum catalyst gave the benzofuran 6.213, with the ethoxyethyl group transferred to C3 (Scheme 6.94). Functionalization at C3 is a well-developed method using palladiumcatalysed cyclization (Scheme 6.48), but the mechanistic pathways are quite distinct, and the groups that can be added at C3 are quite different. This reaction has been used in the synthesis of a precursor to vibsanol 6.218,103 a benzofuran natural product from Viburnum awabuki (Scheme 6.95). The alkynyl phenolic ether precursor 6.216 was formed by a Sonogashira reaction between iodide 6.214 and alkyne 6.215, and cyclized, with transfer of the benzyloxymethylene group from O to C3, on treatment with platinum(II) chloride.

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Organic Synthesis Using Transition Metals MeO I

MeO

MeO Br

MeO

dppfPdCl2, LiCl, Na2CO3

+

Br

MeO MeO

B(OH)2 6.202

6.201

MeO MeO

6.203

MeO MeO N OMe Boc 6.204 dppfPdCl2 B

PtCl2 N Boc MeO 6.205

MeO

MeO

MeO MeO

MeO

H HCHO, H +

N

N

Boc MeO

MeO

MeO

6.206

MeO

6.207

Scheme 6.92

OBn

OBn TBSO

O I

H 6.208

OBn O

I

Ph3PAuCl, AgBF 4

H 6.209

OH

NNMe2 1. Δ 2. H 2, Pd/C

pinB NNMe2 (Ph3P)4Pd, NaOMe

O N H 6.211

H 6.210

Scheme 6.93

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Electrophilic Alkene and Alkyne Complexes

223

OMe OEt PtCl2, COD

OMe O

O OEt

6.212

6.213

Scheme 6.94 OEE

I

EEO

+

(Ph3P)4Pd, CuI, Et3N OCH2OBn

OMe 6.214

OEE 6.215

OEE

OBn

OMe PtCl2, COD EEO

EEO

OEE O

OCH2OBn OEE

OEE

6.216

6.217

OMe

OH HO

OH O OH

6.218

OMe

Scheme 6.95

O

TsN

AuCl 3, MeCN

6.219

TsN 6. 2 20

OH

Scheme 6.96

6.2.4

The Hashmi Phenol Synthesis

The intramolecular reaction between furans and alkynes often does not yield the expected hydroarylation products, but, instead, gives phenols 6.220 in an efﬁcient and selective manner (Scheme 6.96).104 This reaction was probably the ﬁrst “surprising” transformation from gold catalysis, indicating that gold could be more than just an electrophilic trigger.105 Running the reaction at a lower temperature using a milder catalyst 6.226 allowed observation of intermediate arene oxide/ oxepane 6.223ab and even the trapping of the arene oxide 6.223a as a Diels–Alder adduct 6.225 (Scheme 6.97).106 This intermediate is believed to arise by a formal cycloaddition of the alkyne to the furan, followed by opening to give a pentadienyl cation 6.222, which recloses to the arene oxide 6.223a. Reopening of the epoxide completes a 1,2-movement of the furan oxygen, and a proton shift completes the formation of the product 6.220.107

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Organic Synthesis Using Transition Metals AuL n

O

O

TsN

O TsN

TsN 6.219

6.221

6.222

TsN

TsN O 6.223a O

O 6.224

Ph N

OH 6.220

O

N N TsN

TsN

Ph

O

N

O

O

N Cl2Au

N N

6.223b

6.225

TsN

O

6.226

O

Scheme 6.97

Me

Me

Me Me

AuCl3

O

Me

Me OH O

O

Me

6.228

6.227

HO

O 6.229

O

6.230

MgBr Me

Me LiAlH4, h ν Me

Me

OH

O 6.232

6.231

Scheme 6.98

The Hashmi phenol synthesis has been used in a short synthesis of jungianol 6.232 (Scheme 6.98).108 Gold-catalysed reaction of the furan 6.227 gave the expected product, plus some minor, but interesting, by-products, 6.229 and 6.230. Addition of a Grignard reagent resulted in the formation of a new oxygen heterocycle 6.231 that results from acid-catalysed cyclization of the initial Grignard adduct. This was ring opened with lithium aluminium hydride under photochemical conditions to give the natural product 6.232 and its diastereoisomer.

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Electrophilic Alkene and Alkyne Complexes MXn

225

MXn

MXn R R

R

6.233

6.234

6.235

MXn

XnM

H+ R

attack at carbon a

R

R'O 6.239

R XnM

R'O 6.238

a

MXn H+ R H

OR'

6.241

H 6.237 b

R

R

XnM

H attack at carbon b

HOR' 6.236

H

R 6.242

OR' 6.240 R 6.243

Scheme 6.99

6.2.5

Ene–Yne Cyclization

The metal-catalysed ene–yne cylization involves an electron-poor ␩2 -alkyne complex, with metals including gallium(III),109 platinum(II), platinum(IV),110 gold(I)111 and gold(III), but the mechanism is not as simple as nucleophilic attack. A proposed mechanism (Scheme 6.99), supported by calculation work, involves formation of a ␩2 -alkyne complex 6.234, alkene cyclopropanation by the complex, with the complex itself converting into a carbene 6.236112 (for a simpler alkyne to carbene conversion see Section 8.2).113 The carbene intermediate may also be viewed as metal-stabilized carbocation 6.237. The carbene and carbocation representations of these intermediates are “mesomeric extremes of a generic picture”.114 The ene–yne cyclization reaction may operate in either an exo- or an endo- mode. The cyclopropyl carbene 6.236 cannot be viewed as two isolated functional groups as the orbitals of the two are interlaced. An anionic ␩1 -complex 6.242 conjugated through a migrated cyclopropane to a carbocation has been put forward as a canonical form. Both forms are useful for understanding the subsequent reactions. In the exo-mode, a nucleophile, such as an alcohol may attack at either of two carbons (a or b) of the cyclopropane 6.236 to deliver either ␩1 -vinyl complex 6.238 or 6.240, which then undergo protio-demetallation to give the cyclization-addition products, 6.239 or 6.241.115 These nucleophilic reactions proceed with stereochemical integrity. Alternatively, demetallation may occur to give a diene 6.243,116 similar to the products of ene–yne metathesis (Section 8.3.7). Related cycloisomerization products can be obtained using palladium, but these are via metallacyclic intermediates (Section 11.5). Related pathways can operate in the endo-mode, yielding the same functionality, but in a different carbon skeleton (Scheme 6.100). Other reactions may also occur, such as demetallation of the carbene to give an alkene 6.248.

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Organic Synthesis Using Transition Metals MXn

MXn

MXn

R

R

R

6.233

6.234

6.244

MXn R

MXn R

H

H 6.248

H

6.247

6.245

H H R 6.246

R

Scheme 6.100 MeO2C MeO2C

Ph3PAuCl, AgSbF6

MeO2C MeO2C

6.249

6.250 exo- only

Scheme 6.101 Ph3PAuCl, AgSbF6

MeO2C MeO2C

MeO2C +

MeO2C

6.251

MeO2C MeO2C

6.252 endo-: exo- = 7:1

6.253

Scheme 6.102

Ts N

Ph3PAuCl, AgSbF6

Ts

N 6.255 endo- only

6.254

Scheme 6.103

Precisely which pathway is followed depends on a balance of structural factors and is inﬂuenced by the choice of catalyst (Schemes 6.101–6.104). In the presence of alcohols, ethers are produced (Scheme 6.105),117 while, in some cases, the carbocationic intermediates can be trapped by suitably placed aryl groups in intramolecular Friedel–Crafts reactions (Scheme 6.106).118 With the right substituents and catalysts, four-membered rings 6.265 may also be produced (Scheme 6.107).119 If an addition alkene is present, then the cyclopropyl carbene intermediate may be intercepted to effect cyclopropanation of the second alkene. Cyclopropanation can become the dominant pathway, as in the platinum-catalysed reaction of enyne 6.266 (Scheme 6.108).120 Whether this occurs, however, once

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Electrophilic Alkene and Alkyne Complexes Ts

N

Ts

Ts N H

Ph3PAuCl, AgSbF6

227

N +

6.257

6.256

6.258

Scheme 6.104 Ph

H

IPrAuNTf 2, MeOH

MeO2C MeO2C

OMe

MeO2C MeO2C

6.259

Ph

6.260

Scheme 6.105 Cy2P AuCl

Ph

MeO2C

AgSbF6

MeO2C

MeO2C MeO2C

Ph

H LAu

6.261

6.262

Ph

via MeO2C MeO2C 6.263

Ph

Scheme 6.106 MeO2C

Ph

Cy2P AuCl

AgSbF6

MeO2C

Ph

MeO2C MeO2C

6.264

6.265

Scheme 6.107 Ph PtCl4

O

O

Ph 6.266

Ph Ph

6.267

Scheme 6.108

again, depends on subtle structural factors, including alkene geometry (Scheme 6.109): the geraniol-derived substrate 6.268 gave the simple cycloisomerization product 6.269, while the isomeric nerol-derived substrate 6.270 gave the double cyclopropanation product 6.271.121 The platinum-catalysed cycloisomerization of ene–yne 6.272 to give diene 6.273 was employed in a synthesis of streptorubin 6.277 (Scheme 6.110).122 After cyclization, the more electron poor of the two double bonds was reduced using a palladium-catalysed reduction with a tin hydride reagent. The ketone 6.274 was reduced and the resulting alcohol was excised by the Barton–McCombie method. The resulting

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Organic Synthesis Using Transition Metals MeO2C MeO2C

MeO2C

Ph3PAuCl, AgSbF6

MeO2C

Z

not involved

6.269

6.268

MeO2C

Ph3PAuCl, AgSbF6

MeO2C

Ph3PAu MeO2C

MeO2C

MeO2C

E

MeO2C

H

6.270

6.271 H

Scheme 6.109 Ts N

Ts N PtCl2

O

n-Pr

O

n-Bu3SnH, Pd(0) O

n-Pr

n-Pr

6.272

1. LiAlH 4 2. PhOC(S)Cl, py 3. n-Bu3SnH

Ts N

6.273

6.274

Ts N

N H2N(CH2)3NH K

n-Bu

n-Bu

6.275

6.276 MeO

H N

N n-Bu NH 6.277

Scheme 6.110

N-tosyl pyrrole 6.275 was converted to a pyrrole 6.276 by treatment with a strong base, and thence to the natural product 6.277. Gold-catalysed ene–yne cyclization has been employed in two closely related and simultaneous syntheses of englerin A 6.278, a sesquiterpene that has shown anti-tumour activity (Scheme 6.111).123 Both syntheses relied upon the intramolecular nucleophilic trapping of the cyclopropyl carbene intermediate 6.280 by a ketone nucleophile, followed by counterattack of the anionic ␩1 -vinyl gold species onto the oxonium ion 6.281 formed in this way, to form the skeleton of the molecule, but differed in their approach to the other functionality.

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Electrophilic Alkene and Alkyne Complexes

229

O Ph

H

O O O

H

O OH

6.278 XnM MXn

O

O 6.279

6.280 MXn O O

6.281

6.282

Scheme 6.111

Both syntheses employed a terpenoid starting material, geraniol 6.283 or citronellal 6.288, and employed aldol chemistry to install the ketone, leading to slightly different cyclization precursors, 6.286 and 6.291 (Scheme 6.112). For the more complex precursor 6.286, the choice of catalyst proved to be the key. A gold NHC complex was found to be most effective. For the simpler alkyne 6.291, the choice of alcohol protecting group proved to be critical. When the TBS ether was employed, the ketone did not participate and enyne 6.292 was converted to the diene 6.294. The free alcohol 6.291, however, gave the desired bicyclic product 6.293 on treatment with a gold(I) catalyst. Both cyclization products, 6.287 and 6.293, could then be converted to the natural product 6.278 through a series of functional group transformations.

6.3 Iron Complexation of alkenes to iron carbonyl fragments increases the electrophilicity of the alkene, owing to the electron-withdrawing ability of the carbonyl ligands. The anion of dimethyl malonate will attack the iron tetracarbonyl complex of methyl acrylate 6.295 (Scheme 6.113).124 The resulting anion 6.296 is obviously related to the intermediates involved in the reactions of Collman’s reagent (Section 4.5.1). Thus, carbonylation and addition of an alkyl halide results in acylation. 6.3.1

Fp Complexes of Alkenes

Much better known, and more widely applicable are the complexes developed over many years by Rosenblum: Fp alkenes.125 The Fp group is CpFe(CO)2 . These are complexes of alkenes with the cyclopentadienyldicarbonyliron moiety and carry a positive charge. They have been found to be much more stable than the simple

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Organic Synthesis Using Transition Metals OH

CHO

6.288

6.283 1. (+)-DET, Ti(Oi -Pr)4, t-BuOOH 2. PPh3, CCl4 3. n-BuLi 4. Et3SiCl, Et3N

1. (PhO)3P, Br2, Et3N 2. KOt-Bu

Et3SiO 6.289 6.284

1. SeO2, t-BuOOH 2. IBX

1. AD-mix 2. NaIO4, SiO2 3. Ph3P=C(Me)CHO TESO

CHO 6.290 CHO 6.285

OBIpc2

i-PrC(OSiCl3)=CH2 Denmark's Lewis base

TESO 6.291 R = H OH

OR

O

O

TBSOTf 2,6-lutidine 6.292 R = TBS

6.286 AuCl or Ph3PAuCl, AgSbF6

IPrAuNCMe SbF6

TESO

TBSO O H

O OH

H

6.287

OH 6.293

Scheme 6.112

6.294

O

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Electrophilic Alkene and Alkyne Complexes

CO2Me

MeO2C

Fe(CO)5, hν or (OC)4Fe Fe 2(CO)9, Δ

Fe(CO) 4

MeO2C

CO2Me 6.295

MeO2C

CO, MeI

CO2Me

O

MeO2C

6.296

MeO2C

231

CO2Me

Me CO2Me

6.297

Scheme 6.113 O C

OC

CO Fe Fe Cp C Cp O 6.298

Na(Hg)

Fp 6.301

6.300

CpFe(CO)2 O 6.299 = Fp

H BF4

Fp

Br

OH R

Fp

R 6.302

OH2

HBF4 Fp

R 6.303

Fp R 6.304

Scheme 6.114

iron carbonyl derivatives, and are often crystalline. Being cationic, they are also much more reactive towards nucleophiles. An extra synthetic convenience is that they can be made in a variety of ways. The chemistry is necessarily stoichiometric – this is because the ␩1 -complex products tend to be very stable. Fp complexes can be made in several ways. Two of the ways to make them take advantage of the nucleophilicity of the Fp anion (Scheme 6.114). The Fp− anion 6.299 itself can be prepared by reductive cleavage of the Cp2 Fe2 (CO)4 dimer 6.298 with sodium amalgam.126 Alkylation of Fp− with methallyl bromide generates a ␩1 -allyl complex 6.300 that is converted to a ␩2 -Fp complex 6.301 on treatment with a strong acid with a noncoordinating counter ion. Alternatively, the anion can be used to open an epoxide. Treatment of the resulting ferri-alcohol 6.302 with acid results in the loss of water and formation of the Fp complex 6.304. Another way to make Fp complexes is by exchange (Scheme 6.115), either of bromide with the iron complex 6.305 with Lewis-acid assistance, or of an alkene from a pre-formed Fp complex. A volatile alkene, such as isobutene, is a good choice in the second method, as its evaporation from the reaction mixture will drive the equilibrium in the desired direction. Although they are drawn as alkenes, the Fp complexes no longer show typical alkene reactivity, being inert to reactions such as catalytic hydrogenation and electrophilic attack. Instead they are susceptible to

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Organic Synthesis Using Transition Metals O C

CO Br2 Fe Fe Cp C Cp O 6.298

OC

R AlBr3

Cp(CO)2FeBr

Fp 6.305

R 6.306 R

Fp 6.301

Scheme 6.115 CO2Me

Fp MeO2C

CO2Me

MeO2C Fp

6.307

6.308

Scheme 6.116 NHBn

BnNH2

Fp

Fp

CH3 6.309

CH3 6.310

Scheme 6.117 O Fp

OEt

EtO CH3 O Fp

CH3 6.311

6.312

Scheme 6.118

nucleophilic attack.127 A simple example is the reaction between the Fp complex of cyclopentene 6.307 and the anion of dimethyl malonate (Scheme 6.116). Nucleophilic attack is trans to the metal. For unsymmetrical alkenes, the position of attack is charge controlled – the nucleophile attacks the carbon that corresponds to the more stable carbocation (Schemes 6.117 and 6.118). This is similar to the ␩2 -complexes of palladium in the Wacker process (Section 6.1). The products are stable ␩1 - complexes: they are 18-electron and, as they are coordinatively saturated, do not undergo ␤-hydride elimination. A second step is required to remove the iron and generate synthetically useful, iron-free products.128 This can be done in mundane ways by treatment with a strong acid or a strong electrophile (e.g. bromine) to achieve electrophilic cleavage of the C–Fe bond. Some other methods are also possible. A Fp-alkene complex can be regenerated by hydride abstraction with the trityl cation129 (the H must be trans to Fe) or by acid treatment if there is a ␤-alkoxy group. Final decomplexation can be achieved by treatment with iodide (Schemes 6.119 and 6.120).

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Electrophilic Alkene and Alkyne Complexes CO2Me

CO2Me

CO2Me MeO2C

MeO2C

CPh3

MeO2C

I

Fp

233

Fp

H 6.308

6.313

6.314

Scheme 6.119

Fp

Nuc

Nuc

Fp

OEt

HBF4

Nuc Fp

OEt

6.315

OEt 6.317 H

6.316 Fp

I Nuc

Nuc 6.318

6.319

Scheme 6.120

Fp base

NH3

Fp

Ag2O

6.320

Fp HN

HN 6.321

6.322

Fp O

HN

N O

6.323

6.324

Scheme 6.121

Alternatively, the Fp complex 6.321 can be oxidized using a strong inorganic one-electron oxidant, such as silver(I) or cerium(IV) (Scheme 6.121).130 This causes the formation of a seventeen-electron radical cation 6.322. This intermediate, which is formally iron(III), can relieve its electron deﬁciency to some extent by CO insertion. The acyl iron complex 6.323 can then be intercepted by a nucleophile such as an amine or an alcohol. This can be either inter- or intramolecular. The reaction follows a different course if the Fp group is ␣ to an oxygen atom, as in complex 6.325 (Scheme 6.122). The Fp radical cation is a leaving group and is expelled to create an oxonium ion 6.327, which can, in turn, be trapped by a nucleophile. Some remarkable examples of stereocontrol have been reported using the Fp complexes of enediol ethers.131 1,2-Diethoxyethene can be used as a vinyl dication equivalent (Scheme 6.123). The Fp complex 6.329 of cis1,2-diethoxyethene reacted with dimethyl copper lithium stereospeciﬁcally to give the syn adduct 6.330. Acid treatment gave the trans complex 6.331 with net inversion of the alkene geometry. Addition of the enolate of cyclohexanone, followed by acidiﬁcation and decomplexation then gave the vinylated ketone 6.334, with the cis alkene, the result of a second inversion.

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Organic Synthesis Using Transition Metals H

OH

H Fp

Ce(IV)

OEt

H

H

OEt

6.325

OH

Fp OEt

OEt

6.326 H

H

OH

O OEt OEt

H

H

OEt 6.327

OEt

6.328

Scheme 6.122 Fp EtO

6.330 O

Me

Fp

OEt

6.329 1.

Fp Me

OEt Me2CuLi

O

HBF4 EtO

OEt

6.331 O

Fp

2. HBF 4

Me

NaI or CH3CN, Δ

6.333

Me 6.334

Scheme 6.123 Cp OC Fe Ph3P

SPh PhS

6.335

Cp OC

SPh

Ce(IV), EtOH Fe

EtO2C

PPh3 6. 3 36

6.337

Scheme 6.124

6.3.2

Fp Complexes of Alkynes

These complexes have been the subject of some investigation,132 but they are less stable than the alkene complexes. Better results appear to be obtained if one carbon monoxide ligand is replaced by a phosphine or a phosphite.133 Addition of nucleophiles, including cuprates, is stereospeciﬁcally trans (Scheme 6.124). The vinyl iron complexes 6.336 produced by these reactions may be oxidized in the presence of alcohols to give esters.134 6.3.3

Alkylation of Allyl Fp Complexes and Formal Cycloadditions

The nucleophilicity of ␩1 -allyl Fp complexes has been exploited to make alkene-Fp complexes (Schemes 6.125–6.128).135 Both ␩1 -allenic Fp complexes 6.338 and propargylic Fp complexes 6.341, in addition to

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Electrophilic Alkene and Alkyne Complexes NC Fp

NC

CN

NC

CN

CN

NC CN

CN CN

• 6.338

CN CN

6.339

Fp

235

6.340 Fp

Scheme 6.125 O

H AlBr3

Me

O

Fp

Fp Me H 6.342

6.341

Scheme 6.126 O

O CO2Et

Fp

O

CO2Et Fp

CO2Me H 6.345

H 6.344

6.343

CO2Et

Ce(IV), MeOH

Scheme 6.127 Fp Fp 6.346

Fp

Fp

6.347

Scheme 6.128

allyl Fp complexes, can also be used. The complexes are sufﬁciently nucleophilic to react with electronpoor alkenes under mild conditions. If the alkene is sufﬁciently electron poor, no extra reagents are needed. Alkenes that are less electron poor may require the addition of a Lewis acid.136 This reaction may be considered as a form of Michael addition and it generates a carbanion 6.339, which may counterattack onto the Fp cation produced.137 The result is a ﬁve-membered ring 6.340 and, hence, the process may be regarded as a formal cycloaddition. Further transformations of the Fp group follow those outlined above, such as oxidative carbonylation. Alkene–Fp complexes themselves are also sufﬁciently electrophilic to participate in addition reactions (Scheme 6.128).138

6.4 Cobaloxime ␲-Cations Despite being studied several decades ago,139 cobaloxime ␲-cations have seen modest use in organic synthesis. The cations can be generated in situ by treatment of ␤-hydroxy or ␤-acetoxy cobaloxime complexes 6.349 with acid (Scheme 6.129). Although these reactions seem to resemble those of the Fp complexes, structurally, these cobalt complexes are not straightforward coordinated alkenes. Low-temperature 13 C NMR studies have

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Organic Synthesis Using Transition Metals

[Co] [Co]

Br

AcO

AcO

6.348

6.350

[Co] 6.349

[Co]

[Co] 6.351

[Co] = Co(dmgh)2NC5H5

Scheme 6.129 OH [Co]

[Co]

TsOH

6.352

Me3Si

6.353

Me3Si

[Co]

OH

1. TEMPO, hν 2. Zn, AcOH

6.354

6.355

Scheme 6.130

OH N

1. Na[Co(dmgh) 2py] OTs 2. PPTS

6.356 [Co]

N 6.358

1. TEMPO, h ν 2. H2, Rh/Al2O3 3. BH 3

[Co]

N 6.357

O H

1. EtOH, Δ 2. Zn, AcOH

N H3B

OH

N

H N

6.359

6.360

Scheme 6.131

shown that the two carbon atoms involved are not equivalent.140 Equilibrating ␤-stabilized carbocations 6.351 has been proposed as a better representation, rather than a ␩2 -complex 6.350. The trapping of these cations with carbon nucleophiles has made them useful for synthesis. The carbon nucleophiles must be stable to the mildly acidic conditions used to generate the cations. Examples are trisubstituted alkenes, in an intramolecular fashion,141 allyl silanes (Scheme 6.130) and pyrrole.142 The ␩1 alkylcobalt complex 6.354 produced may be converted to an alcohol 6.355 by free radical methods as the carbon–cobalt bond undergoes photochemical homolysis. The intramolecular trapping by a pyrrole has been used in a short synthesis of tashiromine 6.360, an indolizidine alkaloid (Scheme 6.131).143 The optically pure cobaloxime complex 6.357, generated from the corresponding alcohol 6.356, was directly trapped by the pyrrole with overall retention of stereochemistry. Reduction of the pyrrole and conversion of the carbon–cobalt bond to a carbon–oxygen bond yielded the alkaloid 6.360 and its diastereoisomer. Another synthesis of this alkaloid may be found in Scheme 2.122.

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

Weber, D.; Tarselli, M. A.; Gagn´e, M. R. Angew. Chem., Int. Ed. 2009, 48, 5733. Jira, R. Angew. Chem., Int. Ed. 2009, 48, 9034. For a comprehensive mechanistic discussion, see Keith, J. A.; Henry, P. M. Angew. Chem., Int. Ed. 2009, 48, 9038. (a) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981; (b) Takacs, J. M.; Jiang, W.-T. Curr. Org. Chem. 2003, 7, 369. ˚ Somfai, P.; Ahman, J. Tetrahedron Lett. 1992, 33, 3791. Pauley, D.; Anderson, F.; Hudlicky, T. Org. Synth. 1993, Coll. Vol. VIII, 208. Reginto, G.; Mordini, A. et al. Tetrahedron Asym. 2000, 11, 3795. Pacquette, L. A.; Wang, X. J. Org. Chem. 1994, 59, 2052. (a) Kongkathip, N.; Kongkathip, B.; Sookkho, R. J. Sci. Soc. Thai 1987, 13, 239; (b) Kongkathip, N.; Sookkho, R.; Kongkathip, B. Chem. Lett. 1985, 1849. Paterson, I.; Razzak, M.; Anderson, E. A. Org. Lett. 2008, 10, 3295. Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 257. Tanaka, Y.; Takahara, J. P. Lempers, H. E. B. Org. Process Res. Dev. 2009, 13, 548. Anderson, K. R.; Atkinson, S. L. G. et al. Org. Process Res. Dev. 2010, 14, 58. For a related observation, see Fuwa, H.; Mizunuma, K. et al. Tetrahedron 2011, 67, 4995. (a) Hegedus, L. S.; McKearin, M. C. J. Am. Chem. Soc. 1982, 104, 2444; (b) Hegedus, L. S.; Holden, M. S.; McKearin, M. C. Org. Synth. 1990, Coll. Vol. VII, 501. Harrington, P. J.; Hegedus, L. S. J. Am. Chem. Soc. 1987, 109, 4335. Cacchi, S. Pure Appl. Chem. 1996, 68, 45. Cacchi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475, 289. Takano, S.; Sato, T. et al. J. Chem. Soc., Chem. Commun. 1991, 462. Semmelhack, M. F.; Kim, C. et al. Pure Appl. Chem. 1990, 62, 2035. Semmelhack, M. F.; Zhang, N. J. Org. Chem. 1989, 54, 4483. McCormick, M.; Monahan III, R. et al. J. Org. Chem. 1989, 54, 4485. Yang, Z.; Xie, X. et al. Org. Biomol. Chem. 2011, 9, 984. Blakemore, P. R.; Browder, C. C. et al. J. Org. Chem. 2005, 70, 5449. (a) Tamaru, Y.; Kobayashi, T. et al. Tetrahedron Lett. 1985, 36, 3207; (b) Gracza, T.; Hasenn¨ohrl, T.; et al. Synthesis 1991, 1108. Gracza, T.; J¨ager, V. Synthesis 1994, 1359. Karlub´ıkov´a, O.; Babjak, M.; Gracza, T. Tetrahedron 2011, 67, 4980. Semmelhack, M. F.; Kim, C. R. et al. Tetrahedron Lett. 1989, 30, 4925. Larock, R. C.; Lee, N. H. J. Am. Chem. Soc. 1991, 113, 7815. Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371. Ham, W.-H.; Jung, Y. H. et al. Tetrahedron Lett. 1987, 38, 3247. Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179. Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737. (a) Streuff, J.; H¨ovelmann, C. H. et al. J. Am. Chem. Soc. 2005, 127, 14586; (b) Mu˜niz, K.; H¨ovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. Hegedus, L. S.; Williams, R. E. et al. J. Am. Chem. Soc. 1980, 102, 4973. Hegedus, L. S.; Darlington, W. H. J. Am. Chem. Soc. 1980, 102, 4980. Masters, J. J.; Hegedus, L. S.; Tamariz, J. J. Org. Chem. 1991, 56, 5666. Masters, J. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 4547. For an alternative synthesis of this interesting alkene, see Akiba, T.; Tamura, O.; Terashima, S. Org. Synth. 1996, 75, 45. Liu, C.; Widenhoefer, R. A. Chem. Eur. J. 2006, 12, 2371. Noyan, S.; Hopp Reutsch, G. et al. Heterocycles 1998, 48, 1793. Kondo, Y.; Shiga, F. et al. Tetrahedron 1994, 50, 11803. Gallagher, T.; Davies, I. W. et al. J. Chem. Soc., Perkin Trans I 1992, 433.

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44. For an example with an aldehyde as the nucleophile, see: Walkup, R. D.; Mosher, M. D. Tetrahedron Lett. 1994, 35, 8545. 45. Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453. 46. Bouyssi, D.; Balme, G. et al. Tetrahedron Lett. 1991, 32, 1641. 47. Luo, F.-T.; Wang, R.-T. Tetrahedron Lett. 1992, 33, 6835. 48. Luo, F.-T.; Schreuder, I.; Wang, R.-T. J. Org. Chem. 1992, 57, 2213. 49. Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581. 50. Arcadi, A.; Cacchi, S. et al. Tetrahedron 1994, 50, 437. 51. Monteiro, N.; Arnold, A.; Balme, G. Synlett 1998, 1111; see also L¨utjens, H.; Scammels, P. J. Synlett 1999, 1079. 52. Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893. 53. (a) Hashmi, A. S. K.; B¨uhrle, M. Aldrich. Acta 2010, 43, 27; (b) F¨urstner, A. Chem. Soc. Rev. 2009, 39, 3208; (c) Gagosz, F. Tetrahedron 2009, 65, 1757; (d) Arcadi, A. Chem. Rev. 2009, 108, 3266; (e) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239; (f) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (g) Hashmi, A. S. K. Chem. Rev., 2007, 107, 3180; Hashmi, A.S.K.; Hutchings, G.J. Angew. Chem. Int. Ed. 2006, 45, 7896; (h) Hoffmann-R¨oder, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387; (i) Arcadi, A.; Di Giuseppe, S. Curr. Org. Chem. 2004, 8, 795. 54. (a) Pradal, A.; Toullec, P. Y.; Michelet, V. Synthesis, 2011, 1501; (b) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283; (c) Li, H.; Lee, S. D.; Widenhoefer, R. A. J. Organomet. Chem. 2011, 696, 316. 55. Bandini, M. Chem. Soc. Rev. 2011, 40, 1358. 56. (a) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133; (b) Ricard, L.; Gagosz, F. Organometallics 2007, 26, 4704. 57. Hirai, T.; Hamasaki, A. et al. Org. Lett. 2009, 11, 5510. 58. Zhang, X.; Corma, A. Chem. Commun. 2007, 3080. 59. Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. 60. Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747. 61. Yeh, M.-C. P.; Pai, H.-F. et al. Tetrahedron 2009, 65, 4789. 62. Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005, 127, 12640. 63. Liu, C.; Han, X. et al. J. Am. Chem. Soc. 2004, 126, 3700. 64. Jiang, T.; Livinghouse, T. Org. Lett. 2010, 12, 4271. 65. Brenzovich Jr., W. E.; Benitez, D. et al. Angew. Chem., Int. Ed. 2010, 49, 5519. 66. Ball, L. T.; Green, M. et al. Org. Lett. 2010, 12, 4724. 67. (a) Bates, R. W.; Vachiraporn, P. Chem. Soc. Rev. 2002, 31, 12; (b) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. 68. Olsson, L.-I., Claesson, A. Synthesis 1979, 743. 69. Kimura, M., Fugami, K. et al. Tetrahedron Lett., 1991, 32, 6359.; see also Meguro, M., Yamamoto, Y. Tetrahedron Lett., 1998, 39, 5421. 70. Lathbury, D.C., Shaw, R.W. et al. J. Chem. Soc., Perkin I, 1989, 2415. 71. Breman, A. C.; Dijkink, J. et. al. J. Org. Chem. 2009, 74, 6327. 72. Sawama, Y.; Sawama, Y.; Krause, N. Org. Biomol. Chem. 2008, 6, 3573. 73. Kinder, R. E.; Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 3157. 74. Bates, R. W., Lu, Y. Org. Lett. 2010, 12, 3938. 75. Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962. 76. Hashmi, A. S. K.; Schwarz, L. et al. Angew. Chem., Int. Ed. 2000, 39, 2285. 77. Bates, R. W.; Dewey, M. R. Org. Lett. 2009, 11, 3706. 78. Tarselli, M. A.; Zuccarello, J. L.; Lee, S. J.; Gagn´e, M. R. Org. Lett. 2009, 11, 3490. 79. (a) Arredondo, V.M.; Tian, S. et al. J. Am. Chem. Soc. 1999, 121, 3633; (b) Tian, S.; Arredondo, V.M. et al. Organometallics 1999, 18, 2568. 80. Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966 81. Weyrauch, J. P.; Hashmi, A. S. K. et al. Chem. Eur. J. 2010, 16, 956. See also Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379; Ritter, S.; Horino, Y. et al. Synthesis 2006, 3309.

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239

82. Surmont, R.; Verniest, G.; de Kimpe, N. Org. Lett., 2009, 10, 2920. For a related palladium(II) catalysed cyclization with elimination of water, see Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22, 4277. 83. Fukuda, Y.; Utimoto, K. Synthesis, 1991, 975. 84. Kirsch, S. F. Synthesis 2008, 3183. 85. Hartman, J. W.; Hiscox, W. C.; Jennings, P. W. J. Org. Chem. 1993, 58, 7613. 86. Jennings, P. W.; Hartman, J. W.; Hiscox, W. C. Inorg. Chimica Acta 1994, 222, 317. 87. Hartman, J. W.; Sperry, L. Tetrahedron Lett. 2004, 45, 3787. 88. Aponick, A.; Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121. 89. Di´eguez-V´azquez, A.; Tzschucke, C. C. et al. Angew. Chem. Int. Ed. 2008, 47, 209. 90. Teles, J. H.; Brode, S. Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415. 91. Patil, N. T.; Mutayla, A. K. et al J. Org. Chem. 2010, 75, 5963. 92. Patil, N. T.; Navthe, R. D.; Sridhar, B. J. Org. Chem. 2010, 75, 3371. 93. Goossen, L. J.; Paetzold, J.; Koley, D. Chem. Commun. 2003, 706. 94. Lumbroso, A.; Vautravers, N. R.; Breit, B. Org. Lett. 2010, 12, 5498. 95. For other examples, see (a) Rotem, M.; Shvo, Y. Organometallics 1983, 2, 1689; (b) Nakagawa, H.; Okimoto, Y. et al. Tetrahedron Lett. 2003, 44, 103; (c) Hua, R.; Tian, X. J. Org. Chem. 2004, 69, 5782. 96. F¨urstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030. 97. Toullec, P. Y.; Blarre, T.; Michelet, V. Org. Lett. 2009, 11, 2888. 98. Oyamada, J.; Kitamura, T. Tetrahedron 2007, 63, 12754. 99. Menon, R. S.; Findlay, A. D. et al. J. Org. Chem. 2009, 74, 8901 100. Menon, R. S.; Banwell, M. G. Org. Biomol. Chem. 2010, 8, 5483. 101. F¨urstner, A.; Kennedy, J. W. J. Chem. Eur. J. 2006, 12, 7398. 102. Staben, S. T.; Kennedy-Smith, J. J. et al. Angew. Chem., Int. Ed. 2006, 45, 4991. 103. Nakamura, I.; Mizushima, Y. et al. Tetrahedron 2007, 63, 8670. 104. Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553. 105. Complexes of other metals can also catalyse this reaction, but gold is superior: Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3, 3769. 106. Hashmi, A. S. K.; Rudolph, M. et al. Angew. Chem., Int. Ed. 2005, 44, 2798. 107. Hashmi, A. S. K.; Rudolph, M. et al. Chem. Eur. J. 2008, 14, 3703. 108. Hashmi, A. S. K.; Ding, L. et al. Chem. Eur. J. 2003, 9, 4339. 109. Chatani, N.; Inoue, H. et al. J. Am. Chem. Soc. 2002, 124, 10294. 110. Oi, S.; Tsukamoto, I. et al. Organometallics 2001, 20, 3704. 111. Jim´enez-N´un˜ ez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. 112. For a discussion of whether this is a metal carbene or a metal-stabilized carbocation or both or something in between, see F¨urstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. Similarly, an oxonium ion, may also be viewed as an oxygen-stabilized carbocation. L Au

L Au R

R O

R O R

R

R

113. Nieto-Oberhuber, C.; Mu˜noz, M. P. et al. Angew. Chem., Int. Ed. 2004, 43, 2402. 114. F¨urstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030. 115. (a) M´endez, M.; Mu˜noz, M. P. et al. J. Am. Chem. Soc. 2001, 123, 10511; (b) M´endez, M.; Mu˜noz, M. P.; Echavarren, A. M. J. Am. Chem. Soc. 2000, 122, 11549; (c) M´endez, M.; Mu˜noz, M. P. et al. Synthesis 2003, 2898; (d) Nevado, C.; C´ardenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2003, 9, 2627; (e) Nevado, C.; Charrault, L. et al. Eur. J. Org. Chem. 2003, 706. 116. See refs 114, and (a) Oi, S.; Tsukamoto, I. et al. Organometallics 2001, 20, 3704; (b) F¨urstner, A.; Szillat, H. et al. J. Am. Chem. Soc. 1998, 120, 8305; (c) F¨urstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863. 117. See reference 56b.

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240 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143.

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Organic Synthesis Using Transition Metals Nieto-Oberhuber, C.; L´opez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178. see reference 117. Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem. 1995, 60, 5567. Nieto-Oberhuber, C.; L´opez, S. et al. Chem., Eur. J. 2006, 12 1694. (a) F¨urstner, A.; Szillet, H. et al. J. Am. Chem. Soc. 1998, 120, 8305; (b) F¨urstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (a) Zhou, Q.; Chen, X.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 3513; (b) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem., Int. Ed. 2010, 49, 3517. Pearson, A. J. Metallo-Organic Chemistry Wiley, Chichester, 1985, pp 166–167. Rosenblum, M. Acc. Chem. Res. 1974, 7, 122. The dimer 6.298 can be prepared from Fe(CO)5 : King, R. B.; Stone, F. G. A. Inorg. Synth. 1963, 7, 110. Chang, T. C. T.; Rosenblum, M.; Simms, N. Org. Synth. 1993, Coll. Vol. VIII, 479. Abram, T. S.; Baker, R. et al. J. Chem. Soc., Perkin I 1982, 285. Rosan, A.; Rosenblum, M.; Tancrede, J. J. Am. Chem. Soc. 1973, 95, 3062. Rosenblum, M.; Foxman, B. M.; Turnbull, M. M. Heterocycles 1997, 25, 419. Marsi, M.; Rosenblum, M. J. Am. Chem. Soc. 1984, 106, 7264. Reger, D. L. Acc. Chem. Res. 1988, 21, 229. Reger, D. L.; Belmore, K. A. et al. Organometallics 1984, 3134. Reger, D. L.; Mintz, E.; Leboida, J. J. Am. Chem. Soc. 1986, 108, 1940. Welker, M. E. Chem. Rev. 1992, 92, 97. Bucheister, A.; Klemarczyk, P.; Rosenblum, M. Organometallics 1982, 1, 1679. Raghu, S.; Rosenblum, M. J. Am. Chem. Soc. 1973, 95, 3060. Rosan, A.; Rosenblum, M.; Tancrede, J. J. Am. Chem. Soc. 1973, 95, 3062. For example, Golding, B. T.; Sayrikar, S. J. Chem. Soc., Chem. Commun. 1972, 1183. Brown, K. L.; Ramamurthy, S. Organometallics 1982, 1, 413. Kettschau, G.; Pattenden, G. Synlett 1998, 783. Gage, J. L.; Branchaud, B. P. J. Org. Chem. 1996, 61, 831. Gage, J. L.; Branchaud, B. P. Tetrahedron Lett. 1997, 38, 7007.

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7 Reactions of Alkyne Complexes 7.1 Alkyne Cobalt Complexes While there are ␩2 -alkyne complexes of many metals, the most important for organic synthesis are the dicobalt complexes 7.2 formed simply by stirring an alkyne 7.1 with dicobalt octacarbonyl in an inert solvent (Scheme 7.1).1 The complexes are tetrahedral with carbon atoms at two vertices and cobalt atoms at the other two (Figure 7.1). They are, however, often drawn as simple alkyne complexes 7.3. Although this is a very convenient shortcut, drawing them in this way may hide much of the chemistry. It is easy to release the alkyne from the hold of the cobalts: decomplexation can be achieved by mild oxidation using a reagent such as FeCl3 or I2 . There are also two immediate structural effects: the C–C–C bond angle is reduced from 180◦ to about 140◦ ,2 and the alkyne has changed from non-bulky to very bulky. The angle effect allows many unstable cyclic alkynes, even diynes,3 to be formed as complexes 7.4. (OC)6Co2 H

(OC)6Co2

Ph

O

OH 7.4

The effect of the angle change is clearly apparent in an intramolecular retro-Claisen condensation (Scheme 7.2). The free alkyne does not react, other than simple deprotonation, because the 180◦ bond angle cannot be accommodated within the 7-membered ring intermediate. The complex, however, does react giving the ring-expanded product.4 The change from a free alkyne to a bulky complexed alkyne can also affect the stereoselectivity in some reactions. One reaction where this is important is the aldol reaction. In a Mukaiyama aldol reaction, the presence of bulky substituents often leads to higher stereoselectivity. A free alkynyl aldehyde reacted with

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals R

R

R

Co2(CO)8

often written as

(OC)3Co Co(CO)3 7. 2

R 7.1

R

R Co2(CO)6 7. 3

[O]

Scheme 7.1

silyl enol ether 7.9 with almost no selectivity, because the alkynyl substituent is non-bulky.5 The complex 7.10, on the other hand, gave a highly diastereoselective reaction (Scheme 7.3). Another demonstration of the size of the complexed alkyne comes from a synthesis of tautomycin intermediates.6 A tetrahydropyran 7.12 was found to exist predominantly with the alkynyl group axial. This was determined from the observation of a 1 Hz coupling constant between Ha and Hb (Scheme 7.4). After complexation with cobalt, a ring ﬂip occurred to the tetrahydropyran 7.13 with a conformation having the alkynyl complex equatorial being favoured, with an Ha –Hb coupling constant of 6.5 Hz. The complexes are inert to many typical alkyne reactions: most forms of catalytic hydrogenation fail, as does hydroboration. As a simple application, the dicobalt complex can be regarded as a protected alkyne. Some methods to achieve simultaneous alkyne reduction and decomplexation have been reported (Scheme 7.5).7 Hydrogenation of the cyclic alkyne complex 7.14 using Wilkinson’s catalyst gives the corresponding decomplexed alkene 7.15, accompanied by the alkene isomerization product 7.16. While tri-n-butyl tin hydride may be used for this transformation, silane reagents and sodium hypophosphite, NaH2 PO2 , (for an example, see Scheme 7.7) offer better chemoselectivity.8

123° 127°

118°

116°

117°

121° 116°

118° 122°

121° 121° 118°

123° 116°

119° 117°

137° 77°

10 10 0° 4°

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139° 78°

95° ° 103

43° 3° 10 99°

103°

Figure 7.1 A dicobalt-alkyne complex 7.2 (R = Ph). Reprinted with permission from Sly, W. G. et al. J. Am. c 1959 American Chemical Society. Chem. Soc. 1959, 81, 18.

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Reactions of Alkyne Complexes Co2(CO)6

O

OH O

Co2(CO)6

O NaH

O O

7.5

7.6

O O Co2(CO)6 Co2(CO)6

O O

O

O 7.8

7.7

Scheme 7.2

TMSO

OHC

Co2(CO)6

Co2(CO)6

Ph 7.11 uncomplexed 1:1.1 complexed 32:1

7.10

7.9

OH

O

BF3.OEt2

Ph

Scheme 7.3 AcO

AcO

O

Hb

Hb

Co2(CO)8

Co2(CO)6

O

Ha

SPh

7.13 Ha

7.12 SPh

Scheme 7.4 H H

(OC)6Co2 I

O

O

H2 > 1000 psi (Ph3P)3RhCl

+

H 7.14

n-Bu3SnH H

O

O

I

I

O

H 7.17

Scheme 7.5

H H

O

O

H

7.15 O

7.16

243

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Organic Synthesis Using Transition Metals

7.2

Propargyl Cations: The Nicholas Reaction

Complexation has two very signiﬁcant chemical effects. The ﬁrst involves carbocation chemistry.9 Propargylic carbocations are not as easily generated as allylic carbocations and also have a tendency to react as allenic systems (SN ’ reaction). If the alkyne is complexed as a dicobalt cluster, ionization becomes easier and the reaction only occurs in the acetylenic mode. This is the Nicholas reaction.10 An example of this method is in a synthesis of the dimethyl ether of pseudopterosin G aglycone 7.25 (Scheme 7.6).11 A propargylic alcohol complex 7.21 was prepared, starting from the addition of an aryl copper reagent 7.18 to an ␩3 -allyl iron complex 7.19 (see Section 9.1). The ester substituent was then extended to form the propargylic alcohol, which was converted into a dicobalt complex 7.21. The complex was treated with a Lewis acid, boron triﬂuoride, to give the cobalt-stabilized cation 7.22. This was trapped by the electron-rich aromatic ring in an intramolecular Friedel–Crafts reaction. Decomplexation of 7.23 by mild oxidation with ferric nitrate gave the desired bicyclic structure 7.24. Although the starting alcohol was a 1:1 mixture of diastereoisomers, the alcohol stereogenic centre was lost on carbocation formation. The cyclization product 7.23 was obtained as a 95:5 mixture of diastereoisomers, controlled by the conformation during cyclization. When combined with reductive decomplexation methods,8 the Nicholas reaction has found extensive use in the synthesis of marine polyether ladder toxins, such as ciguatoxin (Scheme 7.7).12 The chemistry has been elegantly used in the synthesis of ene-diynes,13 the essential subunit of a remarkable class of DNA-cleaving agents (Scheme 7.8). This synthesis also relies on another property of the clusters – the change of alkyne bond angle. The starting alkynes were made by sequential Sonogashira coupling (see Section 2.8) of cis-1,2-dichloroethylene 7.29 with two terminal alkynes, followed by a Reissert addition to a quinoline 7.32. The required cobalt complex 7.33 was then prepared by treatment of the diyne with

OMe M

OMe OMe

CO2Et

+

Fe(CO)3 7.18 M = Cu(CN)ZnBr

EtO2C

7.19

7.20

OMe

OMe OMe

1. Mg, MeOH 2. DIBAL 3. BrMg OMe 4. Co2(CO)8

BF3

intramolecular OMe Friedel-Crafts reaction

OH (OC)3Co (OC)3Co

SiMe3

(OC)3Co (OC)3Co

7.21

7.22

OMe

OMe OMe

(OC)3Co (OC)3Co

SiMe3

OMe OMe

FeCl3

OMe

H SiMe3 7.23

SiMe3

7.24

Scheme 7.6

7.25

SiMe3

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Reactions of Alkyne Complexes H

PivO (OC)6Co2

O

H

OMe BF3.OEt2

PivO PivO

OMe

HO 7.26

H

PivO H

O

O

H

H

OMe OMe

O

PivO

OH

H

(OC)6Co2

245

H OH 7.27

OMe

NaH2PO4 O

PivO PivO

H

H

OMe OH

7.28

Scheme 7.7

dicobalt octacarbonyl. Cobalt preferentially complexed with the less hindered alkyne, and only small amounts of the isomeric and double complexed by-products were formed. Cyclization to give ene-diyne complex 7.36 was achieved after deprotection by treatment with triﬂic acid and a highly hindered base, 2,6-di-t-butyl-4methylpyridine. A polar solvent mixture, nitromethane–dichloromethane, was found to be essential. After cyclization, oxidative decomplexation to give the target ene–diyne 7.37 was achieved using iodine.

OTHP 1. Cl

Cl 7.29

2.

(Ph3P)4Pd, CuI, n-BuNH2 SiMe3 (Ph3P)4Pd, CuI, n-BuNH2 Me3Si 1.

OTHP

7.30

1. LiOH 2. EtMgBr

N Co2(CO)6

OTBS

BrMg 7.31

EtO2C 7.32 EtOCOCl N 2. PPTS, EtOH 3. Co2(CO)8

OTHP

OH OTBS

Co2(CO)6 Tf2O, base

EtO2C N

OTf

Co2(CO)6 - OTf

OTBS

EtO2C N OTBS

7.34

EtO2C

N

7.33

7.35

O

I2

EtO2C

N

O

Co2(CO)6 7.36

Scheme 7.8

7.37

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Organic Synthesis Using Transition Metals R R

R

R

Δ

O

R'

(OC)3Co Co(CO)3

R'

R'

7 .2

7 .3 8

R'

Scheme 7.9

7.3

The Pauson–Khand Reaction

The alkyne complexes undergo a remarkable cyclization reaction on heating with an alkene and carbon monoxide. This is the Pauson–Khand reaction,14,15 which is a formal cycloaddition of a complexed alkyne 7.2, an alkene and a molecule of carbon monoxide to give a cyclopentenone 7.38 (Schemes 7.9 and 7.10). The mechanism proceeds via initial CO dissociation from one of the 18 electron cobalt atoms of the complex 7.2 (Scheme 7.11). This opens up a coordination site for an alkene molecule. The coordinated alkene then inserts into one of the C–Co bonds, starting to open up the tetrahedron. CO insertion into the newly formed C–Co bond is followed by reductive elimination. This generates a cyclopentenone, still coordinated to cobalt. Under the reaction conditions, decomplexation occurs to give the product 7.38. For unsymmetrical reactions, modest regioselectivity is observed, with the larger alkyne substituent (Scheme 7.10) and the larger alkene substituent (Scheme 7.12) ending up ␣- to the carbonyl group. The reaction is more efﬁcient, and issues of regioselectivity are solved, when the reaction is carried out in an intramolecular fashion (Scheme 7.13). A chiral centre in the tether may also control the stereoselectivity of the reaction.16 Allenes can also provide the alkene component (Scheme 7.14); which of the two alkene moieties of the allene participates depends upon the precise structure.17,18 In many cases, yields have been modest. Various “tricks” have been introduced to boost yields. The Pauson–Khand reaction can be promoted by a wide range of additives, including amine oxides,19 phosphine oxides,20 sulfoxides,21 amines22 and sulﬁdes.23 Water can have an effect.24 Special reaction conditions, including ultrasonication,25 ultraviolet irradiation26 and “dry-state absorption” on silica gel,27 have been employed. A problem is that the Pauson–Khand reaction uses two equivalents of cobalt. More efﬁcient versions, many of them catalytic,28 using other metals have been developed. These include carbonyl complexes of titanium,29 molybdenum,30 tungsten (Scheme 7.15),31 rhodium32 and ruthenium (Scheme 7.16).33 Rhodium, iridium34,35 and iron (Scheme 7.17)36 have also been used with two alkynes to give cyclopentadienones, often as complexes 7.59. A version of the Pauson–Khand reaction employing a nickel catalyst and an isonitrile in place of CO has been developed.37 The product is an imine, which can be hydrolysed to a cyclopentenone. A rhodium-catalysed Pauson–Khand reaction of an allenic alkyne 7.60 was employed to form the cyclopentenone ring of Achalensolide 7.65, a guaianolide natural product (Scheme 7.18).38 The butenolide ring was then constructed by free radical chemistry.

Me (OC)3Co Co(CO)3

Me +

+ Co(CO)2

7.39

O 7.40

Scheme 7.10

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Reactions of Alkyne Complexes R

R

R

R

±CO

(OC)3Co Co(CO)3 7.2

R'

R'

(OC)2Co Co(CO)3 7.41

R

R

(OC)2Co Co(CO)3 7.42 R'

R

R' R

alkene insertion

R'

R

R' R

Co(CO)3 Co(CO)2

±CO

7.44

7.43 R

R' R

R' R Co(CO)3 Co(CO)2

R'

±CO R'

7.45

O

O

CO insertion

Co(CO)3 Co(CO)3

R'

R'

R reductive Co(CO)3 elimination Co(CO)3 7.46

R

R' R

R' O

R R in situ Co(CO)3 decomplexation O Co(CO)3 R' R' 7.47 7.38

Scheme 7.11

Me

OTHP Me

Me

+

Me

O

Co2(CO)6 7.49

7.48

OTHP

Scheme 7.12

TBSO

TBSO

Co2(CO)8 Δ

O

7. 5 0

7. 5 1

H

Scheme 7.13

MeS •

Fe(CO)4NMe3 hν

O MeS 7.53

7.52

Scheme 7.14

247

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Organic Synthesis Using Transition Metals

W(CO)5.THF

O

7.54

7.55

Scheme 7.15 Et Et

EtO2C EtO2C

Ru3(CO)12, CO EtO2C EtO2C

O 7.57

7.56

Scheme 7.16 (OC)3Fe Fe(CO) 5, CO

O

7 .5 8

7 .5 9

Scheme 7.17 •

1. K2CO3, MeOH OMOM 2. PhSH, MgBr2 3. Br2, OEt OPiv

OMOM [(cod)RhCl]2 dppp, CO O OPiv 7.60

7.61 1. AIBN, n-Bu3SnH 2. CrO3, H3O+ OEt 3. H2, Pd/C

O O 7.62 1. NaBH4, CeCl3 2. TBSCl, C3H4N2 3. LDA, H2C=O

H

H

O O

O 7.63 H

Br H

H

H

H O

TBSO

O

PCC

O O

O

H 7.64

7.65

H

Scheme 7.18

7.3.1

Asymmetric Pauson–Khand Reaction

Asymmetric variants of the Pauson–Khand reaction have been explored employing chiral auxiliaries. Attachment of a chiral auxiliary to the alkene moiety gave good stereochemical induction (Scheme 7.19). This chemistry was used in a formal synthesis of hirsutene 7.69.39 Chiral auxiliaries can also be attached to the alkyne moiety.40 Chiral catalysts have also been used with good results (Scheme 7.20). These include chiral titanocene complexes 7.70,41 as well as complexes of rhodium42 and iridium43 with chiral phosphines.

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Reactions of Alkyne Complexes

Co2(CO)8

O H

O Ph 7.66

249

1. Li, NH3 2. SmI2

O

7.67 Ph Me H

H O

H H

H

7.68

7.69

Scheme 7.19

7.3.2

The Hetero-Pauson–Khand Reaction

The alkene component of the Pauson–Khand reaction can be replaced by a carbonyl group, leading to the formation of butenolides. This reaction has proved useful in butenolide synthesis using molybdenum complexes with labile ligands. It was used in a short synthesis of an epimer of dihydrocanadensolide 7.76 from aldehyde 7.74 (Scheme 7.21).44 It was also used in a short synthesis of mintlactone 7.79 from citronellol 7.77 (Scheme 7.22).45 In an interesting transformation, citronellol 7.77 was de-methylated to the alkynol, which was oxidized to the aldehyde 7.78. Carbonylation of the aldehyde 7.78 was achieved using an activated molybdenum carbonyl species. Another synthesis of mintlactone may be found in scheme 4.43.

Ph Ph O

CO, catalyst

O

7.70

O H

7.71

O catalyst =

OC Ti CO

or [(cod)RhCl]2

7.72

O O O

PPh2 or (S)-tolBINAP PPh2 ent-1.38 7.73

Scheme 7.20 n-Bu

O Mo(CO)3(DMF)3

O 7 .7 4

O

O 7 .7 5

Scheme 7.21

1. H2, Pd/C 2. RuCl3, NaIO4

H O O

O H 7.76

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Organic Synthesis Using Transition Metals

1. NaNO2, AcOH 2. PCC

Mo(CO)3(DMF)3

OH

O O

O

7.77

7.79

7.78

Scheme 7.22

F

(OC)6Co2

O O

BF3

7.82

7.80

O

Co2(CO)6

7.83

7.81 MeO (OC)6Co2

OMe O

MeOH

1. NaBH4, CeCl3 2. SiO2, Δ

O

7.84

OH

7.85

Scheme 7.23

7.4

Synthesis Using Multiple Cobalt Reactions

Advantage can be taken of several effects of the cobalt complexation of alkynes (Scheme 7.23). This is most often by using the cation stabilization effect to form the substrate for the Pauson–Khand reaction. The dicobalt complex of vinyl acetylene 7.82 underwent a Friedel–Crafts like acylation reaction, via a cobalt-stabilized cation 7.83.46 The cation was then trapped by an added nucleophile, methanol. Reduction of the ketone 7.84, followed by an intramolecular Pauson–Khand reaction yielded the tricyclic compound 7.85. The Nicholas and Pauson–Khand reactions, as well as the bond-angle effect, have been combined in a single synthetic scheme to make more efﬁcient use of the cobalt. This has been done in a synthesis of epoxydictamine 7.90 (Scheme 7.24).47 The Nicholas reaction was employed, in which a carbocation 7.87, generated from acetal 7.86, was trapped by an allylsilane nucleophile intramolecularly, to form the eight-membered ring

H

Co2(CO)6 O

H Me3SiOTf

OEt H Me3Si

Co2(CO)6 O

H Me3Si

7.86

7.87

O Co2(CO)6

H

H

H

O 7.88

Δ

H

H

H H O

O H

H

H 7.89

Scheme 7.24

H 7.90

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Reactions of Alkyne Complexes O CO2Me

251

OH

1. Li SiMe3 2. K2CO3, MeOH

CO2Me

7.91

7.92 OH

(OC)6Co2

CO2Me

SH BF3.OEt2

(OC)6Co2

CO2Me 7.94

7.93 H Δ

S (OC)6Co2

S

O

CO2Me

7.95 H CuI, DIBAL

O

H LiOH

S 7.97 H

CO2Me

7.96

CO2Me

O

S 7.98 H

CO2H

Scheme 7.25

cobalt complex 7.88 with good diastereoselectivity. The subsequent Pauson–Khand reaction then appended two ﬁve-membered rings. A similar Nicolas–Pauson–Khand combination was used in a synthesis of the ketone analogue of biotin 7.98, required for biochemical studies (Scheme 7.25).48 In this case, the Nicholas reaction was intermolecular, between allyl thiol as the nucleophile and carbocation 7.94 generated from alcohol 7.93. The Pauson–Khand reaction was then between the dicobalt complexed alkyne 7.95 and the double bond from the thiol moiety. The Pauson–Khand reaction proceeded with no stereoselectivity, and the diastereoisomers had to be chromatographically separated at a later stage. The synthesis was completed by reduction of the alkene of cyclopentenone 7.96, without using palladium-catalysed hydrogenation due to the sulﬁde moiety, and ester hydrolysis.

References 1. Iron also forms complexes of this type (Cotton, F. A.; Jamerson, J. D.; Stults, B. R. J. Organomet. Chem. 1975, 94, C53), but they have attracted little interest from synthetic organic chemists. 2. (a) Sly, W. G. J. Am. Chem. Soc. 1959, 81, 18; (b) Cotton, F. A.; Jamerson, J. D. et al. J. Am. Chem. Soc. 1976, 98, 1774. 3. Isobe, M.; Hosokawa, S. et al. Chem. Lett. 1996, 473. 4. Najdi, S. D.; Olmstaed, M. M. et al. J. Organomet. Chem. 1992, 431, 335. 5. (a) Ju, J.; Reddy et al. J. Org. Chem. 1989, 54, 5426; (b) Mukai, C.; Suzuki, K. et al. J. Chem. Soc., Perkin Trans I 1992, 141; (c) Caddick, S.; Delissar, V. M. et al. Tetrahedron 1999, 55, 2737; for the reaction with allyl boranes, see (d) Ganesh, P.; Nicholas, K. M. J. Org. Chem. 1997, 62, 1737. 6. Jiang, Y.; Ichikawa, Y.; Isobe, M. Tetrahedron 1997, 53, 5103. 7. Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609. 8. Takai, S.; Ploypradith, P. et al. Synlett 2002, 588.

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252 9. 10. 11. 12.

13. 14. 15.

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

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Organic Synthesis Using Transition Metals D´ıaz, D. D.; Betancourt, J. M.; Mart´ın, V. S. Synlett 2007, 343. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. Le Brazidec, J.-Y.; Kocienski, P. J. et al. J. Chem. Soc., Perkin Trans. I 1998, 2475. (a) Isobe, M.; Hamajima, A. Nat Prod. Rep. 2010, 27, 1204; (b) Baba, T.; Takai, S. et al. Synlett 2004, 603; (c) Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59, 6851; (d) Hosokawa, S.; Isobe, M. Synlett 1995, 1179; (e) Hosokawa, S.; Isobe, M. Synlett 1996, 351; (f) Isobe, M.; Yanjai, C. Synlett 1994, 916. Magnus, P. D.; Fortt, S. M. J. Chem. Soc., Chem. Commun. 1991, 544; see also Magnus, P.; Miknis, G. F. et al. J. Am. Chem. Soc. 1997, 119, 6739. Khand, I. U.; Knox, G. R. et al. J. Chem. Soc., Perkin Trans. I 1973, 977. (a) Schore, N. E. Chem. Rev. 1988, 88, 1081; (b) Schore, N. E. Org. React. 1991, 40, 1; (c) Pauson, P. L. Tetrahedron 1985, 41, 5855; (d) Geis, O.; Schmalz, H.-G. Angew. Chem., Int. Ed. 1998, 37, 911; (e) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263; (f) Sugihara, T.; Yamaguchi, M.; Nishizawa, M. Chem. Eur. J. 2001, 7, 1589. Exon, C.; Magnus, P. D. J. Am. Chem. Soc. 1983, 105, 2477. (a) Narasaka, K.; Shibata, T. Chem. Lett. 1994, 315; (b) Shibata, T.; Koga, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1995, 68, 911. Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63, 6535. (a) Shambayati, S.; Crowe, W. E. et al. Tetrahedron Lett. 1990, 31, 5289; (b) Apparently an essential additive for electron poor alkenes: Ahmar, M.; Autras, F.; Cazes, B. Tetrahedron Lett. 1999, 40, 5503. Billington, D. C.; Helps, I. M. et al. J. Organometal. Chem. 1988, 354, 233. Chung, Y. K.; Lee, B. Y. et al. Organometallics 1993, 12, 220. Sugihara, T.; Yamada, M. et al. Angew. Chem., Int. Ed. Engl. 1997, 109, 2884. Sugihara, T.; Yamada, M. et al. Synlett 1999, 771. Clive, D. L. J.; Cole, D. C.; Tao, Y. J. Org. Chem. 1994, 59, 1396. Ford, J. G.; Kerr, W. J. et al. Synlett 2000, 1415. Brown, S. W.; Pauson, P. L. J. Chem. Soc., Perkin Trans. I 1990, 1205. Smit, W. A.; Gybin, A. S. et al. Tetrahedron Lett. 1986, 27, 1241. Shibata, T. Adv. Synth. Catal. 2006, 348, 2328. Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5881. Jeong, N.; Lee, S. J. et al. Tetrahedron Lett. 1993, 34, 4027. Hoye, T. R.; Suriano, J. A. J. Am. Chem. Soc. 1993, 115, 1154. (a) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249; (b) Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73; (c) Jeong, N.; Lee, S.; Sung, B. K. Organometallics 1998, 17, 3642. Kondo, T.; Suzuki, N. et al. J. Am. Chem. Soc. 1997, 119, 6187. Shibata, T.; Yamashita, K. et al. Tetrahedron 2002, 58, 8661. Shibata, T.; Yamashita, K. et al. Org. Lett. 2001, 3, 1217. Pearson, A. J.; Dubbert, R. A. J. Chem. Soc., Chem. Commun. 1991, 202. Zhang, M.; Buchwald, S. L. J. Org. Chem. 1996, 61, 4498. Hirose, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2008, 73, 1061. Castro, J.; Sorensen, H. et al. J. Am. Chem. Soc. 1990, 112, 9388. (a) Verdaguer, X.; Moyano, A. et al. J. Organomet. Chem. 1992, 433, 305; (b) Verdaguer, X.; V´azquez, J. et al. J. Org. Chem. 1998, 63, 7037. Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 7026. (a) Shibata, T.; Tosjida, N.; Takagi, K. J. Org. Chem. 2002, 68, 7446; (b) Kwong, F. Y.; Lee, H. W. et al. Adv. Synth. Catal. 2005, 347, 1750. (a) Shibata, T.; Toshida, N. et al. Tetrahedron 2005, 61, 9974; (b) Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852. Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 778. Gao, P.; Xu, P.-F.; Zhai, H. J. Org. Chem. 2009, 74, 2592. Gybin, A. S.; Smit, W. A. et al. J. Am. Chem. Soc. 1992, 114, 5555. Jamieson, T. F.; Shambayati, S. et al. J. Am. Chem. Soc. 1994, 116, 5505. McNeill, E.; Chen, I.; Ting, A. Y. Org. Lett. 2006, 8, 4593.

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8 Carbene Complexes A carbene is a molecule that contains a divalent carbon atom. In synthetic organic chemistry, the term is used for both free carbenes 8.1, and species that are almost carbenes, and behave like carbenes, such as the zinc carbenoid 8.2 involved in the Simmons–Smith reaction (Scheme 8.1). Indeed, this reaction and other cyclopropanation methods is the main use of carbenes (and carbenoids) in organic synthesis. For many years, it was accepted dogma that all carbenes were unstable and had to be generated in situ. This changed with the discovery of Arduengo’s N-heterocyclic carbenes 8.3, which have found widespread use in organometallic chemistry (Section 1.2.3). Nevertheless, these are the exception to the rule. In organotransitionmetal chemistry, the term carbene strictly refers to complexes containing a carbon metal double bond 8.4. Some chemistry of the related nitrene complexes 8.5 is included in Section 8.5.3. Many transition metals can form carbene complexes, often generated indirectly due to the instability of the corresponding carbene. While some of these complexes are reactive and unstable intermediates, many are stable and some are even commercially available. Carbene complexes are divided into two types: Fischer and Schrock carbenes. Fischer carbenes, such as chromium complex 8.6 (Figure 8.1), contain metals from groups VI to VII, have ␲-acceptor ligands, especially carbon monoxide, and are electrophilic. A donor atom on the carbene carbon stabilizes the carbene. Schrock carbenes, such as tantalum complex 8.7, involve early transition metals, do not have ␲-acceptor ligands and are nucleophilic.

8.1 Fischer Carbenes Fischer chromium carbenes, with an electron-donating atom on the carbene carbon, were amongst the ﬁrst carbene complexes prepared, alongside their molybdenum and tungsten analogues.1 A lone pair of the heteroatom stabilizes the electron-poor carbene system (Scheme 8.2). They have found multiple uses in organic synthesis.2,3 Displaying a wide and, sometimes, bewildering array of reactivity, they have been described as “chemical multitalents.”4 The complexes are relatively easily made by the reaction of chromium hexacarbonyl with an organolithium reagent to give an anionic “ate” complex 8.9, followed by O-alkylation (Scheme 8.3) to give the carbene 8.10. As the negative charge of the “ate” complex 8.9 is well stabilized by the Cr(CO)5 moiety, a powerful alkylating agent, such as Meerwein’s salt, is often used. Alkyl iodides may be used under phase-transfer conditions.5 Alternatively, conversion of the water-soluble lithium salts to the organically soluble tetramethyl

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals R

H

R' 8. 1

R

ZnI

Ar N

I

H 8. 2

R [M]

N Ar

N [M]

R'

8 .3

8. 4

8. 5

Scheme 8.1

O(2)

C(7) O(6) C(6)

O(4) C(4)

OMe (OC)5Cr

C(9)

Ph 8.6

C(8)

C(13) C(12) C(11)

C(2) C(1) O(1)

Cr C(5)

Cp

C(3) O(3)

Cp Ta CH2

O(5)

Me

C(10)

8.7

Figure 8.1 Chromium carbene 8.6. Mills, O. S.; Redhouse, A. D. J. Chem. Soc. (A) 1968, 646. Reproduced by permission of The Royal Society of Chemistry

OMe

OMe (OC)5Cr

(OC)5Cr

Ph

Ph 8.6

8.8

Scheme 8.2

ammonium salts 8.11 allows acylation. These acylated carbenes 8.12 are unstable, as the acyl oxygen is a poorer electron donor, but may be intercepted in situ by a nucleophile such as an alcohol. Exchange of the acyloxy group for an alkoxy group occurs in the same way as for a mixed anhydride. This allows synthesis of carbenes with alkoxy group for which no Meerwein’s salt is available. Amino carbenes may be synthesized from alkoxy carbenes by exchange. Hydridocarbenes 8.19 are not available by this route. They can be prepared from formamides by reaction with the highly nucleophilic pentacarbonylchromium dianion 8.15, itself prepared by reduction of chromium hexacarbonyl with potassium/graphite (Scheme 8.4). The oxygen atom of the adduct 8.16 is removed using two equivalents of trimethylsilyl chloride. Chromium carbenes show a rich and diverse chemistry – perhaps wider than any other functional group. Some of their chemistry parallels that of carboxylic derivatives with the Cr(CO)5 moiety replacing the carbonyl oxygen (Table 8.1), although the Cr(CO)5 is more strongly electron withdrawing. Some of the reactions in Scheme 8.3 can be understood in this light and useful parallels can be drawn between different kinds of carbenes and carboxylate derivatives.

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O

RLi

(OC)6Cr

4:59

Me3O+ BF4

Li

OMe

(OC)5Cr

(OC)5Cr R

R

8.9

8.10

Me4N+ Br

R'NH2

Me4N

O

NHR'

(OC)5Cr

(OC)5Cr

R 8. 11

R

8.14

O Br O O

OBn

BnOH (OC)5Cr

(OC)5Cr 8.12

R

8.13

R

Scheme 8.3 O (OC)6Cr

K/graphite

(OC)5Cr

2

O H

NBn2

H

(OC)5Cr

8. 15 Me3SiO H (OC)5Cr

Me3SiCl

NBn2

NBn2 8.16

SiMe3 Me3Si O H NBn2

(OC)5Cr

8.17

NBn2 (OC)5Cr H

8.18

8.19

Scheme 8.4 Table 8.1 Chromium carbenes and carboxylic derivatives chromium carbene

carboxylic equivalent

OMe

ester

(OC)5Cr R

carboxylate anion

O (OC)5Cr R

OAc

mixed anhydride

(OC)5Cr R NR'2

amide

(OC)5Cr R

OMe

OMe (OC)5Cr

(OC)5Cr R

R

255

enolate

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Organic Synthesis Using Transition Metals

OMe (OC)5Cr

R'NH2

R

OMe O

R'NH2

NHR'

OMe (OC)5Cr

(OC)5Cr

NHR' R

R

NHR'

OMe O

R

O

NHR' R

R

Scheme 8.5

OMe

OMe

O

OMe

O

7 days 25 °C 70:30

O

OMe

OMe

(OC)5Cr

OMe

3 hours 25 °C 92:8

(OC)5Cr

(OC)5Cr 8.20

"para"

"ortho"

Scheme 8.6 OEt (OC)5Cr

N N 8.21

(OC)5Cr

N

Cr(CO)5 N

+ N

EtO

N Ph

Ph

OEt

N N

Ph

8.22

Scheme 8.7

The mechanisms are also parallel. The reaction between an alkoxy carbene and an amine to give an amino carbene is equivalent to the exchange reaction between an ester and an amine to give an amide (Scheme 8.5). The parallel can be extended. Vinyl carbenes are powerful dienophiles in Diels–Alder reactions, better than the corresponding esters or amides (Scheme 8.6).6 For the reaction between methyl acrylate and isoprene, compared to the reaction between vinyl carbene 8.20 and isoprene, the rate enhancement is about 2 × 104 ; in comparison, a rate enhancement of 7 × 105 is obtained by adding AlCl3 to the methyl acrylate reaction. They are also excellent Michael acceptors (Scheme 8.7). The alkynyl carbenes are also very good in both regards.7 The ␣-protons of the alkyl substituent are acidic, just as the protons ␣- to an ester carbonyl group are acidic. Measurement of pKa values for carbene complexes is not straightforward as such numbers are often determined in an aqueous environment in which the conjugate base of the carbene is unstable. A value of 12.5 for the methoxy substituted methyl chromium carbene in 1:1 H2 O/ CH3 CN appears reasonable. Values for

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Carbene Complexes

OMe (OC)5W Me

1. n-BuLi O Me 2. O S F O

257

OMe (OC)5W 8.24

8.23

Scheme 8.8

(OC)5Cr

OMe 1. n-BuLi 2. BrCH2CO2Me Me

8.25

OMe

OMe CO2Me

(OC)5Cr

CO2Me

+ (OC)5Cr

8.26

8.27

CO2Me

Scheme 8.9

(OC)5Cr

1. n-BuLi O OMe 2. Et BF3.OEt2 (OC)5Cr Me

8.28

OMe

8.29

O

Et

(OC)5Cr O

8.30

Et

Scheme 8.10

O (OC)5Cr

1. n-BuLi 2. H 3C O

8.31

O (OC)5Cr 8.32

CH3

Scheme 8.11 OMe (OC)5Cr

PhCHO Et3N, Me3SiCl

OMe (OC)5Cr

Me 8. 3 3

8 .3 4

Ph

Scheme 8.12

carbenes of the other two group-VI metals are very similar.8 Naturally, these values are solvent dependent.9 For comparison, the pKa of methyl acetate is 25.6, showing how powerful (OC)5 Cr is as an electron-withdrawing group. Treatment with bases generates anions, which are equivalent to enolates. Simple alkylation is difﬁcult due to the high stabilization of the anion, and highly reactive alkylating agents, such as methyl ﬂuorosulfonate (“magic methyl”) and methyl bromoacetate are needed (Schemes 8.8 and 8.9).10 The Lewis-acid assisted ring opening of epoxides leads to cyclic carbenes 8.30 (Scheme 8.10), as the liberated alkoxy group can counterattack onto the carbene. The equivalent of aldol reactions also work, to give ␤-hydroxycarbenes or ␣,␤-unsaturated carbenes (Schemes 8.11 and 8.12).11

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Organic Synthesis Using Transition Metals OMe (OC)5Cr

OMe

Ce(NH4)2(NO3)6

O n-Bu

n-Bu 8.35

8.36

Scheme 8.13 OMe

OMe

(OC)5Cr

(OC)5Cr H

8.35

H (OC)5Cr

N

N H

8.37

OMe

reductive elimination

8.38

OMe (OC)5CrPy 8.39

Scheme 8.14

8.1.1

Demetallation

The principle method for demetallation is by oxidation, for instance with cerium(IV). The product is the corresponding carboxylic compound (Scheme 8.13). Alternatively, demetallation to give enol ethers 8.39 can be achieved by treatment with pyridine (Scheme 8.14).12 Under these conditions, as pyridine is a weak base, an equilibrium is established between the carbene 8.35 and its anion 8.37. The anion, however, can also reprotonate on chromium to give a chromium hydride 8.38. This is followed by reductive elimination. The enol ether 8.39 is obtained as its Z-isomer, a consequence of the carbene anion having E-geometry to keep the alkyl group away from the bulky Cr(CO)5 moiety; the chromium is converted into a pyridine complex. 8.1.2

The D¨otz Reaction

In addition to the carboxylate-like reactivity of carbenes, these complexes also display a rich and quite remarkable metal-based chemistry. This can be divided into two types: thermal and photochemical. The principle thermal reaction is the D¨otz reaction with alkynes (Scheme 8.15).13 This involves heating an ␣,␤unsaturated carbene 8.40 with an alkyne and results in the formation of a phenol 8.41. The phenolic carbon is derived from CO. The ␣,␤-unsaturation may be a part of a benzene ring, in which case a naphthol will be formed. If the reaction is run in the presence of acetic anhydride and a base, the corresponding acetate is RS

OMe RS

(OC)5Cr

RL

8.40

Δ

RL

MeO

OH 8.41

Scheme 8.15

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Carbene Complexes OMe

OMe

± CO (OC)4Cr

(OC)5Cr

RL RS coordination

OMe (OC)4Cr

RL

8.43

8.42

259

RS 8.44

OMe

OMe

alkyne insertion

CO

(OC)4Cr RL

RL

RS

8.47 OMe

RS

RL

•

tautomerism

RL O Cr(CO)4

Cr(CO)4 8.48

RL

O

OMe

electrocyclic ring closure

RS

(OC)4Cr

8.46

MeO

O

MeO

RS

8.45 RS

CO insertion

(OC)5Cr

RS RL HO Cr(CO)4

8.49

8.50

Scheme 8.16

formed. This is useful in the case of acid-sensitive substrates and products. Silylation can be done similarly. The donor substituent of the carbene (OMe below) will be p- to the phenol, the large substituent of the alkyne will be o- to the phenol. The mechanism of the D¨otz reaction involves substitution of a CO ligand by the alkyne to give a ␩2 intermediate 8.44 (Scheme 8.16). The alkyne can then insert into a Cr–C bond. This leaves the other Cr–C bond intact in a process that is a formal [2+2] cycloaddition giving a metallacyclobutene 8.46 after recoordination of CO. This step determines the regioselectivity of the reaction: the smaller of the alkyne substituents is favoured to be next to the quaternary centre. The chromium is very electron poor at this stage as it is no longer beneﬁting from donation of the oxygen lone pair. CO insertion results, giving a metallacyclopentenone 8.47 that opens to a coordinated vinyl ketene 8.48. Electrocyclic ring closure of this ketone gives a dienone complex 8.49 that gives the phenol product as its Cr(CO)3 complex 8.50 after tautomerism. In some cases, the ␩6 -complex 8.50 is labile and decomplexes under the reaction conditions, in other cases the free arene can only be obtained by oxidative decomplexation. As the free arene is highly electron rich, however, this is usually accompanied by oxidation to the quinone 8.51 (Scheme 8.17). As there is considerable interest in quinone antibiotics, this can be an advantage! On the other hand, decomplexation may sometimes be achieved by heating with CO. This procedure generates Cr(CO)6 as a by-product, which may be recovered. O

OMe RS

RS

Ce(NH4)2(NO3)6

RL HO Cr(CO)4 8.50

RL O 8.51

Scheme 8.17

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Organic Synthesis Using Transition Metals i-Pr3SiO i-Pr3SiOTf, 2,6-lutidine, Δ

Cr(CO)5 OMe

SPh OMe

8.52

(OC)3Cr OMe SPh OMe

8.53

8.54

i-Pr3SiO

i-Pr3SiO

i-Pr3SiO

LDA

I2 (OC)3Cr OMe SPh OMe

(OC)3Cr OMe SPh OMe

8.55

OMe SPh OMe

8.56

8.57

Scheme 8.18

OTBS OMe (OC)5Cr

OAc OTBS

EtO Ac2O, Et3N O

O

OEt OMe

8.58

8.59

Scheme 8.19

Alternatively, the arene can be left complexed so that the chemistry of the ␩6 -arene complex can be exploited (see Section 10.3).14 The D¨otz reaction between the cyclohexenyl carbene 8.52 and the benzylic alkyne 8.53 in the presence of a silylating agent gave the ␩6 -complex 8.54 (Scheme 8.18). Treatment of this complex with LDA resulted in formation of the anion ␣- to sulfur 8.55 that cyclized by nucleophilic attack onto the chromium-complexed aromatic ring. Oxidative work-up then gave the tetracycle 8.57. The D¨otz reaction may employ heteroaryl substituted carbenes. The furyl carbene 8.58 gave the benzofuran 8.59 (Scheme 8.19).15 The reaction may also be intramolecular, taking advantage of the acylation of the “ate” complex 8.60 to introduce the alkyne (Scheme 8.20).16

(OC)6Cr

1. PhLi 2. Me4NBr

O

1. AcBr NMe4 2. HO

(OC)5Cr Ph 8.60 OH

O

Δ

(OC)5Cr Ph

8.61

O

Scheme 8.20

8.62

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Carbene Complexes

261

One important group of antibiotics are the anthracyclinones, such as daunomycinone 8.63. Clearly, various routes to this compound are possible using D¨otz chemistry.17

O

OH

O

D

C

B

MeO

O

OH OH

A

OH

8.63

One approach is to react the tetracarbonylchomium carbene 8.65, prepared from the pentacarbonyl complex 8.64 by heating so that the methoxy group replaces a CO as a ligand, with an alkyne 8.66 (Scheme 8.21).18 As the quinone was not desired at this stage, a non-oxidative decomplexation was employed: heating the ␩6 -complex 8.67 under a high CO pressure to give the free arene 8.68 and recovered Cr(CO)6 . Methylation of the free phenolic hydroxyl group was followed by conversion of the ketone 8.69 to a homologated

O

HO Cr(CO) 3

Δ -CO

O

OMe

OMe MeO

O

MeO

Cr(CO)5 8.64

O 8.66

Cr(CO)4

O MeO

8.65 HO

OMe 8.67

MeO

O

CO (75 bar), Δ

O OMe

MeO

O O MeO

8.68

MeO

O

O

Ts NC KOt-Bu

O MeO

HO2C OMe

O

CH2N2

O Cr(CO)6

O

F3C

OMe

O O

8.69 MeO O

CF3

OMe O

MeO 8.70

8.71

MeO

O

1. MgBr 2. Hg(OAc)2, H2O

O

O

1. SeO2 OAc 2. NaOMe MeO

OMe O 8.72

Scheme 8.21

OH MeO

O

OH

8.63

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Organic Synthesis Using Transition Metals Br 1. NaOMe, MeO2C

CO2Me

MeO2C

2. NaH, Br

CO2Me

CO2Me 1. KOH then HCl 2. Δ 3. CH2N2 CO2Me 8.73

OMe CO2Me CO2Me

MeO

OH CO2Me

MeO (OC)4Cr

OMe 8.75

8.74

MeO

O

OH

OMe

CO2Me 8.76

O OH

O

OH

OH

8.77

Scheme 8.22

carboxylic acid 8.70 using Tosmic. This enabled the subsequent Friedel–Crafts ring closure to establish ring B. The dioxolane-protecting group was also lost under the acidic Friedel–Crafts conditions. The ketone 8.71 is a known precursor for 11-deoxydaunomycinone 8.63, using acetylene chemistry to install the methyl ketone. Another approach, this time to the 4-demethoxy derivative 8.77, was to use the D¨otz reaction to form the B ring (Scheme 8.22).19 The alkyne 8.74 was prepared by malonate chemistry and reacted with the tetracarbonylchromium–carbene complex 8.75. The ␩6 -product decomplexed easily on warming to give the air-sensitive anthracene 8.76. Arizonin C1 8.83 was also prepared using a D¨otz reaction to form a naphthoquinone (Scheme 8.23).20 Reaction of a chromium–carbene complex 8.79 with an alkynyl ether gave the naphthol, which was converted to the ether 8.80. The side chain was then extended using the Doebner modiﬁcation of the Knoevenagel reaction. The major product of this reaction 8.81 had the alkene in conjugation with the naphthalene, rather than with the ester. Asymmetric dihydroxylation then gave the lactone 8.82. The ﬁnal ring closure was achieved with modest selectivity on treatment with acetaldehyde under Lewis-acidic conditions. Oxidation of the central ring to a quinone, gave the natural product 8.83 and its diastereoisomer. The minor isomer could be converted to the natural product 8.83 at this stage on acid treatment. A combination of an intramolecular D¨otz reaction and a palladium-catalysed carbonylative cyclization has been employed to make deoxyfrenolicin 8.91 (Scheme 8.24).21 The required carbene 8.86 was made via an O-acyl complex. Following the D¨otz reaction, an oxidative decomplexation-arene oxidation was used to give naphthoquinone 8.88. After oxidation, the ethano-linker was cleaved by a curious procedure involving prolonged treatment with aqueous sulfuric acid, followed by reduction. Palladium-catalysed carbonylative cyclization (see Section 6.1.1) then installed the remaining ring, but gave the ester 8.90 as a 3:1 mixture of isomers. Interestingly, deprotection with a Lewis acid also resulted in isomerization of the minor cis isomer to trans. Saponiﬁcation completed the synthesis.

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Carbene Complexes MeO MeO

Br

263

MeO MeO 1. n-BuLi OTBS MeO 2. Cr(CO)6 Cr(CO)5 1. 3. Me3O+ BF42. MeI, K2CO3

8.78 MeO MeO MeO

8.79 MeO MeO 1. TBAF 2. TEMOP, PhI(OAc)2 MeO 3. HO2C CO2Me + OAcC H NH 5 10 OTBS

MeO

CO2Me

MeO

8 .8 0

8 . 81 MeO MeO

K2OsO4, (DHQD)2PHAL, MeO MeSO2NH2, K3Fe(CN)6

OH

O

MeO

O

8.82 MeO 1. CH3CHO, BF3 2. Ce(NH4)2(NO3)6

O

MeO

O

8.83

O

O O

Scheme 8.23

8.1.3

Not the D¨otz Reaction

Not all alkynes give D¨otz products. Ethyl 3-t-butylpropiolate 8.91 yields a cyclobutenone 8.92 (Scheme 8.25).22 Other acyl alkynes, without the bulky group, tend to give the D¨otz product 8.95 as a minor product, the major product 8.96 appearing to arise from an 8␲-electrocyclic reaction involving the carbonyl group (Scheme 8.26).23 More generally, if the carbene employed does not possess ␣,␤-unsaturation, the D¨otz mechanism cannot fully operate. The intermediates that do form can be intercepted in other ways. Both alkenes and alcohols are capable of reacting with ketenes, giving cyclobutanones and esters, respectively. A pendant alkene can, therefore, intercept the ketene intermediate 8.97 by [2 + 2] cycloaddition to give a cyclobutanone 8.98 (Scheme 8.27).24 If the alkyne contains an alcohol group, this may attack the ketene intermediate leading to a lactone after oxidative removal of the chromium (Scheme 8.28). This reaction has been used in syntheses of blastmycinone 8.106 and antimycinone 8.107, starting from a protected lactaldehyde 8.102, and employing the Mozingo method at the end to remove the undesired keto group from the ketene cyclization product 8.105 (Scheme 8.29).25 Without such a nucleophilic intervention, carbenes 8.108 with side chains containing an ␣-hydrogen give cyclopentenones 8.109 and 8.110 (Scheme 8.30).26 This may be from ␤-hydride elimination–reinsertion following formation of the metallacyclobutene. When ene–ynes are used as the substrate, interesting bicyclic compounds can be produced, depending on the precise substitution pattern (Scheme 8.31).27

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1. n-BuLi 2. Cr(CO)6 3. Me4NBr 4. AcCl 5. alcohol 8.85

MeO Br

(OC)5Cr MeO

8.84

OMe O

OMe O

OH

O

OMe O

8.88

n-Pr

1. aq. H2SO4 2. NaBH4

OH

O

(MeCN)2PdCl2, CO, MeOH

8.89 OMe O

n-Pr

O

OH

O

8.87

n-Pr

1. BBr3 2. KOH

O

n-Pr

DDQ

n-Pr (OC)3Cr

8.86

O

35°C

OMe O

O

O

O

O

CO2Me

8.90 trans: cis = 3:1

CO2H

8.91

O

HO

8.85

Scheme 8.24

EtO2C

OMe + t-Bu

(OC)5Cr

CO2Et

Ph

t-Bu

8.92

8. 1

OMe Ph O 8. 93

Scheme 8.25 OH OMe (OC)5Cr

O +

R4

O + O

R5

R5

O 8.20

R5

R4

8.94

OMe 8.95

Scheme 8.26

264

R4

OMe 8.96

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O •

OMe

O OMe

(OC)5Cr

H

Me

Me

OMe Me

8.97

8.25

8.98

Scheme 8.27

OEt +

(OC)5Cr

OH

O

1. Δ, CH3CN 2. [FeCl2(DMF)3][FeCl4]

O

O

8.100

8.99 Et

O •

EtO (OC)5Cr

OH 8.101

Scheme 8.28

TESO CHO

1. Li SiMe3 2. TBSCl, base 3. K2CO3, MeOH

OEt

1. (OC)5Cr 2. H3O+

HO

O

O O

TBSO

R TBSO

1. HS(CH 2)2SH, BF3 2. Ni(R), H2 3. i-BuCOCl, py i-BuCO2

R

8.105

OEt

R

OTBS 8.103

8.102

O •

HO

O

8.104

O

R 8.106 blastmycinone R = Et 8.107 antimycinone R = n-Bu

Scheme 8.29 O

R +

(OC)5Cr

RL

O

RL

RS

OMe

RS

8.108

R OMe

RL

R

RS

8.109

OMe 8.110

Scheme 8.30

O

OMe (OC)5Cr 8.25

+ O

8.111

Scheme 8.31

265

8.112

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Organic Synthesis Using Transition Metals OMe

OMe

n-Bu

+

(OC)5Cr

(OC)4Cr n-Bu

8.113

(OC)4Cr

8.114

OMe n-Bu

n-Bu

OMe

O

n-Bu 8.115

8.116

8.117

Scheme 8.32

OMe (OC)5Cr

(OC)5Cr

Br

OMe

KOH, n-Bu4NBr

8.25

8.118 Me

O

1. NaOMe, MeOH 2. K-selectride 3. Ac 2O, DMAP

Δ

Me

H 8.119 Me

OAc

1. O3; Me2S 2. AgNO 3, NaOH 3. H+

H

Me O

O O

H 8.120

8.121

Scheme 8.33

If the alkene is present in the carbene side chain, but not conjugated to the carbene, cyclopropanation can be observed (Scheme 8.32).28 This is consistent with the metallacyclobutene 8.114 of the D¨otz mechanism being formed, but breaking down to give a new carbene 8.115. An intramolecular cyclopropanation follows. As the product is, initially, an enol ether 8.116, facile hydrolysis yields a ketone 8.117. This reaction has been used in a formal synthesis of carabrone, a cyclopropane-containing sesquiterpene (Scheme 8.33).29 Methoxy methyl carbene 8.25 was dialkylated under phase-transfer conditions. Heating the new carbene 8.118 with propyne in a sealed tube resulted in cyclopropanation of one of the nearest alkenes. Diastereoselective reduction of the ketone 8.119 and protection of the alcohol as its acetate 8.120 then allowed ozonolysis of all of the surviving alkenes. Formation of a lactone completed the synthesis of a known caraborone precursor 8.121. Cyclopropyl carbenes 8.122 can give either seven-membered cyclic ketones 8.123 or ﬁve-membered cyclic ketones 8.124 depending on whether the metal in the carbene is tungsten or chromium – a rare example of the identity of the group VI metal having such a signiﬁcant effect (Scheme 8.34). In both cases, opening of the cyclopropyl ring occurs, but in the chromium case, two carbons are subsequently lost as ethylene.30

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Carbene Complexes

267

O RL RS

M=W

MeO 8.123

OMe (OC)5M

+

RL

RS

8.122

O M = Cr

RL RS

OMe 8.124

Scheme 8.34

8.1.4

Fischer Carbene Photochemistry

An alternative mode of reactivity for these carbenes is photochemical (Scheme 8.35).31 This chemistry has opened up an enormous number of possibilities. Chromium carbenes possess a metal to ligand charge-transfer (MLCT) band in the near-ultraviolet. This excitation results in the promotion of an electron from a metalcentred orbital to an orbital centred on the carbene ligand. This results in loss of electron density by the chromium atom in the excited state 8.125, already electron poor because of the ﬁve carbon monoxide ligands. While one route to relieve this situation is relaxation to the ground state, another is by insertion of carbon monoxide into the chromium–carbon double bond. The result is (formally) a metallacyclopropanone 8.127, which is a resonance structure of a coordinated ketene 8.126. In fact, the photolysis solution behaves in many ways like a ketene solution. If photolysis is carried out in the presence of a reagent that can trap a ketene, then the expected ketene derived product is obtained.32 As this method of ketene formation is reversible, by relaxation back to the carbene, typical by-products that arise during classical ketene forming reactions are not observed.

X (OC)5Cr

hν relaxation

*

δ+ δ- X (OC)5Cr R 8.125

R

CO insertion X R

X

R R'

(OC)4Cr

(OC)4Cr

N

R"

• O 8.126

O 8.127 R'OH

N

8.128

R' R

O

X

8.129

Scheme 8.35

R'

X NHR'

R

O O

R" 8.131

X R

R'

O

R'NH2

OR'

R X

8.130

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Organic Synthesis Using Transition Metals Ph Ph

O

O N

hν

O

N

O

(OC)5Cr

N N

H

O

8.132

8.133

Scheme 8.36 R' Ph

O

Ph R'

RO2C NH2 hν

N (OC)5Cr

RO2C

N

N H

R 8.134

O O

R

8.135

Scheme 8.37 Ph

O N

(OC)5Cr

Ph 1. n-BuLi 2. PhCHO

(OC)5Cr

Me 8.136 Ph O (OC)5Cr N O •

O N

HO

CO, hν

8.137 Ph

Ph

O N

O O

HO

Ph 8.138

Ph

8.139

Scheme 8.38

Alcohols give esters 8.128, and amines give amides 8.129. In the presence of imines, ␤-lactams 8.131 are obtained.33 If a carbene 8.132 with a chiral auxiliary is used, high diastereoselectivity may be obtained (Scheme 8.36).34 Electron-rich alkenes react to give cyclobutanones 8.130, showing the same patterns of reactivity and stereoselectivity as are observed with ketenes generated in classical ways.35,36 While alkoxy carbenes work well, the more electron rich N-alkyl carbenes do not give cyclobutanones. The less electron rich N-aryl and N-pyrrolocarbenes, on the other hand, do react.37 In both cases, the nitrogen lone pairs are delocalized over aromatic systems. The reaction with aldehydes to give ␤-lactones works best in an intramolecular fashion.38 Photolysis of amino carbenes in the presence of alcohols results in the formation of amino acid derivatives (Scheme 8.37).39 Once again, the use of a carbene 8.134 with a chiral auxiliary gives useful stereoselectivity. Esters of amino acids and even short peptide chains can be used as the nucleophile in a highly unusual way to build up peptides.40 Double diastereoselectivity may be observed as a result of the chiral centres in both the carbene and the nucleophile. The carbene photochemistry may be combined with the enolate-like chemistry (Scheme 8.38).41 Both reactions are capable of showing high diastereoselectivity.

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Carbene Complexes

269

R

R

•

H

R

[M]

H

H 8.140

8.141

8.142

Scheme 8.39 D

D Ph3P(p-cymene)RuCl2 NH4PF6, Δ

8.143

O

O

D

8.144

D •

[Ru]

[Ru]

O

O

8.145

8.146

Scheme 8.40

(OC)5W.THF • 8.147

I

I

(W(CO)5 8.148

8.149

I

Scheme 8.41

8.2 Vinylidene Complexes Formally, vinylidene complexes 8.142 can be considered as complexes of vinylidene carbenes with transitionmetal fragments. Free, uncomplexed vinylidene carbenes 8.140 are postulated in organic chemistry as intermediates on the way to terminal and some internal alkynes (the Fritsch–Buttenberg–Wiechell rearrangement) (Scheme 8.39). They can, in some cases, be trapped by nucleophiles. It can be postulated that the equilibrium between the alkyne and the vinylidene carbene, usually entirely in favour of the alkyne, would be less one sided if complexation to a transition metal were involved. Once generated, one way to trap a vinylidene complex could be in an electrocyclic reaction. Indeed, treatment of an alkyne 8.143, having a dienyl unit attached, with a ruthenium catalyst yields a tricyclic product 8.144 (Scheme 8.40).42 Deuterium-labeling experiments are consistent with the alkyne–vinylidene isomerization. A tungsten catalyst, W(CO)5 .THF, may also be used.43 Hydrogen is not the only atom that can participate in this migration. Iodide can also migrate during the generation of an intermediate vinylidene complex 8.148 (Scheme 8.41).44 Vinylidene complexes 8.150, generated in situ by the reverse Fritsch–Buttenberg–Wiechell rearrangement, may also be trapped with heteroatom nucleophiles. Alkynols may be converted to oxygen heterocycles 8.153, or carbene complexes 8.152, according to the conditions used (Scheme 8.42).45 The organometallic reagent

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Organic Synthesis Using Transition Metals M(CO)6 L, hν LM(CO)5

HO

HO

•

M(CO)5

8.150

CH3CHO

L = THF O 8.152

M(CO)5

O

M(CO)5

O

8.151

L = Et 3N

PhCHO

O

Ph

O

8.153

8.154

M(CO)5

8.155

Scheme 8.42

M(CO)5THF HO

O

OH 8.156

(OC)5M

OH

M = Cr, W 8.157 1. I n-C7H15 (Ph3P)2PdCl2, CuI, i -Pr2NH 2. H2, Pd/C

O

Ce(NH4)2(NO3)6

O

O

O

OH

n-C12H25 OH

8.158

8.159

Scheme 8.43

or catalyst for these reactions is generated from the corresponding hexacarbonyl complex (M = Cr, Mo, W), in the presence of a Lewis base, L, that then becomes a labile ligand. When this ligand is THF, proton transfer to carbon occurs to give a stable carbene; when this ligand is triethylamine, elimination of the metal occurs to give an enol ether (compare to Scheme 8.14). In the presence of aldehydes, aldol products, 8.154 and 8.155, are formed. This chemistry has been used to synthesize butyrolactone natural products, such as muricatacin 8.159 (Scheme 8.43),46 taking advantage of the facile oxidation of Fischer carbenes to the carbonyl compounds (see Scheme 8.13). Treatment of the C2-symmetrical diol 8.156 with the activated metal-carbonyl complex generated the carbene complex 8.157. Both the chromium and tungsten complexes were used, with similar results. Oxidation of the carbene 8.157 yielded the butyrolactone 8.158. The carbon chain could then be extended by Sonogashira coupling of the surviving alkyne, and, ﬁnally, hydrogenation gave the natural product 8.159. One application of the corresponding enol ether formation is in the synthesis of D-decosamine 8.165 (Scheme 8.44),47 a deoxysugar that appears in many naturally occurring antibiotics. The required alkynol 8.162 was prepared from a ␤-siloxyaldehyde 8.160 by addition of trimethylsilylacetylene anion. As the ␤-substituent exerted little stereocontrol over the new stereogenic centre, a chiral ligand was included in this

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Carbene Complexes

OTBS

OTBS Zn(OTf)2, SiMe3 (+)-N-methylephedrine CHO 8.160

W(CO)6, DABCO, hν

SiMe3

1. MsCl, Et3N 2. NaN3 3. LiAlH4 4. Boc2O 5. TBAF

OH

NHt-Boc 8.162

OH 8.161 O

O

1. NaH, MeI 2. LiAlH4

8.163

O

OsO4, Me3NO, citric acid

OH

NMe2

OH NMe2

8.164

8.165

NHBoc

271

Scheme 8.44 OH ON Ph3P

Mn

AgSbF6

ON Mn Ph3P

I

O

8.167

8.166

Scheme 8.45

addition reaction. A series of functional group interconversions installed a protected amine. Cyclization to the enol ether 8.163 was achieved with a catalyst photogenerated from tungsten hexacarbonyl and DABCO. To complete the synthesis, the protected amine was converted to an N,N-dimethyl amino group, and the alkene was dihydroxylated. Complexes with other ligands and other metals may also be used to generate the cyclic carbenes, some of which have been characterized by X-ray crystallography (Scheme 8.45, Figure 8.2).48 C(5)

C(2) C(1) C(3) C(4)

C(13) C(12)

C(

14

C(24)

Mn(1) O(2) C(7)

C(15)

C(23)

N(1)

C(10)

C(6)

O(1)

P(1)

C(25)

)

C(10)

C(11)

C(22) C(16)

C(8) C(17)

C(9)

C(27) C(26)

C(21)

C(20)

C(18)

C(19)

Figure 8.2 Manganese carbene 8.167. Reprinted with permission from Semmelhack, M. F.; Lindenschmidt, A.; c 2001 American Chemical Society Ho, D. Organometallics 2001, 20, 4114.

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Organic Synthesis Using Transition Metals BnO BnO BnO

BnO BnO BnO

additive = O

O

Cp(Ar3P)2RuCl, n-Bu4N PF6, Ar3P, additiv e

OH

Ar = p-FC6H4

O

O N ONa

8.169

O BnO

8.168 BnO BnO

O

O

Ar = p-MeOC6H4 additive =

O 8.170

O

N OH

O

Scheme 8.46

A ruthenium-catalysed version of this cycloisomerization has been reported49 and used in various syntheses (Scheme 8.46). It has the advantage that, if a suitable oxidant is present, the product is a lactone 8.170. The identity of the phosphine ligand on ruthenium is also important. A remarkable allylic alcohol–alkyne combination reaction, catalysed by a ruthenium complex, is believed to proceed via a vinylidene complex (Scheme 8.47).50 The proposed mechanism, again, involves a reverse Fritsch–Buttenberg–Wiechell rearrangement, followed by nucleophilic attack on the resulting vinylidene

R

CpRu(PPh3)2Cl, NH4PF6, Δ

OH

+

H

R O 8.171

CpRu(PPh3)2Cl R O reductive elimination

±Cl

8.171

CpRuL2

R

H

coordination

L RuCpL

R

CpRuL2 R 8.172

O C-O bond cleavage

8.176

H isomerisation

R

R RuCpL O

H H+ R

8.175 nucleophilic attack

• RuCpL H

L HO 8.174

Scheme 8.47

• RuCpL2 8.173 HO coordination/ dissociation

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Carbene Complexes

OH

OAc +

CpRu(PPh3)2Cl, NH4PF6

273

O OAc 8.178

8.177 O

1. OsO4, NMO 2. TsOH

O

1. LiOH 2. DMSO, Δ OAc

8.179

8.180

Scheme 8.48 Cp

Cp

(OC)3W

(OC)3W OH BF3.OEt2

OMe MeO

OH

OMe

8.181

8.182

Cp Cp

(OC)3W •

OH

O

(OC)3W

MeMgBr

O

MeO 8.183

8.184

8.185

Scheme 8.49

complex 8.173. It is, however, suggested that this nucleophilic attack is facilitated by prior coordination of the allyl alcohol double bond to ruthenium. After nucleophilic attack, the C–O bond of complex 8.175 is activated towards cleavage to form a ␲-allyl complex 8.176. Reductive elimination and dissociation yields the product 8.171 and regenerates the catalyst. Propargylic alcohols, however, follow a different pathway.51 This reaction was employed to synthesize the perfumery compound, rosefuran 8.180 (Scheme 8.48) by the ruthenium-catalysed combination of alkyne 8.177 with an allylic alcohol.52 Dihydroxylation of the product 8.178 was followed by acid-catalysed dehydration. Hydrolysis of the ester and thermal elimination of water gave the natural product 8.180. Another synthesis of rosefuran can be found in Scheme 2.15. Vinylidene complexes may also be formed by the reaction of ␩1 -alkynyl complexes with electrophiles (Scheme 8.49).53 Again, if an alcohol is present, a carbene complex will be formed. In this case, the carbene complex 8.184 was converted to a gem-dimethyl group by reaction with a Grignard reagent.

8.3 Metathesis Reactions Involving Carbene Complexes What is metathesis? The term is very general and it describes an outcome, rather than any speciﬁc process. The term metathesis implies nothing about the mechanism followed. Metathesis refers to any process in which a pair of groups bonded together swap partners with another pair, thus, A-B reacts with X–Y to give A–X and B–Y (Scheme 8.50). The bonds being exchanged may be single, double, triple or even ionic. A Wittig reaction may be regarded as a metathesis reaction.

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Organic Synthesis Using Transition Metals

Na Cl

O

A

X

B

Y

A X B Y Na NO3

+ Ag NO 3

PPh3 CH2

CH2

+ AgCl

PPh3 O

Scheme 8.50 WO3, SiO2

Scheme 8.51

For organic chemists, the term metathesis is used most often to mean alkene or oleﬁn metathesis. This process, which can be catalysed by a range of transition metals, was discovered accidentally in the petrochemical industry. Its ﬁrst commercial application was in the Phillips trioleﬁn process in which propene was converted to an equilibrium mixture of ethene, 2-butene and the starting propene at 400 ◦ C in the presence of an unknown tungsten species (Scheme 8.51). The process was in use between 1966 and 1972. Interestingly, with changes in feedstock prices and demands, the process is now run in reverse, producing propene from ethene and 2-butene. The mechanism of the reaction was proposed by Chauvin in 1970 and has stood the test of time and experiment (Scheme 8.52).54 He proposed, daringly for the time, that metal–carbene complexes were involved that reacted with the alkene to form metallacyclobutanes. These then fragmented in the opposite direction to give a new carbene that could add to a second alkene. Fragmentation again gave the product and the starting carbene. A metathesis of this type between two similar alkenes suffers from the problem that ⌬ G is very small, near to zero, and, hence, K is about one, leading to mixtures. While the petrochemical industry can work efﬁciently by separation and recycling, this is not practical for organic synthesis. A driving force must be added. These include ring closing for medium-sized rings and ring opening for strained rings. In addition, le Chatelier’s principle can be used. One component may be added in excess. Also, in the common case when ethene or propene is a by-product, its escape from the reaction mixture due to volatility can drive the equilibrium. 8.3.1

Tebbe’s Reagent

Tebbe’s reagent 8.188 is a nucleophilic carbene (Scheme 8.53).55 It is made by treatment of titanocene chloride with trimethyl aluminium to give a chloro-bridged complex 8.187. The reagent is released in the presence of a Lewis base, such as pyridine or DMAP, which will coordinate the aluminium. Even THF can function as an effective Lewis base. Its principle use in organic synthesis has been as a substitute for methylene triphenylphosphorane, Ph3 P= CH2 , in cases where the classical Wittig reaction is too basic and causes side reactions. It is also used for the

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Carbene Complexes

275

?

dissociation

M

coordination

M

M fragmentation

M M fragmentation

M M M coordination

dissociation

Scheme 8.52

Cl

AlMe3

Cp2Ti Cl 8.186

N Cp2Ti

Cl

Cp2Ti

AlMe2

8.187

8.188

Scheme 8.53

O

O

Cp2TiCl 2, AlMe 3

8.189

O

8.190

Scheme 8.54

conversion of the carbonyl group of esters and lactones to alkenes, a process that is not usually possible with phosphorus-based reagents (Scheme 8.54). The disadvantage of Tebbe’s reagent in comparison to Wittig reagents, is that only a few are possible. Tebbe’s reagent is made by ␣-elimination from organotitanium complexes. If the chain attached to the titanium is longer than one carbon, and is not ␤-blocked, then ␤-hydride elimination is observed instead. The same applies to the related Petasis reagent, Cp2 TiMe2 , prepared from titanocene chloride and methyl lithium (Scheme 8.55).56 The related benzyl, cyclopropyl (Scheme 8.56)57 and vinyl analogues (Scheme 8.57) have been prepared and used for the synthesis of enol ethers, 8.190 and 8.191, and allenes 8.193.

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Organic Synthesis Using Transition Metals Cp2TiCl 2 2 MeLi O

O

O

Cp2TiMe 2

8.189

8.190

Scheme 8.55 Cp2TiCl 2 2

O

Li

Cp2Ti

O

O

8.1 89

8.191

Scheme 8.56 Cp2TiCl2 2

MgBr

O

• Cp2Ti

8 .1 9 2

8 . 19 3

Scheme 8.57

An outstanding application of Tebbe’s reagent in organic synthesis is in a synthesis of capnellene 8.205b.58 The synthesis started with the ␣,␣-dimethyllactone 8.194. Partial reduction, Horner–Wadsworth–Emmons oleﬁnation and an in situ oxa-Michael addition gave the tetrahydrofuran 8.195 (Scheme 8.58). This was ring opened and trapped in that form using LDA and tosyl chloride. Treatment of the tosylate 8.196 with the magnesium derivative of cyclopentadiene resulted in alkylation. The corresponding sodium and potassium derivatives could not be used due to the formation of by-products through Michael addition. Warming the alkylation product 8.197 at 75 ◦ C gave the Diels–Alder adduct 8.199. This is formed by, ﬁrst, a 1,5-sigmatropic shift, then the cycloaddition. The tricyclic structure 8.199 contains two of the rings required for capnellene, it also contains the inherent ring strain to drive metathesis chemistry forwards. Treatment of the Diels–Alder adduct 8.199 with Tebbe’s reagent in the presence of DMAP yielded the sensitive cyclobutene 8.200 (Scheme 8.59). This is formed by initial addition of Tebbe’s reagent to the alkene with the bulkier Cp2 Ti moiety avoiding the more hindered terminus. Fragmentation of the metallcyclobutane 8.201 generates a new carbene 8.202, which undergoes a metathesis reaction with the ester carbonyl to give the cyclobutene 8.200 and an oxa-titanium by-product.

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Carbene Complexes 1. DIBAL 2. (EtO)2P

O O

O

277

CO2t-Bu CO2t-Bu NaH

TsO

O

8.194

CO2t-Bu

LDA, TsCl

8.195

8.196

CO2t-Bu 1,5-sigmatropic shift

CO2t-Bu

8.197

8.198 intramolecular Diels-Alder reaction CO2t-Bu

t-BuO2C

8.199

Scheme 8.58

Cp2Ti

AlMe2 Cl DMAP

H

CO2t-Bu 8.199

Cp2Ti

AlMe2

Cl 8.187

DMAP

H H t-BuO

8.200 Cp2Ti O

Cp2Ti

TiCp 2 CO2t-Bu 8.201

t-BuO

O

TiCp 2

8.202

Scheme 8.59

As the cyclobutene 8.200 is also an enol ether, it was too sensitive to carry through in the same form, so it was reprotected as a dioxolane 8.203 (Scheme 8.60). The next few steps were required to convert the vinyl group to the desired methyl group: ozonolysis with reductive work-up gave an alcohol, which was converted to a phosphoramidate. The C–O bond could then be cleaved under modiﬁed Birch conditions to give the methyl substituted compound 8.204. With the vinyl group removed, it was then necessary to expand the four-membered ring. The best way to do this was found to be by treatment with ethyl diazoacetate because this gave the best regioselectivity. The superﬂuous ester group could then be removed under Krapcho conditions. The ﬁnal step, conversion of the ketone 8.205a to an exo-methylene, was found to work best using Tebbe’s reagent, rather than the Wittig reagent, giving the natural product 8.205b. Quite different syntheses of capnellene can be found in Scheme 4.13 and Scheme 5.40.

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Organic Synthesis Using Transition Metals

OH

HO

H H

H H O

TsOH H

t-BuO 1. H3O+ 2. BF3.OEt2 CO2Et N2

8.203

H H

3. NaCl, DMSO, Δ H O

H O

8.200

H H O

1. O3, MeOH; NaBH4 2. (Me2N)2P(O)Cl, Et3N 3. Li, t-BuOH, Et2NH

X

H

8.204 8.205a X = O Cp2Ti

AlMe2

Cl DMAP

8.205b X = CH2

Scheme 8.60

8.3.2

Alkene (Oleﬁn) Metathesis

This chemistry became useful for organic chemists with the development by Grubbs and by Schrock of stable carbene catalysts that could operate under mild conditions,59 and rapidly became a standard carbon–carbon bond-forming tool.60 The Grubbs catalysts are the more stable to ordinary handling – they can be weighed out in air and do not require glove-box techniques – and have become the most widely used for synthesis. The ﬁrst generation of the Grubbs catalyst 8.206 (Grubbs I) possesses two tricyclohexylphosphine ligands.61 (Figure 8.3) The introduction of the second generation of Grubbs catalysts 8.207 (Grubbs II), utilizing Nheterocyclic carbene ligands, has expanded their scope.62 The next major modiﬁcation of this family of catalysts was the use of a carbene substituent with a weak donor substituent. These catalysts, the Hoveyda–Grubbs catalysts 8.209 and 8.210, (HG I and HG II), have improved thermal stability. Both ﬁrst generation (two tricyclohexylphosphine ligands) and second generation (with one NHC ligand) are known. The Hoveyda–Grubbs catalysts offer the possibility of further modiﬁcation by adding substituents to the aryl group. The addition of an electron-withdrawing substituent, such as a nitro group, para to the isopropoxy group makes the oxygen into an even weaker ligand, raising the reactivity of the catalyst.63 Catalysts with an indenyl group supplying the carbene ligand, 8.212 and 8.213, have also been studied. Both water-soluble64 and solid-supported catalysts have also been prepared.65 Given this array of possibilities, which catalyst should be chosen for a given reaction? While it appears that the Grubbs I catalyst is more than competent in many simple cases, the Grubbs II catalyst and the Hoveyda–Grubbs family are more reactive. In any given reaction, if the simpler catalysts do not function effectively, the more advanced catalysts must be surveyed.66 The reaction conditions, especially temperature, must also be studied. Signiﬁcant temperature and solvent effects has been noted, with the use of 70 ◦ C in toluene being recommended.67 In many metathesis reactions, ethene is a by-product and it may slow the reaction as it can react with the catalyst. Removing ethene by bubbling an inert gas, nitrogen or argon, through the reaction mixture can also be beneﬁcial.

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Carbene Complexes

279

i-Pr i-Pr Cy3P Cl Ru Cl Cy3P

MesN Ph

8.206 Grubbs (1st generation) Grubbs I

Cl Ru Cl Cy3P

i-PrO 8.209 Hoveyda-Grubbs (1st generation) HG I

F 3C F 3C

Ph

N Ph

O Mo O

F 3C F3C 8.208 Schrock

8.207 Grubbs (2nd generation) Grubbs II MesN

Cy3P Cl Ru Cl

NMes

NMes

MesN

NMes

Cl Ru Cl

Cl Ru Cl

i-PrO

i-PrO

8.210 Hoveyda-Grubbs (2nd generation) HG II

8.211 Z = NO2, SO2NMe2

MesN

Cy3P Cl Ru Cl Cy3P

Ph

Z

NMes Ph

Cl Ru Cl Cy3P

8.212

8.213

Figure 8.3 A selection of alkene metathesis catalysts

8.3.3

Ring-Closing Metathesis

RCM was the ﬁrst application of metathesis in synthesis.68 The reaction is driven to completion not only by loss of ethene from the reaction mixture, but also by entropy as one molecule is converted into two. The mechanism follows that outlined by Chauvin (Scheme 8.61; compare Scheme 8.52). The Grubbs catalyst must ﬁrst dissociate one of the two phosphine ligands to generate a 14-electron monophosphine carbene.69 The mechanism then follows the steps laid down by Chauvin through metallacyclobutanes 8.217 and 8.219 and the carbene 8.218. It should be noted that the Grubbs catalyst is the benzylidene complex (R = Ph). This is purely for stability as the methylene complexes are unstable. In the catalytic cycle, R = Ph can only work for the ﬁrst round, thereafter, it is the methylene species with R = H. There are numerous examples of RCM in the literature and ring sizes from 5 upwards have been formed in this way. RCM was used for the formation of both a ﬁve-membered ring and a six-membered ring in a synthesis of the core structure of the dumsins (Scheme 8.62).70 Treatment of the substrate 8.221 for the ﬁrst RCM with the ﬁrst-generation Grubbs catalyst resulted in formation of the spirocyclic cyclopentene

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Organic Synthesis Using Transition Metals

EtO2C

EtO2C EtO2C

Grubbs I

EtO2C

8.215

8.214 L Cl Ru Cl L

Ph

±L EtO2C EtO2C

EtO2C

8.215 EtO2C EtO2C

EtO2C

Cl2RuL

8.214

R

EtO2C EtO2C

[Ru]

[Ru]

8.219

R

8.216

EtO2C EtO2C

EtO2C EtO2C

[Ru]

[Ru] R

8.217 EtO2C EtO2C 8.218

[Ru]

R

Scheme 8.61

8.222 without participation by the other, more-hindered alkenes. After introduction of an additional two allyl groups, the second RCM could be carried out to give the tricyclic target 8.225. RCM was used to form the seven-membered ring of sundiversifolide 8.232 (Scheme 8.63).71 The substrate 8.229 was assembled by an asymmetric aldol reaction and cyclized using the Grubbs second-generation catalyst. Reduction of the enone 8.230 formed allowed lactone formation by Claisen rearrangement, iodocyclization and deiodination. Further steps lead to the natural product 8.232. In a synthesis of thapsigargin, a seven-membered ring 8.234 was closed with enol ether functionality in the substrate 8.233 and product 8.234 (Scheme 8.64): asymmetric dihydroxylation then formed an ␣hydroxyketone 8.235.72 An RCM to form an eight-membered ring was employed in a synthesis of australine 8.244 (Scheme 8.65).73,74 The metathesis substrate 8.239 was constructed by reaction of a highly oxygenated alcohol 8.236 with an isocyanate. Base treatment resulted in nucleophilic opening of the epoxide to give a cyclic carbamate 8.238. The second alkene was then introduced by an interesting acetonide migration and an oxidation–Wittig pair of reactions. RCM then proceeded smoothly to give the eight-membered ring 8.240. The formation of eight-membered rings is notoriously difﬁcult. The presence of the acetonide, biasing the conformation towards cyclization, may assist in this case. The metathesis product 8.240 was converted

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Carbene Complexes

O

O

Br

1. LDA, 2. repeat

Grubbs I

8.220 O

281

8.221 Br

1.

1. Li, NH3(l) 2. Br

Zn, ))) 2. PCC O 8.222

8.223

Grubbs I O

O 8.224

8.225

Scheme 8.62

to the required bicyclic structure 8.243 by a transannular reaction. To achieve the transannular reaction, the protecting-group regime was modiﬁed, presumably to provide greater ﬂexibility for the later steps. The alkene formed by RCM was epoxidized. Hydrolysis of the carbamate then resulted in transannular ring opening of the epoxide by the released amine 8.242. Finally, debenzylation gave the natural product 8.244. Much larger rings can be constructed using RCM. Perhaps the ﬁrst example of the use of ring-closing metathesis in natural product synthesis is in Martin’s synthesis of manzamine 8.249, with two challenging

O CHO +

O N

8.226

Bn

1. MeONHMe.HCl, Me3Al 2. TBSOTf, 2,6-lutidine 3. MgCl

OH

O

n-Bu2BOTf, Et3N

O

8.227

N 8.228

TBSO

O O

Bn OH

O 1. Grubbs II 2. Red-Al® TBSO

8.230

8.229 1.MeO OMe NMe2 2. I2 3. n-Bu3SnH

O

H O

O

HO

TBSO

8.232

8.231

Scheme 8.63

H

O

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Organic Synthesis Using Transition Metals H

OMOM Grubbs II

TBDPSO

TBDPSO

H OTES OEt

H

8.233 H AD-mix-α

OMOM

H

OEt OTES

8.234 OMOM

TBDPSO

OH H

O OTES 8.235

Scheme 8.64

RCM reactions (Scheme 8.66).75 The ﬁrst involves the formation of a large ring across one face of the molecule by RCM of tetraene 8.245, the second involves closure of an eight-membered ring to form 8.248. An earlier aspect of this synthesis is in Scheme 2.60. Ring-closing metathesis can be used to couple together two separate alkenes. Provided that the alkenes contain a functional group such as an alcohol, they can be tethered together via an atom such as silicon (Scheme 8.67). RCM can then be used. If desired, the two Si–O bonds can be cleaved later.76 Phosphate

O

HO

O

•

N i-Pr2NEt

O

O H N O

8.236

O

O

O O

8.237

OH O

1. KOt-Bu 2. H+ N O

O

O

O

O

O

O

O

8.240

HN

O

OBn

OBn

N

LiOH

8.241 HO

OBn

H

OBn OBn

OBn N

HO

H

OH

H2, Pd(OH)2 N

8.243

Scheme 8.65

OH OH

OH HO 8.242

O

O

1. aq. H+ 2. BnBr, NaH 3. mcpba

Grubbs I O

N

8.238

O N

O

1. (COCl)2, DMSO, Et3N 2. Ph3P=CH2

8.244

O 8.239

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Carbene Complexes MeO H

OMe

MeO H

H

N

Grubbs I

O

OMe

N 8.245

N

H

OH O

O

8.246

CHO H

O

N

O

H

1. KOH, MeOH COCl 2. Et3N

H

N

Grubbs I

CHO OH

H

N

N

283

O

N 8.248

8.247

1. DIBAL 2. Dess-Martin periodinane 3. tryptamine, H+ 4. DDQ, Et3N

N H N

N H OH

H N

8.249

Scheme 8.66

groups have also been used as the tether.77 Silicon can also be used to tether an alcohol to an allyl group in an O–Si–C fashion. After RCM, the nucleophilic properties of the allyl silane can then be exploited in Sakurai chemistry.78 A problem that can arise in larger rings is the formation of E/Z isomers of the newly formed alkene. In smaller rings, only the E isomer is possible, but larger rings have sufﬁcient ﬂexibility to accommodate both, as in a synthesis of recifeiolide (Scheme 8.68).79 The principle limitations in RCM arise from three sources: steric hindrance, unfavourable molecular conformations and coordination of the ruthenium by a donor atom in the substrate. Steric hindrance around the alkenes can slow down or prevent carbene formation on the substrate. The introduction of newer,

Et O

O Si Et Ph Ph

Grubbs I

8.250

O Ph Si O Ph 8.251

Scheme 8.67

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Organic Synthesis Using Transition Metals O

O

O

O

Grubbs I

8.252

8.253 E:Z = 4.7:1

Scheme 8.68 EtO2C CO2Et

EtO2C CO2Et Grubbs II

8.254

8.255

Scheme 8.69

more-active catalysts can provide a solution to this problem in many cases (Scheme 8.69). The diene 8.254 failed to undergo RCM with the Grubbs I catalyst, but did so rapidly with Grubbs II.80 Another way to solve the problem is by relay metathesis (Scheme 8.70). Given that formation of the desired carbene by the intermolecular reaction between the catalyst and the substrate 8.256 is not feasible, the concept is to attach a more available alkene, which can react with the catalyst to form a carbene 8.259, and then acts as a relay to transfer the ruthenium to the desired site by a facile RCM, leading to formation of the desired product 8.257. Relay metathesis was employed to synthesize a building block 8.262 for peluroside (Scheme 8.71).81 While the silicon-tethered diene 8.261 gave the desired product, the yield was low even with a very high catalyst desired reaction prevented by steric hindrance

Y

X Z "normal" substrate 8.256

Y X

Z

8.257

Y

Y [Ru]

[Ru]

X Z "relay" substrate 8.258

X

Z

8.259 Y

Y desired RCM

"relay"-RCM [Ru] X

X

Z

Z

8.260

Scheme 8.70

8.257

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Carbene Complexes

285

Et

O

O SiPh2

< 20% yield

CN 8.261

Grubbs II O

Et 92% yield

O

O SiPh2

CN

O SiPh2

8.262

CN 8.263

Scheme 8.71

loading (45 mol%). The relay substrate 8.263, on the other hand, gave a high yield with a lower catalyst loading. Even if carbene formation goes ahead at one alkene, an unfavourable molecular conformation may make the desired ring-closing metathesis unfavourable compared to undesirable competitive processes. There is an obvious need for the two alkenes to be able to come into proximity. Many molecules are sufﬁciently ﬂexible to be able to allow this. In other cases, rigidity of structure or conformation may prevent this. In a short synthesis of frontalin 8.268, a dienyl acetal 8.266 was prepared as a mixture of isomers (Scheme 8.72).82 On treatment with the Grubbs ﬁrst-generation catalyst, the isomer with the two alkene substituents cis underwent RCM, leaving the other isomer. Hydrogenation of the RCM product 8.267 delivered frontalin 8.268, while

BnO O 8.264

Br Me3SiO Sn(II)-catecholate, (+)-DIPT, DBU, CuI 2. LiAlH4 3. Me3SiCl, Et3N 8.265 1.

O

O

O Me3SiOTf

O Grubbs I

O

OH

8.266

SO3H

O O

+

8.267

O

trans-8.266

H2, Pd/C O O 8.268

Scheme 8.72

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Organic Synthesis Using Transition Metals

n-Bu MeO

Et3SiO

OMe

n-Bu MeO

Grubbs I, Grubbs II or Schrock MeO

OSiEt3

OMe

OMe

n-Bu

OSiEt3

8.269

8.270 HO

1. TBAF 2. H2, PtO2 3. PhSH, K2CO3, Δ

n-Bu HO

HO

OH

OH

n-Bu

OH 8.271

Scheme 8.73

the unreacted diene isomer could be recycled. Another example of the importance of proximity for RCM can be found in Scheme 6.68. In other circumstances, the failure of an RCM reaction may lead to dimerization. As many natural products are dimers, this can be useful for their synthesis. This approach was used to prepare the cylindrocyclophanes 8.271 (Scheme 8.73).83 The diene starting material 8.269 could not undergo simple RCM due to the paradisubstituted aromatic ring. Instead, a cross-metathesis (see below) occurred, followed by a macrocyclic RCM to give 8.270. The natural product 8.271 could then be obtained by reduction of the two alkenes and deprotection. Even in cases where two similar alkenes both appear to be available, conformational factors may result in valuable stereoselectivity, as in a synthesis of the AB rings 8.273 of ciguatoxin, one of the ladder toxins (Scheme 8.74).84 Donor atoms in the molecule may coordinate to the 14-electron ruthenium-catalytic species and, thereby, take up a vacant site. Basic nitrogen atoms have this effect, although there are exceptions.85 Nevertheless, metathesis reactions have proved very effective for the synthesis of nitrogen heterocycles,86 as this effect can be suppressed. One way to suppress this effect is by use of an electron-withdrawing protecting group, such as a sulfonamide,87 a carbamate or an amide (Scheme 8.75).88 Another way is to carry out the reaction in the presence of acid, so that it is the salt 8.278 with no lone pair, that cyclizes.89 The problem is less severe with less-basic amines, including anilines.90

OBn O O

H

OBn O

Grubbs I OBn

OBn 8.272

O

H

OBn OBn 8.273

Scheme 8.74

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Carbene Complexes

R

H N

Grubbs I

R

H N

R = Bn Cbz t-Boc

287

0% 95% 91%

8.275

8.274

Grubbs I Bn N

Bn N

8.276

8.277

H+

Bn N H 8.278

base

Grubbs I

Bn N H 8.279

Scheme 8.75 Cbz

1. Grubbs I, HCl 2. TsNHNH 2, NaOAc 3. LiAlH4

N

Me

N

N

N 8.280

8.281

Scheme 8.76 Cbz

N

N

1. Grubbs I, HCl 2. H2, Pd/C

HN

8.283

8.282

Scheme 8.77

Both techniques were used in a synthesis of nicotine 8.281 (Scheme 8.76)91 (for the synthesis of the starting diene, see Scheme 9.45) and the closely related anabasine 8.283 (Scheme 8.77),92 as the substrates, 8.280 and 8.282, contained two nitrogen atoms each. A Boc group was used in a synthesis of swainsonine 8.290, an indolizidine alkaloid and glycosidase enzyme inhibitor (Scheme 8.78).93 The RCM substrate 8.286 was prepared by regio- and stereoselective ring opening of a vinyl epoxide 8.284 with allyl amine. Protection of the nitrogen atom then allowed the ring-closing metathesis, followed by construction of the bicyclic skeleton. The diol was then introduced by dihydroxylation. Two formal syntheses of swainsonine, in which the use of tertiary amines precluded N-protection, employed the protonation method (Scheme 8.79).94 Another limitation is found in substrates with weaker donor atoms near to the reaction site, which can chelate at the intermediate carbene stage. Carbonyl groups can interfere in this way. The diene 8.293 in which

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Organic Synthesis Using Transition Metals OH

O

PMBO

H2N TsOH

PMBO

8.284

Boc2O, Et3N 8.285

OH

OH

PMBO

1. NaH, BnBr 2. CF3CO2H 3. PPh3, CBr4

PMBO

8.286 BnO

HN

Grubbs I

N

Boc

8.287 BnO

H

H

AD-mix-α N

N

8.288

N

Boc

HO

OH OH

H N

8.289

OH OH

8.290

Scheme 8.78 PGO

PGO

H

PG = Bn: Grubbs I, TsOH PG = TBS: Grubbs II, TsOH

H N

N 8.291

8.292

Scheme 8.79 O Bn

O

N

Grubbs I

Bn

8.293

N

8.294

O Bn

N

[Ru]

O Et

Grubbs I

8 . 2 95

Bn

N

8.296

Scheme 8.80

both alkenes are monosubstituted fails to give the product as an unreactive ruthenium chelate 8.294 forms, blocking coordination of the second alkene (Scheme 8.80).95 If the troublesome alkene is made disubstituted, the reaction proceeds through a carbene that is not susceptible to chelation and the product 8.296 is obtained. Ester carbonyls, if at the right distance, can also cause problems, again due to chelation. This phenomenon was observed in a synthesis of gleosporone 8.299 (Scheme 8.81).96 The diene 8.297 failed to undergo metathesis in the presence of the Grubbs ﬁrst-generation catalyst, but gave an 80% yield when titanium

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Carbene Complexes

OTBS

O

Grubbs I Ti(Oi-Pr)4

O

OTBS O

n-C5H11

O n-C5H11

8.297 O 1. KMnO4, Ac 2O 2. aq. HF

289

8.298 E:Z = 2.7:1 OH

O

O

O n-C5H11

8.299

Scheme 8.81

tetraisopropoxide was also added. The titanium additive breaks up the unreactive chelate complex by coordinating to the ester oxygen. The metathesis product, obtained as an E/Z mixture, was oxidized to an ␣-diketone, which cyclized to the natural product 8.299 upon deprotection. Coordination by a sulfur atom of a nearby dithiane was suggested to be the cause of the difﬁculty in forming an unsaturated lactone in a synthesis of the anticancer agent EBC-23 8.302, from the Australian rain forest tree Cinnamomum laubatii (Scheme 8.82).97 The ring-closing metathesis reaction of diene 8.300 was ultimately successful using the second-generation Hoveyda–Grubbs catalyst under microwave conditions. The reason for the failure of an RCM may not always be obvious, and may be attributed to various factors. One example is the synthesis of dactylol (Scheme 8.83) 8.309.98 The starting material was prepared by addition of a methyl copper reagent to cyclopentenone 8.303, and trapping the resulting enolate with an aldehyde. The aldol product 8.304 was dehydrated and the conjugated alkene 8.305 was selectively reduced. This reaction was not only regioselective, but also stereoselective, giving the trans isomer 8.306. Addition of a Grignard reagent gave the diene 8.307 as a separable mixture of isomers. The desired isomer was treated with Schrock’s catalyst, but no product was found. This might be due to either interaction between the alcohol and the catalyst, or the substrate not having a suitable conformation with the two alkenes in proximity. This problem was solved by silylation. The silyl ether 8.308 underwent RCM and deprotection gave the natural product 8.309.

O

TBS O O

O HG-II, μw

SS O

n-C13H27

O

TBS O O

O SS O

n-C13H27 8.300

TBSO

8.301 H

OH

1. HF, H 2O, CH3CN 2. (NH4)2Ce(NO3)6

O

OH n-C13H27

O 8.302

Scheme 8.82

H

O

O

TBSO

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Organic Synthesis Using Transition Metals 1. MeLi, CuI, Bu3P 2. O

O

O

O OH

MsCl, DMAP

8.303 8.304

8.305

O MgBr HO CeCl3

n-Bu3SnH, ZnCl2, Pd(PPh3)4

+ isomer

regio- and steroselective 8.306

NHSiMe3

8.307

Me3SiO

HO

1. Schrock's catalyst 2. TBAF

OSiMe3

H 8.308

8.309

Scheme 8.83

N HO SO2 OH N

NSO2Py

HG II PhthN

NPhth 8.311

8.310

Scheme 8.84

In a synthesis of an intermediate for a Cathepsin K inhibitor, carried out on a 5.7 kg scale (Scheme 8.84),99 removal of impurities from the starting material 8.310 proved to be the critical factor, as some were able to act as catalyst inhibitors. In a synthesis of a pharmaceutical precursor on a 100 g scale, the more robust Grela catalyst 8.211 (Z = NO2 ) was employed to allow lower loading and lower dilution (Scheme 8.85).100 RCM has also been used to synthesize unusual structures, such as helicenes (Scheme 8.86).101 PNBO

H N

O

PNBO

t-Boc N CO2Me

N O

O

8.211 Z = NO2

O

H N

O O

8.313

8.312

Scheme 8.85

t-Boc N CO2Me

N O

O

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Carbene Complexes

OTf OTf

1. MeOH, CO, Pd(OAc)2, dppp 2. LiAlH4 3. PCC 4. Ph3P=CH2

291

Grubbs II

8.314

8.315

8.316

Scheme 8.86

8.3.4

Cross-Metathesis

The intermolecular metathesis between two alkenes is known as cross-metathesis.102 With the Grubbs 1st generation catalyst, there were few useful applications. This changed with the introduction of the Grubbs 2nd generation catalyst. An obvious problem with cross-metathesis is in ensuring selectivity as the alkenes may not only undergo metathesis with each other (“self-metathesis”), but also with themselves (Scheme 8.87). For a cross-metathesis between two terminal alkenes, three products are possible, as well as the ethene by-product. In general, one alkene should be used in excess. This should be an alkene that has a strong tendency to undergo cross-metathesis, but a weaker tendency for self-metathesis. Electron-poor alkenes, such as methyl acrylate, appear to ﬁt into this category. One approach to predicting the selectivity of cross-metathesis is to categorize alkenes according to their reactivity, including their reactivity towards self-metathesis.103 As the different catalysts have different reactivities, this has to be done catalyst by catalyst. The categorization of some alkenes for the widely used Grubbs second-generation catalyst is shown below (Table 8.2). Most simple alkenes undergo fast selfmetathesis and are type I. Electron-poor alkenes undergo slow self-metathesis and are type II. This category also includes some sluggish alkenes of other types. Type III alkenes are more bulky versions of type I and type II alkenes, and type IV alkenes are either very bulky or very electron poor. Cross-metathesis of two type I or two type II alkenes will result in a statistical mixture, as the rates of the desired cross-metathesis and the two self-metathesis reactions will all be similar. To obtain a synthetically useful result, one partner must be used in large excess. A more productive and efﬁcient cross-metathesis reaction can be achieved using a type I alkene with either a type II or a type III alkene (Scheme 8.88). The type II alkene will undergo self-metathesis slowly (or not at all); the type I alkene may undergo self-metathesis, but its self-metathesis product 8.317 may re-enter and undergo productive metathesis itself. A modest excess of one of the two alkenes is usually used. Another efﬁcient combination is to combine a type II alkene with a type III alkene (Scheme 8.89). An example would be the metathesis of a 1,1-disubstituted alkene 8.319 with an acrylate ester 8.320. This process can be made more efﬁcient if the acrylate (R = H) is changed to a crotonate (R = Me), making its self-metathesis even slower.

R1

R2

Grubbs II

R1

Scheme 8.87

R2

R1

R1

R2

R2

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Organic Synthesis Using Transition Metals Table 8.2 Cross-metathesis reactivities type II: slow self-metathesis

type 1: fast self-metathesis

(R = alkyl, Ph)

R HO

X2B

HO

HO

R3Si

PG

(Z = CO2R, CO2H, CHO, COR)

Z

O

O

HN

(RO) 2P

F2n+1Cn

type III: no self-metathesis

type IV: inactive – mere spectators

R

R

O 2N

R

R

R

PGO

R PGO PhSO2

OH

OH OAc

type II

Grubbs II

type I

OAc

8.318

slow OH

self-metathesis

OH

Grubbs II

secondarymetathesis

OH AcO

OAc

8.317

Scheme 8.88

R 8.319

CO2Et

Grubbs II

8.320 R = H, Me

Scheme 8.89

CO2Et 8.321 E:Z = 2:1

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Carbene Complexes + O

Grubbs II AcO

OAc

OAc O

8.323

8.322

293

8.324

Scheme 8.90

8.325

SiMe3

H N

O O

Grubbs II

H N

O

Me3Si

8.326

OTr

O

OTr

Scheme 8.91

On-Bu i-Pr

On-Bu catalyst

Br

i-Pr

8.328 Z:E > 98:2

Ar =

N

OTBS

Ph

N Mo

Br

OAr catalyst

8.327 OAc

N

N

OAc

AcO catalyst

8.329 Z:E = ca 8:1

t-BuCO2

Ru O

i-Pr

catalyst

Scheme 8.92

Application of these principles even allows selectivity when one component has two alkenes (schemes 8.90, 8.91).104 Using the Grubbs second-generation catalyst, the product of cross-metathesis is the E-isomer. Some specialized Z-selective catalysts have been designed (Scheme 8.92).105 A simple example of the use of cross-metathesis is in a synthesis of Diospongin A 8.336 in which an isolated alkene was converted into a Michael acceptor by cross-metathesis (Scheme 8.93).106 The starting homoallylic alcohol 8.330 was converted to the corresponding protected epoxide 8.333 with syn-stereochemistry via an iodolactonization protocol. Ring opening with a vinyl Grignard reagent then gave the cross-metathesis substrate 8.334. Cross-metathesis with phenyl vinyl ketone converted the relatively unreactive isolated vinyl group to a good Michael acceptor 8.335, so that, upon removal of the silyl protecting group, cyclization occurred to give the natural product 8.336. Another synthesis of this natural product may be found in Scheme 6.29.

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Organic Synthesis Using Transition Metals O Boc2O, DMAP, CH3CN

OH Ph

Ot-Boc

I2, CH3CN - 20 °C

Ph

8.330

O

I

Ph 8.332

8.331

1. MeOH, K2CO3 2. TBSCl, imid.

TBSO

O

MgBr CuBr

O

Ph

TBSO

OH

Ph

8.333

8.334

O

OH

Ph Grubbs II

TBSO

OH

SO3H MeOH

O

Ph

Ph

O Ph

8.335

O 8.336

Ph

Scheme 8.93

Cross-metathesis was employed to couple the two sides of the molecule in a synthesis of nupharamine 8.340 (Scheme 8.94).107 Reduction of the alkene 8.339 and removal of the two protecting groups enabled stereoselective reductive amination to give the alkaloid 8.340. All three of the alkenes in the C1–C14 fragment 8.347 of amphidinolide were installed by a combination of asymmetric allylation and cross-metathesis (Scheme 8.95).108 Cross-metathesis of the homoallylic alcohol 8.341 with acrolein gave the aldehyde 8.342 that was subjected to asymmetric allylation with the Duthaler titanium reagent 8.343. The resulting alcohol was acetylated because it was found that acetylation deactivates the nearest double bond to cross-metathesis, thereby promoting selectivity for the next cross-metathesis, also using acrolein, at the terminal alkene 8.344. Another asymmetric allylation–acetylation–cross-metathesis sequence, this time with ethyl acrylate, gave the desired natural product fragment 8.347. Ethenolysis, the cross-metathesis with ethene, while an important process for bulk chemicals, is only occasionally used in organic synthesis. It was used in a synthesis of tuberostemonine 8.351 to convert an allyl group to an ethyl group (Scheme 8.96).109 The allyl group was introduced by Keck allylation of selenide 8.348. The alkene was then isomerized to the internal isomer 8.350 using a catalyst derived from the Grubbs II metathesis catalyst (see Section 8.3.10), then subjected to cross-metathesis to excise the unwanted carbon atom, followed by alkene hydrogenation to give the natural product 8.351. O

O HG II

+ NHt-Boc OH

8.337

NHt-Boc

O OH

8 . 33 8

1. H2, Pd/C 2. CF3CO2H 3. NaBH4 OH

N H H H 8.340

Scheme 8.94

O

8 . 3 39

O

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Carbene Complexes CHO HG II

OH PMPO

PMPO

CHO

8.341

8.342

OAc

OAc

OAc

CHO HG II PMPO

PMPO

OAc CHO

8.344 1. Ti reagent X 2. Ac 2O, py

1. Ti reagent 8.343 2. Ac 2O, py

OH

8.345 OAc

OAc

CO2Et HG II

OAc

PMPO 8.346

OAc

OAc

OAc

Cp

CO2Et

PMPO

O

Ph Ph

Ti

8.347

O

O Ph Ph

O

titanium reagent 8.343

Scheme 8.95

O

O H H

O

SnPh3

H PhSe

N H

H H

O O

O

H

H

AIBN

N H

8.349

8.348 O Grubbs II, i-Pr2NEt NHCPh3

H H

O H

N

O

O

H

H

8.350 O 1.

O

HG-II, TsOH 2. H2, Pd/C

H

O

H

H H N H

O

H 8.351

Scheme 8.96

O

O

295

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Organic Synthesis Using Transition Metals Br

BzO Grubbs II

+ B O

BzO

B O

O

Br2, NaOMe

O

BzO

8.352

8.353

Scheme 8.97

Some alkenes with heteroatoms can be used in cross-coupling reactions. Vinyl boranes are an important group, as the carbon–boron bond can subsequently be converted into so many other functional groups, such as halides (Scheme 8.97).110 An example of cross-metathesis of a vinyl borane, followed by Suzuki coupling, can be found in Scheme 11.40. An example of a vinyl silane metathesis can be found in Scheme 2.110. 8.3.5

Ring-Opening Metathesis

As the opposite of ring-closing metathesis, ring-opening metathesis proceeds most reliably with strained cyclic alkenes. These can be three-membered rings and four-membered rings, as well as bicyclic structures, such as norbornenes (Scheme 8.98),111 and larger rings. Examples with unstrained rings have also been reported (Scheme 8.99).112 Ring opening of the cyclic alkene on reaction with the carbene generates a new carbene, which typically reacts with a second, unstrained alkene. In the absence of the second alkene, ring-opening metathesis polymerization (ROMP) is usually observed. An acetal 8.358 of the very strained cyclic alkene cyclopropenone was used as a keystone in a synthesis of the spiroketal moiety of bistramide A (Scheme 8.100).113 Ring opening metathesis in the presence of a phthalimide containing alkene 8.359, followed by acetal hydrolysis gave a dienone 8.360. This compound was subjected to a cross-metathesis with an alkene 8.361 containing the functionality needed for the remainder of the spiroketal. After cross-metathesis, hydrogenation of the two alkenes and the three benzyl ethers liberated a triol that underwent spontaneous intramolecular condensation to give the spiroketal 8.363. The single remaining free alcohol group could be extended using a chromium-mediated reaction (in place of a Wittig reaction). Ring-opening metathesis can also be combined with ring-closing metathesis (Scheme 8.101). The basic system employs a cyclic alkene 8.365 with two alkenyl side chains. ROM–RCM then opens the original ring and creates two new rings 8.368 via the intermediate carbenes 8.366 and 8.367. This is an equilibrium reaction. The balance between the monocyclic starting material and the product is determined by thermodynamics.

O

Ar Grubbs I

O O

Ar O

8.354

O

O 8.355

Scheme 8.98 CO2H HG II

HO2C

8.356

CO2H 8.357

Scheme 8.99

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Carbene Complexes

OBn

O

NPhth

O

OBn NPhth

8.359

8.358

8.360

OBn BnO

O

1. Grubbs II 2. H3O+

OBn

O

OBn NPhth

BnO

8.361 Grubbs II

297

8.362 1. Dess-Martin Oxidation 2. CrCl2, MeCOCBr2Me NPhth 3. (R)-CBS, catechol borane 4. MeNH2, MeOH

O H2, Pd/C

O OH

O

NPhth

O

8.363

8.364 OH

Scheme 8.100

This strategy was employed in a short synthesis of dumetorine 8.371 (Scheme 8.102).114 The triene substrate 8.369 was assembled by employing ␲-allyl palladium chemistry (Section 9.2) to install the nitrogen functionality. Treatment with the Grubbs ﬁrst-generation catalyst, with the addition of titanium tetra(isopropoxide) to suppress chelation by the carbonyl group, resulted in rearrangement of the system to the dumetorine skeleton 8.370. The synthesis was completed by deprotection and reductive methylation of nitrogen, followed by selective hydrogenation of the less-substituted alkene. 8.3.6

Asymmetric Metathesis

At ﬁrst glace, it would appear odd that a reaction that principally involves the manipulation of sp2 -hybridized carbon atoms should lend itself to a useful asymmetric version. If the initially generated carbene is, however, offered the choice of two enantiotopic alkenes, then a useful asymmetric reaction can be contemplated (Scheme 8.103). Either enantiomer of the product can be formed depending on which of the two enantiotopic alkenes is selected. Signiﬁcant modiﬁcation of the metathesis catalyst with incorporation of chirality can be needed to achieve this aim. [Ru]

x

x

z

y

8.365

z

y

8.366 [Ru]

x

z

y

8.367

Scheme 8.101

x

y

8.368

z

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Organic Synthesis Using Transition Metals 1.

AcO

OH

N H t-Boc

H

O

NH2 Pd(OAc)2, PPh3 2. Boc2O, Et3N 3. CO2H DCC, DMAP

O

N t-Boc

1. CF3CO2H 2. HCHO, NaBH4 3. H2, (Ph3P)3RhCl

O

O

Grubbs I Ti(Oi-Pr)4

O

O

8.369

N H Me

8.370

H

8.371

Scheme 8.102

RCM

RCM

initiate here 8.372

Scheme 8.103

Bn Me

Bn

Mo-catalyst

N

N

1. H2, (Ph3P)3RhCl 2. H2, Pd(OH)2

H

N

Me 8.374 e.r. = 93.5:6.5

8.373

Mo-catalyst =

8.375

Ph

t-Bu Mo OO

8.376

t-Bu

Scheme 8.104

A Schrock-type molybdenum catalyst 8.376 with an axially chiral biaryloxide ligand was employed in a synthesis of (R)-coniine 8.375 (Scheme 8.104).115 It is notable that the molybdenum catalyst tolerates the basic nitrogen atom in the substrate 8.373. A modiﬁed catalyst 8.380, in which the molybdenum is also a stereogenic centre was employed in a synthesis of quebrachamine 8.379 (Scheme 8.105).116 An alternative scenario is the enantioselective ROM–RCM combination in which the initiating carbene has a choice between two enantiotopic methyne groups in a C2-symmetrical alkene (Scheme 8.106). Such

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N

N

N H2, PtO2

Mo-catalyst N H 8.377

N H 8.379

N H 8.378 e.r. = 98:2

i-Pr i-Pr

Ph

Mo

N Mo-catalyst =

O Cl

Cl TBSO 8.380

Scheme 8.105

TBSO

Mo-catalyst 8.382

TBS O

1. 9-BBN; H2O2, NaOH 2. TPAP, NMO 3. dppp2RhCl, Δ

H 8.381 TBS O

8.383

1. acacRh(CO)2, CO, H2 2. NaBH4

8.384

H 8.386

1. o-O2NC6H4SeCl, Bu3P 2. mcpba 3. KNH(CH2)3NH2

H

H

TBS O

TBS O

8.385

1. TBAF 2. CH2I2, Et2Zn

OH

HO

H

i-Pr

8.387

Mo-catalyst =

i-Pr Ar

THF Mo Ph

OO

8.382 Ar

Scheme 8.106

299

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Organic Synthesis Using Transition Metals

O

Ph

Ph Ru-catalyst A

O O

O

8.354

O

O

8.388 76% e.e.

Scheme 8.107

AcO OAc Ru-catalyst B

TIPSO 8.389

TIPSO OAc 8.390 52% e.e.

Scheme 8.108

a strategy was used in a synthesis of africanol 8.387 involving ring opening of a substituted norbornene 8.381 with the molybdenum catalyst 8.382.117 The vinyl group of the metathesis product 8.383 was converted to a methyl group by conversion to an aldehyde and rhodium-catalysed decarbonylation (see Section 4.7). An additional carbon was installed by an unregioselective hydroformylation reaction (Section 4.4), followed by a sequence to introduce an alkene and isomerize it into an endo-cyclic isomer 8.386. Deprotection and cyclopropanation118 then yielded africanol 8.387. Chiral ruthenium complexes, 8.391 and 8.392, have been used in a variety of asymmetric metathesis reactions, including ring-opening metathesis (Scheme 8.107, compare with Scheme 8.98) and cross-metathesis (Scheme 8.108).119 The chirality of the complexes resides both in the backbone of the carbene ligand by the placement of substituents, and also in the conformation of the aryl substituents on the carbene nitrogen atoms.

Ph

t-Bu MeO

N i-Pr Ru Cy3P

Ph i-Pr N

OMe

t-Bu Ph

Ru catalyst A 8.391

8.3.7

Ph

i-Pr N i-Pr

Ph i-Pr N

Ru Ph Cy3P Ru catalyst B 8.392

i-Pr

Ene–Yne Metathesis

Alkynes can also participate in alkene metathesis chemistry. The reaction between an alkene and an alkyne is known as ene–yne metathesis.120 The mechanism is slightly more complicated then for alkene metathesis and it is unclear whether it starts with the alkene or the alkyne (Scheme 8.109). In any event, the same product, a conjugated diene 8.394, is obtained. If the catalytically active carbene species ([Ru] = ) reacts ﬁrst with the alkyne,

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Carbene Complexes

301

ene-yne metathesis 8.394

8.393

8.393

8.394 [Ru]

[Ru] 8.397

[Ru]

Cycle 1 "yne-first"

8.401

8.400 [Ru]

Cycle 2 "ene-first"

[Ru] [Ru]

8.396

[Ru] [Ru]

8.399 8.398

8.395 8.393

Scheme 8.109

cycle 1 (“yne-ﬁrst”) results. A metallacyclobutene 8.395 is formed that breaks down to give a vinyl-substituted carbene 8.396. This forms a metallacyclobutane 8.397 by an intramolecular reaction, which breaks down to give the product 8.394 and regenerates the original carbene. On the other hand, the original carbene could react with the alkene to generate, by metathesis, the alkyne-substituted carbene 8.398 of cycle 2 (“ene ﬁrst”). An intramolecular reaction with the alkyne then generates a bicyclic metallacyclobutene 8.399 that breaks down to a vinyl carbene 8.400, isomeric to its counterpart in cycle 1. This then undergoes a metathesis reaction with a second molecule of the starting material 8.393 to generate the product 8.394, and regenerate the alkyne-substituted carbene 8.398, rather than the original carbene. Calculations have indicated that the “ene ﬁrst” cycle 2 is likely to be the preferred route.121 During a synthesis of differolide 8.404, the authors took the opportunity to run their ene–yne metathesis reaction in an NMR tube and were able to observe signals corresponding to the cycle 2 “ene ﬁrst” intermediates (Scheme 8.110).122 The natural product 8.404 is the result of Diels–Alder dimerization of the ene–yne metathesis product 8.403. Facile Diels–Alder dimerizations O O O

O Grubbs I

O

O

Diels-Alder O

8.402

8.403

Scheme 8.110

O

8.404

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Organic Synthesis Using Transition Metals R' R' = Me under Ar 91% 20% R' = H under Ar under H2C=CH2 90%

R' Grubbs I N Ts

N Ts

8.405

8.406

Scheme 8.111

of butadienes with electron-withdrawing groups in the 2-position are well known.123 A practical issue with these reactions is that, for terminal alkynes, higher yields and higher reactivity are obtained if the reaction is carried out under an atmosphere of ethene, rather than an inert gas.124 The N-tosyl pyrrolidine 8.405 with a methyl substituent was formed cyclized in 91% yield using a ﬁrst generation catalyst under inert gas, but the corresponding terminal alkyne gave just 21% (Scheme 8.111). In contrast, when this reaction was carried under ethene, a 90% yield was obtained. Ene–yne metathesis has been employed in an elegant synthesis of stemoamide 8.415 (Scheme 8.112).125 The starting lactam 8.407, available itself from glutamic acid, was N-alkylated, then subjected to deprotection, Swern oxidation and application of the Corey–Fuchs method for installation of an alkyne by Wittig

1. NaH Br O 2. MeOH, TsOH

EEO N H

HO N

8.407

H

8.408

MeO2C

O 1. LDA 2. MeOCOCl

N

N

8.409 CO2H 1. NaBH4, MeOH 2. NaOH

O

N

H

8.411

H

O

N

O

+

H

O

8.413

N

H

O O

O

8.414 Et3N

NiCl2, NaBH4

N

O

8.412

Br O O

O Grubbs I

8.410

CO2Me H

1. (COCl)2, DMSO, Et3N 2. CBr4, PPh3 O 3. n-BuLi

H

N

O

8.415

Scheme 8.112

1. NaOH 2. CuBr2, Al 2O3

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Carbene Complexes H

O

O

O

H 8.416

H 8.417 Grubbs II O

H O O

8.418

1. LDA 2. MeI

H Grubbs II

O

303

H O O

H

O

8.419

H

Scheme 8.113

methodology. The alkyne 8.409 was converted into a propiolic ester 8.410 and this was the substrate for the ene–yne metathesis, which generated the seven-membered ring 8.411. The electrophilic double bond conjugated to the ester was reduced with NaBH4 and the ester was saponiﬁed and cyclized in an interesting procedure involving treatment with CuBr2 on alumina in a 5-endo manner. This gave a mixture of the ␤-bromolactone 8.413 and the unsaturated lactone 8.414. The former could be converted into the latter by simple treatment with a mild base. The synthesis was completed by stereoselective reduction of the butenolide double bond with nickel boride. A different synthesis of stemoamide can be found in Scheme 4.44. Intramolecular ene–yne metathesis was also used in a synthesis of dihydroxanthatin to form a sevenmembered ring 8.419 (Scheme 8.113).126 After ring closure, the butyrolactone 8.417 could be methylated with good diastereoselectivity. This reaction had to be done after closure of the seven-membered ring, as the greater rigidity of the bicylic system was needed to obtain diastereoselectivity: methylation before ring closure was not selective. After methylation, the synthesis was completed by a cross-metathesis reaction with MVK. Some earlier steps in this synthesis can be found in Scheme 6.33. Ene–yne metathesis was used to construct one of the rings of galanthamine 8.425,127 an amaryllidaceaae alkaloid used for the treatment of Alzheimer’s disease (Scheme 8.114). The ene–yne 8.421 was attached to a highly substituted phenol 8.420 by a Mitsunobu reaction. Ene–yne metathesis then generated a six-membered ring 8.423. Hydroboration-oxidation of the vinyl group then allowed closure of an additional ring by an intramolecular Heck reaction. The ﬁnal ring could then be formed by nucleophilic substitution after allylic oxidation.

8.3.8

Ene–Yne–Ene Metathesis

A natural extension of ene–yne metathesis is ene–yne-ene metathesis in which the carbene generated by the reaction of the alkyne is intercepted by a second alkene (Scheme 8.115). In an unsymmetrical system, in which the two alkene arms are not identical, it is critical to ensure that the desired “ene” component reacts with the catalyst to start the sequence. If the other “ene” component reacts, then an isomeric product will be formed (Scheme 8.116). This can usually be achieved by ensuring that the intended ﬁrst “ene” component is the least substituted. In a comparison of closely related substrates, the alkene with the least substitution was the one where the reaction initiated, giving isomeric products depending on whether R1 or R2 was a hydrogen or a methyl group.128 This question arose in a synthesis of lepadin 8.429 in which the natural product was to be built up from the simpler unsaturated bicyclic amine 8.430, using the secondary alcohol to direct reduction of the diene

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Organic Synthesis Using Transition Metals t-Boc N Me I

t-Boc N Me I

SiMe3 1. DIAD, Ph3P 2. K2CO3, MeOH

+ OH

O

HO

OMe 8.420

H

OMe 8.421

8.422

t-Boc N Me 1. 9-BBN; NaOH, H2O2 2. Pd(OAc)2, dppp, Ag 2CO3

I

Grubbs I

O OMe

t-Boc N Me

OH

O

H 8.423

1. SeO2, NaH2PO4 2. MsCl, Et3N 3. CF3CO2H, then NaHCO3

OMe

Me N

O OMe

H 8.425

Scheme 8.114

[Ru]

[Ru]

[Ru]

Scheme 8.115

R1 O

O

O Grubbs II

Grubbs II

NC 8.426

R1 = H; R2 = Me

R1 = Me; R2 = H

NC 8 . 42 7

NC R2

Scheme 8.116

8.428

H

8.424

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Carbene Complexes

305

HO H

OH

OH

O O

N H H

N H H

8.429

8.430 alkene A first

HO

HO

alkene A alkene B first OH

OH alkene B

N H H

8.431

8.432

CHO

CO2Me

+ BnO

CuBr

+ PMBHN

8.433

8.434

8.435

BnO

8.436

N H H

BnO 1. LiAlH4 2. (COCl)2, CO2Me DMSO, Et3N 3. MgBr N H PMB

OH

8.437

BnO

H

N PMB

BnO OH

Grubbs I H

1. TBSCl, C3H4N2 2. H2, Pd/C

N PMB

8.438

H

OTBS

N H H

8.439

Scheme 8.117

(Scheme 8.117).129 The bicyclic amine can be further disconnected to the diene–yne substrate 8.431. The strategy will only work if alkene A reacts with the catalyst before alkene B can do so. If alkene B reacts ﬁrst, the product will be the alternative, undesired [5.3.0] system 8.432. The solution was to add an extra methyl group to alkene B, and to leave the secondary alcohol free so that it could exert a directing effect through coordination. The substrate 8.437 was constructed in a remarkably short sequence by a three-component coupling of an aldehyde 8.433, an amine 8.434 and an alkyne 8.435, followed by a redox sequence and a Grignard addition, with useable stereoselectivity throughout. The ene–yne–ene metathesis then gave the desired quinolizidine structure 8.438 exclusively. Interestingly, the ﬁrst-generation Grubbs catalyst proved superior to the later versions: lower reactivity, in this case, translates into a lower ability to catalyse side reactions. The free alcohol group could then be converted into a bulky silyl ether to ensure that hydrogenation of the diene occurred from the opposite, less-crowded face, delivering the desired diastereoisomer 8.439. The synthesis was ﬁnished by installation of the side chains.

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Organic Synthesis Using Transition Metals CO2Me MeO2C Grubbs II OSiEt3

OSiEt3

8.440

8.441

Scheme 8.118 Me O

Me O

O Grubbs II

O

8.443

8.442

Scheme 8.119

In a synthesis of the guanacastepene skeleton (Scheme 8.118), two methyl groups were attached to the “undesired” alkene to ensure that ene–yne–ene metathesis proceeded as desired.130 Electronic control may also be used. If there is a choice between a simple alkene and an electron-poor alkene, the reaction will initiate at the simple alkene (Scheme 8.119).131 8.3.9

Tandem Reactions

Alkene metathesis chemistry is ideally suited for tandem processes by designing substrates with multiple alkenes. This example includes ring opening, ring closing and cross-metathesis (Scheme 8.120). A sequence involving a ROM featured as part of a synthesis of deoxypukalide 8.455, a cembranoid from a Paciﬁc octocoral (Scheme 8.121).132 The starting material was prepared by carboalumination of butynol 8.446, followed by an iodine quench. After oxidation to the aldehyde, a second alkene was added as a Grignard reagent, and the alcohol 8.448 was converted to an ester 8.450 with a mixed anhydride 8.449 of cyclobutene carboxylic acid. Treatment of the ester 8.450 with methallyl alcohol and the Grubbs secondgeneration catalyst resulted in a tandem process consisting of an RCM, forming the butenolide, and ROM, opening the cyclobutene, and a cross-metathesis with the methallyl alcohol, giving the lactone 8.451. The iodo-substituted alkene played no part in the tandem reaction. The synthesis was completed by a Stille coupling with the furyl stannane 8.452 to attach the furan moiety, followed by macrocycle formation using the Hiyama–Nozaki–Kishi reaction and some functional group interconversions. 8.3.10

Metathesis Side Reactions

A surprising result was found during an attempt to carry out a ring-closing metathesis during a synthesis of 3-deacetoxy-6-deacetylcalicophirin, a marine natural product (Scheme 8.122).133 When the triene 8.456 H

Et Grubbs I

Et OTBS

TBSO

8.444

H 8.445

Scheme 8.120

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Carbene Complexes

OH

I

1. AlMe 3, Cp2ZrCl2 2. I2

OH

8.446 O t-Bu

OH 8.448

8.447

OH

O OH

I

O

LiHMDS 8.449

I O 8.450

OTBDPS

O

Grubbs II

O 8.452 O (Ph3P)4Pd, CuI

O O

OTBDPS O

O

n-Bu3Sn

OH

O

1. Ph3P, NBS 2. CrCl2

O O O

8.453 CO2Me

OTBDPS OH O

O

I

1. Dess-Martin 2. MgBr

O

1. Et3SiH, CF3CO2H 2. TBAF 3. MnO2 4. MnO2, HOAc, NaCN

8.454

O

O

8.455

O

Scheme 8.121

H

H

Me3SiO H

O

Schrock's catalyst

H Me3SiO

H

isomerisation

H

O

Me3SiO

H 8.458

Scheme 8.122

O

H

H

H

Me3SiO

H

8.457 not formed

8.456

H

H

H H

O

H

8.459

8.451

307

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Organic Synthesis Using Transition Metals

was treated with the Grubbs 1st generation catalyst, a mixture of products was obtained. When the Schrock catalyst was used, a ring-closed product 8.459 was obtained, but with one carbon fewer than expected. This result was attributed to alkene isomerization prior to metathesis, the missing carbon ending up in propylene. Isomerization can also be observed with the Grubbs ruthenium catalysts, both before and after metathesis.134 The isomerization reaction is believed to be catalysed by ruthenium hydride species, such as 8.460, generated by decomposition of the Grubbs catalyst.135

N Mes N

Ru N

N RuCl3

H Mes

8.460

An example is the treatment of the diene 8.461 with the Grubbs second generation catalyst to give a mixture of the seven- and eight-membered ring containing products, 8.462 and 8.463 (Scheme 8.123).136 In contrast, the Grubbs ﬁrst generation catalyst gave only the expected eight-membered ring product 8.463, but in low yield. Methods to suppress isomerization have been developed. These involve the use of additives such as benzoquinone,137 which can destructively oxidize any ruthenium hydrides, tricyclohexylphosphine oxide,138 phenyl phosphoric acid,139 stannous halides140 and phenol.141 Alternatively, isomerization post metathesis can be useful, and methods have been developed to encourage this kind of reactivity. Grubbs catalysts, modiﬁed by addition of hydrogen or hydrogen sources,142 or by heating in methanol,143 can become efﬁcient alkene isomerization catalysts. Cyclic enol ethers are interesting building blocks for synthesis, forming them by RCM would require, ﬁrst, synthesizing vinyl ethers. Allyl ethers, on the other hand are much easier to make. RCM of these compounds 8.464, followed by alkene isomerization then gives the desired enol ether 8.466 (Scheme 8.124).144 An example of the use of this chemistry can be found in Scheme 5.11. In the presence of excess hydrogen, metathesis catalysts can become hydrogenation catalysts, so that metathesis and reduction can be carried out in a one-pot process (Scheme 8.125).145 In contrast, addition of a diamine as well as hydrogen generates a species that is highly selective for ketone rather than alkene reduction, allowing a choice of products after cross-metathesis with an ␣,␤-unsaturated ketone (Scheme 8.126). O

O

O

O

O

Grubbs II

8.461

O

O

O

O

+

8.462

8.463

Scheme 8.123 Grubbs II then N2, H2 or NaH Ph

O

8.464

Ph

O

8.465

Scheme 8.124

Ph

O

8.466

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Carbene Complexes

N O

Grubbs II, 40 °C; then H2 (100 psi), 70°C

309

N i-Pr

i-Pr

O 8.468

8.467

Scheme 8.125

O

O Grubbs II

+

Ph

Ph 8.469 add NH2 H 2N H2, NaOH

add H2, 70 °C

O

OH

Ph

Ph 8.470

8.471

Scheme 8.126

Advantage was taken of the tandem reactivity of the Grubbs catalysts in a synthesis of lycoﬂexine 8.477 (Scheme 8.127).146 An ene–yne–ene metathesis reaction established a ﬁve- and a nine-membered ring in a single step. Addition of hydrogen then converted the metathesis catalyst to a hydrogenation catalyst that showed selectivity for the less hindered of the two double bonds, giving tricycle 8.474. The remaining double bond could then be used to introduce a second ketone by hydroboration, followed by oxidation with IBX, rather than a more traditional oxidant. The synthesis was completed by a transannular Mannich reaction.

H

H

Grubbs II, then H2 O

O 8.472

N t-Boc

8.473

O Nt-Boc

H 1. BH 3.THF 2. IBX

Nt-Boc

H

H O HCHO, HCl

O 8.475

8.474

O

O Nt-Boc

O

OH

8.476

Scheme 8.127

N

8.477

N

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Organic Synthesis Using Transition Metals CH3 CH3

H 3C

OH

W(CO)4Br -10 °C

CH3

8.479

8.478

Scheme 8.128 n-Pr n-Bu

Mo(CO)6, p-ClC6H4OH Δ or hν

n-Bu n-Bu

8.480

n-Pr

+ n-Pr 8.481

8.482

Scheme 8.129

8.4

Carbyne Complexes

Compared to their carbene cousins, carbyne complexes, containing a metal–carbon triple bond, have seen very little development. One example is an interesting phenol synthesis by the reaction of a diyne 8.478 with a carbyne complex (Scheme 8.128). The reaction is remarkable for the low temperature at which it proceeds.147 As in the D¨otz reaction, the aromatic carbon atom bearing the hydroxyl substituent is derived from a carbon monoxide ligand. 8.4.1

Alkyne Metathesis

Alkyne metathesis was ﬁrst observed in heterogeneous catalytic systems at high temperatures.148 Early homogeneous catalytic systems, which consisted of a mixture of molybdenum hexacarbonyl and a phenol, required a lower, but still high, temperature (Scheme 8.129).149 Alternatively, the reaction could be photochemical. It is assumed that a carbyne complex is generated as the active catalyst. Alkyne metathesis, using either preformed carbyne complexes, or carbyne complexes generated in situ, has started to ﬁnd use in recent years, particularly as more reactive catalysts have been developed.150 The introduction of stable carbyne complexes, such as tungsten complex 8.483, as more-active catalysts started to make the reaction practicable for organic synthesis.151 t-Bu C W(Ot-Bu)3 8 .4 8 3

Ph C Mo(OSiPh3)3 8. 48 4

An alkyne metathesis catalyst 8.484, with greater reactivity and wider functional group tolerance was developed employing bulky silanol ligands.152 A disadvantage of these molybdenum carbyne catalyst is their sensitivity. They have been found to be more robust towards storage and handling as complexes with Lewis bases, especially bidentate Lewis bases (Scheme 8.130).153 Thus, the crystalline 1,10-phenanthroline complex 8.485, with a nitrido ligand in place of the carbyne, has good benchtop stability. The active complex can be released in situ by providing a mild Lewis acid to compete for the coordination of the phenanthroline. Naturally, the nitride complex itself is not the catalyst. It undergoes an alkyne metathesis in situ to generate the active species 8.487.

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Carbene Complexes

N Ph3SiO Mo Ph3SiO

N

R

N Mo Ph3SiO OSiPh3 Ph3SiO

OSiPh3 MnCl2

R

8.486 active, but unstable

N

R

Ph3SiO Mo OSiPh3 Ph3SiO 8.487 +

+

8.485 stable, but inactive

Cl2Mn

311

R

N

N

N

Scheme 8.130

One advantage of alkyne metathesis over alkene metathesis is that Z-alkenes can be readily obtained in a high state of geometrical purity by subsequent Lindlar reduction. This property was exploited in a synthesis of dehydrohomoancepsenolide 8.493 (Scheme 8.131).154 The alkyne substrate 8.491 was synthesized from a bromomethacrylate ester 8.489 using a zinc/copper-mediated three-component coupling. Ring-closing metathesis using the Grubbs I catalyst formed the butenolide moiety. Interestingly, the lower reactivity of the Grubbs I catalyst proved advantageous. This catalyst proved completely selective for the desired RCM reaction, without interfering with the alkyne. This was not so with the more-reactive Grubbs II catalyst. Alkyne metathesis, a pseudodimerization, was achieved with the tungsten carbyne complex 8.483, and the synthesis was completed by Lindlar reduction. A synthesis of the closely related ancepsenolide using cycloisomerization may be found in Scheme 11.79.

O

1. IZn 2. CuCN, LiCl Br 3. I Me

OH HO2C 8.488

Br

DEAD, PPh 3

O

8.489

8.490

O

Me

O

1. Grubbs I 2. (t-BuO)3W≡Ct-Bu

8.491

O

O

O

O 8.492

O

O

O

O 8.493

Scheme 8.131

H2, Lindlar's catalyst, quinoline

ZnI

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Organic Synthesis Using Transition Metals Me

(t-BuO)3W≡Ct-Bu

O O

8.494

Me

H2, Pd/BaSO4 quinoline O

O

O

8.495

O

8.496

Scheme 8.132

CH3

O

H

CH3

H

1. (Ph 3SiO)3Mo≡CPh 2. H 2, P2-Ni O

H

O

O H

O O 8.498

8.497

Scheme 8.133

Alkyne metathesis can also be used in ring-closing mode, but only for the formation of large rings, as the presence of the alkyne prevents medium-sized rings from being stable. The macrocyclic lactone musk 8.496 and its higher homologue, required for studies in perfumery were prepared by an alkyne metathesis, reduction sequence (Scheme 8.132).155 The macrolactone 8.496 was found to be “musky, warm and metallic”. The more reactive molybdenum catalyst 8.484 was employed to close the macrocyclic ring in the penultimate step of a protecting group free synthesis of Ecklonialactone A 8.498 (Scheme 8.133).156

8.5

Carbene Complexes from Diazo Compounds

Diazo compounds, with or without metal catalysis, are well-known sources of carbenes. For synthetic purposes a metal catalyst is used.157 The diazo compounds employed are usually ␣- to an electron-withdrawing group, such as an ester or a ketone, for stability. In the early days, copper powder was the catalyst of choice, but now salts of rhodium are favoured. The chemistry that results looks very like the chemistry of free carbenes, involving cyclopropanation of alkenes, cyclopropenation of alkynes, C–H insertion reactions and nucleophilic trapping. As with other reactions in this chapter, free carbenes are not involved. Rhodium–carbene complexes are responsible for the chemistry. This has enormous consequences for the synthetic applications of the carbenes – not only does the metal tame the ferocity of the carbene, but it also allows control of the chemo-, regio- and stereoselectivity of the reaction by the choice of ligands. In many cases, a given substrate can follow different pathways according to the catalyst used. The rhodium complexes used typically have either carboxylate or amide ligands. Tremendous differences in reactivity can

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Carbene Complexes

313

Ph Rh2(cap)4

Ph

Rh2(pfb)4

N2 O 8.500

O

8.499

8.501

O

Scheme 8.134

t-Bu N

MeO

8.502

O N2 Rh2(cap)4

Rh2(pfb)4

t-Bu N

O MeO

N

8.503

t-Bu

MeO

O

8.504

Scheme 8.135

be obtained by structure variation within this small group (Scheme 8.134). For instance, the diazoketone 8.500 gives the product of intramolecular cyclopropanation 8.499 using a rhodium–caprolactam complex, but the product of C–H insertion 8.501 with a perﬂuorobutyrate complex.158 Similarly, with a substrate bearing an electron-rich aryl ring 8.502, the caprolactam complex favoured CH insertion, while the perﬂuorobutyrate complex led to predominant attack on the aryl ring in a Buchner reaction (Scheme 8.135). 8.5.1

Nucleophilic Trapping

Trapping by nucleophiles such as alcohols, which can also be drawn as insertion into the O–H bond, is a useful process. Cyclic ethers can be formed under very mild conditions (Scheme 8.136).159 Similarly, amines and other nitrogen derivatives can be employed to trap the carbene, most notably in the commercial synthesis of the antibiotic thienamycin in which a ﬁve-membered ring is annulated onto an existing ␤-lactam 8.507 (Scheme 8.137).160 The carbenes may also be trapped by nucleophilic groups that lack a hydrogen atom. The use of carbonyl groups, in an intramolecular fashion, in this way generates unstable, reactive oxonium ylids (Scheme 8.138). These ylids 8.511 are 1,3-dipoles and can participate in a cycloaddition reaction with an added dipolarophile.161,162 Many tandem processes can be designed around this concept.163 N2 R

O

CO2t-Bu Rh2(OAc)4 OH

O

R

O

8.506

8.505

Scheme 8.136

CO2t-Bu

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Organic Synthesis Using Transition Metals HO

HO

N2

H H

CO2PNB NH

H H

Rh2(OAc) 4

O

N

O O

O 8.507

8.508

CO2PNB

Scheme 8.137 O

O N2

O [Rh]

Rh2(OAc)4

O

8.509

O

OR

O

8.510 OR

8.511 OR

CO2Me

O

MeO2C O

1,3-dipolar cycloaddition

CO2Me

8.512 OR CO2Me

Scheme 8.138

An ylid formation–cycloaddition sequence was used to generate one ring of the alkaloid ipalbidine 8.519 (Scheme 8.139).164 An ␣-sulfonyldiazoamide 8.513 was used so that, after the cycloaddition, the adduct collapsed to the desired six-membered ring with expulsion of benzenesulﬁnate. The resulting hydroxypyridone 8.517 was converted to a triﬂate and subjected to Stille coupling to install the aryl substituent. Subsequent reduction of the pyridone ring, with removal of the other sulfonyl group, completed the synthesis. Other approaches to ipalbidine can be found in Scheme 2.88 and Scheme 3.21. O N2 N

PhSO2

O

PhSO2

Rh2(OAc)4

SO2Ph N

O

O

1,3-dipolar cycloaddition

8.514

8.513 SO2Ph

SO2Ph

SO2Ph

O

PhSO2

N O

O

N

HO

O 8.516

8.515

1. PhNTf 2, Et3N 2. p-MeOC6H4Snn -Bu3, Pd(0)

MeO

N O 8.517

SO2Ph N

N O

8.518

Scheme 8.139

HO

8.519

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Carbene Complexes

N

Cu(acac)2

N

[2,3]

315

N H

N2

O

O 8.520

O 8.522

8.521

Scheme 8.140

N

CO2Bn Rh2(OAc)4 or Cu(acac)2

N

CO2Bn

[1,2]

O

N2 O

8.524

8.523

OH

N

CO2Bn 1. HS(CH 2)2SH, BF3 H 2. LiAlH4 O 3. Na, H2NNH2, Δ

8.525

H N

8.526

Scheme 8.141

Tertiary amines are also nucleophilic groups that lack a hydrogen atom. When they react with carbenes, a nitrogen ylid is formed. The fate of this ylid depends on the substituents in the vicinity. With a suitably placed vinyl group, a [2,3]-sigmatropic rearrangement can follow (Scheme 8.140).165 In contrast, the compound 8.523 with a chain one carbon longer and with an ester group in place of the vinyl group, underwent a Stevens [1,2]-rearrangement (Scheme 8.141).166 The resulting quinolizidine 8.525 was converted to the alkaloid epilupinine 8.526, using the Mozingo method to remove the carbonyl group. Interestingly, in these reactions, copper catalysts could be as good as, or better than, the rhodium catalysts. Ylid trapping was used to establish the tricyclic system 8.529 in a synthesis of pseudolaric acid (Scheme 8.142), using a chiral rhodium complex to achieve better stereoselectivity in favour of the desired isomer.167 8.5.2

C–H Insertion Reactions of Carbene Complexes

Carbene complexes, generated by the reaction between metal salts and diazo compounds can insert into C–H bonds in a form of CH activation168 (see Chapter 3 for other CH activation reactions). While early reactions involved the use of copper salts as catalysts (Schemes 8.143 and 8.144),169,170 rhodium complexes are now more widely used. In molecules such as cyclohexane, there is no issue of regioselectivity, but this issue is critical for the use of the reaction in synthesis. Both steric and electronic factors inﬂuence selectivity. Carbon atoms where a build up of some positive charge can be stabilized are favoured. Hence, allylic positions and positions ␣- to a heteroatom such as oxygen or nitrogen, are favoured. The reaction at tertiary C–H bonds, rather than primary C–H bonds is also favoured for the same reason, but, in this case, are also disfavoured by steric effects. Reactivity and selectivity are also inﬂuenced by both the structure of the catalyst, and the

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O

O

PMBO

O

O

Rh2[(S)-bptv)4] O

O O

Et Et

O

Et

8.527

8.528

Et BnO

BnO O

O

H

+

O

O

H O

O O

Et Et

O

Et

8.529

8.530

Et

Scheme 8.142

+ N2

CO2Et

CuSO4

CO2Et 8.531

Scheme 8.143 N2 O

O Me Me H H

CuO

H

Me

H

H

8.532

H

H H 8.533

Scheme 8.144

substituents present on the diazo compound carbene precursor. In general, stabilizing substituents, such as a phenyl group, lead to better selectivity through less reactive intermediates. In addition, the use of chiral ligands on the catalyst can result in enantioselective insertion reactions (Schemes 8.145 and 8.146).171,172 With intramolecular reactions, the restrictions imposed by molecular structure impose greater constraints, leading to both regio and stereoselectivity. The intramolecular insertion into a tertiary C–H bond was employed in a synthesis of pentalenolactones E and F to install a ␦-lactone moiety (Scheme 8.147).173 8.5.3

C–H Insertion Reactions of Nitrene Complexes

Like their carbene cousins, the insertion of nitrenes into C–H bonds is a useful method for functionalizing molecules (Scheme 8.148).174 The nitrenes are typically generated by the oxidation of an amine derivative in the presence of the metal catalyst, most often, but not exclusively, a rhodium complex. Widely used oxidants are iodosobenzene diacetate and iodosobenzene. These react with the amine derivative to form an

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Ph +

CO2Me Rh [(S)-DOSP] 2 4

N2

CO2Me

Ph 8.534 95% e.e. Scheme 8.145 t-Boc N

+

N2

t-Boc Ph N

CO2Me Rh [(S)-DOSP] 2 4

CO2Me

Ph 8.535

Scheme 8.146 H

H O

O

Rh2(OAc)4

O

O

H O

O O

N2

O 8.537

8.536

Scheme 8.147 NHTs

TsN IPh or TsNH 2, PhI(OAc)2 Ru(TPFPP)(CO) or Mn(TPFPP)Cl

8.539

8.538

Scheme 8.148 NH2 O

O CO2t-Bu

PhI

O HN Rh2(OAc)4, PhI(OAc)2, MgO

O

O

8.540

CO2t-Bu 8.541

via

N O CO2t-Bu 8.542

Scheme 8.149

iminoiodinane, either in a separate step or in situ (Scheme 8.149).175 The nitrogen derivative always includes an electron-withdrawing group, such as a carbonyl or sulfonyl group. Once again, the intramolecular version of the reaction can result in excellent regio- and stereochemical control, with a strong preference for either ﬁve- or six-membered ring formation, as well as a catalyst-dependent preference for insertion into tertiary C–H bonds, over secondary C–H bonds and even benzylic secondary bonds (Scheme 8.150).176 A sulfonyl linker showed a signiﬁcant tendency towards six-membered ring

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O O S NH O

Rh2(O2CR)4, PhI(OAc)2, MgO

Ph

O O S HN O

+

Ph

Ph R = CH3 1.5:1 R = CPh3 14:1

8. 5 44

8.543

8 .5 4 5

Scheme 8.150 O O S H2N O

O O S HN O

Rh2(Oct)4, PhI(OAc)2, MgO

Ph

CO2Et

Ph

8.546

1. CbzCl, NaOt-Bu 2. KOAc

CbzHN

OAc CO2Et

Ph

CO2Et

8.548

8.547

Scheme 8.151 O O S H2N Nt-Boc Ph

O O S HN Nt-Boc

Rh2(esp)2, PhI(OAc)2, MgO

Me

Ph

8.549

Me 8.550

Scheme 8.152

H

O O S O NH2

H

Rh2(OAc)4, PhI(OAc)2, MgO H

8.551

HN

O S O O

8.552

Scheme 8.153 O O

O

O H

O OTBS

N2

Rh2(HNCOCPh3)4

O

OTBS O

O 8.554

O 8.553

O

Cl

PivO

PivO

O 8.555

O H Rh2(HNCOCF3)4 PhI(OAc)2, MgO

O

O

Cl

OH

O

O

HOO

O O

8.556

HO HN H2N

NH O

318

O

NH OH 8.557

Scheme 8.154

O

O

O

O

O

O

OH OH

H NH2 O

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formation, reactions proceeding with good selectivity. Amino alcohol derivatives 8.547 were formed as, predominantly, the syn isomer (Scheme 8.151), while diamine derivatives 8.550 tended to be anti (Scheme 8.152). Insertion into tertiary CH bonds proceeded with retention of stereochemistry (Scheme 8.153).177 The heterocyclic products undergo useful nucleophilic ring opening (Scheme 8.151).178 Both C–H insertion by a carbene and C–H insertion by a nitrene were employed in a synthesis of tetrodotoxin 8.557, the highly toxic alkaloid of the fugu ﬁsh (Scheme 8.154).179

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

24. 25. 26. 27. 28. 29. 30.

31.

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Cy3P Cl Ru Cl Cy3P

Ph Ph

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103. Chatterjee, A. K.; Choi, T.-L. et al. J. Am. Chem. Soc. 2003, 125, 11360. 104. Brummer, O.; Ruckert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441. 105. (a) Meek, S. J.; O’Brien, R. V. et al. Nature 2011, 471, 461; (b) Endo, K.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 8525; (c) Yu, M.; Wang, C. et al. Nature 2011, 479, 88. 106. Bates, R.W.; Song, P. Tetrahedron, 2007, 63, 4497. See also Bressy, C.; Cossy. J. Synlett 2006, 3455. 107. Gebauer, J.; Blechert, S. Synlett 2005, 2826. 108. Cossy, J.; BouzBouz, S. Org. Lett. 2001, 3, 1451. 109. Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225. 110. Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031. 111. Cluny, G. D.; Cai, J.; Hauske, J. R. Tetrahedron Lett. 1997, 38, 5237. 112. Randl, S.; Connon, S. J.; Blechert, S. Chem. Commun., 2001, 1796. 113. Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 9546; for earlier examples, see Michaut, M.; Parrain, J.-L.; Santelli, M. Chem. Commun. 1998, 2567. 114. R¨uckert, A.; Deshmukh, P. H.; Blechert, S. Tetrahedron Lett. 2006, 47, 7977. 115. Sattely, E. S.; Cortex, G. A. et al. J. Am. Chem. Soc. 2005, 127, 8526. 116. (a) Malcolmson, S. J.; Meek, S. J. et al. Nature 2008, 456, 933; (b) Sattely, E. S.; Meek, S. J. et al. J. Am. Chem. Soc. 2009, 131, 943. 117. Weatherhead, G. S.; Cortez, G. A. et al. Proc. Nat. Acad. Sci. 2004, 101, 5805. 118. Fan, W.; White, J. B. J. Org. Chem. 1993, 58, 3557. 119. Berlin, J. M.; Goldberg, S. D. Angew. Chem., Int. Ed. Engl. 2006, 45, 7591. 120. (a) Mori, M. Adv. Synth. Catal. 2007, 349, 121; (b) Li, J.; Lee, D. Eur. J. Org. Chem. 2011, 4269. 121. Lippstreu, J. J.; Straub, B. F. J. Am. Chem. Soc. 2005, 127, 7444. According to these calculations, metallacyclobutenes are not local minima. 122. Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277. 123. (a) Bates, R. W.; Pinsa, A.; Kan, X. Tetrahedron 2010, 66, 6340; (b) B¨ackvall, J.-E.; Juntunen, S. K. J. Am. Chem. Soc. 1987, 109, 6396; (c) Poly, W.; Schomburg, D.; Hoffmann, H. M. R. 1988, 53, 3701; (d) Marvel, C. S.; Brace, N. O. J. Am. Chem. Soc. 1949, 71, 37. 124. Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082. 125. Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356. 126. Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371. 127. Satcharoen, V.; McLean, N. J. et al. Org. Lett. 2007, 9, 1867. 128. Oguri, H.; Hiruma, T. et al. J. Am. Chem. Soc. 2011, 133, 7096. 129. Niethe, A.; Fisher, D.; Blechert, S. J. Org. Chem. 2008, 73, 3088. 130. Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. 131. (a) Choi, T.-L.; Grubbs, R. H. Chem. Commun. 2001, 2648; (b) Chatterjee, A. K.; Morgan, J. P. et al. J. Am. Chem. Soc. 2000, 122, 3783. 132. Tang, B.; Bray, C. D. et al. Tetrahedron 2010, 66, 2492. 133. Joe, D.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8635. 134. Schmidt, B. Eur. J. Org. Chem. 2004, 1865. 135. Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414. 136. De Bo, G.; Mark´o, I. E. Eur. J. Org. Chem. 2011, 1859. 137. Hong, S. H.; Sanders, D. P. et al. J. Am. Chem. Soc. 2005, 127, 17160. 138. Bourgeois, D.; Pancrazi, A. et al. J. Organomet. Chem. 2002, 643-644, 247. 139. Gimeno, N.; Formetin, P. et al. Eur. J. Org. Chem. 2007, 918. 140. Meyer, W. H.; McConnell, A. E. et al. Inorg. Chim. Acta 2006, 359, 2910. 141. Forman, G. S.; McConnell, A. E. et al. Organometallics 2005, 24, 4528; Schmidt, B.; Kunz, O.; Biernat, A. J. Org. Chem. 2010, 75, 2389. 142. Schmidt, B. Eur. J. Org. Chem. 2004, 1865. 143. Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481. 144. (a) Sutton, A. E.; Seigal, B. A. et al. J. Am. Chem. Soc. 2002, 124, 13390; (b) Schmidt, B. J. Org. Chem. 2004, 69, 7672.

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Carbene Complexes 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179.

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Louie, J.; Bielawski, C. W. et al. J. Am. Chem. Soc. 2001, 123, 11312. Ramharter, J.; Weinstabl, H.; Mulzer, J. Am. Chem. Soc. 2010, 132, 14338. Sivavec, T. W.; Katz, T. J. Tetrahedron Lett. 1986, 26, 2159. Pannella, F.; Banks, R. L. et al. J. Chem. Soc., Chem. Commun. 1968, 1548. Mortreux, A.; Delgrange, J. C. et al. J. Mol. Cat. 1977, 2, 73. Zhang, W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93. (a) Wengrovius, J. H.; Sancho, J.; Schrock, R. R. J. Am. Chem. Soc. 1981, 103, 3932; (b) Coutelier, O.; Mortreux, A. Adv. Synth. Catal. 2006, 348, 2038. Heppekausen, J.; Stade, R. et al. J. Am. Chem. Soc. 2010, 132, 11045. Heppekausen, J.; Stade, R. et al. J. Am. Chem. Soc. 2010, 132, 11045. F¨urstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463. Kraft, P.; Berthold, C. Synthesis, 2008, 543. Hickmann, V.; Alcarazo, M.; F¨urstner, A. J. Am. Chem. Soc. 2010, 132, 11042. (a) Doyle, M. P. Chem. Rev. 1986, 96, 919; (b) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348. Padwa, A.; Austin, D. S. et al. J. Am. Chem. Soc. 1993, 115, 8669. (a) Davies, M. J.; Moody, C. J.; Taylor, R. J. J. Chem. Soc., Perkin Trans I 1991, 1; (b) Davies, M. J.; Moody, C. J. J. Chem. Soc., Perkin Trans I 1991, 9. Shih, D. H.; Baker, F. et al. Heterocycles 1984, 21, 29. (a) Padwa, A.; Hornbuckle, S. Chem. Rev. 1991, 91, 263; (b) Padwa, A. Acc. Chem. Res. 1991, 24, 22. Padwa, A.; Carter, S. P. et al. J. Am. Chem. Soc. 1988, 110, 2894. Padwa, A. Chem. Soc. Rev. 2009, 38, 3072. Sheehan, S. M.; Padwa, A. J. Org. Chem. 1997, 62, 438. (a) Clark, J. S.; Hodgson, P. B. J. Chem. Soc., Chem. Commun. 1994, 2701; (b) Clark, J. S.; Hodgson, P. B. Tetrahedron Lett. 1995, 36, 2519. (a) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 115, 1177; (b) West, F. G.; Naidu, B. N. Tetrahedron 1997, 53, 16565. Geng, Z.; Chen, B.; Chiu, P. Angew. Chem., Int. Ed. 2006, 45, 6197. (a) Doyle, M. P.; Duffy, R. et al. Chem. Rev. 2010, 110, 704; (b) Davies, H. M. L.; Dick, A. R. Top. Curr. Chem. 2010, 292, 303; (c) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857. Scott, L. T.; DeCicco, G. J. J. Am. Chem. Soc. 1974, 96, 322. Greuter, F.; Kalvoda, J.; Jeger, O. Proc. Chem. Soc. 1958, 349. Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. Cane, D. E.; Thomas, P. J. J. Am. Chem. Soc. 1984, 106, 5295. Du Bois, J. Org. Process Res. Dev. 2011, 15, 758. (a) Yu, X.-Q.; Huang, J.-S. et al. Org. Lett. 2000, 2, 2233; (b) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598; (c) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562. Fiori, K. W.; Espino, C. G. et al. Tetrahedron 2009, 65, 3042. (a) Espino, C. G.; When, P. M. et al. J. Am. Chem. Soc. 2001, 123, 6935; (b) Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 2777. Bower, J. F.; Rujirawanich, J.; Gallagher T. Org. Biomol. Chem. 2010, 8, 1505. Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

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9 ␩3- or ␲-Allyl Complexes In an ␩3 - or ␲-allyl complex, all three carbons of the allyl unit are coordinated to the metal and are in a plane. This can be seen in the X-ray structure of the ferrilactone complex 9.1 (Figure 9.1), which also contains three coordinated carbon monoxide molecules and an ␩1 -acyl unit. The chemistry of these iron complexes is discussed further in Section 4.5.1.

9.1 Stoichiometric Reactions of ␲-Allyl Complexes These complexes can be made using many different transition metals and are often stable. Cationic iron complexes can be made from allylic alcohols or dienes via their ␩2 - or ␩4 -complexes by treatment with acid (Schemes 9.1 and 9.2). The non-coordinating BF4 − counter ion is often used. ␲-Allyl complexes of many other elements can also be easily made. One way is to use a nucleophilic metal complex. Substitution of bromide or chloride from an allylic halide gives an ␩1 -allyl complex, 9.9 or 9.12. While these often spontaneously convert to the ␩3 -complex, with loss of one ligand (Scheme 9.3), in other cases the ␩1 -complex may be sufﬁciently stable to be isolated and requires heating to convert it to the ␩3 -complex (Scheme 9.4).1 ␩3 -Allyl complexes may also be formed by the insertion of dienes into carbon–metal bonds (Scheme 9.5). The easily prepared acyl cobalt complex 9.14 reacts with 1,3-dienes to give the ␩3 -allyl cobalt complex 9.16.2 The CO ligands are electron withdrawing and these allyl complexes are electrophilic. The iron complexes, being cationic, are the more reactive.3 Very weak nucleophiles such as enol ethers, allyl silanes and electronrich aromatics may be used (Scheme 9.6). Malonate anions, amines and organozinc reagents have also been used. The resulting ␩2 -complexes are usually quite unstable 9.18 and decomplex on exposure to air to give the allylation product 9.19. In the case of aromatics, this is a mild way of carrying out a Friedel–Crafts reaction. The cobalt complexes are also electrophilic, but, being neutral, less so.4 The intramolecular reactions are particularly effective (Scheme 9.7).5 The iron complexes have found a particular value in rendering allyl cations chiral.6 An ordinary allyl cation is planar and, therefore, achiral. Coordination to iron can retain the chirality as coordination of the metal distinguishes the two faces. It has been shown that the ␩2 -sulfonyl alkene complex 9.23 can be formed in good d.e. and recrystallized to complete purity (Scheme 9.8). Acid treatment yields the desired cationic ␩3 -allyl complex 9.24, and treatment of this with suitable nucleophiles yields the allylated products, after Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals

Fe

(OC)3Fe

N

O 9.1

Figure 9.1 Allyl Iron Complex 9.1 Fe2(CO)9

HBF4

OH

OH Fe(CO)4 9. 3

9.2

Fe(CO)4 BF4

OH2 Fe(CO)4 9.4

9 .5

Scheme 9.1 HBF4 BF4 Fe(CO)3

Fe(CO)4

9.6

9 .7

Scheme 9.2 Br

(OC)4Co

Co(CO)4 9 .8

Co(CO)3

9 .9

9.10

Scheme 9.3 Cl Mn(CO)5 9 .11

(OC)5Mn 9 .1 2

Scheme 9.4

Δ -CO

Mn(CO)4 9 . 13

Ph

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η3 - or π -Allyl Complexes O

327

Me

MeI, CO

Co(CO)4

(OC)4Co

9 . 14

Me

O

(OC)3Co

9.1 5

9.16

Scheme 9.5 MeO

OMe

MeO

OMe

MeO

OMe

Fe(CO)4 Fe(CO)4

9.17

9.19

9.18

Scheme 9.6 O

TsHN

•

(OC)4Co Et3N

O

Me

Me

Me

TsHN Co(CO)3

9.20

O

9.21

9.22

N Ts

Scheme 9.7 SO2Ph

SO2Ph Fe (CO) 2 9

BnO Fe(CO)4 9.24

BnO 9.23 1. SO2Ph

HBF4

SO2Ph

2. I2

N Me

Fe(CO)4 9 .2 5

9 .2 6

N Me

Scheme 9.8

oxidative work up. As the optical purity of the products is very high, all the steps must be proceeding with excellent stereocontrol. The optically pure allyl complexes react with a wide range of mild nucleophiles: malonate anions, silyl enol ethers,7 electron-rich arenes and heteroarenes,8 amines,9 organozinc reagents,10 organocopper reagents11 and allyltrimethylsilane.12 The allylated products are obtained in very high e.e. with overall retention of conﬁguration (based on the starting ether) after oxidative removal of the iron tetracarbonyl. An example of cuprate addition can be found in Scheme 7.6. The sulfone group can be used subsequently to stabilize a carbanion for further alkylation, as in a synthesis of myophorone 9.30,13 in which the allyl complex 9.25 was trapped by an enol ether, and other natural products (Scheme 9.9).14 The cyclic complexes 9.32 and 9.33, derived from alkene 9.31, have been studied (Scheme 9.10).15 The major product of complexation is the less stable cis complex 9.32, implying that the iso-propoxy group has a directing effect. The minor trans complex 9.33 reacts rapidly with allyltrimethylsilane in the presence of a Lewis acid to give the product 9.37 with retention in very high e.e. In contrast, the major cis complex 9.32

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Organic Synthesis Using Transition Metals OSiMe3

SO2Ph

1.

SO2Ph

2. Ce(NH4)2(NO3)6

Fe(CO)4 9.25

O SO2Ph

1. H2, Pd/C 2.(CH2OSiMe3)2

O

O

9.28

9.27

1. n-BuLi 2. furfural 3. (COCl)2, DMSO, Et3N

O

O Zn, AcOH

SO2Ph O O

O

O 9.30

O

9.29

Scheme 9.9 Fe(CO)4 Fe2(CO)9 i-PrO 9.31

N Ac

O

i-PrO 9.32

N Ac

O

Fe(CO)4 +

i-PrO SiMe3

18 hrs

BF3.OEt2

Fe(CO)4 N Ac

O

O N Ac 9.33

3:1

3 hrs Fe(CO)4 N Ac

9.34

O 9.35

N Ac

O

9.36 55% e.e.

N Ac

O

9.37 > 95% e.e.

Scheme 9.10

reacts slowly to give the product 9.36 with inversion but low e.e. (Scheme 9.10). This is because the leaving group and the iron are cis, an unfavourable arrangement for ionization.

9.2

Catalysis: Mostly Palladium

␲-Allyl palladium 9.39 complexes can be made directly from alkenes in a process that involves C–H activation (Scheme 9.11 – see Section 3.4), though they are more often made from allyl halides by treatment with a source of palladium(0) (Scheme 9.12). They are stable, isolable compounds, usually existing as dimers with

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η3 - or π -Allyl Complexes

PdCl2

329

Cl Pd

Pd Cl

9.38

9.39

Scheme 9.11

Cl

Nuc

Cl

Pd(0)

Pd

Nuc

Pd

Cl 9. 41

9.40

9 . 42

Scheme 9.12 OAc

Nuc

Pd(0)

Nuc

L2Pd(0)

Nuc

OAc coordination

dissociation

OAc

Nuc L2Pd

L2Pd

ionisation

nucleophilic attack Nuc

AcO

L2Pd - H+

Scheme 9.13

either halide or acetate bridging the two palladium atoms. The complexes are often electrophilic. The ␲-allyl complexes react with nucleophiles to give allylation products and, again, palladium(0) by-products. As the reaction of allyl halides is with palladium(0), this reaction can clearly be made catalytic (Scheme 9.13). In fact, the catalytic reaction has a very wide scope and a variety of allyl compounds take part, not just allylic halides. Allylic derivatives with usually poor leaving groups, such as esters and carbonates are most commonly used.16 Other leaving groups include nitro,17 phosphate,18 benzotriazole,19 and sulfonyl.20 Even alcohols have been used.21 The advantages of using these derivatives, rather than the halides, is their greater stability, better ease of handling and lower toxicity. Higher yields may also be achieved, compared to classical allylation reactions (Scheme 9.14).22 If only a base, but no nucleophile is available, elimination will occur to give a 1,3-diene. Examples of elimination reactions can be found in Schemes 9.78 and 9.79. A wide range of nucleophiles have been used.23 Nitrogen derivatives of various kinds, including simple amines (Scheme 9.15), have proven to be very effective. Stabilized carbon nucleophiles, such as the anions of malonates (Scheme 9.16),24 ␤-ketoesters, ␣-sulfonyl esters, have been widely employed. Oxygen nucleophiles have been less widely used, but are known (Scheme 9.17).25

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Organic Synthesis Using Transition Metals O

O X reagents

O 9. 43

O 9.44

X = Br; NaOH X = OAc; R3N, Pd(0) catalyst

34% 94%

Scheme 9.14

Ar2CHNH2 (Ph3P)4Pd

OAc

Ar

9 .4 5

9 .4 6

N H

Ar

Ar = p-MeOC6H4

Scheme 9.15 CO2Me +

OAc

(Ph3P)4Pd

CO2Me

CO2Me

9.47

CO2Me

9.48

Scheme 9.16

OH

OTBS

NaH, Me3SnCl Pd(OAc)2, Ph3P

H O H OTBS

OBz 9.49

9.50

Scheme 9.17

+

Me3Sn

OMe

Pd(dba)2, DMF, LiCl

OMe

OAc 9.51

Scheme 9.18

Main-group organometallics can also be allylated in this way, provided that they are not so reactive that they attack the acetate carbonyl group. Organotin compounds are suitable (Scheme 9.18).26 Mechanistically, the reaction is slightly different as the “nucleophile” does not transfer to the allyl group directly, but via the palladium. This is similar to the Stille coupling (Section 2.5). The stereochemical consequence of this is discussed below (Section 8.1.3). Allyl halides may also be coupled with allyl stannanes (Scheme 9.19). Regioisomeric mixtures result, unless one end of the allyl system is distinctly more hindered.27 Zinc28 and silicon29 reagents have also been employed (Scheme 9.20).

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η3 - or π -Allyl Complexes

Br

Snn-Bu3 + 9.52

BnPd(PPh3)2Cl, ZnCl2

+

331

9.54

9.53 9.55

Scheme 9.19

OAc

Pd(OAc)2 P(2-Fu)3

+ BrZn

9.56

CO2Et

CO2Et 9.57

9.58

Scheme 9.20

9.2.1

Regioselectivity

An important feature of the reaction is that an ␩3 -allyl complex is the key intermediate that is attacked by the nucleophile. In principle, the nucleophile can attack either of the two termini. In practice, it is found that this depends on the catalyst. With the commonly used palladium-phosphine systems, the less-hindered terminus is attacked. A synthetic consequence is that either of the two isomeric allyl derivatives may be used, but will give the same product (Scheme 9.21). The two isomeric acetates 9.59 and 9.60 gave the same mixture of products 9.62 and 9.63, with nucleophilic attack on the common intermediate ␩3 -allyl complex 9.61 ␣ to the less bulky methyl group being substantially favoured.30 On the other hand, molybdenum catalysis results in predominant attack at the more-hindered position when non-bulky nucleophiles are employed (Schemes 9.22 and 9.23). While the use of the palladium–phosphine system gives the product under steric control, with the molybdenum carbonyl system, attack is now under charge control. The carbon better able to support positive charge, i.e. the more substituted carbon, is the site of attack. More-hindered nucleophiles, however, again favour attack at the less hindered terminus,31 OAc Me

OAc Ph

Ph

Me

9.59

9.60 LnPd(0) PdL2 Me

Ph 9.61 CO2Et CO2Et

EtO2C

EtO2C

CO2Et

CO2Et 92:8

Me

Ph

Me

9.62

Ph 9.63

Scheme 9.21

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Organic Synthesis Using Transition Metals MeO2C OAc

MeO2C

MeO2C CO2Me catalyst

CO2Me CO2Me

9.63

9.64 product using Pd(PPh3)4 steric control

9.65 product using Mo(CO)6

MLn charge control

9.66

Scheme 9.22 Br 9.67

OAc

MeO2C CO2Me Mo(CO)6

CO2Et O

Br

Mo(CO)6

Br 9.68

EtO2C

9. 6 9

MeO2C CO2Me 5:1 mixture of regioisomers

O

Scheme 9.23 CO2Et CO2Et catalyst

O OAc 9.70

CO2Et CO2Et

O

EtO2C

9.71 Mo(CO)6 Mo(CO)2(NCt-Bu)4

O CO2Et

9.72

42 : 58 90 : 10

Scheme 9.24

while moderately hindered nucleophiles give mixtures. For molybdenum catalysis, the identity of the ligand is critical. If some of the carbonyl ligands are exchanged for t-butyl isonitrile, the nucleophile once again attacks the less-hindered terminus (Scheme 9.24).32 This is because the isonitrile is a better ␴-donor, and therefore more effective at stabilizing the positively charged intermediate. Iridium catalysis can also lead to this sense of regioselectivity, favouring attack at the more substituted terminus (Scheme 9.25).33 Even a quaternary centre could be made, but needed a slightly better leaving group (Scheme 9.26). A number of examples are known where the steric hindrance at the two termini is about the same, but one terminus has a polar group, such as an alcohol or a carboxylic acid (Scheme 9.27). In these cases, the nucleophile attacks the terminus of intermediate 9.80 most distant from the polar group.34 Another example may be found in Scheme 9.33.

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η3 - or π -Allyl Complexes MeO2C

MeO2C

CO2Me

333

CO2Me CO2Me

OCO2Me [Ir(COD)Cl]2, (PhO)3P

97:3

9.73

9.74

CO2Me

9. 75

Scheme 9.25 MeO2C

CO2Me

MeO2C

CO2Me

CO2Me

OCOCF3 [Ir(COD)Cl]2, (PhO)3P 9.76

9.77

95:5

CO2Me 9.78

Scheme 9.26 CO2Me

O O H

(Ph3P)4Pd

9.79

CO2

PdL2

+

9.80

CO2Me

HO2C

MeO2C

CO2Me

9.81

Scheme 9.27

Steric factors can control the regioselectivity even in cyclization reactions, where ring size might also be considered.35 Even when the ring size is unfavourable, it is usually the less-substituted allyl terminus that is attacked. An excellent example of a macrocyclization can be found in a synthesis of roseophilin 9.88 (Scheme 9.28).36 Treatment of the molecule 9.82, which has a sulfonyl ester as the nucleophile and a vinyl epoxide as the electrophile, with a palladium(0) catalyst gave the thirteen-membered ring 9.83. The functional groups that served to stabilize the negative charge of the nucleophile both served a second function. The ester group was incorporated into an allylic lactone 9.84 by cyclization onto the hydroxyl group derived from the epoxide opening (see Section 9.2.6). This enabled a second palladium-catalysed reaction to establish pyrrole 9.85. The sulfonyl group underwent elimination at a later stage to allow introduction of the iso-propyl substituent by in situ conjugate addition of an iso-propyl nucleophile. This gave the acyl pyrrole 9.87, which could be further elaborated to the natural product 9.88. 9.2.2

Internal versus Terminal Attack

Following early examples,37 a debate has continued sporadically over the possibility of attack at the central carbon, rather than at a terminal carbon of the allyl system. It is now clear that internal attack is easily possible. It is more efﬁcient using simple ketone enolates or nitrile anions and is strongly favoured by the use of chelating diamine ligands for palladium. Treatment of the isolated ␲-allyl palladium 9.89 with a nitrile carbanion yielded a stable palladacyclobutane 9.90 that was characterized by X-ray crystallography (Scheme 9.29). Exposure to CO triggered reductive elimination to give the cyclopropane 9.91.38 Numerous additional examples have been reported.39 Similarly, it has been found that the 2-chloroallyl complex 9.92 undergoes only terminal attack if triphenylphosphine is used as a ligand, but both central and terminal attack if bipyridyl or TMEDA is employed (Scheme 9.30).40 It is likely that the electron-accepting phosphine ligands increase the positive charge on the allyl ligand, which is mostly on the terminal carbons as in allyl carbocations. A charge-controlled nucleophilic attack yields the observed product. Amino ligands are good donors and are not ␲-acceptors, thus reducing the

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Organic Synthesis Using Transition Metals O

OH

TBSO

TBSO

(Ph3P)4Pd, dppe PhSO2 9.82

9.83 PhSO2 CO2Me

MeO2C

1. TBAF 2. Dess-Martin

PhSO2 O

1. Me 2C=C(NMe)2Cl 2. SnCl 4

O

BnNH2, (Ph3P)4Pd PhSO 2 HO2C

O 9.84

9.85

PhSO2 9.86

NBn

1. i-PrMe2ZnMgCl, KOt-Bu 2. Ca, NH 3 3. KH, SEMCl

N Bn

O

i-Pr

i-Pr N MeO O

N SEM 9.87

O NH 9.88

Cl

Scheme 9.28

CN Ph

Ph CN N

Pd

N

CN Ph

Ph N

9.89

Pd

CO

N

Ph

9.90

Ph 9.91

Scheme 9.29

Cl

EtO2C Me CO2Et EtO2C CO2Et Me

Cl CO2Et CO2Et Me

Pd+ L L 9.92

9.93 L = PPh 3 nucleophile =

9.94 L,L = bipy, TMEDA

CO2Et

EtO2C

Me

Scheme 9.30

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η3 - or π -Allyl Complexes Cl OAc

+

Ph

EtO2C

CO2Et

Pt(H2C=CH2)(PPh3)2

Ph

O 9.97

O 9.95

9. 9 6

335

Scheme 9.31

positive charge on the ligand. Nucleophilic attack may be directed towards the central carbon if the reaction is frontier-orbital controlled. Some calculations have shown that this carbon has the highest LUMO coefﬁcient. Allyl complexes of other metals have also been found to exhibit this chemistry.41 A novel furan synthesis has been uncovered during this debate (Scheme 9.31); it involves both central and terminal attack on chloroacetate 9.95.42 9.2.3

Stereoselectivity

The stereochemical results of these reactions have been carefully studied.43 If a chiral acetate is employed, then the product is found to have retention of stereochemistry. Hence, the cis acetoxy ester 9.98 gives the cis product 9.100, while the trans acetoxy ester 9.101 gives the trans product 9.103 (Scheme 9.32).44 Retention is a result of two inversions – inversion during formation of the ␩3 -allyl complexes, 9.99 and 9.102, and a second inversion during attack by the nucleophile. In the case of the acetoxy esters 9.98 and 9.101, a curious observation can be made when the substrate is non-racemic. It is found that the product is racemic. This is not a general observation. It occurs here, because the intermediate ␩3 -allyl complexes, 9.99 and 9.102, each have a plane of symmetry – they are meso compounds and the nucleophile is equally likely to attack either terminus. Systems without the symmetrical intermediate do not show racemization (Scheme 9.33). Inversion is not observed when an organometallic capable of transmetallation is used in place of the nucleophile (Scheme 9.34). Treatment of the cis-acetoxy ester 9.98 with phenyl trimethyltin and a palladium catalyst gives the trans isomer 9.108,45 while use of a malonate anion gives the cis product 9.100 (see Scheme 9.32 above). Both products are formed via the same ␩3 -allyl complex 9.99, one by nucleophilic attack trans to Pd, one by transmetallation (presumably after acetate–chloride exchange). The same stereochemical result has been observed with silicon,46 boron47 and aluminium reagents (Scheme 9.35).48 The lactone 9.110 reacts with the vinyl aluminium reagent 9.109 to give the trans acid 9.111. CO2Me oxidative OAc addition (inversion)

Nuc (inversion)

CO2Me

9.100 CO2Me

CO2Me L2Pd(0)

OAc

Nuc

PdL2 9.99 meso-

9.98

9.101

CO2Me

CO2Me L2Pd(0)

Nuc Nuc

PdL2 9.102

Scheme 9.32

9.103

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Organic Synthesis Using Transition Metals

HO

OAc

(Ph3P)4Pd, PhthN

HO

HO PdL2 9.105

9.104

NPhth

9.106

Scheme 9.33 CO2Me

CO2Me

MeO2C CO2Me (Ph3P)4Pd CO2Me

9.100 cis

CO2Me

PhSnMe3, LiCl (dba)2Pd

Ph

OAc

CO2Me

9.98 cis nucleophilic attack

9.108 trans reductive elimination

CO2Me MeO2C

CO2Me PhSnMe3

CO2Me

transmetallation PdL2 9.99

L2Pd Ph 9.107

Scheme 9.34 n-Bu

O DIBAL n-Bu

n-Bu

Ali-Bu2

O

(Ph3P)4Pd 9.110

9.109 HO2C

9.111

Scheme 9.35

Inversion during coupling with a silicon reagent was employed in a synthesis of a deoxypancratistatin analogue 9.118 (Scheme 9.36).49 A cyclohexenyl alcohol with a cis-nitrogen substituent was prepared by the hetero-Diels–Alder cycloaddition of an in situ generated nitroso compound 9.113 with cyclohexadiene 9.112, followed by cleavage of the N–O bond. After derivatization of the alcohol as a carbonate 9.115, palladium-catalysed coupling with an aryl silane 9.116 proceeded with modest regioselectivity. The desired isomer 9.117 was subjected to Bischler–Napieralski cyclization and alkene oxidation. Inversion during formation of the ␩3 -allyl complex is not always observed. For the tricyclic compound 9.119, the endo face is sterically blocked, and only the exo face is accessible (Scheme 9.37). It was observed that only the exo isomer reacted with a malonate nucleophile in the presence of a molybdenum catalyst.50 It was argued that the molybdenum catalyst displaced acetate by a syn reaction and the resulting ␩3 -allyl molybdenum complex 9.120 was attacked by the nucleophile, also in syn fashion, to give the product of retention – this time by double retention. Also, it was noted that reaction rate was slowest for the best leaving group (triﬂuoroacetate; R = CF3 ), but highest for the worst leaving group (R = Me2 N). The rationale for this was that precoordination of the catalyst by the carbonyl group of the leaving group is beneﬁcial for the syn mechanism. The carbamate, the worst leaving group, is also the best donor. Coordination in a syn fashion can be caused by strong donor groups in other systems (Scheme 9.38).51 In the case of compounds such as 9.122, the phosphorus directs the palladium to be syn to the leaving group,

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η3 - or π -Allyl Complexes HO HN

CO2Et

n-Bu4N+IO4O N 9.112 O

337

OCO2Et O N CO2Et 9.114

CO2Et

9.113

1. Mo(CO)6, H2O 2. EtO2COCl, py

9.115 NHCO2Et

OH HO

Si(OEt)3 1. POCl3, Me3SiOSiMe3 2. H2O2, HCO2H NHCO2Et 3. NaOH

O

9.116 O Pd(dba)2, TBAF

O

O NH

O

9.117

9.118

O

Scheme 9.36

Nuc-

Mo(CO)6 MoLn

syn OCOR complexation

H

syn

H Nuc

9.119

9.120

9.121

Scheme 9.37 Pd(PPh3)4

Ph2P N

OAc

EtO2C

CO2Et

Bn

Ph2P

CO2Et N

Bn 9.122 complexation cis to N; cis to OAc

CO2Et 9.123

Ph2P

PdL

N

EtO2C CO2Et attack trans to Pd

Bn 9.124

Scheme 9.38

but nucleophilic attack is still trans to the metal. The net result is a single inversion leading to the trans product 9.123. 9.2.4

Asymmetric Allylation

For an allylic acetate such as 9.125 in which the substituents at each end are the same, reaction with a source of palladium(0) will generate an achiral palladium complex 9.126, and then a racemic product 9.127, regardless of the original chirality of the starting material (Scheme 9.39). If the ligands on the palladium are chiral, then the intermediate ␩3 -allyl complex will not be a symmetrical compound. Under the right circumstances, the nucleophile may be directed so that a non-racemic product is obtained.

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Organic Synthesis Using Transition Metals OAc

PdL2

L2Pd

Ph

Ph

Ph

Nuc

Nuc Ph

Ph

9.125

9.126

Ph 9.127

Scheme 9.39

A number of such ligands have been developed. They typically include a diphenylphosphino aryl unit connected to a chiral group. Bisamides 9.128 derived from trans-1,2-diaminocyclohexane, and also other diamines, have proved valuable,52 as have phosphinooxazoline derivatives, such as 9.129.53

O

O

O NH HN

N

Ph2P

PPh2 Ph2P 9.128

9.129

The use of chiral ligands has also been employed with meso-substrates in which there are two leaving groups available, which would lead to enantiomeric products. In this way, the adenosine nucleoside 9.137 could be prepared from a meso di-benzoate 9.131, itself available by oxidation of furan 9.130 (Scheme 9.40).54 O 9.130

Cl Cl

Pb(OBz)4 O

BzO

+

OBz

N

N

N

N dba3Pd2.CHCl3, L*

N BzO O

N

N H 9.132

N 9.131 CO2Bn

BnO2C

N

N

OCO2Bn Pd(0), Cs2CO3

9.133

Cl OCO2Bn CO2Bn CO2Bn O

N

N

9.134

Cl

1. OsO4, NMO 2. Me2C(OMe)2, H+

Cl

N

N N

N OCO2Bn 1. H2, Pd/C CO2Bn 2. ArSO 2Cl, Et3N N N CO2Bn 3. HOBT, DCC, NaBH O 4 O

O

OH

N O O

O

9.135

9.136

NH2 1. NH3 2. H3O+

N

Ph N

N N

O NH HN

OH

N

9.137 HO

Ph

O L*= 9.138

O OH

Scheme 9.40

PPh2 Ph2P

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η3 - or π -Allyl Complexes Me O P N O Me

Me O P N O Ir cod

[Ir(cod)Cl]2 base

Ph Ph

9.139

339

Ph Ph

9.140

Scheme 9.41

Ph

OCO2Me

[Ir(cod)Cl]2, L MeO2C CO2Me

MeO2C

CO2Me

Ph

9.141

9.142 96% e.e.

Scheme 9.42

Palladium-catalysed reaction of the dibenzoate 9.131 with a chloropurine 9.134 gave either enantiomer according to the choice of ligand. The remaining benzoate could then be replaced by a substituted malonate to give the disubstituted product 9.135, again with palladium catalysis. After dihydroxylation of the double bond, the malonate moiety could be stripped down to provide the hydroxymethyl substituent. Substitution of the chloride by ammonia and removal of the acetonide gave the nucleoside 9.137. With iridium catalysis, the nucleophile tends to attack the more substituted carbon (Section 9.2.1). Simple allylic acetates, therefore, give rise to chiral products directly. These products will be racemic unless an effective chiral ligand is added.55 While a range of phosphorus-based catalysts have been studied, phosphoramidites 9.139 have been found to be especially effective. Interestingly, these act as more than simple phosphorus ligands: attack of the iridium onto a C–H bond of one of the methyl groups generates the active species 9.140 (Scheme 9.41).56 The addition of an amine base promotes this reaction. Asymmetric allylation using the phosphoramidite system (“L* ”), or its analogues, can be applied to a range of nucleophiles, including malonates (Scheme 9.42),57 nitro compounds (Scheme 9.43),58 bicarbonate, giving an hydroxy group (Scheme 9.43),59 and amines (Scheme 9.44).60 An asymmetric, iridium-catalysed allylation of pyridine derivative 9.148 was employed for a synthesis of nicotine (Scheme 9.45) – see Scheme 8.76 for later steps, including ring-closing metathesis.61 Another application of this reaction is in a synthesis of the alkaloid xenovenine 9.150 (Scheme 9.46),62 one of many isolated from tropical frogs, which acquire the compound from their diet. While asymmetric allylation provided the original stereogenic centre, Suzuki coupling, the Wittig reaction and reductive amination were each employed for key bond-forming reactions. Additional syntheses of xenovenine can be found in Section 6.2. The readily available allylic carbonate 9.152 was reacted with the diacylammonia derivative 9.153 in the presence of an iridium complex and the chiral pre-catalyst (Scheme 9.47). The NO2 [Ir(cod)Cl]2, L*, Cs2CO3

O2N Ph 9.144

Ph

OCO2Me 9.143

OH [Ir(cod)Cl]2, L*, KHCO3 aq.

Ph 9.145

Scheme 9.43

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Organic Synthesis Using Transition Metals BnNH2, [Ir(cod)Cl]2, L*, base MeO2CO

N Bn 9.147 99% e.e.

OCO2Me 9.146

Scheme 9.44

HN OCO2t-Bu H2N [Ir(COD)Cl]2 L*

N

N

9.148

9.149

Scheme 9.45

Wittig

Suzuki

H PGO

CHO N allylation H aza-Michael 9.151

N H3C reductive Wittig amination

9.150

PGO

OCO2Me 9.152

n-Bu

Scheme 9.46

OCO2Me

TBDPSO

N 9.153 OHC Cbz [Ir(COD)Cl]2, L*

TBDPSO N OHC Cbz 9.154 97% e.e.

9.152 1. KOH 2. 9-BBN CO2Me 3. I dppfPdCl2, Ph3As, Cs2CO3

CO2Me

TBDPSO NHCbz

1. DIBAL CO2Me 2. Ph P=CHn-Bu 3

TBDPSO

N Cbz 9.156 1. TBAF 2. (COCl)2, DMSO, Et3N 3. Ph3P=COCH3

KOt-Bu

9.155

TBDPSO

N Cbz 9.157

n-Bu

H

O N Cbz 9.158

n-Bu

N

H2, Pd/C H3C

9.150 n-Bu

Scheme 9.47

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η3 - or π -Allyl Complexes NH2

O

Boc2O, NaOH

NHBoc

O

341

I2, AgO 2CCF3

O

O 9.160

NHBoc

O O

9.161

HCl, Br2, AcOH

NH2

O

CF3CO2H

Bu4NI O

I 9.162

X

AcO

9.164

9.163 H N

O O

TsO

Pd(PPh3)4 TMG, <50 °C

X

O

X = Br

9.165

H N

O Br

L2Pd

9.166

AcO

N

O

Herrmann's catalyst Bu4NOAc, Δ

O N O

O

H

Br 9.167

9.168

Scheme 9.48

product 9.154 could be selectively N-deformylated. Hydroboration, followed by Suzuki coupling then installed the Michael acceptor. Treatment of the Suzuki product 9.155 with KOt-Bu at low temperature gave the trans pyrrolidine 9.156. The two side chains could then be separately extended using the Wittig reaction in each case. Palladium-catalysed hydrogenation of the double Wittig product 9.158 then unleashed a tandem sequence of double alkene reduction, N-deprotection and reductive amination to give the alkaloid 9.150.

9.2.5

Synthesis Using Palladium Allyl Chemistry

An intramolecular allylation was employed in a synthesis of cephalotaxine 9.168 (Scheme 9.48).63 The benzene ring of the starting amine 9.160 was halogenated – this process requires that the nitrogen be protected or, in the case of bromination, protonated. The halogenation was not straightforward. The substrate would appear to be electron rich due to the oxygen substituents on the ring, but they are poor donors as they are sp3 -hybridized. To fully donate their lone pairs into the ring, they would have to be sp2 -hybridized, but the resulting 120◦ bond angles would impose too much strain. The halogenated amine 9.163 was then alkylated with tosylate 9.164 to install the allylic acetate moiety. Allylic alkylation only worked using the bromide substrate 9.165 (X = Br). It seems likely that, with X = I, the palladium is not selective for the allylic acetate, leading to side products. With the less-reactive bromo compound, the palladium selectively attacks at the allylic acetate. The resulting ␲-allyl palladium complex 9.166 is then attacked by nitrogen at the nearer (“proximal”) terminus, giving the spirocyclic amine 9.167. The geometry of the ring formation overcomes the usual preference for attack at the less-hindered terminus. With the second ﬁve-membered ring

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Organic Synthesis Using Transition Metals SO2Ph I

O

PhSO2

Pd(PPh3)4, Et3N O

O

O O

O

9.169

9.170 NHPMB

NPMB

PhSO2 O OMOM

O 9.171

S

S

Pd(PPh3)4, TMG, CH3CN, Δ

O OMOM

O S

TMG = Me2N

NH NMe2

S

9.172

Scheme 9.49

formed, the seven-membered ring could be closed by a Heck reaction. The usual catalysts failed in this case. A high temperature was required, and the usual catalysts often decompose on excessive heating. Herrmann’s catalyst (see Scheme 5.17) is particularly robust and worked. The Heck reaction gives a single stereoisomer 9.168 with the newly formed C–C bond cis to nitrogen. A different approach to the cephalotaxine ring system also used ␩3 -allyl palladium chemistry (Scheme 9.49).64 Tetramethylguanidine (TMG), which is a stronger base than triethylamine by at least two orders of magnitude, was found to be the base of choice for the cyclization of allylic sulfone 9.171. The sulfone leaving group was also essential to the synthesis of the earlier intermediate 9.170 by allowing alkylation to introduce the aminopropyl side chain.65 Double allylation was used in a synthesis of huperazine A 9.179, an acetyl choline esterase inhibitor and, hence, potential anti-Alzheimer’s compound, isolated from a Chinese club moss (Scheme 9.50).66 Treatment of the ␤-ketoester 9.173 with an allylic diacetate in the presence of a palladium catalyst and tetramethylguanidine resulted in a two-fold allylation to give the bicyclic product 9.174. This sets up the huperazine ring system in a single step. The ﬁrst process in this reaction must be allylation between the two carbonyl groups (␣ to the ester), followed by allylation at the ␥ -position. Allylation of a simple enolate is less well known, especially with such a modest base and, in this case, must be favoured by being intramolecular. Two additional carbons were installed by Wittig oleﬁnation. This gave predominantly the wrong isomer, and this had to be corrected by a free radical method to give the desired isomer 9.175. Degradation of the ester to a carbamate, a process involving Curtius rearrangement, changed the ester to an amine derivative 9.178. Finally, deprotection reactions and an alkene isomerization yielded the natural product 9.179. Sulﬁnates have also been used as the leaving group, even though sulﬁnic acids are not strong acids. The usefulness of this approach is that the sulfone group, as a good carbanion-stabilizing group, can also be used to synthesize the substrate. This was used in a synthesis of the Monarch butterﬂy pheromone 9.184 (Scheme 9.51).67 Michael addition of the anion of sulfone 9.180 to MVK gave a ketone 9.181 that was subjected to a Horner–Wadsworth–Emmons reaction. Displacement of the sulﬁnate by the anion of dimethyl malonate with a palladium catalyst, followed by Krapcho decarboxylation, gave the pheromone 9.184.

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η3 - or π -Allyl Complexes N

OMe AcO

Pd(OAc)2, PPh3, TMG

AcO

HO

N O

CO2Me 9.173

343

OMe

CO2Me 9.174

1. Ph3P=CHCH3 2. PhSH, AIBN

N CO2Me

N

1. NaOH OMe 2. (PhO)2P(O)N3

9.175

-N2

OMe

N

O

MeOH

OMe

N N3

9.176

9.177

C O

N

OMe

H N

1. Me3SiI; MeOH 2. TfOH

O

NH2

NHCO2Me 9.178

9.179

Scheme 9.50 1. n-BuLi 2. SO2Ph

O

O

(MeO)2P(O)CH2CO2Me, KOt-Bu

SO2Ph 9.181

9.180

CO2Me SO2Ph

MeO2C CO2Me (dppe)2Pd

MeO2C

9.182

LiI, DMF, Δ

CO2Me

MeO2C 9.183 CO2Me

MeO2C 9.184

Scheme 9.51

9.2.6

Base-Free Allylation

Carbonates 9.185 (Scheme 9.52)68 and epoxides69 are widely used as leaving groups. They have the advantage, in the case where the nucleophile must be generated by deprotonation, that the leaving group itself can act as a base. Malonate is an example of a nucleophile of this kind and the reaction becomes “base free”, meaning that no base needs to be added as it is generated internally.

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Organic Synthesis Using Transition Metals

OCO2Et + MeO2C

CO2Me

CO2Me

Pd(0)

CO2Me

9.185

9.186

CO2Me

L2Pd(0)

O

CO2Me

OEt

9.185 O

9.186 CO2Me

O

CO2Me

L2Pd

OEt

O 9.187

L2Pd 9.189 L2Pd MeO2C

CO2Me

CO2 + EtO

9.188

MeO2C

CO2Me

Scheme 9.52

EtO2C AcO

Ot-Bu O

OCO2Me

NaH, Pd(dba)2, PPh3

CO2Et

AcO

9.189

9.190

O

Ot-Bu

Scheme 9.53

In fact, carbonates turn out to be better leaving groups than acetates, and selective reactions can be achieved (Scheme 9.53). The selective reaction at an allylic carbonate over an allylic acetate in cyclopentene 9.189 was employed in the early stages of a synthesis of strychnine.70 Further aspects of this synthesis can be found in Scheme 2.58 and Scheme 4.12. Vinyl epoxides also constitute a “base-free” system (Scheme 9.54). The alkoxide 9.193 generated by the palladium-mediated ring opening of epoxide 9.191 acts as the base. HO

CO2Et

O

CO2Et

(Ph3P)4Pd CO2Et EtO2C

9.191

OEt

OEt O

O H

9.192

O

O

PdL2

OEt 9.193

Scheme 9.54

HO PdL2

O OEt 9.194

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η3 - or π -Allyl Complexes

345

O C O O

CO2 CO2Et Pd(OAc)2, (i-PrO)3P

O

CO2Et PdL2

9.195 O O

9.196

O O

O

O

CO2Et PdL2

CO2Et 9.198

9.197

Scheme 9.55

The alkoxide released is also nucleophilic and may be trapped with electrophiles such as CO2 and isocyanates prior to attack on the ␲-allyl complex (Scheme 9.55). The attack of the alkoxide on CO2 generates a hemicarbonate 9.197, which can close back on the ␲-allyl complex. The isocyanate trapping method was employed in a synthesis of an unusual sugar, acosamine 9.209, as its O-methyl, N-acetyl derivative (Scheme 9.56).71 The substrate for the palladium chemistry was prepared from methyl lactate 9.199, which is readily and cheaply available as its (S)-enantiomer. The alcohol was protected,

CO2Me 1. TBSCl, Et 3N 2. DIBAL OH 9.199

CHO TBSO 9.200

Ti(Oi-Pr)4, (+)-DET, t-BuOOH

OH TBSO 9.201

1. (MeO) 2P(O)CH2CO2Me, LiCl, i-Pr2NEt 2. DIBAL

O OH TBSO 9.202

1. (COCl)2, DMSO, Et3N 2. Ph 3P=CH2

O

TBSO

TBSO

9.203

9.204

TBSO

NTs

O

TBSO

1. Na C10H8 2. R2BH; H2O2, NaHCO3

NH

9.208

O

TBSO

9.206 O

PdL2

1. NaOH, Δ 2. Ac 2O OMe 3. MeOH, H+ OMe

NH

9.205

1. PCC, CH 2Cl2 OH 2. (Me3O)3CH, MeOH, PPTS

9.207

OMe O HO AcHN 9.209

Scheme 9.56

NTs

TBSO

O

O O

NTs

O

(dba)3Pd2.CHCl3 P(Oi-Pr)3, TsNCO

O

O O

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Organic Synthesis Using Transition Metals L2Pd CO2Me

O 9.210

CO2Me

O

9.211

C-alkylation

O CO2Me 9.212

Scheme 9.57

the ester reduced and the resulting aldehyde 9.200 subjected to a Horner–Wadsworth–Emmons reaction under the mild Masamune–Roush conditions. 1,2-Reduction of the ester, this time all the way down to the alcohol, gave an allylic alcohol 9.201. Sharpless asymmetric epoxidation gave a hydroxy epoxide. This was oxidized using the Swern method and the double bond was installed by a Wittig reaction. Treatment of the vinyl epoxide 9.203 with a palladium(0) catalyst in the presence of tosyl isocyanate gave the oxazolidinone 9.205 with retention of stereochemistry via a ␲-allyl palladium intermediate 9.204. The synthesis was completed by removal of the tosyl group under reductive conditions using sodium naphthalenide, hydroboration-oxidation, alcohol oxidation and acetal formation. The oxazolidinone was then cleaved by alkaline hydrolysis. Selective N-acetylation and acid-catalysed cyclization gave the sugar derivative 9.209. Enolates can be used as the leaving group (Scheme 9.57). If they are, then they will also become the nucleophile. Enolates are ambident nucleophiles and can be O- or C- alkylated. O-alkylation is redundant as it leads back to starting material 9.210, whereas C-alkylation leads to the product 9.212.72,73 Even a carbon–carbon bond can be broken to form the ␲-allyl complex, provided that the resulting carbanion leaving group is well stabilized, and ring strain is released as a result. This reaction was employed in order to control stereochemistry in a synthesis of (±)-clavukerin A 9.218 (Scheme 9.58).74 Treatment of the cyclopropane 9.213 with a palladium(0) catalyst and formic acid, as a reducing agent, resulted in ring

H

H Pd2dba3.CHCl3, CO2Me Et3NH+ HCO2-

CO2Me CO2Me

CO2Me O

O

9.213 H

H CO2Me

1. H2, Pd/C 2. (EtO)2POCl, base

9.215

H CO2Me CO2Me

(EtO)2P(O)O H

MeMgI, Ni(acac)2

9.214 H

CO2Me O

Pd(PPh3)2

9.216

H 1. DIBAL CO2Me 2. (COCl) , DMSO, Et N 2 3 3. TiCl 4, Zn CO2Me 9.217

Scheme 9.58

H

9.218

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η3 - or π -Allyl Complexes O

O

347

O

O 9.219

Ph

Pd(OAc)2, PPh3 Ph

-CO2

9.220

Scheme 9.59

opening to the ␲-allyl complex 9.214, which was reduced by hydride transfer from formate. Unlike most other nucleophiles (see Schemes 9.32 and 9.34), formate transfers hydrogen with retention, giving the required stereochemistry for the natural product. Completion of the synthesis included a nickel-catalysed Kumada coupling to convert the ketone, via an enol phosphate 9.216, into a methyl group and a McMurry reaction to close the seven-membered ring. 9.2.7

Allylation with Decarboxylation

Enolates can also be revealed by decarboxylation.75 Allyl or related esters of ␤-ketoesters undergo ionization on treatment with palladium(0). The released ␤-ketocarboxylate loses CO2 to give a simple enolate, which counterattacks onto the ␲-allyl complex.76 The result is a clean allylation reaction without the use of bases, driven by decarboxylation (Schemes 9.59 and 9.60).77 Other groups capable of stabilizing the anion generated by decarboxylation may be present in place of the ketone group. These include esters (so that the substrate is a malonate),78 nitriles,79 nitro groups,80 imines81 and sulfones.82 Even alkynes may be used, although the stereochemical outcome of the reaction indicates that, in this case at least, the nucleophile remains bound to palladium (Scheme 9.61).83 Decarboxylation of heteroatom derivatives, such as allyl carbamates, is included in Section 9.2.8. O

O

O O

(Ph3P)4Pd

9.221

9.222 O

O LnPd(0)

O 9.221

nucleophilic attack 9.222 and dissociation O

coordination O

LnPd

O O 9.223

9.225 ionisation CO2 decarboxylation

O

O

O

LnPd O 9.224

Scheme 9.60

PdLn

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Organic Synthesis Using Transition Metals CO2Me

CO2Me O

(Ph3P)4Pd

O Ph

9 .2 2 6

Ph

9. 2 2 7

Scheme 9.61

HO enolate coupling

N

hydroboration-oxidation allylation O

H 9.228

conjugate addition

Scheme 9.62

A concise synthesis of lycopladine, an unusual and modestly cytotoxic lycopodium alkaloid, illustrates the remarkable ability of this reaction to introduce a carbon substituent at a crowded centre (Scheme 9.62).84 By virtue of hydroboration-oxidation, the hydroxypropyl substituent can be introduced via allylation. The central ﬁve-membered ring can be constructed by sequential conjugate addition and enolate coupling (see Section 2.11). The synthesis was achieved by copper(I)-catalysed addition of the carbanion derived from a methyl pyridine 9.229 to an unsaturated ␤-ketoester 9.230, trans to the existing methyl substituent (Scheme 9.63). Ring closure O Cl +

MeO2C

MeO2C

OH

Cl

n-BuLi; CuI

N 9.229

N

9.230

MeO2C KOt-Bu, Pd2dba3, SPhos N

9.231

O

O

O OH n-Bu8Sn4O2Cl4 N

H 9.232

H 9.233

HO O (Ph3P)4Pd

N

O 1. H4C6O2BH, (Ph3P)3RhCl 2. NaBO3.4H2O

H 9.234

Scheme 9.63

N

H 9.228

O

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η3 - or π -Allyl Complexes O

O

Me

O 9.235

Me

O

Pd2dba3, Trost Ligand 9.128 Me

349

Me

Me

Me 9.236 er = 93:76

Scheme 9.64 O O

O Me O Pd2dba3, L* = 9.129

9.237 O

O Me

Me

9.239 91-92% e.e.

O 9.238

Scheme 9.65

by intramolecular enolate coupling failed with the use of simple ligands for the palladium catalyst, but was successful when SPhos 1.16 was employed, giving the tricycle 9.232. Transesteriﬁcation of the methyl ester to the allyl ester 9.233 could then be achieved using the Otera catalyst,85 simpler transesteriﬁcation methods proving fruitless. Decarboxylative allylation was then achieved on treatment with a palladium(0) catalyst, thereby installing the challenging quaternary centre in tricycle 9.234. Hydroboration, catalysed by Wilkinson’s catalyst, and oxidation delivered the natural product 9.228. Another synthesis of lycopladine can be found in Scheme 6.93. As for the original allylation reaction, decarboxylative allylation may be made asymmetric by the inclusion of chiral ligands (Scheme 9.64).86 Similar results are obtained using either the ␤-ketoester 9.238 or the enol carbonate 9.237 (Scheme 9.65).87 With iridium catalysis, the ␲-allyl intermediate is attacked by the nucleophile at the more-substituted terminus.88 Again, the inclusion of a chiral ligand yields an optically active product (Scheme 9.66). Double asymmetric allylation was employed in a synthesis of cyanthiwigin 9.248 (Scheme 9.67).89 A bis␤-ketoester 9.243 was prepared as a mixture of all possible stereoisomers by pseudodimerization of diallyl succinate 9.242. Double asymmetric decarboxylative allylation set two stereogenic centres simultaneously, but also produced some of the meso-isomer. The di-allylation product 9.244, with two quaternary centres, could be converted to the natural product. Conversion of one ketone group to a vinyl triﬂate allowed installation of a side chain by Negishi coupling. A one-pot combination of a ring-closing metathesis reaction and a

O Ph

O

[Ir(COD)Cl]2, L* = 9.139

O 9.240

O

O

O

Ph 9.241 94% e.e.

Scheme 9.66

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Organic Synthesis Using Transition Metals O O O

O

O 1. 2. K2CO3, MeI

O O

O O

9.242

O

O Me

Me O

9.243

1. KHMDS; PhNTf2 2. IZn

Me

Pd(dmdba)2, L* = 9.129

Me

(Ph3P)4Pd Me O

Me O

9.244

pinB HoveydaGrubbs II

1. NaBO3, H2O 2. t-BuSH, AIBN

Me

O

H

Me H

pinB Me O 1. KHMDS; PhNTf2 2. i-PrMgCl, CuCN, dppfPdCl2

9.245

i-Pr

Me O 9.247

9.246

H

Me H

Me O

9.248

Scheme 9.67

cross-metathesis reaction of tetraene 9.245 established the seven-membered ring (for metathesis chemistry, see Chapter 8). Closure of the ﬁnal ring under radical conditions, and the coupling of a Grignard reagent (or in situ cuprate) completed the synthesis. 9.2.8

Allyl as a Protecting Group

The mild and selective nature of the palladium-catalysed allylation reaction has made it suitable for protection.90 Allyl ethers, esters, amines and carbamates can usually be easily formed by standard procedures. The allyl group can be removed later by exposure to a palladium catalyst and a competitive nucleophile, “Y− ” (Scheme 9.68). This is an allyl transfer reaction. Commonly used competitive nucleophiles for allyl esters of carboxylic acids include sodium 2-methylhexanoate,91 secondary amines such as pyrrolidine (Scheme 9.69)92 and morpholine,93 and dimedone.94

PdL2, YH X

XH +

+ Y PdL2

Scheme 9.68

Y

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η3 - or π -Allyl Complexes O

O

HH H N S

Ph N

N H

OAc

O O

9.249

(Ph3P)4Pd Ph3P

HH H N S

351

+

Ph N

N

OAc

O O

O

OH

9.250

Scheme 9.69

O

O

O O

O

O Bn N

(Ph3P)4Pd n-BuCH(Et)CO2H -CO 2

O

NHBn

O

O

O

O

9.252

9.251

H

N Bn

Scheme 9.70 TBSO

TBSO

TBSO

N

Pd(PPh3)4, THF -CO2

O O

9.253

Grubbs II, TsOH

H N

N

9.255

9.254

Scheme 9.71 CO2Et

CO2Et O

Et Et

+ O AcHN

N

O

MeN

NMe

1. Pd(OAc)2, PPh3 2. H3PO4

O

9.256

Et Et

O AcHN

NH2.H3PO4

9.257

Scheme 9.72

Similar reagents can be used for aloc-protected amines (Scheme 9.70);95 in the absence of the competitive nucleophile, the nitrogen undergoes allylation after decarboxylation, converting an allyl carbamate into an allyl amine in an “allyl contraction”. This reaction, applied to carbamate 9.253, was employed in a formal synthesis of swainsonine when direct allylation was inefﬁcient (Scheme 9.71).96 An earlier part of this synthesis can be found in Scheme 5.71. R 9.257 Amines may be deallylated, as in the ﬁnal step of a large-scale (29 g) preparation of tamiﬂu (Scheme 9.72). N, N -dimethylbarbituric acid is often the competitive nucleophile of choice.97 Additional examples of amine deallylation can be found in Scheme 2.162 and Scheme 11.87.

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Organic Synthesis Using Transition Metals

+

PhBr, Pd(OAc) 2, Ph P(o-tol)3

HN

9.258

9.259

Ph

N

+ 9.260

Ph

9.261

N

9.261 nucleophilic attack

Ph

N H

9.259

PhBr oxidative addition

L2Pd

L2Pd Br

HBr

9.262 dissociation

PdLBr Ph

L LnPdHBr

9.266

Ph

Ph

β-hydride elimination

η1 → η3

Br

9.260

LBrPd Ph

L

9.265

9.263

LPd

Ph

Br Pd

coordination

9.258

insertion 9.264

Scheme 9.73

9.2.9

Other Routes to ␩3 - or ␲-Allyl Palladium Complexes

These highly useful complexes can be generated in other ways. For instance, they can be formed by a modiﬁcation of the Heck reaction. Insertion of dienes into vinyl or aryl–palladium(II) bonds generates ␲-allyl complexes. These can be trapped by external nucleophiles, but the product of ␤-hydride elimination will also be obtained (Scheme 9.73). After insertion of one double bond of the diene 9.258 into the carbon–palladium bond of the ␩1 -intermediate 9.262, ␤-hydride elimination may occur to give the expected Heck product 9.260. However, the ␩1 -intermediate 9.265 is in equilibrium with its ␩3 -equivalent 9.266 and, if an appropriate nucleophile is present, this complex may be trapped to give the allylated product 9.261. Intramolecular trapping is more efﬁcient. This has been used, for instance, to prepare dihydroindoles 9.269 (Scheme 9.74).

I

Pd(OAc)2, PPh3, Et3N

+

N H

NH2 9.267

9.268

9.269

Scheme 9.74

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η3 - or π -Allyl Complexes

n-Bu + 9.270

Br

+

NH

9.271

Pd(OAc)2, L n-Bu

9.259

+

9.272

N

N

n-Bu 9.273

n-Bu

9.273

9.271

Br

LnPd(0)

nucleophilic attack 9.259

353

oxidative additon

NH

9.274 PdLnBr n-Bu 9.270 coordination and insertion

n-Bu 9.279

PdLnBr η1 → η 3

n-Bu 9.272 β-hydride elimination

dissociation PdLnBr

9.275

n-Bu n-Bu PdL Br n 9.278 re-insertion into Pd-H bond

H PdLnBr

β-hydride elimination

n-Bu 9.276

Scheme 9.75

Even simple alkenes, such as 1-hexene 9.270, can yield ␲-allyl complexes on reaction with vinyl halides under Heck conditions (Scheme 9.75). This is only apparent when a nucleophile is present, such as a secondary amine98 or a malonate anion.99 The ␲-allyl complex 9.279 is generated by isomerization of the corresponding ␩1 -complex 9.278 that is itself generated by a ␤-hydride elimination–reinsertion sequence from the initial insertion product 9.275. Nucleophilic attack on the ␲-allyl complex gives the three component coupling product 9.273, while the Heck product, diene 9.272, can arise from dissociation from ␩2 -complex 9.276 or ␤-hydride elimination from the ␩1 -intermediate 9.278. Again, the reaction is particularly effective in an intramolecular sense.100 A powerful piece of methodology has been developed involving nucleophilic attack on both an ␩2 and an 3 ␩ -complex in an adaptation of the Wacker reaction.101 Treatment of cyclohexadiene 9.268 with palladium acetate in acetic acid gives an ␩2 -complex 9.281 (Scheme 9.76). If the reaction is done in the presence of sodium acetate, this salt will act as a nucleophile to give an ␩3 -complex 9.283 via an initial ␩1 -complex 9.282. Reductive elimination to form a bond between a ring carbon and the acetate ligand from palladium then gives the diacetate product 9.280. As the ﬁrst acetate attacks trans to Pd, and the second acetate comes from Pd, the product is the trans isomer. The palladium is now in its zero oxidation state, but inclusion of benzoquinone reoxidizes it to palladium (II) and makes the entire process catalytic. There is an occasional

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Organic Synthesis Using Transition Metals OAc Pd(OAc)2, LiOAc, BQ 9.268

OAc

re-oxidation (benzoquinone)

Pd(OAc)2

9.280

co-ordination

OAc

9.281 Pd(0)

9.280 OAc reductive elimination

(AcO)2Pd AcO nucleophilic attack trans to Pd

(AcO)Pd (AcO)Pd 9.283

9.282

OAc

OAc

η1

→

η3

Scheme 9.76

technical problem associated with the use of benzoquinone: as the starting materials are 1,3-dienes, by products from the Diels–Alder reaction with benzoquinone may be isolated. An intramolecular nucleophile, such as an alcohol, may also be used in place of the ﬁrst acetate (Scheme 9.77). Treatment of the dienyl alcohol 9.284 with palladium acetate gives the ␩3 -allyl complex 9.285 by intramolecular nucleophilic attack, which gives the trans-acetate 9.287 by reductive elimination. In the presence of a small amount of lithium chloride, however, ligand exchange at palladium occurs. Now, the ␩3 -palladium complex 9.286 does not have an acetate available for intramolecular transfer. Instead,

OH no LiCl Pd(OAc)2 9.284

O

AcO

O PdX 9.285 X = OAc

reductive elimination with OAc

9.287

0.2 eq LiCl

O

AcO

trans attack by AcO

2 eq LiCl

9.286 X = Cl

9.288

O

Cl 9.289

Scheme 9.77

trans attack by Cl

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Cl Pd(OAc)2, LiCl, BQ

355

CO2Me MeO2C Pd(OAc)2, PPh3

AcO 9.268

9.290 CO2Me

1. Pd(0) CO2Me 2. NaCN, DMSO, Δ 9.291

AcO

1. DIBAL 2. PhthNH, DEAD, PPh3 3. H2NNH2 4. CbzCl, NaHCO3

CO2Me 9.292

NHCbz 9.293

Cl

H

Pd(OAc)2, LiCl, BQ H

H

N 9.294 Cbz

O O

MgBr 9.295

H

N Cbz

Li2CuCl4

9.296

O O 1. H2, PtO2 2. POCl3 3. LiAlH4 H

1. POCl3 2. H2, PtO2 3. LiAlH4 H

H

H N

N

H

H

O

O O

9.297

O

9.298

Scheme 9.78

intermolecular nucleophilic attack by acetate occurs, to give the cis acetate 9.288. If a large excess of lithium chloride is used, then chloride acts as the nucleophile to give the cis chloride 9.289.102 Nitrogen nucleophiles, including amides, carbamates and sulfonamides, have also been used.103 The reaction has been used to synthesize both ␣-lycorane 9.297 and ␥ -lycorane 9.298 by cyclization of a carbamate 9.293 in the presence of excess lithium chloride (Scheme 9.78).104 The starting material was 1,3-cyclohexadiene 9.268. Two palladium-catalysed reactions gave the cis acetoxy-malonate 9.291. In the second step – allylic substitution – chloride is more reactive than acetate. Elimination of acetate with a palladium(0) catalyst, followed by straightforward transformations, including Krapcho decarboxylation, gave the carbamate substrate 9.293. This was cyclized to the cis-chloride 9.294 using palladium(II) acetate and excess lithium chloride. The chloride was then displaced in an SN ’ fashion by a copper reagent, formed in situ from Grignard reagent 9.295, with inversion of stereochemistry. The last ring of lycorane was closed by a Bischler–Napieralski reaction. If the alkene 9.296 was reduced before Bischler-Napieralski ring closure, the

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Organic Synthesis Using Transition Metals

MeO

Li +

O

1. EtO2COCl, py 2. (Ph3P)4Pd

MeO

N

N

9.299

HO

9.300

9.301 Cl

Pd(OAc)2, BQ, LiCl, LiOAc

MeO

1. NaNHTs, (Ph 3P)4Pd 2. K2CO3, MeOH

MeO N

N

OAc

9.303

9.302 TsHN

TsHN

1. H2, PtO2 2. SOCl2

MeO

K2CO3, MeOH

MeO

N

N 9.304

OH Ts N

MeO

Cl

9.305 H N

Cl N

N

9.307

9.306

Scheme 9.79

product could be subsequently reduced to ␣-lycorane 9.297. Surprisingly, if the Bischler–Napieralski reactions was done ﬁrst, then the diastereoisomer, ␥ -lycorane 9.298, was formed. Another synthesis of ␥ -lycorane can be found in Scheme 2.87. Epibatidine 9.307, an analgesic more than 200 times more potent than morphine, isolated from a South American frog, has been synthesized using this chemistry (Scheme 9.79).105 The diene starting material was prepared by addition of a pyridyl lithium reagent 9.299 to cyclohexenone 9.300, followed by elimination of water using ␩3 -allyl palladium chemistry. The palladium-catalysed addition of acetate and chloride to diene 9.302 proceeded with the expected high stereoselectivity giving the cis-isomer 9.303. In addition, the reaction was regioselective, consistent with the ﬁrst nucleophilic attack, by acetate, being on the ␩2 -complex of palladium with the less substituted of the two alkenes. A third use of palladium catalysis was to convert the more reactive chloride to a sulfonamide with retention of stereochemistry. A more classical substitution with inversion was then employed to convert the acetate, via its reduced free alcohol, to a chloride 9.305, with the trans stereochemistry for cyclization. Cyclization proceeded to give the bicyclic structure 9.306 whose conversion to the natural product was already known. Another synthesis of epibatidine 9.307 can be found in Scheme 5.52. Allenes are also valuable precursors for ␩3 -allyl palladium complexes (Scheme 9.80). Inclusion of carbon monoxide allows a three-component coupling to give an unsaturated ketone (Scheme 9.81).

Ph PhI, Pd(PPh3)4, K2CO3

HO2C

•

O 2C

9.308

O 9 .3 0 9

Scheme 9.80

PdL2I

O 9 .310

Ph

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η3 - or π -Allyl Complexes

TsHN

•

PhI, Pd(PPh3)4, K2CO3, CO

357

O N Ts

9.311

Ph 9.312

Scheme 9.81 Ph 9.313

PhZnCl, (Ph3P)4Pd

Ph •

X

Ph

9.314

Scheme 9.82 (EtO)2P

O

Ph

BF3K (Ph3P)4Pd, NaHCO3

Ph

9.315

• 9.316

Scheme 9.83 CO2Me

Pd(OAc)2, PPh3, CO

•

OCO2Me 9. 31 7

9 .3 1 8

Scheme 9.84

9.3 Propargyl Compounds Although superﬁcially similar, propargyl compounds do not form ␩3 -complex intermediates, but give ␩1 allenic complexes.106 As part of a catalytic cycle, these can undergo typical reactions, such as coupling (Schemes 9.82 and 9.83),107,108 reduction by formate, alkene insertion and carbonylation (Scheme 9.84).

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

McClennan, W. R.; Hoehn, H. H. et al. J. Am. Chem. Soc. 1961, 83, 1601. Heck, R. F. J. Am. Chem. Soc. 1963, 85, 3383. Zhou, T.; Green, J.R. Tetrahedron Lett. 1993, 34, 4497. (a) Hegedus, L. S.; Inoue, Y. J. Am. Chem. Soc. 1982, 104, 4917; (b) Hegedus, L. S.; Perry, R. J. J. Org. Chem. 1984, 49, 2570. Bates, R. W.; Rama-Devi, T.; Ko, H.-H. Tetrahedron 1995, 51, 12939. (a) Enders, D.; Jandeleit, B.; von Berg, S. Synlett. 1997, 421; Enders, D.; von Berg, S.; Jandeleit, B. Org. Synth. 2001, 78, 189. Enders, D.; Franck U. et al, J. Organomet. Chem. 1996, 519, 147. Enders, D.; Jandeleit B. et al, Angew. Chem., Int. Ed. Engl. 1994, 33, 1949. (a) Enders, D.; Finkam, M. Synlett, 1993, 401; (b) Enders, D.; Finkam, M. Liebig’s Ann. Chem. 1993, 551. Enders, D.; von Berg, S.; Jandeleit, B. Synlett 1996, 18. Le Brazidec, J.-Y.; Kocienski, P. J. et al. J. Chem. Soc., Perkin Trans. I 1998, 2475.

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12. Enders, D.; Jandeleit, B.; Prokopenko, O. F. Tetrahedron Lett. 1995, 51, 6273. 13. Enders, D.; Jandeleit, B. Synthesis 1994, 1327. 14. (a) Enders, D.; Jandeleit, B. Liebig’s Ann. 1995, 1173; (b) Enders, D.; Jandeleit, B.; Prokopenko, O. F. Tetrahedron 1995, 51, 6273. 15. Koot, W.-J.; Hiemstra H. et al, J. Chem. Soc., Chem. Commun. 1993, 156. 16. Trost, B. M. Acc. Chem. Res. 1980, 13, 385. For application to cyclizations, see Hyland, C. Tetrahedron 2005, 61, 3457. 17. (a) Tamura, R.; Kai, Y. et al. J. Org. Chem. 1986, 51, 4375; (b) Ono, N.; Hamamoto, I.; Kaji, A. Synthesis 1985, 950. 18. Ziegler, F. E.; Cain, W. T. et al. J. Am. Chem. Soc. 1998, 110, 5442. 19. Katritzky, A. R.; Yao, J.; Yang, B. J. Org. Chem. 1999, 64, 6066. 20. For examples, see Schemes 9.49 and 9.51. 21. (a) Atkins, K. E.; Walker, W. E.; Manyik, R. M. Tetrahedron Lett. 1970, 43, 3821; (b) Yang, S.-C.; hung, C.-W. J. Org. Chem. 1999, 64, 5000; (c) Ohshima, T.; Miyamoto, Y. et al. J. Am. Chem. Soc. 2009, 131, 14317. 22. Trost, B. M.; Curran, D. P. J. Am. Chem. Soc. 1980, 102, 5699. 23. Trost, B. M. Tetrahedron 1977, 33, 2615. 24. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730. 25. Williams, D. R.; Meyer, K. G. Org. Lett. 1999, 1, 1303. 26. Del Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990, 55, 3019. 27. Godschalx, J.; Stille, J.K. Tetrahedron Lett. 1980, 21, 2599. 28. Doucet, H.; Brown, J. M. Bull. Soc. Chim. Fr. 1997, 134, 995. 29. Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471. 30. Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51, 723. 31. (a) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1983, 105, 3343; (b) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1987, 109, 1469. 32. Trost, B. M.; Merlic, C. A. J. Am. Chem. Soc. 1990, 112, 9590. 33. Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647. 34. Trost, B. M.; Klun, T. P. J. Am. Chem. Soc. 1979, 101, 6756. 35. Trost, B. M.; Angew. Chem., Int. Ed. Engl. 1989, 28, 1173. 36. F¨urstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817. 37. Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem. 1980, 45, 5193. 38. Hoffmann, H. M. R.; Otte, A. R. et al, Angew. Chem., Int. Ed. Engl. 1995, 34, 100. 39. (a) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A. Angew. Chem., Int. Ed. Engl. 1992, 31, 234; (b) Wilde, A. Otte, A. R.; Hoffmann, H. M. R. J. Chem. Soc., Chem. Commun. 1993, 615; (c) Otte, A. R.; Wilde A. et al., Angew. Chem., Int. Ed. Engl. 1994, 33, 1280. 40. Casta˜no, A. M.; Aranyos A. et al, Angew. Chem., Int. Ed. Engl. 1995, 34, 2551. 41. (a) Ephritikhine, M.; Francis B. R. et al, J. Chem. Soc., Dalton Trans. 1977, 1131; (b) Tjaden, E. B.; Stryker, J. M. J. Am. Chem. Soc. 1990, 112, 6420. 42. Ohe, K.; Matsuda H. et al, J. Am. Chem. Soc. 1994, 116, 4125. 43. Heumann, A.; R´eglier, M. Tetrahedron 1995, 51, 975. 44. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730. 45. Del Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990, 55, 3019. 46. (a) Brescia, M.-R.; DeShong, P. J. Org. Chem. 1998, 63, 3156; (b) Correira, R.; DeShong, P. J. Org. Chem. 2001, 66, 7159. 47. Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384. 48. Matsushita, H.; Negishi, E.-i. J. Chem. Soc., Chem. Commun. 1982, 160. 49. Shkla, K. H.; Boehmier, D. J. et al. Org. Lett. 2006, 8, 4183. 50. Dvor´ak, D.; Stary, I.; Ko˘covsk´y, P. J. Am. Chem. Soc. 1995, 117, 6130. 51. Farthing, C. N.; Ko˘covsk´y, P. J. Am. Chem. Soc. 1998, 120, 6661. 52. Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747. 53. von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566.

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η3 - or π -Allyl Complexes 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98.

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Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037. Helmchen, G.; Dahnz, A. et al. Chem. Commun. 2007, 675. Kiener, C. A.; Shu, C. et al. J. Am. Chem. Soc. 2003, 125, 14272. Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43, 4595. Dahnz, A.; Helmchen, G. Synlett 2006, 697. G¨artner, M.; Mader, S. et al. J. Am. Chem. Soc. 2011, 133, 2072. Welter, C.; Dahnz, A. et al. Org. Lett. 2005, 7, 1239. Welter, C.; Moreno, R. M. et al. Org. Biomol. Chem. 2005, 3, 3266. G¨artner, M.; Weihofen, R.; Helmchen, G. Chem. Eur. J. 2011, 17, 7605. Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264. Jin, Z. Fuchs, P. L. Tetrahedron Lett. 1996, 37, 5253. (a) Jin, Z.; Fuchs, P. L. Tetrahedron Lett. 1996, 37, 5249; (b) Jin, Z.; Fuchs, P. L. Tetrahedron Lett. 1993, 34, 5205; (c) Lee, S. W.; Fuchs, P. L. Tetrahedron Lett. 1993, 34, 5209. Campiani, G.; Sun, L.-Q.; Kozikowski, A. P. et al. J. Org. Chem. 1993, 58, 7660. Trost, B. M.; Schmuff, N. R.; Miller, M. J. J. Am. Chem. Soc. 1980, 102, 5979. Tsuji, J.; Shimizu I. et al, J. Org. Chem. 1985, 56, 1523. (a) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969; (b) Takahashi, T.; Miyazawa M. et al., Tetrahedron Lett. 1986, 27, 3881. Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115, 9293. Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792. (a) Trost, B. M.; Runge, T. A.; Jungheim, L. M. J. Am. Chem. Soc. 1980, 102, 2840; (b) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103, 7550. Watson, S. P.; Knox, G. R.; Heron, N. M. Tetrahedron Lett. 1994, 35, 9763. Shimizu, I.; Ishikawa, T. Tetrahedron Lett. 1994, 35, 1905. (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199; (b) Tsuda, T.; Chujo, Y. et al. J. Am. Chem. Soc. 1980, 102, 6381. There is evidence in some cases that allylation may precede decarboxylation; see ref. 77. Weaver, J. D.; Recio III, A. et al. Chem. Rev. 2011, 111, 1846. Tsuji, J.; Yamada, T. et al. J. Org. Chem. 1987, 52, 2988. Tsuda, T.; Chujo, Y. et al. J. Am. Chem. Soc. 1980, 102, 6381. Imao, D.; Itoi, A. et al. J. Org. Chem. 2007, 72, 1652. Weaver, J. D.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002. (a) Weaver, J. D.; Tunge, J. A. Org. Lett. 2008, 10, 4657; (b) Weaver, J. D.; Ka, B. J. et al. J. Am. Chem. Soc. 2010, 132, 12179. Rayabarapu, D. K.; Tunge, J. K. J. Am. Chem. Soc. 2005, 127, 13510. DeLorbe, J. E.; Lotz, M. D.; Martin, S. F. Org. Lett. 2010, 12, 1576. Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307. Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. Mohr, J. T.; Behenna, D. C. et al. Angew. Chem., Int, Ed. 2005, 44, 6924. He, H.; Zheng, X.-J. et al. Org. Lett. 2007, 9, 4339. Enquist, Jr., J. A.; Stoltz, B. M. Nature 2008, 453, 1228. (a) Guib´e, F. Tetrahedron 1998, 54, 2967; (b) Protective Groups in Organic Synthesis, Wuts, P. G. M.; Greene, T. W. Wiley, Hoboken, 2007. Jungheim, L. N. Tetrahedron Lett. 1989, 30, 1889. Deziel, R. Tetrahedron Lett. 1987, 28, 4371. Kunz, H.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1984, 23, 71. Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. Engl. 1984, 23, 436. Jeffrey, P. D.; McCombie, S. W. J. Org. Chem. 1982, 47, 587. Bates, R. W.; Dewey, M. R. Org. Lett. 2009, 11, 3706. Harrington, P. J.; Brown, J. D. et al. Org. Process Res. Dev. 2004, 8, 86. Patel, B. A.; Heck, R. F. J. Org. Chem. 1978, 43, 3898.

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99. Nylund, C. S.; Klopp, J. M.; Weinreb, S.M. Tetrahedron Lett. 1994, 35, 4287. 100. Larock, R. C.; Yang H. et al. Tetrahedron Lett. 1998, 39, 237. 101. (a) Nystr¨om, J.-E.; Nordberg, R. E. J. Am. Chem. Soc. 1985, 107, 3676; (b) B¨ackvall, J.-E. Pure Appl. Chem. 1999, 71, 1065. 102. (a) B¨ackvall, J.-E.; Nystrom, J.-E.; Nordberg, R. E. J. Am. Chem. Soc. 1985, 107, 3676; (b) B¨ackvall, J.-E.; Andersson, P. G. J. Am. Chem. Soc. 1992, 114, 6374; (c) B¨ackvall, J.-E.; Andersson, P. G. J. Org. Chem. 1991, 56, 2274. 103. B¨ackvall, J.-E.; Andersson, P. G. J. Am. Chem. Soc. 1990, 112, 3683. 104. B¨ackvall, J.-E.; Andersson, P. G. et al. J. Org. Chem. 1991, 56, 2988. 105. Palmgren, A.; Larsson, A. L. E.; B¨ackvall, J.-E. J. Org. Chem. 1999, 64, 836. 106. Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589. 107. (a) Elsevier, C. J.; Stehouwer P. M. et al. J. Org. Chem. 1983, 48, 1103; (b) Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149. 108. Molander, G. A.; Sommers, E. M.; Baker, S. R. J. Org. Chem. 2006, 71, 1563.

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10 Diene, Dienyl and Arene Complexes 10.1 ␩4 -Diene Complexes The best-known ␩4 -diene complexes are those of iron.1 They can be prepared by treatment of dienes with either Fe(CO)5 or Fe2 (CO)9 (Scheme 10.1).2 The complexation reaction can be promoted in various ways, including ultrasonically.3 If non-conjugated dienes are used, one alkene may migrate to give the ␩4 -complex. This is particularly useful for the synthesis of some cyclic complexes, as non-conjugated dienes are products of Birch reduction. Decomplexation may be achieved by oxidation. Trimethylamine-N-oxide and cerium(IV) are commonly used reagents for this. Complexes of electron-poor dienes may be photochemically decomplexed in the presence of acetic acid (Scheme 10.2). This proceeds with partial reduction.4 In cases where the diene is unstable, a dihalo starting material may be used with the iron carbonyl acting as a reducing agent. Both the trimethylene methane complex 10.5 (Scheme 10.3)5 and the cyclobutadiene complex 10.7 (Scheme 10.4)6 have been made in this way. The cyclobutadiene–iron complex 10.7 is a convenient storable form of this highly unstable diene. It can be liberated by oxidation and, if this is done in the presence of a dienophile, the Diels–Alder product is obtained. The Diels–Alder reaction with 2,5-dibromobenzoquinone gave the expected endo-product 10.8. An intramolecular photochemical [2+2] cycloaddition, followed by a Favorskii reaction, gave a cubane dicarboxylic acid 10.10.7 Interestingly, the cyclobutadiene, when liberated from the complex can act as either the diene or the dienophile in a Diels–Alder reaction, sometimes as both (Scheme 10.5).8 The iron–carbonyl complexes can be viewed as a protected form of the diene, as the complexes do not undergo typical diene or alkene reactions. Complexation to iron–tricarbonyl fragments has been used in dendralene chemistry in this way.9 When the [3]dendralene 10.14 was complexed to iron tricarbonyl, employing a cinnamaldehyde imine as a catalyst, the two complexed alkenes lost typical alkene reactivity, while the uncomplexed alkene retained it (Scheme 10.6). Cyclopropanation, dihydroxylation and crossmetathesis of the uncomplexed alkene proceeded as expected. The monocomplexed [4]dendralene 10.19 underwent Diels–Alder reactions at the uncomplexed alkenes (Scheme 10.7).9 Tropones are another class of trienes that can be treated in this way. Both Michael additions and Diels–Alder reactions of the ␩4 -tropone complex 10.21 occur exclusively at the uncomplexed alkene (Scheme 10.8).10 Addition in all cases was opposite the bulky Fe(CO)3 moiety.

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals

Fe(CO) 5 or Fe2(CO)9

Fe(CO) 3

10.1

Scheme 10.1 O

O

(OC)3Fe

Ph h ν, AcOH

Ph 10.3

10.2

Scheme 10.2 Fe(CO) 5 or Fe2(CO)9

Cl

Fe(CO) 3

Cl 10.5

10.4

Scheme 10.3 Br

Cl

Cl 10.6 hν

O

Fe(CO)5 or Fe2(CO)9

O

Fe(CO)3 Br Ce(NH4)2(NO3)6

Br O

O Br

10.7 O

O

Br

Br

10.8 KOH

HO2C CO2H

Favorskii reaction 10.9

10.10

Scheme 10.4 H Fe(CO)3

O

H

Ce(NH4)2(NO3)6 O

O

O 10.12 as a diene

10.11

Scheme 10.5

+

O

O 10.13 as a dienophile

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(OC)3Fe Et2Zn, CH2I2

Fe2(CO)9, Ph

ArN

(OC)3Fe

10.14

10.16

OsO4

10.15

Ce(NH4)2(NO3)6

OH

(OC)3Fe

OH

10.17 CO2Me (OC)3Fe

HGII

CO2Me

10.18

Scheme 10.6 O + (OC)3Fe 10 .19

O

NMe

(OC)3Fe

O

NMe 1 0. 20

O

Scheme 10.7 O

H OSiMe3

O

OSiMe3

(OC)3Fe

H 10.22 O

(OC)3Fe 10.21

CO2Et CO2Et

CO2Et (OC)3Fe

CO2Et 10.23

Scheme 10.8

Treatment of the ␩4 -tropone 10.21 complex with a diazo compound resulted in cyclopropanation of the uncomplexed alkene (Scheme 10.9). Decomplexation by mild oxidation gave the free diene 10.25;11 decomplexation photochemically gave the non-conjugated alkene 10.26.12 The alkene 10.26 could be converted to the sesquiterpene cyclocolorenone 10.30 by isomerization of the alkene into conjugation, conversion to a silyl enol ether 10.27 by cuprate addition, and reaction of the silyl enol ether with a cobalt-stabilized propargyl cation (see Section 7.2). The alkyne was decomplexed and subjected to hydration to give a ketone 10.29. The hydration proved to be regioselective, possibly because of neighbouring-group participation by the existing ketone, and permitted a subsequent intramolecular aldol reaction to give the natural product 10.30.

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Organic Synthesis Using Transition Metals O Me3N O

O

O 1.

N2

10.25 O

2. Δ (OC)3Fe

(OC)3Fe 10.21

10.24

h ν, AcOH

10.26 OSiMe3

1. NaOH 2. Me2CuLi; Me3SiCl

O

(OC)6Co2

(OC)6Co2

10.27

O

10.28

O 1. Ce(NH4)2(NO3)6 2. Hg2+, H3O+

KOH, EtOH

H

O 10.29

10.30

Scheme 10.9

AlBr3, CO Fe(CO) 3

Fe(CO) 3 10.31

O

10.32

H 10. 33

O

Scheme 10.10

Diene complexes can also be decomplexed by treatment with strong Lewis acids (Scheme 10.10). CO insertion occurs, leading to formation of a cyclopentenone 10.33.13 This reaction is, formally, a cycloaddition of carbon monoxide with a diene, followed by migration of the resulting alkene into conjugation. The iron complexes show two-fold reactivity. They react with both strong electrophiles and with strong nucleophiles as the iron can stabilize both the cationic and anionic intermediates. While the electron-withdrawing iron moiety activates the diene to nucleophilic attack, it deactivates it towards electrophilic attack. Electrophilic attack is still useful – the iron stabilizes the diene to all the side reactions that could go along with electrophilic attack, and stabilizes the cationic product. 10.1.1

Electrophilic Attack

A seemingly simple example of electrophilic attack is shown by Friedel–Crafts acylation of the parent butadiene complex 10.34 (Scheme 10.11).14 Two products, 10.37 and 10.38, can be obtained with the acetyl

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O Fe(CO)3

10.34

CH3COCl AlCl3 acylation on iron

CH3

(OC)3Fe

(OC)3Fe migration

CH3

10.36 H

10.35

Fe(CO)3 -H

O

Fe(CO)3 O

+

O

CH3

CH3 10.37 endo

10.38 exo

isomerisation

Scheme 10.11 Fe(CO) 2L CH3COCl AlCl3

(OC)2LFe Ha

10.1 L = CO 10.41 L = PPh3

COCH3

- Ha

(OC)2LFe

COCH3

Hb 10.39

10.40

Scheme 10.12

group endo or exo. Under the right work-up conditions, and with enough time, the more-stable exo-product 10.38 becomes the exclusive product. Stereochemical and other studies have shown that acylation occurs on iron, as this is where the HOMO is located. The acetyl group subsequently migrates to carbon and the products are obtained via loss of a proton from an unstable ␩3 -intermediate 10.36. This has an interesting consequence with the ␩4 -cyclohexadienyl complex 10.1 (Scheme 10.12). As acylation is initially on iron, the iron and the acetyl group are cis in the ␩3 -intermediate 10.39. The proton that is lost must be cis to iron (perhaps via transfer to iron in a reverse of the acylation sequence). The more acidic proton, Hb , ␣- to the newly installed acetyl group is trans to iron and, therefore, not available. The proton lost, therefore, is Ha on the other side resulting in net movement of the diene system to give diene complex 10.40. Better yields are obtained with the more electron rich monotriphenylphosphine complex 10.41 (L = PPh3 ), than the tricarbonyl complex (L = CO).15 In the cycloheptatriene complex 10.43, one of the three double bonds is uncomplexed. This double bond is more reactive towards electrophiles (Scheme 10.13). Thus, acylation of the complex gives the Friedel–Crafts product as an ␩5 -dienyl complex 10.44 that can be converted to the ␩4 -diene complex 10.45 by addition-elimination of methoxide.16 Intramolecular molecular acylation of iron complexes is also possible (Scheme 10.14).17 Another example of electrophilic chemistry is provided by the myrcene complex 10.48 (Scheme 10.15). The iron tricarbonyl complex 10.48 undergoes cyclization via a carbocation 10.49 on acid treatment.18 The 16e ␲-allyl complex 10.50 produced may then lose a proton (in a way similar to benzene in electrophilic cyclization) to give a ␩4 -diene complex 10.51 or gain an additional ligand, CO if supplied, to give a stable 18e ␲-allyl complex 10.52.

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Organic Synthesis Using Transition Metals (OC)3Fe

(OC)3Fe CH3CO BF4

Fe(CO) 5, hν

10.42

10.43

10.44 O

(OC)3Fe

CH3

1. MeO 2. silica 10.45 O

CH3

Scheme 10.13

Fe(CO) 3

Fe(CO) 3

AlCl3

COCl

O 10.47

10.46

Scheme 10.14

Fe(CO) 3 18e

-H+ Fe(CO) 3

Fe(CO) 3

Fe(CO)3

10.51

H+ 16e 10.48

10.49

Fe(CO)4

+ CO

10.50

18e

10.52

Scheme 10.15

10.1.2

Nucleophilic Attack

The iron diene complexes may also be attacked by strong nucleophiles, such as the anion of acetonitrile (Scheme 10.16).19 The kinetic position of attack on the cyclohexenyl complex 10.1 is at C2 giving an ␩1 , ␩2 complex 10.53. If the products are exposed to CO at low temperature, CO insertion occurs. The intermediate 10.54 formed in this way is clearly similar to those formed by alkylation-CO insertion reactions of Collman’s reagent (Section 4.5.1). Addition of an alkylating agent such as methyl iodide causes alkylation of iron, which is followed by reductive elimination. The cyanomethyl group and the acetyl group of the product 10.56 are trans because the original nucleophilic attack was trans to iron, while alkylation was on iron. On the other hand, if the kinetic addition product is allowed to warm up, the thermodynamic ␩3 -allyl complex 10.57 is obtained. An acidic quench then gives a mixture of alkenes, 10.58 and 10.59.

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367

CH3CN n-BuLi or LDA CO

CN

CH2CN, -78 °C

CN O

Fe(CO)3

(OC)3Fe

(OC)3Fe

10.1

10.53

10.54 Me

RT

I CN

CN

CN

CN

H+

O (OC)3Fe

10.59

Fe(CO)3 10.57

10.58

Me

10.55 O

CN 10.56

Scheme 10.16

The ability of the iron tricarbonyl group to both protect and activate a diene can be exploited.20 Treatment of the ␩4 -tropone complex 10.21 with an organozinc reagent resulted in Michael addition to the uncomplexed alkene; after manipulation of the carbonyl group, generation of the enolate 10.62 resulted in intramolecular nucleophilic attack onto the diene complex giving interesting bicyclic structures after CO insertion (Scheme 10.17). The stereochemical role of the Fe(CO)3 moiety is apparent throughout this scheme. Both O

O M

(OC)3Fe 10.21

CO2Et

M = Cu(CN)ZnI (OC)3Fe

CO2Et 10.60

TBSO 1. NaBH4 2. TBSOTf, 2,6-lutidine

LDA CO2Et

(OC)3Fe 10.61 TBSO 1. CO 2. H+ (OC)3Fe

CO2Et 10.62

Scheme 10.17

OHC TBSO CO2Et 10.63

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Organic Synthesis Using Transition Metals

O

CO2Et

H+

Fe(CO) 3

Fe(CO)3

10.65

OEt

10. 5

10.64

CO2Et

Br

CO2Et 10.66

Scheme 10.18

NC

Cp

Cu ZnI

NPhth 1. NaBH , AcOH 4 2. TsCl, Na 2CO3

NPhth

Mo(CO)2

Cp

Mo(CO)2 10.68

10.67

H NHTs

Cp

Mo(CO)2 10.69

NHTs

NO+ BF4-

Mo(CO)(NO) Cp 10.70

Et3N N H Ts 10.71

Scheme 10.19

attack of the carbon nucleophile on 10.21 and delivery of hydride to ketone 10.60 from sodium borohydride occur trans to the iron for steric reasons. Trimethylene methane complexes are also susceptible to nucleophilic attack.21 Powerful nucleophiles attack at a methylene carbon to give anionic ␩3 -allyl complexes 10.64, which may be protonated or alkylated (Scheme 10.18). There are diene complexes of other metals that are also electrophilic. The cationic molybdenum complex 10.67 reacts with an organocopper reagent to give the product 10.68 of C1 attack (Scheme 10.19).22 Removal of the phthaloyl group and tosylation gives the sulfonamide 10.69. The ␩3 -allyl molybdenum complex is not sufﬁciently electrophilic to undergo a second nucleophilic attack. If, however, one of the CO ligands is replaced with a nitrosyl ligand so that the complex becomes cationic, the second attack does occur. The product is the cis isomer 10.71: both nucleophilic attacks occur trans to the metal. This molybdenum chemistry has been employed in heterocyclic systems. An enantiomerically pure ␩4 -diene molybdenum complex 10.77 was prepared from arabinose 10.72 (Scheme 10.20),23 a sugar that is unusual in that it is naturally available in both enantiomeric forms. The anomeric hydroxy group was exchanged for a methoxy group and the triol was differentiated by formation of a cyclic ortho-ester 10.73. This reaction is selective for the pair of hydroxy groups with the cis-relationship. Thermolysis (200 ◦ C) of the cyclic ortho-ester 10.73 gave the alkene 10.74, which could then be converted into the allylic bromide 10.75, the starting material for the organometallic chemistry. Treatment of bromide 10.75 with a reactive molybdenum(0) complex 10.76, generated by the reaction between molybdenum hexacarbonyl and acetonitrile, gave a ␩3 allyl complex 10.77 that was converted to the desired Cp derivative 10.78 by treatment with cyclopentadienyl

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369

OEt OH HO

O OH 1. MeOH, HCl 2. HC(OEt) 3, H+

O

HO

O

HO

HO Δ

MeO O 10.73

10.72

PPh3, CBr4, Bu4NBr

MeO

Mo(NCMe)2(CO)2Br

Br

(MeCN)3Mo(CO)3 10.76

MeO

MeO

O

(OC)2CpMo

MoCp(CO)2

Li

O 10.77

10.75

MeMgI

HBF4 MeO

O 10.74

low yield

O 10.78

O 10.79

MoCp(CO)2

MeOH TsOH

HBF4 MeO

O 10.80

O

MoCp(CO)2

MoCp(CO)2 OMe

Ph3C PF6 Me

O

H

Me

10.81

10.82

MoCp(CO)2

Me

1. KOH, MeOH 2. CF 3CO2H

H2, PtO2 Me

O 10.83

O

CO2Me

O 10.84

Me CO2H

O 10.85

CO2H

Scheme 10.20

lithium. Treatment of the new ␩3 -allyl complex 10.78 with HBF4 gave only a low yield of the desired ␩4 diene complex 10.79. This is because the leaving group is cis to the metal and the elimination of methanol is steroelectronically difﬁcult. A good yield was obtained by treatment of 10.78 with methanolic tosic acid to epimerize the anomeric centre. Treatment of epimer 10.80 with HBF4 then gave a good yield of the desired diene complex 10.79. These diene complexes react with a wide range of nucleophiles including Grignard reagents, malonate anions, enolates and acetylides. Treatment of the complex 10.79 with methyl magnesium iodide gave an ␩3 -allyl complex 10.81 with addition of the methyl group trans to the molybdenum. Attack was exclusively ␣-to oxygen. One approach to using the complex for a second time is to regenerate the ␩4 -diene complex by hydride abstraction. In principle, there are three hydrides available, but two of them are cis to the molybdenum, so the abstraction is selective for the third hydride. Addition of a nucleophile, in this

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Organic Synthesis Using Transition Metals CO2Me CO2Me

CO2Me (OC)3Co

(OC)3Co

10.86

CO2Me

10.87

CO2Me CO2Me

MeO2C

CO2Me

MeO2C

CO2Me 10.88

Scheme 10.21

case the enolate of methyl acetate, was again stereoselective, giving ester 10.83. Saponiﬁcation of the ester and decomplexation with acid gave the dihydropyran 10.84 as a mixture of alkene isomers. Reduction of the double bond then gave the cis-tetrahydropyran 10.85. This compound is a natural product, isolated from the scent glade of the civet cat, civetta viverra. As cations, cobalt tricarbonyl diene complexes 10.86 are also more electrophilic than the iron tricarbonyl complexes (Scheme 10.21). The product of nucleophilic attack is a ␩3 -allyl cobalt complex 10.87, which is still electrophilic and may undergo a second attack.24

10.1.3

Deprotonation

Complexation of a diene to a metal fragment may also affect the allylic protons, by increasing their acidity, and stabilizing the resulting anions (Scheme 10.22).25 Surprisingly, the anions are unstable and rearrange to the corresponding trimethylenemethane anions 10.91, although the diene form can be stabilized by transmetallation onto zinc. This rearrangement is opposite to that experienced by the equivalent cations (see Scheme 10.34). The anions can be quenched with various electrophiles. The alcohol 10.94 is ipsdienol, a bark beetle pheromone.

OH Li LDA, THF, -78 °C Fe(CO)3 10.89

O Fe(CO)3

Fe(CO)3

10.90

10.93

-30 °C

H2O2 OH

H+ Li Fe(CO)3 10.92

Fe(CO)3 10.91

Scheme 10.22

10.94

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371

H4a

1.06

H1

H3’

C2’

H2’

0.72

C3’

C4 1.01

1.588(11)

1.511(13)

H4b

C1

1.415(12)

C2

1.588011 1.05

H2

Mn

C3 1.01 H3

1.780001

C6’ C5 1.16309

O2

1.797181

O1

C6 1.1521101

O2

Figure 10.1 A η5 -dienyl manganese complex. Reprinted with permission from Churchill, M. R.; Scholer, F. R. c 1969 American Chemical Society. Inorg. Chem. 1969, 8, 1950.

10.2 ␩5 -Dienyl Complexes One route to ␩5 -dienyl complexes is by hydride abstraction from readily available ␩4 -diene complexes using a hydride acceptor, such as the trityl cation (Scheme 10.23).26 For an additional example involving a cobalt diene complex, see Scheme 11.23. Hydride abstraction is most easily done using cyclic complexes, which have the required Z-geometry. Acyclic complexes can be made in this way, but the Z-geometry is less easily obtained. ␩5 -Dienyl complexes are also available by loss of a leaving group from suitably substituted ␩4 -diene complexes. This is done by treatment of ethers or alcohols with acid, in a way that is analogous to the formation of ␩3 -allyl complexes from ␩2 -alkene complexes (Scheme 10.24; compare to Scheme 9.1).

Fe(CO) 3

Fe(CO) 3

+ Ph3CH 10.1 H

10.95 Ph3C

Scheme 10.23

OH 10.96

Fe(CO)4PPh3 hν

OH HBF4 Fe(CO)2PPh3 10.97

Scheme 10.24

Fe(CO)2PPh3 10.98

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Organic Synthesis Using Transition Metals SO2Ph 10.99

BnO

Fe2(CO)9 then separate Fe(CO)3 SO2Ph Fe(CO)3

BnO

SO2Ph BnO

10.100a

10.100b HBF4

HBF4 SO2Ph

(OC)3Fe

SO2Ph

(OC)3Fe 10.101a

10.101b

Scheme 10.25

As with the ␩3 -allyl complexes (Scheme 9.8), optically active ␩5 -complexes can be prepared in this way (Scheme 10.25). While the initial formation of the ␩4 -complex 10.100a,b may not be stereoselective, after separation each may be converted to the corresponding ␩5 -complex 10.101a,b.27 The diene complexes may also be prepared by resolution.28 10.2.1

Nucleophilic Attack

As cations, the ␩5 -complexes are more electrophilic than the corresponding ␩4 -diene complexes and react with a wide range of nucleophiles (Scheme 10.26), in a manner similar to the ␩3 -allyl complexes (Section 9.1).29 Alkoxides, aliphatic amines,30 aromatic amines,31 phthalimide,32 stabilized enolates,33 NHPh

O (OC)3Fe

(OC)3Fe

PhNH2

O O

10.102

O SiMe3

10.105

(OC)3Fe

(OC)3Fe 10.95 O

10.103 O

Me3SiO

NPhth

OSiMe3 N

(OC)3Fe

(OC)3Fe O

10.106

Scheme 10.26

10.104

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Diene, Dienyl and Arene Complexes MgBr

373

Ph3P(OC)2Fe

Ph3P(OC)2Fe 10.108

10.107

Scheme 10.27

malonates, organozinc reagents,34 electron-rich aromatics (including heterocycles)35 and silicon reagents36 are all competent nucleophiles. As with the ␩4 -complexes, the addition of the nucleophile occurs trans to iron; in each case, the product is a ␩4 -complex. With reactive organometallic nucleophiles such as Grignard reagents, the corresponding monotriphenylphosphine complexes 10.107 often give better results (Scheme 10.27).37 Regioselectivity is difﬁcult to explain and to predict, but attack is often at the terminus furthest from the substituent.38 The methoxy group appears to be particularly effective in directing the nucleophile. For instance, a Reformatsky reagent attacks complex 10.110 (prepared from anisole by Birch reduction, complexation and hydride abstraction) selectively para to the methoxy group, leading to the ␥ -substituted cyclohexenone 10.113, after hydrolysis of the intermediate enol ether 10.112 (Scheme 10.28).39 Nucleophilic addition of a primary amine to the dienyl complex 10.114 proceeded regioselectively with initial attack para to the methoxy group, despite the additional substituent at that position. Cyclization in situ gave a spiro-substituted complex 10.116 that was converted to enone 10.117 on decomplexation and hydrolysis (Scheme 10.29).40 Nucleophilic attack by bicarbonate onto a dienyl complex 10.118 with an ester substituent also proceeded regioselectively. Starting from the resolved complex, methyl shikimate 10.122 could be prepared in optically active form using this reaction (Scheme 10.30).41 Protection of the alcohol and decomplexation gave the free diene 10.121, which underwent selective dihydroxylation trans to the TBS ether. Desilylation gave the natural product ester 10.122. The ␩5 -complex may also function as the electron-withdrawing group in a Michael sense, activating a conjugated, but not complexed, alkene (Scheme 10.31).42 In this case, alkene migration occurred during oxidative decomplexation to rearomatize the ring. MeO

MeO

Fe(CO)5 or Fe2(CO)9

Na, NH3

MeO

Fe(CO)3

Ph3C+

10.109 MeO

MeO

Fe(CO)3 BrZn

Fe(CO)3 Ce(NH4)2(NO3)6

CO2Et

10.110

10.111 EtO2C MeO

O H3O

EtO2C

10.112

+

EtO2C

Scheme 10.28

10.113

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Organic Synthesis Using Transition Metals MeO

MeO Fe(CO) 3

O

MeO Fe(CO) 3

Fe(CO) 3

BnNH2 NHBn

OTs 1 0.1 14

1. Me 3NO 2. H 3O+ NBn

NBn

OTs 10.115

1 0.11 6

10.117

Scheme 10.29 MeO2C

Fe(CO) 3

MeO2C Ph3

C+

MeO2C

Fe(CO)3

aq. KHCO 3

Fe(CO) 3

HO 10.118

10.119

10.120

MeO2C

1. TBSCl, i-Pr2NEt 2. Me 3NO

MeO2C 1. OsO 4 2. TBAF

TBSO

HO

OH OH

10.121

10.122

Scheme 10.30 MeO

Fe(CO) 3 1. M

MeO NHBoc

CO2Bn 2. Me 3NO 10.123

M = IZn(CN)Cu

NHBoc 10.124

CO2Bn

Scheme 10.31

The product of nucleophilic attack is an ␩4 -complex. This may be oxidatively decomplexed to give the free ligand or, to gain better value from the metal, reoxidized to a new ␩5 -complex. This can then be subjected to a second nucleophilic attack. This strategy has been used, for instance, to generate nitrogen heterocycles by combining a C-nucleophile and an N-nucleophile (Scheme 10.32). Initial C-addition of anion 10.125 to complex 10.95 gave the ␩4 -complex 10.126. Various oxidants can be used to regenerate the ␩5 -complex; in this case the ferrocinium ion was chosen, giving ␩5 -complex 10.128 after removal of the only available proton trans to iron.43 Nucleophilic attack by nitrogen then gave the tricyclic product 10.129. Use of excess oxidant leads to decomplexation and aromatization of the product. In the case of electronrich aromatic products, oxidation can go further to quinone-like compounds. This has been used in the synthesis of carbazole natural products (Scheme 10.33).44 The substituted aniline 10.130 underwent electrophilic substitution by the iron complex 10.95. Regioselective oxidation to give a new ␩5 -complex 10.312 allowed a second nucleophilic attack to generate the carbazole skeleton 10.133 in situ. Further oxidation resulted in decomplexation, aromatization of the ring to give carbazole 10.134 and some formation of iminoquinone 10.135.

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Diene, Dienyl and Arene Complexes (OC)3Fe (OC)3Fe

10.95

N MeO2C 10.125

N MeO2C

10.126

(OC)3Fe HN

tautomerise

Cp2Fe+ PF6-

CO2Me H 10.127 (OC)3Fe

H

(OC)3Fe

N

HN H

CO2Me 10.128

CO2Me

10.129

Scheme 10.32

(OC)3Fe (OC)3Fe

10.95

OMe CH3CN, Δ H2N

OMe H H2N

Me Ph 10.130

Me Ph 10.131

(OC)3Fe

(OC)3Fe Cp2Fe+ PF6-

OMe OMe H2N

N H

Me

Ph 10.132 Cp2Fe+ PF6-

OMe N H

Me Ph 10.133

O

+

Me

N

Me

Ph

Ph

10.134

10.135

Scheme 10.33

375

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Organic Synthesis Using Transition Metals

X

Fe(CO) 3 X = OAc: BF 3.OEt2 X = OH: H+

Fe(CO) 3

10.136

10.137 SiMe3

MeOH

Fe(CO) 3

(OC)3Fe

10.138

OMe

10.139

Scheme 10.34

Ph

Ph PhLi

O2 O

Fe(CO) 2PPh3

Fe(CO) 2PPh3

10.140

10.141

10.142

Scheme 10.35

H NaBH4 Fe(CO)3 10.143

H +

Fe(CO)3 10.144

2:1 Fe(CO)3 10.145

Scheme 10.36

Parallel chemistry is observed with the trimethylene methane complexes 10.136 (Scheme 10.34).45 In this case, however, the cationic ␩5 -complex 10.137, although observable by NMR at low temperature,46 cannot be isolated. It could be trapped with nucleophiles, but different nucleophiles gave different types of product. Allyltrimethylsilane gave a new trimethylene methane complex 10.138,47 while methanol yielded an ␩4 -diene complex 10.139. The different structural types produced, trimethylene methane versus diene complex, are likely to be due to kinetic and thermodynamic control as addition of methanol would be expected to be reversible under acidic conditions. With ␩5 -complexes of different skeletons, nucleophilic attack is not always at the terminal carbon (Scheme 10.35). The identity of both the ligands and the nucleophile also affects this selectivity (Scheme 10.36). The products can undergo oxidatively induced CO insertion and reductive elimination to give interesting products.48 In other cases, CO insertion has to be forced using high pressure (Scheme 10.37). Oxidatively induced reductive elimination has also been observed leading to cis-1,2-divinyl cyclopropanes 10.152 that undergo a facile [3,3]-sigmatropic shift, especially after ester reduction, to cycloheptadienes 10.154 (Scheme 10.38).49

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Diene, Dienyl and Arene Complexes

377

Ph CO (200 atm), Δ

PhLi Fe(CO)2L

Fe(CO)2P(OPh)3 10.146

10.147

Ph

isomerisation

Ph

O

O 10.149

10.148

Scheme 10.37

Ce(NH4)2(NO3)6

MgBr MeO2C

MeO2C

Fe(CO) 3 10.150

Fe(CO) 3 10.151

LiAlH4

< RT

CO2Me 10.152

OH 10.153

OH 10.154

Scheme 10.38

10.3 ␩6 -Arene Complexes A wide range of metals form ␩6 -arene complexes, but the best-known complexes are with chromium tricarbonyl. Complexes of iron, manganese50 and ruthenium51 have also been used. These complexes have the Cr(CO)3 moiety or other metallic fragment above the ␲-system of the aromatic ring (Figures 10.2 and 10.3), thereby making the two faces distinct. This can be exploited for stereochemical control purposes. The Cr(CO)3 complexes are usually made by heating the arene with chromium hexacarbonyl in a highboiling solvent (Scheme 10.39). This procedure can be complicated by the tendency of chromium hexacarbonyl to sublime out of the reaction mixture and into the condenser. This problem can be overcome by the use of a special Strohmeier condenser,52 or by the judicious choice of solvent.53 Complexes such as the cationic Mn(CO)3 complex 10.158 can be made in a slightly different way from the Cr(CO)3 complexes.54 A Lewis acid is used to remove bromide from the complex Mn(CO)5 Br to generate a coordinatively unsaturated manganese carbonyl that can react with the arene. Decomplexation is usually by oxidation, often by addition of a mild oxidant such as iodine, or sometimes by air, but can also be by heating in the presence of a good donor ligand, such as acetonitrile.

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Organic Synthesis Using Transition Metals C16 C6

C11 C2

C1

C6

C15

C12 C3

C4 C14

C13

Cr

C8 O8

Cl

Cl Cl Cl

C7

Cl Cl Cr(CO)3

O7

C9

10.155

O9

Figure 10.2 An arene-chromium tricarbonyl complex. Reprinted with permission from Gassman, P. G and C 1994 Deck, P. A. Tricarbonyl(η6 -hexachlorobenzene)chromium(0). Organometallics 1994, 13(5), 1934–1939. American Chemical Society. C4 C5

C2

O11

O3

C3

O7

H

O5

C1

O10 O6

N

O1 O9

H

Mn(CO)3 10.156

O3

Figure 10.3 An indole manganese tricarbonyl complex. Reprinted from Inorganica Chimica Acta, 211, Ryan, W. J.; Peterson, P. E. et al., “Synthesis and Reactivity of (indole)Mn(CO)3 complexes. Electrophilic Activation of c (1993), with permission from Elsevier. the indole 4 and 7 positions, Inorganica Chimica Acta, 211, 1, 1–3.

Coordination to the metal has a number of profound effects on the arene (Figure 10.4):55 the ring becomes electrophilic and subject to nucleophilic attack,56 the acidity of the ring protons increases and the acidity of any benzylic protons also increases. In addition, the formation of benzylic cations is facilitated, as the metal can stabilize them. Finally, the metal provides huge steric bulk on one face of the arene. Complexes of heteroarenes are also known. ␩5 -Pyrrole complexes 10.159 can be prepared, especially using mild conditions (Scheme 10.40). If more forcing conditions are employed, complexation of a benzene ring is preferred.57 The complexes are quite labile and will transfer their chromium unit to another arene readily.58 Mn(CO)5Br AlCl3 or AgBF4

Cr(CO)6, Δ R

R

I2

R

R

Cr(CO)3

Mn(CO)3 MeCN, Δ

10.157

Mn(CO)3(NCMe)3

Scheme 10.39

10.158

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Diene, Dienyl and Arene Complexes stabilisation of carbocations, carbanions and radicals

379

activated to nucleophilic attack

R H

H

Cr(CO)3

shielding by the bulk of the metal fragment

increased acidity

Figure 10.4 Cr(CO)3 N

(MeCN)3Cr(CO)3 50 °C

10.159

N Cr(CO)6 160 °C

N Cr(CO)3 10.160

Scheme 10.40

The thiophene complex 10.161 can be prepared and displays some expected electrophilic reactivity (Scheme 10.41).59 Complexes of pyridine are more difﬁcult to prepare because formation of a ␴-complex using the Nlone pair is strongly favoured. The ␩6 -complex 10.166 of pyridine itself can only be prepared indirectly (Scheme 10.42). The ␩6 -complex of 2,6-bis(trimethylsilyl)pyridine 10.165 or 2-(t-butyldimethylsilyl)pyridine can be prepared, and then desilylated.60 The bulky silyl groups prevent ␴-coordination to nitrogen. Mn(CO)3 NC

KCN Mn(CO)3

Mn(CO)5OTf S

S

S 10.162

TfO

10.161

1. NaBH 4 2. HCl 3. MeCN

+ (MeCN)2Mn(CO)3Cl S 10.163

Scheme 10.41 Cr(CO)3

Cr(CO)6 Δ Me3Si

N 10.164

SiMe3

Cr(CO)3 TBAF

Me3Si

N 10.165

Scheme 10.42

SiMe3

N 10.166

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Organic Synthesis Using Transition Metals Table 10.1 Electrophilicity of Arene Complexes

Fe

2+

Fragment Fe(C6 H6 )+ Ru(C6 H6 )+ Mn(CO)3 + Mn(CO)2 PPh3 + FeCp+ Cr(CO)3

10.3.1

Mn(CO)3

Mn(CO)2PPh3

Fe

Cr(CO)3

Relative electrophilicity of the arene complex 200 × 106 6 × 106 11 000 160 1 “small”

Nucleophilic Attack

The Cr(CO)3 is strongly electron withdrawing. Other metal units can also be electron withdrawing. In particular, cationic units are even more electron withdrawing and this can have advantages in synthesis. The relative reactivity of these complexes with different metal fragments has been quantiﬁed (Table 10.1), based upon kinetic data,61 although a number could not be assigned to the most widely used, but less-reactive, chromium tricarbonyl fragment. A straightforward application of the electrophilicity of the complexes is in nucleophilic aromatic substitution. Chlorobenzene does not react with nucleophiles itself, but p-nitrochlorobenzene 10.167 does, giving the substitution product 10.169 via the intermediate Meissenheimer complex 10.168 (Scheme 10.43). The nitro group acts as a reservoir for the incoming electrons. The Cr(CO)3 moiety fulﬁlls the same role, allowing nucleophilic substitution on the aromatic ring by acting as a reservoir for the incoming electrons in an addition–elimination reaction involving an anionic ␩5 -intermediate 10.171 (Scheme 10.44). Coincidentally, p-nitrochlorobenzene 10.167 and the chlorobenzene–chromium tricarbonyl complex 10.170 undergo nucleophilic substitution at a similar rate.62 Weaker nucleophiles fail to attack the Cr(CO)3 complexes. For instance, phenoxide does not participate in this reaction, but the products, diaryl ethers, would be valuable as this functionality is found in a number of antibiotic natural products (for another approach to diaryl ethers, see Section 2.12.2). A solution to this problem is to switch to one of the more electron-withdrawing metal units,63 such as Mn(CO)3 + (Scheme 10.45),64 FeCp+ (Scheme 10.46)65 or RuCp+ (Scheme 10.47).66 The anions of ␤-diketones, which are also only modestly nucleophilic, can be used to attack cationic ruthenium complexes (Scheme 10.48).67 Studies using powerful nucleophiles (so that addition is faster than elimination) at low temperature have shown that the mechanism is not so simple.68 Kinetic attack is meta to the substituent giving an anionic ␩5 -complex 10.183 (Scheme 10.49). At low temperatures the addition product 10.183 can be intercepted. Mild oxidation gives the free, functionalized arene 10.184. If the addition product 10.183 is allowed to warm up, addition reverses and ultimately addition is at the ipso position, followed by elimination to give the substitution product 10.186 via ␩5 -complex 10.185. A logical extension is that complexed rings without any leaving group are also attacked by strong nucleophiles (Scheme 10.50).69 Addition to a ␩6 -arene complex 10.187 gave the anionic ␩5 -product 10.188 that could be oxidized to give the free arene 10.189 or protonated to give diene 10.191. The intermediate 10.188

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Diene, Dienyl and Arene Complexes OMe

Cl O

O

N O

OMe

Cl

MeO

- Cl O2N

N O

10.167

10.169

10.168 Meissenheimer complex

Scheme 10.43

OMe

MeO Cl

- Cl

OMe

Cl

Cr(CO)3

Cr(CO)3

Cr(CO)3 η6 10.170

η5 10.171

10.172

Scheme 10.44 OMe

Me MeO

Me

O

Cl

MeO

OMe O

(OC)3Mn

(OC)3Mn t -BocHN 10.173

CO2Me

CO2Me

t -BocHN

10.174

10.175

Scheme 10.45

Cl

O

O

Br

+ OMe

CpFe

Br

10.176

CpFe

10.177

OMe 10.1 78

Scheme 10.46

Cl

OH

RuCp

H N

t-BocHN O

10.179

O N H

CO2Me

1. t-Bu

O

O

2. hν , CH3CN

t-Bu H N

t-BocHN O

Ph

10.180

Scheme 10.47

O N H Ph

CO2Me

381

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Organic Synthesis Using Transition Metals O Cl

O

CpRu

O

t-Bu

t-Bu

O

O

10.181

10.182 CpRu

Scheme 10.48

could also be intercepted by alkylating agents. Alkylation of the chromium is followed by CO insertion leading to a dearomatized product 10.194 after reductive elimination. As the initial alkylation occurs trans to the metal and alkylation is on the metal, the product has trans stereochemistry. A similar stereochemical outcome was observed using ␩4 -diene complexes (see Scheme 10.16) The nucleophilic attack–electrophilic trapping sequence has been applied to the synthesis of the cytotoxic acetoxytubipofuran 10.201, isolated from a Japanese coral. A valine-derived chiral auxiliary was employed to deliver the sensitive lithium ethoxyalkene nucleophile with control of both the regiochemistry – ortho – and the stereochemistry (Scheme 10.51).70 A chiral bidentate ligand for the lithium atom was also able to exert control over the absolute stereochemistry, although a little less effectively. The trans stereochemistry was then lost on enolate alkylation to install a methyl group. The second ring could be formed by an aldol reaction in tandem with hydrolysis of enol ether 10.197. After stereoselective reduction of the ketone, the carbon atoms required for the third ring could be installed by a Johnson–Claisen reaction. Iodocyclization, followed by a series of functional group interconversions then gave the natural product 10.201 with its furan moiety. Nucleophilic attack may also be intramolecular and can be used to make a variety of bicyclic, including spiro, systems (Scheme 10.52).71 Treatment of the chromium complex 10.202, which has a nitrile on the side chain, with LDA gave an anion 10.203 that cyclizes to give the ␩5 -intermediate 10.204. Protonation gave a mixture of enol ether isomers, 10.205 and 10.206, which yielded the same enone 10.207 on acidic hydrolysis. Double functionalization with dearomatization can also be achieved by a double nucleophilic attack. This requires that the ␩5 -intermediate is reactivated by a ligand substitution in a similar way to methods for diene complexes (Scheme 10.19). For the ␩6 -complex 10.208, addition of a Grignard reagent gave a ␩5 -complex 10.209 that could be reactivated by substitution of a CO ligand by NO+ (Scheme 10.53).72 The second cationic CN CN

Cl

Cl -78 °C (OC)3Cr 10.170

RT

Cl (OC)3Cr

(OC)3Cr

η5 10.183

CN

η5

10.185 - Cl

I2, -78 °C CN

Cl 10.184

Scheme 10.49

CN (OC)3Cr

10.186

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Diene, Dienyl and Arene Complexes

S

S S Li

S

S Br

S

η5

η5

(OC)3Cr

(OC)3Cr

(OC)3Cr

10.187

10.188

10.192 CO insertion

H+

I2

S

S S

S

S

S η5

10.189

(OC)3Cr

(OC)3Cr

H

10.190

10.193

O reductive elimination

reductive elimination

S

S O

S

S

10.191

10.194

Scheme 10.50 i-Pr

i-Pr

OMe

Li

OMe N H

N OEt

O H

1. MeI, CO 2. NaOEt, MeI

OEt

OEt (OC)3Cr

(OC)3Cr

10.195 OPMB H

1. H3O+ 2. NaBH4, CeCl3 3. PMBI, NaH

Me O 10.197

10.196 NMe2

MeO OMe

OPMB H

NMe2 O

Me OH 10.198

1. I2, KI, NaHCO3 2. n-Bu3SnH 3. LDA, PhSeCl; H2O2

Me 10.199 OPMB H O O

1. DDQ 2. DIBAL 3. AcOH 4. Ac 2O, py

Me H 10.200

Scheme 10.51

OAc H O Me 1 0 .2 01

383

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Organic Synthesis Using Transition Metals

MeO

MeO

LDA

CN

CN Cr(CO)3

Cr(CO)3 10.202

10.203 OMe

OMe

NC

CN

CN

H+

MeO Cr(CO)3

10.205

10.204

10.206

O CN 10.207

Scheme 10.52 Me

MeMgX Mn(CO)3

Mn(CO)3 10.209

10.208

NO+ PF6Me

O

Mn(CO)2NO

O

1. P(OPh) 3 2. O O

10.210 OEt

OEt O

O

CO2Et Me

CO2Et Me

Mn(CO)(NO)P(OPh)3

Mn(CO)2NO

10.212

10.211

FeCl 3 or Me3NO CO2Et

O Me 10.213

Scheme 10.53

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Diene, Dienyl and Arene Complexes

Br CO2Me Br NaH, DMF Cr(CO)3

385

CO2Me Cr(CO)3

10.214

10.215

Scheme 10.54

CO2Me Cr(CO)3 trans-10.216

Bn CO2Me

NaH, BnBr, DMF

Cr(CO)3 10.217

NaH, BnBr, DMF

CO2Me Cr(CO)3 cis-10.216

Scheme 10.55

complex 10.210 could then be attacked by a second nucleophile, even a modest nucleophile such as the anion of a ␤-ketoester or a malonate. An improved yield of addition could be obtained by a second ligand change, from a carbonyl to a phosphorus ligand. This appears to reduce by-product formation from direct attack on the CO ligands. The metal-free product 10.213 were be obtained by mild oxidation. As both nucleophilic attacks were trans to the metal, the two substituents are cis to each other, in contrast to the nucleophile/electrophile sequence with Cr(CO)3 (see Scheme 10.50).

10.3.2

Deprotonation

A simple demonstration of the ability of the Cr(CO)3 unit to stabilize a negative charge in the benzylic position is in the alkylation behaviour of methyl phenylacetate (Scheme 10.54).73 Treatment of the uncomplexed ester with sodium hydride and 1,3-dibromopropane gave no product as the benzylic protons are not sufﬁciently acidic to be removed. Under the same conditions, the Cr(CO)3 complex 10.214 gave the expected cyclobutane 10.215. In addition, the stereochemistry of alkylation is controlled by the Cr(CO)3 group. For the indane complexes, cis- and trans-10.216, alkylation occurred exclusively trans to the metal, regardless of the original stereochemistry of the ester (Scheme 10.55), both giving the same isomer 10.217 of the product, via a common enolate.74 An extreme example of benzylic alkylation is provided by the hexamethyl benzene complex 10.218 with the more strongly electron-withdrawing FeCp+ unit (Scheme 10.56). Hexa-allylation can be achieved, albeit slowly, using a base as mild as KOH, giving a product 10.219 described as a “tentacled sandwich”.75 Even more prolonged reaction times result in formation of the dodeca-allylation product 10.220. The Cr(CO)3 unit also activates the ring protons towards removal. Ring deprotonation can be made easier and be directed if a substituent with lone pairs is present on the ring. A lone pair can coordinate to the lithium of the incoming base and direct deprotonation to the ortho position. In many cases this reaction – ortho-metallation – is already possible without metal complexation, but complexation makes it easier. Not all substituents show this behavior equally.76 A ﬂuorine substituent is particularly effective, even more effective than a methoxy substituent in a competition experiment (Scheme 10.57),77 while, amongst ethers, the methoxymethoxy substituent proved best.78

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Organic Synthesis Using Transition Metals Br KOH, Δ 3 days, 40-60 °C

Fe

Fe

10.218

10.219

Br KOH, Δ 10 days, 40 °C

Fe

10.220

Scheme 10.56 Li F

SiMe3 F

F Me3SiCl

n-BuLi MeO

MeO

Cr(CO)3

MeO

Cr(CO)3 10.222

10.221

Cr(CO)3 10.223

Scheme 10.57

O F Cr(CO)3 10.224

n-BuLi

O O F

F Li

O Cr(CO)3

Cr(CO)3 10.225

10.226 O

(CO)3Cr

O

10.227

Scheme 10.58

When a halogen atom is employed to direct ortho-metallation, the Cr(CO)3 unit then allows substitution to follow, provided that an appropriate electrophile is employed (Scheme 10.58).79 In the case of butyrolactone, ring opening by the lithium reagent 10.225 releases an alkoxide that counterattacks onto the arene, leading to formation of lactone 10.227. A sophisticated use of deprotonation chemistry is in a synthesis of dihydroxycalamenene 10.234 (Scheme 10.59).80 Two methyl groups and an iso-propyl group had to be introduced regioselectively. First, a

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Diene, Dienyl and Arene Complexes OMe OMe

H

1. n-BuLi 2. Me 3SiCl

OMe 1. n-BuLi 2. MeI

OMe

H Cr(CO)3

SiMe3 Cr(CO)3

10.228 Me

387

10.229 Me

OMe

Me

OMe

1. n-BuLi 2. i-PrI

OMe

OMe

OMe

TBAF

SiMe3 Cr(CO)3

SiMe3 Cr(CO)3 H 10.230

H Cr(CO)3

10.231 Me

10.232

OMe

Me OMe

1. n-BuLi 2. MeI

OMe

OH

1. I 2 2. BBr 3

OH

Me Cr(CO)3

Me

10.233

10.234

Scheme 10.59

silyl group was employed to block the most easily deprotonated position that is activated by the neighbouring methoxy group. Sequential deprotonations and alkylations brought in one methyl group and the iso-propyl group. The benzylic position near to the methoxy group of 10.229 is the more easily deprotonated, placing the methyl group in the right position. The second benzylic deprotonation, involving 10.230, is then in the second benzylic position, placing the iso-propyl group as desired. It should be noted that both alkylations occur trans to the metal and, therefore, cis to each other, giving the desired stereochemical outcome. The remaining aryl proton, present in 10.231, is unchanged as it is not near to an oxygen atom, and it is crowded by the neighbouring silyl group. Desilylation and the third deprotonation-alkylation left only oxidative removal of the chromium from complex 19.233 and deprotection to complete the synthesis.

10.4 ␩2 -Arene Complexes In ␩2 -complexes, only two carbons of the arene are bonded to the metal, the remaining ring atoms being uncomplexed. This has a profound affect on the chemistry.81 Reduction of an osmium(III) complex in the presence of an arene results in the formation of a ␩2 -complex of osmium(II) 10.235 (Scheme 10.60). The arene may be benzenoid, naphthalene or heterocyclic. Pyridines can be used, but only if the nitrogen lone

Os(NH3)5(OTf) 3

C6H6, Mg

2+

(H3N)5Os

10.235

Scheme 10.60

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Organic Synthesis Using Transition Metals OH Os(NH3)5(OTf) 3

C6H5OH, Mg

2+

(H3N)5Os

10.236

Scheme 10.61 OH

O py

2+

2+

(H3N)5Os

O

(H3N)5Os 10.236

10.237

O

OH

2+

i-Pr2NEt

(H3N)5Os

OH

2+

Δ

(H3N)5Os

O

O

10.238

10.239

O 10.240

Scheme 10.62

pair is prevented from coordination to osmium by either the presence of steric hindrance, or by protonation. A remarkable number of substituents can be present, including carbonyl groups and ethers. The exception is an alkene, which will preferentially coordinate the osmium. If the arene is substituted, the osmium will complex so that the remaining double bonds and the substituent maintain the greatest degree of conjugation. Thus, phenol is coordinated at C2–C3, leaving the remaining double bonds and the hydroxyl group as a dienol 10.236 (Scheme 10.61). The subsequent chemistry of these complexes is not directly the chemistry of the osmium complex, but the chemistry of the remaining portion of the arene, which behaves as if dearomatized. Treatment of the phenol complex 10.236 with pyridine and a Michael acceptor yields the 4-alkylated dienone complex 10.238 (Scheme 10.62).82 The ring may be rearomatized on treatment with an amine base (stronger than pyridine) and decomplexed by heating. For less-acidic complexes, such as those of aniline,83 and for nonacidic complexes, such as those of anisole and furan, acidic or Lewis-acidic conditions may be used to promote Michael addition (Scheme 10.63). The intermediates may be rearomatized or trapped with an added nucleophile.

OMe

Ph

Ph 2+

(H3N)5Os

O 10.241

OMe BF3.OEt2

2+

(H3N)5Os

MeOH O

10.242

Scheme 10.63

Ph

OMe 2+

(H3N)5Os

O 10.243

OMe OMe

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389

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

(a) Gree, R. Synthesis 1989, 341; (b) Pearson, A. J. TransitionMetal Chem. 1981, 6, 67. Kn¨olker, H.-J. Chem. Rev. 2000, 100, 2941. Ley, S. V.; Low, C. M. R.; White, A. D. J. Organometal. Chem. 1986, 302, C13. Frank-Neumann, M.; Martina, D. et al. Angew. Chem., Int. Ed. Engl. 1978, 17, 690. Emerson, G. F.; Ehrlich, K. et al. J. Am. Chem. Soc. 1966, 88, 3172. Emerson,, G. F.; Watts, L.; Pettit, R. J. Am. Chem. Soc. 1965, 87, 131. Barborak, J. C.; Watts, L.; Pettit, R. J. Am. Chem. Soc. 1966, 88, 1328. Limanto, J.; Khuong, K. S. et al. J. Am. Chem. Soc. 2003, 125, 16310. Toombs-Ruane, H.; Osinski, N. et al. Chem., Asian J. 2011, 6, 3243. Rigby, J. H.; Ogbu, C. O. Tetrahedron Lett. 1990, 31, 3385. Frank-Neumann, M.; Martina, D. Tetrahedron Lett. 1975, 1759. Saha, M.; Bagby, B.; Nicholas, K. M. Tetrahedron Lett. 1986, 27, 915. (a) Frank-Neumann, M.; Michelotti, E. L. et al. Tetrahedron Lett. 1992, 33, 7361; (b) Frank-Neumann, M.; Vernier, J. M. Tetrahedron Lett. 1992, 33, 7365. Greaves, E. O.; Knox, G. R. et al. J. Chem. Soc., Chem. Commun. 1974, 257. Birch, A. J.; Raverty, W. D. et al. J. Organomet. Chem. 1984, 260, C59. Johnson, B. F. G.; Lewis, J.; Randall, G. L. P. J. Chem. Soc., Dalton Trans. 1972, 456. Frank-Neumann, M.; Gross, L. M.; Nass, O. Tetrahedron Lett. 1996, 37, 8763. Pearson, A. J. Aust. J. Chem. 1976, 29, 1841. Semmelhack, M. F.; Herndon, J. W. et al. J. Am. Chem. Soc. 1983, 105, 2497. Yeh, M.-C. P.; Hwu, C.-C. Organometallics 1994, 13, 1788. Donaldson, W. A.; Hossain, M. A.; Cushnie, C. D. J. Org. Chem. 1995, 60, 1611. Yeh, M.-C. P.; Chang, C.-N. J. Chem. Soc., Perkin Trans. I 1996, 2167. Hansson, S.; Miller, J. F.; Liebeskind, L. S. J. Am. Chem. Soc. 1990, 112, 9660. Barinelli, L. S.; Tao, K.; Nicholas, K. M. Organometallics 1986, 5, 588. Semmelhack, M. F.; Fewkes, E. J. Tetrahedron Lett. 1987, 28, 1497. Fischer, E. O.; Fischer, R. D. Angew. Chem. 1960, 72, 919. Enders, D.; Jandeleit, B.; von Berg, S. J. Organomet. Chem. 1997, 533, 219. Tao, C.; Donaldson, W. A. J. Org. Chem. 1993, 58, 2135. Pearson, A. J. Acc. Chem. Res. 1980, 13, 463. Birch, A. J.; Cross, B. E. et al. J. Chem. Soc. (A) 1968, 332. Birch, A. J.; Liepa, A. J.; Stephenson, G. R. J. Chem. Soc. Perkin Trans. I 1973, 1882. Sar, A.; Lindeman, S.; Donaldson, W. A. Synthesis 2011, 924. Birch, A. J.; Chamberlain, M. A. et al. J. Chem. Soc. Perkin Trans. I 1982, 713. Birch, A. J.; Pearson, A. J. Tetrahedron Lett. 1975, 16, 2379. Kane-Maguire, L. A. P.; Mansﬁeld, C. A. J. Chem. Soc., Chem. Commun. 1973, 540. Birch, A. J.; Kelly, L. F.; Narula, A. S. Tetrahedron 1982, 34, 1813. Pearson, A. J.; Yoon, J. Tetrahedron Lett. 1985, 26, 2399. Pearson, A. J. Acc. Chem. Res. 1980, 13, 463. Pearson, A. J.; Richards, I. C. Tetrahedron Lett. 1983, 24, 2465. Pearson, A. J.; Ham, P.; Rees, D. C. J. Chem. Soc. Perkin Trans. I 1982, 489. Birch, A. J.; Kelly, L. F.; Weerasuria, D. V. J. Org. Chem. 1988, 53, 278. Dunn, M. J.; Jackson, R. F. W.; Stephenson, G. R. Synlett 1992, 905. Kn¨olker, H.-J.; El-Ahl, A.-A. et al. Synlett 1994, 194. (a) Kn¨olker, H.-J.; Baum, E.; Hopfmann, T. Tetrahedron Lett. 1995, 36, 5339; (b) Kn¨olker, H.-J.; Baum, E.; Hopfmann, T. Tetrahedron 1999, 55, 10391; (c) Kn¨olker, H.-J. Chem. Soc. Rev. 1999, 28, 151. Donosh, P. A.; Lillya, C. P. et al. Inorg. Chem. 1980, 19, 228. Bonazza, B. R.; Lillya, C. P. et al. J. Am. Chem. Soc. 1979, 101, 4100. Donaldson, W. A.; Hossain, M. A.; Cushnie, C. D. J. Org. Chem. 1995, 60, 1611.

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48. (a) McDaniel, K. F.; Kracker II, L. R. et al. Tetrahedron Lett. 1990, 31, 2373; (b) Hirschfelder, A.; Eilbracht, P. Synthesis 1994, 1375. 49. Wallock, N. J.; Donaldson, W. A. Org. Lett. 2005, 7, 2047. 50. Sun, S.; Dullaghna, C. A.; Sweigart, D. A. J. Chem. Soc., Dalton Trans. 1996, 4493. 51. Pigge, F. C.; Coniglio, J. J. Curr. Org. Chem. 2001, 5, 757. 52. Strohmeier, W. Chem. Ber. 1961, 94, 2490. 53. Mahaffy, C. A. L.; Pauson, P. L. Inorg. Synth. 1979, 19, 154. 54. Pauson, P. L.; Segal, J. A. J. Chem. Soc., Dalton Trans. 1975, 1677. 55. Pike, R. D.; Sweigert, D. A. Coord. Chem. Rev. 1999, 187, 183. 56. Kane-Maguire, L. A. P.; Honig, E. D.; Sweigart, D. A. Chem. Rev. 1984, 84, 525. ¨ 57. Ofele, K.; Dotzauer, E. J. Organomet. Chem. 1971, 30, 211. 58. Goti, A.; Semmelhack, M. F. J. Organomet. Chem. 1994, 470, C4. 59. Lesch, D. A.; Richardson, J. W. et al. J. Am. Chem. Soc. 1984, 106, 2901. 60. Davies, S. G.; Shipton, M. R. J. Chem. Soc., Perkin Trans. I 1991, 501. 61. Pike, R. D.; Sweigart, D. A. Coord. Chem. Rev. 1999, 187, 183. 62. Nicholls, B.; Whiting, M. C. J. Chem. Soc. 1959, 551. 63. Pike, R. D.; Sweigart, D. A. Synlett, 1990, 565. 64. Pearson, A. J.; Shin, H. Tetrahedron 1992, 48, 7527. For other nucleophiles, see (a) Rose-Munch, F.; Aniss, K. Tetrahedron Lett. 1990, 31, 6351; (b) Pearson, A. J.; Zhu, P. Y. et al. J. Am. Chem. Soc. 1993, 115, 10376; (c) Miles, W. H.; Brinkman Tetrahedron Lett. 1992, 33, 589. 65. Holden, M. S.; Petrich, S. R. Tetrahedron Lett. 1999, 40, 4285; (b) see also Nilsson, J. P., Andersson, C.-M. Tetrahedron Lett. 1997, 38, 4635; (c) iron–arene complexes have been reviewed: Astruc, D. Tetrahedron 1983, 39, 4027. 66. Janetka, J. W.; Rich, D. H. J. Am. Chem. Soc. 1995, 117, 10585; see also Pearson, A. J.; Park, J. G. J. Org. Chem. 1992, 57, 1745. 67. Pigge, F. C.; Fang, S. Tetrahedron Lett. 2001, 42, 17. 68. Semmelhack, M. F.; Hall, H. T. J. Am. Chem. Soc. 1974, 96, 7091; 7092. 69. (a) Semmelhack, M. F.; Clark, G. R. et al. Tetrahedron 1981, 37, 3957; (b) K¨undig, E. P. Pure Appl. Chem. 1985, 57, 1855. 70. K¨undig, E. P.; Cannas, R. et al. J. Am. Chem. Soc. 2003, 125, 5642. 71. Semmelhack, M. F.; Thebtaranonth, Y.; Keller, L. J. Am. Chem. Soc. 1977, 99, 959. 72. (a) Chung, Y. K.; Sweigart, D. A. et al. J. Am. Chem. Soc. 1985, 107, 2388; (b) Lee, T.-Y.; Kang, Y. K. et al. Inorg. Chim. Acta 1993, 214, 125. 73. Simonneaux, G.; Jaouen, G. Tetrahedron 1979, 35, 2249. 74. Des Abbayes, H.; Boudeville, M.-A. J. Org. Chem. 1977, 42, 4104. 75. Moulines, F.; Gloaguen, F.; Astruc, D. Angew. Chem., Int. Ed. Engl. 1992, 32, 458. 76. Dickens, P. J.; Gilday, J. P. et al. Pure Appl. Chem. 1990, 62, 575. 77. (a) Gilday, J. P.: Widdowson, D. A. J. Chem. Soc., Chem. Commun. 1986, 1235; (b) Gilday, J. P.: Widdowson, D. A. Tetrahedron Lett. 1986, 27, 5525. 78. Sebhat, I. K.; Tan, Y.-L. et al. Tetrahedron 2000, 56, 6121. 79. Ghavshou, M.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. I 1983, 3065. 80. (a) Schmalz, H.-G.; Hollander, J. et al. Tetrahedron Lett. 1993, 34, 6259; (b) H¨orstermann, D.; Schmalz, H.-G.; Kociok-K¨ohn, G. Tetrahedron 1999, 55, 6905; (c) Schmalz, H.-G.; Arnold, M. et al. Angew. Chem., Int. Ed. Engl. 1994, 33, 109. 81. Harman, W. D. Chem. Rev. 1997, 97, 1953. 82. Kopach, M. E.; Harman, W. D. J. Am. Chem. Soc. 1994, 116, 6581. 83. Gonzalez, J.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 1993, 115, 8857.

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11 Cycloaddition and Cycloisomerization Reactions Cycloaddition reactions are of enormous importance in organic synthesis, but they are necessarily limited by the Woodward–Hoffman rules. The majority of cycloaddition reactions used in organic synthesis form six-membered ring carbocycles through the Diels–Alder reaction. Some four-membered rings can be formed, and a range of ﬁve-membered ring heterocycles can be formed by 1,3-dipolar cycloadditions. The use of transition metals can not only facilitate the formation of these “convenient” ring sizes, but also permit the formation of other ring sizes.1 In addition, conventional cycloadditions almost always involve the adding together of two components, such as a diene and a dienophile, while transition metals can allow three separate components to be brought together. The participation of the transition metal means that all of these reactions become formal cycloadditions, and have multi-step mechanisms.

11.1 Formal Six-Electron, Six-Atom Cycloadditions 11.1.1

The [4 + 2] Cycloaddition

The Diels–Alder reaction is a cornerstone of organic synthesis, but it has its limitations. Principal among these is that diene/alkene pairs without suitable electronic activation react very slowly, if at all. Usually, an electron-poor alkene is employed. Enormous rate accelerations can be achieved with Lewis-acid catalysis. This form of catalysis requires that the substrate possesses a group conjugated to the alkene that is capable of coordination to the Lewis acid. An alternative means of catalysis is to use a transition metal, which works by coordinating directly to the ␲-systems, bringing them together and forming the bonds one by one. An effective catalyst for this reaction with diene–ynes and diene-allenes2 is Ni(COD)2 with added phosphite ligands. This can result in a reduction of the temperature required for the reaction from 160 ◦ C to room temperature (Schemes 11.1 and 11.2).3 Other catalysts, such as rhodium complexes,4 have also been used (Schemes 11.2 and 11.3). The use of chiral ligands allows asymmetric cycloadditions (Schemes 11.4 and 11.5).5,6

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Organic Synthesis Using Transition Metals OTBS Ni(COD)2 (o-biPhO)3P

OTBS 11.2

11.1

Scheme 11.1 OTBS H Ni(COD)2 (o-biPhO)3P

OTBS

11.4 OTBS H

•

11.3

[Rh(COD)Cl]2 (o-biPhO)3P

11.5

Scheme 11.2 H ([(F3C)2CHO]3P)3RhCl 11.6

TBSO

11.7

H

TBSO

Scheme 11.3 SiMe3 SiMe3 O

[(C8H14)2RhCl]2, L*

O H 11.9 87% e.e.

11.8 L* =

H3C Ph

O

PPh2

O

PPh2

11.10

Scheme 11.4 H (NBD)Rh(S)-BINAP SbF6

O

O H 11.12 > 98% e.e.

11.11

Scheme 11.5

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Cycloaddition and Cycloisomerization Reactions

NH2

1. BrH2C Na2CO3 2.

N H 11.13

SiMe3 N O H 11.14

Et3N

Ni(COD)2, P[OCH(CF3)2]3

SiMe3

N

COCl

393

SiMe3 1. H 2, (Ph3P)3RhCl 2. TsOH 3. POCl 3; NaBH 4

N N O H 11.15

N

H

N

H2, PtO2 N H H

N H H H 11.16

H

11.17

Scheme 11.6

One application of this reaction was in the synthesis of yohimban 11.17 (Scheme 11.6).7 The cycloaddition precursor 11.14 could be easily built up from tryptamine 11.13 and the cyclization employed a nickel/phosphite catalyst system. Selective reduction of the less-hindered alkene, protio-desilylation and a Bischler–Napieralski reaction gave the desired pentacyclic system 11.16. Reduction of the remaining alkene gave yohimban 11.17 and its diastereoisomer. A plausible mechanism for this kind of cycloaddition reaction would involve formation of a nickellacyclopentane, which would then undergo reductive elimination through its ␩3 -form (Scheme 11.7).

L2Ni reductive elimination and dissociation

coordination

NiL2 NiL2

η1 → η3 NiL2

Scheme 11.7

oxidative cyclisation

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Organic Synthesis Using Transition Metals

Ni, Δ

Scheme 11.8

HO

HO 3

OH

OH

OH

Ni(CO)2(PPh3)2

+

11.18

11.19

11.20 OH

OH

Scheme 11.9

11.1.2

The [2 + 2 + 2] Cycloaddition

The [2 + 2 + 2] cycloaddition of three distinct ␲-components goes beyond the Diels–Alder reaction, removing the requirement that two of the ␲-components must be conjugated as a diene.8 In these reactions it is not necessary that all of the ␲-components are C–C bonds; C–heteroatom bonds can also be involved. Cyclotrimerization of acetylene would be an elegant method for the formation of benzene. This reaction was achieved by Berthelot in the nineteenth century by heating acetylene in a nickel tube (Scheme 11.8).9 Either the nickel surface or a nickel compound catalysed the cycloaddition. This chemistry has been reinvestigated at various times since then. The Reppe group in Germany in the 1940s built upon the foundations laid by Berthelot by employing nickel complexes for the catalytic trimerization of different alkynes, including propargyl alcohol 11.18 (Scheme 11.9)10 and even tetramerizations of acetylene to give cyclooctatetraene 11.21 (Scheme 11.10).11 A reasonable mechanism would involve formation of a bis-alkyne complex, followed by oxidative cyclization to give a metallacyclopentadiene (Scheme 11.11). Coordination of a second alkyne, followed by insertion and reductive elimination from a metallacycloheptatriene, would yield the trimeric product. An analogous mechanism may be drawn for the formation of cyclooctatetraene, but with an additional alkyne coordination–insertion sequence prior to reductive elimination, a process that seems to be favoured by employing a nickel catalyst with fewer ligands. In support of this mechanism12 is the fact that stable cobaltacyclopentadienes 11.23, with an additional PPh3 ligand can be prepared (Scheme 11.12).13 These cobaltacycles undergo further reactions with alkynes, alkenes,14 azides15 and diazo compounds16 to give a variety of cyclic products.17 Cyclobutadiene complexes 11.26, cyclopentadienone complexes 11.27 and arenes 11.28 can also be formed (Scheme 11.13).18

Ni(CN)2, CaC2, O ,Δ

11.21

Scheme 11.10

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Cycloaddition and Cycloisomerization Reactions

2 [M]

reductive elimination

coordination

[M] [M] oxidative cyclisation

insertion

[M] [M] coordination

Scheme 11.11

Me CO2Me

Me

Me

CpCo(PPh3)2 MeO2C

CO2Me Co Ph3P Cp 11.23

11.22

Scheme 11.12

CpCo

Δ

11.26

O

Co PPh3

Me 11.24

CO

Cp

CpCo(PPh3)2

Me

CpCo Me

Me Me

Me

11.27 Me

11.25 Me Me

Δ

Me

Me Me Me 11.28 Me

Scheme 11.13

395

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Organic Synthesis Using Transition Metals Me3Si CpCo(CO)2

11.30

11.29 Me3Si

SiMe3

CoCp

CoCp

-2 CO

11.31 SiMe3

SiMe3

SiMe3

SiMe3

Co Cp

Co 11.33 Cp

11.32

SiMe3 11.34

Scheme 11.14

For synthesis, the problem has always been how to control the reaction so that three different alkynes can be coupled together selectively. One answer is to arrange for two of the alkynes to be connected by a tether, so that part of the reaction is intramolecular.19,20 The third alkyne should then be one that it reluctant to selftrimerize, such as bis(trimethylsilyl)acetylene, which is quite hindered, or other trimethylsilyl-substituted alkynes.21 It is likely that the cobalt catalyst coordinates the two alkynes of the diyne (Scheme 11.14). Oxidative cyclization then gives a metallacyclopentadiene 11.31. Coordination of bis(trimethylsilyl)acetylene is followed by insertion and reductive elimination. The reaction conditions, involving heating, are required for the ﬁrst step, which is dissociation of CO from the cobalt. The ﬁnal product 11.34 also contains two silyl groups. These are also very useful as they undergo facile electrophilic ipso-substitution. As two of the alkynes are part of a diyne, the reaction produces a bicyclic compound. Remarkably, even benzocyclobutenes 11.35 can be formed in good yield (Scheme 11.15). These are especially useful as thermolysis results in an electrocyclic ring opening to an o-xylylene, which can be trapped in situ in a (classical) Diels–Alder reaction. This strategy was used in an outstanding synthesis of estrone 11.42 (Scheme 11.16).22 The diyne 11.38, with a pendant alkene ready for the Diels–Alder step, was constructed by speciﬁc enolate chemistry. Heating diyne 11.38 with bis(trimethylsilyl)acetylene gave the benzocyclobutenes 11.39 as a mixture of diasteroisomers, accompanied by some of the Diels–Alder product. Further heating of the benzocyclobutene mixture resulted in complete conversion to the Diels–Alder product 11.41. Both diastereoisomeric benzocyclobutenes gave the same o-xylyene 11.40, and, hence, the same Diels–Alder product. Conversion to estrone 11.42 was achieved by protio-desilylation at C2 with good, but not complete selectivity, followed by oxidative cleavage of the C3 carbon–silicon bond. Another application of o-xylylene chemistry can be found in Scheme 3.65.

CpCo(CO)2 SiMe3

SiMe3

Me3Si

SiMe3 11.35

Scheme 11.15

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Cycloaddition and Cycloisomerization Reactions OSiMe3 I

397

CpCo(CO)2, Δ SiMe3 Me3Si

O LiNH2

+

11.36

11.38

11.37

O

O

Δ electrocyclic ring opening

Me3Si Me3Si

Diels-Alder reaction

Me3Si Me3Si

11.39

11.40 O

O 1. CF3CO2H 2. Pb(OAc) 4

H

Me3Si H Me3Si

H

H

H

11.41

H

HO

11.42

Scheme 11.16

Cyclotrimerization is not limited to cobalt23 or nickel.24 Catalysts based upon various metals including ruthenium,25,26 rhodium (Schemes 11.17 and 11.18),27–32 niobium,33 titanium,34 iridium35 and, Berthelot’s original metal, nickel36 have been reported. In many cases, the requirement for using a silyated alkyne as one partner seems to not apply and even acetylene gas itself may be used; interestingly, in the case of iridium catalysis, the regioselectivity of cycloaddition can be decided by the choice of ligand (Scheme 11.19).37

OBn BnO BnO

OBn H H (Ph3P)3RhCl

O BnO O

BnO BnO

O BnO O

11 .4 3

11.4 4

Scheme 11.17 OH Ph N Ts

OH

(Ph3P)3RhCl N Ts

11 .45

Scheme 11.18

Ph

11.45

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Organic Synthesis Using Transition Metals

n-Bu

MeO2C MeO2C

n-Bu

11.47 major product, ligand = DPPF

[Ir(cod)Cl]2, ligand

MeO2C MeO2C

11.46 MeO2C MeO2C

n-Bu 11.48 major product, ligand = DPPE

Scheme 11.19

Boron substituents are tolerated by the reaction conditions. The [2 + 2 + 2] cyclotrimerization can even tolerate three boron atoms to give triborylated arenes, capable of selective Suzuki coupling reactions (Scheme 11.20).38 All three alkynes can be incorporated into a single molecule, making the reaction entirely intramolecular. This has been used in a synthesis of Cryptoacetalide 11.60 (Scheme 11.21).39 The triyne 11.58 was constructed by coupling a diyne 11.56 containing a carboxylic acid with an alkynol 11.57. A ruthenium catalyst was found to be most effective for the cyclotrimerization, combined with microwave heating. The synthesis was completed by deprotection and free-radical spiroketal formation. The cyclotrimerization can also be used to form unusual and challenging aromatic systems, including biaryls and helicenes (Scheme 11.22).40 The triyne substrate 11.63 was constructed by a Sonogashira reaction of

pinB Bpin + Bpin

11.49

HN

B

NH

(COD)2RhBF4, Tol-BINAP pinB

11.50

HN B

N H

11.51

OMe

CF3 1. p-MeOC6H4I, dppfPdCl2, K2CO3 2. H3O+ 3. p-F3C6H4I, dppfPdCl2, K2CO3

O Bpin =

11.52

OMe

Scheme 11.20

B O

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Cycloaddition and Cycloisomerization Reactions

I

NC

CN

OTBS

11.53

OTBS

11.54

OTBS

1. DIBAL 2. Ph 3P, CBr 4 3. BuLi

1. TBAF 2. Jones' reagent CO2H

11.56

11.55

O O

OH

OPMB

OPMB

Cp*Ru(COD)Cl μW

11.57 DCC, DMAP 11.58

O

O

O OPMB

1. DDQ 2. I 2, PhI(OAc)2, hν

O O

11.59

11.60

Scheme 11.21 Cl 1. Ga, In Br

Cl

CHO

(Ph3P)2PdCl2, CuI, Et3N

2. Ac 2O, py, DMAP

CHO TfO

CHO

11.61

11.62 Cl Cl Cl OAc 1. CpCO(CO) 2, PPh3 2. SiO 2, Δ Cl

OAc 11.63

11.64

Cl

Scheme 11.22

399

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Organic Synthesis Using Transition Metals

CpCo(CO)2

O

CpCo

Ph3C+

O

SiMe3 11.65

11.66 SiMe3

CpCo O 11.67 SiMe3

CuCl2

t-BuLi CpCo

O 11.68

O

t-Bu

11.69 SiMe 3

SiMe3

Scheme 11.23

triﬂate 11.61 with acetylene, followed by a propargylic Barbier reaction. Cyclotrimerization, followed by elimination of acetate, gave helicene 11.64. The reaction has also been applied to the combination of two alkynes and an alkene, especially in an all-intramolecular fashion (Scheme 11.23), although there are examples where the alkene is in a second molecule. The diene products are often obtained as their ␩4 -complexes with cobalt 11.66, ensuring that the reaction is not catalytic.41 The diene 11.68 can either be liberated from the complex, or further use can be made of the cobalt, particularly after hydride extraction to give the more electrophilic ␩5 -cationic complexes 11.67. The cyclotrimerization can be extended to the synthesis of heterocycles by the use of either cumulenes or nitriles in place of an alkyne (Scheme 11.24). Nitriles yield pyridines on reaction with diynes,42 the alkyl group of the nitrile usually going to the less-hindered alkyne.43 A synthesis of the methyl ester of the anti-tumor antibiotic lavendamycin 11.72 employed a [2 + 2 + 2] cycloaddition of a diyne with a nitrile to form one ring of an azacarbazole (Scheme 11.25).44 The diyne precursor 11.73 was constructed using a Sonogashira reaction to form alkyne 11.74, and a Negishi reaction to couple alkyne 11.76 with iodide 11.75. The regioselectivity of the cycloaddition of diyne 11.73 with methyl cyanoformate was found to depend on the catalyst, a bulky ruthenium catalyst giving the desired isomer 11.77, while a rhodium catalyst45 favoured the undesired isomer. After the cycloaddition, the synthesis was completed by reducing the nitro group and introducing the quinone by oxidation. Other heteroatom-containing partners that can be part of the [2 + 2 +2] ensemble, include carbon dioxide (Scheme 11.26)46 and stable ketenes (Scheme 11.27).47 Ketones may give the expected products (Scheme 11.28), but a more complex situation occurs with aldehydes.48

n-Bu

n-Bu N CpCo(CO)2

N

Et 11.71 Et

11.70

Scheme 11.24

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I

Sonogashira

CO2Me

Me

N

NHTs

N

N H

Ts

N O 11.72

O

11.73

O

OMe

O

Negishi N NO2 N 11.75 OMe

I

NH2

H2N

I

CH3

CH3 (Ph3P)2PdCl2, CuI, NEt3

1. TsCl, py 2. KHMDS, Ph(TfO)I 3. TBAF

SiMe3

NH2

NH2 11.74 CH3

Me 1. KHMDS, ZnBr2 2. 11.75, Pd2dba3, PPh3

N

OMe

Ts 11.76

N Ts

N 11.73 MeO

H3C

H3C

CO2Me 1. H2, Pd/C 2. Ac 2O 3. PhI(OAc)2 4. H3O

N N C CO2Me Cp*Ru(COD)Cl

NO2

N H

CO2Me N

N H N

N O

MeO

O

OMe O2N

H2N

11.77

11.72

Scheme 11.25

O • O

MeO2C 11 .78

Ni(COD)2, IPr

O

MeO2C

O

11. 7 9

Scheme 11.26

Ph

Et Ni(COD)2, dppb

TsN 11. 8 0

• O

TsN 11.81

Scheme 11.27

401

Ph Et O

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Organic Synthesis Using Transition Metals O

EtO2C EtO2C EtO2C EtO2C

Ni(COD)2, SiPr

+

EtO2C EtO2C EtO2C EtO2C

11.82

O

11.83

Scheme 11.28 CO2Et

+

CO2Et

Cp*Ru(COD)Cl

Ph

Ph 11.84

11.85

11.86

Scheme 11.29

11.2 Cycloadditions Involving Fewer than Six Atoms 11.2.1

Four-Membered Rings

Several [2 + 2] cycloadditions catalysed by transition metals have been reported (Scheme 11.29).49 Further examples can be found in Schemes 11.72 and 11.73, and Scheme 6.107. 11.2.2

Five-Membered Rings through TMM Methods

A cycloaddition to form a cyclopentane or a cyclopentene ring would be very valuable as a lower homologue of the Diels–Alder reaction. The difﬁculty comes from the need for a suitable 1,3-dipole or diradical. Trimethylenemethane (TMM) 11.87 is one such species, but it is highly reactive. It has been used in intramolecular reactions, generated by photolysis of bicyclic azo compounds. Transition-metal complexes of trimethylenemethane have been known for some time and can be easy to make, including the iron–tricarbonyl complex (Section 10.1).50 While it is relatively easy to make, trapping of the TMM after oxidative release can be inefﬁcient,51 in contrast to the analogous chemistry employing the cyclobutadiene complexes.

11.87

A precursor 11.89 for a palladium–TMM system has been designed, using acetate as a leaving group to form the cationic arm and silyl or stannyl groups to form the anionic arm (Scheme 11.30).52 The precursors may be formed in various ways. The most direct involves dilithiation of methallyl alcohol 11.88 and quenching with trimethylsilyl chloride, followed by acetylation of the alcohol.

OH

1. 2 n -BuLi 2. Me 3SiCl 3. Ac 2O

Me3Si

11.88

OAc 11.89

Scheme 11.30

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Cycloaddition and Cycloisomerization Reactions

OAc 11.89 Pd(0), P(Oi -Pr)3

403

Me3Si CO2Me CO2Me

CO2Me 11.91 CO2Me

11.90

Scheme 11.31

Me3Si

O O

OAc 11.89 Pd(0), P(Oi-Pr)3

H

MeO2C

O O

CO2Me 11.93

11.92 H

OH

O O

HO H

11.94

Scheme 11.32

The silyl acetates undergo palladium-catalysed cycloaddition with a range of electron-poor alkenes (Scheme 11.31). The yields are usually good, especially with tri-iso-propylphosphite as a ligand. With cyclic alkenes, the cycloaddition occurs, as might be expected, on the less-hindered face. With acyclic alkenes, a stereogenic centre in the allylic position can exert useful stereo-control (Scheme 11.32). In this case the cycloaddition product 11.93 was an intermediate in a synthesis of brefeldin 11.94.53 It is unlikely that ␩4 -trimethylenemethane complexes are involved. Equilibrating zwitterionic ␩3 -allyl complexes 11.96 are more plausible intermediates (Scheme 11.33). The mechanism is likely to involve Michael addition to the alkene, followed by back-attack of the newly formed enolate 11.97 onto the ␩3 -allyl complex. This can be demonstrated using isomeric silyl acetates, 11.99 and 11.100 (Scheme 11.34).54 With an alkene such as cyclopentenone, which reacts slowly, the isomeric ␩3 -allyl complexes, 11.101, 11.102, have time to

L2Pd AcO

L2Pd

11.89

CO2Me

SiMe3

SiMe3

11.96

11.95 AcO

L2Pd 11.97 CO2Me

Scheme 11.33

11.98

CO2Me

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Organic Synthesis Using Transition Metals

L2Pd AcO

SiMe3 Me

Me

11.99

11.101 O

O

L2Pd AcO

SiMe3 Me 11.100

Me 11.102

11.103

Scheme 11.34

MsO

SiMe3 11.104

(Ph3P)4Pd NH4PF6

IrCl(CO)(AsPh3)2

Me3Si

(Ph3P)2Pd

OC Ir AsPh3 Cl

PF6

11.106

11.105

Scheme 11.35

equilibrate fully and yield the same product. With more reactive alkenes, such as alkylidene malonates, trapping is faster than equilibration and the different isomers of the starting silyl acetate give different product mixtures. Similarly, the behavior of E and Z alkenes indicates a stepwise mechanism. While E-alkenes give trans products, Z-alkenes tend to give mixtures, indicating an intermediate capable of bond rotation.55 This situation is quite unlike the classical Diels–Alder reaction. Interestingly, trimethylsilylmethyl-substituted allyl complexes of palladium 11.105 and molybdenum can be obtained from the reaction of the corresponding mesylate 11.104 (a much better leaving group than acetate) in the absence of any silophilic nucleophile, while some other metals, including iridium, did give a TMM complex 11.106 (Scheme 11.35).56 The silyl group is unnecessary when the trimethylene methane precursor bears an electron-withdrawing group (Scheme 11.36). The anionic component can be generated by deprotonation rather than desilylation.57 Both cyano and sulfonyl groups have been used as the electron-withdrawing group. SO2Tol

SO2Tol

SO2Tol dba3Pd2.CHCl3, dppe

+ O

via PdLn

O

OCO2Et 11.107

11.108

Scheme 11.36

11.109

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Cycloaddition and Cycloisomerization Reactions

+ AcO

CHO

Ph

11.110

Pd(OAc)2, PPh3 Me3SnOAc

SiMe3

Ph

11.89

405

O 11.111

Scheme 11.37

SiMe3

AcO

Ph N

Ph 11.112

Ph

11.89 Ni[P(OEt)3]4

Ph

N 11.113

Scheme 11.38

Carbon–heteroatom double bonds can also participate in this reaction. These include both carbonyl compounds (Scheme 11.37) and imines (Scheme 11.38).58 Addition to aldehydes is co-catalysed by tin(II) or indium(III) salts. Under these conditions, tetrahydrofurans are obtained.59 The presence or absence of the co-catalyst can also switch the reaction from one mode to another (Scheme 11.39).60 An indium cocatalysed cycloaddition to a ␥ -pyrone aldehyde 11.117 was used in a synthesis of aureothin 11.122 and Nacetylaureothamine 11.123 (Scheme 11.40).61 Cross-metathesis of the exo-cyclic alkene 11.118 allowed a subsequent Suzuki coupling with a gem-dibromide 11.120 that showed the expected selectivity (Section 2.1.4.2). This reaction required the use of thallium ethoxide as the Lewis base to suppress the formation of side products. A Negishi coupling completed the synthesis of aureothin 11.122. Reduction and acylation of the nitro group yielded N-acetylaureothamine 11.123. The latter compound is active against Helicobacter pylori, a bacterium behind stomach ulcers. The TMM system has also been extended to other ring sizes. Reactions with dienes can give sevenmembered rings (Scheme 11.41),62 and reactions with tropone 11.126 (Scheme 11.42) can form ninemembered rings.63

11.2.3

Other Five-Membered Ring Formations

Systems for [2 + 3] cycloaddition can also be generated from methylene cyclopropanes (Scheme 11.43). Treatment of methylene cyclopropanes with either a nickel or a palladium catalyst in the presence of an alkene trap can lead to useful yields of the ﬁve-membered ring cycloaddition product 11.130 through oxidative O O Pd(OAc)2, P(Oi -Pr)3 11.115

dba3Pd2, PPh3, In(acac)3

11.114 + AcO

SiMe3 11.89

Scheme 11.39

O

11.116

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O

O AcO

O O

SiMe3

11.89 OMe (Ph3P)4Pd, In(acac)2

O O

11.117 O

11.118 O

Br 11.120

OMe

O pinB

pinB Grubbs II

Br O2N

O

OMe

O

(Ph3P)4Pd, TlOEt

11.119

OMe

O Br

O2N

11.121

O Me2Zn, (t-Bu3P)2Pd

O

OMe

O

O Me

O2N

1. Zn, NH 4Cl 2. AcCl, py

11.122

O O Me

AcHN

11.123

Scheme 11.40

SO2Ph

SO2Ph

OAc Pd(OAc)2, P(Oi -Pr)3

TBSO

SiMe3 11.124

TBSO 11.125

11.89

Scheme 11.41

OAc O 11.126

Me

Me + 11.127

Pd(OAc) 2, P(Oi-Pr)3 SiMe3

O 11.128

Scheme 11.42

EtO2C

Ni(cod)2, Ph3P

EtO2C EtO2C

CO2Et 11.12 9

1 1.130

Scheme 11.43

406

OMe

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Cycloaddition and Cycloisomerization Reactions O

407

O Pd(0), Ph2PMe

11.131

11.132

Scheme 11.44 Ph

Ph Ph

Ph

Pd(dba)2, P(Oi-Pr)3 CO2Me Me3SiO

Me3SiO

11.133

CO2Me 11.134

Scheme 11.45 n-C5H11 H

n-C5H11 Pd(dba)2, P(Oi-Pr)3 O

O

CO2Me 11.135

11.136

CO2Me

Scheme 11.46 O

O

O

O

Ni(COD)2, IPr

Ph + Me O 11.137

Me

Ph

O

NiLn

Ph

11.138

11.139

O

11.140

Scheme 11.47

addition to one of the carbon–carbon bonds of the strained ring.64 In some cases, however, rearrangement of the methylene cyclopropane occurs to yield alternative products (Scheme 11.44).65 Intramolecular versions of this reaction have also been studied (Schemes 11.45 and 11.46).66,67 Even cyclopropanes lacking a methylene or vinyl group can be involved in formal cycloadditions. Cyclopropyl ketones 11.137 undergo cycloaddition to enones under nickel catalysis with an NHC ligand (Scheme 11.47); in the absence of the enone, their dimerization is observed.68 The reaction is proposed to proceed via a metallacyclic enolate complex 11.140, perhaps after initial oxidative addition to one of the cyclopropyl C–C bonds.

11.3 Cycloadditions Involving More than Six Atoms 11.3.1

The [5 + 2] Cycloaddition

One way to form a seven-membered ring would be to add a ﬁve-atom component to a two-atom component. This has been achieved using a vinyl cyclopropane 11.141 as the ﬁve atom component, and rhodium catalysis

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Organic Synthesis Using Transition Metals Me Me

MeO2C MeO2C

(Ph3P)3RhCl

MeO2C MeO2C

11.141

11.142

Scheme 11.48

+

Me

CO2Me

1. [Ru(CO) 2Cl]2 2. HCl, EtOH

TBSO

Me O MeO2C

11.143

11.145

11.144

Scheme 11.49

(Scheme 11.48).69 The reaction, employing Wilkinson’s catalyst, (Ph3 P)3 RhCl, is made more rapid by the addition of silver(I) ions. These halophilic ions abstract chloride from the catalyst to generate a more reactive cationic rhodium complex. Use of chiral ligands can give excellent enantioselectivity.70 A ruthenium catalyst, [Ru(CO)2 Cl]2 , is more effective for hindered substrates; the reaction can be intermolecular in special cases, using alkoxy cyclopropanes (Scheme 11.49).71 The [5 + 2] cycloaddition was used in a synthesis of core structure of the cyathane diterpenes 11.146, tricyclic compounds that promote nerve growth factor (Scheme 11.50).72 The synthetic strategy revolved around using the cycloaddition of vinyl cyclopropane 11.147 to create the six- and seven-membered rings in a single step. The chosen starting material was limonene 11.148, which could be cut down to a ﬁve-membered ring 11.149 by a sequence involving an intramolecular aldol reaction (Scheme 11.51). The side chain for the alkynyl arm could then be partly installed by a stereoselective Claisen rearrangement, placing an aldehyde group trans to the iso-propyl group. The vinyl cyclopropyl moiety could be attached with acetylene chemistry, prior to the completion of the alkynyl arm. The ketonic substrate 11.147 underwent smooth and selective cycloaddition on treatment with a rhodium catalyst; in contrast the alcohol 11.154 gave a complex mixture. The mechanism proposed involves formation of a metallacyclopentene 11.156, followed by strain-driven ring opening of the cyclopropane to form a metallacyclooctadiene 11.157 (Scheme 11.52). This ring expansion is then followed by reductive elimination.

O

HO

H

O

HO

11.146

11.147

Scheme 11.50

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Cycloaddition and Cycloisomerization Reactions

1. DIBAL 2. OEt Hg2+, Δ CHO

1. H 2, PtO2 2. OsO 4, NaIO4 3. piperidine

CHO

11.150

11.149

11.148 1. NaBH 4 2. TBSCl, C3H4N2 3. O 3; Me 2S

OTBS

1. Li CeCl3 2. LiAlH 4, NaOMe

OH

O

OH 11.152

11.151 OH

O

1. Dess-Martin 2. BrMg

Dess-Martin OH

OH

11.154

11.147 O

[Rh(CO)2Cl]2 HO

H

11.146

Scheme 11.51

O

O

HO

H

RhLn

reductive elimination

coordination OH O

O

11.146 HO

H

11.147 RhLn

OH

11.157

RhLn

11.155 O

cyclopropane ring opening

H HO

RhLn

11.156

Scheme 11.52

oxidative cyclisation

409

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Organic Synthesis Using Transition Metals O Ts N

O

(Ph3P)3RhCl, AgOTf

Ts N

11.158

11.159

Scheme 11.53

CO2Me +

O

O

O

1. CO, [Rh(CO)2Cl]2 2. H3O+

H CO2Me

CO2Me

Et OMe

O

11.160

Et 11.161

OH Et 11.162

Scheme 11.54

Small variations on this theme allow it to be extended to the formation of eight-membered rings: a substrate containing a vinyl cyclobutanone 11.158 yields a cyclooctenone 11.159 (Scheme 11.53),73 while addition of CO can yield a cyclooctadione 11.161 that may undergo an intramolecular aldol reaction (Scheme 11.54).74

11.3.2

The [4 + 4] Cycloaddition

This cycloaddition is thermally forbidden under the Woodward–Hoffmann rules, but can be achieved by the transition metal catalysed coupling of two dienes (Scheme 11.55). The transformation of butadiene into a variety of products, including cyclooctadiene 11.163, has been known for many years. The [4 + 4] cycloaddition reaction has been applied in an intramolecular fashion to form eight-membered rings (Scheme 11.56). In the presence of a source of nickel(0) and phosphine ligands, tetraene 11.164 cyclizes to the bicyclic product 11.165, mainly as the cis-isomer. The ratio of isomers is dependent on the phosphine.75 A stereogenic centre present in the tether between the two dienes can result in useful diastereoselectivity, once again dependent on the phosphines.76,77 This chemistry has been used to synthesize asteriscanolide 11.166, which contains a substituted cyclooctane, by intramolecular cycloaddition of tetraene 11.168 to

Ni catalysis 11.163

Scheme 11.55

Ni(COD)2, PPh3

MeO2C MeO2C 11.164

MeO2C MeO2C 11.165

Scheme 11.56

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Cycloaddition and Cycloisomerization Reactions O

O

O O

O

H

H

O

H

H O 11.166

11.167

11.168 (i-PrCO)2O

CHO + BrMg

O

OH 11.170

11.169 1. LDA 2. LiAlH4 3. (COCl)2, DMSO, Et3N

O

Li 11.173

O 1. Me3SnCl 2. n-BuLi, CO2

11.171

HO CHO 11.172

Red-Al®;

411

O O

O Ni(COD)2, PPh3

11.168

11.167

H

H

O 1. Red-Al®, CuBr 2. BH3.THF 3. PCC

O

11.166

H

H O

Scheme 11.57

diene 11.167, which is related to asteriscanolide 11.166 by redox processes (Scheme 11.57).78 The tetraene 11.168 was synthesized from acrolein using a sequence involving a highly regioselective ester enolate Claisen rearrangement of 11.171, and organotin chemistry to install the lactone. An intermediate, the propargylic alcohol 11.173, could be converted to the optically active form by a second Swern oxidation, followed by reduction with lithium aluminium hydride in the presence of Darvon alcohol. The tetraene 11.168 underwent stereoselective cyclization with nickel catalysis. The electron-poor double bond in the product 11.167 could then be reduced using in situ copper hydride. The synthesis was completed by hydroboration-oxidation of the remaining double bond from the less hindered face, creating the desired ketone 11.166. 11.3.3

The [6 + 2] and [6 + 4] Cycloadditions

A small number of concerted cycloadditions of trienes are known, but the reaction is not common. A more versatile process is the formal cycloaddition of ␩6 -triene complexes with alkynes, alkenes and dienes.79 Heating or photolysis of an ␩6 -triene complex 11.174 with a diene results in the formation of the bicyclo[4.1.4]

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Organic Synthesis Using Transition Metals

X

(OC)3Cr

hν

H

X

H

X = CH2, SO2, NAc, NCO2Me

11.175

11.174

Scheme 11.58 O O S

SiMe3 hν (uranium glass filter)

O2S SiMe3

(OC)3Cr 11.174a

hν (vycor filter) -SO2

11.176

SiMe3 11.177

Scheme 11.59

ring system 11.175 with retention of the stereochemistry of the diene double bonds (Scheme 11.58).80 The reaction conditions, heat or photolysis, are required to open up a vacant site on the chromium for coordination of the diene. An interesting question is whether this is by dissociation of CO, or by a change from ␩6 - to ␩4 -coordination. For synthetic purposes, the reaction is remarkably tolerant of diene substituents, which can be varied from strongly electron-donating alkoxy and silyloxy groups to electron-withdrawing ester groups. The reaction may also be intramolecular.81 An alkyne may also be used in place of the diene component. With the cyclic sulfone complex 11.174a, this leads to an interesting synthesis of cyclooctatetraenes as the initial cycloadduct 111.76 is photochemically unstable and readily loses SO2 (Scheme 11.59).82 The adduct may be isolated if uranium glass ﬁlters are employed to exclude the high-energy wavelengths. Subsequent photolysis with the more transparent vycor ﬁlters causes chelotropic elimination of sulfur dioxide to give the tetraene 11.177. The intramolecular cycloaddition is particularly convenient, as the starting material may be prepared by the addition of an organozinc compound to the stable ␩7 -complex 11.178 (Scheme 11.60). The initial 7-alkyl

SiMe3 M SiMe3 M = ZnI.CuCN.LiCl

(OC)3Cr

(OC)3Cr

11.178

11.179 SiMe3

Δ Me3Si Cr(CO)3 11.180

11.181

Scheme 11.60

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Cycloaddition and Cycloisomerization Reactions OTBS

Ph OTBS

Ph

413

H

H

h (OC)3Cr 11.182

11.174b

Scheme 11.61 H

(OC)3Cr

CO2Et

hν pyrex filter

OMe 11.183

11.184

CO2Et OMe

Scheme 11.62

product 11.179 isomerizes under the reaction conditions, only one of the possible isomers, the 1-alkyl isomer 11.180, being capable of undergoing cycloaddition to give the tricyclic product 11.181.83 Allenes84 can also be employed (Scheme 11.61), as can alkenes, but the alkenes must be electron poor (Scheme 11.62).85 The cycloaddition is highly stereoselective, perhaps because the ester carbonyl group can act as a ligand for the chromium. High diastereoselectivity can be achieved with chiral auxiliaries (Scheme 11.63).86 The product 11.186 (R* = (−)-8-phenylmenthyl) of the cycloaddition between complex H

NCO2Me +

N

hν pyrex filter

O O

CO2Me

H O

(OC)3Cr

O

Ph

11.174d

11.185

MeO

OMe H

11.187

MeO

N CO2Me

N CO2Me CO2R* H

1. H3O+ 2. MeMgBr 3. LiAlH4 4. Dess-Martin

H

11.186

1. LiOH 2. i -BuOCOCl, NMM 3.

Tl(NO3)3.3H2O MeOH

OMe H

Ph

; t-BuSH S

N Na O

O Me

H N Me H 11.189

11.188

Scheme 11.63

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Organic Synthesis Using Transition Metals

11.174d and chiral alkene 11.185 was converted to the alkaloid ferruginine 11.189. After oxidative ring contraction using thallium(III) to form the tropane skeleton, the stereo-controlling and activating ester group was removed by saponiﬁcation and Barton decarboxylation. Some straightforward transformations then gave the natural product 11.189.

11.4 Isomerization Many transition metals are capable of isomerizing alkenes, moving them to a position of lower energy in the molecule. This can be a side reaction in other transition-metal processes. Sometime, it adds value to the reaction (see Section 5.1.7 and Scheme 8.124), at other times it gives unexpected and troublesome products (Section 8.3.10). It can also be used to convert a readily prepared alkene to an isomer that is otherwise difﬁcult to obtain. 2-Methylenecyclopentanone 11.190 is readily available by the aldol reaction between cyclopentanone and formaldehyde. Treatment with rhodium(III) chloride in ethanol converts the exo-methylene isomer to 2-methylcyclopentenone 11.191 (Scheme 11.64).87 Isomerization of terminal to 1,2-disubstituted alkenes is also efﬁcient (Scheme 11.65).88 Alkene 11.193 was needed for a synthesis of peloruside A (see Scheme 8.70 for another aspect of this synthesis). The decomposition products of the Grubbs metathesis catalysts are competent isomerization catalysts, which can be a curse, or can be useful.89 The largest-scale isomerization process is a part of the Takasago process for the industrial synthesis of menthol 11.197 on a multitonne scale (Scheme 11.66).90 Unlike the reactions in Schemes 11.64 and O

(H2CO)n PhNH2Me CF3CO2

O

O RhCl3, EtOH 11.190

11.191

Scheme 11.64 Bn

Bn Et

Et O RhCl3, EtOH

N

O

O

O 11.192

O

N O

11.193

Scheme 11.65

NEt2

(S)-BINAPRh(COD)

NEt2

11.194

11.195

1. H 3O+ 2. ZnBr2

H2, Ni OH 11.196

OH 11.197

Scheme 11.66

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Cycloaddition and Cycloisomerization Reactions

415

O (dppe)2Rh

OH

11.199

OH 11.198

OSiMe3

Me3SiO

NSiMe3

11.200

Scheme 11.67

Cl

CHO (Ph3P)3RuHCl

+ OH 11.201

Cl OH O

11.202

11.203

Scheme 11.68

11.65, this isomerization does not involve the movement of an alkene to a more substituted position, but, rather, into conjugation with an amine to give an enamine 11.195. Subsequent hydrolysis gives citronellal, which undergoes an intramolecular ene reaction on treatment with a Lewis acid to give isopulegol 11.196. Hydrogenation of the alkene then gives menthol 11.197. The use of a chiral ligand, (S)-BINAP 1.36, in the isomerization delivers material with very high enantiopurity.91 A cationic rhodium complex proved to be highly effective in isomerizing allylic alcohols to enols 11.198 (Scheme 11.67).92 Remarkably, the enols had a sufﬁcient lifetime for their 1 H NMR spectra to be recorded, or to be trapped by added reagents. On the other hand, in the absence of added reagents, they slowly tautomerized to their ketone or aldehyde form 11.199. The enols produced by isomerization may also be trapped in aldol (Scheme 11.68)93 and Mannich reactions.94 A nickel catalyst was found to be superior for the isomerization of a lithium alkoxide to enolate 11.205, which could then be trapped as an aldol product 11.206 (Scheme 11.69).95 This provides a method for the generation of enolates that avoids the use of LDA.

11.5 Cycloisomerization and Related Reactions In a transition-metal-catalysed cycloisomerization reaction, an isomerization occurs through a metallacycle intermediate. Strictly speaking, the starting material and the product are isomeric; in practice, for synthesis, the organometallic intermediates may be intercepted by added reagents to add functionality to the products.

OH

11.204

1. n-BuLi 2. (Cy3P)2NiCl2

O

O

H

OH

PhCHO 11.205

Scheme 11.69

Ph 11.206

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Organic Synthesis Using Transition Metals

H

Scheme 11.70

The ene reaction, or Alder-ene reaction, is a cycloisomerization involving the migration of an atom, typically hydrogen, across two nonconjugated double or triple bonds (Scheme 11.70). The reaction often requires high temperatures or the addition of strong Lewis acids. A related transformation can be achieved using transition metals as catalysts at much lower temperatures (Scheme 11.71). As with the cycloaddition reactions, a key feature is that the transition metals act as templates to draw the two unconnected double or triple bonds together. Palladium(II) can be a good catalyst for these reactions, coordinating to both the alkene and the alkyne.96 Oxidative cyclization then gives a metallacycle 11.210 with palladium in the +4 oxidation state. ␤-Hydride elimination then generates a new alkene 11.211, and reductive elimination completes the cycle. ␤-Hydride elimination occurs preferentially in an exo fashion as the hydrogen outside of the metallacycle ring is more accessible. Evidence for such metallacyclopentene intermediates includes the isolation of cyclobutene products arising from reductive elimination at this stage, in a formal [2 + 2] cycloaddition (Scheme 11.72).97 Indeed, a small change of ligand may be enough to switch the course of the reaction between the cycloisomerization and [2 + 2] pathways (Scheme 11.73).98 Pd(OAc)2

CO2Et CO2Et

CO2Et CO2Et

11.207

11.208

CO2Et CO2Et

Pd(OAc)2

CO2Et CO2Et

coordination

11.208 reductive elimination

H (AcO)2Pd

11.207

CO2Et CO2Et

CO2Et CO2Et

(AcO)2Pd

11.211

11.209

β-hydride

oxidative cyclisation

elimination IV

CO2Et

(AcO)2Pd

CO2Et

11.210

Scheme 11.71

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Cycloaddition and Cycloisomerization Reactions

417

Pd(II)

EtO2C EtO2C

EtO2C EtO2C CO2Me

11.212

11.213

CO2Me

Scheme 11.72

CoBr2L, Zn, ZnI2

Ph +

Ph

Ph L = dppp L = dppe

11.214

Ph 11.215

98:2 25:75

Scheme 11.73

This cyclization has been used in an efﬁcient synthesis of chokol A 11.219, an anti-fungal compound (Scheme 11.74).99 The acetal 11.216, in which the tartrate moiety functions as an economical chiral auxiliary, cyclized using palladium acetate to give an 8.5:1 mixture of stereoisomers. Acidic hydrolysis removed the acetal to give a ketone 11.217, which could be taken through to the natural product 11.219 by selective reduction of the electron-poor alkene, stereoselective addition of a methyl group, allylic oxidation and desilylation. Ene–yne cycloisomerization was used as a key step in a synthesis of hamayne 11.225, a crinane alkaloid and acetylcholineesterase inhibitor (Scheme 11.75).100 The cyclisomerization, which creates a quaternary centre was challenging. As a thermal Alder-ene reaction, without palladium, the reaction of 11.220 did not proceed. It was successful employing a palladium(II) catalyst with a bis-imine ligand, providing that microwave heating was used. Further, the alkyne could not be terminal. If a terminal alkyne was employed (R = H), intermolecular alkyne–alkyne coupling was observed (see Schemes 11.90–11.94), and a substituted

1. Pd(OAc)2 2. H 3O+

O EtO2C

O

EtO2C

(Ph3PCuH)6 O

SiMe3

11.216

SiMe3 11.217

1. MeCeCl2 2. SeO 2, t-BuOOH 3. KOt-Bu, DMSO O

SiMe3

OH

OH

11.218

Scheme 11.74

11.219

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Organic Synthesis Using Transition Metals TBSO

TBSO O

Ns

N

Pd(OAc)2, BBEDA N Ns

O

1. K 2OsO4, NMO, citric acid 2. PhI(OAc) 2

O O

11.220

11.221

R TBSO

O O N Ns

HO

TBSO 1. K 2CO3 2. NaBH(OAc) 3

O N H

O

11.222 HCO2

H2CO, HCO 2H

O

11.223

HCO2

HO

HO O

N

O

NH3, MeOH N

O

11.224

O

11.225

BBEDA = PhHC N

N CHPh

Scheme 11.75

alkyne (R = Me) had to be used to block this pathway.101 Selective cleavage of the exo-cyclic alkene of 11.221 allowed removal of the N-protecting group by an elimination–reduction sequence, which also reduced the ketone. Pictet–Spengler ring closure was accompanied by conversion of both the alcohol and the TBS ether to formate esters; cleavage of the formate esters then yielded the natural product 11.225. An alternative mechanism involves the use of metal hydrides (Scheme 11.76). Palladium(0) complexes can oxidatively add to acetic acid to generate such a hydride. Rather than an oxidative cyclization occurring, a sequence of insertion into the palladium–hydrogen bond, followed by insertion into the palladium–carbon bond forms the new bicyclic complex 11.230. ␤-Hydride elimination then releases the product 11.227 and regenerates the acetoxypalladium hydride.102 The alkyl palladium(II) species 11.230, which has no counterpart in the Pd(II)/Pd(IV) mechanism of Scheme 11.71, is particularly interesting. As with such species in the Heck reaction (Section 5.1.10), if it does not have a ␤-hydrogen available, it can be intercepted in other ways resulting in tandem processes. Multiple cyclizations are possible, for instance via a long sequence of neopentyl intermediates (Scheme 11.77).103 Intermolecular reactions are possible, although, strictly, they should not be referred to as cycloisomerization reactions, as they involve the coupling of two components. Without the discipline provided by being intramolecular, these reactions can suffer from the issue of regioselectivity. While this is not a problem with symmetrical alkynes, as in the synthesis of diene 11.233 (Scheme 11.78),104 little or no selectivity is observed with many simple substrates. One solution is to employ a propargyl alcohol as the substrate.105 Coordination of the hydroxy group to ruthenium then provides the required regiocontrol. This concept has been employed in a synthesis of ancepsenolide 11.237 by reaction of a chiral propargylic alcohol 11.235 with 1,11-dodecadiene

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SiMe3

SiMe3 Pd(0), HX N

N O

11.226

O

11.227

L2Pd oxidative AcOH addition

SiMe3

SiMe3

OAc L2Pd N

N

H

coordination

O 11.227 β-hydride elimination OAc LnPd

SiMe3 N

11.226

H SiMe3 Pd

AcO

H

O

N

11.230 O

O 11.228

insertion

AcO

H Pd

insertion

H

SiMe3 N O

11.229

Scheme 11.76 OMe

EtO2C EtO2C 11.231 OMe

Pd2dba3.CHCl3 AcOH, Ph3Sb

EtO2C EtO2C

11.232

Scheme 11.77 Ph + Ph

CO2Me Ru(COD)(COT)

Ph

CO2Me Ph 11.233

Scheme 11.78

419

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Organic Synthesis Using Transition Metals CpRu(COD)Cl

+ EtO2C 11.234 O

11.235

OH

O H2, (Ph3P)3RhCl 11.236 O

O

O

O

11.237

O

O

Scheme 11.79

ROC N

RhCl3, i -BuOH

11.238

ROC N 11.239

Scheme 11.80

11.234 (Scheme 11.79). The double cycloisomerization proceeds with double lactonization. The undesired double bonds, being the less hindered, were removed by hydrogenation using Wilkinson’s catalyst to give the natural product 11.237. A synthesis of the related natural product, dehydrohomoancepsenolide, can be found in Scheme 8.131. Cycloisomerization of dienes is also possible. Catalysts that have been used include rhodium (Scheme 11.80),106 ruthenium107 and palladium108 salts (Scheme 11.81) in alcohol solvents. Palladium NHC complexes are also efﬁcient catalysts.109 The most likely mechanism involves the formation of a metal hydride, which acts as the catalyst.110 In some cases, alkene migration may also be observed and, with the right choice of catalyst, may become the exclusive pathway, as in the formation of cyclopentene 11.242.111,112

(C3H5)PdCl(PCy3) MeO2C MeO2C

MeO2C MeO2C

11.241 B[3.2.0]DPOPdCl2, NaBAr4 MeO2C MeO2C

11.240

11.242

Scheme 11.81

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Cycloaddition and Cycloisomerization Reactions

+

CO2Me

HO

DEAD, PPh3

11.244

NHTs 11.243

CO2Me

N Ts

11.245

Grubbs II H2C=CHOSiMe3

(Ph3P)3(OC)RuHCl N Ts

CO2Me 11.246

O

CO2Me N Ts

421

N H

11.247

n-C18H37 11.248

Scheme 11.82

An intermolecular diene cycloisomerization was the key step in a synthesis of the putative structure of ﬁstulosin 11.248, an anti-fungal compound from Welsh onion roots (Scheme 11.82).113 The substrate 11.246 could be prepared by Mitsunobu alkylation of a sulfonamide 11.243, followed by migration of the double bond with a ruthenium catalyst. The cycloisomerization was achieved using a species generated from the Grubbs second-generation catalyst and the silyl enol ether of acetaldehyde. When the target structure 11.248 was ﬁnally reached, the spectroscopic data showed that the reported structure of the natural product was incorrect. The alkene component of the ene–yne cycloisomerization can be replaced with a carbonyl group (Scheme 11.83). Treatment of the alkynyl ketone 11.249 with a low-valent nickel catalyst gave a nickellacycle 11.250. When an organozinc reagent was used in the presence of the nickel catalyst, the reaction is not strictly a cycloisomerization, as additional atoms are transferred. With dimethyl zinc, a methyl group is transferred, with diethyl zinc, a hydrogen atom is transferred as ␤-hydride elimination is rapid (compare to Scheme 4.92).114 Silyl hydrides, however, prove to be a more convenient source of the hydrogen atom, and directly deliver protected alcohols.115 This reaction has been used with a highly functionalized alkyne 11.253 in a synthesis of allopumiliotoxin 339A 11.255 (Scheme 11.84).116

Me HO

O

R

Ni(COD)2, n-Bu3P

O

L Ni

Me2Zn R

11.251

H Et2Zn

11.249

11.250

R

H HO

11.252

Scheme 11.83

R

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Organic Synthesis Using Transition Metals O O N

Et3SiH, Ni(COD)2, n-Bu3P

CHO O

OBn

N

O

H

11.253

OSiEt3 OBn 11.254 OH

1. HF.py 2. H 3O+ 3. Li, NH 3(l)

OH N H

OH

OH 11.255

Scheme 11.84

The reaction also works in an intermolecular fashion using N-heterocyclic carbene ligands (Scheme 11.85).117 With unsymmetrical alkynes, the regioselectivity can be controlled by the choice of ligands.118 With a bulky ligand, the larger alkyne substituent is preferentially far from the nickel in the intermediate; with a carbene ligand with low steric demand, the situation is reversed. Diynes may also be substrates for cycloisomerization (Scheme 11.86), and analogous mechanisms involving hydridopalladation maybe drawn.119 The diyne reductive cyclization was employed in a synthesis of streptazolin 11.265, an antibiotic (Scheme 11.87).120 The diyne substrate 11.263 was constructed by alkyne additions to a chiral imine 11.260 derived, originally, from mannitol. Reductive cyclization gave the diene 11.264 with deﬁned stereochemistry. Cyclization of the tosyl-bearing side chain onto the oxazolidinone nitrogen under strongly basic conditions then created the second ring, and the synthesis was completed by desilylation. Another synthesis of this natural product may be found in Scheme 5.46.

O H

i -Pr2N

+

Ph

Me

Ni-Pr2

Ar N

Ni(COD)2,t -Bu2SiH2

N Ar

Ni(COD)2,i-Pr3SiH

OSiHt-Bu2

OSii-Pr3

n-Pr

Me

Me

n-Pr

11.256

11.257

Scheme 11.85

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Cycloaddition and Cycloisomerization Reactions

423

OMe TBSO

TBSO

OMe Pd2(dba)3.CHCl3 (o -tol)3P, Et 3SiH 11.258

11.259

Scheme 11.86

PMBO

OPMB N 11.260

O O

Li

PMBO

O O

TsO 1. (COCl)2, DMSO, Et3N 2. MgBr 3. TBSCl, C3H4N2 4. DDQ 5. TsCl, py

HN O

N H 11.261

Me3Al

1. [Pd(dba)2]2, o-C6H4(SH)CO2H 2. PhOCOCl, NaHCO3 3. H+; K2CO3

Pd2(dba)3, OTBS HCO2H, Et3SiH

HN

O 11.262

O O

11.263

TsO OTBS

HN

1. NaH 2. TBAF

OH N

O O

11.264

H

O

O

11.265

Scheme 11.87

A different course of events is followed by diynes in the presence of a ruthenium catalyst and water (Scheme 11.88).121 The mechanism is believed to involve the formation of a ruthenacyclopentadiene 11.268, which is attacked by water at the less-hindered position. Break-up of the ruthenacycle and protonolysis of the carbon–ruthenium bond delivers the product 11.267. This reaction was employed to synthesize the cyclindricine alkaloids, including cyclindricine C 11.275 (Scheme 11.89; for another synthesis, see Scheme 4.14).122 The diyne substrate 11.272, prepared in a short sequence from 1,7-octadiyne 11.271, gave the hydrated cyclization product 11.273 on treatment with water and a ruthenium catalyst. Chain extension using an aldol reaction set the stage for the double Michael addition upon N-deprotection and free basing. Removal of the remaining protecting group gave the natural product 11.275. ␣,␻-Diynes, such as 11.276 undergo a remarkable cycloisomerization–macrocyclization on treatment with a palladium(II) salt and an electron-rich phosphine (Scheme 11.90) to give a large ring alkyne 11.277.123

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Organic Synthesis Using Transition Metals CpRu(NCMe)3 PF6 H2O

TsN

TsN

11.266

11.267

O

TsN CpRu(NCMe)3

O 11.267

TsN

H+

TsN 11.270

11.266

RuCpLn

TsN

RuCpLn 11.268

OH H2O H+ TsN 11.269

RuCpLn HO

Scheme 11.88 O

NHt-Boc 11.271

11.272

CpRu(NCMe)3 PF6 H2O

O n-C6H13 NHt-Boc 11.274

OTBDPS

11.273

OTBDPS

1. LDA; n-C6H13CHO 2. MsCl, Et 3N

NHt-Boc

1. CF 3CO2H 2. K2CO3, Δ 3. TBAF

H

O

N

n-C6H13 11.275

OTBDPS OH

Scheme 11.89

Pd(OAc) 2 [o-(MeO)2C6H3]3P 11.277

11.276

Scheme 11.90

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425

O CO2Me

Pd(OAc) 2 [o-(MeO)2C6H3]3P

O 11.279

OH

11.278

Scheme 11.91

SiMe3 CO2Me

Pd(OAc) 2 [o-(MeO)2C6H3]3P

CO2Me Me3Si

Me

11.280

Scheme 11.92

With suitably placed hydroxy and ester functional groups, tandem lactonization can ensue (Scheme 11.91). The intermolecular coupling of two alkynes with this system is also possible (Scheme 11.92), provided that only one alkyne is terminal, and the acceptor alkyne is electron poor, otherwise extensive self-coupling of the alkynes may result.124 The mechanism may involve terminal palladation of one alkyne, followed by insertion of the second and protonolysis of the vinyl–palladium bond (Scheme 11.93). The intramolecular reaction will be limited to the larger reaction sizes, due to the strain inherent in cyclic alkynes of smaller size. The intramolecular alkyne coupling of diyne 11.281 was used in a synthesis of bryostatin 11.283 to close the macrocycle 11.282 (Scheme 11.94).125 This reaction was followed by a gold(I)-catalysed 6-endo ring closure of 11.282 and some routine transformations to complete the synthesis. As so often in macrocyclizations, a low concentration (0.002 M) was found to be important.

L2PdX2 HX

HX PdLnX

PdLnX

insertion

coordination

PdLnX

Scheme 11.93

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Organic Synthesis Using Transition Metals H

H

MeO2C O

OPiv

O OTES HO

H

H

O

O

OPiv

MeO2C Pd(OAc)2 O [o-(MeO)2C6H3]3P

OTES HO

O

O

O OTBS

OTBS 11.281

CO2Me

MeO2C H

H

O

O

OPiv

MeO2C

OH 1. Ph 3PAuCl, AgSbF6 2. Piv2O, DMAP 3. TBAF

O

11.282

H

O O OH

CO2Me

11.283

Scheme 11.94

OTBDPS O

O

Me3Si

O

O PMB

11.284

H

OTBDPS

R O

O

CpRu(NCMe)3 PF6

O

O PMB O

11.286

OH

OTBS

OTBS

R = SiMe3 NBS R = Br

11.285

Scheme 11.95

The fact that cycloisomerization and related reactions provide a mild method for carbon–carbon bond formation, with the need for strong acids and bases, is further demonstrated by the fact that another of these reactions was used earlier in the same synthesis to combine alkyne 11.285 with alkene 11.284 to give the pyran 11.286 (Scheme 11.95).

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Cycloaddition and Cycloisomerization Reactions 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125.

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Abbreviations

Ac acac Ad AIBN Aloc Ar 9-BBN BBEDA BINAP o-biPh bipy Bn Bz BQ Boc Bu CBS Cbz COD COE COT Cp Cp* Cy DABCO dba DBS DBU DCC DDQ DEAD DET DIAD DIBAL

acetyl acetoacetyl adamantyl azobis-iso-butyronitrile allyloxycarbonyl aryl 9-borabicyclononane bisbenzylidene ethylene diamine 1,1’-bi-2-naphthol o-biphenyl 2,2’-bipyridyl benzyl benzoyl benzoquinone t-butoxycarbonyl butyl the Corey-Bakshi-Shibata catalyst benzyloxycarbonyl 1,4-cyclooctadiene cyclooctene 1,3,5,7-cyclooctatetraene cyclopentadienyl pentamethylcyclopentadienyl cyclohexyl 1,4-diazabicyclo[2.2.2]octane dibenzylidene acetone dibenzosuberyl 1,8-diazabicyclo[5.4.0]undec-7-ene dicyclohexylcarbodimide 2,3-dichloro-5,6-dicyano-1,4benzoquinone diethyl azodicarboxylate diethyl tartrate di-iso-propyl azodicarboxylate di-iso-butylaluminium hydride

DIPT DMAP DME DMF dmgh dmpe DMPU DMSO dppb dppbz dppe dppf dppm dppp dtbpy dvds EBTHI EE Et Fp Fu HATU

HOBT HOMO Ipc IBX KHMDS LDA LUMO mcpba

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

di-iso-propyl tartrate 4-dimethylaminopyridine 1,2-dimethoxyethane N,N-dimethylformamide the dimethylglyoxime ligand 1,2-bis(dimethylphosphino)ethane 1,3-dimethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinone dimethylsulfoxide 1,4-bis(diphenylphosphino)butane 1,2-bis(diphenylphosphino)benzene 1,2-bis(diphenylphosphino)ethane 1,1’-bis(diphenylphosphino)ferrocene bis(diphenylphosphino)methane 1,3-bis(diphenylphosphino)propane 2,6-di-t-butylpyridine 1,3-divinyl-1,1,3,3tetramethyldisiloxane ethylene-1,2-bis(␩5 -4,5,6,7-tetrahydro1-indenyl) ethoxyethyl ethyl cyclopentadienyldicarbonyliron furyl O-(7-benzotriazol-1-yl)-N,N,N’,N’tetramethyluronium hexaﬂuorophosphate N-hydroxybenzotriazole highest occupied molecular orbital isopinocampheyl 2-iodoxybenzoic acid potassium hexamethyldisilazide lithium diisopropylamide lowest unoccupied molecular orbital m-chloroperbenzoic acid

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Me MOM Ms Naph NBS NBD NCS NHC NIS NMO NMP Oct PCC PDC PG Ph phen Phth pin Piv PMB PNB PMP PPTS Pr Py

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Abbreviations

methyl methoxymethyl methanesulfonyl naphthyl N-bromosuccinimide norbornadiene N-chlorosuccinimide N-heterocyclic carbene N-iodosuccinimide N-methylmorpholine-N-oxide N-methylpyrrolidinone n-octyl pyridinium chlorochromate pyridinium dichromate protecting group phenyl phenanthroline phthalimido pinacolato pivaloyl p-methoxybenzyl p-nitrobenzyl 1,2,2,6,6-pentamethylpiperidine pyridinium p-toluenesulfonate propyl pyridine or pyridyl

RCM RT TBAF TBDPS TBS TEMPO Tf THF THP TIPS TMEDA TMG TMP TMS o-tol TON TPAP Ts h␯ ))) ␮W

ring closing metathesis room temperature tetra-n-butylammonium ﬂuoride t-butyldiphenylsilyl t-butyldimethylsilyl 2,2,6,6-tetramethyl-1-piperidinyloxy radical triﬂuoromethanesulfonyl tetrahydrofuran tetrahydropyranyl tri-iso-propylsilyl N,N,N’,N’tetramethylethylenediamine tetramethylguanidine 2,2,6,6-tetramethylpiperidinyl trimethylsilyl o-tolyl turnover number tetra-N-propylammonium perruthenate p-toluenesulfonyl irradiation with visible or ultraviolet light ultrasound microwave heating polymer or solid support

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Index

acetal, 195 N,O-acetal, 214 acetal, bicyclic, 194 acetoxytubipofuran, 382 N-acetylaureothin, 405 acetylene, 62, 397 acetylene, trimethylsilyl, 62, 63 acetylide, copper, 61 achalensolide, 246 acid chlorides, coupling, 42, 66 acid chlorides, Heck reaction, 157 acosamine, 345 acridine, synthesis, 73 adenosine, 338 AD-mix, 50 africanol, 300 ailanthoidol, 62 alcohol coupling, 76, 78 aldehydes, CH activation of, 100 Alder ene reaction, 416 aldol reaction, 96, 140, 193, 241, 257, 280, 408, 414 alkene metathesis, 278 alkenes, complexes of, 3, 192 alkenes, double addition, 203 alkenes, reactivity, 192 alkyne metathesis, 310 alkynes, carbonylation of, 129 alkynes, carbonylative coupling, 119 alkynes, complexes of, 3, 192 alkynes, cyclic, 241 alkynes, nucleophilic attack upon, 207, 217, 425 alkynols, carbonylation of, 130 allene, cyclization, 206, 213 allenes, 141, 195 allenes, carbonylation, 356 allenes, in Pauson-Khand reaction, 246 allenols, carbonylation of, 130 allocolchicine, 94 allopumiliotoxin 339A, 421

allyl complex, 92, 93, 166, 325 allyl complex, cobalt, 141 allyl complex, from CH activation, 103 allyl complex, molybdenum, 368 allylation, asymmetric, 337, 339, 349 allylation, base-free, 344 allylation, regioselectivity, 331 allylation, stereoselectivity, 335 alnuson, 68 aluminium, in coupling reactions, 22, 35 amide coupling, 73 amides, by carbonylation, 122 amides, synthesis, 268 amine coupling, 78 amine oxide, 14, 246 amino acid, 268 ammonia surrogate, 73 amphidinolide, 294 anabasine, 135, 287 anatoxin, 193 ancepsenolide, 418 ancepsenolide, dehydro, 311 anhydrides, by carbonylation, 122 anthracene, 262 anthracyclinones, 261 antimycinone, 263 aphidicolin, 140 arabinose, 368 arcyriacyanin, N-methyl, 94 Arduengo, 9, 253 arene complexes, 4, 377 arene complexes, alkylation, 385 arene complexes, deprotonation, 385 arene complexes, electrophilicity, 380 arene complexes, nucleophilic attack, 380 arene oxide, 223 arene, ␩2 -complex, 387 arene, ␩6 -complex, 260, 377 arizonin C, 262

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Index

aromatic substitution, nucelophilic, 380 asteriscanolide, 410 “ate” complex, 46, 57, 253, 260 aureothin, 405 aureothin, N-acetyl, 405 australine, 280 avenaciolide, 145 avermectin, 143 azetidines, carbonylation of, 124 aziridine, N-tosyl, 185 aziridines, carbonylation of, 124 azole, vinylation, 99 Barbier reaction, 130, 400 barbituric acid, dimethyl, 351 bark beetle, 370 Barton decarboxylation, 414 Barton-McCombie, 227 9-BBN, 50 benzazepine, hetero, 72 benzocyclobutene, 111, 396 benzocyclobutenes, 111 benzodiazepine, synthesis, 73 benzofuran synthesis, 62, 197, 205, 221, 260 benzoquinone, 63 benzotriazole, as leaving group, 329 benzyne, 31, 179 Berthelot, 394 Berzelius, 18 biaryl, synthesis, 42, 52, 93, 398 bidentate ligands, 7 bimetallic catalysis, 35 BINAP, 7, 8, 72, 81 BINOL, 81 biotin, 251 biphephos, 132 Birch reduction, 277, 373 bis(trimethylsilyl)acetylene, 396 Bischler-Napieralski reaction, 53, 336, 355, 393 bismuth, coupling, 67 bistramide A, 296 blastmycinone, 263 ␤-blocked complexes, 17 bollworm, pink, 25 borane, vinyl, cross-metathesis, 296, 405 boranes, alkenyl, 48 boron reagents, synthesis, 46 boronic acids, 47 borylation, by CH activation, 102 brasilenyne, 60 Bredt’s rule, 16, 169, 172

brefeldin, 403 brettphos, 6 brevicomin, 50 bryostatin, 425 Buchner reaction, 313 butenolide synthesis, 123, 130, 161, 246, 306 butterﬂy, Monarch, 342 butyrolactone, opening, 386 butyrolactone, synthesis, 270, 303 Cadiot-Chodkiewitz reaction, 66 caffeine, CH activation of, 99 calabar bean, 167 calamenene, dihydroxy, 386 calichemicin, 63 calicophirin, 3-deacetoxy-6-deacetyl, 306 capnellene, 119, 166, 276 carabrone, 266 carbamate coupling, 73 carbapenem, 73 carbazole, synthesis, 73, 374 carbene complexes, 3, 9, 253 carbene, chromium, 205 carbene, cyclopropyl, 226, 228 carbene, gold, 225 carbenes, aldol reaction, 257 carbenes, alkylation, 257 carbenes, from diazo compounds, 312 carbenes, hydrido, 254 carbenes, pKa value, 256 carbenes, vinyl, 256 carboalumination, 306 carbomagnesiation, 182 carbomycin B, 132 carbon dioxide, 146, 149, 345, 400 carbon monoxide, 2, 4, 12, 13, 14, 16, 117, 139, 204, 233, 246, 253, 258, 267, 366 carbonates, for allylation, 344 carbonylation, 204, 262 carboxylic acid, CH activation of, 109 carboxylic acids, by carbonylation, 122 carbozirconation, 36, 175, 177 carbyne complexes, 3, 310 Castro-Stephens reaction, 61 catalysis, 18 catalysis, asymmetric, 8 catalytic cycle, 18 catechol borane, 48 Cathepsin K inhibitor, 291 cations, propargyl, 244 CC1065, 181

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Index cembranoid, 306 centrolobine, 156 cephalotaxine, 340 CH activation, 2, 55, 89 CH activation, with carbenes, 316 CH activation, with nitrenes, 316 Chatt-Dewar-Duncanson model, 3, 4 Chauvin, 274, 279 Chauvin, Nobel prize, 1 chelotropic elimination, 412 chiraphite, 138 chiraphos, 8 chlorides, in coupling reactions, 24 chlorotricholide, 48 chokol A, 417 chromene, synthesis, 220 chromium, arene complexes, 377 ciguatoxin, 244, 286 Cinnamomum laubatii, 289 citronellol, 249 civet cat, 370 Claisen rearrangement, 280, 408, 411 Claisen, retro-, 241 clathculin B, 62 clavaicipitic acid, 181, 195 clavukerin A, 346 club moss, Chinese, 342 cobaloxime p-cations, 235 cobalt, allyl complex, 141, 325 cobalt, complexes with alkynes, 241 cobalt, diene complex, 370, 400 cobaltacyclpentadiene, 394 cockroach, 33 Collman’s reagent, 139, 229, 366 cone angle, 10 coniine, 298 coordination, 14 coral, Japanese, 382 coralydine, 111 Corey-Fuchs method, 302 coriolic acid, 41 Corriu-Kumada reaction, 22 crassifolone, 221 crispine, 135 cross-metathesis, 286, 291, 303, 361, 405 cryptoacetalide, 398 cubane, 361 Curtius rearrangement, 111, 342 cyanide, coupling, 82 cyanolide, 198 cyathane diterpenes, 408

439

cycloaddition, 391 cycloaddition, 2+2, 402, 416 cycloaddition, 2+2+2, 394 cycloaddition, 4+4, 410 cycloaddition, 5+2, 407 cycloaddition, 6+2, 411 cycloaddition, 6+4, 411 cycloaddition, asymmetric, 391 cycloaddition, formal, 235, 259 cycloaddition, photochemical, 361 cyclobutadiene, 361, 394 cyclobutane, 385 cyclobutanone, 410 cyclobutanone, synthesis, 263, 268 cyclobutene, 306 cyclobutene, synthesis, 276 cyclobutenone, synthesis, 263 cyclocolorenone, 363 cycloheptadiene, 374 cycloheptatriene, complex of, 365 cyclohexenone, 373 cyclohexyne, 179 cycloisomerization, 272, 415, 426 cycloisomerization, alkynyl ketones, 421 cycloisomerization, diynes, 417, 423 cyclooctatetraene, synthesis, 394 cyclopentadiene, 166, 276 cyclopentadienone, 394 cyclopentadienyl ligand, 4 cyclopentenone, 246, 263, 289, 364 cyclopropanation, 167, 225, 226, 266, 300, 312, 361, 383 cyclopropane, amino, 186 cyclopropane, cyclopropylidene, 160 cyclopropane, dibromo, 53 cyclopropane, divinyl, 374 cyclopropane, methylene, 405 cyclopropane, stannyl, 53 cyclopropane, vinyl, 101, 407 cyclopropanes, in cycloadditions, 407 cyclopropanol, synthesis, 185 cyclopropenation, 312 cyclopropyl carbocation, 188 cyclopropyl zinc, 53 cyclotrimerization, 394 cylindricine C, 120, 423 cylindrocyclophane, 286 dactylol, 289 Darvon alcohol, 411 daunomycinone, 261 davephos, 6

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Index

decarbonylation, 6, 43, 100, 148, 157, 300 decarboxylation, 149, 347 decomplexation, 232, 244, 259, 361, 377 decosamine, 270 dehydroancepsenolide, 311 dehydrobufotenine, 181 demetallation, 258 dendralenes, iron complexes of, 361 dendralenes, synthesis, 28 Denmark modiﬁcation, 57 deoxyerythronolide B, 104 deoxyfrenolicin, 262 deoxypancratistatin, 336 diaryl ether, synthesis, 76, 380 diazo compounds, 312 diazonium salt, in Heck reaction, 155 diazonium salts, in coupling reactions, 24 Dictyodendrin A, 28 dictyostatin, 48 Diels-Alder reaction, 42, 48, 64, 92, 93, 111, 132, 160, 223, 256, 276, 301, 336, 354, 361, 391, 396 diene complexes, 4, 361 diene complexes, cobalt, 370, 400 diene complexes, deprotonation, 370 diene complexes, electrophilic attack, 364 diene complexes, iron, 361 diene complexes, molybdenum, 368 diene complexes, nucleophilic atack, 366 dienyl complexes, 371 differolide, 301 dihydrocanadensolide, 249 dihydrofuran, 25 dihydropyran, 25 dihydroxanthatin, 203, 303 dihydroxycalamenene, 386 dihydroxylation, 262, 271, 280, 287, 339, 361, 373 dihydroxylation, asymmetric, 50 diimide, 94 diospongin A, 200, 202, 293 DIPAMP, 8 diphos, 7 1,3-dipolar cycloaddition, 213, 313 disiloxane coupling, 57 dissociation, 14 diyne, hydration, 423 diynes, synthesis, 66 dmpe, 7 D¨obereiner, 18 Doebner modiﬁcation, 262 dofetilide, 73 dolabelide, 132

d-orbitals, 2 D¨otz reaction, 258 DPEphos, 7 dppb, 7 dppbz, 7 dppe, 7 dppf, 7 dppm, 7 dppp, 7 dry-state absorption, 246 dubamine, 44 dumetorine, 297 dumsin, 280 Duthaler reagent, 294 EBC-23, 289 EBTHI, 183 ecklonialactone A, 312 eighteen electron rule, 11 electrocyclic ring closing, 111, 221, 259, 269 electrocyclic ring opening, 53, 111, 188 elimination, chelotropic, 412 enaminone, 98 ene reaction, 415, 416 ene-diyne, 63, 244 ene-yne cyclisation, 225 ene-yne metathesis, 300 ene-yne-ene metathesis, 303 ene-ynes, in D¨otz chemistry, 263 englerin A, 228 enol esters, by carbonylation, 122 enol ether, 194, 327 enol ether, silyl, 327 enol ether, synthesis, 258, 266, 270, 275, 280, 308 enolate coupling, asymmetric, 70 enolate, coupling, 69 enols, synthesis, 415 enones, addition of boronic acids, 174 epibatidine, 356 epiglobulol, 101 epi-lupinine, 315 epoxidation, enantioselective, 50 epoxidation, Sharpless, 143 epoxide, opening, 175 epoxide, vinyl, 142 epoxides, carbonylation of, 124 epoxides, for allylation, 344 epoxides, vinyl, 344 epoxydictamine, 250 erythrocarine, 146 Eschenmoser’s salt, 181

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Index

441

esperamycin, 63 esters, by carbonylation, 122 estrone, 396 eta number, 3 ethene, 278 ethene, in Heck reaction, 159 ethene, in metathesis, 294 ethene, with palladium(II), 192 ether synthesis, 76 ether, allenic, 195 ether, cyclic, synthesis, 313 ethers, in coupling reactions, 24 eupomatilone, 55 eutypine, 122

goniofufurone, 200 goniotine, 197 Grela catalyst, 291 Grignard reagent, 21, 25, 38, 27, 28, 31, 182, 185, 221, 224, 273, 289, 293, 305, 369, 373, 382 Grignard, Nobel prize, 1 Grubbs, 278 Grubbs catalyst, ﬁrst generation, 279 Grubbs catalyst, second generation, 9, 279 Grubbs catalysts, 5, 278, 311, 414 Grubbs, Nobel prize, 1 guaianolide, 246 guanacastepene, 306 guanidine coupling, 73

Favorskii reaction, 361 ferrilactam, 142 ferrilactone, 142, 325 ferrocene, 2, 4 ferrocinium ion, as oxidising agent, 374 ferruginine, 203, 414 Fischer carbenes, 253 Fischer indole synthesis, 76 Fischer, Nobel prize, 1 ﬁscuseptine, 65 ﬂavonone synthesis, 119 ﬂuviricin B1 , 183 formate, 346 formate, as hydride source, 82, 170, 172 formyl ligand, 16 formylation, 98, 122 Fp group, 229 Frankland, 2, 32 Friedel-Crafts reaction, 127, 226, 244, 250, 262, 325, 365 Fritsch-Buttenberg-Wiechell rearrangement, 269, 272 frontalin, 194, 285 fugu ﬁsh, 319 Fujiwara-Heck reaction, 91, 98, 103, 112 furan, 223 furan, synthesis, 214, 216, 335

halide, coupling, 82 hamayne, 417 hapto number, 3 Hashmi phenol synthesis, 223 Heck, 131 Heck reaction, 5, 57, 153, 195, 206, 303, 342 Heck reaction, asymmetric, 164 Heck reaction, carbonylative, 127 Heck reaction, intramolecular, 163, 181 Heck reaction, ligand destruction, 81 Heck reaction, regioselectivity, 160 Heck reaction, stereoselectivity, 160 Heck reaction, tandem, 169 Heck reaction, with boronic acids, 174 Heck reaction, with dienes, 352 Heck, Nobel prize, 1 helicene, 398 helicene, synthesis, 291 Helicobacter pylori, 405 heliotridane, 145 Herrmann’s catalyst, 5, 55, 158 heteroatom coupling, 70 heterocycle carbonylation, 124 N-heterocyclic carbenes, 1, 9, 28, 53, 278 heterogeneous catalysis, 10 hirsutene, 248 Hiyama reaction, 22, 42, 57 Hiyama reaction, role of Lewis base, 57 Hiyama-Nozaki-Kishi reaction, 306 HOMO, 365 homocoupling, 67 homoenolate, 32 Horner-Wadswoth-Emmons reaction, 276, 342, 346 Hoveyda-Grubbs catalyst, 278 huperazine A, 342 hydrazine coupling, 73

galanthamine, 303 gambierol, 52 germanium, coupling, 67 Glaser coupling, 66 gleosporone, 289 glycosidase inhibitor, 287 gold, 1 gold, activation of alkenes, 211 gold, activation of alkynes, 216, 425 gold, activation of allenes, 213

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Index

hydrazine surrogate, 76 hydride abstraction, 232 ␤-hydride elimination, 16, 56, 161, 193, 202 hydroalumination, 35, 48 hydroboration, 48, 52, 303, 348, 349, 411 hydroformylation, 130, 300 hydroformylation, asymmetric, 138 hydroformylation, directed, 135 hydroformylation, tandem, 133 hydrometallation, 35 hydrosilation, 60 hydroxamic acid, CH activation of, 109 hydroxylamine, allenic, 214 hydrozirconation, 36, 37, 175 hypophosphite, 244 ibogamine, 93 imidazole, CH activation of, 99 imidazolium salts, 9 imine, CH activation, 109 indanomycin, 38 indium co-catalysis, 405 indium, coupling, 67 indole, 211 indole synthesis, 68, 76, 161, 171, 181, 196, 197, 205, 207 indole, CH activation, 103, 114 indole, coupling, 94 indole, vinylation, 93 indoles, dihydro, 352 indoline synthesis, 181 indolizidine, 65, 236, 287 insertion, alkenes, 15 insertion, alkynes, 15 insertion, CO, 16 iodine acetate, 108 iodosobenzene diacetate, 106, 108 ipalbidine, 53, 98, 314 ipsdienol, 370 iridium, allyl complex, 332 iron catalysis, coupling, 31 iron, activation of alkenes, 229 iron, activation of alkynes, 235 iron, allyl complex, 325 iron, arene complexes, 377 iron, diene complexes of, 361 isoavenaciolide, 145 isocyanates, 280, 346 isoferrilactone, 142 isoindoline, 28 isomerisation, alkene, 156, 242, 342, 363, 414

isomerization, in Heck reaction, 162 isomintlactone, 130 isopulegol, 415 isoretronecanol, 145 jackiephos, 6 Jeffery conditions, 159 johnphos, 6 Johnson-Claisen reaction, 96, 382 jungianol, 224 kallolide, 214 Keck allylation, 294 ketal, 194 ketene, intermediate, 263, 267 ketene, vinyl, 259 ketenes, in cycloadditions, 400 ␤-ketoester, synthesis, 124 ketone synthesis, 193, 266, 356 ketones, allenic, 214 ketones, synthesis, 117, 140 kinase inhibitor, 53 Knoevenagel reaction, 262 Knowles, Nobel prize, 1 Krapcho decarboxylation, 166, 277, 342, 355 Kulinkovich reaction, 185 Kumada coupling, 22, 27, 42, 185, 347 Kursanov-Parnes reduction, 69 lactam, 302 ␤-lactam, 73 ␤-lactam, synthesis, 143, 268, 313 lactone, synthesis, 263, 270, 272, 303, 425 ␤-lactone, synthesis, 143, 268 lactones, by carbonylation, 122, 130, 143, 200 ladder toxin, 244 lanthanum complexes, 216 Larock, 171 laulimalide, 188 lavendamycin, 400 le Chatelier, 14 Le Chatelier’s principle, 14, 43, 153, 158, 274 Leaving groups, in coupling reactions, 23 lennoxamine, 69 lepadin, 303 Lewis acid, 231 ligand engineering, 5 Lindlar reduction, 311 lithium reagents, 27 LUMO, 335 lupinine, 135

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Index luteolin, 119 lycoﬂexine, 309 lycopladine A, 221, 348 lycopodium alkloids, 348 lycorane, 53, 355 malonate, 166, 327 manganese complex, from CH activation, 89 manganese, arene complexes, 377 Mannich reaction, 309, 415 manumycin, 38 manzamine, 42, 282 Masmune-Roush conditions, 346 McMurry, 347 Me-DUPHOS, 8 Meerwein’s salt, 253 Meissenheimer complex, 380 menthol, 414 Mephos, 6 mesylates, in coupling reactions, 24 metallacyclopentadiene, 396 metallation, 89 metallation, ortho, 28, 52, 385 metalloproteinase inhibitor, 79 metathesis, 273 metathesis, alkene, 1 metathesis, alkene reactivity, 291 metathesis, alkyne, 310 metathesis, asymmetric, 297 metathesis, chelation effects, 288 metathesis, diastereoselective, 286 metathesis, N-containing compounds, 286 metathesis, relay, 284 metathesis, sigma bond, 89 metathesis, tandem, 306 metathesis, titanium additive, 289, 298 metathesis, vinyl silanes, 60 metathesis, with hydrogenation, 308 metathesis, with isomerization, 308 metathesis, Z-selective, 293 N-Methyliminodiacetic acid, 47 Michael addition, 120, 140, 256, 276, 293, 340, 261, 367, 373, 387, 403 mintlactone, 130, 249 mitomycin, 72 Mitsunobu reaction, 96, 112, 205, 303, 421 Miyaura borylation, 46, 48 Mizoroki-Heck reaction, 153 molybdenum, allyl complex, 331 molybdenum, carbonyl derivative, 145 molybdenum, diene complex, 368

Monarch butterﬂy, 342 Mond, Ludwig, 2 morphine, 164 Mozingo method, 263 Mukaiyama reagent, 98 multitalents, 253 musk, 312 mycolactone, 36, 37 myophorone, 327 naphthol synthesis, 258 naphthoquinone, synthesis, 262 naproxen, 138 Natta, Nobel prize, 1 Nazarov cyclisation, 119 negamycin, 205 Negishi reaction, 22, 32, 36, 3753, 173, 349, 400, 405 Negishi, Nobel prize, 1 neocryptolepinine, 93 neolaulimalide, 188 neopentyl complex, 16 Nicholas reaction, 244, 250, 363 nickel, catalysis of coupling, 35 nickelalactone, 146 nicotine, 135, 287, 339 nitrene complexes, 316 nitride complex, 310 nitro, as leaving group, 329 nitrone, in cycloaddition, 213 nitrosyl cation, 382 norbornene, 132, 169, 172, 300 norbornyl complex, 16, 17 nornicotine, 153 Noyori, Nobel prize, 1 nucelophilic aromatic substitution, 380 nupharamine, 294 octocoral, 306 Oleﬁn metathesis, 278 Onion roots, Welsh, 421 organo tin by-products, 41 ortho-ester, 368 osmium, arene complexes, 387 Otera catalyst, 349 oxetanes, carbonylation of, 124 oxidative addition, 15, 56, 89, 207 oxidative cyclisation, 17 Oxidative Heck reaction, 91 oximes, as nucleophiles, 213 oximes, CH activation, 105

443

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Index

palladium, allyl complex, 328 pancratistatin, deoxy-, 336 parviﬂorin, 123 Pauson-Khand reaction, 246 Pauson-Khand reaction, asymmetric, 248 Pauson-Khand reaction, hetero-, 249 Pectinophora gossypiella, 25 peluroside, 285 pentalenolactone, 316 pentamethylcyclopentadienyl ligand, 4 PEPPSI catalyst, 36 peptide, 268 peptide, tri-, 32 perovskite, 10, 55, 65 Petasis reagent, 275 phenanthroline, 310 phenol coupling, 76 phenol, complex, 387 phenol, synthesis, 223, 258, 310 phenoxide coupling, 70, 109 pheromone, 32, 33, 342, 370 Phillips trioleﬁn process, 274 phosphate, as leaving group, 329 phosphates, in coupling reactions, 24, 52 phosphine coupling, 81 phosphine oxide, 246 phosphine, coordination by copper, 45 phosphines, 5 phosphites, as ligands, 8 phosphoramidites, as ligands, 339 photochemistry, 267 physostigmine, 167 physovenine, 167 Pictet-Spengler reaction, 418 pinacolatoborane, 47 piperidine synthesis, 133, 287, 294 platinum, activation of alkenes, 211 platinum, activation of alkynes, 218 plicatin, 155 polycavernoside, 198 pre-catalyst, 18, 21 propargylic alcohol, 35, 244 propargylic complexes, 357 prostaglandin, 202 protecting group, allyl, 350 epi-pseudoconhydrine, 133 pseudolaric acid, 315 pseudoptersin G, 244 psycholeine, 168 purine, chloro, 339 pybox ligand, 35

pyrazole, bromo, 28 pyrenophorin, 43 pyridine, complex, 379, 387 pyridine, halo, 23, 48, 65 pyridine, halo, carbonylation of, 124 pyridine, halo, Heck reaction of, 153, 159 pyridine, synthesis, 221, 400 pyridines, CH activation of, 98, 107, 109 Pyridones, 44, 314 pyridyl sulfonyl group, 114 pyrrole, 236 pyrrole, CH activation, 98, 103, 114 pyrrole, complex, 378 pyrrole, synthesis, 217, 333 pyrrolidine synthesis, 211, 212, 221, 287, 302 pyrrolizidine synthesis, 212, 213, 216 Qphos, 6 Qphos, synthesis, 94 quadrigemine, 168 quebrachamine, 298 quinidine, 50 quinine, 50 quinoline, dihalo, 94 quinolines, CH activation of, 98, 107 quinolizidine synthesis, 305, 315 quinone, 374 quinone, synthesis, 259 quinuclidine, 50 rapamycin, 38 rare earths, 212 RCM, see ring closing metathesis recifeiolide, 283 reductive amination, 294, 339 reductive elimination, 15 reductive elimination, oxidatively induced, 105, 143 Reformatsky reagent, 70, 373 Reissert, 245 relay metathesis, 284 Reppe, 394 retronecine, 213 rhazinal, 96 rhazinicine, 103 rhopaloic acid, 206 ring closing metathesis, 185, 279, 311, 349, ring closing metathesis, tethered, 283 ring closure, electrocyclic, 259 ring-opening metathesis, 296 ROMP, 296 rosefuran, 27, 273

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Index Rosenblum, 229 roseophilin, 333 Ruphos, 6 ruthenium, arene complexes, 377 Sabatier, 2 Sabatier, Nobel prize, 1 saliniketal, 194 Sandmeyer reaction, 156 sandwich, tentacled, 385 sarain A, 42 scandium complexes, 212 Schrock, 278 Schrock carbenes, 253 Schrock catalyst, 278, 308 Schrock, Nobel prize, 1 Schrock’s catalyst, 185 Schwartz’s reagent, 175 sedinine, 214 selectﬂuor, 212 selectivity, in coupling reactions, 25, 26 serine, 32 Sharpless, Nobel prize, 1 shikimate, methyl, 373 sigmatropic shift, 276, 315, 374 silacyclobutane, 57 silane, synthesis, 60 silanes, coupling, 57 silanol, coupling, 57 silver salts, in Heck reaction, 158 silver, activation of alkenes, 211 silver, activation of alkynes, 216 silver, activation of allenes, 213 skewphos, 8 slime mould, 94 Sonogashira reaction, 23, 25, 26, 37, 61, 122, 123, 160, 170, 21, 270, 398, 400 Sonogashira reaction, with acid chlorides, 66, 94 Sphos, 6 spiro-compound, 373, 382 spiroketal, 143, 218, 296, 398 spiroketal, benzo-, 186 stannane, homocoupling, 68 Stannanes, aryl, 42 stannanes, by coupling, 38 stannanes, heteroaryl, 42 stannanes, vinyl, 41 stemoamide, 130, 302 stemona alkaloids, 130 stenine, 130 steroids, 105, 173, 220

445

Stevens rearrangement, 315 Stille coupling, 22, 27, 37, 46, 67, 168, 200, 204, 205, 306, 314, 330 streptazolin, 170, 422 streptorubin, 227 Strohmeier condenser, 377 strychnine, 41, 119, 344 substitution, nucelophilic aromatic, 380 sulfonamide coupling, 73 sulfone, as leaving group, 329, 342 sulfoxide, as ligand, 104 sulfoximine coupling, 73 sundiversifolide, 280 supellapyrone, 33 Suzuki coupling, 22, 25, 31, 36, 42, 65, 102, 109, 160, 170, 221, 339, 405 Suzuki coupling, role of Lewis bases, 46 Suzuki, Nobel prize, 1 Suzuki-Miyaura Reaction, 22 swainsonine, 214, 287, 351 Swern oxidation, 123, 302, 346, 411 synergistic effect, 3 Takai reaction, 50, 123 Takasago process, 414 tamiﬂu, 351 tandem reactions, 198, 306, 309, 313 tashiromine, 65, 236 taxol, 163 Tebbe’s reagent, 274, 276, 277 teleocidin, 109 telomerase inhibitor, 28 terprenin, 25 tetracarbonyl ferrate ion, 139 tetrahydopyran synthesis, 195, 198, 370 tetrahydrofuran synthesis, 198, 276, 405 tetrodotoxin, 319 tetronasin, 202 thallium hydroxide, 48 thapsigargin, 280 thienamycin, 313 thioesters, in coupling reactions, 24, 66 thiol coupling, 78, 81 thiophene, as surrogate alkyl group, 212 thiophene, CH activation of, 99, 114 thiophene, complex, 379 thyroxine, 79 tin reagents, 37, 38 titanocene, 177 titanocene chloride, 274 tolBINAP, 8

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Index

torcetrapib, 72 Tosmic, 262 transannular reaction, 281 transmetallation, 15, 33, 35 tri-(2-furyl)phosphine, 5, 45 tricholomenyn A, 63 tricyclohexylphosphine, 6 tricyclopentylphosphine, 6 triene complexes, 411 triﬂamide, as counter ion, 211 triﬂate, in Heck reaction, 155 triﬂates, in coupling reactions, 24, 44 triﬂates, pyridyl, 44 triﬂates, vinyl, 44 triﬂuoroborate salts, 48, 53, 79 trimethylene methane, 361, 368, 370, 376, 402 tri-n-butylphosphine, 6 trioleﬁn process, 274 tri-o-tolylphosphine, 5 triphenyl phosphine, 5 triphenylarsine, 5, 45 triphenylphosphine, 1 triphenylstibine, 5 tris(pentaﬂuorophenyl)phosphine, 5 tri-t-butylphosphine, 6 trityrosine, 48 trixiephos, 6 tropane derivative, 53 tropone, 405 tropone, complexes of, 361, 363 tuberostemonine, 294 tungsten, carbonyl derivative, 145 turnover number, 19 tylophorine, 221

Ullmann, 78 ultrasound, 246 urea coupling, 73 vernolepin, 165 vibsanol, 221 Vilsmeier-Haack formylation, 98 vinyl boronic acid, 48 vinylidene complexes, 3, 269, 272 vitamin D, 161 vodka, 61 von Braun demethylation, 181 Wacker reaction, 129, 192, 353 Wilkinson, 2, 131 Wilkinson, Nobel prize, 1 Wilkinson’s catalyst, 124, 149, 242, 349, 408, 420 Wittig reaction, 25, 120, 196, 200, 273, 274, 281, 302, 339, 342, 346 Xantphos, 7 xenovenine, 212, 213, 216, 339 o-xylylene, 111, 396 ylid, nitrogen, 315 yohimban, 393 Zeise, 2 Zeise’s salt, 3 Ziegler, Nobel prize, 1 zinc reagents, 32 zirconium, in coupling reactions, 22, 35 zirconocene, 177

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Index of Principle Transition Metal Catalysts and Reagents

AgBF4 , 6.63 AgNO3 , 6.69, 6.74 Ag2 O, table 2.2 AgOTf, 6.68 AgSbF6 , 3.70, 3.71 AuCl3 , 6.53, 6.70, 6.71, 6.74, 6.76, 6.96, 6.98 biph(t-Bu)2 PAu(NCMe)+ , ﬁgure 1.10 biph(t-Bu)2 PAuCl, 6.55, 6.81 biph(Cy)2 PAuCl, 6.106, 6.107 dppm(AuBr)2 , 6.6 JohnphosAu(NCMe) SbF6 , 6.91 LAuCl, 6.67 NaAuCl4 , 6.77 NHC-Au complexes, 6.105, 6.112 (PhO)3 PAuCl, 6.72 Ph3 PAuCl, 6.52, 6.54, 6.56, 6.61, 6.64, 6.66, 6.84, 6.87, 6.93, 6.101, 6.102, 6.103, 6.104, 6.109, 6.112, 11.94 Ph3 PAuMe, 6.83 Ph3 PAuNTf2 , 6.75, 6.88 CoBr2 , DPEphos, 3.25 Co(CO)− 4 , 9.3, 9.6 Co2 (CO)8 , 4.29, 4.32, 4.76, 7.1, 7.4, 7.8, 7.13, 7.19 CpCo(CO)2 , 11.14, 11.15, 11.16, 11.22, 11.23, 11.24 CpCo(PPh3 )2 , 11.12, 11.13 dppeCoBr2 , 11.73 dpppCoBr2 , 11.73 Na[Co(dmgh)2 py], 6.129, 6.131 Cr(CO)6 , 1.6, 8.4, 8.20, 8.24, 10.39, 10.40, 10.42 Cr(CO)5 .THF, 8.43 (MeCN)3 Cr(CO)3 , 10.40 Cu(acac)2 , 8.140, 8.141 (MeCN)4 CuPF6 , 2.169 CuO, table 2.2, 8.144 Cu(OAc)2 , 2.178, 2.179, 2.180 Cu(OTf)2 , 2.168, 2.175 CuSO4 , 8.143 [CpFe(CO)2 ]2 , 6.114, 6.115

Fe(acac)3 , 2.29, 2.30, 2.31 Fe(CO)5 , 6.113, 7.17, 10.1, 10.3, 10.4, 10.13, 10.28 Fe2 (CO)9 , 4.79, 4.80, 4.83, 4.85, 6.113, 9.1, 9.8, 9.10, 10.1, 10.3, 10.4, 10.6, 10.25, 10.28 Fe(CO)4 NMe3 , 7.14 Fe(dbm)3 , 2.28 K2 Fe(CO)4 , 4.72, 4.73 Na2 Fe(CO)4 , 4.74, 4.75 In(acac)2 , 11.39, 11.40 (Ind)Ir(COD), 3.38 IrCl(CO)(As3 Ph)2 , 11.35 [Ir(COD)Cl]2 , 3.43, 9.25, 9.26, 9.41, 9.42, 9.43, 9.44, 9.45, 9.46, 9.66, 11.19 [Ir(COE)Cl]2 , 3.69 [Ir(COD)(OMe)]2 , 3.39, 3.40, 3.41 Cp*2 LaCH(SiMe3 )2 , 6.73 BnMn(CO)5 , 3.4 Mn(CO)− 5 , 9.4 Mn(CO)5 Br, 10.39 Mn(CO)5 OTf, 10.41 CpMo(CO)− 3 , 4.87 (MeCN)3 Mo(CO)3 , 10.20 Mo(CO)3 (DMF)3 , 7.21, 7.22 Mo(CO)6 , 4.21, 8.129, 9.23, 9.24, 9.36, 9.37 (Ph3 SiO)3 Mo≡CPh, 8.133 Schrock catalyst, 8.73, 8.83, 8.122 (Cy3 P)2 NiCl2 , 11.69 dppeNiCl2 , 2.183 dpppNiCl2 , 2.8, 2.18, 2.20 Ni(acac)2 , 2.40, 2.41, 9.58 NiBr2 , 2.184 Ni(CN)2 , 11.1 Ni(CO)4 , 4.3, 4.91, 4.92, 4.93, 4.94 Ni(COD)2 , 2.98, 2.142, 2.185, 4.100, 4.101 Ni(COD)2 , pybox, 2.42 NiCl2 diene complex, 2.23, 2.24 NiCl2 , dppbz, 2.19

Organic Synthesis Using Transition Metals, Second Edition. Roderick Bates. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

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Index of Principle Transition Metal Catalysts and Reagents

(Ph3 P)4 Ni, 2.43, 2.134, 2.141 (Ph3 P)2 NiCl2 , 2.8, 5.78 (Ph3 P)2 Ni(CO)2 , 4.99, 11.9 Os(NH3 )5 (OTf)3 , 10.60, 10.61 [(allyl)PdCl]2 , 2.69, 2.100, 2.101, 2.104, 2.109, 2.110, 2.121, 2.157, 4.7 [(allyl)PdCl]2 , BINAP, 5.40, 5.41 (allyl)PdCl(PCy3 ), 11.81 BnPd(PPh3 )2 Cl, 2.64, 2.65, 9.19 (t-Bu3 P)2 Pd, 2.48, 11.4 [(cinnamyl)PdCl]2 , 4.35, 4.36 (Cy3 P)2 PdCl2 , 2.12 DPEphosPdCl2 , 2.12, 2.48 dppbPdCl2 , 2.11, table 2.2 (dppe)2 Pd, 9.51 dppfPdCl2 , 2.26, 2.38, 2.71, 2.77, 2.85, 2.125, 2.162, 6.92, 9.47, 9.67, 11.20 Herrmann’s catalyst, 5.18, 5.19, 5.54, 9.48 (MeCN)2 PdCl2 , 2.51, 2.59, 2.118, 2.119, 2.120, 2.129, 3.73, 3.74, 4.8, 4.14, 5.50, 6.13, 6.15, 6.16, 6.18, 6.21, 6.35, 6.70, 8.24 (MePh2 P)2 PdCl2 , 4.26 Na2 PdCl4 , 3.47, 3.48, 6.11, 6.12 PdBr2 , t-Bu2 MeP, 2.111 Pd/C, 2.46, 2.122, 2.162 PdCl2 , 3.44, 3.49, 4.41, 4.42, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10, 6.14, 6.19, 6.22, 6.23, 6.24, 6.25, 6.27, 6.28, 6.29, 6.34, 6.38, 6.39, 6.40, 6.41, 6.42, 6.43, 9.11 PdCl2 , PPh3 , 4.34 Pd2 (dba)3 or Pd(dba)2 , 2.1, table 2.3, 2.105, 2.107, 2.137, 2.166, 5.10, 5.23, 5.25, 5.42, 9.18, 9.36, 9.40, 9.58, 9.64, 9.65, 11.87 Pd2 (dba)3 , BINAP, 2.140, 2.146, 2.148, 2.163, 2.164, 5.37, 5.38, 5.39 Pd2 (dba)3 , t-Bu3 P, 5.19 Pd2 (dba)3 , dppe, 11.36 Pd(dba)2 , Johnphos, 2.108, 2.154 Pd2 (dba)3 , Ph3 As, 2.45, 4.12 Pd(dba)2 , PPh3 , 9.53, 11.25 Pd2 (dba)3 , Ph3 Sb, 11.77 Pd2 dba3 , Qphos, 2.95, 2.138, 2.147, 2.167 Pd2 (dba)3 , SPhos, 2.92, 2.93, 2.94, 3.42, 9.63 Pd2 dba3 , (o-tol)3 P, 2.35, 2.144, 11.86 Pd2 (dba)3 , trixiephos, 2.151 Pd2 dba3 , Xphos, 2.73 Pd NHC complexes, 2.22, 2.91 Pd(OAc)2 , 2.139, 2.164, 3.6, 3.7, 3.8, 3.9, 3.10, 3.13, 3.18, 3.20, 3.21, 3.27, 3.28, 3.45, 3.46, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.59, 3.60, 3.61, 3.62, 3.63, 3.64, 3.66, 3.67, 3.68, 4.19, 4.38, 5.3, 5.7,

5.11, 5.12, 5.13, 5.14, 5.22, 5.28, 5.29, 5.45, 5.55, 6.18, 6.26, 6.30, 6.31, 6.32, 6.36, 6.37, 9.76, 9.77, 9.78, 9.79, 11.71, 11.74 Pd(OAc)2 , Ar3 P, 11.90, 11.91, 11.92, 11.94 Pd(OAc)2 , BBEDA, 11.75 Pd(OAc)2 , BINAP, 2.159, 5.36 Pd(OAc)2 , t-Bu2 MeP, 2.99 Pd(OAc)2 , t-Bu3 P, 2.149, 2.151, 2.153, 3.60, 3.65, Pd(OAc)2 , t-BuBrettphos, 2.158 Pd(OAc)2 , Cy3 P, 2.22 Pd(OAc)2 , Davephos, 2.150, 2.151, 3.19, 3.20 Pd(OAc)2 , DIOP, 5.35 Pd(OAc)2 , DPEphos, 2.156, 2.160, 2.161 Pd(OAc)2 , dppf, 4.27 Pd(OAc)2 , dppp, 3.16, 8.86, 8.114 Pd(OAc)2 , Np(t-Bu)2 P, 2.21 Pd(OAc)2 , P(2-Fu)3 , 9.2 Pd(OAc)2 , PPh3 , 2.46, 2.78, 2.102, 2.103, 2.130, 2.187, 3.17, table 5.1, 4.22, 4.28, 5.21, 5.26, 5.46, 5.48, 5.49, 6.46, 6.47, 9.17, 9.50, 9.59, 9.72, 9.74, 9.75, 9.78, 9.84, 11.37 Pd(OAc)2 , (i-PrO)3 P, 9.55, 9.56, 11.39, 11.41, 11.42, 11.45 Pd(OAc)2 , Ruphos, 2.76 Pd(OAc)2 , Sphos, 2.82, 2.88 Pd(OAc)2 , tol-BINAP, 2.181, 5.42 Pd(OAc)2 , (o-tol)3 P, 5.2, 5.4, 5.5, 5.6, 5.20, 5.30, 5.32, 9.73 Pd(OAc)2 , Xantophos, 2.152, 2.155, 2.165 Pd(O2 CCF3 )2 , 3.43 PEPPSI, 4.6, 4.11 perovskites, 2.96 (PhCN)2 PdCl2 , 2.49, 2.113 PhPd(PPh3 )2 I, 4.4 (Ph3 P)4 Pd, 2.9, 2.10, 2.13, 2.14, 2.15, 2.16, 2.17, 2.26, 2.32, 2.33, 2.36, 2.39, 2.44, 2.47, 2.49, 2.53, 2.58, 2.60, 2.61, 2.62, 2.63, 2.66, 2.68, 2.79, 2.80, 2.81, 2.83, 2.84, 2.86, 2.87, 2.88, 2.89, 2.90, 2.97, 2.115, 2.116, 2.117, 2.128, 2.132, 2.133, 2.135, 2.182, 2.186, 3.11, 4.5, 4.13, 4.15, 4.16, 4.37, 5.33, 5.43, 5.44, 5.47, 5.51, 6.49, 6.93, 6.95, 7.8, 8.121, 9.15, 9.16, 9.27, 9.28, 9.33, 9.34, 9.45, 9.38, 9.48, 9.49, 9.54, 9.60, 9.61, 9.63, 9.67, 9.69, 9.70, 9.71, 9.79, 9.80, 9.81, 9.82, 9.83, 11.35, 11.40 (Ph3 P)2 PdBr2 , 4.20 (Ph3 P)2 PdCl2 , table 2.1, 2.34, 2.37, 2.50, 2.52, 2.104, 2.114, 2.116, 2.123, 2.124, 2.126, 2.136, 3.11, 3.14, 3.19, 4.10, 4.23, 4.24, 4.25, 4.39, 5.9, 5.45, 5.52, 5.53, 6.48, 11.22, 11.25 (Ph3 P)2 Pd(O2 CCF3 )2 , 5.36

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Index of Principle Transition Metal Catalysts and Reagents (TMEDA)PdMe2 , 2.143 (o-tol3 P)4 Pd, 2.15 (t-Bu3 P)Pt(dvds), 2.109 (COD)PtCl2 , 6.57 K2 PtCl4 , 3.58 PtCl2 , 6.58, 6.78, 6.79, 6.80, 6.84, 6.89, 6.92, 6.94, 6.95, 6.110 PtCl4 , 6.82, 6.84, 6.85, 6.108 Pt(H2 CCH2 )Cl− 3 , ﬁgure 1.3 Pt(H2 CCH2 )2 (PPh3 )2 , 9.31 Cp*Re(CO)3 , 3.42 (acac)Rh(CO)2 , 4.49, 4.51, 4.55, 4.57, 4.59, 4.64, 4.65, 4.67, 4.68, 4.69, 5.56, 5.57, 5.58 [(C8 H14 )2 RhCl]2 , 11.4 [(CH2 CH2 )2 RhCl]2 , 5.59 (COD)2 RhBF4 , 5.58, 11.20 (COD)Rh(BINAP)+, 11.66 [(COD)RhCl]2 , 3.33, 3.35, 4.52, 4.53, 4.54, 6.86, 7.18, 7.20, 11.2, 11.51 (COD)Rh(NCMe)2 BF4 , 2.108 [(COE)2 RhCl]2 , 3.23 [Cp*RhCl2 ]2 , 3.70, 3.71 Cp*Rh(C6 Me6 ), 3.36 (dppe)2 Rh+ , 11.67 dppeRhCl, 8.106 dppe2 RhClO4 , 3.29, 3.32 dppe2 RhOTf, 3.31 (NBD)Rh(BINAP) SbF6 , 11.5 (Ph2 MeP)3 RhCl, 4.98 (Ph3 P)3 RhCl, 4.95, 4.96, 4.97, 11.17, 11.18, 11.48, 11.53 (Ph3 P)3 RhH(CO), 4.61 Rh2 (bptv)4 , 8.142 Rh2 (cap)4 , 8.134, 8.135 [RhCl(CO)2 ]2 , 3.22, 3.24, 11.49, 11.54 RhCl(Pi-Pr3 )2 (N2 )2 , 3.37 RhCl3 , 11.64, 11.65, 11.80 Rh4 (CO)12 , 4.6 Rh(COD)(COT), 11.78 Rh2 (DOSP), 8.145, 8.146 Rh2 (esp)4 , 8.152 Rh2 (HNCOR)4 , 8.154

435

Rh2 (OAc)4 , 4.48, 4.56, 4.63, 8.136, 8.137, 8.138, 8.139, 8.141, 8.147, 8.149, 8.150, 8.153 Rh2 (Oct)4 , 8.151 Rh2 (pfb)4 , 8.134, 8.135 [Cp*RuCl2 ]2 , 3.42 Cp(Ar3 P)2 RuCl, 8.46, 8.47, 8.48 Cp*Ru(COD)Cl, 11.21, 11.25, 11.29 CpRu(COD)Cl, 11.79 CpRu(NCMe)3 PF6 , 11.88, 11.89, 11.95 Grela catalyst, 8.85 Grubbs I, 4.94, 5.11, 6.68, 8.61, 8.62, 8.65, 8.66, 8.67, 8.68, 8.72, 8.73, 8.74, 8.75, 8.76. 8.77, 8.78, 8.79, 8.80, 8.81, 8.98, 8.102, 8.110, 8.111, 8.112, 8.114, 8.117, 8.120, 8.131 Grubbs II, 8.63, 8.64, 8.69, 8.71, 8.73, 8.79, 8.86, 8.88, 8.89, 8.90, 8.93, 8.96, 8.97, 8.100, 8.113, 8.116, 8.118, 8.119, 8.121, 8.123, 8.124, 8.125, 8.126, 8.127, 11.40, 11.82 HG-II, 8.82, 8.84, 8.94, 8.95, 8.96, 8.99, 9.67, 10.6 Ph3 P(p-cymene)RuCl2 , 8.4 (Ph3 P)3 RuHCl, 11.68 (Ph3 P)3 (OC)RuHCl, 11.82 [(i-PrPh)RuCl2 ]2 , 6.86 RuH2 (CO)(PPh3 )2 , 3.72 Ru3 (CO)12 , 3.26, 4.31, 4.43, 4.44, 7.16 [Ru(CO)2 Cl]2 , 11.49 Ru(COD)(COT), 3.34 Sc complexes, 6.59 Sm complexes, 6.73 Cp2 TiCl2, 8.53, 8.54, 8.55, 8.56, 8.57 Tebbe’s reagent, 8.59, 8.60 Ti(Oi-Pr)4 , 5.79, 5.80, 5.81, 5.83, 5.84, 5.85, 5.86, 5.87, 5.88, 8.102 t-BuC≡W(Ot-Bu)3 , 8.131, 8.132 CpW(CO)− 3 , 4.89 MeC≡W(CO)4 Br, 8.128 W(CO)6 , 8.45 W(CO)5 .THF, 7.15, 8.41, 8.42, 8.43 Cp2 ZrCl2 , 2.48, 5.63, 5.65, 5.68, 5.76, 5.78, 8.121 Cp2 ZrHCl, 2.49, 5.60, 5.61, 5.64 Cp2 ZrMeCl, 5.73, 5.74 (EBTHI)ZrCl2 , 5.77, 5.78