Handbook of Functionalized Organometallics: Applications in Synthesis Vol.1 & 2

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Handbook of Functionalized Organometallics

Edited by Paul Knochel

Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

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Handbook of Functionalized Organometallics Applications in Synthesis

Edited by Paul Knochel

Editor Prof. Paul Knochel Department of Chemistry Ludwig-Maximilians-Universität Butenandtstraûe 5±13 Haus F 81377 München Germany

&

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at . 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form ± nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany. Printed on acid-free paper. Cover Design Grafik-Design Schulz, Fuûgönheim Typesetting Kühn & Weyh, Satz und Medien, Freiburg Printing betz-druck GmbH, Darmstadt Bookbinding Litges & Dopf Buchbinderei GmbH, Heppenheim ISBN-13: ISBN-10:

978-3-527-31131-6 3-527-31131-9

V

Contents Preface

XV

List of Authors Volume 1

XVII

1

1

Introduction 1 Paul Knochel and Felix Kopp

2

Polyfunctional Lithium Organometallics for Organic Synthesis Miguel Yus and Francisco Foubelo

2.1 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.3 2.3.1 2.3.2 2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.5 2.5.1 2.5.2 2.5.3 2.5.4

Introduction 7 a-Functionalized Organolithium Compounds 8 3 sp -Hybridized a±Oxygenated Organolithium Compounds 8 2 sp -Hybridized a-Oxygenated Organolithium Compounds 13 3 sp -Hybridized a-Nitrogenated Organolithium Compounds 14 2 sp -Hybridized a-Nitrogenated Organolithium Compounds 16 2 Other sp -Hybridized a-Functionalized Organolithium Compounds b-Functionalized Organolithium Compounds 18 3 sp -Hybridized b-Functionalized Organolithium Compounds 19 2 sp -Hybridized b-Functionalized Organolithium Compounds 22 c-Functionalized Organolithium Compounds 24 c-Functionalized Alkyllithium Compounds 24 c-Functionalized Allyllithium Compounds 26 c-Functionalized Benzyllithium Compounds 27 c-Functionalized Akenyllithium Compounds 28 c-Functionalized Alkynyllithium Compounds 30 d-Functionalized Organolithium Compounds 31 d-Functionalized Alkyllithium Compounds 31 d-Functionalized Allyl and Benzyllithium Compounds 32 d-Functionalized Alkenyllihium Compounds 33 d-Functionalized Alkynyllithium Compounds 34


7

18

VI

Contents

2.6 2.6.1 2.6.2 2.6.3

Remote Functionalized Organolithium Compounds 34 Remote Functionalized Alkyllithium Compounds 34 Remote Allyl and Benzyllithium Compounds 35 Remote Functionalized Alkenyl- and Alkynyllithium Compounds

3

Functionalized Organoborane Derivatives in Organic Synthesis 45 Paul Knochel, Hiriyakkanavar Ila, Tobias J. Korn, and Oliver Baron

3.1 3.2

Introduction 45 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes 45 Preparation from Polar Organometallics 45 Preparation from Aryl Halides and Sulfonates by Cross-coupling 50 Synthesis of Functionalized Aryl Boranes by Catalytic Aromatic C±H Borylation 54 Synthesis of Functionalized Trifluoroborates and their Palladiumcatalyzed Suzuki±Miyaura Cross-coupling Reactions 57 Palladium-catalyzed Suzuki±Miyaura Cross-coupling Reactions of Functionalized Aryl and Heteroaryl Boronic Esters 58 Copper-mediated Carbon±Heteroatom-Bond-forming Reactions with Functionalized Aryl Boronic Acids 68 Palladium-catalyzed Acylation of Functionalized Aryl Boronic Acids 73 Miscellaneous C±C-bond Formations of Functionalized Aryl Organoboranes 74 Miscellaneous Reactions of Functionalized Alkenyl Boronic Acids 78 Preparation and Reactions of Functionalized Alkenyl Boranes 79 Synthesis of Alkenyl Boronic Acids by Transmetallation of Alkenyl Grignard Reagents with Boronate Esters 79 Synthesis of Functionalized Alkenyl Boronic Acids by Hydroboration of Functionalized Alkynes and their Suzuki Cross-coupling Reactions 79 Synthesis of Functionalized Alkenyl Boronic Esters by Crossmetathesis 81 Synthesis and Palladium-catalyzed Cross-coupling Reactions of Functionalized Alkenyl Trifluoroborates 82 Palladium-catalyzed Cross-coupling of Functionalized Alkenyl Boronates with Cyclopropyl Iodides 83 Intermolecular Suzuki Cross-coupling Reactions of Functionalized Alkenylborane Derivates: Application in Natural Product Synthesis (Alkenyl B-Alkenyl Coupling) 83 Intramolecular Macrocyclization via Suzuki Cross-coupling of Functionalized Alkenyl Boronic Esters (Alkenyl B-Alkenyl Coupling) 84 Three-component Mannich Reaction of Functionalized Alkenyl Boronic Acids (Petasis Reaction): Synthesis of b,c-Unsaturated a-Amino Acids 85

3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.2.7 3.2.8 3.2.9 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6

3.3.7 3.3.8

36

Contents

3.3.9 3.3.10 3.4 3.5 3.6 3.7 3.7.1 3.7.2

3.7.3 3.7.4 3.7.5 3.7.6 3.7.7 3.8

Oxidation of Functionalized Alkenyl Boronic Esters to Aldehydes with Trimethylamine Oxide 86 Lewis-acid-catalyzed Nucleophilic Addition of Functionalized Alkenyl Boronic Esters to Activated N-acyliminium Ions 86 Preparation and Reactions of Functionalized Alkynlboron Derivatives 87 Synthesis and Reactions of Functionalized Allylic Boronates 88 Synthesis and Reactions of Functionalized Cyclopropyl Boronic Esters 90 Synthesis and Reactions of Functionalized Alkyl Boron Derivates 91 Synthesis of Aminoalkyl Boranes by Hydroboration and their Suzuki Cross-coupling Reaction 91 Synthesis of Functionalized Alkyl Boronates by Nucleophilic 1,4Conjugate Addition of Borylcopper Species to a,b-Unsaturated Carbonyl Compounds 92 Preparation and B-alkyl-Suzuki±Miyaura Cross-coupling Reactions of Functionalized Alkyl Trifluoroborates 93 Silver(I)-promoted Suzuki Cross-coupling of Functionalized n-Alkyl Boronic Acids 94 Alkyl-Alkyl Suzuki Cross-coupling of Functionalized Alkyl Boranes with Alkyl Bromides, Chlorides and Tosylates 95 Synthesis of Natural and Unnatural Amino Acids via B-alkyl Suzuki Coupling of Functionalized Alkyl Boranes 95 Application of Intermolecular B-alkyl Suzuki Cross-coupling of Functionalized Alkyl Boranes in Natural Product Synthesis 96 Conclusion 104

4

Polyfunctional Magnesium Organometallics for Organic Synthesis Paul Knochel, Arkady Krasovskiy, and Ioannis Sapountzis

4.1 4.2

Introduction 109 Methods of Preparation of Grignard Reagents and their Uncatalyzed Reactions 110 Direct Oxidative Addition of Magnesium to Organic Halides 110 Metalation Reactions with Magnesium Amides 111 The Halogen±Magnesium Exchange Reaction 113 Early Studies 113 The Preparation of Functionalized Arylmagnesium Reagents 115 Halogen±Magnesium Exchange Using Lithium Trialkylmagnesiates 128 The Preparation of Functionalized Heteroarylmagnesium Reagents 129 The Preparation of Functionalized Alkenylmagnesium Reagents 136 Preparation of Functionalized Alkylmagnesium Reagents 142 Preparation of Functionalized Alkylmagnesium Carbenoids 143 Further Applications of Functionalized Grignard Reagents 146

4.2.1 4.2.2 4.2.3 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.2.4 4.2.5 4.2.6 4.3

109

VII

VIII

Contents

4.4 4.4.1 4.4.2 4.4.3 4.5

Application of Functionalized Magnesium Reagents in Cross-coupling Reactions 155 Palladium-catalyzed Cross-coupling Reactions 155 Nickel-catalyzed Cross-coupling Reactions 157 Iron-catalyzed Cross-coupling Reactions 159 Summary and Outlook 164

5

Polyfunctional Silicon Organometallics for Organic Synthesis Masaki Shimizu and Tamejiro Hiyama

173

5.1 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.3 5.3.1 5.3.2 5.3.3 5.4 5.4.1 5.4.2 5.4.3 5.5

Introduction 173 Allylic Silanes 174 Intermolecular Reactions of Polyfunctional Allylic Silanes 174 Intramolecular Reactions of Polyfunctional Allylic Silanes 176 Tandem Reactions of Polyfunctional Allylic Silanes 180 Sequential Synthetic Reactions of Metal-containing Allylic Silanes 183 Alkenylsilanes 189 Intermolecular Reactions of Polyfunctional Alkenylsilanes 189 Intramolecular Reactions of Polyfunctional Alkenylsilanes 190 Synthetic Reactions of Metal-containing Alkenylsilanes 191 Alkylsilanes 193 Synthetic Reactions of Polyhalomethylsilanes 193 Synthetic Reactions of Cyclopropyl, Oxiranyl, and Aziridinylsilanes 195 Synthetic Reactions of Polysilylmethanes 196 Miscellaneous Preparations and Reactions of Polyfunctional Organosilicon Reagents 197

6

Polyfunctional Tin Organometallics for Organic Synthesis Eric Fouquet and Agns Herve

6.1 6.2 6.2.1 6.2.1.1 6.2.1.2 6.2.1.3 6.2.1.4 6.2.1.5 6.2.1.6 6.2.1.7 6.2.2 6.2.2.1 6.2.2.2 6.2.2.3 6.2.2.4 6.3

Introduction 203 Metal-Catalyzed Coupling Reactions 203 The Stille Cross-Coupling Reaction 203 Mechanism 204 Organotins for the Stille Reaction 205 Substrates 208 Intermolecular Stille Cross-coupling 210 Intramolecular Stille Cross-coupling 212 Solid-Phase-Supported Stille Coupling 214 Stille Coupling Catalytic in Tin 215 Other Metal-Catalyzed Coupling Reactions 215 Palladium-Catalyzed Reactions 215 Copper-Catalyzed Reactions 215 Nickel-Catalyzed Reactions 216 Rhodium-Catalyzed Reactions 216 Nucleophilic Additions 217

203

Contents

6.3.1 6.3.1.1 6.3.1.2 6.3.1.3 6.3.1.4 6.3.1.5 6.3.2 6.3.2.1 6.3.2.2 6.3.2.3 6.4 6.4.1 6.4.2 6.4.2.1 6.4.2.2 6.4.3 6.4.3.1 6.4.3.2 6.4.4 6.5 6.5.1 6.5.2 6.5.2.1 6.5.2.2 6.5.3 6.6

Nucleophilic Addition onto Carbonyl Compounds 217 Introduction 217 Functionalized Allyltins 217 Catalytic Use of Lewis Acid 221 Enantioselectivity 221 Others Organotin Reagents 222 Nucleophilic Addition onto Imines and Related Compounds Reactions with Imines 224 Other Imino Substrates 225 Catalytic Enantioselective Addition 227 Radical Reactions of Organotins 227 Introduction 227 Allyltins 227 Mechanistic Overview 227 Functionalized Allyltins 229 Other Organotin Reagents 230 Tetraorganotins 230 Modified Organotins 231 The Stereoselective Approach 231 Transmetallations 232 Introduction 232 Tin-to-lithium Exchange 233 a-Heterosubstituted Alkyltins 233 Alkenyltins 235 Tin to Other Metal Exchanges 236 Conclusion 236

7

Polyfunctional Zinc Organometallics for Organic Synthesis Paul Knochel, Helena Leuser, Liu-Zhu Gong, Sylvie Perrone, and Florian F. Kneisel

7.1 7.2 7.2.1 7.2.2 7.2.2.1 7.2.2.2

224

251

Introduction 251 Methods of Preparation of Polyfunctional Organozinc Reagents Classification 252 Preparation of Polyfunctional Organozinc Halides 252 Preparation by the Oxidative Addition to Zinc Metal 252 Preparation of Organozinc Halides using Transmetallation Reactions 261 7.2.3 Preparation of Diorganozincs 270 7.2.3.1 Preparation via an I/Zn Exchange 270 7.2.3.2 The Boron±Zinc Exchange 273 7.2.3.3 Hydrozincation of Alkenes 278 7.2.4 Diverse Methods of Preparation of Allylic Zinc Reagents 278 7.2.5 Preparation of Lithium Triorganozincates 281 7.3 Reactions of Organozinc Reagents 282

252

IX

X

Contents

7.3.1 7.3.2 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.3 7.3.4 7.3.5 7.4 Index

Uncatalyzed Reactions 283 Copper(I)-catalyzed Reactions 292 Substitution Reactions 293 Acylation Reactions 303 Addition Reactions 305 Michael Additions 309 Palladium- and Nickel-catalyzed Reactions 316 Reactions Catalyzed by Titanium and Zirconium(IV) Complexes Reactions of Zinc Organometallics Catalyzed by Cobalt, Iron or Manganese Complexes 332 Conclusion 333

326

I1

Volume 2

347

8

Polyfunctional 1,1-Organodimetallic for Organic Synthesis Seijiro Matsubara

347

8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 8.2.6 8.2.7 8.2.8 8.2.9 8.2.10 8.3 8.3.1 8.3.2 8.3.3 8.4

Introduction 347 gem-Dizincio Compounds 348 General View 348 Methylenation with Bis(iodozincio)methane 351 gem-Dizincio Species from gem-Dihaloalkane 357 Alkenylsilane, -Germane, -and Borane Synthesis 360 Stepwise Coupling Reaction with Two Different Electrophiles 361 Reaction with Acyl Chloride and Cyanide 364 1,4-Addition of bis(iodozincio)methane to a,b-unsaturated ketones 365 Cyclopropanation Reaction 367 Pinacolone Rearrangement with Unusual Diastereospecificity 368 gem-Dizincio Reagent Working as Carbenoid 370 Chromium Compounds 371 General View 371 Alkylidenation 371 a-Halogen Atom Substituted gem-Dichromium Reagent 373 Conclusion 375

9

Polyfunctional Organocopper Reagents for Organic Synthesis Paul Knochel, Xiaoyin Yang, and Nina Gommermann

9.1 9.2 9.2.1 9.2.2

Introduction 379 Preparation of Functionalized Organocopper Reagents 379 Preparation by the Direct Insertion of Activated Copper 379 Preparation by a Halogen±Copper Exchange Reaction 382

379

Contents

9.2.3 9.2.4 9.3 9.4

Preparation of Functionalized Copper Reagents Starting from Organolithium Reagents 386 Preparation of Functionalized Alkenylcopper Derivatives Starting from Organozirconium Compounds 389 Applications of Functionalized Copper Reagents 391 Conclusion 394

10

Functional Organonickel Reagents Tien-Yau Luh and Li-Fu Huang

10.1 10.2 10.3 10.3.1 10.3.2 10.3.3 10.3.4 10.3.5 10.3.6 10.3.7 10.4 10.5 10.5.1 10.5.2 10.5.3 10.5.4 10.5.5 10.5.6 10.6 10.7 10.8 10.9 10.10

Introduction 397 Homocoupling Reactions 397 Cross-coupling Reactions 400 Kumada±Corriu Reactions 401 Negishi Reaction 403 Suzuki Reaction 405 Stille Coupling 407 Heck Reaction 407 Miscellaneous Coupling Reactions 407 Aliphatic Substrates 409 Carbozincation Reactions 411 Cycloadditions 413 [2+2] Cycloaddition 413 [4+2] Cycloaddition 414 [4 + 4] Cycloaddition 415 [2 + 2 + 2] Cycloaddition 416 [3 + 2 + 2] Cycloaddition 418 [4 + 2 + 1] Cycloaddition 419 Intramolecular Coupling of Enynes or Alkynes 420 Reactions of Enones with Alkynes 422 Reaction of Simple Aldehydes or Ketones with Alkynes Miscellaneous Reactions 436 Conclusion 443

11

Polyfunctional Metal Carbenes for Organic Synthesis Karl Heinz Dötz, Alexander Koch, and Martin Werner

11.1 11.2 11.2.1 11.2.2 11.2.3 11.3 11.4

Introduction 451 Chromium-Templated Cycloaddition Reactions 451 Cyclopropanation 452 Benzannulation 455 Cyclization of Chromium Oligoene(-yne) Carbenes 461 Reactions of Higher Nuclearity Chromium and Tungsten Carbenes Metathesis Reactions Catalyzed by Group VI and VIII Metal Carbenes 473 Transmetallation 477

11.5

397

429

451

467

XI

XII

Contents

11.6 11.7 11.8 11.9

Metal Carbenes in Peptide Chemistry 481 Stereoselective Syntheses with Sugar Metal Carbenes 483 Sugar Metal Carbenes as Organometallic Gelators 495 Conclusion 496

12

Functionalized Organozirconium and Titanium in Organic Synthesis Ilan Marek and Helena Chechik-Lankin

503

12.1 12.2 12.2.1 12.2.2 12.2.3 12.2.4 12.3 12.3.1

Introduction 503 Functionalized Organozirconocene Derivatives 503 Preparation of Functionalized Alkenylzirconocene Derivatives 503 Preparation of Functionalized Alkylzirconocene Derivatives 511 Preparation and Reactivity of Acylzirconocene Derivatives 514 Preparation of Functionalized Low-valent Zirconocene Derivatives 519 Functionalized Organotitanium Derivatives 520 Preparation of Functionalized Substrates via Titanocene Derivatives 521 12.3.1.1 Intramolecular Reductive Cyclization 521 12.3.1.2 Allenylation of Functionalized Carbonylic Compounds 525 12.3.2 Preparation of Functionalized Substrates via Titanium (ii) Alkoxide Derivatives 526 12.3.2.1 Generation of g2-Alkene, g2-Alkyne Complexes and their Utilization as Vicinal Dianionic Species 526 13

Manganese Organometallics for the Chemoselective Synthesis of Polyfunctional Compounds 541 GØrard Cahiez and Florence Mahuteau-Betzer

13.1 13.2 13.2.1

Introduction 541 Preparation of Organomanganese Compounds 541 Preparation of Organomanganese Compounds by Transmetallation 541 0 Preparation of Organomanganese Compounds from Mn 543 1,2-Addition to Aldehydes and Ketones 544 Chemoselective 1,2-Addition of Organomanganese Reagents to Carbonyl Compounds 544 Manganese-Mediated Barbier- and Reformatsky-like Reactions 547 Preparation of Ketones by Acylation of Organomanganese Reagents 548 Acylation of Organomanganese Reagents 548 Manganese-Catalyzed Acylation of Grignard Reagents 554 1,4-Addition of Organomanganese Reagents to Enones 555 Transition-Metal-Catalyzed Cross-coupling Reactions 559 Copper-Catalyzed Cross-coupling Reactions 559 Iron-Catalyzed Cross-coupling Reactions 560 Palladium-Catalyzed Cross-coupling Reactions 561

13.2.2 13.3 13.3.1 13.3.2 13.4 13.4.1 13.4.2 13.5 13.6 13.6.1 13.6.2 13.6.3

Contents

13.6.4 13.7 13.7.1 13.7.2

Nickel-Catalyzed Cross-coupling Reactions 562 Manganese-Mediated Cross-coupling Reactions 563 Manganese-Catalyzed or -Mediated Cross-coupling Reactions Mixed (Mn/Cu)-Catalyzed Cyclizations 565

14

Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis 569 G. Richard Stephenson

14.1

Introduction to Multihapto-Complexes and Discussion of Nomenclature 569 Classes of Nucleophile Addition Pathways to MultihaptoComplexes 571 Unsymmetrically Placed Substituents in Stoichiometric Electrophilic Multihapto-Complexes 575 2 Electrophilic g Complexes 575 3 Electrophilic g Complexes 576 4 Electrophilic g Complexes 577 5 Electrophilic g Complexes 578 6 Electrophilic g Complexes 585 Branched Electrophilic p Systems 589 Conjugate Addition to Unsaturated Extensions of Electrophillic Multihapto-Complexes 590 Internal Addition of Nucleophiles 592 Caveats and Cautions 595 Examples of the Use of Electrophilic Multihapto-Complexes in Organic Synthesis 598 Alkyl-derived Directing Effects in Synthetic Applications of MultihaptoComplexes 598 Electron-withdrawing Groups with x-Directing Effects in Synthetic Applications of Multihapto-Complexes 599 Aryl Substituents with x-Directing Effects in Synthetic Applications of Multihapto-Complexes 600 Electron-donating Groups with Ipso-Directing Effects in Synthetic Applications of Multihapto-Complexes 611 Electron-donating Groups with x-Directing Effects in Synthetic Applications of Multihapto-Complexes 612 Electron-donating Groups with b-Directing Effects in Synthetic Applications of Multihapto-Complexes 614 Halogen Substituents with Ipso-Directing Effects in Synthetic Applications of Multihapto-Complexes 615 Remote Nucleophile Addition in Synthetic Applications of MultihaptoComplexes 615

14.2 14.3 14.3.1 14.3.2 14.3.3 14.3.4 14.3.5 14.3.6 14.3.7 14.3.8 14.4 14.5 14.5.1 14.5.2 14.5.3 14.5.4 14.5.5 14.5.6 14.5.7 14.5.8

563

XIII

XIV

Contents

14.5.9 14.6

Design Efficiency in the Synthetic Applications of MultihaptoComplexes 616 Conclusions 617

15

Polyfunctional Zinc, Cobalt and Iron Organometallics Prepared by Electrosynthesis 629 Jacques PØrichon and Corinne Gosmini

15.1 15.2 15.3

Introduction 629 Electrochemical Device and General Reaction Conditions 632 Electrochemical Synthesis Involving Functionalized Organo-Cobalt or -Iron Intermediates Derivatives 633 Introduction 633 Carbon±Carbon Bond Formation Using Electrogenerated Functionalized Organocobalt Species 635 Electrosynthesis of Dissymmetric Biaryls 635 Electrochemical Addition of Aryl Halides onto Activated Olefins 637 Electrochemical Vinylation of Aryl Halides using Vinylic Acetates 638 Cross-coupling between Aryl or Heteroaryl Halides and Allylic Acetates or Carbonates 639 Carbon±Carbon Bond using Electrogenerated Functionalized Organometallic Iron 640 Coupling of Activated Aliphatic Halides with Carbonyl Compounds 640 Electrochemical Allylation of Carbonyl Compounds by Allylic Acetates 641 Conclusion 642 Electrosynthesis of Functionalized Aryl- or Heteroarylzinc Compounds and their Reactivity 642 Introduction 642 Electrosynthesis of Aryl or Heteroaryl Zinc Species from the Corresponding Halide via a Nickel Catalysis [14] 643 Electrosynthesis of Aryl or Heteroaryl Zinc Species from the Corresponding Halide via a Cobalt Catalysis 645 In DMF/Pyridine or CH3CN/Pyridine as Solvent [15] 645 In CH3CN as Solvent 648 Conclusion 650 General Conclusion 650

15.3.1 15.3.2 15.3.2.1 15.3.2.2 15.3.2.3 15.3.2.4 15.3.3 15.3.3.1 15.3.3.2 15.3.3.3 15.4 15.4.1 15.4.2 15.4.3 15.4.3.1 15.4.3.2 15.4.3.3 15.5 Index

I1

XV

Preface Since the pioneering work of Frankland and Wurtz, organometallic intermediates have occupied a central position in organic synthesis. The chemical behavior of organometallic reagents depends greatly on the nature of the metal and on the carbon hybridization. Each metal has intrinsic chemical properties, which confer a specific reactivity for forming new carbon-carbon bonds to the organic moiety attached to it. The nature of the metal substituents (ligands) enables a modulation and adjustment to this reactivity of the organometallic to the organic substrate. Choosing the correct metal and ligand sphere to achieve any given transformation represents a major task for the synthetic chemist. During the course of the last thirty years, chemists have realized that this fine-tuning of the reactivity of organometallics has a number of synthetic advantages (selectivity, yields, reaction conditions, etc.). However, they have also noticed that a broad range of functionalities can be present in the organometallic intermediate itself and therefore these reagents allow for the preparation of polyfunctional molecules without the need for multiple protection and deprotection steps. This book summarizes the synthetic knowledge available as of 2005 for preparing functionalized organometallics and the optimum conditions for their reacting with electrophilic species. It also covers main group and transition organometallics while outlining in detail the functional group compatibility for each class of organometallics in the various book chapters. Organometallic chemistry is a field of chemistry that is constantly experiencing discoveries and is one of the motors of chemistry. Thus it can be expected that numerous new synthetic methods based on the use of functionalized organometallics will be added to the chemistry presented in this book within the next few years. An effort has been made to present the material in an attractive layout with many equations and numerous practical details, allowing for rapidly entry in the field. Therefore, this book is well suited for master and PhD students, for advanced undergraduate students, as well as industrial process and research chemists. Munich, August 2005


Paul Knochel

XVII

List of Authors Oliver Baron Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Gerard Cahiez Departement de Chimie, ESCOM UniversitØ de Paris 13, Boulevard de l'Hautil 95092 Cergy-Pontoise France Helena Chechik-Lankin Department of Chemistry Technion-Israel Institute of Technology Technion City Haifa 32000 Israel Karl-Heinz Dötz KØkulØ-Institut für Organische Chemie und Biochemie Gerhard-Domagk-Strasse 1 53121 Bonn Germany

Francisco Foubelo Departamento de Química Orgµnica Facultad de Ciencias and Instituto de Síntesis Orgµnica (ISO) Universidad de Alicante Apdo. 99 03080 Alicante Spain Eric Fouquet Laboratoire de Chimie Organique et Organometallique UniversitØ de Bordeaux I 351, Cours de la Liberation 33405 Talence Cedex France Nina Gommermann Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Liu-Zhu Gong Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany


XVIII

List of Authors

Corinne Gosmini Laboratoire d'Electrochimie, Catalyse et Synthse Organique 2 à 8, rue Henri-Dunant B. P. 28 94320 Thiais France Agns Herve Laboratoire de Chimie Organique et Organometallique UniversitØ de Bordeaux I 351, Cours de la Liberation 33405 Talence Cedex France Tamejiro Hiyama Department of Material Chemistry Graduate School of Engineering Kyoto University Kyoto University Katsura Nishikyo-ku Kyoto 615-8510 Japan Li-Fu Huang Institute of Chemistry Academia Sinica Nangang Taipei Taiwan 125 Hiriyakkanavar Ila Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Florian F. Kneisel Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany

Paul Knochel Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Alexander Koch KØkulØ-Institut für Organische Chemie und Biochemie Gerhard-Domagk-Strasse 1 53121 Bonn Germany Felix Kopp Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Tobias J. Korn Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Arkady Krasovskiy Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Helena Leuser Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany

List of Authors

Tien-Yau Luh Institute of Chemistry Academia Sinica Nangang Taipei Taiwan 125

Ioannis Sapountzis Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany

Florence Mahuteau-Betzer Departement de Chimie, ESCOM UniversitØ de Paris 13, Boulevard de l'Hautil 95092 Cergy-Pontoise France

Masaki Shimizu Department of Material Chemistry Graduate School of Engineering Kyoto University Kyoto University Katsura Nishikyo-ku Kyoto 615-8510 Japan

Ilan Marek Department of Chemistry G. Richard Stephenson Technion-Israel Institute of Technology Wolfson Materials and Catalysis Centre Technion City School of Chemical Sciences and Haifa 32000 Pharmacy Israel University of East Anglia Norwich NR4 7TJ Seijiro Matsubara United Kingdom Graduate School of Engineering

Kyoto University Kyoutodaigaku-katsura Nishikyo Kyoto 615-8510 Japan

Jacques PØrichon Laboratoire d'Electrochimie, Catalyse et Synthse Organique 2 à 8, rue Henri-Dunant B. P. 28 94320 Thiais France Sylvie Perrone Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany

Martin Werner KØkulØ-Institut für Organische Chemie und Biochemie Gerhard-Domagk-Strasse 1 53121 Bonn Germany Xiaoyin Yang Department of Chemistry Ludwig-Maximilians-Universität Butenandtstrasse 5±13, Haus F 81377 München Germany Miguel Yus Departamento de Química Orgµnica Facultad de Ciencias and Instituto de Síntesis Orgµnica (ISO) Universidad de Alicante Apdo. 99 03080 Alicante Spain

XIX

1

1 Introduction Paul Knochel and Felix Kopp

Achieving selectivity in chemical reactivity is one of the most important goals in synthetic chemistry. This holds especially true for organometallic compounds in which the carbon attached to the metallic center behaves as a nucleophile. The nature of the metal or of the metallic moiety (MetL n) is exceedingly important for tuning this reactivity. An ionic character of the carbon±metal bond leads to a polarity of this bond and to a high reactivity towards electrophilic species. This high reactivity precludes the presence of many functional groups in organometallics like organolithiums. However, by lowering the reaction temperature and using a solvent of moderate polarity, it is also possible to prepare functionalized organolithiums. Especially interesting was the pioneering work of Parham, who showed that a bromine±lithium exchange can be readily performed at ±100 C in a THF-hexane mixture leading to the functionalized organolithium compound 1. O Br

CN

Li

nBuLi THF/hexane -100 ºC

Ph

CN Ph

OH

CN

2: 86%

1

Br

Li

THF/hexane -100 ºC

O

, TMSCl

nBuLi

CN

1) CuCN⋅2LiCl 2) O

CN

-78 ºC to 0 ºC, 5h

3

Scheme 1.1 Preparation of nitrile-functionalized aryllithiums by a low-temperature Br±Li exchange. Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

CN 4: 93%

2

1 Introduction

Its reaction with benzophenone provides the desired alcohol 2 in 86% yield [1]. The need for keeping the highly reactive lithium intermediate 1 at ±100 C is a preparative limitation, which can be avoided by performing a transmetallation of the functionalized aryllithium to a less electropositive metal, such as zinc or copper. The resulting organometallic species is stable at much higher temperatures (0±25 C), but still reactive enough to undergo efficient conjugated 1,4-addition. Thus, the cyano-substituted aryllithium 3, readily prepared by a bromine±lithium exchange at ±100 C, reacts within a few minutes at this low temperature with the THF-soluble salt CuCN´2LiCl [2] and provides a functionalized copper reagent that reacts smoothly with cyclohexanone in the presence of TMSCl and provides the Michael-adduct 4 in 93% yield (Scheme 1.1) [3]. Even many sensitive functional groups, such as a ketone and an epoxide, can be present in a polar organometallic species, like an organolithium. Thus, the bicyclic bromide 5 undergoes an efficient Br±Li exchange reaction at ±100 C in THF/TMEDA affording the unstable polyfunctional lithium reagent 6, which is trapped with benzaldehyde affording the benzylic alcohol 7 in 79% yield (Scheme 1.2) [4]. Low temperature allows the preparation of highly reactive organometallics, but only very active electrophiles react with these reagents at low temperature, which is a serious limitation. Furthermore, large-scale syntheses involving very low temperatures are difficult to set up and to apply in industry. An alternative constitutes a Barbier procedure [5], in which the reactive polyfunctional lithi-

O

O

O

Br

tBuLi (2 equiv)

Li

PhCHO

O

-100 ºC, THF/TMEDA

O

-100 ºC

5

Ph O 7: 79%

6

Scheme 1.2 Low-temperature preparation of an organolithium species bearing an epoxide and a ketone.

H O

H OHOMe

Li/THF sonication H

H

Br

9: 95%

8 OH + CHO 10

Br

OH

OH

Zn sat. NH4Cl/THF 20 ºC

OH 11: 75%

Scheme 1.3 Barbier reactions using polyfunctional substrates.

1 Introduction

umorganic is directly generated in the presence of the electrophile. Thus, the sensitive bromoketone 8 can be converted in situ to the corresponding lithium species by the direct treatment with lithium metal when sonication is applied, leading to the bicyclic tertiary alcohol 9 in 95% yield [6]. Barbier reactions allow the generation of organometallic intermediates that are difficult to store or to generate in the absence of an electrophile. Thus, it was possible to perform the addition of an allylzinc moiety to an aldehyde, such as 10, bearing a free hydroxy group in a 5:1 mixture of saturated aq. NH 4Cl/THF at room-temperature affording the product in 75% yield without the need of a protecting group (Scheme 1.3) [7]. New types of reactions, such as carbozincation reactions of alkynes using functionalized allylic zinc reagents can be readily accomplished. Thus, the reaction of a silylated propargyl alcohol with t-butyl(2bromomethyl)acrylate (12) in the presence of zinc in THF at 45 C under sonication provides the addition product 13 in 81% yield with excellent regioselectivity (Scheme 1.4) [8]. CO2tBu CO2tBu Br

12

Zn, THF + H

CH2OSiMe3 45 ºC, ultrasonication

OSiMe3 13: 81%

Scheme 1.4 Regioselective addition of a functionalized allylic bromide to alkynes.

The examples above show that the preparation of polyfunctional lithium reagents can be mastered in many cases, but often low temperature and very careful control of the reaction conditions have to be applied. The use of protecting groups is mandatory and reduces the overall yield of the reaction sequences including the protection and deprotection steps. The use of organometallics bearing more covalent carbon±metal bonds would avoid extreme reaction conditions. In 1988 it was found that organozinc iodides bearing numerous functional groups, such as an ester or a ketone can be readily prepared by the direct insertion of zinc dust at 45±50 C. The resulting organozinc species has unfortunately a moderate reactivity and a transmetallation is required to adjust the intrinsic low reactivity of the zinc reagent. Therefore, the reaction of the functionalized alkyl iodide 14 with zinc dust produces within 4 h at 30 C the corresponding alkylzinc iodide 15. It is important in this reaction to keep the reaction temperature below 35 C in order to avoid competitive deprotonation of the comparably acidic protons in the alpha position to the carbonyl group. Under these conditions, the desired zinc reagent can be prepared in high yield. The addition of CuCN´2LiCl allows the preparation of the corresponding copper reagent 16 within a few minutes, which is readily acylated with PhCOCl providing the desired product 17 in 80% yield (Scheme 1.5) [2].

3

4

1 Introduction

Zn, THF

PhCOCl

CuCN⋅2LiCl

0 ºC, 10 h

30 ºC, 4 h O

O

O O

I

O O

O

O

Cu(CN)ZnI

ZnI

O Ph

15

14

R

ZnI

16

17: 80%

ZnI

CuX

X

R

R

Cu(X)ZnI

Cu 18

19

20

Scheme 1.5 Fine tuning of the reactivity of functionalized organometallic species by transmetallation.

The success of this transmetallation for adjusting the reactivity of the zinc organometallic relies on two main facts. Organozincs 18 undergo a series of transmetallations with transition metal salts due to the presence of empty p-orbitals of appropriate energy that facilitate 4-membered transition states such as 19, leading to the copper±zinc species 20. Secondly, the resulting copper reagent, although being thermodynamically more stable (more covalent carbon±copper bond) is also more reactive due to the presence of nucleophilic, nonbonding d-electrons that interact in an oxidative process with the electrophile and catalyze the formation of the new carbon±carbon bond. This concept is quite general and Negishi has shown the importance of sequential transmetallations for adjusting the reactivity in cross-coupling reactions [9]. Thus, the reaction of alkenylalane 21 with 3-iodotoluene does not proceed directly. After one week at 25 C less than 1% of the cross-coupling product is obtained. On the other hand, in the presence of zinc chloride rapid cross-coupling takes place within one hour leading to the styrene derivative 22 in 88% yield. This reaction takes place via an alkenylzinc species that is readily obtained by transmetallation from the alkenylalane 21 (Scheme 1.5). This example shows the importance of mixed metal catalysis. Recently, it was found that, while the cross-coupling of arylmagnesium derivatives with aryl iodides catalyzed by Fe(acac) 3 produces only homo-coupling products, the reaction of the corresponding magnesium cuprate 23 furnishes smoothly the desired cross-coupling product 24 in 75% yield (Scheme 1.6) [10].

References

I Et

Et Pd(PPh3)4 (5 mol%)

Et +

H

AlBu2

Me

21

Et

Me

25 ºC, t without additive: < 1% of product (1 week) with ZnCl2: 22: 88% (1 h)

CO2Et Cu(CN)MgCl

COPh I +

COPh

Fe(acac)3 (10 mol%) DME, 25 ºC, 10 h

23

EtO2C 24: 75%

Scheme 1.6 Mixed metal catalysis for efficient cross-coupling reactions.

These general concepts can be applied to a number of organometallic compounds and over the years have allowed the development of an arsenal of synthetic methods for preparing polyfunctional organometallics and for selective reactions of these versatile intermediates. This book intends to cover the broad aspects of this chemistry that should find broad application in industry and universities.

References 1 (a) W. E. Parham, L. D. Jones, J. Org.

2 3 4

5

5

Chem. 1976, 41, 1187; (b) W. E. Parham, L. D. Jones, J. Org. Chem. 1976, 41, 2704. P. Knochel, N. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem. 1988, 53, 2390. C. E. Tucker, T. N. Majid, P. Knochel, J. Am. Chem. Soc. 1992, 114, 3983. (a) P. A. Wender, L. A. Wessjohann, B. Paschke, D. B. Rawlins, Tetrahedron Lett. 1995; (b) P. A. Wender, T. E. Glass, Synlett 1995, 516. C. Blomberg, The Barbier Reaction and Related One-Step Processes, SpringerVerlag 1993, Springer-Verlag Berlin, Heidelberg, New-York.

6 B. M. Trost, B. P. Coppola, J. Am. Chem.

Soc. 1982, 104, 6879.

7 C. Einhorn, J. L. Luche, J. Organomet.

Chem. 1987, 322, 177.

8 P. Knochel, J. F. Normant, J. Organomet.

Chem. 1986, 309, 1.

9 (a) E. Negishi, T. Takahashi, S. Baba,

D. E. van Horn, N. Okukado, J. Am. Chem. Soc. 1987, 109, 2393; (b) E. Negishi, S. Baba, J. Chem. Soc., Chem. Commun. 1976, 596; (c) E. Negishi, N. Okukado, A. O. King, D. E. van Horn, B. I. Spiegel, J. Am. Chem. Soc. 1978, 100, 2254. 10 I. Sapountzis, W. Lin, C. C. Kofink, C. Despotopoulos, P. Knochel. Angew. Chem. Int. Ed. Engl. 2004, in press.

7

2 Polyfunctional Lithium Organometallics for Organic Synthesis Miguel Yus and Francisco Foubelo 2.1 Introduction

Multifunctional organic molecules can be achieved by reacting functionalized organolithium compounds [1] with electrophilic reagents, this fact makes these intermediates of relevant interest in synthetic organic chemistry [2]. Another remarkable fact concerning organolithium compounds, compared with other organometallic compounds is that they can be prepared following a great number of different methodologies [3]: hydrogen±lithium exchange (deprotonation), halogen±lithium exchange, transmetallation reactions, carbon±heteroatom bond cleavage and carbolithiation of multiple carbon±carbon bonds. However, the highly ionic character of the carbon±lithium bond [4] makes these compounds extremely reactive and also unstable, so the synthetic processes should be carried out in some cases under very mild reaction conditions. Regarding the stability of functionalized organolithium compounds, it depends mainly on three factors, the most important one being the compatibility of the functional group with the carbon±lithium bond, so in some cases the functionality should be protected. The hybridization of the carbon atom bonded to the lithium atom is also important, so sp derivatives are more stable than the corresponding 2 3 sp and these are more stable than the sp ones as it happens to the corresponding carbanions. Finally, the relative position of the functionality and the carbanionic center is also relevant, probably the b-functionalized derivatives being the most unstable species due to the existence of two consecutive carbon atoms with opposite polarities, the b-elimination process to give an olefin is extremely favored. Stabilized organolithium compounds, such as lithium enolate intermediates [5], a-organolithium compounds bearing electron-withdrawing groups (RSO, RSO 2, CN, NO 2, etc.) and heteroatoms such as sulfur [6], selenium and phosphorus as well as functionalized aryllithium compounds will not be consider in depth in this chapter due to the limited length of this review. The following study is ordered based on the relative position of the functionality and the carbanionic center, as well as on the hybridization of that center. Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

8

2 Polyfunctional Lithium Organometallics for Organic Synthesis

2.2 a-Functionalized Organolithium Compounds

There are several examples of a-oxygen- and nitrogen-functionalized organo2 3 lithium compounds with sp and sp hybridization in acyclic and cyclic systems of general structures I±IV. These compounds show a tendency to undergo a-elimination processes to generate carbene intermediates. Li

Li

X ( )n

X I

II

Li

Li

X ( )n

X III

IV

2.2.1 sp 3-Hybridized a±Oxygenated Organolithium Compounds 3

sp -Hybridized a-oxygenated organolithium compounds of general structure I are accessible mainly through halogen±lithium exchange, tin±lithium exchange and by direct deprotonation of appropriate precursors, which means systems with hydrogens at a benzylic or allylic position. Lithiomethyl alkyl ether 2 has been prepared by chlorine±lithium exchange from the corresponding chloromethyl ether 1, lithium powder in the presence of a catalytic amount of 4,4¢-di-tert-butylbiphenyl (DTBB) [7], or naphthalene, as well as biphenyl-supported polymers [8], being used as lithiating reagents (Scheme 2.1). Li, DTBB (5 mol%) O

Cl

1

THF, -90ºC

O 2

Li

1. E 2. H2O

O

X

3 (21-87%)

[E = RCHO, R2CO, CO2, PhCN, PhCONMe2, CyNCO, PhN=CHPh] Scheme 2.1

In the case of chiral lithiomethyl ethers 4 bearing the menthol unit, the lithiation was performed either in the presence of the electrophile (Barbier-reaction conditions) [9] at 0 C or at ±90 C in a two-step process, which means lithiation followed by addition of the electrophile. Low stereoselectivity was observed in the case of using electrophiles with prostereogenic centers [10]. Similar results were obtained also in the case of preparing intermediates 4 and 5 through a tin±lithium exchange [11]. The O-chloroalkyl carbamates 6 were also lithiated by means of lithium in the presence of a catalytic amount of DTBB under Barbier-reaction conditions, because the step by step process at any temperature tried was not effective or gave poor yields. Final hydrolysis with lithium hydroxide or reduction with DIBALH gave 1,2-diols in the case of using carbonyl compounds as electrophiles [12].


O O

Li

4

O

Li

O

N

Li

5

ent-4

9

Li O

R

6

It is possible to transform stereoselectively the anomeric position of a sugar unit into a organolithium compound by chlorine±lithium exchange using a stoichiometric amount of lithium naphthalene as the lithiating reagent [13]. The same kind of intermediates were prepared also by tin±lithium transmetallation [14] and sulfur±lithium exchange in phenyl sulfides and sulfones [15]. In the case of the dianion 8 derived from galactopyranose, the deprotonation of the amide moiety in compound 7 should be performed prior to heteroatom±lithium exchange. The reaction of this intermediate with electrophiles provided a-C-glycosides 9 (Scheme 2.2). BnO OBn O BnO AcHN Cl

BnO OBn O BnO AcLiN Li

1. n-BuLi, THF, -90ºC 2. LiC10H8 (2.2 equiv), -90ºC

7

1. E 2. NH4Cl-H2O

8

BnO OBn O BnO AcHN X 9 (72-86%)

[E = MeOD, RCHO, CO2] Scheme 2.2

High diastereoselectivity was observed in the reaction of intermediate 11 (prepared by tin±lithium exchange from compound 10, which derived from L-valine) with benzaldehyde to give the corresponding adducts in a 91:9 diastereomeric ratio. Final hydrolysis yields the 1,2-diol 13 and the chiral auxiliary 12 (Scheme 2.3) [16].

O

Ph O

SnBu3

n-BuLi (2 equiv) THF/Et2O, -78ºC

O

Ph O

10

Li

1. PhCHO, -78ºC 2. CSA, MeOH, rt

11 OH

O

OH Ph

12

+

Ph

OH

13 (91%)

Scheme 2.3

Compounds 14[11]-18 have also been prepared from the corresponding stannanes. Surprisingly, cyclic a-alcoxy-b-aminoalkyllithium compounds 15 and 16

10


are stable at ±78 C, because, taking into account Baldwin's rules along with the microscopic reversibility principle, a b-elimination process (which would lead to a olefin) is the reverse of the n-endo-trig cyclization. Thus, the stability of intermediates 15 decreases with increasing ring size [17]. In the case of other a-stannylated hydroxycompounds, the corresponding transmetallation occurs only for their carbamate derivatives [18] but not in the case of O-MOM protected systems [19]. The reaction of intermediates 17 with aldehydes followed by reduction with AlH 3 gave 1,2-diols. The lithiation of enantiomerically enriched a-propargyloxy stannanes proceeds with complete inversion of the configuration and has been applied to study the Wittig rearrangement. In the case of compounds 18 the selectivity of 2 [2,3] versus [1,2] rearrangement is dependent of the nature of the R substituent on the acetylenic moiety [20]. Li

Li

Li

MOMO

O

N ( )n P f 14

O Pf N

15 (n = 0-2)

R2

O NEt2

O Li

R

16

O

Li R1

17

18

[Pf = 9-phenyl-9-fluorenyl]

The a-alkoxy alkyllithium derivative 20, prepared from compound 19 by tin± lithium exchange with retention of the configuration, undergoes 5-exo-trig cyclization to form first the cyclic compound 21 and finally the trans-disubstituted tetrahydrofuran 22 through a b-elimination process (Scheme 2.4) [21].

Ph

H

OMe SnBu3

n-BuLi, THF -78ºC

O

H

Ph

O

OMe

19

20

Li

Ph

Li

Ph OMe

O

O 21

22 (56%)

Scheme 2.4

The a- and b-configurated glycosyl anions 23±26 were prepared by tin±lithium exchange. C-Glycosilated aminoacids were obtained by reaction of intermediate 23 with lactams [14], meanwhile the reaction of compounds 24 and 25 with electrophiles led to a- and b-C-galactosides [22], respectively, intermediate 26 being used in the stereocontrolled synthesis of carba-C-disaccharides [23].

2.2 a-Functionalized Organolithium Compounds BnO OBn O BnO AcLiN

Li

BnO OBn O BnO Li OLi

23

BnO OBn O BnO LiO Li

24

11

OBn O

BnO BnO

Li

25

26

As commented above, this kind of functionalized organolithium compounds can also be prepared through deprotonation processes. The deprotonation can be also performed in a diastereoselective way, for instance, in the presence of (±)-sparteine [24]. Treatment of O-alkyl carbamate 27 with s-BuLi in the presence of (±)-sparteine at ±78 C gave the organolithium compound 28 with high ee, which upon carboxylation and acidic hydrolysis led to (R)-pantolactone 29 (Scheme 2.5) [25]. OCONR2 O

O N

OCONR2 O

O

s-BuLi, (-)-sparteine Et2O, -78ºC

Li

1. CO2, -78ºC to rt

OH

2. 2 M HCl 3. 5 M HCl, 90ºC

N

O O

O

O 27

29 (80%, >95% ee)

28

Scheme 2.5

The organolithium compound 30 was also prepared by an enantioselective deprotonation in the presence of (±)-sparteine. It is configurationally stable, but when reacting with electrophiles retention or inversion of its configuration is observed [26]. The deprotonation can also be performed in the presence of a chiral bisoxazolidine to give benzylic anions 31±33, which reacted with electrophiles to yield the corresponding reaction products with good stereoselectivity. In this case, the stereoselectivity was explained by a dynamic thermodynamic mechanism instead of through an enantioselective deprotonation [27]. The a-lithiated O-protected propargyl alcohol 34 was prepared by deprotonation with n-BuLi and used in the synthesis of a cyclic enediyne related to maduropeptin chromophor [28]. OMe O Li Ph

O 30

Me

O

Ph 31

Li

O

Li

O 32

Li

Ph

Li

OMe 33

Me3Si

34

Lithiated epoxides [29] of general structure II (X = O, n = 0) were first postulated as intermediates by Cope, and many of them act as carbenoid species: they can undergo (a) b-elimination to give an enolate, (b) a-ring opening followed by

12


1,2-hydride shift to give an enolate or (c) a-ring opening followed by attack of an alkyllithium and subsequent elimination of lithium oxide affording an olefin. Only stabilized anions carrying electron-withdrawing or coordinating substituents, or heteroatomic, aromatic or unsaturated groups are stable enough to react with electrophiles. Lithiooxirane 35 was prepared by deprotonation with s-BuLi in the presence of TMEDA in THF at ±98 C and reacted with electrophiles [30] with retention of the configuration. The same reaction conditions were used in the preparation of oxazolinyloxiranyllithiums 36 [31], which reacted with nitrones to give, after hydrolysis and catalytic hydrogenation, a-epoxy-b-aminoacids [32]. Oxyranyllithium 37 was prepared by lithiation a to the silicon with n-BuLi in ether at ±116 C with retention of the configuration of the oxirane [33]. Ethynyl oxirane anionic species 38 was prepared by deprotonation with n-BuLi at the propargylic position and trapped with electrophiles to give trisubstituted oxiranes [34].

Ph

N

O

O

R

O Li

Me 35

Li

36

TBDMS

R

Li

TMS

O

O OTMS Li

37

38

Nonstabilized oxiranyl anions were generated by lithiation of terminal epoxides in the presence of a diamine ligand [35], this methodology being applied to the asymmetric deprotonation of meso-epoxide 39 in the presence of (±)-sparteine. The resulting organolithium compound 40 reacted with different electrophiles to give compounds 41 in up to 86% ee (Scheme 2.6) [36]. R O R 39


Li

R

O R 40

1. E

R

2. H2O

R

X O

41 (48-84%, 73-86% ee)

[E = CD3OD, PhCHO, PhCONMe2, EtCHO, Et2CO, EtCONMe2, EtOCOCl, n-Bu3SnCl, Me3SiCl, MeI] Scheme 2.6

A a-oxygenated organolithium compound acts as a reaction intermediate in a spiroannulation reaction from 2-cyanotetrahydropyrans. The key feature of this method is the use of a nitrile to facilitate alkylation (to generate the corresponding precursor) and as a precursor of an alkyllithium reagent. Thus, reductive decyanation of compound 42 led to the intermediate 43 [37], which underwent intramolecular carbolithiation and, after carboxylation and reaction with CH 2N 2, gave spirocyclic ester 44 as a single diastereomer (Scheme 2.7) [38].


LiDTBB,THF -78 to -40ºC H

O

CN

H

O

Li

CO2Me

43

42

O

1. CO2 2. CH2N2

44 (75%)

Scheme 2.7

2.2.2 sp 2-Hybridized a-Oxygenated Organolithium Compounds

Simply vinyl ethers, such as compound 45, and other vinyloxygenated systems undergo deprotonation with t-BuLi at low temperatures to give vinyl lithium derivatives of general structure III (X = OR) that react with different electrophiles [39]. For instance, the reaction of the intermediate 46 with chlorotrimethylgermane gave, after acidic hydrolysis, acylgermanane [40] (Scheme 2.8), compound 46 being an acyl anion equivalent [41]. The lithiation of 1-alkoxyallene 47 takes place more easily, using in this case n-BuLi as base at ±78 C in ether or THF as solvents (Scheme 2.8), intermediate 48 being stable at this temperature for several days [42]. Calculations and spectroscopic data suggest a 1,3-bridged structure for the anion 48 [43]. The reaction of this anion with a,b-unsaturated amides, followed by spontaneous Nazarov-type cyclization, gives methylene cyclopentenones [44]. The enantioselective variant of this synthesis was performed with the lithiated allene derived from D-glucose 49 [45]. Li OEt 45

t-BuLi, THF -100ºC

OEt 46

.

O

47

OMe n-BuLi, THF -78ºC

.

O

OMe Li

48

Scheme 2.8

Cyclic akenyl ethers of general structure IV (X = O), like dihydrofuran and dihydropyran 50 (n = 1, 2) are deprotonated by means of either t-BuLi in a mixture of pentane and THF or with n-BuLi and TMEDA in hexane or pentane at 0 C [41]. These compounds reacted with a great variety of electrophiles, their reaction with carbonyl compounds, followed by acid treatment, giving spirocyclic ketones after suffering pinacol rearrangement [46]. Enantiomerically enriched spirocyclic compounds were obtained from the intermediate 51 (prepared from tin±lithium exchange) [47], or a-lithiated glucals 52 and 53 (prepared by direct deprotonation with t-BuLi) [48].

13

14


OMe MeO MeO

O

.

MeO O 49

Li

Li

OTBS OTIPS

O ( )n

O

50 (n = 1, 2)

51

Li

Li

O

OTBS OTBS

OTIPS

Li

52

O 53

Similarly, 2,3-dihydro-1,4-dioxin can be lithiated at a vinylic position with either n-BuLi at 0 C or t-BuLi at ±30 to ±20 C [43a]. Related benzocondensed systems 54 were lithiated with LDA at ±78 C to give the dianionic intermediates 55, which were converted into lactones 56 upon successive reaction with acetaldehyde and propanoic acid [49] (Scheme 2.9). O O R

CO2H

O 54

O LDA THF/hexane -78ºC

R

O 55

CO2Li Li

O 1. MeCHO 2. EtCO2H PhMe

O R

O 56 (88-93%)

Scheme 2.9

2.2.3 sp 3-Hybridized a-Nitrogenated Organolithium Compounds

There are two types of a-aminoalkyl organolithium compounds of general structures I (X = NRR¢) and II (X = NR): those unstabilized (derived from tertiary alkylamines) and those dipole-stabilized. The stabilized derivatives can be prepared by a-deprotonation of compounds where the nitrogen lone pair of electrons are involved in conjugation with unsaturated systems using strong bases [50]. This situation makes the nitrogen a more electron-withdrawing group, a stabilization of the organolithium compound occurring sometimes by intramolecular coordination of the metal with the functional group that contains the nitrogen atom. In the case of hindered amides alithiation to the amide nitrogen leads to stable organolithium compounds. Stereospecific deprotonation with t-BuLi of N-(a-methylbenzyl)-N-isopropyl-p-methoxybenzamide gave the corresponding configurationally stable tertiary benzyllithium derivative 57, which underwent a stereospecific dearomatization-cyclization with >99% retention of the stereochemistry. This methodology was used in the synthesis of kainic acid derivatives [51]. Other stabilized a-nitrogenated organolithium compounds have been prepared by deprotonation of the appropriate precursors. The pyrazole derivative 58 was obtained by deprotonation with n-BuLi [2a], whereas in the case of the formamidine derivative 59 t-BuLi was used as base [52]. In the case of the lithiated cyclic N-nitrosoamine 60, the deprotonation was performed with LDA to give exclusively the axial lithium derivative, which is stabi-


lized by interaction with the LUMO of the adjacent p-system [53]. Quinuclidine N-oxide was lithiated with t-BuLi to give the intermediate 61 [54]. All these anionic systems 57±61 reacted with electrophiles to give functionalized molecules in good yields. O N N MeO

Ph

Li

N

Ph N

Li

57

N

N Li

58

59

N O _

Li 60

+ N O

Li

61

Dipole-stabilized a-aminoorganolithium compounds are less reactive than the unstabilized ones and for that reason more resistant to suffer racemization. Enantioselective deprotonation of N-Boc pyrrolidine 62 with s-BuLi and (±)-sparteine gave the chiral configurationally stable [55] organolithium compound 63. Due to the fact that (±)-sparteine is only available in one enantiomeric form, O'Brien et al. reported the synthesis of a (+)-sparteine surrogate, which worked as a successful chiral ligand in the same processes as (±)-sparteine, so both enantiomers are available by choosing the right diamine ligand [56]. The enantio-determining step is the formation of the organolithium derivative, the reaction of this intermediate with electrophiles leading to chiral compounds with high stereoselectivity [57]. For instance, when 1-pyrrolidinecarbonyl chloride was used as electrophile, the corresponding amide 64 was obtained in 85% ee [58] (Scheme 2.10). Intermediate 63 can also be prepared by tin±lithium exchange from the corresponding enantiopure 2-(tributylstannyl)pyrrolidine because tin±lithium exchange takes place with retention of the configuration [59].

N Boc


62

N Boc 63

Li

1. (CH2)4NCOCl 2. AcOH

N N Boc O 64 (57%, 85% ee)

Scheme 2.10

The unchelated dipole-stabilized a-aminobenzyl organolithium compound 65 was prepared by deprotonation and used in the synthesis of the azaphenanthrene alkaloid eupolauramine [60]. The N-lithiomethylcarbamate 66 was prepared by DTBB-catalyzed lithiation of the corresponding chlorinated precursor in the presence of carbonyl compounds as electrophiles, the resulting adducts being transformed into the corresponding b-aminoalcohols [61]. Chiral N-lithiomethylpyrrolidine 67 was prepared through either a tin±lithium exchange with n-BuLi or by carbon±sulfur bond cleavage with lithium 4,4¢-di-tert-butylbiphenyl (LiDTBB) from the corresponding prolinol derivatives. The reaction of the intermediate 67 with aldehydes gave b-aminoalcohols in good yields but poor diastereoselectivity [62]. The corresponding unchelated a-amino organolithium compound 68 was also

15

16


prepared by tin±lithium transmetallation and reacted with electrophiles in moderate yields [63]. Reductive lithiation of a bicyclic oxazolidine with lithium in the presence of a catalytic amount of naphthalene (10 mol%) gave the benzylic organolithium compound 69, which is stabilized by the alkoxide group. Epimerization at the benzylic position takes place rapidly and one of the diastereomers reacts faster than the other with alkyl halides to give mainly syn-products [64]. Nonstabilized aziridinyl anions can be prepared by direct deprotonation of aziridine borane complexes. Thus, deprotonation with s-BuLi of 1-(tert-butyldimethysililoxyethyl)aziridine borane occurred syn to the boron substituent to give intermediate 70, while lithiation of 1-(tert-butyldimethysililoxyethyl)-2-trimethylstannylaziridine borane occurred anti to the boron and tin, due probably to steric effects. When the deprotonation was performed in the presence of (±)-sparteine, stereoselectivity went up to 70% ee [65]. O

O

NMe

N 65

O

Li

LiO

Li N Me

66

OMe

N

O

N Me

Li 67

Li

Li

Li N

68

Ph

_ N+ H3B (CH2)2OTBS 70

69

A trifluoromethyl stabilizing aziridinyl anion 72 was generated by deprotonation of the optically active N-tosyl-2-trifluoromethylaziridine 71 with n-BuLi. The organolithium intermediate 72 reacted with electrophiles to give the corresponding adducts 73 in good yields (Scheme 2.11), the whole reaction occurring with retention of the configuration at the stereogenic carbon center [66]. Ts H

N

F3C 71

Ts n-BuLi, THF -100ºC

Li

N

F3C

Ts 1. E 2. NH4Cl

72

X

N

F3C 73 (27-95%)

[E = PhCHO, Ph2CO, PhCOMe, EtO2CCHO, PhCOCl, MeOCOCl, EtCOCl, BnOCOCl] Scheme 2.11

2.2.4 sp 2-Hybridized a-Nitrogenated Organolithium Compounds

Recently, different a-lithioenamines 75 have been prepared by chlorine±lithium exchange from the corresponding chloroenamines 74 and reacted with electrophiles to give functionalized enamines 76. A mixture of lithium and a catalytic amount of DTBB was used as the lithiating reagent (Scheme 2.12) [67]. The process can be performed either step-by-step (lithiation-reaction with the electrophile) at ±90 C or under Barbier-reaction conditions at ±40 C. In the case of using carbonyl compounds as electrophiles, after acidic hydrolysis, a-hydroxyketones were obtained, intermediates 74 acting in this case as acyl anion equivalents [41].


NR22 1

R

Cl 1

Li, DTBB (5 mol%) THF, -90ºC

NR22 R

i L 1

R 74

NR22

1. E 2. H2O

1

17

1

R

X R1 76 (55-81%)

R 75

[E = D2O, Me3SiCl, PhCOCH=CHPh, CO2, CyNCO] Scheme 2.12

Some formamidines underwent lithiation of a vinylic position a to nitrogen, so for instance vinyllithium compound 77 was prepared by deprotonation with t-BuLi of the corresponding formamidine [68]. In the case of hydrazones, a double lithiation occurred leading, for instance, to intermediate 78, where the second C-lithiation took place at the trigonal carbon atom a to the C=N bond [69]. Lithiated cyclic enamines 79 were prepared by tin±lithium transmetallation and coupled with different electrophiles [70]. Organolithium compounds with a nitro2 gen at the a-position and sp -hybridation can be prepared by direct metallation of nitrogen-containing aromatic heterocycles [71]. Thus, direct deprotonation of N-methylimidazol gave 2-lithio-N-methylimidazol 80 [72]. Direct lithiation of N-benzyloxypyrazole with n-BuLi gave compound 81, which reacted with diethyl N-Boc-iminomalonate in the synthesis of N-hydroxypyrazole glycine derivatives [73]. 2-Lithiobenzothiazole 82 reacted with galactonolactone being used in saccharide chemistry [74]. Selective monobromo±lithium exchange from the corresponding dibromopyridine [75] gave intermediate 83, which by reaction with a first electrophile and subsequent new lithiation and reaction with a second electrophile was used in the synthesis of a ceramide analog [76]. Using LiTMP as a base, organolithium compound 84 was prepared from 2-chloropyrazine and, after reaction with aldehydes, the resulting products were used in a route to the wheat-diseaseimpeding growth agent septorin [77]. The pyrazolopyrimidine lithium derivative 85 was prepared by tellurium±lithium transmetallation [78].

N

Li

N

N R

Li N

R2 R

Li

Li 77

Li

Me N

1

N Ts 79

78

Li

N

N

N OBn

80

81 Li

Li

N 83

Br

N

Li

N

N

Cl

N Ph

84

N N 85

N Li S 82

18


2.2.5 Other sp 2-Hybridized a-Functionalized Organolithium Compounds

Two general strategies have been followed for preparing a-haloalkyllithiums: (a) a-deprotonation of vinyl halides with strong bases and (b) halogen±lithium exchange in 1,1-dihaloalkenes [43a,79]. In both cases the processes having to be carried out at low temperature (±100 C). The deprotonation of (Z)-1-chloro-1,3butadiene 86 with lithium 2,2,6,6-tetramethylpiperidine (LiTMP) at ±90 C gave (Z)-1-lithio-1-chloro-1,3-butadiene 87. The reaction with benzaldehyde as electrophile took place with retention of the configuration of the double bond, giving compound 88 after hydrolysis (Scheme 2.13) [80]. Cl Cl

Cl

LiTMP, THF -90ºC

Li

86

Ph

1. PhCHO

87

2. H2O 88

OH

Scheme 2.13

Although vinyl bromides and iodides are useful precursors of vinyllihiums by reaction with alkyllithiums through a halogen±lithium exchange, in the case of chlorinated materials, deprotonation occurs preferentially. Thus, treatment of 1,1diphenyl-2-chloroethylene with n-BuLi in THF at ±100 C gave the vinyllithium derivative 89 (deprotonation) [81], whereas under the same reaction conditions, chlorotrifluoroethylene gave intermediate 90, (deprotonation is not possible) so a fluoro-stabilized vinyllithium compound by a chlorine±lithium exchange is formed [82]. Li Ph

Li Cl

Ph 89

F

F F 90

2.3 b-Functionalized Organolithium Compounds

Organolithium compounds bearing a functional group at b-position are unstable species. They show a great tendency to undergo a b-elimination process to give olefins, the better leaving group the higher instability. The hybridization of the 3 carbon atom attached to the metal could be sp (general structures V and VI) as 2 well as sp (general structures VII±X) in both cyclic and acyclic systems.


Li

Li

X

X

Li

Li

Li

Li X

X

X

X X

V

VI

VII

VIII

X

IX

2.3.1 sp 3-Hybridized b-Functionalized Organolithium Compounds

One way to prevent the decomposition of b-functionalized organolithium compounds V-X (X = OR, NR 2) is by reducing the b-elimination process developing a negative charge on the heteroatom. These intermediates have been prepared following three general strategies: (a) mercury±lithium transmetallation, (b) chlorine±lithium exchange (in both cases oxygen and nitrogen deprotonation should be carried out first) and more recently by (c) reductive opening of epoxides and aziridines [83]. Deprotonation of organomercurials 91 with phenyllithium followed by mercury±lithium transmetallation with lithium metal gave organolithium intermediates 92, which are stable at ±78 C and reacted effectively with electrophiles to give polyfunctionalized compounds 93 (Scheme 2.14) [84]. YH HgBr

R 91

1. PhLi, THF, -78ºC 2. Li, -78ºC

YLi Li

R

1. E 2. H2O

92

YH R

X

93 (32-90%)

Y = O, NPh E = H2O, D2O, CO2, Me3SiCl, R1Br, Me2S2, R1R2CO, R1CH=NR2 Scheme 2.14

Since enantiomerically pure epoxides are easily accessible or commercially available, chiral products can be obtained through a reductive cleavage followed by reaction with electrophiles. The DTBB-catalyzed lithiation of epoxide 94, derived from D-glucose, led to the organolithium derivative 95. In the case of unsymmetrically substituted epoxides, the regiochemistry of the ring opening always led to the most stable organolithium compounds, what is the case of the primary intermediate 95. Its reaction with electrophiles followed by hydrolysis gave the corresponding 3C-substituted D-glucose derivatives 96 (Scheme 2.15) [85].

19


20

O O O


O O O

O O

Li

94

OLi O

O O

1. E 2. H2O

O O

OH O X

O O

96 (20-75%)

95

[E = H2O, D2O, Me3SiCl, CO2, R2CO] Scheme 2.15

Enantiomerically pure intermediates 97 and 98 of type V (X = OLi) were prepared from the corresponding chiral chlorohydrines by deprotonation first with n-BuLi and subsequent chlorine±lithium exchange with lithium naphthalenide [86]. The reaction of these dianions with prostereogenic carbonyl compounds showed low diastereoselectivity. The same strategy was followed in order to prepare these intermediates but starting from b-(phenylsulfanyl)alcohols through a sulfur±lithium exchange [87]. Oxygen functionalized organolithium compounds 99 [88] and 100 [89] were prepared by reductive opening of the corresponding chiral epoxides with LiDTBB and used in the synthesis of calcitriol lactone and diterpene forskolin, respectively. Dianionic intermediate 101 was also prepared by DTBB-catalyzed lithiation of the corresponding epoxide derived from (±)-menthone and used in the synthesis of functionalized terpenes [90].

OLi

LiO Li

Li

O

LiO O

LiO Li

OLi

Li

MEMO

Li

97

98

99

100

101

Dilithium derivatives 102±105 were generated by reductive opening of epoxides derived from D-glucose, D-fructose, estrone and cholestanone, respectively, and trapped with different electrophiles. In this way, 6C-substituted 6-deoxy-D-glucose, 3C-substituted D-psycose [85], 17C-substituted-17b-estradiol and 3C-substituted-3a-cholestanol [91] derivatives were prepared. Li LiO

OLi OEOM O O O

O O

O

O OLi Li

Li MOEO

102

103

Li

O

OLi 104

105


As has been described before, one of the most important problems to be over3 come in the preparation of sp -hybridized b-functionalized organolithium compounds is their decomposition by a b-elimination process to give olefins. Advantage of this reaction can be taken to prepare olefins starting from organomercurials, chlorohydrins and epoxides by performing the lithiation process at higher temperatures [92]. The reductive opening of aziridines 106 should be performed at ±78 C with an excess of lithium in the presence of a catalytic amount of an arene. A limitation in this methodology is that a phenyl or aryl group should be present as a substituent either at the nitrogen or at one of the carbon atoms of the aziridine ring. Regarding the regiochemistry of the process, the most stable primary organolihium intermediate 107 is always formed that by reaction with electrophiles and final hydrolysis led to the corresponding functionalized amines 108 (Scheme 2.16) [93]. NR1 R2

Li, C10H8 (5 mol%) THF, -78ºC

R1NLi Li

R2

1. E 2. H2O

107

106

R1NH X

R2

108 (50-93%)

3 4

[E = H2O, D2O, RHal, Me2S2, RCHO, R R CO, (EtO)2CO, CH2=CHCO2Et] Scheme 2.16

The enantiomerically enriched b-nitrogenated organolithium compound 109 was prepared by reductive opening of the aziridines derived from (±)-ephedrine [93], whereas compounds 110 and 111 were generated from the corresponding chlorinated precursors through a DTBB-catalyzed lithiation by a chlorine±lithium exchange [94]. The same methodology but using lithium naphthanelide was employed to prepare the intermediate 112. Compound 113 was formed by stereoselective deprotonation of the corresponding N-Boc-cyclopropylamines [96]. The reaction of all these intermediates 109±113 with electrophiles yielded chiral regioselectively functionalized nitrogenated compounds. MeNLi Li Ph 109

PhCONLi Li 110

Li

Ph 111

R3

t-BuOCONLi

PhCONLi

Li

SEMO 112

Li

R2 BocNR1 113

Although allylic organolithium compounds of the type VI decompose easily to give allenes, deprotontation of methyl isopropenyl ether with a mixture of n-BuLi/ t-BuOK at ±78 C gave the allylic intermediate 114, which was trapped with electrophiles. At ±30 C compound 114 decomposes to give allene [97]. The organolithium derivative 115 was prepared by deprotonation with LDA at 0 C and decomposed immediately to give the corresponding allene [98]. However, cyclic allylic organolithium compounds 116 [99] and 117 [100], which are more stable,

21

22


were also prepared by direct deprotonation with LDA and t-BuLi, respectively, intermediate 116 being used in the synthesis of tetrahydropyranones.

OMe

Ph

Li

OTBS Li

N CO2Li

Li

O

Ph 115

114

Li

CO2Et

116

117

2.3.2 sp 2-Hybridized b-Functionalized Organolithium Compounds

Alkenyllithium compounds of type VII have been prepared mainly by halogen± lithium exchange. b-Ethoxyvinyllithium derivatives 118 and 119 were accessible from the corresponding vinyl bromides by stereospecific bromine±lithium exchange with n-BuLi at ±78 C. The (Z)-isomer 119 is much more stable than the (E)-isomer 118 because in this case an antiperiplanar elimination of lithium ethoxide is more favorable. In the case of (Z)- and (E)-diethoxyvinyllithiums 120 and 121, they have been prepared by deprotonation with t-BuLi at ±78 C of the corresponding diethoxyethylenes. The (Z)-isomer 121 is also more stable than the (E)isomer 120 due to the previously mentioned antiperiplanar b-elimination of lithium ethoxide. However, compounds 120 and 121 are much more stable than the monoethoxy substituted derivatives 118 and 119 due to the inductive effect of the oxygen atom at the a-position. All these intermediates reacted with electrophiles regio- and stereoselectively [101]. b-(Trimethylsilyl)vinyllithium 122, generated from b-(trimethylsilyl)vinyl bromide with t-BuLi, reacted with b-alkenoyl acylsilanes to give eight-membered carbocycles [102]. Many vinyllithium compounds with other functional groups have been described in the literature, for instance, the cyclic b-bromoderivative 123 that was prepared from the corresponding dibromide through a selective monobromo±lithium exchange with t-BuLi at ±78 C [103]. In this case, decomposition through a synplanar process is obviously inhibited. Intermediates of type X are, in general, stable species and therefore useful functionalized organolithium reagents in order to prepare aromatic compounds. They have received much attention and are generated by direct deprotonation [71,104a] or by halogen±lithium exchange [75,104b]. For instance, the aryllithium 124 was prepared by iodo-lithium exchange with n-BuLi in toluene and used in the synthesis of antitumor antibiotics duocarmycins [105]. Br OEt OEt Li

OEt 118

Li

OEt

Li OEt 119

120

Li

Li Br

OEt 121

Li

Li

Me3Si 122

123

Br

BnO 124


Dianions 126, alkenyllithium compounds of type VIII, have been obtained by halogen±lithium exchange from the corresponding chlorinated or brominated precursors 125 using lithium naphthalenide; it was necessary to carry out a previous deprotonation with PhLi. The reaction of 126 with electrophiles gave regioselective functionalized allyl amines 127 (Scheme 2.17) [106]. Hal

Li

1. PhLi, THF, -78ºC 2. LiC10H8, -78ºC

NHR 125

Li NR

1. E 2. H2O

X NHR 127 (68-93%)

126

Hal = Cl, Br E = H2O, D2O, Me2S2, R1R2CO, CH2=CH2CH2Br Scheme 2.17

Vinyllithium derivatives 128±131 have been generated through a bromine±lithium exchange with t-BuLi. In the case of 128, used in the synthesis of (±)-wodeshiol, a deprotonation of the alcohol functionality was performed prior lithiation [107]. Intermediates 129 were also used in the synthesis of triquinanes [102,108], meanwhile 130 acted as an intermediate in a synthetic route to (+)-pericosine B [109]. Dianionic species 131 showed an unexpected intramolecular carbometallation upon addition of TMEDA to give dilithiated dihydropyrroles, which finally reacted with different electrophiles [110]. Li OR

OLi O

OMe Li

Li

TESO TESO

( )n

O 128

Li Li

RN

129 (n = 0, 1)

OTES

130

131

Vinyllithium acetals 133, compounds of type IX, were prepared from the corresponding chlorinated precursor 132 by a DTBB-catalyzed lithiation at low temperature. They reacted with electrophiles to give compounds 134. In the case of using chiral starting materials (132, R = Me), the reaction with prostereogenic carbonyl compounds took place with almost null stereoselectivity (Scheme 2.18) [111]. R

R

O

O

R Cl


132 [E = H2O, D2O, Me3SiCl, RCHO, Scheme 2.18

R

O

O

133 R1R2CO]

R Li

1. E 2. H2O

O

R O

X

134 (51-98%)

23

24


2.4 c-Functionalized Organolithium Compounds

Organolithium compounds with a functional group at the c position can be represented by a great number of general structures (XI±XX) depending on the hybridization of the carbon atoms bearing both the lithium and the functional group. Li

X

Li

X

Li

XII

X

Li

X

Li XIV

XIII

XV

Li

X

X

X X

Li

X XVII

XVI

Li

Li

X XI

X

X

XVIII

Li

XIX

XX

2.4.1 c-Functionalized Alkyllithium Compounds

Functionalized organolithium compounds of type XI can be accessible through a large number of methodologies. They are accessible by halogen±, sulfur±, or selenium±lithium exchange, tin±lithium transmetallation, reductive opening of fourmembered heterocycles and also by carbolithiation of cinnamyl systems. Enantiomerically pure oxygen functionalized organolithium compounds 135±138 have been prepared by halogen±lithium exchange. The precursor of 135 was the corresponding chlorohydrin and lithium naphthalenide the lithiating reagent [86], meanwhile intermediates 136 [112], 137 [113] and 138 [114] were prepared by iodine±lithium exchange by means of t-BuLi. All of them reacted with electrophiles to yield polyfunctionalized compounds, compound 137 being used in the synthesis of scopadulcic acid A.

O

Li

Li 135

OLi

OBn

OLi

O 136

Li

O

O

( )3

Li CF3

137

138

The carbolithiation of cinnamyl methyl ether 139 with an alkyllithium in the presence of TMEDA led to the corresponding benzylic organolithium intermediates 140, which by reaction with electrophiles gave compounds 141 with high diastereoselectivity (Scheme 2.19) [115].


Li Ph

RLi, TMEDA Et2O, 0ºC

OMe

OMe

X 1. E 2. NH4Cl-H2O

Ph R 140

139

25

OMe

Ph R 141 (59-68%)

[E = MeOH, MeOD, CO2, (MeS)2, MeI] Scheme 2.19

When the carbolithiation of tert-butyl cinnamyl ether is performed in the presence of (±)-sparteine, chiral organolithium compounds 142 were obtained, so chiral 2-alkyl-3-phenylpropanols were the reaction products, after hydrolysis [116]. Dianionic species 143±145 were prepared by reductive opening of different heterocycles [83] by an arene-catalyzed lithiation and reacted with electrophiles to give polyfuncionalized molecules in good yields. Enantiomerically pure oxetanes [117,118] (for 143), 4-phenyl-1,3-dioxolanes [119] (for 144) and 2-phenyl-substituted azetidines or tietanes [120] (for 145) were the starting heterocycles used. The reductive cleavage always gave the most stable intermediate: the primary alkyllithium compounds for the chiral oxetanes and the benzylic derivatives for the other. Although c-halogenated organolithium compounds have a great tendency to undergo c-elimination reactions, the norbornane derivative 146 (prepared from the brominated derivative by treatment with t-BuLi at ±125 C) could be trapped with carbon dioxide to give the corresponding carboxylic acid in 47% yield [121]. t-BuO

Li

Li

OLi O

Li

O

Ph

Li

OLi

YLi F

Ph

R 142

O

Ph

R 144

143

Li

145 (Y = S, NR)

146

Masked lithium homoenolates of type XII are of interest in synthetic organic chemistry and can be considered as three-carbon homologating reagents with umpolung reactivity [122]. The lithiation of the b-chloro orthoester 147 with lithium in the presence of a catalytic amount of DTBB, under Barbier-reaction conditions, and using carbonyl compounds as electrophiles, followed by acidic hydrolysis, led to lactones 149 as reaction products, the masked lithium homoenolate 148 being proposed as a reaction intermediate (Scheme 2.20) [123]. Cl

O O O 147

Scheme 2.20

Li, DTBB (5 mol%) R1R2CO THF, -78ºC

Li

O O O 148

1. phosphate buffer -78ºC to rt 2. PTSA

R1 R2 O

O

149 (37-45%)


26

Cyclopentanone dioxolane lithium homoenolate 150 was prepared by reductive lithiation with LiDTBB of the corresponding b-penylsulfanyl derivative and alkylated with allylic bromides in the presence of copper salts [124]. The acyclic dioxane lithium homoenolate 151 was prepared by bromine±lithium exchange and used for the synthesis of highly functionalized porphyrins [125]. Carbolithiation of a cinnamyl acetal with t-BuLi in toluene gave the lithium homoenolate 152, which reacted with electrophiles to give reaction products with high diastereoselectivity [126]. The chiral benzylic homoenolate 153 was prepared by deprotonation of the corresponding amide with 2 equiv of s-BuLi in the presence of TMEDA at ±78 C. First deprotonation deactivates the functionality and the second deprotonation is directed to the b-position of the carboxamide by the so-called complexinduced proximity effect (CIPE) [127]. In the reaction of intermediate 153 with electrophiles an almost 10:1 mixture of diastereomers was obtained [128]. Lithiated imines 154, which were prepared by DTBB-catalyzed lithiation of the corresponding chlorinated derivatives, underwent intramolecular cyclization through an endo-trig process to yield 2-substituted pyrrolidines, after hydrolysis [129].

O

O

Li

Li

O

Li O

O

Li

Ph

O

N

Ph

t-Bu

R1

Ph R1

OLi

N

Li 150

151

152

154

153

2.4.2 c-Functionalized Allyllithium Compounds

Functionalized allyllithium compounds of type XIII are also homoenolate equivalents [122,130], but in their reaction with electrophiles sometimes it is not possible to control the regioselectivity. These compounds have been prepared mainly by either deprotonation or tin±lithium exchange. Deprotonation of (E)-cinnamylN,N-diisopropylcarbamate 155 with n-BuLi in the presence of (±)-sparteine in toluene gave a configurationally stable lithiated O-allyl carbamate (epi-156), which equilibrates at ±50 C to give the (R)-intermediate 156. Whereas the reaction of these compounds with MeI and MeOTs gave the c-attack, however acylation, silylation and stannylation took place at the a-position (Scheme 2.21) [131].

Ph

O

Ni-Pr2 O

155

n-BuLi (-)-sparteine

Ph

O

Ni-Pr2

PhMe, -78ºC Li

O

epi-156 Scheme 2.21

Ph

O Li 156

Ni-Pr2 O


27

The allylic intermediate 157 was prepared by deprotonation with LDA and reacted with 1,2-dialkyloxiranes in the synthesis of parasorbic acid [132]. Direct deprotonation of silyl allyl ether with s-BuLi gave the allylic compound 158, which reacted with electrophiles at the c-position [133]. Tin±lithium transmetallation of a 3-stannylated enamine led to the intermediate 159, which after reaction with electrophiles and acidic hydrolysis gave 3-funcionalized cyclohexenones [134]. The chiral endo-aminoallyllithium 160 was also prepared by tin±lithium transmetallation of the corresponding O-methylprolinol derivative, and alkylated to give after hydrolysis b-alkylated ketones [135]. Direct deprotonation with t-BuLi of N-methallylaniline gave the dianionic intermediate 161, of type XIV [136]. OMe PhS

OMe Li

Li 157

N

Li

OTBS 158

O

PhNLi

N Li

159

161

160

Starting from the symmetrical allylic diselenanyl compound 162, and through a selenium±lithium exchange with n-BuLi, methylselenanyl methallyllithium compound 163 was prepared, which after reaction with electrophiles afforded products 164 (Scheme 2.22) [137]. MeSe

SeMe

n-BuLi, THF -78ºC

Li

162

SeMe 163

1. E 2. H2O

X

SeMe

164 (34-72%)

[E = RBr, R1R2CO] Scheme 2.22

2.4.3 c-Functionalized Benzyllithium Compounds

Functionalized benzyllithium compounds of type XV are prepared by proton abstraction at the benzylic position with appropriate bases. Trilithiated 2,6dimethylphenol 165 was prepared by deprotonation with n-BuLi under hexane reflux and its tetrameric structure was determined by X-ray diffraction [138]. In the case of 2-methoxy benzyl ether, reductive cleavage of the benzylic carbon±oxygen bond by means of a naphthalene catalyzed lithiation at ±10 C in THF gave the benzyllithium derivative 166 [139], other benzyllithium compounds being prepared through this methodology. On the contrary, the benzyllithium derivatives 167 were generated by carbolithiation of o-vinyl substituted N-Boc protected aniline with n-BuLi in diethyl ether at ±78 C. Further reaction with DMF followed by final acidic hydrolysis yielded functionalized indoles in a one-pot process [140]. Dianions 168 [141] and 169 [142] were prepared by double deprotonation with LDA and n-BuLi, respectively, the first one being used in the synthesis of b-resorcylic acid derivatives [141].

Li

28

Li


OLi

Li LiNBoc

Li

OMe

OMe

n-Bu

Li O

CO2Li N

Li 165

166

Li

MeO 167

NLiPh

168

169

Benzylic organolithium compounds are in general configurationally unstable. However, the lateral lithiation of tertiary 2-alkyl-1-naphthamides, such as 170, was stereoselective and yielded a single diastereomeric atropisomer 171 [143], which reacted with several electrophiles with retention, to give compounds 172 [144], except with trialkyltin halides for which an inversion of the configuration was observed (Scheme 2.23) [144a]. O

Ni-Pr2

O

Ni-Pr2 Li

s-BuLi, THF -78ºC 170

O

Ni-Pr2 X

1. E 2. H2O 171

172 (64-97%, >97:3 dr)

[E = MeOD, RX, RCHO, R1R2CO, R1CH=NR2, Me3SiHal]

Scheme 2.23

2.4.4 c-Functionalized Akenyllithium Compounds

Vinyllithium compounds of type XVI show Z/E-configuration and can be prepared by tin± or halide±lithium exchange, because deprotonation occurs mainly at the allylic position, except in very special cases. O-Silyl protected c-lithiated allyl alcohol 173 has been prepared by iodine±lithium exchange with t-BuLi in hexane or THF at 0 C, the process being totally stereospecific, so the resulting vilyllithium compound kept the configuration of the starting iodide [145]. The silylated compound 174 was prepared by tin±lithium transmetallation and reacted with cyclopentenones in the presence of zinc salts for the synthesis of prostaglandins [146]. Azasilacines and azagermacines were synthesized in a direct way from the trianion 175 [147], which was prepared by a sequential deprotonation at a vinylic position [136,148] followed by a tin±lithium transmetallation from (Z)-allyl-3-(tri-n-butyltin)allylamine. Reagent 176, which derived from a protected diol, was prepared by bromine±lithium exchange and used in the synthesis of butenolide fugomycin [149]. The N-methoxyimine derived from (Z)-b-iodo acrolein was lithiated with n-BuLi in hexane at ±78 C to give vinyllithium intermediate 177, which was trapped with isocyanates to give the corresponding amides [150].


O Li

Li Li

N

Li

Li

29

Li

O

Li

OTBS

NOMe

OTBS 173

176

175

174

177

b-Chloro E-a,b-unsaturated ketone acetals 178 underwent stereoselective DTBB-catalyzed lithiation to give vinyllithium derivatives 179, which after reaction with electrophiles and final acidic hydrolysis led to regioselectively functionalized a,b-unsaturated carbonyl compounds 189. In the reaction of enantiomerically 2 enriched starting materials 180 (R = Me) with prostereogenic carbonyl compounds, no diastereoselectivity was observed (Scheme 2.24) [111,151]. R2

R2

R2

O

O R1

Cl

Li, DTBB (4%) THF, -90ºC

O

O 1. E 2. H2O 3. (CO2H)2-H2O CH2Cl2, silica gel

O R1

Li

178

R2

179

R1

X

180 (43-90%)

[E = H2O, D2O, R3R4CO] Scheme 2.24

Aryllithium compounds of type XVIII are generated mainly either by direct deprotonation [71,104] or by halogen±lithium exchange [75,105]. In the case p-methoxybenzaldehyde dimethyl acetal, ortho lithiation with n-BuLi (to give the intermediate 181), followed by reaction with electrophiles and final acidic hydrolysis, led to polyfunctionalized benzaldehydes in high yields [152]. Vinyllithium derivatives 182 and 183 (of type XIX) have been prepared from the corresponding vinylic halides by treatment with t-BuLi. The silyl ether derivative 182 was used in the synthesis of the C1 alkyl side chains of Zaragozic acids A and C [153] and the intermediate 183 was involved in the total synthesis of marine metabolites (+)-calyculin A and (±)-calyculin B [154]. The chlorovinyllithium derivative 184 was accessible through a tin±lithium transmetallation and used in the synthesis of the marine sesquiterpenoid (±)-kelsoene [155]. Cyclic vinyllithium intermediate 185 was used in the construction of seco-taxanes, being prepared from the corresponding ketone trisylhydrazone applying the Shapiro reaction [156]. OMe Li

Li

O

O

OBn Li

OMe OTBS

Cl

Li

MeO 181

Li 182

183

184

185

Iron-catalyzed carbolithiation of the internal alkyne 186, bearing an alkoxy group at the homopropargylic position, led to the vinyllithium compound 187,

30


which was trapped with electrophiles to give the corresponding functionalized olefins 188 with a defined stereochemistry and in high yields (Scheme 2.25) [157].

OR

n-BuLi (3 equiv) Fe(acac)3 (5 mol%) PhMe, -20ºC

Li n-Bu

X OR

186

1. E 2. HCl

n-Bu

187

OR

188 (69-96%)

1 2

[E = D2O, Me2SiHCl, R R CO] Scheme 2.25

2.4.5 c-Functionalized Alkynyllithium Compounds

Functionalized alkynyllithium compounds of type XX were prepared almost exclusively by deprotonation of the corresponding terminal alkynes and therefore, the functionality sometimes have to be protected in order to tolerate the presence of the base and to resist the conditions for the acetylenic proton to be removed. Functionalized lithium acetylide 189 was prepared by deprotonation of the corresponding O-protected propargyl alcohol and further alkylated with butadiene bis-epoxide in order to prepare dienediyens [158]. The alkynyl anion 190 was used in the synthesis of (±)-laulimalide, a microtube-stabilizing agent [159]. The intermediate 191, prepared from Garner's aldehyde, reacted with aldehydes in high yields [160] and the orthoester reagent 192 acted as the acetylenic anion of propyolic acid and reacted with carbonyl compounds in good yields [161]. Boc H

O

OO

N O

O

OTHP Li

Li 189

Li

Li 190

191

192

The lithium orthopropyolate 194 was prepared by a silicon±lithium exchange from the trimethylsilylacetylene derivative 193 and reacted with acetylenic aldehydes to give diacetylenic alcohols 195, which were easily transformed into the corresponding ketones by treatment with manganese dioxide (Scheme 2.26) [162]. OEt OEt OEt

TMS

OH

OEt n-BuLi THF, 0ºC

Li

OEt OEt

1. RC CCHO 2. H2O

R

OEt OEt OEt

193

Scheme 2.26

194

195 (74-80%)

2.5 d-Functionalized Organolithium Compounds

31


The number of possible structural devices increases as functionality gets further from the anionic center in functionalized organolithium compounds. So, d-functionalized organolithium compounds can be classified according to the hybridization of the carbon atom bonded to the lithium in alkyllithium compounds (XXI and XXII), allylic and benzylic derivatives (XXIII±XXV) and alkenyl (XXVI±XXVIII) and alkynyl systems (XXIX). X Li

X XXI

Li

X XXII

X

XXIII

XXIV

Li Li

X XXVI

X Li

Li X

Li

XXV Li

X

Li

XXVII

X

X

XXVIII

XXIX

2.5.1 d-Functionalized Alkyllithium Compounds

Different alcohols and protected alcohols (as hemiacetals, silyl, methoxymethyl or phenyl ethers) were lithiated at the d-position to give the corresponding organolithium compounds. In the case of alcohols, a previous deprotonation of the hydroxyl functionality is required. The chiral intermediate 197 was prepared from the phenylsulfanyl derivative 196 first by deprotonation followed by carbon±sulfur bond cleavage with LiDTBB at low temperature. The reaction of the dianionic system 197 with c- and d-lactones in the presence of cerium(III) salts gave, after hydrolysis, spiroketal pheromones 198 (Scheme 2.27) [163]. OH PhS 196

1. n-BuLi, THF, -78ºC 2. LiDTBB, -78ºC

OLi Li 197

O 1. CeCl3 O O 2. 3. HCl

O ( )n

( )n

198 (30-41%)

Scheme 2.27

Similarly to cinnamyl alcohols and ethers, which undergo carbolithiation by reaction with alkyllithiums [115,116], treatment of (E)-4-phenyl-3-buten-1-ol with two equivalents of n-BuLi in the presence of (±)-sparteine gave the organolithium compound 199, which after hydrolysis afforded the corresponding alcohol with 72% ee [164]. The optically active intermediate 200 was prepared by bromine± lithium exchange with t-BuLi in ether and was used in the synthesis of the C28±C40 fragment of azaspiracids [165]. Masked bishomoenolates 201 and 202

32


were prepared by means of a DTBB-catalyzed lithiation of the corresponding cchloro orthoesters [166] and phenylsulfanyl derivative [167], respectively. Functionalized methyl esters were obtained when the lithiation leading to the intermediate 201 was performed in the presence of electrophiles followed by hydrolysis with methanol and a catalytic amount of p-toluenesulfonic acid [166]. The lithio-thioacetal 202 reacted with N-phenethylimides, pyrroloisoquinolinones being obtained in good yields after acyliminium ion cyclization [167]. n-Bu

S

O

Ph

OLi

Li

Li

199

O OEt

OTBS

Li 200

201

Li 202

S SiMe3

2.5.2 d-Functionalized Allyl and Benzyllithium Compounds

Dianion 203 was prepared by double deprotonation of 3-methyl-3-buten-1-ol with n-BuLi in the presence of TMEDA and reacted with alkyl halides in the synthesis of different pheromones, the best results being obtained using diethyl ether as solvent [168]. However, the dianionic allylic isomer 204 was prepared through a tin±lithium transmetallation starting from the corresponding tri-n-butyltin derivative. The reaction of compound 204 with aldehydes took place at the internal position of the allylic system [169]. Reductive opening of heterocycles bearing the heteroatom at an allylic or benzylic position, as well as cyclic aryl ethers and thioethers, leads to functionalized organolithium compounds in a direct way [83]. The d-amino functionalized organolithium compound 205 was prepared through an allylic carbon±nitrogen bond cleavage by a DTBB-catalyzed lithiation from N-phenyl-2,3-dihydropyrroline and reacted with electrophiles regioselectively [170]. The dilithium derivatives 206 and 207 have also been prepared from 2-phenyltetrahydrothiophene (Y = S) [171], N-isopropyl-2-phenylpyrrolidine (Y = NPh) [170], thiophthalan (Y = S) [172] and N-phenylisoindoline (Y = NPh) [170] under the same reductive reaction conditions. In all these cases, a benzylic carbon± heteroatom bond cleavage took place, their reaction with electrophiles leading to polyfunctionalized molecules in a regioselective manner. Ph

Li OLi 203

OLi

Li 204

NPh Li

Li 205

YLi Li

206 (Y = S, i-PrN)

YLi Li 207 (Y = S, PhN)

In addition, the lithiation of phthalan 208 could be directed to the introduction of two different electrophiles at both benzylic positions in a sequential manner. Thus, after the reductive opening of compound 208, the resulting dianionic inter-


33

mediate 209 reacted with a first electrophile followed by hydrolysis to give the functionalized alcohols 211. However, when, after the addition of the first electrophile, the resulting alcoholate 210 was allowed to react in the highly reductive reaction medium at room temperature, a new benzylic carbon±oxygen bond cleavage took place to give a new organolithium intermediate 212. The addition of a second electrophile and final hydrolysis led to polyfunctionalized o-xylene derivatives 213 (Scheme 2.28) [173]. Functionalized benzyllithium compound 209 has found a wide applicability in organic synthesis. Depending on the electrophile it has been used in the synthesis of tetrahydroisoquinolines [174] and structurally modified sugars [85b], steroids [91b] and monoterpenes [175]. In the presence of different metallic salts, intermediate 209 participated in conjugate addition processes, acylation reactions, dimerization and alkylation with allylic systems, as well as in chemoselective additions to carbonyl compounds [176].

O 208

OLi Li

Li, DTBB (2.5 mol%) THF, rt

OLi X1

E1

209

210

212

OH X1 211 (51-82%)

Li X1 [E1,E2 = H2O, D2O, CO2, RCHO, R1R2CO, R1CH=NR2]

H2O

X2 X1

1. E2 2. H2O

213 (26-88%)

Scheme 2.28

2.5.3 d-Functionalized Alkenyllihium Compounds

Vinyllithium compounds with a functional group at the d-position have been prepared stereospecifically from the corresponding vinylic precursors, mainly by halogen± or tin±lithium exchange. They are not accessible by direct deprotonation due to the lack of influence of the functional group, which is located too far away from the vinylic proton to be removed. The alkenyllithium derivative 214 (of type XXVII) was prepared from the corresponding ketone by means of a Shapiro reaction, acting as an intermediate in the synthesis of the antibiotic nodusmicin [177]. Meanwhile, the (E,E)-dienyllithium compound 215 (of type XXVIII) has been generated from 1-(tri-n-butylstannyl)-4-ethoxy-1,3-butadiene by a tin±lithium exchange and used in the synthesis of a polyene macrolide roflamycoin [178]. Reductive opening of benzofurane with lithium and a catalytic amount of DTBB at 0 C gave the (Z)-organolithium derivative 216 that reacted with electrophiles in a regio- and stereoselective manner and was applied to the synthesis of substituted o-vinylphenol derivatives. In the case of using carbonyl compounds as electrophiles, the resulting diols gave substituted chromenes in high yields, after dehydration under acidic conditions [179].

34


2.5.4 d-Functionalized Alkynyllithium Compounds

As previously commented for other acetylenic anions, functionalized alkynyllithium compounds of the type XXIX were prepared almost exclusively by deprotonation of the corresponding terminal alkynes. Thus, the dihydropyran derivative 217 has been used for the convergent synthesis of trans-fused polytetrahydropyrans, which are present in marine toxins by coupling with triflates [180]. Li BnO

OTBS Li

TBSO O

OEt

O Li 216

OBn

214

215

Li

Li O 217

A different strategy towards d-functionalized alkynyllithium compounds consists in the treatment of gem-dibromoalkenes (accessible from the corresponding aldehydes) with an excess of n-BuLi. Following this methodology, intermediate 219 was prepared from the dithiane derivative 218 and alkylated with methyl iodide to give the corresponding alkyne 220 (Scheme 2.29) [181]. S Br

S Br 218

1. n-BuLi (3 equiv) THF, -78ºC 2. MeOH 3. t-BuLi

S

Li

S

S

MeI S

219

220 (58%)

Scheme 2.29

2.6 Remote Functionalized Organolithium Compounds

The influence of the functional group on the reactivity and the stability of functionalized organolithium compounds decreases as it gets further from the carbanionic center, so these compounds behave in many cases as normal organolithium compounds and can be prepared through classical methodologies. They can be classified according to the hybridization of the anionic carbon as in the previous section.

2.6.1 Remote Functionalized Alkyllithium Compounds

In general, organolithium compounds bearing a leaving group at the e-position undergo an intramolecular nucleophilic substitution to give the corresponding cyclic

2.6 Remote Functionalized Organolithium Compounds

35

systems. Treatment of the iodinated methoxy compound 221 with two equivalents of t-BuLi in heptane at ±78 C gave the e-functionalized organolithium compound 222, which upon addition of TMEDA, suffered intramolecular S N2¢ cyclization to give the vinylcyclopropane 223 in almost quantitative yield (Scheme 2.30) [182]. I

OMe

t-BuLi, n-C7H16 -78ºC

Li

221

OMe

1. TMEDA 2. H2O

222

223 (93%)

Scheme 2.30

On the other hand, the silyl-substituted vinyllithium 224, prepared by bromine±lithium exchange, did not cyclize and reacted with 3-fluoro-3-buten-2-one to give the corresponding alcohol, which was used in the synthesis of (±)-dammarenediol [183]. The e-oxido functionalized intermediate 225 was prepared from the corresponding chlorohydrine by a chlorine±lithium exchange with lithium naphthalenide after deprotonation, and reacted with iodoarenes to give the expected coupling products [184]. The organolithium compound 226, containing a masked acylsilane functionality, was prepared from the corresponding iodinated precursor by treatment with t-BuLi, and reacted with substituted cyclopent-2enones to give the expected 1,2-addition products. This strategy was used for the synthesis of isocarbacyclin, a stable analog of prostacyclin [185]. 2.6.2 Remote Allyl and Benzyllithium Compounds

The allyllithium compound 227 was generated from the phenylsulfanyl precursors by means of lithium naphthalenide in THF at ±78 C in the presence of TMEDA and underwent a irreversible retro- [1,4]-Brook rearrangement to give an almost 4:1 mixture of syn,trans and anti,trans diastereomers [186]. SiMe3

OLi

TBPSO Li

Li 224

225

O

Li

O

TMS

Li 226

Ph 227

A diastereomeric mixture of isopentenyldimethylcyclopentanols 230 was obtained through a lithium-ene cyclization starting from the oxido allylic intermediate 229, which was generated by LiDTBB carbon±sulfur bond cleavage of 228, the lithium oxide unit facilitating the cyclization. The corresponding magnesium derivatives participated in the same cyclization process (Scheme 2.31) [187].

36

2 Polyfunctional Lithium Organometallics for Organic Synthesis OH

OLi 1. MeLi 2. LiDTBB, THF, -78ºC

Li

PhS 228

OH 1. -78ºC to rt 2. H2O

229

OH +

230 (75%, 1:2.5)

Scheme 2.31

Dianionic benzylic intermediates 231 [171], 232 (Y = O [188], Y = S [189], Y = NPh [170]), 233 (Y = O [190], Y = S [191], Y = NMe [190]), and 234 (Y = O [190], Y = S [190,192], Y = NMe [190]), were all prepared through a benzylic carbon±heteroatom bond cleavage from the corresponding heterocycles by an arenecatalyzed lithiation and reacted with electrophiles to give polyfunctionalized molecules in a regioselective manner. In a similar way to phthalan 208 (Scheme 2.28), after the reaction with a first electrophile intermediates 233 (Y = S) [191] and 234 (Y = O) [192], underwent a second benzylic carbon±heteroatom bond cleavage to give a new organolithium compound, which reacted with a second electrophile, yielding polyfunctionalized biphenyls and naphthalenes, respectively after hydrolysis. Li

Li

YLi

YLi

YLi

Li Ph

Li

SLi 231

232 (Y = O, S, NPh)

233 (Y = O, NMe, S)

234 (Y = O, NMe)

2.6.3 Remote Functionalized Alkenyl- and Alkynyllithium Compounds

As an example of a remote functionalized alkenyllithium compound, the alkoxy functionalized polyenyllithium 236 (prepared from 235 by bromine±lithium exchange with t-BuLi) reacted with carbonyl compounds to give after acidic hydrolysis the corresponding polyenic aldehydes 237 (Scheme 2.32) [193]. OR t-BuLi, Et2O -70ºC

Br 235

236 R1

CHO R2 237 (54-59%)

Scheme 2.32

OR

Li

1. R1R2CO 2. 1 M HCl

References

37

Lithium (Z)-5-lithio-5-methyl-4-penten-1-olate 238 was also prepared by bromine±lithium exchange, after the deprotonation of the hydroxy unit, and acylated with amides in the synthesis of the enantiomer of natural epolactaene [194]. Dienyllithium 239 containing a masked carbonyl functionality (prepared by a bromine±lithium exchange) reacted with a lactam being used in the synthesis of trisporic acids [195]. Meanwhile, the lithium acetylide 240 with a remote oxide functionality was prepared by double deprotonation of the corresponding alkynol with n-BuLi and alkylated with 1-iodooctane, the resulting product being an intermediate in the synthetic route to the marine sponge natural products R-strongylodiols A and B [196]. Finally, the silyl enediyne lithium derivative 241 was prepared by deprotonation of the corresponding monoprotected enediyne with LiHMDS at ±78 C and used in the synthesis of antitumor agent (±)-calicheamicinone [197]. LiO Li

OLi 238

Li

Li

O O

239

Li 240

References 1 (a) C. Nµjera, M. Yus, Trends Org. Chem.

1991, 2, 155±181. (b) C. Nµjera, M. Yus, Recent Res. Dev. Org. Chem. 1997, 1, 67±96. (c) A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem. Int. Ed. 2000, 39, 4414±4435. (d) C. Nµjera, M. Yus, Current Org. Chem. 2003, 7, 867±926. 2 (a) J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon, Oxford, 2002. (b) D. M. Hodgson (Ed.), Organolithiums in Enantioselective Synthesis, Springer Verlag, Berlin, 2003. 3 (a) M. Gray, M. Tinkl, V. Snieckus, in Comprehensive Organometallic Chemistry II, E. W. Abel, F. G. A. Stone, G. Wilkinson, A. Mckillop (Eds.), Pergamon, Oxford, 1995, Vol. 11, 2±81. (b) R. Bartsch, C. Drost, U. Klingebiel, in Synthetic Methods of Organometallic and Inorganic Chemistry, N. Auner, U. Klingebiel (Eds.), G. Thieme Verlag, Stuttgart, 1996, Vol. 2, 2±24. (c) F. Leroux, M. Schlosser, E. Zohar, I. Marek, in The Chemistry of Organolithium Compounds (Part 1), Z. Rappoport, I. Marek (Eds.), Wiley, Chichester, 2004, 435±494.

4 (a) A. Streitwieser, S. M. Bachrach,

5

6

7

8

A. Dorigo, P. von R. Schleyer, in Lithium Chemistry: A Theoretical and Experimental Overview, A.-M. Sapse, P. von R. Schleyer (Eds.), Wiley, New York, 1995, 2±15. (b) E. D. Jemmis, G. Gopakumar, in The Chemistry of Organolithium Compounds (Part 1), Z. Rappoport, I. Marek (Eds.), Wiley, Chichester, 2004, 2±6. For a review, see: D. J. Berrisford, Angew. Chem. Int. Ed. Engl. 1995, 34, 178±180. (a) D. Seebach, Synthesis 1969, 17±36. (b) G. Boche, Angew. Chem. Int. Ed. Engl. 1989, 28, 277±297. (c) M. Yus, C. Nµjera, F. Foubelo, Tetrahedron 2003, 59, 6147±6212. (d) A. B. Smith III, C. M. Adams, Acc. Chem. Res. 2004, 37, 365±377. (a) A. Guijarro, M. Yus, Tetrahedron Lett. 1993, 34, 3487±3490. (b) A. Guijarro, B. Mancheæo, J. Ortiz, M. Yus, Tetrahedron 1996, 52, 1643±1650. (a) C. Gómez, S. Ruiz, M. Yus, Tetrahedron Lett. 1998, 39, 1397±1400. (b) C. Gómez, S. Ruiz, M. Yus, Tetrahedron 1999, 55, 7017±7026.

241

TMS

38

2 Polyfunctional Lithium Organometallics for Organic Synthesis 9 (a) C. Blomberg, The Barbier Reaction

and Related One-Step Processes, Springer Verlag, Berlin, 1993. (b) F. Alonso, M. Yus, Recent Res. Dev. Org. Chem. 1997, 1, 397±436. 10 J. Ortiz, A. Guijarro, M. Yus, An. Quim. Int. Ed. 1997, 93, 44±48. 11 V. L. Ponzo, T. S. Kaufman, Can. J. Chem. 1998, 76, 1338±1343. 12 (a) A. Guijarro, M. Yus, Tetrahedron Lett. 1996, 37, 5593±5596. (b) J. Ortiz, A. Guijarro, M. Yus, Eur. J. Org. Chem. 1999, 3005±3012. 13 (a) O. Frey, M. Hoffmann, H. Kessler, Angew. Chem. Int. Ed. Engl. 1995, 34, 2026±2028. (b) F. Burkhart, H. Kessler, Tetrahedron Lett. 1998, 39, 255±256. 14 (a) M. Hoffmann, H. Kessler, Tetrahedron Lett. 1997, 38, 1903±1906. (b) F. Burkhart, M. Hoffmann, H. Kessler, Angew. Chem. Int. Ed. Engl. 1997, 36, 1191±1192. (c) M. A. Dechantsreiter, F. Burkhart, H. Kessler, Tetrahedron Lett. 1998, 39, 253±254. (d) B. Westermann, A. Walter, N. Diedrichs, Angew. Chem. Int. Ed. 1999, 38, 3384±3386. 15 (a) J.-M. Lancelin, L. Morin-Allory, P. Sinaþ, J. Chem. Soc., Chem. Commun. 1984, 355±356. (b) J.-M. Beau, P. Sinaþ, Tetrahedron Lett 1985, 26, 6189±6192. 16 R. P. Smyj, J. M. Chong, Org. Lett. 2001, 3, 2903±2906. 17 M. I. Calaza, M. R. Paleo, F. J. Sardina, J. Am. Chem. Soc. 2001, 123, 2095±2096. 18 J. M. Chong, N. Nielsen, Tetrahedron Lett. 1998, 39, 9617±9620. 19 (a) W. C. Still, J. Am. Chem. Soc. 1978, 100, 1481±1487. (b) W. C. Still, C. Sreekumar, J. Am. Chem. Soc. 1980, 102, 1201±1202. 20 K. Tomooka, N. Komine, T. Nakai, Synlett 1997, 1045±1046. 21 K. Tomooka, N. Komine, T. Nakai, Tetrahedron Lett. 1997, 38, 8939±8942. 22 F. Burkhart, M. Hoffmann, H. Kessler, Tetrahedron Lett. 1998, 39, 7699±7702. 23 R. Angelaud, Y. Landais, L. ParraRapado, Tetrahedron Lett. 1997, 38, 8845±8848. 24 For reviews, see: (a) V. K. Aggarwal, Angew. Chem. Int. Ed. Engl. 1994, 33, 175±177. (b) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park,

S. Thayumanavan, Acc. Chem. Res. 1996, 29, 552±560. (c) D. Hoppe, T. Hense, Angew. Chem. Int. Ed. Engl. 1997, 36, 2282±2316. 25 M. Paetow, H. Ahrens, D. Hoppe, Tetrahedron Lett. 1992, 33, 5323±5326. 26 (a) C. Derwing, D. Hoppe, Synthesis 1996, 149±154. (b) F. Hammerschmidt, A. Hanninger, Chem. Ber. 1995, 128, 1069±1077. 27 (a) N. Komine, L.-F. Wang, K. Tomooka, T. Nakai, Tetrahedron Lett. 1999, 40, 6809±6812. (b) K. Tomooka, L.-F. Wang, N. Komine, T. Nakai, Tetrahedron Lett. 1999, 40, 6813±6816. (c) K. Tomooka, L.-F. Wang, F. Okazaki, T. Nakai, Tetrahedron Lett. 2000, 41, 6121±6125. 28 (a) J. Suffert, D. Toussaint, Tetrahedron Lett. 1997, 38, 5507±5510. (b) J. Suffert, B. Salem, P. Klotz, J. Am. Chem. Soc. 2001, 123, 1210712108. 29 For reviews, see: (a) T. Satoh, Chem. Rev. 1996, 96, 3303±3326. (b) D. M. Hodgson, E. Gras, Synthesis 2002, 1625±1642. 30 V. Capriati, S. Florio, R. Luisi, I. Nuzzo, J. Org. Chem. 2004, 69, 3330±3335. 31 (a) A. Abbotto, V. Capriati, L. Degennaro, S. Florio, R. Luisi, M. Pierrot, A. Salomone, J. Org. Chem. 2001, 66, 3049±3058. (b) V. Capriati, S. Florio, R. Luisi, A. Salomone, Org. Lett. 2002, 4, 2445±2448. 32 R. Luisi, V. Capriati, L. Degennaro, S. Florio, Org. Lett. 2003, 5, 2723±2726. 33 C. Courillon, J.-C. MariØ, M. Malacria, Tetrahedron 2003, 59, 9759±9766. 34 (a) G. P. Pale, J. Chuche, Tetrahedron: Asymmetry 1993, 4, 1991±1994. (b) S. Klein, J. H. Zhang, M. Holler, J.-M. Weibel, P. Pale, Tetrahedron 2003, 59, 9793±9802. 35 D. M. Hodgson, S. L. M. Norsikian, Org. Lett. 2001, 3, 461±463. 36 D. M. Hodgson, E. Gras, Angew. Chem. Int. Ed. 2002, 41, 2376±2378. 37 (a) S. D. Rychnovsky, J. P. Powers, T. J. LePage, J. Am. Chem. Soc. 1992, 114, 8375±8384. (b) D. J. Kopecky, S. D. Rychnovsky, J. Org. Chem. 2000, 65, 191±198. (c) S. D. Rychnovsky, T. Hata, A. I. Kim, A. J. Buckmelter, Org. Lett. 2001, 3, 807±810. 38 S. D. Rychnovsky, L. R. Takaoka, Angew. Chem. Int. Ed. 2003, 42, 818±820.

References 39 J. A. Soderquist, L. Castro-Rosario, in

Encyclopedia of Reagents for Organic Synthesis, L. A. Paquette (Ed.), Wiley, London, 1995, Vol. 5, 3408±3410. 40 K. K. Banger, C. Birringer, R. U. Claessen, P. Lim, P. J. Toscano, J. T. Welch, Organometallics 2001, 20, 4745±4748. 41 For a review, see: C. Nµjera, M. Yus, Org. Prep. Proced. Int. 1995, 27, 383±456. 42 W. B. Jang, H. Hu, M. M. Lieberman, J. A. Morgan, I. A. Stergiades, D. S. Clark, M. A. Tius, J. Comb. Chem. 2001, 3, 346±353. 43 For reviews, see: (a) M. Braun, Angew. Chem. Int. Ed. 1998, 37, 430±451. (b) R. W. Friesen, J. Chem. Soc., Perkin Trans. 1 2001, 1969±2001. 45 P. E. Harrington, M. A. Tius, Org. Lett. 2000, 2, 2447±2450. 46 (a) L. A. Paquette, S. Brand, C. Behrens, J. Org. Chem. 1999, 64, 2010±2025. (b) L. A. Paquette, D. R. Owen, R. Todd Bibart, C. K. Seekamp, A. L. Kahane, J. C. Lanter, M. Alvarez Corral, J. Org. Chem. 2001, 66, 2828±2834. (c) L. A. Paquette, J. C. Lanter, D. R. Owen, F. Fabris, R. Todd Bibart, M. Alvarez Corral, Heterocycles 2001, 54, 49±53. 47 L. A. Paquette, J. C. Lanter, J. N. Johnston, J. Org. Chem. 1997, 62, 1702±1712. 48 L. A. Paquette, M. J. Kinney, U. Dullweber, J. Org. Chem. 1997, 62, 1713±1722. 49 C. Bozzo, M. D. Pujol, Tetrahedron 1999, 55, 11843±11852. 50 For reviews, see: (a) P. Beak, D. B. Reitz, Chem. Rev. 1978, 78, 275±316. (b) P. Beak, W. J. Zajdel, D. B. Reitz, Chem. Rev. 1984, 84, 471±523. 51 (a) J. Clayden, C. J. Menet, D. J. Mansfield, Chem. Commun. 2002, 38±39. (b) J. Clayden, F. E. Knowles, C. J. Menet, Tetrahedron Lett. 2003, 44, 3397±3400. 52 A. I. Meyers, W. Ten Hoeve, J. Am. Chem. Soc. 1980, 102, 7125±7126. 53 (a) R. R. Fraser, T. B. Grindley, S. Passannanti, Can. J. Chem. 1975, 53, 2473±2480. (b) B. Renger, H. O. Kalinowski, D. Seebach, Chem. Ber. 1977, 110, 1866±1878.

54 D. H. R. Barton, R. Beugelmans,

55 56

57

58 59

60

61

62

63 64 65

66

67 68

69

R. N. Young, Nouv. J. Chim. 1978, 2, 363±364. K. B. Wiberg, W. F. Bailey, J. Am. Chem. Soc. 2001, 123, 8231±8238. (a) M. J. Dearden, C. R. Firkin, J.-P. R. Hermet, P. O'Brien, J. Am. Chem. Soc. 2002, 124, 11870±11871. (b) J.-P. R. Hermet, D. W. Porter, M. J. Dearden, J. R. Harrison, T. Koplin, P. O'Brien, J. Parmene, V. Tyurin, A. C. Whitwood, J. Gilday, N. M. Smith, Org. Biomol. Chem. 2003, 1, 3977±3988. (a) S. T. Kerrick, P. Beak, J. Am. Chem. Soc. 1991, 113, 9708±9710. (b) R. K. Dieter, C. M. Topping, K. R. Chandupatla, K. Lu, J. Am. Chem. Soc. 2001, 123, 5132±5133. J. R. Harrison, P. O'Brien, Synth. Commun. 2001, 31, 1155±1160. R. E. Gawley, G. Barolli, S. Madan, M. Saverin, S. O'Connor, Tetrahedron Lett. 2004, 45, 1759±1761. C. Hoarau, A. Couture, H. Cornet, E. Deniau, P. Grandclaudon, J. Org. Chem. 2001, 66, 8064±8069. (a) A. Guijarro, J. Ortiz, M. Yus, Tetrahedron Lett. 1996, 37, 5597±5600. (b) J. Ortiz, A. Guijarro, M. Yus, Tetrahedron 1999, 55, 4831±4842. I. Coldham, S. Colman, M. M. S. LangAnderson, J. Chem. Soc., Perkin Trans. 1 1997, 1481±1490. D. M. Iula, R. E. Gawley, J. Org. Chem. 2000, 65, 6196±6201. U. Azzena, L. Pilo, E. Piras, Tetrahedron Lett. 2001, 42, 129±131. (a) E. Vedejs, J. T. Kendall, J. Am. Chem. Soc. 1997, 119, 6941±6942. (b) E. Vedejs, A. S. Bhanu Prasad, J. T. Kendall, J. S. Russel, Tetrahedron 2003, 59, 9849± 9856. Y. Yamauchi, T. Kawate, T. Katagiri, K. Uneyama, Tetrahedron 2003, 59, 9839±9847. M. Yus, J. Ortiz, C. Nµjera, ARKIVOC 2002, 2, 38±47. A. I. Meyers, P. D. Edwards, T. R. Bailey, G. E. Jagdmann, J. Org. Chem. 1985, 50, 1019±1026. R. M. Adlington, J. E. Baldwin, J. C. Bottaro, M. W. D. Perry, J. Chem. Soc., Chem. Commun. 1983, 1040±1041.

39

40

2 Polyfunctional Lithium Organometallics for Organic Synthesis 70 M. D. B. Fenster, B. O. Patrick,

G. R. Dake, Org. Lett. 2001, 3, 2109±2112. 71 For a review, see: R. Chinchilla, C. Nµjera, M. Yus, Chem. Rev. 2004, 104, 2667±2722. 72 K. Worm, F. Chu, K. Matsumoto, M. D. Best, V. Lynch, E. V. Anslyn, Chem. Eur. J. 2003, 9, 741±747. 73 P. Calí, M. Begtrup, Tetrahedron 2002, 58, 1595±1605. 74 A. Dondoni, A. Marra, M. Mizuno, P. P. Giovannini, J. Org. Chem. 2002, 67, 4186±4199. 75 For reviews, see: (a) N. Sotomayor, E. Lete, Curr. Org. Chem. 2003, 7, 1±26. (b) C. Nµjera, J. M. Sansano, M. Yus, Tetrahedron 2003, 59, 9255±9303. 76 J. Chun, L. He, H.-S. Byun, R. Bittman, J. Org. Chem. 2000, 65, 7634±7640. 77 C. Fruit, A. Turck, N. PlØ, L. Mojovic, G. QuØguiner, Tetrahedron 2001, 57, 9429±9435. 78 (a) O. Sugimoto, M. Sudo, K. Tanji, Tetrahedron Lett. 1999, 40, 2139±2140. (b) O. Sugimoto, M. Sudo, K. Tanji, Tetrahedron 2001, 57, 2133±2138. 79 M. Shimizu, T. Kurahashi, T. Hiyama, J. Synth. Org. Chem. Jpn. 2001, 59, 1062±1069. 80 A. Kasatkin, R. J. Whitby, Tetrahedron Lett. 1997, 38, 4857±4860. 81 G. Köbrich, H. Trapp, I. Hornke, Tetrahedron Lett. 1964, 1131±1136. 82 F. Tellier, R. Sauvtre, J. F. Normant, Y. Dromzee, Y. Jeannin, J. Organomet. Chem. 1987, 331, 281±298. 83 (a) F. Foubelo, M. Yus, Rev. Heteroatom Chem. 1997, 17, 73±107. (b) M. Yus, F. Foubelo, Targets Heterocycl. Syst. 2002, 6, 136±171. (c) M. Yus, Pure Appl. Chem. 2003, 75, 1453±1475. 84 (a) J. Barluenga, F. J. Faæanµs, M. Yus, G. Asensio, Tetrahedron Lett. 1978, 2015±2016. (b) J. Barluenga, F. J. Faæanµs, M. Yus, J. Org. Chem. 1979, 44, 4798±4801. (c) J. Barluenga, F. J. Faæanµs, J. Villamaæa, M. Yus, J. Org. Chem. 1982, 47, 1560±1564. 85 (a) T. Soler, A. Bachki, L. R. Falvello, F. Foubelo, M. Yus, Tetrahedron: Asymmetry 1998, 9, 3939±3943. (b) T. Soler, A. Bachki, L. R. Falvello, F. Foubelo,

M. Yus, Tetrahedron: Asymmetry 2000, 11, 493±517. 86 C. Nµjera, M. Yus, D. Seebach, Helv. Chim. Acta 1984, 67, 289±300. 87 (a) F. Foubelo, A. GutiØrrez, M. Yus, Tetrahedron Lett. 1997, 38, 4837±4840. (b) F. Foubelo, A. GutiØrrez, M. Yus, Synthesis 1999, 503±514. 88 R. E. Conrow, Tetrahedron Lett. 1993, 34, 5553±5554. 89 D. Behnke, L. Hennig, M. Findeisen, P. Welzel, D. Müller, M. Thormann, H.-J. Hofmann, Tetrahedron 2000, 56, 1081±1095. 90 (a) A. Bachki, F. Foubelo, M. Yus, Tetrahedron: Asymmetry 1995, 6, 1907±1910. (b) A. Bachki, F. Foubelo, M. Yus, Tetrahedron: Asymmetry 1996, 7, 2997±3008. 91 (a) L. R. Falvello, F. Foubelo, T. Soler, M. Yus, Tetrahedron: Asymmetry 2000, 11, 2063±2066. (b) M. Yus, T. Soler, F. Foubelo, Tetrahedron: Asymmetry 2001, 12, 801±810. 92 (a) J. Barluenga, M. Yus, P. Bernad, J. Chem. Soc., Chem. Commun. 1978, 847. (b) J. Barluenga, M. Yus, J. M. Concellón, P. Bernad, J. Chem. Research (S) 1980, 41. (c) J. Barluenga, M. Yus, J. M. Concellón, P. Bernad, J. Org. Chem. 1981, 46, 2721±2726. (d) J. Barluenga, M. Yus, J. M. Concellón, P. Bernad, J. Org. Chem. 1983, 48, 609±611. 93 (a) J. Almena, F. Foubelo, M. Yus, Tetrahedron Lett. 1993, 34, 1649±1652. (b) J. Almena, F. Foubelo, M. Yus, J. Org. Chem. 1994, 59, 3210±3215. 94 (a) F. Foubelo, M. Yus, Tetrahedron Lett. 1994, 35, 4831±4834. (b) F. Foubelo, M. Yus, Tetrahedron: Asymmetry 1996, 7, 2911±2922. 95 M. N. Kenworthy, J. P. Kilburn, R. J. K. Taylor, Org. Lett. 2004, 6, 19±22. 96 Y. S. Park, P. Beak, Tetrahedron 1996, 52, 12333±12350. 97 F. Taherirastgar, L. Brandsma, Chem. Ber. 1997, 130, 45±48. 98 P. Langer, M. Döring, D. Seyferth, H. Görls, Chem. Eur. J. 2001, 7, 573±584. 99 A. Armstrong, F. W. Goldberg, D. A. Sandham, Tetrahedron Lett. 2001, 42, 4585±4587. 100 J. Tholander, J. Bergman, Tetrahedron 1999, 55, 12595±12602.

References 101 M. Schlosser, H. Wei, Tetrahedron 1997,

53, 1735±1742. 102 K. Takeda, H. Haraguchi, Y. Okamoto, Org. Lett. 2003, 5, 3705±3707. 103 C. Yip, S. Handerson, G. K. Tranmer, W. Tam, J. Org. Chem. 2001, 66, 276±286. 104 For reviews, see: (a) W. E. Parham, C. K. Bardher, Acc. Chem. Res. 1982, 15, 300±305. (b) P. Beak, V. Snieckus, Acc. Chem. Res. 1982, 15, 306±312. 105 K. Yamada, T. Kurokawa, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc. 2003, 125, 6630±6631. 106 J. Barluenga, F. Foubelo, F. J. Faæanµs, M. Yus, J. Chem. Soc., Perkin Trans. 1 1989, 553±557. 107 X. Han, E. J. Corey, Org. Lett. 1999, 1, 1871±1872. 108 (a) L. A. Paquette, L. H. Kuo, A. T. Hamme, R. Kreuzholz, J. Doyon, J. Org. Chem. 1997, 62, 1730±1736. (b) J.-K. Ergüden, H. W. Moore, Org. Lett. 1999, 1, 375±378. 109 T. J. Donohoe, K. Blades, M. Helliwell, M. J. Waring, N. J. Newcombe, Tetrahedron Lett. 1998, 39, 8755±8758. 110 (a) J. Barluenga, R. Sanz, A. Granados, F. J. Faæanµs, J. Am. Chem. Soc. 1998, 120, 4865±4866. (b) F. J. Faæanµs, A. Granados, R. Sanz, J. M. Ignacio, J. Barluenga, Chem. Eur. J. 2001, 7, 2896±2907. 111 A. Bachki, F. Foubelo, M. Yus, Tetrahedron 1997, 53, 4921±4934. 112 J. Aigner, E. Gössinger, H. Kählig, G. Menz, K. Pflugseder, Angew. Chem. Int. Ed. 1998, 37, 2226±2228. 113 M. E. Fox, C. Li, J. P. Marino, L. E. Overman, J. Am. Chem. Soc. 1999, 121, 5467±5480. 114 S. P. Götzö, D. Seebach, J.-J. Sanglier, Eur. J. Org. Chem. 1999, 2533±2544. 115 C. Mück-Lichtenfeld, H. Ahlbrecht, Tetrahedron 1999, 55, 2609±2642. 116 S. Norsikian, I. Marek, S. Klein, J. F. Poisson, J. F. Normant, Chem. Eur. J. 1999, 5, 2055±2068. 117 B. Mudryk, T. Cohen, J. Org. Chem. 1991, 56, 5760±5761. 118 A. Bachki, L. R. Falvello, F. Foubelo, M. Yus, Tetrahedron: Asymmetry 1997, 8, 2633±2643. 119 U. Azzena, L. Pilo, Synthesis 1999, 664±668.

120 (a) J. Almena, F. Foubelo, M. Yus, Tetra-

hedron 1997, 53, 5563±5572. (b) J. Almena, F. Foubelo, M. Yus, Tetrahedron 1994, 50, 5775±5782. 121 L. Garamszegi, M. Schlosser, Angew. Chem. Int. Ed. 1998, 37, 3173±3175. 122 For a review, see: I. Kuwajima, E. Nakamura, Top. Curr. Chem. 1990, 115, 1±39. 123 I. M. Pastor, M. Yus, Tetrahedron Lett. 2001, 42, 1029±1032. 124 S. Zhu, T. Cohen, Tetrahedron 1997, 53, 17607±17624. 125 X. Feng, M. O. Senge, J. Chem. Soc., Perkin Trans. 1 2001, 1030±1038. 126 N. Bremand, I. Marek, J. F. Normant, Tetrahedron Lett. 1999, 40, 3383±3386. 127 For reviews, see: (a) P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356±363. (b) M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed. 2004, 43, 2206±2225. 128 D. J. Pippel, M. D. Curtis, H. Du, P. Beak, J. Org. Chem. 1998, 63, 2±3. 129 M. Yus, T. Soler, F. Foubelo, J. Org. Chem. 2001, 66, 6207±6208. 130 For reviews. see: (a) H. Ahlbrecht, U. Beyer, Synthesis 1999, 365±390. (b) A. R. Katritzky, M. Piffl, H. Lang, E. Anders, Chem. Rev. 1999, 99, 665±722. 131 K. Behrens, R. Fröhlich, O. Meyer, D. Hoppe, Eur. J. Org. Chem. 1998, 2397±2403. 132 R. Tiedemann, F. Narjes, E. Schaumann, Synlett 1994, 594±596. 133 M. Lombardo, S. Spada, C. Trombini, Eur. J. Org. Chem. 1998, 2361±2364. 134 H. Ahlbrecht, P. Weber, Synthesis 1992, 1018±1025. 135 H. Ahlbrecht, R. Schmidt, U. Beyer, Eur. J. Org. Chem. 1998, 1371±1377. 136 J. Barluenga, F. J. Faæanµs, F. Foubelo, M. Yus, J. Chem. Soc., Chem. Commun. 1988, 1135±1136. 137 A. Krief, W. Dumont, Tetrahedron Lett. 1997, 38, 657±660. 138 S. Harder, M. Lutz, A. Streitwieser, J. Am. Chem. Soc. 1995, 117, 2361±2362. 139 U. Azzena, S. Carta, G. Melloni, A. Sechi, Tetrahedron 1997, 53, 16205±16212. 140 C. M. Coleman, D. F. O'Shea, J. Am. Chem. Soc. 2003, 125, 4054±4055.

41

42

2 Polyfunctional Lithium Organometallics for Organic Synthesis 141 Q. Yang, H. Toshima, T. Yoshihara,

Tetrahedron 2001, 57, 5377±5384. 142 M. Poirier, F. Chen, C. Bernard, Y.-S. Wong, G. G. Wu, Org. Lett. 2001, 3, 3795±3798. 143 J. Clayden, J. H. Pink, Tetrahedron Lett. 1997, 38, 2561±2564. 144 (a) J. Clayden, J. H. Pink, Tetrahedron Lett. 1997, 38, 2565±2568. (b) J. Clayden, J. H. Pink, S. A. Yasin, Tetrahedron Lett. 1998, 39, 105±108. (c) J. Clayden, N. Westlund, F. X. Wilson, Tetrahedron Lett. 1999, 40, 3331±3334. (d) J. Clayden, M. N. Kenworthy, L. H. Youssef, M. Helliwell, Tetrahedron Lett. 2000, 41, 5171±5175. 145 R. Polt, D. Sames, J. Chruma, J. Org. Chem. 1999, 64, 6147±6158. 146 K. Furuta, K. Tomokiyo, T. Satoh, Y. Watanabe, M. Suzuki, Chembiochem 2000, 283±286. 147 (a) J. Barluenga, R. Gonzµlez, F. J. Faæanµs, Tetrahedron Lett. 1992, 33, 831±834. (b) J. Barluenga, R. Gonzµlez, F. J. Faæanµs, M. Yus, F. Foubelo, J. Chem. Soc., Perkin Trans. 1 1994, 1069±1077. 148 J. Barluenga, F. J. Faæanµs, F. Foubelo, M. Yus, Tetrahedron Lett. 1988, 29, 4859±4862. 149 M. Braun, J. Rahematpura, C. Bühne, T. C. Paulitz, Synlett 2000, 1070±1072. 150 K. Kuramochi, H. Watanabe, T. Kitahara, Synlett 2000, 397±399. 151 A. Bachki, F. Foubelo, M. Yus, Tetrahedron Lett. 1994, 35, 7643±7646. 152 H. P. Plaumann, B. A. Keay, R. Rodrigo, Tetrahedron Lett. 1979, 4921±4924. 153 J. Bach, M. Galobardes, J. García, P. Romea, C. Tey, F. Urpí, J. Vilarrasa, Tetrahedron Lett. 1998, 39, 6765±6768. 154 (a) A. B. Smith III, G. K. Friestad, J. J.-W. Duan, J. Barbosa, K. G. Hull, M. Iwashima, Y. Qiu, P. G. Spoors, E. Bertounesque, B. A. Salvatore, J. Org. Chem. 1998, 63, 7596±7597. (b) A. B. Smith III, G. K. Friestad, J. Barbosa, E. Bertounesque, K. G. Hull, M. Iwashima, Y. Qiu, B. A. Salvatore, P. G. Spoors, J. J.-W. Duan, J. A. Chem. Soc. 1999, 121, 10468±10477. 155 E. Piers, A. Orellana, Synthesis 2001, 2138±2142.

156 D. Bourgeois, J.-Y. Lallemand,

A. Pancrazi, J. Prunet, Synlett 1999, 1555±1558. 157 M. Hojo, Y. Murakami, H. Aihara, R. Sakuragi, Y. Baba, A. Hosomi, Angew. Chem. Int. Ed. 2001, 40, 621±623. 158 W. Pitsch, B. König, Synth. Commun. 2001, 31, 3135±3139. 159 A. K. Glosh, Y. Wang, J. T. Kim, J. Org. Chem. 2001, 66, 8973±8982. 160 X. Serrat, G. Cabarrocas, S. Rafel, M. Ventura, A. Linden, J. M. Villalgordo, Tetrahedron: Asymmetry 1999, 10, 3417± 3430. 161 P. Ducray, H. Lamotte, B. Rousseau, Synthesis 1997, 404±406. 162 J. E. Baldwin, G. J. Pritchard, R. E. Rathmell, J. Chem. Soc., Perkin Trans. 1 2001, 2906±2908. 163 H. Liu, T. Cohen, J. Org. Chem. 1995, 60, 2022±2025. 164 S. Klein, I. Marek, J. F. Poisson, J. F. Normant, J. Am. Chem. Soc. 1995, 117, 8853±8854. 165 J. Aiguade, J. Hao, C. J. Forsyth, Tetrahedron Lett. 2001, 42, 817±820. 166 (a) I. M. Pastor, M. Yus, Tetrahedron Lett. 2001, 42, 1029±1032. (b) M. Yus, R. Torregrosa, I. M. Pastor, Molecules 2004, 9, 330±348. 167 (a) I. Manteca, N. Sotomayor, M. J. Villa, E. Lete, Tetrahedron Lett. 1996, 37, 7841± 7844. (b) I. Manteca, B. Etxarri, A. Ardeo, S. Arrasate, I. Osante, N. Sotomayor, E. Lete, Tetrahedron 1998, 54, 12361±12378. 168 (a) G. Cardillo, M. Contento, S. Sandri, Tetrahedron Lett. 1974, 2215±2216. (b) K. H. Yong, J. A. Lotoski, J. M. Chong, J. Org. Chem. 2001, 66, 8248±8251. 169 D. Behnke, S. Hamm, L. Henning, P. Welzel, Tetrahedron Lett. 1997, 38, 7059±7062. 170 J. Almena, F. Foubelo, M. Yus, Tetrahedron 1996, 52, 8545±8564. 171 J. Almena, F. Foubelo, M. Yus, Tetrahedron 1997, 53, 5563±5572. 172 J. Almena, F. Foubelo, M. Yus, J. Org. Chem. 1996, 61, 1859±1863. 173 J. Almena, F. Foubelo, M. Yus, Tetrahedron 1995, 51, 3351±3364. 174 F. Foubelo, C. Gómez, A. GutiØrrez, M. Yus, J. Heterocycl. Chem. 2000, 37, 1061±1064.

References 175 M. Yus, B. Moreno, F. Foubelo, Synthesis

2004, 1115±1118. 176 (a) I. M. Pastor, M. Yus, Tetrahedron Lett. 2000, 41, 1589±1592. (b) I. M. Pastor, M. Yus, Tetrahedron 2001, 57, 2365± 2370. (c) I. M. Pastor, M. Yus, Tetrahedron 2001, 57, 2371±2378. (d) M. Yus, I. M. Pastor, J. Gomis, Tetrahedron 2001, 57, 5799±5805. (e) M. Yus, J. Gomis, Tetrahedron Lett. 2001, 42, 5721±5724. (f) M. Yus, J. Gomis, Eur. J. Org. Chem. 2002, 1989±1995. 177 E. Auer, E. Gössinger, M. Graupe, Tetrahedron Lett. 1997, 38, 6577±6580. 178 M. J. Dabdoub, V. B. Dabdoub, P. G. Guerrero Jr., C. C. Silveira, Tetrahedron 1997, 53, 4199±4218. 179 (a) M. Yus, F. Foubelo, J. V. Ferrµndez, Eur. J. Org. Chem. 2001, 2809±2813. (b) M. Yus, F. Foubelo, J. V. Ferrµndez, A. Bachki, Tetrahedron 2002, 58, 4907± 4915. 180 K. Fujiwara, H. Morishita, K. Saka, A. Murai, Tetrahedron Lett. 2000, 41, 507±508. 181 A. B. Smith III, S. A. Lodise, Org. Lett. 1999, 1, 1249±1252. 182 W. F. Bailey, Y. Tao, Tetrahedron Lett. 1997, 38, 6157±6158. 183 W. S. Johnson, W. R. Bartlett, B. A. Czeskis, A. Gautier, C. H. Lee, R. Lemoine, E. J. Leopold, G. R. Luedtke, K. J. Bankcroft, J. Org. Chem. 1999, 64, 9587±9595.

184 J. F. Gil, D. J. Ramón, M. Yus, Tetra-

hedron 1993, 49, 4923±4938.

185 T. Mandai, S. Matsumoto, M. Kohama,

M. Kawada, J. Tsuji, S. Saito, T. Moriwake, J. Org. Chem. 1990, 55, 5671±5673. 186 C. Gibson, T. Buck, M. Noltemeyer, R. Brückner, Tetrahedron Lett. 1997, 38, 2933±2936. 187 (a) D. Cheng, K. R. Knox, T. Cohen, J. Am. Chem. Soc. 2000, 122, 412±413. (b) D. Cheng, S. Zhu, T. Cohen, J. Am. Chem. Soc. 2001, 123, 30±34. 188 J. Almena, F. Foubelo, M. Yus, Tetrahedron 1995, 51, 3365±3374. 189 J. Almena, F. Foubelo, M. Yus, J. Org. Chem. 1996, 61, 1859±1862. 190 U. Azzena, S. Demartis, L. Pilo, E. Piras, Tetrahedron 2000, 56, 8375±8382. 191 M. Yus, F. Foubelo, Tetrahedron Lett. 2001, 42, 2469±2472. 192 F. Foubelo, B. Moreno, M. Yus, Tetrahedron 2004, 60, 4655±4662. 193 D. Soullez, G. PlØ, L. Duhamel, J. Chem. Soc., Perkin Trans. 1 1997, 1639±1645. 194 S. Marumoto, H. Kogen, S. Naruto, Tetrahedron 1999, 55, 7145±7156. 195 M. R. Reeder, A. I. Meyers, Tetrahedron Lett. 1999, 40, 3115±3118. 196 J. E. D. Kirkham, T. D. L. Courtney, V. Lee, J. E. Baldwin, Tetrahedron Lett. 2004, 45, 5645±5647. 197 I. Churcher, D. Hallett, P. Magnus, J. Am. Chem. Soc. 1998, 120, 10350±10358.

43

45

3 Functionalized Organoborane Derivatives in Organic Synthesis Paul Knochel, Hiriyakkanavar Ila, Tobias J. Korn, and Oliver Baron 3.1 Introduction

Organoboranes have quite covalent carbon±boron bonds, which are compatible with a broad range of functional groups [1]. Thus, numerous highly functionalized boron derivatives can be prepared by various synthetic methods (hydroboration, transmetallation, cross-coupling). The synthetic utility of the resulting organoboranes is enhanced through transition-metal catalysis especially by the use of palladium complexes (Suzuki±Miyaura cross-coupling) [2]. In this chapter, we wish to describe the recent developments of polyfunctional organoboron compounds in organic synthesis. In particular, we will focus on methods for the preparation of polyfunctional aryl, heteroaryl, alkenyl, alkynyl, allylic and alkyl boron derivatives and try in each case to demonstrate the synthetic utility of the organoboron intermediates.

3.2 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes 3.2.1 Preparation from Polar Organometallics

The preparation of functionalized aryl boronic reagents can be achieved by directed metallation followed by a transmetallation of aryllithiums with organoboron compounds. Thus, Caron and Hawkins have described a directed ortho-metallation of aryl neopentyl esters such as 1 for the synthesis of substituted ortho-boronyl neopentyl benzoates using lithium diisopropylamide (LDA) as the base and B(OiPr)3 as an in situ trap [3]. The crude boronic acids obtained by acidic hydrolysis were subsequently treated with ethanolamine and converted to stable diethanolamine complexes such as 2. This methodology allows the preparation of a new class of boronic acids with ortho-carbonyl substituents and other functionalities Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

46

3 Functionalized Organoborane Derivatives in Organic Synthesis

especially bromine, which is not possible by a standard lithium±halogen exchange reaction (Scheme 3.1).

O

O

O 1) LDA, B(O-i-Pr)3, THF

R

2) diethanolamine

O O B O

R

1: R = 4-Cl; 2-Br; 4-Br; 3-F; 2-CF3; 4-CF3; 4-OMe

H

N

2: 70 - 93 %

Scheme 3.1 Preparation of boronic esters via metallation.

Furthermore, Vedsù and Begtrup have demonstrated that ortho-lithiation, in situ borylation using lithium 2,2,6,6-tetramethylpiperidide (LTMP) in combination with triisopropylborate, is highly efficient and represents an experimentally straightforward preparation of ortho-substituted arylboronic esters such as 3 [4]. The mild reaction conditions allow the presence of functionalities such as ester or cyano groups or halogen substituents that are usually not compatible with the conditions used in directed metallation of arenes (Scheme 3.2). HO FG

LTMP, B(OiPr)3

FG

THF, - 78 ºC B(OiPr)2

HO toluene, rt

FG = CO2Et; CN; F; Cl

FG B O

O

3: 61 - 98 %

Scheme 3.2 Ortho-lithiation and borylation of functionalized aromatics.

Morin has reported the preparation of 4-mercaptophenyl boronic acid as a potential melanoma-seeking agent suitable for boron neutron capture therapy [5]. This synthesis involves a metallation-boration sequence starting from 4-bromo-tbutyldimethylsilyl thioether 4. The parent 4-mercaptophenyl boronic acid, generated by boration could subsequently be S-alkylated yielding 4-carboxymethylthiophenyl boronic acid 5 after hydrolysis of the t-butyl ester without the need of protecting the boronic acid group leading to the corresponding acid 6 (Scheme 3.3).

3.2 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes Br

SSiMe2tBu

1) n-BuLi 2) B(OiPr)3

(HO)2B

CF3CO2H

SSiMe2tBu

47

(HO)2B

4

SH 88 %

(HO)2B

BrCH2CO2tBu

SCH2CO2R 5: R = tBu, 71 % 6: R = H, 80 %

K2CO3, MeCN, NaI TFA, CH2Cl2

Scheme 3.3 Synthesis of a functionalized boronic acid via a Br/Li-exchange.

Although, the reaction of organolithiums with boronic esters (B(OR)3) is an excellent method for preparing polyfunctional boronic esters, its scope and practicability is limited by the high reactivity of the intermediate organolithiums. They are compatible with a limited number of functional groups and their generation often requires low reaction temperature [6,7]. Organomagnesium derivatives have a much better functional group compatibility and are readily available via a halogen±magnesium exchange reaction [8]. Recently, it was shown that by using the mixed Li/Mg-species: i-PrMgCl´LiCl [9], the performance of bromine±magnesium exchange occurs under mild conditions and is compatible with a broad range of functional groups like a nitrile, amide or an ester. The resulting Grignard reagents display also an enhanced reactivity due to the complexation with lithium chloride that confer them a magnesiate character making the aryl moiety more nucleophilic. Thus, the reaction of 1,2-dibromobenzene 7 with i-PrMgCl´LiCl furnishes the corresponding Grignard reagent 8 that reacts with 2-methoxy-4,4,5,5tetramethyl-1,3,2-dioxaborolane 9 affording the corresponding ester 10 in 85% yield. The functionalized aryl halides 11 and 12 give rise, under similar reaction conditions, to the arylmagnesium species 13 and 14 that react with the borate 9, yielding the boronic esters 15 and 16 in 89±91% yield (Scheme 3.4) [10]. O Br Br

MgCl

i-PrMgCl· LiCl THF, -20 ºC, 2 h

Br

7

O

O B

B OMe 9

-20 ºC to rt, 1 h

Br 10: 85 %

8 O

Br

Br Br

i-PrMgCl· LiCl

Br

MgCl

THF, -50 ºC, 2 h

11

Br

O

B OMe 9

-50 ºC to rt, 1 h

13 O I CO2Et

12

MgCl

i-PrMgCl· LiCl THF, -78 ºC, 15 min

CO2Et

O

B OMe 9

-78 ºC to rt, 1 h

14

Scheme 3.4 Preparation of boronic esters from arylmagnesium reagents.

O

Br

O B

O

Br 15: 89 % O B

O

CO2Et 16: 91 %

48


Functionalized boronic esters can be alternatively prepared from readily available iodoaryl boronic esters such as 17 and 18. I/Mg-exchange with i-PrMgCl´LiCl provides a bimetallic B/Mg-species such as 19 and 20 that react with a range of electrophiles (aldehyde, allyl bromide, acid chloride, 3-iodo-2-cyclohexenone) providing the products 21 in good yields (Scheme 3.5) [11]. The Pd-catalyzed reaction of such polyfunctional boronic esters like 21b with various aryl halides provides the desired cross-coupling products like 22 in high yields [10,11]. Interestingly, a one-pot reaction allowing the selective reaction with two electrophiles is possible. Thus, the treatment of the meta-iodophenyl boronic pinacol ester 18 with i-PrMgCl´LiCl followed by a transmetallation to the copper derivative and subsequent reaction with 2-methyl-3-iodocyclohexenone provides the intermediate boronic ester 23 that after a Suzuki±Miyaura cross-coupling, furnishes the heterocyclic product 24 in 52% yield (Scheme 3.6) [11].

O

B

O

i-PrMgCl· LiCl

O

B

O

O PhCHO

O

B

THF, -78 ºC, 1 h I

OH

MgCl Ph 19: p-MgCl 20: m-MgCl

17: p-I 18: m-I

O

B

O

O

Ph

B

O

O

O

B

21a: para: 83 % 21b: meta: 71 %

O

O

B

O

O

B

O

CO2Et

O O

21c: 77 %

21d: 72 %

21e: 73 %

21f: 68 %

21g: 67 %

Scheme 3.5 Preparation of polyfunctional boronic esters via B/Mg-bimetallic aromatics.

Finally, this approach can be extended to various heterocyclic systems allowing the preparation of polyfunctional boronic esters such as 25±27 (Scheme 3.) [11]. The boronic esters 26 and 27 have been converted to the polyfunctional heterocycles like- 28 and 29 in excellent yields using the Suzuki±Miyaura cross-coupling reaction (Scheme 3.7).

3.2 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes

49

CN

O

B

O

PdCl2(dppf) cat. K2CO3, THF, 60 ºC OH

OH

Br

NC

Ph

Ph 22: 92 %

21b

N O

B

O

1) i-PrMgCl· LiCl

O

B

3) PdCl2(dppf) cat.

O

THF/DME/H2O K2CO3, 60 ºC Br

THF, -78 ºC, 1 h 2) CuCN· 2LiCl O

I 18

N

23

I

O 24: 52 %

O

Scheme 3.6 Successive copper-catalyzed cross-coupling and Suzuki±Miyaura cross-coupling reaction. O I

I

1) i-PrMgCl· LiCl THF, -78 ºC, 1 h I

N SO2Ph

2)

O B O N SO2Ph

O B OMe O

Br

Br N

O B

Br

O

I

I N

2) CuCN·2LiCl EtCOCl

O N SO2Ph

N O

26: 75 %

O

O B

I N

B OMe O

PdCl2(dppf) cat. K2CO3, DME/H2O, reflux N ZnCl S

N

1) i-PrMgCl· LiCl THF, -78 ºC, 1 h 2)

O

25: 81 %

B OMe O

Et B

76 %

1) i-PrMgCl· LiCl THF, -78 ºC, 1 h 2)

1) i-PrMgCl· LiCl THF, -78 ºC, 1 h

O

O B

S N

28: 77 % O B

1) i-PrMgCl· LiCl THF, -78 ºC, 1 h 2) CuCN·2LiCl Br

27: 76 %

Scheme 3.7 Synthesis of heterocyclic boronic esters via magnesium intermediates.

O

N 29: 83 %

O

50


3.2.2 Preparation from Aryl Halides and Sulfonates by Cross-coupling

A direct synthesis of substituted aryl boronic esters has been recently reported by Masuda [12,13]. Thus, coupling of pinacol borane 30 with aryl halides or triflates in the presence of a catalytic amount of PdCl2(dppf) and a base like triethylamine allows the preparation of aryl boronates having a variety of functional groups such as carbonyl, cyano, nitro, and acylamino of type 31 in high yields. The product distribution 31 versus 32 (reduced product) is strongly dependent on the choice of the base employed. In the presence of triethylamine as a base, selective formation of boronates 31 was observed with negligible amount of the reduced aromatic compound 32 (Scheme 3.8).

X

PdCl2(dppf) (3 mol %)

O HB O 30

R

Et3N

O B R

H

O

R

31: 55 - 84 %

32

R = 4-Cl, 4-CN, 4-NMe2, 4-NHAc, 4-CH2CN, 4-COMe, 4-CO2Me, 3-COMe; X = Br, I, OTf Scheme 3.8 Preparation of aryl boronic esters by palladium-catalyzed borylation.

Baudoin has prepared a range of sterically crowded ortho-substituted functionalized aryl boronates of type 33 as advanced intermediates for the synthesis of rhazinilam analogs [14]. This was accomplished by a palladium-catalyzed borylation of ortho-substituted phenyl halides with pinacol borane (30) using a sterically crowded phosphine ligand 34 that significantly improved the yields of borylated products in comparison with dppf. With halides such as 2-bromonitrobenzene and 2-bromoacetophenone, however only little or no pinacol boronates were obtained (Scheme 3.9).

X

O

O B

Pd(OAc)2 (5 mol %)

O

HB R

O

R 33: 57 - 90 % 34: 20 mol %

Cy2P

R = NH2; NHBoc; CH2CN; Et

Et ; Et

Et

CN

OSiEt3

Scheme 3.9 Synthesis of aryl boronic esters by palladium-catalyzed borylation with pinacolborane.

X = Br, I


51

Begtrup and Vedsù have developed a new gramme scale synthesis for 2- and 3-substituted 3- or 3-thienylboronic acids and esters 35 from 2,3-dihalothiophenes using a combination of halogen±metal exchange followed by trapping with an electrophile and palladium-catalyzed borylation of the resulting 2- (or 3-) bromo-3(or 2-) substituted thiophenes 36 [15]. Under optimized conditions the borylation of bromothiophenes were performed in THF at 40 C using Pd(P(tBu)3)2 as catalyst with Et3N as base and pinacol borane (30) as borylation agent, providing in general, the desired 2,3-substituted thienylboronic acids and esters in good to excellent yields. The borylation protocol is compatible with a range of functional groups, however strongly electron withdrawing substituents decreased the stability of the thienylboronic acids and esters that were used as such without isolation in the subsequent coupling (Scheme 3.10).

Br E

S

O HB O

E or S

Br

30

Pd(P(tBu)3)2 (0.5 - 3 mol %), Et3N; THF, 40 ºC

36: E = CO2Et; CONHtBu; CHO; CN; COMe; NO2; SiMe3

B(OR)2 S

E or

E

B(OR)2

S

35: 79 - 91 % (crude yields) 43 - 88 % (isolated yields)

Scheme 3.10 Synthesis of heteroaryl boronic esters by palladium-catalyzed borylation.

The cross-coupling reaction between bis(pinacol)diborane 37 and aryl halides or triflates in the presence of PdCl2(dppf) and a base like potassium acetate was first reported by Miyaura and coworkers [16,17]. It is an efficient and direct method for the preparation of functionalized aryl boronates. In contrast to more traditional organometallic approaches involving transmetallation between organomagnesium/lithium reagents and boronate esters, Miyaura's procedure enables facile access to boronic acid derivatives in the presence of sensitive functionalities such as an ester, aldehyde, ketone, cyano, nitro or halogens. A heteroaryl triflate from 7-hydroxycoumarine (38) gave the corresponding boronate 39 in 84% yield (Scheme 3.11). O X

R

O

O

O


B B

KOAc, solvent, 80 ºC

O

B

R

O

37 R = 4-COMe; 4-CO2Me; 4-CHO; 4-CN; 4-SMe; 4-Br; 4-I; 4-NO2; 2-NO2; 2-OMe X = Br, I, OTf O

O


O

KOAc, solvent, 80 ºC

B B O

O

OTf 38

O 37

Scheme 3.11 Synthesis of aryl boronates by palladium- catalyzed borylation of aryl halides with bis(pinacol)diborane (37).

O

64 - 93 %

O 39: 84 %

B O

O

52


In a subsequent paper, Miyaura demonstrated that several chloroarenes of type 40 are also efficient substrates for the cross-coupling reaction of bis(pinacol)diborane (37) in the presence of Pd(dba)2, the sterically crowded ligand tricyclohexylphosphine (Cy3P) and potassium acetate as a base leading to pinacol boronic esters of type 41 in 72±84% yield [18]. The reaction is compatible with a range of functional groups in the chloroarene. The catalyst system is also shown to be effective for analogous couplings with aryl bromides and triflates shortening significantly the reaction time for arylation (6±7 h) compared with previous procedures catalyzed by PdCl2(dppf) in DMSO (Scheme 3.12). O Cl

FG

O

O

40: FG = 4-CO2Me; 4-OH; 4-CN; 2-CN; 4-NO2; 2-NO2; 4-NMe2

O

Pd(dba)2, PCy3

B B

KOAc, dioxane, 80 ºC

O

B

FG

37

O 41: 72 - 98 %

Scheme 3.12 Coupling of chloroarenes with bis(pinacol)diborane (37).

Fürstner has described a synthesis of aryl boronates of type 42 bearing electronwithdrawing groups by cross-coupling of the respective para-substituted chloroarenes 43 with bis(pinacol)diborane (37) in the presence of a catalyst formed in situ from Pd(OAc)2 and the imidazolium chloride 44 [19]. A particularly noteworthy aspect of this reaction is the very significant rate acceleration, if the borylation is carried out with microwave heating. This allows the reduction of the overall reaction time from several hours to 10±20 min without affecting the yields (Scheme 3.13).

N

N Cl 44 O

R

Cl

Pd(OAc)2 cat. (3 - 6 mol %), KOAc, THF

43: R = CO2Me; COPh; COMe; CHO; CN; NO2; CF3

O

O B B

O

X

B O

42: 63 - 90 % (THF, heating) 57 - 72 % (MW, heating)

O 37

Scheme 3.13 Cross-coupling using a Pd-catalyst bearing carbene ligand.

Zhang has developed a modification of Miyaura's aryl boronate synthesis by using a ligandless palladium catalyst [20]. Pd(OAc)2, a much cheaper palladium catalyst is found to be highly effective for such coupling reactions with aryl bromides bearing electron-withdrawing groups such as COMe, CN, CO2Me and NO2.


53

However, aryl bromides substituted with electron-donating groups such as NMe2 and OMe poorly undergo the palladium-acetate-catalyzed cross-coupling. This modified procedure is advantageous compared to the original Miyaura synthesis in ease of work-up, catalyst removal and low catalyst cost (Scheme 3.14). O Br

FG

O

O

37

O

a or b

B B

B

FG

O

FG = 4-COMe; 3-CN; 4-NO2; 2-Me und 4-CO2Me (a) Pd(OAc)2 (3 mol %), KOAc, DMF, 80 ºC; (b) Pd/C (3 mol %)

O 70 - 90 %

Scheme 3.14 Ligandless palladium-catalyzed cross-coupling.

Wang has synthesized boronic acids derived from nitrophenols such as 45 and 46 with possible use as a recognition and signalling unit for the construction of polyboronic acid sensors [21]. Synthesis of boronic acid 45 involves cross-coupling of 2-bromo-4-nitroanisole with 37 followed by hydrolysis of boronate ester and deprotection of the methoxy group, whereas the dinitrophenyl boronic acid 46 is prepared by nitration of 2-methoxyboronic acid and subsequent cleavage of the methoxy ether with BBr3. The resulting functionalized boronic acids are both obtained in 90% yield (Scheme 3.15).

O OMe

O OMe O B

B B O

Br

37

O

OH O

PdCl2(dppf), KOAc, DMSO NO2

OMe

1) NaIO4, 2 N HCl, 70 % 2) BBr3, CH2Cl2

NO2

NO2

20 %

45: 90 %

OMe B(OH)2

H2SO4, HNO3

OH B OH

O2N

OH B(OH)2

BBr3, CH2Cl2

O2N

B(OH)2

- 10 ºC NO2

NO2

50 %

46: 90 %

Scheme 3.15 Synthesis of functionalized aryl boranes by palladium-catalyzed cross-coupling or nitration.

Yamamoto has reported the synthesis of (4-boronylphenyl)alanine (BPA), used clinically for treatment of malignant melanoma and brain tumors in neutron capture therapy by Pd-catalyzed coupling of triflate 47 with the diboron derivative 48 [22]. The boronic ester 49 could be easily cleaved by hydrogenolysis to give L-BPA 50 in 74% yield, whereas the corresponding pinacol ester yielded mixture


54

of products on hydrolysis with NaIO4 (Scheme 3.16). On the other hand, Morin has reported the synthesis of L-BPA 50 by Pd-catalyzed cross-coupling of 4-iodophenylalanine with bis(pinacol)diborane (37) [23]. Ph Ph OTf

Ph O O B B O O

Ph NHCbz

Ph O

B

B(OH)2

48 Pd(OH)2/C

Ph

PdCl2(dppf)/dppf (8 mol %) KOAc, DMF, 100 ºC, 3 h

NHCbz

CO2Bn 47

O

CO2Bn 49: 65 %

H2

NH2 CO2H 50: L-BPA, 74 %

Scheme 3.16 Synthesis of (4-boronylphenyl)alanine.

3.2.3 Synthesis of Functionalized Aryl Boranes by Catalytic Aromatic C±H Borylation

Direct borylation of aliphatic and aromatic hydrocarbons provides a more efficient and convenient route to alkyl and aryl boronic compounds, because of their wide availability and low cost [24]. Hartwig has reported the C±H coupling of benzene 4 with bis(pinacol)diborane (37) catalyzed by Cp*Re(CO)3 [25] or Cp*Rh(g -C6Me6) [26] under photoirradiation or by using temperatures above 150 C. Similar reactions 5 with pinacol borane (30) in the presence of a (g -C9H7)Ir(COD)-dppe(-dmpe) [27] or a (Cp*RhCl)2 [28] have also been developed by Smith. Clearly, the synthetic utility of the catalytic borylation hinges on the demonstration of functional-group tolerance and regioselective activation for substituted arenes. It was shown in initial studies [29,30] that both Ir and Rh precatalysts gave an approximately statistical distribution of meta and para isomers in borylation of mono-substituted arenes, demonstrating that borylation regioselectivity is sterically controlled for the most substituted arenes. 4 Thus, aromatic borylation by pinacol borane with Hartwig's catalyst Cp*Rh(g C6Me6) has been amply demonstrated by Smith and coworkers [29]. Borylation of several 1,3-substituted aromatic species ranging from electron rich (1,3-(NMe2)2C6H4) to electron deficient groups (1,3-(CF3)2C6H4) in cyclohexane at 150 C yields 5-borylated arenes, whereas 1,2-disubstituted arenes such as veratrole were selectively borylated at the 4-position. Selective borylation in 3-position of N-triisopropylsilylpyrrole has also been demonstrated providing a valuable heteroaryl borane reagent for cross-coupling reaction (Scheme 3.17).


O Ar H

Cp*Rh(η4-C6Me6) (2.0 mol %)

HB

O H2

Ar B

cyclohexane, 150 ºC

O

55

O

30 CF3

OMe

NMe2

Ar =

OMe NMe2

CF3 88 %

75 %

NMe2 69 %

N Si(iPr)3

OMe 82 %

81 %

Scheme 3.17 Direct borylation of aromatics with pinacol borane (30).

Miyaura has demonstrated that the iridium complex derived from the reaction of [Ir(OMe)(COD)2] with 4,4¢-di-ter-butyl-2,2¢-bipyridine is a highly active catalyst for aromatic C-H borylation by bis(pinacol)diborane (37) allowing for the first time, room-temperature borylation with stoichiometric amount of arenes [31]. The reactions are tolerated with a wide range of functionalities such as MeO, I, Br, Cl, CO2Me, CN and CF3 yielding aryl boronates in highly regioselective fashion. Thus, the reaction occurs regioselectively with disubstituted arenes and 1,2-, 1,3and 1,4-dichlorobenzenes are yielding a single product. The borylation of 1,3- disubstituted benzenes bearing electron donating or electron withdrawing groups occurs only at the meta position (Scheme 3.18).

O

O Ar H

H2

Ar B

hexane, 25 ºC

O

O

O

1/2[Ir(OMe)(COD)]2/dtbpy(3 mol %)

B B

O

37 Cl Ar =

Cl

Br

Cl

CF3

Cl

Cl

CN

CO2Me

CN

53 %

84 %

Cl Cl 82 % Cl

CF3

83 %

84 %

80 %

CF3

But

tBu

DTBPy = I

Br

OMe

82 %

91 %

81 %

Scheme 3.18 Synthesis of functionalized aryl boronic esters by transition-metal-catalyzed C-H borylation of arenes.

N

N

56


The [IrCl(COD)]2dtbpy system was also found to be effective for borylation of five-membered aromatic heterocycles such as thiophene, furan, pyrrole and their benzo fused derivatives yielding 2-borylated products exclusively in high yields, whereas six-membered heterocycles including pyridines and quinolines selectively gave 3-borylated products (Scheme 3.19) [32]. Regioselective synthesis of 2,5-bisborylated heteroaromatics was also achieved by using equimolar amounts of substrates and bis(pinacol)diborane (37) (Scheme 3.19). The regiochemistry can be tuned by varying the steric hindrance of the substituents in triisopropylsilylpyrrole and the corresponding indole derivative that gave selectively 3-borylated products. The 2,6-dichloropyridine is shown to undergo c-borylation (Scheme 3.19) [27].

HetAr H

1/2[IrCl(COD)] (1.5 mol %) dtbpy (3 mol %)

O

O B B

octane, 80 ºC, 16 h

O

O

O HetAr B

But

37

O tBu

dtbpy = N

HetAr = N Si(iPr)3

N Si(iPr)3

79 %

X = NH: 67 % X = O: 83 % X = S: 83 %

X = NH: 92 % X = O: 91 % X

83 % O

O B B X

X

N

O

O

1/2[IrCl(COD)] (1.5 mol %) dtbpy (3 mol %) octane, 80 ºC, 16 h

37

O B O

O

B O

X

X = NH: 80 % X = O: 71 % X = S: 80 %

Cl

N

Cl

O HB O

O

Ir[η5-C9H7)(COD)]/dppe (3 mol %)

B

O

hexane, 25 ºC Cl

30 Scheme 3.19 Synthesis of heteroaryl boronates by transitionmetal-catalyzed borylation of heteroarenes via C±H activation.

N 69 %

Cl


57

3.2.4 Synthesis of Functionalized Trifluoroborates and their Palladium-catalyzed Suzuki±Miyaura Cross-coupling Reactions

Molander has demonstrated in a detailed study on Suzuki coupling reactions using aryl and heteroaryl trifluoroborates that these fluoroborates are more robust, easier to handle and less prone to protodeboronation [33]. A wide array of electron-withdrawing and electron-donating groups such as fluoro-, acetyl-, nitro-, trifluoromethyl and methoxy groups are tolerated in aryl trifluoroborates used in 2 Suzuki cross-coupling reactions both under ligandless and ligand-added catalytic protocols [34]. In general, lower loading of catalyst, lower temperature and shorter reaction time as well as lack of inert atmosphere is needed in these reactions (Scheme 3.20).

KHF2 (2.5 - 3 equiv)

ArB(OH)2

MeOH, H2O, rt

Br ArBF3K

CN a, b or c

Ar

CN 70 - 99 %

Ar = 4-MeOC6H4; 3-MeOC6H4; 4-FC6H4; 4-MeCOC6H4; 3-NO2C6H4; 3,5-(CF3)2C6H3; 2,6-F2C6H3 (a) Pd(OAc)2 (0.5 mol %), K2CO3 (3 equiv), MeOH reflux; (b) Pd(OAc)2, (0.5 mol %), Ph3P (0.5 mol %), K2CO3 (3 equiv), MeOH reflux; (c) PdCl2(dppf)· CH2Cl2 (0.5 mol %), Et3N (3 equiv), EtOH reflux Scheme 3.20 Synthesis and cross-coupling of functionalized potassium aryl trifluoroborates.

Batey has reported Pd-catalyzed cross-coupling reactions of tetraalkylammonium aryl trifluoroborate salts bearing functional groups such as acetyl, nitro and chloro with functionalized aryl bromides under mild conditions [35]. These tetraalkylammonium organofluoroborates are prepared from the respective boronic acids using counter ion exchange protocol. They are air and moisture stable and are soluble in various organic solvents (Scheme 3.21).

Br R1

R2 BF3 n-Bu4N

R2 Pd(OAc)2· dppb (5 mol %) Cs2CO3, DME-H2O (1 : 1) 50ºC, 24 h

R1 60 - 92 %

1

R = 4-MeCO, 3-NO2, 4-Cl, 3-Cl R2 = 4-CHO, 3-CHO, 4-MeCO Scheme 3.21 Palladium-catalyzed cross-coupling of functionalized tetraalkylammonium aryl trifluoroborates.

Potassium pentafluorophenyl and trifluorovinyl trifluoroborates containing electron-poor substituents such as 51 undergo facile cross-coupling with p-substituted iodoarenes such as 52 in the presence of Pd(OAc)2/2 PPh3 and a stoichio-


58

metric amount of silver oxide yielding fluorinated cross-coupled products of type 53 in very good yields (Scheme 3.22) [36].

F

F

F

F BF3

F

K

I

NO2

F 51

F2C CF-BF3 K

Pd(OAc)2, 2 PPh3 Ag2O, K2CO3 toluene, 100 ºC

52

I

F

F

NO2 F

F

53: 81 %

F

Pd(OAc)2, 2 PPh3 Ag2O, K2CO3 toluene, 100 ºC, 8 h

F C F2C

F 76 %

Scheme 3.22 Palladium-catalyzed cross-coupling reactions of perfluoroorgano trifluoroborates.

3.2.5 Palladium-catalyzed Suzuki±Miyaura Cross-coupling Reactions of Functionalized Aryl and Heteroaryl Boronic Esters

Buchwald has reported that the sterically crowded ligand o-bis(t-butyl)phosphinobiphenyl (54) is a very effective ligand for Pd-catalyzed Suzuki cross-coupling for a wide array of aryl chlorides with substituted boronic acids at room temperature (Scheme 3.23, Eq. 1) [37]. Simultaneously, Fu reported a versatile method for Suzuki cross-coupling of aryl chlorides (which are otherwise not reactive under normal Suzuki conditions) using the sterically crowded and electron-rich trialkylphosphane P(t-Bu)3 (Scheme 3.23, Eq. 2) [38]. Deactivated and sterically hindered aryl chlorides were suitable substrates for this catalytic system. Fu subsequently demonstrated that KF is a more effective additive than Cs2CO3 that allowed Suzuki coupling of activated aryl chlorides including heteroaryl chlorides to proceed at room temperature [39]. The Pd/P(t-Bu)3-based catalytic system exhibits a highly unusual reactivity profile that has unprecedented selectivity for the coupling of an aryl chloride in preference to an aryl triflate (Scheme 3.23, Eq. 3). Despite a large variety of functional groups that can be tolerated in aryl chlorides, only a limited number of substituted aryl boronic acids with functionalities like MeCO, CF3 and OMe have been used as coupling partners in these reactions (Scheme 3.23).

3.2 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes Cl

Pd(OAc)2 (0.5 - 1.5 mol %)

(OH)2B

X

59

Y

(eq. 1)

KF (3 equiv) P(tBu)2 THF, rt,

Y

X 88 - 98 %

54: (1 - 3 mol %), X = 4-NO2, 4-CN, 4-CO2Me, 4-Me, 4-OMe, 2-COMe, 2-CH2CN, 3,5-(OMe)2; Y = 3-COMe, H, 2-OMe

Cl

[Pd2(dba)3] (1.5 mol %)

(OH)2B

X

Y

X = 4-COMe, 4-Me, 4-OMe, 4-NH2, 2-Me;

P(tBu)3 (3.6 mol %) Cs2CO3 (1.2 equiv), dioxane 80 - 90 ºC

(eq. 2) Y

X 82 - 92 %

Y = 4-CF3, 4-OMe, H, 2-Me

Me TfO

Me [Pd2(dba)3] (1.5 mol %)

(OH)2B

Cl

(eq. 3)

TfO

P(tBu)3 (3 mol %) KF (3 equiv), THF, rt

95 %

Scheme 3.23 Suzuki cross-coupling of aryl chlorides with functionalized boronic esters.

A heavily functionalized atropisomeric biphenyl derivative (designed for use as liquid crystal dopant) has been recently synthesized, although in low yield, with Suzuki coupling as the key step [40]. The coupling reaction is complicated by rapid hydrolytic deboronation of the sterically crowded electron-deficient boronate ester 55. Rigorously anhydrous conditions are required to avoid the deboronation step (Scheme 3.24). F

NC F

Br

F O

C7H15

B O 55

Me

OC8H17

F

NC

C7H15

OC8H17 Me Me

Me PdCl2(PPh3)2, CsF, DME, 90 ºC, 2 d

F

F

Me

C7H15

OC8H17 Me NC

21 %: separable by chiral HPLC Scheme 3.24 Synthesis of sterically crowded biphenyls by Suzuki coupling.

A new synthesis of biologically important 1,4-benzodiazepines and 3-amino1,4-benzodiazepines (56) using a Pd-catalyzed cross-coupling reaction of imidoyl chlorides with a variety of functionalized organoboronates or boronic acids as the key step has been described by Nadin et al. [41]. Examples of C±C bond formations using Pd(0)-catalyzed reactions of imidoyl halides or triflates are surprisingly rare (Scheme 3.25).


60

R1 N

R1 N

O O

Pd(PPh3)4 (0.01 equiv)

B R2

NHBoc Cl

NHBoc

Na2CO3 (2 equiv) DME-H2O, 100 ºC

O

N

O

N R2

or ArB(OH)2

56: 44 - 93 %

R1 = Me, H, CH2CONH2 O R2 =

; 4-ClC6H4; 4-CF3C6H4;

; O

N

O

F

O

F

; N

O

O n = 1,2 ; n

; N Boc

O

Scheme 3.25 Cross-coupling of functionalized aryl boronic esters with heterocyclic imidoyl chlorides.

An efficient large-scale chromatography free synthesis of cathepsin K inhibitor 57 has been recently reported involving Suzuki coupling of aryl bromide 58 with unprotected piperizinoaryl boronic acid 59 [42]. The residual palladium generated in the Suzuki coupling was efficiently removed from crude 57 via simple extractive work-up using lactic acid (Scheme 3.26).

H N

Br HCl-HN O

N B(OH)2

CN

HN

58

N H N

PdCl2(dppf) (3 mol %) K2CO3, DMF/toluene, 80 ºC

59

CN

O 57: 89 %

Scheme 3.26 Synthesis of potent cathepsin K inhibitor.

The Suzuki±Miyaura reaction has also found applications in nucleoside chemistry. Thus, Shaughnessy has reported an aqueous-phase modification of unprotected halonucleosides involving cross-coupling of either 8-bromodeoxyguanosine (or guanosine) and 8-bromodeoxyadenosine (or adenosine) with various substituted aryl boronic acids using a catalytic system derived from palladium acetate and water soluble tris(3-sulfonatophenyl)phosphine (TPPTS; 60) in a 2:1 wateracetonitrile mixture giving 8-aryl adducts of the corresponding nucleosides in excellent yields [43]. This coupling protocol has also been extended to 5-iodo-2¢deoxyuridine (5-IDU) (Scheme 3.27).


61

O

O N

NH

Br N HO

B(OH)2

N

N

NH2

O

N

Na2CO3, H2O:CH3CN (2:1) 80 ºC, 2 h 60: TPPTS NaO3S (6.25 mol %)

R

OH X

N

HO

OH X

X = H: 77 - 95 %; X = OH: 85 - 99 %

3

NH2

NH2 N N HO

B(OH)2

N

Br

NH2

O

P

R = H, CH2OH, OCH3, F, CO2Na

NH

R

Pd(OAc)2 (2.5 mol %)

N

N

N

Na2CO3, H2O:CH3CN (2:1) 80 ºC, 2 h

O

R

HO

OH X

N

O

60: TPPTS (6.75 mol %)

NaO3S

N

R

Pd(OAc)2 (2.7 mol %)

OH X

P R = H, OCH3, F, CH2OH

X = H: 77 - 90 %; X = OH: 85 - 99 % 3

Scheme 3.27 Suzuki±Miyaura cross-coupling of unprotected halonucleosides.

Firooznia has reported the synthesis of 4-substituted phenylalanine derivatives via cross-coupling of protected (4-pinacolylboron)phenylalanine derivatives such as 61 with aryl and alkenyl iodides, bromides and triflates [44]. They have further shown that BOC derivatives of (4-pinacolylboron)phenylalanine ethyl ester 61 or the corresponding boronic acids undergo Suzuki±Miyaura reactions with a number of aryl chlorides in the presence of PdCl2(PCy)3 or NiCl2(dppf), respectively providing diverse sets of 4-substituted phenylalanine derivatives of type 62 [45]. This strategy has also been used for the synthesis of enantiomerically enriched 4-substituted phenylalanine derivatives (Scheme 3.28) [46].

O B O ArCl

O

N H

O OEt

Ar

O O

PdCl2(PCy3)2 CsF, NMP, 100 ºC 12 - 18 h

61 Ar = 4-CF3C6H4, 4-CO2MeC6H4, 2-CNC6H4, 3-MeOC6H4, 3-NO2C6H4 Scheme 3.28 Synthesis of substituted phenylalanine derivatives by Suzuki±Miyaura cross-coupling.

O

N H

O OEt

62: 41 - 62 %

62


Palladium-mediated cross-coupling of 2-pyrone-5-boronate (63), prepared by coupling of 5-bromo-2-pyrone with pinacol borane (30), with a range of androsterone-derived alkenyl triflates 64 affords bufadienolide type steroids 65 in high yields (Scheme 3.29) [47]. OTf

O

O

O

O PdCl2(dppf) R

R1

R2

O

64

B

K3PO4, DMF, 60 ºC, 6 h O 63 R

O O

BH O 30

O

R1

R2

65: 75 - 91 %

PdCl2(PPh3)2 Et3N

Br

Scheme 3.29 Suzuki cross-coupling of heteroaryl boranes.

An efficient and flexible two-step synthesis of nemertelline (66), a quaterpyridine neurotoxin isolated from a hoplonemertine sea worm, involving regioselective Suzuki cross-coupling of chloropyridinyl boronic acids to give 2,2¢-dichloro3,4¢-bipyridine (67) on the multigram scale followed by its coupling with excess of pyridin-3-yl boronic acid has been recently described by Rault (Scheme 3.30) [48]. Br B(OH)2 N

Cl

N

Cl

B(OH)2 I N

Cl

N

Cl

63 % B(OH)2

N Pd(PPh3)4 aq. Na2CO3 dioxane heating 66 %

Cl

N N

N Pd(PPh3)4, aq. Na2CO3, dioxane, heating

N 67

Cl

N

N

66: nemertelline: 67 %

Scheme 3.30 Selective Suzuki coupling of functionalized heteroaryl boronic acids.

Williams has reported the synthesis of biaryl moiety of proteasome inhibitors TMC-95/A/B by Suzuki cross-coupling of boronic ester 68 with indolyl iodide 69 to give precursor 70 in 90% yield [49]. The boronic ester 68 was obtained from the tyrosine derivative 71 with bis(pinacol)diborane (37), Pd(dppf)Cl2 and KOAc via the Miyaura protocol (Scheme 3.31).

3.2 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes O

O B B

I

O

MOMO

O

OMe

O O

37

PdCl2(dppf)

NHBoc

B

MOMO

O

OMe NHBoc

KOAc, DMSO, 80 ºC 80 %

H

H 68

71 O CbzN

PdCl2(dppf) aq. DME, K2CO3

H

O

O

CbzN

N H

MOMO

O

H 69

O

O

OMe NHBoc I

H

70: 90 %

N H

Scheme 3.31 Synthesis of polyfunctional heterocycles via Suzuki±Miyaura cross-couplings. OBn

O

O B(OH)2

O I

Pd(OAc)2 (3 mol %)

O

KF (3 equiv), MeOH, 20ºC

N H

CO2Me NPhth Me

BnO

N H O

OMe NPhth

72: 64 %

NH O HO HO

NH O

HO

N H

O CONH2

NH O R1 R2 O N H

Me

O

TMS-95A: R1 = Me; R2 = H TMS-95B: R1 = H; R2 = Me

Scheme 3.32 Cross-coupling of isatin derivatives.

The biaryl moiety of proteasome inhibitor TMC-95 has been prepared via a ligandless Pd(OAc)2-catalyzed Suzuki-coupling reaction of 7-iodoisatin with sterically hindered tyrosine-derived aryl boronic acid using potassium fluoride as a

63


64

base in 64% yield [50]. It should be noted that the product 72 was obtained previously only in a yield of 19% under standard Suzuki-coupling conditions (Scheme 3.32) [51]. The macrocyclic core of diazonamide A, a cytotoxic marine natural product has been prepared by Vedejs via Suzuki coupling of boronic acid 73 and the triflate 74 yielding interconverting mixture of two atropisomers that on treatment with LDA at ±23 C affords the macrocyclic ketone 75 in 57% yield (Scheme 3.33) [52]. B(OH)2

1) PdCl2(dppf), THF, Cs2CO3, 65 ºC, 65 %

O

O

N Boc

TfO

MeO

N

N

Me

O N Boc

O

2) LDA, THF, -23 ºC

O O O 73

74

O

75: 57 %

Scheme 3.33 Macrocyclic heterocycle synthesis.

The synthesis of anti-MRSA carbapenam has been reported as a multigram scale synthesis involving Suzuki±Miyaura cross-coupling between carbapenam triflate 76 and the highly functionalized aryl boronate salt 77 as the key step by Merck scientists yielding polyfunctional product 78 in 60% yield over four steps. It highlights the versatility and efficiency of the Suzuki±Miyaura cross-coupling reaction (Scheme 3.34) [53]. H H

TESO Me

O

Me OTf

N O

n TfO-; 2-n Br-

CO2pNB

N (HO)2B

2) pH 2.2 - 2.4 THF/H2O 3) NaOTf

N O

76

77

1) Pd(dba)2, LiCO3 DMF/CH2Cl2/H2O 30 - 35 ºC

NH2

O 2 TfOMe HO

N

H H N

Me

O

CO2pNB

N O

NH2

78: 60 % Scheme 3.34 Synthesis of a carbapenam derivative via Suzuki±Miyaura cross-coupling.

Kozikowski has reported the synthesis of a novel class of spirocyclic cocaine analogs 79a and b by using Suzuki cross-coupling of the ortho-functionalized aryl


boronic acids 80 and 81 and an bicyclic enol triflate 82 as the key step followed by further transformations of the resulting cross-coupled products 83 and 84, respectively (Scheme 3.35) [54]. B(OH)2

Me N

Me OTBDPS

CO2Me

N

Pd2(dba)3

CO2Me

LiBr, aq. Na2CO3 DME, heating

OTf

TBDPSO 82 Me

80 Me

N

83: 72 %

N

CO2Me

CO2Me

X

X 79a: X = CH2 79b: X = S Me N CO2Me

B(OH)2 SMe

Me Pd2(dba)3

N CO2Me

LiBr, aq. Na2CO3 DME, heating

OTf

MeS 82

81

84: 82 %

Scheme 3.35 Synthesis of biologically important natural products and their analogs.

The first total synthesis of biologically significant bis-indole alkaloid dragmacidin D (85) has been reported by Stoltz [55]. The key steps in this synthesis involve a series of thermally and electronically modulated palladium-catalyzed Suzuki cross-coupling reactions of highly functionalized indole-3-boronic acid and ester derivatives furnishing the core structure of this guanidine and amino imidazole marine natural product (Scheme 3.36). A novel macrocyclization procedure involving two distinct cross-coupling manifolds in a domino fashion has been reported by Zhu for the synthesis of biphenomycin model 86 [56]. Thus, treatment of linear bis-iodide with bis(pinacol)diborane (37) in the presence of Pd(dppf)2Cl2 under defined conditions affords the biphenyl macrocyclic compound 86 in 45% yield through a Miyaura aryl boronic ester formation followed by its intramolecular Suzuki cross-coupling. The diiodide containing a free phenol function (R=H) gave the macrocycle (R=H) in only 22±25% yield under these conditions (Scheme 3.37).

65

66

Br


Ts N

Ts N

N

I

N

OMe

Br

Pd(PPh3)4, MeOH, C6H6

N Br

Na2CO3, H2O, 23 ºC, 72 h Br

(HO)2B

OMe

N

71 % Ts N TBSO Me

Br

N OMe

N BnO

N SEM

Me O B O

TBSO

82 % H N

HN HN

Pd(PPh3)4, MeOH, C6H6 Na2CO3, H2O, 50 ºC, 72 h

Br

CF3CO2N

OBn

N SEM

N Me

O

85: dragmacidin D

NH

HO

N H

Scheme 3.36 Synthesis of bis-indole compounds via Suzuki±Miyaura cross-coupling.

RO I

NHBoc H N

O

O

CO2Me

O

N H

OR MeO

O B B O

(1.1 equiv) 37

PdCl2(dppf)2 (0.05 equiv) KOAc, DMSO, 80 - 85 ºC

O (1.1 equiv)

I OMe

O H N

BocHN

N H

CO2Me

O

86: R = Me: 45 % R = H: 20 - 25 %

Scheme 3.37 Macrocyclization using the Suzuki±Miyaura reaction.

Vaultier has developed a solid-phase synthesis of macrocyclic systems by intramolecular Suzuki±Miyaura aryl-aryl macrocyclization of polymer ionically bound borates 87 obtained by trapping of the respective aryl boronic acids by an ammonium hydroxide form Dowex ion exchanger resin (D-OH), leading to macrocycles of type 88 in 16±22% yield (Scheme 3.38) [57].


67

O

O N 2

(HO)3B

O

Pd(OAc)2 (5 mol %) 2

n

N

Me N

N

Me N

O

n

N

TPPDS (20 mol %) THF/H2O (4:1), 40 ºC, 40 h

Br 88: n = 1-3: 16-22 % 87: (1 equiv)

NMe3

TPPDS = triphenylphosphine disulfonic acid disodium salt

Scheme 3.38 Solid-phase intramolecular macrocyclization.

Dehaen has developed several approaches for the synthesis of highly soluble rodlike diketopyrrolopyrrole oligomers of specified lengths by employing Pd-catalyzed Suzuki cross-coupling reactions of bis-boronate 89 and the brominated 1,4-dioxo-3,6diphenylpyrrolo[3,4-c]pyrroles (DPP) 90 and 91 [58]. An example of a convergent approach for the synthesis of trimer of DPPS (92) is shown. These compounds are useful for the construction of organic light emitting devices (Scheme 3.39). O B O t-Bu

Br

n-Hex

n-Hex

t-Bu O B O

O

t-Bu

t-Bu

89 O

N N

N t-Bu

O

Pd(PPh3)4, Na2CO3 toluene, heating

N

O

n-Hex

t-Bu R

n-Hex O B O

R

t-Bu

90: R = H 91: R = Br

t-Bu 91 (3 fold excess) Pd(PPh3)4, Na2CO3 toluene, heating

t-Bu t-Bu

t-Bu

t-Bu t-Bu

O

N

O

O

N O

t-Bu

n-Hex

R

N

n-Hex

R

N n-Hex O

t-Bu

N

N

O

n-Hex t-Bu

t-Bu t-Bu t-Bu 92: 69 %

Scheme 3.39 Synthesis of highly functionalized polymers and oligomers.

t-Bu

68


3.2.6 Copper-mediated Carbon±Heteroatom-Bond-forming Reactions with Functionalized Aryl Boronic Acids

Cu(II)-mediated N-arylation of amines and azoles with aryl boronic acids has been reviewed recently [59]. Pfizer chemists have demonstrated that N-arylpyrroles can be prepared from aryl boronic acids and electron-deficient pyrroles via Cu(OAc)2 mediated coupling reaction at room temperature in air [60]. These reaction conditions are compatible with a variety of functional groups on boronic acids, but are sensitive to steric hindrance. The method could be successfully applied for the synthesis of compound 93 bearing a 4-cyanoaryl group which is a pivotal intermediate in the synthesis of MMP inhibitor AG3433 (Scheme 3.40). O

O

OEt O

H O

Ar-B(OH)2

N H

Cu(OAc)2 (1.5 equiv) pyridine (2 equiv) CH2Cl2, rt, air

OEt O

H N Ar

O

87 - 100 % Ar = 4-OMe, 4-Me2N, 4-I, 4-Br, 4-COMe, 4-CF3, 3-NO2, 4-Me; 2-OMe: 14 % O

O

H O

N H

O

OEt NC

B(OH)2


OEt O

H N O

CN 93: 93 % Scheme 3.40 Copper-mediated N-arylation of amines.

The copper-catalyzed amination developed by Buchwald is an effective method for catalytic coupling of aryl boronic acids with amines [61]. Yudin has recently shown that N-arylation of aziridines is possible under modification of Buchwald's method and is successful with a range of functionalized aryl boronic acids (Scheme 3.41) [62].


O

O

OEt O

H O

Ar-B(OH)2

N H


69

OEt O

H N Ar

O

87 - 100 % Ar = 4-OMe, 4-Me2N, 4-I, 4-Br, 4-COMe, 4-CF3, 3-NO2, 4-Me; 2-OMe: 14 % O

O

H O

O

OEt NC

B(OH)2

N H


O

H N O

CN 93: 93 % Scheme 3.41 Copper-mediated N-arylation of aziridine.

An unprecedented copper-mediated cross-coupling of N-hydroxyphthalimide and aryl boronic acids yielding aryloxyamines 94 in high yields has been reported by Kelly [63]. The reaction proceeds with both electron-rich and electron-deficient aryl boronic acids and works well in the presence of additional functional groups including halides, esters, ether, nitrile and aldehyde. The phthalimide group can be removed using hydrazine affording the corresponding free aryloxyamines of type 94 (Scheme 3.42).

OEt

70


O

O

R Cu(OAc)2 or CuCl (1 equiv)

N OH O

N O

pyridine (1.1 equiv) 4 Å mol sieves, CH2Cl2, 24-48 h

B(OH)2

O R 94: 52 - 90 % 4-OMe: 37 %

R = 4-OMe, 4-CF3, 4-I, 4-Br, 4-CO2Me, 4-CHO, 4-CN, 4-CH=CH2, 3-CF3, 3-OMe, 3-F, 3-iPr, 3,5-F2C6H3 O

H2N N2H4

N O

O

MeOH:CHCl3 12 h, rt

O

R

R 94

95: 77-90 %; R = H, m-CF3 Scheme 3.42 Copper-mediated O-arylation of N-hydroxyimides.

Evans has developed a direct synthesis of diaryl ethers while investigating the coupling of functionalized phenolic tyrosine derivatives 96 and 97 [64]. The desired diaryl ethers were obtained in good to excellent yields with pyridine as base and no observed racemization. The thyroxine intermediate 98 was obtained in 81% yield under these conditions using a mixture of pyridine/Et3N (1:1) (5 equiv) as a base (Scheme 3.43). Boc

OH

NH

(HO)2B

MeO O

96

Boc

Cu(OAc)2 (1 equiv) R1

pyridine, 4 Å molecular sieves CH2Cl2, rt

O 95 - 98 %

I

I NHAc

OH I

O

97

R1

MeO

R1 = H, 4-Me, 4-F, 4-OMe, 3-OMe, 3-NO2 R1 = Cl: 7 %; R1 = 2-OMe: 37 %

EtO

O

NH

(HO)2B

NHAc

Cu(OAc)2 (1 equiv) R

Et3N/py (1:1) (5 equiv) 4 Å molecular sieves CH2Cl2, rt

EtO

O I

R

O 98: 81 % R = OMe: Nacylthyroxine

Scheme 3.43 Copper-promoted arylation of phenols.

Evans has also developed an intramolecular version of the Cu(II)-assisted boronic acid O-arylation reaction and has applied it to the synthesis of macrocyclic biphenyl ether hydroxamic acid inhibitors of collagenase 1 and gelatinases A and B [65]. The reaction proceeds under sufficiently mild conditions to accommodate chemical functionalities commonly used in peptidomimetics synthesis (Scheme 3.44).

3.2 Preparation and Reaction of Functionalized Aryl and Heteroaryl Boranes R1

OH B(OH)2

t BuO2C

N H

O

Cu(OAc)2, Et3N

R1

O

HN

R O

R

CO2tBu R = CO2Me, R1 = H: 54% R = CONHMe, R1 = H: 52 % R = R1 = H: 43 % R = CO2Me, R1 = OMe: 52 %

Scheme 3.44 Synthesis of macrocyclic biaryl ethers.

Evans has elaborated a total synthesis of tiecoplanin aglycon (99) based on the coupling reaction of aryl boronic acid 100 and the phenol 101 [66]. In the key step, the diaryl ether 102 was obtained in 80% yield with no detection of epimerization at any of the three stereogenic centers. An elegant sequence of reactions subsequently led to the completion of the synthesis of 99 (Scheme 3.45). NO2 OMe

NO2

H3C

F

O

100

NH

H N

N H

O MeO

B(OH)2

O

O MeO

F

O

NHBoc

CF3

Cu(OAc)2, O2, pyr 4 Å molecular sieves CH2Cl2, rt

O

HO

H N

N H

O

O H3C

OMe

NH

O

OMe

OMe NHBoc 102: 80 %

101 OH O HO

Cl O

Cl O

O

N H

O

H N O

NH HO

N H

O

NH

HO O

HO

OH OH 99: teicoplanin aglycon

Scheme 3.45 Copper-promoted O-arylation of phenols.

NH2

NH O

O

OH

CF3

71

72


Guy has explored copper-mediated S-arylation of thiols and aryl boronic acids [67]. Earlier studies revealed that the reactions were slow for S-arylation under the conditions developed previously for N- and O-arylation reactions because of a significant disulfide formation. However, it was shown later that the reaction of a wide range of electronically diverse aryl boronic acids with a range of thiolate substrates proceeded well when heated at 155 C in DMF affording crosscoupled products in good yields. Similarly cysteine phenyl sulfide 103 and an arylthio glycoside 104 were also prepared in 50±80% yields (Scheme 3.46). SH

(HO)2B

Cu(OAc)2 (1.5 equiv) R 2 equiv

pyridine, 4 Å MS DMF, reflux

S R 65 - 88 %

OAc SH Cbz

N H

AcO

S

O

Cu(OAc)2 (1.5 equiv) PhB(OH)2 (2 equiv) pyridine, 4 Å MS DMF, reflux

O

Cbz

N H

O O

S

OAc O

OAc

104: 51 %

103: 79 % Scheme 3.46 Copper-mediated thioether synthesis.

A new synthesis of thioethers involving copper-catalyzed cross-coupling of aryl boronic acids with N-aryl/heteroaryl thiosuccinmides has been described by Liebeskind and coworkers [68]. The reaction proceeds in the absence of base under mild conditions utilizing various aryl boronic acids. S-arylation is now possible for the first time under nonbasic conditions (Scheme 3.47). CO2Cu OH

O RS N

ArB(OH)2

(20-30 mol %) THF, 45-50 ºC

O Scheme 3.47 Copper-catalyzed cross-coupling of organothiolimides with boronic acids.

RS-Ar 51 - 83 %


73

3.2.7 Palladium-catalyzed Acylation of Functionalized Aryl Boronic Acids

Carbonylative cross-coupling reactions of aryl boronic acids with aryl electrophiles like aryl bromides, iodides and triflates proceeds smoothly under an atmospheric pressure of carbon monoxide in the presence of PdCl2(PPh3)2/K2CO3 (for aryl iodides) or PdCl2(dppf)/K2CO3, KI (for aryl bromides and triflates) in anisole at 80 C to give the diaryl ketones in good to excellent yields. The carbonylation of the o-substituted phenylboronic acid 105 with benzyl bromide gives the o-substituted phenylbenzyl ketone 106 that is readily converted to isoflavone (107) (Scheme 3.48) [69].

X R1

R

B(OH)2

K2CO3 (3 mmol), anisole (6 mL) CO (1 atm)

X = I, Br, OTf

B(OH)2 OMOM 105

O

PdCl2(PPh3)2 (3 mol %) or (X = I) PdCl2(dppf) (3 mol %), KI (X = Br, OTf)

R1

R 63 - 89 %

BrCH2C6H5 PdCl2(PPh3)2 K2CO3, anisole 80 ºC, 5 h CO (1 atm)

O

O

OMOM

O

106: 78 %

Scheme 3.48 Pd-catalyzed carbonylative cross-coupling of aryl boronic acids.

It was reported by Bumagin that a ligandless palladium-catalyzed reaction of aryl boronic acids with benzoyl chloride gives unsymmetrical diaryl ketones in high yields (Eq. 1, Scheme 3.49) [70]. Gooûen has developed a one-pot high yielding synthesis of unsymmetrical aryl (or alkyl) aryl ketones directly from a variety of functionalized alkyl and aryl carboxylic acids by their cross-coupling with a number of substituted aryl boronic acids catalyzed by a Pd/phosphine complex [71]. A small amount (2 equiv) of water was shown to be essential for this reaction and boronic acids with many functional groups were tolerated (Scheme 3.49).

107: 79 %

74


ArB(OH)2

PhCOCl

PdCl2 (1 mol %), Na2CO3

Ar = 2-, 3-, 4-MeC6H4; 4-Me-3-NO2C6H4;

O R

PhCOAr

76 - 96 %

(eq. 1)

Me2CO:H2O, 20 ºC

ArB(OH)2

OH

(1 mmol)

(1.2 mmol)

Br

;

OHC

S

S

O

(tBuCO)2O (1.5 mmol) R

Pd(OAc)2 (0.03 mmol) L (0.035-0.07 mmol) THF, H2O (2.5 equiv) 60 ºC, 16 h

Ar

(eq. 2)

54 - 90 %

L = P(4-MeOC6H4)3, PPh3, dppf, PCy3 Scheme 3.49 Pd-catalyzed acylation reactions with boronic acids.

3.2.8 Miscellaneous C±C-bond Formations of Functionalized Aryl Organoboranes

Gooûen has also reported a palladium-catalyzed cross-coupling reaction between aryl boronic acids or esters and a-bromoacetic acid derivatives which allows the synthesis of various substituted aryl acetic acid derivatives in good to excellent yields under mild conditions [72]. Aryl boronic acids with a range of electron-withdrawing and -donating substituents are tolerated in this reaction (Scheme 3.50). O Ar-B(OH)2

Br

X

or O Ar B O

X = OEt X = O-(CH2)4-Br X= N

O

Pd(OAc)2 (3 mol %) P(Nap)3 (9 mol %) K3PO4, H2O-THF or K2CO3

Ar

X 63 - 90 %

Ar = Ph, 4-MeOC6H4, 3- or 4-MeC6H4, 4MeCOC6H4, 4-CHOC6H4, 3-ClC6H4, 3-AcNHC6H4 Ar = 3-NO2C6H4, X = OEt: 40 %

Scheme 3.50 Palladium-catalyzed cross-coupling of aryl boronic acids and boronates with a-bromoacetic acid derivatives.

Rhodium(I)-complexes are known to be excellent catalysts for the conjugate additions of aryl- and alkenyl boronic acids to a,b-unsaturated ketones, esters and amides [73,74]. Batey has recently prepared aryl and alkenyl trifluoroborates as airand moisture-stable reagents for the nucleophilic addition to enones in the presence of a Rh(I)-catalyst to give b-functionalized ketones in good yields [75]. A number of aryl fluoroborates with electron-withdrawing substituents were also tolerated in this reaction. An unprecedented Rh-catalyzed 1,4-addition of aryl boro-


nic acids for stereoselective synthesis of C-glycosides has also been reported by Maddaford [76]. The reaction is stereoselective for the a-isomer and a variety of aryl boronic acids can be used including electron donating or withdrawing, alkenyl and sterically congested groups (Scheme 3.51). R1

Rh(acac)(CO)2 (3 mol %)

R1BF3K O

dppb (3 mol %) MeOH/H2O, 50 ºC

O

R1 = aryl, alkenyl

AcO

59 - 100 %

O ArB(OH)2

AcO

Rh(I)(cod)2BF4 (5 mol %) dioxane/H2O, heating, 4 h

O Ar = aryl, alkenyl

AcO

O

Ar

AcO O 50 - 81 %

Scheme 3.51 Rhodium-catalyzed 1,4-conjugate additions.

A first example of catalytic asymmetric synthesis of 4-arylpiperidiones (Ar = 4-FC6H4, 4-ClC6H4) has been described using a rhodium-catalyzed 1,4-addition of 4-fluoro- or 4-chlorophenylboroxine and one equivalent of water with the chiral BINAP ligand [77]. The (R)-4-(4-fluorophenyl)-2-piperidione obtained in this reaction is a key intermediate for the synthesis of pharmacologically important (±)-paroxetine (108). The enantioselective Rh-catalyzed addition of aryl boronic acids to dehydroalanine has also been performed in the presence of C2-symmetric aryl diphosphite ligands allowing the synthesis of unnatural amino acid esters such as 109 in moderate enantioselectivity (Scheme 3.52) [78]. Petasis has demonstrated that aryl and heteroaryl boronic acids participate in one step three component Mannich reactions with glyoxylic acid and diarylamines to give the corresponding a-aryl/heteroarylglycine derivatives in good yields after deprotection of the diarylamine [79]. Several examples of the reaction with parasubstituted aryl boronic acids as well as 2- and 3-thienyl, -furyl or -benzo[b]thienyl boronic acids are described (Scheme 3.53) [80]. Petasis has also reported an efficient one-step and highly versatile three component reaction of boronic acids with amines and a-hydroxyaldehydes to give anti-bamino-alcohols in a highly diastereo-controlled manner [81]. A variety of boronic acids including alkenyl, 2-bromoalkenyl, aryl and heteroaryl derivates participate readily in this process. The experimental procedure is very simple and does not require anhydrous or oxygen free conditions and can be adapted to parallel synthesis for the construction of combinatorial libraries. Since aldehyde racemization does not occur under the reaction conditions, enantiomerically pure (> 99%) amino-alcohols can be obtained by using chiral a-hydroxy aldehydes. Thus, use of enantiomerically pure glyceraldehydes and aminodiphenylmethane followed by hydrogenolysis of the resulting 3-amino-1,2-diol derivative and its subsequent

75


76

Ar Rh(acac)(C2H4)2

(ArBO)3/H2O

(R)-binap (3 mol%) dioxane, heat

O

N H

O

N H

F Ar = 4-FC6H4: 84 %, 98 % ee Ar = 4-ClC6H4: 88 %, 98 % ee

O O O N H

108: (-)-paroxetine Ar

O MeO2C

N H

O

ArB(OH)2 Me

Rh(acac)(C2H4)2 dioxane-H2O (R)-BINAP, NaF

MeO2C

N H

Me

109a: Ar = Ph: 77 %, 55 % ee 109b: Ar = 4-AcC6H4: 36 %, 37 % ee 109c: Ar = 4-MeOC6H4: 73 %, 56 % ee

Scheme 3.52 Enantioselective Rh-catalyzed 1,4-conjugate additions.

Ar

B(OH)2 CHO CO2H

Ar

H2N

Ar

HN

Ar

NH3Cl

AcOH, H2O, HCl

CO2H Ar = 4-MeOC6H4

PhMe, 25 ºC Ar = 4-MeOC6H4 90 %

CO2H

Ph Ph B(OH)2

H2N

OHC-CO2H PhMe, 25 ºC

X

HN

Me

B(OH)2 OHC-CO2H CH2Cl2, 25 ºC

Me CO2H

X

Ar2NH X

62 %

X

Ar N Ar

X = OMe: 82 % (35 % de) X = CH=CH2: 77 % (28 % de)

Cl NH3

AcOH, H2O, HCl S

CO2H X = O,S: 79 - 92 % Ar = 4-MeOC6H4

CO2H 79 - 80 %

Scheme 3.53 Synthesis of amino-acids using the Petasis reaction.

conversion to the NBoc derivative gave N-protected b-amino alcohol in > 99% ee. Prakash, Petasis and Olah have extended this reaction for the synthesis of anti-a(trifluoromethyl)-b-amino alcohols and anti-a-(difluoromethyl)-b-amino alcohols 4 (R = CF3 and CF2H), in a highly stereoselective fashion [82]. Further, the coupling


77

of enantiomerically pure (R)- and (S)-a-(trifluoromethyl)-a-hydroxy aldehydes with bromostyryl boronic acid and dibenzylamine gave the expected anti-amino alcohols with high enantioselectivity [83]. Also, it was shown that unprotected fluoroalkylamino alcohols can be prepared by this method using diallylamine as the amine component followed by catalytic deallylation of the bis(diallyl)amino alcohol 110 in the presence of Pd(PPh3)4 and dimethylbarbituric acid as the allyl group scavenger (Scheme 3.54). R2 OH B OH R1

N H

R3 R2

O 4

R

H

R3

N

R4

R1

,EtOH, 25 ºC

OH

OH

>> 99 % de, > 99 % ee Ph

B(OH)2

Ph

HN

Ph2CHNH2 Ph

OH

O

Ph OH OH

OH Et2O, H2O, 24 h

NHBoc

H2, Pd/C (Boc)2O NEt3

Ph

70 %, > 99 % de > 99 % ee Ph

Ph

OH

Br

H

F3C

Ph

O

Ph B(OH)2

Ph N H

N

EtOH rt

OH OH

Br

F3C

Ph OH

(R) 85 % ee (S) 96 % ee

(R, R) 74 %, 85 % ee (S, S) 79 %, 92 % ee

OH Ph

CF2H N

Pd(PPh3)4/CH2Cl2 dimethylbarbituric acid heating

OH Ph

110

CF2H NH2 62 %

Scheme 3.54 Stereoselective synthesis of b-amino-alcohols using the Petasis-reaction.

A practical synthesis of several aryl bromides and chlorides has been recently described via halodeboronation of a range of arylboronic acids especially with electron-withdrawing groups using DBDMH or DCDMH (1,3-dibromo or 1,3-dichloro-5,5-dimethylhydantoin). [84,85]. This methodology could be also extended for the synthesis of 2-bromo-3-fluorobenzonitrile. Addition of a catalytic amount of NaOMe has beneficial effects on the rate and yields of these reactions.

78


3.2.9 Miscellaneous Reactions of Functionalized Alkenyl Boronic Acids

In previous studies, Petasis had reported the synthesis of geometrically pure E- or Z-alkenyl halides by reaction of alkenyl boronic acids with N-halosuccinimides (NIS, NBS or NCS) (Scheme 3.55) [86]. O X = Br, Cl B(OH)2

X

N

R

N X

(1.1 equiv.) X

O NaOMe (5 mol %) MeCN, 25 ºC

R R = 2-F, 3-NO2, H, 2-Me, 3-COMe, 4-COMe, 2-OMe; X = Br: 77 - 99 % X = Cl: 43 - 97 % for 2-OMe: 18 % O

F

1) LDA, B(OiPr)3 THF, 0 ºC 2) HCl, 75 %

CN

F B(OH)2 CN

Br

N

N Br

(1.1 equiv.)

F Br

O NaOMe (5 mol %) MeCN, 25 ºC

CN 88 %

B(OH)2 Br

NIS, MeCN or NCS, CHCl3

Br B(OMe)2

X

X = I: 71 % X = Cl: 76 %

I

62 %

Br Br

Scheme 3.55 Synthesis of aryl bromides and chlorides by halodeboronation of arylboronic acids.

An efficient conversion of functionalized aryl boronic acids to the corresponding phenols has been accomplished by Prakash, Petasis and Olah by simply adding aqueous hydrogen peroxide solution [87,88]. They have further developed a one-pot coupling sequence for the preparation of symmetrical diaryl ethers via partial conversion of aryl boronic acids to phenols as precursors for the coupling sequence. The H2O2/arylboronic acid ratio is critical for the outcome of this reaction sequence, whereas 0.25 equivalents of H2O2 furnished the highest overall yields. A variety of substituents are tolerated in the aryl boronic acids (Scheme 3.56).

3.3 Preparation and Reactions of Functionalized Alkenyl Boranes

B(OH)2

R

H2O2 (30 %) (1 equiv.)

OH

R

H2O

60 - 88 % B(OH)2

R

1) H2O2 (30 %) (0.25 equiv.) 2) 4 Å MS, Cu(OAc)2/NEt3

O R

R 55 - 90 %

Scheme 3.56 Oxidation of boronic esters.

3.3 Preparation and Reactions of Functionalized Alkenyl Boranes 3.3.1 Synthesis of Alkenyl Boronic Acids by Transmetallation of Alkenyl Grignard Reagents with Boronate Esters

Jiang has described the successful preparation of a-(trifluoromethyl)ethenyl boronic acid by reaction of readily available 2-bromotrifluoropropene, magnesium and an alkyl borate in an one-pot process [89]. The trifluoromethyl boronic acid 111, thus obtained, was found to be stable for several months even in the presence of air and moisture (Scheme 3.57). THF F3C

Br

Mg

B(OMe)3

25 ºC, 4 h

H+ F3C

B(OMe)2

F3C

B(OH)2

111: 90 % Scheme 3.57 Synthesis of functionalized alkenyl boronic esters by transmetallation of an alkenyl Grignard reagent with (MeO)3B.

3.3.2 Synthesis of Functionalized Alkenyl Boronic Acids by Hydroboration of Functionalized Alkynes and their Suzuki Cross-coupling Reactions

Witulski has reported the first hydroboration of 1-alkynylamides. Thus, the hydroboration of ynamide 112 with catechol borane in THF proceeded chemo- and regioselectively yielding only the monohydroboration product, alkenyl boronic ester 113 [90]. However, the isolation of the boronic ester 113 was complicated due to its instability and difficulties of storage and purification. Therefore, it was directly subjected to Suzuki±Miyaura cross-coupling yielding (E)-b-arylenamide and 3-(2¢-amidovinyl)indoles such as 114 (Scheme 3.58).

79

80

Bn N

SO2Tol


O SO2Tol H Bn N

HB O THF, 70 ºC, 2 h

Pd(PPh3)4 (10 mol%) NaOH, 80 ºC

B O O

H

H

112

SO2Tol H Bn N

Ar -X

H

Ar

114: 61 - 80 %

113

Scheme 3.58 Alkenyl boronic esters by hydroboration of functionalized acetylenes.

Konno has investigated the hydroboration of fluoroalkylated internal alkynes that proceeds in a highly regio- and stereoselective manner to give the corresponding fluoroalkylated alkenyl boranes in excellent yields [91]. These alkenyl boranes were reacted with a range of aryl halides without isolation under Suzuki±Miyaura cross-coupling conditions providing a practical one-pot synthesis of fluoroalkylated trisubstituted olefins 115 in high yields with complete retention of the olefinic geometry (Scheme 3.59). Cy2BH (1.2 equiv.) F3C

Ar C6H6, rt

F3C Cy2B

Ar

R1I

H

Pd(PPh3)2Cl2 (10 mol%) NaOH

F3C R1

Ar H

115: 62 - 99 %, cis isomer (> 99 %)

Ar = C6H5; 4-ClC6H4; 4-MeOC6H4; 4-CO2EtC6H4; 4-NO2C6H4; 4-MeC6H4. R1 = C6H5, 4-MeOC6H4; 4-CO2EtC6H4; 4-NO2C6H4; 2-ClC6H4; 3-ClC6H4; 4-ClC6H4. Scheme 3.59 Synthesis of fluoroalkylated alkenyl boranes by hydroboration.

Srebnik has reported the synthesis of phosphono boronates by hydroboration with pinacol borane (30) [92]. The reaction proceeds well with terminal alkenyl phosphonates whereas internal alkenyl phosphonates gave complex mixtures. Hydroboration of the corresponding alkynyl phosphonates under identical conditions gave alkenyl phosphonates that were difficult to isolate and were in situ subjected to Suzuki coupling with phenyl iodide to give trisubstituted phosphonates providing a new one-pot synthesis of this class of compounds (Scheme 3.60). O

n R

P(O)(OEt)2

BH O 30 (1 or 2 equiv.) 70 - 110 ºC

O B O

n R 70 - 99 %

Scheme 3.60 Synthesis of boronic-esters-substituted phosphonates.

P(O)(OEt)2


3.3.3 Synthesis of Functionalized Alkenyl Boronic Esters by Cross-metathesis

Grubbs has reported the synthesis of functionalized alkenyl pinacol boronates suitable for cross-coupling reactions using ruthenium-catalyzed olefin crossmetathesis of 1-propenyl pinacol boronate (116) and various functionalized alkenes [93]. The 1-propenyl pinacol boronate (116) is readily synthesized from the commercially available reagents in significantly higher yields than its vinyl analog that led primarily to use 116 along with the carbene-substituted catalyst 117 in these studies [94]. The resultant boronate cross-products are stereoselectively converted into Z-alkenyl bromides and E-alkenyl iodides, respectively, by bromination or iodination (Scheme 3.61).

O B

Me

Grubb's-catalyst (5 mol%) O

R

R

CH2Cl2, heating

116

O B

O

58 - 99 %

R = TIPS-CH2, AcO(CH2)4, BzO(CH2)2, HO(Me)2C

Me

O B

Grubb's-catalyst (5 mol%) O

X

X

X

O B

O

CH2Cl2, heating X = OBz: 58 % X = NPhth: 65 %

catalyst =

N

N

Cl Ru Cl Ph PCy3 117 Scheme 3.61 Synthesis of functionalized alkenyl boranes by cross-metathesis.

Danishefsky has applied the cross-metathesis reaction for the synthesis of highly functionalized alkenyl boronate precursor 118 from the terminal olefin 119 and vinyl pinacol boronate in the presence of first generation' Grubbs-catalyst 121 [95]. The metathesis reaction was driven to completion by increasing the amount of vinyl boronate ester 120 affording the polyfunctional boronic ester 118 in 93% yield and with exclusive trans-stereochemistry. The alkenyl boronic ester 118 was subsequently used in the synthesis of epothilone 490 via intramolecular Suzuki macrocyclization (Scheme 3.62).

81

82

3 Functionalized Organoborane Derivatives in Organic Synthesis O

O

OTES O

B O 120

OTroc

O

OTES O

OTroc

HO

HO PCy3 Cl Ru Cl PCy3 Py

119

B O

O

118: 93 %

121

Scheme 3.62 Synthesis of functionalized alkenyl boronates by cross-metathesis.

Pietruszka has reported the synthesis of styryl and cyclopropyl boronic esters with an acrylate functionality by applying a cross-metathesis reaction [96]. Thus, the reaction of cyclopropyl boronate 122 with methyl acrylate gave the E-enoate 123 in 52% yield (Scheme 3.63). Ph O

Ph

MeO2C

OMe OMe

B O Ph

Ph

Grubb's-catalyst: Cl

O

Grubb's-catalyst 121 (0.15 equiv.) CH2Cl2, reflux

Ph OMe OMe

B

122 Cl

Ph

CO2Me (2 equiv.)

O Ph

Ph

123: 52 %

PCy3 Ru Ph PCy3 121

Scheme 3.63 Synthesis of functionalized cyclopropylalkenyl boronic esters.

3.3.4 Synthesis and Palladium-catalyzed Cross-coupling Reactions of Functionalized Alkenyl Trifluoroborates

Cross-coupling reactions of functionalized alkenyl trifluoroborates 124 with 4-bromobenzonitrile in the presence of catalytic amounts of PdCl2(dppf) has been studied by Molander [97,98]. Herein functionalized 4-cyanostyrenes of type 125 were obtained in satisfactory yields (Scheme 3.64).

3.3 Preparation and Reactions of Functionalized Alkenyl Boranes PdCl2(dppf)·CH2Cl2 (2 mol %)

R Br

CN

BF3K

R

i-PrOH, H2O, t-BuNH2

124

CN 125a: R = Cl-(CH2)3: 52 % 125b: R = MeO2C(CH2)3: 33 %

Scheme 3.64 Preparation and cross-coupling reactions of functionalized alkenyl trifluoroborates.

3.3.5 Palladium-catalyzed Cross-coupling of Functionalized Alkenyl Boronates with Cyclopropyl Iodides

Charette has reported the first cross-coupling reaction of aryl/alkenyl boronic esters with cyclopropyl iodides [99]. The alkenyl boronates with the protected hydroxy group gave coupled products in moderate to good yields. Similarly the Pdcatalyzed cross-coupling of benzyloxymethylcyclopropyl boronate with trans-benzyloxy-methyliodocyclopropane gave the symmetrical benzyloxy substituted biscyclopropane in 71% yield (Scheme 3.65) [100].

RO

O B

I O

R = Bn R = TBDMS

BnO

B O

O

OBn

RO

Pd(OAc)2 (0.1 equiv.) PPh3 K2CO3, Bu4NCl

I

OBn

OBn R = Bn: 64 % R = TBDMS: 35 %

OBn

BnO

Pd(OAc)2 (0.1 equiv.) PPh3 (0.5 equiv.) K2CO3, Bu4NCl

71 %

Scheme 3.65 Cross-coupling of boronic esters with cyclopropyl iodides.

3.3.6 Intermolecular Suzuki Cross-coupling Reactions of Functionalized Alkenylborane Derivates: Application in Natural Product Synthesis (Alkenyl B-Alkenyl Coupling)

Roush has demonstrated that thallium(I) ethoxide promotes Suzuki-coupling for a range of functionalized alkenyl boronic acids and functionalized aryl or alkenyl halides in good to excellent yields [101]. This reagent offers distinct advantage over thallium(I) hydroxide in terms of its commercial availability, stability and ease of use (Scheme 3.66).

83

84


Me O

O Me

OTBS O Br

Me Me OOMe

O (HO)2B

OTBS O

OH

Pd(PPh3)4 (10 mol%) TlOEt (1.8 equiv.) THF:H2O (3:1) THF

Br

O Me

Me OOMe

Br

HO 81 %

CO2Me

CO2Me

Scheme 3.66 Suzuki cross-coupling of functionalized alkenyl boronic acids.

A highly convergent synthesis of bafilomycin A, a macrolide antibiotic has been recently reported by Roush. A Suzuki cross-coupling reaction was performed between the functionalized alkenyl boronic acid 126 and the alkenyl iodide 127 generating appropriately protected macrocyclic precursor 128 in 65% yield (Scheme 3.67) [102]. TBSO OTES

OH

OH B(OH)2

Me Me

Me

CO2Me

I Me

OMe

Me

Me

OH

aq. TlOH, THF, rt

OH CO2Me

Me Me

OMe

127

126 TBSO OTES

Me

Pd(PPh3) (20 mol%)

Me

OMe

Me

Me

Me

Me

(-)-bafilomycin A1

OMe

128: 65 % Scheme 3.67 Palladium-catalyzed cross-coupling of functionalized alkenyl boronic acids: synthesis of natural products (by an alkenyl B-alkenyl coupling).

3.3.7 Intramolecular Macrocyclization via Suzuki Cross-coupling of Functionalized Alkenyl Boronic Esters (Alkenyl B-Alkenyl Coupling)

A highly convergent synthesis of rutamycin B, a 26-membered lactone macrolide antibiotic has been achieved by intramolecular macrocyclization through Suzuki coupling of a linear alkenyl boronate with a terminal alkenyl iodide as the key step in high yield as reported by White et al. (Scheme 3.68) [103].


85

OR OR O O

B

OR

OR O

OR O

I

PdCl2(MeCN)2 (40 mol%)

O

O

OR O O O

Ph3As, Ag2O, THF

O

O

O O

O

OR

OR

70 % R = TBS

HF, Pyr. 70 %

R = H, rutamycin Scheme 3.68 Intramolecular macrocyclization via Suzuki±Miyaura coupling.

Danishefsky has reported the total synthesis of epothilone 490 (129) via an intramolecular Suzuki macrocyclization of alkenyl boronic ester 130 bearing a terminal alkenyl iodide group [104]. The corresponding alkenyl boronate fragment was prepared by alkenyl boronate cross-metathesis as reported by Grubbs (Scheme 3.69) [105,106]. S

S O

N

O OTES

O

N

O OTES

Pd(PPh3)4, Ag2O THF, heating, 5 h

I O

O

B O

O OTroc

OTroc 130

129: epothilone 490: 35 %

Scheme 3.69 Synthesis of epothilone 490 via Suzuki±Miyaura cross-coupling.

3.3.8 Three-component Mannich Reaction of Functionalized Alkenyl Boronic Acids (Petasis Reaction): Synthesis of b,c-Unsaturated a-Amino Acids

A new general synthesis of b,c-unsaturated a-amino acids involving a three-component variant of the Mannich reaction with a number of alkenyl boronic acids, primary and secondary aliphatic or aromatic amines and a-keto acids has been reported by Petasis [107,108]. A remarkable feature of this reaction is that it is triply convergent and gives products with multiple sites for introducing molecular diversity. By using readily cleavable amines, i.e. bis(4-methoxyphenyl)methyla-


86

mine, it is possible to prepare free amino-acids. Use of (S)-2-phenylglycinol gave alkenyl amino acid 131 as a single diastereomer (> 99% de). Subsequent hydrogenation of 131 gave R-homophenylalanine hydrochloride (132) with > 99% ee (Scheme 3.70). R5 N R6 H

3

R

B(OR)2

R2

R3 R4 R2

R4

1

R

R1

O

O

Ph

Ph

Ph

H2N

OH

54 - 94 %

OH EtOH, CH2Cl2 or PhMe 25 ºC

OH B OH

R5 6 N R O

OH

CHOCO2H H2O, CH2Cl2 25 ºC, 12h

HN Ph

OH

NH3Cl

H2/Pd/C CO2H

131: 78 % (> 99 % de)

MeOH, HCl

Ph

CO2H

132: 76 % (> 99 % ee)

Scheme 3.70 Synthesis of b,c-unsaturated a-amino acids using the Petasis reaction.

3.3.9 Oxidation of Functionalized Alkenyl Boronic Esters to Aldehydes with Trimethylamine Oxide

Danishefsky has developed a mild oxidative procedure for the conversion of highly functionalized alkenyl boronates (obtained by alkenyl boronate cross-metathesis) to the corresponding aldehydes with trimethylamine N-oxide that was found to be compatible with hydroxyl, ketone and acid functionalities present in alkenyl boronates without protection [109]. For example, by using this methodology, it was possible to oxidize the iodoalkenyl boronate intermediate 133 to the aldehyde 134 that was subjected to intramolecular Nozaki±Kishi macrocyclization yielding 11-hydroxy deoxyepothilone precursor 135 in 40% yield (Scheme 3.71). 3.3.10 Lewis-acid-catalyzed Nucleophilic Addition of Functionalized Alkenyl Boronic Esters to Activated N-acyliminium Ions

Batey has reported the first example of the reaction of alkenyl boronic acids and esters with activated N-acyliminium ion precursors under Lewis-acid catalysis giving 2-functionalized heterocycles in good yields [110]. This methodology has been further extended for the synthesis of fungal metabolite (1R*,-8aR*)-1-hydroxyindolizidine (136) by concomitant deprotection and tosylation of the adduct followed by hydrogenation and cyclization in the presence of a palladium catalyst (Scheme 3.72).

3.4 Preparation and Reactions of Functionalized Alkynlboron Derivatives

S

87

S O

N

O

O

N

OTES

O OTES

Me3NO, THF reflux, 4 h

I O

I

O

B O

O

OTES 133

O OTES

134: 95 %

S O

O

N

OTES

HO

CrCl2, NiCl2 DMF:THF (3:1) rt, 5 h

O OTES 135: 40 %

Scheme 3.71 Oxidation of functionalized vinyl boronates to aldehydes.

OH

O

OH

R B O

OH N CBZ

R N CBZ

BF3· Et2O, CH2Cl2 - 78ºC to rt

136: 64 - 99 % 1) TsCl, ET3N, py CH2Cl2, 0 ºC

OH

N CBZ

OH

2) H2/Pd/C EtOH, 4 ºC

OH H N 136: 53 %

Scheme 3.72 Nucleophilic addition of functionalized alkenyl boronic acids and esters to activated N-acyliminium ion precursors.

3.4 Preparation and Reactions of Functionalized Alkynlboron Derivatives

Molander has reported the synthesis of functionalized alkynyl trifluoroborates by transmetallation of alkynyllithium compounds with boronates followed by in situ treatment with KHF2 [111]. These alkynyl trifluoroborates are crystalline solids possessing excellent air stability and are shown to undergo facile cross-coupling for example with 4-bromobenzonitrile to give functionalized arylacetylenes in high yields. Thus, the reaction is tolerant to a variety of sensitive functional

88


groups as shown by the reaction of potassium (4-t-butyldimethylsiloxy-1-butyn-1yl) trifluoroborate or potassium (trimethylsilylethynyl) trifluoroborate that afforded coupled products in, respectively, 88% and 60% yields. Interestingly both TBDMS and TMS groups survived cross-coupling reactions despite the presence of fluoride ions (Scheme 3.73). 1) n-BuLi (1 equiv.) -78 ºC, THF, 1h R

H

2) B(OMe)3 (1.5 equiv.) -78 ºC, 1h to - 20ºC, 1h 3) KHF2/H2O -20 ºC, 1h to rt, 1h

R

BF3K

66 - 85 %

PdCl2(dppf)·CH2Cl2 (9 mol%) NC

Br

R

BF3K

Cs2CO3 (3 equiv.) THF/H2O reflux, 12 h

NC

R 60 - 98 %

Scheme 3.73 Synthesis and reactions of functionalized alkynyl boronic derivatives.

Alkynyl boronic acid derivatives were not used earlier in Suzuki couplings. An effective Suzuki±Miyaura reaction between alkynyl ate¢ complexes (alkynyltrialkoxy borate complexes) has been reported by Colobert [112] Oh [113]. 1-Alkynyl(triisopropoxy) borates (137) were prepared by borylation of the corresponding alkynyl lithium species. These stable borate complexes were subsequently used in Suzuki coupling leading to products of type 138 (Scheme 3.74).

TBDMS Li

PdCl2(PPh3)2 (5 mol%)

B(Oi-Pr)3 TBDMS ether, rt quantitative

B(Oi-Pr)3Li 137

CuI, ArI DMF

TBDMS Ar 138: 34 - 67 %

Scheme 3.74 Synthesis and reactions of functionalized alkynyl boronates.

3.5 Synthesis and Reactions of Functionalized Allylic Boronates

Grubbs has reported the synthesis of functionalized allyl boronates via olefin metathesis and developed a one-pot, three-component cross-metathesis/allylboration protocol for the synthesis of highly functionalized homoallylic alcohols by in situ reaction of these functionalized allylic boronates with benzaldehyde in high anti- diastereoselectivity [114]. Of particular importance is the direct incorporation of a halomethyl side-chain (R = CH2Br and CH2Cl) through previously unknown c-haloallyl boronate (139, R = CH2Br, CH2Cl) thus, highlighting the utility of olefin metathesis for the synthesis of highly functionalized and reactive reagents not

3.5 Synthesis and Reactions of Functionalized Allylic Boronates

89

available through traditional methods leading here to the anti-homoallylic alcohols 140 (Scheme 3.75). O

R

B O

B

catalyst 117 R

R R

R

O

R

or

OH

O

R

PhCHO 23 ºC

R

139

140: 63 - 75 % major anti

= CH2OAc, CH2OTBS, CH2OBn, CH2Br, CH2Cl O

=

catalyst =

N

O

N

Cl Ru Cl Ph PCy3 117

Scheme 3.75 Synthesis of functionalized allylic boronates by cross-metathesis and their one-pot allylboration with aldehydes.

Synthesis of a series of novel functionalized achiral and chiral allyl boronates has been recently reported by Ramachandran via nucleophilic SN2¢-type addition of copper boronate species (generated from the boronates 37, 141, 142 under Miyaura conditions) [115,116] to various functionalized allyl acetates that were prepared either via vinylalumination or by Baylis±Hillman reaction with various aldehydes [117]. The resulting allylic boronates bearing an ester moiety (X = OR) were subsequently used for the synthesis of a-alkylidene-b-substituted-c-butyrolactones by allylboration of aldehydes (Scheme 3.76). O

OAc O R2

O

O

B B X

O

O

R2

CuCl, LiCl, KOAc DMF

R1

R1

B O

X O

70 - 99 %, E/Z > 95 % R1 = H, Me; R2 = Ph, Me; X = OMe, OEt, OBn, OMenth, Me O

O

O

B B O

O 37

O B B

O

O

EtO2C

O

EtO2C

O

141

O

CO2Et

O

CO2Et

B B 142

Scheme 3.76 Allylic boronates via Hosomi±Miyaura borylation.

Palladium-catalyzed cross-coupling of alkenyl stannanes with pinanediol bromomethyl boronate (143) has been reported to give homologous allylic boronates


90

in good yields [118]. Cross-coupling proved compatible with a wide range of functionalities such as methyl ester, nitrile, benzyl ether and even an unprotected hydroxy group (Scheme 3.77). MeO2C

SnBu3 MeO2C

B O O

Br

B O O

Pd2(dba)3· CHCl3 HMPA

143

78 %

Scheme 3.77 Synthesis of functionalized allylic and benzylic boronates.

3.6 Synthesis and Reactions of Functionalized Cyclopropyl Boronic Esters

Pietruszka has reported the synthesis of stable enantiomerically pure functionalized cyclopropyl boronic esters via highly diastereoselective cyclopropanation of the respective alkenyl boronic esters with diazomethane catalyzed by Pd(OAc)2 [119]. The enantiomerically pure alkenyl boronic esters were prepared by direct hydroboration of the respective alkynes with the chiral 1,3,2-dioxaborolane (144). The ter-butyldimethylsilyl protecting group in the boronic ester could be selectively deprotected and the resulting hydroxymethyl alkenyl boronate was also cyclopropanated to give hydroxymethylcyclopropyl boronic esters with good diastereoselectivity (Scheme 3.78). Ph HO HO Ph

Ph

Ph

BH3-SMe2

OMe OMe

CH2Cl2, 50 ºC

Ph

O HB O Ph

Ph

Ph R

OMe OMe

R

HF/ MeCN

Ph R

O B O Ph

R = TPSO(CH2)3 R = TBSOCH2 R = HOCH2

Ph OMe OMe

95 70 80

Ph

R

O O Ph

Pd(OAc)2 (5 mol%) CH2N2/Et2O 0 ºC

Ph

Ph

5 30 20

Scheme 3.78 Synthesis of cyclopropyl boronates.

Ph

R = TPSO(CH2)3: 83 % R = TBSOCH2: 91 % R = HOCH2: 98 %

OMe OMe

B

B Ph

144

Ph OMe OMe

O

Ph

Ph

O

total yield 89 % " " 90 % " " 98 %

3.7 Synthesis and Reactions of Functionalized Alkyl Boron Derivates

91

This cyclopropyl boronic ester was converted into bis-cyclopropanes through a series of transformations shown in Scheme 3.79 [120]. The iodo bis-cyclopropyl boronic acid ester 145, however gave a complex product mixture on attempted Suzuki coupling with phenylboronic acid. On the other hand, the less bulky hydroxy protected bis-cyclopropyldioxaborinane 146 obtained by transesterification underwent smooth cross-coupling with iodobenzene giving the phenyl substituted bis-cyclopropane product 147 in 79% yield (Scheme 3.79). Ph

HO

O B O Ph

1) cat. TPAP, NMO, CH2Cl2 Ph OMe 2) NaH, THF, MeOCOCH2PO(OMe)2 OMe 3) DIBAL-H, THF, -78 ºC 97 % Ph

Ph

HO O B O

Ph NHTs NHTs

X

O

Ph OMe OMe

B O Ph

O O Ph

2-mercaptopyridine N-oxide DCC, DMAP, cyclohexene, CHI3, reflux

TPSO

PhI, Pd(PPh3)3 Ph

TPSO

O 146

Ph

91 %

B KOtBu, DME

Ph OMe OMe

B

Ph

X = CO2H 145: 33 % X = I

147: 79 %

Ph

HO NaIO4, cat. RuCl3

Ph

Et2Zn, CH2I2 ZnI2, CH2Cl2 L*

L* =

Ph

Ph OMe OMe

O

Scheme 3.79 Synthesis of functionalized bis-(cyclopropyl)boronic esters.

3.7 Synthesis and Reactions of Functionalized Alkyl Boron Derivates 3.7.1 Synthesis of Aminoalkyl Boranes by Hydroboration and their Suzuki Cross-coupling Reaction

A highly convenient method for introducing alkoxycarbonyl-protected b-aminoethyl groups into arenes and alkenes has been reported by Overman [121]. This one-pot reaction involves hydroboration of benzyl vinylcarbamate to give b-carbobenzyloxyborane that is in situ coupled with various aryl and alkenyl halides or triflates to give b-aminoethyl substituted arenes and alkenes in high yields. Overman has subsequently utilized these intermediates 148 for asymmetric synthesis of trans-hydroisoquinolones 149 (Scheme 3.80) [122].

1) TPSCl imidazole, CH2Cl2 2) LAH/THF NH4Cl 3) 1,3-propanediol

92

3 Functionalized Organoborane Derivatives in Organic Synthesis OTBDPS I OTBDPS (9-BBN)2/THF NHCbz

-10 ºC to rt

NHCbz

NHCbz

R2B

PdCl2(dppf) (9 mol%) 3 N NaOH, rt

OTIPS

H

NH2

EtO2C

148: 82 %, 94 % ee

O

N H nPr 149: 87 %, 87 % ee

Scheme 3.80 Synthesis of b-amino derivates via Suzuki±Miyaura cross-coupling.

3.7.2 Synthesis of Functionalized Alkyl Boronates by Nucleophilic 1,4-Conjugate Addition of Borylcopper Species to a,b-Unsaturated Carbonyl Compounds

A copper-catalyzed nucleophilic borylation of a,b-unsaturated carbonyl compounds yielding b-borylated carbonyl compounds in good yields has been simultaneously reported by Hosomi and coworkers [123] and Miyaura and coworkers O

O B B

O

O

37

1

R

R

O

O O

O 37

O R1

50 - 96 %

O

B B O

O

R

CuOTf (0.05 equiv.) Bu3P (0.11 equiv.) DMF, 25 ºC, 36 h O

B

O B O

CuOTf (0.05 equiv.) Bu3P (0.11 equiv.) DMF, 25 ºC, 36 h

O

67 %

O NH

O

n B O O

KCN (NH4)2CO3

HN

EtOH:H2O 90 - 95 %

n

O

10 M HCl 150 ºC

H2N

CO2H

n B O O

B O O n = 1,3

Scheme 3.81 Synthesis of functionalized alkyl boronates by nucleophilic addition of borylcopper species to a,b-unsaturated carbonyl compounds.


93

[124,125]. The transmetallation between the diboron derivate 37 and Cu(I)-salt generating a boryl copper species has been proposed as the key step in this reaction. Kabalka et al. used this copper-mediated 1,4-borylation reaction for the synthesis of boron containing unnatural amino acids as potential therapeutic agents in boron neutron capture therapy (BNCT) (Scheme 3.81) [126]. 3.7.3 Preparation and B-alkyl-Suzuki±Miyaura Cross-coupling Reactions of Functionalized Alkyl Trifluoroborates

Molander has recently reported the preparation of various 3-functionalized propyl trifluoroborates from the corresponding allyl derivatives following various literature protocols for hydroboration of alkenes [127]. The 3-heteropropyl trifluoroborates were obtained as crystalline air-stable solids by treatment of hydroboronated products with KHF2. Palladium-catalyzed cross-coupling of these 3-heteropropyl trifluoroborates with 4-acetylphenyl triflate gave functionalized alkylarenes in good yields (Scheme 3.82). a or b X

X

B(OH)2

X = Cl X = PhS

X = Cl: X = PhS:

75 % 80 %

KHF2 (3 equiv.) Et2O:H2O

X

BF3K

X = Cl: 90 % X = PhS: 93 % X = PhSO2

MCPBA

(a) = HSiEt3, BCl3, CH2Cl2, - 78ºC, 30 min then H2O:Et2O for X = Cl (b) = HBBr2· Me2S (2equiv.), CH2Cl2, reflux, 24 h then H2O:Et2O for X = SPh pinacol boron (1.5 equiv.) RhCl(PPh3)3 (1 mol%) CH2Cl2, 25 ºC X

X = BzO X = NHTs

X = BzO: 85 % X = TsNH: 60 %

X

BF3K

TfO

Ac

B O

O

X

KHF2 (3 equiv.)

KHF2 (3 equiv.) Et2O:H2O 72 %

BF3K

X = BzO: 75 % X = TsNH: 67 %

PdCl2(dppf) (9 mol%)

Ac

Cs2CO3 (3 equiv.) THF:H2O (10:1), reflux X

X = Cl, PhS, BzO, TsNH, PhSO2: 66 - 75 %

TMSCH2B(OH)2

X

MeCN:H2O

Br

CN

TMSCH2BF3K

TMSCH2 PdCl2(dppf)·CH2Cl2 (9 mol%) Cs2CO3 (3 equiv.) THF:H2O (20:1) reflux, 6-8 h

Scheme 3.82 Preparation and Pd-catalyzed Suzuki cross-coupling of functionalized alkyl trifluoroborates.

CN 55 %

94


Molander has also described the preparation and cross-coupling of potassium (trimethlsilyl)methyl trifluoroborate with various functionalized aryl bromides and triflates leading to (trimethylsilyl)methyl substituted arenes in moderate to good yields (Scheme 3.82) [127]. Likewise, potassium alkyl trifluoroborates bearing cyano, keto, bromo and ester groups participate smoothly in cross-coupling reactions with both functionalized aryl and alkenyl triflates in good yields [128]. These functionalized alkyl trifluoroborates are readily available from Grignard reagents as well as by hydroboration of the appropriate alkenes employing several different hydroborating protocols. The inclusion of water in the cross-coupling reaction was found to be essential and Cs2CO3 was found to be the most effective base (Scheme 3.83). PdCl2(dppf)· CH2Cl2 (9 mol%) MeCO(CH2)4BF3K

MeCO

OTf

CO2Et TfO

BzO(CH2)6BF3K

Cs2CO3 (3 equiv.) THF:H2O, reflux 18h

MeCO

(CH2)4OCMe 79 % CO2Et

PdCl2(dppf)· CH2Cl2 (9 mol%) Cs2CO3 (3 equiv.) THF:H2O, reflux 18h

BzO

6

68 %

Scheme 3.83 Suzuki cross-coupling reactions of functionalized alkyl trifluoroborates with triflates.

3.7.4 Silver(I)-promoted Suzuki Cross-coupling of Functionalized n-Alkyl Boronic Acids

n-Alkyl boronic acids are shown to be less reactive in Suzuki±Miyaura cross-coupling reactions resulting in poor yields even under forcing conditions. Falck has shown that Ag(I)-salts significantly enhance Suzuki±Miyaura coupling of n-alkyl boronic acids and a variety of functional groups are tolerated on the boronic acid moiety (Scheme 3.84) [129]. PdCl2(dppf) (0.1 equiv.) B(OH)2

Br

CO2Et

PdCl2(dppf) (0.1 equiv.) MeO2C

B(OH)2

I

OTBDPS

CO2Et

Ag2O, K2CO3 THF, 80 ºC

Ag2O, K2CO3 THF, 80 ºC

Scheme 3.84 Ag(I)-promoted Suzuki±Miyaura cross-coupling of functionalized n-alkylboronic acids.

77 %

MeO2C

OTBDPS 5

4

90 %


95

3.7.5 Alkyl-Alkyl Suzuki Cross-coupling of Functionalized Alkyl Boranes with Alkyl Bromides, Chlorides and Tosylates

Fu has developed an efficient cross-coupling of primary alkyl bromides (Eq. 1), [130] chlorides (Eq. 2) [131] and tosylates (Eq. 3) [132] with functionalized alkyl boranes. The catalytic species are generated from Pd(OAc)2 or [Pd2(dba)3] and PCy3 (for coupling of bromo and chloro alkanes). In the case of alkyl tosylates, Pd(OAc)2 and Pt-Bu2Me gives the best results. This process takes advantage of the high tolerance of organoboron derivatives with most functional groups that makes this reaction a powerful synthetic tool (Scheme 3.85) [133].

NC-(CH2)6-Br

MeO2C(CH2)10(9-BBN) (1.2 equiv.)

t-BuCO2(CH2)6-Cl

BnO(CH2)5(9-BBN)

Pd(OAc)2 (4 mol%) PCy3 (8 mol%) K3PO4· H2O (1.2 equiv.) THF, 25 ºC Pd2(dba)3 (5 mol%) PCy3 (20 mol%) CsOH·H2O (1.1 equiv.) dioxane, 90 ºC

MeO2C(CH2)16CN 81 %

(eq.1)

BnO(CH2)11t-BuCO2 65 %

(eq.2)

Pd(OAc)2 (4 mol%) PtBu2Me (16 mol%) MeCO(CH2)6OTs

TESO(CH2)11(9-BBN)

NaOH (1.2 equiv.) dioxane, 50 ºC

TESO(CH2)17COMe 55 %

Scheme 3.85 Alkyl-alkyl Suzuki cross-coupling of functionalized alkylboranes with functionalized alkyl bromides, chlorides and tosylates.

3.7.6 Synthesis of Natural and Unnatural Amino Acids via B-alkyl Suzuki Coupling of Functionalized Alkyl Boranes

Functionalized organoboron reagents of type 150, which are readily available from serine via hydroboration of alkenes 151, undergo efficient Suzuki-coupling reactions under mild conditions with a range of aryl and alkenyl halides [134]. These adducts 152 are easily transformed into a variety of known and novel nonproteinogenic N-protected amino acids via a one-pot hydrolysis-oxidation procedure leading to amino acid derivatives such as 153. The methodology has been extended for the synthesis of R,R-diaminopimelic acid (DAP) and R,R-2,7-diaminosuberic acid (DAS) in enantiopure form (Scheme 3.86).

(eq.3)


96

OMe

9-BBN Boc

9-BBN-H

N O

Boc

THF

O

151 CO2Me NHBoc Br O

K3PO4 (3M) THF:DMF

1) Jones reagent (1M)

N

2) CH2N2 or TMSCHN2

O

BocHN

152: 71 %

150

9-BBN

BocN

N

4-MeOC6H4I PdCl2(dppf)·CHCl3 Boc (5 mol%)

OMe

CO2Me

153: 54 %

CO2Me

NH2

NHBoc

PdCl2(dppf)·CHCl3 K3PO4 (3M)

CO2H

THF:DMF BocN

H2N O

76 %

CO2H

R, R-DAP

Scheme 3.86 Application of B-alkyl Suzuki cross-coupling for the synthesis of natural and unnatural amino acids.

3.7.7 Application of Intermolecular B-alkyl Suzuki Cross-coupling of Functionalized Alkyl Boranes in Natural Product Synthesis

Glycals are versatile readily available synthetic intermediates with a wide range of application in the synthesis of carbohydrate analogs, C-aryl glycosides and a variety of other natural products. A flexible efficient method for converting glycals to C1-alkyl glycals using a B-alkyl Suzuki±Miyaura cross-coupling has been reported [135]. This method provides access to a range of C1-substituted glycals that are not available by direct alkylation of C1-lithio glycals by utilizing a number of functionalized olefins and glycal coupling partners. It has further been shown that commonly observed side reactions involving reduction of halide coupling partners during B-alkyl Suzuki couplings can be suppressed by preincubation of the borane coupling partner with aqueous NaOH prior to addition to the C1-iodo glycals such as 151 and to the Pd-catalyst leading to polyfunctional products such as 152 (Scheme 3.87).


CO2Bn TIPSO

O

I

TIPSO OTIPS 151

NHFmoc

TIPSO

1) 9-BBN, THF, rt 2) 1N NaOH (3 equiv.) 3) Pd(dppf)Cl2 (20 mol%) THF, H2O, rt

O

CO2Bn NHFmoc

TIPSO OTIPS

152: 95 %

Scheme 3.87 Synthesis of polyfunctional glycals.

Polyhydroxy piperidines and related azasugars are known to be potent inhibitors of oligosaccharide-processing enzymes called glycosidases and glycosyl transferases, therefore these class of compounds has received considerable attention. Johnson has developed the synthesis of linked azasugars, a novel class of glycomimetic compounds, involving B-alkyl Suzuki coupling as the key step [136,137]. Thus, Suzuki coupling of the cycloalkenyl bromide intermediate 153 with alkyl boranes derived via hydroboration from olefinated carbohydrate precursors such as 154 was used to form the C-glycoside bond. The azasugar ring of 155 was obtained by subsequent ozonolysis of the coupled products 156 and selective reduction of the resultant carbonyl function. The fully deprotected azasugars were obtained upon acid deprotection (Scheme 3.88).

MOMO

OMOM OMOM O

MOMO

O O

1) 9-BBN-H, THF 2) PdCl2(dppf), K3PO4, DMF Br O

O

154

MOMO O

ZHN

OTBS 153 HO 1) O3, DMS 2) NaBH3CN, pH 4 buffer, THF

OH OH N H·HCl OH 9·HCl

O HO

OH OH 155: 68 %

Scheme 3.88 Synthesis of azasugars.

NHZ OMOM OMOM OMOM 156: 73 %

HO

3) Pd/C, 40 psi H2, MeOH 4) 6 N HCl, MeOH

OTBS

97

98


B-alkyl Suzuki-coupling strategy for elongation of unsaturated side chains has been used as the key step in the synthesis of marine alkaloid (+)-halichlorine [138,139] and the related marine natural product pinnaic acid, [140,141] an inhibitor of cytosolic phospholipase A2. Thus, the hydroboration of the common protected aminoalkene precursor 157 followed by Pd-mediated Suzuki coupling with iododienoic acid ester (158) afforded compound 159 that was converted into pinnaic acid in several steps (Scheme 3.89). CO2Et Me

BocHN Me

H

TBDPSO

1) 9-BBN-H, THF Me 2) I CO2Et 158 PdCl2(dppf)· CH2Cl2 AsPh3, Cs2CO3, DMF H2O

BocHN Me

H

TBDPSO

157

159: 75 %

Scheme 3.89 Synthesis of advanced intermediates of pinnaic acid.

The B-alkyl Suzuki coupling reactions are used extensively in the synthesis of the anticancer agents epothilone A, B, and F [142]. In the earlier approaches, [143] alkenyl iodide 160 was coupled with organoborane derived from the alkene 161a. Zhu [144] has applied a closely related reaction using intermediate 161b in the preparation of epothilone A. In the subsequent synthesis, Danishefsky has used a more elaborate and sensitive substrate, i.e. b-ketoester 162 as the olefinic coupling partner [145]. Thus, the coupling of iodide 160 in the presence of a Pd-catalyst afforded 163 in 65% yield after acidic work-up while the ester functionality and the two carbonyl groups remains unaffected under these conditions. Recently, Danishefsky and coworkers [146,147] and other groups [148] have utilized the C1± C11 olefinic coupling partner 164 with a protected OH group in 3-position of desoxyepothilone F and B, the corresponding 26-(1,3-dioxanyl) derivative in the synthesis of epothilone A (Scheme 3.90).

3.7 Synthesis and Reactions of Functionalized Alkyl Boron Derivates TrOCO

99

S N

TrocO

S

t-BuO

t-BuO OH O

O O

1) 9-BBN-H, THF 2) PdCl2(dppf)·CH2Cl2

N OTBS

AsPh3, CsCO3 THF:DMF

O OTroc

O

O OTroc

I 160

162

163: 65 % t-BuO

O OTES

Y X

3

OR1 OR

O OTroc

161a: X = Y = OMe; R1 = TPS; R = TBS 161b: X = H, Y = OTBS; R1 = TBS; R = Bn R2

S

164

S

S

R N

N

N O 1

O R1

O

O OH

13 12

R1

O

O OH

3

O

OH

26

O O OH

epothilone A, R = Me; R1 = H epothilone B, R = Me, R1 = Me epothilone F, R = CH2OH, R1 = Me

O OH R1 = CH3; R2 = OH (desoxyepothilone F)

O

O OH

26-(1,3-dioxolanyl)-12,13desoxyepothilone B

R1 = CH3, R2 = H (desoxyepothilone B)

Scheme 3.90 Synthesis of epithilones using Suzuki±Miyaura cross-couplings.

Sasaki has developed an efficient and practical methodology for the polycyclic ether framework present in marine natural products such as ciguatoxins, brevetoxins, etc., based on palladium-catalyzed B-alkyl Suzuki cross-coupling reactions of alkyl boranes with cyclic ketene acetal triflates or phosphates [149,150,151]. He reported the first total synthesis of (±)-gambierol [152], a marine polyether toxin isolated from Gambierdiscus toxicus involving convergent union of ABC and EFGH ring fragments 165 and 166 via a B-alkyl Suzuki coupling as the key step

100


leading to endocyclic enol ether 167 in high yield that was converted to (±)-gambierol through a series of transformations. The same group has reported [153] the synthesis of the FGH ring system of gambierol through PdCl2(dppf)-promoted room-temperature B-alkyl Suzuki coupling of the lactone derived enol phosphate 168 with 169 as the main step leading to the cross-coupling product 170 in 97% yield (Scheme 3.91). OBn Me Me O B A C O O H H H

BnO

H OPMB (PhO)2OPO

1) 9-BBN, THF 2) aq. Cs2CO3, PdCl2(dppf)·CH2Cl2 DMF, 50 ºC

165

OBn Me Me O

BnO

H

HO

H

BnO

A O

B H

H

H O

H O

H H

O

166

OPMB H O H F O G Me Me O H

C O

E

H O

H O

H H

O

167: 86 % OH Me Me H H O O H O H A B D C E H H F O O O O H H H H H Me G H Me O H GAMBIEROL OH Me

PO(OPh)2 H O O H

O F

BnO

O H F G Me O H

E O Me

O

1) 9-BBNH BnO Ph THF, rt

O H

OTBS

2) PdCl2(dppf) DMF, rt, 24 h aq. NaHCO3

168

169

H

TIPSO

O F

HO

Me

H

H

H O

H G O Me H

Scheme 3.91 Synthesis of gambierol.

O O H

H

O

H

H O H

F BnO

O Ph O H

OTBS 170: 97 %


101

Sasaki has also applied a B-alkyl Suzuki coupling for the preparation of fused polyethers in the convergent synthesis of ABCD ring fragment 171 of ciguatoxin [154,155], the causative toxin for ciguatera fish poisoning, via convergent union of the olefin 172 and the seven-membered lactone phosphate 173 through hydroboration and Pd-mediated C±C coupling leading to the cross-coupling product 174 in 97% yield. They further elaborated this methodology for the construction of the FGHIJKLM ring fragment of ciguatoxin on the basis of extensive use of B-alkyl Suzuki±Miyaura reaction (Scheme 3.92) [156]. MOMO

O (PhO)2PO

O B

OBn 1) 9-BBN THF, rt

O D

BnO

OBn

OTBS OBn 172

173

H A O

H

O B

H

H C O

O

H

O

BnO

OTBS OBn 174: 97 %

O

H O

PMP O H

171

Scheme 3.92 Synthesis of ciguatoxin.

Trost has utilized B-alkyl Suzuki coupling in an enantioselective total synthesis of sphingofungin E (175), an antifungal agent that blocks the biosynthesis of sphingolipids leading to apoptosis in both yeast and mammalian cells [157,158]. The strategy involves coupling of the polar head 176 and lipid tail unit 177. Thus, under palladium catalysis, the alkenyl iodide 176 smoothly reacted with B-alkylborane 177 to give the polyfunctional alkene 178 in excellent yield that was subsequently converted to sphingofungin E in several steps (Scheme 3.93).

O N

I O 176

9-BBN

Cs2CO3, DMF:THF:H2O rt, 2 h

4

OPMB 177 Ph

OPMB O H O

O

n-Hex

O

n-Hex O

PdCl2(dppf) (5 mol%) Ph3As (5 mol%)

Ph

OPMB O H

N

5

178: 92 %

OH OH n-Hex

CO2H 5

O

OPMB O

Scheme 3.93 Synthesis of sphingofungin E.

O

OBn OBn

2) Pd(PPh3)4 (10 mol%) aq. NaHCO3 (3 equiv.) DMF, 50 ºC

D

H H OTIPS

BnO

HO

175: sphingofungin E

NH2 OH

102


Although formation of five- and six-membered rings via intramolecular B-alkyl Suzuki coupling was reported to occur readily [159,160], the feasibility of this reaction for transannular macrocyclization as an effective method was demonstrated by Chemler and Danishefsky [161]. Regioselective terminal olefin hydroboration with 9-BBN-H followed by palladium-catalyzed intramolecular Suzuki reaction in the presence of base such as thallium ethoxide at high dilution generates macrocycles with high degree of olefin geometry control. Thus, isomerically pure E or Z alkenyl iodides of type 179 afford the macrocycles E-180 and Z-180 in high stereoselectivity and good yields. These reactions are complimentary to ring-closing metathesis macrocyclization and may prove superior in cases where control of olefin geometry is required (Scheme 3.94). I 1) 9-BBN (1.5 equiv.) THF, 23 ºC

TBSO MeO

Me OTBS

MeO

2) Pd(dppf)Cl2 (20 mol%) AsPh3 (20 mol%) TlOEt (3 equiv.) E-179

E-180: 60 %

TBSO I

MeO

1) 9-BBN (1.5 equiv.) THF, 23 ºC

Me

2) Pd(dppf)Cl2 (20 mol%) AsPh3 (20 mol%) TlOEt (3 equiv.)

Z-179

OTBS

MeO

Z-180: 46 %

Scheme 3.94 Macrocyclization via B-alkyl Suzuki-coupling.

An enantioselective total synthesis of (+)-phomactin A (181) has been recently reported by Halcomb using intramolecular Suzuki coupling of a B-alkyl-9-BBN derivative to prepare the macrocycle in the final step [162,163]. Thus, a regioselective hydroboration of the terminal olefin in the precursor 182 gave an internal alkylborane that was cyclized using modification of Johnson¢s conditions [164]. The reaction illustrates the mildness of the Suzuki reaction since the coupling was carried out in the presence of the sensitive dihydrofuran ring (Scheme 3.95).

Me

O OTMS OTES

Me

O

Me H Me

1) 9-BBN, THF, 40 ºC then Pd(dppf)Cl2 AsPh3, Tl2CO3 THF:DMF:H2O (6:3:1), rt 2) TBAF

Me

O OH OH

Me

O

Me H Me

I 182

Scheme 3.95 Synthesis of (+)-phomactin A.

181: (+)-phomactin A: 29 %


103

An intramolecular B-alkyl Suzuki coupling has been used to construct the core macrocyclic structure of benzolactone enamide salicylhalamide A [165]. Thus, diastereoselective hydroboration of acyclic alkenyl iodide 183 with (dppf)PdCl2 catalyst/NaOH gave the macrocyclic lactone 184 in 48% yield. Because of the high dilution, a large amount of catalyst (20 mol%) was used. The steric hindrance at the ester group probably retards the cleavage of the lactone under basic conditions (Scheme 3.96). OPMB

OMe O

1) 9-BBN, THF (5 equiv.) 2) Pd(dppf)Cl2 (20 mol%)

OMOM

O

OPMB

OMe O

OMOM

O

C6H6:H2O, NaOH 80 ºC, 12 h

I 183

Me 184: 48 %

H N O

OH O

OH

O

salicylhalamide A Me

Scheme 3.96 Synthesis of an advanced intermediate for the salicylhalamide A synthesis.

Xestocyclamine A, a polycyclic alkaloid isolated from xestospongia sp. is an inhibitor of PKCb and is of biomedical interest. During the course of the total synthesis of xestocyclamine A, Danishefsky has reported the elaboration of an ansa bridge using intramolecular B-alkyl Suzuki coupling as the key step. Thus, the intermediate 185 was obtained in 60% yield by regioselective hydroboration of 186 at the terminal alkenyl group followed by subsequent treatment with Pd(dppf)Cl2 catalyst in the presence of triphenylarsine and thallium carbonate as a base (Scheme 3.97) [166].

TBDPSO Ts

N O

HO H H

186

H

1) 9-BBN, THF, rt 2) H2O, rt

TBDPSO Ts

3) Pd(dppf)Cl2, AsPh3 Tl2CO3, THF:DMF

N

OH H

I N

N O

HO H H

H

N

185: 60 % N

xestocyclamine A Scheme 3.97 Macrocyclisation for the xestocyclamine A synthesis.

104


3.8 Conclusion

The chemistry of polyfunctional boronic esters has greatly been developed because of the multiple synthetic approaches to these molecules and their ability to participate in a variety of cross-coupling reactions. The high functional group compatibility and development of efficient cross-coupling procedures will certainly lead to further spectacular applications of boronic esters.

References 1 (a) A. Pelter, K. Smith, H. C. Brown,

Borane Reagents, Academic Press, New York, 1988; (b) D. S. Matteson, Stereodirected Synthesis with Organoboranes, Springer, New York, 1995; (c) V. Snieckus, Chem. Rev. 1990, 90, 879; (d) T. Ishiyama, N. Miyaura, J. Organomet. Chem. 2000, 611, 392; (e) E. Tyrell, P. Brookes, Synthesis 2003, 469; (f) T. Ishiyama, N. Miyaura, J. Organomet. Chem. 2003, 680, 3. 2 (a) A. Suzuki in Metal-Catalyzed CrossCoupling Reactions (Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998, pp. 49±97; (b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; (c) S. P. Stanforth, Tetrahedron 1998, 54, 263; (d) A. Suzuki, J. Organomet. Chem. 1999, 576, 147; (e) S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. 2001, 113, 4676; Angew. Chem. Int. Ed. 2001, 40, 4544; (f) A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350; Angew. Chem. Int. Ed. 2002, 41, 4176; (g) S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633; (h) A. Suzuki, J. Organomet. Chem. 2002, 653, 83; (i) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115, 5558; Angew. Chem. Int. Ed. 2003, 42, 5400. 3 S. Caron, J. M. Hawkins, J. Org. Chem. 1998, 63, 2054. 4 J. Kristensen, M. LysØn, P. Vedsù, M. Begtrup, Org. Lett. 2001, 3, 1435. 5 A. Brikh, C. Morin, J. Organomet. Chem. 1999, 581, 82. 6 J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon Press, Oxford 2002.

7 M. C. Whisler, S. MacNeil, V. Snieckus,

P. Beak, Angew. Chem. 2004, 116, 2256; Angew. Chem. Int. Ed. 2004, 43, 2206. 8 For a review, see: P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, V. A. Vuh, Angew. Chem. 2003, 115, 4438; Angew.Chem. Int. Ed. 2003, 42, 4302. 9 A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396; Angew. Chem. Int. Ed. 2004, 43, 3333. 10 O. Baron, A. Krasovskiy, T. Korn, P. Knochel, manuscript in preparation. 11 O. Baron, P. Knochel, Angew. Chem. Int. Ed. 2005, 44, 3133. 12 M. Murata, S. Watanabe, Y. Masuda, J. Org. Chem. 1997, 62, 6458. 13 M. Murata, T. Oyama, S. Watanabe, Y. Masuda, J. Org. Chem. 2000, 65, 164. 14 O. Baudoin, D. GuØnard, F. GuØritte, J. Org. Chem. 2000, 65, 9268. 15 C. Christophersen, M. Begtrup, S. Ebdrup, H. Petersen, P. Vedsù, J. Org. Chem. 2003, 68, 9513. 16 T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60, 7508. 17 T. Ishiyama, Y. Itoh, T. Kitano, N. Miyaura, Tetrahedron Lett. 1997, 38, 3447. 18 T. Ishiyama, K. Ishida, N. Miyaura, Tetrahedron 2001, 57, 9813. 19 A. Fürstner, G. Seidel, Org. Lett. 2002, 4, 541. 20 L. Zhu, J. Duquette, M. Zhang, J. Org. Chem. 2003, 68, 3729. 21 W. Ni, H. Fang, G. Springsteen, B. Wang, J. Org. Chem. 2004, 69, 1999.

References 22 H. Nakamura, M. Fujiwara,

Y. Yamamoto, J. Org. Chem. 1998, 63, 7529. 23 C. Malan, C. Morin, J. Org. Chem. 1998, 63, 8019. 24 For a review, see: T. Ishiyama, N. Miyaura, J. Organomet.Chem. 2003, 680, 3. 25 H. Chen, J. F. Hartwig, Angew. Chem. 1999, 111, 3597; Angew. Chem. Int. Ed. 1999, 38, 3391. 26 H. Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Science 2000, 287, 1995. 27 J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, Jr., M. R. Smith, III, Science 2002, 295, 305. 28 S. Shimada, A. S. Batsanov, J. A. K. Howard, T. B. Marder, Angew. Chem. 2001, 113, 2226; Angew. Chem Int. Ed. 2001, 40, 2168. 29 J.-Y. Cho, C. N. Iverson, M. R. Smith, III, J. Am. Chem. Soc. 2000, 122, 12868. 30 T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390. 31 T. Ishiyama, J. Takagi, J. F. Hartwig, N. Miyaura, Angew. Chem. 2002, 114, 3182; Angew. Chem. Int. Ed. 2002, 41, 3056. For a related reference with bipyridyl (bpy) ligand see: T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390. 32 J. Takagi, K. Sato, J. F. Hartwig, T. Ishiyama, N. Miyaura, Tetrahedron Lett. 2002, 43, 5649. 33 G. A. Molander, B. Biolatto, J. Org. Chem. 2003, 68, 4302. 34 G. A. Molander, B. Biolatto, Org. Lett. 2002, 4, 1867. 35 R. A. Batey, T. D. Quach, Tetrahedron Lett. 2001, 42, 9099. 36 H.-J. Frohn, N. Yu. Adonin, V. V. Bardin, V. F. Starichenko, Tetrahedron Lett. 2002, 43, 8111. 37 J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 9550. 37 A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110, 3586; Angew. Chem. Int. Ed. 1998, 37, 3387. 39 A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020.

40 A. N. Cammidge, K. V. L. CrØpy, J. Org.

Chem. 2003, 68, 6832.

41 A. Nadin, J. M. S. López, A. P. Owens,

D. M. Howells, A. C. Talbot, T. Harrison, J. Org. Chem. 2003, 68, 2844. 42 C.-y. Chen, P. Dageneau, E. J. J. Grabowski, R. Oballa, P. O'Shea, P. Prasit, J. Robichaud, R. Tillyer, X. Wang, J. Org. Chem. 2003, 68, 2633. 43 E. C. Western, J. R. Daft, E. M. Johnson, II, P. M. Gannett, K. H. Shaughnessy, J. Org. Chem. 2003, 68, 6767. 44 Y. Satoh, C. Gude, K. Chan, F. Firooznia, Tetrahedron Lett. 1997, 38, 7645. 45 F. Firooznia, C. Gude, K Chan, Y. Satoh, Tetrahedron Lett. 1998, 39, 3985. 46 F. Firooznia, C. Gude, K. Chan, N. Marcopulos, Y. Satoh, Tetrahedron Lett. 1999, 40, 213. 47 E. C. Gravett, P. J. Hilton, K. Jones, F. Romero, Tetrahedron Lett. 2001, 42, 9081. 48 A. Bouillon, A. S. Voisin, A. Robic, J.-C. Lancelot, V. Collot, S. Rault, J. Org. Chem. 2003, 68, 10178. 49 B. K. Albrecht, R. M. Williams, Org. Lett. 2003, 5, 197. 50 D. Ma, Q. Wu, Tetrahedron Lett. 2001, 42, 5279. 51 D. Ma, Q. Wu, Tetrahedron Lett. 2000, 41, 9089. 52 E. Vedejs, M. A. Zajac, Org. Lett. 2001, 3, 2451. 53 N. Yasuda, M. A. Huffmann, G.-J. Ho, L. C. Xavier, C. Yang, K. M. Emerson, F.-R. Tsay, Y. Li, M. H. Kress, D. L. Rieger, S. Karady, P. Sohar, N. L. Abramson, A. E. DeCamp, D. J. Mathre, A. W. Douglas, U.-H. Dolling, E. J. J. Grabowski, P. J. Reider, J. Org. Chem. 1998, 63, 5438. 54 S. Sakamuri, C. George, J. Flippen-Anderson, A. P. Kozikowski, Tetrahedron Lett. 2000, 41, 2055. 55 N. K. Garg, R. Sarpong, B. M. Stoltz, J. Am. Chem. Soc. 2002, 124, 13179. 56 A.-C. Carbonnelle, J. Zhu, Org. Lett. 2000, 2, 3477. 57 V. LobrØgat, G. Alcaraz, H. BienaymØ, M. Vaultier, Chem. Commun. 2001, 817. 58 M. Smet, B. Metten, W. Dehaen, Tetrahedron Lett. 2001, 42, 6527.

105

106

3 Functionalized Organoborane Derivatives in Organic Synthesis 59 S. V. Ley, A. W. Thomas, Angew. Chem.

Int. Ed. 2003, 42, 5400. 60 S. Yu, J. Saenz, J. K. Srirangam, J. Org. Chem. 2002, 67, 1699. 61 J. C. Antilla, S. L. Buchwald, Org. Lett. 2001, 3, 2077. 62 M. Sasaki, S. Dalili, A. K. Yudin, J. Org. Chem. 2003, 68, 2045. 63 H. M. Petrassi, K. B. Sharpless, J. W. Kelly, Org. Lett. 2001, 3, 139. 64 D.A. Evans, J. L. Katz, T. R. West, Tetrahedron Lett. 1998, 39, 2937. 65 C. P. Decicco, Y. Song, D. A. Evans, Org. Lett. 2001, 3, 1029. 66 D. A. Evans, J. L. Katz, G. S. Peterson, T. Hintermann, J. Am. Chem. Soc. 2001, 123, 12411. 67 P. S. Herradura, K. A. Pendola, R. K. Guy, Org. Lett. 2000, 2, 2019. 68 C. Savarin, J. Srogl, L. S. Liebeskind, Org. Lett. 2002, 4, 4309. 69 T. Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N. Miyaura, J. Org. Chem. 1998, 63, 4726. 70 N. A. Bumagin, D. N. Korolev, Tetrahedron Lett. 1999, 40, 3057. 71 L. J. Gooûen, K. Ghosh, Angew. Chem. 2001, 113, 3566; Angew. Chem. Int. Ed. 2001, 40, 3458. 72 L. J. Gooûen, Chem. Commun. 2001, 669. 73 R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem. 2003, 68, 6000. 74 Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai, N. Miyaura, J. Am. Chem. Soc. 1998, 120, 3379. 75 R. A. Batey, A. N. Thadani, D. V. Smil, Org. Lett. 1999, 1, 1683. 76 J. Ramnauth, O. Poulin, S. S. Bratovanov, S. Rakhit, S. P. Maddaford, Org. Lett. 2001, 3, 2571. 77 T. Senda, M. Ogasawara, T. Hayashi, J. Org. Chem. 2001, 66, 6852. 78 C. J. Chapman, K. J. Wadsworth, C. G. Frost, J. Organomet. Chem. 2003, 680, 206. 79 N. A. Petasis, A. Goodman, I. A. Zavialov, Tetrahedron Lett. 1997, 53, 16463. 80 For reaction of arylboronic acids with salicylaldehyde/amine: N. A. Petasis, S. Boral, Tetrahedron Lett. 2001, 42, 539. 81 N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1998, 120, 11798.

82 G. K. S. Prakash, M. Mandal,

S. Schweizer, N. A. Petasis, G. A. Olah, Org. Lett. 2000, 2, 3173. 83 G. K. S. Prakash, M. Mandal, S. Schweizer, N. A. Petasis, G. A. Olah, J. Org. Chem. 2002, 67, 3718. 84 R. H. Szumigala, P. N. Devine, D. R. Gauthier, R. P. Volante, J. Org. Chem. 2004, 69, 566. 85 C. Theibes, G. K. S. Prakash, N. A. Petasis, G. A. Olah, Synlett 1998, 141. 86 N. A. Petasis, I. A. Zavialov, Tetrahedron Lett. 1996, 37, 567. 87 J. Simon, S. Salzbrunn, G. K. S. Prakash, N. A; Petasis, G. A. Olah, J. Org. Chem. 2001, 66, 633. 88 For ipso-nitration of arylboronic acids, see: S. Salzbrunn, J. Simon, G. K. S. Prakash, N. A. Petasis, G. A. Olah, Synlett 2000, 1485. 89 B. Jiang, Q.-F. Wang, C.-G. Yang, M. Xu, Tetrahedron Lett. 2001, 42, 4083. 90 B. Witulski, N. Buschmann, U. Bergsträûer, Tetrahedron 2000, 56, 8473. 91 T. Konno, J. Chae, T. Tanaka, T. Ishihara, H. Yamanaka, Chem. Commun. 2004, 690. 92 I. Pergament, M. Srebnik, Org. Lett. 2001, 3, 217. 93 C. Morrill, R. H. Grubbs, J. Org. Chem. 2003, 68, 6031. 94 H. E. Blackwell, D. J. O'Leary, A. K. Chatterjee, R. A; Washenfeldes, D. A. Bussmann, R. H. Grubbs, J. Am. Chem. Soc. 2000, 122, 58. 95 J. T. Njardarson, K. Biswas, S. J. Danishefsky, Chem. Commun. 2002, 2759. 96 P. G. Garcia, E. Hohn, J. Pietruszka, J. Organomet. Chem. 2003, 680, 281. 97 G. A. Molander, C. R. Bernardi, J. Org. Chem. 2002, 67, 8424. 98 G. A. Molander, M. R. Rivero, Org. Lett. 2002, 4, 107. 99 A. B. Charette, A. Giroux, J. Org. Chem. 1996, 61, 8718. 100 A. B. Charette, R. P. De Freitas-Gil, Tetrahedron Lett. 1997, 38, 2809. 101 S. A. Frank, H. Chen, R. K. Kunz, J. Schnaderbeck, W. R. Roush, Org. Lett. 2000, 2, 2691.

References 102 K. A. Scheidt, A. Tasaka, T. D. Bannister,

M. D. Wendt, W. R. Roush, Angew. Chem. Int. Ed. 1999, 38, 1652. 103 J. D. White, R. Hanselmann, R. W. Jackson, W. J. Porter, Y. Ohba, T. Tiller, S. Wang, J. Org. Chem. 2001, 66, 5217. 104 J. T. Njardarson, K. Biswas, S. J. Danishefsky, Chem. Commun. 2002, 2759. 105 A. K. Chatterjee, R. H. Grubbs, Angew. Chem. Int. Ed. 2002, 41, 3172. 106 H. E. Blackwell, D. J. O'Leary, A. K. Chatterjee, R. A. Washenfelder, D. A. Bussmann, R. H. Grubbs, J. Am. Chem. Soc. 2000, 122, 58. 107 N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997, 119, 445. 108 N. A. Petasis, Z. D. Patel, Tetrahedron Lett. 2000, 41, 9607. 109 J. T. Njardarson, K. Biswas, S. J. Danishefsky, Chem. Commun. 2002, 2759. 110 R. A. Batey, D. B. Mackay, V. Santhakumar, J. Am. Chem. Soc. 1999, 121, 5075. 111 G. A. Molander, B. W. Katona, F. Machrouhi, J. Org. Chem. 2002, 67, 8416. 112 A.-S. Castanet, F. Colobert, T. Schlama, Org. Lett. 2000, 2, 3559. 113 C. H. Oh, S. H. Jung, Tetrahedron Lett. 2000, 41, 8513. 114 S. D. Goldberg, R. H. Grubbs, Angew. Chem. Int. Ed. 2002, 41, 807. 115 K. Takahashi, T. Ishiyama, N. Miyaura, Chem. Lett. 2000, 982. 116 K. Takahashi, T. Ishiyama, N. Miyaura, J. Organomet. Chem. 2001, 625, 47. 117 P. V. Ramachandran D. Pratihar, D. Biswas, A. Srivastava, M. V. R. Reddy, Org. Lett. 2004, 6, 481. 118 J. R. Falck, M. Bondlela, J. Ye, S.-D. Cho, Tetrahedron Lett. 1999, 40, 5647. 119 J. E. Luithle, J. Pietruszka, J. Org. Chem 1999, 64, 8287. 120 J. E. A. Luithle, J. Pietruszka, J. Org. Chem. 2000, 65, 9194. 121 A. Kamatani, L. E. Overman, J. Org. Chem. 1999, 64, 8743. 122 A. Kamatani, L. E. Overman, Org. Lett. 2001, 3, 1229.

123 H. Ito, H. Yamanaka, J.-I. Tateiwa,

A. Hosomi, Tetrahedron Lett. 2000, 41, 6821. 124 K. Takahashi, T. Ishiyama, N. Miyaura, Chem. Lett. 2000, 982. 125 K. Takahashi, T. Ishiyama, N. Miyaura, J. Organomet. Chem. 2001, 625, 47. 126 G. W. Kabalka, B. C. Das, S. Das, Tetrahedron Lett. 2001, 42, 7145. 127 G. A. Molander, C-S. Yun, M. Ribagorda, B. Biolatto, J. Org. Chem. 2003, 68, 5534. 128 G. A. Molander, T. Ito, Org. Lett. 2001, 3, 393. 129 G. Zou. Y. K. Reddy, J. R. Falck, Tetrahedron Lett. 2001, 42, 7213. 130 M. R. Netherton, C. Dai, K. Neuschütz, G.C. Fu, J. Am. Chem. Soc. 2001, 123, 10099. 131 J. H. Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 1945. 132 M. R. Netherton, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 3910. 133 D. J. Cardenas, Angew. Chem. Int. Ed. 2003, 42, 384. 134 P. N. Collier, A. D. Campbell, I. Patel, T. M. Raynham, R. J. K. Taylor, J. Org. Chem. 2002, 67, 1802; For similar synthesis of amino acids, see also: M. Sabat, C. R. Johnson, Org. Lett. 2000, 2, 1089. 135 J. S. Potuzak, D. S. Tan, Tetrahedron Lett. 2004, 45, 1797. 136 B. A. Johns, Y. T. Pan, A. D. Elbein, C. R. Johnson, J. Am. Chem. Soc. 1997, 119, 4856. 137 B. A. Johns, C. R. Johnson, Tetrahedron Lett. 1998, 39, 749. 138 D. Trauner, J. B. Schwarz, S. J. Danishefsky, Angew. Chem. Int. Ed. 1999, 38, 3542. 139 D. Trauner, S. J. Danishefsky, Tetrahedron Lett. 1999,40, 6513. 140 M. W. Carson, G. Kim, M. F. Hentemann, D. Trauner, S. J. Danishefsky, Angew Chem. Int. Ed. 2001, 40, 4450. 141 M. W. Carson, G. Kim, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4453. 142 A. Balog, C. Harris, K. Savin, X.-G. Zhang, T.-C. Chou, S. J. Danishefsky, Angew. Chem. Int. Ed. 1998, 37, 2675.

107

108

3 Functionalized Organoborane Derivatives in Organic Synthesis 143 D. Meng, P. Bertinato, A. Balog,

D.-S. Su, T. Kamenecka, E. J. Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073. 144 B. Zhu, J. S. Panek, Org. Lett. 2000, 2, 2575. 145 C. B. Lee, T. C. Chou, X.-G. Zhang, Z.-G. Wang, S. D. Kuduk, M. D. Chappell, S. J. Stachel, S. J. Danishefsky, J. Org. Chem. 2000, 65, 6525. 146 C. B. Lee, Z. Wu, F. Zhang, M. D. Chappell, S. J. Stachel, T. C. Chou, Y. Guan, S. J. Danishefsky, J. Am. Chem. Soc. 2001, 123, 5249. 147 M. D. Chappell, C. R. Harris, S. D. Kuduk, A. Balog, Z. Wu, F. Zhang, C. B. Lee, S. J. Stachel, S. J. Danishefsky, T.-C. Chou, Y. Guan, J. Org. Chem. 2002, 67, 7730. 148 K.-H. Altmann, G. Bold, G. Caravatti, D. Denni, A. Flörsheimer, A. Schmidt, G. Rihs, M. Wartmann, Helv. Chim. Acta 2002, 85, 4086. 149 M. Sasaki, H. Fuwa, M. Inoue, K. Tachibana, Tetrahedron Lett. 1998, 39, 9027. 150 M. Sasaki, K. Noguchi, H. Fuwa, K. Tachibana, Tetrahedron Lett. 2000, 41, 1425. 151 M. Sasaki, C. Tsukano, K. Tachibana, Org. Lett. 2002, 4, 1747.

152 H. Fuwa, N. Kainuma, K. Tachibana,

M. Sasaki, J. Am. Chem. Soc. 2002, 124, 14983. 153 H. Fuwa, M. Sasaki, K. Tachibana, Tetrahedron Lett. 2000, 41, 8371. 154 M. Sasaki, M. Ishikawa, H. Fuwa, K. Tachibana, Tetrahedron 2002, 58, 1889. 155 M. Sasaki, H. Fuwa, M. Ishikawa, K. Tachibana, Org. Lett. 1999, 1, 1075. 156 H. Takakura, M. Sasaki, S. Honda, K. Tachibana, Org. Lett. 2002, 4, 2771. 157 B. M. Trost, C. Lee, J. Am. Chem. Soc. 2001, 123, 12191. 158 B. M. Trost, C. H. Lee, J. Am. Chem. Soc. 1998, 120, 6818. 159 N. Miyaura, M. Ishikawa, A. Suzuki, Tetrahedron Lett. 1992, 33, 2571. 160 J. A. Soderquist, G. Leon, J. C. Coleberg, I. Martinez, Tetrahedron Lett. 1995, 36, 3119. 161 S. R. Chemler, S. J. Danishefsky, Org. Lett. 2000, 2, 2695. 162 P. J. Mohr, R. L. Halcomb, J. Am. Chem. Soc. 2003, 125, 1712. 163 N. C. Kallan, R. L. Halcomb, Org. Lett. 2000, 2, 2687. 164 C. R. Johnson, M. P. Braun, J. Am. Chem. Soc. 1993, 115, 11014. 165 M. Bauer, M. E. Maier, Org. Lett. 2002, 4, 2205. 166 A. Gagnon, S. J. Danishefsky, J. Angew. Chem. Int. Ed. 2002, 41, 1581.

109

4 Polyfunctional Magnesium Organometallics for Organic Synthesis Paul Knochel, Arkady Krasovskiy, and Ioannis Sapountzis

4.1 Introduction

Since their discovery at the beginning of the last century by Victor Grignard, [1] organomagnesium reagents have played a pivotal role in synthetic organic and organometallic chemistry. This pioneering work was honored 1912 with the Nobel Price ± ªfor the discovery of the so-called Grignard reagent, which in recent years has greatly advanced the progress of organic chemistryº ± and this statement still holds true today. Their easy synthesis, good stability and their excellent reactivity towards a wide range of different electrophiles made Grignard reagents one of the most powerful means for carbon±carbon bond formation used by generations of chemists. Furthermore, organomagnesium reagents have found numerous applications in industrial processes and a variety of these organometallics have become commercially available. Besides their use in nucleophilic addition or substitution reactions, Grignard reagents can act as a base, transfer an electron in a single-electron transfer processes (SET) to other organic molecules or generate another Grignard reagent in a halogen±magnesium exchange reaction. The capability of organomagnesium reagents to undergo transmetallation reactions with a variety of main group- and transition-metal salts, particularly to organocopper reagents, [2] opened new synthetic avenues in organic chemistry. In addition, the work of Kharasch [3] and later, the nickel-catalysis of Kumada [4] as well as Corriu [5] are often regarded as the first reactions of modern cross-coupling chemistry [6,7,8]. Several comprehensive reviews and books have been published, encompassing the preparation and use of Grignard reagents [9] as well as the chemical and physical properties, [10] mechanistic investigations of the formation [11] and studies of the structures in solution and in solid state [10d,12]. In this chapter, we will focus on the formation of functionalized alkyl-, alkenyl-, aryland heteroaryl-magnesium halides and describe the scope and limitations of their applications in carbon±carbon and carbon±heteroatom bond forming reactions [13]. Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

110

4 Polyfunctional Magnesium Organometallics for Organic Synthesis

Where possible we will try to point out the advantages of Grignard reagents and compare them to other organometallics. A separate section will deal with recent developments in transition-metal-catalyzed reactions, where Grignard reagents again occupy a central position, especially in the interesting field of iron-catalyzed reactions.

4.2 Methods of Preparation of Grignard Reagents and their Uncatalyzed Reactions 4.2.1 Direct Oxidative Addition of Magnesium to Organic Halides

Grignard reagents are sensitive to air and moisture. An inert atmosphere is therefore always advantageous for their preparation and further reactions. The usual method used for the preparation of organomagnesium reagents is the reaction of organic halides with magnesium metal in a polar, aprotic solvent like THF or diethyl ether (Scheme 4.1, Eq. 1). For large-scale industrial process, [14] these volatile and highly flammable ethers represent safety hazards and can be substituted by ªbutyl diglymeº (C4H9OC2H4OC4H9) that possesses a high flashpoint (118 C) and a low water solubility. RX

2 RMgX

Mg THF or Et2O

RMgX

R2Mg

(1)

+

MgX2

(2)

Scheme 4.1 Synthesis of Grignard reagents by oxidative addition (Eq. 1) and Schlenk equilibrium (Eq. 2).

Magnesium turnings or powder are usually covered with a small amount of solvent and to this suspension a solution of the organic halide is added. This reaction is exothermic and cooling is often necessary after the induction period. The magnesium metal is, as received or after exposure to air, covered with an ªoxideº layer (mainly Mg(OH)2), [11e] that passivates the metal. This ªoxideº layer is responsible for the induction period that is normally observed in the synthesis of Grignard reagents. An activation with the promoter 1,2-dibromoethane can help to reduce this induction time. 1,2-Dibromoethane reacts with magnesium to ethene and MgBr2. It also accelerates the formation of the Grignard reagent, leading to an activated magnesium metal surface [15]. The mechanism of this reaction is not yet fully clarified, but a radical mechanism is generally accepted [11,16]. In solution, a Grignard reagent (RMgX) is in equilibrium (so-called Schlenk equilibrium, Scheme 4.1, Eq. 2) with R2Mg and MgX2, depending on temperature, solvent and the anion X. This equilibrium can be shifted to the right side, by pouring a solution of RMgX into dioxane, which does not dissolve MgX2, leaving R2Mg in solution. Most Grignard reagents (RMgX) or diorganomagnesium compounds

4.2 Methods of Preparation of Grignard Reagents and their Uncatalyzed Reactions

crystallize with four-coordinated Mg in a distorted tetrahedron, but if the ligands can fit, five- (CH3MgBr in THF) and six- (MgBr2 in THF) coordinated structures can be observed [17]. All experimental evidence indicates similar coordination numbers in solution, emphasizing the role of coordinating etheral solvents in Grignard reagents. The presence of sensitive functional groups makes the preparation of Grignard reagents more complicated and many functional groups are not tolerated with this insertion method. If, however, the direct oxidative addition is conducted at * low temperatures with activated metals, such as Rieke magnesium (Mg ), the preparation of functionalized Grignard reagents is possible, but generally still shows limitations for the functional-group tolerance (Scheme 4.2) [18]. CO2tBu

THF, -78 ºC 2) PhCHO

Br

CN Br

CO2tBu

1) Mg* Ph OH

CN

1) Mg* THF, -78 ºC 2) PhCOCl CuI (cat)

86%

Ph O

62%

Scheme 4.2 Preparation of functionalized Grignard reagents using Rieke-magnesium (Mg*).

These Grignard reagents could be trapped directly with benzaldehyde or in the presence of a catalytic amount of CuI (10 mol%) reacted with benzoyl chloride. 4.2.2 Metalation Reactions with Magnesium Amides

The direct deprotonation of organic molecules with kinetically poor bases, such as organolithium or magnesium compounds is limited. However, the addition of amines or the presence of directing groups, breaking the aggregation of these reagents can lower this barrier. Indeed, various alkyllithiums or lithium dialkylamides have been used for the directed ortho-metallation and metallation of aromatic and heteroaromatic compounds [19]. The major drawback of these lithium reagents is the high reactivity towards electrophilic groups excluding the presence of many sensitive functionalities. In comparison to their lithium counterparts, the use of magnesium dialkylamides or Grignard reagents in metallation reactions has received little attention. The direct metallation of organic substrates with alkylmagnesium halides requires a greater kinetic acidity for the C±H bond than for the conjugated acid of the Grignard reagent. Strongly coordinating solvents like HMPT help to promote these reactions. One of the major applications is the metallation of acetylene derivatives, like the monometallation of acetylene by nBuMgCl to form ethynylmagnesium chloride [20].

111

112


Unlike to their lithium analogues, Hauser bases (R2NMgBr) are much more stable in THF (up to reflux conditions). Eaton reported in 1989 the use of magnesium bis(2,2,6,6-tetramethylpiperamide), (TMP)2Mg, as a selective metalating reagent (Scheme 4.3) [21]. CO2Me

(TMP)2Mg THF, rt, 45 min

CO2Me

CO2Me

1) CO2

MgTMP

2) CH2N2

CO2Me 81%

Scheme 4.3 Selective ortho-magnesiation of methyl benzoate.

Of special interest is the ease with which ortho-magnesiation reactions can be accomplished in the presence of an ester function, which is normally susceptible to nucleophilic attack using conventional Li-based reagents [22]. This methodology was applied to the deprotonation of cyclopropylamides [23] as well as to numerous heterocycles (Scheme 4.4) [24]. O S

O

1) iPr2NMgCl THF, rt, 10 min 2) PhCHO

O S

O

OH Ph

1

2: 60%

Me

Me

Me

N SO2Ph

iPr2NMgCl THF, rt

3 SO2Ph N

MgNiPr2 N SO2Ph

PhCHO THF, rt

1) iPrMgCl (3 equiv.) 5 mol% iPr2NH THF, rt, 10 min 2) allyl bromide

4

OH N Ph SO2Ph 5: 80%

SO2Ph N

6: 52%

Scheme 4.4 Selective ortho-magnesiation of heterocycles 1,3 and 4.

Thus, ethyl thiophene-2-carboxylate (1) is selectively metalated in the 5-position using iPr2NMgCl, readily prepared from nBuMgCl and iPr2NH, and afterwards reacts with benzaldehyde furnishing 2 in 60% yield (Scheme 4.4). Nitrogen-heterocycles, such as indole 3 and pyrrole 4 undergo a metallation reaction as well, leading, for example, to the magnesiated intermediates, which can react with a variety of electrophiles, leading to the functionalized heterocycles 5 and 6 in 80% and 52% yield, respectively. In the case of the N-phenylsulfonylpyrrole (4) it turns


out that a catalytic amount of iPr2NH is sufficient to accelerate the deprotonation reaction. In addition, magnesium bisamides are used for the regio- and stereoselective formation of enolates [25] and the use of optically pure magnesium amides opens the field of asymmetric synthesis to this versatile substance class [26]. 4.2.3 The Halogen±Magnesium Exchange Reaction

The halogen±lithium exchange reaction discovered by Wittig [27] and Gilman [28] allows the preparation of a broad range of organolithium compounds and has become one of the most important ways for the preparation of aromatic, heteroaromatic and alkenyl lithium compounds, starting from the commercially available alkyllithium reagents and the corresponding organic halides, mainly bromides and iodides [29]. Although this reaction is very fast and normally proceeds at low temperatures (typically ±78 C) the functional-group tolerance is only moderate. In contrast, the halogen±magnesium exchange has been found to be the method of choice for preparing new functionalized organomagnesium reagents of considerable synthetic utility. The major reason for this great functional-group tolerance of Grignard reagents is that the reactivity of carbon±magnesium bonds is strongly dependent on the reaction temperature. Only reactive electrophiles like aldehydes and most ketones react rapidly at temperatures below 0 C. Performing the halogen±magnesium exchange at temperatures below 0 C has therefore the potential for the preparation of magnesium organometallics bearing reactive and sensitive functional groups.

4.2.3.1 Early Studies The first example of a bromine±magnesium exchange reaction was briefly reported in 1931 by PrØvost [30]. Thus, the reaction of cinnamyl bromide 7 with EtMgBr furnished cinnamylmagnesium bromide 8 although only in modest yield (Scheme 4.5). Similarly, Urion reported the preparation of cyclohexylmagnesium bromide 9 via a Br/Mg-exchange [31]. Br

MgBr

EtMgBr

7

EtBr

8: 14% Br

MgBr EtMgBr

EtBr 9: 12%

Scheme 4.5 First examples of a bromine±magnesium exchange.

113

114


The halogen±magnesium exchange is an equilibrium process favoring the formation of the most stable organomagnesium compound. To shift this equilibrium to the desired side, the resulting organomagnesium species has to be more stable 2 2 than the Grignard reagent used for the exchange reaction (sp>sp (vinyl)>sp (ar3 3 yl)>sp (prim.)>sp (sec.)). Although the mechanism of the exchange reaction is not fully clarified, a halogen-ate complex is believed to be an intermediate, as proposed for the halogen±lithium exchange [32]. One of the first synthetically useful procedures, employing a halogen±magnesium exchange reaction, was reported by McBee and coworkers who were successful in preparing perfluoroalkylmagnesium halides of type 10 starting from the perfluorinated iodide 11 and phenylmagnesium bromide (Scheme 4.6) [33]. O C3F7 I 11

PhMgBr Et2O, 15 min -40 to -50 ºC

OH C3F7

C3F7 MgBr + Ph–I 10

90%

Scheme 4.6 Synthesis and reaction of heptafluoropropylmagnesium bromide (10).

This procedure had significant advantages compared to the oxidative addition, such as higher yields or less side reactions and is still one of the best methods for the synthesis of perfluorinated Grignard reagents [34]. The halogen±magnesium exchange reaction was later used by VilliØras, who developed a general approach to magnesium carbenoids [35]. He showed, that the reaction of iPrMgCl with CHBr3 at ±78 C furnishes the corresponding magnesium carbenoid 12 that could be trapped with chlorotrimethylsilane leading to product 13 in 90% yield (Scheme 4.7). This pioneering work paved the way to the systematic study of magnesium carbenoids [36] demonstrating that the halogen± magnesium exchange rate is enhanced by the presence of electronegative substituents. CHBr3

iPrMgCl –78 ºC

CHBr2MgCl 12

iPrBr

Me3SiCl

CHBr2SiMe3 13: 90%

Scheme 4.7 Preparation of magnesium carbenoid 12 via bromine±magnesium exchange.

This behavior was confirmed a few years later by the work of Tamborski who showed that the electronic properties of both, the halogen atom and the organic molecule play an important role in the formation rate of the new Grignard reagent [37]. Only for very electron-poor systems, such as the tetra- or pentafluorobenzenes, was the exchange of a chlorine possible, requiring elevated temperatures and longer reaction times then for the corresponding bromines and iodines. The reactivity order (I>Br>Cl>>F) is influenced by the bond-strength, the electronegativity and the ease of polarizability of the halide. For these reasons, aryl iodides are usually used as starting materials, although the use of bromides would be advan-


tageous from an economical point of view. For instance, the exchange reaction of 1-chloro-2,3,4,5,6-tetrafluorobenzene (14a) with EtMgBr, requires 1 h at room temperature to reach complete conversion to the Grignard reagent, whereas the corresponding bromo- and iodo-congeners 14b and 14c react already at 0 C within 1 min to compound 15 (Scheme 4.8). F

F

F

F

EtMgBr F

X F

F

F

14a: X=Cl 14b: X=Br 14c: X=I

MgBr F

F

F 15

Br F

MgBr

F X=Cl; rt, 1 h X=Br; 0 ºC, 1 min X=I; 0 ºC, 1 min

F

EtMgBr -78 ºC, 15 min

F

F

F

F

Br

MgBr

16

17: 93 %

Scheme 4.8 Preparation of polyhalogenated Grignard reagents 15 and 17.

It was shown that 1,4-dibromo-2,3,5,6-tetrafluorobenzene (16) is readily converted to the corresponding 1,4-dimagnesium species 17 with EtMgBr (Scheme 4.8). Similarly, Furukawa showed that 2-iodopyridine leads to the corresponding Grignard reagent within 0.5 h by reaction with EtMgBr at 25 C [38]. These early results indicate the synthetic potential of the halogen±magnesium exchange reaction and recent developments will be discussed in the following chapters [39].

4.2.3.2 The Preparation of Functionalized Arylmagnesium Reagents Functionalized aryl iodides react readily with iPrMgBr or iPrMgCl in THF below 0 C leading to a range of functionalized arylmagnesium iodides [40]. Sensitive carbonyl group derivatives like nitriles, esters or amides are well tolerated. Typically, the treatment of methyl 4-iodobenzoate (18) with iPrMgBr in THF at ±20 C for 30 min produces the functionalized Grignard reagent 19, which is stable for several hours below 0 C and reacts smoothly with aldehydes at ±20 C leading to the expected alcohols 20a and b in 72±83% yield (Scheme 4.9) [41]. Aromatic iodides bearing electron-donating groups, such as compound 21, undergo the iodine±magnesium exchange as well, but usually higher temperatures (25 C) and elongated reaction times are necessary [40,42]. The addition of the resulting arylmagnesium species to diethyl N-Boc-iminomalonate 22 [43] furnishes adduct 23 in 79% yield. Saponification followed by decarboxylation leads to a-amino-acid 24 in 81% yield (Scheme 4.10) [42].

115

116

4 Polyfunctional Magnesium Organometallics for Organic Synthesis OH CHO I

MgBr

MeO2C

NC

iPrMgBr

CN 20a: 83 %

-20 ºC, 0.5 h

THF, –20 ºC

OH

CO2Me

CO2Me

18

19

c-HexCHO -20 ºC, 0.5 h

c-Hex MeO2C

20b: 72 %

Scheme 4.9 The reaction of ester containing arylmagnesium reagent 19 with aldehydes.

I

H2N 1) iPrMgBr THF, 25 ºC, 1 h 2) EtO2C

OMe 21

EtO2C

22 N Boc

-78 ºC, 1 h 3) HCl, ether, rt OTBS

I OMe

TMS

H2 N

CO2H

2) 1N HCl 50 ºC, 15 min OMe

OMe

23: 79 %

24: 81 %

1) iPrMgCl

MeO MeO

CO2Et CO2Et 1) 2N LiOH THF, rt, 2 h

THF, -25 ºC 2) O O O

OTBS MeO

25

TMS

O

MeO OMe HO

O

26: 56 %

Scheme 4.10 Reactions of electron-rich arylmagnesium reagents.

Schmalz showed in their synthesis of colchicine, [44] that even building block 25, possessing a very electron-rich aromatic system with three methoxy groups and an additional alkyl chain, undergoes an I/Mg exchange reaction under very mild conditions. Thus, the addition of iPrMgCl at ±25 C furnishes the magnesiated intermediate that reacts with succinic anhydride leading to compound 26 in 56% yield (Scheme 4.10). As already mentioned, the use of bromides would be advantageous, but the Br/Mg-exchange reaction is significantly slower than the I/Mg-exchange. Using iPrMgCl or iPrMgBr, the exchange is sufficiently fast below 0 C only for systems bearing electron-withdrawing groups [45,46]. A few further examples are reported in the literature, where aryl bromides are used as starting materials. For example, Leazer from Merck Process Research (USA) found the Br/Mgexchange reaction the most reliable and safe method for the preparation of Grignard reagent 27, a valuable building block for the synthesis of a new neurokin 1 receptor agonist (Scheme 4.11) [47]. It is known, that trifluoromethylphenyl


117

Grignard reagents and some polyhalogenated Grignard reagents can detonate at high temperatures like their lithium counterparts [48]. This makes a low-temperature process more eligible for this potent substance class, frequently encountered in pharmaceutical drugs and synthetic intermediates. O F3C

Br

iPrMgBr

F3C

MgBr

THF, 0 ºC, >

CO2Me R

PhMe2Si H

O

H 42

Scheme 5.10 Diastereo- and enantioselective synthesis of dihydropyrans.

179

180

5 Polyfunctional Silicon Organometallics for Organic Synthesis

5.2.3 Tandem Reactions of Polyfunctional Allylic Silanes

Allylic silanes having a functional group at the b-carbon are extremely versatile synthetic reagents. For example, (2-trimethylsiloxy)allylsilane 43 behaves as an acetone a,a¢-dianion equivalent as is evidenced by the reaction with acetals or aldehydes in the presence of titanium tetrachloride. Double C±C bond formation readily takes place to give rise to b,b¢-dioxygenated ketone 44 (Scheme 5.11) [18]. From a mechanistic point of view, the reagent is working as a double silyl enol ether rather than an allylsilane. OMe

OSiMe3

TiCl4 (4 eq)

+

SiMe3

CH2Cl2 -78 to 0 ºC 88%

OMe

43

(4 eq)

≡ MeO

O

O

OMe

44

Scheme 5.11 Double condensation reaction of 43. H + O

BF3•OEt2 2,6-di-tert-butylpyridine

SiMe3 O

O

CH2Cl2, -78 ºC (CH2)2OSi(iPr)3

(CH2)2OBn 45

46

"cyclization"

SiMe3 O

OH

O

(CH2)2OBn

78% yield (5.5 : 1 at C9)

(CH2)2OSi(iPr)3 47

9 O

OH

OH

(CH2)2OBn

O

O

O

(CH2)2OSi(iPr)3 48

O iPr

Scheme 5.12 Tandem aldol±Prins cyclization.

OMe O

leucascandrolide A macrolide

5.2 Allylic Silanes

Although alkyl enol ethers often undergo oligomerization under electrophilic conditions due to extremely reactive oxocarbenium ion intermediates, intramolecular trapping by an allylsilane moiety of such reactive species leads to an extremely versatile strategy. Aldol-type reaction of aldehyde 45 with allylic silane enol ether 46 is catalyzed by BF3.OEt2 to generate oxonium ion 47, which stereoselectively undergoes cyclization through intramolecular allylation to produce cis2,6-disubstituted tetrahydropyran 48 (Scheme 5.12) [19]. The synthetic utility of this method is demonstrated by a formal total synthesis of leucascandrolide A. The tandem aldol±allylation strategy is also applicable to stereocontrolled polyketide/macrolide synthesis. (E)- and (Z)-Crotyl(enol)(pinacolato)silanes 49 and 51 react stereoselectively with cyclohexanecarbaldehyde to produce 1,3-diols 50 and 52, respectively, with high diastereoselectivities (Scheme 5.13) [20]. It is noteworthy that the reaction of (E,E)-crotyl(enol)silane 53 is capable of constructing of O Si

OH

O 49

O

OH

60% 50 (89 : 11 dr)

O H

toluene 40 ºC

O OH

Si O

OH

O 51

71% 52 (91 : 9 dr) O Si O

OH

O

OH

53 benzene, 40 ºC 60%

54 (86 : 11 : 3 : 1 dr)

Si

O

O H

Cy 55

Scheme 5.13 Strain-induced tandem aldol±allylation.

181

182


four contiguous chiral centers with fairly high diastereoselectivity. The strain on silicon induced by the pinacol ligand is essential for the stereoselective aldol reaction; no reaction takes place when pinacol is replaced by 2,4-dimethyl-2,4-pentanediol. The stereochemical outcome of the reaction is explained in terms of a chairlike six-membered transition state 55 for intramolecular crotylsilylation of b-siloxy aldehydes. Bis(allyl)homoallyloxysilanes 56a and 56b are designed for a tandem intramolecular silylformylation±allylsilylation reaction, which has turned out to be an efficient approach to construct polyol and polyketide frameworks [21]. For example, heating a solution of 56 in benzene at 60 C in the presence of Rh(acac)(CO)2 under CO atmosphere followed by the Tamao oxidation gives syn,syn-triols 59 stereoselectively via oxasilacyclopentanes 57 and 58 (Scheme 5.14). Bis(cis-crotyl)silane 56b is readily prepared by double Pd-catalyzed 1,4-hydrosilylation of 1,3butadiene with dichlorosilane followed by reduction with LiAlH4 and alcoholysis with the corresponding homoallylic alcohol. R

R

O

Si

H

1) Rh(acac)(CO)2 (3 mol%) CO (900 or 1000 psi) benzene, 60 ºC

OH

OH

OH

2) H2O2, NaHCO3, MeOH

R

92 : 8 ds

59a (R = H: 59% yield) 59b (R = Me: 67% yield)

56a (R = H) 56b (R = Me)

[O]

b a O iPr

Si H

R

O R H

R path a

O iPr

57

Si H

O

R

58

Scheme 5.14 Tandem silylformylation±allylation of alkenes.

The tandem silylformylation±allylation methodology is extended to remote 1,5stereocontrol [22]. Thus, treatment of homopropargylic hydrosilyl ethers 60, produces, in a manner similar to homoallylic hydrosilyl ethers 56, 3-silyl-1,5-diol 61 whose oxidation or protodesilylation/acetylation gives, respectively, 1,5-anti diol 62 or diacetate 63 with high diastereoselectivity (Scheme 5.15). The 1,5-anti selectivity contrasts sharply to the one obtained in the tandem reaction of homoallylic silyl ethers 56.

5.2 Allylic Silanes

R

R

O

Si

Rh(acac)(CO)2 (0.4 or 1.0 mol%) CO (1000 psi)

R O

H

Si

O

benzene, 60 ºC R 61a (R = H) 61b (R = Me)

60a (R = H) 60b (R = Me) H2O2, NaHCO3 or KHF2, THF/MeOH ∆

OH

O

(R = H)

1) Bu4NF, THF, ∆ 2) Ac2O, pyridine 83%

OH

OAc

R 62a (R = H, 71%, 89 : 11 dr) 62b (R = Me, 65%, 96 : 4 dr)

OAc

63 (anti : syn = 89 : 11)

Scheme 5.15 Tandem silylformylation±allylation of alkynes.

Diallyl(diisopropyl)silane 64 delivers its two allyl groups on silicon sequentially to methyl vinyl ketone in the presence of BF3.OEt2 (Scheme 5.16) [23]. b-Silyl cation 65 is first generated by 1,4-addition and then intramolecularly allylated by the remaining allyl group to afford double allylation product 66.

Si(i-Pr)2 2

MeCOCH=CH2 BF3•OEt2

O

CH2Cl2, rt

Si(i-Pr)2

64 65 O

62%

66 (R = SiF(i-Pr)2) 67 (R = OH) R

[O] 89%

Scheme 5.16 Tandem double allylation of a,b-unsaturated ketone.

5.2.4 Sequential Synthetic Reactions of Metal-containing Allylic Silanes

Metal-containing organosilanes are versatile reagents from two synthetic viewpoints. Synthetic reactions of the silicon functionality provide an efficient method for the preparation of polyfunctional organometallic reagents, whereas synthetic

183

184


transformations based on the metal part provides polyfunctional organosilicon reagents. Typical examples are a-boryl allylic silanes 69 that are stereoselectively prepared by gem-silylborylation of allylic chlorides 68 (Scheme 5.17) [24]. Treatment of 68 with LDA at ±98 C generates the corresponding lithium carbenoids, which smoothly react with coexisting (dimethylphenylsilyl)(pinacolato)borane to give 69 with complete retention of configuration. With benzaldehyde as an electrophile, 69 reacts as an allylic silane in the presence of Me3SiOBn and Me3SiOTf in CH2Cl2 at ±78 C to afford (E)-alkenylboranes 70 with high stereospecificity. On the other hand, allylation as an allylic borane takes place with benzaldehyde under thermal conditions, giving rise to (Z)-alkenylsilane 71 with opposite stereospecificity. Silane 71 is converted into disubstituted dihydropyran 72 through the Overman's procedure (see Section 5.3.2). R1

PhMe2Si–Bpin LDA

Cl

THF, -98 ºC to RT

R2 1

R1

Bpin R2

2

68a (R = Pr, R = H) 68b (R1 = H, R2 = Pr)

SiMe2Ph

69a (75%) 69b (79%) BnO

Me3SiOBn Me3SiOTf

69a or 69b

CH2Cl2, -78 ºC

-78 ºC

Bpin

Ph

PhCHO

R1 R2 70a (83%, 95% ds) 70b (94%, 91% ds)

69a

1) NaH, MEMCl 55%

HO THF 100 ºC

Ph Pr

SiMe2Ph

71 (87%, 93% ds)

2) TiCl4, CH2Cl2 -78 ºC, 82%

O Ph Pr 72

Scheme 5.17 Stereocontrolled synthesis and stereoselective allylation of a-borylallylsilanes.

Silylborylation of allenes readily produces b-borylallylsilanes, which are useful for stereoselective preparation of functional alkenylboranes and trans-1,2-benzooxadecalines (Scheme 5.18) [25]. TiCl4-promoted allylation of propanal diethyl acetal with 73 gives (E)-alkenylborane 74 stereoselectively. Meanwhile, treatment of 73 with propanal in the presence of Me3SiOTf produces tricyclic compound 75, in which two propanal molecules are incorporated, as a single diastereomer. The proposed mechanism involves allylation of propanal followed by acetal formation with second propanal and Prins-type oxonium ion±alkene cyclization. Asymmetric synthesis of 73 is also demonstrated [26].

5.2 Allylic Silanes

OEt

EtCH(OEt)2 TiCl4, CH2Cl2, -78 ºC 94%

Bpin

Bpin (CH2)2Ph

Et 74

SiMe2Ph Et

(CH2)2Ph

H

O

73

2 EtCHO Et

Me3SiOTf, CH2Cl2 -78 to 0 ºC 92%

pinB 75

Scheme 5.18 Lewis acid-promoted reactions of b-borylallylsilane.

Rhodium-catalyzed conjugate addition of c-borylallylsilane 76 to benzalacetone (77) proceeds upon heating, providing f-ketoallylsilane 78, which undergoes intramolecular allylation with the aid of Bu4NF to give vinylcyclobutanol 79 as a single isomer (Scheme 5.19) [27]. [RhCl(cod)]2 (1.5 mol%)

O Me3Si

B(OiPr)2

+

Ph

Me 77

76 O

Me

MeOH/H2O 100 ºC 84% Me

Bu4NF Me3Si Ph

THF 0 ºC 79%

78

H OH Ph 79

Scheme 5.19 Cyclobutanol synthesis with c-borylallylsilane.

Hydrogenolysis of allyl acetates 80 with triethylammonium formate gives allylsilanes substituted at the a-position (81) (Scheme 5.20) [28]. Disilyl reagent 81a reacts with octanal in the presence of BF3.OEt2 at ±40 C to yield tert-butyldimethylsilyl-substutited product 82a solely, while allylation with 81b proceeds at ±78 C to give 82b. Thus, the carbon±tin bond in 81b is cleaved much faster than the carbon±silicon bond.

185

186


R

HCO2H/Et3N Pd2dba3 (2 mol%) PPh3 (16 mol%)

OAc

Me3Si

R Me3Si

1,4-dioxane, 100 ºC

81a (90%) 81b (99%)

80a (R = SitBuMe2) 80b (R = SnBu3) C7H15CHO -40 ºC 73%

BF3•OEt2

C7H15

tBuMe2Si

OH 82a

CH2Cl2 PhCHO

Ph

Me3Si

-78 ºC 91%

82b

OH

Scheme 5.20 Preparation and Lewis acid-promoted aldehyde addition of a-silyl- and -stannylallylsilanes.

Geminally silylated allylsilanes, conveniently prepared by isomerization of gemdisilylalkenes with 10% Pd/C in diethyl ether [29], are used for stereoselective synthesis of trans-2,3-disubstituted oxepanes. For example, 84 reacts with benzaldehyde to give 85 that bears trans-2-silylethenyl and phenyl groups, via an acetalization±cyclization sequence (Scheme 5.21). HO(CH2)4

SiMe3 SiMe3 83

H2 (1 atm) 10% Pd/C

HO(CH2)4

Et2O, 25 ºC 91%

PhCHO

SiMe3 SiMe3 84

O

Me3SiOTf (2 eq) CH2Cl2, -78 ºC 61%

Ph SiMe3 85

Scheme 5.21 Synthesis and cyclization of a-silylallylsilane.

One-pot stereoselective synthesis of all-cis-2,3,5-trisubstituted tetrahydrofurans is accomplished starting with a-silylmethyl allylic silane 86 (Scheme 5.22), which is treated with double amounts of benzyloxyacetaldehyde in the presence of BF3.OEt2 to give tetrahydrofuran 88 with high 2,2-cis, 2,5-cis-selectivity possibly by sequential intramolecular allylations [30]. Starting material 86 is readily available from disilanyl homoallyl ether 89 through intramolecular bissilylation, ring-opening with PhLi, and dehydration.

5.2 Allylic Silanes

2 BnO

SiMe2Ph

OBn

CHO

O BnO

SiMePh2

BF3•OEt2, CH2Cl2 -78 ºC to RT 68%

86

88

OBn LAO

SiMe2Ph

O

BnO

SiMe2Ph

BnO 87

PhMe2Si

89

Pd(OAc)2 (2 mol%) tBuNC (8 mol%)

MePhSi O

toluene, reflux 80% 89

Ph Si

PhLi

SiMe2Ph

O

Et2O 80%

90 1) o-NO2C6H4SeCN

HO

SiMe2Ph

SiMe2Ph 2) H2O2, pyridine 60-68%

SiMePh2

SiMePh2 86

91 Scheme 5.22 One-pot synthesis of 2,3,5-trisubstituted tetrahydrofurans with a-silylmethyl allylic silane.

Double deprotonation of 2-methylpropene followed by bissilylation gives (b-silylmethyl)allylsilane 92, which behaves as a trimethylenemethane dianion, as 92 reacts with bis(acetal) in the presence of TiCl4 to provide 3,5-dimethoxy(methylene)cyclohexane 93 (Scheme 5.23) [31]. BuLi/TMEDA

2 Me3SiCl

-30 ºC

-78 to 20 ºC 60%

MeO MeO

Me3Si

SiMe3 92

OMe OMe

TiCl4, CH2Cl2, -70 to -5 ºC 93%

MeO

OMe 93

Scheme 5.23 Cyclization of (b-silylmethyl)allylsilane with bis(acetal).

187

188


Intramolecular electrophilic reaction of (b-silylmethyl)allylsilane with an imino group is an efficient approach to an 1-azabicyclo[3.2.1]octane framework [32]. For example, treatment of 94 with formaldehyde in CH3CN at room temperature and then with trifluoroacetic acid produces 97 as a trifluoroacetate salt, presumably through domino cyclization through 95 and then of 96 (Scheme 5.24). 1) aqueous CH2O CH3CN, RT

SiMe3 H2N

SiMe3

N

2) CF3CO2H, RT 88%

94 97

SiMe3

CH2O/H+

N

SiMe3

HN 95

SiMe3

96

Scheme 5.24 Sequential double cyclization of amino containing (b-silylmethyl)allylsilane.

An alternative trimethylenemethane dianion equivalent is (b-stannylmethyl)allylsilane 98 [33]. Since allyltin is more reactive than allylsilane, 98 first reacts as an allyltin and then as an allylsilane. For example, asymmetric aldehyde addition of 98 utilizing a BINOL-titanium catalyst followed by the acetalization±cyclization protocol gives rise to optically active cis-2,6-disubstituted pyrans 100 with high enantiomeric excess (Scheme 5.25). R2

SnBu3

OH a or b

c or d

O

R1 SiMe3 98

SiMe3 99

R1 100

condition a : R1CHO, [(R)-BINOL]Ti[OCH(CF3)2] (5 mol%), PhCF3, -20 ºC, 54~94% yield, 90~97% ee condition b : R1CHO, [(R)-BINOL]Ti[OCH(CH3)2] (10 mol%), CH2Cl2, -20 ºC, 74~96% yield, 90~96% ee condition c : R2CHCl(OMe), iPrNEt2, CH2Cl2, 0 to 23 ºC, then Me3SiNTf2 (10 mol%), -78 ºC, 84~91% yield, 33 : 1~55 : 1 d.r. condition d : R2CHO, Me3SiOTf, Et2O, -78 ºC, 95~98% yield, >99 : 99% Z)

4-EtO2C-C6H4-I

EtO2C

OMe

BnPdCl(PPh3)2 CuI, DMF 50 ºC

EtO2C 4-MeO-C6H4-I Bu4NF 50 ºC 65%

129

SiMe2(OiPr) 128

Scheme 5.33 Transition metal-catalyzed preparation and transformations of 2-stannylalkenylsilane.

5.4 Alkylsilanes 5.4.1 Synthetic Reactions of Polyhalomethylsilanes

Organometallic compounds bearing a leaving group such as halogen at the metallated carbon are called carbenoids that are thermally labile due to the ease of a-elimination taking place by intramolecular coordination of the leaving group to the metal [46]. Such intramolecular coordination is suppressed totally by the use of a nonmetallic counter-cation. The resulting anionic species may be called a naked anion. To generate naked anions, nucleophilic activation of organosilanes with an ammonium or sulfonium fluoride is extremely useful [47]. For example, (trichloromethyl)trimethylsilane 130 reacts with 3-methyl-2-butenal in the presence of tris(diethylamino)sulfonium difluorotrimethylsilicate (TASF) to give trichloromethylated alcohol 131 in high yield (Scheme 5.34) [48]. It is noteworthy that the 1,2-addition proceeds at room temperature, in sharp contrast to the reaction of polyhalomethyllithiums that needs extremely low reaction temperatures. Under the same conditions, dichlorobis(trimethylsilyl)methane 132 adds aldehyde double to afford 1,3-diol 133.

193

194


CHO 1) TASF (25 mol%) THF, RT Me3Si

CCl3 131

1) 2 PhCHO TASF (13 mol%) THF, RT

Cl

Me3Si

CCl3

2) HCl–MeOH 88%

130

Cl

OH

SiMe3

Cl

Cl

Ph

2) HCl–MeOH 82%

Ph OH OH 133

132

Scheme 5.34 Fluoride-catalyzed aldehyde addition of polyhalomethylsilanes.

Ph RR'CO Bu4NF (cat)

CF3 135 (85%)

OH

THF 0 ºC to RT CF3 OH

136 (92%)

O RCO2Me dried Bu4NF (cat) Me3SiCF3 134

Ph

CF3 137 (85%) O

pentane -78 ºC to RT

CF3 138 (72%) O

O tBu

S

tBu N

R

S

CF3 N H

Ph

139 (80%, 97% dr)

Bu4NSiPh3F2 (cat) THF -55 ºC

O tBu

S

CF3 N H

Cy

140 (88%, 99% dr) Scheme 5.35 Nucleophilic trifluoromethylation with trifluoromethyl(trimethyl)silane.

5.4 Alkylsilanes

The fluoride-induced activation strategy [49] is applicable to the generation of a trifluoromethyl anion equivalent from trifluoromethyl(trimethyl)silane (134), which, in the presence of a catalytic amount of Bu4NF in THF, gives CF3-aldehyde (or ketone) adducts (Scheme 5.35) [50]. Under similar conditions, methyl carboxylates are converted into the corresponding trifluoromethyl ketones [51]. Use of a commercial THF solution of Bu4NF dried with activated MS4A prior to use is essential for success of transformation. Imine addition of a CF3 group using 134 is effected using Bu4NSiPh3F2 [52]. In particular, highly stereoselective trifluoromethylation of optically active sulfinylimines 139 and 140 is achieved as shown in the bottom of Scheme 5.35. 5.4.2 Synthetic Reactions of Cyclopropyl, Oxiranyl, and Aziridinylsilanes

Cyclopropyl anionic reagents are also accessible by the fluoride-based nucleophilic activation of the corresponding silylated precursors [53]. Methyl 1-trimethylcyclopropanecarboxylate (141, R = CO2Me) reacts with acetaldehyde in the presence of Bu4NF to give adduct 142, while the aldehyde addition of 1-cyano-1-trimethylsilylcyclopropane (141, R = CN) is smoothly mediated by benzyltrimethylammonium fluoride (Scheme 5.36). (R = CO2Me)

SiMe3

MeCHO Bu4NF

Me OH

THF, 0 ºC 90%

CO2Me 142

R

PhCHO BnMe3NF

141 (R = CN)

THF, 0 ºC 83%

Ph OH CN 143

Scheme 5.36 Aldehyde addition of cyclopropylsilanes.

Upon treatment with a fluoride ion of trimethylsilyl-substituted oxiranes (144 and 146), and -aziridine (148) generate, the corresponding naked anionic species, which react with aldehydes to give the corresponding adducts (145, 147, and 149) with retention of configuration (Scheme 5.37) [54]. In the presence of TiCl4, trimethylsilylmethylated cyclopropyl ketone 150 undergoes desilylative ring-opening reaction to generate (Z)-enolate 151, which then reacts with cinnamaldehyde, giving rise to syn-adduct 152 stereoselectively (Scheme 5.38) [55].

195

196


O

n-C7H15

MeCHO Bu4NF

F

F

SiMe3

O

SiMe3 O

H Ph

F Me OH

145 OH

1) p-MeO-C6H4CHO Bu4NF, MS4A THF/hexane, RT

O

2) HF aq., MeCN 62%

O

C6H4-p-OMe

146 Ts N

O

F

THF -40 ºC 85%

144

O

n-C7H15

O 147

PhCHO Bu4NSiPh3F2

H

H

148

H

Ph

THF, 40 ºC 60%

SiMe3

Ts N

Ph

OH 149 (98 : 2 ds)

Scheme 5.37 Fluoride-mediated aldehyde addition of oxiranyl- and aziridinylsilanes.

O Me3Si

Ph 150

CHO

Ph TiCl4

OH Ph

CH2Cl2 -78 ºC 79%

O Ph

152 (syn : anti = 12 : 1)

OTi Ph 151 Scheme 5.38 Lewis acid-promoted reaction of cyclopropylmethylsilane with aldehyde.

5.4.3 Synthetic Reactions of Polysilylmethanes

Bis(trimethysilyl)methane derivatives react with aldehydes and ketones in the presence of a fluoride ion to afford di- and trisubstituted alkenes in one pot [56]. The reaction involves the fluoride-catalyzed carbonyl addition followed by Peterson elimination. For example, a,a-bis(trimethylsilyl)acetonitrile 153 produces b-phenylacrylonitrile 154 with high E-selectivity, whereas tris(trimethylsilyl)methane 155 reacts with anisaldehyde at room temperature to give alkenylsilane 156 (Scheme 5.39).

5.5 Miscellaneous Preparations and Reactions of Polyfunctional Organosilicon Reagents PhCHO TASF (10 mol%)

Me3Si Me3Si

CN

CH2Cl2, -100 ºC 90%

153 Me3Si

p-MeO-C6H4CHO TASF (10 mol%)

Me3Si

Ph

SiMe3

H

CN 154 (E : Z = 95 : 5) p-MeO-C6H4

THF, 20 ºC 94%

155

H

H

H SiMe3 156 (E : Z = 73: 37)

Scheme 5.39 Fluoride-catalyzed reaction of polysilylmethanes.

The strategy described above is applicable to fluorotris(trimethylsilyl)methane (157); it reacts with two molecules of benzaldehyde to give 2-fluoroallyl alcohol 158 (Scheme 5.40) [57]. The reaction involves five events in a single operation: generation of a naked methyl anion, aldehyde addition, Peterson elimination, gen2 eration of a naked sp anion, and the second aldehyde addition. Me3Si Me3Si

Ph

2 PhCHO KF/18-Crown-6

F

Ph

DMF, RT 74%

SiMe3

F

HO 158 (E : Z = 65 : 35)

157

Scheme 5.40 Reaction of fluorotris(trimethylsilyl)methane with aldehyde.

5.5 Miscellaneous Preparations and Reactions of Polyfunctional Organosilicon Reagents

A silicon±silicon bond of hexamethyldisilane (159) is cleaved by Bu4NF in hexamethylphosphoric triamide (HMPA) to produce a naked silyl anion and fluorotrimethylsilane [58]. The resulting silyl anion undergoes aldehyde addition to afford, after acidic workup, 1-trimethylsilyl-1-alcohols like 160 (Scheme 5.41). The silyl anion can react with 1,3-dienes to give 1,4-bis(trimethylsilyl)-2-butene 161 with high (E)-selectivity. n-C10H21CHO Bu4NF (5 mol%) Me3Si

SiMe3 159

n-C10H21

+

then H3O

OH

67%

HMPA RT

SiMe3

160 Me3Si

78%

SiMe3 161 (E : Z = 100 : 0)

Scheme 5.41 Fluoride-catalyzed reaction of hexamethyldisilane.

197

198


The 1,4-disilylation of 1,3-dienes with phenyl-containing disilanes 162 is catalyzed by such a transition metal complex as Ni(PPh3)4 or Pt(CO)2(PPh3)2 (Scheme 5.42) [59]. The presence of a phenyl group is essential for the successful addition.

Ph MeSi

MePh(vinyl)Si

Ni(PPh3)4 mesitylene 220 ºC 92%

SiMe3

SiMe3 163

R 162

Me2PhSi Pt(CO)2(PPh3)2 THF, CO 130 ºC 91%

SiMe3 164 (E : Z = 82 : 18)

Scheme 5.42 Transition metal-catalyzed addition of disilanes to 1,3-dienes.

Direct silylation of aromatic compounds is carried out with 1,2-di-tert-butyl1,1,2,2-tetrafluorodisilane (165) that serves as a silylating reagent in the presence of an iridium catalyst [60]. For example, the Ir-catalyzed C±H activation reaction of o-xylene selectively proceeds at the aromatic C±H bond rather than the benzylic one to give 166 in a high yield (Scheme 5.43). The synthetic utility of the products o-xylene 1/2[{Ir(OMe)(cod)}2] tBuF2Si

SiF2tBu

SiF2tBu

4,4'-di-tert-butyl2,2'-bipyridine (3 mol%) 120 ºC

165

166 (99%)

CO2Me O I

b a

O O

OMe

167 (86%)

168 (97%)

conditions a : [{η3-(C3H5)PdCl}2] (2.5 mol%), Bu4NF (2 eq), DMF, 100 ºC conditions b : [Rh(cod)2]BF4 (5 mol%), Bu4NF (3 eq), THF, 60 ºC Scheme 5.43 Ir-catalyzed synthesis and reactions of tert-butyldifluorosilylated arenes.

5.5 Miscellaneous Preparations and Reactions of Polyfunctional Organosilicon Reagents

(e.g. 166) is demonstrated by the Pd-catalyzed cross-coupling with 4-iodobenzoic acid methyl ester as well as the Rh-catalyzed 1,4-addition to methyl vinyl ketone. Triallyl(aryl)silanes are stable and readily accessible organosilicon reagents that undergo the Pd-catalyzed cross-coupling reaction as an arylmetal in the presence of a fluoride ion [61]. The particular silanes can be used as a bifunctional reagent containing both allylsilane and arylsilane fucntionalities [62]. Thus, 169 delivers an allyl group to p-bromobenzaldehyde with the aid of Bu4NF, and then a phenyl group by a newly added PdCl2/PCy3 catalyst system and additional Bu4NF (Scheme 5.44). Br

CHO

Si Bu4NF (0.5 eq) DMSO, RT

3

169 PdCl2 (5 mol%) PCy3 (10 mol%) Bu4NF (3.9 eq) DMSO-H2O (2 : 1) 80 ºC, 60%

OH 170

Scheme 5.44 Sequential reaction of triallyl(aryl)silane.

Acylsilanes having an alkynyl moiety undergo intramolecular cyclization in the presence of [RhCl(CO)2]2 to give a-alkylidenecyclopentanones and -hexanones, as shown by the example of 171 in Scheme 5.45 [63]. Use of acetic acid or trifluoroacetic acid increases the yield of product 172. O SiPhMe2

[RhCl(CO)2]2 (5 mol%) AcOH (10 eq)

Ph

toluene, 70 ºC 77%

171 Scheme 5.45 Rh-catalyzed cyclization of acylsilane.

O

H Ph

172

199

200


References 1 J. Emsley, The Elements, 3rd edn, Oxford

University Press, Oxford, 1998, p. 190. 2 Reviews on synthetic organosilicon chemistry: (a) T. H. Chan, I. Fleming, Synthesis 1979, 761. (b) E. W. Colvin, Silicon in Organic Synthesis, Butterworths, London, 1981. (c) P. D. Magnus, T. Sarkar, S. Djuric, in Comprehensive Organometallic Chemistry, Vol. 7 (Eds. G. Wilkinson, F. G. A. Stone, E. W. Abel), Pergamon Press, Oxford, 1982, p. 515. (d) H. Sakurai, Pure & Appl. Chem. 1982, 54, 1. (e) W. P. Weber, Silicon Reagents for Organic Synthesis, Springer, Berlin, 1983. (f) E. W. Colvin, Silicon Reagents in Organic Synthesis, Academic Press, London, 1988. (g) A. Hosomi, Acc. Chem. Res. 1988, 21, 200. (h) D. Schinzer, Synthesis 1988, 263. (i) I. Fleming, J. Dunogues, R. H. Smithers, Org. React. 1989, 37, 57. (j) S. Patai, Z. Rappoport, The Chemistry of Organic Silicon Compounds, John Wiley & Sons, Chichester, 1989. (k) G. Majetich, in Organic Synthesis: Theory and Applications, Vol. 1 (Ed. T. Hudlicky), JAI Press Inc., Greenwich, 1989, pp. 173. (l) I. Fleming, in Comprehensive Organic Synthesis, Vol. 2 (Eds. B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, p. 563. (m) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207. (n) E. W. Colvin, in Comprehensive Organometallic Chemistry II, Vol. 11 (Eds. E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon, Oxford, 1995, p. 313. (o) C. E. Masse, J. S. Panek, Chem. Rev. 1995, 95, 1293. (p) M. A. Brook, Silicon in Organic, Organometallic, and Polymer Chemistry, John Wiley & Sons, Inc., New York, 2000. (q) J. A. Marshall, Chem. Rev. 2000, 100, 3163. (r) I. Fleming, Science of Synthesis, Vol. 4, Georg Thieme Verlag, Stuttgart, 2002. (s) L. Chabaud, P. James, Y. Landais, Eur. J. Org. Chem. 2004, 3173. 3 Review on uses of organosilicon compounds in synthesis of natural products: E. Langkopf, D. Schinzer, Chem. Rev. 1995, 95, 1375.

4 (a) J. S. Panek, M. Yang, J. Org. Chem.

1991, 56, 5755. (b) J. S. Panek, M. Yang, J. Am. Chem. Soc. 1991, 113, 6594. See also, (c) J. S. Panek, T. D. Clark, J. Org. Chem. 1992, 57, 4323. 5 Reviews on remote stereocontrol: (a) K. Mikami, M. Shimizu, H.C. Zhang, B. E. Maryanoff, Tetrahedron 2001, 57, 2917. (b) H. Sailes, A. Whiting, J. Chem. Soc., Perkin Trans. 2000, 1, 1785. (c) H. J. Mitchell, A. Nelson, S. Warren, J. Chem. Soc., Perkin Trans. 1999, 1, 1899. 6 N. F. Jain, N. Takenaka, J. S. Panek, J. Am. Chem. Soc. 1996, 118, 12475. 7 (a) T. Hu, N. Takenaka, J. S. Panek, J. Am. Chem. Soc. 1999, 121, 9229. (b) T. Hu, N. Takenaka, J. S. Panek, J. Am. Chem. Soc. 2002, 124, 12806. 8 (a) J. S. Panek, N. F. Jain, J. Org. Chem. 1994, 59, 2674. (b) J. V. Schaus, N. Jain, J. S. Panek, Tetrahedron 2000, 56, 10263. 9 (a) C. T. Brain, E. J. Thomas, Tetrahedron Lett. 1997, 38, 2387. (b) L. C. Dias, R. Giacomini, Tetrahedron Lett. 1998, 39, 5343. 10 K. Miura, H. Saito, T. Nakagawa, T. Hondo, J.-i. Tateiwa, M. Sonoda, A. Hosomi, J. Org. Chem. 1998, 63, 5740. 11 K.-i. Imamura, E. Yoshikawa, V. Gevorgyan, Y. Yamamoto, J. Am. Chem. Soc. 1998, 120, 5339. 12 Reviews on transition metal-catalyzed carbocyclization: (a) I. Ojima, M. Tzamarioudaki, Zhaoyang Li, R. J. Donovan, Chem. Rev. 1996, 96, 635. (b) E.-i. Negishi, C. CopØret, S. Ma, S.-Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365. 13 C. Fernandez-Rivas, M. Mendez, A. M. Echavarren, J. Am. Chem. Soc. 2000, 122, 1221. 14 A. M. Castano, J.-E. Bäckvall, J. Am. Chem. Soc. 1995, 117, 560. 15 I. E. Markó, A. Mekhalfia, D. J. Bayston, H. Adams, J. Org. Chem. 1992, 57, 2211. 16 (a) I. E. Markó, D. J. Bayston, Tetrahedron Lett. 1993, 34, 6595. See also, (b) T. Sano, T. Oriyama, Synlett 1997,

References 716. (c) I. E. Markó, J.-M. Plancher, Tetrahedron Lett. 1999, 40, 5259. 17 H. Huang, J. S. Panek, J. Am. Chem. Soc. 2000, 122, 9836. 18 A. Hosomi, H. Hayashida, Y. Tominaga, J. Org. Chem. 1989, 54, 3254. 19 D. J. Kopecky, S. D. Rychnovsky, J. Am. Chem. Soc. 2001, 123, 8420. 20 (a) X. Wang, Q. Meng, A. J. Nation, J. L. Leighton, J. Am. Chem. Soc. 2002, 124, 10672. See also, (b) L. M. Frost, J. D. Smith, D. J. Berrisford, Tetrahedron Lett. 1999, 40, 2183. 21 (a) M. J. Zacuto, J. L. Leighton, J. Am. Chem. Soc. 2000, 122, 8587. (b) S. D. Dreher, J. L. Leighton, J. Am. Chem. Soc. 2001, 123, 341. (c) M. J. Zacuto, S. J. O'Malley, J. L. Leighton, J. Am. Chem. Soc. 2002, 124, 7890. 22 S. J. O'Malley, J. L. Leighton, Angew. Chem. Int. Ed. 2001, 40, 2915. 23 T. Akiyama, K. Asayama, S. Fujiyoshi, J. Chem. Soc., Perkin Trans. 1 1998, 3655. 24 (a) M. Shimizu, H. Kitagawa, T. Kurahashi, T. Hiyama, Angew. Chem. Int. Ed. 2001, 40, 4283. See also, (b) Y. Yamamoto, H. Yatagai, K. Maruyama, J. Am. Chem. Soc. 1981, 103, 3229. (c) D. S. Matteson, D. Majumdar, Organometallics 1983, 2, 230. 25 (a) M. Suginome, Y. Ohmori, Y. Ito, J. Am. Chem. Soc. 2001, 123, 4601. (b) M. Suginome, Y. Ohmori, Y. Ito, Chem. Commun. 2001, 1090. 26 M. Suginome, T. Ohmura, Y. Miyake, S. i. Mitani, Y. Ito, M. Murakami, J. Am. Chem. Soc. 2003, 125, 11174. 27 Y. Yamamoto, M. Fujita, N. Miyaura, Synlett 2002, 767. 28 (a) M. Lautens, P. H. M. Delanghe, Angew. Chem. Int. Ed. Engl. 1994, 33, 2448. (b) M. Lautens, R. N. Ben, P. H. M. Delanghe, Tetrahedron 1996, 52, 7221. 29 D. M. Hodgson, S. F. Barker, L. H. Mace, J. R. Moran, Chem. Commun. 2001, 153. 30 T. K. Sarkar, S. A. Haque, A. Basak, Angew. Chem. Int. Ed. 2004, 43, 1417. 31 B. Guyot, J. Pornet, L. Miginiac, Tetrahedron 1991, 47, 3981. 32 T. Kercher, T. Livinghouse, J. Am. Chem. Soc. 1996, 118, 4200.

33 (a) C.-M. Yu, J.-Y. Lee, B. So, J. Hong,

Angew. Chem. Int. Ed. 2002, 41, 161. (b) G. E. Keck, J. A. Covel, T. Schiff, T. Yu, Org. Lett. 2002, 4, 1189. 34 I. E. Markó, B. Leroy, Tetrahedron Lett. 2001, 42, 8685. 35 Reviews on cross-coupling reaction of organosilicon compounds: (a) T. Hiyama, in Metal-catalyzed Cross-coupling Reactions (Eds. F. Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998, p. 421. (b) T. Hiyama, E. Shirakawa, Top. Curr. Chem. 2002, 219, 61. (c) S. E. Denmark, R. F. Sweis, Acc. Chem. Res. 2002, 35, 835. (d) S. E. Denmark, R. F. Sweis, in Metal-Catalyzed Cross-Coupling Reactions, Vol. 2 (Eds. A. de Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004, p. 163. 36 M. Yamane, K. Uera, K. Narasaka, Chem. Lett. 2004, 33, 424. 37 (a) L. E. Overman, A. Castaneda, T. A. Blumenkopf, J. Am. Chem. Soc. 1986, 108, 1303. See also, (b) I. E. Markó, D. J. Bayston, Tetrahedron 1994, 50, 7141. 38 (a) N. Asao, T. Shimada, Y. Yamamoto, J. Am. Chem. Soc. 1999, 121, 3797. (b) N. Asao, T. Shimada, T. Shimada, Y. Yamamoto, J. Am. Chem. Soc. 2001, 123, 10899. 39 S. E. Denmark, S.-M. Yang, J. Am. Chem. Soc. 2002, 124, 2102. 40 S. E. Denmark, S.-M. Yang, J. Am. Chem. Soc. 2002, 124, 15196. 41 (a) W. B. Roush, A. N. Pinchuk, G. C. Micalizio, Tetrahedron Lett. 2000, 41, 9413. (b) W. B. Roush, P. T. Grover, Tetrahedron 1992, 48, 1981. 42 W. B. Roush, G. J. Dilley, Synlett 2001, 955. 43 (a) T. Hata, H. Kitagawa, H. Masai, T. Kurahashi, M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 2001, 40, 790. (b) T. Kurahashi, T. Hata, H. Masai, H. Kitagawa, M. Shimizu, T. Hiyama, Tetrahedron 2002, 58, 6381. See also, (c) M. Shimizu, T. Kurahashi, H. Kitagawa, T. Hiyama, Org. Lett. 2002, 5, 225. (d) M. Shimizu, T. Kurahashi, H. Kitagawa, K. Shimono, T. Hiyama, J. Organomet. Chem. 2003, 686, 286. 44 Reviews on vic-dimetalation of unsaturated bonds: (a) M. Suginome, Y. Ito,

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5 Polyfunctional Silicon Organometallics for Organic Synthesis Chem. Rev. 2000, 100, 3221. (b) I. Beletskaya, C. Moberg, Chem. Rev. 1999, 99, 3435. 45 M. Murakami, T. Matsuda, K. Itami, S. Ashida, M. Terayama, Synthesis 2004, 1522. 46 Reviews on carbenoid chemistry: (a) G. Boche, J. C. W. Lohrenz, Chem. Rev. 2001, 101, 697. (b) M. Braun, Angew. Chem. Int. Ed. 1998, 37, 431. (c) K. G. Taylor, Tetrahedron 1982, 38, 2751. (d) H. Siegel, in Topics in Current Chemistry, Vol. 106, Springer-Verlag, Berlin, 1982, p. 55. (e) A. Krief, Tetrahedron 1980, 36, 2531. (f) G. Köbrich, Angew. Chem. Int. Ed. Engl. 1972, 11, 473. 47 Review on synthetic reactions of organosilicon compounds with nucleophilic activation: G. G. Furin, O. A. Vyazankina, B. A. Gostevsky, N. S. Vyazankin, Tetrahedron 1988, 44, 2675. 48 M. Fujita, M. Obayashi, T. Hiyama, Tetrahedron 1988, 44, 4135. 49 Review on perfluoroalkylation with fluorinated organosilicon reagents: G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757. 50 (a) G. K. S. Prakash, R. Krishnamurti, G. A. Olah, J. Am. Chem. Soc. 1989, 111, 393. (b) R. Krishnamurti, D. R. Bellew, G. K. S. Prakash, J. Org. Chem. 1991, 56, 984. 51 J. Wiedemann, T. Heiner, G. Mloston, G. K. S. Prakash, G. A. Olah, Angew. Chem. Int. Ed. 1998, 37, 820. 52 G. K. S. Prakash, M. Mandal, G. A. Olah, Angew. Chem. Int. Ed. 2001, 40, 589. 53 C. Blankenship, G. J. Wells, L. A. Paquette, Tetrahedron 1988, 44, 4023.

54 (a) T. Dubuffet, R. Sauvetre,

J. F. Normant, Tetrahedron Lett. 1988, 29, 5923. (b) K. Kuramochi, H. Itaya, S. Nagata, K.-i. Takao, S. Kobayashi, Tetrahedron Lett. 1999, 40, 7367. (c) V. K. Aggarwal, E. Alonso, M. Ferrara, S. E. Spey, J. Org. Chem. 2002, 67, 2335. 55 V. K. Yadav, R. Balamurugan, Org. Lett. 2003, 5, 4281. 56 C. Palomo, J. M. Aizpurua, J. M. Garcia, I. Ganboa, F. P. Cossio, B. Lecea, C. Lopez, J. Org. Chem. 1990, 55, 2498. 57 (a) M. Shimizu, T. Hata, T. Hiyama, Tetrahedron Lett. 1999, 40, 7375. (b) M. Shimizu, T. Hata, T. Hiyama, Bull. Chem. Soc. Jpn. 2000, 73, 1685. 58 T. Hiyama, M. Obayashi, I. Mori, H. Nozaki, J. Org. Chem. 1983, 48, 912. 59 (a) M. Ishikawa, Y. Nishimura, H. Sakamoto, T. Ono, J. Ohshita, Organometallics 1992, 11, 483. (b) Y. Tsuji, R. M. Lago, S. Tomohiro, H. Tsuneishi, Organometallics 1992, 11, 2353. 60 T. Ishiyama, K. Sato, Y. Nishio, N. Miyaura, Angew. Chem. Int. Ed. 2003, 42, 5346. 61 (a) Y. Nakao, T. Oda, A. K. Sahoo, T. Hiyama, J. Organomet. Chem. 2003, 687, 570. (b) A. K. Sahoo, Y. Nakao, T. Hiyama, Chem. Lett. 2004, 33, 632. 62 Y. Nakao, T. Oda, T. Hiyama, unpublished result. 63 (a) M. Yamane, T. Amemiya, K. Narasaka, Chem. Lett. 2001, 1210. Reviews on acylsilane chemistry: (b) P. F. Cirillo, J. S. Panek, Org. Prep. Proc. Int. 1992, 24, 553. (c) P. C. B. Page, S. S. Klair, S. Rosenthal, Chem. Soc. Rev. 1990, 19, 147. (d) A. Ricci, A. Degl'Innocenti, Synthesis 1989, 647.

203

6 Polyfunctional Tin Organometallics for Organic Synthesis Eric Fouquet and Agns Herve 6.1 Introduction

The use of functionalized organotins in organic syntheses has considerably increased in the last two decades. Some reactions, such as the Stille coupling or the nucleophilic allylation, can even be considered as cornerstones for numerous synthetic applications. The increasing popularity of organotins is mainly due to the ease of their preparation, even in the optically active form, associated to a good balance between stability and reactivity. The only drawbacks involved in the use of organotins could be related to environmental considerations, but in contrast with other heavy metals this aspect has not led organotin chemistry to decline. Nowadays organotin chemistry is still flourishing both from the methodological aspect and for the synthetic use. As this chapter cannot treat the subject in an exhaustive way, it will focus on the formation of carbon±carbon bonds by the use of organotin reagents

6.2 Metal-Catalyzed Coupling Reactions 6.2.1 The Stille Cross-Coupling Reaction

The palladium-catalyzed cross-coupling of organotin reagents with organic electrophiles is one of the most important reactions leading to the formation of a new C±C bond. The first examples were reported during the period 1976±77, by Eaborn and coworkers [1] and Kosugi et al. [2]. The following mechanistic studies and synthetic applications performed by Stille [3] made this reaction a standard method in organic synthesis. The reason for this is two fold. First, the reaction is a particularly mild process with neutral conditions and tolerates a wide variety of functional groups such as carboxylic acid, ester, amide, nitro, ether, amine, hydroxyl, ketone and even aldehyde, as well as a high degree of stereochemical comOrganometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

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6 Polyfunctional Tin Organometallics for Organic Synthesis

plexity in either the organotin or the electrophilic coupling partner. Secondly, organostannanes are accessible by numerous methods, and easy to handle since they are relatively insensitive to moisture and oxygen.

6.2.1.1 Mechanism In terms of mechanism, the stille coupling is characterized by a sequence of: (i) 0 active Pd species formation, (ii) oxidative addition, (iii) transmetallation and (iv) reductive elimination. Detailed mechanisms will not be discussed here, but the reader can refer to recent reviews [4]. If both the oxidative addition and the reductive elimination are reasonably understood, the transmetallation step is still a matter of intense debate. In any case, it is noteworthy that the nature of the ligands on the palladium may exert a dramatic influence on the kinetics of the transmetallation step. Moreover, the transmetallation rate was also found to depend on the nature of the group transferred from the organotin with the generally accepted order: alkynyl>alkenyl>aryl>allyl>benzyl>>>alkyl. There is no ideal catalytic system for a given reaction and several factors (ligands, additives, cocatalyst, solvents) have to be considered.

Ligands and Catalysts Pd(PPh3)4 is a commonly used catalyst for the Stille cross-coupling reaction. However, several studies demonstrated that the Pd/phosphine ratio exerts a dramatic influence on the kinetics, in the fact that an excess of ligand would inhibit the coupling by slowing the formation of the coordinatively unsaturated PdL2 active species. Pd(PPh3)4 can be replaced by the correct combination of Pd2dba3/phos6.2.1.1.1

N

I

OO S + SnMe3

N O

CO2CHPh2

N

OO S N

O

+ I CO2CHPh2

N Pd2dba3 THF

OO S N

NO2

O

65%

CO2CHPh2

N Me3Sn

CONH2

Pd2dba3 THF

OO S

O CO2CHPh2 78%

Scheme 6.1

CONH2

N

6.2 Metal-Catalyzed Coupling Reactions II

phine ligand or Pd (PPh3)2Cl2, reduced in situ to provide the active catalytic species. A large acceleration rate was observed in some cases with ligands of reduced donicity such as tri(2-furyl)phosphine (TFP) [5], phosphites and triphenylarsine [6]. Sterically demanding ligands such as tris(o-tollyl)phosphine-, tri(ter-butyl)phosphine and di(ter-butyl)methylphosphine were employed to favor the ligand dissociation step [7]. The use of air-stable trialkylphosphonium salts was also reported [8]. Finally, it is noteworthy that several Stille couplings were performed under ªligandlessº conditions without altering the stability of the catalyst [9] as exemplified by the preparation of new cephalosporins [10] (Scheme 6.1).

Cocatalysts Discovered by Liebeskind and Fengl [11], the beneficial effect of Cu(I) on the rate of sluggish Stille cross-couplings, referred as the ªcopper effectº, is well documented [12]. The function performed by copper in the catalytic cycle is solvent deI pendent. In ethereal solvents, Cu is a scavenger for free neutral ligands that otherwise causes retardation of the rate-limiting transmetallation step. In highly polar I solvents, the rate-accelerating effect of Cu is due to a preliminary transmetallation reaction from the organostannanes to generate more reactive organocopper species that further enter in the catalytic cycle. Other salts such as zinc [13] and cadmium [14] chlorides were also used as additives. In the case of unreactive triflates under classical conditions [15], the use of LiCl is recommended in ethereal solvents [16]. Nevertheless, the addition of such a stabilizing chloride source was observed to inhibit the reaction in polar solvents [17]. A remarkable effect of LiCl was reported in the Stille cross-coupling of allenyltins with a wide range of organic iodides to give the corresponding aryl-, alkenyl and disubstituted allenes [18]. The use of nucleophiles (amines, fluoride sources) to increase the reactivity of the organotin species, via hypercoordinate intermediates, is a well-established strategy (see Section 6.2.1.2.5). 6.2.1.1.2

Solvents and Media Solvents used for the Stille coupling include hydrocarbons, organic chlorides, ethereal solvents, highly polar solvents and even water, but most of the reactions are conducted in THF, DMF or NMP. The reaction was also adapted to the fluorous biphasic catalysis [19]. Stille reactions were also performed in ionic liquids [20], supercritical CO2 [21] and in aqueous medium [22] by using water soluble ligands. 6.2.1.1.3

6.2.1.2 Organotins for the Stille Reaction Alkynyltins Alkynyltins are considered to be the most reactive organotins and their coupling generally proceeds smoothly [23]. They were used for different types of reactions 6.2.1.2.1

205

206


such as the preparation of substituted alkkynylpyrones [24], a one-pot sequence of the Stille/iodolactonization reaction furnishing 2(2H)-pyranone derivatives [25] and a tandem Stille/carbopalladation sequence affording highly substituted enynes [26]. A recent application has concerned the introduction of alkynyl substituents to the C2-position of benzodiazepin dilactams (Scheme 6.2) [27].

MeO

SEM N

O H N

MeO

Stille coupling

O

R

R=H,Ph Scheme 6.2

6.2.1.2.2 Alkenyltins The Stille cross-coupling of alkenyltins has been widely used in organic chemistry, the major synthetic application being the preparation of polyconjugated systems via vinyl±vinyl cross-couplings (see Section 6.2.1.4.1 or 6.2.1.5.1). The transfer of alkene proceeds with retention of the double-bond stereochemistry and the reaction is not affected by the steric hindrance of the electrophile. However, when a-vinylstannanes are used as coupling partners, the rate of the Stille coupling is decreased and an alternative reaction, the cine substitution, sets in [28]. In this case, adding copper salts in combination with LiCl may solve the problem [29]. Several fluoroalkenylstannanes [30] were used to prepare functionalized fluoroalkenes, potential intermediates in the syntheses of fluorine-containing bioactive compounds [31]. a-Stannyl enamides [32] were coupled with a range of halides such acylhalides to give the corresponding a,b-unsaturated ketones that may serve as highly functionalized Michael acceptors (Scheme 6.3). Ts + SnBu3

Pd2dba3/AsPh3 CuCl

O

N CH2Ph

Cl

O

Ts N

CH2Ph

THF, 50ºC 65%

Scheme 6.3

The coupling of allenyltins is also efficient and affords allenyl [33] or propargyl [34] products depending on the nature of the substrates. An elegant example is the palladium-catalyzed regio and stereoselective annulation of allenylstannanes by b-iodo vinylic acids to give the corresponding a-pyrones via a Stille reaction/ cyclization sequence [35] (Scheme 6.4).

6.2 Metal-Catalyzed Coupling Reactions

Bu3Sn

n-Pent +

Me I

Me

Pd(OAc)2/PPh3 Na2CO3/n-Bu4NBr

OH

DMF/rt

O

207

n-Hex

O

O

84% Scheme 6.4

Aryl- and Heteroaryltins Both electron-deficient and electron-rich aryltins are suitable partners for the Stille reaction. The only limitation of the reaction was an ortho substitution on the organotin and the substrate until the recent use of electron-rich and sterically demanding ligands such as P(t-Bu)3, which permitted the synthesis of tetra-orthosubstituted biaryls. A plethora of heterocyclic stannanes [36] were used in Stille couplings. Their major applications concern the synthesis of pharmacologically interesting compounds, as illustrated by the synthesis of an endothelin antagonist [37] (Scheme 6.5), as well the preparation of supramolecular compounds. 6.2.1.2.3

Me t

S

Bu S O

N

H N O

O

O

N

Stille coupling

87% Scheme 6.5

Allyl and Benzyltins Benzyl- and allyltins present a much lower reactivity in Stille coupling than orga2 notins containing a Sn±Csp bond. Allyltins have not been frequently used, due in part to the tendency of products to reconjugate after the cross-coupling when olefinic or aromatic substrates are used as electrophilic partners [38], and the frequent loss of regioselectivity observed whith c-substituted allyltins [39]. A nice application is represented by the reaction of a b,c-disubstituted allyltin with a naphthoquinone-bromide used in a biomimetic-type synthesis of benzo [a]naphthacene quinines related to Pradimicinone [40] (Scheme 6). 6.2.1.2.4

O

MeO

OMe

O Br

HO

Bu3Sn

HO O Scheme 6.6

O

O

O

CO2Me

Pd(PPh3)4/CuBr dioxane

MeO OMe

CO2Me

HO HO O

81%

O

O

O

208


6.2.1.2.5 Alkyltins There are relatively few examples of the successful introduction of alkyl groups with the Stille cross-couplings. This is probably due to the competitive b-hydride elimination when using alkylstannanes bearing b-hydrogens. In most cases, the transfer of alkyl groups requires harsh conditions [41] and methyl, ethyl and butyl groups were transferred from the corresponding tetraalkyltins at elevated temperatures [42]. Nevertheless, it is noteworthy that alkyltins bearing a heteroatom in the a position to the tin atom cross-couple with success, the heteroatom enhancing the nucleophilicity of the carbon to be transferred [43]. In 1992, Vedejs et al. [44] and Brown et al. [45] independently reported that intramolecular coordination of amine to tin greatly accelerates the transfer of the alkyl group from tin. This 11 methodology was applied to the transfer of radiolabelled CH3 (Scheme 6.7) [46] and to the synthesis of bioactive sulfonamide [47]. 11

I N Sn

+

11

CH3

CH3

Pd(allylchloride)2 DMF decay corrected radiochemical yield 90%

Scheme 6.7

The activation, involving the expansion of the coordination sphere at tin [48], was recently used with externally coordinating ligands such as the fluoride ion [49] and permitted the transfer of alkyl groups from alkylfluorostannates [50]. Similar activation with diethylamine was also reported [51] as well as the transfer of the synthetically useful silylmethyl group via a 2-pyridyldimethyllsilyl(triorgano)tin reagent [52].

6.2.1.3 Substrates Organic Halides Aryl iodides and bromides couple with a large range of organostannanes. Contrary to this, and for a long time, only activated aryl chlorides were thought to be suitable substrates, the oxidative addition becoming the rate-limiting step of the reaction [53]. In 1999, however, Fu and coworkers reported that, when associated with a fluorine source, a combination of Pd/P(t-Bu)3 could serve as a versatile catalyst for the Stille reaction of nonactivated and very congested aryl chlorides [54]. Three other catalytic systems were also described to permit the coupling of aryl chlorides [55]. Heteroaryl halides were used in numerous reactions with aromatic-, heteroaromatic- and vinylstannanes such as in the synthesis of Deoxyvariolin B [56] (Scheme 6.8). 6.2.1.3.1


SMe SMe

I N

+ N

N

N

N

N Pd2dba3/PPh3 LiCl/CuI dioxane

Me3Sn

N

209

N

N N

H2N

H2N

Scheme 6.8

Of particular synthetic interest is the coupling of 5-halouracyls, 5-halouridines, 2-halopurines, 6-halopurines, 5-iodocytosine and 5-iodo-2-deoxythiouridine and their applications in the synthesis of modified nucleosides [57] as exemplified by the coupling of 8-bromo-1-ribofuranosidylpurin [58] (Scheme 6.9).

O NMe2 + Br

N N

O H N N

NHCOCHMe2

O OR

SnBu3 RO

N

Pd(PPh3)4 toluene R=SiMe2tBu

N Me2N

N

NHCOCHMe2

O OR

85%

OR

H N

RO

OR

Scheme 6.9 3

Few examples involving Csp -X electrophiles are reported. If, P(tBu)2Me was successfully used for the coupling of alkyl bromides with vinylstannanes, this ligand was shown to be ineffective for couplings with arylstannanes [59]. The ligand of choice for coupling aryl stannanes with alkyl bromides and iodides appeared to be the electron-rich cHex(Pyr)2P [60]. Acyl chlorides, chloroformates and carbamoyl chlorides couple efficiently with organotins giving access to various aldehydes, ketones and a,b-unsaturated ketones, a,b-unsaturated esters and amides, respectively. This reaction, which represents an alternative to the carbonylative three-component coupling reaction, was applied in total synthesis of cytotoxic mycalozol [61] , 10,11-dihydroleukotriene B metabolites [62] and 9-methoxystrobilurin [63]. Recently, a convenient and general one-pot synthesis of a-substituted amides and N-protected amines by a palladium-catalyzed three-component-coupling of imines, acyl chlorides or chloroformates, and organotin reagents was also described [64].

Sulfonates Aryl and heteroaryl sulfonates are extensively used as electrophilic coupling partners. The reaction of vinyl sulfonates is generally limited to triflates, even if some couplings of mesylates and tosylates are reported. It was observed that the addi6.2.1.3.2

210


tion of halide salts such as LiCl, is necessary when the coupling is performed in nonpolar solvents. The catalytic activity can be optimized when replacing strongly donating ligands by triphenylarsine ligands. The mechanism of the coupling with organic triflates is not well understood and remains a matter of debate. It is noteworthy that other sulfonate substrates including mesylates, [65] tosylates, [66] fluorosulfonates [67] and nonaflates [68] were employed.

6.2.1.3.3 Miscellaneous Various salts such as hypervalent iodines [69] aryldiazonium salts [70] and sulfonium salts [71] undergo facile Stille coupling. Acetates [72], carbonates [73] and phosphates [74] are also quite reactive. Finally, heteroaromatic tioethers [75] and sulfonyl chlorides [76] were recently reported to couple under palladium-catalyzed copper-mediated catalysis.

6.2.1.4 Intermolecular Stille Cross-coupling

6.2.1.4.1 Vinyl±Vinyl Coupling Vinyl±vinyl coupling was extensively used for the preparation of polyconjugated systems and widely applied to the preparation of complex natural molecules such as Cochlemycin A, [77] (+)-Crocacin D [78] (Scheme 6.10), Gambierol [79], Bafilomycin V1 [80], (±)-Sanglifehrin A [81] and Apoptolidin [82]. Stille coupling of a vinylstannane with cyclic vinyl halides was used for the preparation of Himbacine derivatives [83].

Me

Stille coupling Me NH

OMe OMe

Me

O

O

N H

OMe O

(+)-Crocacin D Scheme 6.10

The use of (E,Z)- or (E,E)-dienyltins and polyenyltins allowed the synthesis of polyconjugated natural products such as Cytostatin [84], (+)-Fostriecin, [85] Dermostatin A (Scheme 6.11) [86], Polycephalin C [87] and (+)-Calyculin A [88].


NaO O P HO O O

OH

OH

Stille coupling

O Me OH (+)-Fostriecin

Stille coupling O

OH O

OH

OH OH OH OH OH OH OH Dermostatin A Scheme 6.11

Some reactions of particular interest are some examples of tandem reactions such as (i) the Stille coupling/elimination sequence with a 1,1-dibromo-1-alkene in the preparation of Callipeltoside [89] or (ii) the Stille coupling/electrocyclization cascade in the synthesis of immunosuppressants (Scheme 6.12) [90] or (iii) distannylated reagents such as 1,2-vinylditin and 1,4-dienyltin used in double Stille reaction sequences [91] and peculiar cascade reactions [92]. O2N Me O2N

Me

I

+

CO2Me

Pd(MeCN)2Cl2

Me3Sn CO2Me

DMF

Me Me Me

40%

Scheme 6.12

Aryl±Aryl Coupling Aryl±aryl Stille coupling is a major tool in organic synthesis and was applied to the preparation of various ligands [93], catalysts [94] and to the design of materials with electronic and optical properties such as oligopyridines [95] and oligothiophenes [96]. All types of aromatic substrates were used and the reaction was shown to be tolerant to a wide range of functional groups such as chlorine or fluorine, trifluoromethyl, acetylenes, nitriles, ethers and thioethers, esters and amides, ketones and aldehydes, ketals, nitro, unprotected amines, hydroxyles or carboxylic acids. As previously mentioned (see Section 6.2.1.2.3), an ortho-substitution may sometimes alter the reaction, whenever some recent examples described the coupling of very hindered aryl substrates [54]. Interesting aspects of 6.2.1.4.2

211

212


this reaction are the possible polysubstitutions on aromatic rings [97] and sequential couplings depending on the intrinsic reactivity of each functionality of the substrate under a given set of conditions [98].

6.2.1.4.3 Carbonylative Coupling When conducted under a CO atmosphere, the organopalladium(II) species resulting from the oxidative addition are able, under a moderate pressure, to give an acyl palladium(II) intermediate that can further react with the organotin by the usual route of transmetallation and reductive elimination to give the carbonylated cross-coupled compound. If aryl, heteroaryl, alkenyl and benzyl halides were used as electrophilic coupling partners, their sulfonate counterparts are the most popular substrates and Stille carbonylative couplings often take place under mild conditions. Other substrates, such as mono- and difluoroiododecanes [99], triaryllantimony(V) diacetates [100], aryl diazonium salts [101] and hypervalent iodine compounds [102], were used as well. Aryl-, alkynyl-, akenyl-, allyl- and simple alkyltins couple even if double bond-migration is the major drawback with allylstannanes. The so-called ªcarbonylative Stille couplingº offers a good synthetic method for the synthesis of unsymmetrical ketones [103], a,b-unsaturated ketones [104] and esters [105]. Addition of LiCl and CuI permitted the palladium-catalyzed carbonylative cross-coupling of sterically hindered vinylstannanes to give the corresponding cross-conjugated 1,4-dien-3-ones [106] (Scheme 6.13). A practical synthesis of photoactivable 4-aroyl-L-phenylalanines from 4-iodo-L-phenylalanines was performed by using a carbonylative Stille cross-coupling as the key step [107]. A carbonylative coupling of organotin compounds with diaryliodonium salts was 11 employed to prepare C-labeled ketones [108].

Bu3Sn

OTf +

Me Pd(PPh3)4/CuBr/LiCl CO/THF SiMe3

O

Me SiMe3

90%

Scheme 6.13

It has to be noted that an interesting alternative to the carbonylative three-component coupling is represented by the use of functionalized acylstannanes. This methodology was applied to the synthesis of a-difluoroketones [109] and a,c-unsaturated ketones [110].

6.2.1.5 Intramolecular Stille Cross-coupling Vinyl±Vinyl Coupling Since the first intramolecular version described by Pierce in 1985 [111], the Stille cross-coupling has proven to be an ideal reaction to get rings ranging from four to 6.2.1.5.1


thirty-two members [112]. The main advantage of this methodology over the classical macrocyclizations lies in the fact that high dilution techniques are not required, so that it has been widely exploited to prepare macrocycles of biological interest. Most intramolecular Stille couplings involve alkenyl±alkenyl cyclizations, and it is noteworthy that the stereochemistry of both the alkene electrophile and the alkenyltin are conserved in the final cyclic structure [113]. An elegant example is the reported synthesis of (±)Macrolactin A, an extremely cytotoxic compound, via palladium-catalyzed Stille couplings for stereospecific constructions of the three isolated dienes, including the ultime macrocyclization [114] (Scheme 6.14). OTBS Bu3Sn

OTBS

I O

O

Pd2dba3, NMP DIPEA rt, 7 days

TBSO

O

O

TBSO TBSO

TBSO

42%

Scheme 6.14

Intramolecular alkenyl±alkenyl Stille cyclization was used in the synthesis of macrocycles such as Bafilomycin A [115], (±)-isocembrene [116], Lankacidins [117], Sanglifehrin [118], (+)-Concanamycin F [119], (±)-Pateamin [120], Apoptolidin [121], Concanamycin F [122], (±)-Lasonolide A [123], Rhizoxin D [124], Amphidinolide A [125], and thiazole derivatives related to Leinamycin [126] (Scheme 6.15). O

O O

Bu3Sn

H N

Br N S

O

Pd2dba3/P(OPh)3 i-Pr2NEt THF O

N

H N

O

S 52%

Scheme 6.15

Aryl±Aryl and Aryl±Vinyl Couplings Aryl±alkenyl and aryl±aryl cyclizations via Stille coupling are far less developed. In the case of alkenyl±aryl couplings, the olefinic moiety can be extracyclic or intracyclic with Z or E stereochemistry. An example is the cyclization of polymerbound alkenylstannane with aryl iodide moiety in the total synthesis of (S)-zearalenone [127] (Scheme 6.16). 6.2.1.5.2

213

214


MEMO

O O

i) Pd(PPh3)4, toluene, 100ºC ii)THF/HCl aq.

OH O O

I

MEMO

nBu nBu Sn

O

HO (S)-Zearalenone O

Scheme 6.16

Aryl±aryl cyclizations were used for the preparation of polyaromatic compounds, cryptands and heterocycles. A particularly interesting version is the Still± Kelly cyclization that was used for the synthesis of phenanthro [9,10-d]pyrazoles involving the intermolecular formation of the aromatic stannane followed by an intramolecular coupling with the aryl halide moiety [128]. Benzo [4,5]furopyridines [129] and dibenz [c,a]azepines [130] were prepared by related intramolecular coupling of diodides in the presence of hexamethylditin. The carbonylative macrocyclization using acyl chlorides and chloroformates as substrates represents an interesting tool for the synthesis of cyclic ketones, lactones, a,b-unsaturated esters. A complementary approach is based on the carbonyl insertion reaction with carbon monoxide and subsequent cross-coupling as exemplified by the approach to the core structure of Phomactins C and D, with an alkyne-enoltriflate carbonylative coupling as the key macrocyclization step [131] (Scheme 6.17).

OTf SnMe3

PdCl2dppf/LiCl CO

O

DMF

Scheme 6.17

6.2.1.6 Solid-Phase-Supported Stille Coupling The solid phase organic synthesis has offered, in the past decade, new investigation fields in the Stille coupling reaction. The first approach, in which the organotin is grafted to the polymer via the tin atom, follows the chemistry initiated by Pereyre and coworkers [132] and Kuhn and Neumann [133] and is illustrated by the synthesis of zearalenone (Scheme 6.16). The second approach in which the organotin is grafted to the polymer via the organic moiety, was exploited for the synthesis of biaryls [134] and benzopyrans [135]. The third approach, in which the substrate is bound to the polymer, has been widely used for aryl±aryl [136], and aryl±alkenyl [137] couplings. Recent illustrative examples are the solid-phase syntheses of 2,6,8-trisubstituted purines [138], substituted pyridylpiperazines [139] or uridines [140]. This methodology was also employed in the carbonylative three-


component Stille coupling as exemplified by the solid-phase synthesis of dissymmetrical diaryl ketones [141]. Finally, it is possible to perform the Stille coupling with polymer-supported palladium catalysts in order to facilitate the recovery and the reuse of palladium species [142].

6.2.1.7 Stille Coupling Catalytic in Tin In order to overcome the reluctance of using organotins, despite their great synthetic potential, Maleczka et al. proposed a vinyl-vinyl Stille coupling catalytic in tin by using a terminal alkyne and an alkenyl halide as substrates [143]. They described a one-pot tandem-catalyzed hydrostannylation [144]/Stille reaction protocol for the stereoselective generation of vinyltins and their subsequent coupling with electrophiles, employing only catalytic amounts of Me3SnCl. During this process, the organotin halide byproduct is recycled back to the organotin hydride by using either polymethylhydrosiloxane (PMHS) with Na2CO3 (the ªSn±O approachº) [145] or PMHS coordinated by KF (the ªSn±F approachº) [146] as the mild hydride donor. Two kinds of palladium catalysts are needed to catalyze both the hydrostannation (PdCl2(PPh3)2) and the cross-coupling (Pd2dba3/TFP). The protocol was recently extended to polymer-supported dibutyltin chloride and dimethylin chloride [147]. 6.2.2 Other Metal-Catalyzed Coupling Reactions 6.2.2.1 Palladium-Catalyzed Reactions

Some palladium-catalyzed reactions of organotins, such as carbostannylations, are not related to the Stille cross-coupling. The history of the transition-metal-catalyzed carbostannylation [148] began with alkynylstannylation of alkynes catalyzed by a palladium-iminophosphine complex [149]. Thus, alkynylstannanes added to a carbon±carbon triple bond of various acetylenes, conjugated ynoates and propargyl amines and ethers in the presence of a catalytic amount of a palladium±iminophosphine complex [150]. The reaction also proceeded with arynes to afford orthosubstituted arylstannanes, which could further be converted into 1,2-substituted arenes via carbon±carbon bond-forming reactions [151]. Me3SnSnMe3 reacted with allenes and aryl iodides in a three-component palladium-catalyzed carbostannylation to afford the corresponding allylstannanes [152]. Finally, Pd2dba3-catalyzed allylstannylations of various alkynes by an a-methylallylstannane were reported [153].

6.2.2.2 Copper-Catalyzed Reactions I It is now well known that the use of cocatalytic Cu salts dramatically enhances the reaction rate of sluggish Stille couplings by transmetallating the organostannane (see Section 6.2.1.1.2). Several studies established that the resulting organo-

215

216


copper species was able to couple with organic elcetrophiles without any palladium. Various cross-couplings of organostannanes with organic halides [154] and I triflates [155] under stoichiometric amounts of Cu were reported [156]. It was also demonstrated that a-heteroatom-substituted alkyltributyltins crossI coupled in the presence of catalytic amounts of Cu [157]. This catalytic use of copper salts was extended to various aryl±aryl, aryl±heteroaryl and aryl±vinyl crosscouplings [158]. I II In addition to the use of Cu [159], Cu salts such as CuCl2 [160] and Cu(NO3)2 [161] efficiently mediated and catalyzed the homocoupling of aryl, alkenyl and alkynylstannanes. Finally, a catalytic enantioselective approach for the formation of allyl a-amino acid derivatives by reaction of N-tosyl-a-imino esters with alkylstannanes catalyzed I by chiral Cu complex was developed [162].

6.2.2.3 Nickel-Catalyzed Reactions The three-component reaction between tetramethyltin, organic halides and carbon monoxide was the first reported example of nickel-catalyzed coupling involving 0 organostannanes [163]. This methodology was further extended to the Ni catalyzed coupling of alkynystannanes, allylchlorides and 1-alkynes for the regio- and stereoselective preparation of 3,6-dien-1-ynes [164], or 1,4-enynes [165]. Aryl mesylates were also used in cross-coupling with aryltins [166]. Nevertheless, recent synthetic applications dealt with the carbostannylation reactions of alkynes [167], 1,2-dienes [168] and 1,3-dienes [169] with alkynylstannanes, allylstannanes and acylstannanes (Scheme 6.18). Various mono- and disubstituted allenes participated in the reaction and acyl stannanes interestingly added mainly at an internal double bond. O O SnMe3

SnMe3

Ni(cod)2

+ Bu

toluene

Bu 79%

Scheme 6.18

6.2.2.4 Rhodium-Catalyzed Reactions The addition of organometallic reagents to carbonyl compounds is the general method to synthesize secondary alcohols and organotins are promising reagents for such chemoselective reactions. The allylation of aldehydes with allylstannanes can be catalyzed by transition-metal complexes such as rhodium [170]. This methodology was further extended to the addition of arylstannanes to carbon±heteroatom bonds in the presence of catalytic amounts of a cationic rhodium complex [171]. The reaction of aldehydes [172], a-dicarbonyl compounds and imines [173] (see also Section 6.3.2.3) with arylstannanes gave the corresponding alcohols,

6.3 Nucleophilic Additions

a-hydroxycarbonyl compounds and amines, respectively. The rhodium-catalyzed conjugated addition of aryl- and vinylstannanes to a,b-unsaturated ketones and esters has been targeted also to prepare arylated ketones and esters [174,175]. This reaction was used for the synthesis of natural and unnatural amino acid derivatives in air and water [176] (Scheme 6.19). O

O OEt SnMe3 + N

O

O

OEt

Rh2(cod)2Cl2 H2O/air sonication

N

O

O 82%

Scheme 6.19

6.3 Nucleophilic Additions 6.3.1 Nucleophilic Addition onto Carbonyl Compounds 6.3.1.1 Introduction

The addition of organotins to carbonyl compounds is a reaction of major importance in organic synthesis, especially with functionalized allyltins. There are several advantages such as (i) the easy preparation and stability of the organometallic reagents even under an enantiopure fashion, (ii) their great reactivity once the carbonyl partner is activated, (iii) the possibility to reach an excellent regio- and stereocontrol of the addition. Importantly, the organotin reagents authorize several mechanisms involving different transition states, so that the selectivity of the reaction appears to be closely dependent on the experimental conditions.

6.3.1.2 Functionalized Allyltins 6.3.1.2.1 Activation of the Carbonyl Compounds The first activation of the carbonyl substrate by a Lewis acid was reported in 1979 [177] and initiated the increasing use of organotin reagents. The reaction proceeds via an open transition state, as the tin does not compete with the Lewis acid in the coordination of the carbonyl. The diastereoselectivity of the reaction can be induced either by the organometallic or the carbonyl partners. Diastereoselectivity induced by c-substituted allyltins: the reaction leads to an excellent syn diastereoselectivity. First reported by Maruyama and coworkers [178], this was explained by proposing an antiperiplanar transition state for the syn selectivity whatever the nature (E or Z) of the crotylstannane. Contrastingly, it was also

217

218


reported that c,c-disubstituted allyltins reacted stereospecifically, (E)-reagent giving a syn adduct and (Z)-reagent giving an anti adduct [179]. The initial proposal was then completed by the synclinal acyclic transition state [180] to account for the diastereoselectivity change. This reaction was applied to various c-substituted allyltins in the total synthesis of complex frameworks [181] with excellent diastereoselectivities (Scheme 6.20). It is worth noting that a-substitution on the allyltin reagent may affect dramatically the syn selectivity as well [182]. Thus, the syntheses of optically active a-oxygenated allyltins and their subsequent rearrangement to c-alkoxyallyltins [183] allowed an easy access to stereocontrolled 1,2 syn diols further applied to synthetic purpose [184]. OBn

O C10H21 MOMO

H O H

MOMO H

SnBu3

.

BF3 OEt2, CH2Cl2, -78ºC

OTs

OH C10H21 MOMO

H O H

OBn OTs

OMOM

80%

Scheme 6.20

In addition to the amount of work done with aldehydes as substrates, there is some evidence of diastereoselective addition of c-substituted allyltins to ketones, leading to tertiary homoallylic alcohols withTiCl4 or SnCl2 as Lewis acid [185]. Diastereoselectivity induced by chiral aldehydes: the substrate plays an important role in the facial diastereoselection, particularly when there is an asymmetric center adjacent to the carbonyl group. In the general case, the approach of the allyltin is assumed to follow the Felkin±Anh model giving the syn adduct preferentially. This induction was used for the synthesis of natural products [186] even as complex as Ciguatoxin or Laulimalide [187]. Chelation control: however, a reversal of the diastereofacial selectivity may arise when the substrate has, in the a or b position of the side chain, a group prone to II complexation with the Lewis acid. Then, the use of bidentate Lewis acids (Mg , II IV IV Zn , Sn or Ti ) allows the reaction to proceeding under a ªchelation controlº, model preferentially provides the syn adduct for a 1,4-chelation. Various a-alkoxy aldehydes [188] were used in carbohydrate chemistry. Similarly, a-amino aldehydes were used as precursors for b-amino alcohols (Scheme 6.21) [189]. On the contrary, a 1,5-chelation control gives predominantly the anti adduct, so that b-alkOH

O SnBu3

H BOC

N

O CH2Cl2

.

BF3 OEt2, -78ºC

.

MgBr2 OEt2, -20ºC Scheme 6.21

BOC

N

OH O

+ BOC

N

O

12

:

88

84% (Felkin-Anh)

83

:

17

87% (chelated)


219

oxy aldehydes are frequently used in total synthesis of complex targets such as Discodermolide [190] or Roxaticin macrolide [191]. Match/mismatch effect: the addition of c-substituted allyltins to a-substituted aldehydes leads to three contiguous asymmetric centers mostly with a good control of each diastereoselectivity and is commonly applied in total synthesis such as for Erythromycin [192] (Scheme 6.22). It has to be noted that when the reaction is done with a chiral aldehyde and a chiral d-substituted allyltin, a ªmatching effectº may happen when both partners imposed a convergent selectivity, or a ªmismatching effectº when the facial selectivity is divergent [193]. Such a stereoconvergent effect was used in the synthesis of the antitumor agent Azinomycin [194].

O

Mes

Mes OTES +

O OR

OBOM

CHO

SnBu3

.

O OTES

BF3 OEt2 CH2Cl2, -78ºC

96% dr = 8:1

O OBOM

OR OH

Scheme 6.22

As an alternative to the use of Lewis acids, Brönsted acids, such as trifluoromethane sulfonic acid, can be used for the allylation of aldehydes in EtOH/H2O [195]. Using the same idea, a chelation control can be carried out without any Lewis acid simply by adding lithium salts such as LiClO4 to the reaction mixture [196].

Activation of the Allyltin Reagent In situ transmetallation: the activation of the allyltin can be ensured by a transmetallation with the Lewis acid prior to the addition on the carbonyl (also called ªreversedº addition). The first example was reported with SnCl4 [197] but other Lewis acids such as TiCl4, AlCl3, InCl3 can be used. The difference lies in the nature of the transient allyl metal, which becomes a stronger Lewis acid, implying a cyclic 6-membered transition state already involved in thermal or high-pressure activated allylations. This changes the diastereoselectivity pattern of the reaction, (E)-crotyltin giving an anti selectivity, when (Z)-crotyltin leads to syn selectivity. It has to be noted that the transmetallation proceeds via the kinetic allylmetal, which turns to the thermodynamic crotyltin. Under thermodynamic control, the homoallylic alcohol is usually obtained with a high level of anti selectivity. The transmetallation can be used with more sophisticated Lewis acids such as the C-2 symmetry Corey's bromoborane, in order to induce a stereoselectivity dominated by the chiral auxiliary [198] (Scheme 6.23). 6.3.1.2.2

220


Ph 1) SnBu3

TBSO

OTBS

Ph

Ts N B Br N Ts

2)

rt, 10h O HO

OPMB

95% dr = 8.5:1

-78ºC, 1.5h

OHC

O

OPMB TBSO

OTBS

Scheme 6.23

Stereochemical outcomes: the easy and efficient access to enantiopure a-substituted allyltins associated to the transmetallation process is at the origin of an impressive progress in the field of enantioselective synthesis [199]. This is due to the ªchirality transferº that occurs in the two steps of the reaction. Thus, an efficient enantioselective synthesis of 1,2 diols can be achieved starting from enantioenriched a-alkoxytins. However, in some case the use of a strong Lewis acid caused a premature decomposition of the allyltin. Marshall et al. circumvented this by using InCl3 [200] and applied it to the enantioselective synthesis of sugar related compounds [201] (Scheme 6.24). OMOM OH OBn

SnBu3 InCl3, EtOAc O

OBn

OMOM via

OTBS MOMO

OBn

InCl2 89%

OTBS

H OBn

OH OBn

InCl3, EtOAc

OMOM via

OTBS

InCl2

OMOM MOMO

OBn

95%

SnBu3 Scheme 6.24

The enantiocontroled preparation of c-substituted allyltins was also used for the enantioselective synthesis of functionalized homoallylic alcohols. A major contribution is given by a comprehensive study of Thomas on various alkoxylated allyltins, which upon transmetallation with SnCl4 gave intramolecularly coordinated trihalogenotins [202]. This coordination appears to be essential either for its stabilization via a rigid cyclic structure, and for the transfer of the chirality by directing the addition on the less hindered face of the trihalogenotin (Scheme 6.25). Interestingly, when using a-chiral aldehydes, the stereochemical induction of the tin reagent prevails over that of the substrate [203] effect. Efficient 1,4-, 1,5-, 1,6-, and 1,7-asymmetric inductions were achieved in that way [204], and have


221

found application in the total synthesis of Epipatulolide and Epothylones macrolides [205], or complex tetrahydrofurans [206]. OH

1) SnCl4, CH2Cl2, -78ºC, 10 min Bu3Sn OSEM

O

2)

via Cl3Sn OSEM

-78ºC, 10 min

OSEM

H 77%

syn:anti = 96:4

Scheme 6.25

Finally, the stoichiometry of the added Lewis acid has to be taken into account. Indeed, this factor is often underestimated but may cause a complete reversal of the stereoselectivity of the addition, by creating a chelation control that can compete with the cyclic 6-membered transition state [207].

6.3.1.3 Catalytic Use of Lewis Acid There is a great effort underway to find a catalytic version of the Lewis-acid-activated reaction. Bulky aluminum reagents may be used (5 to 10 mol%), for which the development of unfavorable interactions with the resulting tributyltin alkoxide moiety is accounted for the decomplexation reaction [208]. Lanthanide triflates (2 mol%) were also used, in the presence of stoichiometric amounts of benzoic acid in order to regenerate the Yb(OTf)3 catalyst [209]. InCl3 can perform allylation and alkynylation addition reactions in a similar way, when associated to trimethylsilylchloride as regenerating reagent [210]. The transmetallation of allyltributyltin with catalytic quantities of dialkyldichlorotin leads to a much more reactive allyldialkylchlorotin. The turnover of the catalytic system is maintained by HCl [211] or Me3SiCl [212]. The catalytic effects of B(C6F5)3 or PhB(C6F5)2 were also evidenced with a good chemoselectivity [213] and appeared to be influenced by the acidity of the Lewis acid [214]. Lastly, an association of triarylmethyl chloride as Lewis acid and chlorosilane as regenerating agent, was described as giving promising results [215].

6.3.1.4 Enantioselectivity In parallel with the search for catalytic systems, has emerged an impressive amount of results in the field of enantioselective allylation. The pioneering work of Marshall using a chiral (acyloxy)borane (CAB) system [216] was readily followed by titanium/BINOL catalysts [217], leading to homoallylic alcohols with enantiomeric excess up to 98%. An extension of this work in fluorous phase was also developed with 6,6¢-perfluoroalkylated BINOLs [218]. Replacing the titanium by zirconium (IV) salts, led to more reactive catalyst for the allylation of aromatic and aliphatic aldehydes [219]. One of the more active catalyst is the zirconium-BINOL system associated with 4-tert-butylcalix [4]arene, which remains active with only 2% of the chiral inductor [220]. The use of activators, such as iPrSSiMe3, iPrSBEt2,

222


iPrSAlEt2 or B(OMe)3 was reported for both systems. They are believed to accelerate the reaction by regenerating Ti [221] or Zr [222] catalysts. It was demonstrated that BINOL catalysts authorize the b- and c-functionalizations of the allyltin reagents without lowering the enantioselectivity level [223], and such a strategy was used in the total syntheses of macrolides [224] or substituted tetrahydropyran units [225]. It was noteworthy that the BINOL-Ti catalysis was extended to the enantioselective allylation of alkyl and aromatic ketones in good yields with up to 96% ee [226]. Silver/BINAP was used as well, with a marked anti selectivity, when using crotyltins whatever is the nature, (E) or (Z) of the double bond [227]. This reaction was extended to other organometallics such as 2,4-pentadienylstannanes [228] or buta-2,3-dienylstannanes [229] (Scheme 6.26). O Ph

OH

(S)-BINOL-TiIV, Et2BSPri

H H +

•

SnBu3

PhCF3, -20ºC, 8h

Ph

74% (ee:97%)

Scheme 6.26

Alternatively, catalysts with nitrogen ligands such as bisoxazolines [230] were introduced as Lewis acids, as well as air-stable and water-resistant (Phebox)rhodium(III) complexes that gave up to 80% ee [231].

6.3.1.5 Others Organotin Reagents Activated Allyltins Monoallyltrihalogenotins prepared without transmetallation [232] by oxidative addition organic halides to stannous halides or stannylene reagents, are interesting because all the tin side products are inorganic, allowing an easy purification and giving a solution to the toxicity problem of tributyltin residues. They have been used for the preparation of homoallylic alcohols [233], and the synthesis of a-methylene-c-butyrolactones and a-methylene-c-butyrolactames when starting from b-functionalized allyltins [234]. The anti/syn selectivity was about 90:10 and is consistent with a cyclic transition state. Adjacent groups to the carbonyl can affect the stereochemistry by hexacoordinating the tin atom and directing the reaction under a chelation control [235]. This ability of allylhalogenotins to extend their coordination sphere allowed the preparation of chiral hypervalent complexes with diamine ligands, which were efficient in the asymmetric synthesis of homoallylic alcohols with up to 82% ee II [236]. Similarly, a chiral hypervalent allyltin was prepared from low valent tin catecholate, chiral dialkyltartrate and allylic halide [237]. The allylation of aldehydes and activated ketones proceeded with high enantiomeric excess. Other developments involving allyltins supported on solid phase are under study and are shown to proceed with the similar diastereoselectivity to that observed in liquid phase [238]. 6.3.1.5.1


223

Allenyl- and Propargyltins Allenyl- and propargyltins are peculiar reagents due to a possible interconversion, catalyzed by Lewis acids, between the two forms, thus leading to a mixture of homopropargylic and homoallenic alcohols. Complementary studies showed that it is possible to get selectively homoallenyl alcohols and homopropargyl alcohols [239] when preparing in situ the organotin reagent. The asymmetric approaches include the preparation of the chiral allenyltin configurationally stable, starting from enantio-enriched propargylic precursors. When submitted to transmetallation with Sn, Bi, or In Lewis acids, prior addition to the aldehyde, the homopropargylic alcohol was obtained in a 95:5 anti/syn fashion and a 90% ee [240]. On the other hand, the use of chiral allenyltin reagent without former transmetallation gave the syn adduct selectively (95:5) [241] (Scheme 6.27). Similarly to what is observed with allyltins, the use of chiral allenyltins and chiral aldehydes may lead to the same ªmatch/mismatchº effect [242]. Both approaches were applied to the synthesis of Discodermolide polyketide or Aplyronine macrolide [243]. 6.3.1.5.2

.

Me BnO

BF3 OEt2, CH2Cl2 H

Me

OH

O SnCl4, hexane H Me

reversed addition

OAc

Me

.

SnBu3

BF3 OEt2, CH2Cl2

H O

SnCl4, hexane reversed addition

(acyclic TS + Cram) syn,syn

(cyclic TS + chelation) anti,anti

OH Me Me BnO OH Me Me

Me

OAc

Me

BnO

•

BnO

Me

BnO

OAc

(acyclic TS + chelation) syn,anti OAc

BnO OH

OAc

(cyclic TS + Cram) anti,syn

Scheme 6.27

Catalytic asymmetric allenylation was explored with the BINOL/Ti system giving selectively the homoallenyl alcohol with up to 95% ee [244]. Nevertheless, the lower reactivity of allenyltins compared to allyltins necessitated a nearly stoichiometric amount of the catalyst. Recently, the system BINOL/Ti/iPrSBEt2, overcame this limitation, making the system truly catalytic, with ee in the range of 81 to 97% [245]. Interestingly, this reaction gave exclusively the allenylation adduct irrespective to the propargyl or allenyl structure of the organotin reagent [246].

6.3.1.5.3 Alkynyltins The nucleophilic addition onto aldehydes was also extended to alkynyltributyltins, which were found to be reactive upon transmetallation with catalytic amount of InCl3 [247]. The direct addition of alkynyltrimethyltins onto b-alkoxy aldehydes

224


was also reported with a 1,3-anti//syn selectivity reaching 94:6 when using MeAlCl2 as Lewis acid [248]. 6.3.2 Nucleophilic Addition onto Imines and Related Compounds 6.3.2.1 Reactions with Imines Introduction Similarly to what was observed with carbonyl compounds, allyltins need the help of Lewis acid to react with imines. This was reported with TiCl4 and BF3.Et2O [249] and extended to various Lewis acids such as MgBr2, Et2AlCl, NbCl5 [250]. It was also demonstrated that TiCl4 participated exclusively by activating the imine, so that contrary to what was observed with aldehydes, the ªreverse additionº failed to give any homoallylic amine with the noticeable exception of SnCl4. Other activating agents such as Selectfluor mediated smooth allylstannation of aldehydes and imines [251]. Similarly to what was evidenced with carbonyl compounds, the activation of the iminyl group can be achieved catalytically by using La(OTf)3 as Lewis acid [252]. Such catalytic activation associated to benzoic acid was applied to the three-component synthesis of homoallylic amines, by the in situ formation of various imines [253]. Such a multicomponent version of the reaction was realized in water with SnCl2.2H2O as Lewis acid [254]. 6.3.2.1.1

Mechanisms and Diastereoselectivity Allyltins are the only allylmetals, with allylboron, to add regioselectively onto imines providing exclusively c-adducts. The syn/anti selectivity of the addition can be explained with two sets of models involving cyclic or open transition states [255]. Crotyltins react regioselectively with a-alkylimines to give exclusively branched products with an excellent syn/anti selectivity up to 30:1, when the imine activation is done at ±78 C prior the addition of the crotyltin. This selectivity, consistent with an acyclic transition state, rapidly fades when operating at higher temperature, as a result of an equilibrium between the two imine/Lewis acid complexes. All the models already discussed for the diastereofacial selectivity in the case of carbonyl compounds are still valid for the imines. However, due to the substitution on the nitrogen atom, imines can possess an additional chiral auxilliary capable of influencing the diastereoselectivity. Carbohydrates, for instance, were used as chiral templates, for the synthesis of N-glycosyl-N-homoallylamines and b-aminoacids [256]. As a consequence, the introduction of chiral centers both on the carbonyl and the amine moieties of the substrate may cause matching or mismatching effects [257]. The first exemple of 1,2-asymmetric induction, reported by Yamamoto et al., involved N-propylaldimines derived from a-phenylpropionaldehyde. The reaction gave mainly the anti product [258], consistent with a Felkin±Ahn approach. The 1,3-asymmetric induction was studied with the imine, prepared from 1-phenyl6.3.2.1.2


225

ethylamine and isovaleraldehyde, leading to a somewhat lower 7:1 diastereoselectivity. Thomas and coworkers were able to extend its 1,5-asymmetric induction concept (see Section 6.3.1.2.2) to the allylation of imines, by using SnCl4 as transmetallating agent [259]. The stereochemistry of the reaction was usually imposed by the organotin partner (Scheme 6.28), whenever, in some cases, a match/mismatch effect could occur between the facial selectivity of the imine and the 1,5-stereoselectivity of the stannane.

OBn

N BuO2C

OBn Bu3Sn

Ph

+

Bu3Sn

Ph

+ BuO2C

HN

Ph

OBn

Ph

OBn

73% (96:4)

CH2Cl2, -78ºC BuO C 2

H

N

SnCl4

H

SnCl4

HN

72% (90:10)

CH2Cl2, -78ºC BuO C 2

Scheme 6.28

There are very few examples with a,b-unsaturated aldimines, but it has to be noted that under TiCl4 activation, they are able to undergo a 1,4-nucleophilic addition of ketene silyl acetal followed by a 1,2-addition of the allyltributyltin on the resulting imine giving the homoallylic amine in good yield [260].

6.3.2.2 Other Imino Substrates Reactions with Iminium Salts Iminium salts are widely used substrates to overcome the lack of reactivity of imines. Most of the iminium salts are prepared in situ, such as acyliminiums, generated from the corresponding a-ethoxycarbamates, which were shown to react with c-alkoxyallyltins to give a-amino alcohols in good yields. The syn/anti selectivity is dependent on the nature of the iminium substituents [261]. This reaction was extended to various cyclic a-alkoxycarbamates with high diastereoselectivities [262]. Imines can also be activated by Me3SiCl to give the corresponding iminium salt reactive enough to undergo the allylation reaction with allyltributyltin [263]. An interesting activation by organoaluminums in the presence of benzoyl peroxide was used to achieve tandem N-alkylation-C-allylation or N-silylation-C-allylation reactions [264] (Scheme 6.29). 6.3.2.2.1

p

N R

An

1) (TMS)2AlCl (2eq), BPO (1.eq) AllylSnBu3

CO2Et

EtCN -20ºC 2) aq KF

Scheme 6.29

H R EtO2C

p

N

An 58 - 93 %

226


In situ formed iminiums were also able to react with alkyltins in an intramolecular fashion, leading to the formation of cyclopropane [265] or cyclopentane rings (Scheme 6.30). Similarly, the intramolecular reaction of c-alkoxystannane with hydrazones, activated by a Lewis acid, was used to prepare 5- or 6-membered b-amino cyclic ethers, for which the trans preference for the cyclization was consistent with an acyclic transition state [266]. SnMe3

SnMe3

SnMe3

MgBr O

THF, -78ºC N Boc OR

TFA HO

CH2Cl2, 0ºC N Boc OR

N Boc OR

N Boc OR 58% two steps

Scheme 6.30

Chiral acyliminiums were used for the preparation of enantiopure piperidines [267]. Recently, the use of enantio-enriched c-alkoxyallyltins onto chiral acyl iminiums [268] provided a new entry into the synthesis of potential precursors of a-amino-b-hydroxy acids or aminosugars, with a total control of the stereochemistry.

6.3.2.2.2 Reactions with N-heterosubstituted Imines These reagents are used as ªprotectedº imines, which upon allylation and subsequent deprotection give an access to primary homoallylic amines. For instance, the use of benzoyl- and acylhydrazones as stable surrogates of imines were exploited in allylation reactions with tetraallyltin [269]. Finally, nitrones can be used as substrates for allylation reactions giving access to homoallylic hydroxylamines [270].

Reactions with Pyridines and Pyridiniums Allyltins also react with similar substrates such as pyridines or pyridiniums selectively to the a position [271]. An enantioselective approach was done with a chiral acyl chloride as activator and enantioselectivity inductor [272]. This approach was applied to heterocycles such as b-carboline, leading to both enantiomers depending on the nature of the allyltin engaged in the reaction (Scheme 6.31) [273]. Similarly, oxazolidinones were used as chiral auxiliaries, to promote the synthesis of chiral 1,4-dihydropyridines [274]. 6.3.2.2.3

6.4 Radical Reactions of Organotins

N CO R 2 N H 91% (ee:84%)

1) All4Sn, SnI4 ClCO2R CH2Cl2, -78ºC 2) NaOH, rt

N N COR*

1)

SnBu3 ClCO2R

CH2Cl2, -78ºC 2) NaOH, rt

227

N CO R 2 N H 98% (ee:86%)

Scheme 6.31

6.3.2.3 Catalytic Enantioselective Addition Organotins are involved in the increasing work related to the catalytic enantioselective addition to imines [275]. The first example of catalytic, enantioselective allylation of imines was reported by Yamamoto and coworkers by using 5% of bis p-allyl palladium complex [276]. Contrary to the BINAP ligand, which was found to be totally ineffective under these conditions, b-pinene ligands used as nontransferable allyl ligands gave up to 81% ee. Nevertheless, it was shown that TolI BINAP-Cu catalysts were also efficient for the allylation of N-tosyl imines [277] giving access to a-amino acids with up to 98% ee. Finally, a polymer-supported p-allyl palladium catalyst was developed, showing promising results in terms of stability and reusability, although leading to a moderate ee (13±47%) [278].

6.4 Radical Reactions of Organotins 6.4.1 Introduction

The radical chemistry of organotins is overwhelmed by the tin hydride chemistry. In the past decades, the knowledge of kinetic parameters authorized the expeditious construction of complex molecules by using cascade radical reaction based on Bu3Sn methodology. Moreover, these strategies also offered an excellent diastereocontrol, especially for the construction of polycyclic skeletons. These synthetic applications of Bu3SnH, which will not be covered in this chapter, were reviewed in recent years [279]. In addition to the tin hydride chemistry, there are several applications of organotins in radical syntheses involving mainly allylstannanes. 6.4.2 Allyltins 6.4.2.1 Mechanistic Overview

Whereas the demonstration of the ability of allyltin reagents to undergo homolytic cleavage of the carbon±tin bond goes back to the early 1970s [280], it was only ten years later that Keck and Yates evidenced the synthetic potential of this reaction

228


[281]. This remains nowadays a particularly useful way for introducing various functionalized allyl groups under mild and neutral conditions. The radical chain mechanism involving allyltins is a SH2¢ mechanism that can be schematized as following (Scheme 6.32): the initiation step (i), producing the tributyltin radical, is done usually by thermolysis of radical initiators or photochemical irradiation of Bu6Sn2. The reaction (ii), forming the initial carbon radical, admits various substrates such as iodides, bromides, selenides, dithio- and thiocarbonates. Less reactive substrates such as chlorides, benzoates or phenylthioethers can be used as well, because the competitive addition of tributyltin radicals to the allyltin reagent is degenerated due to the reverse b-fragmentation of the resulting radical. By the way, less reactive substrates such as chlorides, benzoates or phenylthioethers can be used efficiently as well. The additions of radicals to the allyltin (iv) are approximately a hundred times slower than the hydride transfer [282], avoiding a premature quenching of the carbon radicals, so that the evolution of the primarily formed radical, via several intra- or intermolecular elementary steps (iii), is technically possible, without using any slow addition or high dilution techniques [283]. This authorizes multicomponent intermolecular coupling reactions, involving activated olefins [284], or carbon monoxide [285] for instance. Finally, a rapid 6 ±1 b-scission (v) with kf being likely over 10 s occurs to regenerate the tributyltin radical. SnBu3 i Bu3Sn R1-X

2

R

ii

v

R2

R1

SnBu3

iii

iv SnBu3

Bu3SnX

R2

Scheme 6.32

The addition of carbon radicals to allylstannane is not severely affected by their nature, whenever the electrophilic radicals attack the allyltin p bond more rapidly than nucleophilic alkyl radicals [286], thus authorizing a wide range of substrates to react. As a consequence, the radical allylic transfer was applied to the synthesis of complex structures such as b-lactams [287], steroids [288], alkaloids [289] or


C-glycosides [290]. Moreover, polycyclic substrates permitted the reaction to proceed with an excellent diastereoselectivity (Scheme 6.33) [291]. O

O H

O

O I

H

H

+

SnBu3

H

O

AIBN

O PhH, 80ºC

N

H

H

N 62%

Scheme 6.33

6.4.2.2 Functionalized Allyltins The synthesis and use of functionalized allyltins has been widely explored and gave contrasting results depending on the substitution position. Baldwin evidenced that the substitution in a-position has to be avoided, as the competitive tin radical addition to the double bond is no longer degenerated and results in an isomerization to the nonreactive c-substituted allyltin. By contrast, the use of allyltins b-substituted by an electron-withdrawing group represents a particularly attractive option, due to their enhanced reactivity towards nucleophilic carbon radicals. For this purpose several allyltins were prepared with amide, ester, chloride, nitrile, trimethylsilyl and sulfones functionalities [292]. They have been used for the synthesis of 1,4-dienes [293] or 10±15 membered a-methylene lactones [294], in aminoacids [295] or carbohydrate chemistry [296]. ~ The -functionalization by nonactivating alkyl groups is tolerated as well and was used in the synthesis of prostaglandins [297] or b-lactams [298]. This was also applied to radical cascade reactions with up to four elementary steps with an excellent diastereoselectivity control (Scheme 6.34) [299].

tBuO

tBuO

I +

O Me

CO2Me SnBu3

AIBN PhH, 80ºC

O

O

H

CO2Me

Me O

68% 81% de

Scheme 6.34

Substitution in the c-position, led to poorly reactive allylstannanes, due to the decreasing rate of the radical additions to the double bond. It has been established that, generally, the competitive allylic hydrogen abstraction became predominant, leading to diene side-products [300]. There are very few successful examples using c-substituted allyltins in an intermolecular fashion [301], however, this limitation can be overcome for the intramolecular cyclization processes [302]. Recent advances showed that a-carbonyl radicals added efficiently to crotylstannanes at

229


230

low temperature with an Et3B/O2 initiation process giving interesting diastereoselectivities (Scheme 6.35) [303]. O O

O

O + R I +

N

Et3B / O2

Bu3Sn

O

O N

R

CH2Cl2, -78ºC

up to 70% dr up to 3.7:1)

Scheme 6.35

6.4.3 Other Organotin Reagents 6.4.3.1 Tetraorganotins

Some related reagent, the 2,4-pentadienyltin, was shown to be reactive as well [304]. Propargyltin was equally found to be efficient for transferring an allene group [305]. However, a larger excess of propargyltin is needed, due to the radical isomerization of the propargyltin to the less reactive allenyltin. This was used in the synthesis of modified nucleosides [306]. Vinyltins were used for synthetic purpose in radical addition/elimination sequences. The main limitation comes from the necessity to functionalize the olefin by suitable groups, such as phenyl [307] or esters [308], in order to stabilize the transient carbon±centerd radical. This was applied to the stereoselective preparation of 1¢-C branched nucleosides (Scheme 6.36) [309]. An intramolecular version was also developed, giving access to methylene cyclopentane units [310]. O NH

O O

O

O

O N

TIPDS O

tBu NH

Br

O

+ Bu3Sn (5 eq)

(Bu3Sn)2; hν Ph

PhH, rt

O

O

N

O Ph

TIPDS O

O O

71% (E:Z = 10:1)

tBu Scheme 6.36

Tin enolates are in metalotropic equilibrium between the O- and C-stannylated forms, so that the enolate form can be considered as the oxygenated analog of an allyl tin. Thus, the SH2¢ reaction can be extended to tin enolates, used as electronrich scavengers for carbon-centerd radicals [311]. A synthetically useful extension of this reaction proposed the carbostannylation of alkenes with tin enolates [312], which can be associated to cascade radical process (Scheme 6.37).


SnBu3 TsN

O +

Bu3Sn

AIBN Ph

TsN

Ph

PhH, 80ºC O

67%

Scheme 6.37

Finally, alkyltins can participate in radical chemistry, especially when the b-elimination is thermodynamicaly favored, leading, for instance, to carbocyclic ring expansions [313]. In a similar way, radical reactions involving a 1,3-stannyl shift could afford 5-exo cyclizations [314].

6.4.3.2 Modified Organotins In contrast with the important amount of work done to solve the purification problems caused by organotin side products in tin-hydride chemistry, very little attention has been paid to the allyl transfer process. Nevertheless, as most of the radical reactions are conducted with an excess of the allyltin, new allyltin reagents were proposed to optimize the purification process. An alternative was developed using monoallyltins, giving after reaction hydrolysable, inorganic tin side products [315]. They were able to transfer efficiently the functionalized allyl group via a radical chain mechanism using XSn [N(TMS)2]2 as the chain-carrier agent [316]. Allyltin reagent supported on polymer underwent free radical allylic transfer with a marked preference for electron-poor carbon radicals [317]. Finally, the fluorous method developed by Curran was recently successfully extended to a four components radical reaction, using fluorinated allyltin reagents [318]. 6.4.4 The Stereoselective Approach

Radical chemistry was long considered to be unable to achieve stereoselective reactions in acyclic reactions. There is actually a continuous interest in finding systems allowing radical chemistry to proceed with high levels of stereoselectivity. With that aim, the Et3B/O2 initiation system is commonly used at low temperature. Most of the work done with allyltributyltin is relevant to the 1,2-asymmetric induction. The first approach consists in making rigid the acyclic transient radical to induce a facial diastereoselection. This can be done either by favoring hydrogen bonding [319], or by adding bidentates Lewis acids, which permit work to be done under chelation control. The use of MgBr2.OEt2 for the allylation of a-iodo-b-alkoxyesters at ±78 C gave de over 100:1 [320]. Lanthanide triflates are able to give up to 10:1 de at refluxing dichloromethane [321]. The ªchelation controlº approach was also used in 1,3-asymmetric induction of a-bromoketones (Scheme 6.38) [322]. Importantly, this methodology can be extended to achiral substrates by using chiral Lewis acids, prepared from Zn (OTf)2 and Pfaltz ligands, reaching up

231

232


to 90% ee [323]. Recent developments with MgI2 and bisoxazoline ligands permitted the successive creation of two chiral centers with the control of relative and absolute stereochemistry [324].

tBu Br HO

nPr O

+

SnBu3

1) MgBr2.OEt2 2) Et3B/O2 CH2Cl2, -78ºC

tBu HO O

nPr yield up to 90% de up to 100:1

Scheme 6.38

The stereocontrolled introduction of the allyl group was studied with various chirality inductors such as chiral sulfoxides [325]. The use of Lewis acid or arylurea additives, to complex the sulfoxide, enhanced the stereoselection up to 50:1 [326]. Chiral auxiliaries such as oxazolidinones were reported to act efficiently when the allylation is done on the oxazolidinone ring [327]. The lower selectivity usually obtained when the reaction is done on the tethering chain of the oxazolidinyl nitrogen [328] was overcome by using a Lewis acid in order to proceed under a chelation control, raising the selectivity up to 100:1 [329]. A recent example of carbon-centerd radical generated in the a position to the nitrogen showed a good diastereoselectivity even without any Lewis acid. The de, up to 98:2, remained, however, strongly dependent on the radical nature [330].

6.5 Transmetallations 6.5.1 Introduction

Discovered by Seyferth and Weiner in 1959 [331], the transmetallation reaction consists of the replacement of the tin atom by another metal and has partly been dealt in this chapter for the activation of allylstannanes by Lewis acids in the nucleophilic addition reactions (Section 6.2.1.2.2) and for coupling reactions mediated by copper (Section 6.1.1.1.2). That apart, tin-to-lithium exchange is by far the most important process from the synthetic point of view and it was widely applied to the synthesis of compounds of biological interest. This popularity can be explained by the reactivity of the tin±carbon bond, which makes organotin reagents better candidates for this reaction than their silicon counterparts as well as by the compatibility of the process with a wide range of functional groups. Other elements including boron and copper are also regularly used in transmetallation reactions.

6.5 Transmetallations

6.5.2 Tin-to-lithium Exchange 6.5.2.1 a-Heterosubstituted Alkyltins

It was established very early that both oxygen and nitrogen atoms considerably increased the stability of a a-carbanion [332] so that a-heterosubstituted organolithiums have gained considerable importance as normal synthetic intermediates. A great deal of knowledge was accumulated about their mode of generation, their stability and their reactivity with various electrophiles [333]. This explains the amount of literature on the use of a-heterosubstituted organotins in tin-to-lithium transmetallation [334]. Another striking point of the process is the complete retention of configuration at the carbanion.

Oxygen-substituted Organotins Since Still introduced the use of a-alkoxyorganostannanes as precursors of a-alkoxyorganolithium by tin±lithium exchange [335], this chemistry was exploited in a variety of applications including the stereocontrolled synthesis of complex natural molecules, such as Zoanthamine [336] and Aspidospermin [337] alkaloids and (+)-Taxusin [338]. The transient alkyloxymethyllithium can react intermolecularly with electrophilic subtrates as illustrated by the diastereoselective addition to aldehydes of an a-alkoxyorganolithium prepared from a chiral derivative of tributylstannylmethanol by lithiodestannylation [339]. 6.5.2.1.1

Ph O

1) n-BuLi 2) PhCHO/THF 3)CSA/MeOH/rt SnBu3

HO

Ph (S) OH

85% (S:R 80:20) Scheme 6.39

The organolithium intermediate can also react intramolecularly [340] as exemplified by the intramolecular anti-selective 5-exo-dig carbolithiation of a-lithiated x-carbamoyloxy-1-alkynyl carbamates for the synthesis of highly enantio-enriched protected 2-alkylidene-cycloalkane-1,3-diols [341] (Scheme 6.40). 1) n-BuLi/LiCl/THF/-100ºC 2)MeOH, -100ºC to rt

OTBS CbO SnBu3 (1S,5RS) d.r. 50:50 >95ee

OCb

TBSO

OCb H

OCb

37% (96% ee) Scheme 6.40

233

234


Nitrogen-substituted Organotins It has been known since 1971 that a-amino organostannanes can serve as useful precursors of a-amino organolithiums [342]. The configurational stability of a-amino organolithiums was applied to the transfer of chiral aminomethyl units via an (aminomethyl)lithium intermediate, thus making the organostannane precursors interesting tools for the enantiosynthesis of b-amino alcohols, a-amino ketones, and unusual a-aminoacids. For synthethic applications, much attention has been given to cyclic systems, in particular to piperidines [343], pyrrolidines [344], pyrrolidinones [345], oxazolidines [346] and oxazolidinones [347]. Gawley and Zhangreported the synthesis of 2-lithiopyrrolidines and piperidines from the corresponding 2-stannyl derivatives and their reaction with different electrophiles [348]. The stereochemistry of the reaction depended on the nature of the electrophile, as ketones, aldehydes and esters reacted with retention, alkyl halides reacted with inversion, while electrophiles such as benzyl bromide, ethyl bromoacetate and benzophenone gave complete racemization. An interesting application is the preparation of N-(a-lithioalkyl) oxazolidinones from the corresponding organotin derivatives and their carboxylation to provide enantiopure a-amino acids with the 11 possibility of labelling the carboxyl group by C (Scheme 6.41) [349]. 6.5.2.1.2

O O

O

SnBu3 N

R

Ph

n-BuLi THF, -78ºC CO2

O

CO2H N

R

Li/NH3 tBuOH/THF

H2N H

CO2H R

Ph

R=iBu (leucine) 85% (ee 95%) R=Me (alanine) 72% (ee 95%) R=BzlS(CH2)2 (homocysteine) 80% (ee 92%) Scheme 6.41

The progress has been much slower with acyclic systems. However, the transmetallation of N-benzyl-N-Cbz- [350], N-Boc-N-methyl- [351], and N-Boc-N-tertbutylthiomethyl- [352] protected aminotins provided the corresponding aminolithium derivatives that may be trapped with electrophiles with complete retention of configuration. This chemistry was applied to the preparation of b-aminoalcohols, N-methyl-b-aminoalcohols and N-methyl-b-amino acids. It can be noted that the preparation of enantio-enriched a- or b-amino carbanions can be achieved starting from linear racemic precursors when the tin-to-lithium exchange is done in the presence of (±)-sparteine [353]. Alternatively, tin-to-lithium exchange was found to be a method of choice for the preparation of 2-azaallyllithium species, which can undergo efficient [3+2], [4+2] and [6+4] cycloaddition reactions with alkenes [354], dienes [355] and trienes [356], respectively. Varous functionalized organotins can be used, such as stannylimines, stannylimidates, stannylthioamidates or stannylamidins. This azaallyl anion route to pyrolidines was used for the synthesis of different alkaloids, such as (±)-Lapidilectine B [357], (+)-Cocaine [358], (±)-Crinine (Scheme 6.42), (±)-6-Epicrinine, (±)-Amabiline and (±)-Augustamine [359].

6.5 Transmetallations

O O Ar

Ar OR

n-BuLi (2 eq.)

SnBu3

N

THF, -78ºC

H

N H H

MOMO

HO O Ar=

N H Crinine

O R=MOM Scheme 6.42

The tin-to-lithium exchange can be applied to aziridin chemistry, as illustrated by the reported synthesis of the Aziridinomitrosene skeleton (Scheme 6.43), by an intramolecular Michael addition after lithiodestannylation followed by a spontaneous aromatization [360]. OMe CO Et 2

1) MeLi 2) PhSeCl

D N OTIPS

OMe CO Et 2

SnBu3 NTr

N

NTr

OTIPS 79%

Scheme 6.43

Finally, an aza-Wittig rearrangement of acyclic enantio-enriched N,N-diallyllic a-amino alkylithium prepared via a tin-to-lithium exchange was reported, the process proceeding predominantly with inversion of configuration at the lithiumbearing carbon terminus [361].

6.5.2.2 Alkenyltins The tin-to-lithium exchange in alkenyltins is characterized by the preservation of the alkene stereochemistry and is compatible with several functionalities on the alkene moiety such as amino, hydroxyl and ester groups. The transmetallation of functionalized vinyltins has found an application in the synthesis of complex molecules such as unsaturated fatty acids [362], prostaglandin side-chain [363], various antibiotics [364] and a biotoxin [365]. 1,1- and 1,2-distannnylalkenes are also lithiated. An interesting example involved the bis stannylated enyne, prepared from an unsymmetrical butadiene. A subsequent regioselective lithiation of the internal tin residue followed by a 1,4retro-Brook rearrangement afforded the functionalized vinylsilane in a stereoselective fashion [366] (Scheme 6.44), which can also be considered as a masked triyne.

235

236


Et3SiO SiMe3

Me3SnCu SMe2-LiBr

n-BuLi SiMe3 THF, -78ºC

SnMe3 Et3SiO SnMe3

SnMe3

SiMe3

Cl

SiMe3

HO SiEt3

H

SiEt3

Scheme 6.44

6.5.3 Tin to Other Metal Exchanges

Until recently tin-to-copper transmetallation involved a transient organolithium species. The first example of direct tin-to-copper exchange was reported in 1988 with the formation of a mixed cuprate by treatment of an alkenylstannane with R2Cu(CN)Li2 [367]. The reaction was applied to allylic cuprates [368] and extended to alkynyltin and aryltin reagents, which were used in coupling reactions. Indeed, as mentioned in SecI tion 6.2.1.1.2, it was observed that in polar solvents, the addition of Cu salts resulted, presumably, in the transient formation of an organocopper species, thus allowing sluggish Stille-coupling reactions to proceed. The transmetallation was applied to the preparation of vinyl, alkynyl and arylboranes via a tin-to-boron exchange. Noticeable examples include the preparation of organoborane Lewis acids [369], the synthesis of alkynyldihaloboranes and their Diels±Alder reaction with 1,3-dienes [370], the formation of cyclooheptatrienyl(dipropyl)borane [371] and the preparation of 1-benzoborepines [372]. In addition to this, the transmetallation tin-to-boron can be applied to allylboron reagents as mentioned in Section 6.3.1.2.2. Finally, several other transmetallations such as tin-to-magnesium [373], tin-toindium [374], tin-to-stibin [372] and tin-to-arsenic [375] are reported as well.

6.6 Conclusion

To be complete one should add the extremely rich tin hydride chemistry, or the halodestannylation reaction as well as the creation of various carbon-heteroelement bonds. We should also add the use of tin oxides or hydroxides as protecting groups in polyol chemistry, the use of organotins as catalysts for many reactions such as transesterifications or amide formation. Finally, we could also mention the use of optically active organotin Lewis acids as efficient chirality inductors. All of these reactions, which are not covered in this chapter tend to prove that the use of organotins for organic synthesis is now undoubtedly established and is not limited to the carbon±carbon bond formation with the aforementioned reactions.

References

References 1 D. Azarian, S. S. Dua, C. Eaborn,

D. R. M. Walton, J. Organomet. Chem., 1976, 117, C55±C75. 2 M. Kosugi, K. Sasazawa, Y. Shimizu, T. Migita, Chem. Lett., 1977, 301±302. For an historical account of the Stille reaction see: M. Kosugi, K. Fugami, J. Organomet., 2002, 653, 50±53. 3 D. Milstein, J. K. Stille, J. Am. Chem. Soc., 1978, 100, 3636±3638. J. K. Stille, Pure Appl. Chem., 1985, 57, 1771. 4 V. Farina, G. P. Roth, Adv. Met.-Org. Chem., 1996, 5, 1±53. P. Espinet, A. M. Echavarren, Angew. Chem. Int. Ed., 2004, 43, 4704±4734. A. Ricci, F. Angelucci, M. Bassetti, C. Lo Sterzo, J. Am. Chem. Soc., 2002, 124, 1060±1071. 5 For a reviw on 2-furyl phosphines see: N. G. Andersen, B. A. Keay, Chem. Rev., 2001, 101, 997±1030 6 V. Farina, B. Krishnan, D. R. Marshall, G. P. Roth, J. Org. Chem., 1993, 58, 5434±5444; V. Farina, Pure Appl. Chem., 1996, 68, 73±78. 7 S. Ito, T. Okujima, N. Morita, J. Chem. Soc., Perkin Trans. 1, 2002, 1896±1905 8 M. R. Netherton, G. C. Fu, Org. Lett., 2001, 3, 4295±4298 9 V. Farina, G. P. Roth, Tetrahedron Lett., 1991, 32, 4243±4246; A. M. Echavarren, O. de Frutos, N. Tamayo, P. Nokeda, P. Calle, J. Org. Chem., 1997, 62, 4524±4527 10 J. D. Buynak, L. Vogeti, H. Chen, Org. Letters, 2001, 3, 2953±2956 11 L. S. Liebeskind, R. W. Fengl, J. Org. Chem., 1990, 55, 5359±5364 12 V. Farina, S. Kapadia, B. Krishnan, C. Wang, L. S. Liebeskind, J. Org. Chem., 1994, 59, 5905±5911; X. Han, B. M. Stolz, E. J. Corey, J. Am. Chem. Soc., 1999, 121, 7600±7605; A. L. Casado, P. Espinet, Organometallics, 2003, 22, 1305±1309; P. H. Mee, J. E. Baldwin, Angew. Chem. Int. Ed., 2004, 43, 1132±1136 13 W. J. Scott, J. K. Stille, J. Am. Chem. Soc., 1986, 108, 3033±3040. 14 D. A. Evans, W. C. Black, J. Am. Chem. Soc., 1993, 115, 4497±4513.

15 J. Scott, J. K. Stille, J. Am. Chem. Soc.,

1986, 108, 3033±3040

16 E. Piers, R. W. Friesen, B. A. Keay, Tetra-

hedron, 1990, 47, 4555±4570; C. M. Hettrick, J. K. kling, W. J. Scott, J. Org. Chem., 1991, 56, 1489±1492 17 V. Farina, B. Krishnan, D. R. Marshall, G. P. Roth, J. Org. Chem., 1993, 58, 5434±5444 18 C.-W. Huang, M. Shanmugasundaram, H.-M. Chang, C.-H. Cheng, Tetrahedron, 2003, 59, 3635±3641. 19 For reviews see: (a) G. Pozzi, I. Shepperson, Coordination Chemistry Reviews, 2003, 242, 115±124; E. Wolf, G. van Koten, B.-J. Deelman, Chem. Soc. Rev., 1999, 28, 37±41; E. G. Hope, A. M. Stuart, J. Fluorine Chem., 1999, 100, 75±83 20 S. T. Handy, X. Zhang, Org. Lett., 2001, 3, 233±236; C. Chaippe, G. Imperato, E. Napolitano, D. Pieraccini, Green. Chem., 2004, 6, 33±36 21 T. Osswald, S. Scneider, S. Wang, W. Bannwarth, Tetrahedron Lett., 2001, 42, 2965±2967; N. Shezad, R. S. Oakes, A. A. Clifford, C. M. Rayner, Tetrahedron Lett., 1999, 40, 221±2224; D. K. Morita, D. R. Pesiri, S. A. David, W. H. Glaze, W. Tumas, Chem. Commun., 1998, 1397±1398 22 S. Venkatraman, T. Huang, C.-J. Li, Adv. Synth. Catal., 2002, 344, 399±405 23 J. K. Stille, J. H. Simpson, J. Am. Chem. Soc., 1987, 109, 2138±2152 24 L. R. Marrison, J. M. Dickinson, R. Ahmed, I. J. S. Fairlamb, Tetrahedron Lett., 2002, 43, 8853±8857 25 M. Biagetti, F. Bellina, A. Carpita, P. Stabile, R. Rossi, Tetrahedron, 2002, 58, 5023±5038; M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi, Eur. J. Org. Chem., 2002, 1063±1076. 26 L. R. Pottier, J.-F. Peyrat, M. Alami, J. D. Brion, Tetrahedron Lett., 2004, 45, 4035±4038. 27 A. C. Tiberghien, D. Hagan, P. W. Howard, D. E. Thurston, Bioorg. Med. Chem. Lett., 2004, 14, 5041±5044 28 E. Fillion, N. J. Taylor, J. Am. Chem. Soc., 2003, 125, 12700±12701; A. Flohr,

237

238

6 Polyfunctional Tin Organometallics for Organic Synthesis Tetrahedron Lett., 1998, 39, 5177±5180; P. Quayle, J. Wang, J. Xu, Tetrahedron Lett., 1998, 39, 482±492; C. A. Busacca, J. Swestock, R. E. Johnson, T. R. Bailay, L. Musza, C. A. Rodger, J. Org. Chem., 1994, 59, 7553±7556; G. Stork, R. C. A. Issacs, J. Am. Chem. Soc., 1990, 112, 7399±7400 29 R. D. Mazzola, Jr., S. Giese, C. L. Benson, F. G. West, J. Org. Chem., 2004, 69, 220±223; G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc., 1996, 118, 2748±2749 30 C. Chen, K. Wilcoxen, Y.-F. Zhu, K.-I. Kim, J. R. McCarthy, J. Org. Chem., 1999, 64, 3476±3482; L. Lu, S. D. Pedersen, Q. Liu, R. M. Narrske, D. J. Burton, J. Org. Chem., 1997, 62, 1064±1071; I. H. Jeong, Y. S. Park, B. T. Kim, Tetrahedron Lett., 2000, 41, 8917±8921; Y. Shen, G. Wang, J. Fluorine Chem., 2004, 125, 91±94. 31 For a review on the use fluorinated organometallics in organic synthesis see: D. J. Burton, Z. Y. Yang, P. A. Morton, Tetrahedron, 1994, 50, 2993±3063 32 S. Minire, J.-C. Cintrat, J. Org. Chem., 2001, 66, 7385±7388; L. Timbart, J.-C. Cintrat, Chem. Eur. J., 2002, 8, 1637±1640 33 I. S. Aidhen, R. Braslau, Synth. Commun., 1994, 24, 789±790; C.-W. Huang, M. Shanmugasundaram, H.-M. Chang, C.-H. Cheng, Tetrahedron, 2003, 53, 3635±3641 34 E. Keinan, M. Peretz, J. Org. Chem., 1983, 48, 5302±5309 35 S. Rousset, M. Abarbbri, J. Thibonnet, A. Duchne J.-L. Parrain, Chem. Commun., 2000, 1987±1988 36 For a recent review on metallated heterocycles and their application in Stille coupling see: R. Chinchillla, C. Nµjera, M. Yus, Chem. Rev., 2004, 104, 2667±2722 37 H. Morimoto, H. Shimadzu, E. Kuushiyama, H. Kawanishi, T. Hosaka, Y. Kawase, K. Yasuda, K. Kushiyama, R. Yamauchi-Kohno, K. Yamada, J. Med. Chem., 2001, 44, 3355±3368 38 J. W. Labadie, D. Tueting, J. K. Stille, J. Org. Chem., 1983, 48, 4634±4642; A. M. Echawarren, J. K. Stille, J. Am. Chem. Commun., 1987, 109, 5478±5486

39 S. Labadie, J. Org. Chem., 1989, 54,

2496±2498

40 K. Krohn, S. Bernhard, U. Flörke,

N. Hayat, J. Org. Chem., 2000, 65, 3218±3222 41 W. G. Peet, W. Tan, J. Chem. Soc., Chem. Commun., 1983, 853±854 42 H. Xie, Y. Shao, J. M. Becker, F. Naider, R. A. Gibbs, J. Org. Chem., 2000, 65, 8552±8563 43 R. J. Lindermann, J. M. Siedlecki, J. Org. Chem., 1996, 61, 6492±6493 44 E. Veddejs, A. . Haight, W. O. Moss, J. Am. Chem. Soc., 1992, 114, 6556±6558 45 J. M. Brown, M. Pearson, J. T. B. H. Jastrrrzebski, G. van Koten, Chem. Commun., 1992, 1440±1441 46 T. Forngren, L. Samuelsson, B. Långström, J. Label. Comp. Radiopharm., 2004, 47, 71±78 47 G. A. Grasa, S. P. Nolan, Org. Lett., 2001, 3, 119±122. 48 E. Napolitano, V. Farina, M. Persico, Organometallics, 2003, 22, 4030±4037 49 E. Abele, K. Rubina, M. Fleicher, J. Popelis, P. Arsennyan, L. Edmuns, Appl. Organomet. Chem., 2002, 16, 141±147; G. A. Grasa, S. P. Nolan, Org. Lett., 2001, 3, 119±122 50 E. Fouquet, M. Pereyre, A. L. Rodriguez, J. Org. Chem., 1997, 62, 5242±5243; E. Fouquet, A. L. Rodriguez, Synlett 1998, 1323±1324. A. Herve, A. L. Rodriguez, E. Fouquet, J. Org. Chem., 2005, 70, 1953±1956. 51 M. T. Barros, C. D. Maycock, M. I. Madureira, M. R. Ventura, Chem. Commun., 2001, 1662±1663 52 K. Itami, T. Kamei, J.-I Yoshidaª J. Am. Chem. Soc., 2001, 123, 8773±8779; K. Itami, M. Mineno, T. Kamei, J.-I. Yoshida, Org. Lett., 2002, 4, 3635±3638 53 For a general review on palladium-catalyzed coupling reactions of aryl chlorides see: A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed., 2002, 41, 4176±4211 54 A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed., 1999, 38, 2411±2413; A. F. Littke, L. Schwarz, G. C. Fu, J. Am. Chem. Soc., 2002, 124, 6343±6348 55 G. A. Grasa, S. P. Nolan, Org. Lett., 2001, 3, 119±122; R. B. Bedford, C. S. J. Cazin, S. L. Hazelwood, Chem.

References Commun., 2002, 2608±2609; W. Su, S. Urggaonkar, J. G. Verkade, Org. Lett., 2004, 6, 1421±1424 56 M. Alvarez, D. Fernandez, J. A. Joule, Tetrahedron Lett., 2001, 42, 315±317 57 L. A. Agrofolio, I. Gillaizeau, Y. Saito, Chem. Rev., 2003, 103, 1875±1916 58 J. L. Sessler, M. Sathiosatham, C. T. Brown, T. A. Rhodes, G. Wiederrecht, J. Am. Chem. Soc., 2001, 123, 36555±3660 59 K. Menzel, G. C. Fu, J. Am. Chem. Soc., 2003, 125, 3718±3719 60 H. Tang, K. Menzel, G. C. Fu, Angew. Chem. Int. Ed., 2003, 42, 5079±5082 61 T. V. Hansen, L. Skattebùl, Tetrahedron Lett., 2004, 45, 2809±2811 62 Y. Nakayama, G. B. Kumar, Y. Kobayashi, J. Org. Chem., 2000, 65, 707±715 63 H. Uchiro, K. Nagasawa, Y. Aiba, S. Kobayashi, Tetrahedron Lett., 2000, 41, 4165±4168 64 J. L. Davis, R. Dhawan, B. A. Arntsen, Angew. Chem. Int. Ed., 2004, 43, 590±594 65 C. M. Hettrick, J. K. Kling, W. J. Scott, J. Org. Chem., 1991, 56, 1489±1492 66 J. P. Marino, J. K. Long, J. Am. Chem. Soc., 1988, 110, 7916±7917; L. Schio, F. Chatreaux, M. Klich, Tetrahedron Lett., 2000, 41, 1543±1547 67 D. Badone, C. Cecchi, U. Guzzi, J. Org. Chem., 1992, 57, 6321±6323 68 T. Okauchi, T. Yano, T. Fukamachi, J. Ichikawa, T. Minami, Tetrahedron Lett., 1999, 40, 5337±5340; B. M. Stoltz, T. Kano, E. J. Corey, J. Am. Chem. Soc., 2000, 122, 9044±9045 69 S.-K. Kang, H.-W. Lee, J.-S. Kim, S.-C. Choi, Tetrahedron Lett., 1996, 37, 3723±3726; K. W. Stagliano, H. C. Malinakova, Tetrahedron Lett., 1997, 38, 6617±6620; K. W. Stagliano, H. C. Malinakova, J. Org. Chem., 1999, 64, 8034±8040; S.-K. Kang, Y.-T. Lee, S.-H. Lee, Tetrahedron Lett., 1999, 40, 3573±3576 70 K. Kikukawa, K. Kono, F. Wada, T. Matsuda, J. Org. Chem., 1983, 48, 1333±1336; D. J. Koza, Y. A. Nsiah, Bioorg. Med. Chem. Lett., 2002, 112, 2163±2165 71 S. Zhang, D. Marshall, L. S. Liebeskind, J. Org. Chem., 1999, 64, 2796±2804

72 Z. Ni, A. Padwa, Synlett 1992, 869±872;

K. Itami, T. Koike, J.-I. Yoshida, J. Am. Chem. Soc., 2001, 123, 6957±6958; W. D. Shipe, E. J. Sorensen, Org. Lett., 2002, 4, 2063±2066; H. W. Lam, G. Pattenden, Angew. Chem. Int. Ed., 2002, 41, 508±511 73 J. Justicia, J. E. Oltra, J. M. Cuerva, J. Org. Chem., 2004, 69, 5803±5806. 74 K. C. Nicolaou, J. L. Gunzer, G.q. Shi, A. Agrios, P. Gärtner, Z. Yang, Chem. Eur. J., 1999, 5, 646±658; C. Buon, L. Chacun-Lefvre, R. Rabot, P. Bouyssou, G. Coudert, Tetrahedron, 2000, 56, 605±614 75 M. Egi, L. Libeskind, Org. Lett., 2003, 5, 801±802; F.-A. Alphonse, F. Suzenet, A. Keromnes, B. Lebret, G. Guillaumet, Org. Lett., 2003, 5, 803±805. 76 S. R. Dubbaka, P. Vogel, J. Am. Chem. Soc., 2003, 125, 15292±15293 77 T. A. Dineen, W. R. Roush, Org. Lett., 2004, 6, 2043±2046 78 J. T. Feutrill, M. J. Lilly, M. A. Rizzacasa, Org. Lett., 2002, 4, 525±527 79 H. Fuwa, M. Sasaki, M. Satake, K. Tachibana, Org. Lett., 2002, 4, 2981±2984 80 J. A. Marshall, N. D. Adams, J. Org. Chem., 2002, 67, 733±740 81 L. A. Paquette, M. Duan, C. Kempmann, J. Am. Chem. Soc., 2002, 124, 4257±4270 82 K. C. Nicolaou, Y. Li, K. C. Fylakakidou, H. J. Mitchell, H.-X. Wei, B. Weyershausen, Angew. Chem. Int. Ed., 2001, 40, 3849±3853 and 3854±3857 83 G. Van Cauwenberge, L.-J. Gao, D. Van Haver, M. Milanesio, D. Viterbo, P. J. De Clercq, Org. Lett., 2002, 4, 1579±1582; L. S.-M. Wong, L. A. Sharp, N. M. C. Xavier, P. Turner, M. S. Sherburn, Org. Lett., 2002, 4, 1955±1957 84 L. Bialy, H. Waldmann, Angew. Chem. Int. Ed., 2002, 41, 1748±1751 85 K. Miyashita, M. Ikejiri, H. Kawasaki, S. Maemura, T. Imanishi, Chem. Commun., 2002, 742±743; T. Esumi, N. Okamoto, S. Hatakkeyama, Chem. Commun., 2002, 3042±3043 86 C. J. Sinz, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2001, 40, 3224±3227

239

240

6 Polyfunctional Tin Organometallics for Organic Synthesis 87 D. A. Longbottom, A. J. Morrison,

D. J. Dixon, S. V. Ley, Angew. Chem. Int. Ed., 2002, 41, 2786±2789 88 O. P. Anderson, A. G. M. Barrett, J. J. Edmunds, S.-I. Hachiya, J. A. Hendrix, K. Horita, J. W. Malecha, C. J. Parkinson, A. VanSicke, Can. J. Chem., 2001, 79, 1562±1592 89 H. F. Olivo, F. Velµzquez, H. C. Trevisan, Org. Lett., 2000, 2, 4055±4058; B. M. Trost, O. Dirat, J. L. Gunzer, Angew. Chem. Int. Ed., 2002, 41, 841±843 90 C. M. Beaudry, D. Trauner, Org. Lett., 2002, 4, 2221±2224 91 D. Nozawa, H. Takikawa, K. Mori, J. Chem. Soc., Perkin Trans. 1, 2000, 2043±2043 92 J. Suffert, B. Salem, P. Klotz, J. Am. Chem. Soc., 2001, 123, 12107±12108 93 M. Janka, G. K. Anderson, N. P. Rath, Inorg. Chim. Acta., 2004, 357, 2339±2344; P. D. Jones, T. E. Glass, Tetrahedron Lett., 2001, 42, 2265±2267 94 U. S. Schubert, C. Eschbaumer, M. Heller, Org. Lett., 2000, 2, 3373±3376 95 For nonexhaustive recent examples of oligopyridines syntheses via Stille coupling see: M. M. M. Raposo, A. M. C. Fonseca, G. Kirsch, Tetrahedron, 2004, 60, 4071±4078; A. Puglisi, M. Benaglia, G. Roncan, Eur. J. Org. Chem., 2003, 1552±1558; P. F. H. Schwab, F. Fleischer, J. Milch, J. Org. Chem., 2002, 67, 443±449; M. Heller, U. S. Shubert, J. Org. Chem., 2002, 67, 8269±8272; C. R. Woods, M. Benaglia, S. Toyota, K., Hardcastle, J. S. Siegel, Angew. Chem. Int. Ed., 2001, 40, 749±751; G. Ulrich, S. Bedel, C. Picard, P. Tisnes, Tetrahedron Lett., 2001, 42, 6113±6115; A. Elghayuory, R. Ziessel, J. Org. Chem., 2000, 65, 7753±7763 96 For nonexhaustive recent examples of oligothiophenes synthesis via Stille coupling see: H. Yu, B. Xu, T. M. Swager, J. Am. Soc., 2003, 125, 1142±1143; B. Jousselme, P. Blanchard, E. Levillain, J. Delaunay, M. Allain, P. Richomme, D. Rondeau, N. Gallego-Planas, J. Roncali, J. Am. Chem. Soc., 2003, 125, 1363±1370; G. Sotgiu, M. Zambianchi, G. Barbarella, F. Aruffo, F. Cipriani, A. Ventola, J. Org. Chem., 2003, 68,

1512±1520; P. A. van Hal, E. H. A. Beckers, S. C. J. Meskers, R. A. J. Janssen, B. Jousselme, P. Blanchard, J. Roncali, Chem. Eur. J., 2002, 8, 5415±5429; C. Xia, X. Fan, J. Locklin, R. C. Advincula, Org. Lett., 2002, 4, 2067±2070; J. Frey, A. D. Bond, .A. B. Holmes, Chem. Commun., 2002, 20, 2424 ± 2425. 97 C. R. Woods, M. Benaglia, S. Toyota, K. Hardcastel, J. S. Siegel, Angew. Chem. Int. Ed., 2001, 40, 749±751 98 T. Bach, S. Heuser, J. Org. Chem., 2002, 67, 5789±5795; T. C. Govaerts, I. Vogels, F. Campernolle, G. Hoornaert, Tetrahedron Lett., 2002, 43, 799±802; W.-S. Kim, H.-J. Kim, C.-G. Cho, Tetrahedron Lett., 2002, 43, 9015±9017; C. Wu, H. Nakumura, A. Murai, O. Shimomura, Tetrahedron Lett., 2001, 42, 2997±3000; W. M. De Borggraeve, F. J. R. Rombouts, E. V. Van der Eycken, S. M. Toppet, G. J. Hoornaert, Tetrahedron Lett., 2001, 42, 5693±5695 99 R. Shimizu, T. Fuchikami, Tetrahedron Lett., 2001, 42, 6891±6894. 100 S.-K. Kang, H.-C. Ryu, S.-W. Lee, J. Organomet. Chem., 2000, 610, 38±41. 101 K. Kikukawa, T. Idemoto, A. Katayama, K. Kono, F. Wada, T. Matsuda, J. Chem. Soc. Perkin Trans. 1, 1987, 1511±1514 102 S.-K. Kang, T. Yamaaguchi, T.-H. Kim, P.-S. Ho, J. Org. Chem., 1996, 61, 9082±9083 103 F. Garrido, S. Raeppel, A. Mann, M. Lautens, Tetrahedron Lett., 2001, 42, 265±266 R. Shimizu, T. Fuchikami, Tetrahedron Lett., 2001, 42, 6891±6894 104 S. Ceccarelli, U. Piarulli, C. Gennari, J. Org. Chem., 2000, 65, 6254±6256 105 R. J. Franks, K. M. Nicholas, Orgnometallics, 2000, 19, 1458±1460. 106 R. D. Mazzola, Jr., S. Giese, C. L. Benson, F. G. West, J. Org. Chem., 2004, 69, 220±223 107 E. Morera, G. Ortar, Bioorg. Med. Chem. Lett., 2000, 10, 1815±1818 108 M. H. Al-Qaahtani, V. W. Pike, J. Chem. Soc., Perkin Trans. 1, 2000, 1033±1036; M. W. Nader, F. Oberdorfer, Appl. Rad. Isotopes, 2002, 57, 681±685 109 M. R. Garayt, J. M. Percy, Tetrahedron Lett., 2001, 42, 6377±6380

References 110 Y. Obora, M. Nakanishi, M. Tokunaga,

Y. Tsuji, J. Org. Chem., 2002, 67, 5835±5837 111 E. Piers, R. W. Friesen, B. A. Keay, Chem. Commun., 1985, 809±810 112 M. A. J. Duncton, G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 1999, 1235±1246; M. A. J. Duncton, G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 1999, 1235±1246 113 E. Marsaults, P. Deslonngchamps, Org. Lett., 2000, 2, 3317±3320 114 A. B. Smith, III, G. R. Ott, J. Am. Chem. Soc., 1998, 120, 3925±3948; A. B. Smith, III, G. R. Ott, J. Am. Chem. Soc., 1996, 118, 13095±13096; Y. Kim, R. A. Singer, E. M. Carreira, Angew. Chem. Int. Ed., 1998, 37, 1261±1263 115 E. QuØron, R. Lett, Tetrahedron Lett., 2004, 45, 4533±4537 and 4539±4543 116 L. Peng, F. Zhang, T. Mei, T. Zao, Y. Li, Tetrahedron Lett., 2003, 44, 5921±5923 117 A. Chen, A. Nelson, N. Tanikkul, E. J. Thomas, Tetrahedron Lett., 2001, 42, 1251±1254 118 K. C. Nicolau, F. Murphy, S. Barluenga, T. Ohshima, H. Wei, J. Xu, D. L. F. Gray, O. Baudoin, J. Am. Chem. Soc., 2000, 122, 3830±3838 119 I. Patterson, V. A. Doughty, M. D. McLeod, T. Trieselmann, Angew. Chem. Int. Ed., 2000, 39, 1308±1312 120 M. J. Remuiæµn, G. Pattenden, Tetrahedron Lett., 2000, 41, 7367±7371 121 K. Toshima, T. Arita, K. Kato, D. Tanaka, S. Matsumura, Tetrahedron Lett., 2001, 42, 8873±8876 122 K. Toshima, T. Jyojima, N. Miyamoto, M. Katohno, M. Nakata, S. Matsumura, J. Org. Chem., 2001, 66, 1708±1715 123 E. Lee, H. Young Song, J. Won Kang, D.-S. Kim, C.-K. Jung, J. Min Jao, J. Am. Chem. Soc., 2002, 124, 384±385 124 I. S. Mitchell, G. Pattenden, J. P. Stonehouse, Tetrahedron Lett., 2002, 43, 493±497 125 H. W. Lam, G. Pattenden, Angew. Chem. Int. Ed., 2002, 41, 508±511 126 L. Breydo, H. Zang, K. S. Gates, Tetrahedron Lett., 2004, 45, 5711±5716 127 K. C. Nicolaou, N. Winssinger, J. Pastor, F. Murphy, Angew. Chem. Int. Ed., 1998, 37, 2534±2537.

128 R. Olivera, R. SanMartin, E. Dominguez,

J. Org. Chem., 2000, 65, 7010±7019

129 S. Yue, J. J. Li, Org. Lett., 2002, 4,

2201±2203

130 L. A. Saudan, G. Bernardinelli,

E. P. Kündig, Synlett 2000, 483±486

131 T. J. Houghton, S. Choi, V. Rawal, Org.

Lett., 2001, 3, 3615±3617

132 G. Ruel, N. Ke The, G. Dumartin,

133 134 135

136

137

138 139 140

141 142

143

144

145

B. Delmond, M. Pereyre, J. Organomet. Chem., 1993, 444, C18±C19 H. Kuhn, W. P. Neumann, Synlett 1994, 123±124 M. S. Brody, M. G. Finn, Tetrahedron Lett., 1999, 40, 415±418 K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc., 2000, 122, 9939±9953 X. Wang, J. J. Parlow, J. A. Porco, Jr., Org. Lett., 2000, 2, 3509±3512; F. Stieber, U. Grether, H. Waldmann, Angew. Chem. Int. Ed., 1999, 38, 1073±1077; Y. Hu, S. Baudart, J. A. Porco, Jr., J. Org. Chem., 1999, 64, 1049±1051 U. Grether, H. Waldmann, Angew. Chem. Int. Ed., 2000, 39, 1629±1632; S. Tan, M. A. Foley, B. R. Stockwell, M. D. Shair, S. L. Schreiber, J. Am. Chem. Soc., 1999, 121, 9073±9087 W. K.-D. Brill, C. Riva-Toniolo, Tetrahedron Lett., 2001, 42, 6515±6518 F. Lourat, P. Gros, Y. Fort, Tetrahedron Lett., 2003, 44, 5613±5616 V. Aucagne, S. Berteina-Raboin, P. Guenot, L. A. Agrofoglio, J. Comb. Chem., 2004, 6, 717±723. W. Yun, S. Li, B. Wang, L. Chen, Tetrahedron Lett., 2001, 42, 175±177 J. K. Stille, H. Su., D. H. Hill, P. Schneider, M. Tanaka, D. L. Morrison, L. S. Hegedus, Organometallics, 1991, 10, 1993±2000; S.-K. Kang, T.-G. Baik, S.-Y. Song, Synlett 1999, 327±329 R. E. Maleczka, Jr., W. P. Gallagher, I. Tierstiege, J. Am. Chem. Soc., 2000, 122, 384±385 For a recent review on metal-catalyzed hydrostannations see: N. D. Smith, J. Mancuso, M. Lautens, Chem. Rev., 2000, 100, 3257±3282. W. P. Gallagher, I. Terstiege, R. E. Maleczka, Jr., J. Am. Chem. Soc., 2001, 123, 3194±3294

241

242

6 Polyfunctional Tin Organometallics for Organic Synthesis 146 R. E. Maleczka, Jr., W. P. Gallagher, Org.

Lett., 2001, 3, 4173±4176; R. E. Malleczka, Jr., J. M. Lavis, D. H. Clarck, W. P. Gallagher, Org. Lett., 2000, 2, 3655±3658. 147 A. G. Hernµn, V. Guillot, A. Kuvshinov, J. D. Kilburn, Tetrahedron Lett., 2003, 44, 8601±8603 148 E. Shirakawa, H. Yoshida, T. Kurahashi, Y. Nakao, T. Hiyama, J. Am. Chem. Soc., 1998, 120, 2975±2976; E. Shirakawa, T. Hiyama, J. Organomet. Chem., 1999, 576, 169±178 149 H. Yoshida, E. Shirakawa, T. Kurahashi, Y. Nakao, T. Hiyama, Organometallics, 2000, 19, 5671±5678 150 E. Shirakawa, T. Hiyama, J. Organomet. Chem., 2002, 653, 114±121 151 T. Matsubara, Organometallics, 2003, 22, 4297±4304; H. Yoshida, Y. Honda, E. Shirakawa, T. Hiyama, Chem. Commun., 2001, 1880±1881 152 F.-Y. Yang, M.-Y. Wu, C.-H. Cheng, Tetrahedron Lett., 1999, 40, 6055±6058 153 E. Shirakawa, H. Yoshida, Y. Nakao, T. Hiyama, Org. Lett., 2000, 2, 2209±2211 154 H. Tanaka, S.-I. Sumida, S. Torii, Tetrahedron Lett., 1996, 37, 5967±5970; T. Takeda, K.-I. Matsunaga, T. Uruga, M. Takakura, T. Fujiwara, Tetrahedron Lett., 1997, 38, 2879±2882 155 S.-K. Kang, J.-S. Kim, S.-C. Choi, J. Org. Chem., 1997, 62, 4208±4209 156 E. Piers, T. Wong, J. Org. Chem., 1993, 58, 3609±3610; T. Takeda, K. Matsunaga, Y. Kabasawa, T. Fujiwara, Chem. Lett., 1995, 771±772; G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc., 1996, 118, 2748±2749 157 J. R. Falck, R. K. Bhatt, J. Ye, J. Am. Chem. Soc., 1995, 117, 5973±5982 158 N. S. Nudelman, C. Carro, Synlett 1999, 1942±1944 159 E. Piers, P. L. Gladstone, J. G. K. Yee, E. J. McEachern, Tetrahedron, 1998, 54, 10609±10626 160 S.-K. Kang, T.-G. Baik, X. H. Jiao, Y.-T. Lee, Tetrahedron Lett., 1999, 40, 2383±2384 161 K. Mitsukura, S. Korekiiyo, T. Itoh, Tetrahedron Lett., 1999, 40, 5739±5742 162 X. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell,

K. A. Jorgensen, J. Org. Chem., 1999, 64, 4844±4849 163 M. Tanaka, Chem. Commun., 1981, 47±48 164 S.-I. Ikeda, D.-M. Cui, Y. Sato, J. Org. Chem., 1994, 59, 6877±6878 165 D.-M. Cui, N. Hashimoto, S.-I. Ikeda, Y. Sato, J. Org. Chem., 1995, 60, 5752±5756. 166 V. Percec, J.-Y. Bae, D. H. Hill, J. Org. Chem., 1995, 60, 6895±6903 167 E. Shirakawa, Y. Yamamoto, Y. Nakao, S. Oda, T. Tsuchimoto, T. Hiyama, Angew. Chem. Int. Ed., 2004, 43, 3448±3451; E. Shirakawa, K. Yamasaki, H. Yoshida, T. Hiyama, J. Am. Chem. Soc., 1999, 121, 10221±10222 168 Y. Nakao, E. Shirakawa, T. Tsuchimoto, T. Hiyama, J. Organomet. Chem., 2004, in press; E. Shirakawa, Y. Nakao, T. Hiyama, Chem. Commun., 2001, 263±264; E. Shirakawa, Y. Nakao, T. Tsuchimoto, T. Hiyama, Chem. Commun., 2002, 1962±1963 169 E. Shirakawa, Y. Nakao, H. Yoshida, T. Hiyama, J. Am. Chem. Soc., 2000, 122, 9030±9031 170 J. M. Nuss, R. A. Rennels, Chem. Lett., 1993, 197±198 171 S. Oi, M. Moro, H. Fukuhara, T. Kawanishi, Y. Inoue, Tetrahedron, 2003, 59, 4351±4361 172 C.-J. Li, Y. Meng, J. Am. Chem. Soc., 2000, 122, 9538±9539 173 S. Oi, M. Moro, H. Fukuhara, T. Kawanishi, Y. Inoue, Tetrahedron Lett., 1999, 40, 9259±9262; T. Hayashi, M. Ishigedani, J. Am. Chem. Soc., 2000, 122, 976±977; M. Ueda, N. Miyaura, J. Organomet. Chem., 2000, 595, 31±35 174 S. Oi, M. Moro, S. Ono, Y. Inoue, Chem. Lett., 1998, 83±84; S. Oi, M. Moro, H. Ito, Y. Honma, S. Miyano, Y. Inoue, Tetrahedron, 2002, 58, 91±97 175 T. Huang, Y. Meng, S. Venkatraman, D. Wang, C.-J. Li, J. Am. Chem. Soc., 2001, 123, 7451±7452; S. Venkatraman, Y. Meng, C.-J. Li, Tetrahedron Lett., 2001, 4459±4462 176 T. S. Huang, C.-J. Li, Org. Lett., 2001, 3, 2037±2039 177 Y. Naruta, K. Maruyama, Chemistry Lett., 881 (1979)

References 178 Y. Yamamoto, H. Yatagai, Y. Naruta,

K. Maruyama, J. Am. Chem. Soc., 1980, 102, 7107±7109 179 Y. Nishigaichi, A. Takuwa, Tetrahedron Lett., 1999, 40, 109±112 180 G. E. Keck, D. E. Abbott, E. P. Borden, E. J. Enholm, Tetrahedron Lett., 1984, 25, 3927±3931; G. E. Keck, K. A. Savin, E. N. K. Cressman, D. E. Abbott, J. Org. Chem., 1994, 59, 7889±7896; T. Hayashi, K. Kabeta, I. Hamachi, M. Kumada, Tetrahedron Lett., 1983, 23, 2865±2869 181 J. A. Marshall, H. Jiang, J. Org. Chem., 1999, 64, 971±975; G. C. Micalizio, W. R. Roush, Tetrahedron Lett., 1999, 40, 3351±3354; B. Leroy, E. Marko, Tetrahedron Lett., 2001, 42, 8685±8688 182 S. Watrelot-Bourdeau, J. L. Parrain, J. P. Quintard, J. Org. Chem., 1997, 62, 8261±8263 183 J. A. Marshall, G. S. Welmaker, B. W. Gung, J. Am. Chem. Soc., 1991, 113, 647±656 184 J. A. Marshall, G. S. Welmaker, J. Org. Chem., 1994, 59, 4122±4125; J. A. Marshall, J. A. Jablonowski, H. Jiang, J. Org. Chem., 1999, 64, 2152±2154 185 M. Yasuda, K. Hirata, M. Nishino, A. Yamamoto, A. Baba, J. Am. Chem. Soc., 2002, 124, 13442±13447; D. Basavaiah, B. Sreenivasulu, Tetrahedron Lett., 2002, 43, 2987±2990 186 K. Y. Lee, C. Y. Oh, J. H. Kim, J. E. Joo, W. H. Ham, Tetrahedron Lett., 2002, 43, 9361±9363 187 A. Tatami, M. Inoue, H. Uehara, M. Hirama, Tetrahedron Lett., 2003, 44, 5229±5233; M. T. Crimmins, M. G. Stanton, S. P. Allwein, J. Am. Chem. Soc., 2002, 124, 5958±5959 188 S. J. Jarosz, B. Fraser-Reid, J. Org. Chem., 1989, 54, 4011±4013; J. A. Marshall, D. V.Yashunsky, J. Org. Chem., 1991, 56, 5493±5495; B. W. Gung, J. P. Melnick, M. A. Wolf, J. A. Marshall, S. Beaudoin, J. Org. Chem., 1994, 59, 5609±5613; M. Adamcyeski, E. Quinoa, P. Crews, J. Org. Chem., 1990, 55, 240±242; J. A. Marshall, G. P. Luke, J. Org. Chem., 1993, 58, 6229±6234 189 J. A. Marshall, B. M. Seletzky, P. S. Coan, J. Org. Chem., 1994, 59, 5139±5140

190 S. S. Harried, C. P. Lee, G. Yang,

T. I. H. Lee, D. C. Myles, J. Org. Chem., 2003, 68, 6646±6660 191 D. A. Evans, B. T. Connell, J. Am. Chem. Soc., 2003, 125, 10899±10905 192 P. J. Hergenrother, A. Hodgson, A. S. Judd, W. C. Lee, S. F. Martin, Angew. Chem. Int. Ed. 2003, 42, 3278±3281 193 J. A. Marshall, J. A. Jablonowski, G. P. Luke, J. Org. Chem., 59, 7825 (1994) 194 R. S. Coleman, J. S. Kong, T. E. Richardson, J. Am. Chem. Soc., 1999, 121, 9088±9095 195 T. P. Loh, J. Xu, Tetrahedron Lett., 1999, 40, 2431±2434; T. P. Loh, J. Xu, Q. Y. Hu, J. J. Vittal, Tetrahedron Asym., 2000, 11, 1565±1569 196 D. J. Dixon, A. C. Foster, S. V. Ley, Org. Lett., 2000, 2, 123±125. 197 M. Fishwick, M. G. H. Wallbridge, J. Organomet. Chem., 1970, 25, 69 198 D. R. Williams, S. V. Plummer, S. Patnaik, Angew. Chem. Int. Ed. 2003, 42, 3934±3938 199 J. A. Marshall, Chem. Rev., 1996, 96, 31±47 200 J. A. Marshall, K. W. Hinkle, J. Org. Chem., 1995, 60, 1920±1921 201 J. A. Marshall, K. W. Hinkle, J. Org. Chem., 1996, 61, 105±108 202 E. J. Thomas, Chemtracts, 1994, 7, 207; E. J. Thomas, Chem. Commun., 1997, 411±412 203 J.S. Carey, E.J. Thomas, Synlett 1992, 585±586 204 Y. Nishigaichi, M. Yoshikawa, Y. Takigawa, A. Takuwa, Chem. Lett., 1996, 961±962; A. H. McNeil, E. J. Thomas, Tetrahedron Lett., 1990, 31, 6239±6242; J. S. Carey, E. J. Thomas, Tetrahedron Lett., 1993, 34, 3935±3938; J. S. Carey, E. J. Thomas, J. Chem. Soc., Chem. Commun., 1994, 283±284 205 E. K. Dorling, E. J. Thomas, Tetrahedron Lett., 1999, 40, 471±474; E. K. Dorling, A. P. Thomas, E. J. Thomas, Tetrahedron Lett., 1999, 40, 475±476; N. Martin, E. J. Thomas, Tetrahedron Lett., 2001, 42, 8373±8377 206 L. Arista, M. Gruttadauria, E. J. Thomas, Synlett 1997, 627±628

243

244

6 Polyfunctional Tin Organometallics for Organic Synthesis 207 B. Leroy, I. Marko, Org. Lett., 2002, 4,

47±50 208 A. Marx, H. Yamamoto, Synlett 1999, 584±586 209 H. C. Aspinall, A. F. Browning, N. Greeves, P. Ravenscroft, Tetrahedron Lett., 1994, 35, 4639±4642; H. C. Aspinall, N. Greeves, E. G. McIver, Tetrahedron Lett., 1998, 39, 9283±9286; H. C. Aspinall, J. S. Bissett, N. Greeves, D. Levin, Tetrahedron Lett., 2002, 43, 319±321 210 M. Yasuda, Y. Sugawa, A. Yamamoto, I. Shibata, A. Baba, Tetrahedron Lett., 1996, 37, 5951±5954 211 J. K. Whitesell, R. Apodaca, Tetrahedron Lett., 1996, 37, 3955±3958 212 A. Yanagisawa, M. Morodome, H. Nakashima, H. Yamamoto, Synlett 1997,1309±1310 213 T. Ooi, D. Uraguchi, N. Kagushima, K. Maruoka, J. Am. Chem. Soc., 1998, 120, 5327; K. Maruoka, T. Ooi, Chem. Eur. J., 1999, 5, 829±833 214 J.M. Blackwell, W.E. Piers, M. Parvez, Org. Lett., 2000, 2, 695±698; D. J. Morisson, W. E. Piers Org. Lett., 2003, 5, 2857±2860 215 C. T. Chen, S. D. Chao, J. Org. Chem., 1999, 64, 1090±1091 216 J. A. Marshall, Y. Tang, Synlett 1992, 653±654 217 A. L. Costa, M. G. Piazza, E. Tagliavini, C. Trombini, A. Umani-Ronchi, J. Am. Chem. Soc., 1993, 115, 7001±7002; G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc., 1993, 115, 8467±8468; G. E. Keck, L. S. Geraci, Tetrahedron Lett., 1993, 34, 7827±7830 218 Y. Yin, G. Zhao, Z. Qian, W. Yin, J. Fluor. Chem., 2003, 120, 117±120 219 P. Bedeschi, S. Casolari, A. L. Costa, E. Tagliavini, A. Umani-Ronchi, Tetrahedron Lett., 1995, 36, 7897±7901; M. Kurosu, M. Lorca, Tetrahedron Lett., 2002, 43, 1765±1769 220 S. Casolari, P. G. Cozzi, P. Orioli, E. Tagliavini, A. Umani-Ronchi, J. Chem. Soc. Chem. Commun., 1997, 2123±2124 221 C. M. Yu, H. S. Choi, W. H. Jung, S. S. Lee, Tetrahedron Lett., 1996, 37, 7095±7098; C. M. Yu, H. S. Choi, W. H. Jung, H. J. Kim, J. Shin, J. Chem. Soc. Chem. Commun., 1997, 761±762;

C. M. Yu, H. S. Choi, S. K. Yoon, W. H. Jung, Synlett 1997, 889±891 222 C. M. Yu, H. S. Choi, W. H. Jung, H. J. Kim, J. K. Lee, Bull. Korean Chem. Soc., 1997, 18, 471 223 G. E. Keck, D. Krishnamurthy, M. C. Grier, J. Org. Chem., 1993, 58, 6543±6544; G. E. Keck, T. Yu, Org. Lett., 1999, 1, 289±291; S. Weigand, R. Brückner, Chem. Eur. J., 1996, 2, 1077 224 A. Fürstner, K. Langemann, J. Am. Chem. Soc., 1997, 119, 9130±9136 225 G. E. Keck, J. A. Covel, T. Schiff, T. Yu, Org. Lett., 2002, 4, 1189±1192; C. M. Yu, J. Y. Lee, B. So, J. Hong, Angew. Chem. Int. Ed., 2002, 41, 161±163 226 S. Casolari, D. Addario, E. Tagliavini, Org. Lett., 1999, 1, 1061±1064; K. M. Waltz, J. Gavenonis, P. J. Walsh, Angew. Chem. Int. Ed., 2002, 41, 3697±3699; S. Kii, K. Maruoka, Chirality, 2003, 15, 68±70 227 A. Yanagisawa, H. Nakashima, A. Ishiba, H. Yamamoto, J. Am. Chem. Soc., 1996, 118, 4723±4724; A. Yanagisawa, A. Ishiba, H. Nakashima, H. Yamamoto, Synlett 1997, 88±90 228 A. Yanagisawa, Y. Nakatsuka, H. Yamamoto, Synlett 1997, 933±935 229 M. Luo, Y. Iwabuchi, S. Hatakeyama, Synlett 1999, 1109±1111; M. Luo, Y. Iwabuchi, S. Hatakeyama, Chem. Commun., 1999, 267±268; C. M. Yu, S. J. Lee, M. Jeon, J. Chem. Soc., Perkin Trans.1, 1999, 3557±3558 230 P. G. Cozzi, P. Orioli, E. Tagliavini, A. Umani-Ronchi, Tetrehedron Lett., 1997, 38, 145±148 231 Y. Motoyama, H. Narusawa, H. Nishiyama, Chem. Commun., 1999, 131±132 232 T. Mukaiyama, T. Harada, S. Shoda, Chem. Lett., 1980, 1507; S. A. S. David, Tetrahedron Lett., 1983, 24, 4009±4012; C. Petrier, J. Einhorn, J. L. Luche, Tetrahedron Lett., 1985, 26, 1449±1452 233 Y. Masuyama, R. Hayashi, K. Otake, Y. Kurusu, J. Chem. Soc., Chem. Commun., 1988, 44±45; Y. Masuyama, J. P. Takaraa, Y. Kurusu, J. Am. Chem. Soc., 1988, 110, 4473±4474; T. Imai, S. Nishida, Synthesis, 1993, 395±399; Y. Masuyama, M. Kishida, Y. Kurusu,

References J. Chem. Soc., Chem. Commun., 1995, 1405±1406 234 E. Fouquet, A. Gabriel, B. Maillard, M. Pereyre,Tetrahedron Lett., 1993, 34, 7749±7752; E. Fouquet, M. Pereyre, A. L. Rodriguez, T. Roulet, Bull. Soc. Chim. Fr., 1997, 134, 959±968 235 E. Fouquet, A. Gabriel, B. Maillard, M. Pereyre, Bull. Soc. Chim. Fr., 1995, 132, 590±598 236 S. Kobayashi, K. Nishio, Tetrahedron Lett., 1995, 36, 6729±6732 237 K. Yamada, T. Tozawa, M. Nishida, T. Mukaiyama, Bull. Chem. Soc. Jpn., 1997, 70, 2301±2308 238 J. Cossy, C. Rasamison, D. Gomez Pardo, J. Org. Chem., 2001, 66, 7195±7198 239 A. Kundu, S. Prabhakar, M. Vairamani, S. Roy, Organometallics, 1999, 18, 2782±2785 240 J. A. Marshall, C. M. Grant, J. Org. Chem., 1999, 64, 8214±8219 241 J. A. Marshall, X. J. Wang, J. Org. Chem., 1990, 55, 6246±6248; J. A. Marshall, J. F. Perkins, M. A. Wolf, J. Org. Chem., 1995, 60, 5556±5559 242 J. A. Marshall, X. J. Wang, J. Org. Chem., 1991, 56, 3211±3213; J. A. Marshall, X. J. Wang, J. Org. Chem., 1992, 57, 1242±1252 243 J. A. Marshall, B. A. Johns, J. Org. Chem., 1998, 63, 817±823; J. A. Marshall, B. A. Johns, J. Org. Chem., 1998, 63, 7885±7892; J. A. Marshall, B. A. Johns, J. Org. Chem., 2000, 65, 1501±1510 244 G. E. Keck, D. Krishnamurthy, X. Chen, Tetrahedron Lett., 1994, 35, 8323±8326 245 C. M. Yu, S. K. Yoon, S. J. Lee, J. Y. Lee, S. S. Kim, Chem. Commun., 1998, 2749±2750 246 C. M. Yu, S. K. Yoon, K. Baek, J. Y. Lee, Angew. Chem. Int. Ed. 1998, 37, 2392±2395 247 M. Yasuda, T. Miyai, I. Shibata, A. Baba, Tetrahedron Lett., 1995, 36, 9497±9500 248 D. A. Evans, D. P. Halstead, B. D. Allison, Tetrahedron Lett., 1999, 40, 4461±4461 249 B. M. Trost, P. J. Bonk, J. Am. Chem. Soc., 1985, 107, 1778±1781; G. E. Keck, E. J. Enholm, J. Org. Chem., 1985, 50, 146±147

250 C. K. Z. Andrade, G. R. Oliveira, Tetra-

hedron Lett., 2002, 43, 1935±1937

251 J. Liu, C.-H. Wong, Tetrahedron Lett.,

2002, 43, 3915±3917

252 C. Bellucci, P. G. Cozzi, A. Umani-

Ronchi, Tetrahedron Lett., 1995, 36, 7289±7292 253 H. C. Aspinall, J. S. Bissett, N. Greeves, D. Levin, Tetrahedron Lett., 1995, 43, 323±325 254 T. Akiyama, Y. Onuma, J. Chem. Soc. Perkin Trans. I, 2002, 1157±1158 255 Y. Yamamoto, T. Komatsu, K. Maruyama, J. Org. Chem., 1985, 50, 3115 256 S. Laschat, H. Kunz, J. Org. Chem., 1991, 56, 5883±5889 257 S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem., Int. Ed. Engl., 1985, 24, 1±30 258 Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu, W. Ito, J. Am. Chem. Soc., 1986, 108, 7778±7786 259 D. J. Hallett, E. J. Thomas, J. Chem. Soc., Chem. Commun., 1995, 657±658; G. W. Bradley, D. J. Hallett, E. J. Thomas, Tetrahedron Asymmetry, 1995, 6, 2579±2582; D. J. Hallett, E. J. Thomas, Tetrahedron Asymmetry, 1995, 6, 2575±2578 260 M. Shimizu, A. Morita, T. Kaga, Tetrahedron Lett., 1999, 40, 8401±8405 261 Y. Yamamoto, M. Schmid, J. Chem. Soc., Chem. Commun., 1989, 1310±1312 262 Y. Yamamoto, H. Sato, J. Yamada, Synlett 1991, 339±341 263 D. K. Wang, L. X. Dai, X. L. Hou, Tetrahedron Lett., 1995, 36, 8649±8652 264 Y. Niwa, M. Shimizu J. Am. Chem. Soc., 2003, 125, 3720±3721 265 S. Hanessian, R. Buckle, M. Bayrakdarian, J. Org. Chem., 2002, 67, 3387±3397; S. Hanessian, U. Reinholdt, G. Gentile, Angew. Chem. Int. Ed., 1997, 36, 1881±1884 266 J. Y. Park, I. Kadota, Y. Yamamoto, J. Org. Chem., 1999, 64, 4901±4908 267 K. T. Wanner, E. Wadenstorfer, A. Kärtner, Synlett 1991, 797±798 268 J. A. Marshall, K. Gill, B. M. Seletsky, Angew. Chem. Int. Ed., 2000, 39, 953±956 269 S Kobayashi, K. Sugita, H. Oyamada, Synlett 1999, 138±140; K. Manabe,

245

246

6 Polyfunctional Tin Organometallics for Organic Synthesis H. Oyamada, K. Sugita, S. Kobayashi, J. Org. Chem., 1999, 64, 8054±8057 270 M. Lombardo, S. Spada, C. Trombini, Eur. J. Org. Chem., 1998, 2361±2364 M. Gianotti, M. Lombardo, C. Trombini, Tetrahedron Lett., 1998, 39, 1643±1646 271 R. Yamaguchi, M. Moriyasu, M. Yoshioka, M. Kawanisi, J. Org. Chem., 1988, 53, 3507±3512 272 T. Itoh, Y. Matsuya, Y. Enomoto, K. Nagata, M. Miyazaki, A. Ohsawa, Synlett 1999, 1799±1801 273 T. Itoh, Y. Matsuya, Y. Enomoto, K. Nagata, M. Miyazaki, A. Ohsawa, Tetrahedron, 2001, 57, 7277±7289 274 S. Yamada, M. Ichikawa, Tetrahedron Lett., 1999, 40, 4231±4234 275 S. Kobayashi, H. Ishitani, Chem. Rev., 1999, 99, 1069±1094 276 H. Nakamura, N. Asao, Y. Yamamoto, Chem. Commun., 1995, 1273±1274; H. Nakamura, N. Asao, Y. Yamamoto, J. Am. Chem. Soc., 1996, 118, 6641 277 X. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell, K. A. Jorgensen, J. Org. Chem., 1999, 64, 4844±4849 278 M. Bao, H. Nakamura, Y. Yamamoto, Tetrahedron Lett., 2000, 41, 131±134 279 M. W. Carland, K. H. Schiesser, in The Chemistry of Organic Ge, Sn and Pb compounds,Pataï, vol 2, 1401±1484, Wiley Chichester, 2001 280 H. Kosugi, K. Kurino, K. Takayama, T. Migita, J. Organomet. Chem., 1973, 56, C11±C13; J. Grignon, M. Pereyre, J. Organomet. Chem., 1973, 61, C33±C35 281 G. E. Keck, J. B. Yates, J. Org. Chem., 1982, 47, 3590±3591; G. E. Keck, J. B. Yates, J. Am. Chem. Soc., 1982, 104, 5829±5831 282 D. P. Curran, P. A. van Elburg, B. Giese, S. Gilges, Tetrahedron Lett., 1990, 31, 2861±2864 283 C. V. Ramana, S. M. Baquer, R. G. Gonnade, M. K.Gurjar, Chem. Commun., 2002, 614±615 284 K. Mizuno, M. Ikeda, S. Toda, Y. Otsuji, J. Am. Chem. Soc., 1988, 110, 1288±1290; G. E. Keck, C.P. Kordik, Tetrahedron Lett., 1993, 34, 6875±6876 285 I. Ryu, H. Yamazaki, K. Kusano, A. Ogawa, N. Sonoda, J. Am. Chem. Soc., 1991, 113, 8558±8560

286 T. Migita, K. Nagai, M. Kosugi, Bull.

Chem. Soc. Jpn., 1983, 56, 2480

287 T. Toru, Y. Yamada, T. Ueno, E. Mae-

kawa, Y. Ueno, J. Am. Chem. Soc., 1988, 110, 4815±4817; L. C. Blaszczak, H. K. Armour, N. G. Halligan, Tetrahedron Lett., 1990, 31, 5693±5696 288 D. J. Hart, R. Krishnamurthy, Synlett 1991, 412±413 289 J. A. Campbell, D. J. Hart, Tetrahedron Lett., 1992, 33, 6247±6250 290 G. E. Keck, E. J. Enholm, D. F. Kachensky, Tetrahedron Lett., 1984, 25, 1867±1870; J. Dupuis, B. Giese, D. Rüegge, H. Fischer, H. G. Korth, R. Sustmann, Angew. Chem. Int. Ed. Engl., 1984, 23, 896±898 291 J. D. Ginn, A. Padwa, Org. Lett., 2002, 4, 1515±1517 292 J. E. Baldwin, R. M. Adlington, D. J. Birch, J. A. Crawford, J. B. Sweeney, J. Chem. Soc., Chem. Commun., 1986, 1339±1340; J. E. Baldwin, R. M. Adlington, C. Lowe, I. A. O'Neil, G. L. Sanders, C. J. Schofield, J. B. Sweeney, J. Chem. Soc., Chem. Commun., 1988, 1030±1032; E. Lee, S. G. Yu, C. U. Hur, S. M. Yang, Tetrahedron Lett., 1988, 29, 6969±6970; A. Padwa, S. Shaun-Murphree, P. E. Yeske Tetrahedron Lett., 1990, 31, 2983± 2986 293 K. Miura, H. Saito, D. Itoh, A. Hosomi, Tetrahedron Lett., 1999, 40, 8841±8844 294 J. E. Baldwin, R. M. Adlington, M. B. Mitchell, J. Robertson, J. Chem. Soc., Chem. Commun., 1990, 1574±1575 295 A. Sutherland, J. F. Caplan, J. C. Vederas, Chem. Commun., 1999, 555± 556 296 B. Giese, T. Linker, Synthesis, 1992, 46± 47 297 Y. Yoshida, N. Ono, F. Sato, J. Org. Chem., 1994, 59, 6153±6155; S. Hanessian, M. Alpegiani, Tetrahedron, 1989, 45, 941±950 298 J. E. Baldwin, R. Fieldhouse, A. T. Russell, Tetrahedron Lett., 1993, 34, 5491± 5494 299 M. P. Sibi, J. Chen, T. R. Rheault, Org. Lett. 2001, 3, 3679±3681; F. Villar, T. Kolly-Kovac, O. Equey, P. Renaud, Chem. Eur. J., 2003, 9, 1566±1570 300 G. E. Keck, J. B. Yates, J. Organomet. Chem., 1983, 248, C21±C28

References 301 D. P. G. Hamon, R. A. Massy-Westropp,

P. Razzino, Tetrahedron 1995, 51, 4183±4194; A. Takuwa, J. Shiigi, Y. Nishigaichi, Tetrahedron Lett., 1993, 34, 3457±3460 302 G. E. Keck, E. N. K. Cressman, E. J. Enholm, J. Org. Chem., 1989, 54, 4345±4349; S. J. Danishefsky, J. S. Panek, J. Am. Chem. Soc., 1987, 109, 917±918 303 M. P. Sibi, H. Miyabe, Org. Lett. 2002, 4, 3435±3498; M. P. Sibi, M. Aasmul, H. Hasegawa, T. Subramanian, Org. Lett. 2003, 5, 2883±2888 304 G. A. Kraus, B. Andersh, Q. Su, J. Shi, Tetrahedron Lett., 1993, 34, 1741±1744 305 J. E. Baldwin, R. M. Adlington, A. Basak, J. Chem. Soc., Chem. Commun., 1984, 1284±1285 306 M. Ethve-Quelquejeu, J. M. ValØry, Tetrahedron Lett., 1999, 40, 4807±4810 307 J. E. Baldwin, D. R. Kelly, J. Chem. Soc., Chem. Commun., 1985, 682±683 308 J. E. Baldwin, D. R. Kelly, C. B. Ziegler, J. Chem. Soc., Chem. Commun., 1984, 133±134 309 K. Haraguchi, Y. Itoh, K. Matsumoto, H. Tanaka, J. Org. Chem., 2003, 68, 2006±2009 310 D. P. Curran, P. A. van Elburg, B. Giese, S. Gilges, Tetrahedron Lett., 1989, 30, 2501±2504 311 G. A. Russel, L. L. Herold, J. Org. Chem., 1985, 50, 1037±1040; Y. Watanabe, T. Yoneda, Y. Ueno, T. Toru, Tetrahedron Lett., 1990, 31, 6669±6672 312 K. Miura, H. Saito, N. Fujisawa, D. Wang, H. Nishikori, A. Hosomi, Org. Lett., 2001, 3, 4055±4057 313 J. E. Baldwin, R. M. Adlington, J. Robertson, J. Chem. Soc., Chem. Commun., 1988, 1404±1405 314 S. Y. Chang, Y. F. Shao, S. F. Chu, G. T. Fan, Y. M. Tsai, Org. Lett., 1999, 1, 945±948 315 E. Fouquet, M. Pereyre, T. Roulet, J. Chem. Soc., Chem. Commun. 1995, 2387±2388 316 E. Fouquet, M. Pereyre, J-C. Rayez, M-T. Rayez, T. Roulet, C. R. Acad. Sci., 2001, 4, 2C, 641±648 317 E. J. Enholm, M. E. Gallagher, K. M. Moran, J. S. Lombardi, J. P. Schulte, Org. Lett., 1999, 1, 689±691

318 I. Ryu, T. Niguma, S. Minakata,

M. Komatsu, Tetrahedron Lett., 1999, 40, 2367±2370 319 S. Hanessian, H. Yang, R. Schaum, J. Am. Chem. Soc., 1996, 118, 2507±2508 320 Y. Guindon, B. GuØrin, C. Chabot, N. Makintosh, W. W. Ogilvie, Synlett 1995, 449±451 321 H. Nagano, Y. Kuno, Y. Omori, M. Iguchi, J. Chem. Soc., Perkin Trans., 1996, 389±391 322 E. J. Enholm, S. Lavieri, T. Cordova, I. Ghiviriga, Tetrahedron Lett., 2003, 44, 531±534 323 J. Hongliu Wu, R. Rakinov, N. A. Porter, J. Am. Chem. Soc., 1995, 117, 11029±11030; N. A. Porter, J. Hongliu Wu, G. Zhang, A. D. Reed, J. Org. Chem., 1997, 62, 6702±6703 324 M. P. Sibi, J. Chen, J. Am. Chem. Soc., 2001, 123, 9472±9473 325 P. Renaud, T. Bourquard, Tetrahedron Lett., 1994, 35, 1707±1710 326 P. Renaud, M. Ribezzo, J. Am. Chem. Soc., 1991, 113, 7803±7805; P. Renaud, N. Moufid, L. Huang Kuo, D. P. Curran, J. Org. Chem., 1994, 59, 3547±3552; D. P. Curran, L. Huang Kuo, J. Org. Chem., 1994, 59, 3259±3261 327 S. Kano, Y. Yuasa, S. Shibuya, Heterocycles, 1990, 31, 1597±1601; S. Kano, T. Yokomatsu, S. Shibuya, Heterocycles, 1990, 31, 13±16 328 R. Radinov, C. L. Mero, A. T. McPhail, N. A. Porter, Tetrahedron Lett., 1995, 36, 8183±8186 329 M. P. Sibi, J. Ji, Angew. Chem. Int. Ed. Engl., 1996, 35, 191±192 330 L. Giraud, P. Renaud, J. Org. Chem., 1998, 63, 9162±9163 331 D. Seyferth, M. A. Weiner, J. Org. Chem., 1959, 24, 1395±1396; D. Seyferth, M. A. Weiner, J. Am. Chem. Soc., 1961, 83, 3583±3586 332 J. S. Sawyer, A. Kucerovy, T. L. Macdonald, G. J. McGarvey, J. Am. Chem. Soc., 1988, 110, 842±853 333 P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res., 1996, 29, 552±560; S. V. Kessar, P. Singh, Chem. Rev., 1997, 97, 721±737; A. Basu, S. Thayumanavan, Angew. Chem. Int. Ed., 2002, 41, 716±738; P. Beak, W. J. Zajdel,

247

248

6 Polyfunctional Tin Organometallics for Organic Synthesis D. B. Reitz, Chem. Rev., 1984, 84, 471±523 334 P. Graæa, M. R. Paleo, F. J. Sardina, J. Am. Chem. Soc., 2002, 124, 12511±12514 335 W. J. Still, J. Am. Chem. Soc., 1978, 100, 1481±1487; W. C. Still, C. Sreekumar, J. Am. Chem. Soc., 1980, 102, 1201±1202 336 G. Hirai, Y. Koiizumi, S. M. Moharram, H. Oguri, M. Hirama, Org. Lett., 2002, 4, 1627±1630 337 M. E. Kuehne, F. Xu, J. Org. Chem., 1998, 63, 9427±9433 338 R. Hara, T. Furukawa, H. Kashima, Y. Horigushi, I. Kuwajima, J. Am. Chem. Soc., 1999, 121, 3072±3082 339 R. P. Smmyj, J. M. Chong, Org. Lett., 2001, 3, 2903±2906 340 G. Gralla, B. Wibbeling, D. Hoppe, Org. Lett., 2002, 4, 2193±2195; G. Christoph, D. Hoppe, Org. Lett., 2002, 4, 2189±2192 341 G. Gralla, B. Wibbeling, D. Hoppe, Tetrahedron Lett., 2003, 44, 8979±8982 342 D. J. Petersen, J. Am. Chem. Soc., 1971, 93, 4027±4031 343 G. Chambournier, R. E. Gawley, Org. Lett., 2000, 2, 1561±1564; R. E. Gawley, E. Low, G. Chambournier, Org. Lett., 1999, 1, 653±655; R. E. Gawley, Q. Zhang, J. Am. Chem. Soc., 1993, 115, 7515±7516 344 M. E. Kopach, A. I. Meyers, J. Org. Chem., 1996, 61, 6764±6765. 345 D. M. Iula, R. E. Gawley, J. Org. Chem., 2000, 65, 6196±6201 346 J.-C. Cintrat, V. LØat, J.-L. Parrain, E. Le Grognec, I. Beaudet, L. Toupet, J.-P. Quintard, Organometallics, 2004, 23, 943±945 347 W. H. Pearson, A. C. Lindbeck, J. W. Kampf, J. Am. Chem. Soc., 1993, 115, 2622±2636 348 R. E. Gawley, Q. Zhang, J. Org. Chem., 1995, 60, 5763±5769 349 F. Jeanjean, G. Fournet, D. Le Bars, J. GorØ, Eur. J. Org. Chem., 2000, 1297±1305; F. Jeanjean, N. Perol, J. GorØ, G. Fournet, Tetrahedron Lett., 1997, 38, 7547±7550 350 W. H. Pearson, A. C. Lindbeck, J. Org. Chem., 1989, 54, 56651±5654 351 J. M. Chong, S. B. Park, J. Org. Chem., 1992, 57, 2220±2222

352 A. Ncube, S. B. Park, J. M. Chong,

J. Org. Chem., 2002, 67, 3625±3636

353 G. Christoph, D. Hoppe, Org. Lett.,

2002, 4, 2189±2192; J. M. Laumer, D. D. Kim, P. Beak, J. Org. Chem., 2002, 67, 6797±6804 354 W. H. Pearson, Y. Mi, Tetrahedron Lett., 1997, 38, 5441±5444; W. H. Pearson, E. P. Stevens, J. Org. Chem., 1998, 63, 9812±9827 355 W. H. Pearson, D. M. Mans, J. W. Kampf, J. Org. Chem., 2004, 69, 1235±1247 356 W. H. Pearson, D. M. Mans, J. W. Kampf, Org. Lett., 2002, 4, 3099±3102 357 W. H. Pearson, Y. Mi, I. Y. Lee, P. Stoy, J. Am. Chem. Soc., 1998, 63, 3607±3617 358 M. Mans, W. H. Pearson, Org. Lett., 2004, 6, 3305±3308 359 W. H. Pearson, F. E. Lovering, J. Org. Chem., 1998, 63, 3607±3617. 360 M. Kim, E. Vedejs, J. Org. Chem,. 2004, 69, 7262±7265; E. Vedejs, J. D. Little, J. Org. Chem., 2004, 69, 1794±1799; E. Vedejs, J. D. Little, L. M. Seaney, J. Org. Chem., 2004, 69, 1788±1793 361 T. Tomoyasu, K. Tomooka, T. Nakai, Tetrahedron Lett., 2003, 44, 1239±1242 362 E. J. Corey, T. M. Eckrich, Tetrahedron Lett., 1984, 25, 2419±2422; E. J. Corey, J. R. Cashman, T. M. Eckrich, D. R. Corey, J. Am. Chem. Soc., 1985, 107, 713±715 363 E. J. Corey, R. H. Wollenberg, J. Org. Chem., 1975, 40, 2265±2266 364 E. J. Corey, B. C. Pan, D. H. Pan, D. R. Deardorff, J. Am. Chem. Soc., 1982, 104, 6816±6818; E. J. Corey, D. H. Hua, B. C. Pan, S. P. Seitz, J. Am. Chem. Soc., 1982, 104, 6818±6820 365 J. D. White, G. Wang, L. Quaranta, Org. Lett., 2003, 5, 4983±4986 366 S. M. Simpkins, B. M. Kariuki, C. S. Aaricó, L. R. Cox, Org. Lett., 2003, 5, 3971±3974 367 J. R. Behling, K. A. Babiak, J. S. Ng, A. L. Campbell, R. Moretti, M. Koerner, B. H. Lipshutz, J. Am. Chem. Soc., 1988, 110, 2641±2643 368 B. H. Lipschutz, R. Crow, S. H. Dimock, J. Am. Chem. Soc., 1990, 112, 4063±4064 369 J. J. Eisch, B. W. Kotowicz, Eur. J. Inorg. Chem., 1998, 761±769 370 S.-W. Leung, D. A. Singleton, J. Org. Chem., 1997, 62, 1955±1960.

References 371 I. D. Gridnev, O. L. Tok, N. A. Gridneva,

Y. N. Bubnov, P. R. Schreiner, J. Am. Chem. Soc., 1998, 120, 1034±1043 372 H. Sashida, A. Kuroda, J. Chem. Soc., Perkin Trans. 1, 2000, 1965±1969 373 R. I. Yousef, T. Rüffer, H. Schmidt, D. Steinborn, J. Organomet. Chem., 2002, 655, 111±114

374 J. D. Hoefelmeyer, M. Schulte,

F. P. Gabaï, Inorg. Chem., 2001, 40, 3833±3834 375 A. J. Ashe, III, X. Fang, J. W. Kampf, Organometallics, 2001, 20, 2109±2113

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7 Polyfunctional Zinc Organometallics for Organic Synthesis Paul Knochel, Helena Leuser, Liu-Zhu Gong, Sylvie Perrone, and Florian F. Kneisel 7.1 Introduction

Organozincs have been known since the preparation of diethylzinc by Frankland in 1849 in Marburg (Germany) [1]. These organometallic reagents were fairly often used to form new carbon±carbon bonds until Grignard [2] discovered in 1900 a convenient preparation of organomagnesium compounds. These reagents were found to be more reactive species toward a broad range of electrophiles and afforded generally higher yields compared to organozincs. However, some reactions were still performed with zinc organometallics such as the Reformatsky reaction [3] or the Simmons±Smith cyclopropanation [4]. The intermediate organometallics (zinc enolate and zinc carbenoid) were more easy to handle and more selective than the corresponding magnesium organometallics. Remarkably, Hunsdiecker reported in a German patent of 1943 that organozinc reagents bearing long carbon chains terminated by an ester function can be prepared [5]. This functional-group tolerance remained largely ignored by synthetic chemists and it became clear only recently that organozinc compounds are prone to undergo a large range of transmetallations due to the presence of empty low-lying p-orbitals that readily interact with the d-orbitals of many transition metal salts leading to highly reactive intermediates [6]. One can wonder why unreactive zinc reagents can produce highly reactive organometallic intermediates reacting with many electrophiles that are unreactive toward organozincs. This can be explained by the presence of d-orbitals at the transition-metal center that makes a number of new reaction pathways available that were not accessible to the zinc precursors since the empty d-orbitals of zinc are too high in energy to participate to most organic reactions. It is the combination of the high tolerance of functionalities of organozinc derivatives with a facile transmetallation to many transition metal complexes, which makes organozincs such valuable reagents. Especially important are the transmetallation of RZnX reagents to organocopper compounds [6] and to palladium intermediates [7] which allow the performance of cross-coupling reactions with high efficiency (Negishi reaction [7]; Scheme 7.1). Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

252

7 Polyfunctional Zinc Organometallics for Organic Synthesis

CuX RCu·ZnX2

RZnX ArPdX

R Pd Ar

Scheme 7.1 Transmetallation of organozinc reagents.

Furthermore, the highly covalent character of the carbon±zinc bond [8] affords organozincs configurationally stable at temperatures where the corresponding organo-magnesiums and -lithiums undergo a racemization. This property makes them good candidates for the preparation of chiral organometallics [9]. In this chapter, we will describe the preparation methods of polyfunctional organozinc compounds followed by a detailed presentation of their reactivity in the absence and in the presence of transition-metal catalysts.

7.2 Methods of Preparation of Polyfunctional Organozinc Reagents 7.2.1 Classification

There are three important classes of organozinc reagents: (i) organozinc halides of 1 2 the general formula RZnX (ii) diorganozincs of the general formula R ZnR in 1 2 which R and R are two organic groups and (iii) zincates of the general formula 1 2 3 R (R )(R )ZnMet in which the metal (Met) is usually Li or MgX. The reactivity of these zinc reagents increases with the excess of negative charge of the zinc center (Scheme 7.2). The reactivity of organozinc halides strongly depends on the electronegativity of the carbon attached to zinc and on the aggregation of the zinc reagent. A stabilization of the negative carbanionic charge by inductive or mesomeric effects leads to a more ionic carbon±zinc bond and to a higher reactivity: _ aryl < benzyl < allyl alkynyl < alkyl < alkenyl < RZnX < R2Zn < R3ZnMgX < R3ZnLi Scheme 7.2 Reactivity order of zinc organometallics.

7.2.2 Preparation of Polyfunctional Organozinc Halides 7.2.2.1 Preparation by the Oxidative Addition to Zinc Metal

The oxidative addition of zinc dust to functionalized organic halides allows the preparation of a broad range of polyfunctional organozinc iodides such as 1±5 [10±14]. Several functional groups such as nitro or azide groups inhibit the radical-transfer reaction leading to the zinc reagent. On another hand, hydroxyl

7.2 Methods of Preparation of Polyfunctional Organozinc Reagents

253

groups form zinc alkoxides that coat the zinc surface and therefore hamper the reaction (a similar behavior was observed for other acidic hydrogen atoms (carboxylic acids, imidazoles)). As a general rule, the nature of the zinc dust is less important than its activation. Finely cut zinc foil or zinc dust (commercially available source (ca. 325 mesh)) can be used. Zinc slowly oxidizes in air and is covered by an oxide layer. Its activation is of great importance; this is done by removing the oxide layer via chemical methods. A very efficient procedure consists of treating zinc with 1,2-dibromoethane (5 mol%) in THF (reflux for 0.5 min) followed by the addition of Me3SiCl (1±2 mol%; reflux for 0.5 min) [10, 15±17]. FG R I

Zn dust THF

FG R ZnI

FG = CO2R, enoate, CN, halide, (RCO)2N, (TMS)2N, RNH, NH2, RCONH, (RO)3Si, (RO)2PO, RS, RSO, RSO2, PhCOS R = alkyl, aryl, benzyl, allyl ZnI

O

N

NC

ZnI

ZnX

ZnI

N

O

AcO

N N

O

O N H

O 1 [10]

ZnI

2 [11]

3 [12]

OAc OAc 5 [14]

4 [13]

Scheme 7.3 Functionalized organozinc compounds prepared by oxidative addition.

Under these conditions, a broad range of polyfunctional alkyl iodides are converted to the corresponding organozinc halides in high yields [6]. In the case of primary alkyl iodides, the insertion occurs at 40±50 C, whereas secondary alkyl iodides already react at 25±30 C. Secondary alkyl bromides also react under these conditions [18], but primary alkyl bromides are usually inert with this type of activation and much better results are obtained by using Rieke-zinc [19±21]. Thus, the reduction of zinc chloride with finely cut lithium and naphthalene produces within 1.5 h highly reactive zinc (Rieke-zinc). Br O

O

ZnBr ZnCl2

Li naphthalene (ca. 20 mol %) rt, 2.5 h

Zn*

6 7

BF3·OEt2 TMSCl pentane, -30 ºC

Scheme 7.4 Preparation of tertiary alkylzinc reagents using Rieke-zinc.

8 : 54 %

254


This activated zinc [22] readily inserts in secondary and tertiary alkyl bromides. Adamantly bromide (6) is converted into the corresponding organozinc reagent (7) and its reaction with cyclohexenone in the presence of BF3ÓEt2 and TMSCl furnishes the 1,4-addition product 8 (Scheme 7.4). Rieke-zinc proves also to be very useful for preparing aryl- and heteroaryl-zinc halides. Thus, the reaction of Rieke-zinc with p-bromobenzonitrile (9) in refluxing THF provides after 3 h the corresponding zinc reagent (10), which is benzoylated leading to the ketone 11 in 73% yield (Scheme 7.5) [18a]. Br

ZnBr +

COPh

68 ºC, 3 h

CuCN·2LiBr

THF

PhCOCl

Zn* (Rieke-Zn)

CN

CN

9

10

CN 11 : 73 %

Scheme 7.5 Preparation of functionalized arylzinc bromides using Rieke-zinc.

Interestingly, many electron-deficient heterocyclic and aryl bromides or iodides are sufficiently activated to react with commercially available zinc powder [14]. In the case of benzylic halides, bromides and even chlorides can be used [12]. Thus, for the functionalized benzylic bromide 12a, the formation of the corresponding benzylic zinc bromide (13a) by the direct insertion of zinc dust is complete within 2 h at 5 C. O

O CH2Br

Zn, THF

ZnBr

Ph

Me Ph

CuCN·2LiCl

5 ºC, 2 h CO2Et

CO2Et

CO2Et

12a

13a

14a : 92 % Me

CH2Cl

Zn, THF

Br

ZnCl

Me

CuCN·2LiCl

40 ºC, 48 h CO2Et

CO2Et

CO2Et

12b

13b

14b : 87 %

Scheme 7.6 Preparation of functionalized benzylic zinc reagents.

After a Michael addition, the expected conjugated addition product 14a is formed in 92% yield. The corresponding benzylic chloride (12b) requires a reaction time of 48 h leading to the benzylic zinc chloride (13b). Allylation of 13b provides the aromatic benzoate 14b in 87% yield (Scheme 7.6). The use of DMSO/ THF mixture has a favorable effect allowing the synthesis of substituted benzylic reagents such as 3 [9]. Similarly, the preparation of alkylzinc iodides is facilitated


255

if the reaction is performed in THF and NMP mixtures. Such solutions of MeO2C(CH2)4ZnI add to benzaldehyde in the presence of TMSCl (2 equiv) in 70% yield [23]. The use of ultrasound also promotes the formation of organozinc compounds [24]. This procedure proved to be especially useful for the preparation of the Jackson reagent (15) derived from serine. The reaction of this zinc derivative with various electrophiles, either in the presence of a copper(I) or palladium(0) catalyst, leads to products of type 16±18 [25]; Scheme 7.7. O NHBoc

O

CO2Bn

I 16 : 56 %

Pd(0) cat.

I

Zn, THF

NHBoc

IZn

ultrasound 35 ºC

CO2Bn

1) CuCN·2LiCl

NHBoc

2) MeO2C

CO2Bn

NHBoc Br

CO2Bn

MeO2C

17 : 49 %

15

NC

N

Br

CO2Bn

Pd(0) cat. NC

N 18 : 48 %

Scheme 7.7 Ultrasound-mediated preparation of the Jackson reagent 15.

H

N

MeO2C

R MeO2C

ZnI 19

+ 20

t-BuO H N MeO2C

H N(R)ZnI 21

F3C O ZnI

H

N

MeO2C

19a

O ZnI

19b

Scheme 7.8 Stability of a-amino alkylzinc reagents.

The decomposition of the zinc reagent 19 leading to methyl but-3-enoate 20 and the zinc amide 21 has been extensively studied by Jackson et al. [26]. It was found that the zinc species 19a undergoes the elimination ca. three times faster than the zinc reagent 19b. This might be surprising since -NHBoc is not as good a leaving group as -NHCOCF3. This may be explained by the chelation of the Bocgroup with the zinc metallic center, which enhances the ate-character of the metal as well as the electron-density of the C±Zn bond and that favors therefore the elimination. This factor seems to be more important than the leaving-group abil-

NHBoc

256


ity of -NHR [27]. Interestingly, a free phenolic function is tolerated in cross-coupling reactions. Me

Me Boc(H)N

I

HN Me3SiCl cat. DMF, 0ºC

23

Me

CH2Cl

Zn dust ZnI O t-BuO

CuBr·Me2S (5 mol %)

Boc(H)N

22

24 : 60 %

Scheme 7.9 Generation of a b-amino alkylzinc reagent in DMF.

Organozinc reagents bearing a free NH-function in b-position such as 22 can be readily prepared by the direct insertion of zinc dust previously activated with TMSCl in DMF in to the corresponding b-iodoamino derivative 23. Interestingly, the best reactivity of this chelate-stabilized zinc species can be obtained by using catalytic amounts of CuBr´Me2S (5 mol%). In the case of the reaction with propargyl chloride the corresponding allene 24 is obtained in 60% yield via an SN2¢mechanism (Scheme 7.9) [28]. During the preparation of allylic zinc reagents, the formation of Wurtz-coupling products may be observed, especially if the intermediate allylic radical is well stabilized. However, the direct insertion of zinc foil to allyl bromide in THF at 5 C is one of the best methods for preparing an allylic anion equivalent. Allylic zinc reagents are more convenient to prepare and to handle than their magnesium- and lithium counterparts [15]. Similarly, electron-rich benzylic bromides such as 25a often lead to homo-coupling products. The use of the corresponding phosphate 25b and catalytic amounts of LiI in dimethyltetrahydropyrimidinone (DMPU) provides the corresponding zinc reagent in quantitative yield (Scheme 7.10) [29]. The presence of LiI generates small concentrations of the benzylic iodide, which is converted to the zinc reagent. Little homo-coupling is observed under these conditions. Zn, LiI (cat.) DMPU, 50 ºC, 12 h X = OP(O)(OEt)2

O

ZnX

O O

X

O 25a : X = Br 25b : X = OP(O)(OEt)2

Zn, THF, 0 ºC, 2 h X = Br

O O

Zn 2

Scheme 7.10 Importance of the precursor for the preparation of benzylic zinc reagents.

The addition of lithium iodide and bromide mixtures allows also the performance of the zinc insertion with primary alkyl chlorides, tosylates or mesylates as starting material (Scheme 7.11) [29]. Thus, the alkyl tosylate 26 is converted in


257

N,N-dimethylacetamide (DMAC) in the presence of lithium iodide (0.2 equiv) and lithium bromide (1.0 equiv) after heating at 50 C for 12 h to the zinc organometallic 27. After transmetallation with CuCN´2LiCl, the zinc reagent 27 undergoes an addition-elimination to 3-iodo-2-cyclohexenone leading to the enone 28 in 85% yield. The addition of both lithium iodide and lithium bromide is necessary in order to observe fast reactions. The direct exchange of a sulfonate to the corresponding iodide with LiI is slow and a stepwise reaction first with LiBr leading to the corresponding alkyl bromide, then a reaction with LiI leading to the corresponding iodide is a faster reaction pathway. The chloroalkyl mesylate 29 is converted to the zinc species 30, which undergoes a substitution reaction with the unsaturated nitro derivative 31 leading to the tetra-substituted nitroolefin 32 in 85% yield; Scheme 7.11 [29, 30]. O Me

Me

Me

Zn, LiI (0.2 equiv)

Me

OTs

Me

LiBr (1.0 equiv) Me DMAC, 50 ºC, 12 h

26

O

I

Me

ZnX CuCN·2LiCl 27 28 : 85 % NO2 SEt NO2

Cl

ZnX

Zn, LiI (0.2 equiv)

OMs

LiBr (1.0 equiv) DMPU, 50 ºC, 12 h

29

Cl

31 CuCN·2LiCl

Cl 30

32 : 85 %

Scheme 7.11 Preparation of alkylzinc derivatives starting from alkyl sulfonates. CN CN

Zn (1.5 equiv) Oct Br

OctZnBr I2 (5 mol %) Me2NCOMe 80ºC, 3h

Cl Oct

Cl2Ni(PPh3)2 (2 mol %), 25 ºC, 1 h

94% CN

Zn (1.5 equiv) EtO2C

Cl

I2 (5 mol %) Me2NCOMe, 80 ºC, 12 h, Bu4NBr (1 equiv)

EtO2C

ZnX

Cl

CO2Et

0.8 equiv

25 ºC, 1 h Cl2Ni(PPh3)2 (2 mol %)

Scheme 7.12 Iodine-catalyzed formation of organozinc bromides.

Alkylzinc bromides bearing various functional groups [31] can be readily prepared by the direct insertion of zinc metal (dust, powder or shot) to alkyl bromides by performing the reaction in the presence of iodine (1±5 mol%) in a polar solvent

CN 94%

258


like DMAC. It is also possible to use alkyl chlorides as starting material. In this case, the reaction is best performed in presence of Bu4NBr (1 equiv). The resulting zinc reagent undergoes a smooth Ni-catalyzed cross-coupling [32] with various aryl chlorides (Scheme 7.12). For polyfluorinated organozinc halides, the zinc insertion is conveniently done with a zinc±copper couple (Scheme 7.13) [33,34]. The preparation of trifluoromethylzinc halides (33) is best achieved using the method of Burton [35], which involves the reaction of CF2Cl2 or CBr2F2 with zinc in DMF. This reaction produces a mixture of CF3ZnX (33) and bis-trifluoromethylzinc (34); Scheme 7.13 [35]. n-C4F9

I

Zn (Cu), dioxane rt, 30 min

Zn

CF2X2 X = Cl, Br CF3 Br

DMF, rt

Zn(Ag) TMEDA THF, 60 ºC, 9 h

n-C4F9 ZnI

CF3ZnX + (CF3)2Zn 33 34

80 - 95 %

CF3 ZnI·TMEDA 35 : 93 %

Scheme 7.13 Preparation of perfluorinated zinc reagents.

Interestingly, the presence of a CF3-substituent facilitates considerably the zinc insertion. Thus, 2-bromo-trifluoropropene reacts with Zn/Ag couple in the presence of TMEDA leading to the expected zinc reagent 35 in 93% yield [35c±e]. The formation of arylzinc reagents can also be accomplished by using electrochemical methods. With a sacrificial zinc anode and in the presence of nickel 2,2bipyridyl, polyfunctional zinc reagents of type 36 can be prepared in excellent yields (Scheme 7.14) [36]. An electrochemical conversion of aryl halides to arylzinc compounds can also be achieved by a cobalt catalysis in DMF/pyridine mixture [37]. The mechanism of this reaction has been carefully studied [38]. This method can also be applied to heterocyclic compounds such as 2- or 3-chloropyridine and 2- or 3-bromothiophenes ([39] and [36d,e]). Zinc can also be electrochemically activated and a mixture of zinc metal and small amounts of zinc formed by electroreduction of zinc halides are very reactive toward a-bromoesters and allylic or benzylic bromides [36f,g]. e- (0.15 A), DMF, ZnBr2 FG-ArX X = Cl, Br

Bu4NBr (cat.), Ni2+ (cat.) 2,2´-bipyridine (cat.)

FG-ArZnX

( 60 - 70 %)

36

Scheme 7.14 Electrochemical preparation of polyfunctional arylzinc halides.


259

The previous results suggest that transition metals may catalyze the zinc insertion reaction. This proves to be the case and the reaction of octyl iodide with Et2Zn in the presence of PdCl2(dppf) (1.5 mol%) in THF at 25 C produces OctZnI within 2 h of reaction time in 75±80% yield [40]. A detailed mechanism is given in Scheme 7.15. Oct

I

Et2Zn, THF

Oct ZnI

75 - 80 %

25 ºC, 5 h Et2Zn L L Pd Oct I

Oct-I

EtZnI

Et2Zn + L2PdX2

L2Pd

Et-Oct

Et2Zn

L L Pd Oct Et EtZn-Oct

H2C=CH2 + H3C-CH3

L L Pd Et Et

OctZnI

Et2Zn

Scheme 7.15 Mechanism of the Pd-catalyzed reaction of alkyl iodides with diethylzinc.

These palladium- or nickel-catalyzed reactions are radical reactions leading to an organometallic product. By using a precursor such as 37 as a 1:1 mixture of diastereoisomers, the palladium-catalyzed cyclization provides, in a stereoconvergent way, the cyclopentylmethylzinc derivative 38 that after allylation produces the unsaturated ester 39 in 71% yield [41]. The intermediate radical cyclizes via a transition state A where all the substituents are in an equatorial position. Interestingly, the analogous reaction using Ni(acac)2 as a catalyst allows the preparation of heterocyclic compounds such as 40. The relative stereochemistry of up to three contiguous centers is set up in this cyclization (Scheme 7.16) [41]. Application of these methods toward the preparation of natural products, such as (±)-methylenolactocin (41) or cis-methyl jasmonate (42) has been accomplished [42]; Scheme 7.17. This reaction can be applied to the preparation of benzylic zinc reagents [40a, 43]. A range of benzylic halides has been reduced with Et2Zn in the presence of Pd(PPh3)4 as a catalyst [43]. Other metallic salts catalyze the I/Zn-exchange reaction. Thus, mixed-metal catalysis using manganese(II) bromide and copper(I) chloride allows the performance of a Br/Zn-exchange with various functionalized alkyl bromides of type 43; Scheme 7.18 [44]. The reaction proceeds in a polar solvent such as DMPU [45] under very mild conditions.


260

EtO2C H

XZn

H Et2Zn (2 equiv.)

BnO

I Me

1) CuCN·2LiCl

Me

BnO

PdCl2(dppf) 1.5 mol% 25 ºC, 5 h

Me

BnO

H

2)

38

CO2Et Br

BnO

1

39 : 71 %

A

37 : 1 : 1 mixture of diastereomers

Me

2 3

O ZnX Ph

I O

Et2Zn

1) CuCN·2LiCl

Ni(acac)2 cat.

O

2) PhCOCl

O

O

O

O

40 : 62 % (> 98 : 2)

Scheme 7.16 Pd- and Ni-catalyzed radical cyclization leading to zinc organometallics.

1) Et2Zn Ni(acac)2 THF, 40 ºC

Me3Si Me3Si

Pent2Zn

Me3Si

CHO

Ti(OiPr)4

NBS, CH2Cl2

OH

N(H)Tf

Br

BuO

Pent

Pent

O

OBu 2) O2, TMSCl THF, -5 ºC

70 %; 92 % ee

N(H)Tf 8 mol% ZnX O SiMe3 O OBu

O

O

OBu

acetone

Pent

55 %

N C N c-Hex Me CO2Me

Pent

O

O 90 %

c-Hex

OBn

HO

1 step

Jones oxid. Pent

BuO

HO2C

HO2C

OHC

I 57 %

I

OBn

Et CO2Me

CO2Me 2) CuCN·2LiCl 3) Br Et -55 ºC, 48 h

86 % ; 95 : 5 1) H2 Pd/BaSO4 cat. pyridine, 92 %

OH

O

Et

Et

Dess-Martin oxid.

2) BCl3, CH2Cl2 -78 ºC to -10 ºC

81 % CO2Me 61 %

O

41 : (-)-methylenolactocin

1) Et2Zn Ni(acac)2 cat. THF, 25 ºC

OBn

O

CO2Me 42 : cis-methyl jasmonate

Scheme 7.17 Preparation of (±)-methylenolactocin (41) and cis-methyl jasmonate (42).

7.2 Methods of Preparation of Polyfunctional Organozinc Reagents FG-RCH2Br + Et2Zn 43 : FG = ester, nitrile, chloride

MnBr2 (5 mol%) CuCl (3 mol%) DMPU

FG-RCH2ZnBr + CH2=CH2 + EtH (> 80 %)

Scheme 7.18 Mixed Mn/Cu-catalyzed alkylzinc bromides synthesis.

Interestingly, low-valent cobalt species obtained by the in situ reduction of CoBr2 with zinc catalyze the reaction of aryl bromides with zinc dust. The reaction allows the preparation of a range of functionalized arylzinc halides such as 44 (Scheme 7.19) [45]. Br

ZnBr CoBr2 (0.1 equiv.) ZnBr2 ( 0.1 equiv.) Zn (3 equiv.) CH3CN, rt, 0.5 h

O O

O O 44 : > 80 %

Scheme 7.19 Cobalt-mediated insertion of zinc to aryl bromides.

In summary, the direct insertion of zinc dust to organic halides is an excellent method for preparing a broad range of polyfunctional organozinc halides bearing various functional groups like an ester [46], an ether, an acetate [47], a ketone, cyano [48], halide [49], N,N-bis(trimethylsilyl)amino [50], primary and secondary amino, amide phthalimide [51], sulfide, sulfoxide and sulfone [52], boronic ester [53], enone [54] or a phosphonate [55]. An alternative method is based on transmetallation reactions.

7.2.2.2 Preparation of Organozinc Halides using Transmetallation Reactions A number of transmetallation procedures leading to zinc organometallics can be performed. Many organometallics having a polar C±Met bond are readily transmetallated by the reaction with a zinc salt to the more covalent organozinc compounds. The synthetic scope of these transmetallations depends on the availability of the starting organometallic species and on its compatibility with functional groups. Although organolithiums are highly reactive organometallic species, it is possible to prepare aryllithium species bearing cyano groups [56] or nitro groups [57] at very low temperature (±100 C to ±90 C). By performing a halogen±lithium exchange reaction, followed by a transmetallation with ZnBr2, functionalized organometallics are prepared that cannot be obtained by the insertion of zinc to the corresponding organic halide. Azides inhibit the direct zinc insertion to an organic halide. However, the reaction of the alkenyl iodide 45 bearing an azide group with n-BuLi at ±100 C followed by the transmetallation with ZnBr2 in THF at ±90 C provides the expected zinc reagent 46 in > 85% yield (Scheme 7.20) [58].

261

262


1) n-BuLi, -100 ºC, 3 min THF/ether/pentane (4/1/1) N3

I

N3

2) ZnBr2, THF, -90 ºC

45

ZnBr 46 : > 85 %

Scheme 7.20 Preparation of an alkenylzinc reagent bearing an azide function.

Br Me3Si

48

1) t-BuLi (2 equiv.) - 78ºC

Me3 Si

ZnCl Me3Si

OH

MeCHO

2) ZnCl2 -78 ºC to rt

Me 50 : 41%; d.r. > 9 : 1

47

Cl Zn

O

Me3Si

Zn

O

Me3Si Cl 49

Scheme 7.21 Preparation of a zinc/silicon bimetallic of type 47.

The mixed 1,2-bimetallic Zn/Si-reagent 47 is a versatile species that reacts with aldehydes in high diastereoselectivity [59]. It is prepared by a bromine±lithiumexchange reaction starting from 48 followed by a transmetallation with ZnCl2. The reaction with acetaldehyde is leading initially to the alkenylzinc species 49, which reacts with Me3SiCl, providing the alkenylsilane 50 in 41% yield and a diastereoselectivity > 9:1. 2-Lithiated oxazoles are unstable and readily undergo a ring opening to the tautomeric isonitriles. This ring cleavage can be avoided by preparing the corresponding 2-zincated oxazole (51) that is much more stable toward a fragmentation reaction (Scheme 7.22) [60]. The lithiation of the O-vinyl carbamate (52) with sec-BuLi followed by transmetallation with zinc bromide provides the convenient acyl anion derivative 53 which undergoes smooth Pd(0)-catalyzed cross-coupling reactions; Scheme 7.22 [61]. This reaction sequence has been extended to lithium enolates. The deprotonation of the aminoester 54 with LDA followed by a transmetallation with zinc bromide in ether furnishes a zinc enolate that readily adds to the double bond providing the proline derivative 55 in high diastereoselectivity and enantioselectivity (Scheme 7.23) [62]. Similarly, zincated hydrazone derivatives of type 56 undergo an intermolecular carbozincation of strained cyclopropene rings such as 57 leading to the adduct 58 with 92% yield [63]. This type of addition can be extended to ethylene [63c]. It proceeds with an excellent stereoselectivity allowing the enantioselective synthesis of a-substituted ketones. Allylic zinc species also add to cyclopropenone acetals


263

allowing an enantioselective allylzincation to take place [63f ]. This reaction provides an entry to quaternary centers with good stereocontrol. Fluorine-substituted alkenes can be readily lithiated by the reaction with a strong base (Scheme 7.24). Ph

N

Ph

1) BuLi, -70 ºC, THF H

N ZnCl

2) ZnCl2

O

O 51 : > 90 % O

O

1) sec-BuLi, THF Br -78 ºC, 1 h

Ph Zn

NEt2 2) ZnBr2

O

OTf

O

O

52

OCONEt2

O OMe

Ph

Pd(0) cat.

NEt2

OMe

53

84 %

Scheme 7.22 Preparation of zinc reagents via a I/Li transmetallation sequence. Me Me N Me

Ph

CO2Me 1) LDA, ether 2) ZnBr2, then H2O

N Me

CO2Me Ph

N H

55 : 96 %; d.r. = 98 : 2

54

O N

N

OMe

O

96 % ee

MeO N N H

57

ZnX

H 56

CO2H

O O

Et

58 : 92 %; 78 % d.s.

Scheme 7.23 Conversion of zinc enolates to organozinc reagents.

1-Chloro-2,2-difluorovinylzinc chloride 59 opens the access to a range of fluorinecontaining molecules via cross-couplings. Normant and coworkers have prepared this zinc reagent by the deprotonation of 1-chloro-2,2-difluoroethene 60 and transmetallation [64]. These two steps can be combined in one and the lithiation of 60 with secBuLi in the presence of ZnCl2 provides the corresponding dialkylzinc 61 as a colorless clear solution [65]. Percy and coworkers [66] and Anilkumar and Burton [67] reported that the deprotonation of 1-chloro-2,2,2-trifluoroethane 62 produces, after elimination and transmetallation, the zinc reagent 59. Especially convenient is the deprotonation of liquid halothane (63) with sec-BuLi in the presence of ZnCl2.

264


F

Cl

1) sec-BuLi

H

2) ZnCl2

F

F F

60 : gas at 25 ºC

F F

F

Cl

LDA

ZnCl

ZnCl2

sec-BuLi

F

H

ZnCl2 (0.5 equiv.)

F

60

62 : gas at 25 ºC

Cl

sec-BuLi

F

Cl

sec-BuLi

ZnCl2

F

Br

ZnCl2

2 Zn^

61

H H

F

59

Cl

Cl

F

CF3-CH(Br)Cl 63 : halothane liquid at 25ºC

Scheme 7.24 Preparation of fluoro-substituted alkenylzincs via lithium intermediates.

F2C=C

OTos

1) "Cp2Zr"

H

2) ZnI2

ZnI F2C=C

65

PhCHO

Hex

+

H

68

H

64

ZrCp2Cl

+ Hex

67

66

Ni(cod)2 (10 mol%)

HO

ZnCl2 (20 mol%)

Hex

Ph Hex 69 : 71%

N

+ 70 Me

BDPSO(CH2)3

H

Ni(cod)2 (10 mol%)

CHO

ZrCp2Cl

Hex

ZnCl2 (20 mol%) 66

H

N OH Me

Cp2Zr(H)Cl

BDPSO(CH2)3 Zr(Cl)Cp2

CH2Cl2, 21 ºC 71 : 94 %

1) Et2Zn, -60 ºC

BDPSO(CH2)3

OH

2) H O

Hex 69%

94 %

Scheme 7.25 Alkenylzinc species obtained from alkenylzirconium derivatives.


Transmetallations starting from alkenylzirconium species that are obtained by hydrozirconation using H(Cl)ZrCp2 are readily accomplished [68,69]. Ichikawa and Minami have elegantly shown that diflurovinylzinc iodide 64 is obtained by the addition of ªZrCp2º to the alkenyl tosylate 65 [68]. In situ transmetallation reactions have also been reported. A new three-component reaction [70] has been made possible by treating an alkenylzirconium reagent of type 66 with an alkyne 67 and an aldehyde 68 in the presence of catalytical amounts of Ni(cod)2 (10 mol%) and ZnCl2 (20 mol%). The resulting pentadienyl alcohols like 69 are obtained in satisfactory yield. The transmetallation of the alkenylzirconium species 66 to the corresponding zinc species is essential for the success of the carbometallation reaction [71]. An intramolecular version of the reaction is possible showing the high affinity of the intermediate alkenylzinc derived from 66 for adding to the alkyne 70. The competitive alternative addition to the aldehyde is not observed. The most general application has been reported by Wipf and Xu [69] who have demonstrated that a range of alkenylzirconium species is readily transmetallated to zinc organometallics. Thus, the reaction of the alkenylzirconium 71 with Et2Zn produces a zinc reagent that adds to an unsaturated aldehyde furnishing the expected allylic alcohol in excellent yield (Scheme 7.25) [69]. Organotin compounds have also occasionally been converted to zinc and then copper compounds by generating first an organolithium derivative (Scheme 7.26) [72]. a-Aminostannanes of type 72 undergo a low temperature Sn/Li-exchange reaction with BuLi in THF and lead after a transmetallation to an organozinc species displaying a moderate reactivity. After a further transmetallation with CuCN´2LiCl, a copper±zinc species such as 73 is obtained. The reaction of 73 with electrophiles affords products of type 74 with variable enantioselectivities. Quenching of the copper±zinc reagent 73 with reactive electrophiles proceeds with retention of configuration with up to 95% ee. Me Boc N H Ph

SnBu3 72

1) BuLi, THF -95 ºC, 5 min 2) ZnBr2 3) CuCN·2LiCl

Me Boc N H Ph

Me

E+

Cu(CN)ZnBr 73

Ph

N

Boc E

74 : 0 - 95% ee

Scheme 7.26 Preparation of zinc organometallics starting from tin reagents.

The weak carbon±mercury bond favors transmetallations of organomercurials [73]. The reaction of functionalized alkenylmercurials such as 75 with zinc in the presence of zinc salts like zinc bromide leads to the corresponding zinc reagents 76 in high yield and excellent stereoisomeric purity (Scheme 7.27) [74]. Interestingly, the required functionalized diorganomercurials can be obtained either by the reaction of functionalized alkylzinc iodides with mercury(I) chloride or by methylene homologation reaction using (ICH2)2Hg (Scheme 7.27) [74]. A range of polyfunctional organomagnesium species are available via an iodine± or a bromine±magnesium exchange reaction [75]. Since the carbon-magnesium bond is less polar than a carbon±lithium bond, considerably more func-

265

266


Cl

Zn, ZnBr2

Hg

Cl

ZnBr

THF, 60 ºC, 5 h

2

75

FG R CH2ZnI

76

Hg2Cl2, THF -20 ºC

(FG R CH2)2Hg

DMF, THF

FG RCu(CN)ZnI

-60 ºC, 15 h (ICH2)2Hg

Scheme 7.27 Preparation of alkenylzinc bromides from organomercurials.

tional groups are tolerated in these organometallics and experimentally more convenient reaction conditions can be used. Thus, the reaction of the aryl iodide 77 with i-PrMgBr in THF at ±10 C for 3 h provides an intermediate magnesium reagent that after transmetallation with ZnBr2 furnishes the zinc reagent 78. Its palladium-catalyzed cross-coupling with the bromofurane 79 provides the crosscoupling product 80 in 52% yield; Scheme 7.28 [76]. Ph

Ph N I

Ph N

1) i-PrMgBr, THF -10 ºC, 3 h

ZnBr

2) ZnBr2 N

N

Ph

Br

N

Pd(dba)2 (5 mol%) tfp (10 mol%) THF, rt, 16 h

N

EtO2C

O

O

79

Ph

77

CO2Et

Ph

78

80 : 52 %

Scheme 7.28 Preparation of arylzinc halides via an I/Mg-exchange.

This exchange reaction allows the preparation of various zinc reagents bearing numerous functional groups [75]. Special methods are available for the preparation of organozinc halides such as insertion reactions using zinc carbenoids like (iodomethyl)zinc iodide [77]. The reaction of an organocopper reagent (81) with ICH2ZnI ICH2ZnI

FG-RCu 81

OTMS

O

FG-RCH2Cu·ZnI2 82

ZnI CHO

1) MeLi

H

1) CuCN·2LiCl

2) Zn(CH2I)2

2) allyl bromide 83

Scheme 7.29 Homologation of zinc enolate using a zinc carbenoid.

84 : 75 %


267

provides a copper±zinc reagent 82 that reacts with numerous electrophiles (Scheme 7.29) [78]. This reaction is quite general and allows for example to homologate lithium enolates leading to the zinc homoenolate 83 that can be readily allylated in the presence of a copper catalyst leading to the aldehyde 84 in 75% yield (Scheme 7.29) [78, 79]. A one-pot synthesis of c-butyrolactones such as 85 can be realized via an intermediate allylic zinc species 86 generated by the homologation of an alkenylcopper reagent obtained by the carbocupration of ethyl propiolate (Scheme 7.30).

CO2Et

1) Cl(CH2)4Cu(CN)ZnI 2) ICH2ZnI

Ph Me

O

CO2Et ZnX

Ph

O

Me

(CH2)4Cl Cl

86

1) DBU, CuI

85 : 82 % O

O

O

O

Met

2) (ICH2)2Zn

87 : Met : Cu·ZnI2

88 : 65 %

Scheme 7.30 Allylic and allenic zinc reagents via methylene homologation.

Interestingly, an intramolecular trapping of an allenylzinc±copper species 87 generated by the homologation of an alkynylcopper can be achieved leading to the spiro-product 88 in 65% yield (Scheme 7.30) [79]. This method allows the homologation of silylated lithium carbenoids [80] and can be extended to the performance of polymethylene homologations [78c]. The use of lithium tributylzincates allows the synthesis of alkylated allenylzinc species such as 89 that react with aldehydes leading to alcohols of type 90 with high diastereoselectivity (Scheme 7.31) [81, 82]. Bu

Bu MeO

1) Bu3ZnLi -85 to 0 ºC

OMe OMs

MeO

MeO

ZnCl OMe

i-PrCHO

OMe

2) ZnCl2 HO 89

90 : 88 %; d.r. = 98 : 2

Scheme 7.31 Preparation of allenic zinc reagents using lithium trialkylzincates.

The reaction of stereomerically well-defined alkenylcopper species 91 obtained by a carbocupration with (ICH2)2Zn leads to a selective double methylene insertion providing the chelate-stabilized alkylzinc reagent 92 that leads, after deuteration with D2O, to the unsaturated sulfoxide 93 in 80% yield. This method has been elegantly extended by Marek (Scheme 7.32) [83].


268

OctCu Bu

S Tol O

THF

O S Tol

Bu Oct

Cu

Zn(CH2I)2 THF, -78 ºC

O S Tol

Oct

D2O

Bu

O S Tol

Oct Bu

Znl

D

92

91

93 : 80%

Scheme 7.32 Double homologation of alkenyl sulfoxide derivatives.

A selective reaction of 1,4-bimetallic alkanes with CuCN´2LiCl allows the preparation of a range of new polyfunctional zinc±copper reagents [84]. Thus, the reaction of 1,4-dizincated butane (94) with CuCN´2LiCl, followed by cyclohexenone in the presence of TMSCl (2 equiv) provides the new zinc±copper reagent 95 that reacts with 3-iodo-2-cyclohexenone furnishing the diketone 96 in 64% yield (Scheme 7.33) [84]. 1)

O

O

OTMS IZn(CH2)4ZnI

1) CuCN·2LiCl

I +

2) cyclohexenone TMSCl, -25 ºC

94

Zn, THF 30 ºC, 3 h

Cu(CN)ZnI 2) H3O 95

96 : 64 %

O

I(CH2)4I

Scheme 7.33 Preparation of alkylzinc±copper reagents via the selective reaction of 1,4-dizincabutane.

The preparation of chiral alkylzinc halides by the direct insertion of zinc is complicated due to the radical nature of the zinc insertion. Nevertheless, the strained secondary alkyl iodide 97 is converted to the corresponding chiral secondary organozinc reagent (98) with high retention of configuration leading, after stannylation with Me3SnCl, to the tin derivative 99 in 72% yield [85]. Interestingly, the trans-b-iodoester 100 is stereoselectively converted to the cis-ester 101 leading, after acylation, to the amino-ketone 102 [86]. The chelation with the ester group may be responsible for the cis-configuration of the zinc reagent 101 (Scheme 1 7.34). H-NMR-studies [87] confirm that secondary dialkylzincs should display a high configurational stability, although it was noticed that the presence of an excess of zinc(II) salts epimerizes secondary alkylzinc reagents [87]. The importance of chelation for the configurational stability of organozinc reagents has been recently demonstrated by Normant and Marek. The reaction of the bimetallic reagent 103, prepared by the allylzincation of the alkenyllithium 104, leads after stereoselective sequential quenching with two electrophiles (MeOD and I2), to the primary iodide 105 as a 34:66 mixture of diastereomers (Scheme 7.34) [88]. Also, alkenylzinc reagents such as 106 display a relatively high configurational stability (little racemization is observed at ±65 C (2 h)). A kinetic


269

resolution with (R)-mandelic imine derivate 107 is possible. Thus, treatment of a racemic mixture of the zinc reagent 106 with half of an equivalent of the imine 107 led to a highly preferential reaction with the (Sa)-enantiomer of 106 leading to the adduct 108. The remaining unreacted (Ra)-106 can now be trapped with an aldehyde such as pivalaldehyde giving the chiral homopropargylic alcohol 109 in 75% yield and 87.5% ee [89]. This kinetic resolution has been used to prepare anti,anti-vicinal amino diols in > 95% ee and d.r. > 40:1 [90]. In general diorganozincs are more easily prepared in optically pure form. This will be discussed in detail in the next section. On the other hand, secondary zinc reagents prepared by the direct zinc insertion to secondary alkyl iodides are obtained without stereoselectivity [91]. I

Me3Sn

IZn NHAc

Zn

NHAc

CuCN·2LiCl

97

NHAc

Me3SnCl

THF/DMSO (1/4), 32 ºC

99 : exo : endo = 98 : 2; 72 %

98 O

CH2Ph

O

N CO2Et

COCl

CO2Et O

Zn/Cu I 100

CH2Ph N

C6H6, DMF

ZnI

(PPh3)2PdCl2 cat.

101

Scheme 7.34 Stereoselective preparation of secondary alkylzinc iodides by the direct insertion of zinc.

O

O EtO2C

102 : 27 %

270


t-Bu

t-Bu 1)

O n-Pr

MgBr

n-Pr

O

Li 2) ZnBr2

MeOD

ZnBr

-10 ºC MgBr

104 103

t-Bu

t-Bu n-Pr

O

n-Pr

I2, 0 ºC

ZnBr

O

D

I D

105 Pr

Pr

ZnBr SiMe3

H (Ra)-106

H (Sa)-106

SiMe3 ZnBr

OTBDMS H Ph 107: 0.6 equiv N Bn

slow reaction

TBDMSO

Pr

ZnBr SiMe3

H

Ph NHBn

Pr

OH

SiMe3

108: d.r. = 9:1

t-BuCHO

t-Bu

Pr

109: 75%; 87.5% ee SiMe3

Scheme 7.35 Synthesis of chiral organozinc halides.

7.2.3 Preparation of Diorganozincs 7.2.3.1 Preparation via an I/Zn Exchange

Diorganozincs are usually more reactive toward electrophiles than organozinc halides. A wide range of methods is available for their preparation. The oldest being the direct insertion of zinc to an alkyl halide (usually an alkyl iodide) lead-


271

ing to an alkylzinc intermediate that, after distillation, provides the liquid diorganozinc (R2Zn) [1]. This method is applicable only to nonfunctionalized diorganozincs bearing lower alkyl chains (up to hexyl) due to the thermic instability of higher homologs. The I/Zn exchange reaction using Et2Zn allows the preparation of a broad range of diorganozincs. The ease of the exchange reaction depends on the stability of the newly produced diorganozincs. Thus, diiodomethane smoothly reacts with Et2Zn in THF at ±40 C providing the corresponding mixed ethyl(iodomethyl)zinc reagent (110) with quantitative yield [92]. The I/Zn exchange is catalyzed by the addition of CuI (0.3 mol%). After the evaporation under vacuum of excess Et2Zn and ethyl iodide formed during the reaction, the resulting diorganozincs 111a±d are obtained in excellent yields; Scheme 7.36 [93]. ICH2I + Et2Zn

THF

neat, 25 - 50 ºC

O Zn

110 : 90 %

CuI cat.

FG-RCH2I + Et2Zn

B CH2

ICH2ZnEt

-40 ºC

Zn

Cl

2

O

(FG-RCH2)2Zn

Zn

EtO2C

Tf N

Ph

Zn

2

2

2

111a

111b

111c

111d

Scheme 7.36 Diorganozincs obtained by I/Zn exchange.

Interestingly, this iodine±zinc exchange can also be initiated by light [94]. Thus, the irradiation (> 280 nm) of an alkyl iodide in CH2Cl2 in the presence of Et2Zn (1 equiv) provides the desired diorganozinc with excellent yields. A more reactive exchange reagent (i-Pr2Zn) can be used instead of Et2Zn. This organometallic has to be free of salts if optically active diorganozincs need to be prepared [95]. However, the presence of magnesium salts has a beneficial effect on the rate of exchange and a range of mixed zinc reagents of the type RZn(i-Pr) (112) can be prepared under mild conditions (Scheme 7.37) [96].

Me

Me Me

Me

i-Pr2Zn, MgBr2 (1.5 equiv.)

H

H I

i-PrZn 112 : ca. 60 %

Scheme 7.37 Preparation of mixed diorganozincs via an I/Zn exchange.

272


Since the isopropyl group is also transferred in the reaction with an electrophile at a comparable rate as the second R group, an excess of electrophile has to be added and tedious separations may be required. A more straightforward approach is possible for diarylzincs. In this case, the I/Zn-exchange can be performed under very mild conditions [97]. 2 Ar I

+

Li(acac) (10mol%)

i-Pr2Zn

Ar2Zn

NMP/ether 25ºC

ArI

+

i-PrI

Li(acac)

i-PrI

Ar

ArZni-Pr

2 i-PrI

Zn(acac) i-Pr

ArI

Li Scheme 7.38 Li(acac) catalyzed synthesis of diarylzincs.

The intermediate formation of a zincate enhances the nucleophilic reactivity of the substituents attached to the central zinc atom and makes it more prone to undergo an iodine±zinc exchange reaction. Thus, the addition of catalytic amounts of Li(acac) to an aryl iodide and i-Pr2Zn allows the transfer of the two i-Pr groups with the formation of Ar2Zn and i-PrI (2 equiv). This method allows the preparation of highly functionalized diarylzinc reagents bearing an aldehyde function like 113 or an isothiocyanate group like 114 (Scheme 7.39). These diarylzinc reagents undergo typical reactions of diorganozincs. Thus, the acylation of 113 with an acid chloride in the presence of Pd(0) provides the polyfunctional ketone 115 in 75% yield, whereas the reaction of the zinc reagent 114 with Me3SnCl gives the aryltin derivative 116 in 66% yield. OAc

OAc MeO

I i-Pr Zn (0.55 equiv.) 2

MeO

Pd(dba)2 (2.5 mol%) THF, rt, 5h

Zn 2

Li(acac) (10 mol%) NMP, 0ºC, 2h CHO 113

CHO

S

C

S N I

EtO2C

C

P (5 mol%)

CHO 115: 75%

COCl (1.5 equiv.)

S Zn 2

EtO2C

c-Hex

3

N

i-Pr2Zn (0.55 equiv.) Li(acac) (10 mol%) NMP, rt, 3h

O

OAc O MeO

114

Scheme 7.39 Functionalized diarylzincs bearing an aldehyde or an isothiocyanate functional group.

N SnMe3

Me3SnCl NMP, rt, 3h

C

EtO2C

116 : 66%


273

Mixed diorganozincs are synthetically useful intermediates, especially if one of the group attached to zinc is preferably transferred. The trimethylsilylmethyl group is too unreactive toward most electrophiles and plays the role of a dummy ligand. The preferential transfer of the second R-group attached to zinc is therefore possible in many cases. The reaction of 4-chlorobutylzinc iodide with Me3SiCH2Li in THF at ±78 C provides the mixed diorganozinc reagent 117 that readily undergoes a Michael addition with butyl acrylate in THF:NMP mixtures (Scheme 7.40) [98]. Barbier-type reactions are also well suited for the synthesis of diarylzincs although the functional-group tolerance of this method has not been investigated in detail [99,100]. CO2Bu Cl(CH2)4ZnI

Me3SiCH2Li THF, -78 ºC

TMSCl

Cl(CH2)4ZnCH2SiMe3

THF/NMP rt, 12 h

117

O

Br H3C

ether, sonication 25 ºC, 0.5 h

2

H3C

O Me

Zn

Li, ZnBr2

CO2Bu

Cl

Ni(acac)2 cat.

118

CH3 119 : 84 %

Scheme 7.40 Various syntheses and Michael additions of organozincs.

The reaction of 4-bromotoluene with lithium in the presence of zinc bromide in ether affords the corresponding zinc reagent 118 that undergoes a smooth 1,4addition to sterically hindered enones and leads to the cyclopentanone 119 in 67% yield [99].

7.2.3.2 The Boron±Zinc Exchange Various organoboranes react with Et2Zn or i-Pr2Zn providing the corresponding diorganozinc. Pioneered by Zakharin and Okhlobystin [101] and Thiele and coworkers [102], the method provides a general entry to a broad range of diorganozincs. The exchange reaction proceeds usually under mild conditions and tolerates a wide range of functional groups. It is applicable to the preparation of allylic and benzylic diorganozincs as well as secondary and primary dialkylzincs [103] and dialkenylzincs [104]. Remarkably, functionalized alkenes bearing a nitro group or a alkylidenemalonate function are readily hydroborated with Et2BH [105] prepared in situ and converted to diorganozinc reagents such as 120 and 121. After a copper-catalyzed allylation the expected allylated products 122 and 123 are obtained in high yields (Scheme 7.41) [103].

274


NO2

1) Et2BH

Zn

NO2

2

2) Et2Zn, 0 ºC

CuCN·2LiCl allyl bromide

120

EtO2C

CO2Et

2) Et2Zn, 0 ºC

122 : 83 %

Zn

1) Et2BH

2

EtO2C

NO2

CO2Et

CuCN·2LiCl allyl bromide

EtO2C

CO2Et

123 : 86 %

121

Scheme 7.41 Preparation of functionalized diorganozincs using a B/Zn exchange.

The hydroboration of dienic silyl enol ethers, such as 124 with Et2BH leads to organoboranes that can be converted to new diorganozincs, such as 125; Scheme 7.42 [106]. More importantly, this method allows the preparation of chiral secondary alkylzinc reagents. Thus, the hydroboration of 1-phenylcyclopentene with (±)IpcBH2 (99% ee) [107] produces, after crystallization, the chiral organoborane 126 with 94% ee. The reaction of 126 with Et2BH replaces the isopinocampheyl group with an ethyl substituent (50 C, 16 h) and provides after the addition of i-Pr2Zn (25 C, 5 h), the mixed diorganozinc 127. Its stereoselective allylation leads to the trans-disubstituted cyclopentane 128 in 44% yield (94% ee; trans:cis = 98:2); Scheme 7.43 [108]. This sequence can be extended to open-chain alkenes and Z-styrene derivative 129 is converted to the anti-zinc reagent 130 that provides, after allylation, the alkene 131 in 40% yield and 74% ee (d.r. = 8:92). OTIPS

OTIPS 12 h, rt 2) Et2Zn, 1 h

124

CO2Et 1) CuCN·2LiCl

1) Et2BH Zn

2)

CO2Et

Ph

CO2Et

2

125

TIPSO

CO2Et Ph 75 %

Scheme 7.42 Preparation of diorganozincs bearing a silyl ether using a boron±zinc exchange.

Similarly, the indene derivative 132 is converted by asymmetric hydroboration and B/Zn-exchange to the trans-indanylzinc reagent 133 that undergoes a Pd-catalyzed cross-coupling with an E-alkenyl iodide leading to the trans-E-product 134 in 35% yield (Scheme 7.43) [108b]. Several functionalized alkenes have been converted in chiral secondary alkylzinc reagents [109]. Especially interesting are unsaturated acetals, such as 135 that can be hydroborated with (±)-IpcBH2 with high enantioselectivity (91% ee) providing, after B/Zn-exchange, the mixed zinc reagent 136. Its trapping with various electrophiles provides chiral products, such as 137±139. The deprotection of 139 furnishes the b-alkynylaldehyde 140 in 88% ee. The exo-alkylidene acetal 141 is converted similarly to the zinc reagent 142 which can be allylated with an excellent diastereoselectivity (d.r. = 96:4) leading to the ketal 143


Ph

(-)-IpcBH2

1) Et2BH, 50 ºC, 16 h

Ph

275

Ph

2) i-Pr2Zn, 25 ºC, 5 h

Et2O, -35 ºC

Zni-Pr

BHIpc 126

127 Ph

CuCN·2LiCl Br 44 %

128 trans : cis = 98 : 2; 94 % ee

Me Ph

H Me

Me 1) (-)-IpcBH2, Et2O 2) Et2BH 3) i-Pr2Zn

129

Me

Zni-Pr

CuCN·2LiCl Br

Me

Ph Me 131 : syn : anti = 8 : 92 74 % ee; 40 %

130

Me 132

Ph

1) (-)-IpcBH2, Et2O

Pd(dba)2 cat.

2) Et2BH 3) i-Pr2Zn

P(o-Tol)3 cat.

Me Zni-Pr

I

Me

n-Bu

133

n-Bu 134 : trans : cis = 99 : 1 56 % ee; 35 %

Scheme 7.43 Synthesis of chiral secondary alkylzincs via B/Zn-exchange.

(Scheme 7.44) [109]. A substrate-controlled hydroboration can also be achieved. Thus, the hydroboration of the unsaturated bicyclic olefin 144 occurs with high diastereoselectivity. B/Zn-exchange leads to the zinc reagent 145 that can be acylated with retention of configuration at C(3) leading to the bicyclic ketone with a control of the relative stereochemistry of 4 contiguous chiral centers as shown in product 146; Scheme 7.45 [110]. The hydroboration of allylic silanes, such as 147 proceeds with high diastereoselectivity as demonstrated by Fleming and Lawrence [111]. It is difficult to use the newly formed carbon±boron bond for making new carbon±carbon bonds due to its moderate reactivity. However, the B/Zn-exchange converts the unreactive carbon±boron bond to a reactive carbon±zinc bond as in compound 148. A further transmetallation with the THF soluble salt CuCN´2LiCl provides copper reagents which can be allylated (149a), alkynylated (149b) or acylated (149c); Scheme 7.45.

276

7 Polyfunctional Zinc Organometallics for Organic Synthesis O O CO2Et

137 : 52 %; d.r. = 95 : 5

1) CuCN·2LiCl CO2Et Br

2)

O

O

O O

1) (-)-IpcBH2, Et2O 2) Et2BH 3) i-Pr2Zn

135

O Zni-Pr

1) CuCN·2LiCl 2) Br

O

139 : 46 % d.r. = 99 : 1

SiMe3

136

SiMe3

1) CuCN·2LiCl HCl (aq.)

2) Br

CHO

O O

SiMe3 138 : 50 % d.r = 97 : 3

O

O

O i-Pr

141

O

1) (-)-IpcBH2, Et2O 2) Et2BH 3) i-Pr2Zn

140 : 92 %; 88 % ee > 99 % trans

Zni-Pr i-Pr

O 1) CuCN·2LiCl 2)

O i-Pr

Br

142

143 : 51 % d.r. = 96 : 4; 76 % ee

Scheme 7.44 Preparation of chiral functionalized zinc organometallics via a boron±zinc exchange.

The hydroboration of allylic amine or alcohol derivatives can be used for the preparation of alkylzinc reagents with excellent diastereoselectivity (Scheme 7.46) [112]. Thus, the diastereoselective hydroboration of the allylic sulfonamide 150 [113] affords after B/Zn-exchange the zinc reagent 151 that leads, after a coppercatalyzed acylation, to the ketone 152 with 62% yield [112]. Rhodium-catalyzed hydroborations are also compatible with the boron±zinc exchange reaction and the exo-methylene silylated alcohol 153 is readily hydroborated with catecholborane [114] in the presence of ClRh(PPh3)3 [115] affording after boron±zinc exchange the zinc reagent 154 leading, after allylation, to the cis-substituted products 155 and 156 [112]. The boron±zinc exchange can be extended to aromatic systems. The required aromatic boron derivatives can be readily prepared from the corresponding arylsilanes such as 157 by using BCl3 [116].

7.2 Methods of Preparation of Polyfunctional Organozinc Reagents OEOM

Et2BH CH2Cl2

O

H

MeO

Zni-Pr

H 145

144

MeO

3) propionyl chloride 59 %

25 ºC, 48 h H

O H

O

1) i-Pr2Zn 2) CuCN·2LiCl

277

H 146 SiMe2Ph

1) CuCN·2LiCl 2) allyl bromide 74 %

SiMe2Ph Ph

SiMe2Ph

1) 9-BBN-H 2) i-Pr2Zn

Ph

147

Ph 149a : dr = 99 : 1

SiMe2Ph

1) CuCN·2LiCl

Zni-Pr

2) Br

Pr 72 %

148

Ph Pr 149b : dr = 99 : 1

1) CuCN·2LiCl 2) EtCOCl 77 %

SiMe2Ph Et

Ph O

149c : dr = 99 : 1

Scheme 7.45 Diastereoselective hydroboration and B/Zn-exchange. O

Zni-Pr 1) CuCN·2LiCl

1) 9-BBN-H

2) propionyl chloride

2) i-Pr2Zn Bn

N

Ts

Bn

150

N

Ts

N Bn Ts 152 : 62 %; d.r. = > 96 : < 4

151

OSiMe2t-Bu 1) CuCN·2LiCl 2) allylic bromide OSiMe2t-Bu

1) catecholborane Rh(PPh3)3Cl cat.

155 : 52 %; d.r. = > 96 : < 4

OSiMe2t-Bu Zni-Pr

2) i-Pr2Zn 153

154

OSiMe2t-Bu 1) CuCN·2LiCl 2) Br Pr Pr 156 : 49 %; d.r. = > 96 : < 4

Scheme 7.46 Diastereoselective hydroboration of allylic derivatives and B/Zn-exchange.

278


The resulting functionalized arylborane 158 readily undergoes a B/Zn-exchange leading to the zinc reagent 159 that can be trapped by various electrophiles, such as propargyl bromide or propionyl chloride leading, respectively, to the allene 160 (73%) and to the ketone 161 (72%); Scheme 7.47. [116].

1) CuCN·2LiCl 2) propargyl bromide SiMe3

BCl2 BCl3, CH2Cl2

i-Pr2Zn

25 ºC, 16 h

25 ºC, 2 h

SiMe3

SiMe3

157

158

SiMe3

Zni-Pr

160 : 73 %

O

SiMe3 159

1) CuCN·2LiCl 2) propionyl chloride SiMe3 161 : 72 %

Scheme 7.47 Synthesis of arylzinc derivatives via a Si/B/Zn-exchange sequence.

7.2.3.3 Hydrozincation of Alkenes Diorganozincs can also be prepared by a nickel-catalyzed hydrozincation. The reaction of Et2Zn with Ni(acac)2 may produce a nickel hydride that adds to an alkene leading after transmetallation with Et2Zn, to a diakylzinc. This reaction proceeds in the absence of solvent and at temperatures between 50±60 C. A number of functionalized olefins, like allylic alcohols or amines can be directly used. They afford the expected products in 60±75% yield; Scheme 7.48. [117]. This method is especially well suited for the preparation of functionalized diorganozincs for the asymmetric addition to aldehydes [117]. 7.2.4 Diverse Methods of Preparation of Allylic Zinc Reagents

Several methods have been described for preparing allylic zinc derivatives. In contrast to alkylzincs, allylic zinc reagents are much more reactive due to the greater ionic nature of the carbon±zinc bond in these organometallics. The chemistry displayed by these reagents is not representative of the usually moderate reactivity of organozinc derivatives. Tamaru and coworkers have converted various allylic benzoates to the corresponding organozinc intermediates in the presence of palladium(0) as catalyst. The resulting allylic zinc reagents of the tentative structure 162 reacts with aldehydes with high stereoselectivity depending on the substitution pattern


Et2Zn

R

Ni(acac)2 cat.

279

Zn

R

2

(-CH2=CH2) R

Et LnNi H

Et LnNi Et

LnNiX2

Et2Zn

R

Et LnNi H

Zn

Et

2

Et2Zn

Piv O

R

H

LnNi

R

Et2Zn

TIPSO(CH2)3CHO

Ni(acac)2 cat. COD cat.

toluene, Ti(Oi-Pr)4

OH

TIPSO PivO

N(H)Tf

68 %; 95 % ee

N(H)Tf 5 mol% Scheme 7.48 Ni-catalyzed hydrozincation of alkenes.

R

OBz

Et2Zn Pd(PPh3)4 cat.

R

ZnEt 162

OH

OH

PhCHO

Ph + R

Scheme 7.49 Umpolung of the reactivity of allylic systems.

(Scheme 7.49) [118,119]. Substituted allylic zinc reagents can be prepared by the fragmentation of sterically hindered homoallylic alcoholates. This method allows the first access to functionalized allylic reagents. Thus, the treatment of the lithium homoallylic alcoholates 163a,b with zinc chloride leads to a fragmentation and produces the new allylic reagents 164a,b that have to be immediately trapped with benzaldehyde providing the new homoallylic alcohols 165a,b in 56±60% yield [120]. The addition of substituted allylic zinc reagents to aldehydes is usually unselective [121]. Furthermore, the direct zinc insertion to substituted allylic halides is complicated by radical homocoupling reactions. Both of these problems are solved by the fragmentation of homoallylic alcohols. Thus, the ketone 166 reacts with

Ph R


280

E O

i L

O

ZnCl2

ZnCl

ZnCl

-78 ºC to rt, 3 h

E

E

164a : E = CO2Et 164b : E = CN 163a : E = CO2Et 163b : E = CN

OH

PhCHO

Ph E 165a : E = CO2Et; 60 % 165b : E = CN; 56 % Scheme 7.50 Preparation of allylic zinc reagents by fragmentation reaction.

BuLi providing a lithium alcoholate that, after the addition of ZnCl2 and an aldehyde, provides the expected addition product 167 with an excellent diastereoselectivity [120]. Oppolzer et al. have shown that the magnesium-ene reaction is a versatile method for adding allylic magnesium reagents to alkenes in an intramolecular fashion [122]. A zinc-ene [123] reaction can be initiated by the addition of BuLi to tert-butyl ketone 168 followed by the addition of zinc chloride. The resulting zincated spiro-derivative 169 is quenched with an acid chloride leading to the ketone 170 in 60% and > 98% syn-diastereoselectivity (Scheme 7.51) [120d]. O t-Bu

OH

1) n-BuLi, THF 0 ºC, 5 min

C6H11

2) C6H11CHO, ZnCl2 -78 ºC to rt, 2 h 167 : 76 %; syn : anti < 2 : 98

166

O t-Bu

1) n-BuLi, THF 0 ºC, 5 min

ZnCl H

2) ZnCl2 -78 ºC to rt, 3 h 168

O ZnCl

3) CuCN·2LiCl, 0 ºC

Ph

4) PhCOCl, 0 ºC, 2 h 169 Scheme 7.51 Diastereoselective reactions of substituted allylic zinc reagents generated by fragmentation.

170 : 60 %; syn : anti < 98 : 2


281

7.2.5 Preparation of Lithium Triorganozincates

Lithium triorganozincates are best prepared by the reaction of an alkyllithium (3 equiv) with zinc chloride or by the addition of an alkyllithium to a dialkylzinc in an etheral solvent [124]. Lithium and magnesium trialkylzincates are more reactive compared to dialkylzincs or alkylzinc halides due to the excess of negative charge at the metallic zinc center that confers a higher nucleophilicity to the organic substituents. Thus, lithium trialkylzincates readily undergo 1,4-addition reactions to enones [125]. A methyl group can serve as a dummy ligand allowing a somewhat selective transfer of the alkyl substituent (Scheme 7.52) [124]. In the presence of chiral nitrogen-chelating ligands, asymmetric 1,4-addition reactions can be performed with moderate enantioselectivity [126]. Interestingly, the addition of Bu3ZnLi to nitrostyrene in a chiral solvent mixture of pentane and (S,S)1,4-dimethylamino-2,3-dimethoxybutane leads to an optically enriched nitroalkane [127]. Triorganozincates can also be obtained by the reaction of the sulfonate 171 with Me3ZnLi leading to the cyclopropylidene-alkylzinc reagent 172. Its reaction with an aldehyde provides the allylic alcohol 173 in 57% yield (Scheme 7.52) [124d]. O

O

O

BuMeZnLi THF, -78 ºC

Me

Bu 3 : 97

(95 % yield) Me

OSO2 171

F

Me3ZnLi (2 equiv.)

Me

THF, 0 ºC, 2.5 h

ZnMe2Li 172

OH

Ph(CH2)2CHO

Ph 173 : 57 %

Scheme 7.52 Preparation and reactions of lithium triorganozincates.

Lithium triorganozincates can also be prepared via an I/Zn-exchange reaction. The exchange is highly chemoselective and tolerates sensitive functional groups like an epoxide or an ester. The reaction of aryl iodides 174a,b with Me3ZnLi provides the functionalized lithium zincates 175a,b that undergo respectively a ring closure and an addition to PhCHO leading to the products 176a,b in satisfactory yields (Scheme 7.53) [128]. Immobilized zincates such as 177 can be prepared by treating serine-bound 4iodobenzoate with t-Bu3ZnLi at 0 C. They react readily with aldehydes. Transmetallation with lithium (2-thienyl)cyanocuprate provides the copper species 178 that undergoes 1,4-additions. Lithium trialkylzincates can be used for the preparation of benzylic zinc reagents using a very elegant approach of Harada. Thus, the treat-

282


OH

ZnMe2Li

I Me3ZnLi N O SO2Ph

OH

25 ºC

+

N O SO2Ph

-78 ºC

174a

N SO2Ph

N SO2Ph

175a

176a : 83 %

ca. 3 %

OH I

ZnMe2Li

Me3ZnLi -78 ºC

MeO2C

Ph

PhCHO

MeO2C

MeO2C

174b

175b

176b : 74 %

Scheme 7.53 Preparation of arylzincates via an I/Zn-exchange reaction.

OH [Zn-ate]

Ph

PhCHO O t-Bu3ZnLi I

0ºC

O

resin cleavage

177

MeO O

O

2-ThCu(CN)Li

O O

R2Cu(CN)Li2 0ºC

O

[Cu-ate]

MeO O

resin cleavage O

178

O

Scheme 7.54 Preparation of zincates on the solid phase.

ment of the iodomesylate 179 with Bu3ZnLi leads to the new zincate 180 that undergoes a 1,2-migration leading to the benzylic zinc reagent 181. It is readily quenched with an aldehyde leading to the alcohol 182 in 80% yield (Scheme 7.55) [130]. Interestingly, lithium and magnesium triarylzincates add to a,b-unsaturated sulfoxides in the presence of catalytic amounts of Ni(acac)2 with good diastereoselectivity (Scheme 7.55) [131].

7.3 Reactions of Organozinc Reagents

The high covalent degree of the carbon±zinc bond and the small polarity of this bond leads to a moderate reactivity of these organometallics towards many electrophiles. Only powerful electrophiles react in the absence of a catalyst. Thus, bromolysis or iodolysis reactions are high-yield reactions. In general, a direct reaction of


Li I

Bu

ZnBu2

Bu rearrangement

Bu3ZnLi

OMs

OMs

179

Ph

ZnBu

180

Pyr

CHO

Ph

OH 182 : 80 %

181

O S p-Tol

Pyr Ph3ZnMgBr Ni(acac)2 (5 mol %) -25 ºC, THF

MeO Oc-Pent

O S

p-Tol

Ph MeO Oc-Pent 90 %, 92 % de

Scheme 7.55 Reactivity of lithium trialkylzincates.

organozincs with carbon electrophiles is not efficient and low yields are obtained. The addition of a catalyst is usually needed. The presence of empty p-orbitals at the zinc center facilitates transmetallations and a number of transition metal organometallics can be prepared in this way. These reagents are usually highly reactive towards organic electrophiles since the low-lying d-orbitals are able to coordinate and activate many electrophilic reagents. Many catalytic or stoichiometric transmetallations using zinc organometallics have been developed in recent years. 7.3.1 Uncatalyzed Reactions

Only reactive electrophiles react directly with organozinc derivatives. Allylic zinc reagents, and to some extent propargylic zinc reagents, are much more reactive. They add readily to carbonyl compounds or imines [132,133]. Thus, the reaction of the ester-substituted allylic zinc derivative 183 with the chiral imine 184 provides the lactam 185 with excellent diastereoselectivity (Scheme 7.56) [133]. An in situ generation of the allylic zinc reagent starting from the corresponding bromide 186 allows the addition to alkynes leading to skipped 1,3-dienes of type 187 [134]. Propargylic zinc derivatives react with aldehydes or ketones with variable selectivity affording a mixture of allenic and homopropargylic alcohols [135]. However, under appropriate reaction conditions, high enantioselectivities and diastereoselectivities can be achieved. Marshall and coworkers have shown that chiral propargylic mesylates such as 188 are converted to allenylzinc reagents 189 through treatment with a Pd(0)-catalyst. Their addition to an aldehyde such as 190

283


284

CO2Et ZnBr

+

Ph

N

THF

CO2Me

183

CO2t-Bu Br

Ph

CO2Me

Ph

185 : 80 %

1) H CH2OSiMe3 Zn, THF

OSiMe3

t-BuO2C

187 : 80 %

2) ultrasound, 45 ºC 30 min

186

O

N

25ºC

Ph 184

Scheme 7.56 Reactions of functionalized allylic zinc reagents.

provides the anti-homopropargylic alcohol 191 in 70% yield as a main diastereoisomer (d.r. = 85 : 15) (Scheme 7.57) [136]. O

OTBS

H H

OMs Pd(OAc) , PPh 2 3 H Et2Zn Me

H MsOZn

188

OH

190 Me

H Me

OTBS Me

189

Me

191 : 70 %; 85 : 15

Scheme 7.57 Preparation and reactions of chiral allenyl zinc reagents.

Interestingly, 1-trimethylsilyl-propargyl zinc reagents add to aldehydes with high regio- and diastereoselectivity leading to anti-homopropargylic alcohols [137]. The direct oxidation of organozincs with oxygen is an excellent method for preparing hydroperoxides [138]. Recently, a new synthesis of propargylic hydroperoxides has been developed by Harada and coworkers using allenylzinc intermediates [139]. The reaction of the mesylate 192 with the lithium zincate (Bu3ZnLi; 2 equiv) produces, after the addition of ZnCl2 (0.5 equiv), the allenylzinc species 193 that reacts at ±40 C with O2 in the presence of trimethylsilyl chloride providing the hydroperoxide 194 in 60% yield (Scheme 7.58) [139]. OMs 1) Bu3ZnLi (2 equiv) Ph H 192

Ph

ZnCl

2) ZnCl2 (0.5 equiv)

Bu 193

O2

Bu Ph O OH 194 : 60 %

Scheme 7.58 Preparation of propargylic hydroperoxides.

The moderate reactivity of zinc organometallics is compatible with the preparation of various hydroperoxides with good selectivity. The use of perfluorinated solvents allows the oxygenation reaction to be performed at low temperature owing


to the exceptionally high oxygen solubility in these media [140]. Functionalized organozincs prepared by hydrozincation, carbozincation or by boron±zinc exchange can be oxidized to the corresponding alcohols or hydroperoxides depending on the reaction conditions [141]. Tosyl cyanide reacts with a range of zinc organometallics providing the corresponding nitriles in excellent yields [142]. The functionalized alkylzinc species 195 is smoothly converted to the corresponding nitrile 196 in 67% yield. Interestingly, whereas the reaction of tosyl cyanide with benzylic bromide produces selectively 1-methylbenzonitrile in 76% yield, the cyanation of the corresponding copper reagent furnishes benzyl cyanide as sole product in 80% yield (Scheme 7.59) [142]. The reaction of 1,1-mixed bimetallics of magnesium and zinc, such as 197 [143] prepared by the addition of allylzinc bromide to (Z)-octenylmagnesium bromide with tosyl cyanide produces the nitrile 198 in 93% yield (Scheme 7.59) [142]. ZnI

(EtO)3Si

TsCN, THF rt, 3 h

195

CN

(EtO)3Si

196 : 67 %

TsCN

(76 %) CN

ZnBr 1) CuCN 2LiCl

CN (80 %)

2) TsCN

ZnBr

ZnBr

Hex

+

Hex

35ºC, 1 h THF

MgBr

MgBr

1) TsCN Hex 2) H2O

197

CN

198 : 93 %

Scheme 7.59 Electrophilic cyanation of organozinc reagents.

The reaction with various chlorophosphine derivatives leads to polyfunctional phosphines with high yield [144]. The hydroboration of b-pinene with BH3´Me2S gives bis-myrtanylzinc 199 in quantitative yield (Scheme 7.60) [144b]. The coupling of 199 with various chlorophosphines or PCl3 provides new chiral phosphines, such as 200 and 201. Polyfunctional chlorophosphines protected as their BH3-complex, such as 202 can be prepared in two steps by the reaction of Et2NPCl2 with polyfunctional organozinc reagents. After protection with BH3, the borane-complexes 203 are obtained in excellent yields. Treatment of 203 with HCl in ether leads to the borane-protected chlorophosphines of type 202 (Scheme 7.60) [145].

285

286


1) PCl3 2)

BH3.

P

BH3

Me2S 200 : 75%

Zn 2

199

H3B

1) Cl2P

PCl2 P

2) BH3. Me2S

P BH3

201 : 70%

(FG-R)2Zn or FG-RZnI

1) Et2NPCl2, Et2O 2) BH3

(FG-R)2PNEt2 BH3

HCl Et2O

203

(FG-R)2PCl BH3 202

Scheme 7.60 Preparation of polyfunctional phosphines.

Similarly functionalized organometallics such as the serine-derived zinc±copper derivate 204 react under mild conditions with ClPPh2. The resulting phosphine was protected as a sulfide providing enantiomerically pure 205 in 75% yield. Modification of the protecting groups furnishes the selectively protected diphenylphosphinoserine 206 in 80% yield (Scheme 7.61) [146a]. A combination of a substitution reaction with a chlorophosphine followed by a hydroboration, boron±zinc exchange allows the preparation of the mixed 1,2diphosphine 207 in good yield (Scheme 7.62) [145]. Reactive organometallic reagents, such as Cr(CO)5´THF readily add diorgano± + zincs leading in the presence of CO (1 atm) and Me3O BF4 (rt, 2 h) to functionalized Fischer-carbene complexes [146b]. Excellent addition reactions are also obtained with iminium trifluoroacetates, such as 208. The reaction of the aminal 209 with trifluoroacetic anhydride in CH2Cl2 at 0 C gives the iminium trifluoroacetate 208 with quantitative yield. Its reaction with phenylzinc chloride furnishes the expected amine 210 in 85% yield [147]. Interestingly, this approach can be extended to functionalized organomagnesium reagents [148]. Functionalized diarylzincs such as 211 add to the activated Schiff base 212 leading to amino-acid 213 in 62% yield [149].


Boc(H)N

I

1) Zn, TMSCl THF/DMF

CO2Me

2) CuCN·2 LiCl 0ºC

Boc(H)N

Cu(CN)ZnI

1) Ph2PCl, 0ºC, rt

CO2Me

2) S8

287

S PPh2 Boc(H)N

204

CO2Me

205: 75%

S PPh2 Fmoc(H)N

CO2H

206: 80% Scheme 7.61 Preparation of chiral functionalized phosphines.

BH3

MgBr

Pent2PCl

THF, 0ºC

BH3 Pent2P

1) Ph2PCl

BH3

1) Et2BH

Zn

Pent2P

2) Et2Zn

Pent2P

2) BH3

2

76%

BH3 BH3

THF PPh2

207 : 78%

97%

Scheme 7.62 Preparation of mixed diphosphines using functionalized zinc organometallics.

N

N

(CF3CO)2O CH2Cl2 0ºC, 0.5 h

PhZnCl, THF N

Ph

208

209

N

-78ºC, 30 min

CF3CO2

210 : 85% AcO 1)

CO2Et

CO2Et 1) PhLi, THF, -100ºC I

2) ZnCl2

Zn

CO2Me

Ph N Ph

212

2) 1N HCl

2

211 Scheme 7.63 Reaction of zinc organometallics with iminium intermediates.

CO2Et CO2Me NH3 Cl 213 : 62%

288

7 Polyfunctional Zinc Organometallics for Organic Synthesis Ph

Ph

EtO2C

PhOCOCl C6H6

N

PhO

H CO2Ph

O

217 : 66%

CH3

O

CH3

O Ph3C BF4

N

O Ph2Zn

N

CH2Cl2 rt, 16 h

O

CO2Et

N

Cl

215

O

Ph

216

25 ºC, 0.5 h

N

214

ZnI

O

218

R*

Ph

CH3

N

CH2Cl2 -78 ºC, 2 h

O 219

220 : 95%; dr = 98.8 : 1.2

Scheme 7.64 Reaction of zinc organometallics with pyridinium derivatives.

The formation of activated iminium intermediates derived from nitrogen-heterocycles has been reported by Comins and coworkers [150]. The activation of pyridine derivative, such as 214 with phenyl chloroformate provides the pyridinium salt 215 that smoothly reacts with the zinc homoenolate 216 [151] leading to the addition product 217 in 66% yield [150]. The reaction of the unsaturated amide ± + 218 with Ph3C BF4 produces N-acyliminium ions of type 219 which react with Ph2Zn in CH2Cl2 producing the desired a-substituted amine 220 in 95% yield (d.r. = 98.8:1.2), Scheme 7.64 [152]. Benzotriazole is an excellent leaving group and the readily available imidazolidin-2-ones of type 221 react with aryl-, alkenyl- or alkyl-zinc derivates via an elimination-addition mechanism providing the transproducts of type 222 with > 99% diastereoselectivity (Scheme 7.65) [153]. N

ZnBr · MgCl2

N N

Ph

Bn N

12 h, reflux

N OMe

O

Ph

THF

221

Bn N

N O

OMe

222 : 68 %; trans:cis > 99:1

Scheme 7.65 Addition of vinylzinc bromide to iminium salts generated from benzotriazole derivatives.

The addition of zinc organometallics to in situ generated oxenium ions by the reaction of mixed acetals with TMSOTf [154] allows a highly stereoselective preparation of protected anti-1,3-diols of type 223 (Scheme 7.66). The addition of TMSOTf also triggers the allylic substitution of glycal derivatives providing the substitution products of type 224 with excellent regio- and diastereoselectivity. The opening of epoxides with zinc reagents is a difficult reaction. However, activated epoxides such as the glycal epoxides 225 react with diorganozincs in the presence of CF3CO2H [155]. Presumably the reaction of R2Zn with CF3CO2H pro-


289

duces the highly Lewis-acidic species RZnOCOCF3 (226). This reaction proceeds smoothly in CH2Cl2 and furnishes the a-C-glycoside 227 in 58% yield. Hex

OAc O

O

Hex

Et2Zn

O

TMSOTf -78 ºC, 2 h

t-Bu

Et O t-Bu 223 : 100%

AcO

O

Cl(CH2)4ZnI

OAc

TMSOTf or BF3 . OEt2

AcO

AcO

O

Cl

AcO 224 : 63 %; α/β = 9 : 1

BnO

O ZnOCOCF3

O + Cl

BnO OBn

CH2Cl2

BnO

0-20 ºC, 5 h 226

225

Cl

O

BnO

OH OBn 227 : 58 %

Scheme 7.66 Reaction of zinc reagents with acetals and related compounds.

Although alkylzinc derivatives add only slowly to aldehydes, alkenylzinc derivatives display a higher reactivity. Thus, the addition of vinylzinc chloride 228 to the amino-aldehyde 229 provides the allylic alcohol 230 in 60% yield [156]. The addition rate can be increased by performing the reaction in the presence of a Lewis acid. Thus, the addition of the homoenolate 216 to the amino-aldehyde 231 provides the aminoalcohol 232 with good diastereoselectivity (Scheme 7.67) [157]. Reactive benzylic or related zinc reagents, such as 233 smoothly add to aldehydes providing the allylic alcohol 234 in almost quantitative yield (Scheme 7.67) [158]. In a noncomplexing solvent, such as dichloromethane, functionalized alkylzinc halides add to a-functionalized aldehydes leading to the addition product 235 again with a remarkable diastereoselectivity (Scheme 7.67) [158]. Benzylic acetates are unreactive toward organozinc compounds. However, various ferrocenyl acetates, such as 236 react with alkylzinc halides in the presence of BF3ÓEt2 with retention of configuration leading to the chiral ferrocenyl derivatives like 237 (Scheme 7.68) [159]. The reactivity of zinc organometallics can be dramatically increased by adding polar solvents like N-methylpyrrolidinone (NMP). Under these conditions various diorganozincs add to a range of Michael acceptors like a,b-unsaturated ketones aldehydes, nitriles or nitro derivatives (Scheme 7.69) [160]. The preparation of mixed diorganozincs bearing nontransferable Me3SiCH2-groups allows a more efficient transfer of the functionalized group to the Michael acceptor (Scheme 7.70) [98].

290


H BocN

O H

ZnCl

R 229

O I

H BocN

THF / Et2O

+

-30 ºC R 230 : ca. 60 %

228

I Zn

Zn / Cu

1) Ti(Oi-Pr)2Cl2

O OEt

OEt

2)

216

H N

O

O

1) Zn, THF, 0 ºC

N

O

O

Ph

Br

EtO2C N

TBDPSO H

CHO H

O Ph

H OH 234 : 97 %

233

O

CO2Et Bn

232 : 80 % (4S) : (4R) = 16 : 1

H

O

2)

OH

H N

O

O Bn 231

EtO2C

OH

+

BF3. Et2O

IZn O

O

Me

Me

CH2Cl2

TBDPSO H

O

H

Me

Fc

Me

236 : 98 % ee Fc = ferrocenyl

+

AcO

Zn 2

O

Me 235 : 53 % ; d.r. = 95 : 5

Scheme 7.67 Addition of organozinc halides to aldehydes.

OAc

OH O

OAc

BF3. Et2O -78ºC to rt

Fc

Me

237 : 70 %, 98 % ee

Scheme 7.68 Substitution with retention on ferrocenyl derivatives.


SiMe3

CN PivO

Zn Me3SiCl, THF / NMP -30 ºC, 1-3 h

2

291

PivO

CN 82 % c-Hex

NO2

Hex

+

THF / NMP

(c-Hex)2Zn

NO2

Hex

-30 ºC, 3 h

83 % O

O 1) Et2BH

Zn

2

2) Et2Zn

THF / NMP

> 95 %

-30 ºC, 3 h 79 %

Scheme 7.69 NMP promoted Michael additions of diorganozincs.

PivO

Zn

(Me3SiCH2)2Zn

OPiv

Zn-CH2SiMe3 TMS-Br (2 equiv) THF / NMP -20 ºC to rt, 12 h

2

ca. 0.6 equiv

Cl(CH2)4ZnI

OPiv

O

O

ca. 1.2 equiv

Me3SiCH2Li

70 %

TMSCl Cl(CH2)4ZnCH2SiMe3

CO2Bu

Cl

THF, -78 ºC

CO2Bu

76 %

THF / NMP -20 ºC to rt, 12 h CHO Bu EtO2C

Zn

SiMe3 THF / NMP, TMSCl -20 ºC to rt, 12 h

Bu EtO2C

CHO 71 %

Scheme 7.70 Mixed diorganozincs for conjugate addition reactions.

In the case of an intramolecular 1,4-addition, no activation is required [161]. The iodoenone 238 is readily converted into the corresponding alkylzinc iodide that undergoes an intramolecular addition at 25 C in THF affording the bicyclic ketone 239 in 65±67% yield [161]. The addition of alkynylzinc halides to enones is best performed in the presence of tert-butyldimethylsilyl triflate. Under these conditions, very high yields of the conjugated adducts, such as 240 are obtained (Scheme 7.71) [162].

292


O

O Zn, THF 25ºC

I 238

239 : 65 - 67% OTBS

O +

TBSOTf Ph

ZnBr Et2O / THF -40 ºC

Ph 240 : 96%

Scheme 7.71 Michael addition of organozinc halides.

The addition of the electrophilic silyl reagent strongly activates the enone. It has also been found that Lewis acids, such as AlCl3, accelerate the reaction of dialkylzincs with acid chlorides in CH2Cl2 [163]. 7.3.2 Copper(I)-catalyzed Reactions

The moderate intrinsic reactivity of zinc organometallics can be increased by transmetallation with various transition metal salts. Especially useful is the transmetallation of diorganozincs or organozinc halides with the THF-soluble complex of copper(I) cyanide and lithium chloride (CuCN´2LiCl) [10]. The simple mixing of organozinc compounds with CuCN´2LiCl produces the corresponding copper FG- R

FG-RZnI

O R

R2

O

R-FG .

CuCN 2LiCl

R2

O R1

R1

RCOCl OH

RCHO R

R-FG R

X

FG-RCu(CN)ZnI 241

FG-R

R X

R

R-FG R

R

R-FG Cu

R

R-FG R

Y

NO2

NO2

Scheme 7.72 General reactivity pattern of zinc±copper reagents.

Y

R


293

species tentatively represented as RCu(CN)ZnX (241). Their reactivity is similar, but somewhat reduced compared to copper species prepared from organomagnesium or lithium compounds [164]. The structure of the mixed copper±zinc reagents is only known by EXAFS spectroscopy, indicating that the cyanide ligand is coordinated to the copper center [165]. In contrast to lithium- or magnesiumderived organocopper reagents, they display an increased thermal stability and alkylzinc±copper reagents can be heated in 1,2 dimethoxyethane (DME) or DMPU at 60±85 C for several hours without appreciable decomposition [166]. A wide range of electrophiles react very efficiently with the copper±zinc compounds 241 leading to polyfunctional products (Scheme 7.72) [6].

7.3.2.1 Substitution Reactions Substitution reactions of zinc- or zinc±copper organometallics with R3SiCl are usually difficult, but R3SnCl reacts much more readily. By using DMF as solvent, the heterocyclic zinc reagent 242 reacts with Ph3SnCl, providing the tin derivative 243 in 37% yield [167]. The b-zincated phosphonate 244 provides, under mild conditions, the expected stannylated product 245 in 81% yield (Scheme 7.73) [55]. Allylation reactions with zinc organometallics proceed in the presence of copper salts with very high SN2¢-selectivity. This is in contrast to the palladium- or nickelcatalyzed reactions that proceed via a p-allyl palladium intermediate and afford generally the coupling product at the less substituted end of the allylic system. Ph3SnCl DMF P

P

ZnI

242

O (EtO)2P

1) Zn, THF Br 2) CuCN . 2LiCl

SnPh3

243 : 37 %

O (EtO)2P 244

Bu3SnCl Cu(CN)ZnBr THF, rt, 1 h

O (EtO)2P

SnBu3 245 : 81 %

Scheme 7.73 Stannylation of zinc±copper reagents.

Thus, the zincated propionitrile 246 [168] reacts with cinnamyl bromide in the presence of CuCN´2LiCl leading to the SN2¢-substitution product 247, whereas in the presence of catalytical amounts of Pd(PPh3)4 the formal SN2-substitution product 248 is obtained (Scheme 7.74). The presence of a functional group, such as an ester like in 249 does not modify this regioselectivity and affords the SN2¢-product 250 in 80% yield (Scheme 7.74) [168b]. Interestingly, the zinc±copper carbenoid ICH2Cu(CN)ZnI affords as an exception the SN2-substitution product 251, allowing an homologation of an allylic bromide by a CH2I unit (Scheme 7.74) [47b]. A range of polyfunctional zinc±copper reagents are readily allylated [6].


294

CuCN. 2LiCl cat

Pd(PPh3)4 cat NC

NC

Ph Ph

248

ZnI

Br

Ph Ph

246

45 ºC, 12 h

Br

CO2Me

ZnI 2)

249

247 : 92 %

0 ºC, 1 h

1) CuCN cat THF, DMAC

EtO2C

CN

EtO2C Br

250: 80 %

CO2Me ICH2ZnI

Br

CuCN. 2LiCl

I

-25 º to -20 ºC 251 : 90% > 90% SN2 selectivity

Scheme 7.74 Regioselective allylations with zinc±copper reagents. Et2B AcO

N

AcO rt, 3 h 99 %

N

N

Et2BH

N

1) Et2Zn, rt, 30 min 2) 0.1 atm, rt, 30 min

AcO

3) allyl bromide, THF CuX cat, -80 ºC to rt N

252

IZn

N

253 : 95% NHBoc CuBr· Me2S (0.1 equiv)

NHBoc

CO2Me

NHBoc + CO2Me

CO2Me

Cl

(ca. 1 : 1)

90 %

MCPBA, CHCl3, rt, 2 h O NHBoc CO2Me 27 %

+

NHBoc CO2Me 49 %

Scheme 7.75 Allylic substitutions with zinc±copper reagents.

A quinine alkaloid derivative containing a vinyl group, such as 252, has been hydroborated, undergo a boron±zinc exchange and copper(I)-catalyzed allylation, leading to the alkaloid derivative 253 [103b]. A new route to hydrophobic amino-


acids is possible by using the reaction of the zinc reagent with prenyl chloride in the presence of CuBr´Me2S (0.1 equiv). Under these conditions, a mixture of SN2 and SN2¢-products (55:45) is obtained. They can be readily separated by taking advantage of the higher reactivity of trisubstituted alkenes compared with terminal alkenes towards MCPBA (Scheme 7.75) [169]. Although zinc±copper reagents do not open epoxides, the more reactive a,b-unsaturated epoxides react readily with various functionalized zinc±copper organometallics [170] or functionalized zinc reagents in the presence of a catalytic amount of MeCu(CN)Li [171]. Thus, the opening of d-epoxy-a,b-unsaturated esters such as 254 with Me2ZnĆuCN proceeds with high anti-stereoselectivity leading to the allylic alcohol 255 in 96% yield. Also the opening of the unsaturated epoxide (256) affords the allylic alcohol 257 in 98% yield (Scheme 7.76). TIPSO

O

Me2Zn (2 equiv)

Me

CO2Et

TIPSO

CO2Et

CuCN (2 equiv) DMF, 0 ºC

+

256

Cl(CH2)4ZnI

Me

Me

254

O

OH

255: 96 %

MeCu(CN)Li (5-10 mol %)

Cl

OH

THF 257 : 98 %

Scheme 7.76 Opening of a,b-unsaturated epoxides with copper±zinc reagents.

Interestingly, the high SN2¢-selectivity of organozinc±copper derivatives allows the performance of multiple allylic substitutions with excellent results. Thus, the reaction of the multicoupling reagent [172] 258 with an excess of copper±zinc reagent provides the double SN2¢-reaction product 259 in 89% yield (Scheme 7.77) [48b]. Propargylic halides or sulfonates react with zinc±copper reagents leading to the SN2¢-substitution product like the allenic amino-acid derivative 260. Interestingly, the regioselectivity is reversed by performing the reaction in the presence of catalytic amounts of palladium(0). Thus, the insertion of zinc powder into the Zalkenyl iodide 261 is complete in THF at 45 C within 21 h. The resulting Z-zinc reagent 262 (Z:E > 99:1) reacts with the propargylic carbonate 263 in the presence of Pd(PPh3)4 (5 mol%) leading formally to the SN2-substitution product 264 in 58% yield (Scheme 7.77) [173]. Propargylic mesylates such as fluorine-substituted derivative 265 react with PhZnCl in the presence of Pd(PPh3)4 (5 mol%) in THF at 0 C within 2 h and provide the anti-SN2¢-product in excellent yield and complete transfer of the stereochemistry leading to the allene 266 (Scheme 7.78) [174]. Copper(I)-catalyzed allylic substitutions with functionalized diorganozincs proceed with high SN2¢-selectivity. Thus, the reaction of the chiral allylic phosphate 267 [175] with 3-carbethoxypropylzinc iodide in the presence of CuCN´2LiCl (2 equiv) furnishes the anti-SN2¢-

295

296


substitution product 268 in 68% yield. By the addition of n-BuLi (1.2 equiv) and TMSCl (1.5 equiv) the bicyclic enone 269 is obtained in 75% yield and 93% ee (Scheme 7.79) [176]. SePh EtO2C

+

Cu(CN)ZnI

SePh

THF

H

Cl

(excess)

CO2Et

25 ºC, 7 h

Cl

259: 89%

258

EtO2C

1) CuCN . 2LiCl NHBoc

NHBoc

IZn

2) HC C CH2Br

CO2Bn

CO2Bn 260: 55 %

Ph I

CO2Et

IZn

CO2Et

45 ºC, 21 h

261

262

CH2OCO2Me 263

Zn, THF

Ph

Pd(PPh3)4 (5 mol %) THF, 50 ºC, 45 min

CO2Et 264 : 58%

Scheme 7.77 Reaction of zinc organometallics with unsaturated halides.

OMs

PhZnCl Pd(PPh3)4 (5 mol %)

F3CF2C Hex 265 : 94 % ee

F3CF2C

THF, 0 ºC, 2 h

H

n-Hex Ph

266 : 70 %; 94 % ee

Scheme 7.78 Stereoselective propargylic substitution reaction.

This reaction can also be extended to open-chain systems. In this case, chiral allylic alcohols have been converted into pentafluorobenzoates that proved to be appropriate leaving groups. Both (E)- and (Z)- allylic pentafluorobenzoates undergo the SN2¢-substitution. In the case of (E)-substrates, two conformations 270 and 271 are available for an anti-substitution providing, besides the major trans-product (trans-272), also ca. 10% of the minor product cis-272 (Scheme 7.79). By using the (Z)-allylic pentafluorobenzoates, only trans-substitution products are produced since the conformation 273 leading to a cis-product is strongly disfavored due to allylic 1,3-strain [177]. Thus, the cis-allylic pentafluorobenzoates (R,Z)-274 reacts with Pent2Zn furnishing only the trans-SN2¢-substitution product (R,E)-275 in 97% yield with 93% ee (Scheme 7.79) [178]. Interestingly, this substitution reaction can be applied to the stereoselective assembly of chiral quaternary centers. The trisubstituted allylic pentafluorobenzoates (E)- and (Z)-276 readily undergo a substitution reaction at ±10 C with Pent2Zn furnishing the enantiomeric products (S)- and (R)-277 with 94% ee.


EtO2C

ZnI

OP(O)(OEt)2 (2 equiv) CuCN . 2LiCl (2 equiv) I

I

THF : NMP (3 : 1) 0º to 25 ºC, 12 h

267: 94 % ee

THF, -70 ºC, 2 h 268: 94 % ee

269 : 75 %, 93 % ee

1

R

H 270

of 180 º

H

antisubstitution

R2

(R, Z)-274 (95 % ee)

271

R1

cis-272

Pent2Zn CuCN . 2LiCl THF : NMP -10 ºC, 2.5 h

H

R 1

R1

trans-272

Bu

R1

antisubstitution

R2

OCOC6F5

H

R-Cu

X

R 1

X

R2

C-C rotation

H

H

O

n-BuLi (1.2 equiv) CO2Et TMSCl (1.5 equiv)

R-Cu R2

Me

297

Me

X

H1

Pent Bu

H H2

R2

(R, E)-275 : 97 %; 93 % ee

Scheme 7.79 Stereoselective anti-SN2¢-substitutions.

The ozonolysis of (R)-277 gives, after reductive work-up, the chiral aldehyde (S)-278 in 71% yield with 94% ee. The anti-selectivity is observed with a wide range of diorganozincs like primary and secondary dialkylzincs, as well as diaryl- and dibenzyl-zinc reagents [178]. It has been applied to an enantioselective synthesis of (+)-ibuprofen 279 (Scheme 7.80). Even sterically hindered allylic substrates like the allylic phosphonate 280 react with mixed diorganozinc reagents of the type RZnCH2SiMe3 in the presence of CuCN´2LiCl providing only the SN2¢substitution product regardless of the presence of the two methyl groups adjacent to the allylic center. The reaction with EtO2C(CH2)2ZnCH2SiMe3 provides the anti-substitution product 281 in 81% with 97% ee. It is readily converted in (R)-a-ionone 282 (45%; 97% ee) The ortho-diphenylphosphanyl ligand orients the SN2¢ substitution in a syn-manner with high regio- and stereoselectivity to the cis-product (Scheme 7.81) [179, 180]. Allylic substitution using organozinc reagents can also be performed using a chiral catalyst [181]. The use of a modular catalyst is an especially versatile strategy and has been applied to the stereoselective preparation of quaternary centers with great success [182]. In the presence of 10 mol% of the modular ligand 283 highly enantioselective substitutions of allylic phosphates like 284, leading to the fish deterrent sporochnol (285: 82% yield, 82% ee), have been performed.

1

R 273

298


Me

Pent2Zn CuCN. 2LiCl

OCOC6F5

Ph

Me

THF, -10 ºC 15 h 84 %

(E)-276

Ph

OCOC6F5

Me

Me

Pent2Zn CuCN. 2LiCl

Me

(S)-277 (94 % ee)

Ph

Ph

1) O3

Me Pent

THF, -10 ºC 15 h 92%

(Z)-276

Me Ph Pent

Me Pent

Me 2) PPh3

(R)-277 (94 % ee)

O H

(S)-278 (94 % ee)

Bu 1) tert-BuLi 2) ZnBr2 3) CuCN. 2LiCl

I

Me

COOH

1) O3 2) Jones oxid.

4) THF, -10 ºC, 20 h i-Bu

Me

Me

i-Bu

i-Bu

OCOC6F5

279 : 80 %; 97% ee (+)-ibuprofen

91 %; 97 % ee

Bu (S, Z)-274; 99 % ee

Scheme 7.80 Preparation of quarternary chiral centers and (+)-ibuprofen synthesis.

O EtO I OP(O)(OEt)2

CO2Et

ZnCH2SiMe3

CuCN·2LiCl, THF:NMP 25 ºC, 45 h

I

1) Me2Zn, Pd(0) 2) LiAlH4 3) Swern-oxid.

281 : 81 %, 97 % ee

280 : 98 % ee O 1) PhSeCl tert-BuOK 2) 30 % H2O2 3) MeMgCl 4) PDC 282 : (R)-α-ionone 45 %, 97 % ee Scheme 7.81 Synthesis of (R)-a-ionone using a stereoselective anti-SN2¢-substitution.


299

Me Me

OP(O)(OEt)2 Zn

+

2

TsO

1) 283 (10 mol %) CuCN (10 mol %) -78 ºC, 48 h

Me Me

2) KOH, aq EtOH, 80 ºC HO

284

285 : 82 %; 82 % ee c-Hex N O

N OiPr

O

H N

NHn-Bu Bn

283

NH2 t-Bu Fe t-Bu 286 (10 mol %)

Cl +

Zn 2

CuBr · SMe2 (1 mol %) 82 %

96 % ee SN2' : SN2 = 98 : 2

Scheme 7.82 Catalytic SN2¢-allylic substitutions.

Sterically very hindered diorganozincs like dineopentylzinc react enantioselectively with allylic chlorides in the presence of the chiral ferrocenylamine 286 with up to 98% ee (Scheme 7.82) [183]. The addition of zinc±copper organometallics to unsaturated cationic metal complexes derived for example from pentadienyliron and pentadienylmolybdenum cations affords the corresponding dienic complexes. 5 Thus, the addition of a zinc±copper homoenolate to the cationic g -cycloheptadienyliron complex 287 leads to the polyfunctional iron-dienic complex 288 in 65% yield [184]. This chemistry has been extensively developed by Yeh and coworkers 6 [185]. The addition of allylic and benzylic zinc reagents to (g -arene)-Mn(CO)3 cat5 ions of type 289 provides with excellent stereoselectivity the neutral (g -cyclohexadienyl)Mn(CO)3 complexes such as 290 in 92% yield. Less-reactive functionalized alkylzinc compounds show a more complicated reaction pathway due to an isomerization of the organozinc species (Scheme 7.83) [186]. Rigby and Kirova-Snover [187] have applied these reactions to the synthesis of several natural products. Thus, the alkylation of the cationic tropylium complex 291 with the functionalized zinc reagent 292 furnishes the chromium complex 293 that was an intermediate for the synthesis of b-cedrene (Scheme 7.83).


300

EtO2C 287

Cu(CN)ZnI CO2Et (OC)3Fe

Fe(CO)3

288 : 65 % Ph ZnBr H

CH3 Mn(CO)3

Me

289

CO2Et

Mn(CO)3 290 H

CO2Et

CO2Et 1) CuCN·2LiCl

CO2Et

150 ºC

Zn, THF I

ZnI

Me

Me 292

dioxane

2)

Me

Cr(CO)3 BF4 (OC)3Cr

80 %

293 : 74 %

291

Scheme 7.83 Reaction of zinc±copper reagents with cationic transition metal complexes.

Yeh and Chuang have shown that such addition reactions provide polyfunctional cationic chromium species, such as 294 that can be converted to highly functionalized bicyclic ring systems (295) which are difficult to prepare otherwise (Scheme 7.84) [49]. EtO2C(CH2)4Cu(CN)ZnI CO2Et (OC)3Cr

294

BF4

THF, rt, 4 h

(OC)3Cr

BF4 H

1) LDA, CO, THF, HMPA, -78 ºC, 1 h H CO Et 2

2) MeI, CO, rt, 2 h O

295 : 66 % Scheme 7.84 Addition of functionalized zinc±copper reagents to cationic chromium complexes and subsequent cyclization.

Alkynyl iodides and bromides smoothly react with various zinc±copper organometallics at ±60 C leading to polyfunctional alkynes [48d]. Iodoalkynes, such as 296 [188] react at very low temperature, but lead in some cases to copper acetylides as byproducts (I/Cu-exchange reaction). 1-Bromoalkynes are the preferred substrates. Corey and Helel have prepared a key intermediate 297 of the side chain of


301

Cicaprost by reacting the chiral zinc reagent 298 with 1-bromopropyne leading to the functionalized alkyne 299 (Scheme 7.85) [189]. This cross-coupling has also been used to prepare a pheromone (300) [48d]. Ph EtO2C

I

Cu(CN)ZnI +

THF, -80 ºC to -55 ºC, 1 h

296

56 %

ZnI Me 298

Et Br -60 ºC, 20 h

OH

O

CuCN·2LiCl

MeO

MeO Me

Et

2) CuCN· 2LiCl 3) I Hex -50ºC, 16 h

AcO(CH2)6

i-Pr3Si

Me

Et

297

299

1) Zn, THF AcO(CH2)6I

CO2Et O

O

O

Ph

Hex

H2 / Lindlar-Pd cat PhCH3 / Py 0 ºC, 48 h

AcO(CH2)6

Hex

300 : 98 % E : Z = 99.4 : 0.6

Scheme 7.85 Cross-coupling of zinc±copper organometallics with 1-haloalkynes.

Substitution at Csp2-centers can also be accomplished as long as the haloalkene is further conjugated with an electron-withdrawing group at b-position. Thus, 3-iodo-2-cyclohexenone reacts with the zinc reagent 301 bearing a terminal alkyne affording the functionalized enone 302 [11]. Similarly the stepwise reaction of 3,4-dichlorocyclobutene-1,2-dione (303) with two different zinc±copper reagents furnishes polyfunctional squaric acid derivatives, such as 304 [190]. By using mixed diorganozinc reagents of the type FG-RZnMe [191], a catalytic additionelimination can be performed with a wide range of b-keto-alkenyl triflates. Thus, the penicillin derivative 305 reacts with the mixed copper reagent 306 providing the desired product 307 in excellent yield (Scheme 7.86) [191]. Functionalized heterocycles such as 308 can be prepared in a one-pot synthesis in which the key step is the addition-elimination of a functionalized copper±zinc reagent 309 to the unprotected 3-iodoenone 310 producing the annelated heterocycle 308 in 41% (Scheme 7.87) [192]. Besides enones, several Michael acceptors having a leaving-group in b-position react with zinc±copper reagents. Thus, diethyl malonate [(phenylsulfonyl)methylene] (311) reacts with zinc±copper reagent 312 providing the addition substitution product 313 in 90% yield [193]. Similarly, the zinc±copper reagent 314 reacts with 2-phenylsulfonyl-1-nitroethylene (315) providing the intermediate triene 316 that cyclizes on silica gel at 25 C within 4 h affording the Diels±Alder product 317 in 85% (Scheme 7.87) [194]. The cross-coupling reaction with unactivated alkenyl

302


O O I

H

1) Zn, THF 2) CuCN·2LiCl

H

I Cu(CN)ZnI THF, -30 ºC, 1 h

H

301

302 : 88 %

O

O

O

1) c-HexCu(CN)ZnI (1.2 equiv) -60 ºC to -40 ºC, 4 h

Cl

Cl

2) AcO(CH2)5Cu(CN)ZnI (1.8 equiv) -78ºC to 0ºC, 1h

303

O

OAc 304 : 67 % CN

1) Zn I(CH2)4CN

2) MeLi -78ºC

CN

ZnMe CuCN·2LiCl (3 mol %)

S N

BocHN

S

306 N O 305

BocHN

O CO2CHPh2

OTf CO2CHPh2

307 : 70 %

-78 ºC to rt, 25 min Scheme 7.86 Addition-elimination reaction with zinc±copper reagents.

iodides requires harsh conditions, but produces the desired products with retention of the double-bond configuration [166]. The alkylation of primary alkyl halides and benzylic halides can be readily performed with diorganozincs treated with one equivalent of Me2CuMgCl in DMPU. This cross-coupling reaction tolerates a range of functionalities (ester, cyanide, halide and nitro group). The methyl group plays the role of a nontransferable group under our reaction conditions. Thus, the reaction of the dialkylzinc 318 with the nitro-substituted alkyl iodide 319 provides the cross-coupling product 320 in 83% yield [195]. A nickel-catalyzed cross-coupling reaction between an arylzinc reagent, such as 321 and a functionalized alkyl iodide can be successfully achieved using 3-trifluoromethylstyrene 322 as a promoter. The role of this electron-poor styrene will be to coordinate the nickel(II) intermediate bearing an aryl- and an alkyl residue and to promote the reductive elimination leading to the cross-coupling product 323 [196,197]. Interestingly, this cross-coupling reaction can be readily performed between two Csp3 centers. Thus, the reaction of primary or secondary alkylzinc iodides with various primary alkyl iodides or bromides in the presence of catalytic amount of Ni(acac)2 (10 mol%), Bu4NI (3 equiv) and 4- fluorostyrene (20 mol%) provides the corre-


303

sponding cross-coupling products in satisfactory yields [199]. More reactive secondary dialkylzincs and the mixed organozinc compounds RZnCH2SiMe3 undergo the cross-coupling in the absence of Bu4NI [198]. HN O I

NC

309

F

HN

Cu(CN)ZnBr

NC

-5 ºC, 20 min, then 3 h, rt

O

O

N H

N H 310

308 : 41 %

EtO2C EtCO2(CH2)3Cu(CN)ZnI 312

EtO2C

CO2Et

THF

SO2Ph

-80 ºC to -55 ºC 1h

+

311

CO2Et

EtO2C 313 : 90%

Me Me Cu(CN)ZnI 314

NO2

+ PhO2S

Me

THF

NO2

-55 ºC 315

316

NO2

SiO2, hexane

H

25ºC, 4 h

H 317 : 85%

Scheme 7.87 Addition-elimination reactions of copper±zinc reagents with various Michael acceptors bearing a leaving group in b-position.

Thus, the secondary diorganozinc 324 obtained by the hydroboration of norbornene with Et2BH and subsequent boron±zinc exchange undergoes a smooth cross-coupling with the iodoketone 325 at ±30 C (16 h reaction time) furnishing stereoselectively the exo-ketone 326 in 61% yield. Polyfunctional products, such as 327 are readily obtained by performing the cross-coupling of functionalized alkylzinc iodides with functionalized alkyl bromides (Scheme 7.88) [198].

7.3.2.2 Acylation Reactions The uncatalyzed reaction of acid chlorides with organozincs is sluggish and inefficient. It is often complicated by side reactions and leads usually to low yields of the desired acylation products. In contrast, the CuCN´2LiCl-mediated acylation of various zinc reagents affords ketones in excellent yields. The reaction of the zinc± copper reagent 328 obtained by the direct zinc insertion to the iodide 329 followed by a transmetallation with CuCN´2LiCl reacts with benzoyl chloride at 25 C leading to the ketone 330 in 85% yield [52b]. The functionalized benzylic bromide 331

304


I (AcO(CH2)4)2Zn

I

DMPU, 0º C, 2 h

NO2

318

CO2Et

Me2CuMgCl

+ NO2 Ph 320 : 83 %

Ph 319

CO2Et

1) i-PrMgBr, THF -40 ºC, 0.5 h 2) ZnBr2, THF

2) i-Pr2Zn rt, 3 h

F3C

ZnBr 321

1) Et2BH 50 ºC, 16 h

OAc

322

(1 equiv)

SPh CO2Et

PhS I Ni(acac)2 (10 mol %) -15 ºC, 2 h

323: 75 %

I(CH2)3COPh 325

Zn

Ni(acac)2 (10 mol %)

2

H 324

Ph H

O 326

F

(20 mol %)

Ni(acac)2 (10 mol %) Bu4NI (3 equiv)

PivO(CH2)4ZnI + PhCO(CH2)3Br F

(20 mol %)

O Ph PivO 327

THF / MNP, -5 ºC, 16 h Scheme 7.88 Cross-coupling reactions with zinc organometallics.

is converted in the usual way into the zinc-copper derivative 332 that is readily acylated leading after aqueous workup to the functionalized indole 333 in 73% yield (Scheme 7.89) [50]. Bis-zinc organometallics, such as 334 and 335 are also acylated after transmetallation with CuCN´2LiCl leading to the corresponding diketones 336 [21] and 337 [200]. Allylic zinc reagents are highly reactive and add to acid chlorides and anhydrides. A double addition of the allylic moiety usually occurs leading to tertiary alcohols [15,20]. The double addition can be avoided by using a nitrile as substrate (Blaise reaction). By using Barbier conditions, it was possible to generate the zinc reagent corresponding to the bromide 338 and to add it to a nitrile. After acidic workup, the unsaturated ketone 339 is obtained in 82% yield (Scheme 7.90) [202,203].


Ph

O

O

O

1) Zn, THF, 8 ºC, 1 h

S 329

I

PhCOCl Ph

2) CuCN·2LiCl 0 ºC, 5 min

Cl Br N(SiMe3)2

S 328

Cu(CN)ZnI

Cu(CN)ZnBr

2) CuCN·2LiCl

rt, 8 h

S

Cl Cl

THF, 0ºC

332

N H 333 : 73 %

O ZnI

1) CuCN·2LiCl 2) MeCOCl

IZn 334

Et2Zn BEt2 BEt2

O 336 : 76 %

Zn

Zn

0 ºC, 0.5 h

O

1) CuCN·2LiCl 2) PhCOCl

O

Ph

Ph 337 : 40 %

335 Scheme 7.89 Acylation of zinc±copper reagents.

Br

TMS

1) Zn, n-C7H15CN THF, 45-50 ºC 2) HCl (dilute)

338

O TMS

Ph

O 330 : 85 %

Cl

N(SiMe3)2

331

Ph

O

Cl

1) Zn, THF 0ºC, 5 h

305

n-C7H15 339 : 82%

Scheme 7.90 Acylation by the addition of an allylic zinc reagent to a nitrile.

7.3.2.3 Addition Reactions Allylic and to the same extent propargylic zinc reagents add to aldehydes, ketones and imines under mild conditions [203]. Thus, 2-carbethoxyallylzinc bromide (340) that is readily prepared by the reaction of ethyl (2-bromomethyl)acrylate [204] with zinc dust in THF (17±20 C, 0.5 h) adds to a range of aldehydes and imines to provide a-methylene-c-butyrolactones and lactams [205]. Chiral lactams can be prepared by adding the allylic zinc (183) to imines bearing amino alcohol substituents [206]. Functionalized allylic zinc reagents have been used to prepare a range of heterocycles, such as 341 [207]. The addition of propargylic zinc halides to aldehydes or ketones often provides mixtures of homopropargylic and allenic alcohols [208]. Interestingly, silylated propargylic zinc reagents, such as 342 may be better viewed as the allenic zinc reagent 343 that reacts with an aldehyde via a cyclic transition state affording only the anti-homopropargylic alcohol 344 with 90% yield

Cl

306


(Scheme 7.91) [137]. Alkylzinc halides react only sluggishly with aldehydes or ketones. This reactivity can be improved by activating the carbonyl derivative with a Lewis acid. Excellent results are obtained with titanium alkoxides [209], Me3SiCl [210] or BF3ÓEt2 [48c]; (Scheme 7.92). Depending on the nature of the catalyst either the 1,2-addition product (345) or the 1,4-addition product (346) is obtained by the addition of the zinc±copper reagent 347 to cinnamaldehyde [48c].

Ph

N

CH2OH

CO2Et ZnBr

+

Ph

THF

Ph

183

N Ph

O CH2OH

340 : 80 % OBn ZnBr

SiMe3 Pr ZnCl 342

O

1) THF, rt, 12 h

+

2) Pd(PPh3)4 (cat) 65 ºC, 16 h

Ph

Pr H 343

Ph O 341 : 83 %

SiMe3

PrCHO

ZnCl

-74 ºC to rt

OH

SiMe3

Pr Pr 344 : 90 %

Scheme 7.91 Reaction of allenic, propargylic and allylic zinc reagents with carbonyl derivatives.

In a noncomplexing solvent like CH2Cl2, alkylzinc reagents, such as 348 and ent-348 react with polyfunctional aldehydes leading to highly functionalized alcohols, such as 349a,b with high diastereoselectivity in the ªmatchedº case; Scheme 7.92 [158, 210]. Polyoxygenated metabolites of unsaturated fatty acids have been prepared by the addition of functionalized zinc±copper reagents to unsaturated aldehydes in the presence of BF3ÓEt2 providing allylic alcohols of type 350 [211]. Allylic zinc reagents readily add to aldehydes with good stereoselectivity in some cases. Thus, the addition of dicrotylzinc [212a] to the amino-aldehyde 351 furnishes the alcohol 352 as one diastereomer in 82% yield. Interestingly, the corresponding Grignard reagent leads to a mixture of diastereoisomers (Scheme 7.93) [212b]. The addition of copper±zinc organometallics to imines is difficult. Benzylic zinc reagents display, however, an enhanced reactivity and react directly under well-defined conditions with in situ generated imines. A diastereoselective one-pot addition of functionalized zinc organometallics can be realized by performing the reaction in 5M LiClO4 (in ether) in the presence of TMSCl. By using Reformatsky reagents and a chiral amine like (R)-phenylethylamine diastereoselectivities with up to 95% have been obtained. With the benzylic zinc reagent 353, the secondary amine 354 is obtained in 60% yield and 70% de [213].


307

OH ZnI

EtO2C

PivO

OH Me

Ph

PhMe, DMAC

PhCHO

+

TMSCl, rt, 18 h

CHO PivO

Ph

EtO2C

Me Cu(CN)ZnI Ph

CHO

BF3·Et2O 345 : 89 %

347

O

O TBDPSO H

O

(matched) H OH O

O

349a : 53 % diastereoselectivity = 95 : 5

CHO O

CHO

346: 92%

1, 4-addition

2) BF3·Et2O, CH2Cl2

H

Ph Me

IZn 348

TBDPSO

PivO

TMSCl

1, 2-addition

1)

Ph 80 %

H

1) BF3·Et2O, CH2Cl2

TBDPSO

(mismatched) H

2)

O

H OH O

O

IZn ent-348

O

O

349b : 51 % diastereoselectivity = 73 : 27

Scheme 7.92 Selectivity in the reaction of zinc and zinc±copper reagents with aldehydes.

Mangeney and coworkers have found that alkylzinc reagents add to reactive imine derivatives and have used this property to prepare chiral amino-acids (Scheme 7.94) [214]. The addition of tert-BuZnBr to chiral a-imino-esters bearing a phenylglycinol unit provides in ether the corresponding adduct 356 with a diastereoselectivity of 96:4. After removal of the chiral inductor by hydrogenolysis, the corresponding amino ester 357 is obtained in 85% ee. Copper±zinc reagents add to various pyridinium salts leading either to the 1,2or to the 1,4-adduct depending on the substituent pattern of the pyridine ring (Scheme 7.95) [150,215].

308


OH AcO

CHO Pent

AcO

BF3 Et2O

Cu(CN)ZnI

+ AcO

.

-78 ºC

CO2Et

AcO

Pent

EtO2C

350 : 55 % NMe2

HO

Zn

Me OHC

NMe2 Me

2

18 h, -30ºC

OTBS

Me

OTBS 352 : 82 % one diastereoisomer

351

CH2ZnBr Ph PhCHO

Ph

5M LiClO4

Me

+

+

NH

ether, Me3SiCl, rt

NH2

CN

Ph

CN

354 : 60 %; 70 % de

353

Scheme 7.93 Addition reactions of zinc and copper±zinc reagents to carbonyl compounds. t-Bu

OEt Ph N

O

2) tert-BuZnBr, ether, 0 ºC, 1 h 3) NH4Cl

OMe 355

t-Bu

Ph

1) ZnBr2, 20 ºC

N H

H2, Pd/C

CO2Et

ethanol 20 ºC

OMe 356 : 68 %

H2N

CO2Et

(R)-357 : 100 %; 85 % ee

Scheme 7.94 Addition of a tertiary alkylzinc reagent to a chiral iminoester.

Cl Cu(CN)ZnI

Cl

Cl PhOCOCl

N

N O

Cl

Cl

N CO2Ph

Cl OPh

66 % CO2Me

CO2Me

CO2Me o-chloranil + N O

toluene, reflux

Cl OEt

Cu(CN)ZnI N CO2Et

Scheme 7.95 Addition of copper±zinc reagents to pyridinium salts.

N 57%


7.3.2.4 Michael Additions Organocopper reagents derived from organolithium or magnesium derivatives add readily to various Michael acceptors [64]. The zinc±copper reagents obtained by reacting organozinc halides with CuCN´2LiCl undergo numerous 1,4-addition reactions with various Michael acceptors. The presence of TMSCl is especially useful and effective [216]. It assures high yields of the conjugate adducts. Thus, the addition of various polyfunctional zinc±copper reagents with cyclohexenone provides the desired 1,4-addition product 358 in the presence of TMSCl in 95% yield [10, 217]. Sterically hindered enones, such as 3-cyclohexyl-2-cyclohexen-1one 359 undergoes a conjugate addition in the presence of BF3ÓEt2 affording the ketone 360 bearing a quaternary center in b-position (Scheme 7.96) [48a]. Unsaturated copper reagents are best added via alkenylzirconium species that are readily prepared by hydrozirconation. In the presence of catalytical amounts of Me2Cu(CN)Li2, they add to various enones affording the unsaturated ketones of type 361 in satisfactory yield (Scheme 7.96) [21]. O

O

CN Cu(CN)ZnI

+

TMSCl, THF

NC

-78 to 25ºC 358 : 97% O

O +

Cl Cu(CN)ZnI

c-Hex

Cl

BF3. Et2O THF -30 to 0ºC

359

c-Hex 360 : 97%

O 1) Cp2Zr(H)Cl 2) MeLi, Me3ZnLi Me2Cu(CN)Li2 (cat) TIPSO

OTIPS

3) cyclopentenone 361 : 88%

Scheme 7.96 Michael addition of zinc±copper reagents to enones.

Arylzinc reagents, obtained by the electrochemical reduction of the corresponding aromatic chloride or bromide using a sacrificial zinc electrode, allows the preparation of zinc reagents bearing a keto group [36]. Exo-methylene ketones such as 362 add various copper±zinc reagents. This methodology has been applied for the synthesis of various prostaglandines, such as 363 [218]. Enantioselective Michael additions have been pioneered by Feringa and coworkers [219] and Alexakis and coworkers [220]. Remarkably, only a catalytic amount of the chiral ligand 364 (4 mol%) and of Cu(OTf)2 (2 mol%) is required. The 1,4-addition product 365 is obtained with an enantiomeric excess of 93% ee [219a]. It has been applied

309

310

7 Polyfunctional Zinc Organometallics for Organic Synthesis O CO2Me 362

O

CO2Me

Cu(CN)ZnI Pent

Pent

Me3SiCl, -78 ºC to 25 ºC

TBDMSO

TBDMSO OTBDMS

OTBDMS

362 O

363 : 86 % O

Cu(OTf)2 (2 mol %) (PivO(CH2)6)2Zn

OPiv 365 : 87 %; 93 % ee

Ph O P N O Ph 364 : 4 mol %

O

O

O

O

SiMe2Ph

Pent CO2Me

1) Cu(OTf)2 (3 mol %)

H

+

O

O

H

Ph

Zn Ph

PhMe2Si HO HO H

CO2Me

Ph

O P N O

2

Ph

ca. 40 %; 94 % ee

Ph

Ph ent-364 : 6 mol % toluene, -40 ºC, 18 h 2) Zn(BH4)2, ether, -30 ºC

HO HO

Pent

H

CO2Me H O 366

Ph O P N O Ph Et

O Ph

O

(2 mol %) +

Et2Zn

CuXn, ether

Ph Cu(OTf)2 : 80 % ee Cu(OAc)2 : 93 % ee CO2Cu : 90 % ee S Cu-naphtalenate : 92 % ee

Scheme 7.97 Stereoselective Michael addition of zinc reagents to enones.


for an enantioselective synthesis of prostaglandin E1 methyl ester (366) [221] and can be used for the performance of a highly regiodivergent and catalytic parallel kinetic resolution [222]. The nature of the copper salt strongly influences the enantioselectivity and copper carboxylates proved to be especially efficient (Scheme 7.97) [220c]. Hird and Hoveyda have developed a very efficient modular ligand based on various amino acids. The modular ligand 367 has been optimized for the enantioselective addition of Et2Zn to the oxazolidinone 368 [223]. The resulting products of type 369 can be converted into other carbonyl compounds (ketones, Weinreb amides, carboxylic acids) by standard methods. A stereoselective synthesis of substituted pyrrolidines has been achieved by a sequential domino Michael addition and intramolecular carbozincation. Thus, the reaction of the acyclic ester 370 with a copper±zinc reagent such as 371 provides with high stereoselectivity the pyrrolidine 372 (d.r. = 95:5). The intermediate zinc±copper reagent obtained after cyclization can be trapped with an electrophile such as allyl bromide providing a product of type 373 in satisfactory yield [224]. The addition to a,b-unsaturated esters is usually difficult. However, under appropriate conditions, the 1,4-addition of diorganozincs to enoates is possible [225]. As mentioned above, Michael addition reactions can also be catalyzed by Ni(II)-salts [99]. The 1,4-addition of functionalized organozinc iodides to enones Ot-Bu O

O

O Ph

N H PPh2

N

O

H N

O NHBoc

O Et

367 : 6 mol % Cu(OTf)2 (2.4 mol %), Et2Zn toluene, -15 ºC, 6 d

368

O

O

Ph

N

369 : 91 %; 86 % ee CO2Me Cu(CN)ZnBr·3LiBr 371 : (2 equiv) Et2O, 25 ºC

N Bn 372: 52%; d.r. = 95 : 5

CO2Me Bn

O

N 370

1) PhCu(CN)ZnBr·3LiBr Et2O, rt 2) allyl bromide

CO2Me Ph N Bn 373: 57 %; d.r. > 95 : 5

Scheme 7.98 Stereoselective additions of zinc±copper reagents to carbonyl compounds.

311

312


in the presence of Ni(acac)2 in the presence of a diamine as ligand and TMSCl provides after hydrolysis the Michael adducts in satisfactory yields [226]. Nitroolefins are excellent Michael acceptors that react with a broad range of nucleophiles in a Michael fashion. The resulting functionalized nitroalkanes can be readily converted into amines by reduction reactions or to carbonyl compounds by a Nef reaction [227]. The addition of nucleophiles to nitroolefins is complicated by the subsequent addition of the resulting nitronate to remaining nitroolefin. Whereas such a side-reaction is quite fast for lithium and magnesium [228] nitronates, it is slow for zinc nitronates. Thus, various functionalized zinc±copper reagents add to nitroalkenes leading to Michael adducts, such as 374 in good yields [11,30]. The reaction with 1-acetoxy-2-nitro-2-propene (375) [172] and functionalized zinc±copper reagents provides an access to terminal nitroolefins, such as 376 [30]. The highly reactive reagent [229] undergoes the allylic substitution reaction already at ±55 C. Similarly, (2-phenylsulfonyl)nitroethylene (377) undergoes an addition-elimination reaction with the copper±zinc species 378 at ±60 C leading to the triene 379 in 92% yield (Scheme 7.99) [30,229]. Cu(CN)ZnI + H

Ph

NO2

-78 ºC to 0 ºC 10 min

NO2 H

Ph 374 : 78 %

NO2 OAc

+

EtO2C(CH2)3Cu(CN)ZnI

THF

NO2 CO2Et

-55 ºC, 10 min

375

376 : 92 %

Cu(CN)ZnI 378

+

NO2

PhO2S

THF -60 ºC, 0.5 h

377

NO2 379 : 92 %

Scheme 7.99 Addition of zinc±copper reagents to nitroolefins.

Interestingly, bis(methylthio)-1-nitroethylene (380) reacts with dimetallic zinc±copper species leading to the corresponding exo-methylene cycloalkenes, such as 381 (Scheme 7.100) [30]. b-Disubstituted nitroolefins are especially difficult to prepare by nitroaldol condensation. The addition of zinc±copper reagents to nitroolefins followed by a reaction with phenylselenyl bromide produces after H2O2-oxidation E/Zmixtures of b-disubstituted nitroalkenes, such as 382 (Scheme 7.100) [230]. Interestingly, the intermediate zinc nitronate resulting from the Michael addition, the oxidative Nef reaction can be directly performed leading to a polyfunctional ketone, such as 383 in high yield; Scheme 7.100 [30]. The addition of copper organometallics to triple bonds (carbocupration) [231] can be realized with copper reagents derived from zinc organometallics. The syn-addition of zinc±copper reagents to activated triple bonds, such as acetylenic esters is especially easy. The


Cu(CN)ZnI Cu(CN)ZnI

SMe +

NO2

MeS

THF

380

EtO2C(CH2)3Cu(CN)ZnI +

Ph

NO2

-30 ºC, 0.5 h 381 : 85 %

NO2

1) THF, 0 ºC 2) PhSeBr, 0 ºC 3) H2O2, rt

CO2Et Ph NO2 382 : 64 %

O CO2Me NO2

+


1) 0 ºC, 1 h 2) O3, CH2Cl2 -78 ºC, 3 h 3) Me2S, -78 ºC

CO2Me CO2Et 383 : 87 %

Scheme 7.100 Reaction of functionalized zinc±copper reagents with polyfunctional nitroolefins.

carbocupration of ethyl propiolate at ±60 C to ±50 C produces the syn-addition product 384 after protonation at low temperature. Interestingly, if the reaction mixture is warmed up in the presence of an excess of TMSCl, an equilibration occurs and the C-silylated unsaturated product 385 is obtained [48d]. The presence of acidic hydrogens of the amid group does not interfere with the carbocupration reaction. Thus, the unsaturated amide 386 affords, after addition, the E-unsaturated amide 387 in 53% as 10% E-isomer (Scheme 7.101) [11]. A formal [3+2]-cycloaddition can be accomplished by adding bis-(2-carbethoxyethyl) zinc to acetylenic esters [232c]. This reaction allows the construction of complex cyclopentenones, such as 388 which is a precursor of (±)-bilobalide (Scheme 7.101) [232c]. The allylzincation of trimethylsilylacetylenes can be performed intramolecularly providing a functionalized alkenylzinc that cyclizes in the presence of Pd(PPh3)4 at 25 C within 3.5 h leading to the bicyclic product 389 in 84% yield (Scheme 7.102) [233]. The addition of allylic zinc halides to various alkynes occurs in the absence of copper salts. The related addition to 1-trimethylsilyl alkynes [234], unsaturated acetals [235] and cyclopropenes [236] occurs readily. Functionalized allylic zinc reagents can be prepared by the carbozincation of a dialkoxymethylenecyclopropane 390 with dialkylzincs. Thus, the reaction of 390 with Et2Zn provides the allylic zinc reagent 391. After the addition of an electrophile, the desired adduct 392 is obtained in good yield. [237]. Allylic zinc reagents are highly reactive reagents that are prone to undergo carbozincation of weakly activated alkenes. [143]. Thus, the addition of the mixed methallyl(butyl)zinc 393 with the vinylic boronate 394 provides the intermediate zinc reagent 395. After the addition of an extra equivalent of ZnBr2, CuCN ´ 2LiCl and allyl bromide, the reaction mixture was worked up oxidatively, providing the alcohol 396 in 83% yield. [238].

313

314


CO2Et 1) -60 ºC, 14 h 2) H3O+, -30 ºC EtO2C(CH2)3Cu(CN)ZnI

+

CO2Et 384 : 95 %; 100 % E

CO2Et

CO2Et TMS

TMSCl, rt, 18 h

CO2Et 385 : 91 %; 100 % Z


+

THF

CONH2

-30 ºC to 0 ºC, 2 h

386

CONH2 CO2Et 387 : 53 %; 100 % E t-Bu

t-Bu

CO2Me O

O H

O H

OTMS

+

EtO2C

Zn 2

CuBr·Me2S HMPA, Et2O, THF

O

OTMS

O CO2Me

388 : 52 % Scheme 7.101 Carbocupration of acetylenic carbonyl derivatives.

Functionalized allylic zinc reagents can also be generated in situ. The direct cyclization of allenyl aldehydes such as 397 with diorganozincs in the presence of Ni(cod)2 (10±20 mol%) provides cyclic homoallylic alcohols such as 398 with good diastereoselectivity [239]. The allylzincation of alkenylmagnesium reagents is a very convenient synthesis of 1,1-bimetallic reagents of magnesium and zinc [240]. Thus, the addition of the ethoxy-substituted allylic zinc reagent (399) to the alkenylmagnesium reagent 400 providing after the addition of Me3SnCl (1 equiv) the a-stannylated alkylzinc species 401 that is readily oxidized with O2 leading to the aldehyde 402 with an excellent transfer of the stereochemistry (Scheme 7.103) [241]. The activation of primary zinc±copper reagents with Me2Cu(CN)Li2 allows to carbocuprate weakly activated alkynes. The carbocupration of the alkynyl thioether 403 is leading to the E-alkene 404 with high stereoselectivity [242]. Although, primary alkylzinc regents do not add to unactivated alkynes, the addition of the more reactive secondary copper±zinc reagents affords the desired product 405 with high E-stereoselectivity [242]. The intramolecular carbocupration proceeds also with primary copper organometallics leading after allylation of the exo-alkenylidene to cyclopentane derivative 406 in 60% yield (Scheme 7.104) [242]. The addition of zinc malonates, such as 407 produces the carbometallation product 408 in 50% yield (Scheme 7.104) [243].


OMe

TMS

TMS

ZnBr

ZnBr

THF

315

Pd(PPh3)4 (cat.)

rt, 2 h

rt, 3.5 h OMe

TMS

389 : 84 % O

Et2Zn O

O

Et

O

Et

O

toluene 60ºC, 2.5h

O O OH

ZnEt 392 : 80%

391

390

B O O Me

Me

394

ZnBr

0ºC - 25ºC 36-48h

393

1) ZnBr2, CuCN·2LiCl 2) allyl bromide 3) H2O2/NaOH

O B O

ZnBr 395 : > 87%

OH

396 : 83%

Scheme 7.102 Allylzincation of unsaturated compounds.

H3C O

HO

H +

Me2Zn

Ni(cod)2 (10 - 20 mo l%)

N Ts

N Ts

397

398 : 70 %; d. r. = 97 : 3

n-C6H13 MgBr

+ EtO ZnBr 399

H

n-C6H13 1) THF, 35 ºC 2) Me3SnCl - 40 ºC to 0 ºC

400 : E : Z = 12 : 88

Scheme 7.103 Allylzincation reactions.

ZnBr

n-C6H13

O2 -15 ºC, 6 h

OEt SnMe3 401

CHO OEt

402 : 56 %; syn : anti = 12 : 88

316


NC

Cu(CN)ZnI +

n-Bu

SMe 403

2) H3O+

1) Me2Cu(CN)Li2 - 45 ºC, 3 h +

H

SMe

NC 404 : 60 %

ZnI

EtO2C

n-Bu

1) Me2Cu(CN)Li2 0 ºC, 3 h

EtO2C

I

H 2) I2

n-C5H11

n-C5H11 405 : 66 %

O ZnI O

2) Bu

Me

1) Me2Cu(CN)Li2 - 45 ºC, 3 h

ZnBr

EtO2C

CO2Et + Bu

CO2Et O Bu O

CO2Et Br

406 : 60 %

CH2(OMe)2 42 ºC, 4 h

Me EtO2C

407

Bu CO2Et

408 : 50 %

Scheme 7.104 Carbozincation and carbocupration of alkynes.

7.3.3 Palladium- and Nickel-catalyzed Reactions

Negishi and coworkers discovered 25 years ago that organozinc halides undergo smooth Pd(0)-catalyzed cross-coupling reactions with aryl, heteroaryl and alkenyl halides as well as acid chlorides [7, 244]. These cross-coupling reactions have a broad scope and have found many applications [7]. They have been performed with a range of polyfunctional organozinc halides [245]. These zinc organometallics may contain a silylated acetylene [246], an alkenylsilane [247], an allylic silane [248], an alkoxyacetylene [249], a polythiophene [250], polyfunctional aromatics [251], heterocyclic rings [252], an ester [21, 253], a nitrile [21, 58], a ketone [254], a protected ketone [252a], a protected aminoester [255], a stannane [256] or a boronic ester [53b]. The cross-coupling reaction with homoenolates proceeds especially well with bis-(tris-o-tolylphosphine)palladium dichloride [253a] leading to the desired cross-coupling products, such as 409. Biphenyls, such as 410, have been often prepared by using Pd(PPh3)4 as a catalyst [21]. Recently, Dai and Fu have demonstrated that Negishi cross-coupling reactions can be efficiently performed by using the sterically hindered phosphine (t-Bu)3P as a ligand that results in very active catalytic species (t-Bu3P)Pd [257]. In these cases, the cross-coupling can be


317

performed with aryl chlorides and tolerates the presence of some functionalities. Thus, the cross-coupling between cheap 2-chlorobenzonitrile and p-tolylzinc chloride proceeds with exceptionally high turnovers (TON>3000) leading to the biphenyl 411 in 97% yield (Scheme 7.105) [257]. O

O +

EtO2C

Zn 2

THF, rt CO2Et

PdCl2[P(o-Tol)3]2 cat

Br

409 : 49 %

CN

CO2Et +

40 ºC, 1 h

BrZn

I

Pd(PPh3)4 (4 mol %)

CN

EtO2C 410 : 82 %

CN CN + ClZn Cl

CH3

Pd(Pt-Bu3)2 (0.03 mol %) THF : NMP 100 ºC

CH3 411 : 97 %

Scheme 7.105 Palladium-catalyzed cross-coupling reactions.

New a-amino acids such as 412 have been prepared in high optical purity by using the reaction of pyridyl bromide 413 with Jackson reagent 15 [25e] Fmoc-protected amino acids are routinely used in automated solid-phase peptide synthesis. The Fmoc-protected zinc reagent 414 is readily prepared from the corresponding alkyl iodide 415. The Pd-catalyzed cross-coupling with various aryl iodides (Pd2dba3 (2.5 mol%), P(o-tol)3 (10 mol%)) in DMF at 50 C furnishes the corresponding arylated amino acid derivatives 416 in 25±59% yield [258]. Removal of the tert-butyl ester is readily achieved with Et3SiH and TFA leading to Fmoc protected amino acids [259]. The reaction of the zinc homoenolate 417 with ketene acetal triflates such as 418 in the presence of a palladium(0)-catalyst (Pd(PPh3)4, 5 mol%) leads to the corresponding cross-coupling product 419. This key sequence has been used for the iterative synthesis of polycyclic ethers [260]. A smooth cross-coupling is observed between (2E, 4E)-5-bromopenta-2,4-dienal 420 and various zinc reagents leading to dienic aldehydes of type 421 in good to excellent yields and high stereomeric purity. Using the isomeric (2E, 4Z)-5-bromopenta-2,4-dienal furnishes the corresponding diene with a partial isomerization of the double bonds (Scheme 7.107) [261]. Negishi cross-coupling reaction can be performed with complex alkenyl iodides such as 422 leading to the steroid derivative 423 in 88% yield. The palladium(0)-catalyst (Pd(PPh3)4) was generated in situ from Pd(OAc)2 (10 mol%) and PPh3 (40 mol%) (Scheme 7.107) [262].

318


+ N 413

PdCl2[P(o-Tol)3]4 cat

NHBoc

IZn

CO2Bn

Br

CO2Bn

C6H6, DMAC, 40ºC, 1h

N

15

N(H)Fmoc

I

412 : 59 %

N(H)Fmoc

ZnI

Zn dust

CO2tBu

NHBoc

ArI

CO2tBu

DMF, rt, 1h

415

Pd(0) cat.

414

CF3CO2H

N(H)Fmoc

Ar

CO2tBu

N(H)Fmoc

Ar

Et3SiH, CH2Cl2

CO2H

416 : 25 - 59 % Scheme 7.106 Synthesis of a-amino acids by Negishi cross-couplings.

BnO

H

CO2Me

IZn

BnO H

O

OTf

418

Pd(PPh3)4 (5 mol %) C6H6, 25ºC

CHO 420

H

BnO

Pd(PPh3)4 (5 mol %)

ZnI + Br

AcO

BnO

417

H

O

CO2Me

419: 78 %

AcO

CHO

THF, rt

421 : 92%

OSiEt3

OSiEt3 Me I Me Me ZnCl

Me

Pd(OAc)2 / PPh3 cat rt, 18h OMe 422

OMe 423 : 88 %

Scheme 7.107 Negishi cross-coupling of zinc organometallics with polyfunctional unsaturated derivatives.

Nickel salts are also excellent catalysts, however, the nature of the ligands attached to the nickel metal center is very important and often needs to be carefully chosen to achieve high reaction yields. Interestingly, nickel on charcoal


(Ni/C) proved to be an inexpensive heterogeneous catalyst for the cross-coupling of aryl chlorides with functionalized organozinc halides. Thus, the cross-coupling of 4-chlorobenzaldehyde with 3-cyanopropylzinc iodide produces in refluxing THF, the desired cross-coupling product 424 in 80% yield [263]. Tucker and de Vries developed an alternative homogeneous cross-coupling. Thus, the use of NiCl2(PPh3)2 (7.5 mol%) and PPh3 (15 mol%) was found to be an excellent crosscoupling catalyst for performing the cross-coupling between aryl chlorides such as 425 and functionalized arylzinc bromides like 426. A complete conversion was obtained at 55 C after a reaction time of 5 h affording the cross-coupling product 427 in 75% yield (Scheme 7.108) [264]. CHO

CHO 5 % Ni / C

+ NC(CH2)3ZnI

PPh3, THF, ∆

Cl

CN 424 : 80 %

CH3 CN +

NiCl2(PPh3)2 (7.5 mol%) PPh3 (15 mol %) 55 ºC, 5 h

ZnBr Cl 425

426

CN

H3C 427 : 75 %

Scheme 7.108 Nickel-catalyzed cross-coupling reactions.

The cross-coupling of alkynylzinc halides or fluorinated alkenylzinc halides with fluorinated alkenyl iodides allows the preparation of a range of fluorinated dienes or enynes [265]. Functionalized allylic boronic esters can be prepared by the cross-coupling of (dialkylboryl)methylzinc iodide 428 with functionalized alkenyl iodides. The intramolecular reaction provides cyclized products, such as 429 (Scheme 7.109) [53c±e]. In some cases, reduction reactions [266] or halogen±zinc exchange reactions [40] are observed. I IZn

O B O O

+ 70 ºC, 3 h CO2Et

428

OH Pd(dba)2, Ph3As CO2Et 429 : 70 %

Scheme 7.109 In situ generation of allylic boronic esters via cross-coupling reactions.

Functionalized heterocyclic zinc reagents are very useful building blocks for the preparation of polyfunctional heterocycles, as shown with the pyridylzinc derivative 430 prepared by reductive lithiation followed by a transmetallation with zinc

319

320


bromide [267]. The cross-coupling of the zinc reagent 430 with a quinolyl chloride provides the new heterocyclic compound 431. The selective functionalization of positions 4 and 3 of pyridines is possible starting from 3-bromopyridine 432 that is selectively deprotonated in position 4 by the reaction with LDA in THF at ±95 C followed by a transmetallation with ZnCl2. The resulting zinc species 433 under1 goes a Pd-catalyzed cross-coupling with various aryl halides (Ar -X) affording 2 products of type 434. The cross-coupling of 434 with a zinc reagent Ar -ZnX in the presence of a Pd(0)-catalyst provides 3,4-diarylpyridines of type 435. [268]. The functionalized iodoquinoline 436 reacts with i-PrMgCl at ±30 C providing an intermediate heteroarylmagnesium species that, after transmetallation to the corresponding zinc derivative 437, undergoes a smooth cross-coupling reaction with 1) Et

Li

OMOM

Et

OMOM

THF, -90 ºC to -78 ºC 2) ZnCl2, -78 ºC to rt MeO

N

Cl

MeO

N

ZnCl

430

CO2Me

CO2Me N

N

N

Cl

OMe

Pd(0), THF, 68 ºC MOMO Et 431 : 81 %

ZnCl Br

Br 1) LDA, -95ºC 2) ZnCl2

N 432

Ar1

Ar1-X Pd(0) cat

Br

Ar1

Ar2ZnCl Pd(0) cat.

Ar2

N

N

N

433

434

435

Me Me EtO2C N I 436

EtO2C

Me

1) i-PrMgCl, THF, -30 ºC EtO2C

EtO2C

OTf 2) ZnCl2

N ZnCl 437

OTf

I

N

Pd(dba)2 (3 mol %) tfp (6 mol %) rt, 1.5 h CO2Et 438 : 74 %

Scheme 7.110 Negishi cross-coupling with heterocyclic zinc reagents.

OTf


ethyl 4-iodobenzoate in the presence of Pd(dba)2 (3 mol%) and tfp (6 mol%) in THF at rt providing the desired cross-coupling product 438 in 74% yield (Scheme 7.110) [269]. The selective functionalization of heterocycles is an important synthetic goal. Purines display multiple biological activities such as antiviral or cytostatic properties. The synthesis of analogs such as 441 can be achieved by a regioselective cross-coupling of functionalized benzylic zinc reagents such as 440 with the dichloropurine derivative 439 in the presence of Pd(PPh3)4 (5 mol%). [270]. L-Azatyrosine 442 is an anticancer lead compound that can be readily prepared using Jackson's reagent 15 and a Negishi cross-coupling reaction with 2-iodo-5-methoxypyridine 443 affording the amino-ester 444 in 59% yield. Its deprotection according to a procedure of Ye and Burke [271] produces L-azatyrosine 442 [272]. Functionalized alkenylzinc species such as 445 can be prepared via an iodine±magnesium exchange followed by a transmetallation with ZnBr2. The Pd-catalyzed crosscoupling reaction with 4-iodobenzonitrile proceeds at 60 C in THF leading to the arylated product 446 in 57% yield [273]. 1,1-Dibromo-1-alkenes of type 447 undergo a highly trans-selective Pd-catalyzed cross-coupling with alkylzinc reagents using bis-(2-diphenylphosphinophenyl) ether (DPE-phos) as a ligand. The use of Pd(t-Bu3P)2 is crucial for achieving stereospecific methylation with nearly 100% retention of configuration (Scheme 7.111) [274]. Ferrocenyl groups are useful tools for stereoselective syntheses. Hayashi and coworkers have discovered a novel class of ferrocenyl catalysts allowing the kinetic resolution of benzylic zinc derivatives, such as 448. [275]. The racemic mixture of the benzylic zinc reagent 448 obtained by transmetallation from the corresponding Grignard reagent reacts with vinyl bromide in the presence of a Pd catalyst and the ferrocenyl aminophosphine 449 leading to the asymmetric cross-coupling product 450 with up to 85±86% ee. Complex ferrocenyl derivatives such as 453 being of interest as molecular materials with large second-order nonlinear optical properties (NLO) have been prepared by the cross-coupling of the ferrocenylzinc reagent 452 with 1,3,5-tribromobenzene. The starting zinc reagent has been prepared starting from the chiral ferrocenyl derivative 451. Selective metallation of 451 with tert-BuLi followed by a transmetallation with ZnCl2 furnishes the zinc reagent 452. Negishi cross-coupling was best performed using PdCl2(PPh3)2 (5 mol%) as catalyst (Scheme 7.112) [276]. Further applications of Negishi's cross-coupling reactions for the synthesis of new chiral ferrocenyl ligands have been reported [277]. Interestingly, cross-coupling reactions can also be performed using triorganozincates, such as 454 [278]. Chloroenyne 455 reacts with various magnesium zincates such as 454 generated in situ in the presence of PdCl2(dppf) (5 mol%) in THF at 66 C showing that alkenyl chlorides insert readily Pd(0)-complexes. Especially easy is the reaction of conjugated chloroenynes such as 455 leading to the enyne 456 (Scheme 7.113) [278]. A selective cross-coupling reaction of (Z)-2,3-dibromopropenoate 457 with organozinc compounds allows the preparation of highly functionalized enoates such as 458 (Scheme 7.113).

321


322

OMe ZnCl

Cl

Cl

Cl

NHBoc

MeO

MeO

CO2H

NHBoc

Pd2dba3, P(o-Tol)3 DMF, 55 ºC

443

N

CO2Me

IZn

I

N

441 : 76 %

439

N

N

N

Pd(PPh3)4 (5 mol %) 60 ºC, 8 h

N

N

440

MeO

N

N

N

CO2Me

444 : 59 %

442

O O

1) i-PrMgCl

O

O

Ph I

O

-30 ºC, 0.5 h 2) ZnBr2 -30 ºC to rt

I

O

O

Ph ZnBr

CN

Br

n-Hept Br

Pd(dba)2 (5 mol %) tfp (10 mol %) 60 ºC, 12 h

447

Ph

CN 446 : 57 %

ZnBr 1) Me3Si PdCl2(DPE-phos) (5 mol %) THF, 0 ºC, 1 h 2) Me2Zn, Pd(t-Bu3P)2

O

O

445

Me

NH2

N

HO

Me

SiMe3

n-Hept Me 85 %; > 98 % E

Scheme 7.111 Negishi cross-coupling reactions.

A flexible and convergent access to 2,3-disubstituted benzo [b]thiophenes, such as 459 has been developed. The most concise approach involves a sequential coupling of an o-bromoiodobenzene, such as 460 with benzylmercaptan and zinc acetylides leading to the adduct 461. Treatment with iodine followed by an iodine± magnesium exchange and acylation provides the polyfunctional benzofuran derivatives like 459 [279]. Zeng and Negishi have recently developed a novel highly selective route to carotenoids and related natural products via Zr-catalyzed carboalumination and Pd-catalyzed cross-coupling of unsaturated zinc reagents. Starting from b-ionone (462), the first cross-coupling sequence affords the unsaturated product (463) that by an iterative reaction sequence and dimerization affords b-carotene (464) with high stereoisomeric purity (Scheme 7.114) [280].


323

Pd(0) cat Me Ph

Me

ZnCl2

MgCl

Ph

Me

Br

ZnX

Ph

Me

448

450: 85 - 86 % ee

NMe2 PPh2 FeCp 449 Br

1) HO

1) tert-BuLi, Et2O

H O

HO

FeCp

OMe

FeCp 451

CpFe

CHO Br CHO PdCl2(PPh3)2 (5 mol %) FeCp rt, 2 h OHC 2) PTSA CpFe CH2Cl2, H2O 453

H

O ZnCl

OMe 2) ZnCl2, THF

Br

452

Scheme 7.112 Ferrocenyl groups in cross-coupling reactions.

Pent ZnCl2

OctMgBr (1.5 equiv.)

Br Br

0.5 equiv

+

R1ZnCl 1

CO2Me

R = alkyl, aryl

Cl

455 Oct3ZnMgBr 454

Pd(PPh3)4

PdCl2(dppf) (5 mol %) THF, 66 ºC, 3.5 h

R1

R2

Pent Oct 456 : 97 %

ZnCl

R1

R2

Br THF, rt

Pd(PPh3)4 CO2Me

457

CO2Me 458

Scheme 7.113 Synthesis of enynes using zinc organometallics.

Acylation of organozincs with acid chlorides is efficiently catalyzed by palladium(0)-complexes [244c,d, 21]. Many functional groups are tolerated in this reaction. The cross-coupling of 3-carbethoxypropylzinc iodide with methacryl chloride provides an expeditive approach to polyfunctional enones, such as 465 [281]. The acylation of serine or glutamic acid-derived zinc species as developed by Jackson [25±27] provides chiral c-keto-a-amino acids in good yields. The acylation of the Jackson reagent with phenyl chloroformate or the direct reaction of an organozinc reagent with carbon monoxide under sonication in the presence of catalytic amounts of (PPh3)2PdCl2 leads to the C2-symmetrical ketone 466 [25k]. In a related reaction, organozinc halides are treated with carbon monoxide and an allylic benzoate in the presence of a catalyctic amount of palladium(0) complex and provides S-ketoesters (Scheme 7.115) [282]. The reaction of syn- or anti-3-iodo-2methylbutanamide 467 with zinc powder furnishes the zinc reagent 468 that reacts with benzoyl chloride in the presence of Pd(0)-catalyst leading to the synproduct 469 (Scheme 7.115) [283].


324

Pd(dba)2 (3 mol %)

Br MeO

dppf, BnSH DMF, Et3N 70 ºC, 3 h

I 460

Br MeO

SBn

Ar

Ar

ZnCl

Pd(0) 100 ºC, 3 h

MeO

SBn 461 I2, CH2Cl2

O

I

Ar' 1) i -PrMgCl

Ar

Ar S

MeO

2) Ar'COCl

MeO

S

459: 98% 1) Me3Al (2 equiv) Cp2ZrCl2 (1 equiv) ClCH2CH2Cl, 23 ºC, 4 h

1) LDA, THF O 2) ClP(O)(OEt)2 3) LDA (2.2 equiv) 462

85 %

2) ZnCl2, Pd2dba3 (o-Furyl)3P, Me3Si

Br

463 : 70 %

3) K2CO3, MeOH, 23 ºC, 3 h

1) Me3Al-Cl2ZrCp2 463

2) ZnCl2, Pd(0) I

Br

, DMF

464: β-carotene : 68 %; > 99 % isomeric purity

23 ºC, 8 h

Scheme 7.114 Further applications of the Negishi cross-coupling reaction.

The reaction of thioesters such as 470 in the presence of nonpyrophoric Pd(OH)2/C (Pearlman's catalyst) with various functionalized organozinc halides leads to functionalized unsymmetrical ketones such as 471 in high yield (Fukuyama reaction) [284]. This catalyst can also be used for Sonogashira and Suzuki reactions [285]. The Ni(acac)2-catalyzed cross-coupling of the functionalized zinc reagent with various thioesters such as 472 provides under mild conditions the acylation product 473 in 74% yield. Interestingly, the addition of the organometallic zinc species to the thiolactone 474 furnishes after acidic treatment the vinylic sulfide 475 in 81% yield. The use of bromine for the activation of zinc dust for the preparation of the zinc reagent was found to be advantageous (Scheme 7.116) [286].


CH3

Pd(PPh3)4 cat

CH3

C6H6, DMAC

O

+ EtO2C(CH2)3ZnI

COCl

325

CO2Et 465 : 88 %

NHBoc

IZn

Pd(PPh3)4 cat

O +

PhO

CO2Bn

BocHN

C6H6, DMAC

Cl

NHBoc CO2Bn

O

BnO2C 466

O CO2Ph + EtO C(CH ) ZnI 2 2 3

Pd(PPh3)4 cat CO, PhMe DMAC, 40 ºC, 24 h CO2Et

O

Zn

I

O

ZnI

i-Pr2N

i-Pr2N

O

PhCOCl Pd(0)

Ph

i-Pr2N O

468

467

469 : 90 %, 99 % syn

Scheme 7.115 Palladium-catalyzed acylation reactions of organozincs. O ZnI

EtO2C

Pd(OH)2/C

+ MeO C 2

O

SEt THF, toluene DMF, rt

470

EtO

O

CO2Me

471 : 78 % O ZnI

EtO2C

+

O

Ni(acac)2 (10 mol %)

CO2Et

SEt THF, toluene 25 ºC, 20 h

MeO

MeO

472

473 : 74 %

O Bn N

N Bn

S

O

+

EtO2C

ZnI

1) Ni(acac)2 (10 mol %) DMF, 20 ºC, 15 h 2) TsOH·H2O, toluene 20 ºC, 18 h

474

Scheme 7.116 Acylation of thioesters with zinc organometallics.

O Bn N

N Bn

S CO2Et 475 : 81 %

326


7.3.4 Reactions Catalyzed by Titanium and Zirconium(IV) Complexes

As mentioned previously, Lewis acids accelerate the addition of zinc organometallics to carbonyl derivatives. Titanium and zirconium(IV) salts are especially efficient catalysts. Oguni and coworkers [287] have shown in pioneering work that various chiral amino-alcohols catalyze the addition of diethylzinc to aldehydes [288]. Yoshioka and coworkers have shown that the 1,2-bis-sulfonamide 476 is an excellent ligand for the asymmetric addition of Et2Zn to various aldehydes [289]. The catalysts of the TADDOL-family such as 477a and 477b are remarkable catalysts that tolerate many functional groups in the aldehyde as well as in the diorganozinc. These catalysts were discovered by Seebach and coworkers and they have found numerous applications in asymmetric catalysis [290]. The convenient preparation of diorganozincs starting from alkylmagnesium halides using ZnCl2 in ether as the transmetallating reagent followed by the addition of 1,4-dioxane constitutes a practical method for the enantioselective addition of dialkylzincs [290f ]. The enantioselective addition of polyfunctional diorganozincs is especially interesting. Thus, the reaction of the zinc reagent 478 with benzaldehyde in the presence of TADDOL 477a provides the functionalized benzylic alcohol 479 in 84% ee [290f ]. The more bulky ligand 477b allows the addition of diorganozincs such as 480 to acetylenic aldehydes leading to propargylic alcohols like 481 in 96% ee (Scheme 7.117) [290g]. H

Ar

O

NHSO2CF3

O

NHSO2CF3

H

476

Ar

Ar OH OH Ar

TADDOL: 477a, Ar = Ph 477b, Ar = 2-naphthyl

[MeOCH2O(CH2)6]2Zn

+

PhCHO

Et2O, Ti(Oi-Pr)4 -78 ºC to -30 ºC, 15 - 20 h

478

CHO

477a (10 mol %)

+

Zn 2

Ph 480

OH O

6

Ph

479 : 68 %, 84 % ee

477b (10 mol %) Et2O, Ti(Oi-Pr)4 -25 ºC, 20 h

O

OH Ph

2

481 : 78 %, 96 % ee Scheme 7.117 Enantioselective addition of functionalized diorganozincs to aldehydes catalyzed by TADDOL.


327

This approach has been extended to the conjugate addition of primary dialkylzincs to 2-aryl- and 2-heteroaryl-nitroolefins and allows the preparation of enantioenriched 2-arylamines [291]. Dendric styryl TADDOLS [292, 293] and polymerbound Ti-TADDOLates [294] have proved to be very practical chiral catalysts for the enantioselective addition to aldehydes. Likewise, the immobilization of BINOL by cross-linking copolymerization of styryl derivatives has allowed several enantioselective Ti and Al Lewis-acid-mediated additions to aldehydes [294]. Dialkylzincs obtained via an I/Zn-exchange or a B/Zn-exchange have also been successfully used for the enantioselective additions to a variety of aldehydes [295]. The use of trans-(1R,2R)-bis(trifluoromethanesulfamido)cyclohexane (476) is an excellent chiral ligand. The presence of an excess of titanium tetraisopropoxide (2 equiv) is, however, required [295]. The addition to unsaturated a-substituted aldehydes gives excellent enantioselectivities leading to polyfunctional allylic alcohols, such as 482 [93b]. Replacement of Ti(Oi-Pr)4 with the sterically hindered titanium alkoxide (Ti(Ot-Bu)4) leads to higher enantioselectivities [296].

CHO

Pr

+

Ti(Oi-Pr)4, PhMe -20ºC, 10 h

1. [PivO(CH2)3]2Zn, 476 cat 2. TBDPSCl 3. AcOH, H2O, THF CHO

Br 482 : 95 %, 94 % ee

OH PivO(CH2)3

4. NMO, Pr4NRuO4 5. [PivO(CH2)3]2Zn, 476 cat 6. Bu4NF, 55 ºC, 12 - 21 h

483

(CH2)5OAc

Pr

[AcO(CH2)5]2Zn

Br

TIPSO

OH

476 (8 mol %)

(CH2)3OPiv OH

484 : (20 %) over 6 steps dr : > 97 : 3 O

O TIPSO

H 485

OH

[AcO(CH2)5]2Zn 476 cat

OAc

TIPSO

1. TBDPSCl 2. TFA 3. PCC

71 %; 91 % ee

OSiPh2t-Bu

H AcO 486 : 70 %; 91 % ee

Scheme 7.118 Enantioselective addition of functionalized dialkylzincs to functionalized aldehydes.

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins [297]. The addition to functionalized aldehydes, such as 483 allows the synthesis of C2-symmetrical 1,4-diols, such as 484 with excellent diastereoselectivity and enantioselectivity [93b, 298]. An extension of this method allows the synthesis of C3-symmetrical diol [299]. Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protec-

328


tion-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 7.118) [300]. The addition to a-alkoxyaldehydes provides a general approach to monoprotected 1,2-diols that can be converted to epoxides, such as 487 in excellent enantioselectivity [301]. The configuration of the new chiral center does not depend on the configuration of the ligand 476. Thus, the reaction of the chiral aldehyde 488 with a functionalized zinc reagent ([PivO(CH2)3]2Zn) in the presence of the ligand 476 and ent-476 gives the two diastereomeric allylic alcohols (489 and 490) with high stereoselectivity (Scheme 7.119) [298a]. O O TIPSO

H

1) [PivO(CH2)5]2Zn 476 cat Ti(Oi-Pr)4, -20 ºC, 12 h 2) Bu4NF, THF 3) NaH, THF, DMF N-tosylimidazole

[PivO(CH2)3]2Zn Ti(Oi-Pr)4, ent-476 cat

PivO 487 : 38 % overall yield 93 % ee

PivO OH OTBDPS OPiv

PivO OHC 488

489 : 64 %; d. s. > 97 : 3 OTBDPS

[PivO(CH2)3]2Zn Ti(Oi-Pr)4, 476 cat

PivO OH OTBDPS OPiv 490 : 73 %; d. s. > 97 : 3

Scheme 7.119 Enantioselective additions of functionalized zinc reagents to chiral aldehydes.

Further applications to the preparation of chiral polyoxygenated molecules [302] and to the synthesis of the natural product (±)-mucocin [303] have been reported. The enantioselective addition of the functionalized diorganozinc reagent 491 to dodecanal in the presence of Ti(Oi-Pr)4 and the chiral ditriflamide 476 provides the desired chiral alcohol 492 with 99% of diastereomeric excess and 65% yield. The diorganozinc reagent was obtained by treating the alkyl iodide 493 with an excess of Et2Zn in the presence of CuCN (3 mol%). The chiral building block 492 was used in the total synthesis of cycloviracin B1 of interest for its selective antiviral activity [304]. An elegant synthesis of (R)-(±)-muscone has been reported by Oppolzer et al. [305]. The alkenylzinc reagent was prepared by hydroboration of the acetylenic aldehyde 494 with (c-Hex)2BH at 0 C, followed by a B/Zn-exchange with Et2Zn. The intramolecular addition in the presence of the chiral amino-alcohol 495 provides the allylic alcohol 496 with 72% yield and 92% ee [104c,305]. The enantioselective addition of dialkylzincs to aromatic ketones is especially difficult. Yus et al. have developed a new chiral ligand 497 allowing the addition of dialkyl-


329

zincs to various aromatic ketones in good yields. The enantioselective addition is promoted by Ti(OiPr)4 and tolerates the presence of several functional groups. Thus, the addition of Et2Zn to phenacyl bromide provides the chiral alcohol 498 in 95% yield and 92% ee (Scheme 7.120) [306]. NHTf NHTf

OBu I

Et2Zn (excess)

Zn

CuCN (3 mol%) 491

493

H

2

(CH2)12CHO

OH

476

OBu

C11H23CHO Ti(Oi-Pr)4

1) (C6H11)2BH, C6H14, 0 ºC 2) Et2Zn, (+)-DAIB (1 mol %), NEt3

OBu

C11H23 492 : 65 %; dr > 99 : 1

HO

3) NH4Cl

494

496 : 72 %; 92 % ee

OH NMe2 495 : (+)-DAIB Et2Zn, toluene -20 ºC to rt, 2 d

O Br

Ti(Oi-Pr)4 (1.2 equiv) H N SO2 H N SO2

Et OH Br Ph 498 : 95 %; 92 % ee

OH OH

497 : 10 mol % Scheme 7.120 Enantioselective additions mediated by titanium salts.

Alkynylzinc species generated in situ catalytically add to various aldehydes in very high enantioselectivities using reagent-grade toluene [307]. Chiral propargylic alcohols such as 499 are obtained in this way. As an application, the functionalized alkyne 500 has been added to (R)-isopropylidene glyceraldehyde 501 in the presence of Zn(OTf)2 and N-methylephedrine providing the propargylic alcohol 502 in 75% and a diastereomeric ratio of 94:6 [308]. The asymmetric addition of alkynylzinc reagents to aldehydes and ketones has recently been reviewed [309]. Especially important has been the stoichiometric addition of alkynylzinc derivatives leading to Efavirenz, a new drug for the treatment of AIDS [310]. The reaction of the chiral alkynylzinc reagent 503 obtained by the reaction of the aminoalcohol 504 successively with Me2Zn, neo-PentOH and the alkynyllithium 505 with

330


the activated trifluoromethyl ketone 506 provides the tertiary alcohol 507 in 91% yield and 97% ee. A catalytic version of this reaction has been described by Anand and Carreira (Scheme 7.121) [311]. NMe2 Ph O Hex

H

+ H

Ph

OH

Me OH

Hex Ph 499 : 94 %, 97 % ee

Et3N, Zn(OTf)2 toluene reagent-grade

Me Me + OTIPS

HO Ph

O

Zn(OTf)2

O H

500

O 501

N

1) Me2Zn 2) neo-PentOH

Me 504

Li 505

N-methylephedrine Et3N, toluene 25 ºC, 48 h

O

Ph

OTIPS

OH 502 : 75 %; d.r. = 94 : 6

THF/ toluene 25 ºC

Zn O

O

O

N Me 503

NH2 O CF3

NH2 OH CF3 O CF3 507

COCF3 506

Scheme 7.121 Enantioselective preparation of propargylic alcohols.

Interestingly, the chiral diamine 508 catalyzes the enantioselective addition of boronic acids to aromatic ketones like acetophenone. The reaction produces interesting tertiary diarylcarbinols such as 509 in up to 93% ee [312]. Bolm and coworkers have shown that this approach can also be used for a simple preparation of chiral diarylcarbinols such as 510 in the presence of the chiral ferrocenyl ligand 511 (Scheme 7.122). [313]. The addition of diorganozincs to imines is a difficult reaction. However, Hoveyda and coworkers have found that the in situ generation of imines in the presence of Zr(Oi-Pr)4´HOiPr, an excess of a dialkylzinc and a catalytic amount of the amino-acid derivative 512 allows an enantioselective addition leading to various amines such as 513 with high enantioselectivity. In the presence of the modular catalyst 514 and Zr(Oi-Pr)4´HOi-Pr (11 mol%), the imine 515 reacts with bis-alkynylzincs in the presence of (Me3SiCH2)2Zn that is a zinc reagent with nontransferable Me3SiCH2 groups. [314]. Under these conditions, an efficient addition reaction proceeds affording the propargylic amine 516 in 83% yield and 90% ee (Scheme 7.122) [315].


B(OH)2

HO Ph

1) Et2Zn / PPh3 / 70 ºC 12 h

O

Me

+ Ph

CH3

331

2)

Br 509 : 93 % ee

Br OH O2S NH HN SO2 HO 508

Ti(Oi-Pr)4, 25 ºC, 24 h OH

B(OH)2

p-ClC6H4CHO Et2Zn

+

O

Cl

N OH Ph Ph

Fe

510 : 95 %, 92 % ee

10 mol % 511 toluene, 10 ºC i-Pr MeO

N H OH

O

CONHBu Bu

Me Me

512 ; 10 mol %

O + H

H N

HN

Zr(Oi-Pr)4·i-PrOH (10 mol %)

H2N OMe

i-Pr

OMe 513 : 80 %, 97 % ee

Zn 2

toluene, 0 ºC to 22 ºC, 36 h i-Pr N H MeO

H N

O

O NHBu Bn

514 ; 10 mol % N Ph

Zr(Oi-Pr)4·HOi-Pr H

515

Me3Si

2

Zn (0.6 equiv)

(Me3SiCH2)2Zn (2 equiv)

HN Ph SiMe3 516 : 83 %; 90 % ee

Scheme 7.122 Enantioselective additions of diorganozincs to unreactive carbonyl derivatives.

332


7.3.5 Reactions of Zinc Organometallics Catalyzed by Cobalt, Iron or Manganese Complexes

The catalysis of reactive main-group organometallics, such as organolithiums or organomagnesiums by transition-metal salts is often complicated by the forma± tion of highly reactive transition-metal-centered ate-species (RnMet ) of transition metal complexes. These are especially prone to undergo b-hydrogen elimination reactions. Consequently, such transmetallations or catalysts have found little applications in organic synthesis [316]. Organozinc reagents, due to their lower reac± tivity, do not have a tendency to produce ate-species (RnMet ) of transition metal complexes, therefore the resulting transition-metal complexes of the type RMetXn have much higher thermal stability and a number of alkyl transition-metal complexes displaying synthetically useful properties can be accessed in this way. Thus, the reaction of cobalt(II) bromide with dialkylzincs in THF:NMP furnishes blue solutions of organocobalt intermediates that have a half-life of ca. 40 min. at ±10 C. Similarly the reaction of FeCl3 with dipentylzinc produces a gray solution of an organoiron intermediate with a half-life of 2.5 h at ±10 C [317]. Interestingly, these new organocobalt(II) species undergo carbonylations at room temperature under mild conditions affording symmetrical ketones, such as 517 in satisfactory yield [318]. The stoichiometric preparation of organocobalt species is not necessary and catalytic amounts of cobalt(II) salts are sufficient to promote the acylation of diorganozincs [317]. Also, allylic chlorides react with zinc organometallics in a stereoselective manner. Thus, geranyl chloride (518) provides the SN2-substitution product (E-519) with 90% yield and neryl chloride (520) affords the corresponding diene Z-519 in 90% yield; (Scheme 7.123) [317]. ZnI ZnI

CoBr2, CO, THF/NMP (3/2)

O

rt, 3 h

517 : 63 %

Cl

Pent2Zn CoBr2 (10 mol %) THF, -10 ºC, 1 h

518

E-519: 90 %, > 98 % E

Pent2Zn Cl 520

CoBr2 (10 mol %) THF, -10 ºC, 1 h Z-519 : 90 %, > 98 % E

Scheme 7.123 Cobalt-mediated reactions of diorganozincs.

References and Notes

The reaction of manganese(II) salts with organozinc reagents does not provide the corresponding organomanganese reagents [319]. However, functionalized bromides can be metallated by Et2Zn in the presence of catalytic amounts of MnBr2 [320] leading to cyclized product, such as 520 in 82% yield (see Scheme 7.124) [321]. Et2Zn, MnBr2 (cat.) CuCl (cat.), DMPU

O

OH

Br 60ºC, 0.5 h 520 : 82 % Scheme 7.124 Mn/Cu-mediated reaction of diorganozinc.

7.4 Conclusion

The synthesis of functionalized zinc organometallics can be accomplished with a variety of methods that have been developed in recent years. The intrinsic moderate reactivity of organozinc reagents can be dramatically increased by the use of the appropriate transition-metal catalyst or Lewis acid. Furthermore, the low ionic character of the carbon±zinc bond allows the preparation of a variety of chiral zinc organometallics with synthetically useful configurational stability. These properties make organozinc compounds ideal intermediates for the synthesis of complex and polyfunctionalized organic molecules.

References and Notes 1 E. Frankland, Liebigs Ann. Chem. 1849,

71, 171 and 213. 2 V. Grignard Compt. Rend. Acad. Sci. Paris, 1900, 130, 1322. 3 (a) S. Reformatsky, Chem. Ber. 1887, 20, 1210; 1895, 28, 2842; (b) A. Fürstner, Synthesis, 1989, 571; (c) A. Fürstner, Angew. Chem. Int. Ed. 1993, 32, 164. 4 (a) H. E. Simmons, R. D. Smith J. Am. Chem. Soc. 1958, 80, 5323; (b) H. E. Simmons, T. L. Cairns, A. Vladuchick, C. M. Hoiness, Org. React. 1972, 20, 1; (c) J. Furukawa, N. Kawabata, J. Nishimma, Tetrahedron Lett. 1966, 7, 3353; (d) M. Nakamura, A. Hirai, E. Nakamura, J. Am. Chem. Soc. 2003, 125, 2341; (e) E. Nakamura, K. Sekiya, I. Kuwajima, Tetrahedron Lett. 1987, 28, 337.

5 H. Hunsdiecker, H. Erlbach, E. Vogt,

German patent 722467, 1942; Chem. Abstr. 1943, 37, 5080. 6 (a) P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 2117; (b) P. Knochel, Synlett 1995, 393; (c) P. Knochel, S. Vettel, C. Eisenberg, Appl. Organomet. Chem. 1995, 9, 175; (d) P. Knochel, F. Langer, M. Rottländer, T. Stüdemann, Chem. Ber. 1997, 130, 387; (e) P. Knochel, J. Almena, P. Jones, Tetrahedron 1998, 54, 8275; (f) P. Knochel, P. Jones, Organozinc Reagents. A Practical Approach, Oxford University Press, 1999; (g) P. Knochel, N. Millot, A. L. Rodriguez, C. E. Tucker, Org. React. 2001, 58, 417; (h) A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem. Int. Ed. 2000, 39, 4415.

333

334

7 Polyfunctional Zinc Organometallics for Organic Synthesis 7 (a) E. Negishi, L. F. Valente,

M. Kobayashi, J. Am. Chem. Soc. 1980, 102, 3298; (b) E. Erdik, Tetrahedron 1992, 48, 9577 8 I. Antes, G. Frenking, Organometallics 1995, 14, 4263. 9 E. Hupe, P. Knochel, K. J. Szabó, Organometallics 2002, 21, 2203. 10 P. Knochel, M.C.P. Yeh, S.C. Berk, J. Talbert, J. Org. Chem. 1988, 53, 2390. 11 H. P. Knoess, M. T. Furlong, M. J. Rozema, P. Knochel, J. Org. Chem. 1991, 56, 5974. 12 S. C. Berk, M. C. P. Yeh, N. Jeong, P. Knochel, Organometallics 1990, 9, 3053. 13 P. Knochel, C. J. Rao, Tetrahedron, 1993, 49, 29. 14 (a) T. M. Stevenson, B. Prasad, J. R. Citineni, P. Knochel, Tetrahedron Lett. 1996, 37, 8375; (b) A. S. B. Prasad, T. M. Stevenson, J. R. Citineni, V. Nyzam, P. Knochel, Tetrahedron 1997, 53, 7237. 15 M. Gaudemar, Bull. Soc. Chim. Fr. 1962, 974. 16 E. Erdik, Tetrahedron, 1987, 43, 2203. 17 (a) J. K. Gawronsky, Tetrahedron Lett. 1984, 25, 2605; (b) G. Picotin, P. Miginiac, Tetrahedron Lett. 1987, 28, 4551. 18 (a) A. Fürstner, R. Singer, P. Knochel, Tetrahedron Lett. 1994, 35, 1047; (b) H. Stadtmüller, B. Greve, K. Lennick, A. Chair, P. Knochel, Synthesis 1995, 69. 19 (a) R. D. Rieke, Science 1989, 246, 1260; (b) R. D. Rieke, S.-H. Kim, X. Wu, J. Org. Chem. 1997, 62, 6921; (c) L. Zhu, R. D. Rieke, Tetrahedron Lett. 1991, 32, 2865; (d) R. D. Rieke, M. S. Sell, H. Xiong, J. Am. Chem. Soc. 1995, 117, 5429; (e) R. D. Rieke, P. M. Hudnall, S. T. Uhm, J. Chem. Soc., Chem. Commun. 1973, 269; (f) R. D. Rieke, P. T.-J. Li, T. P. Burns, S. T. Uhm, J. Org. Chem. 1981, 46, 4323; (g) R. D. Rieke, S. T. Uhm, Synthesis 1975, 452; (h) M. V. Hanson, J. D. Brown, R. D. Rieke, Tetrahedron Lett. 1994, 35, 7205; (i) M. V. Hanson, R. D. Rieke, Synth. Commun. 1995, 25, 101; (j) R. D. Rieke, M. V. Hanson, J. D. Brown, J. Org. Chem. 1996, 61,

2726 (k) A. Guijarro, R. D. Rieke, Angew. Chem. Int. Ed. Engl. 1998, 37, 1679. 20 (a) M. V. Hanson, R. D. Rieke, J. Am. Chem. Soc. 1995, 117, 10775; (b) L. Zhu, R. M. Wehmeyer, R. D. Rieke, J. Org. Chem. 1991, 56, 1445. 21 (a) B. H. Lipshutz, M. R. Wood, J. Am. Chem. Soc. 1994, 116, 11689. (b) B. H. Lipshutz, M. R. Wood, J. Am. Chem. Soc. 1993, 115, 12625. 22 M. V. Hanson, J. D. Brown, R. D. Rieke, O. J. Niu, Tetrahedron Lett. 1994, 35, 7205. 23 T. Ito, Y. Ishino, T. Mizuno, A. Ishikawa, J. Kobayashi, Synlett 2002, 2116. 24 (a) P. Knochel, J. F. Normant, Tetrahedron Lett. 1984, 25, 4383; (b) D. Peters, R. Miethchen, J. Prakt. Chem. 1995, 337, 615; (c) T. Kitazume, N. Ishikawa, J. Am. Chem. Soc. 1985, 107, 5186; (d) H. Tso, T. Chou, Y. Lai, J. Org. Chem. 1989, 54, 4138; (e) J. P. Sestelo, J. L. Mascarenas, L. Castedo, A. Mourino, J. Org. Chem. 1993, 58, 118; (f) L. A. Sarandeses, A. Mourino, J. L. Luche, J. Chem. Soc. Chem. Commun. 1992, 798. 25 (a) M. J. Dunn, R. F. W. Jackson, J. Pietruszka, N. Wishart, D. Ellis, M. J. Wythes, Synlett 1993, 499; (b) R. F. W. Jackson, N. Wishart, M. J. Wythes, Synlett 1993, 219; (c) M. J. Dunn, R. F. W. Jackson, J. Pietruszka, D. Turner, J. Org. Chem. 1995, 60, 2210; (d) C. Malan, C. Morin, Synlett 1996, 167; (e) R. F. W. Jackson, M. J. Wythes, A. Wood, Tetrahedron Lett. 1989, 30, 5941; (f) R. F. W. Jackson, A. Wood, M. J. Wythes, Synlett 1990, 735; (g) M. J. Dunn, R. F. W. Jackson, J. Chem. Soc., Chem. Commun. 1992, 319; (h) R. F. W. Jackson, N. Wishart, A. Wood; K. James, M. J. Wythes, J. Org. Chem. 1992, 57, 3397; (i) C. S. Dexter, R. F. W. Jackson, J. Chem. Soc., Chem. Commun. 1998, 75; (j) J. L. Fraser, R. F. W.Jackson, B. Porter, Synlett 1994, 379. (k) R. F. W. Jackson, W. Neil, M. J. Wythes, J. Chem. Soc., Chem. Commun. 1992, 1587. 26 R. F. W. Jackson, I. Rilatt, P. J. Murray, Chem. Commun. 2003, 1242. 27 R. F. W. Jackson, I. Rilatt, P. J. Murray, Org. Biomol. Chem. 2004, 2, 110.

References and Notes 28 C. Hunter, R. F. W. Jackson, H. K. Rami,

29 30 31 32

33

34

35

36

J. Chem. Soc., Perkin Trans. 1, 2001, 1349. C. Jubert, P. Knochel, J. Org. Chem. 1992, 57, 5425. C. Jubert, P. Knochel, J. Org. Chem. 1992, 57, 5431. S. Huo, Org. Lett. 2003, 5, 423. (a) B. H. Lipshutz, P. A. Blomgren, S. K. Kim, Tetrahedron Lett. 1999, 40, 197; (b) B. H. Lipshutz, P. A. Blomgren, J. Am. Chem. Soc. 1999, 121, 5819; (c) C. Dai, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 2719. (a) H. Blancou, A. Commeyras, J. Flourine Chem. 1982, 20, 255; (b) H. Blancou, A. Commeyras, J. Flourine Chem. 1982, 20, 267; (c) S. BeneficeMalouet, H. Blancou, A. Commeyras, J. Flourine Chem. 1985, 30, 171. (a) R. N. Haszeldine, E. G. Walaschewski, J. Chem. Soc. 1953, 3607; (b) W. T. Miller, E. Bergman, A. H. Fainberg, J. Am. Chem. Soc. 1957, 79, 4159; (c) R. D. Chambers, W. K. R. Musgrave, J. Savoy, J. Chem. Soc. 1962, 1993; (d) D. J. Burton, Tetrahedron 1992, 48, 189; (f) D. J. Burton, Z.-Y. Yang, P. A. Morken, Tetrahedron 1994, 50, 2993. (a) D. J. Burton, D. M. Wiemers, J. Am. Chem. Soc. 1985, 107, 5014; (b) D. M. Wiemers, D. J. Burton, J. Am. Chem. Soc. 1986, 108, 832; (c) B. Jiang, Y. Xu, J. Org. Chem. 1991, 56, 733; (d) P. A. Morken, H. Lu, A, Nakamura, D. J. Burton, Tetrahedron Lett. 1991, 32, 4271; (e) P. A. Morken, D. J. Burton, J. Org. Chem. 1993, 58, 1167. (a) S. Sibille, V. Ratovelomanana, J. PØrichon, S. Sibille, M. Troupel, Synthesis 1990, 369; (b) M. Durandetti, M. Devaud, J. PØrichon, New J. Chem, 1996, 20, 659; (c) S. Sibille, V. Ratovelomanana, J.-Y. NØdØlec, J. PØrichon, Synlett 1993, 425; (d) C. Gosmini, J.-Y. NØdØlec, J. PØrichon, Tetrahedron Lett. 1997, 38, 1941, (e) N. Zylber, J. Zylber, Y. Rollin, E. Dunach, J. PØrichon, J. Organomet. Chem. 1993, 444, 1; (f) Y. Rollin, S. Derien, E. Dunach, C. GØbØhenne, J. PØrichon, Tetrahedron 1993, 49, 7723.

37 (a) P. Gomes, C. Gosmini, J. PØrichon,

Synlett 2002, 10, 1673; (b) P. Gomes, H. Fillon, C. Gosmini, E. LabbØ, J. PØrichon, Tetrahedron 2002, 58, 8417; (c) H. Fillon, E. Le Gall, C. Gosmini, J. PØrichon, Tetrahedron Lett. 2002, 43, 5941; (d) C. Gosmini, Y. Rollin, J.-Y. NØdØlec, J. PØrichon, J. Org. Chem. 2000, 65, 6024. 38 S. Seka, O. Buriez, J.-Y. NØdØlec, J. PØrichon, Chem. Eur. J. 2002, 8, 2534. 39 (a) M. Mellah, E. LabbØ, J.-Y. NØdØlec, J. PØrichon, New. J. Chem. 2001, 25, 318; (b) C. Gosmini, J.-Y. NØdØlec, J. PØrichon, Tetrahedron Lett. 1999, 41, 201. 40 (a) H. Stadtmüller, R. Lentz, C. E. Tucker, T. Stüdemann, W. Dörner, P. Knochel, J. Am. Chem. Soc. 1993, 115, 7027; (b) H. Stadtmüller, A. Vaupel, C. E. Tucker, T. Stüdemann, P. Knochel, Chem. Eur. J. 1996, 2, 1204; (c) A. Vaupel, P. Knochel, J. Org. Chem. 1996, 61, 5743. 41 (a) H. Stadtmüller, C. E. Tucker, A. Vaupel, P. Knochel, Tetrahedron Lett. 1993, 34, 7911; (b) A. Vaupel, P. Knochel, Tetrahedron Lett. 1994, 35, 8349. 42 (a) A. Vaupel, P. Knochel, Tetrahedron Lett. 1995, 36, 231; (b) H. Stadtmüller, P. Knochel, Synlett 1995, 463. 43 K. A. Agrios, M. Srebnik, J. Org. Chem. 1993, 58, 6908. 44 (a) I. Klement, P. Knochel, K. Chau, G. Cahiez, Tetrahedron Lett. 1994, 35, 1177; (b) E. Riguet, I. Klement, C. K. Reddy, G. Cahiez, P. Knochel, Tetrahedron Lett. 1996, 37, 5865. 45 (a) H. Fillon, C. Gosmini, J. PØrichon, J. Am. Chem. Soc. 2003, 125, 3867; (b) P. Gomes, C. Gosmini, J. PØrichon, Synthesis, 2003, 1909; (c) I. Kazmierski, M. Bastienne, C. Gosmini, J.-M. Paris, J. PØrichon, J. Org. Chem. 2004, 69, 936; (d) I. Kazmierski, C. Gosmini, J. M. Paris, J. PØrichon, Tetrahedron Lett. 2003, 44, 6417; (e) S. Seka, O. Buriez, J. PØrichon, Chem. Eur. J. 2003, 9, 3597. 46 (a) T. N. Majid, P. Knochel, Tetrahedron Lett. 1990, 31, 4413; (b) A. S. B. Prasad, P. Knochel, Tetrahedron Lett. 1997, 53, 16711; (c) S. C. Berk, P. Knochel, M. C. P. Yeh, J. Org. Chem. 1988, 53,

335

336

7 Polyfunctional Zinc Organometallics for Organic Synthesis 5789 ; (d) J. L. van der Baan, H. Stichter, G. J. J. Out, F. Bickelhaupt, G. W. Klumpp, Tetrahedron Lett. 1988, 29, 3579; (e) J. van der Louw, J. L. van der Baan, H. Stichter, G. J. J. Out, F. J. J. de Kanter, F. Bickelhaupt, G. W. Klumpp, Tetrahedron 1992, 48, 9877; (f) J. van der Louw, J. L. van der Baan, G. J. J. Out, F. J. J. de Kanter, F. Bickelhaupt, G. W. Klumpp, Tetrahedron 1992, 48, 9901; (g) T. A. van der Heide, J. L. van der Baan, F. Bickelhaupt, G. W. Klumpp, Tetrahedron Lett. 1992, 33, 475; (h) G. A. Molander, D. C. Shubert, J. Am. Chem. Soc. 1986, 108, 4683. 47 (a) C. E. Tucker, S. A. Rao, P. Knochel, J. Org. Chem. 1990, 55, 5446; (b) P. Knochel, T. S. Chou, H. G. Chen, M. C. P. Yeh, M. J. Rozema, J. Org. Chem. 1989, 54, 5202; (c) T. S. Chou, P. Knochel, J. Org. Chem. 1990, 55, 4791; (d) P. Knochel, T. S. Chou, C. Jubert, D. Rajagopal, J. Org. Chem. 1993, 58, 588. 48 (a) M. C. P. Yeh, P. Knochel, W. M. Butler, S. C. Berk, Tetrahedron Lett. 1988, 29, 6693; (b) H. G. Chen, J. L. Gage, S. D. Barrett, P. Knochel, Tetrahedron Lett. 1990, 31, 1829; (c) M. C. P. Yeh, P. Knochel, L. E. Santa, Tetrahedron Lett. 1988, 29, 3887; (d) M. C. P. Yeh, P. Knochel, Tetrahedron Lett. 1989, 30, 4799; (e) C. Retherford, M. C. P. Yeh, I. Schipor, H. G. Chen, P. Knochel, J. Org. Chem. 1989, 54, 5200. 49 M. C. P. Yeh, C.-N. Chuang, J. Chem. Soc. Chem. Commun. 1994, 703. 50 H. G. Chen, C. Hoechstetter, P. Knochel, Tetrahedron Lett. 1989, 30, 4795. 51 M. C. P. Yeh, H. G. Chen, P. Knochel, Org. Synth. 1991, 70, 195. 52 S. AchyuthaRao, C. E. Tucker, P. Knochel, Tetrahedron Lett. 1990, 31, 7575; (b) S. AchyuthaRao, T.-S. Chou, I. Schipor, P. Knochel, Tetrahedron, 1992, 48, 2025. 53 (a) P. Knochel, J. Am. Chem. Soc. 1990, 112, 7431; (b) G. Kanai, N. Miyaura, A. Suzuki, Chem. Lett. 1993, 845. (c) T. Watanabe, N. Miyaura, A. Suzuki, J. Orgamomet. Chem. 1993, 444, C1;

(d) T. Watanabe, M, Sakai, N. Miyaura, A. Suzuki, J. Chem. Soc. Chem. Commun. 1994, 467. 54 (a) C. Janakiram Rao, P. Knochel, J. Org. Chem. 1991, 56, 4593; (b) P. Knochel, C. Janakiram Rao, Tetrahedron, 1993, 49, 29; (c) B. S. Bronk, S. J. Lippard, R. L. Danheiser, Organometallics, 1993, 12, 3340. 55 C. Retherford, T.-S. Chou, R. M. Schelkun, P. Knochel, Tetrahedron Lett. 1990, 31, 1833. 56 W. E. Parham, C. K. Bradsher, Acc. Chem. Res. 1982, 15, 300. 57 J. F. Cameron, J. M. J. Frechet, J. Am. Chem. Soc. 1991, 113, 4303; (b) P. Wiriyachitra, S. J. Falcone, M. P. Cava, J. Org. Chem. 1979, 44, 3957. 58 C. E. Tucker, T. N. Majid, P. Knochel, J. Am. Chem. Soc. 1992, 114, 3983. 59 E. M. E. Viseux, P. J. Parsons, J. B. J. Pavey, Synlett 2003, 861. 60 B. A. Anderson, N. K. Harn, Synthesis, 1996, 583. 61 S. Superchi, N. Sotomayor, G. Miao, B. Joseph, V. Snieckus, Tetrahedron Lett. 1996, 37, 6057. 62 (a) E. Lorthiois, I. Marek, J.-F. Normant, Tetrahedron Lett. 1997, 38, 89; (b) P. Karoyan, G. Chassaing, Tetrahedron Lett. 1997, 38, 85; (c) P. Karoyan, J. Quancard, J. Vaissermann, G. Chassaing, J. Org. Chem. 2003, 68, 2256; (d) P. Karoyan, G. Chassaing, Tetrahedron: Asymmetry 1997, 8, 2025; (e) P. Karoyan, A. Triolo, R. Nannicini, D. Giannotti, M. Altamura, G. Chassaing, G. E. Perrotta, Tetrahedron Lett. 1999, 40, 71; (f) P. Karoyan, G. Chassaing, Tetrahedron Lett. 2002, 43, 253; (g) J. Quancard, H. Magella, S. Lavielle, G. Chassaing, P. Karoyan, Tetrahedron Lett. 2004, 45, 2185. 63 (a) E. Nakamura, K. Kubota, J. Org. Chem. 1997, 62, 792; (b) K. Kubota, E. Nakamura, Angew. Chem. Int. Ed. Engl. 1997, 36, 2491; (c) M. Nakamura, T. Hatakeyama, K. Hara, E. Nakamura, J. Am. Chem. Soc. 2003, 125, 6362; (d) M. Nakamura, H. Isobe, E. Nakamura, Chem. Rev. 2003, 103, 1295; (e) M. Nakamura, N. Yoshikai, E. Nakamura, Chem. Lett. 2002, 146;

References and Notes (f) M. Nakamura, T. Inoue, A. Sato, E. Nakamura, Org. Lett. 2000, 2, 2193. 64 (a) J. P. Gillet, R. Sauvetre, J.-F. Normant, Synthesis 1986, 538; (b) J.-F. Normant, J. Organomet. Chem. 1990, 400, 19. 65 (a) T. Shigeoka, Y. Kuwahara, K. Watanabe, K. Satro, M. Omote, A. Ando, I. Kumadaki, J. Fluorine Chem. 2000, 103, 99; (b) T. Shigeoka, Y. Kuwahara, K. Watanabe, K. Satro, M. Omote, A. Ando, I. Kumadaki, Heterocycles, 2000, 52, 383. 66 J. M. Bainbridge, S. J. Brown, P. N. Ewing, R. R. Gibson, J. M. Percy, J. Chem. Soc. Perkin Trans 1, 1998, 2541. 67 R. Anilkumar, D. J. Burton, Tetrahedron Lett. 2002, 43, 6979. 68 J. Ichikawa, M. Fujiwara, H. Nawata, T. Okauchi, T. Minami, Tetrahedron Lett. 1996, 37, 8799. 69 (a) P. Wipf, W. Xu, J. Org. Chem. 1996, 61, 6556; (b) P. Wipf, W. Xu, Tetrahedron Lett. 1994, 35, 5197. 70 Y. Ni, K. K. D. Amarasinghe, J. Montgomery, Org. Lett. 2002, 4, 1743. 71 E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, B. I. Spiegel, J. Am. Chem. Soc. 1978, 100, 2254. 72 R. K. Dieter, R. T. Watson, R. Goswami, Org. Lett. 2004, 6, 253. 73 E. Frankland, D. Duppa, Liebigs Ann. Chem. 1864, 130, 117. 74 M. J. Rozema, D. Rajagopal, C. E. Tucker, P. Knochel, J. Organomet. Chem. 1992, 438, 11. 75 P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. Int. Ed. 2003, 42, 4302. 76 A. E. Jensen, P. Knochel, J. Organomet. Chem. 2002, 653, 122. 77 (a) D. Seyferth, H. Dertouzos, L. J. Todd, J. Organomet. Chem. 1965, 4, 18; (b) D. Seyferth, S. B. Andrews, J. Organomet. Chem. 1971, 30, 151. 78 (a) P. Knochel, N. Jeong, M. J. Rozema, M. C. P. Yeh, J. Am. Chem. Soc. 1989, 111, 6474; (b) P. Knochel, S. Achyutha Rao, J. Am. Chem. Soc. 1990, 112, 6146; (c) M. J. Rozema, P. Knochel, Tetrahedron Lett. 1991, 32, 1855; (d) M. R. Burns, J. K. Coward, J. Org. Chem. 1993, 58, 528; (e) A. Sidduri,

M. J. Rozema, P. Knochel, J. Org. Chem. 1993, 58, 2694; (f) A. Sidduri, P. Knochel, J. Am. Chem. Soc. 1992, 114, 7579. 79 P. Knochel, M. J. Rozema, C. E. Tucker, C. Relhwford, M. Furlong, S. Achyutha Rao, Pure. Appl. Chem. 1992, 64, 361. 80 E. Negishi, K. Akiyoshi, J. Am. Chem. Soc. 1988, 110, 646; (b) E. Negishi, K. Akiyoshi, B. O'Connor, K. Takagi, G. Wu, J. Am. Chem. Soc. 1989, 111, 3089. 81 T. Katsuhira, T. Harada, K. Maejima, A. Osada, A. Oku, J. Org. Chem. 1993, 58, 6166. 82 (a) T. Harada, K. Hattori, T. Katsuhira, A. Oku, Tetrahedron Lett, 1989, 30, 6035 and 6039; (b) T. Harada, T. Katsuhira, K. Hattori, A. Oku, J. Org. Chem. 1993, 58, 2958; (c) T. Harada, T. Katsuhira, A. Oku, J. Org. Chem. 1992, 57, 5805. 83 J. P. Varghese, I. Zouev, L. Aufauvre, P. Knochel, I. Marek, Eur. J. Org. Chem. 2002, 4151. 84 S. Achyutha Rao, P. Knochel, J. Org. Chem. 1991, 56, 4591; 85 R. Duddu, M. Eckhardt, M. Furlong, H. P. Knoess, S. Berger, P. Knochel, Tetrahedron, 1994, 50, 2415. 86 (a) M. Sakurai, T. Hata, Y. Yabe, Tetrahedron Lett. 1993, 34, 5939; (b) S. Sakami, T. Houkawa, A. Asaoka, H. Takei, J. Chem. Soc. Perkin Trans 1, 1995, 285; (c) T. Houkawa, T. Ueda, S. Sakami, M. Asaoka, H. Takei, Tetrahedron Lett. 1996, 37, 1045. 87 C. Darcel, F. Flachsmann, P. Knochel, Chem. Commun. 1998, 205. 88 F. Wang, J. Tang, L. Labaudinire, I. Marek, J.-F. Normant, Synlett 1995, 723. 89 J.-F. Poisson, J. F. Normant, J. Am. Chem. Soc. 2001, 123, 4639. 90 J.-F. Poisson, J. F. Normant, Org. Lett. 2001, 3, 1889. 91 I. Wilson, R. F. W. Jackson, J. Chem. Soc. Perkin Trans 1, 2002, 2845. 92 (a) J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron Lett. 1966, 7, 3353; (b) J. Furukawa, N. Kawabata, Adv. Organomet. Chem. 1974, 12, 83. 93 M. J. Rozema, A. Sidduri, P. Knochel, J. Org. Chem. 1992, 57, 1956;

337

338

7 Polyfunctional Zinc Organometallics for Organic Synthesis (b) M. J. Rozema, C. Eisenberg, H. Lütjens, R. Ostwald, K. Belyk, P. Knochel, Tetrahedron Lett. 1993, 34, 3115. 94 A. B. Charette, A. Beauchemin, J.-F. Marcoux, J. Am. Chem. Soc. 1998, 120, 5114. 95 E. Hupe, M. I. Calaza, P. Knochel, J. Organomet. Chem. 2003, 680, 136. 96 L. Micouin, P. Knochel, Synlett 1997, 327. 97 F. F. Kneisel, M. Dochnahl, P. Knochel, Angew. Chem. Int. Ed. 2004, 43, 1017. 98 (a) S. Berger, F. Langer, C. Lutz, P. Knochel, T. A. Mobley, C. K. Reddy, Angew. Chem. Int. Ed. 1997, 36, 1496; (b) P. Jones, C. K. Reddy, P. Knochel, Tetrahedron 1998, 54, 1471. 99 C. Petrier, J. De Souza Barbosa, C. Dupuy, J.-L. Luche, J. Org. Chem. 1985, 50, 5761. 100 E. J. Corey, J. O. Link, Y. Shao, Tetrahedron Lett. 1992, 33, 3435. 101 L. I. Zakharin, O. Y. Okhlobystin, Z. Obshch. Chim. 1960, 30, 2134; Engl. Trans, p. 2109, Chem. Abstr. 1961, 55, 9319a. 102 (a) K.-H. Thiele, P. Zdunneck, J. Organomet. Chem. 1965, 4, 10; (b) K.-H. Thiele, G. Engelhardt, J. Köhler, M. Arnstedt, J. Organomet. Chem. 1967, 9, 385. 103 (a) F. Langer, J. Waas, P. Knochel, Tetrahedron Lett. 1993, 34, 5261; (b) F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant, P. Knochel, J. Org. Chem. 1996, 61, 8229. 104 (a) M. Srebnik, Tetrahedron Lett. 1991, 32, 2449; (b) W. Oppolzer, R. N. Radinov, Helv. Chim. Acta 1992, 75, 170; (c) W. Oppolzer, R. N. Radinov, J. Am. Chem. Soc. 1993, 115, 1593. 105 R. Köster, G. Griasnow, W. Larbig, P. Binger, Liebigs Ann. Chem. 1964, 672, 1. 106 A. Devasagayaraj, L. Schwink, P. Knochel, J. Org. Chem. 1995, 60, 3311. 107 H. C. Brown, A. K. Mandal, N. M. Yoon, B. Singaram, J. R. Schwier, P. K. Jadhav, J. Org. Chem. 1982, 47, 5069. 108 (a) L. Micouin, M. Oestreich, P. Knochel, Angew. Chem. Int. Ed. Engl. 1997, 36, 245; (b) A. Boudier, F. Flachsmann,

P. Knochel, Synlett 1998, 1438; (c) E. Hupe, P. Knochel, Org. Lett. 2001, 3, 127. 109 E. Hupe, P. Knochel, Angew. Chem. Int. Ed. Engl. 2001, 40, 3022. 110 A. Boudier, E. Hupe, P. Knochel, Angew. Chem. Int. Ed. Engl. 2000, 39, 2294. 111 I. Fleming, N. J. Lawrence, J. Chem. Soc. Perkin Trans 1, 1992, 3309. 112 (a) E. Hupe, M. I. Calaza, P. Knochel, Tetrahedron Lett. 2001, 42, 8829; (b) E. Hupe, M. I. Calaza, P. Knochel, Chem. Eur. J. 2003, 9, 2789. 113 K. Burgess, M. J. Ohlmeyer, J. Org. Chem. 1991, 56, 1027. 114 (a) K. Burgess, M. J. Ohlmeyer, Chem. Rev. 1991, 91, 1179; (b) A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307. 115 (a) D. A. Evans, G. C. Fu, A. H. Hoveyda, J. Am. Chem. Soc. 1988, 110, 6917; (b) K. Burgess, M. J. Ohlmeyer, Tetrahedron Lett. 1989, 30, 395. 116 E. Hupe, M. I. Calaza, P. Knochel, Chem. Commun. 2002, 1390. 117 (a) S. Vettel, A. Vaupel, P. Knochel, Tetrahedron Lett. 1995, 36, 1023; (b) S. Vettel, A. Vaupel, P. Knochel, J. Org. Chem. 1996, 61, 7473. 118 (a) Y. Tamaru, A. Tanaka, K. Yasui, S. Goto, S. Tanaka, Angew. Chem. Int. Ed. Engl. 1995, 34, 787; (b) M. Shimizu, M. Kimura, S. Tanaka, Y. Tamaru, Tetrahedron Lett. 1998, 39, 609. 119 (a) Y. Tamaru, J. Organomet. Chem. 1999, 576, 215; (b) M. Kimura, I. Kiyama, T. Tomizawa, Y. Horino, S. Tanaka, Y. Tamaru, Tetrahedron Lett. 1999, 40, 6795; (c) M. Kimura, S. Matsuo, K. Shibata, Y. Tamaru, Angew. Chem. Int. Ed. Engl. 1999, 38, 3386; (d) M. Kimura, T. Tomizawa, Y. Horino, S. Tanaka, Y. Tamaru, Tetrahedron Lett. 2000, 41, 3627; (e) K. Shibata, M. Kimura, M. Shimizu, Y. Tamaru, Org. Lett. 2001, 3, 2181; (f) M. Kimura, Y. Horino, R. Mukai, S. Tanaka, Y. Tamaru, J. Am. Chem. Soc. 2001, 123, 10401. 120 (a) P. Jones, N. Millot, P. Knochel, Chem. Commun. 1998, 2405; (b) P. Jones, N. Millot, P. Knochel, J. Org. Chem. 1999, 64, 186; (c) P. Jones, P. Knochel Chem. Commun. 1998, 2407;

References and Notes (d) N. Millot, P. Knochel, Tetrahedron Lett. 1999, 40, 7779; (e) C. Piazza, N. Millot, P. Knochel, J. Organomet. Chem. 2001, 624, 88. 121 R. Benn, E. G. Hoffmann, H. Lehmkuhl, H. Nehl, J. Organomet. Chem. 1978, 146, 103. 122 W. Oppolzer, H. Bienayme, A. GenevoisBorella, J. Am. Chem. Soc. 1991, 113, 9660. 123 C. Meyer, I. Marek, J.-F. Normant, Tetrahedron Lett. 1996, 37, 857. 124 (a) W. Tückmankel, K. Oshima, H. Nozaki, Chem. Ber. 1986, 119, 1581; (b) R. M. Fabicon, M. Parvez, H. G. Richey, J. Am. Chem. Soc. 1991, 113, 1412 and 6680; (c) A. P. Purdy, C. F. George, Organometallics 1992, 11, 1955; (d) H. Toshiro, H. Wada, A. Oku, J. Org. Chem, 1995, 60, 5370. 125 (a) M. Isobe, S. Konda, N. Nagasawa, T. Goto, Chem. Lett. 1977, 679; (b) R. A. Kjonaas, R. K. Hoffer, J. Org. Chem, 1988, 53, 4133; (c) R. A. Kjonaas, E. J. Vawter, J. Org. Chem, 1986, 51, 3933. 126 (a) J. F. G. A. Jansen, B. L. Feringa, Tetrahedron Lett. 1988, 29, 3593; (b) J. F. G. A. Jansen, B. L. Feringa, J. Chem. Soc. Chem. Commun. 1989, 741; (c) J. F. G. A. Jansen, B. L. Feringa, J. Org. Chem, 1990, 55, 4168. 127 D. Seebach, W. Langen, Helv. Chim. Acta 1979, 62, 1701 and 1710. 128 (a) M. Uchiyama, M. Koike, M. Kameda, Y. Kondo, T. Sakamoto, J. Am. Chem. Soc. 1996, 118, 8733; (b) Y. Kondo, N. Takazawa, C. Yamazaki, T. Sakamoto J. Org. Chem, 1994, 59, 4717. 129 Y. Kondo, T. Komine, M. Fujinami, M. Uchiyama, T. Sakamoto, J. Comb. Chem. 1999, 1, 123; (b) G. Reginato, M. Taddei, Il Farmaco 2002, 57, 373. 130 T. Harada, T. Kaneko, T. Fujiwara, A. Oku, J. Org. Chem, 1997, 62, 8966. 131 I. N. Houpis, A. Molina, I. Dorziotis, R. A. Reamer, R. P. Volante, P. J. Reider, Tetrahedron Lett. 1997, 38, 7131. 132 (a) P. Knochel, in Comprehensive Organic Synthesis, Vol. 1 (eds: B. M. Trost, I. Fleming, S. L. Schreiber) Pergamon, Oxford 1991, p. 221; (b) L. Miginiac, in The Chemistry of the Metal-Carbon Bond (eds: F. R. Havey, S. Patai), Wiley, New

York, 1985, vol. 3, p. 99; (c) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1984, 25, 1475; (d) G. Rousseau, and J. Drouin, Tetrahedron 1983, 39, 2307; (e) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1984, 25, 4383. 133 Y. A. DembØlØ, C. Belaud, P. Hitchcock, J. VilliØras, Tetrahedron: Asymmetry, 1992, 3, 351. 134 P. Knochel, J.-F. Normant, J. Organomet. Chem. 1986, 309, 1. 135 H. Yamamoto, in Comprehensive Organic Synthesis, Vol. 2 (eds: B. M. Trost, I. Fleming, S. L. Schreiber), Pergamon, Oxford, 1991, 81. 136 (a) J. A. Marshall, Chem. Rev. 2000, 100, 3163; (b) J. A. Marshall, M. M. Yanik, J. Org. Chem. 2001, 66, 1373; (c) B. W. Gung, X. Xue, N. Katz, J. A. Marshall, Organometallics 2003, 22, 3158. 137 G. Zweifel, G. Hahn, J. Org. Chem, 1984, 49, 4565. 138 K. Nützel, In Methoden der Organischen Chemie, Metallorganische Verbindungen Be, Mg, Ca, Sr, Ba, Zn, Cd, vol. 13/2a, Thieme : Stuttgart, 1973, p. 552. 139 T. Harada, E. Kutsuwa, J. Org. Chem, 2003, 68, 6716; (b) T. Harada, A. Oku in Organozinc Reagents. A Practical Approach, P. Knochel, P. Jones, Eds. Oxford University Press; Oxford, NY, 1999, Chapter 6. 140 J. G. Giess, M. Le Blanc, Angew. Chem. 1978, 90, 654. 141 (a) I. Klement, P. Knochel, Synlett 1995, 1113; (b) I. Klement, H. Lütjens, P. Knochel, Tetrahedron 1997, 53, 9135. 142 I. Klement, K. Lennick, C. E. Tucker, P. Knochel, Tetrahedron Lett. 1993, 34, 4623. 143 (a) M. Gaudernar, C. R. Acad. Sci. Paris 1971, 273, 1669; (b) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1986, 27, 1039, 1043 and 4427; (c) I. Marek, J.-F. Normant, Chem. Rev. 1996, 96, 3241; (d) I. Marek, J.-F. Normant, J. Org. Chem. 1994, 59, 4154; (d) D. Beruben, I. Marek, J.-F. Normant, N. Platzer, J. Org. Chem. 1995, 60, 2488. 144 (a) F. Langer, P. Knochel, Tetrahedron Lett. 1995, 36, 4591; (b) F. Langer, K. Püntener, R. Stürmer, P. Knochel, Tetrahedron: Asymmetry, 1997, 8, 715.

339

340

7 Polyfunctional Zinc Organometallics for Organic Synthesis 145 A. Longeau, F. Langer, P. Knochel,

Tetrahedron Lett. 1996, 37, 2209. 146 (a) S. J. Greenfield, A. Agarkov, S. R. Gilbertson, Org. Lett. 2003, 5, 3069; (b) H. Stadtmueller, P. Knochel, Organometallics 1995, 14, 3163. 147 N. Millot, C. Piazza, S. Avolio, P. Knochel, Synthesis 2000, 941. 148 N. Gommermann, C. Koradin, P. Knochel, Synthesis 2002, 2143. 149 F. Lamaty, R. Lazaro, J. Martinez, Tetrahedron Lett, 1997, 38, 3385. 150 (a) D. L. Comins, S. O'Connor, Tetrahedron Lett. 1987, 28, 1843; (b) D. L. Comins, M. A. Foley, Tetrahedron Lett. 1988, 29, 6711. 151 E. Nakamura, S. Aoki, K. Sekiya, H. Oshino, I. Kuwajima, J. Am. Chem. Soc. 1987, 109, 8056. 152 M. Ludwig, K. Polborn, K. T. Wanner, Heterocycles 2003, 61, 299. 153 A. R. Katritzky, Z. Luo, Y. Fang, P. J. Steel, J. Org. Chem. 2001, 66, 2858. 154 (a) S. N. Thorn, T. Gallagher, Synlett 1996, 185; (b) S. D. Rychnovsky, N. A. Powell, J. Org. Chem. 1997, 62, 6460. 155 (a) S. Xue, K.-Z. Han, L. He, Q.-X. Guo, Synlett 2003, 870; (b) J. D. Rainier, J. M. Cox, Org. Lett. 2000, 2, 2707. 156 W. J. Thompson, T. J. Tucker, J. E. Schwering, J. L. Barnes, Tetrahedron Lett. 1990, 31, 6819. 157 A. E. Decamp, A. T. Kawaguchi, R. P. Volante, I. Shinkai, Tetrahedron Lett. 1991, 32, 1867. 158 U. Koert, H. Wagner, U. Pidun, Chem. Ber. 1994, 127, 1447. 159 J. J. Almena Perea, T. Ireland, P. Knochel, Tetrahedron Lett. 1997, 38, 5961. 160 (a) C. K. Reddy, A. Devasagayaraj, P. Knochel, Tetrahedron Lett. 1996, 37, 4495; (b) M. Kitamura, T. Miki, K. Nakano, R. Noyori, Tetrahedron Lett. 1996, 37, 5141. 161 B. S. Bronk, S. J. Lippard, R. L. Danheiser, Organometallics 1993, 12, 3340. 162 S. Kim, J. M. Lee, Tetrahedron Lett. 1990, 31, 7627. 163 M. Arisawa, Y. Torisawa, M. Kawahara, M. Yamanaka, A. Nishida, M. Nakagawa, J. Org. Chem. 1997, 62, 4327.

164 (a) G. Posner, Org. React. 1972, 19, 1;

(b) B. H. Lipshutz, Synthesis 1957, 325; (c) B. H. Lipshutz, S. Seugepta, Org. React. 1992, 41, 135; (c) G. Posner, Org. React. 1975, 22, 253. 165 T. Stemmler, J. E. Penner-Hahn, P. Knochel, J. Am. Chem. Soc. 1993, 115, 348. 166 S. Marquais, G. Cahiez, P. Knochel, Synlett 1994, 849. 167 H. T. Teunissen, F. Bickelhaupt, Tetrahedron Lett. 1992, 33, 3537. 168 (a) M. C. P. Yeh, P. Knochel, Tetrahedron Lett. 1988, 29, 2395; (b) H. Ochiai, Y. Tamaru, K. Tsubaki, Z. Yoshida, J. Org. Chem. 1987, 52, 4418; (c) M. Arai, T. Kawasuji, E. Nakamura, J. Org. Chem. 1993, 58, 5121; (d) E. Nakamura, K. Sekiya, M. Arai, S. Aoki, J. Am. Chem. Soc. 1989, 111, 3091; (e) K. Sekiya, E. Nakamura, Tetrahedron Lett. 1988, 29, 5155. 169 H. J. C. Deboves, U. Grabowska, A. Rizzo, R. F. W. Jackson, J. Chem. Soc. Perkin Trans 1, 2000, 4284. 170 A. Hirai, A. Matsui, K. Komatsu, K. Tanino, M. Miyashita, Chem. Commun. 2002, 1970. 171 B. H. Lipshutz, K. Woo, T. Gross, D. J. Buzard, R. Tirado, Synlett 1997, 477. 172 (a) P. Knochel, D. Seebach, Tetrahedron Lett. 1982, 23, 3897; (b) D. Seebach, P. Knochel, Helv. Chim. Acta 1984, 67, 261. 173 S. Ma, A. Zhang, J. Org. Chem. 2002, 67, 2287. 174 T. Konno, M. Tanikawa, T. Ishihara, H. Yamanaka, Collect. Czech. Chem. Commun. 2002, 67, 1421. 175 A. Yanagisawa, Y. Noritake, N. Nomura, H. Yamamoto, Synlett 1991, 251. 176 M. I. Calaza, E. Hupe, P. Knochel, Org. Lett. 2003, 5, 1059. 177 R. W. Hoffmann, Chem. Rev. 1989, 89, 1841. 178 N. Harrington-Frost, H. Leuser, M. I. Calaza, F. F. Kneisel, P. Knochel, Org. Lett. 2003, 5, 2111. 179 D. Soorukram, P. Knochel, Org. Lett. 2004, 6, 2409. 180 B. Breit, P. Demel, Adv. Synth. Catal. 2001, 343, 429; (b) B. Breit, P. Demel, Tetrahedron 2000, 56, 2833.

References and Notes 181 (a) A. S. E. Karlström, F. F. Huerta,

G. J. Meuzelaar, J. E. Bäckvall, Synlett 2001, 923; (b) G. J. Meuzelaar, A. S. E. Karlström, M. van Klaveren, E. S. M. Persson, A. del Villar, G. van Koten, J.-E. Bäckvall, Tetrahedron 2000, 56, 2895; (c) A. Alexakis, C. Malan, L. Lea, C. Benhaim, X. Fournioux, Synlett 2001, 927; (d) A. Alexakis, K. Croset, Org. Lett. 2002, 4, 4147; (e) H. Malda, A. W. van Zijl, L. A. Arnold, B. L. Feringa, Org. Lett. 2001, 3, 1169; (f) O. Equey, E. Vrancken, A. Alexakis, Eur. J. Org. Chem. 2004, 2151; (g) K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. Int. Ed. 2004, 43, 2426. 182 C. A. Luchaco-Cullis, H. Mizutani, K. E. Murphy, A. H. Hoveyda, Angew. Chem. Int. Ed. 2001, 40, 1456. 183 (a) F. Dübner, P. Knochel, Tetrahedron Lett. 2000, 41, 9233; (b) F. Dübner, P. Knochel, Angew. Chem. Int. Ed. 1999, 38, 379. 184 W. Blankenfeldt, J.-W. Liao, L.-C. Lo, M. C. P. Yeh, Tetrahedron Lett. 1996, 37, 7361. 185 (a) M. C. P. Yeh, M.-L. Sun, S.-K. Lin, Tetrahedron Lett. 1991, 32, 113; (b) M. C. P. Yeh, S. J. Tau, J. Chem. Soc. Chem. Commun. 1992, 13; (c) M. C. P. Yeh, C.-J. Tsou, C.-N. Chuang, H.-C. Lin, J. Chem. Soc. Chem. Commun. 1992, 890; (d) M. C. P. Yeh, B.-A. Shen, H.-W. Fu, S. I. Tau, L. W. Chuang, J. Am. Chem. Soc. 1993, 115, 5941. 186 M. C. P. Yeh, C.-C. Hwu, A.-T. Lee, M.-S. Tsai, Organometallics 2001, 20, 4965. 187 J. H. Rigby, M. Kirova-Snover, Tetrahedron Lett. 1997, 38, 8153. 188 H. Sörensen, A. E. Greene, Tetrahedron Lett. 1990, 31, 7597. 189 E. J. Corey, C. J. Helel, Tetrahedron Lett. 1997, 38, 7511. 190 A. Sidduri, N. Budries, R. M. Laine, P. Knochel, Tetrahedron Lett. 1992, 33, 7515. 191 B. H. Lipshutz, R. W. Vivian, Tetrahedron Lett. 1999, 40, 2871. 192 J.-J. Liu, F. Konzelmann, K.-C. Luk, Tetrahedron Lett. 2003, 44, 3901. 193 C. E. Tucker, P. Knochel, Synthesis 1993, 530.

194 C. Retherford, P. Knochel, Tetrahedron

Lett. 1991, 32, 441.

195 C. E. Tucker, P. Knochel, J. Org. Chem.

1993, 58, 4781.

196 (a) R. Giovannini, T. Stüdemann,

G. Dussin, P. Knochel, Angew. Chem. Int. Ed. 1998, 37, 2387; (b) A. Devasagayaraj, T. Stüdemann, P. Knochel, Angew. Chem. Int. Ed. 1995, 34, 2723. 197 R. Giovannini, P. Knochel, J. Am. Chem. Soc. 1998, 120, 11186. 198 A. E. Jensen, P. Knochel, J. Org. Chem. 2002, 67, 79. 199 M. Piber, A. E. Jensen, M. Rottländer, P. Knochel, Org. Lett. 1999, 1, 1323. 200 (a) H. Eick, P. Knochel, Angew. Chem. Int. Ed. 1996, 35, 218; (b) A. S. Bhanu Prasad, H. Eick, P. Knochel, J. Organomet. Chem. 1998, 562, 133; (c) Y. Tamaru, H. Ochiai, F. Sanda, Z. Yoshida, Tetrahedron Lett. 1985, 26, 5529. 201 (a) K. Soai, T. Suzuki, T. Shono, J. Chem. Soc. Chem. Commun. 1994, 317; (b) N. El Alami, C. Belaud, J. VilliØras, J. Organomet. Chem. 1987, 319, 303. 202 (a) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1984, 25, 4383; (b) G. Rousseau, J. M. Conia, Tetrahedron Lett. 1981, 22, 649; (c) G. Rousseau, J. Drouin, Tetrahedron 1983, 39, 2307. 203 (a) L. Miginiac in The Chemistry of Metal-Carbon Bond, F. R. Hartley, S. Patai; Eds., Wiley, New York, 1985, vol. 3, p. 99; (b) P. Knochel, in Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, S. L. Schreiber, Eds.; Pergamon, Oxford 1991, vol. 1, p. 211. 204 (a) J. VilliØras, M. Rambaud, Synthesis, 1982, 924; (b) J. VilliØras, M. VilliØras, Janssen Chimica Acta 1993, 11, 3. 205 (a) N. E. Alami, C. Belaud, J. VilliØras, Tetrahedron Lett. 1987, 28, 59; (b) N. El Alami, C. Belaud, J. VilliØras, J. Organomet. Chem. 1988, 348, 1. 206 Y. A. DembØlØ, C. Belaud, J. VilliØras, Tetrahedron : Asymmetry, 1992, 3, 511. 207 (a) J. van der Louw, J. L. van der Baan, F. Bickelhaupt, G. W. Klumpp, Tetrahedron Lett. 1987, 28, 2889; (b) J. van der Louw, J. L. van der Baan, H. Stieltjes, F. Bickelhaupt, G. W. Klumpp, Tetrahedron Lett. 1987,

341

342

7 Polyfunctional Zinc Organometallics for Organic Synthesis 28, 5929; (c) J. van der Louw, J. L. van der Baan, Tetrahedron 1992, 48, 9877. 208 (a) J. L. Moreau, in The Chemistry of Ketenes, Allenes and Related Compounds, S. Patai, Ed.; Wiley, New York, 1980, p. 363; (b) M. Suzuki, Y. Morita, R. Noyori, J. Org. Chem. 1990, 55, 441. 209 H. Ochiai, T. Nishihara, Y. Tamaru, Z. Yoshida, J. Org. Chem. 1988, 53, 1343. 210 J. Berninger, U. Koert, C. EisenbergHöhl, P. Knochel, Chem. Ber. 1995, 128, 1021. 211 P. Quinton, T. Le Gall, Tetrahedron Lett. 1991, 32, 4909. 212 (a) H. Lehmkuhl, I. Döring, R. McLane, H. Nehl, J. Organomet. Chem. 1981, 221, 1; (b) R. L. Soucy, D. Kozhinov, V. Behar, J. Org. Chem. 2002, 67, 1947. 213 M. R. Saidi, N. Azizi, Tetrahedron: Asymmetry 2002, 13, 2523. 214 K. P. Chiev, S. Roland, P. Mangeney, Tetrahedron: Asymmetry 2002, 13, 2205. 215 (a) M.-J. Shiao, K.-H. Liu, L.-G. Lin, Synlett 1992, 655; (b) W.-L. Chia, M.-J. Shiao, Tetrahedron Lett. 1991, 32, 2033; (c) T.-L.Shing, W. L. Chia, M.-J. Shiao, T.-Y.Chau, Synthesis 1991, 849; (d) M.-J. Shiao, W. L. Chia; T.-L. Shing; T. J. Chow, J. Chem. Res. (S) 1992, 247; (e) C. Agami, F. Couty, J.-C. Daran, B. Prince, C. Puchot, Tetrahedron Lett. 1990, 31, 2889; (f) C. Agami, F. Couty, M. Poursoulis, J. Vaissermann, Tetrahedron 1992, 48, 431; (g) C. AndrØs, A. Gonzµlez, R. Pedrosa, A. PØrezEncabo, S. García-Granda, M. A. Salvadó, F. Gómez-Beltrµn, Tetrahedron Lett. 1992, 33, 4743; (h) J.-L.Bettiol, R.-J. Sundberg, J. Org. Chem. 1993, 58, 814; (i) J. Yamada, H. Sato, Y. Yamamoto, Tetrahedron Lett. 1989, 30, 5611. 216 (a) C. Chuit, J. P. Foulon, J.-F. Normant, Tetrahedron 1981, 37, 1385 and Tetrahedron 1980, 36, 2305; (b) M. BourgainCommercon, J. P. Foulon, J. F. Normant, J. Organomet. Chem. 1982, 228, 321; (c) E. J. Corey, N. W. Boaz, Tetrahedron Lett. 1985, 26, 6015 and 6019; (d) A. Alexakis, J. Berlan, Y. Besace, Tetrahedron Lett. 1986, 27, 1047; (e) Y. Horiguchi, S. Matsuzawa, E. Nakamura, I. Kuwajima, Tetrahedron

Lett. 1986, 27, 4025; (f) E. Nakamura, S. Matsuzawa, Y. Horiguchi, I. Kuwajima, Tetrahedron Lett. 1986, 27, 4029; (g) Y. Horiguchi, S. Matsuzawa, E. Nakamura, I. Kuwajima, Tetrahedron Lett. 1986, 27, 4025; (h) M. Bergdahl, E.-L. Lindtstedt, M. Nilsson, T. Olsson, Tetrahedron 1988, 44, 2055; (i) M. Bergdahl, E.-L. Lindtstedt, M. Nilsson, T. Olsson, Tetrahedron 1989, 45, 535; (j) M. Bergdahl, E.-L. Lindtstedt, T. Olsson, J. Organomet. Chem. 1989, 365, C11; (k) M. Bergdahl, M. Nilsson, T. Olsson, J. Organomet. Chem. 1990, C19; (l) M. Bergdahl, M. Eriksson, M. Nilsson, T. Olsson, J. Org. Chem. 1993, 58, 7238. 217 Y. Tamaru, H. Tanigawa, T. Yamamoto, Z. Yoshida, Angew. Chem. Int. Ed. Engl. 1989, 28, 351. 218 (a) H. Tsujiyama, N. Ono, T. Yoshino, S. Okamoto, F. Sato, Tetrahedron Lett. 1990, 31, 4481; (b) T. Yoshino, S. Okamoto, F. Sato, J. Org. Chem. 1991, 56, 3205; (c) K. Miyaji, Y. Ohara, Y. Miyauchi, T. Tsuruda, K. Arai, Tetrahedron Lett. 1993, 34, 5597. 219 (a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. de Vries, Angew. Chem Int. Ed. 1997, 36, 2620; (b) E. Keller, J. Maurer, R. Naasz, T. Schader, A. Meetsma, B. L. Feringa, Tetrahedron Asymmetry 1998, 9, 2409; (c) R. Naasz, L. A. Arnold, M. Pineschi, E. Keller, B. L. Feringa, J. Am. Chem. Soc. 1999, 121, 1104; (d) R. Imbos, M. H. G. Britman, M. Pineschi, B. L. Feringa, Org. Lett. 1999, 1, 623; (e) L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. De Vries, R. Naasz, B. L. Feringa, Tetrahedron 2000, 56, 2865; (f) F. Bertozzi, P. Crotti, B. L. Feringa, F. Macchia, M. Pineschi, Synthesis 2001, 483. 220 (a) A. Alexakis, J. Burton, J. Vastra, P. Mangeney, Tetrahedron: Asymmetry 1997, 8, 3987; (b) A. Alexakis, G. P. Trevitt, G. Bernadelli, J. Am. Chem. Soc. 2001, 123, 4358; (c) A. Alexakis, C. Benhaim, S. Rosset, M. Humann, J. Am. Chem. Soc. 2002, 124, 5262; (d) O. Knopff, A. Alexakis, Org. Lett. 2002, 4, 3835; (e) A. Alexakis, C. Benhaim, Eur. J. Org. Chem. 2002,

References and Notes 3221; (f) A. Alexakis, S. March, J. Org. Chem. 2002, 67, 8753. 221 L. A. Arnold, R. Naasz, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc., 2001, 123, 5841. 222 R. Naasz, L. A. Arnold, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int. Ed. 2001, 40, 927; 223 A. W. Hird, A. H. Hoveyda, Angew. Chem. Int. Ed. 2003, 42, 1276. 224 F. Denes, F. Chemla, J. F. Normant, Eur. J. Org. Chem. 2002, 3536. 225 G Cahiez, P. Verregas, C. E. Tucker, T. N. Majid, P. Knochel, J. Chem. Soc. Chem. Commun. 1992, 1406. 226 D. H. Yang, J. X. Wang, Y. Hu, J. Chem. Research (S) 2002, 79. 227 (a) D. Seebach, E. W. Colvin, F. Lehr, T. Weller, Chimia 1979, 33, 1; (b) A. Yoshikoshi, M. Miyashita, Acc. Chem. Res. 1985, 18, 284; (c) A. G. M. Barrett, G. G. Graboski, Chem. Rev. 1986, 86, 751; (d) R. Tamura, A. Kamimura, N. Ono, Synthesis 1991, 423. 228 (a) S. B. Bowlus, Tetrahedron Lett. 1975, 3591; (b) A.-T. Hansson, M. Nilsson, Tetrahedron, 1982, 38, 389; (c) S. Stiver, P. Yates, J. Chem. Soc. Chem. Commun. 1983, 50. 229 C. Rutherford, P. Knochel, Tetrahedron Lett. 1991, 32, 441. 230 S. E. Denmark, L. R. Marcin, J. Org. Chem. 1993, 58, 3850. 231 J.-F. Normant, A. Alexakis, Synthesis 1981, 841. 232 (a) M. T. Crimmins, P. G. Nantermet, J. Org. Chem. 1990, 55, 4235 ; (b) M. T. Crimmins, P. G. Nantermet, B. W. Trotter, I. M. Vallin, P. S. Watson, L. A. McKerlie, T.-L. Reinhold, A. W.-H. Cheung, K. A. Steton, D. Dedopoulou, J. L. Gray, J. Org. Chem. 1993, 58, 1038; (c) M. T. Crimmins, D. K. Jung, J. L. Gray, J. Am. Chem. Soc. 1993, 115, 3146. 233 J. van der Louw, C. M. D. Komen, A. Knol, F. J. J. de Kanter, J. L. van der Baan, F. Bickelhaupt, G. W. Klumpp, Tetrahedron Lett. 1989, 30, 4453. 234 (a) E. Negishi, J. A. Miller, J. Am. Chem. Soc. 1983, 105, 6761; (b) G. A. Molander, J. Org. Chem. 1983, 48, 5409.

235 A. Yanagisawa, S. Habane,

H. Yamamoto, J. Am. Chem. Soc. 1989, 111, 366. 236 K. Kubota, M. Nakamura, M. Isaka, E. Nakamura, J. Am. Chem. Soc. 1993, 115, 5867. 237 (a) M. Nakamura, N. Yoshikai, E. Nakamura, Chem. Lett. 2002, 146; (b) K. Kubota, E. Nakamura, Angew. Chem. 1997, 109, 2581. 238 M. Nakamura, K. Hara, T. Hatakeyama, E. Nakamura, Org. Lett. 2001, 3, 3137. 239 (a) J. Montgomery, M. Song, Org. Lett. 2002, 4, 4009; (b) S.-K. Kang, S.-K. Yoon, Chem. Commun. 2002, 2634. 240 (a) M. Gaudemar, C.R. Hebd. Sceances Acad. Sci., Ser. C 1971, 273, 1669; (b) Y. Frangin, M. Gaudemar C.R. Hebd. Sceances Acad. Sci., Ser C 1974, 278, 885; (c) M. Bellasoued, Y. Frangin, M. Gaudemar, Synthesis 1977, 205; (d) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1986, 27, 1039; (e) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1986, 27, 1043; (f) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1986, 27, 4427; (g) P. Knochel, J.-F. Normant, Tetrahedron Lett. 1986, 27, 5727; (h) D. Beruben, I. Marek, L. Labaudinire, J.-F. Normant, Tetrahedron Lett. 1993, 34, 2303; (i) J.-F. Normant, J.-C. Quirion, Tetrahedron Lett. 1989, 30, 3959; (j) I. Marek, J.-M. Lefrançois, J.-F. Normant, Synlett 1992, 633; (k) I. Marek, J.-M. Lefrançois, J.-F. Normant, Tetrahedron Lett. 1992, 33, 1747; (l) I. Marek, J.-M. Lefrançois, J.-F. Normant, Tetrahedron Lett. 1991, 32, 5969; (m) I. Marek, J.-F. Normant, Tetrahedron Lett. 1991, 32, 5973. 241 P. Knochel, C. Xiao, M. C. P. Yeh, Tetrahedron Lett. 1988, 29, 6697. 242 S. A. Rao, P. Knochel, J. Am. Chem. Soc. 1991, 113, 5735. 243 M. T. Bertrand, G. Courtois, L. Miginiac Tetrahedron Lett. 1974, 1945. 244 (a) M. Kobayashi, E. Negishi, J. Org. Chem. 1980, 45, 5223; (b) E. Negisihi, Acc. Chem. Res., 1982, 15, 340; (c) E. Negisihi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller, A. T. Stoll, Tetrahedron Lett. 1983, 24, 5181; (d) R. A. Grey, J. Org. Chem. 1984, 49, 2288.

343

344

7 Polyfunctional Zinc Organometallics for Organic Synthesis 245 (a) E. Negishi, A. O. King, N. Okukado,

J. Org. Chem. 1977, 42, 1821; (b) R. Rossi, F. Bellina, A. Carpita, R. Gori, Synlett 1995, 344; (c) E. Negishi, H. Matsushita, M. Kobayashi, C. L. Rand, Tetrahedron Lett. 1983, 24, 3823; (d) J. G. Millar, Tetrahedron Lett. 1989, 30, 4913; (e) S. Hyuga, N. Yamashina, S. Hara, A. Suzuki, Chem. Lett. 1988, 809; (f) A. Löffler, G. Himbert, Synthesis 1992, 495; (g) R. C. Borner, R. F. W. Jackson, J. Chem. Soc. Chem. Commun. 1994, 845; (h) T. Sakamoto, Y. Kondo, N. Takazawa, H. Yamanaka, Tetrahedron Lett. 1993, 34, 5955; (i) A. Minato, K. Suzuki, K. Tamao, M. Kumada, Tetrahedron Lett. 1984, 25, 2583; (j) C. A. Quesnelle, O. B. Familoni, V. Snieckus, Synlett 1994, 349; (k) T. Sakamoto, S. Nishimura, Y. Kondo, H. Yamanaka, Synthesis 1988, 485; (l) T. Sato, A. Kawase, T. Hirose, Synlett 1992, 891. 246 E. Negishi, H. Matsushita, M. Kobayashi, C. L. Raud, Tetrahedron Lett. 1983, 24, 3823; 247 S. Hyuga, N. Yamayshina, S. Hara, A. Suzuki, Chem. Lett. 1988, 809. 248 A. Minota, K. Suzuki, K. Tamao, M. Kumada, Tetrahedron Lett. 1984, 25, 2583. 249 A. Löffler, G. Himbert, Synthesis 1992, 495. 250 G. Mignani, F. Leising, R. Meyrueix, H. Samson, Tetrahedron Lett. 1990, 31, 4743. 251 C. A. Quesnelle, O. B. Familoni, V. Snieckus, Synlett 1990, 349. 252 (a) T. Sakamoto, Y. Kondo, N. Murata, H. Yamanaka, Tetrahedron Lett. 1992, 33, 5373; (b) T. Sakamoto, Y. Kondo, N. Takazawa, H. Yamanaka, Heterocycles 1993, 36, 941; (c) D. Trauner, J. B. Schwartz, S. J. Danishefsky, Angew. Chem. Int. Ed. Engl. 1999, 38, 3543; (d) A. S. Bell, D. A. Roberts, K. S. Ruddock, Synthesis 1987, 843. 253 (a) E. Nakamura, I. Kuwajima, Tetrahedron Lett. 1986, 27, 83; (b) T. Sakamoto, S. Nishimura, Y. Kondo, H. Yamanaka, Synthesis 1988, 485. 254 Y. Tamaru, H. Ochiai, T. Nakamura, Z. Yoshida, Angew. Chem. Int. Ed. 1987, 99, 1193.

255 R. F. W. Jackson, M. J. Wylhes, A. Wood,

J. Chem. Soc., Chem. Commun. 1989, 644. 256 T. Sato, A. Kawase, T. Hirose, Synlett 1992, 891. 257 C. Dai, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 2719. 258 H. J. C. Deboves, C. A. G. N. Montalbetti, R. F. W. Jackson, J. Chem. Soc. Perkin Trans. 1, 2001, 1876. 259 A. Mehta, R. Jaouhari, T. J. Benson, K. T. Douglas, Tetrahedron Lett. 1992, 33, 5441. 260 (a) I. Kadota, H. Takamura, K. Sato, Y. Yamamoto, J. Org. Chem. 2002, 67, 3494; (b) Y. Tamaru, H. Ochial, T. Nakamura, Z. Yoshida, Tetrahedron Lett. 1986, 27, 955; (c) Y. Tamaru, H. Ochial, T. Nakamura, K. Tsubaki, Z. Yoshida, Tetrahedron Lett. 1985, 26, 5559. 261 N. Vicart, G.-S. Saboukoulou, Y. Ramondenc, G. PlØ, Synth. Commun. 2003, 33, 1509. 262 A. Przezdziecka, A. Kurek-Tyrlik, J. Wicha, Collect. Czech. Chem. Commun. 2002, 67, 1658. 263 B. H. Lipshutz, P. A. Blomgren, J. Am. Chem. Soc. 1999, 121, 5819. 264 (a) J. A. Miller, R. P. Farrell, Tetrahedron Lett. 1998, 39, 6441. (b) C. E. Tucker, J. G. de Vries, Top. Catal. 2002, 19, 111. 265 (a) J. P. Gillet, R. Sauvtre, J.-F. Normant, Synthesis 1986, 538; (b) J.-P. Gillet, R. Sauvtre, J.-F. Normant, Tetrahedron Lett. 1985, 26, 3999; (c) F. Tellier, R. Sauvtre, J.-F. Normant, J. Organomet. Chem. 1986, 303, 309; (d) F. Tellier, R. Sauvtre, J.-F. Normant, Y. Dromzee, Y. Jeannin, J. Organomet. Chem. 1987, 331, 281; (e) P. Martinet, R. Sauvtre, J.-F. Normant, J. Organomet. Chem. 1989, 367, 1. 266 (a) K. Yuan, W. J. Scott, Tetrahedron Lett. 1989, 30, 4779; (b) K. Yuan, W. J. Scott, J. Org. Chem. 1990, 55, 6188; (c) K. Park, K. Yuan, W. J. Scott, J. Org. Chem. 1993, 58, 4866. 267 N. Murata, T. Sugihara, Y. Kondo, T. Sakamoto, Synlett 1997, 298. 268 (a) G. Karig, J. A. Spencer, T. Gallagher, Org. Lett. 2001, 3, 835; (b) C. G. V. Sharples, G. Karig,

References and Notes G. L. Simpson, J. A. Spencer, E. Wright, N. S. Millar, S. Wonnacott, T. Gallagher, J. Med. Chem. 2002, 45, 3235. 269 A. Staubitz, W. Dohle, P. Knochel, Synthesis 2003, 233. 270 M. Hocek, I. Votruba, H. Dvoraka, Tetrahedron 2003, 59, 607. 271 B. Ye, T. R. Burke Jr., J. Org. Chem. 1995, 60, 2640. 272 A. W. Seton, M. F. G. Stevens, A. D. Westwell, J. Chem. Res. (S), 2001, 546. 273 J. Thibonnet, V. A. Vu, L. Berillon, P. Knochel, Tetrahedron 2002, 58, 4787. 274 J.-C. Shi, X. Zeng, E.- I. Negishi, Org. Lett. 2003, 5, 1825. 275 (a) T. Hayashi, T. Hagihara, Y. Katsuro, M. Kumada, Bull. Chem. Soc. Jpn. 1983, 56, 363; (b) T. Hayashi, J. Organomet. Chem. 2002, 653, 41. 276 V. Mamane, T. Ledoux-Rak, S. Deveau, J. Zyss, O. Riant, Synthesis 2003, 455. 277 (a) M. Lotz, G. Kramer, P. Knochel, Chem. Commun. 2002, 2546; (b) R. J. Kloetzing, M. Lotz, P. Knochel, Tetrahedron: Asymmetry, 2003, 14, 255; (c) T. Bunlaksananusorn, K. Polborn, P. Knochel, Angew. Chem. Int. Ed. 2003, 42, 3941; (d) T. Bunlaksananusorn, A. P. Luna, M. Boniu, L. Micouin, P. Knochel, Synlett 2003, 2240. 278 (a) J.-F. Peyrat, E. Thomas, N. L'Hermite, M. Alami, J.-D. Brion, Tetrahedron Lett. 2003, 44, 6703; (b) M. Alami, S. Gueugnot, E. Doingues, G. Linstrumelle, Tetrahedron 1995, 51, 1209. 279 B. L. Flynn, P. Verdier-Pinard, E. Hamel, Org. Lett. 2001, 3, 651. 280 F. Zeng, E. Negishi, Org. Lett. 2001, 3, 719. 281 Y. Tamaru, H. Ochiai, T. Nakamura, Z. Yoshida, Org. Synth. 1989, 67, 98. 282 Y. Tamaru, K. Yasui, H. Takanabe, S. Tanaka, K. Fugami, Angew. Chem. Int. Ed. 1992, 31, 645. 283 M. Asaoka, M. Tamaka, T. Houkawa, T. Ueda, S. Sakami, H. Takei, Tetrahedron 1998, 54, 471. 284 H. Tokuyama, S. Yokoshima, T. Yamashita, T. Fukuyama, Tetrahedron Lett. 1998, 39, 3189. 285 Y. Mori, M. Seki, J. Org. Chem. 2003, 68, 1571.

286 (a) T. Shimizu, M. Seki, Tetrahedron Lett.

2002, 43, 1039; (b) T. Shimizu, M. Seki, Tetrahedron Lett. 2001, 42, 429; (c) see also M. Kimura, M. Seki, Tetrahedron Lett. 2004, 45, 1635. 287 (a) N. Oguni, T. Omi, Y. Yamamoto, A. Nakamura, Chem. Lett. 1983, 841; (b) N. Oguni, T. Omi, Tetrahedron Lett. 1984, 25, 2823; (c) N. Oguni, Y. Matsuda, T. Kaneko, J. Am. Chem. Soc. 1988, 110, 7877. 288 (a) K. Soai, S. Niwa, Chem. Rev. 1992, 92, 833; (b) D. A. Evans, Science 1988, 240, 420; (c) R. Noyori, M. Kitamura, Angew. Chem. Int. Ed. Engl. 1991, 30, 49. 289 (a) M. Yoshioka, T. Kawakita, M. Ohno, Tetrahedron Lett. 1989, 30, 1657; (b) H. Takahashi, T. Kawakita, M. Yoshioka, S. Kobayashi, M. Ohno, Tetrahedron Lett. 1989, 30, 7095; (c) H. Takahashi, T. Kawakita, M. Ohno, M. Yoshioka, S. Kobayashi, Tetrahedron 1992, 48, 5691. 290 (a) A. K. Beck, B. Bastani, D. A. Plattner, W. Petter, D. Seebach, H. Braunschweiger, P. Gysi, L. VaVecchia, Chimia 1991, 45, 238; (b) B. Schmidt, D. Seebach, Angew. Chem. Int. Ed. Engl. 1991, 30, 99; (c) D. Seebach, L. Behrendt, D. Felix, Angew. Chem. Int. Ed. Engl. 1991, 30, 1008; (d) B. Schmidt, D. Seebach, Angew. Chem. Int. Ed. Engl. 1991, 30, 1321; (e) J. L. von dem BusscheHünnefeld, D. Seebach, Tetrahedron 1992, 48, 5719; (f) D. Seebach, D. A. Plattner, A. K. Beck, Y. M. Wang, D. Hunziker, W. Petter, Helv. Chim. Acta 1992, 75, 2171; (g) D. Seebach, A. K. Beck, B. Schmidt, Y. M. Wang, Tetrahedron 1994, 50, 4363. 291 H. Schafer, D. Seebach, Tetrahedron 1995, 51, 2305. 292 D. Seebach, A. K. Beck, A. Hechel, Angew. Chem. Int. Ed. 2001, 40, 92. 293 B. P. Rheiner, H. Sellner, D. Seebach, Helv. Chim. Acta 1997, 80, 2027. 294 H. Sellner, C. Faber, P. B. Rheiner, D. Seebach, Chem. Eur. J. 2000, 6, 3692. 295 (a) L. Schwink, P. Knochel, Chem. Eur. J. 1998, 4, 950; (b) W. Brieden, R. Ostwald, P. Knochel, Angew. Chem., Int. Ed. Engl. 1993, 32, 582.

345

346

7 Polyfunctional Zinc Organometallics for Organic Synthesis 296 S. Nowotny, S. Vettel, P. Knochel, Tetra-

312 O. Prieto, D. J. Ramon, M. Yus, Tetra-

297

313 (a) J. Rudolph, T. Rasmussen, C. Bolm,

298

299 300

301 302 303 304

305

306 307 308 309 310

311

hedron Lett. 1994, 35, 4539. (a) R. Noyori, M. Suzuki, Angew. Chem. Int. Ed. Engl. 1984, 23, 847; (b) M. Suzuki, A. Yanagisawa, R. Noyori, J. Am. Chem. Soc. 1990, 307, 3348; (c) Y. Morita, M. Suzuki, R. Noyori, J. Org. Chem. 1989, 54, 1785; (d) R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kitamura, Pure Appl. Chem. 1988, 60, 1597. (a) S. Vettel, P. Knochel, Tetrahedron Lett. 1994, 35, 5849; (b) R. Ostwald, P.-Y. Chavant, H. Stadtmüller, P. Knochel, J. Org. Chem. 1994, 59, 4143; (c) W. R. Roush, K. Koyama, Tetrahedron Lett. 1992, 33, 6227. H. Lütjens, P. Knochel, Tetrahedron: Asymmetry 1994, 5, 1161. P. Knochel, W. Brieden, M. J. Rozema, C. Eisenberg, Tetrahedron Lett. 1993, 34, 5881. C. Eisenberg, P. Knochel, J. Org. Chem. 1994, 59, 3760. A. Fürstner, T. Müller, J. Org. Chem. 1998, 63, 424. S. Bäurle, S. Hoppen, U. Koert, Angew. Chem. 1999, 111, 1341. A. Fürstner, M. Albert, J. Mlynarski, M. Matheu, E. DeClercq, J. Am. Chem. Soc. 2003, 125, 13132. W. Oppolzer, R. N. Radinov, J. de Bradander, Tetrahedron Lett. 1995, 36, 2607. M. Yus, D. J. Ramón, O. Prieto, Tetrahedron: Asymmetry 2003, 14, 1103. D. Boyalli, E. Frantz, M. Carreira, Org. Lett. 2002, 4, 2605. A. Fettes, E. M. Carreira, Angew. Chem. Int. Ed., 2002, 41, 4098. L. Pu, Tetrahedron 2003, 59, 9873. L. S. Tan, C. Y. Chen, R. D. Tillyer, E. J. J. Grabowski, P. J. Reider, Angew. Chem. Int. Ed. 1999, 38, 711. N. K. Anand, E. M. Carreira, J. Am. Chem. Soc. 2001, 123, 9687.

hedron: Asymmetry 2003, 14, 1955.

P.-O. Norrby, Angew. Chem. Int. Ed. 2003, 42, 3002; (b) J. Rudolph, N. Hermanns, C. Bolm, J. Org. Chem. 2004, 69, 3997; (c) C. Bolm, J. Mueller, Tetrahedron, 1994, 50, 4355; (d) C. Bolm, J. Mueller, G. Schlingloff, M. Zehnder, M. Neuburger, J. Chem. Soc., Chem. Commun. 1993, 2, 182; (e) C. Bolm, G. Schlingloff, K. Harms, Chem. Ber. 1992, 124, 1191; (f) C. Bolm, N. Hermanns, A. Classen, K. Muniz, Bioorg. Med. Chem. Lett. 2002, 12, 1795. 314 J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 10409. 315 J. F. Traverse, A. H. Hoveyda, M. L. Snapper, Org. Lett. 2003, 5, 3273. 316 T. Yamamoto, A. Yamamoto, S. Ikeda, J. Am. Chem. Soc. 1971, 93, 3350. 317 C. K. Reddy, P. Knochel, Angew. Chem. Int. Ed. Engl. 1996, 35, 1700. 318 A. Devasagayaraj, P. Knochel, Tetrahedron Lett. 1995, 36, 8411. 319 (a) G. Cahiez, Actual Chim. 1984, (Sept), 24; (b) B. Weidmann, D. Seebach, Angew. Chem. Int. Ed. Engl. 1983, 22, 31; (c) G. Cahiez, B. Laboue, Tetrahedron Lett. 1989, 30, 3545; (d) G. Cahiez, B. Laboue, Tetrahedron Lett. 1989, 30, 7369; (e) G. Cahiez, M. Alami, Tetrahedron 1989, 45, 4163; (f) G. Cahiez, P.-Y. Chavant, E. Metais, Tetrahedron Lett. 1992, 33, 5245; (g) G. Cahiez, B. Figadre, P. ClØry, Tetrahedron Lett. 1994, 35, 3065; (h) G. Cahiez, K. Chau, P. ClØry, Tetrahedron Lett. 1994, 35, 3069. 320 E. Riguet, I. Klement, C. K. Reddy, G. Cahiez, P. Knochel, Tetrahedron Lett. 1996, 37, 5865. 321 T. Stüdemann, M. Ibrahim-Ouali, G. Cahiez, P. Knochel, Synlett 1998, 143.

347

8 Polyfunctional 1,1-Organodimetallic for Organic Synthesis Seijiro Matsubara 8.1 Introduction

The first experience using resinous ball and stick molecular model is so impressive to give us a feeling that we can prepare any compound. However, we learn the difference between the model and the real molecule as soon as we begun an 3 organic reaction experiment. The parts of the model for an sp carbon atom have two balls and two projections, which make free connection between the parts possible. If one gave such ability to the real carbon atom, we could take a step to the free construction of organic molecules. This is not an absurd idea. An idea for such a reagent is the use of 1,1-organodimetallic species (i.e. gem-dimetallic species) and many types of gem-dimetal species have already been reported. The preparation of gem-dimetal compounds has been achieved mainly by the following three methods: 1) Double deprotonations from the methyl or methylene carbon, which connects with one or two anion-stabilizing groups, 2) a regioselective carbometallation or hydrometallation to alkenylmetal compound as well as double metallations to alkyne, and 3) a halogen±metal exchange of gem-dihaloalkane (Scheme 8.1). As the chemistries of 1) and 2) including both preparation and reaction had been well discussed in the excellent reviews [1], the geminated dimetal compounds prepared by method 3) will be particularly discussed in this chapter. It should be emphasized that only this method is applicable for the preparation of gem-dimetallic methane that is the simplest 1,1-organodimetallic species. This simple reagent can show fully its polyfunctionality that comes from the feature as gem-dimetallic structure. Preparation of 1,1-organodimetallic compounds via halogen±metal exchange reaction starts from 1,1-dihaloalkyl compounds 1 (Scheme 8.1). The reduction into the corresponding dimetallic compound proceeds with two steps. The carbenoid species is formed as an intermediate after the first reduction. Before its decomposition, the species should be reduced into 1,1-dimetallic compound that is relatively more stable. The difficulty exists on this second reduction step. Overcoming the difficulty, several metals can reduce 1.1-dihaloalkyl compounds into the target reagents. Among them, zinc and chromium reagents have shown wide Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

348

8 Polyfunctional 1,1-Organodimetallic for Organic Synthesis 1) Deprotonation

R

Electron withdrawing group

CH2

2) Carbometallation R

Mtl1 +

Mtl

2

3) Halogen-Metal exchange R X CH X

(1, R: H, Alkyl, Silyl etc)

Base (e.g. BuLi)

Mtl R

Electron withdrawing group

C Mtl R

Carbometallation

Mtl1 Mtl2

R

Reduction Mtl

CH Mtl

Scheme 8.1 Typical way of gem-dimetallic compounds preparation.

varieties of the original functions [2]. They will be introduced here. It should be also mentioned that a metal-carbene complex is equivalent to gem-dimetal species, 3 but their chemistry is different from sp -geminated organodimetallics [3]. They will not be discussed in this chapter.

8.2 gem-Dizincio Compounds 8.2.1 General View

Organozinc reagents have been widely used in organic synthesis. They are not so reactive, compared to the corresponding magnesium or lithium ones. On the contrary, they have reasonable stability that makes the handling easy. A direct reduction of dihalomethane with zinc may be the easiest way to prepare gem-dizinc compound, but is also well known as a preparation of halomethylzinc, that is a Simmons±Smith reagent [4,5]. The typical procedure to prepare Simmons±Smith reagent is treatment of diiodomethane with zinc±copper couple in ether as solvent. When this procedure is examined in THF as solvent, gem-dizinc species is formed to some extent. A Simmons±Smith reagent reacts with alkenes electrophilically as a carbenoid species but does not attack carbonyl compounds nucleophilically. On the other hand, the nucleophilicity of a gem-dizinc species, which was formed via the further reduction of Simmons±Smith reagent, would be enhanced by doubly substituted electropositive zinc atoms. Once a gem-dimetal species adds to a carbonyl group, the pathway may lead to Wittig-type olefination. In 1966, Fried and coworkers used the gem-dizinc species that was prepared from diiodomethane and a zinc±copper couple in THF, to the methylenation of steroid derivatives (Scheme 8.2) [6,7]. In this substrate, a hydroxyl group on the a-position of ketone plays an important role. A chelation enhanced the nucleophilicity of the dizinc species [8].

8.2 gem-Dizincio Compounds

CO2Me

CO2Me

CH2 I2 / Zn(Cu) THF, reflux AcO

HO

AcO O

HO

CH2

Scheme 8.2 Methylenation of a-hydroxy ketone with CH2I2-Zn(Cu) in THF.

Not only a zinc±copper couple, but also a zinc±lead couple forms a gem-dimetal species starting from diiodomethane, according to Nysted's patent in 1975 [9]. He also insisted that treatment of dibromethane with a zinc±lead couple in THF at 80 C forms a characteristic gem-dizinc species 2 in Fig. 8.1. However, there was 1 1 no further evidence concerning the structure except H-NMR data. H-NMR spectroscopy was not enough for the determination of this structure. The obtained compound was definitely a gem-dizinc species, but the written structure 2 is still suspected. The white solid 2 was obtained as a dispersion in THF, and would not dissolve into DMF and DMI. This THF dispersion is commercially available from Aldrich Co. as Nysted reagent. Nysted also showed that this dizinc compound was effective for the methylenation of a-hydroxy ketone moiety in steroid derivatives.

Br

Zn H 2C

O Zn

Zn Br CH2

2

Fig. 8.1 Proposed structure of Nysted reagent prepared from CH2Br2 and Zn.

Nozaki and cowrokers reported in 1978 that the reagent prepared from diiodomethane, zinc, and titanium (IV) chloride was effective for the methylenation of ketones [10a]. In this procedure, a reagent was prepared by mixing diiodomethane (3.0 eq), zinc powder (9.0 eq), and titanium (IV) chloride (1.0 eq) in THF for 30 min at 25 C. A ketone (1.0 eq) was added to the prepared reagent. Instead of titanium (IV) chloride, other metal halides were also examined (Scheme 8.3). Among them, titanium (IV) chloride gave the best result. Methylenations of highly enolizable ketones, a- and b-tetralone, were performed by the reagent system. Treatment of these ketones with methylenetriphenylphosphorane did not give any methylenated product [10b]. In these reports, the zinc powder that had been used by Nozaki and coworkers in Kyoto University was pyrometallurgy zinc. It contains 0.04±0.07% lead (Pb) originally. This lead played an important role for the acceleration of further reduction of Simmons±Smith reagent into gem-dizinc species, according to Takai and coworkers' report in 1994 [11]. This effect was consonant with Nysted's result [9].

349

350

8 Polyfunctional 1,1-Organodimetallic for Organic Synthesis

O

CH2

Zn (9.0 ), Metal halide (1.0 ) CH2X2 (3.0 )

(1.0)

CH2I 2, Me3Al CH2I 2, AlCl3 CH2I 2, VCl4 CH2I 2, TICl4 CH2Br2, TICl 4

62% 42% 70% 83% 89%

Scheme 8.3 Methylenation of 4-dodecanone with Zn-CH2X2-Lewis acid.

In other words, the aging period for the preparation of dizinc reagent should be much longer, when pure zinc without lead was used for this purpose. Actually, this method was claimed not to be reproducible and was modified by Lombardo in 1982 [12]. Lombardo applied Takai and Oshima's procedure to the methylenation of gibberellin derivative with Zn (pure, without lead)±CH2Br2TiCl4, and only decomposition of the substrate was observed. He showed an improved procedure. According to Lombardo's report, the aging period for the preparation of the reagent should be three days (Scheme 8.4). This method is effective for methylenation of ketones. Methylenation of the ester group with this system did not proceed efficiently, except for a few examples [13].

Zn (440 mmol) + CH 2Br2 (144 mmol) + TiCl 4 (103 mmol) 3 days, 5 ºC [ active species] THF (250 ml) O

H2C

H

OH O

MeO2C (100 mmol)O

3 H

3

OH O

MeO2C O

90%

Scheme 8.4 Methylenation of gibberellin derivative by Lombardo's method.

Lombardo's method had been applied to various types natural product synthesis. In Scheme 8.5, some examples are shown [14±16]. The problem about the aging period for preparation of reactive species 3, argued by Lombardo, should not be attributed only to the formation of gem-dizinc species. As titanium(IV) chloride is also reduced with zinc powder, [17] the titanium salt that works as a mediator would be the low-valent one. The reduction process of titanium(IV) may also sometimes cause the problem of reproducibility of methylenation reaction. In 1998, Matsubara and coworkers reported a general

8.2 gem-Dizincio Compounds

CH2 OPMB

OH H2C

O

BnO HO BnO O

OMe

CH2

O 6-epi-sarsolilide A [14]

(–)-necrodol [15]

amphidinolide A [16]

Scheme 8.5 Examples of methylenation in natural product synthesis with Zn-CH2X2-TiCl4.

procedure for the preparation of bis(iodozincio)methane 4, which was obtained as THF solution (Scheme 8.6) [18]. The detailed structural study of the solution by EXAFS implied that the gem-dizinc species prepared from diiodomethane and zinc is the monomeric bis(iodozincio)methane (4) [19]. Formation of polymethylene zinc 5 via Schlenk equilibrium was not observed under the reaction condition. A solution of 4 in THF can be kept unchanged at least for a month in a sealed reaction vessel. Starting from the reagent 4, various reactions and chemistries were developed. cat. PbCl2

I CH2

I +

IZn CH2 ZnI

Zn

IZn CH2 ZnI

THF, 0 ºC

IZn CH2Zn THF, 25 ºC

4 (50% yield)

n

I

+ n ZnI2

5

Scheme 8.6 Preparation of bis(iodozincio)methane in THF.

8.2.2 Methylenation with Bis(iodozincio)methane

Aldehydes were methylenated by bis(iodozincio)methane (4) [18]. Commercially available Nysted reagent 3 was also effective for this transformation; in this case, an addition of catalytic amount of BF3Óet2 improved the yield (Table 8.1) [20]. Methylenation reactions of ketones at ambient temperature with 4 required addition of titanium salt to obtain the good yield. As shown in Table 8.2, 2-dodecanone was treated with bis(iodozincio)methane (4) in the presence of various titanium salts. As titanium chloride, b-TiCl3, which had been prepared from titanium (IV) chloride and hexamethyldisilane by following Girolami's procedure, [21] was shown to be the most effective. Hermes and Girolami's report corrected the errors in the Naula and Sharma's result: Naula and Sharma had reported that TiCl2 was formed from the reaction of titanium(IV) chloride and hexamethyldisilane

351

352

8 Polyfunctional 1,1-Organodimetallic for Organic Synthesis Table 8.1 Methylenation of Aldehydes with Bis(iodozincio)methane (4) and Nysted Reagent (2)

H

H Dizinc (2 or 4)

R

a

O

Additive

R

CH2

Br

O Zn

Zn

Br

CH2(Znl) 2 4

Zn 2

Entry

R-CHO (1.0 mmol)

1

CH3(CH2)10CHO

b

Dizinc

Additive

Alkene

4 (1.0 mmol)

none

74%

2

4 (2.0 mmol)

none

96%

3

2 (1.0 mmol)

none

68%

4

2 (1.0 mmol)

BF3.OEt2 (0.1 mmol)

83%

5

PhCH2CH2CHO

4 (1.0 mmol)

none

46%

6

(E)-PhCH=CHCHO

4 (1.0 mmol)

none

47%

7

(E)-PhCH=CHCHO

2 (1.0 mmol)

BF3.OEt2 (0.1 mmol)

69%

8

(S)-PhCH(CH3)CHO

4 (1.0 mmol)

none

64%

a b c

c

Nysted reagent was weighed according to the structure 2, that is shown in the original patent [9]. RCHO (1.0 mmol), dizinc (1.0 or 2.0 mmol), and additive were mixed in THF. No epimerization was observed.

(Scheme 8.7) [22]. Girolami pointed out that hexamethyldisilane cannot reduce titanium(III) chloride into titanium(II) or (I) chloride regardless of the stoichiometry (Scheme 8.8). Matsubara and coworkers used the titanium chloride prepared from titanium(IV) chloride and hexamethyldisilane in their olefination citing Naula and Sharma's report [23]. In their series of reports, the salt was written as TiCl2. It should be b-TiCl3, according to Girolami's correction in 1998, although all procedures and results in their olefination reactions are correct [24]. TiCl4 +

TiCl2 +

Me3SiSiMe3

2 Me3SiCl

Naula and Sharma (1985) Scheme 8.7 Reduction of TiCl4 into TiCl2 with Me3Si-SiMe3 by Naula and Sharma.

2 β-TiCl3 + 2 Me3SiCl

2 TiCl4 + Me3SiSiMe3 β-TiCl3 + Me3SiSiMe3

//

No further reduction Hermes and Girolami (1998)

Scheme 8.8 Reduction of TiCl4 into TiCl3 with Me3Si-SiMe3 by Hermes and Girolami.

8.2 gem-Dizincio Compounds Table 8.2 Titanium salt mediated methylenation of ketones with

bis(iodozincio)methane (4).a O

CH2

CH2 (ZnI) 2 (4)

n-C10 H21

Ti salt , 25 ˚C

CH3

entry

Ti salt

1

b

n-C 10H21 c

4

Alkene

None

1 eq

15%

10%

2

TiCl4

1

26

97% R = Me, C6H4, p-MeC6H4, p-FC6H4

Homo-coupling involving alkenyl halides has been performed efficiently using an electro-assisted nickel-complex catalysis [23]. This coupling reaction can even work with simple aliphatic substrates to give the corresponding dimeric products [21,24]. R2 R1

NiBr2bpy, e-

H

R2

H R1 + isomers

R1

X

H

R-X + 2e-

NiBr2bpy

R2

R-R

R = C8H17 (48%), Bn (75%), 4-CF3C6H4 (86%) Ph2CCl2 + 2 e-

NiBr2bpy 68%

Ph2C=CPh2

It is well documented that the nickel catalysts or reagents are useful for the cleavage of carbon±sulfur bonds [25]. Thus, Ni(0)-catalyzed reductive dimerization of aryl thioethers affords the corresponding dimers in satisfactory yield [26].

N SMe N

NiCl2/PPh3, Zn 68%

N

N

N

N

10.3 Cross-coupling Reactions

Transition-metal-catalyzed cross-coupling reactions of an organic electrophile with a carbon nucleophile have been shown to be one of the most important reactions leading to Csp2±Csp2 bond formation [2,3]. Nickel catalysts have played a pivotal role in this important class of transformations. Various leaving groups in organic


electrophiles can be used. Thus, carbon±halogen, carbon±oxygen, carbon±sulfur, carbon±nitrogen, etc., can readily be displaced by carbon±carbon bonds. The reaction is particularly useful for substrates having such a leaving group on the Csp2 carbon. Recent advances suggest that simple unactivated aliphatic substrates can also work smoothly under various conditions. References covered in earlier reviews will not be duplicated here [27±32]. 10.3.1 Kumada±Corriu Reactions

Cross-coupling reactions of 3-pyridylmagnesium chlorides with haloazines or halodiazines in the presence of a catalytic amount of Ni(acac)2 and dppe at room temperature afford the corresponding 3-pyridylazines in good yields [33]. MgCl + N

Cl

Ni(acac)2/dppe

N

76%

N

N

The cross-couplings of dienyl phosphates with Grignard reagents have been shown to be useful for the synthesis of 2-substituted 1,3-dienes [34]. OPO(OPh)2

NiCl2(dppe) PhMgBr 92%

The use of imidazolinylidene ligands 1 has been shown to be particularly useful to enhance the reactivity of the cross-couplings of aryl chlorides [35] and fluorides [36] with aryl Grignard reagents. X + BrMg

F3C

R

Ni(acac)2/L 95-99%

R

R = t-Bu or OMe

X = Cl or F

Me Y L=

F3C

Ar N

N Ar 1

Ar =

Pr-i

Me

Y = Cl or BF4 Me

Pr-i

Vinylic and aryl carbon±sulfur bonds can also be replaced by carbon±carbon bonds by means of nickel-catalyzed cross-coupling reactions [25,37,38]. Thus, triphenylpyrimidine is synthesized by such reaction in excellent yield [26].

401

402

10 Functional Organonickel Reagents

N SMe N

N

NiCl2(dppe), PhMgBr > 99%

N

Substitution of neopentyloxysulfonyl group by an aryl group is achieved by the NiCl2(dppf)-catalyzed cross-coupling reactions of biphenylsulfonates with an aryl Grignard reagent. The reaction can be used for the synthesis of unsymmetrical terphenyls [39]. Z

O O S RO

BrMg

Y

Y

Z NiCl2(dppf)

In the presence of a chiral ligand, Ni(COD)2 serves as an active catalyst for the asymmetric synthesis of chiral binaphthyls in excellent selectivity from dinaphthothiophene. The remaining mercapto-moiety can be methylated and oxidized to give the corresponding sulfoxides that can further react with MeMgI in the presence of Ni(acac)2 leading to the coupling products. A similar reaction for the synthesis of axially chiral biaryls has been reported [40,41]. 1. Ni(COD)2/L* RMgX S

O

R SH

+

2. H , H2O

L* =

Ni(acac)2, MeMgI Ph SMe 76%

PPh2 N

Ph Me

O

Me S Me

Ph S Ph

4-MeC6H4MgBr Ni(COD)2, (S)-H-MOP

MeMgI Ni(COD)2, (S)-H-MOP

Me Me

Ph Ph

Tol SH

Me SH


403

Benzylic and allylic dithioacetals undergo olefination reactions with Grignard reagents in the presence of NiCl2(PPh3)2 catalyst [42]. The reaction is particularly useful in the synthesis of vinylsilanes [43], and has been extended to the regioregular synthesis of silylene-spaced copolymers [44,45]. Reactions of cyclopropyl Grignard reagents with benzylic dithioacetals provide an interesting entry for the synthesis of substituted butadienes [46,47]. b-Heteroatom elimination has been observed in these reactions [48]. S

S

TMSCH2MgCl

Ar

H

NiCl2(PPh3)2 85%

Ar

SiMe3

S MgBr

S

NiCl2(PPh3)2 70%

Br

S 2-Naph

S

X

MeMgI NiCl2(PPh3)2

2-Naph

X = OMe 75% X = SMe 73%

Nickel-catalyzed cross-couplings of aryl ether bonds is well documented [49,50]. A recent example has demonstrated a convenient route for the synthesis of a teraryl [51]. MeO

O

NMe2

MgBr +

NiCl2(PCy3)2/2 PCy3 88%

10.3.2 Negishi Reaction

There has been increasing interests in the use of organozinc reagents in organic synthesis [52,53]. The most important advantage of using zinc reagent in the cross-couplings is that, unlike the Kumada reaction, several functional groups are stable under the reaction conditions. Aryl and vinyl mesylate behave silimilarly [54]. The reaction has been used for the synthesis of 10,11-dihydroleukotriene B4 and related metabolites [55,56]. OR

Me Me O

O B

MeLi R2

Me Me

OR

O Me B O

Li R2

R1

+ Br

NiCl2(PPh3)2

R1

R2

404


Cross-coupling reaction of aryl iodides with organozinc iodides in the presence of Ni(acac)2 can proceed smoothly. An extension to the corresponding resin-substituted aryl iodides also affords the coupling products. It is noteworthy that amides or esters remain intact under the reaction conditions [57]. R2ZnI Ni(acac)2/p-FC6H4-CH=CH2

O 1

R

O R1

Bu4NI, THF/NMP 70-84%

X

R2

R1 = OEt, NMe2 X = I, ONf

In situ generated Ni(0) on charcoal has been shown to be an efficient heterogeneous catalyst for mediating carbon±carbon bond formation involving chloroarenes and functionalized organozinc reagents [58]. O

O Cl

EtO

NC-(CH2)4ZnI

MeO

CN

EtO

Ni/C, PPh3 84%

MeO

Aryl chlorides are known to undergo nickel-catalyzed cross-coupling reaction of aryl Grignard reagents in the presence of zinc [59]. Vinylphosphates [60] and sulfoxides or sulfones [61] behave similarly to yield the corresponding coupling products. CN

Ni(acac)2/P(Oi-Pr)3

+ p-TolMgCl

Me

CN

Zn, MeMgCl 72%

Cl

OPO(OEt)2

S NiCl2(dppe)

+ S O

ZnBr

90%

O O

X O HO S

N

ZnBr R

Ni(acac)2

+

O

N

X = lone-pair electrons R = n-C4H9 73% X=O R = n-C8H17 70%

HO R


The carbon±nitrogen bond in substituted nitroethenes can be replaced by a carbon±carbon bond in good to excellent yield upon treatment with organozinc halides in the presence of Ni(acac)2 and a diamine ligand [62]. R-ZnI +

CH=CH-NO2

R1

L=

CH2NEt2 CH2NEt2

Ni(acac)2/L R1

CH=CH-R

CH2N

or

CH2N

10.3.3 Suzuki Reaction

The use of palladium catalyst in Suzuki reaction has been to be particular appealing for the formation of aromatic carbon±carbon bonds [63,64]. However, leaving groups such as aryl sulfonates are unreactive because these substrates show poor reactivity toward oxidative addition in the catalytic cycle. A stronger nucleophile such as Ni(0) is essential to increase the reactivity of this cross-coupling reaction by enhancing the rate of the oxidative addition step. Thus, in the presence of 10 mol% NiCl2(dppf) and 1.7 equiv of Zn and 3.0 equiv of K3PO4 in THF, aryl mesylate can couple with arylboronic acid to give the corresponding coupling products. Either electron-donating groups (Me or MeO) or electron-withdrawing groups (CO2Me or Ac) are stable under the reaction conditions, although the latter substituents gave better yield of the reaction [65]. Aryl chloride behaves similarly [66±68]. The reaction has been extended to the synthesis of sterically hindered (disubstitution at the ortho positions) biaryls [69]. O OMs +

B(OH)2

NiCl2(dppf), Zn

Me

K3PO4 51%

O Me

NiCl2(PCy3)2 associated with PCy3 promotes the selective cross-coupling of aryltosylates with arylboronic acids under relatively mild conditions, and a variety of function groups are tolerated in both arenes [70]. It is particularly noteworthy that no reducing agent such as Zn is required in this reaction. More recently, roomtemperature nickel-catalyzed Suzuki coupling reactions of arenesulfonates with arylboronic acids have been disclosed [71]. Ar-OSO2Ar" + (HO)2B-Ar'

Ni(COD)2/ PCy3

Ar-Ar'

405

406


The Ni(0) catalyst, generated in situ from the reduction of NiCl2(PPh3)2) with BuLi, has been shown to be active for the Suzuki couplings of aryl chloride with boronic acids [72]. Me

Me Me NiCl (dppf) 2 dppf O

B(OH)2 + Cl

Me

Me Me Me

Me

O 78%

Using the heterogeneous catalyst Ni/C, biaryl bonds can be made between functionalized aryl chlorides and boronic acids in good yields [73]. Aryl bromides and iodides can be coupled with phenylboronic acid in good yields using NiCl2.6H2O as a catalyst precursor. Neither a reducing agent, such as Zn, nor phosphine ligands is required [74]. B(OH)2

Cl

R'

Ni/C

+

R

R'

R

R = 3-CF3 R' = 4-CHO 67% R=H R' = 2-CN 87%

Nickel-catalyzed reaction of 1,3-disubstituted allylic carbonates and lithium aryl- and alkenylborates provided a regio- and stereoselective route under mild conditions for the synthesis of the corresponding substitution products [75]. R1

R2

+

R3 B

NiCl2(dppf) Li

R1

R2 R3

OCO2Et R1 = Ph, CO2Et R2 = n-C5H11

A catalytic system consisted of Ni(COD)2) and 1,3-bismesitylimidazole carbene ligand in the presence of CsF has been shown to catalyze Suzuki reaction of aryl trimethylammonium ion. Substituents such as ether, ester or fluoride on either electrophiles or nucleophiles are stable under these conditions [76,77]. NMe3OTf

B(OH)2 +

Bu

Ni(COD)2/IMes.HCl CsF N

N

IMes 98%

Bu


407

10.3.4 Stille Coupling

The use of nickel catalysts in the Stille coupling reactions has been sporadically explored. In general, the yields of the reactions are not satisfactory. Dimerization products are occasionally side products [78,79]. MeO2C OMs + (n-Bu)3SnPh

MeO2C

Ph 24% +

NiCl2(PPh3)2 Zn, Et4NI MeO2C

CO2Me 64%

Br

CHO Br + MOMO

Ni

Sn(Bu)3

CHO

Ni Br

35%

OMOM

MOMO

10.3.5 Heck Reaction

Recent studies show that Ni(0) catalyst is effective for the inter- or intramolecular Heck reaction leading to carbon±carbon bond formation [80]. Br

CO2Et

[Ni(P(OEt)3]4

+

CO2Et

Ph

K2CO3, NMP 76%

O

O N I

Ph

Me

[Ni(P(OPh)3]4 K2CO3, NMP 79%

N

Me

Me

10.3.6 Miscellaneous Coupling Reactions

Stereo and regiodefined alkenylmetals containing Al or Zr react with aryl and alkenyl iodides and bromides in the presence of catalytic amounts of Ni complexes containing phosphine ligands such as PPh3, to give the corresponding coupling products [81±84].

OMOM

408


n-C4H9

H

H

I

n-C8H17

H H

Ni 70%, 95% E,E n-C8H17

H

n-C4H9

H

H

H

Al(Bu-i)2

n-C4H9

I

H

H

n-C8H17

n-C4H9 H

Ni 57%, 90% Z,E

R

H

H

ZrCp2Cl

ArX Ni(PPh3)4

> 99%E

H

H

R

H

H

Ar

H

Benzylic chlorides incorporated with heteroaromatic rings can also be used for such reaction [85]. R

n

R1

+ M

R

Ni(0)

n

R1

2

R

R2

Cl M = Me2Al ClCp2Zr

Aryl iodides couple with aryl aldehydes in the presence of NiBr2(dppe) and Zn to give the corresponding biaryl ketones. The use of a bidentate ligand is critical to the success of this catalytic reaction [86]. O I R

+ Ar-CHO

Ni(L)2Br2/Zn

Ar

R

L2 =

PPh2 n

PPh2

n =1-4

Aryl chlorides are converted to the corresponding anilines using catalytic t amounts of Ni(COD)2, dppf. and NaOBu . Electron-rich or -poor aryl chrodies as well as chloropyridine derivatives can be combined with primary and secondary amines to give the desired aryl amins in moderate to excellent yields. NiCl2(dppf) or NiCl2(phen) can also be used in place of air-sensitive Ni(COD)2 catalyst [87].


Cl +

MeO

Ni(COD)2/DPPF NaOt-Bu 88%

H2N Me

N H

MeO

Me

Arylacetic ethyl esters are prepared from arylzinc chlorides and ethyl bromoacetate with a catalytic amount of Ni(acac)2 and a phosphine ligand at ±5 C [88]. ArZnCl + BrCH2COOEt

Ni(acac)2/PCyPh2

ArCH2COOEt

Olefination of an aldeyhde with one equivalent of the organozinc reagent in the presence of 30 mol% of NiCl2(PPh3)2 and 2 equivalents of Me3SiCl. Chloro, bromo or hydroxyl substituents are stable under the reaction conditions [89]. O H + EtO2CCH2ZnI

NiCl2(PPh3)2 Me3SiCl 66%

OEt O

10.3.7 Aliphatic Substrates

More recently, the use of unactivated aliphatic electrophiles in the transition-metal-catalyzed cross-coupling reactions has attracted much attention [90,91]. In general, cross-coupling of a secondary alkyl halide is difficult because of a slow oxidative step and a fast b-hydride elimination process. Nickel catalysts again have played a very important role in these reactions. In the presence of 1,3-butadiene, nickel-catalyzed reactions of alkyl halides (Br, Cl, or OTs) with Grignard reagents yield the corresponding cross-coupling products. An anionic Ni(II) intermediate is suggested to be involved in the overall transformation leading to the formation of carbon±carbon bonds [92].

R'

R-X

+

Ni

R'-MgX

Mg+X

NiCl2 1,3-butadiene

R-R'

R = alkyl X = Cl, Br, OTs R' = aryl, alkyl

Interestingly, diene moiety can participate into the reaction leading to the three-component coupling products in good yields [93].

409

410

10 Functional Organonickel Reagents R1

R1 R2

R-Br +

+ Ph-MgBr

R2

NiCl2(dppf)

R

R2 R

R1 R = i-C3H5, R1 = Me, R2 = H R = c-C6H11, R1 = H, R2 = Ph

Ph

2 1

R

91% (E/Z = 67:33) 60% (E/Z = 100:0)

Unactivated secondary alkyl bromides and iodides have been shown to proceed Suzuki couplings with arylboronic acid in the presence of Ni(COD)2 and bathophenathroline ligand [94]. Ralkyl-X

+

Ni(COD)2/bathophenanthroline KOt-Bu Ph Ph

(HO)2B-R

X = Br, I

N

Ralkyl-R

N

bathophenanthroline

Negishi cross-coupling reactions of primary and secondary alkyl bromides and iodides are achieved when Ni(COD) is employed as the catalyst in the presence of a diamine ligands such as bupybox [95]. O

O I +

BrZn

O

NEt2

H O

N H

H

R1

NEt2

O H

N N

N R1-Pybox

4

78%

O

N N

R1

4

Ni(COD)2/s-Bu-Pybox

Indanyl-Pybox

Recently, nickel-catalyzed cross-couplings of organosilicon reagents with unactivated secondary alkyl bromides have been disclosed. Functional groups such as fluoride, chloride, ether, lactones, ketones, acetals, and cyanides are stable under the reaction conditions. Bathophenanthroline appears to be the best ligand for these transformations [96]. Ralkyl -X + F3Si Ph

NiBr2.diglyme/bathophenanthroline CsF Ralkyl -X (Yield %) H O

(60) O H

NC

I I (73)

Ralkyl -Ph

10.4 Carbozincation Reactions

In the presence of Bu4NI and 4-fluorostyrene, unreactive primary and secondary alkylzinc iodides undergo nickel-catalyzed cross-couplings with various primary alkyliodides or bromides at low temperature. More reactive secondary dialkylzincs and the mixed zinc organometallics undergo the cross-coupling reaction in the absence of Bu4NI. Retention of configuration has been observed [97± 101]. It is noteworthy that free NH groups are tolerated in the cross-coupling, allowing the synthesis of aminated products. Internal alkyne gives the cross-coupling product in satisfactory yield [102]. Presumably, chelation of the remote functional group to nickel may facilitate the reaction. RZnI

+

FG-(CH2)n-I

SiMe3

Ni(acac)2/p-FC6H4-CH=CH2 Bu4NI, THF/NMP

SiMe3

Et2Zn, Ni(acac)2 -78 ºC to - 40 ºC

I

FG-(CH2)n-R

Et

Chelation-assisted activation of aliphatic C±S bonds in dihtioacetals has been described [103±105]. Representative examples are shown below: S

S

S

S

NiCl2(dppf) Me MeMgI 80%

S S

Nickel-catalyzed olefination of unactivated aliphatic dithioacetals gives the corresponding alkenes in good yields [106]. The use of trialkylphosphine is essential for this cross-coupling reaction. Ni(acac)2/P(t-Bu)3

S

PhMe2SiCH2MgCl 91%

S S S

Ni(acac)2/P(t-Bu)2Me Me3SiMgCl 73%

SiMe2Ph

SiMe3

10.4 Carbozincation Reactions

The nickel-catalyzed hydrozincation or carbozincation of double or triple bonds are worthy of note. Thus, treatment of an alkene with diethylzinc in the presence of a catalytic amount of Ni(acac)2 and COD affords the corresponding organozinc reagent. Since diethylzinc will react with aliphatic bromide or iodide, such zinc±

411

412


halogen exchange may occur to furnish intramolecular cyclization leading to cyclopentylmethyl zinc intermediate for further transformations [107]. This cyclization reaction has been used in the synthesis of natural products having tetrahydrofuran and butyrolactone skeletons [108,109]. Functional groups like hydroxyl, ester, or ether groups are stable under the reaction conditions. HO2C

CH2

Pent O O (-)-methylenolactocin

I O

H

O

O H

Ni(0) Et2Zn

H H

ZnI O

O

CO2Et

i-Pr

O

CO2Et

O

O

BuO

O

50% (> 99% trans)

61%

OBn

BnO 1. Et2Zn, Ni(acac)2

I

CO2Me

2. CuCN.2LiCl then 1-bromobutyne 86%

CO2MeEt

The organozinc intermediate thus obtained can be oxidized with oxygen to give the corresponding alcohols [110,111]. Ph

Ph

Ph Ni(acac)2 Et2Zn, LI Br

O2, THF ZnX

OH overall yield 63%

Nickel-catalyzed carbozincation can also proceed smoothly with alkynes for the synthesis of substituted alkenes regio- and stereoselectively. The reaction may proceed via an intramolecular version leading to tri- or tetrasubstituted alkenes. Thus, treatment of x-iodoalkyne with R2Zn in the presence of 7.5 mol% Ni(acac)2 in THF and NMP yield the cyclopentane derivative in 62% yield [102,112]. Presumably, a reductive elimination step from the corresponding organonickel intermediate may occur. It is noteworthy that no cyclization is observed when internal alkyne is used.

10.5 Cycloadditions

CH2OR1 +

Ph

R22Zn

THF, NMP Ni(acac)2

R2

H

Ph

OR Ph

Ph

H

R2Zn, THF:NMP

H

Ni(acac)2 62%

I

n-C5H11

Diaryltellurides and diarylditellurides undergo a smooth tellurium±zinc exchange reaction in the presence of catalytic amounts of Ni(acac)2 leading to arylzinc derivatives. Intramolecular cyclization may also occur [113]. ArTeAr or ArTe-TeAr

Et2Zn Ni(acac)2

Ar-ZnEt

Me BnO

TePh O

1. Et2Zn, Ni(acac)2 2. H2O O 56%, cis:trans = 95:5 OBn

10.5 Cycloadditions 10.5.1 [2+2] Cycloaddition

When a solution of norbornadiene and methylenecyclopropane in benzene in the presence of Ni(COD)2 and Ph3P is allowed to stand for 24 h at room temperature, the dimeric product containing cyclobutaine moiety is obtained in 86% yield [114].

+

Ni(COD)2/PPh3 86%

A nickel-catalyzed similar reaction using substituted norbornadiene and maleic imide under more drastic conditions gives an exo/endo mixture of [2 + 2] adduct [115].

413

414


MeO MeO

+ O

N Ph

O

O

Ni(COD)2/PPh3 1,2-dichloroethane 69% (5:1)

N Ph O

Oxa and aza-benzonormornadienes undergo [2 + 2] cycloaddition with alkynes in the presence of NiCl2(PPh3)2, Ph3P and Zn powder in toluene to afford the corresponding exo-cyclobutene derivatives in fair to excellent yields [116,117]. O

MeO

+ Ph

CH(OEt)2

Ph

O

MeO NiCl2(PPh3)2

OMe

CHO

PPh3 96% OMe

10.5.2 [4+2] Cycloaddition

The nickel(0)-catalyzed stereoselective intramolecular [4 + 2] cycloaddition between dienes and unactivated allenes or alkynes has been shown to be an efficient complement to the uncatalyzed concerted Diels±Alder reaction that often requires stereoelectronic restrictions. In a typical reaction, treatment of dienyne with 10 mol% Ni(COD)2 and 30 mol% of tri-o-biphenyl phosphite at room temperature TMS

H

Ni(acac)2/Et2AlOEt P(O-iC3HF6)3 TMS

O N

Ni(COD)2/P(O-iC3HF6)3 81%

Me

TMS

O TMS

N

OTBS H Ni(COD)2/P(O-o-BiPh)3 Me

97% Me H

[Rh(COD)Cl]2/P(O-o-BiPh)3 90%

OTBS

10.5 Cycloadditions

affords cyclohexadienes in 98% yield [118]. The reaction has been shown to occur with retention of stereochemistry and is not significantly influenced by electronic effects [119]. This process provides convenient access to 6,6- and 6,5-fused ring systems including nitrogen heterocycle [118±120]. Extension of this cycloaddition reaction to diene-allene has been executed. Cycloadducts are obtained in a 2:1 ratio in excellent yield [121]. It is interesting to note that 6,5-fused ring is obtained when [Rh(COD)Cl] is used as the catalyst. A complex of mixture of products is obtained when the reaction is carried out at 185 C without metal catalysts [122]. 10.5.3 [4 + 4] Cycloaddition

Oligomerization of 1,3-dienes selectively yields four-, six- eight-, or twelve-membered rings, depending on the nature of catalysts and reaction conditions [4,123]. Ni(COD)2-PPh3 catalyst has been shown to efficiently promote intramolecular cyclooctadiene formation in good yield from the corresponding bisdienes [124]. The product distribution depends on the nickel±phosphine ratio and the best yield of A (70% cis/trans = 19/1) is obtained when bisdiene is treated in toluene at 60 C with 11 mol% Ni(COD)2 and 33 mol% Ph3P [124]. When a phosphite ligand is used, cyclohexene B or cyclopentane C derivatives are the major products. Functional groups such as esters, ketones, or ethers remain intact under the reaction conditions. The reaction is stereoselective and has been used for the synthesis of polycyclic natural products [125±128]. For example, the key intermediate for the enantioselective synthesis (+)-asteriscanolide is obtained from a similar synthetic route [128]. The use of this strategy for the construction of a taxan skeleton has been briefly explored [129].

H Ni(COD) PPh3

E E

E E

+ E E B

A

E = CO2Et O H

E E

+

C O

O

O Ni(COD)2

O H H

O H H

H

PPh3 H

H

O (+)-asteriscanolide

TBDMSO

TBDMSO Ni(COD)2/P(O-o-BiPh)3 74% (7/1)

415

416


10.5.4 [2 + 2 + 2] Cycloaddition

As mentioned in the previous section, substituted norbornadienes can proceed [2 + 2] cycloaddition with highly reactive dienophiles (maleic imide or strained alkene) in the presence of a nickel(0) catalyst leading to the formation of cyclobutane derivatives. With less reactive dienophiles, the reaction seems to be prone to [2 + 2 + 2] cycloaddition giving homo-Diels±Alder reaction products. These two types of reactions appear to be competitive in certain cases to give a mixture of products [130±133]. OTBS OTBS Ni(COD)2/ PPh3

+

+ O

OMe +

Ac

N Ph

O

1,2-dichloroethane 93% (anti:syn = 90:10) (exo:endo = 98:2)

Ni(COD)2/PPh3 1,2-dichloroethane 78%

Ac

H

H O

Ni(COD)2/PPh3 COMe

O

N Ph

OMe

1,2-dichloroethane 54%

COMe

Quadricyclene also undergoes similar [2 + 2 + 2] cycloaddition in the presence of a nickel catalyst [134].

+

CO2Me

Ni(acrylonitrile)2 58% (60:40)

CO2Me H

+

H CO2Me

Oxa or azabenzonorbornadienes can react with two equivalents of alkynes in the presence of NiCl2(PPh3)2 producing the corresponding cyclohexadienes. A one-step synthesis of pentacyclic product can be achieved when bis-alkyne is used in this cycloaddition reaction [135,136].

10.5 Cycloadditions

O + Ph

H

SO2-p-CH3C6H4 N +

O

NiCl2(PPh3)2/PPh3 95%

Ph

Ph

SO2-p-CH3C6H4 N

NiCl2(PPh3)2/PPh3/Zn 75%

An extension of this cycloaddition reaction has been observed in the derivatization of C60 [137]. O

O C60

NiCl2(PPh3)2 Zn, PPh3 70%

+ O

O

Enones also undergo nickel-catalyzed [2 + 2 + 2] cycloaddition reaction to form the indane derivatives [138]. O

CO2Et CO2Et

+

NiI2(PPh3)2

O CO2Et CO2Et

ZnI2, Zn 70%

Polysubstituted benzene derivatives are obtained from the nickel-catalyzed [2 + 2 + 2] cycloaddition reaction of an allene with two equivalents of alkynes. The reaction appears to be highly regioselective to give the adduct in good yields [139,140]. One of the alkyne moieties in conjugated diynes can react with bis-alkyne to give highly substituted tetralene derivatives in good yield [141].

NiBr2(dppe), Zn + CO2Me

MeO2C

65% CO2Me

417

418

10 Functional Organonickel Reagents CO2Me

CO2Me

NiBr2(dppe), Zn

+

86%

R1 1

R

R2

R2

NiBr2(dppe), Zn

R2

R2

R1

R1

Cocyclotrimerization of arynes with allenes in the presence of NiBr2(dppe)-Zn afford phenanthrene derivatives in moderate to good yields [142].

H OTf

NiBr2(dppe), Zn

+

CsF 64%

TMS

The cycloaddition reaction can also proceed smoothly with carbon dioxide [143] or isocyanate [144] to yield the corresponding substituted pyrones or pyridones, respectively. EtO2C EtO2C EtO2C EtO2C

Me

Me

Ni(COD)2/L 1 atm CO2 97%

EtO2C EtO2C EtO2C EtO2C

Me O O Me Me

NCO Ni(COD) /L 2 78%

Me +

TsN Me

Pr-i

Cl L=

Ar N

N Ar

TsN

N

Ph O

Me

Ar = Pr-i


A new nickel-catalyzed [3 + 2 +2] cycloaddition reaction from methylenecyclopropane and two moles of alkynes has recently been disclosed. In a typical conditions,

10.5 Cycloadditions

Ni(COD)2 is used as the catalyst together with Ph3P in toluene at room temperature and the yield ranges from moderate to good. The regioselectivity is similar to that described in an Ikeda reaction [145]. CO2Et CO2Et + R

Ni(COD)2/PPh3

H

R = (CH3)3C R = 4-FC6H4

89% 59%

R R

Nickel(0) has been shown to react with Fischer carbenes yielding different kinds of products depending on the reaction conditions. Thus treatment with Ni(COD)2 in THF gives the corresponding dimeric product in excellent yield. In the presence of acrylonitrile, cyclopropanation product is obtained in 85% yield. When the same nickel reagent is allowed to react with vinyl chromium carbenes and a terminal alkyne, cycloheptatriene tricarbonylchromium is obtained in good yield. Three equivalents of alkynes are found to react with Fischer carbenes under nickel(0)-mediated conditions to yield the corresponding [2 + 2 + 2 + 1] cyclization product [146]. Again, the reaction is regioselective. MeO

OMe

Ph

OMe

Ni(COD)2 Ph

THF 90%

(OC)5Cr

Ph

CN Ni(COD)2 MeCN 85%

OMe NC

Ph

Ph MeO MeO2C H Ni(COD)2 75%

CO2Me MeO2C

Me OMe (CH2)3CN OMe + NC(H2C)3 (OC)5Cr

H

Me

Ni(COD)2

NC(H2C)3

96% (syn:anti = >98:2)

Cr(CO)3 (CH2)3CN


Treatment of diene-yne with Me3SiCHN2 in the presence of 10 mol% Ni(COD)2 yields the corresponding bicycle[5.3.0]decane skeleton efficiently [147]. O Me Ph

Ni(COD)2 N2CHSiMe3 74% (> 95:5)

Me

SiMe3

O Ph

H

Me

419

420


10.6 Intramolecular Coupling of Enynes or Alkynes

Intramolecular carbometallations have been shown to be a useful approach for the construction of cyclic systems under very mild conditions. The nickel(1) catalyst generated in situ from the reduction of NiCl2(PPh3)2 with sodium naphthalenide in THF has been shown to be active for the cyclization of enynes. The reducing agent can be replaced by CrCl2 and similar results are obtained. Either five- or six-membered rings can be constructed conveniently under these conditions [148]. EtO2C EtO2C

NiCl2(PPh3)2/CrCl2 82%

EtO2C EtO2C

NiCl2(PPh3)2/CrCl2 59%

HO

HO

Within a similar context, nickel(0) complex has been shown to promote cyclization of enynes and isocyanides to form bicyclooctenone derivatives in good yields [149]. Phosphine or diimine ligands are required in these reactions [150]. TBSO

TBSO Ph

Ni(COD)2, PBu3 ArNC 83% (10:1)

Ph

TBSO NAr

H

N (9-Anth)

Ph

CSA

O H

N (9-Anth)

It is interesting to note that, in the absence of phosphine ligands, dienes are obtained as the major products [151]. n-Pr O

n-Pr n-Bu

n-Bu

Ni(COD)2, ArNC O

60% (+ iminocyclopentene, 28%)

The couplings of 1,6- and 1,7-internal diynes or oxygen-linkage mixed terminal/internal diyne with isocyanides provide useful entries for constructing bicyclic cyclopentenone skeletons [152]. The cyclizations of symmetric or unsymmetric diynes bearing amine moiety at the tethered chain proceeded with modest to good regioselectivity in acceptable isolated yield [151,153].

10.6 Intramolecular Coupling of Enynes or Alkynes

R R

Ni(COD)2

+ ArNC

n

R

n = 3, R = TMS n = 4, R = Et

R CSA

NAr

n

88% 94%

421

O

n

R

R

Ph Ph O

Ni(COD)2 82%

+ ArNC SiMe3

O

NAr SiMe3

In the presence of silylhydrides, intramolecular cyclizations of 1,7-diynes give stereoselectively the corresponding terminally substituted dienes in good yields [153, 154]. H O

H

H + H-SiMe2(O-i-C3H7)

O H

H

Ni(acac)2/DIBALH 73% Z/E = 95/5

O

SiMe2(O-i-C3H7)

O H

Interestingly, bisdiene also undergoes a similar cyclization ± hydrosilation across the two diene units to form trans-1,2-divinylcyclopentane derivatives as a mixture of olefin geometrical isomers [151]. MeO2C MeO2C

+ H-SiMe2(O-i-C3H7) SiMe2(O-i-C3H7)

MeO2C MeO2C

+ (2

Ni(acac)2 /DIBALH/PPh3 60% SiMe2(O-i-C3H7)

MeO2C MeO2C

:

1)

When a disilane is employed in the above hydrosilation reaction under similar conditions, a bicyclic silacyclepentadiene (silole is formed via a nickel-silylene intermediate [151]. R R + H-SiR2SiX3 R

Ni(acac)2

SiR

DIBALH R

TBSO

OTBS

TBSO

OTBS

+ HPh2SiSiMe3 Ni(acac)2/PEt3/DIBALH ~40% S S S

Si Ph Ph

S

422


Silaborative dimerization of two molecules of internal alkynes in the presence of a silylborate is catalyzed by Ni(0) generated in situ [155]. (CH2)3OTBS

(CH2)3OTBS O

Ni(acac)2/DIBALH

+

PhMe2Si B O

78%

TBSO(H2C)3

SiHMe2Ph B(pin)

TBSO(H2C)3

(CH2)3OTBS

(CH2)3OTBS

10.7 Reactions of Enones with Alkynes

Nickel catalyst has been shown to be effective for the three-component couplings of alkynyltins with enones and alkynes leading to stereodefined conjugated enynes in good yields [156±158]. DIBALH is used to generated active nickel catalyst for this transformation. It is noteworthy that enones can be either cyclic or acyclic. O +

R1

H

+ R2 R1

SnR3 R1

H

H

+

Ni(acac)2 / DIBALH

H3O

Me3SiCl R2

R2

Me3SiO

O

2

In this reaction, R has to be phenyl or trimethylsilyl group. Simple alkyl-substituted alkynes fail to give the corresponding tandem product. In order to remedy this situation, alkynylzinc reagent is used to replace alkynylstannanes and tandem coupling products are thus obtained in satisfactory yield [159]. Bu O

O

Bu +

+

Bu

Zn 2

H

Ni(acac)2 Me3SiCl

Bu

54% (>98% regioselectivity) H

Tandem coupling of chlorotrimethylsilane, a,b-enones, terminal or internal alkynes and dimethyl zinc in the presence of catalytic amounts of Ni(acac)2 and Ph3P affords the corresponding three-component coupling products [160].


OTMS O Me

Ni/PPh3 TMSCl, Me2Zn n-C6H13 H

C6H13 H

hydrolysis

O

OTMS

Me NiLnCl

C6H13 H

Attempts to use chiral oxazolines as auxiliary for the asymmetric induction of this reaction have been only partially successful [161]. O

O

Et +

+ ZnMe2 Et

Ni(acac)2, Me3SiCl

Me

triglyme O

Et Et

H3C N tBu 78% (81% ee)

O

SiMe3 +

O Ni(acac)2, Me3SiCl

+ ZnMe2 H

diglyme O

Me SiMe3

H3C N tBu 51% (66% ee)

Intramolecular cyclization of alkynyl enones by means of Ni(COD)2 catalyst in the presence of dimethyl zinc gives the corresponding cyclic product. When Bu2Zn is used in the presence of Ph3P, reductive cyclization occurs to give the corresponding reduced product [162±164]. Cyclic enones interestingly give the spiro products in satisfactory yields.

423

424


Me2Zn/MeZnCl Ni(COD)2 82%

O Ph

Me

O

H Ph

H H

O Bu2Zn/BuZnCl Ni(COD)2/PPh3 92%

O H

Me2Zn/MeZnCl Ni(COD)2 72%

H Ph

O H

H

H Me

In the presence of Me3Al and Ni(acac)2, cyclotrimerization of a,b-enones and alkynes proceeds smoothly to give the corresponding cyclic adducts [165]. Terminal alkynes give the product having substituents at both ortho and para positions to the carbonyl group as the major product. Presumably, the regioselectivity is due to steric and/or electronic characteristics of enones and alkynes. O

O

(CH2)2OTBDMS

1. Ni(acac)2/PPh3/Me3Al/PhOH

+ TBDMSO(H2C)2

2. DBU, in air 81% (o,m:o,p:m,m = 92:97:3 dr)

H

Oxygen- and nitrogen-tethered alkynyl enones give the corresponding heterocycle with stereoselective exocyclic olefins [169]. O

O ZnMe2

Me

Ni(COD)2 58%

O

Me H

Me O

H O

Me H

O Me

O

Ph N

H

ZnMe2

Me

Ni(COD)2 70%

N O

Ph

The reaction has been extended to the synthesis of (+)-a-allokainic acid and provided a new entry to the isogeissoschizoid skeleton [170±173].

Ph

426

10 Functional Organonickel Reagents H3C HO2C HO2C

N H (+)-α-allokainic acid

N

H

H N

N

Me2Zn, Ni(COD)2

O TIPSO

TIPSO H

84%, 95:5 dr

N

Me

Me H O

N H H

N

O

OMe

O

O

± -deformyl-isogeissoschizine

O O O

H O

O N

Me

Me CO2H

OTIPS N

O

O

OTIPS

Me

O Ni(COD)2/ZnCl2 74%

Cp2ClZr Me

Me

O

HO2C

N O

N

HO2C

O O

Me N H

5'(R)-isodomoic acid G

Interestingly, no cyclization occurs when alkyne moiety is replaced by an alkene or a diene group. The Michael-addition product becomes the predominant or exclusive product [174,175]. When a stoichiometric amount of Ni(COD)2 is used, the nickelacyclopentene intermediate is treated with oxygen in the presence of bidentate ligands such as tmeda, bicyclohexane is obtained. When an electrophile is used, cyclization leading to bicyclooctene is observed [176]. A plausible mechanism is proposed. A seven-membered nickelacycle intermediate has been isolated and characterized [177,178]. O R1

R2

Ni(COD)2 tmeda

N

Ni

R1

N R2

Ph

O

O2

R1

1. Ni(COD)2 tmeda 2. MeI 68%

L + ONi O

R1

O O R2

R2

OH

O H

O

Me H

O Ph

N Ni N Ph

N N

= bipyridine or tmeda


Attempts to use chiral diamine ligand for asymmetric synthesis of such bicyclooctene derivatives have been partially successful [179]. O

O N

for alkylative cyclization: 99:1)

Et2Zn, Ni(acac)2

OEt I

Lactones are obtained in good yield from intramolecular cyclization under similar reaction conditions [204,205]. CN Br

CHO +

CO2Me

NiBr2(dppe), Zn 80%

NC

O O n-C5H11

I

O

OH

O

+ n-C5H11

CO2Me

NiBr2(dppe), Zn

O O

80% O

O

Intramolecular alkylative cyclizations of allenes with aldehydes furnish homoallylic alcohols [206]. Tetudinariol A is synthesized by using this strategy [207]. R O H

O

X

R1

CH2

R1

Ni(COD)2 X

70% (dr>97:3)

X = CH2, R1 = Phc, R = Meb

71% (cis:trans >97:3; Z/E >97:3)

H OBn

C

C

HO

X = NTs, R1 = H, R = Mea

OMEM

H

R2Zna or RLi/ZnCl2b

Ni(COD)2, Me2Zn Ti(O-i-Pr)4 62%

OBn

H

H O

O

OMEM

H

HO

OH OH testudinariol A

The reaction of 1,3-dienes and aldehydes in the presence of Et3SiH using a catalytic amount of Ni(COD)2 and Ph3P yields regio- and stereoselectively homoallylic alcohols [208,209]. The reaction also proceeds intramolecularly to give five- to seven-membered cyclic homoallylic alcohols [210±218]. DIBAL(acac) can also be used as the reducing agent for this transformation, but gives different regioselectivity [213±215].


434

MOMO O

OSiEt3

Et3SiH

+

Ni(COD)2/PPh3 MOMO 59%

H

CO2Me

CO2Me OSiMe3 Et3SiH Ni(COD)2/PPh3 67% OMe

O

OMe OBn OH

OBn

H

DIBAL(acac)

OMe

Ni(COD)2/PPh3 75%

OBn

CO2Me O

H

O

HO CO2Me

Ni(COD)2/PPh3, DIBAL(acac) 1,3-cyclohedadiene 54%

O

O

O HO CO2H HO

OH Prostaglandin F 2α

OH O +

CO2Me

Ph

H

Et3B Ni(acac)2 91%

Ph CO2Me OH

Et2Zn CHO Ni(acac) 2 80% (syn:anti 1:>20)

+

+ O

OH

Et3B Ni(acac)2 OH 99%

MeO2C

OH

CO2Me

Ni(acac)2 n

CHO

Et3B or Et2Zn Et2Zn, n = 1 72% Et3B, n = 2 68%

n

OH

10.8 Reaction of Simple Aldehydes or Ketones with Alkynes

435

Et3B or Et2Zn behave similarly to facilitate both inter- or intra-molecular coupling reactions [219±221]. Remarkably, the reaction is effective in water and alcohols, thus allowing aqueous solutions of glutaraldehyde and cyclic hemiacetals to be used in these reactions [222]. In contrast, the intra- and intermolecular alkylative cyclizations are less studied. Several transmetallation agents lack a b-hydrogen, for instances, Me2Zn or Ph2Zn, or Grignard reagents are active participants in such catalytic couplings [223±226]. O +

99% H R = Ph R = Cyclohexyl 73%

R

Ni

O

O

R

O

OH

Ni(COD)2/PPh3 O

OH

Ni(acac)2 ,Me2Zn

MgBr O

75%

O

O

O

The use of Me3SiSnBu3 in these nickel-catalyzed coupling reactions of dienes with aldehydes results in the formation of stannylated cyclic product homoallylic alcohols. The reaction may proceed via the oxidative addition of Ni(0) into the Si± Sn bond [227]. Moderate chiral induction is observed in this reaction when a monodentate phosphine ligand is employed [228]. MeO2C MeO2C

CHO

Ni(COD)2/PMe2Ph Me3SiSnBu3 51% (1:7.5)

MeO2C MeO2C

OSiMe3 +

H

Ni(COD)2/L (EtO)3SiH L=

MeO2C MeO2C

OH

SnBu3

SnBu3

O MeO2C MeO2C

MeO2C MeO2C

OSi(OEt)3

P Ph

83% (73% ee)

Either conjugated or nonconjugated enynes also couple with aldehydes under nickel-catalyzed conditions to give the corresponding allylic alcohols [229,230].

436


n-C4H9

Me

+

Me Me

O

88% (> 95:5)

i-C3H7

H

Ni(COD)2, Et3B

i-C3H7 n-C4H9

Me

> 95 OH

3

H

OH

Me

n-C6H13

O

Me

Ni(COD)2/P(c-C5H9)3

+

3

i-C3H7

Ni(COD)2, Et3B

:

i-C3H7 + n-C6H13 5

P(c-C5H9)3

5 i-C3H7

HO 3

n-C6H13 < 95

:

10.9 Miscellaneous Reactions

In a similar manner, three-component coupling of allyl chlorides or acetates with 1-alkynes and alkynyltins in the presence of a nickel catalyst prepared in situ from Ni(acac)2 and DIBALH provides a convenient regio- and stereoselective synthesis of 3,6-dien-1-ynes [231,232]. It is interesting to note that no phosphine ligands are required in these reactions. A p-allylnickel intermediate is proposed. Me Cl

H + Me3Si

+ HO

SnBu3 HO

R1

H

Ni(acac)2/DIBALH

Me Ni Cl 2

Me3Si

In the presence of a phosphine ligand, coupling of alkynyltin with allyl chloride is obtained [233]. Cl

+ Bu

H

+ Ph

SnBu3

Ni(acac)2/DIBALH/PPh3 54%

Ph

The tandem reaction of allyl electrophiles with alkynes and Me3Al or Me2Zn occurs in the presence of Ni(acac)2 to give a regioisomeric mixture of the threecomponent coupling products [234]. The reaction can also proceed intramolecularly to give cyclic nonconjugated dienes.


X

+

R1

R2

R1

Ni(acac)2 Me2Zn or Me3Al

R2

Me

Cl MeO2C MeO2C

Ni(acac)2, Me2Zn

MeO2C MeO2C

68%

Me

Intermolecular three-component assembly of allenes, aryl iodides and alkenylzirconium reagents provided the synthesis of 1,4-dienes [235]. Both vinyl and aryl iodides are active participants for generating highly regio- and stereoselective assemblies. R1

ClCp2Zr + R1 I

NiCl2(PPh3)2, Zn

+

R

R2

R

R2

Carbostannylation of unsymmetric alkynes in the presence of Ni(COD)2 catalyst affords the corresponding coupling products [236]. The regioselectivity is strongly dependent on the nature of the substituent. Interestingly, unlike the corresponding palladium-catalyzed carbostannylation of alkynes, phosphine ligands inhibit the reaction. SnBu3 + Me3Si

CO2Et

SnBu3

Ni(COD)2 78%

Me3Si

CO2Et

In a similar manner, acylstannanes also undergo acylstannylation of alkynes under similar conditions. In addition, carbostannylation can also be achieved with alkynylstannnes regioselectively. Me Me SnBu3 + n-C3H7

H

n-C3H7

Ni(COD)2

SnBu3 H

87%

O N

Pr

Pr

O SnBu3 + n-C3H7

n-C3H7

Ni(COD)2

N

SnBu3

66% n-C3H7

Pr

CF3

CF3 SnBu3 + n-C6H13

H

Ni(COD)2 82%

SnBu3 n-C6H13

H

437

438


Ni(COD)2-catalyzed tandem carbostannylation of alkynes and allenes with alkynylstannes in the presence of a phosphine ligand results in highly chemoselective synthesis of dienyne stannanes. The stereoselectivity of the reaction depends strongly on the chelation nature of the ligands [237]. For example, when tris(4-trifluoromethylphenyl)phosphine is used, the D/E ratio is 98:2. On the other hand, when a bidentate ligand (e.g. [o-(dimethylamino)phenyl)diphenylphosphine] is employed, the D/E ratio becomes 6:94. R1

+

SnMe3

+

R2

Bu R1

R1

SnMe3

SnMe3

Ni(COD)2

+ Bu

55-67%

R2

R2

Bu

D

E

1,3-Dienes also undergo acylstannylation to furnish the corresponding coupling products [238]. O R1

SnR23

+

R3

R4

R3 Ni(COD)2

R4

R4

1

R3

1

R

R SnR23 +

O R1 = Ph, R2 = Me, R3 = Me, R4 = Me R1 = (CH2)5N, R2 = Bu, R3 = Me, R4 = Me

SnR23

O 73% 73%

n-Alkenyl trichloroacetamides undergo nickel-catalyzed cyclization to afford functionalized lactams. A radical mechanism is suggested. The reaction has been used for the synthesis of a range of naturally occurring materials [239±241]. CCl3 O N O O

O

Ni, AcOH, AcONa 60%

O H

O O O

Br

H

N

N

γ-lycorane

Br

H Cl3C Me

O N

Bn

Ni/AcOH (PhSe)2 81%

Cl2HC Me PhSe

O N N

Bn

H

H O

O (-)-dendrobine

H


Incorporation of CO2 into the product has been found in the nickel-catalyzed coupling reaction of a terminal alkyne with an organozinc reagent [242,243]. CO2Et

IZn

BnO

CO2 (1 atm)

+

CO2H CO2Et

Ni(COD)2, DBU 82%

OBn

Similarly, reaction of dienes with CO2 in the presence of Ni(COD)2 affords p-allylnickel complex. Upon treatment with Me2Zn, the corresponding dicerbonxylic acid is isolated. On the other hand, when the nickel intermediate is allowed to react with HCl, only monocarboxylation product is obtained [244]. Asymmetric induction is observed when (S)-MeO-MOP ligand is used [245,246]. Ph Ni(COD)2

Ph + CO2

Ph

DBU

O + Ni O

HCl

CO2H

Ph

Me2Zn

CO2H

+ Ph

CO2H 68%

H Ni(acac)2/PPh3 CO2 (1 atm), Me2Zn X = NTs 94% X = C(CO2Me)2 91%

CO2Me

X

Me H

H X

CO2H

Ph

77% (40:60)

X

O

Ni O

CO2Me

1. Ni(acac)2/(S)-MeOMOP

X CO2 (1 atm), R2Zn 2. CH2N2 H X = NTs, R = Ph 81% (95% ee) X = C(CO2Me)2, R = Me 100% (94% ee)

R

OMe PPh2

(S)-MeO-MOP

Reductive couplings of internal alkynes with epoxides in the presence of Ni(COD)2/Et3B/PBu3 furnish efficient synthesis of homoallylic alcohols. The reaction can occur both inter- or intramolecularly [247].

439

440


Ph +

Me O

Ni(COD)2/PBu3 Et3B

Me

Ph Me

OH

Me Ph

H X

O

Ni(COD)2/PBu3 Et3B 45-88%

OH

Ph X

X = O, NBn, CH2, C(CO2Me)2

Nickel-catalyzed reactions of 7-heteronorbornadienes and norbornenes with various organic halides give ring-opening products stereoselectively [248,249]. OH O +

MeO MeO

NiCl2(PPh3)2, Zn

Br

85%

MeO MeO

Interestingly, when alkynes are used, similar ring-opening products are obtained [250]. n-Pen

OH

O + n-Pen

NiCl2(dppe) H

ZnCl2, Zn 70%

An interesting cyclization involving 7-oxabenzonorbornadienes and alkyl propriolates in the presence of NiBr2(dppe) and Zn yields benzocoumarin derivatives with high regio- and stereoselectivity [251]. Intramolecular lactonization may also occur under these conditions [252]. O O + Me3Si

MeO MeO

CO2Et

NiBr2(dppe), Zn 66%

O MeO MeO

H SiMe3

H MeO2C

O MeO2C MeO2C

+ n-Bu

CO2Me

NiBr2(dppe), Zn

H

O

66%

CO2Me O

Bu-n


When o-iodobenzoates are used, coumarins are also conveniently obtained in satisfactory yield [253]. O O

O

I

NiBr2(dppe), Zn

+

68%

CO2Me

Me CO2Me

CO2Me Me

In the absence of alkyl halides or terminal alkynes, reductive ring opening becomes the predominant pathway [254]. CO2Me N Ni((S)-binap)I2

MeO2C

NH

84%, 80%ee

Dialkylacetylenes react with aryl iodides in the presence of nickel halides, Zn powder and pyridine to give unsymmetrical biaryls in moderate yields [255]. It is striking to note that this reaction involves the cleavage of a carbon±carbon bond. n-C3H7 I + n-C3H7

n-C3H7

NiBr2, Zn 50%

Cl

n-C3H7

n-C3H7

Cl

n-C3H7

n-C3H7

b-iodoenones react with symmetric internal akynes in the presence of NiBr2 and Zn powder to give spiro compounds in good yields [256]. The addition of Ph3P decreases the yield of annulation products. O O Me + n-C H 2 5 I

n-C2H5

NiBr2, Zn 84%

n-C2H5 n-C2H5

Me n-C2H5 n-C2H5

Conjugated dienes react with b-iodoenones in the presence of a catalytic amount of NiBr2 and Zn affords the corresponding homo-1,4-addition products in good yields [257].

441

442


O

O

O

NiBr2/PPh3, Zn

+

82%

I

The silicon±boron bond of silylborane is stereoselectively added to acyclic dienes in a 1,4-fashion to give 4-boryl-1-silyl-2-alkenes in the presence of a Ni(0) catalyst generated in situ from Ni(acac)2 and DIBAL. Sterically bulky phosphine ligands such as P(c-hex)Ph2 are essential to facilitate the stereoselectivity [258]. Ni(acac)2/DIBALH

O +

PhMe2Si B

PCyPh2 93% (cis:trans = >99:1)

O

O PhMe2Si

B O

Similar silaboration of vinylcyclopropane gives the corresponding bora-substituted allylsilanes selectively [259]. F

F O

Ni(acac)2/DIBALH, PCy3

+

PhMe2Si B O

O B

81%

O

SiMe2Ph

The transfer of boron and cyano moieties from cyanoboranes to carbon±carbon triple bond has been shown to occur intramolecularly. The reaction requires nickel catalyst, presumably via a similar pathway to that in silaboration [260]. (i-C3H7)2N O Et

B CN

Ni(COD)2 63%

(i-C3H7)2N O B

CN

Et

N,N¢-disubstituted carbodiimides are synthesized from the reaction of isocyanides with primary amines in the presence of a Ni(II) catalyst using oxygen as the oxidant [261]. Cl

Cl

NH2 + CNC(CH3)2CH2CH3 CN

N=C=NC(CH3)2CH2CH3

NiCl2, O2, Na2SO4 62% CN

References

Nickel-catalyzed hydroamination of conjugated dienes at room temperature has been shown to be an efficient synthesis of allylamines in excellent yields [262]. + HNMeBn

Ni(COD)2/DPPF, TFA 94%

NMeBn

10.10 Conclusion

Over the past two decades, the use of organonickel chemistry in organic synthesis has evolved into a new era. A wealth of fascinating work has attested to the wide popularity using this metal in organic synthesis. Not only have the traditional cross-coupling reactions reached a new stage, but also new multi-component coupling processes have provided powerful arsenal for the synthesis of complex molecules. The mechanistic insight of these reactions can pave the way to make predictions of other opportunities for new transformations and room for new inventions emanating from the present results abound. In particular, given the reactivity trends of nickel reagents or catalysts and functional-group tolerance, such a prospect provides a major impetus for continuing the use of organonickel compounds in organic synthesis.

References 1 For a review, see: Fischer, K.; Jonas, K.

Misbach, P.; Stabba, R.; Wilke, G. Angew. Chem. Int. Ed. 1974, 12, 943±953. 2 Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374±4376. 3 Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun. 1972, 144. 4 Jolly, P. W.; Wilke, G. The Organic Chemistry of Nickel, Vols 1, 2; Academic Press, New York, 1974. 5 Tetrahedron Symposia-in-Print, No 69, Lipshutz, B. H.; Luh, T.-Y., Eds. Tetrahedron 1998, 54, 1021±1316. 6 For a recent review, see: Baudoin, O.; Gueritte, F. Stud. Nat. Prod. Chem. 2003, 29, 355±417. 7 Müllen, K.; Wegner, G. Electronic Materials: The Oligomer Approach; Wiley-VCH, 1998. 8 Hassan, J.; Sevingnon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359±1469.

9 Nelson, T. D.; Crouch, R. D. Org. React.

2004, 63, 265±555.

10 Semmelhack, M. F.; Helquist, P. M.;

Jones, L. D. J. Am. Chem. Soc. 1971, 93, 5908±5910. 11 For a review, see: CaubØre, P. Angew. Chem. Int. Ed. 1983, 22, 599±613. 12 For synthetic applications of lithium naphthalide, see: Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152±161. 13 Duæach, E.; Franco, D.; Olivero, S. Eur. J. Org. Chem. 2003, 1605±1622. 14 Tomohiro, Y.; Satake, A.; Kobuke, Y. J. Org. Chem. 2001, 66, 8442±8446. 15 Kobuke, Y.; Ogawa, K. Bull. Chem. Jpn. 2003, 76, 689±708. 16 Kondo, S.; Nagamine, M.; Yano, Y. Tetrahedron Lett. 2004, 44, 8801±8804. 17 Lin, G.-Q.; Hong, R. J. Org. Chem. 2001, 66, 2877±2880. 18 Chen, C. Synlett 2000, 1490±1492. 19 Hu, Q.-S.; Zheng, X.-F.; Lin, P. J. Org. Chem. 1996, 61, 5200±5201.

443

444

10 Functional Organonickel Reagents 20 de França, K. W. R.; Navarro, M.;

LØonel, É.; Durandetti, M.; NØdØlec, J. Y. J. Org. Chem. 2002, 67, 1838±1842. 21 Raynal, F.; Barhdadi, R.; PØrichon, J.; Savall, A.; Troupel, M. Adv. Synth. Catal. 2002, 344, 45±49. 22 Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 176±185. 23 Cannes, C.; Condon, S.; Durandetti, M.; PØrichon, J.; NØdØlec, J.-Y. J. Org. Chem. 2000, 65, 4575±4583. 24 Barhdadi, R.; Courtinard, C.; NØdØlec, J. Y.; Troupel, M. Chem. Commun. 2003, 1434±1435. 25 For a review, see: Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89±103. 26 Itami, K.; Yamazaki, D.; Yoshida, J.-I. J. Am. Chem. Soc. 2004, 126, 15396±15397. 27 Stang, P. J.; Diederich, F. Cross-coupling Reactions; Wiley-VCH, 1998. 28 Miyaura, N. Cross-Coupling Reactions: A Practical Guide, Topics in Current Chemistry, Vol. 219; Springer-Verlag, 2002. 29 Beletskaya, I. P.; Cheprakovv, A. V. Comprehensive Coordination Chemistry; McCleverty, J. A.; Meyer, T. J., Eds.; Elsevier, 2003, Vol. 9, pp 305±368. 30 Tamao, K. Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Elsevier, 1991, Vol 3, pp 435±480. 31 Knight, D. W. Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Elsevier, 1991, Vol 3, pp 481±520. 32 J. Organomet. Chem. 2002, 653, 1±303. (Special Issue dedicated to the ªthirty years of cross-coupling reactionº, Tamao, K.; Hiyama, T.; Negishi, E.-I., Eds.) 33 Bonnet, V.; Mongin, F.; TrØcourt, F.; Breton, G.; Marsais, F.; Knochel, P. Synlett. 2002, 1008±1010. 34 Karlström, A. S. E.; Itami, K.; Bäckvall, J.-E. J. Org. Chem. 1999, 64, 1745±1749. 35 Böhm, V. P. W.; Weskamp, T.; Gstöttmayr, C. W. K.; Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 1602±1604. 36 Böhm, V. P. W.; Gstöttmayr, C. W. K.; Weskamp, T.; Herrmann, W. A.

Angew. Chem. Int. Ed. 2001, 40, 3387±3389. 37 Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 43±46. 38 Wenkert, E.; Ferreira, T. W. Michelotti, E. L. J. Chem. Soc., Chem. Commun. 1979, 637±638. 39 Cho, C.-H.; Kim, I.-S.; Park, K. Tetrahedron 2004, 60, 4589±4599. 40 Shimada, T.; Cho, Y.-H.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396±13397. 41 Cho, Y.-H.; Kina, A.; Shimada, T.; Hayashi, T. J. Org. Chem. 2004, 69, 3811±3823. 42 Luh, T.-Y. Acc. Chem. Res. 1991, 24, 257±263. 43 Ni, Z.-J.; Yang, P.-F.; Ng, D. K. P.; Tzeng, Y.-L.; Luh, T.-Y. J. Am. Chem. Soc. 1990, 112, 9356±9364. 44 Chen, R.-M.; Chien, K.-M.; Wong, K.-T.; Jin, B.-Y.; Luh, T.-Y.; Hsu, J.-H.; Fann, W. J. Am. Chem. Soc. 1997, 119, 11321±11322. 45 Cheng, Y.-J.; Luh, T.-Y. Chem. Eur. J. 2004, 10, 5361±5368. 46 Ng, D. K. P.; Luh, T.-Y. J. Am. Chem. Soc. 1989, 111, 9119±9121. 47 Yu, C.-C.; Ng, D. K. P.; Chen, B.-L.; Luh, T.-Y. Organometallics 1994, 13, 1487±1497. 48 Shiu, L.-L.; Yu, C. C.; Wong, K.-T.; Chen, B.-L.; Cheng, W.-L.; Yuan T.-M.; Luh, T.-Y. Organometallics 1993, 12, 1018±1020. 49 Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc. 1979, 101, 2246±2247. 50 Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49, 4894±4899. 51 Dankwardt, J. W. Angew. Chem. Int. Ed. 2004, 43, 2428±2432. 52 Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275±8319. 53 See Chapter 7. 54 Kobayashi, Y.; William, A. D.; Mizojiri, R. J. Organomet. Chem. 2002, 653, 91±97. 55 Kobayashi, Y.; Nakayama, Y.; Kumar, B. Tetrahedron Lett. 1998, 39, 6337±6340. 56 Nakayama, Y.; Kumar, B.; Kobayashi, Y. J. Org. Chem. 2000, 65, 707±715.

References 57 Jensen, A. E.; Dohle, W.; Knochel, P.

Tetrahedron 2000, 56, 4197±4201. 58 Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999, 121, 5819±5820. 59 Tucker, C. E.; de Vries, J. G. Top. Catal. 2002, 19, 111±118. 60 Wu, J.; Yang, Z. J. Org. Chem. 2001, 66, 7875±7878. 61 Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817±4830. 62 Hu, Y.; Yang, S.; Wang, J.-X.; Yin, Y. Synlett 1998, 1213±1214. 63 Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633±9695. 64 Suzuki, A.; Brown, H. C. Organic Synthesis via Boranes: Vol. 3 Suzuki Coupling; Aldrich Chemical Co., 2003. 65 Percec, V.; Bae, J.; Hill, D. H. J. Org. Chem. 1995, 60, 1060±1065. 66 Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513±3516. 67 Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetrahedron Lett. 1998, 39, 3985±3988. 68 Leadbeater, N. E.; Resouly, S. M. Tetrahedron 1999, 55, 11889±11894. 69 Griffiths, C.; Leadbeater, N. E. Tetrahedron Lett. 2000, 41, 2487±2490. 70 Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049±3051. 71 Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058±3059. 72 Saito, S.; On-tani, S.; Miyaura, N. J. Org. Chem. 1997, 162, 8024±8030. 73 Lipshutz, B. H.; Sclafani, J. A.; Blomegren, P. A. Tetrahedron 2000, 56, 2139±2144. 74 Zim,D.; Monteiro, A. L. Tetrahedron Lett. 2002, 43, 4009±4011. 75 Kobayashi, Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996, 61, 5391±5399. 76 Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 6046±6047. 77 Wenkert, E.; Han, A.-L.; Jenny, C.-J. J. Chem. Soc., Chem. Commun. 1988, 975±976. 78 Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895±6903. 79 Kaiser, F.; Schmalz, H.-G. Tetrahedron 2003, 59, 7345±7355. 80 Iyer, S.; Ramesh, C.; Ramani, A. Tetrahedron Lett. 1997, 38, 8533±8536.

81 For a review, see: Negishi, E.-I. Acc.

Chem. Res. 1982, 15, 340±348.

82 Baba, S.; Negishi, E.-I. J. Am. Chem.

Soc. 1976, 98, 6729±6731.

83 Negishi, E.-I.; Van Horn, D. E. J.

Am. Chem. Soc. 1977, 99, 3168±3170.

84 Negishi, E.-I.; Takahashi, T.; Baba, S.;

Van Horn, D. E.; Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393±2401. 85 Lipshutz, B. H.; Kim, S.-K.; Mollard, P.; Blomgren, P. A.; Stevens, K. L. Tetrahedron 1998, 54, 6999±7012. 86 Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem. 2002, 67, 1682±1684. 87 Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054±6058. 88 Klingstedt, T.; Frejd, T. Organometallics 1983, 2, 598±600. 89 Wang, J.-X.; Fu, Y.; Hu, Y. Angew. Chem. Int. Ed. 2002, 41, 2757±2760. 90 Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. Rev. 2000, 100, 3187±3204. 91 Cµrdenas D. J. Angew. Chem. Int. Ed. 2003, 42, 384±387. 92 Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222±4223. 93 Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.; Kambe, N. Adv. Synth. Catal. 2004, 346, 905±908. 94 Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340±1341. 95 Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726±14727. 96 Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788±7789. 97 Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186±11187. 98 Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 2387±2390. 99 Piber, M.; Jensen, A. E.; Rottländer, M.; Knochel, P. Org. Lett. 1999, 1, 1323±1326. 100 Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G. Knochel, P. J. Org.Chem. 1999, 64, 3544±3553. 101 Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79±85. 102 Stüdemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1997, 36, 93±95. 103 For a review, see: Luh, T.-Y. Synlett 1996, 201±208.

445

446

10 Functional Organonickel Reagents 104 Wong, K.-T.; Luh, T.-Y. J. Am. Chem. Soc.

1992, 114, 7308±7310. 105 Wong, K.-T.; Yuan, T.-M.; Wang, M. C.; Tung, H.-H.; Luh, T.-Y. J. Am. Chem. Soc. 1994, 116, 8920±8929. 106 Huang, L.-F.; Huang, C.-H.; de Meijere, A.; Luh, T.-Y. Org. Lett. 2003, 5, 4489±4491. 107 Vaupel, A.; Knochel, P. Tetrahedron Lett. 1995, 36, 231±232. 108 Vaupel, A.; Knochel, P. Tetrahedron Lett. 1994, 35, 8349±8352. 109 Stadtmüller, H.; Knochel, P. Synlett 1995, 463±464. 110 Klement, I.; Lütjens, H. Knochel, P. Tetrahedron 1995, 36, 3161±3164. 111 Vettel, S.; Vaupel, A.; Knochel, P. Tetrahedron Lett. 1995, 36, 1023±1026. 112 Stüdemann, T.; Ibrahim-Ouali, M.; Knochel, P. Tetrahedron 1998, 54, 1299±1316. 113 Stüdemann, T.; Gupta, V.; Engman, L.; Knochel, P. Tetrahedron Lett. 1997, 38, 1005±1008. 114 Noyori, R.; Ishigami, T.; Hayashi, N.; Takaya, H. J. Am. Chem. Soc. 1973, 95, 1674±1676. 115 Lautens, M.; Edwards, L. G.; Tam. W.; Lough, A. J. J. Am. Chem. Soc. 1995, 117, 10276±10291. 116 Huang, D.-J.; Cheng, C.-H. J. Organomet. Chem. 1995, 490, C1±C7. 117 Huang, D.-J.; Rayabarapu, D. K.; Li, L.-P.; Sambaiah, T.; Cheng, C.-H. Chem. Eur. J. 2000, 6, 3706±3713. 118 Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432±6434. 119 Wender, P. A.; Smith, T. E. J. Org. Chem. 1996, 61, 824±825. 120 Wender, P. A.; Smith, T. E. J. Org. Chem. 1996, 60, 2962±2963. 121 Wender, P. A.; Smith, T. E. Tetrahedron 1998, 54, 1255±1275. 122 Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843±1844. 123 Jolly, P. W. In Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: Oxford, 1982, Vol 8, pp 613±797. 124 Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678±4679. 125 Wender, P. A.; Ihle, N. C. Tetrahedron Lett. 1987, 28, 2451±2454.

126 Wender, P. A.; Nuss, J. M.; Smith, D. B.;

Suarez-Sobrino, A.; Vagberg, J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908±4909. 127 Wender, P. A.; Tebbe, M. J. Synthesis 1991, 12, 1089±1094. 128 Wender, P. A.; Ihle, N. C.; Correia, C. R. J. Am. Chem. Soc. 1988, 110, 5904±5906. 129 Wender, P. A.; Snapper, M. L. Tetrahedron Lett. 1987, 28, 2221±2224. 130 Lautens, M.; Edwards, L. G. Tetrahedron Lett. 1989, 30, 6813±6816. 131 Lautens, M.; Edwards, L. G. J. Org. Chem. 1991, 56, 3761±3763. 132 Lautens, M.; Tam, W.; Edwards, L. G. J. Chem. Soc., Perkin Trans. 1 1994, 132, 2143±2150. 133 Lautens, M.; Edwards, L. G.; Tam. W.; Lough, A. J. J. Am. Chem. Soc. 1995, 117, 10276±10291. 134 Noyori, R.; Umeda, I.; Kawauchi, K.; Takaya, H. J. Am. Chem. Soc. 1975, 97, 812±820. 135 Huang, D.-J.; Sambaiah, T.; Cheng, C.-H. New. J. Chem. 1998, 1147±1149. 136 Sambaiah, T.; Huang, D.-J.; Cheng, C.-H. J. Chem. Soc., Perkin Trans. 1, 2000, 195±203. 137 Hsiao, T.-Y.; Santhosh, K. C.; Liou, K. F.; Cheng, C.-H. J. Am. Chem. Soc. 1998, 120, 12232±12236. 138 Sambaiah, T.; Li, L.-P.; Huang, D.-J.; Lin, C.-H.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem. 1999, 64, 3663±3670. 139 Jeevanandam, A.; Korivi, R. P.; Huang, I.-W.; Cheng, C.-H. Org. Lett. 2002, 4, 807±810. 140 Shanmugasundaram, M.; Wu, M.-S.; Jeganmohan, M.; Huang, C.-W.; Cheng, C.-H. J. Org. Chem. 2002, 67, 7724±7729. 141 Shanmugasundaram, M.; Wu, M.-S.; Cheng, C.-H. Org. Lett. 2001, 3, 4233±4236. 142 Hsien, J.-C.; Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun. 2004, 532±533. 143 Louie, J.; Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. J. Am. Chem. Soc. 2002, 124, 15188±15189. 144 Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438±11439.

References 145 Saito, S.; Masuda, M.; Komagawa, S. J.

Am. Chem. Soc. 2004, 126, 10540±10541. 146 Barluenga, J.; Barrio, P.; López, L. A.; Tomµs, M.; García-Granda, S.; Alvarez-Ra, C. Angew. Chem. Int. Ed. 2003, 42, 3008±3011. 147 Ni, Y.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 11162±11163. 148 Trost, B. M.; Tour, J. M. J. Am. Chem. Soc. 1987, 109, 5268±5270. 149 Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 1286±1288. 150 Zhang, M.; Buchwald, S. L. J. Org. Chem. 1996, 61, 4498±4499. 151 Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 539±546. 152 Tamao, K.; Kobayashi, K.; Ito, Y. J. Org. Chem. 1989, 54, 3517±3519. 153 Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478±6480. 154 Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478±6480. For an intermolecular version, see: Lappert, M. F.; Nile, T. A.; Takahashi, S. J. Organomet. Chem. 1974, 72, 425±439. 155 Suginome, M.; Matsuda, T.; Ito, Y. Organometallics 1998, 17, 5233±5235. 156 For a review, see: Ikeda, S. Acc. Chem. Res. 2000, 33, 511±519. 157 Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, 5975±5976. 158 Ikeda, S.; Kondo, K.; Sato, Y. J. Org. Chem. 1996, 61, 8248±8255. 159 Ikeda, S.; kondo, K.; Sato, Y. Chem. Lett. 1999, 1227±1228. 160 Ikeda, S.; Yamamoto, H.; Kondo, K.; Sato, Y. Organometallics 1995, 14, 5015±5016. 161 Ikeda, S.; Cui, D.-M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712±4713. 162 For reviews, see: Montgomery, J. Acc. Chem. Res. 2000, 33, 467±473; Montgomery, J. Angew. Chem. Int. Ed. 2004, 43, 3890±3908. 163 Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099±2100. 164 Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911±4920. 165 Ikeda, S.; Mori, N.; Sato, Y. J. Am. Chem. Soc. 1997, 119, 4779±4780. 166 Mori, N.; Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 2722±2727.

167 Ikeda, S.; Sanuki, R.; Miyachi, H.;

168 169

170

171

172

173

174 175

176

177

178

179

180

181 182

183

Miyashita, H.; Taniguchi, M.; Odashima, K. J. Am. Chem. Soc. 2004, 126, 10331±10338. Lozanov, M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124, 2106±2107. Montgomery, J.; Chevliakov, M. V.; Brielmann, H. L. Tetrahedron 1997, 53, 16449±16462. Chevliakov, M. V.; Montgomery, J. Angew. Chem. Int. Ed. 1998, 37, 3144±3146. Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139±11143. Fornicola, R. S.; Subburaj, K.; Montgomery, J. Org. Lett. 2002, 4, 615±617. Ni, Y.; Amarasinghe, K. K. D.; Ksebati, B.; Montgomery, J. Org. Lett. 2003, 5, 3771±3773. Savchenko, A. V.; Montgomery, J. J. Org. Chem. 1996, 61, 1562±1563. Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911±4920. Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6775±6776. Amarasinghe, K. K. D.; Chowdhury, S. K.; Heeg, M. J.; Montgomery, J. Organometallics 2001, 20, 370±372. Montgomery, J.; Amarasinghe, K. K. D.; Chowdhury, S. K.; Oblinger, E.; Seo, J.; Savchenko, A. V. Pure Appl. Chem. 2002, 74, 129±133. Hratchian, H. P.; Chowdhury, S. K.; GutiØrrez-García, V. M.; Amarasinghe, K. K. D.; Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23, 4636±4646. Mahandru, G. M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2003, 125, 13481±13485. Montgomery, J.; Seo, J. Tetrahedron 1998, 54, 1131±1144. Seo, J.; Chui, H. M. P.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 476±477. Savchenko, A. V.; Montgomery, J. J. Org. Chem. 1996, 61, 1562±1563.

447

448

10 Functional Organonickel Reagents 184 Cui. D.-M.; Yamamoto, H.; Ikeda, S.;

Hatano, K.; Sato, Y. J. Org. Chem. 1998, 63, 2782±2784. 185 García-Gómez, G.; Moretó, J. M. Chem. Eur. J. 2001, 7, 1503±1509. 186 Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065±9066. 187 Qi, X.; Montgomery, J. J. Org. Chem. 1999, 64, 9310±9313. 188 Lozanov, M.; Montgomery, J. Tetrahedron Lett. 2001, 42, 3259±3261. 189 Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698±3699. 190 For the reviews, see: Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymmetry 2003, 42, 3619±3625; Ikeda, S.-I. Angew. Chem. Int. Ed. 2003, 42, 5120±5122. 191 Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221±4223. 192 Chan, T.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 11514±11515. 193 Colby, E. A.; O'Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998±999. 194 Miller, K. M.; Luanphaisarnnont, T.; Monlinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130±4131. 195 Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442±3443. 196 Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156±166. 197 Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098±6099. 198 Patel, S. J.; Jamison, T. F. Angew. Chem. Int. Ed. 2003, 42, 1364±1367. 199 Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743±1745. 200 Majumdar, K. K.; Cheng, C.-H. Org. Lett. 2000, 2, 2295±2298. 201 Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun. 2002, 942±943. 202 Rayabarapu, D. K.; Yang, C.-H.; Cheng, C.-H. J. Org. Chem. 2003, 68, 6726±6731. 203 Stüdemann, T.; Ibrahim-Ouali, M.; Cahiez, G.; Knochel, P. Synlett 1998, 143±144. 204 Rayabarapu, D. K.; Chang, H.-T.; Cheng, C.- H. Chem. Eur. J. 2004, 10, 2991±2996.

205 Rayabarapu, D. K.; Cheng, C.-H. J. Am.

Chem. Soc. 2002, 124, 5360±5361.

206 Montgomery, J.; Song, M. Org. Lett.

2002, 4, 4009±4011.

207 Amarasinghe, K. K. D.; Montgomery, J.

J. Am. Chem. Soc. 2002, 124, 9366±9367.

208 Takimoto, M.; Hiraga, Y.; Sato, Y.;

Mori, M. Tetrahedron Lett. 1998, 39, 4543±4546. 209 Loh, T.-P.; Song, H.-Y.; Zhou, Y. Org. Lett. 2002, 4, 2715±2717. 210 Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771±9772. 211 Sato, Y.; Takimoto, M.; Mori, M. Tetrahedron Lett. 1996, 37, 887±890. 212 Sato, Y.; Takanashi, T.; Hoshiba, M.; Mori, M. Tetrahedron Lett. 1998, 39, 5579±5582. 213 Sato, Y.; Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000, 122, 1624±1634. 214 Sato, Y.; Takimoto, M.; Mori, M. Chem. Pharm. Bull. 2000, 48, 1753±1760. 215 Sato, Y.; Sawaki, R.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 656±662. 216 Sato, Y.; Sawaki, R.; Mori, M. Organometallics 2001, 20, 5510±5512. 217 Sato, Y.; Saito, N.; Mori, M. Chem. Lett. 2002, 18±19. 218 Yeh, M. C. P.; Liang, J.-H.; Jiang, Y.-L.; Tsai, M.-S. Tetrahedron 2003, 59, 3409±3415. 219 Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033±4034. 220 Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew. Chem. Int. Ed. 1999, 38, 397±400. 221 Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org. Lett. 2001, 3, 2181±2183. 222 Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y. Angew. Chem. Int. Ed. 2001, 40, 3600±3602. 223 Kimura, M.; Matsuo, S.; Shibata, K.; Tamaru, Y. Angew. Chem. Int. Ed. 1999, 38, 3386±3388. 224 Kimura, M.; Shibata, K.; Koudahashi, Y.; Tamaru, Y. Tetrahedron Lett. 2000, 41, 6789±6793. 225 Shibata, K.; Kimura, M. Kojima, K.; Tanaka, S.; Tamaru, Y. J. Organomet. Chem. 2001, 624, 348±353.

References 226 Sato, Y.; Takanashi, T.; Mori, M. Organo-

metallics 1999, 18, 4891±4893. 227 Sato, Y.; Saito, N.; Mori, M. J. Am. Chem. Soc. 2000, 122, 2371±2372. 228 Sato, Y.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 9310±9317. 229 Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130±4131. 230 Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342±15343. 231 Ikeda, S.; Cui, D.-M.; Sato, Y. J. Org. Chem. 1994, 59, 6877±6878. 232 Cui. D.-M.; Tsuzuki, T.; Miyake, K.; Ikeda, S.; Sato, Y. Tetrahedron 1998, 54, 1063±1072. 233 Cui, D.-M.; Hashimoto, N.; Ikeda, S.; Sato, Y. J. Org. Chem. 1995, 60, 5752±5756. 234 Ikeda, S.; Miyashita, H.; Sato, Y. Organometallics 1998, 17, 4316±4318. 235 Wu, M.-S.; Rayabarapu, D. K.; Cheng, C.-H. J. Am. Chem. Soc. 2003, 125, 12426±12427. 236 Shirakawa, E.; Yamasaki, K.; Yosida, H.; Hiyama, T. J. Am. Chem. Soc. 1999, 121, 10221±10222. 237 Shirakawa, E.; Yamamoto, Y.; Nakao, Y.; Oda, S.; Tsuchimoto, T.; Hiyama, T. Angew. Chem. Int. Ed. 2004, 43, 3448±3451. 238 Shirakawa, E.; Nakao, Y.; Yosida, H.; Hiyama, T. J. Am. Chem. Soc. 2000, 122, 9030±9031. 239 Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 8995±8998. 240 Cassayre, J.; Zard, S. Z. Synlett 1999, 501±503. 241 Cassayre, J.; Zard, S. Z. J. Organomet. Chem. 2001, 624, 316±326. 242 Takimoto, M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3, 3345±3347. 243 Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2002, 4, 2323±2325. 244 Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2001, 123, 2895±2896.

245 Takimoto, M.; Mori, M. J. Am. Chem.

Soc. 2002, 124, 10008±10009.

246 Takimoto, M.; Nakamura, Y.; Kimura, K.;

247 248

249

250

251

252 253

254

255 256 257

258

259

260

261 262

Mori, M. J. Am. Chem. Soc. 2004, 126, 5956±5957. Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076±8077. For a review, see: Rayabarapu, D. K.; Cheng, C.-H. Pure Appl. Chem. 2002, 74, 69±75. Feng, C.-C.; Nadi, M.; Sambaiah, T.; Cheng, C.-H. J. Org. Chem. 1999, 64, 3538±3543. Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H. Org. Lett. 2002, 4, 1679±1682. Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem. Int. Ed. 2001, 40, 1286±1288. Rayabarapu, D. K.; Cheng, C.-H. Chem. Eur. J. 2003, 9, 3164±3169. Rayabarapu, D. K.; Shukla, P.; Cheng, C.-H. Org. Lett. 2003, 5,4903±4906. Li, L.-P.; Rayabarapu, D. K.; Nandi, M.; Cheng, C.-H. Org. Lett. 2003, 5, 1621±1624. Kong, K.-C.; Cheng, C.-H. J. Chem. Soc., Chem. Commun. 1991, 423±424. Kong, K.-C.; Cheng, C.-H. Organometallics, 1992, 11, 1972±1975. Jou, D.-C.; Hsiao, T.-Y.; Wu, M.-Y.; Kong, K.-C.; Cheng, C.-H. Tetrahedron 1998, 1041±1052. Suginome, M.; Matsuda, T.; Yoshimoto, T.; Ito, Y. Org. Lett. 1999, 1, 1567±1569. Suginome, M.; Matsuda, T.; Yoshimoto, T.; Ito, Y. Organometallics 2002, 21, 1537±1539. Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem. Soc. 2003, 125, 6358±6359. Kiyoi, T.; Seko, N.; Yoshino, K.; Ito, Y. J. Org. Chem. 1993, 58, 5118±5120. Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669±3679.

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451

11 Polyfunctional Metal Carbenes for Organic Synthesis Karl Heinz Dötz, Alexander Koch, and Martin Werner 11.1 Introduction

Since the discovery of the first metal carbene complex by Fischer and Maasböl in 1964, the applications of transition-metal carbenes have been developed into a powerful toolbox in the hand of synthetic working chemists. Their impressive synthetical potential, based on the strongly electrophilic carbene atom, the a-CHacidity of an alkylcarbene substituent and the template properties of a low-valent metal center, allowed for the development of a broad variety of transformations that ± in part ± are unprecedented in classical organic chemistry. In particular, the metal-carbene fragment LnM=C turned out to be a versatile functionality that, beyond the isolobal analogy with the carbonyl group O=C, may be involved in reaction patterns characteristic for and restricted to organometallic processes. In addition, a proper selection and control of the reaction conditions can be applied to secure C±C bond formation with high chemo-, regio- and diastereoselectivity. In this chapter, we present an overview of organometallic transformations of Fischer-type carbene complexes relevant to organic synthesis with a specific focus on chromium carbenes bearing multiple functionalities.

11.2 Chromium-Templated Cycloaddition Reactions

The group 6 Fischer carbene complexes are attractive reagents for the synthesis of carbocycles and heterocycles [1]. Chromium carbenes are versatile starting materials for cycloaddition and cyclization reactions affording small- and medium-sized rings ranging from three- [2] and four-membered [3] rings up to seven- [4] and eight-membered [5] rings; also larger ring systems are available [6]. While some types of reactions are restricted to the carbene ligand exploiting the metal-carbene unit as an activating organometallic functional group, the majority of processes directly involves the metal as a template in stepwise C±C bond formation. Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

452

11 Polyfunctional Metal Carbenes for Organic Synthesis

Since two excellent recent reviews on the synthetic potential of unsaturated metal carbenes are available [7] this chapter will focus on illustrative examples highlighting cyclopropanation and benzannulation reactions [8] as well as cyclization reactions of metal carbenes bearing oligoene and oligoyne functionalities, respectively. 11.2.1 Cyclopropanation

Alkyl-, aryl- and alkenylalkoxycarbene complexes are suitable carbene transfer reagents for the cyclopropanation of a variety of alkenes [9]. Steric hindrance in the alkene caused either by the number or the size of substituents may be a limitation of the cyclopropanation reaction [9c]; moreover, insertion of the carbene ligand into an olefinic C±H bond may be observed as a side reaction [9,10]. The mechanism proposed for the cyclopropanation differs with the electronic balance. Electron-poor alkenes generally require higher temperatures and are involved in a mechanism characterized by primary decarbonylation followed by coordination of the alkene, generation of a metallacyclobutane 1 and reductive elimination to give cyclopropane derivatives 3 (Scheme 11.1) [11]. Cyclopropanation of electron-rich alkenes starts with their addition to the electrophilic carbene carbon atom forming a zwitterionic intermediate 2 which undergoes ring closure R

R

OMe OMe

(CO)4M

1

(CO)5M

OMe

(CO)5M 1

R(R )

2

Z

R

X +

1 2

2

X

Z

R

50ºC 10 atm CO

65-100ºC

R OMe

R

2 Z R 37-89 %

1

OMe

X 33-80 %

3

4 M=Cr, Mo, W R=alkyl, aryl, alkenyl 1 R =aryl, alkenyl

2

I

R =H, alkenyl, aryl, COOR I Z=COOR , CONMe2, CN, SO2Ph I PO(OMe)2, CH=NR I I I X=OR , OSiR 3, NR 2

Scheme 11.1 Different mechanisms for the cyclopropanation of electron-poor and electron-rich alkenes.


to the cyclopropanation product 4 [12]. These reactions proceed under slightly milder thermal conditions; the intermolecular versions often have to be performed under CO pressure to avoid competing olefin metathesis [13]. The cyclopropanation of electron-poor olefins generally proceeds with low diastereoselectivity, and often leads to equimolar mixtures of cis- and trans-isomers; conjugated systems, either in the carbene ligand or the olefin, allow for better diastereoselectivities (Scheme 11.2) [14]. Ph OMe

80ºC

+ (CO)5Cr

CO2Me

Ph

OMe +

OTBS

OMe

81% 60% de

CO2Me

25ºC 100 atm CO

MeO

49% >90% de

(CO)5Cr

OTBS

Scheme 11.2 Diastereoselective cyclopropanation of electron-poor and electron-rich alkenes. I

NR 2 (CO)5M R +

+

Z THF 100ºC

R

2

toluene 111ºC I R 2N R

N R

2

R Z

42-67% 24-54% de

30-70% 30->95% de

M= Mo, W

M= Cr I

NR 2=N(alkyl)2 I

N

NR 2=

R= COOR

1

1

R = Me, t-Bu 2

R = alkyl, alkenyl, Ph R= Ph, Me Z= CO2Me, CN

Scheme 11.3 Cyclopropanation with aminocarbene complexes.

453

454


Reaction of aminocarbene complexes with electron-deficient olefins typically involves a formal Csp2H-insertion of the carbene carbon atom and affords acyclic products. More electrophilic pyrrol-derived aminocarbene complexes, however, effect cyclopropanation [15]. A recently reported example involves the cyclopropanation of simple alkenes with aminocarbene complexes (Scheme 11.3) [16]. Catalytic cyclopropanation of electron-rich olefins has been realized by dia2 zoalkanes 5 in the presence of catalytic amounts of pentacarbonyl(g -cis-cyclooctene)chromium [2b,17]. Conjugated ene-yne ketones 7 afford cyclopropanation products when reacted with alkyl- and donor-substituted olefins in the presence of catalytic amounts of the pentacarbonylchromium tetrahydrofuran complex [18]. Nonheteroatom-stabilized carbene complex intermediates 6 and 8 are involved in both cases (Scheme 11.4).

(CO)5Cr

OEt

+

2 mol%

N2

OEt

CH2Cl2, 20ºC

93% 5

Cr(CO)5 6 Ph

Ph O

Et

(CO)5Cr(THF) 5 mol%

+

O Et Et

Et THF, 20ºC

7

93% Ph O Cr(CO)5 8

Scheme 11.4 Catalytic cyclopropanation reactions.


The more electron-rich double bond of diene 10 undergoes a regioselective cyclopropanation upon reaction with methoxy(phenyl)carbene complex 9; the vinylcyclopropane 11 is formed in a diastereoselective manner (Scheme 11.5) [19]. Ph OMe

OMe

+ Me Ph

(CO)5Cr

CO2Me

9

79% 80% de

Me

CO2Me

10

11

Scheme 11.5 Regio- and diastereoselective cyclopropanation reactions.

11.2.2 Benzannulation

The thermal [3+2+1]benzannulation reaction of a,b-unsaturated alkenyl- or arylcarbene complexes with alkynes represents the unique and most synthetically valuable reaction of chromium carbenes [20]. A variety of densely substituted benzenoid compounds is accessible by this Cr(CO)3-templated one-pot cyclization reaction. Experimental and theoretical studies support a stepwise C±C bond formation according to a mechanism (Scheme 11.6) that starts with a reversible decarbonylaRS Cr(CO)5

Cr(CO)4

∆

-CO

X

X RS

X

RL Cr(CO)4

RL

CO

C

B

A

X

X

RS

RS

X

RS

RL

RL C

Cr(CO)3

RL [Cr]

Cr(CO)3

O

H O

E

F

(E)-D or

X

[Cr]

RS X

RL

RL RS

Cr(CO)3 OH G

(Z)-D [Cr]= Cr(CO)4

Scheme 11.6 Suggested mechanism of the benzannulation reaction.

455

456


tion from the pentacarbonyl carbene complex A [21]; it represents the rate-determining step of the overall reaction and is routinely effected by mild thermal conditions (55 C), but can also be induced photochemically [22], sonochemically [23] ± or microwave assisted [24]. It generates a coordinatively unsaturated 16 e tetracarbonyl carbene complex B that is subsequently trapped by the alkyne to give complex C; this intermediate undergoes insertion of the alkyne into the chromium± carbene bond to afford intermediate D that may be described as either an E- or 1 3 Z-r,p-allylidene or a (g :g )-vinylcarbene complex. Intermediate D has two options to proceed [25]: CO insertion into the chromium±carbene bond of the E-isomer 4 4 leads to g -vinylketene E that undergoes electrocyclization to g -cyclohexadienone F [26] and ± after tautomerization ± produces Cr(CO)3-coordinated phenol derivative G as the final benzannulation product. The alkyne incorporation occurs regioselectively provided both alkyne substituents differ considerably in their steric demands that is generally true for terminal alkynes. Chiral starting materials offer a diastereoselective version producing enantioenriched planar chiral benzannulation products. Chiral arene chromium complexes are attractive reagents for stereoselective synthesis but the conventional methods to obtain them in optically pure form are tedious [27]. The chiral information can be introduced in the alkyne side chain as demonstrated for bulky a-chiral propargylic ethers 13 that result in very high diastereoselectivities for the annulation of chromium alkenylcarbene 12 (Scheme 11.7) [28]. TBDMSO OCPh3 CH Cl , 60ºC Me 2 2

OMe + Me

(CO)5Cr

12

Me

13

TBDMSCl NEt(i Pr)2

OCPh3 Me Cr(CO)3

OMe 14

Scheme 11.7 Diastereoselective benzannulation with propargylic ethers.

In a more general and attractive alternative readily available chiral alcohol auxiliaries such as (+)- or (±)-menthol have been incorporated into the carbene ligand. Benzannulation of chromium carbene 15 afforded arene complexes 16 and 17 (d.e. 81%) that have been diastereopurified by chromatography and characterized by X-ray analysis (Scheme 11.8) [29]. Due to its chemo- and regioselectivity, tolerance of functional groups and mild conditions the benzannulation reaction has been applied as a key step in the total synthesis of various natural products such as vitamins, antibiotics and steroids. The concept of central-to-axial chirality transfer is demonstrated in the benzannulation of carbene complex 18 with 1-pentyne (Scheme 11.9) [30] that affords configurationally stable allocolchicin derivatives like 19 as a single diastereomer bearing a functionalized C ring. Modification of both oxygen functionalities at C-8 and C-11 (see 19) and the choice of the alkyne component used in the benzannulation allow for a flexible substitution pattern at positions C-8 through C-11 of the allocolchicin C ring.


O (CO)5Cr Ph 1) t Bu t BuOMe, 55ºC

15

2) TBDMSCl, NEt3, rt 55%

OTBDMS

OTBDMS

t Bu

t Bu Cr(CO)3

Cr(CO)3 *

*

OR

OR

16

17

10

:

1

*

R = (-)-menthyl Scheme 11.8 Diastereoselective benzannulation with (+)- or (±)-menthyloxycarbene complexes.

MeO OMe

Cr(CO)5

n-Pr 1) 1-pentyne, C6H6

MeO MeO

2) air

MeO

Ot-Bu MeO

50% 100% de

OH

MeO

Ot-Bu MeO

18

19

Scheme 11.9 Diastereoselective benzannulation to configurationally stable allocolchicin derivatives.

Complementary synthetic strategies based on benzannulation have been conceived for the aglycon synthesis of anthracyclines, a class of clinical antitumor drugs bearing adjacent hydroquinone and quinone rings B and C. Two similar synthetic routes to 11-deoxydaunomycinone 20 aim at the construction of ring C via benzannulation of chromium anisylcarbenes 23 or 24 by propargylic cyclohexane derivatives 25 or 26 (Scheme 11.10) [31]. The use of metal carbene chelate 23 allows separation of the rate-determining decarbonylation from the C±C bondforming steps that secures better yields and milder conditions.

457

458


O

OH

O OMe

+

C

D

O

A O

Cr(CO)4

MeO

O

O

OMe OMe 21

23

25

O

D

C

OMe O

O

B

A

OH

OH

Me OH

20

D

O

O

OH

Me

Me

C

A CO2Me

OMe OMe 22

OMe + MeO

Cr(CO)5 24

CO2Me 26

Scheme 11.10 Diastereoselective C-ring benzannulation to 11-deoxydaunomycinone.

Even highly complex targets can be addressed by the benzannulation strategy. The regiospecific intermolecular benzannulation of chromium carbene 27 with the highly functionalized alkyne 28 has been applied to the construction of the B ring in the final stage of the antitumor antibiotic fredericamycin 30 (Scheme 11.11) [32]. The benzannulation product 29 is formed as a single regioisomer and a 3:1 mixture of diastereomers. The regioselectivity results from the dominating sterical demand of the a-branched alkyne side chain in 28 that is placed next to the phenolic group. In the presence of an excess of small alkynes the typical [3+2+1]benzannulation has to compete with a [2+2+1+1] (two-alkyne) annulation resulting from two consecutive alkyne insertion steps. The selectivity for this variant is increased for an intramolecular reaction. Diynyl-arylcarbene complexes 31 and 32, in which the carbene moiety is tethered by an appropriate spacer to two alkyne functionalities, are formed in a chemoselective Diels±Alder reaction of the more electron-deficient CºC bond in the triyne carbene precursor complexes 35 and 36 with Danishefsky's diene; a final thermal two-alkyne annulation affords the steroid skeleton 33. The sequence can be performed as a one-pot procedure in yields of 30%


OTBDMS O

O

OMe

MeO

Cr(CO)5

+ RO

O

BnO

O

EtO 27

O

N 28

O

OMe OTBDMS

MeO B O

O

OH

OR BnO EtO

N

29

O

OH

A

B

O

OH

O

MeO D

C

E

O HO

F O

N H

30 Scheme 11.11 Diastereoselective B-ring benzannulation to fredericamycin.

and 51% depending on the nature of the metal (chromium or tungsten) used and offers a novel strategy in steroid synthesis (Scheme 11.12) [33]. o-Quinone and o-hydroquinone skeletons are accessible via a photoinduced reaction of a,b,c,d-unsaturated carbene complexes along which the formation of ketene intermediates is favored under a carbon monoxide atmosphere [34]. This protocol has been applied to the synthesis of the lipid peroxidation inhibitor carbazoquinocin C via carbonylative annulation of chromium pyrrylcarbene 37. The

459

460


(CO)5M

OTBDMS

Me OMe

A OMe

C6H6, 19h

+

TBDMSO M= Cr: 31 M= W: 32

(CO)5Cr Me

OMe

Cr: 110ºC W: 75ºC

Me HO C A

D

B

TBDMSO M= Cr: 35 M= W: 36

M= Cr: 33 (30%) M= W: 34 (51%)

Scheme 11.12 [2+2+1+1] (Two-alkyne) annulation towards the steroid skeleton.

resulting carbazole 38 is converted into the carbazoquinocin C 39 in a two-step oxidation/deprotection procedure (Scheme 11.13) [35]. MeO

n-hept N

OH

MeO

Cr(CO)5

Me

hν, CO THF 65%

Me

N

Bn

Bn

37

38

n-hept

72% two steps

O

O

Me N

n-hept

H 39 Scheme 11.13 Photoinduced ortho-benzannulation towards carbazoquinocin C.


11.2.3 Cyclization of Chromium Oligoene(-yne) Carbenes

Metal carbonyl carbene fragments are potent electron acceptors and as such effectively promote [n+2]cycloaddition reactions of vinyl- and alkynylcarbene complexes. Typical examples of regioselective [2+2] and [4+2]cycloaddition reactions are depicted in Schemes 11.14 [36a, b] and 11.15 [36c]. OEt (CO)5Cr

(CO)5Cr

Ph +

OSiMe3

35ºC, 4h Et2O 57%

OEt

Me3SiO Ph

Scheme 11.14 Regioselective [2+2]cycloaddition reaction of alkynylcarbene complexes.

OMe

OMe

(CO)5Cr

(CO)5Cr + SiMe3

Me3SiO

25ºC, 24h Et2O

SiMe3

OSiMe3

Scheme 11.15 Regioselective [4+2]cycloaddition reaction of alkynylcarbene complexes.

The [3+2]cycloaddition of metal alkenylcarbenes with 1,3-dipoles is generally regioselective but produces diastereomeric mixtures of cycloadducts. This problem has been overcome by incorporating 8-phenylmenthol as a chiral auxiliary into a,b-unsaturated carbene complexes; their reaction with diazoalkanes results in the formation of single pyrazoline diastereomers [37]. This concept has been successfully extended to other types of 1,3-dipoles and their reaction with chiral carbene complexes. The one-pot reaction of the chromium (±)-menthyloxycarbene 40 with nitrilimine 41 generated in situ affords a single diastereomer of 2 D -pyrazoline ester 42 after oxidative work-up; neither regioisomer 43 nor its diastereomer could be detected (Scheme 11.16) [38]. In terms of both regio- and diastereoselectivity metal alkoxycarbenes are superior to their isolobal ester analogs as demonstrated by the cycloaddition of the (±)-8phenylmenthol-derived chromium carbene 44 with nitrilimine 41 (Scheme 2 11.17). Whereas complex 44 affords a 55% yield of D -pyrazoline ester 45a/b in a 92:8 mixture of diastereomers, its cinnamate congener 47 produces a 38:62 ratio of regioisomers 45 and 46, although in quantitative yield, as diastereomeric mixtures (d.r. = 32:68 for 45a/b and 71:29 for 46a/b). The regio- and diastereoselective [3+2]cycloaddition of azomethine ylide 49 generated in situ with (±)-8-phenylmenthol-derived carbene complex 48 has been applied to the total synthesis of phosphodiesterase inhibitor (+)-rolipram 51

461

462

11 Polyfunctional Metal Carbenes for Organic Synthesis *

OR

OR

*

O

(CO)5Cr

+ [R2C=N=N-Ph]

R

73% d.r. >95:5

1

R

N

Ph

N

R

2

42

41

40

1

*

OR (CO)5Cr

Ph

R

1

N

2

N

R

*

RO R

1

O

*

R OH = (±)-menthol Ph

N

2

N

R

43 Scheme 11.16 Diastereoselective [3+2]cycloaddition with (±)-menthyloxycarbene complexes.

*

*

O

(CO)5Cr 44

OR

OR

*

OR

Ph

R N

Ph

N

1

O

R N

Ph

Ph

N

+

[R C=N=N-Ph]

*

*

41

RO

RO R

*

Ph

45b

45a 2

OR

1

1

O

1

O

R

O 47

Ph

Ph

N N

Ph

46a

Ph

N N

Ph

46b

*

R OH = (-)-8-phenylmenthol Scheme 11.17 Diastereoselective [3+2]cycloaddition reactions of chromium styrylcarbene 44 and its isolobal cinnamate analog 47.

(Scheme 11.18) [39]. The five-step sequence (cycloaddition, oxidation, ester hydrolysis, carbonyl deprotection, decarboxylation) required for the transformation of chromium carbene chelate 50 into the benzyl-protected rolipram precursor has been performed without isolation of any intermediates; after the final debenzylation (+)-rolipram 51 is obtained in low overall yield.


OR

*

OMe

(CO)5Cr

OR

S

(CO)4Cr

S +

O

OMe

48

*

Ph

O S

N CH2 58% d.r. >95:5

S

N Ph

49

50

*

R OH = (-)-8-phenylmenthol

OMe O

O

N H 51

Scheme 11.18 Regio- and diastereoselective [3+2]cycloaddition to (+)-rolipram.

A remarkable solvent effect has been observed in the addition of enolates to vinyl metal carbenes. The diastereoselectivity of the cyclopentannulation of chromium carbene 52 by methyl ketone enolate can be controlled by the coordinating abilities of the solvent used for the reaction (Scheme 11.19) [40]. Strongly coordinating solvents like THF or cosolvents such as N,N,N¢,N¢,N²-pentamethyldiethylentriamine (PMDTA) favor the formation of cis-isomer 55, whereas less-coordinating solvents like Et2O give its diastereomer 57. This outcome can be rationalized in terms of a primary 1,2-addition of the enolate to the carbene carbon atom. Cyclization of the intermediates 54 and 56 followed by demetallation and decoordination results in the final cyclopentene diastereomers 55 and 57. The transstereochemistry in 57 may reflect a closed transition state arising from chelation of the lithium cation. The substitution pattern in the enolate is crucial for the ring size of the cyclization product. Upon reaction with carbene complex 58 b-substituted lithium eno2 lates 59a (R ¹ H) lead to densely substituted cyclopentanols 60 suggesting a 2 [2+2+1]cycloaddition pathway. b-Unsubstituted lithium enolates 59b (R = H), however, form 1,3,3,5-tetrasubstituted cyclohexane-1,4-diols 61 that indicates a [2+2+1+1] sequence [41]. The branching point in the mechanism seems to be intermediate B formed upon addition of the allyl magnesium bromide to pentacarbonylchromate intermediate A. Intermediate B formed from b-substituted enolates 59a is supposed to undergo an intramolecular carbometallation reaction to give cyclopentanol derivative 60. In contrast, intermediate B originating from

463

464


b-unsubstituted enolates 59b, is prone to migratory insertion of a carbon monoxide to yield acyl tetracarbonylchromate D as a putative precursor of exo-methylene-cyclohexane-1,4-diol 61 (Scheme 11.20) [42]. Li

OLi

O

[M]

R

R H

[M]

MeO

OMe O

MeO

O

O

R OH

H 55

54 THF

OMe OLi +

(CO)5Cr

R

O 52

53 Et2O

[M] MeO

O

MeO

OLi H

[M]

O Li

OMe

R H R

O

H

O 56

OH R

57

Scheme 11.19 Solvent effects on the diastereoselectivity of the cyclopentannulation of carbene complex 52.

An unexpected versatile chemistry arises from the reaction of b-aminovinylcarbene complexes 62 with alkynes to give highly substituted 3-ethoxycyclopentadienes 63 which represent ªmasked cyclopentenonesº. They undergo ready hydrolysis to functionalized cyclopentenones 64, versatile building blocks for a variety of fused five-membered rings (Scheme 11.21) [43]. Bicyclo[3.3.0]oct-2-en-4-ones 68 and 8-azabicyclo[3.3.0]octenones 69 are formed via intramolecular aldol reaction of dicarbonyl compounds, derived from cyclopentenones 64 containing an acetal1 protected aldehyde or ketone carbonyl group in the substitutent R or R , respectively [44]. 1 Cyclopentenone 64 bearing a carbonyl group in the substitutent R may serve for the synthesis of the angularly fused triquinane skeleton 66 based on a double Michael addition to the cyclopentadienone generated via base-promoted elimination of the dialkylamine [45]. Spiro[4.4]nonenone 65 appears as the relevant intermediate from the first Michael addition. Biscyclopentannulated cyclobutane 67


OLi

OMe

2

+ (CO)5Cr

R

R 2

1

R = H : 59a 2

R = H: 59b

R 58

[2+2+1+1]

[2+2+1]

1

R OH

MgBr

R

R

1

OH H

2

R OMe

MeO R

OH 61

60 HCl

HCl

1

R OH

O R

R

(CO)5Cr Li

1

OMgBr 2

R

1

(CO)5Cr

O R Me

R

2

R

2

R OMe

R OMe O

Li A

Li F

C

R

1

OMgBr

1

OMgBr

R

2

R

(CO)4Cr (CO)5Cr B

R OMe

R

1

OMgBr 2

R

2

Li

O D

R OMe

R (CO)4Cr OLi

R OMe

E

Scheme 11.20 Competition of [2+2+1]- vs. [2+2+1+1]cycloaddition.

results from a [2+2]cyclodimerization of a cyclopentadiene intermediate originating from 64 via N-quaternization and subsequent Hofmann elimination [43]. A unique spirocyclization connecting chromium b-silyl-aminovinylcarbene 70 and 3 equivalents of alkyne afforded spiro[4.4]nonatrienes 71 and 72. The formal [3+2+2+2]cyclization putatively involves an unprecedented triple alkyne insertion (Scheme 11.22) [46].

465

466

11 Polyfunctional Metal Carbenes for Organic Synthesis 2

OR

NR2

(CO)5Cr 62

R

+ RL

1

RS

1

RL

R NR2

RS OR 63

2

O R

N

1

RL

OH

RS 69

Me2N RL

R NR2

RS O 64

O

RL=RS=Ph

OH

66

O

O

R RL

RS

1

RL

RL

RL

O 68

Ph

Ph RS O

H H 67

O

O 65

Scheme 11.21 ªMasked cyclopentenoneº-precursors 63 for versatile building blocks.

OEt (CO)5Cr 70

Ar H EtO

Ar EtO

H

NMe2 H

Ar

Ar H

Ar

+

SiMe3

+ H

NMe2

Ar 71

Scheme 11.22 [3+2+2+2]Cycloaddition to spiro[4.4]nonatrienes.

NMe2 Ar 72

11.3 Reactions of Higher Nuclearity Chromium and Tungsten Carbenes


Metal carbene centers may be connected via either the carbon or the heteroatom carbene chain [47]. The first example of a homodimetallic biscarbene complex has been synthesized by trapping a metal carbene anion ± generated in situ by a-deprotonation of chromium oxacyclopentylidene 73 ± by its exo-methylene congener 74 formed upon the addition of the same chromium carbene anion to formaldehyde in a Michael-type addition reaction [48]. A more satisfactory yield of bischromium biscarbene 75 has been obtained by using the formaldehyde equivalent ClCH2OCH3 as source of the C1-bridge and LiI (Scheme 11.23). O

O

1) n BuLi

(CO)5Cr

(CO)5Cr 2) HCHO/H2O MeOH

73

O + (CO)5Cr

74

Cr(CO)5

(CO)5Cr 1) n BuLi, LiI

O

O

2) 0.5 eq. ClCH2OMe

75

Scheme 11.23 Synthesis of bimetallic biscarbenes via Michael addition.

This strategy can be extended to more functionalized metal carbenes as demonstrated for psicosecarbene complexes 76 and 77. The chiral information in the carbohydrate moieties allows for a pronounced diastereoselectivity for the biscarbene complex formation: Single C2-symmetrical (R,R)-diastereomers of mono- and bistungsten complexes 79 and 80 are isolated from reactions in THF at ±78 C in moderate yields whereas bischromium analog 78 is obtained as a 2:1 mixture of (R,R)- and (R,S)-diastereomers (Scheme 11.24) [49]. O O

O

O

1) n BuLi -78ºC, THF

O

2)

O O

O O O

O

O

(CO)5M1

O O O

M1(CO)5

M2(CO)5

76a: M1 = Cr 76b: M1 = W

2

77a: M = Cr 2 77b: M = W

M1 78 Cr 79 W 80 W

M2 Cr Cr W

R/R R/S 22 % 10 % 32 % 38 % -

O O

(CO)5M2

R

O

R/S

O O O

O O 78 - 80

O

Scheme 11.24 Diastereoselective coupling of sugar metal carbenes.

467

468


Enantiomerically pure chromium biscarbenes have been prepared from (R)and (S)-BINOL precursors that have been subjected to bis-ortho-lithiation and subsequent addition to hexacarbonyl chromium and alkylation to give a 50% overall yield of enantiopure bischromium complex 81 (Scheme 11.25) [50]. Cr(CO)5 OMe

OMe

1) t BuLi 2) Cr(CO)6 3) Me3OBF4

OMe

OMe

50 %

OMe OMe Cr(CO)5

81

Scheme 11.25 Bischromium carbene functionalization of BINOL derivatives.

Bidirectional benzannulation of bischromium complex 81 with alkynes proceeds in a bisangular fashion to give ± after oxidative work-up ± enantiopure bisphenanthrene quinones 82 and 83 that undergo further cyclization upon subsequent ether cleavage by TMSI to afford [5]oxahelicene 84 (Scheme 11.26) [51]. The bidirectional benzannulation concept may be also applied to the extension of heterohelicenes. Bischromium complexes 87 and 88 accessible from their bisbromo precursors 85 and 86 via the Fischer methodology undergo annulation with terminal and internal alkynes and afford bisquinones 89±95 after oxidative workup (Scheme 11.27) [52]. This type of reaction reveals rare cases of competition of angular and linear benzannulation: While internal alkynes prefer a bisangular annulation, an angular-linear annulation mode is favored by terminal alkynes bearing sterically demanding groups next to the CºC bond. R1 Cr(CO)5 OMe OMe 1)R1 OMe 2) CAN

Cr(CO)5

O

Et O

O OMe TMSI OMe for 83

R2

OMe (R)-81

Et R2

O

O O

O R2

O 1

R 82 R1 = H, R2 = n Bu (36 %) 83 R1 = R2 = Et (56 %)

Scheme 11.26 Bidirectional benzannulation of BINOLderived chromium biscarbenes to enantiopure bisphenanthrene quinones and [5]oxahelicenes.

O

Et Et 84 (36 %)


Br

1) n BuLi 2) Cr(CO)6 3) Me3OBF4

O X

Br

(CO)5Cr

48 %

O

O OMe OMe

X O

(CO)5Cr

85: X = Si-tBu2 86: X = CPh2

87, 88 1

R2

1) R

13 - 39 %

2) CAN

O

O

R1

R2

O 1 R R 1

O O

R2 X

R2

or

R2 O

O

R1 O

X

O O

O O 89 90 91 92

R1 = Et R1 = Et R1 = n Pr R1 = Oct

R2 = Et R2 = Et R2 = H R2 = H

X = Sit Bu2 X = CPh2 X = CPh2 X = CPh2

93 R1 = t Bu R2 = H X = Sit B u2 94 R1 = n Pr R2 = H X = Sit Bu2 95 R1 = t Bu R2 = H X = CPh2

Scheme 11.27 Bisquinone functionalization of heterohelicenes via bidirectional benzannulation: Bisangular versus angular-linear annulation.

Double benzannulation can be applied to the diastereoselective synthesis of biaryls. Upon reaction with diphenylbutadiyne the biscarbene complex 96 bearing a C2-symmetric (2R,3R)-butane-2,3-diol bridge affords a single R,R,S-diastereomer of the tethered 2,2¢-binaphthol 97 in moderate yield (Scheme 11.28) [53]. Ph HO

(CO)5Cr

O

O

Cr(CO)5 Ph

O

Ph THF, 75ºC 23 %

96

OH

Ph

O

H

H 97

Scheme 11.28 Diastereoselective biaryl synthesis via double benzannulation.

469

470


Cyclophane skeletons bearing two or four metal vinylcarbene moieties are accessible via a multiple 1,4-addition of diamines to a,b-unsaturated biscarbene complexes. Room-temperature double 1,4-addition of diamines 100±102 to chromium biscarbene 98 generated from 1,3-diethynylbenzene gave bimetallic complexes 105±107 as single isomers in good to excellent yields. Chromium and tungsten biscarbenes 98 and 99 react with 2 equivalents of linear aromatic diamines 103 and 104 to afford bisenaminocarbene complexes 108±111 that upon addition of another equivalent of metal biscarbene undergo a double Michael addition to cyclophane-type homo- and heterometallic tetrakiscarbene complexes 112±116 (Scheme 11.29) [54]. OEt

OEt 1) n BuLi 2) Cr(CO)6 3) Et3OBF4

(CO)5M

M(CO)5

98 M = Cr (26 %) 99 M = W (yield not reported) CH2Cl2 r.t.

A = 1,4-phenyl B = 4,4´-biphenyl C = (CH2)3

(CO)5M1

103 X = A H2N X NH2 104 X = B 68 - 100 %

M2(CO)5

M = Cr NH2 100 X = A X 101 X = B 53 - 100 % 102 X = C

H2N

(CO)5Cr

(CO)5M

OEt EtO

OEt

N X H

N X NH2 H

N H

OEt H N

98 or 99

N X H

X

THF r.t. 41 - 75 %

N H

OEt EtO (CO)5M1 112 113 114 115 116

N H

N X NH2 H

OEt

OEt M2(CO)5

M1 = M2 = Cr, X = A M1 = M2 = W, X = A M = Cr, M2 = W, X = A M1 = M2 = Cr, X = B M1 = M2 = W, X = B

(CO)5Cr

(CO)5M 108 109 110 111

M = Cr, X = A M = W, X = A M = Cr, X = B M = W, X = B

105 X = A 106 X = B 107 X = C

Scheme 11.29 Ambient temperature 1,4-addition of diamines to metal bisalkynylbiscarbenes as a strategy to bis- and tetrakis metal carbene functionalized cyclophanes.

The addition of amines to a,b-unsaturated alkoxycarbene complexes is temperature dependent. At low temperature (±78 C) 1,4-addition (Michael addition) is overruled by direct addition of the amine at the carbene carbon atom (aminolysis).


Under these conditions, another class of tethered biscarbene complexes such as 124±129 with the carbene centers linked by the diamine spacer are formed by reaction of alkoxy carbene complexes 117 and 118 with diamines 119±123 (Scheme 11.30) [55]. In contrast, at room temperature the formation of biscarbene complexes resulting from an aminolysis-Michael addition sequence is favored. R1

R1 R2 H2N

N H

119 120 121 122

OEt (CO)5M THF -78ºC

H

R3

N (CO)5M

R1 = R2 = R3 = H R1 = R3 = H, R2 = Me R1 = R2 = Me, R3 = H R1 = R2 = H, R3 = Me 30 - 80 %

117 M = W 118 M = Cr

H2N

123

R2 3 R N

124 125 126 127 128

Ph Ph M = W, R1 = R2 = R3 = H M = W, R1 = R3 = H, R2 = Me M = W, R1 = R2 = Me, R3 = H M = W, R1 = R2 = H, R3 = Me M = Cr, R1 = R2 = R3 = H

H

H

NH2

M=W 40 %

M(CO)5

N

N (CO)5W

W(CO)5 Ph Ph

129

Scheme 11.30 Dinuclear bisaminocarbene complexes via low-temperature aminolysis.

Aminolysis of alkoxycarbene complexes with primary or secondary amines may generate E/Z-mixtures of aminolysis products the configuration of which may be controlled within certain limits by the reaction conditions. For example, the reaction of tris(2-aminoethyl)amine with chromium methoxy(phenyl)carbene 130 carried out at ±30 C in ethereal solution gives a 91% yield of a 1:1-mixture of the E/E/E- and the E/E/Z-isomers of tripodal trischromium aminocarbene 131, whereas at ambient temperature the pure E/E/Z-isomer is formed in 74%. The ring-opening aminolysis of chromium oxacyclopentylidene 73 carried out at ±78 C in a 1:1-mixture of DMF and CH2Cl2 affords a nearly quantitative yield of the tripodal E/E/Eamino(hydroxypropyl)carbene complex 132 (Scheme 11.31) [56]. Similar to aminolysis, the alcoholysis reaction can be applied to the synthesis of higher nuclearity metal carbenes as well. Low-temperature addition of 0.4 equivalents of pentaerythritol in DMF to a solution of chromium acetoxycarbene generated in situ from benzoyl chromates 133 (or 134) affords moderate yields of tetrakischromium carbene 135 (or 136) which undergoes complete benzannulation with 3-hexyne to give an 80% yield of the spherical tetrakishydroquinone 137 after in situ protection of the naphthol intermediate with TBDMSCl and subsequent oxidative demetallation (Scheme 11.32) [57].

471

472

11 Polyfunctional Metal Carbenes for Organic Synthesis H 2N Et2O

NH2

N

OMe

DMF / CH2Cl2 -78ºC O

(CO)5Cr

(CO)5Cr

NH2

130

73

N H

Cr(CO)5

N

N

N N

(CO)5Cr (CO)5Cr

Cr(CO)5

Cr(CO)5

N

N H

N

H HO

131

-30ºC : 91 % (E/E/E:E/E/Z = 1:1) r.t. : 74 % (E/E/Z)

Cr(CO)5

OH OH 132 (95 %, E/E/E)

Scheme 11.31 Tripodal aminocarbene complexes: Control of configuration by reaction conditions. R

O NMe4 (CO)5Cr

(CO)5Cr

1) AcBr, CH2Cl2 -40ºC

R

2)

133 R = H 134 R = OMe

HO 0.4 eq. HO

R Cr(CO)5 O

O

O

O

OH OH

(CO)5Cr

DMF, -30ºC

Cr(CO)5

R

R

135 R = H (30 %) 136 R = OMe (25 %) 1) 3-hexyne TBDMSCl, NEt3 THF, 55ºC 2) CAN, r.t.

R = OMe

Et

TBDMSO

OTBDMS Et Et

Et

O

O

O

O

Et

Et Et TBDMSO

Et 137 (80 %)

OTBDMS

Scheme 11.32 Tetradirectional benzannulation of a pentaerythritol-based chromium carbene.

11.4 Metathesis Reactions Catalyzed by Group VI and VIII Metal Carbenes

11.4 Metathesis Reactions Catalyzed by Group VI and VIII Metal Carbenes

Olefin metathesis has been developed to one of the most powerful and versatile reactions in organic synthesis in the past decade [58]. Although applied to commercial processes as early as in the 1960s [59,60], a mechanistic basis has been elaborated only slowly after the major breakthrough by Chauvin who suggested a nonpairwise exchange of alkylidene fragments via a metallacyclobutane intermediate formed in a [2+2]cycloaddition of a metal carbene M=C and an alkene C=C moiety [61]. Experimental support for a [2+2]cycloaddition/cycloreversion sequence has been provided by the stoichiometric reaction of a well-defined tungsten carbene complex (CO)5W=CPh2 138 with 1-methoxy-1-phenylethylene resulting in comparable amounts of (CO)5W=C(OMe)Ph and 1,1-diphenylethene (Scheme 11.33) [62]. In this early stage the diphenylcarbene and the (methoxy)phenylcarbene complexes of tungsten have been found to initiate the metathesis of unsymmetrical alkenes [63] as well as the ring-opening polymerization of cycloalkenes [64].

OCH3

OCH3

+

(CO)5W

32ºC 6h

+

(CO)5W

24 %

138

26 %

Scheme 11.33 Tungsten carbenes in stoichiometric olefin metathesis.

The concept of higher oxidation state metal carbenes pioneered by Schrock [65] has led to oxo and dialkoxy tungsten alkylidene complexes 139 and 140 which ± after modification into their cationic analogs upon reaction with Lewis acids ± turned out to be more efficient precursors of metathesis catalysts [66,67]. Further elaboration of this approach inspired the design of complexes such as 141 bearing bulky alkoxy, imido and alkylidene ligands that are able to stabilize coordinatively unsaturated metal centers; substitution of the oxo group for the sterically demanding imido ligand resulted in reduced tendency for decomposition (Scheme 11.34) [68]. R R t Bu

t Bu PEt3 W O

Cl Et3P Cl

139

O O t Bu

O

Br

W

W Br 140

t Bu

R

O

N

R 141a : R = CH3, 141b : R = CF3

Scheme 11.34 Development of tungsten-based metathesis catalysts.

473

474


Metal tuning of tetracoordinated metal carbenes revealed that replacement of tungsten for molybdenum renders the metal carbene a more selective although less reactive species. Molybdenum carbene 142b has emerged as a well-defined metathesis catalyst [69] that dominated the area until Grubbs developed ruthenium-based complexes highlighted by his first-generation catalyst 143 (Scheme 11.35) [70]. R R

Ph O Mo

R

O

N

R 142a : R = CH3, 142b : R = CF3

Cl Cl

PCy3 Ru PCy3

Ph

143

Scheme 11.35 Schrock's molybdenum carbene 142b and Grubbs' first-generation ruthenium carbene 143 as the first routinely applied olefin metathesis catalysts.

These two types of complexes combine high activity with an impressive tolerance of polar functional groups and have made olefin metathesis one of the key reactions in modern organic synthesis. They, and higher-generation Grubbs catalysts, including a strongly coordinated N-heterocyclic (NHC) coligand and/or a hemilabile chelating carbene ligand, are widely applied in the synthesis of fine chemicals and in polymer chemistry and allowed the development of a variety of metathesis reaction patterns including cross-metathesis (CM) [58d], acyclic diene metathesis (ADMET) polymerization, ring-closing metathesis (RCM) and ringopening metathesis polymerization (ROMP) [58]. Moreover, the metathesis concept has been extended to enynes [71] and alkynes [72]. Compared to Grubbs catalyst 143, the Schrock-type catalysts like commercially available 142b are more sensitive to moisture and oxygen and less compatible with functional groups; on the other hand, they are generally more reactive and, for instance ± in contrast to 143 ± allow for the formation of tri- and tetrasubstituted double bonds. The basics and the synthetic potential of olefin metathesis has been recently presented in a comprehensive handbook and several reviews [58]. Thus, this chapter will be restricted to demonstrate the scope and flexibility of this type of reaction in the total synthesis of a complex natural product skeleton such as epothilone. The first total syntheses of these antitumor-active 16-membered macrolactones were based on a ringclosing metathesis (RCM) strategy (Scheme 11.36) [73]. Grubbs catalyst 143 has been used for the construction of the endocyclic 1,2-disubstituted C12±C13 double bond in epothilone C 148 that, after epoxidation, affords epothilone A 150 [74]. In this approach, ruthenium carbene 143 is more efficient than Schrock molybdenum catalyst 142b [75a]. However, the RCM-route to epothilone D 149, the desoxy precursor of epothilone B 151 bearing a trisubstituted C=C bond, requires the molybdenum carbene catalyst 142b; attempts to initiate ring-closure with 143 failed [75].

11.4 Metathesis Reactions Catalyzed by Group VI and VIII Metal Carbenes R1

R S 1. RCM; catalyst: 143 for 144, 145 HO N 142b for 146, 147 2. deprotection

R2 O O 144 145 146 147

1

R3

O 2

12

R = H, R = OH, R = OTBS 1 2 3 R = H, R = R = OTBS 1 2 3 R = CH3, R = R = OTBS 1 2 3 R = CH3, R = R = OTBDMS

N

OH O

148 R = H : epothilone C 149 R = CH3 : epothilone D epoxidation R

ref. [74b] [74a,c] [75a] [75b]

retrosynthetic pathway 150 => 148 => 144 150 => 148 => 145 151 => 149 => 146 151 => 149 => 147

S

O O

3

13

O S

HO

N O O

OH O

150 R = H : epothilone A 151 R = CH3 : epothilone B

Scheme 11.36 Ring-closing metathesis as key step in total syntheses of epothilones A±D.

Olefin metathesis generally suffers from stereounselective C=C bond formation. However, this problem can be overcome by RCM of diynes [72] that is effected by metal carbynes; the resulting cycloalkyne undergoes Lindlar-type reduction to give the desired (Z)-cycloalkene. A typical example is the stereoselective synthesis of the macrocyclic musk civetone 155 using tungsten alkylidyne complex 153 as ring-closing alkyne metathesis (RCAM) (pre)catalyst to form cycloalkyne 154 (Scheme 11.37) [76]. Sterically hindered trisamido molybdenum(III) precatalysts of the general type [Mo{(tBu)(Ar)N}3] in the presence of halide sources like CH2Cl2 or TMSCl further improve the scope of alkyne metathesis, demonstrating the efficiency and versatility of alkyne metathesis reactions. Operating under mild conditions and tolerating a variety of polar functional groups, this methodology has been exploited in the total synthesis of sensitive and polyfunctional natural products including epothilones A 150 and C 148 [77]. The moderate reactivity of first generation Grubbs ruthenium catalyst 143 can be enhanced by substitution of the phosphine for N-heterocyclic carbene ligand(s). NHC complexes 156 and 157 as second-generation ruthenium catalysts combine reactivities comparable to that of molybdenum catalyst 142b with excellent tolerance of functional groups and easier handling [78]. They reflect a successful ligand tuning directed to the metathesis of sterically demanding alkenes and to cross-metathesis (CM) with electron-deficient substrates (a,b-unsaturated carbonyl compounds), and further allow for often excellent (E/Z)-selectivities with the (E)-isomer favored. More recently, Grubbs introduced third-generation bispyridine complexes like 158 that are easily accessible from 156 upon ligand exchange with various pyridines (Scheme 11.38) [79].

475

476


O

O O H2, Lindlar catalyst

[(t BuO)3W CCMe3] 153 (10 mol%) 65 %

94 %

152

154

155

Scheme 11.37 Synthesis of civetone 155 by an alkyne metathesis/syn-hydrogenation sequence.

Mes Mes

Mes N Cl Ru Cl PCy3

Ph

Mes

Mes

N Cl Ru Cl O

Mes N Cl N Ru Cl N

Ph

Br Br

156

157

158

Scheme 11.38 Second- and third generation Grubbs catalysts.

Recent advances focus on the chiral modification of molybdenum-based catalysts and their application in enantioselective olefin metathesis. Both reactivity and selectivity can be controlled by structural variation of the alkoxide and imido coligands. Alkoxide ligands offer a straightforward option for the incorporation of chiral information via readily available enantiomerically pure bishydroxy ligands such as biphenyl and binaphthyl derivatives. Representative examples are molybdenum alkylidene complexes 159±161 (Scheme 11.39) showing high levels of induction in kinetic asymmetric ring-closing (ARCM) and ring-opening (AROM) metathesis [80]. So far, enantioselective olefin metathesis has the largest impact on organic synthesis in the desymmetrization of achiral polyenes [81]; an illustrative example refers to the total synthesis of endo-brevicomin [82]. The catalytic asymmetric cyclization of achiral trienes and meso-tetraenes via ARCM proceeds in excellent enantioselection (e.e. > 99 %) as demonstrated for dihydrofuran 163 (Scheme 11.40). Molybdenum-catalyzed ARCM has been applied to the enantioselective synthesis of 7- or 8-membered heterocycles [83] as well as for midsized cyclic tertiary amines [84]. Chiral molybdenum catalysts allow for efficient kinetic resolution of 1,6-dienes and diallyl ethers.

11.5 Transmetallation

N

Me

Mo O

O

Ph Me

(S)-159 i Pr

i Pr

i Pr i Pr O O

N Mo O

N

O

i Pr

O

Me Ph Me

i Pr i Pr

i Pr

Mo

i Pr Me Ph Me

i Pr (R)-160

(R)-161

Scheme 11.39 Representative chiral molybdenum alkylidene complexes for enantioselective metathesis.

O

O 2 mol % (S)-159

162

neat RT, 5 min 93 % 99 % ee

H 163

Scheme 11.40 Molybdenum-catalyzed enantioselective desymmetrization of dienes.

More complex heterocyclic structures have been synthesized efficiently and with high stereoselectivities using tandem AROM-RCM sequences [85]; similarly, application of tandem AROM/CM to functionalized norbornenes affords enantiopure highly functionalized cyclopentanes [86]. A polymer-supported chiral molybdenum catalyst for enantioselective metathesis efficiently promotes ARCM (kinetic resolution as well as desymmetrization) and AROM reactions and can be recycled [87].


Although transmetallation is a key step in transition-metal catalysis, carbene transfer from one metal to another is rather rare. The transfer of a diaminocarbene ligand between group VI metal complexes observed for the thermal dispro-

477

478


portionation of imidazolinylidene complexes is an early example [88]; more recent examples refer to the synthesis of late transition-metal carbenes (Rh, Pd, Pt, Cu, Ag, Au) from imidazolidinylidene complexes [89]. Alkoxycarbene ligands have been transferred from metals of the chromium triad to iron [90] as well as to gold centers [91]. The temperatures required for the carbene transfer depend on the nature of the metal and, in particular, on the carbene substitution pattern. While, for example, the thermal decomposition of terminal benzylidene (pentacarbonyl)tungsten complexes, resulting in carbene dimerization to stilbenes, occurs already at room temperature or below [92], the dimerization of heteroatom-stabilized carbene ligands such as in chromium alkoxycarbenes requires temperatures of 130 C and above [93]; chromium biscarbenes have been proposed as intermediates in the thermal carbene dimerization [93b]. The presence of palladium compounds initiates dimerization of carbene ligands under considerably milder conditions; with chromium and tungsten carbenes the temperatures required for alkoxy- and aminocarbene dimerization can be lowered by ~100 C to ambient temperature [94]. While a series of Pd(0)- and Pd(II)-compounds are similarly efficient in catalyzing carbene dimerization with alkoxy(aryl)carbene complexes 164±166 (Scheme 11.41), the Pd(OAc)2/NEt3 system fails in carbene dimerization with chromium methylcarbenes 170 and 171 and, instead, effects a-deprotonation to give vinylethers 172 and 173. Nonbasic palladium catalysts afford an E/Z-mixture of endiol ether 174 as the expected carbene dimer (Scheme 11.42) [94b]. RO

OR (CO)5M

OR product (yield)

catalyst

catalyst

THF, RT

10 mol% Pd(OAc)2/ 167 (53 %) 168 (62 %) NEt3 169 (46 %)

X X 2 mol% Pd(OAc)2/ X NEt3 164 M = Cr, X = H, R = Me 167 X = H, R = Me 165 M = Cr, X = Br, R = Me 168 X = Br, R = Me 3 mol% Pd(PPh ) 3 4 166 M = W, X = H, R = Et 169 X = H, R = Et

167 (58 %)

168 (55 %)

Scheme 11.41 Pd-catalyzed carbene dimerization with alkoxy(aryl)carbene complexes.

X

X 10 mol% Pd(OAc)2/NEt3

O 172 X = H (unstable) 173 X = Me (65 %)

O

(CO)5Cr CH3 170 X = H 171 X = Me

catalyst (10 mol%) for 170

BnO H3C

catalyst Pd(PPh3)4 Pd(C) Pd2(dba)3 . CHCl3

Scheme 11.42 Tuning of palladium catalysts towards carbene dimerization versus a-deprotonation.

OBn

174 yield 87 % 70 % 76 %

CH3


The dimerization reaction is compatible with the presence of an additional metal center in the carbene complex. Homobimetallic biscarbenes 175±178 undergo a Pd(OAc)2-catalyzed intramolecular dimerization to give cyclic endiol ethers 179± 182 in yields which decrease with increasing ring size for six- to nine-membered rings (Scheme 11.43) [94b]. Unsaturated carbene ligands afford enediynes, trienes and higher conjugated polyenes. The palladium-catalyzed dimerization may be rationalized in terms of two consecutive Cr to Pd transmetallation steps to generate a palladium biscarbene intermediate that ends up in metal elimination. Palladium catalysis is also effective in formal [2,3]- and [1,2]-sigmatropic rearrangements of chromium allyloxy(aryl)carbenes that occur under CO atmosphere [95]. Cr(CO)5

n

Cr(CO)5

O

n

175 176 177 178

10 mol% Pd(OAc)2 Et3N rt

O

n=0 n=1 n=2 n=3

O

179 180 181 182

O

n = 0 (70 %) n = 1 (64 %) n = 2 (21 %) n = 3 (14 %)

Scheme 11.43 Palladium-catalyzed intramolecular carbene dimerization.

Transmetallation is not restricted to palladium and has been extended to rhodium and copper, so far. [(COD)RhCl]2 promotes the room-temperature p-cocyclization of cross-conjugated chroma- and tungsta-amino-1-metalla-1,3,5-hexatrienes with alkynes to give vinylcyclopentadienes as single isomers [96]. Alternatively, vinylcyclopentadienes are also formed from 1-alken-3-ynes and 4-amino-1. metalla-1,3-butadiene complexes of chromium and tungsten; RhCl3 3 H2O in methanol turns out to be the most efficient (pre)catalyst (Scheme 11.44) [97]. OEt (CO)5M

M = Cr, W

Ph

R1 +

NR2

R1 Ph 1 mol% RhCl3 . 3 H2O

R2

THF/MeOH (4:1) 20ºC - M(CO)6

NR2

R2

OEt

Scheme 11.44 Vinylcyclopentadienes by rhodium-catalyzed condensation of 1-alken-3-ynes with 4-amino-1-metalla-1,3butadienes.

Cu(I)-catalysis [CuI (5 mol%) in the presence of NEt3 (8 mol%)] effects the formation of a spirocyclic vinylcyclopentadiene from a tungstaoctatetraene complex. Unfortunately, replacement of NEt3 by chiral amines or diamines does not result in enantioselective spirocylization [98]; stable copper(I) carbenes have been isolated and fully characterized [99,100]. A cross-coupling affording highly function-

479

480


alized alkenes and dienes results from the reaction of chromium alkoxycarbenes and ethyl diazoacetate catalyzed by CuBr (15 mol%) (Scheme 11.45) [100]. While methoxycarbene complexes 183±185 are unable to control the E/Z configuration, the enantiopure (±)-menthyloxy analog 186 exclusively forms the (E)-stereoisomer.

(CO)5Cr 183-186

15 mol % CuBr R2O OR2 THF, 25ºC + N2CHCO2Et 80-95 % 1 R1 R

183,187

184, 188

Ph

Bu

R1

185, 189

O

R2

CH3

CH3

186, 170

O

CO2Et

E/Z 187 1:1 188 1:1 189 1:1 190 >30:1

CH3

Scheme 11.45 Copper(I)-catalyzed cross-coupling reactions.

Changing the CuBr catalyst to [Cu(CH3CN)4][PF6] (15 mol%) results in a clean dimerization of the alkenylcarbene ligand in complex 185 to give a 95% yield of triene 191 formed in a 10:1 ratio of E/Z-isomers (Scheme 11.46). A copper biscar1 bene [Cu{=CR (OCH3}2(CH3CN)n][PF6] has been proposed as intermediate [100]. Trienes resulting from Cu(I)-catalyzed dimerization of chromium-coordinated alkenylcarbenes have been applied to Nazarov-type cyclization reactions to give 2-alkoxy-2-cyclopentenones in nearly quantitative yield. CuBr also catalyzes the dimerization of vinyl(amino)carbene ligands to give 3,4-bisaminotrienes that undergo a [3,3]sigmatropic rearrangement to vic-bisaminobenzenes [101]. O OCH3

[Cu(CH3)4][PF6] 15 mol %

(CO)5Cr

OCH3

CH2Cl2 25ºC

185

O

H3CO 191 95 % E:Z = 10:1

Scheme 11.46 Cu(I)-promoted alkenylcarbene dimerization.

O

11.6 Metal Carbenes in Peptide Chemistry

11.6 Metal Carbenes in Peptide Chemistry

A growing interest focused on the implementation of organometallic reaction patterns in natural products and pharmaceuticals has coined the term ªBioorganometallic Chemistryº in the past decade [102]. This research area aims at a mutal insemination of organometallic principles and biological applications and has stimulated an organometallic functionalization of various biologically active molecules. The incorporation of an organometallic functionality into biomolecules may address two complementary aspects: From a synthetic point of view the ample chiral information present in the biomolecule is attractive for stereoselective organic synthesis. Moreover, organometallic reaction patterns offer additional options for the modification and derivatization of natural products. On the other hand, metal fragments may be attractive as nonconventional protective or activating groups as well as for a regioselective labelling within the biomolecule. This chapter concentrates on metal carbene modified amino acids and peptides while sugar metal carbenes are dealt with in Section 11.7. The potential of metal carbenes in amino acid and peptide chemistry became obvious already in the 1970s when the aminolysis reaction of metal alkoxycarbenes was found to be compatible with amino acid esters. Pentacarbonylchromium and -tungsten carbene fragments have been introduced as protective groups in peptide synthesis (Scheme 11.47) [103]. Aminocarbene complex 192, readily available via aminolysis of the chromium methoxycarbene precursor [(CO)5Cr=C(C6H5)(OCH3)], undergoes hydrolysis to the N-protected amino acid 193 without any side reactions at the metal carbene protective group. The chromium carbene protected alanine 193 can be applied to the conventional amino acid coupling methodologies (e.g. NHS/DCCD-assisted coupling with alanine ester 194) to give C- and N-diprotected dipeptide Crpc-Ala-Ala-OMe 195 [104]. Repeating this sequence tripeptide Crpc-Ala-Ala-Ala-OMe 196 and larger oligopeptides up to the sequence 14±17 (-Gly-Gly-Pro-Gly-) of the human proinsulin-Cpeptide have been obtained. The metal carbene N-protective group is finally cleaved with trifluoracetic acid under mild conditions. An independent access to metal carbene functionalized peptides is provided by olefin metathesis (see also Section 11.4). The Crpc-labelled dipeptide 199 has been synthesized from imino acrylamide 197 in a stoichiometric metathesis reaction with chromium carbene 198 (Scheme 11.48) [105]. The isoindole 200 is a side product of this labeling procedure originating from 199 by cleavage of the metal carbene bond, ring closure and subsequent sigmatropic 1,3-H shift; it is formed nearly quantitatively, however, by oxidation of the carbene complex 199 with Na2PdCl4 in methanol. As a characteristic feature of all metal carbonyl complexes the strong m(C=O) absorptions of the Cr(CO)5 moiety underline the potential of this type of organometallics as biomarkers.

481

482


Ph

Ph (CO)5Cr

(CO)5Cr

O

O NH

NH OMe

Me 192

O + H 2N OMe

Me

OH

Me

194

193

Ph (CO)5Cr

O NH

O Me NH Me

OMe

195

Ph O

(CO)5Cr NH

O Me NH

O Me NH Me

196

OMe

Scheme 11.47 The pentacarbonylchromium carbene (Crpc) fragment as N-protective group in peptide synthesis.

Ph

Ph

Ph

Ph N

N

Cr(CO)5

OMe O

O

+ (CO)5Cr Ph

N

OMe + Ph

N

198 Ph

O

Ph

O MeO

MeO 197

199

+ Ph

N H

O 200

Scheme 11.48 Labeling of peptides by metal carbonyl markers.

Ph

NH O

OMe

11.7 Stereoselective Syntheses with Sugar Metal Carbenes

Apart from aminolysis and olefin metathesis the photoactivation of aminocarbene complexes offers another nonconventional entry into peptide synthesis. Irradiation into the hypsochromic MLCT-band of chromium aminocarbenes such as 201 generates a ketene-like intermediate 204 that is trapped by amino acid esters such as 202 or 205 to produce dipeptides 203 or 206 after enantioselective protonation (Scheme 11.49) [106]. This photochemical protocol generally combines good yields with high diastereoselectivities and is especially attractive for the incorporation of a-alkyl a-amino acid esters into peptides that may be hampered in conventional peptide synthesis methodologies due to steric hindrance [106c]. O H Me +

H 2N

N H

hν

N

CO2R 202

O

H Me

Me CO2R

Ph

O

203

N Ph

(CO)5Cr Me 201

O Ph Ph +

H 2N

hν

N

CO2Me 205

Ph Ph

Me

O

N H

CO2R

Ph 206

O Me (CO)4Cr

N .

Ph

O 204 Scheme 11.49 Photoactivation of chromium aminocarbenes for peptide synthesis.


The manifold chiral information readily available in customary carbohydrates provides an attractive approach to a chiral modification of metal carbenes that may be applied to either metal-mediated stereoselective organic synthesis via sugar auxiliaries or to carbohydrate synthesis via organometallic methodologies [107, 108]. The sugar moiety can be incorporated into metal carbenes by well-established procedures such as nucleophilic addition to the metal-coordinated carbene carbon atom or conjugate addition to the vinylogous position in alkenyl or alkynyl car-

483

484


bene ligands as demonstrated for the addition of selectively monodeprotected isopropylidene furanoses 209±211 to chromium and tungsten alkynylcarbenes 207 and 208 (Scheme 11.50) [109]. The sugar-containing metal alkenylcarbenes 212± 217 are obtained in good yields as mixtures of E/Z isomers with the E-isomers preferred or even as single E-isomers when d-allofuranose 210 is used. The addition of the a-anomer 211 results in partial epimerization to give mixtures of aand b-anomeric complexes of 216 and 217. OEt

OEt

(CO)5M

+

207 M = Cr 208 M = W

O

RO =

ROH

O

O O

209, 212, 213

O

OR

M E:Z %

209 - 211

O O O

(CO)5M

Ph

Ph

O

Na / THF 20ºC

O

O O

O

O

O O O O

212 213 214 215 216 217

Cr W Cr W Cr W

64:16 63:21 89 92 35:9 (a) +37:9 (b) 35:7 (a) +36:7 (b)

211, 216, 210, 214, 215 217

Scheme 11.50 Sugar-vinylcarbene complexes via conjugate addition to metal alkynylcarbenes.

An alternative access to metal sugar-vinylcarbenes arises from the activation of sugar-derived propargylic alcohols 218±221 at a coordinatively unsaturated metal fragment formed from a W(CO)5THF precursor to give metal allenylidene intermediates that are trapped by external nucleophiles such as methanol [110]. This isomerization/addition sequence can be applied to acyclic (218, 219) as well as to pyranose sugar alkynols (220, 221) and affords the metal sugar-vinylcarbenes 222± 224 exclusively as E-isomers whereas the pyranose derivative 225 bearing an exocyclic double bond is obtained as the Z-isomer (Scheme 11.51). An extension of this strategy to sugar nucleophiles such as 1,2:3,4-isopropylidene-a-d-galactopyranose 226 as trapping reagents affords moderate yields of organometallic O,C-disaccharides (227, 228) in which two sugar moieties are connected by a metal vinylcarbene spacer (Scheme 11.52). Another route to vinylcarbene C-glycosides is based on a TiCl4-assisted aldol condensation of pentacarbonyl[(methoxy)methylcarbene]chromium (229) and formyl glycosides 230±232. This reaction is trans-selective and affords sugar carbene complexes 233±235 in good yields (Scheme 11.53) [111]. The straightforward access to O-glycosidic metal carbenes relies on the nucleophilic addition of an unprotected sugar alcohol to the electrophilic carbene carbon. In order to overcome problems arising from the inherent steric bulk of protected sugar nucleophiles the electrophilicity of metal oxycarbenes can be enhanced by O-acylation. Acyloxycarbene complexes are temperature-sensitive intermediates but readily accessible from tetramethylammonium [acyl(pentacarbonyl)]metalates


such as 236 by an acylation/alcoholysis sequence to give O-glycosidic chromium carbenes 239±243. Subsequent aldol condensation with galactose-derived aldehyde 230 affords chromium E-vinyl O,C-disaccharides 244±248 in good to excellent yields; the more reactive benzaldehyde does not require Lewis acid activation to give nearly quantitative yields of C-glycosidic E-styrylcarbene complexes (Scheme 11.54) [112]. HO

MeO

W(CO)5THF MeOH rt 20-60%

R

222 - 224

218 - 220

R O

O

O

O O

O

W(CO)5

OH

O

O

W(CO)5THF MeOH r.t. 30%

O

OMe

O

W(CO)5

225

221 O BnO

OBn OBn OBn OBn

OBn OBn OBn

R=

218, 222

O O

O O

219, 223

220, 224

Scheme 11.51 Synthesis of sugar-vinylcarbene complexes based on a metal-templated isomerization of sugar alkynols.

O

HO

OH

O

+

W(CO)5THF THF rt

O

R

O

O O

O

218, 220

O

226

O 227 : 21 % E:Z= 9:1 228 : 15 % E only

O BnO

R=

O

O OBn OBn OBn

218, 227

O

O O

220, 228

Scheme 11.52 Metal-assisted coupling of sugar alkynols and a selectively deprotected sugar to organometallic O,C-disaccharides.

R

O W(CO)5

485

486


OCH3

O

(CO)5Cr CH3

H 230 - 232

229

OCH3 (CO)5Cr R

233 - 235

OBn

O

R=

1. TiCl4 2. i Pr2NEt TMSCl 45-82%

R

+

O O

230, 233

O

BnO BnO

O

OBn

O

O O

O

231, 234

O

O

232, 235

Scheme 11.53 Trans-selective aldol reaction to metal sugar-vinylcarbenes.

O NMe4 (CO)5Cr 236

(CO)5Cr

CHO

+ CH3

230

O

R=

O

O

O

O

O O

CH3 OR

O O

239 - 243

239 - 243 (CO)5Cr

O

O

(CO)5Cr

2. ROH 209, 211, 226, 237, 238 29-86%

CH3 O

OR

OR

1. AcBr

1. TiCl4 2. i Pr2NEt TMSCl 52-89% O

O

O O O

O 244 - 248

O

O O O

O

O

O O 226, 241, O 209, O 211, 240, 245 246 239, 244 O O

O

O

O

O O

O

237, 242, 247

O

O

O

O

238, 243, 248

Scheme 11.54 Chromium carbene O,C-disaccharides via tandem alcoholysis/aldol condensation.

Acyclic pentoses and hexoses undergo a metal carbene functionalization at C-1 by coupling of a sugar electrophile and an organometallic nucleophile. The low-temperature addition of potassium pentacarbonyl metalates 251±253 to pentanoic and hexanoic acid chlorides 249 and 250 affords acyl metalate intermediates that undergo O-alkylation by trimethyloxonium tetrafluoroborate to give sugar methoxycarbene complexes 254±257 in moderate to good yields. Ammonolysis under low-temperature conditions results in substitution of the methoxy for the amino group without affecting the acetyl protective groups as shown for 256 and


257 to give sugar aminocarbene complexes 258 and 259 in excellent to quantitative yields (Scheme 11.55) [108, 113]. Cl

1. K2M(CO)5 251-253

O R

MeO R

2. Me3O BF4 42-64%

249, 250

H2N

M(CO)5 NH / -30ºC 3

M(CO)5 OAc

for 256 and 257

AcO

254 - 257

AcO

R=

OAc

OAc

OAc

AcO AcO

AcO AcO

249, 254

OAc OAc OAc

OAc

M = Cr : 251, 254, 255 Mo : 252, 256, 258 W : 253, 257, 259

250, 255 - 257

258 : 85 % 259 : quant.

Scheme 11.55 C-1 Metal carbene functionalization of acyclic pentose and hexose derivatives.

The cycloisomerization of sugar-derived butynols ± easily accessible by c-addition of allenyl magnesium bromide to protected carbohydrate aldehydes, ketones and lactones ± at low-valent chromium and tungsten templates leads to chiral 2-oxacyclopentylidene complexes. The addition of the Grignard reagent to ketones 260 and 262, derived from d-glucose and d-fructose, respectively, and to mannolactone 261 occurs under chelate control and affords a single diastereomer of butynols 264±266. In contrast, diastereomeric mixtures resulted from the Grignard addition to cyclic formyl glycosides 230, 232, 263 and to open-chain sugar aldehydes (Scheme 11.56); separation of the diastereomers is achieved by chromatography after the following cycloisomerization. The cyclization of the butynols at the M(CO)5 template (M = Cr, W) affords 2-oxacyclopentylidene complexes 76a/b and 270±279 in moderate to good yields (Scheme 11.57) [114]. O

O

O

O

O O

O

O O O O

O

O

261

O

O

262

O

O

O CHO

O

O

O

260

O

O

O

O

O O

263

Et2O, -78ºC

O O O O

OH O

OH O O O

264

O

O

265

O

O

O OH O

O O

O

230

232

MgBr

OHC CHO

O

O

O O

OH

266

O

O

OH

O O

O OH

O

O O

O

267

Scheme 11.56 Synthesis of sugar butynols via c-addition of allenyl magnesium bromide to sugar carbonyl precursors.

268

269

487

488


O

O

O

O

O O

O

O

M(CO)5 76a M = Cr 76b M = W

O O O

O

(CO)5M

O

O O

272 M = Cr 273 M = W

M(CO)5

M(CO)5THF r.t. M = Cr, W 46-85 %

O

O

O

M(CO)5 270 M = Cr 271 M = W 264 - 267

M(CO)5

O

O O O

O

O O

O

O

O (CO)5M O

O

278 M = Cr 279 M = W 1.7 : 1

O O

274 M = Cr 275 M = W 3.2 : 1

O

276 M = Cr 277 M = W 3.5 : 1

Scheme 11.57 Metal-assisted cycloisomerization of sugar butynols to metal oxacyclopentylidenes.

The potential of metal carbenes in stereoselective synthesis is based on both the pronounced acidity of the a-CH in the alkyl side chain ± which may be exploited in aldol and Michael-type reactions ± and on cycloaddition reactions centered either on the metal or the carbene ligand. The incorporation of a carbohydrate backbone into the carbene ligand generally allows for an asymmetric modification of these carbon±carbon bond-forming reactions. Deprotonation of 2-oxacyclopentylidene complexes 76a/b and 270±279 generates the conjugate bases that can be O O O O

35-40%

(CO)5Cr

O 282 3(S) 9.5 : 1 283 3(R) 16.7 : 1

O

(CO)5Cr 280 3(S) 281 3(R)

O O OR

(CO)5Cr

for 280 26-60%

Scheme 11.58 Diastereoselective [4+2] and [2+2]cycloaddition reactions of a-exo-methylene oxacyclopentylidene complexes.

O 284 R = t.-butyl d.e. = 70 % 285 R = n-butyl OR d.e. = 67 %


modified into their a-exo-methylene derivatives upon reaction with methylenedimethyl-iminium chloride. The exocyclic double bond is activated for cycloaddition reactions by the metal carbene moiety as shown for both a-exo-methylene chromium complex diastereomers 280 and 281 which undergo Diels±Alder reactions with 2,3-dimethylbutadiene with excellent diastereoselectivities. [2+2]Cycloaddition of enol ethers to complex 280 result in the formation of spirocyclobutane derivatives with good diastereomeric ratios (Scheme 11.58) [114c,115]. Similarly, a-exo-methylene psicosecarbene complexes 77a and 77b (derived from 76a and 76b, respectively) give moderate to good yields combined with excellent diastereoselectivities in Diels±Alder reactions revealing a stereopreference for the approach of the dienes from the top face (re-side). As determined by X-ray structure analyses the chromium trisspiro carbenes 286 and 288 are formed as the major diastereomers (Scheme 11.59) [116].

O O

O

O

O

O

O O O

O

M(CO)5

O O

286 M = Cr 67 % 98 % d.e. 287 M = W 37 %* 93 % d.e.

M(CO)5 77a M = Cr 77b M = W

O

O

O

O O O

288 M = Cr 51 % 93 % d.e. 289 M = W 50 %* 94 % d.e.

M(CO)5 Scheme 11.59 Diastereoselective [4+2]cycloaddition reactions to trisspiro oxacyclopentylidene complexes (* Yield referring to complex 76a; because of its low stability complex 77b was prepared in situ and transformed without previous separation).

In contrast, [2+2]cycloaddition of 77a and 77b with achiral enol ethers results in only low diastereoselectivities of the spirocycles 290±295 (Scheme 11.60) [116]. The diastereoselectivity of Diels±Alder reactions with acyclic sugar-vinylcarbene complexes depends on the nature of the diene. Whereas the tungsten vinylcarbene 222 gives all four possible diastereomers of cycloadduct 296 upon reaction with cyclopentadiene, only one pair of diastereomers of 297 is observed with 2,3-dimethylbutadiene (Scheme 11.61) [110]. O-Glycosidic styrylcarbene complexes 298±302 prepared from chromium methylcarbenes 239±243 and benzaldehyde in a trans-selective aldol condensation undergo a chromium-templated benzannulation upon reaction with per-benzyl-protected ethynyl glucopyranose 303. Oxidative demetallation results in the formation of hydroquinoid C- and O-biphenyl disaccharides 304±308 (Scheme 11.62) [117].

489

490


OR

O

O

290 M = Cr, R = t butyl 75 %, 42 % d.e. 291 M = W, R = t butyl 31 %*, 38 % d.e. 292 M = Cr, R = n butyl 91 %, 12 % d.e. 293 M = W, R = n butyl 24 %*, 4 % d.e.

O OR

O O O 77a/b

M(CO)5 O

O

O

OO 294 M = Cr 41 % 23 % d.e. 295 M = W 24 %* 40 % d.e.

O O O M(CO)5

Scheme 11.60 [2+2]Cycloaddition reactions to trisspiro oxacyclopentylidene complexes (* Yield referring to complex 76a; because of its low stability complex 77b was prepared in situ and transformed without previous separation). MeO

W(CO)5

W(CO)5 W(CO)5 BnO

OMe BnO

OBn

BnO

OBn

OBn

OBn

OBn 296

OMe

53 % (7 : 1)

OBn

87 % (10 : 9 : 1.5 : 1)

222

OBn 297

OBn

OBn

Scheme 11.61 [4+2]Cycloaddition reactions of acyclic sugar-vinylcarbene complexes. OR

H

(CO)5Cr

OR

O

TMSCl NEt3

+ CH3

(CO)5Cr

87-97%

239-243 298-302 OH OBn OBn OBn

O BnO 304-308 O O

O O O

O

R= 239, 298, 304

TBME 60ºC 26 h 67-88%

OR

O

O

O O O O O 240, 299, 305

O

O 241, 300, O 306

O O

OBn

303

O O

O

OBn O

BnO BnO

O

O

O

O

O 242, 301, 307

Scheme 11.62 Chromium-templated benzannulation of O-glycosidic styrylcarbene complexes to hydroquinoid C- and O-biphenyl disaccharides.

O

O

O

O

243, 302, 308


The modification of the anomeric center of cyclic carbohydrates into a metalcoordinated carbene carbon leads to glycosylidene complexes. This type of sugar metal carbenes requires different synthetic strategies that may be based on either stochiometric olefin metathesis (see also Section 11.4) of 1-enitols with a strongly electrophilic metal carbene or on a glycal metallation/electrophilic addition sequence. Furanosylidene complexes were synthesized by olefin metathesis of hept-1-enitol 309 with diphenylcarbene complexes 310. Whereas the chromium furanosylidene 311a is obtained in synthetically useful yield, only marginal amounts of the tungsten analog can be isolated under various conditions (Scheme 11.63) [118]. This result may reflect the oxophilicity of tungsten and side reactions arising therefrom. O

O O

O M=Cr; RT, 90 min M=W; 90ºC, 90 min

O O

O

309 + (CO)5M CPh2

n-heptane

a M = Cr bM=W

M(CO)5

O O

O

311a: 65% 311b: 3% + H2C CPh2

310a,b Scheme 11.63 Synthesis of metal furanosylidenes based on stoichiometric olefin metathesis.

The olefin metathesis approach cannot be extended as an attractive route to metal pyranosylidenes. Instead, an alternative strategy has been developed starting from lithioglycals that are generated in situ by transmetallation of stannylated precursors. As shown for the glucose series, lithiation of stannyl glucals 312 followed by addition of hexacarbonyl chromium gives the acyl chromates which upon alkylation afford the a,b-unsaturated chromium glucal carbenes 317 (route D) according to the Fischer route. Modification of the chromium electrophile by substitution of one carbonyl ligand for a more labile ligand such as THF, however, favors the addition of the lithioglucal to the metal center generating the chromium enolates 314 (route A). At temperatures above 0 C, these intermediates undergo a Ferrier-type rearrangement under elimination of the protected hydroxy group at C-3 to give the a,b-unsaturated chromium glycosylidenes 316 (route C). At low temperature, the elimination can be avoided and the chromium enolates can be trapped with electrophiles to afford the desired 2-deoxy-glycosylidene complexes 315 (route B). Depending on the nature of the electrophile used deuterated or C-2 linked C-glycosidic complexes are also accessible. The stereochemical outcome of the addition of the electrophile can be controlled by the pattern of the protective groups; diastereoselectivities range from 4 to ³90% d.e. (Scheme 11.64) [119].

491

492


O

RO

SnBu3

O

RO

Cr(CO)5

O

RO

Cr(CO)5

B

A

RO

RO

RO

OR´ 315a,b

OR´ 314a,b

OR´ 312a,b

E

C D

Cr(CO)5 O

RO

OMe

O

RO

Li

RO

RO

A: 1) THF, n BuLi, -78ºC 2) [(CO)5CrTHF], -78ºC -> 0ºC B: THF, EX, -78ºC -> 0ºC

EX

316a,b

C: T>0ºC D: 1) THF, n BuLi, -78ºC 2) Cr(CO)6 3) Me3OBF4

2-R/S

Yield [%]

only S detectable

59

CF3COOD

58 : 42

50

HCl

-

71

I

315a

I

6 : 94

74

CF3COOD

RT, 96%

OTIPS

OTIPS

321

322

Scheme 11.66 Demetallation of chromium iminopyranosylidenes to enamides.

ring-closure affords the adenine based chromium iminofuranosylidene 325 that represents the first example of a novel organometallic nucleoside (Scheme 11.67) [121]. N O

BnO

H

N

N

Cr(CO)5 O

adenine DMF 76%

O

H N

N

Cr(CO)5 O O OH

BnO 324

323

DEAD, PPh3 THF 29%

H N

N

N

N N

Cr(CO)5

BnO O

O

325 Scheme 11.67 Metal carbene nucleosides via ring opening/recyclization.

The predictable SN2-stereochemistry of the Mitsunobu reaction and the ready availability of common d-sugar starting materials make the ring-opening/recyclization protocol an attractive route for the synthesis of unnatural l-iminosugar derivatives. Moreover, organometallic reaction patterns based on the metal carbene functionality allow for further elaboration of the sugar backbone by C±C bond formation.

11.8 Sugar Metal Carbenes as Organometallic Gelators

11.8 Sugar Metal Carbenes as Organometallic Gelators

O-Protected sugar metal carbenes as discussed so far represent lipophilic organometallics that are soluble in typical organic solvents. Deprotection of the carbohydrate moiety, however, is expected to enhance their solubility in protic media. Previous investigations of glycosaminocarbene complexes that indicated a significant solubility in water as a result of free hydroxy groups in the pyranose ring [122] prompted more detailed studies directed towards organometallic amphiphiles based on metal carbenes. Acyclic sugar metal carbenes such as chromium methoxycarbenes 254±257 and aminocarbenes 258, 259, 318 and 320 are closely related to aldonic esters and amides based on the isolobal analogy of the Cr(CO)5 fragment and the oxygen atom [123], and aldonic amides bearing longer N-alkyl groups are known to form supramolecular aggregates in aqueous media [124, 125]; moreover, some derivatives turned out to be efficient hydrogelators [126]. Replacement of the amide oxygen in N-n-octyl-d-gluconamide that is supposed to play an important role in the aggregation process for the pentacarbonyl chromium fragment leads to a significant increase of the solubility in organic solvents. The n-octylaminocarbene complex derived from glucose is synthesized from penta-acetylated gluconic acid chloride 326; addition of potassium pentacarbonyl chromate 251 followed by methylation gives chromium methoxycarbene 327 that undergoes low-temperature aminolysis with n-octylamine and O-deprotection under basic conditions to afford chromium n-octylaminocarbene 328 (Scheme 11.68) [127]. OAc OAc Cl

OAc OAc OAc

O

OAc OAc

H3CO

1) 251 2) (CH3)3OBF4

OAc

Cr (CO)5

326

OAc OAc 327

1) H2N(CH2)7CH3 2) NH3/CH3OH

OH

OH

NH Cr (CO)5

OH OH

OH

328 Scheme 11.68 Synthesis of amphiphilic sugar metal carbenes as organometallic gelators.

In spite of the bulky metal carbonyl fragment and the missing amide oxygen functionality efficient hydrogen bonding in combination with hydrophobic interactions allow for gelation of chlorinated and aromatic solvents and mixtures

495

496


thereof containing 0.35±1.3 wt% of 328. The gelation is thermoreversible and occurs within the temperature range of 30±70 C. The gel-to-solution phase-transition temperatures (Tgel) depend on the cooling rate: Tgel-values observed for turbid gels obtained upon rapid cooling are found to be appr. 5±10 C lower than those for clear gels formed in a slower gelation process. CD-Studies revealed that aggregation increases De by two orders of magnitude indicating a distinct supramolecular effect; the gelation represents a rare example in which the sign of the Cotton effect can be controlled by the cooling rate [128]. Based on temperature-dependent IR- and NMR-studies, STM- and SAXS-investigations an aggregation model is proposed relying on superposed elemental cylinders with a diameter of appr. 3.3 nm (Scheme 11.69) [129].

Scheme 11.69 Aggregation model for gelation of chlorinated and aromatic solvents by amphiphilic sugar metal carbene gelators.

11.9 Conclusion

The potent electron-acceptor properties of a metal carbonyl fragment imposes synthetically useful properties on a carbene coligand. In the most intensively studied chromium and tungsten carbenes the Cr(CO)5 fragment renders the carbene carbon atom strongly electrophilic and favors the addition of carbon and heteroatom nucleophiles. Moreover, it reveals more remote effects on carbene ligands: It enhances the a-CH-acidity of alkylcarbene substituents which allows for C±C coupling with a variety of carbon electrophiles under basic conditions, and also assists [2+n]cycloaddition and Michael-type addition reactions to a,b-unsaturated carbene side chains. However, the metal carbonyl fragment is more than a mere functional group. The CO ligand represents a useful C1-synthon that can be exploited in either direct carbonylation of the carbene ligand to generate ketene intermediates or in insertion reactions into M±C bonds later in the reaction pathway. Finally, the low-valent metal center may act as a template for unprecedented cycli-

References

zation reactions that allow for the construction of densely functionalized arene skeletons or for oligocyclic structures from more simple acyclic precursors. The metal carbene moiety is often compatible with a variety of additional functionalization that makes this type of metal carbenes attractive for the synthesis and further elaboration of multifunctional compounds as often encountered in natural products. This trend is also obvious from sugar metal carbenes that upon O-deprotection can be modified into amphiphilic organometallics revealing a promising supramolecular chemistry.

References 1 For most recent reviews, see: (a)

J. Barluenga, J. Santamaría, M. Tomµs, Chem. Rev. 2004, 104, 2259; (b) K.H. Dötz (ed.) Metal Carbenes in Organic Synthesis, Top. Organomet. Chem. 13, Springer-Verlag, Berlin Heidelberg 2004; (d) A. de Meijere, H. Schirmer, M. Duetsch, Angew. Chem. 2000, 112, 4124; Angew. Chem. Int. Ed. Engl. 2000, 39, 3964; (c) R. Aumann, Eur. J. Org. Chem. 2000, 17. 2 (a) N.D. Hahn, M. Nieger, K.H. Dötz, Eur. J. Org. Chem. 2004, 5, 1049; (b) J. Pfeiffer, M. Nieger, K.H. Dötz, Angew. Chem. 1997, 109, 2948; Angew. Chem. Int. Ed. Engl. 1997, 36, 2828; (c) J. Barluenga, S. López, A.A. Trabanco, J. Flórez, Chem. Eur. J. 2001 7, 21, 4723; (d) J. Barluenga, A.L. Suµrez-Sobrino, M. Tomµs, S. García-Granda, R. Santiago-García, J. Am. Chem. Soc. 2001, 123, 10494; (e) M. Buchert, M. Hoffmann, H.-U. Reiûig, Chem. Ber. 1995, 128, 605. 3 (a) J. Barluenga, F. Aznar, M.. Palomero, J. Org. Chem. 2003, 68, 537; (b) J. Barluenga, F. Aznar, M.. Palomero, Chem. Eur. J. 2002, 8, 4149; (c) R. Aumann, D. Vogt, X. Fu, R. Fröhlich, P. Schwab, Organometallics 2002, 21, 1637; (d) K.L. Faron, W.D. Wulff, J. Am. Chem. Soc. 1990, 112, 6419; (e) K.L. Faron, W.D. Wulff, J. Am. Chem. Soc. 1988, 110, 8727. 4 (a) J. Barluenga, P. Barrio, L.A. López, M. Tomµs, S. García-Granada, C. Alvarez-Ra, Angew. Chem. 2003, 115, 3116; Angew. Chem. Int. Ed. Engl.

2003, 42, 3008; (b) J. Barluenga, Pure Appl. Chem. 2002, 74, 1317. 5 (a) J. Barluenga, A. DiØguez, F. Rodriguez, J. Flórez, F.J. Fananµs, J. Am. Chem. Soc. 2002, 124, 9056; (b) J. Barluenga, F. Aznar, M.. Palomero, Angew. Chem. 2000, 112, 4514; Angew. Chem. Int. Ed. Engl. 2000, 39, 4346. 6 Y. Luo, J.W. Herndon, F. Cervantes-Lee J. Am. Chem. Soc. 2003, 125, 1272. 7 (a) Y.-T. Wu, A. de Meijere, in K.H. Dötz (ed.) Metal Carbenes in Organic Synthesis, Top. Organomet. Chem. 13, 21, SpringerVerlag, Berlin Heidelberg 2004; (b) J. Barluenga, F. Rodríguez, F.J. Faæanµs, J. Flórez, in K.H. Dötz (ed.) Metal Carbenes in Organic Synthesis, Top. Organomet. Chem. 13, 59, SpringerVerlag, Berlin Heidelberg 2004. 8 For a recent review, see: A. Minatti, K.H. Dötz, in K.H. Dötz (ed.) Metal Carbenes in Organic Synthesis, Top. Organomet. Chem. 13, 123, Springer-Verlag, Berlin Heidelberg 2004. 9 (a) J.W. Herndon, S.U. Tumer, J. Org. Chem. 1991, 56, 286; (b) D.F. Harvey, M.F. Brown, Tetrahedron Lett. 1990, 31, 2529; (c) A. Wienand, H.-U. Reissig, Organometallics 1990, 9, 3133; (d) J.W. Herndon, S.U. Tumer, Tetrahedron Lett. 1989, 30, 4771; (e) A. Wienand, H.-U. Reissig, Tetrahedron Lett. 1988, 29, 2315; (f) K. H. Dötz, E.O. Fischer, Chem. Ber. 1972, 105, 1356; (g) E.O. Fischer, K.H. Dötz, Chem. Ber. 1970, 103, 1273. 10 (a) A. Wienand, H.-U. Reissig, Angew. Chem. 1990, 102, 10, 1156; Angew.

497

498


11 12

13

14

15 16

17 18 19

20

21 22

23 24

25 26

Chem. Int. Ed. Engl. 1990, 29, 1129; (b) M.D. Cooke, E.O. Fischer, J. Organomet. Chem. 1973, 56, 279. C.P. Casey, M.C. Cesa, Organometallics 1982, 1, 87. (a) J. Barluenga, A. Ballesteros, R. Bernardo de la Ra, J. Santamariµ, E. Rubio, M. Tomµs, J. Am. Chem. Soc. 2003, 125, 1834; (b) J. Barluenga, A. Ballesteros, J. Santamariµ, R. Bernardo de la Ra, E. Rubio, M. Tomµs, J. Am. Chem. Soc. 2000, 122, 12874. (a) C.K. Murray, D.C. Yang, W.D. Wulff, J. Am. Chem. Soc. 1990, 112, 5660; (b) B. Dorrer, E.O. Fischer, W. Kalbfus, J. Organomet. Chem. 1974, 81, C20; (c) E.O. Fischer, K.H. Dötz, Chem. Ber. 1972, 105, 3966. (a) J. Barluenga, M. Tomµs, J.A. López-Pelegín, E. Rubio, J. Chem. Soc. Chem. Commun. 1995, 665; (b) A. Wienand, H.-U. Reissig, Chem. Ber. 1991, 124, 957. I. Merino, L.S. Hegedus, Organometallics 1995, 14, 2522. J. Barluenga, F. Aznar, I. Gutíerrez, S. García-Granda, M.A. Llorca-Baragano, Org. Lett. 2002, 4, 4273. J. Pfeiffer, M. Nieger, K.H. Dötz, Eur. J. Org. Chem. 1998, 1011. K. Miki, F. Nishino, K. Ohe, S. Uemura, J. Am. Chem. Soc. 2002, 124, 5260. (a) J. Barluenga, F. Aznar, M. Fernµndez, Chem. Eur. J. 1997, 3, 1629; (b) W.D. Wulff, D.C. Yang, C.K. Murray, J. Am. Chem. Soc. 1988, 110, 2653. K.H. Dötz, Angew. Chem. 1975, 87, 18, 672; Angew. Chem. Int. Ed. Engl. 1975, 14, 644. K.H. Dötz, H. Fischer, J. Mühlemeier, R. Märkl, Chem. Ber. 1982, 115, 1355. Y.H. Choi, K.S. Rhee, K.S. Kim, G.C. Sin, S.C. Sin, Tetrahedron. Lett. 1995, 36, 1871. J.P.A. Harrity, W.J. Kerr, Tetrahedron 1993, 49, 5565. E.J. Hutchinson, W.J. Kerr, E.J. Magennis, Chem. Commun. 2002, 2262. For a more detailed discussion of carbene complex D, see:[8]. (a) K.H. Dötz, Angew. Chem. 1984, 96, 573; Angew. Chem. Int. Ed. 1984, 23,

27

28

29

30

31

32

33

34

587; (b) for EH-MO and quantum chemical calculations on the benzannulation, see: M.M. Gleichmann, K.H. Dötz, B.A. Hess, J. Am. Chem. Soc. 1996, 118, 10551; (c) P. Hofmann, M. Hämmerle, G. Unfried, New J. Chem. 1991, 15, 769; (d) P. Hofmann, M. Hämmerle, Angew. Chem. 1989, 101, 7, 940; Angew. Chem. Int. Ed. Engl. 1989, 28, 908. (a) K. Muniz, in E.P. Kündig (ed.) Transition Metal Arene p-Complexes in Organic Synthesis and Catalysis, Top. Organomet. Chem. 7, 205, Springer-Verlag, Berlin Heidelberg 2004; (b) S.E. Gibson, H. Ibrahim, C. Pasquier, J.W. Steed, Tetrahedron 2002, 58, 4617; (c) S.E. Gibson (nØe Thomas), E.G. Reddington, Chem. Commun. 2000, 989. (a) R.P. Hsung, J.F. Quinn, B.A. Weisenberg, W.D. Wulff, G.P.A. Yap, A.L. Rheingold, Chem. Commun. 1997, 615; (b) R.P. Hsung, W.D. Wulff, J. Am. Chem. Soc. 1994, 116, 6449. (a) K.H. Dötz, C. Stinner, Tetrahedron: Asymmetry 1997, 8, 1751; (b) K.H. Dötz, C. Stinner, M. Nieger, J. Chem. Soc. Chem. Commun. 1995, 2535. (a) A.V. Vorogushin, W.D. Wulff, H.-J. Hansen, J. Am. Chem. Soc. 2002, 124, 6512; (b) A.V. Vorogushin, W.D. Wulff, H.-J. Hansen, Org. Lett. 2001, 3, 2641. (a) K.H. Dötz, M. Popall, Chem. Ber. 1988, 121, 665; (b) W.D. Wulff, Y. C. Xu, J. Am. Chem. Soc. 1988, 110, 2312; (c) K.H. Dötz, M. Popall, Angew. Chem. 1987, 99, 11, 1220; Angew. Chem. Int. Ed. Engl. 1987, 26, 1158; (d) K.H. Dötz, M. Popall, G. Müller, J. Organomet. Chem. 1987, 334, 57. (a) D.L. Boger, O. Hüter, K. Mbiya, M. Zhang, J. Am. Chem. Soc. 1995, 117, 11839; (b) D.L. Boger, I.C. Jacobson, J. Org. Chem. 1991, 56, 2115; (c) D.L. Boger, I.C. Jacobson, J. Org. Chem. 1990, 55, 1919. J. Bao, W.D. Wulff, V. Dragisich, S. Wenglowsky, R.G. Ball, J. Am. Chem. Soc. 1994, 116, 7616. C.A. Merlic, D. Xu, J. Am. Chem. Soc. 1991, 113, 7418.

References 35 (a) C.A. Merlic, Y. You, D.M. McInnes,

A.L. Zechman, M.M. Miller, Q. Deng, Tetrahedron 2001, 57, 5199; (b) M. Rawat, W.D. Wulff, Org. Lett. 2004, 6, 329. 36 (a) K.L. Faron, W. D. Wulff, J. Am. Chem. Soc. 1990, 112, 6419; (b) K. L. Faron, W.D. Wulff, J. Am. Chem. Soc. 1988, 110, 8727; (c) W. D. Wulff, P.-C. Tang, K.-S. Chan, J.S. McCallum, D.C. Yang, S.R. Gilbertson, Tetrahedron, 1985, 41, 5813. 37 (a) J. Barluenga, F. Fernµndes-Marí, E. Aguilar, A.L. Viado, B. Olano, S. García-Granda, C. Moya-Rubiera, Chem. Eur. J. 1999, 5, 833; (b) J. Barluenga, F. Fernµndes-Marí, E. Aguilar, A. L. Viado, B. Olano, J. Chem. Soc. Perkin. Trans. I 1997, 2267. 38 J. Barluenga, F. Fernµndes-Marí, R. Gonzµlez, E. Aguilar, G.A. Revelli, A.L. Viado, F.J. Faæanµs, B. Olano, Eur. J. Org. Chem. 2000, 1773. 39 J. Barluenga, M.A. FernµndezRodríguez, E. Aguilar, F. FernµndezMarí, A. Salinas, B. Olano, Chem. Eur. J. 2001, 7, 3533. 40 (a) J. Barluenga, J. Alonso, F.J. Fananµs, J. Am. Chem. Soc. 2003, 125, 2610; (b) J. Barluenga, J. Alonso, F. Rodríguez, F.J. Fananµs, Angew. Chem. 2000, 112, 14, 2555; Angew. Chem. Int. Ed. Engl. 2000, 39, 2459. 41 For [2+2+1+1]benzannulation, see also Scheme 11.12. 42 J. Barluenga, I. PØrez-Sµnchez, E. Rubio, J. Flórez, Angew. Chem. 2003, 115, 6040; Angew. Chem. Int. Ed. Engl. 2003, 42, 5860. 43 Y.-T. Wu, B. Flynn, H. Schirmer, F. Funke, S. Müller, T. Labahn, M. Nötzel, A. de Meijere, Eur. J. Org. Chem. 2004, 724. 44 H. Schirmer, F. J. Funke, S. Müller, M. Noltemeyer, B. Flynn, A. de Meijere, Eur. J. Org. Chem. 1999, 2025. 45 J. Milic, H. Schirmer, B. L. Flynn, M. Noltemeyer, A. de Meijere, Synlett 2002, 6, 875. 46 H. Schirmer, B. L. Flynn, A. de Meijere, Tetrahedron 2000, 4977. 47 For a recent review, see: M.A. Sierra Chem. Rev. 2000, 100, 3591.

48 C.P. Casey, W.R. Brunsvold J. Organo-

met. Chem. 1975, 102, 175.

49 K.H. Dötz, A.W. Koch, unpublished

results.

50 K.H. Dötz, P. Tomuschat, M. Nieger,

Chem. Ber. 1997, 130, 1605.

51 P. Tomuschat, L. Kröner, E. Steckhan,

52

53

54

55 56 57 58

59

M. Nieger, K. H. Dötz, Chem. Eur. J. 1999, 5, 700. J. Schneider, M. Nieger, K. Nättinen, B. Lewall, E. Niecke, K.H. Dötz, Eur. J. Org. Chem., 2005, 1541. J. Bao, W.D. Wulff, M.J. Fumo, E.B. Grant, D.P. Heller, M.C. Whitcomb, S.-M. Yeung, J. Am. Chem. Soc. 1996, 118, 2166. (a) I. Fernµndez, M.A. Sierra, M.J. Mancheæo, M. Gómez-Gallego, S. Ricart, Organometallics 2001, 20, 4304; (b) I. Fernµndez, M.J. Mancheæo, M. Gómez-Gallego, M.A. Sierra, Org. Lett. 2003, 5, 1237. J.M. Moretó, S. Ricart, K.H. Dötz, E. Molins, Organometallics 2001, 20, 62. K.H. Dötz, L. Quast, unpublished results. L. Quast, M. Nieger, K.H. Dötz Organometallics 2000, 19, 2179. For recent reviews on olefin metathesis, see: (a) Handbook of Metathesis (R.H. Grubbs, ed.), Wiley-VCH, Weinheim 2003; (b) B. Schmidt, J. Hermanns, in K.H. Dötz (ed.) Metal Carbenes in Organic Synthesis, Top. Organomet. Chem. 13, 223, Springer-Verlag, Berlin Heidelberg 2004; (c) J. Mulzer, ibid., 269; (d) S. J. Connon, S. Blechert, Angew. Chem. 2003, 115, 1944; Angew. Chem. Int. Ed. Engl. 2003, 42, 1990; (e) R.R. Schrock, A.H. Hoveyda, Angew. Chem. 2003, 115, 4740; Angew. Chem. Int. Ed. Engl. 2003, 42, 4592; (f) R.R. Schrock, Chem. Rev. 2002, 102, 145; (g) A. Fürstner, Angew. Chem. 2000, 112, 3140; Angew. Chem. Int. Ed. Engl. 2000, 39, 3012; (h) A. Fürstner, in (A. Fürstner, ed.) Alkene Metathesis in Organic Synthesis, Top. Organomet. Chem. 1, Springer, Berlin Heidelberg 1998, 37; (i) M. Schuster, S. Blechert, Angew. Chem. 1997, 109, 2124; Angew. Chem. Int. Ed. Engl. 1997, 36, 2036. Phillips Petroleum Company, Hydrocarbon Process 1967, 46, 232.

499

500

11 Polyfunctional Metal Carbenes for Organic Synthesis 60 (a) E.R. Freitas, C.R. Gum, Chem. Eng.

Prog. 1979, 75, 73; (b) Shell International Chemical Company, SHOP - Linear Alpha Olefins (Company publication), 1982. 61 J.H. HØrisson, Y. Chauvin, Macromol. Chem. 1971, 141, 161. 62 (a) C.P. Casey, T.J. Burkhardt, J. Am. Chem. Soc. 1974, 96, 7808; (b) C.P. Casey, H.E. Tuinstra, M.C. Saemen, J. Am. Chem. Soc. 1976, 98, 608; (c) C.P. Casey, T.J. Burkhardt, C.A. Bunell, J.C. Calabrese, J. Am. Chem. Soc. 1977, 96, 2127. 63 J. McGinnis, T.J. Katz, S. Hurwitz, J. Am. Chem. Soc. 1976, 98, 605. 64 (a) T.J. Katz, S.J. Lee, N. Acton, Tetrahedron Lett. 1976, 17, 1592; (b) T.J. Katz, N. Acton, Tetrahedron Lett. 1976, 17, 4251. 65 For a recent review, see: R.R. Schrock, in (G. Bertrand, ed.) Carbene Chemistry ± From Fleeting Intermediates to Powerful Reagents, Marcel Dekker, New York 2002, 205. 66 J.H. Wengrovius, R.R. Schrock, M.R. Churchill, J.R. Missert, W.J. Youngs, J. Am. Chem. Soc. 1980, 102, 4515. 67 J. Kress, M. Wesolek, J.A. Osborn, J. Chem. Soc. Chem. Commun. 1982, 514. 68 R.R. Schrock, R.T. DePue, J. Feldman, C.J. Schaverien, J.C. Dewan, A.H. Liu, J. Am. Chem. Soc. 1988, 110, 1423. 69 R.R. Schrock, J.S. Murdzek, G.C. Bazan, J. Robbins, M. DiMare, M. O'Regan, J. Am. Chem. Soc. 1990, 112, 3875. 70 (a) S.T. Nguyen, L.K Johnson, R.H. Grubbs, J.W. Ziller, J. Am. Chem. Soc. 1992, 114, 3974; (b) P. Schwab, R.H. Grubbs, J.W. Ziller, J. Am. Chem. Soc. 1996, 118, 100. 71 (a) S.T. Diver, A.J. Giessert, Chem. Rev. 2004, 104, 1317; (b) M. Mori, in (R.H. Grubbs, ed.) Handbook of Metathesis, Vol.1: Catalyst Development, Weinheim 2003, 176; (c) C.S. Poulsen, R. Madsen, Synthesis 2003, 1; (d) M. Mori in (A. Fürstner, ed.) Alkene Metathesis in Organic Synthesis, Top. Organomet. Chem. 1, Springer-Verlag, Berlin Heidelberg 1998, 133.

72 Alkyne metathesis catalyzed by metal

carbynes combined with subsequent stereoselective reduction provides an option to overcome the problem of insufficient E/Z-selectivity in olefin metathesis. For a leading reference, see: A. Fürstner, in (R.H. Grubbs, ed.), Handbook of Metathesis, Vol.2: Application in Organic Synthesis, Wiley-VCH, Weinheim 2003, 432. 73 For reviews, see: (a) K. C. Nicolaou, F. Roschangar, D. Vourloumis, Angew. Chem. 1998, 110, 2120; Angew. Chem. Int. Ed. Engl. 1998, 37, 2014; (b) C. R. Harris, S. J. Danishefsky, J. Org. Chem. 1999, 64, 8434. 74 (a) D. Meng, D.-S. Su, A. Balog, P. Bertinato, E.J. Sorensen, S.J. Danishefsky, Y.-H- Zheng, T.-C. Chou, L. He, S. B. Horwitz, J. Am. Chem. Soc. 1997, 119, 2733; (b) Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K.C. Nicolaou, Angew. Chem. 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; (c) D. Schinzer, A. Limberg, A. Bauer, O.M. Böhm, M. Cordes, Angew. Chem. 1997, 109, 543; Angew. Chem. Int. Ed. Engl. 1997, 36, 523. 75 (a) D. Meng, P. Bertinato, A. Balog, D.-S. Su, T. Kamenecka, E. J. Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10092; (b) S. A. May, P. A. Grieco, Chem. Commun. 1998, 1597. 76 (a) A. Fürstner, G. Seidel, J. Organomet. Chem. 2000, 606, 75. 77 (a) A. Fürstner, C. Mathes, K. Grela, Chem. Commun. 2001, 1057; (b) A. Fürstner, C. Mathes, C. W. Lehmann, Chem. Eur. J. 2001, 7, 5299. 78 (a) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953; (b) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 8168; (c) S. Gessler, R. Randl, S. Blechert, Tetrahedron Lett. 2000, 41, 9973. 79 J. A. Love, J. P. Morgan, T. M. Trnka, R. H. Grubbs, Angew. Chem. 2002, 114, 4207; Angew. Chem. Int. Ed. Engl. 2002, 41, 4035. 80 (a) A. H. Hoveyda, R. R. Schrock, Chem. Eur. J. 2001, 7, 945; (b) S. A. Aeilts,

References

81

82 83

84

85

86

87

88

89

D. R. Cefalo, P. J. Bonitatebus Jr., J. H. Houser, A. H. Hoveda, R. R. Schrock, Angew. Chem. 2001, 113, 1500; Angew. Chem. Int. Ed. Engl. 2001, 40, 1452. (a) J. B. Alexander, D.S. La, D.R. Cefalo, A.H. Hoveyda, R.R. Schrock, J. Am. Chem. Soc. 1998, 120, 4041; (b) D.S. La, J.B. Alexander, D.R. Cefalo, D.D. Graf, A.H. Hoveyda, R.R. Schrock, J. Am. Chem. Soc. 1998, 120, 9720. S.D. Burke, N. Müller, C.M. Beaudry, Org. Lett. 1999, 1, 1827. A.F. Kiely, J.A. Jernelius, R.R. Schrock, A.H. Hoveyda, J. Am. Chem. Soc. 2002, 124, 2868. S.J. Dolman, E.S. Sattely, A.H. Hoveyda, R.R. Schrock, J. Am. Chem. Soc. 2002, 124, 6991. (a) J.P.A. Harrity, D.S. La, D.R. Cefalo, M.S. Visser, A.H. Hoveyda, J. Am. Chem. Soc. 1998, 120, 2343; (b) G.S. Weatherhead, J.G. Ford, E.J. Alexanian, R.R. Schrock, A.H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 1828; (c) D.R. Cefalo, A.F. Kiely, M. Wuchrer, J.Y. Jamieson, R.R. Schrock, A.H. Hoveyda, J. Am. Chem. Soc. 2001, 1232, 3139; (d) X. Teng, D.R. Cefalo, R.R. Schrock, A.H. Hoveyda, J. Am. Chem. Soc. 2002, 124, 10779. (a) D.S. La, J.G. Ford, E.S. Sattely, J.P.L. Bonitatebus, R.R. Schrock, A.H. Hoveyda, J. Am. Chem. Soc. 1999, 121, 11603; (b) D.S. La, E.S. Sattely, J.G. Ford, R.R. Schrock, A.H. Hoveyda, J. Am. Chem. Soc. 2001, 123, 7767. K.C. Hultzsch, J.A. Jernelius, A.H. Hoveyda, R.R. Schrock, Angew. Chem. 2002, 114, 609; Angew. Chem. Int. Ed. Engl. 2002, 41, 589. a) K. Öfele, M. Herberhold, Angew. Chem. 1970, 82, 775; Angew. Chem. Int. Ed. Engl. 1970, 9, 739 ; b) C.G. Kreiter, K. Öfele, G.W. Wieser, Chem. Ber. 1976, 109, 1749. a) S.-T. Liu, T.-Y. Hsieh, G.-H- Lee, S.-M. Peng, S.-T. Liu, Organometallics 1998, 17, 993; b) R.-Z. Ku, J.-C. Huang, J.-Y. Cho, F.-M. Kiang, K.R. Reddy, Y.-C. Chen, K.-J. Lee, J.-H. Lee, G.-H. Lee, S.-M. Peng, S.-T. Liu, Organometallics 1999, 18, 2145; c) for a review,

90

91 92

93

94

95 96

97 98

see : S.-T. Liu, K.R. Reddy, Chem. Soc. Rev. 1999, 28, 315. a) E.O. Fischer, H.-J. Beck, Angew. Chem. 1970, 82, 44; Angew. Chem. Int. Ed. Engl. 1970, 9, 72; b) E.O. Fischer, H.-J. Beck, Chem. Ber. 1971, 104, 3101; c) E.O. Fischer, H.-J. Beck, C.G. Kreiter, J. Lynch, J. Müller, E. Winkler, Chem. Ber. 1972, 105, 162. R. Aumann, E.O. Fischer, Chem. Ber. 1981, 114, 1853. H. Fischer, S. Zeuner, K. Ackermann, J. Schmid, Chem. Ber. 1986, 119, 1546; for another examples of the thermal behavior of (CO)5W=CPh2 see [62]. a) E.O. Fischer, B. Heckl, K.H. Dötz, J. Müller, J. Organomet. Chem. 1969, 16, P29; b) C.P. Casey, R. L. Anderson, J. Chem. Soc., Chem. Commun. 1975, 895; for intramolecular examples, see : c) D.W. Macomber, M.-H. Hung, A.G. Verma, Organometallics 1988, 7, 2072; d) J. Bao, W.D. Wulff, M.J. Fumo, E.B. Grant, D.P. Heller, M.C. Whitcomb, S.-M. Yeung, J. Am. Chem. Soc. 1996, 118, 2166; e) H.T. Huy, P. LeFloch, J.M. Louis, M. Fetizon, J. Organomet. Chem. 1986, 311, 79. a) M.A. Sierra, M.J. Mancheæo, E. Sµez, J.C. del Amo, J. Am. Chem. Soc. 1998, 120, 6812; b) M.A. Sierra, J.C. del Amo, M. J. Mancheæo, M. Gómez-Gallego, J. Am. Chem. Soc. 2001, 123, 851; c) M.A. Sierra, J.C. del Amo, M. J. Mancheæo, M. Gómez-Gallego, M.R. Torres, Chem. Commun. 2002, 1842; d) M.A. Sierra, P. Ramírez-López, M. Gómez-Gallego, T. Lejon, M. J. Mancheæo, Angew. Chem. 2002, 114, 3592; Angew. Chem. Int. Ed. Engl. 2002, 41, 3442; e) F. Robin-Le Guen, P. Le Poul, B. Caro, N. Faux, N. Le Poul, S.J. Green, Tetrahedron Lett. 2002, 43, 3967. H. Sakurai, K. Tanabe, K. Narasaka, Chem. Lett. 1999, 75. R. Aumann, I. Göttker-Schnetmann, R. Fröhlich, O. Meyer, Eur. J. Org. Chem. 1999, 2545. I. Göttker-Schnetmann, R. Aumann, Organometallics 2001, 20, 346. I. Göttker-Schnetmann, R. Aumann, K. Bergander, Organometallics 2001, 20, 3574.

501

502

11 Polyfunctional Metal Carbenes for Organic Synthesis 99 B.F. Straub, P. Hofmann, Angew. Chem.

100

101

102

103 104

105 106

107 108 109 110 111 112 113

2001, 113, 1328; Angew. Chem. Int. Ed. Engl. 2001, 40, 1288. J. Barluenga, L.A. López, O. Löber, M. Tomµs, S. García-Granda, C. Alvarez-Ra, J. Borge, Angew. Chem. 2001, 113, 3495; Angew. Chem. Int. Ed. Engl. 2001, 40, 3392. J. Barluenga, P. Barrio, R. Vicente, L.A. López, M. Tomµs, J. Organomet. Chem. 2004, 689, 3793. (a) K. Severin, R. Bergs, W. Beck, Angew. Chem. 1998, 110, 1722; Angew. Chem. Int. Ed. Engl. 1998, 37, 1634; (b) for a conference report, see: Chem. Eng. News 2002, 80, 23. K. Weiû, E.O. Fischer, Chem. Ber. 1973, 106, 1277. Crpc = pentacarbonyl-chromium-phenylcarbenyl, see: K. Weiû, E.O. Fischer, Chem. Ber. 1976, 109, 1868 and references therein. H. Dialer, K. Polborn, W. Beck, J. Organomet. Chem. 1999, 589, 21. (a) C. Dubuisson, Y. Fukumoto, L.S. Hegedus, J. Am. Chem. Soc. 1995, 117, 3697; (b) J.R. Miller, S.R. Pulley, L.S. Hegedus, J. Am. Chem. Soc. 1992, 114, 5602; (c) for a recent review of photoinduced reactions of metal carbenes with amino acids and peptides, see: L.S. Hegedus in K.H. Dötz (ed.) Metal Carbenes in Organic Synthesis, Top. Organomet. Chem. 13, 157, Springer-Verlag, Berlin Heidelberg 2004. R.O. Duthaler, A. Hafner, Chem. Rev. 1992, 92, 807. K.H. Dötz, R. Ehlenz, Chem. Eur. J. 1997, 3, 1751. R. Aumann, Chem. Ber. 1992, 125, 2773. K.H. Dötz, D. Paetsch, H. Le Bozec, J. Organomet. Chem. 1999, 589, 11. E. Janes, K.H. Dötz, J. Organomet. Chem. 2003, 669, 1. E. Janes, K.H. Dötz, J. Organomet. Chem. 2001, 622, 251. (a) K.H. Dötz, W. Straub, R. Ehlenz, K. Peseke, R. Meisel, Angew. Chem. 1995, 107, 2023; Angew. Chem. Int. Ed. Engl. 1995, 34, 1856; (b) K.H. Dötz, R. Ehlenz, W. Straub, J.C. Weber, K. Airola, M. Nieger, J. Organomet. Chem. 1997, 548, 91.

114 (a) K.H. Dötz, O. Neuû, M. Nieger,

Synlett, 1996, 995; (b) R. Ehlenz, O. Neuû, M. Teckenbrock, K.H. Dötz, Tetrahedron 1997, 53, 5143; (c) B. Weyershausen, M. Nieger, K.H. Dötz, Organometallics 1998,17, 1602. 115 K.H. Dötz, A.W. Koch, unpublished results. 116 K.H. Dötz, M. Nieger, A.W. Koch, unpublished results. 117 E. Janes, M. Nieger, P. Saarenketo, K.H. Dötz, Eur. J. Org. Chem. 2003, 2276. 118 (a) K.H. Dötz, C. Jäkel, W.-C. Haase, J. Organomet. Chem. 2001, 617±618, 119; (b) W.-C. Haase, M. Nieger, K.H. Dötz, Chem. Eur. J. 1999, 5, 2014. 119 C. Jäkel, K.H. Dötz, Tetrahedron 2000, 56, 2167. 120 C. Jäkel, K.H. Dötz, Z. Anorg. Allg. Chem. 2003, 629, 1107. 121 K.H. Dötz, E. Gomes da Silva, Synthesis, 2003, 12, 1787. 122 S. Abrats, Ph.D. Thesis, University of Bonn, 1998. 123 (a) F.G.A. Stone, Angew. Chem. 1984, 96, 85; Angew. Chem. Int. Ed. Engl. 1984, 23, 89; (b) R. Hoffmann, Angew. Chem. 1982, 94, 725; Angew. Chem. Int. Ed. Engl. 1982, 21, 734. 124 J. H. Fuhrhop, W. Helfrich, Chem. Rev. 1993, 93, 1565. 125 For an excellent review on low-molecular mass gelators, see: P. Terech, R. G. Weiss, Chem. Rev. 1997, 97, 3133. 126 R.J.H. Hafkamp, M.C. Feiters, R.J.M. Nolte, J. Org. Chem. 1999, 64, 412. 127 G. Bühler, M.C. Feiters, R.J.M. Nolte, K.H. Dötz, Angew. Chem. 2003, 115, 2599; Angew. Chem. Int. Ed. 2003, 42, 2494. 128 K. Murata, M. Aoki, T. Suzuki, T. Harada, H. Kawabata, T. Komori, F. Ohseto, K. Ueda, S. Shinkai, J. Am. Chem. Soc. 1994, 116, 6664. 129 G. Bühler, F. Zschoche, T. Klawonn, N. Hüsing, M.C. Feiters, R.J.M. Nolte, N. Theyssen, W. Assenmacher, K.H. Dötz, manuscript in preparation.

503

12 Functionalized Organozirconium and Titanium in Organic Synthesis Ilan Marek and Helena Chechik-Lankin

12.1 Introduction

The time is apt for chemists to fully enter the world of functionalized organozirconium and organotitanium chemistry. Both of these metal complexes are versatile intermediates due to their ambiphilic nature (1) utilization of these complexes as a source of carbanions (carbon±metal r-bond) (2) Utilization of these complexes is based on late transition-metal behavior, such as coordination of a carbon±carbon multiple bond, oxidative addition, reductive elimination, b-hydride elimination or addition reaction [1]. This chapter surveys the preparation and synthetic application of these two group IV early transition-metal complexes with a special emphasis on the synthesis of stable functionalized carbon nucleophiles. Functionalized reactive intermediates as well as chemoselective reactions on functionalized electrophiles will not be addressed in this chapter. 12.2 Functionalized Organozirconocene Derivatives 12.2.1 Preparation of Functionalized Alkenylzirconocene Derivatives

One of the major sources of access to alkenylzirconocene intermediates [2] is through the hydrozirconation of alkynes with the Schwartz reagent Cp2Zr(H)Cl. Kinetically and thermodynamically favored syn-addition of this complex onto a terminal or internal alkyne followed by in situ treatment with electrophiles affords polysubstituted alkenes in high stereochemical purity (Scheme 12.1).

R1

R2

(H)ZrCp2Cl solvent

R1

R2

H

ZrCp2Cl

E+

R1

R2

H

E

Scheme 12.1 Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

504

12 Functionalized Organozirconium and Titanium in Organic Synthesis

In general, the functional group compatibility of the process is limited by the oxophilic, hard Lewis-acid character of the Schwartz reagent. The following examples demonstrate the scope of this tolerance. Hydrozirconation of the tert-butyl ester of 5-hex-ynoic acid 1 proceeds in 81% yield with little discernible competitive reduction of the ester functional group, whereas comparative hydrozirconation of the methyl ester gave only 41% of the desired zirconium alkenyl, with a large amount of reduced carboxylate product [3] (Scheme 12.2). OBu-t

H 1

(H)ZrCp2Cl

O

benzene

H ClCp2Zr

OBu-t O

O 1)

Ph

O

O

C5H11 t-BuMe2SiO

O

Ni(acac)2/DIBAL-H 2)

Ph

H3O+

OBu-t

O C5H11 t-BuMe2SiO 66 %

Scheme 12.2

Treatment of Cp2ZrCl2 with LiEt2BH in THF leads also to the formation of Cp2Zr(H)Cl. Subsequent introduction of terminal acetylenes gives the hydrozirconation reaction without compromising the acid-sensitive functionality present in the alkyne (Scheme 12.3) [4]. Cp2ZrCl2 LiEt3BH THF, 1h r.t.

O O

Cp2Zr(H)Cl + Et3B

O

Cp2ClZr

2O

O

I2

Ph Ph

I

O

80 %

N O O Cp2ClZr

N O

O H2O

N O 87 %

Scheme 12.3

O

2

Ph

12.2 Functionalized Organozirconocene Derivatives

505

The extreme mildness and rapidity with which vinyl zirconocenes undergo transmetallation reactions with cyanocuprate at low temperatures leads directly to the corresponding functionalized mixed cuprate with internal electrophiles. Introduction of an a,b-unsaturated ketone affords the expected 1,4-adduct in good isolated yield. This simple, one-pot process has been applied to alkynes, which possess a nitrile 2, ester 3 or chloride 4 residues (Scheme 12.4) [5].

CN

ClCp2Zr

THF, r.t.

H

1. Me2CuCNLi2 THF, -78 ºC

Cp2Zr(H)Cl CN

O

CN

O 2.

2

75 % OSi(Pr-i)3 H

Cp2Zr(H)Cl

OSi(Pr-i)3

ClCp2Zr

THF, r.t.

O

O

3a 1. Me2CuCNLi2 THF, -78 ºC

O

OSi(Pr-i)3 O

O 2.

78 %

OSi(Pr-i)3

OSi(Pr-i)3

ClCp2Zr

THF, r.t.

O

H

Cp2Zr(H)Cl O

3a 1. Me2CuCNLi2 THF, -78 ºC

O

OSi(Pr-i)3 O

O 2.

78 %

O

Cp2Zr(H)Cl

Ph O

H

O

ClCp2Zr

THF, r.t.

Ph O

3b 1. Me2CuCNLi2 THF, -78 ºC

O

O

Ph O

O 2.

71%

Cl

Cp2Zr(H)Cl THF, r.t.

H 4

Scheme 12.4

ClCp2Zr

Cl

1. Me2CuCNLi2 THF, -78 ºC

O

Cl

O 2. 95%

506


Alternatively, the hydrozirconation of 4 can be performed with i-BuZrCp2Cl generated in situ by the treatment of Cp2ZrCl2 with i-BuMgCl in benzene at 50 C [5c]. When the sequence described in Scheme 12.4 is applied to 5-hexynoic acid ethyl or methyl ester (3c,d), no transmetallation-1,4-addition reaction was observed. These failures to transmetallate may be a consequence of intra- and/or intermolecular chelation of the ester carbonyl group with the Zr(IV) present (Scheme 12.5) [5]. O RO

ZrCp2Cl

ClCp2Zr

O

5e

O ClCp2Zr

N(Pr-i)2

OR

O ClCp2Zr

R = Et 3c R = Me 3d R = N(Pr-i)3 3e R = N(TMS)2 3f

N(TMS)2 5f

Scheme 12.5

Indeed, intra-or intermolecular chelation shuts down ligand exchange with Me2CuCNLi2 and, hence, vinylcuprate formation. However, replacement of R = OEt, OMe with R = OSi(Pr-i)3 on steric or stereoelectronic grounds completely restores the transmetallation pathway (Scheme 12.4). In support of these arguments, all attempts to effect the above-described sequence with amides 3e,f produces the alkenes 5e and 5f, respectively, but they do not undergo transmetallation reactions [5]. Several other examples of the hydrozirconation of functionalized alkyne were further described and the reactivity of the corresponding vinyl zirconocene derivatives was explored in detail either by addition of a Lewis acid [6] or by a transmetallation reaction into alkenyl zinc derivatives [7±10] as described in Scheme 12.6. The asymmetric addition of organozinc reagents to aldehydes is one of the most thoroughly studied and successful enantioselective processes. While chiral ligand selection is much more delicate for the Zr±Zn system, due to the fast background addition reaction mediated by the achiral zirconocene that is present in stoichiometric amounts in the reaction mixture, chiral allylic alcohols can be obtained in >92% when amino thiols are used as chiral inducers (Scheme 12.7) [11]. Treatment of 1-tributylstannylalkynes with Cp2Zr(H)Cl affords olefinic inter2 mediates substituted by both Bu3Sn and Cp2ZrCl groups on the terminal sp -like carbon (Scheme 12.8) [12].

12.2 Functionalized Organozirconocene Derivatives Ph

O

(H)ZrCp2Cl

Ph

O

O

O

Ph

O ZrCp2Cl

507

O

O

AgClO4, 5% ref. 6

OH 68 %

Ph

O

O

Ph OH 92 % syn:anti = 85:15

1. Me2Zn -65 ºC

1. Me2Zn -65 ºC

2. PhCH(Me)CHO 0 ºC, 1.5h

2. PentCHO 0 ºC

Ph

O Pent

O

OH

ref. 7

72 %

ref. 9

HZrCp2Cl

OSi(Pr-i)3 O

ClCp2Zr

CH2Cl2 ref. 8

OSi(Pr-i)3 O Me2Zn -78 ºC to 0 ºC

CHO OH

O

Bu3Sn

MeZn OSi(Pr-i)3

CHO Bu Sn 3 OSi(Pr-i)3

ref. 10

0 ºC, 3 h

O

44 %

73 %

CHO 0 ºC, to r.t./3h

H

OH OSi(Pr-i)3 O 60 %

Scheme 12.6

H

1. Cp2Zr(H)Cl OTIPS 2. Me2Zn, toluene O

3.

NMe2 10 mol% SH 4. PhCHO, -30 ºC

Scheme 12.7

OH OTIPS

Ph

Et

OSi(Pr-i)3 OH

O 67 % 92 % ee

O

508


O

O

SnBu3

Cp2Zr(H)Cl

(i-Pr)3SiO SnBu3

(i-Pr)3SiO

THF r.t.

O

1. MeLi 2. Me(L)CuCNLi2 L = 2-thienyl

SnBu3

(i-Pr)3SiO 75 %

Br

3.

ZrCp2Cl

Scheme 12.8

The stereodefined Sn/Zr reagent can be selectivity transmetallated at the zirconium center to afford the corresponding cuprate that react in a clean SN2¢ reaction with allylbromide. The functionalized Z-vinyl tin derivative is therefore easily formed in 75% yield. From this preliminary discussion, the hydrozirconation reaction of alkynes is a valuable process but the scope of functional groups present in the carbon skeleton is rather limited to specific esters. In order to circumvent the limitations, acylsilanes were designed as a synthetic equivalent to carbonyl groups. Treatment of 6 with Cp2Zr(H)Cl afforded a 80% yield of the desired olefin 7 with no detectable amount of the carbonyl 1,2-adduct (Scheme 12.9) [13]. O H

(CH2)5 SiEt3

6

1. Cp2Zr(H)Cl THF, r.t. 30 min 2. H+

O (CH2)5

SiEt3

7 80 %

Scheme 12.9

By switching to the triisopropylsilyl (TIPS) analog, however, hydrozirconation fully consumes the alkynes 8 and 9 to ultimately afford the vinyl zirconocene 10 and 11, respectively, in quantitative yields (Scheme 12.10) [13]. O Si 3

O

Cp2Zr(H)Cl THF, r.t. 30 min

8 O O

Si 3 9

Si 3

3

10

80 %

O O

Si

ZrCp2Cl

O

H+

O

Si 3

3 11

Scheme 12.10

Br

Si

Cp2Zr(H)Cl THF, r.t. 30 min

O

ZrCp2Cl NBS

83 %


509

Notwithstanding the heartiness of this group in resisting reduction by Schwartz' reagent or its reluctance to serve as a Lewis base toward zirconocene intermediates, its manipulation to other-valued functionality is straightforward. Thus, following hydrozirconation of 8, transmetallation and 1,4-addition of cuprate 12, followed by treatment of the final adduct 13 with NBu4F in THF smoothly affords the ketoaldehyde 14 in 93% yield (Scheme 12.11) [13]. O

1. Cp2Zr(H)Cl/THF 2. Me2CuCNLi2 THF, -78 ºC

Si 3 8

O

CuCNMeLi2

Si 3 12

O

O Si 3

THF r.t.

13 86 %

O

O

NBu4F

O -78 ºC then H3O+

H 14 93 %

Scheme 12.11

Thus, carbonyl surrogate TIPS acylsilanes are resistant to 1,2-addition by Cp2Zr(H)Cl therefore allowing the hydrozirconation of the alkyne but can be further transmetallated into organocopper derivatives for subsequent transformations. The selective one-pot synthesis of ketones from acid halides and functionalized alkynes based on a hydrozirconation-copper(I)-catalyzed addition reaction has also been reported as a very efficient transformation even in the presence of very labile functionality (Scheme 12.12) [14]. I

1. Cp2Zr(H)Cl, THF, 20 ºC, 20 min 2. CuBr·Me2S (cat) 35 ºC, 20 min

O Ph

I

O Ph

Cl

Scheme 12.12

No overaddition of the organometallic reagent, a side reaction that is typical for ketone synthesis from acid halides, was observed. Hydrozirconation of functionalized alkyne 8 in CH2Cl2 with the Schwartz reagent followed by in situ transmetallation to Me2Zn and addition of N-diphenylphosphinoylimine 15 provides the functionalized trans-aminocyclopropane 16 in 60% yield [15]. The cyclopropane formation can be rationalized by the formation of a transient zinc-carbenoid species from CH2Cl2, which subjected the intermediate allylic amine derivative to an efficient Simmons±Smith-type cyclopropanation.

510


To improve the yield, CH2I2 was added to the reaction mixture and the desired amino cyclopropane was obtained in 73% yield (Scheme 12.13) [15]. O Si(Pr-i)3

H

Ph

(i-Pr)3Si

2. Me2Zn 3. Ph N PO Ph Ph 15

O

8

1. Cp2Zr(H)Cl

HN 16 d.r. > 95:5 73%

P

O

Ph Ph

4. CH2I2, 2h, CH2Cl2 Scheme 12.13

Interestingly, the order of addition of reagents proved to be crucial for product formation. Indeed, addition of CH2I2 to the reaction mixture prior to imine led to a switch from cyclopropylamine 16 to the homoallylic amine 17 in moderate yield and diastereoselectivity (Scheme 12.14) [16]. O Si(Pr-i)3

H O 8

Ph P NH Ph Ph

1. Cp2Zr(H)Cl 2. Me2Zn 3. CH2I2 4. Ph

O Si(Pr-i)3 17

N Ph

O P

anti:syn = 62:38 48 %

Ph

CH2Cl2, Scheme 12.14

Several natural products total syntheses used the hydrozirconation-transmetallation strategy for the construction of a structurally elaborated carbon framework such as the preparation of polyene segment in (+)-curacin A and in the manumycin family [17]. An interesting diastereoselective transmetallation reaction of functionalized Zr to Zn was also recently reported in the synthesis of fostriecine 18 [18] and an enantioseletive transformation of functionalized Zr to Zn followed by reaction with an aldehyde was also reported at a late stage of the total synthesis of (+)-halichlorine 19 (Scheme 12.15) [19].


511

O 1. Cp2Zr(H)Cl i-PrO

O

i-PrO H 2. Me2Zn 3. O

H

O

OTES CH3

H

O 4. TESCl

NaHO3PO O

O

H

OH OH

H3C OH Fostriecine 18

H O

N

O

2. Me2Zn, heptane 3. 10mol %

OBu-t

H

H 1. Cp2Zr(H)Cl CH2Cl2

H HO 4. R

Cl

H

H

Cl

Ph R

Cl

N O

OBu-t

Ph N

O

N

OH

OH

CHO

(+) - Halichlorine 19

67 % dr = 4:1

Scheme 12.15

12.2.2 Preparation of Functionalized Alkylzirconocene Derivatives

As described for the hydrozirconation of alkynyl derivatives containing a triisopropylsilyl acylsilane moiety (see Schemes 12.9 and 12.10), the hydrozirconation of alkene 20 and subsequent hydrolysis led to the alkane 21 in 94% yield (Scheme 12.16) [13]. O

O

Cp2Zr(H)Cl

(i-Pr)3Si

THF, r.t. 30 min 20

(i-Pr)3Si

H

ZrCp2Cl

O

H2O (i-Pr)3Si

94 % 21

Scheme 12.16


512

In the presence of 3±10 mol% of Cu(I) salts such as CuBr´Me2S, functionalized alkylzirconocenes add readily to a,b-unsaturated ketones, as described in Scheme 12.17 [20]. O OTIPS Cp2Zr(H)Cl Cp2ClZr O

OTIPS

THF, 15 min.

O

O

CuBr·Me2S 10 mol%

OTIPS

40 ºC, 10 min O

78 %

Scheme 12.17

5-Chloro-1-pentene 22 also undergoes the hydrozirconation reaction and can be either trapped with O-(mesitylsulfonyl) hydroxylamine (MSH) [21] 23 or with 2-chlorotetrahydropyran 24 [22] to lead to the corresponding primary amine 25 and ether 26, respectively, in good isolated yield (Scheme 12.18). SO2ONH2

23 (MSH)

Cp2(H)ZrCl Cl

THF, 0 ºC

Cl

ZrCp2Cl

Et2O, 10 min

Cl

NH2 25 78 %

22 O Cl 24 CuCl 10 mol %

Cl

O 26 83 %

Scheme 12.18

Although the reactions of Cp2Zr(H)Cl with oxirane derivatives have been reported to reduce the three-membered ring in a regioselective manner to give the corresponding alcohol [23], the treatment of an equimolar mixture of oxirane 27 and alkene 28 with 1 equivalent of Cp2Zr(H)Cl yielded an exclusive hydrozirconation reaction of the alkene and no traces of the oxirane ring-opening product (Scheme 12.19) [24].

12.2 Functionalized Organozirconocene Derivatives Cp2Zr(H)Cl

BnO O

+

27

BnO

BnO

CH2Cl2, r.t.

O

+

ZrCp2Cl

BnO

28

Scheme 12.19

As the hydrozirconation of alkene Z- and E-29 is faster than the reduction of oxirane, the reaction of Cp2Zr(H)Cl with those vinyloxiranes 29 in CH2Cl2 was reported to be an original alternative to optically active cyclopropyl carbinols 30 (Scheme 12.20) [24].

O

H

H

Ph

OH

1. Cp2Zr(H)Cl/CH2Cl2 r.t. Ph

2. aq. NaHCO3

30 syn

Z-29 O

Ph

H

H

OH

1. Cp2Zr(H)Cl/CH2Cl2 r.t. Ph

2. aq. NaHCO3

OH +

Ph

30 anti, trans / anti, cis: 3.9

E-29

Scheme 12.20

The same strategy was applied to the formation of cyclopentylcarbinol derivatives 32 as described in Scheme 12.21 [25].

1

R R2

O

H 3

R

Cp2Zr(H)Cl 4

R

CH2Cl2, r.t.

1

R R2

O

BF3·OEt2

H ZrCp2Cl

R3 31

4

R

R2 3

R

R1

OH H

R4 32 50-77 %

Scheme 12.21

Without the addition of a Lewis acid, the cyclization did not take place and only the alkylzirconocene 31 is present. The intramolecular nucleophilic attack of the organometallic to the oxirane ring was promoted by adding a silver salt or BF3ÓEt2. In all examined cases, the cyclization proceeds through an inversion of configuration at the reacting oxirane center and only the 5-exocyclization mode was observed. Attempts to prepare four- and six-ring types failed [25]. The hydrozirconation reaction of monosubstituted alkenes with i-BuZrCp2 can be accelerated by addition of catalytic amounts of various Lewis acids. For example, 9-decenyl benzoate reacted with i-BuZrCp2Cl and 5 mol% of Cl2Pd(PPh3)2 to give, after protonolysis, decyl benzoate in 74% yield [26].

513

514


12.2.3 Preparation and Reactivity of Acylzirconocene Derivatives

Acylzirconocene chloride derivatives are readily accessible in a one-pot procedure through the hydrozirconation of alkene or alkyne derivatives with zirconocene chloride hydride and subsequent insertion of carbon monoxide into the alkyl± or alkenyl±zirconocene bond under atmospheric pressure. The pioneering study on the preparation and reactivity of acylzirconocene dated back to the initial study of Schwartz [27] and revealed that an acyl group can be converted into a large variety of carboxylic acid derivatives (Scheme 12.22). alkenes 1. Cp2Zr(H)Cl or alkynes 2. CO (1 atm)

H3O+

O

RCHO R

ZrCp2Cl

H2O2

O R

2 Br H O H3 C

N BS

Acylzirconocene chloride

O Br

R

O OH

R

OMe

Scheme 12.22

A convenient method for the transformation of suitably protected propargyl alcohol into 3,5-disubstituted butenolides has been developed by using the acylation reaction of vinyl zirconocene derivatives (Scheme 12.23) [28]. R1

OR3 Cp2Zr(H)Cl

R2

C6H6

R1

R2

R1 OR3

R2

CO C6H6

ClCp2Zr

ClCp2Zr O

1

R R2

I2

I

I

R1 R2

O 34

R2

O R1 37

Scheme 12.23

+

R3I

O O R3 R1

35

O

33

R2

O R3O

OR3

OR3

36

, I-


This one-pot procedure was carried out essentially as described originally by Schwartz and the in situ treatment of 33 with I2 provides the butenolides 37 via the formation of E-a,b-unsaturated acyl iodide 34. In the presence of excess I2, 34 is in equilibrium with its Z-isomer 35 that is subjected to intramolecular nucleophilic attack by the adjacent ether oxygen to form the zwitterionic intermediate 3 36. Loss of R -I from 36 gives 37. This organozirconium-based method transforms optically active propargylic alcohol into the corresponding butenolides with no loss of optical activity [28]. Acylzirconocene reacts also with aldehydes, in the presence of a Lewis acid such as BF3ÓEt2, to give the corresponding a-ketol in moderate to good yields (Scheme 12.24) [29]. O n-H13C6

O ZrCp2Cl

+

Ph

BF3. OEt2

H

CH2Cl2

O Ph

n-H13C6

OH 79 %

Bu

BF3. OEt2

O ZrCp2Cl + O

Ph

H

Bu Ph

CH2Cl2

O

OH 69 %

Scheme 12.24

The steric bulk of the alkyl group of the aldehyde severely impedes the reaction and for instance, no reaction takes place with pivaldehyde and only 50% is obtained with hydrocinnamaldehyde. Moreover, when a stoichiometric amount of BF3ÓEt2 was added to N-benzylideneaniline with acylzirconocene chloride, no a-amino ketone was obtained. Lanthanide Lewis acid (3 mol% Yb(OTf)3/TMSOTf 1:1) is the best solution for the formation of the expected a-amino ketone (Scheme 12.25) [30]. Ph

O n-C8H17

ZrCp2Cl

N

Ph

O

Yb(OTf)3/TMSCl 20 mol %

+ H

THF, 2h

Ph

n-C8H17 Ph

NH

63 % Scheme 12.25

This reaction is restricted to derivatives of N-benzylideneaniline since cyclohexane carbaldehyde or pivaldehyde with aniline give the product in less than 10% yield. More surprisingly, the reaction of acylzirconocene chloride 38 with imine proceeds with a Brönsted acid, even in aqueous media. Although, the hydrolysis of acylzirconocene into aldehyde is a well-known process (see Scheme 12.22), the reaction with N-phenyl imine is much faster. Under 20 mol% HCl/THF, the

515

516


imine derived from cyclohexane carboxaldehyde and aniline gives the a-aminoketone in 60% yield (Scheme 12.26) [31]. O n-C8H17

Ph ZrCp2Cl

+

O HCl (g)/ THF

N

38

R

n-C8H17 20 mol% R THF, r.t., 24 h

Ph

NH

50%< y < 80% Scheme 12.26

The reaction of acylzirconocene 38 with N-salicylideneaniline, which possesses a free ortho±phenolic hydroxyl group in the benzylidene moiety proceeded in the absence of catalyst to afford the a-amino ketone 39 in 67% yield (Scheme 12.27) [31]. OH

O n-C8H17

ZrCp2Cl 38

+

N

Ph

O THF n-C8H17 Ph

NH

OH

39 67 % Scheme 12.27

In this case, the presence of the free phenolic hydroxyl group at the ortho position (and also in the para-position) of benzylidene moieties served to fill the role of protic additive in the reaction. The reactivity of these unmasked acylzirconocenes can also be increased by transmetallation reactions as described in the following scheme. The palladium-catalyzed coupling reactions with organic halides [32], nucleophilic acylation of a,b-enones [33], enantioselective 1,2-addition to enone [34] and 1,4-addition to ynone [35] were therefore successfully developed (Scheme 12.28). Acylzirconocene derivatives can also be further transmetallated by addition of a catalytic amount of a copper salt. These species behave as organocopper derivatives and undergo SN2¢ reactions with allyl- [36] and propargylic halides [36], but also undergo Michael-type addition with allenyl ketones and enones [37] and finally react with acetyl chlorides [38] (Scheme 12.29). Copper-catalyzed carbonylative coupling of (E)-a-(ethylselanyl)-vinyl zirconocene chloride derivatives with alkynyliodonium tosylates has been reported to be a mild method for the preparation of vinyl alkynyl ketones in good yields (Scheme 12.30) [39]. The reaction proceeds via an acylzirconocene chloride species, formed in situ, and the subsequent Cu(I) (3 mol%)-catalyzed coupling reaction gives the corresponding a-ethyl selanyl±substituted vinyl alkynyl ketone derivative. The stereochemistry is maintained during the coupling reaction [40].


O

O

R1X 1

R

R

R

Pd(PPh3)2Cl2

O

Pd(PPh3)2Cl2 ZrCp2Cl

R1

HO COR1

( Pd

Cl 2 h 3) 2 PP

Pd BF (O A 3 .O c) Et 2

O R2

2

R1

1

O R1

R2

Pd(OAc)2 (R)-MOP

O

R OC O R1

R

R

O

O O HO

R

Scheme 12.28

R OCOMe

CuI, 10 mol% DMF CH3COCl

O R

(E + Z) 40 %

CuI, 10 mol% DMF, 0 ºC

O R

Ph-(H2C)4

ZrCp2Cl

R 91 %

Br


O R

O

O

O


R

Br

60 %

61 %

Scheme 12.29

R

SeEt

R'

X

Cp2Zr(H)Cl

R

CuI (3 mol%)

R

H

ZrCp2Cl

CO (1 atm)

H

R' O

Scheme 12.30

SeEt

SeEt

H X = halogen or hypervalent iodine

R

SeEt ZrCp2Cl O

R

517

518


Vinyl zirconocene derivatives react also with sterically unhindered isocyanides, such as n-BuNC, to give the isocyanide-insertion products. Acidic hydrolysis leads to the corresponding one-carbon homologated aldehydes in good yields (Scheme 12.31) [41].

R

H

R

Cp2Zr(H)Cl

n-BuNC

H

ZrCp2Cl H

N n-Bu

ZrCp2Cl

R H+ OHC R

Scheme 12.31

This strategy has been further developed for the preparation of several iminoacyl complexes that have found extensive applications in the synthesis of polycyclic derivatives [42]. 2 Zirconocene g -imine complexes formed by a C±H activation route from a variety of amines can be trapped by x-halo-alkenes or alkynes to afford functionalized adducts (Scheme 12.32) [43]. R R'

R

NH

1. n-BuLi 2. Cp2ZrMeCl H or 1. n-BuLi 2. Cp2ZrCl2 3. MeMgCl

R

R'

Cp Cp Zr Me N

R

H

n

Cl Br n

R

H

R' n

SiMe3 Cl

ZrCp2

R'

Si e3 M 1. + O H3 . 2

NH

N

Cp2 N Zr

R' H n Br MeOH

R

NH

R'

n Me

Scheme 12.32

Br


519

12.2.4 Preparation of Functionalized Low-valent Zirconocene Derivatives

The coupling reaction of zirconocene alkyne complexes with a second alkyne provides a general method for the preparation of asymmetrically substituted zirconacyclopentadienes. The overall transformation is the chemoselective and regioselective intermolecular cross-coupling reaction of two alkynes (Scheme 12.33) [44].

H

(CH2)3 Cl

Cp2Zr(H)Cl CH2Cl2

Cl (H2C)3 H

40

r.t. - CH4

ZrCp2Cl

Cl (H2C)3

MeMgBr/CH2Cl2 0 ºC

H

41

Cl (H2C)3

H

Me t-Bu Si Me

Zr Cp2 43

Bu

H Cl (H2C)3

Bu Zr Cp2

Me Si Bu-t Me

44 Bu Me Si Bu-t Me

H+ Cl (H2C)3

ZrCp2Me 42

45 67 % Scheme 12.33

Hydrozirconation of the 5-chloro-1-pentyne 40 with the Schwartz's reagent yields the chlorovinyl zirconocene 41, which is converted to the methyl vinyl zirconocene 42 with methylmagnesium bromide in CH2Cl2 (or MeLi in THF). Compound 42 loses methane at room temperature to form an intermediate alkynecomplex 43, which couples with a second alkyne to form the metallacyclopentadiene 44. The metallacycle 44 is converted to the functionalized diene 45 after treatment with aqueous acid. The regioselectivity of the coupling reactions is, in most cases, predictable based on the nature of the four substituents [45]. Functionalized zirconacycles can also be generated from zirconocene±benzyne complex [45], by the ortho-lithiation procedure combined with zirconocene±benzyne chemistry; 3-acyl-1-substituted benzene derivatives were obtained by acidic hydrolysis of the azazirconacycle intermediate, which resulted from the coupling of a nitrile with a zirconocene±benzyne complex (Scheme 12.34) [46]. Alternatively, functionalized zirconacyclopropene and zirconacyclopropane can be easily prepared by using the Negishi reagent (Cp2ZrCl2 + 2 n-BuLi) [47]. In the presence of an additional unsaturated system, a carbocyclization reaction occurs to lead to the corresponding zirconacyclopentene or zirconacyclopentane derivatives [47]. When the substrate possesses a stereocontrol unit such as an amide moiety, a diastereoselective carbocyclization occurs [48] (Scheme 12.35).

520

12 Functionalized Organozirconium and Titanium in Organic Synthesis O

N(Pr-i)2

O

Li

t-BuLi

O

N(Pr-i)2

O Cp2ZrMeCl

N(Pr-i)2

O

heat Ph C N

ZrCp2

N(Pr-i)2 ZrCp2Me

N(Pr-i)2 Cp2 Zr N

O

N(Pr-i)2

H+ O Ph

Ph

80 %

Scheme 12.34

SiMe3

Me3Si SiMe3

Cp2ZrBu2 THF r.t.

O NEt2

H O

H

H2O

Me H

ZrCp2 H NEt2

Et2NOC

H

93 % d.r. > 40:1 Scheme 12.35

12.3 Functionalized Organotitanium Derivatives

At the beginning of the 1980s, it was discovered that certain organotitanium (IV) reagents behave very selectively with functionalized electrophiles and therefore by adjusting the electronic property and the steric environment around the metal, the chemo-, regio- and stereoselective reactions with carbonyl compounds, alkyl halides and other electrophiles were reported [49]. This type of bond formation was not based on typical transition-metal behavior, such as oxidative coupling, b-hydride elimination or CO insertion but rather on the traditional r-carbanion chemistry. However, these titanium-based organometallic derivatives were always prepared by transmetallation reaction between organolithium or organomagnesium derivatives and titanium derivatives, which precluded the presence of sensitive moieties on the carbon skeleton. A synthetically important variation concerns the generation of functionalized zinc reagents RZnBr or R2Zn followed by addition of ClTi(Oi-Pr)3 [50]. Presumably, this generates the corresponding titanium reagents that add smoothly to aldehydes. As the preparation of functionalized zinc reagents are nowadays well developed, corresponding functionalized titanium reagents were found to be synthetically useful. However, this part will not be treated in this chapter since the preparation of the functionalized moiety derived from the zinc derivatives is described elsewhere in this book.


In addition to the titanation of traditional carbanions, several routes to organotitanium reagents are now available. These new approaches to a special class of organotitanium reagent are based on the reduction of Ti(IV) by organometallics such as alkyllithium or magnesium derivatives. The reagent, which can be considered to be either a new Ti(IV) reagent 46a or a Ti(II)-alkene complex 46b, interacts with unsaturated system for further reactions. The generation of divalent titanium complexes and their utilization in organic synthesis has therefore attracted considerable interest over a number of years [51±57] (see Scheme 12.36). Cp2TiCl2 + Na or Mg

"Cp2Ti"

Ref 51

Cp2TiCl2 + CO + reductant

Cp2Ti(CO)2

Ref 52

Cp2TiCl2 + PMe3 + Mg

Cp2Ti(PMe3)2

Ref 53

(ArO)2TiCl2 + Na(Hg)

"Ti(OAr)2"

Ref 54

TiCp2

Ref 55

Cp2TiCl2 + 2 EtMgBr

Me3Si Cp2TiCl2 + Me3Si

SiMe3 + Mg

TiCp2

Ref 56

Me3Si Ti(Oi-Pr)4 + 2 i-PrMgCl

Ref 57

Ti(OR)2

R

R Ti 46a

Ti 46b

Scheme 12.36

12.3.1 Preparation of Functionalized Substrates via Titanocene Derivatives 12.3.1.1 Intramolecular Reductive Cyclization

The original reaction procedure for intramolecular reductive cyclization [58] involved the reduction of Cp2TiCl2 with Na/Hg and PhPMe2 in the presence of the enyne. Although, several alternative routes were further developed, they suffered the drawback of lack of tolerance for polar functionalities such as esters [59]. By using the combination of Cp2TiCl2 with EtMgBr (Scheme 12.36), provided an effective reagent for the reductive cyclization of enynes, including those containing esters, to bicyclic titanacyclopentenes 47 and 48 (Scheme 12.37) [55].

521

522


2 EtMgBr + Cp2TiCl2

THF - 78 ºC

EtOOC

TiCp2

TiCp2 R

EtOOC

47

r.t. 3h

COOEt

R

EtOOC

EtOOC COOEt

CO CHCl3

Me

EtOOC

COOEt COOEt

Cp2Ti

R

EtOOC O R = Ph 58% 49a R = CH3 58 % 49b

48

CO, HCCl3 COOEt COOEt

O 58 % 50 Scheme 12.37

Both 1,6- and 1,7-enynes could be cyclized, but carbonylation proceeded only in the presence of CHCl3. Addition of tert-butyl isocyanide to a titanacycle such as 51 gave the corresponding iminocyclopentene 52 (Scheme 12.38) [55]. COOMe Cp2TiCl2 2 EtMgBr

t-BuNC

COOMe

N t-Bu

67 % 52

Cp2Ti

Cp2Ti 51

Scheme 12.38

COOMe

COOMe

N t-Bu


A practical titanium-catalyzed synthesis of functionalized bicyclic cyclopentenones was then described. The process converts enyne substrates to iminocyclopentenes using 10 mol% of the air- and moisture-stable precatalyst Cp2TiCl2 in the presence of n-BuLi and triethylsilyl cyanide. The resulting iminocyclopentenes can be hydrolyzed to cyclopentenone in overall moderate yields [60] (Scheme 12.39).

EtOOC

COOEt

COOEt

H

1. 10 mol% Cp2TiCl2

Me2(H)Si

20 mol% n-BuLi toluene - 78 ºC, 1h 2. 1 eq. Et3SiCN 45 ºC, 12h 3. HCl

COOEt O 53 45%

Scheme 12.39

The Cp2Ti(CO)2 system displays a better level of functional-group compatibility and also leads directly to the corresponding ketone in better yield (Scheme 12.40) [61].

EtO2C R

Ph

Ph 5-20 mol% Cp2Ti(CO)2 18 psig CO toluene, 90 ºC 12-48 h

EtO2C

O

R 54 R = COOEt 95% 55 R = CN 75% (dr = 1:1) 56 R = COCH3 93% (dr=1:1)

Scheme 12.40

Results with monosubstituted alkenes described in Scheme 12.40 show that yield of the cyclocarbonylation is excellent and polar functional groups such as esters, nitriles and ketones are compatible with the Cp2Ti(CO)2 catalyst. When the olefin is disubstituted, as in examples described in Scheme 12.41, the cyclocarbonylation still proceeds in good to excellent yields [61]. 1,1- as well as 1,2-disubstituted alkenes cyclized using 5 to 10 mol% of catalyst (57 and 58, respectively). Even tricylic cyclopentenone 60 is produced in excellent yield. However, by utilizing a geometrically pure cis substrate, it was found that cyclization occurs with considerable olefin isomerization. When a chiral titanocene was used, such as (S,S)-(EBTHI)Ti(CO)2, enantioselective catalyze Pauson± Khand-type cyclization occurs in good enantiomeric excess (Scheme 12.42) [62]. The heteroatom variant of the intramolecular Pauson±Khand reaction mediated by Cp2Ti(PMe3)2 in which the alkyne has been replaced with a carbonyl group was also reported (Scheme 12.43) [63]. This ªhetero-Pauson±Khandº reaction is a complete diastereoselective synthesis of c-butyrolactones from the condensation of an alkene, a carbonyl moiety and CO. In a single process, two carbon±carbon bonds and two rings are constructed. The catalytic variant of this procedure has been also established on conjugated aromatic ketones (Scheme 12.44) [64].

523

524

12 Functionalized Organozirconium and Titanium in Organic Synthesis t-BuOOC

CH3

CH3 t-BuOOC

5 mol% Cp2Ti(CO)2

t-BuOOC

O

94 %

t-BuOOC

18 psig CO toluene

CH3

57 Et

Ph

Et

Ph 5 mol% Cp2Ti(CO)2

Et

18 psig CO toluene

Et

O

58

91 %

60 CH3

CH3 5 mol% Cp2Ti(CO)2

Et

Et O

18 psig CO toluene

Et CH3

Et

67 % (4:1 trans)

CH3 CH3

Et

CH3

Et

Et

5 mol% Cp2Ti(CO)2

O Et

18 psig CO toluene

H3C

CH3

Scheme 12.41

OC Ti CO

(S,S)-(EBTHI)Ti(CO)2

R R

EtOOC EtOOC

5 mol% 61

EtOOC

14 psig CO, toluene 12h, 90 ºC

O

EtOOC 62 R = Ph 94% ee, 82 % 63 R = n-Pr, 89% ee, 94% 64 R = CH3 87% ee, 90%

Scheme 12.42

H3C O

H

Cp2Ti(PMe3)2 CO2Et

EtO2C

CO2Et

O

Scheme 12.43

15 psig CO 70 ºC, 18 h Cp2Ti(PMe3)2 15 psig CO 70 ºC, 18 h

H3C O

COOEt

O 90 % O O

CO2Et CO2Et

61%

58 % (2:1 cis)


O CH3

7.5 mol% Cp2Ti(PMe3)2

O

CH3

O

COOBu-t

18 psig CO, PMe3 toluene 12-18h

t-BuOOC

93 % Scheme 12.44

Titanocene derivatives catalyze reductive cyclization of an alkene with a heteroatom-containing functional group and the cleavage of the titanium±oxygen bond in these metallacycles was promoted by reaction with silanes, with concomitant formation of Ti±H and Si±O bonds via a r-bond metathesis process (Scheme 12.45) [65]. EtO2C

R

CO2Et

HO R

10 mol% Cp2Ti(PMe3)2 60 % PMe3 Ph2SiH2, toluene

O

CH3 EtO2C

CO2Et

R = H 65% R = CH3 68% Scheme 12.45

12.3.1.2 Allenylation of Functionalized Carbonylic Compounds Carbonyl allenation proceeds quite efficiently with titanocene alkenylidene intermediate, formed in situ from alkenyltitanocene precursors. Indeed, these compounds are easily prepared from titanocene dichloride 65 and 2 equiv of alkenylmagnesium bromide 66 followed by the addition of carbonyl derivatives 68 (Scheme 12.46) [66]. O

OMe

O MeO

MeO OMe Cp2TiCl2 + 2 MgBr 65

66

68

Cp2Ti 67

MeO OMe 81 %

Scheme 12.46

O

525

526


When valuable alkenyl groups are used, the use of alkyl alkenyl titanocene prepared from the monochlorotitanocene also leads to the unstable titanocene alkenylidene intermediate that is similarly trapped in situ by the carbonyl compound [66]. Methylenetitanocene complex 70, generated from the dimethyltitanacyclobutane 69 reacts with acid chlorides and anhydrides [67]. However, as acid chloride is more reactive towards 70 than ester, the succinic acid monoester monochloride 71 is converted indo aldol 73 via methyl ketone enolate 72 with high selectivity (Scheme 12.47) [67b]. O EtO

Cl O

Me Cp2Ti

Cp2Ti

OTiClCp2 71

EtO

Me

O 70

69 O PhCHO

72

Ph

EtO

OH O 73 53%

Scheme 12.47

12.3.2 Preparation of Functionalized Substrates via Titanium (ii) Alkoxide Derivatives 12.3.2.1 Generation of g2-Alkene, g2-Alkyne Complexes and their Utilization as Vicinal Dianionic Species

The preparation and reactions of titanium±olefin complexes with a nonmetallocene structure have also been known since the pioneering work of Kulinkovich et al. for the preparation of cyclopropanols, starting with an ester, Ti(OPr-i)4 and an ethyl Grignard reagent (Scheme 12.36) [55]. The reaction involves dialkoxytitanacyclopropane as an actual reagent effecting the active transformation (Scheme 12.48). RCOOR' R Ti(Oi-Pr)4 + 2 EtMgBr Scheme 12.48

- C2H6

Ti(Oi-Pr)2

OTi(OR'')3

H+

R

OH


527

Obviously, as carbonyl derivatives react with titanium derivatives the presence of functional groups is therefore limited. However, a very useful adaptation of the original protocol for the conversion of esters to cyclopropanols with titanacyclopropane towards a highly versatile preparation of cyclopropylamines has been developed [68]. N,N-dialkylaminocyclopropanes with up to three additional substituents are readily obtained from carboxylic acid N,N-dialkylamides and ethyl- as well as substituted ethylmagnesium bromide in the presence of titanium tetraisopropoxide. These transformations were also possible with substoichiometric amounts of Ti(OPr-i)4, but the yields were significantly better with stoichiometric amounts. If titanacyclopropane reacts faster with one of the reagents, namely the ester or the dialkylamide, the functionalized cyclopropyl derivative can be selectively obtained. In the hydroxycyclopropanation of alkenes, esters may be more reactive than N,N-dialkylamide when succinic acid mono ester monoamide 74 was used (Scheme 12.49) [69]. However, the reactivities of both ester, as well as amide-carbonyl groups can be significantly influenced by the steric bulk around them. Thus, in an intermolecular competition for reaction between N,N-dibenzylformamide 75 and tert-butyl acetate 76 as well as between N,N-dibenzylacetamide 77 and tert-butyl acetate 76, the amide won both times to yield only the corresponding cyclopropylamine (Scheme 12.49). O OMe

N

+

OTiPS

O

OH

c-C5H9MgCl TIPSO

N

ClTi(OPr-i)3 O

74

58% O

O H

NBn2

+

EtMgBr OBu-t

75

76

O

O

Me

NBn2

+

20 ºC, 14 h

76

NBn2

MeTi(OPr-i)3

+ OBu-t

40%

BuMgBr OBu-t

20 ºC, 60 h 77

O

MeTi(OPr-i)3

Me Et

NBn2 87%

E/Z = 2.1/1

Scheme 12.49

Organozinc reagents are less nucleophilic than organomagnesium compounds and can be easily prepared with a variety of functional groups (see Chapter 7), several of them were tested for the reductive cyclopropanation of amides. Therefore, a new protocol was devised for the efficient preparation of various tert-butoxycarbonyl and chloroalkylsubstituted cyclopropylamine derivatives (Scheme 12.50) [70].

528


O

O Zn

Me2Ti(OPr-i)2 OBu-t

H

Zn

Me2N

MeMgCl O

2

OBu-t

63% trans:cis = 1.3:1

NMe2

Me2Ti(OPr-i)2

Cl 2

H

Cl

Me2N

MeMgCl O

65% trans:cis = 1.2:1

NMe2

Scheme 12.50

Treatment of internal functionalized alkynes with Ti(OPr-i)4/2 i-PrMgCl leads to the corresponding titanacyclopropene derivatives that may react in situ with a variety of electrophiles, including two different electrophiles in consecutive order as described in Scheme 12.51 [71]. Me3Si

Ti(OPr-i)4/2 i-PrMgCl

I

I

Et2O

SiMe3

1.2 equiv

Ti

SiMe3 s-BuOH 1.25 equiv

SiMe3

I2 I

OPr-i

i-PrO

I TiX3

I 95% regioselectivity = 97:3

Scheme 12.51

Conjugated acetylenic esters and amides afforded the corresponding acetylene complexes as shown in Scheme 12.52 [72].


H13C6 O H13C6 OBu-t

H13C6

OPr-i

Ti(OPr-i)4

D+

Ti

2 i-PrMgCl

D

t-BuO

D

OPr-i

t-BuO

529

O O

77% EtCHO

i-PrO OPr-i H13C6 Ti

H13C6 H+

t-BuO

O

t-BuO

O

Et

O

OH Et

regioselectivity = 90:10 Me3Si O SiMe3 R

OPr-i

Ti(OPr-i)4 2 i-PrMgCl

OPr-i

R

Me3Si

D+

Ti

D

R=NEt2 Et2N

O

D O 89%

PhCHO R = OBu-t i-PrO Me3Si

+

O

t-BuO O

Me3Si

OPr-i

Ti

Ph

H

t-BuO

OH O

Ph

regioselectivity = 98:2

Scheme 12.52

The cross-coupling reaction between internal and terminal acetylenes is also described to give the corresponding conjugated dienes after hydrolysis (Scheme 12.53) [71]. Functionalized titanacyclopentadienes such as 78, generated from two unsymmetrical acetylenes have been shown to react with ethynyl p-tolyl sulfone 79 to afford an aryltitanium compound 80 as shown in Scheme 12.54 [73a]. Titanacyclopentadiene 81 can also react with sulfonitrile 82 to lead to the pyridyltitanium 83 before aqueous workup (Scheme 12.55) [73b]. The reaction, as the one described in Scheme 12.54 with alkynyl sulfone instead of sulfonitrile, proceeds via a metallative Reppe reaction. If propargyl bromide is used instead of sulfonitrile, functionalized benzyltitanium species are formed [73c].


530

Me3Si

O

Ti(OPr-i)4

Me3Si OR

C6H13

Ti(OPr-i)2

2 i-PrMgBr RO O

RO

Me3Si

Ti

OR

Me3Si

C6H13

RO

H+ RO

O

C6H13 O 78%

Scheme 12.53 O H13C6 t-BuO C6H13 +

OBu-t

Ti(OPr-i)4

C6H13

2 i-PrMgBr

O

SO2Tol-p

Ti

79

C6H13 78 O

OBu-t

H13C6

TiX3

O E+

OBu-t

H13C6

E

C6H13

C6H13

80

E = H 57% E = I 56%

Scheme 12.54

O R1 Et2N

1

R + O

2

R

NEt2

Ti(OPr-i)4

Ti(OPr-i)2

2 i-PrMgBr

NCSO2Tol-p 82

2

R 81 O (i-PrO)2Ti R1

CONEt2 N

NEt2

R1

N

SO2Tol R2

O

NEt2

R1

N

Ti(OPr-i)2 SO2Tol

TiX3 R2 83 R1 = C6H13 R2 = C6H13 65% R1 = C6H13 R2 = Ph 70% R1 = C6H13 R2 = SiMe3 55%

Scheme 12.55


531

When functionalized halogenoalkynes 84 were used with titanacyclopropane derivatives, alkynyltitanium compounds 85 were easily and quantitatively obtained as described in Scheme 12.56 [74]. Cl FG

Ti(OPr-i)4

Cl

FG

2 i-PrMgBr

n

i-PrO

Et2O

Ti

OPr-i

84

Pr-i O

OH

Cl Ti OPr-i OPr-i

i, ii

O

FG

91%

O

i, ii

i, ii

I Pr-i

OH

O 72%

OH

ii

i, ii

EtO

Pr-i

85

93% Pr-i

Br

i

TsO

O

Pr-i OH 81%

Pr-i

85%

OH

EtO O

68%

i) i-PrCHO (1 equiv), -50ºC to -30ºC ii) ClTi(OPr-i)3 (1 equiv), -50ºC

Scheme 12.56

Addition of aldehydes to 85 led to the corresponding propargylic alcohols in good overall yields. However, the coaddition of a mild Lewis acid such as ClTi(OPr-i)3 is beneficial for this reaction. As described in Scheme 12.56, this methodology tolerates a large variety of functional groups on its carbon skeleton; halides like bromide or iodide, tosylate, carbonate, ester and b-ketoester are compatible with the formation of the organometallic derivatives. The chemoselective reaction between a functionalized alkynyltitanium derivatives and a functionalized electrophile has been performed for the preparation of polyfunctional compounds in a one-pot procedure (Scheme 12.57) [75]. When the leaving group is in a b-position, as in 86, allenyl species are formed. It is therefore easy to prepare the allenyl titanium reagents having a functional group as exemplified in Scheme 12.58. Functionalized homopropargyl alcohols are obtained by their reaction with carbonyl compounds [76]. Carbonates of c-vinyl alcohols such as 87 undergo the intermolecular nucleophilic acyl substitution reaction to afford the corresponding alkyltitanium complex 88 having a lactone moiety (Scheme 12.59). The titanium±carbon bond in the

OH

532


resulting b-titanacarbonyl compounds can be trapped by electrophiles to give the lactone having a functionalized side chain at the a-position [77]. 2 i-PrMgBr Cl

Ti(OPr-i)3

Et2O

I

I

Ti(OPr-i)4 -80ºC to -50ºC O

OH

H

1. Ph

Ph

O

I

+

2. H3O

O 71%

Scheme 12.57

Me3Si

O O O

Ti(OPr-i)4 OEt

O

2 i-PrMgBr

i-PrO OPr-i Ti SiMe3 O EtO

O

• O

OEt

OEt O

86 O n-C5H11CHO

EtO

SiMe3 O H11C5

OH

88% d.r = 76:24 Scheme 12.58

Several substituents can be present in the carbon skeleton of 88. The carbonate of 3,5-dienyl alcohol 89 also underwent similar cyclization to lead to the corresponding allyltitanium species 90 also having a lactone moiety. This allylic moiety exists most probably as an internal titanium derivative stabilized by intermolecular coordination. The addition of aldehydes leads to the corresponding alcohol via a six-membered transition state (Scheme 12.60) [78]. The same concept was also used for the synthesis of pyrrolidines 91, indolizines 92 [79] and a-substituted b-c-unsaturated ester 93 [80] as described in Scheme 12.61. It should be noted that the reaction of 4-silyl-3,4-dienyl carbonate proceeds with excellent chirality transfer.


O O

OEt

(OPr-i)2 Ti

Ti(OPr-i)4 2 i-PrMgBr

533

O O

OEt

Et2O

87

O O

(i-PrO)2Ti OEt 88

HCl

I2 O

O O

O

90%

92%

I

Scheme 12.59

O O

OEt

Ti(OPr-i)4

O

2 i-PrMgBr

Ti (OPr-i)2

Et2O

89

O O

O + 74% 9:1

O

OEt

OEt Ti(OPr-i)2

H2O

O

O O 90

RCHO

HO R R = Ph 89% R = Et 72%

Scheme 12.60

This intramolecular nucleophilic acyl substitution reaction of acetylenic carbonates proceeds similarly to afford lactones or a,b-unsaturated esters after hydrolysis 2 of the resulting titanium complexes (Scheme 12.62) [81]. This sp organotitanium species 94 can also be trapped with an aldehyde, which easily undergoes recyclization to give a substituted butenolide after acidic workup.

O O

534


O

Ti(OPr-i)4 N

Me

HO

(OPr-i)2 O Ti

+

H

N

2 i-PrMgBr N

O

O

O 91

OH

O

R

55%

R

N O

O 92 40 to 60% EtO

R

•

O

H O

Ti(OPr-i)4 OEt

O O R

O

2 i-PrMgBr

TiX3 R

R

Ti(OPr-i)2

X = OPr-i, OEt

OEt H

O

OH 93 57% R = SiMe2Ph ee = 88%

Scheme 12.61 O

Ti(OPr-i)4

Me3Si

(OPr-i)2 O Ti

2 i-PrMgBr

O OEt

OEt

Me3Si

O

O EtO(i-PrO)2Ti O Me3Si 1. PhCHO 2. HCl 1N

O O

HO Me3Si 65%

Scheme 12.62

OTiX3

H

ee = 89%

H2O

OEt H

Ph

Ph Me3Si

94 H+

O

OH O O

O

Me3Si 68%


535

In contrast to the reaction of alkynyl carbonates, the reaction of esters of acetylenic acids 95 proceeds satisfactorily, only when the ester is an i-propyl group (Scheme 12.63) [77]. On the other hand, the reaction of esters of acetylenic alcohols 96 proceeds nicely even with methyl ester (Scheme 12.63) [77]. Me3Si O OPr-i

Ti(OPr-i)4

(i-PrO)3Ti

2 i-PrMgBr

Me3Si

O Me3Si

O

95

O

I

I2

67% O

O Me3Si

Ti(OPr-i)4

O

2 i-PrMgBr

Me O

96

(i-PrO)2Ti

Me

Me

+

H

Me3Si

Me3Si

OH

O58%

Scheme 12.63

Optically active N-heterocyclic compounds such as pyrrolidines or piperidines are easily prepared by reaction of N-propargylated ester [82]. The piperidine formation reaction has been applied for the total synthesis of allopumiliotoxine 267A [82]. Treatment of alkynyl malonates with the Ti(OPr-i)4/2 i-PrMgBr combination results in an unexpected carbon±carbon migration of one of the ester fragment (Scheme 12.64) [83].

Ph

Ti(OPr-i)4 OEt OEt

Me

Ph

O R

O

2 i-PrMgBr Et2O

O

EtO EtO

Ti(OPr-i)2

Ph O Ti i-PrO OPr-i

R

CO2Et OOEt

CO2Et CO2Et

H+ Ph

R 46% Scheme 12.64

A titanium±acetylene complex reacts with allyl derivatives through regioselective titanacycle formation and subsequent b-elimination to lead to functionalized 1,4-dienyl derivatives (Scheme 12.65) [84].

536


H7C3

H7C3

CONEt2 Ti(OPr-i)2

+

Ti(OPr-i)2

OCO2Et

H7C3

C3H7

EtO2CO

CONEt2 OH

H7C3

Ti(OR)3

H7C3

PhCHO CONEt2

H7C3

Ph CONEt2

H7C3 75% E:Z > 95:5

Scheme 12.65

Functionalized titanacyclopentene 98, easily generated from conjugated diene 97 and the Ti(OPr-i)4/2 i-PrMgCl combination, reacts with aldehyde in a highly regio- and stereoselective manner to give the adduct 99, which, after hydrolysis, gives 100 with a quaternary carbon center and an (E)-olefin (Scheme 12.66) [85]. CO2Bu-t H13C6

SiMe3

Ti(OPr-i)4

t-BuO2C

2 i-PrMgCl

SiMe3

Ti(OPr-i)2

Et2O

C6H13

97

98

C8H17CHO C6H13 t-BuO2C H18C7 OH 72% d.r: 93:7 101

SiMe3

C6H13 H+

C6H13

t-BuO2C H18C7

SiMe3

O Ti(OPr-i)2 99

1. I2 2. HCl

t-BuO2C H18C7 OH

SiMe3 I

51% d.r: 95:5 100

Scheme 12.66

The Me3Si group in 99 can be easily desilylated and more importantly, iodinolysis of 99 gives iodide 100 as a 95:5 mixture of two isomers. Replacing the tert-butyl ester to chiral (±)-8-phenylmentol led to a single diastereoisomer of 101 after chromatography. Intramolecular alkene±acetylene cyclization of tert-butyl enynoate proceeds to afford the titanacycle, which in turn reacts regioselectively with electrophiles at


537

the titanated ester portion (methyl or ethyl ester ynoate is followed by a second ring closure at the carbonyl moiety) as described in Scheme 12.67 [86]. SiMe3

SiMe3 CO2Bu-t

Ti(OPr-i)2

Me3Si

1. i-PrOD 2. H+

CO2Bu-t

CO2Bu-t D 84%

Scheme 12.67

This type of cyclization of ethyl ester dienolates provides bicyclic ketones and was recently used for the preparation of carbacycline [87]. EtO2C

CO2Et Ti(OPr-i)4

O EtO

H11C5

Ti(OPr-i)2

2 i-PrMgCl Et2O

EtO2C TiO

CHO

C5H11

EtO2C OEt O X3Ti C5H11

EtO2C

HO H

H

Carbacycline O

H Scheme 12.68

538


References 1 Titanium and Zirconium in Organic

Synthesis, Ed. I. Marek, Wiley-VCH, Weinheim, 2002 2 Original preparation of Cp2Zr(H)Cl was reported by: Wailes, H. Weijold, J. Organomet. Chem., 1970, 24, 405. Pioneer synthetic application: J.A. Labinger, D. W. Hart, E. E. Seibert, J. Schwartz, J. Am. Chem. Soc., 1975, 97, 679 3 J. Schwartz, M. L. Loots, H. Kosugi, J. Am. Chem. Soc., 1980, 102, 1333 4 B. H. Lipshutz, R. Keil, E. L. Ellsworth, Tetrahedron Lett., 1990, 31, 7257 5 a) B. H. Lipshutz, R. Keil, J. Am. Chem. Soc., 1992, 114, 7919 b) B. H. Lipshutz, M. R. Wood, J. Am. Chem. Soc., 1994, 116, 11689 c) D. R. Swanson, T. Nguyen, Y. Nodal, E. Negishi, J. Org. Chem., 1991, 56, 2590 6 P. Wipf, W. Xu, J. Org. Chem., 1993, 58, 825 7 P. Wipf, W. Xu, Tetrahedron Lett., 1994, 35, 5197 8 P. Wipf, P. D. G. Coish Tetrahedron Lett., 1997, 38, 5073 9 P. Wipf, W. Xu, H. Takahashi, H. Jahn, P. D. G. Coish, Pure Appl. Chem., 1997, 69, 689 10 P. Wipf, P. D. G. Coish, J. Org. Chem., 1999, 64, 5053 11 (a) P. Wipf, W. Xu, H. Takahashi, H. Jahn, P. D. G. Coish, J. Org. Chem., 1998, 63, 6454 (b) P. Wipf, C. Kendall, Chem. Eur. J., 2002, 8, 1779 12 B. H. Lipshutz, R. Keil, Inorg. Chem. Acta., 1994, 220, 41 13 B. H. Lipshutz, C.Lindsley, A. Blandari, Tetrahedron Lett., 1994, 35, 4669 14 P. Wipf, W. Xu, Synlett, 1992, 718 15 (a) P. Wipf, C. Kendall, C. J. Stephenson, J. Am. Chem. Soc., 2001, 123, 5122 (b) P. Wipf, C. Kendall, C. J. Stephenson, J. Am. Chem. Soc., 2003, 125, 761 16 P. Wipf, C. Kendall, Org. Lett., 2001, 3, 2773 17 P. Wipf, R. L. Nunes, Tetrahedron, 2004, 60, 1269 18 D. E. Chaves, E. N. Jacobsen, Angew. Chem. Int. Ed., 2001, 40, 3667

19 D. Trauner, J. B. Schwarz,

S. J. Danishefski, Angew. Chem. Int. Ed., 1999, 38, 3542 20 P. Wipf, W. Xu, J. H. Smitrovich, R. Lehman, L. M. Venanzi, Tetrahedron, 1994, 50, 1935 21 B. Zheng, M. Srebnik, J. Org. Chem., 1995, 60, 1912 22 S. Pereira, B. Zheng, M. Srebnik, J. Org. Chem., 1995, 60, 6260 23 J. T. Wang, Y. W. Zhang, Y. M. Xu, G. C. Bai, Youji Huaxue, 1989, 9, 41 24 S. Harada, N. Kowase, T. Taguchi, Y. Hanzawa Tetrahedron Lett., 1997, 38, 1957 25 S. Harada, N. Kowase, N. Taguchi, Y. Dobashi, A. Dobashi, Y. Hanzawa, Tetrahedron, 1998, 54, 753 26 H. Makase, E. Negishi Eur. J. Org. Chem., 1999, 969 27 a) C. A. Bertelo, J. Schwartz, J. Am. Chem. Soc., 1975, 97, 228 b) J. A. Labinger, D. W. Hart, W. E. Scibert, J. Schwartz, J. Am. Chem. Soc., 1975, 97, 3851 28 S. L. Buchwald, Q. Fang, S. M. King, Tetrahedron Lett., 1988, 29, 3445 29 S. Harada, T. Taguchi, N. Tabuchi, K. Narita, Y. Hanzawa, Angew. Chem. Int. Ed, 1998, 37, 1696 30 A. Kakuuchi, T. Taguchi, Y. Hanzawa, Tetrahedron Lett., 2001, 42, 1547 31 A. Kakuuchi, T. Taguchi, Y. Hanzawa, Eur. J. Org. Chem., 2003, 116 32 Y. Hanzawa, N. Tabuchi, T. Taguchi Tetrahedron Lett., 1998, 39, 6249 33 Y. Hanzawa, N. Tabuchi, T. Taguchi Tetrahedron Lett., 1998, 39, 8141 34 Y. Hanzawa, N. Tabuchi, K. Saito, S. Noguchi, T. Taguchi, Angew. Chem. Int. Ed., 1999, 38, 2395 35 Y. Hanzawa, A. Kakuuchi, M. Yabe, K. Narita, N. Taguchi, T. Taguchi, Tetrahedron Lett., 2001, 42, 1737 36 Y. Hanzawa, K. Narita, T. Taguchi, Tetrahedron Lett., 2000, 41, 109 37 Y. Hanzawa, K. Narita, M. Yabe, T. Taguchi, Tetrahedron, 2002, 58,10429 38 Y. Hanzawa, K. Narita, T. Taguchi, Tetrahedron Lett., 2000, 41, 109 39 A. M. Sun, X. Huang, Tetrahedron, 1999, 55, 13201

References 40 A. M. Sun, X. Huang, Heteroatom

Chem., 2000, 11, 91 41 E. Negishi, D. R. Swanson, S. R. Miller, Tetrahedron Lett., 1988, 29, 1681 42 a) G. D. Probert, R. J. Whitby, S. J. Goote, Tetrahedron Lett., 1995, 36, 4113 b) J. M. Davis, R. J. Whitby, A. Jaxa-Chanuec, Tetrahedron Lett., 1992, 33, 5655 c) J. M. Davis, R. J. Whitby, A. Jaxa-Chanuec, Synlett, 1994, 110 d) N. Coles, R. J. Whitby, J. Blagy, Synlett, 1990, 271 e) N. Coles, R. J. Whitby, Synlett, 1990, 143 f) S. L. Buchwald, B. T. Watson, M. W. Wannamaker, J. Am. Chem. Soc., 1989, 111, 776 g) S. L. Buchwald, B. T. Watson, M. W. Wannamaker, J. C. Dewan, J. Am. Chem. Soc., 1989, 111, 4486 h) R. B. Grossman, W. M. Davis, S. L. Buchwald, J. Am. Chem. Soc., 1991, 113, 2321 i) M. Jensen, T. Livinghouse, J. Am. Chem. Soc., 1989, 111, 4495 j) T. Taguchi, Y. Hanzawa, Tetrahedron Lett., 1992, 33, 4469 43 M. C. J. Harris, R. J. Whitby, J. Bragg, Tetrahedron Lett., 1995, 36, 4287 44 S. L. Buchwald, R. B. Nielsen, J. Am. Chem. Soc., 1989, 111, 2810 45 S. L. Buchwald, R. B. Nielsen, Chem. Rev., 1988, 88, 1047 46 S. Akai, A. J. Peat, S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 9119 47 E. Negishi in Synthesis and Reactivity of Zirconocene Derivatives in Titanium and Zirconium in Organic Synthesis (Ed. I. Marek), Wiley-VCH, Weinheim, 2002, 1 48 B. L. Pagenkopf, E. C. Lund, T. Livinghouse, Tetrahedron, 1995, 51, 4421 49 a) M. T. Reetz in Organotitanium Reagents in Organic Synthesis SpringerVerlag; Berlin-Heidelberg, 1986 b) B. Weidmann, D. Seebach, Angew. Chem. Int. Ed. Engl., 1983, 22, 31 c) M. T. Reetz in Titanium in Organic Synthesis in Organometallic in Synthesis; A manual (Ed. A. Schlosser), Wiley Chichester, 1994, 195 d) M. T. Reetz in Organotitanium Chemistry in Organometallic in Synthesis; A manual (Second edition, Ed. A. Schlosser), Wiley Chichester, 2002, 817 50 a) P. Knochel, J. F. Normant, Tetrahedron Lett., 1986, 27, 4431 b) M. C. R. Yeh, P. Knochel,

51 52

53

54 55 56

57 58 59

60 61

62 63

64

65

66 67

L. E. Santa, Tetrahedron Lett., 1998, 29, 2395 F. Sato, H. Urabe, S. Okamoto, Chem. Rev., 2000, 100, 2835 D. J. Sikora, D. W. Macomber, M. D. Rausch, Adv. Organomet. Chem., 1986, 25, 317 L. B. Kool, M. D. Rausch, H. G. Ah, M. Herberhold, O. Thewalt, B. Wolf, Angew.Chem. Int. Ed. Engl., 1985, 24, 394 G. J. Balaich, I. P. Rothwell, J. Am. Chem. Soc., 1993, 115, 1581 R. B. Grossman, S.L. Buchwald, J. Org. Chem., 1992, 57, 5803 V. V. Burlatiov, A.V. Polyakov, A. I. Yanovsky, Y. T. Struchkiv, V. B. Shur, M. E. Volpin, V. Rosenthal, H. Gorls, J. Org. Chem., 1994, 476, 197 O. G. Kulinkovitch, S. V. Sviridov, D. A. Vasileski, Synthesis, 1991, 234 W. A. Nugent, J. C. Calabrese, J. Am. Chem. Soc., 1984, 106, 6422 a) T. V. Rajan Babu, W. A. Nugent, D. F. Taber, P. J. Fagan, J. Am. Chem. Soc., 1988, 110, 7128 b) G. W. Parshall, W. A. Nugent, D. M. T. Chan, W. Tam, Pure Appl. Chem., 1985, 57, 1809 c) E. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, J. Am. Chem. Soc., 1985, 107, 2568 F. A. Hicks, S. C. Berk, S. L. Buchwald, J. Org. Chem., 1986, 61, 2713 a) F. A. Hicks, N. M. Kaslaoui, S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 9450 b) F. A. Hicks, N. M. Kaslaoui, S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 5881 F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 11688 N. M. Kaslaoui, F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 5818 N. M. Kaslaoui, F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc., 1997, 119, 4424 a) W. E. Crowe, M. J. Rachita, J. Am. Chem. Soc., 1995, 117, 6787 b) N. M. Kaslaoui, S. L. Buchwald, J. Am. Chem. Soc., 1995, 117, 6785 N. A. Petasis, Y. H. Hu, J. Org. Chem., 1997, 62, 782 a) K. A. Brown-Wensley, S. L. Buchwald, L. Lannizo, L. Clawon, S. Ho,

539

540

12 Functionalized Organozirconium and Titanium in Organic Synthesis D. Meinhardt, J. R. Stille, D. Straus, R. H. Grubbs, Pure Appl. Chem., 1983, 55, 1733 b) J. R. Stille, R. H. Grubbs, J. Am. Chem. Soc., 1983, 105, 1664 68 V. Chaplinski, A. de Meijere, Angew. Chem. Int. Ed. Engl., 1996, 35, 413 69 S. Y. Cho, J. Lee, R. K. Lammi, J. K. Cha, J. Org. Chem., 1997, 62, 8235 70 S. Weidmann, I. Marek, A. de Meijere, Synlett, 2002, 879 71 T. Hamada, D. Suzuki, H. Urabe, F. Sato, J. Am. Chem. Soc., 1999, 121, 7342 72 a) H. Urabe, T. Hamada, F. Sato, J. Am. Chem. Soc., 1999, 121, 2931 b) T. Hanazawa, S. Okamoto, F. Sato, Tetrahedron Lett., 2001, 42, 5455 73 a) D. Suzuki, H. Urabe, F. Sato, J. Am. Chem. Soc., 2001, 123, 7925 b) D. Suzuki, R. Tanaka, H. Urabe, F. Sato, J. Am. Chem. Soc., 2002, 124, 3518 c) R. Tanaka, Y. Nakano, D. Suzuki, H. Urabe, F. Sato, J. Am, Chem. Soc., 2002, 124, 9682 74 N. Morlander-Vais, J. Kaftanov, I. Marek, Synthesis, 2000, 917 75 A. Liard, J. Kaftanov, H. Chechik, S. Farhat, N. Morlander- Vais, C. Averbuj, I. Marek, J. Organomet. Chem., 2001, 624, 26 76 T. Nakagawa, A. Kasatkin, F. Sato, Tetrahedron Lett., 1995, 36, 3207

77 S. Okamoto, A. Kasatkin, P. K. Zubaidha,

F. Sato, J. Am, Chem. Soc., 1996, 118, 2208 78 P. K. Zubaidha, A. Kasatkin, F. Sato, J. Chem. Soc., Chem. Commun., 1996, 197 79 L. Ollero, G. Mentink, F. P. J. T. Rutjes, W. N. Speckamp, H. Hiemstra, Org. Lett., 1999, 1, 1331 80 Y. Yoshida, S. Okamoto, F. Sato, J. Org. Chem., 1996, 61, 7826 81 a) A. Kasatkin, S. Okamoto, F. Sato, Tetrahedron Lett., 1995, 36, 6075 b) Z. P. Mincheva, Y. Gao, F. Sato, Tetrahedron Lett., 1998, 39, 7947 82 S. Okamoto, M. Iwakubo, K. Kobayashi, F. Sato, J. Am, Chem. Soc., 1997, 119, 6984 83 A. Kasatkin, T. Yamazaki, F. Sato, Angew. Chem. Int. Ed. Engl., 1996, 35, 1966 84 S. Okamoto, Y. Takayama, Y. Gao, F. Sato, Synthesis, 2000, 975 85 H. Urabe, K. Suzuki, F. Sato, J. Am, Chem. Soc., 2003, 125, 6074 86 H. Urabe, K. Suzuki, F. Sato, J. Am, Chem. Soc., 1997, 119, 10014 87 S. Okamoto, K. Subburay, F. Sato, J. Am. Chem. Soc., 2000, 122, 11244

541

13 Manganese Organometallics for the Chemoselective Synthesis of Polyfunctional Compounds GØrard Cahiez and Florence Mahuteau-Betzer 13.1 Introduction

The use of organomanganese compounds for organic synthesis started in 1970 [1]. Organomanganese halides allow various reactions such as 1,2 and 1,4 additions, acylation, alkylation, alkenylation, arylation, etc., to be performed. They are very interesting for preparative organic chemistry, especially on a large scale, since they generally react under mild conditions (very often 0 C to rt) to give high yields without involving any toxic or expensive catalyst, solvent or ligand. Moreover, manganese is a very cheap and toxicologically benign metal. The topic of this review is to illustrate the use of organomanganese halides for the chemoselective preparation of polyfunctional compounds. Note that the chemistry of manganese enolates [2] is not treated herein. Very often, it appears that organomanganese halides behave as soft Grignard reagents having a medium reactivity between organozinc and organomagnesium compounds (e.g. 1,2 addition, acylation). However, it is important to underline that, in fact, the course of their reactions can also be very different from those of these organometallics (e.g. reductive dimerization of enones).

13.2 Preparation of Organomanganese Compounds 13.2.1 Preparation of Organomanganese Compounds by Transmetallation

As for most organometallics derived from a transition metal, organomanganese halides are prepared by a metal±metal exchange reaction from organolithium or organomagnesium compounds in ether or in THF [3]. Manganese iodide, bromide and chloride can be used as the starting manganese halide. Manganese chloride, a cheap starting material, is especially attractive for large-scale applications. Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

542

13 Manganese Organometallics for the Chemoselective Synthesis of Polyfunctional Compounds

RMnI *

RLi (or RMgX)

+

MnI2

Ether

RMnI

+

LiI (or MgXI)

r. t. Ether RLi

+

MnBr2

RMnBr

+

LiBr

RMnBr

+

MgXBr

RMnCl

+

LiCl

RMnCl

+

MgXCl

r. t.

RMnBr * Ether RMgX

+

MnBr2.2LiBr

RLi

+

MnCl2

r. t. THF

+

2LiBr

+

2LiCl

r. t. RMnCl ** THF RMgX

+

MnCl2.2LiCl

r. t.

* RMnI and RMnBr can also be prepared in THF. ** RMnCl can only be prepared in THF since MnCl2 is insoluble in ether. Scheme 13.1

In most cases, the transmetallation reaction can be performed between 0 C and 20 C (±20 C to ±10 C when R= s- or t-alkyl) and the Li±Mn or Mg±Mn exchange occurs quantitatively and almost instantaneously. This method allows the preparation of alkyl, alkenyl, alkynyl, aryl or allylmanganese reagents. In fact, by varying the ratio RLi:MnX2 or RMgX¢:MnX2, it is also possible to prepare the symmetrical organomanganeses R2Mn as well as the organomanganates R3MnLi2 and R4MnLi or R3MnMgX¢ and R4Mn(MgX¢)2. Interestingly, various functionalized organomanganese reagents can be prepared since organomanganese halides do not react with many functional groups, such as esters, nitriles, amides (see below). In fact, the only limitation is the preparation of the functionalized organolithium or magnesium precursors. Some examples of functionalized aryl, alkenyl and alkynylmanganese reagents are given in Scheme 13.2.

Me3Si

MnBr

O ( )5

Cl ( )3

MnBr

Cl

O

PhSCH2

MnI

MnBr

MnX

MnBr FG

FG = o-, m-, p-CN, p-Cl, p-CO2Menthyl, p-OPiv Scheme 13.2

13.2 Preparation of Organomanganese Compounds

13.2.2 Preparation of Organomanganese Compounds from Mn 0

Organomanganese reagents can also be prepared directly from manganese metal and organic halides like Grignard reagents. RX

+

Mn0

RMnX

Scheme 13.3

Thus, Mn-mediated Barbier and Reformatsky reactions can be performed by using commercial manganese metal alone or in the presence of a catalytic amount of metallic salts (ZnX2, CuX2 ...) [4]. The activation of manganese by TMSCl/PbCl2 [5] or to a slight extent by iodine [6] was also used. However, these procedures are only convenient for reactive organic halides (allylic halides, a-halogenoesters ...). With the less reactive ones (i.e. alkyl halides) activated manganese metal (Mn*) is required. This one can be obtained by reducing a manganese halide with lithium aluminum hydride [7] or more efficiently with potassium/graphite [8]. However, the simplest route is to perform the reduction with lithium in the presence of an electron carrier: naphthalene [9] or 2-phenylpyridine [10]. The latter is much more convenient as it is easily eliminated during the final work-up by acid washing. This method allows the preparation of manganese compounds on a large scale. Of course, this route seems very attractive for the preparation of functionalized organomanganese reagents since it is thus possible to circumvent the limitations due to the use of organomagnesium or lithium compounds as an intermediate. However, until now, only a few examples have been described since the activated manganese is often too reactive to be sufficiently chemoselective. Nevertheless, the first alkylmanganese bromide bearing an ester group has been prepared by this route (Scheme 13.4). Mn* (Fürstner) K/C MnCl2

Mn*

MnCl

MnBr FG

FG FG = m-CF3, p-F, p-Br, p-OAc Mn* (Rieke) MnCl2

Li Naphtalene

Mn*

FG = o-CF3, p-OTBS, o-F Mn* (Cahiez) Li Mn* 2-PhPyridine

MnCl2

MnI NC Scheme 13.4

O BrMn

OMenthyl

543

544


13.3 1,2-Addition to Aldehydes and Ketones 13.3.1 Chemoselective 1,2-Addition of Organomanganese Reagents to Carbonyl Compounds

In ether, organomanganese halides readily add to aldehydes and ketones at 0 C, affording the corresponding alcohols in high yields. However, they react neither with nitriles nor with less reactive carbonyl compounds such as amides and esters, except with formates [11] (Scheme 13.5). BuMnBr

CO2Et

+ O

Et2O

CO2Et Bu OH

20ºC

91% Bu NC BuMnBr

CHO

NC

Et2O

+

OH

20ºC 95% Scheme 13.5

Contrary to organolithium or organomagnesium compounds, organomanganese halides add chemoselectively to aldehydes in the presence of ketones (Scheme 13.6) [12]. The scope of the reaction is very large since n- or s-alkyl, alkenyl, aryl and alkynylmanganese halides are always completely aldehyde-selective at room temperature, in ether as in THF. RMnBr HexCHO

+

PrCOPr

HexCHOHR

+

PrCOPr

Et2O

R

Yield (%)*

Bu

93

Ph

94

Me2C=CH

98

Bu C C

80

* PrCOPr is quantitatively recovered Scheme 13.6

On the other hand, aliphatic (n-, s- or t-alkyl), ethylenic and aromatic aldehydes have been selectively converted in high yields into the corresponding secondary alcohols in the presence of aliphatic, ethylenic or aromatic ketones.

13.3 1,2-Addition to Aldehydes and Ketones

545

Hydroxyketones are thus very efficiently prepared from ketoaldehydes in almost quantitative yields under mild conditions (Scheme 13.7). BuMnX

EtCO(CH2)9CHO

+

20ºC

EtCO(CH2)9CHOHBu

BuMnBr, Et2O :

90 % ( Selectivity > 99% )

BuMnCl, THF :

89 % ( Selectivity > 99 % )

Scheme 13.7

Organomanganese reagents also selectively react with diketones when the two carbonyl groups have different steric environments (Scheme 13.8). O PrMnBr

+

O

O

( )5

Et2O, 20ºC

OH Pr ( )5 Pr

85 % ( Selectivity > 99 % ) Scheme 13.8

The following example is interesting since propylmanganese bromide selectively adds to the conjugated carbonyl group that is the more accessible but also the less reactive (electronic effect). This result underlines the importance of the steric effects in the case of organomanganese reagents. O PrMnBr

+ Ph

OH O

O ( )5

Et2O, 20ºC

Ph Pr

O +

( )5 80 %

Ph

OH ( )5 Pr Pr

14 %

( Selectivity : 85 % ) Scheme 13.9

This strong influence of the steric environment of the carbonyl group on the rate of the addition reaction is also observed in the case of aldehydes (Scheme 13.10). It allows good results in various aldehyde-aldehyde competition reactions to be obtained. To the best of our knowledge, such a selectivity has never been described with other organometallics. BuMnBr.LiBr + HexCHO + t-BuCHO

BuMnCl.MgCl2 + HexCHO + Et2CHCHO Scheme 13.10

Et2O, 20ºC

Et2O, 20ºC

HexCHOHBu + t-BuCHOHBu 95 %

4%

HexCHOHBu + Et2CHCHOHBu 90 %

9%

546


The diastereoselectivity of the 1,2-addition of various organomanganates on cyclic ketones has been studied [13,14]. The best results have been obtained by using heteromanganates such as (R¢COO)2RMnLi or (R¢COO)2RMnMgX. The nature of the (R¢COO) group greatly influences the selectivity of the reaction (Scheme 13.11). Me(n-BuCO2)2MnLi

Me

Et2O, -50ºC to r.t.

O

OH

+

OH

88%

Me :

96

4

OH

O Me(t-BuCO2)2MnLi

Me

THF, -50ºC to r.t. 90%

Me

:

91

OH

+ 9

Scheme 13.11

Organomanganese halides and organomanganates prepared by transmetallation from organolithium and Grignard reagents add smoothly to enantiopure acylsilanes and aldehydes bearing a chiral center in the a-position of the carbonyl group (Scheme 13.12). The desired alcohols are obtained with satisfactory diastereoselectivities in good to excellent yields and the starting product is not enolized during the reaction (no isomerization of the chiral center) [15]. OBn

1) RMnCl, THF SiMe3

2) Bu4NF

O R= Bu R= allyl

O

O CHO

BuMnCl, THF

OBn R OH 60% (syn>90%) 66% (syn>75%)

O

O

-50ºC to r.t.

Bu HO 76% (syn/anti= 85/15)

Scheme 13.12

13.3 1,2-Addition to Aldehydes and Ketones

547

13.3.2 Manganese-Mediated Barbier- and Reformatsky-like Reactions

Manganese metal (commercial quality) without any special preparation allows Barbier or Reformatsky reactions, respectively, to be performed from allylic bromides and a-halogenoesters. The use of manganese is of real preparative interest since these reactions have a large scope of application and occur under mild conditions to give high yields of 1,2-addition products [16]. It should be noted that numerous functional ketones (keto-esters, keto-acetals, x-chloro-ketones) were converted into the corresponding functional alcohols very efficiently (Schemes 13.13 and 13.15). O Br +

O

Mn + O O

Br +

Cl

Mn +

AcOEt

OH Bu

O

50ºC, 4h 87% OH

AcOEt

Pr

Cl

50ºC, 4h 79%

Scheme 13.13

One-pot treatment of manganese metal by a catalytic amount of ZnCl2 (or CdCl2 or HgCl2) is sometimes required to facilitate the attack of the metal by the organic halide, for instance in the case of various substituted allylic bromides (Scheme 13.14). Under these conditions, it should be emphasized that allylic chlorides can be used successfully. Finally, note that the reaction can often be performed in THF or in ethy lacetate as a solvent. Br

+

Mn

BuCOBu

+

10% ZnCl2 AcOEt, 50ºC

OH Bu Bu 87%

Br

+

Mn

+

BuCOBu

OH


Bu Bu 87%

Br

+

Mn

+

HexCHO

OH


Hex 79%

O Cl

+

Mn

+

OMe OMe

10% ZnCl2

OH MeO

THF, 50ºC MeO

Scheme 13.14

O

95%

548


Mn

+

R1 R2

Br CO2Et

+

R3COR4

Ac2O

+

R3 R4

AcOEt, 60ºC

α-haloester

Carbonyl compound

BrCH2CO2Et

HexCHO

80

BrCH2CO2Et

PhCHO

89

BrCH2CO2Et

HeptCOMe

86

HexCHO

81

Me Me

OAc

10% ZnCl2

Br CO2Et

CO2Et R1 R2

Yield (%)

Scheme 13.15

13.4 Preparation of Ketones by Acylation of Organomanganese Reagents 13.4.1 Acylation of Organomanganese Reagents

Organomanganese bromides and iodides prepared in ether react, under mild conditions, with a vast array of acylating agents (RCOCl, (RCO)2O, RCO2CO2Et, etc.) to give the corresponding ketones in high yields (Scheme 13.16). The acylation reaction is highly chemoselective and numerous functional groups are tolerated (e.g. halides, nitriles, esters, and even ketones ...) [3a]. BuMnl

+

O

Ether

RCOCl

Bu

-10ºC to 20ºC

O RCOCl

( )3

Cl

Yield (%)

O SPh

91

Cl

O Br

( )10 95

Cl

O CN

( )4 86

Cl

R

O ( )6 OEt 97

O Cl

O ( )6 Et 90

Scheme 13.16

Organomanganese chlorides prepared in THF are also acylated in high yields under mild conditions. The reaction is always very chemoselective. As an illustration, it is possible to prepare various mono- and dichloromethylketones in spite of the high reactivity of the chlorine atoms in the a-position of the carbonyl group (Scheme 13.17).

13.4 Preparation of Ketones by Acylation of Organomanganese Reagents

O HeptMnX

+

Cl

O Cl

Cl Ether (X= I) THF (X= Cl)

Hept traces 70%

O HeptMnX

+

Cl

O Cl

Cl Cl

Hept Cl

Ether (X= I) THF (X= Cl)

50% 69%

Scheme 13.17

The yield of ketones can be sometimes improved by working in the presence of copper salts as catalyst (1 to 5%), especially in the case of methyl and s- or t-alkylmanganese chlorides (Scheme 13.18). MeMnCl

+

THF

HeptCOCl

MeCOHept

-10ºC to 20ºC without catalyst, 1h30 1% CuCl, 30 min

t-BuMnCl

+

THF

HeptCOCl

40% 91%

t-BuCOHept

-10ºC to 20ºC without catalyst, 1h30 1% CuCl, 30 min

0% 92%

Scheme 13.18

The acylation reaction has been applied successfully to the preparation of various polyfunctional natural ketones. Thus, lactarinic acid was obtained in high yield (Scheme 13.19). It should be noted that a similar synthesis via the acylation of organocadmium reagent affords lactarinic acid in only 30% yield [17]. 1) MnI2, Et2O C12H25Li 2) ClCO(CH2)4CO2Et 3) KOH/EtOH 4) H3O+

O C12H25

O ( )4

OH

Lactarinic acid 95%

Scheme 13.19

Organomanganese reagents allow preparation of 2- and 3-acylfurans, under mild conditions, in excellent yields. In this way, miscellaneous natural furanic ketones were efficiently synthesized (Scheme 13.20) [18]. Organomanganese

549

550


reagents compare very favorably to the other organometallic compounds used until now (Cd [19], Zn [20], Sn [21], Cu [22], Mg [23]). The use of iron(III) acetylacetonate as a catalyst should be emphasized since it allows to acylate successfully, at low temperature, the tetra-3-furylmanganate that is not stable above ±50 C. 1% CuCl

+ O

COCl

MnCl

)4MnLi2 i-PentCOCl

O

THF, -10ºC

O Elsholtzione 90% O

3% Fe(acac)3

+ THF, -70ºC

O

O Perilla ketone 89%

Scheme 13.20

Ketosteroids derived from cheno- and ursodesoxycholic acids have also been prepared (Scheme 13.21) [24]. Let us note that the chemoselectivity of organomanganese halides allows protection of the hydroxyl groups as acetates but also as formates in spite of the reactivity of these esters. Moreover, the reaction was performed in the presence of various cosolvents such as dichloromethane or ethyl acetate that are not commonly used in organometallic chemistry. These solvents are necessary to dissolve the starting carboxylic acid chlorides that are practically insoluble in ether. CO2H O

1) SOCl2 2) i-BuMnI, Et2O-CH2Cl2 AcO

H

OAc

AcO

H

OAc 93% O

CO2H

R

1) (COCl)2 2) RMnI, Et2O-CH2Cl2 HCOO

H

OOCH

HCOO

H R

Scheme 13.21

OOCH Yield

i-Bu

89%

Me2C=CH

78.5%

Pr-C C

73.5%


Enantiomerically pure a-acyloxy ketones were readily prepared by reacting alkyl, alkenyl, alkynyl and arylmanganese halides with chiral a-acyloxy carbocyclic acid chlorides (Scheme 13.22) [25]. The reaction takes place under mild conditions in ether or in THF to give the expected ketones in high yields with an excellent enantiomeric purity. OAc +

RMnX

O

OAc

-10ºC

Cl

R

Ether or THF

O ee 97-99%

R

Yield (%)

n-Bu

93

t-Bu

90

Ph

89

Me2C C

87

Pent C C

64

Scheme 13.22

Various optically active d-ketobutanolides were also prepared in good yields, with an excellent purity, from a butyrolactonic acid chloride derived from (L)-glutamic acid (Scheme 13.23) [26]. COCl

COR RMnX (1.1 equiv.), THF

O

O -10ºC, 3h (A)

O

or 3% CuCl, -30ºC, 20 min (B)

O ee 97-99%

R

Conditions

Yield (%)

n-Bu

A

93

t-Bu

B

90

Ph

B

89

Pent C C

A

64

Scheme 13.23

It is possible to perform a one-pot acylation-alkylation sequence by adding a Grignard reagent or an organolithium compound to the reaction mixture upon completion of the acylation reaction. It is important to note that under these conditions the 1,2-addition reaction is clearly slowed since it lasts 2 h at 0±20 C whereas the addition of a Grignard to a ketone generally occurs quickly at ±50 C.

551

552


A mechanistic study has evidenced that this difference of reactivity is due to the in situ formation of a complex between the ketone and the manganese salts formed during the acylation step [27]. This one-pot procedure is efficient and easy to carry out since the reaction conditions are very mild, in addition it is not necessary to isolate the intermediate ketone. It has been applied to the synthesis of an antihistamine: the chlorophenoxamine (Scheme 13.24). 1) PhMnBr, 0ºC to 20ºC Cl

COCl 2) MeLi, 0ºC to 20ºC

1) NaNH2

Cl

Cl

Me OH

Me O

2) ClCH2CH2NMe2 N

81%

Scheme 13.24

Bisabolol, a terpenic alcohol was also obtained in excellent yield (Scheme 13.25) [28].

COCl

1)

MnBr

OH

0ºC to 20ºC

2) MeLi, 0ºC to 20ºC

80% Scheme 13.25

Various polyfunctionalized a,b-alkynyl ketones were easily prepared from many simple or functionalized terminal alkynes according to a one-pot procedure metallation-transmetallation-acylation (Scheme 13.26) [29]. Interestingly, this method allows preparation of miscellaneous polyunsaturated ketones that are usually very difficult to prepare by an organometallic route since they are too reactive (polymerization, 1,4-addition, etc.). Functionalized alkenyl- and arylmanganese halides, prepared from alkenyl or aryl halide by halogen±lithium exchange then transmetallation, are readily acylated in good yields (Scheme 13.28) [30]. Functionalized organomanganese reagents prepared from activated manganese can also be acylated. A catalytic amount of copper salts is sometimes required to perform the reaction (Schemes 29 to 31) [8,31].


R

MnBr2

Li

O

R'COCl R

R

MnBr Et2O

1h30, r.t.

R'

O

Me3Si

O Pr 61%

80%

82% O

Cl

O

Cl

( )5 HCOO

EtO

( )5

Hept

O

EtO

O O

( )3

O

( )3

( )6 CO2Me

PhSCH2 73%

82%

553

73%

Scheme 13.26

H Cl

O

1) EtLi, Et2O 2) MnBr2

Cl

3) MeCH=CH-CH=CHCOCl

78%

Scheme 13.27

COCl

1) BuLi, -90ºC, Et2O I

Cl

Cl

Cl

MnI Et2O, -10ºC

2) MnI2, -50ºC to -10ºC

70%

O Cl

1) BuLi, -100ºC NC

Br

NC

O

( )3Cl

( )3

MnBr

2) MnBr2.2LiBr, -90ºC

3% CuCl, THF

NC 73%

Scheme 13.28

I NC

O

1) Mn* (Fürstner) 2)

F

COCl

NC

F 61%

Scheme 13.29

Cl

O

554


1) Mn* (Rieke)

Cl

O

2) PhCOCl 5% CuI

FG

FG 71-84%

FG = m-CF3, p-F, p-Br, p-OAc Scheme 13.30

O Br

1) Mn* (Cahiez) O

O

2) PhCOCl, 5% CuCl

O

Ph

O 76%

Scheme 13.31

13.4.2 Manganese-Catalyzed Acylation of Grignard Reagents

Grignard reagents are readily acylated in the presence of a catalytic amount of manganese chloride, in THF under very mild conditions (0 to 10 C), to give the corresponding ketones in excellent yields (Scheme 13.32) [32]. A mechanistic study evidenced that organomanganates are probably the effective intermediates of this reaction. The scope of this procedure is very large; alkyl, alkenyl and arylmagnesium reagents have been used successfully. The selectivity of the reaction allows preparation of various functionalized ketones from carbocyclic acid chlorides bearing functional groups (Cl, Br, esters, nitriles and even ketones). BuMgCl

+

3% MnCl4Li2

RCOCl

O Bu

THF, 0º to 10ºC O RCOCl

Cl

Yield (%)

Scheme 13.32

O Cl ( )3

58

Cl

O Br ( )10

71

Cl

O CN ( )6

84

Cl

R

O ( )4 OEt 83

O Cl

O ( )5 Et 91

13.5 1,4-Addition of Organomanganese Reagents to Enones


Organomanganese reagents react with alkylidenemalonic esters or related compounds to give the conjugate addition products in good yields [33]. They are very chemoselective, thus the conjugate addition product is exclusively obtained even in the presence of an ester or a ketone (Scheme 13.33). CO2Et

BuMnCl +

Bu

CO2Et +

BuCOBu

CO2Et

87% CO2Et

BuMnCl +

CO2Et

BuCOBu

CO2Et

THF

Bu

92%

CO2Et +

BuCO2Et THF

BuCO2Et

CO2Et 71%

98%

Scheme 13.33

Moreover, the reaction of b-alkoxyalkylidenemalonic esters with organomagnesium compounds leads to the dialkylated product (addition-elimination-addition), whatever the stoichiometry of the reactants (Scheme 13.34). With organomanganese reagents such a drawback is never observed and it is possible to prepare at 0 C the monoaddition product. It is also possible to obtain the addition-elimination product after acidic hydrolysis.

RMgX

CO2Et

R

CO2Et

CO2Et

R

CO2Et

+ EtO

CO2Et BuMnCl

THF, 0ºC

Bu

then H2O

EtO

CO2Et 86%

+ EtO

CO2Et

CO2Et THF, 0ºC

Bu

CO2Et

then 1N HCl H

CO2Et 87%

Scheme 13.34

It should be emphasized that with less reactive Michael acceptors such as enones, organomanganese reagents generally lead to a mixture of 1,4-addition product and reductive b-dimerization products. In addition, the formation of the 1,2 addition product is sometimes also observed. The 1,4 addition product is only exceptionally obtained as a main product.

555

556


O

O

O

O

Bu OH

BuMnX + Ether, 3h, -30ºC

+

Bu 26%

35%

3%

Scheme 13.35

On the other hand, the reaction sometimes gives the reductive b-dimerization product in good yields [34]. O

O

O

RM

RM

Reaction conditions

Yield (%)

EtMgBr + MnBr2 (5%) i-Pr2Mn

Ether, 20ºC THF, -30ºC

80 89

Scheme 13.36

The presence of copper salts as a catalyst deeply influences the course of the reaction since the conjugate addition product is very often formed exclusively in high yields. This Cu-catalyzed 1,4 addition reaction takes place under mild conditions (THF, 0 C). O

O BuMnCl, 1% CuCl THF, 0ºC, 30 min

Bu 95%

Scheme 13.37

Moreover, it is very efficient and compares favorably to the classical procedures involving Cu-catalyzed Grignard reagents or even organocuprates (Scheme 13.38) [35]. The scope of the reaction is very large, thus b-disubstituted enones that are frequently less reactive with organocuprates readily react with Cu-catalyzed organomanganese reagents. The reaction has also been extended to a,b-ethylenic esters (Scheme 13.39) and to a,b-ethylenic aldehydes (Scheme 13.40). The Cu-catalyzed conjugate addition of organomanganese reagents to a,b-ethylenic aldehydes gives similar results than those obtained via lithium organocuprates in the presence of trimethylchlorosilane (Scheme 13.41) [36]. However, the reaction is easier to carry out since the aldehyde is obtained in one step instead of the two steps required with an organocuprate. It is important since the partial aldoli-


BuM

Bu

O

O

BuM

Reaction Conditions

Isolated yield (%)a

BuMgCl

30% MnCl2, 3% CuCl, THF, 0ºC, 2h

94

BuMnCl

3% CuCl, THF, 0ºC, 1h

95

BuMgCl

5% CuCl, THF, 0ºC

51b

BuCu

Ether-Me2S, -50ºC to -10ºC

43c

BuCu

1.1 eq Me3SiCl, Ether, -10ºC

70c

Bu(CN)CuLi

Ether, -50ºC to -10ºC

13

0.6 eq Bu2CuLi


33

1.2 eq Bu2CuLi


85d

1.2 eq Bu2CuMgCl

THF, -50ºC to -10ºC

47d

0.6 eq Bu2(CN)CuLi2

Ether, -78ºC 5h then 0ºC

69d,e

a) All reactions have been performed on a 30 mmol scale. b) The conjugate addition of copper-catalyzed butylmagnesium halide to pulegone gives a better yield in THF than in ether. c) BuCu from CuBr-Me2S. d) Yield based on the starting enone e) 1, 2 addition partially occurs.

Scheme 13.38

CO2Et

i-PrMnCl, 3% CuCl, 1.2 eq Me3SiCl

CO2Et

i-Pr

THF, 0ºC to 20ºC, 1h

96%

Scheme 13.39

CHO

HeptMnCl, 5% CuCl THF, - 30ºC, 30 min

CHO

Hept 88%

Scheme 13.40

zation of the aldehyde during the hydrolysis of the trimethylsilyl enol ether is very difficult to prevent! Furthermore, the use of trimethylchlorosilane and HMPA, a very hazardous material, is avoided. Finally, the yields reported in the case of organocuprates are based on the transfer of only one of the two R groups of the cuprate. Interestingly, in the case of the a,b-ethylenic aldehydes, organomanganese halides allow the 1,4-addition or 1,2-addition product to be obtained selectively by working with or without copper salts (Scheme 13.42) [37].

557

558


PhMnCl, 5% CuCl

CHO

Ph

CHO

THF, -30ºC, 30 min 60%

CHO

1) Ph2CuLi, Me3SiCl (1.2 equiv) Et2O, Et3N-HMPA (3/1), -30ºC

Ph

CHO

2) Oxalic acid, THF-H2O, 1h 55% Scheme 13.41

BuMnCl

CHOHBu

THF, 20ºC, 30 min 76%

CHO BuMnCl, 5% CuCl

Bu

THF, -30ºC, 30 min

CHO

78% Scheme 13.42

Conjugate addition of functionalized aryl and alkenylmanganese reagents to a,b-ethylenic ketones and esters has also been performed successfully (Scheme 13.43) [30].

O

1) BuLi, -78ºC Cl

Cl

I

MnI

O

Cl 3% CuCl, 0ºC, 2h

2) MnI2, -50ºC to -10ºC

85%

1) BuLi, -100ºC NC

Br 2) MnI2.2LiI, -90ºC

NC

CO2Et

MnI

3% CuCl, Me3SiCl -60ºC to -10ºC

Ph 1) BuLi, -90ºC, Et2O Cl

I

Cl 2) MnI2, -50ºC to -10ºC

MnI

NC CO2Et 61%

CO2Et

Ph CO2Et

CO2Et -20ºC to r.t.

Cl

CO2Et

71%

Scheme 13.43

13.6 Transition-Metal-Catalyzed Cross-coupling Reactions

13.6 Transition-Metal-Catalyzed Cross-coupling Reactions 13.6.1 Copper-Catalyzed Cross-coupling Reactions

Butylmanganese halides prepared in THF easily react with alkyl iodides or bromides at room temperature in the presence of both copper salts (3 to 5% CuCl) and NMP (4 to 9 equivalents). The alkylated products are generally obtained in excellent yields (Scheme 13.44) [38]. This procedure is as simple to carry out as the classical Cu-catalyzed Grignard reaction but the yields are generally better and the chemoselectivity is clearly superior. Indeed, numerous functional groups are tolerated such as alkyl halides, tosylates, nitriles, esters and even ketones. BuMnCl

+

Br ( ) Cl 3

3% CuCl2.2LiCl

Bu

THF-NMP, r.t.

BuMnCl

+

Br ( ) OTs 3

3% CuCl2.2LiCl

Cl ( )3 94%

Bu

THF-NMP, r.t.

OTs ( )3 74%

O BuMnCl

+

Br

( )2

3% CuCl2.2LiCl OEt

O Bu

THF-NMP, r.t.

( )2

OEt

78% Scheme 13.44

In the case of x-halogenoalkylketones the chemoselectivity of the coupling reaction is very impressive. Indeed, in the absence of copper salts, only the 1,2addition product is obtained in excellent yields (Scheme 13.45), whereas in the presence of copper salts the cross-coupling product is formed in high yields and no trace of alcohol is detected (Scheme 13.46). MeMnBr I

I O

HO 94%

Et2O, r.t.

Scheme 13.45

BuMnCl Br

Bu O

Scheme 13.46

3% CuCl2.2LiCl THF-NMP, r.t.

90%

O

559

560


The competition between alkylation and conjugate addition reaction has also been studied. Both reactions take place in the presence of copper salts but it is possible to choose the course of the reaction by adding, or not, NMP as cosolvent (Scheme 13.47).

C9H19Br

BuMnCl

+

O

O 3% CuCl THF 0ºC

+

Bu 95%

C9H19Br

BuMnCl

+

C9H19Br 98%

+

C13H28

O 3% CuCl2.2LiCl THF-NMP, r.t.

93%

O 98%

Scheme 13.47

Thus, x-bromo enones can be selectively alkylated (Scheme 13.48). 3% CuCl4Li2

O OctMnCl

+

Br

( )5

O Oct ( )5

THF-NMP, r.t. 66%

Scheme 13.48

13.6.2 Iron-Catalyzed Cross-coupling Reactions

Fe-catalyzed alkenylation of organomanganese reagents is easily performed at room temperature [39]. The coupling product is obtained in high yields and the stereoselectivity is excellent since no trace of isomerization is detected (Scheme 13.49). 3% Fe(acac)3 OctMnCl

+

Bu

I

THF- NMP, r.t.

Bu

Oct

90% (cis>99%) I OctMnCl

3% Fe(acac)3

Oct

+ Bu

THF- NMP, r.t.

Bu 84% (trans>98%)

Scheme 13.49

13.6 Transition-Metal-Catalyzed Cross-coupling Reactions

It is interesting to note that alkenyl iodides, bromides and chlorides can be used successfully. In all cases the coupling takes place instantaneously. 3% Fe(acac)3 OctMnCl

+

Bu

X

Bu Oct THF- NMP, r.t. X= I: 90%, X= Br: 89%, X= Cl: 88%

Scheme 13.50

The chemoselectivity of this reaction deserves to be emphasized. Thus, in the presence of 3% iron acetyacetonate, organomanganese halides react with x-ketoalkenyl chloride to give exclusively the coupling product (Scheme 13.51). O +

Cl

3% Fe(acac)3

O

BuMnCl

Bu THF-NMP r.t., 1h

Scheme 13.51

13.6.3 Palladium-Catalyzed Cross-coupling Reactions

Formation of aryl±aryl bonds is easily achieved by reacting an aryl bromide with an aryl manganese chloride in the presence of palladium salts [40]. This method is very efficient and chemoselective (CN, CO2R, etc.) (Scheme 13.52). 1% PdCl2(dppp) Br GF

+

2

MnCl DME (4 equiv), THF

GF

0 to 20ºC, 30 min GF = o-, m-, p-CN, o- or m-CO2Et, p-COPh, p-COBU

75-98%

Scheme 13.52

The reaction can also be performed with alkyl, alkenyl and alkynylmanganese chlorides (Scheme 13.53).

561

562


RMnCl (2 equiv.), 1% "Pd" NC

NC

Br

R

THF, DME (4 equiv.) 0ºC to 20ºC R

Catalyst

Yield (%)

n-Oct

PdCl2(dppf)

91

Pent C C

PdCl2(dppf)

91

PhCH2

Pd(OAc)2 + dppp

91

Me2C=CH

PdCl2(dppp)

92

Scheme 13.53

The reaction has been extended to alkenyl halides. Various functionalized alkenyl iodides were used successfully (Scheme 13.54). 1% PdCl2(PPh3)2 NC

I

+

2 PhMnCl

Ph

NC DME (4 equiv), THF

91%

0 to 20ºC, 30 min Scheme 13.54

13.6.4 Nickel-Catalyzed Cross-coupling Reactions

The Ni-catalyzed cross-coupling reaction between aryl chlorides and organomanganese reagents is very efficient. Functionalized aryl chlorides such as 4-chlorobenzonitriles can be used efficiently (Scheme 13.55). 1% NiCl2(dppf) NC

Cl

+

2

MnCl

NC DME (4 equiv), THF 0 to 20ºC, 30 min

98%

Scheme 13.55

Aryl chlorides do not react under Pd-catalysis, it is thus possible in the case of 1-chloro-4-iodobenzene to perform selectively two consecutive arylations, the first under Pd-catalysis and the second under Ni-catalysis (Scheme 13.56).

13.7 Manganese-Mediated Cross-coupling Reactions

MeO

MnCl (1.2 equiv)

I

Cl

MeO

Cl

1% PdCl2(dppp) THF-DME (2.4 equiv)

MnCl (3 equiv) MeO 3% NiCl2(dppf) THF-DME (6 equiv) Scheme 13.56

13.7 Manganese-Mediated Cross-coupling Reactions 13.7.1 Manganese-Catalyzed or -Mediated Cross-coupling Reactions

The discovery of new economical and environmentally friendly alternatives to Pdand Ni-catalyzed-cross-coupling reactions between organic halides and organometallic compounds is of current interest, especially for large-scale applications. In the presence of the complex MnCl2.2LiCl (3%), soluble in THF, conjugated chlorodienes and chloroenynes stereoselectively react with alkyl Grignard reagents in THF-DMPU to afford, respectively, enynes and dienes in good to excellent yields [41]. The chemoselectivity of the reaction allows preparation of various multifunctionalized polyunsaturated compounds (Scheme 13.57). The selectivity observed in the presence of aliphatic chlorides and aromatic bromides must be especially underlined. R Cl

+

BuMgCl

3% MnCl2.2LiCl

R Bu

THF, DMPU

Cl

NC 51%

Bu

Bu

78%

Me3Si Bu Br Scheme 13.57

88%

Bu 71%

563

564


The Mn-catalyzed substitution of activated aryl halides and aryl ethers by Grignard reagents is also highly chemoselective (Scheme 13.58). In all cases, the activating groups (nitriles, imines, oxazolidines) remain unchanged [42]. Cl

MgBr CN

+

10% MnCl2

2

CN

THF, 0ºC

77% Bu

NBu

Cl

+

NBu

10% MnCl2

2 BuMgBr

THF, 0ºC 92%

Scheme 13.58

This reaction is used for the preparation of a synthetic intermediate for the industrial preparation of Irbesartan, an antihypertensive (Scheme 13.59). CN

20% MnCl2

Cl

N N

+

CN

MgBr THF, 5-10ºC 90%

N NH

O

N N

Irbesartan

Scheme 13.59

Recently, a new efficient substitution reaction of ortho-acylated aryl chlorides by organomanganese reagents has been reported [43]. Yields are generally excellent and the reaction readily takes place under very mild conditions with an excellent chemoselectivity (Scheme 13.60). Indeed, halogenoalkanes (Cl, Br, I), nitriles, esters and ketones are tolerated. CN Cl

O +

2 NC

MnCl

O THF, -10ºC

80%

Scheme 13.60

13.7 Manganese-Mediated Cross-coupling Reactions

565

From ortho-chlorobenzoyl chloride it is possible to perform a one-pot acylationsubstitution sequence in excellent yields (Scheme 13.61). Cl

O

Bu Cl

O

BuMnCl (2.5 equiv)

Bu 99%

Scheme 13.61

It should be noted that it is possible to perform selectively the acylation then the substitution reactions. Oct O OctMnCl (1.5 equiv)

Bu

THF, 0ºC Cl

O

BuMnCl (1.2 equiv) Cl 3% CuCl, THF, -40ºC

Cl

O

97% Bu Ph

O

PhMnCl (1.5 equiv)

Bu

THF, 0ºC 77% Scheme 13.62

13.7.2 Mixed (Mn/Cu)-Catalyzed Cyclizations

Unsaturated alkyl bromides undergo a stereoselective ring closure when treated with diethylzinc in the presence of MnBr2 (5%)/CuCl (3%) catalytic mixed-metal system at 60 C in DMPU affording five membered carbo- and heterocycles [44]. Interestingly, functional groups like esters and ketals are well tolerated in these reactions (Scheme 13.63).

566

13 Manganese Organometallics for the Chemoselective Synthesis of Polyfunctional Compounds 1) Et2Zn (1.1 equiv)

EtO2C CO2Et

MnBr2 (5 mol%), CuCl (3 mol%)

EtO2C CO2Et Br

DMPU, 60ºC, 7h E

2) H3O+ or I2 E = H, 71% E = I, 75% 1) Et2Zn (1.1 equiv) Br O

DMPU, 60ºC, 7h

O

( )5

O

2) H3O+ or I2

Br

H

CO2Et O 71%

Et2Zn (1.1 equiv)

O AcO

H

MnBr2 (5 mol%), CuCl (3 mol%)

MnBr2 (5 mol%), CuCl (3 mol%) DMPU, 60ºC, 0.5-3h

HO ( )5 AcO 73%

Scheme 13.63

References 1 Reviews: a) G. Cahiez, Encyclopedia of

Reagents for Organic Synthesis, Ed. L. Paquette, Wiley, Chichester (England) 1995, 3227. b) G. Cahiez, Encyclopedia of Reagents for Organic Synthesis, Ed. L. Paquette, Wiley, Chichester (England) 1995, 925. c) G. Cahiez, Annales de Quimica 1995, 91, 561±578. 2 a) G. Cahiez, B. Figadre, P. ClØry, Tetrahedron Lett. 1994, 35, 3065±3068. b) G. Cahiez, K. Chau, P. ClØry, Tetrahedron Lett. 1994, 35, 3069±3072. c) G. Cahiez, B. Figadre, P. ClØry, Tetrahedron Lett. 1994, 35, 6295±6298. d) G. Cahiez, M. Kanaan, P. ClØry, Synlett 1995, 191. e) G. Cahiez, F. Chau and B. Blanchot, Organic Syntheses 1998, 76, 239. 3 a) G. Friour, G. Cahiez, J. F. Normant, Synthesis 1984, 37±40. b) G. Cahiez, B. Laboue, Tetrahedron Lett. 1989, 30, 3545±3546. 4 G. Cahiez, P.-Y. Chavant, Tetrahedron Lett. 1989, 30, 7373±7376.

5 K. Takai, T. Ueda, T. Hayashi,

T. Moriwake, Tetrahedron Lett. 1996, 37, 7049±7052. 6 T. Hiyama, M. Sawahata, M. Obayashi, Chem. Lett. 1983, 1237±1238. 7 T. Hiyama, M. Obayashi, A. Nakamura, Organometallics 1982, 1, 1249. 8 A. Fürstner, H. Brunner, Tetrahedron Lett. 1996, 37, 7009±7012. 9 a) S. H., Kim, M. V. Hanson, R. D. Rieke, Tetrahedron Lett. 1996, 37, 2197±2200. b) S. H., Kim, R. D. Rieke, Tetrahedron Lett. 1997, 38, 993±996. c) R. D. Rieke, S. H., Kim, X. Wu, J. Org. Chem. 1997, 62, 6921±6927. d) S. H., Kim, R. D. Rieke, Synth. Commun. 1998, 28, 1065±1072. e) S. H. Kim, R. D. Rieke, J. Org. Chem. 1998, 63, 6766±6767. 10 G. Cahiez, A. Martin, T. Delacroix, Tetrahedron Lett. 1999, 40, 6407±6410. 11 G. Friour, G. Cahiez, A. Alexakis, J. F. Normant, Bull. Soc. Chim. Fr. 1979, 515±517. 12 G. Cahiez, B. Figadre, Tetrahedron Lett. 1986, 26, 4445±4458.

References 13 C. Boucley, G. Cahiez, unpublished

results 14 M. T. Reetz, H. Haning, S. Stanchev, Tetrahedron 1992, 33, 6963±6966. 15 C. Boucley, G. Cahiez, S. Carini, V. Cere, M. Comes-Franchini, P. Knochel, S. Pollicino, A. Ricci, J. Organomet. Chem. 2001, 223±228. 16 G. Cahiez, P.-Y. Chavant, Tetrahedron Lett. 1989, 30, 7373±7376. 17 S. Bergström, G. Aulin-Erdtman, B. Rolander, E. Steinhagen, S. Östling, Acta Chem. Scand. 1952, 1157. 18 G. Cahiez, P.Y. Chavant, E. MØtais, Tetrahedron Lett. 1992, 33, 5245±5248. 19 T. Matsuura, Bull. Chem. Soc. Jpn. 1957, 30, 430. 20 D S. Ennis, T. L. Gilchrist, Tetrahedron 1990, 46, 2623±2632. 21 a) T. Ueda, Y. Fujita, Chem Ind. 1962, 1618±1619. b) T. R. Bailey, Synthesis 1991, 242±243. 22 Y. Kojima, S. Wakita, N. Kato, Tetrahedron Lett. 1979, 20, 4577±4580. 23 G. Buechi, E. Kovats, P. Enggist, G. Uhde, J. Org. Chem. 1968, 33, 1227±1229. 24 G. Cahiez, Tetrahedron Lett. 1981, 22, 1239±1242. 25 G . Cahiez, E. MØtais, Tetrahedron Lett. 1995, 36, 6449±6452. 26 G. Cahiez, E. MØtais, Tetrahedron Asymm. 1997, 8, 1373±1376. 27 G. Cahiez, J. Rivas-Enterrios, H. Granger-Veyron, Tetrahedron Lett. 1986, 27, 4441±4444.

28 G. Cahiez, J. Rivas-Enterrios, P. ClØry,

Tetrahedron Lett. 1988, 29, 3659±3662.

29 G. Cahiez, B. Laboue, P.Tozzolino, Eur.

Pat. Appl. EP 374 015 FR. Appl. 88/16598, 1988. 30 I. Klement, H. Stadtmüller, P. Knochel, G. Cahiez, Tetrahedron Lett. 1997, 38, 1927±1930. 31 S.-H. Kim, R. D. Rieke, J. Org. Chem. 2000, 65, 2322±2330. 32 G. Cahiez, B. Laboue, Tetrahedron Lett. 1992, 33, 4439±4442. 33 G. Cahiez, M. Alami, Tetrahedron 1985, 45, 4163±4176. 34 G. Cahiez, M. Alami, Tetrahedron Lett. 1986, 27, 569±572. 35 G. Cahiez, S. Marquais, M. Alami, Organic Syntheses 1993, 72, 135. 36 G. Cahiez, M. Alami, Tetrahedron Lett. 1989, 30, 7365±7368. 37 C. Chuit, J. P. Foulon, J. Normant, Tetrahedron 1980, 36, 2305±2310. 38 G. Cahiez, S. Marquais, Synlett 1993, 45. 39 G. Cahiez, S. Marquais, Tetrahedron Lett. 1996, 37, 1773±1776. 40 E. Riguet, M. Alami, G. Cahiez, Tetrahedron Lett. 1997, 38, 4397±4400. 41 M. Alami, P. Ramiandrasoa, G. Cahiez, Synlett 1998, 325±327. 42 G. Cahiez, F. Lepifre, P. Ramiandrasoa, Synthesis 1999, 2138±2144. 43 G. Cahiez, D. Luart, F. Lecomte, Org. Lett. 2004, 24, 4395±4398. 44 E. Riguet, I. Klement, C. Kishan Reddy, G. Cahiez, P. Knochel, Tetrahedron Lett. 1996, 37, 5865±5868.

567

569

14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis G. Richard Stephenson

The attachment of a transition metal to an unsaturated hydrocarbon ligand transforms the reactivity properties of the ligand. Whereas the classic chemistry of alkenes and arenes is that of electrophilic addition and substitution reactions, the classic reactivity of multihapto-complexes is their reactions with nucleophiles. Such complexes need not be cationic to be good electrophiles, but it helps, and not surprisingly, the most powerful electrophilic multihapto-complexes have positive charge stabilized by the metal.

14.1 Introduction to Multihapto-Complexes and Discussion of Nomenclature

The intention of this chapter is to set out the patterns of reactivity of electrophilic multihapto-complexes with nucleophiles, with particular regard to the effects of substituents on the haptyl portion of the ligand. Addition of a nucleophile to an n electrophilic multihapto-complex reduces hapticity by 1. Thus a cationic g elecn + n±1 trophile { [g ] } is converted into a neutral product { [g ] } when, for example, a nucleophile adds at one end of the p-system, as illustrated in Fig. 14.1. If the elecn n±1 ± trophilic complex is neutral, then the corresponding reaction is: { [g ] } ® { [g ] }, and the product is an anion. When the nucleophile adds at an internal position (see Section 14.3.8), the outcome is essentially the same, but it is the sum of the hapticities n in the product that adds to a value that is one less than n' in the g starting material. There are in general two classes of electrophilic multihapto-complexes: those with cyclic p-systems, referred to as ªclosedº complexes [1], and those in which the p-system is ªopenº (e.g., linear). To further complicate the situation, the haptyl section of an open ligand can also be branched, and exocyclic extensions can embellish cyclic p-systems. More than one haptyl region can be present in an individual ligand, and several unsaturated ligands can bind to the same metal. Thus a wide range of selectivity issues are encountered: there can be competition between ligands in the same cationic metal complex, there can be competition between haptyl regions attached to the same metal, and there can be competition between the different atoms of most reactive haptyl portion of the complex. Each Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

570

14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis

η n electrophile cationic electrophile

a

product from nucleophile addition (Nu = nucleophile) 2 from η :

3 from η :

n from η :

Nu

Nu

Nu

+ M

( )(n-2)

multihapto electrophile: n >1

M

M

M

η 1 product

( )(n-2)

η 2 product

η (n-1) product

metal ( M ) - ligand bonding

b

σ bond + π bonds

σ bond

chiral cationic electrophile

+ M

racemic planar chirality

π bonds

+

Nu

Nu

Nu

( )(n-2)

σ bond

+ π bond

creation of stereogenic ("chiral") centres from planar chirality in the electrophile

R

c

σ bond

R M

R

R

M

( )(n-2)

( +- ) η 1 product

Figure 14.1 a, b) Bonding in the products from nucleophile addition to open multihapto-organometallic electrophiles: g2 electrophiles produce a r-bonded product, but electrophiles with higher hapticities produce multihapto products with both r and p bonds between the metal and the ligand (for neutral multihapto-organometallic electrophiles, the products have the corresponding structures but are anions). Simple closed multihaptoorganometallic electrophiles always produce open multihapto products, and closed multihapto-organometallic electrophiles with an exocyclic extension produce multihapto products that can be either open or closed,

η 2 product

M

( +- ) η (n-1) product

depending on the site of nucleophile addition. c) In this chapter, when a racemic complex with planar chirality controls the formation of chirality at carbon by the stereocontrolled attachment of a nucleophile to an atom in the ligand, the structure drawn for the product defines the relative stereochemistry, but only one enantiomer is depicted. The racemic nature of this product is shown by use of the (+/±) symbol beside the structure. Racemic structures with only one stereogenic feature are drawn without representation of stereochemistry, and in these cases, the (+/±) symbol is omitted.

14.2 Classes of Nucleophile Addition Pathways to Multihapto-Complexes

of these factors in part will be influenced by the presence of substituents on the ligand and unsymmetrical substitution patterns will open up a diversity of regiochemically distinct pathways. When considering the directing effects of organic substituents, there are still extrapolations needed to complete the pattern, and experimental work to check such postulates is still valid.

14.2 Classes of Nucleophile Addition Pathways to Multihapto-Complexes

The original classification of open and closed ligands [1] made an important point, restricting the discussion to kinetic control in the reactions with nucleophiles (see Section 14.4). As with earlier work, this chapter will concentrate on elucidating control effects under kinetic control, but it is important to be aware of the alternatives (see Section 14.4), especially when apparent exceptions to typical reactivity patterns are encountered. Taken as a whole, the general class of electrophilic multihapto-complexes corresponds to the most versatile and structurally diverse class of electrophiles known to organic chemistry. Classifying control effects [2,3] across such a wide range of structural types is a major endeavor. 2 The simplest starting point is an g alkene complex (see Section 14.3.1) as the only possibility is an addition to one end of the p system. When a substituent is present, nucleophile addition can be at either the substituted or unsubstituted end. This is referred to as the regiodirecting effect of the substituent. The monosubstituted case corresponds to a single example, and with two substituents there are three possible structures to consider. Once the regiodirecting effects of substituents are defined in the monosubstituted cases, the issue arises whether they show the same properties in combination, or behave differently. Current attempts to categorize regiodirecting effects for multiple substituents have reached the conclusion that pairs of substitutents can either show mutually reinforcing directing 3 effects or be opposed to one another1 [4,5]. In g allyl complexes, nucleophiles can add at an end (see Section 14.3.2), or at the internal position (see Section 14.3.8), and substituents can be terminally or internally positioned, so far more possibilities arise, but the principle of analysis of mutually reinforcing or opposed regio3 directing effects still holds. The g ligand system can be open (linear) or closed 4 (cyclic). Progressing to g complexes (see Section 14.3.4), open, branched and closed structures are now possible, but in the branched and closed monosubstituted cases, there is only a single possibility for the structure of the multihapto electrophile, and the increased symmetry of the ligand also reduces the number 1) For discussion of synthesis design based on

the manipulation of competing regiodirecting effects, see [4]; this same concept has been discussed in terms of ªmatchedº and ªmismatchedº pairs of substituents (see [5]), by an extension of the nomenclature used for double stereodifferentiation, but since double stereodifferentiation effects can arise

in the addition of chiral nucleophiles to the planar chirality of nonracemic multihaptocomplexes, to avoid confusion of the two concepts, we use ªreinforcingº and ªopposedº when describing the combination of regiodirecting effects of substituents.

571

572


of regioisomeric products that need to be distinguished in categorizing regiocontrol (just four/three possibilities in these cases, instead of the 10 that are possible 4 for monosubstituted cisoid g diene complexes). This type of analysis can be con5 7 tinued onwards through g to g complexes with increasing structural diversity both in terms of regiochemically distinct starting materials, and the range of possible products accessible from each. Because the best and most typical examples of electrophilic multihapto-complexes are cationic and tend to react at a terminus of the p-system, the directing effects of substituents on the p-system are most simply described in a fashion that clearly distinguishes the two ends. When the directing substituent is itself at a terminus, addition at the site of substitution can be referred to as ipso (i). The alternative, which is addition at the far end of the p-system, is then described as omega (x) [6]. When the substituent is at an internal position, ipso addition would, of course, now denote an internal approach of the nucleophile. Competition between the ends of the p-system is most commonly described in this case as a and 4 5 x. For example in g and g complexes, the end nearest to the substituent is the a 2 position [6±8] and the end furthest from the substituent is x. The advantage of this method of describing the regiocontrol effects is that the nomenclature is independent of the hapticity of the complex, and so allows the systematic comparison of directing effects across a series of complexes of different sizes. An extension of the i,x / a,x descriptors presented in Figs. 14.2 and 14.3 has been developed to allow comparisons to be made across the full diversity range of ligand types 2 7 (open, closed and branched) and sizes (g ±g ), while retaining compatibility with our earlier usage of the terms of the i, a, and x, in the literature. The starting point in all cases is to define as ipso (i) the atom carrying the substituent (the ªreference substituentº). Next, it is necessary to identify the shorter and longer paths from the substituent to the ends of the p-system, or in the case of cyclic ligands, to the atom(s) nearest to and furthest from the reference substituent. This furthest position is defined as x in the cyclic ligand series. In the acyclic cases, since the primary directing influence is derived from unsymmetrically placed substituents, the reference substituent must always be nearer to one end than the other, so this stage will produce an unambiguous result. The alpha (a) position is now defined as the atom adjacent to the substituent on the shorter path (in most common open ligands, this will in fact correspond to an end of a p-system carrying an internal substituent, or to the ortho position of a cyclic closed structure). The far end of the p-system (i.e., the end of the longer path) is defined as omega (x), thus in many simple cases placing a and x at the two extremities of the ligand. The remaining positions can be designated by counting along the shorter path sequentially to the end [a (already defined), b, c, etc.]. Finally the longer path is designated by starting with the nearest atom to the substituent, and taking the next available Greek character, then counting sequentially to the penul2) For our definition of the term ªa positionº,

see [6]. There is an older usage of the terms a and c in the discussion of palladium-catalyzed allylic displacement reactions, where

the reference point is the position of the leaving group (see [7,8]).

ωa

α

α

+ M

R

+ M

ωs

i

η4

ω

i

ωs

ω

β

β

α

i

+ M

ωa

R i

+ M

+ M

R

ω

η5

η3

α

ωs

β

R i

ω

α

ω

+ M

+ M

ωa

α

η5

i R + M

η4

β

α

R i R i

η4

η4

ω

i

η5

γ

ω

R

α

ωs

R

ω

β

β

i

+ M

α

β

ωa

+ M

ωs

η5

i R + M

ω

ωs

β α

ω

R

i

+

+ M

ωa

η5

M

i R

α

β

δ

+ M

i R

α

γ

β

α

η7

ω

α

η6

η6

γ

R i

η5

ωa

γ

β

α

β

+ M

i

R

+ M

ωs

ω

α

η5

δ

R i

η6

γ

R i

δ

α

η6

ω

+ M

β

from g4 ± g5 (reference substituent = R). Electrophilic centers in structures with greater hapticity can be designated by a simple extension of these patterns.

+ M

ωa

+ M

η5 β

+ M

i R

α i R

β

α

η5

Figure 14.2 Labelling system for electrophilic centers in monosubstituted multihapto-organometallic electrophiles of common sizes: a) open ligands from g3 ± g6; b) closed ligands from g3 ± g7; c) branched ligands

c

b

a

R

η3

14.2 Classes of Nucleophile Addition Pathways to Multihapto-Complexes 573

i

α

ω

ωa

+ M

ωa

+ M

R

i

α

β

β + M

ω

ωa

ωs + M

βa

R i α

ω

R

β

i

α β

β

γ

i α

ωa R

ωs

i

ωs ωa

+ M

ω

β

βa

+ M

R

+ M

βs α

η6

R

i

α

γ

R i

γ

β

ω

γs

Figure 14.3 Extension of the labelling system for electrophilic centers in monosubstituted multihapto-organometallic electrophiles with closed ligands with exocyclic extensions from g4 ± g7 (reference substituent = R). The procedure for figure 14.2 is still valid here, identifying short and long

R

ωs

α

i + M

R

βs α

R

i

η5

η4

i

α

ωs

paths to assign a, b, c, etc, but it is clearer to think in terms of counting to the true end of the p system (exocyclic position). When both paths are the same length, the direct path to the true end of the p system is then used first assign a, b, etc.

+ M

ω

+ M

ωa

β γ

δ

β

ωa

+ M

ωs

i + M

R

βa

α

a

α

δ

R

γ

βs

η7 574


14.3 Unsymmetrically Placed Substituents in Stoichiometric Electrophilic Multihapto-Complexes

timate atom (the final position is already defined as x). A complete set of examples to illustrate these definitions is presented in Fig. 14.2 for open/acyclic ligands, and the closed/cyclic alternatives. 4 Branched ligand geometries (e.g., trimethylenemethane g ligands; see Section 14.3.6), and cyclic complexes with exocyclic extensions to the p-system (e.g., fulva6 lene g ligands) require more careful consideration (Fig. 14.3) as it is possible to encounter (for example) two regiochemically distinct x positions. Fortunately, the standard syn/anti method for describing substitution patterns on multihaptoligands provides a simple means to cope with these structures. The xs (xsyn) position is the x atom of the portion of the haptyl ligand that is displayed in the syn direction (spatially near to the reference substituent). Similarly, the xa (xanti) position is the x atom displayed in the anti direction (spacially remote from the reference substituent). Corresponding procedures define as (asyn), bs (bsyn), aa (aanti), and ba (banti) positions. The far ends of branched ligands are both termed x (i.e. xs and xa and with exocyclic structures, the furthest atom on the portion and the atom at the end of the exocyclic extension are x positions.

14.3 Unsymmetrically Placed Substituents in Stoichiometric Electrophilic Multihapto-Complexes 14.3.1 Electrophilic g 2 Complexes 2

+

The most common example to illustrate the g case is the classic Fe(CO)2Cp se2 ries of complexes. These are electrophilic at the open g alkene ligand, not the 5 closed g cyclopentadienyl ligand. With a donor substituent, for example the OMe group in complex 1 [9], nucleophiles add to the ipso position (see Scheme 14.1). Electron-withdrawing groups, such as the acyl group in 2 [10], have the opposite influence, and direct nucleophiles x. The same control effect has been identified + in the analogous Ru(CO)2Cp complex [11]. When donor and acceptor substituents are placed at the same end of the alkene [12], they are opposed to each other, and the effect of the OEt group dominates. When it comes to assessing steric 2 effects, the g case is a special case, because the product has a r bond, and after nucleophile addition, the metal is attached tightly to just one carbon. There is a common tendency for the bulky metal complex to dominate the control effects and move to the unsubstituted carbon atom to release steric strain, as can be seen for example in regiocontrol effects of the palladium-catalyzed Wacker oxidation of terminal alkenes, which proceeds by nucleophilic addition of water to the alkene at the substituted end [13], and can be seen in other palladium-mediated nucleo+ phile additions to alkenes [14]. A recent example in the Fe(CO)2Cp series involves the addition of isopropoxide, which although proceeding in low yield, and under conditions that are potentially reversible (see Section 14.4), is reported to give single regioisomers of ipso addition products [15]. With donor and alkyl substituents

575

576


MeO

+ Fe(CO)2Cp

-

O

O

THF, -78 ºC, 1 h, 90%

1

Fe(CO)2Cp

MeO

+ Li

Ref. 9

O

+ Fe(CO)2Cp

Me 3SiO

O

CH3CN, 0 ºC, 1 h, >58%

2

Fe(CO)2Cp

O

Ref. 10 Scheme 14.1

at the same end of the of the alkene [16], ipso addition is still straightforward, as it is assisted by the release of steric strain when FeCO)2Cp moves to become r bonded to the unsubstituted end (see Table 14.1 in Section 14.5: entry 10). 14.3.2 Electrophilic g 3 Complexes 3

Turning to the g case, the terminal ester substituent in a neutral dimeric stoichiometric palladium complex [17], provides an early example of x direction of nucleophile addition. An A ring ketone [18] has a similar x-directing influence in a steroid ring system. As in Section 14.3.1 (concerning Wacker oxidation), parallels can 3 be seen with regiocontrol in palladium-catalyzed processes, as cationic g palladium intermediates in allylic substitution reactions show similar control effects [7,8,19,20]. To save space, however, in this chapter attention will focus on elucidating control effects in the stoichiometric examples, though provided care is taken over the possibility of alternative mechanisms (e.g., the ªmemory effectº [21] and addition via the metal [22]) the conclusions hold in the interpretation of regiocontrol in catalytic examples as well [23]. + The Fe(CO)4 allyl complexes provide the most widely studied class of stoichiometric allyl complexes. The methyl substituted examples [24,25] give mixtures of products with the preferential site of addition at the less-hindered end of the p-system. With two methyl groups at the same end, the x-directing effect is quite ± strong (with (MeO2C)(MeCO)CH as the nucleophile, the i : x ratio is 1 : 4 [26]) and in some cases gives complete regiocontrol. With 3, the nucleophile is even directed in to a substituted position [27]. Similar steric-based effects are seen with functionalized alkyl substituents [28±32] and trimethylsilyl directing groups [33]. Results with electronically interacting substituents such as acyl [34], ester [35] and SO2Ph groups [36] again illustrate that electron-withdrawing substituents direct to the x end of the p-system. For example, enolate addition to 4 affords 5 after oxidative removal of the metal (see Scheme 14.2). The x-directing effects of


577

the ester and SO2Ph groups are strong enough to allow nucleophiles to add to a position carrying a methyl group, despite the steric block at the electrophilic center [37,38]. Amines [39] and silylenol ethers [40] have been used as nucleophiles in + this procedure. With electron-withdrawing substituents, the catalytic Pd(PPh3)2 + + [41] and stoichiometric Fe(CO)4 [42] and less common Mo(CO)(NO)Cp [43] systems all show x addition. Examples of ipso addition relative to donor substituents are best drawn from the regiocontrol of palladium-catalyzed allylic substitution [20,44,45]. + Fe(CO)4

3

MeO2C

+ Fe(CO)4

1) PhCH2CuCN THF, -10 ºC, 3h, 62% 2) loss of metal (silica column then short path distillation) Ref. 27

1)

O-

Si tBuMe 2

-78 - 0 ºC, THF, 8 h

4

Ph

2) (NH 4)2Ce(NO3)6, 0 ºC, THF/H2O, 51% for two steps Ref. 35

MeO2C

Si t BuMe2 O

5

Scheme 14.2

14.3.3 Electrophilic g 4 Complexes 4

The g class of electrophiles are best represented by the widely explored cationic molybdenum(dicarbonyl)cyclopentadienyl and -indenyl series of complexes. As + with the Fe(CO)2Cp system described in Section 14.3.1, nucleophiles react at the 4 open g ligand, not at the closed cyclopentadienyl and indenyl p systems. In the indenyl case, the 1-methyl-substituted example provides a good illustration of a simple x-directing steric effect [46]. Similar, but incomplete x direction of enolate addition is provided by an internally placed Me group (x : a ratio: 2 : 1) [47]. As 2 3 4 + with the g and g examples, in the g Mo(CO)2Cp complexes, donor substituents again direct ipso. The oxygen atom in the ring in 6 is strong enough to overcome the steric effect of the methyl group (see Scheme 14.3) [48]. When an OEt group replaces the methyl group at this position, the donor substituent and the oxacyclic feature mutually reinforce their directing influences [48±50]. The complex 7 provides an example of an internally positioned (C-2) substituent. The x-directing effect is strong, and addition at the far end of the p system predominates (Scheme 14.3), and is the only outcome in all but one of the cases examined [51]. The cyclopentadienyltungsten complex 8 reacts with organocuprate reagents at the unsub-

578


stituted end of the p-system. This would be easier to interpret if the example lacking the Me group were available, but the regiocontrol observed with 8 is consistent with an a-directing effect from the C-2 ester group (see Sections 14.3.1 and 14.3.4). An unusual feature of the organotungsten diene complexes is their ability 4 to bind transoid structures as g complexes. While the dimethylcuprate reagent still reacts predominantly a with respect to an ester, the x pathway now competes [52], and in some cases only x addition is observed [53], but care must be taken in interpreting this as it is an example with a heteroatom nucleophile and these often show reversible reactions (see Section 14.4). When the ester directing group is placed at the end of the p system, the outcome is much more clear cut. The x-directing effect is enough to overcome the steric bulk of the methyl group at the 4 site of nucleophile addition [54]. A cationic Co(CO)3 g complex provides an example of an x-directing effect of a methyl group on a closed cyclobutadiene ligand [55]. Me + Mo(CO)2Cp

O

6 SPh + Mo(CO)2Cp

Me

MeMgBr

O

Mo(CO)2Cp

THF, 0 ºC, 2 h, 88% Ref. 48

SPh

NaCH(CN)2

Mo(CO)2Cp

THF, 0 ºC, 0.5 h, 81%

CH(CN)2

Ref. 51

7

CO2Me + W(CO)2Cp

Me

Me CO2Me

Me2CuLi

W(CO)2Cp

Et2O, 0 ºC, 0.5 h, 50% Me

Ref. 52

8

( +- )

Me

Ref. 35 Scheme 14.3

14.3.4 Electrophilic g 5 Complexes 5

+

The classic g cyclohexadienyl complexes of Fe(CO)3 first investigated by Fischer and Fischer [56], and subsequently by many research groups (including my own) provide a wealth of examples of studies of regiodirecting effects of substituents. With simple alkyl groups, steric effects send the nucleophile to the x position


[57±61], though in the acyclic series [where complications arise from possibilities for cisoid/transoid equilibration (see Section 14.4)] there are notable exceptions [24], and often mixtures are obtained [62,63]. With amine nucleophiles, product ratios depend on the basicity of the nucleophile [64]. Larger Et and n-Pr groups gave complete control of x addition in the acyclic series with PPh3 as the nucleophile [59]. Similarly with cyclohexadienyl complexes, cuprate addition to 9 followed the x pathway (Scheme 14.4) [65]. In some cases, however, ipso addition relative to alkyl substituents predominates with hydride and dimethyl malonate nucleophiles in the acyclic case, and changing from Fe(CO)3 to Fe(CO)2PPh3 was found to produce good ipso selectivity [66]. In contrast, with Knochel-type functionalized organozinc nucleophiles, good control for the x addition pathway has been obtained. Similarly, with 10 where the directing group is at C-2, there is also x addition [67]. In the cyclic series (11) the C-2 Me group is a weak directing group, and often gives a/x mixtures (see Section 14.5.1) but with the right choice of nucleophile (for example 12 [68]), good x selectivity is possible. With an n-Bu group at C-2, good x control has been achieved to introduce 2'-deoxyganosine [69]. Trifluoromethyl groups at either C-1 [70,71] or C-2 [70] direct x. This effect of CF3 may be largely steric, but seems to give more reliable control than is encountered with CH3 groups. Et + Fe(CO)3

Fe(CO)3

THF, 0 ºC, 2 min, 70%

9

Me + Fe(CO)3

Et

Me2CuLi

Ref. 65

Me

( +- ) Me

EtO2CCH2CH2Cu(ZnI)CN, THF, 5 ºC then 25 ºC, 2h, 99%

Fe(CO)3 EtO2C

Ref. 67

10 OSiMe3

12

OSiMe3

Me + Fe(CO)3

11

O

CH3CN, -20 ºC, 10-15 min

Me Fe(CO)3

( +- )

then dry MeOH, HCl, rt, 24h, 78%

Ref. 68 Scheme 14.4

Donor substituents at the end of the p-system (Scheme 14.5) direct ipso in cyclic (13 [72]) and acyclic (14 [73]) cases. The alternative, for example 15, is to put the donor substituent at the internal position, where it now directs x [74±86] and

579

580


has been used in nonracemic examples to control absolute stereochemistry [87±89]. With some organolithium reagents, however, a,x mixtures are encountered [90]. A C-2 OMe group can efficiently overcome the steric effects of methyl and larger (e.g., MeO2CCH2CHMeCH2; see Table 14.1 in Section 14.5: entry 16) alkyl groups at C-4 [91]. By far the most widely explored case, however, puts x-directing C-2 OMe groups in opposition to C-5 methyl (Scheme 14.6) [92±98] and alkyl groups [99], to establish quaternary centers in the products. This has also been explored in the nonracemic series [100]. Similarly with bicyclic ligands [101], quaternary centers are formed at ring junctions, though in this case, if the steric block is made too great, poor regiocontrol [102] or deprotonation not nucleophile addition [103], occurs. Although the extra methyl group in 17 is centrally placed, 17 was more prone to deprotonation than 16, but this problem was overcome by the use of trimethylsilyl cyanide [104]. The use of the C-2 donor group to promote nucleophile addition to substituted positions also works well in the acyclic pentadienyl series, as illustrated by 18 [105]. With OMe groups at both C-1 and C-4 in 19 (Scheme 14.7), the directing effects of the two donor substituents are mutually reinforcing, and this has proved to be a useful way to elaborate the simple dimethoxy cyclohexadienyl complex to afford more advanced substitution patterns [4,72,106±111]. The same regiocontrol is + seen with the corresponding Fe(CO)2PPh3 complex [112]. An example of terminal and internal directing effects in opposition is provided by structure 20. A mixture of products was obtained, but the ipso effect of the terminal OMe group can be seen to dominate [113]. OEt + Fe(CO)3

13

Ph

PhLi

Fe(CO)3

CH2Cl2, -78 ºC, 70% Ref. 72

( +- )

OMe + Fe(CO)3

15 Scheme 14.5

Me

MeLi

OMe Fe(CO)3

CH2Cl2, -78 - 10 ºC, 75%

14

OMe + Fe(CO)3

OEt

( +- )

Ref. 73

OMe

(EtO2CCH2)2CuLi THF, -78 ºC - rt, 30 min, 91% Ref. 79

EtO2C

Fe(CO)3

( +- )

14.3 Unsymmetrically Placed Substituents in Stoichiometric Electrophilic Multihapto-Complexes OMe + Fe(CO)3 Me

OMe

CO2 Me

-

16

O

Fe(CO)3

THF, 0 ºC, 15 min, >99%

MeO2C

Me

17

Me O

Ref. 75

OMe Me + Fe(CO)3

581

OMe

Me3SiCN

Me Fe(CO)3

CH3CN, reflux, 95% (monitored by IR) NC

Me

Ref. 104

( +- )

OMe + Fe(CO)3 Me

18

OMe

PPh3 95 %

Fe(CO)3

Ref. 105

(representative general conditions: CH2CH2, rt, 16-24 h) Ref. 59

+ Ph3P

Me

( +- )

Scheme 14.6

OMe + Fe(CO)3

Ref. 108

OSiMe3

OMe OMe + Fe(CO)3

20

Fe(CO)3

Et2O / CH2Cl2, -100 ºC - rt, 68%

19

OMe

OMe

H2C=C(Me)Li

MeO2C

OMe

CH3CN, rt (heat generated by reaction), 2h, 64% Ref. 113

( +- )

OMe

OMe

OMe OMe Fe(CO)3

( +- )

OMe

+

Fe(CO)3 MeO2C

10 : 3

Scheme 14.7

Switching from donors to acceptors as a terminal substituent (Scheme 14.8) also reverses the directing effect. The ester groups provide typical examples and are strongly x directing [114±116]. In 21 the x-directing ester is in opposition to the methyl group [117], but in 22, the ester and OMe x-directing effects reinforce each other [118]. Other electron-withdrawing groups, for example, formyl substit-

( +- )

582


uents [119,120], acyl [121], sulfonyl group [122], triflate [123] and nitrile groups [124] also direct x. With a nitrile opposing the methyl group, the x directing is again strong enough to overcome the steric effect of a methyl group [124]. Less is known about the control effect when an ester is at the internal position, in part because in the tricarbonyl(cyclohexadienyl)iron(1+) series, the compound was obtained as a mixture with other regioisomers [125], and reacts easily with water. However, the structure of the alcohol formed by water addition is consistent with an a-directing effect from a C-2 CO2Me group, again corresponding to a reversal of regiodirecting properties when the polarity of the substituent is reversed. Subsequently, the salt has been obtained pure by a decarboxylation reaction [126]. This type of reversal effect is especially important in synthesis when the two substituents are capable of similar subsequent elaboration. An example is the replacement of OEt by OAc [127]. The acetoxy group directs nucleophiles to the x position. CO2Me

CO2Me

+ Fe(CO)3 Me

H2O >60%

Ref. 117

21

HO H Me

Fe(CO)3

(- )

Br

CO2Me OMe + Fe(CO)3

22

CO2Me

ONa

Br

Br

Fe(CO)3

THF, -65 ºC, 2 h, 99% Ref. 118

OMe

O Br

( +- )

Scheme 14.8

Aryl substituents tend to give mixed results (Scheme 14.9). Malonate addition to the acyclic 1-phenypentadienyl complex 23 [62] shows the ipso-directing effect that should be expected by analogy with 14 as electronically, both OMe and Ph groups are good at stabilizing positive charge. However, there are also cases of x addition as, for example, when PPh3 is the nucleophile [5]. In the open cyclic series, a 1-phenyl substituent in 24 directs x because the aromatic ring is twisted out of plane [72,128]. This sterically derived x-directing effect is relatively weak, and can be overcome by putting a suitably placed OMe group to oppose it in 25. Internally positioned aryl substituents [129] also direct x, and although this could be steric, the tendency for reversal of directing effects to follow reversal of polarity, and the fact that the x-directing effect is slightly greater with anisyl than with phenyl (i.e., Scheme 14.10: a bigger directing effect in 26 from a more electronically active group), suggest that it is not unreasonable to ascribe this effect to an electronic influence, not a steric one. The ipso effect of a C-1 Ph group in the acyclic


583

series is also weak and can be overcome by an opposed C-2 methyl substituent [61]. There have been a number of examples in this section that suggest that the 5 x-directing effect of Me at C-2 is stronger in the g acyclic complexes than in the cyclohexadienyl case. When this x effect is placed opposite a Ph group at the end of the dienyl system, the nucleophile adds to the substituted position (ipso to Ph), not the CH beside the methyl group [61]. Ph + Fe(CO)3

LiCH(CO2Me)2

(MeO2C)CH

Fe(CO)3

THF, 50 % Ref. 62

23

( +- )

Ph + Fe(CO)3

24

Ph

Ph

NaCH(CO2Me)2

(MeO2C)2CH Fe(CO)3

THF, 0 ºC, 15 min, 83%

(MeO2C)2CH

Ref. 72

( +- )

Ph

+ 85 : 15

Ph + Fe(CO)3

(MeO2C)2CH

NaCH(CO2Me)2

Ph Fe(CO)3

THF, 0 ºC, 15 min, 75% OMe

25

Ref. 72

OMe

( +- )

Scheme 14.9

OMe

OMe

NaCH(CO2Me)2 + Fe(CO)3

26

THF, rt, 1h, 80% Ref. 129

Fe(CO)3 CH(CO2Et)2

( +- )

Scheme 14.10

Alkynes at C-1 of a cyclohexadienyliron(1+) complex have also been examined, and found to direct nucleophiles x, but with some a addition (see Section 14.3.8) [6]. Despite its charge-stabilizing capabilities, a C-1 PhS group directs x. Similarly, trimethylsilyl groups at either C-1 or C-2 have been found to direct x, despite the cation-stabilizing properties of SiMe3 [130±132]. In the acyclic series, this effect is

Fe(CO)3

( +- )

584


strong enough to send the nucleophile into a position substituted by a methyl group [132]. In fact, in general, the larger period three elements tend to be x directing. The highly substituted complex 27 (Scheme 14.11), has groups at both ends of the p-system (and additional rings). Faced with this steric blockade, unusually, MeLi adds a methyl group to the closed cyclopentadienyl ligand [133]. SiMe3 + CoCp

Me3Si

MeLi

Me

H Co

THF, -78 - 0 ºC, 59% Ref. 113

( +- )

27 Bu

Bu

Complex 28 formed in situ;

Co +

Co Bu

nBuLi, THF, -30 ºC, o/n, 82% Ref. 142 TfO

O

28 Scheme 14.11

The effects discussed in cyclohexadienyliron complexes and their acyclic counterparts are mostly reproduced in larger ring sizes, if complications from internal (see Section 14.3.8) nucleophile addition are set aside. To minimize internal addition, Fe(CO)2 phosphine and phosphite complexes have been widely studied, but + 5 even in the parent (g -cycloheptadienyl)Fe(CO)3 series with Knochel-type functionalized organometallic nucleophiles, good yields (as high as 93%) of the 1,3-diene products can be obtained [134]. Because of the larger ring sizes, unsymmetrical substitution in the saturated section of the cyclic ligand is possible, and nucleophiles add under steric control (x addition) to the less hindered end of the p system [135,136]. The ispo-directing effect of a C-1 OMe group is also seen in the cycloheptadienyliron series [137]. Ketones within the ring of cyclohexadienyl complexes interact with both ends of the p system, though in the presence of this symmetrically imposed electronic effect, the simple steric effects from both C-1 and C-2 methyl groups seem strong, and both direct x [138,139]. An A ring steroid complex of iridium provides another example of a cyclohexadienylone ligand [140]. It is possible that steric distortions of the ligand bias the strengths of interactions of the ketone with the two ends of the haptyl section of the ligand, inducing an electronic effect. In the cycloheptadienyl and cyclooctadienyl cases, the ketone substituent in the correspond-


ing position is unsymmetrically placed and is a powerful x-directing influence in its own right [141]. 5 Cyclopentadienyl g complexes are relatively unreactive, and if there is an alternative electrophilic center in a complex, then normally nucleophile addition will occur there. However, the cobalt complex 28 (Scheme 14.11) shows a good example of x direction from the butyl group in a closed ligand [142]. Nucleophile additions to 27 and 28 are unusual, as the carbon±carbon bond formation is followed by a hydride shift between the metal-bound rings. An unusual organomanganese complex of thiophene gives a rare example of addition to a metal-bound hetero5 atom in a closed ligand system. Nucleophiles add at the sulfur atom in the g thiophene ring, and this is a strong enough effect to overcome the influence of flanking methyl groups in the 2,5-dimethyl compound [143]. 14.3.5 Electrophilic g 6 Complexes 6

In the g series, cyclic closed ligands predominate, though there are occasional 6 6 + examples of g open ligands (Scheme 14.12). The g cyclooctadiene FeCp complex 29, for example, reacts with nucleophiles at the least-hindered end of the complexed triene [144]. CH(CO2Me)2

CH(CO2Me)2 NaCH(CO2Me)2 THF, rt, 2 h, 87%

( +- )

+ FeCp

29

Ref. 144

CH(CO2Me)2 FeCp

( +- )

Scheme 14.12

In the closed ligand series, the analysis of substituent effects is a complicated issue [23,145]. Only the most clear-cut effects will be presented here. Methyl substituents promote the b pathway, though not completely. With the carbonylmangenese complex of toluene, the b : a ratio is about 3 : 2. However, Mn(CO)[+ P(OEt)3]2 increased the b : a ratio to about 5 : 1 [146]. With a large silatrane [N(CH2CH2)3Si-] substituent, selective a addition is observed with Grignard reagents in CH2Cl2 [147]. Methoxy groups have a strong b (meta)-directing effect + in the Mn(CO)3 series [148] (Scheme 14.13) and this overcomes the influence of the methyl group in 30 [149], and also promotes addition adjacent to Cl when the ligand is 4-chloroanisole [149]. With 31, regiocontrol switched dramatically with solvent (see Section 14.4), showing a addition in CH2Cl2 but x addition in THF. In CH2Cl2, with a 4-methoxy substituent opposite the silyl group, the a-directing silatrane and the b-directing OMe group reinforce each other, and there are several completely controlled examples of nucleophile addition in this case [147]. The

585

586

14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis 6

1,3-dimethoxy case gives clear b control [149]. The OMe group in (g -anisole)Cr(CO)3 complex behaves similarly [150±155], as does an OPh donor substitutent [156]. Since the product of the initial nucleophile addition step is now an anion, it is typically converted into a further product by electrophile addition [153] or oxidation [154]. Conversion (Scheme 14.14) of 32 into a substituted arene demonstrates the b-directing effect of the OMe group [154]. An x-directing effect from t a bulky TIPS silyl ether [156], and a large (SO2 Bu) electron-withdrawing group [157] have been reported. OMe

OMe + Mn(CO)3

LiAlH4 Mn(CO)3

THF, -78 ºC, 90% Me

30

Ref. 149

Si(CH2CH2)3N + Mn(CO)3

31

Me

Si(CH2CH2)3N Me

MeMgBr CH2Cl2, 0 ºC, 30 min, 72% Ref. 147

Mn(CO)3

( +- )

Scheme 14.13

Oxazolines [158±161], imines (e.g., 33 [159], Scheme 14.14) [159±161] and hydrazones [162] have been used to promote an a addition pathway, an effect ascribed to precoordination of the incoming organolithium by the side-chain heteroatom. Similar a addition can be achieved with heteroatom donor substituents by careful control of conditions and choice of nucleophile [163±165] overcoming the natural b control of the donor group. In examples where the arene carries a leaving group, metal-promoted SNAr reactions are observed, though in some cases, mechanisms can be complex (Scheme 14.15) [145]. The formation of the 1,2-disubstituted product 36 from the 1,4-disubstututed complex 35 is best explained by addition b (meta) to the fluorine (a to the methyl group), followed by rearrangement of the position of hapticity 5 3 in the g intermediates to put the leaving group at an sp center. In this case, 6 rapid loss of fluoride reforms the g -arene ligand. This process is referred to as a tele-meta-SNAr reaction [166]. The formation of 38 from 37 provides an example of a cine-SNAr mechanism [167], in which the initial site of nucleophile addition is adjacent to the leaving group. With a 1,3 disubstitution pattern, the product corresponds to addition at the less hindered of the two possible cine-SNAr sites [168]. A rarer case is tele-para-SNAr [169], which occurs when the cine-SNAr and tele-meta-SNAr pathways are obstructed by substituents flanking the leaving group, as in 39.

14.3 Unsymmetrically Placed Substituents in Stoichiometric Electrophilic Multihapto-Complexes OMe

OMe

Li

Cr(CO)3

1) MeO , iPr2NH (from the generation of the enolate),

CO2Me

THF, -78 ºC, 30 min, then 2) I2, -30 ºC - rt, 10 h, 65%

32

Ref. 154

1) PhLi,

N

O MeO

OMe

Ph

toluene, -78 ºC, 4h Cr(CO)3

33

2) BrCH2CCSiMe3, HMPA, -78 - 20 ºC, 3) H2O, 93% Ref. 159

SiMe3

( +)

Scheme 14.14 1) LiCMeSO2Tol, THF hexane/TMEDA, -78 °C, 1 h, -10 °C, 10 min, 0 °C, 20 min

F Cr(CO)3 Me

35

Cr(CO)3

TolO2S

2) F3CCO2H -78 °C -rt, 56% Ref. 166

Me

( +- )

36

Cl D Cr(CO)3 Me

37

Cl Me

Me Cr(CO)3

39

1) LiEt3BD, THF, reflux, 2 h

Cr(CO)3

2) F3CCO2H, 2 h, >99% Ref. 167

1) LiCMe2CN, THF hexane, -78 °C, 30 min 2) F3CCO2H -78 °C - rt, 89% Ref. 169

Me

Me

38

Me Cr(CO)3 CMe2CN

Scheme 14.15

Despite these complications with cine and tele pathways, it turns out that the more obvious ipso-SNAr pathway, in which the nucleophile adds at the position that carries the leaving group (i.e., ipso addition), is also quite common (see Section 14.5.7). In the case of 40 (Scheme 14.16), the indenyl substituent isomerized

587

588


after the nucleophile addition. Treatment of the product with n-butyllithium and repeated addition of the fluorotoluene complex introduced a second arene onto the indene [170]. The ipso-SNAr reactions in this series seem very tolerant to steric effects, and starting with fluorene (generating C13H8Li as the nucleophile), the sequence of two ipso-SNAr reactions produced a hindered 9,9-bis-tolyl double adduct. Similarly, the replacement of both chlorines from a 1,2-dichloroarene ligand seems to point to repeated ipso-SNAr [171]. This gives way to a addition with an unusual and very bulky lithiocarborane nucleophile [172]. The chemistry of the 6 + g FeCp complexes of arenes is dominated by the nucleophilic substitution reac+ tions of chloroarene complexes. The reaction of (chlorobenzene)FeCp could be accounted for by any of the SNAr mechanisms discussed above, but regiocontrolled substitution of 41 points to ipso-SNAr [173]. A series of p-substituted benzenes made in this way illustrate the reliable application of the ipso-SNAr process in the presence of other substituents [174]. The nucleophilic replacement of Cl from the chlorobenzene complex has recently been modified so it can be performed in water [175]. Carbamates (HONHCO2t-Bu) [176] and imidazole [177] + nucleophiles have been examined in FeCp -promoted SNAr reactions. Similar + results are obtained with RuCp complexes [178,179]. F +

Li

Cr(CO)3 Me

-

THF/HMPA, -78 ºC, 3 h then rt ,16 h, 66%

40

Cr(CO)3 Me

Ref. 170

Cl

CH(SO2Ph)CN

+ FeCp Me

CH2(SO2Ph)CN, K2CO3 DMF, rt, 7 h, 88%

41

Ref. 173

+ FeCp Me

Cl

Me

Cl + FeCp

42

-

O

N

+ N

OEt , nBuLi,

hexane/THF, -78 ºC, 2.5 h, >99%

CpFe

N

-O + N

OEt

Ref. 180

Scheme 14.16

In some cases, however, products corresponding to other addition pathways can be isolated. The chlorobenzene complex 42 reacts with a nucleophile prepared from 3-ethoxy-6-methylpyridazine-1-oxide to give the product from a addition


589

adjacent (ortho) to the chlorine [180]. Products of a addition next to nitrile and nitro groups have also been isolated [181]. Addition a to Cl has also been reported + for an RuCp complex, but as this reaction was intramolecular, preferences for a particular ring size may have influenced regiocontrol. Nonetheless, the result shows that the a pathway is accessible [182]. 14.3.6 Branched Electrophilic p Systems

The first situation at which branching can become a consideration when analyz4 ing regiocontrol pathways arises with g complexes, but as can be seen from Fig. 14.2c, a very substantial degree of complexity quickly emerges once this boundary is crossed, as with increasing hapticity, the number of distinct regioisomers rises quickly. It is also the case that the branched examples have been far less extensively studied than their linear counterparts. 4 With a phenyl directing group on a neutral (g -trimethylenemethane)Fe(CO)3 complex 43, n-butyllithium addition follows an x pathway (xs : xa = 1 : 1; Scheme 14.17), but the effect is not general, as Ph2CHLi gives similar amounts of x and ipso products. In the x case, however, there is now a tendency to favor xs (xs : xa = 7 : 1) as deduced from the ratio of E : Z products isolated after protonation of the anion formed by the nucleophile addition step. Ph2CHLi may not be a representative nucleophile, but nonetheless, it is interesting to note the high selectivity (5 : 2) for ipso rather than x addition with a methyl group in the place of the phenyl group in 4 the g electrophile 43 [183]. Larger alkyl groups (the example is CH2CH2CH=CH2) with an enolate nucleophile provide a case where there is exclusively x addition in high yield (88%; the reported product mixture arises from lack of control of protonation, not nucleophile addition) [184]. This enolate gives similarly high x selectivity with the phenyl directing group, but using LiCMe2CN, a trace of the ipso product is reported. This example, however, provides a case that indicates Ph Fe(CO)3

2) F3CCO2H, -78 ºC, 1 h, 85%

43

nBu

Ref. 183

+

44

Scheme 14.17

H2C=CHCH2SiMe3 CH2Cl2, AcOBF3 (from formation of 44 ), 20 ºC, 82% Ref. 184

Me

Me 1

CO2Me Fe(CO)3 +

Ph

Ph

1) nBuLi, THF/HMPA, -78 ºC, 1 h,

nBu :

1

Fe(CO)3 CO2Me

CO2Me Fe(CO)3

+

2

:

1

590


substantial selectivity for xa in preference to xs (4.6 : 1). Where nucleophile addition favors xa, the nucleophile is adding to the less hindered of the two x positions, so the outcome may be the result of steric effects [184]. In the cationic Mo(CO)2Cp series, large, functionalized, alkyl substituents again direct x, but in this case, xs is the site of reaction [28]. 5 Turning to the far more structurally diverse g system, the alkyl groups direct xs with a substantial degree of selectivity (9 : 1 ± 99 : 1), the minor pathway being ipso [185,186]. These reactions afford trimethylenemethane products, and the preference is strong enough to control nucleophile addition even to a position bearing two Me groups. This is a good example of product-derived control (see Section 14.4). The ester directing group in 44, however, overcomes this effect and directs x, but the xs : xa selectivity is only 2 : 1 [184]. 14.3.7 Conjugate Addition to Unsaturated Extensions of Electrophillic Multihapto-Complexes

In all of the examples discussed so far, the haptyl portion of the ligand corresponds to the whole of the conjugated p system. In cases where only part of the p system is bound to the metal, the issue arises whether nucleophiles add to the haptyl section, or to the uncomplexed section (i.e., ªlocallyº, or ªremotelyº relative to the metal3 [187]). The cationic Fe(CO)2Cp complex 45 [188] provides a good example (Scheme 14.18) of remote (ªconjugateº or ªMichaelº) addition in which the methyl group is introduced to the alkene that is not bound to the metal. 2 Because the alkene is in conjugation with the cationic g complex, it is activated as an electrophile. The principle is general to all the sizes of hapticity discussed in this chapter, and the issue of local versus remote reaction pathways can be exam3 ined for the whole class of structures. Examples in the g series tend to occur in palladium-catalyzed processes [189±194] and are complicated by many selectivity factors, but nonetheless can be interpreted in terms of local versus remote addi4 tion [23]. A stoichiometric g example has been examined. Reduction with NaBH3CN gave a product consistent with initial remote addition of hydride to the 5 + alkene [49]. In the g series, using the classic Fe(CO)3 complexes, a detailed study has been made by my own group. With a simple ethenyl extension to the 5 g cyclohexadienyl, selectivity for local/remote addition was found [195] to depend on the nature of the nucleophile. Borohydride, cyanide and NaCH(CO2Me)2 gave exclusively products from local addition in which the CH=CH2 group directed x. However, when organocuprates were used, remote addition was the major outcome. The local addition pathway can be stopped by placing an additional directing group on the cyclohexadienyl ligand, as shown by the example 46, where the 3) A recent paper by Trost ([187]) describes

these pathways as ªdirectº and ªSN2¢º, but since palladium-catalyzed allylic substitution can be discussed in terms of ªdirectº and ªvia the metalº (ªindirectº) pathways, we pre-

fer the usage ªlocalº and ªremoteº to describe reactions that take place in the haptyl section of the ligand, and in the part that is not bound to the metal.


591

x influence of the OMe group opposes the x-directing CH=CH2 susbstituent [196]. When a substituent on the alkene is placed at the remote electrophilic center itself, remote addition becomes much harder, but changing to the Fe(CO)2PPh3 series transforms the situation. Both sodium and lithium enolates and Ph2CuLi.SMe2 now add remotely [110]. The electrophilic center is prochiral. The organocuprate case gave the best stereocontrol (an 8 : 1 ratio of diastereoisomers). Electron-withdrawing ester substituents have been placed on the alkene extension. In the C(CO2Me)=CH2 case, the effect is to promote efficient remote addition in reactions with organocuprate reagents, and the cyclohexadienyliron complex and the ester are working together to promote this pathway [107]. With E-CH=CHCO2Et, no remote addition occurs and with NaCH(CO2Et)2 as the nucleophile, x addition relative to the CH=CHCO2Et group corresponded to about a third of the product, with internal addition (see Section 14.3.8) accounting for the rest [197]. + Fe(CO)2Cp

Cp(CO)2Fe

Me2CuLi,

Me

Et2O / THF, -78 - -20 ºC, 1 h, 72% Ref. 188

45

CH(CO2Me)2 + Fe(CO)3

NaCH(CO2Me)2 THF, 0 ºC, 5 min, 73%

Fe(CO)3

Ref. 195

OMe

OMe

46

C(Me)2CN

1) LiCMe2CN, THF, 0 ºC, (CO)3Cr

2) NH4Cl aq, -78 - 0 ºC, 0.5 h, 81%

( +- )

47

Ref. 198

(CO)3Cr

Scheme 14.18

The organochromium complex 47 provides a good example of remote addition 6 to an g complex (Scheme 14.18) with stereocontrolled reaction with the nucleophile and trapping the anion [198]. Similar examples have been reported by Uemura's group [199], establishing the general principles of remote nucleophile 6 addition to g Cr(CO)3 complexes. An example from Müller in Munich has used i ± this effect to add PrS to an allenylbenzene ligand [200].

( +- )

592


The (arene)Cr(CO)3 complex is neutral and so is not a very powerful electrophile. In the styrene case, when an ester is placed at the other end of the alkene, Michael addition to the acrylate unit occurs in high yield. Even with a chlorine leaving group on the arene complex (see Section 14.3.5), no local addition was observed [201]. Comparable examples of cationic RuCp complexes with cyanide and thiophenol as the nucleophile give examples where the nucleophile has added to the face of the ligand that carries the metal, and it is proposed that this is the favored kinetic approach [202]. 14.3.8 Internal Addition of Nucleophiles

In the examples discussed so far in Section 14.3, the survey has concentrated on situations where nucleophiles add to the ends of open p systems, though occasionally mention has been made of competing addition at internal positions. Two general points appear to develop in the issue of terminal versus internal nucleophile addition. The first is that neutral and relatively unreactive electrophiles tend to be prone to internal nucleophile addition in reactions with powerful nucleophiles (this must relate to issues of charge versus orbital control, see Section 14.4). Secondly, and a more straightforward point, when substantial steric effects impede the approach of nucleophiles to both termini (all termini in the case of branched systems), the internal positions can be favored even with cationic electrophiles. The difference between charged and neutral complexes is well illustrat4 + ed in the g series by comparing Fe(CO)3 and Co(CO)3 cyclohexadiene complexes. 3 The cationic cobalt complex gives the g product of terminal nucleophile addition [203], but the corresponding neutral iron complex 48 reacts at the internal position 1 2 [204] to form anionic g ,g structures that can be intercepted by electrophiles (Scheme 14.19). These processes can form the first stage of synthetically useful 5 cyclization reactions [67,205±208]. Similarly, a neutral g Mn(CO)3 pentadienyl 1 3 complex has been reported to show internal addition to form anionic g ,g intermediates (which can be protonated under a CO atmosphere to make isolable + Mn(CO)4 complexes [209]) while the corresponding cationic Fe(CO)3 complex (see Section 14.3.4) reacts at the terminus [24,58]. Care must be taken not to overinterpret this comparison, however, because the preferred pathway is dependent on the choice of nucleophile, as amines have been reported [210] to react at the terminus in the organomanganese series. Reducing the electophilicity of the cat+ ionic complex by switching to the Fe(CO)2PPh3 series can give rise to substantial amounts of the internal addition product with some nucleophiles (e.g., MeLi) [211]. For comparison, in the cyclohexadienyl series, even with a neutral Mn(CO)3 group as the source of activation, nucleophile addition occurs at the terminus of the p system [212], and follows the same path as the widely studied Fe(CO)3 case. 5 With a suitable metal, there can be internal addition to other cationic g structures, even at the center of the pentadienyl [213] and cycloheptadienyl [214,215] complex3 es. There are also examples of g allyl intermediates in catalytic cycles that give organic products that are best interpreted by addition of the nucleophile to the


CMe2CN Fe(CO)3

1) LiCMe2CN, O

2) CO, then MeI, 87%

48 Me Fe(CO)3

( +- )

( +- )

Ref. 204

1) LiSiMe2Ph, THF, 0 ºC, then 25 ºC, 20 h, 2) F3CCO2H, 0 ºC, then 25 ºC, 1 h, 41% Ref. 235

Me

( +- ) SiMe2Ph

49

Ph

Ph LiCCPh, + Fe(CO)2P(OPh)3

( +- )

THF, -78 ºC - rt, 1 h, 59%

Fe(CO)2P(OPh)3

Ref. 236

50

Ph

( +- )

Scheme 14.19

central atom of the allyl ligand, producing two metal±carbon r bonds [216±218], 3 and with neutral stoichiometric g allyl complexes, this seems to be quite a common outcome [219]. Catalytic substitution of Cl from the center of an allyl ligand 3 has been reported using cationic platinum complexes [220]. Cationic g allyl com+ + + + plexes of Ir(C5Me5)(PMe3) [221], Rh(C5Me5)(PMe3) [221], MoCp2 [222], WCp2 [222] are also known to react with nucleophiles at the central carbon atom. Cycloheptadienyliron complexes also frequently show examples of internal nucleophile addition [214,215,224±227]. Steric effects are conventionally cited to explain the tendency of cycloheptadienyl complexes to give internal addition products (whereas cyclohexadienyl complexes react at the termini). There is kinetic evidence to support this, as cycloheptadienyl complexes have been shown to be less reactive than cyclohexadienyl complexes [223]. The CH2 of the cyclohexadienyl complexes, and the CH2CH2 of the cyclohepadienyl complexes fold out away from the metal in these structures, and in the cycloheptadienyl case, each CH2 blocks a terminus of the p system. Nucleophilic attack is displaced to the internal posi1 3 4 tions, forming g ,g products in competition with the g products from the normal addition pathway [214,215,224±230]. With larger metals [Ru(CO)3 and Os(CO)3], 1 3 this effect becomes more pronounced, and the g ,g products can predominate [230,231]. The nature of the nucleophile can also influence the preferred pathway (see Section 14.4). With ªsoftº nucleophiles, cycloheptadienyl complexes show the terminal addition pathway, while hard nucleophiles add internally [232]. Further

593

594


increase of the steric bulk of the saturated part of the ring in the cyclooctadienyl case displaces nucleophile addition to the internal electrophilic center [233,234]. An unusual case of internal addition in the cyclohexadienyliron series has been reported. An alkynyl substituent that normally directs x (see Section 14.3.4), gave competing a addition when cyanide was used as the nucleophile (a : x ratio= 2 : 9) [6]. The main purpose of this chapter is to discuss the directing effects of functional groups in these reactions. As one would expect, steric effects direct internal nucleophile addition to the less hindered of the electrophilic centers as in the formation of 49. With a C-1 OMe substituent, a addition has been proposed [235]. Internal nucleophile addition to the less hindered of the electrophilic centers has also been reported for 50 [236]. Other examples give mixtures [237]. On the other 5 hand, 1,4-dimethyl substitution on the g cycloheptadienyl ligand shows regiocontrol dominated by the C-1 Me group (c selectivity; ipso to the C-4 Me group) [229]. Electron-withdrawing substituents seem to promote internal nucleophile addi5 tion (Scheme 14.20). This is most clearly demonstrated in acyclic (g -pentadie+ nyl)(FeCO)3 complexes. The C-1 ester group in 51 promotes a addition [116,238,239], but when this is opposed by the steric effect of a C-2 methyl group, besides the main x product, traces of c addition relative to the ester are observed [240]. The extended example with E-CH=CHCO2Et is discussed in Section 14.3.7, and gives the a and c products 52 and 53, as well as the simple x adducts [197]. With substituents at both ends of the p system, further examples of a addition relative to the ester have been reported [241,242]. This result is particular to acetylide and amide nucleophiles, as stabilized enolate and triphenylphosphine add x to the ester/ipso to the Ph group (see Section 14.3.4). Competing internal addition has also been observed (Scheme 14.21) with the alkynyl-substituted complex 54 [6], and the acyclic C-1 acetoxy-substituted complex 55 [73] and provides an interesting comparison (see Section 14.3.4) with the cyclic analog where the acetoxy CO2Me

CO2Me + Fe(CO)3

LiCH(CO2Me)2

(MeO2C)2CH

CO2Me

Fe(CO)3

+

THF, 0 ºC, 1 h, 66%

Fe(CO)3 CH(CO2Me)2

9 : 1

Ref. 238

51 CO2Me

CO2Me

+ Fe(CO)3

NaCH(CO2Me)2

(MeO2C)2CH

Fe(CO)3

THF, 0 ºC, 10 min, 40% Ref. 197

Scheme 14.20

CO2Me

+

4 : 3

52

Fe(CO)3

CH(CO2Me)2

plus ω addition products

53

14.4 Caveats and Cautions

595

group directs x [127]. The acetoxy group in 55 directs a for internal addition. The same result was obtained with a benzoyl group. Even in the cyclohexadienyl series, an SO2Ph-directing group at C-1 has been shown to send some nucleophiles to the a position, though this is a side reaction compared to the normal x addition [122]. The normally x-directing OAc group (see Section 14.3.4), again gives the a adduct when the x position carries an Me group [73]. The same is seen in the + Fe(CO)2PPh3 series with benzoyl substituents at C-1, but strangely the disubstituted case with the extra Me group now shows competing a and x pathways [73]. Ph

Ph

Ph KCN + H2O, CH3CN, 0 ºC, 30 min, 84% Fe(CO)3 Ref. 6

Fe(CO)3 CN ( +)

54 OAc

-

Me

CH2Cl2, -78 - 10 ºC, 61%

55

NC

9 : 2

OAc

MeLi + Fe(CO)3

+

Ref. 73

Fe(CO)3

( +- )

Scheme 14.21


In order to keep within the length limits for a chapter of this type, the examples of directing effects presented above are illustrated by the most clear-cut cases. The intention has been to focus on relatively simple directing groups, and examine the patterns of their effects when present at different positions in the ligand, and in ligands of differing hapticities. The preliminary conclusions form part of a much longer and more fully referenced survey that is already in preparation [23]. In this chapter, representative examples have been chosen to illustrate these effects, which usually will need to have been apparent in a wide selection of examples to merit inclusion, or be an additional analogous example of a type of substituent for which the effects are well established in the typical case. A few examples are presented in this chapter where substituents show varying effects (aryl groups stand out as a clearest case), and this can often be rationalized by differences in steric effects in different orientations. Indeed, the groups discussed here have essentially been rather simply classified as electronically active, or steric, in their main mode of action, and it is entirely accepted that a more detailed discussion

Fe(CO)3

( +- )

596


based on charge/orbital control could be useful [203,243±248]. Based on the guidelines presented in this chapter, however, empirical predictions of regiocontrol can now be made with considerable confidence when directing effects stand alone or are mutually reinforcing. When directing influences are opposed, the situation is more difficult, and we need to work towards a ranking order of directing power (which will also be related to positions the opposed groups take up in the molecule). A few clear-cut examples have been presented in the preceding sections, but the general case is beyond the scope of the discussion made here. Indeed, despite 2 7 the well-established status of the chemistry of the g ±g organometallic multihapto electrophiles, there are relatively few examples of truly detailed studies of opposed multiple substitution patterns that weigh up their relative directing powers [129]. This is in part due to the fact that the types of nucleophiles employed need also to be taken into account. It is already clear that some types of nucleophiles are intrinsically ªwell directedº (stabilized enolates would be an example: see Sections 5.1 and 5.5; see also more specialized nucleophiles such as 12 in Scheme 14.4) whereas others (e.g., cyanide and hydride nucleophiles and organolithium reagents) tend to be more prone to give mixtures when opposed directing effects leave several outcomes finely balanced. Thus, the study of relative strengths of directing effects needs to take this into account. Choose too well behaved a nucleophile, and a deceptively simple picture emerges; choose too capricious a nucleophile, and the conclusions are confused by too many special cases. The proper approach will be to identify a ªpanelº of probe nucleophiles of different ªdirectibilitiesº, and identify for each pair of opposed directing groups, the point in the directibility sequence where the control breaks down. Effectively, the relative directing powers of opposed substituents, and the relative ease with which the approach of different nucleophiles can be controlled, are linked concepts, and need to be studied together. This is in progress in Norwich [249], but it is a long task, and develops slowly. Further complications arise in some special situations, and a full discussion of exceptions to the general patterns of control discussed in this chapter cannot be presented here. When apparent contradictions are encountered, however, the explanations are often entirely rational. Changes between kinetic and thermodynamic control (see Section 14.5.2), competitions between different mechanisms (nucleophile addition/electron transfer [90,250±252]), between pathways for nucleophile addition, (e.g., via CO ligands [109,253±255] or via the metal [22,256±261]) and between starting-material/product control (early/late transition states) are the most commonly encountered explanations. Thermodynamic control [262] is encountered when reactions are reversible [15,53,213,263,264]. The classic test to identify this uses crossover experiments [45]. If thermodynamic and kinetic control are favoring different products, changes in product ratios when reactions are stopped before completion, or when characterized products are reintroduced to reaction conditions, are usually reliable indicators. Similarly, nucleophile addition via carbonyl ligands, or via the metal, often result in changes in the relative stereochemistry of addition, which can be a useful tell-tale (see, for example, the stereochemistry of hydride transfer to the cyclohexadienyl ligand of the cobalt complex


27 in Scheme 14.11). Starting-material/product control issues are harder to spot, but when two distinct product classes are accessible (examples are linear and 5 branched products from nucleophile addition to branched g electrophiles [184±186] and cisoid/transoid products [6,58,59,62,63,117,132,265±269] from acyclic pentadienylmetal systems) it can be important to consider these issues carefully. In the case of product-derived control, there have been attempts [243,270,271] to identify distortions in starting materials that correspond to the direction the metal must move during the hapticity change associated with nucleophile addition. If the starting structure already resembles one product more than another in terms of representative metal±carbon bond lengths, the 6 regiocontrol outcome may be predetermined. Conformational effects in g complexes [247,272±276], on the other hand, when the metal/fragment [e.g., Cr(CO)3, + Mn(CO)3 ] has a symmetry that is reproduced in the multihapto-ligand, may reveal special cases in starting material control in which effects of substituents are relayed by the way they influence the conformational preferences of the M(CO)3 tripod; there have been many studies that indicate preferential nucleophile addition to positions in the multihapto-ligand that are eclipsed by M±CO bonds in the favored conformer [272±276]. These two illustrations, however, may be interrelated. Distortions in metal±ligand bonding in eclipsed situations, and conformational consequences of effects arising in the lateral displacement of the metal towards a specific product, need to be explored. A more systematic treatment of this topic will need to take into account the fact that X-ray structure information indicates only an example of an accessible conformation, and not necessarily the one in which the reaction takes place. The analysis needs to be extended to evaluate all accessible conformations, and the contributions they are likely to make to competing reaction pathways. There are many examples in the references cited in this chapter where changes of solvent, counterions, and types of nucleophiles result in switches in regiocontrol preferences, which may owe their origin to mechanistic and structural differences between apparently similar processes. Much more work needs to be done to fully elucidate what is happening in these finely balanced cases. The simplest starting point is to check for reversibility of reactions when anomalies are found, and survey crystal structure data bases for bond-length and angle data. These efforts are in hand, and supplemented by the now hugely powerful capabilities of theory calculations [245,246,277±283] (there have been many attempts over 20 years to use calculations to elucidate control effects [243,244,247,271±276] but recent advances now improve the prospects of success) there is a real prospect that the full range of factors that impinge on the control of nucleophile addition to multihapto-metal complexes will ultimately be fully elucidated. The most clearcut directing effects described in this Chapter, however, are sufficiently reliable to be exploited in organic synthesis, as illustrated in Section 14.5.

597

598


14.5 Examples of the Use of Electrophilic Multihapto-Complexes in Organic Synthesis 14.5.1 Alkyl-derived Directing Effects in Synthetic Applications of Multihapto-Complexes

The use of functionalized multihapto-complexes in synthesis has a long history, and some simple examples where nucleophilic addition was required at the 3 unsubstituted end of 1-alkyl g complexes are provided by applications of organopalladium allyl complexes as isoprene building blocks [284,285]. Such stoichiometric uses of palladium were soon superseded by catalytic procedures [7,8,19,20], but the early work served to establish that the x-directing effect of the 1-alkyl group provided a synthetic equivalent for an isoprene cation disconnection [284], and a geranyl cation equivalent [285]. The more highly substituted ring system in steroidal structures made regiocontrol more difficult because of competing x-directing effects from alkyl groups and ring fragments at the ends of the allyl unit. A nice example, however, successfully established the stereochemistry of the 4 steroid side-chain [286]. More recent attempts to use g molybdenum complexes in a conceptually elegant synthetic route to the terpene target silphinene (56) show just how difficult it can be to predict the outcome of competition between sterically derived x-directing effects. The intention (Table 14.1: entry 1) was that a methyl group (at the CHMe position on the spirocyclic ring) would block the approach of nucleophiles to the CH end of the diene complex, so overcoming the x-directing effect of the carbon±carbon bond in the ring fused to the cyclopentadiene, leading to the formation of a quaternary center when introducing the final methyl group from Me2CuLi to complete the terpene skeleton. Although success was obtained with spirocyclic model compounds, ultimately the x-directing effect of the 1-alkyl substituent on the diene proved too strong, and the methyl group 4 was transferred to the unsubstituted end of the g complex [287]. This synthesis (Table 14.1: entry 2) also required a regiocontrolled hydride reduction of the 3 4 3 2 g product of nucleophile addition, corresponding to a linear4 (g ® g ® g [2,288]) multiple use of the metal in the synthesis. The competition between the 4 two ends of the g complex 58 was more straightforward. In a synthesis of a fragment of the target molecule tylosin (57), malonate addition to 58 at the less hindered x end gave the correct regioisomer, which was cyclized after decarboxyla4 3 2 tion during removal of the metal (again a linear g ® g ® g section of the route) [289]. In this case, however, 58 was itself made by nucleophilic delivery of Me to 4 4 3 4 an unsubstituted g cyclohexadiene complex, so iterative (g ® g ® g ) and linear methods were combined in this synthesis (i.e., the full sequence of the use of the 4 3 4 3 2 metal is: g ® g ® g ® g ® g ). The chemistry of cycloheptadienyliron complexes described in Section 14.3.4 utilizes a similar x control effect with 59 and 4) The terms ªlinearº and ªiterativeº refer to

reaction sequences that make multiple use of the metal: the hapticity of the electrophile decreases with each step in a linear

sequence, but an iterative sequence alternates between hapticties (see [2,4,288]).

14.5 Examples of the Use of Electrophilic Multihapto-Complexes in Organic Synthesis

with 61 in the stereocontrolled synthesis (Table 14.1: entry 3) of the Prelog± Djerassi lactone (60) [290]. Here two methyl groups are introduced in sequence 5 4 5 4 5 via an iterative approach (g ® g ® g ® g ). The same approach in the g series of electrophiles has been used towards tylosin, employing Fe(CO)2P(OPh)3 complexes to minimize the internal addition of nucleophiles (see Section 14.3.8) that tends to complicate the use of cycloheptadienyliron complexes. Turning to directing effects from 2-alkyl substituents, the best examples are in 5 the g series. Such groups tend to be only weakly x directing (see Section 14.3.4), but if easily directed nucleophiles are used, then good control is sometimes possible. Thus while early approaches to a-phellandrene [87] and carvone [291] required the separation of regioisomers, a route towards bilobanone was shown to be capable of good regiocontrol because of the use of a stabilized enolate as the nucleophile [292,293]. Nonetheless, even the synthesis of a-phellandrene was sufficiently effective for it to serve to define the absolute configuration of the electrophilic multihapto-complex tricarbonyl[(2R)-(±)-(1,2,3,4,5-g)-2-methylcyclohexadienyl]iron hexafluorophosphate [87]. A larger functionalized 2-C alkyl substituent gave effective introduction of a cyclopentenone at the x position in a reaction that was aiming to establish access to prostaglandin analogs with interphenylene features in the upper (carboxylate-terminating) side-chain [294]. An unusual iridium complex in a steroid A ring has also been elaborated using the x direction available from the carbon±carbon bonds of the A/B ring junction of estradiol [140]. 14.5.2 Electron-withdrawing Groups with x-Directing Effects in Synthetic Applications of Multihapto-Complexes

To gain strong x-directing effects from C-1 substituents, it is better to employ electron-withdrawing substituents (Table 14.1: entries 4±8) such as ketones and esters. Once again, the early stoichiometric studies with palladium provide good examples in the steroid series [18]. Enantioselective stereocontrolled syntheses of gabaculine (62) [114], shikimic acid (64) [115] from 63 by Birch's group, and 5-HETE 5 (65) [116] from 51 by Donaldson's group, utilizing optically pure g tricarbonyliron complexes, however, provide the best examples. These target structures suit the selection of an x-directing ester group at one end of the p system. A 1-pentyl-pentadienyliron(1+) complex has also been examined in work motivated by HETE synthesis [62,63]. An organoiron route (Table 14.1: entry 7) to sections of macrolactin A (66) cleverly exploits reversible addition of nucleophiles to the Fe(CO)2PPh3 complex 67 [262] to switch from a addition to the required x product exploiting thermodynamic control (see Section 14.4). There have been substantial efforts made to address macrolactin synthesis using organoiron methodology [295,296]. In the electrophile 22, C-1 esters and 2-C methoxy groups (see below, and Section 14.5.5) mutually reinforce their x-directing effects. This places the approach [118] to analogs of SK&F L94901 (68) on a secure footing. Both electronic effects, and the natural steric effects, were favoring the required product (Table 14.1: entry 8).

599

3

2

1

Entry

Me

Me

HO2C

(sugar)O

Me

H

O

Me

Me

O

O

60

Me

O O(sugar)

57

Me

Me

56

Target molecule

H

O Me

Me

O

hydride reducing agent

nucleophilic cyclisation during decomplexation

organocuprate reagent

Me

O

O

malonate nucleophile then decarboxylation


H

Me


Disconnections

Me

+ Mn(CO)2Cp

59

58

61

Me + Fe(CO)3

+ Fe(CO)2P(OPh)3

Me

+ Mn(CO)2Ind

Multihapto electrophile

patterns, based on the analysis of regiocontrol from functional groups on the haptyl section of the ligand.

Table 14.1 Examples of synthetic applications of multihapto-organometallic electrophiles with unsymmetrical substitution

Synthesis completed.

Fragment synthesis completed from both 58 and 59.

CHMe not strong enough directing group - need electronically active group.

Status

290

289

287

Ref.

600


7

6

5

4

Entry

HO

HO

MeO2C

HO

HO2 C

HO2 C

OH

OH

OH

OH

O

NH 2

66

O

65

64

62

Target molecule

nucleophile addition

HO

HO

hydroxide addition


dihydroxylation

OH

OH

H2NBoc-derived nucleophile, then deprotection

O

O

lactonisation

nucleophile addition

control adjacent to second diene complex

OH

functional group interconversions

O

NH 2

OH deprotection

MeO2C

deprotection

MeO2C

Disconnections

MeO2 C

MeO2C

MeO2C

51

+ Fe(CO)3

63

+ Fe(CO)3

67

CO2Me + Fe(CO)2PPh3

63

+ Fe(CO)3


Model studies.

Enantiocontrolled synthesis completed.



Status

262

116

115

114

Ref. 14.5 Examples of the Use of Electrophilic Multihapto-Complexes in Organic Synthesis 601

10

9

8

Entry

HO2C

NH2

O

Br

Br

O

71

68

N

NH

O

CO2Et

69

H2 N

OH

Target molecule

Ph

Br

decomplexation and oxidative aromatisation

enolate addition then elimination of OEt and decarboxylation

O

deprotection

aminomalonate nucleophile then decarboxylation

CO2Et

Fe(CO)3

H2 N

NHCOCF3

modifications

CO2Me

CO2Me

phenolate addition

Br

O

OMe

Disconnections

EtO

Ph

OMe

22

72

+ Fe(CO)2 Cp

70

+ Fe(CO)3

CO2Me + Fe(CO)3


118

Ref.


16

Correct regiochemistry (15:1) obtained 78 in nucleophilic addition step.

Model studies (see Scheme 14.8)

Status

602


13

12

11

Entry

O

O

OH

Me

Me

O

O

76

75

73

Target molecule

O

O

deprotect to reveal OH

carbonylation

O

O

Me



Grignard reagent

OH

Me

intercept metal acyl species with pentan-3-ol

Disconnections

MeO

MeO

MeO

Me

+

77

+ Fe(CO)3

15

+ Fe(CO)3

74

Cp(CO)2 Fe

O



Synthesis completed in non-racemic series at low ee.


Status

291

87

297

Ref.

14.5 Examples of the Use of Electrophilic Multihapto-Complexes in Organic Synthesis 603

16

15

14

Entry

MeO

O

O

N

HO

N H

MeO

Me

O

N

79

78

81

O

OH

Me

Me

OMe

Target molecule

N

Me

N

dihydroxylation via epoxide

O remote addition Me to alkeneextended η5 electrophile

O

lactonisation

cyclisations

OH

cyanide addition

HO

cyclisation

O

O

N H

Me

OMe

oxidative cyclisation and aromatisation


MeO

MeO

tetrasubstituted aniline addition

Disconnections

Me

O

OMe

MeO

82

OMe

+ Fe(CO)3

O

80

OMe

OMe + Fe(CO)3

15

+ Fe(CO)3


Model study.

Model study.

Model study.

Status

91

299

298

Ref.

604


19

18

17

Entry

O

HO

O

N

O

N

OMe

NMe2

OMe

Target molecule

87

OMe

85

83

OMe

N

OMe OMe

alkylation

malononitrile addition and decarboxylation

OMe

reductive amination

O

Michael addition after decomplexation

O

NC

OMe


Michael addition after reduction of nitrile and decomplexation

O

O

CN


Disconnections

MeO

MeO

MeO

OMe

84

O + Fe(CO)3

86

88

O

OMe

OMe + Fe(CO)3

+ Fe(CO)3

OMe


Formal total synthesis completed.

Electrophile 86 synthesised.


Status

106

72

4

Ref.


21

20

Entry

HO

Me

N H H

H

O

H

N

Me

O

OH

Target molecule

91

OH

90

89 stabilised enolate addition

stabilised enolate addition

OH

stabilised enolate addition

then functional group interconversions Fischer indole synthesis

N H H

N

alkylation of ketone

HO

Me

Wittig

functional group interconversion

SiMe2Ot Bu


Me

H

O

H

Michael addition after decomplexation


MeO

1,4-reduction


Disconnections

iPrO

MeO

92

+ Fe(CO)3

OMe

16

Me + Fe(CO)3


Model study.



Status

94

301

Ref. 606


23

22

Entry

Me

O

HO

HO

Me Me

Me

H

Me

HO

O

O

H

94

Me

OMe

93

OH

Target molecule

enolate addition

OMe

Me

O

O

Me

OMe

TMSCN, then addition to nitrile

conjugate addition / enolate trapping

Me Me

Me

H

O

alkenyllithium reagent (Mn series) or organocuprate (Fe series)

Me

O


HO

HO

MeO2C

Disconnections

MeO

MeO

Me

Me

ruled out

MeO

MeO

17

Me

95

+ Mn(CO)3

Me

+ Fe(CO)3

CO2Me

Me + Fe(CO)3

16

Me + Fe(CO)3


Model study.

Model study.

Status

307

306

Ref.


26

25

24

Entry

AcHN

HO

O

O

H N

O

O

O

O

O

N H

96

OH

O

100

OH

98

CO2 H

OH

O

Target molecule

HO O

O

AcHN O

H N

O acyl anion equivalent

desilylation

O

O

CO2H

phenolate addition

OH

Pd cat cyclisation and carbonylation

functional group interconversions

organolithium reagent

O


Disconnections

BocHN

Me3Si

Me

MeO

101

Cl + RuCp

99

Cr(CO)3

CO2H

OMe

97

Cr(CO)3


Model studies.

Formal total synthesis completed.


Status

318

311

310

Ref. 608


28

27

Entry

H N

O

O

HO

N H H

O

O

O(sugar)

N H

Me

Me

H

Target molecule

102

O

O

105

OH

O(sugar)

O

N H H

OH

OH

NH 2

O

O

H


Me

OH

NH 2

OH

O

OH

phenolate addition

Me

protonation of anion controlled by Cr

HO

O

phenolate addition

N H H

O

Disconnections

Cl

Cl

HO2C

104

106

OMe

Cr(CO)3

OMe

+ RuCp

103

NHBoc

NHBoc

OMe

HO2 C

OH

+ RuCp


Enantiocontrolled synthesis of seco-analogue as the aglycone.

Model studies.

Status

321

319

179

Ref.


31

30

29

Entry

O

O

N H

BocHN

Me

N

O

N

Br

CO2Bn

O

O

N H

O

Target molecule

110

OH

108

Br

107

OMe

O

Me


O

N H

O

H

N

O

O

protonation

OMe

carboxylate addition

OH

nitroso cycloaddition then reduce N-O bond

conjugate addition

Br

organozinc reagent

O

cyclisation

CO2Bn aromatisation of triene

Br

BocHN

organozinc reagent

Disconnections

+ Fe(CO)3

R = H R = CH 2CH2OAc

113

R = OEt

R

109

+ Fe(CO)3

112

111

MeO

MeO

46

OpNB

+ Fe(CO)3 OMe


Model studies.

Model studies.

Synthesis of the protected amino acid

Status

340

338

76

322

77

Ref. 610



14.5.3 Aryl Substituents with x-Directing Effects in Synthetic Applications of Multihapto-Complexes

As indicated in Section 14.3.4, the directing effects of aryl substituents are complicated by the need to consider the orientation of the arene, which itself can be influenced by electronic effects in the arene, or the metal complex. There are examples of 1-Ar substituents directing either ipso or x, and perhaps because of this uncertainty, there are no examples yet of target molecule syntheses planned to start from a simple 1-aryl substituted multihapto-complex (but see Section 14.5.5 for 1-aryl-4-methoxycyclohexadienyl examples). The x-directing 2-aryl substitution pattern on cyclohexadienyliron complexes has been used in work directed towards unnatural amino acid side-chain features (Table 14.1: entry 9). Addi± tion of the Shiffs base nucleophile (MeO2C)Ph2N=CH [78] and an aminomalonate ± derivative (H2N)(CO2Et)(Me3SiCH2CH2O2C)C [80] 70 to have been used to introduce a glycine moiety to a side-chain that after decomplexation and aromatization would produce a biaryl feature in 69. In the silylalkyl ester case, desilylation and concomitant decarboxylation afforded the unbranched amino acid. 14.5.4 Electron-donating Groups with Ipso-Directing Effects in Synthetic Applications of Multihapto-Complexes

A synthesis of isopiperitone (71) in Rosenblum's group provides an early synthetic example where the power of the C-1 donor substituent in 72 was employed [16]. Although it only produced one carbon±carbon bond, the metal featured twice in this synthesis (Table 14.1: entry 10), and the strategy can be classed as iterative 2 1 2 (g ® g ® g ). Similarly in 74, the metal moves to the least-hindered end, and the relatively large size of the organic group in the donor does not present a problem for ipso addition [297]. This is a key step (Table 14.1: entry 11) in the enantioselective synthesis of ent-sitophilate (73). Our own work in Norwich (Table 14.1: entries 15, 17±19) addressing the alkaloid targets has also made use of ipso-directed nucleophile addition followed by removal of the electron-donating directing group to establish an iterative approach to key aryl-substituted quaternary centers (entries 17±19) and ring junctions (entries 15, 31) in the targets. The reactions that produce the electrophilic functionalized multihapto-complexes 84 [4], 86 [128] and 88 [106] provide good examples, and again, the regiocontrol at this stage of the synthesis was on a secure basis because of the mutually reinforcing directing effects of the unsymmetrically placed substituents in 19. This work is discussed in more detail later (see Section 14.5.5) where the use of C-2 x-directing donor substituents in the creation of quaternary centers is described.

611

612


14.5.5 Electron-donating Groups with x-Directing Effects in Synthetic Applications of Multihapto-Complexes

As discussed in Section 14.3.4, when the donor substituent is placed at the inter5 nal unsymmetrical location of an g dienyl complex, reactivity at the a position is drastically reduced, and nucleophiles add to the x carbon. This is simply illustrated (Table 14.1: entry 12) in a synthesis of the small terpene cryptone (75) [87], which was performed to establish the absolute configuration of the electrophilic multihapto-complex [(2R)-(±)-tricarbonyl[(1,2,3,4,5-g)-2-methoxycyclohexadienyl]iron hexafluorophosphate (15) [87]. Similarly (entry 13), sylvecarvone (76) [291] was synthesized exploiting the x-directing effect of the OMe group in 77, with none of the regiocontrol problems that afflicted the synthesis of carvone described in Section 14.5.1, in which the directing group was a methyl group. This same effect has been put to good use (Table 14.1: entry 14) towards the carbazole alkaloid carbomycin D (78) by Knölker's group [298], and in the synthesis of tetrahydrocarbazolones [85], and to overcome the tendency for side-chain deprotonation in the CH2CO2Me group of 80, which was examined in work in Norwich exploring an approach (entry 15) towards the Amaryllidaceae alkaloid lycorine (79) [299,300]. The required salt 80 for this work was made from 20 employing a silylketene acetal as the nucleophile (see Scheme 14.7) in a step in which the x-directing 2-OMe group was overcome by the ipso-directing effect of the opposed 1-OMe group (in this case this proved the stronger directing group) [113]. The anticipated 5 4 5 4 route to lycorine will use the metal twice in an iterative (g ® g ® g ® g ) fashion. We have also examined approaches towards (entry 16) dihydrodioscorine (81), in which the challenge is much more straightforward to address. In 82, the internally placed alkyl and OMe groups have opposing x-directing effects, but despite the relatively large size of the alkyl substituent (which is envisaged as the source of the lactone ring in the target), the OMe group easily dominated the regiocontrol [91]. At present, 82 is available as a mixture of diastereoisomers, but extension of the use of diastereoselective remote addition of nucleophiles (see Sections 3.7 and 5.8) to a C-2 propenyl case should establish the required relative stereochemistry between the side-chain and the planar chirality of the metal complex in a prospec5 4 5 4 5 tive (g ¢ ® g ® g ® g ; g ¢ denotes an alkenyl-extended multihapto electrophile) synthetic route. These examples form part of an ongoing organoiron-based strategy for regiocomplementary syntheses of the Amaryllidaceae alkaloids (see below) and isoquinuclidines [91]. As seen above, at least in the cyclohexadienyl series, C-1 aryl groups tend to direct x for steric reasons (the electronic effect is only seen when the arene lies in the plane of the complexed p system). In Norwich, we have been applying the well-established x-directing effect of a C-2 OMe group (see below for examples from Pearson's work) to overcome the steric blockade when an aryl substituent is at the far end of the p system (opposed x-directing effects). In the case of the targets O-methyljoubertiamine (83) [4] and mesembrine (85) [72], relatively nonbulky aryl groups are present in the natural products (Table 14.1: entries 17 and 18).


Both the required salts were easily accessible from 19 as described in Section 14.5.3. The viability of this approach has been shown by successful completion of a simple synthesis of (+/±)-O-methyljoubertiamine from 84 [4]. A detailed crystallographic study of conformational effects in an extended series [109,128] of 1-arylsubstituted cyclohexadienyliron complexes had established, as expected, that ortho substituents on the aromatic ring substantially impeded the nucleophile's approach, and could switch the control to predominantly x control by the aryl group. However, with an o-alkoxy substituent, the conformation with the substituent below the plane of the dienyl system is easily accessible (and characterized in an X-ray structure [128]) opening the way for more ambitious synthetic applications [109]. This conformational effect has been put to use in a formal total synthesis (entry 19) of lycoramine (87) from 88 [106]. Electronic effects from additional donor substituents also flatten the ring and open up the aryl-substituted position [128], effects that will be put to work in ongoing work towards maritidine and crinine. The completed O-methyljoubertiamine and lycoramine syntheses make multiple use of the metal to form both bonds at the aryl-substituted quater5 4 5 4 nary center, and so can be classified as iterative (g ® g ® g ® g ) synthetic routes. The definitive studies on the power of the C-2 donor groups as x-directing substituents have been brought to fruition in elegant terpene and alkaloid syntheses. The salt 16 was first studied in Birch's group [74], but the great synthetic applications (for examples, see Table 14.1: entries 20±22) have been published by Pearson [92±98]. This ªPearson's saltº5 gives efficient regioselective formation of quaternary centers through the applications of control of opposed x-directing effects from the 2-OMe group and the methyl group at the required site of nucleophilic addition. Once again, stabilized enolates are good for this purpose and were used in a synthesis in trichodiene (89), but the classic synthesis (entry 20) of trichodermol (90) used a refined organotin methadology [301]. Because of its success in these syntheses, in our work on access to optically pure cyclohexadienyliron complexes, we identified ªPearson's saltº as a key example and achieved resolution by entrainment [302], so (1S,4R)-(±)-tricarbonyl(1,2,3,4,5-g)-4-methoxy-1-methylcyclohexadienyl)iron hexafluorophosphate [(±)-16] is now accessible optically pure [302] and is of known absolute configuration [87]. A number of related syntheses have been examined using Pearson's salt, by Chandler addressing quassinoid targets [303] and by Mincione and by Pearson addressing steroid targets [96,98]. Pearson also 5) It would also be nice to acknowledge the 1-

ester substituted salts 63 and 51 as ªBirch's saltº and ªDonaldson's saltº, respectively. We are not referring to 19 as ªStephenson's saltº, though if the literature were to adopt tricarbonyl[(1,2,3,4,5-g)-1,4-dimethoxycyclohexadienyl]iron hexafluorophosphate (19) in that way it would be pleasing, as although, like Pearson's salt, it was first described by Birch ([74] reports its hydrolysis to the 4methoxycyclohexa-2,4-dien-1-one complex),

it has been our work that has developed the use of this cyclohexadienyliron salt to underpin the 1,1-iterative strategy for our studies on alkaloid synthesis (for discussion of 1,1 and 1,2 iterations, see [288]) and to give efficient access the alkenyl and alkynyl series of substitution patterns that we have used to establish methods for remote nucleophile addition procedures (see Section 14.3.8).

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completed (Table 14.1: entry 21) a synthesis of aspidospermine (91) [94], again with opposed directing effects, and with the larger side-chain in 92, the bulk of the alkyl substituent on the donor ether group was also increased. There is potentially a general advantage to this strategy [102,304] and McCague took the same approach in his work on tamoxifen analogs, which required the use of exceptionally bulky organolithium nucleophiles. For approaches to histrionicotoxin [305] (which required extensive studies on spirocyclization methods) and aphidicolin (93: entry 22) [306], however, Pearson retained the original OMe directing group opposite a long functionalized side-chain, but as in the histrionicotoxin case the product of nucleophile addition is a spirocycle, it is possible that nucleophilic addition first displaced the OTs group, followed by intramolecular delivery of the nucleophile to the cyclohexadienyliron complex. Work in Norwich towards tri5 dachiapyrone natural products such as tridachione (94) follows, in the g series, the approach so well established by Pearson's group, but seeks to compare it (Table 14.1: entry 23) with an alternative approach that uses b-directing OMe 6 groups on cationic g Mn(CO)3 arene complexes. This addresses a conceptual n issue in the design of synthesis using g electrophiles, namely that a rational attempt should be made to identify the most suitable hapticity for the electrophile based on patterns of regiocontrol in sequences of metal-mediated bond-forming steps 5 4 5 4 [2]. In the case of tridachione, we also set out to compare iterative (g ® g ® g ® g ) 6 5 4 and linear (g ® g ® g ) reaction sequences [307]. The salt 17 has been made available in optically pure form and in defined absolute configuration {(1R)-(+)-tricarbonyl[(1,2,3,4,5-g)-4-methoxy-1,3-dimethylcyclohexadienyl]iron hexafluorophos6 phate} [308]. In the g series, 95 has been prepared [307] and surprising variation in its regiocontrol effects was observed. The anticipated b-directing effect of the OMe group (see Sections 14.3.5 and 14.5.6) was confirmed, but sometimes nucleophiles preferred to add to the more hindered of the two b positions [209]. 14.5.6 Electron-donating Groups with b-Directing Effects in Synthetic Applications of Multihapto-Complexes

A synthesis of acorenone (96) employing lithiated organonitrile compounds as nucleophiles chose a sequence of two nucleophile additions to a methoxyaryl Cr(CO)3 complex 97, with selective reaction at the less hindered of the two b positions (Table 14.1: entry 24) [310]. A silyl blocking group was used in a synthesis of deoxyfrenolicin [which constitutes a formal total synthesis of frenolicin (98)] to 6 force nucleophile addition next to the alkyl substituent on the g complex 99 (entry 25) [311]. Similar OMe-derived directing effects have been used in the elaboration of Cr(CO)3 derivatives of podocarpic acid [312,313] and steroid [314] structures. In the related Mn(CO)3 series, regiocontrol depended on the stereochemistry of complexation, with one diastereoisomer showing the normal b selectivity, but the other giving substantial amounts of the a adduct [315].


14.5.7 Halogen Substituents with Ipso-Directing Effects in Synthetic Applications of Multihapto-Complexes

The use of transition-metal complexes to activate haloarenes for SNAr reactions has been used as a strategy for important skeletal bond formation steps in a number of syntheses. An example of carbon±carbon bond formation in this way can be found in ± amino acid synthesis. The Shiffs base nucleophile (MeO2C)(Ph2C=N)CH displaces fluorine from (fluorotoluene)Cr(CO)3 [316]. This type of substitution reaction has been applied in a model study for the diaryl ether section of SK&F L-94901 (68) using a cationic cyclohexadienyliron complex (see Scheme 14.16) [180]. Typically, however, heteroatom nucleophiles have been employed in these metal-promoted SNAr reactions, as in the formation of an aryl ether derivative of + tyrosine using the Mn(CO)3 complex of chlorobenzene [317]. This type of procedure has been used to great effect (Table 14.1: entries 26 and 27) in key cyclization steps in syntheses of the ACE inhibitor K-13 (100) [318], and a portion of ristocetin (102). Two different complexed haloarene amino acid derivatives were used in the 6 + ristocetin case [179,319]. These examples, which employ g RuCp complexes 101, 103 and 104, show the power of the ipso-SNAr reaction (see Section 14.3.5) in the closure of macrocycles at bonds to aromatic structures. A five-membered ring has been made in an intramolecular displacement of fluoride from a Cr(CO)3 complex during the elaboration of a b-lactam derivative [320]. 14.5.8 Remote Nucleophile Addition in Synthetic Applications of Multihapto-Complexes

Conjugate addition to alkenes activated by adjacent multihapto-complexes (see Section 14.3.7) is conceptually important because in this way, the metal can reach out beyond its location in the ligand to give activation and control. This adds to the flexibility available in planning syntheses that make multiple use of the metal. A nice example is seen in a synthetic approach to pseudopterosin (105) in which the isoprene side-chain is added by nucleophile addition to an alkene that is acti6 vated by an g Cr(CO)3 complex 106 (Table 14.1: entry 28). Seco-pseudopterosin has been prepared in this way but conjugate addition is difficult with the additional methyl group at the remote electrophilic center [321]. Similarly (entry 29), the Jackson type of iodoserine-derived nucleophile has been used in conjugate addition with the alkene-extended cyclohexadienyliron complex 46 [77]. The prod4 uct is an g triene complex, which aromatizes on decomplexation, so an aromatic ring is introduced into the protected amino acid 107 in this way without the need 5 for an oxidation step (compare with entry 9). This same alkene-extended g cyclohexadienyliron complex 46 has been proposed to account for a key cyclization in Knölker's studies (entry 30) for the synthesis of discorhabdin C (108) from 109 [322].

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14.5.9 Design Efficiency in the Synthetic Applications of Multihapto-Complexes

Finally, turning to work in Norwich that aims to complete an enantiocontrolled asymmetric synthesis of the alkaloid hippeastrine (110; Table 14.1: entry 31) provides the chance to establish important points about access to enantiopure complexes, and conceptual issues concerning the steps that introduce and remove the metal in the synthetic applications of multihapto-complexes. We have long been interested in replacing standard complexation and decomplexation steps by reactions that form significant skeletal bonds in the same process [323]. Indeed, in the case of complexation reactions, some nice examples are available from the work of other groups [324±331]. Similarly, the internal nucleophile additions discussed in Section 14.3.8, which can be followed by carbonylative cyclizations [67,205±208], provide examples of carbon±carbon bond formation during decomplexation, though as yet they lack generality of application [332]. Decomplexation of tricarbonyl[(1,2,3,4-g)-cyclobutadiene)iron(0) can be combined with cycloaddition reactions [333±336]. This also achieves useful bond formation. The method has been used in the synthesis of cubane [337]. Our work towards hippeastrine starts with a standard diastereoselective complexation reaction that gives access to 111 in enantiopure form [338] but ends with a novel in situ trapping procedure that uses nitrosocycloaddition to intercept the diene ligand during the decomplexation step [339,340]. In this way, two key stereogenic (ªchiralº) centers in the C ring of the target are made during the step that removes the metal. Prior to that stage, by an 5 4 5 4 iterative approach (g ® g ® g ® g ) the stereochemistry of the B/C ring junction is established starting from 112 [76]. We also have methods [340] that use the ipso-directing effect of a 1-ethoxy donor substituent to introduce the CH2CH2X (X=OAc; in hippeastrine: X = NMe) side-chain to the C ring that will be needed to access the key building block 113 (ultimately this will form the D ring by means of a modified Mitsunobu ring closure with X = OH [341]). This allows the anticipated synthesis to start with a microbial biodioxygenation of phenetol, followed by diastereoselective introduction of the tricarbonyliron complex [340] to give access to enantiomerically pure complexes that are equipped with several leaving groups to allow a series of iterative nucleophile addition steps [starting from 111, the pro5 4 5 4 5 4 spective route is g ® g ® g (113)® g ® g ® g ]. This is on-going work, but the series of successful model studies for key steps establish the principles of the route [76,338], and the efficient utilization of the decomplexation step to make key skeletal bonds [339,340], and the subsequent successful closure of the D ring [341]. The absolute configuration of the key tricarbonyliron complex {(1S,6S)-(±)tricarbonyl[(1,2,3,4,5-g)-1-ethoxy-6-methoxycyclohexadienyl]iron hexafluorophosphate} (111) has been established in this work [340].

14.6 Conclusions

14.6 Conclusions

The examples given in Section 14.5 show that the general control effects elucidated for each hapticity (see Section 14.3), taken as a whole, provide a uniform pattern that has predictive value in the design of organic synthesis. The availability of many types and sizes of electrophilic multihapto-complexes (Figs. 14.2 and 14.3) and generally applicable complete6 control of stereochemistry (Fig. 14.1c) are important benefits in this type of approach. In open ligand systems, terminal electron-donating substituents direct ipso, and internally placed electron-donating substituents direct x. When the electron-donating substituent is on a cyclic (closed) ligand it directs b. Electron-withdrawing substituents at the end of an 6 open p system direct x, and when internally placed, they direct a (g triene complexes have not been examined). When located on cyclic (closed) ligands, electronwithdrawing substituents also direct a. Terminally located aromatic substituents when coplanar with the haptyl section of the ligand direct ipso, but when twisted out of plane they direct x. When more than one substituent is considered, the directing effects can be mutually reinforcing, or opposed. In the former case, prediction of regiocontrol is now reliable, based on the considerations indicated above, but with opposed groups, the relative powers of each group must be assessed. Neither time, nor indeed space in a multiauthor volume such as this, permits in this chapter a fully comprehensive survey of the current state of knowledge of regiodirecting effects of substituents on electrophilic multihapto-complexes, though this will be presented in a later publication [23], but the examples given here should suffice to illustrate the nature of the most clearly understood control effects, and the general nomenclature for a universal description of this topic is presented here (Section 14.2). If generally adopted, this will ultimately permit the full classification of this chemistry, both from a conceptual point of view, and in the laboratory in experiments that aim to complete the gaps in the state of knowledge of the directions of control effects, and their relative powers when placed in opposed combinations. The simple directing effects presented here, however, provide enough examples to guide synthetic applications, and establish the frame6) Nucleophiles add to the face of the ligand

opposite to that which bears the metal when reactions occur by a direct addition pathway and under kinetic control ([2]). This stereocontrol effect is very strong (100% diastereoselective), so the planar chirality of the metal complex can dominate other stereodirecting influences. There are no conventional stoichiometric control systems that can match the generality, versatility and reliability of this metal-mediated strategy for asymmetric induction. In the case of stoichiometric-control methods, it is essential that the multiple use is made of the control group (otherwise

a catalytic approach would be more desirable), and as the complexity of the molecule increases, the diversity of competing control influences also increases. For this reason, it is necessary to have very powerful control groups to systematically overcome all conventional diastereodirecting effects. There is a strong argument that nucleophile addition 2 7 to g ±g multihapto-electrophiles is the method of choice for a general approach to meeting these requirements in a wide variety (Table 14.1) of target structures.

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work for the rational use of these exceptionally powerful general electrophiles in many situations. There has been considerable progress over the 50 years or so that have elapsed since research began on the chemistry of electrophilic multihaptocomplexes.

Acknowledgement

The discussion of organometallic SNAr mechanisms presented in Section 14.3.5 is strongly influenced by the analysis made of this topic in a definitive review by Rose and Rose-Munch [145].

References 1 S.G. Davies, M.L.H. Green,

D.M.P. Mingos, Tetrahedron, 1978, 34, 3047. 2 G.R. Stephenson, R.P. Alexander, C. Morley, P.W. Howard, Phil. Trans. R. Soc. Lond. A, 1988, 326, 545±556; G.R. Stephenson, in ªOrganic Synthesis via Organometallicsº, K.H. Dotz, R.W. Hoffmann, Eds, Vieweg: Braunschweig (1991); 169±185. 3 F.J. McQuillin, D.G. Parker, G.R. Stephenson, Transition Metal Organometallics for Organic Synthesis, Cambridge University Press: Cambridge, (1991) p. 217. 4 G.R. Stephenson, H. Finch, D.A. Owen, S. Swanson, Tetrahedron, 1993, 49, 5649±5662. 5 W.A. Donaldson, M.-J. Jin, P.T. Bell, Organometallics, 1993, 12, 1174±1179. 6 E. van den Beuken, S. Samson, E.J. Sandoe, G.R. Stephenson, J. Organometal. Chem., 1997, 530, 251±253. 7 H. Inami, T. Ito, H. Urabe, F. Sato, Tetrahedron Lett., 1993, 34, 5919±5922. 8 H. Urabe, H. Inami, F. Sato, Chem. Commun., 1993, 1595±1597; S.-W. Zhang, T. Mitsudo, T. Kondo, Y. Watanabe, J. Organometal. Chem., 1993, 450, 197±207. 9 T.C.T. Chang, T.S. Coolbaugh, B.M. Foxman, M. Rosenblum, N. Simms, and C. Stockman, Organometallics, 1987, 6, 2394.

10 A. Rosan and M. Rosenblum, J. Org.

Chem., 1975, 40, 3621.

11 R.S. Tanke and R.H. Crabtree, Tetra-

hedron Lett., 1988, 29, 6737±6740.

12 T.C.T. Chang and M. Rosenblum, Tetra-

hedron Lett., 1983, 24, 695.

13 J. Smidt, W. Hafner, R. Jira, J. Sedlmeier,

R. Sieber, R. Ruttinger, and H. Kojer, Angew. Chem., 1959, 71, 176; J. Smidt, W. Hafner, R. Jira, R. Sieber, J. Sedlmeier, and A. Sabel, Angew. Chem., Int. Ed. Engl., 1962, 1, 80; J. Smidt, Chem. & Ind., 1962, 54; J. Tsuji, Synthesis, 1984, 369; J.-E. Bäckvall, B. kermark, S.O. Ljunggren, J. Am. Chem. Soc., 1979, 101, 2411; J.K. Stille, R. Divakaruni, J. Am. Chem. Soc., 1978, 100, 1303; P.E.M. Siegbahn, J. Am. Chem. Soc., 1995, 117, 5409±5410. 14 L.S. Hegedus, R.E. Williams, M.A. McGuire, and T. Hayashi, J. Am. Chem. Soc., 1980, 102, 4973. 15 H.S. Clayton, J.R. Moss, M.E. Dry, J. Organometal. Chem., 2003, 688, 181±191. 16 T.C.T. Chang, M. Rosenblum, J. Org. Chem., 1981, 46, 4103. 17 W.R. Jackson, J.U.G. Strauss, Tetrahedron Lett., 1975, 16, 2591. 18 D.J. Collins, W.R. Jackson, R.M. Timms, Tetrahedron Lett., 1976, 17, 495. 19 S.G. Pyne, G.W. O'Meara, D.M. David, Tetrahedron Lett., 1997, 38, 3623±3626; D.M. David, G.W. O'Meara, S.G. Pyne, Tetrahedron Lett., 1996, 37, 5417±5420;

References H. van der Deen, A. van Oeveren, R.M. Kellogg, B.L. Feringa, Tetrahedron Lett., 1999, 40, 1755±1758; A. Arcadi, E. Bernocchi, S. Cacchi, L. Caglioti, F. Marinelli, Gazz. Chim. Ital., 1991, 121, 369±371; M. Sakakibara, A. Ogawa, Tetrahedron Lett., 1994, 35, 8013±8014; E. Keinan, Z. Roth, J. Org. Chem., 1983, 48, 1769; J. Godschaix, J.K. Stille, Tetrahedron Lett., 1980, 21, 2599; Gollaszewski, J. Schwartz, Organometallics, 1985, 4, 417; B.M. Trost, E. Keinan, Tetrahedron Lett., 1980, 21, 2595; Y. Tsuji, N. Yamada, S. Tanaka, J. Org. Chem., 1993, 58, 16±17; E. Bernocchi, S. Cacchi, E. Morera, G. Ortar, Synlett, 1992, 161±164; R. Kling, D. Sinou, G. Pozzi, A. Choplin, F. Quignard, S. Busch, S. Kainz, D. Koch, W. Leitner, Tetrahedron Lett., 1998, 39, 9439±9442; J. Tsuji, M. Yuhara, M. Minato, H. Yamada, F. Sato, Y. Kobayashi, Tetrahedron Lett., 1988, 29, 343; J. Tsuji, M. Yuhara, M. Minato, H. Yamada, F. Sato, Y. Kobayashi, Tetrahedron Lett., 1988, 29, 343; A. Godleski, E.B. Villhauer, J. Org. Chem., 1984, 49, 2246; S.A. Godleski, E.B. Villhauer, J. Org. Chem., 1984, 49, 2246; J. Tsuji, M. Yuhara, M. Minato, F. Sato, Y. Kobayashi, Tetrahedron Lett., 1998, 29, 343; T. Hirao, J. Enda, Y. Ohshiro, T. Agawa, Tetrahedron Lett., 1981, 22, 3079; T. Okano, H. Matsubara, T. Kusukawa, M. Fujita, J. Organometal. Chem., 2003, 676, 43±48; M. Attolini, M. Maffei, B. Principato, G. Peiffer, Synlett, 1997, 384±386. 20 N. Vicart, J. GorØ, B. Cazes, Tetrahedron, 1998, 54, 11063±11078. 21 B.M. Trost, R.C. Bunt, J. Am. Chem. Soc., 1996, 118, 235±236. 22 H. Matsushita, E. Negishi, Chem. Commun., 1982, 160; J.S. Temple, M. Riediker, J. Schwartz, J. Am. Chem. Soc., 1982, 104, 1310; E. Keinan, N. Greenspoon, Tetrahedron Lett., 1982, 23, 241; Y. Hayasi, M. Riediker, J.S. Temple, J. Schwartz, Tetrahedron Lett., 1981, 22, 2629. 23 G.R. Stephenson, monograph in preparation. 24 A.J. Birch, A.J. Pearson, J. Chem. Soc., Perkin Trans. 1, 1976, 954.

25 G.S. Silverman, S. Strickland,

K.M. Nicholas, Organometallics, 1986, 5, 2117. 26 T.H. Whitesides, R.W. Arhart, R.W. Slaven, J. Am. Chem. Soc., 1973, 95, 5792±5793. 27 M.-C.P. Yeh, S.-I. Tau, Chem. Commun., 1992, 13±15. 28 G.-M. Yang, G.-M. Su, R.-S. Liu, Organometallics, 1992, 11, 3444±3451. 29 L.S. Barinelli, K. Tao, K.M. Nicholas, Organometallics, 1986, 5, 588. 30 L.S. Hegedus, Y. Inoue, J. Am. Chem. Soc., 1982, 104, 4917. 31 J.W. Dieter, Z. Li, K.M. Nicholas, Tetrahedron Lett., 1987, 28, 5415. 32 L.S. Hegedus, Y. Inoue, J. Am. Chem. Soc., 1982, 104, 4917. 33 C. Gajda, J.R. Green, Synlett, 1992, 973±975. 34 T. Zhou, J.R. Green, Tetrahedron Lett., 1993, 34, 4497±4500. 35 D. Enders, P. Fey, T. Schmitz, B.B. Lohray, B. Jandeleit, J. Organometal. Chem., 1996, 514, 227±232. 36 D. Enders, B. Jandeleit, S. von Berg, G. Raabe, J. Runsink, Organometallics, 2001, 20, 4312±4332. 37 D. Enders, S. von Berg, B. Jandeleit, Synlett, 1996, 18±20. 38 D. Enders, B. Jandeleit, G. Raabe, Angew. Chem., Int. Ed. Engl., 1994, 33, 1949±1951. 39 D. Enders, M. Finkam, Synlett, 1993, 401±403. 40 D. Enders, F. Udo, P. Fey, B. Jandeleit, B.B. Lohray, J. Organometal. Chem., 1996, 519, 147±159. 41 A.D. Cuiper, R.M. Kellogg, B.L. Feringa, Chem. Commun., 1998, 655±656. 42 W.-J. Koot, H. Hiemstra, W.N. Speckamp, Chem. Commun., 1993, 156±158 43 R.H. Yu, J.S. McCallum, L.S. Liebeskind, Organometallics, 1994, 13, 1476±1486. 44 N. Vicart, B. Cazes, J. GorØ, Tetrahedron Lett., 1995, 36, 535±538. 45 N.Vicart, J. GorØ, B. Cazes, Synlett, 1996, 850±852. 46 M. Green, S. Greenfield, M. Kersting, Chem. Commun., 1985, 18. 47 A.J. Pearson, A.R. Douglas, Organometallics, 1998, 17, 1446±1448.

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68 A.J. Birch, A.S. Narula, P. Dahler,

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59

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62 63 64 65

66 67

C.-M. Andersson, Organometallics, 1999, 18, 5606±5613. A. Rubio, L.S. Liebeskind, J. Am. Chem. Soc., 1993, 115, 891±901. S. Hansson, J.F. Miller, L.S. Liebeskind J. Am. Chem. Soc., 1990, 112, 9660±9661. S.-S.P. Chou, H.-T. Sheng, Organometallics, 1996, 15, 4113±4115. M.-H. Cheng, Y.-H. Ho, C.-C. Cheng, G.-H. Lee, S.-M. Peng, S.-Y. Chu, R.-S. Liu, Organometallics, 1994, 13, 4082±4091. M.-H. Cheng, Y.-H. Ho, S.-L. Wang, C.-Y. Cheng, S.-M. Peng, G.-H. Lee, R.S. Liu, Chem. Commun., 1992, 45±46. P. McArdle, A.G. Ryder, D. Cunningham, Organometallics, 1997, 16, 2638±2645. L.S Barinelli, Z. Li, K.M. Nicholas, Organometallics, 1989, 8, 2474. E.O. Fischer and R.D. Fischer, Angew. Chem., 1960, 72, 919. R.S. Bayound, E.R. Biehl, P.C. Reeves, J. Organometal. Chem., 1978, 150, 75; B.F.G. Johnson, J. Lewis, D.G. Parker, S.R. Postle, J. Chem. Soc., Dalton Trans., 1977, 974. R.S. Bayoud, E.R. Biehl, P.C. Reeves, J. Organometal. Chem., 1979, 174, 297±303. W.A. Donaldson, L. Shang, M. Ramaswamy, C.A. Droste, C. Tao, Organometallics, 1995, 14, 5119±5126. W.A. Donaldson, M.J. Jin, P.T. Bell, Organometallics, 1993, 12, 1174±1179. M.A. Hossain, M.-J. Jin, W.A. Donaldson, J. Organometal. Chem., 2001, 630, 5±10. W.A. Donaldson, M. Ramaswamy, Tetrahedron Lett., 1988, 29, 1343±1346. W.A. Donaldson, M. Ramaswamy, Tetrahedron Lett., 1989, 30, 1343. G. Maglio, R. Palumbo, J. Organometal. Chem., 1974, 76, 367. I.J. Alexander, N.J. Hales, G.R. Stephenson, J. Organometal. Chem., 1993, 453, 111±115. W.A. Donaldson, L. Shang, Tetrahedron Lett., 1995, 36, 1575±1576. M.-C.P. Yeh, B.-A. Sheu, H.-W. Fu, S.-L.Tau, L.-W. Chuang, J. Am. Chem. Soc., 1993, 115, 5941±5952.

70

71

72

73

74 75 76 77

78

79 80

81

82 83

84

G.R. Stephenson, L.F. Kelly, Tetrahedron Lett., 1980, 21, 979. G.A. Potter, R. McCague, M. Jarman, Chem. Commun., 1992, 637±638. G.R. Stephenson, P.W. Howard, S.C. Taylor, J. Organomet. Chem., 1991, 419, C14±C17. A.J. Pearson, A.M. Gelormini, A.A. Pinkerton, Organometallics, 1992, 11, 936±938. D.A. Owen, G.R. Stephenson, H. Finch, S. Swanson, Tetrahedron Lett., 1990, 31, 3401±3404; D.A. Owen, PhD Thesis, University of East Anglia, Norwich, 1990, p. 182. J.A.S. Howell, A.G. Bell, P.J. O'Leary, G.R. Stephenson, M. Hastings, P.W. Howard, D.A. Owen, A.J. Whitehead, P. McArdle, D. Cunningham, Organometallics, 1996, 15, 4247±4257. A.J. Birch, P.E. Cross, J. Lewis, S.B. Wild, J. Chem. Soc., A, 1968, 332. A.J. Pearson, P.R. Raithby, J. Chem. Soc., Perkin Trans.1, 1980, 395±399. S.T. Astley, G.R. Stephenson, Synlett, 1992, 507±509. M.J. Dunn, R.F.W. Jackson, G.R. Stephenson, Synlett, 1992, 905±906. J.-P. Genet, R.D.A. Hudson, W.D. Meng, E. Roberts, G.R. Stephenson, S. Thorimbert, Synlett, 1994, 631±634. A. McKillop, G.R. Stephenson, M. Tinkl, Synlett, 1995, 669±670. R.D.A. Hudson, S.A. Osborne, G.R. Stephenson, Synlett, 1996, 845±847. A.J. Birch, K.B. Chamberlain, M.A. Haas, D.J. Thompson, J. Chem. Soc., Perkin Trans. 1, 1973, 1882; A. Pelter, K.J. Gould, Chem. Commum., 1974, 1029±1030. S.T. Astley, G.R. Stephenson, J. Chem. Soc., Perkin Trans., 1, 1993, 1953±1995. A.F.H. Siu, L.A.P. Kane-Maguire, S.G. Pyne, R.M. Lambrecht, J. Chem. Res., 1996, 395. A.V. Malkov, L. Mojovic, G.R. Stephenson, A.T. Turner, C.S. Creaser, J. Organomet. Chem., 1999, 589, 103.

References 85 G.R. Stephenson, J. Organomet. Chem.,

1985, 286, C41±C43. 86 C. E. Anson, C. S. Creaser, A. V. Malkov, L. Mojovic, G. R. Stephenson, J. Organometal. Chem., 2003, 668, 101±122. 87 A.J. Birch, W.D. Raverty, G.R. Stephenson, J. Org. Chem., 1981, 46, 5166±5172. 88 J.A.S. Howell, M.J. Thomas, J. Organometal. Chem., 1983, 247, C21; J.A.S. Howell, M.J. Thomas, Organometallics, 1985, 4, 1054. 89 A.J. Birch, L.F. Kelly, J. Org. Chem., 1985, 50, 712. 90 B.M.R. Bandara, A.J. Birch, T.-C. Khor, Tetrahedron Lett., 1980, 21, 3625. 91 G.R. Stephenson, R.D. Thomas, F. Cassidy, Synlett, 1992, 247±248. 92 A.J. Pearson, J. Chem. Soc., Perkin Trans. 1, 1980, 400±405. 93 A.J. Pearson, G.C. Heywood, Tetrahedron Lett., 1981, 22, 1645. 94 A.J. Pearson, P. Ham, C.W. Ong, T.R. Perror, D.C. Rees, J. Chem. Soc., Perkin Trans.1, 1982, 1527±1534. 95 A.J. Pearson, Chandler, M., J. Chem. Soc., Perkin Trans.1, 1980, 2238±2243. 96 E. Mincione, P. Bovicelli, S. Cerrini, D. Lamba, Heterocycles, 1985, 23, 1607. 97 A.J. Pearson, E. Mincione, M. Chandler, P.R. Raithby, J. Chem. Soc., Perkin Trans. 1, 1980, 2774. 98 A.J. Pearson, M.K. O'Brien, Tetrahedron Lett., 1988, 29, 869±872. 99 C.W. Ong, C.J. Chien, Organometallics, 1993, 12, 241±243. 100 A.J. Birch, G.R. Stephenson, Tetrahedron Lett., 1981, 22, 779±782. 101 A.J. Pearson, J. Chem. Soc., Perkin Trans.1, 1977, 2069±2074. 102 A.J. Pearson, T.R. Perrior, D.A. Griffin, J. Chem. Soc., Perkin Trans, 1, 1983, 625. 103 A.J. Pearson, J. Chem. Soc., Perkin Trans. 1, 1978, 495. 104 R.P. Alexander, T.D. James, G.R. Stephenson, J. Chem. Soc., Dalton Trans., 1987, 2013; R.P. Alexander, C. Morley, G.R. Stephenson, J. Chem. Soc., Perkin Trans. 1, 1988, 2069±2074. 105 W.A. Donaldson, M.-J. Jin, Bull. Soc. Chim. Belg., 1993, 102, 297±298. 106 E.J. Sandoe, G.R. Stephenson, S. Swanson, Tetrahedron Lett., 1996, 37, 6283±6286.

107 R.D.A. Hudson, S.A. Osborne,

G.R. Stephenson, Tetrahedron, 1997, 53, 4095±4104. 108 C.E. Anson, R.D.A. Hudson, S.A. Osborne, D.G. Smyth, G.R. Stephenson, Tetrahedron Lett., 1998, 39, 7603±7066; R.D.A. Hudson, PhD Thesis, University of East Anglia, Norwich, 1996, p. 156. 109 A.V. Malkov, A. Auffrant, C. Renard, E. Rose, F. Rose-Munch, D.A. Owen, E.J. Sandoe, G.R. Stephenson, Inorg. Chim. Acta, 1999, 296, 139±149. 110 R.D.A. Hudson, C.E. Aanson, M.F. Mahon, G.R. Stephenson, J. Organometal. Chem., 2001, 630, 88±103. 111 R.D.A. Hudson, S.A. Osborne, E. Roberts, G.R. Stephenson, Tetrahedron Lett., 1996, 37, 9009±9012. 112 C. Guillou, N. Millot, V. Reboul, C. Thal, Tetrahedron Lett., 1996, 37, 4515±4518. 113 I.M. Palotai, G.R. Stephesnon, W.J. Ross, D.E. Tupper, J. Organomet. Chem., 1989, 364, C11±C14; I.M. Palotai, PhD Thesis, University of East Anglia, Norwich, 1989, p. 203. 114 B.M.R. Bandara, A.J. Birch, L.F. Kelly, J. Org. Chem., 1984, 49, 2496. 115 A.J. Birch, L.F. Kelly, D.V. Weerasuria, J. Org. Chem., 1988, 53, 278. 116 C. Tao, W.A. Donaldson, J. Org. Chem., 1993, 58, 2134±2143. 117 R. GrØe, M. Laabassi, P. Mosset, R. CarriØ, Tetrahedron Lett., 1985, 26, 2317±2318. 118 F. Hossner, M. Voyle, J. Organomet. Chem., 1988, 347, 365. 119 G.R. Stephenson, I.J. Alexander, unpublished results; I.J. Alexander, PhD thesis, University of East Anglia, Norwich, 1990, p. 93. 120 V.I. Ivanov, M. Slupchinkski, F.S. Bayauova, Issled. V. Obl. Neftekhimii, 1976, 32±40. 121 G.R. Stephenson, P.W. Howard, J. Chem. Soc., Perkin Trans. 1, 1994, 2873±2880. 122 S.-S.P. Chou, C.-H. Hsu, Tetrahedron Lett., 1996, 37, 5373±5376. 123 M.R. Attwood, T.M. Raynham, D.G. Smyth, G.R. Stephenon, Tetrahedron Lett., 1996, 37, 2731±2334. 124 Y. Takemoto, N. Yoshikawa, C. Iwata, Chem. Commun., 1995, 631±632.

621

622

14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis 125 A.J. Birch, D.H. Williamson, J. Chem. 126 127

128

129

130

131 132

133

134

135

136 137

138

139

140

141

Soc., Perkin Trans. 1, 1973, 1892±1990. A.J. Birch, B.M.R. Bandara, Tetrahedron Lett., 1980, 21, 3499. G.R. Stephenson, P.W. Howard, D.A. Owen, A.J. Whitehead, Chem. Commun., 1991, 641. E.J. Sandoe, G.R. Stephenson, unpublished work; E.J. Sandoe, PhD Thesis, University of East Anglia, Norwich, 1996. D.A. Owen, G.R. Stephenson, H. Finch, S. Swanson, Tetrahedron Lett., 1989, 30, 2607±2610; D.A. Owen, MSc Thesis, University of East Anglia, Norwich, 1988, p. 85. M. Keil, F. Effenberger, Chem. Ber., 1982, 1103; F. Effenberger, M. Keil, Chem. Ber., 1982, 1113. L.A. Paquette, R.G. Daniels, R. Gleiter, Organometallics, 1984, 3, 560. W.A. Donaldson, P.T. Bell, M.-J. Jin, J. Organometal. Chem., 1992, 441, 449±456. E.D. Sternberg, K.P.C. Vollhardt, J. Am. Chem. Soc., 1980, 102, 4839; E.D. Sternberg, K.P.C. Vollhardt, J. Org. Chem., 1984, 49, 1564±1573. W. Blankenfeldt, J.-W. Liao, L.-C. Lo, M.-C.P. Yeh, Tetrahedron Lett., 1996, 37, 7361±7364. A.J. Pearson, Y.-S. Lai, K. Srinivasan, Aust. J. Chem., 1992, 45, 109±119; A.J. Pearson, K. Srinivasan, Synlett, 1992, 983±984. A.J. Pearson, K. Srinivasan, Tetrahedron Lett., 1992, 33, 7295±7298. A. Hirschfelder, D. Drost, S. Meinhardt, P. Eilbracht, Chem. Ber., 1996, 129, 845±851. H. Seo, S.-G. Lee, D.M. Shin, B.K. Hong, S. Hwang, D.S. Chung, Y.K. Chung, Organometallics, 2002, 21, 3417±3425. J. Le Bras, H. El Amouri, J. Vaissermann, Organometallics, 1996, 15, 5706±5712. J. Le Bras, M.N. Rager, Y. Besace, H. Amouri, J. Vaissermann, Organometallics, 1997, 16, 1765±1771. N. Morita, S. Ito, T. Asao, J. Organometal. Chem., 1993, 460, 67±72.

142 M. von der Gruen, C. Schaefer,

R. Gleiter, Organometallics, 2003, 22, 2370±2372. 143 J. Chen, V.G. Young, R.J. Angelici, Organometallics, 1996, 15, 325±331. 144 O. Reimelt, J. Heck, Organometallics, 2003, 22, 2097±2107. 145 F. Rose-Munch, V. Gagliardini, C. Renard, E. Rose, Coord. Chem. Rev., 1998, 178±180, 249±268. 146 F. Rose-Munch, C. Susanne, C. Renard, E. Rose, J. Vaissermann, J. Organometal. Chem. 1996, 519, 253±259. 147 S.S. Lee, J.-S. Lee, Y.K. Chung, Organometallics,1993, 12, 4640±4645. 148 S. Sun, C.A. Dullaghan, D.A. Sweigart, J. Chem. Soc., Dalton Trans., 1996, 4493±4507. 149 F. Balssa, V. Gagliardini, F. Rose-Munch, E. Rose, Organometallics, 1996, 15, 4373±4382 150 M.F. Semmelhack, G.R. Clark, J. Am. Chem. Soc., 1977, 99, 1675. 151 A.J. Pearson, A.V. Gontcharov, P.D. Woodgate, Tetrahedron Lett., 1996, 37, 3087±3088. 152 M.F. Semmelhack, H.-G. Schmalz, Tetrahedron Lett., 1996, 37, 3089±3092. 153 M.F. Semmelhack, G.R. Clark, J.L. Garcia, J.J. Harrison, Y. Thebtaranonth, W. Wulff, A. Yamashita, Tetrahedron, 1981, 37, 3957; M.F. Semmelhack, G.R. Clark, R. Farina, M. Saeman, J. Am. Chem. Soc., 1979, 101, 217. 154 H. Rudler, V. Comte, E. Garrier, M. Bellassoued, E. Chelain, J. Vaissermann, J. Organometal. Chem., 2001, 621, 284±298. 155 J.C. Boutonnet, F. Rose-Munch, E. Rose, A. Semra, Bull. Soc. Chim. Fr., 1987, 640. 156 K. Narasaka, H. Sakurai, C. Liu, Bull. Chem. Soc. Jpn., 1994, 67, 1156±1160. 157 S.E. Gibson (nØe Thomas), N. Guillo, A.J.P White, D.J. Williams, J. Chem. Soc., Perkin Trans. 1, 1996, 2757±2581. 158 D. Beruben, E.P. Kündig, Helv. Chim. Acta, 1996, 79, 1533±1536. E.P. Kündig, A. Ripa, R. Liu, G. Bernardinelli, Angew. Chem., Int. Ed. Engl., 1992, 31, 1071. 159 A. Amurrio, K. Khan, E.P. Kündig, J. Org. Chem., 1996, 61, 2258±2259.

References 160 E.P. Kündig, A. Ripa, R. Liu,

G. Bernardinelli, J. Org. Chem., 1994, 59, 4773±4783. 161 E.P. Kündig, A. Ripa, R. Liu, D. Amurrio, G. Bernardinelli, Organometallics, 1993, 12, 3724±3737. 162 E.P. Kündig, D. Freitzen, A. Ripa, R. Liu, G. Bernardinelli, Chem. Eur. J. 1998, 4, 251±259. 163 J. Blagg, S.G. Davies, C.L. Goodfellow, K.H. Sutton, Chem. Commun., 1986, 1283±1285. 164 J. Blagg, S.G. Davies, C.L. Goodfellow, K.H. Sutton, J. Chem. Soc., Perkin Trans. 1, 1990, 1133±1144. 165 J.A. Heppert, J. Aube, M.E. Thomas-Miller, F. Takusagawa, Organometallics, 1990, 9, 727. 166 F. Rose-Munch, R. Khourzom, J.P. Djukic, A. Perrotey, E. Rose, J. Brocard, J. Organometal. Chem., 1994, 447, 195±206. 167 J.-P. Djukic, F. Rose-Munch, E. Rose, F. Simon, Y. Dromzee, Organometallics, 1995, 14, 2027±2038. 168 J.-P. Djukic, F. Rose-Munch, E. Rose, Chem. Commun., 1991, 1634±1635. 169 F. Rose-Munch, E. Rose, A. Semra, M. Filoche, J. Organometal. Chem., 1989, 363, 123±130. 170 F.-E. Hong, Y.-C. Yang, S.-C. Lo, C.-C. Lin, Polyhedron, 1997, 16, 2005±2012. 171 M. Uemura, T. Minami, K. Hirotsu, Y. Hayashi, J. Org. Chem., 1989, 54, 469±477. 172 T.J. Henly, C.B. Knobler, M.F. Hawthorne, Organometallics, 1992, 11, 2313±2316. 173 A.S. Abd-El-Aziz, C.R. de Denus, J. Chem. Soc., Perkin Trans. 1, 1993, 293±298. 174 A.A. Vasil'ev, L. Engman, P.J. Storm, C.-M. Andersson, Organometallics, 1999, 18, 1318±1325. 175 F. Moulines, M. Kalam-Alami, V. Martinez, D. Astruc, J. Organometal. Chem., 2002, 643±644, 125±129. 176 M.S. Holden, K.A. Cole, Synth. Commun., 1992, 22, 2579±2586 177 R.G.M. Roberts, J. Organomet. Chem., 1992, 430, 327±334. 178 C.W. West, D.H. Rich, Org. Lett., 1999, 1, 1819±1822.

179 A.J. Pearson, P.O. Belmont, Tetrahedron

Lett., 2000, 41, 1671±1675.

180 R.C. Cambie, S.J. Janssen, P.S. Rutledge,

P.D. Woodgate, J. Organomet. Chem., 1992, 434, 97±114. 181 S. Motallebi, P. Müller, Organometallics, 1993, 12, 4668±4672. 182 F.C. Pigge, S. Fang, N.P. Rath, Org. Lett., 1999, 1, 1851±1854. 183 W.A. Donaldson, M.A. Hossain, Tetrahedron Lett., 1992, 33, 4107±4110. 184 W.A. Donaldson, M.A. Hossain, C.D. Cushnie, J. Org. Chem., 1995, 60, 1611±1618. 185 R. Brünner, H. Gerlach, Tetrahedron Asym., 1996, 7, 1515±1520. 186 M. Franck-Neumann, A. Kastler, Synlett, 1995, 61±63. 187 B.M. Trost, R.C. Bunt, J. Am. Chem. Soc., 1998, 120, 70±79. 188 P. Lennon, A.M. Rosan, M. Rosenblum, J. Am. Chem. Soc., 1977, 99, 8426±8439. 189 B.M. Trost, R.C. Bunt, J. Am. Chem. Soc., 1996, 118, 235±236. 190 B.M. Trost, F.W. Gowland, J. Org. Chem., 1979, 44, 3448. 191 Y.I.M. Nilsson, P.G. Andersson, J.-E. Bäckvall, J. Am. Chem. Soc., 1993, 115, 6609±6613. 192 B.M. Trost, R.C. Bunt, Tetrahedron Lett., 1993, 34, 7513±7516. 193 A.R. Sulsky, D.R. Magnin, Synlett, 1993, 933±934. 194 B.M. Trost, N. Ito, P.D. Greenspan, Tetrahedron Lett., 1993, 34, 1421±1424. 195 G.R. Stephenson, M. Voyle, S. Williams, Tetrahedron Lett., 1990, 31, 3979±3980; S. Williams, PhD Thesis, University of East Anglia, Norwich, 1990, p. 176. 196 C.E. Anson, R.D.A. Hudson, D.G. Smyth, G.R. Stephenson, Appl. Organomet. Chem., 2001, 15, 16±22. 197 G.R. Stephenson, M. Voyle, S. Williams, Tetrahedron Lett., 1991, 32, 5265; S. Williams, PhD Thesis, University of East Anglia, Norwich, 1990, p. 154. 198 M.F. Semmelhack, W. Seafort, L. Keller, J. Am. Chem. Soc., 1980, 102, 6584±6586. 199 M. Uemura, T. Minami, Y. Hayashi, Chem. Commun., 1984, 1193. 200 M. Ansorge, K. Polborn, T.J.J. Müller, J. Organometal. Chem., 2001, 630, 198±204.

623

624

14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis 201 C. Baldoli, S. Maiorana, E. Licandro,

D. Perdicchia, B. Vandoni, Tetrahedron Asym., 2000, 11, 2007±2014. 202 R.M. Moriarty, L.A. Enache, R. Gilardi, G.L. Gould, D.J. Wink, Chem. Commun., 1998, 1155±1156. 203 P. Sautet, O. Eisenstein, K.M. Nicholas, Organometallics, 1987, 6, 1845. 204 M.F. Semmelhack, J.W. Herndon, Organometallics, 1983, 2, 363. 205 G. Schiavon, C. Paradisi, J. Organomet. Chem., 1981, 210, 247±251. 206 D.G. Gresham, D.J. Kowalski, C.P. Lillya, J. Organomet. Chem., 1978, 114, 71. 207 J. Chen, Y. Yu, J. Sun, Organometallics, 1997, 16, 3608. 208 Y. Yu, J. Chen, J. Chen, P. Zheng, Organometallics, 1993, 12, 4731. 209 B.C. Roell Jr, K.F. McDaniel, J. Am. Chem. Soc., 1990, 112, 9004±9006. 210 M.A. Paz-Sandoval, R.S. Coyotzi, N.Z. Villarreal, R.D. Ernst, A.M. Arif, Organometallics, 1995, 14, 1044±1052. 211 K.F. McDaniel, L.R. Kracker II, P.K. Thamburaj, Tetrahedron Lett., 1990, 31, 2373±2376. 212 B.C. Roell Jr, K.F. McDaniel, W.S. Vaughan, T.S. Macy, Organometallics, 1993, 12, 224±228. 213 P. Powell, J. Organometal. Chem., 1979, 165, C43±C46. 214 R. Edwards, J.A.S. Howell, B.F.G. Johnson, J. Lewis, J. Chem. Soc., Dalton Trans., 1974, 2105. 215 B.F.G. Johnson, J. Lewis, T.W. Matheson, I.E. Ryder, M.V. Twigg, Chem. Commun., 1974, 269. 216 A.M. Formica, A. Musco, R. Pontellini, J. Mol. Catal., 1993, 84, 239±251. 217 M. Ephritikhine, M.L.H. Green, R.E. MacKenzie, Chem. Commun., 1976, 619. 218 L.S. Hegedus, W.H. Darlington, C.E. Russell, J. Org. Chem., 1980, 45, 5193±5186. 219 A. Wilde, A.R. Otte, H.M.R. Hoffmann, Chem. Commun., 1993, 615±616; R.M.R. Hoffmann, A.R. Otte, A. Wilde, Angew. Chem., Int. Ed. Engl., 1992, 31, 234±236. 220 E.B. Tjaden, J.M. Stryker, J. Am. Chem. Soc., 1990, 11, 6420±6422.

221 J. Kadota, S. Komori, Y. Fukumoto,

S. Murai, J. Org. Chem., 1999, 64, 7523±7527. 222 M. Ephritikhine, B.R. Francis, M.L.H. Green, R.E. MacKenzie, M.J. Smith, J. Chem. Soc., Dalton Trans., 1977, 1131. 223 L.A.P. Kane-Maguire, E.D. Honig, D.A. Sweigart, Chem. Commun., 1984, 345; H. Mayr, K.-H. Müller, D. Rau, Angew. Chem., Int. Ed. Engl., 1993, 32, 1630±1632. 224 A.J. Deeming, S.S. Ullah, A.J. Domingos, B.F.G. Johnson, J. Lewis, J. Chem. Soc., Dalton Trans., 1974, 2093. 225 A.L. Burrows, B.F.G. Johnson, J. Lewis, D.G. Parker, J. Organometal. Chem., 1980, 194, C11. 226 R.J.H. Cowles, B.F.G. Johnson, P.L. Josty, J. Lewis, Chem. Commun., 1969, 392. 227 E.G. Bryan, A.L. Burrows, B.F.G. Johnson, J. Lewis, G.M. Schiavon, J. Organometal. Chem., 1977, 129, C19. 228 A. Hirschfelder, P. Eilbracht, Synthesis, 1995, 587±591. 229 P. Eilbracht, I. Winkels, Chem. Ber., 1991, 124, 191. 230 B.A. Sosinsky, S.A.R. Knox, F.G.A. Stone, J. Chem. Soc., Dalton Trans., 1975, 1633±1640. A.L. Burrows, B.F.G. Johnson, J. Lewis, D.G. Parker, J. Organometal. Chem., 1980, 194, C11±C13. 231 A.J.P. Domingos, PhD Thesis, University of Cambridge, 1972. 232 A.J. Pearson, S.L. Kole, T. Ray, J. Am. Chem. Soc., 1984, 106, 6060±6074. 233 G. Shiavon, C. Paradisi, C. Boanini, Inorg. Chim. Acta, 1975, 14, L5±L6. 234 C. Shiavon, C. Paradisi, J. Organometal. Chem., 1981, 210, 247. 235 M.-C.P. Yey, P.-Y. Shen, J.-X. Ho, Y.-L. Chiang, D.-Y. Chiu, U.N. Rao, J. Organometal. Chem., 2003, 675, 13±20. 236 A.J. Pearson, K. Srinivasan, J. Org. Chem., 1992, 57, 3965±3973. 237 A. Hirschfelder, P. Eilbracht, Synthesis, 1996, 488±494. 238 W.A. Donaldson, L. Shang, C. Tao, Y.K. Yun, M. Ramaswamy, V.G.

References Young Jr., J. Organometal. Chem., 1997, 539, 87±98. 239 Y.K. Yun, K. Godula, Y. Cao, W.A. Donaldson, J. Org. Chem., 2003, 68, 901. 240 Y.K.Yun, H.Bärmann, W.A. Donaldson, Organometallics, 2001, 20, 2409±2412. 241 M. Labassi, R. GrØe, Bull. Soc. Chim. Fr., 1992, 129, 151. 242 S. Chaudhury, W.A. Donaldson, D.W. Bennett, D.T. Haworth, T.A. Siddiquee, J.M. Kloss, J. Organometal. Chem., 2004, 689, 1437±1443. 243 O. Eisenstein, W.M. Butler, A.J. Pearson, Organometallics, 1984, 3, 1150±1157. 244 D.A. Brown, N.J. Fitzpatrick, M.A. McGinn, J. Organomet. Chem., 1985, 293, 235±248. 245 D.A. Brown, J.C. Burns, P.C. Conlon, J.P. Deignan, N.J. Fitzpatrick, W.K. Glass, P.J. O'Byrne, Organometallics, 1996, 15, 3147±3153. 246 T. Suzuki, G. Okada, Y. Hioki, H. Fujimoto, Organometallics, 2003, 22, 3649±3658. 247 C.H. Suresh, N. Koga, S.R. Gadre, Organometallics, 2000, 19, 3008±3015. 248 P. Le Magures, S.V. Lindeman, J.K. Kochi, Organometallics, 2001, 20, 115±125. 249 G.R. Stephenson, unpublished data. 250 A.J. Pearson, J. Yoon, Tetrahedron Lett., 1985, 26, 2399. 251 J. Powell, M.J. Horvath, Organometallics, 1993, 12, 4073±4076. 252 P.M. Miller, D.A. Widdowson, J. Organometal. Chem., 1986, 303, 411. 253 J. Chen, Y. Yu, L. Hu, Z. Jin, J. Organometal. Chem., 1993, 447, 113±122. 254 M.-C.P. Yeh, S.-I. Tau, Chem. Commun., 1992, 13±15. 255 A.J. Birch, G.R. Stephenson, J. Organometal. Chem., 1981, 218, 91. 256 H.J. Dauben Jr, D.J. Bartelii, J. Am. Chem. Soc., 1961, 83, 497. 257 H.J. Dauben Jr, D.J. Bartelii, J. Am. Chem. Soc., 1961, 83, 497. 258 M.A. Hashmi, J.D. Munro, P.L. Pauson, J. Chem. Soc. A, 1967, 240. 259 R.C. Larock, K. Takagi, S.S. Hershberger, M.A. Mitchell, Tetrahedron Lett., 1981, 22, 5231. 260 A.M. Rosan, M. Rosenblum, J. Tancrede, J. Am. Chem. Soc., 1973, 93, 3062.

261 A. Rosan, M. Rosenblum, J. Organo-

metal. Chem., 1974, 80, 103.

262 H. Bärmann, V. Prahladd, C. Tao,

Y.K. Yun, Z. Wang, W.A. Donaldson, Tetrahedron, 2000, 56, 2283±2295. 263 P. Del Buttero, C. Baldoli, G. Molteni, T. Pilati, Tetrahedron Asym., 2000, 11, 1927±1941; A.L. Burrows, K. Hine, B.F.G. Johnson, J. Lewis, D.G. Parker, A. Poe, J. Chem. Soc., Dalton Trans., 1980, 1135. 264 S.-S.P. Chou, C.-H. Hsu, J. Chinese Chem. Soc., 1996, 43, 355±364. 265 W.R. Roush, C.K. Wada, Tetrahedron Lett., 1994, 35, 7347±7350. 266 M. Kaser, A. Salzer, J. Organomet. Chem., 1996, 508, 219. 267 N.A. Clinton, C.P. Lilya, J. Am. Chem. Soc., 1970, 92, 3065. 268 J.E. Mahler, R. Pettit, J. Am. Chem. Soc., 1963, 85, 3955±3959. 269 W.A. Donaldson, M.-J. Jin, P.T. Bell, Organometallics, 1993, 12, 1174. 270 O. Eisenstein, R. Hoffmann, J. Am. Chem. Soc., 1980, 102, 6148. 271 D.W. Clack, M. Monshi, L.A.P. Kane-Maguire, J. Organometal. Chem., 1976, 107, C40. 272 E.L. Muetterties, J.R. Bleeke, E.J. Wucherer, T.A. Albright, Chem. Rev., 1982, 82, 499. 273 Z.Y. Todres, E.A. Ionina, J. Organometal. Chem., 1993, 453, 197. 274 E. Elian, R. Hoffmann, Inorg. Chem., 1975, 14, 1058. 275 J. Brocard, J. Lebibi, J. Organometal. Chem., 1987, 320, 295. 276 O. Eisenstein, R. Hoffmann, J. Am. Chem. Soc., 1980, 102, 6148. 277 P.-O. Norrby, B. kermark, F. Hñffner, S. Hansson, M. Blomberg, J. Am. Chem. Soc., 1993, 115, 4859±4867. 278 H. Hagelin, B. kermark, P.-O. Norrby, Organometallics, 1999, 18, 2884±2895. 279 P.E. Blöchl, A. Togni, Organometallics, 1996, 15, 4125±4132; T.R. Ward, Organometallics, 1996, 15, 2836±2838. 280 K.J. Szabó, J. Am. Chem. Soc., 1996, 118, 7818±7826. 281 K.J. Szabó, Organometallics, 1996, 15, 1128±1133; V. Branchadell, M. Morano-Maæas, R. Pleixats, Organometallics, 2002, 21, 2407±2412.

625

626

14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis 282 V. Branchadell, M. Morano-Maæas,

F. Pajuelo, R. Pleixats, Organometallics, 1999, 18, 4934±4941. 283 I. Macsµri, K.J. Szabó, Organometallics, 1999, 18, 701±708. 284 P.S. Manchand, H.S. Wong, J. F. Blount, J. Org. Chem., 1978, 43, 4769. 285 B.M. Trost, L. Weber, J. Org. Chem., 1975, 40, 3617. 286 B.M. Trost, T.R. Verhoeven, J. Am. Chem. Soc., 1976, 98, 630. 287 D.J. Norris, J.F. Corrigan, Y. Sun, N.J. Taylor, S. Collins, Canad. J. Chem., 1993, 71, 1029±1040. 288 G.R. Stephenson in Advanced Asymmetric Synthesis, G.R. Stephenson, Ed. Chapman and Hall, London, 1996, p. 321 and 331. 289 A.J. Pearson, M.N.I. Khan, J. Am. Chem. Soc., 1984, 106, 1872. 290 A.J. Pearson, Lai, Y.-S. Lu, W. Pinkerton, A.A., J. Org. Chem., 1989, 54, 3882. 291 G.R. Stephenson, J. Chem. Soc., Perkin Trans. 1, 1982, 2449±2456. 292 G.R. Stephenson, Milne, K., Aust. J. Chem., 1994, 47, 1605. 293 I.M. Palotai, G,R, Stephenson, L.A.P. Kane-Maguire, J. Organometal. Chem., 1987, 319, C5. 294 A.J. Birch, P. Dahler, A.S. Narula, G.R. Stephenson, Tetrahedron Lett., 1980, 21, 3817±3820. 295 T. Benvegnu, L. Schio, Y. Le Floc'h, R. GrØe, Synlett, 1994, 505. 296 V. Prahlad, W.A. Donaldson, Tetrahedron Lett., 1996, 37, 9169±9172. 297 K.-H. Chu, W. Zhen, X.-Y. Zhu, M. Rosenblum, Tetrahedron Lett., 1992, 33, 1173±1176. 298 H.-J. Knölker, M. Bauermeister, J.-B. Pannek, Tetrahedron Lett., 1993, 49, 841. 299 G.R. Stephenson, I.M. Palotai, W.J. Ross, D.E. Tupper, Synlett, 1991, 586±588. 300 M. Tinkl, G.R. Stephenson, unpublished work; M. Tinkl, PhD Thesis, University of East Anglia, Norwich, 1994, p. 135. 301 A.J. Pearson, C.W. Ong, J. Am. Chem. Soc., 1981, 103, 6686; A.J. Pearson, Y.S. Cheng, J. Org. Chem., 1986, 51, 1939; A.J. Pearson, M.K. O'Brien, J. Org. Chem., 1989, 54, 4663±4673.

302 G.R. Stephenson, Aust. J. Chem., 1981,

34, 2339±2345.

303 M. Chandler, E. Mincione, P.J. Parsons,

Chem. Commun., 1985, 1233±1234.

304 G.A. Potter, R. McCague, Chem. Com-

mun., 1992, 635±637.

305 A.J. Pearson, Ham, P.; Rees, D.C., Tetra-

hedron Lett., 1980, 21, 4637±4640.

306 A.J. Pearson, G.C. Heywood,

M. Chandler, J. Chem. Soc., Perkin Trans. 1, 1982, 2631±2639. 307 R.P. Alexander, C. Morley, G.R. Stephenson, J. Chem. Soc., Perkin Trans. 1, 1988, 2069±2074. 308 W.D. Meng, G.R. Stephenson, unpublished work; W.D. Meng, PhD Thesis, University of East Anglia, Norwich, 1990. 309 R.P. Alexander, G.R. Stephenson, J. Organometal. Chem., 1986, 314, C73. 310 M.F. Semmelhack, A. Yamashita, J. Am. Chem. Soc., 1980, 102, 5924. 311 M.F. Semmelhack, A. Zask, J. Am. Chem. Soc., 1983, 105, 2034. 312 R.C. Cambie, P.S. Rutledge, R.J. Stevenson, P.D. Woodgate, J. Organometal. Chem., 1994, 471, 133±147. 313 R.C. Cambie, P.S. Rutledge, R.J. Stevenson, P.D. Woodgate, J. Organometal. Chem., 1995, 486, 199±210. 314 H. Künzer, M. Thiel, Tetrahedron Lett., 1988, 29, 3223±3226. 315 K. Woo, P.G. Williard, D.A. Sweigart, N.W. Duffy, B.H. Robinson, J. Simpson, J. Organometal. Chem., 1995, 487, 111±118. 316 F. Rose-Munch, K. Aniss, E. Rose, J. Vaisserman, J. Organometal. Chem., 1991, 415, 223±255. 317 A.J. Pearson, H. Shin, Tetrahedron, 1992, 36, 7527±7538. 318 J.W. Janetka, D.H. Rich, J. Am. Chem. Soc., 1997, 119, 6488±6495. 319 A.J. Pearson, J.-N. Heo, Tetrahedron Lett., 2000, 41, 5991±5996. 320 P. Del Buttero, C. Baldoli, G. Molteni, T. Pilati, Tetrahedron Asym., 2000, 11, 1927±1941. 321 A. Majdalani, H.-G. Schmalz, Tetrahedron Lett., 1997, 38, 4545±4548. 322 H.-J. Knölker, K. Hartmann, Synlett, 1991, 428±430. 323 G.R. Stephenson in Advanced Asymmetric Synthesis, G.R. Stephenson, Ed.

References

324 325

326

327

328 329 330 331 332

Chapman and Hall, London, 1996, pp. 354±363. H.A. Staab, J. Ipaktschi, Chem. Ber., 1971, 104, 1170. H.-J. Knölker, J. Heber, C.H. Mahler, Synlett, 1992, 1002; H.-J. Knölker, J. Heber, Synlett, 1993, 924. A.J. Pearson, R.J. Shively Jr., Organometallics, 1994, 13, 578; A.J. Pearson, Shively, Jr., R.J.; Dubbert, R.A., Organometallics, 1992, 11, 4096. H.-J. Knölker, A. Braier, D.J. Bröcher, P.G. Jones, H. Pitrowski, Tetrahedron Lett., 1999, 40, 8075. A.J. Pearson, Yao, X., Synlett, 1997, 1281. H.-J. Knölker, S. Cämmerer, Tetrahedron Lett., 2000, 41, 5035. A.J. Pearson, Dubbert, R.A., Organometallics, 1994, 13, 1656. A.J. Pearson, A. Perosa, Organometallics, 1995, 14, 5178. M. Balazs, G.R. Stephenson, J. Organomet. Chem., 1995, 498, C17.

333 G.D. Burt, R. Pettit, Chem. Commun.,

1965, 517.

334 L. Watts, J.D. Fitzpatrick, R. Pettit,

J. Am. Chem. Soc., 1965, 87, 3253.

335 W. Pritschins, W. Grimme, Tetrahedron

Lett., 1982, 23, 1151.

336 M. Franck-Neumann, D. Martina,

F. Brion, Angew. Chem., Int. Ed. Engl., 1981, 864. 337 J.C. Barborak, L. Watts, R. Pettit, J. Am. Chem. Soc., 1966, 88, 1328. 338 S.T. Astley, M. Meyer, G.R. Stephenson, Tetrahedron Lett., 1993, 34, 2035±2038. 339 C.E.Anson, S. Hartmann, R.D. Kelsey, G.R. Stephenson, Polyhedron, 2000, 19, 6, 569. 340 A.M. Balfe, G.R. Stephenson, unpublished work; A.M. Balfe, PhD Thesis, University of East Anglia, Norwich, 1995. 341 C. Roe, G.R. Stephenson, unpublished results.

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629

15 Polyfunctional Zinc, Cobalt and Iron Organometallics Prepared by Electrosynthesis Jacques PØrichon and Corinne Gosmini 15.1 Introduction

The electroreduction of polyfunctional substrates (FG)3CX, with X= halogen or pseudohalogen and FG = functional group, may be an attractive route to generate ± carbanionic species (FG)3C according to:

(FG)3C- + X-

(FG)3C-X + 2e

(1)

This carbanionic species is associated to a metal cation either initially present in the medium as a dissociated salt (a supporting electrolyte) usually a quaternary ammonium salt or simultaneously electrogenerated from an easily oxidable metal used as the anode, e.g. Mg or Al (Eq. (2)). This method has been called the ªsacrificial anodeº process.

M - ne

(2)

Mn+ 2+

3+

The derived ions Mg or Al , which are reduced at low potentials, do not interfere with the reduction process and ensure a good conductivity of the medium. In many cases, organometallic intermediates formed by this method are poorly stable. They react with classical organic solvents used in electrochemistry (dimethylformamide, acetonitrile, N-methylpyrrolidinone, etc.). However, they can also react more rapidly with some electrophiles present in the medium, leading to interesting C±C bond-forming reactions. For example, the direct electroreduction, in DMF, of functionalized aryl halides (ArX) substituted by an electron-donating or -withdrawing group using a sacrificial Mg anode proved to be very effective for some C±C bond synthesis. This topic has been reviewed [1] (Scheme 15.1). Recently, a novel coupling reaction, based on the used of pinacolborane as an efficient reagent for the electrochemical functionalization of aryl halides in the presence of an Mg anode afforded arylboronic pinacol esters [2]. However, this reaction presents some limitations: low faradic efficiencies with aryl chlorides, Organometallics. Paul Knochel Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31131-9

630

15 Polyfunctional Zinc, Cobalt and Iron Organometallics Prepared by Electrosynthesis

ArCHO

Mg anode ArX + 2e "ArMgX" DMF CO2

ArCO2-

Scheme 15.1 Electroreduction with a magnesium anode.

poor yields with electron-withdrawing group and in most cases, only partial consumption of the starting aryl halides. A route to aryltrimethylsilanes was also described by this process [3]. In THF± HMPA, the carbanions Ar generated by cathodic reduction are trapped by Me3SiCl to form ArSiMe3. This reaction is possible because Me3SiCl is reduced at a more negative potential than aryl halides. In THF-DMPU instead of THFHMPA the electrochemical reductive silylation of trifluoromethylbenzene led to the corresponding mono-, bis- or tris-trimethylsilyl derivatives, respectively, PhCF2SiMe3, PhCF(SiMe3)2 and PhC(SiMe3)3 [4]. On the other hand, the consumable anode process does not allow access to lessreactive organometallic compounds such as zinc species. Indeed, the metallic ion generated by the oxidation of the anode has to be reduced at more negative poten2+ tial than the halide. The use of a zinc anode indeed produces Zn ions, which are in most cases more easily reduced than organic halides. Consequently, organozinc species can only be obtained by this method from easily reduced halides. The same remarks apply to other metals such as cadmium or copper. For example, the preparation of cadmium, zinc [5], and copper compounds [6] can be performed from CF3Br, which is easily reduced. (Scheme 15.2). At anode M - 1or 2e M+ or 2+ (M= Cd, Zn, Cu) At cathode CF3Br + 2e CF3- + BrIn solution CF3- + Br- + M+or 2+ CF3M or CF3MBr or (CF3)2M Scheme 15.2 Electrosynthesis of trifluoromethylmetal compounds.

The trifluoromethylation of aldehydes with CF3Br can also be conducted electrochemically in DMF in the presence of a zinc anode. However, it is worth noting that CF3ZnBr and (CF3)2Zn species, which are stable, have been found to show a lower reactivity towards carbonyl compounds (aldehydes and ketones) than the transitory species denoted ªCF3Znº stemming from the electroreduction of CF3Br in the presence of the substrate (Scheme 15.3) [7]. Zn2+ CF3Br + 2e

RCHO "CF3Zn"

R-CH(O-)-CF3

RCHO CF3ZnBr + (CF3)2Zn

no reaction

Scheme 15.3 Electrochemical trifluoromethylation of aldehydes.

15.1 Introduction

Trifluoromethylzinc compounds prepared by electrolysis of CF3Br allowed the identification of a new activation method of solid zinc by electroscoring. Faradaic yields are higher than 100%, thus indicating the occurrence of a chemical route at the surface of the anode along with the electrochemical process. It was found, in keeping with these results, that this chemical process only takes place during electrolysis. Solid zinc activation has been used with success for the formation of stable organozinc compounds from functionalized benzylic bromides [8] and has been applied to the condensation of activated halides with nitriles [9] (Blaise reaction) or carbonyl compounds [10] (Reformatsky reaction). In this case, solid zinc is activated by catalytic generated zinc formed by electroreduction of anhydrous ZnBr2 solution in acetonitrile as solvent. Results and practical approaches have been reported [11]. Although these electrochemical methods of zinc activation are very simple, and complement the known chemical methods, they are only efficient with easily reducible organic halides. They are unfortunately not preparatively convenient for aromatic halides. Nevertheless, the electroreduction of not easily reducible organic compounds (FG)3C-X is possible at a more positive potential (±0.8 to ±1.5 V/ECS) when homogeneous catalysis by a transition metal is associated with the consumable anode 0 or I Ln (L= ligand) that reacts with the process. The low-valent transition metal Mt organic halide is generally formed from its corresponding halide by electroreduction. The electroreductive reaction can be achieved by the following sequence (Scheme 15.4): MtX2Ln + 1 or 2e Mt I

or 0

Ln + (FG)3C-X

(FG)3C-Mt II

or III

X Ln

Mt I

or 0

Ln + 1 or 2X-

(FG)3C-Mt II substrate

or III

X Ln

coupling product + Mt I

or II

X Ln

Scheme 15.4 Electroreductive reaction in the presence of a transition-metal catalysis.

When the reaction is conducted in the presence of a transition metal, the reducII tion of (FG)3CX is near the reduction potential of Mt X2Ln. Therefore, an organometallic intermediate is formed transiently by oxidative addition of the low-valent transition metal to the organic moiety. In fact, this latter species can turn out to be effective towards various substrates. In these conditions, many synthetic reactions combining electroreduction and transition-metal catalysis have thus appeared during the last decade and not all but many of them can really compete with the conventional chemical methods as new efficient synthetic routes. Generally, these C±C bond-forming reactions are carried out in the presence of a sacrificial anode. It has progressively appeared that the role of the anodically generated ions is often decisive in some cases, but this phenomenon is not yet fully understood. Different electrochemical reactions from polyfunctionalized substrates involving a transient organometallic species from a transition metal have been reported

631

632


in a review [12]. Various electrochemical coupling reactions of organic derivatives through catalysis by nickel and palladium complexes have been well investigated and recently reviewed [13]. Consequently, after this short overview of the methods and issues of the electrosynthesis of organometallic, and the presentation of the electrochemical devices and general reaction conditions, the third part of this chapter will focus on the most advanced results obtained recently using direct electrochemical coupling reactions involving cobalt or iron catalysts. The electroreduction of organic halides (FG)3C-X by using a sacrificial anode is easier, with higher reduction potentials (±0.8 to ±1.5 V/ECS), when it is associated with a catalysis by a low-valent transition-metal complex. Thus, if the reaction is run in the presence of a metallic cation not easily reduced at these potentials, for 2+ instance a Zn ion, it becomes possible to generate the corresponding organometallic, for example an organozinc species. Indeed the metallic cation can react, under these conditions, with the transient organometallic compound to form a stable organometallic. Consequently, the catalyst precursor is regenerated according to:

(FG)3C-Mt II X Ln + ZnX2

(FG)3C-ZnX + MII X Ln

(3)

The electrochemical synthesis of arylzinc or heteroarylzinc species bearing electron-donating or -withdrawing groups can thus be carried out using nickel [14] or cobalt [15] as catalyst under mild conditions. Subsequently, the fourth part of this chapter will deal with formations of these species prepared by electrochemical reaction catalyzed by nickel or cobalt complexes, along with their reactivity. The mechanism leading to the formation of these arylzinc compounds has been studied by electrochemistry. This work is required to improve these reactions and define the scope and limitations of these processes. On the basis on recent studies, a new and facile chemical synthesis of functionalized arylzinc species has been found and will be presented in the conclusion of this chapter.

15.2 Electrochemical Device and General Reaction Conditions

The undivided electrochemical glass cell and other equipment commonly used in the laboratory for many reactions described below are shown in Fig. 15.1. The anode is a rod of magnesium, iron or zinc; it is held by an open-top cap equipped with a joint and screwed on the top of the glass cell. The cathode is concentric and made of a grid of stainless steel or carbon fiber, or foam of nickel. The apparent 2 cathode surface is 10±20 cm . The electrodes are connected by stainless steel wires to the DC power supply that can provide up to 1 A current intensity. Side arms equipped with screw caps allow the introduction of solvent (usually 30±50 mL), the reagents, as well as a permanent supply of an inert gas (N2 or Ar), and for the connection of the cathode. Dipolar aprotic solvents are used, mainly dimethylformamide (DMF) and acetonitrile (ACN), or their mixture with pyridine (Pyr),

15.3 Electrochemical Synthesis

633

and distilled before use though a quite high dryness is not required. A low concentration (0.01±0.02 M) of tetrabutylammonium salt, bromide, iodide or tetrafluoroborate, is added to the medium to ensure a good initial conductivity. However if the electrolysis is conducted in the presence of Zn(II) (either ZnBr2 or ZnCl2) added to the medium the ammonium salt is unnecessary. Electrolyzes are usually conducted under argon at 0±60 C under constant current density of 0.5± 2 5 A/dm of cathode. Under these reaction conditions current electrolyzes allows preparation of 1±15 millimoles of product. DC POWER SUPPLY

_

+ Sacrificial anode (Mg, Zn, Fe) Output of inert gas

Cathode Stirring bar Cooling or heating bath

Fig. 15.1 Electrochemical cell used at laboratory scale for electrosynthesis of zinc reagents and C±C bond.

15.3 Electrochemical Synthesis Involving Functionalized Organo-Cobalt or -Iron Intermediates Derivatives 15.3.1 Introduction

Electrochemical cross-coupling reaction from functionalized organic halides requires generally catalytic amounts of a transition metal. This transition metal is most often nickel. The success of these reactions is due to the formation and the reactivity of an organometallic intermediate formed in situ by electrochemistry. To the best of our knowledge, these compounds have not been yet isolated and characterized. II I For example, the compounds ArNi X or Ar2Ni and even ArNi resulting from the electroreduction of ArNiX [16], are assumed to arise in the cross-coupling be-

634


tween substituted aryl halides (ArX) and various compounds ( ArX, CO2, activated alkyl halides) [17]. More recently, attempts to synthesize arylcobalt(II) complexes have been carried out. The electroreduction of CoBr2 in a DMF/pyridine (9/1) mixture in the presence of an aryl bromides (ArBr) and a cobalt rod as the sacrificial anode afforded the monoarylcobalt(II) complex via the following process (Scheme 15.5) [18]. - 1.4 V/SCE CoBr2 + e

CoI(Pyr)n

ArBr

- 1.4 V/SCE ArCoIIIBr(Pyr)n

ArCoIIBr(Pyr)n

Scheme 15.5 Electrosynthesis of arylcobalt(II) complexes in DMF/pyridine. II

Probably this ArCo Br(Pyr)n converts rapidly into a diarylcobalt by a metathesis reaction and regenerates the CoBr2:

ArCoIIX(Pyr)n

(5)

1/2 CoX2 +1/2 Ar2Co(Pyr)n

Both the lifetime (around some seconds to several minutes) and the reactivity in solution of these arylcobalt complexes Ar2Co depend on the nature of the substituent on the aromatic nucleus. In the presence of zinc salts, this intermediate leads to the stable arylzinc compound by simple metal exchange according to:

Ar2Co + 2 ZnBr2

(6a)

2ArZnBr + CoBr2

These electrogenerated arylcobalt compounds also react with allyl acetate to form the allylated aryl derivatives according to:

Ar2Co + 2 AcO

2 Ar

+ Co(OAc)2

(6b)

In the absence of reagent, Ar2Co produces spontaneously a mixture of ArAr and ArH. In this part, the principal results developed during recent years concerning the catalyzed cross-coupling between organic halides and various reagents involving simple cobalt and iron complexes are presented. Electrochemical analysis of these processes demonstrated that these reactions involve an intermediate organometallic species generated from the transition metals (Fe or Co). Some characteristic experimental procedures will be described.


635

15.3.2 Carbon±Carbon Bond Formation Using Electrogenerated Functionalized Organocobalt Species

Recently, it was shown that the electroreduction of catalytic simple cobalt salts in the presence of functionalized organic halides leads to an organometallic compound [19] that can react with different substrates in DMF or acetonitrile containing pyridine as ligand (Scheme 15.6).

CoX2 + e

- 1.1 to -1.3V/SCE CoI DMF/Pyr (v/v=9/1) or ACN/Pyr (v/v=9/1)

ArX

ArCoIIIX

e, - 1.1 to -1.3V/SCE ArCoIIX reagent coupling product + CoI or CoII

Scheme 15.6 Carbon±carbon bond formation using electrogenerated organocobalt species.

Reactions are conducted in an undivided cell fitted with an iron rod as the sacrificial anode. Iron ions arising from the oxidation of anode can act as a Lewis acid towards II I ArCo X making easier its electroreduction in ArCo (Eq. (6c)) or can regenerate II the initial cobalt precursor through a ligand exchange between Fe and a cobalt complex reducible at low potential, for example (Eq. (7)) [20].

ArCoIIX + Fe 2+ + e

Co(OAc)2 + Fe2+

(6c)

ArCoI + FeX+

(7)

Co2+ + Fe(OAc)2

15.3.2.1 Electrosynthesis of Dissymmetric Biaryls The electrochemical procedure allowing the synthesis of various 4-phenylquinoline derivatives was described [21] according to the general conditions given in Scheme 15.7. Cl X FG1 + 1-2 eq

FG1

e, CoCl2 0.26 eq Fe anode FG2

N 1 eq

CH3CN, DMF, Pyridine I = 0.2A, RT

X = I, Br FG1 = Me, OMe, CO2Et FG2 = H, Me, Ph Scheme 15.7 Electrosynthesis of 4-phenylquinoline derivatives.

FG2 N 48-68%

636


4-phenylquinoline derivatives are obtained in moderate to good yields. It should be pointed out that the choice of an iron rod anode was of crucial importance for the efficiency of this electrochemical process. The electrolysis is conducted until complete disappearance of the starting 4-chloroamine. Under the same conditions, the use of an iron anode is also necessary for the reductive dimerization of aryl halides (p-MeOPhBr, p-EtOCOPhBr, etc.). With a Mg or Al sacrificial anode, or if electrolysis is conducted in a divided cell, aryl bromide (ArBr) is principally converted to the reduction product (ArH) [22]. This catalytic process was also applied to the direct cross-coupling between two different functionalized aryl halides according to Scheme 15.8 [23]. e, CoX2 0.2-0.3 eq Fe anode Ar1X + Ar2X 1 eq.

2 eq.

Ar1-Ar2 CH3CN/Pyridine (v/v= 9/1) RT, I = 0.2A

Scheme 15.8 Electrosynthesis of unsymmetrical biaryls.

In this case, unsymmetrical biaryls are formed even if the iron anode is replaced by zinc, aluminum or iron/nickel (64:36) anodes. Nevertheless, iron anode leads to better yields as already described in the previous reaction. In this reaction, an excess of the more reactive aromatic halide towards the electrogenerI ated Co is introduced. Furthermore, this coupling reaction is compatible with various electron-donating or -withdrawing substituents and different halogens on the aromatic nucleus according to Schemes 15.9±15.11.

I

Br FG1 + 1 eq.

e, CoX2 cat Fe anode

FG2

FG2 2 eq.

FG1 CH3CN/Pyridine (v/v= 9/1) RT, I=0.2A

72-90% isolated

FG1 =CN, CO2Me, CO2Et FG2 = H, OMe, CF3 Scheme 15.9 Coupling between functionalized aryl iodides and bromides.

Br FG1 + 1 eq.

e, CoX2 cat Br Fe anode FG2 CH3CN/Pyridine (v/v= 9/1) RT, I=0.2A 2 eq.

FG2 FG1 50-84% isolated

FG1 =CN, CO2Me, CO2Et, Cl, CF3, OMe FG2 = CO2Et, Scheme 15.10 Coupling between two functionalized aryl bromides.


CO2Me e, CoX2 cat Cl Fe anode

Cl + MeO2C

NC 1eq

2eq

CH3CN/Pyridine (v/v= 9/1) RT, I=0.2A

NC 60% isolated

Scheme 15.11 Coupling between two functionalized aryl chlorides.

The cross-coupling between an aromatic halide and 3-bromothiophene is also investigated leading to 3-aryl-thiophenes (Scheme 15.12). The latter are of great interest in the synthesis of poly(3-substituted) thiophenes. 1) FeBr2 2) e, CoX2 cat Br Fe anode

S + Br 1eq

S

CH3CN/Pyridine (v/v= 9/1) RT, I=0.2A

EtO2C 1eq

CO2Et 50% isolated

Scheme 15.12 Coupling between aryl bromide and 3-bromothiophene.

This very versatile process compares favorably with the procedure described by Lemaire [24] since the excess of the more reactive aromatic halide does not bring additional difficulties in the separation steps. Obviously, the large excess of the more reactive aryl halide induces the formation of the large amount of the corresponding homocoupling biaryl. In most cases, this corresponding symmetric biaryl, even as the major product in the medium, does not influence the extraction and the purification of the unsymmetrical biaryl Ar1±Ar2. The symmetric biaryl stemming from the less reactive halide only occurs as traces.

15.3.2.2 Electrochemical Addition of Aryl Halides onto Activated Olefins The same consumable anode process as described in Section 15.3.2.1 allows the electrochemical arylation of activated olefins from functionalized aryl halides when cobalt halide is used as catalyst, either associated with bipyridine and pyridine in DMF, or with only pyridine in acetonitrile as solvent. This electrochemical coupling is efficient between aryl bromides and methyl vinyl ketone as activated olefin (Scheme 15.13) [25]. With aryl chlorides, for instance with p-chloroacetophenone, the addition product is obtained in low yield (20%). When the reaction conditions optimized with methyl vinyl ketone are then applied to the arylation of other activated olefins such as acrylate esters and acrylonitrile, yields are also low due to the formation of the reduction product ArH and the dimer Ar±Ar. However, both the Heck deriva-

637

638


O 1 eq

O

e, CoX2 Fe anode

Br FG +

CH3CN/Pyridine 60ºC,I=0.2A

FG

2eq

FG = CO2Et, CO2Me, CN

55-70% isolated

Scheme 15.13 Electrochemical arylation of methyl vinyl ketone catalyzed by CoBr2.

tive and the 1±4 addition product are obtained with various ratios when this electrochemical reaction between aromatic halides and acrylate ester is conducted in the presence of a cobalt salt as catalyst associated with bipyridine in excess, according to Scheme 15.14 [26].

Br FG 1 eq

e, CoX2 0.2 eq Fe anode +

CO2R

2 eq

CH3CN/Pyridine/ Et3N (v/v/v= 7/2/1) Bpy 1.3 eq 70ºC, I=0.2A

CO2R FG

18-56% isolated

+ CO2R FG

22-45% isolated

FG = H, Me, CH(Me)3, OMe, N(Me)2, SMe, CO2Et, COMe, CN R = Me, Et, nBu Scheme 15.14 Coupling of aryl bromides with acrylate esters catalyzed by CoBr2.

As already mentioned for the electrochemical addition of aryl halides onto olefins, the use of a consumable iron is necessary for the reaction to be catalytic in cobalt. With less reactive aryl chlorides, the chloride is not consumed and only traces of Heck and conjugated addition products are formed. This Heck reaction can not be extended to other types of olefins (acrylonitrile, methyl vinyl ketone, styrene, etc.).

15.3.2.3 Electrochemical Vinylation of Aryl Halides using Vinylic Acetates Under the same conditions as described before (Sects. 15.3.2.1 and 15.3.2.2), the electroreduction of aryl halides ArX (X= Cl, Br) allows the coupling reaction with vinylic acetates in the presence of stoichiometric amount 2,2¢-bipyridine and catalytic amounts of cobalt bromide This new carbon±carbon bond synthesis successfully led to styrene derivatives that are hardly accessible by other methods according to Scheme 15.15 [27]. The reaction is particularly efficient with aryl chlorides activated by the presence of an electron-withdrawing group on the aromatic nucleus. This simple procedure appears to be a mild and useful method for the synthesis of various vinylaryl compounds. Moreover, the presence of an ortho substituent strongly affects


R Br FG +

R

e, CoX2 cat Fe anode CH3CN/pyridine Bpy 1 eq RT, I = 0.2A

OAc 2 eq

1 eq

FG

X = Br 40-62% isolated X = Cl 47-92% isolated

X= Br FG = H, MeO, iPr, Me, OPh, CO2Et, CN X= Cl FG = Me, OMe, SMe, CO2Me, COMe, CN, CF3, F R

Me = OAc

OAc

OAc ,

,

OAc

Scheme 15.15 Coupling reaction between aryl bromides and vinyl acetates catalyzed by CoBr2.

the coupling with this catalytic system. This process was extended to heteroaromatic chlorides. Under the same conditions, good yields were obtained in the reaction of isoprenyl acetate with 4-chloroquinoline (65%) and 3-chloropyridine (73%).

15.3.2.4 Cross-coupling between Aryl or Heteroaryl Halides and Allylic Acetates or Carbonates This uses basically the same conditions, in the absence of 2,2¢-bipyridine, as described previously for the electrochemical vinylation of aryl halides using vinylic acetates (Scheme 15.16) [28]. e, CoBr2 0.15 eq

X FG

+

OAc

FG Fe anode CH3CN/Pyr (v/v= 9/1) RT, I=0.2A

X=Br

FG= CO2Et, CN, CF3, F, Cl, OMe

X=Cl

FG= CN, CO2Me, COMe

Scheme 15.16 Coupling reaction between aryl halides and allyl acetate catalyzed by CoBr2.

This new method gives high yield of coupling product from aryl bromides substituted by an electron-withdrawing or an electron-donating group or from aryl chlorides substituted by an electron-withdrawing (51±86%) group. Furthermore, yields do not depend on the position of the functional group on the aromatic nucleus. This process was extended to the coupling between several heteroaromatic halides with allyl methacrylates. Conditions are similar to those used with aromatic halides. From 3-bromothiophene, 2-chlorothiophene and 4-chloroquinaldine, the reaction provides good yields 70, 63 and 69%, respectively. For this reaction, a mechanism was proposed [20]. An important point is the presence of elec-

639

640

15 Polyfunctional Zinc, Cobalt and Iron Organometallics Prepared by Electrosynthesis 2+

trogenerated Fe ions. Their presence allows the regeneration of the initial cobalt II precursor through a ligand-exchange reaction between Fe ions arising from the oxidation of the anode and Co (OAc)x that is no longer reducible at ±1.3 V/SCE. II Several metals can be used as anode, for example zinc. The Zn ions generated by oxidation of the anode play the same role as iron ions, but iron anode gives better yields in the coupling product. Experimental procedure: Coupling of aryl halides with allyl acetate In an undivided cell using a consumable iron anode and stainless steel grid as cathode, containing 7.5 mmol of ArX (0.16 M), 1 mmol (for ArBr) or 2 mmol (for ArCl) of CoBr2 (0.02 M), 7.5 mmol of ArX and 20 mmol of allyl acetate were placed in a mixture solvent of acetonitrile/pyridine or DMF/pyridine (45 mL/5 mL). The ionic conductivity of the medium is ensured by addition of NBu4BF4 (0.5 mmol) as supporting electrolyte. The solution was electrolyzed and heated at 50 C at constant current intensity of 0.2 A 2 (0.01 A/cm ) under argon until the aryl halide fully reacted. The reaction mixture was poured into a solution of 2 M HCl (50 mL) and extracted with diethyl ether (225 mL). The organic layer was washed with brine and dried over MgSO4, and the solvent was evaporated under vacuum. Coupling products were isolated by column chromatography 1 13 on silica gel with pentane/ether as eluent and were characterized by NMR ( H, C, 19 F) and mass spectrometry. 15.3.3 Carbon±Carbon Bond using Electrogenerated Functionalized Organometallic Iron 15.3.3.1 Coupling of Activated Aliphatic Halides with Carbonyl Compounds

The electroreduction in DMF of a mixture of activated alkyl halide (a-chloro- or a-bromoester or a-chloronitrile) and a carbonyl compound (aldehyde or ketone) in the presence of the complex FeBr2(Bpy)x, associated with an iron sacrificial anode leads to the cross-coupling product with moderate to high yields according to Scheme 15.17 [29]. R1

Cl + R

R2

FG

O

R R1 FG DMF, Fe anode R2 OH RT, I=0.2A e, FeBr2, Bpy

FG= CO2Et, CN R= H, Me

30-90% isolated

R1, R2 =H, alkyl, Ph, Thiophenyl, etc…

Scheme 15.17 Electrochemical coupling between activated aliphatic chlorides and carbonyl compound catalyzed by iron complexes.

Under the same procedure, the coupling between carbonyl compounds and a-chloroketones or a,a-dichloroesters is also efficient, according to Schemes 15.18 and 15.19, respectively.

15.3 Electrochemical Synthesis O

O Cl

e, FeBr2(Bpy)n

+

+ DMF, Fe anode RT, I=0.2A

OH O

O

40% isolated

48% isolated

Scheme 15.18 Electrochemical coupling between cyclohexenone and a-chloroketone.

+ Cl2CH-CO2Et

O

e, FeBr2(Bpy)n

O

+ CO2Et

DMF, Fe anode RT, I=0.2A

66% isolated

HO

CO2Et

11% isolated

Scheme 15.19 Electrochemical coupling between 3-pentenone and a,a-dichloroester.

The reaction is regiospecific. No conjugated addition was observed with enone. In the case of dissymmetric carbonyl compounds, two diastereoisomers were obtained with moderate diastereoselectivity depending on the nature of the carbonyl compound. I The electroanalytical study shows the formation of Fe Br(Bpy)n from electroreI duction of FeBr2(Bpy)n [30]. The subsequent step is an oxidative addition of Fe to the activated halide. This latter iron organometallic species reacts with carbonyl compounds.

15.3.3.2 Electrochemical Allylation of Carbonyl Compounds by Allylic Acetates Homoallylic alcohols were synthesized from aldehydes or ketones and allylic acetates in moderate to good yields (40±86%) using the same electrochemical process and catalytic complex. The use of acetonitrile as solvent allows suppression of 2, 2¢bipyridine as ligand of iron (Scheme 15.20) [31]. O OAc

+

e, FeBr2 CH3CN, Fe anode RT, I=0.2A

1eq.

3eq.

OH

73% isolated

Scheme 15.20 Electrochemical allylation of cyclohexanone catalyzed by iron complexes.

In this case, allyl acetate is used as the reagent as well as the ligand of the iron salt. Reactions are regioselective: the branched product is the major product and sometimes the only one.

641

642


Experimental procedure: Coupling of carbonyl compounds with allyl acetate 2 In an undivided cell equipped with a nickel sponge (area 20 cm ) as the cathode and a consumable iron as the anode, under argon, tetrabutylammonium tetrafluoroborate (0.6 mmol) was dissolved as supporting electrolyte in DMF (40 mL) 1,2-dibromoethane (1.25 mmol) was introduced. A short electrolysis was run at constant current intensity (0.3 A) and at room temperature within 15 min to generate a small amount of iron ions. Then the current was turned off. Carbonyl compounds (10 mmol) and an excess of allyl acetate (30 mmol) were added. The electrosynthesis was run at constant current intensity (0.25 A). The reaction was monitored by GC and stopped after carbonyl com±1 pound was consumed. A charge of 4 F mol was used in most reactions. The reaction mixture was then hydrolyzed with 1 N HCl (50 mL), diluted in diethyl ether and extracted with diethyl ether (225 mL). The organic layer was washed with brine and dried over MgSO4, and the solvent was evaporated under vacuum. The oil thus obtained was purified by column chromatography on silica gel with pentane/ether as eluent and 1 13 19 was characterized by NMR ( H, C, F) and mass spectrometry. In the absence of a carbonyl compound, the electroreduction leads to the formation of hexadiene, thus implying the formation of a p-allyl iron complex I formed by addition of Fe on allyl acetate. Certainly, this is the p-allyl iron complex that reacts with carbonyl compounds leading to homoallylic alcohols.

15.3.3.3 Conclusion Electrochemical processes using especially a consumable iron anode associated with the transition-metal catalysis by simple cobalt or iron complexes permits the carbon±carbon bond-forming reaction by simple and efficient reactions. Unambiguously, functionalized transient cobalt or iron organometallic are formed in these reactions.

15.4 Electrosynthesis of Functionalized Aryl- or Heteroarylzinc Compounds and their Reactivity 15.4.1 Introduction

It has been investigated if transient organonickel and organocobalt intermediates obtained via oxidative addition of aromatic halides on Ni(0) and Co(I), respectively, undergo transmetallation with zinc salt introduced or electrogenerated in the medium together with the recovering of the original Ni(II) or Co(II) precursor:

ArMtIIXLn + Zn2+ Mt= Ni, Co

ArZnX + Mt2+Ln

(8)

Thus, organozinc reagents were synthesized in good yields via this procedure and the results are presented in the next section. Furthermore, these aryl- or heteroaryl

15.4 Electrosynthesis of Compounds and their Reactivity

species prepared by electrochemistry and especially by in-situ-generated cobalt(I) catalysis present a particular reactivity. These results will be thus developed in the next section. 15.4.2 Electrosynthesis of Aryl or Heteroaryl Zinc Species from the Corresponding Halide via a Nickel Catalysis [14] 0

Zerovalent nickel complexes Ni (bpy)n with n=1 or 2, formed by electroreduction of NiX2(bpy)n (X= Cl, Br, BF4) in DMF rapidly add oxidatively to aryl halides according to:

ArNiXbpy + 2X- + n-1 bpy

ArX + 2e + NiX2(bpy)n

II

(9)

0

So the overall reaction occurs at a redox potential close to that of Ni /Ni system, II i.e. at ±1.1 V/SCE whereas Zn ions are reduced at ca. ±1.4 V/SCE in DMF, and aryl halides are reduced at between ±2 and ±2.7 V/SCE. In addition, apart from NO2, sensitive functional groups can be present on the ring. a-arylnickel compounds are reducibly converted into Ar±Ar (para or meta-substituted compounds) or into Ar±H (ortho-substituted compounds). The arylzinc halide is the major product (Eq. (10)) if the reaction is run in the presence of a zinc salt (ZnBr2 or ZnCl2), a Mg or Zn anode, and excess of bipyridine compared to the nickel catalyst. X FG + ZnBr2

e, Mg or Zn anode Ni(BF4)2Bpy3 0.1 eq Bpy 0.2 eq DMF, I= 0.15 - 0.2A RT 0.3 – 1.2 eq

1 eq X= Br, Cl FG= OMe, Cl, CF3, COME, N(ME)2

ZnX FG + ZnBr2

(10) 75–80%

Bipyridine, when used in excess, is very likely responsible for the success of this reaction. Indeed, its more favorable coordination to Ni(II) than to Zn(II) enables the metal exchange (Eq. (11)), whereas, with only one bipyridine per nickel no transmetallation occurs.

ArNiXBpy + ZnBr2

ArZnX + NiX2(bpy)n

(11)

In the case of ortho-substituted aryl halides, which are less reactive towards 0 Ni (bpy)n the formation of the arylzinc intermediate likely involves the occurrence 0 of Ni -bpy-Zn(II) complex, which by reduction leads directly to the oxidative addition-transmetallation process. According to this, the nickel catalyst is NiBr2bpy, without extra bipyridine. It is thus possible to prepare arylzinc halides from not

643

644


easily reduced 2-chlorotoluene or 2-chloroanisole, but also, more importantly, from aryl bromides or chlorides bearing reactive functional groups (COR, CO2R, CN). These compounds can be added to enone via a copper catalysis (Eq. (12)) [14a], coupled with aryl halides via a Palladium catalysis (Eq. (13)) [32] or with 2-halogenopyridine by a Ni (2, 2¢-Bpy) complex (equation 14) [33]. O

O Cl

CO 2Me

ClZn

CO2Me

CO 2Me CuI cat

54%

(12)

CN Cl

CF3

ClZn

CF3

Br

Br

COMe

BrZn

CF3

NC Pd(0) cat

N

COMe

83%

Cl

Ni cat

(13)

(14)

NC N

40%

Experimental procedure: Electrosynthesis of aryl zinc compounds and their coupling with 2-chloropyridine All the reactions were carried out in an undivided cell fitted with a consumable magnesium anode and a nickel-foam cathode. A solution in DMF (40 mL) of ArX (7.5 mmol), Ni(BF4)2bpy3 (0.5 mmol), bpy (1 mmol) and ZnBr2 (8 mmol) was electro2 lyzed under argon at a constant current intensity of 0.2 A (0.01 A/cm ) until 1600 C had passed at room temperature. When the electrolysis was stopped, 2-chloropyridine (7.5 mmol) was added and the solution stirred at room temperature for para- and metasubstituted compounds or at 60 C for the ortho-substituted compounds. The reaction was monitored by gas chromatography (GC) and run until the disappearance of ArZnX (ca. 1 h). The solution was hydrolyzed with NH4Cl and extracted with diethylether; the organic layer washed with brine, dried and the solvent evaporated. The product were isolated by flash column chromatography on silica gel with pentane/ether as eluent and 1 13 19 characterized by NMR ( H, C, F) and mass spectrometry. This method can be applied to the preparation of heteroaryl zinc halides such as 2- and 3-chloropyridine or 2- and 3-bromothiophene: S

Br

e, Mg anode ZnBr2 1.1 eq NiBr2Bpy 0.1 eq DMF, RT I=0.2A

S

EtO2C

Br EtO2C

ZnBr

Pd(0) cat

S

(15)

15.4 Electrosynthesis of Compounds and their Reactivity

645

The electrochemical conversion of 2,5-dibromo-3-substituted thiophenes to the corresponding monothienylzinc species has also been carried out in DMF in an undivided cell fitted with a zinc sacrificial anode using catalytic amount of NiBr2Bpy according to [34]: Br

S Br FG

BrZn e, Zn anode ZnBr2 cata NiBr2Bpy cata DMF, RT I=0.2A

Br

S Br

+

S ZnBr

(16)

FG

FG

A

B

The regioselectivity of the reaction is moderate (A/B=60±80) to excellent (A/B=100/0) depending to the substituent in the 3 position. The main product obtained is generally the 3-substituted 2-bromo-5-(bromozincio)thiophene (A). The formation of 2, 5-di(bromozincio) thiophenes is never observed in significant yields (

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