The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B

OXAZOLES: SYNTHESIS, REACTIONS, AND SPECTROSCOPY Part B

Edited by

David C. Palmer Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Raritan, New Jersey

AN INTERSCIENCE PUBLICATION JOHN WILEY & SONS, INC.

OXAZOLES: SYNTHESIS, REACTIONS, AND SPECTROSCOPY, PART B

This is the sixtieth volume in the series THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGRAPHS

EDWARD C. TAYLOR AND PETER WIPF, Editors ARNOLD WEISSBERGER, Founding Editor

OXAZOLES: SYNTHESIS, REACTIONS, AND SPECTROSCOPY Part B

Edited by

David C. Palmer Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Raritan, New Jersey

AN INTERSCIENCE PUBLICATION JOHN WILEY & SONS, INC.

Copyright # 2004 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400, fax 978-646-8600, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services please contact our Customer Care Department within the U.S. at 877-762-2974, outside the U.S. at 317-572-3993 or fax 317-572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print, however, may not be available in electronic format. Library of Congress Cataloging in Publication Data is available. Palmer, David C. Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B ISBN 0-471-21925-8 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

To my wife, Vicki, with love

The Chemistry of Heterocyclic Compounds Introduction to the Series

The chemistry of heterocyclic compounds is one of the most complex and intriguing branches of organic chemistry, of equal interest for its theoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocycles. The Chemistry of Heterocyclic Compounds has been published since 1950 under the initial editorship of Arnold Weissberger, and later, until his death in 1984, under the joint editorship of Arnold Weissberger and Edward C. Taylor. In 1997, Peter Wipf joined Prof. Taylor as editor. This series attempts to make the extraordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has traditionally dealt with syntheses, reactions, properties, structure, physical chemistry, and utility of compounds belonging to a specific ring system or class (e.g., pyridines, thiophenes, pyrimidines, three-membered ring systems). This series has become the basic reference collection for information on heterocyclic compounds. Many broader aspects of heterocyclic chemistry are recognized as disciplines of general significance that impinge on almost all aspects of modern organic chemistry, medicinal chemistry, and biochemistry, and for this reason we initiated several years ago a parallel series entitled General Heterocyclic Chemistry, which treated such topics as nuclear magnetic resonance, mass spectra, and photochemistry of heterocyclic compounds, the utility of heterocycles in organic synthesis, and the synthesis of heterocycles by means of 1,3-dipolar cycloaddition reactions. These volumes were intended to be of interest to all organic, medicinal, and biochemically oriented chemists, as well as to those whose particular concern is heterocyclic chemistry. It has, however, become increasingly clear that the above distinction between the two series was unnecessary and somewhat confusing, and we have therefore elected to discontinue General Heterocyclic Chemistry and to publish all forthcoming volumes in this general area in The Chemistry of Heterocyclic Compounds series. The chemistry and synthetic applications of oxazoles were first covered in 1986 in an comprehensive volume edited by I. J. Turchi (Volume 45 of The Chemistry of Heterocyclic Compounds series). In the meantime, the number of synthetic strategies directed toward oxazole assembly as well as the use of these versatile heterocycles as intermediates, catalytic ligands, and pharmaceutical building blocks has vastly increased. We felt that a supplement and update of oxazole chemistry would be welcomed by the international chemistry community, and we are delighted that Dr. Palmer and his colleagues have accomplished this onerous mission. This volume represents another outstanding service to the organic and vii

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The Chemistry of Heterocyclic Compounds: Introduction to the Series

heterocyclic chemistry literature that we are pleased to publish within The Chemistry of Heterocyclic Compounds series. Department of Chemistry Princeton University Princeton, New Jersey

EDWARD C. TAYLOR

Department of Chemistry University of Pittsburgh Pittsburgh, Pennsylvania

PETER WIPF

Foreword

The subject of heterocyclic chemistry, prior to 1950, had been viewed as the domain of a small group of organic chemists. The perception prevailed that these individuals simply added ingredients together to make a witch’s brew, heated it to 150–250
C, and ultimately isolated a heterocyclic compound. This may be a somewhat exaggerated description of the subject but nevertheless makes the point that up to that time, it was assumed that one needed special training and knowledge to engage in this subject. However, in spite of this, a large number of molecularly distinct heterocyclic compounds were prepared and subsequently found to have highly important uses in medicine, polymers, dyes, and a number of other areas. As biology and biochemistry matured into a true science during the past 50 years, more and more biological phenomena were found to involve heterocyclic systems. This led to an increased appreciation of heterocycles, their chemical properties, and the reactions they undergo. As a result, these ring systems were subsequently regarded as more than a narrow field of chemistry. There is now little need to convince the informed scientific community of the incredible value of heterocyclic compounds. As organic chemistry entered a new level of sophistication in the 1950s and understanding of chemical reactions was actively pursued, heterocyclic compounds were also included in this exploration and found to play a major role in many important chemical reactions, both as intermediates and as final products. As this writer predicted in 1974 in a monograph entitled ‘‘Heterocycles in Synthesis,’’ these ring systems will not only be crucial to the scientific areas already mentioned above but will also find great importance in the synthesis of all types of organic compounds. In fact, in the current climate, heterocycles and their properties are so well accepted that they pervade all areas of medicine and biology, as well as chemistry. The present updated volumes relating to oxazoles, oxazolines, and oxazolones are very timely works since these simple five-membered ring heterocycles have contributed much to the knowledge we have acquired in various fields of biological and chemical sciences. For example, we may envision oxazolones as tautomeric derivatives of the old and well-known azlactones, first reported in 1883. They may also be viewed as ‘‘cyclized’’ amino acid derivatives or their dehydro analogs and therefore would be expected as constituents of many biologically active natural products. In addition, these ring systems have shown their versatility in the synthesis of a variety of ligands for metal catalysts, as well as precursors or vehicles to reach many types of functionalized compounds. Furthermore, their chiral counterparts—oxazoles, oxazolines, and oxazolones containing a stereogenic center—have been major players in a very large number of asymmetric syntheses. Hardly a day passes that some journal does not describe the involvement of these chiral, non-racemic heterocycles for preparing an organic compound in very high ix

x

Foreword

enantiomeric excess. Thus, oxazoles and their derivatives, whose synthesis, properties, and reactivity are described in the following two volumes, represent an immensely versatile family of heterocyclic compounds for future exploitation by both synthetic and medicinal chemists. Fort Collins, Colorado November, 2002

A. I. MEYERS

Preface

By far the most comprehensive review of the synthesis and reactions of mononuclear oxazoles and derivatives is The Chemistry of Heterocyclic Compounds, Volume 45, edited by I. J. Turchi and published in 1986. This work is the definitive reference for oxazole chemistry through 1983. Subsequently, literally tens of thousands of references appeared in the period 1983–2001 pertaining to this remarkable small ring heterocycle. Oxazoles and derivatives continue to be of great interest and importance in all aspects of synthetic chemistry with applications in medicinal and agricultural chemistry, material sciences, photographic dyes, peptide chemistry, asymmetric catalysis, and polymer chemistry. Indeed, more than 250 reviews focusing on specific aspects of the chemistry and biology of oxazoles, oxazolones, oxazolines, and chiral bis(oxazolines) have been published from 1983 to 2001. The continuing interest in oxazoles together with the wealth of new information warrants a second review of this exciting area. It would require a Herculean effort to prepare a complete discussion and review of every report related to the synthesis, reaction, or application of an oxazole while tabulating every oxazole, oxazolone, oxazoline, and chiral bis(oxazoline) prepared and evaluated during the period of 1983–2001. Such an undertaking is beyond the scope of this review. Furthermore, the ease with which electronic databases, including the patent literature, can be searched, the data retrieved, and the information tabulated would render such a project somewhat redundant. Rather, the intent of the current project is to provide the reader with a discussion and leading examples of significant advances made in the synthesis, reactions, and applications of mononuclear oxazoles, oxazolones, oxazolines, and chiral bis(oxazolines) during this time frame. The material focuses on the more recent literature, although an update of the older synthetic literature is included wherever possible. In an effort to be selective, references to relevant reviews of material, not discussed in a chapter, are provided. Completely reduced oxazoles, that is, oxazolidines as well as benzo-fused derivatives, are outside the scope of this review. The coverage is similar to that of Volume 45, although the presentation has been changed and the scope has been expanded to include a chapter devoted to the exciting area of chiral bis(oxazolines). The material is presented in nine chapters and two volumes. In some cases, the organization of the individual chapter contents is different from that in Volume 45 to reflect the changing emphasis on newer methodologies and synthetic targets. For example, in Part A, Chapter One contains an expanded section that deals specifically with the synthesis of selected naturally occurring mono-, bis-, and tris(oxazoles) to reflect the significant synthetic challenges therein. In addition, the discussion of cycloaddition and Diels–Alder reactions of oxazoles is introduced in Chapter One but is covered in detail in Chapter Three. In Part B, oxazolones are defined by the structure of the individual xi

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Preface

regioisomer and discussed in Chapters Five, Six, and Seven, respectively. Chapter Eight describes the syntheses and reactions of oxazolines including asymmetric methodogy employing monooxazoline ligands. A new chapter, Chapter Nine, was added to include the recent developments in asymmetric synthesis utilizing chiral bis(oxazolines). Discussion of material from the patent literature has been included as an integral part of the volumes. Primary emphasis has been given to general syntheses and reactions. However, reactions that are more limited in scope and yet are singularly unique may also be described. Tables are included in every chapter. Wherever possible, these contain a variety of selected examples to provide the reader with the scope and limitations of synthetic methods and reactions. However, in some cases a table will contain only the examples reported. No attempt has been made to provide an exhaustive compilation of every oxazole, oxazolone, or oxazoline prepared since 1983. Part A is devoted specifically to the synthesis, reactions, and spectroscopic properties of oxazoles and encompasses four chapters: Chapter 1—Synthesis and Reactions of Oxazoles; Chapter 2—Spectroscopic Properties of Oxazoles; Chapter 3—Oxazole Diels–Alder Reactions; and Chapter 4—Mesoionic Oxazoles. Part B is comprised of the following five chapters: Chapter 5—2(3H)-Oxazolones and 2(5H)-Oxazolones; Chapter 6—4(5H)-Oxazolones; Chapter 7—5(2H)Oxazolones and 5(4H)-Oxazolones; Chapter 8—2-Oxazolines; and Chapter 9— Chiral Bis(oxazolines). Acknowledgments: I thank the authors for their individual contributions and patience through several iterations of the chapters. I am indebted to the library staff at Johnson & Johnson Pharmaceutical Research & Development who secured even the most obscure references in a timely manner. A very special acknowledgment and thanks are due to Dr. Fuqiang Liu for his critical insights, suggestions, comments, and review of individual chapters during preparation of these volumes. I thank Dr. Mayra Reyes and Dr. Brigitte Segmuller for their help with the indices for Part B. The series editors, particularly Professor Ted Taylor, offered many helpful suggestions and guidance. I thank Dr. Darla Henderson and Ms. Amy Romano at John Wiley & Sons for their constant encouragement and support. Special thanks are due to Ms. Shirley Thomas and her staff at John Wiley & Sons for their patience and understanding during preparation of these volumes. Finally, I am deeply thankful to my wife, Vicki, for her continual support, patience, and understanding during this entire project. The reader may well encounter errors in a work of this magnitude, particularly in one with several thousand structures. I hope such errors will not detract from the overall intent of the volumes. Nonetheless, any errors are the responsibility of the editor. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Raritan, New Jersey

DAVID C. PALMER

Contents - Part B

Contents - Part A

xv

Abbreviations

xvii

5.

2(3H)-Oxazolones and 2(5H)-Oxazolones T. KUNIEDA and H. MATSUNAGA

1

6.

4(5H)-Oxazolones D. C. PALMER

7.

5(2H)-Oxazolones and 5(4H)-Oxazolones C. CATIVIELA and M. D. DIAZ-DE-VILLEGAS

129

8.

2-Oxazolines G. S. K. WONG and W. WU

331

9.

Chiral Bis(oxazolines) A. GHOSH, G. BILCER, and S. FIDANZE

529

53

Author Index

595

Subject Index

635

xiii

Contents - Part A

Abbreviations

xv

1.

Synthesis and Reactions of Oxazoles D. C. PALMER and S. VENKATRAMAN

1

2.

Spectroscopic Properties of Oxazoles D. LOWE

391

3.

Oxazole Diels–Alder Reactions J. I. LEVIN and L. M. LAAKSO

417

4.

Mesoionic Oxazoles G. W. GRIBBLE

473

Author Index

577

Subject Index

599

Abbreviations

2-MI 9-BBN Ac acac Acm ADH ADHD AHMHA AHPBA Aib AIBN Alloc or AOC AMNT BARF BDMS BINAP BINOL BINOL-box Bn Boc Boc-Ox BOP BOP-Cl BPA BPO Bt Bz C3diPhe Cbz Cbz-Ox CDI CIP CNS cod Cp CPTS CSA CSI

2-methylimidazole 9-borabicyclo[3.3.1]nonane acetyl acetylacetonate acetamidomethyl asymmetric dihydroxylation attention-deficit hyperactivity disorder 4-amino-3-hydroxy-6-methylheptanoic acid 3-amino-2-hydroxy-4-phenylbutyric acid 2-aminoisobutyric 2,20 -azobisisobutyronitrile allyloxycarbonyl aminomalononitrile p-toluenesulfonate tetrakis[3,5-bis(trifluoromethyl)phenyl]borate biphenyldimethylsilyl 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl [1,10 ]binaphthalenyl-2,20 -diol 3,30 -bis(2-oxazolyl)-1,10 -bi-2-naphthol benzyl tert-butyloxycarbonyl 2-oxo-3(2H)-oxazolecarboxylic acid tert-butyl ester benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate N,N-bis-(2-oxo-3-oxazolidinyl)phosphonic chloride L-4-boronophenylalanine dibenzoyl peroxide benzotriazol-1-yl or 1-benzotriazolyl benzoyl trans-1-amino-2,3-diphenyl-1-cyclopropanecarboxylic acid benzyloxycarbonyl 2-oxo-3(2H)-oxazolecarboxylic acid benzyl ester 1,10 -carbonyldiimidazole 2-chloro-1,3-dimethylimidazolium hexafluorophosphate central nervous system cyclooctadiene cyclopentadiene collidine p-toluenesulfonate camphorsulfonic acid chlorosulfonylisocyanate xvii

xviii

Cy CZE DAST dba dbg DBF-box DBN DBU DCC DCE DDQ de DEAD DECP or DEPC Deoxo-fluor DIAD DIBALH DIPEA DMAC DMAD DMAP DME DMF DMI DMPU DMT DOPA Dpg DPPA dppb DPPC dppe dppf DPPOx dppp ECF EDCI or EDAC EEDQ EGB ETHP ETMG EVL EWG FMO

Abbreviations

cyclohexyl capillary zone electrophoresis diaminosulfur trifluoride dibenzylideneacetone dibenzylglycine 2,20 -(4,6-dibenzofurandiyl)bis[4,5-dihydro-4-phenyloxazole] 1,5-diazabicyclo[4.3.0]non-5-ene 1,8-diazabicyclo[5.4.0]undec-7-ene N,N0 -dicyclohexylcarbodiimide 1,2-dichloroethane 2,3-dichloro-4,5-dicyano-1,4-benzoquinone diastereomeric excess diethyl azodicarboxylate diethylcyanophosphonate, diethylphosphoryl cyanide bis(2-methoxyethyl)aminosulfur trifluoride diisopropyl azodicarboxylate diisobutylaluminum hydride diisopropylethylamine dimethylacetamide dimethyl acetylenedicarboxylate 4-(dimethylamino)pyridine 1,2-dimethoxyethane dimethylformamide 1,3-dimethyl-2-imidazolidinone 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone dimethoxytrityl 3,4-dihydroxyphenylalanine dipropylglycine diphenylphosphoryl azide 1,4-bis(diphenylphosphino)butane diphenylphosphoryl chloride, diphenyl phosphochloridate 1,4-bis(diphenylphosphino)ethane 1,4-bis(diphenylphosphino)ferrocene diphenyl-(2-oxo-3(2H)-oxazolyl)phosphonate 1,4-bis(diphenylphosphino)propane ethyl chloroformate 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline electrogenerated base 2-ethyl-1,4,5,6-tetrahydropyrimidine 2-ethyl-1,1,3,3-tetramethylguanidine ethoxyvinyllithium electron-withdrawing group frontier molecular orbital

Abbreviations

Fmoc HATU HBTU 1

H NMR Het HMPA HMTA HOAt HOBt HOMO HPLC HydrOx IBCF ICI IIDQ Im KDN KHMDS L-(þ)-DET

LAH LDA LDEA LG LiHMDS LTMP LUMO m-CPBA MeBmt MEK MEM 2-MI MIBK MOM morphoCDI Ms MTM NaHMDS NBS NCS

xix

9-fluorenylmethoxycarbonyl O-(7-azabenzotriazol-1-yl)-N,N,N0 ,N0 -tetramethyluronium hexafluorophosphate O-benzotriazol-1-yl-N,N,N0 ,N0 -tetramethyluronium hexafluorophosphate proton NMR heterocycle hexamethylphosphoric triamide hexamethylenetetraamine 1-hydroxy-7-azabenzotriazole 1-hydroxybenzotriazole highest occupied molecular orbital high-performance liquid chromatography hydroxy-oxazoline isobutyl chloroformate Imperial Chemical Industries 2-isobutoxy-N-isobutoxycarbonyl-1,2-dihydroquinoline imidazole 3-deoxy-D-glycero-D-galacto-2-monulosonic acid potassium hexamethyldisilazane, potassium bis(trimethylsilyl)amide L-(þ)-diethyl L-tartrate lithium aluminum hydride lithium diisopropylamide lithium diethylamide learning group lithium hexamethyldisilazane, lithium bis(trimethylsilyl)amide (LHMDS) lithium 2,2,6,6-tetramethylpiperidide lowest unoccupied molecular orbital m-chloroperoxybenzoic acid (MCPBA) (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)6-octenoic acid methyl ethyl ketone 2-methoxyethoxymethyl 2-methylimidazole methyl isobutyl ketone methoxymethyl N-cyclohexyl-N0 -2-(N-methylmorpholinio)ethylcarbodiimide p-toluenesulfonate methanesulfonyl (mesyl) methylthiomethyl sodium hexamethyldisilazane, sodium bis(trimethylsilyl)amide N-bromosuccinimide N-chlorosuccinimide

xx

NIS NLO NMM NMO NMP NOE Nos NPM PB PCC PDC PEG PET PhosOx Phth piv PMB PPA PPE PPL PPTS PyBOP PyBroP PyrOx RaNi SelOx SEM SES SulfOx TADDOL TBAB TBAF TBDMS or TBS TBDPS TBTU TCNE TEAHC TEAP TECM TEMPO TEOF TES Tf

Abbreviations

N-iodosuccinimide nonlinear optical 4-methylmorpholine (N-methylmorpholine) 4-methylmorpholine N-oxide N-methyl-2-pyrrolidinone nuclear Overhauser effect p-nitrobenzenesulfonyl (nosyl) N-phenylmaleimide probase pyridinium chlorochromate pyridinium dichromate poly(ethylene)glycol positron emission tomography phosphine-oxazoline phthaloyl pivaloyl p-methoxybenzyl poly(phosphoric acid) polyphosphate ester porcine pancreatic lipase pyridinium p-toluenesulfonate benzotriazol-1-yl-N-oxytris(pyrrolidino)phosphonium hexafluorophosphate bromotris(pyrrolidino)phosphonium hexafluorophosphate pyridine-oxazoline Raney nickel selenide-oxazoline 2-(trimethylsilyl)ethoxymethyl 2-(trimethylsilyl)ethanesulfonyl sulfide-oxazoline a,a,a0 ,a0 -tetraaryl-1,3-dioxolane-4,5-dimethanol tetrabutyl ammonium bromide tetra n-butylammonium fluoride tert-butyldimethylsilyl tert-butyldiphenylsilyl O-benzotriazol-1-yl-N,N,N0 ,N0 -tetramethyluronium tetrafluoroborate tetracyanoethylene tetraethylammonium hydrogen carbonate tetraethylammonium perchlorate tandem Erlenmeyer condensation macrolactamization 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical triethyl orthoformate triethylsilyl trifluoromethanesulfonyl (triflyl)

Abbreviations

TFA TFAA TFE THF THP TIA Tic TIG TIPP TIPS TMANO TMEDA TMG TMP TMS Toac Tol-BINAP TosMIC TPAP Tr Troc Ts or Tos VDMO

trifluoroacetic acid trifluoroacetic anhydride 2,2,2-trifluoroethanol tetrahydrofuran tetrahydropyran-2-yl N,N,N0 -triisopropylacetamidine 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1,2,3-triisopropylguanidine H- Tyr- Tic- Phe- Phe-NH2 triisopropylsilyl trimethylamine N-oxide N,N,N0 ,N0 -tetramethyl-1,2-ethylenediamine 1,1,3,3-tetramethylguanidine 2,2,6,6-tetramethylpiperidine trimethylsilyl 2,2,6,6,tetramethyl-4-amino-1-oxypiperidine-4carboxylic acid 2,20 -bis(di-p-tolylphosphino)-1,10 -binaphthyl tosylmethyl isocyanide, [(p-toluenesulfonyl)methyl] isocyanide tetrapropylammonium perruthenate trityl 2,2,2-trichloroethoxycarbonyl p-toluenesulfonyl (tosyl) 4,4-dimethyl-2-vinyl-5(4H)-oxazolone

xxi

CHAPTER 5

2(3H)-Oxazolones and 2(5H)-Oxazolones Takehisa Kunieda Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan

Hirofumi Matsunaga Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan

5.1. 2(3H)-Oxazolones (4-Oxazolin-2-ones) . . . . . . . . . . . 5.1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2.1. From Acyclic Carbamates. . . . . . . . 5.1.2.2. From 2-Allyloxyoxazoles . . . . . . . . 5.1.2.3. From a-Amino Acid Esters . . . . . . . 5.1.2.4. From Benzoin and Isocyanates . . . . 5.1.2.5. From 1,2-Diketones . . . . . . . . . . . . 5.1.2.6. From b-Enaminosulfoxides . . . . . . . 5.1.2.7. From Hydroxamic Acids. . . . . . . . . 5.1.2.8. From 2-Oxazolidinones . . . . . . . . . 5.1.2.9. From Oximes . . . . . . . . . . . . . . . . 5.1.2.10. From 2,4-Thiazolidinediones . . . . . . 5.1.2.11. From 1,2,4-Triazolium Salts . . . . . . 5.1.2.12. Via Three Component Condensation 5.1.2.13. Miscellaneous . . . . . . . . . . . . . . . . 5.1.3. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3.1. Hydrogenation . . . . . . . . . . . . . . . . 5.1.3.2. Electrophilic Additions . . . . . . . . . . 5.1.3.3. Radical Additions . . . . . . . . . . . . . 5.1.3.4. Pericyclic Additions . . . . . . . . . . . . 5.1.3.5. C-Substitution . . . . . . . . . . . . . . . . 5.1.3.6. N-Substitution . . . . . . . . . . . . . . . . 5.1.3.7. Miscellaneous . . . . . . . . . . . . . . . . 5.2. 2(5H)-Oxazolones (3-Oxazolin-2-ones) . . . . . . . . . . . 5.2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.3. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . .

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The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

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2 2 3 3 7 7 8 8 12 12 14 16 17 18 18 20 22 22 23 25 32 36 38 42 45 45 45 46

2

2(3H)-Oxazolones and 2(5H)-Oxazolones

5.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Addendum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47 47 49

This chapter deals with recent advances in the chemistry of 2-oxazolones, namely, 2(3H)-oxazolone (4-oxazolin-2-one, 1) and 2(5H)-oxazolone (3-oxazolin2-one, 2). Of the five isomeric oxazolones, the former is prominently cited in nearly all the literature reported since the 1980s.

O

NH

O

N

O

O

1

2

2(3H)-Oxazolone

2(5H)-Oxazolone

Figure 5.1

5.1. 2(3H)-OXAZOLONES (4-OXAZOLIN-2-ONES) 5.1.1.

Introduction

The first example of 2(3H)-oxazolone heterocycles appeared in 1905, as part of a description of the intramolecular cyclodehydration of N-phenacylurethane.1 This methodology has been widely modified for a versatile synthesis of this class of compounds. The 2(3H)-oxazolones (4-oxazolin-2-ones) exsist predominantly in the keto rather than the enol forms and contains both enol and enamine moieties as masked amino and hydroxy molecules. Thus, a wide variety of possible addition modes at the 4,5-olefinic moiety strongly suggest the potential versatility of the heterocycles as a building block for 2-amino alcohols of biological and of general synthetic interest. Enantiocontrolled ionic, radical, and pericyclic additions at the 4,5-olefinic moiety of the 2-oxazolone ring followed by ring opening provide a useful strategy for the chiral construction of 2-amino alcohols. The 2-amino alcohol skeleton is a structural unit that is found in a substantial number of bioactive compounds such as peptide enzyme inhibitors, amino sugar antibiotics, and sympathomimetic amines as well as alkaloids. Such functional structures also serve as chelating bidentate ligands for metal catalysts in organic synthesis. Another aspect is based on the chemical stability of 2-oxazolone heterocycles that permits their synthetic use as protecting groups and leaving groups. The important advances in the chemistry of 2(3H)-oxazolones since 1984 have been surveyed in this chapter, which is divided into two sections, synthesis and reactions.

2(3H)-Oxazolones (4-Oxazolin-2-ones)

5.1.2.

3

Synthesis

5.1.2.1. From Acyclic Carbamates A strategy involving the intramolecular cyclization of acyclic urethanes as a key step has been widely employed since the first synthesis of this class of compounds.2 The reaction of ethyl N-arylcarbamates 3 with 1-bromo-3,3-dimethyl-2-butanone or 1-bromo-3-ethyl-3-methyl-2-pentanone 4 in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) results in the one-step synthesis of 3-aryl-5tert-butyl-2(3H)-oxazolones 7 in fair to good yields (Fig. 5.2; Table 5.1, Fig. 5.3).3 This method is efficient for the preparation of bulky 5-substituted-2(3H)-oxazolones.

X

R

O

R

LiHMDS

Br

+ R Me

EtO2C N H

Me

X

DMF

O EtO

R

N O

3

5

4 DMF = dimethylformamide

R

Me

R R

base

Me

R

X O EtO

X

N

O

O

55-97%

N O 7

6 Figure 5.2

The N-(a-hydroxyphenacyl)urethanes 8 react smoothly with aromatics in concentrated sulfuric acid to give Friedel–Crafts type products 9, which are readily converted into 4-aryl-5-phenyl-2(3H)-oxazolones 10 on heating or by treatment with phosphorus pentachloride (Fig. 5.4).4 Treatment of 1,3-dihalo-2-propyl and 2,3-dichloropropyl N-arylcarbamates 11 and 14 with ammonium fluoride results in the regioselective transformation to the 2(3H)-oxazolones 12 and 15 or to the exocyclic methylene derivatives 13 and 16 depending on the temperature (Fig. 5.5).5

4

2(3H)-Oxazolones and 2(5H)-Oxazolones

TABLE 5.1. SYNTHESIS OF 3-ARYL-5-tert-BUTYL-2(3H)-OXAZOLONES FROM ETHYL N-ARYLCARBAMATES AND a-BROMO KETONESa

X

R

O

X

LiHMDS

Br

+ R Me

EtO2C N H

R

Me

O

DMF

R 3

N O 7

4 Figure 5.3

R H H H H H H H H Me a

X

% Yield

4-Cl 4-F 2,4-di-Cl 3,4-di-Cl 3,5-di-Cl 2-F, 4-Cl 3-CF3 4-MeO 2-F, 4-Cl

60 86 97 55 56 80 78 90 63

Data from Ref. 3.

Ph OH Ph

C C NHCO2R H O

Ar

ArH

Ph H2SO4

C C NHCO2R H

O

Ar

PCl5

O

NH

POCl3

O 8

9

(R=Me, Et)

10 Ar=Ph: 73% Ar=Tol: 75%

Figure 5.4

Anodic oxidation of the carbamates 17 and 23 in methanol, followed by reaction with chlorodiphenylphosphine affords the a-diphenylphosphinylcarbamates 20 and 25, from which the readily generated carbanions react with aldehydes to give the 4-phosphinyl-2-oxazolidinones 21 and 26. The removal of the diphenylphosphinyl group by a mild thermal treatment provides a route to the 2(3H)-oxazolones 22 and 27 (Fig. 5.6).6 Lead tetraacetate oxidative cyclization of the N-(1-naphthylvinyl)urethane 30, derived from 10 -acetonaphthone 28, yields 4-naphthyl-2(3H)-oxazolone 32 as the

2(3H)-Oxazolones (4-Oxazolin-2-ones)

5 CH2

Me CH2X

Bu4NF•3H2O

R N CO2CH H CH2X

O

O

N R

N R

50 ˚C

O

O

9-79%

12

11

13

R=Ph, 4-ClC6H4, 1-naphthyl, c-C6H11 X=F, Cl, Br CH2

Me CH2X

Bu4NF•3H2O

R N CO2CH2CH H X

O

N R

O

N R

r.t.

O 14

O

17-51%

16

15

R=Ph, c-C6H11 X=Cl

Figure 5.5

Et

N CO2Me H

NaH MeI

Me

−2e−

MeO

MeOH

17

N CO2Me H

65%

N CO2Me

18

Me

ClPPh2

19 Me O

Ph2P O

1. LDA 2. PhCHO

PPh2 N Me

O

N CO2Me

Ph

Me

∆

O

47%

Me

O

O 21

−2e−

N Me

96%

20

N

MeO

Me

Ph

AcOH 90%

Me

22 O

1. LDA 2. EtCHO

ClPPh2

PPh2

O

MeOH 86%

N

CO2Me

OMe

AcOH 89%

N

PPh2

62%

N

CO2Me

CO2Me

Et O

O 23

24

25

∆

N

96%

Et O

O 27

Figure 5.6

26

6

2(3H)-Oxazolones and 2(5H)-Oxazolones

major product, in addition to a rearranged product, the 1-naphthaleneacetamide 33 (Fig. 5.7).7 CO2Et Me

COMe BnNH2 o 5 A MS 89%

28

(EtOCO)2O

Pb(OAc) 4

∆ 92%

AcOH

29 O

a

N Bn

CH2

NBn

30

OEt N Bn

(AcO)3Pb

a

b

O

N Bn 45% O

31

32 b

O CH2C

CO2Et N Bn 21%

33

Figure 5.7

Treatment of the a-methoxycarbonylbenzyl carbamate 34 with diisobutylaluminum hydride (DIBAL-H), followed by dehydration of the resulting 4-hydroxy-2oxazolidinone 35 with NH4Cl gives the 5-phenyl-2(3H)-oxazolone 36 (Fig. 5.8).8 MeO2C H

O

Ph

H N

OMe

OH

DIBAL-H

O

Ph O

N

OMe

OMe O

OMe 35

34 Ph NH4Cl

O

N

OMe 19%

O

OMe 36

Figure 5.8

2(3H)-Oxazolones (4-Oxazolin-2-ones)

7

Protonation of the N-aryl-N-(3-triisopropylsilylpropargyl) carbamate 37 with trifluoromethanesulfonic acid generates a b-silylvinyl cationic intermediate 38 that is attacked by the carbamate carbonyl group (but not the aromatic ring) to give good yields of the 2(3H)-oxazolone 40 (Fig. 5.9).9 TIPS OMe

OMe

TIPS TfOH

N

TFA

N

MeO2C

MeO2C

38

37 (TIPS=triisopropylsilyl)

OMe

TIPS O

N

OMe

TIPS 90%

O

N O

O

39

40 Figure 5.9

5.1.2.2. From 2-Allyloxyoxazoles The scope of the thermal [3,3]-sigmatropic rearrangement of a series of 2-allyloxy-substituted 4,5-diphenyloxazoles 41 has been examined.10,11 These systems, on heating, undergo a facile aza-Claisen rearrangement to give 3-allyl4,5-diphenyl-2(3H)-oxazolones 42 (Fig. 5.10). In marked contrast to the thermal results, photolysis of the 2-allyloxy- or 2-benzyloxy-substituted oxazole gives rise to an isomeric mixture of 2(5H)- and 2(3H)-oxazolones, indicative of the recombination of a radical pair generated by allyl-O bond scission.

5.1.2.3. From a-Amino Acid Esters a-Amino acids serve as good precursors to 5-alkoxy-2(3H)-oxazolones 47. The compounds are synthesized by the N-chlorocarbonylation of an a-amino acid ester 45 with phosgene or the equivalent, followed by treatment with a variety of bases (Fig. 5.11; Table 5.2, Figs. 5.12, 5.13).12

8

2(3H)-Oxazolones and 2(5H)-Oxazolones

Ph

Ph

benzene-pyridine

hv

N

(8:2)

R1

Ph

R1

N

R2

O

Ph

O

41

O

R2

O

N

O

O

42

43

a: 85% b: 97% c: 100%

a: 71%

R1=R2=H

a: b: R1=H, R2=Me c: R1=R2=Me

Ph

Ph R1

hv

N

O

R2

+ 42

O 44 a: 77% b, c: 83%

a: 0% b, c: 17%

Figure 5.10

R2 R1

OR3

N H

O 45

COCl2 Na2CO3 or (CCl3O)2CO NEt3

R3O

R2 R1 O

OR3

N Cl

R2

NEt3

O

46

N R1

O O 47

Figure 5.11

5.1.2.4. From Benzoin and Isocyanates Aromatic a-ketols 48 react with (diethylamino)tributyltin to afford a mixture of (Z)- and (E)-1,2-enediol-types of bis-organostannylated compounds 49 that cyclize upon heating with phenyl isocyanate to give a 3,4,5-triaryl-2(3H)-oxazolone 50 (Fig. 5.14).13

5.1.2.5. From 1,2-Diketones Reduction of a-imino ketones 52, prepared from 1,2-diketones 51 and 1 equiv of an amine, with sodium in ether, followed by treatment with ethyl chloroformate or

2(3H)-Oxazolones (4-Oxazolin-2-ones)

9

TABLE 5.2. SYNTHESIS OF 5-ALKOXY-2(3H)-OXAZOLONES FROM a-AMINO ACID ESTERS

R1

OR3

N H

R3O

COCl2 Na2CO3

R2

N R1

O

or (CCl3O)2CO

O

R2

O

NEt3

Figure 12

47

45 R1

R2

R3

Reagentsa; b

i-Pr CH2Ph CH2Ph CH2Tol (dl)-CHMePh (R)-CHMePh (S)-CHMePh (S)-1-Phenylethyl (R)-1-Phenylethyl (S)-1-Phenylethyl 3,4-di-MeO-C6H3CH2 (1-Naphthyl)methyl (R)-1-(1-Naphthyl)ethyl CHPh2 CHPh2

H H H H H H H H H H H H H H H

Me Me (‘)-Menthyl Me Me Me i-Pr Ph (‘)-Menthyl (‘)-Menthyl Me Me Me Me (‘)-Menthyl

% Yield

A B B B B B A A B B B B B B B

82 26 76 86 76 67 98 98 69 68 33 43 60 66 62

B

95

B B B B A B A B B

76 75 67 68 62 65 95 49 8

Me

i-Pr i-Pr i-Pr Ph (R)-1-Phenylethyl (R)-1-(1-Naphthyl)ethyl CHPh2 Furfuryl Furfuryl a b

O

H

CHPh2

Me2PhC Figure 13 Me Et c-C6H11 Me Me i-Pr Me Me 4-Pentenyl

Me Me Me Me Me Me Me Et Et

A ¼ triphosgene, NEt3; B ¼ COCl2, Na2CO3. Data from Ref. 12.

Ar Ar

OH

Ar

O

Bu3SnNEt2

Ar

OSnBu3

Ar

OSnBu3

Ar

PhNCO

N Ph

O

48

49 Figure 5.14

O 50

70%

10

2(3H)-Oxazolones and 2(5H)-Oxazolones Ph

Ph

O

N R

ClCO2Et

Ph O

Ph

RNH2

Ph

O

EtOH

O

Ph N R

Ph

Na

O

Ph

54

Et2O

NaO

NaN R

Ph

CS2

51

52

Ph

53 O

N R S 55

Figure 5.15

carbon disulfide, leads to the 4,5-disubstituted-2(3H)-oxazolones 54 and the corresponding 2-thiones 55, respectively (Fig. 5.15; Table 5.3, Fig. 5.16).14,15 A one-pot, highly convergent synthetic strategy from 1,2-diketones 56 and isocyanates, has been used for the preparation of 4,5-dimethylene-2-oxazolidinones 57. Thermal Diels–Alder reactions of the N-substituted-4,5-dialkylidene-2-oxazolidinones 57 with the dienophiles 58–61 proceed stereo- and regioselectively to afford a variety of bicyclic 2(3H)-oxazolones 62–67. The regioselectivity is greatly improved by the use of Lewis acids such as TiCl4 and AlCl3, and the nitrogen atom

TABLE 5.3. CYCLIZATION OF a-IMINO KETONES TO 4,5-DIPHENYL-2(3H)-OXAZOLONES AND 2-THIONESa

Ph Ph

Ph N R

O

Na

ClCO2Et

Et2O

or CS2

Ph N R or

O

52

Ph

Ph

O

N R

O

S

54

55

Figure 5.16 R

% Yield of 54

Pr i-Pr Bu Ph Tolyl CHMePh

33 35 35 45 55 35

a

Data from Refs. 14, 15.

% Yield of 55 35 32 36 48 50 49

2(3H)-Oxazolones (4-Oxazolin-2-ones)

11

Me O

O

+ R2NCO

R1 56 Li2CO3 NEt3

18-69%

O

CO2Me

R1 CO2Me

O

N

R1

58 CO2Me

N

CO2Me

N Ph N

O

62 R1=H:

O

(R2=Ph)

Ph

O

O

O 59

N R2

O

O

R1

Ph

R2

O 63

57

R1=H, R2=Ph: 75%

56%

R1=Me: 85%

R1=Me, R2=4-ClC6H4: 79%

CO2Me

Ac

O

O 60

O N

CO2Me

O

61

TiCl 4

O

TiCl 4

N

Ph 64

R1=H

R1=H

R2=Ph

R2=Ph

Ph 66

+

+

O

O

O N

O

Ac

N

Ph

CO2Me

Ph 65 67

57

70%; 64:65 = 95:5

68%; 66:67 = 92:8 R1=Me

120 ˚C

Me O

Ph N

R2=Ph

O Me O +

O N

N Ph

O O

Ph 68

69

50%

16%

Figure 5.17

12

2(3H)-Oxazolones and 2(5H)-Oxazolones

of the 2-oxazolidinone ring appears to control the orientation of the dienophile approach. Dimerization of the dienes 57 proceeds in a highly selective manner to give only one dimeric isomer 68, in addition to the [1,5] rearranged product, 4-methyl-3-phenyl-5-vinyl-2(3H)-oxazolone 69 (Fig. 5.17).16

5.1.2.6. From b-Enaminosulfoxide The one-pot reaction of the a-(difluoromethyl)-b-sulfinylenamine 70 with trifluoroacetic anhydride in CHCl3, followed by treatment with silica gel affords 4-(difluoromethyl)-5-p-tolylthio-2(3H)-oxazolone 74 (Fig. 5.18). This reaction proceeds via a Pummerer-type rearrangement, followed by [1,3]-proton shift and the simultaneous elimination of trifluoroacetic acid and benzyl alcohol.17,18

HN Cbz

O p-Tol

S

(CF3CO)2O

p-Tol

CHF2

HN Cbz

CF3COO S

Pummerer rearrangement

CHF2

p-Tol

N S

CF3CO2

HN p-Tol

S

Cbz

CHF2 OCOCF3

71

70

Cbz

p-Tol

72 S

CHF2

silica gel

CHF2 OCOCF3

−PhCH2OH −CF3CO2H

O

NH

82%

O 74

73 Figure 5.18

5.1.2.7. From Hydroxamic Acids The reaction of N-aryl-N-(hydroxy)acylacetamides 75 with 4-nitrobenzenesulfonyl chloride (nosyl chloride) in the presence of NEt3 gives 3-aryl-5-substituted-2(3H)-oxazolones 78 via the three-membered ring a-lactams 77, which have also been proposed as intermediates in the isoxazoline–oxazoline transformation.19 A good leaving group on the nitrogen atom greatly accelerates the reaction. In the same manner, 5-alkyl-3-aryl-4-halo-2(3H)-oxazolones 80 are synthesized from the corresponding N-aryl-N-(hydroxy)-a-halo acylacetamides 79 that are prepared via halogenation of 75 (Fig. 5.19; Table 5.4, Fig. 5.20; Table 5.5, Fig. 5.21).20

2(3H)-Oxazolones (4-Oxazolin-2-ones)

O

O

X

O

4-NO2C6H4SO2Cl

O

13

X

2 NEt3

R

N

R

N

OH

O SO2

75

O

O

R

CF3SO2Cl or Br2

N

NO2 77

76

O

X

O

X

4-NO2C6H4SO2Cl

R

Y

R

X

X

2 NEt3

R

N Y

O

N

O

N

OH O 79

O 78

80

Y=Cl: 34-85% Y=Br: 61-82%

Figure 5.19

TABLE 5.4. SYNTHESIS OF 5-ALKYL-3-ARYL-2(3H)-OXAZOLONES FROM N-ARYL-N-(HYDROXY)ACYLACETAMIDESa

O

O

R

R

X N OH

4-NO2C6H4SO2Cl

X

O

N

2 NEt3

O 78

75 Figure 5.20 X

R

% Yield

H H 4-F 3-Cl 4-Cl 4-Cl 4-Cl 4-Br 3-Me 4-Me 4-Me

Et Pr Me Me Me Et Pr Me Me Me Et

58 39 69 65 80 63 39 75 75 66 42

a

Data from Ref. 20.

14

2(3H)-Oxazolones and 2(5H)-Oxazolones TABLE 5.5. SYNTHESIS OF 5-ALKYL-3-ARYL-4-HALO-2(3H)-OXAZOLONES FROM N-ARYL-N-(HYDROXY)-a-HALO ACYLACETAMIDES

O

O

R

X

Y

X

4-NO2C6H4SO2Cl

R

N Y

O

N

2 NEt3

OH

O 80

79 Figure 5.21 X

Y

R

H H 3-Cl 4-F 4-F 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Br 4-Br

Cl Br Cl Cl Br Cl Cl Cl Cl Br Br Cl Br

Me Me Me Me Me Me Et Pr i-Pr Me Et Me Me

a

% Yield 37 40 73 53 (unstable) 56 51 60 57 28 40 60 (unstable)

Data from Ref. 20.

5.1.2.8. From 2-Oxazolidinones Both 4-hydroxy- and 4-methoxy-2-oxazolidinones are routinely employed as good synthetic precursors for 2(3H)-oxazolones. Anodic oxidation of 2-oxazolidinones 81 in methanol using Et4NþOTs as a supporting electrolyte yields the 4-methoxylated derivatives 82 that undergo a facile elimination of methanol to give 2(3H)-oxazolones such as 83 and 84.21 An improved procedure for the preparation of 2(3H)-oxazolone 1 involves refluxing 82 with an equimolar amount of acetic anhydride in acetic acid (Fig. 5.22).22 Treatment of 4-methoxy-2-oxazolidinone 86 with indolylmagnesium bromide 87, followed by N-protection with a tert-butoxycarbonyl (Boc) group affords N,N0 di-Boc-4-(3-indolyl)-2-oxazolidinone 88. Subsequent treatment with N-bromosuccinimide (NBS) in the presence of azobisisobutyronitrile (AIBN) followed by electrochemical reduction yields the protected 4-(3-indolyl)-2(3H)-oxazolone 90 (Fig. 5.23). The Boc groups are easily removed by pyrolysis.23,24

2(3H)-Oxazolones (4-Oxazolin-2-ones)

15

OMe O

−2e−

N R

R=Me, Et

O

MeOH 86%

O

N R

O

−MeOH

O

81

O

83 AcOH (excess)

R=H

Ac2O (1 equiv)

N Ac

O

50%

O

R=Me: 80% R=Et: 75%

O

82 Ac2O

N R

NH O

84

1 Figure 5.22

1.

OMe −

O

NH

Boc N

Br

N MgBr

87

BF3•OEt2

−2e

O

NBS

N Boc

O

NH

MeOH

64% 2 steps

O

85

O

86

88

Boc

N Boc O 89

H N

N

electrochemical reduction

O AIBN 58%

2. (Boc)2O

O

72%

Boc N

160 ˚C

O

O

N Boc

NH

95%

O

O

91

90 Figure 5.23

The addition of hydrazine to diphenylvinylene carbonate 92 quantitatively affords a 1:1 mixture of perhydro-1,3,4-oxadiazin-2-one 93 and 2-oxazolidinone 94 derivatives, both of which are smoothly dehydrated with P2O5 to afford 1,3,4oxadiazin-2-one 95 and 3-amino-2(3H)-oxazolone 96 (Fig. 5.24), respectively.25 Addition of primary amines to diphenylvinylene carbonate results in exclusive formation of 3-alkyl-2(3H)-oxazolones, previously investigated as amino protecting groups in peptide synthesis.26,27

16

2(3H)-Oxazolones and 2(5H)-Oxazolones Ph

O

Ph

N O H H

O

Ph

O

Ph

N

O 46%

Ph

Ph

93

N2H4

O

NH

95

P2O5

+

O Ph O

92

+ Ph

Ph OH N NH2

O

NH

Ph

O

N NH2

45%

O

O

96

94

Figure 5.24

5.1.2.9. From Oximes The reaction of aliphatic and aromatic ketone oximes 97 with a dialkyl carbonate 98 in the presence of K2CO3 at 180–190
C yields 3-alkyl-4,5-disubstituted-2(3H)oxazolones 104 in 22– 48% yields. Mechanistically, it is proposed that N-alkylation of the initially formed oxime O-carbonate 99 yields 100, which affords the enamine 101 in the presence of base. A [3,3] sigmatropic rearrangement ensues to produce 102, which then cyclizes to 104. In cases where 97 contains two methylene groups in N bond, one of which is benzylic, the above reaction sequence is proximity to the C regioselective for the benzylic methylene group (Fig. 5.25; Table 5.6, Fig. 5.26).28 N OH C R2 R1 97

N

K2CO3

+ R3O

C

autoclave 180-190 ˚C

OR3

R1

OR3

O

3

R

(R3O)2CO

R2

O

C R1

99

O

N

OCO2R3 O OR3 base

R2

O

100

98

R3 R2

N C

O O CH

OR3

sigmatropic

rearrangement

R3 R2

N C

OR3

O O

C

R1

R1

101

102

R1 H

R2

base

O

N

H

Figure 5.25

R1

R2 R3

N R3

O

O

O

103

104

2(3H)-Oxazolones (4-Oxazolin-2-ones)

17

TABLE 5.6. 3-ALKYL-4,5-DISUBSTITUTED-2(3H)-OXAZOLONES FROM OXIMES AND DIALKYLCARBONATESa

R1 R3O

N OH

OR3

K2CO3

+

C R2

R2 N R3

O autoclave 180-190 ˚C

O

R1 97

O 104

98 Figure 5.26

R1

R2

R3

Ph Pr Me Et Ph

Me Me Me Me Me Me Me Et Et

 (CH2)4  (CH2)5 Me Et Ph Ph Ph  (CH2)4 Ph a

Me

%Yield 48 22 28 22 31 37 37 31 35

Data from Ref. 28.

5.1.2.10. From 2,4-Thiazolidinediones The intramolecular base-induced ring transformation of 3-phenacyl-2,4-thiazolidinediones 105 with sodium hydroxide or triethylamine smoothly proceeds to give 5-aryl-2(3H)-oxazolones 108 (Fig. 5.27).29 R

O NEt3 or NaOH

S

O

N

NH

R O

O

O

108

105

O S

R

N R O

R=Ph: 71% R=4-BrC6H4: 52%

N

S O

O

107

106 Figure 5.27

O O

18

2(3H)-Oxazolones and 2(5H)-Oxazolones

Similarly, 6-methyl-3-phenacyl-1,3-oxazine-2,4(3H)-diones 110 are transformed into 5-aryl-2(3H)-oxazolones 108 under phase-transfer catalysis (Fig. 5.28).30 O

R

K2CO3

HN O

O

Et3N+CH2Ph Cl−

O

K2CO3

N O

Me

Bu4N+ HSO4

O

O

Me

110

109 + RCOCH2X

R

N O

O

O O

111

R

R

O

Me

N O

O

Me O

NH

O

O

112

108 R=Ph: 45% R=4-MeC6H4: 35% R=4-ClC6H4: 36% R=4-BrC6H4: 37%

Figure 5.28

5.1.2.11. From 1,2,4-Triazolium Salts Treatment of the phenacyliminium salt 114, derived from 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine 113 and phenacyl bromide, with 2 equiv of triethylamine gives rise to the 2-iminooxazoline 118 by way of the in situ generated intermediary N-ylides 115. Acidic hydrolysis affords the 3-(2-pyrimidinyl)-2(3H)-oxazolone 119.31,32 Similarly, the [1,2,4]triazolo[1,5-a]pyridinium salt 121 affords 5-phenyl-3-(2pyridinyl)-2(3H)-oxazolone 122 (Fig. 5.29).33

5.1.2.12. Via Three Component Condensation The 2(3H)-oxazolones may be synthesized by the direct condensation of three components. Thus, a mixture of a-halo ketones 123, carbon dioxide, and primary amines can be heated at 80–100
C under gas pressure of 50 kg/cm2 to result in the direct formation of 3-substituted 2-oxazolones 124 in 4–25% yield (Fig. 5.30).34

2(3H)-Oxazolones (4-Oxazolin-2-ones)

N N Me

Me

Me

Me

N

N 113

NEt3

N N

BrCH2COPh

Br N 114 CH2COPh

NEt3

N N

(1.1 equiv)

N

Me

19

Me

N

115

CHCOPh

(2.3 equiv)

35%

64%

Me

Me

Ph N Me

Me NEt3

N N

N

N

O 73%

Me

H

N

N

N

NH

N

(1.1 equiv)

C Me

CH

N

N

O

CH2COPh

Ph 118 H+

116

117

70%

Me Ph N Me

N

N

O O

119 Ph N N

N N

N

N

N

Br CH2COPh

N

O

56%

O

121

120

122 Figure 5.29

CO2 (50 kg/cm2)

R1

H C C R2 O Cl

R2

R1

R3NH2 MeCN-NEt3

N R3

O O

123

124 Figure 5.30

CN

R1=Me, R2=H, R3=Pr: 5% R1=Me, R2=H, R3=Ph: 4% R1=R2=Me, R3=Pr: 25% R1=Ph, R2=H, R3=Pr: 6%

20

2(3H)-Oxazolones and 2(5H)-Oxazolones

Direct condensation of propargyl alcohols 125 (Fig. 5.31), carbon dioxide, and propylamine can be realized by Ru3(CO)12 catalysis at 80
C under CO2 pressure of 50 kg/cm2. The reaction mechanism is rationalized as shown below. When diethylamine is used in place of a primary amine, 2-oxoalkyl N,N-diethylcarbamates are isolated in moderate yields.35

H

R CO2 (50 kg/cm2) PrNH2

R HC C C OH H

Ru

cat. Ru3(CO)12

C

R

O

HC

O

O PrNH3

CH2 O

O

OH Me

R Pr

N CO2CHCMe H O

R O

N Pr O

O 129

Me

−H2O

N Pr

O

O 128

−Ru

O

127

R

R PrNH2

−PrNH2

O 126

125

PrNH3

Ru

O

130

131 R=H: 13% R=Me: 28%

Figure 5.31

5.1.2.13. Miscellaneous The 1,3-dipolar cycloaddition of a-keto carbenoids to the polar double bond of heterocumulenes provides a direct access to five-membered heterocycles. The reaction of a-diazo ketones 132 with phenyl isocyanate in the presence of a Rh2(OAc)4 catalyst affords the 1,3-cycloadduct, 3-phenyl-2(3H)-oxazolones 133 (Fig. 5.32).36

R C CH O N2

PhNCO

O

O

or R C CH

N Ph

R C CH

O 132

R

R C C ML

Rh2(OAc) 4 (0.01 equiv)

O α-keto carbenoid

O 133 R=Ph: 43% R=CO2Et: 37%

Figure 5.32

2(3H)-Oxazolones (4-Oxazolin-2-ones)

21

Heating a-hydroxy amides 135 in xylene with the cumulated phosphorus ylide 134 gives the 2(3H)-oxazolones 140. The reaction proceeds via an addition– cyclization–intermolecular-Wittig olefination sequence, which implies three different types of phosphorus ylides, 134, 136, and 137, respectively, of increasing ‘‘ylide activity’’ (Fig. 5.33; Table 5.7, Figs. 5.34, 5.35). 37 Ph3P

C C O O

+ O R1

N H

OH

R1

R2

cat. PhCO2H

134

R1

R2

NH

PPh3

O

O

CH2 PPh3 +

N R2

O O

136

135

O

137

R1

CH2

R1

O

N R2

O

138

Me N R2

O

O

139

140 Figure 5.33

TABLE 5.7. 2(3H)-OXAZOLONES FROM a-HYDROXY AMIDES AND PHOSPHORUS YLIDE 134a

R1

O Ph3P

C C O +

R1

N H

OH

Me

cat. PhCO2H

R2

N R2

O O

135

134

140

Figure 5.34 1

R2

% Yield

H Me Me

CH2Ph CH2Ph CHMePh

51 81 40

R

O Me

CH2 Ph Ph Ph Ph a

Data from Ref. 37.

Figure 5.35 c-C6H11 CH2Ph CHMePh 4-MeOC6H4

O 48 71 40 50

22

2(3H)-Oxazolones and 2(5H)-Oxazolones

The condensation of a 2-aminobenzoxazole 141 with a-bromo ketones 142 gives 2(3H)-oxazolones 148 on heating in ethanol. Isotope labeling studies with 18O have shown that the additional oxygen that is incorporated into the ring is derived from the solvent, ethanol (Fig. 5.36).38 Cl

N NH2 R1

O 141

R1

R2

EtOH

+ R1

H

Br Cl

Cl

O

N

R2

N

R2 NH

NH2 O

O Br

O

O

144

143 142 R1 Cl

R

R2 Cl

OH

N

1

N

O

NH

O NH2

O 145

146 R1

R2

EtOH

Cl

N

R2

R2

R1

O

N

Cl

Br−

O

O OEt

O

147

HO 148

R1=4-MeSO2C6H4, R2=Ph: 26% R1=4-MeOC6H4, R2=Ph: 13% 1=R2=Ph: 31% R

R1=Ph, R2=4-MeSO2C6H4: 24% Figure 5.36

5.1.3.

Reactions

5.1.3.1. Hydrogenation Certain erythro-2-amino alcohols such as ()-ephedrine 150, ()-N-methylephedrine 151 and ()-conhydrine 153 are synthesized with complete stereochemical control by the catalytic hydrogenation of the corresponding 4,5-disubstituted 2(3H)-oxazolone derivatives 22 and 27, followed by ring opening (Fig. 5.37).6

2(3H)-Oxazolones (4-Oxazolin-2-ones) Ph

Me

HO

HN Me

23

(±)-ephedrine Ph

Me

Ph

1 atm H2

Me

KOH

PtO2

O

N Me O

150

95%

O

AcOH 79%

N Me 70%

O

LiAlH4

149

22

Ph

Me

HO

NMe2

(±)-N-methylephedrine

151 1 atm H2 PtO2

N

Et O

O

KOH

N

AcOH 95%

Et

91%

O

(±)-conhydrine N H

Et HO

O 27

152

153

Figure 5.37

Condensation of benzyl glycinate p-toluenesulfonate salt with 4,5-diphenyl-1,3dioxol-2-one affords 154, which can be converted to the 4,5-diphenyl-3-substituted2(3H)-oxazolones 155 by sequential treatment with an aldehyde/LiHMDS followed by diaminosulfur trifluoride (DAST). Hydrogenolysis then affords the b-fluoro-aamino acids 156 in excellent yields without any concomitant cleavage of the carbon–fluorine bond (Fig. 5.38).39 Ph

Ph

Ph

O

N

CO2Bn

Ph

O

N O

O 154

R

Pd-C H2 (45 psi)

CO2Bn

H2N

CO2H

R

F

F

155

156

R=Me: 41% R=Et: 40% R=Pr: 52% R=i-Bu: 45%

R=Me: 99% R=Et: 88% R=Pr: 89% R=i-Bu: 91%

Figure 5.38

5.1.3.2. Electrophilic Additions A 3-acyl-4,5-unsubstituted-2(3H)-oxazolone 157 smoothly undergoes electrophilic addition with Br2 (or NBS) and PhSeCl in methanol to give trans-5-bromo-4methoxy- and trans-4-methoxy-5-phenylselenenyl-2-oxazolidinones 158, respectively, with full regio- and trans-selectivity (Fig. 5.39). Both substituents thus

24

2(3H)-Oxazolones and 2(5H)-Oxazolones

introduced are sufficiently reactive to be replaced in a stepwise manner under ionic and radical conditions, indicative of the versatility of the 2(3H)-oxazolone heterocycle as a building block for the stereodefined construction of 2-amino alcohols.40–46 X

Y

Br2 or PhSeCl MeOH

O

N

R

O

O

O

N

X=Br or PhSe Y=OMe

O

O

157

R

158 Figure 5.39

Optically active 3-(2-exo-alkoxy-1-apocamphanecarbonyl)-2(3H)-oxazolones 159 can be used successfully for the preparation of the versatile chiral synthons 161 and 163 (Fig. 5.40). The reactions proceed with excellent diastereoselectivity [>96% diastereomeric excess (de)] and interestingly with a thoroughly reversed enantiomeric selectivity.40 This finding is rationalized by assuming that selenenium ions approach the less hindered diastereotopic face in the most predominant conformer to give thermodynamically favored intermediates, whereas coordination of bromine with the oxygen atoms of the 2-alkoxy substituents (see Fig. 5.41; Table 5.8, Fig. 5.42 and Table 5.9, Figs. 5.43 and 5.44) accelerates the attack from the alkoxy substituent site. The versatility of the synthons 161 and 163 is demonstrated by the chiral synthesis of typical hydroxy-amino acids such as 3-hydroxyglutamic acid 168,41,42 statine 165,41 AHPBA 164,43 AHMHA 166,43 and others44 as well as the bicyclic lactone 172.45 Br

Br2

OMe

OMe

MeC(OMe)3

O

4

O

R1

O

O 5

O

N R2

NH O 161

160

N O

O

R1

R2

159 PhSe

OMe

OMe

PhSeCl MeOH

O

N O

O O

R1

NH

R2

162 Figure 5.40

O 163

2(3H)-Oxazolones (4-Oxazolin-2-ones)

25

Figure 5.41. Proposed electrophilic attack on the 2-oxazolone moiety. TABLE 5.8. DIASTEREOSELECTIVE METHOXYBROMINATION OF 3-ACYL-2(3H)-OXAZOLONES 159a

5

Br

4

OMe

Br2

O

N

MeC(OMe)3

2

O

R1

O

R

O

N O

O

R1

R2

160

159 Figure 5.42 R1 (exo)

R2 (endo) O

OMe OBu OCH2CH2OMe OCH2OEt H Me a

H H H H OMe H

Temp (
C) 78 78 78 78 78 78 78

% Yield (% de) 58 (80) 89 (85) 85 (85) 79 (89) 79 (96) 36 (0) 80 (0)

Data from Ref. 40.

The (þ)- and ()-4,5-dialkoxy-2-oxazolidinones 173 and 174 prepared through the 5-bromo-4-methoxy- derivatives serve as reliable chiral synthons for the preparation of a wide variety of optically active a-amino acids 176 and a-amino aldehydes 177 (Fig. 5.45).46

5.1.3.3. Radical Additions 5.1.3.3.1.

Attack of Alkyl Radicals

The 4,5-olefinic moiety of 2(3H)-oxazolones functions well as a radical acceptor in a variety of radical reactions. The RuCl2(PPh3)3 catalyzed addition of polyhalomethanes, CCl4 and CBrCl3, to 3-acetyl-2(3H)-oxazolone 84 leads to the exclusive formation of the trans-4-halo-5(trichloromethyl)-3-acetyl-2-oxazolidinones 178.47 In the presence of a radical

26

2(3H)-Oxazolones and 2(5H)-Oxazolones TABLE 5.9. DIASTEREOSELECTIVE METHOXYSELENYLATION OF 3-ACYL-2(3H)-OXAZOLONES 159a

5

PhSe

4

OMe

PhSeCl

O

N R1

O

O

O

MeOH

R2

N R1

O

O

R2

162

159 Figure 5.43 R1 (exo)

Temp (
C)

R2 (endo) O

OMe OBu OCH2CH2OMe OCH2CH2OMe H Me a

% Yield (% de)

0 0 0 0 20 0 0

H H H H OMe H

52 (71) 83 (60) 76 (85) 94 (90) 82 (96) 94 (0) 80 (0)

Data from Ref. 40.

Asp Pepstatin

Amastatin

Val Val

Val

OC HO2C HO

Bestatin

HO

166

NH2 O

165

HO2C OMe HO

NH

O

NH O 161

O 163

NH2

Ala

statine

statine

CO2H

HO

HN

OMe

AHMHA HO2C

Val

HO

NH2 164 AHPBA

Leu OC

R

NH2

167 cyclohexylstatine Me(CH2)12 OH

168 (2S,3R)-3-hydroxyglutamic acid

HO

OH

NH

169 dihydrosphingosine

n-C6H13 O

OH

171

NHR O Ph 170 OH

O O OH OBz OAc taxol Figure 5.44

NH2

O O N 172 H (−)-Geissman-Waiss lactone

2(3H)-Oxazolones (4-Oxazolin-2-ones) R1O

OR2

R1O

R"2CuLi

R3

R3

BF3•OEt2

O

PDC

NH

O

O 173 O

R1O

N Boc

OR2

O

HO2C N Boc H 176

Pd-C H2

O 175

NH O 1

27

R1=Bn

R3

1

R =Me, Bn R2=Me, t-Bu R3=Bu, i-Pr, t-Bu, Ph, allyl, vinyl

NH O 174

OHC N Boc H 177

Figure 5.45

initiator, benzoyl peroxide (BPO), free-radical telomerization of 84 with a chaintransfer agent, CCl4, proceeds smoothly at 80
C to give the polyfunctional telomers 179 with high trans- and head-to-tail selectivity.48,49 The Ru(II)-catalyzed addition of polyhalomethyls to 3-(2-exo-alkoxy-1-apocamphanecarbonyl)-2(3H)oxazolone 180 gives a 1:1 mixture of trans-stereoisomers 181 and 182 with no diastereoselectivity.47 This result is in sharp contrast to the intramolecular radical cyclization of the derivative with a pendant trichloroacetyl group 185, which proceeds in excellent diastereoselectivity (>99% de) and high yield.50 The straightforward manipulation of the resulting 12-membered macrolides 186 yield

Cl3C

Cl RuCl2(PPh3)3

O

N Ac

Cl3C

BPO

O

N Ac

CCl4

CCl4 or CBrCl3

n N Ac

O

O

O

O

178a: X=Cl 178b: X=Br

84

179

Cl3C

Cl

(n=1,2,3)

X Cl3C

O

O

O CXCl3

NH2 183

181

N

+ (X=Cl, Br)

O

HO

O 40%

RuCl2(PPh3)3

O

CO2H

N

O 180

O

Cl3C

X Cl2HC

O

CO2H

N O

O

HO

O

NH2

41% 182

Figure 5.46

184

28

2(3H)-Oxazolones and 2(5H)-Oxazolones

Figure 5.47

optically active b-hydroxy-a-amino acids including N-tert-Boc-2,2-difluorostatine methyl ester 187 (Figs. 5.46, 5.47). This methodology can be successfully applied to a chiral synthesis of the key amino acid components with three contiguous chiral centers found in cyclosporins (MeBmt, 190) 51 and bleomycins 191 (Fig. 5.48).52 O O Ru(II)

O

N O

Cl O

O

O

(TMS)3SiH

R

OMe O

Cl O

R O

N O

188

O 189

R=Me: 77% R=CH2OBn: 75% R=2-butenyl: 56% R=2-butenyl

R=Me, CH2OBn

Me

Me HN Me

Me

CO2H HO2C OH

NH2 OH

190

191

MeBmt (in cyclosporin)

(in bleomycin)

Figure 5.48

2(3H)-Oxazolones (4-Oxazolin-2-ones)

29

Other examples include the intramolecular radical cyclization of 3-bromoalkyl2(3H)-oxazolones 192 and 196 with tributyltin hydride/azobisisobutyronitrile to give the pyrrolooxazolidinones 194, 198, and 199. The 2,5-disubstituted pyrrolidine derivatives 195 are produced enantioselectively (Fig. 5.49).53,54

H Bu3SnH

R

AIBN

O

N O

Br

∆

>>

N

H

R

O

R

O

192

193A

H O

O

N

R O 194

193B

R=Me: 72% R=CH2OTBDPS: 78% R=Bu: 69% R=4-MeOC6H4CH2: 69% R=1-butenyl: 76%

OH

R

N

O

N H 195

Bu3SnH AIBN

O

N O

Br R 196

Me

∆

Me

R

R

H O

Me N

<

N

H

O

O

O

197A

197B Me

Me

H O

H N

+ O

N

R

R

O

O 198 R=H R=Me

199 1 : 2.1 1 : 2.4

Figure 5.49

In a similar manner, intramolecular cyclization of the O-stannyl ketyl derivatives 201 and 206, generated from the oxazolyl aldehydes 200 and 205, provides a facile method for the chiral synthesis of 3-hydroxy-2-(hydroxymethyl)5-substituted-pyrrolidines 202 and 203 and the piperidine analogues 207 and 208 that can be successfully transformed into naturally occurring amino alcohols, (þ)-bulgecinine 204 and ()-desoxoprosopinine 209, respectively (Fig. 5.50).55,56

30

2(3H)-Oxazolones and 2(5H)-Oxazolones OX

Bu3SnH

R

AIBN

O

N

∆

CHO

H

200

> O

O

CH2OBn

O

R

OX N

N H

201A OH α

H O

+ O

201B

OH β

H

N

O

O

HO

N CH2OBn

CH2OBn O 202

OH

O

2:1 83%

CO2H

N H 204

203

(+)-bulgecinine OX

Bu3SnH

O

N

R

AIBN

CHO

∆

O

R H O

R

206A

205 HO H α

>

N O

H

XO O

N O

206B

HO β H

HO (R=1-butenyl)

O

+ O

N R

O

1:2

207

N R

O

OH

C12H25

209

208

R=Me: 85% R=1-butenyl: 83%

N H

(−)-desoxoprosopinine Figure 5.50

5.1.3.3.2.

Attack of Alkenyl Radicals

Treatment of the alkenyl bromides 210 with tributyltin hydride in the presence of AIBN involves an intramolecular radical addition to the 2(3H)-oxazolone moiety, resulting in the diastereoselective formation of the oxazolidinopiperidines 211. These are readily converted to the protected 2,6-disubstituted 3-hydroxypiperidine derivatives 212 (Fig. 5.51).57 Hudlicky and co-workers58,59 reported a stepwise radical cyclization approach for the preparation of the complete morphinan ring skeleton 216 (Fig. 5.52). One of the key steps involves the intramolecular radical cyclization of cyclohexenyl

2(3H)-Oxazolones (4-Oxazolin-2-ones)

O

N O

HO H

H

Bu3SnH AIBN

Br

31

O

∆

R

O

N R

O

R

O

211

210

N

212

R = Me: 72%

O : 52%

R = CH2CH2O Figure 5.51

radicals, generated from the vinylic bromide 213, to the 2(3H)-oxazolone ring, giving rise to a 1 : 2 mixture of the isomeric isoquinoline derivatives 214 and 215 in excellent combined yield. The lack of selectivity in the ring closure was attributed to the lack of a significant steric effect by the distant acetonide group (Fig. 5.52).

O

O Br O

Bu3SnH AIBN

N

∆

O O O

213

O

H

O

H +

O

O

N O

1:2 89%

N O 215

214

MeO OH O H

NMe

O 216 morphinan skeleton Figure 5.52

32

2(3H)-Oxazolones and 2(5H)-Oxazolones

5.1.3.3.3.

Polymers

The 2(3H)-oxazolone homopolymer 217 and the 2(3H)-oxazolone copolymer 219 with a carbon–carbon bond backbone structure are readily obtained by heating a 3-acyl-2(3H)-oxazolone alone or with styrene, respectively, at 70
C in the presence of BPO with the exclusion of air.48,49,60 The N-acetyl polymers serve as regioselective and chemoselective acylating reagents for amines and alcohols (Fig. 5.53).60–63

O

N

n

R′

BPO

BPO

O

R

N

O

R

N

X n R

R′-X

O

O

O

O

O

157

217 (n=30-50)

218 (n=1,2,3)

styrene BPO

(CHCH2)

1

O

Ph

O

N O

3

R

O

n

219 Figure 5.53

5.1.3.4. Pericyclic Additions 5.1.3.4.1.

[4þ2] Cycloadditions

The 3-acyl-2(3H)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes.64,65 Thus, the thermal reaction of 3-acetyl-2(3H)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels–Alder reactions of 3-(2-exo-alkoxy-1-apocamphanecarbonyl)-2(3H)-oxazolones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries.66–71 The conformationally rigid ‘‘roofed’’ structures play a crucial role in affording excellent chiral induction (Fig. 5.54). The thermal [4 þ 2] cycloaddition of 3-acetyl-2(3H)-oxazolone 84 to the reactive dienes, o-quinodimethane 224 and isobenzofuran 226, generated from benzocyclobutane and 1-ethoxydihydroisobenzofuran, respectively, proceeds

2(3H)-Oxazolones (4-Oxazolin-2-ones) Me

Me

Me

Me

Me

Me 220

33

Me Me

Me

Me

O N

R O

N

R

139 ˚C

72% de

O O

221

O

O

Me

Me

Me

157 Me

Me

O

N R

R= OR'

94% de

O O

223

Me 222

Figure 5.54

O O

N Ac + 230 ˚C

O

90%

O

98%

N

O

Ac 84

224

225 O

84 +

O

O 60 ˚C

N Ac

226

endo only

227 Figure 5.55

smoothly to afford the polycyclic 2,3-diheterotetrahydronaphthalene derivatives 225 and 227 (Fig. 5.55).72 The thermal cycloaddition of 3-acyl-2(3H)-oxazolones 157 to dialkyl azodicarboxylates 228 proceeds smoothly under mild conditions (at 80
C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist: neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives trans-5-hydrazino-4-methoxy-2-oxazolidinone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56; Table 5.10, Fig. 5.57).73,74

34

2(3H)-Oxazolones and 2(5H)-Oxazolones

O

N COR O 157

O

+

CO2R′ O

N N CO2R′ H

N

OMe

N

O

∆

N CO2R′

CO2R′ N

N

O

COR

N CO2R′

O OR′

COR

229

232

228

OR′

N O

N CO2R′

N

N CO2R′

O COR

O

N

N

O

R′′

O

O

R′′

OR′

HO2C NH2

COR

230

O O

234

233

231

NH

Figure 5.56

TABLE 5.10. DIASTEREOSELECTIVE [4þ2] CYCLOADDITION OF AZODICARBOXYLATES TO 2(3H)-OXAZOLONESa

O

CO2R2

N

N

O O

O

OR1

O N

+ benzene ∆

N CO2R2 N CO2R2

O

N

CO2R2 O

N

N

O

O OR2 +

O

O

R1O

R1O A

N OR2

B

Figure 5.57 R1 Me Me Pr Pr CH2CMe3 CH2CMe3 a

R2 Me i-Pr i-Pr Bn i-Pr Bn

Data from Refs. 73, 74.

Time (h) 6 12 12 6 19 18

% Yield

A:B

% de

83 93 76 86 85 93

34:66 24:76 22:78 18:82 15:85 14:86

32 52 56 64 70 72

2(3H)-Oxazolones (4-Oxazolin-2-ones)

35

The ene-reaction, which is mechanistically related to the Diels–Alder reaction, has also been reported. The thermal addition of 3-tert-butoxycarbonyl-2(3H)oxazolone 236 to 2,20 -biindole 235 affords 4-(2,20 -biindol-3-yl)-2-oxazolidinone 237, probably via the indoline derivative. The product is further converted to the fused aromatic compound 238 by bromination with NBS and AIBN, followed by dehydrobromination (Fig. 5.58).23,24

N H

N H 235

Boc N

(Boc)2O

+ O

Boc N

∆ 40%

94%

O

N Boc

N Boc O O 237

236 H N

H N

NBS AIBN ∆ 32%

O

N Boc O 238

Figure 5.58

5.1.3.4.2.

[3þ2] Cycloaddition

3-Acetyl-2(3H)-oxazolone 84 serves as a good 1,3-dipolarophile in the [3þ2] cycloaddition to N-alkyl-a-phenylnitrones 239, giving a mixture of the four possible isomers 240–243, but with the predominant formation of the exo-syn adduct 240 (Fig. 5.59). Diastereoselective cycloadditions proceed when mixtures of optically active 3-(2-exo-alkoxy-1-apocamphanecarbonyl)-2(3H)-oxazolones and N-benzyl- and N-tert-butyl-a-phenylnitrones are heated at 110
C.75 5.1.3.4.3.

[2þ2] Cycloaddition

The photocycloaddition of 3-acetyl-2(3H)-oxazolone 84 with 9,10-phenanthrenequinone 244 gives the spirooxetane 245 regioselectively as a major cycloadduct. Irradiation of 3,4,5-trisubstituted-2(3H)-oxazolones 247 in the presence of 244 results in the predominant formation of dioxane derivatives 248. When duroquinone 249 is irradiated in the presence of the 3,4,5-trisubstituted-2(3H)-oxazolone 247a,

36

2(3H)-Oxazolones and 2(5H)-Oxazolones R N O H O O

R H N Ph O H + H N Ac O N

Ph H H

+

Ac

N Ac O O 84 +

R

240

241

exo-syn

endo-syn

∆

N O Ph 239

R=PhCH2, t-Bu

O

R H Ph H

R Ph H

N O H O

N O H

+

N Ac

O

N Ac

O

O

242

243

exo-anti

endo-anti

Figure 5.59

the initially formed, photochemically labile 2,5-cyclohexadienones 250 rearrange to the spirooxetanes 251 (Fig. 5.60).76 Acetone-sensitized [2þ2]-photocycloaddition of 2(3H)-oxazolones 247a to maleic anhydride and dimethylmaleic anhydride gives the corresponding anticyclobutane cycloadducts 253 as the major products. Similar photoreaction of 2(3H)-oxazolones with 1,6-anhydro-4-O-benzyl-2,3-dideoxy-b-D-erythro-2-hexenopyranose 254 results in the exclusive formation of the anti-cyclobutane-type adduct 255 (Fig. 5.61).77

5.1.3.5. C-Substitution The Friedel–Crafts type acylation of 4-methyl-2(3H)-oxazolone 256 with acyl chlorides in the presence of AlCl3 proceeds smoothly to give the 5-acyl-4-methyl2(3H)-oxazolones 257 (Fig. 5.62).78 Treatment of 3-trimethylsilylethoxymethyl(SEM)-2(3H)-oxazolone 258 with tert-BuLi at 78
C, followed by the addition of tributyltin chloride gives the stannyloxazolones 259. Cross-coupling of 259 with 2-formyl-3-iodoindole in the presence of Pd(PPh3)4 catalyst affords a 1 : 1 mixture of isomeric 4- and 5-(3-indolyl)-2(3H)-oxazolones 260. These compounds can be further transformed into the tetracyclic carbazoles 262 (Fig. 5.63).79 The 5-methyl-2(3H)-oxazolone sulfonamide derivatives 265 are obtained from the sulfonamides 263 via bromination and subsequent Stille coupling reaction with tetramethyltin in the presence of palladium catalyst (Fig. 5.64).80

2(3H)-Oxazolones (4-Oxazolin-2-ones)

37

O O

244

O Ac

hv

+ O

O +

N

N Ac

O

O

O

O

N Ac

O

O

O 84

R1

246

60%

12%

R1

O

244 +

245

N

R2

O

hv

2 R1 R N

R1=Me, R2=Ac: 37% O

O O

R1

R1=Ph, R2=Ac: 77% R1=R2=Ph: 98%

O

248

247 O Me

Me Me

Me

O

O 249

Me Me R1 Ac N

O hv

+ R1

R1

O

Me Me

R1

O

hv

O

O

Me

Me

O

Me Me R1

O O

N Ac O 247a

R1 N Ac

250 (Photochemically labile)

251 R1=Me:

6%

R1=Ph: 30% Figure 5.60

38

2(3H)-Oxazolones and 2(5H)-Oxazolones R1

R1

O

R1 R2

R2 N Ac +

O

O

O

O N

R2 O

Ac

O

247a

O

O

hv

R1 R2 O 253

252

R1=R2=H:

43%

R1=H, R2=Me: 56% (syn: 16%; anti: 40%) R1=R2=Me: 43% O hv

247a R1 = H + O

Ac N

OBn

O

OBn

O

37% (anti only) O 254

O

255 Figure 5.61

Me

ROC

Me

1. AlCl 3 2. RCOCl

O

NH

O

O

NH

RCO = 4-(1H-imidazol-1-yl)carbonyl, benzoyl, pentanoyl, (4-pyridinyl)carbonyl

O

256

257 Figure 5.62

5.1.3.6. N-Substitution 5.1.3.6.1.

N-Acylation and N-Alkoxycarbonylation

The parent 2(3H)-oxazolone moiety functions as a bifunctional leaving group when carboxyl groups are activated for acylations and condensations, similar to other five- and six-membered heterocycles such as imidazole, triazole, and 2-pyridinethiol. The excellent leaving ability of a 2(3H)-oxazolone moiety has led to the development of versatile reagents.81 Thus, 3-acyl- and 3-alkoxycarbonyl2(3H)-oxazolones serve as ‘‘ready-to-use’’-type agents for the regioselective and chemoselective N-protection of amino alcohols, amino phenols and polyamines.60,61 The 2-benzoxazolinone moiety is also effective for carboxy-activation as a comparable leaving group. In contrast, the saturated 2-oxazolidinone skeleton fails to show such a high leaving ability.62 Regioselective acylation of the primary

2(3H)-Oxazolones (4-Oxazolin-2-ones)

39 H N

OHC SnBu3

1. t-BuLi 2. Bu3SnCl

O

N

2-formyl-3-iodoindole

SEM

O

N

SEM

Y

Pd(PPh3)4

O

O 258

X O

259

260 X=N-SEM, Y=O: 33% X=O, Y=N-SEM: 29%

SEM = 2-(trimethylsilyl)ethoxymethyl Z

Z

Z

O

Z O

N HC

TBAF THF (Z=MOM)

C

Y

Me

or t-BuOK t-BuOH-THF (3:1) (Z=SO2Ph)

X O

N

Y

X O 262

261 MOM = methoxymethyl

Z=MOM: X=N-SEM, Y=O: 80% X=O, Y=N-SEM: 82% Z=SO2Ph: X=N-SEM, Y=O: 24% X=O, Y=N-SEM: 11% Figure 5.63

O

CHCl3

N R1 O

Me4Sn Pd(OAc) 2

Br

P(o-tolyl)3 NEt3, DMF

N R1

O

Me N R1

O O

O 263

O S NBn2

O S NBn2

Br2

O

O

O

O S NBn2

264

265 R1=C6H5: 71% R1=4-FC6H4: 40% R1=3-MeC6H4: 79% R1=4-MeC6H4: 37% R1=3,4-di-Cl-C6H3: 53%

Figure 5.64

40

2(3H)-Oxazolones and 2(5H)-Oxazolones

hydroxyl group of polyalcohols is readily achieved with 157 in the presence of zirconium complexes.63 N-Acylation and 3-alkoxycarbonylation reactions may be achieved by conventional acylation procedures. A variety of 3-acyl derivatives 157 can be prepared most conveniently by the treatment of DPPOx 266 with carboxylic acids in the presence of a tertiary amine.82 tert-Butoxycarbonyl (Boc-Ox, 236) and benzyloxy carbonyl (Cbz-Ox, 267) (Cbz ¼ benzyloxycarbonyl) compounds are of practical use for introduction of nitrogen protecting groups.61 Homo and copolymers 268 derived from 3-acetyl-2(3H)-oxazolone are sufficiently reactive to support the smooth acetylation of the amino groups under heterogeneous conditions (Fig. 5.65).61

O

O

ClP(OPh)2

O

NH

RCO2H

O

N P(OPh)2

N COR

O

O [DPPOx]

O

1

266

157

COCl2 t-BuOH

O

O

N CO2t-Bu

[Acyl-Ox]

BPO

ClCO2Bn

O

N CO2Bn

O [Boc-Ox]

O [Cbz-Ox]

236

267

BPO

n

O

N COR O 268

Figure 5.65

5.1.3.6.2.

N-Phosphorylation

The activated phosphorus reagents 269 and 270 are conventionally prepared by the reaction of 2(3H)-oxazolone with the corresponding phosphorus chlorides in the presence of triethylamine. The phosphorus chlorides employed include phosphoryl chloride, thiophosphoryl chloride, mono- and dichlorophosphates, and phosphinic chloride (Fig. 5.66). The above reagents serve as condensing reagents and have different reactivities for peptides 279,82,83 b-lactams 281,84,85 esters,85 thioesters,85,86 and mixed phosphates,87 as well as for the direct preparation of 3-acyl-2(3H)-oxazolones.82 The bis(2-oxo-3-oxazolinyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67).87

2(3H)-Oxazolones (4-Oxazolin-2-ones)

41

X L1

P N

X

O L3

L2

P N

O

X=O [P(O) reagents] X=S [P(S) reagents]

O

L4

O

270

269

O

O

O (ArO)2P N

N P N

O

O

O

N P N

O

OAr O

O

O

N

O

O O O

O 272

271 S O

S

S

N P N

O

O

N P N

Me

O

P N

O O

O

Me

Cl

N

O

273

O

O

O

O 274

275

276

Figure 5.66 O O

N

P(OPh)2

O [DPPOx]

R′

R Cbz

277

R

266

Cbz

NHCHCO2H + H2NCHCO2R′′

R′

NHCHCO NHCHCO2R′′

NEt3

278

279 O

O

N O

P

N

N

O O O

O 273 NEt3

S

S

HO2C N H

N

O

280

281

O O

R1OH

N P N

O

O

R2OH

R1O P N

Mn(acac)3

OR O

57%

O

O R1O P OR2

Zr(acac)4

OR

OR

O

O 282

283 acac = acetylacetonate

Figure 5.67

284 (R1,

R2

= 1˚, 2˚)

42

2(3H)-Oxazolones and 2(5H)-Oxazolones

5.1.3.7. Miscellaneous The PCC oxidation of 3-amino-4,5-diphenyl-2(3H)-oxazolone 96 affords monodiazobenzyl 286 as the primary decomposition product obtained via loss of carbon monoxide from the postulated N-nitrenolactam 285.25 Oxidation of 96 with tert-BuOCl / NEt3 at 108
C results in a deep green solution of 285, which reacts with dimethyl sulfoxide (DMSO) to give the sulfoximide 288 (Fig. 5.68).88 Ph

Ph −CO

PCC

N N

O

0 ˚C

60%

Ph

O

Ph

O

Ph

Cl

HCl

N2

Ph

70%

O Ph

Ph N NH2

O

285

286

287

nitrenolactam

monodiazobenzyl

desylchloride

PCC = pyridinium chlorochromate

O 96

Ph

tBuOCl NEt3

Ph O

DMSO

285

−108 ˚C

N N

O

SMe2

64%

O 288 Figure 5.68

The alkylation of the 2(3H)-oxazolones 289 with Meerwein’s salt (Et3Oþ BF 4) occurs readily and in excellent yield, thus providing an efficient route to the 2-ethoxyoxazoles 290. Although the yield of 290 (R ¼ Me) is low, the process can be carried out on large scale starting from commercially inexpensive acetoin (Fig. 5.69).89 R

R

R

R

1. Et3O+ BF4

O

NH

O

N

2. dil. KOH

O 289

R=Ph: 96% R=Me: 11%

OEt 290 Figure 5.69

5-Alkoxy-2(3H)-oxazolones 47 react with aliphatic and aromatic aldehydes in the presence of Lewis acid catalysts to produce alkyl 2-oxazolidinone-4-carboxylates 29190 by successive ring opening and reclosure. Similarly, reaction with imines affords alkyl 2-imidazolidinone-4-carboxylates 293 via [2þ2] cycloadducts 292. Treatment of the isolated cycloadducts 292 with trifluoroacetic acid (TFA) yields 2,3-diaminocarboxylates 294.91

2(3H)-Oxazolones (4-Oxazolin-2-ones)

43

5,5-Dialkoxy-2-oxazolidinones 295, which are prepared by reaction of 5-alkoxy2(3H)-oxazolones 47 with acetals in the presence of Lewis acid catalysts, are hydrolyzed in the presence of a protonic acid to produce a-amino acid esters 296 (Fig. 5.70; Table 5.11, Fig. 5.71; Table 5.12, Fig. 5.72; Table 5.13, Fig. 5.73; Table 5.14, Fig. 5.74).92 R5

R3O

R4

N

R3O

R2 N R1

O

R2

R4CH=NR5 cat. Lewis acid

O

R1

N

R4

CO2R3

O

R2 N R1

R4CHO cat. Lewis acid

O

O

O 47 292

291 R4OR5 cat. Lewis acid

TFA

CO2R3

R4

CO2R3

R4

R2 R5

N R1

N

R2 R5

N R1 H

N H

R5O R4 R3O

R3O2C

N R1

O

O

R4

H+

R2

N R1 H

O

293

294

R2

295

296 (or R5O2C-)

Figure 5.70 TABLE 5.11. SYNTHESIS OF ALKYL 2-OXAZOLIDINONE-4-CARBOXYLATES FROM 5-ALKOXY-2(3H)-OXAZOLONESa

R3O

R2

O

N

R4CHO cat. Lewis acid

R1

R4

CO2R3

O

R2 N R1 O

O 47

291 Figure 5.71

R1

R2

R3

R4

Lewis Acid

Ph2CH Ph2CH Ph2CH (R)-1-Phenylethyl (S)-1-Phenylethyl Ph2CH PhCH2

H H H H H Me Me

Me Me Me Me i-Pr Me Me

Ph i-Pr CO2Me Ph Ph Ph Ph

BF3OEt2 BF3OEt2 TMSOTf TMSOTf TMSOTf TMSOTf TMSOTf

a

Data from Ref. 90.

% Yield 100 100 28 95 97 95 97

44

2(3H)-Oxazolones and 2(5H)-Oxazolones

TABLE 5.12. SYNTHESIS OF ALKYL 2-IMIDAZOLIDINONE-4-CARBOXYLATES AND ALKYL 2,3-DIAMINOPROPANE-1-CARBOXYLATES FROM 5-ALKOXY-2(3H)-OXAZOLONESa

R3O

R2

R4CH=NR5 cat. Lewis acid

N R1

O

R5

R4

CO2R3

N

R2 N R1

O

O

47

293

R4

CO2R3

N H

R2 N R1 H

or R5

294

Figure 5.72 Compd. No.

R1

293 293 293 293 293 293 294

Ph2CH Ph2CH Ph2CH (R)-1-Phenylethyl (R)-1-(1-Naphthyl)ethyl Ph2CH Ph2CH

a

R2

R3

H H H H H Me H

R4

Me Me Me Menthyl Me Me Me

Lewis Acid

R5

Ph CO2Me CO2Me CO2Me Ph CO2Me CO2Me

Ts Ph2CH (R)-1-Phenylethyl Ph2CH Ts Ph2CH Ph2CH

% Yield

TMSOTf 99 TMSOTf 99 TMSOTf 94 BF3OEt2 97 BF3OEt2 100 TMSOTf 99 BF3OEt2 45

Data from Ref. 91.

TABLE 5.13. SYNTHESIS OF 5,5-DIALKOXY-2-OXAZOLIDINONES FROM 5-ALKOXY-2(3H)OXAZOLONESa

R3O

R5O R4

R2

R4OR5 cat. Lewis acid

R3O

N R1

O

R2 N R1

O

O

O

47

295 Figure 5.73

R1 Ph2CH Ph2CH (R)-1-Phenylethyl (R)-1-(1-Naphthyl)ethyl (R)-1-(1-Naphthyl)ethyl a

Data from Ref. 92.

R2

R3

H H H H Me

Me Me Me Me Me

R4 H CH(OMe)Ph CH(OMe)Ph CH(OMe)Ph H

R5

Lewis Acid

% Yield

Me Me Me Me Me

TMSOTf TMSOTf TMSOTf TMSOTf BF3OEt2

81 96 89 83 90

2(5H)-Oxazolones (3-Oxazolin-2-ones)

45

TABLE 5.14. SYNTHESIS OF a-AMINO ACID ESTERS FROM 5,5-DIALKOXY2-OXAZOLIDINONESa

R5O R4 R3O

R4

R2 N R1

O

R3O

H+

R2 N R1 H

2C

O 295

(or R5O2C-)

296 Figure 5.74

R1 Ph2CH Ph2CH (R)-1-(1-Naphthyl)ethyl a

R2

R3

R4

R5

% Yield

H H Me

Me Me Me

H CH(OMe)Ph H

Me Me Me

100 100 95

Data from Ref. 92.

5.2. 2(5H)-OXAZOLONES (3-OXAZOLIN-2-ONES) 5.2.1.

Introduction

Only a few compounds of this class have been reported since 1984 and three papers are surveyed in this section. 5.2.2.

Synthesis

The UV irradiation of the 2-allyloxy-4,5-diphenyloxazole 41 results in the predominant formation of 5-substituted-2(5H)-oxazolones 44, in contrast to the thermal aza-Claisen rearrangement which readily affords the 2(3H)-oxazolones 42. The photolysis proceeds via allyl-O bond scission with the generation of a radical pair that subsequently recombines to produce 5-substituted-2(5H)-oxazolones. Similar results were obtained with 2-(benzyloxy)-4,5-diphenyloxazole (Fig. 5.75).10 Ph

R1

N

R2

O

Ph

Ph O

Ph

R1 N

+

O

N

R2 2

R

O

1

Ph

Ph

hv

R1

O O

41

44

42

2

a: 77% b, c: 83%

a: 0% b, c: 17%

a: R =R =H b: R1=H, R2=Me c: R1=R2=Me

Figure 5.75

46

2(3H)-Oxazolones and 2(5H)-Oxazolones

On treatment with phosphorus pentachloride, 4,5-diaryl-2(3H)-oxazolones 297 are reported to afford 5-chloro-4,5-diaryl-2(5H)-oxazolones 298, rather than the expected 2-chloro-4,5-diaryloxazoles. The 5-chloro-products react with methanol to give 4,5-diaryl-4,5-dimethoxy-2-oxazolidinones 299, which are further converted on heating to 4,5-diaryl-5-methoxy-2(5H)-oxazolones 300 (Fig. 5.76).93 R

Ph

R PCl5

O

Ph

R

Cl

MeOH

NH

O

Ph OMe NH

MeO

N

O

R

Ph

MeO O

N

quant.

O

O

297

O

298

O

299

300

R=Ph: 71% R=Tol: 68%

R=Ph: 76% R=Tol: 71% Figure 5.76

Dehydration of 4-hydroxy-4,5,5-trimethyl-2-oxazolidinone 301 with a catalytic amount of p-toluenesulfonic acid affords the isomeric dimers 303 and 304 in a ratio of 1 : 2. The former type of dimer, that is, 303 likely results from coupling of the isomeric 2(5H)-oxazolone 302A with 4-methylene-2-oxazolidinone 302B, which are the initially formed dehydration products. On prolonged heating in CH2Cl2, the 2(5H)-oxazolone dimer 303, completely isomerizes to the 4-methylene-2-oxazolidinone dimer 304 (Fig. 5.77).94 Me Me O

OH Me NH

Me Me O

cat. TsOH

Me

Me Me O

N

NH

O

O

O

301

302A

302B

Me Me

Me Me Me Me O + O

Me NH N

O

O

O

Me NHHN O

O

303

Me Me O

304 93%

29%

57%

Figure 5.77

5.2.3.

Reactions

There is nothing new to report on reactions of 2(5H)-oxazolones.

Addendum

47

5.3. SUMMARY Most of the reports, since the 1980s, on the chemistry of 2-oxazolones concern 2(3H)-oxazolones (4-oxazolin-2-ones) 1 and only few reports have appeared on the isomeric 2(5H)-oxazolones (5-oxazolin-2-ones) 2. Thus, the emphasis of this chapter has been to survey information on the synthesis and reactions of the 2(3H)-oxazolones 1 that has appeared over the past two decades. The synthetic methods used to prepare 2(3H)-oxazolones since 1984 are largely based on minor modification of previous methodologies. However, some entirely new strategies for the construction of this class of heterocycles have also appeared, which include the application of intramolecular rearrangements such as Claisentype and Pummerer rearrangements, ring formation catalyzed by transition metal reagents such as Ru3(CO)12, Rh2(OAc)4, and Pd(OAc)4, and the ingenious use of in situ generated N- and P-ylides. Recent developments have largely focused on the synthetic potential of the 2(3H)-oxazolone 1 as a building block that contains both masked amino and hydroxy moieties. Enantiocontrolled addition reactions at the 4,5-olefinic moiety of the 2(3H)-oxazolone ring in a variety of ionic, radical, and concerted addition modes provide a versatile strategy for achieving a chiral synthesis leading to the preparation of 2-amino alcohols of biological interest. The reactions also open up routes to chiral 2-oxazolidinone auxiliaries and chiral amino alcohol ligands that are of general use in asymmetric synthesis. Another feature based on the chemical stability of the 2(3H)-oxazolone ring skeleton permits its use as a protecting group, as well as for ‘‘ready-to-use’’-type of reagents.

5.4. ADDENDUM Condensation of 3-nosyloxy-2-keto esters 305 with methyl carbamate in refluxing toluene in the presence of p-toluenesulfonic acid provides 2(3H)oxazolone-4-carboxylates 306 in good yields (41–80%). Alternatively, condensation of 3-bromo-2-keto esters 307, derived from the bromination of a-keto esters with CuBr2, with methyl carbamate in the presence of AgOTf and ptoluenesulfonic acid under similar conditions provides the 2(3H)-oxazolone4-carboxylates 306 in comparable yields (30–79%) (Fig. 5.78; Table 5.15, Fig. 5.79).95,96 The tandem condensation of isocyanates with an a-ketol in DMF leads to the 2-oxazolidinone derivatives 308 that are dehydrated to the 2(3H)-oxazolones 309 by refluxing in DMSO (Fig. 5.80).97 Treatment of the N-mesyloxyamide 310 with sodium hydride yields 5-ethoxy-3methyl-2(3H)-oxazolone 311. This intramolecular cyclization is considerably enhanced under sonication (Fig. 5.81).98

48

2(3H)-Oxazolones and 2(5H)-Oxazolones NsO ONs

O

CO2Et +

R

MeO

O 305

p-TSA

NH2

O

toluene reflux, 16 h

OH CO2Et

R

OH CO2Et

R

O

NH

NH

OMe

OMe

(Ns = 4-nitrobenzenesulfonyl) OH CO2Et

R NsO

O

R

H2NCO2Me

Br

AgOTf

−H2O

NH O

CO2Et

p-TSA

O

+ NsOMe

NH O

CO2Et

R

toluene reflux

O 307

306 Figure 5.78

TABLE 5.15. SYNTHESIS OF ETHYL 2(3H)-OXAZOLONE-4-CARBOXYLATES FROM 3-NOSYLOXY-2-KETO ESTERS OR 3-BROMO-2-KETO ESTERSa

O

CO2Et +

R

p-TSA

O MeO

O

toluene reflux, 16 h

NH2

NH O

305

306 H2NCO2Me

Br

AgOTf p-TSA

O CO2Et +

R

CO2Et

R

ONs

MeO

toluene reflux

NH2

O

R

CO2Et

O

NH O 306

307 Figure 5.79

R Bn H (Me ester) Pentyl i-Bu i-Pr Me Ph MeO2CCH2 (Me ester) a

Data from Refs. 95, 96.

% Yield from 305

% Yield from 307

80 51 84 70 41 56 46

64 43 63 68 30 60 64

% Yield from 307 (with p-TSA) 75 54 79 75 60 49

REFERENCES Me

Me HO

Me Li2CO3

O

Me

Me

DMSO

O DMF 25 ˚C, 12 h

+

Me

NEt3

OH

49

N R

O

N R

reflux, 8 h

O

O

308

309

O C N R

R=Ph: 90% R=4-ClC6H4: 97% R=4-MeC6H4: 80% R=ClC2H4: 98%

Figure 5.80

EtO O

O Me

EtO

N OMs 310

NaH

O

N Me

THF

under sonication: 83% (5 h) without sonication: 50% (32 h)

O 311 Figure 5.81

REFERENCES 1. Maselli, C. Gazz. Chim. Ital. 1905, 35, 86–94. 2. Rao, Y. S.; Filler, R. In Turchi, I. J., Ed., Oxazoles, Vol. 45, The Chemistry of Heterocyclic Compounds; John Wiley & Sons, Inc., New York, 1986, p. 660. 3. Kudo, N.; Taniguchi, M.; Sato, K. Chem. Pharm. Bull. 1996, 44, 699–702. 4. Bal’on, Ya. G.; Smirnov, V. A. Zh. Org. Khim. 1985, 21, 2230–2231; Chem. Abstr. 1986, 105, 133784. 5. Shimizu, M.; Yoshioka, H. J. Chem. Soc., Chem. Commun. 1987, 689–690. 6. Shono, T.; Matsumura, Y.; Kanazawa, T. Tetrahedron Lett. 1983, 24, 4577–4580. 7. Lenz, G. R.; Costanza, C.; Lessor, R. A.; Ezell, E. F. J. Org. Chem. 1990, 55, 1753–1757. 8. Kano, S.; Yuasa, Y.; Shibuya, S. Heterocycles 1985, 23, 395–398. 9. Magnus, P.; Mitchell, I. S. Tetrahedron Lett. 1998, 39, 4595–4598. 10. Padwa, A.; Cohen, L. A. Tetrahedron Lett. 1982, 23, 915–918. 11. Padwa, A.; Cohen, L. A. J. Org. Chem. 1984, 49, 399–406. 12. Miyata, H.; Ataka, K.; Satake, N.; Hagihara, M. PCT Intl. Appl. WO 9822449, 1998; Chem. Abstr. 1999, 129, 27937. 13. Sakai, S.; Murata, M.; Wada, N.; Fujinami, T. Bull. Chem. Soc. Jpn. 1983, 56, 1873–1874. 14. Roy, J.; Mehrotra, K. N. Indian J. Chem., Sect. B 1983, 22, 78. 15. Mehrotra, K. N.; Singh, I. S.; Roy, J. Bull. Chem. Soc. Jpn. 1985, 58, 2399–2402. 16. Mandal, A. B.; Go´mez, A.; Trujillo, G.; Me´ndez, F.; Jime´nez, H. A.; de Rosales, M. J.; Martı´nez, R.; Delgado, F.; Tamariz, J. J. Org. Chem. 1997, 62, 4105–4115. 17. Bravo, P.; Crucianelli, M.; Fronza, G.; Zanda, M. Synlett 1996, 249–251. 18. Volonterio, A.; Zanda, M.; Bravo, P.; Fronza, G.; Cavicchio, G.; Crucianelli, M. J. Org. Chem. 1997, 62, 8031–8040.

50

2(3H)-Oxazolones and 2(5H)-Oxazolones

19. Gagneux, A. R.; Go¨schke, R. Tetrahedron Lett. 1966, 5451–5454. 20. Sato, K.; Kinoto, T.; Sugai, S. Chem. Pharm. Bull. 1986, 34, 1553–1560. 21. Wang, P.-C. Heterocycles 1985, 23, 2237–2238. 22. Tavernier, D.; Van Damme, S.; Ricquier, P.; Anteunis, M. J. O. Bull. Soc. Chim. Belg. 1988, 97, 859– 865; Chem. Abstr. 1989, 110, 181559. 23. Pereira, E. R.; Spessel, V.; Prudhomme, M.; Martre, A.-M.; Mousset, G. Tetrahedron Lett. 1995, 36, 2479–2482. 24. Pereira, E. R.; Prudhomme, M.; Sancelme, M.; Ollier, M.; Severe, D.; Riou, J. F.; Crevel, H.; Savineau, J. P.; Fabbro, D.; Meyer, T. Chem. Pharm. Bull. 1997, 45, 733–736. 25. Wilson, R. M.; Chow, T. J. Tetrahedron Lett. 1983, 24, 4635–4636. 26. Sheehan, J. C.; Guziec, F. S., Jr., J. Am. Chem. Soc. 1972, 94, 6561–6562. 27. Sheehan, J. C.; Guziec, F. S., Jr., J. Org. Chem. 1973, 38, 3034–3040. 28. Marques, C. A.; Selva, M.; Tundo, P.; Montanari, F. J. Org. Chem. 1993, 58, 5765–5770. 29. Shvaika, O. P.; Korotkikh, N. I.; Chervinskii, A. Yu.; Artemov, V. N. Zh. Org. Khim. 1983, 19, 1728– 1739; Chem. Abstr. 1984, 100, 103228. 30. Kumar, S.; Singh, S.; Singh, P.; Singh, H. J. Chem. Res., Synop. 1992, 200–201. 31. Hori, M.; Tanaka, K.; Kataoka, T.; Shimizu, H.; Imai, E.; Kimura, K.; Hashimoto, Y. Tetrahedron Lett. 1985, 26, 1321–1322. 32. Hori, M.; Tanaka, K.; Kataoka, T.; Shimizu, H.; Imai, E.; Kimura, K.; Hashimoto, Y. J. Chem. Soc., Perkin Trans. 1 1985, 2333–2336. 33. Hori, M.; Kataoka, T.; Shimizu, H.; Imai, E.; Yokomoto, M.; Tanaka, K.; Kimura, K.; Hashimoto, Y. Heterocycles 1986, 24, 2563–2570. 34. Sasaki, Y. Jpn. Kokai Tokkyo Koho JP 63,227,577, 1988; Chem. Abstr. 1989, 110, 135227. 35. Sasaki, Y.; Dixneuf, P. H. J. Org. Chem. 1987, 52, 4389– 4391. 36. Bien, S.; Kimmel, T.; Tirosh, N. Acta Chem. Scand. 1993, 47, 218–220. 37. Lo¨ffler, J.; Schobert, R. Liebigs Ann. / Recueil 1997, 217–220. 38. Roy, P. J.; Landry, K.; Leblanc, Y.; Li, C.; Tsou, N. Heterocycles 1997, 45, 2239–2246. 39. Pansare, S. V.; Vederas, J. C. J. Org. Chem. 1987, 52, 4804–4810. 40. Ishizuka, T.; Ishibuchi, S.; Kunieda, T. Tetrahedron Lett. 1989, 30, 3449–3452. 41. Kunieda, T.; Ishizuka, T.; Higuchi, T.; Hirobe, M. J. Org. Chem. 1988, 53, 3381–3383. 42. Ishizuka, T.; Ishibuchi, S.; Kunieda, T. Tetrahedron 1993, 49, 1841–1852. 43. Ishibuchi, S.; Nagatani, T.; Ishizuka, T.; Kunieda, T. Nat. Prod. Lett. 1992, 1, 21–24. 44. Ishizuka, T.; Morooka, K.; Ishibuchi, S.; Kunieda, T. Heterocycles 1996, 42, 837–848. 45. Kouyama, T.; Matsunaga, H.; Ishizuka, T.; Kunieda, T. Heterocycles 1997, 44, 479–486. 46. Morita, T.; Nagasawa, Y.; Yahiro, S.; Matsunaga, H.; Kunieda, T. Org. Lett. 2001, 3, 897–899. 47. Ishizuka, T.; Osaki, M.; Ishihara, H.; Kunieda, T. Heterocycles 1993, 35, 901–908. 48. Abe, Y.; Kunieda, T. Tetrahedron Lett. 1979, 5007–5010. 49. Kunieda, T.; Abe, Y.; Iitaka, Y.; Hirobe, M. J. Org. Chem. 1982, 47, 4291–4297. 50. Yamamoto, T.; Ishibuchi, S.; Ishizuka, T.; Haratake, M.; Kunieda, T. J. Org. Chem. 1993, 58, 1997– 1998. 51. Matsunaga, H.; Ohta, H.; Ishizuka, T.; Kunieda, T. Heterocycles 1998, 49, 343–354. 52. Morita, T.; Matsunaga, H.; Sugiyama, E.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1998, 39, 7131– 7134. 53. Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Chem. Commun. 1994, 455–456. 54. Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1996, 465–473. 55. Yuasa, Y.; Ando, J.; Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 1525–1526.

REFERENCES

51

56. Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1996, 793–802. 57. Yuasa, Y.; Kano, S.; Shibuya, S. Heterocycles 1991, 32, 2311–2314. 58. Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R.; Abboud, K. Tetrahedron Lett. 1996, 37, 8155–8158. 59. Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis 1998, 665–681. 60. Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Tetrahedron Lett. 1982, 23, 1159–1160. 61. Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Tetrahedron Lett. 1980, 21, 3065–3066. 62. Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Chem. Pharm. Bull. 1984, 32, 2174–2181. 63. Kunieda, T.; Mori, T.; Higuchi, T.; Hirobe, M. Tetrahedron Lett. 1985, 26, 1977–1980. 64. Scholz, K. H.; Heine, H. G.; Hartmann, W. Liebigs Ann. Chem. 1977, 2027–2035. 65. Deyrup, J. A.; Gingrich, H. L. Tetrahedron Lett. 1977, 3115–3118. 66. Matsunaga, H.; Kimura, K.; Ishizuka, T.; Haratake, M.; Kunieda, T. Tetrahedron Lett. 1991, 32, 7715–7718. 67. Kimura, K.; Murata, K.; Otsuka, K.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1992, 33, 4461– 4464. 68. Hashimoto, N.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1994, 35, 721–724. 69. Otsuka, K.; Ishizuka, T.; Kunieda, T. Chem. Pharm. Bull. 1994, 42, 748–750. 70. Ishizuka, T.; Kunieda, T. J. Synth. Org. Chem., Jpn. 1995, 53, 95–103. 71. Ishizuka, T.; Kunieda, T. in Oae, S. Ed.; Rev. Heteroat. Chem. MYU, Tokyo, 1996, 15, 227–241. 72. D’Andrea, S. V.; Freeman, J. P.; Szmuszkovicz, J. J. Org. Chem. 1990, 55, 4356–4358. 73. Matsunaga, H.; Ishizuka T.; Marubayashi, N.; Kunieda, T. Chem. Pharm. Bull. 1992, 40, 1077–1079. 74. Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 1997, 53, 1275–1294. 75. Ishizuka, T.; Matsunaga, H.; Iwashita, J.; Arai, T.; Kunieda, T. Heterocycles 1994, 37, 715–718. 76. Sekreta´r, S.; Kopecky, J.; Martvon, A. Collect. Czech. Chem. Commun. 1983, 48, 2812–2818. 77. Sekreta´r, S.; Kopecky, J.; Cerny, M. Collect. Czech. Chem. Commun. 1986, 51, 899–902. 78. Schnettler, R.; Dage, R. C.; Jones, W. D. Eur. Pat. Appl. EP329070, 1989; Chem. Abstr. 1990, 112, 77169. 79. Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Heterocycles 1996, 43, 1847–1854. 80. Puig, C.; Crespo, M. I.; Godessart, N.; Feixas, J.; Ibarzo, J.; Jime´nez, J. M.; Soca, L.; Cardelu´s, I.; Heredia, A.; Miralpeix, M.; Puig, J.; Beleta, J.; Huerta, J. M.; Lo´pez, M.; Segarra, V.; Ryder, H.; Palacios, J. M. J. Med. Chem. 2000, 43, 214–223. 81. Kunieda, T.; Hirobe, M. J. Synth. Org. Chem., Jpn. 1983, 41, 77–83. 82. Kunieda, T.; Abe, Y.; Higuchi, T.; Hirobe, M. Tetrahedron Lett. 1981, 22, 1257–1258. 83. Katoh, T.; Ueki, M. Int. J. Peptide Protein Res. 1993, 42, 264–269. 84. Kunieda, T.; Nagamatsu, T.; Higuchi, T.; Hirobe, M. Tetrahedron Lett. 1988, 29, 2203–2206. 85. Otsubo, T.; Matsukawa, C.; Ishizuka, T.; Kunieda, T. Heterocycles 1992, 33, 131–134. 86. Kunieda, T.; Abe, Y.; Hirobe, M. Chem. Lett. 1981, 1427–1428. 87. Nagamatsu, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 2375–2378. 88. Chow, T. J.; Ding, M.-F.; Wu, M. Y. Bull. Inst. Chem., Acad. Sin. 1985, 32, 25–31; Chem. Abstr. 1986, 105, 172336. 89. Whitney, S. E.; Rickborn, B. J. Org. Chem. 1991, 56, 3058–3063. 90. Miyata, H.; Satake, N.; Honma, T.; Ataka, K. PCT Intl. Appl. WO 9902508, 1999; Chem. Abstr. 1999, 130, 110256. 91. Miyata, H.; Satake, N.; Honma, T.; Ataka, K. Jpn. Kokai Tokkyo Koho JP 2000007660, 2000; Chem. Abstr. 2000, 132, 64258.

52

2(3H)-Oxazolones and 2(5H)-Oxazolones

92. Miyata, H.; Honma, T.; Yamamoto, Y.; Ataka, K.; Satake, N. Jpn. Kokai Tokkyo Koho JP 2000007666, 2000; Chem. Abstr. 2000, 132, 78548. 93. Bal’on, Ya. G.; Smirnov, V. A. Zh. Org. Khim. 1987, 23, 899–900; Chem. Abstr. 1988, 108, 55944. 94. Joumier, J. M.; Grainger, R.; Bruneau, C.; Dixneuf, P. H. Synlett 1993, 423–424. 95. Hoffman, R. V.; Johnson, M. C.; Okonya, J. F. Tetrahedron Lett. 1998, 39, 1283–1286. 96. Okonya, J. F.; Hoffman, R. V.; Johnson, M. C. J. Org. Chem. 2002, 67, 1102–1108. 97. Martı´nez, R.; Jimenez-Va´zquez, H. A.; Tamariz, J. Tetrahedron 2000, 56, 3857–3866. 98. Hoffman, R. V.; Reddy, M. M.; Cervantes-Lee, F. J. Org. Chem. 2000, 65, 2591–2595.

CHAPTER 6

4(5H)-Oxazolones David C. Palmer Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Raritan, New Jersey

6.1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. 2-Alkyl(Aryl)-4(5H)-Oxazolones and Thiooxazolones. . . . . . . . 6.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. 2-Amino-4(5H)-Oxazolones. . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. 2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones (2,4-Oxazolidinediones) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.2. 2-Alkoxy-4(5H)-Oxazolones. . . . . . . . . . . . . . . . . . . . 6.4.3. 2-Hydroxy-4(5H)-Oxazolones (2,4-Oxazolidinediones) . 6.4.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Addendum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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53 55 55 63 67 67 68 82

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89 89 91 94 94 108 120 121 122

6.1. INTRODUCTION The first derivatives of the 4(5H)-oxazolone ring system 1 were prepared almost 90 years ago when Traube and Ascher1 described the synthesis of 2-amino-4(5H)oxazolones (pseudohydantoins) 2 via condensation of guanidine with a-hydroxy esters (Scheme 6.1). This is quite remarkable in that it was 36 years later before Sheehan and Izzo2 prepared the first example of a simple 2-aryl analogue via

The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

53

54

4(5H)-Oxazolones O N O 1 O NH

R CO2Et + R1 OH

H2N

N H2N

NH2

R R1

O 2

Scheme 6.1

reaction of benzoyl isocyanate with diazomethane to afford 2-phenyl-4(5H)oxazolone, 3 (Scheme 6.2). Since these two reports, the 4(5H)-oxazolone ring system has been a rich source of derivatives and analogues prepared and evaluated as antibiotics, tranquilizers, antiinflammatory agents, antidepressants, antimalarials, fungicides, herbicides, antiviral agents, antidiabetic agents, dual 5-lipoxygenase (5-LO) and cyclooxygenase (CO) inhibitors, antiulcer agents, agents for the treatment of metabolic bone disorders, as selective cyclooxygenase (CO) inhibitors, photographic dyes, and nonlinear optical materials.

Ph

O

O

O NCO

N

N

CH2N2

N2+

Ph O

Ph

O 3

Scheme 6.2

A comprehensive review of the synthesis and reactions of 4(5H)-oxazolones and analogues was published over 15 years ago.3 In addition, there are several reviews more limited in scope that have appeared recently.4–7 This chapter will survey the synthesis and reactions of 4(5H)-oxazolones and derivatives covering the period from 1983 to 2001. It will follow the basic format presented by Rao and Filler3 although several areas will be covered in more detail. In those cases where tautomeric structures are possible, the exclusive or predominant tautomer will be shown (Fig. 6.1). Thus, 1 is predicted to be the most stable tautomer in the gas phase and in solution. It is the only tautomer observed experimentally in solution and will be used to represent 4(5H)-oxazolones.8,9 The tautomeric mesoionic anhydro-4-hydroxyoxazolium hydroxide 1b has not been observed spectroscopically but has been trapped in cycloaddition reactions.5,10,11 The amino tautomer 2 has been shown to be the exclusive and/or predominant tautomer for simple 2-amino-4(5H)-oxazolones.7,12,13 Rapi and

2-Alkyl(Aryl)-4-(5H)-Oxazolones and Thiooxazolones

R

O

O

OH

HN

N

N R

O

R

O

1a

O

O

OH

HN

N H2N

O

HN

O 2

2a SH

O 2b

S

N R

O 1b

1

N H2N

55

N R

O 4a

O 4

Figure 6.1. 4(5H)-Oxazolone tautomers.

co-workers13 presented an excellent discussion of tautomerism in 2-amino-4(5H)oxazolones. Similarly, the thione 4 is the predominant tautomer.5

6.2. 2-ALKYL(ARYL)-4-(5H)-OXAZOLONES AND THIOOXAZOLONES 6.2.1.

Synthesis

There are relatively few syntheses of simple 2-alkyl- or 2-aryl-4(5H)-oxazolones and these have been summarized previously.3 An excellent and comprehensive review of the synthesis and reactions of 4(5H)-oxazolones covering the early literature up to 1983 has been published.6 Subsequent to this work extensions of earlier methods and a few additional examples have appeared in the literature and these will be described in detail. Hydrolysis of a suitably 4-substituted oxazole has been reported to produce the corresponding oxazolone but the yields are not very high and the isolations can be difficult. For example, alkaline hydrolysis of 5 affords a low yield of mandelic acid presumably via the intermediacy of 6 (Scheme 6.3).14 As part of a study Br

O

N Me

N

NaOH

O 5

Ph

Me

Ph O 6

Scheme 6.3

Ph

CO2H HO

56

4(5H)-Oxazolones

to prepare all eight metabolites of 2,5-diphenyloxazole, the 4-acetoxy derivative, 8 was prepared via cyclization of 7 (Scheme 6.4). Brief alkaline hydrolysis of 8 produced 9 as part of a complex mixture. Only after treatment of this mixture  was it possible to isolate a propylated with 1-iodopropane/(n-Bu)þ 4 OH 15 derivative.

O Ph

HN Ph

O

Cl

OAc

Et3N Ac2O

Ph

Ph

O

7

O

NaOH

N

N Ph

Ph

O 9

8 Scheme 6.4

Abou-Gharbia and co-workers16 described a general synthesis of 5,5-diphenyl-2substituted-4(5H)-oxazolones as an extension of their earlier work.17 Reaction of diphenylketene with a series of N-acylsulfilimines 10a–d produced an intermediate N-acyl a-lactam that then rearranged to afford 11a–d in 56–80% yield (Scheme 6.5). Examples are shown in Table 6.1 (Fig. 6.2).

Ph

O

R C O +

Ph

Ph

R

N

Ph

O

R Ph

S

N

R

O 10a-d

Ph

O C

S NCR1

R1

O

R1

R = Me, Ph R1 = Me, CF3, Ph, CH(Ph)2, O N R1

Ph O

Ph

11a-d R = Me, Ph R1 = Me, CF3, Ph, CH(Ph)2, Scheme 6.5

The reaction was sensitive to substitutents present in the aromatic ring of 10. For example, S,S-dimethyl-N-benzoylsulfilimine, 10b, reacted completely with diphenylketene after 4 h in refluxing toluene. In contrast, the corresponding

2-Alkyl(Aryl)-4-(5H)-Oxazolones and Thiooxazolones

57

TABLE 6.1. 5,5-DIPHENYL-2-SUBSTITUTED-4(5H)-OXAZOLONES FROM SULFILIMINES AND DIPHENYLKETENEa

O Ph

R C O +

Ph

N

O S NCR1

R1

Ph O

R

Ph

11a-d

10a-d Figure 6.2 Product

R

R1

11a 11b 11c 11d

Ph Me Ph Ph

CH(Ph)2 Ph Me CF3

a

Conditions

% Yield

CH2Cl2/reflux toluene/reflux CH2Cl2/reflux xylene/reflux

73 80 56 68

Data from Ref. 16.

N-p-nitrobenzoyl analogue was unreactive after 24 h under the same reaction conditions. Reaction of 10b with tert-butylcyanoketene 12 produced none of the expected 4(5H)-oxazolone. Instead, the imide 13, the product of an apparent Pummerer reaction,18 was isolated in low yield (Scheme 6.6).

O t-Bu S NCPh + NC Me

Me

10b

toluene,

t-Bu

O

NC

N H

O

C O reflux

12

Ph

13

Scheme 6.6

As part of a mechanistic and synthetic study of nucleophilic carbenes the spirocyclic 4(5H)-oxazolone 18 has been obtained from benzoyl isocyanate (Scheme 6.7).19 Thermal extrusion of nitrogen from the 1,3,4-oxadiazoline 14 produced the carbonyl ylide 15 that fragmented via loss of acetone to the aminooxycarbene 16. Spectroscopic data [gas chromatography–mass spectrometry (GC–MS), infrared (IR), proton and C-13 nuclear magnetic resonance (1H and 13C NMR)] of the crude thermolysate was consistent with 18. The formation of 18 was rationalized to result from nucleophilic addition of 16 to benzoyl isocyanate followed by cyclization of the dipolar intermediate 17. Thermolysis of 19 and 21 under similar reaction conditions afforded 20 and 22 respectively, also identified spectroscopically as the major products in the thermolysate.

58

4(5H)-Oxazolones O N N

N O

Ph O

O

−N2

Me

N

+/

Me Me

Ph

− acetone

O

O

O

N

Ph O

Me

14

15

16

Ph N

PhC(O)NCO benzene, reflux

O

O O + N

O Ph

N Ph

O O

Ph

N

O

O 17

18 O N

O

N

N

Me

O

N

O

Me Me

PhC(O)NCO,

Ph Me

benzene 90 ˚C, 24 h

20

MeO

N

N

O

19

N

O O

O

OMe O

Me Me 21

N

PhC(O)NCO, benzene 110 ˚C, 24 h

Ph

OMe O

OMe

22

Scheme 6.7

The syntheses and reactions of salts of variously substituted 4(5H)-oxazolones were described in Ref. 3. This area is the subject of extensive investigations in the Russian chemical literature and has been reviewed recently.6 Several very well established and preparatively useful methods to prepare analogues of 23 (Fig. 6.3) are presented in these references and will not be described further. They include  Reaction of a-haloacetyl bromides with amides in the presence of strong acids ðpK < 1Þ.  Reaction of a-chloroacetamides with acid chlorides.  Cyclization of a-hydroxy carboxylic acid amides with anhydrides in the presence of strong acids (pK < 1).  Cyclization of cyanohydrins with aliphatic acid anhydrides in the presence of strong acids (pK < 1) or aromatic acids halides in the presence of SnCl4.

2-Alkyl(Aryl)-4-(5H)-Oxazolones and Thiooxazolones

59

O HN R

R1 X O

R2

23 R = alkyl, aryl R1 = H, alkyl, aryl, cycloalkyl R2 = H, alkyl, aryl, cycloalkyl X− = ClO4, Br, SbCl 6, 1/2 SnCl6−2, HSO4, CF3CO2, polyphosphate Figure 6.3. 4(5H)-Oxazolonium salts.

German workers20 reported that 5-acyloxy-4(5H)-oxazolonium salts 24 are readily prepared by reaction of acyl cyanides and acid anhydrides in the presence of a strong acid (Scheme 6.8). Analogues like 24 are not available using the traditional methods (see above). O

O R1

HN

(RCO)2O, H2SO4

CN

R

10 to 60 ˚C

HSO4 OCOR

O

R1 24

R = alkyl, chloroalkyl, Ph R1 = alkyl, cycloalkyl, aryl, heteroaryl Scheme 6.8

The manner in which a carbene was generated was found to be critical to the product distribution in a synthesis of 4(5H)-thiooxazolones (Scheme 6.9). Treatment of diethyl bromomalonate with excess triethylamine in the presence of benzoyl isothiocyanate afforded a mixture of the 4(5H)-thiooxazolone 25 (44%) and the 1,3-oxathiole 26 (minor). However, if the carbene was generated via copper-catalyzed decomposition of diethyl diazomalonate, then 26 was isolated as the major product, albeit in low yield (22%).21 S EtO2C

CO2Et

Et3N, rt

Br

CO2Et

N

PhC(O)NCS

Ph

S CO2Et + Ph O

CO2Et

25 major EtO2C

CO2Et N2

PhC(O)NCS, Cu, benzene, rt

25 26 minor + major

Scheme 6.9

N O

O 26 minor

OEt

60

4(5H)-Oxazolones

A recent report on trifluoromethylsulfenylation of b-keto acids and derivatives describes isolation of 29 in good yield from reaction of 27 with trifluoromethylsulfenyl chloride (Scheme 6.10).22 Mechanistically, this was rationalized via electrophilic attack of trifluoromethylsulfenyl chloride on the enamine tautomer 27a to generate 28 followed by intramolecular cyclization through the imide oxygen with concomitant loss of CF3SH to produce 29. The product was characterized spectroscopically.

O Ph

S

NPh

N H

O

Ph

Ph

S N H

27 S H

CF3SCl CHCl3

Ph

reflux −HCl

27a S

NHPh N

−CF3SH

N

Ph

Ph

SCF3 Ph

NHPh

NHPh

O

O

Ph

28

29 Scheme 6.10

During investigations of the synthesis of tetracycline ring A analogues, Moskalyk and co-workers23 unexpectedly isolated 4(5H)-oxazolones 31 and 33 following reaction of 30 and 32 with sodium ethoxide then chloroacetyl isocyanate. Further reaction of 31 effected ring opening of the 4(5H)-oxazolone to yield 34 (Scheme 6.11).

Me

Me

OH

Me

1. NaOEt/EtOH

Me

OH

NH2

NH3

Me

Me N

2. ClCH2CONCO

MeOH

CONH2

O

O

O

30

O

O 31 NHCOPh

NHCOPh OH

34

OH

1. NaOEt/EtOH 2. ClCH2CONCO

N O O

O 32

O 33

Scheme 6.11

2-Alkyl(Aryl)-4-(5H)-Oxazolones and Thiooxazolones

61

Base-catalyzed cyclization of N-benzoyl-a-chloroacetamide is a classical method used to prepare 2-phenyl-4(5H)-oxazolone.3 Extension of this methodology to the N-aroylcinnamides 35 afforded a series of 5-arylidene analogues 37 albeit in unstated yield (Scheme 6.12).24 Thus, acylation of the sodium salt of a benzamide with a cinnamoyl chloride gave the imides 35 that were converted to 36 via a bromination–dehydrobromination sequence. Cyclization to 37 was affected with sodium hydride in 1,2-dimethoxyethane (DME). The authors noted that catalytic reduction of 37 afforded the 5-(arylidene)oxazolidine from which 37 could be regenerated in the presence of air. O

O

1. NaH/THF

3-R-C6H4CONH2

4-X-C6H4

2. 4-X-C6H4CH=CHCOCl

N H

R = H, Me

35 O

O

1. Br2/AcOH 2. Et3N/CHCl3

C6H4-3-R

NaH/DME

4-X-C6H4

N H

Br

C6H4-3-R

reflux

36 O N 3-R-C6H4

H O

C6H4-4-X 37 R = H, Me X = H, Cl, Me, 4-NO2 Scheme 6.12

Roesky and co-workers25 unexpectedly isolated the unique 14 membered macrocycle 38 containing arsenic, carbon, oxygen, and nitrogen atoms in the skeletal framework from reaction of arsenic(III) cyanide and hexafluoroacetone (Fig. 6.4). The structure of 38 was confirmed by single-crystal X-ray. CF3 O

CF3

CF3 N

N

CF3

As

O

CF3 As O NC N CF3

CF3 CN CF3

O O

CF3

N

CF3 O

CF3

CF3 38 Figure 6.4. Arsenic containing macrocyclic 4(5H)-oxazolone.

62

4(5H)-Oxazolones

Japanese workers26–28 prepared examples of 2-alkenyl-4,5-oxazolediones 40a and 40b, which are key intermediates in the synthesis of alkenoyl isocyanates 41a and 41b (Scheme 6.13). These reactive monomers are precursors to a variety of functionalized polymers including instantaneously curable compositions. Thus, reaction of oxalyl chloride with acrylamide 39a or methacrylamide 39b affords 40a and 40b isolated as hydrochloride salts in high yields. Subsequent decomposition of the 2-alkenyl-4,5-oxazolediones in the presence of a metal halide or synthetic zeolite affords 41a and 41b contaminated with varying amounts of 42a and 42b. The synthesis and reactions of other 2-substituted 4,5-oxazolediones have been described independently by Speziale and co-workers29,30 and Sasaki and coworkers.31,32 O R

CONH2

N

ClCOCOCl

R

>90%

O

O

1,2-dichlorobenzene or 1,2-dichloroethane heat

40a R = H 40b R = Me

39a R = H 39b R = Me R

HCl

CON=C=O

R

CON=C=O CH2Cl

41a R = H 41b R = Me

42a R = H 42b R = Me

44-90%

0-13% Scheme 6.13

Almazole D, 43a is a relatively rare naturally occurring 2,5-disubstituted oxazole that was isolated recently (Fig. 6.5).33 The proposed structure is based on NMR evidence and conversion of 43a to 43b by reaction with diazomethane but it has not yet been confirmed by total synthesis.

RO N

O O

H NMe2

N H CH2N2

43a R = H Almazole D 43b R = Me

Figure 6.5. Almazole D.

2-Alkyl(Aryl)-4-(5H)-Oxazolones and Thiooxazolones

6.2.2.

63

Reactions

For a brief survey of typical reactions of 4(5H)-oxazolones the reader is directed to Rao and Filler’s previous review.3 Kul’nevich and co-workers6 presented a more comprehensive discussion of this topic. Extensions of previous methodology or new reactions will be presented in this section. Condensation products of 4(5H)-oxazolonium salts with aldehydes and orthoesters are the subject of a series of papers by Kosulina and co-workers.34–36 Reaction of 2-methyl-4(5H)-oxazolonium perchlorates 44 with an ortho ester gives rise to an enol ether, which reacts with furanamides to afford the trans-eneamides 45 (Scheme 6.14).34 Using electron deficient anilines in a three component condensation affords either 46 or 47 in 64–80% and 78–84% yields, respectively, depending on whether the reaction is performed in acetic acid or acetic anhydride. Electron-rich anilines are unreactive since they are merely protonated by the perchloric acid present in the reaction medium.36

N Me

N

TEOF

OAc

Ac2O

O

EtO

OAc O Me

Me

Me

Me

ClO4

O

R

ClO4

O

R

44 R = H, Me

R1

R = H, Me

O O

R1

76-80%

O

R

CONH2

O

R1 = Me, Br

N N H

ClO4 OAc

O Me

Me

45 R = H, Me R1 = Me, Br R1

O

R ClO4

O2N

N

+ N H

N

OAc N

O Me

O ClO 4

R

NO2

OAc O

Me

Me O

Me

46

47

R = H, Me

R = H, Me Scheme 6.14

Me

64

4(5H)-Oxazolones

TABLE 6.2. 2-[2-(a-HETEROARYL)ETHENYL]-4(5H)-OXAZOLONIUM PERCHLORATES FROM OXAZOLONIUM SALTS AND ALDEHYDESa

R

O ClO4 N

OAc

X

R3

O

Me Me

R1

R2

R = H, Me X = O, S, CH=CH 48 Figure 6.6 X

R

R1

R2

O O O O O S S

H H H H H H H

H H H H H H H

H H H H H H H

a

R3 Ph 4-Me C6H4 4-Br C6H4 4-NO2 C6H4 C6H4 3-NO2 H Br

% Yield

Product

73 83 74 64 56 60 70

38a 38b 38c 38d 38e 38f 38g

Data from Ref. 35.

A recent extension of this methodology includes condensation of 44 with a variety of substituted benzaldehydes, furfurals, and thiophene carboxaldehydes afforded analogues of 48 in good to excellent yield as shown in Table 6.2 (Fig. 6.6). These products were completely characterized spectroscopically with an excellent discussion of the effects of substituents on the corresponding UV, IR, MS, and NMR spectra. Neutralization of 48 with sodium bicarbonate in aqueous ethanol produced the corresponding free bases uneventfully. These compounds were evaluated both as cyanine dyes and for biological activity.35 Condensation of 44 with (E)-3-(5-methylfuran-2-yl)-2-propenal affords the expected (E, E)-dienes 49a and 49b in 50 and 90% yield, respectively (Fig. 6.7). Russian workers37 reported a high-yield synthesis of the 1,2,4-triazoles 51a and 51b from reaction of 50a or 50b with hydrazines in a continuation of their earlier R

O ClO4 N

Me

O O

OAc Me Me

49a R = H 49b R = Me Figure 6.7. (E,E)-Dienes from a 2-methyl-4(5H)-oxazolonium perchlorate.

2-Alkyl(Aryl)-4-(5H)-Oxazolones and Thiooxazolones

65

studies (Scheme 6.15). For R1 6¼ H there was no evidence for formation of regioisomers 52a or 52b consistent with attack at C-2 by the primary amino group of the hydrazine. The synthesis of triazolium salts and 1,3,5-triazines from reactions of 50a and 50b with other hydrazines and guanidines has been described previously.6 O HN R

O

R X Me

R1NHNH2 benzene or i-PrOH

Me

reflux 80-100%

N N

Me N R1

X = ClO4 or CF3CO2

Me OH

51a R = Me, R1 = H, Ph 51b R = Ph, R1 = H, Ph

50a R = Me 50b R = Ph Me

Me

HO N N N

R

R1 52a R = Me, R1 = H, Ph 52b R = Ph, R1 = H, Ph

Scheme 6.15

Additional examples of the utility of ring cleavage and recyclization of 4(5H)oxazolones to prepare interesting heterocycles have been described (Scheme 6.16). Ttreatment of 4-aminothymol 53 with 54 in refluxing pyridine yields the 4imidazolidinones 55 evaluated as antimicrobial and antitubercular agents.38 The authors listed an extensive series of analogues (25 compounds) but reported a yield for only C6H4). Condensation of 2-phenylone example, 55 (63% for R1 ¼ Ph, R2 ¼ 4-MeO 4(5H)-oxazolone 56 with substituted hydrazines affords excellent yields of the 1,2,4-triazoles 57, important precursors to the previously unknown 1(H)-1,2,4-triazole5-carboxaldehydes 58.39 Representative examples are shown in Table 6.3 (Fig. 6.8). R1

Me NH2

O

HO

R1

reflux

Me

RNHNH2 EtOH

O

56

Me

54 O

N

R2

HO

Me 53

Ph

R2

O

55 Ph

Ph

N

N N

OH

N

N

N

R

R

57

58

Scheme 6.16

O

N

pyridine

N

+

Me

N

Me

CHO

66

4(5H)-Oxazolones TABLE 6.3. 5-(HYDROXYMETHYL)-3-PHENYL-1H-1,2,4TRIAZOLES FROM 2-PHENYL-4(5H)-OXAZOLONE AND HYDRAZINESa

Ph N N

OH N R 57

Figure 6.8 Entry 57a 57b 57c 57d 57e 57f a

R

% Yield

Me Bn Ph 4-Me C6H4 4-Br C6H4 4-NO2 C6H4

91 94 94 87 87 95

Data from Ref. 39.

Barrett and Kohrt40 and Kelly and Lang41 independently reported the first examples of oxazole triflates (Scheme 6.17). In both cases, the requisite 2-aryl4(5H)-oxazolone, 56 or 59, was treated with trifluoromethanesulfonic anhydride (Tf2O) to afford 60a or 60b, respectively, which were then coupled successfully with a variety of organostannanes. Kelly and Lang41 attempted to extend this methodology to prepare the key oxazole triflates 63 in their approach to sulfomycin I. However, they were unexpectedly thwarted when 61 could not be cyclized to the requisite 4(5H)-oxazolone precursors 62.41 Schaus and Panek42 described an improved procedure to prepare 56 in 90% yield very recently. O N O

R

OTf N

Tf2O/CH2Cl2 2,6-lutidine

O

R

56 R = H 59 R = OMe

60a R = H 60b R = OMe O

X

H N

Me O

toluene

CH2Cl O

61 X = CH2 or O

reflux

X

N

OTf X

O

N O

Me

Me

62 X = CH2 or O

63 X = CH2 or O

Scheme 6.17

67

2-Amino-4(5H)-Oxazolones

Theoretically, the regioselectivity observed in photochemical [2 þ 2] cycloaddition of 56 with 1,1-dimethoxyethene is in good agreement with experimental results and has been explained on the basis of pertubational molecular orbital theory.43 Hartke and co-workers44,45 described an interesting contrast in the reactivity of tropolones in an intramolecular Diels–Alder reaction (Scheme 6.18). Thus, alkylation of 64a and 64b with 65 gave 66a and 66b, respectively, that were subjected to cyclization in refluxing toluene. Whereas 66a decomposed under the reaction conditions, 66b afforded 67b in high yield.

NCN

R3

R3

O

Ph

O

Cl

N

CN

65

OH R2

R1

Ph

O Et3N, DMAP CH2Cl2

R2

64a R1 = R2 = R3 =H 64b R1 = R2 = R3 =Me

R1

66a R1 = R2 = R3 =H 46% 66b R1 = R2 = R3 =Me 64%

toluene, reflux

R3 R2

O

N R1

O N Ph

67a R1 = R2 = R3 =H 0% 67b R1 = R2 = R3 =Me 87% Scheme 6.18

6.3. 2-AMINO-4(5H)-OXAZOLONES 6.3.1.

Introduction

The synthesis of 2-amino-4(5H)-oxazolones has been a very productive area of research since Traube and Ascher1 first prepared 2 nearly 90 years ago. Subsequently, literally hundreds of analogues have been prepared and evaluated, primarily as medicinal agents. For example, pemoline (Cylert1) 68 (Fig. 6.9), a central nervous system (CNS) stimulant relatively devoid of side affects has been

68

4(5H)-Oxazolones O

O HN

N H2N

O

HN

Ph

O

68

Ph

68a Me 6 N H

H 5 O

O N NHMe

69 Figure 6.9. Pemoline and indolmycin.

used clinically to treat attention-deficit hyperactivity disorder (ADHD).46 On the other hand, the naturally occurring analogue, indolmycin 69 (Fig. 6.9), is a potent, selective inhibitor of bacterial tryptophanyl enzyme and, as such, has stimulated interest in the design of new antibacterial agents.47 The classical approaches to analogues of 2 were described briefly3 and reviewed more extensively by Nekrasov7 and include      

Cyclization of a-hydroxy esters with guanidine. Cyclization of a-halo carboxylic acid ureides. Cyclization of a-hydroxy or a-halo amides. Aminolysis or hydrazinolysis of 2-thiones. Displacement of the 2-amino group with primary and secondary amines. Alkylation of 2 or other analogues.

In addition, Rapi and co-workers13 summarized their investigations of tautomerism in 2-amino-4(5H)-oxazolones (Section 6.1 and Fig. 6.1). Interesting extensions of the earlier approaches to 2 as well as discussions of synthetic work related to 68 and 69 will be described in more detail in this section. 6.3.2.

Synthesis

The cyclization of a-halo carboxylic acid ureides can be complicated with products from different modes of cyclization. For example, bromination of 70 at low pH affords the 2-amino-4(5H)-oxazolone 71 in excellent yield, whereas bromination at pH 5–6 generates a mixture of hydantoins 72 and 73 in poor yield (Scheme 6.19).48 Japanese workers49 reported that cyclization of a-bromoisovalerylurea with 28% aqueous ammonia yields 2-amino-5-isopropyl-4(5H)-oxazolone 74, not 75 or 76. The structure of 74 was established spectroscopically and confirmed by hydrolysis to 77 (Scheme 6.20).

69

2-Amino-4(5H)-Oxazolones CO2 K H N

O

Br2/H2O pH = 1-3

NH2

N H2N

90%

O

CO2H

O

O

Br 71

70 Br2/H2O pH = 5-6 18.4%

O HN O

CO2H

N H

R 72a R = Br 72b R = H Scheme 6.19

Me

O

O

O

Me

N H

Br

O

N

28% aq. NH3

HN

1 M HCl

NH2

Me H2N

O

Me O

O

Me 74

73

Me 77

28% aq. NH3

O Me

HN Me or O

N H 75

O

Me

O N H

Me

NH2

76 Scheme 6.20

An example of anomalous behavior in closely related systems was reported some time ago during an investigation of the cyclization products derived from coumarin semicarbazones (Scheme 6.21).50 Thus, 78a reacted cleanly with chloroacetic acid to yield 79a, which cyclized to the expected product 80a upon treatment with sodium acetate. On the other hand, 79b did not cyclize under the same reaction conditions. This was attributed to the absence of the ‘‘enolizable’’ hydrogen (Ph vs. H). The authors did not comment on the possibility of cyclization of 79b to 80b. The closely related urea analogue 81 did not react with chloroacetic acid thereby

70

4(5H)-Oxazolones OH

OH CH=N NHCONHR

CH=N NHCONR

ClCH2CO2H NaOAc/EtOH reflux

O

O

O

Cl 79a R = H 79b R = Ph

78a R = H 78b R = Ph

for R = H

OH

OH

Ph CH=N N

CH=N NH

N

N

O O

O

O

O

O

80a 90% from 78a

80b

O

OH CH=N

NH2

O 81

Scheme 6.21

precluding cyclization to the corresponding 2-amino-4(5H)-oxazolone. On the other hand, condensation–cyclization of the chloroacetic acids 82 with a series of N-aryl ureas 83 afforded good-to-excellent yields of the corresponding 2(arylimino)-4(5H)-oxazolones 84, which showed some promise as antifungal agents (Scheme 6.22).51 O O R

CO2H Cl

82 R = H, Me

+

H 2N

NaOAc/EtOH reflux, 20 h

NHC6H4-X

60-80%

HN X-C6H4N

R

O 84

83a-k

O N X-C6H4HN

O

R

R = H, Me X = H, 2-Cl, 3-Cl, 4-Cl, 4-Br, 2-MeO, 3-MeO, 4-MeO, 2-Me, 3-Me, 4-Me

Scheme 6.22

71

2-Amino-4(5H)-Oxazolones

Recently, Manthey, Christopherson, and co-workers52 unexpectedly isolated a spirocyclic 2-amino-4(5H)-oxazolone during their investigations of dihydroorotase inhibitors as potential antimalarial agents (Scheme 6.23). The authors anticipated that bromination of the ureide 85 with concomitant cyclization would yield 86 that would then be converted to the potential dihydroorotase inhibitor 87 as shown. However, the product isolated from this four-step reaction sequence was the thiohydantoin 88b. It was assumed that bromination of 85 produced the hydantoin 89 that was then converted to 88b (see above). Surprisingly, the product isolated in 89% yield from the bromination reaction was not 89 but the spirocyclic 2-amino-4(5H)-oxazolone 90a that was treated with tributyltin hydride to afford 90b. It was postulated that 90b rearranged to 88a during the thiation reaction. Subsequent cleavage of the 2bromo-4-methoxybenzyl group (Ar1) with trifluoroacetic acid then produced 88b. O CONHCONH2

Br2/DMF

Br

HN CO2Ar

pyridine

O

N H CO2Ar1

85

86 Br2/DMF pyridine then 1-3

1. (n-Bu)3SnH 2. Lawesson's reagent 3. TFA

O

S

HN NH

S

HN CO2R

O

88a R = Ar 1 88b R = H

N H CO2H 87

O HN

Br2/DMF

85

1,2,3

NH

O pyridine

88b

CO2Ar1 Br TFA

89

NH2 O

O

HN

N S

O

S CO2Ar1 H

CO2Ar1 X 90a X = Br (n-Bu)3SnH

90b X = H

O

NH2

Lawesson's reagent

N

Ar = CH2C6H4-4-OMe Ar1= CH2C6H3-2-Br-4-OMe

Scheme 6.23

NH2 CO2Ar1 H+

72

4(5H)-Oxazolones

Benkovic and co-workers53 also isolated spirocyclic 2-amino-4(5H)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with O-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H218 O as the solvent they demonstrated that there was no 18O incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray.

O

NR OH

HN

Me

pH = 4.8

H2N

H2N

N

N

Me

N

MeONH2 or NH2CONHNH2

O O

91

N H

92a R = OMe, 39% 92b R = NHCONH2, 57% Scheme 6.24

Other examples of spirocyclic 2-amino-4(5H)-oxazolones have been prepared and evaluated for their CNS activity and as potential antiviral agents.54,55 In these reports, cyclization of the appropriate a-hydroxy ester with guanidine afforded the novel analogues 93, albeit in low-to-modest yields. Representative examples are shown in Table 6.4 (Fig. 6.10). German workers56 have also isolated a novel spirocyclic 4(5H)-oxazolone 96 in high yield by reaction of 95 with hydroxylamine sulfate (Scheme 6.25). This was part of an investigation of the synthesis and reactions of 95. The classical cyclization routes to pemoline 68 and similar 2-amino-4(5H)oxazolone analogues continue to be refined and improved. For example, Japanese workers57 have prepared an extensive series of heterocyclic analogues, 100, via several classical routes including cyclization of a-hydroxy esters or activated acids

O OH CONH2

NH2CN H2O, rt 92%

OH

NH2OH H2O, rt

N NH2 O CONH2

NOH O

81%

NH2 O

94

95 Scheme 6.25

N 96

73

2-Amino-4(5H)-Oxazolones TABLE 6.4. SPIROCYCLIC 2-AMINO-4(5H)-OXAZOLONES FROM a-HYDROXY ESTERS AND GUANIDINE

O

O

N H2N

H2N

O

N

R2 H2N

O

O

R3

n

R4

R5 93f-j

93a-e O

93k

O

N H2N

O

R1

N

N H2N

O

O

N R

93m-q

93l

Figure 6.10 Compound

n

%Yield

Reference

93a 93b 93c 93d 93e

0 1 2 3 4

15 16 16 21 31

54 54 54 54 54

Compound

R1

R2

R3

R4

R5

% Yield

Reference

93f 93g 93h 93i 93j

H Me Me Me Me

H H Me Me H

H H Me H Me

Me H H Me H

H H H Me Me

11 31 15 28 36

54 54 54 54 54

Compound

% Yield

Reference

93k 93l

13 31

54 54

Compound 93m 93n 93o 93p 93q a

R H PhCH2CH2 Bn Et i-Pr

% yield from Ref. 54.

% Yield a

32 48 50 37 36a

References 54, 55 54 54 54 54, 55

74

4(5H)-Oxazolones

with thioureas or guanidines (Scheme 6.26). Some of these have shown excellent promise as anti-Heliobacter pylori agents.

R1

R3 H2N

Z Y

S

S

O

R2

R2

R1

N

N R4

R4

OP

R3 CONH OH

Y

X

X

97

98

Z = Cl, N3, OCOR, OSu, OBt, etc. P = MOM, MEM, MTM, THP, Bn, etc MOM = methoxymethyl MEM = 2-methoxyethoxymethyl MTM = methylthiomethyl THP = tetrahydropyran-2-yl O

NH

R2

R1

R3

CO2Me Y

N

N

R4

R4

R3

N

R3

R1

N O

R4

R2

OH Y

X

X 100

99

X = NH, O, S; Y = CH or N R1 = H or Me; R2 = H or Me; R3 = H or Me R4 = CONHR, CONHAr, CONHHet, CO 2R, COAr, COHet, COCH=CHHet, SO2R, SO2Ar Scheme 6.26

Subtle yet significant refinements in the stoichiometry and reaction conditions for the base catalyzed reaction of cyanamide with a mandelate ester have been described recently in the patent literature (Scheme 6.27).58,59 The advantages include fewer impurities and avoidance of the notoriously unstable guanidine free base. In both cases, excellent yields of very pure 68 (up to 99.87A%) have

OH Ph

CO2R

R = alkyl, aryl

O NH2CN/Base solvent <10 to 150 oC 78-89%

N H2N

O 68

Scheme 6.27

Ph

75

2-Amino-4(5H)-Oxazolones

been obtained from a wide variety of conditions. Interestingly, it does not appear to be critical to prepare a single enantiomer of 68 since rapid epimerization of the benzylic hydrogen ‘‘obscures any potential enantioselective pharmacology.’’46 However, very recently, Bonk and co-workers60 described a spontaneous resolution of the enantiomers of pemoline with >96% enantiomeric excesses possible. Chinese workers61 reported the first separation of the enantiomers of 68 using cyclodextrin-mediated capillary zone electrophoresis (CZE). Enantioselective highperformance liquid chromatography (HPLC) separations employing chiral stationary phases have been an area of intense investigation. Armstrong’s group62 recently demonstrated this technique as applied to 68 using a covalently bonded macrocylic antibiotic, ristocetin A as the chiral stationary phase. Nekrasov and co-workers63,64 prepared 2-amino-5-substituted-4(5H)-oxazolones 102 as part of a program to investigate the chemistry of 2,3-dihydrofuran-2,3diones (Scheme 6.28). The target oxazolones were evaluated as antispasmodics, analgesics, antiinflammatory agents, antihypoxic agents, and antimicrobial agents. Thus, ring opening of a 5-substituted 2,3-dihydrofuran-2,3-dione 101 with cyanamide followed by recyclization affords the desired 2-amino-5-substituted-4(5H)oxazolones 102 in excellent yields.

X

O

O N

NH2CN benzene, rt

4-R-C6H4

O

O

82-96%

H2N

X O O

C6H4-4-R

102

101

X = H, Br, Me R = H, MeO, Cl, Me Scheme 6.28

Displacement of a suitable leaving group is a usually reliable method to introduce a nitrogen substituent at C-2 although there can be considerable variation in the yields.3,7 Recently, reports have employed this methodology to prepare substituted di-tert-butylphenols for evaluation as dual 5-lipoxygenase and cyclooxygenase inhibitors or as selective cyclooxygenase-2 inhibitors (Scheme 6.29).65–67 Knoevenagel condensation of 103 with 104 followed by methylation gave 105. Examples of products obtained from 105 by displacement with hydroxylamines 106, cyanamide 107, and guanidine 108, respectively, are shown in Table 6.5 (Fig. 6.11). Interestingly, attempts to prepare 110 by Knoevenagel condensation of 103 with 109 failed. However, hydrolysis of 105 afforded 110 in acceptable yield. The unusual ring-opened product 111 was isolated from reaction of 105 with O-methyl hydroxylamine in refluxing ethanol. The structure of 111 was confirmed by X-ray crystallography.

76

4(5H)-Oxazolones O HN

O t-Bu

S

CHO

O

t-Bu N

104

HO t-Bu

O

HO

1. NaOAc/AcOH 2. MeI/Et3N, THF

SMe

t-Bu

103

105 HCl/H2O EtOH 53% O HN O

t-Bu

CHO

O

O

t-Bu

109

NH HO

HO

NaOAc/AcOH reflux

t-Bu

O O

t-Bu 110

103

OH RNH2 HCl or

t-Bu

N

105 RNH2, KOtBu EtOH, reflux

SMe NOMe

NOMe

HO t-Bu

111

Scheme 6.29 TABLE 6.5. 5-(BENZYLIDENE)-2-SUBSTITUTED-4(5H)-OXAZOLONES FROM 5-(BENZYLIDENE)-2-(METHYLTHIO)-4(5H)-OXAZOLONE

O t-Bu N O

HO t-Bu

R

106 - 108 Figure 6.11 Compound 106a 106b 106c 106d 107 108

R NHOH NHOMe NHOEt NHOallyl NHCN NH)NH2 NHC(

Conditions NHOH  HCl, KOtBu/EtOH, rt NHOMe  HCl, KOtBu/EtOH, 0
C to rt NHOEt  HCl, KOtBu/EtOH, 30
C NHOallyl  HCl, KOtBu/EtOH, 40
C NH2CN, KOtBu/EtOH, reflux NH2C( NH)NH2  HCl, KOtBu/EtOH, reflux

% Yield 13 29 7 18 38 55

References 67 67 67 67 66 65, 66

77

2-Amino-4(5H)-Oxazolones

Czech workers68 described an interesting oxidative ring contraction that affords 2-amino-5-(carboxyalkyl)-4(5H)-oxazolones 113a–e (Scheme 6.30; Table 6.6, Fig. 6.12). Prolonged reaction of an o-(2-amino-6-hydroxy-4-oxo-3,4-dihydropyrimidine-5-yl)alkane acid or ester 112a–f with 30% hydrogen peroxide in concentrated aqueous ammonia gave 113a–e in 52–65% yield. The structures of 113a–e were confirmed spectroscopically. The authors ruled out the isomeric hydantoins 114a–e as possible products based on the following evidence. Hydrolysis of 113d (n ¼ 4) gave 115a, whereas hydrolysis of the isomeric hydantoin 114d (n ¼ 4) would have yielded 115b. Finally, the hydantoins were independently synthesized and were clearly different from the isolated products. Conversion of 116 to 117 was effected in comparable yield.

O CO R n 2

HN H2N

28% aq. NH4OH pH = 8-9

N

30% H2O2 rt 1 to 2 weeks 52-65%

OH

O N H2N

CO2H n

O n = 1-5 113a-e

112a-e R = H 112f R = Me O N H2N

Ba(OH)2/H2O

O

CO2H

HO2C

CO2H

170 ˚C, autoclave

R

4

113d

115a R = OH 115b R = NH2

O HN O

CO2H n

N H 114a-e

O

H2N

O

28% aq. NH4OH pH = 8-9

HN N

OH

CO2H

30% H2O2 rt, 2 weeks 51%

116

CO2H

N H2N

O 117

Scheme 6.30

Mechanistically, the authors proposed initial hydroxylation at C-5 followed by anion formation of the 5-hydroxyl group, attack at C-2 and rearrangement to the 2amino-4(5H)-oxazolone upon work-up (Scheme 6.31). To support this premise they oxidized 112d to 118, which rearranged to 113d upon exposure to 5% aqueous ammonia at room temperature, consistent with previous work.69

78

4(5H)-Oxazolones TABLE 6.6. 2-AMINO-5-(CARBOXYALKYL)-4(5H)-OXAZOLONES FROM OXIDATIVE RING CONTRACTION OF 2-AMINOPYRIMIDINONESa

O N H2N

O

CO2H n

113a-e Figure 6.12 Compound

n

% Yield

113a 113b 113c 113d 113e

1 2 3 4 5

58 52 60 60–65 62

a

Data from Ref. 68.

O

O

HN H2N

nCO2H N

OH

K2Cr2O7 5 M H2SO4 67%

OH

HN H2N

nCO2H N

O

118 n = 4

112d n = 4

5% aq. NH4OH, rt 75%

O N H2N

O

CO2H n

113d n = 4 Scheme 6.31

The naturally occurring 4(5H)-oxazolone antibiotic indolmycin 69 (Fig. 6.13) has been a focus of several synthetic programs since the structure was first elucidated by Schach von Wittenau and Els nearly 40 years ago.70 These syntheses can be broadly classified as either involving classical cyclization to construct the 4(5H)-oxazolone ring or as elaboration of an existing 4(5H)-oxazolone. The classical cyclization routes will be discussed at this time, whereas routes involving elaboration of an existing 4(5H)-oxazolone will be described in Section 6.3.3.

79

2-Amino-4(5H)-Oxazolones Me 6 N H

H 5 O

O N NHMe

69 Figure 6.13. Indolmycin.

The first, and one of the most straightforward, syntheses of racemic 69 was that of Schach von Wittenau and Els70 after they had determined the structure. Friedel– Crafts alkylation of indole with ethyl 2,3-epoxybutyrate gave the a-indolmycenic acid ester 119a. Cyclization of 119a with N,N0 -dimethylguanidine yielded both 69 and isoindolmycin 120 (Scheme 6.32). In this case, facile epimerization of H-5 had occurred under the basic cyclization conditions. Me CO2Et N H

CO2R

SnCl4/CCl4

O

+

−10 ˚C

OH

N H

Me

119a R = Et 119b R = Me N,N′-dimethylguanidine HI NaOMe/MeOH, rt 1 day

Me 6 N H

H 5 O

Me

O N NHMe

69

6

+ N H

H 5 O

O N NHMe

120

Scheme 6.32

Preobrazhenskaya and co-workers71 employed a similar cyclization strategy in their synthesis of optically active indolmycin (Scheme 6.33). Conversion of indole to the requisite indolmycenic acids 121 was uneventful. Resolution of 121 with aphenethylamine yielded a-indolmycenic acid 121a and b-indolemycenic acid 121b. These were separated, independently esterified with diazomethane and then cyclized with N,N0 -dimethylguanidine to afford 69 and 120, which were separated by fractional crystallization. In addition, these authors also prepared 122 and 123 from cyclization of 119b with urea or thiourea and guanidine, respectively. Shortly after this work, Chan and Hill72 reported the absolute configuration of 69 to be (5S, 6R).

80

4(5H)-Oxazolones Me

N H

CO2H

1. MeCHO/i-PrNH2 AcOH/benzene

3. NaOH/H2O HCl

2. AcOCH(CO 2Et)2 Na/xylene, reflux

4. xylene, reflux

OH

N H 121

46% 4 steps Me

Me CO2H

α-phenethylamine

CO2H +

OH

N H

OH

N H

121a

121b Me CO2R N H

OH

119b R = Me guanidine nitrate or thiourea, NaOEt/EtOH reflux

urea, NaOEt EtOH, reflux

Me

H

Me

O

N H

O

N H

O

O N

NH O

H

NH2 123

122 Scheme 6.33

Mukaiyama and Takeda73 described the first asymmetric synthesis of 69 in which 127 was obtained utilizing their methodology to prepare enantiomerically enriched 3-substituted alkanoic acids (Scheme 6.34).74,75 In their approach, 3formylindole was first protected as the carbobenzyloxy (Cbz) derivative and then treated with 124 to yield 125a and 125b as a 1.5 : 1 ratio of (Z/E) isomers. Thermal isomerization of 125a to 125b followed by addition of methylmagnesium bromide gave 126, which was transformed into 127 in four steps. With the synthesis of 127 secured, they turned their attention to prepare the 4(5H)-oxazolone using conditions that would preclude epimerization at C-5. Thus, protection of the alcohol and saponification followed by a benzoxazolium 128 mediated coupling with Nmethylthiourea gave a mixture of 129 and 130. Thermal rearrangement of the isothiourea 129, hydrolysis of the tetrahydropyran-2-yl (THP) protecting group and now, a benzoxazolium 128 mediated ring closure completed the synthesis of 69.

81

2-Amino-4(5H)-Oxazolones

O CHO

N Me

O

N H

Me

1. CbzCl/NaH, THF 2. 124/TiCl 4-pyridine

N

O

Ph

N

Me

O

Ph

Cbz O

+

O O

125a

Me

O

124

Ph N heat

O

N Me

Cbz

Me

125b MeMgBr, THF

Me

Me O CO2Me

O

4 steps

Ph

OH

N H

N

O

N Me

Cbz 127

Me

126 O Cl N

BF4

Me

Et

1. Dihydropyran TsOH, Et2O

128

2. LiOH,aq. THF

MeNHCNH2

O

Y X

127 N H

S

NHMe

OTHP

Et3N, CH2Cl2/HMPT

129 X = S, Y = NH heat

130 X = NH, Y = S 1. AcOH, aq THF 2. 128, Et3N, MeCN

Me 6 N H

5 O

O N NHMe

69 Scheme 6.34

H

82

4(5H)-Oxazolones

6.3.3.

Reactions

2-Amino-4(5H)-oxazolones can react with or without ring opening depending upon the reaction conditions.3,7 Examples of synthetically useful reactions without ring cleavage include hydrolysis to 2,4-oxazolidinediones, transamination of the 2amino group with primary and secondary amines, and aldol condensations with aromatic aldehydes. However, in some cases, simple alkylation or acylation reactions are complicated by regioselectivity issues and frustratingly poor yields. Similarly, Mannich reactions can yield multiple and sometimes unexpected products. Hydrolysis can affect ring cleavage to produce both a-hydroxy acids and ahydroxy amides although this is not usually a synthetically useful process. On the other hand, hydrolytic ring cleavage with concomitant recyclization can be a useful method to prepare hydantoins. Hydrazinolysis also affects ring cleavage to afford intermediate acylamino guanidines that undergo cyclodehydration to generate 5-(ahydroxyalkyl)-1,2,4-triazolines. Recent representative examples of some of these reactions together with noncyclization approaches to indolmycin 69 will be described in this section. The frustrating and sometimes capricious nature of simple reactions of 2-amino4(5H)-oxazolones is exemplified in the following reports. Ramsh and co-workers76 acetylated 68 with acetyl chloride in benzene but isolated both a poor yield and a poor mass balance of 131 together with dehydroacetic acid 132. Attempts to transaminate 131 with diethylamine in the absence of a solvent or with aniline in benzene failed. The authors recovered 68, which is in stark contrast to an earlier report from Hansen and Masch77 that acetylation of 68 with acetic anhydride gave 131 in 87% yield. In addition, these same authors reported that reaction of 131 with diethylamine at room temperature gave 134 in excellent yield (Scheme 6.35). O H2N

N

benzene, 0-5 ˚C

Ph

O

O

O

AcCl, Et 3N

N

AcHN

68

O

+ Me Ph

O

O

O

131

132

5%

10%

Me

O Ac2O, 100 ˚C

68

N

Et2NH, rt

131 87%

Et2N

85%

Ph

O 134

O

O

HN PhN

O 133

Ph

EtOH, reflux

Ph(Me)N

O

Me

N

Me2SO4, NaOEt

N O

Ph

+

PhN

O

135

136

26%

9%

Scheme 6.35

Ph

83

2-Amino-4(5H)-Oxazolones

Finally, Ramsh and co-workers78 methylated 133 and isolated a 3:1 mixture of 135 and 136 albeit, in only 35% combined yield. The Russian authors offered a much different mechanistic rationale to account for these results than earlier work.79 Mannich reactions of 68 lead to markedly different results depending on the amine component (Schemes 6.36; 6.37). For example, 137 was isolated in poor yield after refluxing a mixture of 68, benzylamine, paraformaldehyde, and acetic acid in methanol.80 The same material was also prepared from 138 under similar conditions. In a continuation of this work, Ramsh and co-workers81 investigated reactions using other primary and secondary amines. When 68 was treated with an excess of formalin and a secondary amine either 139 or 140 was isolated, albeit in fair to modest yield. However, some primary amines gave rise to the oxazolo[3,2-a]1,3,5-triazines 141a–d, whereas other primary amines led to the O O

H2N

Ph

BnNH2, (CH2O)n AcOH, MeOH, reflux

N Ph

O

O

11%

N

BnN

68

O 137 (CH2O)n, AcOH MeOH, reflux 5%

O N BnHN

Ph

O 138

Scheme 6.36

H2N

Ph

O

reflux

68

O RNH2, aq. CH2O EtOH

O 68

H2N

HN

Ph

Ph

141a R = n-Bu, 5% 141b R = t-Bu, 12% 141c R = Me2NCH2CH2, 3% 141d R = Ph, 100%

Scheme 6.37

O

N

OH O

Ph

R

N N

NR2 O

140a R = Pr, 14%

O

R

Ph

N

NR2 O

N

O

R2N

N

139a R = Et, 30% 139b R = (CH2)5, 11%

N H 2N

O

R2NH, aq. CH2O AcOH, EtOH

O N

OH

N R

N N

O

Ph

142a R = Me, 9% 142b R = cyclohexyl, 6%

84

4(5H)-Oxazolones

oxazolo[3,2-a]1,3,5,7-tetrazocines 142a and 142b. Among these bicyclic analogues only 141d, derived from aniline, was isolated in a synthetically useful yield. Lee and co-workers82 reported an interesting example of a conjugated polymer obtained by polymerizing 5-phenyl-2-(propynylamino)-4(5H)-oxazolone in the presence of palladium or platinum chlorides. The authors predict this unique material may have applications for polymer electrolytes, semiconductors, and nonlinear optical (NLO) materials. Indolmycin continues to attract the interest of synthetic chemists as a lead compound for preparation of new antibacterial agents. As such, considerable effort has been expended to develop shorter, more efficient syntheses that can be readily adapted for preparation of analogues. A Pfizer group83 described the first preparation of 148 that did not involve a late stage construction of the 4(5H)-oxazolone (Scheme 6.38). Instead, their strategy Me X N

Me2N

Cbz 145a X =Cl 145b X = OMs

O Li

O N

N

LDA, THF −78 ˚C to rt

O

Me2N

143

THF, −78 ˚C to rt 70%

O 144

Me 6

H 5 O

N H

Me

O

6

40% aq. MeNH2

N

N H

Me CO2Bn O 6 NMe2 5

144 N H 149

O

N

Me

O

N

LDA, THF

O

N

148

145a

N

O

NHMe

146 5SR, 6RS 147 5SR, 6SR

ROCH 2

5 O

146

NMe2

H

O

145a

N

−78 ˚C to rt

N Cbz

150a R = Me 150b R = CH2OCH2CH2OMe 150c R = CH2OBn

O N

CH2OR

151a R = Me 151b R = CH2OCH2CH2OMe 151c R = CH2OBn

MeNH2, −6 ˚C

(+)-indolmycin acetone

Scheme 6.38

2-Amino-4(5H)-Oxazolones

85

employed 143 as a key intermediate to install this ring system very early in the synthetic scheme. Thus, treatment of 143 with lithium diisopropylamide (LDA) gave the enolate 144, which was alkylated with 145a to afford a 2.2:1 mixture of the diastereomers 146 and 147 in 70% yield. These were separated chromatographically and 146 was converted quantitatively into racemic indolmycin 148. However, efforts to adapt this strategy for an asymmetric synthesis of 69 were uniformly disappointing. All attempts to prepare an optically active alkylating agent 145a (X ¼ Cl) gave completely racemic material. A model study for alkylation of 144 with racemic 145b (X ¼ OMs) yielded the unexpected 5-carbobenzyloxy derivative 149 thereby precluding this approach. Preparation of 150a–c incorporating a proline chiral auxillary was straightforward. Alkylation of these analogues with 145a gave 151a–c from which amine exchange with methylamine under nonepimerizing conditions afforded (þ)-indolmycin. However, the enantiomeric excess (ee) was a disappointing 9–17%. Nonetheless, the authors demonstrated an overall strategy that was efficient and convergent requiring only five steps to prepare racemic indolmycin in 34% yield. More recent syntheses of indolmycin derivatives and analogues have also capitalized on the strategy of the Pfizer group (see above). For example, Witty and co-workers84 utilized 143 and 152 to prepare a series of analogues that were evaluated as inhibitors of Staphylococcus aureus (Scheme 6.39). In their work, the lithium enolates 144 and 153 were reacted with 145a and 154a–g followed by a straightforward reaction sequence to yield the target compounds 148 and 155–163. The respective diastereomers of 148, 155, 156, and 159–163 were separated chromatographically and evaluated individually. In all cases, the diastereomers with the same relative stereochemistry as indolmycin were the most active. This same group47 also utilized 144 in their attempts to prepare the conformationally restricted indolmycin analogue 164. Initially, the authors envisioned construction of the [5,6,6] tricylic ring on a fully elaborated intermediate containing a 4(5H)-oxazolone side chain (Scheme 6.40). Conversion of 2-methyl-3-nitrobenzoic acid to the requisite indole precursor 165 was readily accomplished in five steps. Reaction of 165 with 144 gave 166 quantitatively, isolated as a mixture of diastereomers. However, at this point the strategy to prepare the [5,6,6] tricyclic ring system was completely frustrated by their inability to functionalize or eliminate the tertiary hydroxyl group. Ultimately, 166 was converted to the openchain indolymycin homologue 167 without incident. An alternative strategy involving addition of 144 to an appropriately functionalized tricyclic system proved to be successful (Scheme 6.41). In this approach, protection of the indole nitrogen fortuitously proved unnecessary. Conversion of 168 to the unstable iodide 169a or to the phenylselenide 169b was straightforward. The key intermediate unsaturated oxindole 170 was isolated in 50% overall yield from 169b. Only one racemic diastereomer 171 of four possible pairs was isolated from low-temperature addition of 144 to 170. Conversion of 171 to the target 172 occurred without detectable epimerization at C-8 or C-11. The C-8 (S), C-11 (S) relative stereochemistry was confirmed crystallographically. Complete

86

4(5H)-Oxazolones

R1

O

Me2N

O

N

O Li LDA

N

THF

R

Me2N

R

O

145a R1 = CHClMe, R2 = Cbz

144 R = H 153 R = Me

143 R = H 152 R = Me

1-3 steps

R2

N

154a R1 = CHClEt, R2 = Cbz 154b R1 = CF(Me)2, R2 = Cbz 154c R1 = CH2NMe3+, R2 = H 154d R1= CH=CHCO2tBu, R2 = TBDMS 154e R1 = CH=CHNO2, R2 = SEM 154f R1 = CHO, R2 = TBDMS 154g R1 = COMe, R2 = TBDMS

R3

Me O Me

O N

N

O NHMe

N H

O NHMe

156

148 R3 = Me 155 R3 = Et 158 R3 = H 162 R3 = OH

Me O

N

O N H

Me

N H

NHMe

157

OH HO2C

O

AcOH H2N

159

N

O NHMe

O

N

N O N H

N

O

N H

O NHMe

160 Me

N H 161

OH O N O

N H 163 Scheme 6.39

NHMe

NHMe

Me

CO2H

O

5 steps 58%

Me

144, THF

N

NO2

100%

TBDMS 165 TBDMS = tert-butyldimethylsilyl

O

O

N O

HO

NHMe

O

Me N

N H

R 166 R = TBDMS, R1 = Me

2 steps 85%

N

Me

N(R1)Me

164

167 R = R1 = H

Scheme 6.40

NaH, I2, THF or PhSeCl

NaIO4, EtOH heat

X

O

O

O

N H

N H

N H

169a X = I 169b X = SePh

168

170

NHMe

NMe2 H

HO

H

N 1. DIBAL-H, CH 2Cl2, −78 ˚C

144, THF

O

−78 to −20 ˚C

HO

N

11

8

O

2. MeNH2, sealed tube

O N H

N H 171

172 NMe2

H

HO

NHMe O HH

N 1. DIBAL-H, CH 2Cl2, −78 ˚C

TMG

171

O

O

2. MeNH2, sealed tube

O N H

N H

173

174

TMG = 1,1,3,3-tetramethylguanidine

Scheme 6.41

87

N

11

8

88

4(5H)-Oxazolones

epimerization occurred at C-11 to produce 173 when 171 was treated with tetramethylguanidine. Recently, Shue85 described further refinements and improvements to the Pfizer strategy (Scheme 6.42). Acylation of 143 with benzyl cyanoformate gave the requisite starting 4(5H)-oxazolone 175. Alkylation of 175 with the gramine analogue 176 yielded 177 quantitatively from which 146 and 147 were obtained as a 1:1.5 mixture of diastereomer pairs. After chromatographic separation each pair was converted independently to ()-indolmycin 148a and ()-isoindolmycin 148b. This synthesis requires four steps to produce 148a in 47% overall yield from readily available starting materials. O 143

Me2N

66%

(n-Bu)3P, MeCN reflux

N

LDA, BnO 2CCN

CO2Bn

O

Me NMe2

175 N H 176 100%

Me CO2Bn

Me 1. H2, 10% Pd-C 2. EtOH, reflux

O N H

O

6

NMe2

N

83%

177

N H

H 5 O

O N NMe2

146 5SR, 6RS 147 5SR, 6SR Me

MeNH2, reflux

6

90%

N H

H 5 O

O N NHMe

148a 5SR, 6RS 148b 5SR, 6SR Scheme 6.42

Very recently, Kamiyama and co-workers86 described a stereocontrolled synthesis of 69 based on Schach von Wittenau and Els original route.70 In this newer approach (Scheme 6.43), ethyl crotonate was converted to ethyl (2S, 3R)-2,3epoxybutanoate using the commercially available asymmetric dihydroxylation mixture, AD-mix-b (Aldrich Chemical Company). The epoxide was then ring opened with indolemagnesium bromide to give ethyl (2S, 3R)-2-hydroxy-3-(indol3-yl)butanoate 119a in very good yield. Cyclization of 119a with guanidine at room temperature afforded 178 in which the 4(5H)-oxazolone ring was created

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

89

without epimerization at C-5. Finally, amine exchange then completed the synthesis of 69.

N

CO2Et Me

CO2Et

AD-mix-β

O

50%

Me

MgBr CH2Cl2 −25 ˚ to 30 ˚C

Me

72%

Me

tBuOH, rt

82%

6 N H

H 5 O

OH

N H

95% ee

guanidine HCl KOtBu,

2 CO2Et

3

119a Me

O 40% aq MeNH2

N

5 ˚C, 3 h

NH2

60%

6 N H

H 5 O

O N NHMe

69

178 Scheme 6.43

6.4. 2-ALKOXY-4(5H)-OXAZOLONES AND 2-HYDROXY-4(5H)OXAZOLONES (2,4-OXAZOLIDINEDIONES) 6.4.1.

Introduction

There are only a few reports of 2-alkoxy-4(5H)-oxazolones and these are limited to highly substituted 4-(arylimino)-2-ethoxy- or 4-(alkylimino)-2-ethoxy-analogues.87–89 There are no reports of a 2-hydroxy-3-unsubstituted-4(5H)-oxazolone that exists as a hydroxy tautomer 179a–179d. Rather, the predominant tautomer for a 2-hydroxy-3-unsubstituted-4(5H)-oxazolone is the 2,4-oxazolidinedione, 179 (Fig. 6.14).5 For example, Codding90 determined the structure of 5,5-diphenyl2,4-oxazolidinedione to be 180 by X-ray crystallography. More recently, Japanese workers91 crystallographically determined the structure of 5-(4-methoxybenzylidene)-2,4-oxazolidinedione to be 181 during their studies of hydrogen-bonding effects in potential nonlinear optical materials. In principle then, these saturated imides and derivatives are beyond the scope of this chapter. However, the synthesis and reactions of some 3-unsubstituted derivatives of 179 are included in the interest of completeness. No attempt has been made to provide an exhaustive review of all examples of 2,4-oxazolidinediones.92 Rather, selected examples from the recent literature that illustrate general synthetic approaches or novel reactions are described.

90

4(5H)-Oxazolones OH N O

O 179b

OH

O

O

O

HN

N

HN O

O 179a

HO

O

O 179c

179

OH N HO

O 179d

O HN O

O Ph

O 180

Ph

OMe

HN O

O 181

Figure 6.14. 2,4-Oxazolidinedione tautomers.

Derivatives that are 3-substituted such as the antiepileptic agents, trimethadione (Tridione1), 182a, or dimethadione (Paradione1), 182b, the fungicides, famoxadone (Famoxate1), 183, chlozolinate, 184 and the herbicide vinchlozolin, 185 are beyond the scope of this chapter (Fig. 6.15). Nonetheless, Refs. 93–100 and references cited therein contain an interesting description of the syntheses and reactions of such analogues. In addition, the reader should also consult the following selected references for further examples.  3-Alkyl- or 3-aryl-2,4-oxazolidinediones via photochemical cyclization,101 organonickel-mediated carbonylation,102 cyclization of N-alkenyl-a-acetamides,103 carboxylation and cyclization of 2-propynamides,104 cyclization of O-carbamates of a-hydroxy acetic acids and esters,105,106 cyclization of ahydroxy acetamides,107 and catalytic asymmetric dihydroxylation (ADH) of N-alkenoyl-2-oxazolidinones.108  3-(Arylideneamino)-2,4-oxazolidinediones via cyclization of arylidine benzilic acid hydrazides109 and 3-amino-2,4-oxazolidinediones from perhydro1,5,2-dioxazine-3,6-diones.110

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones O

Me N O

PhHN

O

O N

Me O

R

91

Me O

OPh 182a R = Me 182b R = Et

183

Cl

Cl O N

Cl O

O Me

O

N

Cl O

CO2Et

Me O

185

184

Figure 6.15. 3-Substituted 2,4-oxazolidinediones.

 3-Alkoxy-2,4-oxazolidinediones via cyclization of N-alkoxy-2-hydroxycarboxamides,111,113–116 and cyclization of 2-hydroxycarbohydroxamic acids.112

6.4.2.

2-Alkoxy-4(5H)-Oxazolones

Kauffman87 prepared the 2-ethoxy-4-(p-tolylimino) derivatives 186a and 186b by thermolysis of ethyl azidoformate in the presence of keteneimines. Mild acid hydrolysis afforded 187a and 187b that were independently converted to 5,5dimethyl- and 5,5-diethyl-2,4-oxazolidinedione, 188a and 188b, respectively, upon more vigorous hydrolysis. Interestingly, 187a and 187b were recovered unchanged after refluxing 8 h in 6 M hydrochloric acid (Scheme 6.44). N-C4H4-4-Me N

N3CO2Et

R2C=C=N-C6H4-4-Me R = Me, Et

100 ˚C 70%

EtO

O

N-C6H4-4-Me

R

3 M AcOH

R

acetone, rt

186a R = Me 186b R = Et O 187a R = Me 187b R = Et

EtOH, reflux

O

R O

R

188a R = Me 188b R = Et Scheme 6.44

O

R O

R

187a R = Me 187b R = Et

HN

12 M HCl

HN

92

4(5H)-Oxazolones

L’abbe´ and co-workers88 described reactions of 186a with a variety of heterocumulenes (X¼C¼Y) to generate 189a–e and/or 190a–e (Table 6.7, Fig. 6.16). The authors proposed a ring-opening cycloaddition that is mechanistically related to the Boulton-Katritzky rearrangement.117 Reaction of 186a with chlorosulfonyl isocyanate also produced the hydrolysis product 191 that was the only isolable product after chromatographic purification. Chromatographic purification of 189c affected hydrolysis of the benzamide yielding only 192. Similarly, 193 was isolated as the sole product from reaction of 186a with bis(ethoxycarbonyl)ketene, whereas diphenylketene reacted with 186a to give the spirocyclic adduct, 194 (Scheme 6.45). No cycloadducts were isolated from phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, methyl acrylate, methyl vinyl ketone, or acrylonitrile.

4-Me-C6H4

N-C6H4-4-Me EtO

X

X=C=Y

N

N

Me

Y

N

Me

O

EtO

Me Me

O

186a

X = TosN, ClSO 2N, PhCON, PhSO2N, (EtO2C)2C Y = O, S

N X

Me Y

N

and/or Y

Me

189a-e

N ClSO2N

Me

NCO2Et

4-Me-C6H4 N

Me O

Me X

190a-e O

4-Me-C6H4

NCO2Et

4-Me-C6H4

NCO2Et

4-Me-C6H4

O

Me

Me O

191

Me

192 O O

4-Me-C6H4 N (EtO2C)2C

Ph Me

O 193

Me

N-C6H4-4-Me

Ph N EtO

Me O

Me

194 Scheme 6.45

This same group89 also investigated the thermolysis of a-bromo amidines as a means to prepare 2-alkoxy-4(5H)-oxazolones. Here, an a-bromo imide 195a or 195b was converted to the corresponding amidine 196a or 196b, which upon

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

93

TABLE 6.7. BOULTON-KATRITZKY REARRANGEMENT PRODUCTS FROM 5,5-DIMETHYL2-ETHOXY-4-(p-TOLYLIMINO)-4(5H)-OXAZOLONE AND HETEROCUMULENESa

NCO2Et

4-Me-C6H4 N X

N

Me Y

Me

Y

NCO2Et

4-Me-C6H4

189

Me Me

X 190

Figure 6.16 X TosN ClSO2N PhCON PhSO2N TosN (EtO2C)2C a

Y

Compound

% Yield

Compound

% Yield

O O O S S O

189a 189b 189c

11% 25% 34%

190a 191

47 20

190d 190e 193

76 71 17

Conditions benzene, reflux, 7 days benzene, 70
C MeCN, reflux benzene, 75
C benzene, 75
C benzene, 80
C

Data from Ref. 88.

heating, eliminated hydrogen bromide with concomitant cyclization and produced the intermediate 2-ethoxy-4(5H)-oxazolone 197a or 197b. Hydrolytic work-up of 197a or 197b then afforded 198a or 198b. Thermolysis of 196a or 196b in the presence of tert-butylamine produced 199a or 199b (Scheme 6.46). Me Br

1. PCl5 2. t-BuNH2

O

R

NHCO2Et

Me Br R

petroleum ether CHCl3, heat

NHCO2Et

195a R = Me 195b R = H

196a R = Me 196b R = H

Nt-Bu N EtO

Nt-Bu

Nt-Bu

H2O

HN

Me O

R

197a R = Me 197b R = H

O

Me O

R

198a R = Me; 20-25% from 195a 198b R = H; 20-25% from 195b Nt-Bu

Me Br R

Nt-Bu NHCO2Et

N

t-BuNH2, heat CHCl3/petroleum ether

t-BuNH

Me O

R

199a R = Me; 30% from 195a 199b R = H; 30% from 195b

196a R = Me 196b R = H Scheme 6.46

94

4(5H)-Oxazolones

There are no reports that alkylation of a 2,4-oxazolidinedione generates a 2-alkoxy-4(5H)-oxazolone. Alkylation of the sodium or potassium salt of a 2,4-oxazolidinedione was described >50 years ago and is an excellent means to prepare the corresponding N-alkyl derivatives.118–121 Reaction of the silver salt of 5,5-dimethyl-2,4-oxazolidinedione 188a with ethyl iodide was shown to yield 5,5dimethyl-4-ethoxy-2(5H)-oxazolone 200118,119 and not 201 as originally reported.122 There was no evidence for the formation of 5,5-dimethyl-2-ethoxy4(5H)-oxazolone 202 (Scheme 6.47). Further examples of 4-alkoxy-5-substituted4(5H)-oxazolones will be described in Section 6.4.3.1. OEt

O HN O

Me

O

Me

O

N

Ag2O, EtI

O O

Ag2O, EtI

188a

Me

N O

O

O

Et

Me O

Me

O 200

188a

HN

Me

N

Me O

Me

201

EtO

Me O

Me

202

Scheme 6.47

6.4.3.

2-Hydroxy-4(5H)-Oxazolones (2,4-Oxazolidinediones)

6.4.3.1. Synthesis The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene.5 A third very useful approach is cyclodehydration of O-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate.5,99 However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfonyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point.123–129 Sa´nchez-Viesca and co-workers123,124 employed both synthetic routes to prepare 203 and 204 (Scheme 6.48). Cyclization of 205 was used to prepare 206, a key intermediate in the synthesis of potential antihyperglycemic agents like 207 and

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

95

208.125–127 Alternatively, Japanese workers128 cyclized 209, a fully elaborated analogue of 205 and prepared 210, which was also evaluated as an antidiabetic agent. O CONH2

HN OMe

HO

(EtO)2CO

O

NaOMe, MeOH

MeO

OMe

O MeO

OMe

OMe 203 OMe

EtO2C

OMe

O HN

urea, NaOEt

OMe

HO

O

EtOH

OMe O

OMe

OMe 204

OBn

CO2Et HO

O urea, NaOMe MeOH, EtOH

OBn

HN O

rt to reflux

O

205

206 82%, Ref. 125 48%, Ref. 127 N O

steps

O

HN

N

O

Me

O

O 207 O

O

HN O

SO2Me

O 208

Me O

CO2Et

Me Ph Me

rt to reflux

HO

O

urea, NaOMe MeOH, EtOH

O

HN O

74%

209

O 210

Scheme 6.48

Ph Me

96

4(5H)-Oxazolones

Pfizer chemists129 prepared a novel series of 5-substituted-2,4-oxazolidinediones 212a–n via cyclization of the corresponding a-hydroxy amides, 211a–n (Scheme 6.49). Among the derivatives prepared, 212a–d, 212g, 212h, 212l, and 212m showed statistically significant hypoglycemic activity.

R

CONH2

EtOH, reflux

OH 211a-n

O

HN O

R

O 212a-n

O

O

O R3

HN

O

(EtO)2CO, NaOMe,

HN O

O R1

Me O

O

O R1

R2

212a R1 = R2 = R3 = H 212b R1 = Me, R2 = R3 = H, cis 212c R1 = Me, R2 = R3 = H, trans 212d R1 = Et, R2 = R3 = H, cis 212e R1 = Et, R2 = R3 = H, trans 212f R1 = R3 = H, R2 = Me 212g R1 = R2 = H, R3 = Me

212h

212i R1 = Me, R2 = H 212j R1 = H, R2 = Me

O

O

O

HN O

O

R2

HN

NH

O

HN O

O

O 212k

212l exo 212m endo

212n

Scheme 6.49

Spriocyclic analogues of 2,4-oxazolidinediones are readily prepared via either methodology although not always in comparable yield or efficiency (Scheme 6.50). For example, Trigo and co-workers130 cyclized ethyl 3-hydroxyquinuclidine-3carboxylate, 213 (R ¼ OEt) with urea to furnish 214 in fair yield. In contrast, cyclization of the corresponding a-hydroxy amide, 213 (R ¼ NH2) afforded 214 in 76% yield. This same group131 found that cyclization of the a-hydroxy amides, 215–217 afforded 218–220 in 66–95% yields. This improvement was significant relative to their earlier work using the corresponding a-hydroxy esters.132

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones OH N

COR

urea, NaOEt EtOH, reflux or (EtO)2CO, NaOEt, EtOH, reflux

97

O

O

NH

N O 214

213

From R = OEt 30% From R = NH2 76% O

O H2N

HN O

HO

O

215

218 66%

O diethyl carbonate NaOMe, MeOH

H2N HO

O HN

reflux

O

O

216

219 74%

O H2N

O

HO HN O

217

O

220 95%

Scheme 6.50

So¨llhuber and co-workers133 also described similar results during their work on ester and sulfonamide bioisosteres (Scheme 6.51). Here, multiple attempts to prepare the spirocyclic 2,4-oxazolidinedione 224 via cyclization of 222 failed completely, starting material was recovered. Alternatively, cyclization of 223 afforded 224 in poor yield. The solution to this problem was treatment of the cyanohydrin 221 with chlorosulfonyl isocyanate to generate 225 from which 224 was isolated after hydrolysis. The trans quinolizidine ring junction was supported by 13C NMR data together with the presence of Bohlmann bands134 in the IR spectrum. The stereochemistry of 225 (2R, 11bS) was based on the 1H NMR spectrum that shows a deshielding affect on the chemical shift of the 11b proton. This finding was attributed to the presence of the C-40 imino group.

98

4(5H)-Oxazolones

1. HCl(g), EtOH, −30 ˚C

N H NC

+

N

2. 10% HCl, CHCl3, rt

N

H

OH

H

HO

221

CO2Et

223

40%

20%

urea, NaOEt EtOH, reflux

CONH2

NaH, (EtO)2CO,

N

222

HO

222

223 CH2Cl2, DMF, 100 ˚C 10%

H O

O NH O 224

12M HCl, MeOH reflux 76%

ClSO2NCO,

221

N

CH2Cl2, DMF, −30˚ to 80 ˚C 56%

H NH

O NH O 225

Scheme 6.51

Spirocyclic 2,4-oxazolidinedione analogues have been prepared and evaluated as cholinergic agents by Japanese workers (Scheme 6.52).135 For example, condensation of the a-hydroxy ester 226 with urea produced 227a quantitatively, whereas reaction with thiourea afforded 227b in poor yield together with 228. OH

O

urea, NaOEt

Me N

Me N

NH

EtOH, reflux 99%

CO2Me

O 227a X = O 227b X = S

226 thiourea, NaOEt EtOH, reflux

NH2

O 227b + Me N 12%

N O 228 18%

Scheme 6.52

X

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

99

Radiolabeled analogues of dimethadione (Paradione1) 182b have been synthesized employing both cyclization methods (Scheme 6.53). Ginos and co-workers136 condensed [2-11C]dimethyl carbonate with 2-hydroxyisobutyramide to prepare [2-11C]5,5-dimethyl-2,4-oxazolidinedione 229 for positron emission tomography (PET) studies. Independently, French chemists137 employed the same strategy to prepare 229 using [2-11C]diethyl carbonate. In both cases, these groups reported comparable chemical and radiochemical yields. Shortly thereafter, Ginos138 reported the results of synthetic approaches to 229 with or without dimethyl carbonate as a carrier. With excess dimethyl carbonate as a carrier, 229 was obtained in higher yields and purity but with a lower specific activity. Diksic139 showed that [11C]phosgene condensed rapidly with 2-hydroxyisobutyramide using powdered potassium hydroxide in acetonitrile to afford 229 in 40–60% radiochemical yield with extremely high chemical (98%) and radiochemical (99%) purity. This ‘‘no-carrier-added’’ approach was superior to previous methods in that no high temperatures (130–150
C) or extensive HPLC purification was required. A Japanese group140 has prepared [2-13C]5,5-dimethyl-2,4-oxazolidinedione 230, the penultimate precursor to [2-13C]trimethadione via condensation of [13C]urea with ethyl a-hydroxyisobutyrate. [2-11C] (MeO)2CO

Me Me

CONH2

NaOMe, MeOH, 150 ˚C or [2-11C] (EtO)2CO

OH

NaOEt, EtOH, 130 ˚C 78-92%

O HN 11C O O

Me

CONH2

KOH, MeCN −5 ˚ to rt, 30 min

OH

Me

229 O

[11C]phosgene

Me

Me

HN 11C O O

Me Me

229 Me Me

CO2Et OH

[13C]urea, NaOEt EtOH, reflux 74%

O HN 13C O O

Me Me

230 Scheme 6.53

Schnur and colleagues at Pfizer141–145 prepared a wide variety of 2,4-oxazolidinediones that have been evaluated as hypoglycemic agents and as aldose reductase inhibitors (Tables 6.8, Fig. 6.17; 6.9, Fig. 6.18; Fig. 6.19). Several approaches were evaluated including a trimethylsilylcyanide-mediated synthesis of cyanohydrins that were then converted to the corresponding imidates in situ followed by cyclization and work-up. This methodology has been successfully

100

4(5H)-Oxazolones TABLE 6.8. 5-ARYL-2,4-OXAZOLIDINEDIONES FROM CYCLIZATION OF a-HYDROXY IMIDATESa

O 1. TMSCN, ZnI2

ArCHO

OEt HCl

HN

CH2Cl2

Ar

2. HCl, EtOH

HN

COCl2, Et3N

O

THF, 0-5 ˚C

HO

O

Ar

231

Figure 6.17 Ar 2-MeO C6H4 2-F C6H4 2-EtO C6H4 5-Cl-2-MeO C6H3  5-F-2-MeO C6H3  2-Cl C6H4 3-Cl C6H4  2-MeO-5-NO2 C6H3 3-F C6H4  2-Me C6H4 2-CF3 C6H4 3-PhO C6H4 2-BnO C6H4 3-CF3 C6H4 2-Cl-6-MeO C6H3  2-Cl-6-F C6H3  2-MeO-5-Me C6H3 Ph  2-MeO 6-NO2 C6H3 2,6-di-F C6H3 a

% Yield 42 60 70 69 60 68 56 60 56 77 54 66 55 53 74 83 63 62 86 57

Data from Ref. 143.

applied to the synthesis of 5-aryl derivatives 231 as well as spirocyclic analogues 232a and 232b.143,144 Other spirocyclic derivatives 232c–f were prepared from an imidate using 1,10 -carbonyldiimidazole (CDI).145 Furanyl- and thienyl-C-5 substituted analogues 233 were also prepared via an a-hydroxy imidate. In contrast, analogues such as 234 were derived from base-catalyzed ring contraction of alloxans.141 Other 5-heteroaryl-2,4-oxazoloidinediones prepared by Schnur and co-workers include 235–240.142 Doya146 disclosed an improved process for preparation of 2,4-oxazolidinediones from a-hydroxy esters and urea in a recent patent. The process effects condensation of the starting materials using a metal oxide, for example, lead oxide at 100–250
C followed by fractional distillation to recover any unreacted a-hydroxy ester. The product is then isolated by distillation. The recovered starting material can be recycled. 5-Methyl-2,4-oxazolidinedione, 212 (R ¼ Me) was isolated in 80.4% yield of 99.4% purity in this manner.

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

101

TABLE 6.9. SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM CYCLIZATION OF a-HYDROXY IMIDATESa

O NH O

O

R X 232 Figure 6.18 Structure

R H 6-Cl 6-Br H 6-F H

232a 232b 232c 232d 232e 232f a

X

% Yield

O O O S S CH2

57 79 38 45 41 28

Data from Ref. 144. O

O

HN O

HN X

O

O

X

O

R

R 234a X = O; furan-2-yl; R = MeO, Me, Ph, 234b X = O; furan-3-yl; R = H, I 234c X = S; thien-2-yl; R = H, MeO 234d X = S; thien-3-yl; R = H

233a X = O; furan-2-yl; R = H, Cl, Br, 233b X = O; furan-3-yl; R = H 233c X = S; thien-2-yl; R = H, Me, Ph, F, Cl, Br, EtO 233d X = S; thien-3-yl; R = H, F, Br, MeO, MeS O

O

O

HN

HN

HN

O

O

O

O

O

N

237

236

O

O

O

HN O

O

N

235

O

R N

HN

HN X

O

O

X

O

O

Y R 238a X = NR 238b X = O 238c X = S

239a X = S, Y = N 239b X = O, Y = N

X

Y

R 240a X = S, Y = N 240b X = O, Y = N

Figure 6.19. 5-Heteroaryl-2,4-oxazolidinediones.

102

4(5H)-Oxazolones BnO

H N

O O

R

O 3 steps

CONH2

R

O

O K2CO3, toluene

R

O

O

N

O reflux

N

R1

N

R1

R1

242

241

243

KOt-Bu DMF

39-54%

O

HO

R1 241

CO2Et

CSI, THF

O R

H2NCOO

CO2Et

1. TMSCN

N

O

O

O 2. HCl, EtOH

R

N R1 244

66-87%

R

N R1 245

Scheme 6.54

Imperial Chemical Industries (ICI) chemists147 prepared a novel series of spirocyclic 2,4-oxazolidinediones 243 derived from 7-substituted isatins (Scheme 6.54). The key intermediate a-acyloxy amides 242 were readily prepared from 241 in three steps. Base-catalyzed cyclization of 242 then afforded the target compounds that were reported to be potent inhibitors of aldose reductase. Pfizer chemists148 approached 5-substituted isatin spirocyclic analogues 243 via ahydroxy esters 244 that were converted to the corresponding a-carbamyloxy esters 245 in good yield using chlorosulfonyl isocyanate. Cyclization of 245 with potassium tert-butoxide then produced 243 in acceptable yield (Scheme 6.54; Table 6.10, Fig. 6.20). So¨llhuber’s group149 extended the scope of their earlier work133 using chlorosulfonyl isocyanate to synthesize spirocyclic 2,4-oxazolidinediones. They prepared 188a, 214, 218, and 232 together with several additional examples using this methodology. On the other hand, Wyeth-Ayerst chemists150 encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium tert-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

103

TABLE 6.10. SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM 5- OR 7-SUBSTITUTED ISATINS

R

H N

O

O O O

N R1 243 Figure 6.20 Compound 243a 243b 243c 243d 243e 243f 243g 243h 243i a

R 7-F 7-CF3 7-Cl 7-CH3 H 5-F 5-Cl 5-Cl 5-Cl

R1

% Yielda

3,4-di-Cl Bn 4-Br Bn 3-CF3 Bn 2-F-4-Br Bn Ph 4-F C6H4 Me i-Pr 4-Cl Bn

NR NR NR NR NR 54 49 48 39

Reference 147 147 147 147 148 148 148 148 148

Not reported ¼ NR.

conversion of 246 to the a-hydroxy amide 248 followed by anion formation with LiHMDS and cyclization with carbonyldiimidazole produced 247 in good yield if R was a cyclohexyl group. The same reaction sequence was also very successful when it was applied to prepare analogues of 250. Cyclization of an a-hydroxy ester with a metal cyanate is also a useful approach to prepare 2,4-oxazolidinediones.151–153 Japanese workers have employed this method to prepare a variety of analogues that have been evaluated as antiulcer agents 251,151 antidiabetic agents 252a–c,152 and as antitumor agents 253a–c (Scheme 6.56).153 2,4-Oxazolidinediones can be obtained from electrochemical reduction of a-halo amides in the presence of carbon dioxide.154–156 Originally, the 2,4-oxazolidinediones were observed as a component in a product mixture isolated during efforts to develop a synthetically useful synthesis of malonamides.154 Mechanistically, the authors proposed that carbon dioxide was reduced to the radical anion at low working potentials. This radical anion then generated the conjugate base of the ahalo amide followed by carboxylation and cyclization. The yields were modest but the authors noted this was the first example where the carbon dioxide radical anion functioned as an electrogenerated base. Further refinements in the reaction conditions resulted in a general synthesis of 3,5-dialkyl- and 3,5,5-trialkyl-2,4-oxazolidinediones including trimethadione

104

4(5H)-Oxazolones O HO

NH

O

CO2Et

O N R

1. CSI, THF

N R

2. KOt-Bu, THF 11-44%

O

O

247

246 NH3

MeOH

HO

CONH2

R = 4-Br-Bn R = 2-F-4-Br-Bn

LiHMDS, THF

247 R = cyclohexyl

N R CDI 63%

O 248 O HO

NH

O

CONH2

O N R

LiHMDS, THF

N R S O

CDI 60-92%

O

S O

249

O

250 R = Me, t-Bu, 2-F-4-Br-Bn Scheme 6.55

O R R1

CO2Et

HN

1. KOCN

R O

n-BuOH 2. 2M HCl 36-98%

OH

O

R1

251 R = H, Me R1 = H, Me, Et, Bn, Ph O

O

HN O

HN O

OR1

O

n

OR 252a n = 1, R = Bn, R1 = Et 252b n = 1, R = Me, R1 = Bn 252c n = 3, R = Bn, R1 = Me

O

R1 n

OR 253a n = 1, R = H, R1 = OMe 253b n = 3, R = Bn, R1 = H 253c n = 5, R = Bn, R1 = H

Scheme 6.56

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

105

(Tridione1), 182a.155 Now, the reaction of 255 and carbon dioxide was carried out in the presence of a probase (PB), for example, tetraethyl ethylenetetracarboxylate, 256 (Scheme 6.57). In this way, the electrogenerated base (EGB) derived from 256 affected quantitative conversion of 255 to the conjugate base. Following carboxylation and cyclization, 182a, and analogues of 257 were isolated in modest to excellent yield. O R1 R

NHR2

CO2, TEAP-DMF PB 40-95%

X

R2 O

255

O N R1 O

R

257 R, R1 = H, Me, R2 = H, Me, Bn, allyl

R, R1 = H, Me, R2 = H, Me, Bn, allyl X = Cl, Br, OTs

TEAP = tetraethylammonium perchlorate PB = probase EtO2C

CO2Et

EtO2C

CO2Et 256

Scheme 6.57

These same authors156 reported that electrochemically generated superoxide ion can also function effectively to activate carbon dioxide to yield a carboxylating agent. In this case, mechanistically, they proposed a peroxycarbonate radical anion. Interestingly, a nonelectrochemical system using carbon dioxide, dicyclohexyl-18crown-6, and a molar equivalent of potassium superoxide was ineffective. Yields of 257 comparable to the electrochemical process were obtained only using a molar excess of potassium superoxide. Very recently, this group157 has succeeded in developing a synthetically useful, nonelectrochemical process. Condensation of an a-halo amide with an excess of tetraethylammonium hydrogen carbonate (TEAHC) in acetonitrile gave 182a and 257 analogues in excellent yields. Similar reaction of a-halo or a-tosyl acetanilides afforded modest yields of 257 (R2 ¼ Ph) owing to the attenuated nucleophilicity of the amide anion. Oxidation of 5-substituted barbituric acids 258 with concomitant ring contraction has been shown to afford 2,4-oxazolidinediones 260 (Scheme 6.58).158 Similarly, examples of 5-aryl- and 5-heteroaryl-2,4-oxazolidinediones, for example, 231 and 233–240 (Table 6.8 and Fig. 6.19) have been prepared from alloxan hydrate 261. Thus, conversion of 261 to the dilauric acid intermediates 262 and reaction with sodium hydroxide gave the target compounds.141–143,159 Swiss chemists160 isolated 265 as a side product (12% yield) from the oxidation of the thymidine base in 263 during their preparation of 264 (Scheme 6.58).

106

4(5H)-Oxazolones O R

O R1

N

O

H2O2, NaOH KH2PO4, 50 ˚C

O

N

R O

N

R

N O

O

259

258

O

R1

O OH

N H

260

R = H, Me R1 = Bn, Ph

OH

HN O

O

R

R

R = H, Me R1 = Bn, Ph O

OH R1

N

OH Ar

HN

O

1M NaOH, rt

231, 233-240 N H

O

261

R = H, Me R1 = Bn, Ph

O

262 O

O Me

NH

TBDPSO

N O

O

Me TBDPSO 2. 4-MeO-BnOCH2Cl DBU, CH2Cl2, MeCN

N

(4-MeO)BOM O

O CO2Me

CHO 263

N

1. PDC, MeOH, rt

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

264 BOM = BnOCH2-

O TBDPSO

Me

HN O

O NH

O

CO2Me

O

265

Scheme 6.58

Poje and co-workers161 obtained the caffolide 268 from uric acid 266 via the alloxanic acid ureide 267 during their studies on biomimetic intermediates in oxidative transformations of purines (Scheme 6.59). Rapi and co-workers162 proposed that oxidation of the 2-aminooxazole moiety in some 17b-(2-aminooxazol-4-yl) steroids allowed these compounds to act as peroxide scavengers (Scheme 6.59). Oxidation of 269 and 271 with hydrogen peroxide generated 270 and 272 among the isolated products. A Japanese group163 isolated the antioxidant 273 from roasted perilla seed (Fig. 6.21), which is the first example of a naturally occurring 2,4-oxazolidinedione. The absolute configuration of 273 has not been determined.

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones O

O

H N

HN

Cl2, H2O

HN

O heat

N H

N H

O

NH2 O

OH H N

O

O

OH H N

N H

O

N N H O H H

O

107

O

N H

267

266 O H N

HN

H2O

O

O

O NH

O 268 NH2 O N

O

OH

O

H N O

O

H2O2

O

MeOH-CH2Cl2 9.8%

H

H O

O 269

270 NH2 O N

HO

HO

OH Me

H

O

O

Me

H

5.0%

F

O O

H2O2 MeOH-CH2Cl2

H N

F O

271

272 Scheme 6.59

H N

O

OH

O O

OH 273

Figure 6.21. A naturally occurring 2,4-oxazolidinedione from roasted perilla seed.

108

4(5H)-Oxazolones

6.4.3.2. Reactions The 2,4-oxazolidinedione ring system readily undergoes reactions at N-3 and C-5 without ring opening or with ring opening and recyclization to generate new heterocyclic systems. Many 3-substituted-2,4-oxazolidinediones, particularly 3-aryl analogues, are conveniently prepared by reaction of an a-hydroxy ester or ahydroxy acid with an isocyanate.92,99,135 On the other hand, direct alkylation of N-3 has been used to incorporate a variety of functional groups in modest to acceptable yields.92,118–122,135,152,153 Direct alkylation can be complicated in that both Nand O-alkylation can and often do occur92,118,119,121 although very efficient and clean N-alkylations have been reported (Scheme 6.60).164–166 Additional examples of N-alkylated 2,4-oxazolidindiones are shown in Table 6.11 (Fig. 6.22).

O HN O

274 O O

O

O

MeOH, reflux 97% Ref. 164

Ph

HN

N

NaOMe, Me2SO4

Et O

O

Me

R R1

Base, DME

276

O

Ph

275 R2

R2X

Et

O

60 ˚C 71-97% Ref. 165

O N

R O

R1

277

O K O

O

N

R O

R1

R2

Cl

S

R2

69-86% Ref. 166

N

S O

R O

278

279

R = R1 = H

R = R1 = H R2 = Br, CHO, Ac

R1

Scheme 6.60

A variety of 2,4-oxazolidinedione moieties have been prepared as precursors to N-acyliminium ions. These, in turn, have been used in synthetic approaches to 13-aza-16-oxasteroids,167 interesting and novel heterocycles,168–174 and natural products such as ()-b-conhydrine, 294b,175 ()-O-methylpallidinine, 297,176 4oxa-2-aza-podophyllotoxin, 299,177 and morphine, 302.178 Introduction of the 2,4oxazolidinedione can be achieved by conventional alkylation.178 However, it is normally introduced through Mitsunobu chemistry179 using diisopropyl azodicarboxylate167–173 or diethyl azodicarboxylate.174–177 The former reagent is favored by

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

109

TABLE 6.11. 3-ALKYL-2,4-OXAZOLIDINEDIONES FROM ALKYLATION OF 2,4-OXAZOLIDINEDIONESa

O HN O

R2X

R O

Base, DME

R1

R2 O

60 oC

276

O N

R O

R1

277 Figure 6.22

Structure 277a 277b 277c 277d 277e 277f 277g 277h 277i

R2X allyl bromide ClCH2CN EtI MeI thien-2-ylCH2Cl BnCl 4-NO2 BrCH2CH2CO2Et BrCH2CH2CH2OH Me2SO4

Base TMGb DBNc 2-MId TIGe ETMGf TIAg ETHPh ETHP

R H H Me Me Me Ph 1-Naphthyl Me H

R1 Me Me Me Et 4-Cl C6H4 Ph H Me Me

R2

% Yield

allyl CH2CN Et Me thien-2-ylCH2 4-NO2-Bn CH2CH2CO2Et CH2CH2CH2OH Me

89 71 82 87 92 97 81 86 87

a

Data from Ref. 165. TMG ¼ 1,1,3,3-tetramethylguanidine. c DBN ¼ 1,5-diazabicyclo[4.3.0]non-5-ene. d 2-MI ¼ 2-methylimidazole. e TIG ¼ 1,2,3-triisopropylguanidine. f ETMG ¼ 2-ethyl-1,1,3,3-tetramethylguanidine. g TIA ¼ N,N,N0 -triisopropylacetamidine. h ETHP ¼ 2-ethyl-1,4,5,6-tetrahydropyrimidine. b

Kano and co-workers.167–173 Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key Nacyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from N-acyliminium ion cyclization are shown in Schemes 6.61–6.63, pp. 110 –112. Acylation at N-3 normally occurs uneventfully with 5-alkyl-2,4-oxazolidinediones, for example, 251 (R ¼ H, R1 ¼ Me) or 5,5-disubstituted 2,4-oxazolidinediones, for example, 180 and 188a to afford the corresponding N-acylated analogues (Scheme 6.64, p. 113).180,181 These N-acyl derivatives have been evaluated as herbicides and as potential antiinflammatory agents. Schulte and co-workers181 converted 251 (R ¼ H, R1 ¼ Me), 180 and 188a to the N-aroyl or N-arylsulfonyl analogues in good yield with no byproducts. Thus, reaction of a 2,4-oxazolidinedione with benzoyl chloride or an arenesulfonyl chloride in the presence of AlCl3/ pyridine cleanly afforded 303 or 304 in 56–82% yield. However, 5-phenyl-2,4oxazolidinedione, 251 (R ¼ H, R1 ¼ Ph) did not yield the expected N-3 aroyl or N-3 arenesulfonyl analogue. Instead, the pyridylated derivatives 305–307 were isolated in low to modest yield.

110

4(5H)-Oxazolones O

O

N

O

N 1. DIBAL-H

O

Me

2. HCO2H

Me Me

65% Ref. 167

280

281

R3

O

O

N

R

R1

283a R = R1 = H; R2 = R3 = Me 283b R = H; R1 = R2 = R3 = Me 283c R = Me; R1 = R2 = H; R3 = Ph Me

Me 1. DIBAL-H

O N

S

S

63–80% Ref. 168, 170

282a R = R1 = H; R2 = R3 = Me 282b R = H; R1 = R2 = R3 = Me 282c R = Me; R1 = R2 = H; R3 = Ph Me O

O

N

R1

S

O

H

1. DIBAL-H 2. HCO2H

R

R3

R2

O

R2

O

Me

O

O

Me

2. HCO2H

O

N

S

68% Ref. 169

Me

Me

285

284

R R 1. NaBH4, MeOH 2. PhSSPh, (n-Bu)3P, benzene

O N

O

Me

H

3. (n-Bu)3SnH,AIBN, benzene 26–42% 3 steps Ref. 171, 172

O 286 R = H, 3-MeO, 4-MeO

N H

O O

287 R = H, 3-MeO, 4-MeO Scheme 6.61

Mannich reactions of 2,4-oxazolidinediones, particularly spirocyclic analogues, for example, 214, and 218–220, usually proceed readily at N-3 in good to excellent yields (Scheme 6.65, p. 114).130,131 Similarly, 5-(arylidene)-2-thio-4-oxazolidinones 312 react readily with formaldehyde to yield the 3-hydroxymethyl derivatives, 313.182 Functionalizing C-5 of 2,4-oxazolidinediones is generally accomplished by alkylation or Knovenagel reaction (Schemes 6.66–6.69). For example, treating 251 (R ¼ H, R1 ¼ Me) with 3 equiv of LDA followed by two equivalents of a protected bromo alcohol and deprotection with dilute hydrochloric acid gave the

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones R

111

R 1. NaBH4, MeOH 2. PhSSPh, (n-Bu)3P, benzene

O N

R1

H

3. (n-Bu)3SnH, AIBN, benzene

O

24–31% 3 steps Ref. 173

O

R1

O

O O

288 R = H, 3-MeO, 4-MeO R1 = Me, Et, Bn, allyl

289 R = H, 3-MeO, 4-MeO R1 = Me, Et, Bn, allyl O

I

N

N

Me Me

O MeO

1. n-BuLi, THF, −78 ˚C 2. TFA, CH 2Cl2 55% Ref. 174

MeO MeO

N n-Bu Me

OMe

O

O Me

291

290 O O N

R1 R

TMS

O

292a R = H; R1 =Me 292b R = H; R1 = Et

H

1. NaBH4, MeOH 2. TiCl 4, CH2Cl2 3. (n-Bu)3SnH, AIBN 65−70% Ref. 175

R1

N O

R

O 293a R = H; R1 =Me 293b R = H; R1 = Et

H

Steps

N H

R1 HO

R

294a R = H; R1 =Me 294b R = H; R1 = Et

Scheme 6.62

5,5-disubstituted derivatives, 314a and 314b, in fair yields (Scheme 6.66). However, only 314b could be converted to an [18F] labeled analogue, which was evaluated as a potential indicator of tissue pH.183 A series of 5-benzyl-2,4oxazoldinediones were prepared by Pfizer chemists184 and found to be potent hypoglycemic agents (Scheme 6.66, p. 115). Their initial approach to these compounds involved protection of 179 with a trityl group to produce 316. Treatment of 316 with methyl magnesium carbonate185 generated the anion, which was added to a benzyl halide to yield 317. Deprotection with TFA then yielded the target 318. Overall, this route was unsatisfactory owing to the low yields (<20%) encountered during the alkylation. However, they were able to develop an alternate and very successful approach involving Knovenagel chemistry (see Scheme 6.68, p. 117). Zask186 described a very clever and general approach to prepare 3-hydroxy2(5H)-furanones in which he described the first report of a dianion of 179 that was utilized to prepare the key intermediate (Scheme 6.67, p. 116). After some experimentation he found that treatment of 179 with 2 equiv of tert-butyllithium and 6 equiv of lithium chloride gave 319 that reacted cleanly with an a-halo ketone to produce 320. Hydrolysis of 320 with refluxing 6 M hydrochloric acid then

112

4(5H)-Oxazolones OMe

O O

MeO

O

N

1. NaBH4, MeOH

MeO

H

O

2. HCO2H

O

63% Ref. 176

N

MeO

O

O 295

296 OMe

MeO steps

O N

MeO

H

Me

297 Bn O

O

O O

N

O

O

O

O MeO

OMe

1. NaBH4, aq. THF 2. Dess-Martin periodinane

H N

O

O O

3. H2, Pd/C, EtOH 4. AcOH 81% 4 steps Ref. 177

MeO

OMe OMe

OMe

299

298 OBz BzO

BzO

OBz OH

1. NaBH4, MeOH

O

N

H 2. BF3 Et2O, CH2Cl2

O

45% Ref. 178

O

O 301

MeO steps

OH O N H

302 Scheme 6.63

O

H

300

HO

N

Me

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones

113

O O

O

HN

4-X-C6H4COCl, AlCl 3

R

O

O

4-X-C6H4

O

R = H, Me, Ph R1 = Me, Ph X = H, OMe, NO2 X

O HN

N

R R1

1:1 pyridine/MeCN 56−77%

251 R = H, R1 = Me 180 R = R1 = Ph 188a R = R1 = Me

O

SO2

3- or 4-X-C6H4SO2Cl, AlCl 3

O

R1

303

251 R = H, R1 = Me 180 R = R1 = Ph 188a R = R1 = Me

O

R

O

1:1 pyridine/MeCN 68−82%

R1

N

R

O

O

R1

304 R = H, Me, Ph R1 = Me, Ph X = 3-H, CF3, Ac X = 4-H, Me, NHAc, Cl, OMe, CO2Et, CO2H O

O HN O

R O

R1

RX, AlCl 3 1:1 pyridine/MeCN 20−41% RX = ClCO2Et, PhCOCl, TosCl

251 R = H, R1 = Ph

HN O

Ph O N

R

305 R = CO2Et 306 R = COPh 307 R = Tos Scheme 6.64

afforded 321 in good to excellent yield. Mechanistically, it was proposed that 319 added to the a-halo ketone to generate a chlorohydrin that cyclized to an intermediate epoxide, which was transformed to the allylic alcohol via proton abstraction at C-5 with concomitant epoxide ring opening. This methodology was used to convert 322 to the naturally occurring fungal metabolite W-3681, 323, which has shown aldose reductase inhibitory activity (Scheme 6.67, p. 116). The Knoevengal reaction has been an extremely versatile method to functionalize C-5. Literally hundreds of 5-alkenyl- and 5-alkyl-2,4-oxazolidinedione analogues have been prepared in this manner. Generally, 2-thio-2,4-oxazolidinedione, 104, is used in these reactions although 179 has been used successfully as well. Some representative examples follow. Unangst and co-workers65,66 condensed 104 with several 3,5-dialkyl-4-hydroxybenzaldehydes followed by alkylation and hydrolysis to afford 110 and other

114

4(5H)-Oxazolones

O

O

NH

N

N

N

O

308 52-57% O

O

R2N

HN

N

O

O 218

R2NH, 40% CH2O

O

EtOH, reflux

R2N

HN O

O

O 309 80-81% O

N O

O

310 65-94%

219 O

O R2N

HN O

O

N O

O

220

311 61-75%

Bn NR2 = NPh,

N

NCH(Ph)2

aq CH2O, acetone

HO

O

O HN S

NR2

O

214

O

O

O

C6H4-X reflux 65-82%

O 312

N S

C6H4-X O 313

X = H, 4-Br, 4-NO 2, 3-NO2

X = H, 4-Br, 4-NO 2, 3-NO2 Scheme 6.65

3,5-dialkyl analogues, which were evaluated as dual 5-lipoxygenase and cyclooxygenase inhibitors (Scheme 6.29). Chemists from Fuji Film Company187 adopted a similar synthetic approach to prepare a series of 5-(benzylidene)-2,4-oxazolidinediones 326 that were evaluated as photosensitive materials and organic nonlinear optical materials (Scheme 6.68, p. 117). Here, the 5-(arylidene)-2-thio-2,4-oxazolidinediones, 324, were methylated to the give 325 from which 326 were obtained by acid hydrolysis. This same strategy has proven to be very useful to prepare

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones O

O

HN O

O

HN

1. LDA, THF, −78 ˚C

R R1

O

Br(CH2)nOTHP 2. 3N HCl

HO

2. [K/2.2.2]+ [18F]−, MeCN

n−1

314a n = 1; 22% 314b n = 2; 30%

O O

1. TsCl, pyridine

Me O

251 R = H, R1 = Me

HN

115

Me O 18F

n-1

315a n = 1; < 1% 315b n = 2; 14-16% O

Trityl N O

MeOCO2MgOMe CO2

ArCH2Cl

DMF, 85 ˚C

85 ˚C 17%

O

O

Trityl N

Ar

O

O 317

316

TFA, rt 61%

TritylCl, Et 3N CH2Cl2 97%

O

O HN

HN O

O

O

Ph

O

Me

Ar O

Ar = 179

N

318 O Scheme 6.66

analogues evaluated as potential antidiabetic agents188 and analogues for the treatment of metabolic bone disorders.189 In the latter example, Roche chemists adopted an alternative process to prepare their targets (Scheme 6.68). Knoevenagel reaction of 104 with aromatic and heterocyclic aldehydes gave 324 as expected. However, they opted to convert the 2-thiones directly to 326 using meta-chloroperbenzoic acid. Reduction of 326 then provided the desired target compounds 327 uneventfully. Variability in the reaction yield is commonly encountered with Knoevenegal condensations of 104. Pfizer chemists184 developed a solution to this problem (Scheme 6.68) to address the poor yields of 318 they obtained by direct alkylation of 316 (see Scheme 6.66). Initially, they found a dramatic disparity in yields of 324 (25–60%) following the literature conditions that used sodium acetate, acetic acid and benzene at reflux.190 This variability in the yields was traced to incomplete reaction since significant amounts of both 104 and the aldehyde were recovered.

116

4(5H)-Oxazolones O HN O

O

2 equiv t-BuLi

Li

6 equiv LiCl THF, −78 ˚C

O

O

179

THF, −78 ˚C X = Cl, Br

Li

O 319

O

O OH

HN O

R1COCH(X)R2

N

6 M HCl, reflux

O R2

O

OH

63-91%

R1

R2

R1

321 R1 = Me, i-Pr, t-Bu, Ph R2= H, Me

320 R1 = Me, i-Pr, t-Bu, Ph R2 = H, Me 1. 319, THF, −78 ˚C 2. 6 M HCl, 100 ˚C

O

O

CO2Me

Ph

O

70.5% overall

OH

Br Ph

HO2C 323

322 Scheme 6.67

Modifying the reaction conditions to continuously remove water by heating an intimate mixture of 104, sodium acetate, and the aldehyde under vacuum then produced 324 consistently in 50–70% yields. The synthesis of 318 was then completed uneventfully by oxidation of 324 with meta-chloroperbenzoic acid and hydrogenation. It is well known that 179 does not react with aromatic aldehydes under basic conditions.92 However, Knoevenagel reactions of 179 have been reported (Scheme 6.69). Thus, in an alternative route to potential antidiabetic agents, Japanese chemists152 condensed 179 with aromatic and heterocyclic aldehydes using piperidine in refluxing acetic acid to generate 328 in a single step. This product could be isolated or immediately converted to 329 via catalytic hydrogenation. The use of 104 to prepare the representative examples shown would have been problematic given the reaction sequence required to convert a 2-thio-2,4oxazolidinedione to 329 (see above). Schnur and co-workers145 summarized typical reactions that can be performed on functional groups of substituted 2,4-oxazolidinediones without ring opening. These reactions include reduction with iron-acetic acid, chlorosulfonation, nucleophilic displacements of aromatic fluorides, and acid hydrolysis with HCl/formic acid. Nonetheless, there are examples of useful ring cleavage reactions involving 2,4-oxazolidinediones.

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones O HN S

MeCN, reflux 27% Ar = 4-MeO-Ph Ref. 187

O 104

O

ArCHO NH4OAc, AcOH

O

HN

N

MeI, K2CO3

Ar

Ar

S

MeCN, rt 100%

O

MeS

O

324

325 66%

HCl, 50 ˚C

O S

O

HN S

reflux 16 - 91% Ref. 189

104

O

O ArCHO NaOAc, AcOH

HN

117

HN

m-CPBA, DMF

Ar

46 - 57%

O

O

Ar

O 326

324

H2

10% Pd/C THF, rt

O HN O

Ar

O 327

O

O S

O 104

S

120-140 ˚C, 0.1 Torr 50-70% Ref. 184

Ar =

O

HN

ArCHO, NaOAc

HN

Ar

2. H2, Pd/C

O 324 O

Ph N

HN

1. m-CPBA, DMF

O

Ar O 327

Me O

Scheme 6.68

Enzymatic hydrolysis of racemic 5-phenyl-2,4-oxazolidinedione, 251 (R¼H, R1 ¼ Ph) afforded D-mandelic acid after refluxing the intermediate carbamoyl191 D-mandelic acid in water (Scheme 6.70). This process is a particularly attractive synthesis of optically active a-hydroxy acids in that the L-enantiomer is epimerized under the reaction conditions. A German group found that reaction of 188a with 80% hydrazine produced the 1,2,4-triazolone 331 (Scheme 6.70).192 It was proposed that hydrazine affected ring opening to give the a-hydroxy acylsemicarbazide 330 that was cyclodehydrated to yield the triazolone. Heimgartner and co-workers193 conducted a detailed mechanistic investigation of the reaction of [15N]labeled 2,2-dimethyl-3-(dimethylamino)-2H-azirine 332 with NH-acidic heterocycles (Scheme 6.71). Based on these studies the authors proved that ring opening of 188a with 332 afforded the imidazolone 336 in which

118

4(5H)-Oxazolones O O

O

ArCH=CHCHO or HetCH=CHCHO

HN

H2, 5% Pd/C

Ar(Het)

O

piperidine, AcOH reflux

O

HN

1 atm, rt

O 328

179 O HN

Ar(Het)

O

O 329

328 Ar =

MeO

MeO

O

BnO

N Ph

OMe

S MeO

Me N

N

O

iPrO F EtO

EtO N Ph

N

O O

Me

O O

Me

O Scheme 6.69

O enzyme

HN O

R

Ph H

CO2H O

O

Ph H

NH2

CO2H OH

R1 O

251 R = H, R1 = Ph O HN O

Me O

188a

Me

O

80% NH2NH2 46%

O Me

H2NHN

N H 330

Scheme 6.70

Me OH

HN NH

−H2O

O

Me N

331

Me OH

2-Alkoxy-4(5H)-Oxazolones and 2-Hydroxy-4(5H)-Oxazolones O HN O

Me O

+

Me

15N

Me

O

Me Me

Me2N

MeCN, rt

H

15

N

O

Me

O

188a

Me

N

83%

Me

119

N

332

Me

Me 333

Me Me

O 15N

O O

Me

15N

Me

Me Me NMe2

N

Me

O

Me

NMe2 N

O O

H

335

334 O Me Me HO

Me Me

15N

O

NMe2

N 336

Scheme 6.71

only N-3 was labeled. This interesting and unexpected result was mechanistically consistent with the formation of a ring-expanded lactam 334 from the initial bicyclo[3.3.0] adduct 333. Transannular cyclization of the [15N]labeled nitrogen TABLE 6.12. IMIDAZOLONES FROM 5,5-DIMETHYL-2,4-OXAZOLIDINEDIONE AND 2H-AZIRINESa

O O HN O

Me2N R

O

R1

+

R2 N

R3

MeCN, rt 3 to 5 days

188a 188a 179 179 180 180 251 251 a

Data from Ref. 194.

R

R1

Me Me H H Ph Ph H H

Me Me H H Ph Ph Ph Ph

R1 HO

N O

N

R3 NMe2

338

337 2,4-Oxazolidindione

R2

R

Figure 6.23 R2 Me

R3

% Yield

Me

83 88 79 95 85 73 77 64

 (CH2)4 Me

Me  (CH2)4

Me

Me  (CH2)4

Me

Me  (CH2)4

120

4(5H)-Oxazolones

atom in 333 with the urethane carbonyl group then produced a second bicyclo[3.3.0] adduct 335 that ring opened to afford 336. The authors have extended this work and developed a high yield, general synthesis of imidazolones including spirocyclic analogues.194 Examples are shown in Table 6.12 (Fig. 6.23).

6.5. SUMMARY The 4(5H)-oxazolone ring system has been and continues to be a rich source of interesting chemistry that has produced a number of useful compounds including trimethadione, dimethadione, famoxadone, chlozolinate, and vinchlozolin. In addition, such diverse areas of research as nonlinear optical materials, photographic and luminescence dyes, antidiabetic, antiulcer, antibacterial, and antitumor agents continues to provide a strong stimulus for further developments in this area.

6.6. ADDENDUM Weiss and co-workers195 prepared a series of oxazolinylidene steroids 343 as luminescence dyes for application as potential intracellular diagnostic agents (Scheme 6.72). The key intermediate 2-aryl-5,5-dimethyl-4(5H)-thiooxazolones 341 were readily available from the corresponding 4(5H)-oxazolones 339. Reaction of 341 with 342, generated in situ from the hydrazone 340, gave 343 as expected. It was not possible to prepare 343 from 3-thio-androsta-1,4-dien-17-one since the requisite corresponding heterocyclic diazo compounds could not be prepared. Smith and co-workers196 adapted Sheehan and Izzo’s2 original synthesis of 2aryl-4(5H)-oxazolones and developed a general synthesis of 2-alkyl-4(5H)-oxazolones. Teatment of an acid halide with AgNCO followed by diazomethane produced 344 that were immediately converted to the 2-alkyl-4-oxazole triflates 345. The authors noted that ethanol-free diazomethane was required to prepare 344. The oxazole triflates 345 were, in turn, key intermediates leading to a variety of 2,4-disubstituted oxazoles required for natural products (Scheme 6.73). Kamiyama and colleagues197 at Takeda Chemical Industries described improvements to their earlier stereoselective synthesis of indolmycin 69.86 Most significantly, the authors noted that 69 was recently shown to be a potent anti-H. pylori agent.198 This finding further emphasized the need and interest in a scaleable, stereoselective syntheses. They abandoned their one-step approach to 178 from 119a (Scheme 6.43). Instead, 119a was saponified to the a-hydroxy acid 121a that was rigorously purified. This material was then converted to 178 in twosteps using guanidine rather than N,N-dimethylguanidine. The authors reported that ˚ molecular sieves the use of guanidine in tert-BuOH in the presence of 4-A was critical to install the 4(5H)-oxazolone ring system with minimal epimerization at C-5. Overall, 69 was prepared in 22% yield and 99.4% ee from ethyl (2S, 3R)epoxybutanoate. This methodology was also applied to prepare metabolites of 69 as well (Scheme 6.74).

Addendum

121 O

O N

Me

R O

Me H2NN

339

340

R = F, Cl, OMe, NO 2, NMe2 Lawesson′s reagent toluene, reflux 33-89%

MnO2, Et2O, rt

O S N

Me

R O

+

Me N2

341

342

R = F, Cl, OMe, NO 2, NMe2 toluene, rt 25-88%

O

Me

Me

O N R

343 R = F, Cl, OMe, NO 2, NMe2

Scheme 6.72

O

O R

1. AgNCO, CH 2Cl2

X

X = Cl, Br

2. CH2N2

R

OTf Et3N, Tf2O

N O

THF, −78 ˚C 48-90%

N R

344 R = Me, Et, tBu, Ph, CH2Br, (CH 2)2Ph, CH(Br)Me Scheme 6.73

O 345

122

4(5H)-Oxazolones Me CO2Et

CO2H

1. Indole, MeMgBr Et2O/CH2Cl2

O

2. NaOH, aq. EtOH

Me

N H

51%

1. HCl, EtOH 2. guanidine HCl

OH

KOtBu, t-BuOH molecular sieves 67%

93.3% ee

121a Me

H

N O

N H

Me

O

NH2

H

40% aq MeNH2 5 ˚C 64%

O N

O

N H

178

NHMe 69

22% overall 99.4% ee Scheme 6.74

Acknowledgments I thank Dr. F. Liu for review of this chapter.

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156. Casadei, M. A.; Cesa, S.; Moracci, F. M.; Inesi, A.; Feroci, M. J. Org. Chem. 1996, 61, 380–383. 157. Cesa, S.; Mucciante, V.; Rossi, L. Tetrahedron 1999, 55, 193–200. 158. Stadlbauer, W.; Kappe, T. Monatsh. Chem. 1985, 116, 1005–1015. 159. Rajeckas, F. J.; Holland, G. F. Fr. Demande FR 2487347, 1982; Chem. Abstr. 1982, 97, 92304. 160. De Mesmaeker, A.; Lebreton, J.; Waldner, A.; Fritsch, V.; Wolf, R. M. Bioorg. Med. Chem. Lett. 1994, 4, 873–878. 161. Poje, M.; Palkovic´, A.; Perina, I.; Vickovic´, I.; Bruvo, M. Tetrahedron 1985, 41, 4681–4684. 162. Rapi, G.; Ginanneschi, M.; Chelli, M.; Chimichi, S. Steroids 1985, 46, 665–676. 163. Nagatsu, A.; Tenmaru, K.; Matsuura, H.; Murakami, N.; Kobayashi, T.; Okuyama, H.; Sakakibara, J. Chem. Pharm. Bull. 1995, 43, 887–889. 164. Brouillette, W. J.; Brown, G. B.; DeLorey, T. M.; Shirali, S. S.; Grunewald, G. L. J. Med. Chem. 1988, 31, 2218–2221. 165. Wlostowski, M.; Jaworski, T. Polish Patent PL 137516, 1986; Chem. Abstr. 1991, 114, 62085. 166. Kobayashi, M.; Kitazawa, M.; Saito, T. Yakugaku Zasshi 1984, 104, 680–690; Chem. Abstr. 1984, 102, 78796. 167. Kano, S.; Yuasa, Y. Heterocycles 1983, 20, 857–861 and references cited therein. 168. Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J. Org. Chem. 1983, 48, 3835–3837. 169. Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. Heterocycles 1983, 20, 2411–2416. 170. Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. Heterocycles 1984, 22, 1411–1415. 171. Kano, S.; Yokomatsu, T.; Nemoto, H.; Shibuya, S. Chem. Lett. 1986, 143–146. 172. Kano, S.; Yuasa, Y.; Yokomatsu, T.; Asami, K.; Shibuya, S. Chem. Pharm. Bull. 1988, 36, 2934– 2939. 173. Kano, S.; Yuasa, Y.; Asami, K.; Shibuya, S. Heterocycles 1988, 27, 1437–1443. 174. Collado, M. I.; Sotomayor, N.; Villa, M-J.; Lete, E. Tetrahedron Lett. 1996, 37, 6193–6196. 175. Kano, S.; Yokomatsu, T.; Yuasa, Y.; Shibuya, S. Heterocycles 1986, 24, 621–624. 176. Kano, S.; Yokomatsu, T.; Nemoto, H.; Shibuya, S. J. Am. Chem. Soc. 1986, 108, 6746–6748. 177. Hitotsuyanagi, Y.; Ichihara, Y.; Takeya, K.; Itokawa, H. Tetrahedron Lett. 1994, 35, 9401–9402. 178. Bottari, P.; Endoma, M. A. A.; Hudlicky´, T.; Ghiviriga, I.; Abboud, K. A. Collect. Czech. Chem. Commun. 1999, 64, 203–216. 179. Mitsunobu, O.; Wada, W.; Sano, T. J. Am. Chem. Soc. 1972, 94, 679–680. 180. Theissen, R. J. U. S. Patent 4,367,090, 1983; Chem. Abstr. 1983, 98, 126066. 181. Schulte, K. E.; von Weissenborn, V.; Loesevitz, B. Arch. Pharm. (Weinheim) 1980, 313, 229–237. 182. Shenberg, N. A.; Ginak, A. I.; Ramsh, S. M.; Khrabrova, E. S. Khim. Geterotsikl. Soedin. 1989, 106– 108; Chem. Abstr. 1989, 111, 153681. 183. Maeda, M.; Tatsuki, Y.; Fukumura, T.; Kojima, M. J. Labelled Compd. Radiopharm. 1989, 27, 553– 563. 184. Dow, R. L.; Bechle, B. M.; Chou, T. T.; Clark, D. A.; Hulin, B.; Stevenson, R. W. J. Med. Chem. 1991, 34, 1538–1544. 185. Finkbeiner, H. J. Am. Chem. Soc. 1965, 87, 4588–4592. 186. Zask, A. J. Org. Chem. 1992, 57, 4558–4560. 187. Uchino, N.; Hioki, T.; Nishigaki, J. Jpn. Kokai Tokkyo Koho JP 05140130, 1993; Chem. Abstr. 1993, 119, 225940. 188. Lohray, B. B.; Lohray, V. B.; Bajji, A. C.; Kalchar, S.; Alla, S. R.; Ramanujam, R.; Vikramadithyan, R. K. PCT Intl. Appl. WO 9852946, 1998; Chem. Abstr. 1998, 130, 38390. 189. Esswein, A.; Schaefer, W.; Tsaklakidis, C.; Honold, K.; Kaluza, K. PCT Intl. Appl. WO 0018745, 2000; Chem. Abstr. 2000, 132, 251142.

128

4(5H)-Oxazolones

190. Ushenko, N. K.; Gorizdra, T. E. Ukrain. Khim. Zhur. 1950, 16, 545–551; Chem. Abstr. 1954, 48, 64281. 191. Olivieri, R.; Eletti Bianchi, G.; Fascetti, E. Ger. Offen. DE 3039132, 1981; Chem. Abstr. 1981, 95, 130993. 192. Leistner, S.; Wagner, G.; Richter, H. Z. Chem. 1974, 267–268. 193. Ametamey, S. M.; Hollenstein, R.; Heimgartner, H. Helv. Chim. Acta 1988, 71, 521–530. 194. Ametamey, S. M.; Heimgartner, H. Helv. Chim. Acta 1990, 73, 1314–1328. 195. Wagner, K.; Weiss, D.; Beckert, R. Eur. J. Org. Chem. 2000, 3001–3005. 196. Smith, A. B., III; Minbiole, K. P.; Freeze, S. Synlett 2001, 1739–1742. 197. Hasuoka, A.; Nakayama, Y.; Adachi, M.; Kamiguchi, H.; Kamiyama, K. Chem. Pharm. Bull. 2001, 49, 1604–1608. 198. Kanamaru, T.; Nakano, Y.; Toyoda, Y.; Miyagawa, K.; Tada, M.; Kaisho, T.; Nakao, M. Antimicrob. Agents Chemother. 2001, 45, 2455–2459.

CHAPTER 7

5(2H)-Oxazolones and 5(4H)-Oxazolones Carlos Cativiela Department of Organic Chemistry, University of Zaragoza, 50009 Zaragoza, Spain

Maria D. Diaz-de-Villegas Department of Organic Chemistry, University of Zaragoza, 50009 Zaragoza, Spain

7.1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. 5(2H)-Oxazolones (3-Oxazolin-5-ones) . . . . . . . . . . . . . . . . . . . . . . 7.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1.1. From Amino Acids: Tautomerism and Racemization 7.2.1.2. C-2 versus C-4 Alkylations . . . . . . . . . . . . . . . . . . 7.2.1.3. Via Sigmatropic Rearrangements . . . . . . . . . . . . . . 7.2.1.4. 4-Arylthio, 4-Alkoxy, and 4-Amino Derivatives. . . . 7.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2.1. Synthesis of Pyrroles . . . . . . . . . . . . . . . . . . . . . . 7.2.2.2. Generation of Nitrile Ylides . . . . . . . . . . . . . . . . . 7.2.2.3. Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones). . . . . . . . . . . . . . . 7.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1.1. Cyclization from Amino Acid Derivatives . . . . . . . 7.3.1.2. Other Cyclization Procedures . . . . . . . . . . . . . . . . 7.3.1.3. Rearrangements of Oxazoles . . . . . . . . . . . . . . . . . 7.3.1.4. From Other Oxazolones . . . . . . . . . . . . . . . . . . . . 7.3.1.5. 2-Alkoxy Derivatives . . . . . . . . . . . . . . . . . . . . . . 7.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2.1. Hydrolysis and Alcoholysis. . . . . . . . . . . . . . . . . . 7.3.2.2. Aminolysis with Amines. . . . . . . . . . . . . . . . . . . . 7.3.2.3. Aminolysis with Amino Acid Derivatives . . . . . . . . 7.3.2.4. Incorporation of Dialkylamino Acids into Peptides . 7.3.2.5. Other Ring-Opening Reactions . . . . . . . . . . . . . . . 7.3.2.6. Dimerization Reactions. . . . . . . . . . . . . . . . . . . . .

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The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

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130 131 131 131 134 136 139 143 143 143 145 151 151 151 155 155 160 177 178 178 183 185 189 191 194

130

5(2H)-Oxazolones and 5(4H)-Oxazolones

7.3.2.7. Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2.8. Reactions with Dienes and Azadienes . . . . . . . . . . . . . . . . . . . . . . 7.3.2.9. Polymerization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2.10. Organometallic Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.3. Structural Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1.1. From N-Acylglycines with Carbonyl Compounds . . . . . . . . . . . . . . 7.4.1.2. From Other N-Acylamino Acid Derivatives and Glycine Equivalents . 7.4.1.3. From Other Unsaturated 5(4H)-Oxazolones. . . . . . . . . . . . . . . . . . . 7.4.2. Ring-Opening Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2.1. Hydrolysis and Alcoholysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2.2. Aminolysis with Amines and Related Compounds . . . . . . . . . . . . . . 7.4.2.3. Reductive Aminolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2.4. Aminolysis with Amino Acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2.5. Other Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2.6. 1,3-Bis(nucleophiles) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2.7. Other Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3. Reactions Involving the Exocyclic Double Bond . . . . . . . . . . . . . . . . . . . . . 7.4.3.1. Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3.2. Michael Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3.3. 1,3-Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3.4. Diastereoselective Cyclopropanations . . . . . . . . . . . . . . . . . . . . . . . 7.4.3.5. Diels–Alder Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3.6. Diastereoselective Diels–Alder Reactions . . . . . . . . . . . . . . . . . . . . 7.4.4. Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.5 Structural Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. Addendum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.1. Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) . . . . . . . . . . . . . . . . . . . . . 7.6.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.1.3. Structural Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.2. Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) . . . . . . . . . . . . . . . . . . . 7.6.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.2.2. Ring-Opening Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.2.3. Reactions Involving the Exocyclic Double Bond . . . . . . . . . . . . . . . 7.6.2.4. Structural Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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195 198 201 202 206 208 210 210 213 217 226 226 235 240 241 243 247 254 256 256 258 262 269 271 277 282 284 287 287 287 287 289 291 292 292 294 297 299 299

7.1. INTRODUCTION The 5-oxazolones or oxazolin-5-ones are very interesting heterocyclic compounds that have been used as intermediates in the synthesis of a variety of organic molecules. Two structural classes are possible, the 5(2H)-oxazolones (or 3-oxazolin-5-ones) and 5(4H)-oxazolones (or 2-oxazolin-5-ones). These structures differ only in the position of the double bond. Apart from the presence of the heteroatoms (N and O), the carbonyl group and the double bond, the 2- or 4-position, respectively, can be saturated or unsaturated. The isomeric 5-oxazolones are

5(2H)-Oxazolones (3-Oxazolin-5-ones) O

O N

O

N

O

1

2

saturated 5(2H)-oxazolones

unsaturated 5(2H)-oxazolones O

O N

O

131

N

O

3

4

saturated 5(4H)-oxazolones

unsaturated 5(4H)-oxazolones

Figure 7.1. General structures of 5-(2H)-oxazolones and 5-(4H)-oxazolones.

shown in Figure 7.1. The saturated analogues 1 and 3 do not have an exocyclic double bond, whereas the unsaturated analogues 2 and 4 do contain an exocyclic double bond. These compounds are very important and, apart from two brief reviews of oxazoles that include oxazolones,1,2 numerous reviews have been published, although the most recent of these was almost 20 years ago.3 Thus, this chapter will survey the significant results published during the last two decades and will discuss new syntheses of 5-oxazolones and focus attention on the use of these intermediates as versatile reagents in organic chemistry. Particular emphasis will be given to their use as building blocks to prepare other important heterocyclic compounds and as suitable reagents for the synthesis of a-amino acids and peptides.

7.2. 5(2H)-OXAZOLONES (3-OXAZOLIN-5-ONES) 7.2.1.

Synthesis

The following section covers only those procedures for the synthesis of 5(2H)oxazolones described during the last 20 years and it should be borne in mind that a number of classical procedures have been described before.3

7.2.1.1. From Amino Acids: Tautomerism and Racemization A saturated 5(2H)-oxazolone, also known as a 3-oxazolin-5-one or a pseudoxazolone, can be considered as the tautomer of a saturated 5(4H)-oxazolone (or 2-oxazolin-5-one) by a 1,3-prototropic shift (Scheme 7.1).

132

5(2H)-Oxazolones and 5(4H)-Oxazolones O N

O

O

N

O

1

3

5(2H)-oxazolone

5(4H)-oxazolone

Scheme 7.1

In fact, the first saturated pseudoxazolone reported, 4-methyl-2-(trifluoromethyl)-5(2H)-oxazolone, was incorrectly assigned as the tautomeric 5(4H)oxazolone and only later did nuclear magnetic resonance (NMR) studies establish the correct structure. This compound was synthesized from alanine and trifluoroacetic anhydride (TFFA). This methodology constitutes, under standard conditions, the most general procedure for the synthesis of 5(2H)-oxazolones. Saturated 5(4H)-oxazolones are easily obtained from N-acylamino acids in the presence of a cyclization agent and have been used extensively in coupling reactions as synthetic equivalents of a-amino acids in the synthesis of peptides. In this context, tautomeric equilibrium can be a significant problem due to the racemization associated with the isomerization. For example, trifluoroacetylation of tryptophan in ether affords the 5(4H)-oxazolone 5 without racemization. However, upon dissolution in acetonitrile, 5 completely racemizes.4,5 Further, upon heating, an aqueous dioxane solution of 5 cleanly isomerizes to the isomeric 5(2H)oxazolone 6 (Scheme 7.2). H

N

H CO2H

NH2

O

TFAA Et2O

N

N

CF3

H

H

O

5 ∆

O

N

N

O CF3

H 6

Scheme 7.2

Interestingly, treating bromotyrosine with TFAA in an autoclave at 80–120
C, affords the corresponding 5(2H)-oxazolone that was used as an intermediate in the synthesis of psammaplin.6

5(2H)-Oxazolones (3-Oxazolin-5-ones)

133

TABLE 7.1. SYNTHESIS OF 5(2H)-OXAZOLONES VIA CYCLIZATION OF AMINO ACIDS OR AMINO NITRILES

O R1

cyclization agent

X

R1 O

N

NHR2

R2

R3

Figure 7.2 X

Cyclization Agent

CO2H CO2H CN CO2H CO2H CO2H CO2H

TFAA TFAA/PCl3 TsOH DFAA TFAA TFAA TFAA

R1 indol-3-ylmethyl 4-ClC6H4 4-ClC6H4 Ph i-Pr s-Bu Ph

R2

R3

H H COCF3 H H H H

CF3 CF3 H CHF2 CF3 CF3 CF3

% Yield 90 & 100 56 48 80–90 80–90 80–90

References 4,5 7 9 10 11 11 11

Cyclizations with perfluoroacylating agents seem to be quite general for the synthesis of 5(2H)-oxazolones with aromatic substituents directly bonded to the heterocyclic ring. For example, perfluoroacylation of a solution of an arylglycine containing a phosphorus trihalide affords 4-aryl-2-(perfluoroalkyl)-5(2H)oxazolones (Table 7.1, Fig. 7.2).7 Similar results were obtained when amino nitriles were used as starting materials.8,9 Difluoroacetic anhydride reacts similarly with alanine and this process affords 2-(difluoromethyl)-4-methyl-5(2H)-oxazolone 7. Treatment of 7 with hydrogen bromide in acetic acid in the presence of ethanethiol yields 8 that was converted to 3,3-difluoroalanine 11 in several steps as shown in Scheme 7.3.10 This reaction opened the way to prepare b,b-difluoro amino acids. O Me

CO2H

(CHF2CO)2O

Me O

N

NH2

HBr/AcOH/EtSH

H2N

SEt CHF2

CHF2 8

7 ZHN

SO2Et CHF2 9

MgBr

ZHN

1) KMnO4/AcOH

CHF2

2) H2/Pd-C

10

H2N

CO2H CHF2 11

m-CPBA = meta-chloroperoxybenzoic acid Scheme 7.3

1) ZCl/Py 2) m-CPBA

134

5(2H)-Oxazolones and 5(4H)-Oxazolones

Racemization observed during coupling reactions in the synthesis of peptides can be attributed, at least in part, to the influence of the base used on the equilibrium of the tautomeric oxazolones. Numerous studies have been undertaken to avoid this problem or, alternatively, to direct the equilibrium to the desired compound. For example, the triethylamine-promoted tautomerization of 4-alkyl5(4H)-oxazolones to 4-alkyl-5(2H)-oxazolones has been studied by proton NMR ð1 H NMRÞ long-range coupling.12 In addition, the kinetics of racemization of 2,4disubstituted-5(4H)-oxazolones obtained from N-acetyl, N-benzoyl, and N-benzyloxycarbonylamino acids have been studied in several solvents, both alone and in the presence of tertiary amines.13 The racemization process is governed by electronic effects of the substituent at C-2 and by steric effects of the substituent at C-4. The thermodynamic data suggest that the 4-benzyl-2-substituted-5(4H)-oxazolones racemize more readily than the corresponding 4-alkyl analogues (alkyl 6¼ benzyl) and that the rate of the base-catalyzed reaction depends on the steric bulk at the nitrogen atom of the tertiary amine as well as on the basicity.

7.2.1.2. C-2 versus C-4 Alkylations The availability of a general procedure to prepare 4-alkyl-2-(trifluoromethyl)5(2H)-oxazolones 12 from a-amino acids and TFAA, and taking into account the tautomerization process, has led to many efforts to direct the alkylation reaction toward C-2 or C-4. For example, in the presence of triethylamine, Michael addition of 12 occurs at C-2 when tert-butylacrylate is used as electrophile.11 The resulting dialkylated products 13 could be easily transformed into a-diketones 15 (Scheme 7.4; Table 7.2, Fig. 7.3). O R1

CO2H

R1

TFAA

N

NH2

O

O CO2t-Bu

R1 O

N

Et3N

CF3

CF3

12 R1

HO

R2M

N

13

R2

O HCO2H

O CF3

CO2t-Bu

R2

R1 O

CO2t-Bu 14

15 Scheme 7.4

5(2H)-Oxazolones (3-Oxazolin-5-ones)

135

TABLE 7.2. SYNTHESIS OF 5(2H)-OXAZOLONES VIA ALKYLATION AT C-2

O

O

R1 N

EWG

O

R1 O

N

R2

R2

EWG

Figure 7.3 R1

R2

EWGb

i-Pr Ph MeSCH2CH2

CF3 CF3 CF3

CO2tBu CO2tBu CO2tBu

a b

% Yield &80 &80 &80

Data from Ref. 11. EWG ¼ electron-withdrawing group.

Alternatively, alkylation of 4-benzyl-2-(trifluoromethyl)-5(2H)-oxazolone 16 in the presence of mild base using active alkyl halides as electrophiles occurs at C-4.14 Subsequent aminolysis of a 4,4-dialkyl-5(4H)-oxazolone like 17 gave an N-(trifluoroacetyl)-a,a-dialkylglycine amide 18 that was used to prepare important peptides incorporating an a,a-dibenzylglycine unit (Scheme 7.5).

Ph

O Ph

CO2H NH2

TFAA

Ph N

O

O

Ph N

CF3 16

O CF3

17

Ph CONHR

Ph

NHCOCF3 18

Scheme 7.5

In principle, 5(4H)-oxazolones 19 could also be used as starting materials to prepare 5(2H)-oxazolones 20 via an alkylation reaction, but this approach depends on many factors. Several years ago3 it was reported that a mixture of isomeric products 20 and 21 is usually obtained (Scheme 7.6) and the site of reaction in basecatalyzed addition reaction of 5(4H)-oxazolones with activated multiple bonds is determined primarily by the nature of the activated multiple bond.

136

5(2H)-Oxazolones and 5(4H)-Oxazolones EWG O

O

O

R1

R1 N

R1

EWG

O

O

N

+

R2

R2 19

O

N

R2

EWG

20

21

EWG = electron-withdrawing group Scheme 7.6

The reaction of 2-aryl-4-phenyl-5(4H)-oxazolones 22 with 4-methylenetriazoles 23 was also studied.15 The direction of the alkylation was strongly dependent on the nature of the substituent on the aromatic ring at C-2 in 22. Thus, oxazolones with electron-rich aryl substituents gave predominantly alkylation at C-4 to yield 24. In contrast, the isomeric products 25 are preferentially obtained when using substrates with electron-withdrawing substituents (Scheme 7.7). R′ N N Ph O

N

O N

O +

N O

N N N

Ph N

O

N +

O

N N N R′

X

R′

X 22

Ph

O

X 23

24 (X = EDG)

25 (X = EWG)

EDG = electron-donating group Scheme 7.7

7.2.1.3. Via Sigmatropic Rearrangements Very interesting interconversions between allyl substituted-5(4H)-oxazolones and allyl substituted-5(2H)-oxazolones have also been described.16,17 In particular, 4-allyl-2-methyl-4-phenyl-5(4H)-oxazolone 27 and 4-(3,3-dimethylallyl)-2-methyl4-phenyl-5(4H)-oxazolone 31 were found to undergo a [3,3] sigmatropic allyl shift on thermolysis to give the corresponding isomeric 5(2H)-oxazolones 28 and 33, respectively. In contrast, on direct irradiation 28 and 32 undergo a [1,3] allyl shift to give the corresponding 5(4H)-isomers 27 and 31. To elucidate the mechanism of these reactions all compounds were synthesized unambiguously; the 5(4H)-oxazolones 27 and 31 by alkylation of 26 and the 5(2H)-oxazolones 28 and 32 by irradiation of azirines 29 and 30 in the presence of carbon dioxide.18 These reactions are shown in Scheme 7.8.

5(2H)-Oxazolones (3-Oxazolin-5-ones)

O

O Ph

base

O

N

hν/CO2

O

N

hν

Me

Me

O

R

Ph

Ph

27

O

N

Ph

∆

Br

137

28

R

N

H

Me

Me

Me

26

O base

Me

Ph

O

N

Br

29 R = H 30 R = Me

O

∆

Ph

hν/CO2

O

N

hν

Me

Me

Me

Me

Me

31

Me

32 ∆

O Ph N

O Me Me

Me

33

Scheme 7.8

Analogously, cyclopropenyl systems 34, 35 were also studied (Scheme 7.9; Table 7.3, Fig. 7.4). Here, further heating of 35 afforded substituted pyridines 36.17,19 Ph

O R

Ph

Ph O

Ph O

N

Me 34

∆

Ph O

N

∆

R

Ph

R

Ph

Me

Ph

N

Me

Ph 35

36

Scheme 7.9

A new synthesis of 2-allyl-4-phenyl-5(2H)-oxazolones 39 has been published20 starting from the corresponding allyl N-acylphenylglycinates 37. The reaction proceeds via the nonisolable oxazoles 38 that undergo a sigmatropic rearrangement under the cyclization conditions. The reductive ring cleavage of the oxazolones is a

138

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.3. SYNTHESIS OF 5(2H)-OXAZOLONES VIA SIGMATROPIC REARRANGEMENT

O

R2

O R1

∆

R1

O

N

R3

R1

CH2 ¼ CHCH2

Ph

R3 Figure 7.4 R3

R2

O

N

R2

% Yield

References

Me

98

16

Me

&100

17

Me

&100

17,19

Ph Ph

Ph Ph Ph Ph

Ph

CH3

very useful procedure for the synthesis of b,g-unsaturated ketones 40 (Scheme 7.10; Table 7.4, Fig. 7.5). The utility of the reaction was extended to include other allyl, propargyl, and cinnamyl N-acylphenylglycinates. Catalytic hydrogenation of the resulting 5(2H)-oxazolones 43 and subsequent reductive ring cleavage gave the corresponding ketones 44. Complete transfer of the chirality was observed starting

TABLE 7.4. SYNTHESIS OF 5(2H)-OXAZOLONES VIA REARRANGEMENT OF 5-ALKOXYOXAZOLESa

O R2

OR3

N H

a

PPh3 Et3N

O

R1 Ph Ph Ph Ph Ph

O

OR3

R1

N

O R2

R2 4-ClC6H4 4-ClC6H4 Ph 4-ClC6H4 4-ClC6H4

Data from Ref. 21.

R1

R1

Figure 7.5 R3  CCH2 PhC  CCH(Me) PhC PhC CCH(Me) PhCH CHCH2 PhCH CHCH(Ph)

O

N R2

R3

% Yield 50 83 56 40 45

5(2H)-Oxazolones (3-Oxazolin-5-ones)

139

R3 O R1

Ph O

N H

O Ph

R2 R2

O

O

PPh3 Et3N

R3

R3

R1

O

N

O

N

Ph

R2 R1

37

39

38 O reduction

R2

R1 R3 40 R2 H O R1

Ph O

N H

O

C R2 H

C

R3

COCl2

R3

C C

O Ph

O

Ph

O

N

Et3N

N

O

R1

R3 C C R2 H

R1 41

43

42 O

1) H2/Pd-C 2) Cr(OAc) 2

R3

R1 R2 H 44

Scheme 7.10

from enantiomerically pure alcohols. Interestingly, either enantiomer of 1,4diphenyl-2-methylbutan-1-one could be obtained from (E)- or (Z)-(R)-4-phenyl-3buten-1-ol.21

7.2.1.4. 4-Arylthio, 4-Alkoxy, and 4-Amino Derivatives The nature of the arylthio substituent at C-4 of a 5(2H)-oxazolone dictates which of two different synthetic strategies can be used.22,23 The first involves the use of sodium cyanodithioformate and the corresponding ketone as starting materials. The reaction occurs through a thiazolone 45 that must be alkylated on the sulfur atom followed by treatment with Hg(OAc)2 to afford the corresponding 4-(alkylthio)5(2H)-oxazolone 47. The second strategy involves the addition of thiophenol to

140

5(2H)-Oxazolones and 5(4H)-Oxazolones O

NaS S

N R1

S

(R)2NH

NC

R2

SNa

O

O

R1 +

NC

R2

(R)2NH

OEt

+ R3SH

TiCl 4

45 O R3X

O

R3S S

N R1

Hg(OAc) 2

R1

46

R2

O

N

R2

O

R1

R3S R2

BF3 Et2O

R3S

O

HN

OEt

47 Scheme 7.11

ethyl cyanoformate to afford a thioimidate followed by the addition of the ketone and a Lewis acid (Scheme 7.11; Table 7.5, Fig. 7.6; Table 7.6, Fig. 7.7). Both synthetic pathways, which are complementary for alkyl or aryl sulfide derivatives, are limited with respect to variation of the substituent on the ketone. Two different methods have also been described24 for the synthesis of 4-alkoxy5(2H)-oxazolones 50. In the first case, 4-(phenylthio)-5(2H)-oxazolones 48 are oxidized to the 4-phenylsulfinyl derivatives that react with the alcohol present in the reaction medium to afford the corresponding 4-alkoxy derivatives. Alternatively, 4-alkoxy-5(2H)-oxazolones 50 have been obtained by condensation of iminooxalates and ketones in acidic medium. (Scheme 7.12; Table 7.7, Fig. 7.8; Table 7.8, Fig. 7.9).

TABLE 7.5. SYNTHESIS OF 4-(ALKYLTHIO)-5(2H)-OXAZOLONES FROM SODIUM CYANODITHIOFORMATE, KETONES AND ALKYLATING AGENTSa

O + NC

O

R2

S SNa

R3

1) (R)2NH

O

R1S S

N

2) R1X

R2

R3

Hg(OAc) 2

R1S O

N R2

R3

Figure 7.6 R1 PhCH2 2,4-(NO2)2C6H3 a

Data from Ref. 23.

R2

R3 (CH2)5 (CH2)5

% Yield 31 8

5(2H)-Oxazolones (3-Oxazolin-5-ones)

141

TABLE 7.6. SYNTHESIS OF 4-(ARYLTHIO)-5(2H)-OXAZOLONES FROM ETHYLCYANOFORMATE, KETONES, AND ARYLTHIOLSa

(R)2NH

NC

+ R1SH

OEt

TiCl 4

R1S

O

HN

OEt

O

O

R2

O

R1S

R3

O

N

BF3

R2

R3

Figure 7.7 R1

R2

Ph Ph 2-naphthyl 2-naphthyl a

R3

% Yield

(CH2)5 Me

28–32 &12 21 17

Me (CH2)5

Ph

CF3

Data from Refs. 22 and 23.

O PhS

O

1) HCl(g)

O

N R1

NC

R2

OEt

+ R3OH 2) Et3N

48 O Ph

O

O

m-CPBA

O

N R1

R3OH

O

N

R2

R1

49

O

R1

R3O

S

R2

R2 BF3

R3O

O

HN

OEt

50 Scheme 7.12

TABLE 7.7. SYNTHESIS OF 4-ALKOXY-5(2H)-OXAZOLONES FROM 4-(PHENYLTHIO)-5(2H)-OXAZOLONESa

O

O PhS

m-CPBA

Ph

O

N R2

O

O

S

R1OH

O

N

R3

R2

R1O O

N

R3

R2

R3

Figure 7.8 R1 Et i-Pr a

Data from Ref. 24.

R2

R3 (CH2)5 (CH2)5

% Yield 40 4

142

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.8. SYNTHESIS OF 4-ALKOXY-5(2H)-OXAZOLONES FROM IMINOOXALATES AND KETONES OR ALDEHYDESa

R1O

O

HN

O

O

R2

R1O

R3

OEt

O

N

BF3

R2

R3

Figure 7.9 R1

R2

R3

Et i-Pr i-Pr

CF3 CF3 H

Ph Ph Ph

a

% Yield 14 28 7

Data from Ref. 24.

Reaction of carbon dioxide with N-[1-chloro-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N 0 ,N 0 -dialkylformamidines has been described25 as a procedure to prepare 4-(dialkylamino)-5(2H)-oxazolones 51 (Scheme 7.13; Table 7.9, Fig. 7.10). Mechanistically, this reaction probably does not proceed via a nitrile ylide given the observed regioselectivities and the dependence of the reaction rate on the solvent. R2 CF3 Cl

H + CO2

N CF3

R1

O

N N

O

N R2 CF3

R1

CF3

51 Scheme 7.13 26

Finally, it has also been reported that the reaction of anilines with ethylimino(ethylthio) acetate fluoroborate and treatment of the resulting product with formaldehyde is an interesting and general procedure for the synthesis of 4(alkylamino)-5(2H)-oxazolones. TABLE 7.9. SYNTHESIS OF 4-(N,N-DIALKYLAMINO)-5(2H)OXAZOLONES FROM AMIDINES AND CARBON DIOXIDEa

R2 CF3 Cl

H + CO2

N CF3

N R2 R1

Me

Me (CH2)2O(CH2)2

a

Data from Ref. 25.

N

O CF3

Figure 7.10 R2

R1

R1

O

N

CF3

% Yield 98 91

5(2H)-Oxazolones (3-Oxazolin-5-ones)

7.2.2.

143

Reactions

7.2.2.1. Synthesis of Pyrroles 4-Alkyl(aryl)-2-(trifluoromethyl)-5(2H)-oxazolones have been used as intermediates to prepare 2-(trifluoromethyl)pyrroles interesting compounds frequently used as insecticides and acaricides. The oxazolones react with electron-deficient unsaturated compounds in the presence of a base. Reaction of 5(2H)-oxazolones, usually with a substituted aryl ring at C-4, with a wide variety of alkynes and alkenes has given rise to numerous 2-(trifluoromethyl)pyrroles 56. For example, dimethyl acetylenedicarboxylate,27,28 2-chloroacrylonitrile,29,30 haloacrylates or haloacrylonitriles,31–35 perhaloalkenes,36 N-[(a-(4-chlorostyryl)pyridinium] tetrafluoroborate,37 2-ethynylpyridine,38 2-(1-chlorovinyl)pyridine39 and, more recently, [60]fullerene40 all have been used as electron-deficient unsaturated compounds. Mechanistically, it is postulated that the anion of the 4-aryl-2-(trifluoromethyl)5(2H)-oxazolone undergoes Michael addition to the activated alkene to generate an intermediate that sequentially cyclizes and decarboxylates to afford a 3H-pyrrole. Subsequent 1,3-proton shift leads to the 1H-(trifluoromethyl)pyrrole41 (Scheme 7.14; Table 7.10, Fig. 7.11). EWG RCH LG

base

O Ar LG

N

O CF3 R

EWG 53

O

O

Ar

N

Ar

N

LG

EWG

EWG

CF3

CF3 R

R 54

55

LG = leaving group O

R

Ar N

O

CF3

CF3

EWG

N

Ar

H

52

56

Scheme 7.14

Similarly, reaction of 4-aryl-2-(trifluoromethyl)-5(2H)-oxazolones 52 with substituted azo compounds, for example, PhN NCO2Et affords (trifluoromethyl)dihydrotriazoles.42

7.2.2.2. Generation of Nitrile Ylides The thermolysis of 4-(alkylthio or arylthio)-5(2H)-oxazolones 57 in the presence of dipolarophiles with activated double bonds leads to five-membered cycloadducts.

144

5(2H)-Oxazolones and 5(4H)-Oxazolones

These results are rationalized on the basis of the intermediate formation of thiosubstituted nitrile ylides 58 that undergo regioselective 1,3-dipolar cycloadditions with the dipolarophiles. Some examples are shown in Scheme 7.15. If a dipolarophile is not present in the reaction mixture the nitrile ylides 58 (R2 ¼ Me) isomerize to give the 2-aza-1,3-butadienes 59 that can be trapped in a Diels–Alder reaction.43,44

−

R2

R2

:

+

R1

N

C

N

−CO2

C

R3S

C

+

O

N

R3S

C

∆

−

R3S

O R3S

R2

R1

57

N

R2 = CH3

R1

R1

58

59 CO2Et EtO2C

CH

R3S N R1 60

CO2Et PhCH2S

PhCH2S CO2Et

N

CO2Et EtO2C

C

C

N

CO2Et

N

O −CO2

PhCH2S

62

EtO2C

O

N

61 Ph

N

CO2Et N N CO2Et

CF3

−CO2

O

Ph PhCH2S N

CF3 O

64 Scheme 7.15

−CO2

63

5(2H)-Oxazolones (3-Oxazolin-5-ones)

145

TABLE 7.10. 2-(TRIFLUOROMETHYL)PYRROLES FROM REACTION OF 5(2H)-OXAZOLONES WITH ELECTRON-DEFICIENT UNSATURATED COMPOUNDS

O

R

Ar

EWG N

+ RCH

O

CF3

LG CF3

R

Ar

N H

Figure 7.11 EWG

Ar

H CF3 H H H H

EWG

base

Ph 4-ClC6H4 3,5-(Me2)C6H3 4-BrC6H4 4-MeOC6H4 Ph

% Yield

References

70–78 70 87 65 74 87

32,41 36 39 41 41 41

CN CF3 2-pyridyl CN CN CF3

On heating, 4-(isopropoxy)-2-phenyl-2-(trifluoromethyl)-5(2H)-oxazolone 65 underwent decarboxylation to the alkoxy-substituted nitrile ylide 66 that was trapped in a 1,3-dipolar cycloaddition by trifluoroacetophenone to generate 68.45 Other dipolarophiles reacted similarly. In the absence of a dipolarophile, cyclization of 66 yielded the isoindole 67 (Scheme 7.16; Table 7.11, Fig. 7.12). O

Oi-Pr

i-PrO N Ph 65

O CF3

∆ − CO2

Ph

+ i-PrO C N C CF3

N H

66

CF3

67 Ph

CF3

i-PrO

Ph

O

N Ph

CF3 O CF3

68 Scheme 7.16

7.2.2.3. Other Reactions Aminolysis of some 4-alkyl-2-(trifluoromethyl)-5(2H)-oxazolones 69 has been published (Scheme 7.17; Table 7.12, Fig. 7.13).46–48 Some degree of asymmetric

146

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.11. GENERATION OF NITRILE YLIDES FROM 5(2H)-OXAZOLONES

O R3X

R2 + R3X C N C R1

∆

O

N R1 R1

Figure 7.12 R3X

R2 (CH2)5

Me CF3 CF3

−CO2

R2

% Yield

PhCH2S PhS 2-naphthylS i-PrO

Me Ph Ph

not not not not

References

isolated isolated isolated isolated

43,44 43,44 43,44 45

induction is observed when chiral amines are used, a phenomenon that depends largely on solvents and on the nature of the amine. For example, aminolysis of 69 with (S)-phenylethylamine gave 70 mainly as the (S,S)-diastereomer. The same direction of induction was observed when chiral amino acid esters were used. For example, (S)-alanine or (S)-valine methyl esters afforded ring opening with high diastereoselectivity to afford (S,S)-dipeptides. In contrast, aminolysis with (S)proline methyl ester gave mostly (R,S)-dipeptides. O

O

R1

R1

R2NH2

N

O

CF3

NHR2

N H

CF3 69

O 70

Scheme 7.17 TABLE 7.12. AMINOLYSIS OF 5(2H)-OXAZOLONES

O R1

O

R2NH2

N

O

CF3

R1 NHR2

N H

CF3

O

Figure 7.13 R1

R2

PhCH2 i-Pr PhCH2 i-Pr PhCH2 i-Pr

(S)-Ph(Me)CH (S)-Ph(Me)CH (S)-PhCH2CHCO2Me (S)-PhCH2CHCO2Me (S)-i-PrCHCO2Me (S)-i-PrCHCO2Me

% Yield not not not not not not

described described described described described described

Reference 47 47 48 48 48 48

5(2H)-Oxazolones (3-Oxazolin-5-ones) O

(MeO)3P

H

P(OMe)3

O

N

CF3

147

N

CF3

CF3

CF3 + H C N C CF3

CF3

71

72

72a

CO2Et

CO2R N

CO2Et

N

CO2R EtO2C

CF3 CF3

C

C

CO2Et

N

N CO2R

N

CF3

N

CF3

RO 2C

73

74

O + P(OMe)3

O

N

CF3

CF3

71

CO2Et

EtO2C

C

R

CH

RCH

R

CH2

N

N

HN CF3

CF3

CF3

CF3

75

76

CF3 CF3 77

Scheme 7.18

Phosphites and 2,2-bis(trifluoromethyl)-5(2H)-oxazolone 71 react with elimination of carbon dioxide to give 2-aza-4-phospha-1,1-bis(trifluoromethyl)-1,3-butadiene 72 that can be used as a synthon for the previously unknown hydrogensubstituted nitrile ylide 72a in [3 þ 2]-cycloaddition reactions.49 Examples of cycloadditions of 72a with dipolarophiles to give heterocyclic compounds 73–77 are shown in Scheme 7.18. 4-Alkyl-2-(trifluoromethyl)-5(2H)-oxazolones 78 react with 3-(dimethylamino)2H-azirines 79 (Scheme 7.19; Table 7.13, Fig. 7.14). This reaction, investigated mechanistically, has been described as a new procedure for the synthesis of 5(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 80.50 O R1 N

O

N + Me

R1 R2

N CF3 78

Me

Me

R3

79

N

R2 O

N H 80

Scheme 7.19

N

R3

Me

148

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.13. 5-(DIMETHYLAMINO)-3,6-DIHYDROPYRAZIN2(1H)-ONES FROM REACTION OF 5(2H)-OXAZOLONES WITH 3-(DIMETHYLAMINO)-2H-AZIRINES O R1 O

N

Me

Me

R1

N + Me N

N

Me

R2

R2

CF3

N

O

R3

N

R3

H

Figure 7.14 R1

R2

a

R3

% Yield

(CH2)5

PhCH2 i-Pr PhCH2 Ph

Me Me Me

57 60 48 58

Me Me Me

Data from Ref. 50.

The double bond of 2,2-bis(trifluoromethyl)-5(2H)-oxazolone 71 reacts with ynamines51 and the resulting cycloadduct 81 is converted into the corresponding amino acid after hydrolysis. The procedure constitutes a new route to 3-alkylsubstituted aspartic acid derivatives 83 (Scheme 7.20; Table 7.14, Fig. 7.15).

O

N

O CF3 71

CF3

R

C

R

O

R C NEt2

N Et2N

O CF3

O

Et2N HCl

O

O

N H

CF3

CF3

81

CF3

82 R Et2N

CO2H O

NH2 83

Scheme 7.20

Some unusual reactions have been described for 2-(4-chlorophenyl)-2-(3,3dimethylallyl)-4-phenyl-5(2H)-oxazolone 84. This compound undergoes a Lewis acid-catalyzed rearrangement to give a tetrahydrofuropyrrole 85.52 On the other hand, depending on the reaction conditions, thermolysis of 84 produces the azabicyclohexene 86 or a substituted 2,3-dihydropyridine 87 together with the caged compound 88 formed by dimerization of the 2,3-dihydropyridine and the azabicyclohexene (Scheme 7.21).53,54

5(2H)-Oxazolones (3-Oxazolin-5-ones)

149

TABLE 7.14. 3-ALKYL ASPARTIC ACID DERIVATIVES FROM REACTION OF 5(2H)-OXAZOLONES WITH YNAMINESa

O

N

O CF3

O

R + R C C NEt2

O

N Et2N

CF3

R HCl

CF3

Et2N

CO2H O

CF3

NH2

Figure 7.15 R

% Yield

Me Et a

95 95

Data from Ref. 51.

Lewis Acid

Me Me

O

O Ph

H N

4-ClC6H4 85 O

Me

Ph N

toluene, ∆

O Me

4-ClC6H4

Me H+

N

4-ClC6H4

4-ClC6H4

84

86

87

Me Me

Me

N 4-ClC6H4

Ph NH C6H4-4Cl

Me

Ph 110 ºC

+

Me

Ph

N

DBU − CO2

Me

− CO2

Me

Ph

Me

C6H4-4Cl N

Me Ph

87

88 Scheme 7.21

5(2H)-Oxazolone N-oxides 91 have been obtained by heating a solution of 5isonitroso-2,2-dimethyl-1,3-dioxane-4,6-dione 90 with the corresponding ketone in toluene. It has been postulated that the reaction occurs through an intermediate nitrosoketene that is generated from 90 via loss of CO2 and acetone, respectively.

150

5(2H)-Oxazolones and 5(4H)-Oxazolones

These cyclic nitrones 91 react with electron-rich olefins in 1,3-cycloaddition reactions to afford fused isoxazolidines 92–94 from which several unusual amino acids 95–97 have been obtained (Scheme 7.22).55 O

O

HO N

HNO2

O

O

Me O

O

Me O

Me

O

89

O

C

∆

N

Me

O

90

O

R1 R2

O EtO

O

N high pressure

O

R1

Me3Si

R2

high pressure

91

H

HH

O

O

H

EtO

O

O N R1

R2

H

O

O N R1

92

R2

Me3Si

93

CO2H O N H

R1

CO2H H

1) aq. NaHCO3 2) ion-exchange 3) H2/Pd-C

CO2H

Me3Si

O N H

OH

96

97

95

R2

94

HH

H H

O

O N

1) aq. NaHCO3 2) ion-exchange

1) aq. NaHCO3 2) ion-exchange

EtO

O

H

H

NH2

Scheme 7.22

Several research groups have focused their attention on the photooxidation of 20 deoxyguanosine that is used as a model compound for DNA. The major photooxidation products of this nucleoside were identified and classified according to their formation through a radical mechanism (type I) or a singlet oxygen-mediated mechanism (type II). The major type I product was identified as 2,2-diamino-[(2deoxy-b-D-erythro-pentofuranosyl)-4-amino]-5(2H)-oxazolone 98 (Fig. 7.16).56–64

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

151

OAc O

OAc

O

HN O

N

NH2

H2N 98

Figure 7.16. 2,2-Diamino-[(2-deoxy-b-D-erythro-pentofuranosyl)-4-amino]-5-(2H)-oxazolone 98.

7.3. SATURATED 5(4H)-OXAZOLONES (2-OXAZOLIN-5-ONES) 7.3.1.

Synthesis

7.3.1.1. Cyclization from Amino Acid Derivatives It was shown previously that saturated 5(4H)-oxazolones or 2-oxazolin-5-ones with only one substituent at C-4 can be considered as the tautomeric form of saturated 5(2H)-oxazolones or 3-oxazolin-5-ones. These compounds can also be considered as amino acid derivatives and, indeed, cyclization procedures are the most commonly used to prepare these compounds. The cyclization reaction employs a variety of cyclodehydrating agents and the general method is shown in Scheme 7.23, with an N-acyl-a-amino acid being the most typical starting material used. In this way, 5(4H)-oxazolones derived from most natural amino acids 99 (R3 ¼ H) have been obtained by heating the corresponding N-acyl derivatives in the presence of acetic anhydride.1,65–68 R3 R2

R3 CO2H

Ac2O

NHCOR1

R2 N

O O R1

99 Scheme 7.23

The procedure is also useful for the synthesis of 4,4-disubstituted 5(4H)oxazolones. For example, cyclization of a 2-aryl(hetaryl)carbonylamino-2-arylpropionic acid afforded the corresponding oxazolones 99 (R3 ¼ Me) that were evaluated as selective herbicides.69 A slight modification of this procedure using N-acyl-a-amino acids obtained from trifluoropyruvic acid and the corresponding nitrile has been described.70 In

152

5(2H)-Oxazolones and 5(4H)-Oxazolones AcO CF3

CF3C(OH)2CO2H + RCN

CO2H

AcO CF3 N

Ac2O

NHCOR

O O R

100 Scheme 7.24

this case, 4-acetoxy-2-substituted-4-(trifluoromethyl)-5(4H)-oxazolones 100 are obtained (Scheme 7.24). The synthesis of 2-(trifluoromethyl) derivatives is more difficult and the compound preferentially obtained depends on the substituents and on the reaction conditions. Thus, the reaction of tryptophan with TFAA gives the 5(4H)-oxazolone without racemization.4,5 However, when this optically active product is dissolved in acetonitrile the racemic 5(4H)-oxazolone is obtained. On the other hand, treatment of the optically active compound with hot aqueous dioxane gave the isomeric 5(2H)-oxazolone (see Scheme 7.2). Treatment of 2-(1-adamantyl)glycine with TFAA gave 4-(1-adamantyl)-2-(trifluoromethyl)-5(4H)-oxazolone in high yield.71 A 2-(trifluoromethyl)-5(4H)-oxazolone derived from serine has been obtained from O-trimethylsilyl-N(trifluoroacetyl)serine diethylamide.72 Cyclization of N-acyl-a-amino acids under acidic reaction conditions is sometimes problematic due to the difficulty in separation of the desired oxazolone from by-products while avoiding decomposition of the reactive oxazolone. This finding is particularly true in the case of 2-phenyl-5(4H)-oxazolone, an interesting compound that is a very useful intermediate to prepare a variety of novel products. The use of carbodiimides as dehydrating agents has been described as a means to improve the results. In particular, treatment of an N-acyl-a-amino acid with N-cyclohexyl-N 0 -2-(N-methylmorpholinio)ethylcarbodiimide p-toluensulfonate (Scheme 7.25) is especially useful as a general synthesis of the desired saturated 5(4H)-oxazolones 101 in excellent yields.73,74 This same carbodiimide was used to study the kinetics of the formation of saturated 5(4H)-oxazolones from N-protected dipeptides.75 TosO

Me N

N

R3 R2

C N

O

R3 CO2H

R2 N

NHCOR1

O O R1

101 Scheme 7.25

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

153

The use of mixed anhydrides derived from N-acyl-a-amino acids has become an interesting strategy for synthesis of saturated 5(4H)-oxazolones 101 (Scheme 7.26). For example, reaction of N-acyl-a-amino acids with methyl chloroformate in the presence of N-methylmorpholine affords racemic 5(4H)-oxazolones.

R3 R2

O

R3 ClCO2R

CO2H

NHCOR1

R2

O

N O

N Me

R1 101 Scheme 7.26

In the cases where optically active substrates were used as starting materials, chiral, saturated 5(4H)-oxazolones were obtained with good enantiomeric excesses (ee).76 Oxazolones derived from N-formyl-a-amino acids are better prepared using isopropenyl chloroformate, rather than methyl chloroformate, in the presence of Nmethylmorpholine.77 2-Phenyl-5(4H)-oxazolone has been obtained during alkaline hydrolysis of pnitrophenyl N-benzoylglycinate. A detailed study of this process has shown that the leaving group expulsion is the rate-determining step for conversion of the glycinate to the 5(4H)-oxazolone.78 In addition to the typical cyclization procedures described above, methods involving the use of other mild, cyclodehydrating agents have been published. For example, cyanuric chloride in the presence of triethylamine,79 2-ethoxy-Nethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or 2-isobutoxy-N-isobutoxycarbonyl-1,2-dihydroquinoline (IIDQ),80 N,N-dimethylchlorosulfitemethaniminium chloride81 and several haloiminium salts82 have proved to be very useful reagents. The use of N-acylated-a-amino nitriles,83 nitrones,84 or a-amino amides85 as starting compounds have also been reported. N-Acylated-a-amino nitriles were converted into 5(4H)-oxazolones 101 in the presence of ethyl chlorooxoacetate (Scheme 7.27).83

R3 R2

CN

ClCOCO2Et

R3 R2 N

NHCOR1

O O R1

101 Scheme 7.27

154

5(2H)-Oxazolones and 5(4H)-Oxazolones

Nitrones such as 102 gave 2-aryl-4-substituted-5(4H)-oxazolones 103 in the presence of acetic anhydride and triethylamine (Scheme 7.28).84 Selected examples of saturated-5(4H)-oxazolones prepared via cyclization of amino acids are shown in Table 7.15 (Fig. 7.17). O

R2 O R1

Ac2O

CH N CO2H

R2

O

N Et3N

R1 102

103 Scheme 7.28

2-Acylamino-N,N-2-trimethylpropionamides 104, obtained from 2,2-dimethyl3-(dimethylamino)-2H-azirine and carboxylic acids, were hydrolyzed to the corresponding carboxylic acids and then cyclized to the 4,4-dimethyl-2-substituted-5(4H)-oxazolones 105. This reaction sequence including ring opening of the 5(4H)-oxazolone with amino acids is a very interesting methodology to prepare Aib-containing peptides 106 (Scheme 7.29).86

TABLE 7.15. SYNTHESIS OF SATURATED 5(4H)-OXAZOLONES VIA CYCLIZATION OF AMINO ACID DERIVATIVES

R2 R1

cyclization agent

X

R2 R1 N

NHCOR3

O O R3

X CO2H CO2H CO2H CO2H CO2H CO2H CO2H CONMe2 CONMe2 CONMe2 a

Cyclization Agent

R1

Figure 7.17 R2

R3

TFAA indol-3-ylmethyl H CF3 Ac2O 4-MeC6H4 H 3-ClC6H4 TFAA H 1-adamantyl CF3 morphoCDIa H H Ph morphoCDIa H H t-Bu morphoCDIa Me Me Ph ClS(O)CHNMe2Cl H Me Ph HCl/toluene Me Me Ph HCl/toluene Me Me 2-HOC6H4 HCl/toluene Me Me Ph2C(OH)

% Yield

References

90 80 86 90 84 82 85 90 85 90

4,5 69 71 74 74 74 81 85 85 85

N-Cyclohexyl-N 0 -2-(N-methylmorpholinio)ethylcarbodiimide p-toluensulfonate.

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Me2N Me N

Me Me

R1CO2H

CONMe2

155 O

Me Me

HCl

O

N

NHCOR1

Me

R1 104 R2

105

CO2R3 NH2

R1

O Me Me H N N H

CO2R3

O

R2

106 Scheme 7.29

7.3.1.2. Other Cyclization Procedures A new and completely different methodology involving a cycloaddition reaction has been described.87 The reaction between diphenylketene, tert-butylcyanoketene or dimethylketene with 2,4,6-trimethylbenzonitrile N-oxide gave the corresponding 5(4H)-oxazolones 107 in moderate yields (Scheme 7.30).

O

R1 Me C Me

+ O N

R1 +

C C O R2

R2

O

N

Me Me

Me Me 107 Scheme 7.30

7.3.1.3. Rearrangement of Oxazoles Allylic esters of N-acyl-a-amino acids were rearranged to the g,d-unsaturated aamino acids 110 through an Ireland–Claisen rearrangement in moderate to good yields and with good diastereoselectivities.88 Under certain conditions this process involves the formation of an intermediate oxazole 108 that was converted to the corresponding oxazolone 109 by [3,3] sigmatropic rearrangement (Scheme 7.31).

156

5(2H)-Oxazolones and 5(4H)-Oxazolones R2 R2 PPh3/CCl4

CO2

O

N

O

N

NHCOPh

CO2H

HO−

R1

R1

Et3N

R1

O

R2

O

R2

R1

NHCOPh

Ph Ph 108

109

110

Scheme 7.31

In a similar way, propargyl esters of N-benzoyl-a-amino acids have been converted into a-allenyl-a-amino acid esters 113 by cyclization to oxazoles 111 followed by Claisen rearrangement to the 4-allenyl-2-phenyl-5(4H)-oxazolones 112. Oxazolone ring opening with methanol then afforded 113 (Scheme 7.32).89

C C CO2 R1

R2 NHCOPh

C

R3

R2

R3

C Et3N

C

O

PPh3/CCl4

R1 N

O

R3

R2

R1

O

O

N Ph

Ph

111

112

R2 MeOH/Et3N

C CO2Me R3

R1

NHCOPh 113

Scheme 7.32

Since the rearrangement occurs via the corresponding 5-alkoxyoxazoles, a new strategy was developed starting from these heterocycles. Nucleophilic displacement of fluoride in 5-fluoro-2-phenyl-4-(trifluoromethyl)oxazole 114 with allylic alcohols gave the allylic ethers 115 that subsequently yielded the saturated oxazolones 116 through a Claisen rearrangement. 2-Substituted 3,3,3-trifluoroalanine derivatives 11790 or a-(trifluoromethyl)-b-substituted aspartic acid derivatives 11891 could be obtained readily from 116 after hydrolysis or hydrolysis followed by oxidation (Scheme 7.33).

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

157

R2 HO

F CF3

R2 R1

O

O

N

R3

CF3

R3

R1 O

N

Ph

Ph 114

115 R1 R3 R2

H3O+

R1 R3

CO2H CF3

NHCOPh

O

R2 CF3

117 1) HO− 2) oxidation

O

N

Ph

R3 R2

116

CO2H CO2H CF3

NHCOPh 118

Scheme 7.33

Similarly, the allenic derivatives 120 and 121 have been obtained from propargylic alcohols as shown in Scheme 7.34.90 The use of 2-(hydroxymethyl)furan or 2-(hydroxymethyl)thiophene as allylic alcohols gives rise to a-(trifluoromethyl)-a-(2-heteroaryl)glycine derivatives 125 after hydrolysis of the corresponding oxazolone 124 as shown in Scheme 7.35.91 R2 R1

CH R2

F HC

CF3

C OH

N

O Ph

114

O

R1

C

CF3 N

C

R2 R1

O

H CF3

O

N

Ph

O Ph

119

120 R2 H3O+

R1 C CO2H

H

CF3 NHCOPh 121

Scheme 7.34

158

5(2H)-Oxazolones and 5(4H)-Oxazolones

X

X

X O

O

CF3

CF3

O

N

CH3

O

N

O

N

Ph

Ph

123 (X = O, S)

124 (X = O, S)

Ph 122 (X = O, S)

O CF3

CH3 H3O+

X CO2H CF3

NHCOPh

125 (X = O, S) Scheme 7.35

Heating 5-(arylmethyloxy)-2-phenyl-4-(trifluoromethyl)oxazoles 126 effects thermal rearrangement to 4-(arylmethyl)-2-phenyl-4-(trifluoromethyl)-5(4H)-oxazolones 127.92–94 In some cases, the formation of 2-(arylmethyl)-2-phenyl-4(trifluoromethyl)-5(2H)-oxazolones has been reported.93 Hydrolysis of 127 constitutes a new general route to a-(arylmethyl)-a-(trifluoromethyl) a-amino acids 128 (Scheme 7.36).92 In this case, isolation of mixed products in crossover experiments indicates that the rearrangement is not a sigmatropic process but involves a 1,3benzyl shift. 5-(Benzyloxy)-2-phenyl-4-(trifluoromethyl)oxazole and 4-benzyl-2phenyl-4-(trifluoromethyl)-5(4H)-oxazolone have been studied as enzyme inhibitors for amino acid decarboxylases and transaminases.94 Ar

Ar

O CF3 O

N

O ∆

CF3 N

CO2H CF3

NHCOPh

Ph

Ph 126

O

Ar H3O+

127

128

Scheme 7.36

b-D-C-Allosyl-(R)-alanine 131 was synthesized from the b-C-glycosyloxazolone 130 that was obtained from the corresponding protected D-glucal by a sequential coupling with N-benzoylalanine followed by a Claisen rearrangement (Scheme 7.37). The oxazolone was obtained as a mixture of two diastereoisomers in a 3:1 ratio. The process involves the formation and rearrangement of an intermediate oxazole 129 that could not be detected.95

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Me

Me

Me

O

O

Me

Me

Me

O

O

O H O

O

Me

O

O

159

O

Et3N

O O

N O

N

NHCOPh

H

Me

Me

O

O

H

PPh3, CCl4

Ph

Ph 129

130 HO HO

HCl, ∆

O

Me

H CO2H NH2

131 Scheme 7.37

It is known that 5-acyloxyoxazoles 132 rearrange to 4-acyl-5(4H)-oxazolones 133 in the presence of 4-(dimethylamino)pyridine or 4-(pyrrolidino)pyridine. Recently, an asymmetric variant of this nucleophile-catalyzed rearrangement that employs a chiral derivative of 4-(pyrrolidino)pyridine has been described. This procedure allows the construction of quaternary stereocenters with high levels of enantioselectivity (Scheme 7.38).96,97 Representative examples of saturated 5(4H)oxazolones prepared via sigmatropic rearrangements are shown in Table 7.16 (Fig. 7.18).

N N

R3 O

R

O

R2

Fe

R

R3 R

R R

N

O

O

O R2 N

O R1

R1

133 ee = 42-95 %

132 Scheme 7.38

160

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.16. SYNTHESIS OF SATURATED 5(4H)-OXAZOLONES VIA SIGMATROPIC REARRANGEMENT OF 5-ALKOXYOXAZOLES

O R2 R1 O

N

R′2 ∆

R1 N

R3 R1

H MeCH CHCH2 Me MeCH CHCH2 PhCH2 HC CCH2 PhCH2 MeC  CCH2  CCHMe HC PhCH2  2-furylmethyl CF3 Me CO2Bn

O R3

Figure 7.18 R02

R2

O

R3

% Yield References

MeCHCH CH2 Ph 65 MeCHCH CH2 Ph 71 CH C CH2 Ph 100 MeC C CH2 Ph 100 CH C CHMe Ph 100 5-methyl-2-furyl Ph 47 CO2Bn 4-MeOC6H4 94

88 88 89 89 89 92 96,97

7.3.1.4. From Other Oxazolones 7.3.1.4.1.

From 5(2H)-Oxazolones

As discussed previously, alkylation of 4-benzyl-2-(trifluoromethyl)-5(2H)-oxazolone 16 in the presence of mild base using active alkyl halides occurs at C-4 to afford a,a-dialkyl-5(4H)-oxazolones (Scheme 7.5).14 7.3.1.4.2.

Saturated 5(4H)-Oxazolones via Modifications at C-2

Saturated 2-vinyl-5(4H)-oxazolones have been widely used as intermediates for the synthesis of polymeric compounds that will be described in Section 7.3.2.9. Apart from these polymerization reactions, the Diels–Alder reactions of 4-substituted-2-vinyl-5(4H)-oxazolones 134 with cyclopentadiene are reported to give norbornenyl oxazolones 13598,99 that are useful to prepare norbornenyl functionalized resins by azlactone ring-opening addition reactions (Scheme 7.39). O

R2 R1

N

N

O

O

134

R1

R2 O

135 Scheme 7.39

The vinyl substituent at C-2 can also act as a Michael acceptor and reaction with certain nucleophiles gives rise to 1,4-addition compounds. For example, p-toluenesulfonic acid catalyzed addition of thiols to 2-vinyl- or 2-isopropenyl-5(4H)oxazolones 136 gave, almost exclusively, the Michael adducts 137 that were used

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

161

as curing agents for epoxy and isocyanate resins.100 On the other hand, acidcatalyzed addition of primary alcohols to 4,4-dimethyl-2-vinyl-5(4H)-oxazolone 136 (R1 ¼ R2 ¼ Me, R3 ¼ H) gave 138 and 139 as an 50:50 mixture, whereas with secondary and tertiary alcohols the Michael adducts 138 were preferentially obtained. Interestingly, the reaction of 4,4-dimethyl-2-isopropenyl-5(4H)-oxazolone 136 (R1 ¼ R2 ¼ R3 ¼ Me) with phenethyl alcohol effected ring opening to afford compound 139 (R1 ¼ R2 ¼ R3 ¼ Me, R4 ¼ CH2CH2Ph) cleanly (Scheme 7.40).101 O

R2 R4SH

R1

R3

O

R2 R1

O

N

p-TsOH

N

SR4

O

137 R3

136

O

R2 R4OH

R1

p-TsOH

R2 O

N

+ R1

CO2R4 NHCOCH=CH2

R3

R3

OR4 138

139

Scheme 7.40

Finally, hydrosilylation of 2-alkenyl-5(4H)-oxazolones in the presence of an appropriate catalyst normally afforded b-addition compounds, for example, 141, although 4,4-dimethyl-2-vinyl-5(4H)-oxazolone 140 also yielded the corresponding a-addition compound 142 (Scheme 7.41).102

Me

Me3SiOSiMe2H

Me

N

O

Me

O O

Me N

O

Me Me

O +

N

(Ph3P)3RhCl

Me

O SiMe2OSiMe3

SiMe2OSiMe3 140

141 Scheme 7.41

142

162

5(2H)-Oxazolones and 5(4H)-Oxazolones

7.3.1.4.3.

Saturated 5(4H)-Oxazolones via Modifications at C-4

ALKYLATION. Saturated 5(4H)-oxazolones are readily available compounds that can be easily obtained from a wide variety of natural amino acid derivatives. These heterocyclic compounds can be considered as nucleophilic synthons of a-amino acids and their most exploited reactivity, apart from oxazolone ring opening, is the reaction at C-4 with a variety of electrophiles. The behavior of 2-substituted- or 2-unsubstituted-5(4H)-oxazolones is completely different. Reaction of electrophiles with 2-substituted-5(4H)-oxazolones usually occurs at C-4, whereas reaction of electrophiles with 2-unsubstituted5(4H)-oxazolones affords the corresponding 5(2H)-oxazolones. The best example of the behavior of 2-unsubstituted-5(4H)-oxazolones involves 4-isopropyl-5(4H)oxazolone 143, the anion of which can be considered as a formyl anion equivalent.103,104 Thus, reaction of 143 with a catalytic amount of triethylamine gives 144 that reacts with a,b-unsaturated carbonyl compounds to afford Michael adducts or with aldehydes to produce the corresponding aldol adducts. Mild acid hydrolysis of 145 yields the corresponding aldehydes (Scheme 7.42). O

i-Pr

O

i-Pr

N

O

N

O

i-Pr

Et3N

O

O

i-Pr

H3O+

E+

O

N

O

N

E-CHO

E 143

144

145 Scheme 7.42

Alkylation of saturated 5(4H)-oxazolones at C-4 is a well-known reaction that can be achieved under a wide variety of conditions. Numerous articles have described this reaction as a means to prepare 4,4-dialkyl-5(4H)-oxazolones 147 that are valuable intermediates to prepare a,a-disubstituted a-amino acids. For instance,105 2-phenyl-5(4H)-oxazolone 146 readily obtained from hippuric acid and N,N 0 -dicyclohexylcarbodiimide (DCC), is alkylated at C-4 with allyl, benzyl, or phenacyl halides if the reaction is conducted in dipolar aprotic solvents in the presence of weak bases. Hydrolysis of the resulting 5(4H)-oxazolones leads to a,adialkylglycines 148 (Scheme 7.43). O weak base

O

N

2 RX

O

R R

R

H3O+

N

O

R

CO2H

NHCOPh Ph

Ph 146

147

148

Scheme 7.43

The alkylation of 2-aryl-4-phenyl-5(4H)-oxazolones like 22 is strongly dependent upon the nature of the substituent on the aromatic ring at C-2. For electron-rich

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

163

aryl substituents, the C-4 alkylated compounds are the main products as shown in Scheme 7.7.15 In other cases, alkylation occurs exclusively at C-4.106 Alkylation of 2,4-disubstituted-5(4H)-oxazolones can be conveniently performed via phase-transfer catalysis. For example, the substrate and an alkyl halide are dissolved in an organic solvent and stirred with an aqueous sodium carbonate solution containing tetrabutylammonium bromide as a phase-transfer catalyst.107 4,4-(Diarylmethyl)-2-phenyl-5(4H)-oxazolones can be prepared in one-step by dialkylation of 146 using magnesium methyl carbonate and the corresponding arylmethyl halide.108,109 4-Methyl(or benzyl)-2-phenyl-5(4H)-oxazolone is benzylated or methylated in the presence of potassium carbonate, potassium hydroxide or diisopropylethylamine and a phase-transfer catalyst to yield the corresponding 4,4dialkyl-5(4H)-oxazolone, which upon hydrolysis affords a-methyl- or a-benzylphenylalanine.110 Recently, a new and generally applicable procedure for efficient a-alkylation of 2-phenyl-4-substituted-5(4H)-oxazolones 149 and 151 has been described.111 A valuable feature of this approach is that, depending on the availability and ease of preparation of the starting oxazolone and the reactivity of the electrophile, two complementary approaches are available (Scheme 7.44). This synthetic methodology opens interesting possibilities for the synthesis of novel a-amino acids that combine two side chains of proteinogenic and non-proteinogenic amino acids— so-called ‘‘chimeras’’. O

H

NaH

R2

O

N

O

R3 R3X

NaH

R2

O

N

H N

R2X

R1

O

R3

R1

R1

149

O

150

151

Scheme 7.44

An asymmetric alkylation of 2-phenyl-4-substituted-5(4H)-oxazolones 152 has been described recently.112,113 This approach is based on palladium-catalyzed allylic alkylations of 152 using 3-acetoxycyclohexene as reagent. The reaction occurs with excellent enantioselectivity for the major diastereoisomer and opens the way for the asymmetric synthesis of quaternary a-amino acids, important building blocks in peptide synthesis (Scheme 7.45). O

O N

O R + OAc

N

O

N

H O

H H PPh2

Ph2P

[{η3-C3H5PdCl}2]

R N

Ph

O Ph

152

153

Scheme 7.45

164

5(2H)-Oxazolones and 5(4H)-Oxazolones

Other allylating agents have been employed in this enantioselective reaction with different results. Moderate-to-low ee’s are obtained with highly symmetrical allylating agents, whereas 1-monosubstituted and 1,1-disubstituted allyl reagents gave ee’s >90%.114,115 This allylation was the key step in the stereoselective synthesis of some sphingosine analogues.116 Alkylation of oxazolones with a-halo ketones under phase-transfer catalysis generated an enolate 155 from initial alkylation at C-4 that immediately translactonized to produce an enol lactone 156 (Scheme 7.46).117 Selected examples of 5(4H)-oxazolones prepared via alkylation are shown in Table 7.17 (Fig. 7.19). O

O

R2 O +

N

X

R3 EtO2C

R1

TBAHSO 4 KHCO3

R4

O

R3 EtO2C

O

R2

O

R4 N

R1

X = halogen 155

154 TBAHSO 4 = tetrabutylammonium hydrogensulfate R3 EtO2C

R4

O

O NHCOR1 R2

H 156

Scheme 7.46

MICHAEL REACTION. 5(4H)-Oxazolones undergo base-catalyzed conjugate addition to activated unsaturated compounds to afford the corresponding C-4 Michael adducts. For example, base-catalyzed addition of a 4-monosubstituted-5(4H)oxazolone 157 to methyl propiolate yields a mixture of diastereomeric methyl 3-(5-oxo-2-phenyl-2-oxazolin-4-yl)acrylates 158. Hydrolytic ring opening of 158 and subsequent oxidation with lead tetraacetate affords 3-acylacrylates 160 (Scheme 7.47).118 O R

HC

N

O

O

MeO2C C

CO2Me

R N

HCl

CO2H

MeO2C

R NHCOPh Ph

Ph 157

O

158

159 O Pb(OAc) 4

MeO2C

R 160

Scheme 7.47

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

165

TABLE 7.17. SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4H)-OXAZOLONES VIA ALKYLATION OF SATURATED 5(4H)-OXAZOLONES AT C-4

O

H R1 N

O

R3 base

O

R1 N

R3X

R2

O R2

X = Br, I, OAc R1

R2

Ph Ph Ph Me Me Me PhCH2 i-Bu t-BuO2CCH2CH2 Me PhCH2 t-Bu Me PhCH2 i-Pr

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

Figure 7.19 R3 Me CH2 CHCH2 EtO2CCH2 Me CH2 CHCH2 EtO2CCH2 t-BuO2CCH2 t-BuO2CCH2 Me 2-cyclohexen-1-yl 2-cyclohexen-1-yl 2-cyclohexen-1-yl Me2C CHCH2 Me2C CHCH2 Me2C  CHCH2

% Yield

Reference

61 77 57 19 49 40 69 68 50 73 75 91 67 62–78 47

107 107 107 107 107 107 111 111 111 112 112 112 115 115 115

This procedure is an excellent method to prepare 1,4-dicarbonyl compounds 163 (Scheme 7.48) and, using triethylamine, has been extended to include other activated double bonds.119 Thus, the starting a-amino acids can be considered as nucleophilic acyl equivalents. Representative examples of 5(4H)-oxazolones prepared via Michael additions are shown in Table 7.18 (Fig. 7.20). O O R2

EWG O

N

O R1

161

Et3N

O

EWG R2

O NaOH

N

O Pb(OAc) 4

EWG R2 O

R1 162

163

Scheme 7.48

In those cases, where conjugated 1,3-dicarbonyl compounds have a leaving group in the b-position, reaction with a 5(4H)-oxazolone occurs via an addition– elimination reaction sequence to give, after cyclization, pyran-2-ones 165

166

5(2H)-Oxazolones and 5(4H)-Oxazolones

TABLE 7.18. SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4H)-OXAZOLONES BY REACTION OF SATURATED 5(4H)-OXAZOLONES WITH MICHAEL ACCEPTORS

O

H

R2

Michael acceptor

R1 N

R1

O

N

R3

O O R3

Figure 7.20 R1

Michael Acceptor

t-Bu PhCH2 MeO2C(CH2)2 PhCONH(CH2)4 i-Pr i-Pr PhCH2 PhCH2 PhCH2 PhCH2

 HC  CCO2Me HC CCO2Me  HC  CCO2Me  CCO2Me HC  CH2 CHCOMe CH2 CHCN CH2  CHCOMe CH2 CHCOPr CH2 CHCN CH2 CHCO2Me

R2

R3

MeO2CCH CH MeO2CCH CH MeO2CCH CH MeO2CCH CH MeCOCH2CH2 NCCH2CH2 MeCOCH2CH2 PrCOCH2CH2 NCCH2CH2 MeO2CCH2CH2

Ph Ph Ph Ph 2,4,6-Me3C6H2 2,4,6-Me3C6H2 2,4,6-Me3C6H2 2,4,6-Me3C6H2 2,4,6-Me3C6H2 2,4,6-Me3C6H2

% Yield

Reference

87 76 85 84 82 82 89 85 87 83

118 118 118 118 119 119 119 119 119 119

(Scheme 7.49). The requisite activated double bond is generated in situ from the 1,3-dicarbonyl compound and a one-carbon synthon such as a trialkyl orthoformate, diethoxymethyl acetate or N,N-dimethylformamide dimethyl acetal.120 It has also been reported121 that some 4-substituted-5(4H)-oxazolones 166 undergo Michael addition to triphenylvinylphosphonium bromide to give the corresponding 4,4-disubstituted-5(4H)-oxazolones 167 from which ring opening O CO2H

R2 + XCH(OR)2 +

NHCOR1

Me O

O O

O

O

R2

R2 CHX + Me O

N

O Me

H O N

R1

Me

O

O NHCOR1

R2CO R1

164 Scheme 7.49

O

165

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) O PPh3 Br

Br Ph3P

1) MeOH/p-TSA

O

N

R2

O

R2

R2

167

N

R1

O

N H

2) NaOMe

R1

R1

166

CO2Me

167

168 R2

CO2Me

N R1 169 Scheme 7.50

and intramolecular Wittig reaction afford pyrroline-2-carboxylic acid esters 169 (Scheme 7.50). ARYLATION. Arylation of 2,4-diaryl-5(4H)-oxazolones 170 with activated aryl halides has been reported to proceed under phase-transfer conditions (Scheme 7.51).122 The yields of 2,4-diaryl-4-(2,4-dinitroaryl)-5(4H)-oxazolones 171 are often modest. Heteroarylation of 170 was accomplished using 2-chloro-3,5dinitropyridine. Representative examples are shown in Table 7.19 (Fig. 7.21).

TABLE 7.19. SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4H)-OXAZOLONES VIA ARYLATION OF SATURATED 5(4H)-OXAZOLONES AT C-4

O

H R1 N

O

base

O

Ar R1 N

ArX

R2

O R2

X = F, Cl Figure 7.21 R1

R2

Ph Ph i-Pr Ph 4-ClC6H4 4-MeOC6H4

4-MeOC6H4 4-MeOC6H4 Ph i-Pr 4-MeC6H4 4-MeC6H4

a

Data from Ref. 122.

Ar 2,4-(NO2)2C6H3 2,4,6-(NO2)3C6H2 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3 2,4-(NO2)2C6H3

% Yield 35 34 28 49 20 52

168

5(2H)-Oxazolones and 5(4H)-Oxazolones R3 X

R3

O Ar2 N

Ar2

O

NO2

O2N

O Base/TBAB

N NO2

O2N

Ar1 170

O Ar1

171 TBAB = tetrabutylammonium bromide Scheme 7.51

ACYLATION. Acylation at C-4 of 4-unsubstituted or 4-monosubstituted 5(4H)oxazolones 172 has been described using two different strategies. Depending on the nature of the substituents in the starting oxazolone, the nature of the acylating agent and the experimental conditions, two different products can be obtained. In general, it should be noted that, in the presence of triethylamine, acylation occurs at C-4, although in some cases the major product is the 5-acyloxyoxazole 173 that arises from O-acylation. In these cases, 173 can be rearranged to the desired 4-acyl-5(4H)-oxazolone 174 with 2- or 4-picoline (Scheme 7.52). For example, acylation of 2-phenyl-5(4H)-oxazolone 172 (R1 ¼ Ph, R2 ¼ H) with propionyl choride in the presence of 2-picoline gives 2-phenyl-4-propionyl-5(4H)oxazolone.123 However, acylation of the same oxazolone with ethyl 7-(chloroformyl)heptanoate in the presence of triethylamine gives the corresponding 5acyloxy-2-phenyloxazole that rearranges to the desired 5(4H)-oxazolone in 4-picoline.124 OCOR3

R2 R3COCl

O

N

R1

O R2 N

173

O

picolines

R1 172

R2 R3COCl

R3CO

Et3N

N

O O R1

174 Scheme 7.52

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

169

Reaction of 4-alkyl(aralkyl)-2-phenyl-5(4H)-oxazolones 175 with difluoro- and trifluoroacetic anhydride yields a-(benzamidoalkyl)-difluoro- and trifluoroketones 178 in good yield in a one-pot procedure (Scheme 7.53).125

O R1

(RFCO)2O

O

N

OCORF

R1

RFCO

O

N Ph

R1 N

R1 RF

O

176

NHCOPh O

Ph

Ph

175

O

177

178

Scheme 7.53

Acylation of 179 with 2,2-difluoro-3-methyl-4-pentenoic acid anhydride yields a-amino ketones 180 that can serve as intermediates to prepare pseudopeptides such as peptidyl a,a-difluoroalkylketones 181126 (Scheme 7.54) or ketomethylene pseudopeptides.127 O Bn

Me

N

O C6H4-4Ph

F CF2CO

F

2O

Bn NHCOC6H4-4Ph

Me

179

O 180 F

F

HO2C

Bn NHCOMe

Me

O 181

Scheme 7.54

In some cases, the product depends on the nature of the acylating agent. Acylation of 182 with 2,2-difluoro-4-pentenoic acid anhydride leads to acylation at C-4, whereas acylation with 2,2-difluoro-4-pentenoic acid choride yields the 5-acyloxyoxazole 185 as the major compound.128 The 5acyloxyoxazole can be rearranged to the 5(4H)-oxazolone 183 upon treatment with 4-(dimethylamino)pyridine. Treatement of 183 with anhydrous oxalic acid promotes decarbonylation to give fluorinated a-amino ketones 184 (Scheme 7.55). Selected examples of 4-acyl-5(4H)-oxazolones are shown in Table 7.20 (Fig. 7.22).

170

5(2H)-Oxazolones and 5(4H)-Oxazolones O

R2 (CH2=CHCH2CF2CO)2O

CH2=CHCH2CF2CO N

O

R2 CH2=CHCH2CF2

O R1

183

NHCOR1 O

184

R2 O

N

DMAP

R1 182

OCOCF2CH2CH=CH2

R2

CH2=CHCH2CF2COCl

O

N

R1 185

Scheme 7.55

Acylation of 186 with an a-substituted ethyl succinyl chloride generates the expected 4-acyl-5(4H)-oxazolones 187 that serve as precursors to ketomethylene and dehydro ketomethylene pseudodipeptides (Scheme 7.56).129 CO2Et

R2

COCl

O R1

R1

R2

CH2CO

O

N

EtO2C

N

Ph

O O Ph

186

187

Scheme 7.56 TABLE 7.20. SYNTHESIS OF SATURATED 4-ACYL-2,4-DISUBSTITUTED 5(4H)-OXAZOLONES VIA ACYLATION OF 2,4-DISUBSTITUTED 5(4H)-OXAZOLONES AT C-4

O

H R1 N

O

base R3COX

O

R3CO R1 N

R2

O R2

X = O2CCF3, O2CHF2, Cl Figure 7.22 R1

R2

R3CO

% Yield

PhCH2 i-Bu PhCH2 i-Bu PhCH2 i-Bu

Ph Ph Ph Ph Ph Ph

CF3CO CF3CO CF2HCO CF2HCO CHCF2CO CH2  CHCF2CO CH2 

63 60 50 22 38 46

Reference 125 125 125 125 128 128

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

171

A general procedure for acylation of 2-aryl-5(4H)-oxazolones using an acylating agent in the presence of 4-(dimethylamino)pyridine and triethylamine has been described.130 The resulting products are useful intermediates for agrochemicals and drugs. INTRAMOLECULAR ALKYLATIONS. Intramolecular spiroalkylation of the suitably functionalized 5(4H)-oxazolone 188 produced 189 in good to excellent yield. Acid hydrolysis of 189 then gave the cyclic amino acid 190 required in the synthesis of the aldose reductase inhibitor sorbinil (Scheme 7.57).131 F

F F O Et3N or

O

N

O

O

O

HCl

K2CO3

O

N

O

CO2H

HCO2H

NH2

Ph

Ph

X 188

190

189 Scheme 7.57

IMINES AND CARBONYL COMPOUNDS. Simple 2-alkyl(aryl)-5-(4H)-oxazolones like 191 can react with aldehydes, ketones, imines, and oximes to afford the corresponding unsaturated analogues 192 (Scheme 7.58). In some cases, this procedure is especially advantageous over the classical one-pot synthesis.132–148 The chemistry of unsaturated 5(4H)-oxazolones like 192 will be discussed in detail in Section 7.4. R3

R3

O

O

O

N

R1

N

R3 or

O

R2

R2

O

N R2

R1

R4

191

192 Scheme 7.58

Imines are particularly useful reagents when hindered electrophiles are considered. In this context, N-(a-methylbenzylidene)benzylamines have been described as alternatives to acetophenones.149 Similarly N-methylbenzophenonimine serves as an alternative to benzophenone150 itself in reactions with 2-phenyl-5(4H)oxazolone 146 to prepare 2-phenyl-4-(a-phenylethylidene)- and 4-(diphenylmethylene)-2-phenyl-5(4H)-oxazolone, respectively. When carbonyl compounds are used as electrophiles reaction with 4-monosubstituted-5(4H)-oxazolones affords substituted serines after subsequent hydrolytic ring opening of the initial aldol product. As an example, 4-methyl-2-phenyl5(4H)-oxazolone 193, prepared from alanine, reacts with benzaldehyde in a base-catalyzed addition to give, after hydrolysis, a 3:1 mixture of threo- and

172

5(2H)-Oxazolones and 5(4H)-Oxazolones

erythro-2-methyl-3-phenylserine 195 (Scheme 7.59).151 Iron sulfate has also been used to catalyze the condensation reaction of 2-phenyl-5(4H)-oxazolone and aromatic aldehydes.79 Ph

O Me N

O

PhCHO

O Ph

HO Me N

HCl

O

Me

Ph

Ph 193

CO2H

HO

194

NH2

195

Scheme 7.59

4-Monosubstituted-5(4H)-oxazolones behave differently upon reaction with imines. Here, 4-methyl-2-phenyl-5(4H)-oxazolone 196 (R1 ¼ Ph, R2 ¼ Me) reacts with imines derived from 2-furancarboxaldehyde or 2-thiophenecarboxaldehyde to give 3-amino-b-lactams 197.152,153 On the other hand, 196 reacts with chlorosulfonyl isocyanate in a [2 þ 2] cycloaddition to give dioxazabicycloheptanones 198 as shown in Scheme 7.60.154 N

R3

R3

X X = O, S

O

R1CONH

O R2 N

N

X R2

197

O R1 R2

196

NSO2Cl

N

ClSO2N=C=O

O

O

O R1

198 Scheme 7.60

Reaction of carbon disulfide with 2-phenyl-5(4H)-oxazolone 146 followed by Salkylation with a methyl halide gives 4-[bis(methylthio)methylene]-2-phenyl-5(4H)oxazolone. The solvolysis and aminolysis of this compound have also been studied.155,156 ENAMINES AND FORMAMIDINES. Enamines, prepared from methylpyridines, methylpyridazines, methylpyrimidines or methyltriazine, and N,N-dimethylformamide dimethylacetal or tert-butoxybis(dimethylamino)methane, react with 2-phenyl5(4H)-oxazolone 146 to afford the unsaturated 5(4H)-oxazolones 199 and 201 that are intermediates in the synthesis of fused pyridones 200157 and pyridotriazinones 202, respectively (Scheme 7.61).158

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Y Y

N

X

N

O O

N

Ac2O

NHCOPh

N

X

Ph

X = N, CH Y = CH, N

O

O Y

X

NMe2

173

199

200

O

N

R1

Ph MeCO 146

N Ac2O R1

N

N

N R2

O

N

NMe2

O NHCOPh

N

N

Ph

N

N

R1

O

N

R2

201

202

R2

Scheme 7.61

Similarly, reaction of 2-dimethylaminomethylene-3-oxoalkanoates or 2-dimethylaminomethylene-1,3-cyclohexanediones with 2-phenyl-5(4H)-oxazolone 146, generated in situ from hippuric acid, affords 6-substituted 3-(benzoylamino)-2-oxo-2H-pyran-5-carboxylates 204 and 3-(benzoylamino)-7,8-dihydro2H-1-benzopyran-2,5(6H)-diones 206, respectively. These compounds showed strong local anesthetic activity (Scheme 7.62).159 O

O

R1

O

O

NMe2 CO2R2

R1

Ph

R1 CO2R2

O CO2H NHCOPh

Ac2O

203

O

N

NHCOPh

O

O

N

R2O2C

204

Ph 146

O

O

O

O

O NMe2

N

O

NHCOPh

O

Ph O

O

205 Scheme 7.62

206

174

5(2H)-Oxazolones and 5(4H)-Oxazolones

Condensation of an N 0 -heteroaryl-N,N-dimethylformamidine or N,N 0 -diphenylformamidine with 2-phenyl-5(4H)-oxazolone 146 gives 4-(aminomethylene)-2phenyl-5(4H)-oxazolones 207 that are synthetic equivalents of b-amino-a,b-dehydro-a-amino acid derivatives 208 (Scheme 7.63).160–163 O

N

R1

N

N R3

O

R2

O R1NH N

Ph

COX

R1NH

O

NHCOPh Ph

146

207

208

Scheme 7.63

AZINE N-OXIDES. Quinoline and isoquinoline N-oxides react readily with 2phenyl-5(4H)-oxazolone 209 (R1 ¼ Ph) and 2-methyl-5(4H)-oxazolone 209 (R1 ¼ Me) in the presence of acetic anhydride to afford 2-substituted 4-(quinol-2yl)- 210 and 4-(isoquinol-1-yl)-5(4H)-oxazolones 211, respectively, in good yields (Scheme 7.64).164 R2

R2

N

N

O

N

O R1

O 210

O

N

O

R1 209 O

N O

N N

O R1

211 Scheme 7.64

Similar results are obtained from reaction of pyridine N-oxide derivatives with 146 and several transformations, including ring opening, have been described.165 Reaction of pyridinium salts and 146166 gives the corresponding 4-substituted1,4-dihydropyridine derivatives 212 (Scheme 7.65).

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) R

X

O

+

N

R

Bn

Me

Me

O

N

175

N

O

Bn

O

N

Ph

Ph 146

212 Scheme 7.65

HALOGENATION REACTIONS. Chlorination of 4-acyl-2-phenyl-5(4H)-oxazolones 213 with sulfuryl chloride leads to the corresponding 4-chloro derivatives 214 (Scheme 7.66). These compounds are useful intermediates in organic synthesis. In particular, hydrolytic cleavage of 214 affords a-chloro-a-acylamino ketones 215.167 Moreover, they are the logical intermediates to prepare 4-(phosphoranylidene)-5(4H)-oxazolones that are very important and useful synthons. O SO2Cl2

O

N

O

RCO

RCO

Cl

O

N

Ph

O AcOH/HCl

NHCOPh

Ph

213

Cl

R

214

215

Scheme 7.66

The first attempt to prepare 2-phenyl-4-(phosphoranylidene)-5(4H)-oxazolone 219 started with 1-benzoylamino-(2,2-dichloroethenyl)triphenylphosphonium chloride 216 and involved the complex reaction sequence shown in Scheme 7.67. The structure and properties of 219 were studied and it was shown that 219 underwent Wittig olefination with benzaldehyde to give the well-known (Z)-4benzylidene-2-phenyl-5(4H)-oxazolone.168 S Cl Ph3P

Cl

PhCONH

Cl

NaSH

Ph3P

SCH2COPh Ph3P

1) PhCOCH2Br

N

O 2) NaClO4

ClO4

Ph 216

O Ph3P

NaOMe

N

O

N

Ph

Ph

217

218

O

219

Scheme 7.67

A more efficient one-pot procedure for the synthesis of 4-(phosphoranylidene)2-substituted-5(4H)-oxazolones from the corresponding 4-unsubstituted-5(4H)oxazolones has also been described and uses trialkyl- or triarylphosphines in the presence of a halogenation agent.169 Wittig reaction of 4-(phosphoranylidene)-2substituted-5(4H)-oxazolones has been used to prepare fluorooxazolones from fluorine-containing carbonyl compounds.170

176

5(2H)-Oxazolones and 5(4H)-Oxazolones

Reaction of the 2-phenyl-4-(phosphoranylidene)-5(4H)-oxazolone 219 with alkyl halides gives 4-alkyl-2-phenyl-5(4H)-oxazolones 220 in good yields.171 Reaction of 219 with acyl iodides or bromides gives C-4- or O-acyl products 221 or 222. Reaction of 219 with acyl chlorides gives 4-(1-chloroalkylidene)-2-phenyl5(4H)-oxazolones 224 that are Wittig-like products. The use of benzoyl fluoride gives rise to 4-(1-benzoyloxybenzylidene)-2-phenyl-5(4H)-oxazolone 223.172 These reactions are summarized in Scheme 7.68. O RX

R O

N

Ph 220 OCOR

O RCO RCOBr

O

O Ph3P/X2

N

O or Ph3P/CX4

Ph 146

O

N

or RCOI

Ph3P

+

N

O Ph

Ph O

N

221 Ph

219

222 Ph

PhCOF

O

PhCOO N

O Ph

223 R RCOCl

O

Cl N

O Ph

224

Scheme 7.68

DIAZONIUM SALTS AS ELECTROPHILES. 2-Aryl-5(4H)-oxazolones 225 couple readily with aryldiazonium salts to give the corresponding 4-arylazo derivatives 226 or 2aryl-4,5-oxazoledione-4-arylhydrazones 227.173,174 Structural studies revealed that these compounds exist as the hydrazone tautomers 227.175 These compounds are valuable synthetic intermediates. For example, nucleophilic ring opening with active methylene compounds176,177 and alcohols178,179 has been described. More interestingly, ring opening with amines and subsequent recyclization affords 1,5diaryl-1,2,4-triazole-3-carboxamides 228 (Scheme 7.69) that have been used in the preparation of agrochemicals, particularly, herbicides, and fungicides.180–195

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) O

Ar2 Ar2

N

N

N X

O

O N

N N

Ar2

O

177 O

N H

N O

N

Ar1

Ar1 225

226

Ar1 227 CONH2 N Ar1

N N Ar2 228

Scheme 7.69

7.3.1.4.4.

From Unsaturated 5(4H)-Oxazolones

One strategy to prepare saturated 5(4H)-oxazolones from unsaturated oxazolones takes advantage of the reactivity of the exocyclic double bond. In this context, numerous reactions have been explored including reductions, Michael reactions, cycloaddition reactions, and many others. These reactions will be discussed in the context of the reactivity of the exocyclic double bond of the unsaturated oxazolones and will be described in Section 7.4.3.

7.3.1.5. 2-Alkoxy Derivatives N-Alkoxycarbonyl-a-amino acids are chirally stable compounds under normal coupling conditions. In the presence of a tertiary amine, most activated Nalkoxycarbonyl-a-amino acids generate 2-alkoxy-5(4H)-oxazolones that are not chirally stable in the presence of the base. Consequently, enantiomerization occurs in the presence of the tertiary amine if the activated residue is not immediately consumed by aminolysis. Many studies have explored this process to minimize the enantiomerization in the coupling reaction including isolation of the intermediate 2-alkoxy-5(4H)-oxazolones. Several methods are now available to prepare 2-alkoxy-5(4H)-oxazolones. For example, the action of triethylamine on N-benzyloxycarbonyl-a-amino acid chlorides gives the 2-benzyloxy-5(4H)-oxazolones. Similarly, 2-[(9-fluorenylmethyl)oxy]-5(4H)-oxazolones with acid-stable protecting groups are accessible from the acid chlorides. Other analogues can be obtained from carbodiimides including DCC and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC). A general route to all types of 2-alkoxy-5(4H)-oxazolones 229 was developed using mixed anhydrides prepared from reaction of an acid with isopropenyl chloroformate in the presence of N-methylmorpholine. The general synthetic procedure is shown in Scheme 7.70.

178

5(2H)-Oxazolones and 5(4H)-Oxazolones O R2 H

O R2

OX act N

O

N

O OR1

OR1 229 Scheme 7.70

In cases where 2-alkoxy-5(4H)-oxazolones are generated from N-alkoxycarbonyl-a-amino acids, the enantiomerization that occurs during preparation and incorporation of these residues into peptides, the properties, and methods of preparation of the 2-alkoxy-5(4H)-oxazolones together with the practical uses of these compounds have recently been reviewed.196 For a,a-dialkylamino acids enantiomerization is not a problem. The preparation of 4,4-dimethyl-2-[(9-fluorenylmethyl)oxy]-5(4H)-oxazolone, an intermediate used in the synthesis of ()-mirabazole C has been described.197 Recently, two new 2alkoxy-5(4H)-oxazolones derived from Toac (2,2,6,6-tetramethyl-4-amino-1-oxypiperidine-4-carboxylic acid) that incorporate Z or 9-fluorenylmethoxycarbonyl (Fmoc) protection at C-2 have been described.198 The Toac analogues were synthesized as part of a study of the crystal structure and ab initio calculations for these interesting systems. Finally, cationic ring-opening polymerization of 2-alkoxy-5(4H)-oxazolones has been used to prepare poly N-alkoxycarbonyl amino acids.199,200 The polymerization was found to be dependent on the nature of the amino acid side chain and the substituent on C-2. 7.3.2.

Reactions

7.3.2.1. Hydrolysis and Alcoholysis The most important reaction in the chemistry of oxazolones is nucleophilic ring opening of the heterocyclic ring. Hydrolysis of 5(4H)-oxazolones gives the corresponding N-acylamino acids that are the usual starting materials for the synthesis of these heterocyclic compounds. Therefore, in principle, this reaction is synthetically unimportant, although it is worth considering certain aspects about the process. However, important transformations can be made, for example, at C-4 and thus the sequence of cyclization of a typical amino acid to the oxazolone, followed by modification at C-4 and subsequent hydrolysis, has become a useful strategy to prepare new, non-proteinogenic amino acids. In addition, the use of an enantioselective or diastereoselective hydrolysis of racemic oxazolones offers another possibility to obtain new synthetic amino acids. Similarly, alcoholysis of 5(4H)-oxazolones gives the corresponding N-acylamino acid esters.

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

179

Finally, it is well known that amino acids can cyclize to oxazolones during the protection–activation reaction sequence. This important reaction must be avoided since tautomerism between saturated 5(4H)-oxazolones and 5(2H)-oxazolones results in undesired epimerization of the amino acid. A number of points should be considered to determine the most appropriate experimental conditions for the desired reaction and, to that end, the kinetics of hydrolysis and ionization of 4-methyl-2-phenyl-, 4-benzyl-2-phenyl-, and 4-benzyl2-methyl-5(4H)-oxazolones have been investigated.201 Deprotonation of 5(4H)oxazolones in aqueous media, which leads to racemization of optically active 5(4H)-oxazolones, is a fast process that competes with the ring opening. The difference between the rate constant for racemization and the ring opening is greater in solvents with dielectric constants less than water and thus, oxazolones racemize faster than they hydrolyze. The rate and equilibrium constants for the reaction of oxyanions with 2-phenyl5(4H)-oxazolones has been also studied.202 This work suggests that attack of phenoxide ion at the carbonyl group is a concerted displacement. In addition, detailed geometric and energetic characteristics of the elementary reaction pathways for the addition of water and ammonia to 2-methyl-5(4H)oxazolone have been determined at the AM1 level using MOPAC programs.203 The authors concluded that an N-acetylamino acid or amide are formed through a twostep procedure that involves the formation of the a-hydroxyimine and subsequent tautomerization. Ring opening of 2-aryl-5(4H)-oxazolones 230, obtained from N-acylglycines, with N,N-dimethyl-2-aminoethanol provides choline esters of N-substituted amino acids 231 (Scheme 7.71).204 Me

Me

O HO

N Me

N Me

CO2

O

N

NHCOR R 230

231 Scheme 7.71

The use of chiral organometallic compounds as catalysts in the enantioselective hydrolysis of saturated oxazolones was reported several years ago and the mechanism of the hydrolysis of 4-benzyl-2-methyl-5(4H)-oxazolone catalyzed by the copper(II) complex of (S)-[(N-benzylprolyl)amino]benzaldoxime has been described.205 Other compounds studied as chiral catalysts include a- and b-cyclodextrins that were used in the hydrolysis of oxazolones although the enantioselectivity in the ring-opening reaction was rather low.206–208 When a phenyl group is present at C-2 in these systems the enantioselectivity of the reaction is somewhat higher. Dynamic kinetic resolution is an excellent methodology to prepare enantiomerically pure compounds209–212 and, in this context, chiral 4-(dimethylamino)pyridine (DMAP) iron213 and ruthenium214 complexes have been reported to catalyze the

180

5(2H)-Oxazolones and 5(4H)-Oxazolones

ring opening of 5(4H)-oxazolones by alcohols. As a result, the dynamic kinetic resolution (deracemization) of chiral saturated oxazolones 232 is possible and leads to enantioenriched protected a-amino acids 233 (Scheme 7.72). The solvent and nucleophile are critical variables that dramatically affect the levels of enantioselectivity observed in these reactions. O R2

CO2R3

R3OH

O N

R2

Me2N

NHCOR1

R1

N M

R

232

R

R

233 R

R

O R3OH

R2

CO2R3

O N

R2 NHCOR1

Me2N

R1 N

ent-232

R

M

ent-233

R

R

R R

Scheme 7.72

Chiral titanium complexes with a, a, a0 , a0 -tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL) ligands are versatile auxiliaries in the Lewis acid catalyzed alcoholysis of racemic 4-(arylmethyl)-2-phenyl-5(4H)-oxazolones 234, providing the corresponding enantiomerically enriched N-protected amino acid esters 235 (Scheme 7.73). The enantioselectivity of the reaction is dependent on the solvent, temperature, and chiral ligand.215,216 Selected examples of the alcoholysis of saturated 5(4H)-oxazolones are shown in Table 7.21 (Fig. 7.23). Recently, it was reported217 that some dipeptide derivatives containing a histidine residue such as cyclo[(S)-His-(S)-Phe] (CHP) catalyze the alcoholysis of

R1

O ArCH2

R2

O

Ar H

Ar O

Oi-Pr

Ti O

O Oi-Pr H Ar Ar

N

O

CO2i-Pr ArCH2 NHCOPh

Ph 234

235 Scheme 7.73

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

181

TABLE 7.21. N-ACYLAMINO ACID ESTERS FROM ALCOHOLYSIS OF SATURATED 5(4H)-OXAZOLONES

O R1

CO2R3

R3O

O

N

R1 NHCOR2

R2 R1

R2

H 4-i-PrOC6H4 Me Ph Et Ph CH2 CH Ph i-Pr Ph Ph Ph PhCH2 Ph 4-MeC6H4 Ph 4-MeOC6H4 Ph 4-ClC6H4 Ph 4-NO2C6H4 Ph

Figure 7.23 R3 Me2N(CH2)2 Me Me Me Me Me i-Pr i-Pr i-Pr i-Pr i-Pr

% Yield 70 98 94 94 95 94 75 60 65 48 74

Reference 204 213 213 213 213 213 215 216 216 216 216

4-benzyl-2-phenyl-5(4H)-oxazolone to afford the corresponding N-benzoyl-L-phenylalanine esters albeit with low or moderate enantioselectivity. Cyclo[(S)-His-(S)Phe] was a more effective and enantioselective catalyst when used together with a chiral auxiliary that possesed both a hydrogen-bond donor and a hydrogen-bond acceptor. Enzymatic systems have been used successfully to effect asymmetric synthesis of amino acids by dynamic kinetic resolution of saturated oxazolones. Oxazolones are versatile substrates for enzyme-catalyzed hydrolysis and alcoholysis using both lipases and proteases to catalyze the nucleophilic ring opening. The first attempts to hydrolyze 2,4-disubstituted-5(4H)-oxazolones using proteases such as a-chymotrypsin, trypsin, and subtilisin were only moderately successful, but a significant breakthrough in this method was achieved when lipases were employed instead of proteases. Initially, it was shown that 4-methyl-2-phenyl-5(4H)-oxazolone undergoes Mucor miehei lipase-catalyzed enantioselective ring opening with 1butanol in diisopropyl ether. This process, in conjunction with partial racemization of the less reactive isomer of the oxazolone under the reaction conditions, yields enantioenriched (S)-N-benzoylalanine n-butyl ester but with modest optical purity.218 Lipases from porcine pancreas (PPL) and from Aspergillus niger are uniquely suited for oxazolone hydrolysis since they catalyze the ring-opening reaction with a high degree of enantioselectivity. Moreover, these lipases exhibited opposite stereochemical preference, thus providing access to both enantiomers of N-benzoyl

182

5(2H)-Oxazolones and 5(4H)-Oxazolones

amino acids 237 and ent-237 in excellent chemical and optical yields. Although both lipases retained their chiral preference with variation of the C-4 substituent, the reaction rate and the degree of enantioselectivity varied markedly depending on the nature of the substituents219,220 and on the solvent used.221 For substrates with limited steric hindrance, the hydrolysis proceeded with moderate to good selectivities, but the reaction rate decreased for substrates bearing bulky C-4 substituents. More importantly, dynamic resolution is achieved owing to the low pKa values of the C-4 proton. Thus, when the hydrolysis is conducted near the pH optimum of the lipase, in situ racemization is sufficient to ensure complete transformation of the substrate (Scheme 7.74). O CO2H

R1

A. niger

O R1

R1

N

NHCOPh

237

O

N Ph

236

CO2H

PPL

O

R1 NHCOPh

Ph ent-236

ent-237

Scheme 7.74

An elegant method to suppress the undesired spontaneous hydrolysis of a 5(4H)oxazolone in aqueous media uses a lipase-catalyzed alcoholysis reaction. Of particular importance is the synthesis of tert-leucine,222 a non-proteinogenic aamino acid that has found widespread use both as a chiral auxiliary and as a component of potentially therapeutic pseudopeptides. Racemic 4-tert-butyl-2phenyl-5(4H)-oxazolone 238 was submitted to Mucor miehei catalyzed alcoholysis using butanol as a nucleophile. Addition of a catalytic amount of triethylamine promoted in situ racemization. In this way, the enantiomerically pure butyl ester of (S)-N-benzoyl-tert-leucine 239 was obtained in excellent yield (Scheme 7.75). O t-Bu

CO2n-Bu

M. meihei

N

O

t-Bu n-BuOH/Et3N

NHCOPh

Ph 238

239 Scheme 7.75

The preparation of protected derivatives of D-allo- and L-allo-threonine by enzymatic hydrolysis of 5(4H)-oxazolones using hog kidney acylase has also been described.223 This methodology has been extended to a wide variety of amino acids and, at present, constitutes a general procedure to prepare non-quaternary amino acids in enantiomerically pure form.224–227 For example, racemic Nethoxycarbonyl-2-amino-1-butanol, rac-240 was resolved via kinetic resolution using M. miehei. In this case, 2-phenyl-5(4H)-oxazolone 146 was used as a convenient derivatizing agent to afford 241, a precursor of Ethambutol as shown in Scheme 7.76.228

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) O

NHCO2Et HO

183

+

+ PhCOHN

HO

O

N

NHCO2Et

NHCO2Et

M. meihei

CO2

Ph rac-240

146

240

241

Scheme 7.76

Although 5(4H)-oxazolones have been considered too unstable stereochemically for use in peptide synthesis, it has been shown229 that they function as acyl donors in protease-catalyzed segment condensations. This methodology represents an interesting approach to prepare peptides containing acidic amino acids. As an example, a-chymotrypsin reacts with the oxazolone ring of a peptide fragment to generate an acyl-enzyme intermediate. This activated intermediate then couples with an amino acid or with the N-terminus of another peptide chain to afford the corresponding oligopeptide. A limitation of this methodology occurs if hydrolysis of the acyl-enzyme intermediate is competitive with the coupling reaction.

7.3.2.2. Aminolysis with Amines By far the most important ring-opening reaction using nitrogen nucleophiles is that using amino acids and this will be considered in Section 7.3.2.3. Apart from this very important case, other nitrogen nucleophiles have been used to prepare compounds of particular interest and some examples have been reported. The general aminolysis reaction is shown in Scheme 7.77 and has been applied to the synthesis of numerous compounds. For example, N,N-disubstituted amides of amethyltryptophan were synthesized by nucleophilic ring opening of the corresponding oxazolone.230 Acetamidopiperidines were prepared from 4-aminopiperidines and 2-phenyl-5(4H)-oxazolones and the resulting products have been shown to reduce blood pressure.231 2-(4-Nitrophenyl)-4-substituted-5(4H)-oxazolones were ring opened with thiosemicarbazides to prepare compounds with potential antitumor activity.232 Herbicidal benzenesulfonylcarboxamides were prepared by ringopening oxazolones with p-toluenesulfonamide.233 Finally, ring opening of 2-(4nitrophenyl)-4-substituted-5(4H)-oxazolones with bis(2-chloroethyl)amine afforded potential antitumor agents.234 2-Phenyl-5(4H)-oxazolone has been also used as an acylating agent for nitrogen-containing heterocycles.235 Nucleophilic ring opening of 2-phenyl-5(4H)-oxazolone 146 with (1S, 2R)-1-aminoindan-2-ol provides an amido alcohol that, upon treatment with O R2

CONHR3 N

O + H2NR3

R2 NHCOR1

R1

242

Scheme 7.77

184

5(2H)-Oxazolones and 5(4H)-Oxazolones

2-methoxypropene affords 243, a versatile chiral glycine enolate equivalent. Alkylation of 243 with a variety of alkyl halides gives the corresponding amino acid derivatives with 90–99% diastereoselectivity (Scheme 7.78).236 H2N

OH

O

Me

Me

PhCONHCH2CON

O

O

N

Ph 146

243

Scheme 7.78

Ring opening of a 4-(hydroxyalkyl)-substituted oxazolone using dimethylamine gives an amide 245 that can be used as an intermediate in a subsequent intramolecular cyclization to prepare lactones 247 (Scheme 7.79).237 OTHP O

(CH2)n Ph N

OTHP HNMe2

O

OH

(CH2)n CONMe2 Ph

PPTS

(CH2)n CONMe2 Ph

NHCOPh

NHCOPh

245

246

HCl

(CH2)n Ph

O

O NHCOPh

Ph 244

247

PPTS = pyridinium p-toluenesulfonate

Scheme 7.79

In some cases, ring opening of oxazolones and subsequent cyclization of the intermediate leads to new heterocyclic systems. For example, reaction of saturated 5(4H)-oxazolones with hydrazonoyl halides under phase-transfer conditions yields the 5-pyrazolones 249.238 Ring opening of 248 with 2-aminothiophenol generates benzothiazoles 250 (Scheme 7.80).239 Cl

O

Ar-NH-N C CO2Me

R2 N Ar

R1CONH N

MeO2C

O

249

R2 N

O R1

248

SH NH2

S

R2

N

NHCOR1 250

Scheme 7.80

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

185

It was also reported240 that the reaction of 4,4-disubstituted-2-(trifluoromethyl)5(4H)-oxazolones 251 with 2,2-dimethyl-3-(dimethylamino)-2H-azirine afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 252 (Scheme 7.81). In this case, the reaction only occurs when electron-withdrawing substituents are present at C-2 of the oxazolone. Me

O

Ph R

N Me Me

N

Me

N

O Ph R

O

N

H Me

N

CF3

Me

251

N

Me Me

252

Scheme 7.81

Several papers have described attempted ring opening of an oxazolone with chiral amines to achieve stereoselective reactions. For example, a chiral bornylamine effected ring opening of racemic oxazolones to produce enantioenriched (S)N-acylamino acid bornylamides.241 Ring opening of 4-isopropyl-, 4-sec-butyl- and 4-benzyl-5(4H)-oxazolones with (S)-phenylethylamine also produced some degree of chiral induction.242–244 In these cases, the reaction rate and the extent of chiral induction depended on the solvent and on the oxazolone substituent. Mechanistically, the authors attributed the results to involve neutral or ionic species.

7.3.2.3. Aminolysis with Amino Acid Derivatives Amino acids have been used as nucleophiles to effect the ring opening of saturated 5(4H)-oxazolones 253 as a coupling method in an attempt to describe a general procedure for peptide synthesis (Scheme 7.82). However, the problems arising from racemization, that is, when a proton is present at C-4 of the oxazolone, render this procedure of limited synthetic utility. O R2

CO2R4 H2N

N

H

R2

R3

O

R1CONH O

R1 253

CO2R4

N R3

254

Scheme 7.82

On the other hand, there have been several attempts to achieve some degree of asymmetric induction during the ring opening of racemic oxazolones with protected chiral amino acids. In these cases the influence of the solvent, temperature and, in general, the experimental conditions, has been studied extensively.245–248 Although some degree of asymmetric induction has been achieved in most cases, this methodology can not be considered as a general procedure for the stereoselective

186

5(2H)-Oxazolones and 5(4H)-Oxazolones

synthesis of peptides. Nevertheless, the diastereoisomers obtained from the reaction of oxazolones with chiral amino acid derivatives are readily separated using highperformance liquid chromatography (HPLC), a fact that makes this technique suitable for the determination of enantiomeric ratios.249 Alternatively, oxazolones have been used as reagents to activate and to couple N-protected dicarboxylic amino acids wherein the carboxylate moiety acts as the nucleophile. For example, 2,4-dimethyl-5(4H)-oxazolone 255 reacts with Nbenzyloxycarbonyl-L-aspartic acid to give a mixture of the anhydrides 256 and 257. Subsequent reaction of 256 and 257 with phenylalanine methyl ester hydrochloride and N-methylmorpholine produces a mixture of the a-isomer 258 and b-isomer 259 of N-benzyloxycarbonyl-aspartylphenylalanine methyl ester (Scheme 7.83).250 O Me O

N

Me 255 CO2H

HO2C

NHZ

Me

Me

NHZ O

MeCONH O

CO2H

+

O

MeCOHN

O

O

O 256

CO2H NHZ

257 CO2Me NMM Ph

NHZ

H MeO2C

NH2

N

H CO2H

MeO2C

CO2H

N

+ Ph

O

Ph

258

O

NHZ

259

Scheme 7.83

Racemization is not encountered when 4-unsubstituted-5(4H)-oxazolones or 4,4disubstituted-5(4H)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(4H)oxazolones function as glycine synthons in the synthesis of N-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(4H)-oxazolone with amethylphenylalanine affords N-(trifluoroacetyl)glycyl-a-methylphenylalanine.251 4,4-Disubstituted-5(4H)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate a,a-disubstituted amino acids. As an example, 4-(arylmethyl)-2-phenyl-4-(trifluoromethyl)-5(4H)-oxazolones 260 are key intermediates

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Ar

R1

CO2R2

Ar CF3

O NH2

CF3 N

O

H

O

260

CO2R2

N

PhCONH

Ph

187

R1

261

Scheme 7.84

in the synthesis of peptides that incorporate a-(trifluoromethyl)amino acids 261 (Scheme 7.84).252 Modification of the properties of bioactive peptides incorporating constrained amino acids into the backbone structures has been explored in recent years. One of the best strategies to obtain good results in this area is to use an a,a-disubstituted amino acid, which has necessitated development of various methodologies to prepare these non-proteinogenic amino acids in enantiomerically pure form.253,254 Resolution of diastereoisomers derived from racemic a,a-dialkylamino acids has become a useful tool to isolate enantiomerically pure compounds. Among the different possibilities, Obrecht’s methodology, which is based on the facile separation of di- and tripeptides containing a phenylalanine residue and an N-acyl-a,adialkylamino acid, is particularly effective and versatile.255,256 The starting racemic 4,4-disubstituted-2-phenyl-5(4H)-oxazolones 262 are obtained from the corresponding N-benzoylamino acids through the action of an activating agent such as N,N-dicyclohexylcarbodiimide or 1,10 -carbonyldiimidazole. Alternatively, alkylation of a 2-phenyl-4-substituted-5(4H)-oxazolone with an electrophile in the presence of sodium hydride is also an effective synthetic strategy.111 Treatment of a dialkylated 5(4H)-oxazolone 262 with a chiral amide derived from phenylalanine provides the diastereomeric dipeptides 263 and 264 that are easily separated by crystallization or column chromatography.257 The bests results are obtained when phenylalanine cyclohexylamide is used to resolve the a,a-dialkylamino acids. This methodology has afforded both enantiomers of a-methylphenylalanine, amethylvaline, a-methylphenylglycine,258 2-(aminomethyl)alanine, 2-(aminomethyl)leucine,259 a-methylglutamic acid, a-methylaspartic acid, a-isobutylaspartic acid,260 and some a,a-disubstituted tyrosine analogues.261 These reactions are shown in Scheme 7.85.

R2 R1 N

O

H2N 1)

CONHCy /NMP H CH2Ph

O 2) recrystallization or chromatography

Ph 262 Cy = cyclohexyl

R1 R2 H N CONHCy BzHN O H CH2Ph

1) CF3SO3H MeOH 2) HCl

R1 R2 H2N

263 R2 R1 H N CONHCy BzHN O H CH2Ph 264

Scheme 7.85

CO2H 265

1) CF3SO3H MeOH 2) HCl

R2 R1 H2N

CO2H

ent-265

188

5(2H)-Oxazolones and 5(4H)-Oxazolones

The authors applied the same synthetic strategy to racemic 4-alkyl-4-(iodomethyl)-2-phenyl-5(4H)-oxazolones 266 and obtained a diastereomeric mixture of oxazolines 267 and 268 (Scheme 7.86). The diastereoisomers were separated chromatographically and then converted into dipeptides incorporating an a-alkylserine residue.262,263 CH2Ph

O

R

N O 1) H2N

ICH2

O

N

CONHCy

Ph

H CH2Ph DIPEA/NMP

R N

CONHCy

H

267

O 2) chromatography

Ph

CH2Ph

O

R

N

266 DIPEA = diisopropylethylamine NMP = N-methyl-2-pyrrolidinone

O

N

CONHCy

H

Ph 268

Scheme 7.86

Finally, when oxazolones 269 bearing a carboxyalkyl chain at C-4 were used, the separation was effected on the mixture of diastereomeric succinimides 270 and 271.263 In this case, the resolved amino acid contains both an aspartic acid and a glutamic acid side chain (Scheme 7.87). Selected examples of amino acids that illustrate the general applicability of Obrecht’s methodology are shown in Table 7.22 (Fig. 7.24). CH2Ph

O

t-BuO2C

N CO2t-Bu O

t-BuCO2

N

CONHCy

BzHN 1)

H2N

CONHCy /NMP H CH2Ph

O 270

O 2) chromatography

Ph

CH2Ph

O

t-BuO2C

N

269 BzHN

O 271 Scheme 7.87

CONHCy

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

189

TABLE 7.22. SUBSTITUTED AMINO ACID AMIDES VIA OBRECHT’S METHODOLOGY FOR AMINOLYSIS OF SATURATED 5(4H)-OXAZOLONES

O

R2

R4NH2

R1

O

N

R2

CONHR4

R1

NHCOR3

R3 Figure 7.24 R4

R1

R2

R3

H H Me Me Me Me Me Me i-Pr Me i-Pr Ph

i-Pr PhCH2 4-MeOC6H4CH2 PhCH2 PhCH2 Ph i-Pr PhCONHCH2 PhCONHCH2 4-MeOC6H4CH2 4-MeOC6H4CH2 4-MeOC6H4CH2

Me PhCH2 Me Ph Ph Ph Ph Ph Ph Ph Ph Ph

% Yield

(S)-PhCH2(CONMe2)CH (S)-PhCH2(CONMe2)CH (S)-PhCH2(CONMe2)CH (S)-PhCH2[CON(CH2)4]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH (S)-PhCH2[CON(CH2)5]CH

Reference

80 73 72 78 77 95 93 80 86 82 81 87

257 257 257 257 258 258 258 259 259 261 261 261

7.3.2.4. Incorporation of Dialkylamino Acids into Peptides The use of oxazolones that readily racemize as starting materials in peptide synthesis is precluded by the loss of optical purity during the coupling reactions used to prepare the oxazolones. Therefore, new reactants that prevent the formation of the oxazolone or minimize the racemization process have been developed. In the early 1960s Kenner and co-workers264–266 showed that the oxazolones 273 obtained from a,a-dialkylamino acid derivatives 272 are excellent intermediates to prepare peptides 274 incorporating such amino acids. The process proceeds via ring opening of the oxazolone with the appropriate nucleophile and is shown in Scheme 7.88. Since then, this strategy, which implies the 4,4-disubstituted-5(4H)-oxazolones 273 as intermediates, has been used extensively. In particular, for achiral analogues of 273 (R2 ¼ R3) the synthesis is easier.

PHN H

O

R3

O

R2 R3 N

CO2H

R2

H2N

O

N

R1 H

R1 PHN

272

CO2R5 R4 H

O PHN H

R1

R2 R3 H CO2R5 N N H O R4 H

H

273

274 Scheme 7.88

190

5(2H)-Oxazolones and 5(4H)-Oxazolones

The simplest amino acid in the series, dimethylglycine or 2-aminoisobutyric acid (Aib), has been widely studied and 4,4-dimethyl-2-substituted-5(4H)-oxazolones have been used to incorporate Aib into model small peptides267–269 and into linear oligopeptides in order to perform structural studies.270–274 Dipropylglycine (Dpg) has been incorporated into model peptides using 4,4-dipropyl-2-(trifluoromethyl)5(4H)-oxazolone275,276 and the structures of the corresponding homooligopeptides have been studied.277 Similar studies have been published that involve dibenzylglycine (Dbg) and use 4,4-dibenzyl-2-(trifluoromethyl)-5(4H)-oxazolone as the starting material.278,279 N-Acyl peptides 277 containing an a,a-di(isopropylthio)glycine residue have also been described. These compounds were prepared as shown in Scheme 7.89. Thus, a 4,4-di(isopropylthio)-2-substituted-5(4H)-oxazolone 276 was prepared from a 2-substituted-5(4H)-oxazolone 275 by reaction with N-(isopropylsulfenyl)succinimide. The starting 2-substituted-5(4H)-oxazolone was prepared by cyclization of an N-acylglycine.280 O

O

i-PrS

N O

O

N

R 275

O

i-PrS

R1

CO2R2 NH2

i-PrS

O

N

R 276

i-Pr i-Pr S

S

H N

RCONH O

CO2R2 R1

277

Scheme 7.89

It is more difficult to prepare a chiral a,a-dialkylamino acid. Nevertheless, when such analogues are incorporated into the backbone of a peptide chain, analogues with modified properties are obtained. In this context, such residues have been evaluated as a new type of conformational constraint for the synthesis of enzymeresistant agonists and antagonists of bioactive peptides. Here, the asymmetric synthesis or the resolution of the chiral quaternary amino acid is necessary and numerous procedures, which have recently been reviewed,253 were developed to produce the requisite amino acids in enantiomerically pure form. Incorporation of an a-methylamino acid into a small model peptide is achieved using oxazolone methodology. a-Methylvaline (aMe)Val281–283 and a-methylphenylalanine (aMe)Phe284,285 have been used frequently in such studies and conformational analyses of the corresponding peptides in solution and in the crystal state have been reported. A comparative study of the influence of the a-methylamino acid on conformation has also been published.286 Achiral cycloalkyl quaternary amino acids have also been incorporated into model peptides using 5(4H)-oxazolones as intermediates. A comparative study between cyclic and acyclic derivatives has been described.287 The influence of the ring size of a homologous series from 1-aminocyclopropanecarboxylic acid to 1-aminocyclononanecarboxylic acid has been studied.288–296

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

191

7.3.2.5. Other Ring-Opening Reactions The oxidation by molecular oxygen297 or the base-catalyzed oxidative decarboxylation of saturated 5(4H)-oxazolones 278298 yields diacylamines and provides an efficient procedure to prepare imides 279 from N-acylamino acids (Scheme 7.90). O R2

O

O

O2

O

N

R1

N

R2

H

R1 278

279 Scheme 7.90

Potassium superoxide in aprotic solvents has also been used as the oxidant but the resulting products depend on the substitution at C-4 of the oxazolone ring. Monosubstituted oxazolones give the corresponding imides. In contrast, with disubstituted analogues, such as 4,4-dimethyl-2-phenyl-5(4H)-oxazolone, potassium superoxide acts as a nucleophile and effects ring opening of the oxazolone to generate an N-benzoylamino acid.299 Saturated oxazolones undergo an acylaminoacylation reaction with aromatic compounds in the presence of Lewis acids to give amino ketones. Subsequent cyclodehydration of these amino ketones then affords 2,5-diaryloxazoles. Some examples of 2,5-diaryloxazoles prepared in this manner are shown in Table 7.23 (Fig. 7.25). The reaction also has been applied to the oxazolone derived from hippuric acid300,301 but it is particularly important for bis(oxazolones) such as 280 that are useful precursors to the bisoxazoles 281 (Scheme 7.91).302,303 TABLE 7.23. 2,5-DIARYLOXAZOLES FROM REACTION OF SATURATED 5(4H)-OXAZOLONES WITH ARENES

Ar

O 1) ArH/Lewis Acid

N

O 2) Cyclodehydration

4-FC6H4 4-FC6H4 4-FC6H4 4-FC6H4 a

Data from Ref. 300.

O R1

R1 R1

N

Figure 7.25 Ar Ph 4-MeC6H4 2,4-Me2C6H3 2,5-Me2C6H3

% Yield    

47 47 38 35

192

5(2H)-Oxazolones and 5(4H)-Oxazolones O

Ar

O

N

O

N ArH/AlCl3

O

N

O

N O

Ar

280

281 Scheme 7.91

The same reaction applied to 2-styryl-5(4H)-oxazolone 282 gives simultaneous acylation and alkylation of the arene to produce the corresponding a-acylamino ketones 283.304 Cyclodehydration of 283 then readily affords a 2,5-disubstituted oxazole (e.g. 284 as shown in Scheme 7.92). O

O

Ph

Ph O

N

PhH/AlCl3

H N

O

Ph

Ph Ph

Ph 282

O

N

Ph

283

284

Scheme 7.92

Wittig olefination of 5(4H)-oxazolones with triphenylphosphonium methylides affords product mixtures that depend on the ylide and the starting oxazolone.305 The product mixtures can include, apart from the expected 5(4H)-oxazolylideneacetates, 5-oxazoleacetates, and other byproducts. Nevertheless, Wittig reaction of ethyl (triphenylphosphoranylidene)acetate with a 4,4-disubstituted-5(4H)-oxazolone 285 affords the corresponding ethyl 5(4H)-oxazolylideneacetates 286 in satisfactory yields (Scheme 7.93; Table 7.24, Fig. 7.26). CO2Et

O

R3 R2

Ph3P=CHCO2Et

N

O

R3 R2 N

R1

O R1

285

286 Scheme 7.93

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

193

TABLE 7.24. 5(4H)-OXAZOLYLIDENEACETATES FROM REACTION OF SATURATED 5(4H)-OXAZOLONES WITH a TRIPHENYLPHOSPHONIUM METHYLIDES

CO2Et

O

R2 R1

R2 R1

Ph3P=CHCO2Et

N

O

O

N

R3

R3 Figure 7.26

R1

R2

R3

% Yield

Ph Ph Me

Ph Me Me

4-MeOC6H4 Ph Ph

67 62 77

a

Data from Ref. 305.

Heating 4-alkyl-2-substituted-5(4H)-oxazolones 287 (R1 ¼ Me, Ph) effects elimination of CO to generate N-acylimines 288 that rearrange to the more stable enamides 289 if an acidic a-hydrogen is present (Scheme 7.94). Representative examples of enamides prepared in this manner are shown in Table 7.25 (Fig. 7.27). R3 R4 R2 H

N

O O

∆ −CO

R3 R2 H

R4

R3

R4

R2

NHCOR1

O

N

R1

R1 287

288

289

Scheme 7.94 TABLE 7.25. ENAMIDES FROM THERMOLYSIS OF SATURATED 5(4H)-OXAZOLONES

R2

O ∆

R1 N

O

−CO

R2

H

R1

NHCOR3

R3 Figure 7.27 R1

R2

R3

% Yield

Me Me Me Me i-Pr i-Pr

H H Me Me H H

Me Ph Me Ph Me Ph

95 99 100 95 90 75

a

Data from Ref. 306.

194

5(2H)-Oxazolones and 5(4H)-Oxazolones

However, in the presence of a quaternary a-carbon this rearrangement is precluded and the N-acylimines 288 may be isolated. Finally, pyrolysis of 4,4-dialkyl5(4H)-oxazolones affords mixtures of N-acylimines and enamides. The composition of the mixture depends on the pyrolysis temperature.306 The mechanism of the thermal conversion of 4-cyclopropenyl-4-substituted5(4H)-oxazolones to pyridines has been studied. A stepwise cycloaddition of the initially generated nitrile ylide has been proposed to account for the observed products.307 Flash vacuum pyrolysis of 2-phenyl-5(4H)-oxazolone 146 effects extrusion of carbon dioxide to produce 3-phenyl-2H-azirine 290 in moderate yield (Scheme 7.95).308 O Ph

600 ˚C

O

N

1.5 x 10−3 Torr

N

Ph 146

290 Scheme 7.95

7.3.2.6. Dimerization Reactions Dimerization of 5(4H)-oxazolones affords two different products depending on the reaction conditions. In one case, 4-benzyl-2-phenyl-5(4H)-oxazolone 291 was converted to the pyrrolidinedione 292 with potassium carbonate followed by acidic hydrolysis (Scheme 7.96).309

O Bn N

O Bn NHCOPh

O

N

Bn

H O

Ph 291

292 Scheme 7.96

A kinetic study of the base-catalyzed dimerization of 5(4H)-oxazolones has shown that 5(4H)-oxazolones with sterically demanding or electron-donating substituents at C-2 are less prone to dimerization.310 Dimerization can also be achieved using nickel peroxide311,312 or through a photooxidation reaction.313 In these cases, 4-monosubstituted-5(4H)-oxazolones 293 are converted to the corresponding 4,40 -bis(oxazolones) 294 (Scheme 7.97;

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

195

Ar O R

O

N

R

O

N

O

R

N

Ar

O O Ar

293

294 Scheme 7.97

Table 7.26, Fig. 7.28). A variety of reactions involving free radical generation from such bis(oxazolones) have been described.314–317

7.3.2.7. Cycloaddition Reactions Mesoionic oxazolones (munchnones) 297 can be generated by cyclodehydration of N-substituted a-amino acids 295 or by alkylation of oxazolones 296 (Scheme 7.98). These compounds are reactive and versatile 1,3-dipoles that undergo cycloaddition reactions with dipolarophiles to generate a variety of heterocyclic systems. In particular, this is an extremely versatile methodology to prepare pyrroles that result from elimination of carbon dioxide from the initial cycloadduct. Numerous examples have appeared in the literature in recent years and several have been selected for discussion. The reader should consult Part A, Chapter 4 for an extensive discussion and additional examples. TABLE 7.26. 4,40 -BIS(OXAZOLONES) FROM DIMERIZATION OF SATURATED 5(4H)-OXAZOLONES

R2 O R1

O N

N

R1 O

O R2

O R1 N

O R2

R1

R2

Ph Ph 4-ClC6H4 Ph Ph Ph

4-MeOC6H4 Ph Ph 2-FC6H4 2-ClC6H4 4-ClC6H4

Figure 7.28 % Yield > 75 > 75 > 70 69 66 74

Reference 311 311 312 316 316 316

196

5(2H)-Oxazolones and 5(4H)-Oxazolones R2

CO2H

Me N COR1

O R2

295

N Me

O R2

O R1

MeX

N

297

O R1

296 Scheme 7.98

Munchnones 298 obtained in situ by N-alkylation of 5(4H)-oxazolones undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate to give N-alkylpyrroles 299.318 1,3-Dipolar cycloaddition of munchnones with triphenylvinylphosphonium bromides affords tri- and tetrasubstituted pyrroles 300. In this case, the interaction of the phosphonium group with the carbonyl group leads to high levels of regioselectivity (Scheme 7.99; Table 7.27, Fig. 7.29).319

CO2Me MeO2C

C

C

CO2Me

R2 CO2Me

N R3

R1

O R2

299 N

R3

O R1

298

R4

R4 PPh3Br

R2 N R3

R1 300

Scheme 7.99

Oxazolones320 react with fumarates and fumaronitrile or acrylates to afford the corresponding cycloadducts 302 or 304. These cycloadducts, in turn, rearrange to 303 and 305 depending on the substituents (Scheme 7.100).

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

197

TABLE 7.27. SUBSTITUTED PYRROLES VIA CYCLOADDITION OF DIPOLAROPHILES WITH MUNCHNONES PREPARED FROM SATURATED 5(4H)-OXAZOLONES

R4

O R1

dipolarophile

N R3

R1

O

R5

N R3

R2

R2

Figure 7.29 R1

R2

Me PhCH2 PhCH2 Me Ph Ph Ph 4-ClC6H4 Ph 4-MeC6H4 Ph i-Pr Ph Ph 4-ClC6H4 Ph Ph 4-ClC6H4 4-MeOC6H4 Ph

R3

Dipolarophile

R4

R5

Me Et H H H H Me Me Me Me

MeO2CC  CCO2Me MeO2CC CCO2Me CHPPh3Br CH2 CH2 CHPPh3Br CH2 CMePPh3Br CH2 CMePPh3Br  CH2  CHPPh3Br CH2 CHPPh3Br CH2 CMePPh3Br CH2 CMePPh3Br

CO2Me CO2Me H H Me Me H H Me Me

CO2Me CO2Me H H H H H H H H

O

R2 X

X

X = CN, CO2Me

O

HN O

X

Ac2O

Me MeCO2 O

R1

X

O

% Yield Reference 87 80 40 35 30 41 53 49 34 35

318 318 319 319 319 319 319 319 319 319

X

X

R1 N R2 COMe

R2 N

302

O

303

R1 301 CO2R3

O

R2

Ac2O

HN O

Me R3O2C

R1

R3O2C 304

R1 N COMe

O

R2

O O 305

Scheme 7.100

Reaction of munchnones 306 with 2-phenylbenzazete provides a simple route to 1,3-benzodiazepines 307321 that thermally rearrange to the corresponding 3Hindoles 308. 1,3-Dipolar cycloaddition reactions of nitrosobenzene and munchnones give the corresponding cycloadducts 309 with a high degree of regioselectivity. Subsequent ring opening of the cycloadducts leads to a variety of substituted 1,2,4-oxadiazoline-3-carboxylic acids 310 (Scheme 7.101).322–325

198

5(2H)-Oxazolones and 5(4H)-Oxazolones Ph

Ph

R2

N

Ph 1) ∆

N R3 O O

R3

N H

R1

R2 N

R1

2) H+

N 307

308

R1 306

O

R2 Ph

N

O

HN Ph N O

HO2C

O R1

309

Ph

R2

N N

O R1

310

Scheme 7.101

Cycloaddition reactions of N-(phenylmethylene)benzenesulfonamide with mesoionic oxazolones 311 produces 2,5-disubstituted imidazoles 313 in a highly regioselective process via cycloreversion of cycloadduct 312 and subsequent loss of benzenesulfinic acid.326 O R2

Ph N

N

O

Me R1 311

SO2Ph

R2

Ph O ON SO2Ph N

Me

Ph R2 N

N

Me R1 312

R1 313

Scheme 7.102

Finally, 5(4H)-oxazolones react as masked 1,3-dipoles with nitrileimines,327 1-nitroso-2-naphthol328 and [60]fullerene329 to give 1,2,4-triazoles, naphth[1,2-d]oxazoles and 50 -phenyl-20 H-pyrrolo[30 ,40 :1,2][60]fullerene, respectively.

7.3.2.8. Reactions with Dienes and Azadienes Reaction of oxazolones with 1-azadienes, for example, imines prepared from 3(2-furyl)acrolein330 or cinnamaldehyde,331–334 affords 2-pyridones 316. Several mechanisms have been proposed to explain the formation of 316. However, products like 315 have also been isolated. The authors proposed that 315 arises from alkylation at C-4 of the oxazolone by the 1-azadiene. Subsequent nucleophilic attack by the amino group with ring opening then yields the 2-pyridone (Scheme 7.103). Representative examples of 2-pyridones prepared from 1-azadienes are shown in Table 7.28 (Fig. 7.30).

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

199

NHR3 O

N

Ar

O

O

O

Ar

R2

R2

R3

N

R2 N

R3 N

R1CONH

O

Ar R1

R1 314

315

316

Scheme 7.103

O

O Me

R

N

N

Me

R

N

R

PhCONH

O

R

N

N

Ph 193

317 Scheme 7.104

In a similar manner, aldazines afford pyridazinones 317 (Scheme 7.104).335 1,3-Diazadienes such as 1-aryl-4-(dimethylamino)-2-phenyl-1,3-diaza-1,3-butadienes or 1-aryl-4-(dimethylamino)-2-methylthio-1,3-diaza-1,3-butadienes react with oxazolones and give rise to pyrimidin-6-ones 319 and 320 as single diastereo-

TABLE 7.28. 2-PYRIDONES FROM CYCLOADDITION REACTIONS OF SATURATED 5(4H)-OXAZOLONES WITH 1-AZADIENES

O R1

R3 R4

N

R2CONH

O

N

O R1

R3 N

R4

R2 Figure 7.30 R1 Me Me Me Me Ph Ph Ph Me Me Ph Me Ph

R2 4-ClC6H4 4-MeOC6H4 4-NO2C6H4 PhCH2 Ph Ph Ph Ph PhCH2 Ph Ph Ph

R3 Ph 4-ClC6H4 4-MeC6H4 4-MeOC6H4 Me C6H11 C6H11 C6H11 C6H11 i-Pr i-Pr Ts

R4 Ph Ph Ph Ph Ph Ph Me Me Me Me Me Ph

% Yield 74 82 72 80 60 60 78 88 78 65 72 80

Reference 332 332 332 332 333 333 334 334 334 334 334 339

200

5(2H)-Oxazolones and 5(4H)-Oxazolones R2 N

O

Ph

N

Me

Me2N

O Me

R2

N

R1CONH H Me2N

N

Ph

319 O

N

R2

R1 318

N N

O

SMe

Me Me2N

R1CONH Me2N H

N

R2

N

SMe

320

Scheme 7.105

isomers. Interestingly, 319 and 320 are formed with a reversal in stereochemistry (Scheme 7.105; Table 7.29, Fig. 7.31).336,337 Highly substituted cyclohexenones 321 are efficiently prepared from dienamines and 5(4H)-oxazolones (Scheme 7.106).338 O

O

Me

Me

NEt2

O

N

PhCONH Et2N

Ph 193

321

Scheme 7.106 TABLE 7.29. PYRIMIDIN-6-ONES FROM CYCLOADDITION REACTIONS OF SATURATED 5(4H)-OXAZOLONES WITH 1,3-DIAZADIENESa

Me

Me2N

N

O

R3

O N

O R1

N

R2

O

Me R1CONH H Me2N

N N

Me

R2

R1CONH Me2N H

or R3

N N

R2 R3

B

A Figure 7.31 R1

R2

R3

% Yield A

4-ClC6H4 Ph Ph 4-ClC6H4 Ph Ph

Ph Ph 4-MeC6H4 Ph Ph 4-ClC6H4

Ph Ph Ph SMe SMe SMe

90 82 87

a

Data from Ref. 337.

% Yield B

94 91 83

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

201

Finally, reaction of 2,4-diphenyl-5(4H)-oxazolone 322 with 4-phenyl-N-tosyl-1azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-N-tosyl-1azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324–327. The marked differences in reactivity of 4-phenyl-N-tosyl-1-azabuta-1,3-diene relative to N-alkyl- or N-aryl1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107).339

N

Ph

NHTs O

Ph Ph

Ts

O

N

r.t.

Ph

O Ph

323 O

N

Ph 322

O Me

N

Ph

Ts

N

PhCONH

Ph

Ts +

110 ºC

+ Ph

Ph

N 325

324 CH2NHTs

Ph

Ph

CH=NTs

Ph +

Ph

N

Ph

Ph

N

Ts 326

Ph

Ts 327

Scheme 7.107

7.3.2.9. Polymerization Reactions Much effort has been invested to use oxazolones as intermediates for the synthesis of polymers. Probably the most important group of oxazolones used for this purpose is the 2-alkenyl-4,4-disubstituted-5(4H)-oxazolones. The reactivity of the exocyclic double bond at C-2 can be exploited to prepare new functionalized oxazolones as well as for copolymerization with other monomers. This possibility, together with the facile ring opening with nucleophiles, has opened very interesting routes to new polymers of industrial interest.

202

5(2H)-Oxazolones and 5(4H)-Oxazolones Me

O

Me

Me

O

Me N

O

N

O Me

140

328

Figure 7.32. 2-Alkenyl-4,4-dimethyl-5(4H)-oxazolone monomers for polymerization reactions.

4,4-Dimethyl-2-vinyl-5(4H)-oxazolone (VDMO) 140 and 4,4-dimethyl-2-isopropenyl-5(4H)-oxazolone 328 have been extensively investigated as monomers (Fig. 7.32). Copolymerization of 140 or 328 with other monomers, for example, acrylates or acrylamides produces reactive polymers that are conveniently further modified by nucleophilic reaction with alcohols, amines, or other nucleophiles.340–383 The preparation of 2-(4-alkenylphenyl)-4,4-disubstituted-5(4H)-oxazolones384 and their use as monomers has also been reported.385 The second group of saturated 5(4H)-oxazolones used as intermediates for polymer synthesis are the 2,20 -bis(oxazolones) with 2,20 -bis[4,4-dimethyl-5(4H)oxazolone] 329 being the simplest member of the series (Fig. 7.33). These compounds, are prepared by cyclization of the corresponding bis(amino acids) and give a wide variety of polymers after ring opening with diamines, dialcohols or other nucleophiles. The physical chemical properties of these polymers depend on the nature of the substituents and the size of the chain. Some selected references describe representative examples.386–396 Me

O

Me N

O

O

N Me

O

Me 329

Figure 7.33. 2,20 -Bis[4,4-dimethyl-5(4H)-oxazolone] 329.

Alternatively, a spacer can be inserted between the heterocyclic rings to further modify the properties of the polymer. Although various spacers have been used, aromatic rings are probably the most frequently employed. In this case, 2,20 -(p-phenylene)bis[4,40 -dimethyl-5(4H)-oxazolone] 330 is the most common monomer (Fig. 7.34). Again, representative examples are described in selected references.397–405

7.3.2.10. Organometallic Complexes As multifunctional compounds, 5(4H)-oxazolones can act as ligands and, as such, they provide interesting organometallic transition metal complexes depending

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Me

203

O

Me N

O

O

N Me

O

Me 330

0

Figure 7.34. 2,2 -( p-Phenylene)bis[4,40 -dimethyl-5(4H)-oxazolone] 330.

upon the coordination mode of the 5(4H)-oxazolone to the metal atom. Reaction of [n-Bu3PMCl2]2 with 2-phenyl-4-substituted-5(4H)-oxazolones 331 generates the corresponding palladium(II) and platinum(II) complexes 332 (Scheme 7.108).406 R

O R O

N

O

Cl n-Bu3P M

[n-Bu3PMCl2]2 M = Pt, Pd

N

O

H Cl

331

332

Scheme 7.108

When phenylene- and ethylene-bridged bis(oxazolones) are used as ligands, dinuclear palladium(II) and platinum(II) 333, 334, and 335 complexes are obtained (Fig. 7.35).407 In some cases, the close proximity of the ortho phenyl-H-atom to the metal rendered these complexes suitable precursors for ortho metalation. Cl Et3P Pt N H Cl

O

H Cl Et3P Pt N

O

Cl

R

Cl Me

O

O O

O

Me

Cl O

Cl

H N Pt PEt3

Me R

Me

O

Et3P Pt N H Cl

Cl

Et3P M

O

N

O Cl (CH2)2 Cl O N M PEt3 O Me Cl Me M = Pt, Pd

333

334

335

Figure 7.35. Dinuclear palladium(II) and platinum(II) complexes with phenylene- and ethylene-bridged bis(oxazolone) ligands.

204

5(2H)-Oxazolones and 5(4H)-Oxazolones

If the anion of 2-(20 -hydroxyphenyl)-5(4H)-oxazolone 336 is used as a ligand, bis-chelate complexes 337 of copper(II), nickel(II), and zinc(II) have been prepared from the corresponding metal acetates. Alternatively, 336 and 2-(20 -aminophenyl)5(4H)-oxazolone 340 can act as ligands with metals including palladium(II), platinum(II), ruthenium(II), nickel(II), and copper(II) to produce a variety of structurally diverse complexes 338, 339, and 341 as shown in Schemes 7.109 and 7.110.407 4-Alkyl-2-phenyl-5(4H)-oxazolones 342 react with the chloro-bridged iridium(III) complex [(Z5-C5Me5)IrCl2]2 to give cyclometalated mononuclear complexes 343. O

O

O

N M

MAc2

N

O

M = Ni, Cu, Zn

O

O 337 O

O

O

N

[R3PMCl2]2

Cl

O

N M

M = Pt, Pd

R3P

HO

O

336

338

O

[(p-cymene)RuCl2]2

Cl

N

O

Ru p-cymene

O

339

Scheme 7.109 O

O

R

R N

O

MCl2 M = Ni, Cu

Cl

N M

or Na2PdCl4

Cl

H 2N

N H

340

H 341

Scheme 7.110

O

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) O

O

R

R [(η5-C5Me5)IrCl2]2

O

N

205

N

O

Ir Cl 342

343

O

O

Cl Ir

5

N

[(η -C5Me5)IrCl2]2

O

Cl

N Ir

146

O

Cl

344

Scheme 7.111

The same iridium(III) complex also reacts with 2-phenyl-5(4H)-oxazolone 146 to give dinuclear complexes 344 (Scheme 7.111).408 Anions of 2-phenyloxazolones 345 add to the p ligands of iron and chromium complexes, for example, [(Z5-C6H7)Fe(CO)3]þ and [(Z7-C7H7)Cr(CO)3]þ to give new organometallic complexes 346 and 347 (Scheme 7.112).408 O R

O N

[(η5-C6H7)Fe(CO)3]+

O

Fe

R

OC O

N

CO CO 346 O

O

345 R

[(η5-C7H7)Cr(CO)3]+

N

Cr OC

CO CO 347

Scheme 7.112

206

5(2H)-Oxazolones and 5(4H)-Oxazolones

Ferrocenoylamino acids have been converted into 2-ferrocenyl-5(4H)-oxazolones 348 and 350 that act as N donors in palladium, platinum, and iridium complexes. Reaction of 348 with chloro-bridged palladium(II) and platinum(II) complexes affords a series of N-coordinated oxazolone complexes 349. Reaction of the unsubstituted 2-ferrocenyl-5(4H)-oxazolone 350 with the chloro-bridged iridium(III) complex [(Z5-C5Me5)IrCl2]2 produces a dinuclear complex 351, analogous to that obtained from 2-phenyl-5(4H)-oxazolone (Scheme 7.113).409 O

O O

O R1

N Fe

R1

[(R2)3PMCl2]2

N

M = Pt, Pd

Cl Cl M P(R2)3

Fe

348

349 O

O O N

O

Fe

N

[(η5-C5Me5)IrCl2]2

Cl

Fe

350

Ir

Ir

Cl

Cl

351 Scheme 7.113

7.3.3.

Structural Analysis

A number of systematic structural analyses have been described for families of saturated oxazolones. First, as mentioned previously, detailed studies of 1H NMR long-range coupling in 2,4-disubstituted-5(4H)-oxazolones and in 5(2H)-oxazolones have been reported.11 Similarly, detailed 1H NMR studies of the kinetics of racemization of 2,4-disubstituted-5(4H)-oxazolones have been performed.12 A theoretical study of the spectral-luminescence properties of some 4-alkyl-2-phenyl5(4H)-oxazolones has been reported410 and an investigation of the infrared (IR) and Raman spectra of 5(4H)-oxazolones, particularly of the carbonyl group vibration, has been reported.411 Electron impact mass spectra of saturated 5(4H)-oxazolones have been published.412 More recently this technique has been used to distinguish between the stereoisomers of some spirocyclopropane oxazolones 352 (Fig. 7.36).413 Finally, several studies of the HPLC behavior of 5(4H)-oxazolones complete a general view for this family of compounds.414,415

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

207

O

O N

O

O Ph

352 Figure 7.36. A spirocyclopropane 5(4H)-oxazolone studied by mass spectrometry.

During the last 20 years, X-ray analyses of several saturated 5(4H)-oxazolones have been performed. Most of the compounds studied are 5(4H)-oxazolones derived from N-acylamino acids and, in particular, from quaternary amino acids since these compounds possess excellent chemical stability and high crystallinity. For example, the X-ray structure of 2-(4-bromophenyl)-4,4-dimethyl-5(4H)-oxazolone, derived from N-2-(4-bromobenzoyl)aminoisobutyric acid,416 2-(4-bromophenyl)-4,4diphenyl-5(4H)-oxazolone, derived from N-2-(4-bromobenzoyl)diphenylglycine,417 2-(4-bromophenyl)-4-ethyl-4-methyl-5(4H)-oxazolone, derived from N-2-(4-bromobenzoyl)isovaline,418 and 2-(4-chlorophenyl)-4-(2-cyclohexen-1-yl)-4-phenyl5(4H)-oxazolone419 have been reported. In general, the ring system of such 4,4disubstituted-5(4H)-oxazolones is nearly planar and the two carbons at C-4 are displaced on the opposite sides of the average plane of the ring. It is noteworthy that the C N bond length corresponds to a C N bond that indicates that this bond is not conjugated with the carbonyl group of the oxazolone moiety. On the other hand, electron delocalization through the C O C group of the oxazolone moiety is small, although it is still significant.420 X-ray crystal structures for spirooxazolones including 4-spirocyclopropane 353 (n ¼ 1, R2 ¼ H),421 4-spiro-(phenyl)cyclopropane 353 (n ¼ 1, R2 ¼ Ph),422 4-spiro(triphenyl)cyclopropane,423 4-spiro-(pivaloyloxy)cyclopropane 353 [n ¼ 1, R2 ¼ PivO (Piv ¼ pivaloyl)],424 4-spirocyclopentane 353 (n ¼ 3, R2 ¼ H),425 4-spirocyclohexane 353 [n ¼ 4, R2 ¼ H],426 4-spiro-(2,2,4,4-tetramethyl-3-oxyl-3-aza)cyclohexane,427 substituted 4-spirocyclohexanone,428 substituted 4-spirocyclohexene,429 substituted 4-spirobicyclo[2.2.1]heptene 354 [n ¼ 1, R2 ¼ (S)-2,2-dimethyl-1,3-dioxolan-4-yl]430,431 and substituted 4-spirobicyclo[2.2.2]octene 354 [n ¼ 2, R2 ¼ (S)-2,2-dimethyl-1,3-dioxolan-4-yl]432 have been determined (Fig. 7.37). The X-ray data for the oxazolone moiety of these compounds did not show striking differences from other 4,4-disubstituted-5(4H)-oxazolones. (CH2)n

O

O

n

R2 N n = 1,3,4

O R1

353

n = 1,2

R2

N

O R1

354

Figure 7.37. General structure of spirocyclic 5(4H)-oxazolones analyzed by X-ray crystallography.

208

5(2H)-Oxazolones and 5(4H)-Oxazolones O

R3 R2

O

N

O

R1

355 Figure 7.38. General structure of 2-alkoxy-5(4H)-oxazolones analyzed by X-ray crystallography.

Crystal structures of the 2-alkoxy-5(4H)-oxazolones investigated 355 (Fig. 7.38) indicate that the oxazolone ring is also nearly planar with bond distances and bond angles similar to those of 2-alkyl-5(4H)-oxazolones.433,434 However, 355 do have a shorter (C-2) O distance that indicates a slightly more effective intraring electron delocalization. In these compounds the lone pair of the exocyclic oxygen on C-2 is  properly positioned for effective interaction with the C  N p-system and the length of the exocyclic C O bond is shorter than that expected for an sp2 single bond. Finally, crystal structures of 5(4H)-oxazolones 356 obtained from peptides containing C-terminal 2-aminoisobutyric acid,435,436 isovaline,437,438 phenylalanine,439 a-methylphenylalanine,440 or a-methylleucine441 residues have been discussed (Fig. 7.39). In these compounds the conformation of the amino acid preceding that involved in the ring system is generally not helical even if this residue is a strong helix former. This may result from the minimization of intramolecular interactions between the atoms of the oxazolone ring, which is nearly planar, and those of the preceding residue.

O

R3 R4

N R1

O NHCOR2 356

Figure 7.39. General structure of dipeptide 5(4H)-oxazolones analyzed by X-ray crystallography.

7.4. UNSATURATED 5(4H)-OXAZOLONES (2-OXAZOLIN-5-ONES) Unsaturated 5(4H)-oxazolones have been well known for many years and new examples are constantly described every year in specialized organic journals. In general, a wide variety of substituted unsaturated oxazolones have been prepared and many applications have been described for these compounds (Fig. 7.40).

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) R2 H

209

H

O

O O

N

O

N

X

R1

O

Y R

W

Z V 357

358

Disperse dyes

Herbicides and fungicides

H

H

O O

N

R1

O Ph

N

R2

O

N

N

O Ph

R2

359

360

Luminophores

Electrophotographic light sensitive materials

H

Me Me

O

N

Me

Me

O

O O

N

Me

A

H

Ph D 361

362

NLO materials

Monomolecular films

Figure 7.40. Structurally diverse unsaturated 5(4H)-oxazolones and their applications.

Unsaturated 5(4H)-oxazolones have been studied as ultraviolet (UV)-absorbing layers,442 as fungicides,443 and as antibacterial agents.444 For example, 4-(3phenoxybenzylidene)-2-substituted-5(4H)-oxazolones 358 have been prepared and used as herbicides and fungicides.445 Many other applications have been described for these compounds and the list is so extensive that it is impossible to cover each example here. Nevertheless, it is noteworthy that appropriately substituted 4-arylidene-5(4H)-oxazolones, for example, 359 and 360 have been reported as organic luminophores446–449 and electrophotographic light-sensitive materials,450–455 respectively. The use of apocarotenoid derivatives such as 362 as monomolecular films has also been described.456 For new materials, a number of water-insoluble oxazolones have been used for dyeing or printing synthetic fibers457 and, in this context, 4-(pyren-1-ylmethylene)2-substituted-5(4H)-oxazolones 357, prepared from pyrene-1-carboxaldehyde, have

210

5(2H)-Oxazolones and 5(4H)-Oxazolones

been used as dyes for polyester fibers.458 Applications of unsaturated 5(4H)oxazolones, for example, 361 as organic nonlinear optical materials have also been described.459,460 Unsaturated 5(4H)-oxazolones have also been used as intermediates to prepare analogues with diverse biological activities. For example, the oxazolone derived from 4-biphenylcarboxaldehyde is a synthetic precursor of the antiinflammatory agent 4-biphenylacetic acid.461 In addition, 2-substituted oxazolones derived from 2-thioarylbenzaldehydes are starting materials for the preparation of dibenzothiepine derivatives that are useful to treat schizophrenia.462 Other oxazolones have been used as intermediates to prepare insecticides and acaricides.463a 7.4.1.

Synthesis

7.4.1.1. From N-Acylglycines and Carbonyl Compounds The first procedure to prepare unsaturated 5(4H)-oxazolones was the Erlenmeyer synthesis463b,c that was described more than one hundred years ago and is still used extensively with some variations in the experimental conditions. In general, the reaction employs an acylamino acid, for example, N-acetyl- or N-benzoylglycine are the most common, and a carbonyl compound, usually an aldehyde, in the presence of a cyclodehydrating agent such as acetic anhydride (Scheme 7.114). Hundreds of unsaturated oxazolones 363 have been obtained via this procedure and these compounds are valuable intermediates for the synthesis of many interesting organic compounds. H H O + R2

CO2H NHCOR1

Ac2O NaOAc

O

R2 N

O

(Z) isomer R1 363 Scheme 7.114

The Erlenmeyer synthesis usually proceeds with a very high degree of stereoselectivity to favor the thermodynamically more stable (Z) isomer that is easily isolated by recrystallization. In some cases, the (Z) isomer is the only product obtained. This general methodology has been used extensively to prepare of a wide variety of unsaturated oxazolones.1–3,464–467 Heterocyclic aldehydes have been used as the carbonyl component and yield the corresponding 4-(heteroarylmethylene)-2-substituted-5(4H)-oxazolones that are also valuable synthetic intermediates. Examples of (heteroarylmethylene)-5(4H)oxazolones of particular interest that have been synthesized include oxazolones derived from furfural,468 pyrazolecarboxaldehyde,469 and chromonecarboxaldehyde.470,471 Indole-containing oxazolones are of special interest owing to the

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

211

diverse biological and pharmacological properties and numerous derivatives have been prepared and studied.472–476 A limited number of references have appeared that use ketones as the carbonyl component. The first example reported477 that acetophenones condense with Nbenzoylglycine under Erlenmeyer conditions to afford a mixture of (Z)- and (E)unsaturated-5(4H)-oxazolones 364 and 365 in which the (Z)-isomer 364 is the major compound, obtained in moderate to good stereoselectivity (Scheme 7.115). The pure (Z) isomer was obtained by recrystallization of the mixture. Me Me

CO2H

O + R1

Ac2O

R1

NaOAc

N

NHCOPh

R1

O Me O +

(Z) isomer Ph

O O

N

(E) isomer Ph

364

365

Scheme 7.115

In the second study, diketones were used as electrophiles and reacted with Nbenzoylglycine to give a (Z/E) mixture of oxazolones 366 and 367 derived from condensation at the less hindered carbonyl group of the 1,2-dicarbonyl compound (Scheme 7.116). The (E)-isomers 367 were used as starting materials to prepare (Z)-5-alkylidene-3-(benzoylamino)-2(5H)-furanones 368.478 R1

R1 O +

CO2H

Ac2O NaOAc

O

NHCOPh R2

O

R2 O

N

O

R2

O R1

O +

N

(Z) isomer Ph

(E) isomer

O Ph

367

366

R2 O H

O NHCOPh

R1 368 Scheme 7.116

Mechanistic studies of the Erlenmeyer reaction suggest that the reaction proceeds through initial rapid and reversible formation of the saturated oxazolone followed by an aldol condensation of the latter with the carbonyl compound and subsequent dehydration.479

212

5(2H)-Oxazolones and 5(4H)-Oxazolones

The classical experimental conditions of the Erlenmeyer synthesis use anhydrous sodium acetate and acetic anhydride to effect cyclodehydration. However, many other reagent combinations have been used to improve the yield and the stereoselectivity of the reaction. With these aims in mind, zinc acetate,480 anhydrous zinc chloride,481 trimethylsilylchloride and acetic anhydride,482 or a mixture of alumina–boric acid in the presence of acetic anhydride483 have also been used. Diethyl pyrocarbonate484 or haloiminium salts, such as N,N-dimethylchlorosulfite methaniminium chloride485 or 2-chloro-1,3-dimethylimidazolium chloride82 have also been described as suitable cyclodehydrating agents. Ion-exchange resins,486 potassium fluoride and alumina487 and zeolites under mild conditions488 are examples of heterogeneous catalysts to prepare unsaturated 5(4H)-oxazolones. Interestingly, microwave accelerated condensations using DCC and dimethylacetamide (DMA) are reported to furnish 4-arylidene-2-phenyl-5(4H)-oxazolones in better yields than simply heating the reagents.489,490 A variety of 5(4H)-oxazolones prepared via the Erlenmeyer synthesis are shown in Table 7.30 (Fig. 7.41). Since most procedures afford the more stable (Z)-isomer 369, some attention has been focused to find specific methods to generate the (E)-isomer 370. Among these TABLE 7.30. SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES FROM N-ACYLGLYCINES AND CARBONYL COMPOUNDS

R1 R1

CO2H

O + R2

cyclodehydrating

O

R2

agent

NHCOR3

N

O R3

R1

R2

H 2-NO2C6H4 H Ph H 4-AcOC6H4 H 3,4-(MeO)2C6H3 H Ph H 4-Me2NC6H4 H 3-MeO-4-HOC6H3 H CF3MeCH H 5-ethoxycarbonylmethylfur-2-yl H thien-2-yl H 5-nitrothien-2-yl H fur-2-yl H 5-nitrofur-2-yl Me Ph Me 4-MeC6H4 Me 4-ClC6H4 Me MeCO Me EtCO Me PhCO

R3 Me Me Me Me Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

Figure 7.41 Cyclodehydrating Agent Ac2O/NaOAc zeolite-HY zeolite-HY zeolite-HY zeolite-HY zeolite-HY zeolite-HY Zn(OAc)2 Ac2O/NaOAc ion-exchange resin ion-exchange resin ion-exchange resin ion-exchange resin Ac2O/Pb(OAc)2 Ac2O/Pb(OAc)2 Ac2O/Pb(OAc)2 Ac2O/Pb(OAc)2 Ac2O/Pb(OAc)2 Ac2O/Pb(OAc)2

% Yield 63 (Z þ E) 73 70 78 80 85 72 100 (Z þ E) 70 38 62 71 77 46 38 40 36 25 86

Reference 465 488 488 488 488 488 488 480 468 486 486 486 486 477 477 477 478 478 478

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

213

TABLE 7.31. UNSATURATED (E)-5(4H)-OXAZOLONES VIA ISOMERIZATION OF UNSATURATED (Z)-5(4H)-OXAZOLONES

R1

R2

O HBr

R2

R1

O

N

O O

N

R3

R3 R1

R2

Figure 7.42 R3

H H H Me Me Me Me Me

Ph 2-MeOC6H4 4-MeOC6H4 Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 4-NO2C6H4

Ph Ph Ph Ph Ph Ph Ph Ph

% Yield

Reference

90 90 96 90 90 92 89 85

491 491 491 477 477 477 477 477

procedures isomerization using hydrobromic acid,477 polyphosphoric acid,491 or irradiation through a pyrex filter with a 450 W medium pressure mercury arc lamp492 are the most noteworthy (Scheme 7.117). Representative examples are shown in Table 7.31 (Fig. 7.42). (Me) H

R1

O HBr or

R1 N

O

O

(Me) H N

PPA or hv

O Ph

Ph 369

370 PPA = poly(phosphoric acid) Scheme 7.117

Other electrophiles such as succinic anhydride,493 imines,494 or 2-(2-aminomethylene)-3-indolinones495 have also been used to prepare 5(4H)-oxazolones.

7.4.1.2. From Other N-Acylamino Acid Derivatives and Glycine Equivalents Other amino acid precursors have been used as starting materials in the Erlenmeyer reaction. A classical reaction of oxazolones is ring opening to give dehydroamino acid derivatives but there are a number of examples when the reverse reaction has been exploited including cyclizations of N-benzoyl-a,b-dehydrophenylalanine,496 a-(acetylamino)cinnamic esters,497 and 2-(acylamino)-2-alkenamides (Scheme 7.118).498

214

5(2H)-Oxazolones and 5(4H)-Oxazolones H

O

H R2

COX

R2

O

N NHCOR1

R1 371

Scheme 7.118

When b-arylserines rather than glycine are used as the starting amino acid, cyclization occurs concomitant with dehydration to afford the corresponding unsaturated 5(4H)-oxazolone.499 Iminophosphoranes derived from readily available a-azidocinnamates react with aroyl chlorides to give the corresponding 2-aryl-4-arylidene-5(4H)-oxazolones 372.500,501 Alternatively, these iminophosphoranes are converted to the corresponding 2-arylamino-4-arylidene-5(4H)-oxazolones 373 via heterocyclization of an intermediate carbodiimide as shown in Scheme 7.119 (Table 7.32, Fig. 7.43).502,503 H

O

H ArCOCl

CO2R2

R1

R1

O

N

N PPh3

Ar 372 H

O

H TBAF

R1

CO2R2

R1

N

N C N Ar

O NHAr

373

Scheme 7.119 TABLE 7.32. SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES VIA CYCLIZATION OF a,b-DIDEHYDROAMINO ACIDS OR a,b-UNSATURATED CARBODIIMIDES

H

O

H COX

R1

R1 N

Y

O R2

R1

Y

Figure 7.43 R2

Ph Ph Ph Ph Ph

NHCOPh N C N-Ph N C N-(4-MeC6H4) N C N-(4-MeOC6H4) N C N-(4-ClC6H4)

Ph NHPh NH-(4-MeC6H4) NH-(4-MeOC6H4) NH-(4-ClC6H4)

% Yield 84 70 96 90 90

Reference 496 502 502 502 502

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

215

Isocyanides have also been used to prepare unsaturated 5(4H)-oxazolones and they are particularly useful for the synthesis of 4-(aminomethylene)-5(4H)-oxazolones 374. For instance, cyclization of an unsaturated isocyanide obtained from condensation of alkyl isocyanoacetates and lactam acetals has been reported (Scheme 7.120).504

N

O

∆

OEt CO2R

+ OEt

N

NC

Me

CO2R

Me

N

NC

Me

N

O H

374 Scheme 7.120

Reaction of methyl 3-(dimethylamino)-2-isocyanoacrylate (R1 ¼ Me) with acyl chlorides gave 2-acyl-4-(dimethylaminomethylene)-5(4H)-oxazolones 375.505 The same reaction with arenesulfenyl chlorides gave either 2-arylthio-4-(dimethylaminomethylene)-5(4H)-oxazolones 376 or an unsaturated 5(4H)-oxazolone 377 containing an imidazole at C-2 depending on the substitution present in the arenesulfenyl chloride. Nitroarenesulfenyl chlorides favored 376.506,507 Selected examples of 372, 375, and 376 are shown in Table 7.33 (Fig. 7.44; Scheme 7.121). 4-(Dimethylaminomethylene)-5(4H)-oxazolones 378 can also be obtained directly from N-acylamino acids,508 N-acylamino esters,509 or N-acylamino H Me

R2COCl

O

N N

Me

O COR2

375 H H Me

ArSCl

CO2R1

N Me

Me

O

N N

Me

NC

O SAr

376 H ArSCl

Me

O

N Me

N

O N

R1O2C N 377 Scheme 7.121

SAr

216

5(2H)-Oxazolones and 5(4H)-Oxazolones

TABLE 7.33. SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES VIA CYCLIZATION OF a,b-UNSATURATED IMINOPHOSPHORANES OR a,b-UNSATURATED ISOCYANIDES

H

O

H R2COCl

R1

CO2R

R1

O

N

Y

R2 H

H

R3Cl

R1

CO2R

R1

O O

N

Y

R3 Figure 7.44

R1 4-MeC6H4 2-MeOC6H4 3,4-(MeO)2C6H3 3,4-(MeO)2C6H3 Me2N Me2N Me2N Me2N Me2N

Y

R2

 N  PPh3 N PPh3 PPh3 N N PPh3 NC NC NC NC NC

R3

% Yield

4-NO2C6H4 4-MeC6H4 Ph 4-ClC6H4 Me Ph

78–82 78–82 78–82 78–82 not described not described  100  100  100

2-NO2-4-ClC6H3S 2-NO2C6H4S 2,4-(NO2)2C6H3S

Reference 501 501 501 501 505 505 506 506 506

amides510 using the Vilsmeier reagent. In some cases508 ring opening followed by nitrosation of the intermediate a,b-didehydroamino acid derivative 379 affords the corresponding alkyl 5-substituted-1,2,4-oxadiazole-3-carboxylate 380 (Scheme 7.122; Table 7.34, Fig. 7.45). H COX

POCl3/DMF

Me

N Me

NHCOR1

O MeOH/NaOH

O

N

R1 378 H Me

CO2Me

N Me

NaNO2/HCl

O

R1

N

N

NHCOR1

CO2Me

379

380 Scheme 7.122

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

217

TABLE 7.34. SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES FROM N-ACYLAMINO ACID DERIVATIVES AND VILSMEIER-HAACK REAGENT

H COX

POCl3/DMF

Me

N Me

NHCOR1

O O

N

R1 Figure 7.45 R1

COX

PhCH CH CH 4-MeC6H4CH 2-MeOC6H4CH CH Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 4-NO2C6H4 Ph

CO2H CO2H CO2H CONHPh CONH-4-MeC6H4 CONH-4-MeC6H4 CONH-4-MeOC6H4 CONH-4-MeOC6H4 CONHNHPh

% Yield

Reference

77 68 64 90 87–94 87–94 87–94 87–94 90

508 508 508 510 510 510 510 510 510

7.4.1.3. From Other Unsaturated 5(4H)-Oxazolones There are cases in which appropriate modification of one unsaturated oxazolone yields a new unsaturated oxazolone analogue. Most of the examples described in the literature involve modification of the substituent on the exocyclic double bond. For example, a series of 4-[2-hydroxy-3-(aminomethyl)benzylidene]-5(4H)-oxazolones 382 that were evaluated for bactericidal and fungicidal activities were obtained from Mannich reaction of 4-(2-hydroxybenzylidene)-5(4H)-oxazolones 381 (Scheme 7.123).511 The exocyclic double bond of 4-arylidene-5(4H)oxazolones 383 reacts with diazomethane in a 1,3-dipolar cycloaddition reaction to give the corresponding

HO

H

HO

O CH2O/HN(R2)2

N

R2

O

H

O

N N

R2

O R1

R1 381

382 Scheme 7.123

218

5(2H)-Oxazolones and 5(4H)-Oxazolones H

N

O CH2N2

Ar N

N

H

O

Ar

N

R

R 383

H

O

Ar

O

N

DMF

Me

O

O +

O

Ar N

R

R

384

O

385

386

Scheme 7.124

spiropyrazolines 384, which usually cannot be isolated. Further reaction of 384 gives a mixture of diastereomeric spiroxazolones 386 together with a 4-(aarylethylidene)-5(4H)-oxazolone 385 in which the double-bond geometry of 383 has been retained (Scheme 7.124). The ratio of the isolated products depends on the stereochemistry of the starting oxazolone and on the experimental conditions of the cycloaddition reaction. Starting from (Z)-oxazolones the 4(a-arylethylidene)-5(4H)-oxazolone 385 is the major product when the reaction is carried out in polar solvents.477,512 Representative examples are shown in Table 7.35 (Fig. 7.46). The synthesis and reactivity of 4-heteromethylene-2-substituted-5(4H)-oxazolones has been reviewed.513 These readily available compounds are easily interconverted using a classical addition–elimination reaction (Scheme 7.125).

TABLE 7.35. SYNTHESIS OF 4-(a-ARYLETHYLIDENE)-5(4H)OXAZOLONES FROM REACTION OF 4-ARYLIDENE-5(4H)OXAZOLONES WITH DIAZOMETHANEa

H

Me

O CH2N2

R1 N

O

O

R1

DMF

R2

N

O R2

Figure 7.46 R1

R2

Ph 4-MeOC6H4 4-MeC6H4 Ph 4-MeOC6H4 4-MeC6H4

Me Me Me Ph Ph Ph

a

Data from Ref. 477.

% Yield 42 33 28 48 50 30

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) R1 Ac2O

CO2H

R1C(OR2)3 +

O

R2O

O

N

NHCOPh

219

Ph 387 H

R

O X2/CHCl3

R N

O

O

X

O

N

X = Cl, Br

Ph

Ph 389

388 H Ac2O

X

CO2H

H

O

H

R1O−

X

O

N

X = Cl, Br

O R1O−

R1O

H

N

CO2H

O +

O

NHCOPh

H

NHCOPh Ph

Ph 390

391

H

H

O R3

HO

O

N

R2S−

HN(R3)2

SOCl2

N R3

H

O

N

Ph

O

R 2S

O

N

Ph

392

O Ph

394

393

Scheme 7.125

Reaction of unsaturated 5(4H)-oxazolones with appropriate nucleophiles affords new unsaturated 5(4H)-oxazolone analogues used as intermediates to prepare a variety of interesting compounds. 4-(Chloromethylene)-5(4H)-oxazolones react with a variety of nucleophiles. For example, 4-(chloromethylene)-2-phenyl5(4H)-oxazolone 395 reacts with imidazole to afford 4-[(imidazol-1-yl)methylene]-2-phenyl-5(4H)-oxazolone 396.514 The authors found no evidence for the product derived from carbon–carbon bond formation, that is, 4-[(imidazol-4yl)methylene]-2-phenyl-5(4H)-oxazolone (Scheme 7.126). N

H

O

Cl N

O

H

O

N

N

H

N

N

O Ph

Ph 395

396

Scheme 7.126

220

5(2H)-Oxazolones and 5(4H)-Oxazolones

The displacement of the chlorine atom in 395 by triphenylphosphine or other phosphorus derivatives leads to the corresponding phosphorylated oxazolones 397 or 398 that have been used to prepare new and interesting substituted vinylphosphonium salts (Scheme 7.127).515,516 Of particular interest is the synthesis of Nacyl-a-(triphenylphosphonio)glycinates as new cationic glycine equivalents.517 H

Cl (R)3P

O

(R)3P

O

N

Ph

H

O

Cl

397

O

N

Ph H

395 R1R2POEt

O

R1 P R2 O

O

N

Ph 398

Scheme 7.127

Displacement of the chlorine atom in 395 by sodium thiomethoxide or other mercaptans was reported recently.518 The same authors also described an efficient synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones 399 from 395 and organostannanes via palladium catalyzed Stille reaction (Scheme 7.128).519 Selected examples are shown in Table 7.36 (Fig. 7.47). TABLE 7.36. SYNTHESIS OF 4-ARYLIDENE-2-PHENYL5(4H)-OXAZOLONES FROM STILLE REACTION OF 4-(CHLOROMETHYLENE)-2-PHENYL-5(4H)-OXAZOLONEa

H

H

O (n-Bu)3SnR2

X

O

N

R2 N

R1 R1

X

Ph Ph Ph Ph

Cl Cl Cl Cl

a

Data from Ref. 519.

O O R1

Figure 7.47 R2 Ph 4-MeOC6H4 fur-2-yl thien-2-yl

% Yield 98 80 97 82

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

H

O

Cl

O

N

O

R

(n-Bu)3SnR

221

O

N

(PPh3)2BnClPd

Ph

Ph 395

399

Scheme 7.128

The reaction of 4-(dichloromethylene)-2-phenyl-5(4H)-oxazolone 400 and triphenylphosphine affords the vinylphosphonium salt 401, from which N-benzoyl (triphenylphosphoranylidene)ketenimine 403 is obtained by hydrolytic ring opening of 401 and subsequent treatment of 402 with triethylamine (Scheme 7.129).520 Cl

O

Cl

O

N

Cl

Cl PPh3

Cl

O H2O

Ph3P N

CO2

Ph3P

O

NHCOPh

Ph

Ph 400

401

402 Et3N

Ph3P

C C NCOPh 403

Scheme 7.129

4-(Ethoxymethylene)-2-phenyl-5(4H)-oxazolone 404, readily available from hippuric acid and triethyl orthoformate, has also been used as a starting material for other unsaturated oxazolones via addition–elimination reactions. Nitrogen nucleophiles are most commonly used and amines give rise to 4-(aminomethylene)-2-phenyl-5(4H)-oxazolones 405 (Scheme 7.130; Table 7.37, Fig. 7.48) which, in many cases have been evaluated as antihypertensives.521–526 TABLE 7.37. SYNTHESIS OF 4-(AMINOMETHYLENE)-5(4H)-OXAZOLONES FROM 4-HETEROMETHYLENE-5(4H)-OXAZOLONES

H

H

O R2R3NH

X N

O

O

R2R3N

O

N

R1

R1 Figure 7.48

R1

X

Ph Ph Ph Ph

Cl Cl Cl EtO

R2R3N imidazol-1-yl 2-methylimidazol-1-yl 4-methylimidazol-1-yl 2-MeOC6H4CH2NH

% Yield

Reference

 50  50  50 97

514 514 514 522

222

5(2H)-Oxazolones and 5(4H)-Oxazolones H CO2H

CH(OEt)3

H

O RNH2

EtO

O

N

NHCOPh

O

RHN

O

N

Ph

Ph 404

405

Scheme 7.130

Heterocyclic amines also react as nucleophiles and, in this context, indole reacts with 404 to yield the unsaturated oxazolone 406, an intermediate in the synthesis of tryptophan (Scheme 7.131).527,528 It is noteworthy that 406 is the product of carbon– carbon bond formation. Imidazole also reacts with 404 but in this case the product is 396, identical with that obtained from the 4-(chloromethylene) derivative 395.528 H

O

H

N

O

H

EtO N

O Ph

O

N

N

Ph

H 406

404

Scheme 7.131

4-(Hydroxymethylene)-2-phenyl-5(4H)-oxazolone 392, obtained from 404, can be used to prepare indoles 408, pyrazoles 409, and fused 1,2,4-triazoles 411 by reaction with phenylhydrazines529 or heteroarylhydrazines.530 Selected examples are shown in Scheme 7.132. NHCOPh PPA

CO2Et N H

H N

PhNHNH2

408 CO2Et

N

NHCOPh

EtOH

407 H

PhCONH

O NaOH

HO

O

N

HO

N

N Ph

Ph 409 392 H N NHNH2

N CO2Et

N

Pb(OAc) 4

N

N

NHCOPh

N

PhCONH

N

410

Scheme 7.132

411

CO2Et

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

223

4-(Aminomethylene)-5(4H)-oxazolones 412 have also been used as starting materials to prepare unsaturated oxazolones. Alkylation of the exocyclic nitrogen gives 4-(N,N-disubstituted-1-aminoalkylidene)-5(4H)-oxazolones 413 that are intermediates for peptides, pharmaceuticals and pesticides (Scheme 7.133).531,532 Heterocyclic rings such benzimidazole or benzotriazole have been prepared as well (Scheme 7.134).533 H

H

O

R2HN

O

N

R3X

R2

O

N

O

N

R3 R1

R1

412

413

Scheme 7.133 H N

O

N

O

N

NH2 H

H

O

N

N X R

O R

414

415 X = CH, N

Scheme 7.134

Carefully controlled base hydrolysis of a 2-aryl-4-(dimethylaminomethylene)5(4H)-oxazolone 416 affords a 2-aryl-4-(hydroxymethylene)-5(4H)-oxazolone 417 (Scheme 7.135).534 H Me

N

O

N

Me

H

O NaOEt

O

HO N

KOH

Ar

O Ar

416

417

Scheme 7.135

4-(Aminomethylene)-2-phenyl-5(4H)-oxazolone 418 has been converted to 4(alkylthiomethylene)-2-phenyl-5(4H)-oxazolones 419 by treatment with carbon disulfide and subsequent alkylation. These 4-(alkylthiomethylene) analogues are useful intermediates for biologically active peptides, pharmaceuticals, and plantprotective agents (Scheme 7.136; Table 7.38, Fig. 7.49).535,536 H

H

O 1) CS2/NaH

H2N N

O 2) RX

O

RS N

O Ph

Ph 418

419

Scheme 7.136

224

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.38. SYNTHESIS OF 4-(ALKYLTHIOMETHYLENE)5(4H)-OXAZOLONES FROM 4-(AMINOMETHYLENE)-5(4H)OXAZOLONESa

H

H

O CS2/NaH

X

O

N

O

R2S

O

N

R2X

R1

R1 Figure 7.49

R1

X

R2

Ph Ph Ph

H2 N H2 N H2 N

Me Pr PhCH2

a

% Yield 84 85 68

Data from Ref. 536.

Transamination reactions have also been described for 4-(aminomethylene)-2substituted-5(4H)-oxazolones. As an example, displacement of the N-methylheteroarylamino group of a 4-[(N-heteroaryl-N-methyl)aminomethylene]-2-phenyl-5(4H)-oxazolone 420 by an a-amino acid derivative produces b-amino-a,bdehydro-a-amino acid precursors 421 (Scheme 7.137).537 Me H

N Me

N

O

R1

CO2R2 NH2

N N

Me

H

R1 N

R2O2C

O

O

H

O

N

Ph

Ph 420

421

Scheme 7.137

Enamine exchange with the weakly basic amino group of 4-(aminomethylene)2-phenyl-5(4H)-oxazolone 418 leads to the 4-[(N-cycloalkenyl)aminomethylene]5(4H)-oxazolones 422, that thermally cyclize to afford [b]-fused bicyclic 4-pyridones 423 (Scheme 7.138).538 X

H

O

O

H2N N

O Ac2O

H

X

N

H

O N Me

N

Ph 418

O

O

NHCOPh

X

O

N

N Ph

422 X = CH2, O, S, CH2CH2, bond

Scheme 7.138

H 423

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

225

4-(N,N-Dimethylaminomethylene)-2-phenyl-5(4H)-oxazolone and 4-(anilinomethylene)-2-phenyl-5(4H)-oxazolone react readily with primary alkylamines via transamination to provide an efficient route to 4-(alkylaminomethylene)-2-phenyl5(4H)-oxazolones.539 Reaction of hippuric acid and N,N-dimethylacetamide in the presence of phosphorous oxychloride affords 4-[1-(dimethylamino)ethylidene]-2-phenyl5(4H)-oxazolone 424540 that is converted to 4-benzoylaminopyrazolones 425 via ring opening and cyclization with hydrazines (Scheme 7.139).540 4-(N,N-Dimethylaminomethylene)-2-substituted-5(4H)-oxazolones react similarly.541 Me Me CO2H +

Me

POCl3/DMF

Me

O

N

NHCOPh

R

O

Me

N

O

1) HCl/MeOH

N

O

N

N

H

2) RNHNH2

Me

PhCONH

Ph 424

Me

425

Scheme 7.139

4-[2-Bromo-1-(dimethylaminoethylidene)]-2-phenyl-5(4H)-oxazolone 426, obtained by bromination of 424, reacts with N,N-dimethyl-N 0 -heteroarylformamidines to afford the interesting heterocyclic unsaturated oxazolones 428 (Scheme 7.140).542 Me

Me Me

BrCH2

O Me

Br2

N

O

N

Me

O

N X

N Me

N

N

R

Me

N

O X = CH, N

Ph

Ph 424

426 Me N

R X Me

N

N

N

N R X Me

O

N Me

Me

Br

O

N N Me N

Ph

O O Ph

427

428 Scheme 7.140

Finally, 4-[(1,2,4-oxadiazol-3-yl)aminomethylene]-2-phenyl-5(4H)-oxazolone 430 has been prepared from 4-[(cyanoamino)methylene]-2-phenyl-5(4H)-oxazolone 429 (Scheme 7.141).543

226

5(2H)-Oxazolones and 5(4H)-Oxazolones H NC

H

N

O

O

O N N

H

N

N

O

N

H

Ph

O Ph

429

430 Scheme 7.141

7.4.2.

Ring-Opening Reactions

In general, unsaturated oxazolones are very useful synthetic intermediates. In this context, one of the most important reactions is the classical nucleophilic opening of the oxazolone ring; the key-step in the synthesis of a wide array of compounds. Hydrolysis, alcoholysis, aminolysis, hydrazinolysis, as well as many other reactions of 2-alkyl(aryl)-4-arylidene-5(4H)-oxazolones,544–546 2-alkyl(aryl)4-heteroarylidene-5(4H)-oxazolones,547–552 or 2-20 -(m-phenylene)bis[4-arylidene5(4H)-oxazolones]553 lead to heterocyclic ring opening to afford the corresponding acids, esters, amides, hydrazides, hydroxamic acids, etc. (Scheme 7.142). In some cases, sonication has been used to promote the nucleophilic ring opening.554 R3

O

R2 N

O

R3 CONu

Nu-H

R2

NHCOR1

R1 431

432

Nu-H = HO-H, RO-H, R 2N-H, RNHNH-H, H2NO-H...... Scheme 7.142

In this chapter, when the product arising from the ring opening is used as a synthetic intermediate, the subsequent reaction of this intermediate will be also considered.

7.4.2.1. Hydrolysis and Alcoholysis One of the fundamental cleavage reactions of the heterocyclic ring in unsaturated oxazolones is the conversion to acids or esters. This process leads to dehydroamino acid derivatives from which a wide variety of amino acids are prepared by hydrogenation. The side chain of the final amino acid is determined by the aldehyde used to prepare the unsaturated oxazolone. For example, benzaldehyde and an N-acylglycine afford 2-acylaminocinnamic acids 434 after hydrolysis of the oxazolone 433.555–557 In turn, 434 are excellent precursors to phenylalanine.

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

O

Ph N

227

H HO−

O

CO2H

Ph

NHCOR R 433

434 Scheme 7.143

The mechanism of the hydrolysis of 4-benzylidene-2-methyl(phenyl)-5 (4H)-oxazolone has been studied.558 There are several general procedures to prepare 2-acylamino-3-arylpropenoic acids that employ various experimental conditions559–561 including phase-transfer catalyzed hydrolysis.562,563 In addition, general procedures for alcoholysis of unsaturated oxazolones leading to the corresponding acrylates have been published.564 Hydrolysis and alcoholysis have been applied to prepare compounds of special interest. For example, 2-acylamino2-butenoic acid esters prepared from 2-methoxyacetaldehyde have been evaluated as plant growth regulators.565 2-Methoxy-1-naphthaldehyde has been used to generate an unsaturated oxazolone that was hydrolyzed to the corresponding acrylic acid using barium hydroxide in aqueous alcohol.566 Other acrylic acid derivatives that have herbicidal activity567 or are useful intermediates for the synthesis of the antiinflammatory agent lonazolac have been prepared via this methodology.568 Other alcohols ring-open unsaturated oxazolones including glycerol that was used to prepare monoglycerides of acylamino acids.569 In addition, alcoholysis with 3,4,4-trifluorobut-3-enol leads to amino acid fluorobutenyl esters that are used as pesticides.570 Finally, (dimethylamino)ethanol571 and other amino alcohols572 have also been used to obtain the corresponding aminoalkyl esters. The hydrolysis and alcoholysis reactions have been extended to the heterocyclic series. A systematic study has been published of the hydrolysis of unsaturated oxazolones derived from a selection of heterocyclic aldehydes.573 A detailed study574 of the synthesis and stereospecific hydrolysis and methanolysis of the (Z) and (E) isomers of 2-methyl (or phenyl)-4-(thienylmethylene)-5(4H)-oxazolones 435 and 437 has also been described (Scheme 7.144). The synthesis of 2-acylamino-3-(indol-3-yl or carbazol-3-yl)acrylic acid derivatives as potential antifertility agents via oxazolone hydrolysis has also been published.575 H

R2OH

Het N

O

Het

H

O

CO2R2

Het

NHCOR1

R2OH

H N

R1 435

Het

O O

H

CO2R2 NHCOR1

R1 437

436

438 Het = heterocycle

Scheme 7.144

228

5(2H)-Oxazolones and 5(4H)-Oxazolones

4-Heteromethylene-5(4H)-oxazolones 439 show similar behavior to that described above. Hydrolysis or alcoholysis of 439 provides the corresponding b-substituted acrylic acids or acrylates 440 (Scheme 7.145). In this context, ring-opening reactions of 4-bis[(methylthio)methylene]- and 4-bis[(benzylthio)methylene]-,576 4-(alkylaminomethylene)-,577 4-(dialkylaminomethylene)-,578 and other 4-heteromethylene-5(4H)-oxazolones579 have recently been described. R3

O

R3 R4OH

R2X N

O

CO2R4

R2X

NHCOR1 R1

439

440 Scheme 7.145

Both stereoisomers of a 4-(a-arylethylidene)-5(4H)-oxazolone 441 and 443, undergo stereospecific hydrolysis–methanolysis to furnish the corresponding (Z) and (E) isomers of 2-acetylamino(or benzoylamino)-3-aryl-2-butenoic acid or methyl ester, 442 and 444, respectively (Scheme 7.146).580,581 The requisite starting oxazolones were prepared by condensation of an acetophenone with an acylglycine or by methylene insertion into the vinyl C H bond of a 4-arylidene-5(4H)oxazolone. Me

Me

O R2OH

Ar N

O

CO2R2

Ar

NHCOR1 R1

441

442

HBr

Ar

Ar

O R2OH

Me N

O

CO2R2

Me

NHCOR1

R1 443

444 Scheme 7.146

If the starting N-acylamino acid contains a leaving group in the acyl group moiety then hydrolysis of the corresponding oxazolone 445 generates an acrylic acid derivative such as 446. Treatment of 446 with ammonia then produces glycyl(b-aryl)-dehydroalanines 447.582 This interesting procedure opens the way for the

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

229

synthesis of peptides directly incorporating dehydroamino acids (Scheme 7.147). Representative examples of dehydroamino acids and esters prepared via hydrolysis and alcoholysis of unsaturated 5(4H)-oxazolones are shown in Table 7.39 (Fig. 7.50). H

O

R N

H

H

HO−

O

NH3

CO2H

R

R

NHCOCH2Cl

CH2Cl 445

CO2H NHCOCH2NH2

446

447

Scheme 7.147 TABLE 7.39. N-ACYL DEHYDROAMINO ACIDS AND ESTERS FROM HYDROLYSIS AND ALCOHOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES

R1

O

R1 R4O

R2 N

O

R2

CO2R4 NHCOR3

R3 R1

R2

R3

Figure 7.50 R4

% Yield

Reference

H H H H H H H H H H H H H H H H H H H Me Me Me Me

Ph Ph 3-NO2C6H4 fur-2-yl PhCH CH thien-2-yl pyrid-3-yl quinol-3-yl thien-2-yl pyrid-3-yl quinol-3-yl Ph 4-MeOC6H4 4-MeC6H4 thien-2-yl thien-2-yl thien-3-yl thien-2-yl thien-3-yl Ph 4-MeOC6H4 Ph 4-MeOC6H4

Me Ph Ph Ph Ph Me Me Me Ph Ph Ph CH2Cl CH2Cl CH2Cl CH2Cl Me Me Ph Ph Me Me Ph Ph

H H H H H H H H H H H H H H H Me Me Me Me Me Me Me Me

98 60 58 55 84 50 70 65 70 48 50 72 45 75 93 81 73 87 65 87 85 95 93

560 559 559 559 559 573 573 573 573 573 573 582 582 582 582 574 574 574 574 581 581 581 581

230

5(2H)-Oxazolones and 5(4H)-Oxazolones

More drastic hydrolysis conditions of unsaturated oxazolones 448 leads to further hydrolysis of the intermediate 2-acylamino-2-alkenoic acid 449 and produces the corresponding a-keto acids 450. For example, phenylpyruvic acid583,584 and other aryl(heteroaryl)pyruvic acids585–587 of biological interest have been obtained in this manner (Scheme 7.148). H

O

H

H H+conc

R2

O

N

CO2H

R2

CO2H

R2 O

NHCOR1 R1

448

449

450

Scheme 7.148

The a-keto acids are extremely versatile intermediates. For example, reduction of an arylpyruvic acid 450 yields the corresponding b-aryllactic acid 451,588,589 condensation of 450 with amines followed by reduction affords amino acid derivatives 454,590 and condensation of 450 with hydroxylamine yields a-oximinoacids 452 as shown in Scheme 7.149.591 H

H CO2H

R2

H CO2H

R2

OH 451

CO2H

R2

O

N

450

452

H

OH

H CO2H

R2 N

R3

453

CO2H

R2

NHR3 454

Scheme 7.149

The dehydroamino acids or esters obtained have been used as intermediates to prepare a diverse array of interesting compounds and some important, representative examples are described in the following sections. CATALYTIC HYDROGENATION OF DEHYDROAMINO ACID DERIVATIVES. Probably the most important reaction of dehydroamino acid derivatives obtained from 5(4H)-oxazolones is hydrogenation of the double bond. Typically, this reaction is performed

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

231

using catalytic systems such as Raney Ni, Na/Hg, or a metal on a support and leads to amino acids after removal of the protecting groups. Among such metal systems, Pd/C or other supports is used most frequently and usually leads to easy and quantitative hydrogenations. This general methodology is a well-known procedure and is especially useful for the synthesis of phenylalanine,592 aryl-substituted analogues of phenylalanine,593–600 tyrosine analogues,601,602 and 3,4-dihydroxyphenylalanine (DOPA).603 In all cases, the amino acids are prepared from the corresponding benzaldehyde and proceed via the intermediate unsaturated oxazolone. In the heterocyclic series, racemic 3-(fur-2-yl)alanine has been prepared from furfural using this approach.604 In addition, b-(pyrid-3-yl)alanine,605 b-(quinol-3yl)alanine,606 a b-(benzofuranyl)alanine derivative,607 2-amino-3-(2,20 -bipyridinyl)propanoic acid,608 and some interesting derivatives of histidines—in particular 1-alkylhistidines with amphiphilic properties609 have all been synthesized using this methodology. The complete reaction sequence starting from an aldehyde and an N-acylamino acid derivative is shown in Scheme 7.150. H H O + R2

CO2H NHCOR1

Ac2O

R2

NaOAc

H

O Nu-H

N

O

CONu

R2

NHCOR1

R1 455 [H2]

CONu

R2

NHCOR1 457

456 H3O+

CO2H

R2

NH2 458

Scheme 7.150

Racemic [3-11C] phenylalanine and [3-11C] DOPA have been prepared using this methodology starting with aldehydes labeled at the carbonyl carbon.610 In addition, fluorine-containing amino acids such as N-acylated 2- and 4-fluorophenylalanines,611,612 4-(polyfluoromethyl)phenylalanines,613,614 4-(trifluoromethyl)valine,615 3-(2,6-difluoro-3,4-dihydroxyphenyl)alanine,616 as well as other fluoro analogues of amino acids617,618 have all been prepared starting from the appropriate fluorinecontaining carbonyl compound. New metallocene phenylalanine analogues were obtained from the appropriate aldehyde following similar methodology. For example, the unsaturated oxazolone prepared from cyclopentadienylcarboxaldehyde manganese tricarbonyl is an intermediate in the synthesis of the corresponding phenylalanine analogue.619 Several cases warrant special mention. As an example, ring opening, hydrogenation, and subsequent transformations of the 5(4H)-oxazolone 459 derived from 2,3-dihydroxy-4-methoxybenzaldehyde affords a biomimetic synthesis of racemic stizolobinic acid 463 as shown in Scheme 7.151.620

232

5(2H)-Oxazolones and 5(4H)-Oxazolones OBn H

OBn H

O

BnO

MeOH

N

MeO

CO2Me

BnO

O

H2/Pd-C

NHCOAr

MeO Ar

459

460 CO2H

OH CO2Me

HO

NHCOAr

MeO

AcOH/AcOOH

CO2Me

MeO

Fe(OAc) 2OH

HO2C

HCl

NHAr

462

461

O CO2H

O

NH2

HO2C 463 Scheme 7.151

Hydrogenation of the double bond in dehydroamino acids prepared from unsaturated 5(4H)-oxazolones derived from unsymmetrical ketones gives rise to two stereogenic centers. As a consequence, four stereoisomers are possible. If the hydrogenation of each geometric isomer is performed separately, then the erythro and threo pair of enantiomers can be obtained independently. In this respect, the unsaturated oxazolones from 2-butanone have been prepared as a (Z/E) mixture. The mixture was separated and each stereoisomer was independently converted to the erythro and threo pairs of enantiomers.621 The geometric isomers 464 and 467 of 5(4H)-oxazolones prepared from acetophenones can be separated. Alternatively, the mixture can be isomerized under the appropriate reaction conditions to obtain the pure of (Z) or (E) isomer. Each isomer can be converted to a pair of enantiomers 466 and 469 (only one enantiomer shown) (Scheme 7.152).622 The b-methyl phenylalanine analogues thus obtained are constrained phenylalanines and the effect of incorporation of a bMePhe or b-MeTyr residue on the biological properties of H-Tyr-Tic-Phe-Phe-NH2 (TIPP, where Tic ¼ 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) a delta opioid receptor antagonist, has been studied.623 The traditional approaches to obtain enantiomerically pure amino acid derivatives from racemic amino acids involve classical chemical resolution using chiral amines624 or enzymatic procedures using hydrolytic enzymes.593–595,603, 605–608,617,618 Alternatively, the diastereoselective or enantioselective hydrogenation of the double bond has been explored as a means to prepare amino acid derivatives asymmetrically. To that end ring opening of an unsaturated oxazolone with a chiral alcohol followed by hydrogenation of the double bond has been investigated but the degree of asymmetric induction is usually not very high.

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Me

Me

O NaOH

Ar

O

N

233

Me CO2H

Ar

NHCOPh

1) H2/Pd-C

CO2H

Ar

NH2

2) HBr

Ph 464 Py

465

466

HBr

Ar

Ar

O NaOH

Me N

O

Me CO2H

Me

NHCOPh

1) H2/Pd-C 2) HBr

CO2H

Ar

NH2

Ph 467

468

469

Scheme 7.152

Asymmetric hydrogenation of dehydroamino acids or their esters with homogeneous organometallic catalysts containing chiral ligands has revolutionized the synthesis of enantiomerically pure amino acids. Many modifications have been described in terms of the nature of the catalyst and/or the nature of the amino acid obtained. Rhodium catalysts that incorporate chiral ligands, particularly diphosphines or aminophosphines among others are usually the most efficient. Starting from the requisite unsaturated 5(4H)-oxazolone such rhodium catalysts permit access to phenylalanine,625 most analogues of phenylalanine,626–628 and a wide variety of fluorine-containing phenylalanines,629 all obtained with extremely high enantiomeric purity. Of particular interest is the synthesis of L-4-boronophenylalanine (BPA) in 96% ee starting from the oxazolone derived from 4-boronobenzaldehyde.630 In the heterocyclic series several heteroarylalanines have been obtained by asymmetric hydrogenation using chiral homogeneous catalysts. For example, replacement of the phenyl ring by furan, thiophene, selenophene, pyridine, or indole yields furylalanines,631,632 thienylalanines,633 2- and 3-selenienylalanines,634 3- and 4-pyridylalanines,635,636 or tryptophan,637 respectively. A comparative study of the reaction rates and enantioselectivities in substrates with different heterocyclic rings during homogeneous catalytic hydrogenation has been reported.638 A study on the combined use of a chiral substrate obtained by alcoholysis of a 4benzylidene-5(4H)-oxazolone with a chiral alcohol coupled with hydrogenation using a chiral catalyst has also been described.639 This work shows that the matching effect of double asymmetric induction in hydrogenation can be modulated by a solvent effect. In the case of electron-rich aromatic rings, for example, 472 it is possible to take advantage of the activating substituents to effect a Pictet–Spengler reaction to prepare the tetrahydroisoquinoline derivative 473 as shown in Scheme 7.153.640

234

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H

O

MeO O

N

MeO

MeO

R2OH

CO2R2

1) H2/Cat*

NHCOR1

MeO

2) HCl

R1 470

471

MeO

CO2H

HCHO

NH2

MeO

MeO

CO2H NH2 Cl

HCl

MeO

472

473 Scheme 7.153

1,3-DIPOLAR CYCLOADDITION REACTIONS. Dehydroamino acid derivatives behave as dipolarophiles in 1,3-dipolar cycloaddition reactions that leads to a variety of interesting compounds. For example, 1,3-dipolar cycloaddition of diazomethane to dehydroamino acid esters 475 and 481 gives the corresponding pyrazolines 476 and hv

H R2

CO2R3 NHCOR1 477

H

R3OH

R2

O

N

Me

N

H

O

CO2R3

R2

CH2N2

N

H R2

∆

CO2R3 NHCOR1

NHCOR1

CO2R3

R2

NHCOR1

R1 474

475

476

478 H N N

BF3

R2 CO2R3 479 R2

R3OH

H N

O

N

R2

O H

CO2R3

CH2N2

R2 H

NHCOR1

N CO2R3 NHCOR1

∆ or hv

R2 H

CO2R3 NHCOR1

R1 480

482

481 Scheme 7.154

483

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

235

482. Thermal or photochemical extrusion of nitrogen from trans-pyrazolines, for example, 482 gives trans-cyclopropylamino acid derivatives 483.641 Photochemical decomposition of cis-pyrazolines 476 leads to cis-cyclopropylamino acid derivatives 477,642–644 whereas thermal decomposition of 476 affords the corresponding 2-acylamino-2-butenoic acid derivatives 478 via methylene insertion into the vinyl C H bond.581 Moreover, in the presence of a Lewis acid, cis-pyrazolines eliminate the acylamino substituent to afford the corresponding 4-substituted-pyrazole-3carboxylic acid esters 479 (Scheme 7.154).645,646 1,3-Dipolar cycloadditions of nitrile oxides647 and nitrile imines647,648 with dehydroamino acid derivatives have also been described. DECARBOXYLATION. Under certain experimental conditions dehydroamino acid derivatives can decarboxylate to produce unsaturated benzamides. In particular, N-[2-(p-hydroxyphenyl)ethyl]-p-chlorobenzamide649 and N-(E)-(4-methoxystyryl)benzamide (alatamide)650 have been prepared in this manner. SYNTHESIS OF HETEROCYCLIC COMPOUNDS. In some cases, dehydroamino acids obtained from unsaturated 5(4H)-oxazolones have been used as intermediates to prepare other heterocyclic compounds. For example, reaction of 2-benzoylamino-3substituted-2-alkenoic acids 485 with alkyl or arylisothiocyanates affords 4-arylmethylene-1,2-disubstituted-5-oxo-4,5-dihydroimidazoles 486 (Scheme 7.155).651 H

HO

R1 N

O

H

H

O

CO2H

R1

NHCOPh

R2N=C=S

O

R1 N

Ph 484

N R2 Ph

485

486

Scheme 7.155

Depending on the reaction conditions used for hydrolysis, either 3-benzoylamino-5-methylpyran-2-one 489 or 3-methylpyrrole 492 have been obtained from the 3-ethoxy-2-methylpropanal derived unsaturated oxazolone 487 (Scheme 7.156).652 Nitrosation of methyl 2-acylamino-3-(dimethylamino)propenoates 494 obtained from the corresponding oxazolones 493 effects the conversion of N-acylglycines to 5-substituted-1,2,4-oxadiazole-3-carboxylates 496 as shown in Scheme 7.157.653

7.4.2.2. Aminolysis with Amines and Related Compounds In general, the reaction of unsaturated 5(4H)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds.

236

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H

O

Me EtO

NaOH

O

N

O

acetone

HO

∆

O

N

NHCOPh

Me

Me

O

O Ph

Ph 487

488

489

KOH/MeOH

H Me

HCl

Me

N

2) NaOMe

NHCOPh

EtO

CO2Me

1) HCl

CO2Me

490

Me

∆

H

N

491

H

492

Scheme 7.156

H Me

N Me

H

O

N

O

Me

R2OH

CO2R2

N Me

HNO2

HO

N

NHCOR1

CO2R2

−H2O

NHCOR1

R1 493

494

495 CO2R2

N O N R1

496 Scheme 7.157

There are a number of comprehensive studies reported of the reactions of a particular unsaturated oxazolone with nitrogen nucleophiles.654–657 On the other hand, unsaturated 5(4H)-oxazolones react with a variety of amines to yield acylamino amides with interesting agrochemical properties.658–661 R3

O

R3

R4NH2

R2 N

O

R2

CONHR4 NHCOR1

R1

498

497 Scheme 7.158

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

237

The mechanism of the aminolysis662 and the electronic effects of substituents at C-2 or C-4 on the kinetics of amide bond formation have been studied.663 In some cases, ring opening with amines occurs with partial isomerization of the exocyclic double bond. However, with more hindered compounds, such as unsaturated oxazolones derived from ketones, ring opening is stereospecific.664,665 Ring opening using diamines has also been described.666 Selected examples of dehydroamino acid amides prepared by aminolysis of unsaturated 5(4H)-oxazolones are shown in Table 7.40 (Fig. 7.51). The direct condensation of unsaturated oxazolones with tryptamine in hydrochloric acid is an important and interesting case that deserves special attention. The reaction occurs via in situ hydrolysis of the oxazolone to a keto acid followed by a Pictet–Spengler-like reaction with tryptamine. This protocol affords a tetrahydro-bcarboline wherein the oxazolone is the synthetic equivalent of an arylacetaldehyde.667 The reaction has been extended to substituted tryptamines 500 thus, allowing access to 1,3,4-trisubstituted tetrahydro-b-carbolines 501 as shown in Scheme 7.159.668–675 Some of these compounds have shown promising central nervous system activity. Bis-4-arylidene-5(4H)-oxazolones are easily obtained from aromatic dialdehydes by the Erlenmeyer synthesis. Such bis(oxazolones) react with a,o-diamines to provide a convenient approach to macrolactams.676 Tandem Erlenmeyer condensation-macrolactamization (TECM) has been used to prepare analogues of naturally occurring, biologically active cyclic peptides such as bastadin-5.

TABLE 7.40. N-ACYLDEHYDROAMINO ACID AMIDES FROM AMINOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES

R1

O

R1 R4NH2

R2 N

O

R2

CONHR4 NHCOR3

R3 Figure 7.51 R4

R1

R2

R3

H H H H H Me Ph Me Ph Me Ph

4-CNC6H4 Ph Ph Ph Ph Ph Me Ph Me Ph Me

Ph Ph Ph Ph Me Ph Ph Ph Ph Ph Ph

i-Pr Ph n-Bu PhCH2 Ph 4-MeC6H4 4-MeC6H4 4-MeOC6H4 4-MeOC6H4 PhCH2 PhCH2

% Yield

Reference

83 88 93 80 90 68 69 71 79 98 86

658 684 684 684 684 664 664 664 664 664 664

238

5(2H)-Oxazolones and 5(4H)-Oxazolones R5

R4 H

O

R5

R4

NH2

N H

HCl

R2

O + R 3

N

R1 499

R3

N R6

R2

N R6

500

501 Scheme 7.159

CYCLIZATION OF DEHYDROAMINO AMIDES TO IMIDAZOLONES. Aminolysis of unsaturated oxazolones has been studied extensively. However, the major focus has been directed to use of the resulting acylamino amides as starting materials to prepare novel heterocyclic compounds. Among these possibilities, cyclization of acylamino amides to unsaturated imidazolinones has been studied in great depth given that these compounds have a diverse range of biological and pharmacological activities. Hundreds of unsaturated oxazolones with a wide variety of substituents at C-2 and C-4 have been described. Most of these compounds were reacted with amines to give the corresponding acylamino amide that can be cyclized to the corresponding imidazolinones. The shear number of compounds described makes coverage of this area beyond the scope of this chapter. Generally speaking, cyclization occurs in the presence of a cyclodehydrating agent to give 4-alkylidene(arylidene)-1,2-disubstituted-2-imidazolin-5(4H)-ones 504 in which the configuration of the exocyclic double bond is retained (Scheme 7.160). The most typical case is exemplified by the reaction of 4-arylidene-5(4H)-oxazolones with a wide variety of substituted anilines or alkylamines and subsequent cyclization of the product. Indeed, numerous papers have been published on this subject677–692 and many pharmacological assays have been performed on the resulting products. R3 R2 N

O

R3

R3

O R4NH2

R2

CONHR4 NHCOR1

−H2O

O

R2 N

R1 502

N R4 R1

503

504

Scheme 7.160

For amides obtained by stereospecific ring opening of (Z)- and (E)-2-phenyl-4(a-phenylethylidene)-5(4H)-oxazolone 505 and 508, cyclization gives the imidazolone 510 or 4-methyl-1-phenyl-3-isoquinolinecarboxylic acid anilide 507. The products are determined by the double-bond geometry in the starting material and by the experimental conditions (Scheme 7.161).693

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) Me

PhNH2

Ph

O

N

Me

Me

O

CONHPh

Ph

CONHPh

POCl3

N

NHCOPh Ph

Ph

505

506

507 AcOH/NaOAc

HBr

Ph

PhNH2

N

Me

Ph

O

Me

239

O

CONHPh

Me

NHCOPh

AcOH

O

Ph N

NaOAc

N Ph Ph

Ph 508

509

510

Scheme 7.161

Aminolysis of 1,4-phenylene bis(oxazolones) 511 and subsequent cyclization to the bis-2-imidazolin-5(4H)-ones 513 has also been described (Scheme 7.162).694 N 1 -(Sulfonamidophenyl)imidazolones are of particular interest as antineoplastic, antibacterial, and antifungal agents and a number of examples have been prepared analogously using the appropriate sulfonamidoaniline.695–697 O

O PhCH

PhCH N

PhCH

CONHR

O

N

NHOC RNH2

O

NH4OAc

COHN

N CHPh

RHNOC

R N CHPh

N CHPh

O

O 511

N R

512

513

Scheme 7.162

Diamines have also been used to ring-open unsaturated 5(4H)-oxazolones. Here, one amino group reacts with the oxazolone while the other amino group is used to incorporate other substituents. Examples include aliphatic diamines,698–700 ophenylenediamines,701,702 and p-phenylenediamines.703–709 Heterocyclic amines have also been used for aminolysis. Subsequent cyclization of the acylamino amides leads to imidazolones that show a diverse range of biological activities as antibacterial, antifungal, antiviral, antihelmintic, and anti-Parkinsonian agents, as well as central nervous systems (CNS) stimulants.

240

5(2H)-Oxazolones and 5(4H)-Oxazolones

Noteworthy among these systems are aminopyrazolones,710 3-aminoindoles,711 2-aminothiazoles,712–715 2-amino-1,3,4-oxadiazoles,716 2-amino-1,3,4-thiadiazoles,717–720 and aminoquinazolinones721–724 together with other heterocyclic compounds.725–732 Unsaturated 5(4H)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride,733 antipyrine,734 chromone,735 indoles,736–739 pyridines,740 quinolines,741 diazines,742 benzoxazoles,743 and benzimidazoles744 have been prepared. Reaction with nitrogen nucleophiles and subsequent cyclization leads to the expected 5(4H)-imidazolones. Amino acids745–747 and aminobenzoic acids748,749 react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4H)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity.

7.4.2.3. Reductive Aminolysis Ring opening of unsaturated 5(4H)-oxazolones 514 with a chiral amine, usually (S)-a-phenylethylamine (although chiral amino acids can be also used), in the presence of a catalyst under a hydrogen atmosphere is an excellent procedure for the direct synthesis of chiral amino acid precursors 515. The reaction occurs sequentially via hydrogenation of the dehydroamino acid that is generated in situ from ring opening of the oxazolone. This method has been applied for the synthesis of numerous amino acids with moderate optical purity (Scheme 7.163; Table 7.41, Fig. 7.52).47,48,750–757 Prior to the development of efficient chiral catalysts for enantioselective hydrogenation of dehydroamino acid derivatives, this procedure was explored as an interesting methodology for the asymmetric synthesis of new non-proteinogenic amino acids. H

Me

O

Me H2N

R2 N

Ph

O H2, PdCl2

R2

CONH Ph NHCOR1

R1 514

515 Scheme 7.163

The influence of different variables including the solvent758–760 and experimental conditions761–767 has been studied and attempts to improve the results using polymer-bonded palladium catalysts768 or chiral palladium-containing macromolecular catalysts769 have been reported. The reductive cleavage of heteromethylene oxazolones using NaBH4 in the presence of NH3 has generated racemic b(heteroarylamino)-a-amino acid derivatives.770

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

241

TABLE 7.41. N-ACYLAMINO ACID AMIDES FROM REDUCTIVE AMINOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES

R1

O

R1 R4NH2

R2

O

N

redn

CONHR4

R2

NHCOR3

R3 R1

R2

Figure 7.52 R3

R4

% Yield

Reference

H H H H Me Me H H H H H

Ph 4-AcOC6H4 Ph 4-AcOC6H4 Me Et 3-MeO-4-AcOC6H3 pyrimidin-2-yl 4-chloro-6-methylpyrimidin-2-yl 6-chloropyridazin-3-yl pyrazinyl

Me Me Ph Ph Ph Ph Ph Ph Ph Ph Ph

PhMeCH PhMeCH PhMeCH PhMeCH PhMeCH PhMeCH PhMeCH H H H H

90–95 90–95 90–95 90–95 90–95 90–95 98 36 55 60 39

753 753 753 753 753 753 762 770 770 770 770

7.4.2.4. Aminolysis with Amino Acids Unsaturated 5(4H)-oxazolones react with amino acids to produce acylamino amides. Ring closure of the acylamino amides leads to the corresponding imidazolinones (cf. Section 7.4.2.2) or, alternatively, to 3-ylidenepiperazine-2,5-diones that are versatile organic substrates.771 Ring opening in the presence of hydrogen and a catalyst affords the corresponding amino acid derivatives (cf. Section 7.4.2.3). However, ring opening in the absence of a reducing agent generates an a,bdehydropeptide. a,b-Dehydropeptides are very interesting compounds that are found in natural peptides of biological interest. In addition, incorporation of an a,b-dehydropeptide residue into peptides can restrict the conformational freedom of the peptide thereby allowing the design of new compounds with improved biological and pharmacological properties. Therefore, suitable unsaturated oxazolones can be used as intermediates to prepare dehydropeptides wherein the synthetic strategy used will depend on the position of the double bond in the final compound. If the double bond is located in the N-terminal amino acid, ring opening of the oxazolone 516 with the appropriate amino acid or peptide generates the desired dehydropeptide 517 directly.772–775 This reaction, shown in Scheme 7.164, has been used frequently starting from 4-arylmethylene-776–778 or 4-heteroarylmethylene-5(4H)-oxazolones reacting with a series of amino acid esters.779–781

242

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H2N

O

CO2R4

O

R3

R2 N

O

R1

R1

H

R2 N

C

H

O

516

H N

CO2R4 R3

517 Scheme 7.164

This synthetic strategy has been used to prepare some interesting dehydropeptides such as chromophoric dehydro analogues of leucine enkephalin,782 potential angiotensin-converting enzyme inhibitors,783 and dehydropeptides substituted with a b-lactam moiety.784 Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4H)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame,785 somatostatin,786 and dermorphin.787 In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. position 2

HO−

H

N

C

H

O

PHN

OH

O position 1

R2

519

O

N position 1

R2

R1

H position 2

O

NHP R1

position 2

518 H2N

CO2R4

O R3

R2

PHN R1

H

N

C

H

O

position 1 520 Scheme 7.165

H N

CO2R4 R3

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

243

SYNTHESIS OF PEPTIDES BY HYDROGENATION OF DEHYDROPEPTIDES. In addition to the interest in dehydropeptides in their own right, these compounds are also used to prepare non-proteinogenic peptides by simple reduction. For example, the electrochemical reduction of dehydropeptides derived from 2,3-dimethoxybenzaldehyde has been described.788 Asymmetric reduction of the double bond of the dehydroamino acid residue in 522 can be effected in different ways since the peptide moiety can act as a chiral auxiliary. Heterogeneous hydrogenations using a Pd/C catalyst are the most frequently used conditions.789 Among the different amino acids evaluated as chiral auxiliaries, proline is the auxiliary of choice and has led to the best diastereodifferentiation.790 It is noteworthy that complexation of a dehydropeptide with Ca2þ or Mg2þ prior to hydrogenation has been reported to improve diastereoselection.791 In cases where a glycine moiety is used, an asymmetric hydrogenation has to be performed (Scheme 7.166). For achiral dehydroamino acids the influence of ligand chirality on the enantioselectivity of hydrogenation has been studied.792

O

H2, cat

R1 H

O

H2N

CO2R4 R3

R2 N

O

R1

N H

R1 521

O

R2

H C

R2 N

C

H

O

CO2R4 R3

523

H N

O

H N

CO2R4 R3

522 O

H2, Rh-L* R3 = H

R1

R2

H

N

C

H

O

N

CO2R4

524 Scheme 7.166

Finally, the appropriate combination of both chiral auxiliary and chiral organometallic catalyst can lead to excellent levels of stereodifferentiation.793–796

7.4.2.5. Other Nitrogen Nucleophiles Other nitrogen nucleophiles such as hydrazines, hydrazides, and Schiff bases have affected ring opening of oxazolones. Most often, hydrazine or substituted hydrazines are used. For example, hydrazinolysis of 525 affords the corresponding hydrazides 526 that, depending upon the substituents and the reaction conditions, can cyclize in the reaction medium to the aminoimidazolone 527 (Scheme 7.167;

244

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H

O H2N-HNR3

R2 N

O

H CONH-NHR3

R2

O

R2

NHCOR1

N

R1

N NHR3 R1

525

526

527

Scheme 7.167

Table 7.42, Fig. 7.53).797–809 Starting from an (E)-oxazolone affords an (E)configured hydrazide.797–798 Hydrazinolysis products obtained from oxazolones 528 are versatile synthetic intermediates and can be further elaborated to a variety of different heterocycles depending on the substituents and on the experimental conditions. For example, Naminoimidazolones 529, isolated from reaction of 528 and hydrazine, have been acylated810 or condensed with carbonyl compounds811 to produce 530 and 531, respectively. On the other hand, ring-opening 528 with hydrazine affords a dehydroamino acid hydrazide 532. Condensation of 532 with aldehydes yields a hydrazone 533 that can be cyclized to an N-iminoimidazolone 534 (Scheme 7.168).812

TABLE 7.42. a-ACYLAMINO HYDRAZIDES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH HYDRAZINES

H

O

H H2N-NHR3

R1 N

O

CONHNHR3

R1

NHCOR2

R2

Figure 7.53 R1

R2

Me 4-ClC6H4 4-NO2C6H4 3,4-(MeO)2C6H3 2-HOC6H4 Ph fur-2-yl Ph fur-2-yl 4-chloro-6-methylpyrimidin-2-yl 4,6-dimethylpyrimidin-4-yl 6-chloropyridazin-3-yl

Me Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

R3 H H H H H H H Ph Ph H H H

% Yield

Reference

22–52 22–52 22–52 22–52 22–52 90 72 60 70 92 55 65

798 798 798 798 798 799 799 799 799 770 770 770

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

O

R2

R3CHO

245

N N CHR3

N

R1 531 H

H

O H2N

R2 N

NH2

R3COCl

R2

O

O

R2

N NH2

N

R1

N NHCOR3

N

R1

528 H2N

H

O

R1 530

529 NH2

H H R2

H

R3CHO

CONH-NH2

POCl3

CONH-N=CHR3

R2

NHCOR1

O

R2

N N=CHR3

N NHCOR1

532

R1

533

534

Scheme 7.168

In some cases triazines have been reported from the reaction of unsaturated oxazolones with hydrazine813 or via alkaline cyclization of the initially formed acylamino hydrazide.799 For example, cyclization of an acylamino hydrazide by heating in the presence of sodium hydroxide affords 1,2,4-triazin-6-ones 537.814–817 In contrast, heating an acylamino hydrazide in the absence of base leads to pyrazolidin-5-ones 536 (Scheme 7.169).814–817 In the particular case where the original oxazolone was derived from cyclohexanone, a spiropyrazolidin-5-one was obtained.818 O

∆

R1CONH N H N

R2 H

O

N

O R1

536

H H2 N

R2

NH2

R2

H

CONH-NH2 NHCOR1 O

535

∆ NaOH

H

R2CH2

N N

N R1

537

Scheme 7.169

246

5(2H)-Oxazolones and 5(4H)-Oxazolones

Pyrazolinoxazolines have been isolated, albeit in low yields, from the reaction of some oxazolones with phenylhydrazine.819 Hydrazides have also been used as nucleophiles for ring opening to give the corresponding bis(acylhydrazides) 540.820 Subsequent cyclodehydration of 540 leads to the 4-alkylidene(arylidene)imidazolones 541 that have been evaluated as anticonvulsant, antihelmintic, antibacterial, antifungal, antiviral, and antitubercular agents (Scheme 7.170).821–824 H

H

O H2N-NHCOR3

R2

CONH-NHCOR3

R2

O

N

H −H2O

O

R2

NHCOR1

N

R1

N NHCOR3 R1

539

540

541

Scheme 7.170

Reaction of 4-(ethoxymethylene)-2-phenyl-5(4H)-oxazolone 542 with a hydrazide gives 1-acyl-3-hydroxy-1H-pyrazoles 544 via an addition–elimination sequence to generate 543 followed by cyclization as shown in Scheme 7.171.825

H

H

O H2N-NHCOR

EtO N

O

N N

RCONHNH

O

RCO

N

O

OH NHCOPh

Ph

Ph 542

543

544

Scheme 7.171

Schiff bases also react with unsaturated 5(4H)-oxazolones and afford different products depending on the substituent at C-2. With 2-methyl-5(4H)-oxazolones 545 as starting materials, 2-styryl-1-substituted imidazolones 546 are obtained (Scheme 7.172).826–830 Selected examples are shown in Table 7.43 (Fig. 7.54). H

H

O R2CH=NR3

R1 N

O

O

R1 N

N R3 CH=CHR2

CH3 545

546 Scheme 7.172

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

247

TABLE 7.43. 2-STYRYL-1-SUBSTITUTED IMIDAZOLONES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH SCHIFF BASES

H

H

O R1CH=NR2

Ph

Ph

O

N

O N R2

N CH3

CH=CHR1 Figure 7.54

R1

R2

Ph Ph 3-NO2C6H4 Ph Ph

Ph 4-ClC6H4 Ph 4-MeC6H4 4-MeOC6H4

% Yield 85 63 66 67 68

Reference 826 826 826 827 827

On the other hand, if a 2-phenyl-5(4H)-oxazolone 547 is the starting material, N-(benzoyl)dehydroamino acid amides 548 or unsaturated imidazolones 549 are obtained depending on the reaction conditions (Scheme 7.173).831 H R2CH=NR3

CONHR3

R1

NHCOPh

H

O 548

R1 N

O Ph H

547 R2CH=NR3

O

R1

NaOAc/HOAc

N

N R3 Ph

549 Scheme 7.173

7.4.2.6. 1,3-Bis(nucleophiles) Reaction of unsaturated 5(4H)-oxazolones with bis(nucleophiles) opens the way for the preparation of diverse heterocyclic compounds depending on the nucleophilic atoms of the reagent. First, if we consider nitrogen-containing bis(nucleophiles), the reaction of anthranilic acid with unsaturated oxazolones 550 gives rise to substituted 3,1-benzoxazin-4-ones 551 (Scheme 7.174).832–840

248

5(2H)-Oxazolones and 5(4H)-Oxazolones H R2 N

O

O

O

O

H

HO

O +

N

R2

H2N R1

NHCOR1

550

551 Scheme 7.174

A widely used bis(nucleophile) is o-phenylenediamine. Several heterocyclic systems have been synthesized depending on the experimental conditions, although benzimidazoles 555 are obtained as the major reaction products (Scheme 7.175).841–847 Alternatively, ring-opening 552 with o-phenylenediamine can produce an N 0 -(2-aminophenyl)imidazolone 553 that cyclizes to an imidazobenzimidazole 554. A complete study of the reactivity of 4-arylidene-2-phenyl-5(4H)oxazolones with various nitrogen-containing bis(nucleophiles) and evaluation of the products as antimicrobial agents has recently been published.848

H

H

O H2N

R2 N

NaOAc

N

N

R2

HOAc

N

N

R1

R1 553

554

NaOAc

H

H

O

R2 N

O

N

R2

H2N + HOAc

H2N

R1COHN

N H

R1 552

555 Scheme 7.175

o-Aminothiophenol also reacts analogously as a bis(nucleophile) to afford benzothiazoles.842,849 Finally, 1,8-diaminonaphthalene reacts with unsaturated 5(4H)-oxazolones to afford perimidines.850 Examples of benzimidazoles and benzothiazoles derived from unsaturated 5(4H)-oxazolones are shown in Table 7.44 (Fig. 7.55). Azoles or azines with an amino group at C-2 have also been used as bis(nucleophiles) to prepare a variety of fused heterocyclic systems. In these cases, the geometry of the bis(nucleophile) permits reaction with both electrophilic centers of the oxazolone. Thus, initial Michael reaction and subsequent ring

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

249

TABLE 7.44. BENZIMIDAZOLES AND BENZOTHIAZOLES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH 2-SUBSTITUTED ANILINES

H

H2N

O

R1

H N

R1

HY

O

N

R2COHN

Y

R2 Figure 7.55 R1

R2

Ph 4-MeOC6H4 4-NO2C6H4 Ph 4-ClC6H4 thien-2-yl Ph 4-MeOC6H4 Ph 4-ClC6H4 thien-2-yl Ph 4-MeOC6H4

Y

Ph Ph Ph Ph Ph Ph 4-NO2C6H4 4-NO2C6H4 Ph Ph Ph 4-NO2C6H4 4-NO2C6H4

NH NH NH NH NH NH NH NH S S S S S

% Yield

Reference

70–75 70–75 70–75 72 78 66 75 70 56 72 55 75 75

841 841 841 842 842 842 842 842 842 842 842 842 842

opening of the oxazolone leads to new heterocyclic compounds. The nature of the bis(nucleophile) and the b-substituent at the C-4 vinyl group determine the structure of the products. Among the 2-aminoheterocycles employed in this reaction are 2-aminopyridines851 (Scheme 7.176) and 2-aminoazoles852 including pyrazoles,853–855 imidazoles,856 thiazoles,851 oxadiazoles,857–859 thiadiazoles,858,860 and triazoles853–855 (Scheme 7.177). R2

O

O

EtO N

N

O + H2N

R1CONH R2

N N

R1 556

557 Scheme 7.176

Reaction of a-hydrazinoheterocycles with 4-(hydroxymethylene)-2-phenyl5(4H)-oxazolone 406 gives rise to N-benzoyl-a-(heteroaryl)glycinates 563 containing a fused 1,2,4-triazole after oxidative cyclization (Scheme 7.178).861 Urea, thiourea, and S-alkylisothiouronium halides have also been used as bis(nucleophiles) in reactions with unsaturated oxazolones.862–865 Reaction with urea and thiourea leads to the corresponding imidazolones. The use of

250

5(2H)-Oxazolones and 5(4H)-Oxazolones H

O

O R1CONH

N X′

EtO

O +

N

H2N

X

N X′

H

N

X

R1 558 H

559 O

O R1CONH

N X′

R2

O

N

+

H2N

X

N X′

R2

N

X

R1 560

561

Scheme 7.177 H

H

O NHNH2

HO N

EtOH

Pb(OAc) 4

N

N

O +

N

N

N

N

N

Ph

CO2Et

PhCOHN

406

PhCOHN

CO2Et

563

562

Scheme 7.178

S-alkylisothiouronium halides usually leads to 2-amino-5-imidazolones 565 although in some cases, depending on the substituents and on the experimental conditions, other products such as pyrimidines 566 have been obtained.862 In this case, Michael reaction and ring opening lead to the observed product (Scheme 7.179). H

H2N SR3 NH HCl

O

R2 N

H

NH2 565

O

R2

N H

O

N

R1 564 H2N SR3 NH HCl

R1CONH HO

Et3N

N N

R2 = OEt

566 Scheme 7.179

SR3

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

251

Antimicrobial imidazotriazoles 568 are obtained when a hydrazidimide, for example, 5-nitro-2-furancarboximidic acid hydrazide, reacts as the bis(nucleophile) with 567 (Scheme 7.180).866

H R2 N

H

R2

O

N

H2N

O +

NO2

O

N

N N

H2NN

O

R1

R1 567

NO2

568 Scheme 7.180

A variety of N,S-bis(nucleophiles) react with unsaturated 5(4H)-oxazolones to produce triazolo-1,3-thiazin-4-ones 570 and 1,3-thiazin-4-ones 572. Mechanistically, Michael addition of the bis(nucleophile) to 569 and 571 followed by ring opening with concomitant cyclization leads to the observed products. 3-Mercapto-1,2,4-triazoles,867–869 2-imidazolidinethione, 2-mercaptobenzimidazole,870 and N-substituted dithiocarbamic acids871–873 have also been used frequently as bis(nucleophiles) (Scheme 7.181). N N

H

O

R3

SH

N H

R2 N

O R1CONH

O

569 H

R3NH

O

O

S HS

N

N N

S 570

O

R2

N

R2

R1

R3

R1CONH

N

R2

R1 571

S

R3 S

572 Scheme 7.181

Bis(nucleophiles) involving carbon atoms also react with unsaturated 5(4H)oxazolones. Among these, enamines874–877 and other related compounds such as iminophosphoranes878 and 2-benzimidazolyl-, 2-benzoxazolyl-, and 2-benzothiazolylacetates879,880 are commonly used. A mechanistically similar process involving initial Michael reaction to the exocyclic double bond followed by ring opening gives 2-pyridones. The degree of unsaturation in the 2-pyridone depends on the

252

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H

N

R3

O

O

R1CONH

N

R4

R2 N

R2 R1

R4

573

574 H

H

R3

O

N

R2

O

O

EtO

O

N

R1CONH

N

R3

R2

R3

R1 575

576 Scheme 7.182

N H

O

O

O n

R2 N

O R1

NHCOR1 n

577

R2 578

Scheme 7.183

starting unsaturated 5(4H)-oxazolones; 4-alkylidene(arylidene)-5(4H)-oxazolones 573 lead to dihydropyridone derivatives 574, whereas 4-(ethoxymethylene)-5(4H)oxazolones 575 give pyridones 576 (Scheme 7.182). Bis C-alkylation is observed using N,N-disubstituted enamines of cycloalkanones and leads to the bicyclic b-diketones 578 (Scheme 7.183).881 Reaction of suitably functionalized phosphonium ylides with unsaturated 5(4H)oxazolones 579 has opened the way for the use of new C,C-bis(nucleophiles). Of particular interest is ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate used to prepare dihydrobenzoxazoles 582 and diastereoisomeric 1,3-cyclohexanedione ylides 583 (Scheme 7.184).882 In contrast, ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate behaves as a C,O-bis(nucleophile) when reacted with unsaturated 5(4H)-oxazolones 584 with a leaving group at the exocyclic b-carbon.883 In this case, initial Michael reaction generates 585 that eliminates HX to produce a resonance stabilized ylide 586. Cyclization of 586 with ring opening leads to the interesting ylide intermediate 587 used for the synthesis of 2H-pyran-2-ones (Scheme 7.185).

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) PPh3 O

H

O

O

O

PPh3 O

O

O EtO2C

O

N

PPh3

EtO2C

EtO2C

R2

253

R2

R1

N

O N

R2

R1

R1 579

580

581 OH EtO2C R2

O N R1 582 + O PPh3

EtO2C

O

R2

NHCOR1 583 Scheme 7.184

PPh3 PPh3 O

H

O

O

PPh3 O

EtO2C

EtO2C

X N

O

O O

O −XH

EtO2C

N

R1

X = EtO, Cl R1 584

O

N

X

R1 585

586 PPh3 EtO2C

O O NHCOR1 587

Scheme 7.185

254

5(2H)-Oxazolones and 5(4H)-Oxazolones

Similar reactivity was observed with typical activated methylene compounds such as dimethyl 1,3-acetonedicarboxylate. With this C,O-bis(nucleophile) the products are also 2H-pyran-2-ones 589 (Scheme 7.186).884 CO2Me

CO2Me

O

H

O

MeO2C

MeO2C

EtO

O

O

N

O R1

NHCOR1

588

589

Scheme 7.186

7.4.2.7. Other Nucleophiles A variety of other nucleophiles effect ring opening of unsaturated 5(4H)oxazolones. Reaction with active methylene compounds containing an electrophilic center is a known procedure to prepare heterocyclic compounds through ring opening and subsequent cyclization.885–887 For example, reaction of unsaturated 5(4H)-oxazolones 590 with alkyl cyanoacetates gives 3-acylamino-1-cyano-2hydroxy-4-substituted-1,3-butadiencarboxylates 591 that are cyclized to pyrrolidin-3-ones 592 (Scheme 7.187). H

O

R2 N

H

CO2Et

K

HO H

CN

O

EtOH/∆

R2

R1

O

CO2Et CN NHCOR1

590

R2

CO2Et

N

HCl(g)

H

591

NH2 592

Scheme 7.187

Reaction of 4-arylidene-2-phenyl-5(4H)-oxazolones 593 with N-phenacylpyridinium bromide888 proceeds by the same sequence to give oxazolo[5,4-b]pyridines 594 (Scheme 7.188) while the reaction of 4-(aminomethylene)-2-phenyl-5(4H)oxazolone 418 and phenyl isothiocyanate889 gives pyrimidin-2-thiones 595 (Scheme 7.189). In this latter case initial attack of the exocylic amino group produces an intermediate thiourea (not shown) that subsequently cyclizes to 595. Ph H

O

N

O

+

Ph

O

Br Ar

N

N

O

NH4OAc

Ph N

AcOH

Ar

Ph 593

594

Scheme 7.188

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

S

O

H2N

H N

PhN=C=S

O

N

255

Ph

N

O Ph

NHCOPh

418

595 Scheme 7.189

Hydride reduction of a 4-arylidene-5(4H)-oxazolone can also be considered as a nucleophilic ring opening. Here, this process, shown in Scheme 7.190, generates a(benzoylamino)cinnamyl alcohols 597.890 H

O

H LiAlH4

Ar

O

N

CH2OH

Ar

NHCOPh Ph 596

597 Scheme 7.190

Unsaturated 5(4H)-oxazolones undergo a Friedel–Crafts reaction with aromatic hydrocarbons in the presence of a Lewis acid. In particular, a 2-aryl-4-benzylidene5(4H)-oxazolone 598 reacts with o- or p-xylene in the presence of aluminum chloride via ring opening and subsequent dearylation to yield 599 as indicated in Scheme 7.191.891 H

Me

O

Me AlCl3

Ph N

O +

ArCONHCH2CO Me

Me

Ar 598

599 Scheme 7.191

In a similar manner, an intramolecular Friedel–Crafts reaction of 2-aryl-4(2-thienylidine)-5(4H)-oxazolones 600 has been reported and, in this case, cyclization and decarboxylation generates thienopyridines 601 (Scheme 7.192).892 H

O

S

S

L.A.

N

O Ar

600

N Ar 601

Scheme 7.192

256

5(2H)-Oxazolones and 5(4H)-Oxazolones

Finally, the intramolecular ring opening of unsaturated 5(4H)-oxazolones derived from 2-hydroxybenzaldehyde is noteworthy. Here, the condensation of hippuric acid and 2-hydroxybenzaldehyde under classical conditions gives a 3(acylamino)coumarin 602 directly without isolation of an intermediate oxazolone.893 Suitably protected 2-hydroxybenzaldehyde derivatives react similarly (Scheme 7.193).894–896 CHO

NHCOPh

NHCOPh

Ac2O

+ NaOAc

CO2H

OR

O

O 602

Scheme 7.193

Deacetylation of 4-[(o-acetoxy)benzylidene]-2-phenyl-5(4H)-oxazolone also immediately affords 602. The starting oxazolone was obtained by cyclodehydration of the corresponding cinnamic acid precursor or by condensation of hippuric acid with 2-acetoxybenzaldehyde in the absence of base. In examples using 2-hydroxyacetophenone, 4-methyl-3-(acylamino)coumarins are obtained.897 7.4.3.

Reactions Involving the Exocyclic Double Bond

Classical ring-opening reactions of unsaturated oxazolones are the most well studied reactions and generate a wide variety of interesting products. However, reactions of the exocyclic double bond have also been investigated and open the way to a tremendous variety of new possibilities.

7.4.3.1. Hydrogenation It is well known that hydrogenation of dehydroamino acid derivatives derived from ring opening of unsaturated 5(4H)-oxazolones affords new racemic amino acids and, in some cases, enantiomerically pure compounds. On the other hand, a number of attempts have been made to hydrogenate the double bond of the unsaturated oxazolone itself. For example, 4-benzyl-2-methyl-5(4H)-oxazolone was prepared from 4-benzylidene-2-methyl-5(4H)-oxazolone using Raney Ni as a catalyst. This process is reported to be a general procedure to prepare saturated oxazolones directly (Scheme 7.194).898,899 R3

R3

O [H2]

R2 N

O

O

R2 N

R1 603

R1 604

Scheme 7.194

O

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

257

Reduction in the presence of methanolic sodium methoxide produces the corresponding N-acetylphenylalanine methyl ester as the final product.900,901 Enzymatic resolution of N-acetylphenylalanine methyl ester then gives phenylalanine in high enantiomeric purity. Magnesium in methanol has also been used to produce nearly quantitative yields of the N-acetylphenylalanine methyl ester without isolation of the intermediate saturated oxazolone.902 Catalytic hydrogenation of the (E)-unsaturated oxazolone 605 and the (Z)unsaturated oxazolone 608, both derived from acetoxyacetone, affords 606 and 609 respectively. Subsequent ring opening of 606 and 609 generated erythro and threo diastereoisomers of racemic g-hydroxyvaline acetates 607 and 610 (Scheme 7.195).903 Further, enantioselective oxidation of the D- or L-enantiomer with D- or L-amino acid oxidase gives the corresponding a-keto acid. The unreacted enantiomer was isolated by ion exchange chromatography.

AcOCH2

AcOCH2

O H2, Pd/C

Me

O

N

O

AcOCH 2 1) HCl

Me

O

N

Ph

NH2

Ph

605

606

Me

H2, Pd/C

N

607

Me

O

AcOCH2

CO2H

Me 2) NH3

O

O

AcOCH2 1) HCl

AcOCH2 N

Ph

O

CO2H

Me 2) NH3

NH2

Ph

608

609

610

Scheme 7.195

Catalytic hydrogenation of the exocyclic double bond of several oxazolones 611, in the presence of acetic acid, gives a-acylamino alcohols 613 via the saturated derivatives 612 (Scheme 7.196).904 Selected examples of amino acid derivatives and amino alcohols available from reduction of unsaturated oxazolones are shown in Table 7.45 (Fig. 7.56).

R3

R3

O H2, Pd/C

R2 N

O AcOH

O

R2 N

R1 611

O R1

612 Scheme 7.196

R3 R2

CH2OH NHCOR1 613

258

5(2H)-Oxazolones and 5(4H)-Oxazolones

TABLE 7.45. AMINO ACID, AMINO ESTER AND AMINO ALCOHOL DERIVATIVES FROM HYDROGENATION OF UNSATURATED 5(4H)-OXAZOLONES

R1

R1

O [H]

R2

R2

O

N

O O

N

R3

R1 X

R2 Y

R3 Figure 7.56

R2

R1 H Me AcOCH2 H H Me

Ph AcOCH2 Me 4-MeOC6H4 Ph Me

R3

X

Y

Me Ph Ph Ph Ph Ph

CO2Me CO2H CO2H CH2OH CH2OH CH2OH

NHCOMe NH2 NH2 NHCOPh NHCOPh NHCOPh

% Yield 95 74 91 50 60 60

Reference 900 903 903 904 904 904

7.4.3.2. Michael Reactions Some examples of the Michael reaction on the exocyclic double bond of an unsaturated oxazolone have been discussed in previous sections. The synthesis of unsaturated 5(4H)-oxazolones from unsaturated 5(4H)-oxazolones via an addition– elimination sequence and the sequential reaction of unsaturated 5(4H)-oxazolones with a 1,3-bis(nucleophile) have already been considered. This section will review Michael additions exclusively and, in this respect, a wide array of nucleophiles has been studied. Although it is well known that sulfur nucleophiles are excellent candidates for Michael reactions, they have scarcely been examined with unsaturated oxazolones. Nevertheless, 4-methyltoluene-a-thiol reacts with 4-benzylidene-2-methyl-5 (4H)-oxazolone 614 to give 615 as a mixture of erythro and threo isomers (Scheme 7.197).905 Ring opening 615 to the methyl ester and separation gives rise to a procedure for the synthesis of S-(4-methylbenzyl)-b-phenylcysteine. Carboxypeptidase A

O

Ph

SH

PhCH N

O

O

S

Me

Me

N

Me

O Me

614

615 Scheme 7.197

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

259

conveniently resolves the N-(trifluoroacetyl)- derivatives of erythro and threo S-(4methylbenzyl)-b-phenylcysteine. Organophosphorous compounds have also been used as nucleophiles with unsaturated oxazolones. Initially, Michael reaction of a trialkyl- or dialkylphosphite gives 617 or 619 that undergo subsequent ring opening to yield a 2-acylamino-3phosphonyl-618 or 2-acylamino-3-phosphinyl-620 derivative of the corresponding carboxylic acid, respectively (Scheme 7.198).906–909

R3O

P

OR3

O

R3O

R3 O

R2

O

P

R3O

N

O

R3O

O

R2 CONu

P

R3O

NHCOR1

R1

R2CH 617

O

N

O

Nu

618

R1 616 R3O

P

O

R3O

OR3

R4

R2

O

P

R4

N

O

R3O

Nu

O

R2 CONu

P

R4

NHCOR1

R1 619

620

Scheme 7.198

4-benzylidene-2-phenyl-5(4H)-oxazolone 621 reacts with hexamethylphosphorus triamide to give 4-a-[bis(dimethylamino)phosphoryl]benzyl-5-(dimethylamino)-2-phenyloxazole 622 (Scheme 7.199).910 H

O

Ph

O P(NMe2)3

N

Ph

NMe2

(Me2N)2 P

O

N

Ph

O Ph

621

622 Scheme 7.199

For carbon nucleophiles sequential addition of 2-potassio-2-nitropropane and oxygen to 4-arylidene-2-phenyl-5(4H)-oxazolones 623 has been reported (Scheme 7.200).911 The process involves a Michael reaction of the 2-nitropropane anion followed by reaction with molecular oxygen and elimination of nitrous acid to yield 2-aryl butenoic acid imides 626. Previously, Friedel–Crafts alkylation of unsaturated oxazolones with xylenes leading to the ring-opened products was described in Section 7.4.2.7. In contrast,

260

5(2H)-Oxazolones and 5(4H)-Oxazolones Me

H

O

O NO2

Ar

Me

O

N

NO2

Me K

Ar

Me

N

Ph

K

O

Ar O2

Me Me

Ph

623

624

−NO2H

O NO2 NHCOPh 625 Ar Me

O Me

NHCOPh 626

Scheme 7.200

Ph PhCH N

O

O

Me

O Me

N

O

O

N

AlCl3

O

N

O

Me

O

CHPh

Ph 627

628 Scheme 7.201

reaction of 2,20 -(1,4-phenylene)-bis(4-phenylmethylene)-5(4H)-oxazolone 627 with toluene in the presence of aluminium trichloride gives the addition adduct 628 (Scheme 7.201).912 Sulfur ylides are among the most interesting carbon nucleophiles and their synthetic importance has been recently reviewed.913 One especially interesting use of these ylides is their application to the synthesis of cyclopropane derivatives using unsaturated oxazolones. For example, stabilized sulfur ylides react with unsaturated oxazolones 629 via a Michael reaction to give oxazolone spirocyclopropanes 630 as shown in Scheme 7.202 and Table 7.46 (Fig. 7.57), whereas the less stabilized sulfur ylides give ring-opened products 631 as the major compounds (Scheme 7.202).914,915 Starting from the chiral oxazolone 632 derived from 1,2-O-isopropylidene-Dglyceraldehyde, diastereoselective cyclopropanation has been reported to occur with dimethyloxosulfonium methylide or (diethylamino)phenyloxosulfonium

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

261

TABLE 7.46. OXAZOLONE SPIROCYCLOPROPANES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH A STABILIZED SULFUR YLIDEa

R1

R1

O Me2S=CHCOPh

R2

R2

O

N

O

PhCO

O

N

R3

R3 Figure 7.57

R1

R2

R3

% Yield

H H H H H Me

Ph 4-AcOC6H4 PhCH CH furan-2-yl 1-acetylindol-3-yl Me

Ph Ph Ph Ph Ph Ph

85 68 59 57 49 84

a

Data from Ref. 914.

methylide as cyclopropanating agents (Scheme 7.203).916 The reaction produces mixtures of cis- and trans-spirooxazolones 633 and 634. The influence of the oxosulfonium methylide and experimental conditions on the cis/trans ratio and on cis and trans diastereoselectivities has been studied. The results are complementary to those obtained from cyclopropanation of 632 using diazomethane (see scheme 7.217). The use of chiral oxazolone 632 provides an entry to versatile precursors leading to enantiomerically pure 2-substituted-1-aminocyclopropanecarboxylic acids. R3

R3

O Me2S=CHCOPh

R2 PhCO

R3 Me2S=CH2

R2

O

N

O O

N

NHCOR1

R1

R1 630

COCH=SMe2

R2

629

631

Scheme 7.202

O H

O

O

Me Me

N

O

O Ph

Ph Et2N

H

O S

CH2

or O S

O

O N

O

633 Scheme 7.203

O

H N

Ph

CH2

632

O +

O

O Ph

634

262

5(2H)-Oxazolones and 5(4H)-Oxazolones

7.4.3.3. 1,3-Dipolar Cycloadditions During the last two decades, the importance of the dipolarophilic nature of unsaturated 5(4H)-oxazolones has been widely recognized and studied with a variety of 1,3-dipoles. Among the systems studied, diazoalkanes, particularly diazomethane, are the most frequently used and have opened the way for the synthesis of aminocyclopropanecarboxylic acid derivatives. There are a number of stereochemical considerations that have to be taken into account in this reaction. 1,3-Dipolar cycloaddition with diazoalkanes occurs to generate an intermediate spiropyrazoline 636 that, in most cases has not been isolated. The presence of EWG on the alkene moiety results in the formation of only one regioisomer of the spiropyrazoline. Two competitive processes are possible upon decomposition of the spiropyrazoline and, apart from the formation of cyclopropane derivatives 637 and 638, homologation of the starting unsaturated 5(4H)-oxazolone to afford 639 is also possible. The stereochemistry of the starting oxazolone, the experimental reaction conditions and the nature and polarity of the solvent can all result in C-methylene insertion as the main reaction.512 Moreover, the decomposition of pyrazolines is not a stereospecific reaction although partial retention of configuration is usually observed. Mixtures of cis- and trans-cyclopropane derivatives are obtained in which the predominant product retains the same relative configuration as the starting compound (Scheme 7.204). H

N

O CH2N2

R2 N

O

H R2

N N

O

636

R2

O

R2 N

R1

R1 635

H

O

O +

O

H

O +

N

R1

R1 637

638 Me

O

R2 N

O R1

639

Scheme 7.204

Since (Z)- and (E)-stereoisomers of unsaturated oxazolones can be obtained using appropriate isomerization procedures, cis and trans isomers of cyclopropane derivatives can be obtained in a stereoselective manner, although special care must be taken with experimental conditions to obtain the best stereoselectivity. Both racemic cis- and trans-1-amino-2-phenylcyclopropanecarboxylic acid 641 and 644 have been obtained from the corresponding (Z)- or (E)-4-benzylidene-2-phenyl5(4H)-oxazolone 621 and 642 using diazomethane. Care was taken to affect the

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

H

O CH2N2

Ph

O

N

O

Ph

O

N

Ph

H Ph

263

CO2H NH2

Ph

621

640

641

HBr

Ph

Ph

O CH2N2

H N

O

O

N

Ph 642

Ph CO2H

H

O

H

NH2

Ph 643

644

Scheme 7.205

nucleophilic ring opening of the oxazolone to avoid cleavage of the cyclopropane ring (Scheme 7.205).422 Extension of this reaction to other 4-arylmethylene-5(4H)-oxazolones and a careful study of the cyclopropanation of (Z)-4-(ethylidene)-2-phenyl-5(4H)-oxazolone have also been reported.917,918 This methodology was used to prepare cyclopropyl tyrosine and 1-amino-2-(4-hydroxyphenyl)cyclopropanecarboxylic acid.919 However, all attempts to obtain 1-amino-2-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid, the cyclopropane analogue of DOPA via cyclopropanation of the oxazolone were unsuccessful. In this case, the intermediate spiropyrazoline 646 was isolated in excellent yield. However, pyrolysis of 646 only produced the homologated oxazolone 647 (Scheme 7.206).920 When 4-heteromethylene-2-phenyl-5(4H)-oxazolones 648 are reacted with diazomethane, a five component mixture 649-653 was obtained. The product ratio depends on the b-heteroatom of double bond (Scheme 7.207).424 4-(Chloromethylene)-2-phenyl-5(4H)-oxazolone 394921 and 2-(acyloxymethylene)-5(4H)-oxazolone424 mainly give a mixture of 2-hetero substituted spirocyclopropanes. For example, the 2-chloro derivatives 654 and 655 have been isolated and further elaborated to both stereoisomers of 1-amino-2-chlorocyclopropanecarboxylic acid 656 and 657 (Scheme 7.208). In contrast, when the same reaction was carried out on 4-(bromomethylene)-2phenyl-5(4H)-oxazolone 658 (X ¼ Br)922 or 4-(iodomethylene)-2-phenyl-5(4H)oxazolone 658 (X ¼ I)424 serendipitous formation of the 2-(halomethyl)spirocyclopropanes 659 and 660 was observed. Both diastereoisomers of 2,3-methanomethionine 663 and 664 have been prepared from the isolated 2-(bromomethyl)spirocyclopropane oxazolones, 659 and 660, respectively. The isolated 2-(iodomethyl)spirocyclopropane oxazolones have been hydrolyzed to furnish the

264

5(2H)-Oxazolones and 5(4H)-Oxazolones H

N N

O

AcO O

N

AcO

O

H CH2N2

O

N

∆

CO2Me

AcO HO2C AcO 645

646 Me

O

AcO O

N

AcO

MeO2C

647

Scheme 7.206 H

H

O CH2N2

X N

O

X

O

X

H

O +

N

Ph

O

XCH2

O +

N

Ph 651

650

649

O +

N

Ph

Ph

648

H

O

XCH2

Me

O

H

O +

N

O

X N

Ph

Ph

652

653

Scheme 7.207 H

H

O CH2N2

Cl N

O

Cl

O

Cl

O +

N

Ph

O

H

O

N

Ph

394

Ph

654

655

HCl

H

HCl

Cl CO2H

Cl

NH2 656

Scheme 7.208

CO2H H

NH2 657

O

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

265

O

H

O

CO2H HOCH2

H

NH2 661

X=I

H

CH2N2

X N X = Br, I

O

662

HCl

H

O

NH2

XCH2

O

XCH2 N

Ph

HCl

X=I

O

+

O

H

O

N

Ph

658

Ph

659 X = Br

660

1) MeSNa/MeOH 2) HCl

H CO2H MeSCH2

NH2 663

X = Br

1) MeSNa/MeOH 2) HCl

MeSCH2 H

CO2H NH2 664

Scheme 7.209

cyclopropylhomoserine derivatives, 661 and 662. In this case, the trans-cyclopropylhomoserine lactonized to 662 under the reaction conditions (Scheme 7.209). The reaction of diazomethane with 2-phenyl-4-(sulfanylmethylene)-5(4H)oxazolone 665, readily obtained from 4-(chloromethylene)-2-phenyl-5(4H)-oxazolone 394, generates the intermediate spirocyclopropane oxazolones 666 and 667, respectively. Both 666 and 667 were independently elaborated to the 2-sulfanyl-1aminocyclopropanecarboxylic acid derivatives 668 and 669—a novel class of conformationally constrained masked cysteines (Scheme 7.210).518 Representative examples of spirocyclopropane oxazolones are shown in Table 7.47 (Fig. 7.58). Diphenyldiazomethane has also been used in 1,3-dipolar cycloadditions with 4arylmethylene-5(4H)-oxazolones 670 to prepare gem-diphenyl-spirocyclopropane oxazolones 671.423,923 A number of 671 analogues were evaluated as antibacterial agents.924 In addition, 671 derivatives were precursors for new 1-aminocyclopropanecarboxylic acid derivatives 672, for example, 1-(benzoylamino)triphenylcyclopropanecarboxylic acid 672 (R ¼ Ar ¼ Ph) (Scheme 7.211). Nitrile imines, generated in situ from the corresponding N-(phenyl)arylhydrazonoyl chlorides, react with unsaturated 5(4H)-oxazolones 673 to give the corresponding spiropyrazoline oxazolones 674.647,648,925–927 The reaction is regioselective and in each case only one regioisomeric cycloadduct is formed. The process is also stereoselective. However, some partial isomerization of an (E)-oxazolone to the (Z)

266

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H

O

Cl N

CH2N2

RS

O

H

O O

N

Ph

RS N

Ph

394

RS

O O +

O

H

O

N

Ph

Ph

665

666

667

H

RS CO2H

RS

NHCOPh 668

CO2H H

NHCOPh 669

Scheme 7.210

TABLE 7.47. OXAZOLONE SPIROCYCLOPROPANES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH DIAZOMETHANE

R1

R1

O CH2N2

R2 N

O

R2

O

N

R3

O R3

Figure 7.58 R1

R2

H Ph Ph H H 4-MeC6H4 4-MeC6H4 H H 4-MeOC6H4 H 4-MeOC6H4 H 4-ClC6H4 H 4-ClC6H4 H 3,4-(MeO)2C6H3 H Cl H AcO H MeS H PhS H PhCH2S H Ph3CS H (S)-2,2-dimethyl-1,3-dioxolan-4-yl

R3 Ph Ph Ph Ph Ph Ph Ph Ph 2-MeO2CC6H4 Ph Ph Ph Ph Ph Ph Ph

% Yield

73 76 70 73 54 67

45 50 60 40 55 45 45 50 33 (Z þ E) (Z þ E) (Z þ E) (Z þ E) (Z þ E) (Z þ E) 73

Reference 918 918 918 918 918 918 918 918 920 424 424 518 518 518 518 933

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

H

Ph2CN2

Ar N

Ph Ph O

H

O O

H

Ph Ph CO2H

KOH

Ar

O

N

R

267

Ar

NHCOR

R

670

671

672

Scheme 7.211

isomer prior to the cycloaddition reaction has been observed. Contradictory regiochemical assignments have been made although alternative syntheses of products obtained from the cycloadducts support the regiochemistry shown in Scheme 7.212. Representative examples are shown in Table 7.48 (Fig. 7.59).

H

O [Ar

R2

C

N

N-Ph]

O

N

Ph N O

N

Ar H R2

O

N

R1

R1

673

674 Scheme 7.212

TABLE 7.48. OXAZOLONE SPIROPYRAZOLINES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH NITRILE IMINESa

H

O [Ar

R1 N

N

R3 C

N

N-Ph]

Ph N O

H

O

R1 R2

N

O R2

Figure 7.59 R1

R2

R3

% Yield

Ph Ph Ph 4-MeC6H4 4-MeC6H4 4-MeC6H4 Ph

Ph Ph Ph Ph Ph Ph Ph

Ph 4-MeC6H4 4-ClC6H4 Ph 4-MeC6H4 4-ClC6H4 4-MeOC6H4

30–70 30–70 30–70 30–70 30–70 30–70 30–70

a

Data from Ref. 927.

268

5(2H)-Oxazolones and 5(4H)-Oxazolones H

O Ar2 C

Ar1 N

N

N

Ar2

O

H Ar1

O

O O O

N

R

R 675

676 Scheme 7.213

The reaction of nitrile oxides with 4-arylmethylene-5(4H)-oxazolones 675 to give the corresponding spiroisoxazoline oxazolones 676 is also well known.647,927,928 The regiochemistry of this cycloaddition reaction was initially incorrectly assigned but a careful study of the reaction showed that the regiochemistry of the 1,3-dipolar cycloaddition of nitrile oxides is the same as that observed with nitrile imines (Scheme 7.213). Examples of spiroisoxazoline oxazolones are shown in Table 7.49 (Fig. 7.60). Both reactions have been utilized to prepare heterocyclic compounds such as pyrazoles 681 (X ¼ N-Ph) and isoxazoles 681 (X ¼ O) as shown in Scheme 7.214.647 Starting from an unsaturated 5(4H)-oxazolone 677, either a cycloaddition–ring-opening reaction sequence (677 ! 678 ! 680) or a ringopening–cycloaddition reaction sequence (677 ! 679 ! 680) affords the same product.

TABLE 7.49. OXAZOLONE SPIROISOXAZOLINES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH NITRILE OXIDES

H

O R3 C

R1 N

N

R3

N O

O O

H

O

R1

N

O R2

R2 Figure 7.60 R1

R2

R3

% Yield

Ph 4-MeC6H4 4-ClC6H4 Ph 4-MeC6H4 4-ClC6H4

Ph Ph Ph Ph Ph Ph

2,4,6-Me3C6H2 2,4,6-Me3C6H2 2,4,6-Me3C6H2 2,6-Cl2C6H3 2,6-Cl2C6H3 2,6-Cl2C6H3

76 47 62 82 80 40

a

Data from Ref. 928.

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

O [Ar

R2

C

N X]

X O

H

O

N

N

Ar R2

X = O, N-Ph

O

N

R1

R1 677

678

MeOH

MeOH

H R2

269

N

Ar [Ar

CO2Me

C

H X = O, N-Ph

X

BF3 Et2O

CO2Me

R2

NHCOR1

N

Ar

X

N X]

679

CO2Me

R2

NHCOR1 680

681

Scheme 7.214

O

NuH

N

H

CONu NHCOPh

EtO H EtO N

O

Ar O

N

O

O [Ar

C

N

O]

H EtO

403

683

O

N

Ph

Ar

Ph 682 H2O

O

N Ar NHCOPh 684

Scheme 7.215

If 4-(ethoxymethylene)-2-phenyl-5(4H)-oxazolone 403 is used as the dipolarophile, reaction with nitrile oxides yields cycloadducts 682 with reversed regiochemistry. Further reaction of 682 can then yield 4-aminoisoxazoline-4-carboxylic acids 683 or 4-amino-3-arylisoxazoles 684 depending on the reaction conditions (Scheme 7.215).929

7.4.3.4. Diastereoselective Cyclopropanations Cyclopropanation of the chiral oxazolone 632 derived from 1,2-O-isopropylidene-D-glyceraldehyde with diazomethane affords a mixture of five compounds.

270

5(2H)-Oxazolones and 5(4H)-Oxazolones

These include the four possible diastereomeric spirocyclopropane derivatives 633, 685, 634, and 686 resulting from methylene insertion into the double bond and a spirocyclopropane 687 derived from methylene insertion into the double bond of a homologated 5(4H)-oxazolone. The amount of 687, the cis/trans selectivity and both the cis and trans diastereoselectivities depend on the reaction conditions. Use of nonpolar solvents avoids formation of 687. In addition, the cis/trans selectivity and both cis and trans diastereoselectivities are very high such that the major compound 633 can be isolated in 75% yield (Scheme 7.216).930 H

O

O O

N

O

Ph 632 CH2N2

O H

H

O

O

O

O N

O

O +

N

O Ph

633

O +

O

O H N

O

H

O +

N

Ph

Ph 685

O

O

O Ph

634

686 Me

O

O +

N

O

O Ph

687 Scheme 7.216

The stereochemical course of this reaction can be rationalized by considering attack of the 1,3-dipole on the Ca-Re face of the exocylic double bond. This process is in accord with the calculated energies of reactants, transition structures, and reaction intermediates at semiempirical and ab initio theory levels.931 The major isolated compound 633 has been transformed into several interesting and enantiomerically pure cyclopropylamino acids 690 via the b-formyl intermediate 689 (Scheme 7.217).932–934

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

H

O

O

CH2N2

N

O

NaOMe

N

O

CO2Me

MeOH

NHCOPh

O

Ph

632

633

688

H

2) NaIO4

O

O

Ph

1) H+

H

O

O

O

271

H CO2Me

OHC

CO2H

R

NHCOPh

NH2 690

689 Scheme 7.217

7.4.3.5. Diels–Alder Reactions Despite the importance and well-known reactivity of the exocyclic double bond of unsaturated oxazolones, this aspect has only recently been exploited in Diels– Alder reactions with dienes. Reaction of (Z)-4-benzylidene-2-phenyl-5(4H)-oxazolone 621 with an excess of butadiene or 2,3-dimethylbutadiene in the presence of Lewis acid catalysts, gives the corresponding spirooxazolone adducts 691.935 Ring opening of 691 followed by hydrogenation and hydrolysis then leads to the synthesis of new constrained phenylalanine analogues. For example, methanolysis of the cyclohexene adduct 691 (R ¼ Me) yields 694 that was hydrogenated to give a mixture from which the major diastereoisomer was isolated. Subsequent acid hydrolysis of this diastereoisomer then gave the corresponding stereoisomerically constrained phenylalanine analogue 695 (Scheme 7.218). Racemic cis-1-amino-2-phenylcyclohexanecarboxylic acid 693 can be prepared by Diels–Alder reaction of (Z)-4-benzylidene-2-phenyl-5(4H)-oxazolone 621 and butadiene in an analogous manner. Coupling N-tert-butyloxycarbonyl-L-proline with 693 yielded diastereomeric dipeptides that were separated chromatographically. The behavior of the individual dipeptides was studied as a means to effect bturn modulation by such cyclohexane analogues of phenylalanine.936 In general, enantiomerically pure analogues of constrained phenylalanines with a cyclohexane skeleton have been obtained from the racemic butadiene Diels–Alder oxazolone adduct. The double bond was hydrogenated and both enantiomeric compounds were resolved using Obrecht’s methodology255,256 for resolution of quaternary amino acids. Following ring opening of the oxazolone with the (S)phenylalanine cyclohexylamide, both diastereomeric dipeptides were separated and isolated by column chromatography. Subsequent hydrolysis then leads to (1R, 2R)and (1S, 2S)-1-amino-2-phenylcyclohexane-1-carboxylic acid.937

272

5(2H)-Oxazolones and 5(4H)-Oxazolones CO2H

NaOH

H

R=H

CO2H

1) H2, Pd/C

NHCOPh

2) HCl

H

NH2

Ph

Ph

R H

R

O

Ph N

O

692

R

693

O

R L.A.

H Ph

O

N

Ph

Ph

621

691

Me

Me

Me CO2Me

NaOMe R = Me

H

1) H2, Pd/C

NHCOPh

Me CO2H

2) HCl

H

NH2 Ph

Ph 694

695 major compound

Scheme 7.218

Methanolysis of 696 followed by reaction with iodine, leads to syn g-hydroxylation relative to the amide group. Further, deiodination and subsequent hydrolysis affords the g-hydroxy-a-amino acid derivative 698.938 This interesting reaction sequence opens the way for the synthesis of hydroxy substituted constrained phenylalanines with defined stereochemistry (Scheme 7.219). OH O NaOH

H Ph

N

MeOH

Ph 696

CO2Me

O

NHCOPh

H

1) I2/dioxane 2) (n-Bu)3SnH 3) TFA

CO2Me NHCOPh

H Ph

Ph 697

698

Scheme 7.219

(Z)-4-Benzylidene-2-phenyl-5(4H)-oxazolone 621 also reacts with cyclopentadiene in the presence of a Lewis acid. In this case, the reaction leads to a mixture of cycloadducts 699 and 700 derived from endo and exo attack of the diene. The mixture of 699 and 700 can be separated chromatographically or simply by filtration after a typical iodolactonization reaction.939,940 In contrast, (E)-4-benzylidene-2-phenyl-5(4H)-oxazolone 642 gave considerable isomerization due to the presence of the Lewis acid under the same reaction conditions necessitating avoidance of these catalysts. Reaction of 642 and cyclopentadiene in mixtures of acetone–water gives the corresponding endo- and exo-cycloadducts 703 and 704 in very high yields after 6 days at room temperature.940 Once again iodolactonization allows the separation of 703 and 704. Each endo- and exo-cycloadduct was

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

CO2H

CO2H

H

NH Ph 2

NH2 Ph

701

702

O

Ph N

O

O L.A.

N Ph

Ph

Ph

N

O acetone/water

Ph 700

Ph O + N

O N

Ph 703

CO2H Ph NH2 705

O

N Ph

O

Ph 642

O +

699

O

H

O

Ph

621

273

Ph O Ph

704

CO2H Ph NH2 706

Scheme 7.220

converted to the corresponding amino acid by hydrogenation of the double bond and subsequent hydrolysis (Scheme 7.220). This reaction sequence independently provides the four d,l-pairs of 2-amino-3-phenylnorbornane-2-carboxylic acids 701, 702, 705, and 706 from (Z)- and (E)-4-benzylidene-2-phenyl-5(4H)-oxazolones. The Diels–Alder reaction of (Z)-4-arylidene-2-phenyl-5(4H)-oxazolone 707 and Danishefsky’s diene is best conducted in toluene at reflux to produce both the endo and the exo stereoisomers of 708.941,942 Base treatment of the cycloadduct mixture promotes aromatization through spontaneous oxidative decarboxylation to give 3aryl-4-benzamidophenols that are converted to 3-aryl-4-aminophenols 709 by acid

274

5(2H)-Oxazolones and 5(4H)-Oxazolones HO 1) NaOH

H

O

1)

NH2

2) HCl

OMe

Ar

OMe O

O

709

TMSO

Ar N

O 2) dil. HCl/THF

H Ar

O

N

Ph 707

Ph 708

O CO2Me

DBU MeOH

H

NHCOPh Ar 710

Scheme 7.221

hydrolysis.942 On the other hand, treatment of the cycloadduct mixture with 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol leads to ring opening and elimination to produce enone 710. Incorporation of an oxygenated functional group at C-4 renders 710 a valuable intermediate for the synthesis of d-substituted conformationally restricted a-amino acids (Scheme 7.221).941 For example, hydrogenation of 711 followed by hydrolysis of the ester and benzamide gives 1-amino-4-oxo-2-phenyl-1-cyclohexanecarboxylic acid 713.941 Stereoselective reduction of the carbonyl group of 712 opens the way for the synthesis of new analogues of 4-hydroxy-1-aminocyclohexanecarboxylic acids 715 and 719 of defined stereochemistry.943 In addition, 714, the stereoisomer with trans disposed benzamide and hydroxy groups, undergoes cyclization and hydrolysis to produce 2-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid 717—a new constrained proline analogue (Scheme 7.222).944 Hydroxylation of 711 at C-2 can be achieved by an intramolecular conjugate addition of the benzamide to the enone system. The reaction takes place in high yield in the presence of a Lewis acid and affords direct hydroxylation with a syn relationship to the amide group via an intermediate 1,3-oxazoline (Scheme 7.223).945 To extend this methodology, Diels–Alder reactions of several (Z)-4-arylidene (heteroarylidene)-2-phenyl-5(4H)-oxazolones with butadiene, 2,3-dimethylbutadiene, cyclopentadiene and Danishefsky’s diene have been studied. This work demonstrated that the products depended on the nature of the aromatic ring and the diene used.946 An interesting application of this methodology is the synthesis of racemic epibatidine 729, a new alkaloid with a 7-azabicyclo[2.2.1]heptane skeleton that has proven to be a very potent analgesic. Preparation of 729 began with the Diels–Alder adduct 726 obtained from (Z)-4-[50 -(20 -chloropyridylmethylene)]-2-

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

275

COPh

N Ph

CO2Me

1) MsCl

Ph CO2H

H

HO

HO

N HCl

H

717

CO2Me

2) KOt-Bu

H

CO2H

HCl

H

NHCOPh

716

NH2 Ph

Ph 714

715

L-Selectride

O

O

O CO2Me H

CO2Me

H2, Pd/C

H

NHCOPh

H

HCl

NHCOPh Ph

CO2H

HCl

711

NH2 Ph

Ph 712

713

NaBH4

HO

HO CO2Me H

CO2H

HCl

H

NHCOPh

NH2

Ph

Ph

718

719

Scheme 7.222

O

Ph H CO2Me

Ph H

O TMSOTf

CO2Me

NHCOPh

Ph H

HO NaBH4

CO2Me N

N

NH2 OH

Ph

Ph 711

CO2Me

2) 2 N HCl

O

O

Ph H

HO 1) TFA

721

720

722

1) PhCOSCl 2) (n-Bu)3SnH

Ph H CO2Me N O

Ph H 1) TFA

CO2Me

2) 2 N HCl

NH2 OH

Ph 723 Scheme 7.223

724

276

5(2H)-Oxazolones and 5(4H)-Oxazolones OMe

H

O

N

O

N

Cl

HO

O

1)

CO2Me

CO2Me

TMSO

1) H2, Pd/C

H

H

NHCOPh

2) dil HCl/THF 3) DBU/MeOH

Ph

N

N

Cl

Cl 725

726

727 H

COPh 1) MsCl

Cl

N

N

1) LiOH

2) KOt-Bu

CO2Me

H

NHCOPh

2) L-Selectride R

N

N

Cl

2) −CO2 3) HCl

H

728

729 Scheme 7.224

phenyl-5(4H)-oxazolone 725 and Danishefsky’s diene. Elaboration of 726 to 729 was accomplished readily as shown in Scheme 7.224.947 A number of other specific reactions have been studied. For example, Diels– Alder reactions of the unsaturated 5(4H)-oxazolone derived from piperonal with 2tert-butyldimethylsilyloxy-1,3-butadiene, piperylene, 1-acetoxy-1,3-butadiene, and Danishefsky’s diene have been described. In these cases, the results are variable and are dependent on the diene with poor yields often obtained even at high temperatures. Moreover, the stereochemical outcome of these reactions has not been determined.948 A tandem Dakin–West/Diels–Alder reaction sequence has been proposed to explain the (trifluoromethyl)bicyclo[2.2.1]heptane a-amino acid precursors 731 and 732 isolated from hippuric acid, trifluoroacetic anhydride, and cyclopentadiene (Scheme 7.225).949 Irradiation of 4-(but-3-enylidene)-2-phenyl-5(4H)-oxazolone 733 leads to the [4 þ 2] adduct 734 derived from 733 acting as both a diene and a dienophile in a solid-state photo Diels–Alder reaction (Scheme 7.226).950

CF3CO2 CO2H NHCOPh

CF3 N

O

N

Ph

N CF3

X = OCOCF3 731

Scheme 7.225

X O +

CF3

Ph 730

O

O

O

TFAA

732

X O Ph

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) H

Me

O

Me

277

O

hv

Me

O

O

N

N O

N

Ph

O Ph

Ph 733

734 Scheme 7.226

Diels–Alder reactions of 4-heteromethylene-5(4H)-oxazolones have been described. (E)-4-(Chloromethylene)-5(4H)-oxazolone 737 reacts with 2,3-dimethylbutadiene in the presence of ethylaluminum dichloride to afford the cycloadduct 738. The cycloaddition reaction is characterized by high diastereoselectivity and occurs without appreciable isomerization of the dienophile. Further synthetic transformations of 738 yield 1-amino-3,4-dimethyl-6-hydroxy-cyclohex-3-enecarboxylic acid 739 (Scheme 7.227).951 Examples of Diels–Alder reactions of acyclic dienes and unsaturated 5(4H)-oxazolones are shown in Table 7.50 (Fig. 7.61). Me H

O

Me

Me

O

Me

Cl

O

N

H Cl

N

Ph

O Ph

735

736 hv

Me

Me Cl

O

H N

O

Me Me

Me

O Cl H

O

CO2H NH2

H OH

Ph

Ph 737

N

Me

738

739

Scheme 7.227

7.4.3.6. Diastereoselective Diels–Alder Reactions (Z)-4-[(S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethylene]-2-phenyl-5(4H)-oxazolone 632 can react as a dienophile in diastereoselective Diels–Alder reactions. Thus, 632 undergoes a thermally induced Diels–Alder reaction with cyclic dienes, for example, cyclopentadiene and cyclohexadiene, to afford a mixture of the four

278

5(2H)-Oxazolones and 5(4H)-Oxazolones

TABLE 7.50. DIELS–ALDER ADDUCTS FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES AND ACYCLIC DIENES

H

R3

R3

O

R2

O

R2

R1 N

O

O

H R1

Ph

N Ph

Figure 7.61 R1

R2

R3

% Yield

Ph Ph 4-ClC6H4 4-ClC6H4 2-MeOC6H4 2-MeOC6H4 Cl Cl (S)-2,2-dimethyl-1,3-dioxolan-4-yl (S)-2,2-dimethyl-1,3-dioxolan-4-yl

H Me H Me H Me Me Me H H

H Me H Me H Me Me H H H

64 91 60 75 57 100 70 50 92 100

Reference 935 935 946 946 946 946 951 951 432 432

possible Diels–Alder adducts.430,432,952 In both reactions the diastereofacial selectivities are extremely high and the adduct mixture is mainly composed of one endoand one exo-adduct. With cyclopentadiene exo-adducts 740 predominate slightly whereas reaction with cyclohexadiene shows a slight endo selectivity and endoadduct 747 is the major compound. Solvent polarity does not have a noticeable effect on either the exo–endo selectivity or on diastereofacial selectivities at room temperature. However, if the reaction is performed at low temperature even better diastereofacial selectivities are obtained. Thermally, the reaction with cyclohexadiene is very slow although it can be accelerated by Lewis acid catalysts. Here, in some cases, the formation of cycloadducts from the (E)-oxazolone is also observed but use of lithium perchlorate can minimize these compounds. After isolation, the major cycloadducts have been transformed into a new class of conformationally constrained (S)-aspartic analogues 743, 745, and 749 as shown in Scheme 7.228.953 Examples of Diels–Alder adducts from unsaturated oxazolones and cyclic dienes are shown in Table 7.51 (Fig. 7.62). In contrast, 632 does not react or reacts very slowly in thermal Diels–Alder reactions with acyclic dienes such as butadiene, 2-methyl-1,3-butadiene, and 2,3dimethylbutadiene. This behavior results in extensive formation of adducts derived from the (E)-oxazolone isomer. However, 632 and acyclic dienes do give good conversions in reasonable reaction times using lithium perchlorate, which also minimizes the formation of adducts derived from the (E)-oxazolone.432 In all cases the diastereofacial selectivities are very high and additionally, reaction of 632 with 2-methyl-1,3-butadiene (R1 ¼ Me, R2 ¼ H) gives a high para-regioselectivity leading to 750 (Scheme 7.229).

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)

CO2Me

CO2Me

CO2H

O

O 743

CO2H

NH2

NH2

O

NH2 CO2H

279

NH2 CO2H

O 742

744

745

1) Column chromatography 2) NaOMe 3) H2, Pd/C

H O N

O

O

N O

O

O

740

O O

O Ph

Ph

632

O

O +

N

O

Ph

N

O

O

O

741

O +

O

N

O

Ph

CO2Me

1) NaOMe 2) H2, Pd/C

O

CO2H

NH2

NH2 CO2H

Ph

O

O

746

O

747

748

749

Scheme 7.228

R1

O

O

O

R2

N

O

R2

R1

H

O LiClO4

Ph 632

H O

O

N Ph

O 750

Scheme 7.229

280

5(2H)-Oxazolones and 5(4H)-Oxazolones TABLE 7.51. DIELS–ALDER ADDUCTS FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES AND CYCLIC DIENES

R1

n

O

O

O

n

R2 N

R1 O + N

O

R2 Ph

Ph

n

N R2

R1 O Ph

Figure 7.62 R1 H Ph H H H H H H

R2 Ph H 4-ClC6H4 4-MeOC6H4 fur-2-yl thien-2-yl (S)-2,2-dimethyl-1,3-dioxolan-4-yl (S)-2,2-dimethyl-1,3-dioxolan-4-yl

n

% Yield

1 1 1 1 1 1 1 2

95 95 100 50 70 71 95 100

Reference 939 939 946 946 946 946 952 432

The chiral (E)-oxazolone derived from 1,2-O-isopropylidene-D-glyceraldehyde has also been used as a dienophile in the Diels–Alder reaction and, in this case, (E/Z) isomerization of the oxazolone can be avoided using heterogeneous catalysts that promote the synthesis of trans-adducts.429 The Diels–Alder reaction of 632 and activated dienes, such as 1-trimethylsilyloxy-1,3-butadiene and Danishefsky’s diene, can be induced thermally. In both cases, adducts 751 derived from endo and exo addition are obtained. There was no endo–exo selectivity in this reaction using Danishefsky’s diene. However, 1trimethylsilyloxy-1,3-butadiene gave rise to a slight preference for exo attack and was a completely diastereoselective reaction. In both cases, further elaboration of 751 led to a single diastereoisomer, 752 and 753, respectively, in good yields.428,954,955 The cycloadduct from 632 and Danishefsky’s diene has also been converted to highly functionalized and interesting analogues including the 1-benzamido-4-oxo-1,2-cyclohexanedicarboxylic acid 1-methyl ester 754955 and the tetrahydrobenzoxazole derivative 755 (Scheme 7.230; Table 7.52, Fig. 7.63).954 A model to rationalize the stereochemical course of the reaction has been proposed. Evaluation of the conformational energy curve derived from rotation C2) bond by AM1 semiempirical calculations shows only one deep around the (C1 minimum that points to the existence of a single conformation. In this conformation, which is supported by NMR studies, the Ca-Si side of the olefinic bond is shielded so that attack of the diene should come almost exclusively from the Ca-Re side as, indeed, has been observed in all cases.952

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) O 1) citric acid 2) MnO2

H

R1 = TMS R 2= H OR1

H

O

O

752 H

R2

N

O

Ph O

OR1 O

R2

O O

N

O

281

O

N

O

∆

O

O CO2Me

Ph

H

O

Ph 632

NHCOPh CO2H

O

751

754

CO2Me

1) HCl 2) DBU

H

R1 = Me R2= TMSO

NHCOPh

O

O X N

HO

O

H

753

Ph

O O

X =CO2Me 755

Scheme 7.230

TABLE 7.52. DIELS–ALDER ADDUCTS FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES AND ACTIVATED DIENES R2

H

R2 O

R3

O R3

R1 N

O

H R1

Ph

N

O Ph

Figure 7.63 R1

R2

R3

Ph 2-NO2C6H4 3-MeOC6H4 2-MeOC6H4 4-ClC6H4 3,4-methylenedioxyphenyl 3,4-methylenedioxyphenyl 3,4-methylenedioxyphenyl (S)-2,2-dimethyl-1,3-dioxolan-4-yl (S)-2,2-dimethyl-1,3-dioxolan-4-yl

MeO MeO MeO MeO MeO MeO H AcO TMSO MeO

TMSO TMSO TMSO TMSO TMSO TMSO TBSO H H TMSO

% Yield 71 64 52 68 65 100 50 72 70 90

Reference 942 942 942 942 942 948 948 948 428 955

282

5(2H)-Oxazolones and 5(4H)-Oxazolones

7.4.4.

Miscellaneous Reactions

A number of other interesting reactions of unsaturated 5(4H)-oxazolones can not be readily classified among the characteristic reactions described in Sections 7.4.2 and 7.4.3. For example, 4-cycloalkylidene-2-phenyl(methyl)-5(4H)-oxazolones 756 are oxygenated in basic medium to give the cycloalkenyl imides 757. This reaction involves a base-catalyzed isomerization, followed by oxygenation and subsequent fragmentation of an intermediate peroxide (Scheme 7.231).956,957 Oxygen addition to 4-arylidene-5(4H)-oxazolones also leads to the corresponding ring-opened products.957,958 ( )n

O

R2

O2

N

O KOH

( )n R2

CONHCOR1

R1 756

757 Scheme 7.231

Fluorination of unsaturated 5(4H)-oxazolones 758 affords the expected difluorinated derivatives 759. Basic hydrolysis of 759 yields a b-fluoro-a-keto acid 760 that is reductively aminated to give an erythro-b-fluoro-a-amino acid 761 (Scheme 7.232).959 R2

R2

O F2

R1 N

O

F

F

O HO

R1 N

O

R2 R1

F CO2H

[H]

O Ph

Ph 758

759

R3NH2

760

R2 R1

F CO2H NHR3 761

Scheme 7.232

Electrochemical reduction of 4-benzylidene-2-methyl-5(4H)-oxazolone to produce racemic N-acetylphenylalanine has been accomplished using lead and cadmium cathodes.960 The p-donor behavior of 4-arylmethylene-2-phenyl-5(4H)-oxazolones 762 with the p-acceptor tetracyanoethylene has also been studied. The initially formed charge-transfer complex is converted via intermediate 763 to a new compound for which a 2-aryl-1-benzamido-3,3,4,4-tetracyanocyclobutanecarboxylic acid 764 has been proposed on the basis of the NMR spectral data (Scheme 7.233).961 Charge-transfer complexes of 2-aryl-4-arylidene-5(4H)-oxazolones with di- and trinitrobenzene as p acceptors have also been prepared.962 Photoreactivities of some (Z)-unsaturated oxazolones 765 have been studied. The authors found that irradiation of 765 with a 450-W medium pressure mercury

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) CN CN O

O ArCH

NC

CN

NC

CN

NC NC

O +

N

Ph

CN CN CO2H

NC NC

NHCOPh

O

N

Ar

283

Ar Ph

762

763

764

Scheme 7.233

lamp and a Pyrex filter effected (Z/E) isomerization as the major reaction. In the absence of a Pyrex filter 765 decarbonylated to a ketenimine 767 that was trapped by protic solvents to afford N-acylimidates 768 and imides 769 (Scheme 7.234).963,964 Solid-state irradiation of 2-aryl-4-cycloalkylidene-5(4H)-oxazolones 770 effects photodimerization to produce centrosymmetric 1,3-diazetidines 771 in very high yields via an uncommon C N cycloaddition (Scheme 7.235).965 H R1

hv

O +

N

Pyrex filter

R1

O

O

H N

Ph

O Ph

765

766 OR2

H

R1

O

N

O

NCOPh

H

hv

R1

R2OH

R1

C

768 C

NCOPh

O

Ph 765

R1

R2 = H

767

NHCOPh 769

Scheme 7.234 R2 O R2

R1

O hv

R1 N

O

O

N

Ar O

N

Ar R1

Ar O

R2 770

771

Scheme 7.235

284

5(2H)-Oxazolones and 5(4H)-Oxazolones

Spectrometric determination of microgram levels of Zn and Cu has been achieved through complexation with unsaturated 5(4H)-oxazolones.966,967 Unsaturated 5(4H)-oxazolones react with ethers under ultrasonic conditions to afford esters.968 In addition, poly(5-imidazolones) with good thermal properties have been prepared from the bis(oxazolone) derived from terephthalaldehyde and primary amines969 while new sensitizing dyes containing unsaturated 5(4H)-oxazolone moieties have been synthesized.970

7.4.5.

Structural Analysis

Spectroscopic studies of series of unsaturated 5(4H)-oxazolones have been performed to correlate spectroscopic behavior with a characteristic substituent N parameter. In this context, some authors have described little effect on the C  and C O IR frequencies in some 4-arylidene-2-phenyl-5(4H)-oxazolones by p  substituents on the C-4 aryl group.971 However, other authors have reported a linear O group with substituent constants in correlation of the IR frequency of the C some 4-arylidene-2-phenyl-5(4H)-oxazolones. This would be expected for a high transmission of the substituent effect through the ring.972 Note that the carbonyl group has a two-component band in the 1768–1812-cm1 region that is sensitive to conformational changes and solvent effects.411 Studies of the UV–visible absorption spectra of 4-arylidene-2-phenyl-5(4H)oxazolones show that the sign of the solvatochromism is substituent dependent in hydrogen-bonding solvents. On the other hand, in non-hydrogen-bonding solvents all substituents show a positive solvatochromism.973 Hydroxy-substituted oxazolones show an additional long-wavelength band in the visible absorption spectra in triethanolamine–acetone mixtures. Prototropic equilibrium constants at different temperatures were determined by detailed studies of this new absorption band.973 In measurements of absorption and fluorescence parameters for various oxazolones, the fluorescence quantum yields are usually <0.01. Oxazolones substituted with a naphthyl group or a p-(dimethylaminophenyl) group are exceptions.974 Rotational barriers about the exocyclic C N bond of 2-aryl-4-[(N,N-dimethylamino)methylene]-5(4H)-oxazolones were determined by careful analysis of NMR spectral data for the methyl protons. A correlation was established between the energy barriers and Hammett’s constants for substituents on the 2-aryl group. Electron-withdrawing substituents in the para position increase the barrier heights, whereas electron-donating substituents have the opposite effect.975 It must be borne in mind that two geometric isomers are possible for unsaturated 5(4H)-oxazolones. In a review published in 1975, Rao showed that in those cases where both geometric isomers had been prepared, different spectroscopic behavior was observed.976 Different spectroscopic behaviors of the two geometric isomers have been studied further and, in some cases, the data allows configurational assignments to be made. More recent results on this subject follow.

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones) 1,3 c J CH

H

≅ 5.5 Hz R1

O

R1 N

N 1,3Jt

CH

772 Figure 7.64. The

O

H

O Ph

1,3

285

≅ 12.5 Hz

O Ph

773

JCH coupling constants for (Z)- and (E)-unsaturated 5(4H)-oxazolones.

NMR is a useful technique to determine the stereochemistry of double bonds and recently it has been applied to the configurational assignment of geometric isomers of some unsaturated 5(4H)-oxazolones. For example, geometric isomers can be distinguished in 1H NMR by benzene-induced shifts. This technique was used to correctly assign the configuration of the (E, Z)- and (E, E)-geometric isomers of unsaturated 5(4H)-oxazolones prepared from (E)-cinnamaldehyde.977 The value of the long-range 13C 1H coupling constants between the olefinic proton and the C-5 carbonyl carbon in the fully coupled 13C NMR (75 MHz) spectra can be used to assign the configuration of (Z)- and (E)-unsaturated 5(4H)oxazolones because 1,3JtCH > 1,3JcCH. The coupling constants for (Z)-oxazolones 772 are 5.5 Hz, whereas for (E)-oxazolones 773 the coupling constants are 12.5 Hz.978 For chiral oxazolones derived from 1,2-O-isopropylidene-D-glyceraldehyde these values are 1,3JCH ¼ 5.5 Hz for the (Z)-oxazolone and 1,3JCH ¼ 12.5 Hz for the (E)-oxazolone930 (Fig. 7.64). The stereochemistry of the double bond in 4-(a-arylethylidene)-2-phenyl-5(4H)oxazolones can be determined by measurements of long-range heteronuclear selective carbon-13 {proton} nuclear Overhauser enhancements. In the (Z)-isomers 774, large nuclear Overhauser enhancements are observed for the carbonyl carbon atom upon presaturation of the methyl group (Fig. 7.65). These effects are much smaller for the (E) isomers.979 Electron impact mass spectrometry is not effective to distinguish between the (Z) and (E) isomers of 4-benzylidene-2-phenyl-5(4H)-oxazolone and 4-(a-phenylethylidene)-2-phenyl-5(4H)-oxazolones because the spectra show only minor differences nOe Me

O

R1 N

O Ph

774 Figure 7.65. Long-range heteronuclear selective carbon-13 {proton} nuclear Overhauser enhancements in (Z)-2-phenyl-4-(a-arylethylidene)-5(4H)-oxazolones.

286

5(2H)-Oxazolones and 5(4H)-Oxazolones

in relative abundances of product ions.980 Nevertheless, collisional spectroscopy has been applied successfully to isomer differentiation. Collisional mass spectra show clear differences for the (Z) and (E) isomers in the relative abundances of ions arising from competing fragmentations. For (E) isomers the [M CO]þ ion is þ the base peak in the spectrum, while for (Z) isomers the PhCO ion is the base peak.981 The (Z) and (E) isomers of 4-benzylidene-2-phenyl-5(4H)-oxazolone and 4-(aphenylethylidene)-2-phenyl-5(4H)-oxazolone also show different behavior as far as dipole moments are concerned. The solution conformation of the phenyl group relative to the degree of substitution and double bond stereochemistry has been studied by comparison of experimental and calculated values of dipole moments.982 The (Z) and (E) isomers of 2-aryl-4-arylidene-5(4H)-oxazolones show different chromatographic behavior.983–985 In general, the relative chromatographic mobility of the (Z) and (E) isomers is dependent upon the oxazolone substituent and the chromatographic conditions. Finally, X-ray analyses of several unsaturated oxazolones have been reported. In some cases an X-ray study has been used to determine the stereochemistry of the double bond, as for (E)-4-(but-2-en-1-ylidene)-2-phenyl-5(4H)-oxazolone,950 (Z)-4-(1-ethoxyethylidene)-2-phenyl-5(4H)-oxazolone,986 (Z)-(N-acetyl-4-[(2-phenor (Z)-4-(acetoxyyl-5-oxo-4(5H)-oxazolidine)methyl-2H]-1H-imidazole,987 methylene)-2-phenyl-5(4H)-oxazolone.424 X-ray analyses of other 4-heteroarylmethylene-5(4H)-oxazolones have been reported and were directed to elucidating the structural features. For example, 4-(aminomethylene)-5(4H)oxazolones show almost perfect planar arrangement of the oxazolone ring and the substituted amino group. This situation indicates the existence of extended conjugation involving the carbonyl group, the exocyclic double bond and the nitrogen atom.505,507,988,989 Other structural features of unsaturated-5(4H)-oxazolones can be deduced from crystallographic data including the effect on planarity of substituents on the exocyclic double bond. For example, 4-benzylidene-5(4H)-oxazolones show a completely planar conformation that favors strong electronic conjugation in both (Z)990 and (E)991 isomers. The same effect has been reported for other 4-arylidene5(4H)-oxazolones.992 In contrast, the presence of ortho substituents on the arylidene group force the aryl group to twist out of the plane, as seen in 2-phenyl-4(2,4,6-trimethylbenzylidene)-5(4H)-oxazolone.466 The phenyl group of trisubstituted 4-benzylidene-5(4H)-oxazolones is nearly planar whereas the styryl moieties in (Z)-2-phenyl-4-(a-phenylethylidene)-5(4H)oxazolone and (Z)-2-methyl-4-(a-phenylethylidene)-5(4H)-oxazolone show significant deviations from planarity.993 The X-ray crystal structure of (Z)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-ylmethylene]-2-phenyl-5(4H)-oxazolone has been determined.994 The analysis shows an almost planar disposition for the entire molecule with the exception of the dioxolane ring that adopts an envelope conformation. As such, the dioxolane ring is mainly situated on the si,si diastereotopic face of the olefinic bond, a situation that accounts for the observed diastereoselectivity in Diels–Alder reactions.

Addendum

287

7.5. SUMMARY Many aspects of the chemistry of the oxazolones have been considered in this chapter including the extensive use of these compounds as key intermediates for the synthesis of interesting and valuable products. The synthesis of new heterocyclic structures with interesting pharmacological properties will be the objective of numerous research groups during the coming years. Oxazolones will be critical intermediates to prepare new specifically substituted heterocycles as chemists design molecules for improved pharmacological properties. For material scientists, polymerization reactions of oxazolones will be an important tool to prepare polymers with specific physical and chemical characteristics. On the other hand, as synthetic equivalents of amino acids, unsaturated oxazolones are and will continue to be very important intermediates for the synthesis of new non-proteinogenic a-amino acids, particularly for the asymmetric synthesis of these compounds using diastereo- or enantioselective methodologies. In addition, the exocyclic double bond will continue as an important focus to build new constrained amino acids for the design of peptides with improved properties.

7.6 ADDENDUM 7.6.1.

Saturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)995a

7.6.1.1. Synthesis A number of recent papers have appeared in the literature related to the synthesis of saturated 5(4H)-oxazolones that were not yet covered in our contribution. 4Acyl-2,4-dialkyl-5(4H)-oxazolones 776 have been obtained from N-acylglycines. Thus, cyclization of an N-acylglycine in the presence of thionyl chloride affords a monosubstituted 5(4H)-oxazolone 775. Acylation of 775 with an aroyl chloride in the presence of magnesium chloride occurred at C-4 to produce 776.995b Hydrolysis and decarboxylation of 776 gave the N-acylamino ketones 777 that are valuable intermediates to prepare oxazoles 778 (Scheme 7.236). 2-Benzyloxy-4-isopropyl(or 4-tert-butyl)-4-methyl-5(4H)-oxazolones 780 have been prepared from an N-benzyloxycarbonylamino acid 779 using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC HCl) as the cyclization agent (Scheme 7.237).996 Treatment of 780 with tetramethylfluoroformamidinium hexafluorophosphate (TFFH) has shown that they are possible intermediates in the fluorination of a-methyl-a-alkyl amino acids by TFFH. Several small peptides 781 possessing an N-terminal b-hydroxy acid have been obtained using the azirine–oxazolone method developed by Heimgartner.997

288

5(2H)-Oxazolones and 5(4H)-Oxazolones O R2

CO2H

SOCl2

N

NHCOR1

O

R2

R2

ArCO

ArCOCl

O

O

N

MgCl2

R1

R1 775

776 Ar-SO2NH2

R2 1) HCl

R2

1) ClSO3H

Ar

NHCOR1

2) ∆

O

O

N

2) NH3

R1 778

777 Scheme 7.236

R2 R1

O

R2 CO2H

EDAC HCl

R1 N

NHCO2Bn

O OBn

780

779 Scheme 7.237

Treatment of these compounds with HCl(g) leads to an intermediate 5(4H)oxazolone 782 that, in absence of an external nucleophile, is captured intramolecularly and undergoes a ring enlargement to afford the corresponding cyclic pentadepsipeptides 783 (Scheme 7.238). R1

O

HO R2

R3

O O R8 R9 H R4 R5 H Me N N N N N O R6 R7 H O R10 R11 Me H

HCl ∆

781

R1

O

HO R2

R3

O R8 R9 R4 R5 H H Cl N N R11 N N R R R10 7 H 6 O H O O

R1 O

R2 R3 H N O

O O

R11 R10

N H

Scheme 7.238

R5 O H N

R9 R8 O 783

782

R4 H

N R6 R7

Addendum

289

7.6.1.2. Reactions Some new ring-opening reactions of saturated 5(4H)-oxazolones have recently appeared in the literature. For example, the reaction of 4-substituted-4-(triphenylphosphonio)-5(4H)-oxazolones with methanol in the presence of DBU depends on the steric bulk of the substituent at C-4. The 5(4H)-oxazolones having a bulky C-4 substituent suffer ring opening whereas those having a small C-4 substituent undergo competitive substitution of the triphenylphosphonium group by methanol.998 Recently, Candida antarctica lipase B (Novozyme) has been used to develop an effective and versatile dynamic kinetic resolution of 2-phenyl-4-substituted-5(4H)oxazolones 784.999 This catalyst tolerates a wide range of substrates that are transformed into optically active N-benzoylamino acid esters 785 in high yield and ee. The presence of a catalytic amount of an organic base usually increases the enantioselectivity of the reaction. However, optimal results are obtained in the absence of a base when tetrahydrofuran or acetonitrile are used as solvents (Scheme 7.239). O

O R1

R1 N

O Ph

784

CO2R2

Novozyme

O

N

R2OH

R1 NHCOPh

Ph ent-784

785

Scheme 7.239

Examples of homooligomer series of new model peptides that incorporate the a,a-disubstituted amino acid 20 ,10 :1,2;100 ,200 :3,4-dibenzocyclohepta-1,3-diene-6amino-6-carboxylic acid (Bip) have been obtained using 5(4H)-oxazolones 787 as key intermediates (Scheme 7.240).1000 N-Acylamino aromatic ketones 790 can be prepared by arylation of saturated oxazolones in the presence of Lewis acids. Cyclodehydration of 790 leads to 2,5diaryloxazoles 791. For example, saturated 5(4H)-oxazolones 789 from N-benzoylalanine or N-benzoylvaline undergo Friedel–Crafts arylation to afford substituted N-benzoylphenacylamines 790. In the presence of POCl3, 790 cyclizes to produce 5-aryl-2-phenyloxazoles 791 (Scheme 7.241).1001 Dimerization of 4-monosubstituted-5(4H)-oxazolones 792 has been reported1002 to occur in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) to give the corresponding 4,40 -bis(oxazolones) 793 (Scheme 7.242). 1,3-Dipolar cycloaddition of 4-arylmethyleneisoxazol-5-ones 794 and 2-methyl4-phenyl-5(4H)-oxazolone 795 leads to pyrrole-3-carboxylic acids that have been isolated as hydroxamates 796. The authors carried out this cycloaddition–nitrile oxide addition as a one-pot reaction (Scheme 7.243).1003

290

5(2H)-Oxazolones and 5(4H)-Oxazolones

O

CO2t-Bu N H

Ac2O

O

O

N

BnO CONH

H-Bip-Ot-Bu

BnO CONH n

n

787

786

CO2t-Bu N H O BnO CONH n+1

788 Scheme 7.240

Ar

O R1

ArH

R1

O

O

N

H

Ar

N

R1

POCl3

N

O

Ph

Ph

Ph

789

790

791

Scheme 7.241

Ar O Ph

O

N

Ph O

TEMPO

N

O

O

O Ph N

O Ar

Ar 792

793 Scheme 7.242

Addendum

291

O Ph

+

N O 794

O

N

CO ONHCOR2

R1

Ph

R1

1) ∆

O

2) R2CNO

Me

Ph

N

Me

H

795

796 Scheme 7.243

Finally, new palladium(II) and platinum(II) complexes from 4-benzyl-4-methyl2-phenyl-5(4H)-oxazolone or C2 symmetric bis(oxazolone) ligands have been described.1004

7.6.1.3. Structural Analysis Molecular orbital calculations have been carried out on 2-(aminomethyl)-5(4H)oxazolone, 2-(aminomethyl)-4-methyl-5(4H)-oxazolone, 2-phenyl-5(4H)-oxazolone, 4-methyl-2-phenyl-5(4H)-oxazolone and on the corresponding cations from protonation. The susceptibility to protonation of the different heteroatoms shows that in all cases protonation occurs preferentially at the ring nitrogen. In contrast, comparison of protonation and metalation of 2-(aminomethyl)-5(4H)oxazolones reveals that lithium and silver cations simultaneously bind two heteroatoms, the amino group and either the ring nitrogen or oxygen. A metal cation coordinated with the two nitrogen atoms 797 is lowest energy isomer (Figure 7.66).1005 X-ray analysis of the saturated 5(4H)-oxazolone from N-benzyloxycarbonyl(Aib)4OH 798 (Fig. 7.67) has been determined.1006 The oxazolone ring is nearly planar. The conformation of the amino acid residue preceding the residue of the ring system is semiextended although the Aib1 and Aib2 residues are folded.

O O

N +M

N H

H

797 Figure 7.66. Proposed structure of 797 derived from metalation of 2-(aminomethyl)-5(4H)-oxazolones.

292

5(2H)-Oxazolones and 5(4H)-Oxazolones O

Me Me N

O Me

BnO CONH

Me 3

798 Figure 7.67. 798, A peptide oxazolone from N-benzyloxycarbonyl-(Aib)4OH analyzed by X-ray diffraction.

Unsaturated 5(4H)-Oxazolones (2-Oxazolin-5-ones)1007a

7.6.2.

7.6.2.1. Synthesis Condensation of N-acylglycines with carbonyl compounds, the Erlenmeyer synthesis, continues to be exploited to prepare of a wide variety of unsaturated5(4H)-oxazolones. The reaction is performed in the presence of a cyclodehydrating agent and recently bismuth(III) acetate has been evaluated in this capacity.1007b Alternatively, unsaturated 5(4H)-oxazolones can be obtained from hippuric acid and a carbonyl compound or from the appropriate dehydroamino acid derivative using 3-(alkoxycarbonyl)benzotriazole-1-oxides as the cyclodehydrating agent.1008 The Erlenmeyer reaction has also been used to prepare new 4-arylmethylene-2-[3chlorobenzo[b]thien-2-yl]-5(4H)-oxazolones 800 from the appropriate N-acylglycine 799 and several aldehydes (Scheme 7.244).1009 The pharmacological activity of these compounds as antibacterial and antiinflamatory agents has been studied. H R1

H O + R1

O

CO2H

N

S NHCO

O S

Cl Cl

799

800 Scheme 7.244

Reaction of N-acylthreonines with Lawesson’s reagent [2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide] affords a mixture of unsaturated 5(4H)oxazolones 801 and 5(4H)-thiazolones 802 (Scheme 7.245).1010 Deprotection of the a,b-didehydroamino acid 803 with TFA unexpectedly afforded the TFA salt of the 5(4H)-oxazolone 804 via an intramolecular cyclization (Scheme 7.246).1011

Addendum O

O

OH CO2H

Me

293

Lawesson´s reagent

MeCH

MeCH N

NHCOR

O +

S

N

R

R 802

801 Scheme 7.245

O CO2H

AcNH BocNH

NHCOPh

AcNH

Et3SiH

NH2

TFA

N

O Ph

803

804 Scheme 7.246

H CO2Me

MeO2C

O

CO2Me + MeO2C

MeO2C

N PPh3 805

H

H RCOCl

N

NHCOR 806

807

O R

Nu

H CONu

MeO2C

NHCOR 808 Scheme 7.247

Acylation of N-vinyl phosphazenes 805 derived from dehydroaspartic acid esters gives N-acylated dehydroaspartic acid esters 806 as well as the corresponding unsaturated-5(4H)-oxazolones 807. Subsequent nucleophilic ring opening of 807 affords N-acylated dehydroaspartic acid derivatives 808 (Scheme 7.247).1012 4-(Ethoxymethylene)-5(4H)-oxazolones are useful intermediates to prepare a variety of other 4-heteromethylene-5(4H)-oxazolones. In this context, 4-(ethoxymethylene)-5(4H)-oxazolones 809 were converted to 4-(aminomethylene)-5(4H)oxazolones 810 by reaction with amines as shown in Scheme 7.248.1013

294

5(2H)-Oxazolones and 5(4H)-Oxazolones H

H

O R2

HNR2R3

EtO N

O

O

N R3

O

N

R1

R1

809

810 Scheme 7.248

O CO2H

EtO

Ac2O CH(OEt)3

NHCO

CO2H

CO2H NHCOR

O

N

811

R

R

O

N

O

N

812

813

Scheme 7.249

For example, 4-(ethoxymethylene)-2-(1-naphthyl)-5(4H)-oxazolone 812, an intermediate for fluorescent 4-(N-substituted-aminomethylene)-2-(1-naphthyl)5(4H)-oxazolones 813, was prepared from 1-naphthoylglycine and triethyl orthoformate.1014 Reaction of 812 with amino acids gave the corresponding amino acid derivative 813 as a mixture of stereoisomers as shown in Scheme 7.249. H COX NHCOR1

POCl3/DMF

Me

H

O H

N Me

N

O

R2NH2

O

N R2

N

R1

R1 814

O

815

Scheme 7.250

Reaction of N-acylamino acids with the Vilsmeier–Haack reagent leads to 2alkyl-4-[(N,N-dimethylamino)methylene]-5(4H)-oxazolones 814. The reactivity of these compounds with various nucleophiles has been studied. Primary alkylamines undergo amine exchange with 814 to afford 2-alkyl-4-[(alkylamino)methylene]5(4H)-oxazolones 815 (Scheme 7.250).1015

7.6.2.2. Ring-Opening Reactions The reactivity of unsaturated 5(4H)-oxazolones can be divided in two main categories according to the reaction site, ring-opening reactions, and reactions of the exocyclic double bond.

Addendum

295

In the context of the nucleophilic ring-opening reactions, the mechanism of the reaction of 4-benzylidene-2-methyl-5(4H)-oxazolone with n-butylamine has been studied.1016 Synthetically, amino acid esters react with a 4-(indol-3-ylmethylene)-5(4H)oxazolone 406 to afford dehydropeptides 816 as shown in Scheme 7.251.1017

H

H2N

O

CO2R2

H N

H

H

R1

O

N

N H

N

C

PhCONH

O

Ph

CO2R2 R1

816

406 Scheme 7.251

The synthesis and antimicrobial activity of new 1-aryl-4-arylmethylene-2-phenyl5(4H)-imidazolones 818, obtained from reaction of 4-arylmethylene-2-phenyl5(4H)-oxazolones 817 and aromatic amines has been reported (Scheme 7.252).1018 H

H

O

R1

ArNH2

N

R2

O

N

R2

Ph

R3

O

R1 N Ar Ph

R3 818

817 Scheme 7.252

Similarly, 4-(furan-2-ylmethylene)-2-phenyl-1-substituted-5(4H)-imidazolones 820, evaluated as antibacterial and antifungal agents, have been synthesized from the 4-(furan-2-ylmethylene)-2-phenyl-5(4H)-oxazolone 819 (Scheme 7.253).1019 Using 4-arylmethylene-2-phenyl-5(4H)-oxazolones as substrates and 2-amino-5methyl-1,3,4-thiadiazoles as nucleophiles the synthesis of the corresponding H

H

O

O

RNH2

N

O

O

N

O

N R Ph

Ph 820

819 Scheme 7.253

296

5(2H)-Oxazolones and 5(4H)-Oxazolones H CO2H

Ar N

O

Me

R1 = Me

N H

O

O

Ar

NH2

O +

N

822

NH2 R1

O

H

821

R1 = Ph

PhCO

H N

Ar N O 823

Scheme 7.254

imidazolones has been performed on solid support under microwave irradiation. Comparing the microwave-assisted reaction with conventional heating it was concluded that the microwave-assisted reaction occurs with a considerable rate enhancement and improved yields.1020 A new method for the synthesis of 4(3H)-quinazolinones 822 and 1,4-benzodiazepine-2,5-diones 823 from reaction of 4-arylmethylene-2-methyl- 821 (R1 ¼ Me) or 4-arylmethylene-2-phenyl-5(4H)-oxazolones 821 (R1 ¼ Ph) with o-aminobenzamide has also been reported (Scheme 7.254).1021 These same authors described the reaction of 4-arylmethylene-5(4H)-oxazolones 824 with 2-(o-aminophenyl)benzimidazole to produce a mixture of substituted benzimidazo[1,2-c]quinazolines 825 and 826 (Scheme 7.255).1022 H

O N

Ar N

O + R1

N H H2N

824 N

N

N

N

+

N H

H

N R1

Ar 825

Scheme 7.255

826

H

Addendum

297

7.6.2.3. Reactions Involving the Exocyclic Double Bond Recently, the cyclopropanation of (Z)-4-benzylidene-2-phenyl-5(4H)-oxazolone 621 with phenyldiazomethane was reported to give the spirocyclopropane, rac-827 in very high yield.1023 Subsequent ring opening and hydrolysis of rac-827 generated trans-1-amino-2,3-diphenyl-1-cyclopropanecarboxylic acid, rac-828 (c3diPhe) (Scheme 7.256). This new, constrained phenylalanine analogue induces a g-turn in the solid state when incorporated into model dipeptides. The enantiomers of the N-Boc (Boc ¼ tert-butyloxycarbonyl) methyl ester of 828 have been resolved by HPLC.1024 Ph

H

PhCHN2

Ph N

O

CO2H

Ph N

O

Ph

NH2

Ph

Ph 621

Ph

O

O

rac-827

rac-828

Scheme 7.256

The use of 4-heteroarylmethylene- and 4-arylmethylene-5(4H)-oxazolones as dienophiles in the Diels–Alder reaction has been recently reviewed.1025 More recently the reactivity of the exocyclic double bond of 4-(alkoxymethylene)-5(4H)oxazolones with several dienes has been assessed. Reaction of 4-(methoxymethylene)-2-phenyl-5(4H)-oxazolone and 1,3-butadiene requires the presence of Et2AlCl as a catalyst and even then the Diels–Alder cycloadduct is obtained in low yield.1026 On the other hand, lithium perchlorate catalyzed Diels–Alder reaction between 4[(ethoxycarbonyloxy)methylene]-2-phenyl-5(4H)-oxazolone 829 and cyclopentadiene is more efficient and affords a mixture of the corresponding exo-830 and endo-831 cycloadducts. These cycloadducts have been converted to 2-amino-3hydroxynorbornenecarboxylic acid derivatives 832 and 833 or to 2-amino-3hydroxynorbornanecarboxylic acids 834 and 835 after a series of careful transformations.1027 In addition, 830 and 831 have been further elaborated to new conformationally constrained serine analogues, the polyhydroxy 2-aminonorbornanecarboxylic acids 836–839 as shown in Scheme 7.257.1028 Two asymmetric Diels–Alder approaches to analogues like 830 and 831 have been described. In the first case, chiral catalysts were employed for an enantioselective Diels–Alder reaction, but unfortunately, none of the chiral catalysts showed any enantioselectivity upon analysis of the reaction mixtures. Alternatively, a chiral oxazolone 840 incorporating a menthyl carbonate at C-4 was prepared and used as a dienophile with cyclopentadiene. In this case, the exo/endo ratio was 60:40 but no significant endo or exo diastereoselectivity was obtained (Scheme 7.258).1029 The chiral adduct 753, obtained from the unsaturated oxazolone 632 derived from (R)-glyceraldehyde and Danishefsky’s diene, has been conveniently elaborated to the valuable azabicyclic intermediate 844 used for the synthesis of

298

5(2H)-Oxazolones and 5(4H)-Oxazolones

CO2H

CO2H

NHCOPh

NHCOPh HO

CO2H HO

NH3 Cl

HO

834

H

832

O

EtO2CO

L.A.

EtO2CO

N

835

O +

O

N EtO2CO

Ph

Ph 829

NH3 Cl HO

833

O

O

N

CO2H

830

O Ph

831

HO HO HO

HO

HO

NH3 Cl

HO

NH3 Cl HO

NH3 Cl

836

838

CO2H

CO2H

CO2H

CO2H HO

OH

HO

HO

NH3 Cl HO 839

837

Scheme 7.257 Me

H

Me

HO N

O

H

OCOCl

O Me

O

MenthylO2CO

L.A.

Ph

Ph 392

O

N

840 O

MenthylO2CO

N

O O +

Ph 841

Scheme 7.258

N MenthylO2CO 842

O Ph

References

299 O

OMe

H

O

O N

O

O

1)

H

TMSO 2) HCl 3) DBU

O

1) H2, Pd/C

CO2Me NHCOPh

O

2) K-Selectride R

Ph 632

753 NH2 Cl

NCOPh 1) MsCl, Et3N

H

2) base 3) CH2N2

O

845 O

MeO2C O

CO2Me NHCOPh

O 843

CO2H

HO2C

OH

NH2 Cl 844 Pr

HO2C 846 Scheme 7.259

enantiomerically pure 2-substituted 7-azabicyclo[2.2.1]heptane-1-carboxylic acids 845 and 846, new conformationally constrained proline analogues.1030 The key step in the construction of the 7-azabicyclo[2.2.1]heptane system was the intramolecular cyclization of the mesylate of 843 as shown in Scheme 7.259.

7.6.2.4. Structural Analysis X-ray analysis of two new unsaturated oxazolones: 4-(ferrocenylmethylene)-2phenyl-5(4H)-oxazolone1031 and 2-phenyl-4-(4-toluidinomethylene)-5(4H)-oxazolone have recently been reported.1032

REFERENCES 1. Boyd, G. V. In Potts, K. T., Ed., Comprehensive Heterocyclic Chemistry Vol. 6, Pergamon, Oxford, UK, 1984, pp. 177–234. 2. Hartner, F. W., Jr. In Shinkai, I., Ed., Comprehensive Heterocyclic Chemistry II, Vol. 3, Pergamon, Oxford, UK, 1996, pp. 261–318. 3. Rao, Y. S.; Filler, R. In Turchi, I. J., Ed., Oxazoles, Vol. 45, The Chemistry of Heterocyclic Compounds; John Wiley & Sons, Inc., New York, 1986, pp. 363–691. 4. Bergman, J.; Lidgren, G. Tetrahedron Lett. 1989, 30, 4597–4600.

300

5(2H)-Oxazolones and 5(4H)-Oxazolones

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330

5(2H)-Oxazolones and 5(4H)-Oxazolones

1003. Grassi, G.; Risitano, F.; Foti, F.; Cordaro, M. Synlett 2001, 812–814. 1004. Bauer, W.; Ponikwar, W.; Beck, W. Z. Naturforsch., B: Chem. Sci. 2000, 55, 946–952; Chem. Abstr. 2001, 134, 172313. 1005. Rodriquez, C. F.; Shoeib, T.; Chu, I. K.; Siu, K. W. M.; Hopkinson, A. C. J. Phys. Chem. A 2000, 104, 5335–5342. 1006. Crisma, M.; Formaggio, F.; Toniolo, C. Acta Crystallogr. Sect. C: Cryst. Struct. Commun. 2000, 56, 695–696. 1007. (a) Section 7.6.2 of the Addendum pertains specifically to unsaturated 5(4H)-oxazolones previously described in Sections 7.4.1 (Synthesis), 7.4.2 (Ring-Opening Reactions), 7.4.3 (Reactions Involving the Exocyclic Double Bond), and 7.4.4 (Structural Analysis). (b) Monk, K. A.; Sarapa, D.; Mohan, R. S. Synth. Commun. 2000, 30, 3167–3170. 1008. Topuzyan, V. O.; Khachvankyan, G. Y. Khim. Zh. Arm., 2000, 53, 81–86; Chem. Abstr. 2001, 134, 29342. 1009. Kalluraya, B.; Gunaga, P.; Banji, D.; Isloor, A. M. Indian J. Heterocycl. Chem. 1999, 9, 47–50. 1010. Ori, M.; Nishio, T. Heterocycles 2001, 54, 201–208. 1011. Mauldin, S. C.; Hornback, W. J.; Munroe, J. E. J. Chem. Soc., Perkin Trans. 1 2001, 1554–1558. 1012. Palacios, F.; Legido, M.; De Heredia, I. P.; Rubiales, G. Heterocycles 2000, 52, 1057–1064. 1013. Coffen, D. L.; Dillon, M. P.; Ford, A. P. D. W.; Gogas, K. R.; Jacobson, L.; Li, Z.; Williams, T. J. PCT Intl. Appl. WO 0055143, 2000; Chem. Abstr. 2000, 133, 252420. 1014. Koczan, G.; Csik, G.; Csampai, A.; Balog, E.; Bosze, S.; Sohar, P.; Hudecz, F. Tetrahedron 2001, 57, 4589–4598. 1015. Singh, R. S.; Singh, R. M. Indian J. Chem., Sect. B 2000, 39, 688–693. 1016. Betlakowska, B.; Banecki, B.; Lankiewicz, L.; Wiczk, W. Pol. J. Chem. 2001, 75, 401–410. 1017. Mandour, A. H.; Shalaby, A. M.; Kassem, E. M. Egypt. J. Chem. 1999, 42, 251–266. 1018. Solankee, A.; Kapadia, K.; Mistry, P.; Patel, J.; Lad, S. Orient. J. Chem. 2000, 16, 155–158. 1019. Sarma, G. V. S. R.; Reddy, V. M. J. Inst. Chem. 2000, 72, 106–110. 1020. Kidwai, M.; Sapra, P.; Bhushan, K. R.; Misra, P. Synthesis 2001, 1509–1512. 1021. Subhashini, N. J. P.; Hanumanthu, P. Indian J. Chem., Sect. B 2000, 39, 198–201. 1022. Subhashini, N. J. P.; Hanumanthu, P. Indian J. Chem., Sect. B 2001, 40, 430–432. 1023. Jimenez, A. I.; Lopez, P.; Oliveros, L.; Cativiela, C. Tetrahedron 2001, 57, 6019–6026. 1024. Jimenez, A. I.; Cativiela, C.; Marraud, M. Tetrahedron Lett. 2000, 41, 5353–5356. 1025. Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.; Zurbano, M. M. Targets Heterocycl. Syst. 1999, 3, 185–214. 1026. Avenoza, A.; Barriobero, J. I.; Cativiela, C.; Fernandez-Recio, M. A.; Peregrina, J. M.; Rodriguez, F. Tetrahedron 2001, 57, 2745–2755. 1027. Clerici, F.; Gelmi, M. L.; Gambini, A. J. Org. Chem. 2000, 65, 6138–6141. 1028. Clerici, F.; Gelmi, M. L.; Gambini, A. J. Org. Chem. 2001, 66, 4941–4944. 1029. Abbiati, G.; Clerici, F.; Gelmi, M. L.; Gambini, A.; Pilati, T. J. Org. Chem. 2001, 66, 6299–6304. 1030. Bun˜uel, E.; Gil, A. M.; Diaz-de-Villegas, M. D.; Cativiela, C. Tetrahedron 2001, 57, 6417–6427. 1031. Ponikwar, W.; Bauer, W.; Beck, W. Z. Kristallogr. 2000, 215, 625–626. 1032. Vasuki, G.; Parthasarathi, V.; Ramamurthi, K.; Singh, R. M.; Srivastava, A. Acta Crystallogr. Sect. E: Struct. Rep. Online, 2001, 57, 120–121.

CHAPTER 8

2-Oxazolines George S.K. Wong Schering-Plough Research Institute, Union, New Jersey

Wenxue Wu Schering-Plough Research Institute, Union, New Jersey

8.1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Synthesis of Oxazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.1. Oxazolines from Carboxylic Acids and Esters . . . . . . . 8.2.2. Oxazolines from b-Hydroxy Amides . . . . . . . . . . . . . . 8.2.2.1. Thionyl Chloride . . . . . . . . . . . . . . . . . . . . . 8.2.2.2. Vilsmeier Reagent . . . . . . . . . . . . . . . . . . . . 8.2.2.3. Strong Acids . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2.4. Acetates, Mesylates, Tosylates, and Triflates . . 8.2.2.5. Burgess Reagent . . . . . . . . . . . . . . . . . . . . . 8.2.2.6. Mitsunobu Reaction . . . . . . . . . . . . . . . . . . . 8.2.2.7. DAST and Deoxo-Fluor . . . . . . . . . . . . . . . . 8.2.2.8. Triphenylphosphine and Carbon Tetrachloride . 8.2.3. Oxazolines from b-Halo Amides. . . . . . . . . . . . . . . . . 8.2.4. Oxazolines from Nitriles . . . . . . . . . . . . . . . . . . . . . . 8.2.4.1. Direct Methods . . . . . . . . . . . . . . . . . . . . . . 8.2.4.2. Indirect Methods . . . . . . . . . . . . . . . . . . . . . 8.2.4.3. Oxazolines from Ritter Reaction . . . . . . . . . . 8.2.5. Oxazolines from N-Acylaziridines. . . . . . . . . . . . . . . . 8.2.6. Oxazolines from Allyl amides (Enamides) . . . . . . . . . . 8.2.7. Oxazolines from Isonitriles . . . . . . . . . . . . . . . . . . . . 8.2.8. Oxazolines from Cycloadditions . . . . . . . . . . . . . . . . . 8.2.8.1. [2 þ 2] Cycloadditions . . . . . . . . . . . . . . . . . 8.2.8.2. [3 þ 2] Cycloadditions . . . . . . . . . . . . . . . . . 8.2.8.3. [4 þ 2] Cycloadditions . . . . . . . . . . . . . . . . . 8.2.9. Miscellaneous Methods . . . . . . . . . . . . . . . . . . . . . . . 8.3. Reactions and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.1. Nucleophilic Reactions . . . . . . . . . . . . . . . . . . . . . . . 8.3.1.1. Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . .

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The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

331

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332 333 333 338 338 347 348 351 361 365 368 373 375 383 384 389 395 398 402 406 407 407 408 410 412 417 417 417

332

2-Oxazolines

8.3.1.2. Substitution at the 2-Position by Other Nucleophiles 8.3.1.3. Nucleophilic Substitution at the 5-Position . . . . . . . 8.3.2. N-Alkylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.3. Proton Abstractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.4. Oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.5. Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.6. Oxazolines as Protecting Groups. . . . . . . . . . . . . . . . . . . . . 8.3.7. Oxazolines as Activating Groups . . . . . . . . . . . . . . . . . . . . 8.3.7.1. a-Proton Abstraction . . . . . . . . . . . . . . . . . . . . . . 8.3.7.2. Michael Additions of 2-Alkenyloxazolines . . . . . . . 8.3.7.3. Diels–Alder Reactions of 2-Alkenyloxazolines . . . . 8.3.8. Dipolar Cycloadditions of Oxazoline N-Oxides . . . . . . . . . . 8.3.9. Oxazolines as Directing Groups for Aromatic Reactions . . . . 8.3.9.1. Metalation and Electrophilic Substitution . . . . . . . . 8.3.9.2. Nucleophilic Substitutions. . . . . . . . . . . . . . . . . . . 8.3.9.3. Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . 8.3.10. Oxazolines as Chiral Directing Groups . . . . . . . . . . . . . . . . 8.3.11. Oxazolines as Ligands in Asymmetric Catalysis . . . . . . . . . . 8.3.11.1. Oxazoline Ligands . . . . . . . . . . . . . . . . . . . . . . . . 8.3.11.2. Allylic Substitution Reactions . . . . . . . . . . . . . . . . 8.3.11.3. Heck Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.11.4. Hydrogenation Reactions . . . . . . . . . . . . . . . . . . . 8.3.11.5. Additions of Dialkylzincs to Aldehydes . . . . . . . . . 8.3.11.6. Hydrosilylation Reactions . . . . . . . . . . . . . . . . . . . 8.3.11.7. Michael Addition Reactions . . . . . . . . . . . . . . . . . 8.3.11.8. Cyclopropanation Reactions . . . . . . . . . . . . . . . . . 8.3.11.9. Miscellaneous Catalytic Reactions . . . . . . . . . . . . . 8.3.12. Polymeric Oxazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.13. Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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427 430 433 435 440 440 442 442 442 445 447 447 448 448 462 469 476 481 483 487 493 495 501 503 504 504 506 507 508 513 513

8.1. INTRODUCTION The first oxazoline was prepared in 1884.1 Despite an early review2 in 1949 on the basic chemical properties of oxazolines, much of the research during the subsequent years focused on polymeric oxazolines. These polymeric oxazolines3,4 found numerous industrial applications including surface protective coatings, as additives in gasolines and lubricating oils, as corrosion inhibitors, and as additives to textile chemicals. It was not until the early 1970s that the synthetic usefulness of oxazolines, in particular, those of 2-oxazolines (4,5-dihydro-1,3-oxazole), in organic synthesis was explored. In 1976, a review5 of the chemistry of 2alkyloxazolines firmly established that they are ideal reagents for the syntheses of chiral and non-chiral carboxylic acids, chiral alcohols, amino acids, aldehydes and ketones. Furthermore, the stability of the oxazoline ring to a wide variety of reagents other than mineral and Lewis acids have also made them ideally suited as a carboxylic protecting group.6 During this period, it was also discovered that 2aryloxazolines undergo electrophilic substitution, through directed ortho-lithiation

Synthesis of Oxazolines

333

of the aromatic nucleus. On the other hand, aryloxazolines derived from o-methoxy or o-fluoro benzoic acids undergo nucleophilic substitution. The predictability of these reactions allowed aryloxazolines as intermediates for the construction of a variety of substituted benzenes and biphenyls, some of which can be difficult to obtain via classical methods. Extensive exploration of oxazolines in these areas continued, evidenced by the publication of a book chapter,7 and reviews8–14 devoted entirely to the use of oxazolines in asymmetric syntheses. Aside from such interests of oxazolines as synthetic intermediates, oxazolines are also found in a variety of marine natural products.15,16 In particular, the oxazoline or dihydroxazole-containing lissoclinamide family of macrocyclic peptides has attracted much interest in their total syntheses.17,18 Another important new development in oxazoline chemistry in the past 10 years or so was the application of these heterocycles as chiral ligands in a wide range of asymmetric catalytic processes.19–23 In this chapter, we will focus primarily on the literature from 1993 forward since Meyers has already comprehensively reviewed the period from 1985 to 1993– 1994.9 The discussion is divided principally into two sections, first reviewing the synthetic methods, followed by recent applications in organic syntheses. We will limit our discussion of oxazolines to synthetic applications in small molecules. In addition, given the frequency with which oxazolines are employed in chiral syntheses and natural product syntheses we have made every effort to reproduce the orientation of the oxazoline in the same manner as that reported in the original literature citation. Therefore, we have sacrificed some degree of structural consistency throughout this chapter. Benzoxazoles will not be included in this chapter. Finally, we will not be covering in detail chemical applications facilitated by bis(oxazoline) ligands in various metal-catalyzed asymmetric syntheses. The reader is referred to Chapter 9 for a comprehensive survey and review of this very important subject in asymmetric catalysis.

8.2. SYNTHESIS OF OXAZOLINES Here, we will mention synthetic methods that are of general application. Because oxazolines are so often used as intermediates in synthesis, it is impossible to include every oxazoline that has been prepared. Instead, we will illustrate with examples the diversity of structures wherein the oxazoline ring structure is first constructed. 8.2.1.

Oxazolines from Carboxylic Acids and Esters

The conceptually simple cyclodehydration of a carboxylic acid and a b-amino alcohol to an oxazoline requires harsh conditions of high temperature with azeotropic water removal (e.g., boric acid in refluxing xylene). Nonetheless, good yields of the oxazoline can be obtained if sensitive functionalities are absent.24–26 A much milder approach has been developed by Vorbru¨ggen27 where the reaction of carboxylic acids with b-amino alcohols is carried out in the

334

2-Oxazolines O R1

R2 OH

R3

PPh3

+ H2N

OH

solvent base

N

R2

O

R3

R1

1 Scheme 8.1

presence of triphenylphosphine. The reaction is typically carried out in carbon tetrachloride (CCl4), acetonitrile (MeCN), or hexachloroethane. The presence of a tertiary base such as triethylamine (Et3N) or diisopropylethylamine (DIPEA), 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), or pyridine (Py), which is sometimes also used as a cosolvent, is absolutely essential to obtain a good yield of the oxazoline. Otherwise, b-chloro amide formation can be a serious side reaction. This one-pot procedure is applicable to both aliphatic and aromatic carboxylic acids. Phenols need not be protected. Selected examples are listed in Table 8.1 (Fig. 8.1; Scheme 8.1).27–33 A number of nonsteroidal antiinflammatory drugs (NSAID) wherein the carboxylic moiety is modified as an oxazoline have been prepared by this method.27 These modified NSAIDs (Table 1, entries 4–6) exhibit antiinflammatory properties. However, they are less potent than their original counterparts. Importantly, they did not reduce stomach ulceration at the efficacious dose, and therefore did not present any advantage over the original NSAID. TABLE 8.1. OXAZOLINES FROM CARBOXYLIC ACIDS

R2

O

R3

+ R1

OH

H2N

OH

N

R2

O

R3

R1

1 Figure 8.1 Entry

Product

% Yield

Reference

74

27

83

27

68

27

N 1

N

2

O N

CO2Me

O

Me

O2N

N 3

O HO

Synthesis of Oxazolines

335

TABLE 8.1 (Continued) Entry

Product

% Yield

Reference

72

27

51

27

83

27

62

28

53

29

87

30

N Cl

O N N

4

F N

5

NH

O

Cl

Cl

N 6

O

TMSO

TMSO

OTMS

S

SMe

N

7

O

N 8

Ph Ph

OH

N

O

O

OMe OMe 9

N

MeO O

336

2-Oxazolines

TABLE 8.1 (Continued) Entry

Product

% Yield

Reference

OH R ¼ H, Z ¼ Bn, 60–70

10

Z

31

R ¼ H, Z ¼ NHTs, 44

N R O

R2

R1

R1 N

R2

N

O

O

R1 ¼ H, Ph, 4-MeO Ph

11

N R2

32

R2 ¼ H, i-Pr, 4-CF3 Ph 20–45 (4 examples)

O

R1 R2 OH R ¼ Ph, t-Bu R1 ¼ NO2, MeO R2 ¼ H, NO2 19–67 (6 examples)

12

N

R1

R O

33

Aliphatic and aromatic carboxylic esters are also directly converted, in one step, to oxazolines using amino alcohols. As expected, harsh conditions are required for this transformation. Typically, the reaction is performed in refluxing xylene in the presence of catalytic quantities of a Lewis acid such as dibromo-34 or dichlorodimethylstannane.35 More recently, lanthanide chloride and samarium chloride have also been reported as useful catalysts for this one-pot transformation in refluxing toluene.36 Representative examples are shown in Table 8.2 (Scheme 8.2).34–36 Isatoic anhydride undergoes a one-step conversion to o-aminophenyloxazolines 2 with amino alcohols via elimination of carbon dioxide.37 The reaction is carried out in the presence of kaolinitic clay in refluxing chlorobenzene. These oaminophenyloxazolines, in particular, those derived from chiral amino alcohols, O R1

R2 OR

R3

H2N

OH

N

catalyst

+ solvent

O

R = Me, Et 1 Scheme 8.2

R2

R1 R3

337

CO2Me

O

N

Ph

N

CO2Et

CO2Et

CO2Me

CO2Et

CO2Et

H2N

H2N

H2N

H2N

H2N

Ph

CO2Me

CO2Et

Me

R

OH

R

OH

OH

OH

OH

OH

NH2

OH

NH2

Amino Alcohol

CO2Me

Ester

O

N

N

Ph

Me

R

Ph

O

N

N

O

N

O

N

O

N

N

R

O

O

N

O

O

Product

TABLE 8.2. OXAZOLINES FROM CARBOXYLIC ESTERS AND AMINO ALCOHOLS

N

N

O

Ph

Me

R R

SmCl3 (82)

LaCl3 (64)

LaCl3 (75)

SmCl3 (54)

LaCl3 (82)

R ¼ H, (97) R ¼ Me, (94)

Me2SnCl2

Me2SnBr2 (52)

Catalyst (% Yield)

36

36

36

36

36

35

34

Reference

338

2-Oxazolines NH2

H N

O O

R

N

amino alcohols

NH

R1

40-70%

O

N

R

O

R1

O

clay, PhCl, reflux

3

2 R1 = i-Pr (R), i-Bu (R), Bn (R), Ph (S), Et(S); R = H; R = R1 = H, Me Scheme 8.3

can be further linked to chloromethylated styrene-divinylbenzene polymer. The resulting chiral polymers 3 may find use in heterogeneous asymmetric catalytic reactions (Scheme 8.3). 8.2.2.

Oxazolines from b-Hydroxy Amides

A popular approach to prepare oxazolines involves the intramolecular cylization of a b-hydroxy amide, through activation of the  OH group as a leaving group. This two-step process is widely applicable for the syntheses of structurally diverse analogues, including 2-, 4-, and 5-monosubstituted oxazolines, as well as multiply substituted oxazolines. The requisite b-hydroxy amides, commonly prepared via acylation of the appropriate amino alcohol with acid chlorides, anhydrides, and via classical peptide coupling methodology, can also be prepared through amidation with an amino alkoxide (from an amino alcohol and sodium hydride or n-BuLi38–40 or methyl aluminum).41 Naphthol has been converted to the corresponding triflate and undergoes CO insertion with valinol to give the corresponding hydroxy amide.42 The most commonly used reagents to effect this cyclodehydration will be discussed in the following sections (Scheme 8.4). O R2

Cl

R1

OH

+ H2N

O

R3 R1

R3

H N

R1 O

OH R2

OR

N

R2

O

R3

R1 1

R = H, Me, Et Scheme 8.4

8.2.2.1. Thionyl Chloride Thionyl chloride (SOCl2) has often been used as a dehydrating agent for primary, secondary, as well as tertiary b-hydroxy amides. With primary hydroxyl amides, the intermediate b-chloro amide can usually be isolated, which will then

Synthesis of Oxazolines MeO2C

MeO2C

OH

HN

SOCl2

O

N3

MeO2C

Cl

HN

THF, 4 ˚C 75%

339

O

+

N3

Cl

HN

O

N3

4

5

6 6:1

Scheme 8.5

require treatment under basic conditions to complete cyclization to the oxazoline in a separate step. Silver triflate has also been used for this purpose.43 Representative examples are shown in Table 8.3 (Fig. 8.2).29,30,39,40,42,44–67 In their synthesis of (þ)-calyculin A and ()-calyculin B, Smith and co-workers observed partial epimerization when the b-hydroxy amide 4 was reacted with SOCl2 despite the mild reaction conditions, 4
C in tetrahydrofuran (THF).43 The mechanism of this epimerization was not discussed (Scheme 8.5). Oxazoline hydrochlorides can sometimes be isolated directly from the reaction.68–70 Holerca and Percec investigated the mechanism for oxazoline ring formation of several primary b-hydroxy amides with SOCl2 by nuclear magnetic resonance (NMR).71 Oxazoline formation was extremely fast with amides 7a–c and the reaction was complete within minutes at 23
C. With amide 7e, the reaction is sufficiently slow so that reaction intermediates can be monitored. Thus, they observed that formation of 10 was preceded by the chlorosulfite 8. The results of this study suggest that pathway A predominates for aryl groups substituted with electron-donating groups because of the enhanced reactivity of the carbonyl group due to resonance stabilization. In these instances, b-chloro amide formation occurs via a slow chloride substitution at the 5-position of the oxazolinium ring. The proposed mechanism clarifies situations when a two-step process is needed for oxazoline ring formation using thionyl chloride (Scheme 8.6). O R

N H

O

O

SOCl2

OH R

7a R = 3,4,5-tri-[O(CH2)11Me]3Ph 7b R = 3,4-di-[O(CH2)11Me]2Ph 7c R = 3,4,5-tri-MeO-Ph 7d R = 4-Me-Ph 7e R = (CH2)8Me

S

Cl

O

N

O path B

R

H 8 −SO2

Cl

N H 10

path A

H N+ R

O Cl

O 9 Scheme 8.6

_

R

N H 10

Cl

340

2-Oxazolines

TABLE 8.3. OXAZOLINES FROM PRIMARY b-HYDROXY AMIDES AND SOCl2 R2

O

H N

R1 R2

O

X

R1

H N

R1

OH

H2N

R2

O

N

R2

R1 O

OH

X = Cl or X = OH, OMe, OEt

Cl

Figure 8.2 Oxazoline

Conditions

Ph

1. SOCl2, DCE, reflux; 2. NaOH, MeOH, THF, reflux

Ph N

N N

O

N

O

N N

N O

29

Ligand preparation

29

SOCl2; 100%

Intermediate for the synthesis of actinoidic acid, degradation product of vancomycin

30

SOCl2, rt

Intermediate for the total synthesis of dengibsin

39

Ligand preparation

40

43%

N O

71%

HO

Reference

Ligand preparation

1. SOCl2, DCE, reflux; 2. NaOH, MeOH, THF, reflux

OH

Comments

OMe OMe N

MeO O O-i-Pr O-i-Pr

83% (from ester)

N O N

N N

O

N

N O

O

OMe

74% (from btrifloylamide)

O

1. SOCl2, reflux; 2. NaOH, MeOH, 40
C

N Ph

Ph Ph

44% (from ester) 1. SOCl2, CH2Cl2, 0
C; 2. MeCN, H2O, K2CO3, reflux

O

N

1. SOCl2, CH2Cl2, rt; 2. t-BuOK, CH2Cl2

Ph

40%

Intermediate for 42 the total synthesis of ()-aphanorphine and ()-eptazocine

Ligand for asymmetric Diels–Alder reaction

44

Synthesis of Oxazolines

341

TABLE 8.3 (Continued) Oxazoline

Ph

O

O

N

N

Conditions

Ph

Ph

1. SOCl2, toluene, reflux; 2. NaOH, MeOH, reflux

Comments

Reference

Ligand for asymmetric Diels–Alder reaction

44

Intermediate for the total synthesis of ()veadeiroic acid

45

Ph 80% 1. SOCl2, rt; 2. 10% NaOH

OMe 70%

N O OMe MeO

Br N R O

R

N Me

O O

Me

Me

N

R

N

R

O O

Me

N

R

1. SOCl2, CH2Cl2, rt; 2. 20% K2CO3, MeCN, reflux R ¼ t-Bu (S); 82% R ¼ Ph (S); 83% R ¼ i-Pr (S); 85% R ¼ Et (S); 77% R ¼ Me (S); 98% R ¼ t-Bu (R); 85%

Intermediates for the 46 total syntheses of ()-herbertenediol, ()-mastigophorene A, and ()mastigophorene B

1. SOCl2, CH2Cl2, rt; 2. K2CO3, MeCN/ H2O, reflux R ¼ Ph, 86% R ¼ t-Bu, 65% R ¼ Bn, 80% R ¼ i-Pr, 71%

Ligand for 47 asymmetric allylic oxidation

1. SOCl2, CH2Cl2, rt; 2. K2CO3, MeCN/ H2O, reflux R ¼ Ph, 74% R ¼ t-Bu, 62% R ¼ Bn, 79% R ¼ i-Pr, 60%

Ligand for 47 asymmetric allylic oxidation

O SOCl2

N

48

75%

O 1. SOCl2, 96%

MeO N

MeO OMe O

Intermediate for the total synthesis of (S)gossypol

49

342

2-Oxazolines

TABLE 8.3 (Continued) Oxazoline R

Conditions

Comments

Reference

OMe

MeO N

MeO

1. SOCl2 R ¼ H, 94% R ¼ CH2OMe, 87%

Intermediate for the total synthesis of (S)-gossypol

49

SOCl2

Intermediate for the total synthesis of calyculins

50

Ligand preparation

51

Ligand preparation

51

O N BocHN

CO2Me

O

59% 1. SOCl2, CH2Cl2; 2. Et3N, CHCl3, reflux

N O

Br

69% N

O

O

O

O N

1. SOCl2, CH2Cl2, rt; 2. KF-alumina, MeCN, rt 88%

N

SOBr2

O

81%

N

52

Br

SOCl2, CH2Cl2

OMe OMe

53

81–85%

N O O

N O

1. SOCl2, reflux; 2. NaOH, EtOH, reflux

Intermediate for the 54 synthesis of hepatic gluconeogenesis inhibitors

67% SOCl2, rt N

O

99%

O

Intermediate for 55 the synthesis of testerone 5areductase inhibitors

O

SOCl2, rt N O

95%

Intermediate for the 55 synthesis of testerone 5areductase inhibitors

Synthesis of Oxazolines

343

TABLE 8.3 (Continued) Oxazoline

Conditions 1. SOCl2; 2. NaOH

N

Br

80%

O

Comments

Reference

Intermediate for the 56 synthesis of RTEM1 b-lactamase inhibitors

R N O OH OH

1. SOCl2, CH2Cl2, rt; 2. K2CO3, MeCN, H2O, reflux R ¼ Ph, 45% R ¼ i-Pr, 38% R ¼ Bn, 65%

Ligand for asymmetric 1,3dipolar cycloaddition of nitrones

57

1. SOCl2, CH2Cl2, rt; 2. K2CO3, MeCN, H2O, reflux R ¼ Ph, 55% R ¼ i-Pr, 55% R ¼ Bn, 44%

Ligand for asymmetric 1,3dipolar cycloaddition of nitrones

57

SOCl2, CH2Cl2

Intermediate for the total synthesis of lacinilene C-7 methyl ether

58

Intermediate for the total synthesis of actinoidic acid derivatives

59

Intermediate for the total synthesis of (þ)-a-curcumene and (þ)xanthorrhizol

60

N R O R N O OH OH N R O

N

O

MeO

OMe

73% (from acid)

Me N Br

O

SOCl2 85% (from amide)

OMe N

SOCl2

O 54%

Br

1. SOCl2, CH2Cl2; rt; 2. NaHCO3

N O

60% (from acid)

61

344

2-Oxazolines

TABLE 8.3 (Continued) Oxazoline

Conditions

N O

Comments

1. SOCl2,, rt; 2. NaOMe, MeOH, reflux

Reference 62

39% (from b-chloroamide)

O 1. SOCl2,, benzene, reflux; 2. NaOH, MeOH, reflux

N N O

Ligands for asymmetric synthesis

63

75% (from acid)

O 64

1. SOCl2, 2. 20% NaOH, Et2O

N

Mn(CO)3

Et 87%

N

R2 1. SOCl2, MeCN; 2. 50% KOH

R1

H

65

O 47%

OMe 1. SOCl2, reflux; 2. NaOH, EtOH, reflux

N O

O

65% from acid (3 steps)

O

N N

OH

66

N HO

1. SOCl2, CHCl3, reflux; 2. NaOH, MeOH

Ligand preparation

67

61% from hydroxyamide

For secondary b-hydroxy amides, the ring closure occurs via an SN2 mechanism with complete inversion at carbon bearing the hydroxyl group. Thus, both cis- and trans-4,5-disubstituted oxazolines can usually be obtained reliably. Representative examples are shown in Table 8.4.64,72–80 However, racemization has been reported. For example, during the total synthesis of mycestericin, Node and co-workers81,82 reported that treatment of enantiomerically pure threo-benzamide 11 with SOCl2 unexpectedly gave a 1: 1 trans- and cis-mixture of oxazolines 13a and 13b. Consistent with this configurational assignment, further reaction with an electrophile would result in a racemic

Synthesis of Oxazolines

345

TABLE 8.4. OXAZOLINES FROM SECONDARY AND TERTIARY b-HYDROXY AMIDES AND SOCl2 Oxazoline

Yields O

91%

64

Me

O

MeO

Ph

H N

Ph N

O

O

Not reported

Catalyst for enantioselective protonation

72

92%

Catalyst for enantioselective protonation

73–75

Not reported

Catalyst for enantioselective protonation

73

O

Ph H N N

Ph O

O

O

References

Ph

N Mn(CO)3

O

Comments

Ph Ph H Ph N N O O

R

N Ph

CO2Me

O N

CO2R

O

Me Ph

Ph

65%

O

O

76

R ¼ CO2Me, 70% R ¼ Me, 83% R ¼ phenacyl, 44%

Ph

N

R ¼ i-Bu, 71%

77

Taxol side-chain synthesis

78

Intermediate for the total synthesis of lactacystin

79

PhS

N

CO2Me

Ph O Ph O N Fe

Ph

36%

Ligand for asymmetric hydrogenation

80

346

2-Oxazolines

product. Indeed, reaction of the crude oxazoline mixtures with formaldehyde in the presence of DBU followed by acetic anhydride resulted in 14 with only 14% enantiomeric excess (ee). Additionally, since enantiomerically pure 14b was obtained from enantiomerically pure oxazoline 13b (cyclization of imidate 15 to oxazoline 13b occurred with retention of stereochemistry), the authors concluded that the configuration at the b-hydroxy carbon atom in benzamide 11 was not completely inverted during the oxazoline forming reaction. The loss in stereoselectivity was attributed to neighboring-group participation from the benzyl ether 12 in during the cyclodehydration process (Scheme 8.7). The reaction of the b-hydroxy amides with SOCl2 can be solvent sensitive. For example, during the semisynthesis of paclitaxel from baccatin III,83–87 the reaction of hydroxybenzamide 16 with SOCl2 in benzene gave a mixture of isomeric 2-oxo1,2,3-oxathiazolidines 17a and 17b together with a small amount of the transoxazoline 18a. If a polar solvent is used, 18a is formed as the exclusive product.84

PhCO NH

Ph

Cl

OH

PhCO NH

SOCl2

O

O S

HN

O

MeO2C

MeO2C BnO

OBn

11

MeO2C BnO

12a Ph

Ph

O

O

+

N

N

OBn

CO2Me

12b

13a Ph

OBn

CO2Me 13b Ph

O

O

1. DBU/(CH2O) 2. Ac 2O/Py

+

N AcOCH2 CO Me 2

OBn

N AcOCH2 CO Me 2

14a

OBn

14b

NH Ph H2N

Ph

Ph

O

O N

MeO2C OBn 15

O

1. DBU/(CH2O) 2. Ac 2O/Py

CO2Me

OBn

13b Scheme 8.7

N AcOCH2 CO Me 2 14b

OBn

Synthesis of Oxazolines

347

O Ph

NH

O

Ph

OMe

Bz

O

SOCl2

S N O

benzene 0 to 5 ˚C

OH 16

Bz Ph Ph N S H + H + Ph O O H H CO2Me CO2Me

17a SO2Cl2

17b

N

Ph

O

CO2Me

N

Ph

O

CO2Me 18a

Ph

19 Scheme 8.8

The expected cis-oxazoline 19 can be prepared using SO2Cl2 instead of SOCl2 (Scheme 8.8). Gibson and co-workers88 reacted tertiary alcohol diamides with SOCl2 to prepare a series of bis(oxazoline) ligands 20a–f that are used as catalysts for asymmetric cyclopropanations. This method was preferred for preparation of 20e–f. Use of a strong acid such as methanesulfonic acid promoted extensive elimination of water to give the corresponding enamides (Scheme 8.9). O OH Ar Ar

O NH HN

R

OH

SOCl2, Et3N

O

Ar Ar

Ar Ar

O N

Ar

N R

R

R

Ar

20a-f R = i-Pr, t-Bu, Ph, Bn Ar = 4-tolyl, 2-naphthyl Scheme 8.9

8.2.2.2. Vilsmeier Reagent Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary b-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10).89 Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. b-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The

348

2-Oxazolines NHCOPh Ph

Vilsmeier reagent

CO2Me

N

Ph

O

CO2Me

Ph

pyridine, rt

OH

18b Scheme 8.10

inexpensive costs of reagents coupled with the ease of removal of byproducts have made the Vilsmeier reagent an attractive reagent for oxazoline formation. Phosphorous oxychloride (POCl3) can also be used without further activation.90 For the synthesis of the antidepressant (R)-()-rolipram 24, cyclization of the bhydroxy amide 21 with POCl3 gave the oxazoline intermediate 22. Diastereoselective conjugate addition of cyanide gave the cyano derivative 23, which was further transformed to (R)-()-rolipram (Scheme 8.11). Unexpected oxazoline formation was observed during a study to prepare nonsedating anxiolytic 1-styrylisoquinolines 27a–h from 2-(trifluoromethyl)arylethylamines 25a–h under Pictet–Gams conditions (POCl3 in refluxing toluene).91 This deviation from the normal reaction pathway was hypothesized to result from the electron-withdrawing effect of trifluoromethyl group that inhibited the formation of a benzylic cation required for isoquinoline formation (Scheme 8.12).

8.2.2.3. Strong Acids Secondary and tertiary b-hydroxy amides can be cyclized to oxazolines in the presence of strong acids such as methanesulfonic acid92 or p-toluenesulfonic acid.79 For tertiary b-hydroxy amides, elimination to the enamide can often be a competing TABLE 8.5. OXAZOLINES FROM b-HYDROXY AMIDES USING VILSMEIER REAGENTa

NHCOR1 R2

R3

Vilsmeier reagent

OH

N

R2

O

R3

R1

Figure 8.3 R1 2-(i-PrS)Ph 2-(PhS)Ph 2-Br Ph 2-Br Ph Ph Ph Ph 2-(BocNH) Ph a

Data from Ref. 89.

R2 Ph Ph (S) i-Pr (S) Ph (S) Ph (S) Ph CO2Me i-Pr (S)

R3 H H H H Me (S) CN H H

% Yield 80 56 85 63 69 55 29 71

Synthesis of Oxazolines

349 OMe

OMe O

POCl3 / toluene

O

92%

NH

HO

O

O N

Ph

Ph 21

22 OMe

OMe Et2AlCN

O

steps

O N

O

O

CN

HN

Ph 23

24 (R)-(-)-rolipram Scheme 8.11

side reaction.88 Some recent examples of acid-catalyzed dehydration are shown in Scheme 8.13. The preparation of several glucofuran[2,1-d]oxazolines 35 and 36 from reaction of 2-amino-2-deoxy-D-glucose 34 with HF has been described.93 Compounds 35a and 35b are formed when the reaction is carried out in formic acid, whereas the orthoesters 36a–c are formed when the reaction is carried out using anhydrides. Further reaction of 35 and 36 with methanol gives methyl glycosides. Thus, 35 and 36 may find use as potential glycosyl donors for the synthesis of 2-amino-2-deoxy sugars (Scheme 8.14).94

R1 R2

CF3

OH

H

N

CF3

CF3 O

R1

POCl3

R1 N

O

95 ˚C, toluene 65-87% 8 examples

R

R 25a-h

26a-h R = H, F, CF 3, NO2 R1 = OMe, R2 = H or R1,R2 = OCH2O Scheme 8.12

N

R2

R2

R 27a-h not observed

350

2-Oxazolines

O OH R

NH

R

O

N

R R

HN

O

MsOH

OH

R = Et, 90% R = Ph, 85%

R N

N

R

O R

N

R

28

29 H N

N

MsOH

OH 88%

O

O

30

31 Ph

HN

TsOH

O

CO2Me

N Ph O

89%

CO2Me OH 32

33 Scheme 8.13

Deprotection of urethane-protected tertiary b-hydroxy amides 37 with trifluoroacetic acid followed by spontaneous cyclization of the liberated hydroxy amide affords oxazolines 38.95 The rate of deprotection is further accelerated by the addition of CaCl2. Examples are shown in Table 8.6 (Fig. 8.4; Scheme 8.15).

HO

O

O O N

HO

(i), (iii)

OH

35a R = Me 35b R = n-C11H23

R

O OH

OH HN

O

O

(ii), (iii)

R′ R 34

O O

O O N

36a R= Me, R′ = Me 36b R = Me, R′ = t-Bu 36c R = n-C11H23, R' = n-C11H23

R (i) HF, 20 ˚C, HCO 2H (ii) HF, −30 ˚C, Ac 2O, t-BuCOCl,or (n-C11H23CO)2O (iii) Et3N Scheme 8.14

Synthesis of Oxazolines

351

TABLE 8.6. OXAZOLINES FROM URETHANE-PROTECTED TERTIARY b-HYDROXY AMIDESa

H N

R

O

NH3

Cl

O

TFA

CF3CO2

+

R

N H

O

N

35˚C

O Cl

Figure 8.4 T1/2 in TFA

R t-Bu  i-Pr   Me(CH2)16 CH2  C(Me) PhNH   Me(CH2)2-NH  C(Me)-C6H4-C(Me)2-NH  CH2  EtO   Me2CHCH2O a

T1/2 in TFA/CaCl2

100 165 225 60 205 295 >450 40 65

30 70 100 15 95 120 180 10 15

Data from Ref. 95.

H N

R

O

O

NH3+

Cl

O

N

TFA

N H

35 ˚C

CF3CO2

+

R O

TFA = trifluoroacetic acid

Cl

38

37 Scheme 8.15

8.2.2.4. Acetates, Mesylates, Tosylates, and Triflates Conversion of the hydroxyl group of a b-hydroxy amide to a mesylate,96–100 triflate,96,101,102 or an acetate103–108 followed by intramolecular displacement of the leaving group is a commonly employed strategy for oxazoline formation. Some examples from the recent literature are listed in Table 8.7.41,96–123 Oxazolines prepared via cyclization to displace an acetate sometimes requires a Lewis acid such as boron trifluoride (BF3OEt2)105 or trimethylsilyl triflate (TMSOTf)107 to improve the leaving group ability. The cyclization is expected to proceed via an SN2 mechanism with overall inversion. Occasionally, epimerization occurs first prior to cyclization, in which case the stereochemical outcome is a net retention. This epimerization is illustrated in the

352

O

O

Ph

O

N

Cbz N

Et

N

O

N

OMs OMs R1 R2

Ph

TBDPSO

O

O

Ph

O

N

N H

MeO2C

O

Product

O

O

Me

N

Ph

OMe

1. MsCl, Et3N; 2. K2CO3, acetone, reflux (96)

MsCl, Et3N, CH2Cl2 R1 ¼ Me, R2 ¼ H (74) R1 ¼ Et, R2 ¼ H (51) R1 ¼ Ph, R2 ¼ H (96) R1 ¼ H, R2 ¼ Me (68) R1 ¼ Ph, R2 ¼ Me (100)

MsCl, Et3N, Py, CH2Cl2, 5 to 20
C (93)

Mesylate (95)

Mesylate (99)

Conditions (% Yield)

TABLE 8.7. OXAZOLINES VIA ACETATES, MESYLATES, AND TRIFLATES

Intermediate for preparation of thromboxane A2 receptor antagonist

Intermediate for D-erythro-sphingnosine and 4,8-sphingadienine derivatives

Comments

112

110, 111

109

97

96

References

353

OH

Ph2(O)P

O

N

O

O

O

MeO2C

O

Me

O

Fe

N

Ph

N

N

O

HN O

O

OTBDPS

Product

TABLE 8.7 (Continued)

N

C6H12

Conditions (% Yield)

MsCl, DMAP, Et3N, CH2Cl2 (97)

MsCl, Et3N (84)

1. MsCl, Et3N, CH2Cl2, 0
C; 2. K2CO3, acetone, reflux (90)

MsCl, Py, toluene, 110
C (85)

Comments

Ligand for asymmetric allylic alkylation

Ligand preparation

Intermediate for preparation of thromboxane A2 receptor antagonist

Intermediate for phytosphingosine-type glucosaminocerebrosides

116

115

114

113

References

354

N

N

N

N

R1

Fe

O

O

O

R2

R

R

O

Ph

Me

N

N

R1

R2

O

R

PPh2

Ph

O

CO2Et

N

S

O

P

Me

Product

TABLE 8.7 (Continued) Conditions (% Yield)

1. MsCl, Et3N, CH2Cl2; 2. MeOH, NaOH (KOH) reflux or KOAc, EtOH reflux R1 ¼ Et, R2 ¼ Bn, i-Pr, t-Bu, PhMe2C, Ph2MeC, Ph3C (73–86) R1 ¼ i-Bu, R2 ¼ t-Bu, Ph2MeC (77–81)

MsCl, Et3N, CH2Cl2, rt (62)

MsCl, Et3N, DMF, or THF R ¼ t-Bu (87) R ¼ cyclohexyl (87) R ¼ Ph (87) R ¼ 2,6-di-Cl-Ph (87) R ¼ adamantyl (82)

MsCl, DABCO, THF R ¼ adamantyl, 3,5-di-t-Bu Ph, t-Bu

MsCl, DMAP, Et3N (93)

Comments

Ligand preparation

Ligand preparation

Ligand for asymmetric cyclopropanation

Ligands for asymmetric allylic alkylation

Intermediate for a ligand for asymmetric allylic alkylation and Heck reaction

121

120

119

118

117

References

355

MeO

BnO

O

O

MeO

MeO

N

O

R

R

Product

O

N

OH

O

Me

O

N

O

OPMB O

N

P(O)Ph2

TBDPSO

Fe

Fe

O

TABLE 8.7 (Continued)

MeO

N

Ph

OMe

OMe

Conditions (% Yield)

Triflate (82)

Triflate (59)

Triflate (96)

TsCl, Et3N, CH2Cl2 R ¼ i-Pr (60) R ¼ t-Bu (53)

TsCl, Et3N, CH2Cl2 R ¼ i-Pr (S), t-Bu (S), Ph (S), i-Pr (R), (53–60)

Comments

Diastereoselective synthesis of chiral oxazolinylferrocene compounds

Ligand preparation

102

101

96

41

122

References

356

N

O

O

U

N Boc

N

Ph

O

O

N

Ph

Ph U ¼ uracil-1-yl

O

O

NHAc

NHR R N

O

O

O

N

OH

Ph U ¼ uracil-1-yl N3 U O

N3

BnO MsO

O

O

Product

TABLE 8.7 (Continued) Conditions (% Yield)

Mesylate (50)

Mesylate

Mesylate

Mesylate R ¼ i-Pr (61) R ¼ Ph (56) R ¼ i-Bu (90)

Triflate, R ¼ Bn (99) Triflate, R ¼ Ph (67)

Comments

100

99

99

98

102

References

357

AcO

AcO

AcO

AcO

R′O

N

R2

OO

R1

OR′

OO

OO

O S

OAc N

OAc H

O

O

R0 ¼ Ac, Me

AcO H

N

H OAc

AcO H

N

H OAc

AcO H

N

H OAc

R0 ¼ Ac, Ts

AcO H

N

H OAc

N

O

Product

CO2H

CO2Me

CO2Me

CO2Me

CO2Me

TABLE 8.7 (Continued)

Acetate TMSOTF (80)

Acetate R0 ¼ Ac (56) R0 ¼ Me (60)

Acetate BF3  OEt2 (96)

Acetate (90)

Acetate R0 ¼ Ac (82) R0 ¼ Ts (89)

1.MsCl, Et3N, CH2Cl2, rt; 2. 5% KOH R1 ¼ H, Ph R2 ¼ H, i-Pr, t-Bu 3 examples (58–78)

Conditions (% Yield) Ligands for asymmetric allylic alkylation

Comments

107, 108

106

105

104

103

123

References

358

2-Oxazolines O Me

Me NH

N

DBU

CO2i-Pr

CHCl3 reflux

O

Ph CO2i-Pr

OMs 39

40

KHCO3 Acetone / H2O 70 ˚C

DBU CHCl3 reflux

Me N

O

Ph CO2i-Pr 41

Scheme 8.16

following example shown in Scheme 8.16.124 Depending on the reaction conditions, either the cis- or trans-oxazoline can be formed. Since the cis-oxazoline 41 does not epimerize to the trans isomer 40, the epimerization occurs first prior to ring formation. A common strategy to invert the stereochemistry at the hydroxyl bearing carbon of an amino alcohol involves oxazoline formation with inversion followed by hydrolysis. This strategy has been applied to Taxol resulting in a practical semisynthesis of 20 -epi-Taxol 44 from Taxol 42 (Scheme 8.17).125 O Ph Ph

O Ph

NH

AcO

O

O

NH

OH H OH O

OH

HO BzO

AcO

O

Taxol

2'-epi-Taxol

42

44

(CF3SO2)2O pyridine

Ph

0.1 N HCl dioxane

O

AcO

O

O OH

N

O Ph HO BzO

AcO

43

Scheme 8.17

O

O

HO H HO BzO

AcO

O

Ph

O

AcO

O

Synthesis of Oxazolines

359

An unusual example of oxazoline formation is illustrated in the following example in which the hydroxyl moiety is masked as a tetrahydrofuran ring.126 Depending on reaction conditions, regioselective ring closure to one of the two oxazolines can be realized. Thus, addition of methanesulfonyl chloride to a mixture of substrate and Et3N resulted in the expected oxazoline 46. On the other hand, addition of <1 equiv of triethylamine to a mixture of substrate and methanesulfonyl chloride, followed by acid catalysis produced oxazoline 47. Intermediate 47, obtained in 72% overall yield from 45, was susequently converted to the human immunodeficiency virus (HIV)-protease inhibitor Nelfinavir1 48 (Scheme 8.18). Similarly, tosylates can be used to prepare oxazolines in high yields.127 An interesting application of this reaction is the use of polymer-bound tosyl chloride to facilitate high-throughput oxazoline synthesis.128 In this case, b-hydroxy amides are captured by polymer-bound tosyl chloride at 0
C followed by a wash step to remove excess reagents and starting materials. Exposure of the resin to a weak base such as pyridine in THF releases the oxazolines from the resin with minimal formation of elimination products. High-purity products are obtained even when the cyclization reaction is less than quantitative since unreacted starting material is polymer bound (Scheme 8.19).

OTs

H3N OH

AcO N a

O O

O

O

46

AcO

N H

OH

b, c

O

45

AcO

CONH-t-Bu O HO

OAc N

47

N N

OH

48 a: Addition of MsCl to substrate with excess Et 3N b: Addition of < 1 equiv of Et 3N to substrate and MsCl c: Ac 2O and conc. H2SO4 Scheme 8.18

OMs

360

2-Oxazolines Ts

HO H2N

O O

TsCl

ArCOCl

R NH

0 ˚C

R

Ar 49 R

N

pyridine

Ar

THF

O 50

Scheme 8.19

Activation of the hydroxyl group as an acetate leaving group to promote oxazoline formation has been applied extensively in carbohydrates to afford bglycosylation with high selectivity. A Lewis acid such as ferric chloride (FeCl3),129 tin chloride (SnCl4),130 or TMSOTf131 is usually added to facilitate cyclization. Several recent examples are shown in Scheme 8.20. Compound 54 has been further elaborated to 1,2-dideoxynojirimycin 54a, a potent b-N-acetylglycosamine inhibitor. Colombo and co-workers132 also developed an oxazoline glycosylation method wherein an acetate is replaced by a vinyl ether. Activation of 55 with iodine in the presence of DBU gave the oxazoline 56. Glycosylation of 56 with a second sugar moiety using TMSOTf afforded the disaccharide 56a in 79% yield (Scheme 8.21).

Ph Ph

O

O

SnCl4

O

O

O

O

AcO

OAc N 33-78% O NHCOR R = Me, i-Pr, i-Bu, t-Bu, Bn, Ph R

AcO

51a-f

52a-f O

HO FeCl3

HO

HO

O

OH 71%

HO 53

NHAc OH

N

1,2-dideoxynojirimycin

54

OAc OAc AcO

HO

O HO

NHAc

NH

O

O

Me OAc

OAc OAc

OAc

O O O

O

OAc NHAc

54a

TMSOTf 60%

OAc

OAc

AcO

O O O O

Me OAc

Scheme 8.20

OAc

OAc O N

OAc

Me

O

Synthesis of Oxazolines OPiv OPiv

OPiv OPiv

I2 / DBU

O AcO

361

O NHAc

O

O

O NHAc BnO

AcO O

OBn OBn

OPiv

TMSOTf

AcO N

79%

OPiv

O

OBn OBn

O-allyl

O 55

56

HO

56a BnO

O-allyl

Scheme 8.21

8.2.2.5. Burgess Reagent Burgess reagent133 has also been used to effect cyclodehydration of b-hydroxy amides to oxazolines. Representative examples are shown in Table 8.8.31,43,134–144 The advantage of this reagent is that the cyclodehydration is performed under essentially neutral and mild conditions, typically in THF at room temperature or reflux. A series of axially chiral bis(oxazolines) 58a–n were prepared by Rippert for stereoselective cyclopropanation studies.145 The use of Burgess reagent proved to be superior than other reagents such as PPh3/CCl4/MeCN or MsCl/Et3N/CH2Cl2 (Scheme 8.22). TABLE 8.8. OXAZOLINE FORMATION USING BURGESS REAGENT Product

AcO

Conditions (% Yields)

N

N R

X

Bn

31, 134

THF, 70
C R ¼ X ¼ H (64) R ¼ H, X ¼ NHTs (54) R ¼ Me, X ¼ H (65)

31, 135

THF, 55
C (84)

43

O

N3 N

References

O

Z

HN

R

Comments

THF, 70
C R ¼ Bn, Z ¼ H (74) R ¼ H, Z ¼ NHBoc (67)

CO2Me

O THF, reflux (83)

BocHN N O

CO2Me

Intermediate for the total synthesis of calyculin C

136

362

2-Oxazolines

TABLE 8.8 (Continued) Product

Conditions (% Yields) THF, 20
C (50)

MeO

Comments

References

Intermediate for the total synthesis of curacin A

137

N O CbzHN

N

CO2Me

THF, reflux (50–67)

138

CO2Bn

THF, reflux (63)

138

O NHBoc BocHN

N O CO2C6H11

Boc Bn N

THF, reflux (73)

Asymmetric alkylation studies

139

THF, reflux R ¼ Me (74) R ¼ Bn (43)

Asymmetric alkylation studies

139

THF, reflux

Intermediate for the 140 total synthesis of hennoxazole A

THF, reflux R1 ¼ H, R2 ¼ Me (S), Bn (S), i-Pr (S), Ph (S) (31–64) R1 ¼ Ph (S), R2 ¼ Bn (S), i-Pr (S), Ph (S) (47–69) R1 ¼ Ph (R), R2 ¼ Bn (S), ¼ i-Pr (S), Bn (S) (47–69)

Ligands for asymmetric allylic alkylation

THF, reflux (66)

Intermediate for the 142 total synthesis of mycobactin S

Ph

N O Cbz

Bn N

N

R TBDMSO

O

Ph

CO2Me

N O N

R2

O

Ph2(S)P R1

141

OBn N O

CO2Bn

Synthesis of Oxazolines

363

TABLE 8.8 (Continued) Product

Conditions (% Yields)

Comments

References

Intermediate for 143 total synthesis of ()-madumycin II

O O OTBDMS N O

MeO2C

THF, reflux (56–69) (from acid)

O N

MeO2C

Ligand for asymmetric diethylzinc addition to benzadehyde

CO2Me

N O

144

rac

Because of the mild and essentially neutral reaction conditions, Burgess reagent was applied for the construction of the oxazoline intermediates 60 required by Pattendon and co-workers146,147 for their syntheses of thiangazole 61 and lissoclinamide 4 63 (Scheme 8.23).148 Similarly, Wipf and co-workers149 also utilized Burgess reagent in the synthesis of lissoclinamide 7 68. To construct 65 with the required allo-threonine residue, Wipf and co-workers first prepared tripeptide 64 from natural threonine. Inversion R3

R3

R2

R2 R4

R4

CONH

HNOC

R5 R6

R1

R5

R1 HO

OH

R6

R4

Burgess reagent 14 examples

R5 R6

N R1

O

R2

R2

R3

R3

57a-n

58a-n

Axial Chirality: M

Axial Chirality: P

R1 = Me, Br R2 = H R3 = H, Br R4 = Me (S), i-Pr (S), Ph (S) R5 = H, Ph R6 = H, Ph

R1 = Me, OMe, Br R2 = H, OMe R3 = H, OMe, Br R4 = Et (S), i-Pr (S), t-Bu (S), Ph (S) R5 = H, Ph R6 = H

Scheme 8.22

R6

O

R1 N

R5 R4

364

2-Oxazolines Me O BocS BocHN

Me

OH

BocS

Burgess reagent

N H

CO2Me

BocHN

70%

N

CO2Me

O

Me

Me

59

60 O

steps

S

N

Me

S

N N

NHMe

Me O

Me

N Me S

61 thiangazole OH

O

O

NH

O

H N

N H

S OH O

S HN

O

N

Burgess reagent

N H

N O

HN

61%

N O

N

H N Ph

S

N

Ph

O O

N

H N Ph

S

Ph

O

lissoclinamide 4 63

62 Scheme 8.23

of the hydroxyl group was accomplished through cyclization to the oxazoline followed by hydrolysis to give the tripeptide 65 containing the unnatural threonine in 80% yield.150 The final step of the synthesis was accomplished by the global cyclization of the b-hydroxy amides and thioamides, and provided the natural product in 90% yield, without epimerization of the thiazoline fragments (Scheme 8.24). A polymer-bound Burgess reagent has also been developed.151 Aside from the mild, neutral cyclization conditions, this reagent also offers the advantage of a clean reaction with little epimerization and an easy work-up. Examples are listed in Table 8.9. In their synthesis of the macrocyclic hexapeptide bistratamide D, Meyers and co-workers152 prepared the trans-oxazoline 70 from the corresponding cis-oxazoline 69 through several steps, the last of which was cyclization to the oxazoline using Burgess reagent. The net outcome is inversion of the stereocenter at the 5-position of the oxazoline (Scheme 8.25).

Synthesis of Oxazolines

HO O

HO

CO2Me

O

365

1. Burgess

NH

CbzHN

2. 0.3 M HCl

N

Ph

Ph 64

steps

NH

CbzHN

reagent

N

CO2Me

O

O

65

CbzHN

Ph

O

H N

N H O OTBDMS

O

H N

Ph

O

N

N H O OTBDMS

NH

O

CO2Me

HO 66 OH

O

O N H

NH

O

H N

S OH O

S HN

steps

O

N

N H

N

Burgess

O

HN

reagent

N O

HN

H N

S

Ph

N

90%

O

Ph

O

N

H N

HO

Ph

S

Ph

O

68

67

lissoclinamide 7

Scheme 8.24

CO2H

CO2Me

O

1. HCl 2. K2CO3

N NHCbz

O

N

3. Al 2O3, MeOH 4. Burgess reagent

69

NHCbz

70

Scheme 8.25

8.2.2.6. Mitsunobu Reaction The Mitsunobu reaction153 has also been applied successfully for the preparation of oxazolines from b-hydroxy amides. This method provides an alternative to the Burgess reagent. Some recent examples are listed in Table 8.10.154–161

366

2-Oxazolines

TABLE 8.9. OXAZOLINE FORMATION USING PEG-SUPPORTED BURGESS REAGENTa Substrate

Product

% Yield

H Cbz-Phe-Ser-OMe

Ph

N

Cbz NH

O

CO2Me

88

H N

CO2Me

Cbz-Val-Thr-OMe

90

O

Cbz NH

H H N

CO2Me

Cbz-Pro-Thr-OMe

85

O

N Cbz

H H N

CO2Me

Cbz-Aib-Thr-OMe

Cbz

88

O

NH

H H N

CO2Me

Cbz-Val-aThr-OMe

76

H

O

Cbz NH

H Ph

Cbz-Phe-c(CSNH)Ser-OMe

Cbz

Ph HO a

H N

H N O

O

Ph OH

Ph H

N

CO2Me

98

S

NH

N

N O

O

Ph H

80

Data from Ref. 151.

Oxazoline formation under Mitsunobu conditions is very facile. As shown in the last example in Table 8.10, as much as 30% of the oxazoline is formed in addition to the desired vinylaziridine that is obtained in 64% yield.161 Only amide groups participate in this cyclization since the oxazoline is not formed when the nitrogen is protected as a benzyloxycarbonyl (Cbz) or tert-butyloxycarbonyl (Boc) derivative. Because of mild reaction conditions, this method has also been applied for a semisynthesis of paclitaxel 42 from the 10-deacetylbaccatin III derivative 71 (Scheme 8.26).162

Synthesis of Oxazolines

367

TABLE 8.10. OXAZOLINES VIA THE MITSUNOBU REACTION OF b-HYDROXY AMIDES Product

Conditions (% Yield) Comments a

O MeHN

O

N

BocHN

CO2Me

O R2 N

Me

154

PPh3, DEADb R1 ¼ Me, ¼ i-Pr, Ph R2 ¼ H, Me 4 examples (61)

Intermediates for the total synthesis of berinanamycin A, a macrocylic peptide antibiotic

155

O

Ph

PPh3, DIAD, THF, rt (74)

Ph

O

Intermediate for the synthesis of thiangazole analogues

Ph

N

R1

PPh3, DIAD (97)

N

O

References

CO2t-Bu

156

PPh3, DEAD, THF, rt (84)

Intermediate for the total synthesis of microginin (ACE inhibitor)

PPh3, DEAD (80)

Asymmetric synthesis 159 of homochiral syn- and anti-3phenylisoserine Intermediate for the 160 total synthesis of anticapsin, a naturally occuring amino acid antibiotic 161 O O O N Ph

Ph

157, 158

N O

CO2Me

N

Ph

Ph

N

CO2Bn

CF3

PPh3, DEAD, THF, rt (90)

O PPh3, DEAD (30)

O N

O

Ph O

64% a b

DIAD ¼ diisopropyl azodicarboxylate. DEAD ¼ diethyl azodicarboxylate.

Wipf and Miller163 reported that cyclization of threonine peptides to oxazolines under Mitsunobu conditions resulted in aziridines instead of the expected oxazolines, whereas allo-threonines peptides give the expected oxazolines (Table 8.11). Oxazoline formation under Mitsunobu conditions requires that the amide substituent be in an antipepriplanar orientation to the activated hydroxyl substituent. With allo-threonines 77, these groups are predisposed in such an orientation in the most stable conformation (transition state 78b). As a result, trans-oxazolines 79 are easily formed. With threonines, the formation of cis-oxazoline 76 is disfavored because of destabilizing gauche interactions between the a-carboxyl

368

2-Oxazolines O CbzO

O

Ph

OTES

NH steps

Ph

HO

O

O

OTES

HO HO

O

O

HO BzO AcO

O HO BzO AcO 72

71 Ph

HO

O

N

O

OTES

PPh3 DEAD

Ph

O

O O HO BzO AcO 73

O Ph NH O

Ph HO

AcO

O

OH

O O HO BzO AcO paclitaxel 42 Scheme 8.26

and b-methyl groups (transition state 75b) (Scheme 8.27). At the same time, rotation to a more stable conformation and deprotonation of 75b by the azodicarboxylate anion 75c present in the reaction mixture gave 75a that is now reactive toward Ei cyclization and accounts for the formation of aziridines. Indeed, when the reaction is carried out in the presence of triethylamine hydrochloride, aziridine formation is completely suppressed since 75c is now neutralized.

8.2.2.7. DAST and Deoxo-Fluor Diethylaminosulfur trichloride (DAST) was first used to cyclodehydrate bhydroxy amides in 1990 by Jones and co-workers.164 In 1995, Lellouche and co-workers165 showed that b-hydroxy amides react efficiently with DAST even at

Synthesis of Oxazolines

369

TABLE 8.11. CYCLIZATION OF THREONINE AND ALLO-THREONINE PEPTIDES UNDER MITSUNOBU CONDITIONSa Substrate

Product

CbzHN

NHMe

O

Cbz

CbzHN

NHMe

O

H N

H N

H N

56

H

N

N Cbz

NHMe

84

H

O

OH

O HO a

NHMe H

O

O

H O

O N

NHMe CbzHN

NHMe

64

NHMe

83

O O

O N

NHMe

O HO

CbzHN

CbzHN

O

O HO

CbzHN

N

OH

H N

N

O

O

H N

% Yield

CbzHN

O

N

CO2Me CbzHN

CO2Me 73

O

Data from Ref. 163.

78
C in CH2Cl2 to afford good yields of the corresponding 2-oxazolines. Since then, it was also demonstrated that DAST is compatible with a wide range of functional groups, and good to excellent yields of the oxazoline can be obtained readily. Recent examples from the literature are shown in Table 8.12.164–170 Bis-(2-methoxyethyl)aminosulfur trioxide (Deoxo-Fluor) has also been used in place of DAST.166 Deoxo-Fluor may have the advantage of increased thermal stability.171 A comparison of the two reagents for the cyclization of several peptidyl b-hydroxy amides has been reported (Table 8.13). In general, fluorination is not a problem. However, in some instances, DAST induced dehydration does result in a low yield of the oxazoline due to competitive fluorination.172 For example, treatment of 80 with DAST resulted in 82, an SN20

370

2-Oxazolines Threonine CO2R

H

O Me

H

CO2R

Me O

H O

O PPh3 N

H

N N

RO 2C

75a

74

PPh3

O

H

N

CO2R CH3

N

CO2R

O

Me

NH

CO2R 76

75b 75c

Allo-threonine O N

CO2R Me

O

PPh3 CO2R

H Me O

77

O

CO2R

H Me O

H N

78a

PPh3

H NH

78b

N

CO2R

O

Me

79

Scheme 8.27 TABLE 8.12. OXAZOLINES FROM b-HYDROXY AMIDES USING DAST Oxazoline

O

O R

Conditions (% Yields)

Comments

Reference

CH2Cl2, rt R ¼ Ph (68) R ¼ Me (58)

164

CH2Cl2, 78
C R ¼ Ph, t-Bu (62–70)

165

CH2Cl2, 78
C R ¼ Ph, Me, t-Bu (57–95)

165

CH2Cl2, 78
C R ¼ Ph, Me, t-Bu (76–93)

165

CH2Cl2, 78
C (53)

166

CH2Cl2, 78
C (86)

166

N

CN N

Me

O

Ph Ph

R

N R O N

Ph

R O CO2Me N

O O

CO2Me

O N O NH

CO2Me

Synthesis of Oxazolines

371

TABLE 8.12 (Continued) Oxazoline N

MeO2C N Cbz

CO2Me

Reference 166

CH2Cl2, 78
C (60)

166

CH2Cl2, 78
C (73)

166

CH2Cl2, 78
C (77)

166

CH2Cl2, 78
C (61)

Catalyst for asymmetric 167 conjugate radical addition

CH2Cl2, 78
C (52)

Catalyst for asymmetric 168 cyclopropanation and aziridination

CH2Cl2, 78
C (78)

Intermediate for the synthesis of ()-hennoxazole A

CH2Cl2 (99)

Intermediate for 170 preparation of catalyst used for asymmetric transfer of diethylzinc to benzaldehyde

O

TBDPSO

CO2Me

N O

O

N

N

N

MeO2C

CO2Me O

O

O

Comments

CH2Cl2, 78
C (90)

O

N PhSO2

Conditions (% Yields) CO2Me

Ph

Ph

N

N

O

O

O Ph

O

N

O

N Ph O

CO2Me

N O

169

TBSO O N Ph

Co Ph

Ph

Ph

CO2Me

372

2-Oxazolines

TABLE 8.13. COMPARISION OF DAST AND DEOXO-FLUOR FOR CYCLIZATION OF PEPTIDYL b-HYDROXY AMIDESa Productb

Substrate

Deoxo-Fluor (%)

DAST (%)

Ph H N

CbzHN

CO2Me

O

OH H N

AllocHN

OH

H N

N AllocHN

72

86

83

92

80

90

72

72

73

92

72

27

61

43

91

86

CO2Me

CO2Me

O

N

CO2Me

O

CbzHN

N

H N

CO2Me

CO2Me

O

H N O

O

N Cbz

OH

CbzHN

CO2Me

O

CbzHN

CO2Me

O HO

N

N

CO2Me

O

Cbz

CbzHN

O

CO2Me

O

CbzHN

N

OH H N

CbzHN

Ph

N

CO2Me OH

CbzHN

O

Ph

N

CO2Me

Ph H N

CbzHN

H N O

a b

CO2Me

O

CbzHN

O

Ph

CO2Me OH

CO2Me OH

Data from Ref. 166. Allyloxycarbonyl ¼ Alloc (or AOC).

N Ph O

CO2Me

Synthesis of Oxazolines OH

F

F

TrO

C7H15

DAST

TrO

C5H11

HN

373

C7H15

O

+

C5H11

HN

TrO

C7H15 HN O

O

80

C5H11

82

81 C7H15

TrO +

N

O C5H11

Tr = trityl

83 Scheme 8.28

substitution product together with 81 in preference to formation of the oxazoline 83 (Scheme 8.28).

8.2.2.8. Triphenylphosphine and Carbon Tetrachloride b-Hydroxy amides undergo cyclodehydration to oxazolines under very mild conditions with triphenylphosphine and carbon tetrachloride. Carbon tetrabromide can also be used. The formation of the corresponding b-chloro amide is generally not a significant problem. The major disadvantage is that removal of the byproduct triphenylphosphine oxide may be difficult at times. Representative examples are shown in Table 8.14 (Fig. 8.5).114,140,173–181 TABLE 8.14. OXAZOLINES FROM HYDROXY AMIDES USING TRIPHENYLPHOSPHINE AND CARBON TETRACHLORIDE

R2 OH

HN R1

O

PPh3 CCl4 or CBr4

R2

N R1 O

Figure 8.5 Oxazoline

MeO2C

N O

O

CO2Bn

Conditions (% Yield)

Comments

PPh3, CCl4, DIPEA, MeCN, rt

Intermediate for thromboxane A2 receptor antagonist

References 114

374

2-Oxazolines

TABLE 8.14 (Continued) Oxazoline

Conditions (% Yield) OTIPS

OMe N

O

Comments

References

(BrCl2C)2, PPh3, MeCN, 2,6-di-tert-butyl-4methylpyridine

Intermediate for the total synthesis of hennoxazole A

140

PPh3, CCl4, Et3N, MeCN R ¼ i-Pr (52) R ¼ Ph (70)

Intermediates for 173 ligands for asymmetric allylic alkylation

PPh3, CCl4, Et3N, MeCN R ¼ i-Pr (89) R ¼ Me (83) R ¼ H (77)

Intermediates for 174, 175 phosphinoferrocenyloxazoline–ligands for asymmetric catalysis

O OMe

N

O

R

N O Cl R N O Fe

PPh3, CCl4, Et3N, MeCN (97)

176

N O

Br

R 1. PPh3, CBr4, THF, rt;

R O

O N

N

O O

Oxz Oxz Oxz Me Me Me R1 N R2 Oxz = O

O

2. NaOH, EtOH, THF, reflux R ¼ {3,5-bis-[O-(4-t-Bu)C6H4)]}-C6H3 (96)

Catalysts for asymmetric Diels–Alder cycloaddition

177

O

PPh3, CCl4, Et3N, MeCN R1 ¼ H, R2 ¼ Ph (80) R1 ¼ Me, R2 ¼ H (50) R1 ¼ i-Pr, R2 ¼ H (81) R1 ¼ t-Bu, R2 ¼ H (67)

178

Synthesis of Oxazolines

375

TABLE 8.14 (Continued) Oxazoline

Conditions (% Yield)

Comments

References

PPh3, CCl4, Et3N, MeCN

Intermediate to catalyst for asymmetric reaction of aldehydes with organozinc reagents

179

PPh3, CCl4, Et3N, MeCN (95)

Ligand for asymmetric allylic alkylation

180

Ligand for asymmetric PPh3, CCl4, pyridine, allylic alkylation MeCN R1 ¼ H, R2 ¼ Ph (48)

181

N O Ru O N

N O

O

O N

R1

R2

Br

R1 ¼ Bn, R2 ¼ H (47)

N R1

R2

8.2.3.

Oxazolines from b-Halo Amides

The preparation of oxazolines from b-hydroxy amides and SOCl2 via the corresponding b-chloro amides under basic conditions is well known and has been discussed earlier. Potassium fluoride on alumina182,183 has been reported as a mild alternative to the aqueous or alcoholic bases that are commonly used. The reaction is typically carried out in acetonitrile or tetramethylene sulfone and moderate to good yields of oxazolines and oxazines can be obtained as shown in Scheme 8.29. In this same study, the authors also reported isolation of oxazoline 90 in moderate yield when propenylbenzamide 88 was reacted with N-bromosuccinimide (NBS) in CCl4. A radical mechanism via intermediates 89a and 89b has been proposed. The generality and scope of this method has not been established (Scheme 8.30).

376

2-Oxazolines O N

KF / Al 2O3

Ph

N H

Br

Ph

76%

84

85

O R

N

KF / Al 2O3

N H

Br

O

Br

Cl n

R

75-93% n = 1-3 R = Ph, Me, C8H19

O

86

n

87 Scheme 8.29

During an investigation of the synthesis of oxazole-4-carboxylates, Shapiro reported that chlorination of amino[(phenylthio)methyl]malonate derivatives 91 with N-chlorosuccinimide (NCS), followed by treatment with Hunig’s base, afforded the oxazolines 93. The oxazolines 93 were then converted to the respective oxazole-4-carboxylates 94–97 through decarbomethoxylation and elimination of thiophenoxide in the presence of methyl iodide. Methyl iodide traps the ejected thiophenoxide that would otherwise demethylate the oxazole-4-carboxylate (Scheme 8.31).184 Powerful Michael acceptors such as 2-chloro-2-cyclopropylidene acetates 98 react with carboxamides 99 to give 4-(cyclopropyl)oxazoline carboxylates 101.185,186 The reaction proceeds in a step-wise fashion involving first Michael addition of 99 to 98 to give an equilibrium mixture of 100a and 100b followed by intramolecular ring closure to the oxazoline 101. Diastereoselectivities as high as 17:1 can be realized when substituted cyclopropylidenes (98 R1 6¼ H) are employed. Examples are listed in Table 8.15 (Fig. 8.6; Scheme 8.32). O N

NBS / CCl4

Ph

Ph

N H

50%

O

88

Br

90

.

− H

O Ph

H N N H

Br

Ph O Br

89a

89b Scheme 8.30

Synthesis of Oxazolines

HN

CO2Me SPh

MeO2C

CO2Me SPh

MeO2C

NCS

HN R

O

O

91 CO2Me

N R

MeOH MeI 40-75%

O

CO2Me

O

Cl

92

K2CO3

CO2Me

N R

55-100%

R

377

SPh

93

R = Me, i-Pr, Ph, PhCH 2CH2, PhCH2OCH2, BocNH(CH2)3

94

t-BuO2C N

CO2Me

i-Pr Ph

O

N

CO2Me

CO2Me

N

N O

O

O 95

96

97

57%

59%

47%

Scheme 8.31

A similar reaction of vincinal aromatic or heterocyclic diamines 104 with 2-benzoylamino-3-chloropropenoic acid 102 resulted in spiro-2-oxazolines fused to a pyrazinone nucleus 108.187 It is believed that the enamide 102 first isomerizes to the N-acyl imine 103 followed by Michael addition of the diamine 104. The resulting Michael adduct 105 cyclizes to 106 or 107 either of which leads to the same oxazoline 108. Single-crystal X-ray confirmed the structure of 108.187 Unsymmetrical diamines gave two isomeric products with the predominant product

+ CO2Me

R1

R1

O

Cl R2

98

NaH

NH2

MeCN 0 to 20 ˚C

MeO2C 100a

R1 N R2 O

R1

CO2Me

101 Scheme 8.32

R2

N O Cl

99

6-72%

R2 HN

MeO2C 100b

O Cl

378

2-Oxazolines TABLE 8.15. OXAZOLINECARBOXYLATES FROM 2-CHLORO-2CYCLOPROPYLIDENEACETATESa

R1 Cl

R1

CO2Me

O

N

+ R2

NH2

R2 O

CO2Me

Figure 8.6 R1 H H H H H H H H H H H H H H H Et Et Et Et Et Et CH2CH2OBn H H H H

R2 Ph 3-C5H4Nb 2-C4H3Oc 4-CN Ph 2-Me Ph 3-Me Ph 4-Me Ph 3-F Ph 4-Br Ph Ph 2-NO2  4-NO2  Ph 2-Cl Ph 4-Cl Ph 2-I Ph 3-I Ph Ph 2-Me Ph 2-I Ph 4-NO2 Ph 3-F Ph 3-C5H4Nb 4-NO2 Ph Me Et n-Pr t-Bu

% Yield 60 38 49 74 70 58 50 75 73 47 47 77 68 72 49 56 68 55 40 46 25 41 6 24 24 25

dr

9:1 17:1 17:1 2:1 7:1 5:1 2:1

a

Data from Ref. 185. Nicotinamide. c Furan-2-carboxamide. b

(108g–h) arising from initial Michael reaction of the most basic amino group (Scheme 8.33). Similarly, Jacquot and co-workers188 observed oxazoline formation from sodium ethyl glycolate (excess) and a 4,4-dichloro-azadiene derivative 109. However, the generality of this reaction has not been established. The product can be rationalized according to the series of reactions shown in Scheme 8.34.

Synthesis of Oxazolines

379 NH2

CO2H

Cl

+ NCOPh

NH2

103

104

CO2H

Cl

NHCOPh

NH2

102 N H NH2 N H

CO2H

Cl

NHCOPh H N

105

CO2H

O Cl

O N Ph

N H

H N

106

O

NHCOPh

107 O

N H N

Ph 108 H N

X Y

H N

O O

N H N

O

N H N

Ph

H N N H N

108c 28%

H N

O O

X

O O

N H N

X

N H N

Ph 108d X = C, 50% 108e X = N, 37%

X

O

Ph 108f 23%

O

H N

Ph

108a X = Y = H, 23% 108b X = Y = Cl, 34% NO2

N

O

H N

O

N H N

Ph

Ph 108g X = NO2 108h X = COPh 108i X = Cl

O

108j X = NO2 108k X = COPh 108l X = Cl

Scheme 8.33

A highly stereoselective synthesis of b-amino-a-hydroxy acids from 3-benzoylamino carboxylates 115 has been developed by Cardillo and co-workers.189,190 This one-pot procedure involves enolate formation of 115 using lithium hexamethyldisilazide followed by quenching the enolate with I2. The iodine is

380

2-Oxazolines Ph

Ph Cl

N

Ph N

Cl

H

Cl

Ph

+ NaO

Ph

DMF

CO2Et

O

109

Cl

O

Cl

EtO2C

110a

110b

Ph

N −NaCl

Cl

EtO2C

Ph

N Ph

Ph

RO

O

N

−

Ph

Cl

O

Cl

Ph Ph

N

ROH

O

Cl

CO2Et

EtO2C

EtO2C 111

112 N

40%

O

O EtO2C

113

Ph Ph CO2Et

114

Scheme 8.34

introduced from the sterically less hindered side to afford a trans-iodo-intermediate 116 in a 98:2 ratio. Under the reaction conditions, the intermediate iodo-compound 116 was cyclized to 117. An alternative approach191 based on a chiral imidazolidinone 119 has also been developed although with less impressive diastereoselectivity (60:40–85:15, depending on reaction conditions). Hydrolysis of 117 or 120 provides anti-b-amino-a-hydroxy acids (Scheme 8.35).

O

O

CO2Me

Ph

CO2Me

Ph

O

N

O N H

Ph 119

CO2Me

Ph

OH

117

a

N

118

O

O Ph

NH

Ph

CO2Me

116

O

O

b

Ph

I 115

N

N

NH

Ph

a

NH

Ph

O

Ph

O

O

N

N

+

N

N

N

O Ph 120 (major) a: LiHMDS, I2; b: 1 M HCl in MeOH

Scheme 8.35

O Ph

Ph 121 (minor)

Ph

Synthesis of Oxazolines

381

CCl3 OH

1. Cl3CN / DBU

OH

Ph

2. ICl

N

O O

Ph I

122

NH CCl3

123 O

Ph

NH

steps

OH OH

Ph

N

Ph

O

CO2Me

Ph

I 18a

124 Scheme 8.36

Kang and co-workers prepared the b-halo amide arrangement required for oxazoline formation from allylic alcohols via a two-step process. For example, treatment of the allylic alcohol 122 with trichloroacetonitrile and base followed by activation of the double bond with iodine monochloride, provides 123.192–194 Hydrolysis of 123 gave 124 from which cyclization provided the oxazoline 18a used for paclitaxel synthesis (Scheme 8.36). During a study of the synthesis of an a-amino-b-hydroxycyclohexenecarboxylic acid 130, Gelmie and co-workers195 noted that photoisomerization of the readily available (Z)-oxazolone 125a gave the (E)-oxazolone 125b in only 50% yield. After chromatographic separation, 125b was then converted to the spirooxazolone 126b. Hydrolysis of 126b provided the desired aminoacid 130 via oxazoline 129a. However, the isomeric spirooxazolone 126a could not be utilized because of incorrect stereochemistry for oxazoline formation. To circumvent the tedious separation of the two oxazolones as well as to improve the overall yield of the synthesis, the authors converted the mixture of isomeric Diels–Alder adducts 126a and 126b to the corresponding N,N-dimethylcarboxamides 127a and 127b. Now, anchimeric assistance from the N,N-dimethylcarboxamido group in the ‘‘wrong’’ isomer provided intermediate 128 with the proper stereochemistry for ring closure to produce 129b that was hydrolyzed to 130 (Scheme 8.37). Obrecht and co-workers found that rac-4-(iodomethyl)-4-methyl-2-phenyl5(4H)-oxazolone 132 yields a separable mixture of diastereomeric oxazolines 133a and 133b upon reaction with (S)-Phe-cyclohexylamide.196 After separation, each one of the diastereomeric oxazolines undergo further conversion to give optically pure (R)- and (S)-bromoazlactones 134a and 134b after reaction with 33% hydrogen bromide in acetic acid. Subsequent methanolysis of 134a and 134b allows the preparation of a wide range of (R)- and (S)-a-methylserine analogues (Scheme 8.38).

382

2-Oxazolines O

O

O

H

O

hv

Ph

Ph Cl

N Cl

N H

125a

O

125b

O

O

O

Ph

Ph

N

N CO2H

Cl

Cl

N

126a

Ph

126b

O H CONMe2

CONMe2

129a

NHCOPh

NHCOPh

Cl

Cl 127b

127a

CONMe2

N

N O

Ph

N O

Ph H

H O

129b

128 CO2H NH2 OH 130 Scheme 8.37

An electrochemical method for the synthesis of a series of 4-(alkylamino)2-phenyloxazolines 139a–f from N-(2,2-dichlorovinyl)amides 135 has been reported.197 The starting N-(2,2-dichlorovinyl)amide 135, readily available from chloral and amides, undergoes facile reaction with amines to give 136. Cathodic reduction of 136 generates chlorocarbanionic intermediates 137 and 138 that

Synthesis of Oxazolines Me

N

I

I NaH, CH2I2

Ph

N

Me

O

O

RNH2

Ph O

383

O

131

N

Me

O

O

Ph

DIPEA

RNH2

132 O RHN

RHN Me

HN

N

I

H N

RNH2 = H2N

Ph O

O

Ph

Ph O Me

O

133a,b RHN

RHN separation

N Ph

O Me +

N Ph

O

O

133a RHN O Me

N Ph

O Me

133b

RHN H N

HBr

HO

Br

R

Ph

O

O

Br H

Me O Me

N NH O

Ph

133a N

Br Me

133b

Ph O

N

HBr

Ph O

O

134a

Br Me O

134b Scheme 8.38

cyclize to provide the oxazoline. Thus far, the method has only been demonstrated for 2-phenyl substituted oxazolines (Scheme 8.39). 8.2.4.

Oxazolines from Nitriles

Nitriles contribute to oxazoline synthesis through several different modes of reaction. They react with amino alcohols directly to give oxazolines. In particular, trichloacetonitrile reacts with a variety of alcohols, and the resulting imidates undergo ring closure to oxazolines with proper activation or with a leaving group b to the imidate. Nitriles also participate in Ritter reactions to give oxazolines.

384

2-Oxazolines O

O

Ph

H

NH2

O

Zn/HOAc

+

Ph

CCl3

O

RNH2

N H

Ph

CCl2

135 O

2e− − Cl−

Ph

_

NHR N H

O

NHR N H

CHCl2

136 NHR

N

60-92%

NHR

Ph

CHCl _

Ph

137

N

CH2Cl

O 139a-f

138 R = Bn, cyclohexyl, i-Pr, Bu, Me, Et Scheme 8.39

8.2.4.1. Direct Methods A common and effective direct approach to unsubstituted or multiply substituted oxazolines is the Lewis acid catalyzed reaction of nitriles with amino alcohols in an alcoholic or aromatic solvent (chlorobenzene) at reflux. The most common Lewis acids employed include ZnCl2, ZnBr2, NiBr2, CuCl2, and kaolinitic clay.198 Microwave irradiation has also been reported to facilitate the transformation.199,200 Alternatively, the condensation can be carried out in the presence of catalytic amounts of potassium carbonate. The method works well for both aliphatic and aromatic nitriles, with retention of stereochemistry. Some representative examples from the recent literature are listed in Table 8.16 (Scheme 8.40).28,35,201–213 R2 R1

OH

CN + H2N

catalyst solvent

R3

N

R2

O

R3

R1

1 Scheme 8.40

2-Heteroaryloxazolines can also form stable metal complexes that quite often can be isolated.207 In the absence of a catalyst, much higher temperatures are required for the reaction. For example, neat succinonitrile reacts with ethanolamine to initially give the iminoazacyclopentanediol 140 and the triol 141, respectively. Further heating at high temperature to distill out ethanolamine effects cyclization of 140 and 141 to the bis(oxazoline) 142.214 Excellent yields of oxazolines can be obtained this manner (Scheme 8.41).

Synthesis of Oxazolines

385

TABLE 8.16. OXAZOLINES FROM NITRILES AND AMINO ALCOHOLS Product

N S

Conditions (% Yield) n SMe

Comments

References

ZnCl2 n ¼ 1 (67) n ¼ 2 (62)

28

ZnCl2 (36)

28

ZnCl2 R ¼ H (68) R ¼ Me (100)

35

O N

N

SMe

O R R

N

O

R

R O

N

ZnCl2, PhCl, reflux

SMe i-Pr

N

Diastereoselective oxidation of sulfide

201

Diastereoselective oxidation of sulfide

202, 203

O STol i-Pr

N O N O TolS

Glycerol, ethylene glycol, cat. K2CO3, 115
C (91) ZnCl2, PhCl, reflux (89)

OH Ph i-Pr

N O N

204

Diastereoselective oxidation of sulfide

205

Glycerol, ethylene glycol, cat. K2CO3, 115
C (94)

OH

O

204

SO2Me NC N

R

N

ZnCl2, PhCl, reflux R ¼ i-Pr (31) R ¼ t-Bu (44)

Ligand for asymmetric allylic alkylation

206

ZnCl2, PhCl, reflux (60)

Ligand for asymmetric allylic alkylation

206

NiBr2, PhCl, reflux (80)

Metal complex

207

O i-Pr

i-Pr N O

N N

O

Me N

N O

Me

386

2-Oxazolines

TABLE 8.16 (Continued) Product

N

Conditions (% Yield)

R2 R1

N O

R R N

R2 R1

N O

R N

Ph

N O

N

N

R2 R1

O R2

R1

N N

Comments

References

ZnCl2, PhCl, reflux R ¼ H, Cl, OMe R1 ¼ H, Ph R2 ¼ H, i-Pr (30–61) (6 examples)

Ligands for asymmetric allylic alkylation

208

ZnCl2, PhCl, reflux R ¼ 4-Me-Ph, t-Bu R1 ¼ H, Ph R2 ¼ H, i-Pr, t-Bu (27–64) (9 examples)

Ligands for asymmetric allylic alkylation

209

CuCl2, 100
C, 10 mbar, neat R ¼ H (82) R ¼ OH (55)

Ligands for asymmetric allylic alkylation

210

Ligands for ZnCl2, PhCl, reflux asymmetric allylic R1 ¼ H, R2 ¼ i-Pr (61) R1 ¼ Ph, R2 ¼ H (22) alkylation R1 ¼ H, R2 ¼ t-Bu (76)

209

ZnCl2, PhCl, reflux R1 ¼ H, R2 ¼ i-Pr (69) R1 ¼ Ph, R2 ¼ H (58)

Ligands for asymmetric allylic alkylation

209

ZnCl2, PhCl, reflux R1 ¼ Me; i-Pr; t-Bu; Bn; CH2OTBDMS R2 ¼ H, Ph (30–60) (5 examples)

Ligands for asymmetric 1,4-addition of Grignard reagents to enones

211

ZnCl2, PhCl, reflux R1 ¼ H, R2 ¼ i-Pr (57) R1 ¼ Ph, R2 ¼ H (42)

Ligands for asymmetric allylic alkylation

209, 212

ZnBr2, PhCN, reflux R ¼ t-Bu, Bn, Me (90–95) (3 examples)

Stereoselective alkylation of sulfoxides and sulfones

213

CuCl2, 100
C, 10 mbar, neat (44)

Ligands for asymmetric allylic alkylation

210

O

Br N

R1

O

R2 R1

R2

N O

N N

SR

O HO N

N O

Ph

Synthesis of Oxazolines

NC

CN

+ HN 2

387

N

OH

N O

90%

O

142 H2NCH2CH2OH, NH3

NH3 N N

N

OH

N H

N

+

HO

OH

N

HO OH 140

141 Scheme 8.41

cis- and trans-[PtCl2(NCR)2] Nitrile complexes 143 have been reported to react with enantiomerically pure 2-chloro-1-propanol with complete inversion to give oxazoline platinum complexes 145 (Scheme 8.42).215 Aliphatic and aromatic nitriles are often converted to the corresponding imidates that then react with amino alcohols to provide oxazolines. This two-step process offers milder conditions. Generally, a mixture of the imidate (free base or hydrochloride) is allowed to react with the amino alcohol in a solvent (alcohols, CH2Cl2, CHCl3) with or without a tertiary base. As expected, the cylization proceeds with retention of stereochemistry when chiral amino alcohols are used. Representative examples are shown in Table 8.17.33,62,63,139,216–225 The ready availability of benzimidates and trimethyl orthobenzoates make them ideal surrogates for benzonitrile.226–229 R CH2OH cis- / trans- [PtCl2(NCR)2] + H Me 143

Cl

n-BuLi

cis- / trans- Cl2Pt

68-83% R = Me, Ph

N Me 145

R Pt

N

O

H Me Cl 144

Scheme 8.42

O

388

2-Oxazolines

TABLE 8.17. OXAZOLINES FROM IMIDATES AND AMINO ALCOHOLS Oxazoline

Conditions (% Yield)

References 33

Imidate HCl, CH2Cl2, 0
C (67)

62

Imidate HCl, CH2Cl2, rt (70)

63

OMe

Imidate HCl, Et3N, CH2Cl2 (63)

139

Ph

Imidate HCl, Et3N, CH2Cl2 (63)

139

R

N

Comments

Imidate  HCl, IPA, reflux R ¼ Ph, CO2i-Pr, CO2i-Bu, CO2t-Bu (73)

OH

O N

OMe

O

Ph

Ph

N O N Cl

O

Ph N O

Me2N N

CO2Me

O

R2

R1

N

CO2Me

O

Me CO2Me

N BocHN

O

N

Me

O

Ph

Imidate HCl, CH2Cl2, Et3N 216 R1 ¼ Bn, CH2CH2CH2Ph R2 ¼ H, Me (85–90) (4 examples) Imidate HCl, CHCl3, Intermediate for oxazolines 217 reflux suitable to graft onto silica (85) as chiral stationary phases Imidate free base, CH2Cl2, rt (80)

Intermediate for synthesis of conformationally restricted oxazole containing di- and tripeptide mimetics

Imidate free base, CH2Cl2, pyridine, rt (99)

218

219

EtO N

N O

N

R1 R2

Imidate free base, chlorobenzene, cat. HCl R1 ¼ H, Et, Ph R2 ¼ H, i-Pr, i-Bu, t-Bu, Bn (67–83) (6 examples)

Ligands for Rh(I)catalyzed asymmetric hydrosilylation

220

Synthesis of Oxazolines

389

TABLE 8.17 (Continued) Oxazoline

Cl

N

_ N

R1

Conditions (% Yield)

R2

O

N

OMe OMe

Comments

References

Imidate free base, EtOH, cat. HCl, reflux R1 ¼ Me, t-Bu R2 ¼ Bn, i-Pr (64–72) (4 examples)

Metal complexes with rhodium and palladium

Imidate HBF4, DCE, reflux (67)

Intermediate for the 222 total synthesis of ()-Omethyllancistrocladine synthesis

Imidate  HCl, CH2Cl2, Et3N, reflux (80)

Intermediate for the total 223, synthesis of iminoribitol, 224 arabinitol, xylitol, and lyxitol Intermediate for the preparation of vinyloxazolines for stereoselective nitrile oxide cycloaddition Intermediate for polymer 225 supported catalyst for asymmetric allylic alkylation

N

221

OMe O N

CO2Me

O

R1 R2

Imidate free base, CH2Cl2, cat. H2SO4, reflux (91)

N

N

Ph

OH

O

8.2.4.2. Indirect Methods Allyl alcohols readily react with trichloroacetonitrile to give the corresponding trichloroacetimidates 145. Activation of the double bond with electrophilic reagents results in ring closure to yield oxazolines 146. The most commonly employed electrophiles include iodine, iodine monochloride, phenylselenyl chloride, and mercuric trifluoroacetate. Other nitriles including cyanogen bromide and N,Ndimethylcyanamide can also be used. Since oxazolines readily hydrolyze to amides, the net effect of this reaction sequence is to produce b-amino alcohols 147 from an allyl alcohol. This strategy has been employed in numerous total syntheses of natural products. Examples are listed in Table 8.18 (Fig. 8.7; Scheme 8.43).230–236 CCl3

CCl3 OH

Cl3CCN

E+

HN

N

O

NH2

H3O +

O

OH

E

E

R

R

R

R

145

146

Scheme 8.43

147

390

2-Oxazolines

TABLE 8.18. CONVERSION OF ALLYLIC ALCOHOLS TO b-AMINO ALCOHOLS VIA OXAZOLINES

CCl3

CCl3 OH

Cl3CCN

HN

E

O

N

+

O

E

R R

R

Figure 8.7 Oxazoline

Conditions (% Yields) O I

TBSO

O

OPMB

Comments

References

1. Cl3CCN / DBU 2. I(collidine)2ClO4 (86)

Intermediate for the symmetric synthesis of tetrodotoxin

230

1. Cl3CCN / DBU 2. IBr (85–90)

Intermediate for the asymmetric synthesis of ()-swainsonine

231

1. Cl3CCN / DBU 2. I2 (76–89)

Intermediate for the asymmetric synthesis of ()-platynecine and ()-hadinecine

232

1. Cl3CCN / DBU 2. PhSeCl (67)

Intermediate for the asymmetric synthesis of N-acetylneuraminic acid

233

1. Cl3CCN / DBU 2. Hg(CO2CF3)2 3. LiBH4, TEMPO (73)

Intermediate for the asymmetric synthesis of (þ)-lactacystin

234

1. Me2NCN, NaH 2. Hg(CO2CF3)2 3. NaBH4 (96)

Intermediate for the 235 total synthesis of methyl a-L-vancosaminide

1. Cl3CCN, DBU, EtCN 2. Hg(CO2CF3)2, THF 3. TEMPO, LiBH4 (45)

Intermediate for the asymmetric synthesis of (þ)-lactacystin

N

O

CCl3 O

O

I OTBS

O

N CCl3

I

OAc

TBSO

OAc O

N CCl3

O Ar

SePh

O

O N

CCl3 TEMPO

O

OH

OTBDPS

O N CCl3 Me O

Me O

OMe

N NMe2

O C Cl3

N

TEMPO

CN OMOM

236

Synthesis of Oxazolines Cl3C

Cl3C

NH O

N

391

SMe

Me _

O

S+

TfO MeSOTf

O

O

Me S N

O

O

O

O

O

CCl3

148

149

149a

CCl3 O

NHCOCCl3

HO

N

SMe SMe + O

O

O

O

150

151

Scheme 8.44

During an investigation237 of the total synthesis of (þ)-mannostatin, reaction of the trichloroacetimidate 148 with methanesulfenyl chloride produced the Nsulfenylimidate 149 as the only product, presumably the result of an inductively deactivated olefin. Activation of 149 for cyclization required the super electrophilic agent methanesulfenyl triflate. Consistent with steric and ring strain considerations, the electrophile was introduced from the less-hindered face of the olefin yielding only the cis-fused oxazoline 150 together with 151 (Scheme 8.44). Epoxytrichloroacetimidates 153 also undergo oxazoline ring formation in the presence of a catalytic amount of Lewis acids.238 Diethylaluminum chloride was found to be superior to boron trifluoride, which tends to further hydrolyze the oxazoline 154 to the trichloroacetamide. Generally, formation of the six-membered ring oxazine 155 is not favored, but it can be a serious side reaction if the epoxide contains substituents that stabilize the incipient cation generated prior to ring closure. Examples from this study are summarized in Table 8.19 (Fig. 8.8; Scheme 8.45). R O R3

O

OH R1

R2

Lewis acid

O R1

R3 R2

152

HO

R

HN

CCl3

R2

R3

R1 R N

O CCl3

153

154 Scheme 8.45

R1

OH

R2 + R3

R N

O CCl3

155

392

2-Oxazolines

TABLE 8.19. OXAZOLINES FROM CYCLIZATION OF EPOXYTRICHLOROACETIMIDATES CATALYZED BY DIETHYLALUMINUM CHLORIDEa

HO

R O

R2

O R1

R3

HN

R2

R3

N

CCl3

OH

R1

R1 R

R2

O

+ R3

CCl3

R N

O CCl3

154

155

Figure 8.8 Substrate

O

% Yield

Oxazoline 154

Oxazine 155

79

100

0

76

100

0

73

100

0

54

100

0

76

58

42

76

25

75

O CCl3

HN BnO O

O HN

O

O CCl3

HN Ph O

O CCl3

HN O

Ph O

O CCl3

HN O HN

a

CCl3

CCl3

Data from Ref. 238.

An epoxytrichloroacetimidate was used as a key intermediate in the total synthesis of (þ)-myriocin.239 The intermediate diene 157 was constructed in several steps from 156. Stereospecific epoxidation of 157, followed by imidate formation gave 158. Treatment of 158 with Et2AlCl provided 159 for which the proper stereochemistry of the amino group is now set for the natural product (Scheme 8.46). Direct displacement of a suitable leaving group a to an imidate is also known. For example, Imperiali and co-workers240 obtained the (syn,anti)-2-amino-1,3-diol

Synthesis of Oxazolines

393

OH HO OBn OPiv

OBn OPiv

156

157

CCl3 HN

CCl3

O

Et2AlCl

N

OPiv

O

steps

(+)-myriocin

73%

O OBn

HO

OBn OPiv 159

158 Scheme 8.46

functional group array present in aminocyclitols via a stereospecific and regiospecific ring closure of the trichloroacetimidate derived from a cyclic sulfate 160. A large excess of trichloroacetonitrile is required to suppress the formation of the epoxide 165 that is the exclusive product using a less reactive reactive nitrile, for example, N,N-dimethylcyanamide (Scheme 8.47). The synthesis of a 20 -amino-20 -deoxyuridine 168 and a 20 amino-20 deoxycytidine 169 from inexpensive uridine has been described. A key transformation in the synthesis is the introduction of an amino functionality via a trichloroacetimidate.241 This approach also avoids the use of azide that is not desirable for large-scale use (Scheme 8.48).

CCl3

OH O

OH

NH

NH3+ X

O O

O SO2 160

OH

O SO2 161

164

Me2NCN

O

CCl3

O N

OSO3H 165

OSO3H 162 Scheme 8.47

OH O CCl3 +

NH OSO3H 163

_

394

2-Oxazolines O O

NH N

DMTO

DMTO O

Cl3CCN

N

O

O

N

O

Et3N reflux 70-80%

O

N

OH CCl3 167

166

NH2

O

N

NH DMTO O

HO

N

O or

DMTO

HO

NH2

168

O

N

O

NH2

169 DMT = dimethoxytrityl Scheme 8.48

Danishefsky and co-workers described a regioselective formation of an oxazoline 171 from a bis(trichloroacetimidate) 170 in their synthesis of staurosporine.242 The observed regioselectivity is apparently a result of a vinylogous Schmidt glycosylation (Scheme 8.49). O

TIPSO

BF3 OEt2

O Cl3C

O

TIPSO

O NH

CCl3

78%

O N CCl3

NH 170

171 Scheme 8.49

Cyanogen bromide reacts with amino alcohols to give 2-aminooxazolines that condense in the presence of benzaldehyde and p-toluenesulfonic acid with loss of ammonia to give aza-bis(oxazolines) 173.243 Aza-bis(oxazolines) such as 173 are emerging as a new and important class of chiral ligands for asymmetric processes with the added advantage that they can be immobilized on solid supports (Scheme 8.50).

Synthesis of Oxazolines OH

O

NH2

a

NH2

H N

O

b

N

89%

t-Bu

395

N

N

59%

t-Bu

O

t-Bu

t-Bu 172

173 O

O

n

c

N

O

55%

N

O N t-Bu

t-Bu

174 a: BrCN, MeOH, 0 ˚C; b: p-TsOH, PhCHO, toluene, reflux c: n-BuLi, MeOPEG-Br

Scheme 8.50

8.2.4.3. Oxazolines from Ritter Reaction Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction.244,245 A Merck group has shown that indene oxide 175a can be converted effectively to cis-1-amino-2indanol, a key fragment of the HIV-protease inhibitor Indinavir via the cisoxazoline 176a.246,247 The reaction is completely regiospecific and the stereochemical outcome is determined solely by the chirality at C-2. With larger rings, both cis- and trans-amino alcohols are formed (Scheme 8.51). O N

Acid

N O +

MeCN

O

n n

n

176a-c

175a-c

177a-c

Acid

cis- / trans-

n=0

TfOH MsOH

100:0 100:0

n=1

TfOH MsOH TfOH MsOH

37:63 50:50 41:59 53:47

n=2

Scheme 8.51

396

2-Oxazolines

O

O n

N

O N

O N

178a n = 1, 60% 178b n = 2, 54% 178c n = 3, 63%

N

179 51%

O

O N

N

180 49% Scheme 8.52

Ritter reaction of cis-indane-1,2-diol with other nitriles leads to C2-symmetric bis(oxazolines) 178–180 that are ligands in a number of transition metal catalyzed processes (Scheme 8.52).248 Alkyl substituted 1,3-dioxolanes react with acetonitrile in the presence of concentrated sulfuric acid to give oxazolines. The reported yields were quite low and did not appear to be synthetically useful.249 Epoxides also participate in the Ritter reaction with nitriles. An investigation of the ring opening of several alkyl-substituted glycidic esters and amides 181 showed that this transformation occurs with inversion and is completely regiospecific.250 Esters appeared to be somewhat more reactive than amides. However, phenylsubstituted glycidic esters and amides 184 are almost totally nonstereoselective. In addition, the oxazolines 186 are isolated in low yield due to the propensity of intermediate 185 to generate an aldehyde byproduct 187 (Scheme 8.53). Epoxides also undergo the Ritter reaction in good yields with retention of configuration via a episulfonium intermediate 190a (double-inversion process).251 For monosubstituted epoxides, the yields of oxazolines are lower due to nondiscriminatory attack of the nitrile on both the primary and the secondary carbon atom of the episulfonium intermediate. Complete retention of configuration is still observed despite the lower yield (Scheme 8.54). Olefins also undergo the Ritter reaction with nitriles in the presence of diphenyl diselenide, ammonium persulfate, and trifluoromethanesulfonic acid to produce oxazolines.252–254 When cyanamide is used, 2-aminooxazolines are obtained. The active electrophilic agent is phenylselenyl sulfate formed by oxidation of diphenylselenide with ammonium persulfate. The reaction is trans-stereospecific.

Synthesis of Oxazolines

O

R3 R2

R1

R = alkyl

COX

R3 R2

BF3

BF3

O

O

R1

R3 R2

COX

181

397

R3 R1 XOC

COX

N+

182a

R2

R1

Me O 183

Me

X = OMe, NH2

N

182b BF3 O

O

COX

+N

COX

N

COX

+ H O

Me

184

O

XOC Ph

Ph

Ph

Ph

186

187

185 Scheme 8.53

HO

OH

OH

O

PhSNa

C8H17

HO

CF3SO3H

SPh

C8H17 S +

C8H17

Ph 188

189

190a R

R

O

N+

RCN

HO

SPh

R = Me, Ph, t-Bu

N

71-82%

C8H17

SPh C8H17

190b

191a-c Scheme 8.54

This reaction has been applied for the synthesis of the Taxol side chain from the trans-alkene (R1 ¼ Ph, R2 ¼ CH2 OAc) (Table 8.20, entry 11, Fig. 8.9; Scheme 8.55). a-Furfuryl amides 196a–c have been prepared via a Lewis acid catalyzed allylic substitution of furfuryl carbinol acetates 195 with nitriles via the Ritter reaction.255 Alkyl nitriles yield the (10 S)-configured amides 196a–c as the predominant products. However, reaction of 195 with benzonitrile resulted in an oxazoline 197 that was hydrolyzed to the (10 R)-configured amide 198. This method of preparation of a-furfuryl amides starts with 195, which is readily available from 3-deoxy-D-glycero-D-galacto-2-nonulosonic acid (KDN)256 and avoids the multistep, low-yield synthesis via amidoalkylation of furan (Scheme 8.56).

398

2-Oxazolines (NH4)2S2O8

R1

R2

N

R1

O

R2

R3

PhSe-SePh R3CN

192 PhSeOSO3

194

R3CN

R1

+ SePh

PhSe

SePh

PhSeOSO3

R1

R2

R2

NHCOR3

NHCOR3

193a

193b Scheme 8.55

TABLE 8.20. OXAZOLINES FROM ALKENESa

R1

(NH4)2S2O8

R2

N

R1

O

R2

R3

PhSe-SePh R3CN

Figure 8.9 Entry 1 2 3 4 5 6 7 8 9 10 11 a

R1

R2

Ph Bn octyl n-Pr

H H H n-Pr cyclopentene cyclohexene

Ph octyl n-Pr Ph Ph

H H n-Pr CH2OMe CH2OAc

R3

% Yield

Me Me Me Me Me Me NH2 NH2 NH2 Ph Ph

60 62 85 87 60 80 54 45 42 60 63

Data from Refs. 252 and 253.

8.2.5.

Oxazolines from N-Acylaziridines

N-Acylaziridines 199 undergo nucleophile-induced (typically by an iodide) rearrangement to oxazolines.257,258 Excellent regiospecific ring-enlargement to a 2,4-disubstituted-oxazoline 201a–d is observed with an alkyl substituted aziridine; on the other hand, mixtures of 2,4- and 2,5-disubstituted oxazolines 200a and 200b

Synthesis of Oxazolines

399 Ph

AcO AcO

O

TMSOTf

CO2Me

N AcO

PhCN

AcO

O

O

197

195

1. HOAc 2. Ac 2O, Py

TMSOTf, RCN

AcO

NHCOR O

AcO

CO2Me

AcO

OAc

NHCOPh O

AcO

CO2Me AcO

OAc

CO2Me

OAc 198

196a R = Me 196b R = CCl3 196c R = CH2OMe Scheme 8.56

are obtained with aziridines containing an electron-withdrawing group. A single example showed that ring enlargement occurred regiospecifically and with total inversion when a phenyl substituted aziridine 204 is subjected to rearrangement with iodide (Scheme 8.57). N

R2

O

R1

Ph

NaI

Ph R = CO2 i-Pr 200a 31% 200b 45%

O

R

R = CH2O-t-Bu, CH(OMe)2, CH(OEt)2, CH(OCH2CH2O)

199

201a-d O Ph

N

EtO OEt

NaI

N

OEt

83%

OEt

O

Ph

202

203

OEt O N

CF3

N

NaI 55%

R

Ph

93-99%

N

200a R1 = H, R2 = CO2i-Pr 200b R1 = CO2i-Pr, R 2 = H

N

NaI

O

CF3

EtO O

Ph 204

205 Scheme 8.57

Ph

400

2-Oxazolines Ph

CO2i-Pr

N

CF3SO3H

O N

N + Ph

Ph

O

O

CO2i-Pr 206

207a

CO2i-Pr

207b 5.7 : 1

O N

CF3SO3H

Ph

N

78%

CO2i-Pr

O

Ph

208

209

OH

R BF3 OEt2

BnO2C NHCOMe

CO2i-Pr

N

R = Me 100%

N

BF3 OEt2

O

211

R = Ph

CO2Bn

CO2Bn

Ph O

210

212

Scheme 8.58

The rearrangement can also be promoted by acid.257,259,260 Under acid catalysis, N-acylaziridines substituted with an electron-withdrawing group produce a 2,4disubstituted oxazoline as the major product.257 Borontrifluoride etherate (BF3OEt2) has also been used successfully for an N-benzoyl, but not an Nacetyl-substituted aziridine (Scheme 8.58).259 Hori and co-workers studied the BF3OEt2 catalyzed isomerization of a chiral N-acylaziridine 213 to the oxazoline 214.261 It was established that the ring expansion proceeds with retention of configuration. The authors have proposed a SNi mechanism for this transformation through the transition state 213a. Ab initio molecular orbital calculations agree well with this hypothesis (Scheme 8.59). CF3

OMe N

Ph

BF3 OEt2

MeO CF3

N

Ph

O

Me 97%

O

214

213

MeO CF3 Ph

BF3 N O 213a

Scheme 8.59

Me

Me

Synthesis of Oxazolines

401

Lectka and co-workers262 studied the ring opening of a series of N-acylaziridines 215a–d to oxazolines 216a–d promoted by Lewis acids such as Zn(OTf)2, Cu(OTf)2, and Sn(OTf)2. Good yields of 216a–d can be obtained, even in the presence of nucleophiles such as trimethylsilyl azide. It was further observed that the rate of reaction is increased if the phenyl ring contains electron-donating substituents. These observations are consistent with the hypothesis of N-coordination263 with the rearrangement proceeding in a heterolytic stepwise fashion. In contrast, treatment of the same N-acylaziridines 215a–d with oxophilic Lewis acids such as Yb(2,20 -biphenol)OTf in the presence of nucleophiles resulted in ringopened products 217a–d with incorporation of the nucleophile. In this case, rate accelerations are observed if the phenyl ring is substituted with electronwithdrawing substituents (Scheme 8.60). N X O O

216a-d

N

cat 30-89%

X 215a-d

X = OMe, H, F, CF 3 cat = Zn(OTf) 2, Cu(OTf) 2, Sn(OTf) 2 X

64-84% cat

H N N3

O

217a-d X = OMe, H, F, CF 3 cat = Yb(biphenol)OTf Scheme 8.60

The exclusive formation of enantiomerically pure, naturally occurring (R)oxytriphine 220 is indicative of an intermediate solvated tight carbocation pair 219 in the rearrangement (Scheme 8.61).262 Cardillo and co-workers259,264–269 extended this rearrangement to N-acylaziridine-2-carboximides. In contrast to acylated aziridine carboxylates, both the

O

O Cu(OTf) 2

Ph N

Ph

N

Ph

Ph N

(TfO)2Cu

+

Ph

O

Ph

(R)-oxytriphine 218

219 Scheme 8.61

220

402

2-Oxazolines

benzoylated and acetylated aziridinylimides rearrange spontaneously in CHCl3, although acetylated derivatives are observed to be slower. The reaction is clearly acid catalyzed since addition of a stronger acid such as Amberlyst H-15 or BF3OEt2 is required when the reaction is carried out in solvents such as toluene or CH2Cl2. The rearrangement proceeds via an SNi mechanism with preservation of the stereochemistry at the aziridine carbon. Finally, note that N-Boc protected aziridines and aziridinylimides do not rearrange to oxazolines. Instead, they ring expand to oxazolidinones in the presence of Lewis acids such as Cu(OTf)2, Zn(OTf)2, or BF3OEt2. Magnesium bromide etherate is not an active catalyst (Scheme 8.62).269,270 R1 O O

O

N

a, b, or c

R2

N

Me N

Me N

Ph

Me

N Me

O R1

8 examples

222a-h

R1HN

Me

N

R2 = Me, i-Pr, Ph

221a-h

O

O

R2

N

71-95% R1 = Me, Et, n-Pr, Ph

Ph

Me

O

O

N

i-Pr O R2

N Ph

O c 95% R1 = Ac, Fmoc R2 = Me, Ph 3 examples

223a-c

Me N Me

O

R2

N Ph

N

O i-Pr

R1HN 224a-c

a: CHCl3, reflux, b: Amberlyst H-15, toluene, reflux, c: CH 2Cl2, BF3 OEt2, −78 ˚C Scheme 8.62

8.2.6.

Oxazolines from Allyl amides (Enamides)

Allyl amides (enamides), for example, 225, 228, and 230 cyclize to oxazolines, for example, 226, 229, and 231 when the double bond is activated by an electrophile. The double bond can also be conjugated to a ketone, or present as an allylic epoxide. Reagents commonly used to promote the cyclization include acids,271 iodine,272,273 selenium reagents,274,275 and trimethylsilyl triflate (Scheme 8.63).276 An interesting transformation of a conformationally restrained allyl amide 232 to an a-hydroxy-cyclopentenyl hydroxylamine 236 has been reported.277 The mechanism is thought to involve a series of reversible reactions leading ultimately to 234, which fragments irreversibly to 235. Hydrolysis of the ester accounts for the observed product 236 (Scheme 8.64).

Synthesis of Oxazolines

O

H N

O

HN

MsOH

N

O

90%

H

HN

H N

O

H N

N

403

NH

Br 225

226

Br H

O

O

O

HO NHCOPh CO2Me

NHCOPh

CH2N2

CO2Me

Pd(OAc) 2

O

Ph

silica gel

N CO2Me

75% (2 steps)

O

O O

O 227

O 228

O

229 O

H CO2Me Ph

O

H CO2Me Ph

TMSOTf

NH

O

90%

Ph

N Ph

230

231

Scheme 8.63

HO N

HO

HO aq. HCl

O

Ph

HO

Ph O

HO

N

O

N

Ph O +

232

233a

233b

HO H2O

HO OH OH N O

NH

HO NH2+ Cl O O

Ph

OH

HO Ph 234

235 Scheme 8.64

236

404

2-Oxazolines OH Ph

Ph

OH

H N

Ph

I OH

O

N

a

O

N

O I

237

238

239

steps

N

O Ph

steps

N

N

OH

Ph H N

N

O

OH

O O 240

241 Indinavir a: N-iodosuccinimide; IPAc; aqueous NaHCO 3 Scheme 8.65

During an investigation278 of the utility of epoxide 240 as an intermediate in the synthesis of the HIV protease inhibitor Indinavir 241, it was found that the amino alcohol 237 must first be protected prior to iodination. Without protection, the iodination of the unsaturated amide 237 gave the unstable oxazoline 239 in 83% yield (Scheme 8.65). Benzamido allylic acetates 242 and 243 undergo palladium-catalyzed cyclization to oxazolines. Excellent yields and very high diastereoselectivity is observed for the conversion of several acyclic primary and secondary benzamido allylic acetates to trans-5-vinyl substituted oxazolines 244.279,280 The diastereoselectivity of the reaction is determined by the the steric interactions between the R group and the hydrogen of the p-allylpalladium complex in the transition state. transOxazolines are obtained since transition state A is favored over transition state B (Scheme 8.66). An interesting application of this methodology is the preparation of a cis-1,2aminocyclopentenol derivative 247 (Scheme 8.67).281 Oxazoline formation from 5-vinyloxazolidinones promoted by palladium (0) is also known.282 Oxidative insertion of palladium with loss of CO2 results in a pair of equilibrating p-allyl palladium complexes. The stereochemistry of the vinyl group is therefore not important. Ring closure from the thermodynamically more stable transition state accounts for the trans-isomer as the major product. Depending on the exact substitution, diastereoselectivities ranging from 2.5:1 to 16:1 can be obtained (Scheme 8.68).

Synthesis of Oxazolines R

405

OAc NHBz

N

K2CO3, MeCN

R

Ph

242 Pd(PPh3)4 68-73% yield 84-100% trans R = Ph, Bn, i-Bu, CH2C6H11

OAc R

O 244

NHBz 243 L

H

+ L L Pd

+

Pd

R

R N

O

L N

O

Ph

Ph

A

B

Scheme 8.66

Me BocHN

Me H N

Me

a

OAc

O

BocHN

N

b

H N

BocHN

O

O HO

245

246

247

a: NaH, cat Pd(PPh3)4, DMF b: 1 N HCl

Scheme 8.67 Ph

O

O

Pd2dba3

N

Ph

N

O

O

dppp CHCl3 74-98% trans-/cis- 2.5:1 to 16:1

R 248

R 249

−CO2

O

N Ph

O R

PdLn

N Ph

A

R

PdLn

B

R = Me, Ph, Bn, CH2CH2SMe, CH2CH2OTBDMS

Scheme 8.68

406

2-Oxazolines

OH

TBSO

OTBS

N

Pd2(dba)3CHCl3

BnO

HN

O

NH

steps

O

N

O

O

O

dppp 79%

OBn 250

OBn

251

252

HN O N H

steps

OH

O BnO

O HO HO

CO2H

253 balanol Scheme 8.69

This reaction was utilized to establish the vincinal amino alcohol stereochemistry required for the construction of key intermediates 251 and 252 for the synthesis of the natural product balanol 253 (Scheme 8.69).283,284 8.2.7.

Oxazolines from Isonitriles

Oxazolines 256a and 256b are produced when a-isocyanoesters 254 react with aromatic aldehydes in the presence of catalytic or stoichiometric quantities of R1 CN

CO2Me

R1

254 or

R2CHO

N

R1

TBAF

N

O

OMe

CO2Me

R2 + O

N

cis-

trans-

256a

256b

t-BuMe2Si O

R1 CO2Me

R2

255

Scheme 8.70

Synthesis of Oxazolines

407

TABLE 8.21. OXAZOLINES FROM a-ISOCYANOESTERSa

R1 CO2Me

CN

R1

or R2CHO

R1

N

TBAF

t-BuMe2Si O

R1 CO2Me

R2 O

OMe

+

CO2Me

R2

N

O

N trans-

cisFigure 8.10

R1

R2CHO

% Yield

cis/trans

O Me

CHO

80

75 : 25

79

88 : 12

0 77 81 51

100 : 0 62 : 38 4 : 96

CHO

O Me

O Me t-Bu Me H a

EtCHO PhCHO MeCHO PhCHO

Data from Ref. 285.

tetrabutylammonium fluoride.285 5-Methoxy-4-substituted-2-(tert-butyldimethylsilyl)oxazoles 255, latent a-isocyanoesters react similarly, except that at least a stoichiometric amount of fluoride is required for the desilylation. The cis/trans-ratio is dependent on the bulkiness of the substituent at the a-carbon of the isocyanoester. Selected examples are summarized in Table 8.21 (Fig. 8.10; Scheme 8.70).

8.2.8.

Oxazolines from Cycloadditions

8.2.8.1. [2 þ 2] Cycloadditions 2,4,5-Trimethyloxazole 257 undergoes photochemically induced [2 þ 2] cycloaddition with aromatic and aliphatic aldehydes to provide bicyclic oxazolines 258 with excellent regiochemical and stereochemical control.286 Diastereoselectivities from 75–99% can be achieved, which is the first reported example of a Paterno-Bu¨chi287,288 reaction involving an oxazole. The oxetane cycloadducts can be hydrolyzed to a-amino-b-hydroxy ketones. Other oxazoles have not been evaluated to determine if they undergo the photochemical cycloaddition (Scheme 8.71).

408

2-Oxazolines Me Me

N Me O

Me

O

RCOR′

N

Me

benzene, hv 100% 75-99% de 4 examples

H2N Me

H+

Me

R′ R OH

Me O

O

R′ R

258

257

259

R Et t-Bu Ph Ph R′ H H H CO2Me Scheme 8.71

8.2.8.2. [3 þ 2] Cycloadditions Azomethine ylides undergo a formal [3 þ 2] cycloaddition with carbonyl compounds to provide oxazolines. Thioimidates, in particular, are effective as ylide precursors. For example, Kohra and co-workers reported that the thioimidate 260, upon activation with cesium fluoride, reacts with aromatic aldehydes and diarylketones to provide oxazolines 261 in modest to good yields.289 Aliphatic aldehydes and simple ketones are unreactive (Scheme 8.72). R1 O

SMe

O

CsF

R2

+ N

N

N

Me

TMS

R1

R2

MeCN 38-77% 12 examples

N

N

N

Me 261

260

R1 = Ph, substituted-Ph, 1-naphthyl, 2-thienyl, 3-pyridyl, cinnamoyl R2 = H, Ph Scheme 8.72

For N-(trimethylsilylmethyl)-S-methylisothioureas 262, cycloaddition with carbonyl compounds results in 2-aminooxazolines 263.290,291 Aliphatic and aromatic aldehydes and ketones can be employed successfully. However, reaction with ketones appears to be poor. Ylide generation with CsF is the method of choice although TBAF and KF have also been used but with lower yields. A polar solvent such as MeCN, DMF, or hexamethylphosphoric triamide (HMPA) is required for a succesful reaction (Scheme 8.73). N-(Methylthiomethylmethylene)glycinate derivatives, for example, 264, also undergo cycloaddition with benzaldehyde in the presence of DBU to provide cisand trans-2-oxazolines 265a and 265b, respectively (Scheme 8.74).292

Synthesis of Oxazolines

409

SMe

N

O N

NR1R2 +

R3

F

262

R4

O

solvent 60 ˚C, 15 h 20-80% 11 examples

R4

TMS

R1, R2 = (CH2)5, (CH2)4 R1 = R2 = Et R1 = Ph, R2 = Me

R2R1N

R3 263

R3 = Ph, 4-Cl-Ph, 4-CF3-Ph, 4-MeO-Ph, styryl, i-Pr, pentyl R4 = H, Me

Scheme 8.73 Ph Ph

O +

MeS

N

CO2Et

Ph

Ph

O

DBU

H

Ph

N

65%

+

O

CO2Et 264

Ph

N

CO2Et

265a

265b

Scheme 8.74

Bazureau and co-workers293–295 reported that imididate 266 reacts with carbonyl compounds to provide good yields of oxazolines 269a–l as the only product. Only one of the two possible regioisomers is formed. Exclusive formation of the 5regioisomer is consistent with FMO calculations based on the assumption that the reaction proceeds via an azomethine ylide intermediate 267. The azomethine ylide is formed via a thermal 1,2-prototropy and can be trapped by aromatic aldehydes or diethyl ketooxalate. Aryl alkyl ketones and dialkyl ketones are unreactive. Aliphatic aldehydes have not been evaluated extensively in this study. Interestingly, when the reaction is carried out in an ionic liquid such as 1-ethyl-3-methylimidazolium tetrafluoroborate, significant rate enhancements and improved yields of the cycloadduct are obtained (Scheme 8.75).296 Me

N

O

CO2Me

70 ˚C

CO2Me

CO2Me CO2Me

O

R2 R1

Me

+ OEt

N

R1

R2

64-91% 12 examples

266

269a-l −EtOH

Me EtO

4

e−

N H 267

CO2Me CO2Me

H N Me EtO O

CO2Me CO2Me R2 R1 268

R1 = Ph, 2-furyl, 2-pyridyl, styryl, 2-CHO-Ph, 3-CHO-Ph, i-Pr, CO 2Et R2 = H, CO2Et, Scheme 8.75

410

2-Oxazolines

N-Cyano- and N-(p-toluenesulfonyl)-N’-(trimethylsilylmethyl)-S-methylisothioureas 269a and 269b have also been utilized as synthetic equivalents of azomethine ylides.290 Reaction of 269a and 269b with aromatic aldehydes and aryl ketones, in the presence of CsF, gives 2-iminooxazolines 270a–e in modest-to-good yield. These 2-iminooxazolines apparently are stable to isolation and do not isomerize to 2-aminooxazolines (Scheme 8.76). SMe TMS

N H

N

269a R1 = CN 269b R1 = Ts

O

CsF

R1 + H

R2

H N

R1

41-84% 5 examples

N

R1 = CN, Ts R2 = Ph, 2,6-di-Cl-Ph, 4-Ph-Ph

O

R2

270a-e

Scheme 8.76

5-Alkoxyoxazoles undergo Lewis acid catalyzed reaction with a variety of aldehydes to give a mixture containing trans-2-oxazoline-4-carboxylates predominately. The reader is directed to a thorough review of this chemistry recently published by Suga.297

8.2.8.3. [4 þ 2] Cycloadditions 4-Nitro-2-phenyloxazole 271a undergoes Diels–Alder [4 þ 2] cycloaddition with both electron-rich and electron-poor dienophiles to give an oxazoline 273 that may not be isolable due to the facile aromatization to a fused oxazole 274.298,299 Examples are shown in Table 8.22 (Scheme 8.77). N

NO2 +

Ph O

271a R=H

O2N N

heat

N + Ph

Ph O

R 272

O

273

274

Scheme 8.77

Nitrooxazoles 271a–c also react with electron-rich ynamines to yield isoxazolines.300 The proposed reaction mechanism involves the Michael addition of the ynamine to give 275, followed by rearrangement to a nitrile oxide 277. Intramolecular 1,3-dipolar cycloaddition of 277 accounts for the exclusive cis stereochemistry observed in the products 278a–c (Scheme 8.78). Unlike ynamines, ethyl vinyl ether requires the more electron-deficient 4-nitro2-phenyl-5-oxazolecarboxylic acid methyl ester 271b for reaction to occur. The initial [4 þ 2] cycloadduct 279 undergoes further reaction with ethyl vinyl ether to give the tricyclic oxazoline 280 in 76% yield (Scheme 8.79).

Synthesis of Oxazolines

411

TABLE 8.22. OXAZOLINES FROM [4 þ 2] CYCLOADDITIONSa Diene

Products

N

Conditions

N

Ph

110
C

Ph O

O

71%

13%

NO2 N

Ph

40
C

N

O NO2

O

19%

66%

Ph

NO2 N

Ph

O NO2

40
C

N O

Ph

53% (products not separable)

NO2 N Ph

O NO2

O

30%

O

Ph

33%

N

150
C

Ph

O

110
C

N

O 21% N

N 55
C

Ph

N

O

N

29%

O

N

N

NMe2

O

N

N

25
C

N

N O

NHCOPh O 67%

a

Data from Ref. 299.

NMe2

412

2-Oxazolines O NO2

N O

NEt2

Ph

O

R

O

R

C NEt2

Me

271a R = H 271b R = CO2Me 271c R = COPh

275

R

+ O N

O

O

N N Me

Ph

N

N + Me

Ph

N

O Ph

NEt2

_

R CONEt2

O Me

276

277 N

N

O

Ph

52-63% R = H, CO2Me, COPh

O

R Me CONEt2

278a R = H 278b R = CO2Me 278c R = COPh Scheme 8.78

EtO O N

NO2

OEt

O

N

40 ˚C

+

Ph

76%

CO2Me

271b

O

N+ O

Ph O

N

N

Ph OEt

279

O

O CO2Me

OEt

280

Scheme 8.79

8.2.9.

Miscellaneous Methods

The Staudinger-aza-Wittig301 cyclization methodology for imine formation can also be applied to the synthesis of oxazolines under essentially neutral conditions.302 Thus, an azido ester such as 281 reacts with triphenylphosphine to give the oxazoline 283 in excellent yield. There was no evidence for cyclization at the benzoate presumably because cyclization to a five-membered ring is faster than

Synthesis of Oxazolines

413

BzO

BzO

OBz

PPh3, THF

OAc

−OPPh3

O

−N2

N3

N

97%

N

O PPh3

281

O

282

283

Scheme 8.80

cyclization to a seven-membered ring. The generality and scope of this reaction apparently has not been fully explored to date (Scheme 8.80). Oxazolines 285a–m are also produced when 1,2-azido alcohols 284 are subjected to a variety of Lewis acids. In particular, boron trifluoride etherate was the most effective.303 The reaction works well with electron-rich and electrondeficient aromatic aldehydes and aliphatic aldehydes. However, ketones are unreactive and a,b-unsaturated aldehydes gave only a modest yield of the oxazoline. The mechanism is believed to proceed via initial hemiketal formation and subsequent dehydration to generate an oxonium ion 286a that is captured by intramolecular attack of the azide to give the cyclic aminal 286b. Elimination of Hþ and N2 from 286b then gives the oxazolines 285a–m in modest to excellent yield (Scheme 8.81). S-Ethenylsulfimines 287 react with amides to yield 2-substituted-oxazolines 289.304 The reaction proceeds via initial Michael addition of an amide anion to 287 to give 288 that collapses to the oxazoline. The reaction is typically carried out at room temperature or 50
C in THF, 1,2-dimethoxyethane (DME), or even MeCN using NaH as the base. Aryl, heteroaryl, and aliphatic amides can be used and the yields of 289 are modest to excellent (Scheme 8.82). O

R2 +

R1

H

N3

HO

N

BF3 OEt2

R1 55-96% 13 examples

O

284

R2

285a-m −H+, −N2

N2

R2 N3

+O R1

H 286a

H

N

R1

O

R2

286b

R1 = Ph, 4-NO2-Ph, 4-MeO2C-Ph, 4-MeO-Ph, Bn, t-Bu, pentyl R2 = H, Ph Scheme 8.81

414

2-Oxazolines

Ar

S

N

NTs

RCONH2

N

R O

NaH

S

NTs

R 53-98%

O

Ar 287

288

289

Ar = Ph, 4-Me-Ph R = Ph, 4-Me-Ph, 2-Me-Ph, 4-Cl-Ph, 3-Cl-Ph, 4-pyridyl, Me, Et

Scheme 8.82

OTBDMS O

O

N3CO2Et

O

OTBDMS O

O

N

O

hv

CO2Me

CO2Me

290

291 H OR H O

steps

O

O X Y 3 N H

O

HO H 293 lankacidin C: X,Y = O, R = H lankacidin A: X,Y = O, R = Ac lankacidinol: X = H, Y = OH, R = H lankacidinol A: X = H, Y = OH, R = Ac

O O

O O O

O H

N3CO2Et

H

O O

hv

O O

O

N

294

295

N3CO2Bn

O

OEt

O

Cbz

hv

H N

OEt

OH O

OTBDPS

OTBDPS

296

297

Scheme 8.83

Synthesis of Oxazolines

415 _

NHOH + (MeO)3C OH 298

+

R1

O

299

H

N O

R O 1

O

R1

300

N O

O N

R1 R2

O

O

R2 301

302 O

H N O

H N OH O

H OH O

R1 R2

38-67% 32-95% de 7 examples

O

R2

R1

O 303

304a-g

R1 = Me, Et, Bn, Ph, (CH2)2CO2Me R2 = Ph, Me, BnOCO

Scheme 8.84

In their synthesis of lankacidin antibiotics,305 Williams and co-workers utilized an insertion reaction of an azidoformate-derived acylnitrene on the electron-rich dihydrofuran 290 to introduce the sterically hindered C-3 amino appendage in the macrocyclic framework. The oxazoline formation is totally stereospecific with the Ph Ph

O Bn

N

N

Ph SMe

O

O

300 nm

MeS

NaBH4 64%

H 305

N

H

N

N H MeS

Bn O

N Bn

306

307

OH steps

O

H2N N H

n-C7H15 308

pseudodistomin A

Scheme 8.85

H O

416

2-Oxazolines R-CO-N=C=S N2+

309 R

+ Ph2CN2

Ph Ph

N _ O

S

310

Ph Ph

N

S

O

Ph Ph

R S

Ph Ph S Ph

NCOR

N2+

S

_ NCOR N2+

N R O

Ph

Ph

Ph N

S

O

Ph Ph

R

Ph Ph Ph Ph

311

PPh3

R = CCl3, CO2Me, Ph, OEt, t-Bu

R

Ph N

Ph

R O

Ph Ph

Ph Ph

N

N + _S

Ph

COR

O Ph Ph

Ph

Ph S

Ph

Scheme 8.86

acylnitrene approaching the olefin from the less-hindered b-face. In contrast, using the lactonized substrate 294, the reaction occurred unexpectedly from the a-face to give 295. During this study, the authors also examined benzyl azidoformate as the source of the acyl nitrene. Even with the simple dihydrofuran 296, a high diastereoselectivity was observed (Scheme 8.83, p. 414). Langlois and co-workers306 developed a stereoselective hetero-Claisen rearrangement of camphor-based oxazoline N-oxides 300, available from hydroxylaminoisoborneol 298 and orthoesters 299. The rearrangement, initiated by acylation of

Reactions and Applications

417

the oxazoline N-oxide, provided 2-(a-acyloxy)oxazolines 302 that spontaneously hydrolyzed to 304. The stereoselectivity observed is consistent with an intermediate (Z)-keteneaminal 301 in which the [3,3]-sigmatropic rearrangement occurs from the a-face (Scheme 8.84, p. 415). 4-Acyl-2-phenyloxazole derivatives undergo a reductive photocyclization in the presence of sodium borohydride to generate a bicyclic oxazoline with a cis-fused pyridinone ring 307. The stereochemistry of the product is consistent with hydride attack from the less hindered surface of the cyclic intermediate 306. The oxazoline containing pyridinone is a key intermediate used for the synthesis of pseudodistomins 308 (Scheme 8.85, p. 415).307 Spirocyclic oxazolines 311 are produced in 37–67% yield from acylisothiocyanates 309 and an excess of diphenyldiazomethane 310.308 The proposed mechanism for product formation is indicated in Scheme 8.86. The reaction has also been demonstrated for 2-diazofluorene. There are no reports for aliphatic diazo compounds.

8.3. REACTIONS AND APPLICATIONS Oxazolines can participate in a diverse range of reactions. Other than the oxygen atom, each position of the oxazoline ring is capable of some type of electrophilic or nucleophilic reaction (Scheme 8.87). The 2-position is susceptible to nucleophilic attack ultimately resulting in ring-opened products (pathway a). The ring-opened product can then undergo further reaction or rearrangement depending on the nucleophile. The nitrogen atom can undergo electrophilic reactions including oxidation, alkylation, and salt formation (pathway b). The 4-position is acidic and can be deprotonated and undergo typical carbanion chemistry (pathway c). The 5-position is susceptible to nucleophilc attack also leading to ring-opened products (pathway d). Reactions may also occur at a remote site of a molecule that can be influenced by the oxazoline ring. Examples of such reactions include those wherein an oxazoline acts as an activating group, directing group, or as a chiral auxilliary. Oxazolines are also used extensively as chiral catalysts in stereoselective synthesis. This section will focus on a discussion of mononuclear oxazolines. A comprehensive discussion of the syntheses and reactions of chiral bis(oxazolines) is found in Chapter 9. 8.3.1.

Nucleophilic Reactions

8.3.1.1. Hydrolysis Hydrolysis is undoubtedly the most common nucleophilic reaction at the 2position. It is generally used to unmask the hydroxy amide or amino alcohol after synthetic manipulations on the oxazoline ring are completed. Hydrolysis under

418

2-Oxazolines secondary reaction products

secondary reaction products

Nu O

NH

O E+

Nu a

b

O

N E+/Base

Nu c

d

H N

Nu

N E

O

H O

N E

Scheme 8.87

strongly acidic conditions gives the amino alcohol. However, the reaction can be stopped at an intermediate stage if it is carried out under mild conditions. For example, the initially formed amino ester can be isolated or trapped in certain cases although it is more commonly rearranged to the hydroxy amide, typically under mildly basic conditions (Schemes 8.88 and 8.89).309 The configuration of the oxazoline at the 4 and 5-positions is normally retained under the hydrolysis conditions as shown in Scheme 8.89. Selected examples are shown in Table 8.23.157–159,185,191,195,230,231,239,241,250,264,268,271,273,281,284,286,310–312 N

R1

R

R1

+ NH3

R1

NHCOR

R2

OCOR

R2

OH

O R2

Scheme 8.88

AcO

O

H O Me N

AcO AcO

H

HCl 93%

O

AcO

OAc

AcO

NH2 AcO

Cl

O Py 66% Cl

AcO

O

AcO

OAc NH

AcO

O Scheme 8.89

Py 45 ˚C 92%

AcO

O

AcO

OH NHAc

AcO

Reactions and Applications

419

TABLE 8.23. HYDROLYSIS OF OXAZOLINES Entry 1

Oxazoline N

Ph

Hydrolysis Conditions (1) 1 N HCl, MeOH/THF, reflux (2) aq. NaHCO3

Ph

O O

Product/Yield Ph

310

OH

O O

O

2

80% O

80% HOAc, rt

O

241

NH DMTO

N

NH HO

O

N

O

O

O

O

N

OH NH2 84%

CCl3 DMT ¼ dimethoxytrityl 1 N HCl Me H N

3

Reference

NHCOPh

NHBoc

O

281

Me H N

NHBoc O

H

OH

67% 4

TFA/water, rt

O O

H

231

O O

N

NHCbz

CCl3

O

OH

H O

5

O

(1) 6 N HCl, reflux (2) Dowex 50  8–200

Ph N

HO OH 90% (after Cbz protection) H2N OH

O

157, 158

CO2H

CO2t-Bu

92% 6

Ph

O

2.5 N HCl, reflux

O

HO

O

OH

O N

OH

HO

OH NH3+ Cl 90%

311

420

2-Oxazolines

TABLE 8.23 (Continued) Entry 7

Oxazoline N

Ph

Hydrolysis Conditions

Product/Yield

(1) 0.5 N HCl/MeOH (2) aq. NaHCO3

Ph

159

Ph

O

NH

O

OH 88% O

(1) 1 N HCl/THF (2) aq. NaHCO3

O O

230

O

OAc NHAc

OAc

N

O

CO2Me

Ph

OMe

8

Reference

O

OH 64% (after acetylation)

Me

9

(1) 5% HCl, reflux (2) NaOH

HN

N

271

HN

O

Br

Br

NH

O HO

NH N H

NH

O

HN O

85% 10

BF3OEt2, water/ CH2Cl2, piperidine

O O

Me

N

Me

Me

Ph

N N

Ph

268

O O N

Me

O

OH

N Ph HN

Ph O

FmocNH

FmocNH

11

N

Me H2NOC

Me

65% Me NHAc

BF3OEt2, water or wet CHCl3, rt, 1 week

O

H2NOC

i-Pr 100%

i-Pr

12

N

1 N HCl, 100
C

Ph

O

13

HO2C

MeO2C

N

Ph

Ph

TFA, THF/water, 80
C

H

Ph

I

OCOPh HO

185

OH

70% after benzoylation MeO2C NH3+ CF3CO2

O HO

OH

NHCOPh

MeO2C

250

I

82%

273

Reactions and Applications

421

TABLE 8.23 (Continued) Entry

Oxazoline

14

Me

N

R

Product/Yield

Me

O

Me

0.1 N HCl/THF, rt

Ph

2

286 NHAc

R

Me R ¼ Et, t-Bu, Ph N MeO C

NHCOPh

O

CO2Me HO 70%

N

MeO2C

6 N HCl, reflux

Ph

NH3+ Cl

O

CO2H HO 95%

H

Cbz

N

Ar

N

(1) 2 N HCl/THF, rt (2) Et3N/MeOH, rt N

OH

72% CO2H

(1) 20% HCl/EtOH (2) Propylene oxide

O N

195

NH2

Me

Ph

Me

OH

O

Me

H

Me

284

NH

Cbz

O

X

Ar

O

H Ar ¼ 4-BnO-Ph-

18

191

HO2C

MeO2C

17

191

MeO2C

MeO2C

16

Reference

OH

O

O

15

Hydrolysis Conditions Water/EtOAc, rt

50–52%

X = MeO, NMe2

19

Me

Me

TsOH/MeOH/ water, rt

N O

Ph

N

N

N

O

O O

HO

Me

NHAc

Ph H N

N

O

NHAc

264

Me

Me

O Me

95% 20

1 N HCl/THF

HO N

CCl3

O

239

HO

CCl3

NH

O H OBn

OH

OPiv

OBn OPiv

100% 21

N O2NO

Ph

57% HNO3, 20
C

312 O2NO

NH3 O

O Ph O2NO

O2NO

96%

NO3

422

2-Oxazolines

TABLE 8.24. UNMASKING THE SIDE-CHAIN OF TAXOL ANALOGUES BY ACID HYDROLYSISa

N

R

Ph

+ NH3 X

R

R

NHCOPh

HX

O

O

O

O Bac

O

OCOPh

O

OH O

Bac′

312

313 P10O

Me Bac =

Bac′

O OP7

10 13

7

1

P1O

2

4

H P2O P4O

O

Scheme 8.90 Entry

Oxazoline

Ph 1

N

Hydrolysis Conditions

O

(1) 1 N HCl/MeOH/THF, rt

(b)

O Bac1 N

N O

(1) 1 N HCl/MeOH, rt

N

(c)

80

78, 162, 314

313d

95

310

313

75

314

312g

84

125

(2) aq. NaHCO3

Ph (1) 0.1 N HCl/EtOH, 95
C

O O (e)

O Bac3

5

313d

Ph

O

Ph

310, 313

(c)

O Bac2

4

93

(2) aq. NaHCO3

O Bac2

Ph

313

(2) aq. NaHCO3

(1) 0.1 N HCl, MeOH, 60–80
C

O

3

References

Ph

O

2

Ph

% Yield

Ph

O

Ph

Product

N

Ph 0.1 N HCl/dioxane, 50
C,

O O O Bac4

(2) aq. NaHCO3

(f)

Reactions and Applications

423

TABLE 8.24 (Continued) Entry

Oxazoline

N

Ph

Hydrolysis Conditions

(1) 1 N HCl/MeOH/THF, 5
C

O

313d

61

86

313d

39

86

313d

50

86

313d

75

85

(h)

N O

Ph (1) 1 N HCl /MeOH/THF, 5
C

O

O

(2) aq. NaHCO3

HN Bac5 Ph

N

(h)

Ph (1) 1 N HCl/MeOH/THF, 5
C

O

8

O (c)

HN Bac2

Ph

N

(2) aq. NaHCO3

Ph 0.1 N HCl, 95
C

O

9

References

(2) aq. NaHCO3

HN Bac5

7

% Yield

Ph

O

6

Product

O O Bac2

(c)

a

Groups P1-P10 denote protecting groups at 1–10 positions, respectively. Bac1: P1 ¼ H, P2 ¼ Bz, P4 ¼ P10 ¼ Ac, P7 ¼ 2,2,2-trichloro-t-butoxycarbonyl. c Bac2: P1 ¼ H, P2 ¼ Bz, P4 ¼ P10 ¼ Ac, P7 ¼ triethylsilyl. d The silyl protective groups on the baccatin core structure were removed under reaction conditions. e Bac3: P1 ¼ H, P2 ¼ Bz, P4 ¼ Ac, P7 ¼ P10 ¼ 2,2,2-trichloroethoxycarbonyl. f Bac4: P1 ¼ H, P2 ¼ Bz, P4 ¼ P10 ¼ Ac, P7 ¼ H. g A solution of 312 in methylene chloride isomerized to 313 at room temperature after 20 h. h Bac5: P1 ¼ dimethylsilyl, P2 ¼ Bz, P4 ¼ methoxycarbonyl, P7 ¼ triethylsilyl, P10 ¼ Ac. b

Partial hydrolysis of an oxazoline to produce the hydroxy amide was used extensively in the synthesis of Taxol analogues (Table 8.24; Scheme 8.90).78,85,86,125,162,310,313,314 It is noteworthy that a solution of the amino ester salt 312 isomerized to 313 after prolonged standing at room temperature (entry 5).125 Vogel and co-workers reported an interesting oxazoline hydrolysis during which the ester group in 314 migrated to give 315.311 Although the authors did not discuss the mechanism for the migration, the product likely results from anchimeric assistance of the 2-amido ester to give an intramolecular nucleophilic substitution at the 5-position rather than typical attack at the 2-position (Scheme 8.91). Alvarez-Ibarra and co-workers reported oxidative hydrolysis of 2-thio substituted oxazolines (Scheme 8.92).315,316 Presumably, the reaction proceeds through a

424

2-Oxazolines O O

Ph

CN

N

O

O

O

Ph

HClO4-H2O

O HN

90%

O

O

O

R

R

314

315 −HCN

H+

H O H Ph N H +

O O

O

Ph

CN

CN

O

O

Ph

OH

H2O

HN

HN

O

O O O + R

O R

−H+

O

CN

O R

Scheme 8.91

sulfoxide or sulfone intermediate that is more reactive for hydrolysis. This appears to be a general method to hydrolyze 2-thiooxazolines. In general, 2-amino-substituted oxazolines are more resistant to acid hydrolysis. For example, the 2-aminooxazoline moiety in the protected azasugar 316 was preserved during acid cleavage of a ketal in the final step of a trehazolin synthesis (Scheme 8.93).102 Oxazolines are generally resistant to basic hydrolysis. For example, the ester in the spirocyclic oxazoline ester 317 was quantitatively hydrolyzed under basic conditions to afford the corresponding acid 318 (Scheme 8.94).185 However, oxazolines can be completely hydrolyzed using strongly basic conditions. For example, Giuliano and Smith hydrolyzed the 2-aminooxazoline 319 with

N

Ph Ph N MeS

SMe

O

NH2 NH2 30% H2O2 HCOOH 80%

Ph

Ph

Ph HO

Ph

SMe EtO2C R

N O

Me

SMe

OH

30% H2O2 HCOOH 85−90%

R = Me, Bn Scheme 8.92

EtO2C R

Me NH2

Reactions and Applications

425 OH

OBn BnO BnO

HO HO

O

O

(1) Pd(OH)2/C, H2 EtOH, TFA

BnO HN

N

OH HN

N

(2) 2 N HCl, r.t.

OH

83%

O

O O

BnO

OH

O

OH

HO

316

OH

trehalamine Scheme 8.93

N

N

5 N NaOH

Ph

Ph THF, r.t. 100%

O

MeO2C

O

HO2C

317

318 Scheme 8.94

aqueous barium hydroxide at reflux and isolated the amino alcohol 320 in excellent yield (Scheme 8.95).235 Meyers and Shimano reported an efficient basic hydrolysis of oxazoline 321 to the amino acid 322 (Scheme 8.96).317 In this case, Nbutylamine was used to scavenge divinyl ketone produced from the piperidinone moiety. O

Me

OMe

Me

O

OMe

Ba(OH)2

H O N

Me

water, reflux 93%

HO H2N

Me

Me2N 319

320 Scheme 8.95

O

N

O

NH2 t-Bu N

Me

CO2H

NaOH/n-BuNH2/H2O

Me

145 ˚C, sealed tube 72%

321

322 Scheme 8.96

426

2-Oxazolines MeO2C

N

MeO2C

OAc

Me

O

84%

Cl

323

CO2Me

pathway a

H N

MeO2C

NH

324

H2O

MeO2C

CO2Me

aq. NaHCO3

MeO2C

Me

O

OH

CO2Me

−HCl

N

Cl

b Me

O

a O

H

325

326

pathway b

OH CO2Me N

CO2Me Ac

Scheme 8.97

Bazureau and co-workers reported an unusual hydrolysis of the tetrasubstituted oxazoline 323. In this case, 323 was unstable and hydrolyzed quickly to the tetrahydroisoquinoline amino ester 324 under mildly basic conditions (Scheme 8.97).295 Although the authors did not discuss the reaction mechanism, it is possible that the facile hydrolysis is facilitated by the formation of the bicyclic intermediate 325 produced via intramolecular trapping of 326. The same group also reported an analogous reaction wherein the oxazoline 327 hydrolyzed under neutral conditions to give the dihydroisoquinoline 328 (Scheme 8.98).294,295 In contrast, with a meta-substituted aldehyde, the oxazoline was stable under the same reaction conditions, which suggests that an intramolecular mechanism is operative and is consistent with the above analysis. MeO2C

N

MeO2C

O

OAc

Me Water 95 ˚C, 170 h

CHO

CO2Me

N

100%

327

328 Scheme 8.98

CO2Me

Reactions and Applications

427

TABLE 8.25. HYDROLYSIS OF OXAZOLINE 329 UNDER BASIC CONDITIONSa

DMTO

DMTO

B

B

O

O

N

B O

O

O

DMTO

NH

OH NH2

O

CCl3 329

330

331

DMT = dimethoxytrityl Scheme 8.99 Entry

Base (B)

Hydrolysis Conditions

% Yield (Product)

O NH

1

N

2.7 N NaOH/dioxane, reflux, 10 h

58 (330), 8 (331)

6 N NaOH/EtOH, reflux, 16 h

79 (331)

aq. Cs2CO3/EtOH, reflux, 18 h

94 (331)

O

O NH

2

N

O

NH2 N

3

N a

O

Data from Ref. 241.

In a special case, basic hydrolysis of 2-(trichloromethyl)oxazolines 329 gave the oxazolidinone 330 or the amino alcohol 331 depending on the reaction conditions as shown in Table 8.25 (Scheme 8.99). Formation of 330 is presumably the result of facile displacement of the trichloromethyl leaving group.

8.3.1.2. Substitution at the 2-Position by Other Nucleophiles Other nucleophiles are known to attack the 2-position of oxazolines. Wipf and co-workers developed a general method to convert oxazolines to thiazolines by thiolysis followed by cyclodehydration (Scheme 8.100).154,318 Initial attack of hydrosulfide at the 2-position of the oxazoline occurs under either acidic or

428

2-Oxazolines O

H N

O N

H2S

Ph

MeHN

Et3N

O

Ph

MeHN

SH

O

O NH2

96%

MeHN O O

O N

Ph

Burgess reagent

MeHN

MeHN

89%

S

HO

H N

Ph

Ph

S

S

Scheme 8.100

moderately basic conditions. The authors found that presence of a base (triethylamine) was crucial to prevent the isomeric ring opening of the initial intermediate. Racemization at the labile amino acid a-carbon atom is usually minimal except in the case of cis-4,5-disubstituted-oxazolines under prolonged reaction conditions. This strategy was successfully applied for the total syntheses of curacin A137,319,320 and kalkitoxin (Fig. 8.11).321 The reaction generally tolerates steric hindrance at the 2-exocyclic position as well as at the 4- and 5-positions. However, the reaction rate was found to be sensitive to steric effects. Thus, thiolysis of a threonine-derived oxazoline 332 was considerably slower than that for the corresponding serine-derived oxazoline 333 (Scheme 8.101).318 The rate difference could be exploited to selectively convert a serine-derived oxazoline to a thioamide in the presence of a threonine-derived oxazoline. Me

N

OMe

S

Me curacin A Me

Me

Me

Me

S

N N O

Me

Me

kalkitoxin Figure 8.11. Curacin A and kalkitoxin.

Reactions and Applications

N

MeO2C

429 H N

MeO2C

NHBz

NHBz

O

S

HO H2S/Et3N

332

0%

MeOH 30 min

Ph

Ph N

MeO2C

H N

MeO2C

NHBz

NHBz

O

S

HO 333

85%

Scheme 8.101

However, this strategy failed when applied to the synthesis of the cyclopeptide lissoclinamide 7. Here, the serine-derived oxazoline moiety could not be selectively thiolyzed in the presence of the threonine-derived oxazoline in the cyclopeptide 334.149 The authors attributed this lack of chemoselectivity to the increased stability and thus reduced reactivity, of the serine-derived oxazoline in the macrocyclic scaffold. All three oxazoline moieties reacted under the prolonged reaction conditions to give the trithio cyclopeptide 335 (Scheme 8.102). The structure of 335 was confirmed by conversion to the tristhiazoline cyclopeptide 336. O

O NH O

N

NH

O

HO H2S/Et3N

HN

N O

Ph

H N

N

S

N

OH

HN

O HN

NH O

MeOH 90%

N

O

Ph O

H N

Ph HN

Ph O HO

334

335

S

O NH

N

Burgess reagent 76%

S

O

S

O HN

N O N

H N

Ph N S

Ph O 336

Scheme 8.102

S

430

2-Oxazolines

8.3.1.3. Nucleophilic Substitution at the 5-Position Nucleophilic attack at the 5-position of an oxazoline normally proceeds under acidic conditions. For example, in their total synthesis of thiangazole, Wipf and coworkers used thiolacetic acid to convert the trisoxazoline 337 to the S-protected cysteine derivative 338 that was further elaborated to thiangazole through aminolysis, cyclodehydration, and oxidation (Scheme 8.103).154 This approach complements the thioamide method to prepare thiazolines.149,154 O O

MeHN

N

SAc

O

N

MeHN

O

N

O

N

O

AcSH

O

SAc

HN

Reflux 56%

N

O HN

H N Ph

Ph 337

O

O

SAc

338 O S

MeHN NH3 40%

TiCl 4

PhSe(O)OH

N

N

O N

S

79%

N S thiangazole Ph Scheme 8.103

Such nucleophilic ring-opening reactions may be carried out under mild conditions. For example, Wuts and co-workers cleanly converted the 2,4-diaryloxazoline 339 to the chloro amide 340 using pyridine hydrochloride (Py  HCl) at room temperature (Scheme 8.104).89 Juge´ and co-workers also reported mild ring opening of the oxazoline carboxylate salt 341 using HBr or HI generated in situ from the corresponding trimethylsilyl halide (Scheme 8.105). The resulting 2halomethyl amino acids 342 were converted to the corresponding phosphonium salts 343.322 Nucleophilc attack becomes a more facile process when the 5-position is activated by an electron-donating group. This strategy has been used extensively in glycoside synthesis, whereby an anomeric oxazoline is used as a glycopyranosyl

Reactions and Applications O

Br

Br Ph

431 Cl

O

Py-HCl

N

N H

Py, rt

339

Ph

340 Scheme 8.104

CO2Na

CO2H

TMSX

O

N

X

H2O 86-93%

NHBz

Ph

X = Br, I

341

342

CO2H

PPh3

Ph3P

93-95%

NHBz

X 343

Scheme 8.105

donor (Scheme 8.106).94 This reaction is promoted by acid and usually results in configurational inversion at the 5-position. A major advantage of this procedure is that the ring-opened product directly incorporates the desired N-acetyl function. OH

OAc

OAc O

O

Lewis acid

O

ROH

AcO N

OR

AcO

AcO O LA

NHAc

+ O N Me

Me Scheme 8.106

This method works very well for reactive glycosyl acceptors such as primary alcohols. It can be carried out without affecting other acid sensitive functionalities including acetonides129 and even orthoesters.93 Nishimura and co-workers successfully employed this method to prepare the trisaccharide monomer 344 (Scheme 8.107).131 After deprotection, the product was copolymerized with acrylamide to give a biologically interesting glycoprotein model. AcO OAc O AcO

AcO OAc

OAc O

O

CSA

OAc Me OAc OAc

O

OAc

N

OAc O

O

AcO

4-Pentenol 38%

O

O

O NHAc

OAc Me

O

OAc

OAc OAc

Me

344 Scheme 8.107

432

2-Oxazolines PivO OPiv

BnO OBn O

PivO OPiv O

O

AcO

79%

OBn

O

N

O

TMSOTf

+ HO

AcO

BnO OBn O OBn Oallyl

NHAc

Oallyl

345

Me

Scheme 8.108

Less reactive alcohols (e.g., secondary alcohols) usually give lower yields.94 However, Colombo and co-workers obtained a good yield of the disaccharide 345 using this method (Scheme 8.108).132 Other useful nucleophiles for this type of substitution include azide and thiolacetic acid. Glaxo researchers utilized such a strategy in their synthesis of the neuraminic acid analogue 346 (Scheme 8.109).108 Itzstein and co-workers used a similar strategy to synthesize a thio analogue of neuraminic acid 347104 and reported that thiolacetic acid was also a suitable nucleophile.105 Base-catalyzed nucleophilic attack at the 5-position is rare although it can be an efficient process under appropriate conditions. For example, in the synthesis of acquired immune deficiency syndrome (AIDS) drug Nelfinavir1, a base-catalyzed thiolysis reaction was used in the final step (Scheme 8.110).126,323 The solvent, AcO

H

AcO AcO

AcO O

CO2Me

TMSN3

H H

O

O

CO2Me

AcO AcHN

93%

N

H

AcO

N3

Me OH H HO

CO2H

O

OH H HO

OH AcHN

S

CO2 NH4+

OH AcHN NH2

HN 347

346

NH2 NH

Scheme 8.109 HO

Me

O

O

NHt-Bu

Me

O

SPh O

NHt-Bu

HO

N H

OH

PhSH KHCO3

H

MIBK, 115 ˚C

H

OH H

82%

Nelfinavir ®

Scheme 8.110

Reactions and Applications

433

methyl isobutyl ketone (MIBK), as well as the choice of base was found to be critical to minimize side products. 8.3.2.

N-Alkylations

The oxazoline nitrogen is a nucleophile and reacts with a variety of electrophiles. Alkylation leads to iminium salts.324,325 Meyers’ group developed the strategy of initial N-alkylation to activate the oxazoline for mild hydrolysis and reduction.9 Holenca and Persec have firmly established that the hydrolysis proceeds through a nucleophilic attack at the 2-position of the oxazolinium salt.71 Reactions of an oxazolinium salt have been used extensively in organic synthesis involving oxazolines. For example, Jones and Ciske hydrolyzed an N-methyloxazolinium iodide in their dengibsin synthesis (Scheme 8.111).324 Alvarez-Ibarra and co-workers reduced an intermediate N-methyloxazolinium triflate to prepare oxazolidine 348 (Scheme 8.112).326,327 Me I N+

N MeI

Oi-Pr

O

OMe

Oi-Pr

O

DMSO 94%

OMe

i-PrO

i-PrO

HO MeO HO2C Oi-Pr

20% NaOH

OH

OMe

MeOH, Reflux 84%

O i-PrO dengibsin

Scheme 8.111 MeS N

MeS SMe O

Me EtO2C Me

Oxalic acid THF/water 86%

MeOTf

N

NaBH4

EtO2C MeHN

MeOTf

O

N

Me

CO2Et Me

SMe

N

SMe O

Me EtO2C Me

84%

CO2Et

Me

N

NaBH4 84%

Me CO2Et

Me

N O

EtO2C

Me CO2Et

MeHN 348

Scheme 8.112

434

2-Oxazolines

Ciufolini and co-workers designed a clever strategy to prepare azaspirocyclic building blocks.31,134,135 The key step in their strategy is the intramolecular trapping of the carbocation 350, generated from oxidation of the phenol 349, by the oxazoline nitrogen atom (Scheme 8.113).31,134 Hydrolysis of the resulting oxazolinium ion 351 gives the spirocycle 352, which undergoes spontaneous Michael addition to produce the tricyclic compound 353 as a single isomer. Alternatively, the initial spirocycle 352 can be trapped as an acetate, 354. A similar cyclization occurs when the indole oxazoline 355 is oxidized (Scheme 8.114). In this case, a 1:1 mixture of diastereomers 358 and 359 was obtained.31,135 O

R

R

O

HO

Z

N

PhI(OAc) 2

Z

TFE, rt 42%

N

R=Bn, Z=H

O

HO

352

PhI(OAc) 2

353 Ac2O/Py

H2O

O Z

N

R

O

R

O

AcO

N

N Z

Z

O

O 350

O

O

349

R

Bn

O

standing

N

O 351

354

R = H, Bn; Z = H, NHTs

Scheme 8.113 Z

Z

O

O

Z N

PhI(OAc) 2

O

N

N H

N H

Z = H, NHTs

355

O

N H 359

358

PhI(OAc) 2

Z

Z O N N 356

Bn

N +

42-48%

Bn

Bn

TFE, rt

O H2O

N N HO 357

Scheme 8.114

Bn

O

Bn

Reactions and Applications

435

Yokozawa reported that the 2-substituent strongly affects the reactivity of a 2substituted-oxazoline 360 with dimethyl 2,2-dicyano-3-ethoxy-1,1-dicarboxylate as shown in Scheme 8.115. Thus, oxazoline itself, 360 (R ¼ H), gave the annulated bicyclic product 361 that resulted from collapse of the zwitterionic intermediate 362, whereas simple 2-alkyloxazolines, 360 (R ¼ Me, Et), gave an alternating (1:1) copolymer. 2-Phenyloxazoline, 360 (R ¼ Ph), was unreactive under the reaction conditions.328 The zwitterionic intermediate 362 (R ¼ Me) was trapped by acetic acid to give the open-chain adduct 363 that resulted from nucleophilic ring opening at the 5-position of the oxazolinium zwitterion. R

MeO2C MeO2C

CN

CN

MeO2C

MeO2C

360

CN

MeO2C

CN

O N

NC CN R

MeO2C

OEt

EtO 362

NC CN R=H

O

N

OEt

MeO2C

O

MeO2C

HOAc

R = Me

N

45%

361

O

O

R

NC CN R = Me, Et

H MeO2C

N MeO2C

OEt CO2Me

Me

NC CN

n

N

OAc

OEt CO2Me 363

R = Ph

No Reaction Scheme 8.115

8.3.3.

Proton Abstractions

Proton abstraction at the 2-position is rare and requires strongly basic conditions. For example, Meyers and Novacheck used tert-butyllithium to deprotonate 364 in their preparation of the 2-bromooxazoline 365 (Scheme 8.116).329 Interestingly, O H t-Bu

N

O

t-BuLi THF

BrCF2CF2Br

O

50-70%

N

Li t-Bu

N

364

Br t-Bu

365 Scheme 8.116

436

2-Oxazolines

deprotonation at the 4-position was not competitive in this case, probably due to the steric hindrance from the tert-butyl group. Cross-coupling reactions of 365 with stannanes are described in Section 8.3.13. It is noteworthy that triflation of the corresponding oxazolidinone gave only the N-Tf-oxazolidinone. Meyers and Shimano discovered the unusual deprotonation behavior of ethoxyvinyllithium–HMPA complex (EVL–HMPA) for the deprotonation of the transoxazoline 366 and the cis-oxazoline 367. The EVL–HMPA complex is prepared by deprotonation of ethyl vinyl ether with tert-butyllithium in THF followed by addition of HMPA. Reaction of the trans-oxazoline 366 with both the EVL– HMPA complex and conventional alkyllithium reagents (RLi) resulted in deprotonation at the benzylic 5-position. In contrast, deprotonation of 367 occurred at the 4-position with an alkyllithium reagent RLi, whereas benzylic deprotonation predominated with the EVL–HMPA complex (Scheme 8.117).330 The authors proposed that EVL–HMPA complexes with the 5-phenyl substituent prior to deprotonation.

O

Ph

t-Bu N

Ph

RLi or EVL-HMPA −78 ˚C

O

Ph

Li

t-Bu

O

E+

t-Bu

N

E

N

OMe

OMe

366

368

OMe

EVL-HMPA

O

Ph

N

Ph

O RLi

t-Bu

−78 ˚C

t-Bu

O

Ph

t-Bu N Li

N

OMe

OMe 367

RLi

E+ = MeOD, MeI

E+

O

Ph

t-Bu N 369

E

Scheme 8.117

Deprotonation at an activated 4-position has been employed extensively in asymmetric synthesis, which is the key step in the Seebach protocol for the preparation of a-alkyl amino acids.331 The existing alkyl group at the 5-position acts as a directing group for the alkylation and is oriented trans to the new alkyl group (Scheme 8.118). This reaction provides an efficient methodology for normally difficult stereoselective construction of a quaternary chiral center. Several groups employed this strategy for the synthesis of lactacystin analogues, an important class of nonprotein neurotrophic factors. For example, in their total

Reactions and Applications N

R1O2C

R3

O

437

E

1. Base

N

R1O2C

2. E+

R2

R3

O R2

Scheme 8.118

synthesis of (þ)-lactacystin, Omura, Smith, and co-workers used this method to construct the key quaternary chiral center (Scheme 8.119).227,229 Here, deprotonation of the oxazoline-4-carboxylic acid ester 370 with LiHMDS followed by reaction with formaldehyde gave the alcohol 371 in good yield with excellent diastereoselectivity (>98% de). Using a milder base (DBU), Node, Kajimoto, Wong, and co-workers also demonstrated the utility of this method in their synthesis of mycestericin D.81,82 OH MeO2C

N

Ph

N

LiHMDS

MeO2C

CH2O

O

Ph

O

85%

>98% de 370

8 steps

371 O

HO2C AcHN

OH

S HO

N H

O

(+)-lactacystin Scheme 8.119

An additional chiral center results using a prochiral electrophile, for example, an aldol reaction with an aldehyde. The stereochemistry at the new chiral center can be controlled following traditional aldol condensation methods. For example, Corey and Choi used a zinc oxazoline enolate in their synthesis of (6R)-lactacystin (Scheme 8.120).332 The authors proposed that, depending on the enolate geometry, either a chair [for the (Z) enolate] or a boat [for the (E) enolate] six-membered transition state may be responsible for the preferred stereochemistry at the new chiral center bearing the hydroxy group. Adams and co-workers used a similar strategy in their total synthesis of clasto-lactacystin b-lactone.79 A stabilized 4-oxazoline enolate can also undergo highly stereoselective Michael addition. Overman and co-workers studied this reaction in their synthesis of sarains A–C. Thus, deprotonation of the oxazoline 372 with LDA at 78 to 65
C followed by reaction with the trans-ester 373 gave a single diastereomer of

438

2-Oxazolines OTES Me N

MeO2C

1. KHMDS 2. ZnCl2

Ph

HO

3.

O R

N

MeO2C

O R

OTES

O

Ph

84%

R = i-Pr, Me

(6R) O

HO2C

9 steps

OH

S HO

AcHN

R

O

N H

(6R)-lactacystin (R = i-Pr) Scheme 8.120

oxazoline 374 by NMR. The other diastereomeric oxazoline 375 was obtained in high selectivity albeit lower yield from reaction using the cis-ester 376 (Scheme 8.121).333 A chelated transition state model was proposed to rationalize the high diastereoselectivity (Fig. 8.12). The olefin approaches the enolate from the opposite face of the neighboring 5-methyl group. The organizational role of the lithium ion in the transition state is supported by the observation that substantially lower selectivity was obtained when HMPA was present.

Ph N

O

MeO2C

Me 372

EtO2C

OTBS

EtO2C

373

LDA/DME 80%

376

Ph N

Ph O

MeO2C EtO2C

OTBS

LDA/DME 58%

N

O

MeO2C EtO2C

Me OTBS 374

Me OTBS 375

Scheme 8.121

Reactions and Applications OTBS

Ph N

Li O

439

O

O

Me H

OEt

OMe

Figure 8.12. Chelated transition state model.

The facile proton abstraction of activated oxazolines offers a convenient method to convert cis oxazolines to the thermodynamically more stable trans isomer. Suga, Ibata, and co-workers took advantage of this property to correctly determine the stereochemistry for the oxazoline obtained from the [3 þ 2] cycloaddition of 5methoxy-2-(p-methoxyphenyl)oxazole with benzaldehyde (Scheme 8.122).334,335 The cis-oxazoline 377 (88% ee) was converted to the trans-oxazoline 378 (70% ee) using triethylamine. A two-step sequence then converted 378 to b-phenylserine 379 thus confirming the cis stereochemistry of 377. Proton abstraction and epimerization of activated oxazolines is comparable to a similar epimerization known for oxazolidinones. For example, Omura and Smith reported an elegant synthesis of all four stereoisomers of 3-hydroxyleucine from (E)-4-methyl-2-penten-1-ol (Scheme 8.123).227,336a One of the key steps was the efficient epimerization of the cis-oxazolidinone ester 380 to the trans-oxazolidinone acid 381 during saponification. Finally, Bazureau and co-workers reported an interesting decarbomethoxylation reaction of the 4,4-oxazolinedicarboxylic acid diester 382. The ester group cis to the neighboring 5-phenyl substituent in 382 was selectively removed to produce the trans-monoester 383.294 However, considering the reaction conditions, the product N

PhCHO

Ar O

OMe

catalyst

N

CO2Me

O

Ph

Ar

Et3N acetonitrile 73%

N

CO2Me

O

Ph

Ar

377

378

88% ee

70% ee

Ar = p-methoxyphenyl Catalyst: (R)-methylaluminum β-binaphthoxide

1. hydrolysis 2. ion exchange

50%

OH CO2H

Ph

NH2 379 Scheme 8.122

440

2-Oxazolines

OH

CO2H

NH2 (1) 2 N KOH

3 steps

O

N Bn

O

OH O

CH2N2

CO2Me

CO2H

N Bn

NH2

(1) 2 N KOH

KOH

O

CO2H

(2) H2/Pd(OH)2

EtOH 96%

N Bn

O

CO2H

(2) H2/Pd(OH)2

OH

O

O

380

381 Scheme 8.123

CO2Me

N

piperidine

CO2Me

Me O

acetonitrile reflux, 48 h 80%

Ph

N

CO2Me

O

Ph

Me

382

383

N

CO2Me

O

Ph

Me

384 Scheme 8.124

is likely the result of equilibration of an initial cis/trans mixture 384 to the thermodynamically more stable trans product 383 (Scheme 8.124). 8.3.4.

Oxidations

Oxazolines are oxidized to the corresponding oxazoles by a variety of oxidants. The reader should consult Chapter 1, Part A of this series336b for detailed discussions and examples. 8.3.5.

Reductions

Oxazolines are reduced to oxazolidines that are usually reduced further to amino alcohols. For example, hydrogenation of the oxazoline 385 was an important step in

Reactions and Applications

441

the semisynthesis of azithromycin (Scheme 8.125).337 In contrast, traditional catalytic hydrogenolysis of oxazoline 386 was unsuccessful, whereas catalytictransfer hydrogenation proved to be quite efficient (Scheme 8.126).227,229 Presumably, 386 initially gives the benzylamino alcohol 387 that undergoes hydrogenolysis to the amino alcohol 388. Cyclization of 388 in situ then gives the desired lactam 389. The reduction can be stopped at the benzylamino alcohol stage using an appropriate reducing agent. For example, in their general strategy to prepare pseudodistomins, Naito and co-workers reduced the bicyclic oxazoline 390 to the

R N

N

O

HO

OH OH

HO N

O

H2/PtO2

O O

O

O O

HOAc 86% R=H

O

OH OH

OH

O

O

O MeO

O O

MeO

OH

OH

azithromycin (R = Me)

385 Scheme 8.125

OH

CO2H HO MeO2C

N

Ph

HCOONH4 Pd, HOAc 91%

O

MeO2C

386

389

2 H2

–H2O

CO2H

CO2H HO

NHBn

MeO2C

O

N H

HO

H2

HO

NH2

MeO2C

OH

387

OH

388 Scheme 8.126

N

442

2-Oxazolines Ph H

OH

O N

BH3 THF

NHBn

H2O2/NaOH

H 64%

N

O

HO

N

Bn

Bn

390

391 Scheme 8.127

benzylamino alcohol 391 using borane (Scheme 8.127).307 Oxazolines are stable to lithium aluminum hydride (LAH) at low temperature217 but they can be reduced to alkylamino alcohols using LAH under more forcing conditions (60
C, THF).334 8.3.6.

Oxazolines as Protecting Groups

Oxazolines have been extensively used as masking groups for either amino alcohols or carboxylic acids. This application has been thoroughly reviewed in Greene’s popular monograph6 and is evident throughout this chapter. Therefore, it is not repeated further here. 8.3.7.

Oxazolines as Activating Groups

The oxazoline ring acts as an electron-withdrawing group for a substituent at the 2-position. Thus, the a-protons of a 2-alkyloxazoline exhibit some acidity and can be abstracted by a base. A 2-alkenyloxazoline can be viewed as a masked acrylic acid derivative and is capable of undergoing Michael addition and Diels–Alder reactions. These reactions can often be carried out stereoselectively using a chiral oxazoline. Other types of chiral auxilliaries, most notably oxazolidinones, are also very effective for these types of applications. However, they are outside the scope of this chapter. The discussion in this section will focus on the new developments with oxazolines.

8.3.7.1. a-Proton Abstraction The carbanion generated by a-proton abstraction of a 2-alkyloxazoline is capable of typical enolate chemistry. Thus, the carbanion was found to react with nitriles to give an enamine,338 with formate esters to give an aldehyde that can be trapped,339 with chiral sulfinate esters to give chiral sulfoxides,204 and with alkylating agents.26,51 A carbamate-protected aminomethyl chiral oxazoline was deprotonated and alkylated with diastereoselectivities up to 92% de.139

Reactions and Applications

443

The proton abstraction typically requires strong bases although weaker bases can be employed if the a-carbon is substituted with an additional activating group, such as an aryl group.340 Deprotonation of chiral arylmethyloxazolines followed by alkylation gave modest levels of diastereoselection (up to 60% de).341 Deprotonation of appropriately substituted 2-(allyloxymethyl)oxazolines resulted in stereoselective [2,3]-Wittig rearrangement.342–344 Ion pair acidities of 2-biphenylmethyl oxazolines have been calculated.62 Experimental data indicated that the anion–metal ion pairs studied did not aggregate in THF. Florio’s group published an interesting series of reports detailing the application of 2-(chloromethyl)oxazolines in organic synthesis.345–351 Deprotonation of 2(chloromethyl)-4,4-dimethyloxazoline 392 yields a carbanion 393 that undergoes a wide variety of synthetically useful reactions (Scheme 8.128). Thus, quenching 393 with a carbonyl compound at 100
C gave chlorohydrins 394 that can be O

N O

OHC

R2

O

R2 R1

R1 399

396 Ref. 345

Cl

N

N

NaOH

O R1

OH R2

i-PrOH Ref. 345, 348

Ref. 351

O

s-BuLi

R2

O

–100˚C

R1

394

397 Ref. 351 –100˚C

–100˚C O

N

Cl

O

Li

N

R4

N

N

R4 –100˚C Ref. 347

O R1

402

398

R3 Ph

–78˚C

N N O

Ph

n-BuLi

R3

N

E N

–78˚C

R3

E+ –78˚C Ref. 346

E

O

O

393

R3

E+

t-Bu

392

N

R2

O

395

R2

O R1

R1 O

Li

N

O

400

R3 401

Scheme 8.128

R3

Ph

R2

444

2-Oxazolines

converted to the 2-oxazoline substituted epoxides 395 upon treatment with a base.345 Further, the oxazoline-epoxide 395 can be converted to an epoxy aldehyde 396.345 If the oxazoline-epoxide 395 is deprotonated, the resulting carbanion 397 can be trapped with an electrophile to give a tetrasubstituted epoxide 398. Alternatively, in the absence of an electrophile, upon warming to room temperature, 397 rearranges to the ketone 399.351 Trapping 393 with a Schiff base derived from aniline gave an N-phenylaziridine 400.346 Deprotonation of 400 followed by quenching with an electrophile produced the tetrasubstituted-N-phenylaziridine 401, analogous to the conversion of 395 to 398.346 Most interestingly, reaction of 393 with nitrones gave a 2-(cis-alkenyl)substituted oxazoline 402. A chelation-based transition state model was proposed to rationalize this unusual cis selectivity.347 The 2-(trans-alkenyl)-substituted oxazoline can be obtained using the analogous des-chloro lithiated 2-alkyloxazoline.347 A chloromethyllithium species substituted with a chiral oxazoline moiety gives an epoxide with modest levels of diastereoselection (up to 33% de) using a symmetrical ketone.348 However, higher levels of diastereoselection were obtained using boron azaenolates.349,350 Thus, treatment of the chiral 2-(chloromethyl) oxazoline 403 with a dialkylboron triflate gave the (Z)-boron azaenolate 404 (Scheme 8.129). Reaction of 404 with ketones followed by base treatment gave the desired epoxide 405 in good yields. For aromatic ketones and 9-BBNOTf the (R) configuration was obtained in the newly created chiral center. However, the stereochemistry was reversed if Bu2BOTf was used. For aliphatic ketones, Bu2BOTf was found to give better selectivities than 9-BBNOTf although the relative configuration of the new chiral center was unchanged. The absolute configuration in the case of aliphatic ketones was not reported. A titanium azaenolate of 403 was also found to give 405 in good yields (50–75%) and selectivities (76–96% de) from aliphatic ketones. However, it gave poor selectivities with aromatic ketones (0–50% de).350 Meyers and co-workers recently reported a ketenimine rearrangement that has been applied to the synthesis of ketones containing a chiral a-quaternary carbon. As MeO

MeO N

Ph

O 403

Cl

L2BOTf base

Ph

MeO

BL2 N O

R2CO

Cl

404

N

base 50-93%

Ph

*

R

O R 405

L2B = 9-BBN, R = Ar: Selectivity = 70-96% de (R) L2B = Bu2B, R = Ar: Selectivity = 64-88% de (S) L2B = 9-BBN, R = alkyl: Selectivity = 33-40% de (NR) L2B = Bu2B, R = alkyl: Selectivity = 80-94% de (NR) Scheme 8.129

O

Reactions and Applications

445

R O

N

2 R3Li/THF

E+ –78˚C

–78˚C to 0˚C

R1

O

aq. oxalic acid reflux

R1

R3 *

E R2

R2 406

407 1. E+

R3Li

2. oxalic acid

R

R

N

R3Li

C

R3

N

R1

R2

OLi R2

R1

408

R

OLi Li

410

OLi

R3

N

R2

R1

Li

411

TMSCl

R N OTMS

C R1

R2

R = i-Pr, t-Bu R1 = Me, Et, i-Pr, n-Bu R2 = Ph, Me R3 = n-Bu, Ph E+ = BnBr, allylBr

409 Scheme 8.130

shown in Scheme 8.130, deprotonation of a 2-alkyloxazoline 406 by an alkyl or aryllithium reagent followed by trapping with an electrophile gave the desired ketone 407 in good yields (50–75%) and enantioselectivities (35–87% ee).352 The selectivity was independent of the configuration at the a-carbon in 406 since both isomers gave the same diastereomeric mixture of ketenimines 408 that were trapped with TMSCl to give the O-TMS ketenimine derivative 409. The authors reported that equilibration of the enamine species 410 and 411 as well as the facial discrimination determined the stereochemical outcome. The choice of THF as the solvent was critical to achieve high selectivities. The absolute configuration of the products was not reported.

8.3.7.2. Michael Additions of 2-Alkenyloxazolines The use of oxazolines as chiral auxiliaries for asymmetric Michael additions has yielded mixed results. For example, Langlois’ group reported modest diastereoselectivities (up to 60% de) for cyanide addition to a number of chiral

446

2-Oxazolines

a,b-unsaturated oxazolines using diethylaluminium cyanide.90,353,354 On the other hand, Meyers’ group capitalized on their earlier successes using a tert-leucinebased oxazoline auxilliary and applied this methodology to their asymmetric syntheses of (þ)-a-curcumene and (þ)-xanthorrhizol. Thus, reaction of an aryllithium with the chiral oxazoline 412 gave the desired adducts 413 with excellent selectivities (Scheme 8.131).60 Ultimately, 413 (R ¼ H or OMe) were converted to (þ)-a-curcumene and (þ)-xanthorrhizol, respectively, in 4–5 steps. However, the yields of 413 were markedly dependent on the method of generation of the lithium reagent. Thus, for 413 (R ¼ H), the best yield was obtained when the lithium reagent was prepared by direct metalation of p-bromotoluene with excess lithium in ether followed by filtration to remove insoluble material. Alternatively, for 413 (R ¼ OMe), the low solubility of the lithium reagent necessitated the preparation by transmetalation of the corresponding bromide using tert-butyllithium. More recently, Quirion and co-workers reported good diastereoselectivities (up to 80% de) for addition of diethyl phosphite to the chiral oxazolines 414 (Scheme 8.132).355 The absolute stereochemistry of the products was not confirmed. The phosphonate 415 can be converted to biologically important b-amidophosphonates by known methods. R t-Bu

N

Me

ArLi –78˚C

Me

72% (R = H) 61% (R = OMe)

O

t-Bu

N

Me

O

412 413 94% de 4-5 steps

Me R Me (S)-α-curcumene (R' =H) (S)-xanthorrhizol (R' = OH) Scheme 8.131

Me

N

R1

O

R2

2 equiv. HPO(OEt) 2 2 equiv. LDA, –78˚C

414

EtO EtO P O

Me N

R1

O

R2

415 80% de R1 = Ph, R2 = H: Yield = 55% R1 = Me, R2 = Ph: Yield = 60% Scheme 8.132

Reactions and Applications

447

8.3.7.3. Diels–Alder Reactions of 2-Alkenyloxazolines New developments in this area from Langlois’ group are primarily and generally on the development of the asymmetric version of these reactions. Most of the reactions employed camphor-derived 2-alkenyloxazolines as dienophiles (Scheme 8.133). In many cases, these reactions were carried out in the presence of trifuoroacetic anhydride to activate the alkene by complexation at the oxazoline nitrogen as well as to limit the number of reactive conformations. The reader should consult the recent and extensive reviews of this chemistry by Langlois.12,13

R1

O

R1 R2

O

N

N R3

R2 TFAA

R3

R1

O N

O N

O

R1

O

CF3

CF3 Scheme 8.133

8.3.8.

Dipolar Cycloadditions of Oxazoline N-Oxides

An oxazoline N-oxide is a versatile dipole and can react with a variety of dipolarophiles (Scheme 8.134). Langlois’ group has been very active in this area and has made extensive use of the N-oxides of camphor-derived oxazolines for these reactions. The initial adduct can be converted to the anti aldol product after hydrolysis and hydrogenolysis. This subject has been thoroughly reviewed by Langlois,12–14 most recently in 2000.14

O N

O

R1 O

R3

R2

R1 R2

N

R3

R3

O R1

R2

O

Scheme 8.134

OH

448

2-Oxazolines

8.3.9.

Oxazolines as Directing Groups for Aromatic Reactions

Oxazoline-directed aromatic substitution and addition reactions provide synthetic chemists with powerful tools for the construction of complex aromatic compounds. Since the last authoritative review by Meyers,9 these technologies have matured and found widespread applications in organic synthesis. While there has been somewhat limited methodological research in this area in the intervening years, one particularly exciting new development is the diastereoselective orthometalations directed by chiral oxazolines. Sections 8.3.9.1–8.3.9.3 will discuss these new developments as well as new synthetic applications of these reactions.

8.3.9.1. Metalation and Electrophilic Substitutions Since the discovery in 1975 by Gschwend356 and Meyers356a the oxazolinedirected aromatic ortho-metalation protocol has been used extensively in organic synthesis. A variety of electrophiles have been reacted with the active aryl metal species to prepare a diverse array of aromatic structures. In a traditional application of this methodology, Misra and co-workers used ortho-lithiation and subsequent reactions in their synthesis of a thromboxane A2 receptor antagonist 420 (Scheme 8.135).114 Lithiation of excess 4,4-dimethyl-2-phenyloxazoline 416 (3 equiv) was performed in THF at –45
C. After reaction with the lactol 417, the resulting oxazoline 418 was hydrolyzed under mild conditions to give the corresponding acid (not shown) that was cyclodehydrated under the reaction conditions to the lactone 419. Further elaboration of 419 then gave the desired target 420. Williams and co-workers reacted an aryllithium intermediate, generated from metalation of the oxazoline 421, with menthyl toluenesulfinate 422 to prepare an authentic aryl-substituted chiral sulfoxide (Scheme 8.136).203,204 The sulfoxide configuration was inverted during the displacement reaction. Similarly, Uemura and co-workers prepared chiral oxazolinyl aryl sulfides in good yields using disulfides as the electrophile.357 Using diarylphosphinyl halides as the electrophile, Pfaltz and co-workers prepared chiral phosphinooxazolines in good yields via the same metalation methodology.358,359 Benzylic deprotonation occurs under normal lithiation conditions when both ortho-positions are occupied. Interestingly, Thomas and co-workers were able to deprotonate a benzylic proton in the presence of an ortho proton (Scheme 8.137).66 Thus, metalation of 2-(2-methylphenyl)oxazoline 424 produced a benzylic lithium species that reacted with a Cbz-protected leucinal 425 to give a modest yield of the iminolactone diastereomers 426 and 427 together with the expected alcohols 428 and 429. The mixture of 426–429 was efficiently hydrolyzed to give the lactones 430 and 431. The authors then applied this strategy in their total synthesis of the anti-ulcer compound AI-77-B (Scheme 8.138). It is noteworthy that the ortho-methoxy group

Reactions and Applications

449 O

O OH

n-BuLi

O

417

O

–45 ˚C to rt 45%

–45 ˚C

Li

N

N

416 OH

O

OH

O

OH

O

O

oxalic acid water, rt 98%

N O

419

418 steps

O N O

H

N O

HO2C 420 Scheme 8.135

O

32%

n-BuLi TMEDA ether, –65˚C

N

Tol

S

O

N i-Pr

i-Pr 421

O

O Tol

S

423 O 422

Scheme 8.136

of 432 did not interfere with the lithiation and the subsequent electrophilic reaction. For example, methylation of the benzyllithium species prepared from 432 gave the expected ethyl homologue 433 in excellent yield. In comparison with the oxazoline-directing group, the authors found that an ethyl ester yielded unreliable results, especially on scale-up.

450

2-Oxazolines OH

N O

OH

N O

+ NHCbz

NHCbz H

H O

426

1. n-BuLi THF, –78 ˚C

N

427 +

2.

MgCl

O

O

OBn

N O

424

N

N

O

+

425 32%

NHCbz

HO

NHCbz

HO

428

429 THF, 77%

3.5 N HCl

O

O +

O

O NHCbz

NHCbz H

H 430

431 87

:

13

Scheme 8.137 OMe O

OMe O N

1. n-BuLi THF, –78 ˚C

silica gel

2. MgCl

CH2Cl2

O NHCbz

OBn

N

H

O

432 1. n-BuLi THF, –78 ˚C

O

30%

2. MeI 96% steps

OMe O OH

O

N O 433

H

OH

H N

CO2 O

AI-77-B

Scheme 8.138

NH3+

OH

Reactions and Applications

O

N

1. n-BuLi THF, 0˚C

O

N

2. ZnCl2

451

Pd (PPh3)4

ZnCl

O

N

X R2

R1

R1

434

435

reflux 31-78%

R2 R1 436

R1 = H, Cl X = Br, I, OTf R2 = H, Me, CF3, NO2, OMe, CO2Me, CO2Et

R1 = H R2 = CF3 93%

MeI

basic hydrolysis

CO2H

CF3

xenalipin Scheme 8.139

Pfizer workers took advantage of both the oxazoline-directed metalation and Negishi’s cross-coupling methodology to devise a new approach to prepare biaryls (Scheme 8.139).360 The initially formed lithium species from 434 was converted to the organozinc reagent 435. Subsequent cross-coupling of 435 with aryl halides or triflates gave the biaryls 436. The reaction is more efficient for electron-deficient aryl iodides and triflates. Aryl bromides tend to react slower and gave lower yields. Other ortho-directing groups, such as amides, can be used in place of oxazoline, but they are not as easily converted to other functional groups. The hypolipidemic agent, xenalipin, was efficiently prepared by hydrolysis of 436 (R1 ¼ H, R2 ¼ CF3) after quaternization with methyl iodide. Evans and co-workers employed a similar approach to prepare aryl ketones. Direct acylation of an aryllithium species by acyl halides is usually complicated by the competitive secondary reactions of the newly formed ketones. Although these ketones can be prepared using other acyl equivalents, such as esters or amides, the reaction conditions have to be carefully controlled. To circumvent these difficulties, Evans and co-workers devised an alternative approach wherein the aryllithium from metalation of an oxazoline was converted to the corresponding arylzinc species by transmetalation. The more tolerant organozinc reagent 437 was then reacted with acid chlorides under the Negishi cross-coupling conditions to afford the corresponding ketones 438 (Scheme 8.140).361 Internal chelation of 437 with the oxazoline nitrogen atom reduces the reactivity and necessitates the use of excess

452

2-Oxazolines

O

N

O

1. t-BuLi

N

2. ZnCl2

O

RCOCl

N O

Pd(PPh3)4 rt, 83-92%

ZnCl

R

437

416

438 R = Ph, cyclopentyl, methallyl

Scheme 8.140

437 to obtain synthetically useful yields of 438. There was no reaction in the absence of the palladium catalyst. Bidentate ferrocene ligands containing a chiral oxazoline substituent possess both planar chiral and center chiral elements and have attracted much interest as asymmetric catalysts.362,363 However, until recently, preparation of such compounds had been limited to resolution. In 1995, four groups simultaneously communicated their results on the asymmetric synthesis of these structures using an oxazoline-directed diastereoselective lithiation (Scheme 8.141).175,364–366 When a chiral oxazolinylferrocene 439 was metalated with butyllithium and the resulting aryllithium species trapped with an electrophile, diastereomer 442 was favored over 443. The structure of the major diastereomer 442 was confirmed, either by conversion to a compound of known stereochemistry365 or by X-ray crystallography of the product itself175 or of the corresponding palladium complex.366 Subsequent studies revealed the scope and generality of this reaction that has been employed extensively for the synthesis of chiral ferrocenyloxazoline ligands.41,174,367,368 Selected examples are listed in Table 8.26 (Scheme 8.142).41,174,364,365,368–374 Sammakia and Latham optimized the reaction conditions

O R

Fe

Li

O R′Li

N

N Fe

439

R

Li

N

+

440

441

E+

E N

E

442 Scheme 8.141

R

Fe

O Fe

O

R +

O N R

Fe

443

453

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

Entry

Me, n-Bu Me, s-Bu CH2OMe, s-Bu CH2SMe, s-Bu CH2OTBS, s-Bu CH2OCH2OMe, s-Bu Bn, s-Bu Bn, s-Bu Ph, s-Bu Ph, s-Bu Ph, s-Bu i-Pr, n-Bu i-Pr, s-Bu i-Pr, s-Bu i-Pr, s-Bu

R, R0

TMSCl Ph2PCl TMSCl TMSCl TMSCl TMSCl TMSCl Ph2PCl TMSCl Ph2PCl Ph2CO C2Cl4Br2 TMSCl Ph2PCl PhSeSePh

Eþ

R

Scheme 8.142

2.

E+

1. R′Li




Lithiation Conditions

439

N Fe

TMEDA/Et2O, 0 C Et2O, 78
C THF, 78
C, ramp to 0
C THF, 78
C, ramp to 0
C THF, 78
C, ramp to 0
C THF, 78
C, ramp to 0
C THF, 78
C, ramp to 0
C Et2O, 78
C THF, 78
C, ramp to 0
C Et2O, 78
C THF, 78
C TMEDA/ether, 78
C TMEDA/hexane, 78
C, ramp to 0
C Et2O, 78
C Et2O, 78
C

Fe

O

dr

N R

>50 : 1 8:1 4:1 3:1 2:1 4:1 3:1 14 : 1 6:1 >199 : 1 NR single isomer >500 : 1 39 : 1 39 : 1

442

E

O

TABLE 8.26. LITHIATION OF OXAZOLINYLFERROCENE 439 AND TRAPPING WITH ELECTROPHILESa

72 25 NR NR NR NR NR 56 NR 55 34 94 94 77 54

% Yield

174 364 365 365 365 365 365 364 365 364 370 369 368 364 364

References

454

Not reported: NR.

i-Pr, s-Bu s-Bu, s-Bu t-Bu, s-Bu t-Bu, s-Bu t-Bu, n-Bu t-Bu, s-Bu t-Bu, n-Bu t-Bu, s-Bu t-Bu, s-Bu t-Bu, s-Bu

16 17 18 19 20 21 22 23 24 25

a

R, R0

Entry

TABLE 8.26 (Continued)

MeI Ph2PCl TMSCl Ph2PCl Bu3SnCl PhSSPh CO2 DMF Ph2CO Se

Eþ Et2O, 78 C Et2O, 78
C TMEDA/hexane, 78
C, ramp to 0
C Et2O, 78
C, ramp to 0
C TMEDA/hexane, 78
C, ramp to 0
C THF, 78
C, ramp to 0
C Et2O, rt THF, 78
C, ramp to 0
C THF, 78
C THF, 78
C




Lithiation Conditions 39 : 1 24 : 1 >500 : 1 13 : 1 >99 : 1 32 : 1 NR NR 27 : 1 NR

dr

58 58 NR 65 99 81 83 73 87 69 (after oxidation to diselenide)

% Yield

364 364 368 41 41 41, 371 41 41 372, 373 374

References

Reactions and Applications

455

and found that the highest diastereoselectivity (>500:1, entry 13) was obtained using sec-butyllithium as the base, hexane as the solvent, and TMEDA as the additive.368 Ahn and co-workers also observed sensitivities of the reaction toward solvent, base and temperature.41 Low yields could often be attributed to incomplete lithiation, over-lithiation (using tert-butyllithium as the base), or decomposition of the ferrocenyllithium reagent itself. The minor diastereomer 443 can be prepared by further reaction of the silylferrocene 444. Thus, lithiation of 444 followed by trapping of the intermediate silylferrocenyllithium (not shown) with an electrophile gives 445. Desilylation of 445 then gives 443 (Scheme 8.143).41,174,175 Both Richards175 and Sammakia127 proposed working models to account for the diastereoselectivity. In an elegantly designed study, Sammakia and Latham convincingly demonstrated that the nitrogen atom is responsible for the directive effect of the oxazoline (Scheme 8.144).127,368 Thus, when the conformationally constrained oxazolinylferrocene 446 was metalated using sec-butyllithium in THF followed by trapping with methyl iodide or TMSCl, only one diastereomer, 447 was detected by chiral HPLC and NMR. The structure of 447 (E ¼ Me) was determined by Xray crystallography and was found to contain the methyl group syn to the oxazoline nitrogen. These results suggest that the nitrogen atom of the oxazoline must be responsible for the directive effect.

O

O 1. BuLi

N R

Fe

2. TMSCl

Fe

439 E

R

2. E+

444 E

O R

TMS

O

TBAF

N Fe

1. BuLi

N TMS

THF, water

N R

Fe

445

443 Scheme 8.143

H

H E

N O Fe

s-BuLi

O

E+

THF, –78˚C 70-82%

Fe

O

E+ = MeI, TMSCl 446

447 Scheme 8.144

N O

456

2-Oxazolines R′ R

Li R′

H

H

O

O

N Fe

H

Fe

R

Li

439A

R′Li

H

O

R Li

N Li

H

439B

R′Li

Fe

N

N O

R Fe

H

Scheme 8.145

Based on the above findings, Sammakia and Latham proposed a model to explain the origin of the diastereoselective lithiation (Scheme 8.145).127 They suggested that the stereoselectivity should be determined by the interaction between the oxazoline substituent and the metalating reagent. The ferrocenyloxazoline exists in an equilibrium of two rotamers 439A and 439B. Rotamer 439A is disfavored due to the steric interaction between the oxazoline substituent and the bottom cyclopentadienyl ring. The butyllithium reagent, presumably bulky due to its association with ligands, preferentially approaches the reaction site from the relatively open top face. Even though rotamer 439A is less populated, it is more reactive toward lithiation because the top face is less sterically congested. The Curtin–Hammett principle dictates the predominance of the product from rotamer 439A. This model would predict higher selectvities for bulkier lithium reagents. Experimental data (Table 8.27; Scheme 8.146) supports this prediction. An unexpectedly lower selectivity was obtained when tert-butyllithium was used to metalate tert-butyl-substituted oxazolinylferrocene. In this particular case, the authors suggested that the reaction may proceed via oxygen directed or a nondirected pathway. Similarly, oxygen-directed metalation was thought to be responsible for the low diastereoselectivity observed in the lithiation of the trans-4,5-diphenyloxazolinylferrocene 449 (Scheme 8.147).367,375 Alternatively, factors other than the unlikely oxygen-directed lithiation may be operative in this case. Since the populations of the rotamers 449A and 449B should be nearly equal because of the pseudo C2 symmetry present in 449, the product ratio is determined solely by the reactivities of the two rotamers. For a nitrogen-directed lithiation, the top face of 449A should still be relatively unhindered compared with that of 449B. However, the top face of 449A is more sterically congested than the top face of a mono-substituted

Reactions and Applications

457

TABLE 8.27. LITHIATION OF OXAZOLINYLFERROCENE 439 AND TRAPPING WITH TMSCla

O

TMS O

O 1. R′Li/THF

N R

Fe

N

2. TMSCl

Fe

439

TMS

R

N

+

R

Fe

444

448

Scheme 8.146 Entry 1 2 3 4 5 6 a

R0

R i-Pr i-Pr i-Pr t-Bu t-Bu t-Bu

Selectivity (444/448)

n-Bu s-Bu t-Bu n-Bu s-Bu t-Bu

3:1 8:1 16 : 1 6:1 36 : 1 6:1

Data from Ref. 127.

oxazolinylferrocene, (e.g., 439) due to the presence of the 5-phenyl group. This explains the lower selectivity observed in 449 in comparison with 439. Dilithiation of a C2-symmetric bis(oxazoline)-substituted ferrocenes as well as biaryls provides a versatile method for preparation of C2-symmetric tetradentate ligands. This reaction was originally described in 1995 by Park, Ahn, and coworkers.366 The same group376 and others have further expanded this reaction to Ph

Ph

O

O N

s-BuLi ether, –78 ˚C

N

Ph2PCl

Ph

Fe

68%

449A

Fe

450 (30% de)

Ph

O

N

N

O

R

Fe

Ph

Fe

Ph

PPh2

449B

439 Scheme 8.147

458

2-Oxazolines

prepare a variety of tetradentate ligands.115,144,179,377 Examples of C2-symmetric tetradentate ligands are described in Chapter 9. Bolm and co-workers expanded the diastereoselective lithiation to include the Z5-cyclopentadienylrhenium(I) tricarbonyl oxazoline complex 451 (Scheme 8.148).378 The selectivity was determined to be 9:1 favoring diastereomer 452. The structure of 452 was determined by crystallography. Interestingly, lithiation of 451 with sec-butyllithium resulted in the formation of nucleophilic addition products.

O N OC Re OC CO 451

O

1. n-BuLi, ether

t-Bu

2. Ph2CO 76%

CPh2OH O

N + CPh2OH t-Bu Re OC Re OC CO OC CO OC 452

N t-Bu

453

Scheme 8.148

Metalation of arenes substituted with both an oxazoline and a methoxy group with a simple alkyllithium reagent usually effects lithiation at positions ortho to the oxazoline, that is, the oxazoline is a much stronger directing group than the methoxy group. However, Meyers and Shimano discovered that the regiochemistry can be dramatically altered using ethoxyvinyllithium complexed with HMPA (EVL–HMPA).379 Oxazoline-substituted methoxyarenes were lithiated at the position ortho to the methoxy group when treated with excess EVL–HMPA. Indeed, even the more powerful directing group, diisopropyl carboxamide ( CONi-Pr2) was not competitive with a methoxy group when EVL–HMPA was used as the base. The results from a variety of arenes demonstrated that this methodology is quite general (Table 8.28; Scheme 8.149). The authors concluded that an oxazoline group was necessary to activate an arene for this type of metalation since reactions with anisole and 1,3-dimethoxybenzene were slower even at higher temperature (56
C). The reaction may be kinetically controlled since the expected regiochemistry was observed when the reaction was carried out at 0
C. The reaction of the oxazoline-substituted naphthalene (Table 8.28, entry 5) represents the first example of lithiation in such a system. Simple alkyllithium reagents only undergo addition to the naphthalene ring (see Section 8.3.9.3). The authors suggest that steric effects created by a large cluster of EVL and HMPA may be responsible for this unexpected regioselectivity. Although lithiation remains the most frequently used metalation reaction, there have been a number of new reports of direct palladation of aryloxazolines. For example, Smoliakova and co-workers prepared the dimeric palladium complex 457 by direct reaction of Pd(OAc)2 with 2-phenyloxazoline in the presence of NaOAc/ HOAc (Scheme 8.150).380 The dimeric complex 457 was converted to the monomeric triphenylphosphine complex 458 for which the X-ray crystal structure was determined. A similar reaction sequence was observed for naphthalenes.381 Muller

Reactions and Applications

459

TABLE 8.28. LITHIATION OF ARENES BY EVL–HMPAa

X

X

X

E

E+

2 equiv. EVL-HMPA

+

THF, –78˚C

E

OMe 454

OMe

OMe

455

456

N X= O Scheme 8.149

Entry

Major Product (455) Eþ: % Yield

Oxazoline 454

X

Minor Product (456)b

X

455/456b

X E >99 : 1

1

E OMe

OMe MeI : 96; DMF : 89

MeO

MeO

X

OMe E

X

MeO

2

X

>93 : 7

E MeOD : 98; MeI : 88; (CH2O)n : 72

MeO

OMe

MeO

X

3

O

OMe

O

X

E MeO

MeO

OMe

MeO

X

OMe

MeO X MeI : 97; ClCO2Et : 92 E

E

O

OMe

O

X

OMe

O

4

O

X

>99 : 1

>99 : 1

E

MeI : 97

X

E

X NR

5

MeO

MeO MeI : 93

a b

Data from Ref. 379. Not reported ¼ NR.

NR

460

2-Oxazolines O

O

O

Pd(OAc) 2

N

NaOAc/HOAc 63%

1. LiCl

N

N

2. Ph3P 99%

Pd

Pd Ph3P

AcO

Cl

2 457

458

Scheme 8.150

and co-authors comprehensively reviewed the coordination chemistry of oxazolines in 1999 in which they discussed this type of cyclopalladation reaction in more detail.20 More recently, Richards and Stevens reported a diastereoselective cyclopalladation of the oxazoline-substituted (Z5-C5H5)(Z4-C4Ph4)Co 459.382 Although this compound resisted lithiation under various conditions, it reacted readily with palladium acetate to form a single diastereomeric cyclopalladation product 460. The configuration of 460 is the opposite to that obtained in the ferrocene lithiation (see above) and was confirmed by nOe analysis. The authors attributed the diastereoselectivity to the instability of rotamer 459A due to the severe steric interaction between the isopropyl group and the (Z4-C4Ph4) phenyl substituents. The reaction proceeds only through rotamer 459B to give the observed product (Scheme 8.151).

i-Pr O

N N

Ph Ph

Co

O i-Pr

Ph

Co

Ph

Ph

Ph

Ph

Ph

459A

459B Pd(OAc) 2 72%

2

Ph Ph

HOAc 95 ˚C

OAc i-Pr N O

Pd Co

Ph Ph

460 Scheme 8.151

Reactions and Applications

461

8.3.9.2. Nucleophilic Substitutions It is well known that ortho-methoxy and ortho-fluoroaryloxazolines undergo facile nucleophilic substitution reactions using a variety nucleophiles.8,9 Although a methoxy group is more commonly used as the leaving group for economic reasons, fluoride is sometimes used as the leaving group to avoid side reactions of the methoxy group, such as demethylation.383 Two groups used the 2-(orthofluorophenyl)oxazolines 461384 and 462385 to prepare the tricyclic phosphinooxazoline ligands 463 and 464 (Scheme 8.152). These ligands were then employed in palladium-catalyzed enantioselective allylic substitution reactions.

O

O KPPh2

F

N

dioxane, rt 68%

Ph2P

N

461

463

O

O LiPPh2

F

N

THF 71%

Ph2P

N

462

464 Scheme 8.152

Although 2-(ortho-chlorophenyl)-4,4-dimethyloxazoline 465 does not react with a Grignard reagent under normal conditions, Cahiez recently reported that the substitution occurred in the presence of a catalytic amount of manganese chloride (10% mol) to give the substitution product 466 in acceptable yield (Scheme 8.153).386 The reaction mechanism has not yet been defined. One of the most useful aspects of the oxazoline-directed aromatic substitution is the synthesis of biaryls. This method nicely complements other well-known biaryl

O Cl

N

O

RMgCl 10% mol MnCl2, rt 63–67%

R

N

R = Ph, Bu 465

466 Scheme 8.153

462

2-Oxazolines

syntheses, such as the Suzuki coupling.387,388 For example, Zhu and co-workers applied oxazoline-directed aromatic substitution methodology in their synthesis of a protected actinoidic acid, a vancomycin substructure.30,59 Meyers’ group has perfected the experimental procedure to prepare unsymmetrical biaryls53 and reported a general synthesis of pyrrolophenanthridine alkaloids,389 such as oxoassoanine,390 pratosine, hippadine, kalbretorine, and ungeremine, using this method. However, a more exciting application of this reaction is the oxazoline-directed synthesis of axially chiral biaryls. The oxazoline system not only activates the ortho-methoxy group for nucleophilic displacement but also determines the stereochemical outcome of the reaction. This provides a convenient method for the introduction of axial-chirality. Meyers’ group continues their earlier lead on this subject with reports of the stereoselective synthesis of tetrasubstituted biphenyls.391,392 Selected examples are shown in Table 8.29 (Scheme 8.154). The best diastereoselectivities were obtained when R1 in the bromide 468 is a noncomplexing group (entries 5–8). Indeed, the opposite stereoisomer is obtained when R1 can complex with magnesium (entries 1, 3–4). Surprisingly, the selectivity is not very sensitive to the 4-substituent of the oxazoline (entries 6–7).

TABLE 8.29. OXAZOLINE-DIRECTED STEREOSELECTIVE SYNTHESIS OF BIPHENYLSa

R2

R2

O

O

N

R1

N

R1

Mg

OMe

+ Br THF reflux

OMe 467

MeO

MeO

468

OMe 469

Scheme 8.154 Entry

468 (R1)

467 (R2)

469 % Yield

% de (Configuration)

i-Pr

90

60 (aR)

i-Pr

78

20 (aS)

i-Pr i-Pr i-Pr i-Pr t-Bu i-Pr

80 75 79 73 67 70

16 (aR) 20 (aR) 80 (aS) 86 (aS) 84 (aS) 86 (aS)

O 1

O O 2 3 4 5 6 7 8 a

O CH2OBn CH2OMe Me CH2OTBS CH2OTBS CH2OTIPS

Data from Ref. 391.

Reactions and Applications

R1

MeO

Me

463

O

O Mg

N

N

Mg

MeO

R2

Me

Br

R2

O

Br

471

470

R1

Me

O

R1

OMe O

OMe N

R2

MeO MeO

O

R1 O

469 (aS isomer)

Mg

MeO Me

O

N R2 Br

472 Scheme 8.155

A chelation-based mechanism was proposed to rationalize the observed diastereoselectivity (Scheme 8.155). Initially, the Grignard reagent approaches the oxazolinylarene from the opposite face of the 4-R2-oxazoline substituent to give the pre-reaction complex 470. Subsequent aryl migration results in the intermediate adduct 471 in which the methoxy group of the Grignard reagent, the methoxy leaving group and the oxazoline nitrogen are all chelated with magnesium. These control elements determine the stereochemical outcome of this reaction. Obviously, the stereoselectivity suffers when the R1 group can compete with the methoxy group to complex with magnesium and forms the isomeric complex 472. This interpretation of the reaction mechanism prompted Rizzacasa and Leighton393 to reinvestigate and improve an earlier synthesis of ()-O-methylancistrocladine reported by Sargent and Rizzacasa.394 Undesired chelation near the reaction center of the Grignard reagent generated from bromide 473 was blocked by TBS protection (R ¼ TBS, Scheme 8.156).393 This strategy was quite successful since the diastereoselectivity of the product biaryl 474 was improved to 92:8. An analogous reaction in the previous synthesis produced a 474 analogue (dr ¼ 69:31) when the CH2OR moiety was a chelating cyclic acetal.394 Further elaboration of 474 should then lead to ()-O-methylancistrocladine. The same group also reported similar synthetic approaches to (þ)-dioncophylline C395 and (þ)-O-methylancistrocline396 (Fig. 8.13).

464

2-Oxazolines OMe OMe OR

OMe OMe

N

Br + O

i-Pr

Mg 76%

MeO

O

MeO

OR

OMe

OMe N

474

473 i-Pr

OMe

OMe OMe

OMe OMe

steps

1. TFA 2. Ac 2O 3. NaOH 78%

dr = 92:8

CO2H MeO

Me Me

MeO

OH

NH OMe

OMe Me (-)-O-methylancistrocladine Scheme 8.156

OH

OMe OMe

OMe

Me

Me Me

MeO

Me

NH OH

Me

(+)-dioncophylline C

N

Me

OMe Me (+)-O-methylancistrocline

Figure 8.13. (þ)-Dioncophylline C and (þ)-O-methylancistrocline.

Although the axial stereochemistry is controlled by the chiral oxazoline, Baker and Sargent reported that a chiral sulfoxide can also introduce axial chirality while acting as a leaving group (Scheme 8.157).397,398 However, this reaction does not proceed via the typical SNAr mechanism, but rather through an initial attack of the Grignard reagent at the sulfur center.399,400 Modest atropisomeric selectivity for the binaphthyl 476 was obtained by reaction of sulfoxide 475 with 1-naphthylmagnesium bromide. The authors also reported better atropisomeric selectivities using an ester or an amide as the activation group.398 The Ullmannn coupling401,402 of aromatic halides does not require activation but the presence of a chiral oxazoline group on the haloarene allows the selective introduction of axial chirality into the biaryl product. This constitutes an important

Reactions and Applications

465

MgBr

Tol

S

O

N

N 71%

O

O

475 (60% ee)

476 Scheme 8.157

method to prepare chiral biaryl-based bisoxazolines (see also Chapter 9). A significant portion of Meyers’ 1998 review on chiral oxazolines was devoted to this subject so only a recent example will be discussed here. In their asymmetric synthesis of mastigophorene, Meyers and Degnan studied the steric effect of the oxazoline substituent in 477 on the diastereoselectivity of the biaryl 478a (Scheme 8.158).46 The selectivity was thermodynamically controlled since the two diastereomers interconvert at the reaction temperature. The stability of the Me

Me

Me OMe

Me Me OMe

O

Cu

OMe

OMe Br N

Me

OMe

Me

O

Me OH

Me

DMF reflux 85% (both isomers)

65%

N N

R R

OMe

477

Me Me

Me

Me (-)-mastigophorene A

Me Me OMe Me OMe O

OMe N N

R

OH

Me

478a (aS isomer)

R

Me Me

Me

O

R

OH OH

6 steps

OMe Me

O Me Me

478b (aR isomer) Scheme 8.158

466

2-Oxazolines TABLE 8.30. DIASTEREOSELECTIVITY IN ULLMANN COUPLING REACTIONS (SCHEME 8.158)a

a

Entry

477 (R)

dr (478a/478b)

1 2 3 4 5

t-Bu Ph i-Pr Et Me

3:1 4:1 6.4 : 1 7.1 : 1 7.2 : 1

Data from Ref. 46.

copper-product chelation complex determines the stereochemical outcome. Interestingly, the smallest oxazoline substituent 477 (R ¼ Me) gave the best diastereoselectivity (Table 8.30, entry 5). The authors rationalized these unexpected results in terms of minimization of interaction between the R group and the arene. The biaryl 478a was subsequently converted to ()-mastigophorene A in six steps. It is most appropriate to conclude this subsection with an elegant demonstration of oxazoline-directed aromatic reactions by Meyers’ group. Meyers and Willemsen took full advantage of the reactions described in this section in their asymmetric total synthesis of (S)-gossypol.49 The initial synthesis (Scheme 8.159) included a Grignard displacement of an ortho-methoxy group of 4,4-dimethyl-2-(2,3,4trimethoxyphenyl)oxazoline 479 to produce 480. After N-methylation, reduction and hydrolysis converted 480 to the key 2,3,4-trisubstituted benzaldehyde 481. After construction of the naphthalene ring, a tert-butyloxazoline was incorporated to direct the subsequent lithiation and Ullmann coupling. Lithiation occurred at the 3-position of 482 rather than the 1-position presumably due to the steric hindrance of the neighboring isopropyl group. Stereoselective Ullmann coupling of the bromide 483 gave the desired binaphthyl 484 in an 11:1 diastereomeric ratio. Removal of the bisoxazolines required hydrolysis to an intermediate bis(amino ester) that was then sequentially acetylated, reduced, and hydrogenated to give the binaphthyl 485. Further eleboration of 485 then gave (S)-gossypol in two steps. The authors redesigned their synthesis and incorporated the formyl group at an earlier step to overcome the unsatisfactory yield for this reaction at a late stage in their first synthesis. Now, taking advantage of an earlier discovery from their group (see Section 8.3.9.1), they were able to selectively lithiate 479 ortho to the methoxy group with EVL–HMPA (Scheme 8.160). The resulting intermediate lithio species (not shown) was converted to the oxazoline 486 in three steps. Similar to their initial synthesis, 486 was now converted to the 2,3,4,5-tetrasubstituted benzaldehyde 487 from which the naphthalene ring of 488 was constructed followed by incorporation of the tert-butyloxazoline ring. Bromination of 488 gave the bromide 489 that was subjected to the Ullmann coupling. The authors noted that this Ullmann coupling required a high concentration of the reactants to achieve a high diastereoselectivity in the binaphthyl product 490. Reductive oxazoline cleavage in 490 gave 491 that was then elaborated to (S)-gossypol in good yield.

Reactions and Applications

N

OMe

N OMe

O

i-PrMgCl

467

i-Pr OMe

O

1. MeOTf 2. NaBH4

96%

OMe

OMe

479

3. H3O+ 82%

480 t-Bu

O

i-Pr

N OMe

H

i-Pr

steps

OMe

O OMe

n-BuLi C2F4Br2 73%

OMe OMe

481

482 t-Bu

i-Pr

t-Bu N

N

MeO

i-Pr OMe

O Br

OMe

O OMe

Cu/DMF

OMe

MeO reflux 81%

MeO O

OMe

OMe N

483

i-Pr

t-Bu 484 (dr = 11:1) i-Pr

1. TFA 2. Ac 2O

MeO

Me

H2 Pd/C 82%

3. LiAlH4 73%

OMe OMe

MeO MeO

Me

OMe i-Pr

485 i-Pr HO

Me

OH

CHO OH

HO

(S)-gossypol

CHO OH Me

OH i-Pr Scheme 8.159

1. BBr3 2. TiCl 4 MeO Cl Cl 34%

468

2-Oxazolines

N

i-Pr

N OMe

O

i-Pr

1. EVL-HMPA, DMF

2. NaBH4

2. LiAlH4 3. NaH, MeI 72%

OMe

1. MeOTf

OMe

O

3. H3O+

OMe

479

486

OMe

t-Bu i-Pr

O

N OMe

H

i-Pr

steps

OMe

O

Br2/HOAc 74%

OMe

OMe OMe

OMe 487

OMe

488 t-Bu i-Pr

t-Bu N

i-Pr OMe

O Br

O OMe

OMe

Cu/DMF

OMe

MeO reflux 80%

OMe OMe

N

MeO

MeO O

MeO

OMe N

OMe

i-Pr

t-Bu 490 (dr = 17:1)

489 i-Pr 1. TFA 2. Ac 2O

MeO

3. LiAlH4 72%

MeO

OH OMe

OMe

3 steps

OMe 68%

MeO

MeO

OMe i-Pr

OH 491 i-Pr HO

Me

OH

CHO OH

HO CHO OH Me

(S)-gossypol

OH i-Pr Scheme 8.160

Reactions and Applications

469

8.3.9.3. Nucleophilic Additions Oxazoline-directed conjugate addition of nucleophiles to a naphthalene nucleus is one of the most useful methods to prepare dihydronaphthalenes. Since Meyers’ last comprehensive review,9 the focus has been directed to stereoselective synthesis of these important compounds. Meyers’ laboratory has continued their preeminence in this field and has expanded the scope and applications of this reaction. Ethoxyvinyllithium (EVL) is an effective lithiation agent at low temperatures (78
C) in the presence of HMPA (see Section 8.3.9.1). However, in the absence of HMPA, it reacts like a normal lithium reagent and cleanly adds to oxazolinylnaphthalenes at higher temperatures (10
C). Thus, addition of EVL to 4,4dimethyl-2-(1-naphthyl)oxazoline 492 generates an intermediate carbanion (not shown) that is alkylated to afford 493, usually as a single diastereomer (dr > 100:1) (Scheme 8.161).403 The resulting vinyl ether in 493 can be easily converted to the corresponding methyl ketone. This reaction is applicable to oxazoline substituted anthracene and phenanthrene rings as well (Table 8.31). In their syntheses of key intermediates 496 and 498 required for ()-aphanorphine and ()-eptazocine respectively, Meyers’ group used a lithiosilane as a surrogate for LiH in the initial conjugate addition (Scheme 8.162).222,404 As expected, the lithiosilane adds to the starting oxazolinylnaphthalene 494 from the face opposite to the bulky isopropyl group. Methylation of the intermediate carbanion then occurs on the face opposite to the bulky silyl group to produce the tandem adduct 495. The use of ether in the solvent mixture was critical to achieve the high diastereoselectivity. It was assumed that the low complexation ability of ether affords some rigidity and order in the transition state. Given the steric demands of the silyl group, it is not surprising that the minor diastereomer arose from the isomeric silyl addition but still coupled with trans-methylation. Subsequent conversion of 495 to 496 and 498 was straightforward. The stereochemistry of the saturated oxazoline 498 was confirmed by X-ray crystallography. Degnan and Meyers recently expanded the utility of this reaction using a silyl group as an oxygen or nitrogen surrogate via Tamao oxidation405 and chemical modifications.406

X

X OEt

E 5 equiv. EVL

E+

THF, –10 ˚C

492

493 N X= O Scheme 8.161

470

2-Oxazolines

TABLE 8.31. DIASTEREOSELECTIVE CONJUGATE ADDITIONS OF EVLa Entry

Substrate

Product

X

E

E, % Yield

X OEt

1

Me, 50

OEt X

X

2

E

Me, 98

OEt X

X E

3

E

Me, 98 allyl, 98

X

X Me, 97

4

X 5

a

E

OEt X OEt Me, 66

Data from Ref. 403.

Meyers and Shimano further expanded the scope of this methodology to include lithium amides as the nucleophile.317,407 The authors meticulously optimized the reaction conditions and determined the scope of the amide addition. Selected examples are listed in Table 8.32 (Scheme 8.163). The best results were obtained when THF was used as the solvent together with a stoichiometric amount of HMPA, relative to the lithium amide. The reaction was quite sensitive to the steric demand of the amide. Thus, lithium diethylamide give no product whereas lithium methyl npentylamide and lithium piperidide gave efficient reaction. Primary amides also failed to react. Unlike analogous reactions with a carbon nucleophile, the initial attack of the lithium amide was reversible. A strong piece of supporting evidence was the exclusive formation of the butyl addition product 504 when n-butyllithium was added after initial formation of the aza enolate 505 (Scheme 8.164). The reaction outcome is therefore heavily dependent on the secondary reaction with the

Reactions and Applications

471

i-Pr i-Pr O

N

O

1. PhMe2SiLi 3:1 ether/THF –78˚C

MeO

N SiMe2Ph

Me MeO

1. TBAF aq THF 2. Rh(PPh3)3Cl Et3N/toluene 67%

2. MeI, –20 ˚C 79%

495 (dr > 20:1)

494 i-Pr

O N

Me MeO

Me 1. MeOTf

CHO

MeO

Me steps

HO N Me

2. NaBH4 3. H3O+ 89%

496

H2/Pd-C

(-)-aphanorphine

86%

i-Pr

O Me MeO

497

N

Me 1. MeOTf

steps

498

HO N Me

2. NaBH4 3. H3O+ 84%

Me

CHO

MeO

499

(-)-eptazocine

Scheme 8.162

electrophile that renders the overall reaction irreversible. Consequently, strong electrophiles readily trap the intermediate carbanion whereas weak electrophiles only lead to recovery of the starting material after work up (Table 8.32, entry 8). The authors proposed a chelating transition state model to explain these results (Fig. 8.14). The thermodynamically more stable intermediate resulting from initial lithium amide addition should have the amino group on the face opposite to the bulky tert-butyl group. Due to the same steric effect, the HMPA ligand should also occupy a position on the b face. The electrophile approaches the enolate from the a face and gives the trans product. For bulky amines, either the aza enolate does not form due to severe steric hindrance or the aza enolate is inactive for the same reason. The utility of this reaction was demonstrated by converting the initial adduct 506 to a b-amino acid 509 and ultimately the b-lactam 510 (Scheme 8.165). It is noteworthy that the oxazoline ring in 506 was stable to cold concentrated HCl and the oxazoline ring in 507 was stable to hot caustic. However, the authors also noted

472

2-Oxazolines

TABLE 8.32. ADDITION OF LITHIUM AMIDES TO OXAZOLINYLNAPHTHALENESa

t-Bu O

t-Bu

O

N

N NR2R2

E

1. R1R2NLi HMPA/THF 2. E+

500

501 t-Bu t-Bu R1R2N N

N 1. R1R2NLi HMPA/THF

O

O E

2. E+

R 502

503 Scheme 8.163

Entry

Oxazoline

1

500

2

500

R1R2NLi

Electrophile

Me2NLi

MeI

94

98.5 : 1.5

MeI

93

>99 : 1

MeI

93

>99 : 1

MeI

0

% Yield

Li Me

N Li

3

500

Me

N

dr

4

500

5

500

N Li

MeI

95

>99 : 1

6

500

N Li

AllylBr

92

>99 : 1

7

500

N Li

BnBr

67

>99 : 1

8

500

N Li

N Li

O 0

EtO

OEt

Reactions and Applications

473

TABLE 8.32 (Continued) Entry

Oxazoline

R1R2NLi

Electrophile

% Yield

dr

O 9

500

N Li

MeI

96

>99 : 1

MeI

91

97.5 : 2.5

MeI

0

MeI

94

>99 : 1

MeI

94

>99 : 1

MeI

94

>99 : 1

MeI

90

>99 : 1

O 10

502 (R ¼ H)

11

502 (R ¼ H)

12

502 (R ¼ H)

13

502 (R ¼ H)

14

502 (R ¼ H)

Me2NLi

N Li

N Li

N Li O N Li O

15

Li

502 (R ¼ OMe)

Me a

N

Data from Ref. 407.

t-Bu O

t-Bu

N

O N

N

Li

Li

N HMPA

500

505

1. n-BuLi 2. MeI

O Me

MeI

O

t-Bu Me

N n-Bu

504 Scheme 8.164

t-Bu N N

474

2-Oxazolines HMPA O

R1 N

N Li

H R E 2

t-Bu

X

Figure 8.14. Chelating transition state model for addition of lithium amides to oxazolinylnaphthalenes.

O Me

O

t-Bu N N

O

O

0 to 20 ˚C 95%

NaOH n-BuOH/H2O 125 ˚C 82%

506 O

N N

conc. HCl

O

Me

t-Bu

Me

507 O

t-Bu Me

N NH2

6 N HCl

CO2H NH2

Me MsCl

NH

NaHCO3 74%

reflux 85%

508

509

510

Scheme 8.165

that the oxazoline ring in 506 is hydrolyzed to a hydroxy amide using 1 N HCl at room temperature. No explanation was given for this unusual behavior. The same authors later reported that although sterically hindered lithium dialkylamides do not react under the normal conditions, they do undergo an unusual 1,6-addition to the oxazolinylnaphthalene 511 in the presence of excess HMPA (8–10 equiv).408 These reactions are also diastereoselective to afford the trans tandem adduct as the major product (Scheme 8.166). A dimeric lithium

O

O

N

E R2NLi

N

E+

HMPA 85–93%

NR2 511

512 60-97% de R = Bn, allyl; E+ = MeI, MeOTf, BnBr, allylBr Scheme 8.166

Reactions and Applications

475

amide–HMPA complex was postulated to rationalize these results in view of the earlier findings (see above). Adduct 512 has been converted to useful d-amino acid derivatives. More recently, Meyers and Kolotuchin reported that nucleophilic addition to the 1-position of the 3-methoxy-(2-oxazolinyl)naphthalene 513 is preferred over methoxy group displacement.409 The reaction works well and as expected for RLi (R ¼ n-Bu, sec-Bu, and Ph). However, 1,2-addition to 513 to give the oxazolidine 515 predominates for RLi (R ¼ Me, tert-Bu, and PhMe2Si) (Scheme 8.167). When 513 contained a chiral oxazoline (R1 ¼ tert-Bu, R2 ¼ H), a single diastereomer of 514 was obtained in moderate yields (56 and 60% for R ¼ n-Bu and Ph, respectively). Standard oxazoline chemistry and functional group manipulations were used to convert 514 to a variety of useful, chiral tetralones 516. OMe O N 513

OMe O

1. RLi 2. MeI

R

R2 R1

OMe R

+

O

R2

Me N

R1

HN

514

515

R2 R1

steps

O CHO R 516

Me

Scheme 8.167

The absence of methoxy group displacement was rationalized in the following manner. Initial nucleophilic addition to the 3-position leads to an intermediate, 517, in which the aromaticity of both rings was destroyed whereas addition to the 1position gives an intermediate 518, which retains the aromaticity of one benzene ring (Fig. 8.15). R

OMe OMe O

Li 517

N

O R

H N Li 518

Figure 8.15. Proposed intermediates for nucleophilic addition to 3-methoxy-(2-oxazolinyl)naphthalene.

476

2-Oxazolines

8.3.10.

Oxazolines as Chiral Directing Groups

Discussions of oxazolines as chiral directing groups are included in the previous sections under the appropriate reaction classifications. Meyers has already published a recent review of chiral oxazolines (1998) that focused primarily on their use in aromatic reactions and Ullmann coupling reactions in particular.11 The examples of oxazolines as chiral directing groups described in this section will include reactions that are not discussed in any previous section of this chapter. Elliott and co-workers reported an asymmetric hetero-Diels–Alder reaction using a chiral 2-(alkenyl)oxazoline 519 as the enophile.110,111,410 Initial addition of the isocyanate to 519 gives the bicyclic [4 þ 2] adduct 520. Depending on the substituents, 520 can undergo a [2 þ 2] cycloaddition with a second molecule of an isocyanate to generate the tricyclic compound 521. For R2 ¼ H, 521 ring opens to give the tetrahydrooxazolopyrimidinecarboxamide 522 (Scheme 8.168). Selected examples are summarized in Table 8.33. In all cases, the initial addition to generate 520 was diastereospecific, that is, the isocyanate always adds to 519 from the face opposite to the 4-ethyl substituent of the oxazoline. In the cases wherein 521 was isolated (Entries 17–20 from Table 8.33), the stereochemistry of the two additional chiral centers from the secondary [2 þ 2] cycloaddition was controlled by the chiral center formed during the initial reaction, that is, the isocyanate reacts with 520 from the opposite face of the neighboring R1 group. For R1 ¼ H, R2 ¼ Me, 519 reacted with an arylisocyanate (R3 ¼ Ar) to give tricyclic adducts 521a and 521b as a 1.7:1 mixture of diastereomers (Entries 18–20). For R1 ¼ Ph, R2 ¼ Me, 519 reacted with phenylisocyanate R1

R1

R2

R2

N

R3NCO

O

N Et 519

O

N

O

R3

R2

R1

O

R3

N

R3NCO

R3N O

O

N Et

Et 520

521 R2 = H

O

R1

R3HN

N O

N Et 522

Scheme 8.168

R3 O

Reactions and Applications

477

TABLE 8.33. HETERO-DIELS–ALDER REACTION OF CHIRAL 2-ALKENYLOXAZOLINES (SCHEME 8.168)a Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 a

R1, R2 Me, H Me, H Me, H Me, H Me, H Et, H Et, H Et, H Et, H Et, H Ph, H Ph, H Ph, H Ph, H Ph, H Ph, Me Ph, Me H, Me H, Me H, Me H, Me H, Me Ph, Me

Temperature (
C)

R3

Time (h)

Ph  4-Br-Ph   4-O2N-Ph 4-MeO-Ph  4-Me-PhSO2 Ph  4-Br-Ph   4-O2N-Ph 4-MeO-Ph  4-Me-PhSO2 Ph  4-Br-Ph   4-O2N-Ph 4-MeO-Ph  4-Me-PhSO2 Ph  Ph  Ph  4-Br-Ph  4-MeO-Ph  4-O2N-Ph  4-Me-PhSO2 4-Me-PhSO2

48 24 21 120 0.5 46 1.25 1

25 25 25 25 25 25 150 150

0.5 1 1 1 1 0.5 30 24 65 18 25

25 150 150 150 150 25 60 150 150 150 150

1 1

25 25

Product (% Yield) 522 (58) 522 (61) 522 (62) 522 (65) 522 (66) 522 (53) 522 (69) 522 (71) 522 (trace) 522 (90) 522 (76) 522 (59) 522 (74) 522 (10) 522 (94) 520 (62) 521 (26) 521 (81) 521 (42) 521 (0–70) 521 (0) 520 (98) 520 (75)

Data from Ref. 111.

(R3 ¼ Ph) to give 521 as a single diastereomer although the yield was low (entry 17). The reaction rate depends on the electronic nature of the substituent (R3) on the isocyanate. Isocyanates with electron-withdrawing groups react faster than those with electron-donating groups. The reaction is also sensitive to the steric bulk on the isocyanate and the oxazoline. Thus, neither tert-butyl- nor benzylisocyanate react under the conditions examined. 4,4-Dimethyl-2-(2-propenyl)oxazoline was unreactive, even under forcing conditions. The authors proposed a stepwise mechanism involving a 1,3-dipolar intermediate 523 to rationalize these results (Scheme 8.169). Computational studies by the same group also supported this mechanism.410 The authors suggested that the asymmetric induction may originate from the reduction of the steric interaction between the isocyanate oxygen atom and the ethyl group during the cyclization of 523. Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-ribo-phytosphingosine.113 The good stereoselectivity observed for 525 can be rationalized by a Felkin–Ahn transition state model although a chelation control mechanism could not be ruled out. In an effort to demonstrate the interesting concept of a catalytic chiral auxilliary, Williams and co-workers showed that the oxazoline-substituted acrylate ester 526

478

2-Oxazolines R1

R1

R2

R2

N

R3NCO

O

N

R1

O

519

R2

O–

N

Et

R3

N

O

R3 O

N

Et

Et

523

520 R3NCO

O

R1

R3HN

N O

N

R3

R1

R2

O

N

R2 = H

R3N O

O

R3 O

N Et

Et 522

521

Scheme 8.169

gave modest levels of diastereoselectivity as well as rate acceleration in a Diels– Alder reaction using cyclopentadiene in competition studies with benzyl acrylate (Scheme 8.171).411 Their strategy relied on a rapid transesterification of 527 with benzyl alcohol to give 528 as the final product. Furthermore, transesterification of the oxazoline alcohol 529 with benzyl acrylate to give 526 had to be equally rapid to support the catalytic cycles.

HO

H TBDPSO

TBDPSO

O

n-C14H29

n-C14H29MgCl

N

O

N

–70 to –20 ˚C 65%

O Ph

Ph

525 (74% de)

524

75%

1. 2 M HCl 2. NaOH

NH2 OH HO

n-C13H27 OH

D-ribo-phytosphingosine Scheme 8.170

Reactions and Applications

479 O

O

O O 528 31% conversion

+

+ Cu(OTf) 2 –10 ˚C

O

MeS O

O

MeS

N

Ph

O

O

N

Ph

O

526

527

O

MeS N

64% conversion 38% de

Ph

HO 529 Scheme 8.171

This same group also devised a stereoselective oxidation of sulfides 530 using a chiral oxazoline as the directing group (Scheme 8.172).203,204 The sulfoxides 531 were obtained in good yields (up to 90%) and selectivities (up to 94% de) using t-BuOOH/Ti(i-PrO)4 or m-CPBA as the oxidant. The authors found that a free hydroxy group in 530 was necessary to achieve high selectivities. Thus, a TIPS protected derivative of 530 gave a much lower selectivity for the sulfoxide with the opposite configuration. The sulfoxide configuration was determined by X-ray crystallography or by authentic synthesis. The oxazoline–sulfoxide ligands 531 were used to examine electronic effects in catalytic allylic substitutions.412 The authors proposed transition state models 532 and 533 to account for the diastereoselectivities observed in metal-catalyzed and m-CPBA oxidations, respectively (Fig. 8.16). The organization as well as directing role of the hydroxy group is

[O]

O

O

Ph R

S

N

Ph R

HO

S

O

N HO

530

531 R = Me, Tol Scheme 8.172

480

2-Oxazolines R Tol

S

O

L N O Ti O O L t-Bu

O

Ph

O Ar

S

O

532

O

N

H

Ph

O

H 533

Figure 8.16. Transition state models for oxidations.

fairly obvious based on the models. Model 533 also explains the strong solvent dependence of the selectivity when the oxidation is carried out with m-CPBA. Solvents with strong hydrogen bonding capabilities disrupt the intramolecular hydrogen bonding resulting in lower selectivities. Uemura and co-workers applied similar principles for their copper-catalyzed sulfimidation of diaryl sulfides (Scheme 8.173).357,413,414 The reaction was carried out in the presence of a copper(II) salt using either tosyliminophenyliodane IPh) or N-chloro-p-toluenesulfonamide (Chloramine-T) sodium salt as the (TsN imidation reagent. A diaryl sulfide 534 was imidated to give the N-tosylsulfimides 535 in modest yield with excellent diastereoselectivity (up to 99% de). In this case, however, a chiral 4-(methoxmethyl)oxazoline directing group gave better results than the corresponding 4-(hydroxymethyl)oxazoline analogue. The tosyl group of 535 was hydrolyzed to afford the sulfimides 536 that were used as chiral ligands in catalytic allylic substitutions.357

O Ph S

N R1O

R2

TsN=IPh or TsN(Cl)Na 3H2O cat. Cu(OTf) 2 MeCN, rt 52-61%

O Ph S

N N

R2

Ts R O 1 535 (up to 99% de)

534 a: R1 = H; R2 = H b: R1 = Me; R2 = H c: R1 = TBS; R2 = H d: R1 = H; R2 = Me e: R1 = Me; R2 = Me f: R1 = TBS; R2 = Me

1. conc. H2SO4 2. NaOH

O Ph S

N NH R1O

R2 536 Scheme 8.173

Reactions and Applications

481

O

O Ph

S

N

S

cat. Cu(OTf) 2 MeCN, rt

OMe

Me

Ph

TsN(Cl)Na 3H2O

N N Ts MeO

Me

534e

535e

TsN(Cl)Na 3H2O cat. Cu(OTf) 2 MeCN

TsNH Tol

N

Cl TsN H

Tol

S

MeCN

Cu

O

Ph

O

S

Cl MeCN

Me

N Cu

O

Ph

O

Me 538

537 Scheme 8.174

The authors proposed a working mechanism to explain the diastereoselectivities (Scheme 8.174). Thus, the prereaction complex 537 reacts with the Chloramine-T to yield an intermediate chlorosulfonium ion 538. Further reaction of 538 with toluenesulfonamide anion effected a configurational inversion to give the observed product. Very recently, Pelter and co-workers showed that oxazolines were a strong geminal directing group, characteristic of all carbonyl compounds in reactions of cyclophanes.176 Thus, bromination of the oxazolinylcyclophane 539 gave exclusively the -geminal bromide 540 in excellent yield (Scheme 8.175). The bromide 540 served as a precursor to potential bidentate ligands, such as the acid 541, the phenyl sulfide 542 and diphenylphosphine 543. 8.3.11.

Oxazolines as Ligands in Asymmetric Catalysis

The use of chiral oxazolines as ligands for catalytic asymmetric synthesis is undoubtedly the most important development in oxazoline chemistry. Compared with other ligands, oxazolines offer the advantage of being easily accessible from chiral amino alcohols that are, in turn, readily available from a chiral pool of amino acids. There have been numerous reports on this exciting use of oxazolines during the last 10 years. Many of the ligands studied to date contain at least two oxazoline units. The synthesis and reactions of bis(oxazolines) are discussed in detail in Chapter 9; the discussions in this section are limited to mononuclear oxazolines.

482

2-Oxazolines

N

N

N O

O Br

O

Br2

1. n-BuLi –78 ˚C

Fe 92%

2. CO2 100%

539

COOH

540 1. n-BuLi, –78 ˚C 2. PhSSO2Ph

56%

52%

541 1. n-BuLi, –78 ˚C 2. Ph2PhCl

N

N O

O PPh2

SPh

542

543 Scheme 8.175

There are many excellent reviews on asymmetric catalysis. Prominent among these reviews are two recently published books. One is a three volume work published in 1999 and edited by Jacobsen, Pfaltz, and Yamamoto.362 The other was published in 2000 and edited by Ojima.363 Moreover, Lemaire and co-authors have extensively reviewed nitrogen-containing ligands for asymmetric catalysis in 2000.415 Pfaltz reviewed the use of chiral heterocycles in asymmetric catalysis.23 These books and reviews provide a comprehensive discussion and examination of various catalytic asymmetric reactions and encompass the topic of this section. Additionally, Pfaltz and Helmchen specifically reviewed the use of phosphinooxazoline ligands, one of the most frequently used subclasses of mononuclear oxazolines, in asymmetric synthesis for the literature up to 2000.21 Therefore, the discussions here are intended to be a brief overview of recent developments (1999–2001) in this very active and fruitful research area. This section is organized to show the diversity of oxazoline structures as well as the type of catalytic reactions in which they function as useful ligands. For a more detailed treatment of catalytic process as well as earlier literature references, the reader is directed to the aforementioned comprehensive reviews.

Reactions and Applications

483

8.3.11.1. Oxazoline Ligands Mononuclear oxazolines useful for asymmetric catalysis are generally bidentate ligands that can be classified into the following four basic catagories: phosphinooxazolines (PhosOx, Figs. 8.17–8.19), pyridine-oxazolines (PyrOx, Fig. 8.20) including the quinoline-oxazolines, sulfide-oxazolines (SulfOx, Fig. 8.21), selenide-oxazolines (SelOx, Fig. 8.22), and hydroxy-oxazolines (HydrOx, Fig. 8.23). Additional coordinating groups can be added to these basic classes of ligand structures and can sometimes provide enhanced levels of selectivity. The coordination chemistry of oxazolines has been reviewed extensively by Muller and co-authors covering the literature up to 1999.20 Unless otherwise warranted, the coordination chemistry is generally not discussed in this section. R1

Ph2P

O N

O

N R3

(R2)2P

N

R1 R2

544

545

a: R1 = t-Bu; R2 = Ph b: R1 = Ph; R2 = Ph c: R1 = adamantyl; R2 = Ph d: R1 = 3,5-di-t-Bu-Ph; R2 = Ph e: R1 = Tr; R 2 = Ph f: R1 = 3,5-di-t-Bu-4-MeO-Ph; R2 = Ph g: R1 = 9-anthracyl; R2 = Ph h: R1 = 2-EtO-1-naphthyl; R2 = Ph i: R1 = Me; R2 = Ph j: R1 = t-Bu; R2 = o-Tol k: R1 = Ph2CH; R2 = Ph l: R1 = Ph2CH; R2 = o-Tol m: R1 = Ph2MeCH; R2 = o-Tol

a: R1 = i-Pr; R2 = H; R3 = Boc b: R1 = t-Bu; R2 = H; R3 = Boc c: R1 = Ph; R2 = H; R3 = Boc d: R1 = H; R2 = i-Pr; R3 = Boc e: R1 = H; R2 = Ph; R3 = Boc f: R1 = H; R2 = CO2Me; R3 = Boc g: R1 = R2 = Me; R3 = Boc h: R1 = i-Pr; R2 = H; R3 = Fmoc i: R1 = i-Pr; R2 = H; R3 = Cbz j: R1 = i-Pr; R2 = H; R3 = Piv k: R1 = i-Pr; R2 = H; R3 = Ac l: R1 = i-Pr; R2 = H; R3 = i-Pr2NCO

Me Me

Ph

Me

P

Me

Ar

O

O

Ph

P Ar

N

N R

R 546

547

a: R = i-Pr; Ar = Ph b: R = t-Bu; Ar = Ph c: R = i-Pr; Ar = 9-phenanthryl d: R = i-Pr; Ar = 9-anthracyl

a: R = i-Pr; Ar = Ph b: R = t-Bu; Ar = Ph c: R = i-Pr; Ar = 9-phenanthryl d: R = i-Pr; Ar = 9-anthracyl

Figure 8.17. PhosOx ligands.

484

2-Oxazolines

R2 O N Fe

O

R1

PPh2

P(R3)2

N R2 R1

548

549 a: R1 = i-Pr; R2 = H; R3 = Ph b: R1 = t-Bu; R2 = H; R3 = Ph c: R1 = Ph; R2 = H; R3 = Ph d: R1 = t-Bu; R2 = H; R3 = cyclohexyl e: R1 = H; R2 = i-Pr; R3 = Ph

a: R1 = i-Pr; R2 = H b: R1 = t-Bu; R2 = H c: R1 = Bn; R2 = H d: R1 = Ph; R2 = H e: R1 = R2 = Ph R3 Fe

O R2

O

N R1

R2P

N

PPh2

i-Pr

550

551

a: R1 = i-Pr; R2 = H; R3 = H b: R1 = Bn; R2 = H; R3 = H c: R1 = t-Bu; R2 = H; R3 = H d: R1 = Ph; R2 = H; R3 = H e: R1 = Bn; R2 = TMS; R3 = H f: R1 = Bn; R2 = H; R3 = Me g: R1 = Bn; R2 = H; R3 = TMS h: R1 = Ph; R2 = H; R3 = TMS i: R1 = Ph; R2 = Me; R3 = H

a: R = Ph; aS isomer b: R = Ph; aR isomer c: R = 3,5-di-Me-Ph; aR isomer

O (R2)2P

N R1 553

O Ph2P

N

552

a: R1 = i-Pr; R2 = Ph b: R1 = Ph; R2 = Ph c: R1 = t-Bu; R2 = Ph d: R1 = CH2t-Bu; R2 = Ph e: R1 = t-Bu; R2 = o-Tol f: R1 = i-Pr; R2 = i-Pr g: R1 = t-Bu; R2 = i-Pr h: R1 = i-Pr; R2 = t-Bu i: R1 = i-Pr; R2 = cyclohexyl j: R1 = t-Bu; R2 = cyclohexyl k: R1 = Ph; R2 = Ph Figure 8.18. PhosOx ligands.

Reactions and Applications

R1

O

O

O

N

R2

Ph2P

485

Ph

R1 N

O O

R2

O

O

P

554 a: R1 = Ph; R2 = H b: R1 = adamantyl; R2 = H c: R1 = ferrocenyl; R2 = H d: R1 = pentaphenylferrocenyl; R2 = H f: R1 =

R2 = H

Co Ph

Ph

Ph Ph g: R1 = ferrocenyl; R2 = i-Pr h: R1 = ferrocenyl; R2 = i-Bu i: R1 = ferrocenyl; R2 = Bn j: R1 = 3,5-di-t-Bu-Ph; R2 = Bn

555 a: R1 = Me; R2 = H b: R1 = Bn; R2 = H c: R1 = Ph; R2 = H d: R1 = i-Pr; R2 = H e: R1 = i-Bu; R2 = H f: R1 = t-Bu; R2 = H g: R1 = Me; R2 = CH2NEt2Me Ts

N

R2

O

O P

P

R1

557

556

Ph

a: R1 = R2 = Ph b: R1 = t-Bu; R2 = Ph c: R1 = t-Bu, R2, R2 = (CH2)4

t-Bu Ts

Ph

Ts

N

N

N

N R2

O

O

N

Ph Ts

R2

R2

Ph

O

O

P O

O O

Ph Ph 558

N P(R2)2

N R1

559 a: R1 = i-Pr; R2 = Ph b: R1 = t-Bu; R2 = Ph c: R1 = t-Bu; R2 = o-Tol d: R1 = t-Bu; R2 = cyclohexyl Figure 8.19. PhosOx ligands.

O

O N

t-Bu

486

2-Oxazolines

R3 R1 R4

O

N

R3

N R2

R1

O

N Ph

O

560

561

a: R1 = i-Pr; R2 = H; R3 = H; R4 = H b: R1 = H; R2 = Ph; R3 = H; R4 = H c: R1 = i-Pr; R2 = H; R3 = Cl; R4 = H d: R1 = i-Pr; R2 = H; R3 = OMe; R4 = H e: R1 = H; R2 = Ph; R3 = Cl; R4 = H f: R1 = H; R2 = Ph; R3 = OMe; R4 = H g: R1 = i-Pr; R2 = H; R3 = H; R4 = Me h: R1 = t-Bu; R2 = H; R3 = H; R4 = Me i: R1 = t-Bu; R2 = H; R3 = OMe; R4 = Me j: R1 = t-Bu; R2 = H; R3 = H; R4 = H

O

N

O

N

R2

R4

a: R1 = H; R2 = H; R3 = CH2CH2COTG b: R1 = H; R2 = t-Bu; R3 = CH2CH2COTG c: R1 = t-Bu; R2 = H; R3 = CH2CH2COTG d: R1 = H; R2 = H; R3 = Ph TG = TentaGel Resin

N R2

N

N N

R1 R2

R1 562 a: R1 = i-Pr; R2 = H b: R1 = H; R2 = Ph c: R1 = t-Bu; R2 = H

O R3

563

N

O

R2 R1 564

a: R1 = i-Pr; R2 = H a: R1 = i-Pr; R2 = H; R3 = H; R4 = H b: R1 = H; R2 = Ph; R3 = H; R4 = H b: R1 = H; R2 = Ph c: R1 = t-Bu; R2 = H; R3 = H; R4 = H c: R1 = t-Bu; R2 = H d: R1 = H; R2 = Bn; R3 = H; R4 = H e: R1 = i-Pr; R2 = H; R3 = Ph; R4 = H f: R1 = CH2SiPh2t-Bu; R2 = H; R3 = Ph; R4 = H g: R1 = Bn; R2 = H; R3 = H; R4 = Me h: R1 = i-Pr; R2 = H; R3 = H; R4 = Me i: R1 = Ph; R2 = H; R3 = H; R4 = Me j: R1 = t-Bu; R2 = H; R3 = H; R4 = Me k: R1 = Bn; R2 = H; R3 = H; R4 = n-Bu l: R1 = Bn; R2 = H; R3 = H; R4 = i-Bu m: R1 = t-Bu; R2 = H; R3 = H; R4 = i-Bu n: R1 = Me; R2 = H; R3 = H; R4 = H o: R1 = Bn; R2 = H; R3 = H; R4 = H p: R1 = Ph; R2 = H; R3 = H; R4 = H Figure 8.20. PyrOx ligands.

Reactions and Applications

O

O

Ph

O

Ph

Ph S

487

N

S

Ph

N Ts

RO 534

Ph

N

Ph

RO 536

a: R = H b: R = Me c: R = TBS

R1 R2S

a: R = H b: R = Me c: R = TBS

R1

N

R3

N NH

RO

535

a: R = H b: R = Me c: R = TBS

S

N O

SR2 R3

O

565

566

a: R1 = i-Pr; R2 = Me; R3 = OMe b: R1 = i-Pr; R2 = i-Pr; R3 = OMe c: R1 = t-Bu; R2 = Me; R3 = OMe d: R1 = t-Bu; R2 = i-Pr; R3 = OMe e: R1 = i-Pr; R2 = Me; R3 = H f: R1 = t-Bu; R2 = Me; R3 = H g: R1 = i-Pr; R2 = i-Pr; R3 = H

a: R1 = i-Pr; R2 = Me; R3 = OMe b: R1 = i-Pr; R2 = i-Pr; R3 = OMe c: R1 = t-Bu; R2 = Me; R3 = OMe d: R1 = t-Bu; R2 = i-Pr; R3 = OMe e: R1 = i-Pr; R2 = Me; R3 = H f: R1 = t-Bu; R2 = Me; R3 = H g: R1 = i-Pr; R2 = i-Pr; R3 = H O i-Pr

R1

N O

SPh

N H

R2

i-Pr

567

568

a: R1 = SPh; R2 = H b: R1 = H; R2 = SPh Figure 8.21. SulfOx ligands.

8.3.11.2. Allylic Substitution Reactions The subject of catalytic asymmetric allylic alkylations has been thoroughly and systematically reviewed by Trost and Van Vranken in 1996.416 Much of the recent literature was reviewed by Pfaltz and Lautens in 1999417 and by Trost and Lee in 2000.418 Many mononuclear oxazoline ligands have been successfully employed in

488

2-Oxazolines O

O

i-Pr

R1

N

N Se

Fe

O

SePh

t-Bu

2

N H

R2

i-Pr

569

570

571

a: R1 = SePh; R2 = H b: R1 = H; R2 = SePh Figure 8.22. SelOx ligands.

N CPh2OH t-Bu Re OC OC CO

Fe

452

t-Bu

CPh2OH N

O

O

O

N CPh2OH R

Fe

572

573

a: R = t-Bu b: R = Ph O

O R

Ph Ph

Co

N Ph Ph

R OH

N Ph

Fe

Ph

Ph Ph

OH

O

R4 HO

N

Ph 574 a: R = H b: R = Me c: R = Ph

R2 R3 R1

576

575

a: R1 = Ph, R2 = Ph, R3 = H; R4 = H b: R1 = Ph, R2 = H, R3 = Ph; R4 = H c: R1 = Ph, R2 = Ph, R3 = H; R4 = t-Bu d: R1 = Ph, R2 = H, R3 = Ph; R4 = t-Bu e: R1 = Ph, R2 = H, R3 = H; R4 = t-Bu f: R1 = Bn, R2 = H, R3 = H; R4 = t-Bu Figure 8.23. HydrOx ligands.

palladium catalyzed allylic substitution reactions. Despite the shortcomings (see below), asymmetric allylic substitution of racemic diphenylallyl acetate 577 using dimethyl malonate (Scheme 8.176) has been a standard reaction used by many researchers to evaluate new chiral ligands. The performance of selected ligands in this reaction is summarized in Table 8.34.98,117,118,123,180,208,209,225,357,413,419–429 Table 8.34 is organized to show a generic ligand structure and the ligand that gave the best results, whether optimized or not.

Reactions and Applications OAc Ph

Ph

CH2(CO2Me)2 Base [(η3-C3H5)PdCl]2 Ligand

489

MeO2C Ph

577

CO2Me * Ph

578 Scheme 8.176

Since the enantioselectivity of this reaction is known to be sensitive to the solvent, base, counterion, and source of catalyst,416–418 one should be cautious in comparing results from different groups. Many groups observed some cooperative effect in the selectivity when additional chirality is present in the ligand. In cases wherein the new chiral elements exert opposite chiral induction (noncooperative), the directive effect of the oxazoline ligand often dominates except in the cases of chiral bridgehead phosphines 546 and 547. Here, the chirality of the phosphine was shown to be more important (entry 3).117 Although axial diastereomers 565e and 566e exist as an equilibrium mixture in solution, only 566e complexes with palladium (entry 18).429 A similar phenomenon was observed for the diastereomers 565f and 566f. It is not surprising that this was not observed for 565g and 566g considering the higher rotation barrier. The origins of enantioselection can be understood through structural analysis by X-ray crystallography419–421,430 and solution NMR.118,420,421 Other soft nucleophiles, such as acetylacetone (ligands 555g and 551b),424 dimethyl methylmalonate (ligand 555g),424 benzylamines (ligand 555g),420,424 and silyl enolates (ligand 544),419 gave similar selectivities.

TABLE 8.34. PALLADIUM-CATALYZED ALKYLATION OF DIPHENYLALLYL ACETATE WITH DIMETHYL MALONATE Entry

Ligand

Best Ligand

578 % Yield

% ee

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

544a–d 545a–l 546a–d, 547a–d 551b 551c 554 555a–f 555g 556a–c-558 559a–d 560a–i 561a–d 562a–c 563a–f 563g–m 564a–c 534a–c-536a–c 565a–g, 566a–g 567, 568 569, 570

544a, 544d 545a 546a 551b 551c 554a, c 555a 555g 556a 559a 560i 561a 562c 563c 563j 564b 536b 1 : 1 565e/566e 567b 569b

95 100 100 99 99 >95 (conv.) 100 95 100 (conv.) 100 (conv.) 94 60–100 93 94 79 88 99 93 98 98

98 (R) 30 (S) 94 (S) 91 (R) 97 (R) 90 (S) 96 (S) 92 (S) 88 (S) 72 (S) 93 (S) 80 (R) 92 (S) 77 (S) 78 (R) 78 (S) 90 (S) 82 (S) 94 (S) 93 (S)

References 118, 419 98 117 420, 421 421 422 423 424 425 426 208, 427 225 209, 427 123, 427 428 427 413, 357 429 180 180

490

2-Oxazolines

TABLE 8.35. PALLADIUM-CATALYZED ALKYLATION OF DIMETHYLALLYL ACETATE AND DIMETHYLALLYL tert-BUTYLCARBONATE WITH DIMETHYL MALONATE

OR Me

Me

MeO2C

CH2(CO2Me)2 Base

CO2Me ∗

Me

[(η3-C3H5)PdCl]2 Ligand

579

Me 580

a: R = Ac b: R = Boc Scheme 8.177 Entry

579 (R)

Ligand

Best Ligand

1 2 3

Ac Boc Boc

536b 544 554

536b 544f 554f

a

580 % Yielda 63 77 >95 (conv.)

% ee

Reference

49 (NR) 82 (R) 70 (S)

357 118, 419 422

Not reported: NR.

At least two groups examined the issue of catalyst recycle by using polymerbound225 or water-soluble ligands.424 Although a diphenylallyl system serves as a good starting point to evaluate chiral ligands, Burgess and Hou suggested that the smaller dimethylallyl system, generated from 579, should be used as a more stringent test for ligand performance.118 Selected examples are listed in Table 8.35 (Scheme 8.177).118,357,419,422 As expected, the enantioselectivities using 579 dropped in comparison with those obtained using the diphenylallyl system 577. It is important to note that the best ligand for the diphenylallyl system may not necessarily give the best selectivity for the dimethylallyl system. A number of groups have also studied alkylation in cyclic allyl systems. Selected examples of reations using 3-acetoxycyclohexene 581 are listed in Table 8.36 (Scheme 8.178).98,419,425,426,431 Although the proline-based PhosOx ligands 545 did not give good selectivities in reactions with 577 (Table 8.34, entry 2), here using 581 the selectivity with 545a was reasonable (Table 8.36, entry 2). Gilbertson and co-workers studied the effects of substrate ring size on the ligand performance and found that 545 gave best selectivities (up to 90%) using 3-acetoxycyclopentene as the substrate.98 Interestingly, good selectivity (80% ee) was still obtained when the PhosOx ligand contained an achiral oxazoline moiety (e.g. 545g). The authors attributed the effect of substrate ring size and the lack of good selectivities in the diphenylallyl system to the small size of the chiral pocket around the catalytic center. When unsymmetrical allylic substrates are used, two regioisomers are produced. Monosubstituted allyl substrates react primarily at the unsubstituted terminus to give an achiral linear product (Scheme 8.179).432 However, Pfaltz and co-workers were able to reverse the regioselectivity and obtain the more highly substituted

Reactions and Applications

491

TABLE 8.36. PALLADIUM-CATALYZED ALKYLATION OF 3-ACETOXYCYCLOHEXENE WITH DIMETHYL MALONATE

MeO2C * CO2Me

OAc CH2(CO2Me)2 Base [(η3-C3H5)PdCl]2 Ligand

581

582 Scheme 8.178

Entry

Ligand

Best Ligand

582 % Yield

% ee

References

1 2 3 4

544a–d 545a 556–558 559

544d 545a 556b 559b

95 93 100 (conv.) 91 (conv.)

79 (S) 80 (S) 71 (R) 41 (R)

419 98, 431 425 426

product enatioselectively using ligands 556–558.425 More recently, the same group reported a selective preparation of either regioisomer using enantiomers of the catalyst as well as enantiomerically enriched disubstituted substrates.433 This alkylation reaction is generally carried out using a palladium catalyst although other metals can be effective as well.416–418 Williams and co-workers recently reported the use of zero-valent platinum complexes as catalysts.430,434 When the PhosOx ligand 553a was used, the enantioselectivities were inferior to results obtained using the corresponding palladium complex. Additionally, the selectivities were sensitive to excess ligand. The authors concluded that the platinum complex is hemilabile, that is, the complex can accept an additional ligand resulting in a loss of chelation. It is noteworthy that the X-ray crystal structures of the PtCl2(553a) and PdCl2(553a) complexes were very similar. Overman’s group improved their earlier versions of chiral catalysts for the rearrangement of allylic imidates 583 to the amides 584 (Scheme 8.180).435 High selectivities were obtained using cyclopalladated catalysts bearing ferrocenyloxazoline moieties 585–587. These catalysts were conveniently prepared by oxidative insertion of Pd(0) to oxazoline-substituted ferrocenyl iodides. The iodide complex was inactive and was converted to the active trifluoroacetate complex using silver trifluoroacetate. The enatioselectivities were generally 75–95% ee although most reactions took more than a day to complete. Not surprisingly, the olefin configuration as well as the chiral catalyst determines the product stereochemistry. The OAc R

CH2(CO2Me)2 Base

M2O2C

MeO2C

CO2Me +

[(η3-C3H5)PdCl]2 Ligand

R

CO2Me ∗

R major product with ligands 556–558

Scheme 8.179

492

2-Oxazolines Ar1 Ar2

N

O

Ar1 Ar2

5% catalyst

N

O

CH2Cl2, 23 ˚C

R

R 583

584 MeO

t-Bu

R1

O

N F3CCOO Pd 2

Fe

TMS Fe

585

Et

O

Et N Pd OCOCF 3 2 586

O N Pd X t-Bu 2

Fe

587

a: R1 = H b: R1 = TMS c: R1 = TES

Scheme 8.180

rearrangement is sensitive to the electronic nature of the aryl groups. Imidates with electron-withdrawing aryl groups react much slower than imidates with electrondonating aryl groups. Similarly, reaction of trichloroacetimidates is too slow to be of any practical use. The best results to prepare the (R) isomer of 584 (96% ee, 89– 97% yield) were obtained using the (Z) alkene 583 (R ¼ i-Bu, Ar1 ¼ Ph or o-Tol, Ph) and catalyst 585b. Ar2 ¼ 4-MeO While intramolecular allylic substitution is a straightforward and attractive strategy for construction of carbocycles, there are surprisingly few reports on the asymmetric variant of this cyclization.416–418 Helmchen and Flubacher have reported a Heck-induced enantioselective intramolecular allylic amination reaction of 588 to produce the 2-substituted piperidine derivative 589 (Scheme 8.181).436 Selectivities as high as 80% were obtained with sterically hindered aryl triflates (Ar ¼ 2,6-di-Me Ph) using the PhosOx ligand 553b. However, the reaction was exceedingly slow and required 10 days to complete. Allylic substitution using hard nucleophiles proceeds through a different mechanism.416–418 Instead of attacking the allyl group of the p allyl–metal complex, hard nucleophiles attack the metal first and the product is subsequently formed by reductive elimination. Nickel(0) complexes have often been used for this purpose. Reports of good enantioselectivities in this type of reaction are limited. Bn

Ar NHBn

ArX Pd(OAc) 2 Ligand

NHBn PdL

588

N * 589

X = I, OTf; Ar = Ph, 2,6-di-Me-Ph; Ligand = 553b, c

Scheme 8.181

Ar

Reactions and Applications

493

Uemura and co-workers recently reported their success using ferrocene-based PhosOx ligands.437,438 Reactions using an arylboronic acid as the nucleophile gave good yields with various allylic substrates although enantioselectivities were moderate (up to 53% ee).437 Better results were obtained using an aryl Grignard reagent as the nucleophile.438 While acyclic substrates gave low selectivities (<40% ee), cyclohexenyl substrates 590 gave better results (Scheme 8.182). The best selectivity for the (S) isomer of 591 (95% ee) was obtained with 3-phenoxycyclohexene (X ¼ OPh) as the substrate, 2-naphthylmagnesium bromide (Ar ¼ 2naphthyl) as the nucleophile, and 548a as the ligand. The PhosOx ligand 553a was less effective than 548, which demonstrated the importance of planar chirality in this reaction. Unlike the reaction with an aryl boronic acid as the nucleophile, the Grignard reagent produced a significant amount of biaryl as the byproduct. The biaryl byproduct was thought to arise from reduction of the Ni(II) precatalyst by the Grignard reagent generating an active Ni(0) species. X

Ar ArMgBr

590

Ni(acac)2 548 acac = acetylacetonato

591

X = OAc, OCO 2Me, OMe, OPh, OH, Br Scheme 8.182

8.3.11.3. Heck Reactions The Heck reaction is a synthetically powerful reaction wherein a carbon–carbon bond is formed between two sp2 hybridized carbon atoms.439 The syn nature of the addition of vinyl–aryl palladium species to carbon–carbon double bond precludes a syn b-hydride elimination for cyclic olefins. As a result, a new chiral center is formed. Shibasaki and Vogl provided a comprehensive review of this subject in 1999.440 Overman and Donde reviewed the intramolecular version of this reaction in 2000.441 Pfaltz and co-authors specifically reviewed this reaction using PhosOx ligands.442 Although BINAP has been proven the most effective ligand system for the asymmetric Heck reaction,440,441 it promotes double bond migration resulting in mixtures of isomers when the engery differences between the isomers are small. In 1996, Pfaltz and co-workers first demonstrated that chiral PhosOx ligands are very effective for highly enantioselective as well as regioselective Heck reactions.443,444 Subsequent research by several groups expanded the structural diversity of the PhosOx ligands leading to some improvements in catalyst activity although selectivities have not yet surpassed the selectivity (99% ee) achieved using by Pfaltz’s best ligand, the tert-leucinol-based PhosOx 553c. The Heck reaction of dihydrofuran 592 and cyclohexenyl triflate 593a or phenyl triflate 593b has been

494

2-Oxazolines

TABLE 8.37. ASYMMETRIC INTERMOLECULAR HECK REACTION Pd2(dba)3

+

ROTf Ligand Base

O 592

O *

R

593a R =

594a R =

593b R =

594b R = Scheme 8.183

Entry 1 2 3 4 5 6 7 8

Ligand 545a,b,d,l 546a–d, 547a–d 549a–e 550a–i 551a,b 551b,c 552 555a–f

Triflate Best Ligand 593a 593a 593a 593b 593b 593b 593a 593b

545a 546b 549b 550g 551a 551c 552 555b

594a % Yield

594b % Yield

99 (conv.) 91 100 (conv.) 75 65 84 91 100

% ee

References

86 (S) 93 (R) 94 (R) 92 (R) 88 (R) 86 (S) 98 (R) 96 (R)

98, 445 117 446 447 448 421 449 450

chosen by many researchers as a model to evaluate the efficiency of the chiral ligands. Selected examples are listed in Table 8.37 (Scheme 8.183).98,117,421,445–450 The stereochemistry of the oxazoline usually determines the stereochemical outcome of this reaction. However, this rule does not apply when planar or axial chirality is involved and exceptions have been described. For example, an exception is the proline-based ligand 545 wherein the chirality of the oxazoline was found unimportant.98,445 Another exception is the ferrocene-based ligand 550 in which the planar chirality is the major factor that determines the stereochemical outcome of the reaction.447 Still another exception is the binaphthyl-based PhosOx 551 wherein the axial chirality dominates. This result was consistent with structural analysis by X-ray crystallography.448 And it is perhaps not very surprising considering the similarity of the binaphthyl-based PhosOx ligands to the powerful BINAP ligands. The low tendency of PhosOx-palladium catalysts to promote double-bond migration permits a wide variety of cycloalkenes and triflates to be used for this reaction.95,421,445,446,449,450 Both reaction rates and regioselectivities as well as enantioselectivities are sensitive to the base as well as the solvent used in the reaction.98,445,446 The origin of the enantioselectivity was investigated using NMR analysis and X-ray crystallography.421,448,450 It is noteworthy that crotyl alcohol has been coupled with phenyl triflate 593b to give moderate yields (up to 54%) of b-phenylbutanal although the enantioselectivity was low (up to 17% ee).450 The Heck reaction yields the final product through a b-hydride elimination whereas hydroarylation or hydrovinylation generates the final product via a reductive elimination. Nonetheless, both reactions share a common first step, that is, addition of an aryl or a vinyl palladium species to an alkene, and thus are briefly discussed here. Norbornene 595 is the most studied alkene to evaluate an the

Reactions and Applications

495

asymmetric version of this reaction.440 Zhou and co-workers recently reported their results using the PyrOx ligands 563 (Scheme 8.184).451 exo-2-Phenylnorbornane 596 was produced exclusively with the best enantioselectivity (74% ee) obtained using 563a. PhI Pd(dba)2

Ph

Ligand Et3N/HCO2H

595

596 Ligand = 563a, c, n-p

Scheme 8.184

8.3.11.4. Hydrogenation Reactions Enantioselective hydrogenation reactions have received the most attention and success in asymmetric catalysis over the years. Historically, high selectivities were achieved primarily with functionalized substrates using Rh(I) or Ru(II) complexes containing chiral diphosphine ligands. Recent advances in this area include the enantioselective hydrogenation of nonfunctionalized substrates and the proliferation of other ligands including oxazolines. This subject has been frequently and systematically reviewed. For example, Noyori and co-authors provided a comprehensive review of asymmetric hydrogenation of various substrates in 2000.452 For a more detailed examination on the reaction with specific substrates, the reader is referred to the following reviews contained in the book edited by Jacobsen, Pfaltz, and Yamamoto: Brown’s chapter on the hydrogenation of functionalized alkenes,453 Halterman’s chapter on the reaction with nonfunctionalized alkenes,454 the chapter by Noyori and Ohkuma on carbonyl substrates,455 and the chapter by Blaser and Spindler on imino substrates.456 This subsection is intended to be a brief overview of recent advances using mononuclear oxazoline ligands. Mononuclear oxazolines are among the most effective ligands for enantioselective hydrogenation of nonfunctionalized alkenes.454 The styrene substrate 597 is one of the most studied nonfunctionalized alkenes used to evaluate the efficiency of new chiral ligands (Scheme 8.185). Selected examples of enatioselective hydrogenation of 597 using iridium catalysts are shown in Table 8.38.359,425,426,457–459 R1

R1 [Ir(cod)L]BARF

R2

50-100 bar H2 rt, CH2Cl2

R3

X

*

R3

X

597

598 CF3 BARF =

B CF3

Scheme 8.185

4

* R2

496

597 (X, R1, R2, R3)

H, Me, Ph, H H, Me, Ph, H H, Me, Ph, H H, Me, Ph, H H, Me, Ph, H H, Me, Ph, H H, Me, Ph, H MeO, Me, Ph, H MeO, Me, Ph, H MeO, Me, Ph, H MeO, Me, Ph, H MeO, Me, Ph, H MeO, Me, Me, H MeO, Me, Me, H MeO, Me, Me, H MeO, Me, Me, H MeO, Me, Me, H MeO, Me, Me, H MeO, Me, Et, H MeO, Me, H, Me MeO, Me, H, Me

Entry

1 2 3 4 5 6 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 544l 553j 554g 554j 556c 558 599d 544l 553j 557 558 599d 544a 553e 554i 557 559d 599d 599d 544a 554g

Best Ligand 0.2% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 0.1% cat., 50 bar, 2 h 0.4% cat., 50 bar, 2 h 4% cat., 100 bar, 2 h 4% cat., 100 bar, 2 h 0.2% cat., 50 bar, 2 h 0.2% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 4% cat., 100 bar, 2 h 4% cat., 100 bar, 2 h 0.6% cat., 50 bar, 2 h 0.6% cat., 50 bar, 2 h 0.3% cat., 50 bar, 2 h 0.1% cat., 50 bar, 2 h 4% cat., 100 bar, 2 h 1% cat., 50 bar, 2 h 0.6% cat., 50 bar, 2 h 0.6% cat., 50 bar, 2 h 0.6% cat., 50 bar, 2 h 0.4% cat., 50 bar, 2 h

Conditions

TABLE 8.38. ASYMMETRIC HYDROGENATION OF STYRENES 597 (SCHEME 8.185)

99 >99 (conv.) 100 (conv.) 100 (conv.) 15 (conv.) 100 (conv.) 99 99 >99 (conv.) 57 (conv.) 98 (conv.) 99 90 >99 (conv.) 100 (conv.) 100 (conv.) 100 (conv.) 99 94 70 100 (conv.)

598 % Yield

95 (S) 99 (R) 97 (R) 98 (R) 94 (R) 75 (R) 98 (S) 93 (S) 99 (R) 92 (R) 62 (R) 97 (S) 80 (S) 61 (R) 96 (R) 85 (R) 75 (R) 91 (S) 84 (NR) 75 (R) 85 (R)

% ee

457 359 458 458 425 425 459 457 359 425 425 459 457 359 458 425 426 459 459 457 458

Reference

497

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

MeO, Me, H, Me MeO, Me, H, Me MeO, Me, H, Me H, Me, CO2Et, H H, Me, CO2Et, H H, Me, CO2Et, H H, Me, CO2Et, H H, Me, CO2Et, H Cl, Me, Ph, H Cl, Me, Ph, H H, H, CH2OAc, Me H, H, CH2OAc, Me H, H, CH2OH, Me H, H, CH2OH, Me MeO, Et, H, H MeO, Et, H, H MeO, Et, H, H H, Et, H, H MeO, Me, Me, Me 558 559d 599d 553i 554h 556c 558 559c 553j 558 544a 544b 544i 599d 544a 554j 599d 544a 553d

4% cat., 100 bar, 2 h 1% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 0.5% cat., 50 bar, 2 h 4% cat., 100 bar, 2 h 4% cat., 100 bar, 2 h 1% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 4% cat., 100 bar, 2 h 0.5% cat., 50 bar, 2 h 0.5% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 1% cat., 50 bar, 2 h 0.3% cat., 50 bar, 2 h 0.1% cat., 1 bar, 2 h 0.3% cat., 50 bar, 2 h 0.3% cat., 50 bar, 2 h 2% cat., 50 bar, 2 h

100 (conv.) 100 (conv.) 95 86 (conv.) 100 (conv.) 32 (conv.) 100 (conv.) 99 (conv.) 99 (conv.) 52 (conv.) 53 95 80 99 99 100 (conv.) 91 99 99 (conv.)

90 (S) 70 (S) 78 (R) 81 (R) 90 (R) 91 (R) 75 (R) 92 (R) 99 (R) 78 (R) 72 (NR) 57 (NR) 67 (NR) 93 (NR) 44 (R) 88 (S) 31 (R) 40 (R) 81 (NR)

425 426 459 359 458 425 425 426 359 425 457 457 457 459 457 458 459 457 359

498

2-Oxazolines O

R1

R2 = 2,6-di-i-Pr-Ph

N R2

N

a: R1 = Ph b: R1 = Bn c: R1 = t-Bu d: R1 = adamantyl

N 599

Figure 8.24. Oxazoline-carbene ligands.

The relationship between selectivity vs. ligand topography was determined for some ligands based on the x-ray crystal structure of the corresponding iridium complexes.426,457,458 The structures of the respective oxazoline-carbene ligands 599a–d are shown in Figure 8.24.459 In a number of thoughtfully designed and carefully executed experiments, Burgess and co-workers demonstrated that double-bond migrations are competitive with hydrogenation in at least some of the reactions using an iridium complex.457 For example, deuteration of (E)-2-(4-methoxyphenyl)-2-butene 597a gave the expected deuterated product 598a with deuterium detected only at the carbon atoms of the double bond and recovered 597a that was completely undeuterated (Scheme 8.186). In contrast, deuterium scrambling was observed from deuteration of (Z)-2-(4-methoxyphenyl)-2-butene 597b and the recovered 597b showed deuterium incorporation into the a-methyl group. Interestingly, no double-bond migration or isomerization in the recovered styrene was observed in the latter reaction. The authors proposed the mechanism in Scheme 8.187 to account for these results. It was suggested that the p-allyl complex 600 produced from 597a was less

D (1.0) 0.3% [Ir(cod)L]BARF

+ MeO 597a

50 bar D2 rt, CH2Cl2 85% L = 544a

D (0.96)

MeO

MeO

598a 80% ee D (0.70) D (1.0)

(0.63) D

0.6% [Ir(cod)L]BARF

+ MeO 597b

50 bar D2 rt, CH2Cl2 75% L = 544a

D (0.91)

MeO 598b

63% ee Scheme 8.186

MeO

Reactions and Applications

499

D(H)

Ar

slow

D(H) IrD(H)

Ir

Ir-D(H)

Ar

Ar 600

597a

addition of H2 or D2

direct addition of H2 or D2

D(H) D(H)

D(H) Ar

Ar

D(H)

D(H)

not detected D(H)

Ar

fast

597b

Ar

Ar addition of H2 or D2

601

direct addition of H2 or D2

Ar

D(H) IrD(H)

Ir

Ir-D(H)

D(H)

D(H) D(H)

Ar

D(H) D(H)

Scheme 8.187

stable than the p-allyl complex 601 prepared from 597b. Therefore, formation of 600 and further reaction does not compete with the direct addition reaction to 597a. However, formation of complex 601 may be sufficiently competitive to allow deuterium scrambling. The possibility of double-bond migration adds some degree of difficulty to the design of ligands for this type of hydrogenation reaction. Using a similar method, this group also demonstrated that double-bond migration is less prevalent in reactions using the new oxazoline-carbene ligands 599a–d.459 In an effort to develop an environmentally friendly process, Pfaltz and coworkers employed supercritical carbon dioxide as the solvent for the hydrogenation of imines 602a,b to produce the a-methylbenzylamines 603a,b (Scheme 8.188).460 Thus, the Ir(I)-553a complex exhibited high activity for the hydrogenation of 602a in supercritical CO2 and produced 603a with an enantioselectivity similar to that obtained in CH2Cl2. The authors also demonstrated successful reaction using the recycled catalyst. However, they cautioned that supercritical CO2 should not be regarded simply as a ‘‘nonpolar substitute solvent’’. For example, hydrogenation of 602b did not exceed 30% conversion in supercitical CO2 even at prolonged reaction times or with higher catalyst loadings whereas the same reaction in CH2Cl2 went to completion within normal reaction time.

500

2-Oxazolines N Ph

R

HN

[Ir(cod)L]BARF

Me 602

10-100 bar H2 scCO2 or CH2Cl2 L = 553a

Ph

R Me

603

a: R = Ph b: R = Bn

a: R = Ph b: R = Bn Scheme 8.188

TABLE 8.39. ENANTIOSELECTIVE TRANSFER HYDROGENATION OF KETONES

O R1

R2 604

OH * R1 R2

0.5% RuCl2Lm(PPh3)n i-PrONa/i-PrOH m = 1, 2; n = 1, 0

605 O

Ph2P L = 548, 553,

N 606

i-Pr

Scheme 8.189 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

604 (R1, R2) Ph, Me Ph, Me Ph, Me Ph, Me Ph, Et Ph, n-Bu Tol, Me 4-F-Ph, Me 4-Cl-Ph, Me 4-Br-Ph, Me 3-Me-Ph, Me 3-F-Ph, Me 3-Cl-Ph, Me 3-Br-Ph, Me 2-Me-Ph, Me 2-F-Ph, Me 2-Cl-Ph, Me 2,4-di-Me-Ph, Me 2-furyl, Me t-Bu, Me cyclohexyl, Me cyclohexyl, Me n-hexyl, Me

Best Catalyst RuCl2(548a)PPh3 RuCl2(548d)PPh3 RuCl2(553a)PPh3 RuCl2(606)2 RuCl2(548d)PPh3 RuCl2(548d)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548a)PPh3 RuCl2(548d)PPh3 RuCl2(548a)PPh3

% Yield 94 (conv.) 95 (conv.) 43 (conv.) 96 99 (conv.) 99 (conv.) 98 (conv.) 99 (conv.) 99 (conv.) 99 (conv.) 98 (conv.) 98 (conv.) 99 (conv.) 77 (conv.) 99 (conv.) 92 (conv.) 99 (conv.) 99 (conv.) 66 (conv.) 81 (conv.) 68 (conv.) 31 (conv.) 99 (conv.)

% ee >99.6 (R) 72 (R) 55 (R) 72 (R) >99.7 (R) 98.7 (R) >99.3 (R) 97.3 (R) 98.7 (R) >99.3 (R) >99.9 (R) >99.6 (R) >99.7 (R) >99.7 (R) >99.9 (R) 96.6 (R) >99.7 (R) >99.9 (R) 95 (R) >99 (S) 52 (S) 66 (S) 26 (S)

Reference 467 467 467 461 467 467 467 467 467 467 467 467 467 467 467 467 467 467 467 467 467 467 467

Reactions and Applications

501

PhosOx ligands were also effective for ruthenium (II)-catalyzed transfer hydrogenation of alkyl ketones 604 (Scheme 8.189). Both Pfaltz’s and Uemura’s groups examined the complexation of PhosOx ligands with ruthenium (II) using spectroscopic techniques including X-ray crystallography.461,462 These studies showed that ligand 606 forms geometric isomers of hexacoordinated RuCl2L2 complexes,461 whereas ligand 548 forms one major diastereomer of the pentacoordinated complex RuCl2LPPh3.462 These complexes, RuCl2(606)2 and RuCl2(548)PPh3 were used in transfer hydrogenation of ketones by i-PrOH, an enantioselective version of the Meerwein–Ponndorf–Verley reduction.463–466 Interestingly, both groups found that mixtures of isomeric complexes can be used in place of isomerically pure complexes without a significant loss in selectivity.461,462 The data in Table 8.39461,467 indicates that extremely high selectivities were obtained using ferrocene-based PhosOx ligands 548a,d.467 The fact that ligand 553a (entry 3) gave poorer conversion and selectivity with acetophenone than ligand 548a (entry 1) suggests the importance of the planar chirality in 548. Additionally, modest-to-excellent selectivities were also obtained with the refractory alkyl methyl ketones (entries 20–22). Kinetic resolution of racemic aryl methyl carbinols can be also achieved using the ferrocene-based PhosOx ligands (yields up to 49% and ee’s up to 99.8%).467

8.3.11.5. Additions of Dialkylzincs to Aldehydes Asymmetric addition of a dialkylzinc reagent to an aldehyde, catalyzed by a Lewis base or a Lewis acid, is a viable alternative to enantioselective reduction of ketones as means to prepare enantiomerically enriched alcohols like 605 and 608.468 The HydrOx ligands are among the most effective Lewis bases for this addition reaction. The asymmetric induction results from complexation of the ligand with the dialkylzinc reagent prior to reaction with the aldehyde. Previously, it was established that phenyl addition proceeds overwhelmingly when an alkyl phenylzinc reagent is used.469 Table 8.40 (Scheme 8.190) summarizes selected recent examples of asymmetric additions of alkylzinc reagents to a variety of aliphatic, aromatic, and heterocyclic aldehydes 607.170,374,378,470,471 Bolm and coauthors suggested that the ferrocenyloxazoline diselenide itself, 571 may serve as a precatalyst and that the active catalytic species may be the alkyl zinc selenide resulting from reaction of 571 and a dialkylzinc reagent.374 A linear correlation between the ee of the ferrocene ligand 572b and ee of the product has been established.370,472 However, there is a remarkable nonlinear effect observed473,474 for the addition of dimethylzinc to benzaldehyde when employing a diastereomeric mixture of the HydrOx ligands 572a and 573.472 Thus, 1-phenylethanol was produced in 95% ee even when a 50:50 mixture of 572a and 573 was used. This discovery suggests that the diasteromeric mixture generated by preparation of these ligands may be useful as an asymmetric catalyst without tedious separation of the individual diastereomers.

502

2-Oxazolines

TABLE 8.40. ASYMMETRIC ADDITION OF DIALKYLZINC REAGENTS TO ALDEHYDES

O H

R1

OH * R2

R2ZnR3 Ligand

R1

607

608 Scheme 8.190

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

607 (R1)

Dialkylzinc (R2, R3)

Me hexyl Ph(CH2)2 Ph(CH2)2 (E)-styryl (E)-styryl Bn i-Pr t-Bu t-Bu t-Bu Ph Ph Ph Ph Tol Tol Tol 4-Cl Ph 4-Cl Ph 4-Cl Ph 4-Cl Ph 4-Cl Ph 4-Cl Ph 2-Br Ph 2-Br Ph 2-Br Ph 2-Br Ph 4-MeO Ph 3-MeO Ph 3-MeO Ph 2,4,6-tri-Me Ph 4-Ph Ph 4-Ph Ph 1-naphthyl 2-naphthyl 2-naphthyl ferrocenyl 2-furyl 2-furyl 2-pyridyl

Ph, Ph Ph, Et Ph, Et Ph, Ph Ph, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Ph Et, Et Et, Et Et, Et Et, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Ph Ph, Ph Ph, Ph Ph, Et Ph, Et Ph, Et Ph, Ph Ph, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Et Ph, Ph Ph, Et Ph, Et Ph, Ph Ph, Et Ph, Et Ph, Ph

Ligand

L mol%

% Yield 608

572a 452 452 572a 452 572a 572a 572a 571 572a 572a 574a 574b 574c 575 452 571 572a 452 571 572a 572a 572a 572b 452 571 572a 572a 572a 452 572a 452 571 572a 572a 571 572a 572a 452 572a 572a

5 2 2 5 2 10 10 10 5 10 5 10 10 10 10 2 5 10 2 5 10 10 5 10 2 5 10 5 10 2 10 2 5 10 5 5 10 5 2 10 5

94 >80 >80 91 >80 97 82 75 85 68 99 >90 (conv.) >90 (conv.) >90 (conv.) >90 (conv.) >80 80 86 >80 85 86 92 99 99 >80 65 64 98 82 >80 99 >80 86 98 99 96 70 89 >80 99 98

% ee 75 (S) 74 (S) 76 (S) 50 (S) 88 (R) 90 (S) 83 (S) 91 (S) 65 (S) 94 (S) 56 (S) 68 (R) 54 (R) 8 (R) 75 (R) 85 (R) 76 (R) 98 (R) 96 (R) 84 (R) 97 (R) 90 (R) 82 (R) 88 (R) 83 (R) 77 (R) 91 (R) 31 (R) 98 (R) 93 (R) 96 (R) 80 (R) 85 (R) 97 (R) 28 (R) 76 (R) 96 (R) >96 (R) 95 (R) 95 (R) 3 (R)

References 470 378 378 470 378 471 471 471 374 471 470 170 170 170 170 378 374 471 378 374 471 470 470 470 378 374 471 470 471 378 471 378 374 471 470 374 471 470 378 471 470

Reactions and Applications

503

8.3.11.6. Hydrosilylation Reactions Nishiyama and Itoh reviewed asymmetric hydrosilylation and related reactions in 2000.475 Although a number of catalytic systems are known to be very effective for the asymmetric hydrosilylation of ketones, reports of efficient catalysts for the analogous reaction with imines are limited.476 Uemura and co-workers recently reported that ferrocene-based PhosOx 548 were effective ligands for iridiumcatalyzed hydrosilylation of imines (Scheme 8.191).477 The best results for 2-phenyl-1-pyrroline 609 were obtained using 548d [>95% yield of (S)-2-phenylpyrrolidine 610, 88% ee]. PhosOx 553a also proved to be an effective catalyst and afforded 610 in comparable yield and ee. Ruthenium(II) catalysts gave similar results, but a rhodium(I) catalyst did not perform as well. Interestingly, the X-ray crystal structure of [Ir(548a)(cod)]BF4 was very similar to that determined for [Rh(548a)(cod)]BF4 (cod ¼ 1,5-cyclooctadiene).

Ph

N 609

0.5%[Ir(cod)Cl]2

acid

Ph2SiH2 Ligand

MeOH

Ph

N H 610

Ligand = 548, 553a Scheme 8.191

The same group also reported ruthenium-catalyzed asymmetric hydrosilylation of ketoximes (Scheme 8.192).478 With (E)-3,4-dihydro-1(2H)-naphthalenone oxime 611, the best results were obtained with PhosOx 548d to afford (R)-1-aminotetralin 612 in 65% yield and 83% ee. Addition of AgOTf was somewhat beneficial to improve both the selectivities and yields. Although the authors did not elaborate on the role of AgOTf, it presumably activates the catalyst by removing a chloride resulting in a more effective cationic species. N

OH

NH2

2% RuCl2L(cod)PPh3 2% AgOTf

acid

Ph2SiH2

MeOH

L = 548a, d

611

612 Scheme 8.192

Palladium-catalyzed enantioselective hydrosilylation of carbon–carbon double bonds is well known.479 Widenhoefer’s group recently extended this reaction to cyclization of functionalized 1,6-dienes. The PyrOx ligands were excellent ligands for this reaction, and comparative evaluations of ligand performance for the hydrosilylation-cyclization of dimethyl diallylmalonate 613 have been reported (Scheme 8.193).480,481 The trans-isomer of 614 is the preferred product and

504

2-Oxazolines

MeO2C

Et3SiH 5% precatalyst CH2Cl2 NaBARF

MeO2C

* Me

MeO2C

613

SiEt3

*

MeO2C

614 Precatalyst = PdCl(Me)(560) Scheme 8.193

diastereomeric excesses are usually >95%. The best enantioselectivity was obtained at 40
C using the PyrOx ligand 560j that gave the (R, R) isomer of 614 in 89% yield and 91% ee. A wide range of silanes and dienes can be used in this reaction with satisfactory results.481 Employing disiloxanes such as pentamethyldisiloxane (HSiMe2OTMS)482 or 1-tert-butyl-3,3-dimethyl-1,1-diphenyldisiloxane (HSiMe2OTBDPS)483 in place of triethylsilane permits facile incorporation of a silyl-protected alcohol into 614.

8.3.11.7. Michael Addition Reactions Asymmetric Michael additions have been reviewed by Tomioka and Nagaoka in 1999484 and Kanai and Shibasaki in 2000.485 Reasonable enantioselectivities were obtained using PhosOx and Sulfox ligands. Pfaltz and Escher recently examined the use of the binaphthyl-based phosphite-oxazoline ligands 615–618 (Fig. 8.25) for the addition of diethylzinc to cyclic enones 619.486 The results of the enantioselective Michael addition are shown in Table 8.41 (Scheme 8.194). These same ligands were also evaluated in the Michael addition of diethylzinc to (E)-4-phenyl3-buten-2-one 621 (Scheme 8.195). Ligand 615f (aS) gave the best results and afford the (S) enantiomer of 4-phenyl-2-hexanone 622 in 99% yield and 87% ee. Williams’ group observed low enantioselectivities for the Michael addition of a prochiral nucleophile, ethyl 2-cyanopropionate 623, to methyl vinyl ketone 624 catalyzed by chiral platinum complexes (Scheme 8.196).487 The NMR analysis indicated that these cationic Pt complexes act as Lewis acids toward nitriles. The Xray crystal structure as well NMR analysis showed that the solvent ligand that is readily displaced by an organic substrate is situated cis to the nitrogen donor in the Pt complex and, therefore, is in a ‘‘chiral pocket’’ created by the oxazoline ring.

8.3.11.8. Cyclopropanation Reactions Catalytic asymmetric cyclopropanations via carbene transfer to alkenes were reviewed by Singh and co-workers in 1997,488 Doyle and Protopopova in 1998,489 and mostly recently by Doyle in 2000.490 The reaction can be catalyzed by copper,491 rhodium,492 and other metals.493 Bis(oxazolines) are known to be among the most effective ligands for this cyclopropanation reaction (see Chapter 9).

Reactions and Applications

505

R O O P O

O O P O

O N

O N

t-Bu

R

t-Bu

615 616

a: R = H b: R = Me c: R = Ph d: R = 4-Ph-Ph e: R = 2,4,6-tri-Me-Ph f: R = 3,5-di-t-Bu-Ph

O O P O

O O P O

O N

O N

t-Bu

t-Bu

617

618

Figure 8.25. Binaphthyl-based phosphite-oxazoline ligands. TABLE 8.41. ASYMMETRIC MICHAEL ADDITIONS TO CYCLIC ENONESa

O

O Et2Zn

n

2.5% Cu(OTf) 2 –20 ˚C

619

* Et

n

620

Ligand = 615-618 (aS and aR isomers) Scheme 8.194 Entry

619 (n)

Best Ligand

% Yieldb

% ee

1 2 3 4

1 2 2 3

615d (aR) 618 (aR) 615b (aR) 616 (aS)

41 69 96 97

94 (R) 90 (R) 90 (R) 94 (NR)

a b

Data from Ref. 486. Not reported: NR.

506

2-Oxazolines O

Et

Et2Zn

Ph

2.5% Cu(OTf) 2 –20 ˚C

O

Ph *

621

622

Ligand = 615-618 (aS and aR isomers) Scheme 8.195

CN

O

1% mol PtL

+ CO2Et

Me 624

i-Pr2NEt 20 ˚C 56-88% yield

623

O CO2Et NC Me 625 16-25% ee

PtL = PtR(553a)(CH2Cl2)+ BF4 , R = Me, Ph Scheme 8.196

Mononuclear oxazolines have been less studied. Moderate enantioselectivities (up to 60%) were obtained using PyrOx as ligands for the copper(I)-catalyzed carbenetransfer reaction of ethyl diazoacetate to styrene.494,495 However, the diastereoselectivities (cis/trans) in these reactions were generally poor.

8.3.11.9. Miscellaneous Catalytic Reactions Mikami and co-workers reported the first examples of an asymmetric Fujiwara– Moritani reaction,496 which is generally catalyzed by chiral Pd(II) complexes (Scheme 8.197).497 Reaction of 1-cyano-1-cyclohexene 626 with benzene gave CN PhH

10% Pd(OAc) 2 10% Ligand

CN Ph

+ PhCO3t-Bu 100 ˚C 6-25%

627 (40-49%)

626

O Ligand =

R2 O

S

NH O

N R1

a: R1 = i-Pr; R2 = Tol b: R1 = i-Pr; R2 = CF3 c: R1 = t-Bu; R2 = CF3 d: R1 = i-Pr; R2 = C4F9 e: R1 = i-Pr; R2 = 3,5-di-CF3-Ph

628 Scheme 8.197

Reactions and Applications

507

(6R)-6-phenyl-1-cyano-1-cyclohexene 627. The optimum reaction conditions produced 627 in 25% yield and 44% ee using 628b as the ligand. Pfaltz and Lu¨cking reported that alkyne couplings can be catalyzed efficiently by palladium–PhosOx catalysts.498 High yields (up to 95%) were obtained for homocouplings of alkynes under solvent-free conditions. More interestingly, using an enantiomerically pure ligand effected kinetic resolution of racemic propargylic alcohols. For example, when ethyl 2-butynoate 629 was cross-coupled with a racemic propargyl alcohol 630 (2.2 equiv) in the presence of the PhosOx ligand 553k, the eneynol 631 was obtained in 46% yield and 53% ee (Scheme 8.198).

CO2Et

HO

CO2Et +

2% Pd(OAc) 2/553k

C6H13 629 (1 equiv.)

C6H13 * OH

46% yield

630 (2.2 equiv.)

631 (53% ee)

Scheme 8.198

Recently, Feng and co-workers reported an asymmetric sulfide oxidation499,500 catalyzed by titanium complexes bearing HydrOx ligands, for example, 576 (Scheme 8.199).501 Enantioselectivities approached a level of synthetic utility for oxidation of aryl alkyl sulfides 632 although the yields of the sulfoxide 633 were poor due to overoxidation to the sulfone 634. The overoxidation is especially significant for reactions with high enantioselectivity. O Ar

S 632

t-BuOOH

R

5% Ti(Oi-Pr)4 10% 576, 0 ˚C

Ar

S

O

*

R

633

+

O S

Ar

R

634

13–68% yield 0-96% ee Ar = Ph, 4-Br-Ph-, 4-Me-Ph-, py; R = Me, Et, Bn Scheme 8.199

8.3.12.

Polymeric Oxazolines

Oxazolines undergo polymerization upon exposure to a variety of cationic initiators such as strong Lewis acids or strong protic acids. Copolymerization between different oxazolines of defined composition can be carried out in a random manner or in a controlled fashion resulting in block polymers. Alternatively, oxazolines can also be grafted onto other types of polymers. It is beyond the scope of this chapter to review in detail this enormous and important subject. Instead, the

508

2-Oxazolines

reader is referred to several excellent reviews that deal with polymerization of oxazolines.502–508 Polymeric oxazolines have diverse industrial applications and are used as amphiphilic copolymer membranes, as ink-receptive layers for ink-jet recording sheets, and as molded castings for solid rocket fuel motors. Polymeric oxazolines can be found as fiber binders in polymer composite materials, as components of interpenetrating polymer networks, as thermoset and powder coating cross-linking agents, and as glass fiber coatings. In addition, polymeric oxazolines are precursors to multifunctional cyclophosphazenes used as novel photoinitiators, are chain extenders or blend compatibilizers to modify elongation, viscosity, and impact strength of polymer blends, and are precursors for hyperbranched polyether– polyamide dendrimers. Polymeric oxazolines have also been used as vehicles for controlled drug release509,510 and DNA transfection,511 as polymeric micelles, which serve as carriers for drug transport (e.g., paclitaxel),512 and as formulation additives for controlled-release of insecticides.513 8.3.13.

Miscellaneous Reactions

Achiral 2-stannyloxazolines are known to undergo Stille coupling with aromatic halides.9 However, Stille couplings with chiral 2-halooxazolines were not reported until Meyers and Novachek prepared the requisite 2-bromooxazoline 365 (see Scheme 8.116) and successfully coupled 365 with a variety of alkynyl and alkenylstannanes to afford chiral 2-substituted oxazolines 635 in reasonable yields (Scheme 8.200).329

O

O

RSnMe3

Br t-Bu

N

Pd(PPh3)4 40-72%

365

R t-Bu

N 635

Scheme 8.200

Molinski and Shafer reported a novel synthesis of 1,4-oxazinones 637 by SeO2promoted oxidative rearrangement of 2-alkyloxazolines 636 (Scheme 8.201).514 The best yields were obtained when R1 was H, t-Bu, or aryl (60–94%). The yield was low (33%) when R1 is i-Pr and no desired product was obtained when R1 ¼ Me. More interestingly, the stereochemical integrity of the oxazoline was preserved during the reaction. For R1 ¼ H, oxazinone 637 is a ‘‘chiral glycine’’ synthon and is useful for asymmetric synthesis of amino acids. The same group later corrected the mechanism proposed in the original paper. After careful kinetic and labeling studies, the authors proposed a mechanism involving rearrangement of intermediate 639 (Scheme 8.201).515

Reactions and Applications

R1

* R2

N

R2 *

SeO2

N

dioxane reflux

O

509

O

R1 O

SeO2

fast

636 R1 = H, t-Bu, Ph, naphthyl R2 = H, i-Pr, Ph

R2

N

LA

O

O

H2O

R1

R2

N

+

–H2O

LA R1

OO

O

–LA+

R2

LA R1

637

H

H 638

639

N O O

O

639a

Scheme 8.201

Ph N

S

R

Ph

O

O

O

Ph N

Heat CHCl3

R Ph

Ph

Ph

Ph

S

640

Ph

N Ph Ph

R Ph

S

Ph

641

642 O N

R Ph

Ph Ph

S

Ph

643 Scheme 8.202

In a special case, the spirocyclic oxazoline 640 was found to be unstable and undergoes rearrangement to the thietane N-acylimine 641 (Scheme 8.202).308,516 A zwitterionic intermediate 642 was proposed to account for the formation of 641. A biradical 643 is also a possible intermediate for this rearrangement. The C C bond in a 5-(alkylidene)oxazoline 644 is activated for electrophilic reactions similar to that in analogous vinyl acetates. Rohm & Haas researchers exploited this property to prepare chloromethyl ketone fungicides 646 (Scheme 8.203).517 The overall process constitutes an indirect chlorination of a-amido ketones since the 5-(vinylidene)oxazolines were prepared from a-amido ketones.

510

2-Oxazolines O Cl

N R3

R1

N

N

O

N

Cl

R1

O

N

Cl

R2

R3

O

O R 1

dilute HCl

R2

heat 58-88% overall

O

R3

R2

N H

Cl O

Cl 644

646

645

R1 = alkyl, aryl; R2, R3 = alkyl Scheme 8.203

NC

CO2Et

CN

N OEt 648

H 2N O

R

pathway a

O

O OEt

NC

647

N

N

HN

O

N

R

O

R

649 NC

H N HN O 647A

R

CO2Et OEt 648

EtO2C

pathway b

NC

H N N O

R

650

Scheme 8.204

In a series of papers, Jarry and co-workers demonstrated the utility of a 2aminooxazoline 647 (Fig. 8.26) to prepare bicyclic heterocycles. This oxazoline undergoes annulation reactions with bifunctional electrophiles to give triazinones or pyrimidinones. Selected examples are summarized in Table 8.42.518–522 The structures of many of the products were confirmed by X-ray crystallography. The ring nitrogen of 647 is known to be more nucleophilic, and thus the initial reaction occurs there normally. This finding is consistent with the product distributions seen for entries 1 and 3. However, acyclic products were also observed when ethoxycarbonyl isocyanate (entry 2) or ethyl 3-ethoxy-2-cyanoacrylate 648 (entries 4 and 6) were used as electrophiles. These acyclic products appear to result from initial reaction with the 2-amino group. Based on a semiempirical computational study, the authors proposed dual pathways for the reaction of 647 with 648 to explain the cyclized and acyclic products (Scheme 8.204).521 Thus, the cyclic product was proposed to arise from initial attack by the ring nitrogen (pathway a) whereas the azadiene arose from initial attack by the 2-amino group (pathway b).

511

647 (R)

Cl, alkoxy, aryloxy, 2
amino

t-BuO, ArO

MeO, PhO

Entry

1

2

3 Et3N, acetone, rt

EtO2CCl

CH2Cl2, 0 C to rt




EtO2CNCO

CHCl3, rt

EtO2CNCS

Eþ (Conditions)

647

O

N

HN

O

HN

O

R

N

None

O N 32–37%

N

O N 53–84% O

S

Cyclic Product

Figure 8.26

H2N

TABLE 8.42. REACTION OF 647 WITH BIFUNCTIONAL ELECTROPHILES

R

R

N

O

HN 68–71%

O

N

17–23% EtO2C

EtO2CHN

None

O

H N

R

Acyclic Product

R

520

519

518

Reference

512

6

2 amino




t-Bu, 2
amino

PhO

4

5

647 (R)

Entry

TABLE 8.42 (Continued)

NC OEt

CO2Et

OEt

CO2Et

OEt

CO2Et

648

648

EtO2C

NC

Eþ (Conditions)

NC

EtO2C

NC N O

N O 43–49%

N

O

O N 65–82%

N

46% O

N

O

Cyclic Product

R

R

R

NC

EtO2C

NC

EtO2C

O

H N

O

37–39%

N

None

41%

N

H N

Acyclic Product

R

R

522

522

521

References

References

513

8.4. SUMMARY 2-Oxazolines continue to find numerous applications in organic synthesis. Since the last review by Meyers in 1994, new reagents have been introduced and new methods for their preparation have been uncovered. The popularity of this ring system in organic synthesis has grown due to the well-understood chemical behavior. The use of oxazolines in directed metalation reactions to construct complex molecules or as protecting groups is ubiquitous throughout the literature. Chiral oxazolines, readily accessible from a large pool of chiral amino alcohols, have been widely employed as auxiliaries in asymmetric syntheses. For example, an important extension in the area of aromatic substitution of aryloxazolines is the development of symmetrical, unsymmetrical and axially chiral biaryl synthesis. Similarly, oxazoline-directed nucleophilic additions to naphthalenes as a synthetic method for the preparation of dihydronaphthalenes have also expanded to include asymmetric versions with excellent stereochemical controls. Another significant development in oxazoline chemistry is the application of oxazoline-containing ligands for asymmetric catalysis, such as palladium-catalyzed allylic substitutions, Heck reactions, hydrogenations, dialkylzinc additions to aldehydes, and Michael reactions. The discovery of diastereoselective metalation of chiral ferrocenyloxazolines has further expanded the availability of chiral ligands for metal-catalytic reactions. Other applications of oxazolines have also been discovered. Anomeric oxazolines have now emerged as useful glycosyl acceptors in the glycosylation of sugars. 2-Alkenyloxazolines have been found to undergo asymmetric Michael addition and hetero-Diels–Alder reactions. Further explorations in these areas of oxazoline chemistry will undoubtedly continue and the list of new applications will grow.

Acknowledgments The authors thank Synthetic Chemistry, Schering-Plough Research Institute for support without which this endeavor would not have been possible.

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450. Yonehara, K.; Mori, K.; Hashizume, T.; Chung, K.-G.; Ohe, K.; Uemura, S. J. Organomet. Chem. 2000, 603, 40–49. 451. Wu, X.-Y.; Xu, H.-D.; Zhou, Q.-L.; Chan, A. S. C. Tetrahedron: Asymmetry 2000, 11, 1255–1257. 452. Ohkuma, T.; Kitamura, M.; Noyori, R. In Ojima, I., Ed., Catalytic Asymmetric Synthesis (Second ed.), Wiley-VCH, New York, 2000, pp. 1–110. 453. Brown, J. M. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 121–182. 454. Halterman, R. L. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 183–195. 455. Ohkuma, T.; Noyori, R. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds. Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 199–246. 456. Blaser, H.-U.; Spindler, F. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 247–265. 457. Hou, D.-R.; Reibenspies, J.; Colacot, T. J.; Burgess, K. Chem. Eur. J. 2001, 7, 5391–5400. 458. Blankenstein, J.; Pfaltz, A. Angew Chem., Int. Ed. Engl. 2001, 40, 4445–4447. 459. Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess, K. J. Am. Chem. Soc. 2001, 123, 8878–8879. 460. Kainz, S.; Brinkmann, A.; Leitner, W.; Pfaltz, A. J. Am. Chem. Soc. 1999, 121, 6421–6429. 461. Braunstein, P.; Graiff, C.; Naud, F.; Pfaltz, A.; Tiripicchio, A. Inorg. Chem. 2000, 39, 4468–4475. 462. Arikawa, Y.; Ueoka, M.; Matoba, K.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Organomet. Chem. 1999, 572, 163–168. 463. Meerwein, H.; Schmidt, R. Ann. Chim. 1925, 444, 221–238. 464. Ponndorf, W. Angew. Chem. 1926, 39, 138–143. 465. Verley, A. Bull. Chem. Soc. Chim. Fr. 1925, 37, 537–542. 466. Verley, A. Bull. Chem. Soc. Chim. Fr. 1925, 37, 871–874. 467. Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organometallics 1999, 18, 2291–2293. 468. Soai, K.; Shibata, T. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds. Comprehensive Asymmetric Catalysis II, Springer, Berlin, 1999, pp. 911–922. 469. For a review on asymmetric arylation reactions, see Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. Engl. 2001, 40, 3284–3308. 470. Bolm, C.; Mun˜iz, K. Chem. Commun. 1999, 1295–1296. 471. Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew. Chem., Int. Ed. Engl. 2000, 39, 3465– 3467. 472. Bolm, C.; Mun˜iz, K.; Hildebrand, J. P. Org. Lett. 1999, 1, 491–493. 473. Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402–411. 474. Kagan, H. B.; Luukas, T. O. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 101–118. 475. Nishiyama, H.; Itoh, K. In Ojima, I., Ed., Catalytic Asymmetric Synthesis (Second ed.), Wiley-VCH, New York, 2000, pp. 111–143. 476. Nishiyama, H. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds. Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 267–287. 477. Takei, I.; Nishibayashi, Y.; Arikawa, Y.; Uemura, S.; Hidai, M. Organometallics 1999, 18, 2271– 2274. 478. Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura, S.; Hidai, M. Chem. Commun. 2001, 2360– 2361. 479. Hayashi, T. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis I, Springer, Berlin, 1999, pp. 319–333. 480. Perch, N. S.; Widenhoefer, R. A. J. Am. Chem. Soc. 1999, 121, 6960–6961.

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481. Perch, N. S.; Pei, T.; Widenhoefer, R. A. J. Org. Chem. 2000, 65, 3836–3845. 482. Pei, T.; Widenhoefer, R. A. Org. Lett. 2000, 2, 1469–1471. 483. Pei, T.; Widenhoefer, R. A. Tetrahedron Lett. 2000, 41, 7597–7600. 484. Tomioka, K.; Nagaoka, Y. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis III, Springer, Berlin, 1999, pp. 1105–1120. 485. Kanai, M.; Shibasaki, M. In Ojima, I., Ed., Catalytic Asymmetric Synthesis (Second ed.), WileyVCH, New York, 2000, pp. 569–592. 486. Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879–2888. 487. Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Williams, J. M. J. Organometallics 1999, 18, 2867–2873. 488. Singh, V. K.; DattaGupta, A.; Sekar, G. Synthesis 1997, 137–149. 489. Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919–7946. 490. Doyle, M. P. In Ojima, I., Ed., Catalytic Asymmetric Synthesis (Second ed.), Wiley-VCH, New York, 2000, pp. 191–228. 491. Pfaltz, A. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis II, Springer, Berlin, 1999, pp. 513–538. 492. Lydon, K. M.; McKervey, M. A. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis II, Springer, Berlin, 1999, pp. 539–580. 493. Charett, A. B.; Lebel, H. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis II, Springer, Berlin, 1999, pp. 581–603. 494. Wu, X.-Y.; Shen, Y.-Y.; Ma, B.; Zhou, Q.-L.; Chan, A. S. C. J. Mol. Catal. A: Chem. 2000, 157, 59–63. 495. Chelucci, G.; Sanna, M. G.; Gladiali, S. Tetrahedron 2000, 56, 2889–2893. 496. Moritani, I.; Fujiwara, Y. Synthesis 1973, 524–533. 497. Mikami, K.; Hatano, M.; Terada, M. Chem. Lett. 1999, 55–56. 498. Lu¨cking, U.; Pfaltz, A. Synlett 2000, 1261–1264. 499. Kagan, H. B. In Ojima, I., Ed., Catalytic Asymmetric Synthesis (Second ed.), Wiley-VCH, New York, 2000, pp. 327–356. 500. Bolm, C.; Mun˜iz, K.; Hildebrand, J. P. In Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis II, Springer, Berlin, 1999, pp. 697–710. 501. Peng, Y. G.; Feng, X. M.; Cui, X.; Jiang, Y. Z.; Chan, A. S. C. Synth. Commun. 2001, 31, 2287– 2296. 502. Aoi, K.; Okada, M. Prog. Polym. Sci. 1996, 21, 151–208. 503. Tsubokawa, N.; Yoshikawa, S. Recent Res. Devel. In Polymer Science, 1998, 2, 211–228. 504. Fujiki, K. Recent Res. Devel. In Polymer Science, 1999, 3, 439–456. 505. Gleria, M.; De Jaeger, R. J. Inorg. Organomet. Polymers 2001, 11, 1–45. 506. Bo¨hme, F.; Clausnitzer, C.; Gruber, F.; Grutke, S.; Huber, T.; Po¨tschke, P.; Voit, B. High Perform. Polym. 2001, 13, S21–S31. 507. Frank, C. W.; Naumann, C. A.; Knoll, W.; Brooks, C. F.; Fuller, G. G. Macromol. Symp. 2001, 166, 1–12. 508. Kobayashi, S.; Uyama, H. J. Polym. Sci., Part A: Polym. Chem. 2001, 40, 192–209. 509. Tarvainen, T.; Karjalainen, T.; Malin, M.; Pohjolainen, S.; Tuominen, J.; Seppala, J.; Jarvinen, K. J. Controlled Release, 2002, 81, 251–261. 510. Tarvainen, T.; Karjalainen, T.; Malin, M.; Perakorpi, K.; Tuominen, J.; Seppala, J.; Jarvinen, K. Eur. J. Pharm. Sci. 2002, 16, 323–331. 511. Jeong, J. H.; Song, S. H.; Lim, D. W.; Lee, H.; Park, T. G. J. Controlled Release, 2001, 73, 391– 399.

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512. Lee, S. C.; Kwon, I. C.; Chung, H.; Kim, C.; Jeong, S. Y. Proceedings—28th International Symposium on Controlled Release of Bioactive Materials and 4th Consumer & Diversified Products Conference, 2001, 1, 584–585. 513. Kamihara, H.; Kosuge, Y. Jpn. Kokai Tokkyo Koho, JP 2000319105, 2000; Chem. Abstr. 2000, 133, 360027. 514. Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61, 2044–2050. 515. Shafer, C. M.; Morse, D. I.; Molinski, T. F. Tetrahedron 1996, 52, 14475–14486. 516. L’abbe´, G.; Francis, A.; Dehaen, W.; Toppet, S. Chem. Commun. 1995, 67–68. 517. Roemmele, R. C.; Rayle, H. L. Eur. Pat. Appl. EP 879819, 1998; Chem. Abstr. 1998, 130, 13987. 518. Jarry, C.; Forfar, I.; Thomas, J.; Leger, J. M.; Laguerre, M. Heterocycles 1993, 36, 2465–2473. 519. Adetchessi, O.; Desor, D.; Forfar, I.; Jarry, C. J. Heterocycl. Chem. 1997, 34, 429–434. 520. Forfar, I.; Bosc, J. J.; Leger, J. M.; Jarry, C. Pharm. Pharmacol. Commun. 1998, 4, 9–12. 521. Chaimbault, C.; Bosc, J. J.; Leger, J. M.; Jarry, C.; Marchand-Geneste, N.; Carpy, A. J. Mol. Struct. 1999, 508, 193–205. 522. Chaimbault, C.; Bosc, J. J.; Jarry, C.; Daulouede, S.; Vincendeau, P. Pharm. Pharmacol. Commun. 2000, 6, 101–105.

CHAPTER 9

Chiral Bis(oxazolines) Arun K. Ghosh Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois

Geoff Bilcer Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois

Steve Fidanze Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois

9.1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Bis(oxazoline) Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Bis(oxazoline)-Metal Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.1. Geometry of Ligand–Metal Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.2. X-ray Crystal Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4. Synthesis of Bis(oxazoline) Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5. Carbon–Carbon Bond-Forming Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.1. Cyclopropanation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.1.1. Styrene and Ethyl Diazoacetate . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.1.2. Styrene and Other Diazoacetates . . . . . . . . . . . . . . . . . . . . . . . . 9.5.1.3. Miscellaneous Cyclopropanations . . . . . . . . . . . . . . . . . . . . . . . 9.5.2. Diels–Alder Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.2.1. Cyclopentadiene and 3-Acryloyl-1,3-oxazolidin-2-one . . . . . . . . . 9.5.2.2. Various Dienes and Dienophiles . . . . . . . . . . . . . . . . . . . . . . . . 9.5.2.3. Bis(oxazoline)-Mediated Diels–Alder Reactions in Total Synthesis 9.5.3. Hetero-Diels–Alder and Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.4. 1,3-Dipolar Cycloadditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.5. Allylic Substitutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.6. Mukiayama Aldol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.7. Conjugate Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.7.1. Free Radical Conjugate Addition . . . . . . . . . . . . . . . . . . . . . . . . 9.5.7.2. Michael Addition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

529

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. . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

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530 530 532 532 533 534 538 538 538 541 541 545 546 551 552 554 561 562 565 567 567 567

530

Chiral Bis(oxazolines)

9.5.8. Allylation and Cyanohydrin Formation . . . . . . . . . . . . . 9.5.9. Alkylation of Imines and Oximes . . . . . . . . . . . . . . . . . 9.5.10. Asymmetric Polymerization . . . . . . . . . . . . . . . . . . . . . 9.5.11. Miscellaneous Carbon–Carbon Bond-Forming Reactions . 9.6. Aziridination and Epoxidation . . . . . . . . . . . . . . . . . . . . . . . . . 9.7. Sulfimidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.8. Allylic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.9. Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.9.1. Hydrosilylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.9.2. Transfer Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . 9.10. Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.12. Addendum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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569 570 572 573 575 576 577 577 577 579 580 582 585 590

9.1. INTRODUCTION As we have seen in the preceding chapters, oxazoles, and oxazolines come in many different forms and have shown numerous useful applications. In this chapter, we will discuss the chiral C 2-symmetric bis(oxazoline). This category of oxazolines has become a powerful tool in the realm of synthetic organic chemistry. The past several decades have seen impressive advances in synthetic medicinal agents for treatment of complex human diseases. Such progress has been fueled by the discovery and development of asymmetric processes since many therapeutic agents often possess multiple asymmetric centers. It is now regulation that these agents be prepared in an enantiomerically pure form. Thus, there has been a major emphasis on the synthesis of organic molecules having defined stereochemistry with a certain degree of predictability. The introduction of chiral C 2-symmetric bis(oxazoline) ligands in asymmetric synthesis has greatly enhanced this skill and led to many improvements in a variety of asymmetric organic transformations.

9.2. BIS(OXAZOLINE) LIGANDS In 1989, the first bis(oxazoline) ligands were introduced by Nishiyama and coworkers.1–2 These bis(oxazolinylpyridines), also called ‘‘py-box’’ ligands 1 were originally used for the enantioselective hydrosilylation of ketones (Fig. 9.1). The bis(oxazoline) ligand bu-box 2 was introduced the following year by Masamune.3 The effectiveness of this ligand was demonstrated in the cyclopropanation reaction of styrene with ethyl diazoacetate. Subsequently, 1991 led to several additions to the library of available bis(oxazoline) ligands. Some of these ligands include those introduced by Evans4 3 and Masamune5 4, 5 that were utilized in cyclopropanation reactions. Corey6 investigated Diels–Alder reactions using the phe-box ligand 6, while ligand 7, introduced by Helmchen,7 was employed in hydrosilylation and transfer hydrogenation reactions. The remainder of the decade

Bis(oxazoline) Ligands

O

O O

O

N

531

O

O

N

N

N

R

R 1a 1b 1c 1d

R = Ph R = i-Pr R = t-Bu R = i-Bu

3

2

O O

O Ph

N

O N

Ph

N

Ph

Ph 5

6 R

O

O

N

N

O

N

N

R

R

O N

N

O

7a R = Ph 7b R = i-Pr 7c R = t-Bu

8

9a R = H 9b R = Me O

O

O Ph

Fe

Ph

N

N

N PPh2 PPh2 N

O R

O N

R

11a R = i-Pr 11b R = t-Bu

12a R = Ph 12b R = i-Pr 12c R = t-Bu

O R

N

N

O

R O

N

R

O 10

O

O

R

Ph

Ph

N

N

4

O

O

O

N

Ph

Ph

R

N

N

N

O N

N

O Ph

Ph 13a R = Ph 13b R = i-Pr 13c R = t-Bu Figure 9.1. Bis(oxazoline) ligands.

14

532

Chiral Bis(oxazolines)

saw the introduction of additional ligands by Corey8 8 (cyclopropanation), Ghosh9 and Davies10 9 (Diels–Alder), Desimoni11 10 (Diels–Alder), Ikeda12 11 (allylic substitution), Andersson13 12 (cyclopropanation), Hayashi14 13 (cyclopropanation), and Curran15 14 (Diels–Alder). This small sampling of bis(oxazoline) ligands and their related reactions demonstrates the power and versatility of this type of ligand in organic synthesis.

9.3. BIS(OXAZOLINE)-METAL COMPLEXES Bis(oxazoline) ligands are generally used in conjunction with a metal cation that is coordinated by the nitrogen atoms of the ligand. The geometry of this complex controls the stereoselectivities observed in the various reactions involving them. Bis(oxazoline)–metal complexes exhibit a number of notable features. These include (1) the presence of a C2-symmetric axis that reduces the number of possible transition states, (2) a metal complex that is conformationally constrained, and (3) a metal center in close proximity to the ligand donor that imposes a strong steric bias on the metal center. 9.3.1.

Geometry of Ligand–Metal Complexes

Many different ligand–metal complexes have been used as catalysts for a variety of organic transformations.16 These complexes are formed in situ by stirring the bis(oxazoline) ligand with various metal salts [CuOTf, Cu(OTf)2, Ni(ClO4)26H2O, MgI2, etc.]. Some of the most commonly used metals are copper, magnesium, and ruthenium. It has been proposed by Corey and Ishihara that the magnesium(II) complex of the phe-box ligand 15 adopts a tetrahedral geometry around the metal.17 In contrast, Evans and co-workers have speculated that the copper(II) complex of the bu-box ligand 16 adopts a square-planar geometry about the metal center, as shown in Figure 9.2.4 The difference between these two conformations, tetrahedral

O

O N Ph

Mg I

O

O N

N Ph

I

15 tetrahedral

N Cu TfO OTf

16 square planar

O

O N

N Ru

Ph

C6H6 L

Ph

17a L = OH2 17b L = NH3 17c L = NH2Me 17d L = NH2Bu tetrahedral

Figure 9.2. Bis(oxazoline)–metal complexes.

Bis(oxazoline)-Metal Complexes

533

and square planar, leads to reversal of enantioselectivity, particularly in the Diels– Alder reaction.4,17 One of the most studied ligand–metal complexes is the bis(oxazoline)–ruthenium(II) complex.18–23 Kurasowa and co-workers proposed that the aqua and amine complexes of bis(oxazoline)–ruthenium(II) 17a–d also adopt a tetrahedral geometry about the metal center.21,22 These are only a few of many examples of the complexes formed between a variety of transition metals and bis(oxazoline) ligands that have been studied.16 9.3.2.

X-ray Crystal Structure

Various X-ray crystal structures of metal–ligand complexes provided evidence of the geometry of the complexes in the solid state, even though the structure of these complexes may differ in solution. The first crystal structure of a bis(oxazoline)– metal complex was determined in 1994 by Brown and co-workers.24 This group crystallized and elucidated the structure of N,N-bis-[2-((4S)-(methyl)-1,3-oxazolinyl)]methane-bi(Z2ethene)rhodium(I), 18a, as depicted in Figure 9.3. The key features of this crystal structure include the C 2-axis of symmetry, the axial positions of the methyl groups and the orientation of the ethene molecules, orthogonal to the complexation square plane. In 1995, Woodward and co-workers were able to crystallize and determine the structure of benzylbis(oxazoline) with ruthenium

H

PhCH2 O

O N

Rh

Cl Ru

N

Cl

Me

Me

O

O H

N N O

N

H O

PhCH2

18a

H Cl Co H Cl

N

H

18c

18b O Ph O

W N H

Ni

R O

W O

N W H Ph 18d

O

Cl N H Ti Cl N H Cl R

W = H2O

R = Ph, i-Pr, i-Bu, t-Bu

18e

Figure 9.3. Bis(oxazoline)–metal crystal structures (two-dimensional representation).

534

Chiral Bis(oxazolines)

and cyclooctadiene 18b.20 Ghosh and co-workers determined the structure of indabox 9a with cobalt 18c.16 Kanemasa and Curran resolved the cationic aqua complex of DBF-box 18d.15 A number of structures of titanium–bis(oxazoline) complexes 18e have been determined by Singh through various spectroscopic techniques.23 Other ligand–metal complexes whose crystal structures have been determined include the complex of i-pr-box with tungsten tetracarbonyl,20 Corey’s phe-box ligand complexed to ruthenium,19,21,22 along with several Nishiyama-type py-box ligands coordinated to palladium25,26 and molybdenum.27

9.4. SYNTHESIS OF BIS(OXAZOLINE) LIGANDS Optically active natural and unnatural amino acids as well as various cyclic amino alcohols have been utilized in the synthesis of a wide variety of bis(oxazoline) ligands. As previously mentioned, the first bis(oxazoline) ligands, py-box 1a–d, were synthesized by Nishiyama and co-workers in 1989.1,2 The common material for their syntheses was pyridine 2,6-dicarboxylic acid 19. Conversion of 19 to the acid chloride was achieved by treatment with thionyl chloride, as illustrated in Figure 9.4. This was followed by condensation with (S)-valinol in the presence of triethylamine. Conversion of the resulting bis(amidodiol) 20 to py-box-ip 1b was achieved by sequential treatment of 20 with thionyl chloride at 50
C followed by cyclization with aqueous sodium hydroxide in methanol to afford py-box-ip 1b in 60% overall yield. The same synthetic scheme can be used to obtain the other

1. SOCl2, reflux, 10 h

HO

N O

H N

2. (S)-valinol, Et3N

OH O

N O

HO

H N O

19

OH

20 1. SOCl2, 50 ˚C, 2 h 2. NaOH, MeOH-H2O

O

O

N N

O N

N

O

N N

R

R 1a R = Ph 1c R = t-Bu 1d R = i-Bu

1b 60% overall Figure 9.4. Synthesis of py-box-ip ligand 1b.

Synthesis of Bis(oxazoline) Ligands

535

1. CH2(CO2Et)2, 80-100 ˚C 2. SOCl2, 50-80 ˚C 3. NaOH, EtOH, THF, 70-80 ˚C

O

O NH2

HO

N

N

NH

21

EtO

NH

22

OEt

Figure 9.5. Synthesis of i-pr-box ligand 22.

isomer and the ligands containing different functionalities on the bis(oxazolines) (structures 1a, 1c, and 1d) by altering the amino alcohol used. Masamune and co-workers reported that i-pr-box 22 can also be obtained from (S)-valinol by a similar strategy (see above).3 Thus, 21 was reacted with diethylmalonate and the resulting diamide was treated with thionyl chloride followed by sodium hydroxide in a mixture of ethanol and tetrahydrofuran (THF) to yield i-prbox 22 (Fig. 9.5). The synthesis of i-pr-box 22 can also be achieved directly by treatment of 21 with diethyl iminomalonate in the presence of triethylamine.5 Evans and co-workers synthesized bu-box 3 starting from commercially available (S)-tert-leucine.4 Lithium aluminum hydride reduction of (S)-tert-leucine afforded the amino alcohol 23 which, as shown in Figure 9.6, was acylated with dimethylmalonyl dichloride 24 to provide the corresponding bis(amidodiol) 25 in O

NH2

HO

O

+ Cl

23

O Cl

Et3N

HO

O

N H

N H

24

OH

25 88% TosCl, Et 3N, DMAP, 82%

PPh3, Et3N, CCl4, ∆, 62%

O

O N

N

3 Figure 9.6. Synthesis of bu-box ligand 3.

536

Chiral Bis(oxazolines)

88% yield. Cyclization was achieved by treatment with triphenylphosphine and triethylamine in carbon tetrachloride followed by heating to yield bu-box 3 in 62% yield. In 1998, Evans published an improved synthesis of bu-box 3 starting from the same amino acid.28 The updated synthesis began with sodium borohydride–iodine reduction to afford amino alcohol 23 followed again by treatment with dimethylmalonyl dichloride 24 to afford 25 in 88% yield (from 23). Cyclization was achieved by treatment of 25 with toluenesulfonyl chloride and triethylamine in the presence of a catalytic amount of dimethylaminopyridine to afford bu-box 3 in 82% yield (Fig. 9.6). Corey and Ishihara’s synthesis of phe-box ligand 29 began with the trifluoroacetyl derivative of (S)-phenylglycine 26. Treatment of 26 with methylmagnesium iodide, as shown in Figure 9.7, followed by potassium hydroxide in methanol afforded amino alcohol 27 in 88% yield (2 steps).17 This was then acylated with dimethylmalonyl dichloride 24 and triethylamine followed by cyclization using methanesulfonic acid at reflux to afford phe-box ligand 29 in 78% yield. Two other synthetic approaches to ring closure can be illustrated with Masamune’s protocol3 for the construction of ligand 31 and Desimoni’s protocol11 for the construction of the structurally related ligand 10 (Fig. 9.8). Thus, starting from bisamide 30, Masamune and co-workers effected ring closure through treatment with dichlorodibutylstannane in refluxing xylene to afford bis(oxazoline) 31. Desimoni’s protocol called for treatment of 30 first with methanesulfonyl chloride and triethylamine in dichloromethane followed by heating with aqueous sodium hydroxide in ethanol. This yielded the isomeric bis(oxazoline) 10. H N

MeO2C

CF3 O

NH2

HO 1. MeMgI, 90% 2. KOH, 98%

26

27 Et3N, O O Cl

Cl 24

O

O N

N Ph

Ph 29

MsOH, ∆, 78%

O

O

N OH H

N H HO 28 98%

Figure 9.7. Synthesis of phe-box ligand 29.

Synthesis of Bis(oxazoline) Ligands O OH

O

OH

NH HN

Ph Ph

537

Ph Ph

30 Bu2SnCl2 xylene, ∆

1. MsCl, Et3N 2. NaOH, EtOH-H2O

O

O Ph

N

N

Ph

Ph

Ph

O

O Ph

N

Ph

N Ph

Ph

31

10

Figure 9.8. Synthesis of tetraphenyl bis(oxazoline) ligands 31 and 10.

The constrained bis(oxazolines) 9a and 9b can be constructed beginning with malononitrile 32 as shown by Ghosh and co-workers.9 Thus, treatment of 32 with anhydrous hydrochloric acid in dioxane, as shown by Lehn and co-workers,29 yielded imidate salt 33 (Fig. 9.9). Condensation of the imidate salt with commercially available (1S,2R)-1-aminoindan-2-ol afforded the conformationally constrained bis(oxazoline) inda-box 9a. Alkylation at the bridging methylene of 9a was carried out by Davies and co-workers.30 Treatment of 9a with lithium diisopropylamide followed by alkylation with methyl iodide afforded 9b. Alternatively, alkylation with diiodoalkanes incorporated ring systems at the bridging position (structures 34a–d).

NC

CN

anhyd. HCl, EtOH, dioxane

HCl•H2N

NH•HCl

EtO

OEt

32

33 (1S,2R)-1-aminoindan-2-ol DMF

R R

N

N

9b R = Me 34a-d R = (CH2)n, n = 2-5

O

O

O

O

LDA, THF, MeI or I(CH2)nI

N

N

9a

Figure 9.9. Synthesis of inda-box ligands 9a,b and 34a–d.

538

Chiral Bis(oxazolines)

9.5. CARBON–CARBON BOND-FORMING REACTIONS Chiral C 2-symmetric bis(oxazoline) ligands have become very important in organic synthesis since their introduction in 1989. They have allowed chemists control over the stereochemical outcome of many different types of reactions. Their utility in many carbon–carbon bond forming reactions is especially well documented. 9.5.1.

Cyclopropanation

One of the many carbon–carbon bond-forming reactions that have been studied using the chiral C2-symmetric bis(oxazoline) ligands is the cyclopropanation reaction. This reaction has been extensively studied by many independent research groups.

9.5.1.1. Stryene and Ethyl Diazoacetate Of the cyclopropanation reactions studied, the reaction between styrene and ethyl diazoacetate has become the benchmark for determining the utility of a bis(oxazoline) ligand in cyclopropanations. In 1990, Masamune and co-workers introduced several bis(oxazoline) ligands including 2 and 35–40 as catalysts for the cyclopropanation of styrene with ethyl diazoacetate.3 The reactive species in these reactions were determined to be the bis(oxazoline) dimers of type 2a and 38a–40a, as shown in Figure 9.10. This complex was generated by treatment of ligand 2, for example, with n-butyllithium followed by addition of 0.5 equiv of copper(II) chloride. This species was purified by column chromatography and used in 1 mol % (relative to ethyl diazoacetate) in the reaction between styrene (3 equiv) and ethyl diazoacetate (1 equiv). The results of these experiments are summarized in Table 9.1 (Fig. 9.11). As can be seen from these results, the yields range from 72–88%, the trans/cis ratios are all approximately equal (70:30), but the enantioselectivities for the isomers

O

O R1

N R

N R

O

O

RR

O

R1

N

N

N Cu

R

R

N

N 35 R = Me, R1 = Ph 36 R = CH2OH, R1 = H 37 R = Et, R1 = H

2 R = t-Bu 38 R = i-Pr 39 R = Ph 40 R = Bn

O N

O

RR 2a, 38a-40a

Figure 9.10. Masamune’s bis(oxazoline)-Cu(II) complexes.

O

Carbon–Carbon Bond-Forming Reactions

539

TABLE 9.1. MASAMUNE’S Cu(II)-BIS(OXAZOLINE)-CATALYZED CYCLOPROPANATIONa 2a, 35a-40a, (CH2Cl)2, rt

O + N 2 41

CO2Et

OEt

+

CO2Et

43

42

44

Figure 9.11 Ligand

Isolated % Yield

trans/cis (43:44)

trans (43) ee (config)

35a 36a 37a 38a 39a 40a 2a

78 88 78 72 76 81 80

71:29 75:25 72:28 71:29 71:29 70:30 75:25

28% (1S,2S) 48% (1S,2S) 19% (1S,2S) 46% (1R,2R) 36% (1R,2R) 60% (1R,2R) 90% (1R,2R)

a

cis (44) ee (config) 30% 36% 31% 31% 15% 52% 77%

(1S,2R) (1S,2R) (1S,2R) (1R,2S) (1R,2S) (1R,2S) (1R,2S)

Data from Ref. 3.

are best with the complex derived from the bulky bu-box ligand 2a (ee ¼ 90% for the trans isomer and 77% for the cis). In 1991, Evans and co-workers employed CuOTf-derived complexes of bis(oxazoline) ligands 2, 3, 7b, 38, and 45 in the same cyclopropanation reaction of TABLE 9.2. EVAN’S Cu(I)-BIS(OXAZOLINE)-CATALYZED CYCLOPROPANATION

O + N 2

41

CuOTf

OEt

+

ligand

CO2Et 43

42

CO2Et 44

O

O N

N

45 Figure 9.12 Ligand 2 3 7b 38 45 a

Data from Ref. 4.

trans/cis (43:44) 77:23 73:27 66:34 64:36 69:31

trans (43) ee (config) 98% (1R,2R) 99% (1R,2R) 3% (1R,2R) 64% (1R,2R) 49% (1R,2R)

cis(44) ee (config) 93% (1R,2S) 97% (1R,2S) 8% (1R,2S) 48% (1R,2S) 45% (1R,2S)

540

Chiral Bis(oxazolines)

styrene and ethyl diazoacetate.4 The active catalyst was prepared by mixing bis(oxazoline) and CuOTf in a 1:1 ratio. It has been shown that the bulky bu-box ligands 2 and 3 provided the best selectivities, for both trans/cis ratio and enantioselectivity (Table 9.2). Evans ligand 3 containing the geminal methyl groups exhibited a slight improvement in enantioselectivities over Masamune’s bu-box 2. These results show that the presence of a six- rather than five-membered metal chelating species (3 vs. 7b), the presence of geminal methyl groups to prevent enolization (3 vs. 2) and the bulky tert-butyl groups (3 vs. 45) are optimal for cyclopropanation using this type of bis(oxazoline) ligand (Fig. 9.12). Other types of bis(oxazoline) ligands have been tested using the reaction of styrene and ethyl diazoacetate. Of note is Nishiyama’s py-box-ip ligand 1b, which was used in 2 mol% and with [Ru(II)Cl2(p-cymene)]2 as a metal source.31,32 The best result from these conditions was a yield of 73%, trans/cis ratio of 91:9 with a trans enantiomeric excess (ee) of 89% and a cis ee of 79%, as shown in Figure 9.13. The selectivity observed in Nishiyama’s reaction can be explained by the following model, shown in Figure 9.14.31,32 This model shows the ligand–metal–substrate

O + N2

41

1b (2 mol%)

+ OEt

[RuCl2(p-cymene)]2 (1 mol%) 73%

CO2Et

42

CO2Et

43 89% ee

44 79% ee

Figure 9.13. Nishiyama’s Ru(II)-py-box-ip catalyzed cyclopropanation.

re-face attack Ph

O N Cl N

H

Ru Cl

CO2Et

N O

46

favored

CO2Et 43

CO2Et 44

Figure 9.14. Transition state for cyclopropanation using Ru(II)-py-box-ip.

Carbon–Carbon Bond-Forming Reactions

541

complex of py-box-ip 1b with ruthenium(II) chloride and diazoacetate. The orientation of the styrene attacking from the re-face is controlled by the isopropyl substituent on the ligand favoring the formation of product 43 containing the trans(1R,2R) stereochemistry. Table 9.3 contains a sampling of various other bis(oxazoline) ligands that have been used in the cyclopropanation reaction of styrene with ethyl diazoacetate (Table 9.3, Fig. 9.15).33–40

9.5.1.2. Styrene and Other Diazoacetates Many ligands have also been evaluated with other alkyl diazoacetates. Of note are the sterically demanding diazoacetate esters, such as tert-butyl and menthyl diazoacetates (Table 9.4, Fig. 9.16). Masamune and co-workers examined bu-box ligand 2a using styrene with both l-()-menthyl and d-(þ)-menthyl diazoacetates.3 It has been shown that the use of these sterically more demanding diazoacetates led to higher selectivities for both trans/cis isomers and enantioselectivities (trans/ cis ¼ 86:14; trans ¼ 98% ee; cis ¼ 96% ee for l-()-menthyl diazoacetate). Evans4 and Nishiyama31 investigated their ligands, 3 and 1b, respectively, with tert-butyl diazoacetate. Evans reported a yield of 75%, trans/cis ratio of 81:19, trans ee of 96% and cis ee of 93%. Nishiyama’s py-box-ip ligand 1b exhibited similar results (trans/cis ¼ 97:3; trans ¼ 94% ee; cis ¼ 85% ee).

9.5.1.3. Miscellaneous Cyclopropanations Cyclopropanations using bis(oxazoline) catalysts are not limited to reactions of styrene; many different types of olefins can be used in cyclopropanations. The work of Masamune and co-workers included an example using 2,3,3-trimethylbutene with his bu-box complex 2a and l-()-menthyl diazoacetate.3,5 The product was obtained in 60% yield, trans/cis ratio of 95:5, trans ee of 80% and cis ee of 91%. Silyl enol ethers can also be used in the cyclopropanation reaction. Reissig showed that the reaction between methyl diazoacetate 53 and various enol ethers 52a–c using bu-box ligand 3 proceeded in moderate yields, as shown in Table 9.5 (Fig. 9.17a), with trans/cis ratios up to 97:3 and ee between 32 and 49%.35 Pfaltz showed that cyclic enol ethers can be used as well.41 Cyclopentenyl enol ether 55 proceeded with methyl diazoacetate 53 and bu-box ligand 3 to afford the cyclopropanation products in 56% yield, a trans/cis ratio of 27:73, trans ee of 87% and cis ee of 92% (Fig. 9.17b, p. 544). Intramolecular cyclopropanations are also well documented in the literature. It has been shown by Koskinen and co-workers that the cyclopropanation of diazomalonate 57, illustrated in Figure 9.18, using benzyl bis(oxazoline) 40 and copper(I) triflate afforded lactone 58 in 73% yield and 32% ee.36 Nishiyama and coworkers showed that cyclopropanations of diazoacetates 59a–c proceeded in yields ranging from 79–93% and 24–86% ee (Table 9.6, Fig. 9.18, p. 544).32

542

Chiral Bis(oxazolines)

TABLE 9.3. CYCLOPROPANATIONS USING VARIOUS METALS AND LIGANDS O + N2

metal

CO2Et

ligand

OEt 42

41

+

CO2Et

43

44

Figure 9.15a Ligand 12ba,c 47a,c 13aa,d 13ba,d 13ca,d 12aa,c 48aa,c 48ba,c 49b,c 50aa,c 50ba,c 50ca,c 50da,c 50ea,c 50fa,c

% Yield

trans/cis (43:44)

trans (43) ee (config)

70:30 70:30 67:33 60:40 59:41 80:20 74:26 68:32 90:10 62:38 75:25 70:30 71:29 65:35 66:34

84% (1R,2R) 84% (1R,2R) 55% (1R,2R) 62% (1R,2R) 87% (1R,2R) 38% (1R,2R) 49% (1R,2R) 74% (1R,2R) 60% (1S,2S) 75% (1R,2R) 69% (1R,2R) 18% (1R,2R) 36% (1R,2R) 57% (1R,2R) 64% (1R,2R)

76 85 43 58 59 64 72 69 51 83 70 85 69 91 85

cis (44) ee (config) 65% 85% 57% 61% 86% 21% 59% 84%

(1R,2S) (1R,2S) (1R,2S) (1R,2S) (1R,2S) (1R,2S) (1R,2S) (1R,2S)

85% 66% 17% 28% 51% 60%

(1R,2S) (1R,2S) (1R,2S) (1R,2S) (1R,2S) (1R,2S)

Metal ¼ CuOTf. Metal ¼ [RuCl2(p-cymene)]2. c A 1 mol% catalyst. d A 2 mol% catalyst. a b

O

O

O O

O

R N

N

N

N

R

O 47

O

48a R = i-Pr 48b R = t-Bu

O

N N

N Ph

49

O

O N

OR

N RO

50a R = COPh 50b R = H 50c R = COMe 50d R = Me 50e R = Bn 50f R = SiMe2t-Bu

Figure 9.15b. Cyclopropanation ligands.

Ph

Reference 33 34 14 14 14 37 38 38 39 40 40 40 40 40 40

Carbon–Carbon Bond-Forming Reactions

543

TABLE 9.4. CYCLOPROPANATION OF DIAZOACETATE ESTERS

O + N2 41

metal

OR

CO2R

ligand

+

CO2R

43

42

44

O

O N

N

OH

HO 51 Figure 9.16

Metal

Ligand

CuCl2 CuCl2 CuOTf CuOTf CuOt-Bu Ru Ru Ru

2a 2a 3 3 51 1b 1b 1b

R

% Yield

l-menthyl d-menthyl t-Bu BHT d-menthyl d-menthyl l-menthyl t-Bu

72 71 75 85 85 87 81

trans/cis (43:44)

trans (43) ee (config)

86:14 84:16 81:19 94:6 83:17 95:5 95:5 97:3

cis (44) ee (config)

98% (1R,2R) 98% (1R,2R) 96% (1R,2R) 99% (1R,2R) 90% (1S,2S) 86% (1R,2R) 95% (1R,2R) 94% (1R,2R)

96% (1R,2S) 80% (1R,2S) 93% (1R,2S) 90% 95% 76% 85%

(1S,2R) (1R,2S) (1R,2S) (1R,2S)

TABLE 9.5. CYCLOPROPANATION OF ENOL ETHERSa

RO

O + N2

52a R = Bu 52b R = i-Pr 52c R = SiMe3

CuOTf

OMe

ligand 3

RO

CO2Me 54a-c

53

Figure 9.17a

R Bu i-Pr SiMe3 a

% Yield 48 54 39

Data from Ref. 35.

trans (1a, 2b, 3b)/ cis (1a, 2a, 3a) 90:10 97:3 97:3

trans % ee 32 40 49

Reference 3 3 4 4 33, 34 31 31 31

544

Chiral Bis(oxazolines) CO2Me CuOTf ligand 3

O

OTMS + N2

CO2Me

OTMS

OMe 53

55

56% yield, 56a:56b = 27:73

OTMS

+

56b 92% ee

56a 87% ee

Figure 9.17b. Cyclopropanation of a cyclic enol ether.

The power of chiral C 2-symmetric bis(oxazolines) in cyclopropanation reactions has also been exhibited in total synthesis. One example is Corey and co-workers’ synthesis of sirenin 63 using bis(oxazoline) ligand 8 (Fig. 9.19).8 They showed that the intramolecular cyclopropanation of diazo derivative 61 proceeded in 77% yield and with 90% ee. Shibasaki and co-workers constructed prostratin 67 through the intermediate cyclopropane 66, also shown in Figure 9.19. Using bis(oxazoline) ligand 64 and copper(I) triflate-derived catalyst, compound 66 was prepared in 70% yield and 92% ee from diazo derivative 65.42

TABLE 9.6. INTRAMOLECULAR CYCLOPROPANATIONSa

O

O

t-BuO

CuOTf ligand 40

O

O t-BuO2C O

73%

N2 57

58 32% ee

O O

N2

O

[RuCl2(p-cymeme)]2

H O

R1

ligand 1b

R2

H

R1

R2

60a R1 = Ph, R2 = H 60b R1 = H, R2 = Ph 60c R1 = R2 = Me

59a R1 = Ph, R2 = H 59b R1 = H, R2 = Ph 59c R1 = R2 = Me Figure 9.18 Product

% Yield

% ee

60a 60b 60c

93 79 91

86 24 76

a

Data from Ref. 32.

Carbon–Carbon Bond-Forming Reactions H

CuOTf ligand 8

CO2Me

N2

545

CO2Me

H

77% 90% ee 61

62

H OH H

OH

63 sirenin

CuOTf

O

OTES

OTES O

O

N2

N

N

H O OTMS

TMSO

64

65

70% 92% ee

66

Me H Me

OAc H H

OH O HO

OH 67 prostratin Figure 9.19. Natural product syntheses using cyclopropanations.

9.5.2.

Diels–Alder Reactions

The Diels–Alder reaction is one of the most powerful synthesis. It allows the formation of up to four contiguous reaction. Asymmetric Diels–Alder reactions,43 in particular Diels–Alder reactions,16,44 have become very important

reactions in organic chiral centers in one catalytic asymmetric because they allow

546

Chiral Bis(oxazolines)

chemists to construct these chiral centers in an efficient and stereopredictable manner.

9.5.2.1. Cyclopentadiene and 3-Acryloyl-1,3-oxazolidin-2-one Metal complexes of bis(oxazoline) ligands are excellent catalysts for the enantioselective Diels–Alder reaction of cyclopentadiene and 3-acryloyl-1,3-oxazolidin-2-one. This reaction was most commonly utilized for initial investigation of the catalytic system. The selectivity in this reaction can be twofold. Approach of the dienophile (in this case, 3-acryloyl-1,3-oxazolidin-2-one) can be from the endo or exo face and the orientation of the oxazolidinone ring can lead to formation of either enantiomer (R or S) on each face. The ideal catalyst would offer control over both of these factors leading to reaction at exclusively one face (endo or exo) and yielding exclusively one enantiomer. Corey and co-workers first experimented with the use of bis(oxazoline)–metal complexes as catalysts in the Diels–Alder reaction between cyclopentadiene 68 and 3-acryloyl-1,3-oxazolidin-2-one 69;6 the results are summarized in Table 9.7 (Fig. 9.20). For this reaction, 10 mol% of various iron(III)-phe-box 6 complexes were utilized at a reaction temperature of 50
C for 2–15 h. The yields of cycloadducts were 85%. The best selectivities were observed when iron(III) chloride was used as the metal source and the reaction was stirred at 50
C for 15 h. Under these conditions the facial selectivity was determined to be 99:1 (endo/exo) with an endo ee of 84%. Corey and co-workers subsequently examined the stereochemical outcome by using substituted phe-box ligand 29 in the same reaction.17 Complexes of iron(III) and magnesium(II) were investigated (Table 9.8, Fig. 9.21). It has been shown that TABLE 9.7. COREY’S DIELS–ALDER REACTION USING Fe(III) HALIDESa

O + O

O

ligand 6 (10 mol%)

N metal -50 ˚C

68

69

O O

N

70 (endo R)

O

+ O

O

N

O

71 (endo S)

Figure 9.20 Metal FeCl2I FeCl3 FeI3/I2 a

Data from Ref. 6.

Time (h) 15 15 2

% Yield

endo/exo

endo ee (config)

85

97:3 99:1 96:4

80% (R) 84% (R) 82% (R)

95

Carbon–Carbon Bond-Forming Reactions

547

TABLE 9.8. COREY’S DIELS–ALDER REACTION USING Fe(III) OR Mg(II) SALTSa

O + O

ligand 29 (10 mol%) metal

O N

O

69

68

O

+

N

O

O

O

70 (endo R)

N

O

71 (endo S)

Figure 9.21 Metal

Time (temp)

FeI3 MgCl2 Mg(SbF6)2 a

% Yield

endo/exo

87 82 84

95:5 97:3 98:2




19 h (50 C) 24 h (80
C) 3 h (80
C)

endo ee (config) 85% (R) 91% (R) 91% (R)

Data from Ref. 17.

the use of magnesium(II) led to improved selectivities (up to 98:2 endo/exo with 91% endo ee for the 2R isomer). Furthermore, ligand–metal complexes prepared from MgI2 and one equivalent of iodine as a cocatalyst or 2 equiv of AgSbF6 furnished similar endo enantioselectivity (91% ee). The observed selectivities for these reactions led to their proposed transition states. The rationalized model for iron chelation (72, Fig. 9.22) shows that iron

H O Me Me

N Ph N

O

Me Me O

Fe3+O

O Ph

O

H

Me

N Ph

Me

N

N

O Me

H

Me

O O

Mg2+ O Ph

H

si-endo attack

si-endo attack

72

73

O N

O

O

70

Figure 9.22. Corey–Ishihara transition state.

N

548

Chiral Bis(oxazolines)

binds in an octahedral complex with the oxazolidinone occupying one axial and one equatorial position on the metal, which is sterically favored over the other possibility of the oxazolidinone binding to both axial positions (binding to both equatorial positions leads to the (2S) adduct, which is not the observed product).6 The magnesium chelation model 73 shows the metal chelating in a tetrahedral complex leading, as in the iron reactions, to the major product with endo facial selectivity and enantioselectivity for the (2R) isomer.17 In 1993, Evans and co-workers examined phe-box 6, i-pr-box 45, and bu-box 3 ligands in the Diels–Alder reaction of cyclopentadiene 68 and 3-acryloyl-1,3oxazolidin-2-one 69 using a weak Lewis acid such as copper(II) triflate.45 The results are summarized in Table 9.9. The reaction was carried out between 50 and 78
C for 3–18 h and achieved selectivities of up to 98:2 (endo/exo) with an endo ee of >98% (using bu-box 3). Interestingly, the enantiomer produced in these reactions was the (2S) configuration, compared to the (2R) isomer obtained with iron(III) and magnesium(II) as reported by Corey.6,17 This observed stereochemistry was explained by the chelation model of the copper(II) complex 74 (Fig. 9.23) TABLE 9.9. CuOTf-MEDIATED DIELS–ALDER REACTIONa

O

O

O ligand

+ O

O

N

O

N

O +

Cu(OTf) 2

68

N

O

71 (endo S)

70 (endo R)

69

O

H O Me Me O

N t-Bu 2+ O Cu N O t-Bu H

O N

re-endo attack 74

Figure 9.23 Ligand 6 45 3 a

Data from Ref. 45.

Time (temp) 3 h (50
C) 3 h (50
C) 18 h (78
C)

% Yield

endo/exo

endo ee (config)

92 93 86

95:5 96:4 98:2

30% (S) 58% (S) >98% (S)

Carbon–Carbon Bond-Forming Reactions

549

in which the copper binds with square-planar geometry in relation to the ligand and oxazolidinone. This leads to re-face approach of the diene and (2S) configuration of the product. Ghosh and co-workers have also demonstrated that the Cu(II)-bis(oxazoline) complexes of conformationally constrained inda-box ligands 9a and ent-9a are excellent catalysts for the enantioselective Diels–Alder reaction.9 Using copper(II) triflate as the metal source, the reaction resulted in selectivities up to >99:1 endo/ exo ratio with endo ee up to 99% (2R isomer), as shown in Table 9.10 (Fig. 9.24). Of particular interest, Cu(II)-phe-box ligand 6-derived catalyst complex exhibited considerably lower enantioselectivity (30%).45 Furthermore, they have shown that the use of Mg(II) as the chelating metal resulted in a reversal of stereochemistry [up to 98:2 endo/exo and 61% endo ee for the (2S) isomer]. Davies also showed that the use of copper(II) triflate with his structurally related inda-box ligands 9b and 34a led to similar selectivities.10 Desimoni and co-workers were able to produce either enantiomer (2R or 2S) of the Diels–Alder cycloadduct using the same isomer of phe-box ligand ent-6 under different reaction conditions (Fig. 9.25, Table 9.11).46,47 They found that when using magnesium(II) perchlorate as the metal source, the reaction produced cycloadduct in >98% yield with an endo/exo ratio of 93:7 and an endo ee of 70% for the (2S) isomer. In contrast, when magnesium(II) perchlorate was used in the presence of 2 equiv of water, the reaction afforded the cycloadduct again in >98% yield with an endo/exo ratio of 93:7, but in this instance, the endo ee was 65% for the (2R) isomer. This selectivity difference was explained by a change in TABLE 9.10. INDA-BOX-MEDIATED DIELS–ALDER REACTION

O + O

68

O N

O ligand CuOTf

O

N

70 (endo R)

69

O O +

O

N

O

71 (endo S)

Figure 9.24 Ligand ent-9a ent-9a 9a ent-9a ent-9a ent-9a 9b 34a

Metal Cu (50 mol%) Cu (8 mol%) Cu (8 mol%) Cu (4 mol%) Mg (100 mol%) Mg (10 mol%) Cu Cu

Time (temp)

% Yield

endo/exo

6 h (78
C) 8 h (78
C) 8 h (78
C) 8 h (78
C) 7 h (78
C) 7 h (78
C)  (65
C)  (70
C)

78 94 98 90 81 76

>99:1 >99:1 >99:1 >99:1 98:2 95:5 130:1 96:1

endo ee (config) Reference 97% 98% 94% 99% 61% 34% 92% 98%

(R) (R) (S) (R) (S) (S) (S) (S)

9 9 9 9 9 9 10 10

550

Chiral Bis(oxazolines)

TABLE 9.11. DIELS–ALDER REACTION USING ANHYDROUS AND HYDRATED Mg(II)

O + O

O

O

ligand CuOTf

N

68

O Me Me

N H N

O

H

N

O

N

O

71 (endo S)

si-endo attack OH2 H N Mg2+ O N O OH2 H Ph

O O Mg2+ O

O O +

70 (endo R)

69

Ph

N

O

O Me re-endo attack

Me O

Ph

O N

Ph

75

76 Figure 9.25

Ligand ent-6 ent-6

Metal Mg(ClO4)2 Mg(ClO4)22H2O

Temperature
C 50 50

% Yield

endo/exo

>98 >98

93:7 93:7

endo ee (config) 70% (S) 65% (R)

Reference 46 47

the chelation geometry about the magnesium in the presence of water. In the absence of water, the metal chelated in a tetrahedral geometry, shown in structure 75, as previously mentioned, allowing for re-face approach of the diene and the formation of the product containing the (2S) isomer.17 In the presence of water, the chelation geometry about the metal became octahedral, as shown in structure 76, thus favoring si-face approach of the diene and the formation of the product containing the (2R) isomer. Interestingly, Ghosh and co-workers showed that when using copper(II) perchlorate hydrates [Cu(ClO4)26H2O], the observed stereochemistry of the cycloadduct did not change as compared to the use of copper(II) triflate, as shown in Figure 9.26.48 This suggests that the metal–ligand–substrate complex in the presence or absence of water remained square planar when using copper(II). Kanemasa, Curran, and co-workers did an extensive study on the metal and counterion effects in the Diels–Alder reaction using the DBF-box ligand 14.15,49 Their results are summarized in Table 9.12 (Fig. 9.27). It has been shown that, for this ligand, the optimal conditions were use of nickel(II) perchlorate at 40
C for 14 h leading to 96% yield of cycloadduct in a ratio of 97:3 (endo/exo) with >99% endo ee.

Carbon–Carbon Bond-Forming Reactions

O + O

O

Cu(ClO4)2•6H2O ligand 9a (10 mol%)

O

N O

69

68

551

N

O

71 (endo S) 88%, endo/exo >99:1 endo ee = 98%

Figure 9.26. Diels–Alder reaction using a Cu(II)-aqua complex.

TABLE 9.12. DBF-BOX-MEDIATED DIELS–ALDER REACTION

O + O

68

O N

ligand 14 metal

O O

69

N

O

+ O

O

70 (endo R)

N

O

71 (endo S)

Figure 9.27 Metal

Time (temp)

Mn(ClO4)2 Fe(ClO4)2 Co(ClO4)26H2O Ni(ClO4)26H2O Ni(ClO4)2 Cu(ClO4)2 þ 3H2O Zn(ClO4)2 þ 3H2O MgBr2 MgI2 MgBr2, I2 Mg(OTf)2 Mg(ClO4)2 Mg(ClO4)2 þ 3H2O

2 h (r.t.) 48 h (40
C) 48 h (40
C) 14 h (40
C) 24 h (40
C) 15 h (40
C) 15 h (40
C) 1 h (r.t.) 2 h (r.t.) 1 h (r.t.) 10 h (r.t.) 10 h (40
C) 48 h (40
C)

% Yield 91 90 97 96 100 99 99 99 89 96 93 100 68

endo/exo 89:11 99:1 97:3 97:3 95:5 97:3 96:4 89:11 91:9 90:10 88:12 97:3 96:4

endo ee (config) Reference 64% (S) 98% (S) 99% (S) >99% (S) 96% (S) 96% (S) 97% (S) 41% (S) 70% (S) 69% (S) 25% (S) 91% (S) 48% (S)

49 49 49 49 49 49 49 15 15 15 15 15 15

9.5.2.2. Various Dienes and Dienophiles Diels–Alder reactions involving bis(oxazoline) ligands are not limited to the reaction between cyclopentadiene and 3-acryloyl-1,3,-oxazolidin-2-one; they can be used with a wide variety of dienes and dienophiles. Evans demonstrated the utility of py-box ligand 1d in the reaction between cyclopentadiene 68 and various

552

Chiral Bis(oxazolines)

TABLE 9.13. DIELS–ALDER REACTIONS WITH SUBSTITUTED ACROLEINSa

+

R

CHO

ligand metal

CHO

R +

R 68

77a R = H 77b R = Br 77c R = Me 77d R = Ph 77e R = Cl

CHO

78a R = H 78b R = Br 78c R = Me 78d R = Ph 78e R = Cl

79a R = H 79b R = Br 79c R = Me 79d R = Ph 79e R = Cl

Figure 9.28 Dienophile

Ligand

77a 77b 77b 77c 77c 77d 77d 77e 77e a

1d 1d 1d 1d 1d 3 3 3 3

Metal Cu(SbF6)2 Cu(OTf)2 Cu(SbF6)2 Cu(OTf)2 Cu(SbF6)2 Cu(OTf)2 Cu(SbF6)2 Cu(OTf)2 Cu(SbF6)2

Time (temp)

endo/exo




94:6 3:97 2:98 4:96 3:97 90:10 91:19 93:7 86:14

18 h (20 C) 60 h (40
C) 12 h (78
C) 120 h (20
C) 8 h (40
C) 24 h (rt) 24 h (rt) 24 h (rt) 24 h (rt)

% ee 85 87 96 85 92 99 96 53 95

Data from Ref. 50.

substituted acroleins 77a–e.50 These results, summarized in Table 9.13 (Fig. 9.28), included yields up to 96% with endo/exo ratios up to 94:6 and 2:98 and ee up to 99%. Ghosh’s9,48 and Kanemasa’s groups49 examined their ligands 9, ent-9 and 14, respectively, in the Diels–Alder reactions of oxazolidinones 80a–d and cyclopentadiene 68. Their results are summarized in Table 9.14 (Fig. 9.29). There are also several other examples of bis(oxazoline)–metal complex catalyzed Diels–Alder reactions of cyclopentadiene and other unsaturated esters.16,51,52 The corresponding cycloadducts were isolated in yields up to 92% with endo/exo ratios up to >99:1 and ee up to >95% (Table 9.15, Fig. 9.30).

9.5.2.3. Bis(oxazoline)-Mediated Diels–Alder Reactions in Total Synthesis Evans has utilized Cu(II)-bis(oxazoline)-mediated Diels–Alder reactions as the key step in several total syntheses. In 1996, Evans and co-workers used bu-box ligand 3 in the intramolecular Diels–Alder reaction of oxazolidinone 87 to form cycloadduct 88 enantioselectively, as shown in Figure 9.31.53 Compound 88 was subsequently converted to (-)-isopulo’upone 89. Diels–Alder reaction of furan 90 and 3-acrylol-1,3-oxazolidin-2-one 69 was effectively carried out with Cu(II)-bu-box 3-derived complex. The corresponding

Carbon–Carbon Bond-Forming Reactions

553

TABLE 9.14. DIELS–ALDER REACTIONS OF N-ACYL OXAZOLIDINONES

O + O

R

O

ligand metal

N

H

R O

80a R = Me 80b R = Ph 80c R = CO2Et 80d R = n-Pr

68

O R O

N

+

HO

N

O

O

82a R = Me 82b R = Ph 82c R = CO2Et 82d R = n-Pr

81a R = Me 81b R = Ph 81c R = CO2Et 81d R = n-Pr

Figure 9.29 Dienophile Ligand 80a 80a 80b 80c 80a 80d 80a 80c

ent-9a ent-9a ent-9a ent-9a 14 14 9a 9a

Metal

Time (temp)

% Yield




Cu 26 h (0 C) Mg 48 h (0
C) Cu 72 h (r.t.) Cu 8 h (45
C) Ni(ClO4)23H2O 20 h (r.t.) 72 h (r.t.) Ni(ClO4)23H2O Cu(ClO4)26H2O 36 h (30
C) Cu(ClO4)26H2O 7 h (78
C)

endo/exo

84 76 78 75 90 100 85 95

92:8 92:8 80:20 93:7 92:8 93:7 95:5 92:8

endo ee (config)

Reference

94% (R) 55% (S) 35% (S) 94% (S) 93% (S) 94% (S) 99% (S) 92% (R)

9 9 9 9 49 49 48 48

TABLE 9.15. DIELS–ALDER REACTIONS WITH VARIOUS DIENOPHILES O +

68

R1

R1

ligand

R

metal

COR

R1 86 exo

85 endo

84a R = OEt, R1 = COPh 84b R = OEt, R1 = SPh 84c R = OCH2CF3, R1 = SPh 84d R = CO2Me, R1 = Ph

Et

COR

+

Et O

O N

N Ph

Ph 83

Figure 9.30 Dieneophile

Ligand

Metal

84a 84b 84c 84d 84d

83 6 6 14 14

MgI2 CuBr2/AgSbF6 CuBr2/AgSbF6 Mg(ClO4)2 Cu(SbF6)2

% Yield 88 92 92 75 50

endo/exo >99:1 15:1 13:1 86:14 94:6

endo ee (config) Reference 87% (R) >95% (S) >95% (S) 30% (R) 68% (R)

51 52 52 16 16

554

Chiral Bis(oxazolines) O TBSO

O

N

N

ligand 3

O

O

O

Cu(SbF6)2 81%

O H

TBSO

H 88 endo:exo >99:1 endo ee 96%

87

O H

N

H 89 isopulo'upone Figure 9.31. Synthesis of isopulo’upone via a Diels–Alder reaction.

cycloadduct 91 was obtained in 97% ee. This cycloadduct was converted to entshikimic acid 92 as shown in Figure 9.32.54 Similarly, cyclocondensation of diene 93 with oxazolidinone 69 formed the cycloadduct 94 (endo ee 98%), which was transformed into ent-
1-tetrahydrocannabinol 95.55 Another example of a bis(oxazoline)–metal complex catalyzed reaction in total synthesis was illustrated by Murai and co-workers in the construction of a precursor for the synthesis of azadirachtin 97.56 The cycloadduct 71 was obtained in 99% ee and 97% yield (Fig. 9.33). 9.5.3.

Hetero-Diels–Alder and Ene Reactions

The addition of olefins to aldehydes can take place via an ene reaction. As shown in Figure 9.34, reaction of methylenecyclohexene 98 with ethyl glyoxylate 99 forms the ene product 100. Evans and co-workers showed that such an ene reaction can be carried out enantioselectively by utilizing bis(oxazoline)–metal complexes. Examples of ene products with yields up to 99% and ee up to 97% are summarized in Table 9.16 (Fig. 9.34).57 Using a diene, the reaction can proceed through the ene pathway as above, or through the hetero-Diels–Alder pathway. For example, the condensation of 2,3dimethyl-1,3-butadiene 103 with glyoxylate esters 99, 104, and 105 can proceed to form either a hetero Diels–Alder cycloadduct 106 or an ene product 107 (Fig. 9.35).

Carbon–Carbon Bond-Forming Reactions

555

O O

ligand 3 Cu(SbF6)2 97%

O

O + O

O

N O

N

69

90

CO2H

HO HO OH

O

92 ent-shikimic acid

91 endo/exo 80:20 endo ee 97%

Me Me

O +

O

ligand 3 Cu(SbF6)2 57%

O

OAc O 93

OAc

O

N

N

O

69 94 endo:exo 73:27 endo ee 98% Me H H Me Me

OH

C5H11

O 95

ent-∆1-tetrahydrocannabinol Figure 9.32. Natural product syntheses using Diels–Alder reactions.

Jørgensen and co-workers showed that in the presence of bu-box ligand 3 complexed with copper(II) triflate or phe-box ligand ent-6 complexed with copper(II) triflate, the above reaction proceeded in a combined yield of up to 86% with product ratios (106:107) varying from 1:2 to 2:1 and ee between 77 and 95% for either product (Table 9.17, Fig. 9.35a).58–62 It has been shown that complete selectivity for the hetero-Diels–Alder cycloadduct 109 (100% endo, 60% ee) can be achieved in the hetero-Diels–Alder reaction of 1,3-cyclohexadiene 108 and ethyl glyoxylate 99 using ent-6 and copper(II) triflate derived catalyst complex. Another interesting reaction introduced by Jørgensen and co-workers was the reaction between 1,3-cyclohexadiene 108 and diethyl ketomalonate 110 to form cycloadduct 111 in 76% yield with an ee of 84% (Fig. 9.35b, p. 558).63

556

Chiral Bis(oxazolines)

O

ligand 2 Cu(OTf) 2 97%

O

+ O

O

N O

N

O

69

68

71

O

MeO2C OH O O

MeO

O

H

O O

HO

OH

O O

AcO MeO2C

OH

ODEIPS

O

96

97 azadirachtin Figure 9.33. Synthetic study toward azadirachtin.

TABLE 9.16. ENANTIOSELECTIVE ENE REACTIONS OF ETHYL GLYOXYLATEa

O O +

H

ligand metal

OEt

OEt

OH

O 99

98

100 O

O Ph

+ H

ligand metal

Ph

OEt

OEt

OH

O 101

99

102 Figure 9.34

Alkene 98 98 101 101 a

Ligand 3 6 3 6

Data from Ref. 57.

Metal Cu(SbF6)2 Cu(OTf)2 Cu(SbF6)2 Cu(OTf)2

% Yield 100

% Yield 102

ee (config)

97 99

97% (S) 87% (R) 93% (S) 89% (R)

90 99

Carbon–Carbon Bond-Forming Reactions O

O

H

OR

ligand Cu(OTf) 2

O

O OR +

+

103

557

OR OH

O 106

99 R = Et 104 R = Me 105 R = i-Pr

107

Figure 9.35

Activated dienes such as Danishefsky’s diene 112 can also be used in the heteroDiels–Alder reaction with alkyl glyoxylates. Ghosh and co-workers showed that this reaction proceeded to form cycloadducts 113a,b in yields up to 76% and ee up to 70% using either bu-box 3, phe-box 6 or inda-box ent-9a.64 The results are summarized in Table 9.18 (Fig. 9.36). Subsequently, Jørgensen and co-workers carried out reactions using Danishefsky’s diene 112 and a-keto esters 114a–d to afford cycloadducts 115a–d in yields up to 95% with ee up to 99% (Table 9.19, Fig. 9.37a).65

TABLE 9.17. ENANTIOSELECTIVE HETERO-DIELS–ALDER AND ENE REACTION PRODUCTSa

O

O

H

OR

ligand Cu(OTf) 2

O

O OR +

+

103

99 R = Et 104 R = Me 105 R = i-Pr

O 106

OR OH 107

Figure 9.35a Ligand

R

3 3 3 ent-6 ent-6 ent-6 3 3 ent-6 ent-6 ent-6

Me Et i-Pr Me Et i-Pr Et Et Et Et Et

a

Data from Ref. 58.

Temperature (
C) 20 20 20 20 20 20 20 30 20 0 30

106 yield (ee)

107 yield (ee)

106:107

25% (90%) 20% (85%) 12% (77%) 36% (81%) 31% (83%) 31% (87%) 20% (85%) 5% (95%) 31% (83%) 22% (85%) 13% (85%)

39% (85%) 36% (83%) 12% (83%) 50% (85%) 50% (88%) 40% (90%) 36% (83%) 4% (94%) 50% (88%) 32% (89%) 7% (90%)

1:1.6 1:1.8 1:1 1:1.4 1:1.6 1:1.3 1:1.8 1:0.8 1:1.6 1:1.5 1:0.6

558

Chiral Bis(oxazolines) Cu(OTf) 2 ent-6

O

O

H

OEt

O

+

H

108

CO2Et 109 60% ee

99

O

Cu(OTf) 2 ent-6, 76%

O

+ EtO

O CO2Et

OEt

CO2Et

O

111 84% ee

110

108

Figure 9.35b. Hetero-Diels–Alder reactions.

Whiting’s group performed an aza-Diels–Alder condensation using Danishefsky’s diene 112 and methyl a-[(4-methoxyphenyl)imino]acetate 116, which afforded the tetrahydropyridone 117 in 67% yield and 92% ee (Fig. 9.37b).66 Enantioselective hetero-Diels–Alder reactions of a,b-unsaturated acyl phosphonates and enol ethers have been reported by Evans in 1998.67,68 As depicted in Figure 9.38a, cyclocondensation of dienes 118a and 118b with enol ethers 119a–c

TABLE 9.18. HETERO–DIELS–ALDER REACTION OF DANISHEFSKY’S DIENE WITH GLYOXYLATE ESTERSa

O

TMSO O

O

H

OR

1. ligand Cu(OTf) 2

+ 2. TFA

OMe

OR

O O

99 R = Et 104 R = Me

112

113a R = Et 113b R = Me

Figure 9.36 Ligand

R

6 6 3 3 ent-9a ent-9a ent-9a

Et Me Et Me Et Me Et

a

Data from Ref. 64.

Time (temp) 9 9 8 9 9 9

h (78
C) h (78
C) h (78
C) h (78
C) h (78
C) h (78
C) 9 h (rt)

% Yield 113a or 113b

ee (config)

27 40 42 37 70 67 76

44% (S) 47% (S) 17% (R) 2% (R) 72% (S) 70% (S) 50% (S)

Carbon–Carbon Bond-Forming Reactions

559

TABLE 9.19. ENANTIOSELECTIVE HETERO-DIELS–ALDER REACTIONS USING DANISHEFSKY’S DIENEa

O TMSO

O

O

R

R1

ligand 3 Cu(OTf) 2

+ O

OMe 112

114a R = Me, R1 = OEt 114b R = Me, R1 = OMe 114c R = Ph, R1 = OEt 114d R = Me, R1 = Me

R1 R

O

115a R = Me, R1 = OEt 115b R = Me, R1 = OMe 115c R = Ph, R1 = OEt 115d R = Me, R1 = Me

Figure 9.37a Ketone 114a 114a 114b 114c 114d

Time (temp)

% Yield

% ee

8 h (r.t.) 30 h (40
C) 23 h (r.t.) 20 h (r.t.) 60 h (40
C)

85 78 95 77 90

92 99 91 77 94

a

Data from Ref. 65.

O

O

TMSO

ligand 3

+ MeO N OMe 112

PMP

FeCl3, 4 Å MS 67%

CO2Me

N PMP

116

117 92% ee

PMP = p-methoxyphenyl Figure 9.37b. Hetero-Diels–Alder reaction of imines.

afforded the cycloadducts 120a–d in up to >99:1 endo/exo ratio with yields up to 98% and selectivities as high as 99% (ee). Selected examples are presented in Table 9.20 (Fig. 9.38a). Ghosez and co-workers also presented a hetero-Diels–Alder reaction using a hetero-atom-containing diene 121 and the oxazolidinone 80a in the presence of bubox 3 complexed with copper(II) triflate to afford the cycloadduct 122 in 80% yield (>99:1 exo/endo, 95% ee) as shown in Figure 9.38b.69 Bis(oxazoline)-mediated hetero-Diels–Alder reactions have also been utilized in total synthesis. For example, Ghosh and co-workers used inda-box 9a in the construction of a key intermediate for the synthesis of laulimalide 123, a potent

560

Chiral Bis(oxazolines) TABLE 9.20. ENANTIOSELECTIVE HETERO-DIELS–ALDER REACTIONS OF a,b-UNSATURATED ACYL PHOSPHONATES

R

R ligand 3

or MeO

P

MeO

MeO

CuX2 119

O

P

MeO

O

O

MeO

OEt

MeO

O

P O

120a R = Me 120b R = OEt

118a R = Me 118b R = OEt

OEt

120c n = 1 120d n = 2

O

119a

n

O

O

O

119b

119c

Figure 9.38a R

Vinyl Ether

X

% Yield

% ee

Reference

119a 119a 119b 119c

OTf SbF6 OTf SbF6

89 98 91 55

99 97 95 92

67 68 67 67

Me OEt Me Me

Me

Me O

TMSO +

N

O

O N

O

ligand 3

Me

HN

Cu(OTf) 2 80%

Ph

Ph

121

O

N O

O

122 95% ee

80a

Figure 9.38b. Hetero-Diels–Alder reactions with aza dienes.

H

O

HO

H OH O

Me

O H

O

H

Me Me

Me Me O

O

O

O Me

O

Me

Me

124 (R)-dihydroactinidiolide

125 (R)-actinidiolide

123 laulimalide Figure 9.39. Natural products via enantioselective hetero-Diels–Alder reactions.

Carbon–Carbon Bond-Forming Reactions

561

antitumor agent.70 Jørgensen and co-workers have also utilized this reaction in the syntheses of (R)-dihydroactinidiolide 124 and (R)-actinidiolide 125 as illustrated in Figure 9.39.71 9.5.4.

1,3-Dipolar Cycloadditions

Lewis acid catalyzed 1,3-dipolar cycloadditions of olefins and nitrones are useful synthetic transformations that have the potential of defining up to three contiguous chiral centers. Presumably, such reactions can also be catalyzed by chiral Lewis acids derived from metal–bis(oxazoline) complexes. Miura and co-workers attempted the cyclization of phenylacetylene 126 with (Z)-a,N-diphenylnitrone 127 to form b-lactams 128 and 129 in the presence of i-pr-box 45 and copper(I) iodide or bu-box 3 and copper(I) iodide, as shown in Figure 9.40 (Table 9.21).72 When the ligands were used in catalytic amounts, precipitation of the copper acetylide was observed and virtually no cycloadduct was formed. However, when the reaction was carried out using 1 equiv of ligand and copper(I) iodide, the trans cycloadduct 128 was formed in up to 54% yield and 68% ee. The Jørgensen73–76 and Desimoni77 groups have also carried out bis(oxazoline)metal complex-catalyzed 1,3-dipolar cycloadditions with nitrones. Cycloaddition of a,b-unsaturated oxazolidinones such as 69, 80a, and 130 with nitrone 127 in the presence of phe-box ligands 6 and ent-6 provided quantitative yields of cycloadducts. Selectivities of up to 100:0 endo/exo ratio and corresponding endo ee as high as 82% were achieved (Table 9.22, Fig. 9.41a). Similarly, cycloaddition of ethyl vinyl ether 119 and 133 afforded an excellent yield of 134 and 135 as shown in Figure 9.41b.76

TABLE 9.21. 1,3-DIPOLAR CYCLOADDITION OF PHENYLACETYLENEa

Ph Ph

H + H 126

O N+ Ph

Ph

ligand CuI

O

Ph

N + Ph

127

Ph 128

O N

Ph

Ph 129

Figure 9.40 Ligand

Ligand/CuI

% Yield

trans % ee

45 45 3

1:0.1 1:1 1:1

45 54 53

40 68 67

a

Data from Ref. 72.

562

Chiral Bis(oxazolines)

TABLE 9.22. ENANTIOSELECTIVE 1,3-DIPOLAR CYCLOADDITION OF a,b-UNSATURATED OXAZOLIDINONES AND NITRONES

O O

O N

R

ligand MgI2

Ph

O

N+

+

Ph N O

N

Ph Ph

69 R = H 80a R = Me 130 R = n-Pr

H

Ph N O

R + O

N

Ph

O

O

O

O endo 131a R = H 131b R = Me 131c R = n-Pr

127

R

O exo 132a R = H 132b R = Me 132c R = n-Pr

Figure 9.41a Alkene

Ligand

80a 130 80a 80a 69 69 69 80a

6 6 ent-6 ent-6 ent-6 ent-6 ent-6 ent-6

Bn + OEt 119

H

Additive

endo/exo 84:16 >95:5 96:4 94:6 73:27 100:0 90:10 97:3

˚ MS 4A H2O ˚ MS 4A H2O

N+

endo % ee

Bn N O

O ligand 3

Reference

75 82 79 73 82 48 36 46

73 73 73 74 75 75 75 77

Bn N O

OEt

OEt

+ CO2Et

133

Cu(OTf) 2 93%

EtO2C

endo/exo = 84:16

134 endo 89% ee

EtO2C 135 exo

Figure 9.41b

9.5.5.

Allylic Substitutions

Pfaltz and co-workers have done substantial work in the area of allylic substitution reactions involving bis(oxazoline) ligands.33,78,79 The substitution reaction of racemic 1,3-diphenylallyl acetate 136 with the anion of dimethylmalonate in the presence of 1–2 mol% palladium-bis(oxazoline) complex afforded enantiomerically enriched diethyl (E)-(1,3-diphenylallyl)malonate 137, as shown in Figure 9.42. The results from various palladium complexes derived from bis(oxazoline) ligands ent-45, 139, and 140 were examined using the above reaction and are

Carbon–Carbon Bond-Forming Reactions

Ph

EtO2C

NaCH(CO2Et)2

OAc

563 CO2Et

(η3-allyl-PdCl)2

Ph

Ph

86%, 77% ee

Ph 137

136

Bn

O

O

N

N

Bn

138 Figure 9.42. Palladium-catalyzed allylic malonate substitution.

shown in Table 9.23 (Fig. 9.43a). The substitution product 137 was obtained in yields of up to 99% and ee up to 97%. Pfaltz’s group also investigated ligand 139 in the reaction involving the asymmetric allylic acetate 141. A substitution ratio (142a/142b) of 93:7 was observed in this case and both products were obtained as pure enantiomers (Fig. 9.43b). Ikeda and co-workers examined ferrocene-based ligands 11a and 11b in the same allylic substitution reaction of racemic acetate 136 (Fig. 9.44, Table 9.24).12 This catalytic system resulted in quantitative yield of 137 with ee of 96 and 99%, respectively. TABLE 9.23. ENANTIOSELECTIVE SUBSTITUTION OF 1,3-DIPHENYLALLYL ACETATE WITH DIETHYLMALONATE NaCH(CO2Et)2

OAc Ph

EtO2C

(η3-allyl-PdCl)2

Ph

ligand

Ph

Ph 137

136 O

O N

CO2Et

O

O Ph

N

N

Ph

N

Bn

Bn

OTBS

OTBS

140

139 Figure 9.43a Ligand

Solvent

% Yield

% ee

139 139 139 ent-45 140

THF THF/Et2O CH2Cl2 THF THF

85 99 97 94 94

76 84 88 94 97

Reference 78 78 78 79 79

564

Chiral Bis(oxazolines) EtO2C

NaCH(CO2Et)2

OAc

CO2Et

EtO2C

CO2Et

(η3-allyl-PdCl)2

Ph

+

Ph

139

Ph

142a 93%

141

142b 7%

Figure 9.43b TABLE 9.24. FERROCENE-BOX–MEDIATED ENANTIOSELECTIVE SUBSTITUTION OF 1,3-DIPHENYLALLYL ACETATE WITH DIETHYLMALONATEa NaCH(CO2Et)2

Ph

EtO2C

(η3-allyl-PdCl)2

OAc

ligand

Ph

CO2Et

Ph

Ph 137

136 Figure 9.44 Ligand

% Yield

% ee

11a 11b

100 100

96 99

a

Data from Ref. 12.

An interesting allylic substitution reaction of (E)-cinnamyl methyl carbonate 143 has been examined by Pfaltz’s group.80 The use of a molybdenum complex of ligand 144 resulted in 145 in 88% yield with an ee of 99% [for the (R) isomer] (Fig. 9.45). MeO2C

Mo(CO)3(EtCN)3

Ph

OCO2Me

NaCH(CO2Et)2 ligand 144, 88%

143

CO2Me

Ph 145 99% ee

O

O NH HN

O

O N

N

144

Figure 9.45. Molybdenum-mediated allylic substitution.

Carbon–Carbon Bond-Forming Reactions

9.5.6.

565

Mukiayama Aldol

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)–metal complexes. Evans has carried out a great deal of the work in this area.81–85 In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (1a–c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(1-tert-butylthio)vinyl]oxy trimethylsilane 147.81,82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Fig. 9.46). In 1997, Evans reported on the aldol reaction using the same enol ether 147 with a variety of glyoxylates and pyruvates using tin triflate and copper triflate. 83,84 As shown in Table 9.26 (Fig. 9.47a), reaction of several pyruvates using bu-box ligand 3 complexed with copper(II) triflate afforded yields of up to 99% with selectivities up to 96% (ee) for adduct 150.84 Evans also investigated the aldol condensation between methyl pyruvate 151 and several different substituted enol ethers 152, again using bu-box 3 and copper(II) triflate. These reactions achieved selectivities up to 98:2 (syn/anti) with syn ee up to 98% and yields up to 96% (Table 9.27, Fig. 9.47b).84 Another type of aldol condensation using cyclic enol ethers was demonstrated by Yamamoto and co-workers in which the condensation of tributyl (1-cyclohexene-1-yloxy)stannane 154 with benzaldehyde proceeded in 74% yield, as shown in Figure 9.48.86 The ratio of anti product 155 to syn product 156 was 36:64 with an anti ee of 84% (Fig. 9.48). TABLE 9.25. MUKAIYAMA ALDOL REACTION OF BENZYLOXYACETALDEHYDE AND A TRIMETHYLSILYL ENOL ETHERa

O BnO

ligand metal

OTMS H

+

146

OH BnO

St-Bu

St-Bu 148

147 Figure 9.46 Ligand 1a 1b 1c 1a 1b 1c

a

Data from Ref. 81.

O

Metal

% ee

Cu(OTf)2 Cu(SbF6)2 Cu(SbF6)2 Zn(OTf)2 Zn(SbF6)2 Zn(SbF6)2

96 85 9 40 36 18

566

Chiral Bis(oxazolines) TABLE 9.26. ENANTIOSELECTIVE ALDOL REACTION MEDIATED BY Bu-BOXa

O RO

OTMS R1

R1 OH O

ligand 3

RO

+ St-Bu

O

Cu(OTf) 2 THF, 1 N HCl

St-Bu O

147

149

150 Figure 9.47a

R

R1

Me Bn t-Bu Me Me Et

Me Me Me Et t-Bu i-Pr

% Yield

% ee

99 99 99 94 94 36

96 95 91 84 94 84

a

Data from Ref. 84.

TABLE 9.27. Cu(II)-Bu-BOX-MEDIATED MUKAIYAMA ALDOL REACTIONSa

O MeO

OTMS

O 151

Me

ligand 3

Me +

R1 R

OH O

MeO

Cu(OTf) 2 THF, 1 N HCl

R1 O

152

R 153

Figure 9.47b R Me Me Me Me i-Bu a

R1 t-BuS t-BuS EtS EtS EtS

Enol Geometry

syn/anti

Z E Z E Z

% Yield

% ee

96 88 90 91 88

96 98 93 98 93

94:6 95:5 94:6 98:2 90:10

Data from Ref. 84.

OSnBu3

ligand 1b Cu(OTf) 2, PhCHO THF, −78˚C

O

OH Ph

O

OH Ph

+

anti/syn = 36:64 74%, 84% ee

154

155 anti

156 syn

Figure 9.48. Cu(II)-py-box-mediated Mukaiyama aldol reaction.

Carbon–Carbon Bond-Forming Reactions

9.5.7.

567

Conjugate Addition

9.5.7.1. Free Radical Conjugate Addition Stereocontrolled free radical conjugate additions have been studied using C 2symmetric bis(oxazoline)–metal complexes. The most common reaction used to study the effectiveness of these ligands in free radical conjugate additions is the reaction of alkyl iodides, electron-deficient alkenes and allyltributyl stannane. Thus, using this reaction, Porter and co-workers have studied bis(oxazoline) ligands 6 and ent-6.87,88 Stoichiometric amounts of these ligands complexed with zinc(II) triflate were employed in the reaction of iodocyclohexane 157a or tert-butyliodide 157b and 3-acryloyl-1,3-oxazolidin-2-one 69 in the presence of allyltributyl stannane 158. The results are summarized in Table 9.28 (Fig. 9.49). The corresponding addition products 159a and 159b were obtained in up to 92% yield with ee up to 90%. Sibi’s group studied a similar reaction using ligands 9b, 34a–c, and 161 with iodides 157b and 157c, tributyltin hydride 160 and N-crotonyl oxazolidinone 80a or N-cinnamoyl oxazolidinone 80b.89,90 As shown in Table 9.29 (entries 7 and 9), the inda-box ligands exhibited optimum results with yields up to 92% and selectivities up to 93% (ee). The use of the ligand–metal complexes in catalytic amounts led to lower yields and enantioselectivities (Fig. 9.50).89

9.5.7.2. Michael Addition Another type of conjugate addition reaction in which bis(oxazoline)–metal complexes have been used is the Michael addition reaction. Early work in this TABLE 9.28. PHE-BOX-MEDIATED FREE RADICAL CONJUGATE ADDITIONa

O O O

O

ligand

+

N 69

R

I

157a R = c-hexyl 157b R = t-Bu

+

SnBu3

O

O N

R

Zn(OTf) 2

158 159a R = c-hexyl 159b R = t-Bu Figure 9.49

Ligand

R

Solvent

% Yield

6 6 6 ent-6

c-hexyl c-hexyl t-Bu t-Bu

CH2Cl2 ether pentane/CH2Cl2 pentane/CH2Cl2

62 61 78 92

a

Data from Ref. 87.

ee (config) 50% (S) 80% (S) 88% (S) 90% (R)

568

Chiral Bis(oxazolines)

TABLE 9.29. ENANTIOSELECTIVE FREE RADICAL CONJUGATE ADDITIONS TO a,b-UNSATURATED N-ACYL OXAZOLIDINONES

O O

O N

O

ligand

R

80a R = Me 80b R = Ph

+

R1

I

+ Bu3SnH metal

157b R1 = t-Bu 157c R1 = i-Pr

O

O N

R1 R

162a R = Me, R1 = t-Bu 162b R = Ph, R1 = i-Pr

160

O

O N

N i-Bu

i-Bu 161 Figure 9.50 Entry 1 2 3 4 5 6 7 8 9

Ligand (mol%) 161 (1.0) 161 (0.5) 161 (0.2) 161 (1.0) 161 (0.2) 9b (1.0) 34a (1.0) 34b (1.0) 34c (1.0)

Metal

R

R1

% Yield

ee (config)

Reference

MgI2 MgI2 MgI2 Zn(OTf)2 Zn(OTf)2 MgI2 MgI2 MgI2 MgI2

Ph Ph Ph Me Me Ph Ph Ph Ph

i-Pr i-Pr i-Pr t-Bu t-Bu i-Pr i-Pr i-Pr i-Pr

88 86 86 90 71 88 88 90 92

82% (R) 79% (R) 67% (R) 82% (S) 70% (S) 89% (R) 93% (R) 82% (R) 82% (R)

89 89 89 89 89 90 90 90 90

area met with limited success. Bernardi and Scolastico, for example, attempted the Michael addition of the silyl enol ether 163 to 2-methoxycarbonylcyclopent-2enone 164.91 These reactions resulted in only moderate yields and poor enantioselectivity (Table 9.30, Fig. 9.51). A number of subsequent Michael reactions catalyzed by bis(oxazoline)–metal complexes however, proceeded with improved enantioselectivity.92–97 For example, Michael reactions of 166a and 166b and oxazolidinone 80a using Cu(II)–bis(oxazoline) 3 provided products 167a and 167b in high ee as shown in Figure 9.52a.92,93 Conjugate additions of O-benzylhydroxylamine 169 to a,b-unsaturated pyrazole derivatives 168a–c have been shown to proceed with good enantioselectivities and isolated yields (Table 9.31, Fig. 9.52a).94 Michael addition of ethylacetoacetate 171 to nitroalkenes, for example, b-nitrostyrene 172 also proceeded with excellent enantioselectivities.95 Evans reported the Cu(II)-bis(oxazoline) catalyzed Michael addition of methylthio enolsilane 174 to the fumarate derivative 80c to provide 175 in 98% ee as shown in Figure 9.52b.95,96

Carbon–Carbon Bond-Forming Reactions

569

TABLE 9.30. POLAR CONJUGATE ADDITION REACTIONa O Ot-Bu

Me

ligand Cu(OTf) 2

O +

CO2Me

CO2Me

OTBS 163

CO2t-Bu

H Me

164

165

Figure 9.51 Ligand

% Yield

% ee

2 6 4

40 50 50

0 33 43

a

Data from Ref. 91.

TABLE 9.31. BIS(OXAZOLINE)-MEDIATED CONJUGATE ADDITIONS O

TMSO

O

O

O

Me

ligand 3

+

O

N

O

Me

O

N

O

Cu(OTf) 2 4 Å MS

R 80a

166a R = H 166b R = Me O

O

N R1 +

H2NOBn

NHOBn

N

ligand 34a

N

R

167a R = H 167b R = Me

N MgBr2

R1

169 170a R1 = Me 170b R1 = Et 170c R1 = Bn

168a R1 = Me 168b R1 = Et 168c R1 = Bn

Figure 9.52a Product 167a 167b 170a 170b 170c

% Yield 89 95 87 84 57

9.5.8.

anti/syn

% ee

8.5:1 24:1

95 91 88 88 70

Reference 92 92 94 94 94

Allylation and Cyanohydrin Formation

Stereoselective addition to aldehydes is another powerful tool in organic chemistry. Two very specific types of this reaction include allylation of aldehydes and cyanohydrin formation. These are both reactions that can benefit from the use of chiral bis(oxazoline) ligands.98,99,100–102 Two examples are summarized in Figure 9.53.

570

Chiral Bis(oxazolines) ligand 34a

NO2

CO2Et + Ph

Me

NO2

Me

Mg(OTf) 2 NMM 98%

171

CO2Et 173 91% ee

172

O

OTMS i-Pr + O

MeS

Ph

O

O

N

CO2Et

174

O

ligand 3 Cu(SbF6)2

O

93% anti/syn >99:1

O

CO2Et O

O N

SMe i-Pr 175 98% ee

80c

Figure 9.52b O Ph

OH

[(c-octene)2RhCl]2

SnBu3

+

98%

H 176

Ph

158

178 77% ee N

N

Bn

Bn 177

O

H OTMS TMSCN MgCl2

H

CN

95% CN

179

O

O N

N

181 94% ee

Ph

Ph 180

Figure 9.53. Nucleophilic additions to aldehydes.

9.5.9.

Alkylation of Imines and Oximes

Stereoselective addition to carbonyl groups is a powerful tool in organic synthesis and has received a great deal of attention. Addition to imines can be equally as powerful, but has received much less attention. Denmark and co-workers first introduced the use of bis(oxazoline) ligands in the addition reactions of imines.103,104 The most successful ligand has been the modified bu-box ligand 182. This ligand was used both stoichiometrically and catalytically in the reaction between various imines and several alkyllithium species. Selected examples are summarized in Table 9.32 (Fig. 9.54). Nakamura and co-workers used i-pr-box ligand 22 stoichiometrically for the addition of alkyl zinc reagents 186a–c to cyclic imines 187a and 187b.105 This

Carbon–Carbon Bond-Forming Reactions

571

TABLE 9.32. ASYMMETRIC ADDITION TO IMINESa

N R

PMP R1

+

Li Et

H

PMP

HN

184a R1 = Me 184b R1 = CH2=CH

Et

183a R = Ph 183b R = PhCH2CH2 PMP = p-methoxyphenyl

R

O

O N

N

R1

185a R = Ph, R1 = Me 185b R = PhCH2CH2, R1 = Me 185c R = PhCH2CH2, R1 = CH2=CH

182

Figure 9.54 R

R1

% Yield

% ee

Ph PhCH2CH2 PhCH2CH2 Ph PhCH2CH2 PhCH2CH2

Me Me CH2 CH Me Me CH2 CH

95 96 95 98 81 82

75 91 89 68 82 82

mol% 182 1.0 1.0 1.0 0.1 0.2 0.2 a

Data from Ref. 103.

TABLE 9.33. ENANTIOSELECTIVE ADDITION OF ALLYLZINC REAGENTS TO CYCLIC IMINESa

R2 ZnBr R H

R2

ligand 22

+ R2

R1

NH

R2

N R1 R

186a R = H, R1 = H 186b R = Me, R1 = H 186c R = H, R1 = Ph

187a R2 = H 187b R2 = OMe

188a R = H, R1 = H, R2 = H 188b R = H, R1 = H, R2 = OMe 188c R = Me, R1 = H, R2 = OMe 188d R = H, R1 = Ph, R2 = OMe

Figure 9.55a R

R1

R2

H H Me H

H H H Ph

H OMe OMe OMe

a

Data from Ref. 105.

% Yield 72 90 96 92

% ee 95 95 97.5 77

572

Chiral Bis(oxazolines) O

O BnO H

N

N

+

Zn

189

NHOBn

82%

Ph

Ph

CO2t-Bu

N

93% ee

CO2t-Bu

191

190

Figure 9.55b

process led to the 1,2,3,4-tetrahydroisoquinolines 188a–d in yields up to 96% with enantioselectivities up to 97.5% (Table 9.33, Fig. 9.55a). Hanessian’s group investigated the addition reactions of oximes using bis(oxazoline) ligand ent-39.106 As shown in Figure 9.55b, reaction of the a-oximino ester 189 and alkyl zinc reagent 190 afforded the homoallylic hydroxyl amine 191 in 82% yield with an enantioselectivity of 93% ee. 9.5.10.

Asymmetric Polymerization

Bis(oxazoline) ligands have also been used to produce polymers containing main chain chirality. Some examples include those by Wagner and co-workers in which i-pr-box 45 is used to mediate the copolymerization of tert-butylstyrene 192 with carbon monoxide to achieve a polymer of type 193 with stereoregularity up to 98%,107,108 Oishi and co-workers’ polymerization of N-substituted maleimides 194109–111 and Risse and co-workers’ polymerization of substituted cyclopropenes 196112 are shown in Figure 9.56. O CO (1 atm) ligand 45

n

t-Bu t-Bu 192

O

N

193

O

BuLi ligand 7

Ph

O

N Ph

194 Me Me

n

O

195 Pd(II) ligand 6

Me Me

n

196

197

Figure 9.56. Bis(oxazoline)-mediated chiral polymerizations.

Carbon–Carbon Bond-Forming Reactions

9.5.11.

573

Miscellaneous Carbon–Carbon Bond-Forming Reactions

Bis(oxazoline) ligands have been shown to be useful in the many carbon–carbon bond-forming reactions previously listed. They have also been used in a myriad of other carbon–carbon bond-forming reactions. For example, Nakamura and coworkers used bis(oxazoline) ligands ent-2, ent-22, and ent-39 in ligand-induced enantioselective allylzincation.113 This reaction consisted of the transformation of the cyclopropenone acetal 198 into allylic cyclopropanone acetal 199 in yields ranging from 73 to 90% with selectivities from >98:2 for the isomer shown to 1:99 (Fig. 9.57). Ukaji and co-workers employed bis(oxazoline) ligands in the asymmetric bis(alkoxycarbonylation) reaction of homoallylic alcohols.114 One example of this reaction, the conversion of homoallylic alcohol 200 to its carbonylation product 201, is illustrated in Figure 9.58. This reaction proceeded in 78% yield with an ee of 50%. Bis(oxazoline) ligands have also been used to mediate the [2,3]-Wittig rearrangements of allylic ethers. Nakai and co-workers demonstrated the rearrangement of (Z)-crotyl benzyl ether 202 using tert-butyllithium and bis(oxazoline) ligand 203 to form a mixture of erythro 204a and threo 204b rearrangement

O

O N R

N Zn

O R

+

O O H

ent-2 R= t-Bu ent-22 R= i-Pr ent-39 R= Ph

199 73-90% from >98:2 to >1:99

198

Figure 9.57. Allylzincation.

4 mol% PdCl2 8 mol% 138

OH

O

O

O 1.5 equiv CuOTf(C 6H6)0.5

OCH3

200

Bn

O

O

N

N

201 78% 50% ee Bn

138 Figure 9.58. Bis(alkoxycarbonylation).

O

574

Chiral Bis(oxazolines) t-BuLi, 203 hexane, −78 ˚C

O

+ HO

Ph 202

Ph

HO

204a erythro

Ph

204b threo

89:11 40% ee (1R,2S) t-BuLi, 203 hexane, −78 ˚C

O

HO

205

206 93% 75% ee (3S,4S) Et

Et O

O N

N

203 Figure 9.59. [2,3]-Wittig rearrangement.

products.115 The reaction conditions favored the formation of erythro product 204a in a ratio of 89:11 with 40% ee for the (1R,2S) isomer (Fig. 9.59). Under the same reaction conditions, (E)-crotyl propargylic ether 205 was converted into homoallylic alcohol 206 in >90% yield [93:7 erythro, 75% ee for (3S, 4S) isomer]. Allene annulation is yet another reaction in which bis(oxazoline) ligands are used for asymmetric induction.10,116,117 One example, shown in Figure 9.60, is the reaction of N-tosyl-2-iodoaniline 207 with 1,2-undecadiene. This reaction proceeds 5 mol% Pd(OAc) 2 5 mol% ent-9a or 5 mol% ent-9b

NHTs + 5.0 equiv n-C8H17CH=C=CH2 I

Ts N n-C8H17

1.2 equiv Ag 3PO4 DMF, 100 ˚C, 24h

207

208 ent-9a = 98%; 77% ee ent-9b = 90%; 86% ee Figure 9.60. Allene annulation.

Aziridination and Epoxidation

575

in the presence of inda-box ligands ent-9a or ent-9b to afford the annulation product 208 in 98% (77% ee) and 90% (86% ee) yields, from ent-9a or ent-9b, respectively. Other reactions that have been attempted using bis(oxazoline) ligands for chiral H insertion reacinduction include the synthesis of chiral fullerenes118 and C tions,119 which met with moderate success. Also, [2þ2] photocycloaddition120 and Meerwein arylation121 have been attempted, but both of these led to low enantioselectivities.

9.6. AZIRIDINATION AND EPOXIDATION Aziridination and epoxidation of olefins are very important transformations in organic synthesis. Attempts to carry out these reactions enantioselectively by using bis(oxazoline)–metal catalysts have been reported. Evans and co-workers investigated aziridination of cinnamate esters 209a–e using [N-(p-toluenesulfonyl)imino]phenyl-iodinane 207 and copper(I) triflate coordinated to several bis(oxazoline) ligands including phe-box 6.122,123 The results are summarized in Table 9.34 (Fig. 9.61). Jacobsen’s group carried out the conversion of (E)-N-benzylideneaniline 211 to aziridines 212a and 212b (Fig. 9.62).124 Knight and co-workers examined the aziridination of styrene 41 using [N-(p-toluenesulfonyl)imino]phenyliodinane 207.37,125 Jørgensen’s group investigated the conversion of the a-imino esters 214a and 214b to aziridines 216a and 216b.126 However, Waegell and co-workers attempted the epoxidation of trans-stilbene 217 with moderate success (Fig. 9.62).127

TABLE 9.34. AZIRIDINATION OF CINNAMATE ESTERSa

Ar

H + PhI

H

Ts

ligand 6

N

NTs CuOTf

R

Ar 207

209

R 210

Figure 9.61 Ar

R

% Yield

% ee

Ph Ph Ph b-Naphthyl a-Naphthyl

CO2Me CO2Ph CO2CMe3 CO2Me CO2Me

63 64 60 73 76

94 97 96 96 95

a

Data from Ref. 122.

576

Chiral Bis(oxazolines)

Ph

N

[CuPF6(MeCN)4]+

Ph

ligand 6 N2CHCO2Et

Ph

Ph

N

N

+ CO2Et

Ph

211

+ PhI

Ts N

NTs CuOTf

207

41

CO2Et 212b

212a ligand 12a

Ph

Ph

Ph 213

N

+

ligand ent-6

N2

214a R = Ts 214b R = Ph

N

CuClO4

H

EtO2C

EtO2C

TMS

216a R = Ts 216b R = Ph

215

O

O

ligand 1b

Ph

Ph

R

TMS

R

+ RuCl3, NaIO4

Ph

Ph

217

Ph

H 219

218

Figure 9.62. Bis(oxazoline)-mediated aziridinations and epoxidation.

9.7. SULFIMIDATION Uemura and co-workers discovered that prochiral sulfides react with [N-(ptoluenesulfonyl)imino]phenyliodinane 207 in the presence of bis(oxazoline) ligands to form the corresponding chiral sulfimides.128–130 For example, (E)cinnamyl phenyl sulfide 220 reacted with 207 in the presence of copper(I) triflate and ent-6 to form the chiral sulfimide 221 in 80% yield (58% ee) as shown in Figure 9.63.

Ts

ligand ent-6 CuOTf

Ph + PhI

PhS 220

NTs

80%

PhS

N

207 221 58% ee

Figure 9.63. Bis(oxazoline)-mediated sulfimidation.

Ph

Reductions

577

9.8. ALLYLIC OXIDATION Oxidation of olefin containing molecules at the allylic position is yet another important synthetic transformation. There are many examples of oxidation of cyclic olefins including those by Pfaltz’s group.131 These reactions consisted of the oxidation of cyclic olefins 222a–c by tert-butyl perbenzoate in the presence of the copper(I) complexes of ligands 1b, 3, 6, and 45. The corresponding benzoates 223a–c were obtained in yields up to 84% with selectivities up to 84% (ee) (Table 9.35, Fig. 6.64). Other examples of this type of reaction include those conducted by Andrus and co-workers using the copper(I) complex of ligand 224 in the allylic oxidation of cyclohexene.132 As shown in Figure 9.65, this reaction afforded the oxidation product, (1S)-2-cyclohexen-1-yl 4-nitrobenzoate 225 in 76% yield and 73% ee. Clark and co-workers also experimented with the allylic oxidation of cyclohexene using inda-box ent-9b to afford the oxidation product, (1S)-2-cyclohexen-1-yl benzoate, 223b in 76% yield (71% ee).133

9.9. REDUCTIONS 9.9.1.

Hydrosilylation

Reductive hydrosilylations of ketones using chiral C 2-symmetric bis(oxazolines) as catalysts have been studied by many different groups.1,2,7,134–139 Nishiyama and TABLE 9.35. BIS(OXAZOLINE)-MEDIATED ALLYLIC OXIDATIONa

O

ligand

(CH2)n

CuOTf PhCO3t-Bu

(CH2)n

222a n = 1 222b n = 2 222c n = 3

O Ph

223a n = 1 223b n = 2 223c n = 3 Figure 9.64

n 1 1 1 2 2 2 2 3 a

Ligand 45 3 6 45 3 6 1b 45

Data from Ref. 131.

% Yield 66 61 84 69 64 77 80 75

% ee 82 84 71 64 77 67 71 74

578

Chiral Bis(oxazolines) O Cu(SbF6) p-NO2-C6H4CO3t-Bu O

222b

O

C6H4p-NO2

Ph N

Me Me

N

225 76% yield 73% ee

Ph

O 224

O ligand ent-9b Cu(MeCN)4PF6

O

Ph

PhCO3t-Bu

222b 223b 76% yield 71% ee

Figure 9.65. Allylic oxidations of cyclohexene.

co-workers used the orignal bis(oxazolines), especially py-box-ip 1b, for the reduction of many ketones.1,134–136 Acetophenone 226 was one of the most common ketones used in these reactions. They used the rhodium complex of ligand 1b as the catalyst and diphenylsilane as the reducing agent to afford (S)-1phenylethanol 227 (Fig. 9.66). Depending on the Lewis acid additive used, 227 was produced in up to 96% yield and up to 94% ee (Table 9.36). Nishiyama and co-workers also used several cyclic ketones in the hydrosilylation reaction.135 For example, 2-methylcyclohexanone 228 was reduced to form a TABLE 9.36. HYDROSILYLATION OF ACETOPHENONEa

O

OH 1. ligand 1b, PhSiH2 RhCl3•3H2O, additive 2. H+/H2O

226

227 Figure 9.66

Additive none BF3OEt2 AgOTf AgBF4 a

Data from Ref. 1.

% Yield

% ee

0 90 96 91

82 89 94

Reductions

579

OH

O 1. ligand 1b, RhCl3 Ph2SiH2

OH Me

Me +

2. H+/H2O 88% yield cis/trans = 59:41

228

229 91% ee

230 89% ee

Figure 9.67. Hydrosilylation of methylcyclohexanone.

mixture (41:59) of trans-2-methylcyclohexanol 229 and cis-2-methylcyclohexanol 230 in a combined yield of 88%. The selectivities of the products were 91% (ee) for the trans alcohol 229 and 89% (ee) for the cis alcohol 230, as shown in Figure 9.67. 9.9.2.

Transfer Hydrogenation

Another asymmetric reduction using bis(oxazoline) ligands is the transfer hydrogenation reaction studied by Zhang and co-workers.140,141 The transfer hydrogenation reaction of many different ketones including 231a–c have been examined. These ketones were reduced using isopropanol in the presence of the ruthenium complex of bis(oxazoline) ligands 232 or 233. The reaction yields varied widely (up to 100%) and selectivities (up to 97% ee) as summarized in Table 9.37 (Fig. 9.68). TABLE 9.37. BIS(OXAZOLINE)-MEDIATED TRANSFER HYDROGENATION OF KETONES O R

OH

[RuCl2(C6H6)]2 base, i-PrOH ligand

R1

R

234a R = Ph, R1 = Me 234b R = i-Bu, R1 = Et 234c R = t-Bu, R1 = Me

231a R = Ph, R1 = Me 231b R = i-Bu, R1 = Et 231c R = t-Bu, R1 = Me O

O

N

Ph

N

Ph

P

R1

HN

N

Ph

N

Ph

O

O

233

232

Figure 9.68 R

R1

Ph i-Bu t-Bu Ph

Me Et Me Me

Ligand 232 232 232 233

% Yield

% ee

Reference

72 100 85 91

79 63 92 97

140 140 140 141

580

Chiral Bis(oxazolines)

9.10. MISCELLANEOUS REACTIONS Many examples of the use of chiral C 2-symmetric bis(oxazoline) ligands have been presented here. Other examples include their use in various heteroannulations, one of which is shown in Figure 9.69. Here, the vinyl iodide, (Z)-3-iodo-2-methyl2-propen-1-ol, 235 is condensed with 1,2-undecadiene to form the 3-methylene-2Hpyran derivative 237.142 When this reaction was run in the presence of 10 mol% of bis(oxazoline) ligand 236 complexed with palladium(II), 237 was produced in 70% yield with 79% ee. Bis(oxazoline) ligands have also been used in Wacker-type cyclizations.143 For example, the phenolic derivative 238 was cyclized in the presence of ligand 13b complexed with palladium(II) to yield the 2,3-dihydrobenzofuran 239 in 86% yield with an ee of 94% (Fig. 9.70). 5 mol% Pd(OAc) 2 10 mol% 236

OH + n-C8H17CH=C=CH2

O n-C8H17

1.2 equiv Ag 3PO4 DMF, 80 ˚C, 4 h

I 235

237 70%; 79% ee O

O N

N Ph

Ph 236

Figure 9.69. Heteroannulation example.

Pd(II)-L*

O

benzoquinone MeOH

OH 238

239 86%; 94% ee O

L* =

N

N O 13b

Figure 9.70. Wacker-type cyclization.

Miscellaneous Reactions

581 Cl

O

O

B

B O

n-BuLi, 6

O

Yb(OTf) 3

240

241 86% ee

O

O N

N Ph

Ph 6

Figure 9.71. Synthesis of (a-chloroalkyl)boronates.

Yet another use for bis(oxazoline) ligands is in the synthesis of (a-chloroalkyl) boronates.144 As shown in Figure 9.71, the alkylboronate 240 was converted to the a-chloro derivative 241 in 86% ee through the use of ytterbium(III) triflatecomplexed phe-box 6. Enantioselective amination of enolsilanes has also benefited from the use of bis(oxazoline) lignads.145 For example, (Z)-1-phenyl-1-(trimethylsilyloxy)-1-propene, 242 was condensed with 243 using copper(II) triflate-complex bu-box ligand 3 to afford 244 in 95% yield (99% ee) as shown in Figure 9.72. Bis(oxazoline) ligands have also been employed in the catalytic enantioselective aza-Claisen rearrangement of allylic imidates,146 chirality recognition in the determination of the ee of 1,10 -bi-2-naphthol,147 and the enantioselective formation of double and triple helicates.148 O

O

TMSO + Cl3CCH2O Ph

N

N

O

O

242

243 10 mol% 3 Cu(OTf) 2 CF3CH2OH, 3 h

O O

O

Ph N

N Troc

3

O

O N

N H

N

O

244

Troc = 2,2,2-trichloroethoxycarbonyl

Figure 9.72. Enantioselective amination of enolsilanes.

582

Chiral Bis(oxazolines)

9.11. CONCLUSION As evident in this chapter, metal complexes of chiral bis(oxazoline) ligands are versatile catalysts for a wide variety of asymmetric transformations. An extensive list of applications has been presented in this chapter. Since the first report of the synthesis of a chiral C2-symmetric bis(oxazoline) by Nishiyama in 1989, innumerable articles dealing with design, synthesis, and applications of bis(oxazoline) ligands have appeared in the literature. Many new catalytic systems have been devised by employing a variety of metals, counterions and ligands designed from natural and unnatural amino acids or amino alcohols. An impressive level of enantioselectivities, isolated yields, and catalytic efficiencies have been achieved in many cases. The effectiveness of these catalysts and the overall importance of enantio- and diastereoselection in synthesis, especially in this pharmaceutical age, insures that chiral C2-symmetric bis(oxazoline) ligands will be an important part of organic synthesis for years to come (Table 9.38).

TABLE 9.38. BIS(OXAZOLINE) LIGANDS Ligand

References

Ligand

O

O O N

N

O

N N

33, 77, 78

N Bn

Bn 1, 2

R

R

References

R = Ph R = i-Pr R = t-Bu R = i-Bu

O

O N

N

33, 34

OH

HO

O

O

N N

N

O

O 39

N

N

42

OTMS

TMSO

O

O Ph 98, 99

N Bn

N

Ph

N

33, 77, 78

N Bn

OTBS

OTBS

Conclusion

583

TABLE 9.38 (Continued) Ligand

References

N

R1

O R1

N

N

N

R

R

R

R

References

O

O

O

Ligand

R = Me, R1 = Ph R = CH2OH, R1 = H R = Et, R1 = H

R = t-Bu R = i-Pr R = Ph R = Bn

O

O Ph

O

O N

Me

Me

N

Ph

N

O

O N

N

5

Et O

O N

103, 104

N

O

Ph

Me

N

Me

N

132

Ph

O Et

Et O

O N

51

N Ph

Ph

O R

N

N

O

O

N

N

R

R 14

O

R

5

Ph

Ph

24

N

Et

3

3

R = Ph R = i-Pr R = t-Bu

7

R = Ph R = i-Pr R = t-Bu

O

O

O 33, 77, 78

Bn

N

N

O

O N

N

Bn Ph

Ph

15

584

Chiral Bis(oxazolines)

TABLE 9.38 (Continued) Ligand

References

Ligand

O

O N

N

8

References

O O

O N

O

N

13

R

R R = Ph R = i-Pr R = t-Bu

O R

N

N

R 38

O O

R = i-Pr R = t-Bu

O NH HN

O

O N

80

N

O N PPh2 PPh2 N

Fe

R R

12

R

O

O N

R = i-Pr R = t-Bu

N

9 ðR ¼ HÞ 10 ðR ¼ MeÞ R=H R = Me

O

O N

R

O

N

4 O

O Ph

N

N

Ph

3

Ph

11

Ph

Ph

O

O

N

6

N

O

O

Ph

Ph

Ph

N

N Ph

Ph

O

O N

N

4

O

O N Ph

17

N Ph

Addendum

585

TABLE 9.38 (Continued) Ligand

References

Ligand

89, 90

N

N

i-Bu

i-Bu

O

O

O

O

References

N Ph

N RO

OR

Ph

40 R = COPh R=H R = COMe R = Me R = Bn R = SiMe2t-Bu

O

O N

142

N

Et

Ph

Ph

Et O

O N

O N P N

Ph

O

140, 141

Ph HN

O

115

N

N

Ph

N

Ph

140, 141

O

9.12. ADDENDUM Chemistry involving chiral C 2-symmetric bis(oxazoline) catalysts remains an exciting and dynamic field, which is evidenced by the number of publications concerning their use since the completion of this chapter. The recent manuscripts deal with a variety of aspects in this field. Some highlights of this research include the use of bis(oxazoline) catalysts in the Mukaiyama-Michael reaction of alkylidene malonates and enolsilanes by Evans and co-workers.149 One example of this reaction shown in Figure 9.73 depicts the reaction of the enolsilane [(1-tertbutylthio)vinyl]oxy trimethylsilane 245 with dimethyl benzylidenemalonate 246. The reaction is catalyzed by 10 mol% of complexed bu-box ligand 3 in a mixture of 2,2,2-trifluoroethanol, toluene and methylene chloride at 78
C and produced the corresponding thioester 247 in 91% yield with 93% ee. Evans also investigated the use of bis(oxazolines) in the catalysis of carbonyl-ene reactions with glyoxylate and pyruvate esters,150 the cycloadditions of silyl ketenes151 and further investigated their utility in hetero Diels–Alder reactions.152 Another recent example of the use of chiral C2-symmetric bis(oxazoline) ligands is the work by Mamai and co-workers.153 This group studied the cyclopropanation reaction of oxazolidinones 80a and 80b using diphenylsulfonium isopropylide 248,

586

Chiral Bis(oxazolines) TMSO

Ph

CO2Me

+ t-BuS

CO2Me

245

246 10 mol% 3 Cu(SbF6)2 CF3CH2OH, PhMe, CH2Cl2, −78 ˚C

O

O

O N

N

Ph CO2Me

t-BuS

CO2Me 3

247 91%, 93% ee

Figure 9.73. Enantioselective Mukaiyama–Michael addition of enolsilanes. TABLE 9.39. CYCLOPROPANATIONS WITH SULFUR YLIDESa Ph

-

S+

O

O

Ph

O

O

248

O

N

R

O

Lewis acid THF, −78 ˚C

N

R

249a R = Me 249b R = Ph

80a R = Me 80b R = Ph O

O N

N Ph

Ph ent-6

Figure 9.74 Substrate 80a 80a 80a 80a 80a 80a 80b 80b a

Lewis Acid

equiv

Zn(OTf)2 ZnBr2 Sn(OTf)2 MgI2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 MgI2

1 1 1 1 0.75 0.75 1 1

Data from Ref. 153.

% Yield 63 60 60 66 65 63 69 70

% ee 95 93 81 46 82 55 36 14

Addendum

587 O Ph

O Me

N

HO Me

OH

Me

N

N

OH

Me OH

O N Ph O 250

251

Figure 9.75. Biaryl bis(oxazolines).

as shown in Figure 9.74. The reaction afforded cyclopropane derivatives 249a and 249b in yields ranging from 60 to 70% and ee as high as 95% (Table 9.39, Fig. 9.74). Many other groups further studied the utility of bis(oxazolines) including Ikeda’s use of biaryl bis(oxazolines) such as 250 (Fig. 9.75) in the zinc-catalyzed asymmetric alkylation of benzaldehyde with diethylzinc.154 This reaction proceeded in yields up to 92% with ee up to 88%. Kodama and co-workers used a biaryl bis(oxazoline) ligand, namely, [1,10 -]binaphthalenyl-2,20 -diol (BINOL)-box 251, in the lanthanide-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones to alkenes.155 Bandini and co-workers studied the zinc triflate-bis(oxazoline)-catalyzed reduction of a-alkoxy-ketones with catecholborane.156 The example in Figure 9.76 shows the reduction of a-methoxyacetophenone 252. 1-Phenyl-2-methoxyethanol 254 was isolated in 78% yield and 82% ee.

O

OH

O B-H

OMe

OMe

O 253-Zn(OTf) 2

252

254 78%, 82% ee O

O N

N

Ph

Ph 253

Figure 9.76. Reduction of a-alkoxy-ketones.

588

Chiral Bis(oxazolines) OH Ph

S

Se Ph

1. base 2. 45

Ph

S

Li

Ph2CO

Ln

S

Ph

*

Ph Ph

Ph

Ph

Ph

255

256

257 93%, 93% ee O

O N

N

45

Figure 9.77. Addition of an a-thioorganolithium reagent to aldehydes.

Nakamura and co-workers examined the use of bis(oxazolines) in the addition of a-thioorganolithiums to various aldehydes.157 One example, shown in Figure 9.77, produced the corresponding hydroxysulfide 257 in 93% yield with an ee of 93%. Glos and co-workers introduced the aza-bis(oxazolines) 258 and 259 (Fig. 9.78) as a new class of chiral C 2-symmetric bis(oxazoline) ligands.158 These catalysts were used in various reactions such as enantioselective allylic substitution and cyclopropanation; it was also shown that these new catalysts could easily be tethered to a polymeric support, as shown in structure 259, allowing for facile recovery of the catalyst. There have been other examples of bis(oxazoline) ligands immobilized on solid supports and their use in catalysis.159–162 These methods have shown mixed results. Another new use for chiral bis(oxazolines) is the Friedel–Crafts reaction of aromatic and heteroaromatic compounds. Jørgensen and co-workers found that the

R1

O

N

O N

M

O

O

n

N

N

R = i-Pr, t-Bu 1

R = H, Me, Bn

t-Bu

M = Cu, Pd 258

N

O

R

R

259

Figure 9.78. Aza-bis(oxazolines).

Cu

O N t-Bu

Addendum

589

TABLE 9.40. BIS(OXAZOLINE)-MEDIATED FRIEDEL–CRAFTS REACTIONS OF INDOLESa

R3

R3 R2 +

260

F3C

CO2Et CF3

10 mol% 4 0 ˚C to rt

O N R1

HO

CO2Et

R2

Et2O

N R1

261

262

O

O N

N

3 Figure 9.79 R1

R2

R3

Me H Me

H H Me

H H H

% Yield 94 93 88

% ee 89 83 94

a

Data from Ref. 163.

use of bu-box 3 with copper(II) triflate catalyzed the condensation of various indoles 260 with ethyl trifluoropyruvate 261.163 This condensation afforded a chiral hydroxy-trifluoromethyl ester substituent in the 3-position of the indole ring in yields up to 94% with ee ranging from 83 to 94% (Table 9.40, Fig. 9.79). Inda-box ent-9a has been used recently in the production of the natural product ()-malyngolide 265.164 The key step of the synthesis by Ghosh and Shirai, as shown in Figure 9.80, is the hetero-Diels–Alder reaction of Danishefsky’s diene 112 and a-ketoester 263 to afford the pyranone derivative 264 in 77% yield and 47% ee that was converted into ()-malyngolide in several additional steps. The preparation of different pyranones was investigated using different a-ketoesters. The selected examples shown above, together with numerous others, represent an extension of the vast amount of information regarding chiral C2-symmetric bis(oxazolines) and their uses in asymmetric transformations. The utility and importance of this chemistry continues to be demonstrated as more applications for these complexes are discovered.

590

Chiral Bis(oxazolines) O

TMSO O

EtO2C

77%

(CH2)8CH3

+ (CH2)8CH3

47% ee

O

OMe 112

263

O

O N

CO2Et 264

Me (CH2)8CH3

N O

O OH

ent-9a

265 (−)-malyngolide

Figure 9.80. Synthesis of ()-malyngolide.

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592

Chiral Bis(oxazolines)

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Author Index

The entries in this index refer to the chapter number (boldface) and the reference number.

Abbady, M. S. 7 730 Abbas, I. M. 7 178 Abbiati, G. 7 1029 Abbotto, A. 8 348, 349 Abboud, K. 5 58 Abboud, K. A. 6 178 Abd El-Fattah, B. 7 742 Abd El-Maged, M. F. 7 686 Abd El-Sami, Z. K. 7 806 Abdallah, M. A. 7 178, 648 Abdelatif, F. M. 7 887 Abdel-Gawad, N. M. 7 840 Abdel-Ghaffar, S. A. 7 67 Abdel-Halim, A. M. 7 470 Abdelhamid, A. O. 7 175 Abdelhamid, H. A. 7 648 Abdelhamid, K. 7 705 Abdell-Rahman, A. R. H. 7 550, 551 Abdel-Motaleb, R. M. 7 176 Abd-el-Rahman, A. H. 7 552 Abdel-Razik, E. A. 7 552 Abdou, S. B. 7 550 Abe, Y. 5 48, 49, 60, 61, 62, 82, 86 Abiko, A. 9 3 Abou-El-Regal, M. M. K. 7 469 Abou-Gharbia, M. 6 16, 17 Abrecht, C. 7 263 Acevedo, M. 7 390, 391, 392, 393 Adachi, K. 8 44 Adachi, M. 6 197 7 538 Adam, W. 7 62, 63 Adams, J. 8 79 Adams, J. B., Jr. 6 94, 96 Addor, R. W. 7 29 Adetchessi, O. 8 519 Adler, F. 7 513 Aebi, J. D. 8 331 Afanasiadi, L. Sh. 7 446, 447, 448, 449, 972 Afifi, A. A. 7 544, 656

Afify, A. A. 7 733, 832, 833, 835, 891 Agarwal, C. 7 726 Agarwal, K. 7 718 Agarwal, R. 7 704, 717, 721, 726 Aggarwal, V. K. 7 913 9 52 Agrios, K. A. 8 137, 319 Aguilar, E. 8 152 Ahluwalia, V. K. 7 811 Ahmad, N. F. 7 175, 178 Ahn, K. H. 8 41, 366, 376 Aicher, T. D. 8 54 Aı¨t-Haddou, H. 9 40 Aitken, D. J. 8 139 Ajo, D. 7 981, 991, 993 Akaji, K. 7 197 Akamatsu, M. 7 995b Akiba, M. 7 16, 17, 19 Akita, M. 8 405 Akopyan, A. Z. 7 777, 778 Al-Ashmawi, M. I. 7 707 Albinati, A. 8 420, 421 9 25 Alcaraz, C. 7 644 Alekseeva, E. A. 8 249 Alekseeva, L. M. 7 495 Alexander, K. 8 88 Ali Harb, A. E. 7 847 Ali, M. 7 493, 899 Ali, M. B. 7 369 Aljaz-Rozic, M. 7 162, 537 Alkaabi, S. S. 7 662 Alla, S. R. 6 188 Allemann, S. 8 311 Allen, J. V. 8 201, 202, 412 Aller, E. 7 502 Allimony, H. A. 7 848 Almario, A. 8 283 Almirante, N. 7 15 Al-Najjar, F. A.-R. 7 133 Alonso, D. A. 8 63

The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

595

596 Alonso, R. A. 8 230 Alp, S. 7 974 Al-Sayyab, A. F. 7 133 Al-Tha’an, R. S. 7 561 Altorfer, M. 7 262, 263 Altorfer, M. 8 196 Alvarado, S. I. 7 233 Alvarez, P. 7 668, 669 Alvarez-Ibarra, C. 8 315, 316, 326, 327 Alvarez-Larena, A. 7 428, 954 8 276 Aly, Y. L. 7 470 Amer, M. M. 7 733 Amer, M. M. Y. 7 832 Ametamey, S. M. 6 193, 194 Amin, A. S. 7 962, 966 Amine, M. S. 7 546 Amir, M. 7 709 Ammar, Y. A. 7 686 Ammar, Y. V. 7 67 Andersch, W. 7 570 Andersen, K. K. 7 317 Anderson, B. A. 9 122 Anderson, E. S. 9 52 Andersson, K. 6 127 Andersson, P. 9 34 Andersson, P. G. 8 63, 283 9 13 Ando, J. 5 53, 54, 55, 56 Ando, K. 8 323 Andracki, M. E. 7 78 Andreasch, R. 8 1 Andre`-Barre`s, C. 8 13 Andrei, M. 7 301 Andreichikov, Yu. S. 6 63, 64 Andreu, R. 8 197 Andronati, S. A. 7 465 Andrus, M. B. 8 47 9 132 Angelov, D. 7 64 Annapurna, J. 7 924 Anteunis, M. J. O. 5 22 Antohe, N. 7 232 Antonenko, V. V. 7 465 Antonious, M. S. 7 973 Aoi, K. 8 502 Aoki, K. 6 26, 27, 28 9 26, 32 Aoyagi, S. 7 461 Aoyama, H. 6 101 Arabori, H. 7 183, 186 Arahori, H. 7 185, 189 Arai, M. 9 113 Arai, T. 5 75 Aref, H. 7 678, 705 Arenal, I. 7 491, 917, 918 Argyropoulos, N. G. 7 927, 928

Author Index Arief, M. M. H. 7 747 Arikawa, Y. 8 367, 462, 477 Arison, B. H. 7 786 Ariza, X. 7 112, 114, 115 Arlandini, E. 7 15, 316 Armstrong, D. W. 6 62 Arnhold, F. S. 7 273 Artemov, V. N. 5 29 Asami, K. 6 172, 173 Asano, H. 9 21, 22 Asano, M. 7 453, 454 Asano, T. 8 321 Ascher, R. 6 1 Asgari, D. 8 47 9 132 Ashare, R. 7 155, 163, 651 Askin, D. 8 278 Aspinall, H. 9 102 Ataka, K. 5 12, 90, 91, 92 Attah, F. U. 7 475 Aube´, J. 8 137, 303, 319 Aubry, A. 7 286, 418, 936, 990 Audia, J. E. 7 667, 670, 671, 672, 673, 674 Aufderhaar, E. 8 4 Augier, C. 9 127 Augustin, M. 7 531, 535, 536, 562, 889 Austin, P. W. 7 458 Avenoza, A. 7 646, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 1025, 1026 8 273 Avetisyan, S. A. 7 468 Azimov, V. A. 7 495 Baba N. 7 925 Babievskii, K. K. 7 474 Babirad, S. A. 7 351, 371 Bachurina, I. B. 7 205 Bacon, F. 7 351 Badawy, M. A. 7 727 Badiang, J. G. 8 303 Badr, M. Z. 7 681, 682 Badr, M. Z. A. 7 688 Baek, H.-H. 8 41 Baeva, G. N. 7 768 Bagno, A. 7 198, 433 Bagnoli, L. 8 252, 253, 254 Bailey, K. L. 7 676 Baird, C. P. 9 129 Bajji, A. C. 6 188 Bakeer, H. M. 7 838 Baker, R. W. 8 397, 398 Bakhmutov, V. I. 7 474 Bakos, J. 7 445, 567 Balaban, A. T. 7 300, 301, 302, 303, 304, 1001

Author Index Balaban, M-C. 7 304 Balaram, P. 7 292, 293, 426 Balashova, E. G. 6 71 Balavoine, G. G. A. 9 40, 107 Balboni, G. 7 787 Baldwin, J. E. 7 620 Balegroune, F. 7 320 Ball, R. G. 6 107 Balog, E. 7 1014 Baloglu, E. 8 83 Bal’on, Ya G. 5 4, 93 Bambury, R. E. 7 350 Bandini, M. 9 139, 156 Bandoli, G. 8 215 Bandyopadhyay, C. 7 655 Banecki, B. 7 1016 Banerjee, A. K. 8 45 Banerjee, S. 8 25 Banerji, A. A. 7 218, 221 Banfi, L. 6 97 Banji, D. 7 1009 Banoub, J. 8 94 Bansal R. K. 7 888, 910 8 325 Bapodra, A. 7 807, 823 Barbosa, J. 8 43 Barco, A. 7 103, 104 Barnes, D. M. 9 28, 54, 55, 95, 122 Barone, V. 7 279, 290, 417 Barrett, A. G. M. 6 40 Barriobero, J. I. 7 1026 Barrish, J. C. 8 114 Barstow, J. F. 7 88 Barta, N. S. 7 876 Barth, J. 7 125 Barthwal, J. P. 7 472, 719, 720, 736, 737 Bartlett, P. A. 7 88 Barton, D. H. R. 8 24 Bartoshevich, Yu. E. 7 595 Baruah, J. N. 7 152, 330, 332, 333 Baruah, P. P. 7 488 Basova, N. Y. 7 866 Basova, Yu. G. 6 76 Bates, R. B. 7 297, 904 Bateson, J. H. 6 47, 84 Batsanov, A. S. 8 120 Batty, C. A. 6 52 Bauer, D. P. 7 593, 900 Bauer, W. 7 406, 407, 408, 409, 1004, 1031 Baum, G. 6 44, 45 Bavoso, A. 7 270, 271, 290, 291, 436 Baxi, A. J. 7 729, 809, 810 Bayeul, D. 7 418 Bayoumy, B. E. 7 806

597

Bazureau, J. P. 8 293, 294, 295, 296 Bazyl, O. K. 7 410 Bebernitz, G. R. 8 54 Beccalli, E. M. 7 519 Bechle, B. M. 6 184 Beck, W. 7 406, 407, 408, 409, 1004, 1031 Beckert, R. 6 195 Bedekar, A. 9 34 Bedekar, A. V. 8 37, 198 9 13 Behnke, M. L. 8 79 Beholz, L. G. 7 876 Belal, A. A. M. 7 967 Beleta, J. 5 80 Belgodere, E. 6 13 Belikov, V. M. 7 791 Bell, P. A. 8 54 Bell, R. A. 7 986 Belluco, U. 8 215 Belokon, Yu. N. 7 205 Belt, J. W. 8 214 Benard, J. F. 7 56, 57 Bendiashvili, T. M. 7 397 Benedetti, E. 7 270, 271, 277, 283, 287, 290, 291, 294, 295, 296, 436 Benetti, S. 7 103, 104 Benicewicz, B. C. 8 182, 183 Benkovic, P. A. 6 53 Benkovic, S. J. 6 53 Bennett, C. D. 7 786 Bennett, L. L., Jr. 8 2 Bennett, S. 9 20 Benoiton, N. L. 7 12, 13, 76, 77, 196, 203, 245, 248, 249, 250, 414, 526 Benovsky, P. 7 876 Benson, M. G. 7 602 Berens, U. 7 639 Berg, D. 7 660 Berger, M. 7 56, 57, 58, 61 Berghot, M. A. 7 696 Bergman, J. 7 4, 5 Berliner, M. A. 8 169 Berman, F. W. 8 321 Bernabe, M. 7 491, 642, 643, 644, 917, 918 Bernardi, A. 9 91 Bernardinelli, G. 9 148 Berranger, T. 8 13 Berridge, M. 6 137 Bertani, R. 8 215 Bertilsson, S. K. 8 63 Bertounesque, E. 8 43 Bes, M. T. 8 186 Betlakowska, B. 7 1016 Beugelmans, R. 8 30

598

Author Index

Bevinakatti, H. S. 7 218, 220, 228 Be´zard, D. 6 106 Bhalerao, U. T. 7 423, 911, 923, 924, 956, 957 Bhalla, M. 7 702 Bhalla, T. N. 7 702, 719 Bhargava, K. P. 7 801 Bhatt, J. J. 7 723 Bhatt, K. N. 7 699, 700 Bhatti, A. M. 7 314 Bhuniya, D. 8 92 Bhushan, K. R. 7 1020 Bhuyan, P. J. 7 324 Bianco, A. 7 427 Bien, S. 5 36 Bieri, J. H. 7 23, 44 Biggers, M. S. 8 360 Bigham, W. S. 7 371 Bigot, A. 8 30 Bihari, F. 7 445, 567 Bilegan, C. 7 569 Billedeau, R. 7 89 Bilodeau, M. T. 9 122, 123 Biradar, J. S. 7 739 Birchler, A. G. 8 323 Bischoff, C. 6 56 Bish, C. J. 7 514 Bitiev, Sh. G. 7 47, 48, 621 Black, D. St. C. 8 68 Blacker, A. J. 8 430, 434, 487 Blackmond, D. G. 8 359, 473 Blacque, O. 8 188 Bland, J. 7 289, 421, 922 Bland, J. M. 7 921 Blank, H. U. 6 20 Blankenstein, J. 8 458 Blasco, J. 7 641, 665 Blaser, H.-U. 8 456 Blubaum, J. E. 8 36 Blu¨chel, C. 9 121 Bobo, S. 8 102 Boden, C. D. J. 8 148 Boeriu, C. 7 594 Boersma, J. 8 381 Boesten, W. H. J. 7 281, 282, 284, 285, 440 Bogdanova, L. I. 7 476 Bogen, S. L. 8 305 Bohdal, U. 7 111, 258, 260, 263 Bohlmann, F. 6 134 Bo¨hme, F. 8 506 Bohus, P. 7 445 Boije, M. 6 127 Bois-Choussy, M. 8 30, 59 Boisnard, S. 8 59

Bojkova, N. 7 45 Boll, P. M. 7 603 Bolm, C. 8 178, 179, 370, 372, 373, 374, 378, 469, 470, 471, 472, 500 Bolton, G. L. 7 230 Bonati, L. 7 326 Bonk, P. J. 6 58, 60 Bonora, G. M. 7 270, 277, 279, 281, 282, 283, 284, 285, 290, 291, 294, 295, 296, 417, 418, 436, 438 Bonse, G. 6 20 Boog-Wick, K. 8 173 Borer, B. C. 8 126 Bornemeier, D. A. 6 67 Boros, P. 7 567 Bortolussi, A. 7 922 Boruah, A. 7 488 Bosc, J. J. 8 520, 521, 522 Bosman, J. 8 308 Bossio, R. 7 505, 506, 507 Bosze, S. 7 1014 Bottari, P. 6 178 Bouchu, D. 8 31 Boulch, R. 8 119 Boullanger, P. 8 94 Boulton, A. J. 6 117 Bourzat, J-D. 6 106 Bousquet, E. 7 812 Boussard, G. 7 990 Bower, J. F. 8 202, 203, 204, 412 Bowers, C. Y. 7 607 Boyce, R. J. 8 146, 147 Boyd, E. C. 8 224 Boyd, G. V. 6 5, 14 7 1 Bozhkova, N. 7 24 Brachaczek, A. 7 998 Brady, S. F. 7 786 Brady, T. E. 7 233 Braemer, B. 7 443 Bran˜a, M. F. 7 145 Brand, G. 9 148 Brand, L. J. 8 54 Bratusek, U. 7 540, 542 Braun, N. A. 8 31, 134, 135 Braunstein, P. 8 461 Bravo, P. 5 17, 18 Bray, D. D. 7 317 Bray, J. D. 8 31, 135 Bremberg, U. 8 210 Breuning, M. 7 215 Brieva, R. 7 220 Bringmann, G. 7 215 8 396 Brinkmann, A. 8 460

Author Index Brittain, D. R. 6 147 Broady, S. D. 8 66 Broersma, R. J. 8 101 Broger, C. 7 258 Bromidge, S. 9 66 Bronder, M. 6 21 Brookhart, M. 9 107, 108 Brooks, C. F. 8 507 Brooks, D. A. 8 169 Brouillette, W. J. 6 164 Brovarets, V. S. 7 168, 170, 515, 516, 520 Brown, B. R. 8 114 Brown, G. B. 6 164 Brown, J. M. 8 453 9 24 Brown, S. A. 7 999 Brown, S. M. 9 20 Broxterman, Q. B. 7 283, 284, 285, 434, 437, 996 Bruneau, C. 5 94 Brunet, J. C. 7 619 Brunner, H. 8 220 9 121 Bruvo, M. 6 161 Bryce, M. R. 8 120 Bu¨chi, G. 8 288 Buchko, G. W. 7 56, 58, 59, 60, 61 Buchman, R. 6 105 Budeanu, C. 7 65, 66, 232 Budnik, J. 7 555, 556 Bunnage, M. E. 8 157, 158, 159 Bun˜uel, E. 7 430, 431, 432, 952, 953, 955, 994, 1030 Bur, D. 7 258 Burger, K. 7 49, 51, 90, 91, 92, 93, 94, 252 Burgess, E. M. 8 133 Burgess, K. 8 118, 419, 457, 459 9 119 Burgey, C. S. 8 230 9 57, 68, 84, 85, 150 Burghard, H. 7 885 Burguete, M. I. 9 159 Burke, A. J. 8 157, 158 Burkhart, J. P. 8 101 Burns, C. T. 8 36 Burrell, G. 8 164 Buschmann, J. 8 302 Busetti, V. 7 991, 993 Busse, J. K. 8 126 Busson, R. 8 172 Busto, J. H. 7 937, 941, 942, 943, 944, 945, 946, 947, 1025 8 273 Butler, D. C. D. 8 170 Butora, G. 5 58, 59 Bychenko, N. V. 6 34, 35, 36 Cabezas, N. 6 131 Cabezas, R. 6 130

599

Cabrera, E. V. 8 45 Cabri, W. 8 125 Caddick, S. 7 211 Cadet, J. 7 56, 57, 58, 59, 60, 61 Cahiez, G. 8 386 Cai, D. 9 39 Cai, Z. 7 126 Calderon, S. 7 789 Calenbergh, C. V. 8 172 Campbell, C. L. 6 94, 96 Campbell, M. 8 104 Campos, K. R. 9 28, 68, 83, 85 Canete, A. 7 328, 1002 Cannella, R. 7 117 Cano, F. H. 7 644 Cantello, B. C. C. 6 125 Cao, B.-X. 8 180 Capecchi, J. T. 7 366 Cappiello, J. 8 19 9 9, 16, 48, 64, 70 Capriati, V. 8 345, 346, 347, 348, 349, 350, 351 Capuano, L. 6 21 Caraculacu, A. A. 7 396 Caraculacu, G. 7 396 Carcano, M. 8 78 Cardelu´s, I. 5 80 Cardillo, G. 8 189, 190, 191, 259, 264, 265, 266, 267, 268, 269 Caroll, P. J. 8 223 Carpy, A. 8 521 Carpy, A. J. M. 7 992 Carroll, M. A. 8 115 Carulla, N. 7 223 Caruso, A. 7 812 Casadei, M. A. 6 154, 155, 156 Cascieri, M. A. 6 107 Casiraghi, G. 7 95 Cassels, R. 6 84 Castelhano, A. L. 7 89 Castelot-Deliencourt, G. 8 355 Castonguay, L. 9 30 Castro, M. 9 40 Cativiela, C. 7 253, 254, 413, 429, 430, 431, 432, 434, 477, 512, 573, 574, 580, 581, 622, 627, 633, 637, 638, 641, 645, 646, 664, 665, 693, 789, 916, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 952, 953, 955, 979, 981, 982, 991, 993, 994, 1023, 1024, 1025, 1026, 1030 8 273 Catt, J. D. 8 338 Cavicchio, G. 5 18 Cavicchioni, G. 7 286 Cawthorne, M. A. 6 125 Cecere, M. 6 100

600

Author Index

Cerny, M. 5 77 Cervantes-Lee, F. 5 98 Cesa, S. 6 154, 155, 156, 157 Cetenko, W. A. 6 65, 66 Chaimbault, C. 8 521, 522 Chalk, R. 8 48 Chambers, R. J. 8 360 Chan, A. S. C. 7 217 8 451, 494, 501 Chan, K. 6 67 Chan, R. 8 161 Chan, T. H. 6 72 7 905 Chandler, M. 8 105, 108 Chang, C.-W. T. 8 141 Chang, H. M. 7 589 Chanteloup, L. 8 310, 313 Chao, J. 8 51 Chaplin, D. A. 7 215 Charbonneau, R. R. 7 344 Charbonnie`re, L. J. 9 148 Charett, A. B. 8 493 Chatten, L. G. 6 23 Chatterjee, R. K. 7 805 Chaturvedi, S. C. 7 511 Chau, P. 8 396 Chaudhary, A. G. 8 85 Chaudhary, C. 7 704 Chaushyan, K. A. 7 777 Chauveau, B. 8 310, 313 Chel’tsova, G. V. 7 47, 48, 242, 751, 758, 764, 766 Chelli, M. 6 13, 162 Chelucci, G. 8 123, 206, 208, 209, 212, 427, 495 Chen, C.-S. 8 84 Chen, F. M. F. 7 12, 13, 76, 203, 245, 248, 250, 414, 526 Chen, J. 7 109 Chen, J. J. 7 108 Chen, S.-H. 8 86, 87 Chen, Y. 7 27, 32, 41 Chen, Y-Q. 7 28 Cheng, H. 8 171 Cheng, X. 8 428 Cherry, P. C. 8 107 Chervinskii, A. Yu. 5 29 Chesney, A. 8 120 Chetry, A. B. 7 483 Chevalier, S. 7 379, 381 Chiara, J. L. 8 102 Chiba, J. 7 959 Chiba, T. 7 874, 879, 880 Chibber, S. S. 7 958 Chieffi, G. 8 287 Chien, K.-M. 8 260 Chifu, E. 7 456

Chimichi, S. 6 162 Chirva, U. Ya. 8 309 Chiyoda, T. 6 140 Cho, C.-W. 8 41, 366, 376 Cho, H. 9 48 Cho, Y.-J. 8 115 Choi, H.-w. 8 193, 233 Choi, S. 8 332 Choi, S-K. 6 82 Choi, W-B. 7 236 Chomei, N. 7 538 Chorev, M. 7 129 Choshi, T. 5 79 Chou, T. T. 6 184 Chow, H.-F. 8 177 Chow, T. J. 5 25, 88 Chowdary, Y. R. 7 864 Christoffers, J. 8 28 Christopherson, R. I. 6 52 Chrystiuk, E. 7 202 Chu, I. K. 7 1005 Chuang, T.-H. 8 178 Chuaqui, C. A. 7 299, 311, 312 Chubb, R. W. J. 8 120 Chueca, J. 7 693 Chun, K. H. 7 964 Chung, H. 8 512 Chung, K.-G. 8 437, 438, 450 Chung, N. N. 7 623 Churakov, A. V. 8 380 Churchill, M. R. 9 19 Cianciosi, S. J. 8 278 Ciarkowski, J. 7 203 Cioranescu, E. 7 302 Cipens, G. 7 251, 309 Cı´sarˇova´, I. 8 122 Ciske, F. L. 8 39, 324 Ciufolini, M. A. 8 31, 134, 135 Ciugureanu, C. 7 232, 234 Clark, D. A. 6 83, 184 Clark, J. E. 8 205 Clark, J. S. 9 133 Clark, M. L. 8 434 Clarke, D. S. 8 199 Clarke, M. L. 8 430, 487 Clark-Lewis, J. W. 6 92 Clausnitzer, C. 8 506 Clerici, F. 7 117, 121, 238, 316, 319, 478, 518, 519, 882, 951, 1027, 1028, 1029 8 195 Cochran, D. W. 7 786 Codding, P. W. 6 90 Coffen, D. L. 7 1013 Cohen, L. A. 5 10, 11 7 16, 17, 19, 307, 618

Author Index Cohen-Suissa, R. 7 129 Colacot, T. J. 8 457 Colceru-Mihul, S. 7 66 Coleman, P. L. 7 354, 357, 359, 363, 367, 368 Collado, M. I. 6 174 Colligan, P. B. 8 380 Colman, B. 8 156 Colombo, D. 8 132 Colombo, G. 9 91 Colombo, L. 7 95 Colsen, K. 8 321 Coman, V. 7 456 Comar, D. 6 137 Combret, J.-C. 8 217 Combret, Y. 8 217 Commercon, A. 6 106 Connell, B. T. 9 85 Connor, D. T. 6 65, 66, 67 Conole, G. 9 20 Conti, S. 8 216 Conway, S. C. 7 661 Cook, G. R. 8 282, 284 Cook, S. 8 88 Coote, S. J. 8 201 Copar, A. 7 157, 158 Coppola, G. M. 6 104 Corbin, C. 8 310, 313 Cordaro, M. 7 1003 Corey, E. J. 8 332 Corey, E. J. 9 6, 8, 17, 100 Cornforth, J. 7 652, 896 Cossu, S. 8 216 Costanza, C. 5 7 Cottam, G. P. 6 125 Cotton, R. 7 14, 278 Coutouli-Argyropoulou, E. 7 647, 927, 928, 929 Couture, P. 6 19 Cox, C. 8 262, 263 Cozzi, P. G. 8 426 9 98, 139, 156 Crespo, M. I. 5 80 Crevel, H. 5 24 Crews, A. D., Jr. 7 233 Crich, J. Z. 7 220 Crisma, M. 7 198, 271, 279, 281, 282, 283, 284, 285, 286, 289, 290, 291, 292, 293, 294, 295, 296, 412, 416, 417, 418, 420, 421, 425, 426, 427, 433, 434, 436, 437, 438, 439, 440, 441, 1000, 1006 Cristoni, S. 7 413 Croft A. P. 7 898 Crossley, M. J. 8 160 Crucianelli, M. 5 17, 18 Csa´ky¨, A. G. 8 315, 316, 326, 327

Csampai, A. 7 1014 Csaszar, A. G. 7 980 Csermely, G. 7 595 Csik, G. 7 1014 Cso¨regh, I. 8 283 Cucek, K. 7 529, 530, 861 Cufos, T. 7 949 Cui, X. 8 459, 501 Cuingnet, E. 7 619 Curcuruto, O. 7 981 Curiel, D. 7 503 Curini, M. 8 125 Curley, P. E. 7 786 Curran, D. P. 8 167 9 15, 49 Cygler, M. 7 466 Cywin, C. L. 8 342 Czuba, I. R 8 396 d’ Angelo, J. 7 428 d’ Orchymont, H. 7 10 D’Amico, M. 7 159 D’Anello, M. 7 122 D’Silva, C. 7 788 Daffe, V. 7 201, 206, 207, 208 Dage, R. C. 5 78 Dahuron, N. 8 353, 354 Dai, G. 7 487 Dai, H. 7 588 Dai, L-X. 7 913 8 180, 371, 447 Dain, J. G. 8 54 Dalko, P. I. 8 306 Dalla Croce, P. 7 339 Dalton, D. R. 8 52, 223 Daly, J. 7 260 Damalidis, T. 8 175 Damon, R. E. 6 104 Danagulyan, G. G. 7 583 D’Andrea, S. V. 5 72 Danesi, A. 8 300 Danishefsky, S. J. 8 242 Das, P. J. 7 483 Date, T. 9 51 Datta, D. B. 7 650 DattaGupta, A. 8 488 Daulouede, S. 8 522 Dave, A. M. 7 699, 700 Dave, U. 7 722, 731 Davidovich, Yu. A. 7 474 Davidson, B. S. 8 16 Davidson, J. S. 6 109 Davies, I. W. 8 248 9 10, 30, 39, 117 Davies, J. S. H. 6 118, 119 Davies, S. G. 8 157, 158, 159

601

602 Davisson, V. J. 7 987 Davtyan, D. A. 7 791 Dawood, N. T. A. 7 837 Dawson, G. J. 8 201 De Angelis, M. 9 156 De Bruyn. A. 8 172 de Frutos, M. P. 7 643, 644 de Gracia, I. S. 8 102 De Heredia, I. P. 7 1012 De Jaeger, R. 8 505 De Jesu´s Rosales, M. 5 16 De Jonghe, S. 8 172 De Keukeleire, D. 8 172 de Meijere, A. 8 185, 186 De Menego, E. 7 417 De Mesmaeker, A. 6 160 De Risi, C. 7 103, 104 De Schryver, F. C. 7 624 de Sousa, S. E. 8 156 Debitsudo, J. K. 7 659 DeCian, A. 9 29 Deems, R. 8 54 Degennaro, L. 8 347 Degnan, A. P. 8 46, 406 Dehaen, W. 8 308, 516 Dehmlow, E.V. 8 213 Dehne, H. W. 7 660 Dekker, J. J. 7 590 Delaney, S. 7 299 Delgado, F. 5 16 DeLorey, T. M. 6 164 Deng, W.-P. 8 447 Deng, X. 7 27 Denmark, S. E. 8 121 9 103, 104 Dennison, K. A. 7 372 Deriu, S. 8 206 Deriu, S. P. 8 208 Derwin, W. S. 7 640 Desai, N. C. 7 723 Desai, U. R. 8 25 Deshpande, V. H. 8 37, 198 Desimoni, G. 9 11, 46, 47, 77 Desor, D. 8 519 Destexhe, R. 6 88 Destree, A. T. 8 79 Destro, R. 7 238, 878 Deyrup, J. A. 5 65 Dhal, R. 8 310, 313 Dhaneshwar, S. R. 7 511 Dhar, D. N. 7 154 Dhasmana, A. 7 472 Dhir, B. S. 7 149 Dhoubhadel, S. P. 7 566, 971

Author Index Di Blasio, B. 7 270, 271, 277, 290, 291, 294, 295, 436 Di Toro, V. 6 100 Diaz, P. 7 949 Diaz-de-Villegas, M. D. 7 253, 254, 430, 431, 432, 477, 512, 573, 574, 581, 641, 645, 646, 665, 916, 930, 931, 932, 933, 934, 935, 940, 952, 953, 955, 981, 982, 991, 993, 994, 1030 Diehl, R. E. 7 33 Diepers, W. 8 4 Dietrich, A. 6 150 Diksic, M. 6 139 Dillon, M. P. 7 1013 DiMaio, J. 7 905 DiMichele, L. M. 8 246, 247 Dimmerling, A. 7 504 Ding, L. 7 588 Ding, M.-F. 5 88 Dirat, O. 8 13, 14 Dirlam, J. P. 6 83 Dirlam, N. L. 7 131 Divanyan, N. M. 7 604 Dixit, K. S. 7 736 Dixneuf, P. H. 5 35, 94 Djarrah, H. 6 25 Djojo, F. 9 118 Dobnikar Tehovnik, M. 7 532 Dobnikar, M. 7 533 Dodd, J. H. 8 38 Doebler, C. 7 629, 631, 632, 635, 636 Doehner, R. F., Jr. 7 233 Doi, K. 7 970 Dolmella, A. 8 215 Domı´nguez-Ferna´ndez, C. 8 326 Donde, Y. 8 435, 441 Dong, J. C. 7 350 Dong, L. 7 126 Dong, X.-W. 8 447 Dong, Y. 6 61 Donghi, M. 8 78 Donia, S. G. 7 839 Dorofeyeva, O. V. 7 482 Doubleday, R. 6 67 Douglas, A. W. 8 247 Douglas, K. T. 7 788 Dow, R. L. 6 184 Downey, C. W. 9 149 Downing, S. V. 8 152 Doya, M. 6 146 Doyle, M. P. 8 489, 490 9 121 Doyle, T. W. 8 86 Drach, B. S. 7 168, 515, 520 Draghici, C. 7 1001

Author Index Drahonˇosvsky´, D. 8 122 Drofenik, I. 7 165 Droste, J. J. 7 667, 670, 671, 672, 673, 674 Drtina, G. J. 7 375 Drury, W. J., III 8 262 Du, M. 7 652, 896 Du, Z. 7 109 Du, Z. M. 7 108 Duan, J. J.-W. 8 43 Dubreuil, J. F. 8 296 Duerr, D. 7 30 Duff, P. T. 6 125 Dumas, F. 7 428 Dunina, V. V. 8 380 Durgaryan, L. K. 7 777, 778 Durko, A. 7 445 Durko, M. 7 567 Dutt, S. K. 7 958 Dutzmann, S. 7 660 Dvorˇa´k, D. 8 122 Dvorˇa´kova´, H. 8 122 Dwivedi, R. 7 857, 860 Dwyer, M. P. 8 352 Dyer, R. D. 6 65, 66, 67 Eastwood, F. W. 8 257 Ebinger, A. 9 41 Ecija, M. 7 502 Edwards, J. P. 8 121 Eggersdorfer, M. 7 49 Eggleston, D. S. 6 47 Eguchi, S. 6 31, 32 Ehrenfreund, J. 7 30 Eid, M. M. 7 727 Eifert, G. 7 445, 567 Eisentra¨ger, F. 8 421 Ekborg-Ott, K. H. 6 62 El Baba, S. 7 792 El Kady, S. S. 7 544 Elagamey, A. A. 7 734 El-Aishy, M. 7 694 El-Amin, S. A. 7 444, 728 El-Baba, S. 7 795 Elbanani, A. A. A. 7 180 El-Borai, M. 7 549 El-Dawany, A. I. 7 728 El-Deen, I. M. 7 547 El-Ebrashi, N. M. A. 7 654 El-Ela Hassan, A. A. 7 136 El-Enany, M. M. 7 742 Eletti Bianchi, G. 6 191 Elfahham, H. A. 7 177 El-Farargy, A. F. 7 694, 912

603

El-Fattah, B. A. 7 808 El-Fedawy, M. 7 701 El-Feky, S. A. 7 806 Elfyn Jones, D. 9 52 El-Ghamry, I. A. 7 552 El-Hashash, M. A. 7 544, 546, 656, 694, 733, 832, 891, 912 El-Housseni, M. S. 7 841 El-Kady, S. S. 7 656, 891 Elkafrawy, A. F. 7 836 El-Kassaby, M. A. 7 469 El-Kateb, A. A. 7 906 El-Khamry, A. A. 7 834 El-Kousy, S. 7 179 Elliott, M. C. 8 110, 111, 410, 433 Ellis, D. 7 602 El-Maghraby, A. M. 7 842 El-Maghraby, M. A. 7 136 El-Mariah, F. A. A. 7 848 Elmoghayar, M. R. H. 7 886 El-Mossalamy E. H. 7 962, 966 Elnagdi, M. H. 7 176, 177, 179, 180, 192, 193, 195, 854, 855, 886, 887 El-Nagdy, S. 7 549, 833, 834, 835 ElNnaggar, G. M. 7 705 Els, H. 6 70 El-Sabagh, U. I. 7 707 El-Said Mustafa, M. 7 70 El-Sawy, A. A. 7 839 El-Sayed, Y. A. 7 973 El-Sharief, A. M. S. 7 545, 686, 725 El-Shenawy, A. I. 7 839 El-Sherief, H. A. 7 802 El-Sherief, H. A. H. 7 681, 682, 705 Eltamany, E. H. 7 553 El-Zahab, M. M. A. 7 846 El-Zimity, M. T. 7 701 Emmett, J. C. 7 602 Endo, T. 7 267 Endoh, K. 7 194 Endoma, M. A. A. 6 178 Eng, K. K. 8 278 Engle, L. P. 7 360, 389 Englisch-Peters, S. 7 903 Enna, M. 9 72 Erba, E. 7 15, 106, 122, 238, 305, 316 Erdelen, C. 7 36, 660 Eremenko, L. T. 8 312 Erian, A. W. 7 179 Erlenmeyer, E., Jr. 7 463b, 463c Erpenbach, H. 7 592 Escher, I. H. 8 486 Eslam, E. E. 7 195

604

Author Index

Esmaiel, A. A. 7 802 Essawy, S. A. 7 839 Es-Sayed, M. 8 185 Esswein, A. 6 189 Esumi, T. 8 239 Etschenberg, E. 7 772, 773, 774, 775 Ettorre, A. 7 294 Eury, R. P. 7 403 Evans, A. R. 7 87 Evans, D. A. 9 4, 28, 45, 50, 53, 54, 55, 57, 67, 68, 81, 82, 83, 84, 85, 96, 97, 122, 123, 145, 149, 150, 151, 152 Evans, J. M. 8 164 Evans, P. A. 8 361 Everett, G. M. 6 121 Evrard, D. A. 7 667, 670, 671, 672, 673, 674 Eweiss N. F. 7 892 Ewenson, A. 7 129 Exsted, B. J. 7 370 Ezell, E. F. 5 7 Ezhova, G. I. 7 167 Ezquerra, J. 7 668, 669 Fabbro, D. 5 24 Faber, K. 7 212 Fabian, W. 6 43 Facchetti, A. 8 62 Fache, F. 8 415 Fadayan, M. 7 708 Fadda, A. A. 7 166 Fadhil, S. 7 776 Faggiani, R. 7 986 Fahmi, A. A. 7 178, 648 Fahrni, C. 9 78 Fahrni, C. J. 8 29 Fairchild, C. 8 86 Faita, G. 9 11, 77 Faiti, G. 9 46, 47 Falciani, M. 7 159 Faleeva, L. N. 6 6, 37 Falorni, M. 8 216 Fang, J.-M. 8 178 Fanta, P. E. 8 402 Farag, A. M. 7 192, 193, 854, 855 Farina, V. 8 86 Fascetti, E. 6 191 Fastrez, J. 7 201, 206, 207, 208 Fatma, N. 7 805 Faucher, A.-M. 8 121 Faul, M. M. 9 4, 122,123 Fawzy, N. M. 7 657 Fayet, J. P. 7 982 Fazio, R. C. 7 352, 358, 384, 385

Fearnley, S. P. 5 58, 59 Feinauer, R. 8 4 Feixas, J. 5 80 Felice, A. 7 812 Fe´lix, C. P. 8 258 Feng, X. M. 8 501 Fernandez, J. 7 627, 633 Ferna´ndez, K. M. 8 370, 372, 373 Fernandez, M. D. 7 642, 643, 644 Fernandez, M. J. 7 633 Fernandez-Alvarez, E. 7 491, 643, 917, 918 Fernandez-Bolan˜os, J. 7 609 Fernandez-Recio, M. A. 7 1026 Feroci, M. 6 156 Ferraccioli, R. 7 326, 339 Ferraris, D. 8 262, 263 Feuillet, S. 8 295 Fiammengo, R. 7 996 Fiege, M. 8 286 Filler, R. 5 2 6 3 7 3, 976 Fillers, W. S. 8 54 Finkbeiner, H. 6 185 Finney, N. S. 9 124 Fiorini, M. 7 625 Fischer, C. 7 639 Fischer, J. 7 21, 53, 54 9 29 Fischer, P. M. 8 77 Fisher, S. L. 7 608 Fishwick, B. R. 7 458 Fitzgerald, M. E. H. 6 119 Flanagan, M. E. 8 53 Fleisher, M. 9 101 Flemming, S. 7 220 Fletcher, F. A. 7 297 Flippen-Anderson, J. L. 7 427 Flores, J. M. 6 123 Florio, S. 8 345, 346, 347, 348, 349, 350, 351 Flubacher, D. 8 436 Fludzinski, P. 7 671, 673, 674 Foces-Foces, C. 7 644 Foley, J. E. 8 54 Folkers, K. 7 605, 607 Folpini, E. 7 882 Ford, A. P. D. W. 7 1013 Forfar, I. 8 518, 519, 520 Formaggio, F. 7 198, 282, 283, 284, 285, 286, 294, 295, 296, 418, 420, 427, 433, 434, 437, 438, 439, 440, 441, 1000, 1006 Formisano, R. 7 215 Fossati, N. 6 97 Foster, B. S. 8 247 Foti, F. 7 1003 Fradet, A. 7 390, 391, 392, 393, 394

Author Index Fraile, J. M. 7 429 9 159, 160 Francis, A. 8 308, 516 Frank, C. W. 8 507 Fraser-Reid, B. 8 230 Fraternali, F. 7 279, 290, 417 Frechet, J. M. 7 378, 382 Fredenburgh, L. E. 8 246, 247 Freeman, J. P. 5 72 Freeze, S. 6 196 Fresneda, P. M. 7 500 Friends, G. D. 7 349 Friestad, G. K. 8 43 Fritch, P. C. 8 149, 318 Fritsch, V. 6 160 Fritschi, S. P. 7 273 Fronczek, F. R. 7 601 Fronza, G. 5 17, 18 Frost, C. G. 8 201 Frump, J. A. 8 3 Fryczkowska, B. 7 310 Fu, G. C. 7 96, 97, 213, 214 Fu, Z. 8 98, 445, 446 Fuchikami, T. 7 617 Fuchs, P. L. 8 237 Fujieda, H. 8 334 Fujiki, K. 8 504 Fujimoto, H. 5 79 Fujimoto, K. 6 75 Fujinami, T. 5 13 Fujita, M. 7 617 Fujita, T. 6 128 Fujita, T. 8 81, 82 Fujiwara, Y. 8 496 Fukumura, T. 6 183 Fukunaga, H. 6 91 Fukuyama, H. 8 238 Fukuzaki, T. 9 56 Fuller, G. G. 8 507 Furch, J. A. 7 29, 33, 37 Furneaux, R. H. 8 129 Furuhata, K. 8 255, 256 Furuike, T. 8 131 Furukawa, I. 8 57 9 155 Furukawa, N. 8 399 Gaa, K. 7 90, 91, 92, 93, 94, 252 Gable, R. W. 8 395 Gaeta, F. C. A. 7 582 Gagneux, A. R. 5 19 Gagnon, D. R. 7 368 Gainsford, G. J. 8 129 Gainza, M. P. 7 645 Gajare, A. S. 8 37

605

Gal, Y-S. 6 82 Galambos, T. 7 595 Galan, E. 7 396 Galdiero, S. 7 296 Galina, T. P. 7 71 Galstyan, L. Kh. 7 604 Galvez, E. 6 130, 131, 132 Ga´lvez, J. 8 197 Galvez, J. A. 7 431, 994 Gambini, A. 7 951, 1027, 1028, 1029 8 195 Gange, D. M. 7 233 Gant, T. G. 8 9, 58 9 8 Ganz, K. T. 9 7 Garavaglia, C. 6 100 Garcı´a Paredes, C. 8 250 Garcı´a Ruano, J. L. 8 250 Garcia, J. I. 7 429, 573, 664, 665, 693, 931, 952, 981, 982 9 159, 160 Garcia, M. V. 6 149 Garcı´a-Verdugo, E. 9 159 Garg, S. P. 7 712 Garrett, C. E. 7 214 Gaset, A. 7 486 Gathergood, N. 9 163 Gatos, M. 7 296 Gaucher, A. 7 1000 Gaud, R. S. 7 511 Gebhardt, I. 7 567 Geffken, D. 6 94, 95, 96, 98, 110, 111, 112, 113, 114, 115 Gehrmann, K. 7 592 Geith, K. 7 90, 91, 92, 93, 94 Gelmi, M. L. 7 107, 117, 121, 122, 238, 305, 319, 327, 478, 518, 519, 878, 882, 883, 951, 1027, 1028, 1029 8 195 Gennari, C. 8 78, 314 Genov, D.G. 8 117 Gentilucci, L. 8 189, 190, 191, 259, 264, 265, 266, 267, 268, 269 George, C. 7 427 George, M. V. 7 315 Gerena, L. 9 30, 39 Germain, G. 7 23, 44, 320 German, A. B. 7 595 Gerus, I. I. 7 613, 614 Gerwick, W. H. 8 321 Gheorghiu, M. D. 7 300, 303, 304 Ghiviriga, I. 6 178 Ghoneim, K. M. 7 742 Ghoneim, M. K. 7 808 Ghosez, L. 9 69 Ghosh, A. K. 8 19 9 9, 16, 48, 64, 70, 164 Ghosh, C. K. 7 655

606

Author Index

Ghosh, G. 7 464 Ghosh, S. 7 650 Giacomelli, G. 8 216 Gianotti, M. 8 267, 268, 269 Gibson, C. L. 8 88 Gieren, A. 7 51 Gil, A. M. 7 1030 Gilbertsen, R. B. 6 67 Gilbertson, S. R. 8 98, 117, 141, 431, 445, 446 Giles, R. 9 52 Gill, A. 8 383 Gilon, C. 7 129 Ginak, A. I. 6 76, 78, 80, 182 Ginanneschi, M. 6 13, 162 Gingrich, H. L. 5 65 7 19, 307 Ginos, J. Z. 6 136, 138 Giomi, D. 8 298, 299, 300 Giongo, M. 7 625 Giralt, E. 7 223 Girges, M. M. 7 696, 846 Giuliano, R. M. 8 235 Gladiali, S. 8 123, 212, 495 Gleria, M. 8 505 Glorius, F. 9 80 Glos, M. 8 243 9 158 Gloster, D. F. 7 317 Godessart, N. 5 80 Godin, J. R. P. 7 466, 782 Godreau, P. V. 7 663 Godunova, L. F. 7 244, 411, 614, 750, 752, 753, 754, 755, 756, 757, 760, 763, 768, 769 Goedeweeck, R. 7 624 Goeth H. 7 852 Gogas, K. R. 7 1013 Goguadze, T. 7 405 Gohar, A. K. M. N. 7 654 Gokhale, A. S. 9 131 Gol’dberg, M. L. 7 448 Gold, M. 7 51 Goldenberg, H. 8 112 Goldenberg, H. J. 8 114 Golic, L. 7 578, 770 Golobic, A. 7 825 Golobicˇ, A. 8 187 Go´mez, A. 5 16 Gomez, B. 7 312 Go´mez, M. 8 20 Go´mez, Ma. R. 6 124 Gommaa, A. M. 7 912 Gonzalez, D. 5 59 Gonzalez, M. 7 939 Goodwin, C. J. 8 157, 158, 159 Goossen, L. J. 8 221

Gorbunova, M. O. 6 37 Gorenc, A. 6 50 Gorizdra, T. E. 6 190 Gormanns, M. 8 95 Gorrichon, J. P. 7 486 Go¨schke, R. 5 19 Goshaev, M. 8 401 Gothelf, K. V. 9 73, 74, 75 Gottwald, K. 7 215, 216 Gou, D.-M. 8 84 Gozzo, F. 6 100 Graci, L. 7 294 Graiff, C. 8 461 Grainger, R. 5 94 Granik, V. G. 7 495 Gras, H. 7 619 Grasshoff, J. M. 7 785 Grassi, G. 7 1003 Graumann, J. 7 84 Graven, A. 9 62 Greeff, D. F. 7 590 Greene, T. W. 8 6 Greeves, N. 9 102 Grenier, L. 8 79 Grenz, A. 8 374 Grieder, A. 7 263 Griehl, C. 7 75, 80 Griesbeck, A. G. 8 286 Grimaldi, P. 7 281 Grimme, W. 8 34 Gronowitz, S. 7 634 8 26 Gross, P.H. 8 100 Groves, D. 8 106 Groves, D. R. 8 103 Gruber, F. 8 506 Gruetzmacher, H. 7 25 Grunewald, G. L. 6 164 Grutke, S. 8 506 Grymel, M. 7 172, 517 Gschwend, H. W. 8 356 Gu, Q. M. 7 229 Gu, R, L. 7 219, 220 Guan, J. 8 38 Guanti, G. 6 97 Guella, G. 6 33 Guenot, P. 8 165 Guerpin, V. 8 217 Guerry, D. 7 380 Guglietta, A. 6 67 Guichard, B. 7 379, 381 Guilhem, J. 7 1000 Guirado, A. 8 197 Guiry, P. J. 9 24

Author Index Gulden, K.-P. 8 396 Gum, A. G. 5 58, 59 Gunaga, P. 7 1009 Gunatilaka, A. A. L. 8 85 Gunst, J. 8 172 Gu¨nther, K. 8 370, 373 Gupta, A. A. 7 683, 695, 716 Gupta, A. K. S. 7 695 Gupta, A. D. 8 92 Gupta, G. P. 7 472 Gupta, K. B. 7 703 Gupta, M. M. 7 716 Gupta, N. 8 325 Gupta, T. K. 7 472, 720 Gu¨rther, S. 9 89 Gutie´rrez, E. 8 326 Guziec, F. S., Jr. 5 26, 27 Haagenson, D. C. 8 380 Haasbroek, P. P. 7 992 Habashy, M. M. 7 834, 973 Haber, M. T. 6 136 Habib, O. M. O. 7 841 Haddou, H. A. 9 107 Hafez, E. A. 7 887 Hagihara, M. 5 12 Hagiwara, K. 7 34, 38 Haidukewych, D. 8 69 Haigh, D. 6 125 Hall, J. 9 29 Hall, S. E. 8 112, 114 Halldin, C. 7 144, 610 Hallman, K. 8 225 9 162 Halterman, R. L. 8 454 Haltiwanger, R. C. 6 47 Halve, A. 7 467 Ham, W. H. 8 279, 280 Hamana, M. 7 164 Hambley, T. 6 52 Hamdan, A. 8 356 Hamed, M. M. 7 912 Hamelin, J. 8 200, 293, 294, 295 Hamid, A. M. 6 117 Hamilton, D. N. 6 105 Hammad, N. I. S. 7 686 Han, W.-C. 8 112, 114 Hanessian, S. 9 106 Hanna, M. A. 7 696, 846 Hannout, I. B. 7 678 Hansel, J.-G. 8 281 Hansen, D. 9 7 Hansen, K. B. 9 124 Hansen, W. 6 77

607

Hansson, U. 8 26 Hanumanthu, P. 7 828, 843, 849, 1021, 1022 Hara, K. 7 995b Hara, K.-j. 8 162 Hara, K.-z. 8 162 Harada, M. 6 135 Haratake, M. 5 50, 66 Harb, A. A. 7 545, 686, 725, 734 Harb, A. F. A. 7 842 Harb, N. M. S. 7 469 Hardy, P. M. 7 14, 275, 276, 277, 278, 279 Hardy, R. A., Jr. 6 79 Harhash, A. H. 7 180 Harigel, K. K. 7 885 Harm, A. M. 8 168 9 37, 125 Harmer, M. A. 9 160 Harnden, M. R. 6 54 Harris, D. N. 8 112, 114 Harris, F. W. 7 403 Harris, N. 7 649 Hartke, K. 6 44, 45 Hartmann, W. 5 64 Hartner, F. W., Jr. 6 4 7 2 Hartwig, A. C. 8 161 Hasain, M. I. 7 706 Hashimoto, N. 5 68 Hashimoto, Y 5 31, 32, 33 8 449 Hashizume, T. 8 130, 423, 424, 450 Hassan, A. A. 7 961 Hassan, H. M. 7 701, 841 Hassan, M. A. 7 469, 549 Hassaneen, H. M. 7 648 Hassanein, H. H. 7 707, 840 Hassila, H. 9 36 Hasuoka, A. 6 197 Hatakeyama, H. 7 626 Hatakeyama, S. 8 238, 239 Hatano, M. 8 497 Haubrich, J. E. 7 374 Haudrechy, A. 8 13 Hauser, E. 8 301 Hayashi, M. 8 442, 444, 449 Hayashi, T. 8 116, 448, 479 9 14, 143 Hazell, R. G. 9 63, 71, 73, 75, 76, 126, 163 Heard, P. J. 9 27 Heck, R. F. 8 439 Hecker, S. J. 6 83 Heil, B. 7 567 Heilmann, S. M. 7 100, 101, 239, 340, 341, 342, 343, 344, 345, 346, 348, 351, 354, 355, 357, 359, 361, 362, 366, 367, 375, 386, 388, 399, 400, 401, 402

608

Author Index

Heimgartner, H. 6 193, 194 7 22, 23, 24, 43, 44, 45, 50, 85, 86, 237, 240, 255, 256, 257, 268, 269, 272, 273, 274, 308, 997 Heine, H. G. 5 64 Heinemann, C. 7 114 Heinz, T. 9 41 Hell, W. 6 21 Hellmann, H. 8 4 Helmchen, G. 8 21, 385, 436 9 7 Hembre, J. I. 7 359 Hemenway, M. S. 8 161 Heminger, E. 8 101 Hendrix, C. 8 172 Henry, S. S. 8 42 Her, G.-R. 8 260 Herbert, R. H. 6 107 Herdeis, C. 7 504, 577 Herdewijn, P. 8 172 Heredia, A. 5 80 Hermanns, N. 8 179, 374, 378, 469, 471 Herrerı´as, C. I. 9 160 Herrmann, W. A. 8 221 Hershenson, F. M. 7 318 Hewage, S. 9 148 Hibbs, D. E. 8 175 Hibino, S. 5 79 Hida, M. 7 626, 796 Hidai, M. 8 367, 462, 467, 477, 478 Hidaka, K. 6 135 Hidasi, G. 7 595 Higashi, K. 7 246, 247 Higuchi, C. 7 560, 596 Higuchi, N. 8 285 Higuchi, R. 7 459, 460 Higuchi, T. 5 41, 60, 61, 62, 63, 82, 84 Hildebrand, J. P. 8 179, 374, 378, 469, 471, 472, 500 Hilgraf, R. 8 425, 426 Hill, D. 7 230 Hill, R. K. 6 72 Hindley, R. M. 6 125, 126 Hinman, M. M. 9 4 Hino, F. 7 298 Hioki, T. 6 187 Hirai, A. 9 105 Hirai, K. 6 99 Hiramatsu, H. 9 51 Hirao, T. 9 12 Hirasawa, R. 6 140 Hiremath, S. P. 7 739 Hirobe, M. 5 41, 49, 60, 61, 62, 63, 81, 82, 84, 86 Hirosawa, C. 8 251 Hirotsu, Y. 8 334

Hirsch, A. 9 118 Hitotsuyanagi, Y. 6 177 Hoarau, O. 9 40 Hoberg, H. 6 102 Ho¨berg, T. 8 283 Hoemann, M. Z. 8 137, 319 Hoerstermann, P. 7 592 Hoess, E. 7 252 Hoffman, R. V. 5 95, 96, 98 Hofmann, M. 7 380 Hoge, R. 6 21 Holerca, M. N. 8 71 Holland, G. F. 6 129, 159 Hollenstein, R. 6 193 Holly, F. W. 7 786 Holmes, G. L. 7 369 Holt, E. M. 7 289, 421, 422 Holubek, J. 6 68 Homami, S. 7 865 Homami, S. S. 7 142, 525, 528, 863, 895 Honda, H. 8 304 Honda, T. 7 330, 335 Honda, Y. 9 51 Hong, W. 7 126 Honma, T. 5 90, 91, 92 Honold, K. 6 189 Hoogsteen, K. 6 107 Hook, W. H. 6 118, 119 Hoornaert, G. 7 83 Hopkinson, A. C. 7 1005 Hori, K. 8 57, 261 9 155 Hori, M. 5 31, 32, 33 6 99 Horie, S. 7 450 Horie, Y. 8 449 Horihata, M. 9 1 Horii, K. 7 199, 200 Horn, G. W. 7 601 Hornback, W. J. 7 1011 Horne, D. A. 8 271 Horne, S. 7 89 Horwell, D. C. 7 230 Hoshi, H. 7 173, 174 Hoshikawa, K. 7 241 Hoshino, O. 7 6, 591 Hosni, A. A. 7 892 Hosogai, A. 7 82 Hosomi, A. 8 290 Hosoya, M. 7 880 Hou, D.-R. 8 118, 419, 457, 459 Hou, X.-L. 8 180, 371, 447 Howard, J. A. K. 8 120 Howell, C. F. 6 79 Howes, P. D. 8 107

Author Index Hoyng, C. F. 7 73, 74 Hsi, J. D. 8 383 Hu, H. 7 109 Hu, H. W. 7 108 Hu, J. 8 142 Hua, W. 7 217 Huang, A. 6 61 Huang, H. 7 79, 235 Huang, S. 8 87 Huang, S.-L. 8 260 Huang, Y. 8 223 Huber, C. P. 7 466 Huber, T. 8 506 Hudecz, F. 7 524, 526, 1014 Hudlicky, T. 5 58, 59 Hudlicky´, T. 6 178 Huebner, T. 7 51 Huerta, J. M. 5 80 Hugener, M. 7 50, 240 Hulin, B. 6 184 Hull, K. G. 8 43 Hulme, A. N. 8 42, 404 Humphries, M. E. 8 430 Hu¨nenberger, P. 8 311 Hursthouse, M. B. 8 175 Hursthouse, M. B. 9 24 Hurtado, F. 7 500 Husain, M. 7 890 Husain, M. I. 7 703, 804, 822 Husson, H.-P. 8 139 Hutchings, R. H. 8 389, 390 Hutchins, R. O. 8 52 Hutchison, A. J. 6 148 Hvala, A. 7 161, 540, 542, 578 Hwang, B. K. 7 229 Iacovino, R. 7 283, 294, 296 Ibarzo, J. 5 80 7 428, 954 8 276 Ibata, T. 8 297, 334, 335 Ibrahim, H. K. 7 553 Ibrahim, M. K. A. 7 182, 886 Ibrahim, M. N. 7 561, 776 Ibrahim, S. S. 7 470 Ichihara, M. 6 135 Ichihara, Y. 6 177 Ichinose, I. 7 181, 188 Ichinose, K. 7 39 Icil, H. 7 974 Icli, S. 7 974 Ide, T. 8 35 Iida, K. 6 140 Iitaka, Y. 5 49 Iitakura, R. 7 347

609

Ikai, K. 8 335 Ikeda, I. 8 144, 377, 429 9 12, 38, 137, 154 Ikeda, K. 8 304 Ikeda, S. 7 796 Imai, E. 5 31, 32, 33 Imai, N. 9 6 Imai, Y. 8 144, 377, 429 9 38, 137, 154 Imberge, P. R. 7 779 Imperiali, B. 8 240 Imperialii, B. 7 608 Inaba, T. 8 323 Inata, H. 7 387 Inesi, A. 6 154, 155, 156 Ingrosso, G. 8 346 Inman, C.G. 8 288 Inomata, K. 9 114 Inoue, Y. 8 40 Invernizzi, A. G. 9 47 Iovel, I. 9 101 Irie, H. 8 238, 239 Isagawa, K. 9 18 Iserloh, U. 8 167 Ishibashi, K. 8 55 Ishibashi, Y. 8 97 Ishibuchi, S. 5 40, 42, 43, 44, 50 8 76 Ishihara, H. 5 47 Ishihara, J. 9 56 Ishihara, K. 8 74 9 17 Ishihara, M. 6 91 Ishii, K. 7 347 Ishii, Y. 8 478 Ishikawa, K. 7 267 Ishikawa, N. 7 70 Ishizuka, T. 5 40, 41, 42, 43, 44, 45, 47, 50, 51, 52, 66, 67, 68, 69, 70, 71, 73, 74, 75, 85 8 35, 76 Islam, A. M. 7 545, 678 Islam, I. E. 7 837 Isloor, A. M. 7 1009 Ismail, I. M. 7 545 Ismail, M. F. 7 831 Ismail, M. M. 7 808 Isobe, T. 7 82 Isono, H. 6 49 Isono, T. 7 26 Istrati, D. 7 1001 Ito, J. 8 57 9 155 Ito, K. 9 93 Ito, T. 6 28 Ito, Y. 8 285 Itoh, K. 8 475 9 1, 31, 32, 134, 135, 136, 147 Itoh. Y. 7 199, 200 9 31, 32 Itokawa, H. 6 177 Ivanova, G. 7 150

610

Author Index

Ivas, E. 7 65 Iwabuchi, Y. 8 239 Iwahara, T. 8 405 Iwasa, S. 8 67 Iwashima, M. 8 43 Iwashita, J. 5 75 Iwata, A. 6 140 Iyengar, D. S. 6 24 7 423, 911, 923, 924, 956, 957, 968 Izquierdo M. L. 7 917 Izzo, P. T. 6 2 Jacobi, H. 7 773 Jacobine, A. F. 7 98, 99 Jacobsen, E. N. 8 362 9 124 Jacobsen, N. W. 6 15 Jacobson, L. 7 1013 Jacquault, P. 8 200 Jacquot, S. 8 188 Jadhav, P. K. 9 144 Jaegers, E. 7 592 Jaeschke, G. 7 215 Jaime, C. 7 665 Jain, A. 7 140 Jain, C. B. 8 325 Jain, J. K. 7 888 Jamali, M. R. 7 706 James, B. 8 403 Jamnicky´, M. 8 207 Jancˇik, F. 6 68 Jancso, G. 7 595 Janda, K. D. 7 297, 904 Janey, J. M. 9 152 Jansen, A. A. 7 590 Jaroch, S. 7 280 8 333 Jarry, C. 8 518, 519, 520, 521, 522 Jarvinen, K. 8 509, 510 Jasperse, C. P. 9 94 Jaworski, T. 6 165 Jendrzejewsky, S. 7 306 Jenkins, K. 7 211 Jensen, K. B. 9 76 Jeong, J. H. 8 511 Jeong, S.Y. 8 512 Jeschkeit, H. 7 80, 443 Ji, J. 9 89, 90, 95 Jiang, Q. 9 140, 141 Jiang, Y. 9 140, 141, 146 Jiang, Y. Z. 8 501 Jimenez, A. I. 7 413, 916, 930, 931, 932, 933, 934, 936, 994, 1023, 1024 Jime´nez, H. A. 5 16 Jime´nez, J. M. 5 80

Jimenez-Va´zquez, H. A. 5 97 Jin, B. 8 105 Jin, S. 7 771 Jnaneshwara, G. K. 8 37, 198 Jnoff, E. 9 69 Jocobs, R. 8 321 Joergensen, K. A. 9 74 Johannsen, M. 9 58, 59, 60, 61, 62, 65, 71 Johnson, D. S. 9 145 Johnson, J. S. 9 28, 53, 67, 68, 151 Johnson, K. W. 7 675 Johnson, M. C. 5 95, 96 Johnsson, S. Y. 8 63 Johnston, J. N. 9 96 Joiner, A. 7 373 Jolly, V. S. 7 467 Jones, D. S. 7 264, 265 Jones, G. 8 170, 181, 422 Jones, G. E. 8 164 Jones, J. B. 8 56 Jones, J. H. 7 514 Jones, W. D. 5 78 Jones, W. D. Jr. 7 548 8 39, 324 Jordan, D. B. 6 96 Jørgensen, K. A. 9 58, 59, 60, 61, 62, 63, 65, 71, 73, 75, 76, 126, 163 Joseph, K. 7 666, 818, 863, 864, 865, 894, 895 Joshi, D. G. 7 824 Joshi, H. D. 7 810 Joshi, H. S. 7 741 Joshi, N. 7 807, 823 Joshi, P. C. 7 58, 61 Joshi, S. N. 7 729 Joumier, J. M. 5 94 Judas, D. 7 393 Juge´, S. 8 322 Juhl, K. 9 126 Jun, C.-H. 9 138 Jun, H.-S. 8 234, 236 Jung, B. 7 68, 492, 963 Jung, G. 8 218 Jurgevica, I. 6 48 Jusoh, A. 7 202 Kabra, V. 8 325 Kabuto, C. 8 40 Kaddah, A. M. 7 891 Kadun, A. L. 8 309 Kagan, H. B. 7 792, 795 8 474, 499 9 44 Kagara, K. 7 462 Kagathara, P. 7 713 Kagiwara, K. 7 39 Kai, T. 8 255

Author Index Kaigorodova, L. N. 7 758, 761, 762 Kainz, S. 8 460 Kaiser, D. 8 218 Kaisho, T. 6 198 Kajimoto, T. 8 81, 82 Kajiwara, M. 6 140 Kajtar, J. 7 524 Kajzar, F. 7 379 Kakimoto, S. 7 462 Kakui, T. 8 405 Kalchar, S. 6 188 Kalish, J. 8 245 Kallmerten, J. 8 342, 343 Kalluraya, B. 7 1009 Kalman, A. 7 53, 54 Kalnin, I. K. 7 243, 759 Kalnins, I. 7 621 Kalsi, P. S. 7 149, 494 Kalsi, R. 7 736, 737 Kaluza, K. 6 189 Kalyagina, E. S. 8 249 Kamat, P. V. 7 315 Kamei, H. 8 116 Kameswaran, V. 7 8, 9, 33 Kametani, T. 7 330, 335 Kamhi, V. M. 7 33, 37 Kamigata, N. 7 19 Kamiguchi, H. 6 197 Kamihara, H. 8 513 Kaminski, Z. J. 7 151 Kamiyama, K. 6 57, 86, 197 Kamphuis, J. 7 281, 282, 283, 284, 285, 286, 418, 434, 437, 438, 440 Kanai, M. 8 485 Kanamaru, T. 6 57, 198 Kanatani, R. 8 405 Kanayama, R. 7 199, 200 Kanazawa, T. 5 6 Kanda, Y. 7 183, 184, 185 Kandeel, E. M. 7 550, 551, 552 Kandeel, M. M. 7 742 Kandeel, Z. E. 7 192, 193, 854, 855, 887 Kandile, N. G. 7 831 Kaneko, C. 7 55, 879, 959 Kaneko, S. 7 453, 454 Kanemasa, S. 8 44, 167 9 15, 49 Kang, S. H. 8 192, 193, 194, 231, 232, 233, 234, 236 Kangas, S. L. 7 370 Kano, S. 5 8, 57 6 167, 168, 169, 170, 171, 172, 173, 175, 176 Kapadia, K. 7 1018 Kappe, T. 6 158

611

Kaptein, B. 7 434, 996 Kar, A. 7 475 Karaghiosoff, K. 7 910 8 325 Karajiannis, H. 7 259 Karalulov, S. 9 24 Karelson, M. M. 6 8 Karjalainen, T. 8 509, 510 Karpavicius, K. 7 611 Karpeiskaya, E. I. 7 47, 48, 242, 243, 244, 411, 621, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 978 Kashyap, J. 7 483 Kassab, R. 7 195 Kassem, E. M. 7 1017 Kataeva, N. A. 8 380 Katagiri, N. 7 55 Katalenic´, D. 8 99 Kataoka, T. 5 31, 32, 33 Katayama, K. 9 21 Katkevich, M. 7 781 Katkevich, M. Yu. 7 110 Katkevics, M. 7 780 Kato, E. 7 347 Kato, H. 7 313 Kato, K. 7 617 8 116 9 143 Kato, S. 6 103 Kato, T. 7 560 Katoh, T. 5 83 7 596 Katritzky, A. R. 6 8, 9, 117 7 239, 386, 388, 399, 400, 401, 402 Katsarava, R. 7 405 Katsarava, R. D. 7 397, 398, 404 Katsuki, T. 8 32 Katsuki, T. 9 92, 93 Katyal, M. 7 314 Kaufmann, W. J. 6 87 Kaur, B. 7 494 Kavrakova, I. 7 479, 983, 984, 985 Kawada, M. 6 152 Kawai, K. 7 330 Kawai, N. 7 462 Kawamatsu, Y. 6 128 Kawamoto, T. 8 239 Keenan, M. 8 442 Keith, D. D. 7 565 Kelleher, F. 6 107 Kellner, K. 7 907, 908, 909 Kelly, N. M. 8 283 Kelly, T. R. 6 41 Kempter. C. 8 218 Kemter, P. 7 907, 908 Kenner, G. W. 7 264, 265, 266

612 Kepe, V. 7 120, 541, 825, 853, 884 Kercher, M. A. 8 338 Keric´, M. 6 50 Kesselgruber, M. 8 179, 374, 378 Kessler, M. 9 20 Ketcha, D. M. 6 16, 17 Keuseman, K. J. 8 380 Khachvankyan, G. Y. 7 1008 Khachvankyan, G. Yu. 7 484, 496 Khalafallah, A. K. 7 819, 854, 855 Khalifa, M. A. E. 7 176 Khan, M. A. 8 33 Khan, N. H. 7 493, 803, 890, 899 Kharadze, D. 7 405 Kharadze, D. P. 7 397, 398, 404 Khatimi, N. 8 258 Khatskevich, I. E. 7 243, 621, 759 Khodeir, M. N. 7 551 Khodeir, M. N. H. 7 550 Khodeir, M. N. M. 7 734 Khoshdel, E. 7 373 Khosruashvili, T. A. 7 404 Khrabrova, E. S. 6 78, 80, 81, 182 Kida, T. 8 377, 429 9 38, 137 Kidwai, M. 7 489, 490, 1020 Kidwai, M. M. 7 803 Kiguchi, T. 8 307 Kikuchi, T. 8 72, 73, 75 Kilpert, C. 7 21 Kim, C. 8 512 Kim, C. M. 8 192 Kim, D. C. 7 69 Kim, G. T. 8 231, 232 Kim, H. 7 68, 492, 963 8 65 Kim, I. O. 6 108 9 138 Kim, J. S. 8 233 Kim, M. 7 558 Kim, S. 7 558 Kim, Y.-H. 8 279, 280 Kimmel, T. 5 36 Kimura, K. 5 31, 32, 33, 66, 67 9 86 Kimura, R. 7 365 Kimura, Y. 7 199, 200 King, S. A. 9 95 King, S. W. 7 422, 785 Kingston, D. G. I. 8 83, 85 Kinoto, T. 5 20 Kiraly, J. 7 567 Kirk, J. 6 52 Kirk, K. L. 7 616, 618 Kirmelashvili, L. 7 405 Kirmelashvili, L. I. 7 397, 398, 404 Kishi, E. 9 14

Author Index Kiso, Y. 7 197 Kitagawa, O. 8 272 Kitajima, H. 9 92, 93 Kitamura, M. 7 209 8 452 Kitayama, K. 9 14 Kitazawa, M. 6 151, 166 7 460 Kiyooka, S. 7 241 Kjaer, A. 7 317 Klabunovskii, E. I. 7 47, 48, 242, 243, 244, 411, 621, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769 Klaic´, B. 8 99 Klajc, B. 7 281 Klebanov, B. M. 7 613 Kleber, M. 7 263 Klein, H. 8 93 Klein, U. 7 21 Klepel, M. 7 443 Kliegel, W. 7 84 Klingstedt, T. 8 26 Kliukiene, R. 7 611, 612 Kmetic, M. 7 508, 653 Knapp, P. W., Jr. 7 7 Knight, J. G. 8 168 9 37, 125 Knoll, W. 8 507 Knorr, D. C. 8 54 Knyaz’kova, N. E. 7 123 Kobayakawa, M. 8 13 Kobayashi, M. 6 151, 166 Kobayashi, S. 8 508 Kobayashi, T. 6 163 Kobayashi, Y. 7 455 Kobgaokab, S. 7 715 Kobori, Y. 7 130 Koc, H. 7 974 Kocevar, M. 7 120, 533, 541, 825, 853, 884 Koch, G. 8 358 Koch, K. 8 360 Koch, K. N. 7 273, 274, 997 Kocy, O. 8 114 Koczan, G. 7 1014 Kodama, H. 8 57 9 155 Kogure, T. 7 793, 794 Kohmura, Y. 8 32 Kohra, S. 8 289, 290 Kohrt, J. T. 6 40 Kojima, M. 6 183 Kok, G. B. 8 103, 104, 106 Kolasa, T. 6 116 Kolb, M. 7 125, 128 Kolbe, A. 7 75 Koleva, V. 7 479, 983

Author Index Kolla, V. E´. 6 63, 64 Kolodziejczyk, A. M. 7 415 Kolotuchin, S. V. 8 61, 409 Kolycheva, M. T. 7 613, 614, 754, 757 Komine, N. 9 115 Kondo, M. 9 1, 134 Kondratenko, M. A. 8 64 Konwar, D. 7 335 Kopecky, J. 5 76, 77 Kora, F. A. 7 67 Ko¨rbl, J. 6 68 Korcagova, E. 7 780 Korchagova, E. Kh. 7 110, 251, 781 Koreshkov, Y. D. 7 767 Korgaokar, S. S. 7 714 Kornsheninnikova, M. I. 6 64 Korolev, A. M. 8 312 Koroleva, E. B. 9 13 Korotkikh, N. I. 5 29 Koski, N. I. 7 359 Koskinen, A. M. P. 8 50, 136 9 36 Kostlan, C. R. 6 66 Kosuge, Y. 8 513 Kosulina, T. P. 6 6, 34, 35, 36 Kotva, R. 6 68 Kouklovsky, C. 8 13, 14 Kouyama, T. 5 45 Kovacs, I. 7 595 Kozjan, V. 7 541 Kozlovskaya, I. N. 6 34 Kozlowski, M. C. 9 81, 82, 84, 85, 97, 149 Kozuka, H. 6 49 Kraatz, U. 7 570 Kraemer, W. 7 660 Kralj, L. 7 578 Krantz, A. 7 89 Krasovitskii, B. M. 7 446, 447, 448, 476, 972 Krasovitsky, B. M. 7 449 Krasutskii, P. A. 7 71 Kraus G. A. 7 948 Krause, H. 7 631 Krause, H. W. 7 629, 632, 635, 636 Krautha¨user, S. 8 34 Kravchenko, N. E. 7 124 Kreile, D. 7 251 Kremer, K. A. M. 7 31 Krentsel, L. B. 7 768, 769 Krˇepelka, J. 6 68 Krepski, L. R. 7 101, 239, 342, 343, 345, 346, 348, 351, 354, 355, 357, 359, 361, 362, 366, 367, 375, 377, 386, 388, 399, 400, 401, 402 Kreuzfeld, H.-J. 7 629, 631, 632, 635, 636 Krikov, V. V. 7 448

613

Krishnan, K. 9 64 Krolikiewicz, K. 8 27 Krotz, A. 9 7 Kruiswijk, E. 8 110, 111, 410 Krutosikova, A. 6 35 Kubiak, T. 7 605 Kubicki, M. M. 8 188 Kubota, Y. 7 181, 188 Kuczma, A. S., Jr. 7 351 Kudo, K. 7 267 Kudo, N. 5 3 Kuhn, D. G. 7 29, 31, 33, 37, 463, 658 Kukhar, V. P. 7 613 Kul’nevich, V. G. 6 6, 34, 35, 36 Kulesˇ, M. 6 50 Kulikova, L. B. 7 123 Kulkarni, Y. D. 7 687, 748 Kumada, M. 8 405 Kumar, A. 7 745 Kumar, B. 7 748 Kumar, K. 7 102 Kumar, P. 7 132, 134, 135, 489, 677, 826, 827 Kumar, R. 7 489, 490 Kumar, S. 5 30 7 920 Kumar, V. 7 804, 822 Kumari, A. S. 7 881 Kumpf, S. 7 790 Kunesch, N. 8 339 Kunieda, T. 5 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 60, 61, 62, 63, 66, 67, 68, 69, 70, 71, 73,74, 75, 81, 82, 84, 85, 86, 87 8 35, 76 Kunzler, J. F. 7 349 Kupce, E´. 6 48 Kuribayashi, T. 8 73, 75 Kurimoto, A. 7 55 Kurita, K. 8 131 Kuriyama, N. 7 197 Kuroda, A. 8 162 Kuroda, K. 7 245 Kuronya, I. 7 445 Kurosawa, H. 9 21, 22 Kurtev, B. 7 479, 983, 985 Kurumisawa, H. 7 313 Kurz, T. 6 98 Kuwata, S. 7 46, 246, 247 Kuz’mina, L. G. 8 380 Kuznetsov, V. V. 8 249 Kuznetsova, T. I. 7 621 Kwan, T. A. 8 89 Kwon, I. C. 8 512 Kwon, O. S. 7 366 Kyota, H. 9 14

614

Author Index

L’abbe´, G. 6 88, 89 8 308, 516 La Londe, M. R. 7 372 La Rosa, C. 7 339 Laangstroem, B. 7 144, 610 Labahn, T. 8 185 Labuche, N. 7 877 Lad, S. 7 1018 Ladva, K. 7 731 Lafargue, P. 8 165 Lafont, D. 8 94 Laguerre, M. 8 518 Lahoz, F. 7 930 Lai, Y. C. 7 364 Laidoudi, A. 7 320 Lal, G. S. 8 171 Lalitha, K. 7 923 Lalitha, N. 7 423, 554, 911, 924, 956, 957, 968 Lalithambika, M. 8 198 Lamar, J. E. 8 352 Lamas, C. 7 668, 669 Lamy, A. 8 310, 313 Lancetta, T. 7 812 Landry, K. 5 38 Lang, F. 6 41 Langer, K. 9 120 Langlois, N. 8 90, 353, 354 Langlois, R. 7 57 Langlois, Y. 8 12, 13, 14, 306 Langran-Goldsmith, A. 7 14, 278, 279 Lankiewicz, L. 7 1016 Lao, X.-F. 7 40, 329 Lapen˜a, Y. 7 434 Larock, R. C. 9 116, 142 Larsen, R. D. 8 246, 248 9 10, 30, 39, 117 Lata, A. 7 801 Latham, H. A. 8 127, 365, 368 Laude, B. 8 188 Laukaitis, V. 7 611 Laurent, A. J. 8 258 Lautens, M. 8 417 Lawrenz, D. 7 965 Lawson, A. 7 133 Lawson, J. P. 8 143 Laxmi Y. S. 6 24 Lazzeri, V. 9 127 Le Bail, M. 8 139 Le Guen, S. 8 310, 313 Leban, I. 7 770, 988 Lebel, H. 8 493 Leblanc, Y. 5 38 Lebreton, J. 6 160 Lechner, U. 7 852 Lectka, T. 8 262, 263

Lectka, T. 9 45 Lee, C. 8 418 Lee, C. B. 7 116 8 96 Lee, C. M. 7 589 Lee, C. W. 7 199 Lee, E. 7 558 Lee, H. 8 511 Lee, I. S. 7 219 Lee, J. 7 236 8 65 Lee, K. 7 68 Lee, K-Y. 8 279, 280 Lee, S. 8 41, 366, 376 Lee, S. C. 8 512 Lee, S.-g. 6 108 9 138 Lee, S.-H. 8 124 Lee, W-C. 6 82 Lee, Y. C. 7 248, 249 Lee, Y.-S. 8 124 Leeson, P. D. 7 602 Leet, J. O. 7 964 Lefebvre, H. 7 394 Leger, J. M. 8 518, 520, 521 Legido, M. 7 1012 Lehene, E. 7 820 Lehmann, C. 7 258, 259, 260, 261, 262 8 196 Lehmann, H. 7 443 Lehmann, J. 7 272 Lehn, J.-M. 9 29 Leighton, B. N. 8 222, 393 Leistner, S. 6 192 Leitner, W. 8 460 Lelj, F. 7 279, 281, 290, 417 Lellouche, J.-P. 8 165 Lemaire, M. 8 415 9 161 Lensky, S. 8 281 Lenz, G. R. 5 7 Leone, V. 7 812 Lepifre, F. 8 386 Leplawy, M. T. 7 151, 264 Lerestif, J. M. 8 293, 294, 295 Lesniak, S. 7 308 Lessor, R. A. 5 7 Lete, E. 6 174 Leung, Y-C. 7 217 Leutenegger, U. 9 78 Le´veˆque, H. 8 217 Levian-Teitelbaum, D. 7 129 Levitina, E. S. 7 244, 411, 750, 752, 753, 754, 755, 756, 757, 760, 761, 762, 763, 768 Lewis, J. 6 25 Lewis, R. T. 6 107 Lex, J. 8 286 Leyendecker, J. 7 11

Author Index Leze, A. 8 310, 313 Li, A-H. 7 913 Li, C. 5 38 8 237 Li, X.-G. 8 428 Li, Z. 7 1013 Liang, J. 7 213 Libscher, J. 7 771 Licini, G. 7 996 Lidgren, G. 7 4, 5 Lidon, M. J. 7 501 Liepina, I. 7 780 Lightfoot, A. 8 359 Lim, C. W. 9 138 Lim, D.W. 8 511 Lim, H.-J. 9 119 Lim, S. 8 18, 140 Lin, H. C. 7 640 Lin, S. C. 7 969 Lin, T.-I. 8 260 Linden, A. 7 272, 273, 274, 997 Lindsey, J. 7 783 Lindstedt, E-L. 6 127 Lingham, I. 7 275, 276, 277 Link, J. T. 8 242 Lipinsky, E. S. 8 288 Lipsbergs, I. U. 7 781 Lisichkina, I. N. 7 791 Lister, C. A. 6 125 Litmanovich, A. D. 7 768, 769 Little, D. L. 7 233 Liu, J. 8 246, 247 Liu, M. 9 94 Liu, T.-Y. 8 260 Liu, Y. 6 62 Liu, Y.-C. 8 84 Livingston, R. S. 6 96 Ljung, B. 6 127 Ljungvist, A. 7 607 Lloyd-Jones, G. C. 8 358 9 79 Lloyd-Williams, P. 7 223 Lobensommer, M. 6 59 Lock, C. J. L. 7 986 Locock, R. A. 6 23 Loesevitz, B. 6 181 Lo¨ffler, J. 5 37 Loft, M. S. 8 430, 434, 487 Lohani, H. C. 7 698 Lohmar, R. 7 105 Lohray, B. B. 6 188 Lohray, V. B. 6 188 Loim, N. M. 8 64 Loiseleur, O. 8 358, 433, 442, 443, 444 Long, B. H. 8 86

615

Longmire, J. M. 9 146 Lo´pez, M. 5 80 Lopez, P. 7 429, 434, 1023 Lopez-Arbeloa, F. 7 624 Lorenzo, A. 7 502 Lorusso, S. 6 100 Loupy, A. 8 200 Lowen, G. T. 7 33 Lowenthal, R. E. 9 3, 5 Lu, Y. 8 339 Lu, Z. 7 487 Lubuzh, E. D. 7 242, 244, 411, 752, 755, 763, 767, 768 Lu¨cking, U. 8 498 Luger, P. 8 302 Luh, T.-Y. 8 260 Lui, N. 7 36 Luis, S. V. 9 159 Luisi, R. 8 345, 347, 348, 349, 350, 351 Lukacs, L. 7 567 Lukevics, E. 7 110, 251, 781 9 101 Luo, Y. 7 27, 32, 41, 42 Luo, Y-R. 7 28 Lupsa, I. 7 569 Luthy, C. L. 6 53 Lutsenko, A. I. 7 752, 755, 756, 767 Lutsenko, M. R. 7 48, 755, 756 Luukas, T. O. 8 474 Lydon, K. M. 8 492 Lynch, G. P. 8 129 Lynch, J. E. 7 236 Lysova, I. V. 7 410, 446, 447, 448, 449, 476, 972 Lyubarskaya, A. E. 7 447, 448 Lyubeznova, M. R. 7 752, 765, 767, 768 Ma, B. 8 494 Ma, J.-A. 8 428 Maassarani, F. 8 381 MacDonald, J. G. 7 16, 17 Macedo, E. 8 225 Mackey, B. 8 104 Macko, L. 9 79 Macleod, A. M. 6 107 MacMillan, D. W. C. 9 83, 84 Macomber, D. W. 7 369 Madalengoitia, J. 9 153 Madkour, H. M. F. 7 546 Maeda, M. 6 183 Magirius, J. E. F. 7 273 Magnus, P. 5 9 Mahapatra, G. N. 6 51 Mahgoub, S. A. S. 7 688 Mahmoud, A. M. 7 802

616 Mahmoudian, M. 8 107 Mahon, M. F. 8 430, 487 Maia, H. L. S. 7 279 Maier, G. V. 7 410 Maier, R. 7 852 Maior, O. 7 301 Majo, V. J. 7 989 Mak, A. L. C. 6 23 Mak, C. C. 8 177 Makihara, N. 9 26 Malara, L. 9 127 Malhiac, C. 8 217 Maligres, P. E. 8 278 Malin, M. 8 509, 510 Malonˇ, P. 8 122 Mamai, A. 9 153 Mammi, S. 7 282, 285 Man, H.-W. 9 144 Mancini, I. 6 33 Mandai, T. 8 162 Mandal, A. B. 5 16 Mandour, A. H. 7 1017 Manjunath, S. Y. 7 739 Manley, P. W. 7 321 Mann, A. 8 28 Mannekens, E. 7 623 Manrao, M. R. 7 149 Mansour, A. K. 7 727 Manthey, M. 6 52 Manthey, M. K. 6 52 Mao, K. 7 235 Mapelli, C. 7 288 Maquestiau, A. 7 875 Marastoni, M. 7 787 Marcaccini, S. 7 505, 506, 507 Marchand, A. 8 176 Marchand-Geneste, N. 8 521 Marcincal, P. 7 619 Marco, J. L. 7 642, 643, 644 Marcotullio, M. C. 8 125 Mardanova, L. G. 6 63 Maricich, S. M. 9 19 Marini, F. 8 252, 253, 254 Markowitz, J. S. 6 46 Maroziene, A. 7 611, 612 Marquart, P. 7 220 Marques, C. A. 5 28 Marquez, A. 7 311, 312, 322, 323, 325, 328 Marquez, B. L. 8 321 Marraud, M. 7 936, 990, 1024 Marshall, J. 6 10 Marshall, J. L. 6 11 Martin, C. J. 8 204

Author Index Martin, R. 8 56 Martin, R. L. 8 395 Martinez, M. 6 130, 131 Martı´nez, R. 5 16, 97 Martinez-Santos, E. 8 315, 326, 327 Martin-Ortega, M. D. 8 102 Martre, A.-M. 5 23 Martvon, A. 5 76 Marubayashi, N. 5 73 Maruyama, M. 7 34, 38 Marvanyos, E. 7 53, 54 Maryanoff, B. E. 8 7 Marzola, G. 7 787 Marzolph, G. 6 20 Masamune, S. 9 3, 5 Masch, L. W. 6 77 Maselli, C. 5 1 Massa, W. 6 44, 45 Masse, C. E. 8 228 Matela, L. 7 800 Mathe´, D. 8 200 Mathias, L. J. 7 353, 356 Mathivanan, P. 8 19 Mathivanan, P. 9 9, 16, 64, 70 Mathur, K. C. 7 697 Matoba, K. 8 462 Matsuda, K. 7 215, 995b Matsukawa, C. 5 85 Matsukawa, T. 6 99 Matsumoto, H. 8 238 9 31, 32 Matsumura, A. 6 26 Matsumura, S. 7 387 Matsumura, Y. 5 6 Matsunaga, H. 5 45, 46, 51, 52, 66, 73, 74, 75 8 35 Matsuno, M. 7 130 Matsuo, S. 8 144 9 154 Matsuo, T. 8 304 Matsuoka, K. 8 131 Matsuoka, R. T. 8 333 Matsutani, E. 6 153 Matsuura, H. 6 163 Matsuzaki, K. 8 229 Matta, M. S. 7 78 Mattay, J. 9 120 Mauduit, M. 8 14 Mauldin, S. C. 7 1011 Mavrodin A. 7 820 Maxwell, A. 8 176 Mayoral, J. A. 7 429, 512, 573, 574, 627, 633, 637, 638, 646, 665, 789, 939, 940, 981, 982, 991, 993 9 159, 160 Mazaleyrat, J-P. 7 1000 Mazurkiewicz, R. 7 169, 171, 172, 310, 517, 998

Author Index Mazurov, A. A. 7 465 McCague, R. 7 222, 226 McCapra, F. 7 746 McCormack, T. A. 8 79 McGee, D. P. C. 8 241 McGough, K. 8 321 McKenna, M. 7 73 McKenna, M. G. 7 74 McKennon, M. J. 8 10 McKervey, M. A. 8 492 McKillop, A. 7 974 McLaughlin, M. L. 7 601 McLeod, R. A. 7 986 Mecozzi, S. 8 138 Medici, S. 8 209 Medzmariashvili, N. 7 405 Meerwein, H. 8 463 Megahed, S. 7 742 Mehrotra, K. N. 5 14, 15 Mehta, D. S. 6 38 Meier, A. 8 302 Meier, P. 8 443 Meijer, E. M. 7 281 Meinwald, J. 8 344 Melancon, K. C. 7 100 Melendez, E. 7 477, 512, 573, 574, 580, 581, 622, 627, 633, 637, 638, 664, 693, 789 Melendez, M. X. 7 1002 Melis, A. 7 478 Mella, M. 9 11 Menchise, V. 7 294, 296 Mencke, N. 7 570 Me´ndez, F. 5 16 Meneghetti, F. 8 215 Menendez, C. 6 132 Mene´ndez, J. C. 6 133, 149 Menjo, Y. 8 292 Menozzi, G. 7 159 Merati, F. 7 878 Merchant, K. J. 6 107 Merritt, J. 7 299 Meshikhina, L. V. 8 312 Metwally, S. A. 7 842, 847 Meyer, F. 8 322 Meyer, T. 5 24 Meyers, A. I. 8 5, 8, 9, 10, 11, 42, 46, 49, 53, 58, 60, 61, 69, 143, 152, 226, 317, 329, 330, 341, 352, 356a, 379, 389, 390, 391, 392, 403, 404, 406, 407, 408, 409 Michael, G. Z. 7 72 Michael, J. P. 8 15 Michalik, M. 7 635 Michel, A. 7 905

Michel, I. M. 8 112, 114 Michelin, R. A. 8 215 Middleton, M. L. 8 85 Miet, C. 8 339 Miethchen, R. 8 93 Mihelich, E. D. 8 5, 69, 356a Mikami, K. 8 497 Mikami, Y. 9 26 Mikuni, K. 8 162 Mikuni, M. 9 114 Milbrath, D. S. 7 354, 357, 359, 363, 367 Miller, C. P. 8 150, 163, 318 Miller, M. J. 6 116 8 142, 281 Miller, S. J. 9 45, 50 Miller, W. A. 7 297 Minbiole, K. P. 6 196 Minidis, A. B. E. 9 79, 131 Minieri, P. P. 8 244 Mink, D. 8 138 Miralpeix, M. 5 80 Mishchenko, N. I. 7 168 Mishra, H. D. 7 134 Mishra, V. S. 7 721 Misra, A. R. 7 867 Misra, P. 7 1020 Misra, R. N. 8 114 Misra, U. 7 690 Misra, V. S. 7 685, 704, 726 Mistry, P. 7 1018 Mita, R. 7 557, 560, 596 Mitchell, I. S. 5 9 Mitchell, M. A. 8 182, 183 Mitra, S. 7 348 Mitrus, I. 7 998 Mitsunobu, O. 6 179 8 153 Miura, M. 9 72 Miyafuchi, K. 7 585 Miyagawa, K. 6 198 Miyake, Y. 8 437, 438 9 130 Miyaki, Y. 9 22 Miyamoto, M. 7 199, 200 9 114 Miyano, S. 8 40 Miyata, H. 5 12, 90, 91, 92 Miyaura, N. 8 387, 388 Miyazawa, T. 7 46, 246, 247 Mizobe, Y. 8 478 Mizuguchi, R. 6 26, 27, 28 Mizuno, K. 6 128 Mloston, G. 7 308 Mndzhoyan, O. L. 7 468, 604, 777 Moad, G. 6 53 Moberg, C. 8 210, 225 Moberg, C. 9 162

617

618

Author Index

Moberg, W. K. 6 94, 96 Mochizuki, S. 7 880 Mocz, A. 7 619 Modena, G. 7 996 Moderhack, D. 6 39 Mohamed, N. K. 7 961 Mohamed, N. R. 7 177 Mohamed, Y. A. 7 67 Mohan, R. R. 7 685, 689, 726 Mohan, R. S. 7 1007b Moharram, H. H. 7 444, 728, 749 Mohey, I. 7 833, 835 Mohlebach, A. 7 380 Mohr, S. 7 950, 965 Mokashi, A. A. 7 221 Molina, P. 7 500, 501, 502, 503 Molinski, T. F. 7 676 8 514, 515 Moller, B. 7 380 Momose, Y. 6 152, 153 Moneer, A. A. 7 808 Mongelli, N. 8 78, 314 Monk, K. A. 7 1007b Monshizadegan, H. 8 112, 114 Montanari, F. 5 28 Moore, B. S. 7 131 Moore, J. A.7 987 Moorlag, H. 8 391, 392 Mootoo, B. 8 176 Moracci, F. M. 6 154, 156 Morelli, J.-F. 8 13 Moren, D. M. 7 101, 355, 361, 362, 375, 401, 402 Morenets, I. P. 6 34, 35, 36 Moretto, V. 7 295, 439 Mori, H. 7 584 8 40 Mori, K. 8 130, 423, 450 Mori, T. 5 63 Morin, B. 7 60, 61 Morita, H. 7 584 Morita, T. 5 46, 52 Moritani, I. 8 496 Moriyama, H. 7 914, 915 Moro, G. 7 326 Morooka, K. 5 44 Mo¨rsdorf, P. 6 21 Morse, D. I. 8 515 Morton, H. E. 9 95 Mortoni, A. 9 77 Morville, M. 6 145 Moskalyk, R. E. 6 23 Mossel, E. 7 434 Mosset, P. 8 119 Mostafa, F. H. 7 847 Mostert, H. F. 7 590

Mosti, L. 7 159 Motherwell, W. B. 8 24 Motoyama, Y. 9 26, 99 Mousset, G. 5 23 Mozzon, M. 8 215 Mucciante, V. 6 157 Muehlebach, A. 7 376 Mueller, B. 7 376 Mueller, G. 7 93 Mueller, K. 7 111, 257, 258, 259, 260, 261, 262, 263, Mukaiyama, T. 6 73, 74, 75 Mukerjee, A. K. 7 132, 134, 135, 137, 138, 139, 140, 141, 142, 155, 156, 163, 498, 523, 525, 528, 559, 651, 666, 677, 684, 784, 799, 818, 826, 827, 844, 845, 862, 863, 864, 865, 893, 894, 895, 897 Mukerji, D. D. 7 679, 680 Mukhopadhyay, P. K. 7 464 Mukhopadhyay, S. 7 600 Mukugi, Y. 8 238 Mu¨ller, D. 9 33 Muller, G. 8 20 Mu¨ller, K. 8 196 Mulqueen, G. C. 8 146, 147 Mulvaney, A. W. 8 174 Mulzer, J. 8 302 Muneer, M. 7 315 Mun˜iz, K. 8 469, 470, 471, 472, 500 Munozy, L. 7 328 Munroe, J. E. 7 1011 Murai, A. 9 56 Murakami, M. 8 285 Murakami, N. 6 163 Murakami, T. 8 109, 113 Murakata, M. 7 6, 591 Murata, K. 5 67 Murata, M. 5 13 Murayama, S. 8 131 Murdoch, G. L. 7 667, 671, 673, 674 Murphy, B. L. 8 205 Murray, T. F. 8 321 Murray, W. V. 8 383 Murry, J. A. 9 50, 82, 85 Murthy, A. K. 7 829, 830 Murthy, N. N. 8 263 Musˇicˇ, I. 8 187 Mustafa, O. E. A. 7 838 Muthiah, J. 7 353, 356 Muxworthy, J. P. 8 277 Myoung, Y. C. 7 558 N’Diaye, I. 6 33

Author Index Nabeya, A. 8 261 Nada, A. 7 177 Nadelson, J. 8 54 Nagahara, K. 7 557 Nagamatsu, A. 7 521, 522 Nagamatsu, T. 5 84, 87 Nagami, K. 8 131 Nagamitsu, T. 8 227, 229, 336a Nagaoka, Y. 8 484 Nagasawa, Y. 5 46 Nagase, H. 7 330 Nagase, Y. 7 461 Nagata, M. 7 395, 450 Nagatani, T. 5 43 Nagato, S. 6 99 Nagatsu, A. 6 163 Nagy, M. 7 445 Naidu, P.V. R. 7 926 Naim, S. S. 7 890 Nair, C. M. K. 7 435 Naithani, P. K. 7 702, 720 Naito, T. 8 307 Nakagawa, R. 9 157 Nakahashi, K. 7 617 Nakai, T. 9 115 Nakajima, K. 8 55 Nakajima, N. 8 121 9 103 Nakamura, E. 9 105, 113 Nakamura, H. 8 67 Nakamura, K. 8 124 Nakamura, M. 8 256 9 105, 113 Nakamura, S. 9 157 Nakamura, T. 7 365 9 1, 134 Nakamura, Y. 7 26 8 155 Nakanishi, K. 8 162 Nakano, J. 7 450 Nakano, Y. 6 198 Nakao, M. 6 57, 198 Nakatsuji, Y. 8 144, 377, 429 9 38, 137, 154 Nakatsuka, Y. 9 86 Nakayama, Y. 6 86, 197 Nakos, S. T. 7 98, 99 Nalepa, K. 7 797, 798, 800, 814, 815, 816, 817 Nalimov, A. M. 7 595 Narita, M. 7 267 Narusawa, H. 9 99 Nasef, A. M. 7 654 Nastopoulos, V. 7 23 Natale, N. R. 8 36 Nath, C. 7 736 Nath, J. P. 6 51 Naud, F. 8 461 Naumann, C. A. 8 507

619

Nautiyal, S. R. 7 679, 680, 712 Nava, H. 8 70 Navarrete, P. 7 322, 323, 325 Neary, A. P. 7 746 Negm, A. M. 7 179, 854, 855 Negro, L. 9 139 Nehring, R. 8 4 Neil, B. 7 445 Neises, B. 7 125, 128 Nekrasov, D. D. 6 7, 63, 64 Nelson, D. L. 7 671, 673, 674 Nelson, D. L. G. 7 675 Nelson, J. D. 8 361 Nemoto, H. 6 171, 176 Nesi, R. 8 298, 299, 300 Nesper, R. 9 25 Nesunts, N. S. 7 204, 571, 572, 777 Neuburger, M. 7 424 9 79 Neuhauser, H. 7 49 Neumann, B. 8 213 Neumann, K. 7 790 Neuville, L. 8 59 Newadkar, R. V. 7 218, 221, 228 Newton, M. G. 7 288 Nguyen, Thi Diem, T. 7 623 Nicaise, O. J-C. 8 121 9 103, 104 Nicholas, E. S. 7 663 Nicholas, K. M. 8 33 Nicotra, A. 7 996 Nie, J.-y. 7 616 Niewoehner, U. 7 11, 20 Niki, H. 7 455 Nikulina, S. N. 6 64 Ninomiya, I. 8 307 Nishi, N. 8 131 Nishi, T. 8 55 Nishibayashi, Y. 8 364, 367, 375, 462, 467, 477, 478 9 128, 129 Nishide, K. 8 81, 82 Nishigaki, J. 6 187 Nishiguchi, T. 8 261 Nishimura, S.-I. 8 131 Nishio, T. 7 1010 Nishiyama, H. 8 67, 475, 476 9 1, 2, 26, 31, 32, 99, 134, 135, 136, 147 Nishiyama, K. 8 291 Nishiyama, S. 8 97 Nishizawa, M. 8 239 Nissen, J. S. 7 667 Nitz, T. J. 7 783 Noble, D. 8 107 Node, M. 8 81, 82 Noe, M. C. 9 8

620

Author Index

Noel, C. 7 379, 381 Nogle, L. M. 8 321 Noguchi, M. 7 851, 914, 915 Noltemeyer, M. 6 25 8 185 Nomura, M. 9 72 Norcross, R. D. 9 50 Norde´n, B. 6 127 Nordin, S. J. M. 8 63 Nordstro¨m, K. 8 225 Northuis, J. M. 8 89 No¨tzel, M. W. 8 185 Novachek, K. A. 8 226, 329 Novak, K. 7 73 Novelli, R. 7 602 Novikova, M. I. 7 71 Noyori, R. 7 209 8 452, 455 Nutt, R. F. 7 786 Nuzillard, J. M. 7 795 O’Brien, P. 8 156 O’Hanlon, P. J. 6 47, 84 O’Hogan, S. 8 281 O’Reilly, N. J. 7 640 Oae, S. 8 399, 400 Oana, D. 7 594 Oba, M. 8 291 Obierey, K. B. 9 52 Obrecht, D. 7 85, 111, 237, 255, 256, 257, 258, 259, 260, 261, 262, 263 8 196 Ochoa, T. 7 223 Oda, M. 8 357 9 130 Odaka, H. 6 152 Oderaotoshi, Y. 9 15, 49 Oganesyan, E. T. 7 471 Ogasawara, M. 8 116, 448 Ogata, K. 8 290 Ogletree, M. L. 8 114 Ogura, H. 8 256 Oh, C. M. 7 964 Oh, C.-Y. 8 280 Oh, E. 7 497 Oh, T. 9 43 Ohba, S. 8 97 Ohe, K. 8 130, 357, 367, 375, 413, 414, 423, 424, 450 9 128, 129, 130 Ohkuma, T. 8 452, 455 Ohta, H. 5 51 Ohta, T. 8 57 9 155 Oishi, T. 9 109, 110, 111 Ojima, I. 7 617, 793, 794 8 363 Okada, M. 7 55 8 502 Okamoto, H. 6 103 Okazaki, M. 6 91

Okino, T. 8 321 Okonya, J. F. 5 95, 96 Okubo, K. 7 521, 522 Okumoto, H. 8 162 Okumura, K. 8 155 Okuro, K. 9 72 Okuyama, H. 6 163 Olhava, E. J. 9 151 Oliver, D. W. 7 992 Oliveros, L. 7 1023 Olivieri, R. 6 191 Olivo, H. F. 8 161 Ollier, M. 5 24 Olson, D. B. 7 366 Omote, Y. 6 101  mura, S. 8 227, 229, 336a O Onimura, K. 9 109, 110, 111 Onishi, M. 9 18 Oonishi, K. 7 455 Opitz, W. 7 772, 773, 774, 775, 779 Ori, M. 7 1010 Orioli, P. 9 98 Oro, L. A. 7 627, 633, 637, 638 Orr, G. F. 7 919 Ortun˜o, R. M. 7 428, 954 Ortu˜no, R. M. 8 276 Osaki, M. 5 47 6 74 Osman, A. 7 553 Osman, A. N. 7 808 Otero, D. A. 8 54 Otomatsu, T. 7 246, 247 Otroshchenko, O. S. 8 401 Otsubo, T. 5 85 Otsuka, K. 5 67, 69 Oullet, R. 7 57 Ousmer, M. 8 31 Overman, L. E. 8 333, 435, 441 Overmeire, I. V. 8 172 Oyamada, A. 8 357 Oza, H. B. 7 824 Padeiskaya, E. N. 6 71 Padhye, A. M. 7 143 Padia, J. K. 7 230 Padwa, A. 5 10, 11 7 16, 17,18, 19, 307 Pak, C. S. 7 902 Pal, D. R. 7 856 Palacios, F. 7 1012 Palacios, J. M. 5 80 Palamareva M. 7 984, 985 Palensky, F. J. 7 100, 341, 342 Paleveda, W. J. 7 786 Palkovic´, A. 6 161

Author Index Palmer, D. C. 8 336b Pan, Y. 6 60 Panda, H. 7 493 Pande, K. 7 719 Pandey, V. K. 7 698, 738 Pandita, S. 7 958 Pandya, A. 7 821 Panek, J. S. 6 42 8 228 Pannecoucke, X. 8 355 Pansare, S. V. 5 39 Pantano, M. 7 282, 285, 418, 438, 441 Panza, L. 8 132 Paoli, P. 7 505, 507 Papaleo, S. 8 298 Papini, A. M. 8 322 Papleux, P. 7 875 Paras, N. A. 9 57, 150 Parekh, H. 7 731, 807, 821, 823 Parekh, H. H. 7 714, 741, 824 Parikh, A. R. 7 691, 713, 722, 729, 809, 810 Paris, M. 7 936, 946 Park, B. 8 65 Park, B. S. 7 492, 963, 964 Park, J. 8 41, 366, 376 Park, M.-S. 8 279, 280 Park, S. B. 9 31, 135, 136 Park, S. W. 7 69 Park, T. G. 8 511 Parkanyi, C. 7 175 Parkanyi, L. 7 53 Parker, A. R. 7 987 Parker, M-C. 7 999 Paronikyan, R. G. 7 777, 778 Paronikyan, R. V. 7 777, 778 Parratt, J. S. 7 222 Parrkh, H. 7 715 Parthasarathi, V. 7 989, 1032 Pascu, M. 7 300 Pasquato, L. 7 996 Pastor, A. 7 668, 669 Patel, H. H. 7 723 Patel, J. 7 1018 Patel, M. M. 8 114 Patel, P. 7 715 Patel, P. H. 7 714 Paterno, E. 8 287 Pathak, A. K. 7 690 Pathre, S. V. 7 101, 102, 239, 362, 388, 402 Patil, R. 7 739 Paton, M. R. 8 224 Patra, A. 7 464 Patrick, K. S. 6 46 Pattenden, G. 8 15, 146, 147, 148

621

Pattnayak, B. K. 6 51 Pavez, H. 7 322, 323, 325 Pavia, M. R. 7 318 Pavlov, P. A. 7 866 Pavlov, P. P. 7 866 Pavone, V. 7 270, 271, 277, 290, 291, 436 Pearce, N. J. 7 602 Pedersen, C. 8 93 Pedone, C. 7 270, 271, 277, 290, 291, 294, 295, 296, 436 Pedregal, C. 7 669 Peet, N. P. 8 101 Peggion, C. 7 434 Peggion, E. 7 282, 285 Pegoraro, S. 7 284 Pei, T. 8 482, 483 Pelli, B. 7 412 Pelter, A. 8 176 Penades, S. 7 917, 918 Peng, S. 7 575 Peng, Y. G. 8 501 Pengo, B. 7 283 Penso, M. 7 117 Penton, H. R. 8 133 Pepino, R. 7 505, 506, 507 Perakorpi, K. 8 510 Percec, V. 8 70, 71 Perch, N. S. 8 480, 481 Peregrina, J. M. 7 935, 936, 937, 938, 940, 941, 942, 943, 944, 945, 946, 947, 1025, 1026 8 273 Pereira, E. R. 5 23, 24 Perina, I. 6 161 Perlmutter, P. 8 257 Perni, R. B. 7 661 Perry, M. C. 8 459 Pershin, G. N. 6 71 Pertel, S. S. 8 309 Perumal, P. T. 7 989 Pesaresi, R. J. 8 171 Peter, A. 7 623 Peters, E.-M. 8 31, 134 Peters, K. 8 31, 134 Peterson, G. S. 9 28 Peterson, M. J. 6 144 Peterson, S. L. 8 284 Petit, A. 8 200 Petric, A. 7 532, 884 Petrov, N. A. 7 595 Pettersson, I. 8 283 Pez, G. P. 8 171 Pfaltz, A. 8 21, 22, 23, 29, 211, 358, 359, 362, 417, 425, 426, 432, 433, 442, 443, 444, 458, 460, 461, 486, 491, 498 9 33, 41, 78, 79, 80, 131

622

Author Index

Pfyffer, P. 7 263 Pharisa, C. 7 380 Phebus, L. A. 7 675 Phelps, D. J. 7 466, 582, 663, 782 Philippe´, J. 8 172 Philippides, A. 6 15 Phillips, A. J. 8 166 Pickardt, J. 8 28 Pickett, T. E. 8 369 Pieper, S. 8 213 Pierwocha, A. W. 7 169, 171, 310, 998 Pietra, F. 6 33 Pihko, P. M. 8 50, 136 Pilati, T. 7 1029 Piniella, J. F. 7 428, 954 8 276 Pinillos, M. T. 7 627, 637, 638 Pinna, G. A. 8 206, 427 Pippel, D. J. 8 348 Piquer, J. A. 7 113 Pires, E. 7 429 Pirrung, M. C. 8 128 Pittalis, A. 7 95 Plamondon, L. 8 79 Plate, N. A. 7 768, 769 Pocar, D. 7 15, 106, 107, 117, 121, 122, 238, 305, 327, 518, 878, 882, 883 Pociene, D. 7 611 Pocock, G. R. 8 397 Pocsfalvi, G. 7 980 Pohjolainen, S. 8 509 Poindexter, G. S. 8 338 Poisson, J. E. 8 339 Poje, M. 6 161 Polanc, S. 7 120, 533, 541, 825, 853, 884 Polborn, K. 7 406, 407, 408, 409 Polinelli, S. 7 281, 284, 440 Pollini, G. P. 7 103, 104 Polo, C. 7 505 Polywka, R. 7 373 Ponikwar, W. 7 1004, 1031 Ponndorf, W. 8 464 Popelis, J. 7 251, 780 Popelis, Y. 9 101 Popovici, D. 7 301 Porte, A. M. 9 119 Porter, N. A. 9 87, 88, 89 Poschenrieder, H. 7 885 Po¨stages, R. 6 94, 96 Postle, S. R. 7 442 Posza´va´cz, L. 8 91 Po¨tschke, P. 8 506 Potts, K. T. 6 10, 11 Pouilhe`s, A. 8 13

Poulin, J. C. 7 792, 795 Pouzar, V. 6 68 Powell, M. T. 8 459 Powles, K. 6 97 Pozgan, F. 7 825 Pradhan, S. D. 7 566 Prain, H. D. 7 602 Prajapati, D. 7 81, 330, 335 Prameela, B. 7 829 Pranis, R. A. 7 375 Prasad, C. R. 7 679, 680 Precigoux, G. 7 286 Pregosin, P. 9 25 Pregosin, P. S. 8 173, 420, 421 9 79 Prem, M. 7 406, 407, 408 Preobrazhenskaya, M. N. 6 71 Preston, J. 7 265, 266 Pre´toˆt, R. 8 358 Preussler, C. 7 907, 908, 909 Prewo, R. 7 23, 44 Price, D. A. 8 352 Price, D. W. 9 24 Prins, T. J. 7 608 Procter, G. 8 277 Prokof’ev, E. P. 7 978 Protopopova, M. N. 8 489 Provent, C. 9 148 Prowse, W. G. 7 668 Prozonic, F. M. 8 171 Prudhomme, M. 5 23, 24 Puff, H. 7 419 Puig, C. 5 80 Puig, J. 5 80 Pummerer, R. 6 18 Pu¨ntener, K. 9 25 Purick, R. M. 8 278 Purohit, D. M. 7 724 Pushkareva, K. S. 6 36 Puts, R. D. 8 51 Qiu, Y. 8 43 Quinones, N. Q. 6 79 Quirion, J.-C. 8 355 Quiroga, M. L. 8 315, 316, 326, 327 Raabe, G. 8 370, 372, 373, 378 Raddatz, S. 7 772, 774, 775, 779 Radinov, R. 9 87 Radvany, B. 7 567 Radwan, A. M. 7 195 Raghavan, S. 8 242 Raghunathan, R. 7 154, 926 Rahm, F. 8 210

Author Index Rai, M. 7 494 Rajanarendar, E. 7 829, 830 Rajaram, S. 7 968 Rajeckas, F. J. 6 159 Rakhshinda 7 493 Ram, S. R. 7 956 Ramamurthi, K. 7 1032 Ramanujam, R. 6 188 Ramiandrasoa, P. 8 386 Ramirez, D. 8 316 Ramirez-de-Arellano, C. 7 503 Ramiz, M. M. M. 7 886 Ramsh, S. M. 6 76, 78, 80, 81, 182 Rao, B. V. 8 230 Rao, C. C. 7 554 Rao, C. V. C. 7 732, 850 Rao, E. T. 7 830 Rao, G. 7 575 Rao, L. 7 141, 894, 895 Rao, P. S. 7 377, 481 Rao, R. B. 7 293 Rao, Y. S. 5 2 6 3 7 3, 976 Raoul, S. 7 58, 59, 61 Rapi, G. 6 12, 13, 162 Rasgoti, A. 7 710 Rasmussen, J. K. 7 100,101, 239, 340, 341, 342, 343, 344, 345, 346, 348, 351, 354, 355, 357, 359, 361, 362, 367, 375, 386, 388, 399, 400, 401, 402 Rasparini, M. 6 97 Rasslan, A. M. 7 855 Rasslan, M. A. M. 7 854 Rassu, G. 7 95 Ratnam, C. V. 7 828 Ravanat, J. L. 7 56, 57, 58 Ravindranathan, T. 8 37, 198 Rawat, N. S. 7 813 Rawson, D. J. 8 204 Rayle, H. L. 8 517 Razavi, Z. 7 746 Reamer, R. A. 8 278 Rebek. J., Jr. 8 138 Rechavi, D. 9 161 Reddy, M. M. 5 98 Reddy, M. S. 7 828 Reddy, R. R. 7 732, 850 Reddy, V. M. 7 735, 740, 743, 744, 1019 Reed, A. D. 9 88 Rees, C. W. 7 321 Reibenspies, J. 8 457 Reibenspies, J. H. 8 419 Reichel, F. 9 63 Reid, A. 8 176

623

Reider, P. J. 7 236 8 246, 247, 248, 278 9 10, 30, 39, 117 Reilly, M. 9 43 Reinmuth, A. 9 112 Reiser, O. 8 243 9 158 Reissig, H. U. 9 35 Ren, Y. 7 599 Reno, M. J. 8 166 Reuman, M. 8 8 Reuter, H. 7 419 Reuter, W. 7 852 Rexhausen, J. E. 8 66 Reyes-Rivera, H. M. 8 52 Reyx, D. 7 379, 381 Rheingold, A.L. 8 117 Riant, O. 9 44 Richards, C. J. 8 170, 174, 175, 181, 369, 382, 422 Richter, H. 6 192 Richter, W. F. 6 44, 45 Rickborn, B. 5 89 Ricker, C. B. 8 186 Ricquier, P. 5 22 Righetti, P. 9 47, 77 Righetti, P. P. 9 46 Ringold, C. E. 7 288 Riocci, M. 7 625 Riordan, J. M. 7 422 Riou, J. F. 5 24 Rippert, A.J. 8 145 Risitano, F. 7 1003 Risse, W. 9 112 Ritter, A. R. 8 281 Ritter, H. 8 95 Ritter, J. J. 8 244, 245 Riva, R. 7 327 Rizzacasa, M. A. 8 222, 393, 394, 395, 396 Roberson, M. 9 63 Roberts, F. E. 8 246, 247 Robin, J.-P. 8 310, 313 Rocamora, M. 8 20 Rodena, R. 7 121 Rodriguez, F. 7 937, 1026 Rodriguez, H. 7 311, 312, 322, 323, 325, 328 Rodriguez-Parada, J. M. 8 70 Rodriquez, C. F. 7 1005 Roeda, D. 6 137 Roemmele, R. C. 8 517 Roesky, H. W. 6 25 7 25 Rogozhin, S. V. 7 474 Roh, E. J. 6 108 Rojas, C. M. 8 305 Romanenko, E. A. 7 168, 520 Romeo, G. 7 812

624

Author Index

Rominger, F. 8 220 Ronchetti, F. 8 132 Roper, J. M. 7 593, 900, 901 Rosati, O. 8 125 Rosner, T. 8 359 Rossen, J. 8 278 Rossi, F. 7 159, 283 Rossi, L. 6 157 Rossi, L. M. 7 107, 316 Roth, B. D. 6 67 7 230 Roth, G. P. 8 87 Rottenberg, D. A. 6 136 Rout, D. N. 6 51 Rovis, T. 9 97, 149 Rowhani, S. M. A. S. 7 687 Rowling, S. 9 20 Roy, J. 5 14, 15 7 155, 156, 576, 813 Roy, M. A. 7 646, 939 Roy, P. J. 5 38 Rubiales, G. 7 1012 Ruble, J. C. 7 96, 213 Ru¨egger, H. 9 79 Ruffieux, R. 7 111, 258, 261 Ruiz-Contreras, R. 7 609 Rumyantseva, Ye. Ye. 7 482 Rush, S. 9 112 Russo, V. 8 351 Ruttens, F. 7 624 Ryabova, S. Yu. 7 495 Ryabukhin, Yu. I. 6 6, 37 Ryan, K. M. 8 246, 247 Ryder, H. 5 80 Ryu, D. H. 8 194 Saad, H. A. 7 848 Saakyan, L. G. 7 583 Saalfrank, R. W. 8 119 Saba, A. 8 123, 206, 208, 209, 212, 427 Sadek, K. U. 7 961 Sadowski, S. 6 107 Sadykov, A. S. 8 401 Saeed, M. S. 7 561, 776 Saeki, S. 7 164 Sagawa, S. 8 323 Sager, J. 8 278 Sah, P. 7 712 Sah, R. 7 736, 737 Saha-Moeller, C. R. 7 62, 63 Sahay, R. 7 697 Saigal, S. 7 858, 873 Saigo, K. 8 384, 449 Sain, B. 7 152, 153, 324, 331, 332, 333, 334, 336, 337, 338, 485

Saishoji, T. 7 190, 191 Saito, T. 6 151, 166 Saitz, C. 7 328 Sakaguchi, H. 9 1 Sakaguchi, S.-I. 9 15 Sakai, S. 5 13 Sakakibara, J. 6 163 Sakamoto, M. 6 101 Sakizadeh, K. 7 239, 386, 388, 399, 400, 401, 402 Saleh, R. M. 7 838 Salem, M. A. I. 7 656 Salomone, A. 8 351 Salvadori, S. 7 787 Salvatore, B. A. 8 43 Sami, S. M. 7 470 Sammakia, T. 8 127, 365, 368 Samsel, E. G. 7 630 Sancelme, M. 5 24 Sanchez, A. 7 223 Sanchez, B. 7 642 Sanchez-Ferrando, F. 7 979 Sa´nchez-Viesca, F. 6 123, 124 Sanderson, I. 6 107 Sandhu, J. S. 7 81, 152, 153, 324, 330, 331, 332, 333, 334, 335, 336, 337, 338, 485, 488 Sandosham, J. 8 77 Sanjayan, G. 7 141 Sanjayan, G. J. 7 784, 865 Sanna, M. G. 8 495 Sano, S. 7 38 Sano, T. 6 179 Santafianos, D. 7 202 Santagati, N. A. 7 812 Santi, C. 8 252, 253, 254 Santiago, B. 8 341 Santini, A. 7 271, 290, 295 Saperstein, R. 7 786 Saporovskaya, M. B. 7 205 Sapra, P. 7 1020 Saraf, A. S. 7 471 Sarapa, D. 7 1007b Sargent, M. V. 8 394, 397, 398 Sarges, R. 6 144 Sarhan, A. A. 7 550 Sarkisov, L. S. 7 471 Sarma, G. V. S. R. 7 735, 740, 743, 744, 1019 Sarosi, L. 7 445 Sartor, K. 7 792 Sartore, L. 7 271 Sasabe, H. 7 460 Sasaki, T. 6 31, 32 Sasaki, Y. 5 34, 35 Sasatani, T. 7 538

Author Index Saso, H. 7 39 Sasse, P. A. 8 338 Satake, N. 5 12, 90, 91, 92 Sato, H. 7 55, 450 Sato, K. 5 3, 20 Sato, M. 7 959 Sato, T. 8 40 Satoh, T. 7 130 Satrusallya, S. C. 6 51 Satsangi, R. K. 7 717, 801 Saviano, M. 7 283, 294, 295, 296 Savineau, J. P. 5 24 Sawada, A. 7 585 Saxena, A. K. 7 472, 702, 720, 745 Sayed, G. H. 7 733 Sayed, M. A. 7 833, 835 Sbrana, G. 6 12 Schaad, D. R. 8 365 Schach von Wittenau, M. 6 70 Schaefer, W. 6 189 Scha¨ffer, M. 8 396 Schaffner, S. 8 358, 426 Schaus, J. V. 6 42 Schenone, P. 7 159 Scheurer, A. 8 119 Schickfluss, R. 7 457 Schierlinger, C. 7 92, 93 Schiketanz, A. 7 300, 301, 303, 304 Schiketanz, I. 7 300, 302, 303, 304, 1001 Schiller, P. W. 7 623 Schinkowski, K. 7 628, 631 Schlanger, J. 6 68 Schmees, N. 8 442, 444 Schmidpeter, A. 7 910 8 325 Schmidt, R. 8 463 Schmidt, U. 7 790 Schmidt, W. 8 10, 341 Schmit, J. L. 6 60 Schmitt, G. 8 188 Schnepp, K. 7 909 Schnettler, R. 5 78 Schnider, P. 8 358, 359 Schnur, R. C. 6 141, 142, 143, 144, 145 Schobert, R. 5 37 Schoemaker, H. E. 7 281, 282, 284, 285, 438, 440 Schoenberger, A. 7 62, 63 Schoenholzer, P. 7 257, 258, 259, 260, 261, 262 Scholz, K. H. 5 64 Scho¨nholzer, P. 8 196 Schreiner, B. 7 406 Schrier, D. J. 6 65, 66, 67 Schro¨der, E. 6 56 Schuermann, G. S. 7 168

625

Schulte, K. E. 6 181 Schulz, E. 8 415 Schulz, G. 7 118 Schumacher, D. P. 8 205 Schumacher, R. 9 35 Schumacher, W. A. 8 114 Schwab, J. M. 7 987 Schwarz, G. 6 115 Schwarz, T. 7 280 Schwender, C. F. 8 38 Schwiertz, M. 7 779 Sclafani, J. A. 9 132 Scolastico, C. 6 97 9 91 Scortanu, E. 7 396 Scrimin, P. 7 996 See, R. F. 9 19 Seebach, D. 7 215, 216 8 331 Seeliger, W. 8 4 Seewald, I. 7 443 Segarra, V. 5 80 Segawa, K. 8 367, 375 Seger, A. 8 370, 372, 373 Segl’a, P. 8 207 Seiferling, B. 7 380 Sekacis, I. 7 309 Sekar, G. 8 488 Sekreta´r, S. 5 76, 77 Selinger, Z. 7 129 Selke, R. 7 639 Selva, M. 5 28 Selvakumar, K. 8 420, 421 Sen, A. K. 7 600 Sen, N. 7 292, 426, 650 Senanayake, C. H. 8 246, 247, 248 9 10, 30, 117 Senet, J. P. 7 379, 381 Sengupta, A. K. 7 683, 710, 716 Seppala, J. 8 509, 510 Sera, H. 7 347 Sercel, A. D. 6 67 Serelis, A. K. 8 219, 340 Sergheraert, C. 7 619 Severe, D. 5 24 Sewald, N. 7 93 Shaaban, M. A. 7 834 Shabana, R. 7 906 Shafer, C. M. 8 514, 515 Shafi, P. M. 7 692 Shah, A. 7 922 Shah, B. R. 7 723 Shah, M. 7 715 Shah, N. S. 7 713 Shah, V. H. 6 38 7 711, 724 Shah, V. P. 7 602

626

Author Index

Shaikh, N. S. 8 37 Shalaby, A. M. 7 1017 Shamina, L. P. 6 76, 81 Shanker, K. 7 702, 720, 745 Shanker, P. S. 8 282, 284 Shapiro, R. 8 184 Sharma, M. K. 7 811 Sharma, R. 7 811 Sharma, R. C. 7 149 Sharma, S. 7 805, 871 Shaughnessy, E. A. 9 55 Shawali, A. S. 7 175, 178, 648, 662 Shay, J. J. 9 94 Shchepinov, M. S. 8 48 Sheehan, J. C. 5 26, 27 6 2 Sheinker, V. N. 6 37 Sheldrik, G. M. 6 25 Shen, X. 7 575 Shen, Y.-Y. 8 494 Shen, Z. 7 606 Shenberg, N. A. 6 182 Sheppard, R. C. 7 264, 265, 266 Sher, P. M. 8 114 Shi, D. 7 487 Shi, X. 8 344 Shi, Y. 7 109 Shi, Y. Z. 7 108 Shiba, S. A. 7 469 Shibasaki, M. 8 440, 485 9 42 Shibata, K. 8 81, 82 Shibata, T. 8 468 Shibuya, S. 5 8, 53, 54, 55, 56, 57 6 168, 169, 170, 171, 172, 173, 175, 176 Shida, T. 7 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194 Shigeta, S. 7 880 Shimada, O. 7 461 Shimano, M. 8 317, 330, 379, 407, 408 Shimizu, H. 5 31, 32, 33 Shimizu, M. 5 5 Shimizu, T. 8 109 Shin, C.-g. 8 155 Shin, K. J. 7 69 Shingu, K. 8 81 Shinkawa, H. 7 183, 184, 185, 186, 187, 188, 189 Shioiri, T. 8 321 Shirai, M. 9 164 Shirali, S. S. 6 164 Shiu, L.-L. 8 260 Shoda, T. 6 128 Shoeib, T. 7 1005 Shoja, M. 7 317 Shono, T. 5 6

Showell, G. A. 7 602 Shpiro, E. S. 7 768 Shrimali, M. 7 736, 737 Shu, L.-H. 7 329 Shu, Y. 7 597 Shue, Y-K. 6 85 Shukla, J. S. 7 708, 718 Shukla, K. N. 7 860, 868 Shukla, S. 7 873 Shukla, S. N. 7 857 Shvaika, O. P. 5 29 Sibi, M. P. 9 89, 90, 94 Sidky, M. M. 7 906 Sih, C. J. 7 219, 220, 224, 227, 229 Sile, D. 7 309, 780 Sile, D. E. 7 110, 251, 781 Simig, G. 8 91 Simmerl, R. 7 51 Simonic, I. 7 161 Simova, E. 7 479 Simpson, G. W. 8 219, 340 Simpson, R. 8 54 Sin, N. 8 343 Sinbandhit, S. 8 294 Singh, A. 7 690 Singh, C. 7 721 Singh, E. 7 709 Singh, G. P. 8 30 Singh, H. 5 30 7 857, 860, 867, 868 Singh, I. S. 5 15 Singh, K. K. 7 509, 510, 534, 539, 975 Singh, M. K. 7 510, 539, 975 Singh, P. 5 30 Singh, R. 7 738 Singh, R. M. 7 509, 510, 534, 539, 975, 1015, 1032 Singh, R. P. 9 23 Singh, R. S. 7 534, 539, 1015 Singh, S. 5 30 7 722 Singh, S. K. 7 805 Singh, S. N. 7 805 Singh, S. P. 7 81, 336, 337, 485 Singh, V. K. 8 92, 488 Sinn, E. 9 20 Sircar, J. D. 6 65, 66 Sisido, M. 7 624 Sitachitta, N. 8 321 Siu, K. W. M. 7 1005 Sˇkaric´, V. 8 99 Slavinska, V. 7 309, 780 Slavinskaya, V. A. 7 110, 251, 781 Slawin, A. M. Z. 8 204 Slebioda, M. 7 13, 76, 415

Author Index Sleim, M. A. 7 887 Slouka, J. 7 568, 586, 587 Smirnov, V. A. 5 4, 93 Smirnov, Yu. D. 7 960 Smith, A. B., III. 6 196 8 43, 227, 229, 336a Smith, F. X. 6 17 Smith, G. R. 8 235 Smith, H. K., II 7 100, 341, 342, 343, 345, 346, 355, 357, 375, 386, 399, 400, 401, 402 Smith, L. R. 6 29, 30 Smith, P. M. 9 102 Smith, P. W. 8 107 Smith, S. A. 6 125 Smith, T. P. 7 369, 377 Smoliakova, I. P. 8 380 Soai, K. 8 468 Sobha, T. D. 7 692 Soca, L. 5 80 Sodeoka, M. 9 42 So¨dergren, M. J. 8 63 Sogah, D.Y. 8 51 Sohar, P. 7 1014 Sohda, T. 6 152, 153 Sokolov, V. I. 8 64 Solankee, A. 7 1018 Soliman, A. Y. 7 733, 832 Soliman, F. M. 7 906 Soliman, F. M. A. 7 837 So¨llhuber, M. M. 6 133, 149 Sollis, S. L. 8 107 Soloshonok, V. A. 7 170 Solyom, S. 7 146, 147, 148 Somogyi, A. 7 980 Song, C. E. 6 108 9 138 Song, S. 7 68 Song, S. H. 8 511 Song, Y. 6 67 Soni, V. C. 7 691 Sorenson, R. J. 6 65, 66, 67 Sorotskaya, L. N. 6 35 Sosa, A. C. B. 8 271 Sotomayor, N. 6 174 Soucy, F. 8 79 Soufiaoui, M. 7 925 Souhassou, M. 7 990 Souka, I. M. 7 837 Souka, L. M. 7 678 Southern, E. M. 8 48 Spalluto, G. 7 103, 104 Sparey, T. J. 9 129 Spassky, A. 7 64 Spek, A. L. 8 381 Spessel, V. 5 23

627

Speybrouck, D. 8 217 Speziale, A. J. 6 29, 30 Spiegler, C. 7 257, 258, 259 Spiegler, M. 8 221 Spielman, M. A. 6 121, 122 Spindler, F. 8 456 Spoors, P.G. 8 43 Sprengeler, P. A. 8 227, 336a Spyvee, M. R. 7 620 Srimal, R. C. 7 738 Srivastava, A. 7 1032 Srivastava, M. 7 689 Srivastava, R. P. 7 805 Srivastava, V. K. 7 720, 801 St. Amand, M. A. 7 13 Stabile, M. R. 5 58, 59 Stachel, H. D. 7 885 Stadlbauer, W. 6 158 Stamford, A. W. 8 160 Stammer, C. H. 7 288, 289, 421, 422, 783, 785, 919, 920, 921, 922 Stammler, H.-G. 8 213 Stanley, A. L. 8 361 Stanovnik, B. 7 157, 158, 160, 161, 162, 165, 508, 537, 540, 542, 578, 653, 770, 988 Stanssens, D. A. W. 8 214 Staples, R. J. 9 85 Stark, M. A. 8 181 Starkey, I. D. 8 107 Staudinger, H. 8 301 Stauffer, D. M. 7 354, 357, 359 Stecher, H. 7 212 Stefely, J. S. 7 372 Steglich, W. 7 11, 20, 21, 52, 53, 54, 105, 118, 119, 280, 306, 408 Steinauer, R. 7 249 Stella, L. 7 949 Stemp, G. 8 164, 168 9 37, 125 Stepinski, J. 7 605 Sˇteˇpnicˇka, P. 8 122 Stepnova, N. P. 7 960 Sternberg, C. G. 6 94, 96 Sternberg, J. A. 6 94, 96 Stevens, A. M. 8 382 Stevens, J. 7 101 Stevenson, R. W. 6 184 Stierli, F. 7 256, 257 Stille, J. R. 7 876 Stoianova, D. 8 60 Sto¨riko, R. 8 220 Storr, R. C. 7 321 Stoughton, R. 6 120 Strah, S. 7 537

628

Author Index

Streitwieser, A. 8 62 Strohauer, K. 6 114 Strohschein, R. J. 8 54 Strube, M. 7 443, 513, 531, 535, 536, 562, 563, 889 Stryukov, M. B. 7 447, 448 Stumbreviciute, Z. 7 611 Suarez, L. J. 6 60 Subhashini N. J. P. 7 843, 849, 1021, 1022 Suda, K. 7 298 Sudhanand, 7 293 Sudo, A. 8 384 Suenkel, K. 7 408 Suga, H. 8 297, 334, 335 Sugai, S. 5 20 Sugawara, S. 8 40 Sugawara, Y. 9 32 Sugino, E. 5 79 Sugiyama, E. 5 52 Sugiyama, Y. 6 128 7 26 Suh, J. 7 497, 558 Sukumar, M. 7 292, 293, 426 Sulikowski, G. A. 9 119 Su¨mmermann, K. 6 102 Sun, C. 7 597 Sun, J. 8 180 Sun, W.-Q. 7 329 Sun, X.-L. 8 255 Sun, Y. 6 61 Sun, Z. 6 61 Sunagawa, K. 7 173, 174 Sunazuka, T. 8 227, 229, 336a Sunel, V. 7 65, 232, 234 Suresh, B. 7 740 Surov, Yu. N. 7 446, 476, 972 Suryakumari, A. 7 977 Suvorov, N. N. 6 71 Suzuki, A. 8 387, 388 Suzuki, K. 7 241 Suzuki, M. 7 919, 920 Suzuki, T. 7 793 8 272, 328 Suzuki, Y. 6 26, 28 Svec, F. 7 378, 382 Svensson, A. 7 634 Svensson, L. 8 26 Svete, J. 7 160, 161, 162, 537, 578, 770, 988 Swallow, S. 9 133 Swern, D. 6 16, 17 Swinson, J. 7 239, 388, 402 Syed, M. A. 7 832 Syrota, A. 6 137 Syvari, J. 7 577 Szafran, M. 6 8

Szczepura, L. F. 9 19 Szekerke, M. 7 524 Szilagyi, F. 7 148 Szilagyi, G. 7 147 Szilagyi, K. 7 146 Szmuszkovicz, J. 5 72 Tada, M. 6 198 Tadros, M. E. 7 681, 682 Tagami, M. 8 328 Tagliavini, E. 9 98 Taguchi, K. 8 113 Taguchi, T. 8 272 Tai, V. W.-F. 8 240 Tajima, M. 9 147 Takada, H. 8 357, 413, 414 9 128, 129, 130 Takada, S. 7 538 Takahashi, K. 7 618 Takahashi, M. 7 459, 460 Takahashi, T. 7 874, 879 Takaoka, A. 7 70 Takayama, M. 9 147 Takayanagi, H. 8 255 Takeda, T. 6 73, 74, 75 Takehana, T. 8 328 Takei, I. 8 467, 477, 478 Takeuchi, K. J. 9 19 Takeuchi, S. 9 114 Takeya, K. 6 177 Talbi, B. 7 320 Talley, J. J. 7 127 Tamao, K. 8 251, 405 Tamariz, J. 5 16, 97 Tamas, V. 7 456 Tamm, C. 7 424 Tamm, M. 8 185, 186 Tammam, G. H. 7 176 Tamura, M. 7 289, 421 Tamura, T. 6 135 Tamura, Y. 7 313 Tanaka, A. 7 453, 454, 970 Tanaka, H. 8 227, 229, 336a Tanaka, J. 9 15, 49 Tanaka, K. 5 31, 32, 33 Tanaka, T. 7 793, 794 Tandon, P. 7 719 Tani, K. 7 313 Taniguchi, M. 5 3 Tanner, D. 8 283 Tararov, V. I. 7 205 Tarraga, A. 7 501, 503 Tartar, A. 7 619 Tarvainen, T. 8 509, 510

Author Index Tatsuki, Y. 6 183 Taudien, S. 7 628 Tavares, F. 8 143 Tavernier, D. 5 22 Tawada, H. 6 57, 128 Taylor, E. A. 8 133 Taylor, G. A. 7 87 Taylor, G. J. 7 89 Taylor, L. D. 7 352, 358, 384, 385 Taylor, M. 9 133 Taylor, P. C. 9 129 Taylor, S. J. C. 7 222 Tchertanov, L. 7 1000 Tedenborg, L. 8 283 Tedrow, J. 9 149 Tedrow, J. S. 9 81, 97 Tehovnik, M. D. 7 543 Tejedor, J. L. 8 327 Temperini, A. 8 252, 253, 254, 275 Temple, D. L. 8 69 Tenmaru, K. 6 163 Terada, M. 8 497 Ter-Zakharyan, Yu. Z. 7 777, 778 Testaferri, L. 8 252, 253, 254, 274, 275 Texier, F. 7 320 Texier-Boullet, F. 8 200 Thakar, K. A. 7 143 Thakrar, V. H. 7 713 Theissen, R. J. 6 180 Thessalonikeos, E. 7 647, 927, 929 Thier, W. 8 4 Thomas, E. J. 8 66 Thomas, J. 8 518 Thomas, M. 7 381 Thondorf, I. 7 513, 531, 535, 536, 562, 563, 889 Thurlby, P. L. 6 125 Thutewohl, M. 8 186 Thyagarajan, G. 7 331 Tian, W. 7 27, 32, 35, 41, 42 Tian, W-S. 7 28 Tiecco, M. 8 252, 253, 254, 274, 275 Tikare, R. K. 7 315 Tikdari, A. M. 7 523, 666, 799, 818, 844, 845, 862, 863 Tilbury, R. S. 6 136 Tingoli, M. 8 274, 275 Tiripicchio, A. 8 461 Tirosh, N. 5 36 Tisler, M. 7 120, 157, 158, 160, 161, 165, 533, 537, 770, 988 Titmas, R. 7 126 Tiwari, D. C. 7 690 Tiwari, S. S. 7 717

629

Tocher, D. A. 9 27 Togo, H. 8 292 Toh, M. 7 194 Tokunaga, M. 7 209 Tokunoh, R. 9 42 Tokura, S. 8 131 Toldy, L. 7 146, 147, 148 Tolhurst, K. F. 9 133 Tolomelli, A. 8 189, 190, 191, 259, 264, 265, 266, 267, 268, 269 Tomasini, C. 8 189, 190, 191, 259, 270 Tomatis, R. 7 787 Tomilov, A. P. 7 960 Tominaga, Y. 8 289, 290 Tomioka, K. 8 484 Tomioka, Y. 7 521, 522 Tomiyama, H. 9 42 Tommasino, M. L. 8 415 Tomoaia-Cotisel, M. 7 456 Tomooka, K. 9 115 Toniolo, C. 7 198, 270, 271, 277, 279, 281, 282, 283, 284, 285, 286, 287, 289, 290, 291, 292, 293, 294, 295, 296, 416, 417, 418, 420, 421, 425, 426, 427, 433, 434, 436, 437, 438, 439, 440, 441, 1000, 1006 Tonnard, F. 8 294 Toppet, S. 6 89 8 516 Topuzyan, V. O. 7 204, 484, 496, 571, 572, 777, 778, 1008 Toros, S. 7 445 Toru, T. 6 31, 32 9 157 Toshimitsu, A. 8 251 Toth, G. 7 623 Toupet, L. 8 294 Tourwe, D. 7 623 Towers, T. D. 8 156 Toyoda, Y. 6 198 Toyota, A. 7 959 Trabesinger, G. 8 173 Traldi, P. 7 412, 413, 980, 981 Traube, W. 6 1 Tregay, S. W. 9 57, 150 Trevedi, G. K. 8 25 Trigo, G. G. 6 130, 131, 132 Trimarco, P. 7 15, 319 Tripathi, R. K. 7 857 Tripathy, P. K. 7 137, 138, 139, 156, 498, 559, 579, 684, 862, 893, 897 Trivedi, B. 7 711 Trivedi, B. K. 7 230 Trivedi, P. 7 511 Trivedi, P. B. 7 699, 700, 723 Trkovnik, M. 6 50

630

Author Index

Trofimkin, Yu. I. 7 495 Troisi, L. 8 346 Trost, B. M. 7 112, 113, 114, 115,116 8 96, 416, 418 Trujillo, G. 5 16 Tsaklakidis, C. 6 189 Tsitlanadze, G. 7 405 Tsou, N. 5 38 Tsubokawa, N. 8 503 Tsuboniwa, N. 6 26, 27 Tsuge, O. 7 851, 914, 915 Tsukada, N. 8 40 Tsukamoto, S-i. 6 135 Tsutsumi, H. 9 109, 110, 111 Tumey, M. L. 7 344 Tundo, P. 5 28 Tuominen, J. 8 509, 510 Turberg, A. 7 36, 570 Turchi, S. 8 298, 299, 300 Turchin, K. F. 6 71 Turek, T. C. 7 375 Turkovky, I. V. 7 781 Turner, N. 7 226 Turner, N. J. 7 222, 999 Turney, L. N. 8 128 Tuskaev, V. A. 7 471 Tyagi, O. D. 7 603 Tzichinovsky, S. 7 325 Uchida, I. 8 323 Uchida, Y. 8 400 Uchino, N. 6 91, 187 Ueda, H. 8 290 Ueki, M. 5 83 Uemura, S. 8 80, 130, 357, 364, 367, 375, 413, 414, 423, 424, 437, 438, 450, 462, 467, 477, 478 9 128, 129, 130 Ueoka, M. 8 462 Uflyand, I. E. 6 37 Ugai, S. 6 99 Ugboaja, C. I. 7 511 Uhr, H. 7 36 Ukaji, Y. 9 114 Ulbricht, H. 6 55 Ulrey, S. S. 6 60 Umani-Ronchi, A. 9 98, 139, 156 Umbricht, G. 9 33, 41, 78 Unangst, P. C. 6 65, 66, 67 Undavia, N. K. 7 699, 700, 723 Underwood, A. H. 7 602 Ungureanu, M. 7 234 Uozumi, Y. 8 116 9 14, 143 Upadhyay, P. 7 821

Upadhyay, P. S. 7 729, 810 Upadhyay, V. 8 278 Urano, K. 7 521, 522 Urano, S. 6 26, 27 Urban, F. J. 7 131 Usada, S. 6 135 Ushenko, N. K. 6 190 Uson, R. 7 627, 633, 637, 638 Uto, Y. 8 166 Uvarova, N. V. 6 71 Uyama, H. 8 508 Uziel, J. 8 322 Vaish, A. 7 869, 870 Val’ter, N. I. 6 35 Valente, E. 7 427 Valenti, R. 8 206, 208, 427 Valentini, M. 8 420, 421 Valk, J.-M. 8 381 Valle, G. 7 198, 279, 282, 286, 289, 292, 293, 294, 296, 416, 417, 418, 421, 425, 426, 427, 433, 437, 438, 439, 440, 441 Van Damme, S. 5 22 Van der Plas, H. C. 6 69 van der Sluis, P. 8 381 Van Haverbeke, Y. 7 877 van Koten, G. 8 381 Van Lier, E. J. 7 56, 57 Van Meervelt, L. 7 168 Van Vranken, D. L. 8 416 Vanden Eynde, J. J. 7 875, 877 Vanderstichele, S. 7 623 Vanotti, E. 8 78, 314 Vaquero, J. J. 7 668, 669 Vargeese, C. 8 241 Varughese, K. I. 7 921 Vashi, B. S. 6 38 Vasil’eva, T. Yu. 7 791 Vasile, A. 7 300 Vassilev, V. P. 8 81 Vasuki, G. 7 1032 Vaughn-Settle, A. 8 241 Veber, D. F. 7 786 Vecchione, A. 8 270 Vedenyapin, A. A. 7 621 Vederas, J. C. 5 39 Vekemans, J. 7 83 Vela, M. A. 7 601 Venkataratnam, R. V. 7 481, 977 Venkatraman, S. 8 151, 154, 318, 336b Venter, D. P. S. 7 590 Verbruggen, A. 6 89

Author Index Vercek, B. 7 120, 529, 530, 532, 533, 543, 861, 884 Vercˇek, B. 8 187 Vergne, F. 8 139 Verhoeven, T. R. 8 246, 248 9 10, 30, 39, 117 Verley, 8 465, 466 Verma, M. 7 745 Verschave, P. 7 83 Vertut, M. C. 7 982 Vickovic´, I. 6 161 Videnov, G. 8 218 Vijayan, M. 7 435 Vikramadithyan, R. K. 6 188 Villa, M-J. 6 174 Villacampa, M. 6 133, 149 Villeneuve, G. 7 905 Vincendeau, P. 8 522 Vinetskaya, Yu. M. 7 449 Vinogradova, T. K. 7 515 Vite, G. D. 8 230 Viziano, M. 7 878 Vlasenko, E. V. 7 777, 778 Vogel, P. 8 311 Vogl, E. M. 8 440 Vogt, J. 7 383 Voit, B. 8 506 Vojkovsky, T. 9 57, 150 Volante, R. P. 7 236 8 278 Vollerthum, R. 8 230 Volonterio, A. 5 18 von Itzstein, M. 8 103, 104, 105, 106 von Matt, P. 8 358, 433 Von Matt, P. 9 50, 78, 79 Von Weissenborn, V. 6 181 Vorbru¨ggen, H. 8 27 Vuayalakshmi, L. 7 989 Vuilhorgne, M. 6 106 Vulpetti, A. 8 78, 314 Vyas, A. 7 741 Vyas, D. M. 8 86 Vyas, J. H. 7 809 Vydzhak, R. N. 7 515, 520 Wada, E. 8 44 9 15, 49 Wada, N. 5 13 Wada, T. 7 460 Wada, W. 6 179 Wade, M. J. 8 68 Waegell, B. 9 127 Wagener, K. B. 7 360, 389 Wagley, P. P. 7 566 Wagner, G. 6 192 Wagner, J. R. 7 59

631

Wagner, K. 6 195 Wagner, M. I. 9 107, 108 Wakselman, M. 7 1000 Waldner, A. 6 160 Walker, G. 6 47, 84 Walker, M. M. 7 354, 357, 359, 363, 367 Walters, D. L. 7 74 Wang, D. 7 597 Wang, H.-S. 8 90, 353 Wang, J. 7 79, 235 Wang, P.-C. 5 21 Wang, X. 8 100 Wang, Y. 7 487 Wang, Z. 9 100 Wanibuchi, F. 6 135 Wantanabe, Y. 9 157 Ward, D. L. 7 876 Ward, R. S. 7 210 Ward, T. J. 7 231 Warkentin, J. 6 19 Watanabe, M. 8 292 Watanabe, T. 7 173, 174, 183, 184, 185, 186, 189, 190, 191, 194 8 72, 75 Watson, W. 8 156 Webb, M. L. 8 112, 114 Weber, B. 9 33 Weber, G. 7 51 Webster, F. X. 8 344 Weerts, P. A. 8 214 Wegmann, H. 7 118, 119 Weigand, S. 7 114 Weigele, M. 7 565 Weinfeld, M. 7 59, 60, 61 Weir, N. G. 8 108 Weiss, D. 6 195 Weiss, S. 6 59 Weissman, S. A. 8 278 Wellmann, D. M. 8 380 Wendlaender, B. 7 965 Wepplo, P. J. 7 233 Westwell, A. D. 8 411 Wetmore, S. I., Jr. 7 18 Wetzel, B. 7 852 White, A. J. P. 8 115 Whithead, R. C. 7 620 Whiting, A. 9 66 Whitney, S. E. 5 89 Wick, L. 7 424 Wiczk, W. 7 1016 Widdowson, D. A. 8 115 Widenhoefer, R. A. 8 480, 481, 482, 483 Wiese, B. 8 385 Wilcke, F. W. 7 631, 632

632

Author Index

Wild, H. 7 52 Wiley, R. H. 8 2 Wilkinson, J. A. 8 277 Willemsen, J. J. 8 49 Williams, A. 7 202 Williams, A. F. 9 148 Williams, D. J. 8 115 Williams, D. R. 8 166, 169, 305 Williams, J. M. J. 8 201, 202, 203, 204, 411, 412, 430, 434, 487 Williams, T. J. 7 1013 Williamson, R. T. 8 321 Willis, M. C. 9 96 Willock, D. J. 8 410 Wilson, P. C. 9 66 Wilson, R. M. 5 25 Winterman, J. R. 7 222, 226 Wipf, P. 7 22, 23, 43, 44, 268, 269 8 17, 18, 140, 149, 150, 151, 154, 163, 166, 318, 320 Withrow, C. D. 6 93 Wittenberger, S. J. 9 95 Witty, D. R. 6 47, 84 Wlostowski, M. 6 165 Wodecki, Z. 7 415 Woerpel, K. A. 9 4, 28 Woitun, E. 7 852 Wolf, R. M. 6 160 Wong, C.-H. 8 81, 82 Wong, H. N. C. 7 564, 589 Wood, R. 6 147 8 199 Woodward, S. 9 20 Wo¨rle, M. 8 420 9 25 Wozniak, J. 8 24 Wright, C. D. 6 65, 66 Wrobel, J. 6 150 Wu, F.-H. 7 40 Wu, H.-M. 7 40, 329 Wu, J. H. 9 87, 88, 89 Wu, M. 8 321 Wu, M. Y. 5 88 Wu, S.-H. 7 40, 329 Wu, W.-Y. 8 105 Wu, X.-W. 8 180 Wu, X.-Y. 8 451, 494 Wuts, P. G. M. 8 6, 89 Xie, D. 8 98, 431, 445 Xie, L. 7 217 Xie, S. 7 378, 382 Xu, H.-D. 8 451 Xu, J.-F 7 40, 329 Xu, W. 8 320 Xu, Z.-L. 7 564, 589

Xue, F. 7 588 Yadav D. S. 7 859, 872 Yadav L. D. S. 7 856, 857, 858, 859, 867, 868, 869, 870, 871, 872, 873 Yadav, R. 7 859, 869 Yagupol’skii, Y. L. 7 754, 757 Yagupol’skii, Yu. L. 7 170, 613, 614 Yahiro, S. 5 46 Yakovlev, I. P. 7 411 Yakushijin, K. 8 271 Yamabe, K. 7 585 Yamada, A. 7 55 Yamada, H. 8 239 Yamada, K. 7 6, 591 8 387 Yamada, T. 7 46, 246, 247 Yamada, Y. 8 35, 323 Yamagishi, T. 7 626, 796 Yamaguchi, A. 7 596 Yamaguchi, M. 7 796 Yamaguchi, S. 9 136 Yamaguchi, T. 7 560 Yamamoto, H. 8 44, 72, 73, 74, 75, 362 9 15, 49, 86 Yamamoto, T. 5 50 8 304 Yamamoto, Y. 5 92 Yamamura, S. 8 97 Yamasaki, N. 7 241 Yamasaki, T. 8 256 Yamauchi, M. 9 51 Yamazaki, K. 7 522 Yamazaki, M. 7 521 Yamazaki, S. 7 183, 184, 185, 186, 187, 188, 189 Yanagisawa, A. 8 72, 73, 74, 75 9 86 Yang, B. V. 8 337 Yang, C. 7 598, 599 Yang, E. 7 497 Yang, H. 8 33 Yang, Q. 8 257 Yang, R.-Y. 9 106 Yang, Z. 7 575 Yano, T. 6 99 Yao, S. 9 61, 62, 63, 65, 71 Yatabe, M. 7 793, 794 Yatagai, M. 7 626 Yazawa, H. 7 462 Yebdri, O. 7 320 Yijima, C. 7 298 Yoda, N. 7 793, 794 Yokokawa, F. 8 321 Yokomatsu, T. 6 168, 169, 170, 171, 172, 175, 176 Yokomoto, M. 5 33 Yokota, K. 8 323

Author Index Yokota, Y. 7 38 Yokoyama, M. 8 292 Yokozawa, T. 8 328 Yon, G. H. 7 902 Yonehara, K. 8 130, 423, 424, 450 Yoo, Y. S. 8 232 Yoon, J. 8 124 Yoon, S. S. 7 497 Yorke, S. C. 8 129 Yoshida, J. 8 405 Yoshida, K. 8 116, 448 Yoshida, M. 8 239 Yoshihara, M. 8 291 Yoshikawa, S. 8 503 Yoshimo, S. 7 557 Yoshinaga, H. 8 377 Yoshioka, H. 5 5 You, S.-L. 8 371 Youn, I. K. 7 902 Youn, J.-H. 8 192, 233, 236 Young, D. A. 8 54 Yousif, M. M. 7 164 Yu, A. 7 41 Yu, F. X. 7 948 Yu, X.-D. 7 40 Yuan, Y. 7 598, 599 Yuasa, H. 7 130 Yuasa, Y. 5 8, 53, 54, 55, 56, 57 6 167, 168, 169, 170, 172, 173, 175 Yunta, M. J. R. 7 145 Yuumoto, Y. 8 307 Zaalishvili, M. M. 7 397, 398 Zabrocki, J. 7 151 Zacharias, D. E. 6 16 Zagal, L. 7 311 Zai, Y-H. 7 28 Zaitsev, L. M. 7 613 Zaks, A. S. 6 64

Zalinyan, M. G. 7 583 Zanda, M. 5 17, 18 Zanirato, V. 7 103, 104 Zankowska-Jasinska, W. 6 22 Zanocco, A. L. 7 1002 Zard, S. Z. 8 24 Zask, A. 6 186 Zav’yalov, S. I. 7 123, 124, 167 Zavyalov, S. I. 7 482 Zayed, S. E. 7 842 Zehnder, M. 7 424 9 79 Zenner, J. M. 9 116, 142 Zerner, M. C. 6 8 Zhai, Y. 8 241 Zhang, D.-W. 7 329 Zhang, G. 9 88 Zhang, H.-Y. 9 6 Zhang, J. 7 79, 235 9 95 Zhang, W. 8 144, 377, 429 9 12, 38, 137, 154 Zhang, X. 7 383 9 140, 141, 146 Zhang, Y. 7 599, 606 Zheltonog, N. G. 6 76 Zhou, P. 8 36 Zhou, Q.-L. 8 211, 428, 451, 494 Zhou, Y.-G. 8 371 Zhu, G. 9 140 Zhu, J. 8 30, 59 Zhuang, W. 9 163 Zhuravlev, A. K. 7 595 Ziemann, K. 7 908 Zimmermann, N. 8 359, 426 Zistler, P. 7 280 Zook, S. E. 8 126 Zorz, L. 7 161 Zottola, M. A. 8 230 Zsako, J. 7 456 Zubareva, N. D. 7 621 Zurbano, M. M. 7 1025 Zyuz, K. V. 7 515, 520

633

Subject Index General oxazolone and oxazoline substitution patterns are described in the text although entries in an associated table may be more specific in accordance to the examples from the original literature. For instance, a table of 4,5-diphenyl-2(3H)-oxazolones can be referred to in the text as 4,5-disubstituted 2(3H)-oxazolones. Tables of oxazolones and oxazolines that incorporate multiple substitution patterns or functional groups are titled with a general designation as 2(3H)-oxazolones, 5(2H)-oxazolones, saturated 5(4H)-oxazolones, unsaturated 5(4H)-oxazolones, and oxazolines. The individual entries in a table are not included in the index. Italicized page numbers refer to tables. Alphabetized lists of the general classes and exact names of oxazolones, oxazolines and bis(oxazolines) follow the subject index. The list of general classes of oxazolones, oxazolines and bis(oxazolines) includes all classes described in the text or tables as either starting materials or products. The entries in these lists are sorted and arranged in accordance with the sort order rules defined in Microsoft Word. The subject index is cross-referenced wherever possible to facilitate locating a general substitution pattern, a synthetic method or a reaction. For example, using a ketone as a starting material, the general classes of compounds that can be prepared include 2(3H)-oxazolones, 3-aryl-5-tert-butyl-2(3H)-oxazolones, 3-aryl-5-phenyl-2(3H)-oxazolones, 4-(alkylthio)-5(2H)-oxazolones, 4-(arylthio)-5(2H)-oxazolones, 4-alkoxy-5(2H)-oxazolones, 4,5diphenyl-2(3H)-oxazolones, 4,5-diphenyl-2(3H)-oxazol-2-thiones, and 5(2H)-oxazolone N-oxides, which are identified as bolded entries. Additionally, all of these bolded entries are included alphabetically in the list of general classes of compounds that follows the subject index. Here, for example, the entry for 2(3H)-oxazolones lists all pages that discuss 2(3H)-oxazolones and will direct one not only to the pages that use ketones as a starting material but to other synthetic methods or reactions as well. A table index follows the subject index.

Acaricides, 143, 210 ACE inhibitor, 367 Acetophenone, 578 Acetylation of 2-amino-4(5H)-oxazolones, 82–83 b-N-Acetylglycosamine inhibitor, 360 N-Acetylneuraminic acid, 390 (R)-Actinidiolide, 560, 561 Actinoidic acid, 340, 343, 462 Activating agents, 187 Acyclic carbamates or urethanes, 3–7, 47 Acyl cyanides, 59 5-acyloxy-4(5H)-oxazolonium salts, 59 Acyl donors, 183

Acyl isocyanates, 120 2-alkyl-4(5H)-oxazolones, 120 2-alkyl-4-oxazole triflates, 120 N-Acyl a-lactams, 56 Acylacetamides, 12–14, 13, 14 3-aryl-5-substituted-2(3H)-oxazolones, 12 5-alkyl-3-aryl-2(3H)-oxazolones, 12, 13 5-alkyl-3-aryl-4-halo-2(3H)-oxazolones, 12, 14 N-aryl-N-(hydroxy), 12, 13 N-aryl-N-(hydroxy)-a-halo, 12, 14 a-lactam intermediates, 12

The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Synthesis, Reactions, and Spectroscopy, Part B, edited by David C. Palmer ISBN 0-471-21925-8 Copyright # 2004 John Wiley & Sons, Inc.

635

636

Subject Index

Acylaminoacylation of 5(4H)-oxazolones, 191–192, 191 bisoxazoles, 191 2,5-diaryloxazoles, 191, 191 2,5-disubstituted oxazoles, 192 preparation of a-acylamino ketones, 192 preparation of amino ketones, 191 Acylating reagents, 32 chemoselective, 32 regioselective, 32 Acylation, 82, 109 N-aroyl-2,4-oxazolidinediones, 109 N-sulfonyl-2,4-oxazolidinediones, 109 of 2-amino-4(5H)-oxazolones, 82 of 5-alkyl-2,4-oxazolidinediones, 109 of 5-phenyl-2,4-oxazolidinedione, 109 of 5,5-disubstituted-2,4-oxazolidinediones, 109 Acylation, synthesis of saturated 5(4H)oxazolones, 168–171, 170, 287 2-phenyl-4-propionyl-5(4H)-oxazolone, 168 4-acyl-2,4-dialkyl-5(4H)-oxazolones, 287 4-acyl-2,4-disubstituted 5(4H)-oxazolones, 170 4-acyl-5(4H)-oxazolones, 169–170 5-acyloxyoxazoles, 168–169 from O-acylation, 168 rearrangement to 4-acyl-5(4H)-oxazolones, 168 C-4 vs. O-acylation, 168–169 ketomethylene pseudodipeptides, 169 ketomethylene pseudopeptides, 170 of 2-aryl-5(4H)-oxazolones, 171 of 2-phenyl-5(4H)-oxazolone, 169 of 2,4-disubstituted 5(4H)-oxazolones, 170 of 4-alkyl(aralkyl)-2-phenyl-5(4H)-oxazolones, 169 of 4-monosubstituted 5(4H)-oxazolones, 169 of 4-unsubstituted 5(4H)-oxazolones, 169 synthesis of a-amino ketones, 169 difluoroketones, 169 trifluoroketones, 169 N-Acylaziridines, oxazoline synthesis, 398–402 2,4-disubstituted-oxazolines, 398, 400 2,5-disubstituted-oxazolines, 398 2-carboximides, 401–402 rearrangement to oxazolidinones, 402 rearrangement to oxazolines, 401–402 mechanistic studies, 400 mechanistic studies, 400 molecular orbital calculations, 400 (R)-oxytriphine, 401 rearrangement to oxazolines using, 398

nucleophiles, 398–399 Lewis acids, 400–401 N-Acylimininium ions, 109 2,4-oxazolidinediones as precursors to a-hydroxy lactams, 109 Acylisothiocyanates, oxazoline synthesis, 417 spirocyclic oxazolines, 417 Acylnitrenes, oxazoline synthesis, 415 lankacidin antibiotics, 415 5-Acyloxyoxazoles, 159, 168–169, 170 2-phenyl-4-propionyl-5(4H)-oxazolone, 168 4-acyl-2,4-disubstituted 5(4H)-oxazolones, 170 4-acyl-5(4H)-oxazolones, 159 quaternary stereocenters, 159 rearrangement to 4-acyl-5(4H)-oxazolones, 168 N-Acylsulfilimines, 56–57 5,5-diphenyl-2-substituted-4(5H)-oxazolones, 56, 57 N-acyl a-lactam, 56 Agrochemicals, 171, 176, 236 AHMHA, 24 AHPBA, 24 Alanine(s), see amino acids and derivatives Alatamide, 235 Aldehydes, 63–64, 64, 210, 292 2-[2-(a-heteroaryl)ethenyl]-4(5H)oxazolonium perchlorates, 64 Erlenmeyer synthesis of unsaturated 5(4H)-oxazolones, 210, 292 reaction with oxazolonium salts, 63–64, 64 Aldol condensation/reaction, 162, 211, 437 (6R)-lactacystin, 437 clasto-lactacystin b-lactone, 437 Aldol reaction, Mukaiyama, see Mukaiyama Aldol reaction Aldose reductase inhibitors, 99, 102, 113 Alkenes, synthesis of oxazolines, 398 2-Alkoxy-5(4H)-oxazolones, 177–178 2-[(9-fluorenylmethyl)oxy]-5(4H)-oxazolones, 177 2-benzyloxy-5(4H)-oxazolones, 177 4,4-dimethyl-2-[(9-fluorenylmethyl)oxy]5(4H)-oxazolone, 178 amino acid chlorides, 177 carbodiimides, 177 enantiomerization, 177, 178 (-)-mirbazole C, 178 mixed anhydrides, 177 ring-opening polymerization, 178 Toac, 178 5-Alkoxyoxazoles, 138, 155–160, 160

Subject Index 2-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(2H)-oxazolones, 158 5-(2H)-oxazolones, 138 sigmatropic rearrangement, 137 4-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(4H)-oxazolones, 158 4-benzyl-2-phenyl-4-(trifluoromethyl)-5(4H)oxazolone, 158 5(4H)-oxazolones, 155–160 saturated 5(4H)-oxazolones, 160 allylic alcohols, 156 Claisen rearrangement, 155–160 propargylic alcohols, 157 Alkylation of 2(3H)-oxazolones, 42 5-ethoxyoxazoles, 42 Meerwein’s salt, 42 Alkylation of 4(5H)-oxazolones and 2,4-oxazolidinediones, 94, 108, 109, 110–111 of 2-amino-4(5H)-oxazolones, 82 of 2,4-oxazolidinediones, 94, 108, 111 3-alkyl-2,4-oxazolidinediones, 108, 109 5-benzyl-2,4-oxazolidinediones, 111 5,5-disubstituted-2,4-oxazolidinediones, 111 at C-5, 110–111 Mitsunobu reaction, 108–109 N- vs O-, 94, 108 preparation of N-acyliminium ion precursors, 108 Alkylation of 5(2H)-oxazolones, 134–136, 135, 160, 162 5(2H)-oxazolones, 135 alkylation at C-2, 135 C-2 vs. C-4, 134–136, 160 a-diketones, 134 Alkylation of 5(4H)-oxazolones, 134–136, 160, 162–164, 165, 171 4,4-(diarylmethyl)-2-phenyl-5(4H)oxazolones, 163 4,4-dialkyl-5(4H)-oxazolones, 162, 163 a,a-dialkyl-5(4H)-oxazolones, 160 saturated 2,4,4-trisubstituted-5(4H)oxazolones, 165 asymmetric, 163 C-2 vs. C-4, 134–136, 160 intramolecular, 171 sorbinil, 171 spiroalkylation, 171 of 2-substituted 5(4H)-oxazolones, 162 dialkylation, 163 a,a-disubstituted amino acids, 162 of 2-unsubstituted 5(4H)-oxazolones, 162 aldol reactions, 162

637

formyl anion equivalent, 162 Michael adducts, 162 of 2,4-disubstituted-5(4H)-oxazolones, 163–164 asymmetric, 163, 164 chimeras, 163 a-halo ketones, 164 palladium catalyzed, 163 phase transfer catalysis, 163, 164 quaternary amino acids, 163 sphingosine analogs, 164 Alkylation of imines and oximes, 570–572, 571, 587 aldehydes, 587 diethylzinc, 587 imines, 570–572 allylzinc reagents, 570, 571 asymmetric addition, 571 bu-box, 570 cyclic, 570, 571 enantioselective, 571 i-pr-box, 570 oximes, 572 alkylzinc reagent, 572 Alkylation of oxazolines, 433–435 oxazolinium salts, 433–435 Allene annulation, 574–575 inda-box, 575 Allyl N-acylphenylglycinates, 137 2-allyl-4-phenyl-5(2H)-oxazolones, 137 sigmatropic rearrangement, 137 Allyl amides (enamides), oxazoline synthesis, 402–406 trans-5-vinyl substituted oxazolines, 404 cis-1,2-aminocyclopentenol derivative, 404 5-vinyloxazolidinones, 404 balanol, 406 Indinavir, 404 Allylation and cyanohydrin formation, 569–570, 587 Allylic alcohols, 381, 389, 390 precursors to b-amino alcohols, 389, 390 precursors to b-halo amides, 381 reaction with trichloroacetonitrile, 381, 389 Allylic oxidation, 577, 577 inda-box, 577 Allylic substitutions, 487–493, 489, 490, 491, 562–564, 563, 564, 588 allylic imidate rearrangements, 491–492 ferrocenyloxazolines, 491 asymmetric allylic acetates, 563 (E)-cinnamyl methyl carbonate, 564 diethylmalonate, 562–564, 563, 564

638

Subject Index

Allylic substitutions (Continued) 1,3-diphenylallyl acetate, 562–564, 563, 564 enantioselective substitution, 563, 564, 588 ferrocene-box, 564 hard nucleophiles, 492 intramolecular allylic amination, enantioselective, 492 nickel (0) catalyzed substitutions, 492 palladium-catalyzed alkylation with, 488–493, 489, 490, 491 3-acetoxycyclohexene, 490, 491 3-acetoxycyclopentene, 490 dimethylallyl acetate, 490, 490 dimethylallyl tert-butylcarbonate, 490, 490 diphenylallyl acetate, 487–489, 489 PhosOx ligands, 490, 491, 492, 493 platinum-catalyzed alkylation, 491 soft nucleophiles, 487–493 acetylacetone, 489 arylboronic acids, 493 benzyl amines, 489 dimethyl malonate, 487–489, 489, 490, 491 dimethyl methylmalonate, 489 silyl enolates, 489 x-ray crystal structure, 489, 491 2-Allyloxyoxazoles, 7 3-allyl-4,5-diphenyl-2(3H)-oxazolones, 7 2(5H)-oxazolones, 7 [3,3]-sigmatropic rearrangement, 7 aza-Claisen rearrangement, 7 photolysis, 7 Allylzincation, enantioselective, 573 Almazole D, 62 Amidines, reaction with carbon dioxide, 142, 142 4-(dialkylamino)-5(2H)-oxazolones, 142 4-(N,N-dialkylamino)-5(2H)-oxazolones, 142 Amination, of enolsilanes, 581 bu-box, 581 cis-1-Amino-2-indanol, 395 20 -Amino-20 -deoxycytidine, 393 20 -Amino-20 -deoxyuridine, 393 a-Amino acid esters, 7, 9, 43, 45 5-alkoxy-2(3H)-oxazolones, 7, 9 N-chlorocarbonylation of amino acid esters, 7 5,5-dialkoxy-2-oxazolidinones, 43, 44, 45 from 5-alkoxy-2(3H)-oxazolones, 43, 45 Amino acid hydroxylases, 72 Amino acids and derivatives, 7, 23, 24, 25, 28, 33, 131–134, 133, 146, 148, 150, 151–155, 156, 158, 162, 163, 165, 171, 174, 177, 178, 179, 180, 181, 181, 182, 184, 185– 189, 189, 189–191, 195, 202, 206, 207,

208, 210, 213-217, 214, 217, 224, 226, 227, 228, 229, 229, 230, 231–233, 234, 235, 237, 237, 240, 241–243, 241, 244, 247, 256, 257, 258, 258, 262–265, 270, 271–274, 276, 282, 287, 289, 291, 292, 294, 295, 436, 471, 475, 536 20 ,10 :1,2;100 , 200 :3,4-dibenzocyclohepta-1,3diene-6-amino-6-carboxylic acid (BIP), 289 N-acetyl, 134, 179 N-acyl, 132, 151–153, 155, 178, 180, 181, 185, 191 207, 210, 212, 213–215, 217, 227– 228, 231, 241, 294 N-acylphenylglycinates, 137 alanine(s), 132, 133, 146, 156, 158, 171, 180, 187, 231, 233, 289 2-(aminomethyl), 187 2-selenienyl, 233 3-(fur-2-yl), 231 3-pyridyl, 233 3-selenienyl, 233 3,3-difluoro, 133 3,3,3-trifluoro, 156 4-pyridyl, 231 b-D-C-allosyl, 158 b-(benzofuranyl), 231 N-benzoyl, 158, 289 N-benzoyl, butyl ester, 180 furyl, 233 b-(pyrid-3-yl), 231 b-(quinol-3-yl), 231 thienyl, 233 N-alkoxycarbonyl, 177, 178 a-alkyl, 436 a-alkyl-a-methyl, 287 a-allenyl, 156 b-amino acid, 471 d-amino acid, 475 b-amino-a,b-dehydro-a-amino acid, 174, 224 equivalents, 174 precursors, 224 2-aminoisobutyric acid, 190, 207, 208 N-2-(4-bromobenzoyl), 207 a-(arylmethyl)-a-(trifluoromethyl), 158 aspartic acids and derivatives, 148, 149, 156, 186, 187, 188, 279, 293 3-alkyl, 148, 149 N-acyl dehydro, 293 N-benzyloxycarbonyl, 186 conformationally constrained, 279 dehydro, 293 a-isobutyl, 187 a-methyl, 187

Subject Index a-(trifluoromethyl)-b-substituted, 156 azabicyclo[2.2.1]heptane, 274, 299 N-benzoyl, 134, 156, 181, 182, 187, 191, 289 N-benzyloxycarbonyl, 134, 177, 186, 287, 291, 292 (Aib)4-OH, 291, 292 chlorides, 177 bicyclo[2.2.1]heptane, 274, 276 bis(amino acids), 202 bromotyrosine, 132 choline esters, 179 conformationally constrained (restricted), 232, 265, 271, 272, 274, 278, 297, 299 cyclohexane, 271–272, 274, 280 cyclohexene, 277 cyclononane, 190 cyclopropane (cyclopropyl), 190, 235, 260–261, 262–265, 266, 270, 297 2-(3,4-dihydroxyphenyl), 263 2-chloro, 263 (c3diPhe), 297 homoserine, 265 triphenyl, 265 cysteine, 258, 259, 265 b-phenyl, 258, 259 conformationally constrained, 265 dehydro(didehydro), 174, 213, 214, 216, 224, 226, 228, 229, 229, 230–235, 237, 237, 238, 240, 242, 243, 244, 247, 256, 292 N-acyl, 229, 237 a,a-dialkyl, 178, 187–189, 189–190 b,b-difluoro, 133 a,a-disubstituted, 162, 186, 187, 289 esters, 295 ferrocenoyl, 206 b-fluoro, 23, 282 N-formyl, 153 glutamic acid(s), 187, 188 a-methyl, 187 glycine(s), 133, 135, 152, 157, 162, 179, 187, 190, 207, 212, 210, 211, 212, 213, 214, 220, 226, 228, 235, 243, 249, 287, 292, 294, 536 1-naphthoyl, 294 2-(1-adamantyl), 152 a-(2-heteroaryl), 157 N-2-(4-bromobenzoyl)-diphenyl, 207 N-acetyl, 210 N-acyl, 179, 190, 212, 226, 228, 235, 287, 292 N-acyl-a-(triphenylphosphonio), 220 aryl, 133 N-benzoyl, 210, 211, 249

639

a-(heteroaryl), 249 a,a-dialkyl, 135, 162 dibenzyl, 135, 190 diphenyl, 207 a,a-di(isopropylthio), 190 dimethyl, 190 dipropyl, 190 a-methylphenyl, 187 (S)-phenyl, 536 a-(trifluoromethyl)-a-(2-heteroaryl), 157 b-(heteroarylamino), 240 hippuric acid, 162, 173, 191, 221, 225, 256, 276, 292 histidine(s), 180, 231 b-hydroxy, 28, 287 g-hydroxy, 172 hydroxy, 24 isovaline, 207, 208 N-2-(4-bromobenzoyl), 207 leucine, 187, 208 2-(aminomethyl), 187 a-methyl, 208 tert-leucine, N-benzoyl, 182 2,3-methanomethionine, 263 a-methyl, 190 norbornane, 273, 297 phenylalanine(s), 163, 181, 186, 187, 190, 208, 213, 226, 231, 232, 233, 257, 263, 271, 272, 274, 282, 297 (2,6-difluoro-3,4-dihydroxy), 231 [3-11C], 231 3,4-dihydroxy (DOPA), 231, 263 [3-11C], 231 cyclopropyl, 263 L-4-(borono) (BPA), 233 4-(polyfluoromethyl), 231 N-acetyl, 257, 282 N-acyl-2-fluoro, 231 N-acyl-4-fluoro, 231 aryl, 231 N-benzoyl, 181, 213 a,b-dehydro, 213 a-benzyl, 163 constrained, 232, 271, 272–274, 297 fluorine containing, 233 metallocene, 231 a-methyl, 163, 186, 187, 190, 208 b-methyl, 232 proline(s), 146, 243, 273, 274, 299 constrained, 274, 299 serine(s), 152, 171, 172, 188, 214, 297 2-methyl-3-phenyl, erythro-, 172 a-alkyl, 188

640

Subject Index

Amino acids and derivatives (Continued) b-aryl, 214 constrained, 297 N-substituted, 179, 195 d-substituted, conformationally restricted, 274 threonine(s), 182, 292 N-acyl, 292 allo, 182 a-(trifluoromethyl), 187 tryptophan, 132, 152, 183, 222, 233 a-methyl, 183 tyrosine(s), 132, 187, 231, 263 bromo, 132 cyclopropyl, 263 a,a-disubstituted, 187 g,d-unsaturated, 155 valine, 146, 187, 190, 231, 257, 289 4-(trifluoromethyl), 231 N-benzoyl, 289 g-hydroxy, 257 a-methyl, 187, 190 Amino acids, synthesis of bis(oxazolines), 534, 536 bis(oxazoline) ligands, 534–536 bu-box, 535–536 phe-box, 536 i-pr-box, 535 py-box, 534 py-box-ip, 534 (S)-tert-leucine, 535 (S)-phenylglycine, 536 b-Amino alcohols and amino alcohols, 22, 24, 29, 38, 333–334, 334–336, 336, 337, 338, 340–344, 347–348, 384, 385–386, 387, 388–389, 389, 390, 394, 404, 417–418, 419–421, 422–423, 424–425, 427, 427, 440–442, 534, 535, 536 2-aminooxazolines, 394 2-heteroaryloxazolines, 384 2-monosubstituted oxazolines, 338 4-monosubstituted oxazolines, 338 5-monosubstituted oxazolines, 338 o-aminophenyloxazolines, 336 bis(oxazoline) ligands, 534–536 bu-box, 535, 536 inda-box, 537 multiply substituted oxazolines, 338, 384 oxazolines, 333–338, 334–336, 337, 385–386 i-pr-box, 535, 536 py-box, 534 py-box-ip, 534 unsubstituted oxazolines, 384 (1S, 2R)-1-aminoindan-2-ol, 537

acylation of, 338 2-amino alcohols, 22, 24 hydrogenation of 2(3H)-oxazolones, 22–23 methoxybromination of 2(3H)-oxazolones, 25 methoxyselenylation of 2(3H)-oxazolones, 26 (þ)-bulgecinine, 29 chemoselective protection, 38 ()-desoxoprosopinine, 29 from allylic alcohols, 389, 390 from hydrolysis of oxazolines, 417–418, 419–421, 422–423, 424–425, 427, 427 from reduction of oxazolines, 440–442 Pictet-Gams reaction, 348 reaction with acids, 333–334, 334–336 cyanogen bromide, 394 esters, 336–337 imidates, 387, 388–389 isatoic anhydride, 336 malononitrile, 537 nitriles, 384, 385–386, 387 phosphorus oxychloride, 348 thionyl chloride, 334, 338–339, 340–344 Vilsmeier reagent, 347–348 regioselective protection, 38 (S)-valinol, 534, 535 a-Amino aldehydes, 25 b-Amino-a-hydroxy acids, 379–380 a-Amino-b-hydroxy ketones, 407 3-Amino-b-lactams, 172 from imines and monosubstituted 5(4H)oxazolones, 172 Amino nitrile cyclizations, 133, 133, 153 5(2H)-oxazolones, 133, 133 5(4H)-oxazolones, 153 N-acylated, 153 Amino phenols, 38 cis-1,2-Aminocyclopentenol derivative, 404 Aminoisobutyric acid (Aib), 154, 190, 207, 208, 291, 292 incorporation into pepetides, 154, 190 Aminolysis, 145, 146, 183–190, 189, 235–240, 237, 241, 241, 242, 295–296 5(2H)-oxazolones, 145, 146 amines and chiral amines, 145–146 amino acid esters, 146 saturated 5(4H)-oxazolones, 183–190, 189 as activating agents for dicarboxylic acid amino acids, 186 as glycine synthons, 186

Subject Index incorporation of a,a-dialkylamino acids into peptides, 185–186, 189–190 Obrecht’s methodology, 187–188, 189 resolution of racemic a,a-dialkylamino acids, 187 preparation of 5-pyrazolones, 184 amino acid bornyl amides, 185 benzothiazoles, 184 chiral glycine enolate equivalents, 184 a,a-dialkyl amino acids, 186–189 lactones, 184 peptides, 185–186, 189–190 ring opening with amines, 183–185 1-amino-2-indanol, 183 2-aminothiophenol, 184 2H-azirines, 185 aminopiperidines, 183 chiral amines, 185 bis-(2-chloroethyl)amine, 183 dimethylamine, 184 ring opening with amino acid derivatives, 185–186, 189–190, 189 Obrecht’s methodology, 187–188, 189 substituted amino acid amides, 189 synthesis of peptides, 185–186, 189–190 ring opening with hydrazonoyl halides, 184 ring opening with thiosemicarbazides, 183 ring opening with p-toluenesulfonamide, 183 unsaturated 5(4H)-oxazolones, 235–237, 237, 238, 239, 240, 241, 241–242, 295–296 arylacetaldehyde equivalents, 237 kinetics, 237 mechanism, 237, 295 microwave assisted reaction, 295 Pictet-Spengler reaction, 237 preparation of N-acylamino acid amides/acylamino amides, 236, 240–241, 241 N-acyl dehydroamino acid amides, 237, 237 amino acids, 240 bastadin-5, 237 benzodiazepines, 296 a,b-dehydropeptides, 241–242, 295 C-terminal or internal amino acid, 242 N-terminal amino acid, 241 imidazolinones, 239 imidazolones, 238, 239, 240, 296 isoquinolines, 238 macrolactams, 237 quinazolines, 296 quinazolinones, 296

641

tetrahydro-b-carbolines, 237 reaction with amines, 235–237, 237, 240, 295 amino acids or amino acid esters, 240, 241–242, 295 a,b-dehydropeptides, 241–242, 295 o-aminobenzamide, 296 aminobenzoic acids, 240 anilines/aromatic amines/heterocyclic amines, 238, 239, 240, 295, 296 chiral amines, 241–242 diamines, 237, 239 tryptamine, 237–238 reductive aminolysis, 240, 241 N-acylamino acid amides, 240–241, 241 asymmetric synthesis of non-proteinogenic amino acids, 240 chiral amines, 240 stereospecific ring opening, 238 tandem Erlenmeyer condensationmacrolactamization (TECM), 237 2-Aminopyrimidinones, 77, 78 2-amino-5-(carboxyalkyl)-4(5H)-oxazolones, 77, 78 oxidative ring contraction, 77, 78 Amphiphilic copolymer membranes, 508 Angiotensin converting enzyme inhibitors, 242 Analgesic(s), 75, 274 Anilines, 142, 248, 249 4-(alkylamino)-5(2H)-oxazolones, 142 reaction with ethylimino(ethylthio) acetate fluoroborate, 142 ring opening of unsaturated 5(4H)-oxazolones, 248, 249 Anodic oxidation, 4, 14 Antibacterial agents (antibiotics), 54, 68, 78, 84, 120, 209, 239, 246, 265, 292, 295, 367 Anticapsin, 367 Anticonvulsant agents, 246 Antidepressants, 54, 348 Antidiabetic agents, 54, 95, 103, 115, 116 Antiepileptic agents, 90 Antifertility agents, 227 Antifungal agents, 70, 239, 246, 295 Anti-Heliobacter pylori (H. pylori) agents, 74, 120 Antihelmintic agents, 239, 246 Antihyperglycemic agents, 94 Antihypertensives, 221 Antihypoxic agents, 75 Anti-inflammatory agent(s), 54, 75, 109, 210, 227, 292, 334 Antimalarial(s) agents, 54, 71

642

Subject Index

Antimicrobial activity (agents), 65, 75, 248, 251, 295 Antineoplastic and antitumor agents, 183, 239 Anti-Parkinsonian agents, 239 Antispasmodic agents, 75 Antitubercular agents, 65, 246 Antitumor agents, 103, 120, 561 Antiulcer agents, 54, 103, 120, 448–449 Antiviral agents, 54, 72, 239, 246 ()-Aphanorphine, 340, 469 Aquired immune deficiency syndrome (AIDS), 432 Arabinitol, 389 Arenes, metalation by EVL-HMPA, 458, 459 N-Aryl ureas, 70 2-(arylimino)-4(5H)-oxazolones, 70 Arylation, 167, 167, 260, 289 2,4-diaryl-4-(2,4-dinitroaryl)-5(4H)oxazolones, 167 2,4,4-trisubstituted 5(4H)-oxazolones, 167 Friedel-Crafts reaction, 289 heteroarylation, 167 of saturated 5(4H)-oxazolones, 167, 289 of unsaturated 5(4H)-oxazolones, 260 Aspartic acid(s), see amino acids and derivatives Asymmetric polymerization, see Polymerization, asymmetric Atropisomer selectivity, 464 Attention deficit hyperactivity disorder (ADHD), 68 Axially-chiral biphenyls (biaryls), 462–468, 462, 466 (þ)-dioncophylline C, 463 (S)-gossypol, 466–468 ()-mastigophorene A, 465–466 ()-O-methylancistrocladine, 463 (þ)-O-methylancistrocline, 463 Aza-bis(oxazolines), 588 allylic substitution, 588 cyclopropanation, 588 polymer-supported, 588 Aza-Claisen rearrangement, 7, 45, 581 2-allyloxyoxazoles, 7 allylic imidates, 581 Azabicyclohexene, 148 Aza-Diels-Alder reaction, 558 1-Azadienes, 198, 199, 199, 200 Azadirachtin, 554 Azido alcohols, oxazoline synthesis, 413 Azido esters, oxazoline synthesis, 412 Stuadinger-aza-Wittig reaction, 412–413 Azine N-oxides, reaction with 5(4H)-oxazolones, 174

4-(isoquinolin-1-yl)-2-substituted 5(4H)oxazolones, 174 4-(quinolin-2-yl)-2-substituted 5(4H)oxazolones, 174 dihydropyridines, 174 isoquinoline N-oxide, 174 pyridine N-oxides, 174 pyridinium salts, 174 quinoline N-oxides, 174 Aziridination and epoxidation, 575–576, 575 aziridines, 575 epoxides, 575 of cinnamate esters, 575, 575 of a-imino esters, 575 of styrene, 575 phe-box, 575 Aziridines, 575 2H-Azirines, 117–119, 119, 147, 148, 154, 185, 194, 287 2,2-dimethyl-3-(dimethylamino), 154, 185 3-(dimethylamino), 147, 148, 185 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)ones, 147, 148, 185 from flash vacuum pyrolysis of a 5(4H)oxazolone, 194 Heimgartner, 287 preparation of imidazolones, 117–119, 119 reaction with 5(2H)-oxazolones, 147 reaction with 5(4H)-oxazolones, 185 reaction with 5,5-dimethyl-2,4oxazolidinedione, 117–119, 119 reaction with carboxylic acids, 154 Azithromycin, 441 Azodicarboxylates, 33–34, 34 diastereoselective [4þ2] cycloaddition, 33, 34 3-acyl-2(3H)-oxazolones, 33, 34 preparation of 2-oxazolidinone auxiliaries, 35 a-amino acids, 35 Azomethine ylides, 408–410 2-aminooxazolines, 408 2-iminooxazolines, 410 cis-2-oxazolines, 408 trans-2-oxazoline-4-carboxylates, 410 trans-2-oxazolines, 408 addition to carbonyl compounds, 408–410 Baccatin III, 346 Balanol, 406 Barbituric acids, oxidative ring contraction, 105–106 5-aryl-2,4-oxazolidinediones, 105–106 5-heteroaryl-2,4-oxazolidinediones, 105–106

Subject Index Bastadin-5, 237 Benzimidazo[1,2-c]quinazolines, 296 Benzimidazole(s), 223, 240, 248, 249, 251, 296 1,3-Benzodiazepines, 197 1,4-Benzodiazepine-2,5-diones, 296 Benzoin, 8, 9 3,4,5-triaryl-2(3H)-oxazolones, 8 cyclization with phenyl isocyanate, 8 Benzopyran-2,5(6H)-diones, 173 Benzothiazoles, 184, 248, 249 Benzotriazoles, 223, 292 Benzoxazin-4-ones, 247 Benzyl bis(oxazoline), 533, 541 cyclopropanation, 541 x-ray crystal structure, 533 Berinanamycin A, 367 (BINOL)-box, 587 1,3-dipolar cycloaddition of nitrones, 587 Bioisosteres, 97 Bis(alkoxycarbonylation) of homoallylic alcohols, 573 Bis(oxazoline) ligands, 530–532, 582–585 aza-bis(oxazolines), 588 benzyl bis(oxazoline), 533, 541 (BINOL)-box, 587 bis(oxazolinyl)pyridine, see py-box bu-box, 530, 532, 535–536, 539, 540, 541, 548, 552, 555, 557, 559, 561, 565, 566, 570, 581, 585, 588–589 DBF-box, 534, 550, 551 inda-box, 534, 537, 549, 549, 557, 559, 567, 574–575, 577, 589 phe-box, 530, 532, 534, 536, 546, 548, 549, 555, 557, 561, 567, 567, 575, 581 i-pr-box, 534, 535, 548, 561, 570, 572 py-box, 530, 534, 551, 565–566 py-box-ip, 534, 540–541, 578 syntheses, 534–537 bu-box, 535–536 Desimoni’s protocol, 536 from amino acids, 534, 536 from amino alcohols, 534, 535, 536 from (S)-tert-leucine, 535 from (S)-phenylglycine, 536 from malononitrile, 537 from (S)-valinol, 534, 535 inda-box, 537 Masamune’s protocol, 536 phe-box, 536 i-pr-box, 535 py-box-ip, 534 Bis(oxazoline)-metal complexes, 532–534, 546, 552, 554, 561, 565, 567, 568, 575

643

geometry, 532 x-ray crystal structures, 533 Bis(oxazolines), chiral, 333, 347, 361, 384, 394, 396, 417, 457, 465, 466, 481, 504, 530– 594, 582–585 allylic oxidation, 577, 577 axially chiral bis(oxazolines), 361 aza-bis(oxazolines), 394 aziridination and epoxidation, 575–576, 575 bis(oxazoline) ligands, 530–532 bis(oxazoline)-metal complexes, 532–534 C2-symmetric bis(oxazolines), 396 carbon-carbon bond forming reactions, 538– 575, 539, 542, 543, 544, 546, 547, 548, 549, 550, 551, 552, 553, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 571, 585–590, 586, 589 alkylation of imines and oximes, 570–572, 571, 587 allylation and cyanohydrin formation, 569– 570, 587 allylic substitutions, 562–564, 563, 564, 588 conjugate additions, 567–569, 567, 568, 569 cyclopropanations, 504, 530, 532, 538–545, 539, 542, 543, 544, 585, 586 Diels-Alder reactions, 545–554, 546, 547, 548, 549, 550, 551, 552, 553 1,3-dipolar cycloadditions, 561–562, 561, 562, 586 Friedel-Crafts reactions, 588–589, 589 hetero-Diels-Alder and ene reactions, 554– 560, 556, 557, 558, 559, 560, 589–590 miscellaneous carbon-carbon bond forming reactions, 573–575 Mukaiyama aldol reaction, 565–566, 565, 566 polymerization, asymmetric, 572 dilithiation of bis(oxazolinyl)ferrocene, 457 miscellaneous reactions, 580–581 reductions, 577–579, 578, 579, 587 hydrosilylation, 577–579, 578 transfer hydrogenation, 579, 579 sulfimidation, 576 synthesis, 534–537 4,40 -Bis(oxazolones), 193, 195 Bistratamide D, 364 Bleomycins, 28 Boc-Ox, 40 Bohlman bands, 97 Boulton-Katritzky rearrangement, 92, 93 a-Bromo amidines, 92–93 2-alkoxy-4(5H)-oxazolones, 92 2-ethoxy-4(5H)-oxazolones, 93 thermolysis, 92–93

644

Subject Index

Bu-box, 530, 532, 535–536, 539, 540, 541, 548, 552, 555, 557, 559, 561, 565, 566, 570, 581, 585, 588–589 alkylation of imines, 570 amination of enolsilanes, 581 Cu(I), 540 Cu(II), 532, 552, 566 cyclopropanation, 530, 539, 540, 541 Diels-Alder reaction, 548, 552 1,3-dipolar cycloaddition, 561 Friedel-Crafts reaction, 588–589 geometry, 532 hetero Diels-Alder reaction, 555, 557 Mukiayama aldol reaction, 565, 566 Mukiayama Michael addition, 585 synthesis, 535–536 Burgess reagent, 361–365, 361–363, 366 axially chiral bis(oxazolines), 361 cyclodehydration of b-hydroxy amides, 361–365 inversion, 363–364 PEG-supported, 364, 366 preparation of bistratamide D, 364 preparation of lissoclinamide 4, 363 preparation of lissoclinamide 7, 363 preparation of thiangazole, 363 C-2 vs. C-4 alkylation of oxazolones, 134–136, 135 4,4-dialkyl-5(4H)-oxazolones, 135 5(2H)-oxazolones, 135 of 5(2H)-oxazolones, 134–136 of 5(4H)-oxazolones, 134–136 C-H insertion reactions, 575 C-Substitution of 2(3H)-oxazolones, 36, 39 4-(3-indolyl)-2(3H)-oxazolones, 36 5-(3-indolyl)-2(3H)-oxazolones,36 5-acyl-4-methyl-2(3H)-oxazolones, 36 5-methyl-2(3H)-oxazolone sulfonamides, 36 stannyl oxazolones, 36 3-(trimethylsilylethoxymethyl)-2(3H)oxazolone, 36 cross-coupling reactions, 36 stannyloxazolones, 36 Stille coupling, 36 4-methyl-2-(3H)-oxazolone, 36 Friedel-Crafts acylation, 36 ()-Calyculin B, 339 (þ)-Calyculin A, 339 Calyculin C, 361 Calyculins, 342 Capillary zone electrophoresis (CZE), 75 Carbamates (Urethanes), 3–7, 4, 47, 48

2(3H)-oxazolone-4-carboxylates, 47, 48 3-aryl-5-tert-butyl-2(3H)-oxazolone(s), 3, 4 4-aryl-5-phenyl-2(3H)-oxazolones, 3 4-naphthyl-2(3H)-oxazolone, 4 5-phenyl-2(3H)-oxazolone, 6 bulky 5-substituted-2(3H)-oxazolones, 3 N-(1-naphthylvinyl)urethane, oxidative cyclization with lead tetraacetate, 4 N-aryl urethanes, 3 N-aryl-N-(3-triisopropylsilylpropargyl) carbamate, 7 b-silylvinyl cations, 7 a-bromo ketones, 3, 4 a-diphenylphosphinylcarbamates via anodic oxidation, 4 ethyl N-arylcarbamates, 3, 4 (hydroxyphenacyl)urethanes, 3 a-methoxycarbonylbenzyl carbamate, 6 methyl carbamate, 47 a-O-(Carbamoyloxy)esters, 94, 102 3-unsubstituted-2,4-oxazolidinediones, 94 spirocyclic 2,4-oxazolidinediones, 102 chlorosulfonyl isocyanate, 94, 102 cyclodehydration, 94 from isatins, 102 Carbenes, 57, 59 4(5H)-thiooxazolones, 59 spirocyclic 4(5H)-oxazolones, 57 aminooxy, 57 Carbodiimides, synthesis of unsaturated 5(4H)-oxazolones, 152, 177, 214, 214 Carbonyl compounds, synthesis of unsaturated 5(4H)-oxazolones, 212 Carbonyl ylide, 57 Carbonyl-ene reactions, 585 glyoxylates and pyruvates, 585 Carboxylic acids and esters, oxazoline synthesis, 333–338, 334–336, 337 oxazolines, 333–338, 334–336, 337 amino alcohols, 333–334, 337 carboxylic acids, 334–336 carboxylic esters, 337 b-chloro amides, 334 cyclodehydration, 333, 336 Lewis acids, 336 Vorbru¨ggen’s methodology, 333–334 Cbz-Ox, 40 Central nervous system activity, 237, 239 Chemoselective protection, 38–40 amino alcohols, 38 amino phenols, 38 Boc-Ox, 40 Cbz-Ox, 40

Subject Index polyalcohols, 40 polyamines, 38 Chimeras, 163 Chiral glycine synthon, 508 Chirality recognition, 581 Chloroacetyl isocyanate, 60 4(5H)-oxazolones, 60 (a-Chloroalkyl)boronates, synthesis, 581 phe-box, 581 Chlorosulfonyl isocyanate, 92, 94, 97, 102, 172 3-unsubstituted 2,4-oxazolidinediones, 94 spirocyclic 2,4-oxazolidinediones, 97, 102 [2þ2] cycloaddition with 5(4H)-oxazolone, 172 dioxazabicycloheptanones, 172 Chlozolinate, 90, 120 Cholinergic agents, 98 Chromatographic mobility, 206, 286 saturated 5(4H)-oxazolones, 206 unsaturated 5(4H)-oxazolones, 286 Cinnamate esters, 575, 575 Claisen rearrangement(s), 155–159, 160 2-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(2H)-oxazolones, 158 4-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(4H)-oxazolones, 158 4-acyl-5(4H)-oxazolones, 159 4-allenyl-2-phenyl-5(4H)-oxazolones, 156 5(4H)-oxazolones, 155–159, 160 [3,3] sigmatropic rearrangement, 155 5-alkoxyoxazoles, 155–159, 160 acyloxyoxazoles, 159 Ireland-Claisen rearrangement, 155 CNS agents, 72 CNS stimulant, 67 Configurational assignments, unsaturated 5(4H)oxazolones, 284–286 chromatographic mobility, 286 dipole moment, 286 1 H NMR, 285 13 C NMR, 285 mass spectrometry, 285 Conformationally constrained (restricted) amino acids, 232, 265, 271, 272, 274, 278, 297, 299 aspartic acid analogs, 278 cysteine, 265 phenylalanine, 232, 271, 272, 297 proline, 274, 299 serine analogs, 297 d-substituted, 274 ()-Conhydrine, 22 ()-b-Conhydrine, 108 Conjugate additions, 567–569, 567, 568, 569

645

bis(oxazoline)-mediated, 567–569, 569 free radical, 567, 567, 568 3-acryloyl-1,3-oxazolidin-2-one, 567 N-cinnamoyl oxazolidinones, 567 N-crotonyl oxazolidinones, 567 enantioselective to a,b-unsaturated N-acyl oxazolidinones, 568 inda-box, 567 phe-box, 567 Michael additions/reactions of, 568–569, 585 O-benzylhydroxylamine, 568 enol silanes, 585 ethyl acetoacetate, 568 methylthio enolsilane, 568 silyl enol ethers, 568 Mukaiyama Michael addition, 585 polar, 569 Corey, 546, 547 Coumarin semicarbazones, 69 Coumarins, 256 Cross-coupling reactions/methodology, 451, 464–468, 508 Negishi, 451 Stille coupling, 36, 508 Ullmann, 464–468 Curacin A, 428 (þ)-a-Curcumene, 343, 446 Curtin-Hammett principle, 456 Cyanamide, 74–75 2-amino-5-substituted-4(5H)-oxazolones, 75 reaction with dihydrofuran-2,3-diones, 75 synthesis of pemoline, 74–75 Cyanine dyes, 64 Cyanogen bromide, 389, 394 aza-bis(oxazolines), 394 Cyanohydrins, 58, 97, 99 spirocyclic 2,4-oxazolidinediones, 97 chlorosulfonyl isocyanate, 97 quinolizidines, trans, 97 Cyclization agents/cyclizations, 132–133, 151–154, 177, 187, 188, 210, 211–212, 225, 253, 287, 292, 294 1,10 -carbonyldiimidazole, 187 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDAC  HCl), 177, 287 2-chloro-1,3-dimethylimidazolium chloride, 212 2-ethoxy-N-ethoxycarbonyl-1,2dihydroquinoline (EEDQ), 153 2-isobutoxy-N-isobutoxycarbonyl-1,2dihydroquinoline (IIDQ), 253 3-(alkoxycarbonyl)benzotriazole-1-oxides, 292

646

Subject Index

Cyclization agents/cyclizations (Continued) acetic anhydride, 151, 154, 210 alumina/boric acid þ acetic anhydride, 212 bismuth(III)acetate, 292 carbodiimides, 152 cyanuric chloride, 153 N-cyclohexyl-N0 -2-(N-methylmorpholinio)ethylcarbodiimide p-toluenesulfonate, 152, 154 dicyclohexylcarbodiimide, 187, 212 diethyl pyrocarbonate, 212 difluoroacetic anhydride, 133 N,N-dimethylchlorosulfitemethaniminium chloride, 153, 212 haloiminium salts, 153, 212 ion-exchange resins, 212 isopropenyl chloroformate, 153 Lawesson’s reagent, 292 methyl chloroformate, 153 microwaves, 212 mixed anhydrides, 153 perfluoroacylating agents, 133 phosphorus oxychloride, 225 phosphorus trihalides, 133 potassium fluoride/alumina, 212 sodium acetate/acetic anhydride, 212 thionyl chloride, 287 triethyl orthoformate, 294 trifluoroacetic anhydride (TFAA), 132, 152 trimethylsilylchloride/acetic anhydride, 212 Vilsmeier-Haack reagent, 294 zeolites, 212 zinc acetate, 212 zinc chloride, 212 Cyclization of amino acids and derivatives, 132– 134, 133, 151–155, 154, 210–212, 212, 213–217, 214, 216, 217, 225, 287–288, 292–294 5(2H)-oxazolones, 131–133, 133, 134 2-(difluoromethyl)-4-methyl-5(2H)oxazolone, 133 4-alkyl-2-(trifluoromethyl)-5(2H)oxazolones, 134 4-aryl-2-(perfluoroalkyl)-5(2H)oxazolones, 133 4-methyl-2-(trifluoromethyl)-5(2H)oxazolone, 132 5(2H)-oxazolones, 132–133, 133 5(4H)-oxazolones, saturated, 151–154, 154, 287 2-(trifluoromethyl)-5(4H)-oxazolones, 152 2-aryl-4-substituted 5(4H)-oxazolones, 154 from nitrones, 154

2-benzyloxy-4-tert-butyl-4-methyl-5(4H)oxazolone, 287 2-benzyloxy-4-isopropyl-4-methyl-5(4H)oxazolone, 287 2-phenyl-5(4H)-oxazolone, 153 4-(1-adamantyl)-2-(trifluoromethyl)5(4H)-oxazolone, 152 4-acetoxy-2-substituted-4(trifluoromethyl)-5(4H)-oxazolones, 152 from 2H-azirines, 154 AiB-containing peptides, 154 4,4-dimethyl-2-substituted-5(4H)oxazolones, 154 4,4-disubstituted-5(4H)-oxazolones, 151 5(4H)-oxazolones, 151, 152, 153, 154, 154, 287 from N-acyl amino nitriles, 153 5(4H)-oxazolones, unsaturated, 210–212, 212, 213–216, 214, 216, 225, 292–294 2-alkyl-4-[(N,N-dimethylamino)methylene]-5(4H)-oxazolones, 294 2-aryl-4-arylidene-5(4H)-oxazolones, 214 from iminophosphoranes, 214 2-arylamino-4-arylidene-5(4H)oxazolones, 214 from carbodiimides, 214, 214 4-(aminomethylene)-5(4H)-oxazolones, 215 from isocyanides, 215 4-(dimethylaminomethylene)-5(4H)oxazolones, 215 4-(ethoxymethylene)-2-(1-naphthyl)5(4H)-oxazolone, 294 4-(heteroarylmethylene)-2-substituted5(4H)-oxazolones, 210 4-[1-(dimethylamino)ethylidene]-2-phenyl5(4H)-oxazolone, 225 4-arylidene-2-phenyl-5(4H)-oxazolones, 212 4-arylmethylene-2-[3-chlorobenzo[b]thien2-yl]-5(4H)-oxazolones, 292 unsaturated 5(4H)-oxazolones, 212, 213, 214, 216, 217, 292 (E)- and/or (Z)-unsaturated 5(4H)oxazolones, 210–213 Cyclizations, 333–334, 336, 338–375, 383–398, 402–405 allyl amides (enamides), 402–405 b-amino alcohols and carboxylic acids, 333–334 b-amino alcohols and carboxylic esters, 336 epoxytrichloroacetimidates, 391–392, 392 b-halo amides, 375–383 b-hydroxy amides, 338–375 nitriles and amino alcohols, 383–384, 387 nitriles and imidates, 387

Subject Index Cycloaddition(s)/reactions, 32–36, 34, 42, 67, 143–144, 145, 147, 150, 155, 160, 172, 177, 194, 195–201, 197, 199, 200, 217, 218, 234–235, 262–269, 266, 267, 268, 269–271, 271–277, 278–281, 278, 280, 281, 283, 286, 289, 297, 561–562, 561, 562, 575, 585, 587 1,3-dipolar, 144, 145, 150, 196, 197, 198, 201, 217, 234–235, 262–269, 266, 267, 268, 289, 407–412, 411, 439, 476, 561–562, 561, 562, 587 [2þ2], 35–36, 67, 172, 407, 476, 575 bicyclic oxazolines, 407 5-alkoxy-2(3H)-oxazolones and imines, 42 oxetanes, 407 Paterno-Bu¨chi reaction with 2,4,5trimethyloxazole, 407 photocycloaddition, 35–36, 575 2-(3H)-oxazolones, 36 3-acetyl-2(3H)-oxazolone, 35 3,4,5-trisubstituted-2(3H)-oxazolones, 35 photochemical, 4(5H)-oxazolones, 67 [3þ2], 35, 147, 408–410, 439 2-aminooxazolines, 408 2-iminooxazolines, 410 cis-2-oxazolines, 408 trans-2-oxazoline-4-carboxylates, 410 trans-2-oxazolines, 408 3-(2-exo-alkoxy-1-apocamphanecarbonyl)2(3H)-oxazolones, 35 3-acetyl-2(3H)-oxazolone, 35 5-alkoxyoxazoles, 410, 439 azomethine ylides, 408–410 FMO calculations, 409 ionic liquids, 409 [4þ2], 32–34, 34, 410–412, 411, 476 tricyclic oxazolines, 410 3-(2-exo-alkoxy-1-apocamphanecarbonyl)2(3H)-oxazolones, 32 diastereoselective Diels-Alder reaction, 32 preparation of a-amino acids, 33 preparation of chiral 2-oxazolidinone auxiliaries, 32–33 3-acetyl-2(3H)-oxazolone, 32 3-acyl-2(3H)-oxazolones, 32, 33 dialkylazodicarboxylates, 33 diastereoselective Diels-Alder reaction, 33, 34 aldazines, 199 1-azadienes and 5(4H)-oxazolones, 198, 199 1,3-diazadienes and 5(4H)-oxazolones, 199, 200 chlorosulfonyl isocyanate, 172

647

diazoalkanes and diazomethane, 234–235, 262–265, 266, 269–271 ethyl vinyl ether, 410 isoxazolines, 410 ketenes, 155 mesoionic oxazolones (munchnones) and dipolarophiles, 195–198, 197 nitrile imines, 235, 265, 267, 267, 269 nitrile oxides, 235, 268–269, 268, 289 nitrones, 35 silyl ketenes, 585 ynamines, 410 Cyclobutanes, 36 Cyclodehydrating agents/cyclodehydration, 151, 153, 191, 192, 195, 210, 212, 238, 246, 256, 289, 292, 333–334, 338–375, 427 b-amino alcohols and carboxylic acids, 333–334 b-hydroxy amides, 338–375 Cyclohexenones, 200 Cyclopalladation, 458, 460 Cyclopeptides, 427 Cyclooxygenase-2 inhibitors, 54, 75 Cyclopropanation(s), 530, 532, 538–545, 539, 542, 543, 544, 586, 585 benzylbis(oxazoline), 541 bu-box, 530, 539, 540, 541 Cu(I)-bis(oxazoline), 539, 539 Cu(II)-bis(oxazoline), 538, 539 diazoacetate esters, 541, 543 diazoacetates, 530, 538–541 diazomalonate(s), 541 diphenylsulfonium isopropylide, 585 enol ethers, 541, 543 cyclic, 541 silyl, 541 Evans, 539 intramolecular, 541, 544, 544 Masamune, 539 oxazolidinones, 587 preparation of prostratin, 544 sirenin, 544 py-box-ip, 540, 541 silyl enol ethers, 541 styrene, 530, 538–541 sulfur ylides, 586, 587 Cyclopropanation, unsaturated 5(4H)-oxazolones, 262–265, 269–271, 297 (Z)-4-(ethylidene)-2-phenyl-5(4H)-oxazolone, 263 (E)-4-benzylidene-2-phenyl-5(4H)-oxazolone, 262

648

Subject Index

Cyclopropanation, unsaturated 5(4H)-oxazolones (Continued) (Z)-4-benzylidene-2-phenyl-5(4H)-oxazolone, 262, 297 2-phenyl-4-(sulfanylmethylene)-5(4H)oxazolone, 265 4-(bromomethylene)-2-phenyl-5(4H)oxazolone, 263 4-(chloromethylene)-2-phenyl-5(4H)oxazolone, 263 4-(iodomethylene)-2-phenyl-5(4H)-oxazolone, 263 4-arylmethylene-5(4H)-oxazolones, 263, 265 diastereoselective cyclopropanation, 269–271 molecular orbital calculations, 270 stereochemistry, 269–271 diazomethane, 262–265, 266, 269–270 diphenyldiazomethane, 265 phenyldiazomethane, 297 Cyclopropenes, 572 Cyclosporins, 28 Dakin-West/Diels-Alder reaction, 276 Danishefsky, 394 Danishefsky’s diene, 273, 274, 276, 280, 297, 557, 558, 558, 559, 589 DAST and Deoxofluor, 23, 368–373, 370–371, 372 competitive fluorination, 369, 373 cyclization of peptidyl b-hydroxy amides, 369, 372 DBF-box, 534, 550, 551 Diels-Alder reaction, 550, 551 x-ray crystal structure, 534 10-Deacetylbaccatin III, 366 Decarbonylation of 5(4H)-oxazolones, 193–194, 193 N-acylimines, 193–194 enamides, 193–194, 193 thermolysis, 193, 194 Dehydrating agents/conditions, oxazoline synthesis, 333–334, 338–347, 348–350, 361–365, 365–368, 368–373, 373–375 Burgess reagent, 361–365 boric acid, 333 DAST and Deoxofluor, 368–373 HF, 349 methanesulfonic acid, 348 Mitsunobu reaction, 365–368, 367, 369 phosphorus oxychloride, 348 thionyl chloride, 338–347, 340–344, 345 toluenesulfonic acid, 348 trifluoroacetic acid, 350

triphenylphosphine/carbon tetrachloride (carbon tetrabromide), 333–334, 373–375 Vilsmeier reagent, 347–348 Vorbru¨ggen conditions, 333–334 Dehydroamino acids and derivatives, 174, 213, 214, 216, 224, 226–230, 229, 230–233, 234–237, 237, 238–240, 243–244, 244, 247, 292 N-(benzoyl)dehydroamino acid amides, 247 biomimetic synthesis of stizolobinic acid, 231 from unsaturated 5(4H)-oxazolones, 226–230, 229, 233, 235–237, 237, 238, 239, 240 aminolysis, 235–237, 237, 238, 239, 240 hydrolysis or alcoholysis, 226–230, 229, 233 from unsymmetrical ketones, 232 reactions, 216, 230–233, 234–235, 237, 240, 243–244, 244, 292 1,3-dipolar cycloaddition reactions, 234–235 catalytic hydrogenation, 230–233, 240 diastereoselective, 232–233 enantioselective, 232–233 cyclizations of dehydroamino acid amides/ derivatives, 213, 214, 216, 238–240 decarboxylation, 235 deprotection, 292 nitrosation, 216 Pictet-Spengler reaction, 233, 237 with hydrazides, 243–244, 244 synthesis of amino acids, 230–233 synthesis of heterocycles, 235, 238–240 synthesis of a-keto acids, 230 synthesis of unsaturated 5(4H)-oxazolones, 213, 214, 216 Dehydroaspartame, 242 Dehydropeptides, 241–243, 295 asymmetric reduction, 243 a,b-dehydropeptides, 241–242, 295 amino acids or esters and unsaturated 5(4H)oxazolones, 241, 295 C-terminal or internal amino acid, 242 N-terminal amino acid, 241 electrochemical reduction, 243 Dengibsin, 340, 433 Dermorphin, 242 Desimoni’s protocol, 536 ()-Desoxoprosopinine, 29 a,a-Dialkylamino acids, 173, 187, 189–190, 289 4,4-disubstituted 5(4H)-oxazolones, 189–190 conformation in peptides, 190 incorporation into peptides, 189–190, 289 Dialkylcarbonates, 16, 17 3-alkyl-4,5-disubstituted-2(3H)-oxazolones, 16, 17

Subject Index 2,3-Diaminopropane-1-carboxylates, alkyl, 44 5-alkoxy-2(3H)-oxazolones, 42, 44 Diastereoselective reactions of 3-acyl-2(3H)oxazolones, 24–25, 25, 26, 32–34, 34 [4þ2] cycloadditions of azodicarboxylates, 33, 34 Diels-Alder reactions, 32 methoxybromination, 25 methoxyselenylation, 26 1,3-Diazadienes, 199, 200 cycloaddition with saturated 5(4H)-oxazolones, 199–200, 200 1,3-Diazetidines, 283 Diazoacetate esters, 541, 543 Diazoacetates, 530, 538–541 tert-butyl diazoacetate, 541 ethyl diazoacetate, 530, 538–541 menthyl diazoacetate, 541 methyl diazoacetate, 541 Diazomalonates, 541 Diazonium salts, reactions with 5(4H)-oxazolones, 176 2-aryl-4-arylazo-5(4H)-oxazolones, 176 2-aryl-4,5-oxazoledione-4-arylhydrazones, 176 1,2,4-triazole-3-carboxamides, 176 tautomers, 176 Dibenzothiepines, 210 1,2-Dideoxynojirimycin, 360 Diels-Alder reaction(s) or adducts, 10–12, 32, 35, 67, 144, 160, 271–277, 277–280, 278, 280, 281, 286, 297–299, 410–412, 447, 476– 477, 477, 477–478, 530, 532–533, 545– 554, 555, 546, 547, 548, 549, 550, 551, 552, 553 2(3H)-oxazolones, 10–12, 32, 35 bicyclic 2(3H)-oxazolones, 10–12 of 3-(2-exo-alkoxy-1-apocamphanecarbonyl)2(3H)-oxazolones, 32 diastereoselective, 32 4(5H)-oxazolones, 67 4(5H)-oxazolones, from tropolones, 67 5(4H)-oxazolones, saturated, 144, 160 4-substituted-2-vinyl-5(4H)-oxazolones, 160 5(4H)-oxazolones, unsaturated, 271–280 (E)-4-(chloromethylene)-5(4H)-oxazolone, 277 (E)-4-benzylidene-2-phenyl-5(4H)oxazolone, 272, 273 (Z)-4-arylidene-2-phenyl-5(4H)-oxazolones, 273 (Z)-4-benzylidene-2-phenyl-5(4H)oxazolone, 271, 272, 273

649

4-(alkoxymethylene)-5(4H)-oxazolones, 297 4-(methoxymethylene)-5(4H)-oxazolone, 297 4-[(ethoxycarbonyloxy)methylene]-2-phenyl5(4H)-oxazolone, 297 4-arylmethylene-5(4H)-oxazolones, 297 4-heteroarylmethylene-5(4H)-oxazolones, 297 acyclic dienes, 271–276, 277, 278, 278 activated dienes, 280, 281 AM1 semi-empirical calculations, 280 benzamidophenols, 273 constrained aspartic acid analogs, 278 constrained phenylalanine analogs, 271–272 constrained proline analogs, 274, 299 constrained serine analogs, 297 cyclic dienes, 277–278, 280 Danishefsky’s diene, 273, 274, 276, 280, 297 diastereoselective Diels-Alder reactions, 277–280, 280, 297–299 enantioselective Diels-Alder reaction, 297 epibatidine, 274 solid-state photo Diels-Alder reaction, 276 spirooxazolones, 271 tandem Dakin-West/Diels-Alder reaction, 276 unsaturated 5(4H)-oxazolones 1-acetoxy-1,3-butadiene, 276 2-tert-butyldimethylsilyloxy-1,3butadiene, 276 Danishefsky’s diene, 276, 297 piperylene, 276 bis(oxazolines), 530, 532–533, 545–554, 555, 546, 547, 548, 549, 550, 551, 552, 553 3-acryloyl-1,3-oxazolidin-2-one, 546–551, 552, 553 acroleins, 551, 552 N-acyl oxazolidinones, 552, 553 bu-box, 548, 552 chelation geometry, see transition state chelation model, see transition state Corey, 546, 547 CuOTf, 548, 549, 550 Cu(II) triflate, 548, 549, 550 cyclopentadiene, 546, 547, 548, 549, 550, 551, 552, 553, 555 DBF-box, 550 dienophiles, 553 Fe(III) halides or salts, 546, 547, 548 geometry affects on enantioselectivity, 532–533, 547–548, 548–549, 550 inda-box, 549, 549 intramolecular reaction, 552

650

Subject Index

Diels-Alder reaction(s) or adducts (Continued) Mg(II) anhydrous or hydrated, 550 Mg(II) salts, 546, 547, 547, 548, 549, 550 Ni(II) perchlorate, 550 phe-box, 530, 546, 548, 549 i-pr-box, 548 py-box, 551 total synthesis, 552–554 azadirachtin, 554 ()-isopulo’upone, 552 ent-shikimic acid, 554 ent-
1-tetrahydrocannabinol, 554 transition state, 547–548, 548–549, 549–550 unsaturated esters, 552 oxazolines, 410–412, 447, 476–477, 477, 477–478 2-alkenyloxazolines, 447, 476–477, 477 asymmetric Diels-Alder reaction, 447 asymmetric hetero-Diels-Alder reaction, 476–477, 477 computational studies, 477 isocyantes, 476–477 diastereoselective Diels-Alder reaction, 477–478 oxazolines from oxazoles and dienophiles, 410–412 Dienes and azadienes, reaction with saturated 5(4H)-oxazolones, 198–201, 199, 200 1-azadienes, 198, 199, 201 1,3-diazadienes, 199, 200, 1,3-dipolar cycloaddition, 201 2-pyridones, 198, 199, 201 2,3-diazadienes (aldazines), 199 cycloaddition reactions, 198, 199, 200 cyclohexenones, 200 dienamines, 200 nucleophilic addition, 201 pyridazinones, 199 pyridines, 201 pyrimidin-6-ones, 199, 200 pyrroles, 201 Dienophiles, 2(3H)-oxazolones, 32 Diethylaluminum chloride, 392 Diethylaluminum cyanide, 446 Diethylmalonate, 562–564, 564 (R)-Dihydroactinidiolide, 560, 561 Dihydrobenzofurans, 580 Dihydrobenzoxazoles, 252 Dihydrofuran-2,3-diones, 75 2-amino-5-substituted-4(5H)-oxazolones, 75 ring opening with cyanamide, 75 Dihydroimidazoles, 235 Dihydroisoquinolines, 426

Dihydronaphthalenes, 469 Dihydroorotase inhibitors, 71 Dihydropyridine(s), 148, 174 Dihydropyridones, 252 Dihydrosphingosine, 26 Dihydrotriazoles, 143 from 4-aryl-2-(trifluoromethyl)-5(2H)oxazolones, 143 1,2-Diketones, 8–12, 10 4-methyl-3-phenyl-5-vinyl-2(3H)-oxazolones, 12 4,5-disubstituted-2(3H)-oxazolones, 10 bicyclic oxazolones, 10 Diels-Alder reaction of 4,5-dialkylidene-2oxazolidinones, 10–12 precursors to a-imino ketones, 8, 10 reaction with isocyanates, 10 Diketones, 211 a-Diketones, 134 b-Diketones, 152 Dimerization reactions, 194–195, 195, 283, 289 saturated 5(4H)-oxazolones, 194–195 4,40 -bis(oxazolones), 194, 195, 195, 289 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), 289 kinetic study, 194 nickel peroxide, 194 photooxidation, 194 pyrrolidinedione 194 unsaturated 5(4H)-oxazolones, 283 1,3-diazetidines, 283 photodimerization, 283 Dimethadione, 90, 99, 120 [2-11C]5,5-dimethyl-2,4-oxazolidinedione, 99 N,N-Dimethylcyanamide, 389, 393 (þ)-Dioncophylline C, 463 Dioxazabicycloheptanones, 172 1,3-Diphenylallyl acetate, 564 Diphenylketene, 56, 57 1,3-Dipolar cycloadditon(s) and reactions, 144, 145, 149–150, 195–198, 197, 201, 217– 218, 218, 234–235, 262–269, 266, 267, 268, 270–271, 289, 297, 447, 561–562, 561, 562, 587 4-(a-arylethylidene)-5(4H)-oxazolones, 218, 218 spiroxazolones, 218 dehydroamino acid derivatives, 234–235 as dipolarophiles, 234–235 cyclopropanations, 234–235 diazomethane, 234 nitrile imines, 235 nitrile oxides, 235

Subject Index 5(2H)-oxazolones, 145, 149–150 N-oxides as cyclic nitrones, 149 precursors to alkoxy substituted nitrile ylides, 145 5(4H)-oxazolones, saturated, 195–198, 197, 289 precursors to munchnones, 195–198 4-methyl-2-phenyl-5(4H)-oxazolone, 289 5(4H)-oxazolones, unsaturated, 217–218, 262–269, 266, 267, 268, 269–271 cyclopropanations, see cyclopropanation, unsaturated 5(4H)-oxazolones, 262–265, 269–271, 297 diazomethane, 217–218, 218, 234–235, 262–265, 266, 269–270 homologation, 217–218, 262, 263, 270 diphenyldiazomethane, 265 4-arylmethylene-5(4H)-oxazolones, 265 nitrile imines, 198, 235, 265, 267, 268 unsaturated 5(4H)-oxazolones, 265 oxazolone spiropyrazolines, 265, 267 nitrile oxides, 235, 268–269, 268, 289 4-arylmethylene-5(4H)-oxazolones, 268 4-(ethoxymethylene)-2-phenyl-5(4H)oxazolones, 269 oxazolone spiroisoxazolines, 268, 268 phenyldiazomethane, 297 preparation of 2,3-methanomethionine, 263 constrained phenylalanine analog, 297 constrained cysteines, 265 cyclopropylamino acids, 262, 263, 265, 270–271, 297 cyclopropylhomoserine, 265 isoxazoles, 268 oxazolone spirocyclopropanes (spirocyclopropane oxazolones), 262, 263, 265, 266 pyrazoles, 268 pyrroles, 289 spiroisoxazolines, 268, 268 spiropyrazolines, 218, 265, 267 bis(oxazolines), BINOL-box, 587 bu-box, 561 enantioselective, 562 nitrones and alkenes, 587 nitrones and ethyl vinyl ether, 561 nitrones and phenylacetylene, 561, 561 nitrones and a,b-unsaturated oxazolidinones, 561, 562 phe-box, 561 i-pr-box, 561 oxazoline N-oxides, 447

651

Dipolarophiles, 35, 143, 144, 145, 147, 195–198, 197, 234, 269, 289 1-nitroso-2-naphthol, 198 2-phenylbenzazete, 197 4-(ethoxymethylene)-2-phenyl-5(4H)oxazolones, 269 4-arylmethyleneisoxazol-5-ones, 289 [60]fullerene, 198 acrylates, 196 dehydroamino acid derivatives, 234–235 dimethyl acetylenedicarboxylate, 196 fumarates, 196 fumaronitrile, 196 nitrosobenzene, 197 N-(phenylmethylene)benzenesulfonamide, 198 triphenylvinylphosphonium bromides, 196 Dipole moments, unsaturated 5(4H)-oxazolones, 286 Displacement reactions, synthesis of 2-amino4(5H)-oxazolones, 75, 89 5-(benzylidene)-2-substituted-4(5H)oxazolones, 76 indolmycin, 89 5-(benzylidene)-2-methylthio-4(5H)-oxazolone, 75, 76 DNA transfection, 508 DPPOx, 40 Dual 5-lipoxygenase and cyclooxygenase inhibitors, 54, 75, 114 Dynamic kinetic resolution, saturated 5(4H)oxazolones, 179, 180, 181–182, 289 deracemization, 180 Electrogenerated base (EGB), 103, 105 Electrophilic additions, 23–25, 25, 26 of 3-(2-exo-alkoxy-1-apocamphanecarbonyl)2(3H)-oxazolones, 24, 25, 26 3-hydroxyglutamic acid, 24 AHMHA, 24 AHPBA, 24 dihydrosphingosine, 26 ()-Geissman-Waiss lactone, 26 hydroxy amino acids, 24 statine(s), 24 of 3-acyl-2(3H)-oxazolones, 25, 26 diastereoselective methoxybromination, 25 diastereoselective methoxyselenylation, 26 of 3-acyl-4,5-unsubstituted-2(3H)-oxazolones, 23 methoxybromination, 23 methoxyselenylation, 23 synthesis of 2-amino alcohols, 24

652

Subject Index

Electrophilic additions (Continued) preparation of 4,5-dialkoxy-2-oxazolidinones, 25 a-amino acids, 25 a-amino aldehydes, 25 Electrophotographic light-sensitive materials, 209 Enamines and formamidines, reactions with 5(4H)-oxazolones, 172–174 4-(aminomethylene)-2-phenyl-5(4H)oxazolones, 174 unsaturated 5(4H)-oxazolones, 173 b-amino-a,b-dehydro-a-amino acid equivalents, 174 benzopyran-2,5(6H)-diones, 173 pyran-2-ones, 173 pyridones, 172 pyridotriazinones, 172 b-Enaminosulfoxides, 12 4-(difluoromethyl)-5-p-tolylthio-2(3H)oxazolone, 12 Pummerer rearrangement, 12 Enantioselective reactions, 530, 546–552, 554, 556, 557, 558, 559, 560, 562, 563, 564, 566, 568, 571, 572, 581, 585–586, 588 addition of allylzinc reagents, 571 aldol reaction, 566 allylic substitutions, 563, 563, 564, 588 allylzincation, 573 amination of enolsilanes, 581 asymmetric addition to imines, 571 asymmetric polymerization, 572 aza-Claisen rearrangement, 581 conjugate addition, free radical, 568 Diels-Alder reaction, 546–552 1,3-dipolar cycloadditons, 562 ene reaction, 554, 556, 557 formation of double and triple helicates, 581 hetero-Diels-Alder reaction, 557, 558, 559, 560 hydrosilylation of ketones, 530 Mukaiyama Michael addition, 585–586 Ene-reaction of 2(3H)-oxazolones, 35 of 3-tert-butoxycarbonyl-2(3H)-oxazolone, 35 2,20 -biindole, 35 Ene reactions, 554–555, 556, 557, 585 2,3-dimethyl-1,3-butadiene, 554 carbonyl-ene reactions of glyoxylates and pyruvates, 585 enantioselective, 554, 556 ethyl glyoxylate, 554, 556 glyoxylates, 554, 556, 585 methylenecyclohexane, 554 pyruvates, 585 selectivity, 555

Enol ethers, 541, 543, 544, 558, 565, 565, 568, 581, 585 amination of enolsilanes, 581 cyclic, 541, 544, 565 cyclopentenyl, 541 cyclopropanation, 541, 543, 544 enantioselective hetero-Diels-Alder reaction, 558 enolsilanes (silyl enol ethers), 541, 565, 565, 568, 581, 585 trimethylsilyl, 565, 565 Michael addition, 568 Mukaiyama aldol reaction, 565, 565 Mukaiyama Michael reaction, 585–586 ()-Ephedrine, 22 Epibatidine, 274 Epoxytrichloroacetimidates, 391–392, 392 ()-Eptazocine, 340, 469 Erlenmeyer synthesis (N-acylglycines and carbonyl compounds), synthesis of unsaturated 5(4H)-oxazolones, 210–212, 213–216, 212, 213, 214, 216, 217, 237, 292, 294 2-aryl-4-arylidene-5(4H)-oxazolones, 214 4-(aminomethylene)-5(4H)-oxazolones, 215 4-(dimethylaminomethylene)-5(4H)oxazolones, 215 4-(ethoxymethylene)-2-(1-naphthyl)-5(4H)oxazolone, 294 4-(heteroarylmethylene)-2-substituted 5(4H)oxazolones, 210 4-arylidene-2-phenyl-5(4H)-oxazolones, 212 4-arylmethylene-2-[3-chlorobenzo[b]thien-2yl]-5(4H)-oxazolones, 292 bis-4-arylidene-5(4H)-oxazolones, 237 unsaturated 5(4H)-oxazolones, 212, 213, 214, 216, 217, 292 (E)- and/or (Z)-unsaturated 5(4H)oxazolones, 210–212 N-acylamino acid derivatives, 215, 217, 294 N-acylamino acids and aldehydes, 210 N-acylglycines, 211, 212, 292 aldol condensation, 211 amino acid precursors, 213 b-arylserines, 214 N-benzoylglycine with diketones, 211 N-benzoylglycine with ketones, 211 carbodiimides, 214, 214 carbonyl compounds, 212 cyclodehydrating (cyclodehydration), 210, 211–212, 292 dialdehydes, 237 a,b-didehydroamino acids, 214, 216 experimental conditions, 211–212

Subject Index iminophosphoranes, 214, 216 isocyanides, 215–216, 216 isomerization, (Z)-unsaturated 5(4H)oxazolones to (E)-unsaturated 5(4H)oxazolones, 212–213, 213 mechanism, 211 microwave accelerated reactions, 212 (E)-unsaturated 5(4H)-oxazolones, 211 (Z)-unsaturated 5(4H)-oxazolones, 210–211 Vilsmeier (Vilsmeier-Haack) reagent, 216, 217, 294 Ester(s), 541, 543, 552, 554, 557, 558, 572, 575, 575, 585, 589 cinnamates, 575, 575 diazoacetates, 541, 543 diazomalonates, 541 glyoxylate(s), 554, 558, 585 a-imino, 575 a-keto, 557, 589 a-oximino, 572 pyruvates, 585 thioesters, 585 unsaturated, 552 Ethambutol, 182 Ethoxycarbonyl isocyanate, 510 Ethoxyvinyllithium (EVL), diastereoselective conjugate additions, 469, 470 Ethoxyvinyllithium-HMPA complex (EVL-HMPA), 436, 458, 459, 466 benzylic deprotonation of oxazolines at C-5, 436 metalation of arenes, 458, 459, 466 Ethyl 3-ethoxy-2-cyanoacrylate, 510 Ethyl cyanoformate, 140, 141 4-(arylthio)-5(2H)-oxazolones, 140, 141 ketones, 139, 141 thioimidates, 140 Evans, 539 Famoxadone, 90, 120 Felkin-Ahn transition state model, 477 Ferrocene-box, 563, 564 allylic substitution, 563 diethylmalonate, 564 1,3-diphenylallyl acetate, 564 enantioselective substitution, 564 Ferrocenes, 452–458, 453–454, 457 bis(oxazoline)-substituted, 457–458 oxazolinyl, 452–457, 453–454, 457 diastereoselective lithiation, 452–457 nitrogen-directed lithiation, 455–456 oxygen-directed lithiation, 456–457 Flash vacuum pyrolysis, 194

653

Fluorescence of unsaturated 5(4H)-oxazolones, 284 Fluorination, 282, 287 saturated 5(4H)-oxazolones with tetramethylfluoroformamidinium hexafluorophosphate (TFFH), 287 unsaturated 5(4H)-oxazolones, 282 Formyl anion equivalent, 162 4-isopropyl-5(4H)-oxazolone, 162 Friedel-Crafts reaction(s), 3, 36, 79, 255, 256, 259–260, 289, 588–589, 589 2(3H)-oxazolones, 3, 36 acylation, 36 4(5H)-oxazolones, 79 alkylation of indole, 79 5(4H)-oxazolones, saturated, 289 arylation, 289 5(4H)-oxazolones, unsaturated, 255, 256, 259–260 arylation, 259–260 intramolecular ring opening, 256 ring opening, 255, 256 bis(oxazolines), 589 bu-box, 589 Fujiwara-Moritani reaction, 506 Fullerenes, 575 Fungicides, 54, 90, 176, 209, 509 2(5H)-Furanones, 111–112, 211 ()-Geissman-Waiss lactone, 26 Glucofuran[2,1-d]oxazolines, 349 Glycine(s), see amino acids and derivatives cationic equivalents, 220 enolate equivalents, chiral, 184 synthons, 186 Glycopyranosyl donors, 430–432 (S)-Gossypol, 341, 342, 466–468 Guanidine(s), 53, 65, 72–74, 73, 74–75, 79, 88–89, 120 2-amino-4(5H)-oxazolones, 53, 74 spirocyclic 4(5H)-oxazolones, 72–74, 73 1,1,3,3-tetramethyl, epimerization of indolmycin, 88 N,N0 -dimethyl, 79, 120 indolmycin, 79 reaction with indolmycenic acid esters, 79–80, 120 pemoline, 74–75 reaction with a-hydroxy esters, 72–74, 73 reaction with indolmycenic acid esters, 88–89 reaction with oxazolonium salts, 65 ()-Hadinecine, 390 a-Halo acetanilides, 105

654

Subject Index

a-Halo amides, 61, 68, 103, 105 2-amino-4(5H)-oxazolones, 68 2-phenyl-4(5H)-oxazolones, 61 3,5-dialkyl-2,4-oxazolidinediones, 103 3,5,5-trialkyl-2,4-oxazolidinediones, 103 5-arylidene-4(5H)-oxazolones, 61 N-aroylcinnamides, 61 condensation with tetraethylammonium hydrogen carbonate, 105 a-halo acetanilides, 105 electrochemical reduction, 103, 105 electrogenerated base, 103, 105 radical anions, 103 superoxide, 105 b-Halo amides, oxazoline synthesis, 338–339, 347, 375–383, 378 2-phenyl substituted oxazolines, 383 4-(alkylamino)-2-phenyloxazolines, 382 4-(cyclopropropyl)oxazoline carboxylates, 376 oxazolinecarboxylates, 378 spiro-2-oxazolines, 377 b-chloro amides, 338–339, 347 electrochemical methodology, 382 Obrecht’s methodology, 381 oxazolines from 2-benzoylamino-3-chloropropenoic acid, 377 2-chloro-2-cyclopropylidene acetates, 376, 378 N-(2,2-dichlorovinyl)amides, 382 3-benzoylamino carboxylates, 379 4,4-dichloro-azadienes, 378 allylic alcohols and trichloroacetonitrile, 381 amino[(phenylthio)methyl]malonates, 376 Michael additions, 376 photoisomerization of oxazolones, 381 propenylbenzamide, 375 spirooxazolines, 377 spirooxazolone, 381 x-ray crystal structure, 377 a-Halo carboxylic acid ureides, 68, 71 2-(arylimino)-4(5H)-oxazolones, 70 2-amino-4(5H)-oxazolones, 68 2-amino-5-isopropyl-4(5H)-oxazolone, 68 spirocyclic 2-amino-4(5H)-oxazolone, 71 hydantoins, 68, 71 thiohydantoins, 71 a-Halo ketones, 111, 113 preparation of, 111, 113 2(5H)-furanones, 111, 113 W-3681, 113 reaction with dianions of 2,4oxazolidinediones, 111, 113

Halogenation of 5(4H)-oxazolones, 175–176 2-phenyl-4-(phosphoranylidene)-5(4H)oxazolone, 175 4-(1-chloroalkylidene)-2-phenyl-5(4H)oxazolones, 176 4-(phosphoranylidene)-2-substituted-5(4H)oxazolones, 175–176 4-(phosphoranylidene)-5(4H)-oxazolones, 175–176 4-alkyl-2-phenyl-5(4H)-oxazolones, 176 chlorination of 4-acyl-5(4H)-oxazolones, 175 precursors to 4-(phosphoranylidene)-5(4H)oxazolones, 175 Wittig olefination, 175–176 Hammett constants, 284 Heck reactions, 493–495, 494 asymmetric intermolecular, 494 double-bond migration, 493–494 enantioselective, 493 PhosOx ligands, 493–494 PyrOx ligands, 495 regioselective, 493 x-ray crystal structure, 494 Heimgartner, 287 ()-Hennoxazole A, 371 Hennoxazole A, 362, 374 Hepatic gluconeogenesis inhibitors, 342 ()-Herbertenediol, 341 Herbicides and herbicidal activity, 54, 90, 109, 151, 176, 183, 209, 227 Hetero-Claisen rearrangement, synthesis of oxazolines, 416–417 2-(a-acyloxy)oxazolines, 417 of oxazoline N-oxides, 416–417 Heteroannulation, synthesis of 2H-pyrans, 580 Heterocumulenes, 92, 93 2,4-oxazolidinediones, 92 Boulton-Katritzky rearrangement, 92, 93 reaction with 5,5-dimethyl-2-ethoxy4-(p-tolylimino)-4(5H)-oxazolone, 93 Hetero-Diels-Alder reaction, 476, 554–561, 557, 558, 559, 560, 585, 589–590 1,3-cyclohexadiene, 555 2,3-dimethyl-1,3-butadiene, 554–555 acyl phosphonates, 558, 560 antitumor agent, 561 aza-Diels-Alder reaction, 558 aza-dienes, 560 bu-box, 555, 557, 559 Danishefsky’s diene, 557, 558, 558, 559, 589 diethyl ketomalonate, 555 enantioselective, 557, 558, 559, 560 enol ethers, 558

Subject Index glyoxylates, 554, 555, 557 esters, 554, 555, 557 alkyl, 557 ethyl, 554, 555 inda-box, 557, 559, 589 a-keto esters, 557, 589 oxazolidinones, 559 phe-box, 557 preparation of (R)-actinidiolide, 561 (R)-dihydroactinidiolide, 561 laulimalide, 559 ()-malyngolide, 589–590 a-pyranones, 589 tetrahydropyridones, 558 1 H NMR spectrometry, 132, 134, 206, 284–285 kinetics of racemization of 2,4-disubstituted 5(4H)-oxazolones, 134, 206 tautomerism, 5(4H)-oxazolones to 5(2H)oxazolones, 132, 134, 206 unsaturated 5(4H)-oxazolones, 284–285 configurational assignments, 284–285 correlation with Hammett constants, 284 nuclear Overhauser enhancements (nOe’s), 285 rotational barriers, 284 Hippadine, 462 Human immunodeficiency virus (HIV)-protease inhibitor, 359, 395, 404 Hydantoins, 68, 77, 82 Hydrazides, ring opening of unsaturated 5(4H)oxazolones, 246, 251 bis(acylhydrazides), 246 hydrazidimide, 251 imidazotriazoles, 251 pyrazoles, 246 Hydrazines, 64, 65, 66, 117 reaction with 2-phenyl-4(5H)-oxazolone, 65, 66 reaction with 2,4-oxazolidinediones, 117 reaction with oxazolonium salts, 64, 65 Hydrazines, ring opening of unsaturated 5(4H)oxazolones, 243–246, 244, 249 a-acylamino hydrazides, 244, 244 aminoimidazolones, 243, 244 dehydroamino acid hydrazides, 244 a-(heteroaryl)glycinates, 249 pyrazolinoxazolines, 246 spiropyrazolidinone, 245 triazines, 245 Hydrogenation, 22–23, 440–441, 495–501, 496–497, 500 4,5-diphenyl-3-substituted-2(3H)-oxazolones, 23

655

4,5-disubstituted-2(3H)-oxazolones, 22 of 4,5-disubstituted 2(3H)-oxazolones, 22 erythro-2-amino alcohols, 22 ()-conhydrine, 22 ()-ephedrine, 22 ()-N-methylephedrine, 22 of oxazolines, 440–441 via mononuclear oxazoline ligands, 495, 496–497, 498, 499, 500, 501 asymmetric hydrogenation of styrenes, 496–497 carbene ligands, 498 deuterium scrambling, mechanism, 498–499 enantioselective hydrogention of alkenes, 495 enantioselective hydrogention of imines, 499 enantioselective transfer hydrogenation of ketones, 500, 501 kinetic resolution, 501 Meerwein-Ponndorf-Verley reduction, 501 PhosOx ligands, 501 ligand topography, 498 supercritical carbon dioxide, 499 x-ray crystal structure, 498, 501 Hydrogenolysis, 23 of 4,5-diphenyl-2(3H)-oxazolones, 23 DAST, 23 b-fluoro-a-amino acids, 23 Hydrolysis and alcoholysis, 55–56, 116, 117, 178–183, 181, 226–230, 229, 233, 289, 417–427, 419–421, 422–423, 427 of 2,4-oxazolidinediones, 116 enzymatic with ring opening, 117 HCl/formic acid without ring opening, 116 of 4-substituted oxazoles, 55–56 4(5H)-oxazolones, 55–56 of 5(4H)-oxazolones, saturated, 178–193, 181, 289 chiral catalysts, 179–180 diastereoselective, 178 dynamic kinetic resolution, 179, 181, 289 enantioenriched amino acids/derivatives, 180, 181, 182 enantioselective, 178–183 enzymatic, 181–183, 289 kinetics, 179 molecular orbital calculations, 179 preparation of N-acylamino acid esters, 178, 180, 181 N-acylglycine choline esters, 179 N-benzoylamino acids, 181–182 N-benzoylamino acid esters, 289 N-benzoylalanine butyl ester, 181

656

Subject Index

Hydrolysis and alcoholysis (Continued) N-benzoyl-tert-leucine butyl ester, 182 N-benzoylphenylalanine esters, 181 Ethambutol, 182 non-proteinogenic amino acids, 178 allo-threonine, 182 racemization, 179 tautomerism, 179 of 5(4H)-oxazolones, unsaturated, 226–230, 229, 233 mechanism, 227 of 4-heteromethylene-5(4H)-oxazolones, 228 phase-transfer catalyzed reactions, 227 preparation of 2-acylaminocinnamic acids, 226 N-acyl dehydroamino acids and esters, 229 acrylates, 227, 228 acrylic acids, 227, 228 aminoalkyl esters, 227 dehydroamino acids and esters, 226–230 fluorobutenyl esters, 227 a-keto acids, 230 monoglycerides, 227 peptides incorporating dehydroamino acids and esters, 229 stereospecific, 227, 228 with chiral alcohols, 233 of oxazolines, 417–427, 419–421, 422–423, 427 amino alcohols from 2-(trichloromethyl)oxazolines, 427 amino alcohols using strong acids, 417–418 amino alcohols using strong bases, 424–425 amino esters and hydroxy amides using mild base, 418, 422–423, 423 dihydroisoquinolines, 426 of 2-aminooxazolines, 424–425 of oxazoline-2-thiones, oxidative hydrolysis, 423–424 of spirocyclic oxazoline esters, 424 of tetrasubstituted oxazolines, 426 Taxol side chain, 422–423 tetrahydroisoquinolines, 426 trehazolin, 424 Hydrosilylation, 161, 503–504 a-addition, 161 b-addition, 161 asymmetric hydrosilylation of imines, 503 asymmetric hydrosilylation of ketoximes, 503 hydrosilylation-cyclization of dienes, 503–504 of 2-alkenyl-5(4H)-oxazolones, 161 of 2-vinyl-5(4H)-oxazolones, 161 of bis(oxazolines), see reductions, hydrosilylation

Hydroxamic acids, 12–14, 13, 14, 47 3-aryl-5-substituted-2(3H)-oxazolones, 12 5-alkyl-3-aryl-4-halo-2(3H)-oxazolones, 12, 14 5-alkyl-3-aryl-2(3H)-oxazolones, 13 5-ethoxy-3-methyl-2(3H)-oxazolone, 47 a-lactams, 12 a-mesyloxyamides, 47 sonication, 47 a-Hydroxy acids, 82, 117 enzymatic hydrolysis of 2,4-oxazolidinediones, 117 a-Hydroxy amides, 21, 21, 58, 68, 82, 94–95, 96, 97, 98, 99, 103 2(3H)-oxazolones, 21, 21 [2-11C]5,5-dimethyl-2,4-oxazolidinedione, 99 2-amino-4(5H)-oxazolones, 68 3-unsubstituted-2,4-oxazolidinediones, 94 5-substituted-2,4-oxazolidinediones, 96 spirocyclic 2,4-oxazolidinediones, 96, 97, 98 cyclization, 58, 68, 94–96, 97, 98, 99, 103 carbonates, 94, 94–96, 97, 98, 99 carbonyldiimidazole, 103 phosgene, 94, 99 strong acids, 58 from hydrolysis of 2-amino-4(5H)-oxazolones, 82 phosphorus ylides, 21 b-Hydroxy amides, oxazoline synthesis, 338–375, 340–344, 345, 348, 351, 352–357, 361– 363, 366, 367, 370–371, 372, 373–375 2-monosubstituted oxazolines, 338 4-monosubstituted oxazolines, 338 cis-4,5-disubstituted oxazolines, 344, 345 trans-4,5-disubstituted oxazolines, 344, 345 5-monosubstituted oxazolines, 338 bis(oxazolines), 347 glucofuran[2,1-d]oxazolines, 349 multiply substituted oxazolines, 338 acetates, mesylates, triflates, 351, 352–357 1,2-dideoxynojirimycin, 360 20 -epi-Taxol, 358 epimerization, 351, 358 b-glycosylation, 360 Nelfinavir1, 359 Taxol, 358 cyclodehydration with, 338–375 Burgess reagent, 361–365, 361–363, 366 DAST and Deoxofluor, 368–373, 370–371, 372 HF, 349 methanesulfonic acid, 348 phosphorous oxychloride, 348

Subject Index Pictet-Gams conditions, 348 (R)-()-rolipram, 348 strong acids, 348–350, 351 thionyl chloride, 338–339, 340–344 Baccatin III, 346 bis(oxazoline) ligands, 347 (þ)-calyculin A, 339 ()-calyculin B, 339 mechanism, 339 mycestericin, 344 NMR study, 339 1,2,3-oxathiazolidines, 346 paclitaxel, 346 racemization, 344, 346 solvent affects, 346–347 toluenesulfonic acid, 348 trifluoroacetic acid, 350, 351 urethane protected, 350, 351 triphenylphosphine/carbon tetrachloride (carbon tetrabromide), 373, 373–375 Vilsmeier reagent, 347–348, 348 b-chloro amides, 347 Taxol, 347 Mitsunobu reaction, 365–368, 367, 369 preparation of, 338 tosylates, via polymer-bound tosyl chloride, 359 urethane-protected, 350, 351 a-Hydroxy esters, 53, 68, 72, 72–74, 73, 74–75, 94–95, 96, 97, 98, 99, 100, 102, 103 2-amino-4(5H)-oxazolones, 53, 68 [2-13C]5,5-dimethyl-2,4-oxazolidinedione, 99 3-unsubstituted-2,4-oxazolidinedione(s), 94 5-methyl-2,4-oxazolidinedione, 100 spirocyclic 2-amino-4(5H)-oxazolones, 72–74, 73 spirocyclic 2,4-oxazolidinediones, 96, 97, 98 cyclization with cyanamide, 74 guanidine, 53, 68, 72–74, 73, 74–75 metal cyanates, 103 urea, 94–95, 96, 97, 98, 99, 100 pemoline, 72, 74 a-Hydroxy imidates, 99–100, 100, 101 5-aryl-2,4-oxazolidinediones, 100, 100 5-heteroaryl-2,4-oxazolidinediones, 100 spirocyclic 2,4-oxazolidinediones, 100, 101 cyclization of with 1,10 -carbonyldiimidazole, 100 3-Hydroxyglutamic acid, 24 5-(Hydroxymethyl)-3-phenyl-1H-1,2,4-triazoles, 66 Hypoglycemic agents, 96, 99, 111 Hypolipidemic agent, 451

657

Imidates, oxazoline synthesis, 387, 388–389 reaction with amino alcohols, 387, 388–389 Imidazobenzimidazoles, 248 Imidazoles, 198, 215, 235, 286 2,5-disubstituted, 198 4-Imidazolidinones, 65 Imidazolidinone-4-carboxylates, 4-alkyl, 42, 44 5-alkoxy-2(3H)-oxazolones and imines, 42 Imidazolinones, 238–240 cyclization of acylamino acid amides, 238–240 Imidazolones, 117–119, 119, 238–240, 243, 246, 247, 248, 249, 250, 284, 295–296 2-styryl-1-substituted, 247 N0 -(2-aminophenyl), 248 amino, 243, 250 from 2(H)-azirines and 2,4-oxazolidinediones, 117–119 microwave-assisted synthesis, 296 polymeric, 284 unsaturated, 247 Imidazotriazoles, 251 Imines and carbonyl compounds, reactions with 5(4H)-oxazolones, 171–172 2-phenyl-4-(a-phenylethylidene)-5(4H)oxazolone, 171 4-(diphenylmethylene)-2-phenyl-5(4H)oxazolone, 171 4-[bis(methylthio)methylene]-2-phenyl5(4H)-oxazolone, 172 unsaturated 5(4H)-oxazolones, 171–172 2-methyl-3-phenylserine, 172 3-amino-b-lactams, 172 carbon disulfide, 172 chlorosulfonyl isocyanate, 172 [2 þ 2] cycloaddition with 5(4H)-oxazolone, 172 dioxazabicycloheptanones, 172 hindered electrophiles, 171 synthesis of unsaturated 5(4H)-oxazolones, 171–172 a-Imino esters, 575 a-Imino ketones, 8, 10, 10 4,5-diphenyl-2(3H)-oxazol-2-thiones, 10 4,5-diphenyl-2(3H)-oxazolones, 10 4,5-disubstituted-2(3H)-oxazolones, 10 Iminooxalates, 140, 142 4-alkoxy-5(2H)-oxazolones, 140, 142 ketones, 140, 142 Iminophosphoranes, synthesis of unsaturated 5(4H)-oxazolones, 214, 216, 293 2-aryl-4-arylidene-5(4H)-oxazolones, 214, 216

658

Subject Index

Iminophosphoranes, synthesis of unsaturated 5(4H)-oxazolones (Continued) 2-arylamino-4-arylidene-5(4H)-oxazolones, 214 unsaturated 5(4H)-oxazolones, 214, 216, 293 aroyl chlorides, 214 carbodiimides, 214, 214 from azidocinnamates, 214 N-vinyl phosphazenes, 293 Iminoribitol, 389 Inda-box, 534, 537, 549, 549, 557, 559, 567, 574–575, 577, 589 allene annulation, 574–575 allylic oxidation, 577 conjugate addition, 567 crystal structure, 534 Diels-Alder reaction, 549, 549 hetero-Diels-Alder reaction, 557, 559, 589 preparation of (R)-actinidiolide, 560, 561 (R)-dihydroactinidiolide, 560, 561 laulimalide, 559 ()-malyngolide, 589–590 Indinavir, 395, 404 3H-Indoles, 197 Indoles, 210, 222, 233, 240 a-Indolmycenic acid and esters, 79–80 cyclization of, 79–80 epimerization, 79 resolution, 79 (þ)-Indolmycin, 85 ()-Indolmycin, 88 Indolmycin, 68, 78, 79–81, 84–89, 120 absolute configuration, 79 asymmetric synthesis, 80, 85, 88–89, 120 conformationally restricted analogues, 85 epimerization, 85, 88 racemic, 79, 85, 88 synthesis from a 4(5H)-oxazolone, 84–89 2-(dimethylamino)-4(5H)-oxazolone, 84–85, 88 synthesis of the 4(5H)-oxazolone ring, 79–81, 88–89, 120 cyclization of thiourea, 80 N,N0 -dimethylguanidine and a-indolmycenic acid and esters, 79–81, 120 guanidine and indolmycenic acid ester, 88–89, 120 isoindolmycin, 79 Insecticides, 143, 210 Ionic liquids, 409 IR spectroscopy, saturated 5(4H)oxazolones, 206

IR spectroscopy, unsaturated 5(4H)-oxazolones, 284 Ireland-Claisen rearrangement, 155 Isatins, 102, 103 spirocyclic 2,4-oxazolidinediones, 102, 103 preparation of a-acyloxy amides, 102 Isocyanates, 8, 10, 54, 57, 60, 62, 92, 94, 97, 102, 120 3,4,5-triaryl-2(3H)-oxazolones, 8 bicyclic 2(3H)-oxazolones, 10 cyclization of 1,2-diketones, 10 cyclization of benzoin, 8 2-alkenyl-4,5-oxazolediones, 62 2-alkyl-4(5H)-oxazolones, 120 2-phenyl-4(5H)-oxazolone, 54 2-substituted-4,5-oxazolediones, 62 spirocyclic 4(5H)-oxazolones, 57 acyl isocyanates, 120 alkenoyl isocyanates, 62 benzoyl isocyanate, 54, 57 benzoyl isothiocyanate, 59 chloroacetyl isocyante, 60 chlorosulfonyl isocyante, 92, 94, 97, 102 Isocyanides, a-isocyanoesters, and isonitriles, 215, 216, 406–407, 407 unsaturated 5(4H)-oxazolones, 215, 216 2-acyl-4-(dimethylaminomethylene)5(4H)-oxazolones, 215 2-arylthio-4-(dimethylaminomethylene)5(4H)-oxazolones, 215 4-(aminomethylene)-5(4H)-oxazolones, 215 unsaturated 5(4H)-oxazolones, 215, 216 isocyanoacetates, 215 isocyanoacrylates, 215 reaction with acyl chlorides, 215 reaction with arenesulfenyl chlorides, 215 reaction with lactam acetals, 215 oxazolines, 406–407, 407 latent a-isocyanoesters, 407 reaction with aldehydes, 406–407 Isoindole, 145 ()-Isoindolmycin, 88 Isoindolmycin, 79 Isomerization (Z)-5(4H)-oxazolones to (E)-5(4H)oxazolones, 213, 213, 283 acid catalyzed, 213 decarbonylation, 283 photochemical, 213, 283 ()-Isopulo’upone, 552, 554 Isoquinolines, 238 Isothiocyanates, 59, 92 4(5H)-thiooxazolones, 59 reaction with carbenes, 59

Subject Index Isotope labeling, 22 Isoxazoles, 268, 269 Isoxazolidines, 150 Isoxazolines, 268, 268, 269, 410 spiro, 268, 268 Kalbretorine, 462 Kalkitoxin, 428 Ketenes, 56–57, 92, 155 2,4-oxazolidinediones, 92 5(4H)-oxazolones, 155 5,5-diphenyl-2-substituted-4(5H)-oxazolones, 56–57, 57 bis(ethoxycarbonyl)ketene, 92 tert-butylcyanoketene, 57 diphenylketene, 56–57, 57, 92 Pummerer reaction, 57 reaction with N-acylsulfilimines, 56 Ketenimines, 91 2-ethoxy-4-(p-tolylimino)-4(5H)-oxazolones, 91 5,5-diethyl-2,4-oxazolidinedione, 91 5,5-dimethyl-2,4-oxazolidinedione, 91 thermolysis of ethyl azido formate, 91 2-Keto esters, 47, 48 2(3H)-oxazolone-4-carboxylates, 47 ethyl 2(3H)-oxazolone-4-carboxylates, 48 3-bromo- with methyl carbamate 47, 48 3-nosyloxy- with methyl carbamate, 47, 48 a-Ketols, 8, 47 3,4,5-triaryl-2(3H)-oxazolones, 8 2(3H)-oxazolones, 47 reaction with isocyantes, 8, 47 Ketones, 3, 4, 10, 18, 20, 22, 138, 139–140, 140, 141, 142, 149, 164, 169, 171, 175, 191, 192, 211, 232, 237, 287, 289, 530, 577– 578, 578, 579, 587 2(3H)-oxazolones, 3, 10, 18, 20, 22 3-aryl-5-tert-butyl-2(3H)-oxazolones, 3, 4 3-aryl-5-phenyl-2(3H)-oxazolones, 3 4-(alkylthio)-5(2H)-oxazolones, 139, 140 4-(arylthio)-5(2H)-oxazolones, 139, 141 4-alkoxy-5(2H)-oxazolones, 140, 142 4,5-diphenyl-2(3H)-oxazolones, 10 4,5-diphenyl-2(3H)-oxazol-2-thiones, 10 5(2H)-oxazolone N-oxides, 149 acetophenone, 578, 578 a-acylamino, 192 N-acylamino, 287, 289 a-alkoxy, 587 a-amino, 169, 191 a-bromo, 4, 22 a-chloro-a-acylamino, 175

659

cyclic, 578 a-diazo, 20 a,a-difluoroalkyl, 169 difluoro, 169 a-halo, 18, 164 a-imino, 8, 10 a-methoxyacetophenone, 587 reduction, 530, 577–579, 578, 579, 587 hydrosilylation, 530, 577–578, 578 transfer hydrogenation, 579, 579 trifluoro, 169 b,g-unsaturated, 138 Kinetic resolution(s), 501, 507 Knoevenagel condensation (reaction), 75, 110, 111, 113–116 5-(benzylidene)-2,4-oxazolidinediones, 114 5-alkenyl-2,4-oxazolidinediones, 113 5-alkyl-2,4-oxazolidinediones, 113 of 2-thio-2,4-oxazolidinedione, 75, 113 of 2,4-oxazolidinediones, 110, 111, 113–116 preparation of, 75, 113, 114, 115 antidiabetic agents, 115, 116 cyclooxygenase inhibitors, 75 dual 5-lipoxygenase and cyclooxygenase inhibitors, 75, 114 metabolic bone disorder agents, 115 non-linear optical materials, 114 Labeling studies, 72 Lacinilene C-7 methyl ether, 343 (þ)-Lactacystin, 390, 437 (6R)-Lactacystin, 437 clasto-Lactacystin b-lactone, 437 Lactacystin and analogues, 345, 436 a-Lactams, 12 5-alkyl-3-aryl-4-halo-2(3H)-oxazolones, 12, 13 3-aryl-5-substituted-2(3H)-oxazolones, 12, 14 b-Lactams, 471, 561 Lactones, 184 Lankacidin antibiotics, 415 Laulimalide, 559 Lawesson’s reagent, 292 Lead tetraacetate, 4 Leucine enkephalin, 242 Lissoclinamide 4, 363 Lissoclinamide 7, 363, 429 Lithiation, 448–458, 453–454, 457 benzylic, 448 Curtin-Hammett principle, 456 diastereoselective, 452, 453–454, 455–458 dilithiation, 457–458 ortho-lithiation, 448 oxazolinylferrocene, 453–454, 455–456, 457

660

Subject Index

Lithiation (Continued) nitrogen-directed, 455–456 oxygen-directed, 456–457 Local anesthetic activity, 173 Lonazolac, 227 Luminescence dyes, 120 Luminescence properties, saturated 5(4H)oxazolones, 206 Luminophores, 209 Lyxitol, 389 Macrocycles, 61 Macrolactams, 237 Macrolides, 27 ()-Madumycin II, 363 Maleimides, 572 Malononitrile, synthesis of bis(oxazolines), 537 ()-Malyngolide, 589–590 Mannich reactions, 83–84, 110, 217 of 2-amino-5-phenyl-4(5H)-oxazolone, 83 oxazolo[3,2-a]1,3,5,7-tetrazocines, 84 oxazolo[3,2-a]1,3,5-triazines, 83 of 5-(arylidene)-2-thio-4-oxazolidinones, 110 of spirocyclic 2,4-oxazolidinediones, 110 (þ)-Mannostatin, 391 Masamune, 539 Masamune’s protocol, 536 Masked 1,3-dipoles, 198 Mass spectrometry, saturated 5(4H)-oxazolones, 206 Mass spectrometry, unsaturated 5(4H)oxazolones, 285–286 ()-Mastigophorene A, 341, 465–466 ()-Mastigophorene B, 341 Mastigophorene, 465 MeBmt, 28 Meerwein arylation, 575 Meerwein’s salt, 42 Meerwein-Pondorf-Verley reduction, 501 Mesoionic oxazolones (munchnones), 195–198, 197 from cyclodehydration of N-substituted a-amino acids, 195 preparation of 1,3-benzodiazepines, 197 2,5-disubstituted imidazoles, 198 naphth[1,2-d]oxazoles, 198 pyrroles, 195, 196, 197 pyrrolofullerenes, 198 1,2,4-triazoles, 198 reaction with dipolarophiles, 195–198, 197 acrylates, 196 dimethyl acetylenedicarboxylate, 196

[60]fullerene, 198 fumarates, 196 fumaronitrile, 196 nitrile imines, 198 nitrosobenzene, 197 1-nitroso-2-naphthol, 198 2-phenylbenzazete, 197 N-(phenylmethylene)benzenesulfonamide, 198 triphenylvinylphosphonium bromides, 196 Metabolic bone disorder agents, 54, 115 Methoxybromination, 23–24, 25 Methoxyselenylation, 23–24, 26 Methyl a-L-vancosaminide, 390 ()-O-Methylancistrocladine, 389, 463 (þ)-O-Methylancistrocline, 463 ()-N-Methylephedrine, 22 ()-O-Methylpallidinine, 108 Meyers, 333, 364, 425, 433, 435, 436, 444, 446, 448, 458, 462, 465, 466, 469, 470, 475, 476, 508 Michael addition(s), adducts, or addition/elimination reactions, 134, 143, 160, 161, 162, 164–167, 166, 177, 218–226, 221, 223, 248–252, 258–261, 261, 376–378, 410, 413, 437–438, 445–446, 504, 505, 568– 569, 585–586 2-aryl-4-(hydroxymethylene)-5(4H)oxazolones, 223 2,4,4-trisubstituted 5(4H)-oxazolones, 166 4-(alkylaminomethylene)-2-phenyl-5(4H)oxazolones, 225 4-(alkylthiomethylene)-5(4H)-oxazolones, 223, 224 4-(aminomethylene)-2-phenyl-5(4H)oxazolones, 221, 221 4-(N,N-disubstituted-1-aminoalkylidene)5(4H)-oxazolones, 223 4-[(1,2,4-oxadiazol-3-yl)aminomethylene]-2phenyl-5(4H)-oxazolone, 225 4-[(N-cycloalkenyl)aminomethylene]-5(4H)oxazolones, 224 4-[(imidazol-1-yl)methylene]-2-phenyl5(4H)-oxazolone, 219 4,4-disubstituted 5(4H)-oxazolones, 166 5(2H)-oxazolones, 134, 143 5(4H)-oxazolones, saturated, 160, 161, 162, 164–167, 166 C-2 vinyl as Michael acceptors, 160–161 formyl anion equivalent, 162 Michael addition to a,b-unsaturated carbonyl compounds, 162 Michael addition to methyl propiolate, 164

Subject Index Michael addition to triphenylvinylphosphonium bromide, 166 nucleophilic acyl equivalents, 165 preparation of 1,4-dicarbonyl compounds, 165 3-acylacrylates, 164 pyran-2-ones, 165 pyrroline-2-carboxylic acid esters, 167 5(4H)-oxazolones, unsaturated, 218–226, 221, 224, 248–252, 258–261, 261 at the exocyclic double bond, 218–221, 258–261 2-nitropropane, 259 amino acid derivatives, 224 carbon disulfide, 223 hexamethylphosphorus triamide, 259 hydrazines, 222, 225 imidazole, 219, 222 indole, 222 phosphites, 259 sodium thiomethoxide, 220 sulfur ylides, 260–261, 261 thiols, 258 toluene, 260 triphenylphophine, 220, 221 ring opening with bis(nucleophiles), 248–252, 254 transaminations, 224–226 bis(oxazolines), 568–569, 585–586 Mukaiyama, 585–586 of O-benzylhydroxylamine, 568 of enolsilanes, 585 of ethyl acetoacetate, 568 of methylthio enolsilane, 568 of silyl enol ethers, 568 oxazolines, 376–378, 410, 413, 437–438, 445–446, 504, 505 2-oxazolines from b-halo amides/precursors, 376–378 asymmetric Michael addition to 2-alkenyloxazolines, 445–446 aryllithium reagents, 446 (þ)-a-curcumene, 446 diethylaluminum cyanide, 446 diethylphosphite, 446 (þ)-xanthorrhizol, 446 asymmetric Michael additions to cyclic enones, 504, 505 prochiral nucleophiles, 504 stereoselective addition of stabilized 4-oxazoline enolates, 437–438 Microginin, 367

661

Microwave accelerated (assisted) reactions, 212, 296, 384 ()-Mirabazole C, 178 Miscellaneous carbon-carbon bond forming reactions, bis(oxazolines), 573–575 [2þ2] photocycloaddition, 575 [2,3]-Wittig rearrangements, 573–574 allene annulation, 573 allylzincation, 573 bis(alkoxycarbonylation), 573 C-H insertion reactions, 575 chiral fullerene synthesis, 575 Meerwein arylation, 575 Miscellaneous reactions, 42–45, 43, 44, 45, 508–510, 511–512, 580–581 2-alkyloxazolines, chiral, 508 2(3H)-oxazolones, 42–45, 43, 44, 45 alkylation, 42 oxidation, 42 tert-butylhypochlorite, 42 pyridinium chlorochromate, 42 5-alkoxy-2(3H)-oxazolones, 42–43, 43 reaction with acetals, 43 5,5-dialkoxy-2-oxazolidinones, 43, 44 amino acid esters, 43, 45 reaction with aldehydes, 42 2-oxazolidinone-4-carboxylates, 42, 43 reaction with imines, 42, 44 2-imidazolidinone-4-carboxylates, 42, 44 2,3-diaminopropane-1-carboxylates, 42, 44 bis(oxazolines), 580–581 amination of enolsilanes, 581 aza-Claisen rearrangement, 581 heteroannulations, 580 synthesis of (a-chloroalkyl)boronates, 581 Wacker-type cyclizations, 580 oxazolines, 508–510, 511–512 annulations of 2-aminooxazoline, 510 bifunctional electrophiles, 510, 511–512 molecular orbital calculations, 510 pyrimidinones, 510 triazinones, 510 x-ray crystal structure, 510 electrophilic reactions of 5(alkylidene)oxazolines, 509 oxidative rearrangement of 2alkyloxazolines, 508 1,4-oxazinones, 508 chiral glycine synthon, 508 Stille couplings, 508 thietane N-acylimines from spirocyclic oxazolines, 509

662

Subject Index

Miscellaneous syntheses, of 2(3H)-oxazolones, 20–22, 21 3-phenyl-2(3H)-oxazolones, 20 a-diazo ketones and phenyl isocyanate, 20 1,3-dipolar cycloaddition, 20 heterocumulenes, 20 a-keto carbenoids, 20 2(3H)-oxazolones, 21, 21 a-hydroxy amides, 21, 21 phosphorus ylide, 21, 21 Wittig olefination, 21 2(3H)-oxazolones, 22 2-aminobenzoxazole and a-bromo ketones, 22 isotope labeling, 22 Mitsunobu reaction, 108–109, 365–368, 367, 369 alkylation of 2,4-oxazolidinediones, 108–109 oxazoline synthesis, aziridines, 367–368 10-deacetylbaccatin III, 366 mechanism, 366, 367–368 paclitaxel, 366 allo-threonines, 367–368, 369 threonines, 367–368, 369 vinylaziridines, 366 Molecular orbital calculations, 67, 178, 280, 291, 400, 409, 477, 510 Morphinan, 30–31 Morphine, 108 Mukaiyama aldol reaction, 565–566, 565, 566 bu-box, 565, 566 enantioselective, 566 enol ethers, 565 of benzaldehyde, 565 of benzyloxyacetaldehyde, 565 of glyoxylates, 565 of methyl pyruvate, 565 of pyruvates, 565 py-box, 565 stannanes, 565 trimethylsilyl enol ether, 565, 565 Mukaiyama Michael reaction, 585–586 alkylidene malonates, 585 bu-box, 585 enolsilanes, 585 Mycestericin, 344 Mycestericin D, 437 Mycobactin S, 362 Negishi cross-coupling, 451 Nelfinavir1, 359, 432 Neuraminic acid analogs, 432 Neurotrophic factors, 436

N-Substitution of 2(3H)-oxazolones, 38, 40–41 3-acyl-2(3H)-oxazolones, 40 acylation and alkoxycarbonylation, 38, 40 Boc-Ox, 40 Cbz-Ox, 40 chemoselective protection, 38 DPPOx, 40 regioselective protection, 38 phosphorylation, 40–41 mixed phosphate esters, 40 Naphth[1,2-d]oxazoles, 198 N-Nitrenolactams, 42 Nitrile imines, 198, 235, 265, 267, 268 Nitrile oxides, 235, 268–269, 268, 289 Nitrile ylides, 142, 143–145, 146, 147, 194 [3þ2]-cycloaddition, 147 1,3-dipolar cycloaddition, 144 alkoxy substituted by decarboxylation of 5(2H)-oxazolones, 145 dipolarophiles, 143, 145 from 2,2-bis(trifluoromethyl)-5(2H)-oxazolone, 147 from 4-(alkylthio or arylthio)-5(2H)oxazolones, 143 from 4-(isopropoxy)-2-phenyl-2(trifluoromethyl)-5(2H)-oxazolone, 145 hydrogen substituted, 147 intermediates to pyridines, 194 thiosubstituted by thermoylsis of 5(2H)oxazolones, 143 Nitriles, oxazoline synthesis, 383–398, 385–386 2-aminooxazolines, 394, 396 2-heteroaryloxazolines, 384 aza-bis(oxazolines), 394 bis(oxazolines), 384 multiply substituted oxazolines, 384 unsubstituted oxazolines, 384 allylic alcohols, 389, 390 b-amino alcohols, 389, 390 cyanamide, 396 cyanogen bromide, 389, 394 aza-bis(oxazolines), 394 N,N-dimethylcyanamide, 389, 393 epoxytrichloroacetimidates, 391–392, 392 (þ)-myriocin, 392 imidates, 387, 388-389 reaction with amino alcohols, 384, 385–386, 387 microwave irradiation, 384 platinum complexes, 387 Ritter reaction, 395–398 cyanamide, 396 Indinavir, 395

Subject Index inversion of configuration, 396 preparation of cis-1-amino-2-indanol, 395 preparation of C2-symmetric bis(oxazolines), 396 preparation of a-furfuryl amides, 397 preparation of Taxol side chain, 397 retention of configuration, 396 with alkenes, 397, 398 with 1,3-dioxolanes, 396 with epoxides, 396 with furfuyl carbinol acetates, 397 with cis-indane-1,2-diol, 396 with olefins, 396–397 trichloroacetimidates, 389, 391–395 20 -amino-20 -deoxycytidine, 393 20 -amino-20 -deoxyuridine, 393 bis(trichloroacetimidate), 394 staurosporine, 394 vinylogous Schmidt glycosylation, 394 diethylaluminum chloride, 392 from allylic alcohols, 389, 390 from cyclic sulfates, 393 (þ)-mannostatin, 391 trichloroacetonitrile, 383, 389, 393 Nitrones, 38, 561–562, 562, 587 NOE of cyclopalladated oxazoline, 460 Non-linear optical materials (NLO), 54, 84, 114, 210 Non-sedating anxiolytic, 348 Non-steroidal anti-inflammatory drugs (NSAIDS), 334 Nucleophilic acyl equivalents, 165 Nucleophilic reactions of oxazolines, 417–433 see: hydrolysis, 417–427 other nucleophiles, 427–429 curacin A, 428 cyclopeptides, 429 kalkitoxin, 428 selective thiolysis, 428 thiazolines from thiolysis of oxazolines, 427–429 substitution at the 5-position, 430–433 anomeric oxazolines as glycopyranosyl donors, 430–432 azide, 432 HBr, 430 HI, 430 Nelfinavir1, 432 neuraminic acid analogues, 432 pyridine hydrochloride, 430 thiangazole, 430 thiazolines, 430 thiolacetic acid, 432

663

Obrecht’s methodology, 187–188, 189, 271, 381 phenylalanine cyclohexylamide, 187 resolution of quaternary amino acids, 271 resolution of racemic a,a-dialkylamino acids, 187 substituted amino acid amides, 189 Organometallic complexes, 202–206, 291 saturated 5(4H)-oxazolones, 202–206 dinuclear, 202–206 mononuclear, 202–206 ortho metalation, 203 C2-symmetric bis(oxazolone) ligands, 291 Orthoesters, reaction with oxazolonium salts, 63 4-Oxa-2-aza-podophyllotoxin, 108 1,2,3-Oxathiazolidines, 346 1,2,4-Oxadiazole-3-carboxylates, 216, 235 1,2,4-Oxadiazoline-3-carboxylic acids, 197 1,3-Oxathiole, 59 1,3-Oxazine-2,4(H)-diones, 18 5-aryl-2(3H)-oxazolones, 18 1,3,4-Oxadiazolines, 57 1,4-Oxazinones, 508 Oxazoles, 7, 42, 45, 46, 55–56, 66, 120, 137, 138, 155–159, 160, 168–169, 191, 191, 192, 259, 287, 289, 376, 407, 410, 417 2-allyloxy-4,5-diphenyl, 7, 45 2-benzyloxy-4,5-diphenyl, 7, 45 2-chloro-4,5-diaryl, 46 2-ethoxy, 42 2,4,5-trimethyl, 407 2,5-diaryl, 191, 191, 289 2,5-disubstitued, 192 4-[a-bis(dimethylamino)phosphoryl]benzyl-5(dimethylamino)-2-phenyl, 259 4-acyl-2-phenyl, 417 4-carboxylates, 376 4-nitro-2-phenyl, 410 4-nitro-2-phenyl-5-carboxylic acid methyl ester, 410 5-(arylmethyloxy)-2-phenyl-4(trifluoromethyl), 158 5-(benzyloxy)-2-phenyl-4-(trifluoromethyl), 158 5-acyloxy, 159, 168–169 5-acyloxy-2-phenyl, 168 5-alkoxy, 137, 138, 155–159, 160, 410 5-aryl-2-phenyl, 289 5-fluoro-2-phenyl-4-(trifluoromethyl), 156 5-methoxy-2-( p-methoxyphenyl), 439 5-methoxy-4-substituted-2-(tertbutyldimethylsilyl), 407 5-oxazoleacetates, 192 bis, 191

664

Subject Index

Oxazoles (Continued) hydrolysis, 55–56 nitro, 410 triflates, 66, 120 2,4-Oxazolidinediones, 89–119, 93, 100, 101, 103, 109, 119 2-alkoxy, 91–94, 93 from a-bromo amidines, 92–93 from heterocumulenes, 92, 93 from ketenimines, 91 3-alkoxy, 91 3-alkyl(aryl), 90 3-(arylideneamino), 90 N-acyliminium ion precursors, 108 anions, 110–111 Boulton-Katritzky rearrangement, 92–93, 93 dianions, 111, 113 preparation of 2(5H)-furanones, 111, 113 reaction with a-halo ketones, 111, 113 natural products, 106 radiolabelled, 99 reactions, 94, 108–120, 109, 119 acylation, 109 alkylation, 94, 108, 108, 109 chlorosulfonation, 116 hydrolysis, 116 Knoevenagel reaction, 110, 113–117 Mannich reaction(s), 110 Mitsunobu reaction, 108–109 nucleophilic displacements, 116 reduction, 116 ring opening, 117–119, 119 (2H)-azirines, 117–119, 119 enzymatic hydrolysis, 117 hydrazines, 117 a-hydroxy acids, optically active, 117 imidazolones, 117–119, 119 triazolones, 117 spirocyclic, 97, 98, 100, 101, 102, 103, 110 synthesis, 94–107, 100, 101, 103 2-aminooxazoles, oxidation, 106 a-O-(carbamoyloxy)esters, 94, 102 cyanohydrins, 97, 99 electrochemical reduction, 103–105 a-halo acetanilides, 105 a-halo amides, 103 a-hydroxy amides, 94–95, 96, 97, 98, 99, 103 a-hydroxy esters, 94–95, 96, 97, 98, 99, 100, 102, 103 a-hydroxy imidates, 99–100, 100, 101 isatins, 102, 103 ring contractions, 100, 105–106 base catalyzed, 100

oxidative, 105–106 a-tosyl acetanilides, 105 tautomerism, 89 x-ray crystal structures, 89 2-Oxazolidinones, 4, 6, 10, 12, 14–16, 23–25, 32, 33, 35, 38, 42, 43, 44, 45, 46, 47 3-alkyl-2(3H)-oxazolones, 15 diphenylvinylene carbonate and amines, 15 3-amino-2(3H)-oxazolone, 15 diphenylvinylene carbonate and hydrazine, 15 4-(3-indolyl)-2(3H)-oxazolone, 14 from 4-methoxy-2-oxazolidinone, 14 5-phenyl-2(3H)-oxazolones, 6 from a 4-hydroxy-2-oxazolidinone, 6 2(3H)-oxazolone(s), 4, 10, 12, 14–15 anodic oxidation of 2-oxazolidinones, 14 Diels-Alder reactions of 4,5-dimethylene-2oxazolidinones, 10–12 electrophilic reactions of 3-acyl-4,5unsubstituted-2(3H)-oxazolones, 23–24 2-oxazolidinone-4-carboxylates from 5-alkoxy2(3H)-oxazolones, 42, 43 2-oxazolidinones from a-ketols and isocyanates, 47 4,5-dialkoxy-2-oxazolidinones, 25 5-alkoxy-2(3H)-oxazolones and aldehydes, 43 5,5-dialkoxy-2-oxazolidinones from 5-alkoxy2(3H)-oxazolones, 43, 44, 45 Oxazolidinones, 546–552, 553, 554, 559, 561, 562, 567, 568, 568, 585 3-acryloyl-1,3-oxazolidin-2-one, 546–552, 567 cyclopropanation, 587 N-acyl oxazolidinones, 553, 568 N-cinnamyl oxazolidinones, 567 N-crotonyl oxazolidinones, 567 Diels-Alder reaction, 546–552, 553, 554 1,3-dipolar cycloaddition reactions, 561, 562 free radical conjugate additions, 567, 568 hetero-Diels-Alder reaction, 559 Michael addition, 568 Oxazolidinopiperidines, 30 Oxazoline N-oxides, 416–417, 447 2-(a-acyloxy)oxazolines, 417 hetero-Claisen rearrangement of oxazoline Noxides, 416–417 ketene aminal, 417 dipolar cycloadditions, 447 Oxazoline directed metalation and electrophilic substitutions, 448–460, 453–454, 455–456, 457, 459 chiral ferrocenyloxazoline ligands, 452, 453–454, 455–456, 457

Subject Index chiral oxazolinyl aryl sulfides, 448 chiral phosphinooxazolines, 448 arenes, 458 EVL-HMPA, 458, 459 benzylic deprotonation, 448 cyclopalladation, 458, 460 diastereoselective, 460 nOe, 460 x-ray crystal structure, 458 diastereoselctive lithiation, 452, 453–454, 455–458 Curtin-Hammett principle, 456 dilithiation of oxazolinylferrocene, 457–458 lithiation of oxazolinylferrocene, 453–454, 455–456, 457 nitrogen directed, 455–456 oxygen-directed, 456–457 x-ray crystal structure, 455, 458 dilithiation, 457–458 metalation of, 448, 456–457, 458 Z5-cyclopentadienylrhenium(I) tricarbonyl oxazoline complex, 458 2-(2-methylphenyl)oxazoline, 448 4,4-dimethyl-2-phenyloxazoline, 448 trans-4,5-diphenyloxazolinylferrocene, 456–457 preparation of anti ulcer compound AI-77-B, 448–449 aryl ketones, 451 biaryls, 451 C2-symmetric tetradentate ligands, 457–458 chiral ferrocenyloxazoline ligands, 452, 453– 454, 457 chiral oxazolinyl aryl sulfides, 448 chiral phosphinooxazolines, 448 thromboxane A2 receptor antagonist, 448 xenalipin, 451 x-ray crystal structure, 452 Oxazoline directed nucleophilic additions, 469– 475 diastereoselective conjugate additions to oxazolinylnaphthalenes, 469–475, 470, 472–473 1,6-addition of lithium dialkylamides, 474– 475 ethoxyvinyllithium (EVL), 469, 470 lithiosilane, 469 lithium amides, 470–471, 474–475, 472–473 RLi, 475 preparation of ()-aphanorphine, 469 ()-eptazocine, 469 b-amino acids, 471

665

d-amino acids, 475 chiral tetralones, 475 dihydronaphthalenes, 469 b-lactams, 471 Tamao oxidation, 469 x-ray crystal structure, 469 Oxazoline directed nucleophilic substitutions, 461–468, 462, 466 phosphinooxazoline ligands, 461 atropisomerism selectivity, 463 preparation of axially chiral biaryls, 462 preparation of biaryls, 461–462, 463–468 actinoidic acid, 462 Suzuki coupling, 462 unsymmetrical, 462 preparation of phosphinooxazoline ligands, 461 preparation of pyrrolophenanthidine alkaloids, 462 stereoselective synthesis of biphenyls, 462 stereoselective Ullmann coupling, 464–468, 466 substitution of, 461, 466 2-(ortho-chlorophenyl)-4,4dimethyloxazoline, 461 2-(ortho-fluorophenyl)oxazoline, 461 4,4-dimethyl-2-(2,3,4trimethoxyphenyl)oxazoline, 466 Oxazolines as activating groups, 442–447 Diels-Alder reactions, 447 Michael additions, 445–446 a-proton abstraction, 442–445 Oxazolines as chiral directing groups, 476–481 as -geminal directing groups, 481 bromination of oxazolinylcyclophanes, 481 for asymmetric hetero-Diels-Alder reaction, 476–477, 477 chiral 2-alkenyloxazolines, 476–477, 477 computational studies, 477 isocyantes, 476–477 for diastereoselective Diels-Alder reaction, 477–479 oxazoline substituted acrylates, 478–479 for diastereoselective Grignard addition, 477 Felkin-Ahn transition state model, 477 oxazoline aldehydes, 477 for diastereoselective sulfimidation, 480 for stereoselective oxidation of sulfides, 479 transition state models, 479–480 preparation of chiral sulfimides, 480 chiral sulfoxides, 479 D-ribo-phytosphingosine, 477 tetrahydrooxazolopyrimidines, 476

666

Subject Index

Oxazolines as directing groups, 448–475 metalation and electrophilic substitutions, 448– 460 nucleophilic additions, 469–475 nucleophilic substitution, 461–468 Oxazolines as ligands in asymmetric synthesis, 481–507, 489, 490, 491, 494 allylic substitution, 487–493 allylic imidate rearrangements, 491–492 ferrocenyloxazolines, 491 hard nucleophiles, 492 intramolecular allylic amination, enantioselective, 492 nickel (0) catalyzed substitutions, 492 palladium-catalyzed alkylation of, 488–493, 489, 490, 491 3-acetoxycyclohexene, 490, 491 3-acetoxycyclopentene, 490 dimethylallyl acetate, 490, 490 dimethylallyl tert-butylcarbonate, 490, 490 diphenylallyl acetate, 487–489, 489 PhosOx ligands, 490, 491, 492, 493 platinum-catalyzed alkylation, 491 soft nucleophiles, 487–493 acetylacetone, 489 arylboronic acids, 493 benzylamines, 489 dimethyl malonate, 487–489, 489, 490, 491 dimethyl methylmalonate, 489 silyl enolates, 489 x-ray crystal structure, 489, 491 cyclopropanations, 504, 506 bis(oxazolines) 504, see also Chapter 9, pp 538–545 PyrOx ligands, 506 dialkylzinc additions, 501, 502 asymmetric addition to aldehydes, 501, 502 dimethylzinc, 501 HydrOx ligands, 501 Heck reactions, 493–495, 494 asymmetric intermolecular, 494 double-bond migration, 493–494 enantioselective, 493 PhosOx ligands, 493–494 PyrOx ligands, 495 regioselective, 493 x-ray crystal structure, 494 hydrogenation, 495–501 hydrosilylation, 503–504 asymmetric hydrosilylation of imines, 503 asymmetric hydrosilylation of ketoximes, 503

hydrosilylation-cyclization of dienes, 503– 504 PhosOx ligands, 503 PyrOx ligands, 503–504 ligand classes, 483–488, 490, 491, 492, 493, 495, 498, 501, 503, 504, 506, 507 carbenes, 498 HydrOx, 483, 488, 501, 507 PhosOx, 483–485, 490, 491, 492, 493–494, 501, 503, 504, 507 PyrOx, 483, 486, 495, 503–504, 506 SelOx, 483, 488 SulfOx, 483, 487, 504 Michael additions, 504, 505 asymmetric addition to cyclic enones, 505 PhosOx ligands, 504 phosphite-oxazoline ligands, 504, 505 prochiral nucleophiles, 504 SulfOx ligands, 504 x-ray crystal structure, 504 miscellaneous reactions, 506–507 alkyne couplings, 507 kinetic resolution, 507 PhosOx ligands, 507 asymmetric Fujiwara-Moritani reaction, 506 asymmetric sulfide oxidation, 507 HydrOx ligands, 507 Oxazolines as protecting groups, 442 2-Oxazolines, 332–528 anomeric oxazolines as glycopyranosyl donors, 430–432 as ligands for asymmetric catalysis, 481–507 bis(oxazolines), 333, 394, 396, 481, 504 aza-bis(oxazolines), 394 C2-symmetric bis(oxazolines), 396 epimerization, 439 ligand classes, 483–488 natural products, 361, 363, 367, 428 calyculin C, 361 curacin A, 428 thiangazole, 363, 367 oxazolinium salts, 433–435 reactions, 417–512 activating groups, 442–447 N-alkylation, 433–435 chiral directing groups, 476–481 directing groups for aromatic reactions, 448– 475 ligands in asymmetric catalysis, 481–507 miscellaneous reactions, 508–512 nucleophilic reactions, 417–433 hydroylsis, 417–427 other nucleophiles, 427–429

Subject Index substitution at the 5-position, 430–433 oxidation, 440 polymeric oxazolines, 507–508 protecting groups, 442 proton abstraction of the oxazoline ring, 435– 440 reductions, 440–442 synthesis, 333–417 N-acylaziridines, 398–402 allyl amides (enamides), 402–406 carboxylic acids and esters, 333–338 cycloaddition reactions, 407–412 [2þ2], 407 [3þ2], 408–410 [4þ2], 410–412 b-hydroxy amides, 338–375 b-halo amides, 375–383 isonitriles, 406–407 miscellaneous methods, 412–417 from acylisothiocyanates, 417 from acylnitrenes, 415 from azido alcohols, 413 from azido esters, 412 from oxazoline N-oxides, 416 from sulfilimines, 413 reductive photocyclization, 417 Staudinger-aza-Wittig reaction, 412–413 nitriles, 383–398 Oxazolinium salts, 433–435 hydrolysis, 433 intramolecular, 434 precursors for azaspirocycles, 434 precursors for dengibsin, 433 reaction with cyclobutanes, 435 reduction, 433 Oxazolinylcyclophanes, 481 Oxazolinylidene steroids, 120 2-aryl-5,5-dimethyl-4(5H)-thiooxazolones, 120 Oxazolinylnaphthalenes, 469–475, 470, 472–473 diastereoselective conjugate additions, 469– 475, 470, 472–473 1,6-addition of lithium dialkylamides, 474– 475 ethoxyvinyllithium (EVL), 469, 470 lithiosilane, 469 lithium amides, 470–471, 474–475, 472–473 RLi, 475 Oxazolo[5,4-b]pyridines, 254 2(3H)-Oxazolones (4-Oxazolin-2-ones), 2–45, 4, 9, 10, 13, 14, 17, 21, 25, 26, 34, 43, 44, 45, 47–49, 48 acylating agents, 32 alkylation, 42

667

bicyclic, 10 C-substitution, 36, 39 cross-coupling reactions, 36, 39 cycloadditions, 32–36, 42 Diels-Alder reactions, 10–12, 32, 35 dienophiles, 32 dipolarophiles, 35 electrophilic additions, 23–25 ene-reaction, 35 Friedel-Crafts acylation, 36 hydrogenation, 22–23 miscellaneous reactions, 42–45 miscellaneous syntheses, 20–22 N-substitution, 38–41 acylation, 38–40 alkoxycarbonylation, 38–40 phosphorylation, 40–41 oxidation, 42 pericyclic additions, 32–36 [2þ2], 35–36 [3þ2], 35 [4þ2], 32–35 radical additions, 25, 27–32 alkenyl radicals, 30–31 alkyl radicals, 25, 27–30 polymers, 32 reactions with acetals, 43 aldehydes, 42 imines, 42 synthesis from, 3–22, 47–49 1,2-diketones, 8–12 1,2,4-triazolium salts, 18 2-allyloxyoxazoles, 7 2-oxazolidinones, 14–16 2,4-thiazolidinediones, 17–18 acyclic carbamates or urethanes, 3–7, 47 a-amino acid esters, 7–8 benzoin and isocyanates, 8, 47 b-enaminosulfoxides, 12 hydroxamic acids, 12–14, 47 oximes, 16–17 via three component condensation, 18–20 2(5H)-Oxazolones (3-Oxazolin-2-ones), 45–46 4,5-diaryl-5-methoxy-2(5H)-oxazolones, 46 5-chloro-4,5-diaryl-2(5H)-oxazolones, 46 from 4,5-diaryl-2(3H)-oxazolones, 46 5-substituted-2(5H)-oxazolones, 45 from irradiation of 2-allyloxyoxazoles, 45 dimers, 46 reactions, 46 synthesis, 45–46 photolysis of oxazoles, 45

668

Subject Index

4(5H)-Oxazolones and thiooxazolones, 53–89, 57, 64, 66, 73, 76, 78, 120 2-alkoxy, see 2,4-oxazolidinediones, pp 89, 91–94 2-alkyl(aryl), 55–62, 120 Almazole D, 62 cycloaddition(s), 67 Diels-Alder reaction, 67 macrocyclic, 61 oxazolonium salts, synthesis, 58–59 oxazolonium salts, reaction with aldehydes and orthoesters, 63–64 reactions, 63–67, 120 [2 þ 2] photochemical cycloaddition, 67 4-aminothymol, 65 Diels-Alder reaction, 67 guanidines, 65 hydrazines, 64, 65 imidazolidinones, 65 oxazole triflates, 66, 120 triazoles, 64, 65 tropolones, 67 spirocyclic, 57 synthesis, 55–62, 120 acrylamide, 62 acyl isocyantes, 120 carbenes, 57, 59 a-halo amides, 61 hydrolysis, 55–56 N-acylsulfilimines, 56–57, 57 trifluoromethylsulfenylation, 60 sulfomycin I, 66 tautomerism, 54 2-amino, 53, 54, 67–89, 120 acetylation and acylation, 82–83 aldol condensation (reaction), 82 alkylation, 82 hydrolysis, 82 indolmycin, 68, 78, 79–81, 84–89, 120 isoindolmycin, 79, 88 Mannich reactions, 83–84 pemoline, 67, 68, 72, 74–75 polymerization, 84 reactions, 81–89 spirocyclic, 71–72, 73, 74 a-hydroxy esters, 72–74, 73 pterins, 72 ureides, 71 synthesis, 53, 67–81, 73, 76 alkylation of 2-amino analogue, 68 aminolysis of a 2-thione, 68 N-aryl ureas and chloroacetic acids, 70 coumarin semicarbazones, 69

dihydrofuran-2,3-diones, 75 displacement of a leaving group at C-2, 68, 75 a-halo carboxylic acid ureides, 68, 71 a-halo amides, 68–69 a-hydroxy amides, 68 a-hydroxy esters, 53, 68, 72–74, 73 indolmycin, 79–81 oxidative ring contraction, 77, 78 pterins, 72 tautomerism, 54–55, 68 transamination, 82 2-hydroxy, see 2,4-oxazolidinediones, pp 89–119 spirocyclic, 57, 71–72, 73, 74 5(2H)-Oxazolones, 131–150, 133, 135, 138, 140, 141, 142, 145, 146, 146, 148, 149 4-heteroaryl, 139–142, 140, 141, 142 C-2 vs. C-4 alkylation, 134–136, 135 intermediates for, 133, 134, 135, 138, 143–145, 146, 147, 148, 149 3-alkyl aspartic acid derivatives, 148, 149 a,a,-dibenzylglycine, 135 b,b-difluoro amino acids, 133 a-diketones, 134 nitrile ylides, 143–145, 146, 147 b,g-unsaturated ketones, 138 nitrile ylides, 143–145, 146 N-oxides, 149–150 from ketones and nitrosoketene, 149 psammaplin, 132 racemization, 132, 134 electronic effects, 134 kinetics, 134 steric effects, 134 reactions, 143–150, 145, 146, 146, 148, 149 aminolysis, 145–146, 146 decarboxylation, 145 1,3-dipolar cycloadditions, 143–145 generation of nitrile ylides, 143–145, 146, 147 via thermolysis, 143 Michael addition, 143 synthesis of 2-(trifluoromethyl)pyrroles, 143, 145 with electron deficient unsaturated compounds, 143, 145 rearrangements, 147–148 2,3-dihydropyridine, 148 azabicyclohexene, 148 tetrahydrofuropyrrole, 148 thermolysis, 148 thermolysis, 143, 148

Subject Index with 2H-azirines, 147, 148 with electron deficient unsaturated compounds, 143, 145 azo compounds, 143 synthesis of 2-(trifluoromethyl)pyrroles, 143, 145 synthesis of (trifluoromethyl)dihydrotriazoles, 143 with phosphites, 147 [3þ2]-cycloaddition, 147 generation of nitrile ylides, 147 with ynamines, 148, 149 synthesis, 131–142, 133, 135, 138, 140, 141, 142, 150 4-alkoxy, 140, 141, 142 oxidation of 4-(phenylthio)-5(2H)oxazolones, 140, 141 4-alkylthio, 139, 140 4-amino, 142, 142 amidines, 142, 142 anilines, 142 4-arylthio, 140, 141 C-2 vs. C-4 alkylation, 134–136, 135 cyclization of amino acids and amino nitriles, 131–134, 133 N-oxides, 149 photooxidation of 2’-deoxyguanosine, 150 rearrangement of 5-alkoxyoxazoles, 137, 138 sigmatropic rearrangement(s), 136–139, 138 tautomerism, 131, 134 NMR studies, 134 5(4H)-Oxazolones, 151–299, 154, 160, 165, 166, 167, 170, 181, 189, 191, 193, 195, 197, 212, 213, 214, 216, 217, 218, 220, 221, 224, 229, 241, 244, 247, 249, 258, 261, 266, 267, 268, 278, 280, 281 saturated, 131, 132, 151–208, 154, 160, 165, 166, 167, 170, 181, 189, 191, 193, 195, 197, 200, 202, 206, 207, 210, 256–257, 287–292, 287, 289, 291 2-alkoxy, 177–178 activating agents for dicarboxylic acid amino acids, 186 acyl donors, 183 deracemization, 180 derivatizing agents, 182 glycine enolate equivalents, 184 glycine synthons, 186 in peptide synthesis, 185–190, 289 masked 1,3-dipoles, 198 reactions, 178–206, 289–290 alcoholysis, 178–183, 181, 289 aminoacylation, 191–192, 191

669

aminolysis, 183–185, 185–190, 189 cycloaddition reactions, 195–198, 197, 198–201, 199, 201, 289 with dipolarophiles, 195–198, 197, 289 with dienes and azadienes, 198–201, 199, 201 decarbonylation, 193, 193 dimerization, 194–195, 195, 289 flash vacuum pyrolysis, 194 Friedel-crafts reaction, 289 hydrolysis, 178–183 incorporation of a,a-dialkylamino acids into peptides, 189–190, 289 organometallic complexes, 202–206, 291 oxidation, 191 oxidative decarboxylation, 191 polymerization, 201–202 pyrolysis, 194 Wittig olefination, 192–193, 193 structural analysis, 206–208, 291 synthesis, 151–178, 256–257, 287–288 Claisen rearrangements, 155–159 cyclization of amino acid derivatives, 151– 155, 154, 287 cycloaddition reactions of ketenes, 155 from amino acids, 156, 288 from saturated 5(2H)-oxazolones, 160 from saturated 5(4H)-oxazolones, 160–176 acylation at C-4, 168–171, 170 alkylation at C-4, 162–164, 171 arylation at C-4, 167, 167 Diels-Alder reaction at C-2, 160 from unsaturated 5(4H)-oxazolones, 177, 256–257 hydrogenation, 256–257 halogenation, 175–176 hydrosilylation, 161 intramolecular alkylation at C-4, 171 Michael reaction at C-2, 160 Michael reaction at C-4, 164–167, 166 reaction with azine N-oxides, 174 reaction with diazonium salts, 176 reaction with enamines and formamidines, 172–173 reaction with imines and carbonyl compounds, 171–172 rearrangement of oxazoles, 155–160, 160 unsaturated, 131, 171, 172, 177, 208–287, 212, 213, 214, 216, 217, 218, 220, 221, 224, 229, 241, 244, 247, 249, 258, 261, 266, 267, 268, 278, 280, 281, 292–299 b-amino-a,b-dehydro-a-amino acid equivalents, 173

670

Subject Index

5(4H)-Oxazolones (Continued) arylacetaldehyde equivalents, 237 cationic glycine equivalents, 220 charge transfer complexes, 282 configurational assignments, 285–287 isomerization, 213, 213, 283 reactions, 226–284, 261, 266, 267, 268, 294– 299 exocyclic double bond, 177, 256–284, 297–299 cyclopropanations, diastereoselective, 269–270 Diels-Alder reactions, 271–280, 278, 280, 280, 297–299 1,3-dipolar cycloadditions, 262–269, 266, 267, 268, 297 hydrogenation, 256–257, 258 Michael reactions, 258–261 electrochemical reduction, 282 fluorination, 282 oxygenation, 282 photodimerization, 283 photoisomerization, 283 ring opening, 226, 226–230, 235–243, 243–256, 294, 296 1,3-bisnucleophiles, 247–254, 249, 296 aminolysis, 235–243, 237, 241, 295–296 hydrolysis and alcoholysis, 226–230, 229, 230 intramolecular, 256 miscellaneous nucleophiles, 254–256 nitrogen nucleophiles, 243–247, 244, 247 reductive aminolysis, 240–243, 295 sonication, 226 structural analysis, 284–286, 299 synthesis, 172–174, 210–227, 212, 214, 216, 217, 218, 220, 221, 224, 292 from N-acylglycines and carbonyl compounds (Erlenmeyer synthesis), 210–212, 212, 292 from amino acid derivatives, 213–216, 217, 292 carbodiimides, 214, 214 a,b-dehydroamino acids, 214, 292 iminophosphoranes, 214, 216, 292 isocyanides, 215, 216 from saturated 5(4H)-oxazolones, 174 from unsaturated 5(4H)-oxazolones, 217– 227, 292 homologation, 218 5(4H)-Oxazolones as synthetic equivalents, 174, 182, 183, 184, 186, 198, 220, 237, 287

saturated, 182, 183, 184, 186, 197 as acyl donors, 183 as activating agents for dicarboxylic acid amino acids, 186 as derivatizing agents, 182 as glycine enolate equivalents, 184 as glycine synthons, 186 as masked 1,3-dipoles, 198 of amino acids, 287 unsaturated, 173, 220, 237 as b-amino-a,b-dehydro-a-amino acid equivalents, 174 as arylacetaldehyde equivalents, 237 as cationic glycine equivalents, 220 Oxazolo[3,2-a]1,3,5-triazines, 83 Oxazolo[3,2-a]1,3,5,7-tetrazocines, 84 Oxazolonium salts, 58–59, 63–64, 64, 65 2-[2-(a-heteroaryl)ethenyl]-4(5H)oxazolonium perchlorates, 64 5-acyloxy-4(5H)-oxazolonium salts, 59 1,2,4-triazoles, 64 cyanine dyes, 64 reactions, 63–64, 64, 65 aldehydes and orthoesters, 63–64, 64 guanidines, 65 hydrazines, 65 synthesis, 58–59 acyl cyanides, 59 a-chloroacetamides, 58 cyanohydrins, 58 a-haloacetyl bromides, 58 a-hydroxy carboxylic acid amides, 58 Oxazolyl aldehydes, 29 Oxidation, 4, 14, 42, 191, 440 anodic of 2-oxazolidinones, 14 anodic of carbamates, 4 tert-butylhypochlorite, 42 3-amino-4,5-diphenyl-2(3H)-oxazolone, 42 lead tetraacetate, oxidative cyclization of carbamates, 4 molecular oxygen, saturated 5(4H)-oxazolones, 191 of oxazolines, 440 see Part A chapter 1, pp 4–16 for oxidations of oxazolines to oxazoles oxidative decarboxylation, 191 potassium superoxide, 191 preparation of N-benzoylamino acid, 191 diacylamines, 191 imides, 191 pyridinium chlorochromate, 42 3-amino-4,5-diphenyl-2(3H)-oxazolone, 42

Subject Index Oxidative ring contractions, 77, 78, 105–106 2-amino-5-(carboxyalkyl)-4(5H)-oxazolones, 77, 78 5-aryl-2,4-oxazolidinediones, 105 5-heteroaryl-2,4-oxazolidinediones, 105 of 2-aminopyrimidinones, 77, 78 of barbituric acids, 105 of uric acid, 106 Oxime O-carbonates, 16 Oximes, 16, 17 3-alkyl-4,5-disubstituted-2(3H)-oxazolones, 16, 17 [3,3] sigmatropic rearrangement, 16 dialkyl carbonates and oximes, 16, 17 oxime O-carbonates, 16 regioselectivity, 16 Oxoassoanine, 462 Oxygenation of unsaturated 5(4H)-oxazolones, 282 (R)-Oxytriphine, 401 Paclitaxel, 346, 366 Paterno-Bu¨chi reaction, 2,4,5-trimethyloxazole with aldehydes, 407 bicyclic oxazolines, 407 Pemoline, 67, 68, 72, 74–75 capillary zone electrophoresis (CZE), 75 cyclization of a-hydroxy esters and guanidine, 72 reaction of cyanamide and a mandelate ester, 74–75 spontaneous resolution, 75 Pericyclic additions of 2(3H)-oxazolones, 32–36 [2þ2], 35–36 [3þ2], 35 [4þ2], 32–35 3-acyl-2(3H)-oxazolones as dienophiles, 32–33 Diels-Alder reaction, diastereoselective, 32 ene reaction of 2(3H)-oxazolones, 35 Perimidines, 248 Pesticides, 223, 227 Phe-box, 530, 532, 534, 536, 546, 548, 549, 555, 557, 561, 567, 575, 581 aziridinations, 575 conjugate additions, free radical, 567, 567 crystal structure, 534 geometry, 532 Diels-Alder reactions, 530, 546, 548, 549 1,3-dipolar cycloaddition reactions, 561 hetero-Diels-Alder reactions, 555, 557 preparation of a-(chloroalkyl)boronates, 581 synthesis, 536

671

2-Phenyl-4(5H)-oxazolone, 54, 61, 65, 66 Phenylalanine(s), see amino acids and derivatives Photocyclization, reductive of 4-acyl-2phenyloxazoles, 417 bicyclic oxazolines, 417 Photocycloaddition, 35, 575 Photographic dyes, 54 Photoisomerization of oxazolones, 381 Photolysis of oxazoles, 7, 45 Photooxidation (photodimerization), 150, 194, 283 2,2,-diamino-[(2-deoxy-b-D-erythropentofuranosyl)-4-amino]-5(2H)oxazolone, 150 4,40 -bis(oxazolones), 194, 195 of 20 -deoxyguanosine, 150 of saturated 5(4H)-oxazolones, 194 of unsaturated 5(4H)-oxazolones, 283 preparation of 4,40 -bisoxazolones, 194, 195 Phytosphinogosine-type glucosaminocerebrosides, 353 D-ribo-Phytosphinogosine, 477 Pictet-Gams conditions, 348 Pictet-Spengler reaction, 233, 237 Planar chirality, 493, 494, 501 Plant growth regulators, 227 Plant-protective agents, 223 ()-Platynecine, 390 Polyalcohols, 40 Polyamines, 38 Polymer-supported reagents, 359, 364, 366, 588 aza-bis(oxazolines), 588 PEG-supported Burgess reagent, 364, 366 tosyl chloride, 359 Polymeric oxazolines, 507–508 Polymerization(s), 84, 160, 178, 201–202, 289, 572 5-phenyl-2-(propynylamino)-(5H)-oxazolone, 84 non-linear optical materials, 84 5(4H)-oxazolones, saturated, 160, 178, 201–202 5(4H)-oxazolones, unsaturated, 289 bis(oxazolines), 572 asymmetric, 572 tert-butylstyrene and carbon monoxide, 572 cyclopropenes, 572 maleimides, 572 i-pr-box, 572 Positron emmission tomography, 99 i-Pr-box, 534, 535, 548, 561, 570, 572 alkylation of imines, 570, 572 Diels-Alder reaction, 548 1,3-dipolar cycloadditions, 561

672

Subject Index

i-Pr-box (Continued) polymerization, asymmetric, 572 preparation of b-lactams, 561 preparation of tetrahydroisoquinolines, 572 synthesis, 535 x-ray crystal structure, 534 Pratosine, 462 Probase, 105 Prochiral nucleophiles, 504 Prostratin, 545 a-Proton abstraction, oxazolines, 442–445 2-(cis-alkenyl)-substituted oxazolines, 444 2-(trans-alkenyl)-substituted oxazolines, 444 2-oxazoline substituted epoxides, 444 of 2-(allyloxymethyl)oxazolines, 443 stereoselective [2,3]-Wittig rearrangement, 443 of 2-(chloromethyl)-4,4-dimethyloxazoline, 443 carbonyl compounds, 443–444 nitrones, 444 Schiff bases, 444 of 2-alkyloxazolines, 442, 445 ketenimine rearrangement, 445 of 2-biphenylmethyloxazolines, 443 ion-pair acidity, 443 of chiral 2-(chloromethyl)oxazolines, 444 boron azaenolates, 444 titanium azaenolates, 444 of chiral arylmethyloxazolines, 443 Proton abstraction of the oxazoline ring, 435–440 2-bromooxazolines, 435 at the C-2 position, 435 at a benzylic C-5 position, 436 ethoxyvinyllithium-HMPA complex (EVL-HMPA), 436 at an activated C-4 position, 436 aldol reacton, 437 a-alkyl amino acids, 436 decarbomethoxylation, 439 epimerization of cis- to trans-oxazolines, 439 (þ)-lactacystin, 437 (6R)-lactacystin, 437 clasto-lactacystin b-lactone, 437 lactacystin analogues, 436 mycestericin D, 437 quaternary chiral centers, 436–437 sarains A-C, 437 Seebach protocol, 436 stereoselective Michael addition, 437–438 Psammaplin, 132 Pseudodistomins, 417, 441–442 Pseudohydantoins, 53 Pseudoxazolone, 131–132

Pterins, 72 spirocyclic 2-amino-4(5H)-oxazolones, 72 Pummerer reaction (rearrangement), 12, 57 Py-box, 530, 534, 551, 565–566 Diels-Alder reaction, 551 hydrosilylation, 530 Mukiayama aldol reaction, 565–566 synthesis, 534 x-ray crystal structure, 534 Py-box-ip, 534, 540–541, 578 cyclopropanation, 540–541 hydrosilylation, 578 synthesis, 534 Pyran-2-ones (a-Pyranones), 165, 173, 235, 252, 254, 589 2H-Pyrans, 580 Pyrazin-2(1H)-ones, 5-(dimethylamino)-3,6dihydro, 147, 148, 185 Pyrazoles, 222, 235, 246, 268 Pyrazolines, 234, 235 Pyrazolinoxazolines, 246 5-Pyrazolones, 184, 225 Pyridazinones, 199 Pyridines, 137, 148, 174, 194, 201 from 5(4H)-oxazolones, 194 nitrile ylides, 194 Pyridones, 172, 198, 199, 224, 251–252 2-pyridones, 172, 198, 199, 251–252 5(4H)-oxazolones and 1-azadienes, 198, 199 unsaturated 5(4H)-oxazolones and enamines, 251 4-pyridones, 224 Pyridotriazinones, 172 Pyrimidin-2-thiones, 255 Pyrimidin-6-ones, 199, 200 Pyrimidines, 250 Pyrimidinones, 510 Pyrroles, 143, 145, 195–197, 197, 201, 235, 289 2-(trifluoromethyl), 143, 145 3-carboxylic acids, 289 3-methyl, 235 preparation from 4-alkyl(aryl)-2-(trifluoromethyl)-5(2H)oxazolones, 143 4-aryl-2-(trifluoromethyl)-5(2H)-oxazolones, 143 5(2H)-oxazolones, 145 4-methyl-2-phenyl-5(4H)-oxazolone, 289 dehydroamino acid derivatives, 235 electron deficient unsaturated compounds, 143, 145 mesoionic oxazolones (munchnones), 195–197

Subject Index dimethyl acetylenedicarboxylate, 196 triphenylvinylphosphonium bromides, 196 Michael addition, 143 Pyrrolidinedione, 194 Pyrroline-2-carboxylic acid esters, 167 Pyrrolo[60]fullerene, 198 Pyrrolooxazolidinones, 29 Pyrrolophenanthridine alkaloids, 462 4(3H)-Quinazolinones, 296 Quinolizidines, trans, 97 Racemization, 131, 134, 206 4-alkyl-5(2H)-oxazolones, 134 electronic effects, 134 kinetics, 134 1 H NMR studies of racemization kinetics, 206 steric effects, 134 Radical additions of 2(3H)-oxazolones, 25, 27–32 alkenyl radicals to 2(3H)-oxazolones, 30–31 morphinan, 30–31 oxazolidinopiperidines, 30 alkyl radicals to 3-acetyl(acyl)-2(3H)oxazolone(s), 25, 27–28 diastereoselectivity, 27 preparation of bleomycins, 28 preparation of cyclosporins (MeBmt), 28 preparation of difluorostatine, 28 preparation of b-hydroxy-a-amino acids, 28 polyhalomethanes, 25, 27 alkyl radicals to 3-bromoalkyl-2(3H)oxazolone(s), 29 enantioselectivity, 29 intramolecular addition, 29 pyrrolooxazolidinones, 29 alkyl radicals to oxazolyl aldehydes, 29–30 amino alcohols, 29 (þ)-bulgecinine, 29 ()-desoxoprosopinine, 29 intramolecular, 29 polymers, 32, 40 2(3H)-oxazolone co-polymers, 32, 40 2(3H)-oxazolone homopolymers, 32, 40 chemoselective acylating reagents, 32 regioselective acylating reagents, 32 Raman spectroscopy, 206 saturated 5(4H)-oxazolones, 206 Rearrangements of oxazoles, synthesis of saturated 5(4H)-oxazolones, 155–160, 160 see Claisen rearrangements see sigmatropic rearrangements Reductions, 256–257, 282, 440–442, 577–579, 578, 579, 587

673

4-benzyl-2-methyl-5(4H)-oxazolone, 256 5(4H)-oxazolones, unsaturated, 256–257, 282 electrochemical, 282 hydrogenation, 256–257, 258 amino acids, 258 amino esters, 258 amino alcohols, 258 saturated 5(4H)-oxazolones, 256–257 bis(oxazolines), 577–579, 578, 579, 587 a-alkoxy ketones, 587 hydrosilylation, 577–579, 578 of acetophenone, 577–579, 578 py-box-ip, 578 transfer hydrogenation of ketones, 578–579, 579 oxazolines, 440–442 borane, 442 catalytic transfer hydrogenation, 441 hydrogenation, 440–441 lithium aluminum hydride, 442 preparation of amino alcohols, 440–442 preparation of azithromycin, 441 preparation of oxazolidines, 440 preparation of pseudodistomins, 441–442 Reductive photocyclization, oxazoline synthesis, 417 bicyclic oxazolines, 417 4-acyl-2-phenyloxazoles, 417 pseudodistomins, 417 Regioselective acylating agents, 32 Regioselective protection, 38–40 amino alcohols, 38 amino phenols, 38 Boc-Ox, 40 Cbz-Ox, 40 polyalcohols, 40 polyamines, 38 Reviews, oxazolines, 332, 333, 410, 442, 447, 448, 460, 468, 469, 476, 482, 483, 487, 493, 495, 503, 504, 508, [3 þ 2] cycloadditions of 5-alkoxyoxazoles and aldehydes, 410 asymmetric allylic alkylation, 487 asymmetric catalysis, 482 asymmetric cyclopropanation, 504 asymmetric hydrosilylation, 503 asymmetric Michael addition, 504 coordination chemistry of oxazolines, 460, 483 Diels-Alder reactions of 2-alkenyloxazolines, 447 dipolar cycloaddition reactions of oxazoline N-oxides, 447 enantioselective hydrogenation, 495

674

Subject Index

Reviews, oxazolines (Continued) Heck reactions, 493 oxazolines, 332, 333, 442, 448, 468, 469, 476 polymeric oxazolines, 508 Ring contractions, 100, 105–106 5-aryl-2,4-oxazolidinediones, 105 5-heteroaryl-2,4-oxazolidinediones, 105 spirocyclic 2,4-oxazolidinediones, 100 of alloxans to spirocyclic 2,4oxazolidinediones, 100 of barbituric acids, oxidative, 105 of uric acid, 106 Ritter reaction of nitriles, 395–398, 398 2-aminooxazolines, 396 bis(oxazolines), 396 cis-oxazolines, 395 cyanamide, 396 Indinavir, 395 inversion of configuration, 396 preparation of cis-1-amino-2-indanol, 395 preparation of C2-symmetric bis(oxazolines), 396 preparation of a-furfuryl amides, 397 preparation of Taxol side chain, 397 retention of configuration, 396 with alkenes, 397, 398 with 1,3-dioxolanes, 396 with epoxides, 396 with furfuyl carbinol acetates, 397 with cis-indane-1,2-diol, 396 with olefins, 396–397 (R)-()-Rolipram, 348 RTEM-1-b-lactamase inhibitors, 343 Sarains A-C, 437 Schiff bases, 246, 247 ring opening of unsaturated 5(4H)-oxazolones, 246, 247 N-(benzoyl)dehydroamino acid amides, 246 imidazolones, 2-styryl-1-substituted, 246, 247 Seebach protocol, 436 Sensitizing dyes, 284 ent-Shikimic acid, 554 Sigmatropic rearrangements, 7, 16, 136–139, 138, 155–158, 160 2-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(2H)-oxazolones, 158 2-allyl-4-phenyl-5(2H)-oxazolones, 137 5(2H)-oxazolones, 138 allyl substituted 5(2H)-oxazolones, 136 [1,3], 136 [3,3], 136

irradiation, 136 pyridines, 137 thermolysis, 136 4-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(4H)-oxazolones, 158 4-acyl-5(4H)-oxazolones, 159 4-benzyl-2-phenyl-4-(trifluoromethyl)-5(4H)oxazolone, 158 5(4H)-oxazolones, 155–159, 160 saturated 5(4H)-oxazolones, 160 1,3-benzyl shift, 158 5-acyloxyoxazoles, 159 5-alkoxyoxazoles, 138, 155–158, 160 Claisen rearrangement, 155–158 2(3H)-oxazolones, 7, 16 [3,3], 7, 16 allyloxyoxazoles, 7 enamines from oxime O-carbonates, 16 Silyl ketenes, 587 Sirenin, 544 Sodium cyanodithioformate, 139, 140 4-(alkylthio)-5(2H)-oxazolones, 139, 140 ketones, 139, 140 thiazolones, 139 Somatostatin, 242 Sonication or ultrasound, 47, 226, 284 unsaturated 5(4H)-oxazolones, 226, 284 nucleophilic ring opening reactions, 226 synthesis of esters, 284 Sorbinil, 171 4,8-Sphingadienine, 352 D-erythro-Sphingnosine, 352 Spirocyclic oxazolines, 417, 424, 508 Spirocyclopropanes, 206, 207, 261, 263, 265, 266, 270, 297 Spiroisoxazolines, 268, 268 Spirooxazolones, 207, 218, 261 Spirooxetanes, 35, 36 Spiropyrazolines, 218, 265, 267 Staphylococcus aureus inhibitors, 85 Statine(s), 24, 26, 28 Staudinger-aza-Wittig reaction, synthesis of oxazolines, 412–413 Staurosporine, 394 Stille coupling (reaction), 36, 220, 220, 508 chiral 2-substituted oxazolines, 508 chiral 2-halooxazolines, 508 Stizolobinic acid, 231 Structural analyses, 132, 134, 206–208, 280, 282, 284–286, 291, 299 saturated 5(4H)-oxazolones, 206–208 chromatographic mobility, 206 1 H NMR spectrometry, 132, 134, 206

Subject Index IR spectroscopy, 206 luminescence properties, 206 mass spectrometry, 206 Raman spectroscopy, 206 x-ray crystal structures, 207–208 unsaturated 5(4H)-oxazolones, 280, 284–286, 299 chromatographic mobility, 286 dipole moment, 286 13 C NMR spectrometry, 285 1 H NMR spectrometry, 280, 284, 285 IR spectroscopy, 284 fluorescence properties, 284 Hammett constants, 284 mass spectrometry, 285–286 UV-visible spectroscopy, 284 x-ray crystal structure(s), 286, 299 Styrene, 538–541, 575 aziridination, 575 cyclopropanation, 538–541 Sulfilimines, 56–57, 57, 413 2-substituted oxazolines, 413 Michael addition, 413 5,5-diphenyl-2-substituted-4(5H)-oxazolones, 56–57, 57 Sulfimidation, 480, 576 diastereoselective, 480 Sulfomycin I, 66 Sulfoximides, 42 Supercritical carbon dioxide, 499 Suzuki coupling, 462 ()-Swainsonine, 390 Synthetic fiber dyes, 209, 210 Tamao oxidation, 469 Tandem Erlenmeyer condensationmacrolactamization (TECM), 237 20 -epi-Taxol, 358 Taxol, 347, 358, 423, 422–423 Telomerization, 27 Testerone 5a-reductase inhibitors, 342 Tetracycline ring A analogues, 60 ent-
1-Tetrahydrocannabinol, 554 Tetrahydrofuropyrrole, 148 Tetrahydroisoquinolines, 426, 572 Tetrahydrooxazolopyrimidines, 476 Tetrahydropyridones, 558 2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical (TEMPO), 289, 290 Tetramethylfluoroformamidinium hexafluorophosphate (TFFH), 287 Tetrodotoxin, 390 Thiangazole, 363, 367

675

1,3-Thiazines, 251 2,4-Thiazolidinediones, 17–18 5-aryl-2-(3H)-oxazolones, 17–18 Thiazolines, 427–429, 430 from thiolysis of oxazolines, 427–429 from thioamides, 430 Thienopyridines, 255 Thietane N-acylimines, 509 a-Thioorganolithium additions, 588 Three component condensation, synthesis of 2(3H)-oxazolones, 18–20 3-substituted-2(3H)-oxazolones, 18 primary amines, carbon dioxide, and a-halo ketones, 18 propylamine, carbon dioxide, and propargyl alcohols, 20 Thromboxane A2 receptor antagonist, 352, 353, 373, 448 a-Tosyl acetanilides, 105 Tranquilizers, 54 Transfer hydrogenation, see reductions, transfer hydrogenation Trehazolin, 424 Triazines, 172, 245 Triazinones, 510 1,2,4-Triazoles, 64, 65, 66, 176, 198, 222, 249, 251 1,5-diaryl-3-carboxamides, 176 from 4(5H)-oxazolones, 65, 66 from oxazolonium salts, 64 fused, 222 1,2,4-Triazolines, 82 1,2,4-Triazolium salts, 18 3-(2-pyrimidinyl)-2(3H)-oxazolone, 18 5-phenyl-3-(2-pyridinyl)-2(3H)-oxazolone, 18 2-iminooxazolines, 18 N-ylide intermediates, 18 1,2,4-Triazolones, from 2,4-oxazolidinediones and hydrazine, 117 Trichloroacetimidates, 389, 391–395 20 -amino-20 -deoxycytidine, 393 20 -amino-20 -deoxyuridine, 393 bis(trichloroacetimidates), 394 staurosporine, 394 vinylogous Schmidt glycolsylation, 394 diethylaluminum chloride, 392 from allylic alcohols, 389, 390 from cyclic sulfates, 393 (þ)-mannostatin, 391 Trichloroacetonitrile, 381, 383, 389, 393 Trifluoromethylsulfenylation of b-keto acids, 60 Trimethadone, 90, 99, 120 Triphenylphosphonium methylides, 192, 193

676

Subject Index

Tryptamine, 237 condensation with unsaturated 5(4H)-oxazolones, 237 Pictet-Spengler reaction, 237 Ullmann coupling, 464–468, 466, 476 axially chiral biaryls, 464–468 diastereoselectivity, 466 (S)-gossypol, 466–468 ()-mastigophorene A, 465–466 Ungeremine, 462 Unsaturated 5(4H)-oxazolones, ring opening reactions, 243–256, 244, 247, 249, 295 see aminolysis, 5(4H)-oxazolones, unsaturated see hydrolysis and alcoholysis, unsaturated 5(4H)-oxazolones 1,3-bis(nucleophiles), 247–254, 295 C,C-bis(nucleophiles), 252 disubstituted enamines, 252 phosphonium ylides, 252 C,N-bis(nucleophiles), 251–252 enamines, 251 iminophosphoranes, 251 C,O-bis(nucleophiles), 252–254 1,3-dimethyl acetonedicarboxylate, 254 N,N-bis(nucleophiles), 247–249, 249, 251, 295 1,8-diaminonaphthalene, 248 S-alkylisothiouronium salts, 249 anilines, 249 heterocyclic amines, 249 heterocyclic hydrazines, 249 hydrazidimide, 251 Michael reaction, 248–249 o-phenylenediamine, 248 thiourea, 249 urea, 249 N,O-bis(nucleophiles), 247 anthranilic acid, 247 N,S-bis(nucleophiles), 248, 249–251, 249 o-aminothiophenol, 248 Michael reaction, 250 substituted anilines, 249 preparation of 3,1-benzoxazinones, 247 benzimidazoles, 248, 249 benzothiazoles, 248, 249 dihydrobenzoxazoles, 252 dihydropyridones, 252 a-(heteroaryl)glycinates, 249 imidazobenzimidazoles, 248 imidazolones, 248, 249, 250 perimidine, 248

pyran-2-ones, 252, 254 pyridones, 251–252 pyrimidines, 250 thiazines, 251 Friedel-Crafts reactions, 255 intramolecular ring opening, 256 coumarins, 256 Friedel-Crafts reaction, 255 thienopyridines, 255 miscellaneous nucleophiles, 254–256 active methylene compounds, 254 aromatic hydrocarbons, 255 Friedel-Crafts reaction, 255 hydride reduction, 254 N-phenacylpyridinium bromide, 254 phenyl isothiocyanate, 254 preparation of coumarins, 256 oxazolo[5,4-b]pyridines, 254 pyrimidine-2-thiones, 254 thienopyridines, 255 nitrogen nucleophiles, 243–247, 244, 247 hydrazides, 246 bis-acylhydrazides, 246 pyrazoles, 246 hydrazines, 243–244, 244 (E)-a-acylamino hydrazides, 244, 244, 247 aminoimidazolones, 243, 244 dehydroamino acid hydrazides, 244 pyrazolinoxazolines, 245 triazines, 245 Schiff bases, 246–247, 247 N-(benzoyl)dehydroamino acid amides, 247 imidazolones, 2-styryl-1-substituted, 246, 247 see aminolysis, 5(4H)-oxazolones, unsaturated see hydrolysis and alcoholysis, unsaturated 5(4H)-oxazolones Unsaturated 5(4H)-oxazolones, synthesis of unsaturated 5(4H)-oxazolones, 172–174, 217–225, 218, 220, 221, 224, 293, 294 from saturated 5(4H)-oxazolones, 172–174 4-(aminomethylene)-2-phenyl-5(4H)oxazolones, 174 unsaturated 5(4H)-oxazolones, 172–173 reaction of 2-phenyl-5(4H)-oxazolone, 172–174 2-dimethylaminomethylene-1,3cyclohexanediones, 173 2-dimethylaminomethylene-3-oxoalkanoates, 173 enamines, 172 formamidines, 174

Subject Index from unsaturated 5(4H)-oxazolones, 217–225, 218, 220, 221, 224, 293, 294 2-alkyl-4-[(alkylamino)methylene]-5(4H)oxazolones, 294 2-aryl-4-(hydroxymethylene)-5(4H)oxazolones, 223 4-(alkylaminomethylene)-2-phenyl-5(4H)oxazolones, 225 4-(alkylthiomethylene)-2-phenyl-5(4H)oxazolones, 223 4-(alkylthiomethylene)-5(4H)-oxazolones, 223, 224 4-(aminomethylene)-2-phenyl-5(4H)oxazolones, 221 4-(aminomethylene)-5(4H)-oxazolones, 221, 293 4-(a-arylethylidene)-5(4H)-oxazolones, 218, 218 4-(N,N-disubstituted-1-aminoalkylidene)5(4H)-oxazolones, 223 4-(N-substituted-aminomethylene)-2(1-naphthyl)-5(4H)-oxazolones, 294 4-[(1,2,4-oxadiazol-3-yl)aminomethylene]-2phenyl-5(4H)-oxazolone, 225 4-[(imidazol-1-yl)methylene]-2-phenyl5(4H)-oxazolone, 219 4-[(N-cycloalkenyl)aminomethylene]-5(4H)oxazolones, 224 4-[2-hydroxy-3-(aminomethyl)benzylidene]5(4H)-oxazolones, 217 4-arylidene-2-phenyl-5(4H)-oxazolones, 220, 220 4-heteromethylene-2-substituted-5(4H)oxazolones, 218 phosphorylated oxazolones, 220 N-acyl-a-(triphenylphosphonio)glycinates, 220 addition-elimination reaction(s), 218, 221 cationic glycine equivalents, 220 diazomethane, 218 1,3-dipolar cycloaddition reactions, 217 4-arylidene-5(4H)-oxazolones, 218 diazomethane, 218 homologation, 218 Mannich reactions, 217 reaction of 2-alkyl-4-(N,N-dimethylaminomethylene)5(4H)-oxazolones, 294 transamination with alkylamines, 294 2-aryl-4-(dimethylaminomethylene)-5(4H)oxazolone, 223 hydrolysis, 223 4-(2-hydroxybenzylidene)-5(4H)oxazolones, 217

677

Mannich reaction, 217 4-(aminomethylene)-2-phenyl-5(4H)oxazolone, 223, 224 carbon disulfide, 223 enamines, 224 4-(aminomethylene)-2-substituted-5(4H)oxazolones, 224 transamination, 224 4-(aminomethylene)-5(4H)-oxazolones, 223, 224 alkylation, 223 4-(anilinomethylene)-2-phenyl-5(4H)oxazolone, 225 transamination with alkylamines, 225 4-(chloromethylene)-2-phenyl-5(4H)oxazolone, 219–221, 220 imidazole, 219 mercaptans, 220 organostannanes, 220 sodium thiomethoxide, 220 Stille reaction, 220, 220 triphenylphosphine, 221 4-(dichloromethylene)-2-phenyl-5(4H)oxazolone, 221 4-(N,N-dimethylaminomethylene)-2-phenyl5(4H)-oxazolone, 225 transamination with alkylamines, 225 4-(ethoxymethylene)-2-(1-naphthyl)-5(4H)oxazolone, 294 amino acids, 294 4-(ethoxymethylene)-2-phenyl-5(4H)oxazolone, 221 amines, 221 imidazole, 222 indole, 222 4-(ethoxymethylene)-5(4H)-oxazolones, 293 amines, 293 4-(heteromethylene)-5(4H)-oxazolones, 221 4-(hydroxymethylene)-2-phenyl-5(4H)oxazolone, 222, 225 hydrazines, 222 4-[1-(dimethylamino)ethylidene]-2-phenyl5(4H)-oxazolone, 225 transamination, 225 4-[2-bromo-1-(dimethylaminoethylidene)]-2phenyl-5(4H)-oxazolone, formamidines, 225 4-[(cyanoamino)methylene]-2-phenyl-5(4H)oxazolone, 225 4-[(N-heteroaryl-N-methyl)aminomethylene]2-phenyl-5(4H)-oxazolones, transamination, 224 4-arylidene-5(4H)-oxazolones, 217, 218, 218

678

Subject Index

Unsaturated 5(4H)-oxazolones, synthesis of unsaturated 5(4H)-oxazolones (Continued) 1,3-dipolar cycloaddition, 217 diazomethane, 217, 218 spirooxazolones, 218 spiropyrazolines, 218 transaminations, 224, 225 alkylamines, 225 a-amino acid derivatives, 224 enamines, 224 formamidines, 225 UV-absorbing layers, 209 UV-visible spectroscopy, 284 unsaturated 5(4H)-oxazolones, 284 prototropic equilibrium constants, 284 Vancomycin, 462 ()-Veadeiroic acid, 341 Vilsmeier (Vilsmeier-Haack) reagent, 216, 217, 294, 347–348, 348 2-alkyl-4-[(N,N-dimethylamino)methylene]5(4H)-oxazolones, 294 4-(dimethylaminomethylene)-5(4H)oxazolones, 216 unsaturated 5(4H)-oxazolones, 217 N-acylamino acid derivatives, 217, 294 Vinchlozolin, 90, 120 Vinylogous Schmidt glycosylation, 394 Vorbru¨ggen’s methodology, 333–334 W-3681, 113 Wacker-type cyclizations, 580 dihydrobenzofurans, 580 [2,3]-Wittig rearrangements, 443, 573–574 stereoselective, 443 Wittig olefination / reaction / reagents, 21, 175–176, 192, 193 2-phenyl-4-(phosphoranylidene)-5(4H)oxazolone, 175 4-(1-benzyloxybenzylidene)-2-phenyl-5(4H)oxazolone, 176 4-(1-chloroalkylidene)-2-phenyl-5(4H)oxazolones, 176 4-(phosphoranylidiene)-2-substituted 5(4H)oxazolones, 176 4-alkyl-2-phenyl-5(4H)-oxazolones, 176

(Z)-4-(benzylidene)-2-phenyl-5(4H)oxazolone, 175 fluorooxazolones, 175 of 2-phenyl-4-(phosphoranylidene)-5(4H)oxazolone, 175–176 acyl bromides, 176 acyl chlorides, 176 acyl iodides, 176 alkyl halides, 176 benzaldehyde, 175 of 5(4H)-oxazolones with triphenylphosphonium methylides, 192, 193 of 5(4H)-oxazolylideneacetates, 192, 193 X-ray crystal structure(s), 61, 72, 75, 89, 207–208, 286, 291, 292, 299, 377, 452, 455, 458, 469, 479, 489, 491, 494, 498, 501, 503, 504, 512, 533–534 (þ)-Xanthorrhizol, 343, 446 Xenalipin, 451 Xylitol, 389 Ylides, 18, 192, 193, 252, 260–261, 261 N-ylides, 18 phosphonium ylides, 252 triphenylphosphonium methylides, 192, 193 sulfur ylides, 260–261, 261 Ynamines, 148, 149, 410 3-alkyl-substituted aspartic acid derivatives, 148, 149 reaction with 2,2-bis(trifluoromethyl)-5(2H)oxazolone, 148 Zinc, reactions and organozinc reagents, 451, 501, 502, 565, 567, 570, 571, 572, 573, 587 alkyl, 570, 572 allyl, 571 allylzincation, 573 dialkylzinc reagents, 501, 502 asymmetric addition to aldehydes, 502 diethylzinc, 587 Negishi cross-couplings, 451 aryl ketones, 451 biaryls, 451 triflate, 567, 587

Subject Index

679

Oxazolines and Bis(Oxazolines) – General Classes Bis(oxazoline)-metal complexes, 532–534, 546, 552, 554, 561, 565, 567, 568, 575 Bis(oxazoline) ligands, 530–532, 582–585 aza-bis(oxazolines), 394, 588 benzyl bis(oxazoline), 533, 541 (BINOL)-box, 587 bis(oxazolinyl)pyridine, see py-box bu-box, 530, 532, 535–536, 539, 540, 541, 548, 552, 555, 557, 559, 561, 565, 566, 570, 581, 585, 589 DBF-box, 534, 550, 551 ferrocene-box, 563, 564 inda-box, 534, 537, 549, 549, 557, 559, 567, 574–575, 577, 589 phe-box, 530, 532, 534, 536, 546, 548, 549, 555, 557, 561, 567, 567, 575, 581 i-pr-box, 534, 535, 548, 561, 570, 572 py-box, 530, 534, 551, 565–566 py-box-ip, 534, 540–541, 578 Oxazoline ligands, 448, 452, 453–454, 456, 457, 461, 482, 483–485, 486, 487, 488, 490, 491, 492, 493, 494, 495, 498, 499, 501, 503, 504, 505, 506, 507 ferrocenyloxazoline ligands, 452, 453–454, 456, 457, 491, 501 hydroxy-oxazolines (HydrOx), 483, 488, 501, 507 oxazoline-carbene ligands, 498, 499 phosphinooxazolines ligands (PhosOx), 448, 461, 482, 483–485, 490, 491, 492, 493, 494, 501, 503, 504, 507 phosphite-oxazoline ligands, 504, 505 pyridine-oxazolines (PyrOx), 483, 486, 495, 503, 504, 506 quinoline-oxazoline ligands, 483 selenide-oxazolines (SelOx), 483, 488 sulfide-oxazolines (SulfOx), 483, 487, 504 Oxazolines 2-(a-acyloxy)oxazolines, 417 2-(cis-alkenyl)-substituted oxazolines, 444 2-(trans-alkenyl)-substituted oxazolines, 444 2-(chloromethyl)oxazolines, 443, 444 2-(ortho-fluorophenyl)oxazolines, 461 2-(trichloromethyl)oxazolines, 427 2-alkenyloxazolines, 442, 445–446, 447, 476, 477 2-alkyloxazolines, 332, 435, 442, 444, 445, 508 2-allyloxymethyloxazolines, 443 2-amino substituted oxazolines, 424 2-aminooxazolines, 394, 396, 408, 410, 424, 512

2-aryloxazolines, 332 2-biphenylmethyloxazolines, 443 2-bromooxazolines, 435, 508 2-halooxazolines, 508 2-heteroaryloxazolines, 384 2-iminooxazolines, 410 2-monosubstituted oxazolines, 338 2-oxazoline substituted epoxides, 444 trans-2-oxazoline-4-carboxylates, 410 cis-2-oxazolines, 408 trans-2-oxazolines, 408 2-phenyl substituted oxazolines, 383 2-stannyloxazolines, 508 2-substituted oxazolines, 413, 435 2-substituted oxazolines, chiral, 508 2-thio substituted oxazolines, 423 2-thiooxazolines, 424 2,4-diaryloxazolines, 430 2,4-disubstituted oxazolines, 398, 400 2,4,5-trisubstituted oxazolines, 407, 415, 442 2,5-disubstituted oxazolines, 398 4-(alkylamino)-2-phenyloxazolines, 382 4-(cyclopropyl)oxazoline carboxylates, 376 4-(hydroxymethyl)oxazolines, 480 4-(methoxymethyl)oxazolines, 480 4-monosubstituted oxazolines, 338 4-substituted oxazolines, 338 4,4-oxazolinedicarboxylic acid diesters, 439 4,5-disubstituted oxazolines, 344, 345, 428 cis-4,5-disubstituted oxazolines, 344, 345, 428 trans-4,5-disubstituted oxazolines, 344, 345 5-(alkylidene)oxazoline, 512 5-(vinylidene)oxazoline, 512 5-monosubstituted oxazolines, 338 5-substituted oxazolines, 338 trans-5-vinyl substituted oxazolines, 404 o-aminophenyloxazolines, 336 anomeric oxazolines, 431–432 arylmethyloxazolines, 443 aryloxazolines, 333, 458 aza-bis(oxazolines), 394, 588 bicyclic oxazolines, 407, 417, 441 bis(oxazolines), 347, 361, 384, 396, 417, 457, 465, 466, 481, 504 tert-butyloxazolines, 466 ferrocenyloxazolines, chiral ligands, 452, 453– 454, 456, 457, 491, 501 ortho-fluoroaryloxazolines, 461 hydroxy-oxazolines (HydrOx), 483, 488, 501, 507 glucofuran[2,1-d]oxazolines, 349

680

Subject Index

ortho-methoxyaryloxazolines, 461 multiply substituted oxazolines, 338, 384 oxazoline acrylate esters, 477 oxazoline aldehydes, 477 oxazoline epoxides, 444 oxazolines, 332, 333–338, 334–336, 337, 339, 340–344, 345, 346, 347, 348, 348, 351, 352–357, 358, 359, 360, 361–363, 365, 366, 367, 369, 370–371, 373, 373–375, 375–376, 381, 383, 385–386, 388–389, 389, 390, 391, 392, 394, 398, 401, 402, 406, 407, 408, 409, 410, 411, 412–413, 415, 417, 419–421, 423, 424, 425, 426– 427, 427, 428–429, 433, 437, 438–439, 440, 441, 442, 443, 444, 448, 451–452, 457, 458, 460, 462, 462, 463, 464, 466, 469, 470, 474, 475, 476, 478, 479, 480, 481 cis-oxazolines, 347, 358, 364, 367, 395, 408, 436, 439 trans-oxazolines, 346, 358, 364, 367, 404, 408, 436, 439 oxazoline-4-carboxylic acid esters, 437 oxazoline-carbene ligands, 498, 499 oxazoline-sulfoxide ligands, 479 oxazoline N-oxides, 416–417, 447

oxazolinecarboxylates, 378, 430 oxazolinium iodides, salts, triflates, 433 oxazolinyl aryl sulfides, chiral, 448 oxazolinylferrocenes, 452, 453–454, 455–456, 457, 501 oxazolinylnaphthalenes, 469, 472–473, 474– 475 phosphinooxazolines ligands (PhosOx), chiral, 448, 461, 482, 483–485, 490, 491, 492, 493, 494, 501, 503, 504, 507 phosphite-oxazoline ligands, 504, 505 platinum complexes, 387 polymeric oxazolines, 332, 507–508 pyridine-oxazolines (PyrOx), 483, 486, 495, 503, 504, 506 quinoline-oxazolines, 483 selenide-oxazolines (SelOx), 483, 488 spirocyclic oxazolines, 377, 417, 424, 509 sulfide-oxazolines (SulfOx), 483, 487, 504 tetrasubstituted oxazolines, 426 tricyclic oxazolines, 410, 461 tricyclic phosphinooxazolines, 461 tris(oxazolines), 430 unsubstituted oxazolines, 384

Oxazolines 2-(2-methylphenyl)oxazoline, 448 2-(chloromethyl)-4,4-dimethyloxazoline, 443 2-(ortho-chlorophenyl)-4,4-dimethyloxazoline, 461 2-phenyloxazoline, 435, 458 3-methoxy-(2-oxazolinyl)naphthalene, 475 4,4-dimethyl-2-(1-naphthyl)oxazoline, 469

4,4-dimethyl-2-(2-propenyl)oxazoline, 477 4,4-dimethyl-2-(2,3,4-trimethoxyphenyl)oxazoline, 466 4,4-dimethyl-2-phenyloxazoline, 448 trans-4,5-diphenyloxazolinylferrocene, 456 oxazoline, 435

Oxazolones – General Classes 2(3H)-Oxazolones 2(3H)-oxazolone-4-carboxylates, 47, 48 2(3H)-oxazolones, 2, 3, 4, 7, 14, 18, 20, 21, 21, 22, 24, 25, 30, 31, 32, 34, 36, 38, 40, 42, 45, 47 3-(2-exo-alkoxy-1-apocamphanecarbonyl)2(3H)-oxazolones, 24, 27, 32, 35 3-acyl-2(3H)-oxazolones, 25, 26, 32, 33, 38, 40 3-acyl-4,5-unsubstituted-2(3H)-oxazolones, 23 3-alkoxycarbonyl-2(3H)-oxazolones, 38 3-alkyl-2(3H)-oxazolones, 15

3-alkyl-4,5-disubstituted-2(3H)-oxazolones, 16, 17 3-allyl-4,5-diphenyl-2(3H)-oxazolones, 7 3-aryl-5-tert-butyl-2(3H)-oxazolones, 3, 4 3-aryl-5-substituted-2(3H)-oxazolones, 12 3-bromoalkyl-2(3H)-oxazolones, 29 3-phenyl-2(3H)-oxazolones, 20 3-substituted 2(3H)-oxazolones, 18 3,4,5-triaryl-2(3H)-oxazolones, 8 3,4,5-trisubstituted-2(3H)-oxazolones, 35 4-aryl-5-phenyl-2(3H)-oxazolones, 3

Subject Index 4,5-diaryl-2(3H)-oxazolones, 46 4,5-diphenyl-2(3H)-oxazolones, 10 4,5-diphenyl-3-substituted-2(3H)-oxazolones, 23 4,5-disubstituted-2(3H)-oxazolones, 10, 22 5-acyl-4-methyl-2(3H)-oxazolones, 36 5-alkoxy-2(3H)-oxazolones, 7, 9, 42, 43, 43, 44 5-alkyl-3-aryl-2(3H)-oxazolones, 12, 13 5-alkyl-3-aryl-4-halo-2(3H)-oxazolones, 12, 14 5-aryl-2(3H)-oxazolones, 17, 18 5-methyl-2(3H)-oxazolone sulfonamides, 36 5-phenyl-2(3H)-oxazolones, 6 5-substituted-2(3H)-oxazolones, 3 bicyclic 2(3H)-oxazolones, 10 ethyl 2(3H)-oxazolone-4-carboxylates, 48 stannyloxazolones, 36 2(5H)-Oxazolones 2(5H)-oxazolones, 7, 46 4,5-diaryl-5-methoxy-2(5H)-oxazolones, 46 5-chloro-4,5-diaryl-2(5H)-oxazolones, 46 5-substituted-2(5H)-oxazolones, 45 4(5H)-Oxazolones including 2,4-Oxazolidinediones and 4,5-Oxazolediones 2-(arylimino)-4(5H)-oxazolones, 70 2-[2-(a-heteroaryl)ethenyl]-4(5H)-oxazolonium perchlorates, 64 2-alkoxy-4(5H)-oxazolones, 89, 91, 92, 94 2-alkyl-4(5H)-oxazolones, 55, 121 2-amino-4(5H)-oxazolones, 53, 54, 55, 67, 68, 70, 72, 82 2-amino-5-(carboxyalkyl)-4(5H)-oxazolones, 77, 78 2-amino-5-substituted-4(5H)-oxazolones, 75 2-aryl-4(5H)-oxazolones, 53, 55, 66, 121 2-aryl-5,5-dimethyl-4(5H)-thiooxazolones, 121 2-ethoxy-4(5H)-oxazolones, 93 2-hydroxy-3-unsubstituted-4(5H)-oxazolones, 89 2-methyl-4(5H)-oxazolonium perchlorates, 63, 64 4(5H)-oxazolones, 53, 54, 55, 57, 58, 60, 61, 63, 65, 66, 78, 80, 84, 85, 88, 120, 121 4(5H)-oxazolonium salts, 59, 63 4(5H)-thiooxazolones, 59, 121 4-(alkylimino)-2-ethoxy-4(5H)-oxazolones, 89 4-(arylimino)-2-ethoxy-4(5H)-oxazolones, 89 4-alkoxy-5-substituted-4(5H)-oxazolones, 94 5-(benzylidene)-2-substituted-4(5H)oxazolones, 76 5-acyloxy-4(5H)-oxazolonium salts, 59 5,5-diphenyl-2-substituted-4(5H)-oxazolones, 56, 57 oxazolonium salts, 64

681

spirocyclic 2-amino-4(5H)-oxazolones, 71, 72, 73 spirocyclic 4(5H)-oxazolones, 57 2-hydroxy-4(5H)-oxazolones, 89, 94 2-thio-2,4-oxazolidinediones, 116 2,4-oxazolidinediones, 72, 82, 89, 90, 94, 99, 100, 103, 105, 106, 107, 108, 109, 109, 110, 116 3-(arylideneamino)-2,4-oxazolidinediones, 90 3-alkoxy-2,4-oxazolidinediones, 91 3-alkyl-2,4-oxazolidinediones, 90, 109 3-amino-2,4-oxazolidinediones, 90 3-aryl-2,4-oxazolidinediones, 90, 108 3-substituted-2,4-oxazolidinediones, 91, 94, 108 3-unsubstituted-2,4-oxazolidinediones, 94 3,5-dialkyl-2,4-oxazolidinediones, 103 3,4,5-trialkyl-2,4-oxazolidinediones, 103 4-alkoxy-5-substituted-4(5H)-oxazolones, 94 5-(arylidene)-2-thio-2,4-oxazolidinediones, 114 5-(arylidene)-2-thio-4-oxazolidinones, 110 5-(benzylidene)-2,4-oxazolidinediones, 114 5-alkenyl-2,4-oxazolidinediones, 113 5-alkyl-2,4-oxazolidinediones, 109, 113 5-aryl-2,4-oxazolidinediones, 100, 105 5-benzyl-2,4-oxazolidinediones, 111 5-heteroaryl-2,4-oxazolidinediones, 101, 105 5-substituted-2,4-oxazolidinediones, 96 5,5-disubstituted-2,4-oxazolidinediones, 109 N-alkylated-2,4-oxazolidindiones, 108 N-aroyl-2,4-oxazolidinediones, 109 N-arylsulfonyl-2,4-oxazolidinediones, 109 spirocyclic 2,4-oxazolidinediones, 96, 97, 98, 100, 101, 102, 103 2-alkenyl-4,5-oxazolediones, 62 2-substituted-4,5-oxazolediones, 62 5(2H)-Oxazolones 2-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(2H)-oxazolones, 158 2-allyl-4-phenyl-5(2H)-oxazolones, 137 4-(alkylamino)-5(2H)-oxazolones, 142 4-(alkylthio)-5(2H)-oxazolones, 139, 140, 143 4-(arylthio)-5(2H)-oxazolones, 139, 141, 143 4-(dialkylamino)-5(2H)-oxazolones, 142 4-(N,N-dialkylamino)-5(2H)-oxazolones, 142 4-(phenylthio)-5(2H)-oxazolones, 140, 141 4-alkoxy-5(2H)-oxazolones, 140, 141, 142 4-alkyl-2-(trifluoromethyl)-5(2H)-oxazolones, 134, 145, 147 4-alkyl-5(2H)-oxazolones, 134 4-alkyl(aryl)-2-(trifluoromethyl)-5(2H)oxazolones, 143 4-aryl-2-(perfluoroalkyl)-5(2H)-oxazolones,133

682

Subject Index

4-aryl-2-(trifluoromethyl)-5(2H)-oxazolones, 143 5(2H)-oxazolone N-oxides, 149, 150 5(2H)-oxazolones, 131-133, 133, 135, 135, 136, 138, 138, 139, 143, 145, 146, 146, 148, 149, 151, 152, 160, 162, 179, 206 allyl substituted-5(2H)-oxazolones, 136 5(4H)-Oxazolones (E)-2-aryl-4-arylidene-5(4H)-oxazolones, 286 (Z)-2-aryl-4-arylidene-5(4H)-oxazolones, 286 (Z)-4-arylidene-2-phenyl-5(4H)-oxazolones, 273 (Z)-4-arylidene(heteroarylidene)-2-phenyl5(4H)-oxazolones, 274 1,4-phenylenebis(oxazolones), 239 2-(4-alkenylphenyl)-4,4-disubstituted-5(4H)oxazolones, 202 2-(4-nitrophenyl)-4-substituted-5(4H)oxazolones, 183 2-(aminomethyl)-5(4H)-oxazolones, 291 2-(trifluoromethyl)-5(4H)-oxazolones, 152, 186 2-[(9-fluorenylmethyl)oxy]-5(4H)-oxazolones, 177 2,20 -(m-phenylene)bis[4-arylidene-5(4H)oxazolones], 226 2-acyl-4-(dimethylaminomethylene)-5(4H)oxazolones, 215 2-alkenyl-4,4-dimethyl-5(4H)-oxazolones, 202 2-alkenyl-4,4-disubstituted-5(4H)-oxazolones, 201 2-alkenyl-5(4H)-oxazolones, 163 2-alkoxy-5(4H)-oxazolones, 208 2-alkyl-4-[(alkylamino)methylene]-5(4H)oxazolones, 294 2-alkyl-4-[(N,N-dimethylamino)methylene]5(4H)-oxazolones, 294 2-alkyl-5(4H)-oxazolones, 208 2-alkyl(aryl)-4-arylidene-5(4H)-oxazolones, 226 2-alkyl(aryl)-4-heteroarylidene-5(4H)oxazolones, 226 2-alkyl(aryl)-5(4H)-oxazolones, 171 2-aryl-4-(2-thienyl)-5(4H)-oxazolones, 255 2-aryl-4-(dimethylaminomethylene)-5(4H)oxazolones, 223 2-aryl-4-[(N,N-dimethylamino)methylene]5(4H)-oxazolones, 284 2-aryl-4-(hydroxymethylene)-5(4H)oxazolones, 223 2-aryl-4-arylazo-5(4H)-oxazolones, 176 2-aryl-4-arylidene-5(4H)-oxazolones, 214, 282 2-aryl-4-benzylidene-5(4H)-oxazolones, 255

2-aryl-4-cycloalkylidene-5(4H)-oxazolones, 283 2-aryl-4-phenyl-5(4H)-oxazolones, 136, 162 2-aryl-4-substituted-5(4H)-oxazolones, 154 2-aryl-4,5-oxazoledione-4-arylhydrazones, 176 2-aryl-5(4H)-oxazolones, 171, 176, 179 2-arylamino-4-arylidene-5(4H)-oxazolones, 214 2-arylthio-4-(dimethylaminomethylene)-5(4H)oxazolones, 215 2-benzyloxy-5(4H)-oxazolones, 177 2-ferrocenyl-5(4H)-oxazolones, 206 2-isopropenyl-5(4H)-oxazolones, 160 2-methyl-5(4H)-oxazolones, 246 2-phenyl-4-substituted-5(4H)-oxazolones, 163, 187, 203, 289 2-phenyl-5(4H)-oxazolones, 179, 183, 205, 247 2-substituted-4-(isoquinol-1-yl)-5(4H)oxazolones, 174 2-substituted-4-(quinol-2-yl)-5(4H)oxazolones, 174 2-substituted-5(4H)-oxazolones, 162 2-unsubstituted-5(4H)-oxazolones, 162 2-vinyl-5(4H)-oxazolones, 160 2,20 -(m-phenylene)bis[4-arylidene-5(4H)oxazolones], 226 2,20 -bis(oxazolones), 202 2,4-diaryl-4-(2,4-dinitroaryl)-5(4H)oxazolones, 167 2,4-diaryl-5(4H)-oxazolones, 167 2,4-disubstituted-5(4H)-oxazolones, 170 4-(1-chloroalkylidene)-2-phenyl-5(4H)oxazolones, 176 4-(2-hydroxybenzylidene)-5(4H)-oxazolones, 217 4-(3-phenoxybenzylidene)-2-substituted-5(4H)oxazolones, 209 4-(alkylaminomethylene)-2-phenyl-5(4H)oxazolones, 225 4-(alkylaminomethylene)-5(4H)-oxazolones, 228 4-(alkylthiomethylene)-2-phenyl-5(4H)oxazolones, 223 4-(alkylthiomethylene)-5(4H)-oxazolones, 224 4-(aminomethylene)-2-phenyl-5(4H)oxazolones, 174, 221, 223 4-(aminomethylene)-2-substituted-5(4H)oxazolones, 224 4-(aminomethylene)-5(4H)-oxazolones, 215, 221, 223, 224, 286, 293 4-(a-arylethylidene)-2-phenyl-5(4H)oxazolones, 285 4-(a-arylethylidene)-5(4H)-oxazolones, 218

Subject Index 4-(arylmethyl)-2-phenyl-4-(trifluoromethyl)5(4H)-oxazolones, 158, 186 4-(arylmethyl)-2-phenyl-5(4H)-oxazolones, 180 4-(chloromethylene)-5(4H)-oxazolones, 219 4-(dialkylaminomethylene)-5(4H)-oxazolones, 228 4-(N,N-dimethylaminomethylene)-2substituted-5(4H)-oxazolones, 225 4-(dimethylaminomethylene)-5(4H)oxazolones, 215 4-(N,N-disubstituted-1-aminoalkylidene)5(4H)-oxazolones, 223 4-(ethoxymethylene)-5(4H)-oxazolones, 293 4-(hydroxyalkyl)-substituted oxazolones, 184 4-(isoquinolin-1-yl)-2-substituted-5(4H)oxazolones, 174 4-(a-phenylethylidene)-2-phenyl-5(4H)oxazolones, 285, 286 4-(phosphoranylidene)-2-substituted-5(4H)oxazolones, 175 4-(phosphoranylidene)-5(4H)-oxazolones, 175 4-(pyren-1-ylmethylene)-2-substituted-5(4H)oxazolones, 209 4-(quinolin-2-yl)-2-substituted-5(4H)oxazolones, 174 4-(N-substituted-aminomethylene)-2-(1naphthyl)-5(4H)-oxazolones, 294 4-[2-hydroxy-3-(aminomethyl)benzylidene]5(4H)-oxazolones, 217 4-[(N-cycloalkenyl)aminomethylene]-5(4H)oxazolones, 224 4-[(N-heteroaryl-N-methyl)aminomethylene]-2phenyl-5(4H)-oxazolones, 224 4-acetoxy-2-substituted-4-(trifluoromethyl)5(4H)-oxazolones, 152 4-acyl-2-phenyl-5(4H)-oxazolones, 175 4-acyl-2,4-dialkyl-5(4H)-oxazolones, 287 4-acyl-2,4-disubstituted-5(4H)-oxazolones, 170 4-acyl-5(4H)-oxazolones, 159, 168, 169, 170 4-alkyl-2-phenyl-5(4H)-oxazolones, 176, 204, 206 4-alkyl-2-substituted-5(4H)-oxazolones, 193 4-alkyl-4-(iodomethyl)-2-phenyl-5(4H)oxazolones, 188 4-alkyl-5(4H)-oxazolones, 134 4-alkyl(aralkyl)-2-phenyl-5(4H)-oxazolones, 169 4-allenyl-2-phenyl-5(4H)-oxazolones, 156 4-arylethylidene-2-phenyl-5(4H)-oxazolones, 284 4-arylidene-2-phenyl-5(4H)-oxazolones, 212, 220, 220, 248, 254, 259, 284

683

4-arylidene-5(4H)-oxazolones, 209, 217, 218, 228, 238, 255, 282, 286 4-arylmethylene-2-[3-chlorobenzo[b]thien-2yl]-5(4H)-oxazolones, 292 4-arylmethylene-2-methyl-5(4H)-oxazolones, 296 4-arylmethylene-2-phenyl-5(4H)-oxazolones, 282, 295, 296 4-arylmethylene-5(4H)-oxazolones, 241, 263, 268, 296, 297 4-benzyl-2-substituted-5(4H)-oxazolones, 134 4-benzyl-5(4H)-oxazolones, 185 4-benzylidene-5(4H)-oxazolones, 286 4-bis[(benzylthio)methylene]-5(4H)oxazolones, 228 4-bis[(methylthio)methylene]-5(4H)oxazolones, 228 4-sec-butyl-5(4H)-oxazolones, 185 4-cycloalkylidene-2-phenyl(methyl)-5(4H)oxazolones, 282 4-cyclopropenyl-4-substituted-5(4H)oxazolones, 194 4-heteroarylmethylene-2-substituted-5(4H)oxazolones, 210 4-heteroarylmethylene-5(4H)-oxazolones, 210, 241, 286, 297 4-heteromethylene-2-phenyl-5(4H)-oxazolones, 263 4-heteromethylene-2-substituted-5(4H)oxazolones, 218 4-heteromethylene-5(4H)-oxazolones, 221, 228, 240, 277, 293 4-isopropyl-5(4H)-oxazolones, 185 4-monosubstituted-5(4H)-oxazolones, 164, 168, 171, 172, 194, 289 4-substituted-2-vinyl-5(4H)-oxazolones, 160 4-substituted-4-(triphenylphosphonio)-5(4H)oxazolones, 289 4-substituted-5(4H)-oxazolones, 166 4-unsubstituted-5(4H)-oxazolones, 168, 175, 186 4,4-(diarylmethyl)-2-phenyl-5(4H)-oxazolones, 163 4,4-di(isopropylthio)-2-substituted-5(4H)oxazolones, 190 4,4-dialkyl-5(4H)-oxazolones, 135, 162, 163, 194 4,4-dimethyl-2-substituted-5(4H)-oxazolones, 154, 190 4,4-disubstituted-2-(trifluoromethyl)-5(4H)oxazolones, 185 4,4-disubstituted-2-phenyl-5(4H)-oxazolones, 187

684

Subject Index

4,4-disubstituted-5(4H)-oxazolones, 166, 186 4,40 -bis(oxazolones), 194, 195, 289 5(4H)-oxazolylideneacetates, 193 allyl substituted-5(4H)-oxazolones, 136 bis-4-arylidene-5(4H)-oxazolones, 237 bis(oxazolones), 191, 194, 195, 195, 202, 203, 237, 239, 284, 289, 291 a,a-dialkyl-5(4H)-oxazolones, 160 ethylene-bridged bis(oxazolones), 203 fluorooxazolones, 175 heteroarylmethylene-5(4H)-oxazolones, 210 methyl 3-(5-oxo-2-phenyl-2-oxazolin-4yl)acrylates, 164 oxazolone spirocyclopropanes, 261, 266 oxazolone spiroisoxazolines, 268 oxazolone spiropyrazolines, 267 phenylene-bridged bis(oxazolones), 203 saturated 2-vinyl-5(4H)-oxazolones, 160 saturated 2,4,4-trisubstituted 5(4H)-oxazolones, 165, 166, 167 saturated 4-acyl-2,4-disubstituted 5(4H)oxazolones, 170

saturated 5(4H)-oxazolones, 131, 132, 151–208, 151, 152, 153, 154, 154, 156, 159, 160, 160, 162, 165, 166, 167, 177, 179, 180, 181, 181, 184, 185, 189, 191, 191, 193, 195, 197, 200, 202, 206, 207, 210, 257, 287–292, 287, 289, 291 unsaturated (E)-5(4H)-oxazolones, 210–212, 213, 257, 285 unsaturated (Z)-5(4H)-oxazolones, 210–212, 213, 257, 282, 285 unsaturated 5(4H)-oxazolones, 131, 171, 172, 177, 208–287, 208, 209, 210, 211, 212, 212, 213, 214, 214, 215, 216, 217, 217, 219, 220, 221, 223, 224, 226, 227, 229, 229, 230, 231, 232, 233, 235, 236, 237, 237, 238, 239, 240, 241, 241, 244, 245, 246, 247, 247, 248, 249, 249, 251, 252, 254, 255, 256, 257, 258, 258, 259, 260, 261, 262, 265, 266, 267, 268, 268, 271, 276, 277, 278, 278, 280, 281, 282, 284, 285, 286, 292–299, 292, 293, 294, 297, 299

Oxazolones 2(3H)-Oxazolones 3-(2-pyrimidinyl)-2(3H)-oxazolone, 18 3-acetyl-2(3H)-oxazolone, 25, 32, 35, 40 3-amino-2(3H)-oxazolone, 15 3-amino-4,5-diphenyl-2(3H)-oxazolone, 42 3-tert-butoxycarbonyl-2(3H)-oxazolone, 35 3-trimethylsilylethoxymethyl-2(3H)-oxazolone, 36 4-(3-indolyl)-2(3H)-oxazolone, 14, 36 4-(difluoromethyl)-5-p-tolylthio-2(3H)oxazolone, 12 4-methyl-2(3H)-oxazolone, 36 4-methyl-3-phenyl-5-vinyl-2(3H)-oxazolone, 12 4-naphthyl-2(3H)-oxazolone, 4 5-(3-indolyl)-2(3H)-oxazolone, 36 5-ethoxy-3-methyl-2(3H)-oxazolone, 47 5-phenyl-3-(2-pyridinyl)-2(3H)-oxazolone, 18 2(5H)-Oxazolones 5,5-dimethyl-4-ethoxy-2(5H)-oxazolone, 94 4(5H)-Oxazolones, 2,4-Oxazolidinediones and 4,5-Oxazolediones [2-11C]5,5-dimethyl-2,4-oxazolidinedione, 99 [2-13C]5,5-dimethyl-2,4-oxazolidinedione, 99 2-(propynylamino)-5-phenyl-4(5H)-oxazolone, 84

2-amino-5-isopropyl-4(5H)-oxazolone, 68 2-amino-5-phenyl-4(5H)-oxazolone, 83 2-phenyl-4(5H)-oxazolone, 54, 61, 65, 66 2-thio-2,4-oxazolidinedione, 113 5-(4-methoxybenzylidene)-2,4oxazolidinedione, 89 5-(benzylidene)-2-methylthio-4(5H)-oxazolone, 76 5-methyl-2,4-oxazolidinedione, 100 5-phenyl-2,4-oxazolidinedione, 109, 117 5,5-diethyl-2,4-oxazolidinedione, 91 5,5-dimethyl-2-ethoxy-4(5H)-oxazolone, 94 5,5-dimethyl-2-ethoxy-4-(p-tolylimino)-4(5H)oxazolone, 93 5,5-dimethyl-2,4-oxazolidinedione, 91, 94, 119 5,5-diphenyl-2,4-oxazolidinedione, 89 5(2H)-Oxazolones 2-(4-chlorophenyl)-2-(3,3-dimethylallyl)-4phenyl-5(2H)-oxazolone, 148 2-(difluoromethyl)-4-methyl-5(2H)-oxazolone, 133 2,2-bis(trifluoromethyl)-5(2H)-oxazolone, 147, 148 2,2-diamino-[(2-deoxy-b-D-erythropentofuranosyl)-4-amino]-5(2H)oxazolone, 150, 150, 151

Subject Index 4-(isopropoxy)-2-phenyl-2-(trifluoromethyl)5(2H)-oxazolone, 145 4-benzyl-2-(trifluoromethyl)-5(2H)-oxazolone, 135, 160 4-methyl-2-(trifluoromethyl)-5(2H)-oxazolone, 132 5(4H)-Oxazolones (E)-2-phenyl-4-(a-phenylethylidene)-5(4H)oxazolone, 238 (E)-4-benzylidene-2-phenyl-5(4H)-oxazolone, 262, 272, 273, 285, 286 (E)-4-(but-2-en-1-ylidene)-2-phenyl-5(4H)oxazolone, 286 (E)-4-(chloromethylene)-5(4H)-oxazolone, 277 (Z)-(N-acetyl-4-[(2-phenyl-5-oxo-4(5H)oxazolidene)methyl-2H]-1H-imidazole, 286 (Z)-2-methyl-4-(a-phenylethylidene)-5(4H)oxazolone, 286 (Z)-2-phenyl-4-(a-phenylethylidene)-5(4H)oxazolone, 238, 286 (Z)-4-(1-ethoxyethylidene)-2-phenyl-5(4H)oxazolone, 286 (Z)-4-(acetoxymethylene)-2-phenyl-5(4H)oxazolone, 286 (Z)-4-(ethylidene)-2-phenyl-5(4H)-oxazolone, 263 (Z)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4ylmethylene]-2-phenyl-5(4H)-oxazolone, 277 (Z)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4ylmethylidene]-2-phenyl-5(4H)oxazolone, 286 (Z)-4-[50 -(20 -chloropyridylmethylene)]-2phenyl-5(4H)-oxazolone, 274 (Z)-4-benzylidene-2-phenyl-5(4H)-oxazolone, 175, 262, 271, 272, 273, 285, 286, 297 2-(20 -aminophenyl)-5(4H)-oxazolone, 204 2-(20 -hydroxyphenyl)-5(4H)-oxazolone, 204 2-(4-bromophenyl)-4,4-dimethyl-5(4H)oxazolone, 207 2-(4-bromophenyl)-4,4-diphenyl-5(4H)oxazolone, 207 2-(4-bromophenyl)-4-ethyl-4-methyl-5(4H)oxazolone, 207 2-(4-chlorophenyl)-4-(2-cyclohexen-1-yl)-4phenyl-5(4H)-oxazolone, 207 2-(acyloxymethylene)-5(4H)-oxazolone, 263 2-(aminomethyl)-4-methyl-5(4H)-oxazolone, 291 2-(aminomethyl)-5(4H)-oxazolone, 291 2-(trifluoromethyl)-5(4H)-oxazolone, 186

685

2-benzyloxy-4-tert-butyl-4-methyl-5(4H)oxazolone, 287 2-benzyloxy-4-isopropyl-4-methyl-5(4H)oxazolone, 287 2-methyl (or phenyl)-4-(thienylmethylene)5(4H)-oxazolone, 227 2-methyl-5(4H)-oxazolone, 174, 179 2-phenyl-4-(2,4,6-trimethylbenzylidene)5(4H)-oxazolone, 286 2-phenyl-4-(4-toluidinomethylene)-5(4H)oxazolone, 299 2-phenyl-4-(a-phenylethylidene)-5(4H)oxazolone, 171 2-phenyl-4-(phosphoranylidene)-5(4H)oxazolone, 175, 176 2-phenyl-4-(sulfanylmethylene)-5(4H)oxazolone, 265 2-phenyl-4-propionyl-5(4H)-oxazolone, 168 2-phenyl-5(4H)-oxazolone, 152, 153, 162, 168, 171, 172, 173, 174, 182, 183, 194, 205, 206, 291 2-styryl-5(4H)-oxazolone, 192 2,20 -(1,4-phenylene)bis(4-phenylmethylene)5(4H)-oxazolone, 260 2,20 -(p-phenylene)bis[4,40 -dimethyl-5(4H)oxazolone], 202, 203 2,20 -bis[4,4-dimethyl-5(4H)-oxazolone], 202 2,4-dimethyl-5(4H)-oxazolone, 186 2,4-diphenyl-5(4H)-oxazolone, 201 4-(1-adamantyl)-2-(trifluoromethyl)-5(4H)oxazolone, 152 4-(1-benzoyloxybenzylidene)-2-phenyl-5(4H)oxazolone, 176 4-(3,3-dimethylallyl)-2-methyl-4-phenyl5(4H)-oxazolone, 136 4-(aminomethylene)-2-phenyl-5(4H)oxazolone, 223, 254 4-(anilinomethylene)-2-phenyl-5(4H)oxazolone, 225 4-(bromomethylene)-2-phenyl-5(4H)oxazolone, 263 4-(but-3-enylidene)-2-phenyl-5(4H)-oxazolone, 276 4-(chloromethylene)-2-phenyl-5(4H)oxazolone, 219, 220, 263, 265 4-(dichloromethylene)-2-phenyl-5(4H)oxazolone, 221 4-(N,N-dimethylaminomethylene)-2-phenyl5(4H)-oxazolone, 225 4-(diphenylmethylene)-2-phenyl-5(4H)oxazolone, 171 4-(ethoxymethylene)-2-(1-naphthyl)-5(4H)oxazolone, 294

686

Subject Index

4-(ethoxymethylene)-2-phenyl-5(4H)oxazolone, 221, 246, 269 4-(ferrocenylmethylene)-2-phenyl-5(4H)oxazolone, 299 4-(furan-2-ylmethylene)-2-phenyl-5(4H)oxazolone, 291 4-(hydroxymethylene)-2-phenyl-5(4H)oxazolone, 222, 249 4-(indol-3-ylmethylene)-5(4H)-oxazolone, 295 4-(iodomethyl)-4-methyl-2-phenyl-5(4H)oxazolone, 381 4-(iodomethylene)-2-phenyl-5(4H)-oxazolone, 263 4-(methoxymethylene)-2-phenyl-5(4H)oxazolone, 297 4-(a-phenylethylidene)-2-phenyl-5(4H)oxazolone, 285 4-[(1,2,4-oxadiazol-3-yl)aminomethylene]-2phenyl-5(4H)-oxazolone, 225 4-[(cyanoamino)methylene]-2-phenyl-5(4H)oxazolone, 225 4-[(ethoxycarbonyloxy)methylene]-2-phenyl5(4H)-oxazolone, 297 4-[(imidazol-1-yl)methylene]-2-phenyl-5(4H)oxazolone, 219 4-[(imidazol-4-yl)methylene]-2-phenyl-5(4H)oxazolone, 219 4-[(o-acetoxy)benzylidene]-2-phenyl-5(4H)oxazolone, 256 4-[1-(dimethylamino)ethylidene]-2-phenyl5(4H)-oxazolone, 225 4-[2-bromo-1-(dimethylaminoethylidene)]-2phenyl-5(4H)-oxazolone, 225

4-[bis(methylthio)methylene]-2-phenyl-5(4H)oxazolone, 172 4-allyl-2-methyl-4-phenyl-5(4H)-oxazolone, 136 4-benzyl-2-(trifluoromethyl)-5(4H)-oxazolone, 135 4-benzyl-2-methyl-5(4H)-oxazolone, 179, 256 4-benzyl-2-phenyl-4-(trifluoromethyl)-5(4H)oxazolone, 158 4-benzyl-2-phenyl-5(4H)-oxazolone, 163, 179, 181, 194 4-benzyl-4-methyl-2-phenyl-5(4H)-oxazolone, 291 4-benzylidene-2-methyl-5(4H)-oxazolone, 227, 256, 258, 282, 295 4-benzylidene-2-phenyl-5(4H)-oxazolone, 227, 259 4-tert-butyl-2-phenyl-5(4H)-oxazolone, 182 4-methyl-2-phenyl-5(4H)-oxazolone, 163, 171, 172, 179, 181, 289, 291 4-methyl-2-(trifluoromethyl)-5(4H)-oxazolone, 132 4,4-dibenzyl-2-(trifluoromethyl)-5(4H)oxazolone, 190 4,4-dimethyl-2-[(9-fluorenylmethyl)oxy]5(4H)-oxazolone, 178 4,4-dimethyl-2-isopropenyl-5(4H)-oxazolone, 161, 202 4,4-dimethyl-2-phenyl-5(4H)-oxazolone, 191 4,4-dimethyl-2-vinyl-5(4H)-oxazolone, 161, 202 4,4-dipropyl-2-(trifluoromethyl)-5(4H)oxazolone, 190

Tables TABLE 5.1: SYNTHESIS OF 3-ARYL-5-tert-BUTYL-2(3H)-OXAZOLONES FROM ETHYL N-ARYLCARBAMATES AND a-BROMO KETONES, 4 TABLE 5.2: SYNTHESIS OF 5-ALKOXY-2(3H)-OXAZOLONES FROM a-AMINO ACID ESTERS, 9 TABLE 5.3: CYCLIZATION OF a-IMINO KETONES TO 4,5-DIPHENYL-2(3H)-OXAZOLONES AND 2-THIONES, 10 TABLE 5.4: SYNTHESIS OF 5-ALKYL-3-ARYL-2(3H)-OXAZOLONES FROM N-ARYL-N(HYDROXY) ACYLACETAMIDES, 13 TABLE 5.5: SYNTHESIS OF 5-ALKYL-3-ARYL-4-HALO-2(3H)-OXAZOLONES FROM N-ARYLN-(HYDROXY)-a-HALO ACYLACETAMIDES, 14 TABLE 5.6: 3-ALKYL-4,5-DISUBSTITUTED-2(3H)-OXAZOLONES FROM OXIMES AND DIALKYLCARBONATES, 17 TABLE 5.7: 2(3H)-OXAZOLONES FROM a-HYDROXY AMIDES AND PHOSPHORUS YLIDE 134, 21

Subject Index

687

TABLE 5.8: DIASTEREOSELECTIVE METHOXYBROMINATION OF 3-ACYL-2(3H)-OXAZOLONES 159, 25 TABLE 5.9: DIASTEREOSELECTIVE METHOXYSELENYLATION OF 3-ACYL-2(3H)-OXAZOLONES 159, 26 TABLE 5.10: DIASTEREOSELECTIVE [4 + 2] CYCLOADDITION OF AZODICARBOXYLATES TO 2(3H)-OXAZOLONES, 34 TABLE 5.11: SYNTHESIS OF ALKYL 2-OXAZOLIDINONE-4-CARBOXYLATES FROM 5ALKOXY-2(3H)-OXAZOLONES, 43 TABLE 5.12: SYNTHESIS OF ALKYL 2-IMIDAZOLIDINONE-4-CARBOXYLATES AND ALKYL 2,3-DIAMINOPROPANE-1-CARBOXYLATES FROM 5-ALKOXY-2(3H)-OXAZOLONES, 44 TABLE 5.13: SYNTHESIS OF 5,5-DIALKOXY-2-OXAZOLIDINONES FROM 5-ALKOXY-2(3H)OXAZOLONES, 44 TABLE 5.14: SYNTHESIS OF a-AMINO ACID ESTERS FROM 5,5-DIALKOXY-2-OXAZOLIDINONES, 45 TABLE 5.15: SYNTHESIS OF ETHYL 2(3H)-OXAZOLONE-4-CARBOXYLATES FROM 3-NOSYLOXY-2-KETO ESTERS OR 3-BROMO-2-KETO ESTERS, 48 TABLE 6.1: 5,5-DIPHENYL-2-SUBSTITUTED-4(5H)-OXAZOLONES FROM SULFILIMINES AND DIPHENYLKETENE, 57 TABLE 6.2: 2-[2-(a-HETEROARYL)ETHENYL]-4(5H)-OXAZOLONIUM PERCHLORATES FROM OXAZOLONIUM SALTS AND ALDEHYDES, 64 TABLE 6.3: 5-(HYDROXYMETHYL)-3-PHENYL-1H-1,2,4-TRIAZOLES FROM 2-PHENYL-4(5H)OXAZOLONE AND HYDRAZINES, 66 TABLE 6.4: SPIROCYCLIC 2-AMINO-4(5H)-OXAZOLONES FROM a-HYDROXY ESTERS AND GUANIDINE, 73 TABLE 6.5: 5-(BENZYLIDENE)-2-SUBSTITUTED-4(5H)-OXAZOLONES FROM 5-(BENZYLIDENE)-2-(METHYLTHIO)-4(5H)-OXAZOLONE, 76 TABLE 6.6: 2-AMINO-5-(CARBOXYALKYL)-4(5H)-OXAZOLONES FROM OXIDATIVE RING CONTRACTION OF 2-AMINOPYRIMIDINONES, 78 TABLE 6.7: BOULTON-KATRITZKY REARRANGEMENT PRODUCTS FROM 5,5-DIMETHYL-2ETHOXY-4-( p-TOLYLIMINO)-4(5H)-OXAZOLONE AND HETEROCUMULENES, 93 TABLE 6.8: 5-ARYL-2,4-OXAZOLIDINEDIONES FROM CYCLIZATION OF a-HYDROXY IMIDATES, 100 TABLE 6.9: SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM CYCLIZATION OF a-HYDROXY IMIDATES, 101 TABLE 6.10: SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM 5- OR 7-SUBSTITUTED ISATINS, 103 TABLE 6.11: 3-ALKYL-2,4-OXAZOLIDINEDIONES FROM ALKYLATION OF 2,4-OXAZOLIDINEDIONES, 109 TABLE 6.12: IMIDAZOLONES FROM 5,5-DIMETHYL-2,4-OXAZOLIDINEDIONE AND 2HAZIRINES, 119 TABLE 7.1: SYNTHESIS OF 5(2H)-OXAZOLONES VIA CYCLIZATION OF AMINO ACIDS OR AMINO NITRILES, 133 TABLE 7.2: SYNTHESIS OF 5(2H)-OXAZOLONES VIA ALKYLATION AT C-2, 135

688

Subject Index

TABLE 7.3: SYNTHESIS OF 5(2H)-OXAZOLONES VIA SIGMATROPIC REARRANGEMENT, 138 TABLE 7.4: SYNTHESIS OF 5(2H)-OXAZOLONES VIA REARRANGEMENT OF 5-ALKOXYOXAZOLES, 138 TABLE 7.5: SYNTHESIS OF 4-(ALKYLTHIO)-5(2H)-OXAZOLONES FROM SODIUM CYANODITHIOFORMATE, KETONES AND ALKYLATING AGENTS, 140 TABLE 7.6: SYNTHESIS OF 4-(ARYLTHIO)-5(2H)-OXAZOLONES FROM ETHYLCYANOFORMATE, KETONES AND ARYLTHIOLS, 141 TABLE 7.7: SYNTHESIS OF 4-ALKOXY-5(2H)-OXAZOLONES FROM 4-(PHENYLTHIO)-5(2H)OXAZOLONES, 141 TABLE 7.8: SYNTHESIS OF 4-ALKOXY-5(2H)-OXAZOLONES FROM IMINOOXALATES AND KETONES OR ALDEHYDES, 142 TABLE 7.9: SYNTHESIS OF 4-(N,N-DIALKYLAMINO)-5(2H)-OXAZOLONES FROM AMIDINES AND CARBON DIOXIDE, 142 TABLE 7.10: 2-(TRIFLUOROMETHYL)PYRROLES FROM REACTION OF 5(2H)-OXAZOLONES WITH ELECTRON DEFICIENT UNSATURATED COMPOUNDS, 145 TABLE 7.11: GENERATION OF NITRILE YLIDES FROM 5(2H)-OXAZOLONES, 146 TABLE 7.12: AMINOLYSIS OF 5(2H)-OXAZOLONES, 146 TABLE 7.13: 5-(DIMETHYLAMINO)-3,6-DIHYDROPYRAZIN-2(1H)-ONES FROM REACTION OF 5(2H)-OXAZOLONES WITH 3-(DIMETHYLAMINO)-2H-AZIRINES, 148 TABLE 7.14: 3-ALKYL ASPARTIC ACID DERIVATIVES FROM REACTION OF 5(2H)OXAZOLONES WITH YNAMINES, 149 TABLE 7.15: SYNTHESIS OF SATURATED 5(4H)-OXAZOLONES VIA CYCLIZATION OF AMINO ACID DERIVATIVES, 154 TABLE 7.16: SYNTHESIS OF SATURATED 5(4H)-OXAZOLONES VIA SIGMATROPIC REARRANGEMENT OF 5-ALKOXYOXAZOLES, 160 TABLE 7.17: SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4H)-OXAZOLONES VIA ALKYLATION OF SATURATED 5(4H)-OXAZOLONES AT C-4, 165 TABLE 7.18: SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4H)-OXAZOLONES BY REACTION OF SATURATED 5(4H)-OXAZOLONES WITH MICHAEL ACCEPTORS, 166 TABLE 7.19: SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4H)-OXAZOLONES VIA ARYLATION OF SATURATED 5(4H)-OXAZOLONES AT C-4, 167 TABLE 7.20: SYNTHESIS OF SATURATED 4-ACYL-2,4-DISUBSTITUTED 5(4H)-OXAZOLONES VIA ACYLATION OF 2,4-DISUBSTITUTED 5(4H)-OXAZOLONES AT C-4, 170 TABLE 7.21: N-ACYLAMINO ACID ESTERS FROM ALCOHOLYSIS OF SATURATED 5(4H)OXAZOLONES, 181 TABLE 7.22: SUBSTITUTED AMINO ACID AMIDES VIA OBRECHT’S METHODOLOGY FOR AMINOLYSIS OF SATURATED 5(4H)-OXAZOLONES, 189 TABLE 7.23: 2,5-DIARYLOXAZOLES FROM REACTION OF SATURATED 5(4H)-OXAZOLONES WITH ARENES, 191 TABLE 7.24: 5(4H)-OXAZOLYLIDENEACETATES FROM REACTION OF SATURATED 5(4H)OXAZOLONES WITH TRIPHENYLPHOSPHONIUM METHYLIDES, 193 TABLE 7.25: ENAMIDES FROM THERMOLYSIS OF SATURATED 5(4H)-OXAZOLONES, 193

Subject Index

689

TABLE 7.26: 4,40 -BIS(OXAZOLONES) FROM DIMERIZATION OF SATURATED 5(4H)-OXAZOLONES, 195 TABLE 7.27: SUBSTITUTED PYRROLES VIA CYCLOADDITION OF DIPOLAROPHILES WITH MUNCHNONES PREPARED FROM SATURATED 5(4H)-OXAZOLONES, 197 TABLE 7.28: 2-PYRIDONES FROM CYCLOADDITION REACTIONS OF SATURATED 5(4H)OXAZOLONES WITH 1-AZADIENES, 199 TABLE 7.29: PYRIMIDIN-6-ONES FROM CYCLOADDITION REACTIONS OF SATURATED 5(4H)-OXAZOLONES WITH 1,3-DIAZADIENES, 200 TABLE 7.30: SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES FROM N-ACYLGLYCINES AND CARBONYL COMPOUNDS, 212 TABLE 7.31: UNSATURATED (E)-5(4H)-OXAZOLONES VIA ISOMERIZATION OF UNSATURATED (Z)-5(4H)-OXAZOLONES, 213 TABLE 7.32: SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES VIA CYCLIZATION OF a,b-DIDEHYDROAMINO ACIDS OR a,b-UNSATURATED CARBODIIMIDES, 214 TABLE 7.33: SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES VIA CYCLIZATION OF a,b-UNSATURATED IMINOPHOSPHORANES OR a,b-UNSATURATED ISOCYANIDES, 216 TABLE 7.34: SYNTHESIS OF UNSATURATED 5(4H)-OXAZOLONES FROM N-ACYLAMINO ACID DERIVATIVES AND VILSMEIER-HAACK REAGENT, 217 TABLE 7.35: SYNTHESIS OF 4-(a-ARYLETHYLIDENE)-5(4H)-OXAZOLONES FROM REACTION OF 4-ARYLIDENE-5(4H)-OXAZOLONES WITH DIAZOMETHANE, 218 TABLE 7.36: SYNTHESIS OF 4-ARYLIDENE-2-PHENYL-5(4H)-OXAZOLONES FROM STILLE REACTION OF 4-(CHLOROMETHYLENE)-2-PHENYL-5(4H)-OXAZOLONE, 220 TABLE 7.37: SYNTHESIS OF 4-(AMINOMETHYLENE)-5(4H)-OXAZOLONES FROM 4-(HETEROMETHYLENE)-5(4H)-OXAZOLONES, 221 TABLE 7.38: SYNTHESIS OF 4-(ALKYLTHIOMETHYLENE)-5(4H)-OXAZOLONES FROM 4(AMINOMETHYLENE)-5(4H)-OXAZOLONES, 224 TABLE 7.39: N-ACYL DEHYDROAMINO ACIDS AND ESTERS FROM HYDROLYSIS AND ALCOHOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES, 229 TABLE 7.40: N-ACYL DEHYDROAMINO ACID AMIDES FROM AMINOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES, 237 TABLE 7.41: N-ACYLAMINO ACID AMIDES FROM REDUCTIVE AMINOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES, 241 TABLE 7.42: (E)-a-ACYLAMINO HYDRAZIDES FROM REACTION OF UNSATURATED 5(4H)OXAZOLONES WITH HYDRAZINES, 244 TABLE 7.43: 2-STYRYL-1-SUBSTITUTED IMIDAZOLONES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH SCHIFF BASES, 247 TABLE 7.44: BENZIMIDAZOLES AND BENZOTHIAZOLES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH 2-SUBSTITUTED ANILINES, 249 TABLE 7.45: AMINO ACID, AMINO ESTER AND AMINO ALCOHOL DERIVATIVES FROM HYDROGENATION OF UNSATURATED 5(4H)-OXAZOLONES, 258 TABLE 7.46: OXAZOLONE SPIROCYCLOPROPANES FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH A STABILIZED SULFUR YLIDE, 261 TABLE 7.47: OXAZOLONE SPIROCYCLOPROPANES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH DIAZOMETHANE, 266

690

Subject Index

TABLE 7.48: OXAZOLONE SPIROPYRAZOLINES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH NITRILE IMINES, 267 TABLE 7.49: OXAZOLONE SPIROISOXAZOLINES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4H)-OXAZOLONES WITH NITRILE OXIDES, 268 TABLE 7.50: DIELS-ALDER ADDUCTS FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES AND ACYCLIC DIENES, 278 TABLE 7.51: DIELS-ALDER ADDUCTS FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES AND CYCLIC DIENES, 280 TABLE 7.52: DIELS-ALDER ADDUCTS FROM REACTION OF UNSATURATED 5(4H)-OXAZOLONES AND ACTIVATED DIENES, 281 TABLE 8.1: OXAZOLINES FROM CARBOXYLIC ACIDS, 334–336 TABLE 8.2: OXAZOLINES FROM CARBOXYLIC ESTERS AND AMINO ALCOHOLS, 337 TABLE 8.3: OXAZOLINES FROM PRIMARY b-HYDROXY AMIDES AND SOCl2, 340–344 TABLE 8.4: OXAZOLINES FROM SECONDARY AND TERTIARY b-HYDROXY AMIDES AND SOCl2, 345 TABLE 8.5: OXAZOLINES FROM b-HYDROXY AMIDES USING VILSMEIER REAGENT, 348 TABLE 8.6: OXAZOLINES FROM URETHANE-PROTECTED TERTIARY b-HYDROXY AMIDES, 351 TABLE 8.7: OXAZOLINES VIA ACETATES, MESYLATES, AND TRIFLATES, 352–357 TABLE 8.8: OXAZOLINE FORMATION USING BURGESS REAGENT, 361–363 TABLE 8.9: OXAZOLINE FORMATION USING PEG-SUPPORTED BURGESS REAGENT, 366 TABLE 8.10: OXAZOLINES VIA THE MITSUNOBU REACTION OF b-HYDROXY AMIDES, 367 TABLE 8.11: CYCLIZATION OF THREONINE AND ALLO-THREONINE PEPTIDES UNDER MITSUNOBU CONDITIONS, 369 TABLE 8.12: OXAZOLINES FROM b -HYDROXY AMIDES USING DAST, 370–371 TABLE 8.13: COMPARISON OF DAST AND DEOXO-FLUOR FOR CYCLIZATION OF PEPTIDYL b-HYDROXY AMIDES, 372 TABLE 8.14: OXAZOLINES FROM HYDROXY AMIDES USING TRIPHENYLPHOSPHINE AND CARBON TETRACHLORIDE, 373–375 TABLE 8.15: OXAZOLINECARBOXYLATES FROM 2-CHLORO-2-CYCLOPROPYLIDENEACETATES, 378 TABLE 8.16: OXAZOLINES FROM NITRILES AND AMINO ALCOHOLS, 385–386 TABLE 8.17: OXAZOLINES FROM IMIDATES AND AMINO ALCOHOLS, 388–389 TABLE 8.18: CONVERSION OF ALLYLIC ALCOHOLS TO b-AMINO ALCOHOLS VIA OXAZOLINES, 390 TABLE 8.19: OXAZOLINES FROM CYCLIZATION OF EPOXYTRICHLOROACETIMIDATES CATALYZED BY DIETHYLALUMINUM CHLORIDE, 392 TABLE 8.20: OXAZOLINES FROM ALKENES, 398 TABLE 8.21: OXAZOLINES FROM a-ISOCYANOESTERS, 407 TABLE 8.22: OXAZOLINES FROM [4 þ 2] CYCLOADDITIONS, 411 TABLE 8.23: HYDROLYSIS OF OXAZOLINES, 419–421

Subject Index

691

TABLE 8.24: UNMASKING THE SIDE-CHAIN OF TAXOL ANALOGS BY ACID HYDROLYSIS, 422–423 TABLE 8.25: HYDROLYSIS OF OXAZOLINE 329 UNDER BASIC CONDITIONS, 427 TABLE 8.26: LITHIATION OF OXAZOLINYLFERROCENE 439 AND TRAPPING WITH ELECTROPHILES, 453–454 TABLE 8.27: LITHIATION OF OXAZOLINYLFERROCENE 439 AND TRAPPING WITH TMSCl, 457 TABLE 8.28: LITHIATION OF ARENES BY EVL-HMPA, 459 TABLE 8.29: OXAZOLINE-DIRECTED STEREOSELECTIVE SYNTHESIS OF BIPHENYLS, 462 TABLE 8.30: DIASTEREOSELECTIVITY IN ULLMANN COUPLING REACTIONS (SCHEME 8.158), 466 TABLE 8.31: DIASTEREOSELECTIVE CONJUGATE ADDITIONS OF EVL, 470 TABLE 8.32: ADDITION OF LITHIUM AMIDES TO OXAZOLINYLNAPHTHALENES, 472–473 TABLE 8.33: HETERO DIELS-ALDER REACTION OF CHIRAL 2-ALKENYLOXAZOLINES (SCHEME 8.168), 477 TABLE 8.34: PALLADIUM-CATALYZED ALKYLATION OF DIPHENYLALLYL ACETATE WITH DIMETHYL MALONATE, 489 TABLE 8.35: PALLADIUM-CATALYZED ALKYLATION OF DIMETHYLALLYL ACETATE AND DIMETHYLALLYL t-BUTYLCARBONATE WITH DIMETHYL MALONATE, 490 TABLE 8.36: PALLADIUM-CATALYZED ALKYLATION OF 3-ACETOXYCYCLOHEXENE WITH DIMETHYL MALONATE, 491 TABLE 8.37: ASYMMETRIC INTERMOLECULAR HECK REACTION, 494 TABLE 8.38: ASYMMETRIC HYDROGENATION OF STYRENES 597 (SCHEME 8.185), 496–497 TABLE 8.39: ENANTIOSELECTIVE TRANSFER HYDROGENATION OF KETONES, 500 TABLE 8.40: ASYMMETRIC ADDITION OF DIALKYLZINC REAGENTS TO ALDEHYDES, 502 TABLE 8.41: ASYMMETRIC MICHAEL ADDITIONS TO CYCLIC ENONES, 505 TABLE 8.42: REACTION OF 647 WITH BIFUNCTIONAL ELECTROPHILES, 510–511 TABLE 9.1: MASAMUNE’S Cu(II)-BIS(OXAZOLINE)-CATALYZED CYCLOPROPANATION, 539 TABLE 9.2: EVANS’ Cu(I)-BIS(OXAZOLINE)-CATALYZED CYCLOPROPANATION, 539 TABLE 9.3: CYCLOPROPANATIONS USING VARIOUS METALS AND LIGANDS, 542 TABLE 9.4: CYCLOPROPANATION OF DIAZOACETATE ESTERS, 543 TABLE 9.5: CYCLOPROPANATION OF ENOL ETHERS, 543 TABLE 9.6: INTRAMOLECULAR CYCLOPROPANATIONS, 544 TABLE 9.7: COREY’S DIELS-ALDER REACTION USING Fe(III) HALIDES, 546 TABLE 9.8: COREY’S DIELS-ALDER REACTION USING Fe(III) OR Mg(II) SALTS, 547 TABLE 9.9: CuOTf-MEDIATED DIELS-ALDER REACTION, 548 TABLE 9.10: INDA-BOX-MEDIATED DIELS-ALDER REACTION, 549 TABLE 9.11: DIELS-ALDER REACTION USING ANHYDROUS AND HYDRATED Mg(II), 550 TABLE 9.12: DBF-BOX-MEDIATED DIELS-ALDER REACTION, 551 TABLE 9.13: DIELS-ALDER REACTIONS WITH SUBSTITUTED ACROLEINS, 552

692

Subject Index

TABLE 9.14: DIELS-ALDER REACTIONS OF N-ACYL OXAZOLIDINONES, 553 TABLE 9.15: DIELS-ALDER REACTIONS WITH VARIOUS DIENOPHILES, 553 TABLE 9.16: ENANTIOSELECTIVE ENE REACTIONS OF ETHYL GLYOXYLATE, 556 TABLE 9.17: ENANTIOSELECTIVE HETERO DIELS-ALDER AND ENE REACTION PRODUCTS, 557 TABLE 9.18: HETERO DIELS-ALDER REACTION OF DANISHEFSKY’S DIENE WITH GLYOXYLATE ESTERS, 558 TABLE 9.19: ENANTIOSELECTIVE HETERO DIELS-ALDER REACTIONS USING DANISHEFSKY’S DIENE, 559 TABLE 9.20: ENANTIOSELECTIVE HETERO DIELS-ALDER REACTIONS OF a,b-UNSATURATED ACYL PHOSPHONATES, 560 TABLE 9.21: 1,3-DIPOLAR CYCLOADDITION OF PHENYLACETYLENE, 561 TABLE 9.22: ENANTIOSELECTIVE 1,3-DIPOLAR CYCLOADDITION OF a,b-UNSATURATED OXAZOLIDINONES AND NITRONES, 562 TABLE 9.23: ENANTIOSELECTIVE SUBSTITUTION OF 1,3-DIPHENYLALLYL ACETATE WITH DIETHYLMALONATE, 563 TABLE 9.24: FERROCENE-BOX MEDIATED ENANTIOSELECTIVE SUBSTITUTION OF 1,3DIPHENYLALLYL ACETATE WITH DIETHYLMALONATE, 564 TABLE 9.25: MUKAIYAMA ALDOL REACTION OF BENZYLOXYACETALDEHYDE AND A TRIMETHYLSILYL ENOL ETHER, 565 TABLE 9.26: ENANTIOSELECTIVE ALDOL REACTION MEDIATED BY BU-BOX, 566 TABLE 9.27: Cu(II)-BU-BOX-MEDIATED MUKAIYAMA ALDOL REACTIONS, 566 TABLE 9.28: PHE-BOX-MEDIATED FREE RADICAL CONJUGATE ADDITION, 567 TABLE 9.29: ENANTIOSELECTIVE FREE RADICAL CONJUGATE ADDITIONS TO a,bUNSATURATED N-ACYL OXAZOLIDINONES, 568 TABLE 9.30: POLAR CONJUGATE ADDITION REACTION, 569 TABLE 9.31: BIS(OXAZOLINE)-MEDIATED CONJUGATE ADDITIONS, 569 TABLE 9.32: ASYMMETRIC ADDITION TO IMINES, 571 TABLE 9.33: ENANTIOSELECTIVE ADDITION OF ALLYLZINC REAGENTS TO CYCLIC IMINES, 571 TABLE 9.34: AZIRIDINATION OF CINNAMATE ESTERS, 575 TABLE 9.35: BIS(OXAZOLINE)-MEDIATED ALLYLIC OXIDATION, 577 TABLE 9.36: HYDROSILYLATION OF ACETOPHENONE, 578 TABLE 9.37: BIS(OXAZOLINE)-MEDIATED TRANSFER HYDROGENATION OF KETONES, 579 TABLE 9.38: BIS(OXAZOLINE) LIGANDS, 582–585 TABLE 9.39: CYCLOPROPANATIONS WITH SULFUR YLIDES, 586 TABLE 9.40: BIS(OXAZOLINE)-MEDIATED FRIEDEL-CRAFTS REACTIONS OF INDOLES, 589