ISOXAZOLES · 2013-07-23 · cyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cyclo-

ISOXAZOLES Part One

Paolo Grunanger Paola Vita-Finzi

University of Pavia,

Pavia, Italy

AN INTERSCIENCE@ PUBLICATION

John Wiley & Sons, Inc. NEW YORK / CHICHESTER / BRISBANE / TORONTO / SINGAPORE

ISOXAZOLES

Part One

This IS a part of the for tyninth volume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS


A SERIES OF MONOGRAPHS

EDWARD C. TAYLOR, Editor

ARNOLD WEISSBERGER, Foiinding Editor

ISOXAZOLES Part One

Paolo Grunanger Paola Vita-Finzi

University of Pavia,

Pavia, Italy

AN INTERSCIENCE@ PUBLICATION

John Wiley & Sons, Inc. NEW YORK / CHICHESTER / BRISBANE / TORONTO / SINGAPORE

In recognition of the importance of preserving what has been written, it is a policy of John Wiley & Sons, Inc. to have books of enduring value published in the United States printed on acid-free paper, and wc exert our best efforts to that end.

An Intersciencea Publication Copyright

All rights reserved. Published simultaneously in Canada.

Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful.

1991 by John Wiley & Sons, Inc.

Library of Congress Cataloging in Publication Data:

Griinanger, Paolo. Isoxazoles/Paolo Griinanger, Paola Vita-Finzi.

p. cm.-(The chemistry of heterocyclic compounds, ISSN 0069-3 154; V. 49)

“An Interscience publication.” Includes bibliographical references. 1. Oxazoles. 1. Vita-Finzi, Paola. 11. Title. 111. Series.

QD401.G897 1990 89-22461 547’. 5 9 2 4 ~ 2 0 CIP ISBN 0-471-02233-0

To the memory of

ADOLFO QUILICO the great pioneer

of isoxaiole renaissance

The Chemistry of Heterocyclic Compounds Introduction to the Series

The chemistry of heterocyclic compounds constitutes one of the broadest and most complex branches of chemistry. The diversity of synthetic methods utilized in this field, coupled with the immense physiological and industrial significance of heterocycles, combine to make the general heterocyclic arena of central importance to organic chemistry.

The Chemistry of Heterocyclic Compounds, published since 1950 under the initial editorship of Arnold Weissberger, and later, until Dr. Weissberger’s death in 1984, under our joint editorship, has attempted to make the extra- ordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has 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 which impinge on almost all aspects of modern organic and medicinal chemistry, 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 heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cycloaddition reactions. These volumes are of interest to all organic and medicinal chemists, as well as to those whose particular concern is heterocyclic chemistry.

It has become increasingly clear that this arbitrary distinction created as many problems as it solves, and we have therefore elected to discontinue the more recently initiated series General Heterocjdic Chemistry, and to publish all forthcoming volumes in the general area of heterocyclic chemistry in The Chemistry of Heterocyclic Compounds series.

Department of Chemistry Princeton University Princeton, New Jersey

EDWARD C. TAYLOR

vii

Preface

In the seventeenth volume of the series The Chemistry of Heterocyclic Compounds, published in 1962, Part I was devoted to Isoxazoles and Related Compounds. The authors, Adolfo Quilico and Giovanni Speroni, covered the entire chemistry of this nucleus in 232 pages, elaborating about 880 references up to 1958. Nowadays, more than 15.500 papers, dealing with the same nucleus, are known in the literature. This huge increase in published work in the past 30-year period necessitated a complete reelaboration of the monograph on this important class of heterocyclic compounds. The material has been divided into three parts, to be published in separate volumes.

This volume, Part 1, is devoted to mononuclear isoxazoles and to their dihydro- and tetrahydro derivatives. Each chapter represents a survey on physical properties, syntheses, and reactions of the three classes of compounds. Owing to the increasing importance of isoxazoles as intermediates in the synthesis of complex molecules, special paragraphs on this subject are added at the end of each chapter. In this volume the literature reported in Chemical Abstracts through 1984 (Volume 101) has been covered. Although every reasonable effort has been made to include in the text all significant material, no attempt has been made to incorporate all available data, deferring the task to the forthcoming tabular survey. Treatment of theoretical and mechanistic aspects has been kept to a minimum. References have been collected in a single list at the end of the volume; see page 1 of Chapter 1 for an explanation of their numbering.

In Parts 2 and 3 of this monograph, chapters on isoxazolones, benzis- oxazoles, anthranils, and other polynuclear isoxazole derivatives, as well as the tabular survey, an updating of Part I , and a chapter on applications of isoxazole compounds, will be provided.

We have been greatly helped in the preparation of this manuscript over several years by many people. First, we wish to acknowledge the continued encouragement and valuable assistance of the late Professor A. Quilico and the constant advice of the late Professor G. Speroni. Outstanding help in collecting data and typing the manuscript has been provided by Drs. G. D’AIO, P. Comotti, and C. Montepiani. Careful reading and critical supervision of the text by our colleagues Professors K. N. Houk. P. Caramella, G. Bianchi, R. Gandolfi, F. Marinone Albini, A. Gamba Invernizzi, A. Corsico Coda, and Dr. G. Mellerio are gratefully acknowledged. Warm thanks are due especially to Professor Franca Marinone Albini also for his attentive check of the proofs and of the camera-ready material, as well as for preparation of the subject index. Grateful thanks are also due to the Consiglio Nazionale delle Ricerche (Rome) for financial support of our multidecade research work on isoxazole chemistry. Our thanks are also due to the series editor Professor E. C. Taylor and to the

ix

X Preface

staff of John Wiley & Sons for their help in improving the language and in solving printing problems.

P. GRUNANGER P. VITA-FINZI

Contents

1 . ISOXAZOLES 1

1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Physicochemical Properties . . . . . . . . . . . . . . . . . . . 3

1.2.1 Infrared Spectra . . . . . . . . . . . . . . . . . . . . . 3 1.2.2 Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . 7 1.2.3 Nuclear Magnetic Resonance Spectra . . . . . . . . . . 24

1.2.3.1 PMR Spectra . . . . . . . . . . . . . . . . . 24 1.2.3.2 I3C-NMR Spectra . . . . . . . . . . . . . . . 45 1.2.3.3 I4N- and "N-NMR Spectra . . . . . . . . . . . 55 1.2.3.4 Other Nuclei NMR Spectra . . . . . . . . . . . 58

1.2.4 Mass Spectra . . . . . . . . . . . . . . . . . . . . . 59 1.2.5 Other Spectra . . . . . . . . . . . . . . . . . . . . . 88

1.2.5.1 Microwave Spectra . . . . . . . . . . . . . . . 88 1.2.5.2 Photoelectron Spectra . . . . . . . . . . . . . 88 1.2.5.3 Electron Paramagnetic Resonance Spectra . . . . 90 1.2.5.4 Electron Spin Resonance Spectra . . . . . . . . 90 1.2.5.5 Nuclear Quadrupole Resonance Spectra . . . . . 91 1.2.5.6 Other Spectra . . . . . . . . . . . . . . . . . 92

1.2.6 Crystal and Molecular Structure . . . . . . . . . . . . . 92 1.2.7 Dipole Moments . . . . . . . . . . . . . . . . . . . . 98 1.2.8 Theoretical Calculations . . . . . . . . . . . . . . . . 103

1.2.8.1 Reactivity, Aromaticity, and Electron Density . . . 103 1.2.8.2 Molecular Geometry . . . . . . . . . . . . . . 106 1.2.8.3 Basicity and Dipole Moments . . . . . . . . . . 107 1.2.8.4 Ionization Potentials . . . . . . . . . . . . . . 109 1.2.8.5 Molecular Core Binding Energy . . . . . . . . . 110 1.2.8.6 Spectroscopic Data and Conformational Analysis . 110

1.2.9 Basicity . . . . . . . . . . . . . . . . . . . . . . . 114 1.2.10 Miscellaneous Data . . . . . . . . . . . . . . . . . . 118 1.2.1 1 Analytical Methods . . . . . . . . . . . . . . . . . . 121

1.3 Methods of Preparation . . . . . . . . . . . . . . . . . . . . 125 1.3.1 [CCC + NO] Processes . . . . . . . . . . . . . . . . 126

1.3.1.1 Oximation of 1, 3-Dicarbonyl (and Related) Compounds . . . . . . . . . . . . . . . . . . 126

1.3.1.2 Oximation of a$-Acetylenic Carbonyl (and Related) Compounds . . . . . . . . . . . . . . 149

1.3.1.3 Oximation of a$-Dihalocarbonyl (and Related) Compounds . . . . . . . . . . . . . . . . . . 155

1.3.1.4 Oximation of z, 8-Ethylenic Carbonyl (and Related) Compounds 8-Substituted with Electron-

xi

xii Contents

Withdrawing Groups . . . . . . . . . . . . . 1.3.1.5 Oximation of a, p-Ethylenic Carbonyl (and

Related) Compounds . . . . . . . . . . . . . 1.3.1.6 Other Oximation Reactions . . . . . . . . . . 1.3.1.7 Synthesis from Unsaturated Compounds and

Nitric (Nitrous) Acid . . . . . . . . . . . . . 1.3.1.8 Nitrosation of Ketodicarboxylic Esters . . . . .

1.3.2.1 Cycloaddition of Nitrile Oxides (or Their Precursors) to Acetylenic Compounds . . . . .

1.3.2.2 Cycloaddition of Nitrile Oxides (or Their Precursors) to Ethylenic Compounds . . . . . .

1.3.2.3 Cycloaddition of Nitrile Oxides (or Their Precursors) with Active Methylene

Cycloaddition of Nitrile Oxides (or Their Precursors) with Sodium Acetylides or Acetylenic Grignard Reagents . . . . . . . . . . . . . .

1.3.2.5 [CNO + 2C] Processes: Syntheses from Nitro Derivatives

1.3.4.1 Synthesis from Oxime Dilithium Salts and Carboxylic Acid Derivatives . . . . . . . . . .

1.3.4.2 Reaction of a-Chloroketoximes with Ylides . . .

1.3.2 [CNO + CC] Processes . . . . . . . . . . . . . . .

Compounds . . . . . . . . . . . . . . . . . 1.3.2.4

Other [CNO + CC] Processes . . . . . . . . .

1.3.4 [CCNO + C] Processes . . . . . . . . . . . . . . . 1.3.3

1.3.5 [CCCN + 01 Process . . . . . . . . . . . . . . . . 1.3.6 Cyclization Processes . . . . . . . . . . . . . . . . .

1.3.6.1 [OCCCN] Processes . . . . . . . . . . . . . 1.3.6.2 [CCCON] Processes . . . . . . . . . . . . . 1.3.6.3 [CCNOC] Processes . . . . . . . . . . . . . 1.3.6.4 [CCCNO] Processes . . . . . . . . . . . . .

1.3.7 From Heterocyclic Compounds . . . . . . . . . . . . From Other 1, 2-Oxazole Derivatives . . . . . .

1.3.7.2 From Other Heterocycles . . . . . . . . . . . 1.4 Chemical Properties . . . . . . . . . . . . . . . . . . . .

1.4.1 Protonation and Quaternization . . . . . . . . . . . . 1.4.2 Complexation . . . . . . . . . . . . . . . . . . . .

1.4.2.1 Metallic Complexes . . . . . . . . . . . . . 1.4.2.2 Molecular Complexes . . . . . . . . . . . . .

1.4.3.1 Hydrogenolytic Ring Cleavage . . . . . . . . . Reductions without Ring Cleavage . . . . . . .

1.4.5 Thermolysis and Photolysis . . . . . . . . . . . . . . 1.4.6 Reactions with Nucleophiles . . . . . . . . . . . . . .

Reactions with Ring Cleavage . . . . . . . . .

1.3.7.1

1.4.3 Reduction Reactions . . . . . . . . . . . . . . . . .

1.4.3.2 1.4.4 Oxidation Reactions . . . . . . . . . . . . . . . . .

1.4.6.1

. 157

. 171

. 173

. 176

. 182

. 183

. 183

. 196

. 203

. 207

. 209

. 209

. 215

. 215

. 218

. 218

. 218

. 218

. 220

. 221

. 221

. 227

. 227

. 248

. 264

. 265

. 268

. 268

. 273

. 273

. 273

. 281

. 284

. 285

. 298

. 298

... Contents X l l l

1.4.6.2 Reactions Without Ring Cleavage . . . . . . . . 319 1.4.7 Carbanionic Condensations . . . . . . . . . . . . . . . 324

1.4.7.1 Metallation . . . . . . . . . . . . . . . . . . 324 1.4.7.2 Other Base-Promoted Condensations . . . . . . . 331

1.4.8 Grignard Reagents . . . . . . . . . . . . . . . . . . . 333 1.4.9 Electrophilic Substitutions . . . . . . . . . . . . . . . 334

1.4.9.1 Nitration . . . . . . . . . . . . . . . . . . . 335 1.4.9.2 Sulfonation . . . . . . . . . . . . . . . . . . 337 1.4.9.3 Halogenation . . . . . . . . . . . . . . . . . 337 1.4.9.4 Other Substitutions . . . . . . . . . . . . . . . 340

Systems . . . . . . . . . . . . . . . . . . . . . . . . 341

Heterocycles . . . . . . . . . . . . . . . . . 342

Heterocycles . . . . . . . . . . . . . . . . . 343

1.4.10 Ring Transformations into Other Heterocyclic

1.4.10.1 Transformations into Three-Membered

1.4.10.2 Transformations into Four-Membered

1.4.10.3 Transformations into Five-Membered Heterocycles,



1.4.10.6 Transformations into Six-Membered Heterocycles,

1.4.10.7 Transformations into Six-Membered Heterocycles,

1.4.10.8 Transformations into Seven-Membered

1.4.10.9 Transformations into Heterocyclic Condensed

Containing One Heteroatom . . . . . . . . . . 343

Containing Two Heteroatoms . . . . . . . . . 347

Containing Three or Four Heteroatoms . . . . . 354

Containing One Heteroatom . . . . . . . . . . 359

Containing More than One Heteroatom . . . . . 366

Heterocycles . . . . . . . . . . . . . . . . . 369

Systems . . . . . . . . . . . . . . . . . . . 370 1.4.1 1 Other Reactions Without Ring Cleavage . . . . . . . . . 371 1.4.12 Use of Isoxazoles as Key Intermediates in Synthetic Design 391

1.4.12.1 Syntheses of Aliphatic Compounds . . . . . . . 393 1.4.12.2 Syntheses of Alicyclic Compounds . . . . . . . 400 1.4.12.3 Syntheses of Aromatic Compounds . . . . . . . 408 1.4.12.4 Syntheses of P-Lactones and P-Lactams . . . . . 413 1.4.12.5 Syntheses of y-Butyrolactams . . . . . . . . . . 413

2 . ISOXAZOLINES (DIHY DROISOXAZOLES) 417

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 417 2.2 2-Isoxazolines . . . . . . . . . . . . . . . . . . . . . . . . 418

2.2.1 Physicochemical Properties . . . . . . . . . . . . . . . 418 2.2.1.1 Infrared Spectra . . . . . . . . . . . . . . . . 418

xiv Contents

2.2.1.2 Ultraviolet and Fluorescence Spectra . . . . . . . 419 2.2.1.3 Nuclear Magnetic Resonance Spectra . . . . . . . 421 2.2.1.4 Mass Spectrometry . . . . . . . . . . . . . . . 441 2.2.1.5 Other Spectra: Circular Dichroism . . . . . . . . 452 2.2.1.6 Crystal and Molecular Structure . . . . . . . . . 452 2.2.1.7 Dipole Moments . . . . . . . . . . . . . . . . 456 2.2.1.8 Theoretical Calculations . . . . . . . . . . . . 457 2.2.1.9 Miscellaneous Data . . . . . . . . . . . . . . 458 2.2.1.10 Chromatographic Analysis . . . . . . . . . . . 459

2.2.2 Syntheses . . . . . . . . . . . . . . . . . . . . . . . 460 2.2.2.1 [CCC + NO] Processes . . . . . . . . : . . . . 461 2.2.2.2 [CNO + CC] Processes: Cycloaddition of Nitrile

Oxides and Their Precursors to Ethylenic Compounds . . . . . . . . . . . . . . . . . . 475

2.2.2.3 [CNO + C + C] Process: Reaction of Nitrile Oxides with Ylides . . . . . . . . . . . . . . . . . . 523

2.2.2.4 [CCNO + C] Processes . . . . . . . . . . . . . 524 2.2.2.5 [CCCNO] Processes . . . . . . . . . . . . . . 525 2.2.2.6 Syntheses from Heterocyclic Compounds . . . . . 530 2.2.2.7 Miscellaneous Methods . . . . . . . . . . . . . 539

2.2.3 Reactions. . . . . . . . . . . . . . . . . . . . . . . 540 2.2.3.1 Reactions without Ring Cleavage . . . . . . . . 541

Reactions with Ring Cleavage . . . . . . . . . . 557

Synthetic Design . . . . . . . . . . . . . . . . 572

2.3 2-Isoxazoline N-Oxides . . . . . . . . . . . . . . . . . . . . 603 2.3.1 Physical Properties . . . . . . . . . . . . . . . . . . . 603 2.3.2 Methods of Preparation . . . . . . . . . . . . . . . . 607

2.2.3.2 2.2.3.3 Use of 2-Isoxazolines as Key Intermediates in

2.3.2.1 From 1, 3-Dinitroalkanes (353: X = NO2) or Their Precursors . . . . . . . . . . . . . . . . . . . 607

2.3.2.2 From 3-Halo-l-nitroalkanes (353: X = Br) (Pathway e) . . . . . . . . . . . . . . . . . . 610

2.3.2.3 From Diazoalkanes (353: X = N:) (Pathway f) . . . . . . . . . . . . . . . . . . 612

2.3.2.4 From Ylides [353: X = R, S(O)+] (Pathway g) . . . . . . . . . . . . . . . . . . 612

2.3.2.5 Miscellaneous Methods . . . . . . . . . . . . . 613

2.3.3 Chemical Properties . . . . . . . . . . . . . . . . . . 614 2.3.3.1 Deoxygenation . . . . . . . . . . . . . . . . 615 2.3.3.2 Dehydration . . . . . . . . . . . . . . . . . . 615 2.3.3.3 Reduction . . . . . . . . . . . . . . . . . . . 617 2.3.3.4 Oxidation. . . . . . . . . . . . . . . . . . . 618 2.3.3.5 Reaction with Grignard Reagents . . . . . . . . 618 2.3.3.6 Rearrangement Reactions . . . . . . . . . . . . 619

Contents xv

2.3.3.7 Miscellaneous Reactions . . . . . . . . . . . . 620

2.4 3-Isoxazolines . . . . . . . . . . . . . . . . . . . . . 2.5 4-Isoxazolines . . . . . . . . . . . . . . . . . . . . .

2.5.1 Physical Properties . . . . . . . . . . . . . . . . 2.5.2 Methods of Preparation . . . . . . . . . . . . .

2.5.2.1 [CNO + CC] Cycloaddition Reaction . . . 2.5.2.2 [CCC + NO] Process . . . . . . . . . . 2.5.2.3 Syntheses from Isoxazole or Isoxazolidine

Derivatives . . . . . . . . . . . . . . . 2.5.2.4 Miscellaneous Methods . . . . . . . . . .

2.5.3 Chemical Properties . . . . . . . . . . . . . . . 2.5.3.1 Thermolysis . . . . . . . . . . . . . . . 2.5.3.2 Other Ring-Opening Reactions . . . . . . 2.5.3.3 Addition Reactions to the CC Double Bond

. . . 621

. . . 625

. . . 626

. . . 630

. . . 630

. . . 637

. . . 638

. . . 640

. . . 641

. . . 641

. . . 646

. . . 647

3 . ISOXAZOLIDINES (Tetrahydroisoxazoles) 649

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 649 3.2 Physicochemical Properties . . . . . . . . . . . . . . . . . . 649

3.2.1 Infrared Spectra . . . . . . . . . . . . . . . . . . . . 650 3.2.2 Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . 650 3.2.3 Nuclear Magnetic Resonance Spectra . . . . . . . . . . 650

3.2.3.1 PMR Spectra . . . . . . . . . . . . . . . . . 651 3.2.3.2 13C-NMR Spectra . . . . . . . . . . . . . . . 666 3.2.3.3 "N-NMR Spectra . . . . . . . . . . . . . . . 669 3.2.3.4 I9F- and 3'P-NMR Spectra . . . . . . . . . . . 669

3.2.4 Mass Spectra . . . . . . . . . . . . . . . . . . . . . 670 3.2.5 Other Spectra . . . . . . . . . . . . . . . . . . . . . 674

Crystal and Molecular Structure . . . . . . . . . . . . . 675 3.2.7 Dipole Moments . . . . . . . . . . . . . . . . . . . . 678 3.2.8 Invertomers . . . . . . . . . . . . . . . . . . . . . . 679 3.2.9 Theoretical Calculations . . . . . . . . . . . . . . . . 683 3.2.10 Basicity . . . . . . . . . . . . . . . . . . . . . . . . 683 3.2.11 Miscellaneous Data . . . . . . . . . . . . . . . . . . 684 3.2.12 Analysis . . . . . . . . . . . . . . . . . . . . . . . 684

3.3.1 [CNO + CC] Processes . . . . . . . . . . . . . . . . 686 3.3.1.1 3.3.1.2

Compounds . . . . . . . . . . . . . . . . . . 710 3.3.1.3 Dimerization of Nitrones . . . . . . . . . . . . 721 3.3.1.4 Cycloaddition of Oximes to Ethylenic

Compounds . . . . . . . . . . . . . . . . . . 722 3.3.2 [CCC + NO] Processes . . . . . . . . . . . . . . . . 725

3.2.6

3.3 Synthesis 685

Cycloaddition of Nitrones to Ethylenic Compounds 686 Cycloaddition of Nitronic Esters to Double-Bond

xvi Contents

3.3.2.1 3.3.2.2 Oximation of qP-Ethylenic Carbonyl

Compounds . . . . . . . . . . . . . . . . . . 725 3.3.2.3 Other Processes . . . . . . . . . . . . . . . . 727

3.3.3 [CCCN + 01 Process . . . . . . . . . . . . . . . . . 728 3.3.4 Cyclization Processes . . . . . . . . . . . . . . . . . . 728

3.3.4.1 [OCCCN] Process . . . . . . . . . . . . . . . 728 3.3.4.2 [NOCCC] Process . . . . . . . . . . . . . . . 729 3.3.4.3 [CCCNO] Processes . . . . . . . . . . . . . . 729

Syntheses from 1, 3.Dihalo Compounds . . . . . . 725

3.3.5 From Heterocyclic Compounds . . . . . . . . . . . . . 730 3.3.5.1 From Other 1, 2-Oxazole Derivatives . . . . . . . 730 3.3.5.2 From Other Heterocycles . . . . . . . . . . . . 732

3.4 Chemical Properties . . . . . . . . . . . . . . . . . . . . . 733 3.4.1 Formation of Salts and Quaternization . . . . . . . . . . 733 3.4.2 Hydrogenolysis . . . . . . . . . . . . . . . . . . . . 734 3.4.3 Oxidation . . . . . . . . . . . . . . . . . . . . . . . 737 3.4.4 Thermolysis . . . . . . . . . . . . . . . . . . . . . . 738

3.4.4.1 1, 3-Dipolar Cycloreversion . . . . . . . . . . . 738 3.4.4.2 N-0 Bond Cleavage . . . . . . . . . . . . . 740 3.4.4.3 Elimination Reactions . . . . . . . . . . . . . 742 3.4.4.4 Decomposition to Carbonyl Compounds . . . . . 742

3.4.5 Photolysis . . . . . . . . . . . . . . . . . . . . . . . 743 3.4.6 Decomposition by Acids . . . . . . . . . . . . . . . . 744 3.4.7 Decomposition by Bases . . . . . . . . . . . . . . . . 747 3.4.8 Nucleophilic Reactivity . . . . . . . . . . . . . . . . . 750 3.4.9 Other Reactions in Side Chains . . . . . . . . . . . . . 752 3.4.10 Use of Isoxazolidines as Key Intermediates in Synthetic

3.4.10.1 Alkaloids via Intermolecular Nitrone

3.4.10.2 Alkaloids via Intramolecular Nitrone Cycloadditions . . . . . . . . . . . . . . . . 761

3.4.10.3 Other Nitrogen-Containing Products . . . . . . 765 3.4.10.4 Nitrogen-Free Systems . . . . . . . . . . . . . 774

Design . . . . . . . . . . . . . . . . . . . . . . . . 753

Cycloadditions . . . . . . . . . . . . . . . . 754

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867

List of Tables

Table 1.1. Table 1.2.

Table 1.3. Table 1.4. Table 1.5. Table 1.6. Table 1.7. Table 1.8. Table 1.9.

Table 1.10. Table 1 .1 1 . Table 1.12. Table 1.13. Table 1.14. Table 1.15. Table 1.16. Table 1.17. Table 1.18. Table 1.19. Table 1.20. Table 1.21. Table 1.22.

Table 1.23. Table 1.24. Table 1.25. Table 1.26. Table 1.27.

Table 1.28.

Table 1.29.

Table 1.30.

Table 1.31. Table 1.32. Table 1.33.

Isoxazole fundamental IR vibrations and assignments, 4 IR data for the CH vibrations of methyl- and dimethylisoxazoles, 5 UV data of isoxazole and alkylisoxazoles, 8 UV data of arylisoxazoles, 10 UV data of 3-(3,5-dichloro-2,4,6-trimethyl)-5-arylisoxazoles, 13 UV data of polyisoxazoles, 14 UV data of isoxazoles with unsaturated substituents, 15 UV data of alkylarylisoxazoles, 17 UV data of isoxazole carboxylic acids and derivatives, nitriles and carbonyl compounds, 18 UV data of 5-isoxazolepolyenealdehydes, 19 UV data of nitroisoxazoles, 20 UV data of hydroxy-, alkoxy- and aminoisoxazoles, 21 PMR data of isoxazole, 25 PMR data of alkylisoxazoles, 26 PMR data of aryl-, diaryl-, and arylheteroarylisoxazoles, 27 PMR data of alkylarylisoxazoles. 29 PMR data of 3,5-diarylisoxazoles, 30 PMR data of 3-, 4-, and 5-monosubstituted isoxazoles, 32 PMR data of disubstituted isoxazoles, 33 PMR data of hydroxy- and methoxyisoxazoles, 35 PMR data of aminoisoxazoles and derivatives, 36 PMR chemical shifts of methyl and other groups in trisubstituted isoxazoles, 38 PMR data of isoxazolium salts, 42 PMR coupling constants of isoxazole and methyl derivatives, 44 I3C-NMR chemical shifts of isoxazole and derivatives, 46 I3C-NMR chemical shifts and I3C-”N coupling constants, 48 I3C-NMR chemical shifts of the isoxazole ring carbon atoms for 3,5-diarylisoxazoles, 49 I3C-NMR chemical shifts of the isoxazole ring carbon atoms for isoxazolium salts, 50

C-NMR chemical shifts of the isoxazole ring carbon atoms of 3-phenoxymethylisoxazolinones and derivatives. 52 I3C-NMR chemical shifts at 30” of 3-aryl- 1 -(3,4-dimethyl-5- isoxazolyl)triazenes, 52 Calculated EHT net charges for isoxazole, 53 Coupling constants JC-H of isoxazoles, 54 Nitrogen chemical shifts of isoxazole and derivatives, 5 5

13

xvii

xviii


Table 1.36. Table 1.37. Table 1.38. Table 1.39. Table 1.40. Table 1.41. Table 1.42. Table 1.43. Table 1.44. Table 1.45. Table 1.46.

Table .47. Table .48. Table .49. Table S O . Table .51.

Table 1.52.


Table 1.56. Table 1.57. Table 1.58. Table 1.59.



Table 1.65.


List of Tables

'J("N-H,) coupling constants, 58 "0-NMR chemical shifts and line widths of furan, isoxazole, and furazan derivatives, 59 MIKE spectrum of isoxazole and stable fragment ions, 60 Mass spectra of isoxazole and methyl derivatives, 62 Mass spectra of alkylarylisoxazoles, 65 Mass spectra of arylisoxazoles, 68 Mass spectra of haloisoxazoles, 7 5 Mass spectra of isoxazolecarboxylic acids and esters, 77 Mass spectra of hydroxylated isoxazoles, 78 Mass spectra of isoxazolylketones, 79 Mass spectra of nitroisoxazoles, 82 Mass spectra of alkoxyisoxazoles, 84 Experimental and calculated (CNDO/S-CI) shake-up energy and intensity of isoxazole, 90 Bond lengths and angles for the rings of isoxazole derivatives, 93 Bond lengths and angles of a methylenetriisoxazole, 94 Bond lengths and angles of diisoxazoles, 96 Electric dipole moments of substituted isoxazoles, 99 Calculated n-electron densities and n-bond orders of isoxazole, 105 Calculated bond lengths and bond angles of the isoxazole molecule, 106 Geometries of N-protonated isoxazole, 106 Calculated dipole moment of isoxazole, 108 MIND0/3 calculations of molecular vibration frequencies of isoxazole, 1 11

N Quadrupole coupling constants, 112 pK, values of isoxazole derivatives, 11 5 pK, values of isoxazole monocarboxylic acids, 1 16 Base strengths (pK, values of conjugated acids) of isoxazolinones and hydroxyisoxazoles, 1 17 Thermodinamic parameters of isoxazole and derivatives, 120 Magnetic susceptibility of metal complexes of isoxazole and derivatives, 121 Isoxazoles from asymmetrically substituted P-diketones, 133 Synthesis of 3- and 5-alkyl-isoxazoles, 160 Synthesis of isoxazoles from P-OR-a,P-ethylenic ketones and aldehydes, 162 Synthesis of isoxazoles from P-NRR'-a,p-ethylenic ketones and aldehydes, 165 Synthesis of isoxazoles from P-halo-a,/?-ethylenic nitriles, 169 Synthesis of isoxazoles from P-substituted a,p-ethylenic nitriles. 170

14

List of Tables xix

Table 1.68.



Table 1.78. Table 1.79. Table 1.80. Table 1.8 1. Table 1.82. Table 1.83.



Table 1.88. Table 1.89. Table 1.90. Table 1.91. Table 1.92. Table 1.93.

Table 1.94.



Reaction of benzonitrile oxides with arylacetylenes: percentage yield of acetylenic oximes in the reaction mixture, 184 Cycloaddition of nitrile oxides to monosubstituted alkynes, 185 Cycloaddition of nitrile oxides to 1,2-disubstituted alkynes, 186 Synthesis of isoxazoles from functionalized nitrile oxides, 190 Cycloaddition of nitrile oxides to P-haloalkenes, 197 Synthesis of isoxazoles from P-azidovinyl ketones and related compounds, 21 9 Synthesis of 3-haloisoxazoles from j-nitroketones, 222 Oxidative conversion of 2-isoxazolines to isoxazoles, 228 Synthesis of isoxazoles from 5-amino-2-isoxazolines, 235 Synthesis of 3-arylisoxazoles and of dimethyl 3-arylisoxazole-4,5- dicarboxylates from norbornadiene derivatives and nitrile oxides, 243 Synthesis of isoxazoles from 3-acylbenzofurans, 249 Metallic complexes of isoxazole derivatives, 270 Reduction of isoxazoles to b-enaminoketones, 275 Selected catalytic hydrogenations of isoxazoles, 282 Thermal isomerization of 5-aminoisoxazoles to azirines, 290 Photochemical conversion of isoxazoles into 1-azirines and oxazoles, 294 Base-promoted isomerization of 3-unsubstituted isoxazoles, 300 Isomerization of 3-unsubstituted isoxazoles to a-cyanocarbonyl compounds, 303 Reactions of isoxazolium salts with Grignard reagents, 31 3 Action of bases on 2,3,5-tri- or tetra-substituted isoxazolium salts, 318 Nucleophilic substitutions in isoxazole side chain, 323 Synthesis of styrylisoxazolium salts, 332 Reactivities toward deuteriodeprotonation, 335 Nitration of aryl-substituted isoxazoles, 336 Ring rearrangements of isoxazole derivatives, 355 Transformations of 5-acylaminoisoxazoles into pyrimidin-4- ones, 367 Synthesis of aminoisoxazoles through Hofmann or Curtius reaction, 383 UV data of 2-isoxazolines, 420 PMR data of 3-unsubstituted 2-isoxazolines, 422 PMR data of 3-substituted 2-isoxazolines, 423 PMR data of 3-substituted-4-methoxycarbonyl-2-isoxazolines, 424 PMR data of 3,5-disubstituted 2-isoxazolines, 425 PMR data of 3,4,5-trisubstituted 2-isoxazolines, 428 PMR data of 4-acyl- and 5-acyl-2-isoxazolines, 430

xx List of Tables



Table 2.16

Table 2.17.




Table 2.25.

Table 2.26.

Table 2.27. Table 2.28. Table 2.29. Table 2.30. Table 2.31. Table 2.32. Table 2.33. Table 2.34.

Table 2.35.

Table 2.36.


PMR data of 3,5,5-trisubstituted 2-isoxazolines, 432 PMR data of 3,4,5,5-tetrasubstituted 2-isoxazolines, 433 PMR data of 5-amino-3-aryl-4-methylene-2-isoxazolines, 434 13C-NMR chemical shifts of 2-isoxazoline carbon atoms, 437 I3C-NMR chemical shifts of methyl groups on 2-isoxazoline ring, 439 Optimum geometries (STO-3G) for 2-isoxazoline, 458 Ring-chain tautomerism of 5-hydroxy-2-isoxazolines, 472 Relative reactivities of dipolarophiles toward benzonitrile oxide, 492 Regioisomer ratios for the cycloaddition of nitrile oxides to CC double bond compounds, 494 Cycloaddition of nitrile oxides to chiral allylic ethers and alcohols, 499 Cycloaddition of nitrile oxides to vinylglycine derivatives, 500 Site-specificity in the cycloaddition of nitrile oxides to azaepta- fulvene derivatives, 502 Cycloaddition of nitrile oxides to 1 ,2-dialkylethylenes7 506 Cycloaddition of nitrile oxides to 5-vinylisoxazole derivatives, 508 Cycloaddition of nitrile oxides to trans-B-methylstyrenes, 5 10 Cycloaddition of nitrile oxides to allenic ethers, 512 Cycloaddition of nitrile oxides to acyclic sulfur-containing olefins, 518 Competition between cyclization and elimination in base treatment of quaternary salts [Arc( = NOH)CHRCHR’NR2”(Me)]+, 527 Oxidative cyclization of phenolic oximes to spiroisoxa- zolines, 528 Alkylation of 2-isoxazolines, 532 Synthesis of 2-isoxazolines from 2-methoxyisoxazolidines, 534 Synthesis of 2-isoxazolines from 4-methylenepyrans, 539 Monocyclic 2-isoxazolinium salts, 542 Nucleophilic substitution at position 3 of 2-isoxazolines, 549 Thermolysis of 2-isoxazoline derivatives, 558 Photolysis products from monocyclic 2-isoxazolines, 560 ?-Amino alcohols from reduction of hydrocarbyl-substituted 2- isoxazolines, 563 ?-Amino alcohols from reduction of oxygenated 2-isoxazolines, 564 Treatment of 5-chloromethyl-2-isoxazoline derivatives with bases, 568 IR and PMR data of 2-isoxazoline N-oxides, 604 Rearrangement reactions of 4-aryl-2-isoxazoline-3,5-dicar- boxylate N-oxide, 620

List of Tables xxi

Table 2.39. Table 2.40. Table 2.4 1.



Table 3.5.





PMR data of 4-isoxazolines, 627 I3C NMR data of 4-isoxazolines, 629 Cycloaddition of nitrones to methyl propiolate and cyanoacetyl- ene, 632 Thermolysis of monocyclic 4-isoxazolines, 645 PMR data of simple isoxazolidines, 652 PMR chemical shifts of methyl groups in polymethylated isoxazolidines, 657 PMR chemical shifts of spiroisoxazolidine derivatives, 660 PMR data of 2,3,3,5-tetrasubstituted isoxazolidine invertomers, 661 PMR data of 2,3,4,5-tetrasubstituted isoxazolidine invertomers, 662 PMR data of 2,3,5-trisubstituted isoxazolidines, 663 "C-NMR chemical shifts of isoxazolidines, 667 Coupling constants of 2-methoxy-4,5-dicyano-3-methoxy- carbonylisoxazolidine invertomers, 669 Bond lengths and angles of some isoxazolidines, 677 Dipole moments of isoxazolidines, 678 Dipole moments of isoxazolizidines, 679 Kinetic measurements of N-substituted isoxazolidines, 680 Relative rate constants for the cycloaddition of nitrones to ethylenic dipolarophiles, 688 Regioisomeric ratios of isoxazolidines, 690 Synthesis of isoxazolidines from a chiral nitrone, 692 Cycloaddition of C,N-diarylnitrones to 1,2-disubstituted olefins, 703 Synthesis of 2-methoxyisoxazolidine derivatives, 71 3 Synthesis of N-substituted isoxazolidines from oximes and olefins, 723

ISOXAZOLES

Part One

This is a part of the fo r tyn in th volume in the series


CHAPTER 1

Isoxazoles

1.1 INTRODUCTION

The chemistry of isoxazole dates from 1888, when Claisen2/888’ proposed the correct structure (3-methyl-5-phenylisoxazole) for the compound isolated some years before’”884 from the action of hydroxylamine on benzoylacetone. He suggested the name monoazole for the five-membered ring C,NO, which was modified by Hantsch”888 to isoxazole, a name derived from the already known isomeric ring oxazole. In 1891, Claisen published his classical paper “Ueber I s o x a ~ o l e , ” ~ / ~ ~ ’ in which the fundamental outline of the isoxazole chemistry was reported. The parent compound of the series, the unsubstituted isoxazole, was synthesized by the same author in 1903”03 by oximation of propargylaldehyde acetal.

From a historical point of view, it is interesting to note that two isoxazole compounds (i.e., eulite and d i s h ) had been isolated as early as 18521i852 from the reaction of concentrated nitric acid with citraconic acid. Nevertheless, their structures remained unknown for a long time, and were not demonstrated to be polynitro derivatives of isoxazole and 3,3’-diisoxazole, respectively, until 19462’4h.814h (see also 0 1.3.1.7b, pp. 178-179).

After the fundamental work of Claisen and co-workers on the oximation of b-dicarbonyl compounds, a few other authors, notably Dunstan and Dymond, 15/89! MOUreU,8/03,9/03.3’04 Wieland,3’03.4’03 and Schmidt, 3’08x/09 explored different methods of synthesis of the isoxazole ring (from nitroalkanes, unsaturated carbonyl or ydicarbonyl compounds, and nitrous or nitric acid). The synthesis from hydroximoyl chlorides and sodium acetylides was discovered in 1927,3/27 but the reemergence of interest in isoxazole chemistry must be ascribed to Quilico and co-workers, as a consequence of their research on the action of nitric acid on acetylenic compounds during the period 1930-1946 (see 0 1.3.1.7c, pp. 179-181).

The discovery by the same authors of the new synthesis from fulminic and nitrile OxideS,5/46.j’50.16/50 later included by H u i ~ g e n ~ ~ ’ ~ ~ in the general scheme

*Editor’s note: References are listed chronologically in the Reference list and are numbered as follows: reference number within yearilast two or three digits of year. Thus 2/888 is the second reference in 1888; 2/46 is the second reference in 1946.

1

2 Isoxazoles

of the 1,3-dipolar cycloadditions, led to a lively revival of interest in this heterocyclic ring. Its peculiar and almost unique properties favored a steadily increasing utilization of this ring as a synthon of various functionalities for the synthesis of heterocycles (see 41.4.10) and complex molecules (see 4 1.4.12). On the other hand, the discovery of the interesting pharmacological activities of some isoxazole derivatives, such as sulfa drugs, modified penicillins, antibiotics, and others (see Part 2 of this work), has contributed notably to the development of isoxazole chemistry.

The trivial name isoxazole, originally proposed by Hantsch, has been adopted by IUPAC and is used in Chemical Abstracts, although the more systematic name 1,2-azole is utilized occasionally by some authors. The three ring positions available for substitution were originally indicated as in structure A below, utilizing the Greek letters CI, p, and y starting from the position next to the oxygen atom. This nomenclature persisted until the 1950s, after which numbering beginning at oxygen atom, as depicted in structure B, predominated and is now used exclusively.

A B

A few compounds with the isoxazole ring have recently been found in natural sources: the dipolar compounds ibotenic acid (1) and muscimol (2), isolated from Amanita muscaria,122165~123'65 A . panther in^,^^'^^.^^^'^^ and A . c ~ t h u r n a t a ~ ~ ~ ~ ~ ~ (Agaricaceae), which have insecticidal and central nervous system (CNS) de-

r;sH3+ 1 2

HO

0

3 4

coo- COOH

1.2. Physicochemical Properties 3

pressant the pigment musca-aurin I (3) from A . muscaria;‘2’x2 and the plant growth regulator triumferol or 4-hydroxyisoxazole (4), isolated from the leaves of Triumfetta rhomboidea (Ti l ia~eae) .~~~’” Furthermore, 4,5-dimethylisoxazole has been detected in the volatile oil of tomato j ~ i ~ e ~ ~ ~ ~ ’ ~ ~ and in the volatile compounds from commercial soybean and trimethyl- isoxazole is present in the ether-soluble portion of cigarette smoke conden- sate ,266/78

1.2 PHYSICOCHEMICAL PROPERTIES

Sections on physicochemical properties are included in reviews on the chemistry of isoxazo1es.78~62~7ci79~243’79~3’4~80~203~84 Some topics can be found in Physical Methods in Heterocyclic Chemistry: s o l ~ b i l i t y , ’ ~ ~ ~ ~ ~ ionization constant^,^^'^' dipole moments,220i71 x-ray d i f f r a ~ t i o n , ~ ~ ~ / ~ ~ ultraviolet (UV),‘01/633 2 1 x / 7 1 infrared (IR),’02’63. 221/7’ photoelectron (PE),2x1i74 nuclear quadrupole resonance (NQR),222’7’ and r n i c r o w a ~ e ~ ~ ~ ’ ~ ~ spectroscopy, and mass spe~trometry.”~’~’

1.2.1 Infrared Spectra

The infrared and Raman spectra of isoxazole and isoxazole-d, have been

planar structure of isoxazole, belonging to the symmetry group C,, comparison with the spectra of other heterocyclic compounds (furan, pyrrole, etc.), and theoretical calculations, full assignments of the absorption frequencies of isoxazole have been made. The IR spectra have been recorded in both

The eight-atom molecule of isoxazole gives rise to 18 normal vibrations: 13 of A’ class and five of A” class. The 13 A’ vibrations can be classified as seven ring vibrations (four for stretching and three for bending modes) and six CH vibrations (three for stretching and three for bending modes). The five A” vibrations involve three CH out-of-plane bending and two ring deformations.52i59 The 18 fundamental vibrations of isoxazole and their more recent a s ~ i g n m e n t s ” ~ ’ ~ ~ ~ ’ ~ ~ ’ ~ ~ are reported in Table 1.1. Furthermore, overtones and combination bands for isoxazole25/59.52/59 and isoxazole-d, 77 /63 have been assigned.

Some differences in the assignments of the vibration frequencies in the region 1200 to lOOOcm-’, attributed to either the ring or the CH deformation mode, are given in various papers.25’59.52’59.64/61.1’3165 Ab solute IR intensities of isoxazole have been determined experimentally and compared with semiempirical Complete Neglect of Differential Overlap (CND0/2) molecular orbital (MO) calculation^.'^^'^^ Raman spectra of isoxazole, methyl- and phenyl-

ave also been reported, with assignments, but they have rarely been used when solving structural problems or identifying isoxazoles.

thoroughly investigated~?5/59.52/59.64/6l.77/63.l13/65.67/6X.1X5/6X.134/74,179/76 Based on the

vapor25/59.52/59. I34/74 and liquid phases25/59.52/59 and in S01Utions.64/6’.’34/74.179/76

iSOxaz01eSXB/40.25/59,52/59.134/74 h

4 Isoxazoles

TABLE 1.1. ISOXAZOLE FUNDAMENTAL, IR VIBRATIONS AND ASSIGNMENTS

A 3161 3131 3089 1557

1429 1366

1260

1217

1128

1091 1026

916 845 89 1 192 765 63 2 595

C-H vibrations: v = stretching

6 = in-plane bending

y = out-of-plane bending

6 = in-plane bending

r = out-of-plane bending

Ring vibrations: v = stretching

IR spectra of methy1-,"/61.'34'74 dimethy1-,25i59,64/6'~134'74 and trimethyl- i s o x a ~ o l e s , ~ ~ ' ~ ' in both the gaseous and liquid states and in solutions, have been measured between 4000 and 200 cm- ' . The frequencies of CH bonds of methyl- and dimethylisoxazoles are reported in Table 1 .2.77/66,134/74

In the vapor state, 3,5-dimethylisoxazole shows the following ring frequen- ~ i e s : ' ~ ' ~ ~ 1621 (v), 1558 (v), 1374 (v), 1415 (v), 1145 (d), 893 (d), 700 (d), 612 (r), and 584 (r), which have been attributed by comparison with those of isoxazole and 3,5-dimethyl-4-nitroisoxazole. The methyl groups on the isoxazole ring show different bands depending on their ring position: 3-methyl a t 1386- 1372 cm-' and 4-methyl at 1396-1 391 and 963-936 cm-I . The higher-frequency bands (at ca. 1380-1 390 cm-') have been attributed to Me symmetrical bending modes, and that at ca. 940cm-' to the vc.c vibrations. Other absorptions, at 1200-1 IOOcm-' and 1030cm-', are probably due to methyl rocking modes.64161

A typical band at 2994-2962cm-I has been found in the IR spectra of 10 substituted 3-methylisoxazoles. Electron acceptor groups in the 4-position raise the vibration frequency of the asymmetric methyl bands, in agreement with the

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ISOXAZOLES · 2013-07-23 · cyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cyclo-