HETEROCYCLIC COMPOUNDS WITH INDOLE AND CARBAZOLE SYSTEMS WARD c. SUMPTER Western Kenfur&yState College, Bowling Geen, Kenturhy F. M. MILLER Uniucrsity of Maryland, Baltimore, Maryland 1954 INTERSCIENCE PUBLISHERS, INC., NEW YORK INTERSC IE NCE PUBLISHERS LTD., LONDON This Page Intentionally Left Blank HETEROCYCLIC COMPOUNDS WITH INDOLE AND CARBAZOLE SYSTEMS Thlj is the eighth volume puhirihed in the series THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGRAPHS ARNOLD W EI S S BERG ER, Consulting Editor HETEROCYCLIC COMPOUNDS WITH INDOLE AND CARBAZOLE SYSTEMS WARD c. SUMPTER Western Kenfur&yState College, Bowling Geen, Kenturhy F. M. MILLER Uniucrsity of Maryland, Baltimore, Maryland 1954 INTERSCIENCE PUBLISHERS, INC., NEW YORK INTERSC IE NCE PUBLISHERS LTD., LONDON Copyright, 1954, Interscience Publishers, Inc. This book or any part thereof must not reproduced ALL RIGHTS RESERVED. be without permission of the publisher in writing. This applies specifically to photo- stat and microfilm reproductions. Library of Congress Catalog Card Number 53-10760 1 S'M<I<SCIISNCE J'I;JJLISHEI<S, INC., 250 1:iftti Avenue, Sew \'or]< I , S,Y. I:or Great Britain and Northern Ireland: Interscicnce Publishers Ltd., 88/90 Chancery I.anc, l,ontlon, \V. C. 3 The Chemistry of Heterocyclic Compounds The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications, for the diversity of its synthetic procedures, and for the physio- logical and industrial significance of heterocyclic compounds. A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modem detailed and com- prehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present series to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds, and ac- commodate the specific interests of the authors. Research Luboratorias ARNOLDWEISSBERGER Eastman Kodak Company Rochester, New York This Page Intentionally Left Blank Preface The chemistry of indole had its begrnnings in the dye industry, and thus for a number of years was intimately associated with dye chemistry. The intensely fertile research of this period produced a very diverse group of closely related compounds ; today the scope of indole chemistry is indeed multiform, extending from the rather simple parent material, through the condensed systems such as carbazole, the oxygenated indole derivatives, to the highly complex materials which occur naturally. In undertaking the preparation of a monograph on compounds con- taining the indole and carbazole rings our purpose has been to present a thorough and comprehensive treatment of the methods of preparation, the properties and the reactions of these compounds without attempting to duplicate the coverage of Beilstein (or of Elsevier’s Encyclopedia when completed) by listing every compound. We have, however, attempted to go beyond a simple listing of basic generalities by including a sufficiently large number of compounds to indicate exceptions and trends away from the general principIes. The literature coverage extends through 1952, and in- cludes several important papers of 1953. In the preparation of this volume, the responsibility for Chapter I (Indole), I1 (Carbazole), V (Isatogens), VI (Indoxyl), and VII (Indigo) was assumed by W. C. S., while Chapters 111 (Isatin) and IV (Oxindole) were rewritten by F. M. M. from earlier reviews on these topics by W. C. S. Chapter VIII was entirely the responsibility of F. M. M. We desire to acknowledge our indebtedness to Miss Josephine Williams and Mr. Phil Wilken for assistance in making the literature survey and for critically reading certain chapters, and to Mrs. Joseph Stewart for typing a large portion of the manuscript. One of us (F. M. M.) is indebted to the National Institutes of Health for a postdoctoral fellowship held at Harvard University in 1948-1949, during which time much of the work on Chapter VIII was done. We are grateful to Drs. C. F. 1-1. Allen and Bernhard Witkop for reading the manuscript and for making helpful suggestions for its improvement. Bowling Green, Kentucky w.c. s. Baltimore, Maryland F. M.M. vii This Page Intentionally Left Blank Contents I . Indole ...................................................... 1 Introduction .............................................. 1 Synthesis of Indole ........................................ 3 Oxidation of Indole ........................................ 23 Tautomerism of Indole .................................... 25 Sulfonation of Indole ...................................... 28 Halogen Derivatives of Indole .............................. 29 Alkyl Derivatives of Indole .................................. 31 Indoline .................................................. 36 Metal Salts of Indole ...................................... 40 Indole Aldehydes .......................................... 40 Acyl Derivatives of Indole .................................. 44 Condensation of Indoles with Aldehydes ...................... 48 Indolylmagnesium Halides .................................. 50 Indole Polymers .......................................... 61 Preparation and Reactions of Gramine ........................ 62 Carboxylic Acids of the Indole Series ........................ 65 I1 . Carbazole .................................................. 70 Introduction .............................................. 70 Preparation of Carbazole .................................... 72 Graebe-Ullman Synthesis ................................ 72 Method of Borsche ...................................... 73 Other Methods of Synthesis of Carbazoles .................. 78 Nitro Derivatives of Carbazole .............................. 81 Aminocarbazoles .......................................... 85 Halogen Derivatives of Carbazole ............................ 87 Carbazolesulfonic Acids .................................... 91 Reduction of Carbazole .................................... 93 Oxidation of Carbazole .................................... 96 Carbazyl Aldehydes and Ketones ............................ 97 Carbazole Carboxylic Acids ................................ 101 N-Acyl Carbazoles ........................................ 104 N-Alkyl Carbazoles ........................................ 105 111 . Isatin ...................................................... 110 Preparation of Isatin ...................................... 111 Properties of Isatin ........................................ 114 Tautomerism ............................................ 115 Reactions of Isatin ........................................ 116 X Contents I11 . Isatin (contimeti) Oxidation and Reduction .................................. 116 Halogenation and Nitration .............................. 118 Acylation and Alkylation .................................. 120 Reactions of the Carbonyl Groups .......................... 121 Grignard Reagents .................................... 121 Amine Derivatives .................................... 122 Miscellaneous Reagents ................................ 126 Active Methylene Groups ................................ 127 Biological Activity of Isatin ................................ 132 Analytical Uses of Isatin .................................... 133 . Oxindole .................................................. 134 IV Preparation of Oxindoles .................................. 134 Properties of Oxindoles .................................... 138 Tautomerism ............................................ 138 Salts .................................................... 138 Reactions of Oxindole ...................................... 139 Reduction .............................................. 139 Halogenation and Nitration .............................. 140 Condensation Reactions .................................. 142 Alkylation and Acylation .................................. 146 Derivatives ................................................ 148 Hydroxyoxindoles ........................................ 148 Dioxindole ............................................ 148 1 -Hydroxyoxindole .................................... 151 Aminooxindoles ........................................ 151 3. 3.Diaryloxindoles ...................................... 152 V . Isatogens .................................................. 154 VI . Indoxyl .................................................... 163 Introduction .............................................. 163 Synthesis of Indoxyl ...................................... 163 Physical Properties ........................................ 165 Reactions ................................................ 165 Acyl Derivatives of Intloxyl ................................ 167 Indoxyl Sulfuric Acid ...................................... 168 Indican .................................................. 168 Indoxylic Acid and Indoxyl-2-aldehyde ...................... 169 VII . Indigo ...................................................... 171 Introduction .............................................. 171 Occurrence of Indigo ...................................... 174 Synthesis of Indigo ........................................ 175 Physical Properties