INDOLES P A R T T H R E E

Edited by

William J. Houlihan Sundoz Phunnuceutrrals

Kc.wurrh and Druelopmenc Vivtbion Eusr HanoIrr, N e w Jenes

('ON I'RIHII'IORS

William A. Remers

Thomas F. Spande 1.ahorurory of ('hemistry

NIAMDD. Nurionul Irtsr~rure\- of Ifculrh fltvhc.\du. Muryland

AN INTERSCIENCEOP PUBLICATION

JOHN WlLEY & SONS

NEW YORK - CHICHESTER - BRISBANE * TORONTO

Ocpurfrncnt of Phurmawutlcul .*iences The University of Arizona

'I'iccson. Arizona

INDOLES

PART THREE

This i s the iwcnry-fifth volrone in rhc series

T H E CHEMISTRY OF HETEROCYCLIC C O M P O U N D S

- _ _

TH E C H E MI S T R Y 0 F H E T E R 0 C Y C I, I C C OM POU N D S

A S E R I E S OF M O N O G R A P H S

A R N O L D WEISSBERGER and E D W A R D C. TAYLOR

Editors

INDOLES P A R T T H R E E

Edited by

William J. Houlihan Sundoz Phunnuceutrrals

Kc.wurrh and Druelopmenc Vivtbion Eusr HanoIrr, N e w Jenes

('ON I'RIHII'IORS

William A. Remers

Thomas F. Spande 1.ahorurory of ('hemistry

NIAMDD. Nurionul Irtsr~rure\- of Ifculrh fltvhc.\du. Muryland

AN INTERSCIENCEOP PUBLICATION

JOHN WlLEY & SONS

NEW YORK - CHICHESTER - BRISBANE * TORONTO

Ocpurfrncnt of Phurmawutlcul .*iences The University of Arizona

'I'iccson. Arizona

An Intcrx-icnce ”’ I’uhlication

Copyright 0 1079 bj John Wile! & Sons, Inc

All rigtits reserved. I’uhlished siniultaneously in C’anada

Kcproduction or translation of any part of this work hcyond that permitted h y Sections 107 or IOX of the 1976 United States Copyright Act without the permission of the copyright owner ih unlawful. Requehth for pcrinission o r furthcr inforniation should he addressed t o

the f’criiiissiom Ikpartnicnt . John Wiley & Som. Inc.

Library of Congres Cataloging in Publication Data

Main critry undcr title: I Il~lolcs.

(The Chemistry o f heterocyclic compounds. v. 2 5 ) lnclutlcx hihliographical rrfercnccs. I . Indole. I . Houlihan. William J . , 1930- cd.

OD101.14 517’.593 7h- I54323 ISBN 0-47 1-05 132-2 (v . 25. pt. 3 1

I 0 9 X 7 h 5 . 1 3 2 1

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 physiological 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 modern detailed and comprehensive 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 accommodate the specific interests of the au- thors.

In order to continue to make heterocyclic chemistry as readily accessi- ble as possible, new editions are planned for those areas where the respective volumes in the first edition have become obsolete by over- whelming progress. If, however, the changes are not too great so that the first editions can be brought up-to-date by supplementary volumes, supplements to the respective volumes will be published in the first edit ion.

ARNOLD WEISSBERGER

Research Loboratories Eustrnan Koda k Cot tipan y

Rochesrer. New York

EDWARD C. TAYLOR

Princeion Uniucrsiiy Princeton, Ncw Jcrscy

V

Acknowledgments

I am grateful to Mrs. Madeline Wizorek for her assistance in prepara- tion of this volume and to the management of Sandoz Pharmaceuticals for providing excellent support facilities.

W. J. H. Emf Hanorer. New Jersey

vii

Contents

Part Three

VIM. Hydroxyindoles, Indole Alcohols, and Indolethiols 1

THOMAS F. SPANDE, Laboratory of Chemistry, NIAMDD, National Institutes of Health, Bethesda, Maryland

IX. Indole Aldehydes and Ketones 357

WILLIAM A. WMERS. Department of Pharmaceutical Sci- ences, The University of Arizona, Tucson, Arizona

Author Index 529

Subject Index 5 69

ix

X

Part One

Contents

1. Properties and Reactbns of Indoles

11. Synthesis of the Indole Nucleus

Part Two

111. Biosynthesis of Compounds Containing an Indole Nucleus

IV. Alkyl, Alkenyl and Alkynyl Indoles

V. Haloindoles and Organometallic Derivatives in Indoles

VI. Indoles Carrying Basic Nitrogen Functions

VII. Oxidized Nitrogen Derivatives of Indole

Part Four

X. Dioxindoles, Isatins, Oxidindoles, Indoxyls, and Isatogens

XI. Indole Acids

INDOLES

PART THREE

This is the twenty-fifth uolunte in rhe series

T H E CHEMISTRY OF HETEROCYCLIC C O M P O U N D S

CHAPTER VIII

Hydroxyindoles. Indole Alcohols. and Indolethiols

THOMAS F . SPANDE

Laboratory of Chemistry. NIAMDD. National Institutes of Health, Bcrhesda, Maryland

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

B . Persulfate and Other Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

A . Fischer Cyclization . . . . . . . . . . . . . . . . . . . . . . . . 1 . Ketones and Aldehydes . . . . . . . . . . . . . . . . . . . . 2 . a-Ketoacids . . . . . . . . . . . . . . . . . . . . . . . . . .

a . Pyruvates . . . . . . . . . . . . . . . . . . . . . . . . . b Other a-Ketoacids . . . . . . . . . . . . . . . . . . . . .

B . Reissert Reduction . . . . . . . . . . . . . . . . . . . . . . . .

11 . Direct Hydroxylation of the Indole Benzene Ring A . The "Udenfriend" and Related Hydroxylating Systems . . . . . . . . .

JII . Synthesis of Hydroxyindoles

3 . The JappKlingemann Reaction

1 . Hydroxyindoles . . . . . . . . . . . . . . . . . . . . . . . . 2 . Methoxy- and Ethoxyindoles 3 . Benzyloxyindoles . . . . . . . . . . . . . . . . . . . . . . .

C . Reduction of Dinitrostyrenes . . . . . . . . . . . . . . . . . . . 1 . Alkoxy- and Hydroxyindoles 2 . Dialkoxy- and Dihydroxyindoles 3 . Tri- and Polyalkoxyindoles

1 . Reduction of Alkoxybenzylnitriles 2 . Reduction of 2-Nitrophenylacetone Derivatives 3 . Reduction of Oximes

1 . Nonaromatic a-Haloketones 2 . Aromatic a-Bromoketones or Benzoin . . . . . . . . . . . . 3 . Related Syntheses . . . . . . . . . . . . . . . . . . . . . . . 5 , 6-Dihydroxyindoles from Aminochromes . . : . . . . . . . . . . 1 . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Preparation of I-Methyl-5, 6-dihydroxyindole

1

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . D . Other Reduction Procedures . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Methoxyindoles from the Bischler Reaction

. . . . . . . . . . . . . . . . . .

F .

. . . . . . . . . . .

6 9 9

11 12 I:! 12 1.5 15 15 17 21 21 21 23 24 24 25 28 29 29 30 31 31 32 33 36 37 31 -11

2 Chapter VIII

3. Preparation of Other 1-Alkyl-5.6-dihydroxyindoles . . . . . . . . 42 4. Preparation of 7-Halo-5,6-dihydroxyindoles . . . . . . . . . . . 42 5 . Other 7-Halo-5,6-dihydroxyindoles . . . . . . . . . . . . . . . 43 6. C-Methyl-5,6-dihydroxyindoles . . . . . . . . . . . . . . . . . 44

G. The Nenitzescu Synthesis of 5-Hydroxyindoles . . . . . . . . . . . . 46

2. Scope of the Reaction . . . . . . . . . . . . . . . . . . . . . 4X a.Quinone Component . . . . . . . . . . . . . . . . . . . . . 48 b. Enamine Component . . . . . . . . . . . . . . . . . . . . 49

3. Synthetic Procedures . . . . . . . . . . . . . . . . . . . . . . 50

6 . Analogous Indole Syntheses . . . . . . . . . . . . . . . . . . 62 H. Alkoxy- and Hydroxyindoles using Miscellaneous Procedures . . . . . 67

1. Reductions of Oxindoles and Isatins with Metals or Metal Hydrides . 2. Miscellaneous Dehydrogenations . . . . . . . . . . . . . . . . 70

3. Methoxyindoles by Ring Contraction of Quinoline Derivatives . . . . 73 4. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . 75

a. Alkoxyindolines . . . . . . . . . . . . . . . . . . . . . . 75 b. Hydroxyindoles . . . . . . . . . . . . . . . . . . . . . . . 75

1V. The Alkoxygramines . . . . . . . . . . . . . . . . . . . . . . . . . 79 A. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

V. Hydroxytryptamines . . . . . . . . . . . . . . . . . . . . . . . . . 83

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 46

4. Orientation Effects . . . . . . . . . . . . . . . . . . . . . . 51 5. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . 55

. 67

a. From lndolines . . . . . . . . . . . . . . . . . . . . . . . 70 b. 4-Hydroxyindoles by Dehydrogenation of 4-Oxotetrahydroindoles 71

B. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . X I

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 1. Bufotenine . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . XS 3. Psilocybin and Psilocin . . . . . . . . . . . . . . . . . . . . . Xh 4. Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . X8

B. Synthesis from Alkoxyindoles . . . . . . . . . . . . . . . . . . . 89 1. Via Gramine Derivatives . . . . . . . . . . . . . . . . . . . . X 9 2. Oxalyl Chloride Procedure . . . . . . . . . . . . . . . . . . . 97 3. Via Alkoxyindole-3-aldehydes and Nitroalkanes . . . . . . . . . . 1 0 1 4. Via Alkoxyindolemagnesium Halides . . . . . . . . . . . . . . . I04

a. Coupling with Q -Haloacetonitriles . . . . . . . . . . . . . . . b. Coupling with a-Chloroacetamides . . . . . . . . . . . . . . I05 c. Reaction with Acyl Chlorides I06

I04

. . . . . . . . . . . . . . . . . d. Reaction with Amines . . . . . . . . . . . . . . . . . . . . I 06 e.Other . . . . . . . . . . . . . . . . . . . . . . . . . . . IOX

5. Alkoxytryptamines from lsatin or Indoxyl Derivatives . . . . . . . I O X 6. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 1

C. Alkoxy- or Hydroxytryptamines from Non-lndolic Precursors . . . . . I I3 I . Fischcr Cyclizations of Alkoxyphenylhvdramnes . . . . . . . . . . 1 I3

a. From Aldehydes . . . . . . . . . . . . . . . . . . . . . . 113 b. From Ketones . . . . . . . . . . . . . . . . . . . . . . . 115 c. From a-Acyl Esters and Alkoxybenzenediazonium Salts . . . . . 120

2. Abramovitch-Shapiro Reaction . . . . . . . . . . . . . . . . . I 2 0 3. Bischler Synthesis . . . . . . . . . . . . . . . . . . . . . . . I27

H ydroxyindoles. Indole Alcohols. and Indolethiols 3

4 . Miscellaneous Syntheses . . . . . . . . . . . . . . . . . . . . i30 D . Hydroxytryptarnine Reactions . . . . . . . . . . . . . . . . . . . i32

1 . OAIkylation or OAcylation . . . . . . . . . . . . . . . . . . 132 2 . N-Alkylation or N-Acylation . . . . . . . . . . . . . . . . . . 132 3 . SaltFormation . . . . . . . . . . . . . . . . . . . . . . . . 133 4 . Formation of @-Carbolines . . . . . . . . . . . . . . . . . . . 133

a . Cyclization of N-Acetyltryptamines or -Tryptophans . . . . . . . 133 h . C'yclization of Tryptamincs o r Tryptophan:; with Aldehydes or

Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . 135 VI . Other Alkoxyindolealkylamines . . . . . . . . . . . . . . . . . . . . 136

B . Hydroxyhomotryptamines . . . . . . . . . . . . . . . . . . . . . 138 C . 3-Aminomethyl Derivatives of Hydroxyindoles . . . . . . . . . . . . 139

A . Hydroxyisotryptamines . . . . . . . . . . . . . . . . . . . . . . 136

VII . Reactions of Hydroxyindoles . . . . . . . . . . . . . . . . . . . . . 141 A . Chromogenic Reactions . . . . . . . . . . . . . . . . . . . . . . 141 B.Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

1 . Simple Hydroxyindoles . . . . . . . . . . . . . . . . . . . . . 142 2 . 5.6-Dihydroxyindoles and Melanin Formation . . . . . . . . . . . 143

C . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 D . Dealkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

1 . Aluminum Halides . . . . . . . . . . . . . . . . . . . . . . . 147 2.Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

E . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 1 . Dissolving Metals in Hydrochloric Acid . . . . . . . . . . . . . . 1.19 2 . Catalytic Hydrogenation and Dehydrogenation . . . . . . . . . . 149 3 . Birch Reduction . . . . . . . . . . . . . . . . . . . . . . . . 150 4 . Miscellaneous Reductions . . . . . . . . . . . . . . . . . . . 150

F . Electrophilic Substitution . . . . . . . . . . . . . . . . . . . . . 151 G . Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . 15.7

VIII . 1-Hydroxyindole and Derivatives . . . . . . . . . . . . . . . . . . . 153 A . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 B . 1-Hydroxy-2-Phenylindole . . . . . . . . . . . . . . . . . . . . 155 C . 1-Hydroxy-2-Methylindole and Analogues . . . . . . . . . . . . . 158 D . 1-Hydroxyindole-2-Carboxylic Acid and Derivatives . . . . . . . . . 159 E . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . 162

IX . The lndole Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . 164 A . Pyrrole-Ring Substituted . . . . . . . . . . . . . . . . . . . . . 164

1 . 2-Indolinols . . . . . . . . . . . . . . . . . . . . . . . . . . 164 a . Introduction . . . . . . . . . . . . . . . . . . . . . . . . 161 b . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 164

(1) . Sodium-Alcohol Reduction of Oxindoles . . . . . . . . . 164 (2) . Action of Hydroxide Ion on lndolenine Salts 164 (3) . Reaction of Acid Chlorides with Indolenines . . . . . . . . 165 (4) . Miscellaneous . . . . . . . . . . . . . . . . . . . . . 165

c . Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 166 2 . 3-Indolinols, Synthesis and Reactions . . . . . . . . . . . . . . 167 3 . 2, 3-Indolinediols . . . . . . . . . . . . . . . . . . . . . 169

a . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 169 b . Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 170

B . Side-Chain Substituted . . . . . . . . . . . . . . . . . . . . . . 170

. . . . . . . .

4 Chapter VIII

. . . . . . . . . . . . 1. Hydroxymethylindoles (Indole Methanols) 170 a. 3-Hydroxymethylindole and Derivatives . . . . . . . . . . . . 170

(1). Synthesis 170 (a). From Gramine 170

(2). Reactions . . . . . . . . . . . . . . . . . . . . . . . 174

(3). Synthesis and Reactions of Other Indole-3-methanols . . . . 176

( 1 ). Synthesis 177 (2). Reactions I79

c. Other Hydroxymethylindoles 1x0 2. Indole Ethanols . . . . . . . . . . . . . . . . . . . . . . . . I80

a. Indole-3-ethanol (Tryptophol) and Derivatives . . . . . . . . . I80 (I). Importance . . . . . . . . . . . . . . . . . . . . . . 180

(a). Tryptophol . . . . . . . . . . . . . . . . . . . . . I80 (b). Other Tryptophols 1x0

(2). Synthesis . . . . . . . . . . . . . . . . . . . . . . . 1x1 (a). Sodium-Alcohol Reduction . . . . . . . . . . . . . 1x1 (b). Lithium Aluminum Hydride Reduction . . . . . . . . 181 (c). Synthesis Using Ethylene Oxide and Its Derivatives . . . 182 (d). Miscellaneous Syntheses . . . . . . . . . . . . . . . I83

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . (b). From lndole-3-aldehydes 172 (c). Other Methods I73

(a). Hydrolysis and Solvolysis 174 (b). Hydrogenolysis I75

I77

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

h. 2-Hydroxymethylindole and its Derivatives

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

(3). Reactions . . . . . . . . . . . . . . . . . . . . . . . 3. Indole Propanols . . . . . . . . . . . . . . . . . . . . . . . 4. Tryptophan01 and Derivatives . . . . . . . . . . . . . . . . . . 5 . /3-Hydroxytryptamines and Miscellaneous Amino Alcohols . . . . . 6. Indole Butanols . . . . . . . . . . . . . . . . . . . . . . . . 7. Indole Ethylene Glycols and Indole Propanediols . . . . . . . . . 8. Indole Glycerol . . . . . . . . . . . . . . . . . . . . . . . . 9. Ascorbigcn . . . . . . . . . . . . . . . . . . . . . . . . . .

X. The lndolethiols . . . . . . . . . . . . . . . . . . . . . . . . . . . A. 2-Substituted . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . a. Introduction . . . . . . . . . . . . . . . . . . . . . . . . b. From Non-indole Precursors . . . . . . . . . . . . . . . . . c. From lndoles . . . . . . . . . . . . . . . . . . . . . . . .

(1). Alkylation of Thiones . . . . . . . . . . . . . . . . . . (2). Disulfur Dichloride, Sulfenyl or Sulfinyl Chlorides (3). Reactions with Sulfur . . . . . . . . . . . . . . . . . .

(a). Indole- and Skatolemagnesium Bromide (b). Indole . . . . . . . . . . . . . . . . . . . . . . .

(4). Misccllancous . . . . . . . . . . . . . . . . . . . . . . d. 2-Alkylthiotryptamines and -indolemethylamines . . . . . . . .

2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . a. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . b. Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . c. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . d. Thiolysis . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . .

. . . . . . . .

1x4 1 XX 1 X 9 189 I90 I92 I92 I 9 X I99 I99 15)')

190 2 0 0 100 200 203 206 '06 'Oh 207 208 209 20') 21 1 211 212

Hydroxyindoles. Indole Alcohols. and Indolethiols 5

e . Aminolysis . . . . . . . . . . . . . . . . . . . . . . . . . f . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . .

B . 3-Substituted . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . .

a . From Non-indole Precursors . . . . . . . . . . . . . . . . . (1) . Fischer Cyclization . . . . . . . . . . . . . . . . . . . (2) . Via N-Chloroanilines . . . . . . . . . . . . . . . . . .

( 1) . Thiourea-Triiodide . . . . . . . . . . . . . . . . . . . (2) . Thiocyanation . . . . . . . . . . . . . . . . . . . . .

(4) . Thionyl Chloride . . . . . . . . . . . . . . . . . . . . (5) . Reactions of Indolemagnesium Bromides

(a) . With Sulfur . . . . . . . . . . . . . . . . . . . . (b) . With SOz. SOCI,. and CS2

( 6 ) . Sulfur snd Indoles . . . . . . . . . . . . . . . . . . . (7) . Miscellaneous . . . . . . . . . . . . . . . . . . . . .

2.Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . a . Desulfurization . . . . . . . . . . . . . . . . . . . . . . . b . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . .

. . . . . 1 . Classical Methods . . . . . . . . . . . . . . . . . . . . . . .

a . Reissert Reaction . . . . . . . . . . . . . . . . . . . . . . h . Fischer Cyclization . . . . . . . . . . . . . . . . . . . . . c . Nenitzescu Reaction . . . . . . . . . . . . . . . . . . . . .

2 . Via Indolines . . . . . . . . . . . . . . . . . . . . . . . . . 3 . Mercaptoindolemethylamines . . . . . . . . . . . . . . . . . .

a . 2-Substituted . . . . . . . . . . . . . . . . . . . . . . . . b . 3-Substituted . . . . . . . . . . . . . . . . . . . . . . . .

4 . Mercaptotryptamines . . . . . . . . . . . . . . . . . . . . . a . Oxalyl Chloride Procedure . . . . . . . . . . . . . . . . . . b . Indolealdehyde-Nitroalkane Route . . . . . . . . . . . . . . c . Abramovitch-Shapiro Synthesis . . . . . . . . . . . . . . . . d . Fischer Cyclization . . . . . . . . . . . . . . . . . . . . .

D . N-Substituted Indole Thioethers . . . . . . . . . . . . . . . . . . E . Side-Chain-Substituted Indolethiols . . . . . . . . . . . . . . . .

1 . 3-Substituted Indolemethylthiol Ethers . . . . . . . . . . . . . . a . Mannich-like Reactions . . . . . . . . . . . . . . . . . . . b . Via Gramine or Its Salts . . . . . . . . . . . . . . . . . . . c . Indolealdehyde and Ammonium Sulfide . . . . . . . . . . . .

2 . 2-Substituted Indolemethylthiol Ethers . . . . . . . . . . . . . . a . Nenitzescu Reaction . . . . . . . . . . . . . . . . . . . . . b . 2, 4-Dinitrophenylsulfenyl Chloride on 2, 3-Dimethylindole . . . .

3 . Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . .

h . Desulfurization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

a . Thioureaor Thiosulfate on lndolealkyl Bromides . . . . . . . .

b . From Indoles . . . . . . . . . . . . . . . . . . . . . . . .

(3) . Disulfur Dichloride . . . . . . . . . . . . . . . . . . .

. . . . . . . . .

. . . . . . . . . . . . . .

C . Synthesis of Indoles with Thiol Function in the Benzene Ring

d . Fischer Synthesis . . . . . . . . . . . . . . . . . . . . . .

a . Nucleophilic Displacement . . . . . . . . . . . . . . . . . .

4 . Thiotryptophols: Derivatives and Homologues

b . Fischer Synthesis . . . . . . . . . . . . . . . . . . . . . .

212 213 215 215 215 215 216 217 217 21x 218 218 221 221 221 222 222 223 223 223 223 223 224 2.34 22-1 7 7 5

225 225 225 236 226 226 226 227 237 237 227 227 778

32X 229 229 229 229 230 230 230 230 2 3 0 231

...

..

6 Chapter Vll l

232 5. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . XI. Acknowledgment 232

3-32 XII. Addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 I

References 3 2 I

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . XIII. Appendix of Tables I-XXXI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. Introduction

Sections 11-VII of this chapter review the synthesis and reactions of indoles substituted in the benzene ring (positions 1, 5. 6 , or 7 ) with one or more hydroxyl or alkoxyl groups. Section VIII treats t h e synthesis and reactions of the formally related hut otherwise distinct class of 1 - hydroxyindoles. and Sections IX and X cover the synthesis iind reactions o f the indole alcohols and thiols. respectively. The literaturc is covered thoroughly through 1973 with some additions (see addenda) through 1077.

The hydroxyindoles and their methyl or benzyl ethers have assumed great importance as synthetic precursors of such physiologically active hydroxytryptamines as the hormones serotonin (1) and melatonin (2), and the naturally occurring hallucinogens psilocin (3). bufotenine (4) and psilocybin (5 ) . The hydroxy- and alkoxytryptamines are themselves im- portant intermediates in the synthesis of the alkaloids physostigmine;'"-' rescrpine.f>l .X7.?31.72 l a h a r r n a l i n e . ~ ~ 7 . ~ ~ ~ ~ . . ~ ~ ~ ~ or harmaline aiialogues.xx,7"'c5J

Hydroxyindoles arc of added importance in alkaloid chemistry as frequently encountered degradation products, for example. physostigmol

1; R=H; R = H % R=CH,; R=COCH,

3; 4-isomer 4; 5-isomer

O P G , P 63 CH,CH,NH(CH,), RO

I I CH,

& H

5 6; R=CH,. C,H,

Hydroxyindoles, Indole Alcohols, and Indolethiols 7

ethers (6) la.b.20.54 from eseroline (325a) ethers, 3-ethyl-5-methoxyindole from aricine,' 1,2-dimcthyl-3-ethyI-S-hydroxyindole from ibogaine,.' and 5-hydroxyindole from violacein"' or ~arpagine.~' ' A number of alkoxyindolines have been synthesized for study as physostigmine analogues3x.sn; some are reported to have appreciable activity:'" Hydrox- yindoles arc also employed as models in the interpretation of the uv spectra of hydroxylated indole alkaloids.4~s.'".'4'

Furthermore, hydroxyindoles have been used as laboratory models for the study of the melanization process, either in furnishing substrate analogues (e.g., C-methylated 5,6-dihydroxyindoIes) o r modified melato-

ins.2xh.w5 It has been primarily through studies using the former that investigators have been able to propose partial structures for melanin (e.g., 7ah or 7b') (see Section VII.B.2). Most syntheses of the hydroxytryptophans-important intermediates in the metabolism of tryptophan-rely on simple hydroxyindole intermediates.

7a

3) / ' 0

O \ 0

0 ' r H - 7b

Synthetic schemes leading directly to hydroxyindoles are few in number and are restricted to the preparation of specific indole systems. Examples are the Nenitzescu synthesis of 5-hydroxyindoles (eq. I ) , the dehydroge- nation of 4oxotetrahydroindoles to 4-hydroxyindoles (eq. 21, the synth- esis of 6-hydroxyindoles by alkaline decomposition of adrenochrome semicarbazones (eq. 3) , and the preparation of 5.6-dihydroxyindoles by reduction of adrenochromes (eq. 4), which result in turn from the oxidation of adrenaline derivatives.

Except for these cases, the hydroxyindoles have been traditionally obtained by demethylation of methoxyindoles with HBr or aluminum halides (see Section V1I.D) or much more satisfactorily, in modern practice, by hydrogenolysis of benzyloxyindoles. Catalytic dehydrogena- tion of alkoxyindolines has recently been developed as a practical route to the alkoxyindoles (Section III.H.2.a).

8 Chapter VIII

I H R

R R, R', R = H, alkyl

R

(4) R, R' = H, alkyl; R" = H, CH,

Most alkoxyindoles have been made by application of the venerable synthetic procedures of indole chemistry. Synthetic reactions that seem particularly suitable are the Fischer cyclization of alkoxyphenylhyd- razones prepared either from alkoxyphenylhydrazines and carbonyl com- pounds or alkoxybenzenediazonium salts and acetoacetic ester derivatives (the Japp-Klingemann reaction); the Reissert reduction of alkoxy-2- nitrophenylpyruvates; the reduction of alkoxy-substituted 2,p- dinitrostyrenes, and lastly, the Bischler synthesis using alkoxyanilines.

Reactions that have been successfully employed but that have received less application are reduction of alkoxy-substituted 2-nitrobenzylnitriles

Hydroxyindoles, Indole Alcohols, and Indolethiols 9

or 2-nitrophenylacetones; routes employing 'the dehydrogenation of 1 - acylindolines: reduction of alkoxy-substituted oxindoles, dioxindoles, or isatins with complex metal hydrides; and procedures based on the ring contraction of quinoline derivatives and the ring closure of m -chloro- alkoxyphenylethylamines to alkoxyindolines via "aryne" intcrmediates.

A recently introduced synthesis employing the reaction between alkox- yanilines and the chlorine complexes of appropriate a-methylthio al- dehydes or ketones has a number of advantages over classical procedures and may in time supplant them as a route to 2-, 3-, or 2,hubstituted al koxy ind~ les .~~ '

One indole synthesis of general utility, the Madelung cyclization, is apparently not applicable to the synthesis of alkoxyindoles, presumably because of the strongly alkaline conditions r e q ~ i r e d . ~ ' . ~ ~ '

The above syntheses all start from alkoxy-substituted non-indole pre- cursors and generally involve several steps, very often including a decar- boxylation. There do exist, however, scattered reports on the direct hydroxylation of the indole benzene ring in simple indoles, tryptamines. or tryptophan. This topic is considered first.

11. Direct Hydroxylation of the Indole Benzene Ring

A. The "Udenfriend" and Related Hydroxylating Systems

I n 1054, Udenfriend and co-workers reportedX that 5-hydroxy- tryptamine and an isomeric hydroxytryptamine, tentatively identified as 7-hydroxytryptamine, were produced in low yield when tryptamine was exposed to a hydroxylating system comprised of air (or oxygen). ferrous ion, EDTA, and ascorbic acid in a neutral phosphate buffer. This system has since become known as Udenfriend's model hydroxylating system.

Several groups have reported the hydroxylation of tryptophan with this system, but disagree about the identity of the resulting hydroxylated products. Dalgliesh""~" claimed to have obtained 5-hydroxytryptophan and an isomer presumed to be 7-hydroxytryptophan on the basis of Udenfriend's results with tryptamine. N o oxindoles o r kynurenines could be detected. Wieland and co-workers, on the other hand, reported"' that the major reaction product (25%) was oxindole-@-alanine with extremely low yields of 5-hydroxytryptophan (0 .3° /~ ) . 6-hydroxytryptophan (0.6% ), and 6-hydroxyoxindole-~-alanine (0.6%). Similar results were noted with simple tryptophan-containing peptides. Eich and Rochelmeyer. in a care- ful but qualitative study, reported" that the Udenfriend system afforded

10 Chapter VIII

all four hydroxytryptophans. No mention was made of oxindoles, al- though it seems likely that these could have been missed in the work-up procedure.

Szara and Axelrod have described the 6-hydroxylation of N",N"- dimethyltryptamine," and Kveder and McIsaac, the 6-hydroxylation of tryptamine using the Udenfriend system." No mention of other isomers was made in either case. Melatonin failed" to undergo hydroxylation with the Udenfriend system. Acheson and King report that indole-3- carboxylic acid is hydroxylated to a mixture of 5- and 6-hydroxyindole-3- carboxylic acid and products of pyrrole ring cleavage.'62

Indole was hydroxylated" to a mixture of the four possible hydroxyin- doles in the following relative yields: 4-hydroxy- (35%), S-hydroxy- (20%). 6-hydroxy- ( ~ S " / O ) , and 7-hydroxyindole ( 10%). Homing and co-workers have shown"." that skatole gives a mixture of all four hydroxyskatoles when hydroxylated with the Udenfriend system in aque- ous acetone. In addition, 3-methyloxindole and o-formamidoaceto- phenone were detected.

When hydrogen peroxide was used instead of oxygen in the Udenfriend system, Eich and Rochelmeyer reported achieving a preparative hydroxy- lation of indole." The four hydroxyindoles were formed in 16% yield and were separated by preparative thin-layer chromatography to give 4- hydroxy- (2S0 /o ) , 5-hydroxy- (33%), 6-hydroxy- ( 2 5 % ) , and 7- hydroxyindole (17%). The significantly different distribution of isomers with this system (a modified Fenton reagent) from that observed with the Udenfriend system implicates different hydroxylating species. ' I

Another system closely related to the Fenton reagent-ferrous ion chelated with polyphosphate and hydrogen peroxide in neutral phosphate buffer-has been employed by Nofre and co-workers in the hydroxylation of tryptophan and indoleacetic acid.'" 5-Hydroxytryptophan and presum- ably 7-hydroxytryptophan are formed from the former and S - hydroxyindole-3-acetic acid from the latter. 5-Hydroxyindole-3-acetic acid was also said to arise from the hydroxylation of tryptamine, although no other reaction products were mentioned. Employing another Fenton- type system (ferrous ion chelated with EDTA and hydrogen peroxide in a neutral phosphate buffer), Nofre and co-workers succeeded in identify- ing" eight products among the 13 or so produced. 5-Hydroxytryptophan, 3-hydroxy- and 5-hydroxykynurenine, and kynurenine were among the major products. In addition, fragments resulting from cleavage of the side chain (e.g., aspartic acid, alanine, and serine) were detected. Nofre and co-workers made the significant observation that greatly different results were obtained using the same hydroxylating system with the rigorous exclusion of air. The yield of 5-hydroxytryptophan increased. but the

Hydroxyindoles, Indole Alcohols, and Indolcthiols 1 1

hydroxykynurenines were absent and kynurenine was formed in much lower yields.

Hydroxylation of tryptophan using ferrous ion chelated with polyphosphate and the oxidant, tetrahydropteridine. in a neutral phos- phate buffer gave 5-hydroxytryptophan in 0.04-0.2% yield, along with an equivalent yield of melanin.'X".h Products of pyrrolc ring cleavage, includ- ing kynurenine (0 .5%) and 3-hydroxykynurenine (0.25%), were also isolated.

B. Persulfate and Other Oxidants

The action of alkaline potassium persulfate on tryptophan resulted only in products of pyrrole ring cleavage. for example. anthranilic acid, 3- hydroxyanthranilic acid sulfate (and probably the 5-hydroxy isomer), and o-aminophenol. Indole is converted to indoxyl sulfate."'

Under weakly acidic conditions, however, skatole (8) is reported" to give a 38% yield of 3-methyloxindole (lo), probably via 2- hydroxyskatole-0-sulfate (9) and a mixture of hydroxyskatole-0-sulfates (11). The latter mixture is identical to the hydroxyindoles resulting from the Udenfriend hydroxylation of skatole," subsequently shown to consist of all four hydroxyskatoies (12) (Scheme 1 ) . l 3 The same result was obtained by Heacock and Mahon2* who identified the hydroxyskatoles after acid hydrolysis of the sulfates; a sulfatase assay had to be abandoned when it was discovered that 4-hydroxyskatole sulfate resisted hydrolysis. The yield of either 6- or 7-hydroxyskatole was estimated to be higher than that of 5-hydroxyskatole. In addition, the formation of

8 9

I 11

H 10

H 12

Weme 1

12 Chapter VIII

ON(W3K)Z, aatone 'WcH3 -* w3 \

I H

15

I H20. PH 7

H I

H

13 14p, R = O H

Scheme 2

14b; R = H

3-methyloxindole and of two products of pyrrole ring cleavage, o- formamidoacetophenone and o-aminoacetophenone, was reported.

The only report of anything approaching the selective introduction of an oxygen function into the benzene ring of an indole is that by Teuber and Staiger23a.h who found that the action of potassium nitrosodisulfo- nate (Fremy's salt) o n 2,3-dihydroskatole (13) in aqueous acetone at pH 7 gave 5-hydroxyskatole (14) and skatole (14b), each in about 25% yield (Scheme 2). Similarly, 2-phenyl-2.3-dihydroindole gave 2-phenyl-S- hydroxyindole (68%) and 2-phenylindole (10%). Treatment of the hyd- roxyindoles with excess reagent afforded 4,s-indolequinones (e.g., 15) in good yields.

111. Synthesis of Hydroxyindoles

A. Fischer Cyclization

1 . Ketones und Aldehydes

The Fischer cyclization of the p-methoxyphcnylhydramnc of acetone proceeds poorly under the usual catalysis with ZnCI,. Chapman and co-workers obtained" only a 1 "/o yield of 2-methyl-5-methoxyindole and Bell and Lindwall reportedz5 their failure to isolate indoles using acetone o- or p-methoxyphenylhydrairone. The former phenylhydrdzone with ZnCI, in acetic acid aHordcd only a 0% yield of 2-methyl-7- methoxyindole.*" Spith and Brunner modified2' the usual Fischer proce- dure and used ZnCI, without a solvent at 110 ' . distilling the indole under vacuum as it formed. This procedure gave 2-methyl-5-niethoxyindole in 43% yield from the acetone p-methoxyphenylhydrdzone."' Bell and Lindwall reported a 20% yield of the same indole using this procedure."

When applied to propionaldehyde p-niethoxyphenylhydrazonc or N- methyl-N-p-methoxyphenylhydramne. this procedure afforded ?-methyl- 5-methoxyindole" and 1 .3-dimethyl-5-methoxyindo1e2" (54% ).?' Using ZnCl, in acetic acid, Cook and co-workers reportcdZA a 30% yield of

Hydroxyindoles, Indole Alcohols, and Indolethiols 13

product in the former reaction and King and Robinson have described2() the successful cyclization of the latter phenylhydrazone with 15% sulfuric acid in ethanol.

Spath and Brunner reported that acetone m-methoxyphenylhydrazone afforded a product assumed to be 2-methyl-6-methoxyindole in 36% yield.” They considered cyclization para to the methoxy group- affording the 6-methoxyindole-more likely than cyclization orfho to this group-giving the 4-methoxy isomer-although no structural proof was offered. The assumption that para substitution predominates in the Fischer cyclization of m-methoxyphenylhydrazones has been accepted by most workers and has received some experimental*” and theoretical’” support. Ockenden and Schofield treated2” the m -methoxyphenyl- hydrazones of butanone and of deoxybenzoin with HCI and acetic acid and obtained products in 25% and 32% yield, respectively. Ozonolysis of these products was carried out in an attempted structure proof but the results were ambiguous and structural assignments were finally made on the basis of their experience with other m -substituted phenylhydrazones. They concluded that the major products were 6-methoxyindoles and the minor product, isolated in the butanone reaction, was 2,3-dimethyl-4- methoxyindole.’” Vejdglek also showed that a mixture of 6- and 4- methoxy-2,3-dialkylindoles was formed when the m-methoxy- phenylhydrazones of butanone or 2-pentanone were cyclized with HCI in acetic acid.3’ In the former reaction, an 82% overall yield of indoles was obtained, and in the latter reaction the two isomeric methoxy-2-methyl-3-ethylindoles were obtained in 19 and 27% yields. No attempt was made to assign structures. Mentzer observed3‘ that the propiophenone m-methoxyphenylhydrazone 16 on treatment with ZnCI, gave the same product, presumably the 6-methoxyindole derivative 17, as was obtained from the Bischler cyclization of m-anisidinc and the bromoketone 18.

H

16

H

17; R = 4-CH30C,H, 18

Neuss and co-workers have claimed” without any evidence that cycli- zation of butanone rn -methoxyphenylhydrazone (neat, with HCI) afforded 2,3-dimethyl-6-methoxyindole in 58% yield. Related to the question of the preferred direction of ring closure of tn- methoxyphenylhydrazones is the observation by Tomlinson and co- workers3.’ that deoxybenzoin and 2-chloro-5-methoxyphenylhydrazones

13 Chapter VlII

failed to cyclize in an attempted synthesis of 2.3-diphenyl-4-mcthoxy-7- chloroindole.

The most widely used procedure for the cyclization of al- koxyphenylhydrazones would appear to be HCI in anhydrous or aqueous acetic acid, although Keglevic and co-workers have recently reportedJ' the formation of 3-methyl- and 3-ethyl-5-benzyloxyindole in 54 and 53% yields, respectively, using 2.5'/;, acetic acid with t z o added mineral acid. Boron trifluoride etherate was found to be unsatisfactory for the cycliza- tion of mcthoxyphenylhydrazones.2'J According to an early report, NiCI2 is a good catalyst for the synthesis of 2-phenyl-5-methoxyin~(~le.Js

On treatment with HCI in acetic acid. butanone p-methoxy- phenylhydrdzonc cyclizes t o 2.3-dimethyl-5-methoxyindolc in 6O0h" and 53%" yields. The corresponding phenylhydrazone of deoxyhenzoin gave"' 2.3-diphenyl-5-mcthoxyindole in 2 1 YO yield.

Vejddek has described" the cyclization of butanone and 2-pentanonc o-methoxyphenylhydrazoncs to the 2.3-dialkyl-7-methoxyincloles in 47 and 51% yields. I n the hands of Borsche and Groth. the former com- pound with HCI in 10"/0 aqueous acetic acid gave 2.3-dimethyl-7- methoxyindole in 57% yield."

The closely related catalyst, H2S0, in acetic acid, has been used in the cyclization of butanone N-methyl-N-p-methoxypheriylhydrazone to I .2,3-trimethyl-5-methoxyindole with a 63% yield..3x Robertson and co- workers have reported the synthesis of the I-phenyl-?-methyl. ?-methyl- 3-phenyl. and 2.3-diphenyi derivatives of 5-methoxyindolc in 2 5 , 24. and 68% yiclds, respectively, o n cyclization o f the p-nicthouyphenyl- hydrazones of propiophenone, phenylacetone, and deoxybenzoin with HCI in cthan~l:~' The same catalyst produced I .2-dimethyl-5- mrthoxyindole in 37% yield from acetone N-methyl-N-p-methoxy- phenylhydrazone.'" The same phenylhydrazine derivative of 2-pentanone was cyclized by Schlittler and co-workers using ZnCI, under reduced pressure to prepare 1.2-dimethyl-3-ethyl-5-methoxyindole in 34% yield:' Likewise. acetophenone N-ethyl- N-p -et hoxyphenylhydrazone on treat - ment with ZnC12 in acetic acid gave 1 -ethyl-2-phcnyl-5-cthoxyindolc in 30% yield.'"

In an early investigation of melanin formation. Clemo and Weiss prepared 2,3-dimethyl-5,6-methylenedioxyindole as the precursor of thc 5.6-dihydroxyindole derivative." Fischer cyclization of hutanone 3.3- methylcnedioxyphenylhydrazone with HCI in acetic acid afforded the indole in 62% yield. Removal of the methylene group was effected with 75% H,SO,. Robertson and co-workers applied the same procedure to butanone 3,J-dimethoxyphenylhydrazone and obtained 7,3-dimethyl-5.6- dimethoxyindole in 33% yield." Here as in the previous case. cyclization

Hydroxyindoles, Indole Alcohols. and lndolethiols 15

para, rather than ortho, to the 3-methoxy group is observed. The dimeth- oxyindole could be demethylated in 78% yield with AIBr, in benzene."

2. a - Ketoacids

Because indolecarboxylic acids are covered in a later chapter this and the following section deal only with the formation of alkoxy- indolecarboxylic acids. produced by Fischer cyclization, that have been decarboxylated to alkoxyindoles. Many of the same compounds are obtainable also by the Reissert reaction and decarboxylation.

The p-methoxyphenylhydrazone of pyruvic acid has been cyclized to 5-methoxyindole-2-carboxylic acid (the ethyl ester is obtained when the reaction is carried out in ethanol) in yields of 20" and 30°/045 with H,SO, in ethanol or 38% with HCI in acetic acid." Decar- boxylation with copper chromite in quinoline" or heating at 205- 2 1 ()044.4.s gave 5-methoxyindole. Rydon and Siddappa reportedJh the formation of ethyl 5-ethoxyindole-2-carboxylate in 27% yield from the p-ethoxyphenylhydrazone of ethyl pyruvate. Saponification and decar- boxylation by fusion afforded 5-ethoxyindole in 46% yield. It has been reported that the p-ethoxyphenylhydrazone of pyruvic acid can be cyc- lized with ZnCI,. whereas the methoxy analogue fails." The N-methyl- N-p-methoxyphenylhydrazone of pyruvic acid has been cyclized with HCI in acetic acid to give 1 -methyl-S-rnethoxyindole-2-carboxylic acid in 2 l,j9 32," or 33'/0'~ yield. Decarboxylation at 200" was reported" to give 1- methyl-5-methoxyindole in 72% yield, whereas fusion at 220-225" gave a yield of 92%.'" The ethoxy analogue was cyclized in acetic acid (41% yield) and decarboxylated at 205" to afford 1 -methyl-5-ethoxyindole.""

'The o-methoxyphenylhydrazone of pyruvic acid gave 7-methoxyindole- 2-carboxylic acid in 40% yield on cyclization with ethanolic sulfuric

although the analogous N-methylphenylhydrazone was reported to cyclize (HCI/HOAc) in very poor yield.*' When the former reaction is conducted in HCI-ethanol, the expected product is produced in poor yields and the major products are the 6-chloro- and 6-ethoxyindole-2- carboxylic acid ethyl ester^.^^^.^" Pappalardo and Vitali attempted this reaction in HOAc-HCI, but failed to identify the resulting indole.j3 The N-methyl-N-rn -methoxyphenylhydrazone of pyruvic acid has been cyc- lized with HCI in ethanol and decarboxylated to give. allegedly, 1 -methyl- 6-met hoxyindole.5'

Blaikie and Perkin in their pioneering study of hydroxyindoles" reported that 3-methyl-5-methoxyindole-2-car- boxylic acid (20) was formed in 43% yield on cyclization of thc p- methoxyphenylhydrazone of 2-ketobutanoic acid (19) in alcoholic sulfuric

a. PYR~WATF.~ .

b. Onim ~-KETOACIDS.

16 Chapter VlII

I H H

19; R = R ' = H M, R = R ' = H 22; R = CH,. R' = C,H, 23; R = CH,. R' = CzH5

cH30wcH2R ( I ) OH-orA, (21 -co,

I H

21; R = H 24, R=CH,

acid. On decarboxylation at its melting point, 20 afforded a 75% yield of 3-met h yl-5 -methoxyindole (21). The isomeric o -met hoxyphen yl hydra- zone was reported to cyclize slowly and only in 23'/0 yield, to afford, after fusion, 7-metho~yskatole.~'

Stedman cycliied'" the N-methyl-N-p-ethoxyphcnylhydra70ne of 2- ketoglutaric acid (25) in SO% acetic acid to the dicarboxylic acid 27 in 27% yield. which was then decarboxylated at 250" to 1.3-dimethyl-S- ethoxyindole (physostigmol ethyl ether) (29) (Scheme 3 ) . Robinson and co-workers established that the t?i -rnethoxyphenylhydrazone of the same acid (26) in alcoholic HCI gave the 6-methoxyindole diacid 28'5 in low yield. The methosyskatolc 32 obtained on decarboxylation proved to he

CH2C02H

I I

R' k CH,

2% R = 4-CZH50. R' = CH, 26; R=3-CH30. R = H

27; R = C H , R=S-CzH,O, \ 29

2% R=6-CH,O; A. -zco, R = H

CH, I

HOAc

CH,O I CH,O C H P CO,H H H 31 32

scheme 3