Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

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Author: William J. Houlihan

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INDOLES

PART TWO

This is the twenty-jfih uolume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGRAPHS

ARNOLD WEISSBERGER and EDWARD C. TAYLOR

Editors

INDOLES PART TWO Edited by

William J. Houlihan Sandoz- Wander, Inc. Research and Development Division Hanover, New Jersey

CONTRlBUTORS

Ronald J. Parry

James C. Powers

Department of Chemistry Stanford University Stanford, Calijornia

Georgia Institute of Technology Atlanta, Georgia

Kent Rush

L. R. Smith

Eosrman Kodak Co. Research Laboratories Rochester, New York

Monsanto Co. S t . Louis, Missouri

F. Troxler

Chemical-Pharmaceutical Research Division Sandoz AG Bask, Switzerland

WILEY-INTERSCIENCE a division of

J O H N WILEY & S O N S , I N C . SYDNEY TORONTO

*

NEW YORK

*

LONDON.

Copyright 0 1972, by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada.

No part of this book may be reproduced by any means, nor transmitted, nor translated into a machine language without the written permission of the publisher. Library of Congress Catalog Card Number: 76-154323 ISBN 0-471-37501-2 10 9 8 7 6 5 4 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 authors. In order to continue to make heterocyclic chemistry as readily accessible as possible, new editions are planned for those areas where the respective volumes in the first edition have become obsolete by overwhelming 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 edition. ARNOLDWEISSBERGER Research Laboratories Eastman Kodak Company Rochester, New York Princeton University Princeton, New Jersey

EDWARDC. TAYLOR

Preface Indoles Part Two begins the detailed coverage of the preparation, properties, reactions and tabulation of compounds containing an indole nucleus. It starts with a chapter on indole biosynthesis since this was the first and only source of indole preparations during the early years of indole chemistry. The editor is grateful to Mrs. Maria Fanlo and Mr. Siegfried Wahrmann for library assistance and to Miss Linda Heuser for typing a portion of the manuscript. WILLIAMJ. HOULIHAN Hanover, New Jersey

Contents

Part Two III. Biosynthesis of Compounds Containing an Indole Nucleus

1

RONALD J. PARRY,Department of Chemistry, Stanford University, Stanford, California

IV. Alkyl, Alkenyl, and Alkynyl Indoles LOWELLR. SMITH,Monsanto Company, St. Louis, Missouri V. Haloindoles and Oqanometallic Derivatives in Indoles

65 127

JAMES C. POWERS,Department of Biochemistry, University of Washington, Seattle

VI. Indoles Carrying Basic Nitrogen Functions

179

FRANZTROXLER, Sandoz Ltd., Basle, Switzerland

W.Oxidized Nitrogen Derivatives of Indole

537

KENT RUSH,Eastman Kodak Company, Rochester, New York Index

607

Part One I. Properties and Reactions of Indoles II. Synthesis of the Indole Nucleus

Part Three VIII. Indole Alcohols and Thiols IX. Indole Aldehydes and Ketones X. Dioxindoles and Isatins XI. Oxindoles, Indoxyls and Isatogens XII. Indole Acids

INDOLES P A R T TWO

Chemistry of Heterocyclic Compounds, Volume25 Edited by William J. Houlihan Copyright 0 1972 by John Wiley & Sons, Inc.

CHAPTER 111

Biosynthesis of Compounds Containing an Indole Nucleus RONALD J. PARRY University Chemical Laboratory, Cambridge, England

I. Introduction

.

.

11. Simple Indole Derivatives

.

.

. .

. . .

. . . . . .

.

.

A. Tryptophan. . . . . B. 3-Indoleacetic Acid . . . 1. Biosynthesis in Higher Plants . . 2. Biosynthesis in Lower Plants . . C. 3-Indolecarboxaldehyde and 3-Indolecarboxylic Acid D. Ascorbigen . . E. Glucobrassicin . . . . F. Violacein . . . . . G. Echinulin . . . . . . H. Psilocybin . 111. Indole Alkaloids . . . A. Gramine . . . . B. Calycanthus Alkaloids . . . . C. Evodia Alkaloids. . . . D. Carboline Alkaloids . . E. Ergot Alkaloids . . F. Monoterpene-Derived Indole Alkaloids . IV. Addenda . . . A. lndolmycin . . B. Ergot Alkaloids . . C. Monoterpene-Derived Indole Alkaloids . . . References . . . . . .

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. .

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. . . . .

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.

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. . .

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. .

*

.

. .

.

I 2 2 9

9

13

14 15 . 16 . 1 7

.

. .

. . . . . . . .

18 19 20 20 22 23 24 26 32

54 . 5 4 . 5 5 . 56

. 5 7

I. Introduction Living plants produce an extraordinarily rich variety of chemical substances, many of which lack any apparent biochemical function. These 1

2

Chapter 111

metabolites have often proved the delight (and the frustration!) of organic chemists for the challenges of structural and synthetic chemistry which they offer. With the advent of radioactive tracers and the development of more sensitive chemical and spectroscopic tools, the doors leading to a deeper understanding of the chemistry of the plant world have been opened: the investigation of natural product biosynthesis has begun. Of the fruits of a field yet in its infancy, those arising from an examination of the biosynthesis of the naturally-occurring indoles have proved among the most tantalizing, and much may be expected of the future. The present account summarizes our knowledge of the biosynthesis of compounds containing an indole nucleus, and covers the literature through November 1968.

11. Simple Indole Derivatives A. Tryptophan

By virtue of its ubiquitous distribution in plant and animal proteins, tryptophan may justifiably be regarded as the most important of the naturallyoccurring indoles. Extensive explorations aimed at unraveling the tangled thread of its biosynthesis are a consequence of this importance. These investigations have been limited almost exclusively to microorganisms, and disappointingly few experiments have been conducted with fungi and higher plants. The subject of tryptophan biosynthesis in microorganisms was carefully reviewed in 1960 by Doy'; Scheme 1 summarizes the metabolic picture presented by the experimental evidence available at that time. More recent work has supplied some of the significant detail absent from this picture. The enzyme which phosphorylates shikimic acid to 5-phosphoshikimic acid (5-PSA) has been isolated from Escherichia cofi by Fewster.%Its optimum pH is 7.0 and it exhibits a requirement for divalent magnesium or manganese. Neither the formation of the enzyme nor its activity is affected by the ultimate products of the aromatic biosynthetic pathway. The same author also reported evidence for the presence of this enzyme system in a variety of microorganisms known to synthesize aromatic amino acids. One of the most fascinating problems in tryptophan biosynthesis, the nature of the so called branch point compound leading either to prephenic acid or to anthranilic acid, has yielded to the patience of the investigators. Early experimental evidenceasuggested that at least one additional substance, called Z, and formulated4 as the 5-enolpyruvyl ether of shikimic acid, was produced from 5-PSA before the branch point. Later work by Srinivasan'

O,YcooH

d

HOOC,.

8H

6H

prephenic acid

shikimic acid

1""

1-

OH

HtNCOCHICH,CHCOOH

I

1

5-ph0~phckshikimic acid (5-PSA)

NH* L-glutamine

COOti

iinthranilic acid 5-phosphorlbosyl-1pyrophosphatc

OH

OH

H indolc-3-slycerol phosphate

HOCti,CH COOH

I

NH*

L-wine

1

0 If ;

N,

IH.

3'

NH,

+HVIOPO,He OH

3-phosphoglyceraldehyde

L-tryptophan

Scheme 1

3

Chapter 111

4

indicated, however, that Z, was not in fact an intermediate in the conversion of 5-PSA to anthranilic acid in cellfree extracts of E. coli, and Levin and Sprinson6 found that 2,is not converted to prephenic acid by extracts of the same organism. These authors present additional data suggesting that the first product formed from 5-PSA and phosphoenolpyruvic acid is 3-enolpyruvylshikimate-5-phosphate (1), which is then dephosphorylated to Z,, proposed to be the 3-enolpyruvyl ether of shikimic acid (2). I n the presence COOH

COOH

bH

t)H 1

2

of fluoride ion, the dephosphorylation reaction is inhibited, and Z,-phosphate, 1, accumulates. Since prephenate formation from 5-PSA and phosphoenolpyruvic acid could be demonstrated, it follows that Z,-phosphate is probably the active intermediate leading to prephenate. Evidence implicating Z,phosphate as a precursor of anthranilic acid was also forthcoming. Cellfree extracts of Aerobacrer aerogenes’ converted shikimic acid or 5-PSA in the presence of phosphoenolpyruvic acid to a substance with properties identical to those of Z,-phosphate as reported by Levin and Sprinson. By using mutants of the same organism which were unable to convert 5-PSA to Z,-phosphate, to anthranilic acid, or to phenylpyruvic acids, the formation of these acids in a cell extract containing Z,-phosphate could be detected. Treatment of the Z,-phosphate containing extract with alkaline phosphatase followed by acid produced a substance supporting the growth of an E. coli mutant requiring shikimic acid. Neither treatment alone produced a growth factor, but either destroyed the substrate for anthranilic acid formation. Addition of fluoride ion improved the yield of anthranilic acid from the substrate. The role of Z,-phosphate in anthranilic acid biosynthesis in E. coli has been studied by Rivera and Srinivasan.s Ammonium sulfate or protamine sulfate treatment of a crude anthranilate forming enzyme preparation from an E. coli mutant gave two fractions. One of these contained an enzyme, named 3-enolpyruvylshikimate 5-phosphate synthetase, that condensed 5-PSA and phosphoenolpyruvic acid to give Z,-phosphate. This enzyme fraction further converted Z,-phosphate to a new, unidentified substance which was itself converted to anthranilic acid by the second enzyme fraction in the presence of L-glutamine, divalent magnesium, nicotinamide adenine dinucleotide (NAD+), and a nicotinamide adenine dinucleotide, reduced form (NADH) regenerating system. The second fraction was unable to convert 2,-phosphate to anthranilate.

Biosynthesis of Compounds Containing an Indole Nucleus

5

Gibson and Gibsons*lo also reported the presence of a new intermediate in aromatic ring biosynthesis in extracts of an A. aerogenes mutant. This substance could be converted by mild chemical treatment into prephenic acid, p-hydroxybenzoic acid, and phenylpyruvic acid ; enzymically, it was transformed into anthranilic, prephenic, phenylpyruvic, p-hydroxyphenylpyruvic, and p-hydroxybenzoic acids. On the basis of this evidence, the substance was judged to be the elusive branch point compound, and was named chorismic acid (chorismic = separating). The obtention of a multiply-blocked auxotroph of A . aerogenes which accumulated the acid allowed its isolation'l as the barium salt and formulationl1*l2 as the 3-enolpyruvyl ether of trans-3,4dihydroxycyclohexa- 1,5-diene carboxylic acid (3). Chorismic acid has also been isolated from a Sacckarom~vescerecisiae mutant by Lingens and Luck.I3 COOH I1

OH

3

The problem of the conversion of chorismic acid into anthranilic acid is still under investigation. Srinivasan and Rivera,14 working with E. coli mutants, demonstrated that an NADH regenerating system and either divalent magnesium or iron were required in addition to L-glutamine; the amino group of anthranilic acid was found to be derived from the amide nitrogen atom of glutamine. More recently, some very informative results have been obtained15 by feeding 3,4-14C-glucoseto an E. coli mutant accumulating anthranilic acid. Earlier isotopic studies of the incorporation of 3,4 %-glucose into shikimic acid established that the carboxyl carbon and carbons 3 and 4 become labeled.I6 Utilizing this information, degradation of the labeled anthranilic acid produced from the radioactive glucose showed that the carboxyl group of shikimic acid becomes the carboxyl group of anthranilic acid, and that the amination of chorismic acid occurs at C-2 rather than at C-6. Examination of trans-2,3-dihydro-3-hydroxyanthranilic acid (4), which has been isolated from Streptoniyces aure~faciens,~'as a '

COOH

4

possible anthranilate precursor in cellfree extracts of E. coli gave negative results, indicating that the actual intermediate probably still bears the

Chapter I11

6

enolpyruvyl moiety. These results were rationalized by the scheme shown in Scheme 2. In a recent report, Lingens et al. claim to have isolated a substance corresponding to A from a mutant of Succhuromyces cereoisiue.ls COOH

COOH --c HOOCCH&H,CHCOOH

I

+

NH, HOOC

A

&zcooH&""'+ COOH

COOH

CH&OCOOH

B

Scheme 2

DeMosslBhas investigated the formation of anthranilic acid in Neurospora crussu. Cellfree extracts will convert shikimic acid into anthranilic acid after an inhibitor that is present has been removed by ammonium sulfate precipitation. The cofactors required for the transformations are identical to those of the bacterial systems studied except that nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) is needed in place of NADH. Omission of L-glutamine from the incubation mixture led to the accumulation of chorismic acid. The enzyme catalyzing the chorismate to anthranilate conversion was purified 83-fold and appeared to be homogeneous. Its activity was completely inhibited by low concentrations of L-tryptophan, and this inhibition was competitively reversed by chorismic acid, suggesting that the conversion of chorismic acid to anthranilic acid is specifically involved in tryptophan biosynthesis.


7

The L-glutamine requirement does not appear to be obligatory. Gibson et al.ao have recently recorded anthranilate biosynthesis that does not require glutamine. A strain of E. coli was obtained that required both glutamine and tryptophan. Cell suspensions of this organism were able to synthesize anthranilic acid by using glucose as the carbon source and ammonium ions as the only nitrogen source; addition of DON (6-diazo-5-oxo-6-norleucine), a glutamine antagonist to the cell suspensions, caused no inhibition of anthranilate formation. It was suggested that the un-ionized form of ammonia may be available for transfer reactions normally requiring glutamine. The steps leading from anthranilic acid to tryptophan have been carefully scrutinized. Yanofsky proposedz*that the first intermediate resulting from the reaction of anthranilic acid and 5-phosphoribosyl-1-pyrophosphate should be N-o-carboxyphenylribosylamine-5-phosphate (5), also known as N-(5'-phosphoribosyl)anthranilic acid or PRA. An Amadori rearrangementas of this substance to 1-(o-carboxyphenylamino)-l-deoxyribulose-5-phosphate (CDRP) (6) was postulated. Early failures to detect the presence of PRA1*23

CH,OPO,H~ H 5

OH

CH,OPO,H~

6

were ascribed to the lability of anthranilic acid g1ycosylamines.l.z4 Evidence supporting this instability was subsequently provided by Doy and cow o r k e r ~The . ~ ~half-life of synthetic PRA at 37°C in aqueous solution, pH 6, was found to be 6 min. The sensitivity of the substance increased with decreasing pH and decreased with increasing pH. This ease of hydrolysis predicts that mutants blocked between PRA and CDRP will appear to accumulate anthranilic acid unless special precautions are taken. An investigation by Doy et aLZ5confirms this prediction; extracts of certain mutant microorganisms (E. coli, A . aerogenes, Salmonella typhimurium), which in whole cell experiments accumulated anthranilic acid, were found to catalyze a reaction between anthranilic acid and 5-phosphoribosyl-1-pyrophosphate leading to an acid labile substance, less fluorescent than anthranilic acid, and readily hydrolyzing back to that compound. The substance was converted enzymically to indole-3-glycerol phosphate, and was surmized to be PRA. DoyZ6 also reported similar behavior in two tryptophan auxotrophs of Pseudomonas aeruginosa which are phenotypically identical, i.e., both require indole or tryptophan for growth and accumulate anthranilic acid. The two strains, however, differ genotypically, because one is blocked between anthranilic acid and PRA while the other is blocked between PRA

Chapter 111

8

and CDRP. The rapid hydrolysis of accumulating PRA results in the apparent accumulation of anthranilic acid by the second mutant. I(-o-Carboxypheny1amino)-I-deoxyribulose,the dephosphorylated Amadori product, was originally detected in cell suspensions of A . aerogenes and in E. coli mutants.27*2o Its identity was based upon R , values, color reactions, absorption spectra, and a DNP derivative as compared with synthetic material. On the basis of Yanofsky's scheme,21the substance is most reasonably considered as an artifact, derived from the actual tryptophan precursor by loss of the 5-phosphate group. Smith and Yanofskyz3have since provided evidence for this by detecting what appears to be the phosphorylated compound in extracts of E. coli and S. zyphimurium mutants; impure CDRP was obtained synthetically from anthranilic acid and the sodium salt of ribose-5phosphate; its properties compared reasonably well with those of the naturally occurring substance. Both the synthetic and natural compounds were converted to indole-3-glycerol phosphate in the extracts. The mechanism of the conversion of CDRP to indole->glycerol phosphate appears to have been little studied. Smith and Yanofsky23 prepared the decarboxylated analog of CDRP, but found that it was not transformed into indole-3-glycerol phosphate by appropriate cell extracts. This implies that the decarboxylated substance is not a free intermediate in the reaction. Mechanistically, it seems reasonable to suppose that the decarboxylation may not occur until after ring closure has taken place, so that this biochemical inertness of the decarboxylated analog need occasion no surprise (Eq. I).

Studies of the tryptophan synthetase enzyme system have elucidated some of the details of the last step in tryptophan biosynthesis. The enzyme obtained from E. coli has been shown to consist of two protein subunits, A and B,28*29 which catalyze three reactions3O (Eqs. 2-4): indole

+ L-serine + L-tryptophan

indole-3-glycerolphosphate + indole + 3-phosphoglyceraldehyde

indole-3-glycerol phosphate + r-serine -+ L-tryptophan

(2) (3)

+ 3-phosphoglyceraldehyde(4)

The B subunit will catalyze Reaction (2) in the absence of the A subunit,3l and the A subunit will catalyze Reaction (3).z8 Reaction (4) only occurs in


9

the presence of the AB complex, and indole is evidently not a free intermediate in the reaction.28 The A protein has been obtained c r y ~ t a l l i n e~haracterized,3~. ,~~ 34 and the has likewise been complete amino acid sequence d e d ~ c e d . The ~ ~ -B~subunit ~ purified;40 it is of much higher molecular weight (ca. 108,000) than the A subunit (ca. 29,000) and requires pyridoxal phosphate as a cofactor to the extent of 2 moles of cofactor to each mole of B protein. The apoenzyme is unable to catalyze Reaction (2), but retains its ability to facilitate Reaction (4) when combined with the A protein. The evidence points to an AB complex containing two A protein units per molecule of B protein. The tryptophan synthetase enzyme system of N. crussa appears to be quite similar to the E. coli system.41The N. crussu enzyme catalyzes the same three reactions discussed above, with a pyridoxal phosphate requirement for Reactions (2) and (3). The conversion of indole-3-glycerol phosphate to tryptophan by the enzyme does not appear to involve free indole as an intermediate.

B. 3-Indoleacetic Acid The discovery of the remarkable plant hormonal properties of 3-indoleacetic acid (7) in 193412 and its subsequent isolation from a higher plantA3 have stimulated an extensive amount of research on the mode of action and metabolism of this substance. These investigations have been the subject of a number of detailed r e v i e w ~ , ~so ~ -that j ~ the discussion here will be limited to the more relevant papers with emphasis placed on recent work.

CXT

CH2COOH

I

H

7

an ”

2p

3’

COOH

N

I

H

8

I . Biosynthesis in Higher Plants The evidence currently available regarding 3-indoleacetic acid biosynthesis in higher plants strongly suggests that the substance is derived from tryptophan. Murakami and Hayashi,sl for example, have shown that the juice from immature rice-grains will convert tryptophan into 3-indoleacetic acid, and that the conversion is stimulated by a-ketoglutaric acid. More recently, LibberP demonstrated the conversion of tryptophan to 7 by pea sprouts in

Chapter 111

10

the presence of a-ketoglutaric acid, and isolated= an enzyme system from the plants which effects the same conversion. There have been various proposals as to the nature of the intermediates involved in 3-indoleacetic acid biosynthesis. One intermediate frequently is 3-indolepyruvic acid (8), the product resulting from transamination of tryptophan. The requirement for a-ketoglutarate noted in the transformations above supports this suggestion. Subsequent decarboxylation of 8 would produce 3-indoleacetaldehyde (9), oxidation of which would yield 1’

N

8-Q

I H

2‘

CHo

--* 7

(5 1

9

3-indoleacetic acid. The possible intermediacy of 9 in the biosynthesis derives credibility from its detections0*s9 in a number of plants, and from the Occurrence of an enzyme system in plantseo which will convert 9 into 7 (Eq. 5). The detection of 3-indolepyruvic acid in plant extracts proves more difficult as the substance decomposes readily during chromatography,60* though the patterns of decomposition are apparently quite character is ti^.^^ 3-Indolepyruvic acid has been tentatively identified in maize,”. and in watermelon tissuea3after the feeding of tryptophan. In a careful chromatographic analysis carried out by Libbert and Brunna4on the products from the metabolism of tryptophan by an 3-indoleacetic acid synthesizing enzyme from pea plants, 3-indolepyruvic acid and tryptophol (10) were detected.

H

10

H 11

Another intermediate along the path from tryptophan to 7 may well be 3-indoleacetonitrile (11). This substance was originally isolated from cabbage (Brussicu oleraceu)65and evidence presented for its Occurrence in other members of the Cruciferae. A variety of other simple indoles including 7, 3-indolecarboxaldehyde, 3-indolecarboxylic acid, and ascorbigen (12), were also found to occur in B. oleracea. Libbert and Ballinaahave since detected 11 in a variety of higher plants and found evidence in many for its enzymatic hydrolysis to 3-indoleacetic acid. Earlier work by Thimanne7and by Seeley and coworkerse6also provides evidence for the presence of an enzyme system effecting the conversion of the nitrile to 3-indoleacetic acid.

Biosynthesis of Compounds Containing an lndole Nucleus

11

An interesting problem resides in the mechanism of the conversion of 3-indolepyruvic acid into 3-indoleacetonitrile. A number of proposals have been madew* 65* 6g and the most attractive of these involve the intermediacy of oximes. Dannenburg and Livermane3postulated the decarboxylation of 3-indolepyruvic acid to 9 followed by oximation and dehydration to 11. Evidence favoring this hypothesis has been reported by Mahadevan and coworkers70,71 who observed the conversion of 3-indoleacetaldehyde oxime into 3-indoleacetonitrile in banana-leaf tissue and in cellfree preparations of cabbage leaves. Furthermore, Underhil17* has recently discovered the conversion of phenylalanine into phenylacetaldehyde oxime in Tropueolum mujus, and Kindl et al. have that 3-indoleacetaldehyde oxime is a product of tryptophan metabolism in B. oleruceu. Alternatively, Stowesohas offered the oxime of 3-indolepyruvic acid as a possible biosynthetic intermediate. The principal support that can be mustered for this idea derives from the in vitro conversion of this oxime to the nitrile under simulated physiological condition^,^^ from the known occurrence of a-ketoacid oximes in plant tissue,74and from the discovery of a transoximase system catalyzing the transfer of an oximino moiety between a-ketoacids.'s* Further indications of a biochemical thread running from tryptophan .~~ through 3-indoleacetonitrile to 7 have been supplied by W i g h t ~ n a n Radioactive 2'J4C-tryptophan (see Section 1I.A for numbering) was incorporated by 15-week old cabbages into 3-indoleacetonitrile and 3-indoleacetic acid, as well as into 3-indolecarboxaIdehyde, 3-indolecarboxylicacid, and ascorbigen. These substances were also obtained radioactive when l'-W-3-indoleacetonitrile was administered to the cabbages. It is of some interest that no evidence could be found for the intermediacy of 3-indolepyruvic acid or its oxime in these transformations; additional tracer experiments indicated that neither 2'J4C-tryptamine(tryptophan numbering) nor l'-*4C-3-indoleacetaldehyde were converted to radioactive 11 in the cabbage tissue. More recent investigations, dealing with ascorbigen, discussed in Section ILD, complicate the interpretation of these results; it now appears7**79 that ascorbigen is an artifact produced during the extraction of the cabbage tissue by enzymic hydrolysis of the mustard-oil glucoside, glucobrassicin (13). This 56e

12

13

hydrolysis also produces 11, and the feeding of l'-W-tryptophan to cabbages apparently does not produce any radioactive 11 or ascorbigen when the

12

Chapter 111

proper precautions are taken during the subsequent extraction. The natural occurrence of 11 in cabbage tissue must therefore be questioned. As indicated earlier, evidence does exist for the presence of 3-indoleacetonitrile in plants other than B. oleracea, and an enzyme catalyzing the conversion of the nitrile to 3-indoleacetic acid has been found in various plants, isolated, and purified.80It is active in the absence of oxygen and is not deactivated by sulfhydryl or heavy metal reagents. Interestingly enough, 3-indoleacetamide, the presumed intermediate in the conversion, is not liberated in detectable concentration during the enzymic hydrolysis, and is itself not readily attacked by the enzyme. Complete hydrolysis thus appears to take place before the enzyme-substrate complex dissociates. This behavior may perhaps explain the observation of Eifert and Eifertel when testing the growth stimulating activity of various substances on the vine, Vitis rinifra. Tryptophan, 8, 9, 11, and tryptamine all produced stimulation while 3indoleacetamide had an inhibitory effect; the amide probably competes with 3-indoleacetonitrile for the hydrolyzing enzyme, and blocks it by virtue of the difficulty with which it is hydrolyzed. The transformation of tryptophan into 3-indoleacetamide in the presence of horse-radish peroxidase and pyridoxal phosphate has been observed by Riddle and Mazelis,82and by Kleambt.83The reaction is very similar to the conversion of methionine into 3-methylthiopropionamide by the same enzyme and cofactor as reported by Mazelis, Ingraham, and We~ton.~' In a more detailed study,85Riddle and Mazelis report that cabbage seedling homogenates contain natural inhibitors of peroxidase activity which are removable by dialysis. After such treatment, the homogenates will convert tryptophan into 3-indoleacetamidc with a small amount of 3-indoleacetic acid also being produced. Whole cabbage seedlings were shown to convert I'-14C-tryptophan into radioactive 11 and 7, but 3-indoleacetamide could not bedetected. Inview of the work described earlier, the occurrence of 11 in cabbage seedlings should be questioned. On the other hand, infiltration of 1'-"C-indoleacetamide (numbered as 11) into the cabbage seedlings resulted in significant hydrolysis to 3-indoleacetic acid after 12 hr. Homogenates of cabbage seedlings were also capable of the same transformation unless dialyzed. These experiments point to the presence of 3-indoleacetamide,which may or may not be derived from 3-indoleacetonitrile, as an intermediate leading to 3-indoleacetic acid in cabbages. To complete this rather complex picture of 3-indoleacetic acid biosynthesis, an alternative pathway needs mention. There is indirect evidence indicating that tryptamine may serve as an 3-indoleacetic acid precursor in higher plants. The presumed pathway involves decarboxylation of tryptophan to tryptamine, transamination of the latter to 3-indoleacetaldehyde7 and oxidation of the aldehyde to the corresponding acid. In support of this


13

hypothesis, the natural occurrence of a variety of tryptaminesBsin higher plants speaks for the presence of a tryptophan decarboxylase system in the Angiosperms. In addition, Skoog7 has demonstrated an auxin activity for tryptamine in oats, and WinteraBhas found that tryptamine produces a marked stimulation of growth in Acena satica coleoptiles, which stimulation was inhibited by the addition of amine oxidase inhibitors. Curiously, tryptophan showed no growth stimulating properties when applied to the coleoptiles. The case is given further strength by the isolation of an amine oxidase from peas which converts tryptamine to 3-indoIea~etaldehyde,~~ and by Libbert’s reportw of the formation of tryptamine from tryptophan in crude enzyme preparations from pea plants. On the other hand, Gordon has stated5’ that, in some plant tissues, inhibitors of amine oxidase do not affect 3indoleacetic acid formation from tryptophan, and he concludes that tryptamine is not a normal intermediate. Libbert’s detection of the production of tryptamine from tryptophan has also recently been questionedg1 on the grounds that no precautions were taken to exclude bacterial contamination. The question of the role of tryptamine in 3-indoleacetic acid biosynthesis thus does not appear to be settled as yet, and its importance as a precursor may in fact vary with different plants.

2. Biosynthesis in Lower Plants The occurrence of 3-indoleacetic acid in the lower plants seems to be rather 92 and the biosynthetic pathways, in so far as they have been wide~pread,4~* elucidated, generally parallel those existing in the higher plants. Srivastava and Shawe3have shown, for example, that the fungus Melampsora lini will convert 2’J4C-tryptophan into 7; 3-indoleacetaldehyde and probably 3indolepyruvic acid appeared to be intermediates in the process while tryptamine and 3-indoleacetonitrile were not. The metabolism of tryptophan by Taphrina deformans also appears to produce 8 as well as 7, 10, and 3-indolelactic acid -(14),Q1 but no tryptamine, as had been originally reported.84

H

14

Cellfree preparations of Acetobacrer xylintrm are also saidg5.96 to metabolize tryptophan to tryptophol (10) and 3-indoleacetic acid, with 3-indoleacetaldehyde being trapped when sodium bisulfite is added to the medium;

14

Chapter 111

a-ketoglutaric acid was required and the production of all three indoles was stimulated by the addition of pyridoxal phosphate. Still another example is provided by Endomycopsis vernalis@'which converts tryptophan to 7, 8, 14, 10, 3-indolecarboxaldehyde, and 3-indolecarboxylic acid; when cellfree preparations were utilized, 3-indoleacetaldehyde could be detected. In the case of the crown-gall organism, Agrobacterium tumefaciens, the reported production of 8 during the biosynthesis of 7" is fortified by a subsequent isolation of an amino transferasees exhibiting broad specificity in transferring an amino group from tryptophan, valine, leucine, or isoleucine to phenylpyruvic acid; the tryptamine pathway is apparently absent in this organism. An unusual pathway to 3-indoleacetic acid has been discovered in PseudoA wild, pathogenic strain converted 1'V-tryptophan monas solunace~rurn.~~ into 3-indoleacetic acid which was only weakly labeled; under the same circumstances, the chain-labeled tryptophan was efficiently incorporated into cellular protein. When ring-labeled tryptophan was employed, the resulting 3-indoleacetic acid displayed a considerably higher level of radioactivity, and radioactive products of the kynurenine pathway for tryptophan metabolism were formed. The results led to the suggestion that the organism may synthesize 7 through the kynurenine pathway rather than by the usual routes. Strangely, a mutant, nonpathogenic strain of the same organism employed the more conventional routes to 7 as both ring- and chain-labeled tryptophan led to radioactive acid. C. IIndolecarboxaldehyde and 3Indolecarboxylic Acid

The biosynthesis of these substances has been discussed by S t o ~ eand ,~~ only the more recent developments are mentioned here. 3-Indolecarboxaldehyde and the corresponding acid seem to be formed biologically from either 3-indoleacetic acid or 3-indoleacetonitrile. Flowering heads of cauliflower,'@' for example, will metabolize both 7 and 11 to 3indolecarboxaldehyde and the corresponding acid; the acid appears to be produced from the aldehyde as the aldehyde is itself converted to the acid by cauliflower tissue. A 3-indoleacetic acid oxidase system isolatedlol from the root tips of Lens culinaris converts ring-labeled 7 into labeled 3-indolecarboxaldehyde. Another 3-indoleacetic acid oxidase system is present in Lupinus albuslo2and, when coupled to a cytochrome oxidase system, will also transform 7 into 3-indolecarboxaldehyde.The intermediate in this conversion may be presumed to be 3-indoleglyoxylic acid (15), though its presence in these systems was not ascertained. The glyoxylic acid has been tentatively identified in cabbages" as a product of tryptophan metabolism, and young


15

tomato plants have been observedlo3to convert 7 into 15, 3-indoleglycolic acid (16), 3-indolecarboxaldehyde, and 3-indolecarboxylic acid. The conversion of 3-indoleacetonitrile to 3-indolecarboxaldehyde and

01

~ = - - j C O O t I Q-fCOOH

I

O - f C N

I

I

H 1s

H

H 17

16

3-indolecarboxylic acid in pea and wheat tissue has been reported.Io4The reaction was suggested to proceed by a-oxidation of the nitrile to either the acyl cyanide (17) or the corresponding cyanohydrin; neither intermediate could be detected, however. The conversion of 3-indolecarboxaldehyde into the corresponding acid in the same tissues was noted. A crude enzyme preparation transforming 11 into 3-indolecarboxylic acid has also been isolated from pea ~eed1ings.I~~ Schiewer and Libbert1OGhave observed the conversion of 11 into 3-indolecarboxaldehyde and the acid by three species of brown algae; no 3-indoleacetic acid was detected. D. Ascorbigen

This curious substance was originally isolated from Brussicu oleruceu and one of the two alternative structures, 18a or 18b, allotted to it.Io7Subsequent

lU8

OH

-lOH

18b

work by Gmelin and Virtanen76and by Kutacek and coworker^'^ has revealed that the substance is in fact an artifact produced during the isolation process, and casts doubt on the original structural proposal. A boiling methanolic extract of intact cabbage leaves was found to yield no ascorbigen, but only the mustard-oil glucoside, glucobrassicin (13). Myrosinase, an enzyme present in cabbage tissue, hydrolyzes this glucoside to 3-hydroxymethylindolo (19), 11, and various other products whose relative proportions are pH dependent. If the enzymic hydrolysis is conducted in the presence of ascorbic

Chapter 111

16

acid (20), which is also present in cabbage tissue, ascorbigen results, and indeed, an excellent yield of ascorbigen can be produced synthetically by the near room temperature reaction of ascorbic acid and 3-hydroxymethylindole.lo8 Feeding 1'-l4C-tryptophan to the cabbage plants yielded only radioactive glucobrassicin; no radioactive ascorbigen or 3-indoleacetonitrile was detected. Furthermore, a-14C-ascorbigenand I'-14C-3-indoleacetonitrile were not incorporated into glucobrassicin. These results contrast with the earlier report by Kutacek and where, care not being taken to avoid enzymic hydrolysis, radioactive ascorbigen and 3-indoleacetonitrile were produced from 1'-l4C-tryptophan while no glucobrassicin, either active or inactive, was detected. The data led Gmelin and Virtanen78to suggest that the original structural proposal was incorrect, and the structure has in fact been reexamined.*1° The product resulting from the reaction of 3-hydroxymethylindole and ascorbic acid is formulated as a mixture of epimers and ascorbigens A and B, differing only at the configuration of the /?-carbon; ascorbigen A (12) is the naturally occurring isomer (Eq. 6).

N

)1

I H

19

CH'oH

+

_.*

0

Ascorbigen A and B

(6)

HO 20

E. Glucobrassicin Glucobrassicin (13) is a representative of a large group of unusual thioglucosides possessing the common property of hydrolyzing to glucose, sulfuric acid, and an isothiocyanate in the presence of the enzyme myrosinase. The chemistry and botanical distribution of this interesting class of natural products has been reviewed.lll*112 Recent biosynthetic work suggests that glucobrassicin is derived from tryptophan. I'-14C-Tryptophan is incorporated and 35S-sulf~r dioxide into the skeleton of the thioglucoside by B. olera~ea,'~ labels the thioether moiety when administered to cauliflower plants113; hydrolysis of the radioactive thioglucoside labeled in this fashion gives the radioactive isothiocyanate21. Schraudolf and Bergmann114similarly observed


17

the incorporation of A r - T - ~ ~ - t r y p t o p h ainto n 13 by Sinapis alba; 35S-sulfate was rapidly utilized in the formation of the thioether group; only L-tryptophan was transformed into 13; D-tryptophan was converted into D-Nrnalonyl-tryptophan. Tracer experiments on the related thioglucoside glucotropaeolin (22) shed some light on possible intermediates in glucobrassicin biosynthesis. ~’-W-DLphenylalanine is an efficient precursor of the thioglucoside a g l ~ c o n e ~ ~ ~ - ~ ~ and 14C-15N-~-phenylalanine is incorporated as a unit, except for the loss of C-3‘ (tryptophan numbering).ll* Subsequent experiments72*117 indicated that phenylacetaldehyde oxime is a more efficient precursor of glucotropaeolin aglycone than phenylalanine, and the conversion of phenylalanine to the aldehyde oxime in Tropaeolum majus was demonstrated.’2 It is stated that analogous experiments in B. oleracea detected 3-indoleacetaldehyde oxime as a product of L-tryptophan r n e t a b ~ l i s m .Furthermore, ~~ isobutyraldehyde oxime and 3-phenylpropionaldehyde oxime act as efficient precursors of the mustard-oil glucosides, glucoputranjivin (23) and gluconasturtiin (24),72 respectively. Thus, a common biosynthetic sequence for the formation of these thioglucosides appears to be operating in a variety of plants, and 3-indoleacetaldehyde oxime is probably the precursor of glucobrassicin in B. oleracea. Studies of the nature of the amino acid to oxime conversion for glucotropaeolin suggest that the N-hydroxyamino acid is an intermediate.’lg

23

24

F. Violacein

This unusual pigment of structure 25 is obtained from C/womobacterium uiolaceum.320Its biosynthesis has been studied by two groups. DeMoss and H

Chapter 111

18

Evanslal*lea found that L-tryptophan was required as the sole carbon source for nonproliferating cells of C. oiolaceum, synthesizing the pigment; oxygen was also required, while D-tryptophan was not converted to the pigment. The incorporation of L-tryptophan labeled with 14Cin either carbons l‘, 2’, or 3’ (Scheme 1) of the side chain proceeded with loss of the carboxyl carbon and retention of the two remaining carbon atoms of the side chain though their activity was diluted somewhat by an unknown endogenous carbon source. 5-Hydroxytryptophan7 which is reportedla3 to be formed by C. oiolaceum, was not incorporated. Sabek and Jagerla4also reported the conversion of L-tryptophan into violacein by C. violaceum; in addition, they found that lyophilized preparations of the washed cells synthesized indole from tryptophan, and that washed, nonlyophilized cells incubated in an atmosphere of indole vapors rapidly produced violacein. From these results, they concluded that tryptophan is converted to violacein through the intermediacy of indole. This conclusion is incompatible with DeMoss and Evan’s results and appears to be unwarranted. The results of both groups may be explained by assuming that tryptophan loses its carboxyl carbon to give an intermediate (26) which

Violacein

H

-C-

N

I

I

I

H

H

26

is in equilibrium with indole and a two-carbon fragment. The dilution of the activity of the side-chain carbons observed by DeMoss and Evans might then be a consequence of the incorporation of an inactive, endogenous twocarbon unit into the intermediate 26 via its equilibration with indole (Eq. 7). Both groups of authors tested the ability of C. violaceurn to convert a wide variety of likely precursors into violacein; negative results were obtained in every case. The nature of the steps leading from tryptophan to the pigment thus remains a mystery. G. Echinulin

The mold metabolite echinulin (27) was first isolated and investigated by Quilico and his school.1a6Birch and his collaboratorslzssubsequentlyemployed


19

tracer studies as an aid to the elucidation of the structure of the molecule. Feeding 2-1PC-mevaloniclactone (28) to Aspergillus amstelodami produced

31

radioactive echinulin, degradation of which indicated the presence of three isoprene units in the metabolite. B-14C-~~-Alanine was shown to be efficiently incorporated into the alanine-derived portion of the diketopiperazine moiety. Birch and Farrarla7 also found significant incorporation of 1 ’ - I 4 C - ~ ~ tryptophan into echinulin, a result taken to indicate that isoprenylation occurs at a stage later than tryptophan in echinulin biosynthesis. MacDonald and have since verified this result and have shown that the incorporation of 14C-~~-tryptophan labeled at the 2-position of the indole ring or in either the 2’ or 3‘ positions of the side chain proceeds as anticipated. 1’l%’-~-Tryptophan was found to be incorporated about twice as efficiently as the D-isomer. This last result is in support of a very recent ORD studylag which concluded, on the basis of the Cotton effects exhibited below 250 mp by echinulin and a series of model diketopiperazines, that echinulin contains an L-tryptophan unit. This conclusion is at variance with that derived earlier from ORD studies limited to the region above 290 mp.I3O

H. Psilocybin The biosynthesis of psilocybin (M), the active principle in certain Mexican hallucinogenic fungi of the genus P~ilocybe,’~~ has only recently been scrutinized. The incorporation of labeled tryptophan into psilocybin was first

20

Chapter I11

recorded by Hofmann's group,'32 and subsequently confirmed by Agurell and coworkers133*134; the latter authors also investigated the utilization of other likely precursors by Psilocybe cubensis. Tryptamine, which is synthesized from tryptophan by the same fungus, was found to be a more efficient precursor than the amino acid, even when it was assumed that only the L-amino acid was utilized. N-Methyltryptamine was a still more efficient precursor, while N,N-dimethyltryptamine was relatively inefficient ; this last result was attended with some ambiguity however, as the amine was poorly absorbed by the fungus. 4-Hydroxytryptophan also proved to be an inefficient progenitor, suggesting ring hydroxylation at a later stage in the biosynthesis; psilocin (29), which also occurs in the fungus, was readily converted into psilocybin. The authors summarized the data in terms of the diagram presented in Scheme 3.

'

I'

I H

H

H

H

29

30

Scheme 3

111. Indole Alkaloids A. Gramine The simple indole alkaloid gramine (31) is present in the sprouting barley ) . Initial ~ ~ ~ . work137* 138 on its biosynthesis revealed plant (Hordeurn ~ ~ d g u r e 136 the ability of sprouting barley plants to convert 1 '-W-tryptophan into grarnine; a continuation of the investigation^'^^ verified the incorporation


21

of the indole ring and C-1’ as a unit. By feeding a mixture of DL-tryptophan labeled at C-2 of the indole ring and DL-tryptophan labeled at C-l‘, gramine was obtained which was labeled solely at the expected positions and with a ratio of activities identical to that in the original tryptophan mixture. SMethyl-14C-methionine has been shown to be the source of the N-methyl groups in gramine.140An examination of various plausible intermediatesI41 between tryptophan and gramine indicated that l’-1JC-3-indolepyruvic acid and I ’-W-3-indoleacrylic acid could act as precursors. The incorporations of these acids were specific, but quite poor. 3-Indoleacetic acid, 3-indoleglyoxylic acid, 3-indolecarboxaldehyde, and 3-indoleacetamide each failed to give rise to gramine. In the light of more recent work, 3-indoleacrylic acid can be dismissed as an intermediate. Very low incorporation was found when the labeled acid was fed to excised barley and the level of radioactivity was in fact higher in the isolated tryptophan than in the gramine. This suggests prior conversion of the acrylic acid to the amino acid before incorporation. O’Donovan and Leete*43have published more conclusive evidence. Administration of a mixture of l’-3H-~~-tryptophan and 1 ’ - 1 4 C - ~ ~ tryptophan to intact barley seedlings yielded radioactive gramine labeled only at C-i’, and with the same 3H/14Cratio as the original tryptophan mixture. Since no loss of tritium was observed, the 1’-methylene group of tryptophan must maintain its integrity during the conversion of the amino acid to gramine. The result may also invalidate 3-indolepyruvic acid and 3-indoleacetic acid as possible precursors since the tritium atoms in these substances would be born by a carbon atom adjacent to a carbonyl function and might therefore be exchanged. CHCOOH

H

I

H 33

I”’ I

32

I

H

I

H 34

Scheme 4

Chapter 111

22

This evidence is compatible with an attractive hypothesis proposed by Wenke~-tl~~ for the conversion of tryptophan to gramine. Tryptophan was postulated to condense with pyridoxal phosphate to yield the Schiffs base 32 which could undergo fragmentation to the protonated 3-methyleneindolenine 33;addition of ammonia to this highly reactive entity would yield 3-aminomethylindole (34), methylation of which would afford gramine (Scheme 4). Support for this scheme derives from two sources. First, 3aminomethylindole and 3-methylaminomethylindole (35) have in fact been

35

36

isolated from barley seedlings and an enzyme preparation obtained from barley shoots which methylates 3-aminomethylindoleto 35 and gramine."'j and Second, Gower and Leete14*have prepared 2-14C-3-aminomethylindole 2-14C-3-methylaminomethylindole and administered them to excised barley shoots. The incorporations of the two amines were quite high, being 14.2 and 24.5% respectively, and the radioactive gramine so obtained was labeled exclusively at C-2.

B. Calycaathus Alkaloids


23

1’-l4C-tryptophan into calycanthine (36), calycanthidine (37), chimonanthine (38), and folicanthine (39) by Culycunthus Joribundu, though the identifications of the alkaloids were uncertain. Additional work on these interesting alkaloids is clearly needed. C. Evodia Alkaloids

Two papers by Yamazaki and coworkers14s.lS0 explore the formation of alkaloids in the fruit of Ecodiu rutaecurpa.1611’-l4C-Tryptophan led to radioactive evodiamine (40) and rutaecarpine (41) whose degradation indicated that most of the activity resided in the tryptamine portion of the bases.

/

Scheme 5

lcl

24

Chapter 111

3H-Anthranilic acid was utilized in the formation of both 40 and 41, but the radioactive alkaloids were not degraded. Sodium W-formate was incorporated primarily into C-3 of rutaecarpine with the remainder of the activity localized in the tryptamine portion of the molecule, a result attributed t o in tlioo condensation between the labeled formate and glycine to give radioactive serine which subsequently transformed into tryptophan. In the case of evodiamine, the formate label was located primarily a t C-3 and in the N-methyl group. Methyl-W-methionine supplied radioactivity exclusively to C-3 and the N-methyl group of evodiamine, and solely to C-3 of rutaecarpine. The specific activity of the evodiamine formed when these C1 donors were fed was lower in comparison with that of rutaecarpine than would have been anticipated on the basis of the presence of two C,-derived carbons in the former alkaloid. This was interpreted to mean that evodiamine does not arise from N-methylation of a rutaecarpine-like precursor, but rather by the introduction of a C, unit at an earlier stage of the biosynthesis to give N-methylanthranilic acid which could be diluted by nonlabeled, endogenous N-methylanthranilic acid. The biosynthetic network illustrated in Scheme 5 was proposed by the authors, though no evidence was provided for dihydronorharman (42) being an intermediate.

D. Carboline Alkaloids The known carboline bases constitute a group of alkaloids derived from simple variations in the oxidation state of the P-carboline ring system.152 These alkaloids have long been a subject of biosynthetic speculation, beginning with the farsighted proposal by Perkin and Robinson in 1919lWthat they arise in uico from a Mannich condensation between a tryptamine derivative and acetaldehyde. Only three papers have thus far appeared that provide experimental data on carboline alkaloid biosynthesis. O’Donovan and Kenneally*5sexamined the formation of eleagine (43), the

43

simplest member of the series,in Elueugnlts angustifoh. 2’-14C-~~Tryptophan and sodium I-IT-acetate were incorporated to give radioactive alkaloid


25

labeled exclusively at C-3 and C-1, respectively, in support of the PerkinRobinson hypothesis (Eq. 8). The extent of incorporation of the two precursors was surprisingly low (0.01 and 0.003 %, respectively), however, in view of their apparently close chemical kinship to the alkaloid. A thorough study of the biosynthesis of harman (44) in Pussiji'oru ed~dis has recently appeared. Slaytor and M ~ F a r l a n eprocured ~~~ convincing evidence that tryptamine and N-acetyltryptamine are intermediates in the tryptophan to harman conversion. N-AcetyI-2'-l4C-tryptophanwas shown not to serve as a precursor for harman, while I'-14C-tryptamine and Nacetyl-l'-l4C-tryptamine were both utilized to form specifically labeled alkaloid. Free tryptamine was detected in the plant, but the presence of Nacetyltryptamine could not be directly established. Its presence in the plant was effectively demonstrated, however, by the use of radiochemical dilution. Unlabeled N-acetyltryptamine was administered to the plant and followed in 24 hr by either labeled tryptophan or tryptamine. The N-acetyltryptamine reisolated after 3 days was radioactive. When SH-14C-~-tryptophanwas administered, the radioactive N-acetyltryptamine obtained had the same 3H/14Cratio as did the amino acid, indicating intact incorporation. The participation of N-acetyltryptamine in harman biosynthesis suggests harmalan (45) as the penultimate biosynthetic intermediate. In fact, the authors demonstrated the efficient incorporation of W-harmalan into harman, but

45

Chapter 111

26

the presence of harmalan in the plant tissues could not be proven, even by isotopic dilution experiments. A crude homogenate prepared from an acetone powder was able to transform harmalan to harman, nevertheless. W-Tetrahydroharman (46) was also able to serve as a precursor for harman. The data were rationalized in terms of the scheme illustrated (Scheme 6). The principal difference between this pathway and that originally suggested by Perkin and Robinson is that harmalan rather than tetrahydroharman is the first tricyclic intermediate; though the conversion of tetrahydroharman to harmalan and harman was found to occur in P. edufis, no tetrahydroharman was detected in the plant. Stolle and Groger*55a have investigated the biosynthesis of harmine (7-methoxy 44) in Peganurn harmala. Both tryptophan and tryptamine specifically labeled in their side chains with I4C and 15N were incorporated with unchanged 14C/16Nactivity ratios. A specific incorporation into C-1 of harmine was observed on feeding 2-W-pyruvic acid while 3-W-pyruvate led to specific labeling of C-10 of harmine. An unspecific labeling pattern resulted from the administration of I- or 2-14C-acetate, and 1,2,3,4tetrahydroharman-3-carboxylic acid did not serve as a harmine precursor.

E. Ergot Alkaloids Fungi of the genus Cfuciceps elaborate a number of indole alkaloids based upon the ergoline skeleton (47). These alkaloids may be divided into two groups; one group contains the ergot alkaloids which are amides of 0

41

48;R = OH 49 ;R = NHCH(CHJCHZ0H 50;R


27

lysergic acid (a), ranging in structural complexity from such simple derivatives as ergometrine (49) to the intricate cyclic peptides, of which ergotamine (50) is representative; the other group is that of the clavine alkaloids, the most important members of which are agroclavine (51), elymoclavine (52),

51;R= H 52;R = OH

53

and chanoclavine-I (53). A great deal of the structural work on these substances is due to Stoll and Hoffmann, who have recently reviewed the fieid.156 The biosynthesis of the ergot alkaloids was reviewed in 1962 by Weygand and Floss,lS7and again in 1966 by A g ~ r e l l The . ~ ~present ~ account focuses attention on recent developments in the field, but necessarily retraces some of the ground previously covered. Early investigations demonstrated the ability of both tryptophan15g166and mevalonic lactone160*167--171 to serve as precursors for the ergot bases. Baxter and coworkers171and PlieningerlB4each obtained evidence indicating that mevalonic lactone was incorporated via either isopentenyl or dimethylally1 pyrophosphate. Baxter’s data demonstrated that the radioactivity derived from 2-14C-mevaloniclactone (28) was diluted in the presence of nonradioactive isopentenyl or dimethylallyl pyrophosphate, and that the carboxyl group of 1-W-mevalonic lactone was not incorporated into the alkaloids. Plieninger reported that deuterated isopentenyl pyrophosphate was utilized in the formation of the clavine alkaloids. Recently, additional substantiation was provided”* when methyl-14C-dimethylallyi pyrophosphate was shown to be incorporated into agroclavine and elymoclavine. The Nmethyl group of the ergot alkaloids has been found to be efficiently derived from methyl-14C-methionine, or less effectively, from sodium “C-formate.173. 174 Relatively little additional information on the formation of ring C of the ergot alkaloids has been deduced since Weygand’s review. Electronic arguments favor a direct electrophilic attack of dimethylallyl or isopentenyl pyrophosphate at either the 5- or 7-position of the indole nucleus rather than at the requisite 4-position. This supposition receives support from the great

Chapter 111

28

disparity between the numbers of naturally occurring 4- or 5-substituted indole derivatives. The work of both BaxterIB2and Plieninger164has cast doubt on an earlier proposal that the 4-position might be suitably activated by hydroxylation at the 5-position. Structural arguments nevertheless require the attachment of an isoprene unit at C-4. This requirement might be met in one of two ways. Electrophilic attack may in fact occur directly at C-4 (54); or, under enzymic mediation to give 4-(y,y-dimethylallyl)trypt0phan~~~ alternatively, condensation might take place at C-2' of tryptophan to yield the substance 55.15' The latter substance can suffer ring closure only at C-4

A

2 /

54

55

for stereochemical reasons. Plieninger has synthesized 54 containing 14C and found176that it is incorporated into elymoclavine with modest efficiency. Weygand, Floss, and M ~ t h e s l prepared ?~ 55 and compared its effectiveness as a precursor in competition with 54; the latter substance was always more efficiently utilized. More recently, Plieninger's group synthesized 54 labeled with I4Cat C-1 of the ally1 side-chain and with 3H at C-2' of the alanine sidechain; the doubly-labeled substance was incorporated into agroclavine and elymoclavine without a change in the 3H/14Cratio, indicating an intact utilization of the c o m p ~ u n d . ~14C-4-(y,y-DimethylaIlyl)tryptamine ~z was by contrast only poorly incorporated into the clavine alkaloids, and in fact served as an inhibitor of alkaloid formation. This result speaks in favor of isoprenylation occurring before the decarboxylation and N-methylation processes, a conclusion that harmonizes with other experimental evi~ ~ found 54 in a d e n ~ e . " ~l?' , Very recently, Agurell and L i r ~ d g r e n lhave Penniserum derived ergot culture supplied with tryptophan and ethionine. The substance was detected as its N-trifluoroacetyl methyl ester by comparison with authentic, synthetic material using a combination of gas chromatographic and mass spectral analysis. A greater volume of experimental data bearing on the biosynthetic relationships between thwarious ergot alkaloids is available. Rochelmeyer proposed179 in 1958 that the clavine alkaloids serve as precursors for the lysergic acid derivatives, a hypothesis that subsequently received thorough experimental vindication. The application of 3H-elymoclavine to the sclera of an ergotamine producing strain of rye ergot, for example, led to specific rates of incorporation (= 100 x specific molar activity of product/specific molar


29

activity of precursor) into that alkaloid of up to 74%; similarly, using submerged cultures of a strain of C. paspali, the specific rates of elymoclavine incorporation into simple lysergic acid amides reached 30 %.lea Complimentary evidence is supplied by Agurell and Johanssonlsl; both 14C-elymoclavine and "C-agroclavine were utilized by the mycelium of C. purpurea in the synthesis of ergotamine, ergotaminine (50 epimeric at C-8), and ergometrine. The data indicate that the lysergic acid derivatives may be derived by the oxidation of the clavine alkaloids. The interrelationships between the clavine alkaloids have been the object of some study. A Claviceps strain isolated from Pennisetum typhoideum irreversibly convertslS2agroclavine and elymoclavine into penniclavine and isopenniclavine. Using the same ergot strain, the biosynthetic interconversions of a variety of ergot bases were unraveled; these relationships are summarized in Scheme 7. Similar data are available from Baxter.ls3

setoclavine isosetoclavine (C-8 epimer)

A glH:

peoniclavine isopenniclavinc (C-8 epimer)

If

1f

N-CHI

CHI

'?~H,oH

--+

H-N festuclavine pyroclavine (C-8 rpimer)

agroclavine

elymoclavine

5!FCH H..

H-N

CH,OH

---* H-N

lyxrgene

Scheme 7

lyserpol isolysergol (C-8 epimer)

Chapter 111

30

More recent experiments supply some interesting details regarding these interconversions. An intermediate in the enzymic oxidation of elymoclavine to penniclavine and isopenniclavine has been isolated and identified as 10-hydro~yelymoclavine.18~The substance is transformed under mild conditions in vitro to the final products. The analogous transformation of agroclavine to setoclavine and isosetoclavine has been accomplished using horse-radish peroxidase, and some evidence presented implicating a peroxidase in the natural biological pr0cesses.1~~ On the other hand, it has recently been argued'8s that the claim of a correlation of the peroxidase content of Cluviceps mycelium with the ratio of elymoclavine to agr~clavine~~' was ill-founded since the method of peroxidase analysis utilized primarily measures the catalase activity. Furthermore, it was found that mycelial homogenates containing both catalase and peroxidase activity would not convert 14C-agroclavine into radioactive elymoclavine in the presence of hydrogen peroxide. The oxygen atoms that must be introduced in the conversion of 4-(y,y-dimethylallyl)-tryptophan to chanoclavine-I and of agroclavine to elymoclavine do not derive from water188;this suggests that they are introduced by direct hydroxylation and are derived from atmospheric oxygen. Such a process finds ample precedent in the microbial hydroxylations of ~ t e r 0 i d s . l ~ ~ One of the more intriguing and puzzling problems in ergot alkaloid biosynthesis concerns the role of chanoclavine within the metabolic network. Much of the available experimentaldata is contradictory, and the discovery1e0 in 1964 of the stereoisomeric chanoclavine bases points a finger of suspicion at all these early results since it is not clear to which stereoisomers the results apply, if indeed pure substances were always utilized. The structures of the three isomeric chanoclavine alkaloids, chanoclavine-I (53), chanoclavine-I1 (56), and isochanoclavine-I (57), are shown here; the absolute configuration

56

57

of chanoclavine-I at C-5 and C-10 was determined by Hofmann's group191by correlation with festuclavine, while the configurations of the other two alkaloids are due to Stauffacher and T ~ c h e r t e r The . ~ ~ ~stereochemistry assigned to chanoclavine-I and isochanoclavine-I was recently confirmed by Arigoni et


31

Though it is not yet certain whether chanoclavine-I is an obligatory intermediate in ergot alkaloid biosynthesis, the ability of the base to serve as an efficient precursor of the tetracyclic ergolines has been amply demonstrated; the incorporation levels into agroclavine, elymoclavine, and lysergic acid amide in C. puspuli range to 4O%.ls3 The details of these transformations have begun to assume a remarkable complexity. Arigoni and collaborators recently reportedlY4that sodium 2-V-~~-mevalonate is incorporated by a Clusiceps strain from P.typhoideum into agroclavine and elymoclavine to give alkaloids carrying over 90% of their respective activities at C-17. This is in accord with previous experimental data*69and with the stereochemistry expected for the conversion of mevalonic acid to dimethylallyl pyrophosphate.lg5 The radioactive chanoclavines isolated had, by contrast, over 90% of their activity in the C-methyl group, regardless of the geometry of the 8,Pdouble-bond. Chanoclavine-I therefore bore an unexpected rrurts-relationship of the labeled atom and the olefinic proton. This labeling pattern and stereochemistry suggested that isochanoclavine-I should be the precursor of the tetracyclic alkaloids. Further experiments proved that this supposition was incorrect, however. Biosynthetically labeled elymoclavine was converted chemically into chanoclavine-I bearing greater than 90% of its activity in the hydroxymethylene carbon. The incorporation of this substance gave labeled agroclavine, shown by degradation to carry over 96 % of the activity at C-7. The conversion of chanoclavine-I into agroclavine must therefore be accompanied by a trans to cis isomerization of the 8,9-double-bond. Experiments under similar conditions with hydroxymethylene labeled isochanoclavine-I failed to disclose any significant incorporation of the compound into the tetracyclic ergolines. have furnished confirmation of these most interestFloss and ing results as well as additional experimental information. Chanoclavine-I bearing tritium at C-9 or C-10 as well as a 14Creference label was prepared biosynthetically from the requisite labeled mevalonic acid. Conversion of the doubly-labeled alkaloid into elymoclavine by CluiGceps strain SD58 proceeded with 100% retention of the label at C-10 and 92% retention of label at C-9. Hence, a double-bond shift to the 9, I0-position during the isomerization process does not occur. The importance of chanoclavine-I as a precursor of the tetracyclic bases was emphasized by the relative efficiencies of conversion of various clavines into elymoclavine; in replacement cultures, the specific incorporations of agroclavine, chanoclavine-I, isochanoclavine-I, and chanoclavine-I1 (each biosynthetically labeled with tritium in the indole ring) were 9.6, 9.0, I .9, and 0.6 %, respectively. On the basis of these findings, and the additional observations of Arigoni et al.lg7that desoxychanoclavine-I and its N-demethylation product are not incorporated into elymoclavine, the biosynthetic sequence involving two isomerizations shown in Scheme 8 was proposed.

Chapter 111

32

The alternative to this proposal, that the isopentenyl pyrophosphate isomerase reaction in Claviceps follows an unexpected steric course, has been ruled out by still further e x p e r i m e n t a t i ~ n .4R~ ~ ~and ~ S - D L - ~ - ' ~43HC, Mevalonic acid were each fed to shake cultures of Clariceps strain SD58.The *

Qj--7pTH-

& & -&lCH,

0JH+

H

H-N

CH,OH

coo11

H-N

ctts

T H - N

H-N

chanwle\ ine -I I (56) isochanoclavine-1 (57)

Scheme 8

elymoclavine isolated displayed I4C incorporations of 9.9 and 10.0 %, respectively, and the 3H/14Cratios were such as to correspond to a 70% retention of the 4R-hydrogen and only 3 % retention of the 4s-hydrogen. The loss of some of the 4R-hydrogens was ascribed to an isotope effect in a subsequent stage of the biosynthesis. The elimination of the 4s-hydrogen demonstrates that the stereochemical outcome of the isopentenyl pyrophosphate isomerase reaction in ergot alkaloid biosynthesis is the same as that observed in other biological systems.199It is therefore a reasonably safe assumption that the over-all stereochemistry of the reaction is also the same as in these systems; this assumption predicts that the label from C-2 of mevalonic lactone should be located in the trans methyl group of the original dimethylallyl moiety. Thus, two isomerizations of the allylic double-bond apparently occur in the formation of the tetracyclic ergolines.

F. Monoterpene-Derived Indole Alkaloids The family of indole bases of which corynantheine (58), strychnine (59), catharanthine (60),and vindoline (61) may be offered as representative


33

members currently includes over six hundred alkaloids152* and undoubtedly constitutes the largest group of naturally occurring indoles. The historical background and earliest investigations dealing with the biosynthesis of these substances have been carefully summarized,2°1,202 so that the present account places emphasis on the more recent advances in this rapidly moving area of research.

58

59

Early experimental efforts established that tryptophan could serve as the precursor for the tryptamine moiety common to almost all these alkaloids,eM and for some time the major hurdle in the way of an understanding of indole alkaloid biosynthesis was the unknown origin of the nine or ten carbon skeleton almost always found combined with tryptamine. Order was brought to the apparently endless structural variety of the alkaloids by the recognition2O4that almost all the known examples contain the Cs-lo skeleton in one of three arrangements. These three arrangements may be conveniently

referred to as205(f) the Curynunthe type with the Ce-l,, skeleton 62 (heavy lines in 58 and 59), (2) the I b u p type, possessing the C,-,, unit of structure 63 (heavy lines in 60), and (3) the Aspidusperma type with a Ce-lo unit of structure 64 (heavy lines in 61). The dashed line in each of these formulations

62

64

34

Chapter 111

indicates that carbon atom which is consistently lost in those alkaloids having only nine skeletal carbons in addition to the tryptamine moiety. In the absence of experimental data, a number of ingenious hypotheses were advanced to account for the origin of the Co-lo unit. The essential features of the four major hypotheses are presented in Scheme 9. The earliest proposal derived the Corynanthe unit from 3,4-dihydroxyphenylalanine plus two one-carbon units utilizing a cleavage of the aromatic ring20s that has come to be called Woodward fission (Eq. 9); the second

Scheme 9


35

hypothesisZo7suggests a derivation of the ten carbons from the condensation of three acetate units, a malonate unit, and a C, unit (Eq. 10); the third postulateZoRargues for a C,-,, skeleton derived from prephenic acid in 209 proposes combination with a C, unit (Eq. 11); and the last suggestionZwb* the cleavage of a cyclopentane monoterpene skeleton to arrive at the required Cglo fragment (Eq. 12). Experimental work by Leete's group initially appeared to substantiate the 210* 211 Incorporation of sodium 14C-formate into second hypothesis,207* ajmaline (65) by RauwolJia serpentina reportedly gave the alkaloid bearing 12% of its activity at C-21. Further experiments, employing sodium lJ4Cacetate, led to a labeling pattern in ajmaline in very close agreement with theory: positions 3 and 19 were each found to carry 26% of the total activity. Similarly, the incorporation of sodium 1-I4C-acetate into serpentine (66)

66

reportedly labeled C-19 with 23 % of the total activity, C-22 being inactive, while 1,3-14C-malonic acid yielded serpentine with 48 % of its activity at C-22, and ajmaline with 74% of its activity at C-17. In contrast, other investigations have yielded data that argues convincingly against an acetate origin for the C,-,, unit. Battersby et a1.21zreported that the radioactive ajmaline isolated when sodium 1-14C-acetatewas admi,.istered to R . serpentinu has the label scattered among the carbons of the C,-,, unit. Sodium 14C-formate yielded ajmaline with very little activity at C-21. Goeggel and Arigoni,213 testing the incorporation of sodium I-I4C acetate into vincamedine (68)and reserpinine (67) by Vinca species, likewise observed scrambling of the label. Finally, Barton and coworkers214recorded that N-methyltryptophan and N-methyltryptamine bearing 14C in the N-methyl groups do not serve as precursors for ajmaline in R. rerticillata. This suggests that C-21 of ajmaline cannot originate from an N-methyl group in a manner analogous to the formation of the C , bridge in the berberine alkal0ids,2*~speaking in other words against the incorporation of a C, unit into the C,-,, skeleton. Administration of methyl-3H-~~-methionine to R . serpentina procured additional evidence against incorporation of a C, unit; the resulting ajmaline carried 97% of its total activity in the N-methyl group.

36

Chapter 111

In the face of the unfavorable evidence, Leete reexamined his earlier results and verified the conclusions of the other investigators.lI6 The data amassed in the testing of the acetate hypothesis not only speaks heavily against an acetate origin for the ubiquitous CB-lounit, but also casts

CHaO

H CHaOOC

68

22

67

a shadow of doubt across the other two hypotheses that require the specific incorporation of a C , unit. Relevant data supporting this doubt was soon forthcoming. Mothes’ group217administered U-14C-shikimic acid to Vinca rosea and degraded the radioactive vindoline (61) to demonstrate that over 90 % of its activity resided in the benzene ring. Since shikimic acid is the usual biological precursor of prephenic acid,21e Wenkert’s suggestion that prephenic acid is the source of the nontryptophan derived portion of the indole alkaloids is untenable. Evidence against the generation of the C,-,, unit by Woodward fission comes from Battersby’s The two ipecac alkaloids, cephaeline (69) and emetine (70), contain a Corynanthe-type skeleton, but condensed with a phenethylamine residue rather than with tryptamine; conclusions derived from tracer studies on the ipecac alkaloids may therefore be applied, with some reservations, to the indole alkaloids. When 2‘-14C-~~-tyrosine (tryptophan numbering, Section 1I.A) was supplied to Cephaelis ipecacuanha, radioactive cephaeline was produced which was specifically labeled at C-3 and C-3’, but not at (2-1’; hence, 3,4-dihydroxyphenylalanine is not a likely precursor for the C,-,, unit of these alkaloids. Adminstration of radioactive phenylalanine gave similar results. A scrambling of label, analogous to that observed in R. serpentina for the indole alkaloids, was obtained when sodium I4C-formate, sodium 1 -14C-acetate, and sodium 1 ,3-14C-malonate were fed to C. ipecacuanha. At this point, three of the plausible pathways to the nontryptophan derived portion of the indole alkaloids had been effectively disproved, and it remained to test the validity of the fourth, implicating a cyclopentanoid monoterpene. Experiments in this area have come primarily from three laboratories, those


37

of Battersby, of Scott, and of Arigoni. Battersby has recently summarized his own work in the field.205 A likely precursor for a cyclopentanoid monoterpene is mevalonic acid,p2o and the incorporation of this substance into the indole alkaloids has been

examined with great thoroughness. Feeding of sodium 2-1JC-~~-mevalonate to Vinca plants afforded radioactive vindoline (61),221-223reserpinine (67),222a ajmalicine (71),223and catharanthine each bearing approximately one quarter of its respective total activity at C-22. These results are consonant with a specific incorporation of mevalonic acid into each of the alkaloids in such a manner that C-2 and C-6 of one mevalonate unit become equivalent, a situation previously encountered in the biosynthesis of plumeride (72).224 COOCH,

I

1s OH 71

72

Further degradation of the catharanthine indicated that 20% of its activity was at C-1 and/or C-18, and 48% at one or more of the carbons -2, -3, -5,

38

Chapter 111

and -19. Scheme 10 presents a schematic rationalization of these labeling patterns.20@

Scheme 10

The same pattern of mevalonate incorporation was observed in another plant genus; Rhazia stricta ~ t i l i z e d zsodium ~~ 2-W-~~-mevalonate in the biosynthesis of I ,2-dehydroaspidospermidine (73). Degradation revealed

73

that about 65 % of the total activity of this alkaloid resided at C-8.Since the skeleton of the alkaloid requires the loss of one carbon atom, the anticipated value for C-8 is 67% if one of the two equivalent 2,6 carbon atoms is lost. Sodium 3J4C-~~-rnevalonate was similarly incorporated by R . sfricfainto 73


39

with 47 % (theory = 50%) of the label being located at C-20, while C-5 and C-21 were inactive. Whatever doubts might still remain concerning the location of the mevalonate carbons in the three types of C,-,, units have been dispelled by additional tracer studies with V. rosea and labeled mevalonate. The results are in complete agreement with those predicted by Scheme 10. Thus, administration of 3-14C-mevalonateto V. rosea gave serpentine225and ajmalicine226with approximately 40% of their individual total activities at C-19; the radioactive vindoline226generated under the same circumstances carried 47 % of its label at C-20 with no activity present at C-5, -21, -22, or in the N- or 0-methyl groups. Using sodium 5-14C-o~-mevalonate, radioactive vindoline and catharanthine*25 unlabeled at C-5, -20, and -21, and at C-4, -20, and -21, respectively, were produced. Further scrutiny of the final location of C-5 of mevalonic acid in the Aspidosperma unit was achieved by mass spectral examination of the deutero-vindoline, presumed to be 74, produced from 5-*H2-mevalonateby V. rosea; of the principal fragment ions of vindoline, ions (a), (b), and (c) showed an enrichment level corresponding to two deuterium atoms, while ions (d) and (e) showed no enrichment227(Scheme 11).

When the above results are taken in conjunction with the additional studies . incorporation ~ ~ ~ of labeled mevalonate into the five by Battersby et ~ 1of the V . rosea alkaloids ajmalicine, serpentine, catharanthine, vindoline, and perivine (76)(see Table I), they provide an almost complete labeling pattern for the Corynanrhe unit; furthermore, the generation of a bond between the C-4 carbon atoms of two mevalonate units is established, supporting the formation of a cyclopentane ring.

Chapter 111

40

TABLE I. Administration of 14C-Labeled Mevalonic Acids to K~JCQ Roseu

Position of I4C in mevalonate

Alkaloid isolated

Carbon atom(s) isolated

Serpentine (66) Ajmalicine (71) Catharanthine (60) Vindoline (61) Serpentine (66) Perivine (76) Catharanthine (60) Vindoline (61) Serpentine (66)

3 16-1 7 20-2 1 20 15 20 4 5 14

% of total activity Theory

Found

50 25 50 50 50 50 50 50 50

43 22 44 45 45 44 48 45 43

The successful incorporation of mevalonic acid into the C,-,, unit of the indole alkaloids provided the long sought key needed to unlock the secrets of indole alkaloid biosynthesis, and the ensuing progress has been rapid. COOCH,

76

Knowledge of the biochemical fate of mevalonic acid218points to geraniol (77) as a likely precursor for the nontryptophan derived portion of the indole alkaloids, and three groups simultaneously recorded the incorporation

Scheme 12


41

of geraniol into the alkaloids of V. rosea. Arigoni and coworkersz2sreported that 2-1*C-geraniol yielded radioactive vindoline carrying all its activity at C-5; identical results were found by B a t t e r s b y ' ~and ~~~ groups. In addition, Battersby established that the radioactive catharanthine produced by V. rosen from 2-I4C-geraniol bore all of its activity at C-4, while the radioactive ajmalicine formed was labeled at one or more of the four carbons -3, -14, -20, and -21 (C-20 expected). By the use of mass spectrometry, Scottzz7localized the deuterium in the vindoline generated in rico from 1-2H2geraniol which was presumed to be 75; ions (a), (b), and (c) each showed enrichment levels corresponding to the presence of one deuterium atom while ions (d) and (e) showed no enrichment, in agreement with expectation. The data obtained with labeled geraniol are readily accommodated by the processes of Scheme 12. With the efficacy of geraniol as an indole alkaloid precursor amply proven, attention was next turned to the known cyclopentanoid monoterpenes in the search for a likely candidate for the postulated ring-cleavage and rearrangements. Fortunately, the field of choice was narrowed somewhat by the isolation of a glucoside called ipecoside from Ipecacuanha plants. The chemical and spectroscopic data led to the constitution 78 for this ~ u b s t a n c e , ~ ~ ~ and further evidence as well as its absolute stereochemistry followed from a correlation with protoemetine (79)23"via dihydroprotoemetine (80) (Scheme 13). The success of the correlation suggests that the corresponding des-Nacetylipecoside may be the actual precursor of protoemetine in Ipecacuanha. Furthermore, the striking biogenetic similarity between protoemetine and corynantheine infers that aldehyde 81 may be the source of the Ca-lo unit in each instance. A consideration of the known cyclopentanoid monoterpenes ledzo5to the selection of four substances as likely precursors of 81; these were verbenalin (82),231genepin (83),232monotropeine (shown as its methyl ester 84),233and toganin (85).z34 Each of these terpenes has now been tested for its ability to serve as a precursor of the indole alkaloids in V. rosea,zo6and the work on all but genepin has been Verbenalin was labeled by base-catalyzed exchange with tritiated water, and a portion of the radioactive compound reduced with borohydride to dihydroverbenalin. Both substances failed to serve as precursors. Methylation of monotropeine with diazomethane in the presence of tritiated water yielded the ester with tritium in the methyl group. The catharanthine, vindoline, ajmalicine, and serpentine isolated when this substance was supplied to V. rosea were all inactive. The result implies not only that the monotropeine system is unsuitable for in ciro conversion to the indole alkaloids, but it also demonstrates that the labeled methyl group has not been removed and mingled with the C , pool of the plant.

T-

HO

OGlu

H'

\

CHjOOC 78

cH -

-

CH,O

CH,O

OGlu

CH,OOC

-cH CH30

CH ,O CH ,O

CHO

79;R=CHO 80; R = CH@H Scheme 13

H' CH300C

H' CHjOOC 81

CHjOOC

82

Ho.*F 83

4

OH

,CHa

,OGlu

H" CHSOOC

H'

\

CHaOOC

84

42

9\

85

O


43

Loganin was similarly converted to O-methyl-3H-loganinby hydrolysis to loganic acid, and methylation with diazomethane in the presence of tritiated water. Administration of the loganin so labeled to V. rosea yielded radioactive catharanthine, vindoline, perivinc, serpentine, and ajmalicine. Zeisel demethylation of 60, 66, and 71 proved that all of the radioactivity resided in the methyl group of the ester moiety in each alkaloid. Hydrolysis of the vindoline to desacetylvindoline (98 % of original activity) followed by reduction with lithium aluminum hydride gave the trial which contained less than 0.1 % of the original activity. No significant amount of activity was therefore present in the N-methyl and 0-methyl groups, again providing evidence against in uiuo exchange of the labeled methyl group to give the labeled C, pool. Hence, loganin may be said to show specific incorporation into the Corynanthe, Aspidosperma, and Iboga alkaloid families. Confirmatory evidence for the role of loganin as the cyclopentanoid precursor of the indole alkaloids in V . rosea was supplied by the demonstration by isotopic dilution methods of its presence in V . rosea plants. l-3HGeraniol was administered and radioinactive loganin added to the plant extracts; reisolation of the loganin as its pentaacetate, hydrolysis, and methylation of the loganic acid afforded loganin of constant specific activity corresponding to 0.02 % incorporation; reconversion to the pentaacetate and further purification did not alter its specific activity. At the time of these preliminary experiments, the structure of loganin was only tentatively established, having been derived from the application of 234 and its stereochemistry biogenetic arguments to limited chemical was unknown. The discovery of loganin’s importance as an indole alkaloid precursor made it imperative to reexamine the substance and eliminate the uncertainties. Thus, the original structural proposal was simultaneously confirmed by two groups in 1968, and the absolute stereochemistry defined as depicted in 85.236,237 Work carried out concurrently established the mevalonate origin of loganin. 4-I4C-Geraniol, on administration to the rhizomes of Menyanfhes frifoliuta, was converted into loganin bearing 85 % of its label at C-4237;rather surprisingly, sodium 2-14C-~~-mevalonate was not incorporated into loganin under similar circumstances, a result best attributed to a failure of the mevalonate to reach the site of loganin biosynthesis. Using Swerfia caroliniensis, both 2-I4C-mevalonate and I -14C-geranyl pyrophosphate were incorporated into the loganic acid found in that The 4-14C-loganin isolated from Menyanthes plants supplied with 4-14Cgeraniol was subsequently fed to V. rosea. Radioactive ajmalicine, vindoline, and catharanthine were produced; degradation revealed that the ajmalicine bore 93 % of its total activity at C-I 8, while the vindoline and catharanthine were labeled exclusively at the positions shown (Scheme 14).239Administration of a mixture (ca. 3: 1) of 2-14C-geranioland 2J4C-nerol (isomeric at the

44

Chapter 111 t

4 t

h

Scheme 14

2,3-double bond) to M. rrifolinra also yielded radioactive loganin. When this labeled material was fed to V. rosea, radioactive serpentine, ajmalicine, catharanthine, vindoline, and perivine were produced. Degradative work demonstrated that the catharanthine was labeled solely at C-4, while the desacetylvindoline and dihydroperivine were labeled to 102 and 96% of their respective total activities at the positions indicated in Scheme 14.240Similarly, I-3H-loganin, prepared biosynthetically from l-3N-geraniol, was supplied to Rauwolfia serpentina. The radioactive ajmaline isolated was shown to be specifically labeled with tritium at C-21 (see Scheme 14). Thus, a second plant species can utilize loganin as a specific precursor for a Corynanthe-type alkal0id.2~~ With the role of loganin as a precursor of the nontryptophan derived portion of the indole alkaloids firmly settled, the subsequent steps along the biosynthetic pathway become accessible to investigation. The constitution of ipecoside and the specific incorporation of loganin therein241suggest that a corresponding cleavage of the five-membered ring of loganin to aldehyde 81 followed by a condensation with tryptamine to give the P-carboline glycoside 86 represent stages in the biosynthesis of the indole alkaloids. This line of reasoning has now received experimental vindication. An extract of Rhaziu to yield an amorphous glucoside to which srricta leaves has been the constitution 86 was assigned, largely on the basis of spectroscopic data; the stereochemistry was left undefined. More recently, the natural occurrence of a glucoside corresponding to 86 has been placed on a firmer footing.


45

Menyanthes trifoliata has been foundzrJ*24'1 to contain three seco-cyclopentane glucosides, called foliamenthin (87), dihydrofoliamenthin (88), and menthiafolin (89). Alkaline hydrolysis of menthiafolin under carefully controlled

87

86

xn

conditions followed by methylation with diazomethane afforded secologanin (81).245Repetition of the procedure using 3H-diazoniethane produced 0-methyl-3H-seco-loganin.Vinca rosea shoots supplied with this glucoside yielded a compliment of alkaloids: 66, 71, 60, and 61. Zeisel demethylation of 71 and 60 proved that 94 and 96%, respectively, of their total activities were localized in the methyl groups of the ester moieties; 61 yielded desacetylvindoline still containing 98 % of the original activity, and following reduction, a trio1 was obtained carrying less than I "/, of the former activity. The absence of significant methyl transfer to the C , pool was assured by the lack of activity in the N-methyl and aryl-0-methyl groups of the vindoline. Thus, the specific incorporation of seco-loganin into the three skeletal families of the indole alkaloids was demonstrated. As a prelude to the condensation of seco-loganin with tryptamine, the ability of V. rosea to convert tritiated tryptamine into the three classes of indole alkaloids was established.2"6Tryptamine was then condensed with secologanin to produce the two epimeric @-carbolines,vincoside (90) and isovincoside (91).240The use of O-methyl-3H-seco-loganingenerated the corresponding labeled P-carbolines which were fed as a mixture to V . rosea. Incorporation into all three types of indole alkaloids was observed. Intact incorporations were assured by the use of doubly-labeled 90 and 91 prepared

Chapter 111

46

O-methyl-3H-loganin and U-3H-tryptamine;degradations of the radioactive alkaloids isolated in this instance disclosed that biosynthesis had taken

90

91

place without a significant alteration in the ratio of the labels present in the two halves of the fi-carbolines.246A separation of the O-methyl-3H-labeled glucosides90 and 91 was subsequently achieved by partition chromatography, and feeding experiments with the individual epimers clearly indicated that only vincoside serves as the indole alkaloid precursor in V. rose^.^^' Evidence for the natural occurrence of seco-loganin, vincoside, and isovincoside derives from various sources. Vinca rosea plants to which 5-3Hloganin had been administered were worked up with the addition of inactive samples of the aforementioned substances as carriers. The isolated secologanin fraction was treated with 3,4-dihydroxyphenethylamine to give i p e c o ~ i d ewhose , ~ ~ activity corresponded to greater than 6 % incorporation of loganin into seco-loganin. Acetylation of the fi-carboline fraction yielded the pentaacetates of vincoside and isovincoside, each of which possessed activities as their N-acetyl derivatives corresponding to 1.5 % i n c o r p ~ r a t i o n . ~ ~ ~ More direct evidence for the natural occurrence of vincoside has come from the isolation of its pentaacetyl derivative from an acetylated extract of V. rosea seedling~,2~~ and from the isolation of N-acetylvincoside from V. rosea plants.247 The results argue compellingly for the role of vincoside as the link between loganin and the three classes of indole alkaloids. The conversion of vincoside into the Corynanrhe-typealkaloids poses no unusual problems, and the more intriguing questions concern the sequence and nature of the steps leading to the rearranged Aspidosperma and Iboga skeletons. Answers to some of these questions are slowly being found. Qureshi and have investigated the sequential formation of indole alkaloids in germinating V . rosea seeds. The presence of alkaloids is detectable by thin-layer chromatography after about 26 hr, and the first alkaloids to be produced are corynantheine (58), corynantheine aldehyde (58, methyl of enol ether replaced by hydrogen), and dihydrocorynantheine (58, vinyl group saturated). After 45 hr, ajmalicine (71) appears, followed by stemmadenine (92) after 50 hr. The presence of stemmadenine was confirmed by the radiochemical dilution technique after


47

administration of 3-W-~~-tryptophan since the amounts produced were inadequate for complete spectroscopic characterization. The Aspidospermatype alkaloid tabersonine (93) appeared after 72 hr of incubation, and the Iboga-type alkaloid catharanthine appeared along with vindoline after 168 hr. This appears to favor the order of alkaloid biosynthesis, Corynanrhe to Aspidosperma to Iboga, a sequence that gains further support from the studies with the labeled alkaloids summarized in Table Il.249 In particular, TABLE 11. Administration of Labeled Indole Alkaloids to V. Rosea Seedlings Alkaloid

precursor

Label

Alkaloid(s) 3H/14C(%) isolated

-

Stemmadenine O-MethyL3H

O-Meth~l-~H, 1I - 1 4 ~ 92.817.2

Tabersonine

O-Meth~l-~H

-

O-Meth~l-~H, I 1-14c

Catharanthine a

O-MethyL3H

95.814.2

-

Specific incorporation (%I 3H/14C(%I

Tabersonine

0.27 0.56 1.76

Tabersonine Catharanthine Vindoline Catharanthine Vindoline

0.10 0.30 0.95

Ca tharan t hine Vindoline

Catharanthine Vindoline Tabersonine

0.809

4.800 0.14b 1.1 ob

I

LiAIH,

I H 25

I H 24

H 23

With N-methylisatin, an excess of phenyl magnesium bromide gave

N-methyl-2,2-diphenylindoxyl(27) and N-methyl-3,3-diphenyloxindole(28). C,H,MgBr I CH3

26

-

Q3z6H C,H3

m z 6 H + 5

I CH3

C6H5

I CH, 28

21

1

CH, 30

LiAIH,

CH, 29

Reduction of 27 with lithium aluminum hydride gave 2,2-diphenyl-3hydroxy-I-methylindoline (29) which produced 2,3-diphenylindole (30) on treatment with hydrochloric A similar synthesis (Eq. 12) utilizes nitroal k a n e ~ . ' ~ ~ RCHJ'Q

,@ ' j - - T N o 2 HI32

31HI

214-21 5 163-1 64

75

42.543.5

bP (OC/mm)

mP picrate

Ref.

113/21

158 148

56,569,149 50, 153, 327 217

120-1 25/2 lOo/O.l

105-106

100-1 10/11 120-122/6.5 128-1 32/12

160-161

173-174.5 153 129 219 156-157 153

61 141-145/1.5 48-49 4849 164-167/1

299 217 149, 217 217 149,217

138-141 141-142 175

58 I 217 35,429 5, 28, 35 153 219. 561 28 148 199

154-1 56

104

TABLE 1X. Indolines Compound

mP (OC)

1-Methyl

bP (OC/mm) 95-96/6

3-Methyl 1,a-Dimethyl 1,3-Dimethyl 1,7-Dimethyl 2,2-Dimet hyl 2,3-Dimethyl 2 ,S-Dimet hyl 2,FDimethyl 3,3-Dimethyl I-Ethyl 2-Ethyl 3-Ethyl 5-Ethyl 1,3,3-Trimethyl 2,3,7-Trimethyl I -Ethyl-3-methyl 1-Isopropyl 3-Methyl-3-propyl I-Butyl 2-Methylene-l,3,3t rimethyl 2-Methylene-I ,3,3trimethyl 3,3-Dimethyl-l-ethyl2-met hylene I-Allyl-3,3-dimethyl-2methylene

227-228 103- 104/ 1 90-92/13 74/2 239-240 240-245 99-102/8 110-111/7 l00/15 238-242 112-115/10 128-132/12 105--108/10

n"

"P

picrate

135, 570, 571, 572, 583, 607 5 74 109 131-133 463 133 1.5518 151-153 567 109, 110 1.5513 109 I09 1.56322 149, 569 1.5603 101-112 583 573,575 547 568 1.5724 132 130 109 238 1.5585 165-166 583, 529 149 164 1.5429 167- 168 583, 529 166-1 68

147-148

578 56

111/12

500

58 1

3,3-Diallyl-2-methylene-

1-methyl 3,3-Dimethyi-2methylene-1-phenyl I-Benzyl 1-Benzyl-2-methyl 3-Benzyl-2,3-dimethyI I-Styryl 1-Methyl-7-phenyl 7-Phenyl 3.3-Diphenyl 2-(2-Naphthyl)

Ref.

542 21.5-22

100-102/0.1 173-175/8 I81-182/19

158-160 177-179

80-82 8 1-82

180-181

68-70 96-97

105

31. 579 137, 583, 529 582 561 151, 584 397 138 566 20

TABLE X. Tetra-hexa- and octahydroindoles Compound

mP

("0

4,FDihydro- I-met hyl 1.4-Dihydro-3-phenyl 1-Methyld ,5,6,7tetrahydro 1,6-Dimethyl-2,3,4,5tetrahydro 1,7-Dimethyl-2,3,5,6tetrahydro 2-Ethyl-1-methyl4,5,6,7-tetrahydro 2-Butyl-1-methyl4,5,6,7-tetrahydro 2-Benzyl- 1-methyl4,5,6,7-tetrahydro 1-Benzyl-2-phenyl4,5,6,7-tetrahydro 72-73 3.6-Dimethyl- 1-phenyl4,5,6,7-tetrahydro 2-Ethyl-1-phenyl4,5,6,7-tetrahydro I-Butyl-2-phenyl4,5,6,7-tetrahydro l-Phenyl-4,5.6,7tetrahydro 104-105 1-Ethyl-2-phenyl4,5,6,7-tetrahydro 1.3-Diphenyl-2-methyl4,5,6,7-tetrahydro 77-79 2-Methyl-3~,4,5,6,7,7~hexa hydro 1,7-Dimethyl-2,3,4,5,6,7hexahydro 9-Methyl-A1(")hexahydro 87.5/20 2-Phenyl-3~,4,5,6,7,7~hexahydro 83-84 1-Methyloctahydro cis-1-Methyloctahydro Methiodide 208 rruns- 1-Methyloctahydro Methiodide 229 2-Methyloctahydro 9-Methyloctahydro Methiodide 321-323 1,7-Dimethyloctahydro 1,9-Dimethyloctahydro

bP (OC/mm)

nz

102-106/15

1.5490"'

mP

9

picrate

Ref.

404 230 590

128-1 29/24

593 176114

59 1

7 1-7212

590

95-9612

590

145-14612

590 601

1 12-1 1510.1

222, 608

107- 108/0.02

223

151-15212

1.5829

601 590

127-12812

1.6015

60 1 589

126-1 29/ 110

126-127

595

72-7311 1

174.5-175.5

591 594

5519 5719

1.4749

183-184 203-205

54.518

lOOl50

171-1 72

228-230

595 191, 597 607 607 607 607 595 594 592 594

106

TABLE X (Conrd.) mP ("C)

Compound

mP

bP (OC/rnrn)

picrat ~

5,6-Dirnethyloctahydro 1-Benzyloctahydro I-Methyl-7-phenyloctahydro 7-Methyl-7-phenyloctahydrohydrochloride 1-Methyl-7a-phenyloctahydro I-Ethyl-7a-phenyloctahydro 1-Methyl-9-phenyloctahydrohydrochloride 1-Phenyloctahydro 2-Phenyloctahydro 5-Phenyloctahydro 7-Phenyloctahydro 7a-Phenyloctahydro 1-Methyl-9-phenyloctahydro hydrochloride 1-Methyl-9-ptolyloctahydro hydrochloride

152-15319

Ref. ~

1.4804 1S369

178-179

596 597 602

345-347

598 1I 5-1 20/12

603

105-107

603

146-148/9.5 107-108/ I 15

604 599 595 604 602 603,605

246 53-54

246

609

238

604 ~

TABLE XI. Cycloarylindoles and Jndolenines

R

n

R

("C) "P

1 2 3

H

H

H

225-227 161 91-92

1 2

c2H5 CH3 CH, CH3

98-98.5 105-106 145-147

3 4

(OC/mrn) bP

150.5/1

107

mP

9

picrate

Ref.

165-167 167-168 183-184 119-120

309 309 309 36 36 36 36

TABLE XII. Indolenium Iodides

rb

1-

Compound I ,2,3,3-Tetramethyl 3-Ethyl-I ,2,3-trimethyl

11 11

3-lsopropyl-l,2,3.trimethyl 3-Isobutyl-l,2,3-trimethyl

11

3-Phenyl-I ,2,3-trimethyl

2-Phenyl-l,3,3-trimethyl I-Methyl-2-phenyl-3,3-tetramethylene

202-203 186.5-188

II 28 28 28

TABLE XIII. Indole Dimers Component 1

Component 2

Ref.

Indole I-Melhylindole 3-Methylindole 3-Met hylindcle Indole 3-Methylindole Indole Indole I ,3.Dimethylindole 1,3-Dimethylindole 3-Propylindole I-Methylindole 3-Met hy lindole

Indole 1-Methylindole 3-Methylindole 3-Methylindole 2-Methylindole 2-Methylindole 1,2-Dimethylindole 1,2-Dimethylindole 1,3.Dimethylindole 1,3-Dimethylindole 3-Propylindole I-Methylindole 3-Methyiindole

435 440 434,436 434 434 438 434 434 434 434 437 440 436

108

Oxalate Hydrochloride Hydrochloride Hydrochloride Hydrochloride Oxidized form Oxidized form

184-185 133-135 214-215 134-1 35 149-151 124-1 25.5 113-1 17 160-1 62 132-133 162-163

TABLE XIV. Diindolylmethanes

164 105-109 235-238 161.5-162.5 184-185 185-1 86 143-1 44 164-165

CH3 CH3 C6H5 C6H5

CH3 CH3 CH3

CH3

CH, CH3 CH3 CH3 CH3 C", C,7H3, CH3CH:CH CeHsCH,

CH3 CH3 CH3 C"3

CH,

'IjH5

CH3 CH3 CH3 CH3 C2H5 C,H,CH

5-CH3 CH3

CH3

'GH5

C6H5 C6H5

CGH5

157 I63 153-155

CH,

CH3

G ' H5

1-C10H7

6-CH3

CH3

CH3

CH3 I'ZH5

:C'H

2-Thienyl

109

185-197 185-186 195-197 I55 130 269-27 1 125 245 191-193 21 2-218 21 2-2 15 237-239 252 99 149-156

186, 443, 444 207 449,458 208 446,450 160,450 447 21 1,443,444 554 444 444,460,463, 553 21 1 459 457 46 457 444 442 443 456 443 443 460 460 554 460 471 443 443 473

TABLE XV. Diindolylalkanes bP (OC/mm)

Compound 1,3-Di(l-indolyl)propane 1,4-DiI-indoly1)butane ( 1,4-Di(3-indolyl)butane 1,4-Di(I ,2dimethyl-3-indolyl)butane 1,5-Di(1 -indolyl)pentane 1.6-Di(l-indolyl)hexane 2,5-Di(1,2-dimethyl-3-indolyI)hexane I ,4-Di(3-indolyl)cyclohexane I ,lo-Di(l4ndolyl)decane x,a’-Di(1-indolyl)-p-xylene I ,2-Di(2,3-dihydro-2-methyl.l-indolyl)ethane 1,3-Di(2,3-dihydro-2-methylI -indolyl)propane 1.4-Di(2,3-dihydro-2-methyl-1-indo1yl)butane 1,6-Di(2-phenyl-4,5,6,7-tetrahydro-lindolyl)hexane

195/0.1

88 174-176 81 84 157-160 218-220 67 111.5

25410.5 230/0.05

Ref. 158 I58 177 463 158 158 463 177 158 158

93-94

582

133-135

582

160

582

114-115

60I

TABLE XVI. Diindolylalkenes Compound 1 ,l-Di(2-methyl-3-indolyl)ethylene I , I -Di( 1-methyl-2-phenyl-3-indolyl)-

201-203

554

193-194 217-219.5 232-234 292-294

1,4-Di(I ,2-dimethyl-3-indolyI)butadiene 2,5-Di(1,2-dimethyl-3-indolyI)hexa-2,4-diene 242 I ,4-Di(2-methyl-3-indolyl)cyclohexa-1,3-diene 261

554 554 553 463 463 463

241

554

320-325

554

224-230 252

457 463

257 300

463 463

330

463

ethylene

I , I-Di( 1,2-diphenyl-3-indolyl)ethylene

1-(3-lndolyl)l-[3(2H-indolidene]ethane

r-(2-Methyl-3-indolyI)-a-(2-methyl-3indoleniny1idene)toluene a-(2-Phenyl-3-indoIyl)-z-( 2-phenyl-3indoleniny1idene)toluene 1,3-Di(2-methyl-3-indolyl)-l,3-diphenyl-

1-butene 3,3’-Diindolylhexacyclotrimethinbromide 2,2’-Dimethyl-3,3’-diindolylhexacyclotrimethine bromide 3,3‘-Diindolylpentacyclotrimethinebromide 2,2’-DimethyL3,3’-diindolylpentacyclotrimethine bromide I10

111

Alkyl, Alkenyl an d Alkynyl lndoles TABLE XVII. Indole Trimen

H H CH, CH3

H CH3 H CH3

250 265 297 320

469 469 469 469

TABLE XVIII. Miscellaneous Indole Dimers and Trimers Compound 1-Skatylindole 1-Skatylskatole 5-Skatylindoline 5-Skatylindole 2,2’-DimethyL3,3’-diindoIe 2,2’-Diskatylmethene perchlorate 3,3‘-Diindolylmethene sulfate

3,3’-Dimethyl-2,2’-benzilidenebisindole 2,2‘,2”-Triskatylmethane 2,2‘,2”-Triskatylmetheneperchlorate 3-(3’-Indolylmethyl)-3-methylindoline 1,3-Dimethyl-3.( 1’-methylindolyl-3‘-methyl)-

indoline 2,3-Dimethyl-3-(2’-methylindolyl-3’-methy1)indoline

76-80 139-140 148 142-143 226-228 162 320-321

186 186 186 186 41 461 445 443,464,465 467 461

132-134

209

66

209

85

209

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A. Mirsky and D. Diengott, andG. Perisutti,Proc.Soc. Exp. B i d . Med.,95,154(1957). R. Williams and F. Martin, Diabefes, 5 , 451 (1956). R. A. Wallace, A. N. Keirtz, and C. Niemann, Biocheniistry, 2(4), 824 (1963). C. Clayton, Proc. Soc. Exp. Bid. Med., 97, 510 (1958). B. B. Stowe and K. V. Thimann, Arch. Biochem. Biophys., 51, 499 (1954). B. L. Zenilz. U.S. Patent 3,238,215 (March 1, 1966). W. R. N. Williamson, J. Cheni. Soc., 1%2, 2834. K. R. Freter, Can. J. Chem, 45, 2628 (1967). W. Reppe et al., Jusfus Lieblps Ann. Chern., 601, 128 (1956). E. S. Domnina, G. G. Skvortsova, N. P. Glazkova, and M. F. Shostakovskii, Khim. Geterot.\ikl. Soedin., Akad. Nauk Lato. SSSR, 3, 390 (1966). 545. K. Kawasaki, Ann. Rept. Shionqpi Res. Lab., 5 , 57 (1955). 546. M. F. Shostakovskii, G. G. Skvortsova, E. S. Domnina, and N. P. Glazkova, USSR., Patent 181, 116 (1966). 547. W. E. Noland and R. J. Sundberg, J. Org. Chenz., 23, 884 (1963). 548. J. M. Weinmann, Dissertation Abstr., 25(3), 1588 (1964). 549. E. Leete, Tetrahedron, 14, 35 (1961). 550. J. Thesing and G. Semler, Justus Liebigs Ann. Cheni., 680, 52 (1964). 551. J. Smuszkovicz, J. Org. Chem., 27, 511 (1962). 552. H. Pleininger, M. Hoebel, and V. Leede, Cheni. Ber., %, 1618 (1963). 553. J. E. Saxton, J . Chem. Soc., 1952, 3592. 554. A. K. King and F. G. Mann, J. Chem. Soc., 1953, 594. 555. N. N. Komzolova, N. F. Kucherova, and V. A. Zagorevskii, Zh. U y . Khim., 1, 1139 (1965). 556. J. Brown, H. Henbest, and E. Jones, J . Chenr. Suc., 1952, 3172. 557. M. F. Shostakovskii. G. G. Skvortsova, E. S. Domnina, and N. P. Glazkova, Zh. Prikl. Khitn., 38(1 I), 2602 (1965). 558. H. Nomori, M. Hatano, and S. Kambara, J. Po/yn. Sci.Part B, 4, 623 (1966). 559. J. V. Braun. Chem. Ber., 37, 2915 (1904); J. V. &dun and Sobecki. Chenz. Ber., 44, 2158 (1911); C. Jackson, Chem. Ber., 14,883 (1881); E. Fischer, Jusfus Liebgs Ann. Cheni., 236, 123 (1886); 0. Carrasco, Gazz. Chim. Ital., 38(ii), 301 (1908); 0. Carrasco and M. Padoa, Gazz. Chitti. Ital., 36(ii), 512 (1906); G . Plancher and Ravenna, Atti. Accad. Naz. Lincei, Rend., Cl, Sci. Fis. Mar. Nut., [ 5 ] 14, 632 (1905); A. Benedicenti, 2. Physiol. Chem., 53, 181 (1907); M. Wenzing, Justus Liebigs Ann. Cheni., 239,239 (1887). 560. R. Huisgen and J. Sauer, Cherri. Ber., 92, 203 (1959). 561. M. Nakazaki, Bull. Chem. Soc. Japan, 32, 588 (1959). 562. F. E. King, J. A. Barttrop, and R. J. Walley, J . Chem. Soc., 1945, 277. 563. J. V. Braun and 0. Baeyer, Cheni. Ber., B58, 387 (1925). 564. H. Adkins and H. L. Co0nradt.J. Afner.Chem. Soc., 63, 1563 (1941); H. Adkins and R. E. Burks, J. Amer. Chem. Soc., 70,4174 (1948). 565. R. Willstatter, F. Seitz, and J. V. Braun, Chetn. Ber., B58, 385 (1925). 566. S. Sarel, J. T. Klug, E. Breuer, and F. D'angeli, TefrahedrotzLett., 1964, 1553. 567. I. Gruda, Acfa Pol. Pharm., 24, 17 (1967). 568. A. P. Terent'ev, M. N. Preobrazhenskaya, and G. M. Sorokina, Zh. Obshch. Khim., 29, 2875 (1959). 569. R. Abramovitch and R. Brown, Org. Prep. Proc., 1, 39 (1969). 570. R. Huisgen, J. Sauer, and A. Hauser, Angew. Chem., 69, 268 (1957). 571. B. Hrutfiord and J. Bunnett,J. Amer. Cheni. Soc., 80, 2021 (1958). 572. F. Minisci and R. Galli, Tetrahedron Lett., 23, 2531 (1966).

535. 536. 537. 538. 539. 540. 541. 542. 543. 544.

126 573. 574. 575. 576. 577.

Chapter 1V R. J. Sundberg, Tetrahedron Lett., 5, 477 (1966). G. Somolinsky, J . Amer. Chem. SOC.,83, 2489 (1961). G. Somolinsky and B. I. Feuer, J. Org. Chem., 29,3097 (1964). C. Paal and H. Landenheimer, Chem. Ber., 25,2974 (1892). H. Brunner, Monafsh., 18, 97 (1897). G. Ciamician and G. Piccinini, Chem. Ber.,

29,2740 (1896). 578. I. I. Levkoev and A. Y. Bashkirova, Zh. Prikl. Khim., 35,688 (1962). 579. E.Berman and J. E. G. Taylor, U.S.Patent 3,231,584 (January 25, 1966). 580. G. Plancher, Atfi. Accud. Naz. Lincei, Rend., Cf. Sci. Fis. Mat. Nat., [ 5 ] 9(i), 115 (1900); [5] ll(ii), 182 (1902). 581. R. Hill and G. Mewkome, Tetrahedron Lef f .,49, 5059 (1968). 582. 1. Gruda, Acfa Pol. Pharm., 21(5), 455 (1964). 583. A. K. Sheinkman and A. N. Kost, Metody Polucheniya Khim. Reacrivov i Preparatov, Gos. Kom. Sou. Min. SSSR po. Khinr, 11, 5 (1964). 584. Y. Omote, K. T.Kuo, N. Fukada, M. Matsuo, and N. Sugiyama, Bull. Chem. SOC. Jup., 40, 234 (1967). 585. T. C. Bruice and R. W. Huffman, J . Amer. Chem. SOC.,89,6243 (1967). 586. G. Baddeley. J. Chadwick, and A. T. Taylor, J. Chem. SOC.,1956,448. 587. J. V. Braun, Chem. Ber., 51,96 (1918). 588. C. Jackson, Chem. Ber., 14,833 (1881); M. Wenzing, Justus Liebes Ann. Chem., 239, 244 (1887); D. Koning, J. Prakt. Chem., 88, 218 (1913). 589. E.B. Hodge and R. Abbott, J. Org. Chem., 27, 2254 (1962). 590. M. A. Volodina, V. 0. Mishina, A. P. Terentev, and G. V. Kiryushina, Zh. Obshch. Khim., 32, 1922 (1962). 591. 0. Cervinka, Chem. and Ind. (London), 1959, 1129. 592. 0. brvinka, Collect. Czech. Chem. Commun., 25, 1183 (1960). 593. R. E.Ireland, Chenz. and fnd. (London), 1958, 979. 594. M. Fetizon and M.Golfier, Bull. SOC.Chim. Fr., 3, 870 (1966). 595. 1. Murakoshi, Y. Shikakura, and J. Haginiwa, Yakugaku Zasshi, 84, 674 (1964). 596. W. L. Drake and A. B. Ross, J . Org. Chem.. 23, 794 (1958). 597. A. Bertho and J. F. Schmidt, Chem. Ber., 97,3284 (1964). 598. A. N. Kost, I. P. Sugrobova, V. A. Krasnova, and S . L. Partnova, Zh. Obshch. Khim., 34, 2416 (1964). 599. A. Bertho and H. Kurzmann, Chem. Ber., 90, 2319 (1957). 600. G. Metayer, Bull. SOC.Chim. Fr., 1948, 1093. 601. M.A. Volodina, V. G. Mishiva, E. A. Pronia, and A. P. Terent’ev, Zh. Obshch. Khim., 33,3295 (1963). 602. A. N. Kost and I. P. Rudakova, Zh. Obshch. Khim., 35, 145 (1965). 603. Parke, Davis and Co., British Patent 856,352 (December 14, 1960). 604. C. F. Boehringer and Soehne, British Patent 989,590 (June 14, 1962). 605. E.F. Godefroi, U.S.Patent 3,035,059 (May 15, 1962). 606. F. E.King and H. Booth, J . Chem. Soc., 1954, 3798. 607. F. E. King, D. M. Bovey, K. G. Mason, and R. L. St. D. Whitehead, J. Chem. Soc., 1953,250. 608. B.Helferich, K. Geist, H. Junger, and D. Wiehle, German Patent 1,054,996 (April 16, 1959). 609. A. Popelak and G. Lettenbaurer, U.S.Patent 3,028.394 (April 3, 1962). 610. F. Pioui and C. Fuganti, Ann. Chim. (Rome), 57, 486 (1967). 611. H. Fikrat and J. Oneto, J. Pharm. Sci., 51, 527 (1962). 612. J. McManus and R. Herbst, J. Org. Chem., 24, 1464 (1959).


CHAPTER V

Haloindoles and Organometallic Derivatives of Indoles JAMES C. POWERS School of Chemisrry. Georgia Institute of Technology Atlanta. Georgia

.

I Ring Halogenated Indoles . . . . . . . A Bromoindoles . . . . . . . . B Side-Chain Bromination C . Bromination of Functionalized Indoles . . . . D Chloroindoles . . . . . . E . Iodoindoles . . . . . . . . F. Fluoroindoles . . . . . . . I1 Side-Chain Halogenated Indoles . . . . . In. Reactions of Haloindoles . . . . . . . IV Physical and Spectroscopic Properties of Haloindoles . V . Organometallic Derivatives of Indoles . . . . A . The Indole Grignard Reagent . . . . . 1 . Structure . . . . . . . 2. Protonation . . . . . . . 3. Alkylation . . . . . . . . 4 . Other Reactions . . . . . . . 5 . Bz.-lndolyl Crignard Reagents . . . . . B. Alkali Metal Salts . . . . . . . C. Other Organometallic Derivatives of Indole . . VI . Tables of Haloindoles and Indole Organometallic Derivatives Table 1 Fluoroindoles . . . . . . Table 1I . Monochloroindoles . . . . . . Table 111. Substituted Monochloroindoles . . . Table 1V Polychloroindoles . . . Table V . Monobromoindoles . . . Table VI Substituted Bromoindoles . . . . Table V1I iodoindoles . . . . . . . Table VIII . Indoles Substituted with Two Different Halogens Table I X . Haloindolines . . . . Table X . Haloindolenines . . . .

.

.

.

.

.

.

. .

.

.

. . .

.

127

.

.

.

.

. . .

. . . .

.

.

.

.

. .

. . .

. . . .

.

.

.

. . . . .

. . . .

. . . .

.

.

.

.

. . . . .

.

. .

. .

. . .

128 131 134 .135 .137 . 139 139 140 . 142 143 143 143 . 144 . 145 .146 .147 . 149 . 149

. .

. . .

.

. . . . .

151

153 154 155 157 159 . 160 162 165 167 . 167 .167

. .

.

128 Table XI. TableXII. Table XIII. Table XIV. Table XV. Table XVI. References .

Chapter V Side-Chain Halogenated Indoles and Indolenines . . . 168 IndoleGrignard Reagents(N-MgX). . 169 Miscellaneous Magnesium Derivatives and Grignard Reagents . 169 Alkali Metal Salts of Indoles . . . 170 Group I 1 Metal Derivatives of Indoles (Except Mg Derivatives) . 171 Miscellaneous Organometallic Derivatives of Indole . . 172 . . . . . . . . . . 173

.

.

. .

.

. .

.

I. Ring Halogenated Indoles Halogenation of simple indoles with a variety of agents leads to products substituted on the pyrrole ring. The first halogen enters the 3-position if this is available. If the 3-position is blocked, substitution occurs preferentially at the 2- or at the 5- and/or 6-position of the benzene ring depending upon the presence of other substituents. Halogenation in aqueous solution with reagents such as N-bromosuccinimide and N-chlorosuccinimide usually leads to oxindoles or to halooxindoles. Since the bromination of indoles has been extensively studied, bromination methods will be discussed in some detail under the section on bromoindoles. The discussion of other halogenation methods will not be as extensive in their respective sections of this chapter unless the nature of the reaction or the products differ from those observed in bromination. Benzene-ring-substituted haloindoles are usually prepared via standard indole ring syntheses such as the Fischer indole synthesis and the Reissert synthesis.5g* 61. 62- 84 But these methods are not without their difficulties. The Fischer indole synthesis gives a mixture of products when applied to mchlorophenylhydrazones. Cyclization of the m-chlorophenylhydrazone of acetone with zinc chloride yielded a mixture of 4-chloro- and 6-chloro-2methylindole.**4In this case the isomers could be separated because of different solubility properties in benzene-ligroin. Carlin has found that the Fischer indole synthesis can lead to a variety of products when applied to certain halophenylhydraz~nes.~~,88 Indolization of 2,6-dichlorophenylhydrazones with stannous chloride yields 7-chloroindoles ( l).63If zinc chloride is used as the cyclizing agent, a rearrangement takes place and 5,7dichloroindoles (2) are obtained.85 Treatment of the 2,6-dichlorophenylhydrazoneof acetophenone with zinc bromide yields a mixture of the dichlocoindole 2 and a bromochloroindole 3 (Scheme 1). Thus, the mechanism of these reactions must involve a halogenation of either one of the indolization intermediates or of a monohaloindole which could be formed initially. Many indole ring syntheses involve reduction of a nitro group as the last step; the indole ring being formed in the course of the reaction. Haloindoles

w:

Haloindoles and Organometallic Derivatives of lndoles

q:J c1

K

246 bnCI, 260

129

1

3

Scheme 1

can be prepared using this method since the reducing conditions (iron or zinc in acetic acid) do not remove the h a l ~ g e n .lA4 ~ . Chloroindoles are also stable to Raney nickel as is illustrated by the unusual synthesisz0in Eq. (1).

I

H

Knncy Ni. 3 hr, cthnnol, relluz

CI

I

H

An elegant synthesis of 5-halo indoles has recently been developed by Thesing and coworkers.''* l5 Sodium I-acetylindoline 2-sulfonate (4) was prepared by reaction of indole with sodium bisulfite followed by acetylation. This salt was brominated and iodinated at the 5-position. Alkaline hydrolysis then regenerated the indole nucleus and gave 5-bromoindole (5) and 5iodoindole (6). A chlorination procedure failed since a mixture of polychlorinated indoles was obtained when the sulfonate 4 was treated with chlorine followed by alkaline hydrolysis.

Chapter V

130

A related method for the synthesis of benzene-substituted indoles involves halogenation of indolines followed by dehydrogenation. Indolines brominate

H

5 Scheme 2

at the 5-position and the resulting bromoindolines can be dehydrogenated to bromoindoles with chloroanil in refluxing xyleneZ8(Eq. 2).

I

H

Iodoline has been converted to 5-chloro and 5-fluoroindole by a similar Nitration of indoline in a mixture of acetic anhydride and nitric acid gave a I-acetyl-5-nitro derivative. This was converted to the corresponding haloindoles by a process that involved a Sandmeyer reaction and chloroanil dehydrogenation. When indoline was nitrated in concentrated sulfuric acid, 6-nitroindoline was ~btained.'~ A similar series of steps was utilized to convert this into 6-chloro and 6-fluoroindole.

Haloindoles and Organornetallic Derivatives of Indoles

131

A. Bromoindoles Bromination of indoles has been more extensively investigated than any other halogenation reaction. This will be discussed first and in depth because the results are directly applicable to the reaction of indoles with the other halogens. Bromination of indole with pyridiniumhydrobromide perbromide in pyridine, with trimethylphenylammonium perbromide, or with dioxane49* 44. ls9 3-Bromoindole is dibromide in dioxane yields 3-bromoind0le.~~~ \

I

H

H 9

Br

Br

’

N

I H

I

CH3

Br

8

I H 10

Scheme 3

also obtained by bromination of N-benzoylindole with bromine in cold CS, or with N-bromosuccinimide followed by alkaline hydrolysis.112*lZ5 2Bromoindole has not yet been prepared. Oxidation of indolylmagnesium bromides with p-nitroperbenzoic acid affords excellent yields of 3-bromoindoles (Section V.A.4). Bromination of skatole with N-bromosuccinimide (NBS) in acetic acid yields a 2-bromo derivative (7).33Further reaction with NBS or bromination with N-bromophthalimide results in the 2,6-dibromo derivative ?19*. 148 Bromination in aqueous solvents or in t-butanol yields oxindoles (9) or s2 Further bromination of the initial oxindole 3-bromooxindoles ( product yields substitution at the 5-position in contrast to the above results with 2-bromo~katole.~ Green and Witkop have detected an unstable intermediate in the reaction of skatole with 1 equiv of NBS to yield the oxindole (13). This was postulated to be a bromohydrin 12 formed by reaction of a bromonium ion 11 with water. It has the ultraviolet (uv) spectrum of an indolinine and can be trapped by a reaction with piperidine. At pH 9-10 a half-life of 20 min is observed, while at pH 5-6 oxindoles are formed in seconds. The mechanism shown in Scheme 4 explains the results.lB1

Chapter V

132

H

a:+-Qz::J H

r-I II

I

tl~o

CH3

I H 13

I2

I

H

Scheme 4

Addition of 1 mole of bromine to a solution of skatole in ether at -70°C gives a yellow precipitate which is unstable at room temperature.Iz0Treatment of this precipitate with piperidine or aqueous sodium hydroxide yields 60-70 % 2-bromo-3-methylindole together with small amounts of 3-methyloxindole. A similar yellow precipitate was obtained in the reaction of 2phenyl-3-methylindole with bromine in acetic acid.92 Further reaction gave 6-bromo-2-phenyl-3-methylindole (15). The yellow precipitate was assigned the perbromide structure 14 (Eq. 3). Both yellow compounds deserve further study.

n 03'". wCH3 d ?+ Ilr,

C,ti,2-II0.Ac

C6H5

H I

NH:NIi,

I: 47

Br

Br-

14

C6H5

I

111111CHCI,.

15

(3)

20

Broniination of 2,3-diphenyl-, 1 -a~etyl-2,3-diphenyl-,~~~* or 3-methyl-2phenylindole116yields the 6-bromo derivatives, although the 4-bromo isomer has not been eliminated as a possibility in these instances. The structure of Bz-brominated indoles is usually determined by preparing the 5-bromo and a mixture of the 4- and 6-bromoindoles by a Fischer indole synthesis from the p- and the m-bromophenylhydrazine, respectively, and comparing the properties of these compounds with those of the bromination product.

Haloindoles and Organometallic Derivatives of lndoles

133

Bromination of 2,3-dimethylindole in concentrated sulfuric acid containing some silver sulfate gives the 5-bromo derivative in 75 % yield. An authentic sample was prepared from the p-bromophenylhydrazone of 2-butanone. In contrast, bromination of 2,3-dimethylindolenine under the same conditions yields a monobromide which is dehydrogenated by chloranil to the 6-bromo2,3-dimethylindole. The 5- and 6-isomers can be distinguished by infrared bands at 590 cm-I (5-isomer) and 1326 cm-' (6-is0mer).'~~ Bromination of I-acetyl-2,3-dimethylindole, followed by hydrolysis and chloranil treatment, also yields 5-brom0-2,3-dimethylindole.'~~ The structures of the intermediates in this reaction sequence are unknown. Bromination of indoles occasionally leads to unusual products because bromination intermediates are often trapped by reaction with nucleophiles. Bromination of I-methylindole, for example, in dioxane yields a dimeric monobromide 16 which is converted by aqueous sodium hydroxide into a diindole ( 17).12The mechanism of this reaction probably involves trapping of

CIi3 17

the intermediate bromoindolenine (Eq. 4) by reaction with the excess 1methylindole in a process very reminiscent of the acid-catalyzed dimerization of indole. The same diindole is obtained by treatment of the orange precipitate from the reaction of I-methylindole with sulfuryl chloride in benzene with 5 % aqueous sodium ~ a r b 0 n a t e . l ~ Bromination intermediates such as 18 can also be trapped by reaction with pyridine or piperidine if the reaction is carried out in the presence of these nucleophiles. Skatole yields a pyridinium indole (Eq. 5) upon treatment with dioxane dibromide in dioxane-pyridine.124.12i Since 2-bromo-3-methylindole undergoes no reaction under these conditions, the product is probably formed as

Chapter V

134

18

shown by reaction of the intermediate bromoindolenine with pyridine followed by dehydrobromination. This mechanism is similar to that proposed by Hinman and Bauman for the formation of oxindoles in the reaction of NBS with indoles. Similar results are obtained with 3-phenylindole.127 Jackson has proposed that all electrophilic substitution reactions on 3-alkylindoles take place initially at the 3-position to give an indolenine which rearranges in a subsequent step to a 2,3-disubstituted ind01e.l~The above bromination reactions in the presence of piperidine or pyridine provide additional support for this hypothesis. Thus, it is most likely that 2-halo-3alkylindoles are formed by the reaction mechanism of Eq. (5).

aR -x+0

I H

-

X

RJ@

R

Y+ H

(5)

I H

B. Side-Chain Bromination

Very few instances in which indoles have been brominated in the side chain are reported. N-Acetyl-2,3-dimethylindole(19) reacts with bromine

1

19

CO I CH3

( I ) Br,. HOAc (2) NH,, HLO

CO

I

CH3 or NH,. 14,O

I

I

co

I CH3

20

H 21

Scheme 5

Haloindoles and Organometallic Derivatives of Indoles

135

in a minimum amount of acetic acid to give the 2-bromomethyl derivative 20. This is easily converted into the corresponding hydroxymethyl derivatives 21 (Scheme 5).ll6 Bromination of 2,3-dimethylindole with NBS in pyridine yields the pyridinium salt 22, certainly via 2-brom0methyl-3-methylindole~~~ (Eq. 6).

Dimethylindole, in contrast to its N-acetyl derivative and the NBS reaction, reactP6 with bromine in acetic acid at the 3-methyl group to give 23 (Eq. 7) after hydrolysis. (1) Br2. HOAc (2) NH,. H,O

I

H

’

(7) I

H 23

C. Bromination of Functionalized Indoles

Brornination of ethyl indole 3-carboxylate with bromine in acetic acid yields either the 6-bromo or the 5,6-dibromo derivative depending upon conditions.10BThese compounds can be converted, respectively, to 6-bromoindole and 5,6-dibromoindole by decarboxylation of the acid obtained through basic hydrolysis. Bromination of ethyl indole 2-carboxylate has been stated to yield an inseparable 1 : l mixture of the 5- and 6-bromo isomers. This mixture could .be transformed into a still unseparable mixture of 5- and 6-bromoind0le.~~ In contrast, Kunori reports that the first product in the brornination of either ethyl indole 2-carboxylate or the corresponding acid is the 3-bromo derivative 24 (Scheme 6). Further bromination takes place at the 5-position to yield 25. The ester 25 (R = C2H5)is also obtained upon direct bromination of 28. Further bromination of 25 (R = C,H,) yields 26 and 27.26 Acheson and Snaith145observed the unusual bromination reactions given in Scheme 7. The triester 29 brorninates in acetic acid to give the 6-bromo derivative 31. When the reaction is carried out in acetic acid-water, the oxindole 30 is obtained. Brornination of 3-acylindoles can take place either at the 5-position or ato the carbonyl to give 32 or 33 depending upon conditions121(Eq. 8).

CO,CH,

wcocHR‘I 7)- If the pH is kept below 7 only di(indolyl-3)-methane is formed.e2*11* Furthermore, 235 has been obtained in fair yield from indoie and diethylaminoacetonitrile by a transamination reaction1*’, 220 or by elimination of water from indolyl-3-acetaldehyde oxime.I3 A favorable method for obtaining nitriles of types 235 and 236 consists in the reaction of indolylmagnesium halides with a-haloalkylnitriles.15*245. 318. 342* 601 gramines unsubstituted in position I and therefore capable of amine elimination (see Section 11.1.4) react as free bases with sodium cyanide yielding predominantly indolyl-3-acetamides1~205* 206 or indolyl-Iacetic and not the expected nitriles. The reduction of the nitriles 235 and 236 to the corresponding tryptamines 246* 556 with LiAIH43s2, 501* 509* 5*g has been effected catalytically with or with sodium and ethanol.342* 489* 601* Tryptamines with a branched side chain [i.e., /?-alkyltryptamines (238) and #?,/?-dialkyltryptamines(239)] are obtained by a process outlined in Scheme 41.362,323

i

l.i,Alli,

23n

Scheme 41

* Addition in proof: Catalytic reduction of indolyl-3-acetonitriles in the presence of dimethylamine yields the corresponding dimethyltryptarnines [M.Julia and Y.R. Pascal, Chimie Therapeutique, 5,274 (1970)l.

t According to Julia, Manoury, and Igolen.286

Chapter V1

230

a-Phenyltryptamines (241) can be prepared from indolyl-3-acetonitriles, which carry a substituent in position I , by reaction with phenylmagnesium bromide to the imines 240 followed by reduction20 (Eq. 41). c', tl:,

,GI%

NH

L ~ A I H )~.

RI

I

~-::;cH-NH,

I

fJ---~6~5-c~

RI

240

I

(41)

24 1

Another versatile tryptamine synthesis starting with gramines proceeds via 3-nitroethylindoles (243) by the method first reported by Snyder and Katz2l6.217* 2e7. wo.kS2* 581 (Eq. 42). Compounds of type 243 are obtained in ~-cH,-N(cH,),

a-;:

R I CH,- I NO,

R,

,C 242 H -NO,

h O t 1 or

Na

(42)

I H

I

H

243

high yield when R and R' are alkyl. Reaction with nitromethane or nitroethane (242, R = H, R' = H or CH,, resp.) leads mainly to diskatylated products.4s2 Diskatylation is suppressed if metallic sodium rather than sodium hydroxide is used as a proton acceptorsse or if gramine is replaced by gamine-N-oxide as the reaction partner.2e5' An analogous reaction of a-nitroesters with gramines affords the nitroester 244 which on hydrolysis gives 243 (R' = H).217* wo Compounds 243 have also been prepared by Fischer c y c l i z a t i ~ n . ~ ~ * R

~ - c H , - I~ - N o ~ COOCH,

I H 244

Reduction of the above nitro compounds to the corresponding tryptamines 215* 227* 492p 586* 581 pallahas been effected catalytically with According to Heinzelman et aL217*227 dium,217-253* 580* 592 or platin~m.~l5 LiAIH4 can also be used (see also Ref. 215). In our hands the reduction of

* Addirion in proo/. According to Plieninger et al., such C-skatylations proceed more readily in the presence of esters of acetylenedicarboxylicacid as dimethylamineacceptors. [H. Plieninger, Ch. Wagner, and H. Immel, Ann. Chem., 743,95 (1971)l.

Chemistry of Jndoles Carrying Basic Functions

231

245 with LiAIH, led predominantly to 4-methylskatole (246), supposedly by a fragmentation mechanism outlined in Scheme 42567(see also the Addenda).

LiAlH

I H 246

&-CH2

Scheme 42

Anomalous reductions of compounds of formula 243 have been reported by Cohen and Heath-Browngoand Young and Snyder.61BAccording to the former authors, hydrogenation of 247a with platinum in methanolic hydrochloric acid leads to a mixture of the dihydro- and octahydroindoles 248 and 249. By means of zinc and ammonium chloride 247b is reduced to the hydroxylamine derivative (250) (see also Ref. 436), the further reduction of which yields the tryptamine 251 (Scheme 43).

I

H

247a; K, = Rz = CH, 247b; R, = H; K, .:-CH,

H

2-48

H 2-49 Scheme 43

Chapter VI

232

Young and Snyder reported difficulties in the hydrogenation of the nitro group of 252a; reduction with palladium in acetic acid at 20°C and approximately 45 psi yielded a mixture of 253 and 254. In contrast to this, the R

I CH,CHNO,

COOC,H,

252b; R

=

CH, y

3

CHZCH NHI

COOC,H,

H

I

H

H 253

254 Scheme 44

COOC,H, 255

reduction of the less hindered nitro group of 2521, occurred easily, yielding the normal reduction product 25fi6l*(Scheme 44). QJJ-CH5~00R

I

H

256

The reduction of the nitroester 256 with LiAIH, leads directly to tryptamine (Hellmann and S t a r ~ k ~ ~ ~ ) ) . c'OCEIlr, I

Scheme 45

Chemistry of Indoles Carrying Basic Functions

233

Graniines can be condensed with Reissert compounds (for reviews on the chemistry of Reissert compounds, see McEwen and Cobbws and Popp411) t o isoq~inolylmethylindoles~~ as outlined in Scheme 45. The tetrahydropyridylethylindole 259 has been obtained by condensation of graminemethiodide with phenacylpyridinium salts to 257, followed by alkaline cleavage to 258 (for other methods of preparation see Section V.B.3.i and V.B.3.j) and reduction of the latter by means of nickel. The 553 (Scheme 46). resulting 259 cyclizes to 260 under the influence of

I

257

258 Ni/llz K

- C2Ilj

259

260 Scheme 46

For partial and complete reduction of the pyridinium ring of compounds of type 258 by means of palladium, LiAIH4, or NaBH,, see also Ref. 125 and 599. (see also Addenda). d. FROM 3-(NlrRovlNYL)INm~es. This method is one of the most useful for the preparation of tryptamines either with branched or unbranched side chain, viz. a-alkyl, P-alkyl-, and aY#3-dialkyltryptamines.It is particularly valuable because the starting materials are easily accessible and the intermediates crystallize readily. The procedure was first applied by Seka4'@and Onda384and further developed by Young618and Ash and WraggZ5Heating 3-formylindoles with nitroalkanes 261 (R2 = H, alkyl, benzyl, aryl) in the presence of,piperidine or ammonium acetate at 100-1 10" leads in nearly quantitative yield to the crystalline intermediates 262 which afford the tryptamines 263 on reduction with LiAlH,25. 114. 181, 215. 217. 252, 528. 587. 600, 818 (Scheme 47) (see also the Addenda). Unfortunately, the reduction of 262 to 263 quite often results in low yields (e.g., 27 % of 5-methoxytryptamine from 5-metho~y-3-nitrovinylindole"~~)

Chapter V1

234

I

I

R

R 262

J

LiAlIl,

I

I It

It 264

26 S

263

Scheme 47

and by-products have been isolated. In the reduction of 5-benzyloxy-3nitrovinylindole, Ash and Wragg isolated 5-benzyloxy-3-hydroxymethylindole as a b y - p r o d u ~ t The . ~ ~ latter substance may have been formed from some 5-benzyloxy-3-formylindolecontaminant in the nitrovinylindole. More important is the observation that, especially under mild conditions, a large amount (up to 50%) of the corresponding skatole 267 is formed in the reduction of 262, probably via an intermediate 266, which yields 267 by the mechanism outlined in Scheme 42567(Scheme 48). Reduction of 262 to 263 can also be achieved with hydrogen/Pd at 20°C and 1400 psi.254Treatment of 262 with iron in dilute acetic acid affords the ketones 268, which are transformed into 263 by reductive amination (nickel, ammonia, hydrogen).386 Meyers and S i ~ c a r ~have ~ * reported the partial reduction of 262 to 269 with NaBH, at pH 3-6. The 1,4-addition of alkylmagnesium halides to 262 followed by reduction leads to P-alkyl-substituted 5*6) tryptamines 265 (if R, = H) and a$-dialkyltryptamines (if R, = alky1320* (Scheme 47). On reduction of 264 (R = H, R’ = 4-CH3, R, = CH,) with LiAIH,, a large amount of 3-ethyl-4-methylindole has been isolated as a by-produ~t.~~’

R,a;J~

Chemistry of Indoles Carrying Basic Functions R, I

R , Q - ~ ~ I

= C -NO,

.

235

K, I

r

0

+O

7

262

i

H

I

266 ~ri~gmcnt;ition and further rcduction 3s oiitlincd in Schunie 42

H

267

R,

R , ~ T c H z C H NI o 2

I

I H 268

H Scheme 48

269

e. BY NITROETHYLATION. The Michael addition of 3-unsubstituted indoles to nitroolefins and nitrostyrenes takes place at room temperature to yield compounds 270 and 271.20*374-3i7. 447 The best yields are obtained when R, is phenyLs7? The condensation of indolylmagnesium halides with nitroethylenes has been examined by Acheson and Hands.6 They found that 5,6-dimethoxyindolylmagnesium halide is substituted exclusively in position 3, whereas in the case of 5-benzyloxyindole the 1 ,3-disubstitution product is obtained. Indoles with blocked position 3 are substituted in position 1. Catalytic ~ ~nickel377 ~ - ~ ~ leads ~ reduction of 270 and 271 with palladium,6 p l a t i n ~ r n , or to tryptamines in good yield.

H CH3

H H H CH,

C6H5

C6H5

H(CH3) H(CH3) H(CH3) CH3 H

CH3 CH, CH3 H C6H5

H C6H5 CaH5 C6H5

C6H5

212

COCl

I

lndolc I R 273

0-

COCONR' R"

I

R

274

Q--CH,CH~NR'R I alkyl

I H

276

275 Scheme 49

236

H H CHs(C6H5) H(CH3)

Chemistry of lndoles Carrying Basic Functions

237

Snyder and MacDonald have prepared the acetyltryptophans 272 by a modification of the above methodje3 (Eq. 43). f. PREPARATION BY THE OXALYLCHLORIDE PROCEDURE. The procedure outlined in scheme 49 has been developed by Speeter and Anthony600-573* 578 as a preferred method for the preparation of tryptamines not branched at the a-carbon atom. The course of the reduction of 274 with LiAlH,74depends on the nature of the substituent R: if R is H, tryptamines 275 are obtained in general, whereas I-substituted 3-indolylglyoxylamides 274 (R = alkyl) are transformed into hydroxytryptamines 276.2s4b+ 572 The rule is not without exception, however, since the course of the reduction depends on the reaction conditions as well. From the LiAlH, reduction of 3-indolylglyoxylamide in refluxing tetrahydrofurane, Brutcher and Vanderwerff 74 isolated 41 7; of 275 and 1 1 of 276 (R’ = R” = H) while in boiling dioxane, 275 was formed exclusively. Bums, Hoffmann, and R e g ~ ~ i e rreduced ’~ 274 ( R = alkyl) with LiAlH, in dioxane to the tryptamines 275.The ease of reduction of 3-indolylglyoxylamides depends of the nature and position of substituents in the six-membered ring.566* In the usual decomposition of the lithium aluminate complex with ethyl acetate, N-ethylation at the basic nitrogen has been observedso2(Eq. 44).

0 7

COCON

I

I H

H

318

319

k. FROMTRYPTOPHOLS BY RII-TER REACTION OR BY DIRECT AMINATION. Tryptophols 320 (prepared from indolyl-3-acetic acid ester and methyl magnesium halide) yield N-formyltryptamines 321 on reaction with HCN.354 The procedure represents a simple way to obtain a,a-dimethyltryptamines (Eq. 53). For direct amination of tryptophols, see the Addenda.

""'07 I

I

CH, CH,-C-OH /

R2

R1

320

CH,COOH> NaCN

CH, R ~ O Q ~ C H , - C ~ N H -/C H O

\CH,

k,

Rz

CH3

(53)

321

1. B Y REDUCTION OF AMIDES OF INDOLYL-3-ACETIC ACIDS. The LiAIH,reduction of indolyl-3-acetic acid amides is a widely used method for the preparation of tryptaminesl. 283. 286* 481, 6oQ, 570 and has also been applied to 275 The reduction of primary or secondary obtain /3,/?-dimethyltryptamine.1M* amides proceeds often with low yield even under forcing conditions which tend to cleave benzyloxy groups present in the molecule.666The starting amides have been obtained either from the acid chlorides (accessible according to the method of Shaw and W o ~ l l e yor ~ ~by~ )reaction of indolylmagnesium halides with a-haloalkanoylarnide~.~~~

m. BY CURTIUS DEGRADATION OF INDOLYL-3-PROPIONYLAZLDE. CUrtiUS degradation of the azide 322 in methanol leads to a mixture of the urethane 323 and the urea 324M4*345* 266 (Scheme 58). In the presence of hydrochloric acid the intermediate isocyanate cyclizes readily to 1,2,3,4-tetrahydro-/3carbolin-l-one.M6-452, 454 Additional applications of this method are given in Refs. 289 and 485a. n. BY REDUCTIVE AMINATION OF CARBONYL COMPOUNDS. The reductive amination of indolyl-3-acetone with ammonia leads to a-methyltryptamine.388 The reduction of the hydrazones of substituted indolyl-3-acetones with platinum in methanol containing acetic acid yields the hydrazine derivatives


247

Q-CH,CH&ON, I H 32 2

~J-CH~CH~NHCOOCH, I H 323

Scheme 58

325."' Preparation and reductive amination of the branched ketone 326

have been described by Julia et al.283

The hydroxylamine derivative 327 has been prepared from indolyl-3acetone oxime with platinum/hydrogen in acidic solution.47

0y

3

CH2CHNHOH

I H 32 7 0. BY AMINOALKYLATION OF INDOLESWITH FREE PosinoN 3. One mole of indolylmagnesiumiodide reacts with 2 moles of 2-dimethylaminoethylchloride to give N,N-dimethyltryptamine in 15-30% yield.lB2Under the same conditions 2-chloro-1-dimethylaminopropane(328) leads to a mixture of the isomeric tryptamines 329 and 330 as well as the corresponding 1-substituted derivativeP' (Scheme 59). Alkylation of indolylsodium salts leads exclusively to 1-substituted products161(see also Section 11I.B.3).

Chapter VI

248

Another tryptamine synthesis consists in the addition of ethyleneimine to indolylmagnesium halides.??.319 Indole as such reacts with the tetrafluoroborate of ethyleneimine and yields a mixture of tryptamine and I-(2-aminoethyl)indole, the ratio of which depends on the reaction temperature. 2-Methylindole leads exclusively to 2-1nethyltryptamine.~~~

I MgBr 328

H

H

329

330

+

+

I C HSCHCH, N (CH,) 2 Scheme 59

Condensation of amino aldehydes with indoles affords diindolylalkylamines of formula 331 (Eq. 54).Zs8

n=1,2

I

H

331

I H

Tryptophan feaCtS p. a-ALKYLATED TRYPTAMINES FROM TRYPTOPHANS. with acetic anhydride and pyridine to give 332.1°1,176 (Dakin- West reaction). The Huang-Minlon reduction of the latter compound yields a-ethyltryptamine (333)*17(Scheme 60).


H

249

I

332 NH,NH,, KOH dielhylene glycol

H2

Q-c"YH: I

H

333

Scheme 60

q. INWLESWITH CYCLICTRYPTAMINE SIDE CHAIN. 3-(3-Pyrrolidinyl)indoles (336) have been prepared by cyclization of the dicarboxylic acid 334 with amines and subsequent reduction of the 3-(3-indolyl)succinimide 335390 (Scheme 61).

334

33s

336

Scheme 61

Compounds of the types 337 and 338 have been synthesized in an analogous manner.z;a. 279

xQ+h*-Rf

N I R

X G Q - IT J

337

R

33n

I

R"

The synthesis of 339 as outlined in Scheme 62 has been described by DeGraw and Kennedy.Is7 r. SYNTHESIS

OF

OPTICALLY ACTIVE6-METHOXY-P-METHYLTRYPTAMINE

FROM (D)-( +)-PULEGONE.An elegant procedure for the preparation of

(D)-( +)-6-methoxy-~-methyltryptamine 347 has been developed by Frey et al.lS6*449* 452* 454 and is outlined in Scheme 63. (D)-(+)-Pulegone (340) was oxidized and the dicarboxylic acid obtained was cyclized to 341. Coupling of the latter with the diazonium salt of m-anisidine (Japp-Klingemann

a I

+ Cbz--N=)CH,CH,COCL

MgBr

-+

q H

x = 11

X

-1

=

Br

m- QpJYJ)

sleps

I

I

H

339

H Scheme 62

N I

Cbz


25 1

reaction) followed by esterification gave the diester 342, which led to the indole 343 by Fischer cyclization. The 2-carbethoxy group of 343 was removed by hydrolysis and decarboxylation of 344 to 345 and the tryptamine derivative 347 was finally obtained by Curtius degradation of the azide 346. For Section V.B.3.s, see the Addenda. 4. Dehydrotryptamines

Dehydrotryptamines, viz. 348, are available by condensation of 3-indolylacetaldehydes with secondary amineslo2 (Eq. 55). From the comparison of

spectral data of compounds 348 with those of “dehydrobufotenine,” Daly and Witkop conclude that the latter is not a derivative of type 348 as supposed by Wielande02 but has a tricyclic structurelo2 (compare also Refs. 348a and 432a). Reduction of 348 (X = H, R = CH,) with LiAIH4 or NaBH, affords dimethyltryptamine whereas catalytic reduction fails.lo2

5 . Homotryptamines (3-[3-Aminopropyf‘Jindoles)* (see also the Addenda) Grandbergleo obtained homotryptamines 351 on refluxing equimolar amounts of 349 and 350 in methanol (Eq. 56).

349

I

H

351

* Addition in prooj: A new synthesis of homotryptamines unsubstituted in position 2: (I. I. Grandberg and S. B. Nikitina, Khim. Geterocikl. Soed., 1971.54). 3-(3-Hydrazinopropyl) indoles from 3-(3-halopropyl)indoles and hydrazine (M.Bernabe, E. Fernandez-Alvarez, M.Lora-Tamayo, and 0. Nieto, Bull. SOC.Chim. Fr., 1971, 1882).

Chapter VI

252

A number of 3-[3-( 1-piperazinyl)propyl]indoles have been prepared by Fischer ~yc1ization.l~~ Homotryptamines have been prepared by amination of 3-(3-halopropyl)indoles5wR. and homotryptamine itself (351; R = H) by Curtius degradation of indolyl-3-butyric acid.zesaOther routes leading to homotryptamines are the reduction of 3-(2-cyanoethyl)indoles (352) with nickel/hydrogen3***36,7 or with sodium/ethanol,M2and the reduction of amides of indolyl-3-propionic acid (353) with LiA1H,505a-5,70 (Eq. 57).

I H

I

H

352: Y 353: Y

-= -

CN CONRK'

The starting nitriles 352 have been prepared by addition of acrylonitrile to indoles in the presence of cupric acetate and boric from 3-(2hydroxyethy1)-indoles (tryptopholes) by conventional methods,124 or from indolylmagnesiumiodide and 3-chloropropionitrile.jJ5 The required amides 353 result from the reaction of indolylrnagnesiumhalides with the appropriate amides of 3-chloropropionic acid.570 3-(3-Dimethylaminopropyl)-4-hydroxyindole355 has been synthesized by reaction of 4-benzyloxyindolylniagnesiumhalide with 3-chloropropionylchloride to the 3-chloropropionylindole 354 followed by treatment with dimethylamine, LiAIH,, and paIladi~m/hydrogen~~~ (Eq. 58).

As reported by Szmuszkoviczi2' the reduction of 3-(3-dimethylaminopropiony1)indole (356)with Li AIH, yields directly the homotryptamine 357, whereas the reduction with NaBH, leads to the hydroxy compound 358 which can be converted into 357 by dehydration to 359 followed by reduction (Scheme 64). The preparation of compounds of type 356 by the Mannich reaction has already been mentioned (see Section 1I.H). Another synthetic approach to a homotryptamine (360),used by Ames et a1.,20is depicted in Scheme 65.


H

H

356

OH I CHCH2CH,N(CH3),

CH=CHCHZN(CH3),

ClCOO H pyxidin2

I H

I

358

357

0-

N.IBII,

Ii

253

Scheme 64

359

CN I

CNCH,COOC,Hs pyridine piperidine

I

CH,

CH,

fJ----;Hr~2~~2~(~~3)Z ,H2C0N(CH3).

t.I,vtt,

I CH3

I

CH, 360

Scheme 65

The homotryptamine-type Compound 362 has been obtained by condensation of 3-formylindole with picolinium salts in the presence of piperidine and subsequent catalytic reduction of the intermediate 361 (Eq. 59).17.

83. 204. 1 3 i

o\J /

‘

N

RhlAI,OJ Ha

CH=CH

I H

CH3 361

’a = - c H . c H .

I

(59)

CH3

I

H

12

362

Reduction of the oxinie of 363 (obtained by addition of methyl vinyl ketone to 2-methylindole) leads to the a-methylhomotryptamine 364525

Chapter VI

254

(Eq. 60). The reductive amination of compounds of type 363,which affords also a-methylhomotryptamines, is described in a patent.478Aryl-substituted

H

H

363

364

hydroxyhomotryptamines of formula 365 have been prepared by reaction of compounds of type 356 with (substit~ted)phenylmagnesiumhalides.~~~

I

R1

365

Reduction of 366 with LiAIH, yields 3-(4-aminobutyl)indoles (367) (bishornotryptarnines) (Eq. 61).312a

I

H

I

H

6 . Methods for the Selectiue Alkylation of Tryptamines Monomethyltryptamines 370a are obtained in high yield by the method of Knabe305and Dannley, Lukin, and Shapiro1O3 by reaction of the tryptamine 368a with ethyl chloroformate followed by LiAIH, reduction of the obtained urethanes 369. The same reactions starting with 368b lead to the dirnethyltryptamines 370b (see also Horner et al.442)(Scheme 66). This methylation method seems to be superior to the older one that consists of tosylation, methylation, and finally detosylation either by means of anilinehydrochlorideM3or sodium in liquid Reduction of N-formylwith LiAIH, also affords tryptaminesqs5and of N,N'-diforrnyltryptamine~~~~ monornethyltryptamines. A new monoalkylation method, which allows the preparation of monomethyltryptamines and monomethyltryptophans in high yield (371b 372b: 84%), has been developed by Eschenmoser et al.391(Scheme 67). --f


368a; R 368b;

= =

R

I

H CH,

255

369

LiAIH,

Q=-CH'CH

NN 'CH, R

H

Scheme 66

~

-

'

"

'

~

CICOCH,CH&!H,CI

I

I

H 371a; R = H 371b; R = COOCH,

372a: R 372b; K

37 0

= =

fil I

I

U

H

COOCH,

Scheme 67

7 . Tryptamine-N-oxides, 2,3- Dihydrotryptamines, Guanidines, and Related Compounds" (see also the Addenda) Tertiary tryptamines, viz. dimethyltryptamine and bufotenine (5-hydroxydimethyltryptamine), form the corresponding N - o x i d e ~574 ~ ~in~ ethanol * with

* A d i f i o n in proof. The formation of isothiouronium salts from tryptamines or 3-(2brornoethy1)indoles[V. S. Murasheva V. N. Buyanov and N. N. Suvorov, Chem. Helerocycl. Comp., USSR, 4,211 (1968)) and indolyl-3-thioformamidiniumsalts from indoles and S,N,N-trialkylchlorothioforrnamidiniurn salts (R. L. N. Harris, Tetrahedron Lett., 1970, 5217).

Chapter VI

256

hydrogen peroxide. According to Yee-Sheng Kao,2942-methyl-N,N-diethyltryptamine resists oxidation with a 3 % hydrogen peroxide solution while 10 and I5 % solutions lead to 373 and 374, respectively. /"\ ~ C O CNHCOCH, H - c H 2

OH

373

374

On heating in DMSO at ca. 80°, N,N-dimethyltryptamine-N-oxideis treatment of the former compound converted in 56 % yield to 3-~inylindole~*~; with ferrous nitrate and oxalic acid results in demethylation and yields m~nomethyltryptamine.~~~ Reduction of serotonin (5-hydroxytryptamine) to 2,3-dihydro-5-hydroxytryptamine has been effected with hydrogen/palladi~rn.~~~ For the Birch reduction of 5-methoxytryptamines see Section V.B.g. Tryptamines are transformed to guanidines by means of cyanamide.397A number of amidines have been prepared from indolyl-3-acetonitriles via the

375

376

corresponding imin~ethers.'~~, 475* 609 The imidazolinyl compound 375 has been prepared by the same method.236Imidazolinylmethylindoles 376 have

CkT

CH,CN

I

H

I

Scheme 68

H


257

been obtained by reaction of indolyl-3-acetonitriles with ethylenediamine toluene ~ u l f o n a t e . ~ ~ ~ 3-Imidazolidinylmethylindoles377 are intermediates in the preparation of indolyl-3-acetaldehydesaccording to the method of PlieningerAo9. u0(Scheme 68). The amidrazone 378 has been synthesized by Doyle116from the iminoether of 3-cyanoindole.

H

378

8. Miscellaneous Methods for the Preparation of Indoles witli Basic Side Chain in Position 3 [see also the Addenda] Indoles with a free position 3 react with 4-vinylpyridine in acetic acid to give 3-pyridylethylindoles 379a and 379b.lg2.lS5*25* The 2-phenyl derivative 379c has been obtained by dehydrogenation of the corresponding indoline c~mpound.’~ 2-Vinylpyridine has been reported to react a n a l o g ~ u s l y . ~ ~

379a; R, = H, CCI,, CH,C,H,; R, = H 379b; R, = H R, = CH, 3 7 9 ~ R;= ; H R, = C,g5

Compounds 379 and their quaternary salts have been reduced to the corresponding piperidine derivatives with platin~m/hydrogen,4~* lQ4while NaBH, reduction of the quaternary salts leads to the 1,2,3,6-tetrahydropyridine compounds.1s4 Indole and pyridine react in the presence of acid chlorides to give the 3-(l-acyl- I ,4dihydropyridyl)indoles 380a and 380b. Substituted pyridines as well as quinolines react in a similar manner.* The N-benzoyl derivative can be reduced to 381 with platinum and hydrogen, and the N-tosyl derivative

* Addition in proof. For further work on this reaction see also: J. 9ergman.J. Hrrerocycl. Chrm., 7, 1071 (1970) and H. Deubel, D. Wolkenstein, H.Jokisch, T. Messerschmitt, S. Brodka, and H. v. Dobeneck, Chem. Ber., 104,705 (1971).

Chapter VI

258

380b readily eliminates p-tolylsulfinic acid to form 38Zlo7(Scheme 69). The transformation of compounds of type 380a into pyridylindoles of indole

1

p>I'idine-R-CI

QQ-CN-R

J

380a. Pt, H,

I

H

380a; R 380b; R

= =

COC,H, S0,C,H4CH,(p)

I

H

381

Scheme 69

I H 382

type 382 has also been accomplished by means of oxygen as described in a patent .OZea The reduction of the methiodide of 382 with NaBH, to 383 has been reported by Beck and Schenker.982-Phenyl-4,5,6,7-tetrahydroindole condenses with quinoline-N-oxide in the presence of benzoylchloride to give 384.@5

I

H

833

834


259

The reaction of indole with quinoliniummethiodide in the presence of sodium ethoxide is thought to lead to the oxidation product 385, the pyrolysis of which yielded 3861°7(Eq. 62). 3-(l-Cyano-l,4-dihydro-4-pyridyl)indole(387)has been obtained from the reaction of indole with cyanogen bromide and ~ y r i d i n e . ~Hydrolysis ~' of this compound with either potassium hydroxide (yield 90 %) or dilute hydrochloric acid (yield 41 %) regenerates indole."' 3-(ZPyridyl)indole (388) is formed in the reaction of indolylmagnesiumhalides with 2-chIor0pyridine.~~~

I H

I H 388

387

The condensation of indoles with formylpyridines in acidic solution affords diindolypyridylmethanes 389.l9*-

389a;

R1= H,CH,; R,

389b; R, = H

=

R2 =

H

CH,

Catalytic reduction of a mixture of indole and 4-formylpyridine with platinum yields 390 in 30% yield and products of type 389.1Q1Compounds

I H

390

J

391a

seo2

391a; R = H

391b; R

=

COOH

I H

H 393

392

Scheme 70

nCH 1

H,C

394

I

397

Scheme 71

260


26 1

of type 390 have also been prepared by reduction of 3-pyridylmethylindoles with sodium in butano1188and 390 itself by condensation of isatin with 4picoline followed by reductions33(compare also Section V. B.3.h). The pyridylmethylindole 391a, which is accessible by the Fischer cyclizationxs*bs3 (see Section V.B.3.a), has also been obtained by reaction of indolylmagnesiumhalide with 2-chloromethylpyridine or by heating the sodium salt of indole with 2-hydro~ymethylpyridine.~~' Oxidation of 391a with selenium dioxide leads to the ketone 392$$while the 3-pyridylmethyl-2indolylcarboxylic acid 391b cyclizes on heating to the indolo [3,2-b]quinolizine 39389(Scheme 70). Reduction of the quaternary salt 394 with NaBH, leads to a mixture of 395 and 396, the former being the main product. Both compounds cyclize to the indolo[2,3-f]morphane 397 on heating with polyphosphoric (Scheme 71). The 3-isoquinolinylmethylindolederivatives 398 and 399 have been prepared from the appropriate indolyl-3-acetic acid amide by Bischler-Napiralski ring c 1 0 s u r e . ~385 ~~~

& " I

H

398

f' JN - - J o c 4 I :I

399

As reported by Zinnes et a1.,622compounds of type 400 rearrange with acid to compounds of type 401 (Eq. 63).

400

401

The 5-(3-indolyl)-benzodiazepine 402 has been obtained by reaction of 3-(o-halobenzoyl)indoleswith ethylenediamine.J3H* lfi2;' The condensation of

Chapter VI

262 N-N-H

\

N

\

I H

I H

402

R

402a

3-aroylvinylindoles with phenylhydrazine led to 3-(2-pyrazolin4yl)indoles of formula 40Za.m7s 9. Spirocyclic Indolines and Indolenines; 4,7- Dihydroindoles

(see also the Addenda)

The course of the reduction of the 5-methoxytryptamine methiodides 403 with lithium in liquid ammonia depends on the reaction conditions and on the substituent in position 1 .427 These relations are displayed in Scheme 72.

Scheme 72

WH% Chemistry of Indoles Carrying Basic Functions

Ar

RCHO

263

m Ar L R H

€1

1

pyridine

p-TosCI

+ Q-JtRr Ar

\

NaBH

I

I

H

H

405a;

oNA-yH4cH3

R' = SO,C,HJX,,

~LiAIH4,orNa/C4HIOH

405b; R' = H

Scheme 73

A route to spiro[indoline-3,3'-pyrrolidines] of formula 405 has been elaborated by Weisbach et aL5W and is depicted in Scheme 73. The synthesis of a spiro [indoline-3,4'-piperidine] (94) by Fischer cyclization has already been mentioned (Section IV.B.1, Scheme 13). Other representatives of this class of compounds are 406 and 4 0 F and 409:O ' prepared by LiAlH, reduction of the spiro-oxindoles,viz. 408(Eq. 64). Several spirocyclic indoline derivatives (410-413) are intermediates in the Woodward total synthesis of strychnineeo7(Scheme 74).

CH, 406

UAIH,

I

H 409

264

Chapter VI

n pyridine

L

COOCZH, COOCH, 413

Scheme 74

10. Naturally Occurring Indolylalkylamines

The literature on the natural occurrence of indolylalkylamines has been ~ ~ recent work on this subject is reported in reviewed to 1960 by B ~ i t . dMore the following papers on the isolation of gamine from phalaris arundinaceass; N-methyltryptamine from Piptadeniaperegrina B e r ~ t h . ~and ~ ' acacia Maidenii F. M ~ e l l .;' N,N-dimethyltryptamhe ~~ from Phalaris t u b e r o ~ a Desmodium ,~~ pulchellum Benth. ex Acacia maidenii F. Muell ?51 and Acacia citrinas@; N,N-dimethyltryptamine-N-oxidefrom Acacia citrinaSge and Acacia porphyriasse; 3-aminomethylindole from barleySBs; 3-methylaminomethylindole from barleysBs; 5-hydroxytryptamine from Paneolus sphinctrinus,5sB Leptodactylus species,'* Acacia citrina,888 and Acacia prophyria5B8; 5-hydroxy-N-methyltryptaminefrom Leptodactylus species,'*


265

Acacia citrina ,568 and Acacia porpliyr ia568; 5 -hyd roxy-N ,N-d i me thy1tryp tamine from Destnodiutn pulchelluni Benth. ex Baker,171Acacia c i t r i n ~and ,~~~ A c a ~ i a p r o p h y r i a5-hydroxy~~~; N , N-dimethyltryptamine- N-oxide from Acacia ~ i f r i n aand ~ ~ Acacia ~ porphjqria568;S-methoxy-N-methyltryptaminefrom Piptadenia peregrina Benth.327; 5-methoxy-N,N-dimethyltryptamine from Phalaris t u b e r o ~ a ,Desmodium ~~ pulchellum Benth. ex Baker,"' Piptadenia peregrina Benth. ,327 Acacia c i t r i n ~ and , ~ ~Acacia ~ p ~ r p h y r i a 5-methoxy~~~; N,N-dimethyltryptamine-N-oxidefrom Desmodium pulchelluni Benth. ex Baker172;bufotenidine from Lepfodactylus specieP3; bufoviridine (dihydrobufothionine) from Bufo ~ i r i d i s ~ ~I-methoxy-N,N-dimethyltryptamine *; (lespadamine) from Lespedezia bicolor var. j a p ~ n i c a ~ ~Chydroxy-N,N'; dimethyltryptamine (psilocine) from Psilocybe haeocjmY2 and Psilocybe cyanescensJ1;4-phosphoryloxy-N,N-dimethyltryptamine(psilocybine) from Conocybe cj*anopus.41Psilocybe cyanesceti~,~'and Psilocj*be seniilunceata Fr.23R;4-phosphoryloxy-N-methyltryptamine(baeocystine) from Psilocybe b ~ e o c y s t i 335; s ~ ~4-phosphoryloxytryptamine ~~ (norbaeocystine) from Psilocybe baeocystisW5; 1.5-di met hoxy-3-di met hyla minomet hyli nd ole ( 1 ,5-d i methoxygramine) from Gyninucranthera paniculafa (A. DC.) Warb. var. zippeliana (Miq.) J. S i n ~ I a i r ~and ' ~ ; 6-hydroxytryptamine (?) from heart of ~~; of structure of 5-methoxy-acetylcrab Carcinus m a r t ~ a s ~elucidation tryptamine (melatonine) see Ref. 330.

1 1. Cypriditia Luciferin* The structure of cypridina luciferin, the substance responsible for the bioluminescence of Cppridina hilgendorfii, has been elucidated and a procedure for its synthesis developed by Kishi et al.,176b* 303* 304 The synthesis and some degradation reactions are outlined in Scheme 75. Cypridina etioluciferin (416), which has been prepared by the procedure shown in the scheme, is condensed with (+)-d-x-oxo-/3-methylvaleric acid. the resulting azomethine 417 reduced with platinum and hydrogen to 418, and the latter cyclized to cypridina luciferin (419) with DDC. The oxidation of 419 to a mixture of cypridina oxyluciferin (420) and 416 with cypridina luciferase and oxygen proceeds with emission of light. Compound 420 is also formed with ammonia but no luminescence occurs under this condition. The action of hydrochloric acid on 420 leads to etioluciferin (416) which is hydrolyzed to etioluciferamine (415) with barium hydroxide. Recently Inoue et published an improved synthetic procedure that involves condensation of etioluciferin (416) with a-oxo-@-methylvaleraldehydein the presence of a small amount of hydrochloric acid to give luciferin (419) directly.

* Addition in prooj: A revised structure for cypridina oxyluciferin has recently been proposed by S. Sugiura, S. lnoue and T. Goto, J. Pharni. Soc. Japan, 90, 71 1 (1970).

CHO

H cypridina luciferase/O, or NH,

N ,N

H

a-c&CHz)sNH-CNH2

I H

420

NH II

+

416

HCI

Scheme 75

266

Ba(OH),

415


267

12. Indolmycine* The structure of indolmycine (421), an antibiotic produced by Srreptomyces species, has been established by Schach v. Wittenau and Els.466The synthesis of 421 has been realized by the same authors4s7and recently by Preobrazhenskaya et al."9 0

I

H

421

13. Violaceine Violaceine, the violet pigment of Chromobacterium oiolaceum, has been assigned structure 422.31 H

k

H 42 2

14. Urorosein For Urorosein, which results from the action of acid on 3-formylindole, Harley-Mason and B u ' l o ~ k ~have ~ ' proposed structure 423 (as the free base). This is supported by the course of the reduction of urorosein with

@JrCHl+ /o N

I

I

\

/

423

* Addition in proof. The absolute configuration of indolmycin has been established as

5S.6R- by T. H. Chan and R. K. Hill [J. Org. Chem., 35, 3519 (1970)l.

Chapter VI

268

LiAIH, which leads to di-(bind~lyl)rnethane.~~~ In the light of this result the alternative structure assigned to urorosein by Fearson and B o g g ~ s t seems '~~ to be untenable. Dobeneck et a1.1°8a disagreed with the formulation of the title compound as 423, and they have provided further evidence that urorosein is a salt of the chromophore 423a.Iwb

VI. Preparation of Indoles with Basic Function in the Six-Membered Ring A. 4, 5-, 6-, and 7-Aminoindoles*

1. By Ring Closure Oxidative cyclization of 424 with silver oxide leads to 5-aminoindole (425) (Eq. 65).208

424

H 425

6-Dimethylaminoindole-2-carboxylicacid (426a), prepared by the indole synthesis of Reissert, forms 6-dimethylaminoindole (426b) by decarboxylation.321. 3x4

426a; R 426b; R

= =

H COOH

H

4-Dimethylaminoindole has been obtained in an analogous manner.567 Adams et al.9-11 synthesized 5-aminoindoles 428 by the method outlined in

* Addition inprooJ Oxidative aminationof 5-hydroxyindolesin position 7 (A. N. Grinev, N. V. Arkangel'skaya, and G . Ya, Uretskaya, Pharntac. Chem. J. USSR, 1969,683).


269

Scheme 76. In a similar manner Domschke et al.l13 prepared 5-dimethylsulfamoylaminoindoles by reaction of 427 with enamines. RI, R'

RCOCI1,COR

"so2NQNso2N 427

RR 'N '

f

SO,N H

aCH(COR), NHSO,N,

:RlR'

428;

Scheme 76

R

=

7 R'

CH,, C,H,

2. From Nitroindoles and Nitroindolines Nitroindoles, nitrotryptamines, and derivatives of nitroindole-carboxylic acids and nitroindole acetic acids have been reduced to the corresponding amino compounds by means of sodium dithionite (Na2S,0,)37*72* w3 (the method failed in the reduction of 4-nitr0tryptamine~~~), stannous chloride71 (the method failed in the reduction of 6-nitroindole71), nickel and hydrog e r ~ , ?229* ~ . 37g nickel and h y d r a ~ i n e ,jg5 ~ ~ .palladium and hydrazine,lsl, palladium and hydrogen,16gpalladium and hydrogen in methanolic hydrochloric acid,170and platinum and hydrogen.350In the reduction of 6-nitroindolyl-3-acetonitrile with nickel and hydrogen, 30 % of 6-aminoindolyl-3acetonitrile has been isolated.'" Hiremath and Sidda~pa*~O reported that this reaction leads to 6-aminotryptamine. According to Berti et al.,53 its course depends o n the reaction conditions. In the catalytic hydrogenation (Pt or Pd) of nitrogramines, Berti et al.53and DeGraw et a1.l"' observed no deamination of the side chain (compare, however, Section 11.1.5) and obtained aminogramines in good yield. According to Papayan et al.,3e6Ptreatment of a methanolic solution of 6-nitrogramine with sulfur in the presence of sodium hydroxide leads to 6-aminogramine, whereas 4-nitrogramine is transformed by this procedure into the tricyclic compound 428a. The reduction of nitroindolines to aminoindolines has been effected with nickel and h y d r a ~ i n e , ~stannous ~' chloride,65*539 palladium and hydroge11,2*~* 255 platinum and hydrogen,302and nickel and hydrogen.273Dehydrogenation of aminoindolines to aminoindoles has been successful using

270

Chapter VI

6j H

I

I

H

4283

chloranil,"O palladium on or manganese dioxide.281 Shaking nitroindolines with Raney nickel in aqueous sodium hydroxide led to aminoin dole^^'^ (Eqs. 66 and 67).

O-CH~COOH

O~N

CH,COOH

NaOH nickcl'li2

"'9 I

(93% yield)

COCH,

I H

(66)

nickeliH

f NaOH (49% yield)

No* COCH,

3. From Haloindoles 4- and 6-Haloindolyl-2-carboxylic acids are converted into 4- and 6aminoindoles respectively, on heating with ammonia at 200°.407.581 In the presence of cuprous chloride this exchange reaction occurs with Cbromoindole

Bra YNH, NH&

'

H2NQJ-J

I H

"'a

T

+

I

I COCeHS

Scheme 77

I

H (1) Hydrolysh (2) MnQp

-7ii7 KNH

+

I

COC, H,

&-J t

H

63 I

CO C, H,


27 1

at 165'; higher temperatures are required with 4-chlor0indole.~~~ 4-Amho-lbenzylindole has been isolated as a by-product in the reaction of 4-bromoindole with benzyl chloride/sodium amide in liquid ammonia.4m The reaction of 5-bromoindole and 1-benzoyl-5-bromoindoline with potassium amide in liquid ammonia leads to a mixture of the corresponding 4- and 5-amino compounds via an aryne intermediate2*' (Scheme 77). An interesting intramolecular modification of this reaction leads to the tricyclic compound 429 (Eq. 68).

4. 5-Aminoindolesfrom 5-Azoindolines Coupling 1-methylindoline with diazotized sulfanilic acid leads to 430 which can be reduced to 5-amino-I-methylindoline (431). Dehydrogenation of its phthaloyl derivative with chloranil yields 5-amino-1-methylindole (432) (Scheme 78).540In an analogous manner, 5-amino-1-benzylindolinehas been prepared by Teuber et aLM4*

HO3s+=NyJ-J

HCI

430

I CH3

HzNo I

CH2.

431

1

H*N chloranil

I CH3

432

Scheme 78

Chapter VI

272

5. 5-Aminoindolines by Beckmann Rearrangement of 5-Acetylindolines

a CHFOa

The oximes of 5-acetylindolines form 5-acetaminoindolines when subjected to a Beckmann rearrangementa2(Eq. 69).

I

(1) (2) NHIOH HCI

CH&O-NH

'

CH,COOH

(69)

I COCH,

H

6. Direct Amination of Indoles in the 5-Position Direct amination of 1-p-chlorobenzoyl-2-methylindolyl-3-acetic acid (433) with dimethylchloroamine to the 5-dimethylamino compound 434 has been described in a ~ a t e n t ~(Eq. ~ 5 70).

61

Cl 433

434

I . Introduction of a Pyridyl Radical in the 5-Position of Indolines Indolines form the 5-pyridyl derivatives 435 on reaction with benzoylpyridinium chloride in the presence of A1C13.313

R

435; R = H,CH,


273

8. Alkylarion of Aminoindoles and Reactions of Indolyl Diazoniuni Salts (see also the Addenda) Methylation of 6-aminoindole with dimethylsulfate/sodium hydroxide DeGrawlsl obtained 5-dimethylaminoled to 6-dimethylamin0indole.~~~ indole by quaternization of 5-aminoindole with dimethylsulfate followed by treatment of the quaternary salt with sodium propoxide. The preparation of N7N-bis(2-chloroethy1)aminoindo1es from aminoindoles has been described by DeGraw and G o ~ d m a n . ~The ~ ~Sandmeyer - ~ ~ ~ reaction with 1-acetyl- and 1-methylindolinyl diazonium salts has been used for the preparation of 5-fl~oroindolines,*~~ 5-~hloroindolines,25~ 5-bromoindoline~,~~~ 378 In addition, 5-i0doindolines,~~~ 6-fluoroindolines,255 and 7-iodoindoline~.1~~* diazotized 1-acetyl-5-aminoindoline forms 1-acetyl-5-hydroxyindoline (436) on warming with an aqueous solution of cupric sulfate. 5-Methoxyindole (437) is obtained in 3 steps (Eq. 71) from 436. The 4-, 6-, and 7-aminoindolines react analogously.65* 249

“a

(1) (2) (CH~OLSO~ HCI

I COCH,

PdiC mesitylenc

cH3 (71)

I H

437

436

B. Indoles with an Aminomethyl Side Chain in the Six-Membered Ring 1. From Hydroxyindoles by Mannich Reaction

See Section I1.G.

2. By Reduction Procedures 5-, 6-, and 7-Indolylcarboxylic acid amides or hydrazides have been reduced with LiAIH,BBB543. 544 to the corresponding aminomethylindoles. R, ,KCH2 R‘

0

438

274

Chapter VI

Similar compounds result from the reduction of azomethines of 4-, 5 - , 6-, and 7-formylindole~~~~ or 4,5-, 6-, and 7-cyanoind01es.~~~ Mannich bases of 40~0-4,5,6,7,-tetrahydroindoleswith the basic side chain in position 5 (438)have been prepared by workers at Endo Laboratorieslm* and by Hauptmann and Martin.”s C. Indoles with an Aminoethyl Side Chain in the Six-Membered Ring

Indoles of the general formula 440 are readily accessible by the method outlined in Scheme 79.Ca The starting formylindoles 439 can be obtained by NO,CH,R’ CH,COONH,

’

k

R

H

439

LiAIH,

H

Scheme 79

440; R = H, CH8; R’ = H, alkyl, benzyl

R

R’

I

H 29; R and R‘ = H or CH, or methiodide

H 441

Scheme 80


275

reduction of the corresponding cyanoindoleswith sodium hypophosphite and nickelsBqaccording to the method described by Backeberg and Sta~kun.~' The conversion of the Mannich bases 29 into the aminoethyl derivative 44166a is outlined in Scheme 80. The Mannich base from 6-hydroxyindole reacts similarly, yielding compounds with an aminoethyl side chain in position 7.wa In an analogous reaction of the 3-methylindole Mannich base 442 with nitroethane, 30% of the furo[3,Ze]indole 444 is formed besides the expected 443 (Scheme 81).668

CH3 I

442

I H

A 'r&7-c C,H,NO*/NaOH

CH,CHNo;q

HOl$--

I H 443

H3C

-

I

444

H

Scheme 81

The reaction of the rnethiodide of 29 with sodium cyanide leads to 4cyanomethyl-5-hydroxyindole,which has been reduced to 4-(2-aminoethyl)Julia et al.284a 5-hydroxyindole (441; R = R' = H) with ni~kel/hydrogen.~'* reported on the analogous reduction of 4-cyanomethyl-5-methoxyindolewith

nickel or LIAIH,. Indoles with a 2-amino-1-hydroxyethyl side chain in position 5 (446)result from 5-(a-chloroacyl)indoles 4 4 P 2 by the procedure outlined in Scheme 82.ss4 R

c Il c H c o ~

445

HNR,R,

R1 R,'

'NcHc R I

Y

k

Scheme 82

446

276

Chapter VI

The synthesis of 447 from 6-acetyl-2,3-dimethylindoleis described in a patent.a6L

H

447

MI. Basic Esters of Indolylcarboxylic Acids Basic esters of the following carboxylic acids have been described : indolyl2- and indolyl-3-carboxylic acid,lZ8 indolyl-3- and indolyl-4-carboxylic l-methyl-3-phenyl-indolyl-2-acetic acid ,329*536 indolyl-3-acetic acid,580 17* and substituted indolyl-3substituted indolyl-5-carboxylic propionic

VIII. Basic Ethers of Hydroxyindoles and Mercaptoindoles (see also the Addenda) Basic ethers of 3-hydro~yindoles~~~~ 16'* 617 and of 5-hydroxyindolesm8 have been prepared by alkylation with the appropriate aminoalkyl halides. Compounds of type 448 result from the alkali-catalyzed condensation of hydroxyindoles with epichlorohydrin and subsequent reaction with primary

448;R

= H, CH,

H

or secondary amine~.~~O 2-Aminoalkylthioindoles have been obtained by alkylation of indoline-2-thiones, viz. by treating them with a~iridine.~~"

Addenda Literature published between July 1969 and July 1970 is reviewed in this supplement. Only papers describing new procedures or novel types of compounds are incorporated. The numbering of the paragraph corresponds to the Section numbering in the main part of this Chapter.


277

Further essential papers appearing before June 1971 have also been mentioned in footnotes of the respective sections. 1I.B. The preparation of Mannich bases of the gramine type using hydroxylamines as amine component has been described by Thesing et a1.660 Alkylhydroxylamines react smoothly to give the expected compounds 449a,whereas 449b could not be isolated from the reaction mixture. For the preparation of 449b from gramine methiodide by amine exchange, see Section V.B.2.d.

H

449a; R = alkyl 449b; R = phenyl

1II.A. Refluxing cinnolines with formic acid and formamide leads to 1-formylaminoindoles (55-74 %) which are reduced to I-methylaminoindoles by means of LiA1H4.624aFor further work on the Arbuzov cyclization, see Ref. 642a. III.B.2. Schubert et aLas3report that in their hands Fischer cyclization to 1-dial kylaminoet hylind oles failed. III.B.3. For examples of the introduction of the dimethylaminopropyl residue in position 1 of compounds of the tryptamine type, see ref. 623. 1V.A. Indole reacts with tosylazide to give 450,Bz6 whereas the analogous reaction with indolylmagnesium salts is reported to give tars.63eCondensation of 1-methylindoles with picrylazide leads to 451,627 a substance that exists in the tautomeric forms 451a and 451b. For an extension of this study to 1,2,3-trirnethylindole, see Ref. 626a.

Q ' ' ct NHSO,

\ 1

CH3

Chapter VI

278

Hino et aLaOreport on the easy autoxidation of 2-aminoindoles to products of formulas 452a and 452b.

CH,

452 b

452a

Further examples of the transformation of 2-aminoindole into tricyclic

(pyrimido[l,2-a]indoles)are described in a patent."43

IV.B.l. Fischer cyclization of the N-methylhydrazone of 2-acetylquinoline yields l-methyl-2-(2-quinolyl)indole.637 For the cyclization of N-methyland N-benzylhydrazones of acetylpyridines to 1-methyl- and l-benzyl-2pyridylindoles respectively, thermal indolization was preferred to the usual acid-catalyzed procedure.65" IV.B.6. 2-Cyanoindoles, prepared from indolyl-2-carboxylic acid amides by means of POCIS, can be readily reduced with LiAIH, to 2-aminomethyl-

in dole^.^^^

IV.B.lO. The above-mentioned 1-methyl-2-(2-quinolyl)indole has been also obtained by reaction of 1-methylindolyl-2-lithiumwith quinoline and subsequent dehydrogenation of the intermediary dihydroquinolinyl comIV.B.12. For the NaBH, reduction of quaternary salts of 2-pyridylindoles to 2-(tetrahydropyridyl)indoles, see also Ref. 654. 2-(Tetrahydropyridy1)indoles of formula 453 dimerize under the influence of acid to products of the presumed structure 454.a7 R

I

%2

R*fJ-7+

H 453

N-R

R'R+ \ N I R

454

IV.B.13. A piperidinomethyl side chain can also be introduced in position 2 by the following method: a 2-methylindole, viz. 455, is transformed into the pyridinium salt 456, which is subsequently reduced to 457 with Pt0,/H,.Q4


279

456

455

Pr:H*

457 Scheme 83

2-Aminomethylindoles are also formed in the Schmidt rearrangement of ketones of formula 458 while Beckmann rearrangement of 458 leads to amides of indolyl-Zacetic acid.650Eq. 72

' ' my1 CHCOR,

HI

HzSO, Nab

'

QQ1;LNHCORz

(72)

HI

458

The oxidative rearrangement of 2-aminomethylindoles of type 146 to benzodiazepines 147612has been extended to analogous rearrangements of 2-aminoethyl- and 2-aminopropylindoles yielding 1,5-benzodiazocines and 1,6-benzodiazononinesrespectively.658 V.A. The 3-nitrosoindoles 459 (or the tautomeric 3-isonitroso-indolenines) (Scheme 84) have been reduced to the corresponding 3-aminoindoles 460 by Schmitt et al.651-652 using Pt/H2 in acetic acid, whereas Huang-Hsinmin and Mannwz prefer ethanol as solvent. In the hands of the latter authors, was less reduction by Zn/HC1645or Zn/CH,COOH, NH,SH, and Na2S2OleS2 satisfactory than catalytic hydrogenation, in which, however, they isolated a small amount of the azo compound 463 as a by-product. Schmitt et al., on the other hand, found a blue dimeric by-product of formula 464, readily reducible to the leuco compound 465 which is quickly reoxidized to 464 by air. The extreme susceptibility of 3-aminoindoles 460 to autoxidation has been also observed by Huang-Hsinmin and Mann?42 who isolated 461 and 462 as oxidation products. The oxidation of 3-aminoindoles to 34minoindolenines (viz. 148a -.+ 148c) has also been effected with chloranil or nitr~benzene.~,~ Addition of equimolar amounts of an azometbine 465a to the isonitrile 466 results also in the

R,

464

461

4.1

0 ' C6H6

R'

462

I H 465

Scheme 84

Ma;

467

R, = H;R, = H,NO, 280


28 1

formation of 3-aminoindole derivatives (467) (Eq. 73).Ssz No indoles are formed if the benzylidene derivative of p-nitroaniline (465; R, = NO2) is used in this reaction. V.B.2.d. The reaction outlined in Eq. (29) is reported to succeed only in an aprotic solvent such as xylene. Under this condition, also pyrazole is skatylated in position I.gz5 V.B.2.g. From the oxidation of 2-methylindole with sodium periodate in aqueous methanol, the indolyl-indoxyl compounds 468 and 469 have been isolated in 33 and 4 % yield

ir 469

468

V.B.2.h. Another method for the preparation of 3-aminomethylindoles consists in the acid-catalyzed addition of benzalanilines to indoles in which position 1 is substituted (Eq. 74).a3s

CH,

CH,

Reaction of the antioxime 470 with tosylchloride/pyridine at -5' led, via a supposed intermediate 471, to the N-chloroimine 472. The proposed mechanism is supported by the fact that the antioxime from 2-acetyl-1-methylindole did not give an analogous reactionaze(Eq. 75). V.B.3.a. The mechanism of the cyclization outlined in Eq. (33) is discussed in Ref. 636a. V.B.3.c. As already reported, reaction of gramine with nitromethane yields predominantely diskatylnitromethane instead of 3-(2-nitroethyl)indole 243 (R = R' = H) (see Eq. 42). The latter compound, however, is obtained in high yield by reaction of gramine methiodide with the magnesium salt of nitroacetic acid (prepared from nitromethane and the so-called magnesium methyl carbonates5ea)followed by a~idification.6~58 Under carefully controlled

Chapter VI

282

conditions, reduction of 258 with NaBH,, usually leading to the tetrahydropyridyl derivatives, can be stopped at the dihydro stage (working in a strong alkaline two-phase liquid mixture of water, methanol, and ether).6s5b

470

I

471

V.B.3.c. and V.B.3.d. According to a patent, reduction of 3-nitroethyland 3-nitrovinylindoles to tryptamines with LiAIHdalso succeeds if position 1 of the indole nucleus is substituted by an aroyl- or heteroaroyl residue (no attack of this group).&L6 V.B.3.f. Oxalyl chloride, which normally substitutes indole on the most nucleophilic position 3, attacks 4,6-dimethoxyindole in position 7 (twice activated by o- and p-methoxy group) instead of position 3.628aIt is to be noted that reaction of indolylmagnesium bromide with oxalic esters does not lead to 3-indolylglyoxylic ester but to the 1-isomer at low temperature or to the 2-isomer at elevated temperature.6448 V.B.3.g. For the reduction of 3-aminopropionylindoles to hydroxytryptamines with threo- and erythro-configuration, see Ref. 648. V.B.3.k. According to Ref. 655a, N-disubstituted tryptamines are obtained in high yield on boiling a solution of tryptophols in benzene or xylene with secondary aniines and a nickel catalyst. V.B.3.s. Tryptamines by Beckmann Rearrangement of 3-(3-Oxobutyl)indoles. With PCI, the oximes 473a undergo Beckmann rearrangement to acetyltryptamines 474 which cyclize under these conditions to the corresponding 3,4-dihydro-/l-carbolines475. Analogous treatment of oximes 473b yields anilides of the corresponding 3-indolylpropionic acid (476) (Scheme 85).844

R' R'

a - & H 2 N

HCOCH,

R' R'

k

I

I I I€

I

ii

N * €1 175

CH3

Scheme 85

V.B.5. A large number of examples of Fischer cyclizations to homo- and bishomotryptamines of type 477 are described in a patent.656

R:

477:

3 or 4

ti

~ i -

Homotryptamines 479 result from the hydrogenation of azepino [3,4-a]indoles 478 with nickel in ethanoP6 (Eq. 76).

a-Il NiiH,

CJWH

I

13 478

~

~

~

~

~

Z

c

H

Z

c

H (CH3 Z N12

(76)

I

14 479

V.B.7. Reaction of dimethyltryptamine-N-oxidewith SO,/formic acid results in demethylation and subsequent cyclization to 2-methyl-l,2,3,4tetrahydro-~-carboline.02*

Chapter VI

284

The iminoether 480 yields the triazinylalkylindoles 481 on warming with hydrazinoethylamines 482633D (Eq. 77). H I

NH

L- COCzHs II

Qj--(C, I

11

a - ( C H z ) n < N > N-NI

R

I

N H,CH,Ct(,NN H:

480; I I

=

R

I

11

482

481;

1-3

(77)

;I =

1-3

V.B.8. 2-Phenyl-3-(2-quinolyl)indole (483) has been prepared by Fischer cyclization of the appropriate phenylhydrazone with ZnC1p637

483

Several condensations of indoles with pyridine-and quinoline-N-oxides in the presence of acylating agents are given in Eqs. (78),6"* 637 (79),Ba7and (80).637*

:icyla!inp

(78)

aa 4

+

+

N

4

I CH,

C'H COCI

/

I CH,

0

+

I 11

I

11

0

If

fyC0OK

N

4

0

Cdi,COCI

I

I

& Y O o R

(80)

I II

* Addition in proof. For further application of such reactions see also H. Hamana and I. Kumadaki, Chem. Phann. Bull., (Tokyo), 18, 1742 (1970).


285

Condensations of indoles with nitrophenazine-N-oxide have been described by Pietra et al.648 The reaction of indole with thiourea in the presence of iodinelpotassium iodide leads to the isothiouronium salt 484.48

I

€i 484

485; X = H, OCH,; R,-R, = H, lower alkyl

V.B.9. A number of Birch reductions of tryptamines to 4,7-dihydrotryptamines of the general formula 485 have been described in a patent.624 For a discussion of the reactions depicted in Scheme 72, see Ref. 628b.* VI.A.8. As already reported, 5-iodoindoline can be prepared by the Sandmeyer reaction of l-acetyl-5-aminoindoline.250According to a an analogous reaction also succeeds in the indole series: diazotization of 1-acetyl-5-aminoindole and treatment of the diazonium salt formed with an aqueous solution of KI led to 1-acetyl-5-iodoindolein 57 % yield. MII. For further examples of the preparation of basic ethers of 2-mercaptoindoles, see Ref. 641.t

Appendix of Tables General Remarks

The tables list compounds in which the indole nucleus does not carry substituents other than the basic side chain, or those substituted by alkyl, halogen, trifluoromethyl, or silyl groups. All hydroxy, alkoxy-, alkylthio-, nitro-, cyano-, acyl- and carbalkoxyindoles have been omitted, since they are summarized in the appropriate chapters. Compounds, however, in which the basic side chain contains further functional groups, such as OH, COOH, COOR, and CN, are taken in account, except for the a-amino acids

* Addirion in pro?/: See also W. A. Remers, G . J. Gibs, Ch. Pidacks and M. J. Weiss J . Org. Chem., 36, 279 (1971), t Addition in proof. See also J. Bourdais, Chimie Thdrapeulic, 5, 409 (1970).

Chapter VI

286

(tryptophan type) which are collected in a later volume. The compounds are classified by the position of the side chain and the distance of the basic center from the nucleus as follows: Crystallization Solvents ac c cyh b bu d dmf e ea et

acetone chloroform cyclohexane benzene butanol dioxane dimethylformamide ethanol ethyl acetate diethyl ether

h hexane iP isopropanol I ligroine m methanol P petroleum ether PY pyridine t toluene thf tetrahydrofuran W water X xylene

R2

NHC6HS

H

NCH3COC6H5 N (CH3) H

CH3

H

CH3 CH3 H H

H

H

H

N=CHC6HS

NH2

NHCH3

NH2

NHCHO NHCHO NHCHO

NH2

R1

‘sH5

CH3 ‘sH5

H

CH3 CH 3 CH3 CH3 ‘6’5

H

CH3

R3

‘2 nH 1 6”2

C17H16N20 ‘17% aN2

‘lSH1 4N2 C16H16N2

C15H12N2

‘gHsN2O C10H10N20 ‘1 lH 1 2N 20 C10H12N2 C10H1ZN2 C14H12N2

‘9’10N2 HC1

Table 1.

140

b.p.

76-77 (h) 140-147(0.35 mm.) 111-112 (et/w) 91-92

10 8 111-112 ( p )

101-102 104

m.p. ,OC 59-60 ( p ) 146-154 (w) 123-125(w) 141-142 (et/w) 170-171 (et/w) 186-187 (et/w) 73-74 (p) b.p.73-75(0.2m)

1-Aminoindoles

594

356 356 624a 356

24

202

202 24

ref. 54,55,202 54 202 624a 624a 624a 202 624a

N

W

N

9)

NNFI

.-I d.-I N "

NNN

m mmm

i ;i

w

U

Q

:

1

r-w m-

wm 1

0

.. ??:

mrl

I

-u -

m u A-9) IEP w-0

9)

P

IN

-

4 r l O

rlmm

N ..

rl

.-IN . I I

a=:5:

I

RpPrlN

m UIm

I

. I

I

P r ( N

9)

N

m

a

cy

a

a

m

X

X CJ

X

X

N

rl

P

m

N

X

V

u X

288

1:

X

X

X

?g

nc(

--a In

0

N I

0

0

N

--

Y 4

xm

v a .r(

h

x

0

N

r-

4

Q1

N

N

za, m u clm

-

a

N

zm

4

rl

X

m

4

V

x0

rl

V

a,

CI

m

0

ON zm

$

c t m X U

-0

. . i 4.4

N

Z a , OJJ

~m

X

h

- 0

4 -d

N

zo

~m

3

xI n r0

4 4

a v a v a v a

N

ON

ON

zo

z0

N

4v

0

%

4 X

w

4

ON zW

4 X

r-

4

v

V

m X

V 0 V In

X N

m

V

B

X

V

-z

-

V

V

m X

X

0

X

X

m

N

m X

V

N X

X

N

m X V

zN X

ln

xN

V

ON

X

m x V

5

x

X v

X

X

x

x

ON

m

m

0 zN

X

V

X

V

N

(O) X

V

$ zN X

V

0 i?N

=N

X

V

289

zN

1: U

In

X

W

In

X

V

u

X

X zN X

8 zN

X

V

W

b V V

CH2C6H5

CH2CH20COC6H5 CH2CH20COCsHS

H

H H

CH2N (CH3)

CH2N (CH3)

23H2gN 2 ’ HC1 methiodide

C20H22N202 HC1 methiodide

‘lEH20N2 HBr picrate methiodide

Table 2 (cont.)

147-149 (m) 154-156

142-143 188-190

157 (e) 96-97 ( e ) 225-235 (e)

122 122 122

122 122 122

547 547 54 7 547

w

a,

w

0

w w

w w

d

mrn

v

N

N

d

m d d V

0

O

I

N zW

a

d

t

N l

m

03 d

o m

sm

zIrl

W

d x u m u

rl 4

(nN

m X

*d

* d 0

I

N

=o

2

N a d *a

X

v x

u a

u x

u o

X

X

X

9

X U

X

4 U

X

X

X

rlV

d X

m

m

d

*

o w

W

I

0 0

.r(

N I

m

0

-a

m

X

a

0

a,

m

N

N

d

I-

zrn

X

* v

--

U

0

f

w

m m 0

3:

X

-

N

m

N

X

n

hl

U Y

YX =N

X

X

%J

V

V

29 1

X

H

H

H

CH2CHZN (CH3)

4-CH3C6H4

4-ClC6H4

‘gH5

‘sH5

4-C1C6H4

‘sH5

H

H

5-C1

5-CH3

H

H

H

‘gH5

H

H

5-c1

H

H

A

5-C1

H

4-C1C6H4

5!6-

H

‘sH5 dl-Cl

H

H

H

CH2CH2N (CH3)

I,

m

NH-C2H5

3

CH*CH2N

‘1 g H 1E C l N 3

C19R18C1N3

HC 1

C18H20N2

HC1

C18H20N2

C18H17N3

‘1 B H 1 gCIN3

C18H16C1N3

‘lSH1 Scl 2 N 3

C18H15C12N3

C17H25N3 di-HC1

Table 3 (cont.)

2 6 4 - 2 6 5 Im)

2 7 0 - 2 7 2 (m)

163

163

117 117 204-205

162

162

163

163

163

163

-

223-224

64-66 (p)

1 8 1 - 1 B 2 (e)

220-223

240-241

2 6 8 - 2 7 0 (el

163

264-266 lip)

-

50% 305a

-

w

W

h)

31

H

I

CH3CHCH2N (CH3)

CH CHCH2N (CH3) 31 CH3

‘sH5

CH-,

H

H

H

H

H

H

H

H

5-CH3

H

C20H24N2

C20H24N2

C20H21N3

CZOHZ1N3

C20H21.N3

CZOHZ1N3

5,6di-CH3

~

C19H22N2

~

H

5 - c ~ ~c

H

CL9HL9N3

C14H19N3

H

H

CH3

H

C6H5

4-C2H5C6H4

m

‘sH3

3 4-di-CH3-

‘gH5

C6H5

4-CH3CgH4

H

a

‘6*5

‘sH5

n

n

C.2X-J

CH CHCH2N (CH3)

H

“

4-CH3C6H4

T a b l e 3 (cont.1

~

165-168(0.05

(m) N

b.p.

170-172(0.05 m.)

117

117

117

-

117

163

163

163

163

117 117

b . p . 168-170(0.05

m.)

m.1

163

163

153

-

196-197 (m)

246-247

205-206 (m)

222-223 (m)

-

b.p.

H 226-228 ~ ~

154 (m)

210-212 (m)

H

”

H

-2i-J N

9

C H 2 4N]

‘gH5

‘sH5 ‘gH5

H

H

2-naphthyl 2- ( 5 , 6 , 7 , 8 tetrahydronaphthyl)

‘gH5

CH3

H

CH 3

4-C2H5C6H4

5-indanyl-

C26H28N2 HC1

C22H23N3

‘2ZH1gN2

C21H26N2

C21H23N3

‘21H21N3

Table 3 (cont.)

175-177 (0.05 ro~n. 1

259 (e)

262 262

262

118 (b)

-

163

163

111 117

163

16 3

199-200 (d

206-208 (d

b.p.

-

227-218

Inv)

m m

0

PI

2! I

z

0 N

N

rl

9

A d

X

d

r l m

u o d X

rl

U I

In

I 4

x X

U

I d

X

N

X

-=m

4

c

N

X

V

Y

295

\ / -CH3

0

CH2CH2-

H

n H

CHJ

H

CH-,

H

CH3

H

H

H

H

n

H

H

H

H

n

H

H

5-Cn3

su1fate methiodicle

C17H18N2

methiodide

sulfate HC1

Ci7HiaN2

C16H22N20

C16H16N2

C16H16N2 HC1

phenylethobromide

HC1

C15H14N2

C12H16N2 oxalate

Table 4 (cont.)

258,192 258,192

251,194

41-45 206-208 151-153

197-198 (W) 185-186 (m)

70-71 ( 1 )

200-201 (w) 120 (e/et) 272-273 (m)

79-80 ( 1 )

90-91 (b)

66 ( h )

211-212 ( i p )

583 583 583

583

583

583,311 583

505

584

195 195,258

35

207

-

35

-

m

m m

Ln

0

0

m In 0

m

0 0

0 0

m m

m

w

W

-4

d I

N

m

I

h N

d

Om N

=+ d

W

m

m

I

d

m m

-$ 2

a 1

I-

W

I W

a

O-4 -4

V I N

N

z.$I

X - 4

xF

v x

V

N

m 1 I N m r l

0)

N

d V

m l n

ln

N

zv

m m w w

0

zal

04

rum w d

xu4

v m

4 3

d

m

X

V

X

X

In I

2

m

m X

X

x

X

X

X

x U m

X

W

X

X

P

N U

m

X

W

X

t

t

N X

B

i,c) =m

-

N

X V

N X V

-

297

a

ln 0

ln

m

ln

ln 0 ln

0

ln

w

w

0 0 lnln

lnln

0 0 lnln

lnv) 0 0

lnln

4

4

m

n

m

Q)

0

4 4 I

w I

4 4

0

u

w

0

N 4

w

ln

0 ri

4

I

I

w

0 0

4 4

4

I

m

0

4

N

m

2

4

V

4 X

B

m

0

X

X

X

3:

1:

X

1:

2:

X

X

X

X

66 ;

m

V

a

X

V

m V X

m

X

m

X

Y .e

I

1:

N

-

1: V

X V

298

W

N

YI

I--N

16 5 CHCH2CH2N(CH3)

C H

H

H C3H7

H

H

CH3

H

H

H

H

H

CH3

CH3

CH3

H

H

H

5-CH3

H

sulfate methibdide

C20H24N2

C19H28N20 HCl

C19H28N2 HC1

'1 9H27N30

'lgH 27N30

C19H26N202 HCL

methiodide

sulfate

C19H22N2

C19H2ZN2 hydrogenoxalate

T a b l e 4 (cont.)

504

583

583

583

505

SO5

504

180-181 ( i p )

505,505a

-

f l - ? 3 (ea)

505a

583 583 505a

583

90-91 (1) 183-185 (u) 227-229 (rn)

-

161a

1 6 9 - 7 1 (ip)

170-175

161a

71-73 (p)

/ -CH3

0

CH2CH2- \

H

B

H

H

‘gH5

C23H28N2 HC1

‘23”2BN2 HC1

C23H22N2 sulfate rnethiod ide

C21H33N3 dl-HC1

n

H

CH3

C21H32N20 2,3,4,5,6, pentachlorobenzochloride

A

H

‘21H30N2 HC 1

C21H25N3

n

H

H

H

Table 4 (cont.)

503 118-119 (1) 229-230 ( w ) 250-252 (m)

504 504

154-159 ( i p )

257 257,194

-

161-162 (m)

505,505a

583 583

505,505a 219-220 ( i p )

505

505

504

504

504a

-

183-184 ( i p )

97-98 (m)

6

4 Q

m mv) 0 D O

m mu,

m m

m m 0

0

-

m I n

m

m

d

W

d

d

r

W

l

k!

m

I-

0

0

0 0

w m

a .a -I

rl

I 0

Ou,

m

drn

d

Nrl

I

1

corn o m

I

(Yd

?

l a N

% m cy

U X

X

9

X

X

X

X

J V

X

x

X 0

m

m

X

-F

N

rl

($ =m

Ty

T 0 1

m X U

d

N

E X

I

N

X

2

5

P I W E

u- v

301

Table 5.

R1

R2

H

R3

x

H

H

CH3

NH2

H

H

H

NHCOCH3

H

H

C2H5

NH2

H

H

CH3

NHCOCH3

H

H

H

N (COCH3)

H

H

H

NHCH2COOC2H5

H

H

H

H

CH2C6H5

2-Aminoindolea

rn.p.OC

-

V8N2 HC1

260 (el

H

NHCOOCH2C6H5

H

5-Br

H

NHCOOCH2C6H5

H

6-Br

H

NHCOOCH2C6H5

H

7-Br

H

NHCOOCH2C6H5

H

5x1

H

NHCOOCH2C6H5

H

6-C1

H

NHCOOCH2C6H5

H

H

H

NHCOOCH2C6H5

H

4-CH3

H

NHCOOCH2C6H5

H

5-CH3

H

NHCOOCH2C6H5

H

6-CH3

C16H13C1N202

1' 7H16N202

302

422

88a 260 (dec)(e) 88a

1' 6H13BrN202

1' 7H16N202

298

88a

-

C16H1 3BrN202

C17H16N202

154-155 (el

88a 260 (dec)(e) 88a

C16H13BrN202

C16H14N202

422 888

-

C16H13BrN202

1' 6H1' 2 N l ' 3

88a

-

167

15H14N2 HCl

4-Br

88a 298

ClOHl2N2 HI

C12H14N202 HBr

H

260 (decl 260 (e)

142

C12H12N202

NHCOOCH2C6A5

429 429

C10H10N20

c11H12N20

H

222-224 (el

-

'gH10N2 HI HC1

ref.

2

116-117

176a

157-158

176a

136-137

176a

125-125

176a

142-144

176a

140-142

176a

112-143(p)

176a.429

119-120

176a

154-155

176a

125-126

176a

8

w

CH2N (CH3)

H

H

H

R3

H

H

X

H

CHIN (CH3)

CH2N (CH3)

CH3

H

CH3

H

H

H

H

H

*T>*cn3

CH2NH2

R2

H

R1

‘lZHl 6N2 picrate methiodide

me thiodide

C12H16N2

‘lZH1lN3

picrate methiodide

CllH14N2

‘gH10N2

-

OC

65-66 (p) 210 (el 180 (dec)

b.p. 105(11 212 (dec)

-

180-81 (ac)

lam.)

b.p. 143-145(6 mi.) 182-184 154-155

69-71

m.p.,

Table 6. 2-Indolyl-C-N Derivatives

524 524 524

488 488

408

276

310 310,613 310,488

310

371

ref.

0

rl

4

m m

w w r l r l

m m

w w

d r l

I

m

0 0

A

0 0

Y

m

N

4 I W N rl

ln

I

m

d

I

0 01

*

4 U

% s rlf8 xm g 4 -4

X

X

X

m

X

X

X

X 0

N

zW

rl

xm

N

v a

X

m

C0l =w X

V

-

N

m

u X

v

zN X

u

PI

X

X

X

X

U

304

X

vl

u X

v,

0

w

H

H

H

n CH3

H

‘1QH1EN2 hemihydrate picrate

H

H

picrate

C14H18N2

C14H16N2 HC 1

H

‘ ‘1 4H1gN 3

C14H12N20

H H

C14H12N2 HC 1 picrate methiodide me thobromide

H

cH3NP

5 H

TX::IH5

a-pyridyl

Table 6 (cont.)

154 (b)

76-78 (h) 154 244-246

80-83 176

81 235-236 (m)

110 511 429b,432

488 613

432 432

276

511

250-260 (w) 206-207 (e) 205-206 248-250

150-53 (c)

293,432 429b 29 3 293 293 429b,432

103-104

0

(D

0

4 I

W

0

4

4

I P 4J

I

g/f Y

4

xrrr

4

V 4 X

U in

4

rl

ln

W

U

V X

3:

P

X

X

z ON YI

m X V

s

X

P

X

X

X

R 0

X

V

3:

X

x

X

X

X

X

306

CH (CH31 n-CjIL,

a-pyridyl

8

‘2’5

‘2’5

u-pyridyl

tH3

a-p yr i dy 1

NH2 C2H5

H

H

CH3

H

C16HL5C1N2 HCl

5-C1

H

H

H

H

‘1!iH20N2

H

C16H16N2 methobromide

‘16’16’2 methobromide


C16H16N2

nci

=1SH2ON2

C15H20N2 HC1

H

H

T a b l e 6 (cont.)

408

82-83 (e)

127 154-155

230

429b,432 4 2 9b, 4 3 2

4 32,429b 432,429b

170 128

429b,430 432

135

42%

612

2 4 3 (e) 67-68

612

-

1 4 2-144

429b,432 42913,432

432

230-235

-

432

78-80

N

m

N

N

m

m

W

m

P 0

m N

I a3 I

w N

N I N

V N

2 m 4

I

I

X

3:

N

z

rl vrl

N

4

V

Y

rl

W

In xN

V

x. V

X

X

s

X

X

308

N

.

N o

m 9 0 .-I

d

m mmm N

“ N

rl

I-

m

.

9

a

m m N

9

N

9

~

N m 9

d d mo, N

9

N

9

N

N

9

9

..

m m A A

m m

NCY

9

9

9

I

N

0

0

-

r-

d

-

d

N

A

n

A

fi

d

ul

I

o,

9

d

P 0

0

I

I

. W b

A d d

I

x

x In

1:

X

N

m

m

N

N I

ul

m N

I N

9

v)

xN

0

I N

X In

X

N

V

V

V

X

X

V

X

Y

m

x

x

X

309

m X

X

9 9

A N OI

cr

* W

0 d

-

al

v

W

I?

-4

rl

d

VI

r-

F3

I N

N

w I

v)

0

N

d

N d

0 d

m v )

V

- a

2 9

NOI

NI?

N

N

N

z*

r(

A

c

Y

rl

8

rlV

o x

=m

rl

o

1

W

31

X

X

X

-

X

N

-

11

X

X

X V

9

U

X

X

X

X

X

0

n 8

m

X

X

E 0

310

X

2

N

C19H2 2N2 picrate HC1

H

C19H24N20 hydrogentartrate

C19H20N202 methiodide

H

H

'19'20N2 HC 1 picrate

H

85 85

C

H

H

CH3-N

n m

1

OCH3

H

CH2CH20H

H

H

H

C2OH2 P N 2 maleate

C20H22N202

C19H26N20 HC 1 nitrate

120-22 (e)

187-188 (ea)

162-163 225-27 232-34

69a

510

381,382,383 381,382 381,382

85

433 325 325 295 116-17 (p) 110-11 218-21 205 (b/t) 196 (e)

510 510

295 295 295

132-34 216

167 233-36 220-21

Po'"' 'ZCH3

CH2CH20H

H

B

C2H5

H

Table 6 (cont.)

H

‘2%

‘CH3

H

CH

C2H5

CH2CHzOH

CH3’

C2H5

H

H

HC1

22H26N2 picrate

HC1

picrate

C21H20N203

C20H24N2 HC1 picx a te

T a b l e 6 (cont.)

-

167-69

225-30 245-50

-

212-14 ( e ) 2 3 0 (e) 228 (e)

1 0 3 - 0 4 (p) 221-23 {m) 211-13 (dmf)

371

4 32,429b 432,429b 432,429b

510 510 510

418 418 418

W

e

w

CH2CHZNHCH

y 3 CH2-C-NH2 I

n

H

*For further compounds see: 3. Chem. SOC., (C) 1971, 3 5 9 .

cn3

//NH CH -C ‘OC2H5

H

H

H

I

R1

C12H16N2 HC1

CllH14N20 HC 1

CllH14N2 HCl

C10H12N2

203-04 (e)

-

-156-15 8

178-180 ( w )

308

308 308

120 120

469 469

98 98

210

99-100

-

ref.

m.p.,oc

127-128 (b) ‘1 qH 16N2 HC 1 187-188 methiodide 191-192 C. J. Cattanach, A . Cohen and B. Heath-Brown,

H

CH 3

n

H

H

CH2CH2NH2

CH 3

H

H

X

H

R3

CH2CH2NHZ

R2

H

R1.

X

Table 7. 2-Indolyl-C-C-N Derivatives

CH I 3 CH2-F-NHCH3

H

H

H

CH2CH2N (CH3)

H

6-pyridyl

y 3 CH -C-NH2 21 CH3

CH3

CH2CH2 N (CH3)

6-pyridyl

CH3

H

H

CH3

H

H

CH3

H

H

H

5-Cl

5-CH3

H

H

H

H

H

‘1 4H1lCIN 2 HC1

C13H18N2

C13H18N2 HC1

‘1 3H18N2 HC1

C13H18N2 hydrogenoxalate

C13H16N2

C13H10N2 bromobenzylate quat. salts

Table 7 (cont.

248

178-90 (subl)

165-66 (IU)

233-234

-

-

109-110 181-82

214-15 (e)

-

165 165

307

307 307

120 120

161a

161a

248 193

233-35(e)

-

248

170-75 (el

w w 0 0 o m

Q)

0

m

W

r-

rl

m

W

- 3

Y

r-

m

N

N

rl I

rl

I

W N

rl

a

I

rl

d

PI

Y

W

W

N I

ln W PI

a,

N2 zo B N

ON zW

4

rl

x c

** Vi t

* rl

X

U

5:

X

W

zw

rl rl

0

m

N 4 I

r4

N

4

ON zO

N rl

V

V

5:

1:

X

X

X

X

m

X

V

X

N

m X

5l

4 sr

V

1

m X 3

$ X

x"

7.

x-

v-u-v N

9 m

2:

X

X

V

x

vN 9 V

N

1:

V

m

0

X

V

X

X

V

‘G

CH2CH2N (CH3) CH3CH2N (CH3) CH2CH2N (CH3)

H

CH3

NCH2COOC2H5

OH y 3 I CH-CH2-N-CO-C6H5

NCH2COOH

‘gH5

CH3

H

H

H

‘sH5

‘gH5

H

H

H

H

H


C1aH20N2 HC1


C17H24N2 HI picrate

H H

‘1 7H22N202

C17H18N202

C15H18N202 (+ CH30H)

H

H

H

Table 7 (cont.)

239-40 (el 247-49 (e)

220 (el

153-54 (ip)

-

554 554 554 45-50 240 (el 184-85 (e)

536 536 536

120 120

161a

161a

248

21

248

107-08 (h)

105-106 (b)

180/220

OD

0

00 0

-P -

-

N

00 0

N

N

I

mul

ulln

QI

q m

v)

v)

P)

I

0

QI

rl

w

lnln

rl

0 0

I

N

N

m

w \Dw m mm

0;

6

W rl

v)

m

0

\b

ul

-

0)

m

IW

0 0 0

I

- 0

FIN

I

I

I

o m

0

N N

rl

v)

0 0

111

N

N

U

c

zN N

zO

zO

b N

xO

xo

X

X

X

X

X

X U

N

-

Ow

ON N

N U

u

N U

0

X

v)

m

xW

U

m X

Y

PPP v)

xW

ul

xW

U

uN

s

X

X

N

X

X

-

N

-

m

X' U

X U! .. X

t7 zN X

U

uN

X U

v)

X

W U N X

m X U

U

317

X

oo

e

W

CH3

H

H

Y-pyridyl

N CH3

.,-pyridyl

H

C

y-pyridyl

H

H

R2

R1

H

‘ZH5

H

H

CH3

H

R3

C15H14N2 methobromide ethobromide C14H18N20 HC1

C14H18N2

C14H16N2

C14H12N2 HC 1

13H10N2

38

38 38 429a,432 429a,432 429b 69b

180 151 315-20 200-03 194-195 (e)

165

165

38

ref.

175-76 (w)

244-45(m)

-

263-65 ( w )

-

OC

Derivatives

m.p.,

and Z-Ind~lyl-(C),~-N

methiodide

Table 8. 2-Indolyl-C-C-C-N

-

N

m 9

m m

m

d

M

0 rl In

0

0

4

d

4-4

E!

v

$

N

9

m

-c

rl

rl

I-

d

I

m

I-

m

ON

N

X

In h d

d

I

I N

I-

rl

0

..

In

N

x,

U

U

W rl

V

X

P m

X

m

X

In

--

N

xIn rl

U

m 4

N

N

d

In rl

rl

zN

zO

X

0

4

X N

U

X

d

N

X

u

I

X

U

P

m

m X V

X

X

X

X

319

X

X

0

0

0

tntn

tn

tn

0

m m

m

m

tn

W

l-

n

t n m

-

I-

I

I

I tn

0

m

I

4

r

4

~n

1

- z m

I-

l

r l r l

ON zm

ON

zln

N X

m

rl

rl

V

V

n

X

V

n X

V

X

X

ON X

V

X

9 ; (?I 9 m

n X

ln

ON X

ON X

x x

v-v

X

=V

N

X N

n

X

m X V

X

x x

u-vN

X

X

v-v

X

V

320

X

0

N

N

N

v)

N

N

N

a

W

m

Y

I

W

rl

d

W

W

-.p 0

W I

a

v)

rl

v)

ON

m

zW

xm

xW

N

V

a/ W

2

ON

zO

B

ON

zm

N

N

V

N

xW

N

V

In

m X W

N

V

m

N

X

V

In X W

xW

V

V

V

X

X

X

0

X V 0

8 u- v-v X

32 1

N

N

w

cH3

H

CH3

CH3

H

‘gH5

H

H

H

H

H

H

R2

H

H

R1

NH2

NHCH (CH3)

N=C (CH3)

NHCOCH3

NH2

NH2

R3

‘1 3’1 6N2 C14HllC1N2

5-C1

C12H16N2

C12H14N2

H

H

H

C10H10N20

‘gH10N2

H H

‘EHEN2 HC1

a1

H

X

x*qI::

Table 9. 3-hinoindoles

471a 471a 424a 471a

91 (PI 119 (e/w) 214

341

471a 587

341 341

ref.

168 (subl)

162-63

128 112-13

117

-

m . p . , oc

W

h)

W

‘sH5 4-CH30C6H4 H

CH3

H

COCH

4-C1C6H4CH2

‘sHSCH2

4-C1C6H4CH2

H

CH3

CH3

CH3

‘gH5

‘sH5

2-CH3C6H4

H

H

H

‘sH5

CH3

H

H

N(CH3)2

H

H

H

H

H

H

H

H

H

H

N (CH3)

NH-CH (CH3)

N=C (CH3)

NH2

:5

NH2

N3

NH2

2OH 2lCIN 2O

c1 BH2 ON2

C18H19C1N2

C17H18N2

C17H16N2

‘1 5H18NZ0 HC1

C15H14N20

‘1 5H14N2 acetate

C15H14N2

C14H1 EN2

C14H12N2

Table 9 (cont.)

613 613

109

613

471a

471a

424a 424a

86

97 (el

94 (cyh)

107 (cyh)

90 (el 235-40 ( e )

389

58 58

81-84 172-173(e/w) 150-151

471a

424a

471a 428

135

75-76

180 174-76

E:

W

.HZ

‘gH5

‘sH5

.HZ

‘dH5

.3 H

H

H

H

N (C2H5)

Addenda : C2H5

CH3

‘sHSCH2

H

H

N (C2H5)2

CH3

CH3

4-C1C6H4CH2

O

W

P

4-C1C6H4CH2

CH3

C6H SCH2

Table 9 (cont.)

‘20H16.2 HC 1

C16H16N2 HC 1

‘21H23‘lN2

C20H24N2

‘20H23‘lN2

C20H22N20

50-53 223-25 (e) 642

242-44 (e) 642

613

613

74 76

613

613 69

94

w

aQ)

m m w w m m

In

W

V

:

0 I ln rl

2 N

I

4

N

zN

s

r l m

0)

4

NI

N

a

N

N

E

0

ZN

a!

zN

4 -

rl

rl

X

2 0 O v )N 4 V X

0 rl

4 4

V

h

m X

X

X

z N

N

X ZN X V

X

ln

N X

\\

m

X U X

zN X V

a

W 4

1 - 4

X

m

N

ln

rl

V

o

W

I In

v

N

m

W N

X

N

rl

0 0 Inln

P

x 4

o m rlx

X

m

w w

m

7

YX

zN X

V

N

N X

m z

X

I

v-2 N X

V

m

X

X

V

X

X

E

X

X

X

X

X

X

X

rl

a

325

o\

W N

H

H

H

H

H

H

H

H

CH2NHNHCOCH

H

H

H

I

H

H

CH2N (CH3)

CllH13C1N2

6-C1

H

H

H

5-1

6-F

C1ZH11N30

C12H11N30

‘1ZH11N3

C l l H 1 4 N 2 0 ’ H2°

methiodide

picrate

‘11H1QN2

‘1 1H13N3’

‘llH131N2

‘11H1JFN2

CllH13m2

‘llHl 3‘lN2

5-C1

5-F

C11H13C1N2

4-Cl

T a b l e 1 0 (cont.)

104 14% 306a

180 265 ( e ) 312

225 225

135-36

317,603 317,603 169

520

420 211

50

121-22

1 41 1 6 8 - 6 9 (m)

134

1 4 8 (ea)

1 5 7 - 5 8 (m/w) 1 5 9 (m)

1 3 8 (el

424

145-46 150

239

516 446

1 3 2 (e)

424,446

150 1 2 9 - 3 1 (e/w)

206

1 4 7 - 4 8 (ac)

H

H

H

H

H

H

CH3

H

H

H

H

H

H

H

CH2N (CH3 1

H

y 3 NHCHCOOH

-0

c,

/rH

I

NCCHH (CH3)

CH CN CHN/ 'CHS

5-Br

H

H

H

H

5 2 % sB=N 2 HC1

C 1 2 H 14N2

C12H14N2

picrate

C12H13N3

oxalate

'lZH 1 3N3 hydrogen-

3'IN2

'12"l

7-C1

hydrogenoxalate

C12H11N3S

H

T a b l e 1 0 (cont.1

266

94,142 424 170-173

620

453

306a

145a

143-45(rn)

141-43

138-140

300

280 (e/w)

266

115-18 (b) 242-43(e)

369

369

453

453

509

130-31

140

m

N

w

H

H

H

H

H

H

H

H

H

H

H

H

H

CH3

H

CH3

H

CH3

CH3

H

H

,CH CHZ-N-CE&Z

'd

'"')-"

a-pyridyl

H

H

H

H

7-CH3

6-CH3

5-CH3

4-CH3

H

H

5-F

5-C1

C13H14N20

O C13H14N2 xalate

1 ' 3H13N3

C13H10N2

1 ' 2% 6' 2

C12H16N2

C12H16N2

methiodide

picrate HC 1

C12H16N2

C12H1gFN2

C12H15C1N2 HC1

T a b l e 1 0 (cant.)

94-96(0.2

130-131 156-58 146-48

170

150-54 ( b )

239

369 369 582 582

104

416

581

445 115-17 ( b ) 119-22

445

445

424

445

114

117

133

138-39

128-29

94 445

491 4 89

489

116-117

m.)

424

94,142

94,142

158-160(t)

1 93

145-146 198-99 ( e t )

b.p.

146-14 7

177-79 ( e l

1 5 7 - 5 9 (m)

A

- - -

9.

I

X

X

X

r

r

r u

m

I?

r

x

r

x

r

u

x

x

329

m

*

0

Y)

0 N

W

0

0

w w

N

N

-B

W

I-

N

I

0,

Y) I

m

N

-

-; U

zW rl

X

m

4

U

Y)

I

N N

-a

Trn

0 T

W

W

9

*

9 0

rl

rl

*

W

w

rl

I

u-Iu x

u

rl

o

rl N rl

ZW

xn rl

4

N N

t N

m

N

rl

xm

rl

N

zW

rl

X

m

rl

U

U

X

X

X

N

U

X

N

N

zN

zN

X U

X U

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

330

I-rlrl

o m

m ow

0

r l m m r m o - o m m m r l

r r m

m

o m o

w rl

w m m m 0 0 r l r l

m

v

(0

0

rl V

m

v

0 Ul

m N

om

..

c)

zm

rl

X

xo

0

d

-

d

V

V

X

X

9

X

V

0

m

Y r X

X

-

N

m ..

X U

m

m

Y Y X

U

X

l

w

X

x

x

N

X 0

m

m

N

I

X

V

X -2

X

X

*

U-V

X

a

X

vX

m

X U

X

X

X U

0

x

0

x

X

0 X

v

33 I

X

x

X

0 X

m m

m

m

m

W

m

W

0

n

0 N

rl

w

m

0 N

w

m Y

OD

m

" 0

p.

m

n

n rl

m

m

N

0

mI

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m

d

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0

On

zn d

X

d V

V

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

n

X

X

X

X

B

m

X

X

0

332

0

N

4

W

0

m

m

rl N

0

0

(YN

rl

W

0

0

0

-

w

rl

I

m m

0

m

rl

N

0 0 N N

W

m

N

Q * 0

QD

N

I4

m v

X

X

X

1:

2

In

0 =N

X U

X

X

X

X

m

m

X U

333

5: U

X

9

X

T

W

15

orl

vn

*--I0

0

0 N

w w N

--

0 N

W

0

--

mI N N

w 4

m

-4 -4 N

W

E

E

m I

0 N

w w

N

I

N

N

% rl

0 N

w

0 N

w

0 N

w

-

0 N

0 N

0 N

m m

-E

m

N 0

*I

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0 N

m w

N 15 1 N N

I

I

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N

zm

rl

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u

u x

v

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% -4

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15

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X

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o n

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X

VI X

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m

X

X

X

X

x

X

u

X

X

X

X

X

n

5:

u

x

x

x

334

X

-

n

9

m

m m

o

In

m r l P m r l

1

Am 2n 4

rl

m m

0

m

rl 0

9 W rl

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P I n

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a

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8 n

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x

X

u

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X

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335

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0-u

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x

x u

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v

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+ : z

336

W

w w m v ) mv)

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0

d N Q

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0 N

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m 0

0 1 0

N

m m

m

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m

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p1

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::

r)U

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X

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ON zW

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v) rl

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4 U

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C

C

I

5;

X

X

X

X

P

X

z

I-

362

,I.

m

a

P)

W

0 PI I 0

0

PI

N

zN

N

z

‘rlj

%I

4

r l a

xo

v

rl

8

4

a

xrl

rl

V

PI

V

X

ru

BI

W

X

W

m

m

X

X

X

X

X

x

v

X

X

X

X

X

X

X

x

x

a

363

V

CH2CHZNH2 CH2CH2NK2 CH2CH2NHCHJ

H

H H H H

n n H H

H H

H

5-C1,7-CH3

‘llHl 3‘lN2 picrate

CH2CH2NH2

226 (decl

-

206-11 (e)

I

H

C11H13BrN2 picrate

5-Br

CH 1 3 CHCH2NB2

H

C11H13BrN2 HCl

104-05 (b) 231-33 ( e )

7%

CH2CHNBZ 5-Br

238 (dec) 93-94

CH2CHNHZ

C11H13BrN2

C11H13BrN2 picrate

-

220

I

186

-

292-95

162-65

95-103

5-Br

5-CH3,7-Br

C11H13BrN2 picrate

C11H13BrN maleate (e)

CllH12C12N2 HC1

4-Br

YH3

5-Br

CH2CH2NH2

CH3

H

5-Br ,7-CH3

5,7-C12

CH3 CH2CHNH2

H

H

190 190 19 19

518 518

449a

215 215 86 86 19 19 19 19 281

H H

H

H H

H CH., B H

H H H

H H

H H H H

5-Cl

5-Cl 5-C1

FH3 CHCH2NH2 CH2CH2NH2 CH2CH2NHCH3

7-C1

6-C1

5-Cl

4-C1

5-CH3,7-C1

CH2CHNH2

5"s

qH3 CH2CHNHZ

fH3 CH2CHNH2

CH3 CHZCHNH2

CH2CH2NH2

C11H13C1N20

C11H13C1N2 HC 1 hydrogen maleinate CllH13C1N2 1lH13' lN2 maleate CllH13C1N2

CllH13C1N2 HC1

'llHl 3'lN2 HC 1

C11H13C1N2 HC1

1' lH1 3'lN2 picrate

119-20 (b)

186-87 (el 210

170-72 99-100 Icyh)

255-57

-

102 (ill 234-36 240-41 (m) 243-45 122-23 (b) 218 220-22

123-25 (ea) 269-70 (m) 266-67

243 (dec)

-

90,436

386,600 451 190 86 86 50 2b

254a 600 518 215 215,254a 600

510

2S4a

451 600

19 19

H

H

CH3

H

CH3 (1

CH2CH2NH2

H

4-CH3

H

H

H

CH2CH2NHCH3

H

H

5-F

y 3 CHCH2NHZ

Fl

H

6-F

H

H

5-F

CH CHNHZ 21 CH3 CH 1 3 CH2CHNH2

H

H

CllH14N2

Clla14N2 oxalate picrate

‘11H11N2 picrate HC1

oxalate picrate

HCL benzoate

C11H14N2

CllH13PN2 picrate

C11H13m2

C11HL3FN2 nci

118-19 (b)

81-83 (et) 107 219 (el 218-219

b.p. 108-110(0.1 mm.) 179 199-01

89-90 176-77 144-45 178-80 178 190 193-95

222-24 (e)

-

104-06 (ea)

86-87 (b) 224-25 (e) 233-234 (thf)

159

265 179,393 265 377,393

2,78,499 489

489

62,243,244 57 3,67a 243 502 265 63b,243 151

190 190

290

518 290

51B

O

m

h

m

X U I-

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Y

Y

Y

V

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m

r)

X

X

H

g

0

Y

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X

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V

c

X

X

X

X

Y

N

X

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X

Y

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-

vN

Xm NX

vN

X"

v-'N

X

c

c

X

X

X

x

X

X

X

x

370

N

2 X

NN

z

o

d

8-70

d

d

d

1

m d

X

N

X

N

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Y

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00 I00

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x

X

X

x

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r!

W

H

H

H

H

H

H

H

H

H

H

H

CH 3

H

H

H

H

H

H

"

CH2CHZN (CH3)

CH3 CH2CH2NHCH3

y 3 CH2F-NHOH

II

C H 12 5 CH2CHNH2

5-1

6-F

5-F

C12H151N2

C12H15FN2 HC1

C12H15FN2

C12H15FN2

C12H15FN2

5-F 6-F

C12H15FN2

C12H15FN2 maleate

4-F

5-F

C12H15C1N20

C12H15C1N2 HC1

7-C1 5-C1

C12H15C1N2 HC1

6-C1

.

Table 11 (cont.)

90,92

211-13 (e)

-

109 (cyh)

502b

227,576

190

48

502b 14 5 101-02 (et)

49

86 86

90

254a 600

254~1,600

100-01 (m)

146-47 (el

-

139-40 (b)

226-28 230-32

235-236

-

N

-4

w

CH 3

H

CH3

H

H

CH 3

H

CH3

CH 3

H

H

H

H

H

H

C2H5

y 3 CH2CHNH2

y 3 CH2CH-NHCH3

CH 2CH2NHCH3

CHZCH2NHC 2H

I

w

CH2CH2NH2

H

H

7-CH

5-CH3

H

1' 2H16N2 picrate

C12H16N2 picrate HC1

C12n16N2

C12H16N2 picrate

C12H16N2 picrate HC 1

'lZH 1gN 2 picrate

C12H16N2 maleate picrate

C12H16N2 picrate

Table 11 ( c o n t . )

205-07

*

198-200 223-27 (et) 226-28

90-91 (b)

82-83 (et) 193-94 (b)

87-88 (et) 186-87 (m) 188-90 (b)

160-62 220-23

100-01 184-85 (e) 224-25

180-81 (b)

179

217 217 518

435

244 244

124 124 67a

179a 179a

179a 86 179a

124

F.l

m

W

N

W

in

rl

hl

N ..

=w

4

xN

4

U

-I

"

m

N

rl T,

rl

I

N

zW

N.4

.i r l U

u a v x

+ I

rl

-1

..

hl

z*

rl

X

N rl

V

rl

4

PI

rl

A

m ~. X

0

d

X

N

V

.I

V X

I

W

X

m N

N

X

x x u-uN

zu

1:

-2

N

= N

N

U

X

=

a

X

z

x

z

3:

X

x

z

X

U

.

X

373

X

X

X

rl

V

X

H

H

HOCHCH2NHCH3 y 3 HOCHCHNHCH3(er)

H

CH3

HOCHCH2N (CH3)

H

H

CH I3 CH2-C-NH 1 2 CH3 (CH3)2C-CH2NHZ

CH3CH I 1 3 CH-CH-NH2

H

H

?zH5 CHCH2NH2

H

H

C12H16N2 acetate C12H16N2 picrate C12H16N2

H H H

C12H16N20

C12H16N20

H H

C12H16N20

H

HC1

picrate

C12H16N2 picrate


H

H

Table 11 (cont.)

572 335a

120-30 (b)

571,579

124 62,244,361 150 361 244,62 124 67a 138-140 (ea)

75/118-20

17 49 71-73 166 170-71 194-95 165-67

323,352 323

492

130-31 204 105-06 228

215 532 532

284 284

103-06 (b) 100-02 (1) 210-11 (el

200-01 (el 202 (e)

-

W

m

ld

rb

m

m

CI In

..

0

m

0

w

m 0

o m

m m Lorn

0

N N

W

0 W

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N 0 I

m

m

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4

ry

ON zW

4

Pi

U

= N

4

U

ON

z

I

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W zo 4 - 4

xN

u

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40

.-i

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M ..

r:

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X

X

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x

X

X

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opp N

X

X

m

X

X

X

x

x

X

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X

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x

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rl

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8

x

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VL

"la

mrl

m

rl

W

N

u"

rl

W

W I-

z

"a x m

U

m

Y

I-

4

J

"

"

I

4

N

X

-

I

z

mI-

v

In

W

1

N

* c

Y

0 I-

I

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4J

Y

m

Irl rl

m

m

P)

Y

W

W

m

a t

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Y

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m

n

64 In

m

X

U

X V

X

X

m

X U

376

2

H

CH3

H

H

CH3

n

H

H

‘2’5

CH3 H B

CH3 CH2CH-NHC2H5 C H 12 5 CH3CH-NH2

7-CR

H

H

H

CH2CH 2NH2

H

CH (CH31

H

5-CH3

CH2CH2NH2

n

H

n

I3

CH2CH2NHCH3

CHZCH2NHCH (CH3)

n

H

CH3

0CH3 CH CH N ‘C2H5

H

CH2CH2NHCH2CH2CH3

n

H

C13H18N2 HC1

C13H18N2 maleate

C13H18N2 HC1

1jH1gN 2 HC1

13H 1EN2 me thiodide

C13H18N2 ma lea te

C13H18N2

‘1 3H1BN2 HC1

C13H18N2

oxalata

C13H18N2 HC1

Table 11 (cont.)

206-07 (m)

-

142 (e)

-

225-26 (ml

-

187-89 (el

-

b.p.

lSO(0.05 mm.) 220-21

152-53 (el

-

99 (cyh)

245-46 (b)

-

120

-

187 (b)

-

227,581

227

227

435

326 326

86

159

67a

502

67a

n H

H

YH2CH2CH3 CH-CH2NH2

CH (CH3) I CH-CH2NH2

H H

n

H

H

CH (CH3)2 I CH2CHNH2

H

H H

H

H H

H

H

TH2CH2CH3 CH2CHNH2

H

CH 1 3 CHCH2N (CHJ) 5-CH3

H

CH I 3 CH2CHN (CH3)

n

H

CH2CH2N (CH3)

H

CH2CH2N (CH3)

CH3

n

C13H18N2 acetate

C13H18N2 acetate picrate

13H18N2 picrate

C13H18N2

C13H18N2 hydrogenmaleate

‘1 3H18N2 dipicrate

106 Ipl 171-72 ( e )

‘1 3H18N2 picrate

116 150 150-60

136 tea) 248 (e)

191-92 ( a )

113 (b)

158 (ea)

94-95

99-100

107-09 104-05 119

93-95 (el 97-98 ( e t ) 176 127-26 ( e ) 238-39 (m)

C13H18N2 picrate maleate methiodide


323 352 323

323,352 323

400 400

217

46

46

161 284 284

284

284

110 244 178 86 244

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1 5 1 5

N

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3:

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w &oi

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E

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m

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0

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m 0

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P)E

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0

m o

to

N

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0 rl

I

Y wY l ?0

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N

I:

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0

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a

m

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v

0

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u-

4-

01

I:

N

Nm

mrl 1 1

m o

o m

rlrl

N

rl

X

X

5:

ci,

a

-

X

N

N

0

X

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-

N

V

az N

% X

V

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383

5-CH3 H

CHZCHZN(CH3) C H 12 5 CH2 CH-N ( CH )

CH3

H

H

H

H

H C2H5CHCH2N (CH3)

H

H

H

CH2CH2NHCH2CH (CH3)

3

H

‘CH3

2

H

CH2Ct12NHCH

CH

H

H

H

,CH

CH2CH2NH (CH2) 3CH3

H

H

HC 1

picrate

‘1QH20N2


C14H2 ON 2 maleate

C14H20N2

maleate

C14H20N2 HC1

C14H20N2 HC 1

C14H20N2 HC1

‘1 4H19N40P

T a b l e 11 (cont.1

284 284

284

73 l e t )

143(e) 1 7 5 Ie)

284 284

86

67a

67a

67a

1 5 4 - 5 5 (e) 1 6 8 - 7 2 (el

1 5 0 - 5 1 (ea)

I

175-77 ( b )

-

203-05 (b)

-

372

85-88 168-70 170-71

372 67a

515

138-139

(C2H5)2C-CH2NH2

H

CH 3

H

CH3

CH3

C2H5

H

H

"

CH3

H

HOCH-CH2N (CH3)

H

H

7-CH3

7zH5 CH2CH-NH2 HOCH-CH2N (C2H5)

H

C H 12 5 CH2CH-NH2

H

H

H

H

H

CH3

C (CH3)3 I HC-CH2NH2

H

H

n

CH2CHNH2

H

H

C (CH3)

72"s CH2CHNHC2H5

H

H

C14H20N20

C14H20N20 py ruva t e C1 CCOOH HCI

C14H20N20

C14H20N2 acetate

C14H20N2 HC 1

C14H20N2

1' q H 2ON 2 picrate

C14H20N2 picrate

C14H20N2 acetate


274-76 (m)

110-12 ( e a )

82-83 ( e a ) 113-16 92-96 109-11

167-68 (ea)

-

-

124

171-72 (b) 233 ( e )

177 (b) 218-19 ( e )

142 (mf

-

20

572 5 72 572 572

579

581,227

227

352

531 531

400 400

227

m

a M

N

rM

E d .A

x-r

E V

X

X

X

X

d

V

X

OO N

m

x

"\

x

u

7

zN

m

m

E K X " X-Vm-O v 0x v

x v 0-2, O X

X

X

vN

X U

vN

X

X

X

X U

\ r/

m X

zN

X

V

X

m &

V

2 x

z

x

X

X

x

X

X

ln

m

V

rl

d

d

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X

M

V

m

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d

X

V

X

zN

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v a

..

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X

d

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v a

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V

X

W

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m m m

=N

ON

2 0J

X

N N N W W W

-re

N

V v

m m

O I O I

X

X

x N

v

386

o

.

r-

m m

m m

m m

3

\

o o

3

o m

Y

I

W

o o

-

3 o

m m

m 1

N

Y

w

o

I

I

o

w

o m r - w

* o rl

o

n

Y

i-

m

w m I

l

o

n

E -

m

w

w

W

D

0

m W

0

-

\o

W

m N 1

Y

o

w l n

N

E

W

W

rl

N

N4

ON

ON

rl .rl

rl

zW

xln rl

xln rl

X

X

m m

r l N

r l r l

rl

4 0 ) N

N

x

rl

Q)

a

z,

5 v" i! xm

X

V

X

X

x

x

F

X

X

X

X

x

V

K z XN

zN

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zX

rl

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x

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X

X V

H

H

H

H

CH3

H

H

H

H

H

H

H

H

H

H

H

H

H

3

CH 2CH 2N

0

C H 2 C H 2 N 3 0

H

T a b l e 11 ( c o n t . )

C15H16N20

picrate HC 1

H

‘1 5H16N202

5 6 - 5 7 (1) 1 6 1 (b) 168(ac) 173-75

1 3 4 - 3 5 (b)

C15H18N20

H

152-53

‘1 5H18N2

H

rac I: 310 rac 11: 2 7 5

CH QcooH H CHZCH2NHC0 (CH2) )COOH

H

‘1 SH1EN2’3

5-Br

C15H19BrN2

135-37 (ac)

-

136

C15H19BrN20

5-Br,7-CH3

119

‘1 gH1gBrN2’

5-CH3,7-Br

95-96 (e)

maleate

H

H

H

CH3

CH2CH2N

H

H

CH2CH2N

CH 3

H

”

H

H

CH2CH2NZ

H

H

H

H

H

H

CH3

H

/-7

T a b l e 11 ( c o n t . )

5-C1

5-CH3,7-C1

CH2CH2Nuo 5-C1,7-CH3

3 3

4-F

C15H19C1N2 maleate

‘1 SH19‘lN2’ C15H19C1N20 ‘1SH1gFN2

1SH1 9FN 2 maleate

5-F

‘1 SH1gFN2 picrate

6-F

H

‘1 gH2 ON2 methiodide HC 1

C15H20N2

H

‘1SH20N2 HC1

H

HC1

105-06 ( e ) 142-43 156

181

110 (m) 208-12 (m)

145-46 ( e ) 149-50 ( b ) 161-62 ( e t ) 204 228-29 (el

220 ( e ) 113-14 (b) 109-10 ( c y 223-27 ( i p )

mm

r-

r-rN N

d

m

0

-9

N N

d

-

m W

t

I

m 0

m

W

VI I

d

d

d

W

m

O

d

I

N

ON

zo

zO

=0

xm

X

X

u

u

u x

X

X

X

N

8

m r m m

0

ON

N

u c

m r u

0

lO

l-

Y

d

N

d

d

v

Ln d

N

m d d V

m

N

ON

zo N

xLn d

v

Y

d

d

0)

X

X

X

9

X

X

rl

€I

M

0

X

X

X

X

X

X

X

X

X

X

V

0

X

V

X

0

390

X

X

V

CH2CH2N (C2H5)

H

CH3

H

H

CH2CH2N(CH3)

H

H

CH2CH2N(C2H5)

CH3

H

H

CH3

C2H5

CH3

H

H

H

H

H

H

T a b l e 11 ( c o n t . ) 5-CH3,7-Br

C15H21BrN2

picrate I

A CH2CH2NuN-CH3

5-CH3, 7-C1

C15H21C1N2 HC1

H

‘1SH21N3 di-HC1

benzochloride CH2CH2N(CH3)

CH2CH2N (C2H5)

CH CH -N

YH

H

H

H

H

C15H22N2 picrate methiodide

165

-

197

280-85 227-229

207-08 ( e t )

C15H22N2 HC1

203 (e)

C15H22N2 HC1

C15H22N2 HCl

/CH3

‘1 SH2ZN 2’ picrate

‘YCH~)~OH

~ H - C H ~ N H (Cc H ~ )

‘1 SH22N20

-

-

124-25 ( e )

-

111( e ) 124-26 t e a )

C2H5 CH3

H

Table 11 (cont.) ?H ~H-CH~NHC (H cH~) H OH I

y 3

CH-CH 2NH-C-CH20H I

H

CH3

H

H

4-C1C6H4

H

'sH5

H

'sH5

H

4-BrC6H4

H

H

H

H

5-Br

H

H

5-C1

CH 2CH2NH2

H

CH2CH2NH2

7-C1

CH 2CH2NH2 CH2CH2NH2

H I-\

CH 2~~ 2 ~ = ~ ~ Q

H

1' SH2 2N20 C15H22N202 picrate C16H13BrN202 methiodide C16H1 qC1 2N20 3

125-26 (

-

146 (e) 149-50 235

131 (e)

-

142 (e) 220

C16H15C1N2 picra te

80 (el 240

C16H15C1N2 picrate

224-27 (

C16H1 SBrN 2 HC 1

C16H15C1N2 C16H15N3

104-106 ( 180-81

N

m

In

P W

001-

NIn

w-m

o o m

--

-

h

- 0

* d m

-* P)W - 1

CCInm I

I

I

W O N

PN * W

I

N N

dlnIn N N N

m m

m m

e e

~m

m m I

O

I N

m m

r l N

- v

m e m i I m N O m d

In 0 W

-

z.2 J

m

-E.

I

e m m m 1-0 w w m e m o

w

w

i

I

d

N

o e

e m o e

I-

P

N

ld

N

m m

--

-

N

A m

m

In

N

N

N

2' m

zW

d

=w

r)lE

X L I

w or)

r)

zW rl

xa d

d 4 v v ar

d U

Urn

O ,

?Q

W U

d

N

X

X

X

-Y

ON zW

d

m

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m

N

Oa 2

W 4

X

xW

xW

U

V

U

X

X

X

d

d U

v x

rl

m

rl

W

r)

N

X

In

X

N

N

X N

zN

X

U ,

X U

N

Inx

Xw

g

v--u

N

X U

zN

2 V X

U

X U

Y

zN

zN X

X

U

X U

X U

vN X U

X

W

N

In

W

xW U

X

X

X

X

X V

X

X

X

X

X

X

X

X

X

X

393

N

m N

h

Q) w

I-

W I

I

W W

d

In 0 W

m

U 0

IOD 4

Y, U

d

- -a 0

Q

W

-4 I-

0

m I

Om

ON

N

%m d

xW

d

V

9

v

d

I-

W

Y)

W

* d

W m

I

W

xW

m

0

W

0

W

I-

I

U

rl

Id

X

X

m 3:

m X

N

Om

%m

zo

X

X

N

d

W

W

d

d

V

U

V

X

X

X

L,

E:

8

x

X

V

m

X

X U

X

3:

m

X X

X

V

0 V

1:

394

V

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

CH2CHZNHC0 (CH2)3COCH3 COOCH3 CH2-

Table 11 (cont.)

C16H20N202

H

C16H20N20

H

H

H

COCZHS I CH2CHNHCOC2H

C16H20N202

138 (acl 128 (ac) rac 1: 1 rac 11:

177

C16H21BrN2 picrate

5-CH3,7-Br

C16H20N202

H

5-Br,7-CH3

W

105-106 (

162

‘1 6H2lBrN2 picrate

5-CH3,7-C1 5-C1,7-CH3

C16H21C1N2 picrate C16H21C1N2 picrate

-

199-200

-

175

H

H

H

H

H

H

H

H

CH3

H

H

H

H

H

CH2CH2N

3

CONH2

Table 11 (cont.) H

H

CH=CHN (C3H,)

H

C16H21N30 C16H22N2

C16H22N2

CH3 5-CH3

C16H22N2

maleate

H

C16H22N2

183-84 t e a )

129-32

100-02 ( b )

150-51 ( e ) 149-51

101-02 ( e a )

H

CH2CH2N

3 3

160-63 (ea)

H

138-40 ( c )

H

CONHNH2 -CONHNH2

CH 2CH 2N

165-66 ( c )

H

H

H

H

H

H

H

H

H

CH2CH2N (C3H7)

n

CH2CH2N02CH20H

Table 11 (cont.)

5-Br H

CH2CH2N (C2H5)

C2H5

H

H

H

H

H

H

H

H

H

H

CH CH N A C Z H 5 '(CH2)qOH

H

C16H23BrN2 HC 1

183

115-16 (ip)

C16H24N2 HC 1

198-99 (b)

C16H2 4N2 HC 1

178-79 (b)

C16H24N2 HC 1

105-110 265-67

C16H23N30 di-HC1

C16H24N20

-

b.p.

195-204(0.05

118 (p)

CH2CH2N=CH-C6H5

227-30 (e)

COCH2NHCOC6HS

130-32 (b)

CH2CH2NHCOC6H5

116-17 (b)

HOCHCH2NH-COC6H5

Table 11 (cont.)

215-17 (e

CH2CH2NHCH2C6H5

C17H18N2 picrate

H

H

‘sH5

CH3

160-62 (e 156 (e/w)

C17H18N2

CH2CH2NH2

CH2C6H5

H

C17H17N30

CH CH NHCgH5 \NHCOCH~

H

H

CH2CH2NHCH2C6H4C1-4

H

H

HOCHCH2NH2

‘gH5

CH3

C H 16 5 CH-CH 2

CH3

H

C H 16 5 CH-CH2NH2

H

CH 3

~

~

H

-

CH3 C H I 16 5 CH- CH-NH2

H

H

CH2CH2NH2

CH2C6H40H-2

H

‘1 7H17C1N2 HC1

C17H18N2 HC 1

2

2 5 0 - 5 2 (b

117-18

-

241-43 (e 232-34

130-32 (e

‘1 7H1eN 2’

158-60

C17H18N2

196-97 (e

C17H18N2 picrate

123-24 (1 204-05 (e

‘1 7H1gN 2 picrate

C17H18N20

-

193 (m)

4

V rl

m

*

W

4

0

4

m m

0

m m

In

N ( Y

3 E

3

m 0

m

0

N

rl

N

ON

CI

4

m

0

4

-

Y

Y

z,

ON zm

X

X

rl

rl

r-

r-

d

rl

V

V

c

8

rl

m e 4

N

m m In

v)

m

m

N

d

15

I

I

1

I

0 In

V

(Y

m I

I

m m

0

o m m r l

rl

N

w

mm

0

N I

m rl

li, N

N

ON

ON

N

X

I N

rl

rl

rl

B

a

S

ON

'2

V

zO N

d 4

x u

r-u

v"

m

6 4 0 \ o m

; I N

N

ON zLc

m

z

N

=,

xr-

X

X

rl

=N

N I-

rl

rl

V

V

N

zN N

xrrl

V

u m

Y

d

r - m

0,

\

I

n

N

rl *

-

- \

4

N

X

X

In

X

X

X

X

B

d

P 4 k

B

m

m

X

N

X

N V V

x

0 1

X

X

ZN

ON V

X

e

m

X

m

V 0

V

v-2,

V

N

X

V

*I X O* X

W

X

V

X

X

X

X

X

X

X

X

X

X

9

X

X

X

X

X

X

399

OOCH

T a b l e 11 (cont.)

103-04 (b)

C17H22N202

H

110-12 (ac)

C17H22N202

H

108-11 (b)

C17H22N202

H

H

CH2CH2N

CH2CH2NHC0 (CH2) 3COOC2H5

C17H22N203

101-02

100-01 ( 1 ) 170-72 ( c ) 188-89 (c)

C17H24N2 picrate

H

157-58 ( i p ) 252-54 t i p )

C17H24N2 RC1

CH3

112-14 (cyh)

C17H24N2

H

167-69 (ea)

C17H23N30

H

T a b l e 11 ( c o n t . ) C17H24N20 HC1

1 ' 7H24N20

C17H24N20

1 ' 7H2gN3 hexamate C17H25N3 di-HC1 C17H2gN2' HC1 1 7 H2 gN2' 2 HC1 C18H14N2 picrate methiodide

177-84 (m) 116-18 ( e a )

230-25 ( i p )

124-28 ( i p )

-

259-62 (e) 68 ( e t ) 1 1 7 (ac) b.p.

232-36(0.05

~IU

131-39 171-72 (e) 163-65 ( e ) 227-28 f p )

H

CH3

H

H

H

H

COCH2NHCOOCH2C6H5

H

H

164- 65

C1 8H14N202

159-60 (m/w)

HocHnJJ

H

H

C18H14N20

H

H

H H

CH 3 H

Table 11 (cont.)

cn2c C18H16N203

-9 ' HN"

2

9

HN

CH2CH2-N=CH-C6H5

"

"OCH HN? D

-

139-40 (m) 210-11 (el 248-SO

'1EH1eN2 picrate HC1

209-11 (ip)

1eH 1EN 2 HC1

215-16(ac)

C18H18N20

93-94 (p)

'lEHleN2

b.p.

'1EH1eN2

160(1

Q

N

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rl

m

0 N

N

-

N

-

In

In

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1

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I

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t

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0

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w ww

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m

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p.

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rl

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a4

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X

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z

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r l 4

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rl rl

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m

N

zO N

X

mrl

rlv

zo J XN h a m u

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N

X

mrl

rlv

v a

v a

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X

X

X

X

X

X

X

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X

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X

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rl

X

l - 4 4

408

X

H

H

H

H

CH20H

H

H

H

H

H

H

H

H

H

H

CH3

H

H

Table 11 (cont.) FH3 CH 2~~2 ; J ~ O6~~ ~ 2 ~ C19H20N20 CH2CH2NHCOCH2C6H5 CH2CH2NHCOCH2CH2C6H5

1' gH2 ON2' C19H20N20

C19H20N20

FH2 (CH3)2C-NHCOC6H5

C19H20N20

CH 1 3 COCH2NCH2C6H5

C H 12 5 CH2CH-NHCOC6H5

1' gH2ON2O

lgH 2 ON'2 '1gH2 ONZO c HN H

2

e OCH3

C19H20N20

104-05 76-77 (e/w) 71-75 (e)

179-80 ( i p ) 14 8 101

2 0 5 - 0 7 (b)

169-70 (m) 162-64

Table 11 (cont.) ?ZH5 H CH2CH2NCHiC6H4C1-3 C19H21C1N2 e thobromide

H

CH2C6H5

H

CH2C6H5

H

H

H

H

H

H

H

H

5-C1

HOCHCH2N (CH3)

‘sH5

CH3

H

HOCHCH2N (CH3)

C6H4C1-2

CH3

H

H

‘sH5

72’5 CH2CH2NCH2C6H5

CH 1 3 CH2CH2NCH2C6H4CH3-2 CH I 3 CH2CH2NCH2C6H4CH3-3 CH 1 3 CH2CH2NCH2C6H4CH3-4 C H I2 5 CH2CH-NH2

C2H5CHCH2NH2 CH2CH2N (CH3)

H H H

H H

n H

-

188-91 (e 117-18 (e

-

204-05 (e

‘1gH2ZN2 methobromide

224-25 (e

‘1gH2ZN2 HC1

‘1gH22*2 methobromide

-

-

152-54 (e

‘1gH2ZN2 Dicrate

201-02 (e

C19H22N2 HCl

164-65 (e

C19H22N2 HC1

189-92 (e


-

-

-

H

CH 3

H

CH2C6H5

H

Table 11 (cont.) CH2CH2N(CH3) C6H5CHCH2N (CH3)

7sH5 yH3 CH-CH-NH2

CH3

(CH3)2CCH2NH2

H

CH2C6H5

CH2CH2NHCH (CH3)

‘gH5

H

CH2CH2NHC3H7

‘sH5

C19H22N2 picrate C19H22N2 picrate citratedihydrate C19H22N2 HC1

HOCHCH2NHC2H5

CH3

CH2CH2N (CH3)

H

-

212

-

199 69

75-76 (b) 215-18 (e)

184

C19H22N2 picrate

97-98 238-40 (el

C19H22N2 HC1

C19H22N2

HOCHCH2N (CH3)

CH3

-

123-26

89-91 (ea)

19 22N20

173-75 (m)

1gH22N 2’

C19H22N20

110-12

m W

0

r-

Y

Y

m

-? OD

0 W

m

N

d

W rl

N

N

N

N

N

ON

ON

ON

ON

ON

ON

zN N

zN

N

z N N

z N N

xm

rl

V

W

- - R I

E

m I

rrl

N

X

m

4

V

zN xm

rl

0

E

VI

r-

0

m I In

I

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r-

4

m

rl

V

WOD

P,

-E

Y

X

w

* r-P**

0 N

l a ,

xm rl rlV

o x

N

PI rl

PI rl

zN

N

xm

4

U

m

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+I

8

0

m I

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r-

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m

m

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X

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zN

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Y m z

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v-

x x

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m

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412

X

V

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*I-

w

a v

I - 0

v

m

m

0

m

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0

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W

m

p.

d

m

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I n -

w I

m

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m

.;I :

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m

m

rl

I

d N I

In

d

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0 CD

m

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N

Om zm N

x i

d U

X

X

I

m

I-

d

In N

v I N

d

ON

N z0

zW

xOI

xOI

U

V

N

N

d

rl

3:

X

X

X

i5

0

m x

u-u-u 4 y xN N

I

3: V

x x

0-UN

89

X U

zN X

X v-VN m3

u N

1:

X U

V

X

X

X

X

X

X

X

X

X

X

X

X

X

X

413

3

H

H

H

H

C2H5

H

H

H

H

H

CH2CH2N

H

H

CH2CH2N

C2H5

H

H

H

CH2CH2N

CH2CH2N

Table 11 (cont.)

CONHNmC (CH3)

3

(CH2)40H

3-

CONHNHCH (CH3)

2

0

H

C19H26N40

184-87 (

-

140-43

1' gH 2gNZ0

H

137-38

C19H28N2 picrate

H

H

C19H28N40

5-C1

CH CH NH-a-naphthyl

CZ0Hl7C1N2

H

CZ0Hl8N2O2

H CH I 3 C=N-NH I CH2CHNHCOCH

H

151-54 ( 240,242 161-62 (W

265-66 (e

C20H20N605

241-43 ( 245-46

CIOH18N202 methiodide

a

9 0

v)

--

a

m o - 0

dv)

m

9 d

E

I-I-

N N

m m N

W

N

2 2 N

O

m

0)

I

I

I l-

m

mrmm

9

W d

wm

m

I4

Om

rl

m 2

d

ON

ON

ON

N

u N N

2N

zN N

zN

xO N

xO N

xo 4

xo

.p

W

I

m

N xO N

V

I I Ov)

44

V

l-

I

m

z

U

q . 4

d

m

d

N

9

9 0

9 d

N N

N O

N

N

I

N

4

N X

0 N

u x

U

U

X

X

X

U

X

X

X

X

X

.-I

V

X

X

W

*I

4 v)

X W

Of1

v, X

u)

Y

m X

m

Y

XW

c zN

=N

X

X

B

X

U

W

u N

X U

0

(OI

P

zN X

X

V

v)

In =W

V

v)

5:

X

X

X

X

U

X

X

X

X

X

X U

m

W

415

H

H

H

H

H

H

H

H

4-C1C6H4

H

4-BrC6H4

H

4-HOC6H4

H

‘sH5 ‘6’5

n

Table 11 (cont.) H

H

5-C1

CH2CH2NHCHCH2 I HO

H

CH2CH2N (C2H5)

5-F

H

NHC6H5 CH CH N/7 NC6H5

2w

CB2CH2NH (CH2)3CH3

H H H H

CH2CH2N (C2H5)

c2 OH2 2N202 C20H23BrN2 ethanesulfonate ‘2 OH2 3‘lN2 ethanesulfonate

218-20 124-25 192-93

116-17 183-84 148-50

‘2 OH2 3FN202

118-20

C20H23N3 C20H23N3 C20H24N2 oxalate 2OH24N2 ethanesulfonate HC1

133-35 132-36

-

230 (el

125-26 210-11 169-71

CH2C6H5

H

H

H

CH2CH2C6H40H-4

H

H

CH2CH2C6H5

H

CH2C6H5

'sH5 'gH5

Table 11 (cont.) (CH3)?CHCHCH2NH2 CH3 (CH212CHCH2NH2

H H

5-CH3

"

H

HOCHCH2N (CH3

4-CH 3C6H4

-

141-42

C20H24N20

168-69 (m

C20H24N20

199-200 (

C20H24N2

160

C20H24N2 picrate

140-42

C20H24N2 picrate

-

118-20 101-02 (ea

131-33

H

HOCHCH2N(CH3)

4-CH30C6H4

118-20

I

HOCHCH2NHCH (CH3)

H

118-19 (e

H

H

H

H

H

H

H

CH3

CH2C6H5

CH3

CH2C6H5

H

H

H

H

H

H

I

Table 11 (cont.)

CH

H

CH2CH2NHCH2CHCH20 I

2 OH2 q N 2’2 tartrate

C20H24N202

ca.

227

113-15

CH30

5-OCH2CONHNH2

CH2CH2NH2

H

CHZCH2NHCH2CHCHZ0

CZ0Hz4N2O3

124-26

C20H30N20

H

139-40 (ea)

CZ0Hz9N30

H

249 ( 8 )

C20H25N30 di-HC1

131 (b) 233-36 (e)

C20H24N402 HC 1

5-OCH2CH2NH2

H

CZ1Hl8N2

-

143-44 166-68(e)

N

N

N

N

m

m

W

N

m

m m

m W

In

r-

rl

In

U

-

h

n . ! ?

1

0

0 In

rI

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m

QD W rl

rl

m m

In

& m

In

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p. In

rl

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..

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rl z

zo

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N

N

X

xrl

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N

N

V

V

V

r

zl

vrl

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X

rl

N

i rl

N

xrl

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0

X

X

8-4

r l x rl

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X

X

In

PI

rl

n m k

m - ,

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0-

=N

0

X

X

X

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In

xm

0

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419

X

X

X

X

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m

--

-

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Lo

m

W

Ja

m I m rl

4

m m

m

I4

m

m

V

a

f i r -

0

m

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r-

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m

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1 - 4

m ON

zN

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zN N

U

rl N

U

xrl N

U

X

X

Xrl N

rl

1

N

N

W N

X

z

0

rl

N xrl

N

N

X

rlrl

U

N U U X

X

X

X

X

X

X

N

X

z.p

N

d

m

X

X

X

X

m

m

X

X

X

X

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X

420

N

U

X V X

U

o

P

m

E:

0

-

- 0 1

I

-

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"

N

l

n

m m

W

N

ln

N

m

v)

m

a

N rol w

r l N

a

O

m

1 . 4

1

a

m

ln

P

I

m -4

v)

I

0

I v )

N

- n

m

0

W

m

* m I

0 W

N

a

N

m I

N rl

I

rl

0

rl

rl

m

4

N

N

N

2;, N

N rl

o

c

NU

4 NU

ON =iP

N N

ON

z

Om

.-I

?r

N N

rl

NU

3:

rl

N

u x

u x

U

U

u x

U

x

X

X

X

X

X

N

X

rl

N U

X

0

N N

U

3:

m

m

3:

X U

0

X

X U

X

42 I

-

X

V

v)

xN

U

H

H

H

H

H

H

H

H

H

H

H

H

CH3

H

H

CH3

H

H

CH I 3 CH CH N E - C 6 H 5

n

CH2CH2NUN-C6H5

Table 11 (cont.) H

H H

. I

.

6-CH3

n

NC6H4CH3-2 2w

CH CH N

n

CH2CH2NuNC6H4CH3-3

n NC6H4CH3-4

CH CH N

2u

H

H

H

H H

C21H25N3

104-06 (

150-53 154-56

‘ 2 l H 2SN3

90-94 94-96

C21H25N3

21H2SN3 C21H25N3 ‘21H2SN3 ‘21H2SN3 C21H25N3 methochloride C21H25N30

170-73 174-75 124-26 164-66 145-50 148-55 90-95 227-29 ( 94-96 ( b

m

m o - 0 rlm

Vo

dd

I 1

0 4 drl rld

o

N m

0 V

W

0

r-

rl

rl

w I

V rl

I

m

-

am

I

m

0

-o - I

m N

m m

)

0

i d r l

-

4

-

)

o N n m I

m o m m r l

rw I m \ D

m

I

1

4

m

rm i y,

w

d m

dr-

o m I

1

dr-

r l d

0

Q)

U

U

w 0

w 0 4 N 7

m c

2

Om

Om

-

zm N

N

X

xd

rl

N V

N

U

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8

rl

N

x

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N

m I m.

V

x

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zW Qm)

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X

rl

x

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m

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0

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zw

2O

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ON

rl

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X

x

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m

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0

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x

x

Y

rl rl Q)

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I

m

x v

Oo xw

x v

xw

I

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c',

N

xW

m

4 u

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x x

v

x

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x

v

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X

X

X V

0

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Y

X

I

m

X N

V

Y

N

m

u

N

m

X

xN

Y

Y

X

zN X

%0

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8 8 V

V

x

X

e

Y

o

m

x

X

x

x

X

X

X

um

u

zN

X

X V 9

W V

m

x

W V

Om

x

v

I V

In

x

W

x

m

X

x

V

I

V

W

x

N

m X N

xW

X

m

-

W

X

423

X

0

r-

,x

xm

V

V

X

m

(om

N

-l.p

ww

m

r-I-

I-I-

W

W

- 0

In

0 In

N

I-

m

N

W

m I

In rl

m

N

ON

ON

xrl

;e, N

xrl N

X

X

zW N

zm

N

N

V

V

8

zN

m

V

v)

N

z,4 X N

N

V

m

E

-

ON

X

Y

Y

)

X

X

3( (-J CI m

X

ON X

V

x x

N

5:

X

U X -2 X X

X V

v-VN X V

X

X

uN

-

N

V

X

X

OW X

I

X

zN

-

m

0-VN X

X

N

X

2 % v-v z

zN

X

vN

0 V

I

N

X

XN

V

N X

v-z

X

X

V

5

V

9

X

X

X

X

X

X

X

X

z

424

X

rn

H

4-C1C6H4

C6H5CHCH2-NH2

C6H5CHCH2NH2

‘gH5

4-C1C6H4CHCH2NH2

‘sH5

H

H

H

H

H

H

H

H

H

H

Table 11 (cont.) H

H

C22H19C1N2 CZ2H19ClN2 C22H20N2

C H 16 5 C6HSCHCHNH2

C22H20N2 picrate C22H20N20

CH2CH2-N\=)

182-84 188(e 180-8

187-88 216-1 250-2

SF3 H

CH2CH2-N

CH2CH2NHCOCH @ - HO~CCH~’ H C -

H

H

C22H20N205

C22H21F3N2

C22H22N205

249-5

152-5

132-3

OD

l

v

N

v

)

w

m

m

In

N

-a -

-.-I W 0

I

.t

0

d

N

ON

N

Om

zrr)

Q

N

ON

zQ

=0

X

R N

N

h"

&rr)

X

4 N U

xN N

xm4

v

v x

v

X

X

X

X

N

N

N N

r(

V

V

B X

I

N

z0

N

N

NU

N

N

N

N

zw

N

xN rl

V

N O V I

X

I

N

% N 4 N v X

rr)

I

m In

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X

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V

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3

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0

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X

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X

426

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N I-

m

m m

m

m

m m

W m

m

N

o

m

I

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m

I

ON

ON

N

m

m m

W I-

0

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--

N

w

-

m

m

al m

o

m

I

m

W

O

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* W

o

4

N

ON zm

N

al

I

ON

zW

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zI- Lc

zm

xN N

xN N

xN N

xN

xN

V

7 N 4

v a

V

0

v x

X

X

X

X

X

X

X

N

V

N

V

N P

N

N

zm N

N

xN N

N

rl

NU

m

m

xW

U

m

-

OV

X

I

CJ--7.

N

m

-

X N

V

zN

X

ON

X

V

I n ~.

xW

v

“‘0 X

V

m

I-

X

Y

m m xN

L”zN

X

! X

9

\N

X mV

x x 0-v

m 3z:

x x vN ‘

X V

0

x

X V

X

m

xW

v N

X

m

X

v

m

X

v

v N

X

V

X

427

X

H

H

H

H

H

CH2C6H5

‘sH5

CH3

‘sH5

H

H

H

H

H

H

H

H

H

H

H

(cent.)

H 5-F

C22H28N202 HC 1 ‘2ZH31FN2

H

162-64

146-47 ( 141-42 151-53 (

H

C6H5CHCH2NHCONH2

188 ( e )

H

C6H5CHCH2NHCOC6H5

143-44 (

H

C H 16 5 CH2CH-NH2

CH2CH2NHC6H5

I

FH2CH = C CH2CH2NCH2CHCHZ0 bH

F

b

\ /

H H H 5-C1

153-55 C23H22N2 picrate ‘2 3H22N2 HC1 C23H24N2

198-99

-

136-38

193 (ac

-

C23H25C1N202 186-88 HC1

V

m

m m

In

m W

N

-3 N

m I

0 v)

rl

4

0

4

m

N

O

V

4

w m I

V

a

m w i I

I

w I

c a m v ) r N

-

4

n

In 0

ln

rl

In N -4

* rl

*In

m N

W

rlrl

ti

*

iIn

-?

W In

N V -4

W

X

X

I

I

rl

m

N

m

N

ON

m

Om

zW N

=iN

ziN

4 N V

8

v

z

ti N

N

zm

N

xm

xm

xmrl &

V

v xx

x

X

X

v

N

N

Nvm

m

c -

4 N

Om

Y x

I

n

X

x

In

A8

In xW

tl zN

X X

V

m V X

X

x

x

m X U

X

x

x

X

X

xW

V

In

X

X = & i

X

V

X U

m X

X

X

u

V

0

V

X

V

It

X

X U

m

429

X

‘sH5

CH3

H

H

T a b l e 11 ( c o n t . ) CH I 3 OCH

-

HOCHCH2N (C3H7)

C23H28N205 HC1 ‘2 jH3 ON2O

76-78 ( 67-69 (

OCH

CH3

H

C H2 - 0 4 C! i 3

H

C23H30N202 C2HSS03H C23H34N2

‘sH5

H

H

H

CH2CH2NHCOCH(C6H5)

H

H

CH=CHN (CH2C6H5)

H

H

H

24H22N2 C24H2ZNZO

118-20 162-64 125-27

129-30 1 4 6 (e)

C H 16 5

180-82

C24H24N2

190(e)

‘2 qH2 3”3

Table 11 (cont.)

‘gH5

‘gH5

CH2CH2NHC6H5

H

CH2C6H40CH3-4

y 3 CH2CH2N-CH2C6H5

‘gH5

CHZCHZN (CH2C6H5)2

H

HOCHCH2N (CH3)

C24H24N2 HC1

-

208 214-15 218-20 (a

151-53 (e

C24H24N20 HC1

83-85 (b)

C24H24N2

C24H24N20

148-49 (e

H H

Pnaphthyl

H

H

H

H

CH2CH2N (C2H5) 0COC6H5 CH CH 2-N

H

114-18 (m 175-17

142-44(b)

C24H28N202

246-48

C24H26N2 2H5S0 jH C24H26N202 methobromide

-

‘6’5

A

tn

0

m

0

m

v)

N

Om

zm

N

=.r

-

rl N

rl

OD

N

0,

tn

0

N

Om

zm

N

=w

V

N V

X

X

N

16 .r N

X

X

m

X 0

X

X

X

X

X

X

X

X

X

X

X

432

II-

0

a

W d

I

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W

m I

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4 J -

Pa N l n

P-m I

1

m

V

O

V

d

d

d

N

d

m

m

m m

m

I - m

m Om

J zln E m u x.cc

v x

v

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X

X

d

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0

m

N

*I

r-

al

d

N

I

m m

0 V

N

d

N

ON zW

d

=ln

N

ON zO

N

X

v)

I-

I In

PI d

N

d

v I m m d

ON

ON

X

X

zO N v)

z*N v)

V

N

V

V

V

2

3:

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X

N

ln

m

X

u

X

V

X

X

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m

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433

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N

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m

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1:

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Table 11 (cont.)

H

C6H5CHCH2N (CH3)

H

C6H5CHCH2NHCOOC2H5

cH3

H

H

H

H

H

H

CH3

H

CH2CH2N (CH3)

4-C6H50C6H4

H

H

CHZCH2N (CH2C6Hs)

H

CH3

'gH5

CH3

'sHS

"3

'sH5

H

g6H5 CH2 HN(CH3)2

H

HOCHCH2N (CH2C6H5)

H H

CH2CHZNHCH CH N /'sH5 \CH,C~H~

C25H24N202 C25H2 6N2 '2 SH 2 6N2

sulfate

2' 5H26N2 C25H26N20

138-39 122-24

-

120 (et 123-4 (

142-43

171-75

C25H27N3 di-HC1

-68 (ip)

C25H27F3N202 HC1

120-22

C25H26N20

-

119-21 (

W P v)

m F.

4 N

F.

I-

F. m

F.

m

-3

m

m

N

w

N

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in

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4

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0

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d

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0

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m I

p.

d

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N

ON = N

m

xo d

mu v x

U

X J J X

c

X

X

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X

X

3:

0

N

m

v)

v)

X

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N

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m v

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ON X U

I

U-2,

X

3 vW

X

W

U

v)

xW

U

v)

v)

xW

V

X

E

Y

0

U

X

m

X

d

xW

X 0

X

438

m X 0

m

u

N

X

X

X U

R1

R2

H

H

H

H

CH 3

H

H

CH3

H

H

H

H

H

H

Table 12. 3-Indolyl-C-C-C-N and 3-Ind0lyl-(C)>~-N Derivatives'

x--$T:: R3

(CH2)-,NH2 (CH21)NHCHO

5"

3 CH2CH2-CH-NH2

(CH2)-,Nil2

I

(CH2)3NHCH3

X

H

I9

CllH14N2 HC1 picrate

H

C12H14N20

H

C12H16N2 creatinine sulfate

H

60-64 169-70 155-56

b.p.

b.p.

b.p.

C12H16N2

H

176 (w)

C12H16N2 pi crate

&

m.p.

I

'C

170-gO(O.1

INIl.1

159-63(1.6 m.)

153-56

-

C12H16N2 HC1

5-CH3 H

*For further compounds: Chas. Pfizer

-

-

166-70(1 M.)

256-57 (m)

07 (et) C12H16N2 Co., Brit. Pat. 1,220,628(1968).

N ln N

IW

IN ln

*

I

I

E

m

Y

0

m

rl

m f .r

W I

rl

rl

N

W

N zO rl

xm

ON

7;, rl

U

4 U

X

X

rl

6

m

Y

4 rl N

3 N

rl

I

W 0 rl

N

Om rl

4 rl

N

zW

4

X

W rl

U

U

X

X

(Y

I

0

X U

zN

X U X X

U

I

X

X

Y

X U

X

X

X

X

X

X

440

H

CH3

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

COCH2CH2N (CH3)

/”

co-w c o - 0 0

- C

N

y-pyridyl

Table 1 2 (cont.)

C13H18N2

H

C13H16N20 picrate HC1 methiodide

H

116-18

175-78 (e) 179-80 (m) 208-09 (m) 92-95

235-36

C14HgC1N20

H

149-51 (b)

‘1 3H18N20

H

C14H12N2

H

C14H12N2

H

C14H12N2

H

C14H11N3

H

C14H10N20

H

235-36 143-44 151-54 108-11 (b) 163

m

N f

.

AJ

21

f

or N

Wr-

0

ww

r - m

m

o*

m

I P)

Y

N

c zN o r l v x

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N

o

4

N

ON

zN

z;, rl

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xo

d 5: rl

U

r(

U

m

N .. z,

N

ON

zW

zo

d

4

X

o

rl

X

o

xf rl

4

4

U

U

U

X

X

m

u X z X

X

X

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m

m

x111

0 uI X

X U

z N

m 3:

U

X

U

N

X U

m X

u

X

X

3:

X

X

X

X

X

X

X

X

X

X

X

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442

m r-

m

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m

m

m m rl

N

m

N r l r l N r l

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cn

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0 F.

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ON

ON

ON

N

zO

xV

V

X

X

-

(Y

m X U X

zV N X

U

-

N

0

X

X

N .-

-

m

x

2

zN X

X

uN

V

U

X

z

X

u

m X

443

N

z

4 0

m

X U

8

m

0 rl

z0

V

-

N N

rm rN m

0 V

V rl

N

N

P O

rl

rl

X

r-

m

X

V

4 V

rl -4

r

zm

rl

X

u a

mrl-N mm

r - w

rlm rl mmmmm

V

m

X

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r(

m

0

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CH3

H

H

H

H

H

H

H

H

C H =,C H G

H

CH=CH

T a b l e 1 2 (conk.) C15H12N2 methiodide et h i o d i d e

C15H12N2

260-65 ( m ) 273 285

-

quat. salts

C15H14N2

H

C15H12N202

H

HC 1 methobromide quat. salts

182-84 (m) 118-20 ( i p ) 157-59 226-27

c2HxN H

C15H14N2

HC 1 methobromide

quat. s a l t s

cHkN H

H

C15H14N2

C15H14N2

149-51 ( i p ) 260-62 211-13 1 7 8 (m)

1 9 7 (m)

rm

.

N

m m W

N

w

N

dl-4

N

m

0

W

w

m m

0

m m

m

m

m

m

m

m

d

N

4

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h

h

0

m

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m

m

0

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I

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d

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zo N

l-4

du

V

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u x

X

X

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al

Q)

1

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In

v)

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N

In

N

IN In

N

i

E

Y

V

m I

I

I

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I

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N

m

IN

I

W N

4

m

n ON zO

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v"

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3:

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c, " m .

m

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zw

4

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N

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m

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X V

2 8 5 xw 9 8 v" $ 2

z

zO N -4

V

N

m

0

xIn

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E

OD OD

v)

(9

--

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0 In

m

X V

X z 0

m

Y

X

V

J f

0 9

z

0

z N

X

N X

vN X V

v N

8

X V

N

8

D

m

X

X

X

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X

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446

H

H

H

H

c

NCH 2COOCH3 NCH2COOCH

T a b l e 1 2 (cont.) H

C16H18N202 C16H20N202

H

178-80 (u) 120-21 (u)

65-66

206-08

HC1

172-73 (e)

C16H22N2

H

170-73 246-48 (m)


H

260-62 (e)

C16H22N2

H

C16H22N2

H

C16H22N2 HC1

H

200-01 ( i p ) 212-15 (e)

138-40 (b)

CH3

C

H

.

6

H

T a b l e 1 2 (cont.) C16H22N2 C16H22N20

1 ' 7H15N30 methiodide

H

C16H22N20

H

H

CH=CH- 0 - c 2 H 5

H

C17H16N2 methiodide ethiodide C17H16N20

C17H18N2 HC1

C2H5

C17H18N2 HI methiodide

H

1 1 2 - 1 4 (cyh) 195-98 (ea) 114-15 ( b )

308

294 248 212-13 (e)

143-44 189-90 (w) 206-07 (w) 45-50 167-69

-

W

m N

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OH

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119-20 (b) 217-18 (e)

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H

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CH=CH OCHzCH2N(C2H5)

El

C26H28N20 HC 1

167

126 (ac

-

236-38

5 N a CH 2 ~ H~~ 6

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-

178-80 ( 82-84 (

CH3

H

H

CH 3

H

H

H

H

H

H

H

H

R2

R1

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7-Aminoindoles

X

R3

m.p., *C

X

H

4-NH2

C8H8N2

7-NH2

H

‘aHsN2

6-NH2

H

‘EHEN2

5-NH2

n

HC1

CH 3

H

H

5-NH2

H

5-NH2

H

6-NH2

‘EHsN2 ‘gH10N2 ‘gH10N2 C9H10N2

105-07 (subl) 108 (etf

127-29 (p) 129-30 ( h ) 130-32 ( w )

66-67 64-67 68-70 241-2 (et)

99-101 (ip) 143-44 156-57 ( h ) 152-56 (subl) 157-59 (b) b.p.1560

mm.1

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7-NH2

CH 3

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H

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C2H5

H

6-NH2

CH 3

CH3

H

5-NH2

CH 3

CH3

H

CH 3

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H

H

H

H

H

H

H

H

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H

COCH3

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H

H H H H H

5-NH2 6-NH2

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4-NHCOCH3 5-NHCOCH3 6-NHCOCH3

C10H10N20 C10H10N20 c1 OH10N20

84-85 (CC14) 185-86 (e/w) 181 154-56 (e) 117-18 170-71 (b) 169 156-60 ( d i s t )

4-NH2

173-74 (e/w) 177-78 C10H12N2

117-18 ( d i s t ) 119-20 (b) 116-18 ( d i s t )

5-NH2

106-07 C10H12N2 HC 1

131-32 (b) 360 ( ? I

H

CH3

H

CH3

H

CH3

CH3

CH 3

C2H5

CH 3

H

C2H5

Table 13 (cont.) 5-NHCOCH3

4-NH2

‘llHlQN2 picrate C11H14N2

7-NH2

CH 3

H

6-NH2

CH3

H

H

H

H

H

H

H

cl 1H12N20 ‘llHllN2

5-NH2 5-NH2

6-NHCOCH

CH3

H

H

H

C11H14N2 C11H14N2

5-N (CH3)

C12H14N20 ‘1 2H1 gN 2 picra te

159-61 (el 127-28 116-18

-

203-05 ( e )

146-48 (sub 148-49 ( d i s t 84-85 96-97 (p)

110-12 ( d i s t 116-117 211-12 ( e )

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200-02 (e)

154-55

‘1 3H 16N2

117-18

4N s C13H16N2 5 - N 3

H

HO

H

n-c4ng

CH3

H

H

'gH5

H

Table 13 (cont.) 4-NH2 5-NH2 5-NH2

1' 3H16N204 C13H18N2 C14H12N2

60 96-98 (di 231-33 (b

191-92 (t

C16H14N20

H

H

5-NHCOC6H5

217-18 ( e )

C15H12N20

H

H

7-NHCOC6H5

166-67 (b

C15H12N20

H

H

H

6 5

H

H

H

H

H

CH 3 CH 3

H

CH3

H

'gH5

H

H

H

CH3

H

H

H

4-NHCOC6H5 5-NHCOC H

6-NHCOC6H5 6-NHCOC6H5

b6

5-NHCOCH3

5-N

H

5-NHCOOC H

H

0

C15H12N20

C16H14N20 picrate

195-96 (e

160-61 ( X ) 151-52

215-16 ( e )

C16H14N20

210 (e)

C16H14N20

C16H1 4N202 17H12N20 2

114-15 211-12 (b

N

ON

zN

N

zm

4

X

x,

rl

d

U

U

d

Pi

0

U

U

A

N Y

m

d

al

0

0 W

rl

In 3:

v)

X

W

W

U

7 x

8X

*

*

u

x

X

r

x

7

-

a

z

n v)

E,

u

xW

N

X

X

X

v)

X

X

KN W

U

ON

ON s

In

xw

2-

U

0

v)

m

s

U

X

W

s

V 0

U

sW

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474

R2

R3

Table 14.

4-,5-,6-and

‘gH10N2

4-CH 2NH2

6-CH2NH2

H

CH3

6-CH 2NHCH

H

H

H

H

n

H

H

H

4-CH 2NHCH

c1OH 12* 2

C10H12N2 CIOHl ZN2

6-CH2NHCH3

CH3

CH3

CH 3

3

7-Indolyl-C-N Derivatives

H

m.~. .OC

X

‘gH10N2

6-CH 2NH2

H

CH3

CH3

CH 3

C11H14N2

5-CH 2NH2

‘llHlQN2

6-CH2NH2

C11H14N2

7-CH 2NH2

C11H14N2

132-34 ( c ) 134-35 ( c ) 90-92 ( c )

120-21 (c) 107-08 ( c ) 133-35 ( c ) 153-55(~yh) 156-58 (et) 117-18 (cyh) 131-32 (cyh)

H

H

H

H

H

H

4-CH2NHCOOC2H5 6-CH2NHCOOC2H5 6-CH2NHCH2CsCH

-a

4-CH 2NH

-4

5-CH2NH 6-CH2NH

-a

H

7-CH2NH

4-CH2NHCH (CH3)

H H

H

5-NH2NHCH (CH3)

Table 14 (cont.) CllH14N202 CllH14N202

84-85 ( c )

89-91 (et)

C12H14N2

96-98 (et)

C12H12N2

C12H14N2 oxalate C12H14N2 hydrogenmaleate C12H14N2 C12H16N2 hydrogenma lea te C12H16N2 hydrogenoxalate

198-99 (m)

-

142-44 (ea) 67-69 (et)

139-40

-

168-70 (m)

H

H

H

H

H

H

7-CH2NHCH (CH3)

H

H

6-CH2NHCH (CH3)

H

H

Table 14 (cont.) C12H16N2 hydrogen-

oxalate

C12H16N2 hydrogen-

maleate

CH3

H

CH3

CH 3

CH3

CH 3

7

3

4-CH2N\ CH2C f CH

C13H14N2

‘1 3H16N202

6-CH2NHCOOC2H5

C13H16N2

CH I 3 6-CH2-NCH2-CH=CH2

C13H14N2

CH I 3 6-CH2NCH2CZ CH

5-CH2N (CH3)

C13H18N2

picrat e HC 1 CH31 6-CH2N (CH3)

C13H18N2

160-63 (m)

122-124 (ac) 60-63 ( e t )

74-76 ( e t ) 78-80 ( e t ) 89-91 (c) 95-96 ( p ) 96-98 195-96 ( e ) 212-14 206-08 ( e t ) 132-33 ( e t )

m

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H

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H

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H H H H H H

YH3 5-CH2CHNH2 CH I 3 6-CH 2CHNH2

OH I 5-CHCH2NHCH3

Table 15 (cont.) ‘11H1QN2 hydrogenoxalate CllH14N2 hydrogenmaleate salts of rac., (+)-and (-)-form:

81-83 (b) 199-201 (m) 138-40 (cI

159-61 (ea) 144-48 (et) 181-84 (b)

5-COCH2N (CH3) CH3 S-C~HNHCH 4-CH2CH2N(CH3)2 C H 12 5 4-CH2CHNH2

C H 12 5 6-CH2CHNH2

‘lZH 14N20 ‘1 ZH16N2 CH 3S0 3H

C12H16N2 C12H16N2 hydrogenmaleate

170-74 (m)

-

148-50 (m) 104-06 (et)

136-39 (ea)

-f

O

ln

ln

.

W 0

*

W *

W

N

W

l n 4

W

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ln

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v)

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zW

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4

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0

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t&

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a

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a m rl

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a

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4J

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c

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m

m

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m

nm m N

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--

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I

m

0

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I

m

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m

I

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4J

rl

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m zP rl

xa 4 V

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o

m

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5 r(

U

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m

0

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h

m

a

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m X

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i!

h

=

m

U

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N

X

zm N

X V

N

m

X V

Y

zN

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-

m

X V

zN

X

v, X

V

bl 0

ru

a

CH2N (CH3)

n

CH2N

W0

COCH-CH2N (CH3) I

-

-

y pyr idyl

CH3CHCH2N (CH3)

0

120

C18H19N30

187-90

C17H2 SN' 3 di-HC1

C18H21N2 dimalea te

CH2CH2NHCOCH3

A

CH-N

-

157 (m)

-

115 (1) 146-47

1' EH2SN3' CH31

265 (ac)

'1BH21N3 di-HC1

C18H25N302 dipicrate

b.p.190-93(0.5 176-78

C18H25N2 b.p.132-34(0.09 dipicratef?) 168-69

C O ~ H C H (~ cN H ~ )

1' EH2 7N '3

m.1 l"I.

18-80

105

'1gH21N3

Y-pyridyl

98 (1) dec. >195

C18H27N30 CH31

CH2CH2NHCOC (CH3)

Y-pyridyl

Y-pyridyl

CH2CH2N (C2H5)

CH2N (CH31

CH2NHCOC6H5

Q Q CH 3

CH3

CH2CH2NH

Y-pyridyl y-pyridyl

CH2N (CH31 CH2CH2 O

C

H

3

CH2CH2NHCOC6H5 CH2N(CH312,

T a b l e 16 (cont.) C19H21N30 di-HC1 ‘1gH21N3’ C19H23N3 di-HC1 C19H27N3

‘1gH2gN3 di-HC1 C20H23N3 d i m a l e at e C20H23N3 di-HC1 C20H23N30

2-CH3

C20H25N3 HC 1 CH31

172 2 4 5 (e) 107(b)

2 2 5 (m)

-

2 1 0 - 1 2 (el

1 6 1( d e c )

-

161 1 0 2 (m)

185-87 121-23 (b)

is

. 4 -I

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m X

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V

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u

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U

x

x

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l

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w

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z

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X

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u

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x

x

s

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x

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Table 1 8 (cont.)

148-50 (t)

1 3 H 17N3’

5-NH2

126-28 (t)

‘1 3H17N3

5-NH2

6-NHCOCH3

6 - N (CH3)

CH2N (CH3)

5-N (CH3)

y 3 CH2CHNH2

C13H17N30 C13H19N3

picrate

CB2CH2N3

=p

‘1 3 H 1gN3

‘1SH21N3 dipicrate

5-NH2

C14H19N3

5-NH2

CH2CH2NHZ

CH2CH2N

C 1 6 H 1SN3’ di-HC1

5-NH2

C19H21N3 dipicrate

169-71

216-17 (ac) 126 ( t ) 90-93 ( t )

211-12 ( e / w )

251-56 (el

215-17 ( d e c )

--

--

0

rl

rl 0

P 0

m

Q,

m

I 4 0

d

E

0

I

I

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(Y

In m X

N v)

V

X

V

xw

v

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V

V 0 V

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v)

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0

X

v)

d

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U

0

%

zN

X

X

V

X

m X

V

m X

V

m

X

V

X

m X U

494

m

d

R1

R1‘

Table 19.

A

H

H

CH2CH2NHCONHCH2CH2

H

H

H

CH-CH2N (CH3)

H

H

H

H

H

H

H H

H

3,3’-di-Indolyl Derivatives

I

R1

R2

H

H

CH2N(CH3)2

CH-CH2NH2

H

CH3

H

C18H17N3 HC 1 ‘20H2 lN3

CH2

CH-CH2NH2

C

‘2 OH2 lN 3

\H / O

‘20H21N3 HC1

m.p. ,OC

162 (e) 210-15 (e) 112 (el

213-15 (el 156 (b) 212-15 (el

210-12 (e/ 218-20

C22H17N3 HCl

159 (el

C21H22N40

C22H17N3 HC 1

155-56 (e/w) 204-05

H H

Table 19 (cont.) C

H/

/G

CHCOOCH2CH2N (CH3)

n

H

CH-CH2N (CH3)

CH3

H

CHCH2N (C2Hs)

H

H

79-80 ( 192-9

C22H23N302 HC1

130 (b 214-15

C22H17N3 HC1

C22H24N4

222 224-2 231 (e

174-7

‘2 2H2 5N3 HC1

202-06

22H2 SN3 HC 1

207 (m

n

H

H

H

CHZN (CH3)

CH2N (CH3)

H

H

H

H

H

CHCOO (CHZ)3N (CH3)

CH 2

H

(CH2)3NHCONH(CH2)

H

CH3

CH

\ /

CH3

C23H2 gN3O2 HC1 2' 3H2gN'4 C23H28N4 C24H21N3

167-68

132-37 124 (e

256 (m

261 (m 190 (d

C24H21N3 HBr

249

HBr

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

CH 3

CH3

H

H

CH 3

C H - 0

C

H

-

0

Table 19 (cont.) C24H21N3 HBr C24H21N3 HC1

CHCOOCH2CH2N (C2H5)

24H2 7N 2'3 HC 1 C24H29N3

CH 3

292 (PY) 227 (dec) 186-88 (b) 224-25

-

204-08 (m) 176-77 (el 181 179 (e) 145-50 (m)

H H H

CH 3

2' gH2gN3'2 HC1

CHCOO(CH2) 3N (C2H5)

2' gH21N3'

CHCH2NHCOC6H5

3

CHCH2N

2' SH2gN3

187-90 195 (b)

128 (e)

172-75 (e) 214 (el 170 (e)

CH3

m m

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m m

X W

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V

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Table 21.

Miscellaneous d i - I n d o l y l Derivatives

-cH*xo R2

R3

CH3

' l g H 1 6N2 HC104

m.p.,

O

-2 3 8

3

CH 3

"

CH3

'sH5

H

-CH

CH3

CH3

C20H18N2 HC104 C21H21N2 c104

-

204

209

CH3

C31H24N2 HC 1

1 2 5 (e)

a P-

W

P-

Q,

-

0

In

I N

0 4

Y

PPI W

0)

Y

0

m

N

ON

z ,N X

dd

m v

u x

N

=W N

xN

m

V

503

m m o m

n n

-2 -2 P

O

I

I

wln w m

w q

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2 2

mr. - l w I I m w 4 w N

4

?

ON

z z 4 ON

4

U

4

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r

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4

4

4

4

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y

v v

I V 4

h

4 0 'D

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ld

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X

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9

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H

H

H

H

H

H

H

H

H

H

T a b l e 22 (cont.)

Qdcc'cH3 -

CH2CH2-

0

C O C H-N>C ~ -

2~

Br

c1

17H17BrN 2'

C17H17C1N20

Br I

214-16 ( 193-98 ( 268-71 260-62 199-200

I

Br

215-17 212-14

c104

156-57 (

c104

188-89

Br

1 9 5 (m)

Br

164

I

143-44 (

I

260-62 (

c104

264-65

H

H

H

H

H

H

H

T a b l e 22 (cont.) C H ~ C H ~ - N ~ C O O C . ~ ~ Br C18H19BrN202 COCH

0

2-@ 08

H

C H 2 C H 2 - N0m

I

C19H151N20

202-03 ( e ) 247-49 (de (W)

'20H171N2' C29H17C1N205

I C104

222-23 (m)

'1gH21BrN2 1 ' gH21I N 2

Br

251-52

C19H191N20

I

C19H19C1N20

c1

C25H19N507

pic

'1gH171N2 C19H17C1N204

C104

211-12 (m)

C H BrN2 19 17 1 ' g H 17'lN2

c1

270-72 ( w )

C19H151N20

I

Br

I

I

1 2 8 (ac)

244-45 (m)

2 2 3 (m) 208 (m) 269-70

218-19 (m) 225-56

(W)

243-44 ( a c )

-

Table 22 (cont.) c1 I C104

pic

F s H 5 C H ~ C H - N ~

H

H

CH 2CH :

H

H

H

H

C104

N

a

OCH3 OCH3

Br I Br I

8

pic

C20H19C1N2 '20H191N2 C20H19C1N204 C26H2 lNS07

C20H23C1N206 C21H21BrN202 C21H2 11N202 2' 2H1 gBrNZ0 2' 2H1 91N2' C23H19N509

192 (m 229 (m 191 (m 234 (m 156-5 219 (m 246-4 199-2 182-8 203-0

W

01

cr;

U

0

4

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m W m

c

h

0 N In

m m

P)

In N

0 rl

N

Om

ON

zO

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In

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Table 2 3 (cont.)

H

H

C13H14N2

H

CH3

C13H14N2

7-cn3


4-CH3

13 H 1qN 2

2 2 1 - 2 3 (m)

1 6 5 - 6 7 (b) 1 1 9 - 2 0 (etl

144-46

cHQ

H

H

&AH3

H

C13H14N2

CH 12 5 CH=N-CH2CHOH

C13H16N20

COCH

C14H14N20

CH31

H

a

C

2

H

5

H

C14H16N2 HC1

1 9 6 - 9 7 (ip

169 (ea) 1 8 5 - 8 6 (b) 217-19

218-19 ( m )

0

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T a b l e 24 ( c o n t . )

217-19

C21H26N202 HC 1

CH3

208

C21H26N2 HC 1

CH 3

Cii3

CH2CH2N (CH2CH=CH2)

H

H

-

C H N b.p.150-54(0.05 23 26 2 HC1 165-66 CH3S03H 118

-

178

HC1

87 ( P )

C26H28N2

‘sH5

C6H5

235-36 (ea)

C24H30N2 HC 1

‘sH5

CH3

‘sH5

‘sH5

‘gH5

CH3

‘gH5

CH3

CH 1 3 CH2CH2N-CH2CH=C (CH3)

H

C22H26N2 HC1 C23H28N2 hydrogen-

maleate

C24H24N2 HC1

240-44 (m)

1 4 1 tea)

-

206-08

-

W

In

In lIn

In

cow

cow

w w

m W

w w

* *

w

w

v

1

i

i

.-

w

0

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old

rl

I

0

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0

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el-

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7 2

N r l

I

I

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d N

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2

X d

wm

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X

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CH3 CH3

Table 2 4 (cont.)

y 3 CH2CHZN-CH2CH2C6H5

A CH2CH2Nd6H5

H

CHZCH2N

CH3

CH3

H

OCH3

-

C26H28N2 oxalate 200-10 C27H29N3 b.p.225-30(0.05tnm) HC 1 242 (ea)

H

CH3

C28H28N2 b.p.220-240(0.04tnm) HC 1 216-17 (ea)

H

CH 3

CH2CH2N

CH3

C28H30N2 b.p.210-20(0.05mm) 188-90 (m) HC 1 CH3S03H 235’36 (ea) maleate

169-70

C29H32N2 b.p.230-32(0.02mm) HC 1 218 (ea) hydroqenmaleate 181-82 (ea) oxalate 229-31 (m) C29H32N20 CH3S03H

-

213 (m)

R2 CH 3

P R

3

=NCH (CH

)

T a b l e 25.

H

X

3- (=RN)-3H-Indoles

m.p.,

C12H14N2

1' 3H1 3FN2

5-F

H

1' 3"13'lN2

5-C1

n

4-C1

H

5-Br

H

I

b.p.60(0.1

OC

mm.)

207-10 (m)

H

H

169-72 (m)

1' 3H1 3'lN2

219-21 (m) 211-13 (m/w) 226-31 (e) 252-54 302-04 (w) 293-96 (m)

C13H14N2 CH31 HI

'14

H

C14H10N2

H

112-15 123-25 (m/w)

H1gN 2

0

0 N

N

W

W

0

N

W

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521

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530

Chapter Vf

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504a. 505.

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J. Thesing and G. Semler, Justus Liebgs Atin. Chem., 680, 52 (1964). J. Thesing and F. Schiilde, Chenz. Ber., 85, 324 (1952). J. Thesing and C. H. Willersinn, Chem. Ber., 89, I195 (1956). Dr. Karl Thomae, GmbH, British Patent 1,093,912 (1964). Dr. Karl Thomae, GmbH, Belgian Patent 693,450 (1900). Dr. Kafl Thomae, GmbH, British Patent 1,111,489 (1965); Cheni. Abstr., 69, 51996 (1968). 560. G. Thuillier, P. Rumpf, and J. Thuillier, C. R. Acad. Sci., Paris, 250, 1674 (1960). 561. A. F. Torralba and T. C. Myers, J. Org. Chetn., 22,972 (1957). 562. F. Troxler, Helu. Chint. Acra, 51, 1214 (1968). 563. F. Troxler, G. Bormann, and F. Seemann, Helc. Chim.Acra, 51, 2031 (1968). 564. F. Troxler, A. Harnisch, G. Bormann, F. Seemann, and L. Szabo, Helu. Chim.Acra, 51, 1616 (1968). 565. F. Troxler and A. Hofmann, Hell.. Chim. Acra, 40, 1706 (1957). 566. F. Troxler, F. Seemann, and A. Hofmann, Hell,. Chim. Acra, 42, 2073 (1959). 567. F. Troxler et at., unpublished results. 567a. S. V. Tsukerman, V. M. Nikitchenko, A. I. Bugai, and V. F. Lavrushin, Khim. Ceterorsikl. Soeditr, 1969, 268. 568. V. E. Tyler and D. Groger, flanra Med., 12, 397 (1964). 569. V. E. Tyler and D. Groger, J. fhartn. Sci.,53,462 (1964). 570. Upjohn Co., U.S. Patent 2,804,462 (1957); Chern. Absfr., 51, 18006 (1957). 571. Upjohn Co., U.S. Patent 2,821,532 (1958); Chem. Ab.sfr., 52, 10203 (1958). 572. Upjohn Co., U.S. Patent 2,825,734 (1958); Chem. Absfr., 52, 12923 (1958). 573. Upjohn Co., U.S. Patent 2,870,162 (1959); Chem. Absrr., 53, 6250 (1959). 574. Upjohn Co., U.S. Patent 2,944,055 (1960); Clienr. Abstr., 55, 18779 (1961). 575. Upjohn Co., U.S. Patent 2,984,670 (1961); Cheni. Absfr., 55, 25984 (1961). 576. Upjohn Co., U.S. Patent 3,133,083 (1962); Cheni. Abstr., 61,4319 (1964). 577. Upjohn Co., U.S. Patent 3,214,438 (1963); Chetn. Absrr., 64. 3490 (1966). 578. Upjohn Co., British Patent 781,390 (1957); Chem. Absrr., 52, 3866 (1958). 579. Upjohn Co., British Patent 809,795 (1959); Chem Abstr., 53,9249 (1959). 580. Upjohn Co., British Patent 886,684 (1957); Cheni. Ahsrr., 57, 7234 (1962). 581. Upjohn Co., British Patent 1,036,413 (1962). 582. Upjohn Co., Netherlands Patent 6,505,983 (1964); Chem. Absrr., 64, 12646 (1966). 583. E. V. Vinogradova, Kh. Daut, A. N. Kost and A. P. Terent'ev, J. Gen. Chem. USSR (Etylish Trans/.),32, 1536 (1962). 584. E. V. Vinogradova, V. N. Mitropolskaya, A. N. Kost, and A. P. Terent'ev, Proc. Akad. Sci. USSR (English Tratisl.), 144, 521 (1962). 585. Z. J. Vejdtlek, Collect. Czech. Chem. Cornmun., 22, 1852 (1957). 586. L. Velluz, G. Muller and A. Allais, C. R. Acad. Sci.,Paris, 247, 1746 (1958). 587. P. Wagner, Justus Liebigs Anti. Cheiir., 242, 383 (1887). 588. G. N. Walker, J. Anter. Chetn. Soc., 77, 3844 (1955). 589. G. N. Walker and M. A. Moore, J. Org. Chem., 26,432 (1961). 590. A. Walser and C. Djerassi, Helu. Chim. Acta, 47, 2072 (1964). 591. E. Walton, F. W. Holly, and S. R . Jenkins, J. Org. Chem., 33, 192 (1968). 592. Warner-Lanibert Pharmaceutical Co., U.S. Patent 3,037,031 (1959); Chem. Absfr., 57, 12439 (1962). 593. Warner-Lambert Pharmaceutical Co., U.S. Patent 3,359,273 (1965); Chem. Abstr., 69,2872 (1968). 594. H. H. Wasserman and H. R. Nettleton, Tefrahedrori L e f f . ,1960, (7), 33. 595. S. Wawzonek and M. M. Maynard, J. Org. Cheni., 32, 3618 (1967). 596. J. S. Weisbach, E. Macko, N. J. DeSanctis, M. P. Cava. and B. Douglas, 1. Med. Chetn., 7, 735 (1964). 554. 555. 556. 557. 558. 559.

536

C h a p t e r VI

597. J. A. Weisbach, K. R. Williams, N. Yim, J. L. Kirkpatrick, E. L. Anderson, and B. Douglas, Chem. fnd. (London), 1966, 662. 598. W. 1. Welstead Jr., J. P. DaVanzo, G. C. Helsley, C. D. Lunsford, and C. R. Taylor, Jr.,J. Med. Chem., 10, 1015 (1967). 599. E. Wenkert and B. Wickberg, J. Amer. Chem. Soc., 87, 1580 (1965). 599a. E. Wenkert, K. G. Dave, and F. Haglid, J . Amer. Chem. Soc., 87,5461 (1965). 599b. E. Wenkert, K. G. Dave, F. Haglid, R. G. Lewis, T. Oishi, R. V. Stevens, and M. Terashima, J. Org. Chem., 33, 747 (1968). 600. B. A. Whittle and E. H . P. Young, J. Med. Chem., 6, 378 (1963). 601. H. Wieland, W. Konz, and H. Mittasch, Justus Liebigs Ann. Cheni., 513, I (1934). 602. H. Wieland and Th. Wieland, Justus Liebgs Ann. Chem., 528, 324 (1937). 603. Th. Wieland and Chi Yi Hsing, Justus Liebgs Ann. Chem., 526, 188 (1936). 604. S. Wilkinson, J . Cheni. SOC.,1958, 2079. 605. E . Winterfeldt, Chem. Eer., 97, 2463 (1964). 606. E. Winterfeldt and J. M. Nelke, Chern. Eer., 101, 3163 (1968). 607. R. B. Woodward, M. P. Cava. W. D. Ollis, A. Hunger, H. U. Daeniker, and K. Schenker, Tetrahedron, 19, 247 (1963). 608. D. W. Woolley, Biochem. Pharmucol., 3, 5 1 (1960). 609. D. W. Woolley and E. Shaw, J. Pharmacol. Exp. Ther., 121, 13 (1957). 610. H . C. Wormser and S. Elkin, J . Pharm. Sci., 50,976 (1961). 611. W. B. Wright and H. J. Brabander, J . Med. Chem.. 11, 1164 (1968). 612. H . Yamamoto, S. Inaba, T. Hirohashi, and K. Ishizumi, Chem. Eer., 101, 4245 (1968). 613. F. Yoneda, T. Miyamae, and Y. Nitta, Chem. Pharm. BUN.(Tokyo), 15, 8 (1967). 614. Yoshitomi Pharmaceutical Industries, French Patent 1,477,152 (1965); Chem. Absrr., 68, 29609 (1968). 615. Yoshitomi Pharmaceutical Industries, Japanese Patent 2708/67; Chem. Absfr., 67, 73520 (1967). 616. Yoshitomi Pharmaceutical Industries, Japanese Patent 18901/68; Chenr. Absrr. 70, 68168 (1969). 617. Yoshitomi Pharmaceutical Industries, Netherlands Patent 6,703,422 (1967). 618. E. H. P. Young, J. Chem. Soc., 1958, 3493. 619. D. V. Young and H . R. Snyder, J. Amer. Chem. Suc., 83, 3160 (1961). 620. G. A. Youngdale, D. G. Anger, W. C. Anthony, J. P. DaVanzo, M. E. Greig, R. V. Heinzelman, H. H. Kaesling, and J. Szmuszkovicz, J. Med. Cheni., 7 , 415 (1964). 621. N. K. Yurashevskii, J . Cen. Cherri. USSR, 11, 157 (1941). 622. H. Zinnes, F. R. Zuleski, and J . Shavel, J. Org. Chem., 33, 3605 (1968). 623. American Cyanamid Co., U.S. Patent 3,494,920 (1966). 624. American Cyanamid Co., U.S.Patent 3,444,174 (1966). 624a. D. E. Ames and B. Novitt, J. Chenz. SOC.,C , 1970, 1700. 625. F. Andreani, R. Andrisano, C. Della Casa, and M. Tramontini, J . Chenr. Soc., C, 1970, 1157. 626. A. S. Bailey, M. C. Chum, and J . J. Wedgewood, Tetrahedron Lett., 1968, 5953. 626a. A. S. Bailey, R. Scattergood, W. A. Warr, T. S. Cameron, C. K. Prout, a n d I. Tickle, Tetrahedron Left., 1970, 2979. 627. A. S. Bailey, W. A. Warr, G. B. Allison, and C. K. Prout, J. Chem. SOC.,C , 1970, 956. 628. P. A. Bather, J. R. L. Smith, R. 0. C. Norman, and J. S. Sadd, Client. Comznun., 1969, 1116. 628a. V. H. Brown, W. A. Skinner, and J. J. DeGraw, J. Heterocycl. Chem., 6,539 (1969). 628b. R. N. Castle, Topics irz Heterocyclic Chemistry, Wiley, New York, 1969, pp. 206ff. 629. M. Cohen, Terruhedroii Letf., 1970, 2165.

Chemistry of lndoles Carrying Basic F u n c t i o n s

537

630. M. Colonna and P. Bruni, Bull. Sci. Fuc. Chim. Ind. Bulogna, 23, 401 (1965). 631. M. Colonna and L. Greci, Gazz. Chirn. Ira/., 99, 1264 (1969). 632. J. A. Deyrup, M. M. Vestling, W. V. Hagan, and H. Y.Yun, Tetrahedron, 25, 1467 (1969). . 35, 1493 (1970). 633. L. J. Dolby and R. M. Rodia, J. 0 ~ q Chem., 633a. Dow Chemical Co., U.S. Patent 3,471,488 (1967). 634. 0. Eichele and E. Mutschler, Arch. Pharm., 302, 741 (1969). 635. Farbenfabriken Bayer A. G . . French Patent 1,561,663 (19 ). 635a. H . L. Finkbeiner and M. Stiles, J. Amer. Chem. Soc., 85,616 (1963). 635b. E. M. Fry and J. A. Beisler, J. Org. Chem., 35, 2809 (1970). 636. R. G. Gluskov, V. A . Volskova, N. P. Kostjufenko. Ju. N. Seinker, and 0. Ju. Magidson, Khircr. Geterutsikl. Soedin., 1970, 277. 636a. I. 1. Grandberg, N. 1. Afonina, and T. 1. Zujanova, Khim. Geferotsikl. Soedin., 1968, 1038. 637. M. Hamana and I. Kumadaki, Chem. Pharm. Bull. (Tokyo), 15,365 (1967). 638. R. L. N. Harris, Tetrahedron Leu., 1969, 4465. 639. J. B. Hendrickson and W. A. Wolf, J. Org. Chem., 33, 3610 (1968). 640. T. Hino, M. Nakagawa, T. Hashizume, N. Yamaji, and Y. Miwa, Tetrahedron Lert., 1970, 2205. 641. T. Hino, K. Tsuneoka, and S. Akabori, Cheni. Pharrn. Bull. (Tokyo), 18,389 (1970). 642. Huang-Hsinmin and F. G. Mann, J. Cheni. Soc., 1949, 2903. 642a. Ju. P. Kitaev, T. V. Troepol'skaja, and A. E. Arbuzov, 2. Obshch. Khini., 34, 1835 (1 964). 643. A. N. Kost, R. S. Sagitullin, V. N. Gorbunov, and N. N. Modjanov, Khim. Geferotsik 1. Soediti ., 1970, 359. 644. K. 1. Kuchkova, A. A. Semenov, and I. V. Terent'eva, Khim. Geterotsikl. Soedin., 1970, 197. 644a. I. I. Lapkin and Yu. P. Dormidontov, Chem. Heferocycl. Comp. USSR, 3,678 (1967). 645. F. G. Mann and R. C. Haworth, J . Chem. Suc., 1944, 670. 646. Merck & Co., U.S. Patent 3,501,465 (1967). 647. Miles Labs., Deutsch. Offenlegungsschrift (DOS) 1,901,637 (1969). 648. L. M. Orlova, M. N. Preobrairnskaja, K. F. Turzin, Z. Starostina,and N. N. Suvorov, Zh. Org. Khim., 5 , 738 (1969). 649. S. Pietra and G. Casiraghi, Guzz. Chini. ltul., 100, 128 (1970). 650. P. Rosenmund, D. Sauer, and W. Trommer, Chem. Ber., 103,496 (1970). 651. J. Schmitt, M. Langlois, and C. Perrin. Bull. Soc. Chirn. Fr., 1969, 1234. 652. J. Schmitt, C. Perrin, M. Langlois, and M. Suquet, Bull. Soc. Chim. Fr., 1969, 1227. 653. H. Schubert, F. Fohringen, and H . Noack, Z. Chenr., 10, 68 (1970). 654. K. N . Schut, F. El. Ward, 0. J. Lorenzetti and E. Hong, J. Med. C'hem., 13, 394 (I 970). 654a. D. A. Scola, D. V. Lopiekes and H. R. Dipietro, J. Chem. Oig. Dafa,14, 1 I I (1969). 655. D. A. Shirley and P. A. Roussel, J. Amer. Chem. Soc., 75, 375 (1951). 655a. V. 1. Shvedov, L. B. Altukhova, L. A. Chernyshkova, and A. N. Grinev. J. Org. Chem. USSR, 5 , 2158 (1969). 656. Sterling Drug, French Patent 1,551,082 (1968). 656a. M. Stiles and H. L. Finkbeiner, J. Amer. Chem. Soc., 81, 505 (1959). 657. E. R. Squibb & Sons, U.S. Patent 3,445,479 (1966). 658. Sumitomo Chemical Co., Deutsche Offenlegungsschrift (DOS) 1,814,332 (1968). 659. Sumitomo Chemical Co., Deutsche Offenlegungsschrift (DOS) 1,935,671 (1969). 660. J. Thesing, H . Uhrig, and A. Muller, Angew. Chem., 67, 31 (1955). 661. L. A. Cohen, J. W. Daly, H. Kny, and B. Witkop, J. Attier. Chem. Soc., 82, 2184 ( 1960). 662. C. J. Cattanach, A. Cohen, and B. Heath-Brown, J. Cheni. Soc., C, 1971, 359.


CHAPTER V11

Oxidized Nitrogen Derivatives of Indole and Indoline KENT RUSH Eastmag Kodak Company, Research Laboratories, Rochester, New York 14650

540 I. Nitroso Derivatives. . . . . . . . . . 540 A. Nitrosoindoles . . . . . . . . . . 544 B. Nitrosoindolines . . . . . . . . . 545 11. Nitro Derivatives . . . . . . . 545 A. Indoles and Indolines with Nuclear Nitro Groups . . . . 545 I . Nitroindoles . . . . . . . . . . 545 a. Preparation . . . . . . . 545 (I). Nitro Derivatives of Indole . . . . . . 547 (2). Nitro Derivatives of Alkyl- and Arylindoles . . . 547 (a). Cyclization of Nitrophenylhydrazones . . . 548 (b). Nitration of Alkyl- and Arylindoles . . . 554 (c). Dehydrogenation of Nitroindolines. . . . (3). Nitro Derivatives of Gramine and Tryptophan . . 554 (4). Nitro Derivatives of Indoles Containing Electronegative sub555 . . . . . . . . stituents . 558 b. Reactions. . . . . . . . . 558 c. Useful Compounds . . . . 559 2. Nitroindolines . . . . . . . . . 559 a. Preparation . . . . . . . . 560 b. Reactions. . . . . . . . . . B. Indoles and Indolines with Side-Chain Nitro Groups . . . 560 560 I. Preparation . . . . . 560 a. 3-(2-Nitroalkyl)indoles . . . . . 563 b. (2-Nitroviny1)indoles . . . . . . . 564 c. 2- and 3-(Nitrophenyl)indoles . . . . . . 565 2. Reactions . . . . . . . . . 111. Azo and Azoxy Derivatives . . . . . . . 567 567 A. Azo Derivatives. . . . . . . 561 1 . Azoindoles . . . . . . . . 2. Azoindolines. . . . . . . . . 572 B. Azoxy Derivatives . . . . . . 573 .

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540

Chapter VII

Diazo Derivatives . . . . . . Azides . . . . . . . Imino Derivatives . . . . . . . . Isocyanates and lsothiocyanates . Tables of Compounds . . . . . . Table I. Nitroso- and Oximinoindoles and -indolines . . . A. Nitrosoindoles . . . . . . B. 3-Oximino-3H-indoles . . . . . C. Nitrosoindolines . . . . . D. Miscellaneous . . . . . . . . Table 11. Nitroindoles and -indolines . . A. Indoles and Indolines with Nuclear Nitro Groups . 1. Mononitroindoles and Alkyl and Aryl Derivatives . . 2. Mononitroindoles Containing Halogen . 3. Mononitrogramines and Alkyl Derivatives . . 4. Mononitrotryptamines and Alkyl Derivatives . . 5 . Nit ro-2,3,3-t rimethyl-3H-indoles . , . 6. Dinitroindoles . . . . . . . . 7. Trinitroindoles . . . . . . 8. Nitroindolines . . . . . . B. Indoles and Indolines with Side-Chain Nitro Groups . . 1. 3-(2-Nitroalkyl)indoles . . . . . . . 2. (2-Nitroviny1)indoles . . . . . 3. 2- and 3-(Nitrophenyl)indoles . . . . . 4. 2-(Nitrobenzylidene)-l,3,3-trimethylindolines . 5. Other Hydrogenated Indoles with Side-Chain Nitro Groups Table 111. Azo- and Azoxyindoles and -indolines . A. Azo- and Hydrazonoindoles . . . 1. 3-Arylazoindoles . . . . . . . . 2. 3-Aryl hydrazono-3H-indoles . . . . . 3. 3.3’-Azobisindoles . . . 4. 3,3-Dialkyl-2-hydrazonomethyl-3H-indoles . . . 5. 2-Hydrazonomethyl-l,3,3-trimethyl-3H-indolium Salts . B. Azoindolines . . . . 1. Arylazoindolines . . . . . . . . 2. 2-Arylazomethylene-l,3,3-trialkylindolines . . C. Azoxyindoles . . . . . . . . . Table IV. 3-Diazo-3H-indoles * . . . . . Table V. 3-Imino-3H-indoles . . . . . . . References . . . . . . . . IV. V. VI. VII. VIII.

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573 575 575 5 76 577 577 577 578 578 579 580 580 580 583 584 585 586 587 587 588 589 589 59 1

593 593 594 594 594 594

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595 596 596 597 597 597 598 598

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I. Nitroso Derivatives A. Nitrosoindoles The reactions of indoles and substituted indoles with nitrous acid and other nitrosating agents were the subject of many early These

Oxidized Nitrogen Derivatives of Indole and lndoline

54 1

reactions are typical of other electrophilic reactions of indoles, the preferred position of attack being Position 3. If this position contains a substituent other than hydrogen, attack occurs at Position 1. The 1-nitrosoindoles and 3-nitrosoindoles that contain a substituent other than hydrogen in Position 1 exist in the true nitroso form (1 and 2, respec-

NO

R 2

1

3

tively). However, the 3-nitroso derivatives of indole and most 2-substituted indoles that contain hydrogen in Position 1 exist in the tautomeric isonitroso or oxirnino form (3). This structure has been supported by many workers.', lo Convincing evidence for this structure was obtained by Campbell and Cooper,ll who showed that large differences exist between the electronic spectra of the nitroso derivatives of 2-phenylindole and 1-methyl-2-phenylindole, the latter of which must be a true nitroso compound. It has been proposed that 2-t-butyl-3-nitrosoindoles are true nitroso compounds rather than oximino compounds.12This proposal is based upon differences between the N-0 stretching frequencies in the infrared spectra of the nitroso derivatives of some 2-methylindoles and the corresponding 2-t-butylindoles. The reaction of indole with nitrous acid is complex. In addition to 3oximino-3H-indole (4), indole red (5) and 6 are ~btained.'"'~ Compound 4

5

3

A0

H

6

is obtained as the sole product by the action of amyl nitrite and sodium ethoxide on ind01e.'~.l8 Compound 5 has also been obtained by the action of tetranitromethane on ind01e.'~

542

Chapter V11

The reaction of 1-methylindole with nitrous acid has not been reported. Reaction of 2-methylindole with nitrous acid in acetic acid is reported to give 2-methyl-3-oximino-3H-indole (7),1° but other workers20-22failed to isolate

7: R 8; K

-

=

C'H, CJI,j

any crystalline product. Compound 7 can be prepared in high yield by the action of amyl nitrite and sodium methoxide on 2-methylindole4*2o at 0°C. If this reaction is conducted in ether at room temperature, both nitrosation and oxidation occur, and the yield of 7 is reduced.23Reaction of nitrous acid with 3-methylindole (skatole) gives 1-nitros0-3-methylindole.~~~ 24 3-0ximino-2-phenyl-3H-indole (8) is obtained in high yield by reaction of 2-phenylindole with nitrous acid in acetic acid,'. 21. 25 with an alkyl nitrite alone,", 26 in the presence of sodium ethoxide,4 or by reaction of 3-0x0-2phenyl-3H-indole with h y d r o ~ y l a m i n e . ' The ~ ~ ~ reaction ~ of 2-phenylindole with alkyl nitrites is quantitative and has been proposed as a method for detection of small quantities of nitritesz6 It is reported that reaction of 2(4-toly1)indole and 2-(4-phenylyl)indole with nitrous acid in acetic acid gives I-nitroso derivatives,z* but these are probably 3-oximino derivatives. Reaction of 1-ethyl-2-phenylindole and 1,2-diphenyIindole with nitrous acid in acetic acid gives the expected 3-nitroso derivative^.^^ Under these

conditions, 1,2-dimethylindole and 2-methyl-1-phenylindole react with 2 moles of nitrous acid to give the corresponding 2-oximinomethyl-3-nitroso derivatives (Eq. This reaction probably proceeds by initial nitrosation of Position 3, which results in activation of the 2-methyl group toward attack by nitrosonium ions. This mechanism is supported by the fact that under these conditions, 2,3-dialkylindoles give only the I-nitroso derivatives.lO, 28. 30


543

The orientation rules given below for the reactions of alkylindoles and aralkylindoles with nitrous acid have been proposed by Verkade, Lieste, and Warner.'O I . indoles containing 3- or 2- and 3-substituents give I-nitrosoindoles. 2. Indoles containing 2-substituents give 3-oximino-3H-indoles. 3. Indoles containing 1 - and 3-, or 1-, 2-, and 3-substituents do not react.

There are exceptions to these rules; for example, 1,2,3-trimethylindole reacts in an unknown manner. Reaction of the indole with nitrous acid in acetic acid is the preferred method for the preparation of true nitrosoindoles. The 3-oximino-3H-indoles are best prepared by reaction of the indole with amyl nitrite in ethanol containing sodium ethoxide. Reaction of 2-r-butylindoles with excess nitrous acid in acetic acid gives good yields of 3-pivaloylindazoles (9) (Scheme 1).l2 With 1 or 3 equiv. of

yp= ! 0

.lNal\iOl

" w C ( c H 3 ) 3

K'

K':

H

CH,('O,kI

~

-C(CH3 3

\

N"

py,:,,

K2 N O

I R'QT:&3)s R'.

H, CH

11

xs NANO?

c H,CO, H

I N;INO* CH,C02H

xs KaNO, R ' Q - q - L m d 3 CHK@H

lt?

K'

H

10

/''pq

NO'

0 k 1 , g p C ~ ; ~ - C (IIC H 3 ~ 3 NH,

N/N H 9

jl.0

K?

'

0

II CH -c -C ( CH3) 3

HhO,

K'

12

Nr

t

Scheme 1

nitrous acid, 10 or 11 is obtained. No mechanism was proposed for forming 9, but i t is conceivable that the first step is hydrolysis of the oximino form of 10 to intermediate 12. Cyclization probably does not occur by loss of water

Chapter VII

544

from 12, since this path would not explain the need for excess nitrous acid. It seems more likely that diazotization of the amino group in 12 occurs, followed by loss of a nitrosonium ion and tautomerimtion. The 3-oximino-3H-indoles undergo the usual reactions of oximes, such as alkylationl and acylation.J*l1 Reduction of 3-nitrosoindoles and 3-oximino3H-indoles either chemically (Na2S,0,)18 or catalytically (H2/Pt0,)31 yields 3-aminoindoles. Oxidation of 3-oximino-2-phenyl-3H-indolewith nitric Treatment of 3-oximino-2-phenylindole acid gives 3-nitr0-2-phenylindoIe.~~ with phosphorus pentachloride gives some 4-oxo-2-phenyl-3,4-dihydroquinazoline (13), but the major product is 14, which probably results from hydrolysis of a tautomer of 13 during ~ o r k u p .34~ ~ . 0

13

14

Condensation of l-alkyl-2-aryl-3-nitrosoindoles with heterocyclic methiodides containing active methyl groups gives cyanine dyes which are useful 33 (Eq. 3). photographic desensiti~ers~~~

CjIJKI; 1

+

H,$cJQ I

c H,

10

C.1l.h A

@IT:,&:: 1 . l l Q l

+

(3)

&@

I

ar.,

CH3@

I@

B. N itrosoi ndol i nes

lndoline and the 2- and 3-alkylindolines, as typical secondary arnines, react with nitrous acid to give l-nitrosoindolines.a The use of sodium nitrite in 80% sulfuric acid gives quantitative yields.35Reaction of l-methylindoline with butyl nitrite in ether followed by dry HCl is reported to give 1-methy1-5-nitro~oindoline.~~ The 1-nitrosoindolines undergo reduction with zinc and acetic acid3j*37 to give the corresponding hydrazines. Treatment with alcoholic HCI effects (Scheme 2). rearrangement to 5-nitro~oindolines~~

m,,,,

WoNlQJa HCI

AcOtl

I

N H:

I

NO

Scheme 2

I

H

Oxidized Nitrogen Derivatives of lndole and Indoline

545

11. Nitro Derivatives A. Indoles and Indolines with Nuclear Nitro Groups

1. Nitroindoles a. PREPARATION. (1). Nitro Deriuatives of Indole. The direct nitration of indole in acidic media yields only intractable tars. This is probably due either to acid-catalyzed polymerization of indoleY3* decomposition initiated by oxidative attack at the 2,3-doubIe bond, or both. Neither 1-nitroindole nor 2-nitroindole has been prepared. Nitration of indole with ethyl nitrate in the presence of sodium ethoxide yields 3-nitroindole (15).39Decarboxylation of 3-nitroindole-2-carboxylica ~ i d , ~which O is obtained by nitration of indole-2-carboxylic acid in nitric acid also gives 15 (Scheme 3).

CJJ -QJc2tl;,oNo~

Hi

NO2

~

yo

0

'

Q 7 N O 2

quinoline

HI

15

HI

COpH

Scheme 3

The preparation of 4,5-, 6-, and 7-nitroindole has been achieved by cyclization of the nitrophenylhydrazonesof ethyl pyruvate in polyphosphoric acid, followed by hydrolysis and decarboxylation of the resulting ethyl nitroindole-2-carbo~ylates~~ (Scheme 4).

( I ) OH(1)ti* (3) CuO, quinoline

chlornnil or

Pd. c'

XJ lenc

I H 5- o r 6-isomer

I

H Scheme 4

Chapter VII

546

The m-nitrophenylhydrazone of ethyl pyruvate gives upon cyclization a mixture ofethyl-4-nitroindole-2-carboxylate and ethyl 6-nitroindole-2-carboxylate, which can be separated by fractional crystallization. A better method for the preparation of 5- and 6-nitroindole is dehydrogenation of 5- and 6n i t r o i n d ~ l i n e , ~respectively ~-~~ (Scheme 4), which are prepared in high yield by nitration of indoline (Section II.A.2.a). Decarboxylation of 6-nitroindole3-carboxylic acid also gives 6-nitr0indole.~~ Nitration of the N-acetyl derivstive of the indole-sodium bisulfite addition product gives, after basification, 5-nitroindole plus a small amount of 7-nitroindole4’ (Scheme 5).

Q&o:N ,a

I H ti

( I ) 0 ’ . HNO, f

I H

tI,SO,

(2) OH

COCH,

5- and 7-isoinrrr

Scheme 5

The preparation of 3,4-, 33-, and 3,7-dinitroindole has been achieved by nitration of ethyl 4-nitroindole-2-carboxylate,ethyl 5-nitroindole-2-carboxylate, and ethyl 7-ni troindole-2-carboxylate, respectively, followed by hydrolysis of the resulting dinitroesters and decarboxylationJO(Scheme 6).

I

/

H

I

H Scheme 6

I

H


547

The second nitro group was shown to be in Position 3 by comparison of the ultraviolet (uv) spectra with those known to have Position 3 occupied, bzalkyldini troindoles, and by nuclear magnetic resonance (nmr) spectroscopy. Attempts to prepare 3,6-dinitroindole by this method were unsuccessful. This compound can be prepared by nitration of 6-nitroindole-3-carboxaldehyde in nitric acid, which results in displacement of the 3-formyl group by a nitro group (Eq. 4). The attempted preparation of 5,7-dinitroindole by dehydrogenation of 5,7-dinitroindoline was u n s u c c e s s f ~ l . ~ ~

H

H

Reaction of I-acetyl-5-nitroindoline with fuming nitric acid gives 3,5,7trinitroindole, which is believed to form by 7-nitration, followed by oxidation to the indole and then 3-nitrati0n.~"

(2). Nitro Dericatires of Alkyl- and Arylindoles. (a). CYCLIZATION OF NITROPHENYLIIYDRAZONES. The Fischer cyclization of dialkylketones and aralkylketones to give nitroindoles of general structure 16 has been the subject of many investigation^.^^-^^ Cyclization of 2- and 4-nitrophenylhydrazones gives 5- and 7-nitro isomers of 16, respectively, while 3-nitrophenylhydrazones give mixtures of the 4- and 6-nitro isomers of 16, which can be separated chromatographically or by fractional crystallization. Although many different acidic catalysts have been used, concentrated hydrochloric acid and polyphosphoric acid appear to give the best results.54 A noteworthy exception to this general procedure is the attempted preparation of 2-methyl-5-nitroindole from acetone 4-nitrophenylhydrazone, which has not been successful under any condition^.'^ Nitrophenylhydrazones of aldehydes can be cyclized successfully only in two-phase systems such as concentrated hydrochloric a ~ i d - - b e n z e n e112*113 . ~ ~ ~ Extraction into the organic phase of the nitroindole as it forms prevents its acid-catalyzed destruction. The many alkyl- and arylnitroindoles prepared by the Fischer indole synthesis are listed in Tables II.A.1 and 1I.A.2. The structures of indoles having the general structure 16 have been proved by oxidative degradation to 2-acylamidonitroacylphenones(17; R', R2 = alkyl or aryl)"*-56 (Scheme 7). If R2 is hydrogen in 16, the degradation product is an N-acylnitroanthranilic acid (17; R2 = OH).19,57. s" The preferred reagents for oxidative degradation are chromic acid in acetic acids5. 56. 5 8 and potassium permanganate in either aqueous alkaline solution57or acetic acid.57,j9

Chapter VII

548

/

1

H

I 16 H

0 II

C--R' N-C-R'

I

II

H O 17 Scheme 7

The preparation of a few 2,3-dialkyl-5,7-dinitroindolesby cyclization of dialkylketone 2,4dinitrophenylhydrazones in glacial acetic acid-sulfuric acid is reported.s4 OF ALKYLAND ARYLINDOLES. The nitration of indoles (b). NITRATION containing vacant 2-positions does not give well-defined products i n acidic media. I n d ~ l e ,l-methylindole,60 ~~ 3-methylind01e,~~* j8 and 1,3-dimethylindolej8 give only high melting amorphous polymers upon treatment with concentrated nitric acid, either alone, in acetic acid, or in sulfuric acid. These polymers presumably result from the initial oxidative attack at Position 2 or at the 2,3-double bond, which are known to be susceptible to this type of attack.61.62 The 2-alkyl- and 2-arylindoles and their alkyl derivatives undergo smooth nitration with nitric acid in sulfuric acid at 0".Nitration of2-niethylindole,~58* 63

Oxidired Nitrogen Derivatives of lndole and Indoline

549

2-phenylind0Ie,~~ I .2-diniethylindole,~~ 2,3-diniethylindole,'@, and 1,2,3trimethylind~le'~ by this procedure gives only the 5-nitro derivatives. usually in high yields. The mechanism by which this reaction proceeds involves nitration of the protonated form (18) of the indole (Scheme 8). This mechanism is supported by the following observations: ( I ) Ultraviolet65* and nmr66. 07 spectroscopy show that 2-alkylindoles are protonated at Position 3 in sulfuric acid solutions; (2) ultraviolet spectra show that 2-phenylindoles are completely protonated at Position 3 in concentrated sulfuric acid and, significantly, that under this condition Position 5 becomes the conjugated position6*; and (3) nitration of 2,3,3-trimethyl-3H-indole (19)19and 1,2,3,3tetramethyl-3H-indolium sulfate (20)6@with nitric acid in sulfuric acid at 0" gives the 5-nitro derivatives. in sulfuric acid. 19, which is a stronger base than 2-alkylindoles and would be protonated on nitrogen, and 20 would exist in forms analogous to 18. I t is significant to note that despite its positive charge, f

the immonium group, -NR-=CH,, directing.

&KH3

is para-directing rather than meta-

CH,

-CH,

19

I CH, 20

In contrast to the reactions described above, nitration of2.3-diphenylindole and 2-methyl-3-phenylindole with nitric acid in sulfuric acid follows a different course (Eq. 5 ) . Nitration in the para-position of the 3-phenyl group is the dominant reaction, giving the 3-(4-nitrophenyl) derivatives (22) as the major products. Smaller amounts of the 5-nitro-3-(4-nitrophenyl) derivatives (23) are also obtained. The formation of these products can be

ii

21 ; R = CH,, C,,H,

22; R' = H 23; K' =: NO,

rationalized if mixtures of the 3-phenylindole (21) and its conjugate acid (protonated at Position 3) exist in sulfuric acid. Nitration of the unprotonated form would give 22; nitration of the coiljugate acid would initially give a

Chapter VII

550

5-nitro intermediate, which in t u r n would undergo nitration (in the unprotonated form) to give 23. The nitration of 2-alkyl- and 2-arylindoles and their I-alkyl derivatives in concentrated nitric acid alone follows a different course than in sulfuric acid. Reaction of 2-methylindole with concentrated nitric acid at 50" gives a vigorous exothermic reaction which, upon workup, gives 3,6-dinitro-2methylindole (24).19. 'l The structure of 24 was proved by chromic acid oxidation to N-acetyl-4-nitroanthranilicacid (25).19 Compound 24 is also obtained as the major product of nitration of2-methyl3-nitroindole (26),as the minor product of nitration of 2-methyl-3-oximino3H-indole (27) [3,4-dinitro-2-methylindole is the major product], and as the only product of nitration of 2-methyl-6-nitroindole (28) in nitric acid.'$ These reactions are shown in Scheme 9.

J'&--'-:

O*N

I H

0

HhO;WO

~

u/,

\

I

O,N

I

H

~Nyo3 23:.

Ja COlfl

CH,

N HCOCH,

2s

/;m(L*500

/$

i.:"'.l,, NO2

$jJLCH3 I

O2N

Q7:: & :7:: I

3H 0 / / /

_-

.).I*

It,,

- u

67:,

OiN

N

@ I 3 C H 3

I

I II

H 28

II\O,

IiW,

2s-

26

J-2:

QI-J::: 27

Scheme 9

Nitration of 2-methylindole or 24 with nitric acid at 90" yields 2methyl-3,4,6-trinitroindole (29). The third nitro group is known to be in Position 4, since 29 can be obtained in low yield by heating 2-niethyl-4nitroindole (30) in nitric acid at 90°.19


551

The polynitration of 1,2-dimethylindole in nitric acid is analogous to that of 2-methylind01e,'~ yielding 1,2-dimethy1-3,6-dinitroindoleat 50" and 1,2dimethyl-3,4,6-trinitroindole at 90".The yields are slightly lower due to the deactivating effect of the I-methyl group.72The products are identical with the N-rnethylation products of 24 and 29, respectively. Nitric acid nitration of 2-phenylindole at room temperature gives 3,6-dinitr0-2-phenylindole,6~ which had been erroneously reported as 3,5-dinitr0-2-phenylindole.~~ A trinitro derivative of 2-phenylindole could not be obtained. Nitration of 2-methyl-5-nitroindole (31) in nitric acid at 90" for 3 min yields 3,5-dinitro-2-rnethylindole(32), as shown by chromic acid oxidation acid (33)18(Scheme 10). Nitration of 32 or the to N-acetyl-5-nitroanthranilic

I-acetyl derivative of 31 (34) gives 2-methyl-3,5,6-trinitroindole(35), as acid (36). shown by chromic acid oxidation to N-acetyl-4,5-dinitroanthranilic The polynitration of 1,2-dirnethyl-5-nitroindolein nitric acid is analogous to that of 2-methyl-5-nitroindole, although yields are again lower.lg After 3 min at 90*, 1,2-dimethyl-3,5-dinitroindoleis obtained, while after 30 min results. These products are identical at 90°,1,2-dimethyl-3,5,6-trinitroindole

552

Chapter VII

with the N-methylation products of 32 and 35, respectively. Nitration of 5nitro-2-phenylindole in nitric acid at room temperature gives 3,5-dinitro-2phenylindole, but a trinitro derivative of 2-phenylindole could not be ob t ai ned. In contrast to the nitration of 2-alkylindoles containing vacancies at Position 3, 2,3-dialkylindoles do not give well-defined nitration products in nitric acid. Only amorphous polymers are obtained from 2,3-dimethylindoleW and 1.2,3-trimethyIind0le,'~even at 0". Nitration of l-acetyl-2,3-dimethylindole in acetic acid gives low yields of a mixture of the 4- and 6-nitro derivatives, in addition to products of oxidation at the 2,3-double bond.j2* 73 The I-acetyl group apparently deactivates the molecule toward oxidation sufficiently to permit nitration. The trinitroindoles 30, 35, 3,5,7-trinitroind0Ie,~" and 2-methyl-3,5,7trinitr~indole'~ are moderately strong acids, having pK, values of 7.3-7.4. Although the structures of many of the polynitro-2-alkylindoles were proved by oxidative degradation to known compounds, the reactions proceed with difficulty and the yields are low. This resistance to oxidation is almost certainly due to delocalization of the 2,3-double bond, the site of initial oxidative attack,61* by resonance interaction with the nitro groups. Polynitroindoles containing a 5-nitro group (para to the indole nitrogen) undergo complete destruction within 30 sec when treated with concentrated aqueous alkali solutions. This is believed to be due to electrophilic attack at Position 7a by hydroxide ion, followed by opening of the pyrrole ring and subsequent decomposition. In contrast, polynitroindoles that do not contain 5-nitro groups, and are, therefore, not activated toward electrophilic attack, are conipletely inert to concentrated aqueous alkali solutions. Evidence was previously presented which shows that in sulfuric acid, 2-alkylindoles undergo nitration in the form of their conjugate acids (protonated at Position 3) to yield 2-alkyl-5-nitroindoles. Since 2-alkylindoles give 3,6-dinitro derivatives as the first isolable products in nitric acid, this reaction must proceed by a totally dilycrent mechanism. This reaction is believed to proceed by nitration of thc unprotonated 2-alkylind0le.~~ This hypothesis is supported by the observation that the 4- and 6-positions of 2-phenylindoles are conjugated with the indolc nitrogen in neutral media.@ While nitration in sulfuric acid occurs smoothly at 0", thermal initiation is required to begin the violently exothermic reaction in nitric acid. This is attributed to two factors: ( I ) Nitric acid alone is known to be a much poorer source of nitronium ions than is nitric acid in sulfuric acid75*7s; and (2) nitric acid is still sufficiently strong to protonate Position 3 of the indole, and thereby prevent attack at this position by a nitronium ion. Heating should favor dissociation of the protonated indole, creating a higher concentration of the reactive free indole. Initial nitration, which almost certainly occurs a t G*

Oxidized Nitrogen Derivatives of Indole and Indoline

553

the highly nucleophilic Position 3, would yield a mononitro derivative of greatly reduced basicity. This intermediate should exist largely in the unprotonated form, which could undergo further nitration very rapidly and sustain the exothermic reaction. The nitration of 2-methylindole in nitric acid can be effected at room temperature if sodium nitrite is used as a ~ata1yst.l~ Since sodium acetate does not catalyze the reaction, the catalytic effect of sodium nitrite is not that of a base diminishing the acidity of the medium to a point where a sufficiently high concentration of unprotonated indole exists to initiate the reaction. These results do suggest that the thermally initiated nitration of 2-alkylindoles might involve an initial nitrosation reaction. The thermal initiation period could be interpreted partly as an induction period during which the nitrosating agent is being formed through reduction of nitric acid by the indole. Once 3-nitrosation has occurred, the nitrosating agent would be formed by the reduction of nitric acid as it oxidizes the nitrosation product to an intermediate mononitroindole. The second nitration would then proceed on the mononitroindole as previously mentioned. From this evidence, the nitration of 2-alkylindoles appears to involve nitration of the unprotonated indole first at Position 3, perhaps by a nitrosation-oxidation mechanism, and then at Position 6 . Since nitration takes place in Position 6 , and sometimes in Position 4, it appears that electronic activation of the benzene ring by the indole nitrogen occurs via the 2.3-double bond and not by direct aniline-type activation when the indole nucleus is not protonated. Nitration of 2-alkyl- and 2-arylindoles with ethyl nitrate in the presence of sodium ethoxide yields the 3-nitro derivative^.^^ The preparation of 3-nitroindole by this method has been described [Section 1I.A. I .a.(l)]. The 3-nitro derivatives can also be prepared by oxidation of 3-oximino-3H-indoles with nitric7', 78 or nitrous acid.57 Nitration of 3-acetyl-2-methylindole in acetic acid also gives 2-rnethyl-3-nitroind0le.'~ The displacement of the 3-acetyl group by a nitro group is discussed in detail in Section II.A.l.a.(4). The results described above lead to the following orientation rules for the nitration of 2-alkyl- and 2-arylindole~'~: (I) Nitration of I-alkylindoles and their alkyl derivatives under conditions of complete protonation and a high concentration of nitroniurn ions (nitric acid in sulfuric acid) at 0-15" yields the 5-nitroindoles. Attempted further nitration by heating leads to decomposition. (2) Nitration of 2-alkylindoles and I,?-dialkylindoles under conditions of incomplete protonation and a low concentration of nitronium ions (concentrated nitric acid alone or in acetic acid) yields, after thermal initiation, the 3,6-dinitroindoles. Further nitration by heating in concentrated nitric acid at 90" yields the 3,4,6-trinitroindoles. (3) Nitration of 2-alkyl-5-nitroindoles by heating in concentrated nitric acid yields first the 3,5.dinitroindoles and then, upon further heating, the 3,5,6-trinitroindoles.

Chapter VII

554

(4) The nitration of 2-arylindoles is analogous to that of 2-alkylindoles except that in concentrated nitric acid thermal initiation is not required and nitration stops at the dinitration stage. (5) Nitration of 2-alkylindolesand 2-arylindoles with ethyl nitrate under basic conditions yields the 3-nitroindoles. (6) Neither tetranitration nor 7-nitration of an indole nucleus has been observed.

(c) DEHYDROGENATION OF NITROINDOLINES. Alkylnitroindoles can be prepared by dehydrogenation of alkylnitroindolines with chloranil or palladium-on-charcoal in refluxing ~yIene.*~. *,* This method is quite useful for the preparation of alkyl-5-nitroindoles and alkyl-6-nitroindoles because the required nitroindolines can be obtained in excellent yields by nitration of the indolines (see Section II.A.2.a). (3) Nitro Derivatives of Gramine and Tryptophan. The four bz-nitro derivatives of gramine (37)have been prepared in good yield by condensation of 4-,78 5-,78 6-,80and 7-nitroind0le~~-with formaldehyde and dimethylamine in glacial acetic acid. These derivatives of gramine have been used to prepare the corresponding nitro derivatives of tryptophan (38)78-81by the classical acetamidomalonate synthesis of tryptophan derivatives (Scheme 1 1). 02N

Q CHZN (CH&

+AcNHCH(CO,C,H,),

\

I H 37

base

H

H

38 Scheme 11

While nitration of indole and alkylindoles containing an open Position 2 under acidic conditions is unsuccessful, gamineE2 and tryptophans3*84 undergo nitration with concentrated nitric acid in acetic acid. Gramine yields mostly 6-nitrogramine, along with some 4nitrogramine, while tryptophan yields 6-nitrotryptophan. The successful nitration of these compounds has been attributed to protonation of the side-chain amino group.s* The resulting positive charge could, through electrostatic repulsion, prevent oxidative attack at Position 2 or the 2,3-double bond, which are vulnerable positions for electrophilic attack.


555

Like gramine, 1-methylgramine yields a mixture of 6-nitro and 4-nitro derivatives when treated with a nitric-acetic acid mixture. In contrast, 2methylgramine and 1 ,Zdimethylgramine yield only the 6-nitro derivatives.R2 The failure of these compounds to undergo 4-nitration is probably due to increased steric hindrance about the Cposition. show little or no pharmacoThe nitrogramineP. 86 and nitrotryptophan~~' logical activity. (4) Nitro Deriratioes of Indoles Containing Electrotiegative Substituents. Indoles containing electronegative substituents in Position 3 are stabilized sufficiently toward oxidative attack to permit successful nitration in nitric acid or a nitric-acetic acid mixture. Nitration usually occurs at the 6- or 6and 4-positions. Displacement of the 3-substituents by a nitro group is also observed, especially if a 2-alkyl substituent is present. Nitration of indole-3-carboxaldehyde with nitric acid in acetic acid gives 6-nitroindole-3-carboxaldehyde (39).'*6, 89 Oxidation of 39 with chromic acid in acetic acid provides a feasible synthetic route to 6-nitroisatin (40)80 (Scheme 12). Nitration of 1-methyl-, 2-methyl-, or 1,2-dimethylindole-3-

I H

ZR'

O2N

J@-JrCHO

* OIN

;;::H

I H 39

m: I H

40

Scheme 12

carboxaldehyde under similar conditions gives quite different results.g0 In every case, mixtures are obtained among which are found the 4-nitro derivatives, the 6-nitro derivatives, the 3-nitro- and the 3,6-dinitroindoles. The structures of the products were proved by oxidative degradation to anthranilic acid derivatives. The orientation of the nitro groups in these products indicates that only the unprotonated form of the aldehyde is undergoing nitration in nitric acid. The nitration of indole-3-carboxaldehyde and its alkyl derivatives in sulfuric acid has also been studied.88*91 In every case, inseparable mixtures of the 5- and 6-nitro derivatives are obtained (Eq. 6) in an approximate ratio of 3:2. The structures of the products were proved by degradation of the

QJtFO R' I

02N-

@)--~~o RI'

5- and 6-isomers

(6)

Chapter VIl

556

mixtures with hydrogen peroxide in acetic acid to anthranilic acid derivatives while the composition of the mixture was determined by uv spectroscopy. The isolation of both 5- and 6-nitro derivatives suggests that both the protonated and unprotonated forms of the indole-3-carboxaldehydes are undergoing nitration. Nitrative displacement of the 3-formyl group does not occur as it did with nitric acid; this might be due to the much lower reaction temperature in sulfuric acid. In acetic acid, 3-acetylindole does not undergo nitration.Q2In nitric acid alone, however, a mixture containing mostly 3-acetyl-6-nitroindole (41) and some 3-acetyl-4-nitroindole (42) is obtained40 (Scheme 13). These 0

0

QJr" CCH,

HI

I

11%

~

~

~

c

HI

-

41; 42;

0

0

I H

c

I tl

R = &NO, R = +NO,

I H 45

Scheme 13

structures were established by deacetylation to 6-nitroindole and 4-nitroindole, respectively. The nitration of 3-acetyl-2-methylindole is accompanied by deacetylation, giving 3-acetyl-2-methyl-6-nitroindole (43), 3-acetyl-2methyl-4-nitroindole (a), and 2-nlethyl-3-nitroindole (45)19 (Scheme 13). Like the indole-3-carboxaldehydes,nitration of 3-acetylindole in sulfuric acid gives an inseparable mixture of the 5- and 6-nitro derivative^.^^ The ability of the 2-methyl group to promote nitrative displacement of 3-formyl and 3-acetyl groups is attributed to its electron-releasing properties and to its steric compression of the 3-acyl group, which would reduce its conjugation with the 2,3-double bond.40 Both factors would increase the nucleophilicity of Position 3, and thereby increase the rate of nitrative displacement. In nitric acid, other 3-acyl derivatives of indole also undergo nitration in indole-3-carboxylic the 4- and &positions. Thus, ethyl indole-3-~arboxylate,"~ N,N,2-trimethyl-indole-3-glyoxamides,B4 ethyl indole-3-gIyo~ylate,~~ and ind0le-3-carbonitrile~~ give mixtures of the 4- and 6-nitro derivatives.

H


557

Displacement of the 3-acyl group during nitration does not occur with these compounds. In contrast to the 3-acylindoles, which all undergo nitration in the Positions 4 and 6, 3-nitroindole (46) and 3-nitroindole-2-carboxylicacid (47) give different results. In nitric acid, 46 gives a mixture of 3,5-dinitroindole (48) (major) and 3,6-dinitroindole (49) (minor), while 47 gives only 3S-dinitroindole-2-carboxylic acid (50) (Scheme 14).'O The formation of 48 might arise

H 46

Scheme 14

by nitration of the protonated aci-nitro form (51) of 46, while 50 could arise by nitration of the nitronolactol form (52) of 47. Both 51 and 52 have an 0I

0-

N-OH

+

tl

immoniuni group adjacent to the benzene ring, a configuration that resulted in 5-nitration in the 2-alkylindole series [Section II.A.l.a.(2).(b)]. In contrast, 2-methyl-3-nitroindole gives only 4- and 6-nitration.19 The lack of 5-nitration in this case can be attributed to steric interaction of the methyl and nitro groups, which would prevent formation of an aci-nitro form analogous to 51. This would lead to normal activation of Positions 4 and 6 . Indole-2-carboxylic acid undergoes 3-nitration" while its ethyl ester undergoes 4-nitrati0n."~This difference is attributed to increased steric hindrance of Position 3 by the ethoxycarbonyl group. It also suggests that

558

Chapter VII

Position 4 might be preferred electronically to Position 6 for electrophilic attack if steric hindrance of Position 4 by a 3-substituent is not a factor. The nitration of indoles containing electronegative 3-substituents can be summarized by the following orientation rules: (1) If the 3-substituent is not a nitro group, nitration with concentrated nitric acid, alone or in acetic acid, yields 6-nitration, sometimes together with 4-nitration. If a 2-alkyl group is present, displacement of the 3-substituent by a nitro group frequently occurs. (2) If the 3-substituent is a nitro group, 5-nitration or a mixture of 5- and 6-nitration occurs in nitric acid. If a 2-alkyl substituent is present, however, only 4- and 6-nitration occur. (3) Nitration in sulfuric acid yields inseparable mixtures of 5- and 6-nitro derivatives.

b. REACTIONS.Mononitroindoles undergo facile reduction to the corresponding amines with hydrogen in the presence of Raney nickel58 or palladium on carbon.95Chemical reduction is less satisfactory; reduction of 2-methyl-5-nitroindole with tin and hydrochloric acid leads to a chlorinecontaining 5-amino-2-methylindole and other products.58 The reduction of di- and trinitroindoles has not been explored. Mononitroindoles containing a vacant Position 3 undergo the usual electrophilic reactions of indoles, such as formylation with dimethylformamide and phosphorus o x y c h l ~ r i d e , ~the ~ - ~Mannich ~ reaction with formaldehyde and dimethylamine,J8* and addition to electron-deficient 0lefins.~8 c. USEFUL COMPOUNDS. Several patent^^^-'^ assigned to Merck and Company claim that nitroindoles derived from indole-3-acetic acid, such as 53, have antiinflammatory activity. Amines such as 54 which are prepared from the reduction product of 53, also possess this activity.

Equation (3) (Section 1.B) illustrates the condensation of 3-nitrosoindoles with 1,2,3,3-tetramethyI-3H-indoliumsalts to give dyes useful as photographic desensitizers. This reaction can also be applied to 5-nitro-I ,2,3,3tetramethyl-3H-indolium salts.29,33 Dyes for polyacrylonitrile fabrics have been prepared from nitroindoles.lO1


559

Several patent^'^*-'^^ describe the use of nitroindole,s in the preparation of 4,7-indoloquinones, which are reported to have broad spectrum antibacterial activity. The key steps are shown in Scheme 15.

Scheme 15

2. Nifroindolines a. PREPARATION. Being typical aromatic amines, indoline, alkylindolines, and their N-acyl derivatives undergo nitration in a manner completely analogous to aniline and its acyl derivatives. Nitration in sulfuric acid occurs meta to the nitrogen atom to give 6-nitroindolines (55) in high yield.3**43-45. lo8 Nitration in nitric acid, followed by alkaline hydrolysis of the products, gives 5-nitroindolines ( 5 6 ) “ 9 Io9 in high yield (Scheme 16). In the nitration of

CORL

H 56

Scheme 16

1-acetylindoline, a small amount of 5,7-dinitroindoline is obtained as a 48 If Position 5 of the I-acylindoline is occupied, fuming nitric by-prod~ct.*~. acid effects nitration in Position 7.*09*I1O The nitration of indoline has historical significance. Tafelllo degraded strychnine with fuming nitric acid to give “dinitrostrycholcarboxylic acid,” which was shown by Menon and Robinson4’ to be 5,7-dinitroindole-2,3dicarboxylic acid (57) Since indoles do not undergo nitration in Position 7, 57 must arise by nitration of a 2,3-dialkylindoline intermediate, followed by subsequent degradation and oxidation to the indole.

560

Chapter VII CO,H

57

b. REACTIONS. The dehydrogenation of nitroindolines to nitroindoles has been discussed [Section 1I.A.1.a.(l).] Catalytic reduction of nitroindolines with Raney nickell10 or with palladium on carbonlOg yields the corresponding aminoindolines. If a halogen atom is present, it is removed by reduction with Raney nickel or palladium on carbon, but not with platinum dioxide. Reduction with Raney nickel in aqueous alkaline solution causes concomitant dehydrogenation of the indoline nucleus, yielding an aminoindole as the product. These reactions are summarized in Scheme 17.

'

Not

I

COCH,

Scheme 17

I I NHz H

B. Indoles and Indolines with Side-Chain Nitro Groups I . Preparation a. ~-(~-NI~OALKYL)INDOLES.The alkylation of nitroalkanes with gramine and its derivatives proceeds smoothly to yield 3-(2-nitroalkyl)indoles114-1zo


561

(Eq. 7). This reaction is usually carried out by heating the gramine derivative

I H

in an excess of the nitroalkane or by heating equimolar amounts of the reactants in an inert solvent such as toluene. Basic catalysts have also been 119Alkylation of the nitroalkane usually stops at used in this rea~tion."~.l l 8 ~ the monoalkylation stage. Under these conditions, however, nitromethane is dialkylated with gramine, giving 3,3'-(2-nitromethylene)diindole (58).lI4

Monoalkylation of nitromethane can be accomplished by using gramine methiodide (59)121or gamine-N-oxide (60)122as alkylating agents, since these reactions proceed under milder conditions (Scheme 18). While gramine

59

H

0-

60

Scheme 18

alkylates nitroalkanes with ease, 3-methyl-Zdimethylaminomethylindole does not.115 In similar fashion, gramine has been used to alkylate ethyl nitroacetate and diethyl nitromalonate, yielding ethyl a-nitroindole-3-propionate (61)123 and ethyl a-carbethoxy-a-nitroindole-3-propionate (62),lZ4,lZ5 respectively

Chapter VII

562

(Scheme 19). Reduction of 61 provides a commercial synthesis of tryptophan (63). Similar reactions have been employed in the synthesis of serotonin and other tryptophan and tryptamine analogs.126-12s

CKJ-

CH, N(CH3)2

Q - C H Z ~ ~ ~ O ~ C Z H ~ ) ~

O,NCH(COzCz1i,h tolucnc, d

I H

I

H

I

62

C,H,ONa C,H,OH

I

H

H.

63

61

Scheme 19

The addition of i n d ~ l e ' *and ~ a l k y l i n d o I e ~ ~to~nitroolefins ~ - ~ ~ ~ also yields 3-(2-nitroalkyl)indoles (Eq, 8). Since polymerization of the nitroolefin is

always a competing reaction, the best yields are obtained with those such as 2-nitrostyreneand 2-methyl-2-nitrostyrene, which do not polymerize readily.lsO Indoles containing 1-alkyl substituents are considerably less reactive than N o product is obtained with 1-methyltheir unsubstituted indole and nitroethylene. The order of reactivity in this reaction appears to C6H;CHBO

+

CH,=CHNO,-

C , C1,CHZOQ - C H F H W ,

J

I

H

Ii,

z .I1111

lo:, I'd

C'

i H

,,'Q-,---C H ~ C HN, H, I

H

64

Scheme 20

563

Oxidized Nitrogen Derivatives of lndole and lndoline

be 2-methylindole > 1,Zdimethylindole > 2-phenylindole > indole > 1methylindole. The use of indole Grignard reagents in place of the free indoles gives slightly higher yields.129* 133, If the 3-alkylindoles are used , addition takes place at the indole nitrogen. The addition of nitroethylene to 5-benzyloxyindole provides the basis for a two-step synthesis of serotonin (Scheme 20). Grignard reagents add to 3-(2-nitrovinyl)indole derivatives (Section 1I.B. 1.b) to give 3-( 1-nitro-2-alky1)indoles (65)136-139 (Eq. 9). R

6.5

The Fischer indole synthesis has been used to prepare 5-benzyloxy-3(2-nitr0propyl)indole.~~~

a-

b. (~-NITROVINYL)INWLES. The preparation of (2-nitrovinyl)indoles (66) by condensation of indole-3-carboxaldehyes with I-nitroalkanes (Eq. 10) has been known for many lJ2 This reaction was virtually uninvestiCH=CRNO,

CHO + K C H , N O ,

(10)

I

I

H

H

gated until 1958, when the synthesis of serotonin and some of its analogs 146 (Scheme 21). Since that time, this based on this reaction was reported143*

I

LIAIH,

HO

CH,CH,NHL

IQJ

H, Pd-C t---

N HI

64

C,H,CH,O

~ c H z C H , " z H I

Scheme 21

reaction has been the subject of numerous publications and patents, many of them dealing with the preparation of serotonin analogs.

Chapter VII

564

The condensation of indole-3-carboxaldehydes with 1-nitroalkanes is usually carried out in the presence of weakly basic catalysts using an excess of the nitroalkane as solvent. Ammonium acetateld3is the preferred catalyst, have also been although alkali metal carbonates143-145 and alkylamine~'~-'~~ used. The reactions are smooth and give good yields. On the basis of spectral evidence, it is believed that the condensation products obtained from 1nitroalkanes and indole-3-carboxaldehydes unsubstituted in Position 1 exist in the nitronate form (67)rather than as true nitro c o m p o ~ n dThe ~.~~~ many 3-(2-nitrovinyl)-indoles prepared by this method are listed in Table II.B.2. 0I

~ c H - c H = N+ , OH - .

67

The condensation of 1-nitroalkanes with indolecarboxaldehydescontaining the formyl group in positions other than Position 3 is equally facile. Reaction conditions similar to those described above are used. Thus, indolecarboxaldehydes which contain the formyl group in Positions 2,14'*148 4,14B*5,14@ 6,1°B and 7,14B* 150 have been condensed with nitroalkanes. The resulting (2-nitroviny1)indoles are listed in Table II.B.2. c. 2- AND 3-(NIrRoPHENYL)INWLES. The cyclization of 2'-nitroacetophenone151 and 3'-nitroacetophenoneI52 phenylhydrazones with polyphosphoric acid gives 2-(2-nitrophenyl)indole and 2-(3-nitrophenyl)indole, respectively. Cyclization of 2-nitrophenylpyruvic acid phenylhydrazone and decarboxylation of the product yields 3-(2-nitrophenyI)ind0lel~~;2-methyl-3(4nitrophenyl)indole and 2-phenyl-3-(4-nitrophenyl)indole are obtained as nitration products of 2-methyl-3-phenylindole and %,fdiphenylindole, re~pectively.'~ Preparation of 3-(2,4-dinitrophenyl)-2-methylindoleby cyclization of 2',4'-dinitrophenylacetone phenylhydrazone is r e ~ 0 r t e d . l ~ ~

c1

Indoles with Position 3 vacant undergo nucleophilic substitution reactions on picryl chloride to give 3-(2,4,6-trioitrophenyl)indole~~~~ (Eq. 11). Initially, only a 1:1 molecular adduct (n-complex) of the indole and picryl chloride forms; subsequent refluxing of a toluene solution of this adduct effects the


565

substitution reaction. Skatole (3-methylindole) does not undergo a substitution reaction with picryl chloride, but gives only the 1 : 1 molecular adduct. Indolines containing a 2-methylene group also undergo nucleophilic substitution reactions with activated chlorobenzene derivative^.'^^ In refluxing benzene, 2-methylene-1,3,3-trimethylindoline (68) reacts with 2,4-dinitrochlorobenzene and picryl chloride to give 2-(2,4-dinitrobenzylidene)-I ,3,3trimethylindoline (69, X = H) and 2-(2,4,6-trinitrobenzylidene)-l,3,3trimethylindoline (69, X = NOz), respectively (Eq. 12).

2. Reactions The 3-(2-nitroalkyl)indoles and ethyl /h1itroindole-3-propionates have been reduced to tryptamine and tryptophan analogs, respectively, with a variety of reducing agents. Catalytic hydrogenation over Raney nickel has been the most widely used method.Il4*123-125* 157 The exact conditions vary with individual compounds, but most require high temperature and/or high pressure (Eq. 13). Other methods which have been employed are catalytic

R3 = H, alkyl. CO,C,H,

hydrogenation over platinum lrn,158 or palladium on carbon,'96, 140 chemical reduction with lithium aluminum hydride in etherllO*126* 127 or or iron and hydrochloric tetrahydrofuran (THF),"' stannous ~hloride,'~~ and electrolytic reduction.IB1Catalytic hydrogenation over palladium acid ,Im on carbon is frequently used in the synthesis of serotonin analogs, since concomitant hydrogenolysis of the 5-benzyloxy protective group also ocof tryptamine,tryptophan, and serotonin have many c u r ~ .140 ~ ~Derivatives ~. interesting pharmacological properties and find use in the pharmaceutical industry. Tryptamine derivatives can also be prepared by reduction of 3-(2-nitroviny1)indoles (Eq. 14). This reduction is almost always carried out with

Chapter VII

566

lithium aluminum hydride in ether143*ld5or THF.136-130 Indoles containing 2-nitrovinyl groups in positions other than Position 3 also undergo smooth reduction with lithium aluminum hydride.147-14g

R'

The reduction of ethyl 3-(2-nitrobutyl)indole-2-carboxylate (70) with stannous chloride is followed by spontaneous cyclization, yielding 3-ethyl-1 oxo-l,2,3,4-tetrahydro-/l-carboline(71)15@ (Scheme 22). This reaction is quite valuable, since this type of /l-carboline derivative can be used as a basis for the synthesis of yohimbine alkaloids and other heterocyclic systems.1sg

-

70

72

+

71

73


567

However, catalytic hydrogenation of 71 over palladium on carbon results in partial reduction of the indole nucleus, giving a mixture of ethyl 3-(2nitrobutyl)-4,5,6,7-tetrahydroindole-2-carboxylate (72) and ethyl 3-(2aminobutyl)-4,5,6,7-tetrahydroindole-2-carboxylate(73).la2Ethyl 3-(2-nitropropyl)indole-2-carboxylate (74) reduces normally (Scheme 22). It is proposed that the side chain of 70 blocks all approaches of the nitro group to the surface of the catalyst, while the shorter side chain of 74 permits contact between the catalyst and the nitro group to occur. The reduction of 3-(2-nitroalkyl)indoles with zinc and ammonium chloride in ethanol yields 3-(2-hydroxylaminoalkyl)indoles rather than 3-(2-aminoa l k y l ) i n d ~ l e s164 ~ ~(Eq. ~ * 15). The attempted reduction of 3-(2-nitropropyl)-

indole to 3-(2-hydroxylaminopropyl)indoleby controlled catalytic hydrogenation in methanol containing hydrochloric acid over platinum resulted instead in reduction of the indole nucleus, giving a mixture of 3-(2-nitropropyl)indoline and 3-(2-nitropropyl)o~tahydroindole.~~~

III. Azo and Azoxy Derivatives A. Azo Derivatives

1. Azoindoles Indole and 2-substituted indoles react with diazonium salts to give 3-arylazoindoles (75a) or the tautomeric 3-arylhydrazono-3H-indoles (75b).'* *5* 166-173 The form in which these products exist has not been

k

75a

75b

determined, but by analogy with nitroso derivatives of 2-substituted indoles, which exist as 3-oximino-3H-indoles, and with other arylhydrazones, it is probable that the hydrazone form, 75b, is the correct structure.

568

Chapter VI1

Indole reacts with benzenediazonium chloride to give a mixture of products from which 3-phenylhydrazono-3H-indolecan be isolated in poor yieldls5 (75b; R1 = H, R2 = C6H,).Other diazonium salts give similar Many of the by-products apparently arise from side reactions of the diazonium salts, since those containing strongly electronegative substituents in the para positions react smoothly with i n d ~ l e . ' ~lB8 ~ . In fact, 4-nitrophenyldiazonium chloride gives 3-(4-nitrophenylhydrazono)-3H-indole (75b; R1 = H, R2 = p-CsH,N02) in nearly quantitative yield.ls7 The reaction of indole with 4-nitrophenyldiazonium chloride has been studied in detail.167The reaction is nearly quantitative over the pH range 4-6, but lower yields result at higher pH values due to side reactions of the diazonium salt. The reaction is first order in both indole and diazonium salt. The reactive form of indole is the neutral molecule and not the conjugate base. Since no deuterium isotope effect was observed with indole-d,, it is probable that the attack of diazonium ion on the indole molecule is the rate-determining step. The 2-alkyl- and 2-arylindoles, which are more nucleophilic than indole itself, react smoothly with most diazonium salts to give 3-arylhydrazono-2substituted-3H-indoles1~z5* 169-173 (Eq. 16). The reaction is usually run in cold

alcohol in the presence of a base. Under the same conditions, 3-substituted indoles react with diazonium salts to give the corresponding 2-arylazoindoles l'IP (76).172*

H

76

Some 1,2-disubstituted-3-arylazoindoIes (77) have been prepared by condensation of the corresponding 3-aminoindoles with nitrosobenzene derivatives in acetic acid3' (Scheme 23). A possible alternative procedure, reaction of the 3-nitrosoindole with an aniline derivative, does not give 77.,l It has been reported elsewhere that 3-nitrosoindoles do not react with primary amines.". 29

Oxidized Nitrogen Derivatives of lndole and lndoline

Q-;? I R’

To X

\ CII,CO,H

NH,

I K’

569

Qx;2=N I

R’

77

x Scheme 23

Some 3-arylhydrazono-3H-indoleshave also been prepared by reaction of indoles with phenylazodiphenylamine in the presence of acetic acid175 (Eq. 17), and by reaction of indoles with arylazoxycarboxamides in the

H

presence of potassium methoxide (Eq. 18). The mechanism by which the latter reaction proceeds is not known.

Some 3.3’-azobisindoles (78)have been prepared by reaction of the indole with picryl azide in ethyl acetate’” (Scheme 24). The products separate as the charge-transfer complexes of’the 3,3’-azobisindole and picramide. These can be decomposed in boiling dioxane or hot dimethyl sulfoxide. The reaction is believed to proceed by initial addition of picryl azide to the 2,3-double bond of the indole, giving the triazoline 79, which in turn gives the dipolar ntermediate 80. Addition of 80 to the indole and elimination of picramide

570

Chapter V1I

gives 78. In place of picryl azide,p-toluenesulfonamidecan be used, although formation of some of the 3-(4-toluenesulfonamido)indole complicates this reaction. Other 3,3’-azobisindoles have been prepared by oxidation of 3-aminoindoles with N-nitro~odiphenylamine,~~ and by oxidation of 1,2-bis(2-phenyl-3-indoly1)hydrazine with amyl nitrite.178* 178 The attempted coupling of diazotized 1,2-dipheny1-3-aminoindolewith 1 ,2-diphenylindole was unsuc~essful.~~ Some 3,3’-azobisindoles have also been isolated as by-products in the platinum-catalyzed hydrogenation of 1,2-disubstituted-3-nitros0indoles.3~ Since it is known that 3-aminoindoles do not condense with 3-nitrosoindoles7 it is believed that the products arise from self-condensation of the intermediate 3-hydroxylaminoindole (81) with the elimination of 2 moles of water (Scheme 25). The 3,3’-azobisindoles are extremely resistant to further reduction.

Scheme 25

If the 2 and 2‘ positions of 78 contain aryl groups, two isomers are frequently isolated. These are apparently the syn- (78a) and anti- (78b) isomers


571

R' I

I

R'

R' 78a

I

R'

78b

of 78. They are unusual in that both forms are highly stable and not interconvertible. The higher melting isomer is assumed to be the more stable anti-form, and is the only isomer isolated in some reactions. Since the isomers are not interconvertible and are resistant to reduction, conclusive evidence for their structures is difficult to obtain. Diazonium salts react with 2,3,3-trimethyl-3H-indoleto give 2-arylhydrazonomethyl-3,3-dimethyl-3H-indoles(82)lEo(Scheme 26). If 2 moles of the diazonium salt are used, formazans such as 83 are obtained.lB1

82

CH, pyridina

Scheme 26

The reaction of 2-methylindole and 2-phenylindole with diazonium salts forms the basis for several patent^.'^^-*^^ The resulting highly colored 3arylhydrazono-3H-indolesare useful dyes for cotton, cellulose ester, polyester, polyamide, polyurethane, and polyacrylonitrile fibers. The monoazo dyes such as 84 are usually yellow or orange; diazo dyes such as 85 are usually red.

84

85

572

Chapter VII

2. A zoindolines

-

Being a typicz. secondary aromatic amine, methylindoline reacts with benzenediazonium chloride to give 2-methyl-1-phenylazoindoline(86), which rearranges to 2-methyl-5-phenylazoindoline(87) in the presence of mineral acidslOo (Scheme 27). Diazotized sulfanilic acid couples with 1-methylindoline to give 1-methyl-5-(4-sulfophenylazo)indoline(88)lo1(Scheme 27).

02

H,C6 -N=N

CH,

C,H.,N2'CICH,CO~N~'

m

C

H

,

%

-CH,

I

I

I H

H

N=N-C6H5

aN=Nm q+@?+ 87

86

N,'Cl-

N CH, I

H03S

SO,H

CH,

88

Scheme 27

Reaction of either 1,2,3,3,-tetramethyl-3H-indolium 193 or 2-1nethylene-1,3,3-trimethylindoline~~~~ with diazonium salts yields 2arylhydrazonomethyl-1,3,3-trimethyl-3H-indoliumsalts (89), which upon treatment with base yield 2-arylazomethylene-1,3,3-trimethylindolines(90)

Q$2: I

CH,

Br-

@+E;=N-NHax CH,

CI89


573

(Scheme 28). Compounds such as 89 are used as dyes for polyacrylonitrile fibers.lg5 Methylation of 90 with dimethyl sulfate gives compounds with general structure 91, which are used as dyes for acrylic,1gs acetate,lgs and polya~rylonitrile'~'fibers.

CH,

CH,SO,91

B. Azoxy Derivatives

Reaction of 3-amino-] -ethyl-2-phenylindole with N,N-dimethyl-p-nitrosoaniline in acetic acid gives 3-(4-dimethylaminophenyl-N'-azoxy)-l-ethyl-2phenylindole (92)31(Eq. 19). The corresponding azoxy derivative of 1,2diphenytindole is obtained similarly.

IV. Diazo Derivatives Diazotization of 3-amino-2-phenylindole6-178* 1p8--202 and 3-amino-2m e t h y l i n d ~ l e203 ~ ~with ~ + nitrous acid in acetic acid, followed by basification of the resulting diazonium salts with alkali or ammonia, gives 3-diazo-2phenylindole (93) (Scheme 29) and 3-diazo-2-methylindole, respectively. These are thermally stable, but light-sensitive compounds. Scheme 29 illustrates some reactions of 93. Reduction with aluminum amalgam1p8or ethanolic potassium hydr~xide"~yields 2-phenylindole. In the latter case, ethanol serves as the reducing agent. Reduction with ethanolic ammonium chloride,17p hydro~ylarnine,"~or phenylhydra~ine''~ yields

Chapter VII

574

3,3’-hydrazobis-(2-phenylindole) (94). Coupling with 2-phenylindole in acetic acid yields 3,3’-azobis-(2-phenylindole) (95).m2Coupling with pnaphthol in benzene yields 1-(2-phenylindol-3-ylaz0)-2-naphthol(96).eo1 The photolysis of 93 has been studied in detaiI2O2 (Scheme 30). These reactions undoubtedly proceed via a carbene intermediate. In alcoholic

H

NH,CI. C,H,OH or NH,OH orN,H4

92

AI(Hg), NaOH or KOH,C,H,OH

( I ) NaNO,, CH,CO,H (2) NaOH or NH,

H I

96

Scheme 29

solvents, reduction to 2-phenylindole occurs. This reaction is not sensitized by benzophenone. In hydrocarbon solvents, the products are those of insertion. In cyclohexane, 3-cyclohexyl-2-phenylindole(97) results; in benzene, 2,3-diphenylindole is obtained. With substituted benzenes, insertion occurs randomly to give all possible isomers (except with anisole, which undergoes insertion only in the para position). In cyclohexene, 3-(l-cyclohexen-l-yl)-2phenyl-3H-indole (98) is formed. This compound rearranges rapidly in the presence of pyridine to give 3-(2-cyclohexen-l-yl)-2-phenylindole (99). In cyclooctene, 3 4 ?-cycloocten-l-yl)-2-phenylindole (100) is obtained in addition to a small amount of the cyclopropane 101. This suggests that with olefinic solvents, the products arise not by insertion but by formation and subsequent rearrangement of a cyclopropane intermediate.


575

V. Azides No azides of indole or indoline have been prepared.

Imino Derivatives Oxidation of 3-amino-2-phenylindole with lead dioxide in benzene gives 3-imino-2-phenylindole (102)27in high yield (Scheme 3 1). Hydrolysis of 102 with mineral acids gives 3-0x0-2-phenyl-3H-indole. Nitrosobenzene derivatives condense readily with 2-phenylindole in the presence of alkali to give intensely colored 3-arylimino-2-phenyl-3H-indoles

Chapter V11

576

I H

102 Scheme 31

(103)'. 204 (Eq. 20). This reaction has been proposed as a test for nitrosobenzene derivative^.^" In a similar manner, 2-anilinoindole (oxindole anil)

condenses with nitrosobenzene to give 2-anilino-3-phenylimino-3H-indole (isatin dianil) (lM)eo5 (Eq. 21). This compound can also be obtained by (0-methylisatin) with aniline.ew reaction of 2-methoxy-3-0~0-3H-indole

H

104

Treatment of 3-diazo-2-phenylindole with 25 ,% sulfuric acid yields 3,3'azinobis-(2-phenylindole) (105)*88(Eq. 22).

105

VII. Isocyanates and Isothiocyanates No isocyanates of indole or indoline have been isolated, although presumably they are intermediates in the preparation of aminoindoles from azides of indolecarboxylic acids. No isothiocyanates of indole or indoline have been reported.

VIII. Tables of Compounds TABLE I. Nitroso- and Oximinoindoles and -indolines

A . Nitrosoindoles

H

R'

R2 H H C6H5 4-C,H4C,H, i-C,H, t-C4H, t-C,H, CGH, 4-BrC6H4 4-C,H4CiH5 C6H5 4-CIC6H, 4-C,H,C6H,

R3 CH, C6H5

CH, CH, NO NO NO NO NO NO NO NO NO NO

R4

R5

mp ("C)

Ref.

€3 H H

H H H H H H CH, H H H H H H H

10-12 60-61 84--85.5 279-289 235 223-224 179--180 144 161-162 214 130-131 137-1 38 164 200-202

24 207 10 28 12 10 12 11 10 28 29, 208 29,208 28 28

H H CH3 CH3 H H H H H H H

577

TABLE

(Cod.)

1.

B. 3-Oxiniin0-3H-indoles

"k5-p: R4

R'

R2

R3

H CH,

H H

C6H5

RS

R4

R6

mp('C)

Ref.

H H

H H

H H

H

H

H

17.18 4 20

H

C6H5 C6H6

CH3 H

H CH3

H H

H H

C6H5

H H

H H

CH3 H

H CH3

H H H H H

H H H H H

H H H H H

H H H H H

I70 198 198-200 244 250 258 dec. 276-278 dec. 280 25 1 262 273 237 232 244 240 277 274-276 249-250 242 245

C6H6

4-CH3CeH4 '4-CIC6H4 4-C,H&H5 4.Pyridyl

2-(IndoI-3-yl)

C. Nitrosoindolines

R'

NO NO

NO

NO

NO NO NO H H CH3

R2

R3

R4

H CH3 H H H CH3 CH, H CH3 H

H H H NO H H CH, NO NO NO

578

rnp(OC) 83

66

54-55 105-106 99.5-100.5 44.5

48.5 84.5-85.5 168

170 (HCI)

Ref. 35 210 21, 35 34 35 211 211 34

211 36

1

4 25 59 11 11 2 11 11 2

11 28 208 28 209 19 16

TABLE I.

(Conrd.) D. Miscellaneous

TTJ Compound

mp ("C)

Ref.

130-132

24

175 160-162

14, 16 15

127-129

15

134

15

NO

I NO

I

NO

579

TABLE 11. Nitroindoles and Nitroindolines A . Indoles and Indolines with Nuclear Nitro Groups

I . Mononitroindoles and AIkyI and Aryl Derivatives

R?

R2

H

H

H

C6HS

CH3 ( 3 5

CH, CH3

q H S

C6HS

H H H H CH3 H

R4

R5

R6

R7

mp (OC)

Ref.

H

H

H

H

40

H H H

H H H

H H H

H H H

H

H

H

H

213-214 210 156-1 57 102 243 247 252-253 240-243

H H H NO, NO, NO, NO, NO, NO,

H H H H H H H H H

H H H H H H H H H

H H H H H H CHa H H

NO,

H

H

H

H H H

H

C6HS

NO, NO, NO, NO, NO, NO,

H H

H H H H H H

H H H H H H

H

H

NO,

H

H

R3

H CH3 H H CH3 CH3

C2H5

i-C3H,

n-C4Ho n-C5H11

C6HS CH3

H

H

580

190-191 125 175 205-206 198-1 99 109.5-112 182 94-97 171-173 172-1 73 174-176 175 176-1 76.5 161-163 163-164 153-154 123-125 120-121 247-248 205-206 203-205 204-205 205 133-136 135-137 140-141 141-I 42

7

90

39 212 90 19 22, 32, 57,59 90 39 32 42 19 113 213 19 53 55 214 52 215 216 56 214 214 214 56, 214 214 53 56 217,218 45 44 47 42

TABLE 11.

(Contd.)

R1

R2

R3

R4

R5

R6

R"

H

CH3

H

H

NO,

H

H

H H H H CH, H

H

H

6 ' "5

H CH, CH3

CzH5 H CH3

H H H H H H

NO, NO, NO, NO, NO, NO,

H H H H H H

CH, H H H H H

H

CH3

C2H5

H

NO,

H

H

H H

NO, NO,

H H

H H

c2H5

H H H

CH,

n-C4HD

H

NO,

H

H

H

CH3

n-C6H1,

CH3

C6H6

H H

NO, NO,

H H

H H

CH3 CH,

4-NOzC6H4 C6H5CH,

C2H5

CH3

C6H5

CH3

H H H H

NO, NO, NO, NO,

H H H H

H H H H

H

C6H5

C6H6

H

NO,

H

H

H H CH,

C6H5 4-N0,C6H4 C6H5 2-Pyridyl CH, CH,

H H H

NO, NO, NO,

H H H

H H

CH, H

CH3

C2H5

H H

SO, H

H NO,

H H

H H H H H

H

CH,

H

H H CH,

CH, CH,

H

H

H

H

H

NO,

H

H

H H H

H H H

NO, NO, NO,

H H H

C2H5

H

rnp(OC) 170 171.5-172.5 176-176.5 220 131-132.5 201-203 94-95 129-130 183-185 184 185-186 186 188 I90 193-194 190-191 191-192 194 I64 166-167 166-1 67.5 I 69 124-125 125-126 116-117 197 197-198 305-307 160-161 182 191-192 I93 194-195 200 210 21 I 198-200 300-302 201-202 136-139 138.5-140.5 111-113 138-140 139-140.5 141-142 144-145 76.5-78.5 107-109.5 113.5-1 14.5 87-89 106-107.5

Ref. 63

44 58

213 19 59 51

58 53, 55 54 214 49, 216 50 52 215 51

56, 216 54 219 214 220 214 51 214 52 214 70 221 54 214 52 70 218 218 217 56 70 221 51 19 222 45 46

44

42 43 19

44

113 19

TABLE 11.

(Contd.)

R'

R2

R3

R4

RS

R'

mp("C)

H

CH3

CH3

H

H

H

126 139-141 141-142

H H H H H H H

CeHs

CeHs

H

H

H

H

H

H

H

H

H H

CH3 CH3

H CH3

H H

H H

H H

H

CH3

CaHs

H

H

H

H

CH3

H H H H H CH3

CH8

CH3 CH3

H

49 53 55,214, 215 142 50, 52 170-171 56,216 152-153 214 110-111 214 86-88 214 193-194 214 204-205 214 56 225-227 53.56, 218 227-228 70,217 95-96 42,223 95-97 47 224 158-160 55 162 216 162-163 214 162.5-163.5 215 164 52, 54 135-136

138 98-99 93-94 88-89 158-159 106

C2HS

121-122 93

C6HS

CH3

582

Ref.

56,216

54 214 214 214 214 54 214 218

TABLE II. (Contd.) 2. Mononitroindoles Containing Halogen

R4

R1

R2

R3

Rs

R4

R6

R7

~~~

C2H6

(4%

H H 4-ClC,H,CH2 H H H

NO2 H H H H H

H H H H

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

H

CH3 H H H H H H

HzBr2 HBr3 H NO, NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 H Br CI I CI I

c1

I

583

(3

(?)

H H H H H H H

H

H H NO2 NO2 H H H H H H

H H H CI I CI

mp (OC) Ref. 203 290 134-135 120-121

-

230 255 228 175-1 76 253 204-205 189 244 108-1 10 1 67-168 202 204 175 239 I41 260

39 39 113 51 95 54 54 54 222 54 51 54 54 113 44 54 54 54 54 54 54

TABLE 11.

(Conrd.)

3. Mononitrogramines and Alkyl Derivatives

R6

R7

Rl

R'

R*

R3

R4

H

H

CH,

NO,

CH3

H

CH3

NO,

H H H

H CH3 H

CH, CH3 CH,

H H H

Hydrochloride Nitrate H Hydrochloride Nitrate NO, NO, H

__

Hydrochloride Hydrochloride Methiodide Nitrate Picrate H Nitrate H

CH,

H

H

CI

H H

H H

CH3

CH3 C,H,

H H

R5

H

Nitrate Nitrate H H Methiodide

R6 H H H H NO,

NO2 NO,

H H

K7

nip ("C)

Ref.

120-122 233-235 203-205 Oil 237-238 198-200 169-1 70 173-175 176-178 178-180 229-230 229-23 1 203-205 162-1 63 198-200 83-85 173 158-160 161-1 63 158-160 180-1 81 69-7 1 79-80 173-174

78, 82 86 82 82 82 82 79 58,64 82, 83 80 80 86 80 82 80 82 82 225 82 82 82 18 81 81

TABLE 11. (Contd.) 4. hlononitrotryptaniines and Alkyl Derivatices

v3

H R'

R,

H

R4

NO, NO, H

H H NO, NO,

RS

R6

mp ("C)

Ref.

H H H H

145-147 115-1 16 136-139

113 113 51

268-210

51

H

H H H H Hydrochloride NO, H

m

H

Hydrochloride NO2 H H

212-213

51

H

Hydrochloride NO, H H

241-248

If2

NHCH2CH2

201.-208

51

265-266

51

H H H H H

R3

H

-.3

H

--N H

i l N\-N-H

CH,

H

Dipicrale H NO, H Hydrochloride NO, H H

H H

H H

H H

CH3

N"2

H

585

Hvdrochloride NO, H NO2 H

215-211 51 185- 186 113 1 7 1.5-1 72.5 113

TABLE 11. ( C o d . )

5. Nitro-2,3,3-trimerhyl-3 H-indoles

R'

R2

RS

mp ('c)

Ref.

NO2

H Methiodide

H

136137 224

226 226 226 226 51 69 54 19 33 69 54 54 54 54 54

NO2 H

H

H H H

H

H

Methiodide NO2

Methobromide Methopicrate NO2 NO2

H

a I

c1 H

-

214 124-125 127 128 130-1 31.5

-

Cl

I

NO2 NO2

NO,

586

175-178 168 192 201 186 175

TABLE II. (Contd.) ~~

6. Dinitroindoles

R'

R2

R3

H H H H H H CH, CH, H H

RS

R4

R6

NO, NO2 H H H H H H H H

R7

H H H H H H H H H H

H

H

H

CH3

H

H

CZH, H H H H H H H H

H H H H H H CH, CH, CH,

H NO, NO, NO, NO, NO, NO2 NO, NO,

~~

GH5

CH,

NO,

mp('C)

Ref.

215.5-271 284-285 284-285 285-287 229-230 309-3 10 201-203 226-228.5 301-302 260 265-261 268 300-302 305 312 3 18-320 293-295 299 >280 260-261.5 265 360 >360 >360 >360 >360 >360

40 19 40 19 19 59 19 19 40 39 227 63 90 19 51 59 90 19 32

40 41 54 54 54 54 54 54

R5*7:: 7. Trinitroindoles

R4

Re

R1

R2

R3

H CH, H CH3 H

CH3 CH, CH, CH, H CH3

NO, NO, NO2 NO2 NO, NO,

H

R4

NO2 NO2

H

H

H H

R'

RI

R5

R6

R7

rnp(OC)

Ref.

H H NO2 NO2 NO2 NO,

NO2 NO2 NO2 NO2 H H

H H H H NO, NO2

254-256 242-244 265-261 261-269 232-233 205-206 213-215

227, 19 19 19 19 47

587

74

19

TABLE 11. (Contd.) 8 . Nitroindolines

R5

R6

R'

mp ("C)

CH3,CH3 NO, H,H H

H NO,

H H

H H

H,CH3

H, H

H

NO,

H

H

146 91-91.5 92-93 92-94 82

H CH3 2-BrC6H4CH, NO

H,H H,CH3 H,CH3 H,CH3

H,H H,H H,H H,H

H H H H

NO, NO, NO, NO,

H H H H

Br H H H

NO CHS H

H,C,H, =CH, H,H

H,H H CH3,CH3 H H,H H

NO, NO, H

H H NO,

H H H

CH3 H

H,H H,CH3

H,H H,H

H H

NO, H NO2 H

R'

R2

R3

CH3 H

=CH, H,H

H

R4

H H

H

H,H

H,CH,

H

NO NO CH3 H NO H

H,CH3 H,H H,H H,H H,CH, H,H

H,H H,CH3 H,H H,H H.H H.H

H H H H H H

588

Hydrochloride H NO, H Hydrochloride H NO, H NO, H H NO, H Br Br H NO, H H NO, NO, H NO,

-

149-151 48-49 96-98 133.5 135 160 203-204 65.5-67 66-67 66.5-67.5 49.4-50.5 50

-

200 15

192 103-104 100

73-74 198-199 108 243-244 244-245

Ref. 226 44 109 45 228 44 109 34 229 34 228 228 230 45 231 44 43 108 44 108 108 108 108 108 44 232 228 44 41

TABLE 11. (Contd.) B. Indoles and Indolines with Side-Chin Nitro Groups

I . 3-(2-Nitroalkyl)indoles R3 R'

R1

Rz

R3

R4

R5

R6

H

H

H

H

H

H

H H

CH3 H

H CH3

H H

H H

H H

H H

H H

C6H6

H CH3

H H

H H

H

bp or mp ("c)

52-54 121 53.5-4 122 55.5-56.1 157 67-68 129 89-90 130 90-91 133 116.5 (dimorphic forms) 99-100 133 178-180 114 (0.5 mm)

-

H

H

H

H

CH3 CH3 H H H H H

CH3 H CH3

H C6H5

H H

H

H H H H H H H

H H

H H

H H

H 5-CI

H

H

H

6-CH3

H H CH3 H H

H H CH3 CH3 CH3

H H

6-F 7-CH3 H H H

H

c6H5

'eH6

C6H5

C6H6 6 H e '

4-CICGH4 'eH5

C6H5 C6H5

C6H5

C6H5

CH3

H

589

H

Ref.

75.5-76 90-9 1 7 1-72 94- 9s 104-105 144-147 147-148 161-162 66.5-68 75-75.2 163-164 60

-

125 (10-4 mm)

-

-

164 119 114

130 130 130,233 130 131 133 114 119 163 163 164 163 117 116

139-140 130 198-199 130 177.5-1 79.5 130 170.5-172.5 (dimorphic forms) 226228 130

TABLE 11.

(Con&.)

R6

bp or mP

H CH3

6-CH3 H

120-130

H H

CH3 CH3

CCH3 5-CI

130-131 92-93

H H H H C6H5

CH3 CH3 CH3 CH3 CH3

5-Br 6-CH3

109-109.5 84-86 93-95 104-107 226-228 206

163 163 119 119 163 163 163 130 114, 115

222

115

R1

RZ

R3

R4

H H

CH3 H

CH3 CH3

H H

H H

H H H H CH3

H H H H CH3

R5

6-C1

7-CH3 H

("C)

-

mm)

-

Ref. 164 163

H H

H H

H H

H H

H

-CH==C(CH&NO, Br -CH=(CH,)NO, CL

H

H H

H ~. H H

H H

R7

H H H

H H H

H H

R'

-CH==C(CH8)NOx H --CH==C(CH,)NOl H -CH==C(CH,)NO1 CH,

CaH, 2-CI,H,

H H H

H

H

H CH,

C1

H CH, Br

H

H H

H

H

RS

H

-CH=C(CH,)NOI

CH,

H

H H H

H

H H

H

H

H H

H H

R'

2. (2-NirrovinyI)indoles

H

--CH=CHNO, -CH==CHNOI --CH4(CH,)NOI

CH, CUH, H CH, H H

H

H

H

H

2 H

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

Indoles. Part 3 (Chemistry of Heterocyclic Compounds, Volume 25c)

Indoles. Part 1 (Chemistry of Heterocyclic Compounds, Volume 25a)

Isoquinolines, Part 1 (The Chemistry of Heterocyclic Compounds, Volume 38)

Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

The Chemistry of Heterocyclic Compounds, The Chemistry of 1,2,3-Thiadiazoles (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 62)

The Chemistry of Heterocyclic Compounds, Acridines

Chemistry of Heterocyclic Compounds The Pyrazines 2C

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

The Chemistry of Heterocyclic Compounds, The Naphthyridines

Quinazolines, Supplement I (The Chemistry of Heterocyclic Compounds, Volume 55)

The Chemistry of Heterocyclic Compounds, Supplement I (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 58)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Triazoles: 1,2,3 (The Chemistry of Heterocyclic Compounds, Volume 39)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Aza-Crown Macrocycles (The Chemistry of Heterocyclic Compounds, Volume 51)

Heterocyclic Scaffolds II: Reactions and Applications of Indoles (Topics in Heterocyclic Chemistry, Volume 26)

Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications

The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 60)

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

The Chemistry of Heterocyclic Compounds, Small Ring Heterocycles (Part 3, Volume 42)

Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 13 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

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Progress in Heterocyclic Chemistry, Volume 18 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

New Types of Persistent Halogenated Compounds (Handbook of Environmental Chemistry, Volume 3 Anthropogenic Compounds, Part K)

Handbook of Heterocyclic Chemistry

Heterocyclic chemistry

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

Indoles. Part 3 (Chemistry of Heterocyclic Compounds, Volume 25c)

Indoles. Part 1 (Chemistry of Heterocyclic Compounds, Volume 25a)

Isoquinolines, Part 1 (The Chemistry of Heterocyclic Compounds, Volume 38)

Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

The Chemistry of Heterocyclic Compounds, The Chemistry of 1,2,3-Thiadiazoles (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 62)

The Chemistry of Heterocyclic Compounds, Acridines

Chemistry of Heterocyclic Compounds The Pyrazines 2C

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

The Chemistry of Heterocyclic Compounds, The Naphthyridines

Quinazolines, Supplement I (The Chemistry of Heterocyclic Compounds, Volume 55)

The Chemistry of Heterocyclic Compounds, Supplement I (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 58)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Triazoles: 1,2,3 (The Chemistry of Heterocyclic Compounds, Volume 39)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Aza-Crown Macrocycles (The Chemistry of Heterocyclic Compounds, Volume 51)

Heterocyclic Scaffolds II: Reactions and Applications of Indoles (Topics in Heterocyclic Chemistry, Volume 26)

Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications

The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 60)

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

The Chemistry of Heterocyclic Compounds, Small Ring Heterocycles (Part 3, Volume 42)

Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 13 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

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Progress in Heterocyclic Chemistry, Volume 18 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

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