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ISOQLJINOLINES Part 3

Edited by

Gary M. Coppola and Herbert F. Schuster

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY & SONS, INC. NEW YORK * CHICHESTER * BRISBANE * TORONTO - SINGAPORE

ISOQUINOLINES

This is a part ofthe thirty-eighth volume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS


A SERIES OF MONOGRAPHS

EDWARD C. TAYLOR, Editor

ARNOLD WEISSBERGER, Founding Editor

ISOQLJINOLINES Part 3

Edited by

Gary M. Coppola and Herbert F. Schuster

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY & SONS, INC. NEW YORK * CHICHESTER * BRISBANE * TORONTO - SINGAPORE

This text is printed on acid-free paper.

Copyright 3;: 1995 by John Wiley & Sons. Inc.

All rights reserved. Published simultaneously in Canada.

Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or furthei information should be addressed to the Permissions Department, John Wiley & Sons, Inc.. 605 Third Avenue, New York, NY 10 f 58-0012.

Library of Congress Cataloging in Publication Data:

Isoquinolines. (The chemistry of heterocyolic compounds, 0069-31 M:

Pt. 2 edited by F.G. Kathawala. Gary M. Coppola, Herbert F. Schuster; pt. 3 edited by Gary M. Coppola and Herbert F. Schuster.

V. 38- .)

"An Interscience-publication." Includes bibliographical references and indexes. 1. Isoquinoline. 2. Isoquinolines. I. Grethe. Guenter.

QD401.183 54T.596 80-1 1510 ISBN 0-471-37481-4 (v. I ) ISBN 0-471-62855-7 (v. 3)

1 0 9 8 7 6 5 4 3 2 1

To Clare and Perer -G. M. C.

To my wife, Maro: my daughter; Kristianu; my son. SteJan

-H. F. S.

Contributors

Hiroshi Hara Herbert F. Schuster Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan

Osarnu Hoshino Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan

Sandoz Research Institute East Hanover, New Jersey

Bunsuke Urnezawa Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan

F. G. Kathawala Sandoz Research Institute East Hanover, New Jersey

The Chemistry of Heterocyclic Compounds Introduction to the Series

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

The Chemistry of Heterocyclic Compounds, published since 1950 under the initial editorship of Arnold Weissberger, and later, until Dr. Weissberger’s death in 1984, under our joint editorship, has attempted to make the extraordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has dealt with syntheses, reactions, properties, structure, physical chemistry, and utility of compounds belonging to a specific ring system or class (e.g., pyridines, thiophenes, pyrimidines, three- membered ring systems). This series has become the basic reference collection for information on heterocyclic compounds.

Many broader aspects of heterocyclic chemistry are recognized as disciplines of general significance which impinge on almost all aspects of modem organic and medicinal chemistry, and for this reason we initiated several years ago a parallel series entitled General Heterocyclic Chemistry, which treated such topics as nuclear magnetic resonance, mass spectra, and photochemistry of heterocyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cycloaddition reactions. These volumes are of interest to all organic and medicinal chemists, as well as to those whose particular concern is heterocyclic chemistry.

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

EDWARD C. TAYLOR

Department of Chemistry Princeton Uniuersiry Princeton, New Jersey

ix

Preface

The isoquinoline skeleton is found in a wide variety of natural and pharma- ceutically interesting compounds. Because the field of isoquinolines is so large, four volumes were planned for the presentation of this material. However, unforeseen circumstances and author delays forced a reorganization of the orginally proposed chapters that were outlined in Isoquinolines: Part One.

This final volume of the Isoquinoline series examines the chemistry surround- ing two classes of isoquinolines, those containing basic functionalities in the side chain and those possessing hydroxyl or thiol substituents. The authors have kindly updated their original manuscripts, and we thank them for their efforts. It is our hope that this volume will serve as a useful reference to those actively involved in isoquinoline research and to those whose interests will lead them into the rich field of isoquinolines.

GARY M. COPPOLA HERBERT F. SCHUSTER

East Hanorer. New Jersey July 1994

xi

Contents

I. ISOQUINOLINES BEARING BASIC SIDE CHAINS 1

H.F. SCHUSTER AND F.G. KATHAWALA

II. ISOQUINOLINES AND THEIR HYDROGENATED DERIVATIVES 225 0. HOSHIYO, H. H A R ~ , 4~ R. UWLAIVA

INDEX 545

ISOQUINOLINES

This is a part of the thirty-eighth volume in the series


Isoquinolines Bearing Basic Side Chains H. F. Schuster and F. Kathawala

I. Introduction 11. Isoquinolines Having Basic-Containing Substituents at C1

A. l-(Aminoalkyl)isoquinolines B. l-(Aminoalkoxy)is~uinolines C. Isoquinolines Containing Aminophenyl Substituents

1. 1-Anilinoisoquinolines (n = 0) 2. I-(Aminobenzyl)isoquinolines (n= 1) 3. 1 -(Aminophenethyl)isoquinolines (n = 2)

I. Five-Membered Heterocycles 2. Six-Membered Heterocycles Isoquinolines

a. Substituted I -(Pyridyl)isoquinolines b. Substituted I-(Piperidyl)isoquinolines c. Conclusion

E. Bis-isoquinolines F. Emetine

A. 2-(Aminoalkyl)isoquinolines B. Substituted 2-(Aminophenyl)isoquinolines C. 2-Heterocyclic Substituted Isoquinolines

D. Isoquinolines Bearing Basic Heterocyclic Substituents at Cl

111. Isoquinolines Having Basic-Containing Substituents at C2

IV. Isoquinolines Having Basic-Containing Substituents at C3 V. Isoquinolines Containing Basic Substituents at C4

VI. Miscellaneous Isoquinolines Having Basic Substituents References

1 2 2

27 35 36 53 65 70 70 14 14 88 89 89

114 133 133 161 I 69 183 204 212 214

1. INTRODUCTION

This chapter discusses the preparation and reactions of side-chain isoquinoline and hydrogenated isoquinoline compounds bearing basic-containing functionalities not directly attached to the isoquinoline nucleus (see Chapter 111 by I. W. Mathison and W. E. Solomons in Isoquinolines. Part Two, F. G. Kathawala, G. M. Coppola, and H. F. Schuster, eds., John Wiley & Sons, New York, 1990). The pharmacological importance of many of these compounds has been the motivation for the syntheses of the numerous variations found in this class of compounds.

1

2 Isoquinolines Bearing Basic Side Chains

11. ISOQUINOLINES HAVING BASIC-CONTAINING SUBSTITUENTS AT C1

A. l-(Aminoalkyl)isoquinoliaes

The search for isoquinolines possessing biological activity has provided a variety of synthesis for 1-(aminoalkyl)isquinolines, which have also been further elaborated into more complex heterocyclic systems.

A general method for the preparation of unsubstituted aminoalkylisoquinol- ines involves the reduction of an appropriate nitrile to an amine. The reaction of l-methyl-3,4-dihydroisoquinoline (1) with acrylonitrile followed by the lithium aluminum hydride reduction of 2 furnishes a modest yield of l-(4-aminobutyl)- 3,4-dihydroisoquinoline (3)' -' (Equation 1). qN-qN-

CHI CH 2 CH 2 CH2 CN

1 2

QN

~ H ~ ( c H ~ ) ~ N H ~

3 (1)

reaction with amines to l-(Alk ylha1ide)isoquinolines can undergo an SN2 furnish unsubstituted or substituted 1-(aminoalky1)isoquinolines. The reaction of l-(chloromethyl)-3,4-dihydroisoquinoline (6), easily prepared in two steps from the appropriately substituted phenethylamine 4, with monosubstituted amines provides 1-(substituted aminomethyl)-3,4-dihydroisoquinolines (7), which can be catalytically reduced to their corresponding 1,2,3,4-tetrahydroiso- quinolines 8'-* (Scheme 1).

8 7

Scbemcl

11. Isoquinolines Having Basic-Containing Substituents at C1 3

Derivatives of 8 were converted into a variety of substituted imidazoC5,l- a]isoquinoIines 9 and pyrazino[2,1-~]isquinoIines 14 by Archer and his Sterling group4-* (Scheme 2).

8 R'

9

I R'

10

11

I R'

14

An alternative pathway that has been extensively employed for the preparation of 1 -(aminoaIkyl)isoquinolines involves the use of acyl phenethyl- amines 15 wherein the nitrogen atom of the basic side chain is suitably pro- tected with either a succinoyl or phthaIoy1 group. Subjecting 15 to the Bischler- Napieralski cyclization reaction affords 16 which can be hydrolyzed to 17.


Catalytic reduction of 17 leads to the 1.2,3,4-tetrahydroisoquinoline 1810.19.22,24.3 1.40.41.43 (&heme 3).

POCI, or

PPA -

0 15

0

16

O H

In their attempt at preparing aza-steroids having hypotensive properties, Burchhalter et al." have reacted 1-(2-aminoethyl)-1,2,3,4-tetrahydroiso- quinolines 19 with the iminoether 20 to produce 21 (Equation 2).

R dHNH2 ~ ~ z C H 2 C O z C t m *

O-SOC CI - CHjO

19

8 R=H b R=OCH,

Shiotani and M i t s u h a ~ h i ~ ~ * ~ ~ * ~ ~ refluxed @-(m-methoxypheny1)-N- phthalimidoacetyl alanine methyl ester (22) for 2 hr with phosphorous oxychloride and phosphorous pentoxide to afford 1-phthalimidomethyl-3-carboethoxy- 6-methoxy-3,4-dihydroisoquinoline (23) which on catalytic reduction with hydrogen over platinum oxide yields the corresponding 1,2,3,4-tetrahydroisoquin-


oline 24. Treatment of 24 with hydrazine hydrate generates 8-methoxy-1,2,5,6- tetrahydro-l,5-iminobenz[dlazocino-4(3H)-one (25) in excellent yield (Scheme 4).

22

H

‘ “ 3 0 y p y H \

25

23

The double cyclization of 26 provides in reasonable yield 4-phenyl-9,10- dimethoxy-6,7-dihydro-2tl-pyrimido[4,3-uJisoquinoline (28)24 (Equation 3).

PZ 01

CHCI, CHJO

H NCPh - cHJo)T II 0

27 ij

26

cH’Olq..ph CH3O


Either 4,Sdimethoxy- or 5,6-dimethoxy-l-phthalirnidomethyl-1,2,3,4-tetrahydroisoquinoline 29a or 29b reacts with p-methylbenzenesulfonyl chloride in pyridine to provide 30 which on refluxing with hydrazine hydrate yields 31. Heating 31 with 37% aqueous formaldehyde for 2 hr resulted in the ring closure at C7 to furnish the 2,3,7,8,9,9a-hexahydro-lH-benzo[d,e][ 1,7]naphthyridines 3% and 32bZ2 (Scheme 5).

0

2!3 a R=4,SdiMeO b R=5,6diMe0

R

py rid, n e

0

N I H ~ ' HzO 1

32 31 scbeme 5

The Reissert compound 33 on basic hydrolysis affords isoquinoline- 1- carboxamide (34) which can be reduced with hydrogen over platinum oxide to the 1,2,3,4-tetrahydroisoquinoline 35. Subsequent reduction with lithium aluminum hydride provides XZ5 (Scheme 6).

36 35

seb#nc6

11. lsoquinolines Having Basic-Containing Substituents at Cl 7

The reduction of the Reissert compound 37 with “Basler” nickel catalyst at 90‘C and 70 atm pressure for 24 hr affords 38 which under acidic hydrolysis yields X3* (Equation 4).

Catalytic reduction of I-cyanoisoquinoline (39) leads to 1-(amino- methy1)isoquinoline (40) which after acylation with an appropriate acid chloride can be cyclized with phosphorous oxychloride to the imidazoC5,f- a]isoquinoline (41) in very good yield4’ (Equation 5).

0 II

I RCCl - CN

NH2 40 41

(5 )

A series of 1 -(a-aminoalky1benzyl)isoquinolines 44 were prepared in reasonable yields by the benzylic oxidation of 1-benzylisoquinoline 42 with selenium dioxide followed by a reductive ~ x i m a t i o n ~ ~ (Equation 6).

Because of the medicinal interest in papavarine-like compounds, a large number of aminoalcohols 46 were prepared by reacting papaveraldine 45 with the appropriate Grignard reagents containing a variety of amino functionality12 (Equation 7).


C H 3 0

C H 3 0 go -

C H 3 0 OCH3

45 46

a R = N(CH& b R = morpholino c R = piperidyl

Isoquinoline analogs 48 of the antihistamine Decapryn were prepared by reacting either methylphenyl( 14soquinolyl)carbinol (47a) or diphenyl( 1- isoquinoly1)carbinol (4%) with b-dimeth ylaminoethyl chloride and sodium in toluene at 60°C followed by refluxing for 15 hrJ5 (Equation 8).

dH 47

a R = C H 3 b R = C I H s

I . CICH,CH,N(CH,),

Naltol uenc/t4J°C

2. 1 1 0 ~ C l l S h

48

1. H,O' 2. NaBH, I (9)

I H CHzCHCH2N' C ~ H P

I OH

51


The acidic character of the methyl group of 1-methylisoquinoline (49) was exploited by Meyer et a1.j’ for the preparation of a-[(t-buty1amino)methyl-1- isoquinoline]ethanol (51). Treating 49 with n-butyllithium and reacting the lithio derivative with t-butylacetonitrile affords 1-[2-amino-3-(~- butylamino)propenyl]isoquinoline (50) which after hydrolysis and reduction with sodium borohydride provides the amino alcohol 51 (Equation 9).

The synthesis of potential antitumor agents such as 5-(N-ethyl-N- alky1amino)- (53), 5-(N-monoalkylamino)- (54), and 5-(N-alkylacetamido)-l- formylisoquinoline thiosemicarbazone (55) from 49 is depicted in Scheme 7.”

R, ,CHzCH2 I . B , H 6

2. sco, 3. H,NNHCNHl I1 @ ____,

\ 0 N

i? CCH3

t H 3

49

CH,

52

R, ,H N I

I . SCO

2. H,NNCNH, A

II S


The isoquinoline alkaloid amphibine I (%), isolated from crude alkaline extracts of Ziziphus arnphibid5, possesses chiral centers at C1 and C9 and a third due to the presence of natural (S)-valine.

H CHjO

CHqO

CHqO

2 NaBH,CN

0 0

n 58

0

- 2. H 2 I Pd - c 3. Separation of isomers

I . HCHOIHCOOH 2. N ~ H I 1

59

56

Scbeme 8


In order to correctly assign the absolute configuration of 56, a total synthesis was undertaken. The condensation of N-phthaloyl-L-alanine with 3,4dimethoxy- phenethylamine affords 57. A Bischler-Napieralski ring closure followed by reduction to the 1,2,3,4-tetrahydroisoquinoline 58 occurs with total racemization of the alanine. Considerable racemization could be avoided when a rapid reduction and work up was employed immediately after ring closure. Alkylation and deprotection of 58 affords 59, which after acylation with (S)-Cbz- valylglycine and separation of the resulting mixture yielded 56. By varying the chirality of the amino acids used, all possible diastereomers were prepared and characterized. From this information it was determined that 56 possesses the Cl-(S),C9-(R), syn absolute c~nfigurat ion~~ (Scheme 8).

TABLE 1. BIOLOGICAL ACTIVITY

Structure Biological Activity Rd.

CNS (central nervous system) 67 R l q N , N N tranquilizer

I R'

CNS depressant, sedative, and 4 . V an ticonvulsant

I R'

Antibacterial

I

An tispasmodic

P'

22

16

12

TABLE 1. (Continued)

Isoquinolines Bearing Basic Side Chains

Structure Biological Activity Ref.

Antihistaminic

8-Adrenergic blocker H

CHzfHCHZN'

29

35

30

C H 3 0

R' ' Antipasmodic hypotensive. antipsychotic, 12 k2 analgesic, anticonvulsant

C H 3 0 7 CH2CHZN

OCH3

OCH3

Antifertility 11.32

CH3

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