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ISOQUINOLINES.

PART TWO

Edited by

F. G. Kathawala Gary M. Coppola

Herbert F. Schuster SANDOZ RESEARCH iNSTlTUTE

EAST HANOVER. NEW JERSEY

AN INTERSCIENCE @ PUBLICATION

JOHN WILEY & SONS

NEW YORK CHICHESTER BRISBANE TORONTO SINGAPORE

This Page Intentionally Left Blank

lSoQUINOLINEs

PART TWO

This is the rhirty-eighth wlumr in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS c

A SERIES OF MONOGRAPHS

EDWARD C. TAYLOR, Editor

ARNOLD WEISSBERGER, Founding Editor

ISOQUINOLINES.

PART TWO

Edited by

F. G. Kathawala Gary M. Coppola

Herbert F. Schuster SANDOZ RESEARCH iNSTlTUTE

EAST HANOVER. NEW JERSEY

AN INTERSCIENCE @ PUBLICATION

JOHN WILEY & SONS

NEW YORK CHICHESTER BRISBANE TORONTO SINGAPORE

An Interscience @ Publication

Copyright 0 1990 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 Sections 107 or I08 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc.

Lihsry'ol C m Cstsloging in PVMiatioa Dsm

Main entry under title: Isoquinoiines

(The Chemistry of Heterocyclic compounds ISSN 0069-3154) "An Interscience-publication." Includes index.

ISBN 0-471 -62856-5

I09 8 7 6 5 4 3 2 I

To my brother Rick

To Didi, Oliver, and Rene

To my wge, Maro my daughter, Kristiana

my son, Stefan

-G.M.C.

-F.G.K.

-H.F.S.

The Chemistry of Heterocyclic Compounds Introduction to the Series

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

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

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

It has become increasingly clear that this arbitrary distinction creates as many problems as it solves, 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.

Department of Chemistry Princeton University Princeton New Jersey

EDWARD C. TAYLOR

ix

Preface

A large number of alkaloids and other natural products carry the isoquinoline skeleton. These natural products provide the basis for many intensive efforts towards the development of new and useful therapeutic agents. As indicated in the preface of Isoquinolines: Part One the purpose of the books on isoquinolines is dual: an introduction for the beginner interested in the general chemistry of isoquinolines and a source of detailed data for the frequent user.

Since the publication of Part One of the isoquinoline series in 1981, unfortun- ate factors delayed publication of the intended Parts Two, Three, and Four, which were originally targeted for the early 1980s. Because of the delay, the chapters in Part Two differ from the projected ones indicated in the contents of Isoquinolines: Part One.

We made a commitment in 1987 to see that the subsequent Isoquinolines volumes were published as soon as possible. This volume is the result of the work of authors who have been prompt in responding to our call to update their chapters.

The present volume gives details of the chemistry of the following isoquinoline derivatives: Halogenated and metallated isoquinolines and their hydrogenated derivatives; isoquinoline carboxylic acids and their hydrogenated derivatives; isoquinolines containing basic functions at the ring and their hydrogenated derivatives; and isoquinolines containing oxidized nitrogen functions and their hydrogenated derivatives. We wish to acknowledge our gratitude and appreciation for the efforts of the authors who contributed to this volume, thus making possible the expeditious publication of this book.

Many thanks are also given to the staff members of the library of Sandoz Research Institute for their much-needed help. Joyce Birch and Ellen Brennan have our appreciation and gratitude for their secretarial services. We also wish to acknowledge the silent support of our family members during the hours spent on editorial tasks.

F. G. KATHAWALA GARY M. COPPOLA

HERBERT F. SCHUSTER

Sandoz Research lnsriture East Hanover. New Jersey May 1989

xi

Con tents

1. Halogenated and Metallated Isoquinolines and Their Hydrogenated Derivatives 1

M. D. NAlR and M. S. PREMILA

11. lsoquinoline Carboxylic Acids and Their Hydrogenated Derivatives 133

F. D. POPP and F. F. DUARTE

Ill. lsoquinolines Containing Basic Functions at the Ring and Their

I. W. MATHISON and W. E. SOLOMONS

Hydrogenated Derivatives 367

IV. lsoquinolines Containing Oxidized Nitrogen Functions and Their

J. W. BUNTING

Hydrogenated Derivatives 479

Index 533

... X l l l

ISOQUINOLINES

PART TWO

771;s is rhe rhirry-eiyhrh colume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUWDS

CHAPTER I

Halogenated and Metallated Isoquinolines and Their

Hydrogenated Derivatives

M. D. NAlR AND M. S. PREMILA

Pharmaceuticals Division, Southern Petrochemical Industries Corporation Limited, Madras, Indie

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methods of Synthesis., . . . . . . . . . . . . . . . . . , . . . , . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Ring-Halogenated Isoquinolines __ . . . . . . . . . . . . . . . . .

(a) General _ . . _ . . . . . . . . . . . . . . . . ........................... (b) Halogenation of the lsoquinoline or its Salts, . . . . . . . . . . . . . . . . . . . . .

( i i ) Swamping Catalyst Method . . . . . . . . . . . . . . . . . . . . . . . . . . . (iii) Halogenation of Activated ...............................

A.

( i l Direct Halogenation . . . . . . . . . . . . , , . . . . . , . . . , . . . , . . . . . . . . . , , , . . . . .

(c) From N-Oxides . . , . . . . . . . . . . . . . . . . . , . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( i ) Halogenation of N-Oxides . . . . . . . . . . . .

(11) Rearrangements of N-Oxides . . . . . , , . . , . . . . . . . . . . , . . . . . . . . . , . I . . . . (d) Conversion of Hydroxyisoquinolines . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . .

(i) Through Nitrilium Salts or Their Equivalents.. . . . . . . . . . . _ . . . , . . . . . ( i t ) Pomeranz-Fritsch Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(iii) One-Step Perchloroisoquinolinc Synt hcsis . . . . . . . . . . . . . . . . . . , , (0 Sandmeyer and Schiemann Reactions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . .

(i) Sandmeyer Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (ti) Schiemann Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(g) Friedel Crafts-Type Ring Clowre . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . (h) Miscellancous Methods . . . . . . . . . . . . . . . . . . . . . . . . . I

(i) Rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _ . . _ . _ . _ _ _ _ _ _ . . . . (ii) Replacement Reactions. . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . , , . . . , , . . , .

( i v ) lnterconversions . . . . . . . . . . . . . . _ , . . . . , . . . . _ . . . _ . . . , _ _ . . . . . . . _ . . . . (v ) Selective Reduction . . . . . . . . . . . . . . , . . , . . . . . . . . . . . . . . . . . . . . . . . . . . .

(vi) Other Methods.. . . . . . . . . . . . B. Bromoisoquinolines . . . . . . . ......................... . . . . . . . _ . . _ . . . _ _ . , . . . . . C. Chloroisoquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Fluoroisoquinolincs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. lodoisoquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. lsoquinolines Substituted by Direrent Halogens . , . . . . . . . . . , . . . . . . . , . . . . . . . . .

(e) Building Up of thc Pyridine Ring of Isoquinolines . . . . . .

(iii) Cleavage Reactions . . . . . . . . . . . . . . . . . . . . .

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

3 4 4 4 4 4 6 8

10 10 11 12 18 18 24 26 26 26 29 29 31 31 33 34 34 35 36 38 40 40 41 41

1 . Halogenated and Metallaced lsoquinolines

111 . Reactions of Halogenated Isoquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Nucleophilic Replacements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Di-Dehydroisoquinolines C Reduction of Haloisoquinolina . . . . . . . . . . . . . . . . . . . D . N-Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Other Reactions Physical and Spcctroscopic Propcrtics of Haloisoquinolincs .......................

. . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV .

Vi . v . Uscs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organometallic Lkrivatives of lsoquinolines .......................

B . Grignard Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Tin Compounds ...............................

. . . . . . . . . . . . . . . . . . . A Lithium Salts

D . Other Organometallic Derivalives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Group I B Elemcnts . . . . . . . . . . . .

(i) Copper ......................................................... (ii) Silver ...........................................................

(b) Group I IA Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(c) Group l l B Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(ii) Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(d) Group I l l A Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

( e ) Group I l l B El

. . . . . .

es . . . . . . . . . . . . . . .

(2) Holmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (3) Ytterbium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(ii) Actinide Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (I) Thorium . . . . . . . . . . . . . . . ...................... ... (2) Uranium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(f) Group IVA Elements .................................................. ( i ) Germanium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(ii) Tin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (iii) Lead ...........................................................

(g) Group IVB Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

(i) Group V B Elements

(i) Chromium ...................................................... . . . . . . . . . . . . .

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

( v ) Rhodium . . . . . . . . . . . . . . . ...........................

41 41 52 53 55 58 62 63 65 65 69 70 70 70 70 71 71 71 71 71 72 12 12 12 72 72 72 73 73 73 73 73 73 73 73 73 73 73 14 74 74 74 74 74 74 75 75 75 76 76 76 76 76 76

Introduction 3

(v i ) Palladium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 (vii) Osmium.. . . . . . . . . . . . . . . . . . . .

(viii) Iridium.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (ix) Platinum.. . . . . . . . . . . . . . . . . . . .

E. Nonmetallic Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Boron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 (b) Silicon .......................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 (c) Sclenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

V l l . Tables of Halogenat uinolines and Isoquinoline Organometidlic Dcrivntivcs. . 81 A. Fluoroisoquinolines.. . . . .................... 81 B. Monochloroisoquinolincs .................... 83 C. Substituted Monochlorois . . . . . . . . . . . . . . . . . . . . . . . . . 87 D. Polychloroisoquinolincs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 E. Bromoisoquinolinn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 F. lodoisoquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 G . lsoquinolines Subsituled with DitTerent Halogens. ........................... 103 H. Organometallic Derivatives of Isoquinolincs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

VIII. Refercnccs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

I. INTRODUCTION

This chapter reviews the preparation, properties, and reactions of halogenated isoquinolines and their hydrogenated derivatives. Also included are organometallic derivatives and complexes incorporating the isoquinoline nucleus.

Many of the possible mono and poly ring-halogenated isoquinolines have been reported and even those that have not yet been prepared may be synthesized by one or more of the general synthetic routes outlined here. Interest in these classes of compounds has centered around their potential utility as starting materials for biologically active preparations or as synthons for the synthesis of polycyclic natural products containing the isoquinolinc nucleus.

Side-chain halogenated isoquinolines are versatile intermediates for the synthesis of potential biologically active molecules because of the relatively higher reactivity of side-chain halogens. However, they have not been included because they do not fall strictly under the defined scope of this chapter. Quarternary derivatives are not included; however, references to N-oxides have been made since they constitute important starting materials for certain halogenated isoquinolines.

Much of the early literature on halogenated isoquinolines sadly lacks exper- imental details; the tables of halogenated derivatives, are therefore, incomplete in certain respects.

Reports on organometallic derivatives of isoquinolines appearing in the literature mostly refer to complexes of ill-defined structure and properties. Nevertheless, they are presented in the tables along with the availible details on their preparation and propcrties.

4 Halogenated and Metallated lsoquinolines

11. RING-HALOGENATED ISOQUINOLINES

A. Methods of Synthesis

(a) General

The success of the reaction and the nature of the isomers obtained in the various procedures for the synthesis of halogenated isoquinolines depend on the conditions used, the nature of substituents in the ring, and the nature of the halogens. Most of the work reported in the literature pertains to the synthesis of chloro- and bromoisoquinolines and their derivatives. Relatively few fluoro- and iodoisoquinolines have been prepared and their properties studied.

Benzene-ring-substituted haloisoquinolines are prepared essentially by direct halogenations or by the Sandmeyer reaction on the corresponding amino derivatives, while pyridine-ring-substituted haloisoquinolines have been prepared by any one of the halogenation procedures. Benzene-ring-substituted haloisoquinolines may also tie prepared by starting with the appropriate halophenyl derivatives and building up the isoquinoline ring system by any of the well-known isoquinoline syntheses according to Bischler-Napieralski, Pictet Spengler, Pictet-Gams. or Pomeranz-Fritsch reactions.' However, since the first three of these ring closures require activated benzene rings for cyclization to take place, such methods have not generally been preferred. In addition, since most of these synthetic methods yield hydrogenated isoquinoline derivatives. a final dehydrogenation step is also needed.

( h ) Halogenation of the Isoquinoline und its Salts

(i) Direct Halogenation

From n-electron density calculations, electrophilic substitution is predicted to take place at the 4 position of the isoquinoline nucleus.2 However, direct halogenation of isoquinoline itself, in the absence of catalysts, does not proceed to any appreciable extent. Jansen and Wibaut' found that bromination at 300 "C in the gaseous phase produced no bromoisoquinoline; at 450°C a small amount of I -bromoisoquinoline was obtained along with some unidentified products. A recent French patent4 describes the bromination of isoquinoline in nitrobenzene to yield the expected 4-bromoisoquinoline.

Edinger and Bossungs found that heating of isoquinoline dibromide or its hydrobromide or hydrochloride salt at 180-200 "C produced 4-bromoisoquinoline (I), besides higher brominated product^.^.' I t has been reported that a tribromoisoquinoline was obtained on warming an alcoholic solution of isoquinoline perbr~mide;~ details are not available.

Bromination of the hydrobromide salt of isoquinoline at 180 "C gave a 73% yield of 4-bromoisoquinoline (I) . More recently, Kress and Constantino8 carried

Ring-Halogenated Isoquinolincs 5

out the reaction of isoquinoline hydrochloride in nitrobenzene with bromine at 180°C and obtained an 81 % yield of 4-bromoisoquinoline (Scheme 1).

Br

X = HCI, HBr I

Br

2

!Scheme I

Direct bromination of isoquinoline has also been reported 9.10 in sulfur monochloride at reflux temperatures, again to yield 4-bromoisoquinolines. In all of these reactions, no attempt has been made to determine the extent of by- product formation consisting of isomeric bromo compounds or polybromo derivatives. A t least in some of these cases, i t does seem possible that 5-bromo derivatives are also formed.

Dewar and Maitlis' ' reported in 1957 that nitration in a strongly acid medium produced the 5-nitro derivative as the major product, indicating that the preferred electrophilic attack is at the 5 position under strongly acid conditions. Bromination in strong acid is reported to give 5-bromoisoquinoline (2)."

lodination of isoquinoline in sulfuric acid is reported to yield both diiodo- and triiodoisoquinolines of undetermined orientation.' lodination of 1.2.3.4-tetra- hydroisoquinoline in sulfuric acid containing silver sulfate gave a mixture of 6-, 7-. and 8-iodo- 1,2,3.4-tetrahydroisoquinolines.' However, iodination of isoquinoline with iodine in hydriodic acid yielded 4-iodoisoquinoline. I d

Direct chlorination of isoquinoline in the vapor phase or through its hydrochloride salt to yield chloro derivatives has not been reported. Chlorin- ation of isoquinoline with sulfur monochloride or sulfur dichloride is said to result in a trichloroisoquinoline as major p r ~ d u c t . ' ~ . ' ~ However, neither the orientation of the halogen atoms in this product nor the yield is reported.


When isoquinoline was passed over cesium tetrafluorocobaltate. a complex mixture of products was obtained, from which the perfluoroisoquinoline (3) and (4) were isolated" (Eq. 1).

3

N-Methyl decahydroisoquinoline was fluorinated electrochemically to give, among other products, a mixture of cis- and trans-perfluoro derivatives.**

(ii) Swamping Catalyst Method

Chlorination and bromination of isoquinoline in the presence of aluminium chloride as a catalyst have been used extensively for the synthesis of chloro- and bromoisoquinolines. Halogenation of the aluminium chloride complexes of isoquinoline gave in good yields halogen derivatives substituted in the benzene ring." The nature of the products and the sequence of the substitution reactions depend on the amount of halogen used, temperature, and time of reaction. Thus, chlorination at 75 "C yielded 31 % of the 5-chloro isomer (5): with 2 eq. chlorine, 5,8-dichloro-(6) and further 5,7,8-trichloro derivatives (7) were obtained (Scheme 2). A modification of this method using a melt of isoquinoline and aluminium chloride at 105-1 10 "C has been employed to prepare 5,6,7,8-tetrachloroisoquin- oline in low (2%) yield." Similar reactions occurred with bromine; 5-bromo-, 5,8-dibromo-, 5,7,8-tribromo- and even 5,6,7,8-tetrabromoisoquinolines have been isolated. A patent" claimed the preparation of hexachloroisoquinoline (8) in 87% yield using this swamping catalyst method. Several interesting points emerge from this process. First, there is the possibility for preparing mono, di, and trihalo derivatives in a selective manner by a relay synthesis. To obtain, for example, a 5,6,8-trihalogeno derivative, it is advantageous to halogenate the 5,g-dihaIo derivative, rather than direct halogenation with an excess of reagent. The orientation of the third-entering halogen in dihaloisoquinolines has led to the proposal of a canonical form, such as (9), as an important contributor in this reaction. The orientation of the products is consistent with the molecular orbital calculations of Dewar and Maitlis" for the protonated forms of isoquinoline.

Similarly, it was observed that 5,8-dibromoquinoline is converted to 5,7,8- tribromoquinoline in keeping with the canonical form (10) for the quinoline complex.

Ring-Habgenaled lsoquinolines

6 7

I c1’

1 . elf# c1 / N

c1 Cl

Cl

8

I Br

9 10

x Halogenated and Metallated lsoquinolines

(iii) Halogenation of Activated Nucleus

Direct halogenation of isoquinolines carrying strong activating groups pro- ceeds in moderate yield^.^*^^ Thus, 7-acetamidoisoquinoline (1 1) upon chlorination gives the 7-acetamido-8-chloroisoquinoline (12) (Eq. 2). I t is significant that such groups are capable of directing the entering substituent to the 8 position in perference to the normal 5 position.

1 1 12

4-Hydroxyisoquinoline, upon bromination in the presence of alkali at room temperature furnishedz3 the 3-bromo compound (13) in 76% yield, whereas heating to 80 ‘C produced 1,3-dibromo-4-hydroxyisoquinoIine (14) in 40% yield (Scheme 3).

dN - &Br

I3

L OH WBr / N

Br

I4

Bromination of alkoxy-substituted isoquinolines yielded the corresponding 8- bromo compounds.24 - ” Thus, 7-hydroxy-6-methoxyisoquinoline, on bromination with bromine in acetic acid containing sodium acetate, followed by methylation, gave 15 in 71% yieldZh (Eq. 3).

Ring-Halogenated Isoqtiinolines 9

I S

Bromination of the mercurated derivative of isoquinoline (16) led to 4- bromoisoquinoline (1) (Eq. 4).

Br HgCl

Ib I

Addition, followed by elimination, has been suggested as a plausible mechanism of this reaction’.10*28 (Scheme 4).

With phosphorus pentabromide, isoquinoline-5-sulfonic acid yielded a mixture of mono- and dibromoisoquinolines of undetermined str~cture.’~

lodination gave even better results; at 20-C, iodine-potassium iodide converted 4-hydroxyisoquinoline to 4-hydroxy-3-iodoisoquinoline in 83% yield, while at 70 C, 1.3-diiodo-4-hydroxyisoquinoline was obtained.”

lodination of 5-hydroxyisoquinoline takes place in the more activated benzene ring. Using iodine monochloride as reagent, 5-hydroxyisoquinoline was converted at 5- C to 5-hydroxy-8-iodoisoquinoline ( 17)30 (Eq. 5).

10 Halogenated and Me talla ted lsoq ui nolines

OH OH

I

17

(c) From N-Oxides

(i) Halogenation of N-Oxides

Even though the electrophilicity in the isoquinoline nucleus is maximum at the 5 and 8 positions when halogenations are carried out in strongly acid medium, instances of a halogen atom entering the 4 position of the nucleus when a partial positive charge resides on the nitrogen atom are also known. Thus, isoquinoline N-oxide facilitates bromination and directs the entering bromine to the 4 position.” These reactions, however, produce the corresponding brominated isocarbostyrils as well, presumably by a rearrangement of the N-oxide under the reaction conditions. In certain cases, deoxygenation also results, for example, bromination of isoquinoline N-oxide in the presence of acetic anhydride gave a mixture of 4-bromoisocarbostyril and 4-bromoisoquinoline ( l p (Eq. 6).

Br

Isoquinoline N-oxide also reacts with cyanogen bromide in ethanol to give 4- bromoisocarbostyril in low yield (4.9%).32

I t is interesting to note that heterocyclic halides do react with isoquinoline N- oxide to yield 4-haloisoquinolines. For example, 2-bromopyridine (Eq. 7), 1- bromois~quinoline,~’ I-chlorois~quinoline,~~ and 2-bromopyrimidineJ4 react with isoquinoline N-oxides to yield 4-bromo- and 4-chloroisoquinolines as minor products.

The mechanism of these halogenation reactions has been disc~ssed.’~ In a related reaction, ptoluenesulphonyl chloride reacts with isoquinoline N-oxide to yield 4-chloroisoquinoline in small amounts, besides 4-p-toluenesulfonamido isoq uinoline and isocarbos tyril. ’ ’

Ring-Halogenated Isoquinolines

+

(ii) Rearrangements of N-Oxides

Rearrangements of isoquinoline N-oxides under Meisenheimer reaction conditions lead to I-haloisoquinolines. The formation of the I-chloro rather than the 3-chloro derivative is attributable to the greater electrophilicity of the 1 position. Of the chlorine-containing reagents, such as phosphorus oxychloride, phosphorus pentachloride, or sulfuryl chloride that form Meisenheimer complexes with isoquinoline N-oxide, phosphorus oxychloride is the most fre- quently used. Isoquinoline-N-oxide itself is converted to 1 -chloroisoquinoline in 56% yield.3s p-Toluenesulfonyl chloride also reacts in a similar fashion. but, as mentioned earlier. leads to a variety of other products. The mechanism of this reaction is illustrated in Scheme 5.

The reaction is also suited to the synthesis of I-haloisoquinoline. especially I - chloroisoquinolines3s carrying other substituents in the nucleus. 7-Chloroiso-

scheme 5


quinoline N-oxide yields I ,7-dichloroisoquinoline, while 6- or 7-methoxyisoquinoline N-oxides are converted to their respective I-chloro derivatives in excellent yields (see also ref. 100). 4-Bromoisoquinoline can be transformed through its N-oxide into I -chloro-4-bromoisoquinolines under the mild conditions of this reaction.J6

Even the presence of a nitro group in the nucleus does not deter the facile rearrangement of isoquinoline N-oxide. Thus, 4-bromo-5-nitroisoquinoline N- oxide (18) yields the 1-chloro derivative (19)” (Eq. 8).

Cl 19

7,8-Dimethoxyisoquinoline N-oxide is readily converted into l-chIoro-7,8- dimethoxyisoquinoline (20)3R (Eq. 9).

Me0 F N 40 - Me0 (9)

OMe Me0 CI 2 0

4-Azidoisoquinoline N-oxide on treatment with phosphorus oxychloride

4-Chloroisoquinoline was obtained in 23% yield during direct acylamination yields the azido- l-chloroisoquinoline in 62% yield.”

of isoquinoline N-oxide using N-phenyl benzimidoyl chloride4’ (Eq. 10).

C1 I

(d ) Conversion of Hydroxyisoquinolines

A facile method for the preparation of 1 -chloro- and I ,3-dichloroisoquinolines and the corresponding bromo analogs involves the treatment of the hydroxy derivatives with reagents like phosphorus oxychloride or bromide. Thus,

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