quinolines · 2013-07-23 · preface the second part of the volume dealing with the chemistry of...

QUINOLINES Part I1

Edited by

Gurnos Jones DEPARTMENT OF CHEMISTRY

UNIVERSITY OF KEELE STAFFORDSHIRE

J O H N W l L E Y & SONS C H I C H E S T E R * N E W YORK - B R I S B A N E - T O R O N T O * S I N G A P O R E

A N INTERSCIENCE@ PUBLICATION

Q U I N O L I N E S

Part I1

This i.7 the rhirrv-second volume in [he series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

.. . . . .._ . ... .. .. . -.-,.....----. _- ._-__._ _.__ ~-.. ..__.. . ------ - -----,---

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGRAPHS

ARNOLD WEISSBERCER and EDWARD C. TAYLOR Editors

--. - ..--------_- --- .-.-----I - -_- - __I-..-.--

QUINOLINES Part I1

Edited by

Gurnos Jones DEPARTMENT OF CHEMISTRY

UNIVERSITY OF KEELE STAFFORDSHIRE

J O H N W l L E Y & SONS C H I C H E S T E R * N E W YORK - B R I S B A N E - T O R O N T O * S I N G A P O R E

A N INTERSCIENCE@ PUBLICATION

An Interscience@ Publication Copyright (. 1982 by John Wiley & Sons Ltd

All rights reserved.

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 Caidoging in Publication Data I Revi.sed) Main entry under title:

Quinolines

(The Chcmistry of hctcrcxjclic compounds; v. 32) "An Interscience publicaticn." Includes hihliographiwl relerences and indexes. I . Quinoline. I . Jones. Gurnos.

QD4OI.Q56 547'.596 76- 26941 ISBN 0471 99437 5 (v . I ) AACRI

British Library Caidoguing in Pub!ication Data.

Quinolines. Part 2 . 4 T h e chemistry of heterocyclic compounds. v.32) 1. Jones. Gurnos J I . Series 547'.5% QD40 I

ISBN 0 471 28055 0

The Chemistry of Heterocyclic Compounds The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. I t 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.

ARNOLD WEISSBERGER Reseurclt LuhoruroriPs Eustmun K o h k Conipunj Rocliesfer. N e w York

EDWARD C. TAYLOR Princeton University Princeton. New Jersey

V

Preface The second part of the volume dealing with the chemistry of quinolines follows the pattern of the first. Every effort has been made to present a comprehensive coverage of the three classes of compound dealt with. A slight departure from the normal procedure has been necessary in Chapter 3, where over 300 references to purely biological properties of the N-oxides have been grouped as a bibliography. As in the first part, tabulated compounds are not generally entered in the subject index.

One of the authors (P. A. C.) is indebted to the City University for leave of absence to enable the final stages of the work to be completed in a reasonable time. He, and I. also thank our wives for help given during the preparation of the manuscripts.

GURNOS JONES University o j Keele Slagordshire

vii

List of Contributors BATY, J . D.

CLARET, P. A.

JONES, G . Department of Chemistry. University of Kccle. Keele.

OSBORNE, A. G .

POPP, F. D.

Department of Biochemical Medicine, University of Dundee. Dundee, UK

Department of Chemistry, City University. London. UK

Staflrdshire , U K

Department of Chemistry, City University. London. UK

Department of Chemistry, University of Missouri-Kansas City, Kansas City, Missouri, USA

ix

Contents 1 Alkylquinolines and Arylquinolines . . . . . . . . 1

P . A . CLARET and A . c . OSBORNE

2 Reissert Compounds and Related N-Acyldihydroquinoliws . . . . 353 F . D . POPP

3 Quinoline N-Oxides . . . . . . . . . . . 377 c . JONES and D . J . BATY

Author Index . . . . . . . . . . . . 607 Subjectlndex . . . . . . . . . . . . 659

xi

Quinolines . Part I I Edited by G . Jones i 1982. John Wiley & Sons . Ltd

CHAPTER 1

Alkylquinolines and Arylquinolines PAUL A . CLARET and ALAN G . OSBORNE

Depurtment of Chemistry . The Cirv Universitv . Northumpton Square. London ECIVOHB . UK

1 . Alkylquinolines and Aralkylquinolines . . . . . . . . . 6 6 8 9

A . Reduction Methods . . . . . . . . . . . . 9 a . Reduction of Halogen Derivatives . . . . . . . . 9 b . Reduction of Hydroxy and Amino Derivatives . . . . . . 10 c . Reduction of Carbonyl Compounds . . . . . . . . 1 1 d . Reduction of Alkenyl and Aralkenylquinolines . . . . . . 12 e . Reduction of Quinoline-I-oxides . . . . . . . . . 13

B . Catalytic Alkylation . . . . . . . . . . . 14 C . Alkylation by Means of Organometallic Reagents . . . . . . 15

I . Preparation by Pyrolysis and Degradation of Natural Products . . . . 2 . Synthesis from Compounds Not Containing a Quinoline Ring System . . . 3 . Synthesis from Compounds Containing a Quinoline Ring System . . . .

a . Nuclear Alkylations . . . . . . . . . . . 15 b . Sidechain Alkylations and Arylations . . . . . . . 18

D . Homolytic Alkylation . . . . . . . . . . . 18 E . Decarboxylation . . . . . . . . . . . . 21 F . Ladenburg Rearrangement . . . . . . . . . . 22

22 H . Miscellaneous Methods . . . . . . . . . . . 24

a . Molecular Rearrangements . . . . . . . . . . 24 b . Photochemical Methods . . . . . . . . . . 24 c . Aromatization . . . . . . . . . . . . 25 d . Nucleophilic Displacement of Halogen . . . . . . . 25 e . Ring Enlargement of lndoles . . . . . . . . . 26 f . Catalytic Side-chain Alkylation . . . . . . . . . 26 g . Side-chain Benzylation . . . . . . . . . . 26 h . Condensation with Qinoline-2-Carbaldehyde . . . . . . 27 i . Alkylation with Fatty Acids . . . . . . . . . 27 j . Alkylation of Reissert Compounds . . . . . . . . 27

27

a . Melting Points and Boiling Points . . . . . . . . 27 b . Dissociation Constants . . . . . . . . . . 28 c . Dipole Moments . . . . . . . . . . . . 29 d . Surface Tension . . . . . . . . . . . . 29 e . Solubility . . . . . . . . . . . . . 29 f . Magnetic Susceptibility . . . . . . . . . . 30 g . Adiabatic Compressibility . . . . . . . . . . 30

B . Acidity of Sidechain Hydrogens . . . . . . . . . 30

G . Oxidation of Dihydro- Tetrahydro- and Decahydroalkylquinolines . . .

4 . Physical Properties . Uses and Methods of Separation . . . . . . A . General Physical Properties . . . . . . . . . . 27

I

2 Alkylquinolines and Arylquinolines

C . Stereochemical Properties . . . . . . . . . D . Biological and Pharmacological Properties and Medical Applications . E . Mixellaneous Properties and Uses . . . . . . . . F . Analysis of Alkylquinolines . . . . . . . . . G . Spectroscopic Properties . . . . . . . . . .

a . Electronic Spectra . . . . . . . . . . b . infrared Spectra . . . . . . . . . . . c . Nuclear Magnetic Resonance Spectra . . . . . . . d . Mass Spectra . . . . . . . . . . .

H . Methods of Separation . . . . . . . . . . a . Distillation . Crystallization and Counter-current Extraction . . b . Chromatographic Methods . . . . . . . . .

5 . Chemical Properties and Reactions . . . . . . . . A . lsomerization and Dealkylation . . . . . . . . B . Oxidation . . . . . . . . . . . .

a . Oxidations Leading to Ring Opening . . . . . . . b . 07onolysis . . . . . . . . . . . . c . Oxidation of Side-chains . . . . . . . . . d . Oxidation of Methyl Substituents to Aldehydes . . . . . e . Dehydrogenation OfTetrahydroacridines . . . . . . f . Oxidation to ,V -Oxides . . . . . . . . . g . Miscellaneous Oxidation Reactions . . . . . . .

C . Reduction . . . . . . . . . . . . a . Dihydroalkylquinolines . . . . . . . . . b . Tetrahydroalkylquinolines . . . . . . . . . c . Decahydroalkylquinolines . . . . . . . . . d . Miscellaneous Reductions . . . . . . . . .

D . Ring-opening Reactions . . . . . . . . . . E . Side-chain Substitutions . . . . . . . . . .

a . Deuterium and Tritium Exchange . . . . . . . b . Side-chain Metalation and Alkylation . . . . . . . c . Side-chain Halogenation . . . . . . . . . d . Miscellaneous Side-chain Substitutions . . . . . .

F . Nuclear Substitutions . . . . . . . . . . a . Deuterium Exchange . . . . . . . . . . b . Nitration . . . . . . . . . . . . c . Sulphonation . . . . . . . . . . . d . Halogenation . . . . . . . . . . . c . Mcrcuralion . . . . . . . . . . . f . FriedelLCrafts Substitutions . . . . . . . .

h . Hydroxylation . . . . . . . . . . . i . Alkylation and Aryldtion . . . . . . . . . j . Homolytic Kuclear Substitutions . . . . . . .

G . Addition Reactions . . . . . . . . . . . a . General Addition Reactions . . . . . . . . b . Reissert Reaction . . . . . . . . . .

H . Syntheses of Condensed Ring Systems . . . . . . . 1 . Condensation Reactions . . . . . . . . . .

a . Condensations with Aldehydes and Ketones . . . . . b . Condensations with Esters . . . . . . . . . c . Condensations with Phthalic Anhydride and Related Derivatives of Di- a

Polycarboxylic Acids . . . . . . . . . . d . Condensations with Amines and Sulphur; Willgerodt-Kindler Reaction

J . Photochemical Reactions . . . . . . . . . . K . Salt Formation and Complexes . . . . . . . .

a . Quaternary Salts . . . . . . . . . . . b . Charge-transfer Complexes . . . . . . . . .

g . Amination . . . . . . . . . . . .

. 31

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nd

Contents

.

I I . Alkenylquinolines and Aralkenylquinolines . c . Complexes with Boron and Metals

I . Preparation . . . . . . . A . Dehydration of Carbinols . . . B . Condensations with Carbonyl Compounds C . Miscellaneous Methods of Preparation .

2 . Physical Properties and Uses . . . . A . General Physical Properties B . Spectroscopic Properties . . . . c . uses . . . . . . .

a . Photographic Uses . . . . b . Biological and Medical Uses . . c . Uses of Polymers . . . . d . Miscellaneous Uses . . . .

3 . Chemical Properties and Reactions . . A . Oxidation . . . . . . B . Reduction . . . . . . C . Addition Reactions . . . . .

a . Addition of Halogens . . . . b . Addition of Organic Molecules . .

D . Polymerization . . . . . E . Miscellaneous Reactions . . . .

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3

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I l l . Alkynylquinolines and Aralkynylquinolines . . . . . . . I . Preparation . . . . . . . . . . . . . 2 . Physical Properties and Uses . . . . . . . . . . 3 . Chemical Properties and Reactions . . . . . . . .

IV . Di- and Polyquinolylalkanes . -Quinolylalkenes and -Quinolylalkynes . . 1 . Preparation . . . . . . . . . . . . .

. . . . . . A . Preparation of Di- and Polyquinolylalkanes B . Preparation of Di- and Polyquinolylalkenes . . . . . . C . Preparation of Di- and Polyquinolylalkynes

2 . Physical Properties and Uses . . . . . . . . . . A . General Physical Properties B . Tautomerism of Diquinolylmethanes . . . . . . . C . Geometrical Isomerism of the 1.2-diquinolylethylenes D.Uses . . . . . . . . . . . . .

A . Chemical Properties of Di- and Triquinolylalkanes . . . . . a . Oxidation , and 'Substitution 'Reactions of Residual Alkane Hydrogens b . Reduction . . . . . . . . . . . . c . Formation of Chelate Compounds . . . . . . . d . Formation of Quinoline Red and Related Compounds . . .

B . Chemical Properties of Diquinolyalkenes . . . . . . . C . Chemical Properties of Diquinolylalkynes . . . . . .

. . . . . .

. . . . . . . . .

. . . .

3 . Chemical Properties and Reactions . . . . . . . .

V . Arylquinolines and Heterodrytquinolines! . . . . . . . . I . Isolation and Synthesis . . . . . . . . . . .

A . Isolation l'rom Plants . . . . . . . . . . B . Arylations with Organometallic Compounds . . . . . . C . Homolytic Arylation . . . . . . . . . .

a . Homolytic Arylation with Diaroyl Peroxides . . . . . b . Homolytic Arylations with Diazo Compounds . . . . . c . Thermal Decomposition of Aralkyl Phenyl Ethers . . . . d . Homolytic Arylation by Decomposition of Triazenes . . . . e . Homolytic Arylation by Heteroaryl Radical Anions . . . . f . Homolytic Arylation by Thermal Decomposition of Nitro Compounds

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D . Other Synthetic Methods Also Applicable to Alkylquinolines . . . . a . Reduction of Chloro Derivatives . . . . . . . . b . Reduction of Hydroxy Compounds or Quinolones c . Decarboxylation of Aryl- and Heteroarylquinolinecarboxylic Acids . . d . Ring Enlargement of lndoles . . . . . . . . . e . Condensation of Methylquinolines uith Amines and Sulphur

( Willgerodt-Kindler Reaction) . . . . . . . . . f . Friedel-Crafts Substitutions . . . . . . . . .

E . Methods Inbohing the Ring Closure of the Substituent Aryl or Heteroaryl Moiety . . . . . . . . . . . . . . a . Arylquinolines . . . . . . . . . . . . b . Benzoxazolyl. . Benzothiazolyl- and Benzimidazolylquinolines c . Oxazolyl. . Pjrazolyl. . Triazolyl.. Tetrazolyl- and Oxadiazolylquinolines . d . Pyrazinyl. . Pyrimidinyl- . Quinoxalinyl- and Quinazolonyl-quinolines . . e . Quinolytriazines . . . . . . . . . . . . f . Isoquinolqlquinolines . . . . . . . . . . .

F . Preparations from Quinoline- I-oxides . . . . . . . . G . Miscellaneous Methods of Preparation . . . . . . . .

2 . Physical Properties and Uses . . . . . . . . . . . A . General Physical Properties . . . . . . . . . .

a . Dipole Moments . . . . . . . . . . . . h . Thermal Stability . . . . . . . . . . . c . tiydrogen Banding And Acidity . . . . . . . . . d . Picrate Formation by bridinylquinolines . . . . . . .

B . Spectroscopic Properties . . . . . . . . . . . a . Electronic Spectra . . . . . . . . . . . b . Nuclear Magnetic Resonance Spectra . . . . . . . .

C . X-ray DifFraction . . . . . . . . . . . . D . Chromatographic Separations . . . . . . . . . . E . llses of Arylquinolines and Heteroarylquinohnes . . . . . .

a . Biological Uscs . . . . . . . . . . . .

c . Dyes and Photosensitive Materials . . . . . . . . d . Polymer Technolog) . . . . . . . . . . .

. . . . .

. . .

C . M a S S S F t r d . . . . . . . . . . . .

h . Medical . Pharmacolagical and Pharmaceutical Applications . . .

3 . Chemical Properties and Reactions . . . . . . . . . . . . . . . . . . . . . . . A Oxidation

B . Reduction . . . . . . . . . . . . . C . Aromatic Suhstitutions . . . . . . . . . . .

a . Electrophilic Substitutions . . . . . . . . . . b . Nucleophilic Substitutions . . . . . . . . . .

D . Formation of Condensed Ring Systems . . . . . . . . E . Miscellaneous Reactions . . . . . . . . . . .

VI . Biquinolyls and Polyquinolyls . . . . . . . . . . . I . Preparation . . . . . . . . . . . . . .

A . Preparations Involving the Synthesis of One or More of the Quinoline Rings . B . General Methods for Heteroarylquinolines . . . . . . .

a . From Hydroxybiquinolyls and Biquinolones . . . . . . b . Dtvarboxylation . . . . . . . . . . . .

C . Action of Alkali Metals or Amides on Quiiiolines . . . . . . D . Ullrnann Reaction . . . . . . . . . . . . E . Thermal and Catalytic Dehydrogenation . . . . . . . . F . Miscellaneous Methods . . . . . . . . . . . G . Preparations of Polyquinolines and Biquinolyl Polymers . . . . .

2 . Physical Properties and U x s . . . . . . . . . . . A . General Physical Properties . . . . . . . . . . B . Optical Activity of Biquinolyls . . . . . . . . .

F . Metal Complexes with Aryl- and Heteroarylquinolines . . . . .

i32 132 i32 I32 132

132 132

133 133 I33 I34 136 137 138 139 142 146 146 146 147 147 147 147 147 148 148 148 148 149 149 I49 150 150 150 150 152 155 155 156 156 156 158 158 158 I58 158 158 158 161 161 162 163 165 165 165 I66

Contents 5

C. Speytroscopic Properties . . . . . . D. X-ray Diffraction Analysis . . . . . E. Chromatographic Separations. . . . . F. Uses . . . . . . . . .

. A. Oxidation . . . . . . . . B. Reduction . . . . . . . . C, Substitution Reactions . . . . . . D. Miscellaneous Reactions . . . . . . E. Complexes with Halogens and Organic Compounds F. Complcxes with Metals and Metal Compounds .

3. Chemical Properties and Reactions of Biquinolyls

VII. Tables of Physical Properties . . . . VIII.

List of Tables

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i67 i68 168 168 168 168 171 171 171 171 172

178 300

TABLE I

TABLE 2. TABLE 3.

TABLE 4. TABLE 5. TABLE 6.

TABLE 8. TABLE 7.

TABLE 9. TABLE 10. TABLE 11. TABLE I!.

TABLE 13. TABLE 14. TABLE IS.

TABLE 16. TABLE 17. TABLF. 18. TABLE 19.

TAHLE 20.

TABLE 2 1 .

TABLE 22. TABLE 23. TABLE 24. TABLE 25. TABLE 26. TARLE 27. TAH1.E 28. TABLE 29. TABLE 30. TABLE 3 I . TABLE 32.

TABLE 33. -4BLE 34.

Alkylquinolines Obtained by Pyrolysis from Petroleum. Coal Tar and Other Natural Sources . . . . . . . . . . . . 6

Alkylquinolines Obtained by Degradation of Alkaloids . . . . . 9 Products Formed by Homolytic Alkylation of Quinoline or 2- or 4-

Methylquinolines . . . . . . . . . . . . 20 Dissociation Constants of Methylquinolines . , . . . . . 28 Dipole Moments of Alkylquinolines . . . . . . . . . 29 'H-Nmr Chemical Shifts for Alkyl-. Aralkyl- and Arylquinolines . . . 35 '"-Nmr Chemical Shifts of Aromatic Carbons of Methylquinolines. . . 39 "C-Nrnr Chemical Shifts of Methyl Carbons of Methylquinolines . . . 41 3J~ll - i l l Ring Proton-Ring Proton Coupling Constants of Alkylquinolines . 42 4J and 'Jtil .. l i t Ring Proton--Ring Proton Coupling Constants for Alkylquinolines 43 'Jill - x I t Methyl Proton-Ring Proton Coupling Constants for Methylquinolines . 44 5 J ~ H . and 6 J~ I t -~ l l Methyl Proton-Ring Proton Coupling Constants for

'Jql qI Methyl Proton-Methyl Proton Coupling Constants for Methylquinolines 44 'Jirc- iIIMethyl Carbon-Methyl Proton Coupling Constants for Methylquinolines I 45 iJkic. f i l l Ring Carbon -Ring Proton Coupling Constants for Quinoline and

Alkylquinolines . . . . . . . . . . . . 45 ' J I ? ~ - t i , Ring Carbon-Methyl Proton Coupling Constants for Methylquinolines 45 'JIJ,. i l l Methyl Carbon.-Ring Proton Coupling Constants for Methylquinolines 45 >Jl sc i l l Ring Carbon-Methyl Proton Coupling Constants for Methylquinolines 46 ' J l y- Ring Carbon-Ring Proton Coupling Constants for Quinoline and

Alkylquinolines . . . . . . . . . . . . 46 Products Obtained by the Oxidation of Alkylquinolines to Carboxylic Acids and

Effect of Alkyl Substituents on the Relative Extents of Reduction of the Hetcrocyclic and Carbocyclic Rings of Substituted Quinolines . . . 60

Reduction of Alkylquinolines to the 1.?,3.4-Tetrahydro Derivatives . . . 61 Products Formed by Sidechain Halogenation of Alkylquinolines . . . 69 Products of Nitration of Alkylquinolines . . . . . . . . 73 Products of Sulphonation of Alkylquinolines . . . . . . . 75 Products of Homolytic Amidation of Alkylquinolines . . . . . 82 Products from Ciaisen Condensations with Alkylquinolines . . . . 90 Alkenylquinolines Formed by Dehydration of Quinolylcarbinols . . . 98 Preparation of Alkynylquinolines . . . . . . . . . I14 Dipole Moments of Some 1.2-Bis(?'-quinolyl)thylenes . . . . . I22 Ultraviolet Absorption Spectra of Some Quinolylethylcnes . . . . 123 2-Aryl- and 2-Heteroarylquinolines Prepared with Organolithium Compounds or

Grignard Reagents. . . . . . . . . . . . 128 Reactions of Quinolyl Radicals with Aromatic Compounds . . . . 131 I-Acyl-2-indolyl Substituents on Quinoline Derivatives in formula (203) . . 142

Methylquinolines . . . . . . . . . . . 4 4

Alkyl Quinolyl Ketones . . . . . . . . 5 4

6

TABLE 36. TABLE 35.

TABLE 37. TABLE 38. TABLE 39.

TABLE 4 I . TABLE 42. TABLE 43. TABLE 44. TABLE 45.

TABLE 40.

TABLE 46. TABLE 47. TABLE 48. TABLE 49. TABLE 50. TABLE 51.

Alkylquinolines and Arylquinolines

Metal Complexes of Aryl- and Heteroarylquinolines . . . . . . Biquinolyls Prepared by Methods Involving the Synthesis of the Quinoline R i n g Complexes Between Biquinolyls and Phenols . . . . . . . Complexes Between Biquinolyls and Metal Ions or Metal Compounds . Al kylquinolines . . . . . . . . . . . . . Cycloal kylquinolines . . . . . . . . . . . . Cyclopolyalkylenequinolines (Cycloalkenoquinolines). . . . . .

Heterodral kylquinolines . . . . . . . . . . .

.

Aralk ylquinolines . . . . . . . . . . . .

Alkenylquinolines . . . . . . . . . . . . Cycloal kenylquinolines . . . . . . . . . . . Aralkenylquinolines . . . . . . . . . . . .

Ary Iquinolines . . . . . . . . . . . . .

Heteroaral kenylquinolines . . . . . . . . . . . Alkynyl-. Aralkynyl- and Heteroaralkynylquinolines . . . . . .

Heteroarylquinolines(5-Membered Rings). . . . . . . . Heteroarylquinolines (6-Membered and 7-Membered Rings. Including

Biquinolyls) . . . . . . . . . . . . .

I59 160 I72 I73 I78 I92 I93 20 1 205 210 213 213 227 23 I 232 263

279

1. Alkylquinolines and Aralkylquinolines 1. Preparation by Pyrolysis and Degradation of Natural Products

Alkylquinoline derivatives, together with quinoline itself, isoquinolines and other organic bases, have been obtained by the thermal degradation of natural organic compounds containing nitrogen. This constitutes an important source of mixed quinoline bases from which individual compounds can frequently be isolated by methods described in Section I.4.H and in the references listed in Table 1 .

Petroleum crude oils and distillates and coal tar are the most important source materials for quinoline bases; in other cases, especially the degradation of alkaloids, the isolation of the quinoline bases is important more as an indication of the composition and structure of the original materials. Other natural products from which quinoline bases have been isolated by pyrolysis or other methods of degradation include shale oil. lignite, soot. tea. soya bean cake and tobacco smoke.

Details of the methods involved can be found in the references given in Tables I and 2, which constitute a list of the alkylquinolines obtained. Their production from coal tars has been reviewed.70~iSP3

TABU I . Alkylquinolines Obtained by Pyrolysis from Petroleum, Coal Tar and Other Natural Sources

Quinoline derivative Source References

2-Methyl- Petroleum (Californian) I . 5 Lignite 16 Coal tar

Sapropel tar 23. 25. 26 Black led aroma 42 Soya bean 43 Shale oil 1597

22. 24. 27. 28. 30. 35, 36. 37, 38. 41. 100. 1592

I . Alkylquinolines and Aralkylquinolines 7

TABLE 1 (Conf.)

Quinoline derivative

3-Methyl-

4-Methyl-

5-Methyl-

6-Methyl-

7-Methyl-

8-Methyl-

2.3-Dimet hyl-

2A-Dimethyl-

2.5-Dimethyl-

2.6-Dimethyl-

2.7-Dimethyl- 2.8-Dimethyl-

3.5-Dimethyl- 3.8-Dimethyl- 4.6-Dimethyl- 5.8- Dimet hyl- 6.8-Dimethyl- 2.3,4-Trimethyl- 2.3.8-Trimethyl-

2,4.6-Trimethyl- 2.4.8-Trimethyl-

2.6.8-Trimethyl- 2,3.4.8-Tetramet hyl- '2.3-Dimethyl-8-alkyI-'

source

Petroleum (Californian) Shale oil Coal tar Green coffee Petroleum (Californian) Coal tar

Sapropel tar Burley tobacco flavour Green cotfee Coal tar Sapropel tar Coal tar Sapropel tar Shale oil Petroleum (Californian) Petroleum (Russian) Shale oil Coal tar Sapropel tar Petroleum (Californian) Shale oil Coal tar Petroleum Petroleum (Russian) Coal tar Petroleum (Californian) Shale oil Coal tar Petroleum (Californian) Tobacco smoke Petroleum (Californian) Coal tar Black tea aroma Tobacco smoke Coal tar Petroleum (Californian) Shale oil Coal tar Petroleum (Californian) Petroleum (Californian) Coal tar Coal tar Coal tar Petroleum (Californian) Petroleum (Californian) Shale oil Coal tar Petroleum (Californian) Petroleum (Russian) Coal tar Coal tar Petroleum (Californian) Petroleum (Russian)

References

I 44 39, 22, 109 1601 I. 5 39, 30, 29, 34, 24, 31, 35, 37, 38. 33, 41, 22, 36, 109 26 45 1601 34, 32, 33, 45, 109 26 39, 38, 53, 41. 109 26, 25 16. 44 I 46 44, 47, 16 39, 34, 38, 33, 41, 36, 109 26. 25 I 44.47. 16 39. 38, 33, 41. 22, 19, 109 15. 3. 49 48 39. 18, 21 5 , 3 16 39, 30, 18. 24, 38, 2 I , 36 5 50 5 39, 38. 21. 41 42 51 21 I . 4 44.41. 16 38 5 49 38, 36 17 18. 41 7 49 47 18 2 52 18 18 7 48


TABLE I (COnf.)


'2,3,4Trimet hyl-8-al kyl-'

2-Ethyl-3-methyl- 8-Ethyl-2-methyl- 8-Ethyl-3-methyl- 2.3-Dimethyl-4-ethyl-

2,3-Dimethyl-S-e1 hyl-

2.4- Dimet hyl-l-et hyl- 4Ethyl-2,3,8-trimethyl-

S-Ethyl-2,3.4-trirnethyl- 4,8-Diethyl-2,3-dimethyl- 2.3-Dimet hyl-8-propyl

2,4-Dimet hy I-8-propyl 8-Isopropyl-2.3.4-trimethyl- 8-Propyl-2,3.4-trimethyl

2,4-Dimethyl-6-( I -methyl-

?,4-Dimethyl-l-( I -methyl-

2.3-Dimethyl-4ethyl-8-

'C , ,-alkyl-' and 'C,-alkyl-' I ,2.3.4-Tetrahydroacridine 'A1 kylquinolines' 'Met hylquinolines.

&Ethyl-

p r o p y b

pr0pyl)-

ProPYl-

dimethylquinolines and; or ethylquinolines'

'Methylquinolines and dimet hy lquiaolines'

'Alkylquinolines'

'Dimethylquinolines' Cycloal kylquinolines

Petroleum (Russian) Petroleum (Californian) Petroleum (Russian) Petroleum (Californian) Petroleum (Californian) Petroleum (Californian) Petroleum (Russian) Petroleum (Californian) Petroleum (Russian) Petroleum (Californian) Petroleum (Californian) Petroleum (Russian) Petroleum (Californian) Petroleum (Californian) Petroleum (Californian) Petroleum (Russian) Petroleum (Californian) Petroleum (Californian) Petroleum (Californian) Petroleum (Russian) Petroleum (Californian)

Petroleum (Californain)

Petroleum (Californian)

Petroleum (Russian) Coal tar Shale oil (Tasmanian) Coal soot

Tobacco smoke

Cane peat Shale oil Petroleum (Russian) Deasphaltizate Petroleum (Californian) Atmospheric pollutants Petroleum (Russian) Petroleum (Russian)

48 I ? 48 12 15. 6 I I 52 15. 6 52. 53 8 11 52 I I . 9 14 7 52, 53 9 13 9 52, 53 10

10

14

54 20 55 40

56

1602 1598. 1599 1506. 1594 1595 1596 1600 1507 1594

2. Syntbesis from Compounds Not Containing a Quinoline Ring System

The many methods available for the synthesis of the quinoline ring system (see e.g. Part I. Chapter 2) can be used for the preparation o f alkyl- and other substituted quinolines. In particular, the methods of Skraup. Doebner, Von Miller, Friedlander. Pfitzinger, Combes, Beyer. Conrad-Limpach. K n o r r and others have been used extensively. Specific references to the use of these methods are given in the Tables of Part I, Chapter 2. Section V1. F o r example, the reaction of anthranil with ketones, alkenes or alkynes gives a

1. Alkylquinolines and Aralkylquinolines

TABLE 2. Alkylquinolines Obtained by Degradation of Alkaloids

9

~ _ _


2-Methyl- CMethyl-

4-Methyl-6-methoxy- 7-Methyl-

8-Methyl-

2-Pentyl- 5.7-Dimet hyl- 8-Ethyl-&methyl- 3-Butyl-6.8-dipropyl- 6-Butyl-3,8-dipropyl- 3-Pent yl-6,R-dipropyl- 6-Pcntyl-3.8-dipropyl- 8-Pentyl-3,6-dipropyI-

P. harmaka Cinchona alkaloids Cinchonine, cinchonidine Quinine, quinidine Annotinine Obscurine Lycopodine Nitramine, Nifrariu

schoberi Angostura bark Lycopodine Tabernanfhe iboga Ormosia alkaloids Ormosanine and ormojanine Onnosanine and onnojanine Ormosanine and ormojanine Ormosanine and ormojanine

57 58 59 59 60, 61 62,228 63 64

65, 66 63 67 68, 69 68,69 68, 69 68, 69 68, 69

variety of 2.3-substituted quinolines in moderate yields (6-3979.306 The use of cycloaliphatic ketones provides a convenient route to 2,3-polymethylene-substituted quinolinss, including tetrahydroacridine. The reaction proceeds by a I ,3-dipolar addition via the quinoline N-oxide.

Methods for the preparation of alkyl- and aralkylquinolines from compounds already containing a quinoline ring are given below.

3. Synthesis from Compounds Containing a Quinoline Ring System

A. Reduction Methods

Alkylquinolines (and other substituted quinolines) can frequently be obtained from compounds containing additional functional groups by modification or elimination of these groups. frequently by reductive processes. The most important examples are the removal of hydroxyl groups (or amido-oxygen), frequently present as a result of synthesis by the Conrad- Limpach or Knorr reactions. This can be done directly or after replacement by halogen. The reduction of carbonyl and alkenyl sidechains also provides useful routes to alkyl quinolines.

a. REDUCTION OF HALOGEN DERlvanvEs Halogens attached to the quinohne ring, particularly those at positions 2 and 4, can be replaced by hydrogen by heating with hydrogen iodide in acetic acid; thus 4-chloro-2-methylquinoline at 250-270 “C gave 2- methylquinoline” (quinaldine), 2-chloro-3-ethylquinoline at 240 “C gave 3-ethylquinoline” and 2-chlor0-7-isopropylquinoline~~ at 220-24OUC, 4-chloro-2,3- d~methylquinoline’~ at 275 “C, 2-chlor0-3-rnethyl-4thylquinoline’~ at 260 “C and 2- chlor0-3,4-diethyIquinoline~~ at 295 “C gave the respective alkylquinolines by this method. Similar results have been achieved with hydrogen iodide and red phosphorus, for example 4-methylquinoline (lepidine) was obtained by this method75 from its 2- chloro derivative at I70 -C and Cethylquinoline from 2-chloro-4-ethylquinoline with hydrogen iodide, red phosphorus and potassium iodide.74 The reduction of 2,Cdichloro- 5-methylquinoline with tin and hydrochloric acid76 gave 5-methylquinoline together


with some 5-methyl-I ,2,3,4-tetrahydroquinoline. Catalytic methods have also been used successfully; thus the following have been reduced to alkylquinolines with hydrogen and PdjC or Ni: 2chloro derivatives of 4-methyL. 6-methyl-, 8-methyl, 5,8-dimethyl- and 6.8- d i m e t h y l q ~ i n o l i n e s , " * ~ ~ ~ . ~ ~ ~ the 4-chloro derivatives of 7-methyl- and 3,Sdimethyl- quinolines" and 4-chloro-2-(dibromomethyl)-3-vinylquinoline96 (the last compound to 2-methyl-3-ethylquinoline). 4,5-Dihydrocyclopenta[d,e]quinoline (2) was formed by reduction of the heptachloroacenaphthene ( In this case nuclear-substituted chlorines in positions other than 2 and 4 were reduced. 5-Methylquinoline was obtained in high yield by the catalytic reduction (H,/Pd. CaCO,) of 5-methyl-8- chloroquinoline.208

( I )

Ill

I

CI I 2

i, H,:Pd, charcoal, N(E0,. (68%); ref. 79

Hydrogen and Raney nickel in the presence of a base (methanolic potassium hydroxide) reduced 2-chloro-4-methylquinoline to Cmethylquinoline in 95?; yield.78 Catalytic reduction of a 4-chlorosubstituent has also been used to prepare 33- dimethylquinoline and 7-methylq~inoline.'~ When a solution of 2-chloro-4- methylquinoline in hydrochloric acid was treated with tin. the double salt was obtained which, on separation and treatment with alkali, gave 4-methylquinoline." Pure 4- methylquinoline can also be prepared from 2-chloro-4-methylquinoline by boiling with hydrazine hydrate and treating the 2-hydrazinolepidine so formed with copper sul- hate.'^ Hydrazine hydrate together with palladized charcoal has also been used to reduce chlorine atoms at position 3 of the quinoline ring.22'.222 (see also Scheme 7 and equation 23, Section I.3.H.e). 2-Chloro-4-methylquinoline has also been reduced with zinc and hydrochloric acid (63-75";) and with zinc and 60% acetic acid (609).49s 3- Trifluoromethylquinoline can be reduced by sodium borohydride to give 3-methylquinoline (360: yield), but the corresponding 2-. 4- and 6-isomers are unaffected. On the other hand. lithium aluminium hydride will reduce 2-, 4- and 6-trifluoromethylquinolines to give 28.401;. 10.6"/; and 65.54, yields of the methylquinolines, respectively, but the 3- isomer gave 3-difluoromethyl-1.2-dihydroquinoline. The mechanism suggested involved nucleophilic attack by hydride 1 0 n . ~ ~ ~

b. REDUCTION OF HYDROXY AND AMINO DERIVATIVES Although these substituent groups can be replaced by hydrogen directly as described below, it is usually better to convert them first to the chloro derivative as the direct methods give less pure products. Hezting with zinc dust, for example, a method that has been widely used, can result in the migration of alkyl groups." By heating 4-methyl-2-quinolone with zinc dust under reduced p r e s ~ u r e ~ ~ . ' ~ Cmethylquinoline was obtained and similarly 3-methyl-2- propylquinoline, together with other products, from 3-methyl-2-propyl-Cq~inolone.'~ 4-Methylquinoline was also obtained from 3-cyano-4-methyl-2-quinolone by distillation with zinc The following alkylquinolines have been obtained by similar methods: 5-rnethylq~inol ine,~~ 6,8-dimethylq~inoline,'~*~~ 6-methylquinolines8 and 8- methylquinoline.*' Reduction has also been reported by distillation over 'glowing' or red hot zinc; in this way 3,4-,89. 90 4.6-,n9 4.7-89 and 4,8-dimethylquinolinee9 were obtained from the respective 2-quinolones, and the last two also by distillation with zinc dust.91

1. Alkylquinolines and Aralkylquinolines I 1

Hydrogen iodide alone or with red phosphorus can be used for the reduction of alkylquinolones and hydroxyquinolines, including compounds having a hydroxyl group in a side-chain, to give alkylquinolines, as shown by the following examples. Quinaldine (2-methylquinoline) was isolated when 3-amino-2-methyl-4-quinolone was heated with hydrogen iodide and acetic acid as a result of elimination of the amino group in addition to the carbonyl oxygen.92 The condensation product of lepidine with chloral (3) gave 4- propylquinoline (4) when heated with fuming hydrogen iodide (d = 1.96) and red phosphorus at 150-160 0C.93 The corresponding dimethylol derivatives (5) and (6) formed by condensation of lepidine and quinaldine with 2 mol of formaldehyde gave 4- and 2-isopropylquinoline (7) and (8), r e ~ p e c t i v e l y . ~ ~ . ~ ~ When weaker hydrogen iodide or hydrogen bromide was used, reduction was incomplete and diiodo (9), hydroxyiodo (10) or hydroxybromo derivatives were formed." See equations 2, 3 and 4.

CHZCHLCH j I

CHzCH( OH )CCI 3

6

i, HI (d = I.%) + red P (150-160'CJ; ii.

10

I 1 ( d =

8 ( 4 )

) + red P (IM-160"C)

More recently. Cmethylquinoline has been obtained in 49% yield by refluxing 4- methyl-2-quinolone with red phosphorus and iodine in xylene for 4 h.95

c. REDUCTION OF CARBONYL COMPOUNIX Quinoline carbaldehydes and alkyl or aryl quinolyl ketones can be reduced to the alkyl- or aralkylquinolines by the Wolff-Kishner or Clemmensen methods. Quinoline aldehydes on reduction by the Wolff-Kishner method gave me thy lqu in~ l ines~ '* '~~~ and, using the Huang-Minlon modification of the Wolff-Kishner reaction (in which the ketone is heated with potassium hydroxide and 8 5 " ~ ~ hydrazine hydrate in ethylene glycol), all of the benzylquinolines have been prepared from the appropriate phenyl quinolyl ketone^.^' Photolysis of phenyl 3- quinolyl ketone in isopropanol gave 3-benzylq~inoline''~ ( 1 2%) together with phenyl-3- quinolylmethanol and the expected pinacol. Irradiation of phenyl-3quinolylmethanol in


isopropanol gave a yield of 3-benzylquinoline and 29", of 3-benzyl-1,2,3,4- tetrahydroquinoline. Quinaldine has also been prepared from carbonyl compounds by the following methods, which involve degradation. 2-Acetonylquinoline(11) was heated at 160-1 70 "C with concentrated hydrochloric acid and 20"; sulphuric acid99 (equation 5) , and quinophthalone (12) was heated with fuming hydrochloric acid at 240"C'00 (equation 6).

0 12

i. HCI (conc.) t H z S 0 4 (?O"~,). 160-170"C: ii HCI (fuming). 240'C

Compounds prepared by the use of Raney nickel as a catalyst for hydrogen transfer reactions include 3-ethyl-5.6,7,X-tetrahydroquinoline from 3 - a ~ e t y l q u i n o l i n e ' ~ ~ ~ with isopropanol as hydrogen donor. Oxidation by one of the methods in Section 1.3.G would give 3-ethylquinoline.

d. REDUCTION OF A L K ~ N Y L AND ARALKESYLQUIVOLINES Under controlled mild conditions. reduction of these compounds gives the corresponding alkyl- or aralkylquinolines. More vigorous conditions result in the further reduction of the heterocyclic ring to g v e alkyl- or aralkyl-l,2,3,4-tetrahydroquinolines. Hydrogen iodide and red phosphorus has been used for the reduction of 2- and 4-styrylquinolinesro' and of 1- ethyl-2-styrylquinolinium iodide'" to give the 2- or 4-(2-phenethyl)quinolines, and more recently this has been accomplished in 80",, yield by refluxing the bases for 24 h at 200 "C with pmethylthiophenol.*Oz

Catalytic hydrogenation has been used extensively for the reduction of alkenylquinolines; thus 2-pentylquinolin: was obtained by hydrogenation of I-(2-quinolyl)pent- I-ene in dilute alcoholic solution at 50 T using a palladized charcoal catalyst.65 and 1- phenyl-4-(2'-quinolyI)butane was formed by the hydrogenation of I-phenyl-3-hydroxy- 4-(2'-quinolyl)-but-I -ene and of 1 -phcnyl-~(2'-quin~l~l)-buta-l .3-diene over Y palladium sponge catalyst.Io3 Hydrogenation of the heteri>iilkefiyl quinolinium salts (13)'".'" gave the 1 -(2'quinolyl)-7-(2"-, 3'- or 4"-pyridyl)ethanes via their quaternary salts (14). More vigorous hydrogenation gave the fully saturatr:d bases (15) (see Scheme I) . 2- Methyl-4-allylquinoline has been reduced by hydrogen and palladized charcoal to 2- methyl-4-propylquinoline. ''

Benzyl alcohol can function both as a reducing agent and as a benzylating agent (see also Section 1.3.H.g). When refluxed for I h with 2-stvrvlquinoline, 2-phenethylquinoline (400; yield) was obtained, and when refluxed for 14 h further rcduction to 2-phenethyl- 1.2,3,4-tetrahydroquinoline occurred.224 Reduction with sodium and ethanol results in the concurrent reduction of the heterocyclic ring so that 2-styrylquinoline and its 4 - methyl-, 6-methyL. 4.6-dimethyl- and 4'-isopropyl- derivatives gave the corresponding 2-(2'-phenethyl) 1.2.3.4-tetrahydroquinolines. IoJ.

I. Alkylquinolines and Aralkylquinolines 13

I4

Bases

Bases

15

i. H2 PrO,. CH3C0,H. 760mmHg. 11. H2/R0,. HCI, 100°C. 100 atrn; iii, OH-

When treated with benzene, aluminium chloride and hydrogen chloride, styryl- quinolines and their o-. m- and p-chloro or -bromo derivatives give 1 ,l-diphenyl-2-(2’- quinoly1)ethanes (16), which has been explained in terms of the reversibility of the Friedel-Crafts reaction’O’. lo’ (see equation 7).

e. REDUCTION OF QUINOLINE- 1 -OXIDES The reduction of appropriate alkylquinoline- I-oxides can form an important step in the preparation of alkylquinolines. Quinaldine-l- oxide can be reduced with zinc and hydrochloric acid to q~ina ld ine”~ and it will also condense with alkyl, aryl and heteroaryl aldehydes in the presence of potassium methoxide to give the appropriately substituted 2-vinylquinoline-1-oxides (17), which can be reduced with hydrogen and Raney nickel to the substituted 2-ethylquinoline-l- oxides and on further hydrogenation to the 2-quinolylethane~”~ (see equation 8).

The 1-oxides can also be reduced by heating at 50-60 ?C with phosphoryl chloride or phosphorus trichloride; 2-methylquinoline- I -oxide, for example, gives 2-methylquinoline together with a chloro derivative.209 2-Methylquinoline-1-oxide can also be deoxygenated by an acid-catalysed reaction with sulphoxides at elevated temperatures. This is a general reaction of N-heterocyclic and other tertiary amine N-oxides which are


17

i. RCHO. MeOK; ii and iii, HJRaney Ni 1111

reported to form an initial coordination complex by attack of the N-oxide oxygen atom on the sulphur atom of the sulphoxide or its conjugate base. This complex, in the case of the heterocyclic N-oxides, is then attacked by the nucleophilic sulphoxide oxygen to give a sulphinate and the amine.2'" Lepidine-I-oxide has been converted quantitatively to lepidine by heating for 10h with Bu,SnH in the presence of 22'-

azobisisobutyronitriIe.'I ' Many quinoline-I-oxides, including 2-methylquinoline-I-oxide. are reduced by

chromium( 11) chloride (CrCI,) in acetone, methanol or chloroform at room temperature, in many cases, but under reflux for 2-methylquinoline- I-oxide, to give the deoxygenated products. Reaction times of 20 min may cause dechlorination of 4-chloroquinoline- 1- oxides and many nitroquinoline- I -oxides could not be reduced successfully by this method. 539

B. Curuljric Alkylurion

Direct alkylation by the Friedel -Crafts reaction using Lewis acid catalysts is restricted owing to the deactivating effect of the ring nitrogen towards electrophilic substitutions, although when electron-donating substituents are present alkylation (and acylation) of the carbocyclic ring is possible."' Other catalytic methods for the direct alkylation of quinoline have been reported and many are the subject of patents. The vapour phase reaction of quinoline with an approximately 8-fold excess of methanol over a Ni/NiOz catalyst in a tubular reactor at 295 'C with a contact time of 10.5s gave 2-methyl- q ~ i n o l i n e . ' ~ ~ ~ 2-Methylquinoline with excess of methanol at 500 'C over an alumina catalyst gave a mixture of 2-eth) I-. 2-isopropyl- and 2-isopropenylquinoline in yields of

7"; and 2",,, respe~tively.'"~ Quinoline is one of the substrates which can be methylated by a carbon monoxide-hydrogen mixture ( 1 : 2) at 454 T and 65.5 bar in the presence of a catalyst (Cr,O,-ZnO, 22:78)."' The product contained 17.79/; of 4- methylquinoline together with 23.6% of unreacted quinoline, 12.5",, of a mixture having a b.p. less than that of quinoline, 34.43; of a mixture with a b.p. between those of quinoline and Cmethylquinoline and 11.87; of a mixture with a b.p. higher than that of 4-methylquinoline. Various but) I- and isomeric octylquinolines have been prepared by refluxing alkanols and alkylamines with quinoline in the presence of ruthenium trichloride (RuCI,) and triphenylphosphine (PPh,).' " By treating quinoline with benzyl iodide, concentrated sulphuric acid and iron, 2- and Cbenzylquinoline and bibenzyl were

Similarly with isopropyl iodide, sulphuric acid, iron and zinc, 2- and 4- isopropylquinoline and 2- and 4-isopropyl- 1.2,3,4-tetrahydroquinoline were obtained.It4 Methylation of quinoline with primary alcohols in the presence of Raney nickel has been reported'I5 to give 701," of 2-methylquinoline and 240,i, of 8-methylquinoline. Alcohols or ethers can also be used as alkylating agents with an AI,O, catalyst

I. Alkylquinolines and Aralkylquinolines 15

at 450 -C to give 3-substituted quinolines (or 4-substituted isoquinolines). For example, methanol and quinoline gave 41"; of 3-methylquinoline and 53"; of the quinoline was recovered. Ethanol similarly gave 3-ethylq~inoIine. ' '~ Alkenes in the presence of an alumina-silica catalyst gave alkylquinolines; thus ethylene gave 2-ethylquinoline, which could be dehydrogenated at 1000°F on a chromium(ii1) oxide-bauxite catalyst to 2- vinylquinoline. I ' Propylene at 250 -C and 2600 Ib in - ' gave 'monoisopropyl- quinolines'. When heated with alkenes and sodium, quinaldine is reported to give higher alkylquinolines.' I' By heating lower alkyl or cyclic ethers with quinoline a t 150-450 'C (preferably at about 300 "C) in the presence of oxides or hydroxides of Al. Th. Zn, Mg, B, Fe or Si or mixtures of these oxides on inert supports, and preferably using a diluent, 2- and Calkyl and 2,Cdialkyl- or cycloalkylquinolines are formed, e.g. 2- isopropylquinoline and 2-cyclopentylquinoline. ' I' Ethylene in the presence of aluminium anilide and 1,2,3,4-telrahydroquinoline gave a 60 7070 yield of 8-ethyl-I ,2.3,4- tetrahydroquinoline, which was dehydrogenated with sulphur a t 220 "C to give 8- ethylquin~line;~'' 2,6-diethylaniline was also formed.

C. Alkylalion by Means of Organometullic Reugenis

a. NUCLEAR ALKYLATIONS The reaction of quinoline with organolithium reagents and Grignard reagents has been reviewed in Part I, Sections IV.1 and IV.2. As with pyridine. I ,2-nucleophilic addition constitutes the initial reaction and oxidation of the 2- substituted 1,2-dihydroquinolines formed by hydrolysis of the primary addition products gives 2-alkyl(or 2-aryl)quinolines. ' 22 -

2-Alkyl- and 2-aralkylquinolines have also been prepared in yields of 8-85?; by the action of Grignard reagents in ether or tetrahydrofuran on quinoline-I-oxide. Some 2- alkylquinoline- 1 -oxide and quinoline were formed concurrently. ' )' Lepidine- I-oxide can be alkylated similarly.' b32 Quinaldylpotassium in liquid ammonia containing potassamide reacts with organic halides; with p-chlorotoluene, for example. 2-@- methy1benzyl)quinoline is formed.'606

An interesting extension of the use of Grignard reagents for the synthesis of 2- alkylquinolines results from the thermal isomerization of the adducts formed from quinoline and vinyl or ally1 Grignard reagents, or the dihydroquinolines formed from them by h y d r o l y ~ i s ' ~ ~ . ~ ~ ~ (see Scheme 2).

20' * ' ''. ' "* ' 5 5 8 * ' 605

i. CH,=CHCH,M$CI: ii. H,O: iii. heat with quinoline: iv. heat


Grignard reagents have also been used in conjunction with a nickel-phosphine complex catalyst to alkylate halogenoquinolines;' ''. 262 see equation 9 for 2chloro- quinoline.

I. R'MgC'l. (Ph,P)Ni<'l,. R ' = PhCH:. C'H,=CH--CH, ii. R'MpC'I. (PhzPC'HzCHLPPh21NiCIz. R' = PhCH'CH,

cyclopentyl. c)clohex) I

The modified catalyst was required in reaction ii. when the potential carbanion of the Grignard reagent had a hydrogen atom bonded to an sp, hybridized P-carbon, as in this case the triphenylphosphine-Ni complex induced an alkene-forming elimination together with reduction of the haloquinoline to quinoline. Selective alkylation at position 4 occurred when 4.7-dichloroquinoline was used, and the normally difficultly accessible 3- position of quinolinr could be alkylated using 3-bromoquinoline (see also ref. 655).

Wittig reagents can be used for the introduction of alkyl (and alkenyl) groups into heterocyclic systems including quinoline."** ' 29 A suitable leaving group on a heterocycle. including chlorine. can be displaced by a Wittig reagent and the resulting heterocyclic ylide converted in s i m either by hydrolysis into an alkyl derivative of the heterocycle. or by reaction with a carbonyl compound into an alkenyl derivative of the heterocycle. Numerous examples are given in the references cited, including many 2- alkyl-, 2-ardlkyl-. 2-alkenyl- and I-aralkenylquinolines. Scheme 3 illustrates the general procedure. The alkenylquinolines can be subsequently reduced to alkylquinolines.

HKI-X -- t i e i - ( ' -=PR\ A Het--C'H,R

HKI-X - t1ci-C H=PPh, Hei-C'H=C,

I

R R'

R S

/

Het X R ' = Phrnyl o r buiyl Rz, RJ= H, alkyl or aryl

I. RCH= PR \ 12 cqui\ I . i i . OH - . 111. CH,= PPh, (2 equiv I:

= Heterocyclic including 2-quinolyl and substituted 2-quinolyls = Good learing group. including chloro

iv, R2LC=0, (-Ph,PO); v. H,/Pd R P

quinolines · 2013-07-23 · preface the second part of the volume dealing with the chemistry of...

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