SPECIAL TOPICS I N HETEROCYCLIC

CHEMISTRY

Edited by

Arnold Weissberger Research Loboraiories

Eastman Kodak Company Rochesrer, New York

Edward C. Taylor Princeton Uniwrsiry

Princeton, New Jersey

A N INTERSCIENCEQPUBLICATION

JOHN W l L E Y & SONS

N E W Y O R K . LONDON * S Y D N E Y .TORONTO

SPECIAL TOPICS IN

HETEROCYCLIC CHEMISTRY

This is the thirtieth volume in rhe series

THE CHEMISTRY OF HETEROCYCLIC C O M P O U N D S

T H E C H E M I S T R Y O F H E T E R O C Y C L I C C O M P O U N D S

A S t K l f i S 01 M O h O G R A P H S

A R N O L D W E I S S B E R C E R rnd E D W A R D C. T A Y L O R

Editors

SPECIAL TOPICS I N HETEROCYCLIC

CHEMISTRY

Edited by

Arnold Weissberger Research Loboraiories

Eastman Kodak Company Rochesrer, New York

Edward C. Taylor Princeton Uniwrsiry

Princeton, New Jersey

A N INTERSCIENCEQPUBLICATION

JOHN W l L E Y & SONS

N E W Y O R K . LONDON * S Y D N E Y .TORONTO

An lnterscience @ Publication

Copyright @ 1977 by John Wiley & Sons, Inc.

All rights reserved. Published simultaneously in Canada.

No part of this book may be reproduced by any means, nor transmitted, nor translated into a machine language without the written permission of the publisher.

Library of Co#gress Cataloging in Publicarion Dam:

Main entry under title:

Special topics in heterocyclic chemistry.

(The Chemistry of heterocyclic compounds: v. 30) "An lnterscience publication." Bibliography: p. 1. Heterocyclic compounds-Addresses, essays, lectures. 1. Weissberger, Arnold, 1898-. Curtis, 1923-

11. Taylor, Edward

QDJOO.SS12 547'.59 76-10672 ISBN 0-471-67253-X

1 0 9 8 7 6 5 3 3 2 I

Contributors

H. L. Blewitt, Uniuersity of Alabama, Tuscaloosa, Alabama

E. Campaigne, Ft. Lewis College, Durango, Colorado

Albert 1. Fritsch, Center for Science in the Public Interest, Washington, D. C.

R. D. Hamilton, Ff. Lewis College, Durango, Colorado

Georges Mnury, Department de Chimie, Faculte' des Sciences, Rabat,

John P. Paolini, Merrell -National Laboratories, Cincinnati, Ohio

K. T. Potts, Department of Chemistry, Rensselaer Polytechnic Institute,

David M . Stunner, Research Laboratories. Eastman Kodak Companv,

Morocco

Troy, New York

Rochester, New York

Canada Alfred Taurins, Department of Chemistry, McGill University, Montreal,

This Page Intentionally Left Blank

The Chemistry of Heterocyclic Compounds

The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds.

A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present series to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specific interests of the au- thors.

In order to continue to make heterocyclic chemistry as readily 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, supple- ments to the respective volumes will be published in the first edition.

ARNOLD WEISSBERGER

Research Laboratories Eastman Kodak Company Rochester, New York

EDWARD C. TAYLOR Princeton University Princeton, New Jersey

This Page Intentionally Left Blank

Concerning Special Topics in Heterocyclic Chemistry

This volume is the first in the series “The Chemistry of Heterocyclic Compounds” to contain collected treatments of topics not necessarily related to each other and not comprising sufficient pages to be issued individually. Since the series’ inception about 25 years ago. volumes have contained exhaustive discussions of syntheses, reactions, properties, structure, physical chemistry, and so on, of compounds belonging to a specific ring system (such as pyridines, thiophenes. pyrimidines. and indoles). This series has become the basic reference collection for infor- mation on heterocyclic compounds.

The series “General Heterocyclic Chemistry,” initiated in 197 1, is devoted to those disciplines of heterocyclic chemistry that are of general significance and application, and that are of interest to all organic chemists as well as to those whose particular concern is heterocyclic chemistry. Each volume in this series surveys the entire field of heterocyc- lic chemistry rather than a particular ring system.

We have long felt a need for an additional forum for discussions of topics of more limited scope whose treatment in a separate monograph might not be appropriatc. We hope that readers and research workers in the field will comment on the usefulness of this new forum; we welcome suggestions for improvements and contributions to future volumes.

ARNOLD WEWRERGER EDWARD C. TAYLOR

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Contents

I. 5,5-Systems With a Bridgehead Nitrogen Atom 1

JOHN P. PAOLINI

11. lndolizine and Am Derivatives With Additional Nitrogens in the 5-Membered Ring 117

H. 1.. BLEWlTT

111. Azaindolizine Systems Having More Than One Nitrogen Atom in the 6-Membered Ring 179

GEORGES MAURY

IV. The Chemistry of Cyclazines 245

ALFRED TAURINS

V. Dithiole and Dithiolium Systems 271

R. D. HAMILTON and E. CAMPAIGNE

VI. Heteropentalenes 317

K. T. POTIS

VII. Borazaromatic Compounds 381

ALBERT J. FRITSCH

VI11. Syntheses and Properties of Cyanine and Related Dyes 441

DAVID M. STURMER

Index 589

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SPECIAL TOPICS IN

HETEROCYCLIC CHEMISTRY

7 l i s is the rhirricth volume in rhr series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

CHAPTER I

5. 5.Systems with a Bridgehead Nitrogen Atom JOHN P . PAOLINI. PH.D.

Memll-Nat&maI Laboratories Cincinnuti, Ohio

I . Introduction .................... ................................ I1 . Synthesis .............................................

A . Pyrroles ...............................................................

C . lmidazoles ...

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

G . Thiazoles ............................................................ H . Thiazolium ................... ..................................... 1 . Oxadiazoles .................. ..................................... J . Thiadiazoles ........................................................... K . Thiadiazolium .......................................................... L . Thiadiazole ....................... ...................... M . Thiadiazolium ............................................... . . . . . N . Simultaneous Formation of Two Rings ...................................

111 . Reactions. ........................... ................................. A . Electrophilic Attack ...................................................

1 . QTrolo[2, 1-blthiazole .............................................. 2 . Imidazo[l, 2-a]imidale ............................................ 3 . Pyrrold1,2-a]benzimidazole ......................................... 4 . lmidazo[2, 1-bIthiazole .............................................. 5 . F'yrrolo[2, l-b]benzothiazole ......................................... 6 . Imidam(2, 1- b]benzothiazole ......................................... 7 . Imidazo[S,I-b]benzothiazole ......................................... 8 . Imidazo[S, 1-blbenzimidazole ........................................ 9 . Thiazolo[3,Z-bl-l,3,4-triazole ........................................

10 . Imidaz42.1 -bl- 1,3, 4-thiadiazole .............................

1

2 3

4 10 1 1 25 31 33 35 46 47 47 49 49 50 5 1

57 57 57 62 63 64 70 71 73 73 74 75

A. Pyrroles.. .. .. 8. Pyrazoles .... C. Imidazoles I . . , D. Triazoles . . . . E. Tnazolium . . . F. Tetrazoles ...

2 5.5-Systems with a Bridgehead Nitrogen Atom

I 1. Thiazolo[3.2-d jrrrrazole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . 12. Pyraj.olo[2,3-u]brnzirnidazole. . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . 13. Isoindolo[ 1,2-h]knrorhiazole. , . 14. I ,3,4-Triawlo[ R.-l-b]henzothiazole. . . . . . . . . . . , . . . . . . , . .

B. Nucleophilic Attack . . . . . . . . . . 1. Pyrrolo[ I,2-u]irnidazole. 2. Pyrrolo[2,1 -h]thiazole. . . . . . . . . . . . . . . , . , , . . . . . . 3. Thia~olo[?,3-c]-.\-1riazole . . . . . . . . . . . 4. Imidaz~2,1-h]bcnzothia~olr . . ......................... 5. Imida~o[5.1-h]henzothiazolc.. .........................

. . , . . . . . . , . . . . . , , , , . , , , , , . . . . . . . . . . . . . . . . . . . . . . . . . . I . . . . . . .

6. Irnidazo[ 1,2-u]henzirnidazole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Imidazo[5.I-b]henzirnidazole. . 8. Isoindol~,benzothiazole . . . . . . . . . . . . . . . , . . . . , . . . . . . . . . . . . . . . . , . , . . . . . . 9. Irnidazol I .2-u Jirnidazole . . . . . ,

10. Pyrrolo[ 1.2-u]hclnzirnidazole. . . . . . . . . . . . . . Ring Openings.. . . . . . . . . . . . . . . . . . .

1. Thiazolo[3,2-d]tetrazolc. . . . . . . .

. . . . . . . . . . . . . . . . . C. ........................

. . . . . . . . . . . . . . . . . . . . . . . . 2. Thiazolo[ 2.3- b][ 1,3,4]thiadiazolium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Irnidazo[ 1.2-n]benzirnidazole . . . . . . . . . . . . . . . . . . . . . . 4. Naphtho[ 1’2’:-l.5]irnidazo[2.1 -b]thiazole . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 . Triazolo[ 3,4-h]benzothiazole. , . . . . . . . . . . . . , . , . . . . . . . . . . . . . . . . . . . . . . . . 6. 5 H-Tetrazolo[ 1,5-a]isoindole . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8. Tetrazolohen2irnidazole. tetra~olohenzothiazole. and tetrazolobenzor- 7. Pyrrolo[ 1,2-u]thiazole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

azole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Condensatiori* . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Pyrazolol3,2-c]-s-triazole . . , . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pyrrolo[2- I-h]thiazolc, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . , . . . . . . . . . 3. Thiazolo[3,2-a]indole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Pyrazol~2,3-n]henzimidazole . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . 5 . Pyrrolo[ 1,2-a Jbenzimidazole . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. lsoindolo[ 1,2-h]benzot 7. Pyrroliziniurn anion. .

I . Azido-tetrazole Tauto 2. Lactarn-Lactirn Tauto 3. Thiol-Thione Tautornerism . . . . . . . . 4. Amine-lmine Tautornerism .................................. 5 . Methylene-NH Tautornerisrn. . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . .

IV. Tautomerisrn , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

V. NMR-Aromaticity.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vi. Theoretical

VII . References , . . . _ . . . . . . _ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. Introduction

75 76 77 78

79 79 79 80 80 80 81 82 82 83 83

84 84 X4 85 87 87 88 88

88 90 91 91 93 93 94 95 YS

96

96 YX 99

100 100

103 103 1 on

The systems we discuss in this chapter are those $5 fused ring systems with a bridgehead nitrogen atom which have T-electrons in mutual cyclic

Synthesis 3

conjugation or for which the tautomeric potential for this condition exists.’ These systems contain 10 .rr-electrons and as the bridgehead nitrogen atoms of such molecules contribute two ?r-electrons, the systems will of necessity be anions (e.g., 1) or contain one or two other heteroatoms that can contribute two r-electrons. The introduction of one other heteroatom contributing two velectrons (e.g., 2) gives a neutral molecule and the introduction of a second heteroatom contributing two r-electrons gives a cation (e.g., 3). Polycyclic systems containing these 5,5 groupings will also be considered. Cyclazines, in which the nitrogen

1 2 3

atom is common to three rings, and mesoionic systems are discussed in other chapters.

N o preference is given to any one definition of aromaticity,2a’b and the term is used in its broadest sense.

The term pyridine type nitrogen refers to a ring nitrogen atom con- tributing one r-electron to the system, and a pyrrole type nitrogen is one that contributes two .rr-electrons to the system.

Chemical Abslrucls has been covered through December, 1972; later selected references are also included.

11. Synthesis

The formation of fused ring systems with bridgehead nitrogen atoms usually involves the building of one ring onto an existing ring, although there are examples in which both rings are formed during the course of the reaction. We deal with the former type first, discussing those ring closures that produced 5 3 systems.

For convenience, the following notation is used in designating systems. Tlie bridgehead nitrogen is “ 1” and the other bridgehead atom “2” and nitrogen is given preference in nomenclature. The example shown would be a [ 1,4,3]thiadiazole.

4 5,5-Systems with a Bridgehead Nitrogen Atom

A. Pyrroles

1. The reaction of a 2-alkyl system (4) with an a-halo carbonyl compound gives a quaternary salt (5) which cyclizes, in base, to a pyrrole ring (6). Sodium bicarbonate,3 ' sodium carbonate,'.' sodium ethox- ide,'."' and triethylamine' and sodium acetate-acetic anhydride have all been used as bases.

H H

I II X R O

base - dRt R

4 5 6

H O I II

R = H, alkyl, aryl or N-C--C6H, R' = alkyl or aryl R" = H or alkyl

X = C1 or Br

This procedure has been used extensively for the preparation pyr- rolo-[ 1,2-a]imida~oles'~~ (7), pyrrolo[ 1,2-~i]benzimidazoles (8),3.4*7*s*'0 pyrrolo[2.1 -bJthiazoles (9),' ' . '**I* pyrrolo[2,1- b]benzothiazoles (10),'3.14 7H-napthor2,l -d]pyrrolo[ 1,2-a]irnidazoles (1 1)' and pyrrolo[ 1,2-b]- 1,2,4- triazole (12)h.

7 9

2. Boekelheide and Fedoruk" prepared pyrrolo[ 1,2-a]imidazoles (7) from 1 -alkyl imidazoles (13) phenacylbromide and ethylpropiolate as shown here. Excess ethylpropiolate is used and serves not only to react

Synthesis 5

with the ylid (15) but also to dehydrogenate the apparent intermediate (16).

R I c-1 13

R=CH,

R

Br 0 14

or benzyl

0 I1 (!ATH5 17 1rh5

3. Dimethylacetylene dicarboxylate reacts with compounds with pyridine type nitrogens. Thiazole and benzothiazole (18) reacted with two moles of diethylacetylene dicarboxylate to give the corresponding triester

6 5,5-Systerns with a Bridgehead Nitrogen Atom

(19).'" The benzothiazole was obtained in better yield (40%) than pyrrolo[2,1-b]thiazole (8.5%). While these workers did not obtain any pyrrolothiazole when a 2-alkyl thiazole was used (they did however obtain some other interesting compounds), Acheson and Tully " were able to obtain a pyrrolo[2, I-b]benzimidazole (21) (among other products) from the reaction of 2-ethyl- 1 -methylbenzimidazole (20) and diethyl- acetylene dicarboxylate. Such a result indicates that the 2-carbon (and alkyl substituent, if any) is one of the two carbon atoms lost in this process.

0 II C-OEt

0 20 21

4. The intramolecular alkylation of benzylhalide of type 22 (followed by abstraction of HX with base) gives fused pyrroles of type 23. This procedure was used 5 y Babichev and KibirevI8 for the preparation of isoindolo[l,2-b]benzothiazole (24), and by a group at Merck" for the preparation of derivatives of imidazoC2,l -a]isoindole (25).

22

X=CIorBt

'/

23

H

24 25

5. Manjunath*' obtained a substance which he called "8,9-( 1,2- cyc1ohexyl)tetrahydrocarbazole" from the interaction of 9-nitroso- 1,2,3,4-tetrahydrocarbazole (26: R = H), cyclohexanone. zinc, and acetic

Synthesis 7

acid. Lions and Ritchie” pointed out that Manjunath had reported an incorrect structural formula. They designated structure 27, a normal product of the Fisher indole synthesis, as being the correct structure.

\ 26 && 27 R

NO

Zn-HOAc

[They prepared a 6-methyl derivative (27; R=CH3) using the same approach.] 8-Methyl-9-nitrosocarbazole (28); in which the ortho position is blocked, failed to give a similar substance, which is to be expected if structure 27 is correct.

28

Manjunath’” also prepared the hydrazone (29) but was unable to effect a Fisher ring closure with it. Preston and Tuckerz2 accomplished this by treating this hydrazone with dry HCI in tetralin at 160” and obtained the tetrahydro indolo[3,2,1 - j , I]carbozole (30).

Q HCI_ (-> I”c”,, 1 6 0 ” \ /

\ / /

29 30

6. The Pschorr reaction was used by Preston and Tucker” to prepare indolo[3,2,1 -j,k]carbazole (22) from 1 -amino-9-phenyl carbazole (31).

31 32

8 5,s-Systems with a Bridgehead Nitrogen Atom

7. Kovtinenko and BabichevZ3 alkylated 1-alkyl-2-methyl ben- zimidazoles (33) with an alkyl halide having the halogen atom on a methylene group, to give quaternary salts of type 34. Treatment of these salts with anhydrides gave pyrrolo[ 1,2-a]benzirnidazoles of type 35.

R R

(q *N,

CH2-R‘ 33 34

tR’C0)ZO

CR”

\ R = CH, or C,H, R‘ = COOC,H,. CN, GH, , or H

X = Cl, Br @yR

R’

R”=CH,.C,H,

3s

8. In their study on diynes, Muller and Z o ~ n t s a s ~ ~ prepared fused pyrroloindoles. Tris(tripheny1phosphine)rhodium chloride acted on the

36

Ph

Ph 38

ph D h

R = Ph or COOC2H,

Ph 39

diacetylenic benzimidazole (36) to give chloro 1 H-pyrrolo[ 1,243- benzimidazole-2,3 -diylidenbis (phenylmethy1idyne)bistriphenylphosphiiie rhodium (37). Treatment of this rhodium compound with selenium gave 1,3-diphenyl- 1 OH-seleno[3‘,4’ : 3,4Ipyrrolo[ 1,2-a]benzimidazole (38). The rhodium compound (37) reacted with disubstituted aceytenes to form

I

Synthesis 9

the 11 H-isoindolo[2,l-a]benzimidazole (39). (These compounds are writ- ten in the “methylene” form but the potential for tautomerism to the N-H form exists-see tautomerism.)

9. Likhitskaya and Babichev” used the reaction of 2-(2-hydroxymethyl- pheny1)benzoselenazole (40) and phosphorous tribromide to prepare isoindolo[ 1,2-b]benzoselenazole as the hydrobromide salt (41). Treat-

CH2 B r-

40 41

42

ment of this salt with sodium hydroxide gives the free base 42. Pyrido- [2,3-c]benzoselenazolo-[3,2-alpyrrole (43).

43

10. Quarternary salts of heterocyclic systems having an active N- methylene group and an open carbon (Y to the nitrogen (e.g., 44) react with picryl chloride (45) to form a pyrrole ring.

CH3

CH3 I

kH2x-

DMSO

NO2 45

,CH3 46

NOz 47

10 S,S-Systems with a Bridgehead Nitrogen Atom

48 49

Reuschling and Krohnke" used this reaction to prepare the 1,3-dinitro- 5-methyl- 1 1 -(4-bromobenzoyl)-5H-benzimidazo[2,l-a]isoindole (46) which was debenzoylated in sulfuric acid (giving 47). In like manner, 6,8- dinitrothiazolo[2,3-a]isoindole (48) was prepared. The electron with- drawing effect of the third nitro group of picryl chloride can be simulated by a fused benzene ring as l-chloro-2,4-dinitronaphthalone was used to prepare 5-nitro-7-methyl-7 H-benzimidazo[2,1 -a]benz[ e]isoindole (49).

B. Pyrazoles

1 .s

1. Becker and Bottcher" used the Wolff reaction to effect the ring contraction of 50 to a pyrazole (51).

50 51

2. Claramunt, Fabrega, and Elguero2' reported that 3,4-diamino- triazole (52) reacts with ethylacetoacetate to give the diazepinone (53). Treatment of this compound in hot acetic anhydride gave the acetyl

H

Synthesis

CH, I

C=O

1 1

R = H, CH,, CJ-l,, and henzyl

compound 54 which, in base, yielded the SH-pyrazolo[s,l-c]-s-triazole (55). This series of reactions had been reported earlier by Gehlen and Drohla" to yield initially the triazepinone (56) and ultimately either the

56 57 58

imidazo[l,2-b-c]-s-triazole (57) or the imidazo[2,l-c-b]-s-triazole (58). Claramunt et ruled out structures 57 and 58 as possible base hydrolysis products on the basis of their nmr studies. The nmr spectra showed hydrogens on carbon atoms which was not attached to a nitrogcn (6's of 5.55, 5.50, and 5.46 for R = H, CH3, and C2HS, respec tively). Such a condition suggested a pyrazole ring and structure 55 was accordingly assigned. [Compound 55 (R = CHd prepared by a different route had been previously reported by Bailey, Knott, and M ~ I T . ~ ~ ]

C. lmidazoles

a3 1,3

1. The most commonly used method for the synthesis of fused 1,3 imidazoles is the alkylation of amines of type 59 with a-halo carbonyl or related compounds.

a. The reaction of an a-haloketone and an amine of type 59 gives quaternary salts (60) which can then by cyclized to form fused imidazoles (61).

12 S.S-Systems with a Bridgehead Nitrogen Atom

x o I I1 (-JNH2 R - C 4 H - C - R .

59

60 61

X-Clor Br

Cyclization of the quaternary salts (60) to the fused imidazole has been effected in aqueous b a ~ e , ~ ( ' - ~ ' aqueous and in hot water.35 A few examples of the direct conversion (i.e., no excess amine in the reaction mixture or no aqueous base used in the work up which would remove HX and promote cyclization) of the amino compound (59) and the bromoketone to imidazoles have been In one of these the ketone used had two phenyl groups'" and the amine in the other example had strong electron withdrawing substituents on the ring3' Thus electronic and/or steric factor appears to be involved.

Kickhofen and Krohnke,3s using the following sequence of reactions, showed that 2-aminothiazole (62) gave 6-phenylimidazo[2,l-b]thiazole (63) rather than the 5-phenyl compound (64). Krohnke, Kickhofen, and

cyN-H & (SyNyC6H5 63 \ / CH~-C-C~HS a I".*

0 I t

H O 0

& 4 H 3 Br-CH2-C-C.H,

-N--CHZ--C--C~H~ II 0

H

Synthesis 13

Thoma" had shown earlier that phenacyl bromide alkylated 2-amino- pyridine on the ring nitrogen. By analogy with these two examples, it seems reasonable to conclude that alkylation of 2-amino compounds of type 59 can be considered to proceed as shown in most instances; however, the possibility that this pattern could be altered by medium or

67

72 0

14 5,s-Systems with a Bridgehead Nitrogen Atom

by large steric or electronic factors should not be ruled out. A steric effect was reported by Rietman" from a study on a 6,s system. 2- Aminopyridine (65) and a -chlorocyclohexanone gave the exocyclic sub- stituted product 66 rather than the ring substituted material 67. This work was confirmed by Campbell and McCal13* who further found that pH was a factor in this reaction. The cyclohexanone (66) was obtained in aqueous sodium carbonate while the imidazopyridine (67) was formed in aqueous sodium bicarbonate.

An effect of time and medium (HCI can be considered to be part of the medium when the salt of a starting material is used) was reported by Simonov, Anisimova. and Borisov3' who found that 1 -alkyl-3-carboxy- methyl-3-iminobenzimidazoline hydrochlorides (68) acylated in acetic anhydride to form compound 69 which then cyclized to the acid (70). De- carboxylation of the acid gave the 2-methylimidazo[ 1,2-~]-benzimidazole (71) which can be acylated with acetic anhydride to give the 2-methyl-3- acetyl derivative (72). Treatment of the free base of the imidazoline (68) in refluxing acetic anhydride for 3 hr gave this same acetyl compound (72), while 3 to 5 min in refluxing acetic anhydride gave the lactam 73 which, on further heating, was converted to the ketone (72).

O=C CHI \

CH, H

74 75

Treatment of imidazo[2, I-b]thiazol-6(SH)one (74) with acetic anhyd- ride in refluxing toluene was found to give a diacylated material which was assigned structure 75* by Paolini and Lendvay."

A variation of this cyclization procedure involves alkylation of 2- methylaminobenzimidazole (76) with methyl chloroacetate, to give the ester (77).

Upon treatment with ammonium hydroxide, it formed 1-methyl imidazo[ 1,2-a]benzimidazoI-2(3H)-one (78) as well as the amide 79.4'

The alkylation of these amines (80) by a-halo carbonyl compounds has electronic limitations as shown by the work of Werbel and Zamora3' on imidazo[2,l-b]thiazoles (81). While no quantitative evaluation was made, these workers found that very strongly electron withdrawing substituents

*There is a typographical error in this paper. The bridgehead nitrogen atom of this structure (74) i s not shown.

Synthesis

H

CI

N O . 0 \ /

NO,

15

reaction

reaction

reaction

no reaction

H H 0 II

CI-CHZ-C-OCHI

76

78 79

in the 5-position of a 2-aminothiazole (80) will inhibit its capacity to react with phenacylbromide.

The acetals of a-haloaldehydes are more stable than the free aldehydes and are often used in reactions of this type.”

80 81

R I Result