Heterocyclic Compounds: Synthesis, Properties and Applications

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Author: Kristian Nylund | Peder Johansson | Z. Puterova | A. Krutosikova | D. S. Zurabishvili | M. O. Lomidze | Sh. A. Samsoniya

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CHEMISTRY RESEARCH AND APPLICATIONS SERIES

HETEROCYCLIC COMPOUNDS: SYNTHESIS, PROPERTIES AND APPLICATIONS

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

CHEMISTRY RESEARCH AND APPLICATIONS SERIES Applied Electrochemistry Vijay G. Singh (Editor) 2010. ISBN: 978-1-60876-208-8 Heterocyclic Compounds: Synthesis, Properties and Applications Kristian Nylund and Peder Johansson (Editors) 2010. ISBN: 978-1-60876-368-9

CHEMISTRY RESEARCH AND APPLICATIONS SERIES

HETEROCYCLIC COMPOUNDS: SYNTHESIS, PROPERTIES AND APPLICATIONS

KRISTIAN NYLUND AND

PEDER JOHANSSON EDITORS

Nova Science Publishers, Inc. New York

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Library of Congress Cataloging-in-Publication Data Heterocyclic compounds : synthesis, properties, and applications / Kristian Nylund and Peder Johansson. p. cm. Includes bibliographical references and index. ISBN 978-1-61324-989-5 (eBook) 1. Heterocyclic compounds. I. Nylund, Kristian, 1956- II. Johansson, Peder, 1945QD400.H467 2009 547'.59--dc22 2009040473



York

CONTENTS Preface Chapter 1

Chapter 2

vii Substituted 2-Aminothiophenes: Synthesis, Properties and Applications Z. Puterová and A. Krutošíková Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles. Methods of Synthesis, Properties and Biological Activity D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze,Sh. A. Samsoniya

Chapter 3

Methods of Synthesis of Pyrroloindoles Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili, N. L. Targamadze

Chapter 4

Palladium-catalyzed Amination of Dihaloarenes: A Simple and Efficient Approach to Polyazamacrocycles Alexei D. Averin, Alexei N. Uglov, Alla Lemeune, Roger Guilard, Irina P. Beletskaya

Chapter 5

Pyrridazinoindoles, Synthesis and Properties Sh. A. Samsoniya, I. Sh. Chikvaidze, M. Ozdesh

1

47

99

119

147

vi Chapter 6

Chapter 7

Chapter 8

Chapter 9

Chapter 10

Chapter 11

Chapter 12

Index

Contents 11-Perfluoroalkyl-substituted 3,3-Dimethyl11-hydroxy-2,3,4,5,10,11-hexahydro-1Hdibenzo[b,e][1,4]diazepin-1-ones: Synthesis and Characterization Tatyana S. Khlebnicova, Veronika G. Isakova, Alexander V. Baranovsky and Fedor A. Lakhvich Synthesis and Biological Activity of some Isomeric Dipyrrolonaphthaline Derivatives Sh. A. Samsoniya, M. V. Trapaidze, N. A. Esakia, K.Kh.Mamulashvili, Z. Sh. Lomtatidze, T. V. Doroshenko

171

183

Some Conversions of 5-acetyl-2-ethoxycarbonyl - 3-p-nitrophenyl Indole N. Narimanidze, Sh. Samsoniya, I. Chikvaidze

201

2-Pyridineselenenyl- and Tellurenyl Chlorides as Building Blocks for Derivatives of 2,3-dihydro[1,3] selen(tellur)azolo[3,2-a] pyridin-4-ium Alexander V. Borisov, Zhanna V. Matsulevich, Vladimir K. Osmanov, Galina N. Borisova and Georgy K. Fukin

211

Synthesis and Antimicrobial Activity of some Adamantyl Containing Indoles and Benzopyrroloindole Derivatives Sh. A. Samsoniya, D. S. Zurabishvili, I. Sh. Chikvaidze, M. O. Lomidze, M. V. Trapaidze, K. Kh. Mamulashvili, Z. Sh. Lomtatidze

219

Photochemistry of Azidopyridine and Related Heterocyclic Azides Mikhayl F. Budyka

225

Progress in the Chemistry of Condensed Thiazolopyrimidines M.A. Metwally and Bakr F. Abdel-Wahab

317 377

PREFACE Heterocyclic compounds are organic compounds containing at least one atom of carbon, and at least one element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure. These structures may comprise either simple aromatic rings or non-aromatic rings. Some examples are pyridine (C5H5N), pyrimidine (C4H4N2) and dioxane (C4H8O2). Many heterocyclic compounds, including some amines, are carcinogenic. This book details the proposed mechanisms of Gewald-like reactions and the wide scope of substituted 2aminothiophenes for real life applications. Literary information about synthesis methods, structure, physical-chemical and biological properties is summarized, and also information about conversion of adamantyl-1 and adamantyl-2 imidazole and benzimidazole derivatives is given. A survey of the literature of thiazolopyrimidines from 2003 to 2008; some of the commercial applications of thiazolopyrimidine derivatives are mentioned. Chapter 1 - Several methods are accessible for synthesis of substituted 2aminothiophenes: cyclization of thioamides and their S-alkylates, Schmidt reaction of 2-nitrothiophenes, Beckmann rearrangement of 2-acetylthiopheneoximes, anyway since 1961 when first report on the Gewald reaction was published it became an universal method for this purpose and has gained prominence in recent times. The availability of the reagents and the mild reaction conditions all contribute to the versatility of this reaction. The improved variations of the Gewald reaction offer several additional advantages such as tolerating a broad range of functional groups. The mechanism of this powerful reaction is not fully clear. Consequently, this chapter details about the proposed mechanisms of Gewald-like reactions and the wide scope of substituted 2-aminothiophenes for real life applications.

viii

Kristian Nylund and Peder Johansson

Title compounds are attractive derivatives, largely used in the industry because of their applications in pharmaceuticals, agriculture, pesticides and dispersed dyes. They exhibit antimicrobiological activity against various Gram (+) and Gram (-) bacteria and fungi. Many of these molecules act as allosteric enhancers of A1-adenosine receptor, glucagon antagonists as well as antioxidant and anti-inflammatory agents. Moreover, they are potent precursors in synthesis oligo- and polythiophene structures, which are employed to create novel types of semi conducting polymers and non-linear optic materials. Chapter 2 - The interest towards adamantylcontaining imidazoles and benzimidazoles is stipulated by broad spectrum of their biological effects and important technical properties. At present, different methods of synthesis are elaborated and definite success in study of the structure features and reactivity of imidazole and benzimidazole derivatives of adamantane series is achieved. In this survey, literary information about synthesis methods, structure, physical-chemical and biological properties is summarized, and also information about conversion of adamantyl-1 and adamantyl-2 imidazole and benzimidazole derivatives is given. The bibliography includes 96 references. Chapter 3 - Two alternative methods of synthesis of unsubstituted pyrroloindoles have been worked out by Professor Sh. Samsoniya and his coworkers at Iv. Javakhishvili Tbilisi State University. According to the first method the attachment of pyrrole ring occurs to benzene ring of indoline; and pursuant to the second method two pyrrole rings are attached to benzene ring. In the both methods for formation of pyrrole rings is used Fischer reaction. In the first method the initial compounds are 5- and 6- aminoindolines. Their diazotization and further reduction gives the corresponging hydrazines, by condensation of which with pyruvic acid ethyl ether are obtained corresponding hydrazones, which in polyphosphoric acid ethyl ether (ppaee) undergo cyclization to yield mixture of angular and linear pyrroloindoline ethers, with great excess of linear isomers. By saponifying of ether with subsequent decarboxylation and simultaneous dehydration on pd/C are obtained fully aromatized, unsubstituted, isopmeric pyrroloindoles. In the second method as initial compound is used m-phenylenediamine, by diazotization and subsequent reduction of which is obtained dihydrazine which condensate with pyruvic acid ethyl ether to yield the corresponding dihydrazone. Its cyclization in ppaee results the built of two pyrrole rings on benzene ring. The mixture of angular and linear pyrroloindole diethers is being formed, with great excess of angular isomers. The subsequent saponifying and decarboxylation of diethers result the corresponding unsubstituted pyrroloindoles.

Preface

ix

Electrophilic substitution reactions have been studied for all the four isomeric pyrrolo-indoles, particularly Vilsmeier-Haack, Mannich, azocoupling and acetylation reactions. Some conversions have been carried out in side chain in order to obtain biologically active compounds. The majority of obtained compounds have been tested on initial biological activity, such as bactericidal, tuberculostatic activities. Three compounds have revealed tuberculostatic activity. Chapter 4 - The following aryl halides were used in the synthesis of previously unknown polyaza- and polyazapolyoxamacrocycles using Pd-catalyzed amination reactions: 1,2- and 1,3-dibromobenzenes, 2,6-dichlorobromobenzene, 2,6- and 3,5-dihalopyridines, 3,3'- and 4,4'-dibromobiphenyls, 1,8- and 2,7dibromonaphthalenes, 1,8- and 1,5-dichloroanthracenes and anthraquinones. Following linear amines were employed in this process: 1,3-diaminopropane, tri-, tetra-, penta- and hexaamines, di- and trioxadiamines. Significant dependence of the results of the amination reactions on the nature of starting compounds was established. The best results were achieved using 1,3-dibromobenzene which provided yields up to 56%. Target macrocycles containing one arene and one polyamine moiety were often obtained together with cyclodimers and cyclooligomers of higher masses. The authors elaborated two alternative approaches to cyclodimers which are also valuable macrocycles possessing larger cavity size: (a) via bis(haloaryl) substituted polyamines and (b) via bis(polyamine) substituted arenes, and demonstrated that the applicability of these methods strongly depended on the nature of the pair aryl halide/polyamine. Scope and limitations for the synthesis of various polyazamacrocycles were established. Chapter 5 - Pyrridazinoindoles can be considered as azaanalogs of different carbolines, and especially β- and γ-, the condensed ring system of which represent the basis of many compounds of high physiological activity. Therefore the unified aromatic system of isomeric pyrridazinoindoles containing three nitrogen atoms in different positions and their derivatives have attracted great attention of researchers. A lot of notifications, dedicated to synthesis of isomeric pyrridazinoindole derivatives and studying their different pharmacological activities, that is not of less value, appeared during the last 2-3 decades. The present survey is the attempt of summarization of numerous data. It cannot be referred to the complete one, while it does not embrace all the notifications concerning this question. The preparative methods of synthesis of isomeric pyrridazinoindoles, jointed in different ways, have been worked out, based on application indole carbonyl

x


derivatives with subsequent built of pyrridazine cycle. For some isomers the attachment of indole ring to pyrridazine appeared to be more convenient. The study of chemical properties of pyrridazinoindoles and intermediate oxoand dioxopyrridazinoindoles in order to find new bioactive substances brought to rather interesting results. Have been synthesized a lot of new derivatives of these systems revealing different useful properties, including frank activity against Alzheimer's disease, Parkinson's disease and Down's syndrome, revealing antitumour, antihypertensive, antiinflammatory, antibacterial, tuberculostatic, inotropic activity, possessing ability of hypnotic and anticonvulsive influence, of inhibition of monoamine oxidases, phosphodiesterase and thromboxanes, of combining central and peripheral benzodiazepine receptors and other. Bibliography contains more than 64 references. Chapter 6 - Novel 11-perfluoroalkyl-substituted 3,3-dimethyl-11-hydroxy2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones are prepared via a simple two-step approach. A treatment of 2-perfluoroalkanoylcyclohexane-1,3diones with ethereal solution of diazomethane gives 5,5-dimethyl-3-methoxy-2perfluoroalkanoylcyclohex-2-en-1-ones as main products and 6,6-dimethyl-3hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones as by-products. Then, an initial methoxy group vinylogous substitution of enol ethers by one of the o-phenylenediamine amino groups and an intramolecular cyclization leads to the title compounds in high yields. Chapter 7 - New heterocyclic systems were synthesized - isomeric dipyrrolonaphthalines: 1H,6H-indolo[7,6-g]indole, 3H,8H-indolo[4,5-e]indole, 3H,8H-indolo[5,4-e]indole and 1H,10H-benzo[e]pyrrolo [3,2-g]indole. On the basis of these heterocyclic compounds were obtained N, N-dialkyl derivatives, phenylazo derivatives, formyl derivatives and was studied their antimicrobial and germicidal activity. The results of investigation revealed that the introduction of phenylazo group in the third position in pyrrole ring of benzopyrroloindole gives the key cycle, 1H,10H-benzo[e]pyrrolo[3,2-g]indole, antimicrobial activity towards different pathogenic bacteria and opportunistic pathogenic bacteria. N, N-dialkyl derivatives of indoloindoles depress the growth and development of plant pathogenic bacteria. Chapter 8 - It was carried out some conversions of 5-acetyl-2ethoxycarbonyl-3-p-nitrophenyl indole functional groups, particularly by reduction of nitrogroup was obtained corresponding amine and its condensation products with carbonyl compounds, mono and diacetyl derivatives. By hydrolysis of ester group and halogenations of obtained acid was synthesized 5-acetyl-3-p-nitrophenyl indole 2-carboxylic acid chloranhydride. It

Preface

xi

was carried out the acylation by chloro-anhydride of substances possessing aminofunctionality. The correstponding series of amides was obtained. Chapter 9 - The reactions of 2-pyridineselenenyl- and tellurenyl chlorides with alkenes lead to the formation of products of a tandem electrophilic addition/cyclization process with the ring closure by the nitrogen atom of the pyridylchalcogeno moiety. By virtue of its extremely high regio- and stereoselectivity selenocyclofunctionalization of unsaturated substrates carrying internal nucleophiles is one of most important and effective methods of synthesis of heterocyclic compounds [1-11]. Much less is known about tellurocyclofunctionalization of unsaturated compounds [12-15]. All these cyclizations proceed with ring closure involving a nucleophilic active group in the molecule of the substrate. Recently the authors described a novel approach to a stereoselective synthesis of condensed sulfur–nitrogen-containing heterocycles based on the interaction of sulfenyl chlorides with unsaturated compounds which occurs by ring closure at the nucleophilic center of the sulfenyl unit [16]. Taking into account these results it can be predicted that corresponding organoselenium and organotellurium reagents are suitable for the preparation of heterocycles containing selenium and tellurium. The authors now report on extensions of this alternative approach to selenenylating and tellurenylating reagents. Chapter 10 - 2-(1-adamantyl)indole, synthesized by Fischer reaction, was transformed into 3-dimethylaminomethyl derivative according Mannich reaction. It was obtained corresponding quaternary salts soluble in water. 2adamantylaminocarbonylindole and 2,9-di(adamantylaminocarbonyl)-1H,10Hbenzo[e]pyrrolo[3,2-g]indole were obtained by interaction between 1aminoadamantane and 2-indolylcarbonic acid. The synthesized compounds revealed biological activity. Chapter 11 - Photochemical properties of azido derivatives of six-member aza-heterocycles (pyridine, pyrimidine, triazine, quinoline, acridine) are discussed. Data on the structure of the reaction products formed under photolysis of azides in different conditions (solvent, temperature, additives), and also data on the matrix isolation spectroscopy of heterocyclic nitrenes, including high-spin nitrenes, produced by low-temperature photolysis of the corresponding azides are shortly examined. Especial attention is paid to the dependence of the azide photoactivity (i.e. quantum yield of azido group photodissociation) on the size and charge of the heteroaromatic system. Heterocyclic azides have been used as convenient model compounds for the study of charge effect, since they can be easily transformed

xii


from the neutral to positively charged form by protonation or alkylation at endocyclic nitrogen atoms. Protonation of a heterocyclic nucleus has been found to decrease slightly the photodissociation quantum yield ( ) of 4-azidopyridine and 4-azidoquinoline, do not influence on the value for 9-azidoacridine, and reduce by two orders of magnitude the value for 9-(4'-azidophenyl)acridine. To reveal the effect of the size and charge on azide photoactivity, the structures of linear cata-condensed heteroaromatic azides from azidopyridine to azidoazahexacene (the size of aromatic -system from 6 to 26 e) are calculated by semiempirical (PM3), ab initio (HF/6-31G*) and DFT (B3LYP/6-31G*) methods. Joint consideration of the experimental and quantum-chemical data results in the conclusion that the azide photoactivity depends on the nature of molecular orbital (MO) that is filled in the lowest excited singlet (S1) state. If the antibonding NN*MO, which is localized on the azido group and is empty in the ground (S0) state, is filled the S1 state, the azide is photoactive ( > 0.1). However, when the size of the -system increases above a certain threshold, aromatic -MO is filled instead of the NN*-MO in the S1 state, and the azide becomes photoinert ( drops below 0.01). The threshold size is predicted to be 22 and 18 -electrons for the neutral and positively charged azides, respectively. Several examples of application of heterocyclic azides for photoaffinity labeling are considered. Important from this point of view are azido-derivatives of acridine, hemicyanine, and ethidium dyes, which possess the most longwavelength visible light sensitivity so far reported for aromatic azides. Chapter 12 - This article covers the methods for preparing different thiazolopyrimidines, also includes their reactions in the last six years, some of which have been applied to the synthesis of biologically important compounds. The title compounds are subdivided into groups according to the position of fusion between thiazole and pyrimidine rings.

In: Heterocyclic Compounds: Synthesis, Properties … ISBN: 978-1-60876-368-9 Editors: K. Nylund et al. pp. 1-45 © 2010 Nova Science Publishers, Inc.

Chapter 1

SUBSTITUTED 2-AMINOTHIOPHENES: SYNTHESIS, PROPERTIES AND APPLICATIONS Z. Puterová1,* and A. Krutošíková2,† 1

Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Kalinčiakova 8, 832 32 Bratislava, Slovakia 2 Department of Chemistry, Faculty of Natural Sciences, University of St. Cyril and Metodius, Nám. J. Herdu 2, 91701 Trnava, Slovakia

PEER REVIEW Chemistry of 2-aminothiophenes is arguably one of the most extensive and dynamic field of present-day thiophene research. Thirty years after the famous review by Norris (cit. 25) and ten years of the last Gewald reaction review by Sabnis et. all (cit.26) appeared the time was ripe for a fresh look at this exiting field of thiophene chemistry. The review starts with an extensive introduction that discusses the most multidisciplinary areas of aminothiophene research with inputs from medicine, pharmacology, chemistry, biology, biochemistry, materials science and physics. In this papers has collected together detailed descriptions of selected important new reactions and works used Gewald reaction.

* †

E-mail: [email protected], [email protected]; Fax: +421-02-50-117357. E-mail: [email protected], [email protected]; Fax: +421-33-5921403.

2

Z. Puterová and A. Krutošíková

The chapters „ Synthesis.. Properties... and Application....of aminothiophenes― are well documented and written in clear language. The article is well structured to provide guidelines for mechanism, specific applications in drug delivery, material science or recent theories. The reader interested in the latter aspects can find further detailed information in the list of references. This review will draw the attention of the chemist community to the fact that the review concise overview of the use of modern Gewald reaction. Ing. Daniel Végh,DrSc., Senior research fellow Institute of Organic Chemistry, Catalysis and Petrochemistry, Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81239 Bratislava, Slovakia, Phone: +421-(02)-59325-144, Fax: +421-(02)-52968560, Email: [email protected]

ABSTRACT Several methods are accessible for synthesis of substituted 2aminothiophenes: cyclization of thioamides and their S-alkylates, Schmidt reaction of 2-nitrothiophenes, Beckmann rearrangement of 2-acetylthiopheneoximes, anyway since 1961 when first report on the Gewald reaction was published it became an universal method for this purpose and has gained prominence in recent times. The availability of the reagents and the mild reaction conditions all contribute to the versatility of this reaction. The improved variations of the Gewald reaction offer several additional advantages such as tolerating a broad range of functional groups. The mechanism of this powerful reaction is not fully clear. Consequently, this chapter details about the proposed mechanisms of Gewald-like reactions and the wide scope of substituted 2-aminothiophenes for real life applications. Title compounds are attractive derivatives, largely used in the industry because of their applications in pharmaceuticals, agriculture, pesticides and dispersed dyes. They exhibit antimicrobiological activity against various Gram (+) and Gram (-) bacteria and fungi. Many of these molecules act as allosteric enhancers of A1-adenosine receptor, glucagon antagonists as well as antioxidant and anti-inflammatory agents. Moreover, they are potent precursors in synthesis oligo- and polythiophene structures, which are employed to create novel types of semi conducting polymers and non-linear optic materials.

Substituted 2-Aminothiophenes: Synthesis, Properties and Applications

ABBREVIATIONS Ac – Ar – Bn – Boc – Bu – DBU – DIBAL-H – DIC – DMAP – DIPEA – DMF – DMF-DMA – DMSO – EDG – EWG – Et – equiv. – h– hGCRG – HMDS – HLE – Me – min – MPS – NBS – PEG – Ph – Pr – PS – Ref. – RNA – RT – TEAHFP – TDP – TFA –

acetyl; aryl; benzyl; tert-butyloxycarbonyl; butyl; 1,8-diazabyciclo 5.4.0 undec-7-ene; diisobutylaluminum hydride; 1,3-diisopropylcarbodiimide; 4-dimethylaminopyridine; diisopropylethylamine; N,N-dimethylformamide; dimethylformamide dimethylacetal; dimethylsulfoxide; electron-donating group; electron-withdrawing group; ethyl; equivalent; hour; hepatic glucagon receptor; hexamethyldisilazane; human leukocyte elastaze; methyl; minute; morpholine polysulfide; N-bromosuccimide; polyethylene glycol; phenyl; propyl; polystyrene; reference; Ribonucleic acid; room temperature; tetraethylammonium hexafluorophosphate; thiamin diphosphate; trifluoroacetic acid.

3

4


1. INTRODUCTION Highly substituted thiophene derivatives are important heterocycles found in numerous biologically active and natural compounds [1-5]. The interest in this kind of heterocycles has spread from dye chemistry [6] to modern drug design [7], biodiagnostics [8], electronic and optoelectronic devices [9], conductivity-based sensors [10] and self-assembled superstructures [11]. 2-Amino-3-aroylthiophenes are agonist allosteric enhancers at the A1 adenosine receptor [12, 13]. A novel class of thiophene-derived antagonists of the human glucagon receptor has been discovered [14]. Traditionally, polysubstituted 2-aminothiophenes with an electronwithdrawing group such as cyano, ethoxycarbonyl or aminocarbonyl in the 3position and alkyl, aryl or hetaryl groups in the 4- and 5-position are prepared utilizing the Gewald reaction [15]. The core structure is formed in the multicomponent reaction between a ketone or aldehyde, an activated nitrile and sulfur in the presence of suitable base. Although this one-pot synthesis is well established, the two-step procedure in which an , -unsaturated nitrile is first prepared by a Knoevenagel-Cope condensation of ketone or aldehyde with an activated nitrile, followed by base-promoted reaction with sulfur has been also widely employed. Generally, there are four basic variations described by Gewald and co-workers [16-20] and about up to fifteen modifications to accomplish the synthesis of highly functionalized 2-aminothiophenes. Recently, the improvements of the Gewald synthesis were announced [21-24]. They are based in diminution of the reaction time by using microwave technology. The chemistry of aminothiophenes has been broadly summarized in 1986 in the monograph of R. K. Norris 25 and later reviewed in 1999 26 . The importance of this field of heterocyclic chemistry gave impetus to the present study, where the data on synthesis, reactivity and application of variously substituted 2-aminothiophenes are systematized and analyzed. Emphasis is given to the recent studies published, in which the most general approaches to the synthesis of basic 2-aminothiophenes via the Gewald reaction and other target structures were considered. Data of the utilization of 2-aminothiophenes in the synthesis of novel type of fused heterocycles and their application are included. Particular attention is given to studies published in the previous 15-20 years.


5

2. SYNTHESIS The chemistry of 2-aminothiophenes has received much attention upon their convenient availability through the most versatile synthetic method developed by Gewald and his co-workers 15 . Many methods of synthesis of substituted 2aminothiophenes published before the Gewald are generally unsuitable because they involve difficult preparation of the starting materials, multi step synthesis and do not produce high yields 26 . The prior to universal synthesis to this kind of product was reported in 1910 by Benary 27 as the multi step reaction of ethyl 4-chloro-2-cyano-3oxobutanoate (1). After the treatment of 1 with potassium hydrosulfide the reactive sufanyl-substituted intermediate 2 was created, which in the subsequent intramolecular addition of sulfanyl group to cyano group proceeded ethyl 2-amino4-hydroxythiophene-3-carboxylate (4) in equilibrium with its cyclic tautomer – the appropriate imine 3 (Scheme 1). The Benary’s method exhibits a very limited scope because of the unavailability of structure 1-like halo-substrates. Fifty years later, in 1961, the substituted 2-aminothiophenes with electron-withdrawing substituents (such as cyano, carbonyl, methoxycarbonyl, aminocarbonyl, etc.) at C-3 position and electron-donating substituents (such as alkyl, aryl, cycloalkyl, etc.) in the C-4 position of the thiophene ring were synthesized in one step process from aliphatic substrates – substituted -sulfanylaldehyde or -sulfanylketone 5 and -substituted acetonitrile 6 (where the substituent is EWG, X = CN, CO2H, Scheme 2) 16 . Since then, the Gewald reaction and its variations have found enormous utility in synthesis of variety of substituted 2-aminothiophenes. The Gewald reaction represents the multi component process to prepare substituted 2-aminothiophenes in generally high yields from -substituted acetonitriles carrying electron-withdrawing groups and -methylene carbonyl compounds (aldehydes or ketones) in the presence of the base – organic bases such as secondary or tertiary amines (diethylamine, morpholine, triethylamine, pyridine) or inorganic bases (e.g. NaHCO3, K2CO3, NaOH). Polar solvents, like DMF, alcohols (methanol, ethanol), 1,4-dioxane enhance the condensation of intermediates – , -unsaturated nitriles with sulfur, which are either prepared in situ or externally. Depending on the used starting substrates and the reaction conditions three basic versions of the Gewald reaction have been developed 16, 28-30 , which were lately enriched by a fourth version 31 .


6 EtO2 C

O

EtO2 C

KHS N

HO

CO2 Et

CO2 Et

N

O

O Cl

NH

S

NH 2

S

SH

1

2

4

3

Scheme 1. Benary reaction [27]. R1

R1

O SH

X

R2

R2 6

5

X

N S

NH 2

7a-f

7a: R1 = R 2 = H, X = CN 7b: R1 = R 2 = (CH2) 4, X = CN 7c: R1 = R 2 = Me, X = CN 7d: R1 = R 2 = H, X = CO2H 7e: R1 = R 2 = (CH 2)4, X = CO 2H 7f: R 1 = R 2 = Me, X = CO2H

Scheme 2. Originally published Gewald reaction [16].

2.1. The First Version of the Gewald Reaction In the first version of this reaction, an -sulfanyladehyde or -sulfanylketone 5a is treated with -activated acetonitrile 6 in the presence of a basic catalyst (usually triethylamine or piperidine). Reaction performed in the solvents like methanol, ethanol or DMF at 50 °C takes place in two subsequent steps – Knoevenagel-Cope condensation 32, 33 and intramolecular ring closure of formed sulfanyl substituted , -unsaturated nitrile 8 (Scheme 3). By this reaction polysubstituted 2-aminothiophenes with electron-donating substitents in C-4 and C-5 positions of the thiophene ring (R1 and R2, mainly alkyl and cycloalkyl chains) are prepared in yields varying between 35-80% (Table 1) 15, 16, 28-30 . Because the instability and difficult preparation of the starting -sulfanylcarbonyl compounds 5a this reaction appears to have a limited scope and more convenient variations are utilized instead of this procedure. R1

R1

O SH R2 5a

N

X

-H2O 6

X

R1

a

X

b R

2

SH 8

N

R2

S

NH 2

7

a: Knoev enagel-Cope condensation: triethylamine or piperidine (cat. amount), 50 °C; b: r ing-closure r eaction.

Scheme 3. Version 1 of the Gewald reaction [15, 16].


7

Table 1. Some of substituted 2-aminothiophenes 7 prepared via the Version 1 of the Gewald reaction R1 Me Me (CH2)4 Me (CH2)4

R2 Et Me

X CN CN CN CO2Me CO2Et

Me

Yield (%) 51 70 70 45 80

Ref. 15 15 16 28 29

2.2. The Second Version of the Gewald Reaction The second version of the Gewald´s process is the most elegant and consist of the one-pot reaction of three components – -methylene carbonyl compound 5b, -activated acetonitrile 6 and sulfur at temperature not exceeding 45 °C in ethanol or methanol. In this case the base, mainly secondary amine (diethylamine, morpholine), is used in 0.5-1.0 molar equivalent amounts. Reaction towards substituted 2-aminothiophenes with an electron-withdrawing substituent in position C-5 (R2) occurs within three base-promoted steps: condensation of starting substrates 5b and 6 – addition of sulfur to , -unsaturated nitrile 9 – ringclosure of the ylidene-sulfur adduct 10 (Scheme 4) 17, 26, 34 . Since the yields are higher than in the first version (45-95%) and the reactants are easily available and non-expensive compounds by this reaction variously substituted 2-aminothiophenes, predominantly with EWG and aromatic substituents in C-5 position of formed thiophene ring (substituent R2), are obtainable by a very comfortable manner (Table 2). R1 O

N

X

-H 2O

R2

5b

R1

a

R1

X

c

R1

X

R2

2

R

N

6

X

b

9

S

N Sx S10

R2

S

NH 2

7

a: K noevenagel-Cope condensat ion: diethylamine or morpholine (0.5 - 1.0 equiv. amount), MeOH or EtOH, RT - 45 °C; b: addit ion of sulf ur , S8 (1.0 equiv. amount); c: r ing-closur e.

Scheme 4. Synthesis of substituted 2-aminothiophenes via the Version 2 of the Gewald reaction [17].


8

Table 2. Substituted 2-aminothiophenes prepared via the Version 2 of the Gewald reaction R1 Me NH2 Me Ph SO2Ph

R2 COMe CO2Et CO2Et Ph 4-BrC6H4

X CO2Me CO2Et CO2Et CN CN

Yield (%) 50 45 60 95 84

Ref. 17 17 17 34 17

2.3. The Third Version of the Gewald Reaction The third two-step version of the Gewald reaction allows the reaction of alkylaryl or cycloalkyl ketones which exhibit limited reactivity under the one-pot conditions. , -Unsaturated nitrile 9 as a product of Knoevenagel-Cope condensation is ahead prepared and isolated and then treated with sulfur and amine (Scheme 5) 35-37 . Alkyl aryl ketones and some cycloalkyl ketones which are not reactive under the one-pot modifications (version 1 or version 2) give acceptable yields of thiophenes in the two-step procedure (Table 3).

R1

R1

X a

R2 N 9

X b

R2 N

S

Sx S 10

R1 R2

X

S 7

a:Addition of sulf ur : secondary or tertiary amine, S8 (1.0 equiv. amount); MeOH or EtOH, RT- 50 °C; b: r ing-closur e; X = CO2 Me, CO 2Et, CN, CO 2H, CO2-t-Bu.

Scheme 5. Third basic version of the Gewald reaction [35-37].

NH2


9

Table 3. Aminothiophenes achievable by the Version 3 of the Gewald reaction R1 / R2

X

Product

Yield (%)

Ref.

Me

CO2Me

CN

51

37

Me

CO2Me

CN

79

37

Et

CO2Me

CN

64

37

Me

CO2Me

CO2Et

45

37

2.4. The Fourth Version of the Gewald Reaction The last from the basic Gewald´s methods represents the latest improvement of the first version. In this particular version the more stable dimeric forms of an -sulfanylcarbonyl compound – substituted 1,4-dithiane-2,5-diols 5c undergo condensation and subsequent cyclization with -activated acetonitrile 6 requiring an amine in stochiometric amount (Scheme 6). Priority of this major modification is the preparation of mono- or disubstituted 2-aminothiophenes with free -position of formed thiophene ring (R2 = H, Table 4) in satisfactory yields (Table 4) 31, 38 . S

1

R

R1 HO

R1

OH N

X

-H 2 O 6

X

b 2

S 5c

R1

X

a R

SH

N

8

R2

S

NH 2

7

a:Condensat ion: secondary or tertiary amine (1.0 equiv. amount), methanol, RT - 50 °C; b: r ing-closur e; R 1 = H or alkyl, R 2 = H.

Scheme 6. Synthesis of mono- and disubstituted 2-aminothiophenes utilizing the fourth major version [31].


10

Table 4. Substituted 2-aminothiophenes obtainable using the Version 4 of the Gewald reaction R1 H Me H H Me

R2 H H H H H

X CO2Me Me CN CONH2 Me

Yield (%) 58 52 72 46 81

Ref. 31 31 38 38 31

2.5. Mechanism of the Gewald Reaction Even if the several reviews and papers on the Gewald reaction and its improvements have been reported in the literature 39-51 the mechanism of this reaction is not fully clear. As it is presented on Schemes 3-6, the substituted 2aminothiophene ring is formed from the aliphatic starting substrates during the multi step reaction sequence: condensation – addition of sulfur – ring-closure. Depending on the type of the used reactants, in some variations of the reaction, the condensation (Version 3) or addition of sulfur step (Versions 2 and 4) is not required.

2.5.1. The Ring Closure The most crucial step in all cases of the basic Gewald reaction and its improvements is the final ring-closure process, which is performed as an intramolecular nucleophilic attack of the sulfur anion to triple bond of the cyano group (Scheme 7). Target 2-aminothiophenes 7 in principle exists in equilibrium with the tautomeric forms – cyclic imines 11 formed during the cyclization. It was proved, that the parent aminothiophene occurs exclusively in the amino form 52-56 .

Substituted 2-Aminothiophenes: Synthesis, Properties and Applications R1

11

X

R2 N

S

ri ng closure

R1

H R2

8

H R1

ami no-imino tautomer ism

X

S

NH

R1 R2

X

S

NH2

X 11

7

R2 N S Sx S10

Scheme 7. Process of the ring-closure of ylidene-sulfur adduct 8 or 10 during the Gewald reaction [59].

In fact, the reaction of the addition of sulfur to , -unsaturated nitrile 9, which is required almost in all types of the Gewald reaction except the versions 1 and 4 where the starting compounds are already sulfanyl substituted (compounds 5a and 5c), is not known in detail. However, it is sure, that S8 has to be activated to react with Knoevenagel-Cope product 9. Some authors report that the activation of sulfur and the following addition of sulfur on a methylene group is base-promoted 57-59 , others details the electrochemical activation of the S8 60-62 .

2.5.2. Base-promoted Addition of Sulfur In the base-promoted addition the elemental sulfur reacts with amines to yield polysulfide anions 63, 64 , that can behave as nucleophiles. The methylene group of appropriate , -unsaturated nitrile 9 is being deprotonated first and then sulfur addition takes place (Scheme 8). The most suitable base for the activation with sulfur and the subsequent sulfur addition morpholine has been proved 59 . The morpholine exhibits the best solubility of sulfur from the entire organic base used in Gewald reaction. Additionally, by mixing the morpholine with sulfur at 150 °C the morpholine polysufide (MPS) is formed, which structure is presumed to contain from 2-5 sulfur atoms within two morpholine molecules 57, 65 . MPS acts then in two ways – as a base needed in each reaction step, and also as a Snucleophile in the addition of sulfur step to the , -unsaturated substrate 9 to create reactive ylidene sulfur adduct 10 (Scheme 8). 2.5.3. Electrochemical Activation of Sulfur In this relatively new synthetic pathway the sulfur, which is electro active, is incorporated in a carbon electrode and used as a sacrificial cathode to yield S3.-, S8.- and S42- 60, 61 . In an upgraded way the cyanomethyl anion (-CH2CN) is


12

generated by galvanostatic reduction of acetonitrile solution (in a mixture with supporting electrolyte tetraethylammonium hexafluorophosphate - TEAHFP) 62 . Formed anion (-CH2CN) is highly reactive and represents the basic species necessary to activate S8 and form S-cyanomethyl anion acting as a promoter of the ylidene sulfur intermediate of the structure 12 (Scheme 9). ring-closure

addi tion of sulf ur R1 O

N

S (S) 2_ 5 S-

X

R1

X

R2

R2 N

H

O

N

N S Sx S-

H H

9

MPS

10

f ormat ion of S-nucl eophile

S S O

S S

NH

R1

S S S S

R2

S

S8

morpholine

X NH2

7

Scheme 8. Base-promoted formation of the ylidene sulfur adduct 10 using polysulfide-like reagent MPS [57-59]. f or mari on of acti ve S-cy anomethyl anion

R1

S S S S

addit ion of sulf ur

S S

NCCH 2 S7 S -

X

NCCH 2

S8

X

R1

R2 N

S S

ri ng cl osur e

R2

NH S S7 CH 2CN

9

12

I= 25 mAcm-2

- NCCH2S6-S-

MeCN/TEAHFP R1 R2

X

S

NH 2

7

Scheme 9. Addition of sulfur to , -unsaturated nitrile 9 via electrochemical activation through nucleophile 12 [62].

Substituted 2-Aminothiophenes: Synthesis, Properties and Applications red esi gned Gewal d reacti on

R1

13

Gewald´ s synthesis of 2-aminothi ophenes

X

R2 N S8 , base

base

addition of sulf ur

Michael addition

R1

9

N

X

N R2 X R1

X

N S S x S-

R2 13

10

r ing closure Thor pe cyclization

R1

NH 2 X CN

X R

R2 H

X

1

R

2

R

2

S8 , base

14 r e-cyclization

X

S

NH

base R R2

1

X

S

amino-imino t aut omerism

11

NH2

7

Scheme 10. Study of the mechanism of the Gewald´s cyclization towards [59] and the redesigned Gewald reaction [68].

Comparing the process of electrochemical activation to standard basepromoted addition of sulfur, the ylidene sulfur adduct 12 is formed by addition of a S-cyanomethyl anion onto cyano group (Scheme 9), while in the previous version the polysulfide-like anion affects the methylene group of the , unsaturated nitrile 10 (Scheme 8). However, if the activation with sulfur does not occur properly, the ylidene-sulfur adduct of presumed structure 10 or 12 is not formed and the side-reaction takes place.

2.5.4. Dimerization vs. Cyclization It is presumed, that the dimerization of Knoevenagel-Cope product - the , unsaturated nitrile 9 to six membered hexa-1,3-diene 14 occurs spontaneously as a side-reaction in the Gewald´s process (Scheme 10) 66 . The yield of a dimer 14 is highly dependent on the reaction conditions. While in some cases the ylidene dimerization is significant and the by-product is isolated in higher yield than the desired 2-aminothiophene derivative 58 , on other hand under the suitable reaction conditions not only straightforward reaction is favored, but also the recyclization of dimerized ylidene 14 to appropriate aminothiophene 7 occurs 59 . The dimer 14 preferably is formed in the less studied, so-called redesigned Gewald procedure which suits to preparation six-membered carbonitriles with free amino

14


group 67 . If the reaction is directed towards formation of derivatives 14, the anion generated from the , -unsaturated nitrile 9 undergoes first to basepromoted Michael addition which is followed by Thorpe cyclization of the adduct 13 to create cyclohexadiene system 14 (Scheme 10) 68 .

2.6. Modifications of the Gewald Reaction From the analyses of four major versions and the mechanism of the Gewald reaction (Chapters 2.1-2.5 ) it is evident that, even if the experimental preparation represents a simple procedure, the sequence of the production of intermediates is not known and can change depending on variable reaction conditions. Because of the tremendous utility of substituted 2-aminothiophenes not only in organic synthesis but also in several applied fields, from the times of Gewald´s method discovery until today many of its new variations have been developed. By the use of improved methods and modified experimental procedures the scope of easily obtainable 2-aminothiophenes ultimately spread. More complex starting substrates, especially starting carbonyl derivatives, such as azepinones 69 , indanones 39 , pyranones 70 , - and - tetralones 71 and many other types 72-75 undergo the modified Gewald reaction. Exploiting the reaction conditions with starting substrates tolerating a broad range of functional groups and alkyl, aryl and heteroaryl substituents about 15 new modifications of the Gewald reaction can be found in literature 76-82 . As it was reported by the authors 58 the use of inorganic bases (e.g. Na2CO3, NaOH, NaHCO3, K3PO4) instead of organic base (morpholine, pyridine, triethylamine) facilitates of the ylidene-sulfur intermediate formation and the ring closure in twostep version of the Gewald reaction (Version 3, Chapter 2.3). Other researchers 50 deal that the use acid-base catalyst (ammonium salts: acetates and trifluoroacetates of diethylammonium, morpholinium, piperidinium) promotes the creation of the Knoevenagel-Cope condensation product ( , unsaturated nitrile) and enhances the yield of final 2-aminothiophene. Ionic liquids used as solvents in combination with ethylenediammonium diacetate were shown to be very efficient in the case of the Gewald synthesis with aliphatic and alicyclic ketones with possibility of regeneration of used liquids 83 . From all of these novel optimizations the most effort is focused on solidsupported synthesis 86 and microwave accelerated the Gewald reaction 24 .


15

2.6.1. Solid-supported Gewald Synthesis Heterogeneous organic reactions using reagents immobilized on porous solid supports have been often proved advantageous over conventional solution phase reactions because of good dispersion of active reagent sites, better selectivity and easier work-up. One of such reagents is commercially available AgroGel® Wang resin 84 , the grafted (polyethylene glycol) polystyrene -PEG-PS. The benefits of the PEG-PS Wang linker during the Gewald synthesis have been highlighted by the authors 85 in synthesis of substituted 2-aminothiophenes with carboxylic acid functionality in the neighboring -position. It was found, that appropriate esters of some Gewald products proved difficult to hydrolyze via traditional saponification. The acylation of AgroGel® Wang resin 15 with cyanoacetic acid (16) under standard DIC/DMAP coupling conditions gave the resin-bound cyanoacetic ester 17. After the dispersion of reagent 17 in ethanol Gewald reaction was performed in QuestTM 210 synthesizer by mixing with the starting compound - -methylene carbonyl compounds 18 and substrates - sulfur and morpholine. Final 2aminothiophene carboxylic acids were isolated as N-acetyl protected derivatives 20 upon the cleavage of the resin with trifluoroacetic acid (Scheme 11).

O NC

HO 15

O

O a

OH 16

NC

R2

O 17

R1 18

b

O R1

R1

CO2H

O

c, d R2

S

NHCOMe

20

R2

S

NH2

19

a: DIC, DMAP, CH 2Cl2; b: morpholine, S8 , EtOH, 75°C; c: AcCl, EtN(i-Pr) 2, CH 2Cl2, RT; d: TFA, H2 O, CH 2Cl2.

Scheme 11. Solid-supported route to 2-aminothiophenes 20 85

Table 5. Substituted 2-aminothiophenes 20 achieved during the solidsupported Gewald´s synthesis


16

Aldehyde/Ketone 18

Product 20

Yield (%) CO2 H

HO2 C

N 5

O

MeO2 C

N 5

S

NHCOMe

92

Et

O S

NHCOMe

97 75

CO2H

Et

O

Me

S

NHCOMe

27

CO 2H

O H

i-Pr

S

NHCOMe

44

2.6.2. Microwave Accelerated Gewald Synthesis of Substituted 2Aminothiophenes Most of the published Gewald synthetic procedures required long reaction times varying between 4 and 48 h. Microwave heating is an area of increasing interest in both academic and industrial laboratories because it can raise the rate of reaction and in many cases improve product yields 86, 87 . The expeditious Gewald synthesis under microwave irradiation was applied for preparation of 2aminothiophenes without the substituents in position C-4 and C-5 of thiophene ring. This process represents the advancement of the basic version 4 (chapter 2.4). Reaction starting from 1,4-dithiane-2,5-diol (21) and -activated acetonitrile 6 was completed after 2 min. in methanol with triethylamine used as a base (Scheme 12) 24 . Comparing to classical reaction conditions [16, 31, 38, 88] the appropriate monosubstituted 2-aminothiophenes (22) were obtained in higher yields with significantly shorter reaction time (Table 6).

S

OH

N

X HO

S 21

X Et3N, MeOH, 50°C, microwave, 2 min. NH2

S 6

22


17

Scheme 12. Microwave-assisted synthesis of 2-aminothiophene-3-carboxylic acid derivatives 24 .

Table 6. Monosubstituted 2-aminothiophenes 22 obtained under the microwave assisted Gewald reaction X

Yield (%) / Ref. Microwave reaction 82 [24] 78 [24] 87 [24] 81 [24] 60 [24]

CO2Me CONH2 CONHPh CO-t-Bu CN

Yield (%) / Ref. Classical conditions 55 [31] 78 [88] 55 [16] 58 [31]

2.6.3. Microwave Assisted Gewald Synthesis on Solid Support Microwave enhanced Gewald reaction in combination with solid-support accelerated method was presented as an easy access to polysubstituted 2aminothiophenes 89, 99 . R1 O

N

X

a or b

R2

R2 5

R1

6

X

S

NH2

23

a: KF alumina, microwave irradiation, 3.5 - 8 min. b: KF-alumina,EtOH, 78 °C, 3.5 - 7 h.

Scheme 13. KF/Al2O3 supported synthesis of 2-aminothiophenes 23 under a) microwave and b) conventional heating 89 .

A variety of ketones 5 were reacted with ethyl cyanoacetate (6a) or malononitrile (6b) and sulfur in the presence of KF-alumina 89 . KF immobilized on Al2O3 represents the heterogeneous catalyst with advantageous properties like better selectivity and easier work upon its use 90 . The application of KF-alumina to a wide range of organic reactions has provided more convenient and efficient methods in organic syntheses 91-95 . Its benefits arise from the strongly basic nature of KF/Al2O3, which has allowed it to replace organic bases in a number of reactions 96-98 . The reaction towards substituted 2-aminothiophenes 23 using KF/Al2O3, was studied under microwave irradiation as well as under conventional


18

heating (Scheme 13) 89 . KF-alumina as a base used in Gewald synthesis proceeded well producing 2-aminothiophene derivatives 23 in good yields. Using the microwave irradiation reaction was carried out in very short times, but alternatively the reaction proceed well also under conventional heating (Table 7). Table 7. KF-alumina supported synthesis of 2-aminothiophenes 23 under a) microwave irradiation and b) conventional heating R1

R2

X

Me Me Me Ph Ph H

Me CO2Et CO2Et H H Et

Me CO2Et CN CO2Et CN CO2Et

Yield (%) Microwave irradiation (Reaction time/min) 57 (3.5) 58 (3.5) 58 (3.5) 61 (7.5) 66 (7.5) 62 (6.0)

Yield (%) Conventional heating (Reaction time/h) 53 (4.0) 50 (4.0) 55 (4.0) 55 (4.0) 61 (4.0) 48 (4.0)

A number of tetrasubstituted N-methoxy-2-acetylaminothiophenes 26 with free carboxylic acid functionality in -position next to protected amino group were achieved via a one-pot microwave assisted Gewald reaction on solid-support 99 . The same Wang type ester linkage 84 was used as was discussed previously (chapter 2.7.1, 85 ). The Gewald reaction of the resin-bound cyanoacetic ester 17 with substituted ketones 5 and sulfur was accomplished under the microwave conditions using DBU as a base in toluene. The protection of amino group was performed with methyl 2-chloro-2-oxoacetate (24) in toluene in the presence of diisopropylethylamine (DIPEA) again under the microwave irradiation. Formed resin-linked methyl oxo(2-thienylamino)acetates 25 were cleaved with trifluoroacetic acid in water-dichloromethane solution into substituted 2{[methoxy(oxo)acetyl]amino}thiophene-3-carboxylic acids 26 (Scheme 14) 99 . The applicability and efficiency of one-pot microwave assisted Gewald reaction on Wang-type solid support is presented in Table 8.


19

O O NC

R1

O R2

O 16

O

a, b R1

R2

O

17

O

Cl 24

NH

S 25

Me

CO2 Me

O

O c

R1 a: S8, DBU, toluene, microwave irradiation, 20 min. b: i-Pr 2 EtN.toluene, microwave, 10 min. c: TFA, H 2O, CH2 Cl2

R2

CO2 H NH

S O

CO 2Me

26

Scheme 14. Synthesis of 2-{[methoxy(oxo)acetyl]amino}thiophenes 26 on PEG-PS solid support using microwave irradiation 99 .

Table 8. Gewald synthesis of 2-acetylaminothiophenes on solid support under microwave irradiation Starting compound

Product

H

i-Pr

NH

S

90

82

90

93

90

99

90

70

CO2Me

O

CO2 H

O t -Bu

HPLC purity (%)

CO2H

O i-Pr

Yield (%)

H

t-Bu

NH

S

CO2 Me

O CO2 H O Ph

H

Ph

NH

S

CO2 Me

O Me

O Bu

Me

Pr

CO2 H NH

S O

CO2 Me

2.6.4. Synthesis of 5-halogen substituted 2-aminothiophenes It has to be mentioned, that from the enormous publications dealing with the variations of the Gewald reaction and reaction itself, none of them is focused on the direct synthesis of 5-halogen substituted 2-aminothiophenes. Finally, in 2003 Scammells and co-workers 100 have presented the synthetic pathway to 5-bromo substituted 2-aminothiophenes 29. The reaction was successful it the R-substituted


20

2-bromo-1-phenylethanones 27 were reacted with 3-oxo-3-phenylpropanenitrile (28) and sulfur in the presence of diethylamine as a base in ethanol (Scheme 15). Because of the inconvenient conditions such as strong base, longer reaction time and difficult purification, the target 5-bromo-2-aminothiophenes 29 were obtained only in moderate yields (Table 9). R O O NC

R

Ph

Br

27

S8 (1.0 equiv.), Et2NH (1.4 equiv.), EtOH, 45°C, 5h.

COPh Br

S

NH2

29

28

Scheme 15. Synthesis of 5-bromo substituted 2-aminothiophenes 29 100 .

Table 9. 5-Bromo-substituted 2-aminothiophenes 29 R 3-CF3C6H4 3-NO2C6H4 4-CF3C6H4 4-NO2C6H4 4-CNC6H4 4-PhC6H4 2-naphtylC6H4

Yield (%) 48 30 52 33 58 48 39

Later, the same research group 101 , have reported on synthesis of two 5bromo substituted 2-aminothiophenes 35 (Table 10) via a two-step Gewald synthesis. In a reaction of 3-trifluoromethylacetophenone (30) with either benzoylacetonitrile or ethyl cyanoacetate (31) in the presence titanium(IV) chloride 102 afforded Knoevenagel-Cope product 32. In subsequent treatment of 32 with sulfur the 2-aminothiophene core 33 is formed under basic conditions. The free C-5 position of derivative 33 is substituted with bromine in two following steps – first the free amino group is being Boc protected and then C-5 position brominated with N-bromosuccinimide (Scheme 16) 101 . The substituted thiophenes 35 were obtained in favorable yields (96 and 99%, Scheme 16). Synthesized 5-bromo substituted 2-aminothiophenes 29 and 35 were investigated as a precursors in the development of new synthetic adenosine A1 receptor agonists with similar activity to those which are already acting as


21

successful therapeutics (marketed as AdenocardTM and TecadenosonTM) 100, 101 .

3. REACTIONS OF 2-AMINOTHIOPHENES The substituted 2-aminothiophenes found enormous utility in dye chemistry 104 , modern drug design 105 , biodiagnostics 106 , electronic and optoelectronic devices 107 , conductivity-based sensors 108 , and self-assembled superstructures 109 . They are unique for their simple synthesis, environmental stability, wide spread possibility of functioning and moreover, they posses good workability and satisfactory solubility in both organic and aqueous media. CF3

O NC O NC

a

R1

R1

O F3 C

F3 C

O

b

R1

NH2

S 30

33

32

31

c CF3

CF3 a: TiCl4, CH 2 Cl2 ; b: S8 , Et2 NH, EtOH or dioxane;

R1

c: Boc2 O, DMAP, dioxane; d: NBS, AcOH, CH 2 Cl2 .

35a: R1 = OEt, 96% yield; 35b: R1 = Ph, 99% yield.

R1

d

O

O Br

S 35a,b

NHBoc

S

NHBoc

34

Scheme 16. Synthesis of 5-bromo substituted 2-aminothiophenes 35 utilizing the two step Gewald synthesis 101 .

The versatility of title compounds as a synthetic entry to fused heterocycles such as thieno 3,4-c thiolactones, thieno 2,3-b pyrroles, thieno 2,3-d pyrimidines and thieno 2,3-b pyridines is highlighted in following chapters.


22

NH2

Br

H2N S

Br CO2Me R

S

NH2

36a-c 36a: R =H 36b: R = CO2Me. 36c: R = CO2-t-Bu

CO2Me

a, b 65-90%

R1

S

CO2Me

c

NHCOMe

91-99%

R1

37a-c

NHCOMe

S

R1

46-51%

S

NHCOMe

e, 38a

19%

Br

O

39a-c

38a-c

37a: R =Br 37b: R = CO2Me. 37c: R = CO2-t-Bu

a: Ac2O, Mg(ClO4)2; b: NBS,CCl4, dibenzoylperoxide; c: thiourea,acetone; d:1M NaHCO3 in MeOH-H2O (1:1); e: 1M NaHCO3 in H2O.

S d

10%

S

O

HS

S

NHCOMe

Br

39a

CO2Me

S

NHCOMe

22% HS

Br

40

CO2H

S

NHCOMe

41

Scheme 17. Synthetic pathway towards substituted thieno 3,4-c thiolactones 110 .

3.1. Synthesis of Substituted thieno 3,4-c thiolactones The synthesis of a series of substituted thieno 3,4-c thiolactones 39a-c as unusual bicyclic 5-5 heteropentalene systems was reported by authors 110 . Starting from substituted 2-aminothiophenes 36a-c, the target fused heterocyclic derivatives 39a-c was prepared in a four step reaction sequence. The free amino group is acylated first and then the methyl group in C-4 position undergoes the radical bromination to create the crucial intermediates 37a-c. The reaction of corresponding bromomethylated thiophenes 37a-c with thiourea in acetone proceeded thiouronium salts 38a-c in almost quantitative yields. The cyclization to a fused thiophene-thiolactone system can be performed either using methanolaqueous 1:1 solution of NaHCO3 110 or in 1M water solution of NaHCO3 111 . In the first case reaction occurs selectively and only desired thieno 3,4c thiolactones 39a-c are being formed. In a second approach the unselective reaction proceeding takes place and the mixture of three compounds 39a, 40 and 41 are created (Scheme 17). Even if the yields of thieno 3,4-c thiolactones are only about 50%, the presented procedure is the unique in organic synthesis and represents the easy route to such fused heteroaromatic systems and best to our knowledge only two other reports deals about the similar structures 112, 113 . In addition, thieno 3,4-c thiolactones 39 seems to be useful intermediates to fully aromatic thieno 3,4-c thiophenes. Such derivatives represent a -heteropentalene


23

system with tetracovalent sulfur nucleus and are investigated from synthetic and theoretical point of view 114, 115 .

3.2. Synthesis of Substituted Thieno 2,3-b pyrroles Other type of bicyclic 5:5 heteropentalene systems with two heteroatoms in each ring 114, 115] - variously substituted thieno[2,3-b]pyrroles 46 can be synthesized through 2-phenylaminothiophenes 44. The reaction reported by authors [116] represents the one-pot synthesis in which the reaction sequence follows the Gewald-like process. The synthesis starts by the condensation of activated methylene compounds 42 with alkyl or aryl isothiocyanates in a basic medium (K2CO3/DMF) giving salt - ketene N,S-acetal 43. The reaction continuation is based on the condensation of the intermediate salt ketene N,Sacetal 43 with the halide (ethyl bromoacetate or chloroacetonitrile) leading to the corresponding aminothio-acetal which smoothly undergo a Dieckmann type cyclization in basic medium at room temperature (Scheme 18). 2Phenylaminothiophenes 44 were easily removed from the crude reaction mixture by rapid hydrolysis in water followed by filtration. The influence of the substituents of the isothiocyanate on its behavior during the condensation under basic conditions has been investigated. Phenyl isothiocyanate has been almost exclusively used for related studies and this choice could be explained by the availability of this compound, but above all it appeared to be the best candidate for this reaction. The replacement of phenyl isothiocyanate by other commercially available ones decreases dramatically the yields of thiophenes 46. The same authors published [117] an improved two step method for the synthesis of N-phenylaminothiophenes 44, which is based on preparation and isolation ketene phenylamino methylthioacetals 45. These compounds were easily obtained in around 90% yields by methylation of the intermediate salt ketene N,Sacetals with methyl iodide (Scheme 18). The synthetic protocol for thieno 2,3-b pyrroles, which is based on the reaction of 1,3-dicarbonyl compounds, can be applied also for preparation of thieno 2,3-b thiophenes. As was reported in [118], the facile one-pot synthesis of polysubstituted thiophenes and thieno 2,3-b thiophenes was completed through cyclization of -oxo ketene (S,S)-acetals.


24

O R2

R1 c method A PhHN O

O

O

R1

a,b R2

R2 O

d 42

43

method B

R2 CO2 Et

N Ph O

R1 PhHN

R1

EtO 2C

e

S-

PhHN

f

44

O

R1

CO 2Et

S

S 46

R2 S

SMe

45 Method A: a: K2 CO 3, DMF, RT; b: PhNCS; c: BrCH2 CO 2Et, K2 CO3 , DMF; f: BrCH2 CO2Et, K2 CO 3, acetone. Method B: a: K2 CO3, DMF; b: PhNCS; d: MeI; e: HSCH2 CO 2Et, K2 CO 3, EtOH.

Scheme 18. Synthesis thieno 2,3-b pyrroles 46 through N-phenylaminothiophenes 44 116, 117 .

3.3. Synthesis of Substituted thieno 2,3-d pyrimidines Substituted thieno 2,3-d pyrimidines are considered to be an universal molecules in a structure-based drug design [119]. Thieno 2,3-d pyrimidine derivatives show pronounced anti-inflammatory [120], anti-tumor [121], radioprotective and anti-convulsing activity [122]. The pharmacological versatility of the above system also present in substances with depressant or sedative properties [123] and compounds used for therapy of malaria [124], tuberculosis [125], Parkinson´s disease [126] and other diseases were designed [127]. Their synthesis relies on the annulation of pyrimidine ring to five-membered thiophenes. The substituted 2-aminothiophenes act as the most suitable synthetic precursors to various thieno 2,3-d pyrimidines. The versatility of this approach lies not only in the ease of controlled introduction of substituents to C-4 and C-5 position into a starting 2-aminothiophene derivative, but also in the ease of incorporation of different electrophilic substituents in the C-3 position that allows for variation of the substitution pattern of the pyrimidine portion of the desired thienopyrimidines. One of the important preparations of 2-aminothieno 2,3d pyrimidines was investigated by authors [128]. From the symmetric ketone 47 the Gewald thiophene synthesis was conducted in a stepwise fashion through Knoevenagel-Cope condensation to give the intermediate 48 followed by basepromoted thiophene cyclization with sulfur [35-37]. From the 2-aminothiophene3-carbonitrile 49a or methyl 2-aminothiophene-3-carboxylate 49b the annulation of pyridine was performed using common pyrimidine annelation with guanidine


25

carbonate 50a or chloroformamidine hydrochloride 50b (Method A, Scheme 19) [129]. In a second approach the aldehyde derivative 49c was prepared first in three steps and then annelated under the same conditions as before (Method B, Scheme 19). The desired products 51a-c were obtained in variable yields (20-80%) by both methods. Presented synthetic approach is relevant also for the preparation other biologically active thienopyrimidine structures. R

BnO BnO

R

CN

OBn

75-80%

S

49c NH

NH 65-85% NH2

OBn

d

c

50a: R = NH 2 50b: R = Cl BnO

BnO

49a: R = CN 49b: R = CO2Me

X

O

NH 2

S

80%

BnO

48a: R = CN 48b: R = CO2Me

a

NH2

CHO

BnO

d, e, f

b

R

BnO

47

S

N

NH 2

50a: R = NH2 50b: R = Cl

N

BnO Method A

X

Method B

51a: R = NH2 51b: R = OH 51c: R = H

a:methylcyanoacetate or malononitrile, NH 4AcOH, AcOH, PhH, reflux; b: S8, EtOH, i-PrOH, 60 °C; Method A: c: 50a or 50b, DMSO, 130-150 °C,. Method B: d: Ph 3CCl, Et3 N; e: DIBAL-H, -15 °C; f: Et3SiH, TFA; f: 50a or 50b, DMSO, 130-150 °C.

Scheme 19. Synthesis of thieno 2,3-d pyrimidines 51a-c through substituted 2aminothiophenes 49a-c 128 .

3.4. Synthesis of Substituted Thieno 2,3-b pyridines 4-Oxo-4,7-dihydrothieno 2,3-b pyridine-5-carbonitriles such as compound 53 are important intermediates in the synthesis of thieno 2,3-b pyridine-5-carbonitrile kinase inhibitors 130, 131 . A facile three step synthesis of 4-oxo-4,753 from substituted 2dihydrothieno 2,3-b pyridine-5-carbonitriles aminothiophene-3-carboxylate esters 7 was developed 132 . The key step of the synthesis is a thermally promoted elimination/decarboxylation followed by nucleophilic cyclization of 52 to give fused thieno-dihydropyridines 53 (Scheme 20) in good yields (Table 10).


26

O

R1

R1

X a,b

R2

S

R2

NH2

7

CN S

CN

R1

X N H

c R2

CO 2-t-Bu

52

S

N H

53

a: DMF-DMA, 100 °C, 2h; b: t-Bu-cyanoacetate, t-BuOH, 2-8 days; c:PhOPh, 255 °C, 2 h.

Scheme 20. Synthesis of 4-oxo-4,7-dihydrothieno 2,3-b pyridines 53 from substituted 2aminothiophenes 7 132 .

Table 10. Yields of synthesis of the acrylates 52 and fused thienodihydropyridines 53 R1

R2

H H H Me Et Ph Bn Me H Me H H H H

H Me i-Pr H H H H Me 4-F-C6H4 4-F-C6H4 4-Cl-C6H4 4-Br-C6H4 4-CH3O-C6H4 2-furyl

X (for 7, 52) CO2Me CO2Et CO2Et CO2Me CO2Et CO2Et CO2Me CO2Me CO2Et CO2Me CO2Et CO2Et CO2Me CO2Et

Yield (%) of 52

Yield (%) of 53

78 64 73 53 33 53 70 69 23 76 70 41 32 55

91 85 78 86 88 90 79 91 87 64 72 77 99 77

4. APPLICATIONS OF 2-AMINOTHIOPHENES Following parts of chapter detail about the utilization of substituted 2aminothiophenes as precursors in synthesis of pharmaceuticals, dyes and potential building blocks in materials chemistry.


27

4.1. Synthesis of Pharmaceuticals and Drugs As we have discussed above (Chapter 3.1.3), substituted thieno 2,3d pyrimidines and thieno 2,3-b pyridines (Chapter 3.1.4) exhibit valuable biological activity in numerous of diseases. Generally, substituted 2aminothiophenes represent an exclusive group of structures widely exploited in medicinal chemistry and in the synthesis of active compounds for pharmaceutical applications. The ultimate position of substituted 2-aminothiophenes in this field comes from their advantageous properties - the thiophene ring as is bioisosteric replacement for phenyl group broadly present in an active drugs, the thiophene core exists in many natural and synthetic pharmaceuticals and moreover, they represent an active precursors in broad range of synthetic pathways towards compounds used in therapy [133, 134].

4.1.1. Synthesis of 3-Deazathiamine The synthesis of 3-deazathiamine (61) was effected in ten chemical steps, though it was necessary to prepare and isolate substituted 2-aminothiophene [135]. As is outlined on Scheme 20, the synthesis starts from 3-acetyldihydrofuran2(3H)-one (54) from which in four-step reaction sequence including the Gewald´s stepwise technique [35-37] appropriate 2-aminothiophene 56 is achieved. Deamination of aminothiophene 56 via the bromide 57 and following cleavage with zinc(0) in acidic media to afford derivative 58 was very efficient, displaying none of side reactions. Conversion of formed ester 58 to final 3-deazathiamine (61) was accomplished in four subsequent steps isolating the crucial intermediates – aldehyde 59 and nitrile 60. The readily available and inexpensive starting materials and reagents, and the lack of protection and de-protection steps make this synthesis very fashionable (Scheme 21) [135]. Deazathiamine diphosphate (deaza-TDP, Figure 1) is an analogue of thiamine diphosphate (TDP, Figure 2), the biologically active for of thiamin (vitamin B1), with a neutral thiophene replacing positively charged thiazolium ring. TDP is coenzyme present in a number of enzymes, including pyruvate decarboxylase, transketolase, pyruvate oxidase.


28 EtO2 C

O O

OAc

EtO2C

CH 3

a, b, c

O

72%

Cl

52

EtO2C

d

e

NC

H2N

82%

53

OAc S

93%

Br

54

OAc S 55

f

87% NH2 O

NC

N

EtO2C

Ph N

OH S

j

N H

OH S

81%

59

i 94%

OH S

g, h 76%

57

58

a: SO2 Cl2 ; b:AcOH, HCl, Ac 2O; c: NCCH2CO 2Et, AcONH 4 , AcOH, PhMe; d: NaSH, EtOH; e: CuBr 2, t-BuONO, CH3CN; f: Zn, AcOH; g: LiAlH 4, Et2O; h: MnO2 , CHCl3; i: PhNH-(CH2)2 CN, NaOMe, DMSO, MeOH; j: CH3 C(=NH)NH2, HCl, NaOEt, EtOH.

Scheme 21. Ten step reaction sequence towards 3-deazathiamine 61 135 .

NH2 N N S

OP2 O6 3-

Deaza-TDP

Figure 1. Deazathiamine diphosphate.

NH2 N N

N S TDP

Figure 2. Thiamine diphosphate.

OP2 O6 3-

OH S 56


29

4.1.2. Synthesis of Thieno 2,3-d 1,3 oxazin-4-ones as Inhibitors of Human Leukocyte Elastase A series of thieno 2,3-d 1,3 oxazin-4-ones 65 was synthesized and evaluated in vitro for inhibitory activity toward Human Leukocyte Elastaze (HLE). The strategy presented by authors [136, 137] is base on the replacement of the benzene ring in benzoxazinones by thiophene one. The study demonstrates the versatility of 2-aminothiophenes as a synthetic entry to serine protease-inhibiting, fused 1,3oxazin-4-ones. The synthetic route to novel thieno 2,3-d 1,3 oxazin-4-ones 65 using alkyl 2-aminothiophene carboxylates 62 as a substrates exhibits a facile three step synthesis, as is presented on Scheme 21. Aminothiophenes 62 were converted to isothiocyanato-thiophenes 63 by the thiophosgene method. Deprotection of tert-butoxycarbonyl group resulted directly to ring closure of the intermediates isothiocyanato-thiophenecarboxylic acids leading directly to 64a,b. These key intermediates were alkylated with appropriate alkyl halides to furnish the final derivatives 65 (Scheme 22) [136]. Extra cellular HLE is a serine protease contained in the azurophilic granules of human neutrophil and has been shown to contribute to the pathogenesis of destructive lung diseases such are pulmonary emphysema, cystic fibrosis, adult respiratory distress syndrome and inflammatory disorders such as rheumatoid arthritis. For that reason, much attention is focused on the inhibition of HLE by low-molecular-weight inhibitors that might serve as therapeutic agents.

O R1 R2

CO2 -t-Bu S

NH2

60

60a: R 1 = R 2 = (CH2)4 60b: R1 = R 2 = Me

a 45-51%

R1 R2

CO2 -t-Bu S

NCS

61

61a: R 1 = R 2 = (CH2)4 61b: R1 = R 2 = Me

b 28-56%

R1 R2

O O N H

S

R1

c S

62

62a: R 1 = R2 = (CH 2)4 62b: R 1 = R 2 = Me

a:CSCl2 , CaCO 3, CH 2Cl2, H2O, 0 °C; b: TFA, CH 2Cl2, 0 °C ; c: MeI or RBr, Na 2CO3, acetone, RT.

28-56%

R2

O N

S

SR

63

63a: R = Me, R1 = R2 = (CH 2)4 63b: R = Me R1 = R2 = Me 63c: R = Et, R1 = R2 = (CH 2) 4 63d: R = Et, R 1 = R2 = Me 63e: R = CH 2Ph, R 1 = R2 = (CH2 )4 63f: R = CH2Ph, R 1 = R2 = Me 63g: R = CH 2CO2 Me, R 1 = R2 = (CH2 )4 63h: R = CH 2CO2 Me, R 1 = R2 = Me

Scheme 22. Synthesis of substituted thieno 2,3-d 1,3 oxazin-4-ones 65 [136].


30

4.1.3. 5-Substituted 2-aminothiophenes as A1 Adenosine Receptor Allosteric Enhancers Adenosine is an important endogenous tissue-protective compound released during ischemia, hypoxia or inflammation. Four receptor subtypes (A1, A2A, A2B, A3) have been defined based on pharmacological properties [137, 138]. Considerable effort has been directed towards developing therapeutic agents targeting these receptors [139]. The first allosteric enhancers acting at the adenosine A1 receptor were reported in early 1990s [140, 141]. Since this initial discovery some molecules have been approved for use in the treatment of supra ventricular tachycardia [142], anti-arrhythmic agent [143] and cardio protective agent [144]. Substituted 2-aminothiophenes of structure 66-69, with alkyl, aryl and cycloalkyl substituents in C-4 and C-5 position and aroyl substituent in C-3 position (Figure 3), maintained the best allosteric enhancer activity [145, 146]. The significant effort in the area of synthetic aminothiophene-based allosteric enhancer is directed to development and synthesis of adenosine receptor agonists with limited side-effects 13, 100, 101, 145, 146 . R

S 64

R

R

O

O

NH 2

S 65

NH2

R O

Ph

O

N S

NH2

Ph Ph

66

O S

NH2

67

R = H, 2-Cl, 3-Cl, 4-Cl, 3,4-di-Cl, 3-CF3, 4-CF3 , 4-CH 3 , 4-NO 2, 4-CO2 H, etc.

Figure 3. Structure of some aminothiophene-based allosteric enhancers.

4.1.4. Important Pharmaceuticals Developed from 2-Aminothiophenes The synthesis and antitumor activity of thieno 2,3-b azepin-4-one based antineoplastic agents was reported 147 . The meaningful structure-activity relationships have been established in monocarbonyl and dicarbonyl series of thieno 2,3-b azepin-4-one 70, 71 (Figure 4) prepared by Dieckmann ring closure reaction in multistep reaction from substituted 2-aminothiophenes. Cinnamyl derivatives of thieno 2,3-d oxazinones 72 (Figure 5) inhibits herpes protease processing in HSV-2 infected cells. The synthesis and pharmacology of

R1 =


31

this series of derivatives was presented by authors 148, 149 from ethyl 2-amino4-methylthiophene-3-carboxylate. R O

O

R1 R2

O

R1 S

R2

N H

O N R

S

70

O

S

71

thieno[2,3-b]azepin-4-ones 70, 71

R = H, 2-Cl, 2-Br, 2-Me, 2-NO 2, 2-EtO

Figure 5. The f amily of herpes prote thieno[2,3-d]oxazinones 7

R

O

O

R1 R2

O S

N R 71

Ph,

R2

= Me, R = tosyl or benzoyl

O

S

N

O 72

R 1 = R2 = Me, R 1 = Ph, R 2 = Me, R = tosyl or benzoyl

Figure 4. Structure of potential antineoplastics thieno [2,3-b]azepin-4-ones 70, 71. Figure 4. Structure of potential antineoplastics

N

H N

H N O 72

R = H, 2-Cl, 2-Br, 2-Me, 2-NO 2, 2-EtO, 4-CHO

herpes5.proteases HSV-2 thieno[2,3-d]oxazinones The f amily of herpes proteases HSV-2 72. ture of potential antineoplastics Figure 5. The family ofFigure thieno[2,3-d]oxazinones 72 o[2,3-b]azepin-4-ones 70, 71 Transglutaminases (TGases) are a family of Ca2 dependent enzymes which are normally expressed at low levels in many different tissues and serve vital roles, such as blood clothing and epithelia formation. Some TGase isoenzymes are involved in diverse pathological conditions like celiac disease, atherosclerosis and neurodegenerative disorders. Thieno 2,3-d pyrimidine-4-hydrazide derivatives related to structure 73 (Figure 6) were discovered as a moderately potent inhibitors of TGase-2 (tissue transglutaminase) 150 . The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had identified a 2-ureido-thiophene-3-carboxylate 74 (Figure 7) as a low micromolar inhibitor. It displayed good antibacterial activity against S. aureus and S. epidermidis. Based on these author observations 151 reported a synthesis of the number of analogs of 74 via the Gewald reaction and evaluated for cytotoxic activity against Rifampicin-resistant S. aureus.


32

O N S

N

S

O

lead structure in inhibition of TGase-2

N

CO2 Et

H N NH 2 S

NH

S

O

O 73

N H

74

Figure 7. 2-Ureido-cyclooctano[b]thiophene-3-carboxylate 74 no[2,3-d]pyrimidine-4-hydrazide Figure 73 7. 2-Ureido-cyclooctano[b]thiophene-3-carboxylate 74 antibacterial agent against S. antibacterial agent against S. aureus structure in inhibition of TGase-2 aureus.

CN O

S

N N

NH O

Cl Cl

N H

74

Figure 6. Thieno[2,3-d]pyrimidine-4-hydrazide 73 of TGase-2. Figure 6. Thieno [2,3-d]pyrimidine-4-hydrazide 73 lead structure in inhibition

N

NH

S

O

73

O

CO2 Et

H N NH 2

N H

75

Figure 8. Thiophene-based antagonist of hGCRG.

A novel class of thiophene-derived antagonists of the human hepatic glucagon receptor (hGCRG) has been discovered 152 . The synthesis of derivatives based on the lead structure 75 (Figure 8) accomplished using the Gewald reaction. The further investigations of such structures are challenging in development of therapeutics of the diabetes mellitus. Diabetes mellitus is a condition characterized by chronically elevated levels of blood glucose caused by incorrect function of the hormone responsible for the hGCRG activation. Because the structure-based drug design program through substituted 2aminothiophenes has been investigated broadly, up to this date there are many other research works dealing with the synthesis, pharmacology and application of thiophene-based structures in medicinal chemistry 7, 12-14, 36, 37, 51, 69, 100,

Figure 7. 2-Ureido-cyclooctano antibacterial agent a


33

101, 119-127 . It is no doubt, that this area of Gewald-like thiophene derivatives exhibits the highest progress in a scope and utilization.

4.2. Synthesis of Building Blocks for Opto-electronic Devices, Sensors and Self-assembled Superstructures Oligothiophenes with well defined structures have recently received a great deal of attentions not only as a model compounds for conducting polymers, but also as a new class of functional -electron systems 153 . Since the initial discovery of organic compounds showing metallic conductivity, for which 2000 Nobel prize in chemistry was awarded 154-156 , oligo- and polythiophenes have attracted much attention as advanced molecules with practical use in electronic devices 157-160 and their potential application in field-effect transistors 161 , photovoltaic devices 162 and organic electroluminescent devices 163 . The employment of substituted 2-aminothiophenes in such areas represents the latest discovery showing a great promise in materials chemistry for the generation of novel oligo- and polythiophene structures.

4.2.1. Synthesis of Thiophene-based Azometines The authors 164, 165 have discovered a facile synthesis of substituted azometines by a condensation of diethyl 2,5-diaminothiophene-3,4-dicarboxylate (76) with thiophene-2-carbaldehyde (77) or 5-(thiophen-2-yl)thiophene-2carbaldehyde (78) the appropriate azometines 79-82 were achieved (Scheme 23). S

EtO2 C

S H 2N

S

S CHO

CO 2Et a

N

EtO 2C

75

94%

77

S

NH2

S

81%

N

S

S CHO

b

a

S 78

74 S

CO 2Et

b

75

H2N

EtO2C

CHO

CO2 Et

S

S CHO

76

EtO 2C

36%

CO2Et S

H 2N

76

50%

S

EtO 2C

CO2 Et S

S

N S 79

S

N

S

N

80

a: n-BuOH, 60 °C, 1.0 equiv. of 75 of 76, b: n-BuOH, 6O °C, 2.0 equiv. of 75 of 76

Scheme 23. Synthesis of thiophene-based azometines 79-82 164, 165 .

S

N


34

Synthesized azometines 79-82 were investigated as promising structures able to transfer the energy because of their „push-pull‖ nature 166-168 . The synthesis of such structures represents surprisingly easy process with possibility of the further development of more complex azometines with various functional groups in the thiophene ring.

4.2.2. Synthesis of -conjugated Thiophenes via Gewald Reaction The first report on the development and the use of substituted 2aminothiophenes and the Gewald reaction was published by authors 59 . The synthesis of -aryl or -heteroaryl substituted 2-aminothiophenes 85 utilizing the Gewald reaction of substituted 3-oxopropanenitriles 83a-d and substituted acetonitriles 84a,b 57 as is presented on Scheme 24. R1

Ar

O

N

N

R1

Ar 81 a-d

morpholine-polysulf ide (MPS), S 8, methanol 50-62%

82 a-c

Product

N

Yield (%)

S

NH 2

83a d

Product

Yield (%)

N

S CO2Me

NC S

62

CO2Me

NC S

NH2

52

NH2

85c

85a

S CN NC S

85b

58

50 N

NH2

CO2Me

NC S

NH 2

85d

Scheme 24. Synthesis of -aryl or -heteroaryl substituted 2-aminothiophenes 85 59 .


35

CO 2Me CO Me 2 S

NH 2 NC

S

S 84

Figure 9. -Conjugated system of three thiophene units.

The free amino group allowed the chain elongation and the growth of conjugated system to achieve structure with three thiophene units 86 (Figure 9) upon its modification via deamination reaction 38, 39, 82, 135 followed by the Gewald reaction. The advantage of this process is in possibility of the prediction of hydrophilic or hydrophobic character of final structures with right choice of starting substrates bearing functional groups.

4.3. SYNTHESIS OF SOME DISPERSED THIOPHENE-BASED AZO DYES Interests in the design of azo dyes containing heterocyclic moieties stem from their high degree of brightness compared to azo dyes derived from anilines 169172 . The 2-aminothiophene based azo dyes are known as dispersed dyes with excellent brightness shade of shade. This class of dyes was established as an alternative to more expensive anthraquinone dyes 173, 174 . The thiophenecontaining azo dyes have many advantages including a color deepening effect as an intrinsic property of the thiophene ring and small molecular structure leading to better dye ability 175, 176 . Increasing the electron-withdrawing strength of the substitutents on the thiophene ring resulted in batochromic shifts. Additionally, the sulfur atom plays a decisive role by acting as an efficient electron sink as explained by valence band theory 177 . The thiophene-based azo dyes 92 are obviously prepared by diazotizing of substituted 2-aminothiophenes 7 using nitrozyl sulfuric acid with appropriate couplers, such as 2,3-dihydroxynaphthalene (87), resorcinol (88), 2-(N-methylanilino)ethanol (89), 2-(N-ethylanilino)ethanol (90), 3- (2-hydroxyethyl)phenyl-amino propionitrile (91) according to Scheme 25. A number of researchers studied azo disperse dyes derived form substituted 2aminothiophenes 90 in the dyeing of synthetic fibres 178-187 , blended polyester wool fibres 188, 189 and also in optical data store devices 190 .


36 R1 R2

X S

R1

a: nitrosylsulfuric acid, 0°C NH2

R2

b:YH

7

For couplers: Y =

For 90: X = CN, CO2 Et, CONH 2, etc. R 1 = R 2 = alkyl, cycloalkyl, aryl or R 1 = alkyl, aryl and R 2 = CN,CO2Et, CONH2 , etc.

X S

N N Y

90

CH2 CH 2OH

HO HO

HO

Me

OH 87

86

85

CH2 CH 2 OH

CH2 CH 2 OH

CH2 CH 2 CN

Et 88

89

Scheme 25. Synthesis of disperse azo dyes derived from substituted 2-aminothiophenes

5. CONCLUSIONS In this chapter we have extended the problems of synthesis of variety of substituted 2-aminothiophenes and their scope and utilization. The title compounds are readily obtainable by the Gewald reaction and its variations widely used since the time of its discovery in 1961 until now. These important heterocyclic compounds represent a group of precursors applied in synthesis of pharmaceutical and disperse dyes and in recent times the preparation of conductive polymers using 2-aminothiophenes is highlighted. The scope of our chapter does not include all of the publications on the chemistry of substituted 2-aminothiophenes, but the most interesting studies in the subject areas are considered.

6. ACKNOWLEDGMENT The support of this work by grants VEGA 1/1005/09, VEGA 1/4453/07, VEGA 1/4300/07 and VVCE 0004-07 and UK 102/2009 is acknowledged.


37

7. REFERENCES [1] [2] [3] [4] [5] [6] [7]

[8]

[9] [10]

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Peer review arranged by authors: Dipl. Ing. Daniel Végh, DrSc., Institute of Organic Chemistry, Catalysis and Petrochemistry, Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81239 Bratislava, Slovakia, Phone: +421-(02)-59325-144, Fax: +421-(02)-52968560, E-mail: [email protected]


Chapter 2

ADAMANTYL-1 AND ADAMANTYL-2 IMIDAZOLES AND BENZIMIDAZOLES. METHODS OF SYNTHESIS, PROPERTIES AND BIOLOGICAL ACTIVITY D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze, Sh. A. Samsoniya Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT The interest towards adamantylcontaining imidazoles and benzimidazoles is stipulated by broad spectrum of their biological effects and important technical properties. At present, different methods of synthesis are elaborated and definite success in study of the structure features and reactivity of imidazole and benzimidazole derivatives of adamantane series is achieved. In this survey, literary information about synthesis methods, structure, physical-chemical and biological properties is summarized, and also information about conversion of adamantyl-1 and adamantyl-2 imidazole and benzimidazole derivatives is given. The bibliography includes 96 references.

48

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.

INTRODUCTION Adamantane derivatives are widely studied at the present stage. There are several monographies [1-3] and review [4-8] dedicated to this problem. The adamantane derivatives are characterised by wide spectrum of biological properties. Among these are antiviral, antimicrobial, anticarcinogenic, anticataleptic, immunotropic, neuro-psychotropic and other activities [2, 3, 8-12]. The wide spectrum of pharmacological activities of adamantane line derivatives are conditioned by the structure of their molecules. The diamond-like firm cyclic structure determines their unique physical, chemical and biological properties. Insoluble in water adamantane changes into a soluble compound inside the cell membrane lipid layer, after it gets in touch with living cell, what leads to increase of the membrane permeability. This property of adamantane became of a great interest of scientists and stipulated research of its pharmacological characteristics in order to use adamantane radicals for delivering the medicinal remedies inside cells and thus enhancing their pharmacological activities [11]. Known already pharmaceutical substances, preparations with hypoglycemic, anticarcinogenic, neuroleptic, hormonal, immunotropic, and other activities were modified by inserting adamantane radicals in their structures. It needs to be mentioned that the presence of adamantane radicals in molecules of medicinal preparations, enhances their activity and depresses the toxicity [9]. Some adamantane line compounds such as Kemantane, Bromantane, and others restore functional activities of nervous, hormonal and immune systems; they also increase mental and physical capacities and resistance of organisms to viral and bacterial infections [11]. The wide spectrum of biological activities of adamantane derivatives makes the research of adamantane containing heterocyclic compounds very promising in direction of both synthesis and biological activities. Imidazole and benzimidazole derivatives out of nitrogen containing heterocyclic compounds have drowned the special interest of scientists by their antispasmodic, antiinflammatory, fungicidal, antimicrobial, anthelmintic and other properties. They are characterized with high biological activities and many compounds made on their basis are widely used in medicine, veterinary and agriculture [13-15]. Based on aforesaid, for the purposes of delivering new medicinal preparations and biologically active compounds, study in direction of adamantanecontaining imidazoles and benzimidazoles is most interesting. In the present observation, different methods of synthesis of adamantanecontaining imidazoles and benzimidazoles are described with interpretation of their biological activities.

Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles

49

ADAMANTYLIMIDAZOLES: SYNTHESIS, PROPERTIES 4-(1-adamantyl)imidazole (1) and 4-(1-adamantylmethyl)imidazole (2) was obtained by boiling bromomethyladamantylketones in formamide. The yield did not exceed 50% [16]:

O (CH 2)n CH 2Br

H 2NCHO

H N (CH 2)n

N

1, 2 (1) n=0; (2) n=1

Treatment of (1-adamantyl)bromomethylketone with sodium azide in methanol [17] leads to formation of (1-adamantyl)azidomethylketone. 2-(1Adamantoyl)-4-(1-adamantyl)imidazole (3) with 73% yield was obtained after boiling this compound in xylene during 15 hour.

H N COCH 2N3

O N

3 2-R-4(5)-(1-adamantyl)imidazoles 1, 4, 5, were obtained by interaction of concentrated ammonia, formalin, benzaldehyde, or isobutylaldehyde with acetoxymethyl(1-adamantyl)ketone in methanol at the presence of copper acetate. 2-(1-adamantoyl)-4(5)-(1-adamantyl)imidazole (3) was obtained at the same conditions, by interaction of concentrated ammonia with acetoxymethyl(1adamantyl)ketone without aldehyde. 2-mercapto-4(5)-(1-adamantyl)imidazole (6) was obtained by interaction of aminomethyl-(1-adamantyl)-ketone hydrobromide with ammonia thiocyanate [18]:

50

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. O

H N

RCHO, NH 3 CH 2OCOCH 3

CH3OH, Cu(OAc) 2

R

N

(1) R=H; (4) R=HC(CH3)2 (5) R=C6H5

1, 4, 5

NH3, CH3OH Cu(OAc)2 H N O N

3 O

H N

NH4SCN CH2NH2. HBr

SH

N

6

Adamantylsubstituted imidazole 7 was obtained with 91%yield [19] by interaction of 1-Adamantanecarbonitrile with isocyanide at the presence of butyllithium at low temperature:

H3C

SCH2NC

CN

N

BuLi, - 78 oC

H3C

S

N H

7 By interaction of adamantylbromomethylketone with imidazole, formation of compound 8 takes place [20]:


N

O

NH

51

O N

N

CH 2Br

C H2

8 Japanese patent [21] describes a method of synthesis of 4-carbamoyl-5(adamantoyloxy)-imidazole (9) with antibacrterial and antiinflammatory activities. It consists in interaction of 4-carbamoyl-5-hydroxyimidazole with adamantanecarboxylic acid chloride in the absolute pyridine environment:

CONH2

COCl

N OH

CONH2 N OCO

C5H5N

N H

N H

9

Derivatives of 2-phenylimidazoles 10, 11 of immunestimulating activities that are obtained by addition of aminomalonic acid amide on hydrochloride iminoester at 0oC, and consequent boiling the mixture in methyl alcohol environment are described in patent [22]: CONH 2

CONH 2 OC 2H 5

H2N

R

N

COOH R

NH . HCl

CH 3OH

OH N H

10, 11 (10) R=AdCONHCO; (11) R=AdCOO

Derivatives of adamantylimidazoles 12-17 characterised by immunopotentiating, antimicrobial, antiviral, fungicidal and anticarcinogenic activities are described in patent [23]:

52

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. R

OOC

R1

N

R2 N H

CONH 2

12-17

(12) R=R1=R2=H; (13) R=F, R1=R2=H; (14)R=Br, R1=R2=H; (15) R=Cl, R1=R2=H; (16) R=Ph, R1=R2=H; (17) R=R1=R2=CH3.

By interaction of hexamethyldisilazane on imidazole and the consequent interaction of 1-adamantylchloride with the obtained N-trimethylsililimidazole, 4(1-adamantyl)imidazole (1) with 52% yield was obtained [24]:

N

[(CH3)3Si]2NH N H

N

AdCl TiCl4, CHCl3

N Si(CH 3)3

N N H

1

2-(1-Adamantyl)imidazole (18) was synthesized by direct insertion of adamantane radical, obtained by oxidative decarboxylation of adamantane carboxylic acid in diluted by silver nitrate sulphuric acid in the presence of ammonia persulfate. N- methylation of the obtained compound led to the synthesis of N-methyl-2-(1-adamantyl)imidazole (19). The experiments conducted on chicken embryos revealed high antiviral activity of both obtained compounds [25]: N N R (18) R=H, (19) R=CH3

18, 19


53

By action of 1-bromoadamantane on N-unsubstituted imidazole with ratio 1:2 at 190-200oC during 2 hours, N-(1-adamantyl)imidazole (20) with 74% yield was obtained [26]. N Br N

N N H

20 German patent [27] describes . (+)-(2-Hydroxy-2-adamantyl)-1-imidazolyl-3tolylmethan (21), dextroenantiomer and its salts as medicinal remedies with antidepressant action: CH 3

OH N

N

C H

21 In 1991-1992 several patents were issued in America and in Europe [28-32], where pharmacologically active adamantanecontaining imidazolylalkylic and olefinic carboxylic acid derivatives were presented as with the following formula: AD

R3 R4

(CH2)n N

(CH2)n N

R1X N n = 0-8; X = O, S

R5 (CH2)nR6

R2

22

54

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. Ad

(CH 2)m

R6

CR 4

N

R5

R2X N

R3

23

m = 0-4; X = O, S

Ad

(CH2)m (CH2)n

N

O

R4 R5

N

R1 X N

R2

R6

R3

24

m = 0-4, n=0-5, X=O, S

CH 2 Ad R4 O N

R N

R2X

R1

N R3 R5

R6

25

X = O, S

Adamantane is connected to imidazole either by substitution directly at N, or is separated by (CH2)n group. Arduengo et al. [33] described the synthesis of 1,3-di-(1adamantyl)imidazole-2-ylidene (26). Through deprotonization by dimsylanion [CH2S(O)CH3] of 1,3-di(1-adamantyl)imidazole hydrochloride in THF at 20oC, in the presence of 1 equivalent sodium hydride, or by deprotonation with t-BuOK in THF, crystal carbene (26) was obtained, which was stabile in dry and oxygen-free environment [33]. Synthesis of stabile, spatially constrained imidazoleketene containing two adamantanes was described in [34]. 1,3-Di-(1-adamantyl)imidazole-2-carbonyl (27) was obtained by action of carbon monoxide on 1,3-di-(1-


55

adamantyl)imidazole-2-ylidene (26) in tetrahydrofuran environment. Although, in other work [35], the authors reinvestigated experimentally the reaction of carbon monoxide with the stable carbene, 1,3-di-1-adamantylimidazol-2-ylidene. They state that reaction of the stable carbene, 1,3-di-1-adamantylimidazol-2-ylidene, with carbon monoxide does not lead to formation of ketene. By interaction of carbene (26) with sulphuric dioxide, synthesis of sulfon (28) takes place [36].

+ N

N

N

NaH Cl

N

CO

:

_

N

N

26

27

C

O

SO2 SO2 N

N

28 In [37], synthesis of the first representatives of the corresponding adamantylsubstituted bicyclic systems – 2-(1-adamantyl)imidazo[2,1-a]pyridine (29) and 2-(1-adamantyl)imidazo[2,1-b]thiazole (30), by the reaction of bromomethyl 1-adamantyl ketone with 2-aminopyridine and 2-aminothiazole correspondingly was presented. It was found that on heating the mixture in absolute alcohol, the reaction proceeds through the intermediate formation of hydrobromides: 2-amino-3-(1- adamantoyl-methyl)pyridinium and 2-amino-3-(1adamantoylmethyl)thiazolium, bromides, which were converted into compounds 29 and 30 by heating in a sodium hydrocarbonate solution [37].

56

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. NH 2 N NH 2

O

N

C N+ H2 O

Br

N

-

29

CH 2Br H N 2 N

H 2N

S O

N

S

N+ C H2

-

N

Br

S

30

In [38], the authors have studied interaction of bromomethyl(1adamantyl)ketone with ureas and thioureas in ethylene glycol at 200-250oC in the presence of К2СО3, when formation of 4-adamantylimidazolin-2-ons (31-33) and -imidazoline-2-thyons (34-37) takes place. X

Br

R1NHC NHR 200-250oC

O

R

X

N N R

31-37

(31) X=O, R=H, R1= H; (32) X=O, R=Ph, R1= H; (33) X=O, R=Ac, R1= H; (34) X=S, R=H, R1= H; (35) X=S, R=Ph, R1= H; (36) X=S, R=Ac, R1= H; (37) X=S, R=Ph, R1= Ph;

As it is known, α-aminoketones are the initial compounds for the synthesis of 2-mercaptoimidazoles. In the paper [18], the synthesis of 2-mercaptoimidazole 6 by use of adamantanesubstituting α -aminoketones is described. In order to study the influence of the radicals by amino- and keto-groups on α-aminoketones reactivity, Makarova and collaborators [39] synthesized 2-mercaptoimidazoles 38, 39 by heating α -aminoketones with potassium thiocyanate at the presence of acetic acid during 6-13 hours.

Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles SH

N

KSCN

O

CH3COOH

57

N R

CH2NHR

38, 39

(38) R= CH3 , 16%; (39) R= p-CH3C6H4, 36%

When R=1-adamantyl, the cyclization does not take place. Low yield of mercaptoimidazoles shows that adamantane radicals prevent cyclization of αaminoketones, while the presence of adamantane by aminogroup makes it impossible [39]. 2-amino-2-ethoxycarbonyladamantane interacts with iminoester in the presence of acetic acid in xylene environment and adamantylimidazolinone spiro derivative 40 is obtained during this process [6]. O

NH NH2

Me3C

O

N

OEt N H

CH3COOH

OEt

CMe3

40

By reaction of 1-adamantanole with 4,5-dinitroimidazole in the presence of sulphuric acid, or mixture of phosphoric and acetic acids, 1-(1-adamantyl)-4,5dinitroimidazole (41) with 75% yield was obtained, and by adamantylation 4(5)nitroimidazole mixture of phosphoric and acetic acids 1-(1-adamantyl)-4nitroimidazol (42) with 20% yield was obtained [40].

O2N N R

(41) R=NO2; (42) R=H

N H

OH

O2N N

H3PO4/CH 3COOH R

N

41, 42.

58


In order to synthesize adamantylimidazoles, the authors of [41] have used interaction of 1,3-dehydroadamantane with imidazoles, which gives only Nsubstituted derivatives 20, 43:

N N H N N

20

N N H

43 N N

The authors of [42] have studied interactions of imidazoles with 1adamantylbromide at 110-180oC. They have stated that interaction of imidazoles with 1-adamantylbromide at rate 8:1, at the mentioned temperatures in odichlorobenzene leads to synthesis not only of 1-(1-adamantly)imidazoles (20, 44) with 46-53% yield, but also of 4-(1-adamantly)imidazoles (1, 45) with 12-14% yield.

N R N N R N H 20, 44 (1, 20 ) R=H ( 44, 45 ) R=CH3

1, 45


59

The authors in [42] conclude that adamantylation takes place simultaneously in 1 and 4 positions and the acidity or alkalinity does not have any significant influence in this direction, while the excess of imidazole have a serious effect on the process. Treatment of 4-(adamantan-1-yloxymethyl)-2,3-dioxobutyric acid benzyl ester (3-step preparation given) with ammonium acetate and cyclohexanecarboxaldehyde in AcOH gave 5-(adamantan-1-yloxymethyl)-2cyclohexyl-1H-imidazole-4-carboxylic acid benzyl ester (49%). After deprotection of the butyrate (96%), followed by amidation with 3-aminobenzoic acid benzyl ester (65.5%) and deprotection of the benzoate (98%), 46 is afforded [43]: H N N

O

CH2 CO H N

COOH

46 The invention provides adamantane derivatives 47, 48, a process for their prepn., pharmaceutical compounds containing them, and their use in therapy [44].

R2

X-R4-Y-R5-Z

E D R1

47, 48 (47) Z= imidazolyl, (48) Z=1-methylimidazolyl

60


The compounds are P2X7 receptor antagonists, useful in particular for effecting immunosuppression, or for treating rheumatoid arthritis or chronic obstructive pulmonary disease [44]. By heating 2-aminopyridine with bromomethyl(adamantan-1-yl)ketone [45] in ethylacetate, followed by boiling the alkylation product in acetic acid, synthesized compound 29 in 84% yield (compare with [37]). When treated with elemental bromine under conditions described, the monobromo derivative 49 is formed. Then it is nitrosated by sodium nitrite converting to compound 50.

R N

1

N

R

29, 49-51 (29) R = H, R1=H; (49) R=Br, R1=H; (50) R=NO, R1=H; (51) R=Br, R1= NHCOCH3

Boiling compound 29 in liquid bromine for 4h also leads to formation of compound 49, but in higher yield. They were not able to add a bromine atom to the adamantane ring even when using catalysts (Lewis acids) conventionally used for difficult bromination reactions. Regardless of the reaction conditions, they could detect formation of only compound 49. They converted compound 49 to the acetoamino derivative via the Ritter reaction [45]. CH 3

CH3

CH3

7

Br

N

+

NH 2

N

NH2 _

Br

O

6

8

5

9

N

_

HBr

4

3

O

a 52a

N

1

2

a

52

b

y


61

CH 3 1(2) NBS

N

CH 3

N

53 Br

N

N

N

52

O

CHBr2

N

H

H2O N

3 NBS

N

Br Br

54

b O2N H N

N

H

NO2

N

N

Br

55

In reaction [46] with equimolar amount or twice the amount of Nbromosuccinimide (NBS) 2-(1-adamantyl)-7- methylimidazo[1,2-a]pyridine (52), obtained from 2-amino-4-methylpyridine and bromomethyl 1-adamantyl ketone, is converted into 2-(1-adamantyl)-3-bromo-7-methylimidazo[1,2-a]pyridine (53). In reaction with three times the amount of N-bromosuccinimide in the presence of trace quantities of water 2-(1-adamantyl)-3-bromo-7-formylimidazo-[1,2a]pyridine (54 ) is formed. They suppose that compound 54 is the product from hydrolysis of 2-(1-adamantyl)-3-bromo-7-dibromomethylimidazo[1,2-a]pyridine (b) formed during the reaction [46]. Imidazopyridines and many derivatives of adamantane possess notable physiological activity important role in which is played by substitutions in the

62


molecules. The authors [47] have carried out work on the synthesis of various functional derivatives of compound 2-(adamantan-1-yl)imidazo[1,2-a]pyridine 29. 1

R

R

R

N

2

N

R3

29, 49, 52, 56-58 (29) R=R1=R2=R3=H; (49) R=R1=R2=H, R3= Br ; (52) R=R2=R3=H, R1=CH3; (56) R=R1=R3=H, R2=CH3; (57) R=Cl, R1=R2=R3=H; (58) R=Br, R1=R3=H, R2=CF3.

The formation of imidazopyridines is known to be a two-step process. It was shown earlier [46] that the first step in the reaction – the alkylation of 2aminopyridine with bromomethyl (adamantan-1-yl) ketone was successfully carried out with a high yield of 1-[3-adamantan-1-yl)-2-oxoethyl]-2-aminopyridinium bromide 29a by boiling the reagents for 1 h in ethanol or ethyl acetate. They have established that the introduction of an electron-acceptor substituent into the pyridine ring, considera-bly hinders the reaction. When 2-aminopyridine, 2-amino-4-methylpyridine, or 2-amino-3-methylpyridine were heated with bromomethyl(adamantan-1-yl) ketone in ethyl acetate for 1 h, the yields of compounds 29a, 52a, 56a varied within the limits of 80-95% and, whereas with 2amino-6-bromo and 2-amino-5-chloropyridine the corresponding alkylation products – compounds 49a, 57a were obtained in yields of only 50%. In the case of 2-amino-5-bromo-3-trifluoromethylpyridine, the formation of only a negligible amount of compound 58a was observed after 1 h and the yield reached 42% only after 5 h The second stage - cyclization - occurred effectively in acetic acid, but not in aqueous sodiumbicarbonate solution, as was previously described. The authors succeeded in obtaining adamantanylimidazo-pyridine 29 in a yield of 84% on heating compound 29a in acetic acid for just 1 h. They note that an electronaccepting substituent in the pyridine ring appeared to have a negative effect in the cyclization stage [47] In the reactions with phosphorus tribromide, 2-(adamantan-1-yl)imidazo[1,2a]pyridine (29) converts into 2-(adamantan-1-yl)-3-bromoimidazopyridine(49).


63

Under more rigid conditions, the reaction pathway with phosphorus tribromide does not alter, while with phosphorus trichloride, 2-(3-chloroadamantan-1yl)imidazopyridines 59 and 60 are formed [48]. R

PBr3 N

R

49, 53

N

7

Br

6 5

N

N

R

PCl3 3

2 a

y

Cl

b

N

59, 60

N

29,52 (29, 49, 59) R=H; (52, 53, 60) R=CH3 .

Complexes of 1,3-di-(1-adamantyl)imidazo-2-yliden (26) with palladium [49] and titanium [50] are used as effective catalysts for polymerization of cyclic amides. Its complexes with Ru and Os [51] and the product of Klaizen condensation [52] are also obtained. The reactivity of N-heterocyclic carbene (NHC) with pseudo-acid (ester in this case) is described. The product results from unusual C–H bond activation. The structure of the product has been established by single crystal diffraction study [52].

N

: N

MeOAc

N +

N

H

+

O

O H

N

_

CH2

OMe

H3C

26

O

N

O

H3C CH3-OH OMe

_ CH

OMe

64


The authors in [53] described adamantane-containing imidazo[1,2a]pyridines. It was stated that presence of adamantane in these compounds has practically no effect on the chemical properties of their imidazole ring, i.e. reactions of bromination, nitrosation proceed in ordinary conditions. Reaction of 2-adamantyl-7-methylimidazopyridine (52) with one, or two moles of Nbromsuccinimide results in introduction of bromine atom in imidazole ring (53), while the reaction with three moles of N-bromsuccinimide - 2-adamantyl-3bromo-7-formylimidazopyridine (54). Interaction of compound 29 with trichlorophosphorus at high temperature, chlorine atom enters adamantane nucleus (59). The authors have carried out Ritter reaction for compound 29 and isolated 2-(3-acetaminoadamantyl-1)-derivative (61) [53] R1

R

3

R

N

N S

N

R2

N

29, 49, 50, 54, 59, 61.

30, 62

(29) R1=R2=R3=H; (49) R1=Br, R2=R3=H; (50) R1=NO, R2=R3=H; (54) R1=Br, R2=CHO, R3=H; (59) R1=R2=H, R3=Cl; (61) R1=R2=H, R3=NHCOCH3; (30) R=H; (62)R= Br. N H3C

N OH

N H3C OH

N H

63

OH N N N N H

OH

64


65

The authors in [54] studied interaction of spatially constrained 2-(2hydroxyphenyl)-2-adamantanole with imidazoles. Products of 1-H-alkylation 63, 64 are isolated. Iodinemethylates (a,b) are obtained from 2-(1-adamantyl)-4-methyl- and 4(1-adamantyl)- phenols by to Mannich's reaction and consequent quaternization by methyl iodide. Consequent interaction with azoles lead to formation of 2-(1-H1-azole-1-ylmethyl)phenols 65, 66, 67 [93]. OH

N

N

Ad

R N H

N R

a

65, 66

OH

CH3

+

X

N(CH3)3

J

OH

_

N N H

Y a,b

H N Ad

N N

b

N

a X=1-adamantyl, Y=CH3 b

N

N

Ad

67

X=H, Y=1-Adamantyl OH

(65) R=H; (66) R= CH3

ADAMANTYLBENZIMIDAZOLES: SYNTHESIS, PROPERTIES Despite many works concerning benzimidazole line, adamantylbenzimidazoles are less studied. 2-(1-adamantyl)benzimidazole (68) was first synthesized in 1969 by Sasaki and co.[55] by interaction of 1-adamantanecarbonyl chloride with ophenylenediamine and cyclization of obtained N-(1-adamantylcarbonyl)-ophenylenediamine in the presence of polyphosphoric acid ester (ppe) in chloroform environment. The yield of 2-(1-adamantyl)benzimidazole (68) made 96%:

66

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. NH2 NHCO

NH2

N

COCl TEA

NH2

N H

68 Efforts to obtain compound 68 by heating o-phenylenediamine with adamantane carboxylic acid in the presense of hydrochloric, or polyphosphoric acids gave no results. By passing dry hydrochloride in alcohol solution of adamantanecarboxylic acid nitrile, Shvekhgeimer and Kuzmicheva [56, 57] have obtained hydrochloride of adamantane carboxylic acid iminoester. After boiling it with equivalent amount of o-phenylenediamine in absolute alcohol area, compound 68 was obtained with yield equal to 72%: NH2 ROH CN

NH . HCl

HCl

N

NH2 ROH

OR

N H

68 Reaction of diiminoester dihydrochloride with stoichiometric amount of ophenylenediamine leads to the synthesis only 1-(benzimidazolyl-2)-3methoxycarbonyladanamtane (69) [58] MeO

NH . HCl NH . HCl

OMe

NH2 NH2

COOMe N N H

69 Containing two fragments of benzimidazole adamantane with 69% yield was obtained as a result of interaction of diiminoester dihydrochloride with quintuple excess of o-phenylenediamine at 20oC, or with 58% yield by boiling the mixture


67

of dinitrile of adamantanedicarboxylic acid and o-phenylenediamine in cumene in the presence of hydrochloric acid [58].

MeO

CN

NH. HCl N NH NH . HCl

CN OMe

N N H

70 Containing fragments of benzimidazole and imidasolyne adamantane 71 was obtained by condensation of ester 69 with ethylenediamine in the presence of kationite KU-2 [58]: COOMe N N N H

KU-2

NH

115oC N N H

71 Boiling ester 69 with o-aminophenole in n-xylole at the presence of kationite KU-2 leads to formation of 1-(benzimidazolyl-2)-3-(benzoxazolyl-2)adamantane (72) [58]:

68


OH

COOMe N

NH2

N O

N H N N H

72 At interaction of compound 69 with methyl iodide, acetylchloride and paraform, corresponding N-substituted 73-75 are obtained . COOMe

COOMe N

N

N H

N

69

R

73-75

(73) R= CH3; (74) R=CH3CO; (75) R= CH2OH.

In 1974-75, works concerning the synthesis of pharmacologically active 1adamantylsubstituted compounds were published [59, 60]. In order to obtain preparations of antiviral activity, benzimidazole derivatives with substituted in the second position adamantyl and adamantoylaminoalkyl groups. First, iminoester was obtained using Pinner reaction and then condensation of the iminoesters with o-phenylenediamines in chloroform environment was provided using King method [61].


NH 2

NH. HCl

NH(CH 2)2CN NH(CH 2)2

C2H5OH

69

NHR OC 2H 5

HCl

O

O

N NH(CH 2)2 N R

O 76 (R=H), 77 (R= CH3). NH.HCl OC2H5 NH

NH2 NH2

N NHCOCH2

O

N

78 The yields of compounds 76 and 77 reaches 50% and 60% respectively and that of compound 78 is only 10%. N CONH N HN CH 3

CH 3

79 By cyclization of N-(1-adamantoyl)-N1-methyl-o-phenylenediamine in absolute chloroform and alcohol environment, in the presence of polyphosphoric acid ester (ppe), 1-methyl-2-(adamantyl)benzimidazole (79) is obtained with 35% yield. 6-nitrobenzimidazole-2-carboxylic acid–(1-adamantylamide)-1-oxyde (80) was obtained with 3% yield by treatment of 1-(N-2,4-dinitrophenylglicylamino)adamantane in pH 8.5 phosphate buffer, at 90oC during 136 hours.

70

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. O2N H N

NO2

NHCOCH 2NH

NHCO N

NO2

O

80 Activities of the isolated compounds against different cultures of influenza viruses are studied in [59, 60]. 2-(1-adamantylmethyl)benzimidazole (81) was synthesized [62] by boiling of adamantylacetic acid chloride with 2-nytroaniline in pyridine environment and consequent hydrogenation of obtained adamantylacetic acid-2-nytroanyline, followed by heating in ethyleneglycol. The total yield made 79%. NH2

CH 2COCl

NO2

H2

NHCOCH2

Pd/C

NO2 NHCOCH 2

NH 2

CH 2OH CH 2OH

N N H

81 Hollan and co. [63] in 1977 managed to obtain 2-adamantylbenzimidazoles (68, 82-84). This was done by interaction of equimolar amounts of adamantanecarboxylic acid and o-phenylenediamine at high pressure and temperature in 1-2N HCl and aqua alcohol. The yield of the synthesized compound 68 was 48% in conditions of 60% ethanole, 1N HCl and 8kbar (1 bar = 986.1 atm.). The authors mention that use of 2N HCl instead of 1N HCl leads to decrease of the yield from 48% to 39%. Without acid, the yield is insignificant (6.5%). Use of diamines that are more alkaline then o-phenylenediamine increases yield of (82-84) products up to 73%.

Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles R

NH2

R1

NH 2

R

N

R1

N H

71

COOH

68, 82-84 (68) R=R1=H; (82) R=Cl, R1=H; (83) R=CH3, R1=H. (84) R=R1=CH3

Hollan obtained compound 68 with 97% yield by boiling N-(1adamantylcarbonyl)-o-phenylenediamine in 50% ethanol in the presence of concentrated HCl at atmospheric pressure and with 91% yield by interaction of adamantanecarboxylic acid with aminoanilide at 8 kbar pressure, 107oC temperature, in 83% ethanol. Without acid, by heating just alcohol solution of aminoanilide, compound 68 cannot be obtained [63].

NHCO

conc. HCl or AdCOOH (8 kbar)

NH 2

C2H5OH

N N H

68 Synthesis of compound 68 by oxidative decarboxylation of adamantane carboxylic acid is described in [25]. Initially, for the synthesis of 2-(1adamantyl)benzimidazole (68), adamantan radical was obtained in sulphuric acid diluted by silver nitrate in the presence of ammonia persulfate. Then, the synthesized radical was inserted directly into the heterocycle. After Nmethylation, 2-(1-adamantyl)benzimidazole (68) was transferred in 1-methyl-2(1-adamantyl)-benzimidazole (79). The experiments carried out on chicken embryo revealed high antiviral activity of both obtained compounds [25]:

72


N N R

68, 79

(68) R= H; (79) R= CH3

5(6)-(1-adamantyl)benzimidazole (85) was synthesized by T. Sasaki and co. [24] by interaction of benzimidazole with hexamethyldisilazane and alkylation of the obtained N-trimethylsilylbenzimidazole by 1-chloroadamantane in the presence of AlCl3 in chloroform at 0°C. The yield was 49% .

Cl

N

[(CH3)3Si]2NH

N

N

N H

N

AlCl3, CHCl3

N H

Si(CH3)3

85 In 1984, Tsupak and co.[64] synthesized 2-(1-adamantyl)benzimidazole (68) with 45% yield by substitution of sulpho group in benzimidazole-2-sulfonic acid with adamantly radical. The reaction was carried out in aqua acetonitrile solution. The adamantyl radical was obtained by oxidativ decarboxylation of adamantanecarboxylic acid with ammonia persulfate in silver nitrate aqua solution.

Ag

-

S2O82 + 2AdCOOH N SO3H N H

. 2Ad + 2CO2 + 2HSO4

Ad

.

N N H

68


73

In 1985, Gonzalez and co. [26] obtained N-(1-adamantyl)benzimidazole (86) by heating 1-bromoadamantane and benzimidazole (1:2) at 190oC with 69% yield. The antiviral activity of the compound was studied.

N

Br

N

N

N H

86 In 1986, Polish scientists [65] obtained benzimidazoles 81, 87-90 with 3242% yield by heating equimolar amounts of 3-R-adamant-1-ylacetic acid and 41

R -1,2–diaminobenzene at 180oC during 1-2 hours. CH 2COOH

R1

R NH 2 NH 2

R1 N

R N H

81, 87-90 (81) R=R1=H; (87) R=H, R1=Cl.; (88) R=H, R1=Br ; (89) R=H, R1=CH3 ; (90) R=OH, R1=H.

By heating compound 81 and alcohol solutions of propylene oxide in fused ampoule (60oC) in the presence of piperidine, N-alkylation product 91 was obtained with 91,67% yield and by action on compound 81 with methylsulfochloride in absolute pyridine environment, it was obtained compound 92 with 85% yield. Antibacterial properties of the synthesized preparations were studied [65].

74


N

O N

91

CH2CHOHCH3

N N H

CH3SO2Cl

N

92 N SO2CH3

Avdyunina and co. [66] synthesized 1-alkyl-2-iminobenzimidazoline-3-acetic acid-N-adamantylamides 93-97 with 71-89% yield by boiling of equimolar amounts of 1-alkyl-2-aminobenzimidazole with N-(chloroacetyl)aminoadamantanes in acetone for 28-30 h. The N-(chloroacetyl) aminoadamantanes were obtained by acylation of 1- and 2-aminoadamantanes with chloroacetyl chloride in benzene. The obtained compounds are characterised by psychostimulant action, which is demonstrated by increase of physical activity and spontaneous motion activity. CH2CONHR1 N

N NH2 N R

NH . HCl

ClCH2CONHR 1 CH3COCH3

N R

93-97 (93) R= CH3, R1=1-Ad; (94) R= C2H5, R1=1-Ad; (95) R= C4H9, R1=1-Ad; (96) R= CH3 , R1=2-Ad; (97) R= C2H5, R1=2-Ad

Morozov and co. [67] synthesized aminomethyl derivatives 98-100 of adamantanecontaining imidazobenzimidazole. By interaction of bromomethylsubstituted imidazobenzimidazole ester with N-methyl-N-(1adamantyl)amine with (1:2) ratio, bromine is easily substituted by amino group. The reaction proceeds at boiling in benzene medium without catalyst. Psychotropic action of 98-100 compounds is elucidated.


N

NHCH 3

COOR 1

N

COOR

N N

75

1

CH 2Br N

R

N

N

H 3C

R

98-100 (98) R=R1=CH3; (99) R=CH3, R1=C2H5; (100) R= Bu, R1= CH3.

Hungarian authors published works [68, 69] on synthesis of new adamantanecontaining benzimidazoles in 1988-89. In these compounds, adamantyl radical is attached to benzimidazole core via heteroatom. They are used as medicinal remedies in medicine and veterinary. R1

A

N (CR 4R5)nR 6 N

R2 R3

101

R1= Ad; R2, R3, R4, R5, R6 is alkyl; A is a heteroatom.

In patent [70], Polish scientists describe obtained by them [65] adamantylbenzimidazole 92 with antiarhythmic and hypotensive activities. A method of synthesis of adamantylbenzimidazoles 102-105 is described in author sertificates of Avdyunina and co. [71-75], issued in 1991. The method consists in interaction of equimolecular amounts of 2-amino-1-R-benzimidazole and bromomethyladamantylketone in acetone medium at room temperature. The yield of the preparation makes 94-97%.

76


CH 2CO N+

COCH 2Br

N

_ NH 2Br

NH 2 N

N

R

R

102-105 (102) R=CH3;

(103)

(104)

R=CH2CH2- N

(105)R=CH2CH2N(C2H5)2

R=CH2CH2- N

O

The compounds are characterised by psychostimulant, anticataleptic, and immunosuppressive actions. In addition, they extend time the action of barbiturates. After cyclization of 104 and 105 compounds in concentrated hydrochloric acid, imidazobenzimidazole dihydrochlorides 106, 107 are obtained, which are characterized by immunosuppressive action [74].

CH 2CO N

conc. HCl

N NH. HBr

N

N R

R

104, 105

106, 107

R=CH2CH2- N

(104, 106)

N

. 2 HCl

O

(105, 107) R= CH2CH2N(C2H5)2;

A method for the synthesis of compound 85 benzimidazole with hexamethyldisilazane followed trimethylsilylbenzimidazole with 1-chloroadamantane aluminum chloride in chloroform at 0°C is known [24]. 85 by the previous method was 49% [24].

by the interaction of by alkylation of Nin the presence of The yield of compound


77

The authors [76] have developed the following method for the preparation of compound 85: NH2

. 2 HCl NH2

HCOOH

N

95-105oC N H

85 A mixture of 4-(1-adamantyl)-1,2-diaminobenzene dihydrochloride and formic acid was heated at 95-105°C for 7 h. The yield of compound 5(6)-(1adamantyl)benzimidazole (85) 98% [76]. The subject of the present invention is new benzimidazole derivatives [77] , method for preparing the same and therapeutical and cosmetic uses thereof. The benzimidazole derivatives according to the invention can be represented by the following general formula: R1

R3 N

R2

R4 N H R5

108-122

in which: (108) R1=OH, R2= H, R3=1-Ad, R4= OH; (109) R1= O-CH2-C6H5, R2= H, R3=1Ad, R4= O-CH2-C6H5, R5=H; (110) R1=H, R2= OH, R3=1-Ad, R4= OH, R5=H; (111) R1=H, R2= OCH3, R3=1-Ad, R4=OCH3, R5=H; (112) R1=H, R2= O-CH2-C6H5, R3=1-Ad, R4= OCH3, R5=H; (113) R1=H, R2= OH, R3=1-Ad, R4=OCH3, R5=H; (114) R1=H, R2= O-CH3, R3=1-Ad, R4= O-CH2-C6H5, R5=H; (115) R1=H, R2= O-CH3, R3=1-Ad, R4= OH, R5=H; (116) R1=H, R2= O-CH2-C6H5, R3= O-CH2-C6H5, R4=1-Ad, R5=H; (117) R1=H, R2= OH, R3= OH, R4= 1-Ad, R5=H; (118) ) R1=H, R2= O-CH2-C6H5, R3=1-Ad, R4= O-CH2-C6H5, R5= O-CH3; (119) R1=H, R2= O-CH2-C6H5, R3=1-Ad, R4= O-CH2-C6H5, R5=H; (120) R1=H, R2= OCOCH3, R3=1-Ad, R4= OCOCH3, R5=H; (121) R1=H, R2= OH, R3=1-Ad, R4= OH, R5= O-CH3; (122) R1=H, R2= OCOCH3, R3=1-Ad, R4=OH, R5=H;

These new benzimidazole derivatives have proved to have , in human or veterinary medicine, good activity with respect to inflammatory and /or

78


immunoallergic conditions. In cosmetics, these new benzimidazole derivatives comstitute particularly advantageous substances in body and hair hygiene [77]. New 2-alkyl and 2-aryl derivatives of 5(6)-(1-adamantyl)benzimidazole have been synthesized. Certain reactions of N-alkylation and N-acylation of these compounds have been studied [78]. NH2

. 2HCl RCOOH

NH2

N R N H

85, 123-126 (85) R = H; (123) R = Me; (124) R = C3H7; (125) R = Ph; (126) R = CH2Ph

They investigated the reactions of N-alkylation and N-acylation of the benzimidazoles 85, 126. These reactions gave an N-adamantyl derivative 127 and N-acyl derivatives 128-130 [78].

R1Hal

N R N H

N

R N

R1 85, 126

127-130

(85) R=H; (126) R = CH2Ph; (127) R = H, R1 = 1-adamantyl; (128) R = H, R1= COPh; (129) R = CH2Ph, R1= COPh; (130) R = CH2Ph, R1 = COCH2Ph.

The results of biological examination of synthesized derivatives of 5(6)-(1adamantyl)benzimidazole showed that some of them exhibit antihelmintic and antimicrobial activities and are of interest for further study [79, 80, 81, 82, 83]. In a patent issued in 1998 [84] adamantanecontaining benzimidazoles 131 are presented characterized by anticarcinogenic activity:


R2

R3 R4

R1

X 1

79

131

2

3

X-benzilimidazolyl; R = H, Hal, alkyl; R = OH, alkyl, acyl, aminocarbonyl; R = H, OH, 4

alkyl; R = H, alkyl, Hal, alkoxy.

In [85] the authors provided alkylation of benzimidazole with 1adamantylbromomethylketone, alkylation product 132 was isolated, the optimum conditions of the reaction were defined:

N

O N N N H

CH2Br

CH2

O 132

New pathways for the preparation of novel classes of stable heteroaromatic carbenes are proposed in [86] for the first time: 1,3-di-(1adamantyl)benzimidazolin-2-ylidene (133) was obtained by thermal a-elimination of acetonitrile from 1,3-di-(1-adamantyl)-2-cyanomethyl-2H-benzimidazoline in vacuum or in organic solvents.

80


N

: N

133 In o-dichlorobenzene solution adamantylation of benzimidazole afforded 1(1-adamantyl)benzimidazole ( 86) and 1,3-di(1-adamantyl)-benzimidazolium bromide (134). They report here on reaction of benzimidazole with 1bromoadamantane at 110-180oC and various reagents ratio [86].

N

N +

N

86

-

N Br

134

The invention [87] relates to the discovery that specific adamantyl or adamantyl group derivatives containing retinoid-related compounds induce apoptosis of cancer cells and therefore may be used for the treatment of cancer, including advanced cancer. It has been shown that such adamantyl compounds, e.g., 2-[3-(1-adamantyl)-4-methoxyphenyl]-5-benzimidazole carboxylic acid (135), can be used to treat or prevent cervical cancers.


81

COOH

N

MeO N H

135

In order to create new immunotropic remedies, the authors [88] synthesized bromides of 3-(1-adamantylcarbonylmethyl)-2-amino-1-alkyl(aralkyl)benzimidazole: CH 2CO N N R

+

Br

-

NH 2

136-141

(136) R=CH3; (137) R= C2H5; (138) R=C3H7; (139) R= i-C3H7; (140) R= C4H9; (141) R=CH2C6H5.

Compounds 140 and 141 have ability to increase functional activity of immune system by stimulating T- and B- lymphocytes. Among the known classes of heteroaromatic carbenes, the benzimidazole derivatives have received the least attention thus far. They [89] present new results in terms of the synthesis and properties of stable heteroaromatic monocarbenes and biscarbenes of the benzimidazole series. One of the major aims in this area was the attachment of sterically bulky groups to the benzimidazole nucleus. The introduction of the 1-adamantyl substituent into the benzimidazole system was achieved by direct adamantylation of benzimidazole using 1bromoadamantane in the presence of sodium acetate in acetic acid. However, in this case the reaction was incomplete and yields of only 33% of pure salt 134 were realized. In o-dichlorobenzene in the presence of potassium carbonate, a 54% yield of 1-(1-adamantyl)benzimidazole (86) can be achieved and this compound can be further quaternized by treatment with 1-bromoadamantane in odichlorobenzene to afford a high yield of salt 134 (90%).As is well known, in the

82


presence of stronger bases benzimidazolium salts generate carbenes which undergo dimerization. Finally, the most improved method for the synthesis of diadamantyl salt 134 comprises a one pot quaternization of benzimidazole by 1bromoadamantane in o-dichlorobenzene in the presence of calcium hydride (the salt yield is 72%). In this case the initial monoadamantylation proceeds effectively quantitatively and this in turn facilitates the subsequent quaternization.

CN

N

N

N

:

+

-

N

N Br

134

142

N H

133

In [89], the authors studied the deprotonation of the 2-unsubstituted benzimidazolium salts 134 in anhydrous acetonitrile. The reaction with sodium hydride resulted in the products of insertion of the corresponding carbenes into the С–Н bond of acetonitrile, namely 2-cyanomethyl-2Н-azolines 142, These compounds were isolated in a pure crystalline state for the first time. for the first time The C–H insertion of carbenes in acetonitrile also proceeded by deprotonation of the sterically hindered 1,3-(1-adamantyl)benzimidazolium salt 134, in which a C2H link is shielded by bulky adamantyl substituents. As mentioned above, sterically hindered compound 142 exhibited enhanced stability upon prolonged storage and did not undergo reaction below 100 °C in a solid state. However, heating solid 142 at 180 °C results in α-elimination of acetonitrile to afford a stable carbene 133. Heating this compound in aromatic solvents (benzene or toluene) gives analogous results. However, more time is required for the process. Thus, for the first time a stable representative of the benzimidazole carbene series has been produced as a colorless highmelting solid that can be crystallized from toluene and stored at room temperature under argon for at least six months without decomposition. Reaction of 133 with sulphur also is studied. Carbene reacts very rapidly (in a few minutes) to form thiones 143 [89].


83

N S N

143 A new stable crystalline carbene 1,3-bis(1-adamantyl)benzimidazol-2-ylidene (133), was synthesized [90], by decomposition of 1,3-bis(1-adamantyl)-2,3dihydro-1H-benzimidazol-2-ylacetonitrile (142) on heating under reduced pressure. Heteroaromatic stable carbene 133 reacted with acetonitrile to give the corresponding insertion products 142. The geometric parameters of 1,3-bis(1adamantyl)benzimidazol-2-ylidene (133), determined by X-ray analysis. 1,3Bis(1-adamantyl)benzimidazol-2-ylidene (133) reacted with molecular sulfur in benzene to give 1,3-bis-(1-adamantyl)-2,3-dihydro-1H-benzimidazole-2-thione (143). The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade. They identified [91] and extended a novel family of 2-(substituted phenyl)benzimidazole inhibitors. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups 144. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma. N

H N O

N N H

H N O

144

84


N-substituted benzimidazole-containing bridged alicyclic compound are manufactured and used [92] to produce thin films having a pore structure on a molecular level, high thermal stability, low relative dielectric const., and low moisture absorptivity, useful in manufacture of semiconductors. Thus, reaction of 1,3,5,7-tetrakis(4-carbonylphenyl)adamantane with 3,31-diaminobenzidine, cyclization of the intermediate with 4-ethynylbenzaldehyde, and reaction of the 2nd intermediate with PhCH2Cl gave tetraethynyl compound 145, which was spincoated from a solution. onto a wafer and thermally polymerised at 400° to give a 220-nm thick film.

H 2C R

N

H2C

CH

N R

R

N H

R= N H

R

145 From 4-(1-adamantyl)phenol, using Mannich's reaction followed by quaternization with methyl iodide, was obtained iodinemethylate. At its interaction with 2-trifluoromethylbenzimidazole, corresponding 2-(1H-azol-1ylmethyl)phenol 146 [93]. OH

N

+

N(CH3)3

J Ad

_

CF3

OH CF3

N

N H

N

Ad

146 For the prognosis of probable activities of adamantane-containing benzimidazoles, the authors in [94] provided virtual screening by internet-system PASS http://www.ibmс.msk.ru/pass/. The results have shown that these compounds are supposed to have Antihelmintic (Nematodes), Cytostatic, Neurotrophic factor enhancer, Antineoplastic (brain cancer), Antiparkinsonian,


85

rigidity relieving; Antiviral (Influenza), Antiviral (Picornavirusn), Antiviral (Adenovirus), Urologic disorders treatment and other activities. 4-(1-Adamantyl)-1,2-diaminobenzene, previously unreported in the literature, has been prepared and a novel series of 5(6)-(1-adamantyl)benzimidazole derivatives synthesized. Nitration, hydrogenation, and side chain reactions have been carried out [95, 96]. The synthesized benzimidazoles were assayed for their biocide, antihelmintic, antitumor, and anti HIV activity revealing compounds with identified activity. NH2

. 2HCl N

RCOOH

NH2

R N H

(147) R = 1-Ad; (148) R = o-C6H4Cl; (149) R = p-C6H4Cl; (150) R = CH2OPh

Condensation of compound 4-(1-Adamantyl)-1,2-diaminobenzene with carboxylic acids was carried out via heating the reagents in the ratios 1: 5 and 1: 10 in order to prepare the novel 5(6)-(1-adamantyl)benzimidazoles 147-150. Condensation of compound 4-(1-Adamantyl)-1,2-diamino-benzene with aromatic acids occurs at high temperature, e.g. in the case of p-chlorobenzoic acid at 230240ºC. Benzimidazolylcarbamates are widely used in the preparation of fungicide and antihelmintic preparations. They have prepared the adamantyl-substituted benzimidazolylcarbamate . NH2 NH2

ClCOOMe N

CaNCN

C

NHCOOMe pH 3, 95–100 oC

pH 12, 35–40 oC

N NHCOOMe N H

151

86


5(6)-(1-Adamantyl)-2-methoxycarbonylaminobenzimidazole (151) was synthesized in two stages. The optimum conditions found for the process were: stage 1, treatment of calcium cyanamide with methyl chloroformate at 35-40ºC and pH 12; stage 2, reaction of the N-cyanomethylcarbamate with compound 4(1-Adamantyl)-1,2-diaminobenzene at 90-100ºC and pH 3. The product 151 was obtained in 49% yield. In order to study the mobility of the methylene group protons of the 5(6)-(1adamantyl)-2-phenoxymethylbenzimidazole (150) they have condensed compound 150 with benzaldehyde at 175-179ºC and obtained the product 152 in 50% yield.

N CH2O N H

PhCHO

N

O

N H

150

152

They have further studied the nitration reaction of 5(6)-(1adamantyl)benzimidazole [95, 96]. The positive inductive effect of the adamantyl radical leads to an increase in electron density in the corresponding ortho positions, i.e. in positions 4 and 6 of the benzimidazole ring. This explains the formation of a mixture of isomers 153 and 154 as a result of the nitration reaction. We hope that the present review will be useful for organic chemists, who work in the field of chemistry of adamantane and heterocyclic compounds and in direction of purposeful synthesis of biologically active compounds.


87

NO2 N N

N H

HNO3/H2SO4

N H

30-35°C

153

N

154

85 N H

O2N 1) H2 , Ni 2) HCl

N H2N

N H

N

10% NaOH H2N

. 2HCl

N H

155

ACKNOWLEDGEMENT The designated project has been fulfilled by financial support of the Georgia National Science Foundation (Grant #GNSF/ST08/4-413). Any idea in this publication is passessed by the author and may not represent the opinion of the Georgia National Science Foundation itself We also would like to thank the Deutsche Academy Austausch Dienst (DAAD) for supporting the partnership and the exchange program between Ivane Javakhishvili Tbilisi State University and Saarland University.

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Chapter 3

METHODS OF SYNTHESIS OF PYRROLOINDOLES Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili, N. L. Targamadze Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT Two alternative methods of synthesis of unsubstituted pyrroloindoles have been worked out by Professor Sh. Samsoniya and his co-workers at Iv. Javakhishvili Tbilisi State University. According to the first method the attachment of pyrrole ring occurs to benzene ring of indoline; and pursuant to the second method two pyrrole rings are attached to benzene ring. In the both methods for formation of pyrrole rings is used Fischer reaction. In the first method the initial compounds are 5- and 6- aminoindolines. Their diazotization and further reduction gives the corresponging hydrazines, by condensation of which with pyruvic acid ethyl ether are obtained corresponding hydrazones, which in polyphosphoric acid ethyl ether (ppaee) undergo cyclization to yield mixture of angular and linear pyrroloindoline ethers, with great excess of linear isomers. By saponifying of ether with subsequent decarboxylation and simultaneous dehydration on pd/C are obtained fully aromatized, unsubstituted, isopmeric pyrroloindoles.

100

Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili et al. In the second method as initial compound is used m-phenylenediamine, by diazotization and subsequent reduction of which is obtained dihydrazine which condensate with pyruvic acid ethyl ether to yield the corresponding dihydrazone. Its cyclization in ppaee results the built of two pyrrole rings on benzene ring. The mixture of angular and linear pyrroloindole diethers is being formed, with great excess of angular isomers. The subsequent saponifying and decarboxylation of diethers result the corresponding unsubstituted pyrroloindoles. Electrophilic substitution reactions have been studied for all the four isomeric pyrrolo-indoles, particularly Vilsmeier-Haack, Mannich, azocoupling and acetylation reactions. Some conversions have been carried out in side chain in order to obtain biologically active compounds. The majority of obtained compounds have been tested on initial biological activity, such as bactericidal, tuberculostatic activities. Three compounds have revealed tuberculostatic activity.

INTRODUCTION Pyrroloindoles are major representatives of indole-containing polycyclic systems. Among pyrroloindole derivatives are found substances possessing high bactericidal, antimicrobial, antitumour activities and other valuable properties [13]. The highly active antitumour antibiotic CC-1065, molecule of which contains pyrroloindole fragment, was isolated in 1987 from Streptomyces zebensis. Its antitumour activity is many times greater than that of other known preparations [4]. This stimulated further development of synthetic methods for the preparation of pyrroloindoles. New methods of synthesis of isomeric pyrroloindole derivatives have been worked out at the department of Organic Chemistry at Iv. Javakhishvili Tbilisi State University 1-4:

Methods of Synthesis of Pyrroloindoles

101

HN

N H N H

N H 2

1 NH H N

N H

N H 3

4

The first method is based on bicyclization of ethylpyruvate m- and pphenylenedihydrazones with simultaneous closure of both pyrrole rings. The second involves the attachment of a pyrrole ring to the indoline ring. In the both methods for closure of pyrrole rings was used E. Fischer reaction. In the first method as initial compounds were used m- and pphenylenediamines. By diazocoupling of m-phenylenediamine with subsequent reduction and condensation of obtained m-phenylenedihydrazine [5] with pyruvic acid ethyl ether was synthesized subsequent m-phenylenedihydrazone 5 as a mixture of geometric isomers. The heating of dihydrazone 5 causes its bicyclisation and formation of isomeric pyrroloindoles of angular 6 and linear 7 structures [5,6]. The usage of polyphosforic acid ethyl ether (PPAEE) rises the yield of these isomers until 74% (65 and 9 % respectively) (Scheme 1). It is known that angular structure of multinuclear aromatic systems is energetically more advantageous than linear structure [7]. The hydrolysis of the diesters 6 and 7 afforded high yields of the corresponding dicarboxylic acids 8 and 9, thermal decarboxylation of which results the formation of corresponding unsubstituted heterocycles 1 and 2 [5,6]. Analogically from p-phenylenediamine was obtained pphenylenedihydrazone of pyruvic acid ethyl ether (10), the indolization of which is followed by resinification and the yield of corresponding pyrroloindole 11 was 8% (Scheme 2) [8].

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Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili et al.

CH3

H3C NH-N C

C N-HN 5 EtOOC

COOEt PPAEE

COOEt HN

EtOOC

COOEt

EtOOC

N H

N H

N H 7

6 COOH HN

HOOC HOOC

COOH N H

N H

N H 9

8 HN

N H

N H

N H 2

1

Scheme 1. CH3 EtOOC

NH-N C COOEt

1. OHNH

PPAEE

NH

2. - CO2

CH3 NH-N C 10

Scheme 2.

COOEt

EtOOC

N H

11

N H

3


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We have worked out the new method for synthesis of isomeric pyrroloindoles through the stage of formation of intermediate pyrroloindoline derivatives, which is based on application of N-acetyl-5- and N-acetyl-6-aminoindolines. This method enables not only yield upgrade but conversion of linear isomer in main product of the reaction as well (schemes 3 and 4). CH3 NH-NC COOEt

N COCH3

12

COOEt H N

NH

N COOEt

H3COC

N

14 13

H3COC MnO2

MnO2 H N

COOEt COOEt

N

NH

N H3COC

15

H3COC

16

H N

COOH COOH

NH

HN

N H 17 18

H N HN N H

3 4

Scheme 3.

NH

104


CH3 N H3COC

NH-N C 19

COOEt COCH3 N

EtOOC COOEt N

HN

N H

H3COC

21

20

MnO2

MnO2

COOEt N

N H

H3COC

COCH3 N

EtOOC HN

22

23

COOH N H

N H

HOOC

H N

HN

24

H N N H

N H 2

Scheme 4.

HN 1


105

CH3 NH-N C COOEt

N COCH3

12

COOEt H N

NH COOEt N

N 13

H3COC

14

H3COC MnO2 H N

COOH NH

COOH N H

N H

H N N H

4

NH

N H

3

Scheme 5.

By diazocoupling of 5- and 6-aminoindolines with subsequent reduction and condensation of hydrazines with pyruvic acid ethyl ether were synthesized subsequent hydrazones 12 and 19 as a mixture of sin- and anti-isomers [9]. Cyclisation of hydrazones 12 and 19 in PPAEE affords the formation of mixture of linear, 13 and 20, and angular, 14 and 21, pyrroloindoles. In the both reactions overall yield of the cyclisation products was 75% and the main products of the reaction were linear isomers 13 and 20. The subsequent dehydration of ethers 13, 14, 20 and 21 was carried out by means of manganese dioxide in boiling acid. The hydrolysis of obtained esters 15,

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16, 22 and 23 by aqueous alkali and by decarboxylation of corresponding acids were obtained unsubstituted pyrroloindoles 1-4. For further conversion of compounds 13 and 14 in corresponding unsubstituted pyrroloindoles we worked out new method comprising simultaneous decarboxylation and dehydration on the last stage of the synthesis (scheme 5). Further we learned electrophylic substitution reactions of pyrroloindoles. Pyrroloindoles are representatives of π- redundant aromatic systems. For this reason for them are characteristic reactions with weak and moderate elecrophyles, such as Mannich, Vilsmeier, azo-coupling and other [10-14]. The effect of different types of condensation of the pyrrole and indole rings on the specific features of electrophilic substitution was of definite interest. Furthermore, the study of the above reactions was also of practical importance, since some of the pyrroloindole derivatives themselves possess physiological activity or can be used in the syntheses of other physiologically active substances. R HN

CH2NMe2

Me2NH2C CH2-NMe2

Me2N-H2C N H R

N H

27

N H

25 R=H, 26 R=COOEt

Me2N-H2C NH

Me2NH2C

H N

Me2N-H2C N H N H Scheme 6.

28

29

CH2NMe2


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Among the indole Mannich bases, the alkaloid gramine (3dimethylaminomethylindole) and its derivatives have found the most extensive applications. They are valuable intermediate products in the synthesis of different important compounds – heteroauxine, tryptophane, and the series of tryptamines. In order to obtain bis-analogues of gramine the amynomethylation of pyrroloindoles was carried out by freshly prepared Mannich base (dimethylamine, formaldehyde, acetic acid). During this process the formation of difficult-to-pump goal products was observed. The desired result was achieved by using crystal Mannich reagent – dimethylmethyleneimmonium chloride [15]. In this case bisgramine 25-29 were formed in a high yield (scheme 6). For investigation of biological activity, the synthesized bifunctional gramine analogues were converted into the corresponding dihydrochlorides and dimethylsulphates. Continuing the study of electrophylic substitution in pyrroloindoles ring we decided to learn Vilsmeier reaction in this series. The formylation of the pyrroloindoles by the dimethylformamide/POCl3 complex proceeds easily. When the reaction is carried out in the presence of a threefold excess of the Vilsmeier reagent at room temperature, the hydrogen atoms in the β-position in the pyrrole rings are substituted. The dialdehydes 30-33 are formed in high yields (scheme 7). O

O

H

O

HN

O

H

C

C

N H

N H

H

C

N H

31

30

O

H

O

C

H

O H

C

H N

NH C N H N H

Scheme 7.

H

C

C 33

32

H

O

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In 1H,6H-pyrrolo[2,3-e]indole (1), the reactivity of the β-positions in the two different pyrrole rings are not the same. Substitution in the 8-position is difficult owing to shielding by the neighbouring pyrrole ring. It was interesting to elucidate how these factors influence the electrophylic substitution reaction for an equimolar reactant ratio. It was established that three monosubstituted products are formed: 3-, 8- and 2-formylpyrroloindoles 34-36 (Scheme 8) [16]. The formylation of 2,7-diethoxycarbonyl-1H,6H-pyrrolo[2,3-e]indole (6) in the presence of 5-fold excess of Vilsmeier reagent proceeds at 750C with formation of 3,8-diformylderivative 37 [14]. The formylation of 2,6-diethoxycarbonyl-1H,7H-pyrrolo[3,2-f]indole (7) proceeds anomalously. Mainly the hydrogen atoms of the benzene ring are substituted forming 4-formylderivative 38 (scheme 8). In order to compare reactivity of different positions of 1H,6H-pyrrolo[2,3e]indole (1)a more selective electophile was used in the Vilmeier reaction – a complex based on dimethylacetamide and POCl3. With this complex pyrroloindole 1 affords four acetylderivatives 39-42 (scheme 9) [13]. The main product in this case is also 3-acetylderivative (39). The acetylation of pyrroloindole 3 affords 1-acetylderivative 43 with high yield (scheme 9). O

HN

H

O C

C

O C

HN

HN

H N H

N H 34 (42%)

N H 35 (34%)

36 (5%)

COOEt O

H

HN

C

O C H

EtOOC

N H

N H C

N H

H 37

Scheme 8.

COOEt

EtOOC

O

38

H


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The acetylation of linear pyrroloindoles using the Vilmeier method ends with tarring, which is connected with necessity to carry out the reaction at elevated temperatures; it shows that angular pyrroloindoles are more stable than linear. In the series of pyrroloindoles was also studied azo-coupling reaction. Aryldiazonium salts are typical weak electrophiles. They are sensitive to small differences in the reactivities of substrates. Phenyldiazonium, p-chloro- and p-nitrophenyldiazonium chlorides were usede as the diazo-components. Complex mixture of the reaction products is formed in all cases of azo-coupling of pyrroloindoles 1-4, from which it was possible to isolate only one product (probably the main one). Others, due to their instability, decompose during the purification. In the azo-coupling of linear pyrroloindoles 2 and 4, mainly the formation of disubstituted products 44-46 and 48 was observed. After the azo-coupling of angular isomers 1 and 3, mainly monosubstituted derivatives 49, 50, 52 and 53 were isolated. In this case, the neighbouring pyrrole ring probably exerts a steric influence (scheme 10) [10-12]. Thus in isomeric pyrroloindoles in the interaction with weaker electophiles βpositions of the pyrrole ring are more reactive and mainly disubstituted products are formed. It has been established that the β-positions of both pyrrole rings in linear pyrroloindoles are equally reactive. In angular isomers steric factors have great influence on electrophylic substitution reactions (azo-coupling reaction and Vilmeier acetylation), mainly monosubstituted products are formed. The reduced reactivity of the system is also due to the introduction of an electron-accepting substituent. HN COCH3 N H

H3COC

COCH3

HN

HN

N H 39 (34%)

H3COC

N H 41 (9%)

40 (19%)

HN

H3COC NH

COCH3 N H

N H 42 (6%)

Scheme 9.

43

110


R-C6H4-N=N

N H

44 R=H;

R'

N=N-C6H4-R

N H 45 R=Cl; 46 R=NO2;

HN N=N-C6H4-R

N H 49 R=R'=H; 50 R=Cl, R'=H;

R'

H N N H

N=N-C6H4-R

47 R'=H, R=NO2; 48 R=H, R'=N=N-C6H5;

R-C6H4-N=N NH N H 52 R=Cl;

53 R=NO2

51 R=Cl, R'=N=N-C6H4-Cl

Scheme 10.

On the basis of acetylation reaction it could be assumed that angular pyrroloindoles are more stable than their linear isomers. In order to obtain biologically active compounds were carried out some conversions in side of synthesized pyrroloindoles, also reactions on the basis of 3,8-diformyl-1H,6H-pyrrolo[2,3-e]indole (30) and its 2,7diethoxycarbonylderivative (37). As a result of condensation of 30 with some CH-acids (nitromethane, nitroethane, acetone and malonic acids), also with aniline (scheme 11), were obtained compounds 54-60 which apart from functional groups contain multiple bond, what gives additional possibility for synthesis of new and interesting compounds from different points of view. The formyl group in position 8 reveals weak reactivity and as a result of mentioned reaction was observed mainly formation of monocondensation compounds by means of group in 3 position [17].

Methods of Synthesis of Pyrroloindoles R

HN

OHC

C C NO2 H

R R H C C NO2

HN

O2N C CH

CH3COONH4

RCH2NO2

N H

HN

OHC

54,55 N H

FA DM , O2 H4 H 2N ON RC CO 3 H C

56,57

HN

OHC

CH2(COOH)2 CHO

N H

C5H5N 3 CO

CH=CH-COOH N H

CH 2 NH H5 C6

30

111

58

CH

3

OHC

HN CH=CH-COCH3

OHC

HN

N H CH=N-C6H5

N H

59

60

54,56 R=H; 55,57 R=CH3

Scheme 11.

Interaction of 2,7-diethoxycarbonyl-3,8-diformyl-1H,6H-pyrrolo[2,3-e]indole (37) with hydrazinehydrate affords corresponding dihydrazone 61, which by boiling, without isolation, in glacial acetic acid transforms into new fivenuclei bispyrridazinopyrroloindole. The last one is not formed as expected dioxoderivative 62, but as corresponding totally aromatic dihydroxyderivative 63, what is probably connected with more energetical stability of the last (scheme 12) [14]. The structure of the synthesized compounds was established by means of IR-, UV-, 1H NMR- and Mass-spectral methods.

112

Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili et al. COOEt OHC

COOEt

HN CHO

NH2-NH2

EtOOC

H2N-N=HC

HN CH=N-NH2

EtOOC N H

HN

N H

37

N H N

O HN

N

O NH N

61

N H N

HO HN

OH N N

63

62

Scheme 12.

EXPERIMENTAL PART The IR spectra were recorded on a Thermo Nikolet FTIR photometer ―AVATAR 370‖ in vaseline oil; UV-spectraon spectrophotometer ―Specord‖ (Germany) in ethanol, 1H NMR-spectraon spectrometer CTF-20 Varian (V0=80 MHz, inner standard –TMS and on spectrometer Bruker 500 and Bruker 300, inner standard –TMS. Mass-spectra were registrated on device MX-1303, energy of ionizing electrons 70eV. The reaction procedure and compounds purity monitoring, and also establishment of Rf were accomplished by means of TLC on Silufol UV-254; as a sorbent for chromatographic column was used silica gel with the size of particles 100-250 µm or aluminum oxide. The values of elemental analysis of obtained compounds correspond the calculated ones. 2,7-Diethoxycarbonyl-1H,6H-pyrrolo[2,3-e]indole (6) and 2,6diethoxycarbonyl-1H,7H-pyrrolo[3,2-f]indole (7). To the heated until 600C 100g of polyphosphoric acid ethyl ethers was added 10,69 g (32 mmole) mphenylenedihydrazone of pyruvic acid ethyl ether (PAEE). Solution was mixed and heated till 70-800C during 20 min. Solution then was cooled and poured into water. Precipitate was filtered off, washed with water until neutral reaction and dried. The reaction product was treated with boiling isopropyl alcohol (3x50ml). The residue was compound 6. Yield 5.85 g (61%). Was purified on column,


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eluent benzene-ether (10:1). Rf 0.52 (benzene-ethylacetate, 5:1) Тmelt. 266-2670С, what corresponds the literary data [5]. The filtrate was evaporated and purified on chromatographic column, eluent benzene-diethyl ether, 10:1. From eluate with Rf 0.52 (benzene-acetone, 5:1) was extracted 0.38 g (4%) of compound 6. From eluate with Rf 0.55 (benzene-ethylacetate, 3:1) was extracted 0.76 g (8%) of compound 7. Тmelt.. 227-2280С, what corresponds the literary data [6]. 5-Acetyl-2-ethoxycarbonyl-6,7-dihydro-1H,5H-pyrrolo[2,3-f]indole (13) and 6-acetyl-2-ethoxycarbonyl-7,8-dihydro-3H,6H-pyrrolo[2,3-f]indole (14). Was obtained similarly to compounds 6 and 7 from 30 mmole of 1-acetyl-5indolinylhydrazone PAEE (12). Integrated yield of compounds 13 and 14 was 74%. Was purified on column, eluent benzene-ether (5:1). From eluate with Rf 0.14 ((benzene-acetone, 9:1) was extracted 5.3 g (65%) of compound 13. Тmelt. 261-2620С, what corresponds the literary data [9]. Isolation of compound 14 was not managed. 5-Acetyl-2-ethoxycarbonyl-1H,5H-pyrrolo[2,3-f]indole (15) and 6-acetyl-2ethoxy-carbonyl-3H,6H-pyrrolo[3,2-e]indole (16). 1g mixture of compounds 13 and 14, 4g MnO2 in 100ml xylene was boiled for 24 hours. The reaction mixture was filtered off, xylene evaporated. Yield 0,75g (75%). The separation of this mixture was carried out on column in order to obtain individual compounds. Eluent hexane-ether (3:1). From eluate with Rf 0.44 (hexane-ether, 1:1) was extracted 0,6 g (60%) of compound 15. Тmelt.. 225-2260С. IR spectrum, v, cm-1: 3330 (NH), 1680,1650 (CO). UV spectrum, λ max, nm (lgε): 208 (4.28), 281 (4.36), 312 (4.29), 323 (4.40), 340 (4.17), 358 (4.06). 1H NMR spectrum (in DMSO-D6), δ, ppm (J,Hz): 11,40 b.s. (1-Н), 7,19 d.d. (3-Н), 8,58 m (4-Н), 7,71 d (6-Н), 6,70 d.d. (7-Н), 7,55 d.d. (8-Н), 2,59 s (СО-СН3), 4,33 q СН2-ethyl), 1,35 t (СН3-ethyl), J13=1,8, J14= J38=J47=J48=0,7, J67=3,6 Hz. Found, %: С 67,07; Н 5,72; N 10,36. С15Н14 N2О3. Calculated, %: С 66,66; Н 5,22; N 10,36. From eluate with Rf 0.48 (hexane-ether, 1:1) was extracted 0,1 g (10%) of compound 16. Тmelt.. 202-2030С. IR spectrum, v, cm-1: 3320 (NH), 1710,1690 (CO). UV spectrum, λ max, nm (lgε): 208 (4.28), 225.5 (4.37), 233 (4.42), 278 (4.01), 312 (4.37), 325 (4.51), 336 (4.45). 1H NMR spectrum (in DMSO-D6), δ, ppm (J,Hz): 11,70 b.s.(3-Н), 7,36 d.d (1-Н), 7,35 d.d. (4-Н), 8,28 d.d. (5-Н), 7,74 d (7-Н), 6,96 d.d. (8-Н), 2,64 s (СО-СН3), 4,33 q (СН2-ethyl), 1,36 t (СН3-ethyl), J13=1.8, J14=J58=0.5, J45= 9.1, J78= 3.6 Hz. Found, %: С 67,0; Н 5,50; N 10,38. С15Н14N2О3. Calculated, %: С 66,66; Н 5,22; N 10,36. 2-Oxycarbonyl-1H,5H-pyrrolo[2,3-f]indole (17). To the solution of 6 g KOH in 60 ml H2O was added 1.34 g (5 mmole) 2-ethoxycarbonyl-5-acetyl-1H,5Hpyrrolo[2,3-f]indole (15). The solution was boiled and mixed for 2 hours, then cooled, filtered and acidified by acetic acid until pH 5, filtered off, washed with

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water and dried. 0,6 g (81%). Rf 0.42 (ether). Тmelt.. 2450С (decomp). IR spectrum, v, cm-1: 3430, 3410 (NH), 1680 (CO). UV spectrum, λ max, nm: 206, 222, 244, 322. 1H NMR spectrum (in DMSO-D6), δ, ppm (J,Hz): 11,60 b.s. (1-Н), 6,89 d (3Н), 7,44 d.d. (4-Н), 10,40 b.s. (5-Н), 7,21 d.d. (6-Н), 6,32 m (7-Н), 7,44 m (8-Н), J47=J58=0.7, J38=0.5, J56=2.7, J57=2.0, J67=3.2 Hz. Found, %: С 65,07; Н 4,27; N 13,42. С11Н8 N2О2. Calculated, %: С 65,66 Н 4,51; N 13,92. 2-Oxycarbonyl-3H,6H-pyrrolo[3,2-e]indole (18). Is obtained similarly to compound 17 from 5 mmole 2-ethoxycarbonyl-6-acetyl-3H,6H-pyrrolo[3,2e]indole (16). Yield 0,55 g (74%). Rf 0.36 (ether). Тmelt. 264-2650С. IR spectrum, v, cm-1: 3440, 3425 (NH), 1670 (CO). UV spectrum, λ max, nm(lgε): 215 (4.44), 252 (4.12), 322 (4.32). 1H NMR spectrum (in DMSO-D6), δ, ppm (J,Hz): 7,20 d.d. (1-Н), 11,30 b.s. (3-Н), 7,30 d.d. (4-Н), 7,13 d.d. (5-Н), 10,8 b.s. (6-Н), 7,20 d.d. (7-Н), 6,61 m (8-Н), J13=1.6, J58=0.3, J14=0.6, J67=2.2, J45=8.8, J78=3.0, J68=1.9 Hz. Found, %: С 65,71; Н 4,35; N 13,62. С11Н8 N2О2. Calculated, %: С 65,66 Н 4,51; N 13,92. 1H,5H-pyrrolo[2,3-f]indole (4). Method A 1g (0,005 mole) 2-oxycarbonyl-1H,5H-pyrrolo[2,3-f]indole (17) was heated during 5 minutes, cooled. The product was extracted with acetone and purified on column. Eluent benzene. Rf 0.5 (benzene). Yield 0,3 g (19%). Тsubl. 199-2000С (according the literary data 199-2000С [9]). Method B. Was obtained by saponification of 10 g mixture of ethers 13 and 14 with 20 g KOH solution in 80 ml H2O in presence of 0,2 g NaHSO3. The reaction mixture was boiled in nitrogen flow for 2 hours. Then cooled, filtered and acidified by acetic acid until pH 5 at 00C. The precipitate was filtered, washed with water and dried. 6,9g (93%) mixture of acids (scheme 5) was obtained. 2g mixture of acids 17 and 18 and 0,7g 10% Pd/C were heated in a test tube for 5 minutes in a torch flame until termination of discharge of white vapor. After cooling, products 3 and 4 were extracted with acetone and separated on column. Eluent benzene. From fraction with Rf 0.5 (benzene) was extracted 0.28 g (18%) of compound 4. From fraction with Rf 0.56 (benzene-acetone, 3:1) was extracted 0.35 g (22%) of compound 3. 3H,6H-pyrrolo[3,2-e]indole (3) was also obtained according the method A described for compound 4 by decarboxylation of 0,005mole of 2-oxycarbonyl3H,6H-pyrrolo[3,2-e]indole (18). Выход 0,4 г (25,6%). Rf 0.56 (benzene-acetone, 3:1). Тmelt. 80-810С (according the literary data 80-810С [8]). 7-acetyl-2-ethoxycarbonyl-5,6-dihydro-1H,7H-pyrrolo[3,2-f]indole (20) and 1-acetyl-7-ethoxycarbonyl-2,3-dihydro-1H,6H-pyrrolo[2,3-e]indole (21) were obtained using the method described for compounds 6 and 7 from 30 mmole 1-


115

acetyl-6-indolinylhydrazone (19). Yield 7.13 g (75%). The mixture of compounds 20 and 21 was separated on the column. Eluent benzene-acetone, 6:1. From eluent with Rf 0.25 (benzene-acetone, 9:1) was extracted 1.3 g (12%) of ether 21. Тmelt. 185-1860С. IR spectrum (vaseline oil), ν, cм-1 : 3320 (N-Н), 1730, 1620 (С=О). UV-spectrum, мах, nm (lg ): 204.5 (4.14); 245 (4.43); 294 (4.08); 306 (4.19); 340 (3.84). NMR spectrum 1Н (Ме2CO-D6), δ, ppm (J, Hz): 1.33 (3Н, t, J=7.0, СН3-СН2-О); 2.20 (3Н, s, СН3-СО); 3.22 (2Н, t, J=8.1, СН2-СН2-N); 4.12 (2Н, t, J=8.1, СН2-СН2-N); 4.27 (2Н, q, J=7.0, СН3-СН2-О); 7.09 (1Н, d.d., J4,5=8.6, J5,8=0.7, Н-5); 7.29 (1Н, d, J4,5=8.6, Н-4); 7.62 (1Н, d.d., J5,8=0.7, J6,8=1.6, Н-8); 11.40 (1Н, w.s., Н-6). Found, %: С 66.5; Н 6.1; N 10.1; m/z 272 [М]+; С15Н16N2О3. Calculated, %: С 66.16; Н 5.92; N 10.29; М=272,2991. Fraction with Rf 0.14 (benzene-acetone, 9:1) contains 6 g (63%) of ether 20. Тmelt. 291-2920С. IR spectrum (vaseline oil), ν cм-1: 3230 (N-Н), 1760, 1690 (С=О). UV-spectrum, мах, nm (lg ): 202 (4.27); 205. (3.39); 229.8 (4.20); 252 (4.25); 260. (4.02); 311. (4.02); 328 (4.27); 339 (4.32). NMR spectrum 1Н (DMSO-D6), δ, ppm (J, Hz): 1.34 (3Н, t, J=7.1, СН3-СН2-О); 2.19 (3Н, s, СН3СО); 3.20 (2Н, t, J=8.3, СН2-СН2-N); 4.14 (2Н, t, J=8.3, СН2-СН2-N); 4.30 (2Н, q, J=7.1, СН3-СН2-О); 6.95 (1Н, d.d., J5,7=1.8, J5,8=0.8, Н-5); 7.32 (1Н, d, J4,8=0.7, Н-4); 8.20 (1Н, m, Н-8); 11.34 (1Н, w.s., Н-7). Found, %: С 66.5; Н 6.0; N 10.2; m/z 272 [М]+; С15Н16N2О3. Calculated, %: С 66.16; Н 5.92; N 10.29; М=272,2991. 7-Acetyl-2-ethoxycarbonyl-1H,7H-pyrrolo[3,2-f]indole (22) was obtained using the method described for compounds 15 and 16 from 4 mmole 7-acetyl-2ethoxycarbonyl-5,6-dihydro-1H,7H-pyrrolo[3,2-f]indole (20). Was purified on column. Eluent benzene-acetone, 3:1. Yield 0,7 g (70,5%). Tmelt. 228-2290С. Rf 0,6 (benzene-acetone, 3:1). IR spectrum, ν см-1: 3260 (NH), 1720, 1685 (C=O). UV-spectrum, λmax, nm, (lgε): 207 (4,51), 219 (4,18), 244 (4,12), 278. (4,39), 288 (4,48), 322 (4,05). NMR spectrum (DMSO-D6), δ (ppm), J (Hz): 11,50 b.s. (1-Н), 7,14 d.d. (3-Н), 7,74 d.d. (4-Н), 6,68 d.d. (5-Н), 7,66 d (6-Н), 8,47 m (8-Н), 2,59 s (СО-СН3), 4,33 q (СН2-ethyl), 1,34 t (СН3-ethyl), J13=1.8, J14=0.4, J38=0.6, J48=0.8, J58=0.3, J56=3.3 Hz. Found, %: С 66,37; Н 5,17; N 10,34. С15Н14N2О3. Calculated, %: С 66,66; Н 5,22; N 10,36. 1-Acetyl-7-ethoxycarbonyl-1H,7H-pyrrolo[2,3-e]indole (23) was obtained using the method described for compounds 15 and 16 from 4 mmole 1-acetyl-7ethoxycarbonyl-2,3-dihydro-1H,6H-pyrrolo[2,3-e]indole (21). Was purified on column. Eluent ether- petroleum ether, 1:3. Yield 0,8 g (80,6%). Tmelt. 190-1910С. Rf 0,55 (benzene-acetone, 3:1). IR spectrum, ν см-1: 3420, 3360 (NH), 1710 (C=O). UV-spectrum, λmax, nm, (lgε): 206 (4,43), 220 (4,33), 242 (4,47), 270 (4,59), 315 (4,28). NMR spectrum (DMSO-D6), δ (ppm), J (Hz): 7.61 d (2-Н),

116


6.73 d (3-Н), 7.46 s (4-Н), 7.46 d (5-Н), 11.0 b.s. (6-Н), 8.10 d.d. (8-Н), 2.75 s (СО-СН3), 4.36 q (СН2-ethyl), 1.38 t (СН3-ethyl), J58=0.7, J23=3.7, J68=2.0 Hz. Found, %: С 66,04; Н 5,22; N 10,53. С15Н14N2О3. Calculated, %: С 66,66; Н 5,22; N 10,36. 2-Oxocarbonyl-1H,7H-pyrrolo[3,2-f]indole (24) was obtained using the method described for compound 17 by saponification 5 mmole of 7-acetyl-2ethoxycarbonyl-1H,7H-pyrrolo[3,2-f]indole (22). Was purified on column. Eluent ether. Yield 0,58 g (78,3%). Tmelt. 2400С (decomp). Rf 0,2 (ether). IR spectrum, ν см-1: 3320 (NH), 1720, 1680 (C=O). UV-spectrum, λmax, nm, (lgε): 212 (4,27), 250 (4,28), 273 (4,11), 327 (4,14). NMR spectrum (DMSO-D6), δ (ppm), J (Hz): 10.8 b.s (1-Н), 7.05 d.d. (3-Н), 7.33 d.d. (4-Н), 6.36 m (5-Н), 7.21 d.d. (6-Н), 10.40 b.s. (7-Н), 7.68 m (8-Н), J13=2.2, J14=0.9, J38= J58=0.8, J57=1.9, J48=1.0, J56=3.0, J67=2.4 Hz. Found, %: С 65,90; Н 4,28; N 13,89. С11Н8N2О2. Calculated, %: С 65,66 Н 4,51; N 13,92. 1H,7H-pyrrolo[3,2-f]indole (2) was obtained using the method A described for compound 4 from 0,01mole 2-oxocarbonyl-1H,7H-pyrrolo[3,2-f]indole (24). Tmelt 215-2160C what corresponds the data [6]. 1H,6H-pyrrolo[2,3-e]indole (1) was obtained by saponification 7 mmole of 1-acetyl-7-ethoxycarbonyl-1H,6H-pyrrolo[2,3-e]indole (23) using the method described for compound 17 and subsequent decarboxylation using the method described for compound 4. Tmelt 134-1350C what corresponds the data [5].

ACKNOWLEGEMENT The designated project has been fulfilled by financial support of the Georgian National Science Foundation (Grant № GNSF/ST07/4-181). Any ideas of this publication possess authors and may not represent the opinion of the Georgian National Science Foundation itself. We also would like to thank the Deutsche Akademische Austausch Dienst (DAAD) for supporting the partnership and the exchange program between Ivane Javakhishvili Tbilisi State University and Saarland University.


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REFERENCES [1]

[2] [3] [4] [5]

[6] [7]

[8] [9] [10]

[11]

[12] [13] [14]

[15] [16]

Sh.A. Samsoniya, M.V. Trapaidze, N.L. Targamadze. I.Sh. Chikvaidze, N.N.Suvorov, N.N.Ershova, V.A. Chernov, Soobshch. Akad. Nauk Gruz. SSR, 100, 337 (1980). Sh.A. Samsoniya, B.A. Medvedev, D.O. Kadzhrishvili, D.M. Tabidze, M.D. Mashkovskii, N.N.Suvorov, Khim-Farm. Zh., (Russian), 1335 (1982) Sh.A. Samsoniya, Z. Sh. Lomtatidze, S.V. Dolidze, N.N.Suvorov, KhimFarm. Zh., (Russian), 1452 (1984). V.H. Rawal, R.J. Jones, M.P. Gava, Heterocycles, 25, 701 (1987). Sh.A. Samsoniya, N.L. Targamadze, L.G. Tret’yakova, T.K. Efimova, K.F. Turchin, I.M. Gvertsiteli, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 938 (1977). Sh.A. Samsoniya, N.L. Targamadze, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 849 (1980). N.N.Suvorov, T.K. Sergeeva, A.N. Gryaznov, V.P. Shabunova, L.G. Tret’yakova, T.K. Efimova,, I.A. Morozova, R.I. Akhvlediani, A.N. Vasil’ev, T.K. Trubitsina, Tr. Mosk. Khim. Tekhnol. Inst. Im. D.I. Mendeleeva, 94 23 (1977). Sh.A. Samsoniya, D.O. Kadzhrishvili, N.N.Suvorov, Khim. Geterotsikl. Soedin. 268 (1981). Sh.A. Samsoniya, D.O. Kadzhrishvili, Gordeev E.N., Zhigachev V.E., Kurkovskaya L.N., N.N. Suvorov, Khim. Geterotsikl. Soedin., 504 (1982). Sh.A. Samsoniya, N.L. Targamadze, L.N. Kurkovskaya, Dzh.A. Kereselidze, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 639 (1980). D.O. Kadzhrishvili, Sh.A. Samsoniya, E.V. Gordeev, L.N. Kurkovskaya, V.E. Zhigachev, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 1219 (1984). Sh.A. Samsoniya, D.O. Kadzhrishvili, Gordeev E.N., N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 1219 (1984). Sh.A. Samsoniya, N.L. Targamadze, T.A. Kozik, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 723 (1977). N.L. Targamadze, N.Sh. Samsonia, D.O. Kadjrishvili, I.Sh. Chikvaidze, Sh.A. Samsoniya, A. Wesquet, U. Kazmaier, Proc. Georg. Acad. Sci., Chem. ser., 2008, v. 34, № 1, p. 35-39. G. Kinast, L-F Tietze, Angew. Chem. 88 261 (1976). Sh.A. Samsoniya, Z.Sh. Lomtatidze, S.V. Dolidze, N.N. Suvorov, KhimFarm. Zh., (Russian), 1452 (1984).

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[17] S.V. Dolidze, Sh.A. Samsoniya, N.N. Suvorov, Khim. Geterotsikl. Soedin., (Russian), 608 (1983).


Chapter 4

PALLADIUM-CATALYZED AMINATION OF DIHALOARENES: A SIMPLE AND EFFICIENT APPROACH TO POLYAZAMACROCYCLES Alexei D. Averin,1, Alexei N. Uglov,1 Alla Lemeune,2 Roger Guilard,2 Irina P. Beletskaya1 1

Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, Moscow, 119991 Russia 2 Institut de Chimie Moléculaire de l’Universite de Bourgogne, ICMUBLIMRES 5260, 9 av. Alain Savary, 21078 Dijon, France

ABSTRACT The following aryl halides were used in the synthesis of previously unknown polyaza- and polyazapolyoxamacrocycles using Pd-catalyzed amination reactions: 1,2and 1,3-dibromobenzenes, 2,6dichlorobromobenzene, 2,6- and 3,5-dihalopyridines, 3,3'- and 4,4'dibromobiphenyls, 1,8- and 2,7-dibromonaphthalenes, 1,8- and 1,5dichloroanthracenes and anthraquinones. Following linear amines were employed in this process: 1,3-diaminopropane, tri-, tetra-, penta- and hexaamines, di- and trioxadiamines. Significant dependence of the results of the amination reactions on the nature of starting compounds was established. The best results were achieved using 1,3-dibromobenzene which provided yields up to 56%. Target macrocycles containing one arene and one

120

Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al. polyamine moiety were often obtained together with cyclodimers and cyclooligomers of higher masses. We elaborated two alternative approaches to cyclodimers which are also valuable macrocycles possessing larger cavity size: (a) via bis(haloaryl) substituted polyamines and (b) via bis(polyamine) substituted arenes, and demonstrated that the applicability of these methods strongly depended on the nature of the pair aryl halide/polyamine. Scope and limitations for the synthesis of various polyazamacrocycles were established.

INTRODUCTION Polyazamacrocycles (or azacrown ethers) attract a thorough and constant interest of the researchers due to their unique ability of selective complexation of various metals, organic and inorganic anions, and some polar molecules. During the last decades hundreds of such compounds were synthesized, which contain nitrogen, oxygen, and sulfur atoms [1]. Many polyazamacrocycles can serve as molecular sensors due to their photochemical or redox properties, they contain aromatic moieties which can be present as substituents at nitrogen atoms or can be incorporated in the cycle. Substantial interest was evoked by the synthesis and coordination properties of different polyazamacrocycles which possess pyridine moiety in the macrocyclic ring [2-14]. This pyridine fragment strongly influences the thermodynamic properties and the complexation kinetics by increasing the conformational rigidity of the ligand and by changing its basicity. In almost all known macrocycles of such type, nitrogen atoms of the polyamine chain and pyridine ring are separated by methylene, methyne or carbonyl groups: a single compound with C(sp2)-N bond was obtained by reduction of the corresponding diamide formed from 2,6-diaminopyridine and bis(acylchloride) [15]. Recently, the synthesis of a number of pyridine-containing macrocycles by the reaction of dimethylpyridine-2,6-dicarboxylates has been reported [16]. Macrocycles containing biphenyl units became a constant interest of researchers due to interesting coordination possibilities of attaching flexible and tunable polyoxa- and polyazacycles to a rigid non-planar aryl moiety. The most of reported macrocycles based on biphenyls were synthesized using non-catalytic approaches. Cyclic polyethers were formed starting from 2,2'-dihydroxybiphenyl [17-19], and studied in coordination with cations like tert-butylammonium [18]. Transport of Li, Na, K cations [20, 21] and of Hg(CF3)2 [22, 23] through a liquid membrane was studided using macrocycles of similar structure, in which one or two polyoxaethylene chains are attached to one biphenyl unit.

Palladium-catalyzed Amination of Dihaloarenes

121

Polyoxadiaminomacrocycles were also synthesized on the basis of 2,2’disubstituted biphenyl and their complexation of primary alkylammonium salts, including chiral ones, was studied [24]. Polyazamacrocycles with 3, 4 and 8 nitrogen atoms were investigated as complexing agents for Cu2+, Zn2+ and [PdCl4]2- ions [25]. More complex macrocycles like peptide-biphenyl hybride [26] and hemispherand macrocycle [27] with bi-and quaterphenyl moieties have been recently reported. Cyclic triamides [28] as well as cyclic Schiff bases (trianglimines) [29, 30] are less known represenattives comprising three 3,3’disubstituted biphenyls, the latter can be also built on the basis of 4,4’disubstituted biphenyls. In some cases macrocycles containing this fragment were synthesized using Pd-catalyzed coupling of two benzene moieties at the last step, as it was in the case of the macrocycle with diazacrown, dipeptide and biphenyl fragments [31]. It is to be mentioned that biphenyls are incorporated in some biologically active compounds, e.g. tricyclic glucopeptides of vancomicine group [32]. Several examples of macrocycles with aromatic fragments were known for decades. The first simplest representatives of the macrocycles containing naphthalene unit were described in the literature 70 years ago [33]. Since that time dozens of works appeared dealing with the synthesis and investigation of naphthalene-based macrocycles of different geometry and with crown ethers functionalized with naphthalene substituents in pendant arms. These macrocycles may possess structural fragments of Schiff bases [34], diamide [35], diimide [36], or lactam [37] groups, naphthalene can be fused to tetraazamacrocycles [38], the molecules may contain phosphorus atoms [39] or have only carbon atoms in the macroring [40]. Naphthalene moieties were also incorporated in more complicated structures like calixarenes [41], catenanes [42], they were combined in defferent manner with porphyrin units [43]. These sophisticated molecules find their application as molecular receptors, mainly of organic anions [44], or even as molecular rotors [45]. The main problem of the synthesis of the macrocycles with aromatic linkers is the use of laborious multistep methods which result in rather low yields of the target products [46-49]. In the majority of cases aromatic groups are separated from the nitrogen atom at least by one methylene or methine group [50-55]. Therefore it was thought important to elaborate an easy synthetic route to such macrocycles, and the aim of this chapter is to demonstrate how Pd-catalyzed amination may serve to solve this problem.

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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.

1. MACROCYCLES ON THE BASIS OF 1,2-DISUBSTITUTED BENZENE Our preliminary investigations revealed that linear polyamines reacted with aryl halides in the following manner: while primary amino groups readily participated in the Pd-catalyzed amination reaction, secondary amino groups were totally inert [56-58]. This fact led us to an idea to use diamination of dihaloarenes with linear polyamines in order to obtain polyazamacrocycles containing disubstituted arene moieties. In these reactions the first step is normal Pdcatalzyed amination while the second step is intramolecular substitution of the second halogen atom. This process should be obviously more difficult due to the donor nature of the first introduced amino group, moreover, it may lead to various by-products – cyclic and linear oligomers. By changing the nature of starting compounds, catalytic systems and conditions we can regulate this process and achieve enough high yields of desired macrocycles. First we tried to employ the simplest dihaloarene – 1,2-dibromobenzene 1 in the reactions with tetraamine 2a and trioxadiamine 2b, in order to obtain macrocycles with ortho-disubstituted benzene as an aromatic spacer [59, 60]. Equimolar amounts of starting compounds were taken, and the catalytic system Pd(dba)2/BINAP (8/9 mol%) was applied. Sodium tert-butoxide served as base, and the reaction was run using dilute (c = 0.02 M) dioxane solutions to prevent formation of linear oligomers. However, ortho-dibromobenzene proved to be enough reluctant to diamination: the reaction with tetraamine 2a provided only 12% yield of the desired macrocycle 3a (Scheme 1). The reaction with trioxadiamine 2b was even more difficult: Pd(dba)2/BINAP system was not efficient, and target macrocycle 3b was synthesized in 14% yield when employing donor phosphane ligand 2dimethylamino-2'-dicyclohexylphosphino-1,1'-biphenyl (DavePHOS). Both reactions demanded 70 h reflux to run to completion. The reason for low yields of the products of diamination is that the substitution of the second bromine atom in the monoaminated intermediate is severely hindered by the amino group in orthoposition.


123

N N NH2 H 2a H H2N NH HN

Pd(dba)2/BINAP 8/9 mol% NaOtBu dioxane

NH HN 3a, 12%

Br Br O

1 NH2

O

O

O NH

H2N

2b

O

NMe2

NH

Pd(dba)2 /

O 3b, 14%

Cy2P 16/18 mol%

Scheme 1.

H2N

N H

H N

H2N

H N

NH2

1a

H2N

N H 1d

1c

H N

H N

NH2

H2N

H N

N H

O 1j

Figure 1.

NH2

NH2

H2N

N H

H2N

H N

N H

1h

NH2

H N

NH2

N H

1e

NH2

H N

O

O

H2N

1f

H2N

O

O

1b

NH2

H2N

H2N

H2N

N H

1g H N 1i O

O 1k

NH2

NH2

N H

NH2

124

Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al. Br Cl

X

Cl Pd(dba)2/BINAP 8/9 mol%

NH Cl

NH

4 NaOtBu dioxane

+ H2N

X

5a,b,d-k

NH2

2a-k

5a, 47% 5b, 24% 5d, 8% 5e, 18% 5f, 17% 5g, 27% 5h, 12% 5i, 10% 5j, 12% 5k, 17%

by-products:

Cl

HN

X

NH

HN

Cl Cl

Cl

X

NH2

Cl

Cl NH

X HN

Cl

Cl NH

6b,g-i,k 6b, 12% 6d, 7% 6g, 7%

6h, 17% 6i, 21% 6k, 10%

7c,j,k 7c, 37% 7j, 27% 7k, 14%

X

HN n

8b,d,k 8b, 9% (n = 1) 8d, 50% (n = 1, 2) (mixture) 8k, 10% (n = 1) 11% (n >1)

Scheme 2.

We decided to increase the reactivity of aryl halide by introducing additional halogen atom and studied the reaction of 2,6-dichlorobromobenzene 4 with a variety of di- and polyamines 2a-k (Figure 1). Almost in all cases (except for the shortest triamine 2c) target macrocycles 5 were obtained in 8-47% yields using column chromatography on silica (Scheme 2). The reactions ran to completion in 24-30 h. The formation of almost all compounds 5 were accompanied by the formation of open-chain and cyclic oligomers 6-8. As expected, the best results were achieved with enough long di- and polyamines 2a,b,g, however, in these reactions we did not observe any dependence of the number of nitrogen atoms on the yields of polyazamacrocycles 5. As we were interested in the synthesis of cyclic dimers 8 due to larger cavity sizes of such macrocycles, we elaborated their synthesis via N,N’di(dichlorophenyl)polyamines 6 obtained in situ from 2.2 equiv. of dichlorobromobenzene 4 and 1 equiv. of corresponding polyamine 2 (Scheme 3). Compounds 6 were obtained in 85-90% yields, the reaction with the second


125

molecule of polyamine 2 was catalyzed with 16 mol% catalyst, and the majority of cyclodimers 8 were isolated in quite reasonable yields 20-30%. Br Cl

H2N Cl Pd(dba)2/BINAP (4/4.5 mol%)

4 2.2 equiv. H2N

X 2a,b,d,j,k

Cl

NH

X Cl

tBuONa dioxane NH2

X

NH2

Cl

2a,b,d,j,k NH Cl

6a,b,d,j,k, in situ 85-90%

Cl

Pd(dba)2/BINAP (16/18 mol%) tBuONa dioxane

Cl

NH

X

NH

HN X

HN

8a,b,d,j,k 8a, 33% 8b, 27% 8d, 19% 8j, 6% 8k, 23%

Scheme 3.

2. MACROCYCLES COMPRISING 1,3-DISUBSTITUTED BENZENE FRAGMENT 1,3-Dibromobenzene (9) was thought to be more suitable for the synthesis of macrocycles due to the fact that the substitution of the first bromine atom for amino group would not seriously affect the substitution of the second bromine atom. The reactions with polyamines 2a-h,j,k were run in the presence of the same Pd(dba)2/BINAP catalytic system (Scheme 4) [61]. The yields of target macrocycles 10 were found to be strongly dependent on the length of the starting polyamines. Triamine 2c (7 atoms in the chain) did not provide the corresponding cycle even not in trace amounts, whereas triamine 2d with a longer chain (9 atoms) afforded target compound 10d in a small yield (15%). Tetraamines 2a,e-g as well as pentaamine 2h gave the desired macrocycles in moderate to good yields, the same was true for oxadiamines 2a,j,k. Almost in all cases cyclodimers 11 were formed as by-products, but these compounds could not be generally isolated in pure state due to the presence of admixtures of cyclooligomers and linear oligomers. We tried also 1,3-dichlorobenzene in the synthesis of macrocycles, but the reaction, run under the same conditions, provided only linear derivatives. The synthesis of cyclodimers of type 11 was more efficient using a two-step procedure, i.e. via the synthesis of intermediate diarylated compounds 12 (Scheme 5). These compounds were obtained in 70-80% yields in the reaction mixtures and isolated in 29-64% yields by column chromatography. In all cases linear oligomeric products 13 were isolated in notable yields (10-21%); they were formed due to an easy diamination of 1,3-dibromobenzene.

126


Br

Pd(dba)2/BINAP 4-8/4.5-9 mol%

Br 9 +

H2N

HN

NaOtBu dioxane

NH

X

HN

NH

X

HN

+

NH X

10a,b,d-h,j,k

X NH2 2a-h,j,k

11a-f,j,k 10a, 29% 10b, 26% 10d, 15% 10e, 39%

10f, 31% 10g, 56% 10h, 33% 10j, 27% 10k, 26%

11a, 36% 11b, 23% 11c, 74% (together with cyclotrimer)

11d, 60% 11e, 14% 11f, 26% 11j, 28% 11k, 5%

Scheme 4.

Br

Br 9

Pd(dba)2/BINAP 4/4.5 mol%

+ H2N

X

NaOtBu dioxane

HN

X

HN

NH

X

HN

NH

X

NH

+ Br

Br

NH2

Br

Br 13a,b,d,f,g,j,k

12a,b,d,f,g,j,k

2a,b,d,f,g,j,k 12a, 52% 12b, 29% 12d, 46% 12f, 64% 12g, 39% 12j, 46% 12k, 59%

13a, 10% 13b, 10% 13d, 13% 13f, 21% 13g, 12% 13j, 16% 13k, 11%

Scheme 5.

To synthesize macrocycles in good yields, the reactions of di(3bromobenzene)polyamines 12 with corresponding polyamines 2 were run in the presence of a double amount amount of catalyst (16 mol%), in dilute dioxane solutions, and in the majority of cases corresponding cyclodimers were formed in reasonable to good yields (up to 44%). HN

X

Pd(dba)2/BINAP 16/18 mol%

NH +

Br

Br

H2N

X

NH2

2a,b,d,f,g,j,k

NaOtBu dioxane

NH

X

HN

NH

X

HN

12a,b,d,f,g,j,k 11a,b,d,f,g,j,k 11a, 36% 11b, 21% 11d, 44%

Scheme 6.

11f, 6% 11g, 30% 11j, 16% 11k, 38%


127

3. MACROCYCLES CONTAINING 2,6-DISUBSTITUTED PYRIDINE MOIETY Having obtained encouraging results with the macrocyclic derivatives of mdisubstituted benzene, we decided to synthesize the macrocycles with the simplest heteroaromatic spacers. For these reasons we investigated the reactions of 2,6dibromopyridine (14b) with a number of polyamines 2a-j taken in equimolar amounts in order to obtain corresponding macrocycles 15 containing one pyridine and one polyamine moiety [62]. The reactions were run using Pd(dba)2/BINAP catalytic system (4-8/6-12 mol%), amination was carried out in dilute dioxane solutions (0.01-0.02 M), and the reactions ran to completion in 5-15 h (Scheme 7). The yields of target macrocycles 15 were found to be strongly dependent on the nature of polyamines 2a-j. While the reactions with tetraamines 2a,f,g afforded 21-32 % yields of macrocycles 15a,f,g, short triamines 2c,d, polyamines with repeating ethylenediamine unit 2e,h,i¸and oxadiamines 2b,j provided low yields of corresponding macrocycles. It is unusual that the yields of oxaazamacrocycles were also low though enough long oxadaimines were used. The major by-products observed in all cases were N-(6-tert-butoxypyridin-2yl)polyamines 16 whose formation proceeded via intermediate 2-bromo-6-tertbutoxypyridine. We tried different catalytic systems previously reported suitable for bromopyridines amination, but they did not give target macrocycles. Attempts to employ donor phosphane ligands were totally unsuccessful. Low yields of the macrocycles might be explained by the formation of some oligomeric compounds which could not be either isolated or identified in the reaction mixtures.

Br

N

Br

14

+ H2N

Pd(dba)2/BINAP 4-6/8-12 mol% X 2a-j

NH2

NaOtBu dioxane

HN

N

NH +

X

Scheme 7.

N

N H

X

NH2

16a-j

15a-j 15a, 24% 15b, 7% 15c, 11% 15d, 14% 15e, 7%

O

15f, 21% 15g, 32% 15h, 11% 15i, 10% 15j, 9%

16a, 32% 16b, 33% 16c, 12% 16d, 51% 16e, 49%

16f, 18% 16g, 44% 16h, 14% 16i, 21% 16j, 26%

128


+ Br

N

Br

N NH2 H


N HH N 2

NaOtBu dioxane

2a

14, 3 equiv.

N NH H

N H HN

N

+

HN

Br

Br

Cl

N

Cl

Pd(dba)2/BINAP 8/9 mol% H2N

X

NH2

2a,f,j

18, 3 equiv.

HN

NaOtBu dioxane

X

HN

NH

N

+

N

Cl

Cl

NH H N

15a, 13%

17a, 28%

+

N H N

N

X

NH2

N Cl

19a, 43% 19f, 40% 19j, 50%

20a, 48%

Scheme 8.

To synthesize macrocycles containing two pyridine and two polyamine fragments (i.e. cyclodimers), we have elaborated two alternative methods [63, 64]. According to the approach (A), polyamines are first hetarylated with two equivalents of 2,6-dihalopyridines to form di(6-halopyridin-2-yl)polyamines which further react with the second equivalent of polyamines giving the desired cyclodimers. In the method (B), the intermediate 2,6-bis(polyamine)pyridines are formed by the reaction of 2,6-dibromopyridine with excess of polyamines 2, and corresponding cyclodimers are formed by their reaction with the second molecule of 2,6-dibromopyridine. The reaction of tetraamine 2a with 3 equivalents of 2,6dibromopyridine (14) provided a mixture of the target bis(bromopyridinyl)substituted tetraamine 17a and macrocycle 15a in 28% and 13% yields, respectively (Scheme 8). The use of 2,6-dichloropyridine (18) (3 equiv.) in this reaction led to higher yields (40-50%) of the desired products 19a,f,j, formation of macrocycles 15 were not observed, but monohetarylated compound 20a was isolated in 48% yield as a by-product. To obtain the intermediates in the method (B), 2,6-dibromopyridine was treated with four equivalents of polyamines 2a,j to give the corresponding bis(polyamine)-substituted pyridines 21a,j in high yields (Scheme 9).

+ Br

N 14

Scheme 9.

Br


X

NH2

2a,j, 4 equiv.

NaOtBu dioxane

H2N

X

N H

N

N H 21a, 90% 21j, 80%

X

NH2

Palladium-catalyzed Amination of Dihaloarenes HN

X

NH

N

N

Hal

NH Hal

17a, Hal = Br 19a,f,j, Hal = Cl

Y

NH2

2a,f,j

N

N H

NH

Pd(dba)2/BINAP 8-18/8-18 mol%

22a, 16-38% 22f, 14% 22j, 39% 22l, 19% 22m, 11%

N

N H

X

(A)

NaOtBu dioxane

+ H2N

129

Y

X HN

N

HN

22a,f,j,l,m

(B) Pd(dba)2/BINAP 13/14 mol% NaOtBu dioxane

X

NH2

H2N

21a,j + Br

N

Br

22a, 49% 22j, 0% 14

22l: X = CH2NH(CH2)2NHCH2 22m: X = CH2NHCH2

Scheme 10.

The problem of isolation and purification of bis(polyamine)-substituted pyridines 21 was found to be quite serious and we decided to use them in situ in the synthesis of cyclodimers, producing them from 1 equiv. of dibromide and 4 equiv. of polyamine to minimize possible excess of polyamines which would lead to macrocycles and not to cyclodimers. Following the method (A), cyclodimers 22a,f,j,l,m were synthesized by the reaction of bis(halopyridinyl)-substituted polyamines 17a and 19a,f,j with polyamines 2a,f,j (Scheme 10). We have found that the use of the dibromo derivative 17a provided the corresponding cyclodimer 22a in a poorer yield (16%) than dichloro derivative 19a (38%) due to excessive formation of linear oligomers. To synthesize other symmetrical cyclodimers 22f,j, the corresponding bis(chloropyridinyl)polyamines 19f,j were used. The same procedure was successful for the synthesis of macrocycles 22l,m containing two different polyamine chains. According to approach (B), we attempted an alternative synthesis of macrocycles 22 via compounds 21a,j obtained in situ. The results of method (B) were different from those of method (A): while 22a was isolated in enough high 49% yield, cyclodimer 22j was observed in small amounts only in the reaction mixture.

4. MACROCYCLES WITH 3,5-DISUBSTITUTED PYRIDINE SPACER Polyazamacrocycles containing 3,5-disubstituted pyridine moiety have been yet unknown, therefore it is of importance to elaborate a simple way to their isomers with an exo-oriented pyridine nitrogen atom (provided the cycles are not enough large). These compounds may possess different complexing properties

130


due to spatially isolated donor sites: pyridine nitrogen atom and secondary amino groups of the polyamine chain. In the beginning of our investigations we employed 3,5-dibromopyridine 23 in the reactions with equimolar amounts of a variety of polyamines 2a-j (Scheme 11) [65]. All polyamines 2a-j gave corresponding macrocycles 24a-j together with side products 25-27 and cyclodimers 28 but the yields of target compounds 24 were substantially different, as it was the case in previous experiments. When using polyamines 2a,b,d,f,g,j yields of the macrocycles ranged from 18 to 42%, whereas with other polyamines the yields did not exceed 5-6%. This is possibly due to the fact that the latter polyamines comprise only ethylenediamine fragments whereas first set of polyamines either do not have such fragments at all, or contain both ethylenediamine and triethylenediamine moieties. Pd(0) from the catalytic complex may form more stable 5-member chelate complexes with ethylenediamine fragments than 6-member complexes with triethylenediamine fragments, thus being eliminated from the catalytic cycle. Polyamines 2c,e,h,i afforded enough high yields of monoaminated pyridines 25 and 26; this fact shows that the second substitution of the bromine atom for amino group proceeds in a much slower rate. Prolonged heating did not lead to notable change in the reaction mixture composition while the change in the reagents ratio led to the increase in the yields of non-cyclic products. The application of the polyamine excess gave rise to bis(polyamine) substituted pyridines 27, but the yield of the macrocycle 24 changed insignificantly. The excess of dibromopyridine led to preferential formation of bis(pyridinyl)substituted polyamines 26. In general, the more was the deviation from the stoichiometric ratio of starting compounds, the less was the yield of the desired macrocycle 24, but simultaneously the less was the formation of unidentified linear oligomeric by-products. Thus stoichiometric ratio of starting reagents is a crucial condition to maximize the yield of the macrocycles. We have also investigated the possibility to use 3,5-dichloropyridine (29) for the synthesis of the macrocycles 24 [66]. The amination reaction with model tetraamine 2a was found to proceed substantially slower than with dibromopyridine, and only long reflux provided 17% yield of the target macrocycle 24a, but the main products were acyclic 30a and 31a (Scheme 12).


131 N

Br

Br +

H2N

N 23

X


NH2

HN

NaOtBu dioxane

2a-j

NH X 24a-j 24a, 36% 24b, 27% 24c, 5% 24d, 42% 24e, 4% 24f, 29% 24g, 18% 24h, 5% 24i, 4% 24j, 22%

By-products:

HN

X

N

NH2

HN

X

N

Br

NH N

Br

25, 10-32% N N H

Br

26, 3-33% HN N H

X

X

HN

N

N

X

NH2

27, 6-14%

NH

H2N

Y

HN

28, 1-6%

Scheme 11. Cl

Cl N N 29

Pd(dba)2/L 8/9 mol%

+

NaOtBu dioxane

N NH2 H

HN

NH H N

HN Cl

N HH N 2

24a, 17%

Scheme 12.

N NH H

N H HN

N

N

Cl

30a + 31a, 31-51% PCy2

PtBu2

Me2N

PCy2

N NH H

+

30a

2a

L = BINAP,

+

N

Cl 31a

N HH N 2

132

Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al. H2N

X

NH2

2a,b,d,j, 0.33-0.45 equiv. Br

Br

HN

X

NH

HN


N 23

X

NH2

+

NaOtBu dioxane

N

Br

N

N

Br

Br

26a, 48-86% 26b, 80% 26d, 90% 26j, 50%

25a, 9-32%

N Br

H2N X NH2 2a,d, 4 equiv.

Br

N H


N 23

N H

X

X

NH2

NaOtBu dioxane

27a, 90% 27d, 90%

H2N

in situ

Scheme 13.

Donor phosphane ligands such as 2-di-tert-butylphosphino-1,1’-biphenyl, 2dicyclohexylphosphino-1,1’-biphenyl, and 2-dicyclohexylphosphino-2’dimethylamino-1,1’-biphenyl were found to be efficient in the amination of aryl chlorides [67]. In our case the first ligand was of the same efficiency as BINAP, and two other ligands were ineffective. It is of interest that these donor ligands were totally inefficient in the amination of 2,6-dihalopyridines. As 3,5-dibromopyridine 23 proved to be enough inert towards diamination, it provided an easy synthesis of dipyridyl substituted polyamines 26 by changing the reaction conditions (Scheme 13). N

HN

X

N

NH

N H NH

Hal

Pd(dba)2/L Hal 8-16/9-20 mol%

N

N

26a,b,d,j, 31a + H2N

X 2a,b,d,j

Scheme 14.

NH2

NaOtBu dioxane 28a, 14% 28b, 15% 28d, 12% 28j, 0%

X

Y

HN

NH

N H

X

NH Pd(dba)2/BINAP 10-16/12-18 mol%

X

NH2

+ Br

Br

12% N 28a,b,d

H2N

27a

NaOtBu dioxane

N 23


133

N,N'-diarylation of polyamines was afforded with 2.2 equivalents of dibromopyridine. Compounds 26a,b,d,j were obtained in 48-90% yields, monoarylated derivative 25a was formed as a by-product in the reaction with tetraamine 2a. The reaction of dibromopyridine with an excess of polyamines 2a,d (4 equivalents) provided the synthesis of 3,5-bis(polyamino) substituted pyridines 27a,d. Using polyamines 2, we have worked out two alternative synthetic routes to cyclodimers which were quite similar to above mentioned for cyclodimers 22 based on 2,6-disubstituted pyridine [66]. Method (A) included the synthesis of dipyridyl substituted polyamine 26 followed by its reaction with the second equivalent of polyamine 2. As the synthesis of 26 demanded only 10% excess of 3,5-dibromopyridine, we used these compounds for the cyclization reaction in situ without purification (Scheme 14). The reaction of 26a provided cyclodimer 28a in 14% after 6 h reflux. Longer heating and the increase in the catalyst loading did not ameliorate the yield of the target molecule. Method (B) included the synthesis of bis(polyamine) derivative 27a followed by the reaction with the second equivalent of 3,5-dibromopyridine (Scheme 14). According to this scheme, cyclodimer 28a was obtained in 12% yield. 3,5-Dichloropyridine 29 can also be used for the synthesis of cyclodimers according to method (A) via intermediate dipyridyl substituted polyamine 30a. In this case Pd(dba)2 with 2-ditert-butylphosphino-1,1’-biphenyl (DavePHOS) was employed as the catalytic system. The same approach (A) was used for the synthesis of cyclodimer 28d which was isolated in 12% yield. We also tried dioxadiamine 2j and trioxadiamine 2b for the synthesis of corresponding cyclodimers. Method (A) gave intermediate dipyridyl substituted dioxadiamine 26j in 50% while 26b was obtained in 80% yield. Further transformation of the latter with the second molecule of diamine 2b provided corresponding cyclodimer 28b in 15% yield while the reaction with 2j gave no result.

5. INTRODUCTION OF 2,4- AND 4,6-DISUBSTITUTED PYRIMIDINE MOIETY Aminopyrimidines are known to be valuable compounds with versatile biological activity. Recently we have investigated amination of 2chloropyrimidine and 2,4-dichloropyrimidine using diamines [68]. Since 2,4dichloropyrimidine 32 was found to form 2,4-bis(diamine) derivatives under noncatalytic conditions, we decided to introduce it in the reaction with equimolar

134


amounts of various diamines to synthesize corresponding macrocycles. We abstained from the use of tri- and tetraamines because chloropyrimidines easily react with secondary amino groups also and no selectivity is observed in this case. The reactions of equimolar amounts of 2,4-dichloropyrimidine 32 and oxadiamines 2b,j,k were catalyzed by Pd(dba)2/BINAP (4-8/16 mol%) and run in 0.05 M dioxane solutions. They afforded corresponding macrocycles 33b,j,k in 725% yields (Scheme 15) [69]. In this process cesium carbonate was used instead of sodium tert-butoxide to prevent alkoxylation reaction. Cl N N

+

H2N

Cl

X

NH2

Pd(dba)2/BINAP 4-8/16 mol% Cs2CO3 dioxane

2b,j,k

32

HN N N

X N H

33b,j,k 33b, 25% 33j, 7% 33k, 17% Scheme 15.

Cl N Cl

N 34

+

H2N

X 2b,j,k

NH2

Pd(dba)2/BINAP 4-8/8-16 mol% Cs2CO3 dioxane

NH X

N

N N H 35b,j,k 35b, 31% 35j, 10% 35k, 31%

Scheme 16.

The reaction of the isomeric 4,6-dichloropyrimidine 34 with the same diamines gave similar results (Scheme 16). Longer diamines 2b,k afforded macrocycles 35b,k in rather good yields (31%) while a shorter 2j provided 35j in 10% yield. We tried other ligands than BINAP to improve the yields, but only N,N-dimethyl-1-[2-(diphenylphosphino)ferrocenyl]ethylamine was of the same efficiency as BINAP; 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xanthphos) and DavePHOS provided only acyclic monoamination products.


135

Thus, like in the case of dibromopyridines, higher reactivity of hetaryl bromides in nucleophilic substitution reactions, as compared to benzene derivatives, did not result in higher yields of the macrocycles, products of intramolecular diamination.

6. MACROCYCLES DERIVED FROM 4,4'- AND 3,3'DIBROMOBIPHENYLS First we tried 4,4’-dibromobiphenyl (36) in the Pd-catalyzed reactions with several oxadiamines 2b,j,k (Scheme 17). Br

HN

+

H2N

X

NH2

Pd(dba)2/BINAP 8/9 mol% X

NaOtBu dioxane

2b,j,k Br

NH

+

HN

36

X

HN

X

HN

NH

37b,k

n

37b, 10% 37k, 5%

38b,j,k, 49-62%

Scheme 17. Br

H2N

X NH2 2a-h,j-l

Pd(dba)2/BINAP 8/9 mol% Br 39

H N X

H N

N H

N H

NH2 2l

X

+

40a,b,d-h,j,k H2N

H N

X

N H

n

41a-h,j-l, 18-61% 40a, 44% 40b, 38% 40d, 25% 40e, 16% 40f, 26%

40g, 41% 40h, 19% 40j, 40% 40k, 44% 40b, 38%

Scheme 18.

The reactions were run with equimolar amounts of starting compounds in standard conditions, however, the yields of the macrocycles 37 comprising one

136


biphenyl and one oxadiamine units were low: 10% in the case of the longest trioxadiamine 2b, 5% for a shorter 2k, and the shortest 2j gave no macrocycle of this type, but only cyclooligomers 38j. Cyclooligomers were also isolated in high yields with diamines 38b,k. The reason for such low yields of target macrocycles is a geometric demand of 4,4’-dibromobiphenyl for the polyamines with sufficiently long chains. Much better results were obtained when using 3,3’-dibromobiphenyl 39 under the same conditions (Scheme 18). In these reactions we used a variety of dioxadiamines 2b,j,k, propane-1,3-diamine 2l, tri-, tetra- and pentaamines 2c-h. As expected, propane-1,3-diamine 2l was too short to give a desired monocycle as was also diethylenetriamine 2c (7 atoms in the chain), and they gave cyclodimers and cyclooligomers 41l and 41c, respectively. Beginning from triamine 2d (9 atoms) target macrocycles 40 were formed successfully in yields from moderate to good. The best yields (44%) were achieved with dioxadiamine 2k and tetraamine 2a, also enough high yields for the macrocyclization reaction (ca 40%) were afforded by trioxadiamine 2b and tetraamine 2g. DavePHOS ligand was also tried instead of BINAP, but it did not show substantial advantage. Amination of 3,3'-dibromobiphenyl again demonstrates that the increase in the number of ethylenediamine fragments in polyamines leads to a notable decrease in macrocycles yields. These reactions also produced substantial amounts of cyclodimers and cyclooligomers 41. Then we decided to compare two approaches to the synthesis of cyclic dimers 41 which were described above. The first, via intermediate N,N'bis(bromobiphenyl) substituted polyamines 42 and 44, was complicated by the formation of linear oligomers 43 and 45 (Scheme 19). In the case of 3,3'dibromobiphenyl 39 Xanthphos proved to be more efficient than BINAP due to its ability to suppress N,N-diarylation of primary amines. The yields of target cyclodimers 38 and 41 were shown to be strongly dependent on the nature of polyamines, and the reactions also gave rise to by-products like cyclotetramers, cyclohexamers and linear oligomers. The attempts to use intermediate linear derivatives 42 and 44 in situ were unsuccessful. One-pot synthesis of cyclodimers 38 and 41 via bis(polyamine)-substituted biphenyls 46 and 47 was more convenient, and in the case of the cyclodimer 41j the yield reached 44% (Scheme 20). Compounds 46 and 47 were employed in situ as it was the case in above-mentioned syntheses.


137

Br HN H2N

X

NH

X NH2 2a,b,j,l

+

Br

N H

X

N H

N H

X

N H

Br

43a, 18%; 43b, 19%

Pd(dba)2/BINAP 4/4.5 mol% Br Br

36 2.2 equiv.

Br

H2N

42a, 22% 42b, 34% 42j, 18% 42l, 34%

X NH2 2a,b,j,l

X NH

HN


38a, 23% 38b, 20% 38j, 9% 38l, 6% HN

Br

HN H2N

X

HN

NH

X NH2 2a,b,j

NH

X

X

NH

Br H N

+

H N

X

Pd(dba)2/L 4/4.5 mol%

Br 39 L = BINAP, Xanthphos 2.2-3 equiv.

Br

Br 44a, 34% (BINAP) 44b, 21% (BINAP), 35% (Xanthphos) 44j, 0% (BINAP), 27% (Xanthphos)

Br

45a, 32% (BINAP) 45b, 14% (BINAP), 19% (Xanthphos) 45j, 5% (Xanthphos)


X

H N

H N

X

NH2

41a, 19% 41b, 30% 41j, 27%

2a,b,j X N H

N H

Scheme 19. Br

X HN

Br

X

NH2

NH

HN

38a, 7% 38b, 10% 38j, 11%

Br Pd(dba)2/BINAP 8/9 mol%

Pd(dba)2/BINAP 4/4.5 mol%

Br 36

H2N Br

X NH2 2a,b,j 4 equiv.

HN

X

NH2

46a,b,ji in situ H N X

Br

HN

H N

NH2

NH

X

X

H N

Br Pd(dba)2/BINAP Br 39

Scheme 20.

N X H 47a,b,ji in situ

NH2

8/9 mol%

N H

X 41a, 9% 41b, 15% 41j, 44%

N H

138


7. INTRODUCTION OF NAPHTHALENE MOIETIES INTO POLYAZAMACROCYCLES In previous investigations of the catalytic arylation of diamines we revealed that 1-bromonaphthalene was among the most reactive aryl halides [70]. Thus we tried 1,8-dibromonaphthalene in the catalytic amination reactions in view of constructing new macrocycles on its basis, but it did not react at all even after a long reflux. Possibly in this case the second bromine atom in peri-position totally hindered the reaction at the step of the oxidative addition of 1,8dibromonaphthalene to Pd(0). Then we ran the reactions using 2,7dibromobiphenyl 48 (Sheme 21), and in this case amination proceeded normally [71]. Desired macrocycles 49 were formed in all cases except for the shortest triamine 2d, in this case only cyclooligomers were obtained. Amines 2f,j provided low yields of corresponding macrocycles 49f,j due to insufficiently long chains, other polyamines gave comparable moderate results. In some cases cyclic dimers and trimers 50 were isolated as by-products. No other regularities were observed for the formation of macrocyclic products. One may assume that generally lower yields of the macrocycles based on naphthalene as compared to those of based on 3,3'-biphenyl are due to a stronger influence of the amino group in one ring on the substitution of the bromine in the other ring in the case of naphthalene derivatives. Synthesis of cyclic dimers 50 was conducted using two approaches: via diarylated derivatives 51 and via bis(polyamine)substituted naphthalenes 54 which were used in situ (Scheme 22). The first route was less efficient due to the formation of by-products 52 and 53 in notable amounts. The second route is more convenient and affords better yields of cyclodimers 50.

HN Br

Pd(dba)2/BINAP (8/9 mol%)

Br

+ 48

H2N

X

NH2

NH

NH

+

NaOtBu, dioxane

2a,b,d,f-h,j,k 49a,b,f-h,j,k

49a, 26% 49b, 26% 49f, 9% 49g, 28% 49h, 19% 49j, 10% 49k, 29%

Scheme 21.

X

X HN

NH

X

HN n

50a,d,j,k 50a, n = 1, 25% 50d, n = 1, 9% n = 2, 10% 50j, n = 1, 32% n = 2, 14% 50k, n = 1, 19% n = 2, 8%


139 Br

Br

Br Pd(dba)2/BINAP (Pd(dba)2/Xanthphos)

48 2.2 equiv.

HN

X

NH

HN

X

NH

Br N

2-4/2.5-4.5 мол%

+

X

NH

+

+ Br H2N

X

Br

51a,b,j

NH

Br

X

HN

NH2

2a,b,j

H 2N

X

Br

Br

51b, 37% 51a, 27% 51j, 27%

52a,b,j 53b,j 52b, 6% 52a, 37% 52j, 13%

NH2

NH

X

HN

X

HN

53b, 10% 53j, 10%

2a,b,j Pd(dba)2/BINAP 8/9 mol%

NH

50a,b,j 50a, 21% 50b, 28% 50j, 11%

Br

Br Pd(dba)2/BINAP (Pd(dba)2/Xanthphos)

HN

X

NH2

Br

Br

NH

X

HN X

4/4.5 мол%

48

+

HN

NH

+ Pd(dba)2/BINAP H2N

X

NH2

2b,g,j 4 equiv.

N H

X

NH2

8/9 mol%

NH

X

HN

54b,g,j in situ 50b,g,j

49b, 29% 49g, 19%

50b, 30% 50g, 22% 50j, 10%

Scheme 22.

8. ANTHRACENE- AND ANTHRAQUINONE-BASED POLYAZA- AND POLYAZAPOLYOXAMACROCYCLES Aminosubstituted anthracenes and anthraquinones attract attention by their optical properties due to a strong adsorption in visible region. Macrocycles comprising anthracene and anthraquinone moieties as exocyclic substitutents or endocyclic spacers are known to be efficient optical sensors for ions and polar molecules. For this reason we elaborated an easy one-pot catalytic procedure for the synthesis of polyaza- and polyazapolyoxamacrocycles by the intramolecular diamination of 1,8- and 1,5-dichloroanthracenes 55, 61 and anthraquinones 58, 64 [72-74]. The reactions were catalyzed with Pd(dba)2/BINAP (8-16/9-18 mol%) system, in the case of dichloroanthracene we applied sodium tert-butoxide as base, and in the case of dichloroanthraquinones we used cesium carbonate. This protocol afforded target macrocycles with 1,8-disubstituted arenes in yields up to 43% (Scheme 23). It was found that the nature of dihaloarene and polyamine notably affected the yield, however, no strict regularities were observed. In some

140


cases cyclic oligomers were formed, and cyclodimers and cyclotrimers were isolated in pure state.

X

HN Cl

NH

Cl

56a,b,d-k 55

H2N

X

NH2

56a, 24% 56b, 25% 56d, 25% 56e, 33% 56f, 36% 56g, 21% 56h, 26% 56i, 22% 56j, 28% 56k, 20%

NH

HN

X

X

+ NH

57b, 10% 57j, 8%

HN

2a,b,d-k Pd(dba)2/BINAP (8-16/9-18 mol%)

Cl

O

Cl

O

tBuONa or Cs2CO3, dioxane

X NH

O

HN

O 58 O

59a, 25% 59b, 37% 59e, 14% 59f, 19% 59g, 10% 59h, 27% 59j, 43% 59k, 33%

NH +

O

X NH

HN X

O

60b, 18% 60k, 12%

HN

59a,b,e-h,j,k O

Scheme 23.

The reactions of isomeric 1,5-dichloroanthracene and anthraquinone 61, 64 were found to be less general because of more strict geometric demands for ring closure (Scheme 24). 1,5-Dichloroanthracene 61 gave macrocycles 62 with tetraamines 2a,f,g which possess 11-13 atoms in chain, while the reaction with a shorter tetraamine 2e (10 atoms) produced only cyclic and linear oligomers. The same was true for oxadiamines: dioxadiamine 2j (10 atoms) afforded only cyclodimer, while longer diamines 2b,k (14 and 15 atoms in chain) gave corresponding macrocycles 62b,k in normal yields (24 and 20%). 1,5Dichloroanthraquinone 64 was even more capricious for it did not produce polyazamacrocycles at all with tetraamines, and gave desired products 65b,k only with enough long oxadiamines. We may suppose that such negative result with tetraamines was due to the formation of strong intramolecular hydrogen bonds N...H...O in a linear product of the first chlorine atom substitution, which strengthened unfavorable conformation of the polyamine chain preventing from the ring closure. As a result, these non-cyclic compounds 67a,e-g were the only products isolated in these reactions.


141

NH Cl

X

HN 62a, 34% 62b, 20% 62f, 20% 62g, 22% 62k, 24%

X H2N

Cl

61

X

NH2

NH

2a,b,e-g,j,k

NH NH

62a,b,f,g,k


Cl

+

X HN

tBuONa or Cs2CO3, dioxane

O

63e, 18% 63f, 10% 63j, 8%

NH

O

X O

HN

Cl

H2 N

O

64

O

X O

+

NH

NH

X

O

NH

+

O 67a,e-g O

NH

Cl

X 65b, 28% 65k, 30%

O

67a, 23% 67e, 28% 67f, 25% 67g, 25%

HN

66j, 18% 66k, 10%

Scheme 24. H2N

Cl

X

NH2

2b,j

Cl

H2N HN

Cl

X

X

NH2

2b,j

NH

Cl

Pd(dba)2/BINAP (4/4.5 mol%)


NH

HN

X tBuONa dioxane

55

tBuONa dioxane

X

NH

HN

68b, 20% 68j, 53%

3 equiv.

57b, 15% 57j, 34%

O H 2N

Cl

O

Cl

X

NH2

H2N

2b,k Pd(dba)2/BINAP (4/4.5 mol%)

Cl

O

HN

X

NH

X

NH2

2b,k O

Cl


NH

O

HN

O

HN

X O 58

Cs2CO3 dioxane

O

69b, 36% 69k, 35%

O

Cs2CO3 dioxane

NH

X

3 equiv. O 60b, 37% 60k, 21%

Scheme 25.

We investigated the possibilities of two approaches to cyclic dimers 57 and 60 [75, 76]. The synthesis of both types of cyclodimers was successful only via

142


N,N'-di(chloroaryl)substituted oxadiamines 68 and 69, and our attempts to employ an easier approach using bis(polyamine) derivatives were totally unsuccessful (Scheme 25). Moreover, we succeeded only in the synthesis of cyclodimers 57b,j and 60b,k which were isolated as by-products in the syntheses of corresponding monomacrocycles 56b,j and 59b,k. Other cyclodimers were not obtained even in trace amounts. This fact may lead to conclusion that in the case of dichlororanthracene and dichloroanthraquinone catalytic amination cyclic oligomers are formed only via N,N'-di(chlororaryl)substituted intermediates.

CONCLUSION We investigated possibilities of the Pd-catalyzed amination of various dihaloarenes with polyamines and oxadiamines for the synthesis of macrocycles containing one or two aromatic fragments in the macrocycle. All tested dihaloarenes provided corresponding aryl-containing macrocycles with certain polyamines, however, the yields were found to be substantially dependent on the nature of starting compounds. Two approaches to cyclodimers were elaborated and their applicability was checked for various pairs arene/polyamine. In the majority of cases the synthesis of cyclodimers via bis(polyamine)substituted arenes was found to be more convenient, however, in certain cases the best results were achieved using intermediate N,N'-di(haloaryl)polyamines.

ACKNOWLEDGMENTS This work was supported by RFBR grants N 06-03-32376, 09-03-00735 and by ARCUS Bourgogne-Russie project.

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[12] [13] [14] [15] [16]

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Chapter 5

PYRRIDAZINOINDOLES, SYNTHESIS AND PROPERTIES Sh. A. Samsoniya, I. Sh. Chikvaidze, M. Ozdesh Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT Pyrridazinoindoles can be considered as azaanalogs of different carbolines, and especially β- and γ-, the condensed ring system of which represent the basis of many compounds of high physiological activity. Therefore the unified aromatic system of isomeric pyrridazinoindoles containing three nitrogen atoms in different positions and their derivatives have attracted great attention of researchers. A lot of notifications, dedicated to synthesis of isomeric pyrridazinoindole derivatives and studying their different pharmacological activities, that is not of less value, appeared during the last 2-3 decades. The present survey is the attempt of summarization of numerous data. It cannot be referred to the complete one, while it does not embrace all the notifications concerning this question. The preparative methods of synthesis of isomeric pyrridazinoindoles, jointed in different ways, have been worked out, based on application indole carbonyl derivatives with subsequent built of pyrridazine cycle. For some

148

Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh isomers the attachment of indole ring to pyrridazine appeared to be more convenient. The study of chemical properties of pyrridazinoindoles and intermediate oxo- and dioxopyrridazinoindoles in order to find new bioactive substances brought to rather interesting results. Have been synthesized a lot of new derivatives of these systems revealing different useful properties, including frank activity against Alzheimer's disease, Parkinson's disease and Down's syndrome, revealing antitumour, antihypertensive, antiinflammatory, antibacterial, tuberculostatic, inotropic activity, possessing ability of hypnotic and anticonvulsive influence, of inhibition of monoamine oxidases, phosphodiesterase and thromboxanes, of combining central and peripheral benzodiazepine receptors and other. Bibliography contains more than 64 references.

SYNTHESIS OF ISOMERIC PYRIDAZINOINDOLES Pyridazino [b] indoles can be observed as azaanalogues of different carbolines (α-, β-, γ-, δ-), in particular β-and γ-carbolines, of condensed ring system which is the basis of many substances with a high physiological activity, including alkaloids rauvolfia [1-11]. Therefore, a unified system of isomeric piridazinoindoles containing three nitrogen atoms in various positions and their derivatives have been attracting close attention of researchers for a long time. The first representative of this group 3-p-nitrophenyl-4-oxo-3H, 5Hpiridazino [4,5-b] indole (9), was obtained by King and Stiller back in 1937 by heating a mixture of p-nitrophenylhydrazine and 2-ethoxycarbonyl-3formylindole in vacuum at 290-3000 C [12]. Later, in 1953, Staunton and Tope synthesized 3-phenyl derivatives (10) [13]. CHO COOC 2H 5 N H 9 R=NO2 , 10 R=H

R

N

NH-NH 2

N N H

R

O 9,10

Thorough study of the possibility of construction of this heterocycle and the synthesis of the derivatives was carried out under the supervision of Professor N. N. Suvorov [2]. The authors developed a general method of obtaining one of the

Pyrridazinoindoles, Synthesis and Properties

149

predominant compounds 13-15 (Scheme 1) depending on the reaction conditions. Therefore, when ratio between reagents 11, 12 and hydrazine hydrate is 1:4, corresponding hydrazone 13 is formed, in the case when hydrazine hydrate is reduced to the proportion of 1:0,725 – azine 14 is formed. Boiling the mixture in ethyl cellosolve in the ratio of 1:10 afforded oxopyridazinoindoles 15 with the yield of 90%. When the oxo compound 15 is processed with phosphoryl chloride, chlorine derivative 16 is obtained up to 65% yield. It should be noted that this method became the classical method of synthesis of derivatives of 5H-pyridazino [4,5-b] indoles. Unfortunately, no specific review of literature in which this issue would be discussed more or less completely is found. We have not observed any attempt at least to systematize sufficiently scarce data on these substances, although they have properties of great interest from many parties, including, first and foremost, the pharmaceutical point of view. This gap was filled in during the last two decades. There were many reports on the synthesis of derivatives of isomeric pyridazinoindoles and, no less valuable, the study of their diverse pharmacological activity. CH=N-NH 2 COOEt N R 13 CHO

CH=N

COOEt

11,12

COOEt

N R

N R

2 14

N

N NH

15

N R

N

POCl3

O 16

N R

Cl

Scheme 1.

Where R=H, CH3 This review is the first attempt in composing the numerous data obtained; it cannot be classified as complete, as it does not cover all the reports on this issue. An important contribution to the development of this area have been made by the group of A. Monge [3,5-7,14-16] and N. Haider [17-22]. In the work of N.

150

Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh

Haider and A. Wobus [20], the synthesis of 4,5-dialkyl derivatives of 1-oxo2H,5H-pyridazino[4,5-b]indoles (23-27) (Scheme 2) and 5-alkyl-1,4-dioxo2H,3H,5H-pyridazino[4,5-b]indoles (35-40) (Scheme 3) was described. COOH

COCH 3

N H

17

COOR

RX / KOH / DMF N

O NH N

N 2H 4 H 2O / EtOH

COCH 3

N

18-22 R

23-27

CH 3

R

18,23 R=Etyl, 19,24 R= n-propyl, 20,25 R=n-butyl, 21,26 R=n-pentyl, 22,27 R=Benzyl

Scheme 2. COOCH 3

28

NH NH

N 2H 4 H 2O / EtOH

COOCH3

N H

O

COOCH 3 RX / KOH / DMF N

COOCH3

29-34 R

35-40

N R

O

29,35 R=Etyl, 30,36 R= n-propyl, 31,37 R=n-butyl, 32,38 R=n-pentyl, 33,39 R=Benzyl, 34,40 R=allyl

Scheme 3. CHO

N N R

N H

N H

COOC2H5 11

N H

O

N H

9,15,42-46

47-53

COOC2H5 41 CH2OH

POCl3/ DMFA

N CONH-NH 2 H

N CONH-NH 2 H 54

NH N R

LiAlH4

N NH N H

55

O 15

42,48 R=2-propyl, 43,49 R=methyl, 9,50 R=phenyl, 44,51 R=CH2-CH2-N(Me)2, 45,52 R=CH2-CH2-CH2-N(Me)2, 46,53 R= CH2-CH2-piperazin-1-yl

Scheme 4.

47


151

5-Alkyl-4-methyl-1-oxo-2H,5H-pyridazino[4,5-b]indoles (23-27) were obtained from 2-acetylindole-3-carboxylic acid (17) by N-alkylation and subsequent intramolecular ring closures using hydrazine hydrate, in one stage, without intermediate hydrazones (18-22). Indolopyridazinones 23-27 were obtained by these authors previously [21] as a result of selective mono-Nalkylation in the original compound (17), taking into account the stoichiometric amount of alkylating agent. However, the last step which is pyridazine ring closure occurs with difficulty in low yields. In case of use of excessive alkylating agent (mainly alkyl iodide), esterification of oxycarbonyl group happens together with N-alkylation. High reactivity of ester group provides smooth reaction process with intramolecular hydrazinolysis during ring closure of pyridazinone. Free carboxylic acids of this type in similar conditions are readily exposed to competitive reaction of decarboxylation [23]. This reaction goes with a low yield (20-49%). Analogous method was utilized by authors [20] also in synthesis of new 5alkyl-1,4-dioxo-2Н,3Н,5Н-pyridazino[4,5-b]indoles(35-40) (scheme 3). These substances are produced by simultaneous N-alkylation and esterification of indole-2,3-dicarboxylic acid [24], with subsequent hydrazinolysis of diethers (2934). The authors managed to prepare dimethyl ethers in a pure state so that they were able to increase yield of corresponding 1,4-dioxo pyridazinoindoles (35-40) up to 62-85%. T. Nogrady and L. Morris; while continuing researches initiated by King and Stiller [12], N. N. Suvorov [2,26] and others [13,27,28]; synthesized a series of 3substituted compounds (9,42-46), at the same time, corresponding tetrahydroderivatives (47-53) (scheme 4). Compound 15 was obtained by two other authors [29,30] from 2ethoxycarbonylindole (41) using similar methods. Analogously, 8-disubstituted (59-61) and 3,5,8- trisubstituted (62-81) derivatives (Scheme 5) were synthesized [31]. N-alkylation of compounds 11,56 was processed in interphase catalysts, in the medium of benzene/concentrated NaOH solution in presence of trimethylbenzylammonium chloride. Aminomethylation of pyridazines 15,59-6 is done with the mixture of formalin and corresponding amine in ethanol. Yields in all steps of scheme 5 are high [31]. In addition to above mentioned works [3,5-7,14-16], A. Monge`s group published several interesting reports [32-34]. The main objective of this work as well as all other works discussed in the scope of this review is to search for new pharmacologically active substances. A. Monge, P. Parrado and others [32] synthesized new derivatives of pyridazinone 15, compounds (90-93) and their sulfur analogs (94-96) containing substituents in the benzene ring (Scheme 6).

152


Closing pyridazine cycle was achieved by boiling formyl derivatives (86-89) in 90% hydrazine hydrate during 2-3 hours, in the way described by the same authors previously [16]. Yields are rather high - from 75 to 98%. Sulfur analogues (94-96) were obtained by interaction of compounds (93-95) with phosphorus pentasulfide in pyridine in the presence of anhydrous calcium chloride with yields of 80-95% [32]. 1,4-dioxo-2H,3H,5H-piridazino[4,5-b]indole (97) was obtained [33] from 2,3-dimethyl ether of indoledicarboxylic acid (28), under the conditions described above (Scheme 3) for 5-alkyl-1 ,4-dioxo-2H,3H,5H-pyridazino[4,5-b]indoles (3540).

N H

COOC2H5

N H

41

N

COOC2H5

N

R

NH N

COOC2H5

R' 11,56-58

11,56

R

CHO

R

CHO

R

POCl3/ DMFA

R

N N

O

N

R'

CH2-R''

O

R'

15,59-61

62-81

R=H,Br, R'= H,C2H5, R''=N(CH3)2, N(C2H5)2, pyrrolidinyl,piperidinyl, morpholinyl

Scheme 5.

N H

P2S5/pyridyne

R

N NH

COOC2H5

N H 86-89

82-85

R

CHO

R

POCl3/ DMFA

R

COOC2H5

N H 90-93

N NH N H

S

94-96

82,86,90,94 R=CH3O, 83,87,91,95 R= C2H5O, 84,88,92,96 R=C6H5-CH2O, 85, 89,93 R=OH

Scheme 6.

O

Pyrridazinoindoles, Synthesis and Properties CHO

BnO

CN

BnO

153 H2N

BnO

N NH

88

N H

N H

COOC2H5

COOC2H5

N H

98

O 99

Scheme 7.

A. Monge and others [34] in a similar scheme synthesized 8-benyloxy-4-oxo3H,5H-piridazino[4,5-b]indole (92) and its sulfur equivalent (96). In this work the authors, using the original approach, produced 1-amino-8-benzyloxy-4-oxo3H,5H-pyridazino[4,5-b]indole (99) from the nitrile (98) (Scheme 7). The reaction was performed in boiling 90% hydrazine hydrate within 13 hours. Nitrile 98 was obtained by boiling aldehyde (88) with nitroethane in acetic acid in the presence of anhydrous sodium acetate during 15 hours. The yield is 49%. G. Zhungietu with collaborators described in the published article [39] in 1982 the synthesis of derivatives 1-oxo-pyridazino[4,5-b]indole (101) and their 6substituted isomers from o- and p- derivatives of 2-acylindole-3-yl-carboxylic acid (100) with acceptable yields (Scheme 8).

R'

COOH

O

R'

NH N

N H

COR

N H

1 00

R 101

R=Me, Ph, P-Cl-Ph, p-Br-Ph; R'=H, Me, OMe, Cl, Br Scheme 8.

N. Kogan and M. Vlasova [36] as the starting compound used hydrazide of indole-2-carboxylic acid (102, Scheme 9). They described the synthesis of 1-aryl4-oxo-1,2,3,4-tetrahydropyridazino[4,5-b]indoles (105) from indoylhydrazone derivatives of benzaldehyde (102), through the intermediate 1-aryl-2-amino-1,2dihydropyrrolo[3,4-b]indole-3-ones (104) according to the scheme 9. Indoyl

154


hydrazones 103, when heated for 3-5 minutes at 12000С in 1-pentanol saturated with HCl, cyclize up to 60-80% yield with the formation of 1-aryl-2-amino-1 ,2dihydropyrrolo[3,4-b]indole-3-ones (104), which further isomerize to 1-aryl-4oxo-1,2,3,4-tetrahydropyridazino[4,5-b]indoles (105). Later [37], these compounds were oxidized to 1-aryl-4-oxo-3,4-dihydropyridazino[4,5-b]indoles (106). N. Kogan and M. Vlasova [38] have proposed an original approach to the synthesis of compounds of type 1-aryl-4-oxo-3,4-dihydropyridazino[4,5-b]indoles (106). They obtained 1,2,3,4-tetrahydropyridazino[4,5-b]indoles (109) from αacetyloxy and α-halogen derivatives of 1-methyl-2-ethoxycarbonyl-3benzylindole 107 (Scheme 10) in reaction with phenylhydrazine. 1,2,3,4tetrahydropyridazino[4,5-b]indoles (109) were, after oxidation with permanganate, converted into corresponding dihydro derivatives 110. Monge and others [34], from 5-benzyloxy-indole-2-carboxylic acid hydrazide (111, Scheme 11) synthesized isomeric 1-oxopyridazino[4,5-a]indole in the form of 7-benzyloxy-1,2-dihydro derivative (112) from which was obtained the corresponding sulfur analogue (113) and full aromatic hydrazine (114). 7Benzyloxy-1,2-dihydro-1-oxopyridazino[4,5-a]indole (112) was formed by boiling a mixture of hydrazide 111, orthoformic ether and dimethylformamide for 5 hours (65% yield). In this paper is described a very interesting transformation of isomeric 7-benzyloxy-pyridazino[4,5]indoles and the research of pharmacological activity of derivatives, which are mentioned below.

N 102

CONHNH2 N

R'

CONHNCHC6H4R

R'

103

C6 H4R

C6H4R

C6 H4R

KMnO 4

NH

N NH2

N

NH N

O

R' 104

R=H, p-Me, p-OMe, p-Cl; R'= H, Me

Scheme 9.

N

R' 10 5

O

NH N

R' 10 6

O


X

155

C 6H 4 R

C 6 H4 R

NH-NHPh N Me 107

COOMe

COOMe

N Me

108 C 6H 4R

C 6H 4R KMnO 4

NH

N

N-Ph N Me R=H, p-NO2, p-Cl;

N-Ph N Me

O

109

O

11 0

X= OCOCH3,Cl,Br

Scheme 10. C 6H 5 H2 CO

C6 H5 H2 CO O N H

CONHNH 2

N

111 112

C 6 H5 H2 CO

N

NH

C 6 H5 H2 CO S

NH-NH 2

N 113

N

N

NH 114

N

N

Scheme 11.

Hungarian chemists [39] developed an original general method for the synthesis of condensed diazine containing heterocyclic systems, including 4oxopyridazino[4,5-b]indoles (119a R = Ph) (Scheme 12). In contrast to the methods already discussed, the target heterocycle (119) are synthesized through attachment of indole ring to pyridazine. The reaction of aminoarylation derivatives of pyridazine 115a (R = Ph, X = Cl) was conducted in a system of

156


dimethyl ether of ethylene glycol / water / Na2CO3 in presence of Pd(Ph3)4 with a high yield (95%) of diarylpyridazinone 116a (R = Ph). Transformations 116 118 119 go smoothly with the yield of 60-72%. The final phase was 117 carried out by boiling in o-dichlorobenzene within 1 hour. 4-Oxopyridazino[4,5b]indoles 119b, (R = H) (Scheme 12) were synthesized as well. The authors [40] used pyridazine derivative as starting substance 115c (R = H, X = I). N. Haider and R. Wanko [41] developed a method for the synthesis of pyridazino[4,5-b]indoles omitting the intermediate stage of oxo derivative production (Scheme 13). The target heterocycle (124) was formed as a result of attachment of indole pyrrole ring(121) as in the case of dienophile to azadiene - to 1,2,4,5-tetrazine ring of compound 122. The reaction is carried out in one stage without the adduct 123. The method worked by thse group of U. Pindur [42] is also based on the use of diene synthesis (Scheme 14). Unlike the previous method (Scheme 13), here derivatives of indole 125 are used as a diene, as dienophile - compounds containing N=N group (126 and 127, Scheme 14). The reaction was carried out in toluene or chlorous methylene at -75 to +200 C for 0,2 - 2 hours. The yields of adducts 128 and 129 were respectively 92% and 82%. B(OH)2

O Me

O

N

NH-Ac Me N Pd(Ph 3)4/Na2CO 3/DME/H 2O

N

N

X R

NH-Ac

R

115a-d

116a,b

O Me

O

O

Me NH2

N N

1) NaNO 2 2)NaN3

N N

R 117a,b R=H, Ph; X=Cl, I; DME = MeOCH2CH 2OMe

Scheme 12.

N3

Me

H N

N N

R

R 118a,b

119ab


N N H 121

F3C

CF3

SMe

N

MeS

F 3C

-N2

N N H 123

CF3 122

N

N

N N

157

H

N

-MeSH N H

CF3

CF3

124

Scheme 13. OMe

O OMe

N R

N

O

N N 126

N H

N

Ph

O

R 128

EtOO C-N =N 127 -COOEt

OMe

125

N N N H

R=H, Alk, SO2Ph

O

N N

Ph

COOEt COOEt

R 129

Scheme 14.

The group of Italian chemists [43] developed a very interesting and original method for the synthesis of isomeric pyridazino[4,3-b]indoles (133, Scheme 15) using isatine as a starting substance (130). Through the interaction of isatine with phosphorus pentachloride in boiling absolute benzene, they obtained 2-chloro-3oxo-indolenine (131), which was condensed with sodium benzoyl acetic ether by boiling in absolute dioxane with the formation of compounds 132. 3-Aryl-4ethoxycarbonyl-5H-pyridazino[4,3-b]indoles (133) were obtained by boiling solution of 132 and hydrazine hydrate in ethyl alcohol with 50% yield. In this work the authors described some transformations of pyridazino[4,3-b]indoles (133) and pharmacological activity of obtained derivatives, which are mentioned below.

158

Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh O

O

Cl

O 130

O

131 N

N O

R COOEt

N H

R

CO

N H

N

N H

133

OE

132

t

R=H, NO 2

Scheme 15.

O

O

R

R CN

CN

N H

N

134

136

R2

R'

N N

R

NH 2

R'

N N

R

NH 2

N H

N R2

135

R'

R=H, Br, Me; R'= H, F, Me, i-Pr, OMe, Cl, Br, NMe2; 2 R =Me, Et, n-Pr, Bn, (CH 2)2NMe2 Scheme 16.

137

R'


159

B. Velezheva and others [44] worked out a method on the basis of isatine derivatives. As an initial substance they used oxonitriles 134 (Scheme 16) obtained from isatine. The compounds 136 were obtained by alkylation of intermediate N-sodium salts of oxonitriles. By boiling oxonitriles 134 and their N-alkylated derivatives 136 with traditional hydrazine hydrate in acetic acid, corresponding pyridazino[4,3-b]indoles 135 and 137 were formed. Further authors described some transformations of pyridazino[4,3-b]indoles (135 and 137) and pharmacological activity of obtained derivatives which are discussed below. Thus, given material allows to conclude that quite an interesting development has been made in this direction, and that in future many, even more, interesting reports can be expected.

2. SYNTHESIS, CHEMICAL PROPERTIES AND PHARMACOLOGICAL ACTIVITY OF THE DERIVATIVES OF PYRIDAZINOINDOLES As noted above, the main goal of the research in this area lies in the synthesis of new substances which are potentially pharmacologically active ingredients of drugs. Substances showing somehow biological activity, as a rule, contain functional groups capable of interacting with biomolecules. In some papers such groups are introduced by the authors beforehand, before the closure of the pyridazine ring [42-44]. In the rest of considered pyridazinoindole groups, mostly they are not in the same way; therefore, the authors of above discussed works investigated the possibility of changing functions or introduction of new groups. Achieving such a goal would be possible by the study of chemical properties of the synthesized indolopyridazinones. Investigation of chemical properties of the synthesized indolopyrridazinone derivatives was carried out by the considered authors, as well as of other papers, with the purpose of changing the functions of carbonyl groups and aromatization of pyridazinone ring. This purpose was achieved through the intermediary chloro or thio derivatives, which possess high reactivity as compared with the cyclic hydrazide carbonyl, as already been considered in the diagrams 1, 6 and 11. In some works authors conducted reduction of chloro and oxo compounds, obtaining the corresponding aza-carbolines [2], and 1,2,3,4-tetrahydroderivatives [22,25]. The

160


ones produced from 1,4-dioxo derivatives 35-40 (Scheme 3) and 1,4-dichloro derivatives (Scheme 17) [20,33] possess rich synthetic possibilities. Corresponding amino- [34], alkylamino- [31], aminoalkylamino [30], hydrazino- [22,32,34,37], piperazino- [31] and other [31,45-47] derivatives, having the ability to interact with biomolecules were obtained from these compounds. It is interesting whe work of Giiven and Jones [46], in which the authors studied the equilibrium of 1,4-diokso-pyridazino[4,5-b]indole among four tautomers (147a-d, Scheme 18) in aqueous solution. In the mixture the dominant one is 4-hydroxy-1-oxopyridazino[4,5-b]indole (147 b). The ratio of the forms 147a: 147b: 147s: 147d occurs as 104,93:108,03:103,6:1. The authors investigated the effect of various substituents. Investigation of not less interest was conducted by Monge and coworkers [32]. They conducted a series of transformations given in Scheme 19. Compounds 148-150 revealed physiological activity (see below).

NH N 15 R

N

N

N

N

N

POCl3 N R

O 16

N

Cl

NH-X

144 R

R=H, CH3 R

P2S5/pyridyne

N

R

N H

N N

NH N H

O

S

N H

94-96

90-93 O NH N

O

R 35-40

H2NHN N

POCl3

N N

N

NHNH2 145

Cl NH

Cl

R 138-143

35,138 R=Etyl, 36,139 R= n-propyl, 37,140 R=n-butyl, 38,141 R=n-pentyl, 39,142 R=Benzyl, 40,143 R=allyl

Scheme 17.

R

N

NH

N N

NHNH2

R 146

Pyrridazinoindoles, Synthesis and Properties O

HO

O NH

N H

N H

N OH H 147b

O

N

NH

N

147a

HO N

NH

NH

161

N N H

O

OH

147d

147c

Scheme 18. R

N

R

R3COOH

N

N N H

N

NHNH2

145

N H

Na NO

2

R

N N 149

/H+

O=CR1R2

R

N N

N N N H

N N N

N H

NHN=CR'R''

148

R3

150

R=H, OH, OMe, OBn; R1=Me, Ph; R2=R3=Me, H;

Scheme 19.

El-Gendy and El-Banna [31] conducted aminomethylation of Mannich derivatives of 4-oxopyridazino[4,5-b]indole (Scheme 20). Compounds 152 in the form of quaternary salts showed antihypertensive activity. R

R

N

N N CH 2- R2

NH

151

N R1

O 152

N R1

O

R=H, Br; R1=H,Et; R2=NMe2, pyrrolidinyl, piperidyl, morpholinyl Scheme 20.

162

Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh R

Cl

Cl

N-Hetaryl

N H

Cl

R'

N

N

N N H 138

N

N

N

N H

NHNH 2

N N 155

154 Me

Me

Cl R

N N

N

N N

N

N N H

R 153

N N H

N N Me

1 56

Me

N H 1 57

N N Me Me

153 R=H, NHNH2, imidazolyl, 4-(2-mtoxyphenyl)piperazinyl; 155R=Cl, COOEt, R'=NH 2NH2, CONHNH 2

Scheme 21.

Monge and others [33], from 1,4-dichloro-pyridazino[4,5-b]indole (138), synthesized mono and dihydrazino derivatives 153, 154 and compounds containing one or two N-heterocycle (156, 157), as well as the derivatives of tetracyclic system 155 (Scheme 21). In literature there are numerous reports in this area [48-64]. However, neither those described substances in these papers, nor the synthetic methods used are fundamentally different from the works considered. Therefore, from these reports, we depict only the results of biological activity. Isomeric pyridazinoindoles are azaanalogues of α-, β-, γ-, and δ- carbolines, condensed ring systems of which is the basis of many substances with a high physiological activity. The core of pyridazino[4,5-b]indole is very interesting from the pharmaceutical point of view due to its bioisostere with β-carboline as seen in the original structure of many bioactive compounds. For many years groups of Monge and Heider, as well as other researchers, thoroughly studied the synthesis and biological activity of derivatives of various representatives of ―azacarboline‖ ring. The focus of authors was mainly on potential antitumor agents [20-22, 48], inhibitors of monoamino oxidases [25,44,47,49,53] and thromboxanes [32-34,59-61], etc. In-vitro screening of compounds synthesized by Heider and others [22] showed that only 159 (R = Ph), 160 (R=CH3, CH2CH2Ph) and 162 (NR1,2=diethyl


163

amino) revealed weak anti-tumor activity. Antiproliferative activity of compounds 159 and 160 with respect to growth of adenocarcinoma cells RKOp27 did not exceed 50%, as for 162 - 72%.

N N N H 158

N

ROC-HNHN

H2NHN

N N

RCOCl

N

34%

N H

Me

N

92% N H

Me 159

H N

CS2 /KOH /EtOH N

S N

Me 160 N

NR'2 Cl CH3COONa EtOH

N

S N N

N N H

R N

POCl3

N H

Me

NR'2

Me 162

161 R= H, Me, Et,(CH2)2Ph, COOEt,CH2COOEt; NR'2=diethylamino, morpholino

Scheme 22.

R3 R3 R1 R2

N

N N H 163

R

N

R3 R

R1

N

R2

N H 164

Scheme 23.

3

N H

N

165

N

R=R1=R2=H,Me;

R3=Me,Et;

164

Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh O NR'R 2 X N N N R

O 166

X=H,Hal, Me,JMe, OCH 2Ph; R=H,C 1-4alkyl; R'=R2=H,C1-4alkyl,CH2Ph, or NR'R 2 =azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl

Scheme 24.

Italian researchers synthesized a new class of DNA intercalators [53], based on the four core containing system of pyridazino-[1',6:1,2]-pyrido[4,3-b]-indole (163, Scheme 23). Compounds 163-165 were used in the form of mesitylsulfonates. In 1999, a group of French researchers patented [54] compounds with general formula of 166 (scheme 24) which had a hypnotic and anti-convulsive effect in the doses of 0.1-1mg / kg. Authors also described a method for the synthesis of these substances. The same group [56], also Japanese [57] and English [64] researchers have identified similar activity of aryl- and hetaryl derivatives of pyridazino[4,3-b]indole and pyridazino[4,5-b]indole. In the patents of the United States in 1998 [55] was reported that the derivatives of pyridazino[4,5-b]indole often revealed expressed activity against Alzheimer's and Parkinson's diseases as well as Down syndrome. The antihypertensive activity of the pyridazino[4,5-b]indole derivatives was reported in publications [3,31,32,37,58,59]. Compounds of type 152 [31], 153 [3,32,58], 106 [37] revealed a weak or average antihypertensive activity. Compounds of type 132, 133, 135, 137 and their derivatives showed ability to bind the central and peripheral benzodiazepine receptors [43,45,48,51,56], thereby promoting restoration of the damaged nerve endings. Effects of anti-inflammatory activity [9,25,61-64] of derivatives of 4-oxo-pyridazino[4,5-b]indole and 3-oxopiridazino[4,3-b]indole were also reported. 2-aryl-3-oxo-pyridazino[4,3-b]indole-4-carboxylic acid and its derivatives revealed activity against gram-positive and gram-negative bacteria together with antifungal activity [52]. It was also reported about tuberculostatic activity and the ability of inhibition of monoamine oxidases [25, 44, 47, 49, 51], phosphor-


165

diesterases [33] and aggregation of blood plate [32, 34, 59-61] and the inotropic activity [33, 34]. Derivatives of 1, 4-dioxopyridazino[4,5-b]indole also possess luminescent properties[33]. In conclusion we can say that numerous significant scientific data were collected in the scientific area of the synthesis and study of isomeric pyridazinoindole derivatives. A number of interesting new substances were synthesized. They draw attention from many sides including the pharmacological point of view. The attempts which have already been done allow us to consider a promising present and future research in this area.

ACKNOWLEDGEMENT The designated project has been fulfilled by financial support of the Georgian National Science Foundation (Grant № GNSF/ST07/4-181). Any ideas of this publication possess authors and may not represent the opinion of the Georgian National Science Foundation itself. We also would like to thank the Deutsche Academy Austausch Dienst (DAAD) for supporting the partnership and the exchange program between Ivane Javakhishvili Tbilisi State University and Saarland University.

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[4] [5]

General Organic Chemistry, edited by D. Barton and W.D. Ollise, Moscow: publ. “Chemistry”, 1985, v. 8, p. 751. (Russian) Suvorov N.N., Ovchinikova G.D., Sheincker U.N. ―Indole derivatives‖. – JOC, 1961, v. 31, p. 2333-2339. Monge A., Aldana I., Alvarez T. and etc. ―1-Hydrazino-4-(3,5-dimethyl-pyrazolyl)-5H- pyridazino[4,5-b]indole, A new antihypertensive agent‖– Eur. J. Med. Chem., 1991, v. 26, p. 655-658. Lerch U., Kaiser J., De 3121137, 1982. Chem. Abstr. 1983, v.98, ref.126140. Monge A., Aldana I., Losa M.J., and etc. “New pyridazino[4,5-b]indole derivatives with inodilator and antiaggregatory activities” – ArzneimForsch., 1993, v.43, p. 1175-80.

166 [6] [7] [8] [9]

[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

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Chapter 6

11-PERFLUOROALKYL-SUBSTITUTED 3,3-DIMETHYL-11-HYDROXY-2,3,4,5,10,11HEXAHYDRO-1H-DIBENZO[B,E][1,4]DIAZEPIN1-ONES: SYNTHESIS AND CHARACTERIZATION Tatyana S. Khlebnicova*, Veronika G. Isakova, Alexander V. Baranovsky and Fedor A. Lakhvich Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha Street 5/2, 220141 Minsk, Belarus

ABSTRACT Novel 11-perfluoroalkyl-substituted 3,3-dimethyl-11-hydroxy-2,3,4,5, 10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones are prepared via a simple two-step approach. A treatment of 2-perfluoroalkanoylcyclohexane1,3-diones with ethereal solution of diazomethane gives 5,5-dimethyl-3methoxy-2-perfluoroalkanoylcyclohex-2-en-1-ones as main products and 6,6dimethyl-3-hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones as by-products. Then, an initial methoxy group vinylogous substitution of enol ethers by one of the o-phenylenediamine amino groups and an intramolecular cyclization leads to the title compounds in high yields. *

[email protected]

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T. S. Khlebnicova, V. G. Isakova, A. V. Baranovsky et al.

INTRODUCTION Benzodiazepines constitute an important class of heterocycles due to their psychopharmacological, analgesic and other kinds of biological activities [1]. Today, many benzodiazepines are widely used as anticonvulsants and muscle relaxants, daytime sedatives, tranquilizers, sleep inducers and anesthetics [2]. In particular, dibenzo[b,e][1,4]diazepines may be active as antidepressants, antihistaminics, anticonvulsants and other pharmacological agents [3]. Although various methods for the synthesis of dibenzo[b,e][1,4]diazepinone derivatives have been reported [4], they continue to receive a great deal of attention. The selective introduction of fluorine atoms or fluoroalkyl groups into an aromatic ring or heterocyclic moiety to modify the bioactivity of organic molecules is a well-established practice [5]. Due to the three electrophilic centers, 2perfluoroalkanoylcyclohexane-1,3-diones present significant interest as versatile agents for introducing polyfluoroalkyl groups in various heterocyclic systems [6]. In this chapter, we wish to report a synthesis of novel dibenzo[b,e] [1,4]diazepinones, bearing a fluoroalkylcarbinol moiety, from 2-perfluoroalkanoylcyclohexane-1,3-diones.

RESULTS AND DISCUSSION We investigated an interaction of 2-acylcyclohexane-1,3-diones 1a–c containing a perfluoroalkylated side chain with o-phenylenediamine. A direct reaction of the latter with o-phenylenediamine produces a mixture of acid cleavage products, as reported for their acyclic analogues [7]. As an alternative approach to the synthesis of perfluoroalkylated dibenzo[b,e][1,4]diazepinones, an interaction of enol ethers of 2-perfluoroalkanoylcyclohexane-1,3-diones 1a–c with o-phenylenediamine is proposed, because of an advanced reactivity of enol ethers to nucleophilic reagents versus the initial cyclic β,β'-triketones [8].

11-Perfluoroalkyl-substituted 3,3-Dimethyl-11-hydroxy-…

O

O

O RF

O 1a-c

CH2N2

H2N

O RF

H2N

OMe

O

O RF H2N NH

2

O

10

9

5

N 5a-c H

6

8 7

O RF OH O

3a-c

O HO RF 11 NH 1

3 4

2a-c

173

RF O 4a-c

RF = CF3(a), C2F5(b), C3F7(c)

We attempted to synthesize methyl enol ethers of 2-perfluoroalkanoylcyclohexane-1,3-diones 1a–c by the methods used for 2-acetylcyclohexane-1,3diones, which included O-alkylation of the silver salts with methyl iodide [9] or their sodium or tetrabutylammonium salts with dimethyl sulfate in acetone [10]. However, target enol ethers have not been isolated, since they appear to be rather labile under reaction conditions and hydrolyzed into β,β'-triketones 1a–c during isolation. The reaction of non-fluorinated cyclic β-diketones with ethereal solution of diazomethane is one of known methods for preparing methyl enol ethers in mild conditions [11]. Nevertheless, for 2-acetylcyclohexane-1,3-diones, a complex mixture of products is formed and target enol ethers have not been obtained [12]. In our case, a treatment of 2-perfluoroalkanoylcyclohexane-1,3diones 1a–c with ethereal solution of diazomethane at 0ºC for 15 min and further stirring for 5 h at room temperature gives 5,5-dimethyl-3-methoxy-2-perfluoroalkanoylcyclohex-2-en-1-ones 2a–c in 58–71% yield and 6,6-dimethyl-3hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones 3a-c as byproducts. The ratio of products changes depending on the length of perfluoroacyl chain (NMR 1H 1.4:1, 2.5:1 and 1.8:1, respectively). Refluxing of compounds 3a– c in benzene for 4 h in the presence of catalytic amount of p-toluene sulfonic acid in benzene leads to dehydration and affords 6,6-dimethyl-3-perfluoroalkyl-6,7dihydrobenzofuran-4(5H)-ones 4a–c in 78–82% yield. Obtained methyl enol ethers 2a–c are easily converted into the title compounds 5a–c by their treatment with an equivalent amount of ophenylenediamine in ether at room temperature for 5 h. Thus, an initial methoxy group vinylogous substitution of enol ethers 2a–c by one of the ophenylenediamine amino groups and an intramolecular cyclization leads to the dibenzo[b,e][1,4]diazepinones 5a–c bearing a fluoroalkylcarbinol moiety in 70–

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72% yield. The cyclic products 5a–c are stabilized by participation of the hydroxyl group in an intramolecular hydrogen bonding with the carbonyl group of the cyclohexenone fragment and presence of a strongly electron-withdrawing group that hinders an elimination of water. As it is known [13], an interaction of enol ethers of non-fluorinated 2-acylcyclohexane-1,3-diones with o-phenylenediamine in similar conditions leads exclusively to acyclic enamino derivatives. The structures of all synthesized compounds are confirmed by elemental analysis, their IR, 1H, 13C and 19F NMR data. IR spectra of enol ethers 2a–c show three characteristic absorption bands at 1720–1735 (unconjugated carbonyl), 1645–1655 (conjugated carbonyl) and 1590–1605 (double bond) cm-1 and in 1H NMR spectra of 2a–c, singlet of methoxy group protons appears at 3.86–3.88 ppm. In IR spectra of 2,3,6,7-tetrahydrobenzofuran-4(5H)-ones 3a–c, the characteristic frequencies in the range of 1610–1655 cm-1 corresponding to conjugated carbonyl (1640–1655 cm-1) and double bond (1610– 1625 cm-1) are found. IR spectra of 6,7-dihydrobenzofuran-4(5H)-ones 4a–c show absorption bands of conjugated carbonyl (1685–1690 cm-1) and double bond (1565–1570 cm1 1 ). H NMR spectrum of 3a is characterized by two pairs of doublets (due to nonequivalence of protons at С2 and С7) at 4.46–4.75 ppm (2J 11.4 Hz) and 2.22– 2.32 ppm (2J 16.4 Hz), but 1H NMR spectra of 3b,c – by three pairs of doublets (due to non-equivalence of protons at С2, С5 and С7) at 4.45–4.85 ppm (2J 11.5 Hz), 2.36–2.42 ppm (2J 17.9 Hz) and 2.21–2.33 ppm (2J 16.4 Hz). In 1H NMR spectra of compounds 4a–c, multiplet signal of vinyl proton appears at 7.66– 7.69 ppm. In 13C NMR spectra of compounds 3a–c, signals of the C2, C3 and C4 carbon atoms are observed at 79.55–79.90, 79.86–80.93 and 194.31–194.66 ppm, while the C2, C3 and C4 carbons signals of compounds 4a–c are observed at 144.18–144.54, 113.38–115.15 and 190.42–191.16 ppm, respectively. The IR spectra of title compounds 5a–c show absorption bands of a conjugated carbonyl (1610 cm-1), a double bond (1540–1550 cm-1) and a vinylogous amide (1505–1510 cm-1). 1H NMR spectra of 5a–c are characterized by three broadened singlets in the range of 5.29–5.40 (NH), 9.06 (NH) and 10.6411.32 (OH) ppm. In 13C NMR spectra of compounds 5a-c, signals of the carbon atoms C1 (carbonyl group), C4a and C11 are observed at δ 200.01–200.53, 160.22–160.65 and 87.68–90.08 ppm, respectively. In 19F NMR spectrum of compounds 5a, singlet at δ -80.54 ppm is assigned to the fluorine atoms of an trifluoromethyl group. In the 19F NMR spectrum of compounds 5b and 5c, signals of fluorine atoms are observed at δ -79.00 (s, 3F), -115.21 (d, JF-F = 273.2 Hz, 1F), -124.75 (d, JF-F = 273.5 Hz, 1F) and at δ -81.97 (m, CF3), -110.53 (dm, JF-F =


175

279.1 Hz, 1F), -120.50 (dm, JF-F = 279.2 Hz, 1F), -123.06 (dd, JF-F = 291.5, 11.3 Hz, 1F), -125.84 (dm, JF-F = 290.5 Hz, 1F), respectively. The complete assignment of all atoms of 5a, including spatial relationships between protons, has been done by use of 2D NMR spectroscopy on 1H, 13C and 15 N nuclei. principal HMBC C-H connections

H

H

H

O

H

HMBC N-H connections

H

O

H

N

H

H

H

H H

H

F

H

N H

H

H

O

H

N

H

H

F H

H

H

F

H

H

H

O

H

H

N H

F H F

H

H

H

F

H

H principal NOESY connections

H

H

H

O

H

H

O

H

N

H

H

H H

H

H

H

F

N H

F H F

H

H

Figure 1. Principal HMBC and NOESY connections of 5a.

The assignment of protonated carbons and nitrogens is straightforward and follows from HSQC, COSY and HMQC 15N correlations. Relative stereochemistry of the cyclohexenone ring protons and methyl groups was established by analysis of NOESY spectrum as well as COSY spectrum (Table 1). Quaternary carbons atoms were deducted via their long-range couplings in HMBC spectrum and the assignment of the aromatic ring protons was confirmed by analysis of HMBC 13C, HMBC 15N spectra and NOE correlations. We assume that the CF3-group is under the plane and the hydroxy group has hydrogen bonding with carbonyl; therefore, axial protons are over the plane and the axial methyl group under the plane. Hence, the protons with resonance at 2.26 (C2) and 2.67 (C4) ppm occupy pseudo-equatorial position. This follows from observation of cross-peak between these protons in COSY spectrum (w-constant) and their appearance as doublet of doublets in 1D 1H NMR spectrum. The equatorial proton at C4 interacts with proton at N5 in the NOESY and N5 in

176


HMBC 15N spectra. Methyl group at 1.04 ppm has more intensive cross-peaks with these protons, and the second methyl group does more intensively with axial protons. Due to that and the value of chemical shift, the methyl group at 1.04 ppm was assigned as axial. The axial protons of the cyclohexenone ring have clear NOE cross-peaks. Discrimination of protons at C6 and C9 was based on observations of their interaction with nitrogen nuclei in HMBC 15N and amine protons in NOESY spectra. Table 1. NMR chemical shifts, assignments and HMBC, NOESY responses in the spectra of 5a

*

#

C, N

H

HMBC correlations*

1 4a 9a

200.53 160.22 135.81

— — —

5a CF3 8 7 9

131.54 127.26 126.78 122.99 122.28

— — 6.98 6.84 7.11

6 11a

122.01 104.54

7.09 —

11 2

87.68 52.13

4

48.15

3 Me2 Me1 N5 N10 OH

32.64 29.45 27.53 130.9 85.7 —

— 2.26eq 2.35ax 2.67eq 2.78ax — 1.09 1.04 9.06 5.29 10.64

HMBC 2, Me2, OH HMBC 4, Me2 HMBC 6, 8, 7 (w), OH, 10 (vw) HMBC 9, 7, 8 (w), 10 (w) — HSQC 9 HSQC 6 HSQC 8, HMBC 10 (w), N10 HSQC 7, HMBC N5 HMBC 4 (s), 2 (w), OH (s), 10 HMBC OH —

s: strong; w: weak; vw: very weak

HMBC N5 HMBC Me, 2, 4 HMBC C1 (w), C4a (w) — HMQC, HMBC 4, 6 HMQC, HMBC OH, 9 —

NOE correlations* — — — — — — — 10 5 — — — 4ax 5 2ax, 5 — ax eq — — 10(w)


177

The carbon atom of trifluoromethyl group has no cross-peaks in HMBC spectrum but can be easily found having coupling with fluorine nuclei. The quaternary carbon C5a and C9a interacts with H9, H7 and H6, H8, respectively (Figure 1). For C5a, the cross-peak was found with proton at N10. Such correlation with H10 also shows C11a, which also has a cross-peak with the axial C4 proton. Two correlations were observed for C4a carbon: with protons of equatorial methyl group and equatorial proton at C4.

CONCLUSION A synthetic route to novel 11-perfluoroalkyl-substituted 3,3-dimethyl-11hydroxy-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones by a methylation of 2-perfluoroacylcyclohexane-1,3-diones into their methyl enol ethers followed by an interaction of the latter with o-phenylenediamine is described. This approach represents an effective synthetic methodology for synthesis of dibenzo[b,e][1,4]diazepin-1-ones bearing a fluoroalkylcarbinol moiety, which can be very important for biological activities.

EXPERIMENTAL Melting points were measured on Boetius apparatus and were uncorrected. The NMR spectra were recorded in 5 mm tubes in CDCl3 (compounds 2a–c, 3a– c, 4a–c) and acetone-d6 (compounds 5a–c) solutions on a Bruker AVANCE–500 spectrometer. Operating at 1Н (500 MHz), 13С NMR (125 MHz) and 19F NMR (470 MHz) tetramethylsilane (TMS) was used as an internal standard for the spectra in CDCl3 and solvent signals (acetone-d6) as indirect internal standards. CCl3F was used as an external standard. 2D Experiments were conducted and processed with standard Bruker program package. The progress of the reactions was monitored by thin-layer chromatography on TLC aluminium backed sheets with Silica gel 60 F254 (Merk), a preparative thin-layer chromatography was carried out on Silica gel 60 HF254 (Aldrich) and a column chromatography was carried out on Silica gel 60 (Aldrich).

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Reaction of 2-Perfluoroalkanoylcyclohexane-1,3-diones 1a–c with Diazomethane To a stirred solution of a triketone 1a–c [14] (1 mmol) in Et2O (10 ml), an ethereal solution of diazomethane (2.5 ml) was added dropwise for 15 min at 0ºC. Then, the reaction mixture was stirred for 5 h at room temperature. Removal of the solvent under reduced pressure and preparative thin-layer chromatography (diethyl ether/hexane) of the residue gave compounds 2a–c and 3a–c in 58% (2a), 71% (2b), 64% (2c) and 42% (3а), 29% (3b), 36% (3c) yields. Recrystallization from diethyl ether/hexane furnished products 2a–c and 3a–c as colorless solids. 5,5-Dimethyl-3-methoxy-2-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (2a). Yield: 58%, white solid. Mp: 77–80ºC. IR ν (cm-1): 1735, 1655, 1605. 1H NMR (CDCl3) δ: 1.14 (s, 6Н), 2.30 (s, 2Н), 2.53 (s, 2Н), 3.88 (s, 3Н). 13C NMR (CDCl3) δ: 28.26, 32.04, 39.32, 49.91, 56.88, 114.48, 115.10 (q, 1J = 291 Hz), 178.03, 184.72 (q, 2J = 38 Hz), 194.54. 19F NMR (CDCl3) δ: -77.16 (s, 3F). Anal.Calcd for С11Н13F3O3: С 52.80; Н 5.24. Found: С 52.68; Н 5.20. 5,5-Dimethyl-3-methoxy-2-(2,2,3,3,3-pentafluoropropanoyl)cyclohex-2-en-1one (2b). Yield: 71%, white solid. Mp: 81–84 oC. IR ν (cm-1): 1725, 1645, 1595. 1 H NMR (CDCl3) δ: 1.15 (s, 6Н), 2.29 (s, 2Н), 2.52 (s, 2Н), 3.86 (s, 3Н). 13C NMR (CDCl3) δ: 28.22, 32.12, 38.78, 49.81, 56.50, 106.36 (tq, 1J = 268 Hz, 2J = 38 Hz), 115.15, 118.08 (qt, 1J = 288 Hz, 2J = 35 Hz), 177.27, 188.08 (t, 2J = 29 Hz), 194.21. 19F NMR (CDCl3) δ: -81.65 (bs, 3F), -122.01 (bs, 2F). Anal.Calcd for С12Н13F5O3: С 48.01; Н 4.36. Found: 48.15; Н 4.42. 5,5-Dimethyl-2-(2,2,3,3,4,4,4-heptafluorobutanoyl)-3-methoxycyclohex-2-en1-one (2c). Yield: 64%, white solid. Mp: 65–68 oC. IR ν (cm-1): 1720, 1650, 1590. 1 H NMR (CDCl3) δ: 1.15 (s, 6Н), 2.29 (s, 2Н), 2.52 (s, 2Н), 3.86 (s, 3Н). 13C NMR (CDCl3) δ: 28.23, 32.12, 38.78, 49.84, 56.42, 107.90 (tt, 1J = 269 Hz, 2J = 32 Hz), 108.77 (tm, 1J = 267 Hz), 115.32, 117.51 (qt, 1J = 288 Hz, 2J = 34 Hz), 177.24, 187.94 (t, 2J = 29 Hz), 194.11. 19F NMR (CDCl3) δ: -80.94 (m, 3F), 119.09 (m, 2F), -126.26 (m, 2F). Anal.Calcd for С13Н13F7O3: С 44.58; Н 3.74. Found: С 44.61; Н 3.79. 6,6-Dimethyl-3-hydroxy-3-trifluoromethyl-2,3,6,7-tetrahydrobenzofuran4(5H)-one (3a). Yield: 42%, white solid. Mp: 68–71ºC. IR ν (cm-1): 1655, 1625. 1 H NMR (CDCl3) δ: 1.11 (s, 3Н), 1.12 (s, 3Н), 2.22 (d, 2J = 16.4 Hz, 1H), 2.32 (d, 2 J = 16.4 Hz, 1H), 2.38 (s, 2Н), 4.46 (dm, 2J = 11.4 Hz, 1H), 4.75 (dm, 2J = 11.4 Hz, 1H). 13C NMR (CDCl3) δ: 28.09, 28.52, 34.27, 37.96, 50.88, 79.55, 80.93 (q, 2 J = 33 Hz), 110.31, 124.64 (q, 1J = 284 Hz), 181.86, 194.31. 19F NMR (CDCl3) δ: -80.04 (s, 3F). Anal.Calcd for С11Н13F3O3: С 52.80; Н 5.24. Found: С 52.92; Н 5.29.


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6,6-Dimethyl-3-hydroxy-3-perfluoroethyl-2,3,6,7-tetrahydrobenzofuran4(5H)-one (3b). Yield: 29%, white solid. Mp: 58–61ºC. IR ν (cm-1): 1640, 1610. 1 H NMR (CDCl3) δ: 1.11(s, 3Н), 1.12 (s, 3Н), 2.21 (d, 2J = 16.4 Hz, 1H), 2.33 (d, 2 J = 16.4 Hz, 1H), 2.36 (d, 2J = 17.9 Hz, 1H), 2.42 (d, 2J = 17.9 Hz, 1H), 4.45 (dt, 2 J = 11.5 Hz, 3J = 2.7 Hz, 1H), 4.85 (dt, 2J = 11.5 Hz, 1H). 13C NMR (CDCl3) δ: 28.11, 28.57, 34.21, 38.01, 50.90, 79.90, 81.59 (t, 2J = 26 Hz), 109.97, 113.72 (tq, 1 J = 261 Hz, 2J = 35 Hz), 119.09 (qt, 1J = 287 Hz, 2J = 36 Hz), 181.57, 194.66. 19F NMR (CDCl3) δ: -80.18 (bs, 3F), -120.86 (dm, JF-F = 275.5 Hz, 1F), -125.28 (dm, JF-F = 275.5 Hz, 1F). Anal.Calcd for С12Н13F5O3: С 48.01; Н 4.36. Found: С 48.17; Н 4.41. 6,6-Dimethyl-3-hydroxy-3-perfluoropropyl-2,3,6,7-tetrahydrobenzofuran4(5H)-one (3c). Yield: 36%, white solid. Mp: 67–70ºC. IR ν (cm-1): 1655, 1620. 1 H NMR (CDCl3) δ: 1.13 (s, 3Н), 1.14 (s, 3Н), 2.23 (d, 2J = 16.4 Hz, 1H), 2.36 (d, 2 J = 16.4 Hz, 1H), 2.37 (d, 2J = 18.0 Hz, 1H), 2.43 (d, 2J = 18.0 Hz, 1H), 4.47 (dm, 2J = 11.6 Hz, 1H), 4.84 (dm, 2J = 11.6 Hz, 1H). 13C NMR (CDCl3) δ: 28.04, 28.52, 34.11, 38.01, 50.94, 79.86, 82.52 (t, 2J = 26 Hz), 109.87 (tm, 1J = 268 Hz), 110.09, 115.45 (tt, 1J = 260 Hz, 2J = 28 Hz), 117.67 (qt, 1J = 288 Hz, 2J = 34 Hz), 181.62, 194.57. 19F NMR (CDCl3) δ: -81.48 (m, 3F), -117.51 (dm, JF-F = 280.9 Hz, 1F), -120.99 (dm, JF-F = 281.6 Hz, 1F), -123.26 (dm, JF-F = 293.5 Hz, 1F), -126.65 (dm, JF-F = 293.5 Hz, 1F). Anal.Calcd for С13Н13F7O3: С 44.58; Н 3.74. Found: С 44.67; Н 3.79. Dehydration of 6,6-Dimethyl-3-hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones (2a–c). A solution of 2a–c (0.4 mmol) and p-toluene sulfonic acid (20 mg) in dry benzene (40 ml) was refluxed for 4 h using a Dean Stark separator to remove the water formed during the reaction. After cooling to room temperature, a reaction mixture was washed twice with 10 ml water and dried over anhydrous MgSO4. Removal of the solvent under reduced pressure and recrystallization of the residue from diethyl ether/hexane afforded 3perfluoroalkyl-6,7-dihydrobenzofuran-4(5H)-ones 4a–c as colorless solids. 6,6-Dimethyl-3-trifluoromethyl-6,7-dihydrobenzofuran-4(5H)-one (4a). Yield: 79%, white solid. Mp: 35–38ºC. IR ν (cm-1): 1685, 1570, 1455. 1H NMR (CDCl3) δ: 1.15 (s, 6Н), 2.42 (s, 2Н), 2.77 (s, 2Н), 7.69 (m, 1Н). 13C NMR (CDCl3) δ: 28.37, 35.05, 37.20, 52.17, 115.15 (q, 2J = 39 Hz), 116.45, 121.55 (q, 1J = 267 Hz), 143.21 (q, 3J = 6 Hz), 167.94, 191.16. 19F NMR (CDCl3) δ: -60.07 s (3F). Anal.Calcd for С11Н11F3O2: С 56.90; Н 4.77. Found: С 56.78; Н 4.72. 6,6-Dimethyl-3-perfluoroethyl-6,7-dihydrobenzofuran-4(5H)-one (4b). Yield: 79%, white solid. Mp: 39–42ºC. IR ν (cm-1): 1685, 1565, 1450. 1H NMR (CDCl3) δ: 1.14 (s, 6Н), 2.41 (s, 2Н), 2.79 (s, 2Н), 7.66 (m, 1Н). 13C NMR (CDCl3) δ: 28.29, 34.83, 37.33, 52.53, 111.35 (tq, 1J = 251 Hz, 2J = 40 Hz), 113.38 (t, 2J = 30

180


Hz), 117.10, 118.80 (qt, 1J = 286 Hz, 2J = 38 Hz), 144.18 (t, 3J = 10 Hz), 168.09, 190.45. 19F NMR (CDCl3) δ: -84.38 (bs, 3F), -109.02 (bs, 2F). Anal.Calcd for С12Н11F5O2: С 51.07; Н 3.93. Found: С 51.14; Н 3.99. 6,6-Dimethyl-3-perfluoropropyl-6,7-dihydrobenzofuran-4(5H)-one (4c). Yield: 82%, white solid. Mp: 59–62ºC. IR ν (cm-1): 1690, 1565, 1445. 1H NMR (CDCl3) δ: 1.15 (s, 6Н), 2.42 (s, 2Н), 2.80 (s, 2Н), 7.67 (m, 1Н). 13C NMR (CDCl3) δ: 28.32, 34.88, 37.43, 52.63, 108.61 (tm, 1J = 265 Hz), 113.63 (t, 2J = 30 Hz), 113.69 (tt, 1J = 253 Hz, 2J = 33 Hz), 117.36, 118.00 (qt, 1J = 288 Hz, 2J = 35 Hz), 144.54 (t, 3J = 10 Hz), 168.11, 190.42. 19F NMR (CDCl3) δ: -80.50 (m, 3F), 106.08 (m, 2F), -125.57 (m, 2F). Anal.Calcd for С13Н11F7O2: С 47.00; Н 3.34. Found: С 47.12; Н 3.41. Synthesis of 3,3-Dimethyl-11-hydroxy-11-perfluoroalkyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones (5a–c). To a stirred solution of a methyl enol ether 1a–c (1 mmol) in Et2O (20 ml), o-phenylenediamine (1 mmol) was added at room temperature. After 5 h stirring, the reaction mixture was concentrated under reduced pressure. A column chromatography (diethyl ether/hexane) of the residue afforded pure compounds 5a–c as colorless solids. 3,3-Dimethyl-11-hydroxy-11-trifluoromethyl-2,3,4,5,10,11-hexahydro-1Hdibenzo[b,e][1,4]diazepin-1-one (5a). Yield: 72%, white solid. Mp: 238–241ºC. IR ν (cm-1): 1610, 1540, 1505. 1H NMR (acetone-d6) δ: 1.04 (s, 3Н), 1.09 (s, 3Н), 2.26 (dd, 1J = 16.6 Hz, 2J = 1.6 Hz, 1H), 2.35 (d, 1J = 16.6 Hz, 1H), 2.66 (dd, 1J = 16.1 Hz, 2J = 1.4 Hz, 1H), 2.78 (d, 1J = 16.0 Hz, 1H), 5.29 (bs, 1Н, NH), 6.84 (td, 1J = 7.6 Hz, 2J = 1.2 Hz, 1H), 6.98 (td, 1J = 7.6 Hz, 2J = 1.2 Hz, 1H), 7.09 (d, 1 J = 8.0 Hz, 1Н), 7.11 (d, 1J = 8.0 Hz, 1Н), 9.06 (bs, 1Н, NH), 10.64 (bs, 1Н, ОH). 13C NMR (acetone-d6) δ: 27.53, 29.45, 32.64, 48.15, 52.13, 87.68 (q, 2J = 29 Hz), 104.54, 122.01, 122.28, 122.99, 126.78, 127.26 (q, 1J = 295 Hz), 131.54, 135.81, 160.22, 200.53. 19F NMR (acetone-d6) δ: -80.54 (s, 3F). Anal.Calcd for С16Н17F3N2O2: C 58.87; H 5.25; N 8.59. Found: С 58.81; H 5.23; N 8.54. 3,3-Dimethyl-11-hydroxy-11-perfluoroethyl-2,3,4,5,10,11-hexahydro-1Hdibenzo[b,e][1,4]diazepin-1-one (5b). Yield: 71%, white solid. Mp: 264–267ºC. IR ν (cm-1): 1610, 1550, 1510. 1H NMR (acetone-d6) δ: 1.06 (s, 3Н), 1.10 (s, 3Н), 2.26 (dd, 1J = 16.6 Hz, 2J = 1.8 Hz, 1H), 2.37 (d, 1J = 16.6 Hz, 1H), 2.68 (dd, 1J = 16.1 Hz, 2J = 1.6 Hz, 1H), 2.80 (d, 1J = 16.1 Hz, 1H), 5.40 (bs, 1Н, NH), 6.81 (td, 1J = 7.6 Hz, 2J = 1.3 Hz, 1H), 6.96 (td, 1J = 7.6 Hz, 2J = 1.3 Hz, 1H), 7.08 (dd, 1J = 8.1 Hz, 2J = 0.9 Hz, 2H), 9.06 (bs, 1Н, NH), 11.13 (bs, 1Н, ОH). 13C NMR (acetone-d6) δ: 27.35, 29.75, 32.39, 48.38, 52.12, 88.86 (t, 2J = 24 Hz), 105.02, 117.26 (tq, 1J = 268 Hz, 2J = 33 Hz), 121.07 (qt,1J = 288 Hz, 2J = 37 Hz), 121.93, 122.06, 122.53, 126.65, 130.93, 135.66, 160.55, 201.01. 19F NMR (acetone-d6) δ: -79.00 (bs, 3F), -115.21 (d, JF-F = 273.5 Hz, 1F), -124.75 (d, JF-F =


181

273.5 Hz, 1F). Anal.Calcd for С17Н17F5N2O2: C 54.26; H 4.55; N 7.44. Found: C 54.31; H 4.58; N 7.49. 3,3-Dimethyl-11-hydroxy-11-perfluoropropyl-2,3,4,5,10,11-hexahydro-1Hdibenzo[b,e][1,4]diazepin-1-one (5c). Yield: 70%, white solid. Mp: 149–152ºC. IR ν (cm-1): 1610, 1540, 1510. 1H NMR (acetone-d6) δ: 1.06 (s, 3Н), 1.10 (s, 3Н), 2.26 (dd, 1J = 16.7 Hz, 2J = 1.8 Hz, 1H), 2.38 (d, 1J = 16.7 Hz, 1H), 2.68 (dd, 1J = 16.2 Hz, 2J = 1.5 Hz, 1H), 2.80 (d, 1J = 16.1 Hz, 1H), 5.39 (bs, 1Н, NH), 6.80 (td, 1J = 7.6 Hz, 2J = 1.3 Hz, 1H), 6.96 (td, 1J = 7.6 Hz, 2J = 1.3 Hz, 1H), 7.05 (dm, 1J = 8.0 Hz, 1H), 7.08 (dm, 1J = 8.0 Hz, 1H), 9.06 (bs, 1Н, NH), 11.32 (bs, 1Н, ОH). 13C NMR (acetone-d6) δ: 27.26, 29.85, 32.34, 48.40, 52.15, 90.08 (t, 2J = 24 Hz), 105.31, 111.99 (tm, 1J = 267 Hz), 118.62 (tt, 1J = 270 Hz, 2J = 29 Hz), 120.02 (qt, 1J = 288 Hz, 2J = 35 Hz), 121.95, 122.04, 122.57, 126.65, 130.91, 135.52, 160.65, 201.01. 19F NMR (acetone-d6) δ: -81.97 (m, 3F), -110.53 (dm, JFF = 279.2 Hz, 1F), -120.50 (dm, JF-F = 279.2 Hz, 1F), -123.06 (dd, JF-F = 291.5, 11.3 Hz, 1F), -125.84 (dm, JF-F = 291.5 Hz, 1F). Anal.Calcd for С18Н17F7N2O2: C 50.71; H 4.02; N 6.57. Found: C 50.78; H 4.04; 6.70.

REFERENCES [1]

[2]

[3]

[4]

(a) Randall, L. O. In Psychopharmacological Agents; Gordon, M., Eds.; Academic Press: New York, 1974; Vol 3, pp 175–281. (b) Greenblatt, D. J.; Shader, R. I. In Benzodiazepines in Clinical Practice; Raven Press: New York, 1974; pp 183–196. (c) Fryer, R. I., In: Comprehensive Heterocyclic Chemistry; Taylor, E. C., Ed.; Wiley: New York, 1991, 50, Chapter II. (a) Narayana, B.; Vijaya Raj, K. K.; Ashalatha, B. V.; Suchetha Kumari, N. Eur. J. Med. Chem. 2006, 41, 417–422. (b) Roma, G.; Grossi, G. C.; Di Braccio, M.; Ghia, M.; Mattioli, F. Eur. J. Med. Chem. 1991, 26, 489–496. (c) Moroz, G. J. Clin. Psychiatry 2004, 65, 13–18. (a) Lehner, H.; Gauch, R.; Michaelis, W. Arzneim.-Forsch. 1967, 17, 185– 189. (b) Hunziker, F.; Lauener, H.; Smutz, J. Arzneim.-Forsch. 1963, 13, 324–328. (c) Squires, R. F.; Saederup, E. Neurochem. Res. 1993, 18, 787– 793. (a) Strakov, A. Y.; Linabergs, Y.; Strutzele, M.; Lauceniece, D. Latv. PSR Zinat. Akad. Vestis, Khim. Ser. 1968, 722–726. (b) Miyano, S.; Abe, N. Chem. Pharm. Bull. Jpn. 1972, 20, 1588–1589. (c) Matsuo, K.; Yoshida, M.; Ohta, M.; Tanaka, K. Chem. Pharm. Bull. Jpn. 1985, 33, 4057–4062. (d) Anders, E. Bull. Soc. Chim. Belg. 1992, 101, 801–806. (e) Tonkikh, N. N.; Strakovs, A. Y.; Rizhanova, K. V.; Petrova, M. V. Chem. Heterocycl.

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[5] [6] [7]

[8] [9] [10] [11] [12]

[13]

[14]

T. S. Khlebnicova, V. G. Isakova, A. V. Baranovsky et al. Comp. 2004, 40, 949–955. (f) Beccalli, E. M.; Broggini, G.; Paladino, G.; Zoni, C. Tetrahedron 2005, 61, 61–68. Bégue, J-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012. Khlebnikova, T. S.; Isakova, V. G.; Baranovskii, A. V.; Lakhvich, F. A. Russ. J. Gen. Chem. 2008, 78, 1954–1963. (a) Pashkevich, K. I.; Krokhalev, V. M.; Saloutin, V. I. Russ. Chem. Bull. 1988, 37, 1202–1206. (b) Krokhalev, V. M.; Saloutin, V. I.; Romas, A. D.; Ershow, B. A.; Pashkevich, K. I. Russ. Chem. Bull. 1990, 39, 316–322. Rubinov, D. B.; Rubinova, I. L.; Akhrem, A. A. Chem. Rev. 1999, 99, 1047–1065. Akhrem, A. A.; Moiseenkov, A. M.; Lakhvich, F. A.; Poselenov, A. I.; Ivanova, T. M. Russ. Chem. Bull. 1971, 20, 305–309. Lakhvich, F. A.; Lis, L. G.; Rubinov, D. B.; Borisov, E. V. Zh. Org. Khim. 1988, 24, 755–759. (a) Eistart, B.; Reiss, W.; Wurzler, H. Lieb. Ann. 1961, 650, 133–156. (b) Cimarusti, C. M.; Wolinsky, J. J. Org. Chem. 1966, 31, 4118–4121. (a) Novy, G.; Riedl, W.; Simon, H. Chem. Ber. 1966, 99, 2075–2082. (b) Akhrem, A. A.; Moiseenkov, A. M.; Lakhvich, F. A.; Poselenov, A. I.; Russ. Chem. Bull. 1972, 21, 128–131. (c) Shestak, O. P.; Balaneva, N. N.; Novikov, V. L.; Paulins, Y. Y.; Elyakov, G. B. Latv. PSR Zinat. Akad. Vestis, Khim. Ser. 1985, 725–732. Strakovs, A. Ya.; Petrova, M. V. Tonkikh, N. N.; Gurkovskii, A. I.; Popelis, Yu.; Kreishman, G. P.; Belyakov, S. V. Chem. Heterocycl. Comp. 1997, 33, 321–332. Khlebnicova, T. S.; Isakova, V. G.; Baranovsky, A. V.; Borisov, E. V.; Lakhvich, F. A. J. Fluorine Chem. 2006, 127, 1564–1569.

Reviewed by Prof. M.M. Krayushkin, N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia


Chapter 7

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SOME ISOMERIC DIPYRROLONAPHTHALINE DERIVATIVES Sh. A. Samsoniya, M. V. Trapaidze, N. A. Esakia, K.Kh.Mamulashvili, Z. Sh. Lomtatidze, T. V. Doroshenko Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT New heterocyclic systems were synthesized - isomeric dipyrrolonaphthalines: 1H,6H-indolo[7,6-g]indole, 3H,8H-indolo[4,5e]indole, 3H,8H-indolo[5,4-e]indole and 1H,10H-benzo[e]pyrrolo [3,2g]indole. On the basis of these heterocyclic compounds were obtained N, Ndialkyl derivatives, phenylazo derivatives, formyl derivatives and was studied their antimicrobial and germicidal activity. The results of investigation revealed that the introduction of phenylazo group in the third position in pyrrole ring of benzopyrroloindole gives the key cycle, 1H,10H-benzo[e]pyrrolo[3,2-g]indole, antimicrobial activity towards different pathogenic bacteria and opportunistic pathogenic bacteria. N, N-dialkyl derivatives of indoloindoles depress the growth and development of plant pathogenic bacteria.

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Sh. A. Samsoniya, M. V. Trapaidze, N. A. Esakia et al.

INTRODUCTION In the present work are described synthesis, antimicrobial, antituberculous and antifungal activities of some dipyrrolonaphthaline derivatives synthesized earlier by us: 1H,10H-benzo[e]pyrrolo [3,2-g]indole (I), 3H,8H-indolo[5,4e]indole(II), 1H,6H-indolo[7,6-g]indole(III) and 3H,8H-indolo[4,5-e]indole (IV) [1-3]. On the basis of heterocycles I-IV were obtained phenylazoderivatives V-XIII, N,N- formylderivatives XIV-XVII and dialkylderivatives XVIII-XXIII. NH N -R

H N

R2

R-N R1 II, XVIII, XIX

I, V-X, XIV, XV R-N

R1

R2

R3

R4

R-N

N-R

N-R III, XX, XXI I, II, III, IV R= R1= R2= R3=R4= H; VII R 1= N=NC6H4Cl-p, R2= H; X

IV, XI-XIII, XVI, XVII, XXII, XXIII

V R 1= N=NC6H5, R 2= H; VIII R 1= N=NC6H4Br-p, R2= H;

R1= N=NC 6H4SO2NH2-p, R 2= H;

XII

R1= R2= R3= H, R 4= N=NC6H4Cl-p;

VI R1= N=NC6H4NO2-p, R2=H; IX R1= N=NC6H4I-p, R2= H;

XI R 1= R 2= R 3= H, R4= N=NC6H5 ; XIII R1= R2= R3= H, R 4= N=NC6H4NO2-p;

XIV R 1= CHO, R2= H; XV R1=R2= CHO; XVI R=R2=R4= H, R1=R3= CHO; XVII R=R1=R 4= H, R 2=R 3= CHO; XVIII, XX R= CH2-CH=CH2; XIX, XXI R=CH2-C CH; XXII

R1= R2= R3=R4= H, R= CH2-CH=CH2;

XXIII R1=R2=R3=R4= H,

R= CH2-C

CH.

Synthesis and Biological Activity …

185

Phenylazoderivatives were synthesized by means of azocoupling reaction of benzopyrroloindole I, indolo[4,5-e]indole IV with substituted phenyldiazonium chlorides in aqueous- dioxane solution with molar ration of substrate and diazonium salt, 1:3 [4-6]. As a result of electrophilic substitution reaction were isolated monosubstituted products (V-VIII): 3-phenylazo- (V), 3-(p-nitrophenylazo)- (VI), 3-(p-chlorophenylazo)-(VII), 3-(p-bromphenylazo)- (VIII), 3-(p-iodphenylazo)(IX), 3-(p-sulphamidephenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (X), 2phenylazo- (XI), 2-(p-chlorophenylazo)- (XII) and 2-(p-nitrophenylazo)-3H,8Hindolo[4,5-e]indoles (XIII). We didn’t manage to obtain disubstituted dipyrrolonaphthaline phenylazoderivatives[7]. Using Vilsmeier-Haack reaction were synthesized mono- and diformylderivatives of benzopyrroloindole (I) and indolo[4,5-e]indole (IV) with different molar ration of substrates and Vilsmeier complexes [4,6]. As a result were isolated: 3-formyl- (XIV), 3,8-diformyl-1H,10H-benzo[e]pyrrolo[3,2g]indoles (XV), 1,9-diformyl-(XVI), 1,10-diformyl-3H,8H-indolo[4,5-e]indoles (XVII). It is known that unsaturated groups in heterocyclic compounds increase their biological activity. For the purpose of direct introduction of allylic and propargyl radicals into the indole ring were studied alkylation reactions by halogenalkyls under condition of interphase catalysis [8]. Alkylation of isomeric indoloindoles 3H,8H-indolo[5,4-e]indole (II), 1H,6H-indolo[7,6-g]indole (III) and 3H,8Hindolo[4,5-e]indole (IV) was carried out in 50% aqueous solution of NaOH using stechiometric quantity of alkylhalogenides, with ration of catalyst-tetrabutylammonium and substrate 1:5 [8]. Alkylation reaction in 1,2-dichloroethane at 40-450C results the formation of N,N-dialkylindoloindoles: 3,8-diallyl-(XVIII), 3,8-dipropargylindolo[5,4e]indoles (XIX), 1,6-diallyl- (XX), 1,6-dipropargylindolo[7,6-g]indoles (XXI), 3,8-diallyl- (XXII) and 3,8-dipropargyl-indolo[4,5-e]indoles (XXIII). The analysis has shown that the reactivity of isomeric indoloindoles (II, III, IV) doesn’t differ considerably. But 3H,8H-indolo[4,5-e]indole undergo N,Ndialkylation easier than II, III; it is connected with its better solubility in 1,2dichloroethane. The structure of the synthesized compounds V-XXIII was established by means of IR-, UV-, NMR- and Mass-spectral methods and is given in the tables.

186

Sh. A. Samsoniya, M. V. Trapaidze, N. A. Esakia et al. IR-spectra (neyol) and UV-spectra (ethanole) of compounds V-XVII IR-spectra, , cm-1 C=O N=N 3 4 _ _

Compo und # 1 V

N-H 2 3485, 3250

VI

3400

_

_

VII

3415, 3385

_

1420

VIII

3430, 3380

_

IX

3410, 3380

_

1320 1260 1630 1560 (NO2) _

X

3400

_

_

XI

3430

_

1400 1370

XII

3430

_

1390 1370

XIII

3450 3410

_

1370. 1530, 1346(NO2)

UV-spectra, max, nm, (lg ) 5 217(4.63), 229(4.73), 251(5.07), 273(4.85), 286(4.51), 317(4.23), 329(4.11). 200(4.35), 217(4.30), 232(4.26), 255(4.26), 264(4.55), 273(4.67), 303(3.93), 325(3.19). 206(4.22), 231(4.55), 274(4.37), 270(4.42), 510(4.54). 208(4.13), 229(4.38), 267(4.12), 568(4.44). 202(4.45), 229(4.59), 264(4.47), 269(4.50), 315(4.08), 540(4.56). 210.5(4.36), 248(4.46), 310(3.86), 319.5(4.01), 336(3.97), 345(3.72). 202(4.45), 233(4.32), 257(4.37), 270(4.22), 294(4.05), 306(4.07), 319(4.11), 467(4.36). 202(4.47), 229(4.39), 256(4.44), 270(4.27), 295(4.09), 305(4.12), 320(4.16), 344(4.07), 480(4.49). 202(4.44), 229(4.33), 253(4.39), 270(4.18), 294(4.04), 322(3.91), 363(3.97), 526(4.45).


187

XIV

3320, 3270

1630

_

224(3.58), 254(3.78), 296(3.13), 307(3.21), 326(3.47). 208, 217, 236, 250, 257, 278, 289, 322, 342, 353.

XV

3390, 3290,

1700, 1650

_

XVI

3220, 3130

1660, 1620

_

212(4.66), 255(4.54), 267(4.53), 275(4.52), 338(3.91), 354(3.88).

XVII

3200, 3130

1640, 1620

_

200(4.27), 222(4.26), 232(4.28), 282(4.39), 357(4.07).

IR- (neyol) and UV-spectra ( ethanole) of compounds XVIII-XXIII compound #

IR-spectra, , cm-1

XVIII

CH2-CH=CH2 750, 1650-1580

XIX XX

CH2-C CH 3260, 2120 720, 1650-1510

XXI

3255, 2120

XXII

730, 1620-1560

XXIII

3270-3255, 2120

UV-spectra, max, nm, (lg ) 210,5(4.46), 218(4.51), 251(4.62), 297(3.70), 310(4.03), 320.5(4.24), 336(4.18), 352(3.71). 220(4.40), 248(4.68), 308(4.11), 320(4.34), 336(4.25), 352(3.88). 256(4.22), 266(4.60), 270(4.82), 289 (3.94), 300(4.01), 324(3.35), 333(3.30), 339(5.52). 264(4.57), 272(4.87), 300(4.05), 324(3.35), 339(3.60), 348(3.61), 356(3.55), 360(3.57), 383(3.64). 204(3.70), 237(3.60) 272(4.42), 339(3.21). 236(4.11), 266(4.09), 268(4.46), 278(4.62), 307(3.84), 328(3.09).

Chemical shift of the protons ( , ppm) and spin-spin interaction constants (J, Hz) of the compounds XIV-XVII (DMSO-d6) in 1H-NMR spectra (acetone-d6) Compo und # XIV XV XVI

XVII

1-H 11.8, bs 11.8, bs 9.81, s (CHO)

2-H 7.86, bs 7.93, bs 8.26, s

3-H 9.69, s (CHO) 9.78, s (CHO) 12.3, bs

4-H 8.3_8.1

, ppm 5-H 6-H 7.4_7.3 7.4_7.3

8.25, dd

7.48, dd

7.48, dd

7.58, d

7.85, d

7.78, d

10.0, s (CHO)

8.13, s

NH ND

7.65, d

7.80, d

7.80, d

1

Compo und #

V

1-H

11,9 bs

2-H 3-H

4-H

7,86 bs

8,1…8,3

5-H

J, Hz 7-H 8.38.1 8.25, dd 7.55, dd

8-H 7.0, dd

9-H 7.4

9.78, s (CHO) 12.6, bs

7.93, bs 10.35, s (CHO)

7.65, d

NH ND

8.13, s

10-H 10.8, bs 11.8, bs 7.80, dd

10.0, s (CHO)

J89=3.0; J810=2.4. J45=6.3; J46=3.4. J23=2.4; J45=9.1; J67=9.0; J710=0.5; J810=1.4. J45=J67=8.8.

H-NMR Spectra of diazocompounds V-XIII (acetone-d6)

6-H

, ppm 7-H

J, Hz 8-H

9-H

10-H 2 -H 6 -H

7,3…… 7,5

8,1…8,3

7,4 Dd

11.0 bs

7,8

Ph 3 -H 5 -H 7,3-7,5

J89=J810=2,7;

VI

11,3 bs

7,99 bs

8,3 m

7,4-7,5

7,9 m

7,09 dd

VII

11.3, bs

7.97, bs (2_H)

8.38, m

7.4_7.5

8.27, m

7.15, dd

VIII

11.3, bs

8.3, m

7.4_7.5

7.9, m

IX*

11.6, bs

7.99, bs (2-H) 7.86, bs (2-H)

8.1_8.3

7.3_7.6

8.1_8.3

X

11,9 bs 8.08, dd

8,05 bs 11.2, bs (3-H) 11.2, bs (3-H)

8,37 dd 7.55, dd

7.55, dd

7.82, d

11.3, bs (3-H)

7.51, dd

7.86, d

XI

XII

8.11, dd

XIII

8.23, dd

* in DMSO-d6.

7.82, d

10,8 bs

7,86 d

8,27 d

J89=3; J810=2,5; J23=J56=9,2

7.45, dd

10.79, bs

7.86, d

7.55, d

7.09, dd

7.4

10.8, bs

7.86, d

8.27, d

J89=2.9; J810=2.2; J910=2.6; J2 3 =J5 6 =8.77 J89=3; J810=2.6; J2 3 =J5 6 =9.2.

7.03, dd

7.4, m

11.0, bs

7.8

8,25 dd 7.4 7.6

6,67 d 10.7, bs

7,17 10,9 d bs 7.4 7.6

7.5 7.6

10.6, bs

7.6

10.7, bs

7.4

7.4 7.5

(3 -H) (4 -H) (5 -H) 7.3_7.5 8,02 7,92 d d 7.87 8.09

7.86, d (2 -H)

7.51, d (3-H)

7.99, d (2 -H)

8.36, d (3 -H)

J89=2,56; J23=J56=9,14 J13=1.8; 5 J14=0.7; J45=8.9. J13=2.1; J45=8.8; JAB=8.6; 5 J14=0.5. J13=1.9; 5 J14=0.7; J46=8.9; JAB=9.14.

1

Compound #

H-NMR Spectra of indoloindoles N,N-dialkylderivatives XVIII-XXIII (CDCl3) J, Hz

, ppm 1-H d

2-H d

3-H d

4-H d

5-H d

d

XVIII

7.04

7.18

_

7.54

8.04

4.85

XIX

7.07

7.30

_

7.64

8.08

_

XX

_

7.20

6.66

7.37

8.03

5.23

XXI XXII

_ 7.25

7.24 7.35

6.69 _

7.80 7.43

8.27 7.72

_ 4.88

XXIII

7.32

7.37

_

7.52

7.77

_

CH2 d

C CH d

_

_

J12=2.9; J45=8.8; JHaHc=16.8; JHcHb=10.2; JHaHb=1.5; JCH2CHc=5.1.

_

5.01

2.43

5.00 (Ha), d 5.23(Hb), d 6.25(Hc), dd _ 5.06(Ha), dd 5.20(Hb), dd 6.07(Hc), dd

_

_

5.38 _

2.49 _

_

5.01

2.42

J12=2.9; J45=8.8; JCH2CH=2.19. J23=2.9; J45=8.8; JHaHc=16.5; JHbHc=10.2. J23=2.9; J45=8.6. J12=3.6; J45=8.8; JHaHc=15.5; JHbHc=10.2; JHaHb=1.5; JCH2Hc=5.1. J12=3.0; JCH2CH=2.0; J45=8.8.

CH2 - C C-Ha Hc Hb 5.08(Ha), dd 5.20(Hb), dd 6.07(Hc), m


191

EXPERIMENTAL CHEMICAL PART The reaction procedure and compounds purity monitoring, and also establishment of Rf were accomplished by means of TLC on Silufol UV-254; IRspectra were taken on analyzer UR-20 (Germany) in petrolatum oil; UV-spectraon spectrophotometer ―Specord‖ (Germany) in ethanol, PMR-spectraon spectrometer Bruker WP-200 SY (USA) with operating frequency 200 MHz, inner standard –TMS. Measurement accuracy of chemical shift ± 0,01 ppm, constant of spin-spin interaction ±0,1 Hz. The yields are given for chromatographically pure compounds. The findings of elemental analysis correspond calculated values.

3-Phenylazo-1H,10H-benzo[e]pyrrolo[3,2-g]indole (V) To the solution 0.32 g (1,5 mmole) of 1H,10H-benzo[e]pyrrolo [3,2-g]indole (I) in 10 ml of dioxane and 10 ml water at -50C is added drop by drop 6 mmole of phenyldiazonium chloride solution, keeping pH 6-7 by adding sodium acetate. The solution is mixed for 30 minutes. The reaction mixture is extracted with ether and dried on anhydrous Na2SO4. The extract is evaporated; the substance is dried and purified on the column with silicagel, eluent - hexane-ether, 5:1. Yield 0,26 g (54%), dark orange crystals. Tmelt. 2030C (decom.). Rf 0.58 (benzene-acetone, 10:1). Found %: M+ 310. C20H14N4. Calculated: M 310. With Ehrlich reagent gives violet colouring at room temperature.

3-(p-Nitrophenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (VI) Is obtained similarly to compound V from 0,41 g (2 mmole) I and 6 mmole pnitrophenyl-diazonium chloride solution. Yield 0,21 g (30%), bordeaux crystals. Tmelt. 3000C (decom.). Rf 0.55 (benzene-acetone, 10:1). C20H13N5O2. With Ehrlich reagent gives violet colouring at room temperature.

3-(p-Chlorophenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (VII) Is obtained similarly to compound V from 0.2 g (1 mmole) I and 3 mmole pchlorophenyldiazonium chloride solution. Yield 0,1 g (30%), orange crystals.

192


Tmelt. 216…2170C (decom.). Rf 0.35 (benzene). C20H13N4Cl. With Ehrlich reagent gives violet colouring at room temperature.

3-(p-Bromphenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (VIII) Is obtained similarly to compound V from 0.2 g (1 mmole) I and 3 mmole pbromphenyldiazonium chloride solution. Yield 0.22 g (59%), bordeaux crystals. Tmelt. 2650C (decom.). Rf 0.6 (benzene-ether, 3:1). C20H13N4Br.

3-(p-Iodphenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (IX) Is obtained similarly to compound V from 0,2 g (1 mmole) I and 3 mmole piodphenyldiazonium chloride solution. Yield 0.34 g (80%), violet crystals. Tmelt. 3500C (decom.). Rf 0.6 (benzene-ether, 3:1). C20H13N4I.

3-(p-Sulphamidephenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (X) Is obtained similarly to compound V from 0.2 g (1 mmole) I and 3 mmole psulphamide-phenyldiazonium chloride solution. Yield 0.3 g (78%), bordeaux crystals. Tmelt. 3550C (decom.). Rf 0.59 (benzene-acetone, 2:1). C20H15N5SO2.

2-Phenylazo-3H,8H-indolo[4,5-e]indole (XI). To the solution of 0.41g (2 mmole) compound IV in 15 ml dioxane and 8 ml water at -50C is added 6 mmole phenyldiazonium chloride solution, keeping pH 67 by adding sodium acetate; the solution is mixed for 2 hours, poured into glacial water, extracted with ether, the extract is washed with 10% NaOH solution, dried on Na2SO4, solvent is evaporated and is obtained 0.45 g (73%) of substance, which is purified on chromatographic column, eluent benzene. Obtained substance represents red crystals. Tmelt. 194-1950C. Rf 0.35 (benzene). C20H14N4.


193

2-(p-Chlorophenylazo)-3H,8H-indolo[4,5-e]indole (XII). Is obtained similarly to compound XI from 0.41 g (2 mmole) IV and 6 mmole p-chlorophenyldiazonium chloride solution. Yield 0.52 g (76%). Tmelt. 216-2170C. Rf 0.45 (benzene), C20H13ClN4.

2-(p-Nitrophenylazo)-3H,8H-indolo[4,5-e]indole (XIII). Is obtained similarly to compound XI from 0.41 g (2 mmole) IV and 6 mmole p-nitrophenyldiazonium chloride solution. Yield 0.59 g (83%). Tmelt. 258-2590C. Rf 0.21 (benzene), C20H13N5O2.

3-Formyl-1H,10H-benzo[e]pyrrolo[3,2-g]indoles (XIV) To 1,16 ml (15mmole) of DMFA at 00C is added drop by drop 0,36 ml (4,2 mmole) distillated POCl3 and mixed for 0,5 h at room temperature. The solution is cooled again to 00C and is added relatively fast the solution of 0,3g (1,4 mmole) substance I in 2 ml DMFA. The solution is mixed for 1 hour at 500C. The reaction mixture is poured into water and alkalized by 10% solution of NaOH up to pH 10. The precipitate is filtered off, washed with water until neutral reaction. The product of the reaction represents mixture of benzopyrroloindole aldehydes. The mixture is separated on chromatographic column with silicagel, eluent benzene. As a result is obtained 0,17 g (50%) of substance XIV, yellow crystals. Tmelt. 293…2940C. Rf 0.62 (benzene-acetone, 1:1). With Ehrlich reagent gives yellow colouring. The dialdehyde XV due to pure solubility couldn’t be eluated on column. Found: M+ 234. C15H10N2O. Calculated: M 234.

3,8-Diformyl-1H,10H-benzo[e]pyrrolo[3,2-g]indole (XV) 1,36 ml (18mmole) of distillated DMFA is cooled to -50C and drop by drop is added 0,47 ml (5 mmole) distillated POCl3, mixed for 0,5 h at room temperature. The solution is cooled again to -50C and is added slowly the solution of 0,2g (1 mmole) substance I in 1,4 ml DMFA. The solution is mixed for 1 hour at 40450C. The yellow precipitate is obtained. The reaction mixture is poured into glacial water, alkalized by 10% solution of NaOH up to pH 10 and left for the

194


night. The precipitate is filtered off, washed with water until neutral reaction, recrystallizated from DMFA. Yield 0,16 g (64%), yellow crystals. Tmelt. 3370C (decomp). Found: M+ 262. C16H10N2O2. Calculated: M 262.

Formylation of 3H,8H-indolo[4,5-e]indole 1,84 ml (24 mmole) of absolute DMFA is cooled to -50C and drop by drop is added 0,55 ml (6 mmole) distillated POCl3, mixed for 1 h at room temperature. The solution of 0,41g (2 mmole) substance IV in 3 ml DMFA is slowly added at -50C. The solution is mixed for 2 hour at 400C, treated by 10% solution of NaOH up to pH 10 and left for the night. The precipitate is filtered off, washed with water until neutral reaction and dried. Is obtained 0,43 g mixture of two aldehydes (TLC, benzene-acetone, 1:1), which are separated on column. 1,9-Diformyl-3H,8H-indolo[4,5-e]indole (XVI) is eluated with mixture benzene-ether, 1:3. 0,11 g of colourless crystals is obtained, Tmelt. 298…2990C. Rf 0.37 (benzeneacetone, 1:1). Found: M+ 262. C16H10N2O2. Calculated: M 262. 1,10-Diformyl-3H,8H-indolo[4,5-e]indole (XVII) is eluated with ethanol. 0,25 g of colourless crystals is obtained, Tmelt. 327…3280C. Rf 0.66 (benzene-acetone, 1:1). Found: M+ 262. C16H10N2O2. Calculated: M 262.

3,8-Diallylindolo[5,4-e]indole (XVIII) To the suspension of 0,25 g (1,2 mmole) 3H,8H-indolo [5,4-e]indole (I) in 8 ml 1,2-dichlorethane is added 10 ml of 50% NaOH, 0,016 g [CH3(CH2)3]NBr and 3,5 g (28,4 mmole) allylbromide. The solution is mixed for 1 h at 40-450C. The water layer is extracted with 1,2-dichlorethane, the organic extract is washed with water until neutral reaction and dried on Na2SO4. The solvent is evaporated at 30400C. The product is purified on chromatographic column, eluent benzenehexane, 1:2. Yield 0,24 g (69%), colourless crystals. Tmelt. 159-1600C. Rf 0.41 (benzene-hexane, 1:1). IR-spectrum, , cm-1: 1580-1650 (C=C), 750 (CH2). UVspectrum, max, nm (lg ): 210,5 (4,46), 218 (4,51), 251 (4,62), 297 (3,70), 310 (4,03), 320,5 (4,24), 336 (4,18), 352 (3,71). Found: M+ 286. C20H18N2. Calculated: M 286.


195

3,8-Dipropargylindolo[5,4-e]indole (XIX) Is obtained similarly to compound XVIII by interaction of 0.21 g (1,02 mmole) 3H,8H-indolo[5,4-e]indole I, 0,017 g (0.07 mmole) benzyltriethylammomium bromide and 0,58 g (4,8 mmole) propargyl bromide. Is purified on column, eluent benzene-hexane, 1:2. Is obtained 0,2 g (69%) XIX, colourless crystals. Tmelt. 201-2020C. Rf 0.39 (benzene-petroleum ether, 2:1), IR-spectrum, , cm-1: 3260 ( CH), 2120 (C C). Found: M+ 282. C20H14N2. Calculated: M 282.

1,6-Diallylindolo[7,6-g]indole (XX) Is obtained similarly to compound XVIII by interaction of 0.08 g (0,39 mmole) 1H,6H-indolo [7,6-g]indole III, 0,012 g [CH3(CH2)3]NBr and 1,4 g (11,5 mmole) allylbromide. For analysis the product is purified using TLC method, eluent benzene-hexane, 1:2. Is obtained 50 mg (45%) of compound XX, colourless crystals. Tmelt. 123-1240C. Rf 0.49 (benzene-hexane, 1:1), IR-spectrum, , cm-1: 1650-1510 (C=C), 720 cm (CH2), UV-spectrum, max, nm (lg ): 256 (4,22), 266 (4,60), 270 (4,82), 289 (394), 300 (4,01), 324 (3,35), 333 (3,30), 339 (3,52). Found: M+ 286. C20H18N2. Calculated: M 286.

1,6-Dipropargylindolo[7,6-g]indole (XXI) Is obtained similarly to compound XVIII by interaction of 0.42 g (2 mmole) 1H,6H-indolo[7,6-g]indole III, 0,017 g benzyltriethylammomium bromide and 1,14 g (9,5 mmole) propargylbromide by intensive mixing for 2 hours. The product is purified on column, eluent benzene-hexane, 1:1. Is obtained 0,39 g (68%) of compound XXI, colourless crystals. Tmelt. 222-2230C. Rf 0.44 (benzenepetroleum ether, 2:1). IR-spectrum, , cm-1: 3225 ( CH), 2120 (C C). Found: M+ 282. C20H14N2. Calculated: M 282.

3,8-Diallylindolo[4,5-e]indole (XXII). Is obtained similarly to compound XVIII by interaction of 0.23 g (1,1 mmole) 3H,8H-indolo [4,5-e]indole IV, 0,016 g [CH3(CH2)3]NBr and 3,2 g (26,4 mmole) allylbromide at room temperature. The product is purified on column, eluent

196


benzene-hexane, 1:2. Is obtained 0,22 g (69%) of compound XXII, colourless crystals. Tmelt. 118-1190C. Rf 0.38 (benzene-hexane, 1:1). IR-spectrum, , cm-1: 1620-1560 (C=C), 730 (CH2), UV-spectrum, max, nm (lg ): 204 (3,70), 237 (3,60), 272 (4,42), 339 (3,21). Found: M+ 286. C20H18N2. Calculated: M 286.

3,8-Dipropargylindolo[4,5-e]indole (XXIII). Is obtained similarly to compound XVIII by interaction of 0.42 g (2,0 mmole) 3H,8H-indolo[4,5-e]indole IV, 0,017 g benzyltriethylammomium bromide and 1,14 g (9,5 mmole) propargylbromide. The product is purified on column, eluent benzene-hexane, 1:1. Is obtained 0,4 g (70%) of compound XXIII, colourless crystals. Tmelt. 196-1970C. Rf 0.38 (benzenepetroleum ether, 2:1). IR-spectrum, , cm-1: 3270, 3255 ( CH), 2120 (C C). Found: M+ 282. C20H14N2. Calculated: M 282.

EXPERIMENTAL BIOLOGICAL PART Antimicrobial activity was studied at the laboratory of infectious diseases chemotherapy at Chemistry of medicinal agents centre (AUSRCPI) by means of in vitro experiments using method of twofold serial cultivation on liquid nutrient solution (antimicrobial activity- in Hottinger broth, antituberculous activity- in Sauto environment, antifungal- in Sabouraud environment) towards microorganisms Staphylococcus aureus 209-p, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 25922, Proteus vulgaris ATCC 6896, Pseudomonas aeruginosa ATCC 27853, Mycobaqterium tuberculosis H37, Mycobaqterium tuberculosis academia, Mycobaqterium tuberculosis bovis 8; towards opportunistic pathogenic bacteria Micobacterium cansasii, Micobacterium intracellulaze, Micobacterium fortuitum; towards pathogenic fungi Microsporum canis № 3/84, Frichophyton gypseum № 5/85, Candida albicans № 1755. The activity of compounds was figured in minimal inhibitory concentration (MIC), µgr/ml. Microbial load during the experiments was 1.105 KOE, in the experiments with micobacteria- 0,02 mg and with fungi- 1.106 KOE/ml. Bacteria were incubated for 18 hours at 370C; tuberculosis micobacteria- 14 days, opportunistic pathogenic bacteria- 9, 7 and 5 days correspondingly, fungi- for 24 hours at 250C in Candida albicans experiments and 5 days in experiments with dermatophytes. Results of the experiments are given in the table.


197

In the course of the experiment was established that compounds V, VII, VIII, X possess high activity towards Staphylococcus aureus 209-p and Bacillus subtilis. High activity towards micobacteria revealed V, VII, VIII, X; towards fungi- compounds V and XIV. The results obtained show that introduction of phenylazogroup in third position of benzopyrroloindole pyrrole ring gives the key heterocycle, 1H,10Hbenzo[e]pyrrolo[3,2-g]indole, antimicrobic activity towards different pathogenic and opportunistic pathogenic bacteria. It was shown that introduction of electroacceptor group in para-position of phenylazogroup doesn’t have influence on activity level. Among studied indoloindole derivatives none of them revealed antimicrobic activity, only compound XXI possess weak antituberculosis activity (MIC 23 µgr/ml). Herbicidal activity of substances was established by means of lunula method. As test-microorganisms were used: Xanthomonas campestris (cause white cabbage bacteriosis, rot), Bacterium tumefaciens, Pseudomonas tumefaciens (cause grapewine cancer), Aspergillus niger, Streptomyces spp., Nocardiophsis spp., Streptomyces allbogriseolus subsp. Aragvi. For bacteria cultivation was used Burkholter environment (potato decoction 1 l, peptone 5g, Na2HPO4 2g, glucose 6g, NaCl 2g, citric-acid decoction 1g, aspargine 1g, agar 20g, distillated water 1 l); for fungi and ray fungi- milieu № 1 of Krasilnikov (KNO3 1g, K2HPO4 0,5g, HgSO4 0,5g, NaCl 0,5g, FeSO4 traces, CaCO3 1g, starch 20g). After 6-day incubation of actinomycetes and fungi and 2-day of bacteria zones of sterility were noticeable. As a control was used solvent. Results are given in the table. From the table it is obvious that compounds XVIII, XIX, XX, XXIII depress growth and development of plant pathogenic bacteria Bacterium tumefaciens, Xanthomonas campestris. It must be noted that compounds XVIII, XIX, XX, XXIII don’t reveal activity towards Streptomyces allbogriseolus subsp, Aragvi; zone of depression doesn’t exceed 1,0 mm (see table 2). Also were studied herbicidal properties of previously [1,2] synthesized compounds IV, XI-XV. Investigated compounds (see table 2) possess selective inhibitory action towards microorganism growth: don’t influence the growth of Aspergillus niger, don’t depress Bacterium tumefaciens and Pseudomonas tumefaciens development, at the same time their activity is very close to inhibitory action. Towards actinomycetes these compounds act selectively, for instance, compound X, XIII almost don’t influence Streptomyces spp. growth but reveal activity towards Nocardiophsis spp., though this action is weak and is noted only at relatively high concentrations.

_ _ 0.08 _ 0.08 _ _ _

Candida albicans 1755

0.55 153 0.08 23 0.08 23 23 3.5

Frichophyton gypse-um 5/85

Mycobacterium tuberculosis H 37 Rv

250 250 250 250 250 250 250 250

Microsporumcanis 3/84

Pseudomonas aeruginosa 165

250 250 250 250 250 250 250 250

Micobacterium fortuitum

Proteus vulgaris 6896 ATCC

250 250 250 250 250 250 250 250

Micobacterium intra-cellulaze

Escherichia coli 25922 ATCC

7.8 250 15.6 62.5 2.0 15.6 125 250

Micobacterium kansasii

Bacillus. subtilis 6633 ATCC

3.9 125 3.9 31.2 2.0 2.0 62.5 250

Mycobacterium tuberculosis bovis 8

Staphylococ cus .aureus 209-p

V VI VII VIII IX X XIV XV

Mycobacterium tuberculosis Academia

Compound

Antimicrobial activity of benzopyrroloindole derivatives V-X, XIV,XV in vitro MIC(µgr/ml)

0.08 23 0.08 _ 0.08 0.08 0.08 0.55

0.08 23 0.08 23 0.55 0.08 23 23

0.08 3.5 0.08 153 0.08 0.08 1000 23

153 1000 1000 _ 0.55 1000 1000 1000

250 250 250 250 7.8 250 15.6 250

250 250 250 250 31.5 250 31.2 250

250 250 250 250 125 250 250 250

Influence of indoloindoles IV,XI-XIII, XVI-XXIII on the microorganisms growth Compound # IV XI XII XIII XVI XVII XVIII XIX XX XXI XXII XXIII

1 2.0 4.0 3.0 2.0 4.0 3.0 _ _ _ _ _ _

Bacterium tumefaciens 2 3 3.0 3.0 2.0 2.0 3.0 2.0 2.0 2.0 3.0 2.0 2.0 2.0 4.0 4.0 4.0 5.0 3.0 5.0 2.0 4.0 4.0 4.0 2.0 3.0

1 1.0 3.0 2.0 0.5 2.0 3.0 _ _ _ _ _ _

Pseudomonas tumefaciens 2 3 2.0 2.0 2.0 1.0 2.0 1.0 0.5 0.0 2.0 2.0 1.0 1.0 _ _ _ _ _ _ _ _ _ _ _ _

Xanthomonas campestris 2 3 _ _ _ _ _ _ _ _ _ _ _ 5.0 4.0 4.0 4.0 3.0 3.0 3.0 2.0 3.0 3.0 3.0 3.0

Streptomyces spp

Nocardiophsis spp

1 1.0 5.0 3.0 0.0 1.0 5.0 _ _ _ _ _ _

1 1.0 2.0 2.0 2.0 0.2 3.0 _ _ _ _ _ _

2 1.0 2.5 2.0 0.0 0.0 4.0 _ _ _ _ _ _

3 2.0 0.0 2.0 0.0 0.0 3.0 _ _ _ _ _ _

2 1.0 1.0 2.0 2.0 0.0 2.0 _ _ _ _ _ _

Note: are given of growth depression of test-microorganisms, in mm (control – 0,0); first volues are concentrations of gr/l, second – 0,1 gr/l, third – 0,01 gr/l.

3 1.0 0.0 2.0 2.0 0.0 2.0 _ _ _ _ _ _

substances 1

200


Compounds XI, XII, XIV, XVII inhibit actinomycetes growth, and their biological activity is almost the same.

ACKNOWLEDGEMENT The designated project has been fulfilled by financial support of the Georgian National Science Foundation (Grant № GNSF/ST07/4-181). Any ideas of this publication possess authors and may not represent the opinion of the Georgian National Science Foundation itself. We also would like to thank the Deutsche Akademische Austausch Dienst (DAAD) for supporting the partnership and the exchange program between Ivane Javakhishvili Tbilisi State University and Saarland University.

REFERENCES [1] [2]

[3] [4] [5] [6]

[7] [8]

Sh.A.Samsoniya, M.V.Trapaidze, N.A.Kuprashvili, A.M.Kolesnikov, N.N.Suvorov. Khim. Geterotsikl. Soedin. № 9, 1222-1224 (1985). Sh.A.Samsoniya, M.V.Trapaidze, S.V.Dolidze, N.A.Esakiya, N.N.Suvorov, A.M.Kolesnikov, F.A.Mikhailenko. Khim. Geterotsikl. Soedin. № 3, 352357 (1984). Sh.A.Samsoniya, M.V.Trapaidze, N.N.Suvorov, I.M.Gverdtsiteli. Soobshch. Akad. Nauk Gruz. SSR. vol.91, № 2, 361-364(1978). M.V.Trapaidze, Sh.A.Samsoniya, N.A.Kuprashvili, L.M.Mamaladze, N.N.Suvorov. Khim. Geterotsikl. Soedin. № 5, 603-607 (1988). Sh.A.Samsoniya, M.V.Trapaidze, N.A.Kuprashvili. Khim.-Farm. Zh.vol.43, № 2, 12-14 (2009). Sh.A.Samsoniya, M.V.Trapaidze, S.V.Dolidze, N.A.Esakiya, L.N.Kurkovskaya, N.N.Suvorov. Khim. Geterotsikl. Soedin. № 9, 12051212 (1988). M.V.Trapaidze, Doctore Thesis in Chemical Sciences, I.Javakhishvili Tbilisi State University, Tbilisi, 2006. Sh.A.Samsoniya, N.A.Esakiya, S.V.Dolidze, M.V.Trapaidze, Z.Sh.Lomtatidze N.N.Suvorov. Khim.-Farm. Zh. № 9, 41-43 (1991).


Chapter 8

SOME CONVERSIONS OF 5-ACETYL-2-ETHOXYCARBONYL3-P-NITROPHENYL INDOLE N. Narimanidze, Sh. Samsoniya, I. Chikvaidze Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT It was carried out some conversions of 5-acetyl-2-ethoxycarbonyl-3-pnitrophenyl indole functional groups, particularly by reduction of nitrogroup was obtained corresponding amine and its condensation products with carbonyl compounds, mono and diacetyl derivatives. By hydrolysis of ester group and halogenations of obtained acid was synthesized 5-acetyl-3-p-nitrophenyl indole 2-carboxylic acid chloranhydride. It was carried out the acylation by chloro-anhydride of substances possessing aminofunctionality. The correstponding series of amides was obtained.

202

N. Narimanidze, Sh. Samsoniya and I. Chikvaidze

INTRODUCTION The purpose of the work is synthesis of potentially biologically active indole derivatives. For this reason were investigated properties of previously synthesized 2-ethoxycarbonyl-3-(p-nitrophenyl)-5-acetylindole (I). Some properties were studied on the basis of transformation of ethoxycarbonyl and 3-p-nitrophenyl groups. By conversion of ester group of 2-ethoxycarbonyl-3-(p-nitrophenyl)-5acetylindole (1) was obtained the corresponding acid chloroanhydride (IV), which by interaction with amino- and hydrazino-group containing compounds affords amides (V-IX) and hydrazides (X). From the methods of organic acids chloroanhydrides synthesis it was proved to be the best the reaction of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (XII) with the thionyl chloride according the scheme: NO2 O

CH3

CH3

C

NO2 O

C

NaOH/to N H

N H

COOC2H5

COONa

II I NO2 NO2

O

O

CH3

CH3

C

C

SOCI2 N H

45oC N H III

COOH

COCI

IV

After the reaction of POCl3 or PCl5, with the relevant salt (XI) the reaction mixture turns into the pitch. Chloroanhydride (IV) is rather active and easily reacts with the aminofunction containing compounds to afford the corresponding acyl products (V - X):

Some Conversions of 5-acetyl-2-ethoxycarbonyl-3-p-nitrophenyl Indole 203 NO

NO2

C

CH3

2

O

O

C

CH3

N H

COCI

N H IV

COR

V-X

V R=-N(CH3)2;

VI R=-NHC6H5;

VIII R=-NHC6H4SO2NH2(p);

VII R=-NHC6H4COCH3(p); COCH3

IX R=-NHC6H4 N H

C2H5OOC X R=-NHNHCO

N

Acylation reactions was carried out in absolute dioxane at room temperature. Reduction of the nitro-group of initial substance (1) was carried out by means of following systems: Fe/H2O, Fe/CH3COOH, SnCl2/HCl, Zn/H2O and Zn/HCl. The best results were obtained in the case of boiling of Fe/H2O suspension in toluene [2]. The yield of corresponding amine appeared to be 85%. In order to obtain new derivatives was carried out acylation and condensation with aldehyde of amine XII according the following scheme:

NO2

H3C-OC

NH2

H3C-OC

COOC2H5

N H

COOC2H5

N H

I

XI

CO-CH3 N=CH--R

H3C-OC

H3C-OC

N R'

N H

XII,XIII

COOC2H5

N H

COOC2H5

XIV-XVII

XII R=C6H5; XIII R=C6H4-NO2(o); XIV R=C6H4-NO2(m); XV R=CH3;

XVI R'=H; XVII R'=CO-CH3

204


By condensation of amino-group with aldehydes were obtained azomethines (XII-XVI). The reactions of condensation were carried out in ethanol in the presence of dry K2CO3 [1]. At the same time intermolecular condensation reaction of 5-acetyl and 3-phenylamine-groups with formation of mixture of oligomerous compounds can be depicted with common structure (XVIII):

CH3 N=

C N H

COOC2H5 n

XVIII

Acetylation of amino-compound (XI) was carried out with acetic anhydride. By boiling of mixture of this compound with glacial acetic acid and acetic anhydride was obtained monoacetyl-derivative (XVII). The same compound was obtained when heated amine (XII) with acetic acid for a short time at 80-90oC. Boiling for 30-40 min mixture which consists of 7 and 8 compounds with ratio approximately 1:1, but by the increase of the boiling time up to 2-3 h practically only diacetyl-derivative (XVIII) was obtained. It should be noted, that there wasn’t observed acetylation of pyrrole NH-group during the reaction. The control on course of reaction, purity of compounds and calculation of Rf values were carried out by thin-layer chromatography on ―Silufol UV-254‖ plates. UV spectra were recorded on spectrophotometer ―Specord‖ (ethanol); IR spectra were recorded on ―UR-20‖ (in white paraffin oil). Mass-spectra were recorded on ―R10-10 Ribermags’s‖ (ionizing energy – 70 eV); NMR spectra - on WP 200 SY (200 MHz).

EXPERIMENTAL PART 2-Oxycarbonyl-3-(p-nitrophenyl)-5-acetylindole (III): A suspension of 0.7g (2 mmol) of ester (1), 50 ml of NaOH 10% solution in water and 10ml of isopropanol was stirred and refluxed until clarification (~1 hour). The obtained solution was cooled and filtered. The filtrated with 10% HCl to pH 1. The precipitate was filtered and dried until neutral reaction and dried in exicator. The

Some Conversions of 5-acetyl-2-ethoxycarbonyl-3-p-nitrophenyl Indole 205 Recrystallization from water gave 0.5g (80%) of acid (XII) as yellow crystals. Rf 0.62 (hexane-ether, 1:1). m.p. 180-183º C. IR-spectra, ν, cm-1: 3160-3250 (NH); 1720, 1670 (C=O); 1340, 1520 (NO2). UV-spectra; λmax, nm (lgε): 205(3.97); 269 (4.12). Found, % C 62.4; H 3.2; N 8.7, M+ 324. C17H12N2O2. Calculated, %: C 62.9; H 3.7; N 8.6; M 324. Chloranhidride of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (IV): to solution of 0.9 (3mmol) of acid (III) in 50 ml of abs. dioxane under regular stirring was dropwise added the solution of 10 ml SOCl2 in 10 ml of abs. dioxane at 0ºC was allowed standing at 45º C for 3 hours. The solvent was evaporated under reduced pressure.The dry residue was dissolved in 30 ml of abs. benzene and was evaporated again until dry residue was formed. This process was repeated twice. Again was dissolved in 30ml of abs. benzene and evaporated to 15ml. Was precipitated with abs. hexane. The precipitate was filtered and in dried vacuum – exicator 0.7g (78%) of yellow crystals were obtained. Rf 0.6 (benzene). m.p 221223ºC. IR-spectra, ν, cm-1: 3310(NH), 1700, 1650(CO),1520, 1355 (NO2). Found, %: C 60.0; H 3.1; N 8.0 C17H11N2O4Cl. Calculated, % C 59.6; H 3.2; N 8.2. Diethylamide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (V): to a solution of 0.5g of chloroanhydride (XIII) in 50 ml of abs. dioxane was added 0.5 ml triethylamine and 0.3 ml of the 33% solution of diethylamine in water and whole, was stirred was allowed standing for 2 hours, diluted with 100 ml of water, the precipitate was washed with water and dried. 0.46g (88%) of amide (XIV) was obtained. Rf 0.35 (chloroform). m.p 216-219ºC. IR-spectra, ν, cm-1:3350 (NH): 3060(NH amide); 1700, 1650 (CO); 1530, 1340 (NO2). UV-spectra, λmax, nm (lgε): 204(3.98); 255(4.31). Found, %: C 65.2; H 5.2; N 12.6; M+ 351. C19H17N3O4 . Calculated, %: C 65.0.; H 4.8; N 12.0. M 351. Anilide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (VI): was obtained in the same way as compound (XIV) from 0.5g (1.5 mmol) of chloroanhydride(XIII), 0.5ml of triethylamine and 0.2 ml (1.5mmol) of aniline in 50 ml of abs. dioxane at room temperature for 3 h. 0.48g (80%) was obtained. Rf 0.42 (hexane-ether, 1:1). M.p. 266-267º C. IR-spectra, ν, cm-1; 3305 (NH); 3050 (NH amide): 1710. 1650 (CO); 1530; 1340 (NO2). UV-spectra,λmax, nm (lgε): 204 (4.39); 260 (4.61): 319 (4.01). Found, %: C 69.4; H 4.4; N 10.7; M+ 399. C23H17N3O4. Calculated, %; C 69.2, H 4.3: N 10.5: M 399. P-acetylanilide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (VII): was obtained in the same way as compound (XV) from 0.5g (1.5mmol) of chloroanhydride (XIII), 0.5 ml of triethylamine and 0.27g (2 mmol) of paminoacetophenone 0.6g (91%) of amide (XVI) was obtained. Rf 0.65 (hexaneether, 1:1). m.p 246-247ºC. IR-spectra. ν, cm-1:3340(NH); 3100(NH-amide); 1700,1650(CO);1530,1340(NO2).UV-spectra, λmax, nm (lgε): 204 (5.36);

206


266(4.74); 322(4.46). Found, %: C 68.2; H 4.6; N 9.6; M+ 442. C25H20N3O5. Calculated, %: C 67.9; H 4.5; N 9.5; M 442. P-sulfamidoanilide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (VIII): was obtained in the same way as compound (XV) from 0.5g(1.5mmol) of chloroanhydride, 0.5ml of triethylamine and 0.35g (2 mmol) of psulfamidoaniline. 0.6g (85%) was obtained. Rf 0.7(ether). m.p 254-256ºC. IRspectra, ν, cm-1: 3305, 3250, 3110 (NH); 1710, 1650, (CO); 1530, 1340 (NO2). UV-spectra, λmax, nm (lgε): 208 (3.85); 266 (3.92). Found, %: C 58.0; H 4.2; N 11.4. C23H18N4O6S. Calculated, %: C 57.7, H 3.8; N 11.7. 2-Ethoxycarbonyl-5-acetylindole-3-yl-p-anilide of 3-(p-nitrophenyl)-5acetylindol-2 carbonic acid (IX): was obtained in the same way as compound (XV) from 0.54g (1.7 mmol) of 2 ethoxycarbonyl-3-(p-aminophenyl)-5acetylindole. 0.78 (83%) as obtained. Rf 0.25 (benzene). m.p 256-258ºC. IRspectra, ν, cm-1: 3380, 3310, 3450 (NH): 1660, 1650, 1630 (CO), 1520 1345 (NO2). UV-spectra, λmax, nm (lgε): 204 (3.61), 270 (4.8). Found, % C 69.2; H 4.6; N 9.3 C36H28N4O7. Calculated, %: C 68.8; H 4.5; N 8.9. Isonicotinoylhydrazide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (X): was obtained in the same way as compound (XV) from 0.3g (2 mmol) of isonicotinoylhydrazide. 0.57g (86%) was obtained. Rf 0.52 (benzene-acetone, 1:2). m.p. 284-287ºC. IR-spectra. ν, cm-1: 3400, 3310 (NH); 1710, 1650 (CO); 1550, 1340 (NO2). UV-spectra, λmax, nm (lgε): 208 (3.98); 265 (3.92). Found, %: C 62.9; H 4.2; N 15.4, C23H17N5O5. Calculated, %: C 62.3; H 3.8; N 15.8. 2-Ethoxycarbonyl-3-(p-aminophenyl)-5-acetylindole (XI) Toluene solution of 1.4 g (4 mmol) of nitro-compound (1) was heated at 100oC and 6 g of activated iron powder and 20 ml of water was added during 6 h. The hot solution was filtered and purified within the column (silicagel), eluent – benzene; yield 1.1 g (85). Rf 0.43 (Benzene-ether, 2:3). m.p. 226-227oC. IR-spectra v, cm-1: 1700 (CO); 3300 (NH2); 3455 (NH). UV-spectra, λmax, nm(lgε): 202(5.0). Found, %: C 70.7; H 5.3; N8.5. M+ 322. C19H18N2O3 . Calculated, %: C 70.8; H 5.6; N 8.7. M 322 2-Ethoxycarbonyl-3-(p-benzylideneiminophenyl)-5-acetylindole (XII) To the solution of 1.6 g (5 mmole) of amine (XI) and 0.64 g (6 mmole) of benzaldehyde in 50 ml of ethanol 0.1 g dry of K2CO3 was added and heated at 50 oC for 5h. Reaction mixture was diluted with 200ml of water, precipitate was filtered and recrystallized from ethanol. Yield 1.35 g (65%). m.p. 198-200 oC. Rf 0.55 (hexane-ether, 2:1). IR-spectra v, cm-1: 1620 (C = N); 1660, 1710 (C = 0); 33003480 (NH). UV-spectra λmax, nm (lgε): 206 (4.2); 249 (2.8) 314 (2.2) Found, %: C 75.3; H 5.6; N 6.4 M+ 410. C26H22N2O3. Calculated, %: C 76.1; H 5.4: N 6.8. M 410

Some Conversions of 5-acetyl-2-ethoxycarbonyl-3-p-nitrophenyl Indole 207 2-Ethoxycarbonyl-3-p-(o-nitrobenzylideneiminophenyl)-5-acetylindole (XIII) This compound was obtained by the method described above. Yield 1.5 g (64.6%). M.p. 220-221 oC. Rf 0.48 (hexane-ether, 2:1). IR-spectra v, cm-1 : 1340, 1560 (NO2); 1630 (C = N); 1660, 1700 (C = O); 3360 (NH). UV-spectra, λmax, nm(lgε): 205 (4.8); 270 (5.8); 335 (3.2). Found, %: C 68.1; H 4.9; N 9.6: M+ 455 C26H21N3O5. Calculated, %. C 68.6; H4.6, N 9.2: M 455. 2-Ethoxycarbonyl-3-p-(m-nitrobenzylideneiminophenyl)-5-acetylindole (XIV) This com-pound was obtained by the same way as described for compound (3). Yield 1.57 g (695). m.p. 228-230 oC. Rf 0.5 (hexane-ether; 1:1) IR-spectra v, cm-1: 1340, 1560 (NO2); 1630 (C = N); 1660, 1700 (C = O); 3365 (NH). UV-spectra, λmax, nm (lgε): 205 (2.2); 256 (2.6); 325 (2.0). Found, %: C 68.4; H 4.3; N 9.4. M+ 455 C26H21N3O5. Calculated, %: C 68.6; H 4.6; N 9.2. M 455 2-Ethoxycarbonyl-3-(p-ethylideniminophenyl)-5-acetylindole (XV) This compound was obtained by the same way as described for compound (3). Yield 0.8 g (46%). m.p. 231-232 oC. IR spectra v, cm-1: 1640 (C = N); 1690, 1740 (C=O); 3320 (NH). UV-spectra, λmax, nm(lgε): 208 (2.4); 268 (3.9). Found, %: C 72.1; H 5.9: N 8.5. M+ 348. C21H20N2O3. Calculated, %: C 72.4; H5.7; N 8.0; M 348. 2-Ethoxycarbonyl-3-(p-acetylaminophenyl)-5-acetylindole (XVI) Method (a): The mixture of 1.6 g (5 mmole) of amine (XI), 10 ml acetic acid of acetic anhydride 10 ml was boiled for 30 min, then cooled rapidly and poured with a thin stream into 300 ml of cold water. The obtained mixture was left 3-4h. Precipitation was filtered and purified within the column. Eluent-(hexan-ether 1:1); yield 0.9 g (50%). Method (b): The mixture of 1.6 g (5 mmole) of amine (2) and 20 g of acetic anhydride was heated for 5-7 h. All the successive steps are analogicalof those in method (a). Yield was 1.13 g (62%). m.p. 235-237 oC. Rf 0.4 (hexane-ether). IRspectra, v, cm-1 : 1660, 1680, 1710 (C = O); 3340, 3420 (NH). UV-spectra, λmax, nm(lgε): 206 (4.0); 245 (4.1): 270 (3.9). Found, %: 68.9; H 5.7; N 8.0. M+ 364. C21H20N2O4. Calculated, %: C 69.2; H 5.5; N 7.7. M 364. 2-Ethoxycarbonyl-3-(p-N,N-diacetylaminophenyl)-5-acetylindole (XVII) The mixture of 1.6 g (mmole) of amine (2) and 20 ml of acetic anhydride was boiled for 3h, then cooled and diluted with 10 ml of cold water. Obtained mixture was left for 4-5 h. Precipitation was filtered and purified within column; eluent chlorophorm. Yield 1.3 g (65%). m.p. 215-218 oC. Rf 0.41 (hexane-ether, 2:1). IRspectra, v, cm-1: 1640, 1685, 1710 (C=O); 3340-3370 (NH). UV-spectra, λmax, nm(lgε): 205 (4.7); 270 (4.6): 306 (2.8). Found, %: C 67.9; H 5.2; N 7.0. M+ 406. C23H22N2O5. Calculated, %: C 68.0; H 5.4; N 6.9. M 406.

1

H-NMR Spectra of diazocompounds V-XIII (acetone-d6)

4H 4/ H 8.16

5H

6H

7H

αH

βH

CH3CO

CH3CH2

CH2CH3

NH

CH3

J, Hz

12.55s

3H 3/ H -

-

7.96dd

7.61d

7.85d

8.35d

2.58s

1.20t

4.27k

-

-

IV

12.45s

-

8.16d

-

7.93dd

7.66d

7.85d

8.33d

2.57

-

-

-

-

VI

11.97s

-

7.78d

-

7.69dd

7.41d

7.77d 8.30d 7.02 - 7.24m

-

-

-

9.36s

2.06

XI

12.04s

-

8.17d

-

7.86dd

7.52d

7.22d

6.67d

2.56s

1.23t

4.25k

5.24s

-

XV D-acetone

11.23s

-

8.33d

-

7.98dd

7.63d

7.79d

7.54d

2.13s 2.57s

1.24t

4.28k

9.27s

-

XII

11.30s

-

8.04d

-

7.98dd

7.75d

7.89d 6.98d

7.48d 7.15m

2.51s

1.2t

4.24k

-

5.21s

XV D-acetone

11.52s

-

8.30d

-

8.03dd

7.69d

7.93d

8.40d

2.58s

1.20t

1.31k

N=CH 5.17k

1.24d

XVII D-acetone

11.25s

-

8.32d

-

8.00dd

7.68d

7.81d

7.50d

2.15s 2.55s

1.23t

4.26k

-

-

J4,6=1.1; J6,7= =Jα,β=8.77 Jethyl=7.0 J4,6=1.3; J6,7=8.9; Jα,β=8.5 J4,6=1.4; J6,7=8.7; Jα,β=8.6 J4,6=1.45; J6,7=8.77; Jα,β=8.4 J4,6=1.7; J6,7=8.96; Jα,β=8.53; Jethyl=7.3 J4,6=1.7; J6,7=8.96; Jα,β=8.53; Jethyl=7.3 J4,6=1.7; J6,7=8.9; Jα,β=9.0; Jethyl=6.0 J4,6=1.7; J6,7=8.96; Jα,β=8.53; Jethyl=7.3

Compound # I

1H

Some Conversions of 5-acetyl-2-ethoxycarbonyl-3-p-nitrophenyl Indole 209


REFERENCES [1]

I. Chikvaidze, N. Narimanidze, Sh. Samsoniya. Et. At. Chemistry of Heterocyclic Compounds. 9 (315), 1993, 1194-1199 (Russian).


Chapter 9

2-PYRIDINESELENENYL- AND TELLURENYL CHLORIDES AS BUILDING BLOCKS FOR DERIVATIVES OF 2,3-DIHYDRO[1,3] SELEN(TELLUR)AZOLO[3,2-A]PYRIDIN-4-IUM Alexander V. Borisov*, Zhanna V. Matsulevich, Vladimir K. Osmanov, Galina N. Borisova and Georgy K. Fukin R. E. Alekseev Nizhnii Novgorod State Technical University, 603950 Nizhnii Novgorod, Russian Federation

The reactions of 2-pyridineselenenyl- and tellurenyl chlorides with alkenes lead to the formation of products of a tandem electrophilic addition/cyclization process with the ring closure by the nitrogen atom of the pyridylchalcogeno moiety. By virtue of its extremely high regio- and stereoselectivity selenocyclofunctionalization of unsaturated substrates carrying internal nucleophiles is one of most important and effective methods of synthesis of heterocyclic compounds [1-11]. Much less is known about tellurocyclofunctionalization of unsaturated compounds [12-15]. All these

*

Fax: +7 831 436 2311. E-mail: [email protected]. ru

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cyclizations proceed with ring closure involving a nucleophilic active group in the molecule of the substrate. Recently we described a novel approach to a stereoselective synthesis of condensed sulfur–nitrogen-containing heterocycles based on the interaction of sulfenyl chlorides with unsaturated compounds which occurs by ring closure at the nucleophilic center of the sulfenyl unit [16]. Taking into account these results it can be predicted that corresponding organoselenium and organotellurium reagents are suitable for the preparation of heterocycles containing selenium and tellurium. We now report on extensions of this alternative approach to selenenylating and tellurenylating reagents. In this work we have explored synthetic possibilities in reactions with alkenes for known 2-pyridineselenenyl chloride (1a) [17] and new reagent 2pyridinetellurenyl chloride (1b), prepared by the interaction of di(2-pyridyl) ditelluride with sulfuryl chloride in CH2Cl2. To the best of our knowledge the compound 1b is the first example of hetarenetellurenyl halides which contain the nitrogen atom in the hetaryl unite. The structure of this compound was determined by X-ray analysis of a single crystal (Figure 1). Crystallographic data for 1b: C10H8Cl2N2Te2, Mr = 482.28, monoclinic, space group P21/n, a = 10.0103(4), b = 8.0519(3) and c = 16.4700(7) Å, = 103.8800(10) , V = 1288.75(9) Å3, Z = 4, T = 100(2) K, F000 = 880, dcalc = 2.486 gcm–3, = 0.414 mm–1, = 2.55–25.99°, reflections collected 7357, independent reflections 2524 [Rint = 0.0228], GOF = 1.057, R = 0.0278 [I > 2 (I)], wR2 = 0.0646 (all data), largest diffraction peak and hole 1.578 / -0.772 e.Å-3. For research of synthetic opportunities of the developed approach, regio- and stereochemistry of cyclization as model substrates we used alkenes 2-7. It is necessary to note that recently in reaction of 2-pyridineselenenyl bromide analogous selenenyl chloride 1a with styrene 2 in methanol is received only solvoadduct – 1-methoxy-1-phenyl-2-(2-pyridylselanyl)ethane – in quantitative yield [18]. We have found that selenenyl chloride 1a and tellurenyl chloride 1b reacts with equimolar amounts of alkenes 2-6 in CH2Cl2 at 20°C to give the derivatives of 2,3-dihydro[1,3]selen(tellur)azolo[3,2-a]pyridin-4-ium 8-12a,b, the products of cyclization with ring closure at the nitrogen atom of the pyridylchalcogeno moiety (Scheme 1, Table 1).

2-Pyridineselenenyl- and Tellurenyl Chlorides as Building Blocks …

213

Figure 1. Molecular structure of 1b. Selected bond lengths (Å): Te(1B)-C(1B) 2.125(4), Te(1B)-N(1A) 2.329(4), Te(1B)-Cl(1B) 2.539(1), Te(1A)-C(1A) 2.120(4), Te(1A)-N(1B) 2.309(3), Te(1A)-Cl(1A) 2.558(1). Selected bond angels (º): C(1B)-Te(1B)-N(1A) 83.10(15), C(1B)-Te(1B)-Cl(1B) 87.25(12), N(1A)-Te(1B)-Cl(1B) 169.87(9), C(1A)Te(1A)-N(1B) 83.32(14), C(1A)-Te(1A)-Cl(1A) 86.48(11), N(1B)-Te(1A)-Cl(1A) 169.35(9).

In a typical experiment a solution of unsaturated compound 2-6 (10 mmol) in CH2Cl2 (10 ml) at 20 ºC was added to a suspension of reagent 1a,b (10 mmol) in CH2Cl2 (10 ml). The mixture was stirred approximately for 1-2 days. After full dissolution of suspension of reagent the solvent was evaporated to leave a solid residue, which was recrystallized from CH2Cl2. The products were obtained in reproducibly high yields (91-96%) under ordinary laboratory lighting conditions. In contrast to the reactions of electrophiles 1a and 1b with alkenes 2-6, interactions of the same reagents with norbornene 7 in CH2Cl2 at 20°C led to the formation of 1,2-chloroselenide 13a and 1,2-chlorotelluride 13b in nearly quantitative yields (Scheme 2).

214

A.V. Borisov, Zh. V. Matsulevich, V. K. Osmanov et al. Scheme 1 2

R 1

1

R

R

+

2-4

-

N

Cl 2

X

R

8-10a,b +

5

N

-

N

XCl

X

Cl

11a,b

1a,b

+

6

N

-

Cl X

a X = Se

12a,b

b X = Te 2,8 R1 = Ph, R2 = H 3,9 R1 = H, R2 = tert-Bu 4,10 R1 = H, R2 = Me3Si

Scheme 1.

Table 1. Reactions of electrophiles 1a,b with alkenes 2-6 Reagent 1a 1a 1a 1a 1a 1b 1b 1b 1b 1b

Alkene 2 3 4 5 6 2 3 4 5 6

Product 8a 9a 10a 11a 12a 8b 9b 10b 11b 12b

Yield, % 95 96 93 92 93 94 93 91 92 95

2-Pyridineselenenyl- and Tellurenyl Chlorides as Building Blocks … Scheme 2

X

CH2Cl2

215

N

Cl 7 N

13a,b

XCl +

N

LiClO4 / MeNO2

1a,b

X

a X = Se b X = Te

ClO4-

14a,b

Scheme 2.

Absolutely other result was observed when the same set of reactions was carried out in MeNO2 in the presence of LiClO4. Under these conditions reactions gave only the products of cycloaddition, the salts 14a and 14b in 88% and 83% yields respectively (Scheme 2). In a typical experimental procedure a solution of LiClO4 (1.06 g, 10 mmol) in MeNO2 (30 ml) was quickly added to a solution of reagent 1a or 1b (10 mmol) in MeNO2 (30 ml) at 20 °C. After 1 min a solution of alkene 7 (0.94 g, 10 mmol) in MeNO2 (10 ml) was added. The mixture was stirred for 1h. The precipitate of LiCl was separated by filtration, and the filtrate was evaporated to leave a solid residue, which was recrystallized from CH2Cl2. The structure of the products has been confirmed by elemental analysis, IR, NMR (1H and 13C) spectroscopy and mass spectrometry. Judging from the 1H NMR spectra, all the studied reactions occurs regiospecifically and stereospecifically. Taking into account the known criteria for determining the stereochemistry of addition to alkenes and also the results we obtained earlier [16], we may assume that formation of the condensed systems 8-12a,b and 14a,b occurs to a cis-cycloaddition scheme. For example, in the 1H NMR spectra of compounds 14a,b the signals from the protons of the CHX and CHN+ moieties appear as doublets with spin–spin coupling constant 7.3-8.3Hz, which suggests an exo–cis configuration for these products [20, 21]. It has been shown previously that the formation of the product of heterocyclization in reactions of hetarenesulfenyl chloride with alkenes can proceed by two routes [16]. Therefore for finding-out of routes of the formation of compounds 8-12a,b and 14a,b we have lead control experiments. NMR-

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monitored experiments demonstrated that reaction of 1a,b with alkenes 2-6 involve the initial formation of usual 1,2-adducts 15a,b, followed by transformation of the latter into heterocyclic products 8-12a,b (Scheme 3). At the same time, control experiments have shown that compounds 13a,b do not undergo intramolecular heterocyclization in CH2Cl2 and LiClO4 - MeNO2 and hence the products 14a,b are formed in the course of the AdE reaction. Thus, we have developed simple and convenient methods for the synthesis of Scheme 3 condensed Se,N- and Te,N-containing hetecycles.

R2 R1 N

Cl 1

2-6

R

R2

H H N

X

-

N

Cl 2

XCl

1a,b

R1

+

X 15a,b

R

8-12a,b

a X = Se b X = Te Scheme 3.

REFERENCES [1] [2] [3] [4] [5] [6]

[7]

Nicolaou, K. C.; Seitz, S. P.; Sipio, W. J.; Blount, J. F. J. Am. Chem. Soc. 1979, 101, 3884-3893. Clive, D. J. L.; Russell, C. G.; Chittattu, G.; Singh, A. Tetrahedron, 1980, 36, 1399-1408. Nicolaou, K. C. Tetrahedron, 1981, 37, 4097-4109. Fujita, K.; Murata, K.; Iwaoka , M.; Tomoda, S. Tetrahedron , 1997, 53, 2029-2048. Wirth, T. Tetrahedron, 1999, 55, 1-28. Tiecco, M. In Topics in Current Chemistry: Organoselenium Chemistry: Modern Developments in Organic Synthesis; Wirth, T. Ed.; Springer: Heidelberg, 2000; 7-54. Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 3741-3749.

2-Pyridineselenenyl- and Tellurenyl Chlorides as Building Blocks … [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

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Petragnani, N.; Stefani, H. A.; Valduga, C. J. Tetrahedron, 2001, 57, 14111448. Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A. Chem. Eur. J., 2002, 8, 1118-1124. Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron, 2004, 60, 5273-5308. Denmark, S. E.; Edwards, M. G. J. Org. Chem., 2006, 71, 7293-7306. Petragnani, N.; Comasseto, J. V. Synthesis, 1991, 897-919. Yoshida, M.; Suzuki, T.; Kamigata, N. J. Org. Chem., 1992, 57, 383-386. Stefani, H. A.; Petragnani, N.; Brandt, C.; Rando, D. G.; Valduga, C. J. Synth. Commun., 1999, 29, 3517-3531. Petragnani, N.; Stefani, H. A. Tetrahedron, 2005, 61, 1613-1679. Borisov, A. V.; Osmanov, V. K.; Borisova, G. N.; Matsulevich, Zh. V.; Fukin, G. K. Mendeleev Commun., 2009, 19, 49-51. Toshimitsu, A.; Owada, H.; Terao, K.; Uemura, S.; Okano, M. J. Org. Chem., 1984, 49, 3796-3800. Toshimitsu, A.; Owada, H.; Terao, K.; Uemura, S.; Okano, M., J. Chem. Soc., Perkin Trans. 1, 1985, 373-378. Clive, D. J. L.; Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen, S. M. J. Org. Chem., 1980, 45, 2120-2126. Barraclough, D.; Oakland, J. S.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1, 1972, 1500-1506. Wirschun, W. G.; Al-Soud, Y. A.; Nusser, K. A.; Orama, O.; Maier, G.-M.; Jochims, J. C. J. Chem. Soc., Perkin Trans. 1, 2000,4356- 4365.


Chapter 10

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME ADAMANTYL CONTAINING INDOLES AND BENZOPYRROLOINDOLE DERIVATIVES Sh. A. Samsoniya, D. S. Zurabishvili, I. Sh. Chikvaidze, M. O. Lomidze, M. V. Trapaidze, K. Kh. Mamulashvili, Z. Sh. Lomtatidze Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT 2-(1-adamantyl)indole, synthesized by Fischer reaction, was transformed into 3-dimethylaminomethyl derivative according Mannich reaction. It was obtained corresponding quaternary salts soluble in water. 2adamantylaminocarbonylindole and 2,9-di(adamantylaminocarbonyl)1H,10H-benzo[e]pyrrolo[3,2-g]indole were obtained by interaction between 1-aminoadamantane and 2-indolylcarbonic acid. The synthesized compounds revealed biological activity.

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Sh. A. Samsoniya, D. S. Zurabishvili, I. Sh. Chikvaidze et al.

INTRODUCTION Indole derivatives are characterized with broad spectrum of pharmacological activity: they have an antimicrobial and antifungal action [1], reveal psychotropic and anti-inflammatory activity, possess antihistaminic and antiadrenalistic properties [2]. Also it is known substances containing adamantane fragment in the molecule and possessing broad spectrum of biological activity [3-5]. Therefore in order to find new biologically active compounds some adamantyl containing indole derivatives and benzopyrroloindole were synthesized in the present work; also was studied antimicrobial activity. According Fischer reaction from 1-acetyladamantane and phenyl hydrazine 2-(1-adamantyl)indole(I) was obtained in polyphosphoric acid. As a result of its aminomethylation according Mannich reaction[7] was obtained an analog of indole alkaloid gramine – 2-(1-adamantyl)-3- dimethylaminomethylindole(III). Reaction was carried out at the condition similar to indole [8]. As a result of interaction between indole-2-carboxylic acid chloride (II) [4] and 1-adamantylamine in absolute benzene was obtained 2-(1-adamantyl)aminocarbonylindole(IV) with 31% yield. Compound III was transformed into watersoluble salt – methylsulphate-V, methyliodide VI and hydrochloride-VII.

R' R

R

N H I, II

N H III, IV

I R=1-adamantyl(Ad); II R=COCl; III R=1-Ad, R'=CH2-N(CH3)2; IV R=CONH-Ad, R'=H Dichloranhydride 2,9-dioxycarbonyl-1Н,10Н-benzo[e]pyrrolo[3,2-g]indole (IX) was synthesized as a result of interaction between di-acid VIII [9] and thionylchloride. By condensation of dichloranhydride IX with aminoadamantane in absolute dioxane was received 2,9-di(adamantylaminocarbonyl)-1Н,10Нbenzo[e]pyrrolo[3,2-g]indole (X).

Synthesis and Antimicrobial Activity …

221

ClOC

HOOC

NH

NH H N COOH

H N

SOCl2

COCl

IX

VIII Ad-HNOC

NH H N

Ad-NH2

CONH-Ad

X Composition and structure of the synthesized compounds were established by means of elemental analysis, IR-, UV- and NMR spectra. Biozidal properties were studied on the basis of microorganisms tests in the Burkholter environment. Activity of compounds was established by means of lunula method. Compounds I, III and IV revealed biozidal properties and suppress bacterium development with different activities (see the table).

Influence of substances II and IV on the growth of some microorganisms Testmicroorganisms

Control Ethanole: Water 10:1 0,0

Compound I

III

IV

6,0* 1,0**

1,0 1,5

6,5

Xanthomonas campestris

0,0

3,0

2,0

4,0

Bacterium tumefaciens

0,0

2,0 1,0

1,0 0,5

5,0

Pectobacterium aroideac

*

Inhibition zone size, mm. Sterile zone, mm.

**

222


The rest substances appeared to be inactive. For compound X was studied antituberculous activity in vitro towards microorganism [10]; was revealed a weak activity against micobacteria: Mycobaqterium tuberculosis H 37, Mycobaqterium tuberculosis academia and Mycobaqterium tuberculosis bovis 8. Minimal inhibitory concentration (MIC) in mkg/ml was consequently 23, 153 and 23.

EXPERIMENTAL PART Reaction progress and individuality of compounds controlled over Silufol UV-254 plates. Infrared spectrum was taken on the ―Specord‖ IR-75 device, UV spectrum – on the spectrometer ―Specord‖ UV VIS in ethanole, NMR spectrum – on the spectrometer WP-200 SY (200 MHz), internal standard – ТМS. 2-(1-Adamantyl)indole (I). Mixture of 1 ml (10 mmol) of phenylhydrazine, 2g (10 mmol) of 1-acetyladamantane and 30 g of polyphosphoric acid were mixed for one hour at 110 С, then cooled and diluted with cold water. Precipitate was filtered, washed with water until рН 7 and dried. It was purified on the column with silica gel in ether-hexane system, 1:7. Rf 0,43. Yield 2,15 g (85%). Tmelt 149-150 С. IR spectrum, , cm-1: 3410 (NH), 3000-2850 (CH-Ad). NMR spectrum (acetone-d6), , ppm, J, Hz : 9,9 (1H,s); 6,1(3H,м); 6,80-7,45 (4H-7H, м); 1,8-2,05(Ad-H, м); J м=2,2; J о=7,7; J37 =0,7. Found, %: С 86,4; Н 8,1; N 5,6. С18Н21 N. Calculated, %: С 86,0; Н 8,4; N 5,6. 2-(1-Adamantyl)-3-dimethylaminomethylindole (III). Solution of 0,5 g compound I and 1,9 g CH2-N+(CH3)2 CI- in 20 ml absolute dimethylformadide were mixed for 6 hours at 25 С, then diluted with 200 ml cold water and alkalified til рН 10. Was extracted with ether (3X50 ml). Extract was dried on KOH and steamed dry. Residue was crystallized from hexane. Yield – 76%. Tmelt - 121-123 С. IR spectrum, , см-1: 3405 (NH), 3000-2800 (CH-Ad). NMRspectrum (aceton-d6), , ppm, J, Hz: 9,7 (1H); 7,55 (4H,kw); 6,8-7,5 (4H-7H, м); 1,8-2,2(Ad-H, м); 2,21 (СH2, s); 2,16 (СH3, s). J м=1,6; J о=7,7. Found,%: С 81,5; Н 8,8; N 9,0. С21Н28 N2. Calculated, %: С 81,7; Н 9,1; N 9,0. 2-(1-Adamantyl)aminocarbonylindole (IV). Mixture of 0,5 ml (3,3 mmol) of 1-adamantylamine in 20 ml absolute benzene was added solution of 0,53 g (3,7mmol) compound II in 25 ml absolute benzene, 0,4 ml triethylamine and mixed for one hour at 60-65 С. Solvent was cooled, filtered and steamed. Residue was purified on the column with silica gel in ether-hexane system, 5:1. Rf 0,7 (hexane-ether, 1:1). Yield 0,28 g (31%). Tmelt -224-225 . IR spectrum, , см-1: 3410 (NH), 3290(NHСО), 3000-2870 (CH-Ad), 1660 (СО). NMR-spectrum

Synthesis and Antimicrobial Activity …

223

(СHСI3), , ppm, J, Hz : 10,0 (1H,s); 6,71(3H,d); 7,1-7,5 (4H-7H, м); 5,87 ( NHCO,s); 1,74-2,16(Ad-H, м); J13=1,7; J о=7,8; Jм =1,9. Found, %: Н 7,1; N 9,6. С19Н22 N2О.; Calculated, %: Н 7,0; N 9,0. 2(1-Adamantyl)-3-dimethylaminomethylindole methylsulphate (V). To the mixture of 1 ml (CH3)2SO4 in 5 ml absolute tetrahydrofuran was added 0,31g (1mmol) compound III in 10 ml absolute tetrahydrofuran and then mixed at 1520 С for 3 hours. Residue was filtered, washed with absolute tetrahydrofuran, absolute ether and dried at vacuum. Yield – 0,24 g (55%). Tmelt - 180 С. 2(1-Adamantyl)-3-dimethylaminomethylindole methyliodide (VI). Solution of 0,31 g (1mmol) of compound III and 1,2 ml (20 mmol) methyliodide in 50 ml absolute ether were mixed at 15-20 С for three hours and left for night. Precipitated crystals were filtered, washed with absolute ether and then dried. Yield – 0,42g (93%). Tmelt - 295 С. 2(1-Adamantyl)-3-dimethylaminomethylindole hydrochloride (VII). To the solution of 0,31g (1 mmol) compound III in 10 ml absolute tetrahydrofuran was added solution of dry НСI in absolute ethanole till рН 1, then mixed for 3 hours and diluted with 100 ml dry ether. Precipitation was filtered, washed with absolute ether and then dried. Yield- 0,25g (73%). Tmelt - 210 С. 2,9-Dioxycarbonyl-1H,10H-benzo[e]pyrrolo[3,2-g]indole dichloranhydride (IX). 0,3 g (1 mmol) of 2,9-dioxycarbonyl-1H,10H-benzo[e]pyrrolo[3,2g]indole(IX) was suspended in 10 ml thionylchloride and boiled for 5 hours by mixing. Then reaction mixture was cooled until 35…40 С, precipitate was filtered, washed several times with absolute ether and dried of vacuum. Yield – 0,24g (90%). Yellow crystals, - Tmelt 240... 241 С. Rf 0,77 (hexane-ether,1:1). IR spectrum, , см-1: 3370 (NH), 1665(С=О). NMR-spectrum (DMSO-d6), , ppm, J, Hz: 11,83(1H,10H,b.s); 7,72(3H,8H,d); 8,29(4H,7H, dd); 7,46(5H,6H,dd), J13=2,19; J 45=9,32; J46=6,22; Found, %: C 58,4; H 2,8; N 8,5; CI 21,1. С16Н8N2 CI2О2. Calculated, %: C 58,1; Н 2,4; N 8,5; CI 21,2. 2,9-Di(1-adamantylaminocarbonyl)-1H,10H-benzo[e]pyrrolo[3,2-g]indole(X). To the mixture of 0,3g (1 mmol) compound IX in 20 ml dioxane was added solution of 0,6 g (4 mmol) aminoadamantane in 10 ml dioxane and mixed for one hour at 70 С. Solvent was cooled, filtered, washed with absolute ether and dried. Yield 0,34g (68%). Yellow crystals, - Tmelt 283…284 С. Rf 0,63 (benzeneacetone, 4:1). IR spectrum, , см-1: 3370. 3340 (NH), 1650(amid I); 1535 (amid II). NMR-spectrum (DMSO-d6), , ppm, J, Hz : 11,63(1H,10H,b.s); 7,89(NH amid, s); 7,61(3H,8H, s); 7,45(4H,7H, b.s), 8,11 (5H, 6H, b.s); 1,79…2.14 (Ad). Found, %: C 76.8; H 6,7; N 9,7.С36Н40N4О2. Calculated, %: C 77,1; Н 7,2; N 10.0.

224



REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9]

Trofimov B.A. Mikhaleva A.I. Beliaevski A.I. and others. Jour. Pharm.chem., №3, pp – 25-29; 1981. Gasteli J., Schivdler W. – Pat. 550788 (Switzerland). Chemsitry, №4, N40/09P,1975. Bagrii E.I. Adamantanes: Preparation, Properties, and Use “Nauka”, Moscow, 1989. Morozov I.S. Petrov V.I. Sergeeva S.A. Pharmacology of Adamantanes. Volgograd Medical Academy, 2001. Аrtsimovich N.G., Galushina T.S., Fadeeva T.A. Intern. J. Immunorehabilitation, 2, 54, 2000. Suvorov N.N. Mamaev V.N. Rodyonov V.M. Reactions and Methods of investigation of Organic Compounds` M.,9-154, 1959. Blik F.F. Organic Reactions. M., 10, 339, 1948. Samsoniya Sh.A. Chikvaidze I.Sh. Suvorov N.N. Reports – AN GSSR, 99, №3, 613; 1980. Zhungiettu G.I. Budilin V.A. Kost A.N. Preparative Chemistry of Indole. Chisinau, 192, 1975.


Chapter 11

PHOTOCHEMISTRY OF AZIDOPYRIDINE AND RELATED HETEROCYCLIC AZIDES Mikhayl F. Budyka* Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432, Chernogolovka, Moscow region, Russian Federation

ABSTRACT Photochemical properties of azido derivatives of six-member azaheterocycles (pyridine, pyrimidine, triazine, quinoline, acridine) are discussed. Data on the structure of the reaction products formed under photolysis of azides in different conditions (solvent, temperature, additives), and also data on the matrix isolation spectroscopy of heterocyclic nitrenes, including high-spin nitrenes, produced by low-temperature photolysis of the corresponding azides are shortly examined. Especial attention is paid to the dependence of the azide photoactivity (i.e. quantum yield of azido group photodissociation) on the size and charge of the heteroaromatic system. Heterocyclic azides have been used as convenient model compounds for the study of charge effect, since they can be easily transformed from the neutral to positively charged form by protonation or alkylation at endocyclic nitrogen atoms. *

E-mail: [email protected]

226

Mikhayl F. Budyka Protonation of a heterocyclic nucleus has been found to decrease slightly the photodissociation quantum yield ( ) of 4-azidopyridine and 4value for 9-azidoacridine, and azidoquinoline, do not influence on the reduce by two orders of magnitude the value for 9-(4'azidophenyl)acridine. To reveal the effect of the size and charge on azide photoactivity, the structures of linear cata-condensed heteroaromatic azides from azidopyridine to azidoazahexacene (the size of aromatic -system from 6 to 26 e) are calculated by semiempirical (PM3), ab initio (HF/6-31G*) and DFT (B3LYP/6-31G*) methods. Joint consideration of the experimental and quantum-chemical data results in the conclusion that the azide photoactivity depends on the nature of molecular orbital (MO) that is filled in the lowest excited singlet (S1) state. If the antibonding NN*-MO, which is localized on the azido group and is empty in the ground (S0) state, is filled the S1 state, the azide is photoactive ( > 0.1). However, when the size of the -system increases above a certain threshold, aromatic -MO is filled instead of the NN*-MO in the S1 state, and the azide becomes photoinert ( drops below 0.01). The threshold size is predicted to be 22 and 18 -electrons for the neutral and positively charged azides, respectively. Several examples of application of heterocyclic azides for photoaffinity labeling are considered. Important from this point of view are azidoderivatives of acridine, hemicyanine, and ethidium dyes, which possess the most long-wavelength visible light sensitivity so far reported for aromatic azides.

INTRODUCTION The photochemistry of aromatic azides receives continuous attention because of their useful applications in heterocyclic syntheses, photoresist techniques and photoaffinity labeling [1,2,3,4,5]. The key reaction in all cases is the photoinduced N-N2 bond dissociation with formation of highly reactive intermediate, nitrene. The main quantitative parameter of this reaction is the photodissociation quantum yield ( ), which determines the azide photoactivity.

RN-N2

h

RN + N2

Photochemistry of Azidopyridine and Related Heterocyclic Azides

227

The photodissociation of arylazides upon direct excitation in the longwavelength absorption band occurs in the lowest singlet excited state (S1). In this case, the quantum yield is determined as = kr/(kr + kf + kic + kisc + kd) ,

(1)

where kr is a rate constant for azido group dissociation in the S1 state, kf, kic and kisc are the rate constants for emission (fluorescence), internal conversion, and intersystem crossing, respectively; and kd characterizes all other possible processes of deactivation of the excited state (energy transfer, other reactions, etc.). Depending on the azide structure, the value can vary by several orders of magnitude. In this respect arylazides are grouped into photoactive azides ( > 0.1) and photoinert azides ( < 0.01) [6]. It is also known that irradiation of azides with light at different wavelengths resulting in occupation of different electronic excited states (S1, S2 , … Sn) can lead to variation of the quantum yield of azide photodissociation due to the change in the rate constant ratio in the denominator in formula (1) for these states [7,8,]. The second parameter characterizing the tendency of azide towards photodissociation is the range of spectral sensitivity, which is determined by the absorption spectrum of azide. Interrelation between azide photoactivity (photodissociation quantum yield) and spectral sensitivity will be discussed below. Taking up heterocyclic azides, one can mark two main peculiarities entered by aza-fuction into general photochemistry of aromatic azides. Both these peculiarities are connected with uncoupled electron pair of the endocyclic nitrogen atom. Due to this, heterocyclic azides can form N-oxides and obtain the possibility of easy transformation from the neutral to positively charged species by protonation/alkylation at endocyclic nitrogen atom. Insertion of the positive charge into the -system of heterocyclic azide can affect strongly the photodissociation quantum yield and reaction product structure. Due to this fact, heterocyclic azides have been used as convenient model compounds for the study of charge effect in photochemistry of aromatic azides; this effect will be discussed in detail below. The second peculiarity is characteristic of heterocyclic azides with -position of azido group relative to endocyclic nitrogen atom and is connected with the azido-tetrazolo tautomerism which can be defined as a 1,5-dipolar cyclization [9].

228

Mikhayl F. Budyka C N N N N

C N

N3

The azide and tetrazole forms are easily distinguishable by their IR spectra: azide has strong band near 2100 cm-1, which is absent in the spectrum of tetrazole. The position of azide-tetrazole equilibrium depends on an electron density at the endocyclic nitrogen atom which, in turn, is defined by the nature and position of substituents in the heterocyclic nucleus. The population of azido and tetrazole forms depends also on the solvent and temperature. Polar solvents favor the tetrazole form, and nonpolar solvents, the azido species. Cleavage of the tetrazole ring is generally an endothermic process in solution, so the azide-tetrazole equilibrium is ordinary shifted to the side of the tetrazole form. The higher temperatures favor the azido species, the formation of azide from tetrazole on heating can be ascribed to entropy. For example, for derivatives of 2-azidopyridine, the enthalpies of the azides are higher than those of the corresponding tetrazolo[1,5-a]pyridines ( H°isom = 13 to -30 kJ mol-1; S°isom = -50 to -59 J mol-1 K-1), as determined by variable temperature 1H NMR spectroscopy in DMSO-d6 or CDCl3 solution [10]. R2

R2 R3 R4

R1 N N N N

R3 R4

R1 N3

N

In 2-azidoquinazoline azido group cyclizes to position 1, and this compound exists exclusively as tetrazolo[1,5-a]quinazoline in the solid state and in chloroform solution at standard temperature and pressure as evidenced by the absence of a peak near 2100 cm-1 in the IR spectrum [11]. N

N N N N N

N

N3

However, addition of trifluoroacetic acid to a solution in CDCl3 causes the formation of the azide tautomer as determined by 1H NMR spectroscopy.


229

Tetrazole is also converted to azide on heating. The calculated energy difference between azide and tetrazole in the gas phase, corrected for zero-point vibrational energy, is 0.16 kcal/mol (B3LYP/6-31G**). The calculated enthalpy difference is 0.86 kcal mol-1, and entropy difference is 5.74 cal mol-1 K-1. Thus, at 298 K, G(gas phase) = -0.88 kcal mol-1, with the azide as the most stable form. In the crystalline state, the lattice energy is likely to stabilize the solid tetrazole. Since G = H - T S, increased temperature will result in a lower G; i.e., it will shift the azide-tetrazole equilibrium toward the azide [11]. Maximal possibility for cyclization to tetrazole has cyanuric azide - 2,4,6triazido-1,3,5-triazine (explosive, very sensitive to shock and heat in crystals!), heterocyclic azide where each of three azido group has -nitrogen atom). However, cyanuric azide exists exclusively in azide form [12], whereas its triphenylphosphane derivatives (obtained by Staudinger reaction) - in tetrazole forms; the tetrazole isomers are stabilized due to the introduction of the PPh3 group [13]. The energy difference between the azide and tetrazole isomers is very small and was estimated to be about 1 kcal mol-1. Tetrazole is insensitive (or much less sensitive than azide) to light, so more prolonged irradiation or conversion to azide form by heating or acidifying is demanded for photochemical decomposition of tetrazole form. In this chapter main especial attention will be devoted to a series of heterocyclic azides, 4-azidopyridine A1 and its higher cata-condensed analogues: 4-azidoquinoline A2, 9-azidoacridine A3, 12-azido-benzo[b]acridine A4, 13-azido6-azapentacene (azidodibenzacridine) A5, and 15-azido-6-azahexacene A6; here the index is equal to the number of aromatic rings (Scheme 1). The first three compounds were studied both experimentally and theoretically, for the last three azides quantum-chemical calculations were performed. N3

N3

N3

N3

N

N

N

N

A1

A2

A4

N3

N3

N

N

A5 Scheme 1.

A3

A6

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Mikhayl F. Budyka

Systematic investigation of this series and some other heterocyclic azides allows revealing general relationship between azide structure and photoactivity. The dependence of photodissociation quantum yield on the size of the azide system and its charge - the size and charge effects and interrelation between them - have been found experimentally and justified quantum-chemically. Derivatives of diazido- and triazido-pyridines proved to be convenient precursors for photochemical generation of high-spin polynitrenes. These species are model systems for investigation of molecular magnetism and development of organic magnetic materials promising for applications in molecular electronics. Due to fast growth of the number of experimental and theoretical data on this subject, it requires separate consideration and will be only touched shortly in this chapter. Finally, the application of azides for photoaffinity labeling will be discussed on some examples. Important from this point of view are azido-derivatives of acridine, hemicyanine, and ethidium dyes, which possess the most longwavelength visible light sensitivity so far reported for aromatic azides and due to this fact enable soft non-destructive visible light to be used on investigation of biomacromolecules.

1. AZIDOPYRIDINES AND AZIDOQUINOLINES Azidopyridines are the simplest and obviously the most investigated heteroaromatic azides. In earlier investigations main attention was paid to identification of various reaction products. Recently, the quantitative structurereactivity relationship was studied based on comparison of the experimental and quantum-chemical data. Many high-spin nitrenes were obtained by photolysis of polyazidopyridines.

1.1. Photolysis Products and Quantum Yields Photolysis of azidopyridines in the presence of nucleophiles (sodium methoxide, diethylamine, etc.) proceeded with ring expansion and produced different derivatives of diazepines, (Scheme 2). 2-Azidopyridines gave derivatives of 1H-1,3-diazepines and 5H-1,3-diazepines [14,15], 3-azidopyridine – derivatives of 2H-1,4-diazepines and 5H-1,3-diazepines[16,17], and 4azidopyridine – derivatives of 6H-1,4-diazepines [17,18].

Photochemistry of Azidopyridine and Related Heterocyclic Azides h

R

R

N

R N3

N

N N N N

H N

h

Base

R

R N

NH + R N B

R

N

N

N3

Base

N

B

R N

Base

R N

Base

R N

B

H N R

N

R

N

N h

B

B

NH

R

N N3

N

N B

N

N

R

N

R

231

N

B

N

B

R N

N

Scheme 2. Photolysis of azidopyridines with ring expansion.

The product structure depended on the relative positions of azido group, pyridinic nitrogen and substituent(s) R (Scheme 2). For example, photolysis of 2unsubstituted 3-azidopyridines in the presence of sodium methoxide resulted in ring expansion to give the 4-methoxy-5H-1,3-diazepines, presumably via the azirine intermediates derived from the initially formed singlet 3-pyridylnitrenes by cyclization at the 2-position of the pyridine ring. On the other hand, in the photolysis of 2-substituted 3-azidopyridines, the cyclization of the nitrenes occurred predominantly at the vacant 4-position giving rise to the 3-methoxy-2H1,4-diazepines (Scheme 2) [19]. Derivatives of 4-azidoquinoline upon photolysis in the presence of sodium methoxide produced corresponding derivatives of 1,4-benzodiazepines [20], while irradiation in ethanethiol gave only 4-aminoquinolines (without insertion of ethylthio group) [21]. Tarry polymer as a major product and a small amount of azo compound were formed in the photolysis of 4-azidoquinoline in acetone [22]. Photolysis of N-oxides of 4-azidopyridine and 4-azidoquinoline gave corresponding azocompounds [22], or hydrogen-abstraction products [23]. No ring-expansion products were detected [23]. It is interesting, that no cross-over azocompound was obtained during photolysis of the mixture of two N-oxides of the azides [22]. Upon laser flash photolysis of 4-azidopyridine-1-oxide at room temperature in 3-methylpentane at 266 or 308 nm two temporally distinct features were

232

Mikhayl F. Budyka

observed: a partially structured bands at 520-560 nm, which were assigned to the triplet nitrene (3A2), and a broader band with an absorbance maximum at 435 nm, which was demonstrated to be dependent on the starting concentration of azide and was assigned to 4,4'-azo-bis(pyridine-1-oxide); the latter was obtained in reaction between the triplet nitrene and starting azide with a diffusion-limited rate [24]. 1N

N3

3N

h N O

+

O N N O

+

N O

+

N N

+

N O

+

The observed rate constant for intersystem crossing (kisc) from the singlet to triplet nitrene was determined to be approximately 2.107 s-1. The singlet nitrene (1A2) was detected by weak and short-lived transient signal at 493 nm upon photolysis in dichloromethane; it decayed in coincidence with the growth of the triplet nitrene. HPLC analysis of the reaction mixture after photolysis showed only one photoproduct - azo-compound. No evidence of products arising from the singlet nitrene was observed, and quantum-chemical calculations indicated that this is due to the significant barrier to nitrene cyclization to the benzazirine and didehydroazepine species. The barrier is significantly larger than those calculated for similar arylnitrene systems and is due to the stabilization of the 1A2 and 3A2 states by spin delocalization due to resonance contributors with iminyl-aminoxyl biradical character; as a result, spin density is withdrawn from sites for potential cyclization. Photolysis of 4-azidopyridine and 4-azidoquinoline in hydrohalogenoic acids gave corresponding 4-aminoazines and 3-amino-4-halogeno compounds via azirine or azacycloheptatetraene intermediates, whereas their N-oxides under similar conditions gave the 4-amino-3-halogeno compounds presumably via nitrenium ion intermediates; similar results were obtained for 3-azidoquinoline and 4-azidoisoquinoline [25]. In alcohols containing sulfuric acid these azides gave the corresponding -alkoxy amino compounds via nitrenium ion intermediates [26].

Photochemistry of Azidopyridine and Related Heterocyclic Azides N3

N

Cl NH2 +

h N

HCl

N3

N

N

N

NH2

h N O

+

HCl

N O

+

N O

233

NH2

N

Cl

+

Systematic quantitative investigations of the spectral properties and photodissociation quantum yields of azidopyridine and azidoquinoline in dependence on charge state (neutral or cationic) were performed in [27,28]. Neutral and protonated 4-Azidopyridine A1 and 4-azidoquinoline A2 have absorption bands in UV region of spectrum, Figure 1 [28]. Azido group as a chromophore (in hydrazoic acid and alkyl azides) possesses a long-wave absorption band in the region of 250 - 320 nm arising from n * transition [29,30]. This transition is forbidden and therefore is of very low intensity ( ~ 20 M-1 cm-1). For azidopyridine and azidoquinoline, this band is masked by the twoorder more intense n- * bands of heteroaromatic nuclei and, also, in azidoquinoline, by the - * band of quinoline nucleus [31,32]. Upon protonation, the long-wave absorption bands of azidoazines increased in intensity by 1.5-2-fold and were shifted to red by ~ 25 nm for 4-azidopyridine and by ~ 30 nm for 4-azidoquinoline, Figure 1. This behavior resembles that of corresponding amino-derivatives of pyridine and quinoline [33]. Azido group in hydrazoic acid is known to be protonated in superacid solutions with formation of aminodiazonium ion, H2N-N2+; in the gas-phase protonation, the iminodiazenium ion, HNNNH+, can be also formed [34]. The protonation of azidopyridine and azidoquinoline takes place definitely at endocyclic ("azine") nitrogen atom; the spectra of protonated azidoazines coincide with those of N-methylated ones. Both 4-azidopyridine and 4-azidoquinoline in their neutral and cationic forms decompose rapidly upon UV irradiation within the absorption bands. Figure 2 and Figure 3 show spectral changes observed upon irradiation of 4-azidopyridinium hydrochloride and 1-methyl-4-azidoquinolinium methylsulphate, respectively. Isosbestic points at the initial period of photolysis testify to selective reaction

234

Mikhayl F. Budyka

passing with retention of the structure and ratio of the reaction products. During further prolonged irradiation, isosbestic points disappeared thus indicating the proceeding of secondary reactions (see Figure 2, curve 7). The photodissociation quantum yields ( ) of the heteroaromatic azides were calculated from the kinetic curves of the azide disappearance and are shown in Table 1. It is seen that both neutral and cationic azidopyridine and azidoquinoline are photoactive azides with quantum yields > 0.1 [28,35]. Nevertheless, one can note some effects. Insertion of positive charge into azide molecule results in decrease of the value; for example, in MeCN, quantum yield decreases from 0.83 to 0.22 on going from 4-azidopyridine A1 to its hydrochloride and in somewhat less extent, from 0.49 to 0.37, on going from 4-azidoquinoline A2 to its hydrochloride. For neutral 4-azidopyridine quantum yield decreases slightly also on going from acetonitrile to acetonitrile-ethanol mixture and further to pure ethanol (Table 1). 4

6.0x10 -1

-1

/ M cm

4

4.0x10

2

4

2.0x10

0.0 200

1

3

250

300

4

/nm

350

Figure 1. The electronic absorption spectra in MeCN: (1) 4-azidopyridine (A1), (2) 4azidopyridinium hydrochloride, (3) 4-azidoquinoline (A2), (4) 4-azidoquinolinium hydrochloride [28].


235

1

0.5

A 0.4

0.3

7 0.2

0.1

0.0 250

300

/nm

350

Figure 2. Spectral changes upon irradiation (254 nm, Hg lamp) of 2.6.10-5 M solution of 4azidopyridinium hydrochloride in ethanol, irradiation time, s, (1) - (7): 0, 60, 120, 180, 300, 420, 1020; light intensity 8.73.10-10 Einstein cm-2 s-1 [27 1.0

A 0.8 8

0.6 1

1

0.4 8

0.2

0.0 200

250

300

/nm

350

Figure 3. Spectral changes upon irradiation (313 nm, Hg lamp) of 1.85.10-5 M solution of 1-methyl-4-azidoquinolinium methylsulphate in MeCN, irradiation time, s, (1) - (8): 0, 5, 14, 27, 44, 66, 97, 210; light intensity 2.7.10-9 Einstein cm-2 s-1 [28].

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Mikhayl F. Budyka

Table 1. Photodissociation quantum yields ( ) for 4-azidopyridine A1 and 4azidoquinoline A2 and their hydrochlorides and methylsulphates (irradiation by Hg arc lamp, 254 nm for A1 and 313 nm for A2) [28] Azide A1 A1 A1 A1HCl A1HCl A1MeSua A2 A2HCl A2MeSub a b

solvent MeCN MeCN/EtOH 1:1 EtOH EtOH MeCN MeCN MeCN MeCN MeCN

0.83 0.40 0.35 0.23 0.22 0.27 0.49 0.37 0.36

1-methyl-4-azidopyridinium methylsulphate. 1-methyl-4-azidoquinolinium methylsulphate.

1.2. Quantum-chemical Calculations To explain the effects observed, the structures of azides in the ground (S0) and lowest excited singlet (S1) states were calculated by different quantum-chemical methods; the data obtained are shown in Table 2. In the ground state, in all azides, the azido group has a quasi-linear geometry, the NNN bond angle NNN ~ 170 °. In the neutral form the N1N2 bond length is 1.27 Å (PM3 data), ab initio and DFT methods predict a somewhat smaller value of 1.24 - 1.25 Å. An important feature is a large positive charge on the terminal nitrogen atoms of the azido group, ~ 0.40 e according to PM3. Obviously, it is an overestimation, as follows from comparison with ab initio and DFT data for azide A1 (Table 2). The azido group is arranged in the plane of the molecule, and due to conjugation between azido group and heteroaromatic nucleus the rotation around the C-N quasi-single bond is hindered. The height of the rotational barriers in isomeric azidopyridines was determined via ab initio molecular orbital calculations (geometry optimization at RHF/6-31G** level, energy improvement as a single-point MP2/6-31G** calculation) [36]. The largest barrier, about 7 kcal/mol, was calculated for 2-azidopyridine (for this isomer the s-cis conformer is slightly more stable than the s-trans one), whereas it amounted to 3.32 and 4.04 kcal/mol for 3-azido and 4-azidopyridine, respectively.


237

Table 2. Selected optimized parameters for 4-azidopyridine (A1), 4azidoquinoline (A2), and their protonated forms in the ground (S0) and lowest excited singlet (S1) states: bond length (r) and bond order (p) for the N1N2 and N1C4 bonds, the N1N2N3 bond angle (amounted), and Mulliken charge (ZN2) on the terminal group N2, calculated by different methods (atom numbering: C4N1N2N3, cations were calculated without counterions) [28] Azide State rN1N2, Å S0 1.27 A1 1.24 1.25 1.24

+

A1H

A2 A2H+

° ZN2, е

rN1C4, Å 1.43 1.41 1.42 1.41

pN1N2 pN1C4 1.35 1.24 1.28 1.36

1.02 0.95 0.88 0.92

169.5 174.2 172.4 172.3

0.40 0.27 0.22 0.21

NNN,

S1 S0

1.35 1.30 1.27 1.26

1.39 1.39 1.36 1.38

1.02 1.18 1.08 1.25

1.36 1.20 1.12 1.05

133.4 168.8 172.1 170.4

-0.03 0.55 0.39 0.34

S1 S0 S1 S0 S1

1.41 1.27 1.35 1.30 1.42

1.35 1.43 1.39 1.39 1.34

0.87 1.34 1.08 1.19 0.89

1.53 1.03 1.38 1.20 1.64

128.1 169.3 137.9 168.7 134.4

0.09 0.41 -0.05 0.55 0.07

Method PM3 HF/6-31G* MP2/6-31G* B3LYP/631G* PM3 PM3 HF/6-31G* B3LYP/631G* PM3 PM3 PM3 PM3 PM3

Protonation induces the electron density transfer from the azido group to the aromatic nucleus, an effect that results in a weakening of the N1N2 bond even in the ground state. The N1N2 bond order decreases with simultaneous increase of the N1C4 bond order (Table 2), the N1N2 bond is elongated by 0.02 - 0.03 Å, and the N1C4 bond is shortened by 0.03 - 0.06 Å.. The electron density transfer results also in an essential charge increase on the N2 group upon protonation, for example, in cation A1H+ charge increases to 0.55 (PM3), 0.39 (HF/6-31G*), 0.34 e (B3LYP/6-31G*). In the lowest excited singlet state, the N-N2 bond is elongated by about 0.1 Å, the NNN valence angle is reduced by about 35°, and the charge at terminal nitrogen atoms decreases by about 0.45e (Table 2). These changes are defined by the nature of molecular orbital (MO) that is filled in the S1 state. In the case of photoactive azides, this is an orbital of definite structure, namely, NN*-MO, which is localized on the azido group and is

238

Mikhayl F. Budyka

antibonding in respect to the N-N2 bond [6]. Figure 4 shows the structure of the frontier molecular orbitals for 4-azidopyridine A1 and its cation A1H+, and Figure 5 – for 4-azidoquinoline A2 and its cation A2H+: the highest occupied MO (HOMO) and the lowest unoccupied MO (LUMO) for the S0 state, the lowest semioccupied MO (LSOMO) and the highest semioccupied MO (HSOMO) for the S1 state. In the both azides, in the ground state both HOMO and LUMO are type MOs localized mainly on the heteroaromatic nucleus with some contribution by the atomic orbitals of azido group. In the S0 state, the NN*-MO (not shown in Figures 4 and 5) is LUMO+1 in neutral azides A1 and A2, and LUMO+2 in cations A1H+ and A2H+. However, upon excitation to the S1 state, as a result of relaxation, the NN*-MO is occupied instead of LUMO in both the neutral and cationic compounds (Figure 4 and Figure 5). Depopulation of

-HOMO, which

becomes LSOMO in the S1 state, and population of NN*-MO, which becomes HSOMO, results in the above structural changes: electron density transfer from aromatic nucleus to azido group, bending of this group and weakening of the NN2 bond (which dissociates). In terms of valence bond method, this means that, on going from the S0 to the S1 state, the type of hybridization of the central atom of the azido group (atom N2) changes from sp to sp2. Thus, the photoactivity ( > 0.1) of both neutral and positively charged derivatives of 4-azidopyridine and 4-azidoquinoline is explained by the fact that NN*-MO, which is antibonding in respect to the N-N2 bond and vacant in the ground state, is occupied in the excited states of these azides. Nevertheless, the protonation (alkylation) causes a decrease in the quantum yield, especially for 4azidopyridine (Table 1). According to the quantum-chemical calculations, this effect may be accounted for by the increase in the activation energy for the N-N2 bond dissociation in the S1 state on passing from the neutral azide to cation. In the ground state, a substantial positive charge is concentrated on two terminal nitrogen atoms of the azido group of azides, while dissociation gives rise to a neutral nitrogen molecule. Therefore, the electron density transfer from the aromatic nucleus to the leaving N2 molecule should be a necessary step of the NN2 bond dissociation. In cationic azide, the positive charge of the aromatic ring creates the charge barrier (Coulomb barrier) for the transfer of electron density and hinders the dissociation.


239

Figure 4. Structure of the frontier molecular orbitals (MOs) for 4-azidopyridine A1 and 4azidopyridinium ion A1H+: the highest occupied MO (HOMO) and the lowest unoccupied MO (LUMO) in the S0 state, and the lowest semioccupied MO (LSOMO) and the highest semioccupied MO (HSOMO) in the S1 state [27].

To test this assumption, the potential energy surfaces (PESs) for A1 and protonated A1H+ in the S1 state were calculated [27]. Figure 6 shows the contour diagram of an area of the PES for A1 over a NNN bond angle range of 123° - 170° and a N-N2 bond length range of 1.27 - 2.45 Å. At the minimum of the PES, the N-N2 bond length rNN2 and NNN bond angle are equal to 1.35 Å and 113.4°. As the N-N2 bond is elongated, the bond angle first increases to 155° and then decreases to attain a value of 127.6° in the transition state, with rNN2 being 2.25 Å. The calculated parameters of the transition state for the dissociation of the azido group in the lowest excited singlet state for A1 and A1H+ are listed in Table 3. As can be seen, the transition states of A1 and A1H+ have similar structural characteristics; at the same time, upon protonation, the activation energy increases from 15.9 to 18.5 kcal/mol. As a result, the rate constant kr decreases (formula (1)) that qualitatively correlates with the experimentally observed decrease in the quantum yield for the dissociation of the azido group.

240

Mikhayl F. Budyka

Figure 5. Structure of the frontier molecular orbitals for 4-azidoquinoline A2 and 4azidoquinolinium ion A2H+, description of the MOs see Figure 4 [28].

cloud shields With increasing size of aromatic the action of the positive charge, so the charge effect appears in less extent in 4azidoquinoline (Table 1) and disappears at all in 9-azidoacridine, where quantum yield remains unchangeable on going from the neutral azide to cation, see below. As discussed above, the quantum yield for the photodissociation of A1 decreases not only upon protonation (alkylation) but also when ethanol is used as the solvent instead of acetonitrile (Table 1). This effect can be explained by the fact that pyridine-based compounds are weak bases capable of forming H-bonded complexes with solvent molecules [37]. H-bond is strengthened in the S1 state, since pyridine compounds become much more basic on excitation [38] (the basicity increase can reach 7–8 orders of magnitude); the limiting case is a full proton transfer. This gives rise to a positive charge increase on the endocyclic nitrogen atom and results in retardation of the N-N2 bond dissociation reaction. Consequently, the value for A1 decreases on going from MeCN to MeCN/EtOH mixture and further to EtOH, becoming closer to that for protonated azide (Table 1).


241

160 155

NNN /

degree

160

155

160

160

150

150

140 150 TS

130

145 155

1.5

1.8 2.1 rN-N2/ A

2.4

Figure 6. Potential energy surface for the S1 state of 4-azidopyridine (A1) calculated by the PM3 method. The dissociation coordinate (minimum-energy path) is shown by the heavy solid line; TS denotes the transition state; the energy is given in kcal mol-1 [27].

Table 3. Parameters of the transition state (calculated by the PM3 method) for the dissociation of the azido group in the S1 state of 4-azidopyridine (A1) and its hydrochloride (A1H+): the distance rTS between the N1 and N2 atoms, bond angle ( NNNTS), effective Mulliken charge (ZTS) on the N2 terminal group, and activation energy Ea [27] Azide

rTS, Å

A1 A1H+

2.25 2.30

NNNTS, deg 127.6 136.4

ZTS, е

Ea, kcal/mol

0.01 0.03

15.9 18.5

1.3. Relative Reactivity of Azido Groups in Polyazidopyridines An interesting data were obtained on the relative reactivity of different azido groups in polyazidopyridines. In low-temperature photolysis (organic glass, 77 K) of the 2,4-diazidopyridine derivatives, the formation of only one of the two possible triplet nitrene was observed by ESR [39].

242

Mikhayl F. Budyka N3

N3 CN

Cl RNH

h

RNH

N3

N

CN

Cl

.

N.

N

.

N. Cl

CN

RHN

N3

N

The signals of two possible isomers, 2-nitreno and 4-nitreno derivatives, should not coincide in the ESR spectra. To discriminate between these isomers, the observed ESR spectra were compared with the spectra of 2-pyridyl nitrenes obtained from 2-(mono)azidopyridines; additionally, the experimental Dparameters were correlated with the C-N bond lengths in nitrenes calculated by PM3 method. The authors [39] came to conclusion that 2-nitreno derivatives matched better to the spectral line positions observed. The selective photolysis of the -azido group was rationalized from the analysis of the energies of two different triplet local-excited states, -T and -T states for dissociation of the - and -azido group, respectively. The energy of the -T state was calculated to be higher by 4 kcal mol-1 than that of the -T state (PM3 data). With the assumption that the higher the energy of the excited state, the higher the probability of the transfer to the repulsive term, the photodissociation of the -azido group in 2,4-diazidopyridine should be the preferable process [39]. Another example of selective decomposition of inequivalent azido groups was found in successive photolysis of 2,4,6-triazido-3,5-dichloropyridine (TAP) [40]. This azide yields two easily identifiable isomeric quintet 2,4- and 2,6dinitrenes upon irradiation with light at > 300 nm.

N3

N3 Cl

Cl N3

N TAP

h

N3

N3

Cl

Cl N

.

h

N.

Cl

. N.

N. Cl N3

N

.

N.

N. Cl

N

Cl

.

.

X

.

N.

N3

N3

h

Cl N3

Cl N

.

N.

h

Cl

. N.

Cl N

.

N.


243

Photolysis (at 77 K) of TAP at 315 nm resulted in the ESR spectrum with the major peak corresponding to 2,6-dinitrene and the tiny peak of 2,4-dinitrene. More intense signal of the latter was also obtained upon irradiation of TAP with light at 335 nm. The results unambiguously showed that triazide underwent selective photodissociation of the -azido groups with formation of quintet 2,6dinitrene as the main photoproduct. The effect was explained similar to the above one for diazidopyridine. The PM3 calculations showed that energy of the -T state of TAP is higher by 2 kcal mol-1 than that of the -T state, and energy of the -exited state of intermediate 2-pyridyl nitrene is 8 kcal mol-1 higher than that of the -excited state. The excited states with the higher energies were assumed to be less stable and decomposed more rapidly, explaining predominant formation of quintet 2,6-dinitrene [40]. Obviously, the explanation on the basis of the relative energies of the triplet excited states is not satisfactory since azido group photodissociation upon direct (non-sensitized) photolysis occurs really in the singlet excited state [8]. However, calculations of the energies of different singlet local-excited states, -S and -S states, at CIS/6-311G* level, contrary to the PM3 data for the triplet local-excited states, showed that the -S state is ~3.8 kcal mol-1 higher than the -S state [41]. Therefore, selective photolysis of the -azido group can be connected, on the contrary, with the lower energy of the local excitation. At the same time, difference in activation energies of two competitive processes favors slightly to the -dissociation: calculated activation energy of the N-N2 bond dissociation in the -S state (7.0 kcal mol-1) is less than that in the -S state (7.5 kcal mol-1) [41]. There is difference in the structures of the - and -azido groups in the ground (S0) state. According to calculations, the -azido groups in TAP lie in the molecular plane, whereas -azido group is twisted out of the plane by ~24.5° (B3LYP/6-311G*). It was assumed that selective photolysis of the -azido group could be determined by stronger - conjugation with pyridine nucleus in the S0 state, and photochemical inertness of the -azido group – by distortion of this group out of the molecular plane [41]. Probably, analysis of the structure of the S1 transition and more correct high-level calculations of the PESs vertical S0 can shed additional light to this problem. Worthwise to note, that in 9-azidoacridine azido group also deviates out of the molecular plane, but this azide decomposes with quantum yield about 1 (see below). If selective photochemical activity of different azido groups in TAP was deduced only from comparison with theoretical ESR spectra, selective thermal

244

Mikhayl F. Budyka

activity of the - and -azido group is evidenced by separation and identification of different reaction products [42]. Recently, photolysis of TAP was restudied in argon matrix at 15 K [43]. In contrast to the discussed above data in frozen organic solutions at 77 K, the preferential photolysis of the -azido group was observed as was deduced from relative intensities of the spectra: contrary to the statistical ratio of the - and nitrenes 2:1, their spectra had nearly the same intensities. Upon matrix photolysis of the TAP analogue, 2,4,6-triazido-3,5-difluoropyridine, both triplet nitrenes, and -nitrene, were also formed in nearly equal yields, but in contrast to TAP, the photolysis was deduced to be not selective [44]. Thus, one can conclude that an interesting problem on relative photoactivity of different inequivalent azido groups in polyazidopyridines (and in polyazides in general) remains challenging.

2. AZIDO DERIVATIVES OF ACRIDINE In this chapter we discuss properties of two azido derivatives of acridine: 9azidoacridine (A3) and 9-(4'-azidophenyl)acridine (APA). These compounds have similar spectral properties in neutral and cationic forms, and similar photochemical activity in neutral forms, but their photodissociation quantum yields in cationic forms differ drastically. Quantum-chemical calculations and consideration of MO structure in the ground and lowest excited states allowed explaining this difference. Structure, spectral and photochemical properties of 9-azidoacridine are discussed in more detail because this azide in cationic form is one of the azides with the most long-wavelength region of the spectral sensitivity. On example of A3 it is easy to trace difference between vertical-excited (Franck-Condon) state, which determines absorption spectrum, and relaxed exited state, which determines azide photoactivity.

2.1. Structure of 9-azidoacridine Structure of 9-azidoacridine has attracted an especial attention in connection with the problem of planarity of azido group. This azide is an example of aromatic azide with non-planar arrangement of azido group. It crystallizes in the rhombic system [45]. X-Ray analysis has shown that the independent crystal structure


245

fragment consists of two crystallographically independent molecules denoted by A and B, see Figure 7. 9-azidoacridine crystal structure fragments are shown in Figure 8. Molecules form stacks along the a crystallographic axis. The distances between the planes of the acridine nuclei of molecules in the stacks are of 3.98 Å (stack of A molecules) and 3.49 Å (stack of B molecules). The acridine nucleus planes in molecules A and B intersect at an angle of 2.3°. The structure-forming factor in the formation of stacks is likely intermolecular contacts between the endocyclic nitrogen atom N7 in the acridine nucleus and the central nitrogen atom N2 of the azido group (which is displaced out of the molecular plane; see below); the distances between these atoms are 3.29 and 3.25 Å in stacks A and B, respectively. According to quantum-chemical calculations (see below), the azido group is strongly polarized with charge alternation -0.45, 0.73, and -0.34e (the PM3 data) and -0.46, 0.40, and -0.23 (B3LYP/6-31G* calculations) on N1, N2, and N3, respectively. The orientation of molecules in stacks ensures the interaction of the central azido group nitrogen atom with a large positive charge on it with the lone pair of the acridine nucleus nitrogen atom, on which a negative charge of -0.06 (PM3 calculations) or -0.60 e (B3LYP/6-31G*) is concentrated.

Figure 7. Molecular structure of 9-azidoacridine (A3) and atom numbering (crystallographically independent molecules are denoted by A and B) [45].

246

Mikhayl F. Budyka

a)

b) Figure 8. Fragment of the crystal structure of 9-azidoacridine (A3): (a) projection onto the bc plane and (b) projection onto the ac plane [45].

Table 4 contains the X-ray structure analysis data obtained for A3 (interatomic distances and angles) in comparison with the results of A3 structure optimization by various quantum-chemical methods. The bond lengths and valence angles of the acridine nucleus are close to those of other acridine derivatives [46,47]. On the whole, both calculation methods used reproduce the geometric parameters of the A3 molecule.


247

The acridine nucleus is elongated along the short axis, and the length of CC bonds oriented along this axis is of from 1.41 to 1.43 Å. The condensed benzene rings have a well-defined ortho-quinoid structure, the C10C11, C12C13, C14C15, and C16C17 bond lengths are within the range 1.34–1.36 Å (Table 4). The azido group in A3, as in the other aromatic azides [48,49], has quasi-linear geometry (the NNN valence angle is of ~170°). This characteristic feature is reproduced by both quantum-chemical methods (Table 4). According to the X-ray data, the molecule of A3 is nonplanar, the N2N1C4C5 dihedral angle denoted as NNCC is 34.6° in molecule A and 28.6° in molecule B, which is close to the angle value predicted at the B3LYP/6-31G* level (32°), see below. Non-planarity of the A3 molecule is explained by the steric interactions of the azido group with the peri-hydrogen atoms of the neighboring benzene rings. According to the B3LYP/6-31G* calculations, the energy of the planar 9azidoacridine structure with the NNCC fixed at 0° and all the other parameters optimized is higher by 0.21 kcal/mol than that of the completely optimized structure, whose parameters are listed in Table 4. In the planar structure, the N1N2 and N1C4 bonds are shortened by 0.003 and 0.008 Å, respectively, because of an increase in conjugation between the azido group and the acridine nucleus. The distance between the N2 nitrogen atom and peri-hydrogen at C14 is 2.3 Å, which is smaller than the sum of the van der Waals radii of these atoms (2.66 Å). The increased steric strain elongates the C4C5 bond by 0.003 Å and increases the N2N1C4 and N1C4C5 valence angles by 3.4° and 1.8°, respectively. The opposite geometric effects are observed in the structure with the perpendicular arrangement of the azido group. According to the B3LYP/6-31G* calculations, the energy of this structure (with fixed NNCC = 90° and the other parameters optimized) is higher by 1.66 kcal/mol than that of the completely optimized structure. The N1N2 and N1C4 bonds in the perpendicular conformer are elongated by 0.002 and 0.024 Å, respectively, because the conjugation chain between the azido group and acridine molecule is broken in it. Simultaneously, the C4C5 bond shortens by 0.009 Å, and the N2N1C4 and N1C4C5 angles decrease by 4.3° and 5.3°, respectively. An analysis of overlap populations shows that the populations of the N1C4 and N2N3 bonds change insignificantly in rotations about the former, to within ±0.02. At the same time, the population of the N1N2 bond decreases from 0.54 at NNCC = 32° to 0.44 at NNCC = 0° and increases to 0.67 at NNCC = 90°. Therefore, the loss of conjugation between the azido group and acridine nucleus in the perpendicular compared with planar conformer results in a considerable increase in the population of the N1N2 bond.

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Mikhayl F. Budyka

Table 4. Structural parameters of 9-azidoacridine, bond lengths and valence angles ( ) according to X-ray structure analysis and calculation data [45] Parameter d/Å N(1)-N(2) N(2)-N(3) N(1)-C(4) C(4)-C(5) C(5)-C(6) C(6)-N(7) N(7)-C(8) C(8)-C(9) C(4)-C(9) C(9)-C(10) C(10)-C(11) C(11)-C(12) C(12)-C(13) C(8)-C(13) C(5)-C(14) C(14)-C(15) C(15)-C(16) C(16)-C(17) C(6)-C(17) /degree N(1)-N(2)-N(3) N(2)-N(1)-C(4) N(1)-C(4)-C(5) N(1)-C(4)-C(9) C(5)-C(4)-C(9) C(4)-C(5)-C(6) C(6)-C(5)-C(14) N(7)-C(6)-C(5) C(17)-C(6)-C(5) C(6)-N(7)-C(8) N(7)-C(8)-C(9) C(13)-C(8)-C(9) C(4)-C(9)-C(8) C(10)-C(9)-C(8) C(11)-C(10)-C(9) C(10)-C(11)-C(12) C(13)-C(12)-C(11)

X-ray structure molecule molecule B A 1.203(13) 1.239(14) 1.150(15) 1.181(14) 1.431(13) 1.424(13) 1.395(16) 1.380(16) 1.413(14) 1.428(13) 1.356(14) 1.322(15) 1.312(15) 1.376(15) 1.433(15) 1.433(15) 1.398(17) 1.385(15) 1.431(16) 1.406(18) 1.341(18) 1.338(19) 1.412(18) 1.408(18) 1.343(18) 1.346(18) 1.429(16) 1.387(17) 1.445(16) 1.423(16) 1.360(15) 1.339(17) 1.409(16) 1.407(16) 1.353(16) 1.395(18) 1.410(15) 1.404(16)

Method of calculations PM3 B3LYP/631G* 1.265 1.236 1.127 1.141 1.444 1.413 1.408 1.414 1.427 1.448 1.358 1.342 1.358 1.342 1.427 1.442 1.408 1.411 1.432 1.427 1.361 1.371 1.425 1.425 1.360 1.369 1.438 1.430 1.432 1.429 1.361 1.372 1.425 1.423 1.360 1.369 1.438 1.430

171.9(11) 121.2(10) 124.9(11) 114.6(10) 120.5(9) 117.2(10) 119.0(10) 123.3(10) 117.7(10) 118.2(10) 123.8(11) 118.2(10) 116.7(10) 119.6(11) 120.3(12) 119.3(13) 123.8(13)

169.6 120.3 119.9 119.7 120.3 118.0 118.0 121.8 119.9 120.0 121.8 119.9 118.0 118.0 120.7 121.0 120.6

170.6(10) 119.2(10) 125.7(10) 112.2(9) 122.1(9) 116.4(10) 117.4(10) 124.1(10) 119.4(11) 118.7(8) 121.1(11) 120.0(11) 117.6(10) 116.6(11) 122.8(13) 118.9(14) 121.2(12)

170.1 122.8 125.1 114.9 119.9 116.7 118.3 124.0 118.6 118.3 123.4 118.5 117.7 119.1 120.5 120.6 120.5

Photochemistry of Azidopyridine and Related Heterocyclic Azides C(12)-C(13)-C(8) C(15)-C(14)-C(5) C(14)-C(15)-C(16) C(17)-C(16)-C(15) C(16)-C(17)-C(6)

118.7(11) 119.6(10) 121.1(11) 118.8(11) 123.0(10)

120.2(11) 121.4(11) 122.5(14) 117.5(14) 121.5(11)

119.8 120.7 121.0 120.6 119.8

249

120.8 120.9 120.8 120.2 121.1

A region of the potential energy surface of A3 along the N2N1C4C5 angle coordinate ( NNCC), which corresponded to azido group rotations about the N1C4 bond, was calculated by various methods [45]. The results are shown in Figure 9. The PM3 method predicts the existence of one barrier of 2.04 kcal/mol height along the reaction coordinate. This barrier corresponds to the passage of the azido group through the acridine nucleus plane, and the potential energy surface minimum corresponds to the perpendicular orientation of the azido group. B3LYP/6-31G* calculations predict two barriers of different heights. The low (0.21 kcal/mol) barrier corresponds to the planar conformation, and the higher (1.66 kcal/mol) barrier, to the passage of the azido group through the plane perpendicular to the acridine nucleus. As mentioned above, the barrier of rotation around the C-N quasi-single bond in 4-azidopyridine is equal to 4.04 kcal mol-1 (MP2/6-31G**//RHF/6-31G** data) [36]. E/ kcal mol

-1

2.0 1

1.5

2

1.0

0.5

0.0 0

20

40

60

80

degree Figure 9. 9-Azidoacridine potential energy surface portion corresponding to rotations about the N1C4 bond (angle N2N1C4C5 = ) calculated by (1) the PM3 method and (2) at the B3LYP/6-31G* level; energies are given with respect to potential energy surface minima [45].

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Mikhayl F. Budyka

In order to evaluate the structural changes induced by protonation and excitation, the structure of 9-azidoacridine in neutral and protonated forms in the S0 and S1 states has been calculated by various quantum-chemical methods [50]. Table 5 summarizes some optimized parameters: the lengths and orders of N1N2 and C4N1 bonds, the N1N2N3 valence angle ( NNN), the C5C4N1N2 dihedral angle ( NNCC), and the Mulliken effective charge on the terminal N2 group. One can see that all of the methods predict a considerable increase in the positive charge on the N2 group upon protonation (by a factor of up to 2). In this case, the N1C4 bond order increases and the N1N2 bond order decreases with corresponding changes in the bond lengths. These changes upon protonation are due to a shift of electron density from the azido group to the aromatic nucleus. Enhanced bonding between the N1 and C4 atoms results in an increase in the rotation barrier about the N1C4 bond; therefore, the C5C4N1N2 dihedral angle decreases to 0° upon protonation in accordance with HF and B3LYP data (Table 5); in protonated form A3 becomes planar already in the S0 state and retains the quasi-linear geometry characteristic for all azides (the NNN bond angle is ~170°). Table 5. Structural parameters of 9-azidoacridine A3 and its protonated cation: the length (r) and order (p) of N1N2 and C4N1 bonds, the N1N2N3 bond angle ( NNN), the C5C4N1N2 dihedral angle ( NNCC), and the Mulliken effective charge on the terminal N2 group (ZN2) in the ground (S0) and the lowest electronically excited (S1) state calculated by various methods (cation 2 was calculated without a counterion) [50] ZN2, е

Method

-91.5 -54.3

0.39 0.24

170.1

-32.0

0.17

1.38 1.21 1.12

144.0 166.7 168.5

-0.8 -12.7 0.0

-0.06 0.54 0.40

1.28

1.04

167.6

0.0

0.32

0.93

1.76

143.5

-5.4

0.10

PM3 HF/631G* B3LYP/631G* PM3 PM3 HF/631G* B3LYP/631G* PM3

Azide

State

rN1N2

rN1C4

pN1N2

pN1C4

A3

S0

Å 1.27 1.24

1.44 1.42

1.36 1.27

0.98 0.93

deg. 169.6 173.6

1.24

1.41

1.38

0.92

1.32 1.30 1.26

1.40 1.39 1.36

1.12 1.20 1.13

1.25

1.38

1.47

1.33

A3H+

S1 S0

S1

NNN

NNCC


251

E, eV 0 LUMO+2 LUMO+1 -1 LUMO -2 LUMO+2

-4

LUMO+1 -5 LUMO -6 -8 HOMO -9 HOMO-1 -10

HOMO-2 HOMO-3

-12

HOMO -13 HOMO-1

A3

A3H+

Figure 10. Structures and energies of the frontier MOs (HOMO and LUMO) and the neighboring occupied and vacant orbitals for 9-azidoacridine A3 and its cation A3H+ in the S0 state (cation was calculated without a counterion) [50].

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Mikhayl F. Budyka

Both neutral and protonated forms of azidoacridine in an excited state exhibited a bending of the azido group (the NNN angle decreased to 144°) and an elongation of the N1N2 bond with a simultaneous decrease in the bond order. Moreover, the charge on the terminal N2 group significantly decreased (Table 5). As mentioned above, these changes in parameters on passing from the S0 to the S1 state are characteristic of photoactive azides. Figure 10 shows the structure and energy of frontier molecular orbitals highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) - and the neighboring occupied and vacant orbitals for azide A3 and its protonated cation A3H+ in the S0 state. It can be seen that both frontier MOs are -orbitals localized mainly on the acridine nucleus in both azides in the ground state. A comparison with the MO structure of unsubstituted acridine shows that the HOMO and LUMO are actually the acridine 4b1 and 5b1 orbitals, respectively [51], with a small contribution of the atomic orbitals of the azido nitrogen atoms. The HOMO-3 is localized at the central part of the -skeleton, and it has a considerable contribution from the orbital of a lone pair of the endocyclic nitrogen atom (Figure 10); that is, it is the acridine n orbital.

Figure 11. Structures of the lowest and highest singly occupied MOs (LSOMO and HSOMO, respectively) in the relaxed S1 state for 9-azidoacridine A3 and its cation A3H+ (cation was calculated without a counterion) [50].


253

In terms of photochemical activity, another orbital, namely, the NN*-MO is the most interesting because its occupancy in the lowest electronically excited singlet state (S1) determines the photoactivity of an azide. As can be seen in Figure 10, the NN*-MO in A3 is the second with reference to LUMO, that is, LUMO + 2. The levels of all of the MOs decrease upon protonation; in this case, a stabilizing effect is more pronounced for virtual orbitals (Figure 10). As a result, the energy gap between HOMO and LUMO decreases from 7.20 to 6.69 eV (this decrease manifests itself in a bathochromic shift of the long-wavelength absorption band; see below). As in the neutral azide, the NN*-MO in the hydrochloride is LUMO + 2, and the energy gap between LUMO and NN*-MO increases on going from neutral to charged species; however, it remains relatively small, being equal to 1.30 or 1.63 eV for A3 or A3H+, respectively. Figure 11 shows the structures of the lowest and highest singly occupied MOs (LSOMO and HSOMO, respectively) in the relaxed S1 state for azides A3 and A3H+. In both of the azides, the LSOMO is a -type orbital (former HOMO in the S0 state), whereas the HSOMO is NN*-MO (former LUMO + 2 in the S0 state). As is demonstrated below, the low-energy (long-wavelength) absorption bands of both of the azides (vertical transitions) are related to electron transfer to lower vacant orbitals (LUMO and LUMO + 1). However, the relaxed state with an electron on the NN*-MO is the lowest singlet excited state in terms of energy. This S1 state is occupied during azide irradiation at the long-wavelength absorption band and is responsible for the photochemical activity of azide. Thus, quantum-chemical calculations predict photoactivity (the photodissociation quantum yield > 0.1) for 9-azidoacridine in the neutral and cationic forms, in full accordance with experimental data.

2.2. Spectral Properties of 9-azidoacridine Figure 12 shows the absorption spectra of neutral 9-azidoacridine and its hydrochloride in the near-UV and visible regions at 300–500 nm. Moreover, intense bands at 250–260 nm were observed in the spectra of both of these compounds in the short-wavelength UV region (Table 6). In general, the spectrum of A3 coincides with that of unsubstituted acridine [52]; however, as compared with the latter, the 362-nm band exhibits a broader long-wavelength shoulder, which manifests itself as an individual maximum at 382 nm in ethanol.

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Mikhayl F. Budyka

Protonation leads to a bathochromic shift of the long-wavelength absorption band toward the visible region to 430 nm and the appearance of a slightly resolved vibrational structure, with the intensity of an absorption band at 360 nm being almost doubled (Figure 12). The presence of an absorption band at 440 nm in the spectra of acridine derivatives is characteristic of compounds protonated at the ring nitrogen atom [53]. It is well known that the acridine long-wavelength absorption band in the region 300–400 nm with a maximum at 354 nm is a superposition of three bands: two acene - * 1La and 1Lb bands (according to the Platt classification) [54] and a low-intensity n- * band due to electron transfer from the lone electron pair of the nitrogen atom. The 1La band represents the HOMO LUMO transition, and 1Lb is a combination of the HOMO-1 LUMO and HOMO LUMO+1 transitions [55]. Table 6 summarizes the vertical excitation energies and oscillator strengths calculated by the ZINDO method for A3 and its hydrochloride and gives the structure of transitions. It can be seen that the ZINDO method underestimates the transition energies, especially, in the case of the neutral A3. In unsubstituted acridine, the n– * transition involving the lone pair of the nitrogen atom ranks third after 1La and 1Lb in terms of energy [51]. As can be seen in Figure 10, the acridine n orbital in A3 is HOMO-3; according to ZINDO data, the transition that involves this MO makes the main contribution to the lowest energy band. /M-1cm-1 9000

6000

2 1

3000

0 350

400

/ nm

450

Figure 12. Absorption spectra of (1) 9-azidoacridine (A3) and (2) its hydrochloride in acetonitrile [50].


255

Table 6. Experimental (in acetonitrile) and theoretical (calculated by ZINDO method) maxima in the absorption spectra of 9-azidoacridine A3 and its hydrochloride A3HCl: absorption band maximum ( ) and the corresponding vertical excitation energy Ev, the logarithmic molar absorption coefficient ( , M-1 cm-1), the oscillator strength (f), and the structure of transition (cation was calculated without a counterion) [50] Azide A3

Experimental Ev, eV , nm

Ev, eV

f

2.24

0.001

380

3.26

lg 3.73

H

L+1

362

3.43

3.82

3.11

0.289

H

L

3.59

3.62

3.52

0.045

H-1

a

a

345

A3HCl

Calculatedb compositionc H-3

L+1

% 23 21 39

L

25 17

H

L+3 L+2

13

254

4.88

4.96

3.73

0.056

H

216

5.74

4.03

3.90

0.019

H-4

L

32

427

2.90

3.76

2.80

0.004

H-3

L+1

23 15

H

L+1 L

410

3.02

3.71

3.06

0.307

H

44

355

3.49

4.01

3.60

0.165

H-3

L

H-1

L

340

3.65

3.72

3.62

0.161

H-1

L

22

301

4.12

3.82

3.93

0.113

H-2

L

39

264

4.70

4.71

12 17

a

Shoulder; in EtOH, a shoulder at 380 nm appeared as an individual peak at 382 nm. b The five lowest singlet excited states with excitation energies lower than 4 eV are given. MO notation: H is HOMO and L is LUMO. c One-electron transitions with a contribution higher than 10% are given.

As noted above, in the context of discussions concerning the photodissociation reaction of the azido group, the occupation of the NN*-MO (i.e., LUMO + 2) in an excited state is of the greatest interest. Calculated data (Table 6) indicate that one-electron excitation with the participation of the NN*MO makes the main contribution to the fourth spectral transition in terms of energy (3.73 eV) in A3 (Table 6); its contribution to the second (3.11 eV) and

256

Mikhayl F. Budyka

third (3.52 eV) transitions is at most 5%. In the protonated species (A3HCl), a configuration involving the NN*-MO contributes (up to 4%) to the third (3.60 eV) and fourth (3.62 eV) transitions. However, as demonstrated above, in the relaxed lowest singlet excited state (S1), an unpaired electron occupies the NN*MO in either neutral or protonated 9-azidoacridine. According to PM3 data, the adiabatic excitation energies in the S1 state are 1.71 and 1.98 eV for A3 and A3HCl, respectively.

2.3. Photochemical Properties of 9-azidoacridine Investigation of photochemical properties of 9-azidoacridine A3 has shown that it undergoes decomposition under exposure to light in both neutral and protonated forms [50,56,57]. It should be noted that 9-azidoacridine hydrochloride in the presence of the traces of water is readily hydrolyzed to yield acridone, 9azido-10-methylacridinium methyl sulphate in the same conditions gives Nmethylacridone [58]. Table 7 summarizes the quantum yields of photodissociation of A3 and its hydrochloride upon irradiation with light at various wavelengths and in various solvents. It can be seen that the quantum yields are high ( > 0.1) on excitation into long-wavelength absorption bands; that is, both of the azides are photoactive. Since the absorption band of the hydrochloride extends to the visible region, this compound decomposes under irradiation with visible light at a wavelength up to 470 nm. Consequently, among the known aromatic azides, hydrochloride A3HCl exhibits one of the longest wavelength light sensitivity. However, tendency of A3HCl to hydrolysis hinders its possible application. The main reaction product of the A3 photolysis in neutral form is 9azoacridine, which was obtained with preparative yield of 81 % under irradiation in methanol and 60 % in benzene [58]. Azoacridine has broad structureless bands at 240, 380, and 470 nm with an intensity ratio of 12 : 1 : 0.6 [59]. Under irradiation of the neutral A3 gradual disappearance of the absorption bands of azide and the appearance of those of azoacridine were observed [50].


257

Table 7. Observed quantum yields of photodissociation of 9-azidoacridine (A3) and its hydrochloride A3HCl depending on irradiation wavelength Azide A3

A3HCl

Solvent EtOH Toluene MeCN MeCN

ex, nm 365 365 365 365 405 436 450 470

0.77 0.94 0.96 0.95 0.90 0.75 0.71 0.65

Spectral changes upon the photolysis of hydrochloride A3HCl were dramatically different and are shown in Figure 13 (to prevent hydrolysis, the anhydrous acetonitrile was used) [50]. In this case, the absorption spectrum of the photolysis product (spectrum 6) has a characteristic pattern with a distinct vibrational structure of the long-wavelength band in the region 370 - 430 nm. The neutralization of the reaction mixture after photolysis led to the disappearance of the low-intensity absorption bands in the central region of the spectrum with maximums at 312 and 326 nm, with the band in the region 360 - 430 nm remaining practically unshifted; however, the vibrational structure became less pronounced. This behavior of the bands at 300 - 450 nm and the presence of an intense short-wavelength band at 260 nm is typical of 9-aminoacridine [60]. The assignment of the A3HCl reaction product to aminoacridine was corroborated by additional experiments and comparison with thermally synthesized compound [50]. Scheme 3 summarizes reaction pathways of 9-azidoacridine photolysis in different reaction conditions. The first photochemical step is the azide photodissociation in a singlet excited state with the formation of the singlet nitrene. Among the variety of the subsequent reaction pathways of aromatic singlet nitrenes, the following two main reactions can be mentioned [8]: intramolecular insertion at the ortho position to form aziridine and then dehydroazepine and intersystem crossing to a triplet state, which is the ground state for nitrene.

258

Mikhayl F. Budyka

A 0.2

h

0.1

1

6 0.0 300

350

400

nm

450

Figure 13. Spectral changes on the irradiation of a 1.14.10-5 M 9-azidoacridinium hydrochloride A3HCl solution in anhydrous acetonitrile. Irradiation time, s: (1) 0, (2) 9, (3) 20, (4) 40, (5) 90, (6) 240. Irradiation wavelength: 365 nm, incident light intensity 4.4.10-9 Einstein cm-2 s-1 [50].

In the case of 9-acridyl nitrene, both of the ortho positions with respect to nitrene are occupied by fused benzene rings, which prevent the intramolecular insertion reaction and thereby stabilize the singlet nitrene to facilitate its conversion into the triplet state. Coordination to the lone pair of the oxygen or nitrogen atom additionally contributes to the stabilization of singlet nitrene when the reaction is carried out in ethanol or acetonitrile, respectively. The main reaction of triplet acridyl nitrene in neutral solvents is dimerization to 9-azoacridine. Another characteristic reaction of triplet nitrenes is the abstraction of hydrogen atoms, for example, from solvent molecules to form aminyl radicals, which combine with solvent radicals to form secondary amines or abstract another hydrogen atom to form primary amines. In accordance with this, when the photolysis of 9-azidoacridine was performed in toluene, whose molecule is a good hydrogen donor, the spectrum of reaction products exhibited absorption bands at 369, 389, 408, and 430 nm, which are characteristic of 9-aminoacridine, along with a broad low-intensity band at 470 nm due to azoacridine. That is, both of the reaction pathways of triplet nitrenes occur in toluene [50].


259

N

N N N3 h

1

1

N3 ~

N

3

N ~

- N2

N

N ~

NH2

A3 [H] + H+

N - H+

N3 +

N H

h

1

N3 ~

+

1

- N2

N ~

+ 3

N ~

+ [H]

A3H+

NH2 +

N H

Scheme 3. Photochemical transformations of 9-azidoacridine A3 and its hydrochloride A3HCl.

Upon the photolysis of 9-azidoacridine hydrochloride, the resulting acridyl nitrene was protonated at the endocyclic nitrogen atom. Evidently, the positive charge of the acridine nucleus prevents the dimerization reaction to the azoacridine dication. Therefore, the consecutive abstraction of two hydrogen atoms from solvent molecules with formation of protonated 9-aminoacridine (Scheme 3), which gives the free amine upon neutralization, is the main reaction route of the acridyl nitrene cation.

2.4. Spectral and Photochemical Properties of 9-(4'azidophenyl)acridine Insertion of the para-phenylene group into the molecule of 9-azidoacridine between acridine nucleus and azido group results in 9-(4'-azidophenyl)acridine (APA). This compound retains many of the spectral and photochemical properties of 9-azidoacridine, and acquires new unique property – its photodissociation quantum yield becomes strongly dependent on the charge of the heteroaromatic system.

260

Mikhayl F. Budyka N3

N

APA

APA has strong near-UV vibrationally resolved absorption band at = 350400 nm characteristic for the acridine moiety (Figure 14, curve 1), the longwavelength edge of the band extends into the visible region, and the intense band at = 254 nm (not shown in Figure 14) [61]. Comparison of Figures 12 and 14 reveals that spectral properties of APA resemble those of 9-azidoacridine. Quaternization of azide at the acridine nitrogen atom leads to bathochromic shift and appearance of additional band at 432 nm in the spectra of N-methyl-9(4'-azidophenyl)acridinium iodide. Comparison of the spectra of the azides and unsubstituted 9-phenylacridine and N-methylated salt without azido group shows that introduction of the latter does not lead to marked changes in the positions of the absorption bands. The spectral changes upon the introduction of an azido group may be seen as indirect evidence for participation of the electron system of the azido group in the electronic transition giving rise to the long-wavelength absorption band and a reason for the photoactivity of the azide upon irradiation at this band. The efficient decomposition of APA is observed upon irradiation within the long-wavelength absorption band, the decomposition quantum yield is collected in Table 8 [61]. It is seen that yield decreases with increasing wavelength of the incident light although remains rather high (> 0.1) Table 8. The photodissociation quantum yields of APA and N-methyl-9-(4'-azidophenyl)acridinium iodide APA-MeI [61] Azide APA

APA-MeI

Solvent CHCl3 CHCl3 EtOH EtOH MeCN

ex,

365 405 405 436 365

nm 0.88 0.69 0.66 0.14 2.3.10-3


261

Figure 14. Electronic absorption spectrum of 9-(4'-azidophenyl)acridine (APA) in chloroform (1) and dependence of the quantum yield ( ) of the photolysis of APA on the wavelength of the exciting light (2) [61].

Figure 14 shows the dependence of the quantum yield on the wavelength of the incident light along with absorption spectrum of the azide. The quantum yield is found to drop with decreasing molar extinction coefficient of the azide. The photodissociation quantum yield of iodomethylate APA-MeI is more than two orders of magnitude less than that of APA (Table 8). Low photoactivity of the N-methylated salt is not connected with possible competitive process of the photoinduced electron transfer from iodide anion to quaternized heteroaromatic cation, as has been shown by replacement of the iodide counter-ion in the salt by the CH3SO4- ion [61]. Therefore, the N-methylated APA cation indeed displays low photochemical activity relative to dissociation of the azide group. If the main reason for activity loss of the N-methylated cation is the positive charge of the acridine moiety, the protonation of APA would result in a similar effect. Since the degree of protonation depends on the acid concentration, the photoactivity of APA can be controlled by changing the acidity of the medium. This assumption has been corroborated experimentally by investigation of the observed photodissociation quantum yield of APA in dependence on acid concentration [62,63]. Acidification of the ethanol solution of APA (see Figure 15, curve 2) results in disappearance of the absorption band of the neutral azide and

262

Mikhayl F. Budyka

appearance of a long-wavelength absorption band with a maximum at = 417 nm, which resembles the spectrum of N-methylated salt and is characteristic of the chromophoric system of the acridine moiety protonated or alkylated at the endocyclic nitrogen atom. The measured pKa value for APA is 3.5 (in EtOH). The compound without azido group, 9-phenylacridine, has a value of pKa 4.8 (in water) [64]. Thus, introduction of the azido group with a positive inductive effect into the molecule of 9-phenylacridine decreases the basicity of the acridine moiety. In the singletexcited state the basicity of APA increases considerably to pKa* = 11.6 [63], as is calculated from the bathochromic shift of the long-wavelength absorption band using the Forster method [65]. Spectra 2-7 in Figure 15 show the changes in the absorbance upon irradiation of the acidic solution of APA. Table 9 collects the observed quantum yields of photodissociation of APA at different HCl concentrations.

A 0.15

0.10

2

1 0.05

7

0.00 300

350

400

/nm

450

Figure 15. Absorption spectrum of a 9.5.10–6 M solution of 9-(4'-azidophenyl)acridine (APA) in EtOH in the absence (1) and in the presence of 0.0219 M HCl (2). Spectral changes upon irradiation of the solution for 25 (3), 90 (4), 150 (5), 300 (6), and 600 s (7); light intensity 4.88.10–9 Einstein cm–2 s–1 [63].


kr

1

- N2

K*a 1APA*

1APAHCl*

+ HCl

h

263

products

2

- N2

h Ka APA + HCl

APAHCl

Scheme 4.

Two photochemical reactions occur simultaneously in the studied range of acid concentrations, i.e., the decomposition of APA and its protonated form APAHCl with the quantum yields 1 and 2, respectively, Scheme 4. From the Scheme 4, the following equation for the observed quantum yield can be deduced obs

=

2

+(

1

-

2)/(1+

[HCl]/Ka),

(2)

where = 1.09 is the ratio of the molar absorption coefficients of protonated and neutral azides at the wavelength of irradiation. According to equation (2) the quantum yield of the hydrochloride APAHCl photodissociation was calculated form the limiting value, lim( obs), under the condition [HCl] , and is equal 2 = 6.9.10-3 [63]. This value is two orders of magnitude lower than for neutral APA, being of the same order as the quantum yield of photodissociation of the Nmethylated cation (Table 8). Table 9. The observed quantum yields of photodissociation of APA at different HCl concentrations (in EtOH) [63] [HCl] 100, M 0 0.063 0.211 0.302

obs

82 32 18 14

100

[HCl] 100, M 0.64 1.36 1.38 1.52

obs

8.8 4.6 4.7 4.2

100

[HCl] 100, M 2.19 3.7 6.25 9.95

obs

3.7 2.8 2.0 1.5

100

264

Mikhayl F. Budyka

0.8125/(

obs-0.0075)

100 80 60 40 20 0 0.00

0.02

0.04

0.06 [HCl]/ M

0.08

0.10

Figure 16. Observed quantum yield of photodissociation of 9-(4'-azidophenyl)acridine (APA) plotted vs. acid concentration in the coordinates of equation (3); correlation coefficient is 0.997 [63].

Taking into account the obtained linearized (

1

-

2)/(

obs

-

2)

1

and β

= 1 + ( /Ka)[HCl].

2

values, equation (2) can be

(3)

Experimental data with the correlation coefficient 0.997 was linearized in the coordinates of equation (3), as shown in Figure 16. As the acid concentration increased to 0.1 M, the obs value decreased by more than 50 times. From the obtained data it follows that, in the excited state, the neutral APA and its protonated form are not equilibrated. For instance, using the acidity constants for the S0 and S1 states of APA (3.5 and 11.6), we can calculate that the content of the nonprotonated form under equilibrium conditions is 33.4% in the S0 state and lower than 4.10–7% in the S1 state at [HCl] = 6.3.10-4 M. Thus, if the excited state had time to achieve the acid-base equilibrium, the observed quantum yield of photodissociation would be determined by the decomposition of the protonated form only, being much lower than the experimentally determined value (0.32) at a given acid concentration. The difference in the photochemical activity of APA in the neutral and cationic forms was explained taking into account the results of quantum chemical calculations [63]. The structural parameters of the azido group in APA and its protonated cation calculated by the PM3 method are given in Table 10. In the ground S0 state, the azido groups of both molecules are quasi-linear (NNN angle


265

is ~170°) with the N-N2 bond length equal to 1.27-1.28 Å and a total charge on the terminal N2 group of ~0.4 e. These parameters are characteristic of all aromatic azides in the S0 state. However, in the lowest singlet-excited S1 state, the neutral APA exhibits changes characteristic of photoactive azides, namely, elongation of the N-N2 bond and a decrease in the NNN bond angle, in the order of the N-N2 bond, and in the positive charge on the terminal N2 group (the leaving nitrogen atom is neutral). At the same time, the bond angle in the protonated cation APAH+ remains almost unchanged and the positive charge on the N2 group is retained. This distinction is related to the fact that in the S1 state of APA the NN*-MO with the antibonding character with respect to the N-N2 bond is occupied, it becomes HSOMO (Figure 17). Occupation of this orbital is a prerequisite for the dissociation of this bond. In the S1 state of cation APAH+ the -MO bond localized on the acridine moiety is occupied and the NN*-MO remains unoccupied (not shown in Figure 17). The difference in structures of the lowest singlet-excited states of two azides explains the difference in their photochemical properties (compare with frontier MOs of the neutral and protonated 9azidoacridine, Figure 11). Table 10. Selected optimized parameters of 9-(4'-azidophenyl)acridine (APA) and its protonated cation: the length (r) and order (p) of the N1N2 bond, the N1N2N3 bond angle ( NNN), and the Mulliken effective charge on the terminal N2 group (ZN2) in the ground (S0) and the lowest electronically excited (S1) state calculated by PM3 method (cation was calculated without a counterion) [63] Azide

State

r, Å

p

APA

S0 S1 S0 S1

1.27 1.34 1.28 1.36

1.35 1.06 1.29 1.10

APAH+

NNN,

169.5 137.1 169.6 168.1

deg.

ZN2, е 0.39 -0.05 0.45 0.57

266

Mikhayl F. Budyka

Figure 17. Structures of the lowest and highest singly occupied MOs (LSOMO and HSOMO, respectively) in the relaxed S1 state for 9-(4'-azidophenyl)acridine (APA) and its cation APAH+ (cation was calculated without a counterion).

In conclusion it is worthwhile to note that APA is a unique example of azide whose photochemical activity can be switched by protonation/deprotonation. This enables an observed quantum yield of the azide photodissociation to be smoothly changed within two orders of magnitude.

3. THEORETICAL INVESTIGATION OF THE HIGHER HETEROCYCLIC AZIDES Examination of photochemical properties of azido derivatives of pyridine, quinoline and acridine shows clearly that azide photoactivity depends on the size and charge of the azide molecule. In turn, the photochemical activity of azide


267

correlates with the type of molecular orbital (MO) that is filled in the lowest singlet exited (S1) state [6]. If the antibonding NN*-MO is filled, the azide is photoactive, i.e. it decomposes with a quantum yield of > 0.1. If the NN*-MO remains vacant in the excited state, azide is photoinert, and its photodissociation quantum yield is < 0.01. To reveal the effect of the size and charge of aromatic -system on the azide structure and on the position of the NN*-MO in the ground state and on the filling of this orbital in the excited state, a series of heteroaromatic azides with monotonically increasing size of aromatic nucleus was investigated systematically by quantum-chemical methods [66,67]. Apart from discussed above azides A1 A3, the series includes their cata-condensed analogues: 12-azido-benzo[b]acridine A4, 13-azido-6-azapentacene (azidodibenzacridine) A5, and 15-azido-6azahexacene A6; here the index is equal to the number of aromatic rings (see Scheme 1). All series of protonated (positively charged) forms A1H+ - A6H+ was also investigated. In this series the size of aromatic -system increases from 6 to 26 e. Table 11. Selected optimized parameters for heterocyclic azides in the ground (S0) and lowest excited singlet (S1) states: bond length (r) and bond order (p) for the N1N2 and N1C4 bonds, the N1N2N3 bond angle ( NNN), and Mulliken charge (ZN2) on the terminal group N2, calculated by PM3 methods (cations A4H+ - A6H+ were calculated without counterions, atom numbering: C4N1N2N3) [67] Azide

State

rN1N2, Å

rN1C4, Å

pN1N2

pN1C4

A4

S0 S1 S0 S1 S0 S1 S0 S1 S0 S1 S0 S1

1.27 1.31 1.30 1.48 1.27 1.34 1.30 1.29 1.27 1.27 1.30 1.29

1.44 1.43 1.39 1.32 1.44 1.45 1.39 1.38 1.44 1.42 1.38 1.39

1.36 1.13 1.19 0.93 1.36 1.09 1.19 1.24 1.36 1.34 1.19 1.27

0.98 1.36 1.22 1.80 0.99 1.33 1.22 1.26 0.99 1.09 1.22 1.17

A4H+ A5 A5H+ A6 A6H+

NNN,

169.5 138.6 166.4 141.5 169.5 133.8 166.9 168.4 169.5 167.7 166.6 168.0

°

ZN2, е 0.39 -0.07 0.54 0.08 0.39 -0.05 0.54 0.43 0.39 0.37 0.55 0.43

268

Mikhayl F. Budyka

The series has been chosen since heterocyclic azides are convenient model compounds for the study of positive charge effect, because they can be easily transformed from the neutral to positively charged form by protonation or alkylation at endocyclic nitrogen atoms, the size of molecular -system being unchanged upon protonation. The structures of azides A1 - A3 are in detail discussed above and will be mentioned shortly for comparison with the higher members of the series and for evaluation of the size effect. Main structural parameters of the azides A4 - A6 in neutral and protonated forms are shown in Table 11. In the ground state, the higher azides A4 - A6 have the structure similar to that of the lower azides A1 - A3: the azido group has a quasi-linear geometry, the NNN bond angle NNN ~ 170°. In the neutral form the N1N2 bond length is 1.27 Å (PM3 data). An important feature is a large positive charge on the terminal nitrogen atoms of the azido group. Protonation induces the electron density transfer from the azido group to the aromatic nucleus, an effect that results in a weakening of the N1N2 bond even in the ground state; the N1N2 bond order decreases with simultaneous increase of the N1C4 bond order (Table 11) (the N1N2 bond is elongated by 0.02 - 0.03 Å, and the N1C4 bond is shortened by 0.03 - 0.06 Å.). The electron density transfer results also in an essential charge increase on the N2 group upon protonation. These effects are the same as found for azides A1 - A3. As stated above, azidopyridine A1 and azidoquinoline A2 have a planar structure of the completely conjugated systems (azido group lies in the plane of aromatic nucleus) in both neutral and protonated forms. In azidoacridine A3, due to steric hindrance by the two hydrogens in the peri-positions of the neighboring benzene rings, the azido group deviates from the plane of the molecule. The higher members A4 - A6 also have non-planar structure with the azido group deviated from the plane of aromatic nucleus. The bond order between the N1 and C4 atoms increases upon protonation, as a result, protonated forms have more planar structure due to increased conjugation between azido group and aromatic nucleus. In the excited (S1) state, the geometry changes depend on the azide structure (size and charge). For the neutral azides A4 - A5 and cation A4H+, as for the lower members of the series, the NNN bond angle decreases to ~ 130 - 140° (azido group accepts a bent geometry), the N1N2 bond is elongated to 1.31 - 1.35 Å in neutral forms and to 1.41 - 1.48 Å in cations, the bond order is reduced by ~ 0.3 in the both cases. An essential charge reduction (by about 0.45 e) on the two terminal nitrogen atoms of the azido group should be also noted (Table 11).


269

At the same time, parameters of A6, A5H+ and A6H+ are not practically changed in the S1 state: the azido group retains the quasi-linear geometry, the N1N2 bond length and order and the positive charge on the N2 group are nearly the same as those in the S0 state (Table 11). Comparison of the obtained results with the data for other aromatic azides [6,68] results in conclusion that the changes in the parameters for azides A1 - A5 and A1H+ - A4H+ on going from S0 to S1 state are characteristic for photoactive azides, while the conservation of the parameters observed for A6, A5H+ and A6H+ is characteristic for photoinert azides.

Figure 18. Structure of the frontier MOs for azidopyridine A1 and azidoazahexacene A6: the highest occupied MO (HOMO), the lowest unoccupied MO (LUMO) and the next unoccupied MOs till the NN*-MO in the ground (S0) state. In A1 the LUMO+1, in A6 it is LUMO+3 [67].

NN*-MO

is

270

Mikhayl F. Budyka

Figure 19. Structure of the lowest semioccupied MO (LSOMO) and the highest semioccupied MO (HSOMO) in the S1 state for azidopyridine A1, azidodibenzacridine A5 and azidoazahexacene A6 [67].

The geometry change and the charge redistribution (or the lack of essential changes) on going from the S0 to S1 state can be easily explained by examining the structure of the frontier MOs in these states. As example, Figure 18 shows the structure of the highest occupied MO (HOMO), the lowest unoccupied MO (LUMO) and some next unoccupied MOs for the first and last members of the series, A1 and A6, respectively, in the neutral form in the S0 state. One can see that both HOMO and LUMO are -type MOs localized mainly on the aromatic nucleus with partial contribution by the atomic p-orbitals of the azido group. One of the higher unoccupied MOs is antibonding NN*-MO, the population of this orbital in the S1 state is a prerequisite for subsequent azido group dissociation [6]. In the S0 state, the NN*-MO is LUMO+1 in azide A1 and LUMO+3 in azide A6 (Figure 18). In the S0 state, the structure of the frontier MOs for protonated cations A1H+ A6H+ is similar to that for corresponding neutral azides. In the excited (S1) state, the type of the filled MO depends on the azide size and charge. In neutral azides from A1 to A5, upon excitation to the S1 state, as a result of relaxation, the NN*-MO is occupied instead of LUMO (Figure 19). Depopulation of the

-HOMO, which becomes the lowest semioccupied MO

(LSOMO) in the S1 state, and population of the NN*-MO, which becomes the highest semioccupied MO (HSOMO), results in the aforementioned structural changes: electron density transfer from aromatic nucleus to azido group, bending


271

of this group and weakening and elongation of the N-N2 bond (Table 11). At the same time, in the excited azidoazahexacene A6, the aromatic -orbital is filled (Figure 19) whereas the NN*-MO remains vacant. As a result, the structure of A6 in the S1 state is similar to that in the S0 state (Table 11). Based on the nature of MO, that is filled in the S1 state, one should expect azides A1 - A5 to be photoactive whereas azide A6 - photoinert. Thus, between azidodibenzacridine A5 and azidoazahexacene A6 a boundary can be drawn that separates photoactive azides (where the NN*-MO is filled in the S1 state) from photoinert ones (where the NN*-MO remains vacant in the S1 state). The behavior of the protonated azides in the excited state is similar to that of the neutral forms: for the first members of the series, the NN*-MO is filled in the S1 state, for the last members this MO remains vacant (Figure 20). In contrast to neutral azides, the boundary, which separates photoactive and photoinert azides, passes between cations A4H+ and A5H+. Thus, for positively charged azides the NN*-MO ceases to be filled in the S1 state at a smaller size of aromatic nucleus (22 -electrons) compared to the neutral azides (26 -electrons).

Figure 20. Structure of the lowest semioccupied MO (LSOMO) and the highest semioccupied MO (HSOMO) in the S1 state for the protonated azides A1H+, A4H+ and A5H+ [67].

272

Mikhayl F. Budyka

The decrease in the population of HOMO, which in the S1 state becomes the lowest single-occupied MO (LSOMO), and the population of the MO, which becomes the highest single occupied MO (HSOMO) results in the observed changes in the structure of photoactive azides: the transfer of the electron density from the aromatic ring to the azido group, bending of the azido group, and the elongation of the N-N2 bond (Table 11). At the same time, the aromatic -MO is populated in the S1 state of photostable azides, and the NN*-MO remains unoccupied. From the viewpoint of the valence bond theory, upon excitation from the S0 to the S1 state, in the photoinert azides, the atomic orbitals of the central atom of the azido group (atom N2) conserve the sp hybridization (valence angle ~ 180°), whereas in the photoactive azides, the rehybridization from sp to sp2 takes place (valence angle ~ 120°). Analysis of the MO diagram provides a reason for existence of a limiting size of the aromatic nucleus, above which the NN*-MO ceases to be filled in the S1 state. Figure 21 shows the molecular orbital diagram for the neutral azides A1 - A6 in the ground (S0) state. One can see that with increasing number of annelated benzene rings the HOMO level gradually increases while the LUMO level decreases. As a result, the energy gap HOMO–LUMO decreases from 8.98 to 5.55 eV (PM3 data) on going from A1 to A6. The striking feature is a little effect of aromatic nucleus size on the NN*-MO level; the energy of this orbital varies insignificantly within -(0.3 0.1) eV for the neutral azides. A slight increase of the NN*-MO energy on going from A2 to A3 is connected with a deviation of the azido group from the aromatic nucleus plane due to steric hindrance with the peri-hydrogens (see above). Owing to the decreased conjugation between the azido group and aromatic -system, the NN*MO is destabilized and its level increases. From Figures 18 and 21 it is seen that in the S0 state of the neutral A1, the NN*-MO is next after LUMO, i.e. LUMO+1, and is located above LUMO by 0.21 eV. Since the

NN*-MO

level is retained while the LUMO level decreases

with increasing aromatic system size, the energy gap between NN*-MO and LUMO increases from 0.21 to 1.87 eV on going from A1 to A6. The space between these orbitals is filled with the -orbitals, localized on the aromatic nucleus, as a result, the

NN*-MO

becomes LUMO+3 in A6.


EMO, eV 0

— — — — — *-MO — — — — — —

NN

-1 -2

-8 -9 || — A1

|| — || —

A2

A3

273

— — LUMO+4 — — — LUMO+3 — — — — LUMO+2 — LUMO+1 — — — LUMO || HOMO — || — || — A4

A5

A6

Figure 21. Molecular orbital diagram for the neutral azides A1 - A6 in the ground (S0) state (PM3 data). The position of the is marked [67].

NN*-MO,

which is LUMO+1 in A1 and LUMO+3 in A6,

Figure 22 shows the molecular orbital diagram for the protonated azides A1H+ - A6H+ in the ground (S0) state. Compared to the neutral azides, there is a general lowering of orbital levels. Nevertheless, the main features found for the neutral azides are observed also for the cations. With increasing number of annelated benzene rings, the HOMO level gradually increases, and despite little change in the LUMO level, the HOMO– LUMO gap decreases from 8.05 to 5.08 eV on going from A1H+ to A6H+. The energy of the NN*-MO in the cations varies within -(4.1 0.1) eV, and the gap between NN*-MO and LUMO increases slightly from 1.52 to 1.61 eV on going from A1H+ to A6H+. In the protonated azidopyridine A1H+ in the S0 state the NN*-MO is LUMO+2, LUMO+1 being aromatic -orbital. With increasing aromatic nucleus size, the -orbital level increases (Figure 22), so this orbital becomes LUMO+2 whereas the A6H+.

NN*-MO

becomes LUMO+1 in the protonated azidoazahexacene

274

Mikhayl F. Budyka

EMO, eV -4

— *-MO — — —

NN

-5 -6

— — — —

-11 -12 -13 || — A1H+

|| — A2H+

— — —

— — — — — — —

— — — — || — || — || — || — A3H+

A4H+

A5H+

LUMO+4 LUMO+3 LUMO+2 LUMO+1

LUMO HOMO

A6H+

Figure 22. Molecular orbital diagram for the protonated azides A1H+ - A6H+ in the ground (S0) state (PM3 data). The position of the LUMO+1 in A6H+, is marked [67].

NN*-MO,

which is LUMO+2 in A1H+ and

Thus, three effects can be noted with the aromatic system size increasing: i) independence (little dependence) of the ii) decrease in the HOMO–LUMO gap, iii) increase in the LUMO– NN*-MO gap.

NN*-MO

level on the size,

As a consequence of (ii) and (iii), in the investigated series of azides, both neutral and protonated, the NN*-MO, which is filled in the S1 state for the first members of the series (large HOMO–LUMO gap, small LUMO– NN*-MO gap), ceases to be filled for the final members of the series (small HOMO–LUMO gap, large LUMO– NN*-MO gap). The boundary, that separates photoactive azides (where the NN*-MO

NN*-MO

is filled in the S1 state) from photoinert ones (where the

remains vacant in the S1 state), passes between A5 and A6 for the neutral azides and between A4H+ and A5H+ for the cations. Therefore, the threshold size of the aromatic nucleus, above which the NN*MO ceases to be filled in the S1 state and the azide becomes photoinert, is


275

calculated to be 22 (in A5) and 18 (in A4H+) -electrons for the neutral and protonated azides, respectively. The positive charge shifts the threshold to the smaller size. Thus, quantum-chemical calculations predict existence of the "size boundary" of photoactivity of aromatic azides. From this point of view, 9-(4'-azidophenyl)acridine (APA) and its cation are interesting examples of azides with the size of the π system equal to 20 e. This is lower than the threshold for neutral azides, but higher than that for cations. In fact, neutral APA is photoactive, whereas its cation is photoinert (see above). Table 12 collects some calculated energetic parameters of azides A1 - A6: heat of formation ( Hf) in the S0 state, vertical (Franck-Condon) excitation energy (Ev) to the lowest excited singlet (S1) state, and relative energy of the S1 state, which corresponds to adiabatic excitation energy (Ead). The heat of formation of azide in both neutral and protonated forms increases with increasing number of the condensed aromatic rings (m), the dependences are described by the linear regressions Hf = 82.25 + 23.04*m kcal mol-1 for the neutral form (correlation factor r = 0.999), and Hf = 238.92 + 18.52*m kcal mol-1 for the protonated form (r = 0.997). Table 12. Selected calculated (PM3) energetic parameters of heteroaromatic azides: heat of formation Hf (in kcal mol-1) in the S0 state, vertical (Ev) and adiabatic (Ead) excitation energies (in eV) to the lowest excited singlet (S1) state (protonated cations A1H+ - A6H+ were calculated without counterions) [67] Azide A1 A2 A3 A4 A5 A6

Hf 107.47 126.02 151.22 173.75 197.42 221.37

Ev 4.707 4.274 3.761 3.285 2.952 2.729

Ead 1.570 1.578 1.714 1.846 2.226 2.496

Azide A1H+ A2H+ A3H+ A4H+ A5H+ A6H+

Hf 261.39 272.99 292.98 311.35 331.29 352.35

Ev 4.162 3.787 3.258 2.595 2.258 1.817

Ead 2.008 1.957 1.978 2.146 1.898 1.488

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Mikhayl F. Budyka

Figure 23 shows the difference between the vertical and adiabatic excitation energies (Ev - Ead) in dependence on the size of azide molecule. Both Ev and Ead are calculated for the systems with the open electronic shells (two unpaired electrons), but Ev is calculated at the fixed geometry of the ground state, whereas Ead is calculated at the relaxed geometry of the excited state. Therefore, the difference (Ev - Ead) can be defined as the energy of relaxation (rearrangement) of the atomic nuclei following the electron transfer upon excitation to the S1 state. This parameter characterizes a change in the geometry of the excited state relative to that of the ground state. The theoretical limit, a zero difference between Ev and Ead, corresponds to the complete absence of relaxation when the geometry of the excited state coincides with that of the ground state and two states differ only in the electron density distribution. In Figure 23 one can see that with azide molecule size increasing the relaxation energy decreases taking minimal values for photoinert A6, A5H+ and A6H+. In photoinert azides the NN*-MO remains vacant, and the geometry of azido group is not practically changed in comparison with the ground state, as a result these azides have the smallest relaxation energy (< 0.4 eV).

E, eV 3

2 1

1

2

0 1

2

3

m

4

5

6

Figure 23. Dependence of the difference (Ev - Ead) between the vertical and adiabatic excitation energies on the number of aromatic rings (m) for the neutral azides A1 - A6 (1) and the protonated cations A1H+ - A6H+ (2).


277

The vertical (Franck-Condon) excitation energy (Ev) itself is an important photochemical characteristic of azide. This calculated parameter corresponds to the experimentally measured maximum of the long-wavelength absorption band and characterizes the region of spectral sensitivity of azide. From Table 12 it is seen that Ev monotonically decreases with an increase in the size of the azide molecule for both neutral and protonated azides. The decrease in Ev is symbatic to the above-discussed decrease in the HOMO–LUMO gap, which is an essential part of Ev, and corresponds to the bathochromic shift of the absorption band observed in the spectra of aromatic compounds with an increase in the number of annelated aromatic rings [55]. Since the absorption spectrum, as well as photoactivity, depends on the size of the -system of azide molecule, we can connect these two experimental parameters with each other. Before, it is noteworthy that besides the "size boundary" there exists also an "energetic boundary" of azide photoactivity. The activation energy for the N-N2 bond thermolysis in aromatic azides is about 35 kcal mol-1 or slightly less [69]. Therefore, the energy of light quantum with wavelength above ~ 800 nm is insufficient for the cleavage of azido group. Thus, both "size boundary", which depends on the population of the NN*MO in the S1 state, and "energetic boundary", which depends on the energy of the N-N2 bond cleavage, lead to the "long-wavelength boundary" of aromatic azide photoactivity: azides possessing absorption bands in the long-wavelength region of the visible spectrum above a certain threshold become insensitive to irradiation light. It should be emphasized here that the results considered refer to the lowest electronically excited singlet (S1) state. This state is populated upon the excitation of a molecule with a light in the long-wavelength absorption band and characterizes the long-wavelength light sensitivity of aromatic azide. Upon irradiation with the shorter wavelength light, the photodissociation quantum yield may change drastically, because, in this case, the highest excited states (Sn) are populated, which differ by the structure and the properties from the S1 state [7]. Taking into account the correlation between the azide photoactivity and the type of molecular orbital populated in the excited state, the experimentally observed correlation between the spectral and photochemical properties of aromatic azides (azidodyes with absorption bands in the visible range are mostly photoinert) finds theoretical basis. Both spectral and photochemical properties of aryl azides are determined by the relative positions of the same frontier MOs. The position of the longwavelength absorption band depends first of all on the value of the HOMO–

278

Mikhayl F. Budyka

LUMO gap, while the population of the

NN*-MO

depends on the ratio between

the HOMO–LUMO and LUMO– NN*-MO energy gaps. For a bathochromic shift of the long-wavelength absorption band, it is necessary to decrease the HOMO– LUMO gap, which may be attained by increasing the size of the aromatic system or converting the compound into a positively charged form (all known azido dyes are cations). However, this inevitably results in the fact that the NN*MO ceases to be filled in the S1 state, and the azide becomes photoinert. Hence, it follows that the requirement of long-wavelength light sensitivity of azides is contradictory. On the one hand, to exhibit bands in the visible region, an azide should be a dye, and most of dyes have an extended system of conjugated bonds and are cations. On the other hand, upon an increase in the size of the system and positive charging, the azide loses photoactivity and the quantum yield of photodissociation of the azido group sharply decreases to < 0.01. This problem is considered below.

4. LONG-WAVELENGTH BOUNDARY OF AROMATIC AZIDE PHOTOACTIVITY Due to its practical importance, the problem of the long-wavelength photosensitivity of aromatic azides has been investigated in more detail [70]. The absorption spectrum of an azide determines the region of its spectral sensitivity, while light sensitivity or photoactivity is determined by the quantum yield of photodissociation of the azido group. To shift the photosensitivity of an aromatic azide toward the long-wavelength region of visible spectrum, it is necessary that, first, the long-wavelength absorption band of the azide occur at a given spectral range and, second, the azide be photoactive; i.e., have a quantum yield of > 0.1 upon illumination at this photodissociation of the azido group of absorption band. The absorption spectra for the series of heteroaromatic azides were calculated and compared with available experimental data [70]. Table 13 presents data on the absorption spectra of azides A1 - A6 and the corresponding cations A1H+ - A6H+ calculated by the TD B3LYP/6-31G* method: the wavelength ( ), the frequency ( ) of the long-wavelength absorption band and the corresponding vertical excitation energy (Ev), the oscillator strength (f), and the structure of the transition. In addition, the energies Ev characterizing the Franck–Condon


279

transition S0 S1 were calculated by the PM3-CI method. Experimentally measured spectra are known for azides A1 - A3 and their hydrochlorides (see above), these spectra are also given in Table 13. Table 13. Calculated and experimental absorption spectra of azides A1 - A6 and their cations A1H+ - A6H+, given are the wavelength ( ) and the frequency ( ) of the long-wavelength absorption band and the corresponding vertical excitation energy (Ev), the logarithmic molar absorption coefficient ( in M-1 cm-1), the oscillator strength (f), and the structure of the transition; calculation on the cations ignoring counterions [70] Azide Ev, eV А1 А1Н+ А2 А2Н+ А3 А3Н+ А4 А4Н+ А5 А5Н+ А6 А6Н+ a b

4.05 4.71 4.65 4.16 3.80 4.27 3.53 3.79 3.26 3.76 2.83 3.26 2.50 3.29 1.89 2.60 1.99 2.95 1.55 2.26 1.60 2.73 1.03 1.82

Caclulateda f structureb

%

0.0004

H

L+1

0.0003

H

0.0003

Experimental , cm-1 Ev, eV

47

, nm 249

40160

4.98

4.01

L+2

48

275

36360

4.51

4.30

H

L+1

42

299

33450

4.15

4.06

0.0621

H

L

40

332

30120

3.73

4.17

0.0777

H

L

41

362

27620

3.42

3.83

0.0682

H

L

41

427

23420

2.90

3.76

0.0558

H

L

41

0.0229

H

L

43

0.0485

H

L

39

0.0176

H

L

42

0.0370

H

L

38

0.0293

H

L

41

lg

TD B3LYP/6-31G*//PM3; the figures given in italic represent PM3-CI calculation data. Notation of molecular orbitals: H is HOMO (highest occupied MO) and L is LUMO (lowest unoccupied MO); given are one-electron transitions with a contribution of more than 10%.

Mikhayl F. Budyka

/103 cm-1

10

900 800 700 600

5

20

500

1

400

/nm

280

2

30

4

300

3

40 6

10

14

18

22

26

n (e) Figure 24. Dependence of the frequency

(wavelength ) at maximum of the azide long-

wavelength absorption band on the number of electrons n in the aromatic system for neutral azides A1 - A6 according to calculations by the (1) B3LYP/6-31G8//PM3 and (2) PM3-CI methods and to (3) experimental data approximated by regression analysis; (4) the size threshold of photoactivity: azides with a smaller

system are photoactive and those

5) the energy threshold of photoactivity: the energy with a larger of light at a longer wavelength is insufficient for breaking the N-N2 bond (see text) [70].

Figure 24 shows the dependence of the frequency (wavelength) at maximum of the long-wavelength absorption band on the size of the aromatic -system (number of electrons) for neutral azides A1 - A6; for comparison, the calculated spectra are matched with the known experimental spectra of the first members of the series A1 - A3 (note that hereinafter the calculations are made for bare molecule, while experimental spectra are measured in acetonitrile). It is seen that the TD B3LYP/6-31G method substantially underestimates the energy of the S0 S1 transition (frequency of the long-wavelength absorption band maximum) for the first member of the series A1 by 0.93 eV (7490 cm–1) relative to the experimental value and that the error for A3 decreases to 0.16 eV (1290 cm–1). The PM3-CI method on average better predicts the position of the band maximum, underestimating Ev by 0.27 eV for A1 and overestimating it by 0.34 eV


281

for A3. As shown in the previous section, the ZINDO method, like TD B3LYP, strongly underestimates the energy of the band for A3 (by 1.02 eV) but predicts Ev for A1H+ accurate to within 0.10 eV. An inspection of the theoretical and experimental plots (Figure 24) shows that both calculation methods predict more gently sloping dependence of the longsystem as wavelength absorption band frequency on the size of the azide compared with the experimental data. The experimental points for azidopyridine A1, azidoquinoline A2, and azidoacridine A3 lie on the straight line described by the equation (correlation factor r = 0.9992) = (49420 – 1570n) cm–1,

(4)

where is the frequency of the azide long-wavelength absorption band and n is the number of electrons of the azide aromatic system. Figure 25 presents the dependence of the long-wavelength absorption band maximum on the size of the system for protonated azides A1H+ - A6H+. A better agreement between the calculated and experimental data was observed for the cations than for their neutral counterparts, especially in the case of the TD B3LYP/6-31G* calculations (Figure 25, curves 1, 3); the standard deviation for A1H+ - A3H+ is 0.14 eV. The regression analysis treatment of the experimental data leads to the equation (r = 0.9998) = (46140 – 1620n) cm–1

(5)

A comparison of equations (4) and (5) shows that the extension of the catacondensed system by one benzene ring in both neutral and protonated azides leads to a bathochromic shift of the band by 6400 cm–1 on average. and n still holds for higher Providing that the linear relation between + + members of the series A1 - A6 and A1H - A6H , it is possible to predict the longwavelength absorption band frequencies for these azides from equations (4) and (5). As mentioned above, quantum-chemical calculations predict that the size threshold of photoactivity is 22 electrons and lies between A5 and A6; i.e., azides A1 - A5 are photoactive (have a photodissociation quantum yield of > 0.1) and azide A6 is photoinert ( < 0.01). For the protonated forms, the size threshold is 18 electrons and lies between A4H+ and A5H+; i.e., azides A1H+ A4H+ are photoactive and azides A5H+ and A6H+ are photoinert.

Mikhayl F. Budyka

/103 cm-1

10

900 800 700 600

5

1

20

500

3 2

400

30

/nm

282

4

300

40 6

10

14

18

22

26

n (e) Figure 25. Dependence of the frequency

(wavelength ) at maximum of the azide long-

wavelength absorption band on the number of n in the aromatic system for + + protonated azides A1H - A6H according to calculations by the (1) B3LYP/6-31G8//PM3 and (2) PM3-CI methods and to (3) experimental data approximated by regression analysis; (4) the size threshold of photoactivity and (5) the energy threshold of photoactivity (see Figure 24) [70].

In Figures 24 and 25, the size boundary of photoactivity is marked by dashed lines 4. The energy threshold of photoactivity, determined by the activation energy of the N-N2 bond dissociation, is shown by dashed lines 5 in these figures. From equation (4), we can calculate that the long-wavelength absorption band of azide A5, which is expected to have a high quantum yield of photodissociation, will lie at 14880 cm–1 (672 nm). This position is consistent with the value of 16040 cm–1 (623 nm) predicted for A5 by the B3LYP/6-31G* calculation; the PM3-CI method predicts the band to lie at a shorter wavelength, 23810 cm–1 (420 nm). For azidobenzacridinium A4H+, which is likewise expected to have a high photodissociation quantum yield, calculation according to equation (5) gives the band maximum at 16980 cm–1 (589 nm). The B2LYP/6-31G* method predicts a lower frequency 15230 cm–1 (657 nm) for A4H+, unlike the PM3-CI method which gives a higher frequency 20930 cm–1 (478 nm). The long-wavelength absorption band (La band) of unsubstituted benzacridinium chloride occurs at 17000 cm–1 (588 nm) [31].


283

In linear acenes, which are unsubstituted homoaromatic analogues of A1 - A6, the two lower excited singlet states denoted as La and Lb (the same symbols are used to denote the absorption bands corresponding to the transition into these states) differ in nature. The La transition is associated with electron transfer from the HOMO to the LUMO and is polarized along the short axis of the molecule. The Lb transition is polarized along the long axis of the molecule and is attributed to the HOMO-1 LUMO and HOMO LUMO+1 electron transfer. The S1 state is of the Lb-type for benzene and naphthalene and of the La-type for anthracene and higher acenes [54]. For linear acenes from naphthalene to octacene, the TD B3LYP method has been shown to predict accurately the energy of the Lb state but underestimates the La energy, wherein the magnitude of error increases with an increase in the size of the π system [55]. In the aza analogues of acenes: pyridine, quinoline, acridine, etc., the basic features of acenes are retained, furthermore, the - * bands are complemented by n- * bands, which overlap with the former because of their high intensity. The spectra of azides of azaacenes additionally exhibit less intense n- * bands due to the azido group. For the higher members of the A1H+ - A6H+ series (Table 13), like for higher acenes, the long-wavelength absorption band is classified as La type and calculation underestimates the energy of this band (overestimates the wavelength). An analysis of the structure of transitions shows (Table 13) that the major contribution to the long-wavelength absorption band of most azides is made by electron transfer from HOMO to LUMO, which are orbitals localized primarily on the aromatic rings in all of the test azides. The exceptions are azides A1 and A2, in which LUMO+1 is involved in the transition, and the cation A1H+, in which the transition involves the LUMO+2. These molecular orbitals in the latter azides are NN* orbitals localized on the azido group. It is the NN*-MO whose population in the S1 state is responsible for the photoactivity of the aromatic azide. In other azides, the NN*-MO remains unoccupied during a vertical (FranckCondon) transition. However, in the relaxed S1 state, the unpaired electron occupies the NN*MO in neutral azides A1 - A5 and cations A1H+ - A4H+, whereas in the higher analogues A6, A5H+, and A6H+, the -molecular orbital is occupied in the relaxed S1 state (see previous section). Thus, the calculation of spectra by means of the TD B3LYP/6-31G* method, as well as the regression analysis of experimental data, for the first members of the series A1 - A3 and A1H+ - A3H+ predicts that there can be photoactive

284

Mikhayl F. Budyka

heterocyclic azides (with > 0.1) whose long-wavelength absorption bands lie in the region 580–670 nm. The calculation predicts the azides that absorb light at longer wavelengths to be photoinert ( < 0.01).

5. PHOTOCHEMISTRY OF AZIDOSTYRYLQUINOLINES The theoretical conclusion stating that for an azide to exhibit a photoactive behavior in both the neutral and cationic forms the azide system should not exceed 18 e was confirmed experimentally in relation to the azido derivatives of isomeric 2- and 4-styrylquinolines [71,72,73,74,75]. The azidostyrylquinoline system includes exactly 18 electrons. Therefore the azido derivatives of styrylquinolines, 2-(4'-azidostyryl)quinoline 2ASQ and 4-(4'-azidostyryl)quinoline 4ASQ, were studied. N3

N 2ASQ

N3

N 4ASQ

Quantum-chemical calculations showed that in the S0 state in the neutral and protonated azidostyrylquinolines both frontier molecular orbitals are -type MOs localized on the aromatic system and the central double bond. As an example, Figure 26 compares the diagram of the HOMO and LUMO, as well as the neighboring unoccupied MOs for 4ASQ and its protonated cation 4ASQH+. The NN*-MO (localized on the azide group and possessing the antibonding character for the N-N2 bond) lies above the LUMO and is second after the LUMO for 4ASQ, i.e., LUMO + 2 (in 2ASQ, NN*-MO is LUMO + 3).


— — — LUMO

* MO-acphazNN = LUMO+2

0 EMO/ eV -3

| — | LSOMO —

HSOMO

-6

285

HOMO

|| —

-9

— = LUMO+7 — — — — — — — LUMO | HSOMO — | LSOMO — NN*

HOMO

— ||

S1

S0

S0

S1

4ASQH+

4ASQ

Figure 26. Energy diagram for frontier and neighboring unoccupied MOs (up to NN*MO) for 4-(4'-azidostyryl)quinoline (4ASQ) and its cation 4ASQH+: in the S0 state, HOMO is the highest occupied MO and LUMO is the lowest unoccupied MO; and in the S1 state, LSOMO is the lowest and HSOMO is the highest singly occupied MO (calculation by the PM3 method) [71].

The unoccupied LUMO and

-MOs localized on the aromatic system lie between the

NN*-MO.

In neutral azidostyrylquinoline the energy gap between

HOMO and LUMO is 7.44 eV and that between LUMO and NN*-MO is 0.95 eV (PM3 calculation). Protonation lowers the levels of all MOs, with the energies of virtual orbitals changing stronger relative to the occupied MOs (Figure 26). As a result, the HOMO–LUMO energy gap drastically decreases to 5.65 eV and the LUMO– NN*-MO gap increases to 3.29 eV for cation 4ASQH+. In cation 4ASQH+, the space between the LUMO and the

NN*-MO

is filled with

orbitals; therefore, the NN*-MO becomes already LUMO+7. The decrease in the HOMO–LUMO gap corresponds to a bathochromic shift in the long-wavelength absorption band, characteristic for heterocyclic cations in comparison with the neutral heterocycles. The ratio between the energy gaps (HOMO–LUMO) >> (LUMO– NN*-MO) leads to the situation that the

NN*-MO,

not the aromatic

286

Mikhayl F. Budyka

is occupied in the relaxed S1 state of the neutral 4ASQ (Figure 26). The same type NN*-MO, rather than LUMO, is occupied also in the relaxed S1 state of the cation 4ASQH+. Thus, calculations suppose the azidostyrylquinolines to be photoactive upon excitation into the S1 state in both neutral and cationic forms [71]. These theoretic conclusions were completely confirmed experimentally. The azidostyrylquinolines were synthesized and their photochemical properties were investigated [72,73]. The absorption bands of these compounds in the neutral form occur in the range of 300-400 nm. As an example, Figure 27 shows spectrum of 2-(4'-azidostyryl)quinoline 2ASQ and spectral changes during its photolysis. The quantum yields of azidostyrylquinolines photodissociation were found to be in the range of 0.7–0.9. Upon protonation, the absorption spectra of azidostyrylquinolines were shifted bathochromically to the visible region of 400480 nm. As a result, the hydrochlorides of these compounds appeared to be sensitive to the visible light: they retained high quantum yields of 0.7–0.9 upon irradiation within long-wavelength absorption band [72]. 2.0

A 1 1.5

1.0

7 0.5

0.0 300

/ nm

400

500

Figure 27. Spectral changes during the photolysis of an air-saturated solution of 2-(4'azidostyryl)quinoline (2ASQ) in ethanol with 365-nm light, intensity 2.23.10-9 Einstein cm2 -1 s , photolysis time (1) 0, (2) 5, (3) 12, (4) 21, (5) 45, (6) 90, and (7) 300 s [72].


287

The study of the products of the 2- and 4-(4'-azidostyryl)quinolines photolysis by the electrospray mass spectrometry showed that, as a result of the photodissociation of the N-N2 bond, a set of products typical of the azide photochemistry were formed: corresponding amines, nitroso, nitro, azo, hydrazo, and azoxy compounds (the last three in insignificant amounts) [74]. In the azide photolysis in the presence of HCl, the ratio of these products changed, and the chlorine-containing compounds were formed in addition. There were some products, which could not be identified by mass spectrometry. In addition, the formation of unsubstituted styrylquinolines was also detected. This finding indicated the photodissociation of the C-N3 bond, a process that is unconventional in the photochemistry of aromatic azides. N-Methylated 4-(4'-azidostyryl)quinoline AHC, which is a derivative of hemicyanine dye, was investigated in more detail [76,77]. This azidodye possesses strong absorption band in the visible region of spectrum, max ( , M-1 cm-1) 417 nm (28900), tailing to 500 nm, and less intensive bands in UV region, 332 nm (6200) and 249 nm (19650), see Figure 28, spectrum 1.

N3

+

N CH3 IAHC

Upon irradiation within the long-wavelength absorption band, azidohemicyanine AHC effectively decomposed. As an example, Figure 28 shows the spectral changes upon irradiation of azide solution with visible light of 485 nm in the absence of oxygen. The reaction was uniform within the initial period of photolysis, which was demonstrated by isosbestic points at 354.1 and 472.5 nm (curves 1 - 4 in Figure 28). At this time point in the reaction mixture there were two main components, as it was shown by electrospray mass spectrometry: the precursor azide whose peak with m/z = 287.105 was maximal in the spectrum (100 %), and the related primary amine whose peak with m/z = 261.116 was 59 % in intensity [76]. Based on this fact, the absorption band at 520 nm, which appeared in the spectrum during irradiation (Figure 28), was definitely be attributed to 1-methyl-4-(4'-aminostyryl)quinolinium iodide, which was practically the only reaction product at the initial period of photolysis in degassed solution.

288

Mikhayl F. Budyka 1

2.0

A 1.5

1.0

0.5

7

0.0 300

400

/ nm

500

600

Figure 28. Spectral changes upon irradiation of 7.4.10-5 M solution of azidohemicyanine dye AHC in degassed EtOH with light of 485 nm, irradiation time, s: (1) - (7) - 0, 60, 120, 240, 480, 1380, 2900; light intensity 1.08.10-9 Einstein cm-2 s-1 [76].

It is noteworthy here that electrospray ionization mass spectrometry (ESI MS) is suitable for this case. To study reaction product structure, the preparative-scale photolysis is ordinary used. However, in this case the azide concentration in the solution is several orders of magnitude higher than that in the kinetic studies, and the composition of the products of the aromatic azide photolysis can change significantly with the change of the concentration [78]. ESI MS can analyze reaction mixtures at the reagents concentration of ca ~ 10–5 M that enables direct comparison with the data of kinetic absorption spectroscopy. During further irradiation of AHC, isosbestic points disappeared thus indicating the proceeding of secondary reactions. The following compounds were identified in the final reaction mixture by electrospray mass spectrometry: the primary amine, which remained the main reaction product (100%), corresponding azo compound (62%), and hydrazo compound (8%). Upon photolysis in the presence of oxygen, the ratio of amine, azo compound and hydrazo compound did not practically change (100, 62 and 8%, respectively), but additional oxygenated products were formed: corresponding nitroso (9%), nitro (4%), and azoxy (6%) compounds. All identified products formation was explained by the reactions of triplet nitrene shown in Scheme 5 [77].

Photochemistry of Azidopyridine and Related Heterocyclic Azides h QuSt-N3

-N2

1(QuSt-N)

3(QuSt-N)

EtOH

QuSt-NH.

EtOH

289

QuSt-NH2

QuSt-NH-NH-StQu QuSt N N StQu O2

QuSt NOO

QuSt : QuSt-NO +

N CH3 I-

EtOH, O2

QuSt-NO + QuSt-NO2

O + QuSt N N StQu QuSt NHOH

Scheme 5. Photolysis of 1-methyl-4-(4'-azidostyryl)quinolinium iodide (azido hemicyanine AHC).

The relatively low quantity of nitroso and nitro compounds is noteworthy. The charged nitrene, generated from azido dye, appears to be less reactive towards oxygen, as compared to a neutral analogue, since comparative photolysis of neutral 4-(4-azidostyryl)quinoline under the same conditions resulted in the final reaction mixture contained much more nitroso (60%) and nitro (40%) compounds. The transient photolysis products, corresponding triplet nitrene, were detected in the low-temperature photolysis of azidodye AHC [75]. It has g = 2.0023, |D/hc| = 0.781 cm–1, and |E/hc| = 0 in the ESR spectrum, and intense absorption band in the visible region with maxima at 420 and 440 nm. The parameters for charged nitrene from azidodye AHC were compared with those for neutral triplet nitrene from azidostyrylquinoline 4ASQ having the same -electron system and differing only by the charge. The comparison showed that the introduction of the positive charge into the nitrene molecule led to the bathochromic shift of the longwavelength absorption band by ~ 40 nm in the absorption spectrum and to a decrease in the parameter D by 0.005 cm–1 in the ESR spectrum. Both effects are associated with the transfer of the electronic (spin) density from the nitrene atom to the aromatic system of styrylquinoline cation. The quantum yield of azidodye AHC decomposition upon irradiation within the long-wavelength absorption band was independent of excitation wavelength (365 - 485 nm) and dissolved oxygen, as follows from Table 14.

290

Mikhayl F. Budyka Table 14. Photodissociation quantum yields ( ) for 1-methyl-4-(4azidostyryl)quinolinium iodide (AHC) in EtOH [76]

ex, a

nm

365 0.80

365 0.86a

479 0.89

485 0.85

485 0.80a

Degassed solution.

According to these data, 1-methyl-4-(4'-azidostyryl)quinolinium iodide (azido hemicyanine AHC) has the longest-wavelength light sensitivity among all known aromatic azides: on irradiation at 485 nm, the quantum yield of its photodissociation is 0.85.

6. SIZE AND CHARGE EFFECTS IN HETEROCYCLIC AZIDE PHOTOCHEMISTRY Thus, from the study of the regularities of the heteroaromatic azides photodissociation, it was shown that the photochemical activity of an azide depends on the filling of the NN*-MO in the excited S1-state, and this, in turn, depends on the size and charge of the conjugated system of the azide molecule. Table 15 collects the photodissociation quantum yields of heteroaromatic azides with different (in size) -systems in the neutral and cationic forms. Table 15. Photodissociation quantum yields of heteroaromatic azides in the neutral ( 0) and cationic ( +) forms Azide A1 A2 A3 2ASQ 4ASQ APA

0

0.83 0.49 0.96 0.73 0.79 0.88

+

0.22 0.37 0.95 0.82 0.69 2.3.10-3


291

Table 16. The size and charge effects in the photochemistry of heteroaromatic azides (n is the number of electrons in the aromatic system, 0 and + are the photodissociation quantum yields of azide photodissociation in the neutral and cationic forms, respectively) n

Charge effect

6 14 20 ≥ 26

weak none strong none

0

>0.1 >0.1 >0.1 0.1 0> + + 0.1) in both neutral and charged forms, but in the charged form the quantum yield slightly decreases. This is the range of the weak charge effect. (2) Azides with middle size of the system (~ 14 e) are also photoactive in both forms, but the photodissociation quantum yield does not change in the charged form. This is the range of the absence of the charge effect with the large quantum yields ( > 0.1) in both forms. (3) Azides with large size of the system (~ 20 e) are photoactive in the neutral form ( > 0.1), but lose the activity on passing into the charged form ( < 0.01). This is the range of the strong charge effect. (4) Azides with the size of the system larger than 26 e are photostable in both neutral and charged forms. This is the range of the absence of the charge effect, but unlike the second range, here azides in both forms have low quantum yields ( < 0.01).

292

Mikhayl F. Budyka

In the first region (6 electrons), a moderate decrease of the quantum yield on passing from the neutral azide to cation is explained by an increase in the activation energy for azide dissociation in the S1 state of the cation. Since a substantial positive charge is concentrated on two terminal nitrogen atoms of the azido group in the ground states of all azides, while dissociation gives rise to a neutral nitrogen molecule, the electron density transfer from the aromatic nucleus to the leaving N2 molecule should be a necessary step of the N-N2 bond dissociation. In cationic azide, the positive charge of the aromatic ring creates the charge barrier (Coulomb barrier) for the transfer of electron density and hinders the dissociation. This effect appears in azidopyridine and in less extent in azidoquinoline which is an intermediate case between azidopyridine and azidoacridine. In the second region (14 electrons), increased -electron cloud of the heteroaromatic nucleus shields the positive charge of the cationic azide, and the quantum yield remains the same on passing from the neutral azide to cation. This effect appears in azidoacridine. It is noteworthy that invariability of the value can testify indirectly to invariability of the rate constants of photophysical processes (emission, internal conversion, and intersystem crossing, see formula 1) on going from the neutral to cationic azide. In the third region (20 electrons), the quantum yield does change drastically on passing from the neutral azide to cation, since in cationic form the NN*-MO ceases to be filled in the S1 state. This effect appears in azidophenylacridine. At last, in the fourth region (26 electrons and more), the quantum yield is low for both the neutral and cationic azide, since in these both forms the NN*-MO remains empty in the S1 state. There are no examples of the neutral azides with system of such size, but all known photoinert azidodyes are cations with large systems. The results of theoretical and experimental studies of heteroaromatic azides of different structure and photoactivity can be generalized using the views of the orbital nature of the electron excited states. The orbital nature is determined by the type of MO that participates in electron transitions [79,80], and quantum yield of a photochemical reaction depends on the relative positions of the terms (potential energy curves). The pattern of terms of the ground and locally excited states for photoactive and photoinert azides vs. the N-N2 bond length is represented in Figure 29. In azides, one can distinguish an 'aromatic' locally excited state in which the aromatic MQ is populated, this corresponds to the S *- term, and an 'azidic'

Photochemistry of Azidopyridine and Related Heterocyclic Azides locally excited state in which the S

*-term.

NN*-MO

293

is populated, this corresponds to the

The results of studies suggest the presence of a small ( 1.40 cm-1 and N > 1.77 (UB3LYP/6-31G*) were photochemically very stable and did not rearrange into carbodiimides. As compared with triplet pyridylnitrenes and pyrimidylnitrenes, triplet nitreno-s-triazines have the highest zero-field splitting parameters. The high Dvalue was explained by the effect of heterocyclic nitrogen atoms, which were poor spin-holding centers due to a small size. The more nitrogen atoms in a heterocyclic ring, the higher the D-values of triplet heteroarylnitrene. The high Evalues of triplet nitreno-s-triazines were assumed to indicate the non-degeneracy of two magnetic orbitals of these species [88]. In contrast to nonhalogenated 4-pyridylnitrene, tetrafluoro- and tetrachloro-4pyridylnitrenes, formed on matrix photolysis of the corresponding azides, were found to be highly photostable in low-temperature matrices, there was no evidence for the formation of an azirine or ketenimine [89,90]. It is interesting to note that on extensive photolysis of tetrachloro-4-pyridylnitrene in the Ar matrix, the starting azide was slowly regenerated in the course of photolysis at 444 nm for 12 h. This can be explained by trapping of the nitrene by molecular nitrogen. A number of 2,4- and 2,6-diazidopyridine derivatives were photolyzed under frozen matrix conditions and, typically, both mononitrene and dinitrene spectral features were observed [91,92,93,94]. In substituted 2,6-diazidopyridines, the yield of quintet dinitrene decreased upon gradual displacement of the chlorine molecule by the cyano group, because intermediate triplet nitrenes underwent the pyridine cycle transformation [91]. This effect was accounted for by the fact that the chlorine atoms on the orthoposition increased the stability of the pyridine ring to photoisomerization, as was shown by the example of the triplet perchloro-substituted pyridyl-4-nitrene [90].


R2

N3

N

X

X

X R1

R1

h

N3

N3

R2 N

299

R1

h

. N.

.

N.

R2 N

.

N.

R1, R2 = Cl, CN

The 2,6-dinitrenes were found to have consistently larger zero-field splitting (zfs) than the related 2,4-dinitrenes. The 2,4-dinitrenes were estimated to have zfs of |D/hc| ~ 0.21-0.24 cm-1 and |E/hc| ~ 0.03-0.04 cm-1, and the 2,6-dinitrenes to have zfs of |D/hc| ~ 0.24-0.27 cm-1 and |E/hc| ~ 0.04-0.05 cm-1. The difference in spectral behavior was attributed to perturbation of spin density distributions and geometry-influenced interactions between the nitrene units in the 2,4- vs the 2,6connectivities [92]. Large ratio of |E/D| for 2,6-dinitrenopyridines was consistent with a dominating dipolar interaction between the two nitrene units having a relative interaction vector angle of about 114°–116° [93]. The stabilizing effect of the chlorine atoms manifested itself also in the photolysis of 2,4,6-triazido-3,5-dichloropyridine TAP (methyltetrahydrofuran, 77 K), when one managed to successively observe and characterize mono-, di-, and trinitrene (dicyano derivative failed to produce high-spin nitrenes) [89, 95, 96]. It was found that, with an increase in the multiplicity (the number of the nitrene centers), the absorption spectrum shifts bathochromically, and the D-parameter of splitting in zero field decreases (Table 17).

Cl N3

Cl N

N3

h

Cl

Cl N3

N

.

N.

N3

N3

N3

.

N.

h

Cl

. N.

Cl N

.

h

N.

Cl

. N.

Cl N

.

N.

TAP

Table 17. The properties of nitrenes, the products of the successive photolysis of 2,4,6-triazido-3,5-dichloropyridine (methyltetrahydrofuran, 77 K) [95, 96] Product Nitrene Dinitrene Trinitrene

Multiplicity Triplet Quintet Septet

, nm 499, 527 576, 620 709

|D/hc|, cm-1 0.955 0.283 0.100

|E/hc|, cm-1 0.000 0.036 0.0005

300

Mikhayl F. Budyka

In contrast to TAP, where predominantly one mono- and one di-nitrene was formed as a result of selective decomposition of the -azido groups, its fluorine analogue, 2,4,6-triazido-3,5-difluoropyridine, produced a full set of possible nitrenes upon photolysis in solid argon at 4 K [44]. High-resolution ESR spectra of all nitrenes were obtained, the fine-structure parameters of the nitrenes were determined with high accuracy from computer spectral simulations. The septet trinitrene (|D/hc| = 0.1018 cm-1, |E/hc| = 0.0037 cm-1) was the final photoproduct and was very stable in argon matrices toward further irradiation, no low-spin products were observed upon prolonged irradiation with light at λ > 305 nm.

N3

N3 F

F N3

N

N3

h

F

F

N3

..

N

h

N

F

..

N

N3

N

..

N

h

F

..

N

F N

.

N.

N. F

N

F

.

.

N. F

.

N.

N3

N3

h

F N3

F N

.

N.

Cyanuric triazide, 2,4,6-triazido-1,3,5-triazine, theoretically also has possibility of trinitrene formation, however, in earlier powder and single-crystal studies, generation of a septet trinitrene was not confirmed [97]. Probably, the oligonitrene species generated were surrounded by the unreacted precursor or by partially reacted nitrenes, and even at low temperatures, reactions between these species could not be excluded completely. The matrix-isolation technique using inert media such as noble gases or nitrogen allows the study of such reactive species by excluding intermolecular reactions completely. Really, upon matrix photolysis of triazidotriazine, the stepwise generation of the corresponding mononitrene, dinitrene, and trinitrene was observed by IR and ESR spectroscopy. The generated species were identified by comparison of their matrix IR spectra with B3LYP/6-31G* computational results and by computer simulation of the EPR spectra [98,99].


N N3

h

N N

N3

N3

N3

N3

N N3

301

N N

h

..

..

N

N

N

N N

..

h

N

.

N. h

. N.

N

N N

h

..

3NCN

N

Generated on the first stage mononitrene could rearrange into a cyclic carbodiimide, but observation of only a weak IR band at around 1900 cm-1 indicated that the rearrangement was a minor process in this case [99]. The final trinitrene readily decomposed into three NCN molecules upon further photoirradiation. The triplet NCN was identified by ESR spectrum (|D/hc| = 1.545 cm-1, |E/hc| = 0.000 cm-1, as determined by simulation), IR band at around 1475 cm-1, and UV/Vis absorption bands: one intense peak at 329 nm accompanied by vibronic bands at 290- 300 nm. Experimental IR frequencies, UV-vis absorption bands, and ESR fine-structure parameters of mono-, di and tri-nitrenes formed from triazidotriazine are collected in Table 18. Recently, new information on zero-field splitting parameters and geometric structure of some pyridyl quintet dinitrenes and septet trinitrenes was obtained upon reinvestigation of these species by matrix isolation spectroscopy [43,44,100,101]. Due to their photochemical stability, high-spin pyridylnitrenes are suitable models for exploration of organic molecular magnetism and spin chemistry. The study of the high spin polynitrenes, the products of polyazide photolysis, is in progress because of the possibility of producing new organic functionality magnetic materials based on them. Table 18. The properties of nitrenes, the products of the stepwise singlecrystal and matrix photolysis of 2,4,6-triazido-1,3,5-triazine [97, 99] Product Nitrene Dinitrene Trinitrene

Multiplicity Triplet Quintet Septet

, cm-1 1339 1438 763, 1326

, nm 344 377 -

|D/hc|, cm-1 1.461 0.280 0.123

|E/hc|, cm-1 0.005 0.058 0.000

302

Mikhayl F. Budyka

8. PHOTOAFFINITY LABELING If organic magnets are as yet only models for possible future application, photoaffinity labeling is already widely used for investigation of biomacromolecules. In combination with modern techniques of instrumental analysis and computer-aided modeling, photoaffinity labeling is one of the most important approaches in studies on the organization of biological systems [102]. Heterocycles are building blocks of nucleic acids, and proteins and active components of many medicaments. Thus, it is not surprising that heterocyclic azides are studied and used as photoaffinity labeling reagents. Important in this respect is the possibility of the short-lived singlet nitrene obtained upon photolysis of azide to react indiscriminately with residues of the macromolecular target present in the binding site of biomacromolecule. Below there are several examples of heterocyclic azides which were used as photoaffinity labels. 9-Azidoacridine was used as photoaffinity label for nucleotide- and aromaticbinding sites in proteins [56,57]. The photochemistry of this azide was discussed in detail above. A radiolabeled [3H]7-azido-4-isopropylacridone upon irradiation specifically labeled (bound covalently to) Cys159 of the bovine mitochondrial ADP/ATP-carrier protein [103]. O N3 N H

CH(CH3)2

Photoaffinity labeling with 2-azidoadenosine 5'-triphosphate was used for identification of amino acid residues at nucleotide-binding sites of chaperonin GroEL/GroES complex (it plays an essential role in the folding, assembly and protection of cellular proteins) [104]. 8-Azidoadenosine and derivatives are used in photoaffinity labeling and in cross-linking studies [105,106,107,108]. To understand the processes by which reactive intermediates derived from 8azidoadenosine bind to and react with targeted proteins and nucleic acids, these species were studied by chemical trapping studies, laser flash photolysis with UVvis and IR detection and modern computational chemistry [109].


303

NH2 N N3

N R

N N HO

R: H, CH3, PhCH2,

O OHOH

Upon photolysis in water or buffer, 8-azidoadenosine released the corresponding singlet nitrene which underwent a hydrogen shift to form closed azaquinodimethane in less than 400 fs, faster then it could relax to a triplet nitrene or react with a biological target molecule. The azaquinodimethane had a lifetime of several minutes in the absence of good nucleophiles, and was the species which forms adducts in cross-linking and photoaffinity labeling experiments via selective reactions with nucleophiles such as amines, thiols, and phenolate ions. Because of the selective reactivity of this closed diazaquinodimethane, it may obviously wander from its original binding site and become attached to a nucleophilic residue at a remote site. The conclusion was made that results of cross-linking experiments using 8-azidoadenosine and its derivatives should be viewed with caution [109]. Azidoatrazine ([14C]-2-azido-4-ethylamino-6-isopropylamino-s-triazine), a derivative of herbicide atrazine which binds to the secondary plastoquinone electron-acceptor site of photosystem 2 (PS2), was used for photoaffinity labeling followed by sequence analysis of peptides derived by proteolysis of the PS2 centers [110]. N3 N

N N H

N

N H

Analogue of deoxycytidine triphosphate, exo-N-{2-[N-(4-azido-2,5-difluoro3-chloropyridine-6-yl)-3-amino-propionyl]aminoethyl}-2'-deoxycytidine-5'triphosphate which has 4-azidopyridine as a photoactive site, was applied for photoaffinity modification of DNA binding proteins [111].

304

Mikhayl F. Budyka H N

H N

N

F

HN O N

F

Cl N3

O N O O O O O P O P O P O O O O OH + 4Li

Another azidopyridine derivative, 1-(2-azido-6-chloropyrid-4-yl)-3phenylurea was used as photoaffinity labeling reagent for cytokinin-binding proteins [112]. In the absence of the 6-chloro substituent, the tetrazole form was the only existing tautomer. The corresponding compound did not exhibit cytokinin activity and was not photolysable. NH-CO-NH-Ph

Cl

N

N3

7-Azido-1-ethyl-3-carboxylate-6,8-difluoroquinolone was proposed for photoaffinity labeling [113]. Photolysis of this azide with diethyl amine gave 7hydrazino-derivative as the major product. This compound was generated by singlet nitrene N-H insertion. In addition, 7-amino-1-ethyl-3-carboxylate-6,8difluoroquinolone was also obtained. O COOH

F N3 F

N C2H5

As mentioned above, most azides used at present are sensitive to hard UV radiation (250-320 nm). At the same time, in the photoaffinity modifications of biomacromolecules it is desirable to expose the system under study to soft longwavelength UV radiation (350 - 400 nm) or to visible light (which is better) in order to prevent the photodestruction of the biological material [114,115]. To this end, the azide should have an absorption band in the specified spectral region and


305

decompose with high quantum yield upon irradiation with light in this spectral region. There are a few azido dyes sensitive to short-wavelength visible light. For instance, 9-azidoacridinium has a long-wavelength absorption band in the region 400 - 470 nm and decomposes with a quantum yield of 0.7 - 1.0 upon irradiation within the band region [50]. However, this compound is readily hydrolyzed with the formation of acridone in the presence of trace amounts of water, that makes practical application of 9-azidoacridinium difficult. Ethidium azide, 3(8)-amino-8(3)-azido-5-ethyl-6-phenyl phenanthridinium, when photolyzed with visible light was found to bind effectively to the DNA of intact lymphocytes since photolysis provoked repair synthesis in these cell suspensions [116]. It attached covalently to calf thymus DNA by photoaffinity labeling and was used to generate antibodies for the drug analog [117]. 3Aminopropionyl derivatives of ethidium azide were established to have high photodissociation quantum yields of 0.6-0.9 on irradiation with visible light at wavelength up to 436 nm [118]. Dissolved oxygen did not affect the quantum yield but changed the structure of the final photolysis products. The derivatives were used for oligonucleotide photomodification [118]. O CF3 O

N H

O N H

N3

N3

N H

+

+

N

N

CF3COO-

CF3COO-

CF3 N H

O

Azido hemicyanine AHC, a derivative of azidostyrylquinoline, has longwavelength absorption band in the visible range tailing to 500 nm and high photodissociation quantum yield on irradiation within this band, and can be potentially used for photoaffinity labeling [77]. Especially promising in this respect can be fluorine-substituted in benzene ring derivatives due to property of ortho-fluorine atoms to stabilize singlet nitrene that promotes insertion of the label to target biomacromolecule [119,120].

306

Mikhayl F. Budyka

CONCLUSION Thus, heteroaromatic azides proved to be convenient objects for studying general structure-reactivity relationship in aromatic azide photochemistry. On the example of the series of cata-condensed heteroaromatic azides from azidopyridine to azidoazahexacene (the size of aromatic -system from 6 to 26 e), the size and charge effects, that is, the dependence of photodissociation quantum yield on the size of the azide -system and its charge, were investigated both quantumchemically and experimentally. These effects are interrelated: the size effect depends on the charge of the azide molecule and vice versa, the charge effect depends on the size of the azide -system. The existence of the size boundary of azide photosensitivity was predicted and substantiated. The threshold size is calculated to be 22 and 18 electrons for the neutral and positively charged azides, respectively. Under this size, the antibonding NN*-MO, which is localized on the azido group and is empty in the ground (S0) state, is filled in the excited S1 state of the azide, and the azide is photoactive ( > 0.1). After this size, aromatic -MO is filled instead of the NN*-MO

in the S1 state of the azide, and the azide becomes photoinert ( drops below 0.01). Theoretical basis was also found for experimentally observed interrelation between azide photoactivity (photodissociation quantum yield) and spectral sensitivity: both these properties are determined by the structure and energy characteristics of the frontier molecular orbitals. At the same time, the problem of relative reactivity of different azido groups in polyazidopyridines is not yet solved because of scarce data on the selective photolysis of these azides. Heterocycles are widespread in nature, and so heterocyclic azides are widely used as photoaffinity labels for exploration of nucleic acids and proteins. A progress should be also noted in the use of polyazides for photochemical production of polynitrenes, high-spin model systems for investigation of molecular magnetism. Application of polynitrenes as molecular magnets in molecular electronics is promising but questionable; the future will show a practicability of this approach.


307

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Chapter 12

PROGRESS IN THE CHEMISTRY OF CONDENSED THIAZOLOPYRIMIDINES M.A. Metwally*a and Bakr F. Abdel-Wahabb a

Chemistry Department, Faculty of Science, University of Mansoura, Mansoura, Egypt b Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt

This article covers the methods for preparing different thiazolopyrimidines, also includes their reactions in the last six years, some of which have been applied to the synthesis of biologically important compounds. The title compounds are subdivided into groups according to the position of fusion between thiazole and pyrimidine rings.

Keywords: Thiazolopyrimidines; Pyrimidine-2-thiones; Aminothiazoles; Thiourea

1. INTRODUCTION Thiazolopyrimidines and their analogues have been in the centre of attention of researchers over many years due to the high practical value of these * Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box23, Mansoura, Egypt email [email protected]

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compounds. In the fist place, the unusually broad spectrum of biological activities. Thiazolopyrimidine derivatives are the bioisosteric analogues of purines and are potentially bioactive molecules. Many derivatives with different substitution patterns display interesting pharmacological activities, such as, antiviral activity against human cytomegalovirus (HCMV) [1], anticancer activity against 60 human tumor cell lines [2], and antipsychotic activity by antagonizing the activity of the corticotrophin releasing factor [3]. In addition, dual antimicrobial and antiinflammatory activity comparable to ampicillin and indomethacin in vivo with no or minimal ulcerogenic effects [4]. Two comprehensive reviews on thiazolo[3,2a]pyrimidines have appeared the later of these covers the literature up to 2002 [5, 6]. The main purpose of this review is to present a survey of the literature of thiazolopyrimidines from 2003 to 2008; some of the commercial applications of thiazolopyrimidine derivatives are mentioned.

2. METHODS OF SYNTHESIS AND REACTIONS 2. 1. Bridgehead Nitrogen Thiazolopyrimidines Bridgedhead thiazolo[3,2-a]pyrimidines, and their isosteres occupy a unique place in medicinal chemistry due to their wide application as drug and drugintermediates [7-11]. Several methods are known for synthesis of thiazolo[3,2a]pyrimidine derivatives, from 2-mercaptopyrimidines and α-halo ketones, and by cyclocondensation of α-aminothiazoles with β-diketones, β-keto aldehydes, and their acetals, β-chlorovinyl ketones and aldehydes.

2.1.1. From 2-Mercaptopyrimidines 2.1.1.1. Reaction with Chloroacetic Acid Derivatives The reaction of dihydropyrimidine-2(1H)-thione (propylenethiourea) 1 with α-halocarboxylic acids gives only the bicyclic thiazolo[3,2-a]pyrimidine. The most convenient procedure for the synthesis of 3,4-dihydropyrimidine-2(1H)thiones (known as the Biginelli reaction) is based on one-pot three-component condensation of aldehydes with β-keto esters and thiourea. Thiazolopyrimidine derivatives (3, Scheme 1) were obtained by a simple one-pot condensation reaction of 1 and 2-bromopropionic acid (2, R3 = H, bromoacetic acid (2, R3 = H, CH3) under microwave irradiation and conventional conditions [12, 13].

Progress in the Chemistry of Condensed Thiazolopyrimidines

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Ph CHO O

H2N

R1

O R2

S H2N

Ph R1

NH S

O

NH R2 1

O

O +

OH Br R3 2

Ph

R1

O N

R2

R3 S

N

3

Sheme 1

(E)-Chalcones 4 were prepared via Claisen-Schmidt condensation of methyl ketones with different aromatic aldehydes. Cycloaddition reaction of 4 with thiourea yielded the corresponding thioxypyrimidine 5 derivatives. Compounds 5 were condensed with chloroacetic acid to yield thiazolopyrimidine 6. Also thione 5 were also condensed, in one pot reaction, with chloroacetic acid and aromatic aldehyde to yield arylmethylene derivatives 7 which could also be prepared directly by condensation of 5 with aromatic aldehydes (Scheme 2) [14-20]. El-Baih in 2004, has described the synthesis of naphtho[1,2-d]thiazolo[3,2a]pyrimidine 10 (Scheme 3), by reaction of 2-arylmethylidene-1-tetralone 8 with thiourea under basic conditions to give naphtho[1,2-d]pyrimidine 9 which then cyclized with chloroacetic acid to afford the target compound 10 [21].


320

S

S O Ar1

H2N

Ar2

HN

NH2

KOH / EtOH

NH

Ar1

4

ClCH2COOH AcOH / Ac2O

Ar2 5

H OO C 2

CH3COONa

H ClC O CH Ar 3

S

Ar3 N

N

Ar3CHO

O

Ar2

Ar1

AcOH / Ac2O Ar2

Ar1

O

N

N

S

6

CH3COONa

7 Scheme 2

S H2N

NH2

ClCH2COOH HN

NH

O S 8

9

O

N

N S 10

Scheme 3

El-Emary and Abdel-Mohsen reported the synthesis of thiazolopyrimidines 12 as depicted in Scheme 4. Equimolar quantities of 1,3-diphenyl-1H-pyrazole-4carboxaldehyde, ethyl cyanoacetate and thiourea were refluxed to yield pyrimidinethione derivative 11. This thione was cyclized to thiazolopyrimidines 12 upon reaction with chloroacetic acid and benzaldehyde [22].

Progress in the Chemistry of Condensed Thiazolopyrimidines H N

S Ph N

CHO

O

+

CN

O

N Ph

NH2

321

NH2

HN

COOEt

+ H2N Ph

S

N N Ph O

S

Cl

Ph

O

OH

11

N

NH2

N

PhCHO

COOEt

Ph N N Ph 12

Scheme 4

Mobinikhaledi et al., in 2007, achieved the synthesis of 3-oxo-2-[(Z)-1phenylmethylidene]-5H-[1,3]thiazolo[3,2-a] pyrimidine derivatives 14 (Scheme 5) in good yields by the reaction of an appropriate 3,4-dihydro-2(H)-pyrimidone 13, chloroacetic acid, sodium acetate and benzaldehyde [23]. R1 R2

NH N

AcONa +

ClCH2COOH

+

O

R1

N

PhCHO

SH

R2

13

S

N

Ph

14 Scheme 5

Abu-Zied reported the synthesis of 2-arylidine-thiazolo[2,3-d]pyrimidine3(3H),5(5H)-dione 16 (Scheme 6) by the reaction of a ternary mixture of 2thioxo-thieno[2,3-d]pyrimidin-4(4H)-one 15, chloroacetic acid, and 4chlorobenzaldehyde[24].


322 O NH S

O

CHO

N H

O

AcONa

+ ClCH2COOH +

N S

S

S

N

Cl 16

15

Cl

Scheme 6 Mohamed in 2002, reported the synthesis of thiazolopyrimidines 18 (Scheme 7), by heterocyclization of pyrimidinethione 17 with chloroacetic acid followed by condensation with aromatic aldehydes (R1 = Cl, O2N) [25]. Ph Ph COOEt

HN S

CHO +

Cl

COOH

O

+ S

N H

COOEt

N

Me

N

R1

Me

R1 17

18

Scheme 7

Djerrari et al., achieved the synthesis of thiazolopyrimidine 19 (Scheme 8) starting from acetoacetylpyrazole , thiourea followed by reaction with chloroacetic acid [26]. O

S

NH2

O

H2N S

S HN

Cl

N

COOH

O

N

N

N NH N NH

N NH 19

Scheme 8


323

4,6-Diamino-1H-pyrimidine-2-thione was coupled with aromatic aldehydes (Ar = Ph, 4-Cl-C6H4) to give the corresponding Schiff bases 20. Treatment of 20 with chloroacetic acid gave thiazolo[3,2-a]pyrimidine 21, which was condensed with p-chlorobenzaldehyde to give compound 22. Compound 22 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 23 as shown in Scheme 9 [27]. Many authors reported the synthesis of thiazolopyrimidines 25 (Ar = substituted Ph, 2-thienyl; X = O, R = H, Me) in good to high yields (Scheme 10), by heterocyclization of arylpyrimidinethiones 24 with chloroacetyl chloride or 2bromopropanoic acid [28-32]. Mobinikhaledi and Foroughifar found that thiazolopyrimidines 26 (Scheme 10) could be readily obtained in high yield by using microwave-assisted cyclocondensation reaction of multi-substituted 3,4-dihydropyrimidine-2(1H)thiones 24 with chloroacetic acid, anhydrous sodium acetate and corresponding aldehyde [33]. Ar

Ar

NH H2N

N H

N

N

NH2 ArCHO

NH N

S

N H

Cl

N N

S

20

21 Ar

Ar N

N

O

CHO N

N

S Cl

Ar

O NH N

NH2OH

N N

S

N

Ar

Ar

Cl

O

COOH

N

S Cl

Ar 23

22 Scheme 9


324

O Ar

Cl

EtOOC

Ar Cl

EtOOC

NH Me

N H

S

O

or

N

R S

N

OH Br

24

Me

O

25

ClCH2COOH, Ar`CHO AcONa, MW

Ar EtOOC H3C

O N S

N

Ar`

26 Scheme 10 When (3-(4-chlorophenyl)oxiran-2-yl)(aryl)methanone 27 (Ar = 3,4dimethylphenyl or 2-thienyl) reacted with thiourea in the presence of an alkaline medium it afforded thioxopyrimidinone derivative 28 (Scheme 11). Thiazolopyrimidine-3,6-dione derivative 29 was proven chemically via reaction of 28 with chloroacetic acid. When the latter compound condensed with pchlorobenzaldhyde, it afforded compound 30 which could be prepared directly via a one pot reaction by treating compound 28 with chloroacetic acid and pchlorobenzaldhyde [34, 35]. Bis-oxiranocycloalkanone derivatives 31 were condensed with thiourea to give the corresponding thioxopyrimidine 32. Treatment of thioxopyrimidine derivative 32 with chloroacetic acid in the presence of anhydrous sodium acetate afforded the corresponding thiazolopyrimidine derivative 33 (Scheme 12), which condensed with aromatic aldehydes in acetic acid/acetic anhydride to give arylmethylene derivative 34. Also, arylmethylene derivative 34 could be prepared by reaction of thioxopyrimidine derivatives 32 with chloroacetic acid, aromatic aldehyde, and sodium acetate in a mixture of acetic acid and acetic anhydride [36].


325

S O

S

Cl

HN

H2N

Ar

NH2

Cl

COOH

Ar

O

N

Ar

NH

N

O OH

27

O

Cl

28 Cl

S

CHO Cl 29

HOOC Cl Cl OHC Ar

N

Cl

S N

O

O

Cl 30 Scheme 11

CHO S H

O

O

S

H H2N

O

HN

NH H

NO2

HOOC

NH2 OH

OH

Cl

32

31

NO2

CHO S O HOOC

Cl

Anh. NaOAc

N

S

N H

O OH

HO

33

NO2 Anh. NaOAc Ac2O / AcOH

N

N H OH

HO 34

Scheme 12


326 Cl

Cl

O Cl + Cl

O

HN

S

EtOH

N

+ S HN

O

Cl

O

N

35 Scheme 13

(2E)-2-(2,4-Dichlorobenzylidene)-6,7-dihydro-2H-thiazolo[3,2-a]pyrimidin3(5H)-one 35 (Scheme 13) was synthesized by mixing 2,4-dichlorobenzaldehyde, ethyl chloroacetate and tetrahydropyrimidine-2-thione in ethanol [37]. 2-[(1,3-Benzodioxol-5-yl)methylene]-6,7-dihydro-5H-thiazolo[3,2a]pyrimidin-3-one 36 (Scheme 14) was synthesized by mixing 1,3-benzodioxole5-carbaldehyde, ethyl chloroacetate and tetrahydropyrimidine-2-thione in ethanol [38]. O

O +

O +

O

HN

Cl

O

O

EtOH N

S HN

H

O

O

N S 36

Scheme 14

Liu et al., reported the synthesis of ethyl 5-(2,6-dichlorophenyl)-7-methyl-2(1-naphthylmethylene)-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6carboxylate 37 (Scheme 15). The reaction of ethyl 2-mercapto-4-methyl-6-(2,6dichlorophenyl)-1,6-dihydro-pyrimidine-5-carboxylate, ethyl chloroacetate and naphaldehyde in acetic acid and acetic anhydride afforded the target molecule 37. In the molecular, the thiazolo[3,2-a]pyrimidine and naphthalene systems are essentially coplanar, with a dihedral angle between the combined plane and the mean plane of the benzene ring of the 2,6-dichlorophenyl substituent of 94.7(4)° [39].


Cl O

CHO

O

Cl + NH

O N

+ Cl

Cl O

AcOH Ac2O

O

Cl O

O

N N

SH

327

S 37

Scheme 15

Alkylation of 1-methyltetrahydropyrimidine-2(1H)-thione (Nmethylpropylenethiourea) with chloro- and bromoacetic acids and their esters gave 8-methyl-3-oxo-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-8-ium chloride or bromide 38 (Scheme 16). The former is readily hydrolyzed in 95% ethanol to 3-[(3-methylamino)propyl]-1,3-thiazolidine-2,4-dione hydrochloride 39 [40, 41].

NH N S CH3

XCHRCOOR` anhdrous acetone, 20 C

Me H N EtOH H boiling

X H N

O O

N S CH3 R

X

- R`OH

OR`

+ R`OH X

N

R

N S CH3 38

O N O

S

R

39 Scheme 16

2.1.1.2. Reaction with Dihalocompounds Thiazolopyrimidines 40 (Scheme 17) were synthesized by a simple one-pot condensation reaction of starting dihydropyrimidine-2-thione derivatives 24 and 1,2-dibromoethane in DMF [28-31]. N-(4-Chlorophenyl)-7-methyl-5-aryl-2,3-dihydro-5H-thiazolol[3,2a]pyrimidine-6-carboxamides 41 (Scheme 18) were accomplished by cyclocondensation of 1,2,3,4-tetrahydropyrimidine-2-thiones and 1,2-


328

dibromoethane, Some of these compounds exhibited significant inhibition on bacterial and fungal growth [42]. Ar EtOOC

Ar

Br

Br

NH

H3C

N H

EtOOC

DMF

S

N

H3C

S

N 40

24 Scheme 17 Cl

Cl

HN

O

+

Br

Br

Ar

HN

O

N

N

Ar

HN

NH S

S 41 Scheme 18

HO Ph

O

HO BrCH2CH2Br

HN HS

O

N N

S

S

N S 42

Scheme 19


329

Aly in 2007, has described the synthesis of thiazolopyrimidine 42 (Scheme 19) in good yield, by reaction of a mercapto-4,5-dihydropyrimidineacetic acid with 1,2-dibromoethane [43]. Aslanoglu et al. reported the cyclization of 5-benzoyl-4,6-diphenyl-1,2,3,4tetrahydro-2-thioxopyrimidine (Scheme 20) with various dibromo compounds to the thiazolopyrimidines 43 [44] O

Br

Ph

O

Br NH

Ph Ph

N H

Ph

R N

Ph

S

Ph

N

R S

43 Scheme 20

Dihydrothiazolo[3,2-a]pyrimidines 46 (Scheme 21) were obtained via S,Ntandem alkylation of 2-thiouracils 44 (R = H, R1 = NH2; R = Et, R1 = Me) with aryl 2,3-dibromopropyl sulfones 45 (Ar = phenyl, subs. phenyl, 2-naphthyl) in ethanol and potassium hydroxide[45].

O

R1

O Br

R

NH N H 44

Ar S O O

+

Br

S

O S O Ar

EtOH / KOH

45

R R1

N N

S

46 Scheme 21

Al-AlShaikh et al. reported the synthesis of thiazolopyrimidinones 48 (Scheme 22) starting from dimedone. Reaction of dimedone with aromatic aldehydes and thiourea using microwave irradition afforded 47 as the major product. Cyclization of 47 with 1,2-dichloroethane gave the target compounds 48 [12].


330

O

O

S +

ArCHO

+

H2N

Ar

MV NH2

NH

5 min

N H

O

S

47 O Cl

Ar N

Cl N

S

48 Scheme 22

Interaction between 3,4-dichloro-N-R-maleimides 49 and 2-thiouracils 50, which contain three nucleophilic centers, in mild conditions led to formation of pyrrolothiazolopyrimidinetriones 51 and 52 (Scheme 23) as a mixture of two equal isomers [R = benzyl, (un)substituted phenyl; R1 = H, Me; R2 = H, Me, Pr; R1R2 = (CH2)3] [46]

O

+

R N Cl O 49

O

O

Cl

R1

HN S

N H

R2

O , Et3N

30-40 °C

O

O

N

R2

O

O

N

R N

S

N

R1

R2

R1

+ R N

N

S O

O

50

51

52

Scheme 23

2. 1.1.3. Reaction with ω- Bromo Ketonic Compounds 3-Substituted 5H-thiazolo[3,2-a]pyrimidine derivatives 54 (R = n-propyl, 4hydroxypheyl, 4-methoxypheyl; R1 = ethoxy, methyl; Ar = subs. phenyl), are useful as acetylcholinesterase(AChE) inhibitors (Scheme 24), were synthesized by the Hantzsch-type condensation of dihydropyrimidines 53 with substituted phenacyl chlorides [47, 48].

Progress in the Chemistry of Condensed Thiazolopyrimidines R

O

O

NH

R1 H3C

N H

O X

S + Ar

O NH

AcOH R1

AcONa

H3C

R

O

R

N

H3C

S

Ar

N

R1

Ar

331

N

S

54

53

Scheme 24

Quan et al. and Wang et al. have been reported the synthesis of thiazolo[3,2a]pyrimidines 55 (Scheme 25) by treatment of 3,4-dihydropyrimidine-2-thiones 24 with bromoacetone in refluxing water [49, 50]. Ar

O EtO

O NH

H3C

N H

EtO

BrCH2COCH3 H2O / refluxing

S

Ar

O N

H3C

N H

Ar

O - H2O EtO S

CH3

N

H3C

N

S

55

24 Scheme 25

Ar HN HS

N

R4

R4 COOEt + Me R

O

O

O Br

3

R2 24

Ar

O

O

R3

S R2

O

56 57 R3

COOEt Me

R2 Ar

PPA R4

N O

N S

O 58

Scheme 26

COOEt

HN N

Me


332

Condensation of (mercapto)dihydropyrimidinecarboxylates 24 with various 3(2-bromoacetyl)coumarins 56 (R2 = H, R3 = H, Cl, Br, MeO, R4 = H, Br; R2R3 = benzo, R4 = H) followed by cyclization of the intermediate ketones 57 (Scheme 26) on heating in polyphosphoric acid (PPA) yielded oxochromenyl-substituted dihydrothiazolo[3,2-a]pyrimidinecarboxylates 58 [51]. 2H,5H,3-Bromoacetylpyrano[3,2-c]benzopyran-2,5-dione on treatment with 2-thiouracil gave 2H,5H,-3-(5'-methyl-7'-oxo-7'H-thiazolo[3',2'-a]pyrimidin-3'yl)-pyrano[3,2-c]benzopyran-2,5-dione 59 (Scheme 27) which showed significant antimicrobial activity [52]. O

O

O

O

Br + O

O

O

O

HS

N

N

HN

S

O

N

O

O 59 Scheme 27

2. 1.1.4. With Halo-Nitriles Mohamed in 2002 reported the synthesis of aminothiazolopyrimidine 60 (Scheme 29). The reaction of pyrimidinethione 17 with chloroaceteonitrile gave the desired compound 60 [25]. Reaction of 2-thiothymine 61 with bromomalononitrile produces thiazolo[3,2a]pyrimidine-2-carbonitrile derivative 62 (Scheme 29). Reacting 64 with malononitrile yielded pyrido[2',3':4,5]thiazolo[3,2-a]pyrimidine-3-carbonitrile derivative 63. [53, 54]. Ph COOEt

HN S

Ph +

ClCH2CN

H2N

COOEt

N N H

Me

S

N 60

17 Scheme 28

Me


333 NH2

NH2

O

N H

N

CN

NH + Br

S

N

O

CN

CN

CH2(CN)2 O

N H

S

62

61

CN

N

S

N H

NH2

63

Scheme 29

2.1.2. From Aminothiazoles Metwally et al., reported the synthesis of thiazolo[3,2-a]pyrimidine derivatives 65 (Scheme 30) and 66 (Z = NH, O) by the treatment of 2aminothiazole or 2-aminobenzothiazole with ketene S,S-acetals 64 (X = CONH2 or COOEt) in ethanol respectively [55]. S N N Z 66

NH2 SMe

CN

N

S X

CN

N

S

Z

NH2

CN

N MeS

SMe 64

EtOH

S

N

SMe

65

Scheme 30

Djerrari and coworkers reported the synthesis thiazolo[3,2-a]pyrimidine 67 (Scheme 31) by reaction of dehydroacetic acid with 2-aminothiazole. The mechanism of formation of the title compound involve simple condensation between NH2 and the ketone group to form imines A and B followed by rearrangement [56]. Treatment of polymer-bound methyl 2-acetylamino-3-(dimethylamino)prop2-enoate 68 with excess 2-aminothiazole in a mixture of toluene, DMF, and acetic acid at 60°C (Scheme 32) yielded the corresponding thiazolo[3,2-a]pyrimidin-6yl)acetamide 69 [57].


334

O

H

CH3

O CH3 + H 3C

O

H 2N

N

S

S H 3C

N

O

O

O

N

A

O

CH3 S

H 3C

O

O

N

S

N

CH3

N

HN

CH3 O

O

O

67

B

Scheme 31

N N +

H2N S

toluene, DMF,

NH O

O O

AcOH, 60 °C

N

S

O

N

N H

O 68

CH3

69 Scheme 32

Reactions of α,β-unsaturated ketones with aminoazole is the most favourable way to the series of natural-like partially hydrogenated azolopyrimidines [10]. Therefore, reaction of 2-aminothiazoline with α,β-unsaturated carbonyl compounds 70 under mild conditions (acetone, room temperature) gave two diastereomers 5-R-7-hydroxy-5H-tetrahydrothiazolo[2,3- a]pyrimidines 71( Scheme 33) [58]


R2

O N

acetone / rt NH2

S

+ R2

335

N

R1

OH

S

N

70

R1

71 Scheme 33

Bonacorso et al. reported that, β-alkoxyvinyl trichloromethyl ketones 72 (R 1 = H, Me,n-pr i-pr, i-Bu; R2 = H, Me) are useful building blocks for the synthesis of thiazolo[3,2-a]pyrimidin-5-ones 73 (Scheme 34) by reaction with 2aminothiazole [59]

N O

R1

Cl3C

OCH3

+ H2N

N S

R2

O

EtOH

S

HN

Cl3C

R1 R2

72

O R2

N S

N

R1

73 Scheme 34 N-Aryl-3-oxobutanethioamides 74 reacted with 2-amino-1,3-thiazole or (2amino-1,3-benzothiazole) 75 in acetic acid to give a mixture of thiazolo[3,2a]pyrimidine-5-thiones 76 and 5-arylimino-7-methyl-5H-[1,3]thiazolo[3,2a]pyrimidines 77 (Scheme 35) whose ratio depends on the nature of the aryl substituent in the initial butanethioamide [60].


336

O

R

S

N Ar + H N 2 N H

Me

S AcOH

S

N

R

Me

N

R

R N

+

S

Ar

Me

N

R S

77

76

75

74

N

R

Scheme 35

Reaction of 2-aminothiazole with 1-benzotriazol-1-yl-3-phenylpropynone in a sealed tube at 120 C in acetonitrile afforded the expected 5-phenylthiazolo[3,2a]pyrimidin-7-one 78 (Scheme 36) in 54% yield [61].

S O

S NH2

+ Ph

Bt

N

MeCN

N

O

N

120 °C

Ph 78

Scheme 36

7-Chloromethyl-6-nitro-5H-thiazolo[3,2-a]pyrimidin-5-one 79 (Scheme 37) was obtained by cyclocondensation of 2-aminothiazole with ethyl 4chloroacetoacetate [62]

S N

O NH2

+

Cl

O

N

S O Cl

N

NO2 O 79

Scheme 37


337

6,7-Dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines 82 (R1 = H, Me, Ph, 4MeOC6H4, 4-ClC6H4; R2 = H, Me) was stereoselectively prepared by cyclocondensation of 2-aminothiazoles 80 (Scheme 38) with fluorinated (gemdihydroxyalkyl)vinyl sulfones 81 (R6 = Me, Ph) [63].

SO2R6

R1 S

R2

NH2

F3C OH SO2R6 HO C C C H H

+

N R1

N

R2

CF3

S

OH 82

81

80

Scheme 38 Schiff bases of 2-aminothiazoles 84 undergo mercaptoacetylative expeditious annulation with 2-methyl-2-phenyl-1,3-oxathiolan-5-one 83 (Scheme 39) to yield substituted 6,7-dihydro-6-mercapto-5H-thiazolo/1,3,4-oxa(thia)highly diazolo[3,2-a]pyrimidin-5-ones 85 stereoselectively [64].

Ph S Me O 83

+ O

N Ar

S

Ar

N

S

MW, 8-12min

HS

N

N O 85

84

Scheme 39 One-pot reactions of glycine, acetic anhydride and thiazole Schiff bases 86 (Ar = Ph, Ar' = Ph, 4-MeOC6H4, 4-ClC6H4; Ar = 4-MeC6H4, Ar' = Ph, 4MeOC6H4, 4-ClC6H4) diastereoselectively and expeditiously annulate a pyrimidine ring on the thiazole nucleus to yield 6,7-dihydro-5H-thiazolo[3,2a]pyrimidin-5-ones 87 (same Ar, Ar') under microwave irradition (Scheme 40) and solvent-free conditions [65].


338

O H2N

+

OH

Ac2O

N +

Ar`

S N

Ar`

MW, 10-15 min Me

Ar

N

O

86

N H

S Ar

N O 87

Scheme 40

The treatment of thiazol-2-yl-N,N-dimethylimidoformamide 88 with monosubstituted ketenes such as phenyl, phenoxy, chloro, bromo, and cyano ketenes, generated, in situ, by the dropwise addition of their corresponding acid chlorides 89 in triethylamine at room temperature (Scheme 41) gave thiazolopyrimidinones 90 [66].

O R S O

N

N N

R

S

+

Cl

R1

CH2Cl2, Et3N , 0°C

N O

O 88

N

R1 89

90

Scheme 41 Condensation of 3-(2-amino-4-thiazolyl)coumarin 91 with α-acetyl-γbutyrolactone in a mixture of polyphosphoric acid and POCl3 afforded thiazolo[3,2-a]pyrimidin-5-one 92, while condensation of 91 with β-keto esters gave 7-methyl-3-(2-oxo-2H-chromen-3-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5ones 93(Scheme 42). Reaction between 91 and diethyl 2(methoxymethylene)malonate under solvent-free conditions yielded 3-(2-oxo-2Hchromen-3-yl)-5-oxo-5H[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate 94 [67].


339

O O

O

O

O O N

PPA / POCl3

Cl

S

N

92

O

O O

O

S N

R O

EtOOC O

NH2

N N

S 91

R

93

OCH3 COOEt COOEt

O O

O

O N S

OEt N

94 Scheme 42

Heating ethyl homovanilate 95 with NaH and 1-(2-chloroethyl)pyrrolidine in DMF provided arylacetate 96. Then, treatment of 96 with Bredereck’s reagent (tert-butoxy-bis-(dimethylamino)-methane) and finally heating of 97 with various


340

2-aminothiazoles using microwave gave bi-heterocyclic compounds 98 (Scheme 43) in high yields[68]. OH

O EtO

NaH, 1-(2-chloroethyl)pyrrolidine, O DMF, 80 °C, 16 h,

OCH3

O

EtO

N

OCH3

95

96 NH2

tert-butoxy-bis(dimethylamino)methane EtO (Bredereck’s reagent), 65 °C, 16 h

Ar

O

O

N

N S

OCH3 AcOH, microwave NMe2 97

O

O Ar

S

N

N

OCH3 N 98 Scheme 43

Sharma has described the synthesis of 3-(7-methyl-5-H-thiazolo-[3,2-a]pyrimidin-5-one-3-yl)-2-methylchromones 100 (Scheme 44) by condensing 3-(2aminothiazol-4-yl)-2-methylchromones 99 with ethyl acetoacetate [69]. O

R1 O R2

NH2

N

O

O

S

O

R1 R2

N

N S

O

Me

Me

O O

Me 100

99 Scheme 44

Abdel-Mohsen in 2003 reported the formation of thiazolo-[3,2-a]-pyrimidine 102 (Scheme 45). Refluxing of thiourea with 5-chloro-acetyl-8-hydroxyquinoline


341

produced 5-(2-Aminothiazol-4-yl)-8-hydroxyquinoline 101, which then reacted with ethyl aceteoacetate to give 102 [70]. OH N

NH2 S

Cl

O

O

OH

H2N H2N

EtOOC

N

N

S 101

O H3C N

OH

N

N

S

102

Scheme 45 S N

Y NH2

S

O

X COOEt

N

S

N S

103 104 R NC

R Ph N

NH2

Ph

S

N S 105

Scheme 46


342

Abdel-Hafez reported the synthesis of fused thiazolo-pyrimidines 104 (Y = NH2, OH) and thiazolo-pyrimidines 105 (R = CN, COOEt) (Scheme 46) by refluxing 103 with active methylene derivatives e.g., diethylmalonate (X = COOEt) or ethyl cyanoacetate (X = CN), or with some arylidine malonitriles (benzylidinemalononitrile (R = CN and ethylbenzylidinecyano-acetate (R = COOEt)) [71]. 4-(2-Aminothiazol-4-yl)-3-methyl-5-oxo-1-phenyl-2-pyrazoline 106 was synthesized via the reaction of 4-bromoacetyl-3-methyl-5-oxo-1-phenyl-2pyrazoline with thiourea (Scheme 47). Fusion of 106 with ethyl cyanoacetate and ethyl acetoacetate gave thiazolo[3,2-a]pyrimidin-5-ones 107 and 108 respectively[72]. Ph

S

N N

O Br Ph

N N

H2N

NH2 Ph

O

N N

S N

NH2

O

O

O

106 O fusion Ph

O

N N O

O N S

N 108

Scheme 47

O

fusion

CN

O

O N S

N 107

NH2


343

O O

NH2

O

+

+

O

S

O

N

N

H2N

O

S

N N 109

O

1- bromination N 23-

N

NH2

S

N N

CH3

O

O

NMe2

Br Cl

Br 110 Scheme 48

Thiazolopyrimidine 110, as mitotic kinesin inhibitors for treatment of cancer, was prepared by the cyclization of ethyl 5-amino-1,3-thiazole-4-carboxylate with trimethyl orthobutyrate and benzylamine to afford the [1,3]thiazolo[5,4d]pyrimidin-7(6H)-one 109 intermediate (Scheme 48), followed by bromination, amination with N,N-dimethylethylenediamine, and amidation with 4bromobenzoyl chloride gave 110 [73]. Youssef and Omar reported the synthesis of 2-thioxo-2Hpyrimido[5,4e]thiazolo[3,2-a]pyrimidine 113 from the corresponding 2-aminothiazole (Scheme 49). Therefore, 2-aminothiazole derivative 106 on reaction with benzylidenemalononitrile afforded thiazolo[3,2-a]pyrimidine-6-carbonitrile 111. The latter compound when reacted with phenyl isothiocyanate in pyridine for 6 h provided 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-(N-phenylthiourea)-7phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile 112. When the reaction mixture was refluxed for 10 h it gave the title compound 113 [74].


344

CN Ph C C H CN

CH3 N N Ph

N

NH2

O

CH3

O

CH3

PhNCS

S

6h

N

S

CN

N

HN Ph CN

N

N

106

S

HN

NH2

S

O

Ph N N

Ph N N

Ph

Ph 111

112

Ph N N O

CH3

Fusion

S

HN N

S

N Ph

N

NH Ph

113 Scheme 49

Landreau et al and El-Din have reported that, thiazole undergo the tandem [4 + 2] cycloaddition/deamination process (Scheme 50), furnishing 5H-thiazolo[3,2a]pyrimidines 114[75, 76]. N N

S N

R

N

H2C C R1 H -NHMe2

R

S N

R

114 Scheme 50

Thiazolo[3,2-a]pyrimidines 115 (Scheme 51) were obtained by fusion of 6aryl-3-cyano-4-methylthio-2H-pyran-2-one with 2-aminothiazole at 100–130°C. The reaction is possibly initiated by attack of the nitrogen nucleophile on the highly vulnerable electrophilic center C6, followed by decarboxylation and ring opening. The ring opened intermediate thus generated in situ re-cyclizes involving C4 of the pyran ring and the ring nitrogen of 2a or 2b, followed by the elimination of methyl mercaptan to yield [7-arylthiazolo[3,2-a]pyrimidin-5ylidene]acetonitrile 115 [77].


345

O SCH3 CN

O N

+ Ar

O

H2N

O

H C N

MeS

- CO2

NH

S

Ar

N S

NC N

SMe

C Ar

N H

SMe

N

N S

N

N

C

Ar

N S Ar

S

N 115

Scheme 51

2.1.3. Miscellaneous Methods Reaction of cycloalkenyl-1-diazenes 116 with tetrahydropyrimidine-2-thione (Scheme 52) in methanol at room temperature give thiazolo[3,2-a]pyrimidine]2,3`-dione- 2-semicarbazones 118 via the intermediate 117 [78] O

S COOEt n(H2C) N

HN

N

n(H2C)

HN

NH

EtOOC S

NH2 MeOH, r.t.

n(H2C)

O

N

N H N

117

116

N

N NH NH2

O

N S

O

NH2

118

Scheme 52

Intramolecular cyclization of 1-allyl- and 1-methallyl-6-amino-2-thiouracils 119 by heating using 48% HBr at 120 °С for 2 h, afforded 5-amino-2,3-


346

dihydrothiazolo[3,2-a]pyrimidin-4-ones 120 in high yields (Scheme 53). While bromination of 119 with two equivalent of bromine gave 5-amino-6bromothiazolopyrimidinones 121 in good to high yields [79]. O N

HN

2Br2 N

S

O

O Br NH2

S

R H2C Br 121

N

HBr

N NH2 H2C C CH2 R

N

S

NH2

R CH3

119

120

Scheme 53

Thiazolo [3,2-c]pyrimidine-5,7-diones 123 (R1 = R2 = R3= H, CH3; R4 = H, CH3) were prepared by reaction of N-(chlorocarbonyl) isocyanate with 2alkylthiazolines 122 (Scheme 54) in acetonitrile containing triethyl amine [80].

R4 N R1

S

R2 R3

Cl

N O

C

N

C

O R4

O

Et3N, CH3CN

O N R1 R2

S R3

HN

O C

O N R1 R2

R4 S R3

123

122 Scheme 54

Cycloaddition reaction of dimethylpyrimidinesulfenyl chloride 124 with ptolylacetylene gave thiazolopyrimidinium salt 125 (Scheme 55) in 89% yield [81].


347

CH3

Me

CH C

Me N

CH3 N

+

N

H3C

SCl

S

N

Me 124

125

Scheme 55 5-{[(2,3-Difluorophenyl)methyl]thio}-7-{[(1S,2S)-2-hydroxy-1(hydroxymethyl)propyl]amino}thiazolo[4,5-d]pyrimidin-2(3H)-one 126 (Scheme 56) which are useful for treating a chemokine mediated diseases such as asthma, allergic rhinitis, COPD, inflammatory bowel disease, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis, cancer, etc., was prepared in a 7-step process, starting from 4-amino-6-hydroxy-2-mercaptopyrimidine and 2,3-difluorobenzyl bromide [82]. OH

NH2

Br

N +

HS N

OH

HN F

S

N

O F

OH

N H

N

F S

F

126 Scheme 56

2,3-Dihydrothiazolo[3,2-a]pyrimidin-5-ones 127 (Scheme 57) were prepared in a one-step reaction based on a Michael-type tandem reaction, by heating 2thiobarbituric acid with ethyl 4-bromocrotonate in ethanol at 60 for 2 h, a 2,3dihydrothiazolo[3,2-a]pyrimidin-5-one was obtained in 73% yield [83].


348 O NH

+

COOEt N

O

S

N H

O

O

O

Br

HO

S

N 127

Scheme 57

A series of thiuronium salts 129 (Scheme 58), which exhibited antimicrobial activities, were synthesized in high yields via the interaction of equimolar amounts of 2-bromothiadiazolopyrimidine with thioamides 128 (R = NH2, NHNH2, CSNH2, NHNHCSNH2) for 2 – 3 h in boiling ethanol [84]. O

O N

H3C

N

R

N S

+

EtOH

S NH2

Br

N

boiling

H3C

N

N

S

NH

.HBr R

S

129

128

Scheme 58

Condensation of 5-amino-3,7-dihydro-3,7-dioxo-2H-thiazolo[3,2a]pyrimidine-6-carbonitrile 130 with phenylisothiocyanate or thiourea (Scheme 59) afforded 7-thioxopyrimido[6,5-d]thiazolo[2,3-b]pyrimidines 131 and 132 respectively[85]. S O

HN

N

N S

NH N 130

O

S

S

Ph

NH2

O H2N

NH2

CN

N S

PhNCS

O

HN

N

N N

O

131 Scheme 59

S

NH2 N 132

O


349

2.2. Thiazolo[3,2-c]Pyrimidines 2-(4-Phenyl-3H-thiazol-2-ylidene)malononitrile 133, was obtained by cyclocondensation of 1-phenyl-2-thiocyanatoethanone with malononitrile, on the reaction with thiourea or guanidine (Scheme 60) led to the formation of thiazolo[3,2-c]pyrimidine 134[86]. Ph O

SCN

NC

H2N CN

NH2

CN

+

S CN

X

NH Ph 133

X = S, NH

S NC

N

X N

NH2 134

Scheme 60

2.3. Thiazolo[4,5-d]Pyrimidines The synthesis of thiazolo[4,5-d]pyrimidines has been successfully accomplished by various methods. 4-Amino-5-ethoxycarbonylthiazole derivative has been cyclized to thiazolo[4,5-d]pyrimidine by its reaction with phenyl isothiocyanate [87]. Many 4-amino-5-carbamoylthiazole derivatives have been cyclized to the corresponding thiazolo[4,5-d]pyrimidines using triethyl orthoformate/acetic anhydride mixture [88-91]. Moreover, 4-amino-5-cyano thiazoles have been used to prepare the same fused ring system via their reaction with triethyl orthoformate, followed by treatment of the intermediate with hydrogen sulfide, guanidine, amines, and isothiocyanates [92, 93]. Other thiazolo[4,5-d]pyrimidines have been obtained from 4-amino-5-cyano, carbamoyl, or ethoxycarbonyl thiazoles via cyclization with acetic anhydride [94] or formic acid [95]. Akbari et al., have described the synthesis of 7-aryl-5-thioxo-4,5,6,7tetrahydro-3H-thiazolo[4,5-d]pyrimidin-2-ones 135 (Scheme 61) by the reaction of 2,4-thiazolidine, thiourea and different aromatic aldehydes [75, 81]


350

Ar HN

S

S

+

ArCHO

H2N

O

S

+

NH

O

NH2

N H

N H

S

135

Scheme 61

Fluorinated spiro[indole-3,2'-thiazolo[4,5-d]pyrimidines] 137 was prepared (Scheme 62) from the reaction of arylidene fluoro spiro thiazolidines 136 and thiourea under monomode microwave reactor [96]. R2

H N

R2

S

S H2N

O S

S

N

MW

N O

R

NH

NH2

R1

O R

N H

R1

N H 137

136 Scheme 62

Microwave-assisted condensation of arylidenerhodanines with arylthioureas (Scheme 63) gave 3,4-diaryl-2-thioxo-6-thioxo-1,2,3,4,6,7hexahydrothiazolo[4,5-d]pyrimidines 138 [R = H, OMe; R1 = H, Br, Cl, OMe] [97].


351

R R R1 R1 S S

S

MW

+ N H

NH2

O

N H

N

S S

N H

N H

S

138 Scheme 63 5-(Alkylamino)-6-aryl-3-phenyl-2-thioxo-2,3-dihydrothiazolo[4,5d]pyrimidin-7(6H)-ones (I; R = alkyl, substituted benzyl; R1 = H, F) 141 were easily synthesized via a tandem aza-Wittig reaction. Treatment of iminophosphorane 139 with aromatic isocyanates gave carbodiimides 140 (same R1), which reacted with fluoro-substituted alkylamines to provide the title compounds 141 (Scheme 64) in 65-87% isolated yields using sodium ethoxide as catalyst [98]. Ph N

N

S S

PPh3

Ph N

ArNCO

N C NAr

S S

COOEt

COOEt

RNH2

Ph N S S

NHR N C

NHAr

COOEt

140

139

Ph N

EtONa / EtOH

N

S

NHR N

S

Ar

O 141 Scheme 64

The reaction of 2-(dialkylamino)-1,3-thiazol-4-amines with aryl isocyanates, led to the formation of thiazolopyrimidinediones 142 (Scheme 65) in good to high yields [99].


352

O R

S

R

N R

+

N

S

N

N

R`NCO

NH2

N

R

N H 142

R` O

Scheme 65 Thiazolopyrimidines 144 was prepared, as chemokine receptor modulators, by reacting 3-bromopropanoic acid with 2-amino-5{[(2fluorophenyl)methyl]thio}thiazolo[4,5-d]pyrimidin-7(4H)-one 143 (Scheme 66) in the presence of (iso-Pr)2NEt and NaI in DMF [100]. COOH

F

F

HO OH

N S

S N H2N

O

+

O

Br

(iso-Pr)2NEt

N

NaI / DMF

N

S

S N H2N

N 144

143 Scheme 66

5,7-Disubstituted thiazolo[4,5-d]pyrimidin-2(3H)-ones 146 (Scheme 67), which used as chemokine CX3CR1 receptor antagonists, were obtained by reaction of (2R)-2-[(2-amino-5-mercaptothiazolo[4,5-d]pyrimidin-7-yl)amino]-4methylpentan-1-ol 145 with (1-bromoethyl)benzene [101].


Br HN S N

+

S

N

N

O

N

H2N

OH

HN

OH

N H

SH

353

N

S

146

145 Scheme 67

(2R)-2-[(2-Amino-5-mercaptothiazolo[4,5-d]pyrimidin-7-yl)amino]-4methylpentan-4-ol 145 was coupled with (1-chloropropyl)benzene (Scheme 68) to give (2R)-2-[[2-amino-5-[(1-phenylpropyl)thio]thiazolo[4,5-d]pyrimidin-7yl]amino]-4-methylpentan-1-ol 147, which used as chemokine CX3CR1 receptor antagonists [102].

OH

HN S N

+

Cl

S N

N

N

H2N

N

H2N

OH

HN

SH

145

N

S

147 Scheme 68

Thiazolopyrimidine 148, useful for treating a chemokine mediated disease such as psoriasis, rheumatoid arthritis, and COPD, were prepared a 5-step synthesis (Scheme 69), starting from 2-amino-5,6-dihydro-5-thioxothiazolo[4,5d]pyrimidin-7(4H)-one and 2,3-difluorobenzyl bromide [103].


354

OH O S

Br NH

H2N N

N H

F

+

H3C

F

NH

S

F

S

F

N

S N H

N

S

148 Scheme 69

Thiazolo[4,5-d]pyrimidinyldiamine 149, are useful for the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease and pain, was prepared by reacting 5-phenylmethylthio-7-chlorothiazolo[4,5-d]pyrimidin-2ylamine (Scheme 70) with DL-2-amino-3-methyl-1-butanol in THF [104]. OH Cl N N H2N

THF S

S N

+

HN N

H2N OH

S

S N H2N

N 149

Scheme 70

Substituted thiazolo[4,5-d]pyrimidines 153 (Scheme 71), which are antagonists of the human CXCR2 receptor, were prepared via the application of tandem displacement reaction. Diazotisation of 150 with iso-amyl nitrite in the presence of bromoform at 50 °C afforded 151. This intermediate was treated with an array of amines at room temperature affording the mono-substituted intermediates 152 efficiently. After an hour, a second set of amines was added and the temperature increased to 100 °C to give the title compounds 153 [105].

Progress in the Chemistry of Condensed Thiazolopyrimidines Cl S N

Cl S

N

H2N

355

N

CHBr3

S

N

Br N

iso-amylnitrite, CH3CN, 50°C

N

S

F

F F

150

F

151

R3

Cl R1R2NH (rt), Et3N

R1 N R2

S

R3R4NH 100 °C

N

N

N

S

R1 N R2

N

S

R4 N

N

S

N

F

F 152

F

F

153

Scheme 71

CH3 CH3 Ph N N Ph N

O

O

H + H2N N H

N H

EtOH

CN

Reflux

N H

S / TEA

Ph N

CN

154

CH3

ArNCS

O

N

CH3

N HC(OEt)3 Ac2O

H O

N N H

S

H2N

N Ar

N Ph N

H N

S

O S

N

S N

155

156 Scheme 72

N Ar


356

N-[3-(4-Methylphenyl)-1-phenyl-1H-pyrazol-4-methylidene]-cyanoacetic acid hydrazide 154; was synthesised in an excellent yield by condensing 3-(4methylphenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde with cyano-acetic acid hydrazide. This intermediate was converted to the 4-amino-3-aryl-5-[3-(4methylphenyl)-1-phenyl-1H-pyrazol-4-methylidenehydrazinocarbonyl]-thiazole2(3H)-thiones 155 (Scheme 72), following the method described by Gewald, it involved the reaction of the cyanoacetic acid hydrazide derivative 154 with sulphur and the appropriate aryl isothiocyanate in the presence of triethylamine as a basic catalyst. Cyclisation of 145 to the 3-aryl-6-[3-(4-methylphenyl)-1-phenyl1H-pyrazol-4-methylideneamino]-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin7(6H)-ones 156 was achieved by heating the former with a mixture of triethyl orthoformate and acetic anhydride (1:1) [4]. 4-Amino-3-aryl-2-[3-(4-methylphenyl)-1-phenyl-1H-pyrazol-4methylidenehydrazono]-2,3-dihydrothiazole-5-carboxamides 157 (Scheme 73) were obtained in excellent yields by condensing the pyrazole aldehyde with the 4amino-3-aryl-2-hydrazono-2,3-dihydrothiazole-5-carboxamides . In an analogous fashion, compounds 157 were utilised to synthesise the thiazolo[4,5d]pyrimidines 158. [4] CH3 CH3 N Ph N

O H2N N

+

S

H

NH2

N

NH2

Ar

O

Ac2O

Ph N

N

O H

NH

S

N N

N Ar

158 Scheme 73

N O H S

N N

N Ar

157

CH3

HC(OEt)3

Ph N

N

NH2 NH2


357

7-Chloro-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thione 160 (Scheme 74), was prepared by reacting cyanoacetamide, sulphur, and phenylisothiocyanate in the presence of triethylamine, according to the procedure reported by Gewald [106] to give 4-amino-5-carbamoyl-3-phenylthiazole-2(3H)thione 159. Cyclization of this amino amide by heating under reflux in acetic anhydride followed by treatment of the product with phosphorous oxychloride gave the required chloro derivative 161 in good yield. Nucleophilic substitution of the chlorine atom by reaction of 161 with the appropriate amine in boiling dry acetone gave 7-(substituted amino)-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine2(3H)-thiones 162 [107]. H3C

H2N NC O

NH2 + S +

Ph

PhNCS O

N

N

H2N

Ac2O S

S

O

159 H3C Ph

N Cl

N S

S

160

H3C

N POCl3

Ph

HN

N S

S

R2NH

N

Ph

N

N

Acetone R2N

S

S

162

161 Scheme 74

4-Amino-3-benzyl-5-cyano-2,3-dihydrothiazol-2-thione 163 was reacted with triethyl orthoacetate in acetic anhydride to yield 3-benzyl-5- cyano-4-(aethoxyethylideneamino)thiazolin-2-thione 164 (Scheme 75). Subsequently, the latter was cyclocondensed with hydrazine hydrate to afford 6-amino-3-benzyl-7imino-5-methyl-2,3,6,7-tetrahydrothiazolo[4,5-d]pyrimidin-2-thione 165 [108]


358

Ph Ph N S

Ph NH2

HC(OEt)3

N S

Ac2O

CN

S

N

OC2H5

N

N S

N2H4

CH3 N

S

CN

S

163

CH3

NH2

NH

164

165

Scheme 75

2-Morpholino- and 2-pyrrolidino-5-bromo-4-pyrimidinamine 156 (R2 = morpholine or pyrrolidine) were successfully reacted with various isothiocyanates (Scheme 76) in the presence of NaNH2 in DMF to form thiazolo[4,5d]pyrimidines 157 [109].

NH2 R2N

Br

H N

N

RNCS / NaNH2 / DMF R2N

N

N

N 166

R N

S 167

Scheme 76 3-Alkyl-6-(2-aryl-2-oxoethyl)-7-oxothiazolo[4,5-d]pyrimidine-2(3H)-thione derivatives 169 (R = Me, Et; R1 = H, Me, MeO, Cl) were prepared by alkylation of thiazolopyrimidinethiones 168 (Scheme 77) with phenacyl bromides [110]

O

S

HN

S N

O

O

O

N R

S

N

Br

S N

+ R1

R1

169

168 Scheme 77

N R


359

Baxter et al. described the production of alkylthiothiazolopyrimidines 172 (Scheme 78). Alkylation of 6-aminothiouracil gave 170, thiocyanation of 170 produced 171. Cyclization of the latter compound gave the title product 172[111]. OH

OH RBr, NaOH, EtOH

N H2N

N

N

H2N

SH

OH 1) KSCN, pyridine, DMF,

N

S

R

NC

S

N

2) Br2, 5 °C H2N

N

170

S

R

171

OH DMF, H2O

S

H2N

N

N N

S

R

172 Scheme 78

Successive condensation of 7-chloro-2-(methylsulfanyl)thiazolo[4,5d]pyrimidine 173 with 3-chloro-4-fluoroaniline and N,Ndimethylethylenediamine gave thiazolopyrimidine 174 (Scheme 79) which used as antagonists of CCR2b receptors for the treatment of chemokine-mediated diseases [112]. F Cl S

N

S N

HN

F

N

+

+ Cl

N

S

NH2

Cl N

HN

NH2

N

N

N 173

174 Scheme 79

When 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin2(3H)-one 175 and p-TsOH in PhMe at 60C was treated with 3,4-dihydropyran and heated with THF, Na2CO3, and D-alaninol afforded 5-[[(2,3difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-


360

(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2(3H)-one 176 (Scheme 80).Treatment of the latter with MeCN/H2O/THF at 65°C and 1N HCl yielded 5[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one 177 [113]. HO Cl S

N

O N H

HN

N

F

1- p-TsOH , PhMe, 60 C

F

S

O

175

2- aq. NaHCO3 / THF NH2 HO

S

N

O N

N

F S

F

O 176

HO F

F

HN

MeCN/H2O/THF

N S

S

HCl

N O

N H 177 Scheme 80

Condensation of p-bis(2-iminothiazolidin-4-one-N2-yl)biphenyl 178 (R1 = H; X = CH2) with ω-bromoalkoxyphthalimides (n = 2-4; Phth = phthalimido) gave the corresponding alkoxyphthalimide derivative 179. The latter were condensed at the reactive methylene group of the thiazolidinone ring with aromatic aldehydes (R2 = Ph, 4-HOC6H4, 4-MeOC6H4) to give p-bis(3-n-alkoxyphthalimido-5arylidene-2-iminothiazolidin-4-one-N2 -yl)biphenyls 180 (Scheme 81). The titled compounds 181 [R2 = Ph, 4-HOC6H4, 4-MeOC6H4] were synthesized by heterocyclization of 180 with urea in the presence of anhydrous sodium acetate in acetic acid medium [114].


H N O

Phth n(H2C) O N N

O

N O

361

O

PhthO(CH2)nBr

S

N

S

N

S

S

N n(H2C)

N H 178

Phth O n(H2C) N N

O

S

N S

R2

H2N R2

N n(H2C)

179

S

O

R2CHO

O Phth

NH2

Anh. NaOAc / AcOH

O Phth

180

Phth O n(H2C) N N

HO N N R2

N

OH N

S

N n(H2C)

N

S R2 O Phth 181

Scheme 81

4-Amino-5-carboxamido-2,3-dihydrothiazole-2-thione 182 (Scheme 82) was prepared form cyanoacetamide, sulphur and 4-fluorophenyl isothiocyanateisothiocyanate according to the procedure reported by Gewald. This compound was cyclized to the thiazolo[4,5-d]pyrimidine 183 using a triethylorthoformate/acetic anhydride mixture as described [84]. 7Mercaptothiazolo[4,5-d]pyrimidine 184 was obtained through reaction of 183


362

with phosphorus pentasulphide, to obtain 7-fluorobenzylthio derivatives 185 (X = H, F) [115]. F

F H2N

NH2 NC

S O +

+

N

H2N O

N C S

HC(OEt)3 S

S

F 182

F

Br

F

X

N

S

N N

S

HN

S

N

P2S5

N

N S

N

F

N S

S

S

O

SH

183

184

X

F 185

Scheme 82

3-Aryl-6-substituted thiazolopyrimidin-2(3H)-thione derivsatives 187 (R = H, Me, MeO or Cl) and 188 (Scheme 83), have been synthesized by reacting thiazolopyrimidines 186 with ω-bromoacetophenones or 2-chloro-N-(2thiazolyl)acetamides [116].


O

R

N

186

R1 R2

S

1

R 2

S

O NH

S N

N

187

Cl

Cl

R

S

N

S N

O

Br

S

HN

S

R

O

O

363

S N

H N

Cl

O

Cl N N

N

N O 188

Scheme 83

2.4. Thiazolo[5,4-D]Pyrimidines 6-{[(1-Chloro-3,4-dihydronaphthalene-2-yl)methylene]amino}-1-phenyl-2thioxo-1,6- dihydro[1,3]thiazolo[5,4-d]pyrimidin-7(2H)-one, which considered as a 7-thia analogue of the natural purine bases, adenine and guanine, was prepared in an excellent yield by condensing 189 with cyanoacetic acid hydrazide followed by Gewald reaction, by reaction of 190 with sulfur and phenyl isothiocyanate in the presence of triethylamine as a basic catalyst to give 191(Scheme 84). Thiazolo[5,4-d]pyrimidinone derivative 192 was prepared by heating 191 with a mixture of triethylorthoformate and acetic anhydride (1:1) [117].


364

Cl

Cl

O

CHO

CN EtOH

+ H2N N

N

H N

CN O

H

S, PhNCS DMF / Et3N

190

189

H2N

Cl N

S

H N

N Ph

O

Cl S Ac O /( EtO) CH 2 3

N

N

S

O

N Ph

S

N

192

191 Scheme 84

S R1 CHO

H2N

OH NH2

R1

S HN NH2

H+

H R1

S

- H2 O

N H

NH2 193

R N

R N

- H+

S

O

R N

R N S

R1

S N H

NH2

O

- H2 O

R

R N

R1

S

N

NH

N

SH

194 Scheme 85

The synthesis of thiazolo[5,4-d]pyrimidines 194 can be achieved from different 5-thiazolidinones, 2-butyl-1H-imidazole-5-carbaldehyde, and thiourea using microwave irradition within 5 min in the presence of HCl. These reactions study the Biginelli condensation reaction, in which the condensation between an aldehyde and urea has some similarities to the Mannich condensation. The generated iminium intermediate 193 (Scheme 85) acts as an electrophile for


365

condensation with the amino group of urea in acidic medium and they were exposed to microwave irradiation for completion of the reaction [118]. 5-Amino-2-(methylthio)thiazole-4-carboxylic acid ethyl ester 195 reacted with benzoyl isothiocyanate (Scheme 86) to furnish thiazolo[5,4-d]pyrimidine-2one 196 [119].

H2N EtO O

H N

S S

N

+ S

PhCONCS

Ph

CH3

S

N O

195

CH3

S N

O 196

Scheme 86 2-Amino-7-chlorothiazolo[5,4-d]pyrimidines 197 (R = Ph, 2,6-Me2C6H3, 4MeC6H4, 4-MeOC6H4, 3-F3CC6H4, 4-O2NC6H4, 3-pyridinyl) were prepared, in good to excellent yields, in single-step process by reaction of 4,6-dichloro-5aminopyrimidine with isothiocyanates (Scheme 87). The utility of intermediates 197 was demonstrated by reaction with alkyl or arylamine nucleophiles to afford differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines 198 [120]. N

Cl + R1NCS NH2

N Cl

N

base N

S N

Cl 197

R1 NH

N

S

N acid or base MW HN

N

R2NH2

R1 NH

R2 198

Scheme 87

Reacting 2-(4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl)thiazolo[5,4d]pyrimidin-7-amine 199 with 3-fluorophenyl isocyanate in THF afforded thiazolo[5,4-d]pyrimidine 200 (Scheme 88) in high yield which act as inhibitors of Tie-2 receptor tyrosine kinase (TEK) [121].


366

F

O HN

H2N NH2 N

NH

N N S CH3 199

NH2 +

N

F

N

C

O N

N N S CH3

N

N N

200 Scheme 88

3. MEDICINAL APPLICATIONS 8-Methyl-5,7-dioxo-6-[4-(2H-tetrazol-5-yl)benzyl]-6,7-dihydro-5Hthiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide 201 is useful for treating cancer or arthritis [122].

O N H F

S N

O N

O

N NH N N

201 5,7-Disubstituted [1,3]thiazolo[4,5]pyrimidin-2(3H)-amines such as 202, which are CX3CR1 receptor antagonists and are thereby particularly useful in the


367

treatment or prophylaxis of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain [123] Me Me OH

HN S

N

H2N N

N

Me S N

F

202

[(Pyridinyl)ethyl]thio[(hydroxymethyl)alkyl]amino[1,3]thiazolo[4,5d]pyrimidinone derivatives such as 203 are disclosed as therapeutic agents of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain [124].

Me Me OH

HN S

N

O N H

N

Me S N

Cl

203 Thiazolopyrimidine derivatives such as 204 was disclosed as modulators of transient receptor potential vanilloid receptor 1 (TRPV1) and should prove useful in pharmaceutical components and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease [125].

368


N

S Cl

HN

N

N Cl

HN CF3

204 5-Amino-3-(2',3'-di-O-acetyl--D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin2-one 205 has immunomodulatory activity [126, 127].

O O

O

OH O H2N

O

N

N O

N

S 205

Thiazolo[4,5-d]pyrimidine derivatives e.g. 206 are prepared as inhibitors of ATP-protein kinase interactions [128].

N

CN HN S N H

N 206

N N


369

2-Substituted-4-aminothiazolo[4,5-d]pyrimidines such as 207 (X = OH, NH2, OCH3, Cl; A = O, S, SO and SO2) are useful as CX3CR1 chemokine receptor antagonists [129].

OH

HN S

N

X N

F

N

F

A

207 N-Thiazolopyrimidinyl- and/or N-thiazolopyridinylurea derivatives 208 are active as adenosine A2B receptor antagonists and useful in the treatment of type 2 diabetes, diabetic retinopathy, asthma and diarrhea [130].

MeO

H N

N S

N

N

NH F

O

N

CF3 208

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INDEX

A absorption coefficient, 255, 263, 279 absorption spectra, 234, 253, 255, 278, 279, 286, 314 absorption spectroscopy, 288 acceptor, 62, 303 accuracy, 191, 300 acetate, 49, 59, 62, 81, 153, 191, 192 acetic acid, 56, 57, 60, 62, 74, 81, 93, 111, 113, 114, 153, 159, 204, 207 acetone, 22, 74, 75, 110, 113, 114, 115, 173, 177, 180, 181, 188, 191, 192, 193, 194, 206, 208, 222, 223, 231 acetonitrile, 5, 6, 7, 9, 12, 16, 72, 79, 82, 83, 234, 240, 254, 255, 257, 258, 280 acetylation, 100, 108, 109, 110, 204 acidic, 27, 262 acidity, 59, 261, 264, 311 actinomycetes, 197, 200 activation, 11, 12, 13, 32, 63, 238, 239, 241, 243, 277, 282, 292, 293, 297 activation energy, 238, 239, 241, 243, 277, 282, 292, 293 activity level, 197 acylation, 15, 74, 78, 201, 203 adamantane, 47, 48, 52, 57, 59, 60, 61, 64, 66, 67, 69, 71, 84, 86, 88, 89, 90, 95, 97, 220 additives, 225

adducts, 156, 216, 303, 315 adenine, 314 adenocarcinoma, 163 adenosine, 2, 4, 20, 30, 43, 314 adiabatic, 256, 275, 276 ADP, 302, 314 adsorption, 139 adult respiratory distress syndrome, 29 agar, 197 ageing, 168 agent, 30, 32, 151, 165 agents, 2, 29, 30, 93, 96, 121, 162, 169, 172, 196 aggregation, 165, 169, 170 aging, 168 agonist, 4, 169 agriculture, 2, 48 air, 286 alanine, 90 alcohol, 51, 55, 66, 69, 70, 71, 73, 112, 157 alcohols, 5, 232, 308 aldehydes, 5, 193, 194, 204 alicyclic, 14, 84, 92, 97 alkali, 106 alkaline, 70 alkalinity, 59 alkaloids, 91, 148

378

Index

alkenes, xi, 211, 212, 213, 214, 215 alkylation, 60, 62, 65, 72, 73, 76, 78, 79, 151, 159, 173, 185, 225, 227, 238, 240, 268 alkylation reactions, 185 allergy, 83, 96 allosteric, 2, 4, 30 alternative, xi, 35, 99, 120, 128, 129, 133, 172, 212 aluminium, 177 aluminum, 76, 112 aluminum oxide, 112 Alzheimer's disease, 148 amide, 51, 83, 92, 93, 174, 205 amine, 7, 8, 9, 74, 151, 176, 201, 203, 204, 206, 207, 220, 259, 287, 288, 304 amines, 5, 11, 95, 119, 136, 258, 287, 303 amino acid, 302, 311, 314 amino groups, 122, 130, 134, 171, 173 ammonia, 49, 52, 71, 72 ammonium, 14, 59, 185 ammonium salts, 14 analgesic, 172 analog, 220, 305 anesthetics, 172 angiotensin II, 90 aniline, 89, 110, 205 antagonist, 32, 90 antagonists, 2, 4, 32, 60, 90, 91, 170 anthracene, 139, 283 antibacterial, 31, 32, 148, 168, 169 antibacterial agents, 31 antibiotic, 100 antibonding, 226, 238, 265, 267, 270, 284, 306 anti-cancer, 96 anticonvulsants, 172 antidepressant, 53 antidepressants, 172 antihypertensive agents, 169 anti-inflammatory agents, 2 antineoplastic, 30 antineoplastic agents, 30 antioxidant, 2 antitumor, 30, 85, 162 anti-tumor, 24

anti-tumor, 163 antitumor agent, 162 antiviral, 48, 51, 52, 68, 71, 73, 89 APA, 244, 259, 260, 261, 262, 263, 264, 265, 266, 275, 290 apoptosis, 80, 96 aqueous solution, 160, 185 argon, 82, 244, 296, 300, 310, 314 aromatic compounds, 277 aromatic rings, 229, 267, 275, 276, 277, 283 Arrhenius equation, 293 arthritis, 29, 60 Aspergillus niger, 197 assignment, 175, 257, 296 asthma, 83 atherosclerosis, 31 atmospheric pressure, 71 atomic orbitals, 238, 252, 272 atoms, 11, 88, 107, 108, 120, 121, 124, 125, 136, 140, 147, 148, 172, 174, 175, 225, 236, 237, 238, 241, 245, 247, 250, 252, 258, 259, 268, 292, 293, 294, 298, 299, 305, 313 ATP, 302, 314 ATPase, 314 attachment, 81, 99, 101, 148, 155, 156 availability, 2, 5, 23 azacrown ethers, 120 azo dye, 35, 36 azurophilic, 29

B Bacillus, 198 Bacillus subtilis, 196, 197 back, 148 bacteria, 2, 164, 183, 196, 197 bacterial, 48 bacterial infection, 48 bacterium, 221 barbiturates, 76, 94 barrier, 232, 236, 238, 249, 250, 292, 293, 297, 309 barriers, 236, 249 basicity, 120, 240, 262

Index behavior, 23, 233, 257, 271, 284, 299 bending, 238, 252, 270, 272 benefits, 15, 18 benzodiazepine, 148, 164, 168, 169 benzodiazepines, 172, 231, 308 binding, 302, 303, 304, 311, 314, 315 bioactive compounds, 162 biochemistry, 1 biological activity, 27, 88, 91, 100, 107, 133, 159, 162, 185, 200, 219, 220, 315 biological systems, 302 biologically active compounds, 48, 86, 88, 100, 110, 121, 220 biomacromolecules, 230, 302, 304 biomolecules, 159, 160 blocks, 26, 302 blood, 31, 32, 165, 169 blood clot, 31 blood glucose, 32 boiling, 49, 51, 60, 62, 66, 70, 71, 74, 105, 111, 112, 152, 153, 154, 156, 157, 159, 203, 204 bonding, 174, 175, 250, 309 bonds, 140, 237, 247, 250, 267, 278 bovine, 302, 314 brain, 84 broad spectrum, 47, 220 bromide, 94 bromination, 22, 60, 64 bromine, 20, 60, 64, 74, 122, 125, 130, 138 buffer, 69, 303 building blocks, 26, 302 by-products, 122, 125, 127, 130, 136, 138, 142, 171, 173

C cabbage, 197 calcium, 82, 86, 152 calf, 305 calixarenes, 121 cancer, 80, 84, 96, 197 cancer cells, 80 Candida, 196, 198 carbenes, 79, 81, 82, 96

379

carbon, 11, 54, 90, 121, 174, 177 carbon atoms, 121, 174 carbon monoxide, 54, 90 carbonyl groups, 120, 159 carboxylates, 29 carboxylic, 15, 17, 18, 52, 53, 59, 66, 69, 71, 80, 85, 151, 153, 154, 164, 167, 168, 169, 201, 220 carboxylic acids, 15, 18, 85, 151, 168, 169 carrier, 302, 314 catalysis, 185 catalyst, 6, 14, 17, 74, 92, 125, 126, 133, 185 catalytic system, 122, 125, 127, 133 cathode, 11 cation, 237, 238, 240, 250, 251, 252, 255, 259, 261, 263, 264, 265, 266, 268, 275, 283, 284, 285, 286, 289, 292 cell, 48, 305 cervical cancer, 80 cesium, 134, 139 CH3COOH, 203 chemical industry, 88 chemical properties, 64, 148, 159 chemotherapy, 196 chicken, 52, 71 chiral, 121 chloride, 20, 51, 65, 70, 74, 76, 89, 107, 149, 151, 152, 191, 192, 193, 202, 212, 215, 220, 282 chlorine, 64, 140, 149, 287, 298, 299 chloroanhydrides, 202 chloroform, 65, 68, 69, 72, 76, 205, 228, 261 cholecystokinin, 91 chromatography, 124, 125, 177, 178, 180, 204 chronic obstructive pulmonary disease, 60 classes, 79, 81 classical, 16, 149 classification, 254 cleavage, 15, 27, 172, 277 closure, xi, 6, 7, 10, 11, 14, 29, 30, 101, 140, 151, 159, 211, 212 C-N, 236, 242, 249, 287 community, 2 competitive process, 243, 261 components, 7, 109, 287, 302

Index

380

composition, 130, 288 concentration, 196, 222, 232, 261, 264, 288 condensation, 4, 5, 6, 7, 8, 9, 10, 14, 23, 24, 33, 63, 67, 68, 92, 99, 101, 105, 106, 110, 201, 203, 204, 220 conducting polymers, 2, 33 conductive, 36 conductivity, 4, 21, 33 configuration, 215, 256, 293 conjugation, 236, 243, 247, 268, 272 conservation, 269 construction, 148 control, 197, 199, 204, 216, 309, 314 conversion, 47, 103, 106, 202, 227, 229, 258, 292, 296 cooling, 114, 179 copper, 49 correlation, 177, 264, 275, 277, 281 correlation coefficient, 264 correlations, 175, 176, 177 cosmetics, 78 Coulomb, 238, 292 coupling, 15, 92, 106, 109, 121, 168, 177, 215 cross-linking, 302, 303 crown, 121 crystal structure, 244, 246 crystalline, 82, 83, 90, 229 crystals, 191, 192, 193, 194, 195, 196, 205, 223, 229 cultivation, 196, 197 cyanamide, 86 cycles, 129 cyclohexyl, 59 cystic fibrosis, 29 cytochrome, 94 cytotoxic, 31, 84

D decomposition, 82, 83, 229, 242, 256, 260, 263, 264, 289, 300, 308, 313 dehydration, 99, 105, 106, 173 dehydrogenase, 314 delivery, 2 delocalization, 232

density, 86, 228, 232, 237, 238, 250, 268, 270, 272, 276, 289, 292, 298, 299, 311, 313 density functional theory, 311 depression, 197, 199 dermatophytes, 196 detection, 302 deviation, 130, 272, 281 DFT, 226, 236 diabetes mellitus, 32 diamines, 70, 133, 134, 136, 138, 140 diamond, 48, 87 dichloranhydride, 220, 223 dichloroethane, 185 diethyl amine, 304 diffraction, 63, 212 diffusion, 96, 232 dimer, 13, 296 dimeric, 9 dimerization, 13, 82, 258, 259 dimethylformamide, 3, 107, 154 dimethylsulfoxide, 3 diseases, 24, 164 dispersion, 15 displacement, 298 dissociation, 226, 227, 238, 239, 240, 241, 242, 243, 261, 265, 270, 282, 292, 293, 295, 311 dissolved oxygen, 289 distress, 29 distribution, 276 DMF, 3, 5, 6, 23 DMFA, 193, 194 DNA, 164, 169, 303, 305, 315 donor, 122, 127, 130, 132, 258 Down syndrome, 164 drug delivery, 2 drug design, 4, 21, 24, 32 drugs, 27, 88, 159 dyeing, 35 dyes, 2, 26, 35, 36, 226, 230, 278, 305

E electrolyte, 12

Index electron, 3, 4, 5, 6, 7, 33, 35, 62, 86, 109, 174, 227, 228, 237, 238, 240, 250, 253, 254, 255, 260, 261, 268, 270, 272, 276, 279, 283, 289, 292, 293, 303, 310, 313 electron density, 86, 228, 237, 238, 250, 268, 270, 272, 276, 292 electron density distribution, 276 electron spin resonance, 313 electrons, 112, 226, 271, 275, 276, 280, 281, 282, 284, 291, 292, 306 elongation, 35, 252, 265, 271, 272 embryo, 71 embryos, 52 emission, 227, 292 emphysema, 29 employment, 33 endothermic, 228 energetic parameters, 275 energy, 34, 112, 204, 227, 229, 236, 238, 239, 241, 242, 243, 247, 249, 252, 253, 254, 255, 272, 273, 275, 276, 277, 278, 279, 280, 282, 283, 285, 292, 293, 294, 306 energy characteristics, 306 energy transfer, 227 entropy, 228, 229 environment, 51, 54, 55, 57, 65, 68, 69, 70, 73, 196, 197, 221 enzymes, 27, 31 epithelia, 31 EPR, 300, 310, 314 equilibrium, 5, 10, 160, 228, 229, 264, 315 Escherichia coli, 196, 198 ESI, 288 ESR, 241, 242, 243, 289, 296, 297, 298, 300, 301 ESR spectra, 242, 243, 296, 298, 300 ESR spectroscopy, 297, 300 ester, 15, 18, 27, 59, 63, 65, 67, 69, 74, 151, 201, 202, 204 esterification, 151 esters, 15, 25, 105 ethane, 212 ethanol, 5, 6, 7, 15, 20, 35, 62, 71, 112, 151, 191, 194, 204, 206, 234, 235, 240, 253, 258, 261, 286, 296

381

ethers, 93, 99, 105, 112, 114, 120, 121, 151, 171, 172, 173, 174, 177 ethyl acetate, 62 ethyl alcohol, 157 ethylene, 56, 156 ethylene glycol, 56, 156 ethylenediamine, 67, 127, 130, 136 ethyleneglycol, 70 excitation, 227, 238, 240, 243, 250, 254, 255, 256, 270, 272, 275, 276, 277, 278, 279, 286, 289, 295 exposure, 256, 296 extinction, 261

F family, 31, 83 ferrocenyl, 134 fibrosis, 29 film, 84 films, 84, 97 filtration, 23, 215 financial support, 87, 116, 165, 200, 209, 224 flame, 114 flow, 114 fluorescence, 227 fluorinated, 173, 174 fluorine, 172, 174, 177, 300, 305 fluorine atoms, 172, 174, 305 folding, 302 formaldehyde, 107 formamide, 49, 89 FTIR, 112 fungi, 2, 196, 197 fungicidal, 48, 51 fungicide, 85

G GABA, 169 gas, 229, 233, 312 gas phase, 229, 312 gases, 300 gastrin, 91

Index

382

gel, 112, 177, 222 generation, 33, 230, 300 glass, 241 glucagon, 2, 3, 4, 32 glucose, 32, 197 glutamate, 314 glycol, 3, 15, 56, 156 gram-negative bacteria, 164 grants, 36, 142 granules, 29 GroEL, 302, 314 groups, 2, 4, 5, 14, 34, 35, 56, 68, 81, 83, 110, 120, 121, 122, 130, 134, 159, 162, 171, 172, 173, 175, 185, 201, 202, 204, 241, 242, 243, 244, 264, 300, 306, 309, 310 growth, 35, 163, 183, 197, 199, 200, 221, 230, 232 guidelines, 2

H H2N3, 309 half-life, 297 Halides, 312 halogen, 19, 122, 124, 154 heat, 229, 275 heating, 16, 17, 18, 55, 56, 60, 62, 66, 70, 71, 73, 82, 83, 85, 101, 130, 133, 148, 228, 229 height, 236, 249, 293 herbicide, 303 herpes, 30, 31 heterocycles, xi, 4, 21, 91, 101, 172, 184, 212, 225, 285 heterogeneous, 17 hexafluorophosphate, 3, 12 hexane, 113, 178, 179, 180, 191, 194, 195, 196, 205, 206, 207, 222, 223 high pressure, 70 high temperature, 64, 85 high-level, 243, 295 high-throughput screening, 31 HIV, 85 HLE, 3, 29 holoenzyme, 31

HOMO, 238, 239, 251, 252, 253, 254, 255, 269, 270, 272, 273, 274, 277, 279, 283, 284, 285 hormone, 32 HPLC, 19, 232 human, 3, 4, 29, 32, 77, 314, 315 hybridization, 238, 272 hydrate, 149, 151, 152, 153, 157, 159 hydrazine, 149, 151, 152, 153, 154, 157, 159, 220 hydride, 3, 54, 82 hydro, 35 hydrochloric acid, 67, 76 hydrogen, 107, 108, 140, 174, 175, 231, 247, 258, 259, 303, 309 hydrogen atoms, 107, 108, 247, 258, 259 hydrogen bonds, 140 hydrogenation, 70, 85 hydrolysis, 23, 61, 101, 105, 201, 256, 257 hydrolyzed, 173, 256, 305 hydrophilic, 35 hydrophobic, 35 hydroxyl, 174 hygiene, 78 hypertensive, 170 hypnotic, 148, 164 hypotensive, 75 hypoxia, 30

I identification, 230, 244, 302 illumination, 278 immune system, 48, 81 immunity, 94 immunosuppression, 60 immunosuppressive, 76 in situ, 5, 124, 129, 133, 136, 138 in vitro, 29, 89, 196, 198, 222 inactive, 222, 307 inclusion, 293 incubation, 197 independence, 274 individuality, 222 industrial, 16

Index industry, 2, 88 inert, 122, 132, 300 inertness, 243 infectious, 196 infectious disease, 196 infectious diseases, 196 inflammation, 30 inflammatory, 2, 24, 29, 77, 164, 220 influenza, 70 inhibition, 29, 32, 148, 164 inhibitor, 31 inhibitors, 25, 29, 31, 83, 91, 162, 169 inhibitory, 29, 170, 196, 197, 222 inorganic, 5, 14, 120 insertion, 52, 82, 83, 168, 231, 257, 258, 291, 304, 305 insight, 313 inspection, 281 instability, 6, 109 interaction, xi, 49, 50, 51, 52, 55, 56, 58, 65, 66, 68, 70, 71, 72, 74, 75, 76, 84, 109, 152, 157, 172, 174, 176, 177, 188, 191, 195, 196, 202, 212, 219, 220, 245, 299 interactions, 58, 213, 247, 299, 309 intermolecular, 204, 245, 300 internet, 84 interphase, 151, 185 intrinsic, 35 ionization, 288 ions, 121, 139, 303, 308 IR spectra, 112, 174, 186, 187, 191, 204, 205, 206, 204, 207, 228, 296, 300 IR spectroscopy, 296, 297 iron, 206 irradiation, 16, 18, 19, 227, 229, 231, 233, 235, 236, 242, 243, 253, 256, 257, 258, 260, 262, 263, 277, 286, 287, 288, 289, 290, 295, 296, 300, 302, 305 ischemia, 30 isoenzymes, 31 isolation, 23, 111, 129, 173, 225, 300, 301, 310, 313 isomers, 86, 99, 100, 101, 105, 109, 110, 129, 148, 153, 229, 242

383

K K+, 314 ketones, 5, 8, 14, 17, 18 kinase, 25 kinetic curves, 234 kinetic studies, 288 kinetics, 120, 293 KOH, 113, 114, 222

L labeling, 226, 230, 302, 303, 304, 305, 314, 315 language, 2 laser, 231, 293, 295, 296, 302 lattice, 229 leukocyte, 3, 29 Lewis acids, 60 lifetime, 303 ligand, 120, 122, 132, 136 ligands, 91, 127, 132, 134, 168 limitations, 120 linear, 2, 99, 100, 101, 103, 105, 109, 110, 119, 122, 125, 129, 130, 136, 140, 226, 275, 281, 283 linear regression, 275 linkage, 18 lipid, 48 lipophilic, 83 liquids, 14 liver, 94 loading, 133 locomotion, 170 low temperatures, 300 low-intensity, 254, 257, 258 low-temperature, 225, 241, 289, 298 LUMO, 238, 239, 251, 252, 253, 254, 255, 269, 270, 272, 273, 274, 277, 278, 279, 283, 284, 285 lung, 29 lung disease, 29 Lyapunov, 144 lymphocytes, 81, 305, 315

Index

384

M M.O., 95, 97 magnetic, 230, 298, 301, 314 magnetic materials, 230, 301 magnetic properties, 314 magnetism, 230, 301, 306 magnets, 302, 306 malaria, 24 manganese, 105 mass spectrometry, 215, 287, 288 materials science, 1 matrices, 313 matrix, 225, 244, 295, 297, 298, 300, 301, 313 matrix condition, 298 media, 21, 27, 300 membrane permeability, 48 membranes, 315 Mendeleev, 217, 309, 311, 312, 313, 314 metals, 120 methanol, 5, 6, 7, 16, 22, 49, 212, 256 methine group, 121 methyl group, 22, 175, 177 methyl groups, 175 methylation, 23, 52, 71, 177 methylene, 5, 7, 11, 13, 15, 23, 86, 120, 121, 156 methylene group, 11, 13, 86 MgSO4, 179 mice, 170 microbial, 196 microorganism, 197, 222 microorganisms, 196, 197, 199, 221 microwave, 4, 14, 16, 17, 18, 19 mitochondrial, 302, 314 mixing, 11, 15, 195, 223 mobility, 86 model system, 230, 306 modeling, 302 models, 301, 302 moieties, 35, 120, 121, 122, 130, 139, 215 moisture, 84 molar ratio, 185 mole, 114

molecular orbitals, 238, 239, 240, 252, 279, 283, 284, 306 molecular oxygen, 296 molecular sensors, 120 molecular structure, 35, 314 molecules, 2, 11, 24, 30, 33, 48, 62, 83, 87, 120, 121, 139, 172, 240, 245, 258, 259, 264, 293, 301, 309, 312 monoamine, 148, 164, 170 monoamine oxidase, 148, 164 motion, 74 MPS, 3, 11, 12 multidisciplinary, 1 multiplicity, 299 muscle, 172 muscle relaxant, 172 mutagenesis, 314 mycobacterium, 198 myelin, 168

N Na+, 314 Na2SO4, 191, 192, 194 N-acety, 15, 103 NaCl, 197 naphthalene, 121, 138, 283 National Academy of Sciences, 171 National Science Foundation, 87, 116, 165, 200, 209, 224 natural, 4, 27 nerve, 164, 168 neurodegenerative, 31 neurodegenerative disorders, 31 neuroleptic, 48 neutralization, 257, 259 neutrophil, 29 NHC, 63 nitrate, 52, 71, 72 NMR, 111, 112, 113, 114, 115, 116, 173, 174, 175, 176, 177, 178, 179, 180, 181, 185, 188, 190, 204, 208, 215, 216, 221, 222, 223, 228 N-N, 226, 237, 238, 239, 240, 243, 265, 271, 272, 277, 280, 282, 284, 287, 292, 294, 295

Index noble gases, 300 non-destructive, 230 norbornene, 213 normal, 122, 140 nuclei, 175, 176, 177, 233, 245, 276 nucleic acid, 302, 306 nucleophiles, xi, 11, 92, 97, 211, 230, 303 nucleus, 23, 64, 81, 226, 228, 233, 236, 237, 238, 243, 245, 246, 247, 249, 250, 252, 259, 267, 268, 270, 271, 272, 273, 274, 292 nutrient, 196

O observations, 31, 176 o-dichlorobenzene, 58, 80, 81, 156 oil, 112, 115, 191, 204 oligomeric, 125, 127, 130 oligomeric products, 125 oligomers, 122, 124, 125, 129, 136, 140, 142 optical, 35, 139 optical properties, 139 optimization, 236, 246 optoelectronic, 4, 21 optoelectronic devices, 4, 21 organic, 5, 11, 14, 15, 18, 21, 22, 33, 79, 86, 120, 121, 172, 194, 202, 230, 241, 244, 301, 302, 312 organic compounds, 33 organic solvent, 79 organic solvents, 79 organoselenium, xi, 212 orientation, 245, 249 oscillator, 254, 255, 278, 279 oxidation, 154 oxidative, 52, 71, 138 oxide, 73, 112, 231 oxides, 38, 227, 231, 232, 308 oximes, 2 oxygen, 54, 120, 258, 287, 288, 289, 296, 305

P palladium, 63

385

Pap, 40 parameter, 226, 227, 276, 277, 289, 298, 299 Parkinson, 24 particles, 112 partnership, 87, 116, 165, 200, 209, 224 patents, 53, 164 pathogenesis, 29 pathogenic, 183, 196, 197 pathology, 83 pathways, 27, 79, 257, 258 PCT, 91, 96, 169, 170 peptide, 121 peptides, 303, 315 permeability, 48 perturbation, 299 pesticides, 2 petroleum, 88, 115, 195, 196 pH, 69, 86, 113, 114, 191, 192, 193, 194, 204 pharmaceutical, 27, 36, 48, 59, 91, 96, 149, 162 pharmaceuticals, 2, 26, 27 pharmacological, 24, 30, 48, 93, 147, 149, 154, 157, 159, 165, 172, 220 pharmacology, 1, 30, 32 pharmacotherapy, 83 phenol, 84 phosphate, 69 phosphodiesterase, 148 phosphor, 164 phosphorus, 62, 121, 152, 157 photochemical, 120, 229, 230, 243, 244, 253, 256, 257, 259, 261, 263, 264, 265, 266, 277, 286, 290, 292, 295, 298, 301, 306, 308, 312, 313 photochemical transformations, 295 Photodissociation, 236, 290, 307, 309, 312 photoinduced electron transfer, 261 photoirradiation, 301 photolysis, 225, 230, 231, 232, 233, 241, 242, 243, 244, 256, 257, 258, 259, 261, 286, 287, 288, 289, 293, 295, 296, 297, 298, 299, 300, 301, 302, 303, 305, 306, 309, 310, 313, 315 photosensitivity, 278, 306 photovoltaic, 33

386

Index

photovoltaic devices, 33 physical activity, 74 physics, 1 physiological, 61, 106, 147, 148, 160, 162 pitch, 202 planar, 120, 244, 247, 249, 250, 268 platelet, 169, 170 Platelet, 167 platelet aggregation, 170 PM3, 226, 236, 237, 241, 242, 243, 245, 248, 249, 250, 256, 264, 265, 267, 268, 272, 273, 274, 275, 279, 280, 282, 285 PM3 method, 241, 242, 249, 264, 265, 267, 285 polyamine, 120, 124, 127, 128, 129, 130, 133, 136, 138, 139, 140, 142 polyester, 35 polyethylene, 3, 15 polymer, 84, 231 polymerase, 31 polymerization, 63 polymers, 2, 33, 36 polystyrene, 3, 15 polythiophenes, 33 poor, 298 population, 228, 238, 247, 270, 272, 277, 278, 283 pore, 84 porous, 15 potassium, 5, 56, 81 potato, 197 powder, 206, 300 prediction, 35 press, 145, 146, 310 pressure, 70, 71, 83, 178, 179, 180, 205, 228 primary products, 295 probability, 242, 293 production, 14, 156, 306 prognosis, 84 program, 31, 32, 87, 116, 165, 177, 200, 209, 224 promoter, 12 propane, 136 propylene, 73 proteases, 31

protection, 18, 27, 302 protein, 302, 314 proteins, 302, 303, 304, 306, 311, 315 proteolysis, 303, 315 protocol, 23, 139 proton pump inhibitors, 91 protons, 86, 174, 175, 177, 188, 215 pseudo, 63, 92, 175 Pseudomonas, 196, 197, 198, 199 Pseudomonas aeruginosa, 196 psychopharmacological, 172 purification, 20, 109, 129, 133 pyridine ring, 62, 120, 231, 298 pyrimidine, 24, 31, 32, 225 pyrrole, 99, 100, 101, 106, 107, 108, 109, 156, 183, 197, 204 pyruvate, 27 pyruvic, 99, 100, 101, 105, 112

Q quantum chemical calculations, 264, 293, 312, 313 quantum yields, 233, 234, 236, 244, 256, 257, 260, 262, 263, 286, 290, 291, 305 quantum-chemical calculations, 229, 232, 238, 245, 253, 275, 281, 295 quantum-chemical methods, 236, 246, 247, 250, 267 quasi-linear, 236, 247, 250, 264, 268, 269

R radiation, 304, 310 radiolabeled, 302 Raman, 311 range, 2, 14, 18, 27, 174, 175, 227, 239, 247, 263, 277, 278, 286, 291, 293, 305 rats, 168 reactant, 108 reactants, 7, 10 reaction center, 315 reaction mechanism, 295 reaction time, 4, 16, 20

Index reactivity, 4, 8, 47, 56, 63, 108, 109, 110, 124, 135, 151, 159, 172, 185, 230, 241, 303, 306 reagent, 12, 15, 107, 108, 191, 192, 193, 212, 213, 215, 304, 315 reagents, xi, 2, 15, 27, 62, 80, 85, 130, 149, 172, 212, 213, 288, 302, 316 receptor agonist, 21, 30 receptors, 30, 90, 121, 148, 164, 168 recrystallization, 179 recrystallized, 206, 213, 215 redistribution, 270 redox, 120 regeneration, 14 regression, 280, 281, 282, 283 regression analysis, 280, 281, 282, 283 regular, 205 relationship, 230, 306 relationships, 30, 169, 175 relaxation, 238, 270, 276, 311 repair, 305 residues, 302, 314 resin, 15, 18 resistance, 48 resolution, 300, 310, 314 resorcinol, 35 respiratory, 29 respiratory distress syndrome, 29 retardation, 240 retention, 234 retinoids, 96 rheumatoid arthritis, 29, 60 rigidity, 85, 120 rings, 99, 100, 101, 106, 107, 108, 109, 229, 247, 258, 267, 268, 272, 273, 275, 276, 277, 283 RNA, 3, 31 room temperature, 3, 23, 75, 82, 107, 173, 178, 179, 180, 191, 192, 193, 194, 195, 203, 205, 231 rotations, 247, 249 Russian Academy of Sciences, 182, 225

387

S salt, 23, 81, 82, 89, 185, 202, 220, 260, 261, 262 salts, 14, 22, 53, 82, 96, 109, 121, 159, 161, 173, 215, 219 Schiff base, 121 Schmid, 309 search, 151 sedative, 24 sedatives, 172 selectivity, 15, 17, 134 selenium, xi, 212 semiconductors, 84 sensitivity, 226, 227, 230, 244, 256, 277, 278, 290, 306, 312 sensors, 4, 21, 120, 139 separation, 113, 244 series, 22, 29, 30, 31, 47, 81, 82, 85, 90, 96, 107, 109, 151, 160, 201, 229, 230, 267, 268, 270, 271, 274, 278, 280, 281, 283, 306 serine, 29 shade, 35 shock, 229, 313 shock waves, 313 shoulder, 253, 255 side effects, 43 signals, 174, 177, 215, 242, 314 silica, 112, 124, 222 silver, 52, 71, 72, 173, 311 simulation, 300, 301 simulations, 300 sites, 15, 130, 232, 302, 311, 314 skeleton, 252 sleep, 172 sodium, 49, 54, 55, 60, 81, 82, 134, 139, 153, 157, 159, 173, 191, 192, 230, 231 solid state, 82, 228 solubility, 11, 21, 185, 193 solvent, 177, 178, 179, 192, 194, 197, 205, 213, 225, 228, 236, 240, 258, 259 solvent molecules, 240, 258, 259 solvents, 5, 6, 14, 79, 82, 228, 256, 258, 308 spacers, 127, 139 spatial, 175

388

Index

species, 12, 227, 228, 230, 232, 253, 256, 296, 298, 300, 301, 302, 303 spectroscopy, 175, 215, 225, 228, 288, 296, 297, 300, 301, 310, 311, 312, 313, 314 spin, 84, 188, 191, 215, 225, 230, 232, 289, 293, 295, 298, 299, 300, 301, 306, 310, 313 stability, 21, 82, 84, 111, 298, 301, 313 stabilization, 232, 258 stabilize, 229, 258, 305 stages, 86 standard deviation, 281 standards, 177 Staphylococcus aureus, 31, 196, 197 starch, 197 steric, 109, 247, 268, 272 storage, 82 strain, 247 strength, 35, 255, 278, 279 streptomyces, 100, 197, 199 structural changes, 238, 250, 270 structural characteristics, 239 styrene, 212 substances, 24, 48, 78, 88, 100, 106, 148, 149, 151, 159, 162, 164, 165, 197, 199, 201, 220, 221, 222 substitution, 24, 54, 72, 100, 106, 107, 108, 109, 122, 125, 130, 135, 138, 140, 171, 173, 185, 313 substitution reaction, 100, 106, 108, 109, 135, 185 substrates, xi, 5, 7, 10, 14, 15, 29, 35, 109, 185, 211, 212 sulfate, 173 sulfur, xi, 4, 5, 7, 8, 10, 11, 12, 13, 14, 15, 17, 18, 20, 23, 24, 35, 83, 120, 151, 153, 154, 212 sulfuric acid, 35, 232, 308 sulphate, 256 sulphur, 82 superposition, 254 supervision, 148 suspensions, 305 symbols, 283 syndrome, 29, 148, 164

T tachycardia, 30 TCC, 196 tellurium, xi, 212 temperature, 3, 7, 23, 50, 64, 70, 71, 75, 82, 85, 107, 173, 178, 179, 180, 191, 192, 193, 194, 195, 203, 205, 225, 228, 229, 231, 241, 289, 293, 295, 296, 298 tetrahydrofuran, 55, 223 therapeutic agents, 29, 30 therapeutics, 21, 32 therapy, 24, 27, 59, 169 thermal decomposition, 313 thermal stability, 84 thermodynamic, 120 thermodynamic properties, 120 thermolysis, 277, 308 thiamin, 3, 27 thiamine, 28 thin films, 84 threshold, 226, 274, 275, 277, 280, 281, 282, 306 thromboxanes, 148, 162 thymus, 305 tissue, 30, 31 titanium, 20, 63 title, 21, 36, 171, 173, 174 toluene, 18, 82, 156, 173, 179, 203, 258 toxicity, 48 tranquilizers, 172 transactions, 92 transfer, 34, 227, 237, 238, 240, 242, 253, 254, 268, 270, 272, 276, 283, 289, 292 transformation, 133, 154, 202, 216, 227, 298 transformations, 91, 157, 159, 160, 259, 295 transglutaminase, 31 transistors, 33 transition, 92, 233, 239, 241, 243, 254, 255, 260, 278, 279, 280, 283, 293, 295 transition metal, 92 transitions, 253, 254, 255, 256, 279, 283, 292, 296 trifluoroacetic acid, 3, 15, 18, 228 trifluoromethyl, 307

Index tuberculosis, 24, 168, 196, 198, 222 tumor, 24, 163 two step method, 23

389

viruses, 70 visible, 139, 226, 230, 253, 256, 260, 277, 278, 286, 287, 289, 304, 305, 312 vitamin B1, 27

U W uniform, 287 UV, 111, 112, 113, 114, 115, 116, 185, 186, 187, 191, 194, 195, 196, 204, 205, 206, 207, 221, 222, 233, 253, 260, 287, 296, 297, 301, 302, 304, 312, 313 UV irradiation, 233, 296 UV radiation, 304 UV spectrum, 113, 114, 222

V vacuum, 79, 148, 205, 223 valence, 35, 237, 238, 246, 247, 248, 250, 272 values, 112, 191, 204, 264, 276, 293, 298 van der Waals, 247 vapor, 114 variation, 24, 227 vector, 299 ventricular tachycardia, 30 versatility, 2, 21, 24, 29 veterinary medicine, 77 vibration, 293

water, 18, 22, 23, 48, 61, 112, 114, 156, 174, 179, 191, 192, 193, 194, 197, 204, 205, 206, 207, 219, 220, 222, 256, 262, 303, 305, 315 water-soluble, 220 wavelengths, 227, 256, 284 wool, 35 workability, 21 workers, 4, 5, 19, 99

X X-ray analysis, 83, 212 xylene, 49, 57, 113

Z zinc, 27 Zn, 203

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