CHEMISTRY RESEARCH AND APPLICATIONS SERIES
HETEROCYCLIC COMPOUNDS: SYNTHESIS, PROPERTIES AND APPLICATIONS
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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.
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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
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Kristian Nylund and Peder Johansson
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
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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
Z. Puterová and A. Krutošíková
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.
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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 .
Z. Puterová and A. Krutošíková
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].
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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].
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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].
Z. Puterová and A. Krutošíková
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
Z. Puterová and A. Krutošíková
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
Z. Puterová and A. Krutošíková
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 .
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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
Z. Puterová and A. Krutošíková
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.
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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.
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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.
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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).
Z. Puterová and A. Krutošíková
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.
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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.
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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].
Z. Puterová and A. Krutošíková
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 =
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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.
Z. Puterová and A. Krutošíková
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
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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 poly- thiophene 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
Z. Puterová and A. Krutošíková
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 .
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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 .
Z. Puterová and A. Krutošíková
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.
Substituted 2-Aminothiophenes: Synthesis, Properties and Applications
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]
In: Heterocyclic Compounds: Synthesis, Properties … ISBN: 978-1-60876-368-9 Editors: K. Nylund et al. pp. 47-97 © 2010 Nova Science Publishers, Inc.
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]:
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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-
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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).
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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]:
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D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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].
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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.
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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]:
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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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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].
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D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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.
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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%.
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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
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
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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:
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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.
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D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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.
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
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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].
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
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D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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,
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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
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D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al.
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.
Adamantyl-1 and Adamantyl-2 Imidazoles and Benzimidazoles
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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D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. diffusion method in agara. Georgian State Zootechnical-Veterinary University, collected scientific works, vol. LXV, 399-407, Tbilisi, 2005 Pfahl, Magnus; Lu Xian-ping; Ride out Darryl; Zhang Hongyue. Preperation of apoptosis inducing adamantyl substituted retinoids for pharmaceutical and cosmetic uses. PCT Int. Appl. WO 9801132 1998, US Appl. 21285, 8. Jul 1996, 95 p. Chemical Abstract, 1998, Vol.128, № 12, 140528q. Danilin, A. A.; Purygin, P. P.; Makarova, N. V.; Moiseev, I. K. Investigation of the reaction of 1-adamantyl bromomethyl ketone with azoles. Chemistry of Heterocyclic Compounds, 1999 Vol.35, No. 6, 674676. Translated from Khimiya Geterotsiklicheskikh Soedinenii, 1999 No. 6, 760-762. Karotkikh, M. I.; Raenko, G. F.; Shvaika, O. P. New approaches to the synthesis of stable heteroaromatic carbenes. Dopovidi Natsional'noi Akademii Nauk Ukraini, 2000, 2, 135-140. Publisher: Prezidiya NatsionalÏnoi Akademii Nauk Ukraini. Pfahl, Magnus; Lu, Xian-Ping; Rideout, Darryl; Zhang, Hongyue. Adamantyl derivatives as anti-cancer agents. Patent WO/2001/056563, Publication date: 09.08.2001. International Application No: PCT/US2001/003717. Klimiva, N.V.; Galushina, T.S.; Avdjunina, N.I.; Pjatin, B.M.; Fadeeva, T.A. Synthesis and the immunotropic properties of the adamantyl substituted salts of benzimidazolium. The international scientific and technical conference « Advances of Chemistry and Applications of Alicyclic Compounds” p.157, Russia - Samara 1-4 of June, 2004. Korotkikh, N. I.; Shvaika, O. P.; Rayenko, G. F.; Kiselyov, A. V.; Knishevitsky A. V.; Cowley, A. H.; Jones, J. ;. Macdonald, C. L.B. Stable heteroaromatic carbenes of the benzimidazole and 1,2,4-triazole series. Regional Issue “Organic Chemistry in Ukraine”ARKIVOC 2005, 10-46. ISSN 1424-6376 ©ARKAT USA, Inc. Page 10-46. Korotkikh, N. I.; Raenko. G. F.; Pekhtereva. T. M.; Shvaika, O. P.; Cowley, A. H.; Jones, J. N. Stable Carbenes. Synthesis and Properties of Benzimidazol-2-ylidenes. Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 12, 1822–1833. Published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 12, 1833–1843. Richards, M.L.; Lio, S. C.; Sinha, Anjana; Banie, H.; Thomas, R. J.; Major, M.; Tanji, M.; Sircar, J. C. Substituted 2-phenylbenzimidazole derivatives: novel compounds that suppress key markers of allergy. European Journal of Medicinal Chemistry, 2006 Vol. 41, No. 8, 950-969.
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[92] Funaki, Yoshinori; Itaya, Ryo; Takaragi, Akira; Okamoto, Kazuki; Torieda, Mayumi. Thin insulating films based on benzimidazole-containing compounds. Eur. Pat. Appl. (2008) Patent No. EP 2003123, Date A2 20081217, Application No. EP 2008-10623, Date 20080611. [93] Osjanin, V.A.; Vostrikov, S.V.; Klimochkin, J.N. Iodmetilaty NNdimethyl-aminomethyladamantyl-phenoles in reactions with Nnucleophiles. XI International scientific-technological conference. Advances of Chemistry and applications of alicyclic compounds. 3-6 june 2008, p.158. Russia, Volgograd. [94] Zurabishvili, D. S.; Lomidze, M. O.; Samsoniya, Sh. A.; Gogolashvili, I. Medical and biologic aspects of the some adamantane containing derivatives alk(ar)oxyanilides and benzimidazoles XI International scientific-technological conference. Advances of Chemistry and applications of alicyclic compounds. 3-6 june 2008, p.122. Russia, Volgograd. [95] Lomidze, M. O. Abstrac of Diss. Cand. Sci. (Chem), Tbilisi (2003). [96] Zurabishvili, D. S.; Lomidze, M.O.; Samsoniya, Sh. A.; Wesquet, A.; Kazmaier, U. Synthesis and reactions of some 5(6)-(1adamantyl)benzimidazoles. Chemistry of Heterocyclic Compounds, 2008 Vol. 44, No. 8, 941-949. Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2008 No. 8, 1172-1182.
In: Heterocyclic Compounds: Synthesis, Properties … ISBN: 978-1-60876-368-9 Editors: K. Nylund et al. pp. 99-117 © 2010 Nova Science Publishers, Inc.
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.
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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:
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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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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
Methods of Synthesis of Pyrroloindoles
103
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
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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
Methods of Synthesis of Pyrroloindoles
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
Methods of Synthesis of Pyrroloindoles
107
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
Methods of Synthesis of Pyrroloindoles
109
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
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Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili et al.
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.
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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-spectra- on spectrophotometer ―Specord‖ (Germany) in ethanol, 1H NMR-spectra- on 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,
Methods of Synthesis of Pyrroloindoles
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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-
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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),
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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).
In: Heterocyclic Compounds: Synthesis, Properties … ISBN: 978-1-60876-368-9 Editors: K. Nylund et al. pp. 119-146 © 2010 Nova Science Publishers, Inc.
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
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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.
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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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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.
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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
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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
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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.
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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%
Palladium-catalyzed Amination of Dihaloarenes
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%
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
+ Br
N
Br
N NH2 H
Pd(dba)2/BINAP 8/9 mol%
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
Pd(dba)2/BINAP 8/9 mol% H2N
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
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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).
Palladium-catalyzed Amination of Dihaloarenes
131 N
Br
Br +
H2N
N 23
X
Pd(dba)2/BINAP 8/9 mol%
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
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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
Pd(dba)2/BINAP 8/9 mol%
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
Pd(dba)2/BINAP 8/9 mol%
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
Palladium-catalyzed Amination of Dihaloarenes
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
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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.
Palladium-catalyzed Amination of Dihaloarenes
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
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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.
Palladium-catalyzed Amination of Dihaloarenes
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
Pd(dba)2/BINAP 8/9 mol%
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)
Pd(dba)2/BINAP 8/9 mol% H2N
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
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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%
Palladium-catalyzed Amination of Dihaloarenes
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
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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.
Palladium-catalyzed Amination of Dihaloarenes
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
Pd(dba)2/BINAP (8/9 mol%)
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%)
Pd(dba)2/BINAP (8/9 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
Pd(dba)2/BINAP (8/9 mol%)
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
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Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al.
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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Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R.M. Aza-Crown Macrocycles, Wiley: New York, US, 1993, p. 51. Stetter, H.; Frannk, W.; Mertens, R. Tetrahedron 1981, 37, 767. Costa, J.; Delgado, R. Inorg. Chem. 1993, 32, 5257. Delgado, R.; Quintino, S.; Teixeira, M.; Zhang, A. J. Chem. Soc., Dalton Trans. 1996, 55.
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In: Heterocyclic Compounds: Synthesis, Properties … ISBN: 978-1-60876-368-9 Editors: K. Nylund et al. pp. 147-170 © 2010 Nova Science Publishers, Inc.
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
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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.
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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
Pyrridazinoindoles, Synthesis and Properties
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).
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Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh
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
Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh
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
Pyrridazinoindoles, Synthesis and Properties
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
Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh
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
