Heterocyclic Compounds: Synthesis, Properties and Applications

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.

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Heterocyclic compounds : synthesis, properties, and applications / Kristian Nylund and Peder

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CONTENTS

Preface vii

Chapter 1 Substituted 2-Aminothiophenes: Synthesis,

Properties and Applications 1 Z. Puterová and A. Krutošíková

Chapter 2 Adamantyl-1 and Adamantyl-2 Imidazoles and

Benzimidazoles. Methods of Synthesis,

Properties and Biological Activity 47 D. S. Zurabishvili, M. O. Lomidze,

M. V. Trapaidze,Sh. A. Samsoniya

Chapter 3 Methods of Synthesis of Pyrroloindoles 99 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 119 Alexei D. Averin, Alexei N. Uglov, Alla Lemeune,

Roger Guilard, Irina P. Beletskaya

Chapter 5 Pyrridazinoindoles, Synthesis and Properties 147 Sh. A. Samsoniya, I. Sh. Chikvaidze, M. Ozdesh

Contents vi

Chapter 6 11-Perfluoroalkyl-substituted 3,3-Dimethyl-

11-hydroxy-2,3,4,5,10,11-hexahydro-1H-

dibenzo[b,e][1,4]diazepin-1-ones: Synthesis

and Characterization 171 Tatyana S. Khlebnicova, Veronika G. Isakova,

Alexander V. Baranovsky and Fedor A. Lakhvich

Chapter 7 Synthesis and Biological Activity of some

Isomeric Dipyrrolonaphthaline Derivatives 183 Sh. A. Samsoniya, M. V. Trapaidze, N. A. Esakia,

K.Kh.Mamulashvili, Z. Sh. Lomtatidze,

T. V. Doroshenko

Chapter 8 Some Conversions of 5-acetyl-2-ethoxycarbonyl

- 3-p-nitrophenyl Indole 201 N. Narimanidze, Sh. Samsoniya, I. Chikvaidze

Chapter 9 2-Pyridineselenenyl- and Tellurenyl Chlorides

as Building Blocks for Derivatives of

2,3-dihydro[1,3] selen(tellur)azolo[3,2-a]

pyridin-4-ium 211 Alexander V. Borisov, Zhanna V. Matsulevich, Vladimir K. Osmanov, Galina N. Borisova

and Georgy K. Fukin

Chapter 10 Synthesis and Antimicrobial Activity of some

Adamantyl Containing Indoles and

Benzopyrroloindole Derivatives 219 Sh. A. Samsoniya, D. S. Zurabishvili,

I. Sh. Chikvaidze, M. O. Lomidze, M. V. Trapaidze,

K. Kh. Mamulashvili, Z. Sh. Lomtatidze

Chapter 11 Photochemistry of Azidopyridine and Related

Heterocyclic Azides 225 Mikhayl F. Budyka

Chapter 12 Progress in the Chemistry of Condensed

Thiazolopyrimidines 317 M.A. Metwally and Bakr F. Abdel-Wahab

Index 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 2-

aminothiophenes 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 2-

aminothiophenes: cyclization of thioamides and their S-alkylates, Schmidt

reaction of 2-nitrothiophenes, Beckmann rearrangement of 2-acetylthiophene-

oximes, 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.

Kristian Nylund and Peder Johansson viii

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 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.

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 2,7-

dibromonaphthalenes, 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

Kristian Nylund and Peder Johansson x

derivatives with subsequent built of pyrridazine cycle. For some isomers the

attachment of indole ring to pyrridazine appeared to be more convenient.

The study of chemical properties of pyrridazinoindoles and intermediate 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.

Chapter 6 - Novel 11-perfluoroalkyl-substituted 3,3-dimethyl-11-hydroxy-

2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones are prepared via a

simple two-step approach. A treatment of 2-perfluoroalkanoylcyclohexane-1,3-

diones with ethereal solution of diazomethane gives 5,5-dimethyl-3-methoxy-2-

perfluoroalkanoylcyclohex-2-en-1-ones as main products and 6,6-dimethyl-3-

hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones as by-products.

Then, an initial methoxy group vinylogous substitution of enol ethers by one of

the o-phenylenediamine amino groups and an intramolecular cyclization leads to

the title compounds in high yields.

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-2-

ethoxycarbonyl-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. 2-

adamantylaminocarbonylindole and 2,9-di(adamantylaminocarbonyl)-1H,10H-

benzo[e]pyrrolo[3,2-g]indole were obtained by interaction between 1-

aminoadamantane and 2-indolylcarbonic acid. The synthesized compounds

revealed biological activity.

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

Kristian Nylund and Peder Johansson xii

from the neutral to positively charged form by protonation or alkylation at

endocyclic nitrogen atoms.

Protonation of a heterocyclic nucleus has been found to decrease slightly the

photodissociation quantum yield ( ) of 4-azidopyridine and 4-azidoquinoline, do

not influence on the value for 9-azidoacridine, and reduce by two orders of

magnitude the value for 9-(4'-azidophenyl)acridine.

To reveal the effect of the size and charge on azide photoactivity, the

structures of linear cata-condensed heteroaromatic azides from azidopyridine to

azidoazahexacene (the size of aromatic -system from 6 to 26 e) are calculated by

semiempirical (PM3), ab initio (HF/6-31G*) and DFT (B3LYP/6-31G*) methods.

Joint consideration of the experimental and quantum-chemical data results in the

conclusion that the azide photoactivity depends on the nature of molecular orbital

(MO) that is filled in the lowest excited singlet (S1) state. If the antibonding NN*-

MO, which is localized on the azido group and is empty in the ground (S0) state,

is filled the S1 state, the azide is photoactive ( > 0.1). However, when the size of

the -system increases above a certain threshold, aromatic -MO is filled instead

of the NN*-MO in the S1 state, and the azide becomes photoinert ( drops below

0.01). The threshold size is predicted to be 22 and 18 -electrons for the neutral

and positively charged azides, respectively.

Several examples of application of heterocyclic azides for photoaffinity

labeling are considered. Important from this point of view are azido-derivatives of

acridine, hemicyanine, and ethidium dyes, which possess the most long-

wavelength 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,†

1Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius

University, Kalinčiakova 8, 832 32 Bratislava, Slovakia 2Department 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.

Z. Puterová and A. Krutošíková

2

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, E-

mail: [email protected]

ABSTRACT

Several methods are accessible for synthesis of substituted 2-

aminothiophenes: cyclization of thioamides and their S-alkylates, Schmidt

reaction of 2-nitrothiophenes, Beckmann rearrangement of 2-acetylthiophene-

oximes, 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 3

ABBREVIATIONS

Ac – acetyl;

Ar – aryl;

Bn – benzyl;

Boc – tert-butyloxycarbonyl;

Bu – butyl;

DBU – 1,8-diazabyciclo 5.4.0 undec-7-ene;

DIBAL-H – diisobutylaluminum hydride;

DIC – 1,3-diisopropylcarbodiimide;

DMAP – 4-dimethylaminopyridine;

DIPEA – diisopropylethylamine;

DMF – N,N-dimethylformamide;

DMF-DMA – dimethylformamide dimethylacetal;

DMSO – dimethylsulfoxide;

EDG – electron-donating group;

EWG – electron-withdrawing group;

Et – ethyl;

equiv. – equivalent;

h – hour;

hGCRG – hepatic glucagon receptor;

HMDS – hexamethyldisilazane;

HLE – human leukocyte elastaze;

Me – methyl;

min – minute;

MPS – morpholine polysulfide;

NBS – N-bromosuccimide;

PEG – polyethylene glycol;

Ph – phenyl;

Pr – propyl;

PS – polystyrene;

Ref. – reference;

RNA – Ribonucleic acid;

RT – room temperature;

TEAHFP – tetraethylammonium hexafluorophosphate;

TDP – thiamin diphosphate;

TFA – trifluoroacetic acid.


4

1. INTRODUCTION

Highly substituted thiophene derivatives are important heterocycles found in

numerous biologically active and natural compounds [1-5]. The interest in this

kind of heterocycles has spread from dye chemistry [6] to modern drug design [7],

biodiagnostics [8], electronic and optoelectronic devices [9], conductivity-based

sensors [10] and self-assembled superstructures [11]. 2-Amino-3-aroylthiophenes

are agonist allosteric enhancers at the A1 adenosine receptor [12, 13]. A novel

class of thiophene-derived antagonists of the human glucagon receptor has been

discovered [14].

Traditionally, polysubstituted 2-aminothiophenes with an electron-

withdrawing group such as cyano, ethoxycarbonyl or aminocarbonyl in the 3-

position 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.


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 2-

aminothiophenes 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-3-

oxobutanoate (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-amino-

4-hydroxythiophene-3-carboxylate (4) in equilibrium with its cyclic tautomer – the

appropriate imine 3 (Scheme 1).

The Benary’s method exhibits a very limited scope because of the

unavailability of structure 1-like halo-substrates. Fifty years later, in 1961, the

substituted 2-aminothiophenes with electron-withdrawing substituents (such as

cyano, carbonyl, methoxycarbonyl, aminocarbonyl, etc.) at C-3 position and

electron-donating substituents (such as alkyl, aryl, cycloalkyl, etc.) in the C-4

position of the thiophene ring were synthesized in one step process from aliphatic

substrates – substituted -sulfanylaldehyde or -sulfanylketone 5 and

-substituted acetonitrile 6 (where the substituent is EWG, X = CN, CO2H,

Scheme 2) 16 . Since then, the Gewald reaction and its variations have found

enormous utility in synthesis of variety of substituted 2-aminothiophenes.

The Gewald reaction represents the multi component process to prepare

substituted 2-aminothiophenes in generally high yields from -substituted

acetonitriles carrying electron-withdrawing groups and -methylene carbonyl

compounds (aldehydes or ketones) in the presence of the base – organic bases such

as secondary or tertiary amines (diethylamine, morpholine, triethylamine,

pyridine) or inorganic bases (e.g. NaHCO3, K2CO3, NaOH). Polar solvents, like

DMF, alcohols (methanol, ethanol), 1,4-dioxane enhance the condensation of

intermediates – , -unsaturated nitriles with sulfur, which are either prepared in

situ or externally. Depending on the used starting substrates and the reaction

conditions three basic versions of the Gewald reaction have been developed 16,

28-30 , which were lately enriched by a fourth version 31 .


6

O

Cl

EtO2C

NKHS

O

SH

N

S

O

NH S

HO

NH2

41 2 3

EtO2CCO2Et CO2Et

Scheme 1. Benary reaction [27].

R2

R1

O

SHN

S

XR1

R2 NH2

7a-f

X

5 6

7a: R1 = R2 = H, X = CN

7b: R1 = R2 = (CH2)4, X = CN

7c: R1 = R2 = Me, X = CN

7d: R1 = R2 = H, X = CO2H

7e: R1 = R2 = (CH2)4, X = CO2H

7f: R1 = R2 = 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 R

2, 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.

N

XR2

R1

O

65a

SH

X

R2

N

8

SH S

XR1

R2 NH2

7

a b

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

-H2O

R1

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


Table 1. Some of substituted 2-aminothiophenes 7 prepared via the Version 1

of the Gewald reaction

R1 R2 X Yield (%) Ref.

Me Et CN 51 15

Me Me CN 70 15

(CH2)4 CN 70 16

Me Me CO2Me 45 28

(CH2)4 CO2Et 80 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 – ring-

closure 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).

N

X

R2

R1

O

65b

S

XR1

R2 NH2

7

a

a: Knoevenagel-Cope condensat ion: diethylamine or morpholine (0.5 - 1.0 equiv. amount), MeOH or EtOH, RT - 45 °C;b: addit ion of sulfur , S8 (1.0 equiv. amount); c: r ing-closure.

-H2O

X

N

9

b

X

N

10

S

R2

Sx

cR1

R2

R1

S-

Scheme 4. Synthesis of substituted 2-aminothiophenes via the Version 2 of the Gewald

reaction [17].


8

Table 2. Substituted 2-aminothiophenes prepared via the Version 2 of the

Gewald reaction


Me COMe CO2Me 50 17

NH2 CO2Et CO2Et 45 17

Me CO2Et CO2Et 60 17

Ph Ph CN 95 34

SO2Ph 4-BrC6H4 CN 84 17

2.3. The Third Version of the Gewald Reaction

The third two-step version of the Gewald reaction allows the reaction of alkyl-

aryl 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).

9

a b

S

XR1

R2 NH2

7

a:Addition of sulf ur : secondary or tertiary amine, S8 (1.0 equiv. amount); MeOH or EtOH, RT- 50 °C;b: r ing-closure; X = CO2Me, CO2Et, CN, CO2H, CO2-t-Bu.

X

N

R1

R2

X

N

10

S

R2

Sx

R1

S

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


Table 3. Aminothiophenes achievable by the Version 3 of the Gewald reaction

R1 / R2 X Product Yield (%) Ref.

CN

51 37

CN

79 37

CN

64 37

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

S OH

R1R1

HO

NX

5c

X

N

8

SH S

XR1

NH2

7

a b

-H2O

6

a:Condensat ion: secondary or tertiary amine (1.0 equiv. amount), methanol, RT - 50 °C;

b: r ing-closure; R1 = H or alkyl, R2 = H.

R2R2

R1

Scheme 6. Synthesis of mono- and disubstituted 2-aminothiophenes utilizing the fourth

major version [31].

CO2MeMe

CO2MeMe

EtCO2Me

CO2MeMe


10

Table 4. Substituted 2-aminothiophenes obtainable using the Version 4 of the

Gewald reaction


H H CO2Me 58 31

Me H Me 52 31

H H CN 72 38

H H CONH2 46 38

Me H Me 81 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 2-

aminothiophene 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 .


X

N

10

S

R2

Sx

X

N

8

S

R2

H

ring closure

S NHR2

H

R1 X

11

amino-iminotautomer ism

S NH2

R1 X

R2

7

R1

R1

S-

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 S-

nucleophile 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 S4

2- 60, 61 . In an upgraded way the cyanomethyl anion (

-CH2CN) is


12

generated by galvanostatic reduction of acetonitrile solution (in a mixture with

supporting electrolyte tetraethylammonium hexafluorophosphate - TEAHFP) 62 .

Formed anion (-CH2CN) is highly reactive and represents the basic species

necessary to activate S8 and form S-cyanomethyl anion acting as a promoter of the

ylidene sulfur intermediate of the structure 12 (Scheme 9).

NHO

S

SS S

S

SSS

NOH

S (S)2_5 S-

morpholine S8

R1 X

N

10

S

R2

SxNO

H

H

S NH2

R1 X

R2

f ormat ion of S-nucleophile

MPS

addition of sulf ur ring-closure

7

X

N

9

R1

R2

S-

Scheme 8. Base-promoted formation of the ylidene sulfur adduct 10 using polysulfide-like

reagent MPS [57-59].

NCCH2

S

SS S

S

SSS

S8

NCCH2

S7 S-

R1 X

R2 NH

SS7 CH2CN

- NCCH2S6-S-

S NH2

R1 X

R2

MeCN/TEAHFP

I= 25 mAcm-2

for marion of activeS-cyanomethyl anion

addit ion of sulf ur

12

ring closur e

7

X

N

9

R1

R2

Scheme 9. Addition of sulfur to , -unsaturated nitrile 9 via electrochemical activation

through nucleophile 12 [62].


XR1

R2

N

9

Gewald´s synthesisof 2-aminothiophenes

red esignedGewald reaction

S8, base

X

N

10

S

R2

Sx

R1

NH2

R2

R1

X X

CN

R2

X

addition of sulf urMichael addition

R2

R1

X X

N

N

13

14

Thorpe cyclizat ion

S NHR2

H

R1 X

11amino-iminotautomerism

S NH2

R1 X

R2

7

S8, base

base

base

re-cyclization

r ing closure

S-

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 base-

promoted addition of sulfur, the ylidene sulfur adduct 12 is formed by addition of

a S-cyanomethyl anion onto cyano group (Scheme 9), while in the previous

version the polysulfide-like anion affects the methylene group of the , -

unsaturated nitrile 10 (Scheme 8). However, if the activation with sulfur does not

occur properly, the ylidene-sulfur adduct of presumed structure 10 or 12 is not

formed and the side-reaction takes place.

2.5.4. Dimerization vs. Cyclization

It is presumed, that the dimerization of Knoevenagel-Cope product - the , -

unsaturated nitrile 9 to six membered hexa-1,3-diene 14 occurs spontaneously as

a side-reaction in the Gewald´s process (Scheme 10) 66 . The yield of a dimer 14

is highly dependent on the reaction conditions. While in some cases the ylidene

dimerization is significant and the by-product is isolated in higher yield than the

desired 2-aminothiophene derivative 58 , on other hand under the suitable

reaction conditions not only straightforward reaction is favored, but also the

recyclization of dimerized ylidene 14 to appropriate aminothiophene 7 occurs 59 .

The dimer 14 preferably is formed in the less studied, so-called redesigned Gewald

procedure which suits to preparation six-membered carbonitriles with free amino


14

group 67 . If the reaction is directed towards formation of derivatives 14, the

anion generated from the , -unsaturated nitrile 9 undergoes first to base-

promoted 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 two-

step 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 solid-

supported synthesis 86 and microwave accelerated the Gewald reaction 24 .


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 2-

aminothiophene carboxylic acids were isolated as N-acetyl protected derivatives

20 upon the cleavage of the resin with trifluoroacetic acid (Scheme 11).

HO

15

NCOH

O

16

a

O

O

NC

17

R2

R1

O

18

b

S

R1

R2 NH2

O

O

19

c, d

S

CO2HR1

R2 NHCOMe

20

a: DIC, DMAP, CH2Cl2; b: morpholine, S8, EtOH, 75°C; c: AcCl, EtN(i-Pr)2, CH2Cl2, RT; d: TFA, H2O, CH2Cl2.

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

Table 5. Substituted 2-aminothiophenes 20 achieved during the solid-

supported Gewald´s synthesis


16

Aldehyde/Ketone 18 Product 20 Yield (%)

92

97

75

27

44

2.6.2. Microwave Accelerated Gewald Synthesis of Substituted 2-

Aminothiophenes

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 2-

aminothiophenes 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

SN

X

21

S

X

NH2

226

Et3N, MeOH, 50°C, microwave, 2 min.OH

HO

N O

HO2C 5

S

CO2H

NHCOMe

N

MeO2C 5

O

S

Et

NHCOMe

O

S

CO2H

NHCOMe

Et

Me

S

CO2H

NHCOMei-Pr

O

H


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

Yield (%) / Ref.

Classical conditions

CO2Me 82 [24] 55 [31]

CONH2 78 [24] 78 [88]

CONHPh 87 [24] 55 [16]

CO-t-Bu 81 [24] -

CN 60 [24] 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 2-

aminothiophenes 89, 99 .

N

X

R2

R1

O

65

S

XR1

R2 NH2

23

a or b

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

Scheme 13. KF/Al2O3 supported synthesis of 2-aminothiophenes 23 under a) microwave

and b) conventional heating 89 .

A variety of ketones 5 were reacted with ethyl cyanoacetate (6a) or

malononitrile (6b) and sulfur in the presence of KF-alumina 89 . KF immobilized

on Al2O3 represents the heterogeneous catalyst with advantageous properties like

better selectivity and easier work upon its use 90 . The application of KF-alumina

to a wide range of organic reactions has provided more convenient and efficient

methods in organic syntheses 91-95 . Its benefits arise from the strongly basic

nature of KF/Al2O3, which has allowed it to replace organic bases in a number of

reactions 96-98 . The reaction towards substituted 2-aminothiophenes 23 using

KF/Al2O3, was studied under microwave irradiation as well as under conventional


18

heating (Scheme 13) 89 . KF-alumina as a base used in Gewald synthesis

proceeded well producing 2-aminothiophene derivatives 23 in good yields. Using

the microwave irradiation reaction was carried out in very short times, but

alternatively the reaction proceed well also under conventional heating (Table 7).

Table 7. KF-alumina supported synthesis of 2-aminothiophenes 23 under a)

microwave irradiation and b) conventional heating

R1 R2 X Yield (%)

Microwave irradiation

(Reaction time/min)

Yield (%)

Conventional heating

(Reaction time/h)

Me Me Me 57 (3.5) 53 (4.0)

Me CO2Et CO2Et 58 (3.5) 50 (4.0)

Me CO2Et CN 58 (3.5) 55 (4.0)

Ph H CO2Et 61 (7.5) 55 (4.0)

Ph H CN 66 (7.5) 61 (4.0)

H Et CO2Et 62 (6.0) 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.


Cl

O

O

O

Me

O

O

NC

16

R2

R1

O

17

a, b

S

R1

R2 NH

O

O

CO2MeO25

c

S

CO2HR1

R2 NH

CO2MeO

26

a: S8, DBU, toluene, microwave irradiation, 20 min.b: i-Pr2EtN.toluene, microwave, 10 min.c: TFA, H2O, CH2Cl2

24

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 Yield (%) HPLC purity

(%)

90

82

90

93

90

99

90

70

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

H

i-Pr

O

H

t -Bu

O

H

Ph

O

Bu Me

O

S

CO2H

i-Pr NH

CO2MeO

S

CO2H

t-Bu NH

CO2MeO

S

CO2H

Ph NH

CO2MeO

S

CO2H

NH

CO2MeO

Me

Pr


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).

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

Ph

O

NC

O

Br

27 28

S

COPh

NH2Br

29

R

R

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

Table 9. 5-Bromo-substituted 2-aminothiophenes 29

R Yield (%)

3-CF3C6H4 48

3-NO2C6H4 30

4-CF3C6H4 52

4-NO2C6H4 33

4-CNC6H4 58

4-PhC6H4 48

2-naphtylC6H4 39

Later, the same research group 101 , have reported on synthesis of two 5-

bromo 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


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.

F3C

O

30

O

R1NC

31

aF3C

32

NCR1

O

b

S NH2

R1

O

33

c

S NHBoc

R1

O

34

d

S NHBoc

R1

O

35a,b

Br

a: TiCl4, CH2Cl2; b: S8, Et2NH, EtOH or dioxane;

c: Boc2O, DMAP, dioxane; d: NBS, AcOH, CH2Cl2.

35a: R1 = OEt, 96% yield;

35b: R1 = Ph, 99% yield.

CF3

CF3 CF3

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

Gewald synthesis 101 .

The versatility of title compounds as a synthetic entry to fused heterocycles

such as thieno 3,4-c thiolactones, thieno 2,3-b pyrroles, thieno 2,3-d pyrimidines

and thieno 2,3-b pyridines is highlighted in following chapters.


22

SNH2

CO2Me

36a-c

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.

R

36a: R =H36b: R = CO2Me.36c: R = CO2-t-Bu

a, b

S NHCOMe

CO2Me

37a-c

R1

Br

37a: R =Br37b: R = CO2Me.37c: R = CO2-t-Bu

c

S NHCOMe

CO2Me

38a-c

R1

S

NH2

H2N

Br

d

S NHCOMe

39a-c

R1

S O

e, 38a

S NHCOMe

39a

Br

S O

S NHCOMeBr

CO2Me

40

HS

S NHCOMeBr

CO2H

41

HS

65-90% 91-99% 46-51%

19% 10% 22%

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 methanol-

aqueous 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 3,4-

c 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


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,S-

acetal 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). 2-

Phenylaminothiophenes 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,S-

acetals with methyl iodide (Scheme 18).

The synthetic protocol for thieno 2,3-b pyrroles, which is based on the

reaction of 1,3-dicarbonyl compounds, can be applied also for preparation of

thieno 2,3-b thiophenes. As was reported in [118], the facile one-pot synthesis of

polysubstituted thiophenes and thieno 2,3-b thiophenes was completed through

cyclization of -oxo ketene (S,S)-acetals.


24

N S

Ph

EtO2C CO2Et

R2R1

a,bO

R2

O

R1

S-PhHN

O

R2

O

R1

method A

method B

d

SPhHN CO2Et

R2

O

R1

PhHN S

R2

O

R1

O

SMe

c

e

f

Method A: a: K2CO3, DMF, RT; b: PhNCS; c: BrCH2CO2Et, K2CO3, DMF; f: BrCH2CO2Et, K2CO3, acetone.Method B: a: K2CO3, DMF; b: PhNCS; d: MeI; e: HSCH2CO2Et, K2CO3, EtOH.

42 43

44

45

46

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 2,3-

d 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 base-

promoted thiophene cyclization with sulfur [35-37]. From the 2-aminothiophene-

3-carbonitrile 49a or methyl 2-aminothiophene-3-carboxylate 49b the annulation

of pyridine was performed using common pyrimidine annelation with guanidine


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.

OOBnBnO

47

a

OBnBnO

48a: R = CN48b: R = CO2Me

R CN

65-85%

b

75-80%S NH2

R

49a: R = CN49b: R = CO2Me

BnO

BnO S NH2

CHO

49c

BnO

BnO

c

Method A Method B

d, e, f

S

BnO

BnO

N

N

R

51a: R = NH2

51b: R = OH

51c: R = H

NH

NH2X

50a: R = NH2

50b: R = Cl

NH

NH2X

50a: R = NH2

50b: R = Cl

80%

a:methylcyanoacetate or malononitrile, NH4AcOH, AcOH, PhH, reflux; b: S8, EtOH, i-PrOH, 60 °C;Method A: c: 50a or 50b, DMSO, 130-150 °C,.

Method B: d: Ph3CCl, Et3N; e: DIBAL-H, -15 °C; f: Et3SiH, TFA; f: 50a or 50b, DMSO, 130-150 °C.

d

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

aminothiophenes 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-4,7-

dihydrothieno 2,3-b pyridine-5-carbonitriles 53 from substituted 2-

aminothiophene-3-carboxylate esters 7 was developed 132 . The key step of the

synthesis is a thermally promoted elimination/decarboxylation followed by

nucleophilic cyclization of 52 to give fused thieno-dihydropyridines 53 (Scheme

20) in good yields (Table 10).


26

S

R1

R2

X

NH2

a,b

S

R1

R2

X

NH

7 52

cCN

CO2-t-BuS

R1

R2

53

NH

OCN

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 2-

aminothiophenes 7 132 .

Table 10. Yields of synthesis of the acrylates 52 and fused thieno-

dihydropyridines 53

R1 R2 X

(for 7, 52)

Yield (%) of 52

Yield (%) of 53

H H CO2Me 78 91

H Me CO2Et 64 85

H i-Pr CO2Et 73 78

Me H CO2Me 53 86

Et H CO2Et 33 88

Ph H CO2Et 53 90

Bn H CO2Me 70 79

Me Me CO2Me 69 91

H 4-F-C6H4 CO2Et 23 87

Me 4-F-C6H4 CO2Me 76 64

H 4-Cl-C6H4 CO2Et 70 72

H 4-Br-C6H4 CO2Et 41 77

H 4-CH3O-C6H4 CO2Me 32 99

H 2-furyl CO2Et 55 77

4. APPLICATIONS OF 2-AMINOTHIOPHENES

Following parts of chapter detail about the utilization of substituted 2-

aminothiophenes as precursors in synthesis of pharmaceuticals, dyes and potential

building blocks in materials chemistry.


4.1. Synthesis of Pharmaceuticals and Drugs

As we have discussed above (Chapter 3.1.3), substituted thieno 2,3-

d pyrimidines and thieno 2,3-b pyridines (Chapter 3.1.4) exhibit valuable

biological activity in numerous of diseases. Generally, substituted 2-

aminothiophenes 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-acetyldihydrofuran-

2(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 co-

enzyme present in a number of enzymes, including pyruvate decarboxylase,

transketolase, pyruvate oxidase.


28

a: SO2Cl2; b:AcOH, HCl, Ac2O; c: NCCH2CO2Et, AcONH4, AcOH, PhMe; d: NaSH, EtOH; e: CuBr2, t-BuONO, CH3CN; f: Zn, AcOH;g: LiAlH4, Et2O; h: MnO2, CHCl3; i: PhNH-(CH2)2CN, NaOMe, DMSO, MeOH; j : CH3C(=NH)NH2, HCl, NaOEt, EtOH.

O O

O

52

a, b, c

72%

EtO2C

NC

OAc

Cl

CH3

53

d

82% SH2N

EtO2C

OAc

54

e

93% SBr

EtO2C

OAc

55

f

S

EtO2C

OH

56

87%

g, h

76%S

OH

57

O

i

94%S

OH

58

NC

PhNH

j

81%SOH

59

N

N

NH2

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

SOP2O6

3-

N

N

NH2

Deaza-TDP

Figure 1. Deazathiamine diphosphate.

N

SOP2O6

3-

N

N

NH2

TDP

Figure 2. Thiamine diphosphate.


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 1,3-

oxazin-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.

45-51%S NH2

CO2-t-BuR1

R2

a:CSCl2, CaCO3, CH2Cl2, H2O, 0 °C; b: TFA, CH2Cl2, 0 °C ; c: MeI or RBr, Na2CO3, acetone, RT.

a

60a: R1 = R2 = (CH2)460b: R1 = R2 = Me

28-56%S NCS

CO2-t-BuR1

R2

b

61a: R1 = R2 = (CH2)461b: R1 = R2 = Me

S

R1

R2

62a: R1 = R2 = (CH2)462b: R1 = R2 = Me

NH

O

O

S28-56%

c

S

R1

R2

63a: R = Me, R1 = R2 = (CH2)463b: R = Me R1 = R2 = Me

63c: R = Et, R1 = R2 = (CH2)4

63d: R = Et, R1 = R2 = Me

63e: R = CH2Ph, R1 = R2 = (CH2)463f: R = CH2Ph, R1 = R2 = Me

63g: R = CH2CO2Me, R1 = R2 = (CH2)463h: R = CH2CO2Me, R1 = R2 = Me

N

O

O

SR

60 61 62 63

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


30

4.1.3. 5-Substituted 2-aminothiophenes as A1 Adenosine Receptor Allosteric

Enhancers

Adenosine is an important endogenous tissue-protective compound released

during ischemia, hypoxia or inflammation. Four receptor subtypes (A1, A2A, A2B,

A3) have been defined based on pharmacological properties [137, 138].

Considerable effort has been directed towards developing therapeutic agents

targeting these receptors [139]. The first allosteric enhancers acting at the

adenosine A1 receptor were reported in early 1990s [140, 141]. Since this initial

discovery some molecules have been approved for use in the treatment of supra

ventricular tachycardia [142], anti-arrhythmic agent [143] and cardio protective

agent [144]. Substituted 2-aminothiophenes of structure 66-69, with alkyl, aryl and

cycloalkyl substituents in C-4 and C-5 position and aroyl substituent in C-3

position (Figure 3), maintained the best allosteric enhancer activity [145, 146].

The significant effort in the area of synthetic aminothiophene-based allosteric

enhancer is directed to development and synthesis of adenosine receptor agonists

with limited side-effects 13, 100, 101, 145, 146 .

S NH2

O

R

64

S NH2

O

R

65

S NH2

O

R

N

66

Ph

S NH2

OPh

Ph

67

O

R

R = H, 2-Cl, 3-Cl, 4-Cl, 3,4-di-Cl, 3-CF3, 4-CF3, 4-CH3, 4-NO2, 4-CO2H, 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


this series of derivatives was presented by authors 148, 149 from ethyl 2-amino-

4-methylthiophene-3-carboxylate.

S

70

R2

R1

NH

O

S

71

R2

R1

NR

O

O

R1 = R2 = Me, R1 = Ph, R2 = Me, R = tosyl or benzoyl

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

S

72

N

O

O

HN

O

R

R = H, 2-Cl, 2-Br, 2-Me, 2-NO2, 2-EtO, 4-CHO

Figure 5. The f amily of herpes proteases HSV-2thieno[2,3-d]oxazinones 72

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

S

70

R2

R1

NH

O

S

71

R2

R1

NR

O

O

R1 = R2 = Me, R1 = Ph, R2 = Me, R = tosyl or benzoyl

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

S

72

N

O

O

HN

O

R

R = H, 2-Cl, 2-Br, 2-Me, 2-NO2, 2-EtO, 4-CHO

Figure 5. The f amily of herpes proteases HSV-2thieno[2,3-d]oxazinones 72

Figure 5. The family of herpes proteases HSV-2 thieno[2,3-d]oxazinones 72.

Transglutaminases (TGases) are a family of Ca2

dependent enzymes which

are normally expressed at low levels in many different tissues and serve vital roles,

such as blood clothing and epithelia formation. Some TGase isoenzymes are

involved in diverse pathological conditions like celiac disease, atherosclerosis and

neurodegenerative disorders. Thieno 2,3-d pyrimidine-4-hydrazide derivatives

related to structure 73 (Figure 6) were discovered as a moderately potent inhibitors

of TGase-2 (tissue transglutaminase) 150 .

The RNA polymerase holoenzyme is a proven target for antibacterial agents.

A high-throughput screening program based on this enzyme from Staphylococcus

aureus had identified a 2-ureido-thiophene-3-carboxylate 74 (Figure 7) as a low

micromolar inhibitor. It displayed good antibacterial activity against S. aureus and

S. epidermidis. Based on these author observations 151 reported a synthesis of

the number of analogs of 74 via the Gewald reaction and evaluated for cytotoxic

activity against Rifampicin-resistant S. aureus.


32

S

73

N

N

O

SO

HN NH2

S NH

CO2Et

NH

74

O

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

Figure 7. 2-Ureido-cyclooctano[b]thiophene-3-carboxylate 74antibacterial agent against S. aureus

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

S

73

N

N

O

SO

HN NH2

S NH

CO2Et

NH

74

O

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

Figure 7. 2-Ureido-cyclooctano[b]thiophene-3-carboxylate 74antibacterial agent against S. aureus

Figure 7. 2-Ureido-cyclooctano[b]thiophene-3-carboxylate 74 antibacterial agent against S.

aureus.

S NH

CN

O NH

75

ON

N

Cl

Cl

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 2-

aminothiophenes 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,


101, 119-127 . It is no doubt, that this area of Gewald-like thiophene derivatives

exhibits the highest progress in a scope and utilization.

4.2. Synthesis of Building Blocks for Opto-electronic Devices,

Sensors and Self-assembled Superstructures

Oligothiophenes with well defined structures have recently received a great

deal of attentions not only as a model compounds for conducting polymers, but

also as a new class of functional -electron systems 153 . Since the initial

discovery of organic compounds showing metallic conductivity, for which 2000

Nobel prize in chemistry was awarded 154-156 , oligo- and polythiophenes have

attracted much attention as advanced molecules with practical use in electronic

devices 157-160 and their potential application in field-effect transistors 161 ,

photovoltaic devices 162 and organic electroluminescent devices 163 .

The employment of substituted 2-aminothiophenes in such areas represents

the latest discovery showing a great promise in materials chemistry for the

generation of novel oligo- and polythiophene structures.

4.2.1. Synthesis of Thiophene-based Azometines

The authors 164, 165 have discovered a facile synthesis of substituted

azometines by a condensation of diethyl 2,5-diaminothiophene-3,4-dicarboxylate

(76) with thiophene-2-carbaldehyde (77) or 5-(thiophen-2-yl)thiophene-2-

carbaldehyde (78) the appropriate azometines 79-82 were achieved (Scheme 23).

S NH2

CO2EtEtO2C

H2N

74

S

CHO

75

S

CHO

S

76

ba

94% 81%

S

CHO

75

S N

CO2EtEtO2C

N

80

S

S N

CO2EtEtO2C

H2N

77

S

S

S N

CO2EtEtO2C

N

78

S

S

S

S

S

CHO

S

76

a

36%

b

50%

S N

CO2EtEtO2C

H2N

79

SS

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 .


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 2-

aminothiophenes 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.

Ar

ON

R1N

S

ArR1

NH2

83a d

N81 a-d 82 a-c

morpholine-polysulf ide (MPS), S8, methanol

50-62%

Product Yield (%) Product Yield (%)

62

52

58

50

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

S

CO2Me

NH2

S

NC

85a

SNH2

NC

S

CN

85b

S

CO2Me

NH2

N

NC

85c

S

CO2Me

NH2

N

NC

85d


S

84

S

S

NH2

NC

CO2Me CO2Me

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 169-

172 . 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 thiophene-

containing 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 2-

aminothiophenes 90 in the dyeing of synthetic fibres 178-187 , blended polyester

wool fibres 188, 189 and also in optical data store devices 190 .


36

S

XR1

R2NH2

a: nitrosylsulfuric acid, 0°C

b:YH

7

S

XR1

R2N

90

N Y

For 90:

X = CN, CO2Et, CONH2, etc.

R1 = R2 = alkyl, cycloalkyl, aryl or

R1 = alkyl, aryl and

R2 = CN,CO2Et, CONH2, etc.

For couplers: Y = HO

HO

85 86

HO OH

CH2CH2OH

Me

87

CH2CH2OH

Et

88

CH2CH2OH

CH2CH2CN

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.


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Peer review arranged by authors: Dipl. Ing. Daniel Végh, DrSc., Institute of

Organic Chemistry, Catalysis and Petrochemistry, Department of Organic

Chemistry, Slovak University of Technology, Radlinského 9, 81239 Bratislava,

Slovakia, Phone: +421-(02)-59325-144, Fax: +421-(02)-52968560, E-mail:

[email protected]



Chapter 2

ADAMANTYL-1 AND ADAMANTYL-2

IMIDAZOLES AND BENZIMIDAZOLES.

METHODS OF SYNTHESIS,

PROPERTIES AND BIOLOGICAL ACTIVITY

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

Sh. A. Samsoniya Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I.

Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT

The interest towards adamantylcontaining imidazoles and

benzimidazoles is stipulated by broad spectrum of their biological effects and

important technical properties. At present, different methods of synthesis are

elaborated and definite success in study of the structure features and

reactivity of imidazole and benzimidazole derivatives of adamantane series is

achieved.

In this survey, literary information about synthesis methods, structure,

physical-chemical and biological properties is summarized, and also

information about conversion of adamantyl-1 and adamantyl-2 imidazole and

benzimidazole derivatives is given. The bibliography includes 96 references.

D. S. Zurabishvili, M. O. Lomidze, M. V. Trapaidze et al. 48

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]:

(CH2)n

(CH2)n

O

CH2Br

H2NCHO

NH

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-(1-

Adamantoyl)-4-(1-adamantyl)imidazole (3) with 73% yield was obtained after

boiling this compound in xylene during 15 hour.

COCH2N

3O

NH

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(1-

adamantyl)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]:


O

CH2OCOCH

3

RCHO, NH3 N

H

NR

CH3OH, Cu(OAc)2

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

ONH

N

NH3, CH

3OH

Cu(OAc)2

3

O

CH2NH

2

NH4SCN

NH

NSH. HBr

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:

CNBuLi,

CH3 SCH

2NC

NH

N

CH3 S

- 78 oC

7

By interaction of adamantylbromomethylketone with imidazole, formation of

compound 8 takes place [20]:


NHNO

CH2Br

NN CH

2

O

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:

NH

N

OH

CONH2 COCl

NH

N

OCO

CONH2

C5H

5N

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]:

NH

OC2H

5

R

H2N

CONH2

COOH

CH3OH

RNH

N

OH

CONH2

. HCl

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]:


NH

N

OOC R1

R

R2

CONH2

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]:

NH

N

N

N

Si(CH3)3

NH

N[(CH3)3Si]2NH AdCl

TiCl4, CHCl3

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


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].

Br

NH

NN

N

20

German patent [27] describes . (+)-(2-Hydroxy-2-adamantyl)-1-imidazolyl-3-

tolylmethan (21), dextroenantiomer and its salts as medicinal remedies with

antidepressant action:

NNCH

CH3

OH

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:

N

N

R1X

R2

(CH2)n

(CH2)n

AD

N

R3

(CH2)nR

6

R5

R4

22

n = 0-8; X = O, S


N

N

R2X

R3

(CH2)mAd

CR4

R5

R6

23

m = 0-4; X = O, S

N

N

R1X

R2

(CH2)mAd

(CH2)n

O

N

R4

R5

R6

R3 24

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

R4 O

N

N

CH2Ad

R2X

R3

N

R

R1

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-(1-

adamantyl)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)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

O

NaH

N

N CO

N

N+

Cl _

:C

26 27

SO2

N N

SO2

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-(1-

adamantoylmethyl)thiazolium, bromides, which were converted into compounds

29 and 30 by heating in a sodium hydrocarbonate solution [37].


O

CH2Br

SN

NH2

N N

N

NH2

S

N

N

SN

NH2

O

CH

2

N

NH2O

CH

2

Br-

+

Br-

+

29

30

In [38], the authors have studied interaction of bromomethyl(1-

adamantyl)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.

O

Br

X

NHR

R

X

N

N

R

R1NHC

200-250oC

31-37

(31) X=O, R=H, R1= H; (32) X=O, R=Ph, R

1= H; (33) X=O, R=Ac, R

1= H; (34) X=S,

R=H, R1= H; (35) X=S, R=Ph, R

1= H; (36) X=S, R=Ac, R

1= H; (37) X=S, R=Ph, R

1= 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.


O

CH2NHR

CH3COOH

KSCN

N

N

R

SH

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 α-

aminoketones, 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].

NH2

O

OEt

Me3C

NH

OEt

CH3COOH

O

N

N

HCMe

3

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)-4,5-

dinitroimidazole (41) with 75% yield was obtained, and by adamantylation 4(5)-

nitroimidazole mixture of phosphoric and acetic acids 1-(1-adamantyl)-4-

nitroimidazol (42) with 20% yield was obtained [40].

N

N

O2N

RNH

N

O2N

R

OH

H3PO

4/CH

3COOH

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


In order to synthesize adamantylimidazoles, the authors of [41] have used

interaction of 1,3-dehydroadamantane with imidazoles, which gives only N-

substituted derivatives 20, 43:

20

43

The authors of [42] have studied interactions of imidazoles with 1-

adamantylbromide at 110-180oC. They have stated that interaction of imidazoles

with 1-adamantylbromide at rate 8:1, at the mentioned temperatures in o-

dichlorobenzene 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

N

R

NH

N

R

20, 44 1, 45

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

NN

NN

NH

N

NH

N


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)-2-

cyclohexyl-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]:

ONH

N

CH2

CO NH COOH

46

The invention provides adamantane derivatives 47, 48, a process for their

prepn., pharmaceutical compounds containing them, and their use in therapy [44].

D

E

R2 X-R4-Y-R

5-Z

R1

47, 48

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


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.

N N

R

R

1

29, 49-51

(29) R = H, R1=H; (49) R=Br, R

1=H; (50) R=NO, R

1=H; (51) R=Br, R

1= 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].

N

CH3

NH2

O

Br N

CH3

NH2

O

N N

CH3

+

Br _ _ HBr

1

23

4

5

6

7

8

9

a b y

a52a

52


N N

CH3

N N

CH3

Br

N N

CHBr2

Br

N N

Br

HO

N N

Br

HNNH

NO2

O2N

1(2) NBS

3 NBS

H2O

52

b

53

54

55

In reaction [46] with equimolar amount or twice the amount of N-

bromosuccinimide (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-[1,2-

a]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


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.

N N

R

R

R

R

1

2

3

29, 49, 52, 56-58

(29) R=R1=R

2=R

3=H; (49) R=R

1=R

2=H, R

3= Br ; (52) R=R

2=R

3=H, R

1=CH3;

(56) R=R1=R

3=H, R

2=CH3; (57) R=Cl, R

1=R

2=R

3=H; (58) R=Br, R

1=R

3=H, R

2=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 2-

aminopyridine with bromomethyl (adamantan-1-yl) ketone was successfully

carried out with a high yield of 1-[3-adamantan-1-yl)-2-oxoethyl]-2-amino-

pyridinium 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 2-

amino-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 electron-

accepting 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[1,2-

a]pyridine (29) converts into 2-(adamantan-1-yl)-3-bromoimidazopyridine(49).


Under more rigid conditions, the reaction pathway with phosphorus tribromide

does not alter, while with phosphorus trichloride, 2-(3-chloroadamantan-1-

yl)imidazopyridines 59 and 60 are formed [48].

49, 53

59, 60

(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

N

N

HN

N

H

CH2

O

OMe

CH3

O

OMe

CH3-OH

O

CH3

O

CHOMe:

MeOAc+ +

_

_

26

N N

R N N

R

Br

N N

R

Cl

23

5

6

7

ab

y

PCl3

PBr3

29,52


The authors in [53] described adamantane-containing imidazo[1,2-

a]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 N-

bromsuccinimide results in introduction of bromine atom in imidazole ring (53),

while the reaction with three moles of N-bromsuccinimide - 2-adamantyl-3-

bromo-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]

R

N

N

R

RN

N

S

R1

2

3

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.

63

64

OH OH

NH

N

CH3

N

N

CH3

OH

NH

N

N

N

OH


The authors in [54] studied interaction of spatially constrained 2-(2-

hydroxyphenyl)-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-H-

1-azole-1-ylmethyl)phenols 65, 66, 67 [93].

65, 66

67

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

NN

R

OH

Ad

CH3

OH

XN(CH

3)3

Y

NH

N

R

NH

N

NH

N

Ad

OH

Ad

OH

N

N

N

N

+

_J

X=1-adamantyl, Y=CH3

X=H, Y=1-Adamantyl

a

b

a

ba,b

ADAMANTYLBENZIMIDAZOLES: SYNTHESIS, PROPERTIES

Despite many works concerning benzimidazole line, adamantyl-

benzimidazoles 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 o-

phenylenediamine and cyclization of obtained N-(1-adamantylcarbonyl)-o-

phenylenediamine in the presence of polyphosphoric acid ester (ppe) in

chloroform environment. The yield of 2-(1-adamantyl)benzimidazole (68) made

96%:


COClN

NH

NH2

NH2

NH2

NHCO

TEA

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%:

CN

OR

NH

NH2

NH2

N

NH

ROH

HCl

.HCl

ROH

68

Reaction of diiminoester dihydrochloride with stoichiometric amount of o-

phenylenediamine leads to the synthesis only 1-(benzimidazolyl-2)-3-

methoxycarbonyladanamtane (69) [58]

N

NH

COOMeNH

NH

MeO

OMe

NH2

NH2

HCl

HCl.

.

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


of dinitrile of adamantanedicarboxylic acid and o-phenylenediamine in cumene in

the presence of hydrochloric acid [58].

NH

NH

MeO

OMe

CN

CN

N

NH

NNH

HCl

HCl.

.

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]:

N

NH

COOMe

N

NH

NNH

KU-2

115oC

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]:


N

NH

COOMeOH

NH2

N

NH

NO

72

At interaction of compound 69 with methyl iodide, acetylchloride and

paraform, corresponding N-substituted 73-75 are obtained .

N

NH

COOMe

N

N

COOMe

R 69 73-75

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

In 1974-75, works concerning the synthesis of pharmacologically active 1-

adamantylsubstituted 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].


O

NH(CH2)2CN

O

NH(CH2)2

NH

OC2H

5

NH2

NHRC2H5OH

HCl

.HCl

O

NH(CH2)2

N

N

R

76 (R=H), 77 (R= CH3).

NH2

NH2

NH

NH

OC2H

5

O

N

N

NHCOCH2

.HCl

78

The yields of compounds 76 and 77 reaches 50% and 60% respectively and

that of compound 78 is only 10%.

NH

CH3

CONH

N

N

CH3

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-dinitro-

phenylglicylamino)adamantane in pH 8.5 phosphate buffer, at 90oC during 136

hours.


N

NH

NO2

NHCOCH2NH

O2N

NO2

NHCO

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%.

NHCOCH2

NH2

CH2OHCH

2OH N

NH

CH2COCl

NH2

NO2

NHCOCH2

NO2

Pd/C

H2

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%.


COOH

NH2

NH2

R

R1N

NH

R

R1

68, 82-84

(68) R=R1=H; (82) R=Cl, R

1=H; (83) R=CH3, R

1=H. (84) R=R

1=CH3

Hollan obtained compound 68 with 97% yield by boiling N-(1-

adamantylcarbonyl)-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].

NH2

NHCON

NH

conc.HCl

or AdCOOH (8 kbar)

C2H5OH

68

Synthesis of compound 68 by oxidative decarboxylation of adamantane

carboxylic acid is described in [25]. Initially, for the synthesis of 2-(1-

adamantyl)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 N-

methylation, 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]:


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% .

N

NH

ClN

NH

N

N

Si(CH3)3

[(CH3)3Si]2NH

AlCl3, CHCl3

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.

S2O82 + 2AdCOOH

Ag 2Ad + 2CO2 + 2HSO4

-.

-

N

NH

SO3H

N

NH

.Ad

68


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.

BrN

NH

N

N

86

In 1986, Polish scientists [65] obtained benzimidazoles 81, 87-90 with 32-

42% yield by heating equimolar amounts of 3-R-adamant-1-ylacetic acid and 4-

R1

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

N

NH

RCH2COOH

R

NH2

NH2

R1

R1

81, 87-90

(81) R=R1=H; (87) R=H, R

1=Cl.; (88) R=H, R

1=Br ; (89) R=H, R

1=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].


91

92

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.

N

N

R

NH2

ClCH2CONHR

1

CH3COCH

3

N

N

R

NH

CH2CONHR

1

. HCl

93-97

(93) R= CH3, R1=1-Ad; (94) R= C2H5, R

1=1-Ad; (95) R= C4H9, R

1=1-Ad; (96) R= CH3 ,

R1=2-Ad; (97) R= C2H5, R

1=2-Ad

Morozov and co. [67] synthesized aminomethyl derivatives 98-100 of

adamantanecontaining imidazobenzimidazole. By interaction of

bromomethylsubstituted imidazobenzimidazole ester with N-methyl-N-(1-

adamantyl)amine with (1:2) ratio, bromine is easily substituted by amino group.

The reaction proceeds at boiling in benzene medium without catalyst.

Psychotropic action of 98-100 compounds is elucidated.

N

NH

O

N

N

CH2CHOHCH

3

N

N

SO2CH

3

CH3SO2Cl


COOR

NCH

2Br

N

R

N

NHCH3

COOR

NN

N

R

N

CH3

11

98-100

(98) R=R1=CH3; (99) R=CH3, R

1=C2H5; (100) R= Bu, R

1= 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.

N

N

(CR4R

5)nR

6

A

R1

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%.


N

N

R

NH2

COCH2Br N

N

R

NH2Br

CH2CO

+ _

102-105

(102) R=CH3; (103) (104) (105)R=CH2CH2N(C2H5)2

NR=CH2CH

2-

N OR=CH2CH

2-

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].

N

N

R

NH

CH2CO

N

R

N

N. HBr

.2 HCl

conc. HCl

104, 105 106, 107

(104, 106)

N OR=CH2CH

2-

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

A method for the synthesis of compound 85 by the interaction of

benzimidazole with hexamethyldisilazane followed by alkylation of N-

trimethylsilylbenzimidazole with 1-chloroadamantane in the presence of

aluminum chloride in chloroform at 0°C is known [24]. The yield of compound

85 by the previous method was 49% [24].


The authors [76] have developed the following method for the preparation of

compound 85:

NH

NNH2

NH2

HCOOH

2 HCl.

95-105oC

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)-(1-

adamantyl)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:

R2

R1

N

NH

R3

R4

R5 108-122

in which: (108) R1=OH, R

2= H, R

3=1-Ad, R

4= OH; (109) R

1= O-CH2-C6H5, R

2= H, R

3=1-

Ad, R4= O-CH2-C6H5, R

5=H; (110) R

1=H, R

2= OH, R

3=1-Ad, R

4= OH, R

5=H; (111) R

1=H,

R2= OCH3, R

3=1-Ad, R

4=OCH3, R

5=H; (112) R

1=H, R

2= O-CH2-C6H5, R

3=1-Ad, R

4= O-

CH3, R5=H; (113) R

1=H, R

2= OH, R

3=1-Ad, R

4=OCH3, R

5=H; (114) R

1=H, R

2= O-CH3,

R3=1-Ad, R

4= O-CH2-C6H5, R

5=H; (115) R

1=H, R

2= O-CH3, R

3=1-Ad, R

4= OH, R

5=H;

(116) R1=H, R

2= O-CH2-C6H5, R

3= O-CH2-C6H5, R

4=1-Ad, R

5=H; (117) R

1=H, R

2= OH,

R3= OH, R

4= 1-Ad, R

5=H; (118) ) R

1=H, R

2= O-CH2-C6H5, R

3=1-Ad, R

4= O-CH2-C6H5,

R5= O-CH3; (119) R

1=H, R

2= O-CH2-C6H5, R

3=1-Ad, R

4= O-CH2-C6H5, R

5=H; (120)

R1=H, R

2= OCOCH3, R

3=1-Ad, R

4= OCOCH3, R

5=H; (121) R

1=H, R

2= OH, R

3=1-Ad, R

4=

OH, R5= O-CH3; (122) R

1=H, R

2= OCOCH3, R

3=1-Ad, R

4=OH, R

5=H;

These new benzimidazole derivatives have proved to have , in human or

veterinary medicine, good activity with respect to inflammatory and /or


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

NH2

NH

N

R

RCOOH

2HCl.

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].

NH

N

R

N

N

R

R 1

R1Hal

85, 126 127-130

(85) R=H; (126) R = CH2Ph; (127) R = H, R1 = 1-adamantyl; (128) R = H, R

1= COPh;

(129) R = CH2Ph, R1= COPh; (130) R = CH2Ph, R

1 = COCH2Ph.

The results of biological examination of synthesized derivatives of 5(6)-(1-

adamantyl)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:


R1

R3R2

X

R4

131

X-benzilimidazolyl; R1

= H, Hal, alkyl; R2

= OH, alkyl, acyl, aminocarbonyl; R3

= H, OH,

alkyl; R4

= H, alkyl, Hal, alkoxy.

In [85] the authors provided alkylation of benzimidazole with 1-

adamantylbromomethylketone, alkylation product 132 was isolated, the optimum

conditions of the reaction were defined:

N

NH

O

CH2Br

N

N

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-(1-

adamantyl)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.


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 1-

bromoadamantane at 110-180oC and various reagents ratio [86].

N

N

N

N

+

Br-

86 134

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.


N

NH

MeO

COOH

135

In order to create new immunotropic remedies, the authors [88] synthesized

bromides of 3-(1-adamantylcarbonylmethyl)-2-amino-1-alkyl(aralkyl)-

benzimidazole:

N

N

R

NH2

CH2CO

+

Br-

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 1-

bromoadamantane 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 o-

dichlorobenzene to afford a high yield of salt 134 (90%).As is well known, in the


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 1-

bromoadamantane 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.

N

N

+

Br-

N

N

N

N H

CN:

134 142 133

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].


N

N

S

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)-2,3-

dihydro-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(1-

adamantyl)benzimidazol-2-ylidene (133), determined by X-ray analysis. 1,3-

Bis(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.

O

NNH

O

N

NH

NH

144


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 spin-

coated from a solution. onto a wafer and thermally polymerised at 400° to give a

220-nm thick film.

R

R

R

R

CH

N

NH

N

NH

CH2

CH2

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-1-

ylmethyl)phenol 146 [93].

OH

N(CH3)3

Ad

N

NH

CF3 NN

CF3

OH

Ad

+

_J

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,


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.

NH

N

RNH

2

NH2

RCOOH

2HCl.

(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 230-

240ºC.

Benzimidazolylcarbamates are widely used in the preparation of fungicide

and antihelmintic preparations. They have prepared the adamantyl-substituted

benzimidazolylcarbamate .

NH2

NH2

NH

N

NHCOOMe

N NHCOOMe

pH 12, 35–40 oC pH 3, 95–100 oCCaNCN

ClCOOMeC

151


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)-(1-

adamantyl)-2-phenoxymethylbenzimidazole (150) they have condensed

compound 150 with benzaldehyde at 175-179ºC and obtained the product 152 in

50% yield.

NH

N

CH2O

NH

N O

PhCHO

150 152

They have further studied the nitration reaction of 5(6)-(1-

adamantyl)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.


153

154

155

NH

N

NH2

NH

N

NH2

NH

N

NO2

NH

N

O2N

NH

N

1) H2 , Ni

2) HCl

10% NaOH 2HCl

HNO3/H2SO4

30-35°C

.

85

ACKNOWLEDGEMENT

The designated project has been fulfilled by financial support of the Georgia

National Science Foundation (Grant #GNSF/ST08/4-413). Any idea in this

publication is passessed by the author and may not represent the opinion of the

Georgia National Science Foundation itself

We also would like to thank the Deutsche Academy Austausch Dienst

(DAAD) for supporting the partnership and the exchange program between Ivane

Javakhishvili Tbilisi State University and Saarland University.

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Chapter 3

METHODS OF SYNTHESIS OF

PYRROLOINDOLES

Sh. A. Samsoniya, I. Sh. Chikvaidze,

D. O. Kadzhrishvili, N. L. Targamadze Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I.


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.

Sh. A. Samsoniya, I. Sh. Chikvaidze, D. O. Kadzhrishvili et al. 100

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 [1-

3].

The highly active antitumour antibiotic CC-1065, molecule of which contains

pyrroloindole fragment, was isolated in 1987 from Streptomyces zebensis. Its

antitumour activity is many times greater than that of other known preparations

[4]. This stimulated further development of synthetic methods for the preparation

of pyrroloindoles.

New methods of synthesis of isomeric pyrroloindole derivatives have been

worked out at the department of Organic Chemistry at Iv. Javakhishvili Tbilisi

State University 1-4:

Methods of Synthesis of Pyrroloindoles 101

NH

HN

NH

NH

1

3

NH

HN

4

NH

NH

2

The first method is based on bicyclization of ethylpyruvate m- and p-

phenylenedihydrazones 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 p-

phenylenediamines. 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 p-

phenylenedihydrazone 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].


NH-N C

CH3

COOEt

NH

NH

COOEt

NH

NH

NH

HN

EtOOC

5

7

6

2

PPAEE

EtOOC

COOEt

NH

NH

COOH

9

HOOC

NH

HN

HOOC

8

COOH

NH

HN

1

N-HNC

H3C

EtOOC

Scheme 1.

NH

NH

EtOOC 11

EtOOC

NH-N

NH-N C

C

CH3

COOEt

CH3

COOEt10

NH

NH

3

PPAEE

1. OH-

2. - CO2

Scheme 2.


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).

N

COCH3

NH-NC

CH3

COOEt

HN

N

H3COC

COOEt

HN

N

H3COC

COOEt

N NH

H3COC

COOEt

12

13

15

N NH

H3COC

COOEt

16

HN

NH

COOH

17

HN

NH

4

HN NH

COOH

18

HN NH

3

MnO2MnO2

14

Scheme 3.


N

H3COCNH-N C

CH3

COOEt

NH

N

H3COC

COOEt

NH

N

H3COC

COOEt

NH

NH

COOH

NH

NH

HN

N

COCH3

EtOOC

HN

N

COCH3

EtOOC

19

20

21

22

24

2

HN

HNHOOC

HN

HN

1

MnO2MnO2

23

Scheme 4.


N

COCH3

NH-N C

CH3

COOEt

HN

N

H3COC

COOEt

HN

NH

COOH

N

NH

H3COC

COOEt

12

1314

NH

NH

COOH

HN

NH

4NH

NH

3

MnO2

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,


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.

NH

NH

28

HN

NH

29

Me2N-H2C

Me2N-H2C

NH

HN

Me2N-H2C

CH2-NMe2

R

R

25 R=H, 26 R=COOEt

Me2NH2C

CH2NMe2

NH

NH

27

Me2NH2C CH2NMe2

Scheme 6.


Among the indole Mannich bases, the alkaloid gramine (3-

dimethylaminomethylindole) 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).

NH

NH

32

HN

NH

33

NH

HN

C

C

30

NH

NH

31

OO

HH

C

O

H

C O

H

C

O

H

C

O

H

C

OH

C

OH

Scheme 7.


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[2,3-

e]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).

NH

HNC

36 (5%)

O

H

NH

HNC

35 (34%)

OH

NH

HN

C

34 (42%)

O

H

NH

HNC

C

37

OO

H

HEtOOC

COOEt

NH

NH

EtOOC COOEt

C

OH 38

Scheme 8.


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 β-

positions 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.

NH

HN

42 (6%)

NH

HNH3COC

40 (19%)

NH

HN

COCH3

39 (34%)

NH

HN

41 (9%)

COCH3

COCH3

H3COC

NH

NH

43

H3COC

Scheme 9.


NH

HN

N=N-C6H4-RR'

NH

NH

52 R=Cl; 53 R=NO2

R-C6H4-N=N

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

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

NH

N=N-C6H4-R

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

NH

R-C6H4-N=N

NH

N=N-C6H4-R

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

HN

R'

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 2,7-

diethoxycarbonylderivative (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].


NH

HN

NH

HN

NH

HN

NH

HN

CHO

OHC

OHC

HC C

R

NO2

CH

C

R

NO2

CHC

R

O2N

RCH 2NO 2

, DMFA

RC

H2N

O2

CH 3COONH 4

CH

3C

OO

NH

4

54,55

56,57

NH

HN NH

HN

OHC

OHC

OHC

CH=CH-COOH

CH=N-C6H5

CH=CH-COCH3

58

59

60

CH2(COOH)2

C5H5N

CH3 COCH

3

C6 H

5 NH

2

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

30

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.


NH

HN

CHOOHC

EtOOC

COOEt

NH

HN

CH=N-NH2

61

COOEt

EtOOC

H2N-N=HC

HN

HN

NHN

N

NHO

O

HN

HN

NN

N

NHO

OH

37

6362

NH2-NH2

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 2,6-

diethoxycarbonyl-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) m-

phenylenedihydrazone 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,


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-5-

indolinylhydrazone 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-2-

ethoxy-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,5H-

pyrrolo[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


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 (3-

Н), 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[3,2-

e]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 199-200

0С [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-oxycarbonyl-

3H,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 80-81

0С [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-


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, СН3-

СО); 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-2-

ethoxycarbonyl-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-7-

ethoxycarbonyl-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),


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-2-

ethoxycarbonyl-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.


REFERENCES

[1] 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).

[2] Sh.A. Samsoniya, B.A. Medvedev, D.O. Kadzhrishvili, D.M. Tabidze,

M.D. Mashkovskii, N.N.Suvorov, Khim-Farm. Zh., (Russian), 1335 (1982)

[3] Sh.A. Samsoniya, Z. Sh. Lomtatidze, S.V. Dolidze, N.N.Suvorov, Khim-

Farm. Zh., (Russian), 1452 (1984).

[4] V.H. Rawal, R.J. Jones, M.P. Gava, Heterocycles, 25, 701 (1987).

[5] 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).

[6] Sh.A. Samsoniya, N.L. Targamadze, N.N.Suvorov, Khim. Geterotsikl.

Soedin., (Russian), 849 (1980).

[7] 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).

[8] Sh.A. Samsoniya, D.O. Kadzhrishvili, N.N.Suvorov, Khim. Geterotsikl.

Soedin. 268 (1981).

[9] Sh.A. Samsoniya, D.O. Kadzhrishvili, Gordeev E.N., Zhigachev V.E.,

Kurkovskaya L.N., N.N. Suvorov, Khim. Geterotsikl. Soedin., 504 (1982).

[10] Sh.A. Samsoniya, N.L. Targamadze, L.N. Kurkovskaya, Dzh.A.

Kereselidze, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 639

(1980).

[11] D.O. Kadzhrishvili, Sh.A. Samsoniya, E.V. Gordeev, L.N. Kurkovskaya,

V.E. Zhigachev, N.N.Suvorov, Khim. Geterotsikl. Soedin., (Russian), 1219

(1984).

[12] Sh.A. Samsoniya, D.O. Kadzhrishvili, Gordeev E.N., N.N.Suvorov, Khim.

Geterotsikl. Soedin., (Russian), 1219 (1984).

[13] Sh.A. Samsoniya, N.L. Targamadze, T.A. Kozik, N.N.Suvorov, Khim.

Geterotsikl. Soedin., (Russian), 723 (1977).

[14] 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.

[15] G. Kinast, L-F Tietze, Angew. Chem. 88 261 (1976).

[16] Sh.A. Samsoniya, Z.Sh. Lomtatidze, S.V. Dolidze, N.N. Suvorov, Khim-

Farm. Zh., (Russian), 1452 (1984).


[17] S.V. Dolidze, Sh.A. Samsoniya, N.N. Suvorov, Khim. Geterotsikl. Soedin.,

(Russian), 608 (1983).



Chapter 4

PALLADIUM-CATALYZED AMINATION OF

DIHALOARENES: A SIMPLE AND EFFICIENT

APPROACH TO POLYAZAMACROCYCLES

Alexei D. Averin,1, Alexei N. Uglov,

1 Alla Lemeune,

2

Roger Guilard,2 Irina P. Beletskaya

1

1Lomonosov Moscow State University, Department of Chemistry, Leninskie

Gory, Moscow, 119991 Russia 2Institut de Chimie Moléculaire de l’Universite de Bourgogne, ICMUB-

LIMRES 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: 1,2- and 1,3-dibromobenzenes, 2,6-

dichlorobromobenzene, 2,6- and 3,5-dihalopyridines, 3,3'- and 4,4'-

dibromobiphenyls, 1,8- and 2,7-dibromonaphthalenes, 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

Alexei D. Averin, Alexei N. Uglov, Alla Lemeune et al. 120

polyamine moiety were often obtained together with cyclodimers and

cyclooligomers of higher masses. We elaborated two alternative approaches

to cyclodimers which are also valuable macrocycles possessing larger cavity

size: (a) via bis(haloaryl) substituted polyamines and (b) via bis(polyamine)

substituted arenes, and demonstrated that the applicability of these methods

strongly depended on the nature of the pair aryl halide/polyamine. Scope and

limitations for the synthesis of various polyazamacrocycles were established.

INTRODUCTION

Polyazamacrocycles (or azacrown ethers) attract a thorough and constant

interest of the researchers due to their unique ability of selective complexation of

various metals, organic and inorganic anions, and some polar molecules. During

the last decades hundreds of such compounds were synthesized, which contain

nitrogen, oxygen, and sulfur atoms [1]. Many polyazamacrocycles can serve as

molecular sensors due to their photochemical or redox properties, they contain

aromatic moieties which can be present as substituents at nitrogen atoms or can be

incorporated in the cycle.

Substantial interest was evoked by the synthesis and coordination properties

of different polyazamacrocycles which possess pyridine moiety in the

macrocyclic ring [2-14]. This pyridine fragment strongly influences the

thermodynamic properties and the complexation kinetics by increasing the

conformational rigidity of the ligand and by changing its basicity. In almost all

known macrocycles of such type, nitrogen atoms of the polyamine chain and

pyridine ring are separated by methylene, methyne or carbonyl groups: a single

compound with C(sp2)-N bond was obtained by reduction of the corresponding

diamide formed from 2,6-diaminopyridine and bis(acylchloride) [15]. Recently,

the synthesis of a number of pyridine-containing macrocycles by the reaction of

dimethylpyridine-2,6-dicarboxylates has been reported [16].

Macrocycles containing biphenyl units became a constant interest of

researchers due to interesting coordination possibilities of attaching flexible and

tunable polyoxa- and polyazacycles to a rigid non-planar aryl moiety. The most of

reported macrocycles based on biphenyls were synthesized using non-catalytic

approaches. Cyclic polyethers were formed starting from 2,2'-dihydroxybiphenyl

[17-19], and studied in coordination with cations like tert-butylammonium [18].

Transport of Li, Na, K cations [20, 21] and of Hg(CF3)2 [22, 23] through a liquid

membrane was studided using macrocycles of similar structure, in which one or

two polyoxaethylene chains are attached to one biphenyl unit.

Palladium-catalyzed Amination of Dihaloarenes 121

Polyoxadiaminomacrocycles were also synthesized on the basis of 2,2’-

disubstituted biphenyl and their complexation of primary alkylammonium salts,

including chiral ones, was studied [24]. Polyazamacrocycles with 3, 4 and 8

nitrogen atoms were investigated as complexing agents for Cu2+

, Zn2+

and

[PdCl4]2-

ions [25]. More complex macrocycles like peptide-biphenyl hybride [26]

and hemispherand macrocycle [27] with bi-and quaterphenyl moieties have been

recently reported. Cyclic triamides [28] as well as cyclic Schiff bases

(trianglimines) [29, 30] are less known represenattives comprising three 3,3’-

disubstituted biphenyls, the latter can be also built on the basis of 4,4’-

disubstituted biphenyls. In some cases macrocycles containing this fragment were

synthesized using Pd-catalyzed coupling of two benzene moieties at the last step,

as it was in the case of the macrocycle with diazacrown, dipeptide and biphenyl

fragments [31]. It is to be mentioned that biphenyls are incorporated in some

biologically active compounds, e.g. tricyclic glucopeptides of vancomicine group

[32].

Several examples of macrocycles with aromatic fragments were known for

decades. The first simplest representatives of the macrocycles containing

naphthalene unit were described in the literature 70 years ago [33]. Since that time

dozens of works appeared dealing with the synthesis and investigation of

naphthalene-based macrocycles of different geometry and with crown ethers

functionalized with naphthalene substituents in pendant arms. These macrocycles

may possess structural fragments of Schiff bases [34], diamide [35], diimide [36],

or lactam [37] groups, naphthalene can be fused to tetraazamacrocycles [38], the

molecules may contain phosphorus atoms [39] or have only carbon atoms in the

macroring [40]. Naphthalene moieties were also incorporated in more complicated

structures like calixarenes [41], catenanes [42], they were combined in defferent

manner with porphyrin units [43]. These sophisticated molecules find their

application as molecular receptors, mainly of organic anions [44], or even as

molecular rotors [45].

The main problem of the synthesis of the macrocycles with aromatic linkers is

the use of laborious multistep methods which result in rather low yields of the

target products [46-49]. In the majority of cases aromatic groups are separated

from the nitrogen atom at least by one methylene or methine group [50-55].

Therefore it was thought important to elaborate an easy synthetic route to such

macrocycles, and the aim of this chapter is to demonstrate how Pd-catalyzed

amination may serve to solve this problem.


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 Pd-

catalzyed 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 2-

dimethylamino-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 ortho-

position.


Br

Br

NH H2N

NHNH2

OH2N

OONH2

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

NaOtBudioxane

1

2a

2b

NH

NH

HN

HN

3a, 12%

Pd(dba)2 /

Cy2P

NMe2

16/18 mol%

NH

NH

O

O

O

3b, 14%

Scheme 1.

H2N

HN

NH2

1c

H2N NH

NH2

1d

H2N

HN

NH

NH2

1e

H2N

HN

HN

NH2

1f

H2N NH

HN NH2

1a

H2N NH

NH

NH2

1g

H2N

HN

NH

HN

NH2

1h

H2N

HN

NH

HN

NH

NH2

1i

H2NO

ONH2

1j

H2N OO NH2

1k

H2N OO

O NH2

1b

Figure 1.


Cl Cl

Br

X NH2H2N

+

4

2a-k

Pd(dba)2/BINAP

8/9 mol%

NaOtBu

dioxane

Cl

NH

NH

X

5a,b,d-k

5a, 47%

5b, 24%

5d, 8%

5e, 18%

5f, 17%

5g, 27%

5h, 12%

5i, 10%

5j, 12%

5k, 17%

X NHHNCl

Cl Cl

ClX NH2HN

X HNNHCl Cl

XNH HN

Cl Cl

6b,g-i,k7c,j,k

8b,d,k

6b, 12%

6d, 7%

6g, 7%

7c, 37%

7j, 27%

7k, 14%

8b, 9% (n = 1)

8d, 50% (n = 1, 2) (mixture)

8k, 10% (n = 1)

11% (n >1)

by-products:

6h, 17%

6i, 21%

6k, 10%

n

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


molecule of polyamine 2 was catalyzed with 16 mol% catalyst, and the majority

of cyclodimers 8 were isolated in quite reasonable yields 20-30%.

Cl

Br

Cl

X NH2H2N

4

2.2 equiv.

2a,b,d,j,k

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

tBuONadioxane

X NHNHCl

Cl Cl

Cl

6a,b,d,j,k, in situ

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

tBuONadioxane

X NH2H2N

2a,b,d,j,k

X HNNHCl

XNH HN

Cl

8a,b,d,j,k

85-90% 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.


X NH2H2N

2a-h,j,k

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

NaOtBudioxane

Br Br

9

+

HN NH

X

+

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

11a-f,j,k10a, 29%10b, 26%10d, 15%10e, 39%

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

X HNNH

XNH HN

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

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

Scheme 4.

Br Br

9

+

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

NaOtBudioxane

X NH2H2N

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

X NHHN

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

Br Br

X HNHN

Br

X NHNH

Br

+

13a,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(3-

bromobenzene)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%).

X NHHN

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

Br Br

+


NaOtBudioxane

X NH2H2N

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

X HNNH

XNH HN

11a,b,d,f,g,j,k

11a, 36%11b, 21%11d, 44%

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

Scheme 6.


3. MACROCYCLES CONTAINING 2,6-DISUBSTITUTED

PYRIDINE MOIETY

Having obtained encouraging results with the macrocyclic derivatives of m-

disubstituted benzene, we decided to synthesize the macrocycles with the simplest

heteroaromatic spacers. For these reasons we investigated the reactions of 2,6-

dibromopyridine (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-2-

yl)polyamines 16 whose formation proceeded via intermediate 2-bromo-6-tert-

butoxypyridine. 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.

+

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

NaOtBudioxane

X NH2H2N

2a-jNBr Br

14

NHN NH

X

NO X NH2NH

+

15a-j 16a-j

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

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

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

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

Scheme 7.


+


NaOtBudioxane

NBr Br

14, 3 equiv.

NH H2N

NHNH2

2a

NH HN

NHNH

N N

Br Br

NHN NH

HN

HN

+

17a, 28% 15a, 13%

+


NaOtBudioxane

NCl Cl

18, 3 equiv.

X NH2H2N

2a,f,j

X NHHN

N N

Cl Cl

+

X NH2HN

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 2,6-

dibromopyridine (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).

+


NaOtBudioxane

NBr Br

14

X NH2H2N

2a,j, 4 equiv.

X NH

H2N N X NH2NH

21a, 90%21j, 80%

Scheme 9.



NaOtBudioxane

Y NH2H2N

2a,f,j

X

NH

NH2

N

X

H2N

NH

X NHHN

N N

Hal Hal

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

+

N

Y

HN

NH

X

NH

HN N

NBr Br

21a,j

14


NaOtBudioxane

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

22a, 49%22j, 0%

22l: X = CH2NH(CH2)2NHCH222m: X = CH2NHCH2

22a,f,j,l,m

(A)

(B)

+

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


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).



NaOtBudioxane

X NH2H2N

2a-j

X

NH

NH2

N

X

H2N

NH

+

N

YNH HN

X HNHN

N

N

Br Br

23

N

HN NH

X

24a-j

By-products:

X NH2HN

NBr

X NHHN

NBr

NBr

25, 10-32% 26, 3-33%

27, 6-14%28, 1-6%

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

Scheme 11.

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

NaOtBudioxane

N

Cl Cl

29

+

NH H2N

NHNH2

2a

N

HN NH

HN HN

24a, 17%

NH HN

NHNH

NH H2N

NHNH

N N NCl Cl

+ +

30a 31a

30a + 31a, 31-51%

L = BINAP,PCy2 PtBu2 PCy2

Me2N

Cl

Scheme 12.



NaOtBudioxane

N

Br Br

23

2a,d, 4 equiv.

N N NBr Br

N


NaOtBudioxane

N

Br Br

23

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

27a, 90%27d, 90%

X NH2H2N

X NH2H2N

X

H2N

NH

X

NH

NH2

X NHHN X NH2HN

+

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

25a, 9-32%

in situ

Br

Scheme 13.

Donor phosphane ligands such as 2-di-tert-butylphosphino-1,1’-biphenyl, 2-

dicyclohexylphosphino-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

Br Br

23

N NHal

N

Pd(dba)2/BINAP

10-16/12-18 mol%

NaOtBu

dioxane

X

H2N

NH

X

NH

NH2

X NHHN

Hal

26a,b,d,j, 31a

+

X NH2H2N

2a,b,d,j N

Y

NH

NH

X

HN

NH

N

+

27a Pd(dba)2/L

8-16/9-20 mol%

NaOtBu

dioxane

28a,b,d

12%28a, 14%

28b, 15%

28d, 12%

28j, 0%

Scheme 14.


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 2-

chloropyrimidine and 2,4-dichloropyrimidine using diamines [68]. Since 2,4-

dichloropyrimidine 32 was found to form 2,4-bis(diamine) derivatives under non-

catalytic conditions, we decided to introduce it in the reaction with equimolar


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 7-

25% yields (Scheme 15) [69]. In this process cesium carbonate was used instead

of sodium tert-butoxide to prevent alkoxylation reaction.

N

N

Cl

Cl

32

+

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

Cs2CO3dioxane

X NH2H2N

2b,j,k N

N

HN

NH

X

33b,j,k

33b, 25%33j, 7%33k, 17%

Scheme 15.

N

N

Cl

34

+


Cs2CO3dioxane

X NH2H2N

2b,j,k

35b,j,k

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

ClN

N

NH

NH

X

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.


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).

+


NaOtBudioxane

X NH2H2N

2b,j,k

Br

Br

36

HN

HN

X

37b,k

37b, 10%37k, 5%

+

38b,j,k, 49-62%

X NHHN

XHN NH

n

Scheme 17.

H2N X NH2

2a-h,j-l

Pd(dba)2/BINAP

8/9 mol%

Br

Br

39

HN

NH

X

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

HN

NH

X

HN

X NH n

41a-h,j-l, 18-61%

+

40a, 44%40b, 38%40d, 25%40e, 16%40f, 26%

H2N NH2

2l40g, 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


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.


H2N X NH2

2a,b,j,l

Pd(dba)2/BINAP

4/4.5 mol%

Br

Br

36

Br

Br

39

HN

HN

XNH

NHX

HN

NH

X

HN

X

NH

2.2 equiv.

HN X NH

Br Br

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

Pd(dba)2/BINAP

8/9 mol%

Br NH

X NH

NH

X NH

Br+

43a, 18%; 43b, 19%

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

H2N X NH2

2a,b,j

Pd(dba)2/L

4/4.5 mol%

HN X NH

Br Br

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

2.2-3 equiv.

+

HN X NH

Br

HN X

HN

Br

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

Pd(dba)2/BINAP

8/9 mol%

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

H2N X NH2

2a,b,j,l

H2N X NH2

2a,b,j

Scheme 19.

H2N X NH2

2a,b,j

Pd(dba)2/BINAP

4/4.5 mol%

Br

Br

Br

Br

HN

HN

XNH

NHX

HN

NH

X

HN

XNH

4 equiv.

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

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

HN

HN X NH2

X NH2

46a,b,ji

in situ

Pd(dba)2/BINAP

8/9 mol%

HN

NH

X NH2

X NH2

47a,b,ji

in situ

Br

Br

Br

Br

36

39

Pd(dba)2/BINAP

8/9 mol%

Scheme 20.


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 1,8-

dibromonaphthalene to Pd(0). Then we ran the reactions using 2,7-

dibromobiphenyl 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.

Br Br

X NH2H2NNaOtBu, dioxane

2a,b,d,f-h,j,k48

HN NH

X

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

+

Pd(dba)2/BINAP

(8/9 mol%)

49a, 26%

49b, 26%

49f, 9%

49g, 28%

49h, 19%

49j, 10%

49k, 29%

X NHHN

XNH 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%

+

Scheme 21.


+

4 equiv.

Br Br

HNX

NH2

NH

XNH2

Br Br

X NH2H2N

2b,g,j

Pd(dba)2/BINAP

8/9 mol%

X HNNH

XNH HN

50b,g,jin situ

+

X NH2H2N

2.2 equiv.

Pd(dba)2/BINAP

(Pd(dba)2/Xanthphos)

2-4/2.5-4.5 мол%

Pd(dba)2/BINAP

8/9 mol%

X NH2H2N

X NHHN

Br Br

Br Br

X HNNH

XNH HN

2a,b,j

2a,b,j

51a,b,j

50a,b,j

54b,g,j

51b, 37%

51a, 27%

51j, 27%

X NHHN

Br XNH HN

Br

52a,b,j

+X NHN

Br Br

Br

+

53b,j52b, 6%

52a, 37%

52j, 13%

53b, 10%

53j, 10%

50a, 21%

50b, 28%

50j, 11%

Pd(dba)2/BINAP

(Pd(dba)2/Xanthphos)

4/4.5 мол%

50b, 30%

50g, 22%

50j, 10%

+

49b, 29%

49g, 19%

HN NH

X

48

48

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


cases cyclic oligomers were formed, and cyclodimers and cyclotrimers were

isolated in pure state.

X NH2H2N

tBuONa or Cs2CO3,

dioxane

2a,b,d-k

Pd(dba)2/BINAP

(8-16/9-18 mol%)

Cl Cl

Cl ClO

O

55

58

HN NHX

56a,b,d-k

NH HNO

O

X

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

56a, 24%

56b, 25%

56d, 25%

56e, 33%

56f, 36%

56g, 21%

56h, 26%

56i, 22%

56j, 28%

56k, 20%

59a, 25%

59b, 37%

59e, 14%

59f, 19%

59g, 10%

59h, 27%

59j, 43%

59k, 33%

HN

HN

X

NH

NH

X57b, 10%

57j, 8%+

HN

HN

X

NH

NH

X

O

O

O

O

60b, 18%

60k, 12%+

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%). 1,5-

Dichloroanthraquinone 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.


X NH2H2N

tBuONa or Cs2CO3,

dioxane

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

Pd(dba)2/BINAP

(8/9 mol%)

Cl

Cl O

O

61

64

Cl

Cl

HN

NH

X

62a,b,f,g,k

HN O

O NH

X

65b, 28%

65k, 30%

X NHH2N O

O Cl67a,e-g

62a, 34%

62b, 20%

62f, 20%

62g, 22%

62k, 24%

67a, 23%

67e, 28%

67f, 25%

67g, 25%

+

NH

X

NH

HN

X

NH

NH

X

NH

HN

X

NH

63e, 18%

63f, 10%

63j, 8%

O

O

O

O

66j, 18%

66k, 10%

+ +

Scheme 24.

X NH2H2N

tBuONa

dioxane

2b,j

Pd(dba)2/BINAP

(4/4.5 mol%)

Cl Cl

Cl ClO

O

55

58

HN

HN

X

NH

NH

X

57b, 15%

57j, 34%

HN

HN

X

NH

NH

X

O

O

O

O

60b, 37%

60k, 21%

3 equiv.

X NHHNCl Cl

68b, 20%

68j, 53%

X NH2H2N

tBuONa

dioxane

2b,j

Pd(dba)2/BINAP

(8/9 mol%)

3 equiv.

X NH2H2N

Cs2CO3

dioxane

2b,k

Pd(dba)2/BINAP

(4/4.5 mol%)

X NHHNCl Cl

69b, 36%

69k, 35%

O

OO

O

X NH2H2N

Cs2CO3

dioxane

2b,k

Pd(dba)2/BINAP

(8/9 mol%)

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


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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Chapter 5

PYRRIDAZINOINDOLES,

SYNTHESIS AND PROPERTIES

Sh. A. Samsoniya, I. Sh. Chikvaidze, M. Ozdesh Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I.


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

Sh. A. Samsoniya, I. Sh. Chikvaidze and M. Ozdesh 148

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, 5H-

piridazino [4,5-b] indole (9), was obtained by King and Stiller back in 1937 by

heating a mixture of p-nitrophenylhydrazine and 2-ethoxycarbonyl-3-

formylindole in vacuum at 290-3000 C [12]. Later, in 1953, Staunton and Tope

synthesized 3-phenyl derivatives (10) [13].

NH

CHO

COOC2H5

NH

N

N

O

RR NH-NH2

9,109 R=NO2 , 10 R=H

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.

N

R

CHO

COOEt

N

R

CH=N-NH2

COOEt

N

R

CH=N

COOEt

N

R

NH

N

O N

R

N

N

Cl

2

POCl3

11,12

13

14

15 16

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.


Haider and A. Wobus [20], the synthesis of 4,5-dialkyl derivatives of 1-oxo-

2H,5H-pyridazino[4,5-b]indoles (23-27) (Scheme 2) and 5-alkyl-1,4-dioxo-

2H,3H,5H-pyridazino[4,5-b]indoles (35-40) (Scheme 3) was described.

NH

COOH

N

R

N

NH

23-27

COCH3

RX / KOH / DMF

N

COOR

COCH3

RCH3

O

N2H4H2O / EtOH

17 18-22

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.

NH

COOCH3

N

R

NH

NH

35-40

COOCH3

RX / KOH / DMF

N

COOCH3

COOCH3

R

O

N2H4H2O / EtOH

28 29-34

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

O

Scheme 3.

NH

NH

N

N

9,15,42-46

COOC2H5

NH

CHO

COOC2H5

41

11

O

R

NH

N

NH

47-53

R

NH CONH-NH2

54

NH

CONH-NH2

55

CH2OHPOCl3/ DMFA

LiAlH4

NH

NH

N

15

O

47

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.


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-N-

alkylation 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 5-

alkyl-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 (29-

34). 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 3-

substituted 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 2-

ethoxycarbonylindole (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).


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 (35-

40).

NH

N

NH

N

COOC2H5 NH

CHO

COOC2H5

41 11,56

O

RR

R

POCl3/ DMFA

N

CHO

COOC2H5

15,59-61

R

R'

R'

N

N

N

O

R

R'62-81

CH2-R''

11,56-58

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

Scheme 5.

NH

NH

NH

N

COOC2H5 NH

CHO

COOC2H5

82-85 86-89

O

RR R

POCl3/ DMFA

90-93

NH

NH

N

S

R

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

P2S5/pyridyne

Scheme 6.


NH

NH

N

NH

CHO

COOC2H5

88O

BnO BnOH2N

98

NH

CN

COOC2H5

BnO

99

Scheme 7.

A. Monge and others [34] in a similar scheme synthesized 8-benyloxy-4-oxo-

3H,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-oxo-

3H,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 6-

substituted isomers from o- and p- derivatives of 2-acylindole-3-yl-carboxylic

acid (100) with acceptable yields (Scheme 8).

NH

COR

COOHR'

NH

R'

N

NH

O

R

100 101

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-aryl-

4-oxo-1,2,3,4-tetrahydropyridazino[4,5-b]indoles (105) from indoylhydrazone

derivatives of benzaldehyde (102), through the intermediate 1-aryl-2-amino-1,2-

dihydropyrrolo[3,4-b]indole-3-ones (104) according to the scheme 9. Indoyl


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 ,2-

dihydropyrrolo[3,4-b]indole-3-ones (104), which further isomerize to 1-aryl-4-

oxo-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 α-

acetyloxy and α-halogen derivatives of 1-methyl-2-ethoxycarbonyl-3-

benzylindole 107 (Scheme 10) in reaction with phenylhydrazine. 1,2,3,4-

tetrahydropyridazino[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). 7-

Benzyloxy-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.

NCONHNH2

102 N CONHNCHC6H4R

N

N

O

C6H4R

NH2

103

104

N

NH

NH

C6H4R

O

105

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

R'R'

R' R'

N

NH

N

C6H4R

O

106R'

KMnO4

Scheme 9.


NCOOMe

107

N

N-Ph

NH

C6H4R

O

109

R=H, p-NO2, p-Cl; X= OCOCH3,Cl,Br

Me

Me

N

N-Ph

N

C6H4R

O

110Me

KMnO4

X C6H4R

N COOMe

108

Me

NH-NHPh

C6H4R

Scheme 10.

NH

CONHNH2

111

C6H5H2CO

N

C6H5H2CO

NNH

O

112

N

C6H5H2CO

NNH

S

113

N

C6H5H2CO

NN

NH-NH2

114

Scheme 11.

Hungarian chemists [39] developed an original general method for the

synthesis of condensed diazine containing heterocyclic systems, including 4-

oxopyridazino[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


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

117 118 119 go smoothly with the yield of 60-72%. The final phase was

carried out by boiling in o-dichlorobenzene within 1 hour. 4-Oxopyridazino[4,5-

b]indoles 119b, (R = H) (Scheme 12) were synthesized as well. The authors [40]

used pyridazine derivative as starting substance 115c (R = H, X = I).

N. Haider and R. Wanko [41] developed a method for the synthesis of

pyridazino[4,5-b]indoles omitting the intermediate stage of oxo derivative

production (Scheme 13). The target heterocycle (124) was formed as a result of

attachment of indole pyrrole ring(121) as in the case of dienophile to azadiene - to

1,2,4,5-tetrazine ring of compound 122. The reaction is carried out in one stage

without the adduct 123.

The method worked by thse group of U. Pindur [42] is also based on the use

of diene synthesis (Scheme 14). Unlike the previous method (Scheme 13), here

derivatives of indole 125 are used as a diene, as dienophile - compounds

containing N=N group (126 and 127, Scheme 14). The reaction was carried out in

toluene or chlorous methylene at -75 to +200 C for 0,2 - 2 hours. The yields of

adducts 128 and 129 were respectively 92% and 82%.

N

N

R

Me

X

O B(OH)2

NH-Ac

Pd(Ph3)4/Na2CO3/DME/H2O N

N

R

Me

O

NH-Ac

N

N

R

Me

O

NH2 N

N

R

Me

O

N3 N

N

R

Me

O

N

H

1) NaNO22)NaN3

115a-d 116a,b

117a,b 118a,b 119ab

R=H, Ph; X=Cl, I; DME = MeOCH2CH2OMe

Scheme 12.


N

N N

N

CF3

CF3

NH

SMe

NH

N

N

F3C

CF3

MeS

H

-N2 -MeSH

NH

N

N

F3C

CF3

122124

121123

Scheme 13.

N

OMe

R

N N

NOO

Ph

N

OMe

R

N

N

N

O

O

PhH

N

OMe

R

N

N

COOEt

COOEt

H

EtOOC-N=N-COOEt127125

126 128

129R=H, Alk, SO2Ph

Scheme 14.

The group of Italian chemists [43] developed a very interesting and original

method for the synthesis of isomeric pyridazino[4,3-b]indoles (133, Scheme 15)

using isatine as a starting substance (130). Through the interaction of isatine with

phosphorus pentachloride in boiling absolute benzene, they obtained 2-chloro-3-

oxo-indolenine (131), which was condensed with sodium benzoyl acetic ether by

boiling in absolute dioxane with the formation of compounds 132. 3-Aryl-4-

ethoxycarbonyl-5H-pyridazino[4,3-b]indoles (133) were obtained by boiling

solution of 132 and hydrazine hydrate in ethyl alcohol with 50% yield. In this

work the authors described some transformations of pyridazino[4,3-b]indoles

(133) and pharmacological activity of obtained derivatives, which are mentioned

below.


NH

O

O

N

O

Cl

NH

O

CO

OEt

R

O

NH

COOEt

R

NN

130 131

132 133

R=H, NO2

Scheme 15.

134

NH

O

RCN

N

O

RCN

R2

R' R'

N

R

R2

R'

NH2

NN

NH

R

R'

NH2

NN

136

135 137

R=H, Br, Me; R'= H, F, Me, i-Pr, OMe, Cl, Br, NMe2;

R2=Me, Et, n-Pr, Bn, (CH2)2NMe

2

Scheme 16.


B. Velezheva and others [44] worked out a method on the basis of isatine

derivatives. As an initial substance they used oxonitriles 134 (Scheme 16)

obtained from isatine.

The compounds 136 were obtained by alkylation of intermediate N-sodium

salts of oxonitriles. By boiling oxonitriles 134 and their N-alkylated derivatives

136 with traditional hydrazine hydrate in acetic acid, corresponding

pyridazino[4,3-b]indoles 135 and 137 were formed. Further authors described

some transformations of pyridazino[4,3-b]indoles (135 and 137) and

pharmacological activity of obtained derivatives which are discussed below.

Thus, given material allows to conclude that quite an interesting development

has been made in this direction, and that in future many, even more, interesting

reports can be expected.

2. SYNTHESIS, CHEMICAL PROPERTIES AND

PHARMACOLOGICAL ACTIVITY

OF THE DERIVATIVES OF PYRIDAZINOINDOLES

As noted above, the main goal of the research in this area lies in the synthesis

of new substances which are potentially pharmacologically active ingredients of

drugs. Substances showing somehow biological activity, as a rule, contain

functional groups capable of interacting with biomolecules. In some papers such

groups are introduced by the authors beforehand, before the closure of the

pyridazine ring [42-44]. In the rest of considered pyridazinoindole groups, mostly

they are not in the same way; therefore, the authors of above discussed works

investigated the possibility of changing functions or introduction of new groups.

Achieving such a goal would be possible by the study of chemical properties of

the synthesized indolopyridazinones.

Investigation of chemical properties of the synthesized indolopyrridazinone

derivatives was carried out by the considered authors, as well as of other papers,

with the purpose of changing the functions of carbonyl groups and aromatization

of pyridazinone ring.

This purpose was achieved through the intermediary chloro or thio

derivatives, which possess high reactivity as compared with the cyclic hydrazide

carbonyl, as already been considered in the diagrams 1, 6 and 11. In some works

authors conducted reduction of chloro and oxo compounds, obtaining the

corresponding aza-carbolines [2], and 1,2,3,4-tetrahydroderivatives [22,25]. The


ones produced from 1,4-dioxo derivatives 35-40 (Scheme 3) and 1,4-dichloro

derivatives (Scheme 17) [20,33] possess rich synthetic possibilities.

Corresponding amino- [34], alkylamino- [31], aminoalkylamino [30],

hydrazino- [22,32,34,37], piperazino- [31] and other [31,45-47] derivatives,

having the ability to interact with biomolecules were obtained from these

compounds.

It is interesting whe work of Giiven and Jones [46], in which the authors

studied the equilibrium of 1,4-diokso-pyridazino[4,5-b]indole among four

tautomers (147a-d, Scheme 18) in aqueous solution. In the mixture the dominant

one is 4-hydroxy-1-oxopyridazino[4,5-b]indole (147 b). The ratio of the forms

147a: 147b: 147s: 147d occurs as 104,93

:108,03

:103,6

:1. The authors investigated the

effect of various substituents.

Investigation of not less interest was conducted by Monge and coworkers

[32]. They conducted a series of transformations given in Scheme 19. Compounds

148-150 revealed physiological activity (see below).

N

R

NH

N

O N

R

N

N

Cl

15 16

NH

NH

N

O

R

90-93

NH

NH

N

S

R

94-96

P2S5/pyridyne

N

R

NH

NH

35-40

O

O

POCl3

POCl3

N

R

N

N

138-143

Cl

Cl

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

R=H, CH3

N

R

N

N

NH-X

144

NH

N

N

NHNH2

R

N

R

N

N

H2NHN

NHNH2

145

146

Scheme 17.


NH

NH

NH

O

O

147a

NH

N

NH

O

OH

147b

NH

NH

N

HO

O

147c

NH

N

N

HO

OH

147d

Scheme 18.

NH

N

N

NHNH2

R

145

NH

N

N

NHN=CR'R''

R

148

NH

N

NR

N N

R3

O=CR1R2

NH

N

NR

N N

N

R3COOH

NaNO2 / H +

149

150

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

Scheme 19.

El-Gendy and El-Banna [31] conducted aminomethylation of Mannich

derivatives of 4-oxopyridazino[4,5-b]indole (Scheme 20). Compounds 152 in the

form of quaternary salts showed antihypertensive activity.

N

NH

N

O

R

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

R1

N

N

N

O

R

R1

CH2-R2

151 152

Scheme 20.


NH

N

N

138

R

R

153 R=H, NHNH2, imidazolyl, 4-(2-mtoxyphenyl)piperazinyl; 155R=Cl, COOEt, R'=NH2NH2, CONHNH2

NH

N

N

Cl

NHNH2

154

NH

N

N

Cl

Cl

N-H

etar

yl

153

NH

N

N

R

155

N N

R'

NH

N

N

Cl

N

156

N

MeMe

NH

N

N

N N

MeMe

NN

Me

Me

157

Scheme 21.

Monge and others [33], from 1,4-dichloro-pyridazino[4,5-b]indole (138),

synthesized mono and dihydrazino derivatives 153, 154 and compounds

containing one or two N-heterocycle (156, 157), as well as the derivatives of

tetracyclic system 155 (Scheme 21).

In literature there are numerous reports in this area [48-64]. However, neither

those described substances in these papers, nor the synthetic methods used are

fundamentally different from the works considered. Therefore, from these reports,

we depict only the results of biological activity.

Isomeric pyridazinoindoles are azaanalogues of α-, β-, γ-, and δ- carbolines,

condensed ring systems of which is the basis of many substances with a high

physiological activity. The core of pyridazino[4,5-b]indole is very interesting

from the pharmaceutical point of view due to its bioisostere with β-carboline as

seen in the original structure of many bioactive compounds. For many years

groups of Monge and Heider, as well as other researchers, thoroughly studied the

synthesis and biological activity of derivatives of various representatives of ―aza-

carboline‖ ring. The focus of authors was mainly on potential antitumor agents

[20-22, 48], inhibitors of monoamino oxidases [25,44,47,49,53] and

thromboxanes [32-34,59-61], etc.

In-vitro screening of compounds synthesized by Heider and others [22]

showed that only 159 (R = Ph), 160 (R=CH3, CH2CH2Ph) and 162 (NR1,2=diethyl


amino) revealed weak anti-tumor activity. Antiproliferative activity of compounds

159 and 160 with respect to growth of adenocarcinoma cells RKOp27 did not

exceed 50%, as for 162 - 72%.

NH

N

N

H2NHN

Me

NH

N

N

ROC-HNHN

MeNH

N

N

N

Me

NR

NH

N

N

N

Me

HN

S

NH

N

N

N

Me

N

S

NR'2

RCOCl POCl3

34% 92%

CS2 /KOH /EtOHCl

NR'2

CH3COONaEtOH

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

158 159 160

161 162

Scheme 22.

NH

NNR1

R2R

R3

R3

NH

NNR1

R2

R3

R3

NH

NN

163

164

165

R=R1=R2=H,Me; R3=Me,Et;

Scheme 23.


N

N

N

RO

NR'R2

O

X

166

X=H,Hal, Me,JMe, OCH2Ph; R=H,C1-4alkyl; R'=R2=H,C1-4alkyl,CH2Ph,

or NR'R2=azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl

Scheme 24.

Italian researchers synthesized a new class of DNA intercalators [53], based

on the four core containing system of pyridazino-[1',6:1,2]-pyrido[4,3-b]-indole

(163, Scheme 23). Compounds 163-165 were used in the form of

mesitylsulfonates.

In 1999, a group of French researchers patented [54] compounds with general

formula of 166 (scheme 24) which had a hypnotic and anti-convulsive effect in

the doses of 0.1-1mg / kg. Authors also described a method for the synthesis of

these substances. The same group [56], also Japanese [57] and English [64]

researchers have identified similar activity of aryl- and hetaryl derivatives of

pyridazino[4,3-b]indole and pyridazino[4,5-b]indole.

In the patents of the United States in 1998 [55] was reported that the

derivatives of pyridazino[4,5-b]indole often revealed expressed activity against

Alzheimer's and Parkinson's diseases as well as Down syndrome.

The antihypertensive activity of the pyridazino[4,5-b]indole derivatives was

reported in publications [3,31,32,37,58,59]. Compounds of type 152 [31], 153

[3,32,58], 106 [37] revealed a weak or average antihypertensive activity.

Compounds of type 132, 133, 135, 137 and their derivatives showed ability to

bind the central and peripheral benzodiazepine receptors [43,45,48,51,56], thereby

promoting restoration of the damaged nerve endings. Effects of anti-inflammatory

activity [9,25,61-64] of derivatives of 4-oxo-pyridazino[4,5-b]indole and 3-oxo-

piridazino[4,3-b]indole were also reported.

2-aryl-3-oxo-pyridazino[4,3-b]indole-4-carboxylic acid and its derivatives

revealed activity against gram-positive and gram-negative bacteria together with

antifungal activity [52]. It was also reported about tuberculostatic activity and the

ability of inhibition of monoamine oxidases [25, 44, 47, 49, 51], phosphor-


diesterases [33] and aggregation of blood plate [32, 34, 59-61] and the inotropic

activity [33, 34].

Derivatives of 1, 4-dioxopyridazino[4,5-b]indole also possess luminescent

properties[33].

In conclusion we can say that numerous significant scientific data were

collected in the scientific area of the synthesis and study of isomeric

pyridazinoindole derivatives. A number of interesting new substances were

synthesized. They draw attention from many sides including the pharmacological

point of view. The attempts which have already been done allow us to consider a

promising present and future research in this area.

ACKNOWLEDGEMENT





Academy Austausch Dienst (DAAD) for supporting the partnership and the



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Chapter 6

11-PERFLUOROALKYL-SUBSTITUTED

3,3-DIMETHYL-11-HYDROXY-2,3,4,5,10,11-

HEXAHYDRO-1H-DIBENZO[B,E][1,4]DIAZEPIN-

1-ONES: SYNTHESIS AND CHARACTERIZATION

Tatyana S. Khlebnicova*, Veronika G. Isakova,

Alexander V. Baranovsky and Fedor A. Lakhvich Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,

Acad. Kuprevicha Street 5/2, 220141 Minsk, Belarus

ABSTRACT

Novel 11-perfluoroalkyl-substituted 3,3-dimethyl-11-hydroxy-2,3,4,5,

10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones are prepared via a

simple two-step approach. A treatment of 2-perfluoroalkanoylcyclohexane-

1,3-diones with ethereal solution of diazomethane gives 5,5-dimethyl-3-

methoxy-2-perfluoroalkanoylcyclohex-2-en-1-ones as main products and 6,6-

dimethyl-3-hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones

as by-products. Then, an initial methoxy group vinylogous substitution of

enol ethers by one of the o-phenylenediamine amino groups and an

intramolecular cyclization leads to the title compounds in high yields.

* [email protected]

T. S. Khlebnicova, V. G. Isakova, A. V. Baranovsky et al. 172

INTRODUCTION

Benzodiazepines constitute an important class of heterocycles due to their

psychopharmacological, analgesic and other kinds of biological activities [1].

Today, many benzodiazepines are widely used as anticonvulsants and muscle

relaxants, daytime sedatives, tranquilizers, sleep inducers and anesthetics [2]. In

particular, dibenzo[b,e][1,4]diazepines may be active as antidepressants, anti-

histaminics, anticonvulsants and other pharmacological agents [3]. Although

various methods for the synthesis of dibenzo[b,e][1,4]diazepinone derivatives

have been reported [4], they continue to receive a great deal of attention. The

selective introduction of fluorine atoms or fluoroalkyl groups into an aromatic

ring or heterocyclic moiety to modify the bioactivity of organic molecules is a

well-established practice [5]. Due to the three electrophilic centers, 2-

perfluoroalkanoylcyclohexane-1,3-diones present significant interest as versatile

agents for introducing polyfluoroalkyl groups in various heterocyclic systems [6].

In this chapter, we wish to report a synthesis of novel dibenzo[b,e]

[1,4]diazepinones, bearing a fluoroalkylcarbinol moiety, from 2-perfluoro-

alkanoylcyclohexane-1,3-diones.

RESULTS AND DISCUSSION

We investigated an interaction of 2-acylcyclohexane-1,3-diones 1a–c

containing a perfluoroalkylated side chain with o-phenylenediamine. A direct

reaction of the latter with o-phenylenediamine produces a mixture of acid

cleavage products, as reported for their acyclic analogues [7]. As an alternative

approach to the synthesis of perfluoroalkylated dibenzo[b,e][1,4]diazepinones, an

interaction of enol ethers of 2-perfluoroalkanoylcyclohexane-1,3-diones 1a–c with

o-phenylenediamine is proposed, because of an advanced reactivity of enol ethers

to nucleophilic reagents versus the initial cyclic β,β'-triketones [8].

11-Perfluoroalkyl-substituted 3,3-Dimethyl-11-hydroxy-… 173

RF

O O

O

RF

O O

OMe

O O

NH

H2N

RF

O

NH

NH

HO RF

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

CH2N2

1a-c

H2N

H2N

2a-c 5a-c

12

3 4 5

6 78

9

1011

O

O

RF

OH

O

O

RF

3a-c 4a-c

We attempted to synthesize methyl enol ethers of 2-perfluoroalkanoyl-

cyclohexane-1,3-diones 1a–c by the methods used for 2-acetylcyclohexane-1,3-

diones, which included O-alkylation of the silver salts with methyl iodide [9] or

their sodium or tetrabutylammonium salts with dimethyl sulfate in acetone [10].

However, target enol ethers have not been isolated, since they appear to be rather

labile under reaction conditions and hydrolyzed into β,β'-triketones 1a–c during

isolation. The reaction of non-fluorinated cyclic β-diketones with ethereal solution

of diazomethane is one of known methods for preparing methyl enol ethers in

mild conditions [11]. Nevertheless, for 2-acetylcyclohexane-1,3-diones, a

complex mixture of products is formed and target enol ethers have not been

obtained [12]. In our case, a treatment of 2-perfluoroalkanoylcyclohexane-1,3-

diones 1a–c with ethereal solution of diazomethane at 0ºC for 15 min and further

stirring for 5 h at room temperature gives 5,5-dimethyl-3-methoxy-2-perfluoro-

alkanoylcyclohex-2-en-1-ones 2a–c in 58–71% yield and 6,6-dimethyl-3-

hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones 3a-c as by-

products. The ratio of products changes depending on the length of perfluoroacyl

chain (NMR 1H 1.4:1, 2.5:1 and 1.8:1, respectively). Refluxing of compounds 3a–

c in benzene for 4 h in the presence of catalytic amount of p-toluene sulfonic acid

in benzene leads to dehydration and affords 6,6-dimethyl-3-perfluoroalkyl-6,7-

dihydrobenzofuran-4(5H)-ones 4a–c in 78–82% yield.

Obtained methyl enol ethers 2a–c are easily converted into the title

compounds 5a–c by their treatment with an equivalent amount of o-

phenylenediamine in ether at room temperature for 5 h. Thus, an initial methoxy

group vinylogous substitution of enol ethers 2a–c by one of the o-

phenylenediamine amino groups and an intramolecular cyclization leads to the

dibenzo[b,e][1,4]diazepinones 5a–c bearing a fluoroalkylcarbinol moiety in 70–


72% yield. The cyclic products 5a–c are stabilized by participation of the

hydroxyl group in an intramolecular hydrogen bonding with the carbonyl group of

the cyclohexenone fragment and presence of a strongly electron-withdrawing

group that hinders an elimination of water. As it is known [13], an interaction of

enol ethers of non-fluorinated 2-acylcyclohexane-1,3-diones with o-phenyl-

enediamine in similar conditions leads exclusively to acyclic enamino derivatives.

The structures of all synthesized compounds are confirmed by elemental

analysis, their IR, 1H,

13C and

19F NMR data. IR spectra of enol ethers 2a–c show

three characteristic absorption bands at 1720–1735 (unconjugated carbonyl),

1645–1655 (conjugated carbonyl) and 1590–1605 (double bond) cm-1

and in 1H

NMR spectra of 2a–c, singlet of methoxy group protons appears at 3.86–3.88

ppm. In IR spectra of 2,3,6,7-tetrahydrobenzofuran-4(5H)-ones 3a–c, the

characteristic frequencies in the range of 1610–1655 cm-1

corresponding to

conjugated carbonyl (1640–1655 cm-1

) and double bond (1610– 1625 cm-1

) are

found. IR spectra of 6,7-dihydrobenzofuran-4(5H)-ones 4a–c show absorption

bands of conjugated carbonyl (1685–1690 cm-1

) and double bond (1565–1570 cm-

1).

1H NMR spectrum of 3a is characterized by two pairs of doublets (due to non-

equivalence of protons at С2 and С7) at 4.46–4.75 ppm (2J 11.4 Hz) and 2.22–

2.32 ppm (2J 16.4 Hz), but

1H NMR spectra of 3b,c – by three pairs of doublets

(due to non-equivalence of protons at С2, С5 and С7) at 4.45–4.85 ppm (

2J 11.5

Hz), 2.36–2.42 ppm (2J 17.9 Hz) and 2.21–2.33 ppm (

2J 16.4 Hz). In

1H NMR

spectra of compounds 4a–c, multiplet signal of vinyl proton appears at 7.66–

7.69 ppm. In 13

C NMR spectra of compounds 3a–c, signals of the C2, C3 and C4

carbon atoms are observed at 79.55–79.90, 79.86–80.93 and 194.31–194.66

ppm, while the C2, C3 and C4 carbons signals of compounds 4a–c are observed at

144.18–144.54, 113.38–115.15 and 190.42–191.16 ppm, respectively.

The IR spectra of title compounds 5a–c show absorption bands of a

conjugated carbonyl (1610 cm-1

), a double bond (1540–1550 cm-1

) and a

vinylogous amide (1505–1510 cm-1

). 1

H NMR spectra of 5a–c are characterized

by three broadened singlets in the range of 5.29–5.40 (NH), 9.06 (NH) and 10.64-

11.32 (OH) ppm. In 13

C NMR spectra of compounds 5a-c, signals of the carbon

atoms C1 (carbonyl group), C4a and C11 are observed at δ 200.01–200.53,

160.22–160.65 and 87.68–90.08 ppm, respectively. In

19F NMR spectrum of

compounds 5a, singlet at δ -80.54 ppm is assigned to the fluorine atoms of an

trifluoromethyl group. In the 19

F NMR spectrum of compounds 5b and 5c, signals

of fluorine atoms are observed at δ -79.00 (s, 3F), -115.21 (d, JF-F = 273.2 Hz, 1F),

-124.75 (d, JF-F = 273.5 Hz, 1F) and at δ -81.97 (m, CF3), -110.53 (dm, JF-F =


279.1 Hz, 1F), -120.50 (dm, JF-F = 279.2 Hz, 1F), -123.06 (dd, JF-F = 291.5, 11.3

Hz, 1F), -125.84 (dm, JF-F = 290.5 Hz, 1F), respectively.

The complete assignment of all atoms of 5a, including spatial relationships

between protons, has been done by use of 2D NMR spectroscopy on 1H,

13C and

15N nuclei.

N

NOO

F

F

F

H

H

H

H

H

H

HH

H

HH

H

HH

H

H

H

N

NOO

F

F

F

H

H

H

H

H

H

HH

H

HH

H

HH

H

H

H

principal HMBC C-H connections

principal NOESY connections

HMBC N-H connections

N

NOO

F

F

F

H

H

H

H

H

H

HH

H

HH

H

HH

H

H

H

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

The assignment of protonated carbons and nitrogens is straightforward and

follows from HSQC, COSY and HMQC 15

N correlations. Relative stereo-

chemistry of the cyclohexenone ring protons and methyl groups was established

by analysis of NOESY spectrum as well as COSY spectrum (Table 1). Quaternary

carbons atoms were deducted via their long-range couplings in HMBC spectrum

and the assignment of the aromatic ring protons was confirmed by analysis of

HMBC 13

C, HMBC 15

N spectra and NOE correlations.

We assume that the CF3-group is under the plane and the hydroxy group has

hydrogen bonding with carbonyl; therefore, axial protons are over the plane and

the axial methyl group under the plane. Hence, the protons with resonance at 2.26

(C2) and 2.67 (C4) ppm occupy pseudo-equatorial position. This follows from

observation of cross-peak between these protons in COSY spectrum (w-constant)

and their appearance as doublet of doublets in 1D 1H NMR spectrum. The

equatorial proton at C4 interacts with proton at N5 in the NOESY and N5 in


HMBC 15

N spectra. Methyl group at 1.04 ppm has more intensive cross-peaks

with these protons, and the second methyl group does more intensively with axial

protons. Due to that and the value of chemical shift, the methyl group at 1.04 ppm

was assigned as axial. The axial protons of the cyclohexenone ring have clear

NOE cross-peaks. Discrimination of protons at C6 and C9 was based on

observations of their interaction with nitrogen nuclei in HMBC 15

N and amine

protons in NOESY spectra.

Table 1. NMR chemical shifts, assignments and HMBC,

NOESY responses in the spectra of 5a

# C, N H HMBC correlations* NOE

correlations*

1 200.53 — HMBC 2, Me2, OH —

4a 160.22 — HMBC 4, Me2 —

9a 135.81 — HMBC 6, 8, 7 (w), OH, 10

(vw)

—

5a 131.54 — HMBC 9, 7, 8 (w), 10 (w) —

CF3 127.26 — — —

8 126.78 6.98 HSQC 9 —

7 122.99 6.84 HSQC 6 —

9 122.28 7.11 HSQC 8, HMBC 10 (w),

N10

10

6 122.01 7.09 HSQC 7, HMBC N5 5

11a 104.54 — HMBC 4 (s), 2 (w), OH (s),

10

—

11 87.68 — HMBC OH —

2 52.13 2.26eq — —

2.35ax 4ax

4 48.15 2.67eq HMBC N5 5

2.78ax 2ax, 5

3 32.64 — HMBC Me, 2, 4 —

Me2 29.45 1.09 HMBC C1 (w), C4a (w) ax

Me1 27.53 1.04 — eq

N5 130.9 9.06 HMQC, HMBC 4, 6 —

N10 85.7 5.29 HMQC, HMBC OH, 9 —

OH — 10.64 — 10(w) * s: strong; w: weak; vw: very weak


The carbon atom of trifluoromethyl group has no cross-peaks in HMBC

spectrum but can be easily found having coupling with fluorine nuclei. The

quaternary carbon C5a and C9a interacts with H9, H7 and H6, H8, respectively

(Figure 1). For C5a, the cross-peak was found with proton at N10. Such

correlation with H10 also shows C11a, which also has a cross-peak with the axial

C4 proton. Two correlations were observed for C4a carbon: with protons of

equatorial methyl group and equatorial proton at C4.

CONCLUSION

A synthetic route to novel 11-perfluoroalkyl-substituted 3,3-dimethyl-11-

hydroxy-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones by a

methylation of 2-perfluoroacylcyclohexane-1,3-diones into their methyl enol

ethers followed by an interaction of the latter with o-phenylenediamine is

described. This approach represents an effective synthetic methodology for

synthesis of dibenzo[b,e][1,4]diazepin-1-ones bearing a fluoroalkylcarbinol

moiety, which can be very important for biological activities.

EXPERIMENTAL

Melting points were measured on Boetius apparatus and were uncorrected.

The NMR spectra were recorded in 5 mm tubes in CDCl3 (compounds 2a–c, 3a–

c, 4a–c) and acetone-d6 (compounds 5a–c) solutions on a Bruker AVANCE–500

spectrometer. Operating at 1

Н (500 MHz), 13

С NMR (125 MHz) and 19

F NMR

(470 MHz) tetramethylsilane (TMS) was used as an internal standard for the

spectra in CDCl3 and solvent signals (acetone-d6) as indirect internal standards.

CCl3F was used as an external standard. 2D Experiments were conducted and

processed with standard Bruker program package. The progress of the reactions

was monitored by thin-layer chromatography on TLC aluminium backed sheets

with Silica gel 60 F254 (Merk), a preparative thin-layer chromatography was

carried out on Silica gel 60 HF254 (Aldrich) and a column chromatography was

carried out on Silica gel 60 (Aldrich).


Reaction of 2-Perfluoroalkanoylcyclohexane-1,3-diones 1a–c with

Diazomethane

To a stirred solution of a triketone 1a–c [14] (1 mmol) in Et2O (10 ml), an

ethereal solution of diazomethane (2.5 ml) was added dropwise for 15 min at 0ºC.

Then, the reaction mixture was stirred for 5 h at room temperature. Removal of

the solvent under reduced pressure and preparative thin-layer chromatography

(diethyl ether/hexane) of the residue gave compounds 2a–c and 3a–c in 58% (2a),

71% (2b), 64% (2c) and 42% (3а), 29% (3b), 36% (3c) yields. Recrystallization

from diethyl ether/hexane furnished products 2a–c and 3a–c as colorless solids.

5,5-Dimethyl-3-methoxy-2-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (2a). Yield:

58%, white solid. Mp: 77–80ºC. IR ν (cm-1

): 1735, 1655, 1605. 1H NMR (CDCl3)

δ: 1.14 (s, 6Н), 2.30 (s, 2Н), 2.53 (s, 2Н), 3.88 (s, 3Н). 13

C NMR (CDCl3) δ:

28.26, 32.04, 39.32, 49.91, 56.88, 114.48, 115.10 (q, 1J = 291 Hz), 178.03, 184.72

(q, 2J = 38 Hz), 194.54.

19F NMR (CDCl3) δ: -77.16 (s, 3F). Anal.Calcd for

С11Н13F3O3: С 52.80; Н 5.24. Found: С 52.68; Н 5.20.

5,5-Dimethyl-3-methoxy-2-(2,2,3,3,3-pentafluoropropanoyl)cyclohex-2-en-1-

one (2b). Yield: 71%, white solid. Mp: 81–84 oC. IR ν (cm

-1): 1725, 1645, 1595.

1H NMR (CDCl3) δ: 1.15 (s, 6Н), 2.29 (s, 2Н), 2.52 (s, 2Н), 3.86 (s, 3Н).

13C

NMR (CDCl3) δ: 28.22, 32.12, 38.78, 49.81, 56.50, 106.36 (tq, 1J = 268 Hz,

2J =

38 Hz), 115.15, 118.08 (qt, 1

J = 288 Hz, 2J = 35 Hz), 177.27, 188.08 (t,

2J = 29

Hz), 194.21. 19

F NMR (CDCl3) δ: -81.65 (bs, 3F), -122.01 (bs, 2F). Anal.Calcd

for С12Н13F5O3: С 48.01; Н 4.36. Found: 48.15; Н 4.42.

5,5-Dimethyl-2-(2,2,3,3,4,4,4-heptafluorobutanoyl)-3-methoxycyclohex-2-en-

1-one (2c). Yield: 64%, white solid. Mp: 65–68 oC. IR ν (cm

-1): 1720, 1650, 1590.

1H NMR (CDCl3) δ: 1.15 (s, 6Н), 2.29 (s, 2Н), 2.52 (s, 2Н), 3.86 (s, 3Н).

13C

NMR (CDCl3) δ: 28.23, 32.12, 38.78, 49.84, 56.42, 107.90 (tt, 1

J = 269 Hz, 2J =

32 Hz), 108.77 (tm, 1J = 267 Hz), 115.32, 117.51 (qt,

1J = 288 Hz,

2J = 34 Hz),

177.24, 187.94 (t, 2J = 29 Hz), 194.11.

19F NMR (CDCl3) δ: -80.94 (m, 3F), -

119.09 (m, 2F), -126.26 (m, 2F). Anal.Calcd for С13Н13F7O3: С 44.58; Н 3.74.

Found: С 44.61; Н 3.79.

6,6-Dimethyl-3-hydroxy-3-trifluoromethyl-2,3,6,7-tetrahydrobenzofuran-

4(5H)-one (3a). Yield: 42%, white solid. Mp: 68–71ºC. IR ν (cm-1

): 1655, 1625. 1H NMR (CDCl3) δ: 1.11 (s, 3Н), 1.12 (s, 3Н), 2.22 (d,

2J = 16.4 Hz, 1H), 2.32 (d,

2J = 16.4 Hz, 1H), 2.38 (s, 2Н), 4.46 (dm,

2J = 11.4 Hz, 1H), 4.75 (dm,

2J = 11.4

Hz, 1H). 13

C NMR (CDCl3) δ: 28.09, 28.52, 34.27, 37.96, 50.88, 79.55, 80.93 (q,

2J = 33 Hz), 110.31, 124.64 (q,

1J = 284 Hz), 181.86, 194.31.

19F NMR (CDCl3) δ:

-80.04 (s, 3F). Anal.Calcd for С11Н13F3O3: С 52.80; Н 5.24. Found: С 52.92; Н

5.29.


6,6-Dimethyl-3-hydroxy-3-perfluoroethyl-2,3,6,7-tetrahydrobenzofuran-

4(5H)-one (3b). Yield: 29%, white solid. Mp: 58–61ºC. IR ν (cm-1

): 1640, 1610. 1H NMR (CDCl3) δ: 1.11(s, 3Н), 1.12 (s, 3Н), 2.21 (d,

2J = 16.4 Hz, 1H), 2.33 (d,

2J = 16.4 Hz, 1H), 2.36 (d,

2J = 17.9 Hz, 1H), 2.42 (d,

2J = 17.9 Hz, 1H), 4.45 (dt,

2J = 11.5 Hz,

3J = 2.7 Hz, 1H), 4.85 (dt,

2J = 11.5 Hz, 1H).

13C NMR (CDCl3) δ:

28.11, 28.57, 34.21, 38.01, 50.90, 79.90, 81.59 (t, 2J = 26 Hz), 109.97, 113.72 (tq,

1J = 261 Hz,

2J = 35 Hz), 119.09 (qt,

1J = 287 Hz,

2J = 36 Hz), 181.57, 194.66.

19F

NMR (CDCl3) δ: -80.18 (bs, 3F), -120.86 (dm, JF-F = 275.5 Hz, 1F), -125.28 (dm,

JF-F = 275.5 Hz, 1F). Anal.Calcd for С12Н13F5O3: С 48.01; Н 4.36. Found: С

48.17; Н 4.41.

6,6-Dimethyl-3-hydroxy-3-perfluoropropyl-2,3,6,7-tetrahydrobenzofuran-

4(5H)-one (3c). Yield: 36%, white solid. Mp: 67–70ºC. IR ν (cm-1

): 1655, 1620.

1H NMR (CDCl3) δ: 1.13 (s, 3Н), 1.14 (s, 3Н), 2.23 (d,

2J = 16.4 Hz, 1H), 2.36 (d,

2J = 16.4 Hz, 1H), 2.37 (d,

2J = 18.0 Hz, 1H), 2.43 (d,

2J = 18.0 Hz, 1H), 4.47

(dm, 2J = 11.6 Hz, 1H), 4.84 (dm,

2J = 11.6 Hz, 1H).

13C NMR (CDCl3) δ: 28.04,

28.52, 34.11, 38.01, 50.94, 79.86, 82.52 (t, 2J = 26 Hz), 109.87 (tm,

1J = 268 Hz),

110.09, 115.45 (tt, 1J = 260 Hz,

2J = 28 Hz), 117.67 (qt,

1J = 288 Hz,

2J = 34 Hz),

181.62, 194.57. 19

F NMR (CDCl3) δ: -81.48 (m, 3F), -117.51 (dm, JF-F = 280.9

Hz, 1F), -120.99 (dm, JF-F = 281.6 Hz, 1F), -123.26 (dm, JF-F = 293.5 Hz, 1F),

-126.65 (dm, JF-F = 293.5 Hz, 1F). Anal.Calcd for С13Н13F7O3: С 44.58; Н 3.74.

Found: С 44.67; Н 3.79.

Dehydration of 6,6-Dimethyl-3-hydroxy-3-perfluoroalkyl-2,3,6,7-tetrahydro-

benzofuran-4(5H)-ones (2a–c). A solution of 2a–c (0.4 mmol) and p-toluene

sulfonic acid (20 mg) in dry benzene (40 ml) was refluxed for 4 h using a Dean

Stark separator to remove the water formed during the reaction. After cooling to

room temperature, a reaction mixture was washed twice with 10 ml water and

dried over anhydrous MgSO4. Removal of the solvent under reduced pressure and

recrystallization of the residue from diethyl ether/hexane afforded 3-

perfluoroalkyl-6,7-dihydrobenzofuran-4(5H)-ones 4a–c as colorless solids.

6,6-Dimethyl-3-trifluoromethyl-6,7-dihydrobenzofuran-4(5H)-one (4a). Yield:


): 1685, 1570, 1455. 1

H NMR (CDCl3)

δ: 1.15 (s, 6Н), 2.42 (s, 2Н), 2.77 (s, 2Н), 7.69 (m, 1Н). 13

C NMR (CDCl3) δ:

28.37, 35.05, 37.20, 52.17, 115.15 (q, 2J = 39 Hz), 116.45, 121.55 (q,

1J = 267

Hz), 143.21 (q, 3J = 6 Hz), 167.94, 191.16.

19F NMR (CDCl3) δ: -60.07 s (3F).

Anal.Calcd for С11Н11F3O2: С 56.90; Н 4.77. Found: С 56.78; Н 4.72.

6,6-Dimethyl-3-perfluoroethyl-6,7-dihydrobenzofuran-4(5H)-one (4b). Yield:


): 1685, 1565, 1450. 1

H NMR (CDCl3)

δ: 1.14 (s, 6Н), 2.41 (s, 2Н), 2.79 (s, 2Н), 7.66 (m, 1Н). 13

C NMR (CDCl3) δ:

28.29, 34.83, 37.33, 52.53, 111.35 (tq, 1J = 251 Hz,

2J = 40 Hz), 113.38 (t,

2J = 30


Hz), 117.10, 118.80 (qt, 1

J = 286 Hz, 2J = 38 Hz), 144.18 (t,

3J = 10 Hz), 168.09,

190.45. 19

F NMR (CDCl3) δ: -84.38 (bs, 3F), -109.02 (bs, 2F). Anal.Calcd for

С12Н11F5O2: С 51.07; Н 3.93. Found: С 51.14; Н 3.99.

6,6-Dimethyl-3-perfluoropropyl-6,7-dihydrobenzofuran-4(5H)-one (4c). Yield:


): 1690, 1565, 1445. 1H NMR (CDCl3)

δ: 1.15 (s, 6Н), 2.42 (s, 2Н), 2.80 (s, 2Н), 7.67 (m, 1Н). 13

C NMR (CDCl3) δ:

28.32, 34.88, 37.43, 52.63, 108.61 (tm, 1J = 265 Hz), 113.63 (t,

2J = 30 Hz),

113.69 (tt, 1J = 253 Hz,

2J = 33 Hz), 117.36, 118.00 (qt,

1J = 288 Hz,

2J = 35 Hz),

144.54 (t, 3J = 10 Hz), 168.11, 190.42.

19F NMR (CDCl3) δ: -80.50 (m, 3F), -

106.08 (m, 2F), -125.57 (m, 2F). Anal.Calcd for С13Н11F7O2: С 47.00; Н 3.34.

Found: С 47.12; Н 3.41.

Synthesis of 3,3-Dimethyl-11-hydroxy-11-perfluoroalkyl-2,3,4,5,10,11-hexa-

hydro-1H-dibenzo[b,e][1,4]diazepin-1-ones (5a–c). To a stirred solution of a

methyl enol ether 1a–c (1 mmol) in Et2O (20 ml), o-phenylenediamine (1 mmol)

was added at room temperature. After 5 h stirring, the reaction mixture was

concentrated under reduced pressure. A column chromatography (diethyl

ether/hexane) of the residue afforded pure compounds 5a–c as colorless solids.

3,3-Dimethyl-11-hydroxy-11-trifluoromethyl-2,3,4,5,10,11-hexahydro-1H-

dibenzo[b,e][1,4]diazepin-1-one (5a). Yield: 72%, white solid. Mp: 238–241ºC.

IR ν (cm-1

): 1610, 1540, 1505. 1H NMR (acetone-d6) δ: 1.04 (s, 3Н), 1.09 (s, 3Н),

2.26 (dd, 1J = 16.6 Hz,

2J = 1.6 Hz, 1H), 2.35 (d,

1J = 16.6 Hz, 1H), 2.66 (dd,

1J

= 16.1 Hz, 2J = 1.4 Hz, 1H), 2.78 (d,

1J = 16.0 Hz, 1H), 5.29 (bs, 1Н, NH), 6.84

(td, 1J = 7.6 Hz,

2J = 1.2 Hz, 1H), 6.98 (td,

1J = 7.6 Hz,

2J = 1.2 Hz, 1H), 7.09 (d,

1J = 8.0 Hz, 1Н), 7.11 (d,

1J = 8.0 Hz, 1Н), 9.06 (bs, 1Н, NH), 10.64 (bs, 1Н,

ОH). 13

C NMR (acetone-d6) δ: 27.53, 29.45, 32.64, 48.15, 52.13, 87.68 (q, 2

J = 29

Hz), 104.54, 122.01, 122.28, 122.99, 126.78, 127.26 (q, 1J = 295 Hz), 131.54,

135.81, 160.22, 200.53. 19

F NMR (acetone-d6) δ: -80.54 (s, 3F). Anal.Calcd for

С16Н17F3N2O2: C 58.87; H 5.25; N 8.59. Found: С 58.81; H 5.23; N 8.54.

3,3-Dimethyl-11-hydroxy-11-perfluoroethyl-2,3,4,5,10,11-hexahydro-1H-

dibenzo[b,e][1,4]diazepin-1-one (5b). Yield: 71%, white solid. Mp: 264–267ºC.

IR ν (cm-1

): 1610, 1550, 1510. 1

H NMR (acetone-d6) δ: 1.06 (s, 3Н), 1.10 (s, 3Н),

2.26 (dd, 1J = 16.6 Hz,

2J = 1.8 Hz, 1H), 2.37 (d,

1J = 16.6 Hz, 1H), 2.68 (dd,

1J

= 16.1 Hz, 2J = 1.6 Hz, 1H), 2.80 (d,

1J = 16.1 Hz, 1H), 5.40 (bs, 1Н, NH), 6.81

(td, 1J = 7.6 Hz,

2J = 1.3 Hz, 1H), 6.96 (td,

1J = 7.6 Hz,

2J = 1.3 Hz, 1H), 7.08

(dd, 1J = 8.1 Hz,

2J = 0.9 Hz, 2H), 9.06 (bs, 1Н, NH), 11.13 (bs, 1Н, ОH).

13C

NMR (acetone-d6) δ: 27.35, 29.75, 32.39, 48.38, 52.12, 88.86 (t, 2

J = 24 Hz),

105.02, 117.26 (tq, 1J = 268 Hz,

2J = 33 Hz), 121.07 (qt,

1J = 288 Hz,

2J = 37 Hz),

121.93, 122.06, 122.53, 126.65, 130.93, 135.66, 160.55, 201.01. 19

F NMR

(acetone-d6) δ: -79.00 (bs, 3F), -115.21 (d, JF-F = 273.5 Hz, 1F), -124.75 (d, JF-F =


273.5 Hz, 1F). Anal.Calcd for С17Н17F5N2O2: C 54.26; H 4.55; N 7.44. Found: C

54.31; H 4.58; N 7.49.

3,3-Dimethyl-11-hydroxy-11-perfluoropropyl-2,3,4,5,10,11-hexahydro-1H-

dibenzo[b,e][1,4]diazepin-1-one (5c). Yield: 70%, white solid. Mp: 149–152ºC.

IR ν (cm-1

): 1610, 1540, 1510. 1

H NMR (acetone-d6) δ: 1.06 (s, 3Н), 1.10 (s, 3Н),

2.26 (dd, 1J = 16.7 Hz,

2J = 1.8 Hz, 1H), 2.38 (d,

1J = 16.7 Hz, 1H), 2.68 (dd,

1J

= 16.2 Hz, 2J = 1.5 Hz, 1H), 2.80 (d,

1J = 16.1 Hz, 1H), 5.39 (bs, 1Н, NH), 6.80

(td, 1J = 7.6 Hz,

2J = 1.3 Hz, 1H), 6.96 (td,

1J = 7.6 Hz,

2J = 1.3 Hz, 1H), 7.05

(dm, 1J = 8.0 Hz, 1H), 7.08 (dm,

1J = 8.0 Hz, 1H), 9.06 (bs, 1Н, NH), 11.32 (bs,

1Н, ОH). 13

C NMR (acetone-d6) δ: 27.26, 29.85, 32.34, 48.40, 52.15, 90.08 (t, 2

J

= 24 Hz), 105.31, 111.99 (tm, 1

J = 267 Hz), 118.62 (tt, 1

J = 270 Hz, 2J = 29 Hz),

120.02 (qt, 1J = 288 Hz,

2J = 35 Hz), 121.95, 122.04, 122.57, 126.65, 130.91,

135.52, 160.65, 201.01. 19

F NMR (acetone-d6) δ: -81.97 (m, 3F), -110.53 (dm, JF-

F = 279.2 Hz, 1F), -120.50 (dm, JF-F = 279.2 Hz, 1F), -123.06 (dd, JF-F = 291.5,

11.3 Hz, 1F), -125.84 (dm, JF-F = 291.5 Hz, 1F). Anal.Calcd for С18Н17F7N2O2: C

50.71; H 4.02; N 6.57. Found: C 50.78; H 4.04; 6.70.

REFERENCES

[1] (a) Randall, L. O. In Psychopharmacological Agents; Gordon, M., Eds.;

Academic Press: New York, 1974; Vol 3, pp 175–281. (b) Greenblatt, D. J.;

Shader, R. I. In Benzodiazepines in Clinical Practice; Raven Press: New

York, 1974; pp 183–196. (c) Fryer, R. I., In: Comprehensive Heterocyclic

Chemistry; Taylor, E. C., Ed.; Wiley: New York, 1991, 50, Chapter II.

[2] (a) Narayana, B.; Vijaya Raj, K. K.; Ashalatha, B. V.; Suchetha Kumari, N.

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Braccio, M.; Ghia, M.; Mattioli, F. Eur. J. Med. Chem. 1991, 26, 489–496.

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Reviewed by Prof. M.M. Krayushkin, N.D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, Moscow, Russia



Chapter 7

SYNTHESIS AND BIOLOGICAL ACTIVITY OF

SOME ISOMERIC DIPYRROLONAPHTHALINE

DERIVATIVES

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

K.Kh.Mamulashvili, Z. Sh. Lomtatidze, T. V. Doroshenko Department of Chemistry, Iv. Javakhishvili Tbilisi State University, I.


ABSTRACT

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.

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

184

INTRODUCTION

In the present work are described synthesis, antimicrobial, antituberculous

and antifungal activities of some dipyrrolonaphthaline derivatives synthesized

earlier by us: 1H,10H-benzo[e]pyrrolo [3,2-g]indole (I), 3H,8H-indolo[5,4-

e]indole(II), 1H,6H-indolo[7,6-g]indole(III) and 3H,8H-indolo[4,5-e]indole (IV)

[1-3].

On the basis of heterocycles I-IV were obtained phenylazoderivatives V-XIII,

N,N- formylderivatives XIV-XVII and dialkylderivatives XVIII-XXIII.

HN

NH

R1

R2N

R-N

R-N

N-R

N-RR-N

-R

R1 R2R3

R4

I, V-X, XIV, XVII, XVIII, XIX

III, XX, XXI IV, XI-XIII, XVI, XVII, XXII, XXIII

I, II, III, IV R= R1= R2= R3=R4= H; V R1= N=NC6H5, R2= H; VI R1= N=NC6H4NO2-p, R2=H;

VII R1= N=NC6H4Cl-p, R2= H; VIII R1= N=NC6H4Br-p, R2= H; IX R1= N=NC6H4I-p, R2= H;

X R1= N=NC6H4SO2NH2-p, R2= H; XI R1= R2= R3=H, R4= N=NC6H5;

XII R1= R2= R3= H, R4= N=NC6H4Cl-p; XIII R1= R2= R3= H, R4= N=NC6H4NO2-p;

XIV R1= CHO, R2= H; XV R1=R2= CHO; XVI R=R2=R4= H, R1=R3= CHO;

XVII R=R1=R4= H, R2=R3= CHO;

XVIII, XX R= CH2-CH=CH2; XIX, XXI R=CH2-C CH;

XXII R1= R2= R3=R4= H, R= CH2-CH=CH2; XXIII R= CH2-C CH.R1=R2=R3=R4= H,

Synthesis and Biological Activity …

185

Phenylazoderivatives were synthesized by means of azocoupling reaction of

benzopyrroloindole I, indolo[4,5-e]indole IV with substituted phenyldiazonium

chlorides in aqueous- dioxane solution with molar ration of substrate and

diazonium salt, 1:3 [4-6].

As a result of electrophilic substitution reaction were isolated

monosubstituted products (V-VIII): 3-phenylazo- (V), 3-(p-nitrophenylazo)- (VI),

3-(p-chlorophenylazo)-(VII), 3-(p-bromphenylazo)- (VIII), 3-(p-iodphenylazo)-

(IX), 3-(p-sulphamidephenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (X), 2-

phenylazo- (XI), 2-(p-chlorophenylazo)- (XII) and 2-(p-nitrophenylazo)-3H,8H-

indolo[4,5-e]indoles (XIII).

We didn’t manage to obtain disubstituted dipyrrolonaphthaline

phenylazoderivatives[7].

Using Vilsmeier-Haack reaction were synthesized mono- and

diformylderivatives of benzopyrroloindole (I) and indolo[4,5-e]indole (IV) with

different molar ration of substrates and Vilsmeier complexes [4,6]. As a result

were isolated: 3-formyl- (XIV), 3,8-diformyl-1H,10H-benzo[e]pyrrolo[3,2-

g]indoles (XV), 1,9-diformyl-(XVI), 1,10-diformyl-3H,8H-indolo[4,5-e]indoles

(XVII).

It is known that unsaturated groups in heterocyclic compounds increase their

biological activity. For the purpose of direct introduction of allylic and propargyl

radicals into the indole ring were studied alkylation reactions by halogenalkyls

under condition of interphase catalysis [8]. Alkylation of isomeric indoloindoles

3H,8H-indolo[5,4-e]indole (II), 1H,6H-indolo[7,6-g]indole (III) and 3H,8H-

indolo[4,5-e]indole (IV) was carried out in 50% aqueous solution of NaOH using

stechiometric quantity of alkylhalogenides, with ration of catalyst-tetrabutyl-

ammonium and substrate 1:5 [8].

Alkylation reaction in 1,2-dichloroethane at 40-450C results the formation of

N,N-dialkylindoloindoles: 3,8-diallyl-(XVIII), 3,8-dipropargylindolo[5,4-

e]indoles (XIX), 1,6-diallyl- (XX), 1,6-dipropargylindolo[7,6-g]indoles (XXI),

3,8-diallyl- (XXII) and 3,8-dipropargyl-indolo[4,5-e]indoles (XXIII).

The analysis has shown that the reactivity of isomeric indoloindoles (II, III,

IV) doesn’t differ considerably. But 3H,8H-indolo[4,5-e]indole undergo N,N-

dialkylation easier than II, III; it is connected with its better solubility in 1,2-

dichloroethane.

The structure of the synthesized compounds V-XXIII was established by

means of IR-, UV-, NMR- and Mass-spectral methods and is given in the tables.


186

IR-spectra (neyol) and UV-spectra (ethanole) of compounds

V-XVII

Compo

und #

IR-spectra, , cm-1 UV-spectra,

max, nm, (lg ) N-H C=O N=N

1 2 3 4 5

V 3485, 3250 _ _ 217(4.63), 229(4.73),

251(5.07), 273(4.85),

286(4.51), 317(4.23),

329(4.11).

VI 3400 _ _ 200(4.35), 217(4.30),

232(4.26), 255(4.26),

264(4.55), 273(4.67),

303(3.93), 325(3.19).

VII 3415, 3385 _ 1420 206(4.22), 231(4.55),

274(4.37), 270(4.42),

510(4.54).

VIII 3430, 3380 _ 1320 1260

1630 1560

(NO2)

208(4.13), 229(4.38),

267(4.12), 568(4.44).

IX 3410, 3380 _ _ 202(4.45), 229(4.59),

264(4.47), 269(4.50),

315(4.08), 540(4.56).

X 3400 _ _ 210.5(4.36),

248(4.46), 310(3.86),

319.5(4.01),

336(3.97), 345(3.72).

XI 3430 _ 1400 1370 202(4.45), 233(4.32),

257(4.37), 270(4.22),

294(4.05), 306(4.07),

319(4.11), 467(4.36).

XII 3430 _ 1390 1370 202(4.47), 229(4.39),

256(4.44), 270(4.27),

295(4.09), 305(4.12),

320(4.16), 344(4.07),

480(4.49).

XIII 3450 3410 _ 1370.

1530,

1346(NO2)

202(4.44), 229(4.33),

253(4.39), 270(4.18),

294(4.04), 322(3.91),

363(3.97), 526(4.45).


187

XIV 3320, 3270

1630 _ 224(3.58), 254(3.78),

296(3.13), 307(3.21),

326(3.47).

XV 3390, 3290, 1700, 1650 _ 208, 217, 236, 250,

257, 278, 289, 322,

342, 353.

XVI 3220, 3130 1660, 1620 _ 212(4.66), 255(4.54),

267(4.53), 275(4.52),

338(3.91), 354(3.88).

XVII 3200, 3130 1640, 1620 _ 200(4.27), 222(4.26),

232(4.28), 282(4.39),

357(4.07).

IR- (neyol) and UV-spectra ( ethanole) of compounds

XVIII-XXIII

compound # IR-spectra, , cm-1 UV-spectra,

max, nm, (lg )

XVIII CH2-CH=CH2 210,5(4.46), 218(4.51), 251(4.62),

297(3.70), 310(4.03), 320.5(4.24),

336(4.18), 352(3.71).

750, 1650-1580

XIX CH2-C CH

3260, 2120

220(4.40), 248(4.68), 308(4.11),

320(4.34), 336(4.25), 352(3.88).

XX 720, 1650-1510 256(4.22), 266(4.60), 270(4.82),

289 (3.94), 300(4.01), 324(3.35),

333(3.30), 339(5.52).

XXI 3255, 2120 264(4.57), 272(4.87), 300(4.05),

324(3.35), 339(3.60), 348(3.61),

356(3.55), 360(3.57), 383(3.64).

XXII 730, 1620-1560 204(3.70), 237(3.60) 272(4.42),

339(3.21).

XXIII 3270-3255, 2120 236(4.11), 266(4.09), 268(4.46),

278(4.62), 307(3.84), 328(3.09).

Chemical shift of the protons ( , ppm) and spin-spin interaction constants (J, Hz) of the compounds

XIV-XVII (DMSO-d6) in 1H-NMR spectra (acetone-d6)

Compo

und # , ppm J, Hz

1-H 2-H 3-H 4-H 5-H 6-H 7-H 8-H 9-H 10-H

XIV 11.8,

bs

7.86,

bs

9.69, s

(CHO)

8.3_8.1 7.4_7.3 7.4_7.3 8.3-

8.1

7.0, dd 7.4 10.8,

bs

J89=3.0;

J810=2.4.

XV 11.8,

bs

7.93,

bs

9.78, s

(CHO)

8.25, dd 7.48, dd 7.48, dd 8.25,

dd

9.78, s

(CHO)

7.93,

bs

11.8,

bs

J45=6.3;

J46=3.4.

XVI 9.81, s

(CHO)

8.26,

s

12.3, bs 7.58, d 7.85, d 7.78, d 7.55,

dd

12.6, bs 10.35,

s

(CHO)

7.80,

dd

J23=2.4;

J45=9.1;

J67=9.0;

J710=0.5;

J810=1.4.

XVII 10.0, s

(CHO)

8.13,

s NH ND 7.65, d 7.80, d 7.80, d 7.65,

d NH ND 8.13, s 10.0, s

(CHO)

J45=J67=8.8.

1H-NMR Spectra of diazocompounds

V-XIII (acetone-d6)

Compo

und # , ppm J, Hz

1-H 2-H

3-H

4-H 5-H 6-H 7-H 8-H 9-H 10-H Ph

2 -H

6 -H

3 -H

5 -H

V 11,9

bs

7,86

bs

8,1…8,3 7,3…… 7,5 8,1…8,3

Dd

7,4 11.0

bs

7,8 7,3-7,5 J89=J810=2,7;

VI

11,3

bs

7,99

bs

8,3 m 7,4-7,5 7,9 m 7,09

dd

10,8

bs

7,86 d 8,27 d J89=3;

J810=2,5;

J23=J56=9,2

VII 11.3,

bs

7.97,

bs

(2_H)

8.38, m 7.4_7.5 8.27, m 7.15,

dd

7.45,

dd

10.79,

bs

7.86, d 7.55, d J89=2.9;

J810=2.2;

J910=2.6;

J2 3 =J5 6 =8.77

VIII

11.3,

bs

7.99,

bs

(2-H)

8.3, m 7.4_7.5 7.9, m 7.09,

dd 7.4 10.8,

bs

7.86, d 8.27, d

J89=3;

J810=2.6;

J2 3 =J5 6 =9.2.

IX* 11.6,

bs

7.86,

bs

(2-H)

8.1_8.3 7.3_7.6 8.1_8.3 7.03,

dd 7.4,

m

11.0,

bs

7.8 (3 -H)

(4 -H)

(5 -H)

7.3_7.5

X 11,9

bs

8,05

bs

8,37

dd

8,25

dd

6,67

d

7,17

d

10,9

bs

8,02

d

7,92

d

J89=2,56;

J23=J56=9,14

XI 8.08,

dd

11.2,

bs

(3-H)

7.55, dd 7.82,

d 7.4 7.6 10.7,

bs 7.4 7.6 7.87 8.09 J13=1.8;

5J14=0.7;

J45=8.9.

XII 8.11,

dd

11.2,

bs

(3-H)

7.55, dd 7.82,

d 7.5 7.6 10.6,

bs 7.4 7.86, d

(2 -H)

7.51, d

(3-H)

J13=2.1;

J45=8.8;

JAB=8.6; 5J14=0.5.

XIII 8.23,

dd

11.3,

bs

(3-H)

7.51, dd 7.86,

d 7.6 10.7,

bs 7.4 7.5 7.99, d

(2 -H)

8.36, d

(3 -H)

J13=1.9; 5J14=0.7;

J46=8.9;

JAB=9.14.

* in DMSO-d6.

1H-NMR Spectra of indoloindoles N,N-dialkylderivatives

XVIII-XXIII (CDCl3)

Compound

# , ppm J, Hz

1-H

d

2-H

d

3-H

d

4-H

d

5-H

d CH2 - C C-Ha

d Hc

Hb

CH2

d C CH

d

XVIII 7.04 7.18 _ 7.54 8.04 4.85 5.08(Ha), dd

5.20(Hb), dd

6.07(Hc), m

_ _ J12=2.9; J45=8.8;

JHaHc=16.8;

JHcHb=10.2;

JHaHb=1.5;

JCH2CHc=5.1.

XIX 7.07 7.30 _ 7.64 8.08 _ _ 5.01 2.43 J12=2.9; J45=8.8;

JCH2CH=2.19.

XX _ 7.20 6.66 7.37 8.03 5.23 5.00 (Ha), d

5.23(Hb), d

6.25(Hc), dd

_ _ J23=2.9; J45=8.8;

JHaHc=16.5;

JHbHc=10.2.

XXI _ 7.24 6.69 7.80 8.27 _ _ 5.38 2.49 J23=2.9; J45=8.6.

XXII 7.25 7.35 _ 7.43 7.72 4.88 5.06(Ha), dd

5.20(Hb), dd

6.07(Hc), dd

_ _ J12=3.6; J45=8.8;

JHaHc=15.5;

JHbHc=10.2;

JHaHb=1.5;

JCH2Hc=5.1.

XXIII 7.32 7.37 _ 7.52 7.77 _ _ 5.01 2.42 J12=3.0;

JCH2CH=2.0;

J45=8.8.


191

EXPERIMENTAL CHEMICAL PART

The reaction procedure and compounds purity monitoring, and also

establishment of Rf were accomplished by means of TLC on Silufol UV-254; IR-

spectra were taken on analyzer UR-20 (Germany) in petrolatum oil; UV-spectra-

on spectrophotometer ―Specord‖ (Germany) in ethanol, PMR-spectra- on

spectrometer Bruker WP-200 SY (USA) with operating frequency 200 MHz,

inner standard –TMS. Measurement accuracy of chemical shift ± 0,01 ppm,

constant of spin-spin interaction ±0,1 Hz. The yields are given for

chromatographically pure compounds. The findings of elemental analysis

correspond calculated values.

3-Phenylazo-1H,10H-benzo[e]pyrrolo[3,2-g]indole (V)

To the solution 0.32 g (1,5 mmole) of 1H,10H-benzo[e]pyrrolo [3,2-g]indole

(I) in 10 ml of dioxane and 10 ml water at -50C is added drop by drop 6 mmole of

phenyldiazonium chloride solution, keeping pH 6-7 by adding sodium acetate.

The solution is mixed for 30 minutes. The reaction mixture is extracted with ether

and dried on anhydrous Na2SO4. The extract is evaporated; the substance is dried

and purified on the column with silicagel, eluent - hexane-ether, 5:1. Yield 0,26 g

(54%), dark orange crystals. Tmelt. 2030C (decom.). Rf 0.58 (benzene-acetone,

10:1). Found %: M+ 310. C20H14N4. Calculated: M 310. With Ehrlich reagent

gives violet colouring at room temperature.

3-(p-Nitrophenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (VI)

Is obtained similarly to compound V from 0,41 g (2 mmole) I and 6 mmole p-

nitrophenyl-diazonium chloride solution. Yield 0,21 g (30%), bordeaux crystals.

Tmelt. 3000C (decom.). Rf 0.55 (benzene-acetone, 10:1). C20H13N5O2. With Ehrlich

reagent gives violet colouring at room temperature.

3-(p-Chlorophenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (VII)

Is obtained similarly to compound V from 0.2 g (1 mmole) I and 3 mmole p-

chlorophenyldiazonium chloride solution. Yield 0,1 g (30%), orange crystals.


192

Tmelt. 216…2170C (decom.). Rf 0.35 (benzene). C20H13N4Cl. With Ehrlich reagent

gives violet colouring at room temperature.

3-(p-Bromphenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (VIII)


bromphenyldiazonium chloride solution. Yield 0.22 g (59%), bordeaux crystals.

Tmelt. 2650C (decom.). Rf 0.6 (benzene-ether, 3:1). C20H13N4Br.

3-(p-Iodphenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole (IX)

Is obtained similarly to compound V from 0,2 g (1 mmole) I and 3 mmole p-

iodphenyldiazonium chloride solution. Yield 0.34 g (80%), violet crystals. Tmelt.

3500C (decom.). Rf 0.6 (benzene-ether, 3:1). C20H13N4I.

3-(p-Sulphamidephenylazo)-1H,10H-benzo[e]pyrrolo[3,2-g]indole

(X)


sulphamide-phenyldiazonium chloride solution. Yield 0.3 g (78%), bordeaux

crystals. Tmelt. 3550C (decom.). Rf 0.59 (benzene-acetone, 2:1). C20H15N5SO2.

2-Phenylazo-3H,8H-indolo[4,5-e]indole (XI).

To the solution of 0.41g (2 mmole) compound IV in 15 ml dioxane and 8 ml

water at -50C is added 6 mmole phenyldiazonium chloride solution, keeping pH 6-

7 by adding sodium acetate; the solution is mixed for 2 hours, poured into glacial

water, extracted with ether, the extract is washed with 10% NaOH solution, dried

on Na2SO4, solvent is evaporated and is obtained 0.45 g (73%) of substance,

which is purified on chromatographic column, eluent benzene. Obtained

substance represents red crystals. Tmelt. 194-1950C. Rf 0.35 (benzene). C20H14N4.


193

2-(p-Chlorophenylazo)-3H,8H-indolo[4,5-e]indole (XII).

Is obtained similarly to compound XI from 0.41 g (2 mmole) IV and 6 mmole

p-chlorophenyldiazonium chloride solution. Yield 0.52 g (76%). Tmelt. 216-2170C.

Rf 0.45 (benzene), C20H13ClN4.

2-(p-Nitrophenylazo)-3H,8H-indolo[4,5-e]indole (XIII).

Is obtained similarly to compound XI from 0.41 g (2 mmole) IV and 6 mmole

p-nitrophenyldiazonium chloride solution. Yield 0.59 g (83%). Tmelt. 258-2590C.

Rf 0.21 (benzene), C20H13N5O2.

3-Formyl-1H,10H-benzo[e]pyrrolo[3,2-g]indoles (XIV)

To 1,16 ml (15mmole) of DMFA at 00C is added drop by drop 0,36 ml (4,2

mmole) distillated POCl3 and mixed for 0,5 h at room temperature. The solution is

cooled again to 00C and is added relatively fast the solution of 0,3g (1,4 mmole)

substance I in 2 ml DMFA. The solution is mixed for 1 hour at 500C. The reaction

mixture is poured into water and alkalized by 10% solution of NaOH up to pH 10.

The precipitate is filtered off, washed with water until neutral reaction. The

product of the reaction represents mixture of benzopyrroloindole aldehydes. The

mixture is separated on chromatographic column with silicagel, eluent benzene.

As a result is obtained 0,17 g (50%) of substance XIV, yellow crystals. Tmelt.

293…2940C. Rf 0.62 (benzene-acetone, 1:1). With Ehrlich reagent gives yellow

colouring. The dialdehyde XV due to pure solubility couldn’t be eluated on

column. Found: M+ 234. C15H10N2O. Calculated: M 234.

3,8-Diformyl-1H,10H-benzo[e]pyrrolo[3,2-g]indole (XV)

1,36 ml (18mmole) of distillated DMFA is cooled to -50C and drop by drop is

added 0,47 ml (5 mmole) distillated POCl3, mixed for 0,5 h at room temperature.

The solution is cooled again to -50C and is added slowly the solution of 0,2g (1

mmole) substance I in 1,4 ml DMFA. The solution is mixed for 1 hour at 40-

450C. The yellow precipitate is obtained. The reaction mixture is poured into

glacial water, alkalized by 10% solution of NaOH up to pH 10 and left for the


194

night. The precipitate is filtered off, washed with water until neutral reaction,

recrystallizated from DMFA. Yield 0,16 g (64%), yellow crystals. Tmelt. 3370C

(decomp). Found: M+ 262. C16H10N2O2. Calculated: M 262.

Formylation of 3H,8H-indolo[4,5-e]indole

1,84 ml (24 mmole) of absolute DMFA is cooled to -50C and drop by drop is

added 0,55 ml (6 mmole) distillated POCl3, mixed for 1 h at room temperature.

The solution of 0,41g (2 mmole) substance IV in 3 ml DMFA is slowly added at

-50C. The solution is mixed for 2 hour at 40

0C, treated by 10% solution of NaOH

up to pH 10 and left for the night. The precipitate is filtered off, washed with

water until neutral reaction and dried. Is obtained 0,43 g mixture of two aldehydes

(TLC, benzene-acetone, 1:1), which are separated on column.

1,9-Diformyl-3H,8H-indolo[4,5-e]indole (XVI) is eluated with mixture

benzene-ether, 1:3.

0,11 g of colourless crystals is obtained, Tmelt. 298…2990C. Rf 0.37 (benzene-

acetone, 1:1). Found: M+ 262. C16H10N2O2. Calculated: M 262.

1,10-Diformyl-3H,8H-indolo[4,5-e]indole (XVII) is eluated with ethanol. 0,25

g of colourless crystals is obtained, Tmelt. 327…3280C. Rf 0.66 (benzene-acetone,

1:1). Found: M+ 262. C16H10N2O2. Calculated: M 262.

3,8-Diallylindolo[5,4-e]indole (XVIII)

To the suspension of 0,25 g (1,2 mmole) 3H,8H-indolo [5,4-e]indole (I) in 8

ml 1,2-dichlorethane is added 10 ml of 50% NaOH, 0,016 g [CH3(CH2)3]NBr and

3,5 g (28,4 mmole) allylbromide. The solution is mixed for 1 h at 40-450C. The

water layer is extracted with 1,2-dichlorethane, the organic extract is washed with

water until neutral reaction and dried on Na2SO4. The solvent is evaporated at 30-

400C. The product is purified on chromatographic column, eluent benzene-

hexane, 1:2. Yield 0,24 g (69%), colourless crystals. Tmelt. 159-1600C. Rf 0.41

(benzene-hexane, 1:1). IR-spectrum, , cm-1

: 1580-1650 (C=C), 750 (CH2). UV-

spectrum, max, nm (lg ): 210,5 (4,46), 218 (4,51), 251 (4,62), 297 (3,70), 310

(4,03), 320,5 (4,24), 336 (4,18), 352 (3,71). Found: M+ 286. C20H18N2.

Calculated: M 286.


195

3,8-Dipropargylindolo[5,4-e]indole (XIX)

Is obtained similarly to compound XVIII by interaction of 0.21 g (1,02

mmole) 3H,8H-indolo[5,4-e]indole I, 0,017 g (0.07 mmole) benzyltriethyl-

ammomium bromide and 0,58 g (4,8 mmole) propargyl bromide. Is purified on

column, eluent benzene-hexane, 1:2. Is obtained 0,2 g (69%) XIX, colourless

crystals. Tmelt. 201-2020C. Rf 0.39 (benzene-petroleum ether, 2:1), IR-spectrum, ,

cm-1

: 3260 ( CH), 2120 (C C). Found: M+ 282. C20H14N2. Calculated: M 282.

1,6-Diallylindolo[7,6-g]indole (XX)

Is obtained similarly to compound XVIII by interaction of 0.08 g (0,39

mmole) 1H,6H-indolo [7,6-g]indole III, 0,012 g [CH3(CH2)3]NBr and 1,4 g (11,5

mmole) allylbromide. For analysis the product is purified using TLC method,

eluent benzene-hexane, 1:2. Is obtained 50 mg (45%) of compound XX,

colourless crystals. Tmelt. 123-1240C. Rf 0.49 (benzene-hexane, 1:1), IR-spectrum,

, cm-1

: 1650-1510 (C=C), 720 cm (CH2), UV-spectrum, max, nm (lg ): 256

(4,22), 266 (4,60), 270 (4,82), 289 (394), 300 (4,01), 324 (3,35), 333 (3,30), 339

(3,52). Found: M+ 286. C20H18N2. Calculated: M 286.

1,6-Dipropargylindolo[7,6-g]indole (XXI)

Is obtained similarly to compound XVIII by interaction of 0.42 g (2 mmole)

1H,6H-indolo[7,6-g]indole III, 0,017 g benzyltriethylammomium bromide and

1,14 g (9,5 mmole) propargylbromide by intensive mixing for 2 hours. The

product is purified on column, eluent benzene-hexane, 1:1. Is obtained 0,39 g

(68%) of compound XXI, colourless crystals. Tmelt. 222-2230C. Rf 0.44 (benzene-

petroleum ether, 2:1). IR-spectrum, , cm-1

: 3225 ( CH), 2120 (C C). Found: M+

282. C20H14N2. Calculated: M 282.

3,8-Diallylindolo[4,5-e]indole (XXII).

Is obtained similarly to compound XVIII by interaction of 0.23 g (1,1 mmole)

3H,8H-indolo [4,5-e]indole IV, 0,016 g [CH3(CH2)3]NBr and 3,2 g (26,4 mmole)

allylbromide at room temperature. The product is purified on column, eluent


196

benzene-hexane, 1:2. Is obtained 0,22 g (69%) of compound XXII, colourless

crystals. Tmelt. 118-1190C. Rf 0.38 (benzene-hexane, 1:1). IR-spectrum, , cm

-1:

1620-1560 (C=C), 730 (CH2), UV-spectrum, max, nm (lg ): 204 (3,70), 237

(3,60), 272 (4,42), 339 (3,21). Found: M+ 286. C20H18N2. Calculated: M 286.

3,8-Dipropargylindolo[4,5-e]indole (XXIII).

Is obtained similarly to compound XVIII by interaction of 0.42 g (2,0 mmole)

3H,8H-indolo[4,5-e]indole IV, 0,017 g benzyltriethylammomium bromide and

1,14 g (9,5 mmole) propargylbromide. The product is purified on column, eluent

benzene-hexane, 1:1. Is obtained 0,4 g (70%) of compound XXIII, colourless

crystals. Tmelt. 196-1970C. Rf 0.38 (benzene- petroleum ether, 2:1). IR-spectrum, ,

cm-1

: 3270, 3255 ( CH), 2120 (C C). Found: M+ 282. C20H14N2. Calculated: M

282.

EXPERIMENTAL BIOLOGICAL PART

Antimicrobial activity was studied at the laboratory of infectious diseases

chemotherapy at Chemistry of medicinal agents centre (AUSRCPI) by means of

in vitro experiments using method of twofold serial cultivation on liquid nutrient

solution (antimicrobial activity- in Hottinger broth, antituberculous activity- in

Sauto environment, antifungal- in Sabouraud environment) towards

microorganisms Staphylococcus aureus 209-p, Bacillus subtilis ATCC 6633,

Escherichia coli ATCC 25922, Proteus vulgaris ATCC 6896, Pseudomonas

aeruginosa ATCC 27853, Mycobaqterium tuberculosis H37, Mycobaqterium

tuberculosis academia, Mycobaqterium tuberculosis bovis 8; towards

opportunistic pathogenic bacteria Micobacterium cansasii, Micobacterium

intracellulaze, Micobacterium fortuitum; towards pathogenic fungi Microsporum

canis № 3/84, Frichophyton gypseum № 5/85, Candida albicans № 1755.

The activity of compounds was figured in minimal inhibitory concentration

(MIC), µgr/ml. Microbial load during the experiments was 1.10

5 KOE, in the

experiments with micobacteria- 0,02 mg and with fungi- 1.10

6 KOE/ml. Bacteria

were incubated for 18 hours at 370C; tuberculosis micobacteria- 14 days,

opportunistic pathogenic bacteria- 9, 7 and 5 days correspondingly, fungi- for 24

hours at 250C in Candida albicans experiments and 5 days in experiments with

dermatophytes. Results of the experiments are given in the table.


197

In the course of the experiment was established that compounds V, VII, VIII,

X possess high activity towards Staphylococcus aureus 209-p and Bacillus

subtilis. High activity towards micobacteria revealed V, VII, VIII, X; towards

fungi- compounds V and XIV.

The results obtained show that introduction of phenylazogroup in third

position of benzopyrroloindole pyrrole ring gives the key heterocycle, 1H,10H-

benzo[e]pyrrolo[3,2-g]indole, antimicrobic activity towards different pathogenic

and opportunistic pathogenic bacteria. It was shown that introduction of

electroacceptor group in para-position of phenylazogroup doesn’t have influence

on activity level.

Among studied indoloindole derivatives none of them revealed antimicrobic

activity, only compound XXI possess weak antituberculosis activity (MIC 23

µgr/ml). Herbicidal activity of substances was established by means of lunula

method. As test-microorganisms were used: Xanthomonas campestris (cause

white cabbage bacteriosis, rot), Bacterium tumefaciens, Pseudomonas tumefaciens

(cause grapewine cancer), Aspergillus niger, Streptomyces spp., Nocardiophsis

spp., Streptomyces allbogriseolus subsp. Aragvi. For bacteria cultivation was used

Burkholter environment (potato decoction 1 l, peptone 5g, Na2HPO4 2g, glucose

6g, NaCl 2g, citric-acid decoction 1g, aspargine 1g, agar 20g, distillated water 1

l); for fungi and ray fungi- milieu № 1 of Krasilnikov (KNO3 1g, K2HPO4 0,5g,

HgSO4 0,5g, NaCl 0,5g, FeSO4 traces, CaCO3 1g, starch 20g). After 6-day

incubation of actinomycetes and fungi and 2-day of bacteria zones of sterility

were noticeable. As a control was used solvent. Results are given in the table.

From the table it is obvious that compounds XVIII, XIX, XX, XXIII depress

growth and development of plant pathogenic bacteria Bacterium tumefaciens,

Xanthomonas campestris. It must be noted that compounds XVIII, XIX, XX,

XXIII don’t reveal activity towards Streptomyces allbogriseolus subsp, Aragvi;

zone of depression doesn’t exceed 1,0 mm (see table 2).

Also were studied herbicidal properties of previously [1,2] synthesized

compounds IV, XI-XV. Investigated compounds (see table 2) possess selective

inhibitory action towards microorganism growth: don’t influence the growth of

Aspergillus niger, don’t depress Bacterium tumefaciens and Pseudomonas

tumefaciens development, at the same time their activity is very close to

inhibitory action. Towards actinomycetes these compounds act selectively, for

instance, compound X, XIII almost don’t influence Streptomyces spp. growth but

reveal activity towards Nocardiophsis spp., though this action is weak and is

noted only at relatively high concentrations.

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

Com

pou

nd

Sta

phylo

coc

cus

.aure

us

209-p

Bac

illu

s. s

ubti

lis

6633 A

TC

C

Esc

her

ichia

coli

25922

AT

CC

Pro

teus

vulg

aris

6896

AT

CC

Pse

udom

onas

aeru

gin

osa

165

Myco

bac

teri

um

tuber

culo

sis

H 3

7 R

v

Myco

bac

teri

um

tuber

culo

sis

Aca

dem

ia

Myco

bac

teri

um

tuber

culo

sis

bovis

8

Mic

obac

teri

um

kan

sasi

i

Mic

obac

teri

um

intr

a-ce

llula

ze

Mic

obac

teri

um

fort

uit

um

Mic

rosp

oru

mca

nis

3/8

4

Fri

chophyto

n

gypse

-um

5/8

5

Can

did

a al

bic

ans

1755

V 3.9 7.8 250 250 250 0.55 _ 0.08 0.08 0.08 153 250 250 250

VI 125 250 250 250 250 153 _ 23 23 3.5 1000 250 250 250

VII 3.9 15.6 250 250 250 0.08 0.08 0.08 0.08 0.08 1000 250 250 250

VIII 31.2 62.5 250 250 250 23 _ _ 23 153 _ 250 250 250

IX 2.0 2.0 250 250 250 0.08 0.08 0.08 0.55 0.08 0.55 7.8 31.5 125

X 2.0 15.6 250 250 250 23 _ 0.08 0.08 0.08 1000 250 250 250

XIV 62.5 125 250 250 250 23 _ 0.08 23 1000 1000 15.6 31.2 250

XV 250 250 250 250 250 3.5 _ 0.55 23 23 1000 250 250 250

Influence of indoloindoles IV,XI-XIII, XVI-XXIII on the microorganisms growth

Compound

#

Bacterium

tumefaciens

Pseudomonas

tumefaciens

Xanthomonas

campestris

Streptomyces spp Nocardiophsis spp

1 2 3 1 2 3 2 3 1 2 3 1 2 3

IV 2.0 3.0 3.0 1.0 2.0 2.0 _ _ 1.0 1.0 2.0 1.0 1.0 1.0

XI 4.0 2.0 2.0 3.0 2.0 1.0 _ _ 5.0 2.5 0.0 2.0 1.0 0.0

XII 3.0 3.0 2.0 2.0 2.0 1.0 - _ 3.0 2.0 2.0 2.0 2.0 2.0

XIII 2.0 2.0 2.0 0.5 0.5 0.0 _ _ 0.0 0.0 0.0 2.0 2.0 2.0

XVI 4.0 3.0 2.0 2.0 2.0 2.0 _ _ 1.0 0.0 0.0 0.2 0.0 0.0

XVII 3.0 2.0 2.0 3.0 1.0 1.0 _ _ 5.0 4.0 3.0 3.0 2.0 2.0

XVIII _ 4.0 4.0 _ _ _ 5.0 4.0 _ _ _ _ _ _

XIX _ 4.0 5.0 _ _ _ 4.0 4.0 _ _ _ _ _ _

XX _ 3.0 5.0 _ _ _ 3.0 3.0 _ _ _ _ _ _

XXI _ 2.0 4.0 _ _ _ 3.0 2.0 _ _ _ _ _ _

XXII _ 4.0 4.0 _ _ _ 3.0 3.0 _ _ _ _ _ _

XXIII _ 2.0 3.0 _ _ _ 3.0 3.0 _ _ _ _ _ _

Note: are given of growth depression of test-microorganisms, in mm (control – 0,0); first volues are concentrations of substances 1

gr/l, second – 0,1 gr/l, third – 0,01 gr/l.


200

Compounds XI, XII, XIV, XVII inhibit actinomycetes growth, and their

biological activity is almost the same.

ACKNOWLEDGEMENT





Akademische Austausch Dienst (DAAD) for supporting the partnership and the



REFERENCES

[1] Sh.A.Samsoniya, M.V.Trapaidze, N.A.Kuprashvili, A.M.Kolesnikov,

N.N.Suvorov. Khim. Geterotsikl. Soedin. № 9, 1222-1224 (1985).

[2] Sh.A.Samsoniya, M.V.Trapaidze, S.V.Dolidze, N.A.Esakiya, N.N.Suvorov,

A.M.Kolesnikov, F.A.Mikhailenko. Khim. Geterotsikl. Soedin. № 3, 352-

357 (1984).

[3] Sh.A.Samsoniya, M.V.Trapaidze, N.N.Suvorov, I.M.Gverdtsiteli.

Soobshch. Akad. Nauk Gruz. SSR. vol.91, № 2, 361-364(1978).

[4] M.V.Trapaidze, Sh.A.Samsoniya, N.A.Kuprashvili, L.M.Mamaladze,

N.N.Suvorov. Khim. Geterotsikl. Soedin. № 5, 603-607 (1988).

[5] Sh.A.Samsoniya, M.V.Trapaidze, N.A.Kuprashvili. Khim.-Farm.

Zh.vol.43, № 2, 12-14 (2009).

[6] Sh.A.Samsoniya, M.V.Trapaidze, S.V.Dolidze, N.A.Esakiya,

L.N.Kurkovskaya, N.N.Suvorov. Khim. Geterotsikl. Soedin. № 9, 1205-

1212 (1988).

[7] M.V.Trapaidze, Doctore Thesis in Chemical Sciences, I.Javakhishvili

Tbilisi State University, Tbilisi, 2006.

[8] Sh.A.Samsoniya, N.A.Esakiya, S.V.Dolidze, M.V.Trapaidze, Z.Sh.Lomta-

tidze N.N.Suvorov. Khim.-Farm. Zh. № 9, 41-43 (1991).



Chapter 8

SOME CONVERSIONS OF

5-ACETYL-2-ETHOXYCARBONYL-

3-P-NITROPHENYL INDOLE

N. Narimanidze, Sh. Samsoniya, I. Chikvaidze Department of Chemistry, Iv. Javakhishvili Tbilisi State University,

I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT

It was carried out some conversions of 5-acetyl-2-ethoxycarbonyl-3-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 was carried out the acylation by chloro-anhydride of

substances possessing aminofunctionality. The correstponding series of

amides was obtained.

N. Narimanidze, Sh. Samsoniya and I. Chikvaidze

202

INTRODUCTION

The purpose of the work is synthesis of potentially biologically active indole

derivatives. For this reason were investigated properties of previously synthesized

2-ethoxycarbonyl-3-(p-nitrophenyl)-5-acetylindole (I). Some properties were

studied on the basis of transformation of ethoxycarbonyl and 3-p-nitrophenyl

groups.

By conversion of ester group of 2-ethoxycarbonyl-3-(p-nitrophenyl)-5-

acetylindole (1) was obtained the corresponding acid chloroanhydride (IV), which

by interaction with amino- and hydrazino-group containing compounds affords

amides (V-IX) and hydrazides (X).

From the methods of organic acids chloroanhydrides synthesis it was proved

to be the best the reaction of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid

(XII) with the thionyl chloride according the scheme:

NH

COOC2H5

NO2

C

O

CH3

NH

NO2

C

O

CH3

NH

NO2

C

O

CH3

NH

NO2

C

O

CH3

COONa

COOH

COCI

NaOH/to

SOCI2

45oC

I II

III IV

After the reaction of POCl3 or PCl5, with the relevant salt (XI) the reaction

mixture turns into the pitch.

Chloroanhydride (IV) is rather active and easily reacts with the amino-

function containing compounds to afford the corresponding acyl products (V - X):

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

203

NH

NO2

C

O

CH3

COCI NH

NO2

C

O

CH3

COR

V-XIV

V R=-N(CH3)2; VI R=-NHC6H5; VII R=-NHC6H4COCH3(p);

VIII R=-NHC6H4SO2NH2(p); IX R=-NHC6H4

NHC2H5OOC

COCH3

X R=-NHNHCO N

Acylation reactions was carried out in absolute dioxane at room temperature.

Reduction of the nitro-group of initial substance (1) was carried out by means

of following systems: Fe/H2O, Fe/CH3COOH, SnCl2/HCl, Zn/H2O and Zn/HCl.

The best results were obtained in the case of boiling of Fe/H2O suspension in

toluene [2]. The yield of corresponding amine appeared to be 85%. In order to

obtain new derivatives was carried out acylation and condensation with aldehyde

of amine XII according the following scheme:

NH

H3C-OC

COOC2H5

NO2

NH

H3C-OC

COOC2H5

NH2

NH

H3C-OC

COOC2H5

N=CH--R

NH

H3C-OC

COOC2H5

N

CO-CH3

R'

I XI

XII,XIII XIV-XVII

XII R=C6H5; XIII R=C6H4-NO2(o); XIV R=C6H4-NO2(m); XV R=CH3; XVI R'=H; XVII R'=CO-CH3


204

By condensation of amino-group with aldehydes were obtained azomethines

(XII-XVI). The reactions of condensation were carried out in ethanol in the

presence of dry K2CO3 [1]. At the same time intermolecular condensation reaction

of 5-acetyl and 3-phenylamine-groups with formation of mixture of oligomerous

compounds can be depicted with common structure (XVIII):

NH

C

COOC2H5

N=

XVIII

CH3

n

Acetylation of amino-compound (XI) was carried out with acetic anhydride.

By boiling of mixture of this compound with glacial acetic acid and acetic

anhydride was obtained monoacetyl-derivative (XVII). The same compound was

obtained when heated amine (XII) with acetic acid for a short time at 80-90oC.

Boiling for 30-40 min mixture which consists of 7 and 8 compounds with ratio

approximately 1:1, but by the increase of the boiling time up to 2-3 h practically

only diacetyl-derivative (XVIII) was obtained. It should be noted, that there

wasn’t observed acetylation of pyrrole NH-group during the reaction.

The control on course of reaction, purity of compounds and calculation of Rf

values were carried out by thin-layer chromatography on ―Silufol UV-254‖ plates.

UV spectra were recorded on spectrophotometer ―Specord‖ (ethanol); IR spectra

were recorded on ―UR-20‖ (in white paraffin oil). Mass-spectra were recorded on

―R10-10 Ribermags’s‖ (ionizing energy – 70 eV); NMR spectra - on WP 200 SY

(200 MHz).

EXPERIMENTAL PART

2-Oxycarbonyl-3-(p-nitrophenyl)-5-acetylindole (III): A suspension of 0.7g (2

mmol) of ester (1), 50 ml of NaOH 10% solution in water and 10ml of

isopropanol was stirred and refluxed until clarification (~1 hour). The obtained

solution was cooled and filtered. The filtrated with 10% HCl to pH 1. The

precipitate was filtered and dried until neutral reaction and dried in exicator. The


205

Recrystallization from water gave 0.5g (80%) of acid (XII) as yellow crystals. Rf

0.62 (hexane-ether, 1:1). m.p. 180-183º C. IR-spectra, ν, cm-1: 3160-3250 (NH);

1720, 1670 (C=O); 1340, 1520 (NO2). UV-spectra; λmax, nm (lgε): 205(3.97);

269 (4.12). Found, % C 62.4; H 3.2; N 8.7, M+ 324. C17H12N2O2. Calculated, %:

C 62.9; H 3.7; N 8.6; M 324.

Chloranhidride of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (IV): to

solution of 0.9 (3mmol) of acid (III) in 50 ml of abs. dioxane under regular

stirring was dropwise added the solution of 10 ml SOCl2 in 10 ml of abs. dioxane

at 0ºC was allowed standing at 45º C for 3 hours. The solvent was evaporated

under reduced pressure.The dry residue was dissolved in 30 ml of abs. benzene

and was evaporated again until dry residue was formed. This process was repeated

twice. Again was dissolved in 30ml of abs. benzene and evaporated to 15ml. Was

precipitated with abs. hexane. The precipitate was filtered and in dried vacuum –

exicator 0.7g (78%) of yellow crystals were obtained. Rf 0.6 (benzene). m.p 221-

223ºC. IR-spectra, ν, cm-1

: 3310(NH), 1700, 1650(CO),1520, 1355 (NO2). Found,

%: C 60.0; H 3.1; N 8.0 C17H11N2O4Cl. Calculated, % C 59.6; H 3.2; N 8.2.

Diethylamide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (V): to a

solution of 0.5g of chloroanhydride (XIII) in 50 ml of abs. dioxane was added 0.5

ml triethylamine and 0.3 ml of the 33% solution of diethylamine in water and

whole, was stirred was allowed standing for 2 hours, diluted with 100 ml of water,

the precipitate was washed with water and dried. 0.46g (88%) of amide (XIV) was

obtained. Rf 0.35 (chloroform). m.p 216-219ºC. IR-spectra, ν, cm-1

:3350 (NH):

3060(NH amide); 1700, 1650 (CO); 1530, 1340 (NO2). UV-spectra, λmax, nm

(lgε): 204(3.98); 255(4.31). Found, %: C 65.2; H 5.2; N 12.6; M+ 351.

C19H17N3O4 . Calculated, %: C 65.0.; H 4.8; N 12.0. M 351.

Anilide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (VI): was

obtained in the same way as compound (XIV) from 0.5g (1.5 mmol) of

chloroanhydride(XIII), 0.5ml of triethylamine and 0.2 ml (1.5mmol) of aniline in

50 ml of abs. dioxane at room temperature for 3 h. 0.48g (80%) was obtained. Rf

0.42 (hexane-ether, 1:1). M.p. 266-267º C. IR-spectra, ν, cm-1

; 3305 (NH); 3050

(NH amide): 1710. 1650 (CO); 1530; 1340 (NO2). UV-spectra,λmax, nm (lgε):

204 (4.39); 260 (4.61): 319 (4.01). Found, %: C 69.4; H 4.4; N 10.7; M+ 399.

C23H17N3O4. Calculated, %; C 69.2, H 4.3: N 10.5: M 399.

P-acetylanilide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid (VII):

was obtained in the same way as compound (XV) from 0.5g (1.5mmol) of

chloroanhydride (XIII), 0.5 ml of triethylamine and 0.27g (2 mmol) of p-

aminoacetophenone 0.6g (91%) of amide (XVI) was obtained. Rf 0.65 (hexane-

ether, 1:1). m.p 246-247ºC. IR-spectra. ν, cm-1

:3340(NH); 3100(NH-amide);

1700,1650(CO);1530,1340(NO2).UV-spectra, λmax, nm (lgε): 204 (5.36);


206

266(4.74); 322(4.46). Found, %: C 68.2; H 4.6; N 9.6; M+ 442. C25H20N3O5.

Calculated, %: C 67.9; H 4.5; N 9.5; M 442.

P-sulfamidoanilide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid

(VIII): was obtained in the same way as compound (XV) from 0.5g(1.5mmol) of

chloroanhydride, 0.5ml of triethylamine and 0.35g (2 mmol) of p-

sulfamidoaniline. 0.6g (85%) was obtained. Rf 0.7(ether). m.p 254-256ºC. IR-

spectra, ν, cm-1

: 3305, 3250, 3110 (NH); 1710, 1650, (CO); 1530, 1340 (NO2).

UV-spectra, λmax, nm (lgε): 208 (3.85); 266 (3.92). Found, %: C 58.0; H 4.2; N

11.4. C23H18N4O6S. Calculated, %: C 57.7, H 3.8; N 11.7.

2-Ethoxycarbonyl-5-acetylindole-3-yl-p-anilide of 3-(p-nitrophenyl)-5-

acetylindol-2 carbonic acid (IX): was obtained in the same way as compound

(XV) from 0.54g (1.7 mmol) of 2 ethoxycarbonyl-3-(p-aminophenyl)-5-

acetylindole. 0.78 (83%) as obtained. Rf 0.25 (benzene). m.p 256-258ºC. IR-

spectra, ν, cm-1

: 3380, 3310, 3450 (NH): 1660, 1650, 1630 (CO), 1520 1345

(NO2). UV-spectra, λmax, nm (lgε): 204 (3.61), 270 (4.8). Found, % C 69.2; H

4.6; N 9.3 C36H28N4O7. Calculated, %: C 68.8; H 4.5; N 8.9.

Isonicotinoylhydrazide of 3-(p-nitrophenyl)-5-acetylindole-2-carbonic acid

(X): was obtained in the same way as compound (XV) from 0.3g (2 mmol) of

isonicotinoylhydrazide. 0.57g (86%) was obtained. Rf 0.52 (benzene-acetone,

1:2). m.p. 284-287ºC. IR-spectra. ν, cm-1

: 3400, 3310 (NH); 1710, 1650 (CO);

1550, 1340 (NO2). UV-spectra, λmax, nm (lgε): 208 (3.98); 265 (3.92). Found, %:

C 62.9; H 4.2; N 15.4, C23H17N5O5. Calculated, %: C 62.3; H 3.8; N 15.8.

2-Ethoxycarbonyl-3-(p-aminophenyl)-5-acetylindole (XI) Toluene solution of

1.4 g (4 mmol) of nitro-compound (1) was heated at 100oC and 6 g of activated

iron powder and 20 ml of water was added during 6 h. The hot solution was

filtered and purified within the column (silicagel), eluent – benzene; yield 1.1 g

(85). Rf 0.43 (Benzene-ether, 2:3). m.p. 226-227oC. IR-spectra v, cm

-1: 1700

(CO); 3300 (NH2); 3455 (NH). UV-spectra, λmax, nm(lgε): 202(5.0). Found, %: C

70.7; H 5.3; N8.5. M+

322. C19H18N2O3 . Calculated, %: C 70.8; H 5.6; N 8.7. M

322

2-Ethoxycarbonyl-3-(p-benzylideneiminophenyl)-5-acetylindole (XII) To the

solution of 1.6 g (5 mmole) of amine (XI) and 0.64 g (6 mmole) of benzaldehyde

in 50 ml of ethanol 0.1 g dry of K2CO3 was added and heated at 50 o

C for 5h.

Reaction mixture was diluted with 200ml of water, precipitate was filtered and

recrystallized from ethanol. Yield 1.35 g (65%). m.p. 198-200 o

C. Rf 0.55

(hexane-ether, 2:1). IR-spectra v, cm-1

: 1620 (C = N); 1660, 1710 (C = 0); 3300-

3480 (NH). UV-spectra λmax, nm (lgε): 206 (4.2); 249 (2.8) 314 (2.2) Found, %: C

75.3; H 5.6; N 6.4 M+ 410. C26H22N2O3. Calculated, %: C 76.1; H 5.4: N 6.8. M

410


207

2-Ethoxycarbonyl-3-p-(o-nitrobenzylideneiminophenyl)-5-acetylindole (XIII)

This compound was obtained by the method described above. Yield 1.5 g

(64.6%). M.p. 220-221 o

C. Rf 0.48 (hexane-ether, 2:1). IR-spectra v, cm-1

: 1340,

1560 (NO2); 1630 (C = N); 1660, 1700 (C = O); 3360 (NH). UV-spectra, λmax,

nm(lgε): 205 (4.8); 270 (5.8); 335 (3.2). Found, %: C 68.1; H 4.9; N 9.6: M+ 455

C26H21N3O5. Calculated, %. C 68.6; H4.6, N 9.2: M 455.

2-Ethoxycarbonyl-3-p-(m-nitrobenzylideneiminophenyl)-5-acetylindole (XIV)

This com-pound was obtained by the same way as described for compound (3).

Yield 1.57 g (695). m.p. 228-230 o

C. Rf 0.5 (hexane-ether; 1:1) IR-spectra v, cm-1

:

1340, 1560 (NO2); 1630 (C = N); 1660, 1700 (C = O); 3365 (NH). UV-spectra,

λmax, nm (lgε): 205 (2.2); 256 (2.6); 325 (2.0). Found, %: C 68.4; H 4.3; N 9.4. M+

455 C26H21N3O5. Calculated, %: C 68.6; H 4.6; N 9.2. M 455

2-Ethoxycarbonyl-3-(p-ethylideniminophenyl)-5-acetylindole (XV) This

compound was obtained by the same way as described for compound (3). Yield

0.8 g (46%). m.p. 231-232 o

C. IR spectra v, cm-1

: 1640 (C = N); 1690, 1740

(C=O); 3320 (NH). UV-spectra, λmax, nm(lgε): 208 (2.4); 268 (3.9). Found, %: C

72.1; H 5.9: N 8.5. M+ 348. C21H20N2O3. Calculated, %: C 72.4; H5.7; N 8.0; M

348.

2-Ethoxycarbonyl-3-(p-acetylaminophenyl)-5-acetylindole (XVI)

Method (a): The mixture of 1.6 g (5 mmole) of amine (XI), 10 ml acetic acid

of acetic anhydride 10 ml was boiled for 30 min, then cooled rapidly and poured

with a thin stream into 300 ml of cold water. The obtained mixture was left 3-4h.

Precipitation was filtered and purified within the column. Eluent-(hexan-ether

1:1); yield 0.9 g (50%).

Method (b): The mixture of 1.6 g (5 mmole) of amine (2) and 20 g of acetic

anhydride was heated for 5-7 h. All the successive steps are analogicalof those in

method (a). Yield was 1.13 g (62%). m.p. 235-237 o

C. Rf 0.4 (hexane-ether). IR-

spectra, v, cm-1

: 1660, 1680, 1710 (C = O); 3340, 3420 (NH). UV-spectra, λmax,

nm(lgε): 206 (4.0); 245 (4.1): 270 (3.9). Found, %: 68.9; H 5.7; N 8.0. M+ 364.

C21H20N2O4. Calculated, %: C 69.2; H 5.5; N 7.7. M 364.

2-Ethoxycarbonyl-3-(p-N,N-diacetylaminophenyl)-5-acetylindole (XVII) The

mixture of 1.6 g (mmole) of amine (2) and 20 ml of acetic anhydride was boiled

for 3h, then cooled and diluted with 10 ml of cold water. Obtained mixture was

left for 4-5 h. Precipitation was filtered and purified within column; eluent

chlorophorm. Yield 1.3 g (65%). m.p. 215-218 o

C. Rf 0.41 (hexane-ether, 2:1). IR-

spectra, v, cm-1

: 1640, 1685, 1710 (C=O); 3340-3370 (NH). UV-spectra, λmax,

nm(lgε): 205 (4.7); 270 (4.6): 306 (2.8). Found, %: C 67.9; H 5.2; N 7.0. M+

406.

C23H22N2O5. Calculated, %: C 68.0; H 5.4; N 6.9. M 406.

1H-NMR Spectra of diazocompounds V-XIII (acetone-d6)

Compo-

und #

1H 3H

3/H

4H

4/H

5H

6H 7H α H β H CH3CO CH3CH2 CH2CH3 NH CH3 J, Hz

I 12.55s - 8.16 - 7.96dd 7.61d 7.85d 8.35d 2.58s 1.20t 4.27k - - J4,6=1.1;

J6,7= =Jα,β=8.77

Jethyl=7.0

IV 12.45s - 8.16d - 7.93dd 7.66d 7.85d 8.33d 2.57 - - - - J4,6=1.3;

J6,7=8.9;

Jα,β=8.5

VI 11.97s - 7.78d - 7.69dd 7.41d 7.77d 8.30d

7.02 - 7.24m

- - - 9.36s 2.06 J4,6=1.4;

J6,7=8.7;

Jα,β=8.6

XI 12.04s - 8.17d - 7.86dd 7.52d 7.22d 6.67d 2.56s 1.23t 4.25k 5.24s - J4,6=1.45;

J6,7=8.77;

Jα,β=8.4

XV

D-acetone

11.23s - 8.33d - 7.98dd 7.63d 7.79d 7.54d 2.13s

2.57s

1.24t 4.28k 9.27s - J4,6=1.7;

J6,7=8.96;

Jα,β=8.53;

Jethyl=7.3

XII 11.30s - 8.04d - 7.98dd 7.75d 7.89d

6.98d

7.48d

7.15m

2.51s 1.2t 4.24k - 5.21s J4,6=1.7;

J6,7=8.96;

Jα,β=8.53;

Jethyl=7.3

XV

D-acetone

11.52s - 8.30d - 8.03dd 7.69d 7.93d 8.40d 2.58s 1.20t 1.31k N=CH

5.17k

1.24d J4,6=1.7;

J6,7=8.9;

Jα,β=9.0;

Jethyl=6.0

XVII

D-acetone

11.25s - 8.32d - 8.00dd 7.68d 7.81d 7.50d 2.15s

2.55s

1.23t 4.26k - - J4,6=1.7;

J6,7=8.96;

Jα,β=8.53;

Jethyl=7.3


209

ACKNOWLEDGEMENT








REFERENCES

[1] I. Chikvaidze, N. Narimanidze, Sh. Samsoniya. Et. At. Chemistry of

Heterocyclic Compounds. 9 (315), 1993, 1194-1199 (Russian).



Chapter 9

2-PYRIDINESELENENYL- AND TELLURENYL

CHLORIDES AS BUILDING BLOCKS FOR

DERIVATIVES OF 2,3-DIHYDRO[1,3]

SELEN(TELLUR)AZOLO[3,2-A]PYRIDIN-4-IUM

Alexander V. Borisov*, Zhanna V. Matsulevich,

Vladimir K. Osmanov, Galina N. Borisova and

Georgy K. Fukin

R. E. Alekseev Nizhnii Novgorod State Technical University, 603950 Nizhnii

Novgorod, Russian Federation

The reactions of 2-pyridineselenenyl- and tellurenyl chlorides with alkenes

lead to the formation of products of a tandem electrophilic addition/cyclization

process with the ring closure by the nitrogen atom of the pyridylchalcogeno

moiety.

By virtue of its extremely high regio- and stereoselectivity

selenocyclofunctionalization of unsaturated substrates carrying internal

nucleophiles is one of most important and effective methods of synthesis of

heterocyclic compounds [1-11]. Much less is known about

tellurocyclofunctionalization of unsaturated compounds [12-15]. All these

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

A.V. Borisov, Zh. V. Matsulevich, V. K. Osmanov et al.

212

cyclizations proceed with ring closure involving a nucleophilic active group in the

molecule of the substrate.

Recently we described a novel approach to a stereoselective synthesis of

condensed sulfur–nitrogen-containing heterocycles based on the interaction of

sulfenyl chlorides with unsaturated compounds which occurs by ring closure at

the nucleophilic center of the sulfenyl unit [16]. Taking into account these results

it can be predicted that corresponding organoselenium and organotellurium

reagents are suitable for the preparation of heterocycles containing selenium and

tellurium. We now report on extensions of this alternative approach to

selenenylating and tellurenylating reagents.

In this work we have explored synthetic possibilities in reactions with alkenes

for known 2-pyridineselenenyl chloride (1a) [17] and new reagent 2-

pyridinetellurenyl chloride (1b), prepared by the interaction of di(2-pyridyl)

ditelluride with sulfuryl chloride in CH2Cl2. To the best of our knowledge the

compound 1b is the first example of hetarenetellurenyl halides which contain the

nitrogen atom in the hetaryl unite. The structure of this compound was determined

by X-ray analysis of a single crystal (Figure 1). Crystallographic data for 1b:

C10H8Cl2N2Te2, Mr = 482.28, monoclinic, space group P21/n, a = 10.0103(4), b =

8.0519(3) and c = 16.4700(7) Å, = 103.8800(10) , V = 1288.75(9) Å3, Z = 4, T

= 100(2) K, F000 = 880, dcalc = 2.486 gcm–3

, = 0.414 mm–1

, = 2.55–25.99°,

reflections collected 7357, independent reflections 2524 [Rint = 0.0228], GOF =

1.057, R = 0.0278 [I > 2 (I)], wR2 = 0.0646 (all data), largest diffraction peak and

hole 1.578 / -0.772 e.Å-3

.

For research of synthetic opportunities of the developed approach, regio- and

stereochemistry of cyclization as model substrates we used alkenes 2-7. It is

necessary to note that recently in reaction of 2-pyridineselenenyl bromide

analogous selenenyl chloride 1a with styrene 2 in methanol is received only

solvoadduct – 1-methoxy-1-phenyl-2-(2-pyridylselanyl)ethane – in quantitative

yield [18].

We have found that selenenyl chloride 1a and tellurenyl chloride 1b reacts

with equimolar amounts of alkenes 2-6 in CH2Cl2 at 20°C to give the derivatives

of 2,3-dihydro[1,3]selen(tellur)azolo[3,2-a]pyridin-4-ium 8-12a,b, the products of

cyclization with ring closure at the nitrogen atom of the pyridylchalcogeno moiety

(Scheme 1, Table 1).

2-Pyridineselenenyl- and Tellurenyl Chlorides as Building Blocks …

213

Figure 1. Molecular structure of 1b. Selected bond lengths (Å): Te(1B)-C(1B) 2.125(4),

Te(1B)-N(1A) 2.329(4), Te(1B)-Cl(1B) 2.539(1), Te(1A)-C(1A) 2.120(4), Te(1A)-N(1B)

2.309(3), Te(1A)-Cl(1A) 2.558(1). Selected bond angels (º): C(1B)-Te(1B)-N(1A)

83.10(15), C(1B)-Te(1B)-Cl(1B) 87.25(12), N(1A)-Te(1B)-Cl(1B) 169.87(9), C(1A)-

Te(1A)-N(1B) 83.32(14), C(1A)-Te(1A)-Cl(1A) 86.48(11), N(1B)-Te(1A)-Cl(1A)

169.35(9).

In a typical experiment a solution of unsaturated compound 2-6 (10 mmol) in

CH2Cl2 (10 ml) at 20 ºC was added to a suspension of reagent 1a,b (10 mmol) in

CH2Cl2 (10 ml). The mixture was stirred approximately for 1-2 days. After full

dissolution of suspension of reagent the solvent was evaporated to leave a solid

residue, which was recrystallized from CH2Cl2. The products were obtained in

reproducibly high yields (91-96%) under ordinary laboratory lighting conditions.

In contrast to the reactions of electrophiles 1a and 1b with alkenes 2-6,

interactions of the same reagents with norbornene 7 in CH2Cl2 at 20°C led to the

formation of 1,2-chloroselenide 13a and 1,2-chlorotelluride 13b in nearly

quantitative yields (Scheme 2).


214

N XCl

R1

R2

N

X

R1

R2

1a,b

2-4+

Cl-

6Cl

-

+N

X

N

X

5

Cl-

8-10a,b

11a,b

12a,b

+

a X = Se

b X = Te

Scheme 1

2,8 R1 = Ph, R

2 = H

3,9 R1 = H, R

2 = tert-Bu

4,10 R1 = H, R

2 = Me3Si

Scheme 1.

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

Reagent Alkene Product Yield, %

1a 2 8a 95

1a 3 9a 96

1a 4 10a 93

1a 5 11a 92

1a 6 12a 93

1b 2 8b 94

1b 3 9b 93

1b 4 10b 91

1b 5 11b 92

1b 6 12b 95


215 Scheme 2

b X = Te

a X = Se

1a,b

N XCl

7

CH2Cl2

LiClO4 / MeNO2

X

Cl

N

N+

X

13a,b

14a,bClO4

-

Scheme 2.

Absolutely other result was observed when the same set of reactions was

carried out in MeNO2 in the presence of LiClO4. Under these conditions reactions

gave only the products of cycloaddition, the salts 14a and 14b in 88% and 83%

yields respectively (Scheme 2). In a typical experimental procedure a solution of

LiClO4 (1.06 g, 10 mmol) in MeNO2 (30 ml) was quickly added to a solution of

reagent 1a or 1b (10 mmol) in MeNO2 (30 ml) at 20 °C. After 1 min a solution of

alkene 7 (0.94 g, 10 mmol) in MeNO2 (10 ml) was added. The mixture was stirred

for 1h. The precipitate of LiCl was separated by filtration, and the filtrate was

evaporated to leave a solid residue, which was recrystallized from CH2Cl2.

The structure of the products has been confirmed by elemental analysis, IR,

NMR (1H and

13C) spectroscopy and mass spectrometry. Judging from the

1H

NMR spectra, all the studied reactions occurs regiospecifically and

stereospecifically. Taking into account the known criteria for determining the

stereochemistry of addition to alkenes and also the results we obtained earlier

[16], we may assume that formation of the condensed systems 8-12a,b and 14a,b

occurs to a cis-cycloaddition scheme. For example, in the 1H NMR spectra of

compounds 14a,b the signals from the protons of the CHX and CHN+ moieties

appear as doublets with spin–spin coupling constant 7.3-8.3Hz, which suggests an

exo–cis configuration for these products [20, 21].

It has been shown previously that the formation of the product of

heterocyclization in reactions of hetarenesulfenyl chloride with alkenes can

proceed by two routes [16]. Therefore for finding-out of routes of the formation of

compounds 8-12a,b and 14a,b we have lead control experiments. NMR-


216

monitored experiments demonstrated that reaction of 1a,b with alkenes 2-6

involve the initial formation of usual 1,2-adducts 15a,b, followed by

transformation of the latter into heterocyclic products 8-12a,b (Scheme 3).

At the same time, control experiments have shown that compounds 13a,b do

not undergo intramolecular heterocyclization in CH2Cl2 and LiClO4 - MeNO2 and

hence the products 14a,b are formed in the course of the AdE reaction.

Thus, we have developed simple and convenient methods for the synthesis of

condensed Se,N- and Te,N-containing hetecycles.

1a,b 15a,b

Scheme 3

N XCl

H

Cl

R1

X

H R2

N2-6

R1

R2

8-12a,b

Cl-

+N

X

R1

R2

a X = Se

b X = Te

Scheme 3.

REFERENCES

[1] Nicolaou, K. C.; Seitz, S. P.; Sipio, W. J.; Blount, J. F. J. Am. Chem. Soc.

1979, 101, 3884-3893.

[2] Clive, D. J. L.; Russell, C. G.; Chittattu, G.; Singh, A. Tetrahedron, 1980,

36, 1399-1408.

[3] Nicolaou, K. C. Tetrahedron, 1981, 37, 4097-4109.

[4] Fujita, K.; Murata, K.; Iwaoka , M.; Tomoda, S. Tetrahedron , 1997, 53,

2029-2048.

[5] Wirth, T. Tetrahedron, 1999, 55, 1-28.

[6] Tiecco, M. In Topics in Current Chemistry: Organoselenium Chemistry:

Modern Developments in Organic Synthesis; Wirth, T. Ed.; Springer:

Heidelberg, 2000; 7-54.

[7] Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 3741-3749.


217

[8] Petragnani, N.; Stefani, H. A.; Valduga, C. J. Tetrahedron, 2001, 57, 1411-

1448.

[9] Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;

Temperini, A. Chem. Eur. J., 2002, 8, 1118-1124.

[10] Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N.

Tetrahedron, 2004, 60, 5273-5308.

[11] Denmark, S. E.; Edwards, M. G. J. Org. Chem., 2006, 71, 7293-7306.

[12] Petragnani, N.; Comasseto, J. V. Synthesis, 1991, 897-919.

[13] Yoshida, M.; Suzuki, T.; Kamigata, N. J. Org. Chem., 1992, 57, 383-386.

[14] Stefani, H. A.; Petragnani, N.; Brandt, C.; Rando, D. G.; Valduga, C. J.

Synth. Commun., 1999, 29, 3517-3531.

[15] Petragnani, N.; Stefani, H. A. Tetrahedron, 2005, 61, 1613-1679.

[16] Borisov, A. V.; Osmanov, V. K.; Borisova, G. N.; Matsulevich, Zh. V.;

Fukin, G. K. Mendeleev Commun., 2009, 19, 49-51.

[17] Toshimitsu, A.; Owada, H.; Terao, K.; Uemura, S.; Okano, M. J. Org.

Chem., 1984, 49, 3796-3800.

[18] Toshimitsu, A.; Owada, H.; Terao, K.; Uemura, S.; Okano, M., J. Chem.

Soc., Perkin Trans. 1, 1985, 373-378.

[19] Clive, D. J. L.; Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen,

S. M. J. Org. Chem., 1980, 45, 2120-2126.

[20] Barraclough, D.; Oakland, J. S.; Scheinmann, F. J. Chem. Soc., Perkin

Trans. 1, 1972, 1500-1506.

[21] Wirschun, W. G.; Al-Soud, Y. A.; Nusser, K. A.; Orama, O.; Maier, G.-M.;

Jochims, J. C. J. Chem. Soc., Perkin Trans. 1, 2000,4356- 4365.



Chapter 10

SYNTHESIS AND ANTIMICROBIAL ACTIVITY

OF SOME ADAMANTYL

CONTAINING INDOLES AND

BENZOPYRROLOINDOLE DERIVATIVES

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

M. O. Lomidze, M. V. Trapaidze,

K. Kh. Mamulashvili, Z. Sh. Lomtatidze Department of Chemistry, Iv. Javakhishvili Tbilisi State University,

I. Chavchavadze ave., 0172 Tbilisi, Georgia

ABSTRACT

2-(1-adamantyl)indole, synthesized by Fischer reaction, was transformed

into 3-dimethylaminomethyl derivative according Mannich reaction. It was

obtained corresponding quaternary salts soluble in water. 2-

adamantylaminocarbonylindole and 2,9-di(adamantylaminocarbonyl)-

1H,10H-benzo[e]pyrrolo[3,2-g]indole were obtained by interaction between

1-aminoadamantane and 2-indolylcarbonic acid. The synthesized compounds

revealed biological activity.

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

220

INTRODUCTION

Indole derivatives are characterized with broad spectrum of pharmacological

activity: they have an antimicrobial and antifungal action [1], reveal psychotropic

and anti-inflammatory activity, possess antihistaminic and antiadrenalistic

properties [2]. Also it is known substances containing adamantane fragment in

the molecule and possessing broad spectrum of biological activity [3-5].

Therefore in order to find new biologically active compounds some adamantyl

containing indole derivatives and benzopyrroloindole were synthesized in the

present work; also was studied antimicrobial activity.

According Fischer reaction from 1-acetyladamantane and phenyl hydrazine

2-(1-adamantyl)indole(I) was obtained in polyphosphoric acid. As a result of its

aminomethylation according Mannich reaction[7] was obtained an analog of

indole alkaloid gramine – 2-(1-adamantyl)-3- dimethylaminomethylindole(III).

Reaction was carried out at the condition similar to indole [8]. As a result of

interaction between indole-2-carboxylic acid chloride (II) [4] and 1-adamantyl-

amine in absolute benzene was obtained 2-(1-adamantyl)amino-

carbonylindole(IV) with 31% yield. Compound III was transformed into water-

soluble salt – methylsulphate-V, methyliodide VI and hydrochloride-VII.

NH

R

NH

R'

R

I, II III, IV

I R=1-adamantyl(Ad); II R=COCl; III R=1-Ad, R'=CH2-N(CH3)2;

IV R=CONH-Ad, R'=H

Dichloranhydride 2,9-dioxycarbonyl-1Н,10Н-benzo[e]pyrrolo[3,2-g]indole

(IX) was synthesized as a result of interaction between di-acid VIII [9] and thio-

nylchloride. By condensation of dichloranhydride IX with aminoadamantane in

absolute dioxane was received 2,9-di(adamantylaminocarbonyl)-1Н,10Н-

benzo[e]pyrrolo[3,2-g]indole (X).

Synthesis and Antimicrobial Activity …

221

NH

HN

COOH

HOOC

NH

HN

COCl

ClOC

SOCl2

NH

HN

CONH-Ad

Ad-HNOC

VIII IX

Ad-NH2

X Composition and structure of the synthesized compounds were established by

means of elemental analysis, IR-, UV- and NMR spectra.

Biozidal properties were studied on the basis of microorganisms tests in the

Burkholter environment. Activity of compounds was established by means of

lunula method. Compounds I, III and IV revealed biozidal properties and suppress

bacterium development with different activities (see the table).

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

Test-

microorganisms

Control

Ethanole:

Water 10:1

Compound

I III IV

Pectobacterium

aroideac

Xanthomonas

campestris

Bacterium

tumefaciens

0,0

0,0

0,0

6,0*

1,0**

3,0

2,0

1,0

1,0

1,5

2,0

1,0

0,5

6,5

4,0

5,0

* Inhibition zone size, mm.

** Sterile zone, mm.


222

The rest substances appeared to be inactive. For compound X was studied

antituberculous activity in vitro towards microorganism [10]; was revealed a weak

activity against micobacteria: Mycobaqterium tuberculosis H 37, Mycobaqterium

tuberculosis academia and Mycobaqterium tuberculosis bovis 8. Minimal

inhibitory concentration (MIC) in mkg/ml was consequently 23, 153 and 23.

EXPERIMENTAL PART

Reaction progress and individuality of compounds controlled over Silufol

UV-254 plates. Infrared spectrum was taken on the ―Specord‖ IR-75 device, UV

spectrum – on the spectrometer ―Specord‖ UV VIS in ethanole, NMR spectrum –

on the spectrometer WP-200 SY (200 MHz), internal standard – ТМS.

2-(1-Adamantyl)indole (I). Mixture of 1 ml (10 mmol) of phenylhydrazine, 2g

(10 mmol) of 1-acetyladamantane and 30 g of polyphosphoric acid were mixed

for one hour at 110 С, then cooled and diluted with cold water. Precipitate was

filtered, washed with water until рН 7 and dried. It was purified on the column

with silica gel in ether-hexane system, 1:7. Rf 0,43. Yield 2,15 g (85%). Tmelt -

149-150 С. IR spectrum, , cm-1

: 3410 (NH), 3000-2850 (CH-Ad). NMR

spectrum (acetone-d6), , ppm, J, Hz : 9,9 (1H,s); 6,1(3H,м); 6,80-7,45 (4H-7H,

м); 1,8-2,05(Ad-H, м); J м=2,2; J о=7,7; J37 =0,7. Found, %: С 86,4; Н 8,1; N 5,6.

С18Н21 N. Calculated, %: С 86,0; Н 8,4; N 5,6.

2-(1-Adamantyl)-3-dimethylaminomethylindole (III). Solution of 0,5 g

compound I and 1,9 g CH2-N+(CH3)2 CI

- in 20 ml absolute dimethylformadide

were mixed for 6 hours at 25 С, then diluted with 200 ml cold water and

alkalified til рН 10. Was extracted with ether (3X50 ml). Extract was dried on

KOH and steamed dry. Residue was crystallized from hexane. Yield – 76%. Tmelt

- 121-123 С. IR spectrum, , см-1

: 3405 (NH), 3000-2800 (CH-Ad). NMR-

spectrum (aceton-d6), , ppm, J, Hz: 9,7 (1H); 7,55 (4H,kw); 6,8-7,5 (4H-7H, м);

1,8-2,2(Ad-H, м); 2,21 (СH2, s); 2,16 (СH3, s). J м=1,6; J о=7,7. Found,%: С 81,5;

Н 8,8; N 9,0. С21Н28 N2. Calculated, %: С 81,7; Н 9,1; N 9,0.

2-(1-Adamantyl)aminocarbonylindole (IV). Mixture of 0,5 ml (3,3 mmol) of

1-adamantylamine in 20 ml absolute benzene was added solution of 0,53 g

(3,7mmol) compound II in 25 ml absolute benzene, 0,4 ml triethylamine and

mixed for one hour at 60-65 С. Solvent was cooled, filtered and steamed. Residue

was purified on the column with silica gel in ether-hexane system, 5:1. Rf 0,7

(hexane-ether, 1:1). Yield 0,28 g (31%). Tmelt -224-225 . IR spectrum, , см-1

:

3410 (NH), 3290(NHСО), 3000-2870 (CH-Ad), 1660 (СО). NMR-spectrum

Synthesis and Antimicrobial Activity …

223

(СHСI3), , ppm, J, Hz : 10,0 (1H,s); 6,71(3H,d); 7,1-7,5 (4H-7H, м); 5,87 ( NH-

CO,s); 1,74-2,16(Ad-H, м); J13=1,7; J о=7,8; Jм =1,9. Found, %: Н 7,1; N 9,6.

С19Н22 N2О.; Calculated, %: Н 7,0; N 9,0.

2(1-Adamantyl)-3-dimethylaminomethylindole methylsulphate (V). To the

mixture of 1 ml (CH3)2SO4 in 5 ml absolute tetrahydrofuran was added 0,31g

(1mmol) compound III in 10 ml absolute tetrahydrofuran and then mixed at 15-

20 С for 3 hours. Residue was filtered, washed with absolute tetrahydrofuran,

absolute ether and dried at vacuum. Yield – 0,24 g (55%). Tmelt - 180 С.

2(1-Adamantyl)-3-dimethylaminomethylindole methyliodide (VI). Solution of

0,31 g (1mmol) of compound III and 1,2 ml (20 mmol) methyliodide in 50 ml

absolute ether were mixed at 15-20 С for three hours and left for night.

Precipitated crystals were filtered, washed with absolute ether and then dried.

Yield – 0,42g (93%). Tmelt - 295 С.

2(1-Adamantyl)-3-dimethylaminomethylindole hydrochloride (VII). To the

solution of 0,31g (1 mmol) compound III in 10 ml absolute tetrahydrofuran was

added solution of dry НСI in absolute ethanole till рН 1, then mixed for 3 hours

and diluted with 100 ml dry ether. Precipitation was filtered, washed with

absolute ether and then dried. Yield- 0,25g (73%). Tmelt - 210 С.

2,9-Dioxycarbonyl-1H,10H-benzo[e]pyrrolo[3,2-g]indole dichloranhydride

(IX). 0,3 g (1 mmol) of 2,9-dioxycarbonyl-1H,10H-benzo[e]pyrrolo[3,2-

g]indole(IX) was suspended in 10 ml thionylchloride and boiled for 5 hours by

mixing. Then reaction mixture was cooled until 35…40 С, precipitate was

filtered, washed several times with absolute ether and dried of vacuum. Yield –

0,24g (90%). Yellow crystals, - Tmelt 240... 241 С. Rf 0,77 (hexane-ether,1:1). IR

spectrum, , см-1

: 3370 (NH), 1665(С=О). NMR-spectrum (DMSO-d6), , ppm, J,

Hz: 11,83(1H,10H,b.s); 7,72(3H,8H,d); 8,29(4H,7H, dd); 7,46(5H,6H,dd),

J13=2,19; J 45=9,32; J46=6,22; Found, %: C 58,4; H 2,8; N 8,5; CI 21,1. С16Н8N2

CI2О2. Calculated, %: C 58,1; Н 2,4; N 8,5; CI 21,2.

2,9-Di(1-adamantylaminocarbonyl)-1H,10H-benzo[e]pyrrolo[3,2-g]indole-

(X). To the mixture of 0,3g (1 mmol) compound IX in 20 ml dioxane was added

solution of 0,6 g (4 mmol) aminoadamantane in 10 ml dioxane and mixed for one

hour at 70 С. Solvent was cooled, filtered, washed with absolute ether and dried.

Yield 0,34g (68%). Yellow crystals, - Tmelt 283…284 С. Rf 0,63 (benzene-

acetone, 4:1). IR spectrum, , см-1

: 3370. 3340 (NH), 1650(amid I); 1535 (amid

II). NMR-spectrum (DMSO-d6), , ppm, J, Hz : 11,63(1H,10H,b.s); 7,89(NH

amid, s); 7,61(3H,8H, s); 7,45(4H,7H, b.s), 8,11 (5H, 6H, b.s); 1,79…2.14 (Ad).

Found, %: C 76.8; H 6,7; N 9,7.С36Н40N4О2. Calculated, %: C 77,1; Н 7,2; N

10.0.


224

ACKNOWLEDGEMENT








REFERENCES

[1] Trofimov B.A. Mikhaleva A.I. Beliaevski A.I. and others. Jour.

Pharm.chem., №3, pp – 25-29; 1981.

[2] Gasteli J., Schivdler W. – Pat. 550788 (Switzerland). Chemsitry, №4,

N40/09P,1975.

[3] Bagrii E.I. Adamantanes: Preparation, Properties, and Use “Nauka”,

Moscow, 1989.

[4] Morozov I.S. Petrov V.I. Sergeeva S.A. Pharmacology of Adamantanes.

Volgograd Medical Academy, 2001.

[5] Аrtsimovich N.G., Galushina T.S., Fadeeva T.A. Intern. J.

Immunorehabilitation, 2, 54, 2000.

[6] Suvorov N.N. Mamaev V.N. Rodyonov V.M. Reactions and Methods of

investigation of Organic Compounds` M.,9-154, 1959.

[7] Blik F.F. Organic Reactions. M., 10, 339, 1948.

[8] Samsoniya Sh.A. Chikvaidze I.Sh. Suvorov N.N. Reports – AN GSSR, 99,

№3, 613; 1980.

[9] Zhungiettu G.I. Budilin V.A. Kost A.N. Preparative Chemistry of Indole.

Chisinau, 192, 1975.



Chapter 11

PHOTOCHEMISTRY OF AZIDOPYRIDINE AND

RELATED HETEROCYCLIC AZIDES

Mikhayl F. Budyka* Institute of Problems of Chemical Physics, Russian Academy of Sciences,

142432, Chernogolovka, Moscow region, Russian Federation

ABSTRACT

Photochemical properties of azido derivatives of six-member 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 from the neutral to positively charged form by

protonation or alkylation at endocyclic nitrogen atoms.

* E-mail: [email protected]

Mikhayl F. Budyka

226

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 long-wavelength visible light sensitivity so far reported for aromatic

azides.

INTRODUCTION

The photochemistry of aromatic azides receives continuous attention because

of their useful applications in heterocyclic syntheses, photoresist techniques and

photoaffinity labeling [1,2,3,4,5]. The key reaction in all cases is the photoinduced

N-N2 bond dissociation with formation of highly reactive intermediate, nitrene.

The main quantitative parameter of this reaction is the photodissociation quantum

yield ( ), which determines the azide photoactivity.

RN-N2 RN + N2

h

Photochemistry of Azidopyridine and Related Heterocyclic Azides

227

The photodissociation of arylazides upon direct excitation in the long-

wavelength absorption band occurs in the lowest singlet excited state (S1). In this

case, the quantum yield is determined as

= kr/(kr + kf + kic + kisc + kd) , (1)

where kr is a rate constant for azido group dissociation in the S1 state, kf, kic and

kisc are the rate constants for emission (fluorescence), internal conversion, and

intersystem crossing, respectively; and kd characterizes all other possible

processes of deactivation of the excited state (energy transfer, other reactions,

etc.). Depending on the azide structure, the value can vary by several orders of

magnitude. In this respect arylazides are grouped into photoactive azides ( > 0.1)

and photoinert azides ( < 0.01) [6]. It is also known that irradiation of azides

with light at different wavelengths resulting in occupation of different electronic

excited states (S1, S2 , … Sn) can lead to variation of the quantum yield of azide

photodissociation due to the change in the rate constant ratio in the denominator

in formula (1) for these states [7,8,].

The second parameter characterizing the tendency of azide towards

photodissociation is the range of spectral sensitivity, which is determined by the

absorption spectrum of azide. Interrelation between azide photoactivity

(photodissociation quantum yield) and spectral sensitivity will be discussed

below.

Taking up heterocyclic azides, one can mark two main peculiarities entered

by aza-fuction into general photochemistry of aromatic azides. Both these

peculiarities are connected with uncoupled electron pair of the endocyclic

nitrogen atom. Due to this, heterocyclic azides can form N-oxides and obtain the

possibility of easy transformation from the neutral to positively charged species

by protonation/alkylation at endocyclic nitrogen atom. Insertion of the positive

charge into the -system of heterocyclic azide can affect strongly the

photodissociation quantum yield and reaction product structure. Due to this fact,

heterocyclic azides have been used as convenient model compounds for the study

of charge effect in photochemistry of aromatic azides; this effect will be discussed

in detail below.

The second peculiarity is characteristic of heterocyclic azides with -position

of azido group relative to endocyclic nitrogen atom and is connected with the

azido-tetrazolo tautomerism which can be defined as a 1,5-dipolar cyclization [9].

Mikhayl F. Budyka

228

C

N

N3

N

N

NN

C

The azide and tetrazole forms are easily distinguishable by their IR spectra:

azide has strong band near 2100 cm-1

, which is absent in the spectrum of tetrazole.

The position of azide-tetrazole equilibrium depends on an electron density at the

endocyclic nitrogen atom which, in turn, is defined by the nature and position of

substituents in the heterocyclic nucleus. The population of azido and tetrazole

forms depends also on the solvent and temperature. Polar solvents favor the

tetrazole form, and nonpolar solvents, the azido species.

Cleavage of the tetrazole ring is generally an endothermic process in solution,

so the azide-tetrazole equilibrium is ordinary shifted to the side of the tetrazole

form. The higher temperatures favor the azido species, the formation of azide

from tetrazole on heating can be ascribed to entropy.

For example, for derivatives of 2-azidopyridine, the enthalpies of the azides

are higher than those of the corresponding tetrazolo[1,5-a]pyridines ( H°isom = -

13 to -30 kJ mol-1

; S°isom = -50 to -59 J mol-1

K-1

), as determined by variable

temperature 1H NMR spectroscopy in DMSO-d6 or CDCl3 solution [10].

N N

N N

N N3

R2

R1R3

R4

R2

R1R3

R4

In 2-azidoquinazoline azido group cyclizes to position 1, and this compound

exists exclusively as tetrazolo[1,5-a]quinazoline in the solid state and in

chloroform solution at standard temperature and pressure as evidenced by the

absence of a peak near 2100 cm-1

in the IR spectrum [11].

N

N N

N N

N

N N3

However, addition of trifluoroacetic acid to a solution in CDCl3 causes the

formation of the azide tautomer as determined by 1H NMR spectroscopy.


229

Tetrazole is also converted to azide on heating. The calculated energy difference

between azide and tetrazole in the gas phase, corrected for zero-point vibrational

energy, is 0.16 kcal/mol (B3LYP/6-31G**). The calculated enthalpy difference is

0.86 kcal mol-1

, and entropy difference is 5.74 cal mol-1

K-1

. Thus, at 298 K,

G(gas phase) = -0.88 kcal mol-1

, with the azide as the most stable form. In the

crystalline state, the lattice energy is likely to stabilize the solid tetrazole. Since

G = H - T S, increased temperature will result in a lower G; i.e., it will shift

the azide-tetrazole equilibrium toward the azide [11].

Maximal possibility for cyclization to tetrazole has cyanuric azide - 2,4,6-

triazido-1,3,5-triazine (explosive, very sensitive to shock and heat in crystals!),

heterocyclic azide where each of three azido group has -nitrogen atom).

However, cyanuric azide exists exclusively in azide form [12], whereas its

triphenylphosphane derivatives (obtained by Staudinger reaction) - in tetrazole

forms; the tetrazole isomers are stabilized due to the introduction of the PPh3

group [13]. The energy difference between the azide and tetrazole isomers is very

small and was estimated to be about 1 kcal mol-1

.

Tetrazole is insensitive (or much less sensitive than azide) to light, so more

prolonged irradiation or conversion to azide form by heating or acidifying is

demanded for photochemical decomposition of tetrazole form.

In this chapter main especial attention will be devoted to a series of

heterocyclic azides, 4-azidopyridine A1 and its higher cata-condensed analogues:

4-azidoquinoline A2, 9-azidoacridine A3, 12-azido-benzo[b]acridine A4, 13-azido-

6-azapentacene (azidodibenzacridine) A5, and 15-azido-6-azahexacene A6; here

the index is equal to the number of aromatic rings (Scheme 1). The first three

compounds were studied both experimentally and theoretically, for the last three

azides quantum-chemical calculations were performed.

N

N3

N

N3

N

N3

N

N3

N

N3

N

N3

A1 A2 A3 A4

A5 A6

Scheme 1.

Mikhayl F. Budyka

230

Systematic investigation of this series and some other heterocyclic azides

allows revealing general relationship between azide structure and photoactivity.

The dependence of photodissociation quantum yield on the size of the azide -

system and its charge - the size and charge effects and interrelation between them

- have been found experimentally and justified quantum-chemically.

Derivatives of diazido- and triazido-pyridines proved to be convenient

precursors for photochemical generation of high-spin polynitrenes. These species

are model systems for investigation of molecular magnetism and development of

organic magnetic materials promising for applications in molecular electronics.

Due to fast growth of the number of experimental and theoretical data on this

subject, it requires separate consideration and will be only touched shortly in this

chapter.

Finally, the application of azides for photoaffinity labeling will be discussed

on some examples. Important from this point of view are azido-derivatives of

acridine, hemicyanine, and ethidium dyes, which possess the most long-

wavelength visible light sensitivity so far reported for aromatic azides and due to

this fact enable soft non-destructive visible light to be used on investigation of

biomacromolecules.

1. AZIDOPYRIDINES AND AZIDOQUINOLINES

Azidopyridines are the simplest and obviously the most investigated

heteroaromatic azides. In earlier investigations main attention was paid to

identification of various reaction products. Recently, the quantitative structure-

reactivity relationship was studied based on comparison of the experimental and

quantum-chemical data. Many high-spin nitrenes were obtained by photolysis of

polyazidopyridines.

1.1. Photolysis Products and Quantum Yields

Photolysis of azidopyridines in the presence of nucleophiles (sodium

methoxide, diethylamine, etc.) proceeded with ring expansion and produced

different derivatives of diazepines, (Scheme 2). 2-Azidopyridines gave derivatives

of 1H-1,3-diazepines and 5H-1,3-diazepines [14,15], 3-azidopyridine –

derivatives of 2H-1,4-diazepines and 5H-1,3-diazepines[16,17], and 4-

azidopyridine – derivatives of 6H-1,4-diazepines [17,18].


231

N

N3

N

N

N

NH B

N

NB

R R R R

N

N3

N

N

N

NH

BR R R

N

N B

R

NNR NH

N

B

R N

N

B

R

N N3

R

N N

N N

R

N

NRNH

N BR

N

N BR

h

h

h Base+

Base

Base

Base

Scheme 2. Photolysis of azidopyridines with ring expansion.

The product structure depended on the relative positions of azido group,

pyridinic nitrogen and substituent(s) R (Scheme 2). For example, photolysis of 2-

unsubstituted 3-azidopyridines in the presence of sodium methoxide resulted in

ring expansion to give the 4-methoxy-5H-1,3-diazepines, presumably via the

azirine intermediates derived from the initially formed singlet 3-pyridylnitrenes

by cyclization at the 2-position of the pyridine ring. On the other hand, in the

photolysis of 2-substituted 3-azidopyridines, the cyclization of the nitrenes

occurred predominantly at the vacant 4-position giving rise to the 3-methoxy-2H-

1,4-diazepines (Scheme 2) [19].

Derivatives of 4-azidoquinoline upon photolysis in the presence of sodium

methoxide produced corresponding derivatives of 1,4-benzodiazepines [20], while

irradiation in ethanethiol gave only 4-aminoquinolines (without insertion of

ethylthio group) [21]. Tarry polymer as a major product and a small amount of

azo compound were formed in the photolysis of 4-azidoquinoline in acetone [22].

Photolysis of N-oxides of 4-azidopyridine and 4-azidoquinoline gave

corresponding azocompounds [22], or hydrogen-abstraction products [23]. No

ring-expansion products were detected [23]. It is interesting, that no cross-over

azocompound was obtained during photolysis of the mixture of two N-oxides of

the azides [22].

Upon laser flash photolysis of 4-azidopyridine-1-oxide at room temperature

in 3-methylpentane at 266 or 308 nm two temporally distinct features were

Mikhayl F. Budyka

232

observed: a partially structured bands at 520-560 nm, which were assigned to the

triplet nitrene (3A2), and a broader band with an absorbance maximum at 435 nm,

which was demonstrated to be dependent on the starting concentration of azide

and was assigned to 4,4'-azo-bis(pyridine-1-oxide); the latter was obtained in

reaction between the triplet nitrene and starting azide with a diffusion-limited rate

[24].

N+

N3

O

N+

N

O

N+

N

O

N+

NO N+

N Oh

1 3

The observed rate constant for intersystem crossing (kisc) from the singlet to

triplet nitrene was determined to be approximately 2.10

7 s

-1. The singlet nitrene

(1A2) was detected by weak and short-lived transient signal at 493 nm upon

photolysis in dichloromethane; it decayed in coincidence with the growth of the

triplet nitrene. HPLC analysis of the reaction mixture after photolysis showed

only one photoproduct - azo-compound. No evidence of products arising from the

singlet nitrene was observed, and quantum-chemical calculations indicated that

this is due to the significant barrier to nitrene cyclization to the benzazirine and

didehydroazepine species. The barrier is significantly larger than those calculated

for similar arylnitrene systems and is due to the stabilization of the 1A2 and

3A2

states by spin delocalization due to resonance contributors with iminyl-aminoxyl

biradical character; as a result, spin density is withdrawn from sites for potential

cyclization.

Photolysis of 4-azidopyridine and 4-azidoquinoline in hydrohalogenoic acids

gave corresponding 4-aminoazines and 3-amino-4-halogeno compounds via

azirine or azacycloheptatetraene intermediates, whereas their N-oxides under

similar conditions gave the 4-amino-3-halogeno compounds presumably via

nitrenium ion intermediates; similar results were obtained for 3-azidoquinoline

and 4-azidoisoquinoline [25]. In alcohols containing sulfuric acid these azides

gave the corresponding -alkoxy amino compounds via nitrenium ion

intermediates [26].


233

N

N3

N

N

N

ClNH

2

N+

N3

O

N+

N

O

N+

NH2

O

Cl

N

NH2

h

HCl

h

HCl

+

Systematic quantitative investigations of the spectral properties and

photodissociation quantum yields of azidopyridine and azidoquinoline in

dependence on charge state (neutral or cationic) were performed in [27,28].

Neutral and protonated 4-Azidopyridine A1 and 4-azidoquinoline A2 have

absorption bands in UV region of spectrum, Figure 1 [28]. Azido group as a

chromophore (in hydrazoic acid and alkyl azides) possesses a long-wave

absorption band in the region of 250 - 320 nm arising from n * transition

[29,30]. This transition is forbidden and therefore is of very low intensity ( ~ 20

M-1

cm-1

). For azidopyridine and azidoquinoline, this band is masked by the two-

order more intense n- * bands of heteroaromatic nuclei and, also, in

azidoquinoline, by the - * band of quinoline nucleus [31,32].

Upon protonation, the long-wave absorption bands of azidoazines increased

in intensity by 1.5-2-fold and were shifted to red by ~ 25 nm for 4-azidopyridine

and by ~ 30 nm for 4-azidoquinoline, Figure 1. This behavior resembles that of

corresponding amino-derivatives of pyridine and quinoline [33].

Azido group in hydrazoic acid is known to be protonated in superacid

solutions with formation of aminodiazonium ion, H2N-N2+; in the gas-phase

protonation, the iminodiazenium ion, HNNNH+, can be also formed [34]. The

protonation of azidopyridine and azidoquinoline takes place definitely at

endocyclic ("azine") nitrogen atom; the spectra of protonated azidoazines coincide

with those of N-methylated ones.

Both 4-azidopyridine and 4-azidoquinoline in their neutral and cationic forms

decompose rapidly upon UV irradiation within the absorption bands. Figure 2 and

Figure 3 show spectral changes observed upon irradiation of 4-azidopyridinium

hydrochloride and 1-methyl-4-azidoquinolinium methylsulphate, respectively.

Isosbestic points at the initial period of photolysis testify to selective reaction

Mikhayl F. Budyka

234

passing with retention of the structure and ratio of the reaction products. During

further prolonged irradiation, isosbestic points disappeared thus indicating the

proceeding of secondary reactions (see Figure 2, curve 7).

The photodissociation quantum yields ( ) of the heteroaromatic azides were

calculated from the kinetic curves of the azide disappearance and are shown in

Table 1. It is seen that both neutral and cationic azidopyridine and azidoquinoline

are photoactive azides with quantum yields > 0.1 [28,35]. Nevertheless, one can

note some effects. Insertion of positive charge into azide molecule results in

decrease of the value; for example, in MeCN, quantum yield decreases from

0.83 to 0.22 on going from 4-azidopyridine A1 to its hydrochloride and in

somewhat less extent, from 0.49 to 0.37, on going from 4-azidoquinoline A2 to its

hydrochloride. For neutral 4-azidopyridine quantum yield decreases slightly also

on going from acetonitrile to acetonitrile-ethanol mixture and further to pure

ethanol (Table 1).

200 250 300 3500.0

2.0x104

4.0x104

6.0x104

43

2

1

/ M-1cm

-1

/nm

Figure 1. The electronic absorption spectra in MeCN: (1) 4-azidopyridine (A1), (2) 4-

azidopyridinium hydrochloride, (3) 4-azidoquinoline (A2), (4) 4-azidoquinolinium

hydrochloride [28].


235

250 300 350

0.0

0.1

0.2

0.3

0.4

0.5

7

1

A

/nm

Figure 2. Spectral changes upon irradiation (254 nm, Hg lamp) of 2.6.10

-5 M solution of 4-

azidopyridinium hydrochloride in ethanol, irradiation time, s, (1) - (7): 0, 60, 120, 180,

300, 420, 1020; light intensity 8.73.10

-10 Einstein cm

-2 s

-1 [27

200 250 300 350

0.0

0.2

0.4

0.6

0.8

1.0

8

8

1 1

A

/nm

Figure 3. Spectral changes upon irradiation (313 nm, Hg lamp) of 1.85.10

-5 M solution of

1-methyl-4-azidoquinolinium methylsulphate in MeCN, irradiation time, s, (1) - (8): 0, 5,

14, 27, 44, 66, 97, 210; light intensity 2.7.10

-9 Einstein cm

-2 s

-1 [28].

Mikhayl F. Budyka

236

Table 1. Photodissociation quantum yields ( ) for 4-azidopyridine A1 and 4-

azidoquinoline A2 and their hydrochlorides and methylsulphates (irradiation

by Hg arc lamp, 254 nm for A1 and 313 nm for A2) [28]

Azide solvent

A1 MeCN 0.83

A1 MeCN/EtOH 1:1 0.40

A1 EtOH 0.35

A1HCl EtOH 0.23

A1HCl MeCN 0.22

A1MeSua MeCN 0.27

A2 MeCN 0.49

A2HCl MeCN 0.37

A2MeSub MeCN 0.36

a 1-methyl-4-azidopyridinium methylsulphate.

b 1-methyl-4-azidoquinolinium methylsulphate.

1.2. Quantum-chemical Calculations

To explain the effects observed, the structures of azides in the ground (S0) and

lowest excited singlet (S1) states were calculated by different quantum-chemical

methods; the data obtained are shown in Table 2. In the ground state, in all azides,

the azido group has a quasi-linear geometry, the NNN bond angle NNN ~ 170 °.

In the neutral form the N1N2 bond length is 1.27 Å (PM3 data), ab initio and DFT

methods predict a somewhat smaller value of 1.24 - 1.25 Å. An important feature

is a large positive charge on the terminal nitrogen atoms of the azido group, ~

0.40 e according to PM3. Obviously, it is an overestimation, as follows from

comparison with ab initio and DFT data for azide A1 (Table 2).

The azido group is arranged in the plane of the molecule, and due to

conjugation between azido group and heteroaromatic nucleus the rotation around

the C-N quasi-single bond is hindered. The height of the rotational barriers in

isomeric azidopyridines was determined via ab initio molecular orbital

calculations (geometry optimization at RHF/6-31G** level, energy improvement

as a single-point MP2/6-31G** calculation) [36]. The largest barrier, about 7

kcal/mol, was calculated for 2-azidopyridine (for this isomer the s-cis conformer

is slightly more stable than the s-trans one), whereas it amounted to 3.32 and 4.04

kcal/mol for 3-azido and 4-azidopyridine, respectively.


237

Table 2. Selected optimized parameters for 4-azidopyridine (A1), 4-

azidoquinoline (A2), and their protonated forms in the ground (S0) and

lowest excited singlet (S1) states: bond length (r) and bond order (p) for the

N1N2 and N1C4 bonds, the N1N2N3 bond angle (amounted), and Mulliken

charge (ZN2) on the terminal group N2, calculated by different methods (atom

numbering: C4N1N2N3, cations were calculated without counterions) [28]

Azide State rN1N2,

Å

rN1C4,

Å

pN1N2 pN1C4 NNN, ° ZN2, е Method

A1 S0 1.27 1.43 1.35 1.02 169.5 0.40 PM3

1.24 1.41 1.24 0.95 174.2 0.27 HF/6-31G*

1.25 1.42 1.28 0.88 172.4 0.22 MP2/6-31G*

1.24 1.41 1.36 0.92 172.3 0.21 B3LYP/6-

31G*

S1 1.35 1.39 1.02 1.36 133.4 -0.03 PM3

A1H+ S0 1.30 1.39 1.18 1.20 168.8 0.55 PM3

1.27 1.36 1.08 1.12 172.1 0.39 HF/6-31G*

1.26 1.38 1.25 1.05 170.4 0.34 B3LYP/6-

31G*

S1 1.41 1.35 0.87 1.53 128.1 0.09 PM3

A2 S0 1.27 1.43 1.34 1.03 169.3 0.41 PM3

S1 1.35 1.39 1.08 1.38 137.9 -0.05 PM3

A2H+ S0 1.30 1.39 1.19 1.20 168.7 0.55 PM3

S1 1.42 1.34 0.89 1.64 134.4 0.07 PM3

Protonation induces the electron density transfer from the azido group to the

aromatic nucleus, an effect that results in a weakening of the N1N2 bond even in

the ground state. The N1N2 bond order decreases with simultaneous increase of

the N1C4 bond order (Table 2), the N1N2 bond is elongated by 0.02 - 0.03 Å, and

the N1C4 bond is shortened by 0.03 - 0.06 Å.. The electron density transfer

results also in an essential charge increase on the N2 group upon protonation, for

example, in cation A1H+ charge increases to 0.55 (PM3), 0.39 (HF/6-31G*), 0.34

e (B3LYP/6-31G*).

In the lowest excited singlet state, the N-N2 bond is elongated by about 0.1 Å,

the NNN valence angle is reduced by about 35°, and the charge at terminal

nitrogen atoms decreases by about 0.45e (Table 2).

These changes are defined by the nature of molecular orbital (MO) that is

filled in the S1 state. In the case of photoactive azides, this is an orbital of definite

structure, namely, NN*-MO, which is localized on the azido group and is

Mikhayl F. Budyka

238

antibonding in respect to the N-N2 bond [6]. Figure 4 shows the structure of the

frontier molecular orbitals for 4-azidopyridine A1 and its cation A1H+, and Figure

5 – for 4-azidoquinoline A2 and its cation A2H+: the highest occupied MO

(HOMO) and the lowest unoccupied MO (LUMO) for the S0 state, the lowest

semioccupied MO (LSOMO) and the highest semioccupied MO (HSOMO) for

the S1 state. In the both azides, in the ground state both HOMO and LUMO are -

type MOs localized mainly on the heteroaromatic nucleus with some contribution

by the atomic orbitals of azido group. In the S0 state, the NN*-MO (not shown in

Figures 4 and 5) is LUMO+1 in neutral azides A1 and A2, and LUMO+2 in

cations A1H+ and A2H

+. However, upon excitation to the S1 state, as a result of

relaxation, the NN*-MO is occupied instead of LUMO in both the neutral and

cationic compounds (Figure 4 and Figure 5). Depopulation of -HOMO, which

becomes LSOMO in the S1 state, and population of NN*-MO, which becomes

HSOMO, results in the above structural changes: electron density transfer from

aromatic nucleus to azido group, bending of this group and weakening of the N-

N2 bond (which dissociates).

In terms of valence bond method, this means that, on going from the S0 to the

S1 state, the type of hybridization of the central atom of the azido group (atom N2)

changes from sp to sp2.

Thus, the photoactivity ( > 0.1) of both neutral and positively charged

derivatives of 4-azidopyridine and 4-azidoquinoline is explained by the fact that

NN*-MO, which is antibonding in respect to the N-N2 bond and vacant in the

ground state, is occupied in the excited states of these azides. Nevertheless, the

protonation (alkylation) causes a decrease in the quantum yield, especially for 4-

azidopyridine (Table 1).

According to the quantum-chemical calculations, this effect may be

accounted for by the increase in the activation energy for the N-N2 bond

dissociation in the S1 state on passing from the neutral azide to cation. In the

ground state, a substantial positive charge is concentrated on two terminal

nitrogen atoms of the azido group of azides, while dissociation gives rise to a

neutral nitrogen molecule. Therefore, the electron density transfer from the

aromatic nucleus to the leaving N2 molecule should be a necessary step of the N-

N2 bond dissociation. In cationic azide, the positive charge of the aromatic ring

creates the charge barrier (Coulomb barrier) for the transfer of electron density

and hinders the dissociation.


239

Figure 4. Structure of the frontier molecular orbitals (MOs) for 4-azidopyridine A1 and 4-

azidopyridinium ion A1H+: the highest occupied MO (HOMO) and the lowest unoccupied

MO (LUMO) in the S0 state, and the lowest semioccupied MO (LSOMO) and the highest

semioccupied MO (HSOMO) in the S1 state [27].

To test this assumption, the potential energy surfaces (PESs) for A1 and

protonated A1H+ in the S1 state were calculated [27]. Figure 6 shows the contour

diagram of an area of the PES for A1 over a NNN bond angle range of 123° - 170°

and a N-N2 bond length range of 1.27 - 2.45 Å. At the minimum of the PES, the

N-N2 bond length rNN2 and NNN bond angle are equal to 1.35 Å and 113.4°. As

the N-N2 bond is elongated, the bond angle first increases to 155° and then

decreases to attain a value of 127.6° in the transition state, with rNN2 being 2.25 Å.

The calculated parameters of the transition state for the dissociation of the azido

group in the lowest excited singlet state for A1 and A1H+ are listed in Table 3. As

can be seen, the transition states of A1 and A1H+ have similar structural

characteristics; at the same time, upon protonation, the activation energy increases

from 15.9 to 18.5 kcal/mol. As a result, the rate constant kr decreases (formula (1))

that qualitatively correlates with the experimentally observed decrease in the

quantum yield for the dissociation of the azido group.

Mikhayl F. Budyka

240

Figure 5. Structure of the frontier molecular orbitals for 4-azidoquinoline A2 and 4-

azidoquinolinium ion A2H+, description of the MOs see Figure 4 [28].

With increasing size of aromatic cloud shields

the action of the positive charge, so the charge effect appears in less extent in 4-

azidoquinoline (Table 1) and disappears at all in 9-azidoacridine, where quantum

yield remains unchangeable on going from the neutral azide to cation, see below.

As discussed above, the quantum yield for the photodissociation of A1

decreases not only upon protonation (alkylation) but also when ethanol is used as

the solvent instead of acetonitrile (Table 1). This effect can be explained by the

fact that pyridine-based compounds are weak bases capable of forming H-bonded

complexes with solvent molecules [37]. H-bond is strengthened in the S1 state,

since pyridine compounds become much more basic on excitation [38] (the

basicity increase can reach 7–8 orders of magnitude); the limiting case is a full

proton transfer. This gives rise to a positive charge increase on the endocyclic

nitrogen atom and results in retardation of the N-N2 bond dissociation reaction.

Consequently, the value for A1 decreases on going from MeCN to MeCN/EtOH

mixture and further to EtOH, becoming closer to that for protonated azide (Table

1).


241

rN-N2/ A1.5 1.8 2.1 2.4

NN

N /

deg

ree

130

140

150

160160160

155

155

150

150

155

160

145TS

Figure 6. Potential energy surface for the S1 state of 4-azidopyridine (A1) calculated by the

PM3 method. The dissociation coordinate (minimum-energy path) is shown by the heavy

solid line; TS denotes the transition state; the energy is given in kcal mol-1

[27].

Table 3. Parameters of the transition state (calculated by the PM3 method)

for the dissociation of the azido group in the S1 state of 4-azidopyridine (A1)

and its hydrochloride (A1H+): the distance rTS between the N1 and N2 atoms,

bond angle ( NNNTS), effective Mulliken charge (ZTS) on the N2 terminal

group, and activation energy Ea [27]

Azide rTS, Å NNNTS, deg ZTS, е Ea, kcal/mol

A1 2.25 127.6 0.01 15.9

A1H+ 2.30 136.4 0.03 18.5

1.3. Relative Reactivity of Azido Groups in Polyazidopyridines

An interesting data were obtained on the relative reactivity of different azido

groups in polyazidopyridines. In low-temperature photolysis (organic glass, 77 K)

of the 2,4-diazidopyridine derivatives, the formation of only one of the two

possible triplet nitrene was observed by ESR [39].

Mikhayl F. Budyka

242

N

N3

N3

RNH

Cl CN

N

N3

NRNH

Cl CN

N

N

N3

RHN

Cl CN

. .

h

. .

The signals of two possible isomers, 2-nitreno and 4-nitreno derivatives,

should not coincide in the ESR spectra. To discriminate between these isomers,

the observed ESR spectra were compared with the spectra of 2-pyridyl nitrenes

obtained from 2-(mono)azidopyridines; additionally, the experimental D-

parameters were correlated with the C-N bond lengths in nitrenes calculated by

PM3 method. The authors [39] came to conclusion that 2-nitreno derivatives

matched better to the spectral line positions observed.

The selective photolysis of the -azido group was rationalized from the

analysis of the energies of two different triplet local-excited states, -T and -T

states for dissociation of the - and -azido group, respectively. The energy of the

-T state was calculated to be higher by 4 kcal mol-1

than that of the -T state

(PM3 data). With the assumption that the higher the energy of the excited state,

the higher the probability of the transfer to the repulsive term, the

photodissociation of the -azido group in 2,4-diazidopyridine should be the

preferable process [39].

Another example of selective decomposition of inequivalent azido groups

was found in successive photolysis of 2,4,6-triazido-3,5-dichloropyridine (TAP)

[40]. This azide yields two easily identifiable isomeric quintet 2,4- and 2,6-

dinitrenes upon irradiation with light at > 300 nm.

N

N3

N3

Cl Cl

N3

N

N3

N

Cl Cl

N3 N

N3

NN

ClCl

N

N

NN

ClCl

N

N

N3

Cl Cl

N3 N

N

N

Cl Cl

N3

. . . . . . . . . .

. .

h h

X . .

h

.

h

.

. .

TAP


243

Photolysis (at 77 K) of TAP at 315 nm resulted in the ESR spectrum with the

major peak corresponding to 2,6-dinitrene and the tiny peak of 2,4-dinitrene.

More intense signal of the latter was also obtained upon irradiation of TAP with

light at 335 nm. The results unambiguously showed that triazide underwent

selective photodissociation of the -azido groups with formation of quintet 2,6-

dinitrene as the main photoproduct. The effect was explained similar to the above

one for diazidopyridine. The PM3 calculations showed that energy of the -T

state of TAP is higher by 2 kcal mol-1

than that of the -T state, and energy of the

-exited state of intermediate 2-pyridyl nitrene is 8 kcal mol-1

higher than that of

the -excited state. The excited states with the higher energies were assumed to be

less stable and decomposed more rapidly, explaining predominant formation of

quintet 2,6-dinitrene [40].

Obviously, the explanation on the basis of the relative energies of the triplet

excited states is not satisfactory since azido group photodissociation upon direct

(non-sensitized) photolysis occurs really in the singlet excited state [8]. However,

calculations of the energies of different singlet local-excited states, -S and -S

states, at CIS/6-311G* level, contrary to the PM3 data for the triplet local-excited

states, showed that the -S state is ~3.8 kcal mol-1

higher than the -S state [41].

Therefore, selective photolysis of the -azido group can be connected, on the

contrary, with the lower energy of the local excitation. At the same time,

difference in activation energies of two competitive processes favors slightly to

the -dissociation: calculated activation energy of the N-N2 bond dissociation in

the -S state (7.0 kcal mol-1

) is less than that in the -S state (7.5 kcal mol-1

) [41].

There is difference in the structures of the - and -azido groups in the

ground (S0) state. According to calculations, the -azido groups in TAP lie in the

molecular plane, whereas -azido group is twisted out of the plane by ~24.5°

(B3LYP/6-311G*). It was assumed that selective photolysis of the -azido group

could be determined by stronger - conjugation with pyridine nucleus in the S0

state, and photochemical inertness of the -azido group – by distortion of this

group out of the molecular plane [41]. Probably, analysis of the structure of the

vertical S0 S1 transition and more correct high-level calculations of the PESs

can shed additional light to this problem.

Worthwise to note, that in 9-azidoacridine azido group also deviates out of

the molecular plane, but this azide decomposes with quantum yield about 1 (see

below).

If selective photochemical activity of different azido groups in TAP was

deduced only from comparison with theoretical ESR spectra, selective thermal

Mikhayl F. Budyka

244

activity of the - and -azido group is evidenced by separation and identification

of different reaction products [42].

Recently, photolysis of TAP was restudied in argon matrix at 15 K [43]. In

contrast to the discussed above data in frozen organic solutions at 77 K, the

preferential photolysis of the -azido group was observed as was deduced from

relative intensities of the spectra: contrary to the statistical ratio of the - and -

nitrenes 2:1, their spectra had nearly the same intensities. Upon matrix photolysis

of the TAP analogue, 2,4,6-triazido-3,5-difluoropyridine, both triplet nitrenes, -

and -nitrene, were also formed in nearly equal yields, but in contrast to TAP, the

photolysis was deduced to be not selective [44].

Thus, one can conclude that an interesting problem on relative photoactivity

of different inequivalent azido groups in polyazidopyridines (and in polyazides in

general) remains challenging.

2. AZIDO DERIVATIVES OF ACRIDINE

In this chapter we discuss properties of two azido derivatives of acridine: 9-

azidoacridine (A3) and 9-(4'-azidophenyl)acridine (APA). These compounds have

similar spectral properties in neutral and cationic forms, and similar

photochemical activity in neutral forms, but their photodissociation quantum

yields in cationic forms differ drastically. Quantum-chemical calculations and

consideration of MO structure in the ground and lowest excited states allowed

explaining this difference.

Structure, spectral and photochemical properties of 9-azidoacridine are

discussed in more detail because this azide in cationic form is one of the azides

with the most long-wavelength region of the spectral sensitivity. On example of

A3 it is easy to trace difference between vertical-excited (Franck-Condon) state,

which determines absorption spectrum, and relaxed exited state, which determines

azide photoactivity.

2.1. Structure of 9-azidoacridine

Structure of 9-azidoacridine has attracted an especial attention in connection

with the problem of planarity of azido group. This azide is an example of aromatic

azide with non-planar arrangement of azido group. It crystallizes in the rhombic

system [45]. X-Ray analysis has shown that the independent crystal structure


245

fragment consists of two crystallographically independent molecules denoted by

A and B, see Figure 7. 9-azidoacridine crystal structure fragments are shown in

Figure 8. Molecules form stacks along the a crystallographic axis. The distances

between the planes of the acridine nuclei of molecules in the stacks are of 3.98 Å

(stack of A molecules) and 3.49 Å (stack of B molecules). The acridine nucleus

planes in molecules A and B intersect at an angle of 2.3°.

The structure-forming factor in the formation of stacks is likely

intermolecular contacts between the endocyclic nitrogen atom N7 in the acridine

nucleus and the central nitrogen atom N2 of the azido group (which is displaced

out of the molecular plane; see below); the distances between these atoms are 3.29

and 3.25 Å in stacks A and B, respectively.

According to quantum-chemical calculations (see below), the azido group is

strongly polarized with charge alternation -0.45, 0.73, and -0.34e (the PM3 data)

and -0.46, 0.40, and -0.23 (B3LYP/6-31G* calculations) on N1, N2, and N3,

respectively. The orientation of molecules in stacks ensures the interaction of the

central azido group nitrogen atom with a large positive charge on it with the lone

pair of the acridine nucleus nitrogen atom, on which a negative charge of -0.06

(PM3 calculations) or -0.60 e (B3LYP/6-31G*) is concentrated.

Figure 7. Molecular structure of 9-azidoacridine (A3) and atom numbering

(crystallographically independent molecules are denoted by A and B) [45].

Mikhayl F. Budyka

246

a)

b)

Figure 8. Fragment of the crystal structure of 9-azidoacridine (A3): (a) projection onto the

bc plane and (b) projection onto the ac plane [45].

Table 4 contains the X-ray structure analysis data obtained for A3

(interatomic distances and angles) in comparison with the results of A3 structure

optimization by various quantum-chemical methods. The bond lengths and

valence angles of the acridine nucleus are close to those of other acridine

derivatives [46,47]. On the whole, both calculation methods used reproduce the

geometric parameters of the A3 molecule.


247

The acridine nucleus is elongated along the short axis, and the length of CC

bonds oriented along this axis is of from 1.41 to 1.43 Å. The condensed benzene

rings have a well-defined ortho-quinoid structure, the C10C11, C12C13, C14C15,

and C16C17 bond lengths are within the range 1.34–1.36 Å (Table 4). The azido

group in A3, as in the other aromatic azides [48,49], has quasi-linear geometry

(the NNN valence angle is of ~170°). This characteristic feature is reproduced by

both quantum-chemical methods (Table 4).

According to the X-ray data, the molecule of A3 is nonplanar, the N2N1C4C5

dihedral angle denoted as NNCC is 34.6° in molecule A and 28.6° in molecule B,

which is close to the angle value predicted at the B3LYP/6-31G* level (32°), see

below. Non-planarity of the A3 molecule is explained by the steric interactions of

the azido group with the peri-hydrogen atoms of the neighboring benzene rings.

According to the B3LYP/6-31G* calculations, the energy of the planar 9-

azidoacridine structure with the NNCC fixed at 0° and all the other parameters

optimized is higher by 0.21 kcal/mol than that of the completely optimized

structure, whose parameters are listed in Table 4. In the planar structure, the

N1N2 and N1C4 bonds are shortened by 0.003 and 0.008 Å, respectively, because

of an increase in conjugation between the azido group and the acridine nucleus.

The distance between the N2 nitrogen atom and peri-hydrogen at C14 is 2.3 Å,

which is smaller than the sum of the van der Waals radii of these atoms (2.66 Å).

The increased steric strain elongates the C4C5 bond by 0.003 Å and increases the

N2N1C4 and N1C4C5 valence angles by 3.4° and 1.8°, respectively.

The opposite geometric effects are observed in the structure with the

perpendicular arrangement of the azido group. According to the B3LYP/6-31G*

calculations, the energy of this structure (with fixed NNCC = 90° and the other

parameters optimized) is higher by 1.66 kcal/mol than that of the completely

optimized structure. The N1N2 and N1C4 bonds in the perpendicular conformer

are elongated by 0.002 and 0.024 Å, respectively, because the conjugation chain

between the azido group and acridine molecule is broken in it. Simultaneously,

the C4C5 bond shortens by 0.009 Å, and the N2N1C4 and N1C4C5 angles

decrease by 4.3° and 5.3°, respectively.

An analysis of overlap populations shows that the populations of the N1C4

and N2N3 bonds change insignificantly in rotations about the former, to within

±0.02. At the same time, the population of the N1N2 bond decreases from 0.54 at

NNCC = 32° to 0.44 at NNCC = 0° and increases to 0.67 at NNCC = 90°.

Therefore, the loss of conjugation between the azido group and acridine nucleus

in the perpendicular compared with planar conformer results in a considerable

increase in the population of the N1N2 bond.

Mikhayl F. Budyka

248

Table 4. Structural parameters of 9-azidoacridine, bond lengths and valence

angles ( ) according to X-ray structure analysis and calculation data [45]

Parameter X-ray structure Method of calculations

d/Å molecule

A

molecule B PM3 B3LYP/6-

31G*

N(1)-N(2) 1.203(13) 1.239(14) 1.265 1.236

N(2)-N(3) 1.150(15) 1.181(14) 1.127 1.141

N(1)-C(4) 1.431(13) 1.424(13) 1.444 1.413

C(4)-C(5) 1.395(16) 1.380(16) 1.408 1.414

C(5)-C(6) 1.413(14) 1.428(13) 1.427 1.448

C(6)-N(7) 1.356(14) 1.322(15) 1.358 1.342

N(7)-C(8) 1.312(15) 1.376(15) 1.358 1.342

C(8)-C(9) 1.433(15) 1.433(15) 1.427 1.442

C(4)-C(9) 1.398(17) 1.385(15) 1.408 1.411

C(9)-C(10) 1.431(16) 1.406(18) 1.432 1.427

C(10)-C(11) 1.341(18) 1.338(19) 1.361 1.371

C(11)-C(12) 1.412(18) 1.408(18) 1.425 1.425

C(12)-C(13) 1.343(18) 1.346(18) 1.360 1.369

C(8)-C(13) 1.429(16) 1.387(17) 1.438 1.430

C(5)-C(14) 1.445(16) 1.423(16) 1.432 1.429

C(14)-C(15) 1.360(15) 1.339(17) 1.361 1.372

C(15)-C(16) 1.409(16) 1.407(16) 1.425 1.423

C(16)-C(17) 1.353(16) 1.395(18) 1.360 1.369

C(6)-C(17) 1.410(15) 1.404(16) 1.438 1.430

/degree

N(1)-N(2)-N(3) 171.9(11) 170.6(10) 169.6 170.1

N(2)-N(1)-C(4) 121.2(10) 119.2(10) 120.3 122.8

N(1)-C(4)-C(5) 124.9(11) 125.7(10) 119.9 125.1

N(1)-C(4)-C(9) 114.6(10) 112.2(9) 119.7 114.9

C(5)-C(4)-C(9) 120.5(9) 122.1(9) 120.3 119.9

C(4)-C(5)-C(6) 117.2(10) 116.4(10) 118.0 116.7

C(6)-C(5)-C(14) 119.0(10) 117.4(10) 118.0 118.3

N(7)-C(6)-C(5) 123.3(10) 124.1(10) 121.8 124.0

C(17)-C(6)-C(5) 117.7(10) 119.4(11) 119.9 118.6

C(6)-N(7)-C(8) 118.2(10) 118.7(8) 120.0 118.3

N(7)-C(8)-C(9) 123.8(11) 121.1(11) 121.8 123.4

C(13)-C(8)-C(9) 118.2(10) 120.0(11) 119.9 118.5

C(4)-C(9)-C(8) 116.7(10) 117.6(10) 118.0 117.7

C(10)-C(9)-C(8) 119.6(11) 116.6(11) 118.0 119.1

C(11)-C(10)-C(9) 120.3(12) 122.8(13) 120.7 120.5

C(10)-C(11)-C(12) 119.3(13) 118.9(14) 121.0 120.6

C(13)-C(12)-C(11) 123.8(13) 121.2(12) 120.6 120.5


249

C(12)-C(13)-C(8) 118.7(11) 120.2(11) 119.8 120.8

C(15)-C(14)-C(5) 119.6(10) 121.4(11) 120.7 120.9

C(14)-C(15)-C(16) 121.1(11) 122.5(14) 121.0 120.8

C(17)-C(16)-C(15) 118.8(11) 117.5(14) 120.6 120.2

C(16)-C(17)-C(6) 123.0(10) 121.5(11) 119.8 121.1

A region of the potential energy surface of A3 along the N2N1C4C5 angle

coordinate ( NNCC), which corresponded to azido group rotations about the N1C4

bond, was calculated by various methods [45]. The results are shown in Figure 9.

The PM3 method predicts the existence of one barrier of 2.04 kcal/mol height

along the reaction coordinate. This barrier corresponds to the passage of the azido

group through the acridine nucleus plane, and the potential energy surface

minimum corresponds to the perpendicular orientation of the azido group.

B3LYP/6-31G* calculations predict two barriers of different heights. The low

(0.21 kcal/mol) barrier corresponds to the planar conformation, and the higher

(1.66 kcal/mol) barrier, to the passage of the azido group through the plane

perpendicular to the acridine nucleus. As mentioned above, the barrier of rotation

around the C-N quasi-single bond in 4-azidopyridine is equal to 4.04 kcal mol-1

(MP2/6-31G**//RHF/6-31G** data) [36].

degree0 20 40 60 80

E/ kcal mol-1

0.0

0.5

1.0

1.5

2.0

12

Figure 9. 9-Azidoacridine potential energy surface portion corresponding to rotations

about the N1C4 bond (angle N2N1C4C5 = ) calculated by (1) the PM3 method and (2) at

the B3LYP/6-31G* level; energies are given with respect to potential energy surface

minima [45].

Mikhayl F. Budyka

250

In order to evaluate the structural changes induced by protonation and

excitation, the structure of 9-azidoacridine in neutral and protonated forms in the

S0 and S1 states has been calculated by various quantum-chemical methods [50].

Table 5 summarizes some optimized parameters: the lengths and orders of N1N2

and C4N1 bonds, the N1N2N3 valence angle ( NNN), the C5C4N1N2 dihedral

angle ( NNCC), and the Mulliken effective charge on the terminal N2 group.

One can see that all of the methods predict a considerable increase in the

positive charge on the N2 group upon protonation (by a factor of up to 2). In this

case, the N1C4 bond order increases and the N1N2 bond order decreases with

corresponding changes in the bond lengths. These changes upon protonation are

due to a shift of electron density from the azido group to the aromatic nucleus.

Enhanced bonding between the N1 and C4 atoms results in an increase in the

rotation barrier about the N1C4 bond; therefore, the C5C4N1N2 dihedral angle

decreases to 0° upon protonation in accordance with HF and B3LYP data (Table

5); in protonated form A3 becomes planar already in the S0 state and retains the

quasi-linear geometry characteristic for all azides (the NNN bond angle is ~170°).

Table 5. Structural parameters of 9-azidoacridine A3 and its protonated

cation: the length (r) and order (p) of N1N2 and C4N1 bonds, the N1N2N3

bond angle ( NNN), the C5C4N1N2 dihedral angle ( NNCC), and the Mulliken

effective charge on the terminal N2 group (ZN2) in the ground (S0) and the

lowest electronically excited (S1) state calculated by various methods (cation

2 was calculated without a counterion) [50]

Azide State

rN1N2 rN1C4 pN1N2 pN1C4 NNN NNCC ZN2, е Method

Å deg.

A3 S0 1.27 1.44 1.36 0.98 169.6 -91.5 0.39 PM3

1.24 1.42 1.27 0.93 173.6 -54.3 0.24 HF/6-

31G*

1.24 1.41 1.38 0.92 170.1 -32.0 0.17 B3LYP/6-

31G*

S1 1.32 1.40 1.12 1.38 144.0 -0.8 -0.06 PM3

A3H+ S0 1.30 1.39 1.20 1.21 166.7 -12.7 0.54 PM3

1.26 1.36 1.13 1.12 168.5 0.0 0.40 HF/6-

31G*

1.25 1.38 1.28 1.04 167.6 0.0 0.32 B3LYP/6-

31G*

S1 1.47 1.33 0.93 1.76 143.5 -5.4 0.10 PM3


251

0

-1

-4

-5

-6

-10

-12

-13

-9

-2

-8

E, eV

HOMO

HOMO-1

HOMO-2

LUMO+1

LUMO

LUMO+2

HOMO-3

LUMO

LUMO+1

LUMO+2

HOMO

HOMO-1

A3 A3H+

Figure 10. Structures and energies of the frontier MOs (HOMO and LUMO) and the

neighboring occupied and vacant orbitals for 9-azidoacridine A3 and its cation A3H+ in the

S0 state (cation was calculated without a counterion) [50].

Mikhayl F. Budyka

252

Both neutral and protonated forms of azidoacridine in an excited state

exhibited a bending of the azido group (the NNN angle decreased to 144°) and an

elongation of the N1N2 bond with a simultaneous decrease in the bond order.

Moreover, the charge on the terminal N2 group significantly decreased (Table 5).

As mentioned above, these changes in parameters on passing from the S0 to the S1

state are characteristic of photoactive azides.

Figure 10 shows the structure and energy of frontier molecular orbitals -

highest occupied molecular orbital (HOMO) and lowest unoccupied molecular

orbital (LUMO) - and the neighboring occupied and vacant orbitals for azide A3

and its protonated cation A3H+ in the S0 state. It can be seen that both frontier

MOs are -orbitals localized mainly on the acridine nucleus in both azides in the

ground state. A comparison with the MO structure of unsubstituted acridine

shows that the HOMO and LUMO are actually the acridine 4b1 and 5b1 orbitals,

respectively [51], with a small contribution of the atomic orbitals of the azido

nitrogen atoms. The HOMO-3 is localized at the central part of the -skeleton,

and it has a considerable contribution from the orbital of a lone pair of the

endocyclic nitrogen atom (Figure 10); that is, it is the acridine n orbital.

Figure 11. Structures of the lowest and highest singly occupied MOs (LSOMO and

HSOMO, respectively) in the relaxed S1 state for 9-azidoacridine A3 and its cation A3H+

(cation was calculated without a counterion) [50].


253

In terms of photochemical activity, another orbital, namely, the NN*-MO

is the most interesting because its occupancy in the lowest electronically excited

singlet state (S1) determines the photoactivity of an azide. As can be seen in

Figure 10, the NN*-MO in A3 is the second with reference to LUMO, that is,

LUMO + 2.

The levels of all of the MOs decrease upon protonation; in this case, a

stabilizing effect is more pronounced for virtual orbitals (Figure 10). As a result,

the energy gap between HOMO and LUMO decreases from 7.20 to 6.69 eV (this

decrease manifests itself in a bathochromic shift of the long-wavelength

absorption band; see below). As in the neutral azide, the NN*-MO in the

hydrochloride is LUMO + 2, and the energy gap between LUMO and NN*-MO

increases on going from neutral to charged species; however, it remains relatively

small, being equal to 1.30 or 1.63 eV for A3 or A3H+, respectively.

Figure 11 shows the structures of the lowest and highest singly occupied MOs

(LSOMO and HSOMO, respectively) in the relaxed S1 state for azides A3 and

A3H+. In both of the azides, the LSOMO is a -type orbital (former HOMO in the

S0 state), whereas the HSOMO is NN*-MO (former LUMO + 2 in the S0 state).

As is demonstrated below, the low-energy (long-wavelength) absorption bands of

both of the azides (vertical transitions) are related to electron transfer to lower

vacant orbitals (LUMO and LUMO + 1). However, the relaxed state with an

electron on the NN*-MO is the lowest singlet excited state in terms of energy.

This S1 state is occupied during azide irradiation at the long-wavelength

absorption band and is responsible for the photochemical activity of azide.

Thus, quantum-chemical calculations predict photoactivity (the

photodissociation quantum yield > 0.1) for 9-azidoacridine in the neutral and

cationic forms, in full accordance with experimental data.

2.2. Spectral Properties of 9-azidoacridine

Figure 12 shows the absorption spectra of neutral 9-azidoacridine and its

hydrochloride in the near-UV and visible regions at 300–500 nm. Moreover,

intense bands at 250–260 nm were observed in the spectra of both of these

compounds in the short-wavelength UV region (Table 6). In general, the spectrum

of A3 coincides with that of unsubstituted acridine [52]; however, as compared

with the latter, the 362-nm band exhibits a broader long-wavelength shoulder,

which manifests itself as an individual maximum at 382 nm in ethanol.

Mikhayl F. Budyka

254

Protonation leads to a bathochromic shift of the long-wavelength absorption band

toward the visible region to 430 nm and the appearance of a slightly resolved

vibrational structure, with the intensity of an absorption band at 360 nm being

almost doubled (Figure 12). The presence of an absorption band at 440 nm in the

spectra of acridine derivatives is characteristic of compounds protonated at the

ring nitrogen atom [53].

It is well known that the acridine long-wavelength absorption band in the

region 300–400 nm with a maximum at 354 nm is a superposition of three bands:

two acene - * 1La and

1Lb bands (according to the Platt classification) [54] and a

low-intensity n- * band due to electron transfer from the lone electron pair of the

nitrogen atom. The 1La band represents the HOMO LUMO transition, and

1Lb

is a combination of the HOMO-1 LUMO and HOMO LUMO+1 transitions

[55].

Table 6 summarizes the vertical excitation energies and oscillator strengths

calculated by the ZINDO method for A3 and its hydrochloride and gives the

structure of transitions. It can be seen that the ZINDO method underestimates the

transition energies, especially, in the case of the neutral A3. In unsubstituted

acridine, the n– * transition involving the lone pair of the nitrogen atom ranks

third after 1La and

1Lb in terms of energy [51]. As can be seen in Figure 10, the

acridine n orbital in A3 is HOMO-3; according to ZINDO data, the transition that

involves this MO makes the main contribution to the lowest energy band.

/ nm350 400 450

/M-1

cm-1

0

3000

6000

9000

12

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

acetonitrile [50].


255

Table 6. Experimental (in acetonitrile) and theoretical (calculated by ZINDO

method) maxima in the absorption spectra of 9-azidoacridine A3 and its

hydrochloride A3HCl: absorption band maximum ( ) and the corresponding

vertical excitation energy Ev, the logarithmic molar absorption coefficient ( ,

M-1

cm-1

), the oscillator strength (f), and the structure of transition

(cation was calculated without a counterion) [50]

Azide

Experimental Calculatedb

, nm Ev, eV lg Ev, eV f compositionc %

A3 380a 3.26 3.73 2.24 0.001 H-3 L+1

H L+1

23

21

362 3.43 3.82 3.11 0.289 H L 39

345a 3.59 3.62 3.52 0.045 H-1 L

H L+3

25 17

254 4.88 4.96 3.73 0.056 H L+2 13

216 5.74 4.03 3.90 0.019 H-4 L 32

A3HCl 427 2.90 3.76 2.80 0.004 H-3 L+1

H L+1

23

15

410 3.02 3.71 3.06 0.307 H L 44

355 3.49 4.01 3.60 0.165 H-3 L

H-1 L

12

17

340 3.65 3.72 3.62 0.161 H-1 L 22

301 4.12 3.82 3.93 0.113 H-2 L 39

264 4.70 4.71 a Shoulder; in EtOH, a shoulder at 380 nm appeared as an individual peak at 382 nm.

b The five lowest singlet excited states with excitation energies lower than 4 eV are given.

MO notation: H is HOMO and L is LUMO. c One-electron transitions with a contribution higher than 10% are given.

As noted above, in the context of discussions concerning the

photodissociation reaction of the azido group, the occupation of the NN*-MO

(i.e., LUMO + 2) in an excited state is of the greatest interest. Calculated data

(Table 6) indicate that one-electron excitation with the participation of the NN*-

MO makes the main contribution to the fourth spectral transition in terms of

energy (3.73 eV) in A3 (Table 6); its contribution to the second (3.11 eV) and

Mikhayl F. Budyka

256

third (3.52 eV) transitions is at most 5%. In the protonated species (A3HCl), a

configuration involving the NN*-MO contributes (up to 4%) to the third (3.60

eV) and fourth (3.62 eV) transitions. However, as demonstrated above, in the

relaxed lowest singlet excited state (S1), an unpaired electron occupies the NN*-

MO in either neutral or protonated 9-azidoacridine. According to PM3 data, the

adiabatic excitation energies in the S1 state are 1.71 and 1.98 eV for A3 and

A3HCl, respectively.

2.3. Photochemical Properties of 9-azidoacridine

Investigation of photochemical properties of 9-azidoacridine A3 has shown

that it undergoes decomposition under exposure to light in both neutral and

protonated forms [50,56,57]. It should be noted that 9-azidoacridine hydrochloride

in the presence of the traces of water is readily hydrolyzed to yield acridone, 9-

azido-10-methylacridinium methyl sulphate in the same conditions gives N-

methylacridone [58].

Table 7 summarizes the quantum yields of photodissociation of A3 and its

hydrochloride upon irradiation with light at various wavelengths and in various

solvents. It can be seen that the quantum yields are high ( > 0.1) on excitation

into long-wavelength absorption bands; that is, both of the azides are photoactive.

Since the absorption band of the hydrochloride extends to the visible region, this

compound decomposes under irradiation with visible light at a wavelength up to

470 nm. Consequently, among the known aromatic azides, hydrochloride A3HCl

exhibits one of the longest wavelength light sensitivity. However, tendency of

A3HCl to hydrolysis hinders its possible application.

The main reaction product of the A3 photolysis in neutral form is 9-

azoacridine, which was obtained with preparative yield of 81 % under irradiation

in methanol and 60 % in benzene [58]. Azoacridine has broad structureless bands

at 240, 380, and 470 nm with an intensity ratio of 12 : 1 : 0.6 [59]. Under

irradiation of the neutral A3 gradual disappearance of the absorption bands of

azide and the appearance of those of azoacridine were observed [50].


257

Table 7. Observed quantum yields of photodissociation of 9-azidoacridine

(A3) and its hydrochloride A3HCl depending on irradiation wavelength

Azide Solvent ex, nm

A3 EtOH 365 0.77

Toluene 365 0.94

MeCN 365 0.96

A3HCl MeCN 365 0.95

405 0.90

436 0.75

450 0.71

470 0.65

Spectral changes upon the photolysis of hydrochloride A3HCl were

dramatically different and are shown in Figure 13 (to prevent hydrolysis, the

anhydrous acetonitrile was used) [50]. In this case, the absorption spectrum of the

photolysis product (spectrum 6) has a characteristic pattern with a distinct

vibrational structure of the long-wavelength band in the region 370 - 430 nm. The

neutralization of the reaction mixture after photolysis led to the disappearance of

the low-intensity absorption bands in the central region of the spectrum with

maximums at 312 and 326 nm, with the band in the region 360 - 430 nm

remaining practically unshifted; however, the vibrational structure became less

pronounced.

This behavior of the bands at 300 - 450 nm and the presence of an intense

short-wavelength band at 260 nm is typical of 9-aminoacridine [60]. The

assignment of the A3HCl reaction product to aminoacridine was corroborated by

additional experiments and comparison with thermally synthesized compound

[50].

Scheme 3 summarizes reaction pathways of 9-azidoacridine photolysis in

different reaction conditions. The first photochemical step is the azide

photodissociation in a singlet excited state with the formation of the singlet

nitrene. Among the variety of the subsequent reaction pathways of aromatic

singlet nitrenes, the following two main reactions can be mentioned [8]:

intramolecular insertion at the ortho position to form aziridine and then

dehydroazepine and intersystem crossing to a triplet state, which is the ground

state for nitrene.

Mikhayl F. Budyka

258

300 350 400 450

0.0

0.1

0.2

h

6

1

A

nm

Figure 13. Spectral changes on the irradiation of a 1.14.10

-5 M 9-azidoacridinium

hydrochloride A3HCl solution in anhydrous acetonitrile. Irradiation time, s: (1) 0, (2) 9, (3)

20, (4) 40, (5) 90, (6) 240. Irradiation wavelength: 365 nm, incident light intensity 4.4.10

-9

Einstein cm-2

s-1

[50].

In the case of 9-acridyl nitrene, both of the ortho positions with respect to

nitrene are occupied by fused benzene rings, which prevent the intramolecular

insertion reaction and thereby stabilize the singlet nitrene to facilitate its

conversion into the triplet state. Coordination to the lone pair of the oxygen or

nitrogen atom additionally contributes to the stabilization of singlet nitrene when

the reaction is carried out in ethanol or acetonitrile, respectively.

The main reaction of triplet acridyl nitrene in neutral solvents is dimerization

to 9-azoacridine. Another characteristic reaction of triplet nitrenes is the

abstraction of hydrogen atoms, for example, from solvent molecules to form

aminyl radicals, which combine with solvent radicals to form secondary amines or

abstract another hydrogen atom to form primary amines. In accordance with this,

when the photolysis of 9-azidoacridine was performed in toluene, whose molecule

is a good hydrogen donor, the spectrum of reaction products exhibited absorption

bands at 369, 389, 408, and 430 nm, which are characteristic of 9-aminoacridine,

along with a broad low-intensity band at 470 nm due to azoacridine. That is, both

of the reaction pathways of triplet nitrenes occur in toluene [50].


259

N

N3

NH

+

N3

NH

+

NH2

N

N

N

N

N

NH2

N

1

~N

3

~N

3

1

~

N

1

~N

3

~N

3

1

~

h

+ H+

- H+

[H]h

[H]

- N2

- N2

A3H+

A3

+ + +

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

A3HCl.

Upon the photolysis of 9-azidoacridine hydrochloride, the resulting acridyl

nitrene was protonated at the endocyclic nitrogen atom. Evidently, the positive

charge of the acridine nucleus prevents the dimerization reaction to the

azoacridine dication. Therefore, the consecutive abstraction of two hydrogen

atoms from solvent molecules with formation of protonated 9-aminoacridine

(Scheme 3), which gives the free amine upon neutralization, is the main reaction

route of the acridyl nitrene cation.

2.4. Spectral and Photochemical Properties of 9-(4'-

azidophenyl)acridine

Insertion of the para-phenylene group into the molecule of 9-azidoacridine

between acridine nucleus and azido group results in 9-(4'-azidophenyl)acridine

(APA). This compound retains many of the spectral and photochemical properties

of 9-azidoacridine, and acquires new unique property – its photodissociation

quantum yield becomes strongly dependent on the charge of the heteroaromatic

system.

Mikhayl F. Budyka

260

N

N3

APA

APA has strong near-UV vibrationally resolved absorption band at = 350-

400 nm characteristic for the acridine moiety (Figure 14, curve 1), the long-

wavelength edge of the band extends into the visible region, and the intense band

at = 254 nm (not shown in Figure 14) [61]. Comparison of Figures 12 and 14

reveals that spectral properties of APA resemble those of 9-azidoacridine.

Quaternization of azide at the acridine nitrogen atom leads to bathochromic

shift and appearance of additional band at 432 nm in the spectra of N-methyl-9-

(4'-azidophenyl)acridinium iodide. Comparison of the spectra of the azides and

unsubstituted 9-phenylacridine and N-methylated salt without azido group shows

that introduction of the latter does not lead to marked changes in the positions of

the absorption bands. The spectral changes upon the introduction of an azido

group may be seen as indirect evidence for participation of the electron system of

the azido group in the electronic transition giving rise to the long-wavelength

absorption band and a reason for the photoactivity of the azide upon irradiation at

this band.

The efficient decomposition of APA is observed upon irradiation within the

long-wavelength absorption band, the decomposition quantum yield is collected

in Table 8 [61]. It is seen that yield decreases with increasing wavelength of the

incident light although remains rather high (> 0.1)

Table 8. The photodissociation quantum yields of APA and

N-methyl-9-(4'-azidophenyl)acridinium iodide APA-MeI [61]

Azide Solvent ex, nm

APA CHCl3 365 0.88

CHCl3 405 0.69

EtOH 405 0.66

EtOH 436 0.14

APA-MeI MeCN 365 2.3.10-3


261

Figure 14. Electronic absorption spectrum of 9-(4'-azidophenyl)acridine (APA) in

chloroform (1) and dependence of the quantum yield ( ) of the photolysis of APA on the

wavelength of the exciting light (2) [61].

Figure 14 shows the dependence of the quantum yield on the wavelength of

the incident light along with absorption spectrum of the azide. The quantum yield

is found to drop with decreasing molar extinction coefficient of the azide.

The photodissociation quantum yield of iodomethylate APA-MeI is more than

two orders of magnitude less than that of APA (Table 8). Low photoactivity of the

N-methylated salt is not connected with possible competitive process of the

photoinduced electron transfer from iodide anion to quaternized heteroaromatic

cation, as has been shown by replacement of the iodide counter-ion in the salt by

the CH3SO4- ion [61]. Therefore, the N-methylated APA cation indeed displays

low photochemical activity relative to dissociation of the azide group.

If the main reason for activity loss of the N-methylated cation is the positive

charge of the acridine moiety, the protonation of APA would result in a similar

effect. Since the degree of protonation depends on the acid concentration, the

photoactivity of APA can be controlled by changing the acidity of the medium.

This assumption has been corroborated experimentally by investigation of the

observed photodissociation quantum yield of APA in dependence on acid

concentration [62,63]. Acidification of the ethanol solution of APA (see Figure 15,

curve 2) results in disappearance of the absorption band of the neutral azide and

Mikhayl F. Budyka

262

appearance of a long-wavelength absorption band with a maximum at = 417

nm, which resembles the spectrum of N-methylated salt and is characteristic of

the chromophoric system of the acridine moiety protonated or alkylated at the

endocyclic nitrogen atom.

The measured pKa value for APA is 3.5 (in EtOH). The compound without

azido group, 9-phenylacridine, has a value of pKa 4.8 (in water) [64]. Thus,

introduction of the azido group with a positive inductive effect into the molecule

of 9-phenylacridine decreases the basicity of the acridine moiety. In the singlet-

excited state the basicity of APA increases considerably to pKa* = 11.6 [63], as is

calculated from the bathochromic shift of the long-wavelength absorption band

using the Forster method [65].

Spectra 2-7 in Figure 15 show the changes in the absorbance upon irradiation

of the acidic solution of APA. Table 9 collects the observed quantum yields of

photodissociation of APA at different HCl concentrations.

300 350 400 450

0.00

0.05

0.10

0.15

7

21

A

/nm

Figure 15. Absorption spectrum of a 9.5.10

–6 M solution of 9-(4'-azidophenyl)acridine

(APA) in EtOH in the absence (1) and in the presence of 0.0219 M HCl (2). Spectral

changes upon irradiation of the solution for 25 (3), 90 (4), 150 (5), 300 (6), and 600 s (7);

light intensity 4.88.10

–9 Einstein cm

–2 s

–1 [63].


263

- N2

APA + HCl APAHCl

- N2

Ka

products

h

1APA* + HCl 1APAHCl*

K*a

h

1

2

kr

Scheme 4.

Two photochemical reactions occur simultaneously in the studied range of

acid concentrations, i.e., the decomposition of APA and its protonated form

APAHCl with the quantum yields 1 and 2, respectively, Scheme 4.

From the Scheme 4, the following equation for the observed quantum yield

can be deduced

obs = 2 + ( 1 - 2)/(1+ [HCl]/Ka), (2)

where = 1.09 is the ratio of the molar absorption coefficients of protonated and

neutral azides at the wavelength of irradiation. According to equation (2) the

quantum yield of the hydrochloride APAHCl photodissociation was calculated

form the limiting value, lim( obs), under the condition [HCl] , and is equal 2

= 6.9.10

-3 [63]. This value is two orders of magnitude lower than for neutral APA,

being of the same order as the quantum yield of photodissociation of the N-

methylated cation (Table 8).

Table 9. The observed quantum yields of photodissociation of APA at

different HCl concentrations (in EtOH) [63]

[HCl] 100, M obs 100 [HCl] 100,

M obs 100 [HCl] 100,

M obs 100

0 82 0.64 8.8 2.19 3.7

0.063 32 1.36 4.6 3.7 2.8

0.211 18 1.38 4.7 6.25 2.0

0.302 14 1.52 4.2 9.95 1.5

Mikhayl F. Budyka

264

[HCl]/ M

0.00 0.02 0.04 0.06 0.08 0.10

0.8

125/(

obs-

0.0

075)

0

20

40

60

80

100

Figure 16. Observed quantum yield of photodissociation of 9-(4'-azidophenyl)acridine

(APA) plotted vs. acid concentration in the coordinates of equation (3); correlation

coefficient is 0.997 [63].

Taking into account the obtained 1 and β 2 values, equation (2) can be

linearized

( 1 - 2)/( obs - 2) = 1 + ( /Ka)[HCl]. (3)

Experimental data with the correlation coefficient 0.997 was linearized in the

coordinates of equation (3), as shown in Figure 16. As the acid concentration

increased to 0.1 M, the obs value decreased by more than 50 times.

From the obtained data it follows that, in the excited state, the neutral APA

and its protonated form are not equilibrated. For instance, using the acidity

constants for the S0 and S1 states of APA (3.5 and 11.6), we can calculate that the

content of the nonprotonated form under equilibrium conditions is 33.4% in the S0

state and lower than 4.10

–7% in the S1 state at [HCl] = 6.3

.10

-4 M. Thus, if the

excited state had time to achieve the acid-base equilibrium, the observed quantum

yield of photodissociation would be determined by the decomposition of the

protonated form only, being much lower than the experimentally determined

value (0.32) at a given acid concentration.

The difference in the photochemical activity of APA in the neutral and

cationic forms was explained taking into account the results of quantum chemical

calculations [63]. The structural parameters of the azido group in APA and its

protonated cation calculated by the PM3 method are given in Table 10. In the

ground S0 state, the azido groups of both molecules are quasi-linear (NNN angle


265

is ~170°) with the N-N2 bond length equal to 1.27-1.28 Å and a total charge on

the terminal N2 group of ~0.4 e. These parameters are characteristic of all

aromatic azides in the S0 state.

However, in the lowest singlet-excited S1 state, the neutral APA exhibits

changes characteristic of photoactive azides, namely, elongation of the N-N2 bond

and a decrease in the NNN bond angle, in the order of the N-N2 bond, and in the

positive charge on the terminal N2 group (the leaving nitrogen atom is neutral). At

the same time, the bond angle in the protonated cation APAH+ remains almost

unchanged and the positive charge on the N2 group is retained.

This distinction is related to the fact that in the S1 state of APA the NN*-MO

with the antibonding character with respect to the N-N2 bond is occupied, it

becomes HSOMO (Figure 17). Occupation of this orbital is a prerequisite for the

dissociation of this bond. In the S1 state of cation APAH+ the -MO bond

localized on the acridine moiety is occupied and the NN*-MO remains

unoccupied (not shown in Figure 17). The difference in structures of the lowest

singlet-excited states of two azides explains the difference in their photochemical

properties (compare with frontier MOs of the neutral and protonated 9-

azidoacridine, Figure 11).

Table 10. Selected optimized parameters of 9-(4'-azidophenyl)acridine (APA)

and its protonated cation: the length (r) and order (p) of the N1N2 bond, the

N1N2N3 bond angle ( NNN), and the Mulliken effective charge on the

terminal N2 group (ZN2) in the ground (S0) and the lowest electronically

excited (S1) state calculated by PM3 method

(cation was calculated without a counterion) [63]

Azide State r, Å p NNN, deg. ZN

2, е

APA S0 1.27 1.35 169.5 0.39

S1 1.34 1.06 137.1 -0.05

APAH+ S0 1.28 1.29 169.6 0.45

S1 1.36 1.10 168.1 0.57

Mikhayl F. Budyka

266

Figure 17. Structures of the lowest and highest singly occupied MOs (LSOMO and

HSOMO, respectively) in the relaxed S1 state for 9-(4'-azidophenyl)acridine (APA) and its

cation APAH+ (cation was calculated without a counterion).

In conclusion it is worthwhile to note that APA is a unique example of azide

whose photochemical activity can be switched by protonation/deprotonation. This

enables an observed quantum yield of the azide photodissociation to be smoothly

changed within two orders of magnitude.

3. THEORETICAL INVESTIGATION OF

THE HIGHER HETEROCYCLIC AZIDES

Examination of photochemical properties of azido derivatives of pyridine,

quinoline and acridine shows clearly that azide photoactivity depends on the size

and charge of the azide molecule. In turn, the photochemical activity of azide


267

correlates with the type of molecular orbital (MO) that is filled in the lowest

singlet exited (S1) state [6]. If the antibonding NN*-MO is filled, the azide is

photoactive, i.e. it decomposes with a quantum yield of > 0.1. If the NN*-MO

remains vacant in the excited state, azide is photoinert, and its photodissociation

quantum yield is < 0.01.

To reveal the effect of the size and charge of aromatic -system on the azide

structure and on the position of the NN*-MO in the ground state and on the

filling of this orbital in the excited state, a series of heteroaromatic azides with

monotonically increasing size of aromatic nucleus was investigated systematically

by quantum-chemical methods [66,67]. Apart from discussed above azides A1 -

A3, the series includes their cata-condensed analogues: 12-azido-benzo[b]acridine

A4, 13-azido-6-azapentacene (azidodibenzacridine) A5, and 15-azido-6-

azahexacene A6; here the index is equal to the number of aromatic rings (see

Scheme 1). All series of protonated (positively charged) forms A1H+ - A6H

+ was

also investigated. In this series the size of aromatic -system increases from 6 to

26 e.

Table 11. Selected optimized parameters for heterocyclic azides in the

ground (S0) and lowest excited singlet (S1) states: bond length (r) and bond

order (p) for the N1N2 and N1C4 bonds, the N1N2N3 bond angle ( NNN), and

Mulliken charge (ZN2) on the terminal group N2, calculated by PM3 methods

(cations A4H+ - A6H

+ were calculated without counterions, atom numbering:

C4N1N2N3) [67]

Azide State rN1N2, Å rN1C4, Å pN1N2 pN1C4 NNN, ° ZN2, е

A4 S0 1.27 1.44 1.36 0.98 169.5 0.39

S1 1.31 1.43 1.13 1.36 138.6 -0.07

A4H+ S0 1.30 1.39 1.19 1.22 166.4 0.54

S1 1.48 1.32 0.93 1.80 141.5 0.08

A5 S0 1.27 1.44 1.36 0.99 169.5 0.39

S1 1.34 1.45 1.09 1.33 133.8 -0.05

A5H+ S0 1.30 1.39 1.19 1.22 166.9 0.54

S1 1.29 1.38 1.24 1.26 168.4 0.43

A6 S0 1.27 1.44 1.36 0.99 169.5 0.39

S1 1.27 1.42 1.34 1.09 167.7 0.37

A6H+ S0 1.30 1.38 1.19 1.22 166.6 0.55

S1 1.29 1.39 1.27 1.17 168.0 0.43

Mikhayl F. Budyka

268

The series has been chosen since heterocyclic azides are convenient model

compounds for the study of positive charge effect, because they can be easily

transformed from the neutral to positively charged form by protonation or

alkylation at endocyclic nitrogen atoms, the size of molecular -system being

unchanged upon protonation.

The structures of azides A1 - A3 are in detail discussed above and will be

mentioned shortly for comparison with the higher members of the series and for

evaluation of the size effect. Main structural parameters of the azides A4 - A6 in

neutral and protonated forms are shown in Table 11.

In the ground state, the higher azides A4 - A6 have the structure similar to that

of the lower azides A1 - A3: the azido group has a quasi-linear geometry, the NNN

bond angle NNN ~ 170°. In the neutral form the N1N2 bond length is 1.27 Å

(PM3 data). An important feature is a large positive charge on the terminal

nitrogen atoms of the azido group.

Protonation induces the electron density transfer from the azido group to the

aromatic nucleus, an effect that results in a weakening of the N1N2 bond even in

the ground state; the N1N2 bond order decreases with simultaneous increase of

the N1C4 bond order (Table 11) (the N1N2 bond is elongated by 0.02 - 0.03 Å,

and the N1C4 bond is shortened by 0.03 - 0.06 Å.). The electron density transfer

results also in an essential charge increase on the N2 group upon protonation.

These effects are the same as found for azides A1 - A3.

As stated above, azidopyridine A1 and azidoquinoline A2 have a planar

structure of the completely conjugated systems (azido group lies in the plane of

aromatic nucleus) in both neutral and protonated forms. In azidoacridine A3, due

to steric hindrance by the two hydrogens in the peri-positions of the neighboring

benzene rings, the azido group deviates from the plane of the molecule. The

higher members A4 - A6 also have non-planar structure with the azido group

deviated from the plane of aromatic nucleus. The bond order between the N1 and

C4 atoms increases upon protonation, as a result, protonated forms have more

planar structure due to increased conjugation between azido group and aromatic

nucleus.

In the excited (S1) state, the geometry changes depend on the azide structure

(size and charge). For the neutral azides A4 - A5 and cation A4H+, as for the lower

members of the series, the NNN bond angle decreases to ~ 130 - 140° (azido

group accepts a bent geometry), the N1N2 bond is elongated to 1.31 - 1.35 Å in

neutral forms and to 1.41 - 1.48 Å in cations, the bond order is reduced by ~ 0.3 in

the both cases. An essential charge reduction (by about 0.45 e) on the two

terminal nitrogen atoms of the azido group should be also noted (Table 11).


269

At the same time, parameters of A6, A5H+ and A6H

+ are not practically

changed in the S1 state: the azido group retains the quasi-linear geometry, the

N1N2 bond length and order and the positive charge on the N2 group are nearly

the same as those in the S0 state (Table 11).

Comparison of the obtained results with the data for other aromatic azides

[6,68] results in conclusion that the changes in the parameters for azides A1 - A5

and A1H+ - A4H

+ on going from S0 to S1 state are characteristic for photoactive

azides, while the conservation of the parameters observed for A6, A5H+ and A6H

+

is characteristic for photoinert azides.

Figure 18. Structure of the frontier MOs for azidopyridine A1 and azidoazahexacene A6:

the highest occupied MO (HOMO), the lowest unoccupied MO (LUMO) and the next

unoccupied MOs till the NN*-MO in the ground (S0) state. In A1 the NN*-MO is

LUMO+1, in A6 it is LUMO+3 [67].

Mikhayl F. Budyka

270

Figure 19. Structure of the lowest semioccupied MO (LSOMO) and the highest

semioccupied MO (HSOMO) in the S1 state for azidopyridine A1, azidodibenzacridine A5

and azidoazahexacene A6 [67].

The geometry change and the charge redistribution (or the lack of essential

changes) on going from the S0 to S1 state can be easily explained by examining

the structure of the frontier MOs in these states. As example, Figure 18 shows the

structure of the highest occupied MO (HOMO), the lowest unoccupied MO

(LUMO) and some next unoccupied MOs for the first and last members of the

series, A1 and A6, respectively, in the neutral form in the S0 state. One can see that

both HOMO and LUMO are -type MOs localized mainly on the aromatic

nucleus with partial contribution by the atomic p-orbitals of the azido group. One

of the higher unoccupied MOs is antibonding NN*-MO, the population of this

orbital in the S1 state is a prerequisite for subsequent azido group dissociation [6].

In the S0 state, the NN*-MO is LUMO+1 in azide A1 and LUMO+3 in azide A6

(Figure 18).

In the S0 state, the structure of the frontier MOs for protonated cations A1H+ -

A6H+ is similar to that for corresponding neutral azides.

In the excited (S1) state, the type of the filled MO depends on the azide size

and charge. In neutral azides from A1 to A5, upon excitation to the S1 state, as a

result of relaxation, the NN*-MO is occupied instead of LUMO (Figure 19).

Depopulation of the -HOMO, which becomes the lowest semioccupied MO

(LSOMO) in the S1 state, and population of the NN*-MO, which becomes the

highest semioccupied MO (HSOMO), results in the aforementioned structural

changes: electron density transfer from aromatic nucleus to azido group, bending


271

of this group and weakening and elongation of the N-N2 bond (Table 11). At the

same time, in the excited azidoazahexacene A6, the aromatic -orbital is filled

(Figure 19) whereas the NN*-MO remains vacant. As a result, the structure of A6

in the S1 state is similar to that in the S0 state (Table 11).

Based on the nature of MO, that is filled in the S1 state, one should expect

azides A1 - A5 to be photoactive whereas azide A6 - photoinert. Thus, between

azidodibenzacridine A5 and azidoazahexacene A6 a boundary can be drawn that

separates photoactive azides (where the NN*-MO is filled in the S1 state) from

photoinert ones (where the NN*-MO remains vacant in the S1 state).

The behavior of the protonated azides in the excited state is similar to that of

the neutral forms: for the first members of the series, the NN*-MO is filled in the

S1 state, for the last members this MO remains vacant (Figure 20). In contrast to

neutral azides, the boundary, which separates photoactive and photoinert azides,

passes between cations A4H+ and A5H

+. Thus, for positively charged azides the

NN*-MO ceases to be filled in the S1 state at a smaller size of aromatic nucleus

(22 -electrons) compared to the neutral azides (26 -electrons).

Figure 20. Structure of the lowest semioccupied MO (LSOMO) and the highest

semioccupied MO (HSOMO) in the S1 state for the protonated azides A1H+, A4H

+ and

A5H+ [67].

Mikhayl F. Budyka

272

The decrease in the population of HOMO, which in the S1 state becomes the

lowest single-occupied MO (LSOMO), and the population of the MO, which

becomes the highest single occupied MO (HSOMO) results in the observed

changes in the structure of photoactive azides: the transfer of the electron density

from the aromatic ring to the azido group, bending of the azido group, and the

elongation of the N-N2 bond (Table 11). At the same time, the aromatic -MO is

populated in the S1 state of photostable azides, and the NN*-MO remains

unoccupied.

From the viewpoint of the valence bond theory, upon excitation from the S0 to

the S1 state, in the photoinert azides, the atomic orbitals of the central atom of the

azido group (atom N2) conserve the sp hybridization (valence angle ~ 180°),

whereas in the photoactive azides, the rehybridization from sp to sp2 takes place

(valence angle ~ 120°).

Analysis of the MO diagram provides a reason for existence of a limiting size

of the aromatic nucleus, above which the NN*-MO ceases to be filled in the S1

state. Figure 21 shows the molecular orbital diagram for the neutral azides A1 - A6

in the ground (S0) state. One can see that with increasing number of annelated

benzene rings the HOMO level gradually increases while the LUMO level

decreases. As a result, the energy gap HOMO–LUMO decreases from 8.98 to 5.55

eV (PM3 data) on going from A1 to A6.

The striking feature is a little effect of aromatic nucleus size on the NN*-MO

level; the energy of this orbital varies insignificantly within -(0.3 0.1) eV for the

neutral azides. A slight increase of the NN*-MO energy on going from A2 to A3

is connected with a deviation of the azido group from the aromatic nucleus plane

due to steric hindrance with the peri-hydrogens (see above). Owing to the

decreased conjugation between the azido group and aromatic -system, the NN*-

MO is destabilized and its level increases.

From Figures 18 and 21 it is seen that in the S0 state of the neutral A1, the

NN*-MO is next after LUMO, i.e. LUMO+1, and is located above LUMO by

0.21 eV. Since the NN*-MO level is retained while the LUMO level decreases

with increasing aromatic system size, the energy gap between NN*-MO and

LUMO increases from 0.21 to 1.87 eV on going from A1 to A6. The space

between these orbitals is filled with the -orbitals, localized on the aromatic

nucleus, as a result, the NN*-MO becomes LUMO+3 in A6.


273

A1 A2 A3 A4 A5 A6

EMO, eV

-9

-8

-2

-1

0

——

——

— —

——

— — — —

— — — — ——

||

||||

||||

||

— — — — — —

— —— — —

— —

LUMO

LUMO+3

HOMO

LUMO+4

LUMO+2

LUMO+1

NN*-MO

Figure 21. Molecular orbital diagram for the neutral azides A1 - A6 in the ground (S0) state

(PM3 data). The position of the NN*-MO, which is LUMO+1 in A1 and LUMO+3 in A6,

is marked [67].

Figure 22 shows the molecular orbital diagram for the protonated azides

A1H+ - A6H

+ in the ground (S0) state. Compared to the neutral azides, there is a

general lowering of orbital levels. Nevertheless, the main features found for the

neutral azides are observed also for the cations.

With increasing number of annelated benzene rings, the HOMO level

gradually increases, and despite little change in the LUMO level, the HOMO–

LUMO gap decreases from 8.05 to 5.08 eV on going from A1H+ to A6H

+. The

energy of the NN*-MO in the cations varies within -(4.1 0.1) eV, and the gap

between NN*-MO and LUMO increases slightly from 1.52 to 1.61 eV on going

from A1H+ to A6H

+.

In the protonated azidopyridine A1H+ in the S0 state the NN*-MO is

LUMO+2, LUMO+1 being aromatic -orbital. With increasing aromatic nucleus

size, the -orbital level increases (Figure 22), so this orbital becomes LUMO+2

whereas the NN*-MO becomes LUMO+1 in the protonated azidoazahexacene

A6H+.

Mikhayl F. Budyka

274

EMO, eV

-13

-12

-11

-6

-5

-4

——

—— —

—— — — — — ——

— — — — —

||

||

||

||||

||

— — — — — —— — — — — —— — —

LUMO

LUMO+3

HOMO

LUMO+4

LUMO+2LUMO+1

NN*-MO

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

Figure 22. Molecular orbital diagram for the protonated azides A1H+ - A6H

+ in the ground

(S0) state (PM3 data). The position of the NN*-MO, which is LUMO+2 in A1H+ and

LUMO+1 in A6H+, is marked [67].

Thus, three effects can be noted with the aromatic system size increasing:

i) independence (little dependence) of the NN*-MO level on the size,

ii) decrease in the HOMO–LUMO gap,

iii) increase in the LUMO– NN*-MO gap.

As a consequence of (ii) and (iii), in the investigated series of azides, both

neutral and protonated, the NN*-MO, which is filled in the S1 state for the first

members of the series (large HOMO–LUMO gap, small LUMO– NN*-MO gap),

ceases to be filled for the final members of the series (small HOMO–LUMO gap,

large LUMO– NN*-MO gap). The boundary, that separates photoactive azides

(where the NN*-MO is filled in the S1 state) from photoinert ones (where the

NN*-MO remains vacant in the S1 state), passes between A5 and A6 for the

neutral azides and between A4H+ and A5H

+ for the cations.

Therefore, the threshold size of the aromatic nucleus, above which the NN*-

MO ceases to be filled in the S1 state and the azide becomes photoinert, is


275

calculated to be 22 (in A5) and 18 (in A4H+) -electrons for the neutral and

protonated azides, respectively. The positive charge shifts the threshold to the

smaller size. Thus, quantum-chemical calculations predict existence of the "size

boundary" of photoactivity of aromatic azides.

From this point of view, 9-(4'-azidophenyl)acridine (APA) and its cation are

interesting examples of azides with the size of the π system equal to 20 e. This is

lower than the threshold for neutral azides, but higher than that for cations. In fact,

neutral APA is photoactive, whereas its cation is photoinert (see above).

Table 12 collects some calculated energetic parameters of azides A1 - A6:

heat of formation ( Hf) in the S0 state, vertical (Franck-Condon) excitation energy

(Ev) to the lowest excited singlet (S1) state, and relative energy of the S1 state,

which corresponds to adiabatic excitation energy (Ead). The heat of formation of

azide in both neutral and protonated forms increases with increasing number of

the condensed aromatic rings (m), the dependences are described by the linear

regressions

Hf = 82.25 + 23.04*m kcal mol-1

for the neutral form (correlation factor r = 0.999), and

Hf = 238.92 + 18.52*m kcal mol-1

for the protonated form (r = 0.997).

Table 12. Selected calculated (PM3) energetic parameters of heteroaromatic

azides: heat of formation Hf (in kcal mol-1

) in the S0 state, vertical (Ev) and

adiabatic (Ead) excitation energies (in eV) to the lowest excited singlet (S1)

state (protonated cations A1H+ - A6H

+ were calculated without counterions)

[67]

Azide Hf Ev Ead Azide Hf Ev Ead

A1 107.47 4.707 1.570 A1H+ 261.39 4.162 2.008

A2 126.02 4.274 1.578 A2H+ 272.99 3.787 1.957

A3 151.22 3.761 1.714 A3H+ 292.98 3.258 1.978

A4 173.75 3.285 1.846 A4H+ 311.35 2.595 2.146

A5 197.42 2.952 2.226 A5H+ 331.29 2.258 1.898

A6 221.37 2.729 2.496 A6H+ 352.35 1.817 1.488

Mikhayl F. Budyka

276

Figure 23 shows the difference between the vertical and adiabatic excitation

energies (Ev - Ead) in dependence on the size of azide molecule. Both Ev and Ead

are calculated for the systems with the open electronic shells (two unpaired

electrons), but Ev is calculated at the fixed geometry of the ground state, whereas

Ead is calculated at the relaxed geometry of the excited state. Therefore, the

difference (Ev - Ead) can be defined as the energy of relaxation (rearrangement) of

the atomic nuclei following the electron transfer upon excitation to the S1 state.

This parameter characterizes a change in the geometry of the excited state relative

to that of the ground state. The theoretical limit, a zero difference between Ev and

Ead, corresponds to the complete absence of relaxation when the geometry of the

excited state coincides with that of the ground state and two states differ only in

the electron density distribution.

In Figure 23 one can see that with azide molecule size increasing the

relaxation energy decreases taking minimal values for photoinert A6, A5H+ and

A6H+. In photoinert azides the NN*-MO remains vacant, and the geometry of

azido group is not practically changed in comparison with the ground state, as a

result these azides have the smallest relaxation energy (< 0.4 eV).

1 2 3 4 5 60

1

2

3

2

1

E, eV

m

Figure 23. Dependence of the difference (Ev - Ead) between the vertical and adiabatic

excitation energies on the number of aromatic rings (m) for the neutral azides A1 - A6 (1)

and the protonated cations A1H+ - A6H

+ (2).


277

The vertical (Franck-Condon) excitation energy (Ev) itself is an important

photochemical characteristic of azide. This calculated parameter corresponds to

the experimentally measured maximum of the long-wavelength absorption band

and characterizes the region of spectral sensitivity of azide. From Table 12 it is

seen that Ev monotonically decreases with an increase in the size of the azide

molecule for both neutral and protonated azides. The decrease in Ev is symbatic to

the above-discussed decrease in the HOMO–LUMO gap, which is an essential

part of Ev, and corresponds to the bathochromic shift of the absorption band

observed in the spectra of aromatic compounds with an increase in the number of

annelated aromatic rings [55].

Since the absorption spectrum, as well as photoactivity, depends on the size

of the -system of azide molecule, we can connect these two experimental

parameters with each other. Before, it is noteworthy that besides the "size

boundary" there exists also an "energetic boundary" of azide photoactivity. The

activation energy for the N-N2 bond thermolysis in aromatic azides is about 35

kcal mol-1

or slightly less [69]. Therefore, the energy of light quantum with

wavelength above ~ 800 nm is insufficient for the cleavage of azido group.

Thus, both "size boundary", which depends on the population of the NN*-

MO in the S1 state, and "energetic boundary", which depends on the energy of the

N-N2 bond cleavage, lead to the "long-wavelength boundary" of aromatic azide

photoactivity: azides possessing absorption bands in the long-wavelength region

of the visible spectrum above a certain threshold become insensitive to irradiation

light.

It should be emphasized here that the results considered refer to the lowest

electronically excited singlet (S1) state. This state is populated upon the excitation

of a molecule with a light in the long-wavelength absorption band and

characterizes the long-wavelength light sensitivity of aromatic azide. Upon

irradiation with the shorter wavelength light, the photodissociation quantum yield

may change drastically, because, in this case, the highest excited states (Sn) are

populated, which differ by the structure and the properties from the S1 state [7].

Taking into account the correlation between the azide photoactivity and the

type of molecular orbital populated in the excited state, the experimentally

observed correlation between the spectral and photochemical properties of

aromatic azides (azidodyes with absorption bands in the visible range are mostly

photoinert) finds theoretical basis.

Both spectral and photochemical properties of aryl azides are determined by

the relative positions of the same frontier MOs. The position of the long-

wavelength absorption band depends first of all on the value of the HOMO–

Mikhayl F. Budyka

278

LUMO gap, while the population of the NN*-MO depends on the ratio between

the HOMO–LUMO and LUMO– NN*-MO energy gaps. For a bathochromic shift

of the long-wavelength absorption band, it is necessary to decrease the HOMO–

LUMO gap, which may be attained by increasing the size of the aromatic -

system or converting the compound into a positively charged form (all known

azido dyes are cations). However, this inevitably results in the fact that the NN*-

MO ceases to be filled in the S1 state, and the azide becomes photoinert.

Hence, it follows that the requirement of long-wavelength light sensitivity of

azides is contradictory. On the one hand, to exhibit bands in the visible region, an

azide should be a dye, and most of dyes have an extended system of conjugated

bonds and are cations. On the other hand, upon an increase in the size of the

system and positive charging, the azide loses photoactivity and the quantum yield

of photodissociation of the azido group sharply decreases to < 0.01. This problem

is considered below.

4. LONG-WAVELENGTH BOUNDARY OF

AROMATIC AZIDE PHOTOACTIVITY

Due to its practical importance, the problem of the long-wavelength

photosensitivity of aromatic azides has been investigated in more detail [70]. The

absorption spectrum of an azide determines the region of its spectral sensitivity,

while light sensitivity or photoactivity is determined by the quantum yield of

photodissociation of the azido group. To shift the photosensitivity of an aromatic

azide toward the long-wavelength region of visible spectrum, it is necessary that,

first, the long-wavelength absorption band of the azide occur at a given spectral

range and, second, the azide be photoactive; i.e., have a quantum yield of

photodissociation of the azido group of > 0.1 upon illumination at this

absorption band.

The absorption spectra for the series of heteroaromatic azides were calculated

and compared with available experimental data [70]. Table 13 presents data on the

absorption spectra of azides A1 - A6 and the corresponding cations A1H+ - A6H

+

calculated by the TD B3LYP/6-31G* method: the wavelength ( ), the frequency

( ) of the long-wavelength absorption band and the corresponding vertical

excitation energy (Ev), the oscillator strength (f), and the structure of the

transition. In addition, the energies Ev characterizing the Franck–Condon


279

transition S0 S1 were calculated by the PM3-CI method. Experimentally

measured spectra are known for azides A1 - A3 and their hydrochlorides (see

above), these spectra are also given in Table 13.

Table 13. Calculated and experimental absorption spectra of azides A1 - A6

and their cations A1H+ - A6H

+, given are the wavelength ( ) and the

frequency ( ) of the long-wavelength absorption band and the corresponding

vertical excitation energy (Ev), the logarithmic molar absorption coefficient

( in M-1

cm-1

), the oscillator strength (f), and the structure of the transition;

calculation on the cations ignoring counterions [70]

Azide Caclulateda Experimental

Ev, eV f structureb % ,

nm

, cm-1 Ev, eV lg

А1 4.05

4.71

0.0004 H L+1 47 249 40160 4.98 4.01

А1Н+ 4.65

4.16

0.0003 H L+2 48 275 36360 4.51 4.30

А2 3.80

4.27

0.0003 H L+1 42 299 33450 4.15 4.06

А2Н+ 3.53

3.79

0.0621 H L 40 332 30120 3.73 4.17

А3 3.26

3.76

0.0777 H L 41 362 27620 3.42 3.83

А3Н+ 2.83

3.26

0.0682 H L 41 427 23420 2.90 3.76

А4 2.50

3.29

0.0558 H L 41

А4Н+ 1.89

2.60

0.0229 H L 43

А5 1.99

2.95

0.0485 H L 39

А5Н+ 1.55

2.26

0.0176 H L 42

А6 1.60

2.73

0.0370 H L 38

А6Н+ 1.03

1.82

0.0293 H L 41

a TD B3LYP/6-31G*//PM3; the figures given in italic represent PM3-CI calculation data.

b Notation of molecular orbitals: H is HOMO (highest occupied MO) and L is LUMO

(lowest unoccupied MO); given are one-electron transitions with a contribution of

more than 10%.

Mikhayl F. Budyka

280

n (e)6 10 14 18 22 26

/nm

300

400

500

600

700800900

/10

3 c

m-1

40

30

20

10

1

2

3

4

5

Figure 24. Dependence of the frequency (wavelength ) at maximum of the azide long-

wavelength absorption band on the number of electrons n in the aromatic system for

neutral azides A1 - A6 according to calculations by the (1) B3LYP/6-31G8//PM3 and (2)

PM3-CI methods and to (3) experimental data approximated by regression analysis; (4) the

size threshold of photoactivity: azides with a smaller system are photoactive and those

with a larger 5) the energy threshold of photoactivity: the energy

of light at a longer wavelength is insufficient for breaking the N-N2 bond (see text) [70].

Figure 24 shows the dependence of the frequency (wavelength) at maximum

of the long-wavelength absorption band on the size of the aromatic -system

(number of electrons) for neutral azides A1 - A6; for comparison, the calculated

spectra are matched with the known experimental spectra of the first members of

the series A1 - A3 (note that hereinafter the calculations are made for bare

molecule, while experimental spectra are measured in acetonitrile). It is seen that

the TD B3LYP/6-31G method substantially underestimates the energy of the S0

S1 transition (frequency of the long-wavelength absorption band maximum)

for the first member of the series A1 by 0.93 eV (7490 cm–1

) relative to the

experimental value and that the error for A3 decreases to 0.16 eV (1290 cm–1

).

The PM3-CI method on average better predicts the position of the band

maximum, underestimating Ev by 0.27 eV for A1 and overestimating it by 0.34 eV


281

for A3. As shown in the previous section, the ZINDO method, like TD B3LYP,

strongly underestimates the energy of the band for A3 (by 1.02 eV) but predicts Ev

for A1H+ accurate to within 0.10 eV.

An inspection of the theoretical and experimental plots (Figure 24) shows that

both calculation methods predict more gently sloping dependence of the long-

wavelength absorption band frequency on the size of the azide system as

compared with the experimental data. The experimental points for azidopyridine

A1, azidoquinoline A2, and azidoacridine A3 lie on the straight line described by

the equation (correlation factor r = 0.9992)

= (49420 – 1570n) cm–1

, (4)

where is the frequency of the azide long-wavelength absorption band and n is

the number of electrons of the azide aromatic system.

Figure 25 presents the dependence of the long-wavelength absorption band

maximum on the size of the system for protonated azides A1H+ - A6H

+. A

better agreement between the calculated and experimental data was observed for

the cations than for their neutral counterparts, especially in the case of the TD

B3LYP/6-31G* calculations (Figure 25, curves 1, 3); the standard deviation for

A1H+ - A3H

+ is 0.14 eV. The regression analysis treatment of the experimental

data leads to the equation (r = 0.9998)

= (46140 – 1620n) cm–1

(5)

A comparison of equations (4) and (5) shows that the extension of the cata-

condensed system by one benzene ring in both neutral and protonated azides leads

to a bathochromic shift of the band by 6400 cm–1

on average.

Providing that the linear relation between and n still holds for higher

members of the series A1 - A6 and A1H+ - A6H

+, it is possible to predict the long-

wavelength absorption band frequencies for these azides from equations (4) and

(5).

As mentioned above, quantum-chemical calculations predict that the size

threshold of photoactivity is 22 electrons and lies between A5 and A6; i.e.,

azides A1 - A5 are photoactive (have a photodissociation quantum yield of >

0.1) and azide A6 is photoinert ( < 0.01). For the protonated forms, the size

threshold is 18 electrons and lies between A4H+ and A5H

+; i.e., azides A1H

+ -

A4H+ are photoactive and azides A5H

+ and A6H

+ are photoinert.

Mikhayl F. Budyka

282

n (e)6 10 14 18 22 26

/10

3 c

m-1

40

30

20

10

/nm

300

400

500

600

700800900

32

5

1

4

Figure 25. Dependence of the frequency (wavelength ) at maximum of the azide long-

wavelength absorption band on the number of n in the aromatic system for

protonated azides A1H+ - A6H

+ according to calculations by the (1) B3LYP/6-31G8//PM3

and (2) PM3-CI methods and to (3) experimental data approximated by regression

analysis; (4) the size threshold of photoactivity and (5) the energy threshold of

photoactivity (see Figure 24) [70].

In Figures 24 and 25, the size boundary of photoactivity is marked by dashed

lines 4. The energy threshold of photoactivity, determined by the activation

energy of the N-N2 bond dissociation, is shown by dashed lines 5 in these figures.

From equation (4), we can calculate that the long-wavelength absorption band of

azide A5, which is expected to have a high quantum yield of photodissociation,

will lie at 14880 cm–1

(672 nm). This position is consistent with the value of

16040 cm–1

(623 nm) predicted for A5 by the B3LYP/6-31G* calculation; the

PM3-CI method predicts the band to lie at a shorter wavelength, 23810 cm–1

(420

nm). For azidobenzacridinium A4H+, which is likewise expected to have a high

photodissociation quantum yield, calculation according to equation (5) gives the

band maximum at 16980 cm–1

(589 nm). The B2LYP/6-31G* method predicts a

lower frequency 15230 cm–1

(657 nm) for A4H+, unlike the PM3-CI method

which gives a higher frequency 20930 cm–1

(478 nm). The long-wavelength

absorption band (La band) of unsubstituted benzacridinium chloride occurs at

17000 cm–1

(588 nm) [31].


283

In linear acenes, which are unsubstituted homoaromatic analogues of A1 - A6,

the two lower excited singlet states denoted as La and Lb (the same symbols are

used to denote the absorption bands corresponding to the transition into these

states) differ in nature. The La transition is associated with electron transfer from

the HOMO to the LUMO and is polarized along the short axis of the molecule.

The Lb transition is polarized along the long axis of the molecule and is attributed

to the HOMO-1 LUMO and HOMO LUMO+1 electron transfer. The S1

state is of the Lb-type for benzene and naphthalene and of the La-type for

anthracene and higher acenes [54]. For linear acenes from naphthalene to

octacene, the TD B3LYP method has been shown to predict accurately the energy

of the Lb state but underestimates the La energy, wherein the magnitude of error

increases with an increase in the size of the π system [55].

In the aza analogues of acenes: pyridine, quinoline, acridine, etc., the basic

features of acenes are retained, furthermore, the - * bands are complemented by

n- * bands, which overlap with the former because of their high intensity. The

spectra of azides of azaacenes additionally exhibit less intense n- * bands due to

the azido group. For the higher members of the A1H+ - A6H

+ series (Table 13),

like for higher acenes, the long-wavelength absorption band is classified as La

type and calculation underestimates the energy of this band (overestimates the

wavelength).

An analysis of the structure of transitions shows (Table 13) that the major

contribution to the long-wavelength absorption band of most azides is made by

electron transfer from HOMO to LUMO, which are orbitals localized primarily

on the aromatic rings in all of the test azides. The exceptions are azides A1 and

A2, in which LUMO+1 is involved in the transition, and the cation A1H+, in

which the transition involves the LUMO+2. These molecular orbitals in the latter

azides are NN* orbitals localized on the azido group. It is the NN*-MO whose

population in the S1 state is responsible for the photoactivity of the aromatic azide.

In other azides, the NN*-MO remains unoccupied during a vertical (Franck-

Condon) transition.

However, in the relaxed S1 state, the unpaired electron occupies the NN*-

MO in neutral azides A1 - A5 and cations A1H+ - A4H

+, whereas in the higher

analogues A6, A5H+, and A6H

+, the -molecular orbital is occupied in the relaxed

S1 state (see previous section).

Thus, the calculation of spectra by means of the TD B3LYP/6-31G* method,

as well as the regression analysis of experimental data, for the first members of

the series A1 - A3 and A1H+ - A3H

+ predicts that there can be photoactive

Mikhayl F. Budyka

284

heterocyclic azides (with > 0.1) whose long-wavelength absorption bands lie in

the region 580–670 nm. The calculation predicts the azides that absorb light at

longer wavelengths to be photoinert ( < 0.01).

5. PHOTOCHEMISTRY OF AZIDOSTYRYLQUINOLINES

The theoretical conclusion stating that for an azide to exhibit a photoactive

behavior in both the neutral and cationic forms the azide system should not

exceed 18 e was confirmed experimentally in relation to the azido derivatives of

isomeric 2- and 4-styrylquinolines [71,72,73,74,75]. The azidostyrylquinoline -

system includes exactly 18 electrons. Therefore the azido derivatives of

styrylquinolines, 2-(4'-azidostyryl)quinoline 2ASQ and 4-(4'-azidostyryl)quinoline

4ASQ, were studied.

N

N3

N

N3

2ASQ

4ASQ

Quantum-chemical calculations showed that in the S0 state in the neutral and

protonated azidostyrylquinolines both frontier molecular orbitals are -type MOs

localized on the aromatic system and the central double bond. As an example,

Figure 26 compares the diagram of the HOMO and LUMO, as well as the

neighboring unoccupied MOs for 4ASQ and its protonated cation 4ASQH+. The

NN*-MO (localized on the azide group and possessing the antibonding character

for the N-N2 bond) lies above the LUMO and is second after the LUMO for

4ASQ, i.e., LUMO + 2 (in 2ASQ, NN*-MO is LUMO + 3).


285

MO-acphaz

EMO/ eV

-9

-6

-3

0

—

—

—

—

—

——

—

—

—

||

||

|

|

|

|

—

——————

—

—

————

LUMO

= LUMO+2

HOMO

S1 S0 S0 S1

LSOMO

HSOMO

NN*

NN*

= LUMO+7

LSOMO

HSOMO

4ASQ 4ASQH+

HOMO

LUMO

Figure 26. Energy diagram for frontier and neighboring unoccupied MOs (up to NN*-

MO) for 4-(4'-azidostyryl)quinoline (4ASQ) and its cation 4ASQH+: in the S0 state, HOMO

is the highest occupied MO and LUMO is the lowest unoccupied MO; and in the S1 state,

LSOMO is the lowest and HSOMO is the highest singly occupied MO (calculation by the

PM3 method) [71].

The unoccupied -MOs localized on the aromatic system lie between the

LUMO and NN*-MO. In neutral azidostyrylquinoline the energy gap between

HOMO and LUMO is 7.44 eV and that between LUMO and NN*-MO is 0.95 eV

(PM3 calculation). Protonation lowers the levels of all MOs, with the energies of

virtual orbitals changing stronger relative to the occupied MOs (Figure 26). As a

result, the HOMO–LUMO energy gap drastically decreases to 5.65 eV and the

LUMO– NN*-MO gap increases to 3.29 eV for cation 4ASQH+. In cation

4ASQH+, the space between the LUMO and the NN*-MO is filled with

orbitals; therefore, the NN*-MO becomes already LUMO+7. The decrease in the

HOMO–LUMO gap corresponds to a bathochromic shift in the long-wavelength

absorption band, characteristic for heterocyclic cations in comparison with the

neutral heterocycles.

The ratio between the energy gaps (HOMO–LUMO) >> (LUMO– NN*-MO)

leads to the situation that the NN*-MO, not the aromatic

Mikhayl F. Budyka

286

is occupied in the relaxed S1 state of the neutral 4ASQ (Figure 26). The same type

NN*-MO, rather than LUMO, is occupied also in the relaxed S1 state of the

cation 4ASQH+. Thus, calculations suppose the azidostyrylquinolines to be

photoactive upon excitation into the S1 state in both neutral and cationic forms

[71].

These theoretic conclusions were completely confirmed experimentally. The

azidostyrylquinolines were synthesized and their photochemical properties were

investigated [72,73]. The absorption bands of these compounds in the neutral

form occur in the range of 300-400 nm. As an example, Figure 27 shows

spectrum of 2-(4'-azidostyryl)quinoline 2ASQ and spectral changes during its

photolysis.

The quantum yields of azidostyrylquinolines photodissociation were found to

be in the range of 0.7–0.9. Upon protonation, the absorption spectra of

azidostyrylquinolines were shifted bathochromically to the visible region of 400-

480 nm. As a result, the hydrochlorides of these compounds appeared to be

sensitive to the visible light: they retained high quantum yields of 0.7–0.9 upon

irradiation within long-wavelength absorption band [72].

300 400 5000.0

0.5

1.0

1.5

2.0

A

/ nm

7

1

Figure 27. Spectral changes during the photolysis of an air-saturated solution of 2-(4'-

azidostyryl)quinoline (2ASQ) in ethanol with 365-nm light, intensity 2.23.10

-9 Einstein cm

-

2 s

-1, photolysis time (1) 0, (2) 5, (3) 12, (4) 21, (5) 45, (6) 90, and (7) 300 s [72].


287

The study of the products of the 2- and 4-(4'-azidostyryl)quinolines photolysis

by the electrospray mass spectrometry showed that, as a result of the

photodissociation of the N-N2 bond, a set of products typical of the azide

photochemistry were formed: corresponding amines, nitroso, nitro, azo, hydrazo,

and azoxy compounds (the last three in insignificant amounts) [74]. In the azide

photolysis in the presence of HCl, the ratio of these products changed, and the

chlorine-containing compounds were formed in addition. There were some

products, which could not be identified by mass spectrometry. In addition, the

formation of unsubstituted styrylquinolines was also detected. This finding

indicated the photodissociation of the C-N3 bond, a process that is unconventional

in the photochemistry of aromatic azides.

N-Methylated 4-(4'-azidostyryl)quinoline AHC, which is a derivative of

hemicyanine dye, was investigated in more detail [76,77]. This azidodye

possesses strong absorption band in the visible region of spectrum, max ( , M-1

cm-1

) 417 nm (28900), tailing to 500 nm, and less intensive bands in UV region,

332 nm (6200) and 249 nm (19650), see Figure 28, spectrum 1.

CH3

N+

N3

AHC

I-

Upon irradiation within the long-wavelength absorption band,

azidohemicyanine AHC effectively decomposed. As an example, Figure 28 shows

the spectral changes upon irradiation of azide solution with visible light of 485 nm

in the absence of oxygen. The reaction was uniform within the initial period of

photolysis, which was demonstrated by isosbestic points at 354.1 and 472.5 nm

(curves 1 - 4 in Figure 28). At this time point in the reaction mixture there were

two main components, as it was shown by electrospray mass spectrometry: the

precursor azide whose peak with m/z = 287.105 was maximal in the spectrum

(100 %), and the related primary amine whose peak with m/z = 261.116 was 59 %

in intensity [76]. Based on this fact, the absorption band at 520 nm, which

appeared in the spectrum during irradiation (Figure 28), was definitely be

attributed to 1-methyl-4-(4'-aminostyryl)quinolinium iodide, which was

practically the only reaction product at the initial period of photolysis in degassed

solution.

Mikhayl F. Budyka

288

300 400 500 6000.0

0.5

1.0

1.5

2.0

A

/ nm

7

1

Figure 28. Spectral changes upon irradiation of 7.4.10

-5 M solution of azidohemicyanine

dye AHC in degassed EtOH with light of 485 nm, irradiation time, s: (1) - (7) - 0, 60, 120,

240, 480, 1380, 2900; light intensity 1.08.10

-9 Einstein cm

-2 s

-1 [76].

It is noteworthy here that electrospray ionization mass spectrometry (ESI MS)

is suitable for this case. To study reaction product structure, the preparative-scale

photolysis is ordinary used. However, in this case the azide concentration in the

solution is several orders of magnitude higher than that in the kinetic studies, and

the composition of the products of the aromatic azide photolysis can change

significantly with the change of the concentration [78]. ESI MS can analyze

reaction mixtures at the reagents concentration of ca ~ 10–5

M that enables direct

comparison with the data of kinetic absorption spectroscopy.

During further irradiation of AHC, isosbestic points disappeared thus

indicating the proceeding of secondary reactions. The following compounds were

identified in the final reaction mixture by electrospray mass spectrometry: the

primary amine, which remained the main reaction product (100%), corresponding

azo compound (62%), and hydrazo compound (8%). Upon photolysis in the

presence of oxygen, the ratio of amine, azo compound and hydrazo compound did

not practically change (100, 62 and 8%, respectively), but additional oxygenated

products were formed: corresponding nitroso (9%), nitro (4%), and azoxy (6%)

compounds. All identified products formation was explained by the reactions of

triplet nitrene shown in Scheme 5 [77].


289

QuSt N N+

StQu

O

QuSt N N StQu

QuSt NOO

QuSt NHOHN+

CH3I-

-N2

h

QuSt :

EtOH

O2

1(QuSt-N) 3(QuSt-N)QuSt-N3QuSt-NH2

QuSt-NO + QuSt-NO2

QuSt-NO

EtOH, O2

QuSt-NH-NH-StQu

QuSt-NH. EtOH

Scheme 5. Photolysis of 1-methyl-4-(4'-azidostyryl)quinolinium iodide (azido

hemicyanine AHC).

The relatively low quantity of nitroso and nitro compounds is noteworthy.

The charged nitrene, generated from azido dye, appears to be less reactive towards

oxygen, as compared to a neutral analogue, since comparative photolysis of

neutral 4-(4-azidostyryl)quinoline under the same conditions resulted in the final

reaction mixture contained much more nitroso (60%) and nitro (40%) compounds.

The transient photolysis products, corresponding triplet nitrene, were detected

in the low-temperature photolysis of azidodye AHC [75]. It has g = 2.0023, |D/hc|

= 0.781 cm–1

, and |E/hc| = 0 in the ESR spectrum, and intense absorption band in

the visible region with maxima at 420 and 440 nm. The parameters for charged

nitrene from azidodye AHC were compared with those for neutral triplet nitrene

from azidostyrylquinoline 4ASQ having the same -electron system and differing

only by the charge. The comparison showed that the introduction of the positive

charge into the nitrene molecule led to the bathochromic shift of the long-

wavelength absorption band by ~ 40 nm in the absorption spectrum and to a

decrease in the parameter D by 0.005 cm–1

in the ESR spectrum. Both effects are

associated with the transfer of the electronic (spin) density from the nitrene atom

to the aromatic system of styrylquinoline cation.

The quantum yield of azidodye AHC decomposition upon irradiation within

the long-wavelength absorption band was independent of excitation wavelength

(365 - 485 nm) and dissolved oxygen, as follows from Table 14.

Mikhayl F. Budyka

290

Table 14. Photodissociation quantum yields ( ) for 1-methyl-4-(4-

azidostyryl)quinolinium iodide (AHC) in EtOH [76]

ex, nm 365 365 479 485 485

0.80 0.86a 0.89 0.85 0.80a a Degassed solution.

According to these data, 1-methyl-4-(4'-azidostyryl)quinolinium iodide (azido

hemicyanine AHC) has the longest-wavelength light sensitivity among all known

aromatic azides: on irradiation at 485 nm, the quantum yield of its

photodissociation is 0.85.

6. SIZE AND CHARGE EFFECTS IN

HETEROCYCLIC AZIDE PHOTOCHEMISTRY

Thus, from the study of the regularities of the heteroaromatic azides

photodissociation, it was shown that the photochemical activity of an azide

depends on the filling of the NN*-MO in the excited S1-state, and this, in turn,

depends on the size and charge of the conjugated system of the azide molecule.

Table 15 collects the photodissociation quantum yields of heteroaromatic azides

with different (in size) -systems in the neutral and cationic forms.

Table 15. Photodissociation quantum yields of heteroaromatic azides in the

neutral ( 0) and cationic ( +) forms

Azide 0 +

A1 0.83 0.22

A2 0.49 0.37

A3 0.96 0.95

2ASQ 0.73 0.82

4ASQ 0.79 0.69

APA 0.88 2.3.10-3


291

Table 16. The size and charge effects in the photochemistry of

heteroaromatic azides (n is the number of electrons in the aromatic system,

0 and + are the photodissociation quantum yields of azide photodissociation

in the neutral and cationic forms, respectively)

n Charge effect Quantum yield

0 + relation of 0 and +

6 weak >0.1 >0.1 0 > +

14 none >0.1 <0.1 0 ≈ +

20 strong >0.1 <0.01 0 >> +

≥ 26 none <0.01 <0.01 0 ≈ +

One can see, that change in photodissociation quantum yield upon insertion of

positive charge (charge effect) depends on the size of heterocyclic azide -

system, and vice versa, change in photodissociation quantum yield upon increase

in size of the azide -system (size effect) depends on the charge of the azide

molecule. Thus, the size and charge effects are interdependent.

To generalize the observed effects, we can select four regions for relation

between photoactivities of neutral and charged azides in dependence on the

number of electrons in the conjugated system (Table 16).

(1) Azides with small size of the system (6 e) are photoactive ( > 0.1) in

both neutral and charged forms, but in the charged form the quantum

yield slightly decreases. This is the range of the weak charge effect.

(2) Azides with middle size of the system (~ 14 e) are also photoactive in

both forms, but the photodissociation quantum yield does not change in

the charged form. This is the range of the absence of the charge effect

with the large quantum yields ( > 0.1) in both forms.

(3) Azides with large size of the system (~ 20 e) are photoactive in the

neutral form ( > 0.1), but lose the activity on passing into the charged

form ( < 0.01). This is the range of the strong charge effect.

(4) Azides with the size of the system larger than 26 e are photostable in

both neutral and charged forms. This is the range of the absence of the

charge effect, but unlike the second range, here azides in both forms have

low quantum yields ( < 0.01).

Mikhayl F. Budyka

292

In the first region (6 electrons), a moderate decrease of the quantum yield on

passing from the neutral azide to cation is explained by an increase in the

activation energy for azide dissociation in the S1 state of the cation. Since a

substantial positive charge is concentrated on two terminal nitrogen atoms of the

azido group in the ground states of all azides, while dissociation gives rise to a

neutral nitrogen molecule, the electron density transfer from the aromatic nucleus

to the leaving N2 molecule should be a necessary step of the N-N2 bond

dissociation. In cationic azide, the positive charge of the aromatic ring creates the

charge barrier (Coulomb barrier) for the transfer of electron density and hinders

the dissociation. This effect appears in azidopyridine and in less extent in

azidoquinoline which is an intermediate case between azidopyridine and

azidoacridine.

In the second region (14 electrons), increased -electron cloud of the

heteroaromatic nucleus shields the positive charge of the cationic azide, and the

quantum yield remains the same on passing from the neutral azide to cation. This

effect appears in azidoacridine. It is noteworthy that invariability of the value

can testify indirectly to invariability of the rate constants of photophysical

processes (emission, internal conversion, and intersystem crossing, see formula 1)

on going from the neutral to cationic azide.

In the third region (20 electrons), the quantum yield does change drastically

on passing from the neutral azide to cation, since in cationic form the NN*-MO

ceases to be filled in the S1 state. This effect appears in azidophenylacridine.

At last, in the fourth region (26 electrons and more), the quantum yield is low

for both the neutral and cationic azide, since in these both forms the NN*-MO

remains empty in the S1 state. There are no examples of the neutral azides with -

system of such size, but all known photoinert azidodyes are cations with large

systems.

The results of theoretical and experimental studies of heteroaromatic azides of

different structure and photoactivity can be generalized using the views of the

orbital nature of the electron excited states. The orbital nature is determined by the

type of MO that participates in electron transitions [79,80], and quantum yield of

a photochemical reaction depends on the relative positions of the terms (potential

energy curves).

The pattern of terms of the ground and locally excited states for photoactive

and photoinert azides vs. the N-N2 bond length is represented in Figure 29. In

azides, one can distinguish an 'aromatic' locally excited state in which the

aromatic MQ is populated, this corresponds to the S *- term, and an 'azidic'


293

locally excited state in which the NN*-MO is populated, this corresponds to the

S *-term. The results of studies suggest the presence of a small (<1 kcal mol-1

)

potential barrier (not shown in Figure 29) for the term S * at a 1.6 - 1.7 Å

distance between the nitrogen atoms.

Evaluation of the barrier height can be made as follows [8]. Measurement of

the rate constant for azido group dissociation in the S1 state (kr in equation 1) by

laser flash photolysis for most azides give values varied in the range of 1012

-1013

s-1

[8]. Taking the pre-exponential factor in the Arrhenius equation for the rate

constant for the spin-allowed process to be ~ I013

s-1

, we get an estimate for the

activation energy of dissociation of the azido group in the excited singlet state

(photoactive azides): Ea < 4 kcal mol-1

(at 293 K). Since the quantum yield of

photodissociation remains high at low temperature, the upper limit of the

activation energy decreases to Ea < 1 kcal mol-1

(at 77 K).

Ab initio quantum chemical calculations give the following Ea values for

azide dissociation in the S1 state: 0.2 kcal mol-1

for HN3 (CASSCF(8,7)/cc-pVDZ

method with inclusion of zero-point vibration energy) [81], 7-9 kcal mol-1

(upper

limit) for 2- and 4-biphenylyl azides, 2 and 5 kcal mol-1

for 1- and 2-naphthyl

azides, respectively (RI-CC2/TZVP method) [82,83].

To make the picture more comprehensive, Figure 29 shows also the position

of the T -term, which is populated in the sensitized photolysis of azides. The

ground state of an azide, like that of most molecules, is a singlet state with a

closed electron shell. The ground state of nitrene is triplet, and the lower singlet

state of nitrene has an open electronic configuration; therefore, these terms

intersect. The relative energies of different states of nitrene determine the

positions of asymptotes in Figure 29. For the simplest nitrene HN, the lower

singlet state (a ) and the excited singlet state (b1 +

) are higher in energy than the

ground triplet state (X3 -

) by 36.0 and 60.7 kcal mol-1

, respectively [5]. According

to CASSCF(8,7)/cc-pVDZ results [81] the calculated intersection point of the T1-

and S0-terms is 40.6 kcal mol-1

higher in energy than the ground state minimum of

HN3, which corresponds to the experimental activation energy for thermal

dissociation. According to data on the kinetics of thermal dissociation of HN3, the

probability of spin-forbidden singlet-triplet transition is 10-3

- 10-2

[84].

In aromatic nitrenes, the energy gaps are considerably narrowed. In PhN, the

singlet-triplet splitting between the ground triplet state (3A2) and the lowest singlet

suite (1A2) is ~ 18 kcal mol

-1, while the excited singlet state (

1A1) is ~ 12 kcal mol

-

1 higher in energy [5]. The RI-CC2/TZVP calculations of the potential energy

surface of 1-azidonaphthalene and biphenylyl azides have shown that the S0- and

S1-terms intersect when the dissociation reaction coordinate (the distance between

Mikhayl F. Budyka

294

the nitrogen atoms) is at ~ 1.7 Å [83]. The authors [83] suggest that the

intersection of these terms may be a pathway to deactivation of azides from the

excited to the ground state.

Th

S

S

S0

E

rN-N

T

x

h

S

S

S0

E

rN-N

Figure 29. Potential energy curves of the ground (S0) and locally excited (S * and S *)

states of photoactive (above) and photoinert (below) azides vs. the N-N2 bond length [8].


295

The position of the * terms is determined by the azido group (or nitrene in

the asymptote), which has similar structure in all azides depending slightly on the

azide structure as a whole. Conversely, the position of the term S * is dictated by

the aromatic system of the azide. The relative arrangement of the terms S0-,

S * and S * determines the spectral and photochemical properties of azides.

The pattern of terms of photoactive azides with small system is presented in

Figure 29 (above). The lower excited singlet (S1) state has the S * nature. Upon

irradiation at long-wavelength absorption band, the Franck-Condon transition

corresponds mainly to the *excitation (see detail discussion above on the

example of 9-azidoacridine). However, the system relaxes rapidly (within

hundreds of femtoseconds) to the S * state, which is followed by N-N2 bond

dissociation at a rate constant of ~ 1012

- 1013

s-1

. The quantum yield of the azido

group photodissociation is high (0.1 - 1.0).

As the size of the aromatic system increases or a positive charge is

introduced, the S * term markedly decreases, and the S1 state acquires the *

character, this is shown in Figure 29 (below); the azide becomes photoinert. In

photoinert azides, excitation at long-wavelength absorption band brings the

system to the potential well of the S * state, which is deactivated through

radiative and non-radiative processes. The rate constant for the N-N2 bond

dissociation decreases by 5-6 orders of magnitude; as a result, the quantum yield

of the azido group photodissociation also decreases (to < 0.01).

7. LOW-TEMPERATURE PHOTOLYSIS OF

HETEROAROMATIC AZIDES. HIGH-SPIN NITRENES

Low-temperature (matrix) photolysis (and also laser flash photolysis),

combined with high-level quantum-chemical calculations, are powerful tools for

investigation of reaction mechanisms. A lot of information has been obtained by

this method relative to the structure and further thermal and photochemical

transformations of arylnitrenes, primary products of arylazides, their rearranged

intermediates (azacycloheptatetraenes). Some recent results on photolysis of

azidopyridines and related heterocyclic azides at cryogenic temperatures are

discussed below.

Photolysis of Ar matrix isolated trifluoromethyl-substituted 2-pyridyl

azides/tetrazolo[1,5-a]pyridines at 12-18 K caused rapid and mostly clean

Mikhayl F. Budyka

296

conversion to the corresponding 1,3-diazacyclohepta-1,2,4,6-tetraenes (cyclic

carbodiimides) absorbing near 2000 cm-1

in the IR [10]. The assignment was

based on comparison with B3LYP/6-31G* calculations, which reproduces the

experimental spectra extremely well. In some cases, the intermediate 2-

pyridylnitrenes were observed by both ESR (|D/hc| ~ 1.05-1.10 cm-1

, |E/hc| ~ 0.0

cm-1

) and IR spectroscopy ( ~ 1250 cm-1

) and converted to the

diazacycloheptatetraenes upon prolonged UV irradiation. Irradiation of the Ar

matrix isolated mixtures of nitrenes and diazacycloheptatetraenes also caused

development of weak carbene transitions (|D/hc| ~ 0.40-0.45, |E/hc| ~ 0.006 cm-1

)

in the ESR spectra.

N N3

N NN

N

R RRh

..

Photolysis (254 nm) of 2-azidopyrimidine in glassy ethanol at 77 K produced

triplet 2-pyrimidylnitrene observed by ESR (|D/hc| = 1.15 cm-1

) and UV-VIS

spectroscopy (broad absorption band between 300 and 400 nm and a highly

structured band between 400 and 450 nm) [85]. A more highly resolved but

similar spectrum was observed by photolysis of azidopyrimidine in argon at 14 K.

Upon continued exposure to light, spectrum of nitrene disappeared and a new

band appeared at 2045 cm-1

, which was assigned to carbodiimide; concurrently

formed broad UV band with max = 350 nm was also attributed to this species. The

experimentally observed IR spectra of different compounds were consistent with

the spectra predicted by B3LYP/6-31G*. Laser flash photolysis of

azidopyrimidine in dichloromethane at ambient temperature produced triplet

nitrene with its characteristic structured absorption between 400 and 450 nm. The

triplet nitrene was formed in an exponential process (kobs = 8.10

7 s

-1, ~ 13 ns,

max = 429 nm) following the laser flash. The transient absorption observed at 455

nm decayed with the same time constant and was attributed to singlet 2-

pyrimidylnitrene. Cyclization of the latter to the 1H-benzodiazirine was not

observed, and the hypothetical process was at least 13 times slower than that of

singlet phenylnitrene to a benzazirine at ambient temperature, at the same time,

the rate constant of intersystem crossing was more than 200 times faster than that

of parent singlet phenylnitrene. Triplet 2-pyrimidylnitrene decayed over tens of

microseconds in a second order process, presumably to form the azo dimer, and

reacted with molecular oxygen.


297

N N

N3

N

N N

N N

N

N N

N

N N

N

h

1 3

Argon matrix photolysis of 2-azidoquinazoline (or its tetrazole isomer)

afforded 2-quinazolylnitrene, which was characterized by ESR (|D/hc| = 1.1465

cm-1

, |E/hc| = 0.0064 cm-1

), UV-vis ( max = 358, 425 and 529 nm), and IR

spectroscopy (comparison with calculated B3LYP/6-31G** spectrum in the

region of 500 - 1200 cm-1

) [11]. The nitrene and/or its ring expansion products

underwent diradicaloid ring opening. The possible diazirene was not observed,

formation of a trace of the ring-expanded carbodiimide 1,3,4-

triazabenzo[e]cycloheptatetraene was assumed on the basis of a very small peak

in IR spectrum (observed value 1990 cm-1

, calculated value 1994 cm-1

, very

strong). The diradical was characterized by ESR spectroscopy (|D/hc| = 0.1187

cm-1

, |E/hc| = 0.0026 cm-1

), it decayed thermally at 15 K with a half-life of ca. 47

min, in agreement with its calculated facile intersystem crossing to the singlet

state followed by facile cyclization/rearrangement to 1-cyanoindazole (calculated

activation barrier 1-2 kcal/mol) and N-cyanoanthranilonitrile, which were the

isolated end products of photolysis.

N

N N3

N

N N

NN

N

N

CN N

H

N

N

H

CNNH

CN

CN

N

NN

h

. .

.

.+

2-Azido-4,6-dichloro-s-triazine, matrix-isolated in Ar at 10 K, yielded triplet

nitrene ( max = 330 and 356 nm and broad band 380 - 490 nm; max = 1467.6,

1446.4 and 1254.5 cm-1

) and the cyclic carbodiimide - 1,3,4,6-tetraazacyclohepta-

Mikhayl F. Budyka

298

1,2,4,6-tetraene ( max = 328 and 352 nm, max = 1957.0, 1951.2 and 1050.0 cm-1

)

upon photolysis [86].

N

N

N

N3

Cl Cl

N

N

N

N

Cl Cl Cl

N N

N

N

Clh+

Ar, 10K

..

The stability to the photochemical rearrangements with the triazine cycle

expansion in the triplet nitreno-1,3,5-triazines increased with an increase in the D-

parameter of splitting in zero field found from the ESR spectra, which, in its turn,

correlated with the spin density N on the nitrene center calculated quantum-

chemically [87]. Triplet nitrenes with |D/hc| > 1.40 cm-1

and N > 1.77

(UB3LYP/6-31G*) were photochemically very stable and did not rearrange into

carbodiimides.

As compared with triplet pyridylnitrenes and pyrimidylnitrenes, triplet

nitreno-s-triazines have the highest zero-field splitting parameters. The high D-

value was explained by the effect of heterocyclic nitrogen atoms, which were poor

spin-holding centers due to a small size. The more nitrogen atoms in a

heterocyclic ring, the higher the D-values of triplet heteroarylnitrene. The high E-

values of triplet nitreno-s-triazines were assumed to indicate the non-degeneracy

of two magnetic orbitals of these species [88].

In contrast to nonhalogenated 4-pyridylnitrene, tetrafluoro- and tetrachloro-4-

pyridylnitrenes, formed on matrix photolysis of the corresponding azides, were

found to be highly photostable in low-temperature matrices, there was no

evidence for the formation of an azirine or ketenimine [89,90]. It is interesting to

note that on extensive photolysis of tetrachloro-4-pyridylnitrene in the Ar matrix,

the starting azide was slowly regenerated in the course of photolysis at 444 nm for

12 h. This can be explained by trapping of the nitrene by molecular nitrogen.

A number of 2,4- and 2,6-diazidopyridine derivatives were photolyzed under

frozen matrix conditions and, typically, both mononitrene and dinitrene spectral

features were observed [91,92,93,94]. In substituted 2,6-diazidopyridines, the

yield of quintet dinitrene decreased upon gradual displacement of the chlorine

molecule by the cyano group, because intermediate triplet nitrenes underwent the

pyridine cycle transformation [91].

This effect was accounted for by the fact that the chlorine atoms on the ortho-

position increased the stability of the pyridine ring to photoisomerization, as was

shown by the example of the triplet perchloro-substituted pyridyl-4-nitrene [90].


299

N

X

NN.. . .

R1 R2

N

X

N3

N3

R1 R2

N

X

NN3

. .

R1 R2

h h

R1, R2 = Cl, CN

The 2,6-dinitrenes were found to have consistently larger zero-field splitting

(zfs) than the related 2,4-dinitrenes. The 2,4-dinitrenes were estimated to have zfs

of |D/hc| ~ 0.21-0.24 cm-1

and |E/hc| ~ 0.03-0.04 cm-1

, and the 2,6-dinitrenes to

have zfs of |D/hc| ~ 0.24-0.27 cm-1

and |E/hc| ~ 0.04-0.05 cm-1

. The difference in

spectral behavior was attributed to perturbation of spin density distributions and

geometry-influenced interactions between the nitrene units in the 2,4- vs the 2,6-

connectivities [92]. Large ratio of |E/D| for 2,6-dinitrenopyridines was consistent

with a dominating dipolar interaction between the two nitrene units having a

relative interaction vector angle of about 114°–116° [93].

The stabilizing effect of the chlorine atoms manifested itself also in the

photolysis of 2,4,6-triazido-3,5-dichloropyridine TAP (methyltetrahydrofuran, 77

K), when one managed to successively observe and characterize mono-, di-, and

trinitrene (dicyano derivative failed to produce high-spin nitrenes) [89, 95, 96]. It

was found that, with an increase in the multiplicity (the number of the nitrene

centers), the absorption spectrum shifts bathochromically, and the D-parameter of

splitting in zero field decreases (Table 17).

N

N3

N3

N3

ClCl

N

N3

NN3

ClCl

N

N3

NN

ClCl

N

N

NN

ClCl

. . . . . . . . . .

. .

h h h

TAP

Table 17. The properties of nitrenes, the products of the successive photolysis

of 2,4,6-triazido-3,5-dichloropyridine (methyltetrahydrofuran, 77 K) [95, 96]

Product Multiplicity , nm |D/hc|, cm-1 |E/hc|, cm-1

Nitrene Triplet 499, 527 0.955 0.000

Dinitrene Quintet 576, 620 0.283 0.036

Trinitrene Septet 709 0.100 0.0005

Mikhayl F. Budyka

300

In contrast to TAP, where predominantly one mono- and one di-nitrene was

formed as a result of selective decomposition of the -azido groups, its fluorine

analogue, 2,4,6-triazido-3,5-difluoropyridine, produced a full set of possible

nitrenes upon photolysis in solid argon at 4 K [44]. High-resolution ESR spectra

of all nitrenes were obtained, the fine-structure parameters of the nitrenes were

determined with high accuracy from computer spectral simulations. The septet

trinitrene (|D/hc| = 0.1018 cm-1

, |E/hc| = 0.0037 cm-1

) was the final photoproduct

and was very stable in argon matrices toward further irradiation, no low-spin

products were observed upon prolonged irradiation with light at λ > 305 nm.

N

N3

N3

F F

N3

N

N3

N

F F

N3 N

N3

NN

FF

N

N

NN

FF

N

N

N3

F F

N3 N

N

N

F F

N3

. . . . . . . . . .

. .

h h

. .

h

.

h

.

. .

Cyanuric triazide, 2,4,6-triazido-1,3,5-triazine, theoretically also has

possibility of trinitrene formation, however, in earlier powder and single-crystal

studies, generation of a septet trinitrene was not confirmed [97]. Probably, the

oligonitrene species generated were surrounded by the unreacted precursor or by

partially reacted nitrenes, and even at low temperatures, reactions between these

species could not be excluded completely. The matrix-isolation technique using

inert media such as noble gases or nitrogen allows the study of such reactive

species by excluding intermolecular reactions completely. Really, upon matrix

photolysis of triazidotriazine, the stepwise generation of the corresponding

mononitrene, dinitrene, and trinitrene was observed by IR and ESR spectroscopy.

The generated species were identified by comparison of their matrix IR spectra

with B3LYP/6-31G* computational results and by computer simulation of the

EPR spectra [98,99].


301

N

N

N

N3

N3

N3

N

N

N

N3

NN3

N

N

N

N3

NN

N

N

N

N

NN

. . . . . .

. . . .

..

h h h

hh3NCN

Generated on the first stage mononitrene could rearrange into a cyclic

carbodiimide, but observation of only a weak IR band at around 1900 cm-1

indicated that the rearrangement was a minor process in this case [99]. The final

trinitrene readily decomposed into three NCN molecules upon further

photoirradiation. The triplet NCN was identified by ESR spectrum (|D/hc| = 1.545

cm-1

, |E/hc| = 0.000 cm-1

, as determined by simulation), IR band at around 1475

cm-1

, and UV/Vis absorption bands: one intense peak at 329 nm accompanied by

vibronic bands at 290- 300 nm. Experimental IR frequencies, UV-vis absorption

bands, and ESR fine-structure parameters of mono-, di and tri-nitrenes formed

from triazidotriazine are collected in Table 18.

Recently, new information on zero-field splitting parameters and geometric

structure of some pyridyl quintet dinitrenes and septet trinitrenes was obtained

upon reinvestigation of these species by matrix isolation spectroscopy

[43,44,100,101]. Due to their photochemical stability, high-spin pyridylnitrenes

are suitable models for exploration of organic molecular magnetism and spin

chemistry. The study of the high spin polynitrenes, the products of polyazide

photolysis, is in progress because of the possibility of producing new organic

functionality magnetic materials based on them.

Table 18. The properties of nitrenes, the products of the stepwise single-

crystal and matrix photolysis of 2,4,6-triazido-1,3,5-triazine [97, 99]

Product Multiplicity , cm-1 , nm |D/hc|, cm-1 |E/hc|, cm-1

Nitrene Triplet 1339 344 1.461 0.005

Dinitrene Quintet 1438 377 0.280 0.058

Trinitrene Septet 763, 1326 - 0.123 0.000

Mikhayl F. Budyka

302

8. PHOTOAFFINITY LABELING

If organic magnets are as yet only models for possible future application,

photoaffinity labeling is already widely used for investigation of

biomacromolecules. In combination with modern techniques of instrumental

analysis and computer-aided modeling, photoaffinity labeling is one of the most

important approaches in studies on the organization of biological systems [102].

Heterocycles are building blocks of nucleic acids, and proteins and active

components of many medicaments. Thus, it is not surprising that heterocyclic

azides are studied and used as photoaffinity labeling reagents. Important in this

respect is the possibility of the short-lived singlet nitrene obtained upon photolysis

of azide to react indiscriminately with residues of the macromolecular target

present in the binding site of biomacromolecule. Below there are several examples

of heterocyclic azides which were used as photoaffinity labels.

9-Azidoacridine was used as photoaffinity label for nucleotide- and aromatic-

binding sites in proteins [56,57]. The photochemistry of this azide was discussed

in detail above. A radiolabeled [3H]7-azido-4-isopropylacridone upon irradiation

specifically labeled (bound covalently to) Cys159 of the bovine mitochondrial

ADP/ATP-carrier protein [103].

NH

O

CH(CH3)2

N3

Photoaffinity labeling with 2-azidoadenosine 5'-triphosphate was used for

identification of amino acid residues at nucleotide-binding sites of chaperonin

GroEL/GroES complex (it plays an essential role in the folding, assembly and

protection of cellular proteins) [104]. 8-Azidoadenosine and derivatives are used

in photoaffinity labeling and in cross-linking studies [105,106,107,108]. To

understand the processes by which reactive intermediates derived from 8-

azidoadenosine bind to and react with targeted proteins and nucleic acids, these

species were studied by chemical trapping studies, laser flash photolysis with UV-

vis and IR detection and modern computational chemistry [109].


303

N

N

NH2

N

N

R

N3

O

OHOH

OH

R: H, CH3, PhCH2,

Upon photolysis in water or buffer, 8-azidoadenosine released the

corresponding singlet nitrene which underwent a hydrogen shift to form closed

azaquinodimethane in less than 400 fs, faster then it could relax to a triplet nitrene

or react with a biological target molecule. The azaquinodimethane had a lifetime

of several minutes in the absence of good nucleophiles, and was the species which

forms adducts in cross-linking and photoaffinity labeling experiments via

selective reactions with nucleophiles such as amines, thiols, and phenolate ions.

Because of the selective reactivity of this closed diazaquinodimethane, it may

obviously wander from its original binding site and become attached to a

nucleophilic residue at a remote site. The conclusion was made that results of

cross-linking experiments using 8-azidoadenosine and its derivatives should be

viewed with caution [109].

Azidoatrazine ([14

C]-2-azido-4-ethylamino-6-isopropylamino-s-triazine), a

derivative of herbicide atrazine which binds to the secondary plastoquinone

electron-acceptor site of photosystem 2 (PS2), was used for photoaffinity labeling

followed by sequence analysis of peptides derived by proteolysis of the PS2

centers [110].

NN

N NH

N3

NH

Analogue of deoxycytidine triphosphate, exo-N-{2-[N-(4-azido-2,5-difluoro-

3-chloropyridine-6-yl)-3-amino-propionyl]aminoethyl}-2'-deoxycytidine-5'-

triphosphate which has 4-azidopyridine as a photoactive site, was applied for

photoaffinity modification of DNA binding proteins [111].

Mikhayl F. Budyka

304

N

N3

F

F Cl

O

OH

N

N

O OP O P P O

O

NHNH

O

NH

O

O

O

O

O

O

4Li+

Another azidopyridine derivative, 1-(2-azido-6-chloropyrid-4-yl)-3-

phenylurea was used as photoaffinity labeling reagent for cytokinin-binding

proteins [112]. In the absence of the 6-chloro substituent, the tetrazole form was

the only existing tautomer. The corresponding compound did not exhibit

cytokinin activity and was not photolysable.

N

NH-CO-NH-Ph

N3

Cl

7-Azido-1-ethyl-3-carboxylate-6,8-difluoroquinolone was proposed for

photoaffinity labeling [113]. Photolysis of this azide with diethyl amine gave 7-

hydrazino-derivative as the major product. This compound was generated by

singlet nitrene N-H insertion. In addition, 7-amino-1-ethyl-3-carboxylate-6,8-

difluoroquinolone was also obtained.

N

O

N3

F

F C2H

5

COOH

As mentioned above, most azides used at present are sensitive to hard UV

radiation (250-320 nm). At the same time, in the photoaffinity modifications of

biomacromolecules it is desirable to expose the system under study to soft long-

wavelength UV radiation (350 - 400 nm) or to visible light (which is better) in

order to prevent the photodestruction of the biological material [114,115]. To this

end, the azide should have an absorption band in the specified spectral region and


305

decompose with high quantum yield upon irradiation with light in this spectral

region.

There are a few azido dyes sensitive to short-wavelength visible light. For

instance, 9-azidoacridinium has a long-wavelength absorption band in the region

400 - 470 nm and decomposes with a quantum yield of 0.7 - 1.0 upon irradiation

within the band region [50]. However, this compound is readily hydrolyzed with

the formation of acridone in the presence of trace amounts of water, that makes

practical application of 9-azidoacridinium difficult.

Ethidium azide, 3(8)-amino-8(3)-azido-5-ethyl-6-phenyl phenanthridinium,

when photolyzed with visible light was found to bind effectively to the DNA of

intact lymphocytes since photolysis provoked repair synthesis in these cell

suspensions [116]. It attached covalently to calf thymus DNA by photoaffinity

labeling and was used to generate antibodies for the drug analog [117]. 3-

Aminopropionyl derivatives of ethidium azide were established to have high

photodissociation quantum yields of 0.6-0.9 on irradiation with visible light at

wavelength up to 436 nm [118]. Dissolved oxygen did not affect the quantum

yield but changed the structure of the final photolysis products. The derivatives

were used for oligonucleotide photomodification [118].

N+

NH

O

NH

CF3

O

N3

N+

NH

O

NH

CF3

O

N3

CF3COO-CF3COO-

Azido hemicyanine AHC, a derivative of azidostyrylquinoline, has long-

wavelength absorption band in the visible range tailing to 500 nm and high

photodissociation quantum yield on irradiation within this band, and can be

potentially used for photoaffinity labeling [77]. Especially promising in this

respect can be fluorine-substituted in benzene ring derivatives due to property of

ortho-fluorine atoms to stabilize singlet nitrene that promotes insertion of the label

to target biomacromolecule [119,120].

Mikhayl F. Budyka

306

CONCLUSION

Thus, heteroaromatic azides proved to be convenient objects for studying

general structure-reactivity relationship in aromatic azide photochemistry. On the

example of the series of cata-condensed heteroaromatic azides from azidopyridine

to azidoazahexacene (the size of aromatic -system from 6 to 26 e), the size and

charge effects, that is, the dependence of photodissociation quantum yield on the

size of the azide -system and its charge, were investigated both quantum-

chemically and experimentally. These effects are interrelated: the size effect

depends on the charge of the azide molecule and vice versa, the charge effect

depends on the size of the azide -system.

The existence of the size boundary of azide photosensitivity was predicted

and substantiated. The threshold size is calculated to be 22 and 18 electrons for

the neutral and positively charged azides, respectively. Under this size, the

antibonding NN*-MO, which is localized on the azido group and is empty in the

ground (S0) state, is filled in the excited S1 state of the azide, and the azide is

photoactive ( > 0.1). After this size, aromatic -MO is filled instead of the

NN*-MO in the S1 state of the azide, and the azide becomes photoinert ( drops

below 0.01).

Theoretical basis was also found for experimentally observed interrelation

between azide photoactivity (photodissociation quantum yield) and spectral

sensitivity: both these properties are determined by the structure and energy

characteristics of the frontier molecular orbitals. At the same time, the problem of

relative reactivity of different azido groups in polyazidopyridines is not yet solved

because of scarce data on the selective photolysis of these azides.

Heterocycles are widespread in nature, and so heterocyclic azides are widely

used as photoaffinity labels for exploration of nucleic acids and proteins. A

progress should be also noted in the use of polyazides for photochemical

production of polynitrenes, high-spin model systems for investigation of

molecular magnetism. Application of polynitrenes as molecular magnets in

molecular electronics is promising but questionable; the future will show a

practicability of this approach.


307

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Chapter 12

PROGRESS IN THE CHEMISTRY OF

CONDENSED THIAZOLOPYRIMIDINES

M.A. Metwally*a and Bakr F. Abdel-Wahab

b

a Chemistry Department, Faculty of Science, University of Mansoura,

Mansoura, Egypt b Applied Organic Chemistry Department,

National Research Center, Dokki, Giza, Egypt

This article covers the methods for preparing different

thiazolopyrimidines, also includes their reactions in the last six years, some

of which have been applied to the synthesis of biologically important

compounds. The title compounds are subdivided into groups according to the

position of fusion between thiazole and pyrimidine rings.

Keywords: Thiazolopyrimidines; Pyrimidine-2-thiones; Aminothiazoles; Thiourea

1. INTRODUCTION

Thiazolopyrimidines and their analogues have been in the centre of attention

of researchers over many years due to the high practical value of these

* Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box23, Mansoura,

Egypt email [email protected]

mailto:[email protected]

M.A. Metwally and Bakr F. Abdel-Wahab

318

compounds. In the fist place, the unusually broad spectrum of biological activities.

Thiazolopyrimidine derivatives are the bioisosteric analogues of purines and are

potentially bioactive molecules. Many derivatives with different substitution

patterns display interesting pharmacological activities, such as, antiviral activity

against human cytomegalovirus (HCMV) [1], anticancer activity against 60

human tumor cell lines [2], and antipsychotic activity by antagonizing the activity

of the corticotrophin releasing factor [3]. In addition, dual antimicrobial and anti-

inflammatory activity comparable to ampicillin and indomethacin in vivo with no

or minimal ulcerogenic effects [4]. Two comprehensive reviews on thiazolo[3,2-

a]pyrimidines have appeared the later of these covers the literature up to 2002 [5,

6]. The main purpose of this review is to present a survey of the literature of

thiazolopyrimidines from 2003 to 2008; some of the commercial applications of

thiazolopyrimidine derivatives are mentioned.

2. METHODS OF SYNTHESIS AND REACTIONS

2. 1. Bridgehead Nitrogen Thiazolopyrimidines

Bridgedhead thiazolo[3,2-a]pyrimidines, and their isosteres occupy a unique

place in medicinal chemistry due to their wide application as drug and drug-

intermediates [7-11]. Several methods are known for synthesis of thiazolo[3,2-

a]pyrimidine derivatives, from 2-mercaptopyrimidines and α-halo ketones, and by

cyclocondensation of α-aminothiazoles with β-diketones, β-keto aldehydes, and

their acetals, β-chlorovinyl ketones and aldehydes.

2.1.1. From 2-Mercaptopyrimidines

2.1.1.1. Reaction with Chloroacetic Acid Derivatives

The reaction of dihydropyrimidine-2(1H)-thione (propylenethiourea) 1 with

α-halocarboxylic acids gives only the bicyclic thiazolo[3,2-a]pyrimidine. The

most convenient procedure for the synthesis of 3,4-dihydropyrimidine-2(1H)-

thiones (known as the Biginelli reaction) is based on one-pot three-component

condensation of aldehydes with β-keto esters and thiourea. Thiazolopyrimidine

derivatives (3, Scheme 1) were obtained by a simple one-pot condensation

reaction of 1 and 2-bromopropionic acid (2, R3 = H, bromoacetic acid (2, R3 = H,

CH3) under microwave irradiation and conventional conditions [12, 13].

Progress in the Chemistry of Condensed Thiazolopyrimidines

319

NH

NH

S

R2

R1

O

Ph

R3

O

OH

Br

N

N

SR2

R1

O Ph

R3

O

+

H2N

CHO

H2N

S

R2

R1

O

Ph

O

1 2 3

Sheme 1

(E)-Chalcones 4 were prepared via Claisen-Schmidt condensation of methyl

ketones with different aromatic aldehydes. Cycloaddition reaction of 4 with

thiourea yielded the corresponding thioxypyrimidine 5 derivatives. Compounds 5

were condensed with chloroacetic acid to yield thiazolopyrimidine 6. Also thione

5 were also condensed, in one pot reaction, with chloroacetic acid and aromatic

aldehyde to yield arylmethylene derivatives 7 which could also be prepared

directly by condensation of 5 with aromatic aldehydes (Scheme 2) [14-20].

El-Baih in 2004, has described the synthesis of naphtho[1,2-d]thiazolo[3,2-

a]pyrimidine 10 (Scheme 3), by reaction of 2-arylmethylidene-1-tetralone 8 with

thiourea under basic conditions to give naphtho[1,2-d]pyrimidine 9 which then

cyclized with chloroacetic acid to afford the target compound 10 [21].


320

Ar3

Ar1

O

Ar2

S

NH2H2N

KOH / EtOH Ar1 Ar2

HN NH

S

ClCH2COOH

AcOH / Ac2O

CH3COONa

Ar1 Ar2

N N

S

O

Ar1 Ar2

N N

S

O

AcOH / Ac2O

CH3COONa

ClCH 2COOH

Ar3CHO

Ar 3CHO

45

6

7

Scheme 2

O

S

NH2H2N

NHHN

S

ClCH2COOH

NN

S

O

1098

Scheme 3

El-Emary and Abdel-Mohsen reported the synthesis of thiazolopyrimidines

12 as depicted in Scheme 4. Equimolar quantities of 1,3-diphenyl-1H-pyrazole-4-

carboxaldehyde, ethyl cyanoacetate and thiourea were refluxed to yield

pyrimidinethione derivative 11. This thione was cyclized to thiazolopyrimidines

12 upon reaction with chloroacetic acid and benzaldehyde [22].


321

NN

Ph

Ph

CHO O

OCN+ +

NH2

S

H2N

NN

Ph

Ph

COOEtHN

SHN NH2

O

OHCl

PhCHO

NN

Ph

Ph

COOEtN

S N NH2

OPh11

12

Scheme 4

Mobinikhaledi et al., in 2007, achieved the synthesis of 3-oxo-2-[(Z)-1-

phenylmethylidene]-5H-[1,3]thiazolo[3,2-a] pyrimidine derivatives 14 (Scheme

5) in good yields by the reaction of an appropriate 3,4-dihydro-2(H)-pyrimidone

13, chloroacetic acid, sodium acetate and benzaldehyde [23].

N

NH

SH

+ ClCH2COOH + PhCHO

AcONa

N

N

S Ph

OR1

R2

R1

R2

13 14

Scheme 5

Abu-Zied reported the synthesis of 2-arylidine-thiazolo[2,3-d]pyrimidine-

3(3H),5(5H)-dione 16 (Scheme 6) by the reaction of a ternary mixture of 2-

thioxo-thieno[2,3-d]pyrimidin-4(4H)-one 15, chloroacetic acid, and 4-

chlorobenzaldehyde[24].


322

NH

NH

S

O

S

+ ClCH2COOH +AcONa

N

N

S

OOCHO

Cl

S

Cl15 16

Scheme 6 Mohamed in 2002, reported the synthesis of thiazolopyrimidines 18 (Scheme

7), by heterocyclization of pyrimidinethione 17 with chloroacetic acid followed

by condensation with aromatic aldehydes (R1 = Cl, O2N) [25].

HN

NH

Me

COOEt

S

Ph

N

N Me

COOEt

S

Ph

O

R1

CHO

R1

Cl COOH+ +

17 18

Scheme 7

Djerrari et al., achieved the synthesis of thiazolopyrimidine 19 (Scheme 8)

starting from acetoacetylpyrazole , thiourea followed by reaction with

chloroacetic acid [26].

NHN

NHN

S

NHN

OO

S

H2N

NH2

Cl COOH

NHN

NN

S

O

19

Scheme 8


323

4,6-Diamino-1H-pyrimidine-2-thione was coupled with aromatic aldehydes

(Ar = Ph, 4-Cl-C6H4) to give the corresponding Schiff bases 20. Treatment of 20

with chloroacetic acid gave thiazolo[3,2-a]pyrimidine 21, which was condensed

with p-chlorobenzaldehyde to give compound 22. Compound 22 was condensed

with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 23 as

shown in Scheme 9 [27].

Many authors reported the synthesis of thiazolopyrimidines 25 (Ar =

substituted Ph, 2-thienyl; X = O, R = H, Me) in good to high yields (Scheme 10),

by heterocyclization of arylpyrimidinethiones 24 with chloroacetyl chloride or 2-

bromopropanoic acid [28-32].

Mobinikhaledi and Foroughifar found that thiazolopyrimidines 26 (Scheme

10) could be readily obtained in high yield by using microwave-assisted

cyclocondensation reaction of multi-substituted 3,4-dihydropyrimidine-2(1H)-

thiones 24 with chloroacetic acid, anhydrous sodium acetate and corresponding

aldehyde [33].

NH

NH

NH2

H2N S

ArCHO NH

NH

N

N S

Ar

Ar

Cl COOH N

N

N

N S

Ar

Ar

O

CHOClN

N

N

N S

Ar

Ar

O

Cl

NH2OH N

N

N

N S

Ar

Ar

O

Cl

NH

20 21

22 23

Scheme 9


324

NH

NH

Ar

SMe

EtOOCN

N

Ar

SMe

EtOOCO

R

O

ClCl

O

OH

Br

or

N

NH3C

EtOOC

Ar

S

O

Ar`

ClCH2COOH, Ar`CHO

AcONa, MW

2425

26

Scheme 10 When (3-(4-chlorophenyl)oxiran-2-yl)(aryl)methanone 27 (Ar = 3,4-

dimethylphenyl or 2-thienyl) reacted with thiourea in the presence of an alkaline

medium it afforded thioxopyrimidinone derivative 28 (Scheme 11).

Thiazolopyrimidine-3,6-dione derivative 29 was proven chemically via reaction

of 28 with chloroacetic acid. When the latter compound condensed with p-

chlorobenzaldhyde, it afforded compound 30 which could be prepared directly via

a one pot reaction by treating compound 28 with chloroacetic acid and p-

chlorobenzaldhyde [34, 35].

Bis-oxiranocycloalkanone derivatives 31 were condensed with thiourea to

give the corresponding thioxopyrimidine 32. Treatment of thioxopyrimidine

derivative 32 with chloroacetic acid in the presence of anhydrous sodium acetate

afforded the corresponding thiazolopyrimidine derivative 33 (Scheme 12), which

condensed with aromatic aldehydes in acetic acid/acetic anhydride to give

arylmethylene derivative 34. Also, arylmethylene derivative 34 could be prepared

by reaction of thioxopyrimidine derivatives 32 with chloroacetic acid, aromatic

aldehyde, and sodium acetate in a mixture of acetic acid and acetic anhydride

[36].


325

Ar

O

OCl

S

NH2H2N

NHHN

OH

S

Ar

Cl

ClCOOH N

N

O

SAr

Cl

O

OHC Cl

N

N

O

SAr

Cl

O

Cl

Cl

HOOC

CHO

Cl

Scheme 11

27 28

29

30

O

O O

H H NH

OH OH

HN H

S

N

HO OH

N H

S

O

N

HO OH

N H

S

O

NO2

S

NH2H2N

ClHOOC

Anh. NaOAc

CHO

NO2

Anh. NaOAcAc2O / AcOH

CHO

NO2

Cl

HOOC

31 32

3334

Scheme 12


326

O

Cl

Cl O

OCl

HN

HN

S N

N

S

OCl

Cl

+ +EtOH

Scheme 13

35

(2E)-2-(2,4-Dichlorobenzylidene)-6,7-dihydro-2H-thiazolo[3,2-a]pyrimidin-

3(5H)-one 35 (Scheme 13) was synthesized by mixing 2,4-dichlorobenzaldehyde,

ethyl chloroacetate and tetrahydropyrimidine-2-thione in ethanol [37].

2-[(1,3-Benzodioxol-5-yl)methylene]-6,7-dihydro-5H-thiazolo[3,2-

a]pyrimidin-3-one 36 (Scheme 14) was synthesized by mixing 1,3-benzodioxole-

5-carbaldehyde, ethyl chloroacetate and tetrahydropyrimidine-2-thione in ethanol

[38].

N

N

S

O OOO

O O

H

HN

HN

S

O

OCl

+ +EtOH

Scheme 14

36

Liu et al., reported the synthesis of ethyl 5-(2,6-dichlorophenyl)-7-methyl-2-

(1-naphthylmethylene)-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-

carboxylate 37 (Scheme 15). The reaction of ethyl 2-mercapto-4-methyl-6-(2,6-

dichlorophenyl)-1,6-dihydro-pyrimidine-5-carboxylate, ethyl chloroacetate and

naphaldehyde in acetic acid and acetic anhydride afforded the target molecule 37.

In the molecular, the thiazolo[3,2-a]pyrimidine and naphthalene systems are

essentially coplanar, with a dihedral angle between the combined plane and the

mean plane of the benzene ring of the 2,6-dichlorophenyl substituent of 94.7(4)°

[39].


327

N

NHO

O

ClCl

SH N

N

S

O

O

O

ClClO

OCl

CHO

+ +AcOH

Ac2O

Scheme 15

37

Alkylation of 1-methyltetrahydropyrimidine-2(1H)-thione (N-

methylpropylenethiourea) with chloro- and bromoacetic acids and their esters

gave 8-methyl-3-oxo-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-8-ium

chloride or bromide 38 (Scheme 16). The former is readily hydrolyzed in 95%

ethanol to 3-[(3-methylamino)propyl]-1,3-thiazolidine-2,4-dione hydrochloride 39

[40, 41].

NH

N S

CH3

XCHRCOOR`

anhdrous acetone, 20 C

N

N S

CH3 R

O

OR`

H

X

- R`OH

+ R`OH

N

N S

CH3

R

O

X

EtOH

boiling

N

S

O

RO

NMe

HH

X 38

39

Scheme 16

2.1.1.2. Reaction with Dihalocompounds

Thiazolopyrimidines 40 (Scheme 17) were synthesized by a simple one-pot

condensation reaction of starting dihydropyrimidine-2-thione derivatives 24 and

1,2-dibromoethane in DMF [28-31].

N-(4-Chlorophenyl)-7-methyl-5-aryl-2,3-dihydro-5H-thiazolol[3,2-

a]pyrimidine-6-carboxamides 41 (Scheme 18) were accomplished by

cyclocondensation of 1,2,3,4-tetrahydropyrimidine-2-thiones and 1,2-


328

dibromoethane, Some of these compounds exhibited significant inhibition on

bacterial and fungal growth [42].

NH

NH

H3C

EtOOC

Ar

S

N

NH3C

EtOOC

Ar

S

BrBr

DMF

2440

Scheme 17

HN NH

OHN

S

Ar

Cl

N N

OHN

S

Ar

Cl

BrBr+

41

Scheme 18

N

HN

HS

OHOPh

S N

N

S

OHO

S

BrCH2CH2Br

Scheme 19

42


329

Aly in 2007, has described the synthesis of thiazolopyrimidine 42 (Scheme

19) in good yield, by reaction of a mercapto-4,5-dihydropyrimidineacetic acid

with 1,2-dibromoethane [43].

Aslanoglu et al. reported the cyclization of 5-benzoyl-4,6-diphenyl-1,2,3,4-

tetrahydro-2-thioxopyrimidine (Scheme 20) with various dibromo compounds to

the thiazolopyrimidines 43 [44]

NH

NH

S

Ph

Ph

Ph

OBr

BrR

N

N

S

Ph

Ph

Ph

O

R

43

Scheme 20

Dihydrothiazolo[3,2-a]pyrimidines 46 (Scheme 21) were obtained via S,N-

tandem alkylation of 2-thiouracils 44 (R = H, R1 = NH2; R = Et, R1 = Me) with

aryl 2,3-dibromopropyl sulfones 45 (Ar = phenyl, subs. phenyl, 2-naphthyl) in

ethanol and potassium hydroxide[45].

NH

NH

S

O

R

R1

+ Br

Br

S

O

O

Ar

EtOH / KOHN

N S

O

R

R1

S

Ar

O

O

464544

Scheme 21

Al-AlShaikh et al. reported the synthesis of thiazolopyrimidinones 48

(Scheme 22) starting from dimedone. Reaction of dimedone with aromatic

aldehydes and thiourea using microwave irradition afforded 47 as the major

product. Cyclization of 47 with 1,2-dichloroethane gave the target compounds 48

[12].


330

O

O

+ ArCHO

S

NH2H2N+

O

NH

NH

Ar

S

Cl Cl

O

N

N

Ar

S

MV

5 min

Scheme 22

47

48

Interaction between 3,4-dichloro-N-R-maleimides 49 and 2-thiouracils 50,

which contain three nucleophilic centers, in mild conditions led to formation of

pyrrolothiazolopyrimidinetriones 51 and 52 (Scheme 23) as a mixture of two

equal isomers [R = benzyl, (un)substituted phenyl; R1 = H, Me; R2 = H, Me, Pr;

R1R2 = (CH2)3] [46]

N

Cl

ClO

O

RHN

NH

R1

R2

O

S

+

O

O, Et3N

30-40 °C N

O

O

R S

N

O

N

R1

R2

N

O

O

R S

N

R2

N

O

R1

+

49 5051 52

Scheme 23

2. 1.1.3. Reaction with ω- Bromo Ketonic Compounds

3-Substituted 5H-thiazolo[3,2-a]pyrimidine derivatives 54 (R = n-propyl, 4-

hydroxypheyl, 4-methoxypheyl; R1 = ethoxy, methyl; Ar = subs. phenyl), are

useful as acetylcholinesterase(AChE) inhibitors (Scheme 24), were synthesized by

the Hantzsch-type condensation of dihydropyrimidines 53 with substituted

phenacyl chlorides [47, 48].


331

NH

NH

H3C S

RO

R1O

X

ArNH

NH3C S

RO

R1

OAr N

NH3C S

RO

R1

Ar

+

AcOH

AcONa

53 54

Scheme 24 Quan et al. and Wang et al. have been reported the synthesis of thiazolo[3,2-

a]pyrimidines 55 (Scheme 25) by treatment of 3,4-dihydropyrimidine-2-thiones

24 with bromoacetone in refluxing water [49, 50].

NH

NH

O

EtO

H3C S

Ar

N

NH

O

EtO

H3C S

Ar

ON

N

O

EtO

H3C S

Ar

CH3BrCH2COCH3

H2O / refluxing

- H2O

2455

Scheme 25

HN

NHS

Ar

COOEt

Me

O O

O

Br

R2

R3

R4

+

O O

OR2

R3

R4

HN

NS

Ar

COOEt

Me

PPA

O

O

R2R3

R4

N N

S

Ar

COOEt

Me

24 5657

58

Scheme 26


332

Condensation of (mercapto)dihydropyrimidinecarboxylates 24 with various 3-

(2-bromoacetyl)coumarins 56 (R2 = H, R3 = H, Cl, Br, MeO, R4 = H, Br; R2R3 =

benzo, R4 = H) followed by cyclization of the intermediate ketones 57 (Scheme

26) on heating in polyphosphoric acid (PPA) yielded oxochromenyl-substituted

dihydrothiazolo[3,2-a]pyrimidinecarboxylates 58 [51].

2H,5H,3-Bromoacetylpyrano[3,2-c]benzopyran-2,5-dione on treatment with

2-thiouracil gave 2H,5H,-3-(5'-methyl-7'-oxo-7'H-thiazolo[3',2'-a]pyrimidin-3'-

yl)-pyrano[3,2-c]benzopyran-2,5-dione 59 (Scheme 27) which showed significant

antimicrobial activity [52].

O

O

O

O

O

Br

NHS

HN

O

+

O

O

O

O

S

NN

O

59

Scheme 27

2. 1.1.4. With Halo-Nitriles

Mohamed in 2002 reported the synthesis of aminothiazolopyrimidine 60

(Scheme 29). The reaction of pyrimidinethione 17 with chloroaceteonitrile gave

the desired compound 60 [25].

Reaction of 2-thiothymine 61 with bromomalononitrile produces thiazolo[3,2-

a]pyrimidine-2-carbonitrile derivative 62 (Scheme 29). Reacting 64 with

malononitrile yielded pyrido[2',3':4,5]thiazolo[3,2-a]pyrimidine-3-carbonitrile

derivative 63. [53, 54].

Scheme 28

HN

NH

Me

COOEt

S

Ph

ClCH2CN

N

N Me

COOEt

S

Ph

H2N+

6017


333

NH

SNH

O+

CN

CN

N

SNH

O

NH2

CNBr

CH2(CN)2 N

SNH

O

N

NH2

CN

NH2

61 62 63

Scheme 29

2.1.2. From Aminothiazoles

Metwally et al., reported the synthesis of thiazolo[3,2-a]pyrimidine

derivatives 65 (Scheme 30) and 66 (Z = NH, O) by the treatment of 2-

aminothiazole or 2-aminobenzothiazole with ketene S,S-acetals 64 (X = CONH2

or COOEt) in ethanol respectively [55].

SMeMeS

X CN

N

S NH2

N

NS

Z

CN

SMe

N

SNH2

EtOH

N

SN

SMe

CNZ

64 6566

Scheme 30

Djerrari and coworkers reported the synthesis thiazolo[3,2-a]pyrimidine 67

(Scheme 31) by reaction of dehydroacetic acid with 2-aminothiazole. The

mechanism of formation of the title compound involve simple condensation

between NH2 and the ketone group to form imines A and B followed by

rearrangement [56].

Treatment of polymer-bound methyl 2-acetylamino-3-(dimethylamino)prop-

2-enoate 68 with excess 2-aminothiazole in a mixture of toluene, DMF, and acetic

acid at 60°C (Scheme 32) yielded the corresponding thiazolo[3,2-a]pyrimidin-6-

yl)acetamide 69 [57].


334

OH3C

O

CH3

ON

SH2N+

OH3C

CH3

O

N

N

S

OH

OH3C

CH3

O

N

HN

S

ON

N

S

O

CH3

O O

CH3

A

B 67

Scheme 31

O

O

N

NH

OS

NH2N +

N

N

O

NH

CH3

OStoluene, DMF,

AcOH, 60 °C

68 69

Scheme 32

Reactions of α,β-unsaturated ketones with aminoazole is the most favourable

way to the series of natural-like partially hydrogenated azolopyrimidines [10].

Therefore, reaction of 2-aminothiazoline with α,β-unsaturated carbonyl

compounds 70 under mild conditions (acetone, room temperature) gave two

diastereomers 5-R-7-hydroxy-5H-tetrahydrothiazolo[2,3- a]pyrimidines 71(

Scheme 33) [58]


335

N

S NH2

+

O

R1R2

acetone / rt N

S N

R2

OH

R1

70 71

Scheme 33

Bonacorso et al. reported that, β-alkoxyvinyl trichloromethyl ketones 72 (R 1

= H, Me,n-pr i-pr, i-Bu; R2 = H, Me) are useful building blocks for the synthesis

of thiazolo[3,2-a]pyrimidin-5-ones 73 (Scheme 34) by reaction with 2-

aminothiazole [59]

R1

OCH3

R2

O

Cl3C

N

S

H2NEtOH

R1

HN

R2

O

Cl3C+

S

N

N

NS

O

R2

R1

72

73

Scheme 34

N-Aryl-3-oxobutanethioamides 74 reacted with 2-amino-1,3-thiazole or (2-

amino-1,3-benzothiazole) 75 in acetic acid to give a mixture of thiazolo[3,2-

a]pyrimidine-5-thiones 76 and 5-arylimino-7-methyl-5H-[1,3]thiazolo[3,2-

a]pyrimidines 77 (Scheme 35) whose ratio depends on the nature of the aryl

substituent in the initial butanethioamide [60].


336

O

Me

S

NH

Ar

N

S

R

RH2N

N

N S

S

Me

R

R

+ N

N S

N

Me

R

R

Ar

+AcOH

Scheme 35

74 75 76 77

Reaction of 2-aminothiazole with 1-benzotriazol-1-yl-3-phenylpropynone in a

sealed tube at 120 C in acetonitrile afforded the expected 5-phenylthiazolo[3,2-

a]pyrimidin-7-one 78 (Scheme 36) in 54% yield [61].

N

SNH2 Ph

O

BtN

SN

O

Ph

+MeCN

120 °C

78Scheme 36

7-Chloromethyl-6-nitro-5H-thiazolo[3,2-a]pyrimidin-5-one 79 (Scheme 37)

was obtained by cyclocondensation of 2-aminothiazole with ethyl 4-

chloroacetoacetate [62]

N

N

S

O

NO2

ClOO

O

Cl

S

N

NH2 +

Scheme 37

79


337

6,7-Dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines 82 (R1 = H, Me, Ph, 4-

MeOC6H4, 4-ClC6H4; R2 = H, Me) was stereoselectively prepared by

cyclocondensation of 2-aminothiazoles 80 (Scheme 38) with fluorinated (gem-

dihydroxyalkyl)vinyl sulfones 81 (R6 = Me, Ph) [63].

N

S NH2R2

R1

CH

CH

SO2R6COH

HO

F3C N

S

R1

R2

OH

CF3

SO2R6

+

80 81 82

Scheme 38

Schiff bases of 2-aminothiazoles 84 undergo mercaptoacetylative expeditious

annulation with 2-methyl-2-phenyl-1,3-oxathiolan-5-one 83 (Scheme 39) to yield

highly substituted 6,7-dihydro-6-mercapto-5H-thiazolo/1,3,4-oxa(thia)-

diazolo[3,2-a]pyrimidin-5-ones 85 stereoselectively [64].

S

O O

Ph

Me

S

N

N

Ar

MW, 8-12min

N

N SAr

HS

O

+

Scheme 39

8483 85

One-pot reactions of glycine, acetic anhydride and thiazole Schiff bases 86

(Ar = Ph, Ar' = Ph, 4-MeOC6H4, 4-ClC6H4; Ar = 4-MeC6H4, Ar' = Ph, 4-

MeOC6H4, 4-ClC6H4) diastereoselectively and expeditiously annulate a

pyrimidine ring on the thiazole nucleus to yield 6,7-dihydro-5H-thiazolo[3,2-

a]pyrimidin-5-ones 87 (same Ar, Ar') under microwave irradition (Scheme 40)

and solvent-free conditions [65].


338

H2N

O

OH+ Ac2O +

S

N

N

Ar` Ar

MW, 10-15 min

N

N SAr

O

Ar`

NH

O

Me

86 87

Scheme 40

The treatment of thiazol-2-yl-N,N-dimethylimidoformamide 88 with

monosubstituted ketenes such as phenyl, phenoxy, chloro, bromo, and cyano

ketenes, generated, in situ, by the dropwise addition of their corresponding acid

chlorides 89 in triethylamine at room temperature (Scheme 41) gave

thiazolopyrimidinones 90 [66].

NN

S

N

R

O

O

ClR1+

CH2Cl2, Et3N , 0°C N N

S

O

R1

O

R

88 8990

Scheme 41

Condensation of 3-(2-amino-4-thiazolyl)coumarin 91 with α-acetyl-γ-

butyrolactone in a mixture of polyphosphoric acid and POCl3 afforded

thiazolo[3,2-a]pyrimidin-5-one 92, while condensation of 91 with β-keto esters

gave 7-methyl-3-(2-oxo-2H-chromen-3-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-

ones 93(Scheme 42). Reaction between 91 and diethyl 2-

(methoxymethylene)malonate under solvent-free conditions yielded 3-(2-oxo-2H-

chromen-3-yl)-5-oxo-5H[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate 94 [67].


339

O

O

S

N NH2

O

O

O

N

N

S

O

PPA / POCl3 Cl

OO

N

N

S

OO

O

R

N

N

S

O

OEt

O

O

O

O R

EtOOC

COOEt

COOEt

OCH3

91

92

93

94

Scheme 42

Heating ethyl homovanilate 95 with NaH and 1-(2-chloroethyl)pyrrolidine in

DMF provided arylacetate 96. Then, treatment of 96 with Bredereck’s reagent

(tert-butoxy-bis-(dimethylamino)-methane) and finally heating of 97 with various


340

2-aminothiazoles using microwave gave bi-heterocyclic compounds 98 (Scheme

43) in high yields[68].

OH

OCH3

O

EtO

O

OCH3

O

EtO

NNaH, 1-(2-chloroethyl)pyrrolidine, DMF, 80 °C, 16 h,

O

OCH3

O

EtO

N

NMe2

tert-butoxy-bis(dimethylamino)methane

(Bredereck’s reagent), 65 °C, 16 h

S

N

NH2

Ar

AcOH, microwave

O

OCH3

N

N

N

O

SAr

95 96

97

98

Scheme 43

Sharma has described the synthesis of 3-(7-methyl-5-H-thiazolo-[3,2-a]-

pyrimidin-5-one-3-yl)-2-methylchromones 100 (Scheme 44) by condensing 3-(2-

aminothiazol-4-yl)-2-methylchromones 99 with ethyl acetoacetate [69].

O

O

Me

S

N NH2

R1

R2

OO

OO

O

Me

S

N N

R1

R2

O Me

99 100

Scheme 44

Abdel-Mohsen in 2003 reported the formation of thiazolo-[3,2-a]-pyrimidine

102 (Scheme 45). Refluxing of thiourea with 5-chloro-acetyl-8-hydroxyquinoline


341

produced 5-(2-Aminothiazol-4-yl)-8-hydroxyquinoline 101, which then reacted

with ethyl aceteoacetate to give 102 [70].

N

OH

S

NH2N

N

OH

OCl

NH2

S

H2NO

EtOOC

N

OH

S

NN

O

H3C

Scheme 45

101

102

S

N

S

NH2 X

COOEt

S

N

S

N

O

Y

NC

R

Ph

S

N

S

N

NH2R

Ph

103104

105

Scheme 46


342

Abdel-Hafez reported the synthesis of fused thiazolo-pyrimidines 104 (Y =

NH2, OH) and thiazolo-pyrimidines 105 (R = CN, COOEt) (Scheme 46) by

refluxing 103 with active methylene derivatives e.g., diethylmalonate (X =

COOEt) or ethyl cyanoacetate (X = CN), or with some arylidine malonitriles

(benzylidinemalononitrile (R = CN and ethylbenzylidinecyano-acetate (R =

COOEt)) [71].

4-(2-Aminothiazol-4-yl)-3-methyl-5-oxo-1-phenyl-2-pyrazoline 106 was

synthesized via the reaction of 4-bromoacetyl-3-methyl-5-oxo-1-phenyl-2-

pyrazoline with thiourea (Scheme 47). Fusion of 106 with ethyl cyanoacetate and

ethyl acetoacetate gave thiazolo[3,2-a]pyrimidin-5-ones 107 and 108

respectively[72].

N

N

Ph

O

S

NNH2

N

N

Ph

OO

Br H2N

S

NH2

O

OCN

N

N

S

O

N NPh

O

NH2

OO

O

N

N

S

O

N NPh

O

fusion

fusion

106107

108

Scheme 47


343

SN

O

O

NH2 O

OO

+H2N

+

N

N

S

N

O

bromination

N NH2

1-

2-

O

Cl

Br3-

N

N

S

N

O

CH3

NMe2O

Br

109

110

Scheme 48 Thiazolopyrimidine 110, as mitotic kinesin inhibitors for treatment of cancer,

was prepared by the cyclization of ethyl 5-amino-1,3-thiazole-4-carboxylate with

trimethyl orthobutyrate and benzylamine to afford the [1,3]thiazolo[5,4-

d]pyrimidin-7(6H)-one 109 intermediate (Scheme 48), followed by bromination,

amination with N,N-dimethylethylenediamine, and amidation with 4-

bromobenzoyl chloride gave 110 [73].

Youssef and Omar reported the synthesis of 2-thioxo-2Hpyrimido[5,4-

e]thiazolo[3,2-a]pyrimidine 113 from the corresponding 2-aminothiazole (Scheme

49). Therefore, 2-aminothiazole derivative 106 on reaction with

benzylidenemalononitrile afforded thiazolo[3,2-a]pyrimidine-6-carbonitrile 111.

The latter compound when reacted with phenyl isothiocyanate in pyridine for 6 h

provided 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-(N-phenylthiourea)-7-

phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile 112. When the reaction

mixture was refluxed for 10 h it gave the title compound 113 [74].


344

N

N

CH3

Ph

O S

N NH2

CH

C

CN

CNPh

NN

CH3

Ph

O

SN

N

Ph

CN

NH2

PhNCS

NN

CH3

Ph

O

SN

N

Ph

CN

HN

S

HN Ph

NN

CH3

Ph

O

SN

N

Ph

HN

S

N Ph

NH

Fusion

6h

106

111 112

113

Scheme 49

Landreau et al and El-Din have reported that, thiazole undergo the tandem [4

+ 2] cycloaddition/deamination process (Scheme 50), furnishing 5H-thiazolo[3,2-

a]pyrimidines 114[75, 76].

N

SR

N

N

H2C CH

R1

-NHMe2

N

SR

N

R

114

Scheme 50

Thiazolo[3,2-a]pyrimidines 115 (Scheme 51) were obtained by fusion of 6-

aryl-3-cyano-4-methylthio-2H-pyran-2-one with 2-aminothiazole at 100–130°C.

The reaction is possibly initiated by attack of the nitrogen nucleophile on the

highly vulnerable electrophilic center C6, followed by decarboxylation and ring

opening. The ring opened intermediate thus generated in situ re-cyclizes involving

C4 of the pyran ring and the ring nitrogen of 2a or 2b, followed by the elimination

of methyl mercaptan to yield [7-arylthiazolo[3,2-a]pyrimidin-5-

ylidene]acetonitrile 115 [77].


345

O

SCH3

CN

OAr

N

SH2N

+

NH

C

Ar

O

OMeS

N

S

N

H- CO2

N

SN

Ar

SMeCN

HS

N

NAr

SMe

CN

N

N SAr

NC

115

Scheme 51

2.1.3. Miscellaneous Methods

Reaction of cycloalkenyl-1-diazenes 116 with tetrahydropyrimidine-2-thione

(Scheme 52) in methanol at room temperature give thiazolo[3,2-a]pyrimidine]-

2,3`-dione- 2-semicarbazones 118 via the intermediate 117 [78]

n(H2C)N

N

O

NH2

NHHN

S

MeOH, r.t.n(H2C)

N

HN

O

NH2

SN

HNCOOEt

EtOOC

n(H2C)

N NH

ONH2

S N

N

O

116 117 118

Scheme 52

Intramolecular cyclization of 1-allyl- and 1-methallyl-6-amino-2-thiouracils

119 by heating using 48% HBr at 120 °С for 2 h, afforded 5-amino-2,3-


346

dihydrothiazolo[3,2-a]pyrimidin-4-ones 120 in high yields (Scheme 53). While

bromination of 119 with two equivalent of bromine gave 5-amino-6-

bromothiazolopyrimidinones 121 in good to high yields [79].

HN

N

O

S NH2

H2C C CH2

R

HBr N

N

O

S NH2

CH3

R

2Br2

N

N

O

S NH2

H2CR

Br

Br

119 120121

Scheme 53

Thiazolo [3,2-c]pyrimidine-5,7-diones 123 (R1 = R2 = R3= H, CH3; R4 = H,

CH3) were prepared by reaction of N-(chlorocarbonyl) isocyanate with 2-

alkylthiazolines 122 (Scheme 54) in acetonitrile containing triethyl amine [80].

N S

R1R2

R3

R4

NS

R1

R2 R3

R4N

O

CO

NS

R1

R2 R3

R4HN

O

C

O

Cl

O

NC

O

Et3N, CH3CN

122 123

Scheme 54

Cycloaddition reaction of dimethylpyrimidinesulfenyl chloride 124 with p-

tolylacetylene gave thiazolopyrimidinium salt 125 (Scheme 55) in 89% yield [81].


347

NN

MeMe

SCl

C

CH

Me

+ N

N S

CH3

H3C

CH3

124 125

Scheme 55 5-{[(2,3-Difluorophenyl)methyl]thio}-7-{[(1S,2S)-2-hydroxy-1-

(hydroxymethyl)propyl]amino}thiazolo[4,5-d]pyrimidin-2(3H)-one 126 (Scheme

56) which are useful for treating a chemokine mediated diseases such as asthma,

allergic rhinitis, COPD, inflammatory bowel disease, osteoarthritis, osteoporosis,

rheumatoid arthritis, psoriasis, cancer, etc., was prepared in a 7-step process,

starting from 4-amino-6-hydroxy-2-mercaptopyrimidine and 2,3-difluorobenzyl

bromide [82].

N

N

HS

OH

NH2

F

FBr

+

N

NS

NH

O

HNOH

OH

SF

F

126

Scheme 56

2,3-Dihydrothiazolo[3,2-a]pyrimidin-5-ones 127 (Scheme 57) were prepared

in a one-step reaction based on a Michael-type tandem reaction, by heating 2-

thiobarbituric acid with ethyl 4-bromocrotonate in ethanol at 60 for 2 h, a 2,3-

dihydrothiazolo[3,2-a]pyrimidin-5-one was obtained in 73% yield [83].


348

NH

SNH

O

OO

O

Br

+

N

N

S

O

HO

COOEt

127

Scheme 57

A series of thiuronium salts 129 (Scheme 58), which exhibited antimicrobial

activities, were synthesized in high yields via the interaction of equimolar

amounts of 2-bromothiadiazolopyrimidine with thioamides 128 (R = NH2,

NHNH2, CSNH2, NHNHCSNH2) for 2 – 3 h in boiling ethanol [84].

N

N

N

S

O

H3C Br

+ S

R

NH2

EtOH

boiling

N

N

N

S

O

H3C S

NH

R

.HBr

128 129

Scheme 58

Condensation of 5-amino-3,7-dihydro-3,7-dioxo-2H-thiazolo[3,2-

a]pyrimidine-6-carbonitrile 130 with phenylisothiocyanate or thiourea (Scheme

59) afforded 7-thioxopyrimido[6,5-d]thiazolo[2,3-b]pyrimidines 131 and 132

respectively[85].

N

NS

O NH2

CN

O

PhNCSN

NS

O HN

O

N

S

Ph

NHH2N NH2

S

N

NS

O HN

O

N

S

NH2

131 132130

Scheme 59


349

2.2. Thiazolo[3,2-c]Pyrimidines

2-(4-Phenyl-3H-thiazol-2-ylidene)malononitrile 133, was obtained by

cyclocondensation of 1-phenyl-2-thiocyanatoethanone with malononitrile, on the

reaction with thiourea or guanidine (Scheme 60) led to the formation of

thiazolo[3,2-c]pyrimidine 134[86].

OSCN

CN

CN

+

CNNC

S NH

Ph

X

NH2

H2N

N

NS

Ph

NH2

NC

X

X = S, NH

134133

Scheme 60

2.3. Thiazolo[4,5-d]Pyrimidines

The synthesis of thiazolo[4,5-d]pyrimidines has been successfully

accomplished by various methods. 4-Amino-5-ethoxycarbonylthiazole derivative

has been cyclized to thiazolo[4,5-d]pyrimidine by its reaction with phenyl

isothiocyanate [87]. Many 4-amino-5-carbamoylthiazole derivatives have been

cyclized to the corresponding thiazolo[4,5-d]pyrimidines using triethyl

orthoformate/acetic anhydride mixture [88-91]. Moreover, 4-amino-5-cyano

thiazoles have been used to prepare the same fused ring system via their reaction

with triethyl orthoformate, followed by treatment of the intermediate with

hydrogen sulfide, guanidine, amines, and isothiocyanates [92, 93]. Other

thiazolo[4,5-d]pyrimidines have been obtained from 4-amino-5-cyano, carbamoyl,

or ethoxycarbonyl thiazoles via cyclization with acetic anhydride [94] or formic

acid [95].

Akbari et al., have described the synthesis of 7-aryl-5-thioxo-4,5,6,7-

tetrahydro-3H-thiazolo[4,5-d]pyrimidin-2-ones 135 (Scheme 61) by the reaction

of 2,4-thiazolidine, thiourea and different aromatic aldehydes [75, 81]


350

SHN

NH

NHS

NH

O

S

Ar

O

+ ArCHO +S

NH2H2N

135Scheme 61

Fluorinated spiro[indole-3,2'-thiazolo[4,5-d]pyrimidines] 137 was prepared

(Scheme 62) from the reaction of arylidene fluoro spiro thiazolidines 136 and

thiourea under monomode microwave reactor [96].

NH

O

NS

O

R2

R1

R

S

NH2H2N

NH

O

NS

NH

R2

R1

R

HN S

136 137

Scheme 62

MW

Microwave-assisted condensation of arylidenerhodanines with arylthioureas

(Scheme 63) gave 3,4-diaryl-2-thioxo-6-thioxo-1,2,3,4,6,7-

hexahydrothiazolo[4,5-d]pyrimidines 138 [R = H, OMe; R1 = H, Br, Cl, OMe]

[97].


351

S

NH

S O

S

NH2NH

R1

R

+MW

S

NH

S NH

R

N

S

R1

138Scheme 63

5-(Alkylamino)-6-aryl-3-phenyl-2-thioxo-2,3-dihydrothiazolo[4,5-

d]pyrimidin-7(6H)-ones (I; R = alkyl, substituted benzyl; R1 = H, F) 141 were

easily synthesized via a tandem aza-Wittig reaction. Treatment of

iminophosphorane 139 with aromatic isocyanates gave carbodiimides 140 (same

R1), which reacted with fluoro-substituted alkylamines to provide the title

compounds 141 (Scheme 64) in 65-87% isolated yields using sodium ethoxide as

catalyst [98].

N

S

Ph

S

COOEt

NPPh3 ArNCO N

S

Ph

S

COOEt

N C NArRNH2

N

S

Ph

S

COOEt

N CNHR

NHAr

EtONa / EtOH N

S

Ph

SN

N

O

Ar

NHR

139 140

141

Scheme 64

The reaction of 2-(dialkylamino)-1,3-thiazol-4-amines with aryl isocyanates,

led to the formation of thiazolopyrimidinediones 142 (Scheme 65) in good to high

yields [99].


352

S

N NH2

N

R

R+ R`NCO

S

NN

R

R NH

N

O

O

R`

142

Scheme 65

Thiazolopyrimidines 144 was prepared, as chemokine receptor modulators,

by reacting 3-bromopropanoic acid with 2-amino-5{[(2-

fluorophenyl)methyl]thio}thiazolo[4,5-d]pyrimidin-7(4H)-one 143 (Scheme 66)

in the presence of (iso-Pr)2NEt and NaI in DMF [100].

N

N

S

N

HO

S

F

H2N

O

OH

Br(iso-Pr)2NEt

NaI / DMF

+

N

N

S

N

O

S

F

H2N

COOH

143144

Scheme 66

5,7-Disubstituted thiazolo[4,5-d]pyrimidin-2(3H)-ones 146 (Scheme 67),

which used as chemokine CX3CR1 receptor antagonists, were obtained by reaction

of (2R)-2-[(2-amino-5-mercaptothiazolo[4,5-d]pyrimidin-7-yl)amino]-4-

methylpentan-1-ol 145 with (1-bromoethyl)benzene [101].


353

OHHN

N

NS

N SH

H2NN

NS

NH

O

S

HNOH

Br

+

145 146

Scheme 67

(2R)-2-[(2-Amino-5-mercaptothiazolo[4,5-d]pyrimidin-7-yl)amino]-4-

methylpentan-4-ol 145 was coupled with (1-chloropropyl)benzene (Scheme 68) to

give (2R)-2-[[2-amino-5-[(1-phenylpropyl)thio]thiazolo[4,5-d]pyrimidin-7-

yl]amino]-4-methylpentan-1-ol 147, which used as chemokine CX3CR1 receptor

antagonists [102].

OHHN

N

NS

N S

H2N

Cl+OH

HN

N

NS

N SH

H2N

145 147

Scheme 68 Thiazolopyrimidine 148, useful for treating a chemokine mediated disease

such as psoriasis, rheumatoid arthritis, and COPD, were prepared a 5-step

synthesis (Scheme 69), starting from 2-amino-5,6-dihydro-5-thioxothiazolo[4,5-

d]pyrimidin-7(4H)-one and 2,3-difluorobenzyl bromide [103].


354

NH

NHS

N

O

S

H2NF

FBr

+

N

NS

NH

NH

S

S

H3C

OH

F

F

Scheme 69

148

Thiazolo[4,5-d]pyrimidinyldiamine 149, are useful for the treatment or

prophylaxis of neurodegenerative disorders, demyelinating disease and pain, was

prepared by reacting 5-phenylmethylthio-7-chlorothiazolo[4,5-d]pyrimidin-2-

ylamine (Scheme 70) with DL-2-amino-3-methyl-1-butanol in THF [104].

H2N

N

N

S

N

Cl

S

OH

H2N+

H2N

N

N

S

N

HN

S

OH

THF

Scheme 70

149

Substituted thiazolo[4,5-d]pyrimidines 153 (Scheme 71), which are

antagonists of the human CXCR2 receptor, were prepared via the application of

tandem displacement reaction. Diazotisation of 150 with iso-amyl nitrite in the

presence of bromoform at 50 °C afforded 151. This intermediate was treated with

an array of amines at room temperature affording the mono-substituted

intermediates 152 efficiently. After an hour, a second set of amines was added and

the temperature increased to 100 °C to give the title compounds 153 [105].


355

N

NS

NH2N

Cl

S

F

F

N

NS

NBr

Cl

S

F

F

iso-amylnitrite, CH3CN, 50°C

N

NS

NN

Cl

S

F

F

R1

R2 N

NS

NN

N

S

F

F

R1

R2

R4R3

CHBr3

R1R2NH (rt), Et3N R3R4NH 100 °C

150 151

152153

Scheme 71

N

N

Ph

O

H

CH3

H2NNH

O

CNEtOH

Reflux

NN

Ph

N

H

CH3

+NH

O

CN

NN

Ph

N

H

CH3

NH

O

S

H2N NS

Ar

ArNCS

S / TEA

HC(OEt)3

Ac2ON

N

Ph

N

H

CH3

N

O

S

N NS

Ar

154

155156

Scheme 72


356

N-[3-(4-Methylphenyl)-1-phenyl-1H-pyrazol-4-methylidene]-cyanoacetic

acid hydrazide 154; was synthesised in an excellent yield by condensing 3-(4-

methylphenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde with cyano-acetic acid

hydrazide. This intermediate was converted to the 4-amino-3-aryl-5-[3-(4-

methylphenyl)-1-phenyl-1H-pyrazol-4-methylidenehydrazinocarbonyl]-thiazole-

2(3H)-thiones 155 (Scheme 72), following the method described by Gewald, it

involved the reaction of the cyanoacetic acid hydrazide derivative 154 with

sulphur and the appropriate aryl isothiocyanate in the presence of triethylamine as

a basic catalyst. Cyclisation of 145 to the 3-aryl-6-[3-(4-methylphenyl)-1-phenyl-

1H-pyrazol-4-methylideneamino]-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-

7(6H)-ones 156 was achieved by heating the former with a mixture of triethyl

orthoformate and acetic anhydride (1:1) [4].

4-Amino-3-aryl-2-[3-(4-methylphenyl)-1-phenyl-1H-pyrazol-4-

methylidenehydrazono]-2,3-dihydrothiazole-5-carboxamides 157 (Scheme 73)

were obtained in excellent yields by condensing the pyrazole aldehyde with the 4-

amino-3-aryl-2-hydrazono-2,3-dihydrothiazole-5-carboxamides . In an analogous

fashion, compounds 157 were utilised to synthesise the thiazolo[4,5-

d]pyrimidines 158. [4]

NN

Ph

O

H

CH3

S

NNH2

O

NH2

Ar

N

H2N

+

S

N NH2

O

NH2

Ar

NN

NN

Ph

H

CH3

HC(OEt)3

Ac2OS

NN

O

NH

Ar

NN

NN

Ph

H

CH3157

158

Scheme 73


357

7-Chloro-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thione 160

(Scheme 74), was prepared by reacting cyanoacetamide, sulphur, and

phenylisothiocyanate in the presence of triethylamine, according to the procedure

reported by Gewald [106] to give 4-amino-5-carbamoyl-3-phenylthiazole-2(3H)-

thione 159. Cyclization of this amino amide by heating under reflux in acetic

anhydride followed by treatment of the product with phosphorous oxychloride

gave the required chloro derivative 161 in good yield. Nucleophilic substitution of

the chlorine atom by reaction of 161 with the appropriate amine in boiling dry

acetone gave 7-(substituted amino)-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-

2(3H)-thiones 162 [107].

NC

O

NH2

S PhNCS

N

S S

PhH2N

O

H2N Ac2O N

S S

PhN

O

HN

H3C

POCl3 N

S S

PhN

Cl

N

H3C

R2NH

AcetoneN

S S

PhN

R2N

N

H3C

159 160

161 162

Scheme 74

+ +

4-Amino-3-benzyl-5-cyano-2,3-dihydrothiazol-2-thione 163 was reacted with

triethyl orthoacetate in acetic anhydride to yield 3-benzyl-5- cyano-4-(a-

ethoxyethylideneamino)thiazolin-2-thione 164 (Scheme 75). Subsequently, the

latter was cyclocondensed with hydrazine hydrate to afford 6-amino-3-benzyl-7-

imino-5-methyl-2,3,6,7-tetrahydrothiazolo[4,5-d]pyrimidin-2-thione 165 [108]


358

N

S

NH2

CNS

Ph

HC(OEt)3

Ac2O

N

S

N

CNS

PhCH3

OC2H5N2H4

N

S

N

S

Ph

CH3

N

NH

NH2

163 164 165

Scheme 75

2-Morpholino- and 2-pyrrolidino-5-bromo-4-pyrimidinamine 156 (R2 =

morpholine or pyrrolidine) were successfully reacted with various isothiocyanates

(Scheme 76) in the presence of NaNH2 in DMF to form thiazolo[4,5-

d]pyrimidines 157 [109].

N

N

NH2

BrR2N

N

N

HNR2N

S

N

RRNCS / NaNH2 / DMF

166 167

Scheme 76

3-Alkyl-6-(2-aryl-2-oxoethyl)-7-oxothiazolo[4,5-d]pyrimidine-2(3H)-thione

derivatives 169 (R = Me, Et; R1 = H, Me, MeO, Cl) were prepared by alkylation

of thiazolopyrimidinethiones 168 (Scheme 77) with phenacyl bromides [110]

HN

N

O

S

NS

R

+

R1

O Br N

N

O

S

NS

R

O

R1

168 169

Scheme 77


359

Baxter et al. described the production of alkylthiothiazolopyrimidines 172

(Scheme 78). Alkylation of 6-aminothiouracil gave 170, thiocyanation of 170

produced 171. Cyclization of the latter compound gave the title product 172[111].

N

N

OH

SHH2N N

N

OH

SH2NR

N

N

OH

SH2NR

SNC

RBr, NaOH, EtOH 1) KSCN, pyridine, DMF,

2) Br2, 5 °C

DMF, H2O

N

N

OH

SN R

SH2N

170 171

172

Scheme 78

Successive condensation of 7-chloro-2-(methylsulfanyl)thiazolo[4,5-

d]pyrimidine 173 with 3-chloro-4-fluoroaniline and N,N-

dimethylethylenediamine gave thiazolopyrimidine 174 (Scheme 79) which used

as antagonists of CCR2b receptors for the treatment of chemokine-mediated

diseases [112].

N

NS

N

S

Cl

NH2

F

Cl

N NH2+ +

N

NS

N

HN

HN

N

Cl

F

173 174

Scheme 79

When 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-

2(3H)-one 175 and p-TsOH in PhMe at 60C was treated with 3,4-dihydropyran

and heated with THF, Na2CO3, and D-alaninol afforded 5-[[(2,3-

difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-


360

(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2(3H)-one 176 (Scheme

80).Treatment of the latter with MeCN/H2O/THF at 65°C and 1N HCl yielded 5-

[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-

methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one 177 [113].

N

NS

NO

O

HN

HO

SF

F

N

NS

NH

O

SF

F

Cl

1- p-TsOH , PhMe, 60 C

O

2- aq. NaHCO3 / THFNH2

HO

N

N

S

NH

O

HN

HO

S

FF

MeCN/H2O/THF

HCl

175176

177

Scheme 80

Condensation of p-bis(2-iminothiazolidin-4-one-N2-yl)biphenyl 178 (R1 = H;

X = CH2) with ω-bromoalkoxyphthalimides (n = 2-4; Phth = phthalimido) gave

the corresponding alkoxyphthalimide derivative 179. The latter were condensed at

the reactive methylene group of the thiazolidinone ring with aromatic aldehydes

(R2 = Ph, 4-HOC6H4, 4-MeOC6H4) to give p-bis(3-n-alkoxyphthalimido-5-

arylidene-2-iminothiazolidin-4-one-N2 -yl)biphenyls 180 (Scheme 81). The titled

compounds 181 [R2 = Ph, 4-HOC6H4, 4-MeOC6H4] were synthesized by

heterocyclization of 180 with urea in the presence of anhydrous sodium acetate in

acetic acid medium [114].


361

N

N

S

N

N

S

O O

H

H

PhthO(CH2)nBr

N

N

S

N

N

S

O O

n(H2C)

n(H2C)

O

Phth

O

Phth

R2CHO

N

N

S

N

N

S

O O

n(H2C)

n(H2C)

O

Phth

O

Phth

R2R2

N

N

S

N

N

S

N

n(H2C)

n(H2C)

O

Phth

O

Phth

NN

N

HO

R2R2

OH

S

NH2H2N

Anh. NaOAc / AcOH

178 179

180

181

Scheme 81

4-Amino-5-carboxamido-2,3-dihydrothiazole-2-thione 182 (Scheme 82) was

prepared form cyanoacetamide, sulphur and 4-fluorophenyl

isothiocyanateisothiocyanate according to the procedure reported by Gewald. This

compound was cyclized to the thiazolo[4,5-d]pyrimidine 183 using a

triethylorthoformate/acetic anhydride mixture as described [84]. 7-

Mercaptothiazolo[4,5-d]pyrimidine 184 was obtained through reaction of 183


362

with phosphorus pentasulphide, to obtain 7-fluorobenzylthio derivatives 185 (X =

H, F) [115].

NCO

NH2

+ S +

F

N C S

N

S S

H2N

O

H2N

F

N

HN S

NS

O

F

HC(OEt)3

P2S5 N

N S

NS

SH

FBr

X

F

N

N S

NS

S

F

X F

182

183 184

185

Scheme 82

3-Aryl-6-substituted thiazolopyrimidin-2(3H)-thione derivsatives 187 (R = H,

Me, MeO or Cl) and 188 (Scheme 83), have been synthesized by reacting

thiazolopyrimidines 186 with ω-bromoacetophenones or 2-chloro-N-(2-

thiazolyl)acetamides [116].


363

HN

N N

S

O

S

Cl

O

Br

R

O

HN

S

N

ClR1

R2

N

N N

S

O

S

Cl

O

R

N

N

NS

O

SCl

O

NHS

N

R1

R2

186187

188 Scheme 83

2.4. Thiazolo[5,4-D]Pyrimidines

6-{[(1-Chloro-3,4-dihydronaphthalene-2-yl)methylene]amino}-1-phenyl-2-

thioxo-1,6- dihydro[1,3]thiazolo[5,4-d]pyrimidin-7(2H)-one, which considered as

a 7-thia analogue of the natural purine bases, adenine and guanine, was prepared

in an excellent yield by condensing 189 with cyanoacetic acid hydrazide followed

by Gewald reaction, by reaction of 190 with sulfur and phenyl isothiocyanate in

the presence of triethylamine as a basic catalyst to give 191(Scheme 84).

Thiazolo[5,4-d]pyrimidinone derivative 192 was prepared by heating 191 with a

mixture of triethylorthoformate and acetic anhydride (1:1) [117].


364

Cl

NN

N

N

SS

PhO

Cl

CHO+ H2N N

H

O

CN EtOH

Cl

N

HN

O

CNS, PhNCS

DMF / Et3N

Cl

N

HN

O

N

S

S

H2N

Ph

Ac2O /( EtO)3CH

189 190

191 192

Scheme 84

R1 CHO

S

NH2H2N S

NH2

HN

R1

OH

S

NH2

N

R1

H

H +

- H2O

H

N

S ON

R

R

- H+

N

SO

N

RR R1

NH

S

NH2 - H2O N

SN

R

R

N

NH

SH

R1

193

194

Scheme 85

The synthesis of thiazolo[5,4-d]pyrimidines 194 can be achieved from

different 5-thiazolidinones, 2-butyl-1H-imidazole-5-carbaldehyde, and thiourea

using microwave irradition within 5 min in the presence of HCl. These reactions

study the Biginelli condensation reaction, in which the condensation between an

aldehyde and urea has some similarities to the Mannich condensation. The

generated iminium intermediate 193 (Scheme 85) acts as an electrophile for


365

condensation with the amino group of urea in acidic medium and they were

exposed to microwave irradiation for completion of the reaction [118].

5-Amino-2-(methylthio)thiazole-4-carboxylic acid ethyl ester 195 reacted

with benzoyl isothiocyanate (Scheme 86) to furnish thiazolo[5,4-d]pyrimidine-2-

one 196 [119].

S

NS

CH3

HNS

N

O

Ph

O

S

NO

EtO

SCH3

H2N

+ PhCONCS

195196

Scheme 86

2-Amino-7-chlorothiazolo[5,4-d]pyrimidines 197 (R = Ph, 2,6-Me2C6H3, 4-

MeC6H4, 4-MeOC6H4, 3-F3CC6H4, 4-O2NC6H4, 3-pyridinyl) were prepared, in

good to excellent yields, in single-step process by reaction of 4,6-dichloro-5-

aminopyrimidine with isothiocyanates (Scheme 87). The utility of intermediates

197 was demonstrated by reaction with alkyl or arylamine nucleophiles to afford

differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines 198 [120].

N

NNH2

Cl

Cl

+ R1NCS

N

N N

Cl

SNH

R1 R2NH2base

acid or baseMW

N

N N

HN

SNH

R1

R2

197 198

Scheme 87

Reacting 2-(4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl)thiazolo[5,4-

d]pyrimidin-7-amine 199 with 3-fluorophenyl isocyanate in THF afforded

thiazolo[5,4-d]pyrimidine 200 (Scheme 88) in high yield which act as inhibitors

of Tie-2 receptor tyrosine kinase (TEK) [121].


366

N

NN

S

NH2

N

N

CH3

H2N

F NC

O+

N

NN

S

NH2

N

N

CH3

HN

ONH

F

199 200

Scheme 88

3. MEDICINAL APPLICATIONS

8-Methyl-5,7-dioxo-6-[4-(2H-tetrazol-5-yl)benzyl]-6,7-dihydro-5H-

thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide 201 is useful for

treating cancer or arthritis [122].

N

N

S

O

NH

FN NH

NN

O

O

201

5,7-Disubstituted [1,3]thiazolo[4,5]pyrimidin-2(3H)-amines such as 202,

which are CX3CR1 receptor antagonists and are thereby particularly useful in the


367

treatment or prophylaxis of neurodegenerative disorders, demyelinating disease,

cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease,

rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain [123]

N

N

S

N

H2N

HN OH

Me

Me

S

Me

N F

202

[(Pyridinyl)ethyl]thio[(hydroxymethyl)alkyl]amino[1,3]thiazolo[4,5-

d]pyrimidinone derivatives such as 203 are disclosed as therapeutic agents of

neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular

atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis,

pulmonary diseases such as COPD, asthma or pain [124].

N

N

S

NH

O

HNOH

Me

Me

S

Me

NCl

203

Thiazolopyrimidine derivatives such as 204 was disclosed as modulators of

transient receptor potential vanilloid receptor 1 (TRPV1) and should prove useful

in pharmaceutical components and methods for treating disease states, disorders,

and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough,

asthma, or inflammatory bowel disease [125].


368

N

NS

N

HN

Cl

Cl

HN

CF3

204

5-Amino-3-(2',3'-di-O-acetyl--D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-

2-one 205 has immunomodulatory activity [126, 127].

N

N S

N

O

O

O

O

OH

O

O

H2N

205

Thiazolo[4,5-d]pyrimidine derivatives e.g. 206 are prepared as inhibitors of

ATP-protein kinase interactions [128].

N

N

S

N

HN

CN

NH

N

206


369

2-Substituted-4-aminothiazolo[4,5-d]pyrimidines such as 207 (X = OH, NH2,

OCH3, Cl; A = O, S, SO and SO2) are useful as CX3CR1 chemokine receptor

antagonists [129].

OHHN

N

NS

N AF

FX

207

N-Thiazolopyrimidinyl- and/or N-thiazolopyridinylurea derivatives 208 are

active as adenosine A2B receptor antagonists and useful in the treatment of type 2

diabetes, diabetic retinopathy, asthma and diarrhea [130].

N

N

S

NHN

O

N NH

F

CF3

MeO

208

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INDEX

A

absorption coefficient, 255, 263, 279

absorption spectra, 234, 253, 255, 278, 279,

286, 314

absorption spectroscopy, 288

acceptor, 62, 303

accuracy, 191, 300

acetate, 49, 59, 62, 81, 153, 191, 192

acetic acid, 56, 57, 60, 62, 74, 81, 93, 111,

113, 114, 153, 159, 204, 207

acetone, 22, 74, 75, 110, 113, 114, 115, 173,

177, 180, 181, 188, 191, 192, 193, 194,

206, 208, 222, 223, 231

acetonitrile, 5, 6, 7, 9, 12, 16, 72, 79, 82, 83,

234, 240, 254, 255, 257, 258, 280

acetylation, 100, 108, 109, 110, 204

acidic, 27, 262

acidity, 59, 261, 264, 311

actinomycetes, 197, 200

activation, 11, 12, 13, 32, 63, 238, 239, 241,

243, 277, 282, 292, 293, 297

activation energy, 238, 239, 241, 243, 277,

282, 292, 293

activity level, 197

acylation, 15, 74, 78, 201, 203

adamantane, 47, 48, 52, 57, 59, 60, 61, 64, 66,

67, 69, 71, 84, 86, 88, 89, 90, 95, 97, 220

additives, 225

adducts, 156, 216, 303, 315

adenine, 314

adenocarcinoma, 163

adenosine, 2, 4, 20, 30, 43, 314

adiabatic, 256, 275, 276

ADP, 302, 314

adsorption, 139

adult respiratory distress syndrome, 29

agar, 197

ageing, 168

agent, 30, 32, 151, 165

agents, 2, 29, 30, 93, 96, 121, 162, 169, 172,

196

aggregation, 165, 169, 170

aging, 168

agonist, 4, 169

agriculture, 2, 48

air, 286

alanine, 90

alcohol, 51, 55, 66, 69, 70, 71, 73, 112, 157

alcohols, 5, 232, 308

aldehydes, 5, 193, 194, 204

alicyclic, 14, 84, 92, 97

alkali, 106

alkaline, 70

alkalinity, 59

alkaloids, 91, 148

Index

378

alkenes, xi, 211, 212, 213, 214, 215

alkylation, 60, 62, 65, 72, 73, 76, 78, 79, 151,

159, 173, 185, 225, 227, 238, 240, 268

alkylation reactions, 185

allergy, 83, 96

allosteric, 2, 4, 30

alternative, xi, 35, 99, 120, 128, 129, 133,

172, 212

aluminium, 177

aluminum, 76, 112

aluminum oxide, 112

Alzheimer's disease, 148

amide, 51, 83, 92, 93, 174, 205

amine, 7, 8, 9, 74, 151, 176, 201, 203, 204,

206, 207, 220, 259, 287, 288, 304

amines, 5, 11, 95, 119, 136, 258, 287, 303

amino acid, 302, 311, 314

amino groups, 122, 130, 134, 171, 173

ammonia, 49, 52, 71, 72

ammonium, 14, 59, 185

ammonium salts, 14

analgesic, 172

analog, 220, 305

anesthetics, 172

angiotensin II, 90

aniline, 89, 110, 205

antagonist, 32, 90

antagonists, 2, 4, 32, 60, 90, 91, 170

anthracene, 139, 283

antibacterial, 31, 32, 148, 168, 169

antibacterial agents, 31

antibiotic, 100

antibonding, 226, 238, 265, 267, 270, 284,

306

anti-cancer, 96

anticonvulsants, 172

antidepressant, 53

antidepressants, 172

antihypertensive agents, 169

anti-inflammatory agents, 2

antineoplastic, 30

antineoplastic agents, 30

antioxidant, 2

antitumor, 30, 85, 162

anti-tumor, 24

anti-tumor, 163

antitumor agent, 162

antiviral, 48, 51, 52, 68, 71, 73, 89

APA, 244, 259, 260, 261, 262, 263, 264, 265,

266, 275, 290

apoptosis, 80, 96

aqueous solution, 160, 185

argon, 82, 244, 296, 300, 310, 314

aromatic compounds, 277

aromatic rings, 229, 267, 275, 276, 277, 283

Arrhenius equation, 293

arthritis, 29, 60

Aspergillus niger, 197

assignment, 175, 257, 296

asthma, 83

atherosclerosis, 31

atmospheric pressure, 71

atomic orbitals, 238, 252, 272

atoms, 11, 88, 107, 108, 120, 121, 124, 125,

136, 140, 147, 148, 172, 174, 175, 225,

236, 237, 238, 241, 245, 247, 250, 252,

258, 259, 268, 292, 293, 294, 298, 299,

305, 313

ATP, 302, 314

ATPase, 314

attachment, 81, 99, 101, 148, 155, 156

availability, 2, 5, 23

azacrown ethers, 120

azo dye, 35, 36

azurophilic, 29

B

Bacillus, 198

Bacillus subtilis, 196, 197

back, 148

bacteria, 2, 164, 183, 196, 197

bacterial, 48

bacterial infection, 48

bacterium, 221

barbiturates, 76, 94

barrier, 232, 236, 238, 249, 250, 292, 293,

297, 309

barriers, 236, 249

basicity, 120, 240, 262

Index

379

behavior, 23, 233, 257, 271, 284, 299

bending, 238, 252, 270, 272

benefits, 15, 18

benzodiazepine, 148, 164, 168, 169

benzodiazepines, 172, 231, 308

binding, 302, 303, 304, 311, 314, 315

bioactive compounds, 162

biochemistry, 1

biological activity, 27, 88, 91, 100, 107, 133,

159, 162, 185, 200, 219, 220, 315

biological systems, 302

biologically active compounds, 48, 86, 88,

100, 110, 121, 220

biomacromolecules, 230, 302, 304

biomolecules, 159, 160

blocks, 26, 302

blood, 31, 32, 165, 169

blood clot, 31

blood glucose, 32

boiling, 49, 51, 60, 62, 66, 70, 71, 74, 105,

111, 112, 152, 153, 154, 156, 157, 159,

203, 204

bonding, 174, 175, 250, 309

bonds, 140, 237, 247, 250, 267, 278

bovine, 302, 314

brain, 84

broad spectrum, 47, 220

bromide, 94

bromination, 22, 60, 64

bromine, 20, 60, 64, 74, 122, 125, 130, 138

buffer, 69, 303

building blocks, 26, 302

by-products, 122, 125, 127, 130, 136, 138,

142, 171, 173

C

cabbage, 197

calcium, 82, 86, 152

calf, 305

calixarenes, 121

cancer, 80, 84, 96, 197

cancer cells, 80

Candida, 196, 198

carbenes, 79, 81, 82, 96

carbon, 11, 54, 90, 121, 174, 177

carbon atoms, 121, 174

carbon monoxide, 54, 90

carbonyl groups, 120, 159

carboxylates, 29

carboxylic, 15, 17, 18, 52, 53, 59, 66, 69, 71,

80, 85, 151, 153, 154, 164, 167, 168, 169,

201, 220

carboxylic acids, 15, 18, 85, 151, 168, 169

carrier, 302, 314

catalysis, 185

catalyst, 6, 14, 17, 74, 92, 125, 126, 133, 185

catalytic system, 122, 125, 127, 133

cathode, 11

cation, 237, 238, 240, 250, 251, 252, 255,

259, 261, 263, 264, 265, 266, 268, 275,

283, 284, 285, 286, 289, 292

cell, 48, 305

cervical cancer, 80

cesium, 134, 139

CH3COOH, 203

chemical industry, 88

chemical properties, 64, 148, 159

chemotherapy, 196

chicken, 52, 71

chiral, 121

chloride, 20, 51, 65, 70, 74, 76, 89, 107, 149,

151, 152, 191, 192, 193, 202, 212, 215,

220, 282

chlorine, 64, 140, 149, 287, 298, 299

chloroanhydrides, 202

chloroform, 65, 68, 69, 72, 76, 205, 228, 261

cholecystokinin, 91

chromatography, 124, 125, 177, 178, 180, 204

chronic obstructive pulmonary disease, 60

classes, 79, 81

classical, 16, 149

classification, 254

cleavage, 15, 27, 172, 277

closure, xi, 6, 7, 10, 11, 14, 29, 30, 101, 140,

151, 159, 211, 212

C-N, 236, 242, 249, 287

community, 2

competitive process, 243, 261

components, 7, 109, 287, 302

Index

380

composition, 130, 288

concentration, 196, 222, 232, 261, 264, 288

condensation, 4, 5, 6, 7, 8, 9, 10, 14, 23, 24,

33, 63, 67, 68, 92, 99, 101, 105, 106, 110,

201, 203, 204, 220

conducting polymers, 2, 33

conductive, 36

conductivity, 4, 21, 33

configuration, 215, 256, 293

conjugation, 236, 243, 247, 268, 272

conservation, 269

construction, 148

control, 197, 199, 204, 216, 309, 314

conversion, 47, 103, 106, 202, 227, 229, 258,

292, 296

cooling, 114, 179

copper, 49

correlation, 177, 264, 275, 277, 281

correlation coefficient, 264

correlations, 175, 176, 177

cosmetics, 78

Coulomb, 238, 292

coupling, 15, 92, 106, 109, 121, 168, 177, 215

cross-linking, 302, 303

crown, 121

crystal structure, 244, 246

crystalline, 82, 83, 90, 229

crystals, 191, 192, 193, 194, 195, 196, 205,

223, 229

cultivation, 196, 197

cyanamide, 86

cycles, 129

cyclohexyl, 59

cystic fibrosis, 29

cytochrome, 94

cytotoxic, 31, 84

D

decomposition, 82, 83, 229, 242, 256, 260,

263, 264, 289, 300, 308, 313

dehydration, 99, 105, 106, 173

dehydrogenase, 314

delivery, 2

delocalization, 232

density, 86, 228, 232, 237, 238, 250, 268, 270,

272, 276, 289, 292, 298, 299, 311, 313

density functional theory, 311

depression, 197, 199

dermatophytes, 196

detection, 302

deviation, 130, 272, 281

DFT, 226, 236

diabetes mellitus, 32

diamines, 70, 133, 134, 136, 138, 140

diamond, 48, 87

dichloranhydride, 220, 223

dichloroethane, 185

diethyl amine, 304

diffraction, 63, 212

diffusion, 96, 232

dimer, 13, 296

dimeric, 9

dimerization, 13, 82, 258, 259

dimethylformamide, 3, 107, 154

dimethylsulfoxide, 3

diseases, 24, 164

dispersion, 15

displacement, 298

dissociation, 226, 227, 238, 239, 240, 241,

242, 243, 261, 265, 270, 282, 292, 293,

295, 311

dissolved oxygen, 289

distress, 29

distribution, 276

DMF, 3, 5, 6, 23

DMFA, 193, 194

DNA, 164, 169, 303, 305, 315

donor, 122, 127, 130, 132, 258

Down syndrome, 164

drug delivery, 2

drug design, 4, 21, 24, 32

drugs, 27, 88, 159

dyeing, 35

dyes, 2, 26, 35, 36, 226, 230, 278, 305

E

electrolyte, 12

Index

381

electron, 3, 4, 5, 6, 7, 33, 35, 62, 86, 109, 174,

227, 228, 237, 238, 240, 250, 253, 254,

255, 260, 261, 268, 270, 272, 276, 279,

283, 289, 292, 293, 303, 310, 313

electron density, 86, 228, 237, 238, 250, 268,

270, 272, 276, 292

electron density distribution, 276

electron spin resonance, 313

electrons, 112, 226, 271, 275, 276, 280, 281,

282, 284, 291, 292, 306

elongation, 35, 252, 265, 271, 272

embryo, 71

embryos, 52

emission, 227, 292

emphysema, 29

employment, 33

endothermic, 228

energetic parameters, 275

energy, 34, 112, 204, 227, 229, 236, 238, 239,

241, 242, 243, 247, 249, 252, 253, 254,

255, 272, 273, 275, 276, 277, 278, 279,

280, 282, 283, 285, 292, 293, 294, 306

energy characteristics, 306

energy transfer, 227

entropy, 228, 229

environment, 51, 54, 55, 57, 65, 68, 69, 70,

73, 196, 197, 221

enzymes, 27, 31

epithelia, 31

EPR, 300, 310, 314

equilibrium, 5, 10, 160, 228, 229, 264, 315

Escherichia coli, 196, 198

ESI, 288

ESR, 241, 242, 243, 289, 296, 297, 298, 300,

301

ESR spectra, 242, 243, 296, 298, 300

ESR spectroscopy, 297, 300

ester, 15, 18, 27, 59, 63, 65, 67, 69, 74, 151,

201, 202, 204

esterification, 151

esters, 15, 25, 105

ethane, 212

ethanol, 5, 6, 7, 15, 20, 35, 62, 71, 112, 151,

191, 194, 204, 206, 234, 235, 240, 253,

258, 261, 286, 296

ethers, 93, 99, 105, 112, 114, 120, 121, 151,

171, 172, 173, 174, 177

ethyl acetate, 62

ethyl alcohol, 157

ethylene, 56, 156

ethylene glycol, 56, 156

ethylenediamine, 67, 127, 130, 136

ethyleneglycol, 70

excitation, 227, 238, 240, 243, 250, 254, 255,

256, 270, 272, 275, 276, 277, 278, 279,

286, 289, 295

exposure, 256, 296

extinction, 261

F

family, 31, 83

ferrocenyl, 134

fibrosis, 29

film, 84

films, 84, 97

filtration, 23, 215

financial support, 87, 116, 165, 200, 209, 224

flame, 114

flow, 114

fluorescence, 227

fluorinated, 173, 174

fluorine, 172, 174, 177, 300, 305

fluorine atoms, 172, 174, 305

folding, 302

formaldehyde, 107

formamide, 49, 89

FTIR, 112

fungi, 2, 196, 197

fungicidal, 48, 51

fungicide, 85

G

GABA, 169

gas, 229, 233, 312

gas phase, 229, 312

gases, 300

gastrin, 91

Index

382

gel, 112, 177, 222

generation, 33, 230, 300

glass, 241

glucagon, 2, 3, 4, 32

glucose, 32, 197

glutamate, 314

glycol, 3, 15, 56, 156

gram-negative bacteria, 164

grants, 36, 142

granules, 29

GroEL, 302, 314

groups, 2, 4, 5, 14, 34, 35, 56, 68, 81, 83, 110,

120, 121, 122, 130, 134, 159, 162, 171,

172, 173, 175, 185, 201, 202, 204, 241,

242, 243, 244, 264, 300, 306, 309, 310

growth, 35, 163, 183, 197, 199, 200, 221, 230,

232

guidelines, 2

H

H2N3, 309

half-life, 297

Halides, 312

halogen, 19, 122, 124, 154

heat, 229, 275

heating, 16, 17, 18, 55, 56, 60, 62, 66, 70, 71,

73, 82, 83, 85, 101, 130, 133, 148, 228, 229

height, 236, 249, 293

herbicide, 303

herpes, 30, 31

heterocycles, xi, 4, 21, 91, 101, 172, 184, 212,

225, 285

heterogeneous, 17

hexafluorophosphate, 3, 12

hexane, 113, 178, 179, 180, 191, 194, 195,

196, 205, 206, 207, 222, 223

high pressure, 70

high temperature, 64, 85

high-level, 243, 295

high-throughput screening, 31

HIV, 85

HLE, 3, 29

holoenzyme, 31

HOMO, 238, 239, 251, 252, 253, 254, 255,

269, 270, 272, 273, 274, 277, 279, 283,

284, 285

hormone, 32

HPLC, 19, 232

human, 3, 4, 29, 32, 77, 314, 315

hybridization, 238, 272

hydrate, 149, 151, 152, 153, 157, 159

hydrazine, 149, 151, 152, 153, 154, 157, 159,

220

hydride, 3, 54, 82

hydro, 35

hydrochloric acid, 67, 76

hydrogen, 107, 108, 140, 174, 175, 231, 247,

258, 259, 303, 309

hydrogen atoms, 107, 108, 247, 258, 259

hydrogen bonds, 140

hydrogenation, 70, 85

hydrolysis, 23, 61, 101, 105, 201, 256, 257

hydrolyzed, 173, 256, 305

hydrophilic, 35

hydrophobic, 35

hydroxyl, 174

hygiene, 78

hypertensive, 170

hypnotic, 148, 164

hypotensive, 75

hypoxia, 30

I

identification, 230, 244, 302

illumination, 278

immune system, 48, 81

immunity, 94

immunosuppression, 60

immunosuppressive, 76

in situ, 5, 124, 129, 133, 136, 138

in vitro, 29, 89, 196, 198, 222

inactive, 222, 307

inclusion, 293

incubation, 197

independence, 274

individuality, 222

industrial, 16

Index

383

industry, 2, 88

inert, 122, 132, 300

inertness, 243

infectious, 196

infectious disease, 196

infectious diseases, 196

inflammation, 30

inflammatory, 2, 24, 29, 77, 164, 220

influenza, 70

inhibition, 29, 32, 148, 164

inhibitor, 31

inhibitors, 25, 29, 31, 83, 91, 162, 169

inhibitory, 29, 170, 196, 197, 222

inorganic, 5, 14, 120

insertion, 52, 82, 83, 168, 231, 257, 258, 291,

304, 305

insight, 313

inspection, 281

instability, 6, 109

interaction, xi, 49, 50, 51, 52, 55, 56, 58, 65,

66, 68, 70, 71, 72, 74, 75, 76, 84, 109, 152,

157, 172, 174, 176, 177, 188, 191, 195,

196, 202, 212, 219, 220, 245, 299

interactions, 58, 213, 247, 299, 309

intermolecular, 204, 245, 300

internet, 84

interphase, 151, 185

intrinsic, 35

ionization, 288

ions, 121, 139, 303, 308

IR spectra, 112, 174, 186, 187, 191, 204, 205,

206, 204, 207, 228, 296, 300

IR spectroscopy, 296, 297

iron, 206

irradiation, 16, 18, 19, 227, 229, 231, 233,

235, 236, 242, 243, 253, 256, 257, 258,

260, 262, 263, 277, 286, 287, 288, 289,

290, 295, 296, 300, 302, 305

ischemia, 30

isoenzymes, 31

isolation, 23, 111, 129, 173, 225, 300, 301,

310, 313

isomers, 86, 99, 100, 101, 105, 109, 110, 129,

148, 153, 229, 242

K

K+, 314

ketones, 5, 8, 14, 17, 18

kinase, 25

kinetic curves, 234

kinetic studies, 288

kinetics, 120, 293

KOH, 113, 114, 222

L

labeling, 226, 230, 302, 303, 304, 305, 314,

315

language, 2

laser, 231, 293, 295, 296, 302

lattice, 229

leukocyte, 3, 29

Lewis acids, 60

lifetime, 303

ligand, 120, 122, 132, 136

ligands, 91, 127, 132, 134, 168

limitations, 120

linear, 2, 99, 100, 101, 103, 105, 109, 110,

119, 122, 125, 129, 130, 136, 140, 226,

275, 281, 283

linear regression, 275

linkage, 18

lipid, 48

lipophilic, 83

liquids, 14

liver, 94

loading, 133

locomotion, 170

low temperatures, 300

low-intensity, 254, 257, 258

low-temperature, 225, 241, 289, 298

LUMO, 238, 239, 251, 252, 253, 254, 255,

269, 270, 272, 273, 274, 277, 278, 279,

283, 284, 285

lung, 29

lung disease, 29

Lyapunov, 144

lymphocytes, 81, 305, 315

Index

384

M

M.O., 95, 97

magnetic, 230, 298, 301, 314

magnetic materials, 230, 301

magnetic properties, 314

magnetism, 230, 301, 306

magnets, 302, 306

malaria, 24

manganese, 105

mass spectrometry, 215, 287, 288

materials science, 1

matrices, 313

matrix, 225, 244, 295, 297, 298, 300, 301, 313

matrix condition, 298

media, 21, 27, 300

membrane permeability, 48

membranes, 315

Mendeleev, 217, 309, 311, 312, 313, 314

metals, 120

methanol, 5, 6, 7, 16, 22, 49, 212, 256

methine group, 121

methyl group, 22, 175, 177

methyl groups, 175

methylation, 23, 52, 71, 177

methylene, 5, 7, 11, 13, 15, 23, 86, 120, 121,

156

methylene group, 11, 13, 86

MgSO4, 179

mice, 170

microbial, 196

microorganism, 197, 222

microorganisms, 196, 197, 199, 221

microwave, 4, 14, 16, 17, 18, 19

mitochondrial, 302, 314

mixing, 11, 15, 195, 223

mobility, 86

model system, 230, 306

modeling, 302

models, 301, 302

moieties, 35, 120, 121, 122, 130, 139, 215

moisture, 84

molar ratio, 185

mole, 114

molecular orbitals, 238, 239, 240, 252, 279,

283, 284, 306

molecular oxygen, 296

molecular sensors, 120

molecular structure, 35, 314

molecules, 2, 11, 24, 30, 33, 48, 62, 83, 87,

120, 121, 139, 172, 240, 245, 258, 259,

264, 293, 301, 309, 312

monoamine, 148, 164, 170

monoamine oxidase, 148, 164

motion, 74

MPS, 3, 11, 12

multidisciplinary, 1

multiplicity, 299

muscle, 172

muscle relaxant, 172

mutagenesis, 314

mycobacterium, 198

myelin, 168

N

Na+, 314

Na2SO4, 191, 192, 194

N-acety, 15, 103

NaCl, 197

naphthalene, 121, 138, 283

National Academy of Sciences, 171

National Science Foundation, 87, 116, 165,

200, 209, 224

natural, 4, 27

nerve, 164, 168

neurodegenerative, 31

neurodegenerative disorders, 31

neuroleptic, 48

neutralization, 257, 259

neutrophil, 29

NHC, 63

nitrate, 52, 71, 72

NMR, 111, 112, 113, 114, 115, 116, 173, 174,

175, 176, 177, 178, 179, 180, 181, 185,

188, 190, 204, 208, 215, 216, 221, 222,

223, 228

N-N, 226, 237, 238, 239, 240, 243, 265, 271,

272, 277, 280, 282, 284, 287, 292, 294, 295

Index

385

noble gases, 300

non-destructive, 230

norbornene, 213

normal, 122, 140

nuclei, 175, 176, 177, 233, 245, 276

nucleic acid, 302, 306

nucleophiles, xi, 11, 92, 97, 211, 230, 303

nucleus, 23, 64, 81, 226, 228, 233, 236, 237,

238, 243, 245, 246, 247, 249, 250, 252,

259, 267, 268, 270, 271, 272, 273, 274, 292

nutrient, 196

O

observations, 31, 176

o-dichlorobenzene, 58, 80, 81, 156

oil, 112, 115, 191, 204

oligomeric, 125, 127, 130

oligomeric products, 125

oligomers, 122, 124, 125, 129, 136, 140, 142

optical, 35, 139

optical properties, 139

optimization, 236, 246

optoelectronic, 4, 21

optoelectronic devices, 4, 21

organic, 5, 11, 14, 15, 18, 21, 22, 33, 79, 86,

120, 121, 172, 194, 202, 230, 241, 244,

301, 302, 312

organic compounds, 33

organic solvent, 79

organic solvents, 79

organoselenium, xi, 212

orientation, 245, 249

oscillator, 254, 255, 278, 279

oxidation, 154

oxidative, 52, 71, 138

oxide, 73, 112, 231

oxides, 38, 227, 231, 232, 308

oximes, 2

oxygen, 54, 120, 258, 287, 288, 289, 296, 305

P

palladium, 63

Pap, 40

parameter, 226, 227, 276, 277, 289, 298, 299

Parkinson, 24

particles, 112

partnership, 87, 116, 165, 200, 209, 224

patents, 53, 164

pathogenesis, 29

pathogenic, 183, 196, 197

pathology, 83

pathways, 27, 79, 257, 258

PCT, 91, 96, 169, 170

peptide, 121

peptides, 303, 315

permeability, 48

perturbation, 299

pesticides, 2

petroleum, 88, 115, 195, 196

pH, 69, 86, 113, 114, 191, 192, 193, 194, 204

pharmaceutical, 27, 36, 48, 59, 91, 96, 149,

162

pharmaceuticals, 2, 26, 27

pharmacological, 24, 30, 48, 93, 147, 149,

154, 157, 159, 165, 172, 220

pharmacology, 1, 30, 32

pharmacotherapy, 83

phenol, 84

phosphate, 69

phosphodiesterase, 148

phosphor, 164

phosphorus, 62, 121, 152, 157

photochemical, 120, 229, 230, 243, 244, 253,

256, 257, 259, 261, 263, 264, 265, 266,

277, 286, 290, 292, 295, 298, 301, 306,

308, 312, 313

photochemical transformations, 295

Photodissociation, 236, 290, 307, 309, 312

photoinduced electron transfer, 261

photoirradiation, 301

photolysis, 225, 230, 231, 232, 233, 241, 242,

243, 244, 256, 257, 258, 259, 261, 286,

287, 288, 289, 293, 295, 296, 297, 298,

299, 300, 301, 302, 303, 305, 306, 309,

310, 313, 315

photosensitivity, 278, 306

photovoltaic, 33

Index

386

photovoltaic devices, 33

physical activity, 74

physics, 1

physiological, 61, 106, 147, 148, 160, 162

pitch, 202

planar, 120, 244, 247, 249, 250, 268

platelet, 169, 170

Platelet, 167

platelet aggregation, 170

PM3, 226, 236, 237, 241, 242, 243, 245, 248,

249, 250, 256, 264, 265, 267, 268, 272,

273, 274, 275, 279, 280, 282, 285

PM3 method, 241, 242, 249, 264, 265, 267,

285

polyamine, 120, 124, 127, 128, 129, 130, 133,

136, 138, 139, 140, 142

polyester, 35

polyethylene, 3, 15

polymer, 84, 231

polymerase, 31

polymerization, 63

polymers, 2, 33, 36

polystyrene, 3, 15

polythiophenes, 33

poor, 298

population, 228, 238, 247, 270, 272, 277, 278,

283

pore, 84

porous, 15

potassium, 5, 56, 81

potato, 197

powder, 206, 300

prediction, 35

press, 145, 146, 310

pressure, 70, 71, 83, 178, 179, 180, 205, 228

primary products, 295

probability, 242, 293

production, 14, 156, 306

prognosis, 84

program, 31, 32, 87, 116, 165, 177, 200, 209,

224

promoter, 12

propane, 136

propylene, 73

proteases, 31

protection, 18, 27, 302

protein, 302, 314

proteins, 302, 303, 304, 306, 311, 315

proteolysis, 303, 315

protocol, 23, 139

proton pump inhibitors, 91

protons, 86, 174, 175, 177, 188, 215

pseudo, 63, 92, 175

Pseudomonas, 196, 197, 198, 199

Pseudomonas aeruginosa, 196

psychopharmacological, 172

purification, 20, 109, 129, 133

pyridine ring, 62, 120, 231, 298

pyrimidine, 24, 31, 32, 225

pyrrole, 99, 100, 101, 106, 107, 108, 109, 156,

183, 197, 204

pyruvate, 27

pyruvic, 99, 100, 101, 105, 112

Q

quantum chemical calculations, 264, 293, 312,

313

quantum yields, 233, 234, 236, 244, 256, 257,

260, 262, 263, 286, 290, 291, 305

quantum-chemical calculations, 229, 232,

238, 245, 253, 275, 281, 295

quantum-chemical methods, 236, 246, 247,

250, 267

quasi-linear, 236, 247, 250, 264, 268, 269

R

radiation, 304, 310

radiolabeled, 302

Raman, 311

range, 2, 14, 18, 27, 174, 175, 227, 239, 247,

263, 277, 278, 286, 291, 293, 305

rats, 168

reactant, 108

reactants, 7, 10

reaction center, 315

reaction mechanism, 295

reaction time, 4, 16, 20

Index

387

reactivity, 4, 8, 47, 56, 63, 108, 109, 110, 124,

135, 151, 159, 172, 185, 230, 241, 303, 306

reagent, 12, 15, 107, 108, 191, 192, 193, 212,

213, 215, 304, 315

reagents, xi, 2, 15, 27, 62, 80, 85, 130, 149,

172, 212, 213, 288, 302, 316

receptor agonist, 21, 30

receptors, 30, 90, 121, 148, 164, 168

recrystallization, 179

recrystallized, 206, 213, 215

redistribution, 270

redox, 120

regeneration, 14

regression, 280, 281, 282, 283

regression analysis, 280, 281, 282, 283

regular, 205

relationship, 230, 306

relationships, 30, 169, 175

relaxation, 238, 270, 276, 311

repair, 305

residues, 302, 314

resin, 15, 18

resistance, 48

resolution, 300, 310, 314

resorcinol, 35

respiratory, 29

respiratory distress syndrome, 29

retardation, 240

retention, 234

retinoids, 96

rheumatoid arthritis, 29, 60

rigidity, 85, 120

rings, 99, 100, 101, 106, 107, 108, 109, 229,

247, 258, 267, 268, 272, 273, 275, 276,

277, 283

RNA, 3, 31

room temperature, 3, 23, 75, 82, 107, 173,

178, 179, 180, 191, 192, 193, 194, 195,

203, 205, 231

rotations, 247, 249

Russian Academy of Sciences, 182, 225

S

salt, 23, 81, 82, 89, 185, 202, 220, 260, 261,

262

salts, 14, 22, 53, 82, 96, 109, 121, 159, 161,

173, 215, 219

Schiff base, 121

Schmid, 309

search, 151

sedative, 24

sedatives, 172

selectivity, 15, 17, 134

selenium, xi, 212

semiconductors, 84

sensitivity, 226, 227, 230, 244, 256, 277, 278,

290, 306, 312

sensors, 4, 21, 120, 139

separation, 113, 244

series, 22, 29, 30, 31, 47, 81, 82, 85, 90, 96,

107, 109, 151, 160, 201, 229, 230, 267,

268, 270, 271, 274, 278, 280, 281, 283, 306

serine, 29

shade, 35

shock, 229, 313

shock waves, 313

shoulder, 253, 255

side effects, 43

signals, 174, 177, 215, 242, 314

silica, 112, 124, 222

silver, 52, 71, 72, 173, 311

simulation, 300, 301

simulations, 300

sites, 15, 130, 232, 302, 311, 314

skeleton, 252

sleep, 172

sodium, 49, 54, 55, 60, 81, 82, 134, 139, 153,

157, 159, 173, 191, 192, 230, 231

solid state, 82, 228

solubility, 11, 21, 185, 193

solvent, 177, 178, 179, 192, 194, 197, 205,

213, 225, 228, 236, 240, 258, 259

solvent molecules, 240, 258, 259

solvents, 5, 6, 14, 79, 82, 228, 256, 258, 308

spacers, 127, 139

spatial, 175

Index

388

species, 12, 227, 228, 230, 232, 253, 256, 296,

298, 300, 301, 302, 303

spectroscopy, 175, 215, 225, 228, 288, 296,

297, 300, 301, 310, 311, 312, 313, 314

spin, 84, 188, 191, 215, 225, 230, 232, 289,

293, 295, 298, 299, 300, 301, 306, 310, 313

stability, 21, 82, 84, 111, 298, 301, 313

stabilization, 232, 258

stabilize, 229, 258, 305

stages, 86

standard deviation, 281

standards, 177

Staphylococcus aureus, 31, 196, 197

starch, 197

steric, 109, 247, 268, 272

storage, 82

strain, 247

strength, 35, 255, 278, 279

streptomyces, 100, 197, 199

structural changes, 238, 250, 270

structural characteristics, 239

styrene, 212

substances, 24, 48, 78, 88, 100, 106, 148, 149,

151, 159, 162, 164, 165, 197, 199, 201,

220, 221, 222

substitution, 24, 54, 72, 100, 106, 107, 108,

109, 122, 125, 130, 135, 138, 140, 171,

173, 185, 313

substitution reaction, 100, 106, 108, 109, 135,

185

substrates, xi, 5, 7, 10, 14, 15, 29, 35, 109,

185, 211, 212

sulfate, 173

sulfur, xi, 4, 5, 7, 8, 10, 11, 12, 13, 14, 15, 17,

18, 20, 23, 24, 35, 83, 120, 151, 153, 154,

212

sulfuric acid, 35, 232, 308

sulphate, 256

sulphur, 82

superposition, 254

supervision, 148

suspensions, 305

symbols, 283

syndrome, 29, 148, 164

T

tachycardia, 30

TCC, 196

tellurium, xi, 212

temperature, 3, 7, 23, 50, 64, 70, 71, 75, 82,

85, 107, 173, 178, 179, 180, 191, 192, 193,

194, 195, 203, 205, 225, 228, 229, 231,

241, 289, 293, 295, 296, 298

tetrahydrofuran, 55, 223

therapeutic agents, 29, 30

therapeutics, 21, 32

therapy, 24, 27, 59, 169

thermal decomposition, 313

thermal stability, 84

thermodynamic, 120

thermodynamic properties, 120

thermolysis, 277, 308

thiamin, 3, 27

thiamine, 28

thin films, 84

threshold, 226, 274, 275, 277, 280, 281, 282,

306

thromboxanes, 148, 162

thymus, 305

tissue, 30, 31

titanium, 20, 63

title, 21, 36, 171, 173, 174

toluene, 18, 82, 156, 173, 179, 203, 258

toxicity, 48

tranquilizers, 172

transactions, 92

transfer, 34, 227, 237, 238, 240, 242, 253,

254, 268, 270, 272, 276, 283, 289, 292

transformation, 133, 154, 202, 216, 227, 298

transformations, 91, 157, 159, 160, 259, 295

transglutaminase, 31

transistors, 33

transition, 92, 233, 239, 241, 243, 254, 255,

260, 278, 279, 280, 283, 293, 295

transition metal, 92

transitions, 253, 254, 255, 256, 279, 283, 292,

296

trifluoroacetic acid, 3, 15, 18, 228

trifluoromethyl, 307

Index

389

tuberculosis, 24, 168, 196, 198, 222

tumor, 24, 163

two step method, 23

U

uniform, 287

UV, 111, 112, 113, 114, 115, 116, 185, 186,

187, 191, 194, 195, 196, 204, 205, 206,

207, 221, 222, 233, 253, 260, 287, 296,

297, 301, 302, 304, 312, 313

UV irradiation, 233, 296

UV radiation, 304

UV spectrum, 113, 114, 222

V

vacuum, 79, 148, 205, 223

valence, 35, 237, 238, 246, 247, 248, 250, 272

values, 112, 191, 204, 264, 276, 293, 298

van der Waals, 247

vapor, 114

variation, 24, 227

vector, 299

ventricular tachycardia, 30

versatility, 2, 21, 24, 29

veterinary medicine, 77

vibration, 293

viruses, 70

visible, 139, 226, 230, 253, 256, 260, 277,

278, 286, 287, 289, 304, 305, 312

vitamin B1, 27

W

water, 18, 22, 23, 48, 61, 112, 114, 156, 174,

179, 191, 192, 193, 194, 197, 204, 205,

206, 207, 219, 220, 222, 256, 262, 303,

305, 315

water-soluble, 220

wavelengths, 227, 256, 284

wool, 35

workability, 21

workers, 4, 5, 19, 99

X

X-ray analysis, 83, 212

xylene, 49, 57, 113

Z

zinc, 27

Zn, 203

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Heterocyclic Compounds: Synthesis, Properties and Applications