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Abstract The reaction of the newly synthesized N-(2,2-dichloro-1-cyanoethenyl)prop-2-enamide and 4-chloro-N-(2,2-dichloro-1-cyanoethenyl)butanamide with methylamine or dimethylamine gave rise to previously unknown 5-amino-1,3-oxazole-4-carbonitriles. In the case of the reaction of N-(2,2-dichloro-1-cyanoethenyl)amides with ethylenediamine diacetate, new (Z)-2,3,5,6,7,8-hexahydro-7-oxo-1H-imidazo[1,2-a][1,4]diazepine-9-carbonitrile and 4-chloro-N-(cyano(imidazolidin-2-ylidene)methyl)butanamide were obtained.

The reaction of substituted 3,3-dichloroprop-2-enenitriles containing an N-methylurea or N,N-dimethylurea residue in the second position with secondary aliphatic amines gives rise to previously unknown 2,5-bis(alkylamino)-1,3-oxazole-4-carbonitriles. In the case of the reaction of N-(2,2-dichloro-1-cyanoethenyl)-N′-methylureas with benzylamines, 4,5-bis(alkylamino)-1-methyl-1H-imidazol-2(5H)-ones were obtained.

A method for the synthesis of a series of new substituted 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones was proposed based on the Diels–Alder type reaction of 4-methoxy-1,3-oxazoles with maleimide derivatives.

A potential of using nickel complexes with 1,3-dicarbonyl compounds for the transformation of heterocyclic aminonitriles into fused systems with a 4-aminopyridine core was evaluated. A possibility of introducing acidophobic groups into the molecules of fused compounds was shown.

Reaction of 2-chloro-N-(2,2-dichloro-1-cyanovinyl)acetamide with dimethylamine gave 5-(dimethylamino)-2-[(dimethylamino)methyl]-1,3-oxazole-4-carbonitrile, where aliphatic dimethylamino group was regioselectively alkylated with iodomethane. The resulting trimethylammonium salt reacted diastereoselectively with aromatic aldehydes to form new substituted 2-(oxiran-2-yl)-1,3-oxazoles.

A preparative method for the synthesis of 1-alkyl-3-methyl-1,4-dihydropyrazolo[4,3-c]pyrazoles was developed. The alkylation of the obtained compounds with halocarboxylic acid esters was also investigated. A principal possibility of creating libraries of compounds based on pyrazolo[4,3-c]pyrazole derivatives was shown.

H-Lithiation and Br-lithiation reactions of 1,3-thiazole were studied in order to obtain new thiazole derivatives. Four isomeric chloromethyl derivatives of 1,3-thiazole containing a protected aldehyde group like 2-(1,3-dioxolan-2-yl)-5-(chloromethyl)-1,3-thiazole, 5-(1,3-dioxolan-2-yl)-2-(chloromethyl)-1,3-thiazole, 4-(1,3-dioxolan-2-yl)-2-(chloromethyl)-1,3-thiazole, and 2-(1,3-dioxolan-2-yl)-4-(chloromethyl)-1,3-thiazole were synthesized. Their nucleophilic substitution reactions with dimethylamine and sodium methylthiolate were studied. New aldehydes of 1,3-thiazole series of low-molecular weight were obtained.

A series of new 5-amino-1H-imidazole-4-carbonitriles were synthesized based on substituted 3,3-di-amino-2-methylideneaminoprop-2-enenitriles.

Acylation and sulfonylation of substituted pyrazolo[3,4-d][1,2,3]triazin-4-ones, as well as reactions with acylating agents proceeding via destruction of the triazine ring are studied.

Novel derivatives of 3,3-dichloroprop-2-enenitrile containing methylurea or phenylurea fragments have been synthesized. The obtained N-(2,2-dichloro-1-cyanoethenyl)-N′-methyl(phenyl)ureas undergo intramolecular cyclization in the presence of triethylamine to form 4-(dichloromethylidene)-5-imino-1-methyl (phenyl)imidazolidin-2-ones. Reactions of N-(2,2-dichloro-1-cyanoethenyl)-N′-methylurea with aliphatic amines have afforded 4-(alkylamino)-4-(dichloromethyl)-5-imino-1-methylimidazolidin-2-ones.

The interaction of available 2-methylsulfonyl-3-ethoxyacrylonitrile with amidine, their analogs, and aminoazoles containing amidine fragment, yielding earlier unknown 4-amino-5-methylsulfonylpyrimidines and their fused derivatives has been studied.

Reactions of 1-acylamino-2,2-dichloroacrylonitriles, diethyl 1-acylamino-2,2,2-trichloroethyl-phosphonates and 1-acylamino-2,2-dichloroethenylphosphonium salts with natural alkaloid cytisine have been studied. A series of novel multifunctional cytisine derivatives containing pharmacophore 1,3-oxazole moiety have been obtained. Composition and structure of the synthesized compounds have been confirmed by mass spectrometry and NMR spectroscopy data.

Alkylation of 4-(phenylthio)-1H-pyrazol-5-ols with methyl bromoacetate has afforded a series of phenyl pyrazolyl sulfides which have been oxidized into sulfones. The resulting esters have been hydrolyzed into the corresponding acids. The synthesized compounds potentially exhibit biological activity.

Reactions of substituted 2-hydroxyalkyl-1,3-thiazole-5-carbaldehydes and 5-hydroxyalkyl-1,3-thiazole-2-carbaldehydes with phenylhydrazine, isoniazid, N-substituted rhodanines were performed as well as Biginelli reaction with acetoacetic ester and urea. As a result, new 1,3-thiazole derivatives were obtained. They are of interest as potential bioactive substances.

Reactions of derivatives of diethyl 1-acylamino-2,2,2-trichloroethylphosphonates with different pharmacophore aminoalkanols afforded new 5-hydroxyalkylamino-1,3-oxazole derivatives. The latter are promising substrates for producing new 4-phosphorylated peptidomimetics containing alcohol residues.

A general approach towards synthesis of 2(5)-hydroxyalkyl-substituted 1,3-thiazole derivatives has been proposed. The method includes lithiation of 1,3-thiazole ring followed by reacting the formed thiazole lithium derivatives with electrophiles.

Reaction of available derivatives of 1-acylamino-2,2-dichloroacrylic acids as well as diethyl esters of 1-acylamino-2,2,2-trichloroethylphosphonic acids with N-methyl-D-glucamine furnished previously unknown 1,3-oxazole derivatives containing nitrile, ester or phosphonyl groups in the position 4 and N-methyl-D-glucamine residue in the position 5.

Interaction of 4-phosphorylated derivatives of 5-amino-2-aminoalkyl-1,3-oxazole with 4-(4-acetoxybenzylidene)-2-phenyl-1,3-oxazol-5-one resulted in the formation of new 1,3-oxazole derivatives. The latter undergo 1,3-oxazole ring opening to give phosphorylated tripeptides with a dehydrotyrosine fragment.

Chlorination of readily available 2-methyl-5-methylsulfanyl-4-tosyl-1,3-thiazole has afforded 2-methyl-4-tosyl-1,3-thiazole-5-sulfonyl chloride. The latter can react with amines to build sulfonamides, efficient electrophilic reagents capable of undergoing nucleophilic substitution reactions. Regiochemistry of the described reactions depends strongly on the nature of nucleophiles, used for regioselective synthesis of some previously unknown trisubstituted 1,3-thiazoles.

Previously unknown methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates have been synthesized. Their reactions with amines and amidines have yielded the corresponding sulfonamides and 6H,7H-[1,3]oxazolo-[5,4-d]pyrimidin-7-ones.

Chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitrile in aqueous acetic acid at 50–60°C afforded new 2-aryl-5-chloro-1,3-oxazole-4-carboxamides. The reactivity of the chlorine atom with respect to the N-, O-, and S-nucleophiles was investigated.

Derivatives of 4-benzylsulfanyl-1,3-oxazole and 4-benzylsulfanyl-1,3-thiazole were synthesized using available amidophenacylating reagents. By the oxidative chlorination compounds obtained were converted to 1,3-oxazole-4-sulfonyl and 1,3-thiazol-4-sulfonyl chlorides. The latter were used to prepare the corresponding sulfonamides.

Reaction of 2-methoxy-5-morpholino-1,3-oxazole-4-carbonitrile with benzylamine, phenethylamine and phenylhydrazine results in the new substituted 5-amino-2,3-dihydro-1H-imidazol-2-ones.

Reaction of 4-cyano-1,3-oxazole-5-sulfonyl chlorides with amidines results in new 7-amino-1,3-oxazolo[5,4-d]pyrimidines. Their structure was confirmed by spectral methods and X-ray diffraction analysis.

There are two strategic approaches to construct the azolopyrimidine system: via cyclization of the pyrimidine ring on an azole or by fusion of azole ring with the pyrimidine. In this work we used two approaches using 2-aroylaminomalonodiamides Ia–Ic as the starting materials [5]. In this case, the target products were 2-aryl-6H,7H-[1,3]oxazolo[5,4-d]pyrimidine-7-thiones Va–Vc and 2-aryl-6H,7H-[1,3]thiazolo[5,4-d]pyrimidine-7-thiones VIa–VIc. The reactions sequence I→II→IV→V has as the initial reaction that of 2-aroylaminomalonodiamides Ia–Ic with ethyl formate in the presence of sodium ethoxide to form 5-aroylamino-6-hydroxypyrimidin-4-ones IIa– IIc. The C NMR spectra of these compounds contain the characteristic signals of the C and C atoms of the pyrimidine ring in the ranges of 102.87–103.34 and 165.75–165.85 ppm, respectively. In the H NMR spectra there are no signals of the primary amide groups, and the singlet of СH proton appears in the range of 8.04–8.07 ppm.

Various approaches to the synthesis of new derivatives of diethyl 5-mercapto-2-R-1,3-oxazole-4-ylphosphonates were considered. The behavior of these compounds in the presence of mineral acids and alkalis resulting in the synthesis of previously unknown 5-mercapto-2-R-1,3-oxazole-4-ylphosphonic acids was studied.

The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acetyl, benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-substituted aminomethylphosphonic acids.

Oxidative chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitrile results in the previously unknown 4-cyano-1,3-oxazole-5-sulfonyl chlorides and N-substituted sulfonamides.

The reaction of substituted 2-oxo-2,3-dihydro-1H-imidazole-4-carbonitriles with Lawesson’s reagent gave new compounds of the fused imidazo[4,5-d][1,3,2]diazaphosphinine system.

Reactions of N-aroyltrichloroethaneimines CCl3C(R)=NCOAr (II, R = COOMe, CN) with phosphorus nucleophiles were studied. The reaction of imines II with o-phenylenediethylamidophosphite proceeded as [4+1]-cycloaddition leading to formation of stable spirocyclic phosphoranes. The structure of one of them was proved by the XRD analysis. The reaction of imine II with acyclic P(III) derivatives [Ph3P, Ph2POEt, (PhO)3P] also includes the formation of labile monocyclic phosphoranes which eliminate phosphine oxide and undergo chlorotropic transfer leading to trichloroazadienes CCl2=C(R)N=C(Cl)Ar. The reaction of imines II with (EtO)2POH in the presence of triethylamine leads to the formation of (EtO)2P(O)Cl and the corresponding dichlorovinylamides CCl2=C(R)NHCOAr.

In the reaction of the available 1-tosyl-2,2-dihlorenamides with the Lawesson’s reagent the derivatives of 4-tosyl-1,3-thiazole were shown to form containing a labile chlorine atom at the C5 position. This fact was used for the synthesis of a number of the previously unknown bifunctionally substituted 4,5-thiazoles.

Reactions of available diethyl 1-acylamino-2,2-dichloroethenylphosphonates with amino acids esters were studied, which in the case of esters of proline, nipecotic and isonipecotic acids resulted in N-substituted derivatives of 5-amino-4-diethoxyphosphoryloxazol in high yields. Their behavior in the acidic and alkaline media was investigated by the example of methyl N-(4-diethoxyphosphoryl-2-R-oxazol-5-yl)isonipecotinate.

The sequential treatment of accessible 2-aroylamino-3,3-dichloroacrylonitriles with excess of amine, triethyl orthoformate, and hydrogen sulfide results in 4-substituted oxazole[5,4-d]pyrimidine-7(4H)-thione. The sequential reactions of the same reagents with sodium methylate, trifluoroacetic acid, triethyl orthoformate, and amines give rise to the 6-substituted oxazole[5,4-d]pyrimidin-7(4H)-one.

A method for the synthesis of a new 4-phenylsulfonyl-substituted 3-aminopyrrole was developed and related pyrrolo[3,2-d]pyrimidine derivatives were synthesized.

An attempt to effect exhaustive alkylation of 2-amino-1-(benzimidazol-2-yl)-3-(4-methoxybenzoyl) indolizine with alkyl iodides in boiling acetone led to the formation of 6,6-dimethyl-8-(4-methoxybenzoyl)-6,7-dihydrobenzo[4′,5′]imidazo[1′,2′: 1,6]pyrimido[5,4-a]indolizine instead of expected N-alkyl derivatives. The product structure was proved by X-ray analysis.

The N-1,1,1,2-Tetrachloroethylamides were found to react with diethyl amidophosphites via the Arbuzov reaction to afford N-substituted amides of ethyl 1-acylamino-2,2,2-trichloroethylphosphonic acids. A convenient method for the synthesis of new 4-phosphorylated 5-amino-1,3-oxazoles on their basis was developed.

Previously unknown 5-amino- and 5-sulfanyl-1,3-oxazole derivatives containing a 1,3,4-oxadiazole, 1,3,4-thiadiazole, or 1,2,4-triazole fragment at C4 were synthesized from accessible 1,3-oxazole-4-carboxylic acid hydrazides.

New synthetic method for preparation of previously unknown 1,2,3-trisubstituted pyrroles based on the reaction of the available phosphorus-containing 4-arylaminoacrylonitriles with chloroacetonitrile or ethyl chloroacetate is developed.

On the basis of methyl esters of 2-aryl-5-hydrazino-1,3-oxazole-4-carboxylic acids the earlier unknown methyl esters of 2-aryl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-1,3-oxazole-4-carboxylic acids as well as their functional derivatives were synthesized. The latter were used for further transformations, in particular, for introducing the residues of highly basic aliphatic amines into the 5 position of oxazole, and the oxazol-2-yl moiety into the 4 position of the oxazole ring.

Diethyl esters of 1-acylamino-2,2-dichlorovinylphosphonic acids and their analogs upon heating with the Lawesson’s reagent are converted into the earlier unknown substituted 1,3-thiazol-4-ylthiophosphonates in high yields.

Reactions of 2-acylamino-3,3-dichloroacrylonitriles with 2-aminothiophenol in the presence of triethylamine was shown to lead to 2-aryl-3,3-bis(2-aminophenylsulfanyl)acrylonitrile, which suffered a transformation into 5-amino-4-(benzothiazol-2-yl)oxazole derivatives at heating without solvent. The formation of the same compounds from these reagents proceeded in one step in the presence of N,N-dimethylaniline. The presence of primary amino groups in the derivatives of 5-aminooxazole was confirmed by acylation and further transformation, which was used also for indroduction of various biophoric sites in 5 position of the oxazole ring.

A method of synthesis of 3-aryl-5-dichloromethyl-1H-1,2,4-triazoles was developed, some chemical transformations of the synthesized compounds were performed, and dichloromethyl fragment in these compounds was shown to exhibit the characteristics of aldehyde group.

A convenient preparative procedure has been developed for the synthesis of previously unknown 2-aryl-5-arylsulfanyl-1,3-oxazole-4-carboxylic acids and their functional derivatives from accessible multicenter substrates of the general formula Cl2C=C(NHCOR)C(O)OMe. The products turned out to be suitable for various subsequent transformations. Some oxazole-4-carboxylic acid hydrazide derivatives containing a substituted oxazol-5-yl fragment at the N2 atom in the hydrazine moiety underwent recyclization on heating in acetic acid; as a result, one oxazole ring was converted into 1,3,4-oxadiazole.

The products of addition of amidines to accessible 5-arylamino-4-cyano-1,3-oxazoles at heating in acetic acid undergo recyclization and afford new derivatives of 6-amino-5-acylaminopyrimidin-4-one, whose structure was reliably established using X-ray diffraction studies.

The available diethyl 5-hydrazino-2-p-tolyl-1,3-oxazol-1-ylphosphonate was readily acylated with chlorides of carboxylic acids of heterocyclic series. On heating in acetic acid it underwent the oxazole ring cleavage, recyclization and diethylation that was used to prepar the substituted 2-p-toluylaminomethylphosphonic acids containing a series of 2-heteryl-1,3,4-oxadiazol-5-yl residues in the α-position relative to the phosponyl group.

The accessible two-center electrophilic substrate 4-tosyl-2-phenyl-5-chloro-1,3-thiazole reacts regioselectively with N-, O-, and S-nucleophiles to eliminate a chloride ion. The analog of this substrate, 4-tosyl-2-phenyl-5-p-chlorophenylsulphonyl-1,3-thiazole, reacts with “soft” and “hard” nucleophiles differently: with the participation of C5 or C4 center, respectively, that seems to be caused by the principle of “symbiosis” in the transition state.

Reactions of accessible 5-alkylamino- and 5-arylamino-1,3-oxazole-4-carbonitriles with hydrazine hydrate on heating involved a complex transformation sequence resulting in the formation of 3,4,5-triaminopyrazole derivatives. The structure of the products was confirmed by their cyclocondensation with acetylacetone, leading to 2-alkyl(aryl)amino-3-acylamino-5,7-dimethylpyrazolo[1,5-a]pyrimidines which were identified by NMR spectroscopy using COSY, NOESY, HMQC, and HMBC techniques.

Reactions of multicenter electrophilic substrates, 2-aryl-4-dichloromethylidene-1,3-oxazol-5(4H)-ones, with 2-aminopyridine, involved cleavage of the dihydrooxazole ring by the primary amino group of nucleophilic reagent and subsequent cyclization to imidazopyridine derivatives. The latter reacted with morpholine and its analogs via recyclization with formation of 5-amino-2-aryl-N-(pyridin-2-yl)-1,3-oxazole-4-carboxamides.

Successive treatment of accessible 2-acylamino-3,3-dichloroacrylonitriles with imidazole and hydrazine hydrate led to the formation of 4-acylamino-3(5)-amino-5(3)-(1H-imidazol-1-yl)pyrazoles, and condensation of the latter with acetylacetone afforded 3-acylamino-2-(1H-imidazol-1-yl)-5,7-dimethylpyrazolo [1,5-a]pyrimidines whose structure was reliably determined by X-ray analysis.